Strategies for the Mechanically Triggered Release of Small Molecules Citation Husic, Corey Christopher (2023) Strategies for the Mechanically Triggered Release of Small Molecules. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/0add-6n09. https://resolver.caltech.edu/CaltechTHESIS:04242023-215416950 Abstract The development of force-responsive molecules called mechanophores is a central component of the field of polymer mechanochemistry. Mechanophores enable the design and fabrication of polymers for a variety of applications ranging from sensing to self-healing materials. Nevertheless, an insufficient understanding of structure–activity relationships limits experimental development, and thus computation is necessary to guide structural design. Herein, we use the constrained geometries simulate external force (CoGEF) method to evaluate a library of covalent mechanophores using density functional theory (DFT). We use these results to identify key parameters that accurately predict experimentally determined mechanochemical reactivity. Polymers that release small molecules upon external stimulation are promising for a wide range of applications, including sensing, catalysis, and drug delivery. Mechanophores are uniquely suited to enable molecular release with excellent selectivity and control. We have designed a general platform for mechanically gated small molecule release that leverages a latent 2-furylcarbinol species masked as a mechanically labile Diels–Alder adduct. Here, we describe the computationally guided design of metastable 2-furylcarbinol derivatives through the prediction of activation energy values and construction of structure–activity relationships. These results enable a molecular release platform suitable for a wide scope of cargo molecules across a broad range of chemical environments. Item Type: Thesis (Dissertation (Ph.D.)) Subject Keywords: polymer mechanochemistry, mechanochemistry, organic chemistry, physical organic chemistry, small molecule release, constrained geometries simulate external force Degree Grantor: California Institute of Technology Division: Chemistry and Chemical Engineering Major Option: Chemistry Thesis Availability: Public (worldwide access) Research Advisor(s): Robb, Maxwell J. Thesis Committee: Reisman, Sarah E. (chair) Robb, Maxwell J. Nelson, Hosea M. Ismagilov, Rustem F. Defense Date: 21 April 2023 Record Number: CaltechTHESIS:04242023-215416950 Persistent URL: https://resolver.caltech.edu/CaltechTHESIS:04242023-215416950 DOI: 10.7907/0add-6n09 Related URLs: URL URL Type Description https://doi.org/10.1021/jacs.0c06868 DOI Article adapted for chapter 1 https://doi.org/10.1021/jacs.9b08663 DOI Parts of article adapted for chapter 2 https://doi.org/10.1021/acscentsci.1c00460 DOI Parts of article adapted for chapter 2 https://doi.org/10.1021/acsmacrolett.2c00344 DOI Article adapted for chapter 3 ORCID: Author ORCID Husic, Corey Christopher 0000-0003-0248-7484 Default Usage Policy: No commercial reproduction, distribution, display or performance rights in this work are provided. ID Code: 15142 Collection: CaltechTHESIS Deposited By: Corey Husic Deposited On: 26 May 2023 22:16 Last Modified: 27 Nov 2023 19:54 Thesis Files PDF - Final Version See Usage Policy. 35MB Repository Staff Only: item control page

STRATEGIES FOR THE MECHANICALLY TRIGGERED RELEASE OF SMALL MOLECULES Thesis by Corey Christopher Husic In Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy CALIFORNIA INSTITUTE OF TECHNOLOGY Pasadena, California 2023 (Defended 21 April 2023) ii  2023 Corey Christopher Husic ORCID: 0000-0003-0248-7484 iii To mountains and music, which kept me going iv ACKNOWLEDGEMENTS Over the past several years, Caltech has served as the grounds for my growth as a human and as a scientist. I will be forever grateful for the friends and acquaintances I have made here. First, I would like to thank my advisor Prof. Maxwell Robb. I joined his lab with uncertain scientific interests, and he provided a space for me to explore and continue to be curious. I am especially grateful for the opportunity he provided for me to branch out from the synthetic focus of the lab to explore computational projects in addition to my experimental work. I would also like to thank my thesis committee members Prof. Sarah Reisman, Prof. Rustem Ismagilov, and Prof. Hosea Nelson for their guidance, support, and keen scientific insights during my time at Caltech. Before arriving at Caltech, I was fortunate enough to have excellent scientific mentors. Prof. Karin Öberg was my first research mentor at Harvard. I knew nothing about the field of astrochemistry, but she welcomed me into her lab and always made time to teach and help in any way that she could. Little did I know that the coding skills she pushed me to learn would make an impact in graduate school, where my focus occasionally took a computational detour. I also owe immense thanks to Prof. George Whitesides for the opportunity to work in his laboratory at Harvard. It was this experience that solidified my intent on pursuing chemistry as a career. George’s unique way of approaching science and thinking about the world left a significant impact on me. I would also like to thank Dr. Lewis Kraft for his excellent scientific mentorship and for his tendency to give unsolicited bad life advice that I still chuckle about to this day. Discussing my time at Harvard would not be complete without mentioning Dr. Ryan Spoering and Prof. Tobias Ritter who ignited my interest in organic chemistry. These two instructors remain some of the best teachers I have v ever had, and I am so thankful for having been introduced to organic chemistry in this manner. Here at Caltech, I have been surrounded by an incredible group of friends. The entire Robb Group has been a wonderful crew to spend the last few years with. I am especially grateful for my Crellin 360 office pals: Anna Overholts, Brooke Versaw, May Zeng, Dr. Peng Liu, Debbie Tseng, and Jolly Patro. These labmates have regularly made me laugh to the point of ending up on the office floor. They have made graduate school bearable. Thank you especially to Anna who has been my best friend and confidant, without whom I may not have pushed through. I would also like to thank Dr. Xiaoran Hu for his mentorship in my early years in the Robb Group. Xiaoran and May were amazing collaborators for much of my work during grad school. Beyond this lab, I am thankful for a host of other Caltech friends who made my time here brighter. Even while speeding her way through her own PhD, Sadie Dutton managed to lift me up from my darkest of places. Isabel Klein and Bryce Hickam always left their door open when I needed some company. Chloe Williams and Sepand Nistanaki downstairs in the Nelson Lab never seemed to mind a mid-afternoon interruption to chat or vent. I am thankful to so many others who I haven’t listed here. Without a tremendous support staff, the chemistry department would not function and my work would have taken significantly longer. I would like to thank Annette Luymes for her work to keep the Robb Group organized, for helping us with the impossible task of scheduling, and for her fountain of campus gossip. Thank you to Joe Drew for keeping the buildings from falling down and always responding promptly to the leaks that plagued Church 320. Scott Virgil has an impossible job of keeping an endless library of instruments running, yet he managed to find time to teach me a ton about his beloved Agilent stacks. vi Thank you to Dave Vander Velde without whom the NMR room (and my email inbox) would be a very different place. I am certainly not alone in feeling grateful for Alison Ross who has kept this program running. Seeing Alison at sunrise at a trailhead in the Eastern Sierra was a happy surprise I won’t soon forget. I am thankful for the beautiful campus here at Caltech, a nice reprieve from the sometimes-overwhelming urban environment. Thanks to Bryan Vejar for keeping the trees healthy and beautiful. Thank you to the turtles that probably run this campus. Hardly a day goes by that I don’t walk past the turtle pond—and it always makes me smile. Thanks especially to that one adorable softshell turtle. Beyond Caltech, so many other people have supported me in one way or another. I am immensely thankful to Solveig Millett for her support and compassion; thank you for all the music. Thank you to Éowyn Lucas for introducing me to the Sierra and igniting my love for that corner of California. I would like to thank Elyssa Collins for her friendship and companionship in the mountains. My birding/nature friends, especially Luke Tiller, Catherine Hamilton, Landy Figueroa, Dave Bell, and Jonathan Feenstra were always down for an evening hang when I needed to stop thinking about chemistry. Thank you to Ally Frickman for pushing me to act and think beyond my comfort zone and for always being willing to jump into a frigid alpine lake with me. Thanks to Ruby Drake for being a wonderful friend and for giving me a glimpse into Hollywood. Amalia Mathewson and her sweet pup Greta have been amazing friends, even though we’ve only known each other for a brief moment. That is the sort of friendship that will last. I also have incredible friends who have supported me from afar; I am so thankful for the texts, phone calls, and letters from Lindsey vii Terrell, Kimberly Rivers, Allison Black, and others that have never failed to brighten my day. Music is an immeasurably important part of my life, and I am grateful for the oldtime music community. Here in LA, the 1842 jam crew has felt like a family to me. I am especially grateful for my friendships with Jeff McLeod, Jonathan Shifflett, Kelly Martin, and Joe Wack. The whole Echo Mountain band has made my time in LA incredibly fun. I’ll never think of corn muffins in the same way. Thank you to David Bunn for opening his home at Deep End Ranch and providing a space for incredible music and memories. I would like to thank my parents Dave and Diane Husic for their never-ending support. They are my biggest inspirations. They always allowed me to be curious and gave me room to explore, which let me become the person I am today. I thank my mom for teaching me how to be a leader and how to make a difference in the world. She taught me how to bake a pie and grow a garden. I couldn’t ask for a better hiking, birding, or travel partner. My dad taught me how to love and play the fiddle. He showed me how to be gentle and thoughtful. There is no one I am more comfortable with on this planet than my dad. I am grateful for my brother who, in his own unique way, has always been there for me. Sometimes that means comforting me while I cry on the phone, other times discussing surface integrals at 3 am. Finally, I would like to thank my tabby, Melvin. I adopted him on February 1st, 2020, and he soon became the greatest roommate I could ask for. He is always up for a conversation or some cuddles. There are few things in my life that compare to the feeling of waking up on a sunny weekend morning to find Melvin stretched out and pressed against me. I am not sure how I would’ve survived the pandemic lockdown without his companionship. viii I haven’t always loved living in Los Angeles, but I will certainly miss this place. The friendships I have made here are some of the deepest connections I have ever felt, and I don’t intend to let those connections fade away. Perhaps more than anything, though, I will miss these mountains. The San Gabriels were my second home, an escape when life began to feel unbearable. The Eastern Sierra quickly became a true love, and I savored every chance I had to be there. These are places I won’t soon forget—the sorts of places that I won’t be able to stay away from. ix ABSTRACT The development of force-responsive molecules called mechanophores is a central component of the field of polymer mechanochemistry. Mechanophores enable the design and fabrication of polymers for a variety of applications ranging from sensing to self-healing materials. Nevertheless, an insufficient understanding of structure–activity relationships limits experimental development, and thus computation is necessary to guide structural design. Herein, we use the constrained geometries simulate external force (CoGEF) method to evaluate a library of covalent mechanophores using density functional theory (DFT). We use these results to identify key parameters that accurately predict experimentally determined mechanochemical reactivity. Polymers that release small molecules upon external stimulation are promising for a wide range of applications, including sensing, catalysis, and drug delivery. Mechanophores are uniquely suited to enable molecular release with excellent selectivity and control. We have designed a general platform for mechanically gated small molecule release that leverages a latent 2-furylcarbinol species masked as a mechanically labile Diels–Alder adduct. Here, we describe the computationally guided design of metastable 2-furylcarbinol derivatives through the prediction of activation energy values and construction of structure–activity relationships. These results enable a molecular release platform suitable for a wide scope of cargo molecules across a broad range of chemical environments. x PUBLISHED CONTENT AND CONTRIBUTIONS Portions of the work described herein were disclosed in the following publications: 1. Hu, X.; Zeng, T.; Husic, C. C.; Robb, M. J. J. Am. Chem. Soc. 2019, 141, 15018. DOI: https://doi.org/10.1021/jacs.9b08663. C. C. H. contributed to the computational work, synthesis, data acquisition and analysis, and manuscript preparation. 2. Klein, I. M.;† Husic, C. C.; † Kovács, D. P.; Choquette, N. J.; Robb, M. J. J. Am. Chem. Soc. 2020, 142, 16364. DOI: https://doi.org/10.1021/jacs.0c06868. †authors contributed equally C. C. H. contributed to the computational work, data preparation and analysis, and manuscript preparation. 3. Hu, X.; Zeng, T.; Husic, C. C.; Robb, M. J. ACS Cent. Sci. 2021, 7, 1216. DOI: https://doi.org/10.1021/acscentsci.1c00460. C. C. H. contributed to the project conception, computational work, synthesis, data acquisition and analysis, and manuscript preparation. 4. Husic, C. C.; Hu, X.; Robb, M. J. ACS Macro Lett. 2022, 11, 948. DOI: https://doi.org/10.1021/acsmacrolett.2c00344. C. C. H. contributed to the project conception, computational work, synthesis, data acquisition analysis, and manuscript preparation. xi TABLE OF CONTENTS Acknowledgements…………………………………………………………...iv Abstract ………………………………………………………………………ix Published Content and Contributions…………………………………….........x Table of Contents……………………………………………………………. xi List of Abbreviations…………………………………………………………xii Chapter 1: Validation of the CoGEF Method as a Predictive Tool for Polymer Mechanochemistry…………………………………………………………….1 1.1 Introduction……………………………………………………………1 1.2 Methods…………………………………………………………….….4 1.3 Results and discussion…………………………………………..……..7 1.4 Conclusions…………………………………………………………...47 1.5 Experimental details…………………………………………………..49 1.6 References…………………………………………………………….51 Chapter 2: Computational Investigation of Structure–Activity Relationships of 2-Furylcarbinol Derivatives for Molecular Release…………69 2.1 Introduction……………………………………………………………69 2.2 Methods…………………………………………………………….….72 2.3 Results and discussion…………………………………………..……..76 2.4 Conclusions…………………………………………………………....93 2.5 References…………………………………………………………..…94 Chapter 3: Incorporation of a Tethered Alcohol Enables Efficient Mechanically Triggered Release in Aprotic Environments…………………………………..98 3.1 Introduction……………………………………………………………98 3.2 Results and discussion..……………………………………………….100 3.3 Conclusions…………………………………………………………...118 3.4 Experimental details…………………………………………………..118 4.5 References…………………………………………………………….143 Appendix A: Summaries of Individual CoGEF Calculations Presented in Chapter 2 ……………………………………………………………………………….…148 Appendix B: A Guide for Implementing the Constrained Geometries Simulate External Force (CoGEF) Method in Spartan……………………………………289 Appendix C: Atomic Coordinates for Molecules Discussed in Chapter 2…..299 Appendix D: A Guide for Simple Transition State Calculations Using Spartan ………………………………………………………………………………326 Appendix E: Spectra Relevant to Chapter 3…………………………………343 xii LIST OF ABBREVIATIONS + diffuse function * (d) ** (d,p) ‡ transition state ± racemic Å angstrom(s) ABq AB quartet Ac acetyl AFM atomic force microscopy AISMD ab initio steered molecular dynamics aq. aqueous Ar aryl ATRP atom transfer radical polymerization Bn benzyl BPA bisphenol A br broad Bu butyl °C degree(s) Celsius calc’d calculated cm-1 wavenumber(s) xiii CoGEF constrained geometries simulate external force δ chemical shift in ppm Δ heat or difference Ð polydispersity d day(s) or doublet d deutero dd doublet of doublets DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DCM dichloromethane DIC N,N’-diisopropylcarbodiimde DFT density functional theory DMAP 4-dimethylaminopyridine DMF N,N’-dimethylformamide DMPU N,N’-dimethylpropyleneurea DMSO dimethylsulfoxide DPTS 4-(dimethylamino)pyridinium 4-toluenesulfonate ε dielectric constant E energy Emax maximum energy Et ethyl equiv. equivalent(s) ESI electrospray ionization F force xiv Fmax maximum force FMPES force-modified potential energy surface G Gibbs free energy G‡ Gibbs free energy of transition states ΔG‡ activation energy g gram g gem gDCC gem-dichlorocyclopropane GPC gel permeation chromatography h hour(s) HF Hartree–Fock HFIP hexafluoroisopropanol HMPA hexamethylphosphoramide HRMS high resolution mass spectrometry IS internal standard J joule J J-coupling K Kelvin kB Boltzmann constant kcal kilocalorie(s) kDa kilodalton(s) kHz kilohertz kJ kilojoule xv LCMS liquid chromatography–mass spectrometry LDA lithium diisopropylamide LiHMDS lithium bis(trimethylsilyl)amide M molar m meter or multiplet m meta Mn number-average molecular weight MALS multiangle light scattering mCBPA meta-chloroperoxybenxoic acid Me methyl Me6TREN tris[2-(dimethylamino)ethyl]amine MHz megahertz min minute(s) mL milliliter(s) mM millimolar mmol millimole(s) mol mole(s) m/z mass-to-charge ratio N newton(s) n normal (e.g., n-BuLi) nm nanometer(s) NMR nuclear magnetic resonance nN nanonewton(s) xvi Nuc nucleophile o ortho [O] oxidation φ dihedral angle p para Ph phenyl PMA poly(methyl acrylate) ppm part(s) per million PPTS pyridinium para-toluenesulfonate q quartet quant. quantitative R generic group Rf retention factor ROMP ring-opening metathesis polymerization RRF relative response factor rt room temperature s second(s) or singlet sat. saturated SET-LRP single-electron transfer living radical polymerization SMFS single molecule force spectroscopy T temperature t tert t1/2 half-life xvii TBAF tetra-n-butylammonium fluoride TBDPS tert-butyldiphenylsilyl TBS tert-butyldimethylsilyl Tf trifloromethanesulfonyl THF tetrahydrofuran THP tetrahydropyranyl TIPS triisopropylsilyl TLC thin-layer chromatography Ts toluenesulfonyl (tosyl) μL microliter μM micromolar μmol micromole(s) UV ultraviolet Vis visible v/v volume concentration W watt(s) X halide or leaving group 1 1 Chapter 1 VALIDATION OF THE CoGEF METHOD AS A PREDICTIVE TOOL FOR POLYMER MECHANOCHEMISTRY 1.1 Introduction The nascent field of polymer mechanochemistry aims to harness mechanical energy to activate chemical transformations.1,2 Force is transmitted to stress-responsive molecules called mechanophores through covalently linked polymer chains, leading to productive chemical changes via mechanically selective bond scission.3 Mechanophores have been designed to undergo a wide variety of mechanochemical reactions including those that produce a change in color or luminescence,4–7 release small molecules,8–10 generate reactive functional groups,11–14 switch electrical conductivity,15 and reveal catalytic activity.16,17 In turn, mechanophores engender polymeric materials with advantageous properties such as the ability to strengthen under typically destructive forces 13 and autonomously report on critical stress and strain through easily detected visible signals. 4 The development of new mechanophores is crucial for both advancing fundamental insight into mechanochemical reactivity and expanding the repertoire of mechanochemically responsive materials. Nevertheless, an underdeveloped knowledge of structure–function relationships along with the time and resource requirements of synthesis and evaluation in the laboratory limit experimental pursuits. A simple, rapid, and reliable computational method for screening the mechanochemical activity of molecules prior to experimental investigation is necessary for accelerating mechanophore discovery. 2 Computational chemistry has had a significant impact on the advancement and fundamental understanding of mechanochemical reactivity. Theoretical studies have revealed that the unique reactivity of mechanophores originates from a distortion of the potential energy surface under large forces, altering the trajectories of chemical reactions.18–20 Several quantum chemical methods have been leveraged over the past two decades to investigate the effects of force and mechanical deformation on molecular reactivity. Ab initio steered molecular dynamics (AISMD) simulations approximate the action of external force on a molecule by applying constant pulling velocities to terminal atoms and following the dynamics of the system over a few picoseconds. 21 Computational methods that consider force explicitly under isotensional stretching have also been introduced, including the force-modified potential energy surface (FMPES), 22 external force is explicitly included (EFEI),18 and enforced geometry optimization (EGO)23 models. While these specialized approaches provide detailed information on the energetics and mechanisms of mechanochemical transformations, they are less suited as screening tools for the experimental development of new mechanophores. The constrained geometries simulate external force (CoGEF) method, 24 on the other hand, is both computationally inexpensive and simple to implement, providing a highly accessible quantum chemistry platform for testing proposed mechanophores in silico. The CoGEF method was developed by Beyer in 2000 and simulates the effect of molecular elongation through constrained geometry optimizations. In a typical CoGEF calculation, the distance between two terminal atoms that represent polymer attachment positions is constrained and the geometry of the truncated molecule is optimized. Increasing the end-to-end distance incrementally and optimizing the constrained geometry 3 at each step simulates isometric stretching and enables prediction of the chemical changes that accompany mechanical distortion of the molecule along the reaction coordinate. The CoGEF technique can be implemented in every major commercial software package using any quantum chemistry method that allows constrained geometry optimizations and the mechanochemical reactivity of moderately sized molecules can be evaluated relatively quickly on a desktop computer. Due to its ease of implementation and accessibility, the CoGEF method has been employed to corroborate experimental observations and has become an important component in the workflow for the development of new mechanophores.3 However, despite the ubiquity of this method in polymer mechanochemistry, CoGEF has yet to be systematically validated. Here we provide a comprehensive investigation and validation of the CoGEF method applied consistently to every covalent mechanophore structure reported in the literature to date. Mechanochemical reactions involving activation of organometallic compounds,16,17,25–28 rotaxanes,29,30 and ionic species31 have been previously described; however, only mechanophores that undergo covalent bond transformations are considered in this study. We identify over 100 mechanophores and compare the results of CoGEF simulations with their experimentally determined mechanochemical reactivity. In addition, the consistency between CoGEF calculations and the experimentally determined behavior of molecules previously demonstrated to exhibit unproductive reactivity via non-specific bond scission under mechanical force are evaluated as negative controls. Excellent agreement is observed between CoGEF calculations and experimental data at the commonly employed B3LYP/6-31G* level of density functional theory (DFT). Furthermore, the maximum force associated with bond rupture obtained from CoGEF 4 calculations is compared to single molecule force spectroscopy (SMFS) measurements across several classes of mechanophores and demonstrated to be a reliable indicator of mechanochemical activity. This comprehensive evaluation, applied broadly to the experimental literature, reveals that the CoGEF method is a powerful predictive tool for polymer mechanochemistry. 1.2 Methods CoGEF calculations were performed for each reported structure at the B3LYP/6- 31G* level of theory, which has been nearly universally employed in the polymer mechanochemistry literature and provides an appropriate compromise between accuracy and computational cost.32,33 The results of each CoGEF simulation were then compared to experimental data from the literature to determine the accuracy of the calculation. Chemical structures were truncated to include tethers that accurately reflect the polymer connectivity in the reported experimental studies. The CoGEF calculation was determined to be successful if the predicted products were consistent with the products of the mechanochemical reaction determined from experiments. To assess the ability of CoGEF to predict features beyond qualitative reactivity, calculated forces were also compared to rupture forces determined experimentally from SMFS measurements and other quantitative metrics reported in the literature. 5 Figure 1.1 Illustration of the CoGEF method applied to representative cyclobutane mechanophore 1. (A) Structures of the truncated mechanophore and products resulting from a formal retro-[2+2] cycloaddition reaction upon stepwise mechanical elongation predicted at the B3LYP/6-31G* level of theory. Blue carbon atoms designate the anchor points defining the distance constraint. Bonds that are broken in the calculation are colored red. (B) Computed structures at critical points in the CoGEF calculation: (i) the force-free equilibrium geometry, (ii) the constrained geometry immediately prior to bond rupture, and (iii) the predicted product(s). The corresponding points in the CoGEF curve are indicated in part C. (C) Relative energy, E, plotted as a function of displacement from equilibrium, D. Emax is the bond dissociation energy associated with the covalent transformation and Fmax is the maximum force, calculated from the slope of the curve immediately prior to bond rupture. As a demonstration of the method, a representative CoGEF calculation is illustrated for the mechanochemical formal retro-[2+2] cycloaddition reaction of cyclobutane mechanophore 1 (Figure 1.1A). The equilibrium geometry of the unconstrained model structure is first computed at the B3LYP/6-31G* level of DFT. Subsequently, the distance between terminal atoms (colored blue), which serve as anchor points, is constrained (Deq). The displacement between anchor points, D, relative to the equilibrium geometry is then increased in increments of 0.05 Å, and a constrained geometry optimization is carried out after each step (Figure 1.1B). This process is repeated until a chemical transformation is predicted to occur, as evidenced by the rupture and reorganization of one or more covalent bonds. In addition to qualitatively identifying the structure of the predicted 6 mechanochemical reaction product(s), the energy of the system relative to the energy of the unconstrained, force-free equilibrium geometry, E, is plotted as a function of displacement to generate the CoGEF potential (Figure 1.1C).24 Two important metrics are obtained from this CoGEF curve. First, the bond dissociation energy is defined as the maximum relative energy immediately prior to bond rupture (Emax). Second, the slope of the CoGEF curve (ΔE/ΔD) at any point along the reaction coordinate reflects the force experienced by the molecule during the simulated isometric stretching. The maximum force, Fmax, along the CoGEF curve represents the force associated with the mechanochemical transformation (see Appendix A for details). As a static quantum chemical method, rupture forces calculated with CoGEF are typically overestimated compared to experiments because thermal effects are neglected. 19 Nevertheless, they provide a useful metric for evaluating the relative mechanochemical activity of mechanophores as demonstrated below. The structures of each molecule investigated are presented in Charts 1–8 and the results of each CoGEF calculation are provided in corresponding Tables 1–8, along with references to the primary literature describing the experimentally investigated mechanochemical reactivity of each compound. Mechanophores are classified based on reaction mechanism, although we note that the actual mechanochemical reaction mechanisms have not been determined for most mechanophores and in such cases compounds are categorized based on their formal reactivity. The bonds that are predicted to break in the CoGEF calculations are colored red. The overall reaction predicted by each CoGEF calculation is identified as being either consistent () or inconsistent () with the reported experimental mechanochemical reactivity. We discuss that in some cases in which 7 the calculation is inconsistent with the reported reactivity, the available experimental data is either insufficient or suggest that a structural revision may be necessary. Calculated values of Fmax and Emax are summarized in the tabulated data for each structure. Complete computational data for each structure are included in Appendix A. 1.3 Results and Discussion 1.3.1 Retro-[2+2] Cycloaddition Reactions The mechanochemical reactivity of molecules containing four-membered rings has been extensively studied. Moore and coworkers reported the mechanochemical generation of cyanoacrylate functional groups resulting from the formal retro-[2+2] cycloaddition reaction of cyano-substituted cyclobutanes in 2010.34 Subsequently, a number of other cyclobutane mechanophores have been identified as well as mechanochemically active heterocyclic 1,2-dioxetane,5 beta-lactam,14 and 1,2-diazetidinone35 compounds (Chart 1.1). CoGEF calculations successfully predict the anticipated mechanochemical reaction for 32 of the 34 structures in this category (Table 1.1). In a seminal paper published in 2011,36 Kryger et al. reported a systematic study of the relative reactivity of substituted cyclobutane mechanophores, comparing the results of ultrasound-induced mechanochemical activation experiments to predictions from CoGEF calculations. A threshold molecular weight was determined for each chain-centered cyclobutane derivative and used as a proxy for mechanochemical activity, with a lower molecular weight threshold indicating a more reactive substrate. The trends in experimental reactivity were generally found to be consistent with the results of CoGEF calculations. In our hands, CoGEF calculations performed on analogous cyclobutane compounds 1–6 8 Chart 1.1 Structures Associated with Formal Retro-[2+2] Cycloaddition Reactions O H H O O R1O 1 OR O H H R1O O OR 1 1 N O H R1O O 1 OR 2 N O H R1O OR 3 R2 O H H O H3C O H H O O H3C 7 CH3 O H3C N H H N H H H H 8 O N H N H CH3 CH3 12 12' H3C Me N O CH3 H H O CH3 H H O O O H H H H H CH3 Cl Cl H O 11 H H 1 O OR1 R O Me Me O O 14 H H H O O O H H O CH3 O CH3 H H H O 10 O 13 H3C O O H H H3C O H H H O H H H H 15 OR1 R O H R2 H R2 O O 1 H O H H H OR1 R1O H O H H H3C CH3 16 O 17 R1O OR1 H H OR1 23 O H N H3C H H H3C OMe H3C CH3 H H 32 O 22 O O H H CH3 O OMe Me Me Controls O O O H3C 27 H3C H H H 26 R1O O O 21 H O Ph 31 O 25 OR1 H H 19 O Ph OR1 20 OMe OMe O OMe CH3 24 N N R1O H R1O O CH3 18 O O Br Br H H H H3C NMe2 CH3 CH3 O O H3C R2 = O CH3 O O H H O H N O O O H N H3C R1 = 1 CH3 OMe H H R2 9 O 6 MeO O O OR 5 H H R2 O N N R1O OR OMe OMe O H H H H MeO O H H MeO O 1 4 H H O R1O O R2 N N O 1 Me Me O Con1 O O CH3 H R2 O O O O 28 H3C R2 CH3 H3C 29 CH3 O Me Me N 30 O CH3 O Con2 produce similar results; however, subtle variation in the truncation of the computed structures compared to those investigated by Kryger et al. reveals an important consideration. Here, cyclobutane mechanophores 1–6 include longer tethers compared to the structures computed by Kryger et al., which contained terminal methyl ester groups directly attached to the cyclobutane cores. Despite the differences in truncation, our calculated values of Fmax closely match those reported previously; however, the calculated values of Emax are highly variable, differing by more than 350 kJ/mol for cyclobutane 2, for instance. This case study typifies a general observation that Fmax is a robust quantitative 9 Table 1.1 CoGEF Results for Formal Retro-[2+2] Cycloaddition Reactions§ Structure Resulta 1 2 3 4 5 6 7 8 9 10 11 12 12′ 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 Con1 Con2             c                       Fmax (nN) 4.6 5.9 4.0 4.8 3.4 5.0 4.5 5.0 2.5 4.4 4.7, 3.8b 5.9 4.4 6.3 5.6 5.9 3.3 3.3 3.3 3.3 5.5 5.2 4.6 3.6 4.0 3.8 3.5 3.7 4.4 5.4 3.5 3.6 4.4 6.3 6.4 Emax (kJ/mol) 460 746 335 426 285 444 413 417 253 364 395, 291b 498 359 658 633 1017 244 241 244 236 692 562 469 332 313 302 278 306 345 331 284 260 495 947 959 Ref. 36 36 36 36 34,36 34,36 37 38 38 39 40 41,42 43 43 44 45 45 45 45 46 47 47 47 47 48 48 48 49 50 14 35 5 51 51 §B3LYP/6-31G* level of DFT. aConsistency between CoGEF prediction and reported experimental reactivity. bComputed values associated with reaction of the gDCC subunit. cStructural revision results in CoGEF prediction matching expected reactivity. metric obtained from CoGEF calculations and a better descriptor of relative mechanochemical activity than Emax. We therefore focus on the calculated values of Fmax in the discussion of quantitative mechanochemical relationships for illustrative examples 10 within each class of mechanochemical reactions and return to a more general discussion of quantitative aspects of CoGEF toward the end of the article. The influence of both stereochemistry and regiochemistry at the polymer attachment positions is evident in the CoGEF results for this class of mechanophores. Another consistent feature that emerges from the data is the impact of cis versus trans stereochemistry at the pulling positions. In particular, cyclobutanes containing a cis pulling geometry are predicted to have lower values of Fmax compared to the corresponding trans isomer, which is again consistent with previous observations of Kryger et al. for cyclobutanes 1–6.36 Furthermore, we note that the reactions predicted for different mechanophores often proceed with a range of synchronicity. In many cases, the reaction occurs in a single elongational step, while asynchronous or stepwise fragmentation of other mechanophores is observed that occurs over multiple steps of the CoGEF profile to ultimately furnish the expected products. These variations potentially reflect differences in mechanism, such as diradicaloid character in an asynchronous reaction, 36 although mechanistic interpretations should be treated carefully due to the constraints imposed on the system and the level of theory employed. Nevertheless, the results presented herein suggest that many mechanistic features are accurately captured using the CoGEF method. Compound 11 is unique among this class of mechanophores, as it possesses two distinct mechanochemically active subunits. Wang et al. demonstrated that each subunit is activated in sequence upon mechanical elongation, illustrating the concept of mechanical gating whereby the ring-opening reaction of the gem-dichlorocyclopropane unit is contingent upon the cycloelimination reaction of the cyclobutane motif. 40 CoGEF simulations are consistent with this result, predicting initial fragmentation of the 11 cyclobutane group via a formal retro-[2+2] cycloaddition reaction with an Fmax value of 4.7 nN followed by further molecular extension that ultimately leads to ring-opening of the more reactive gem-dichlorocyclopropane at a lower Fmax value of 3.8 nN. The concept of gating has led to a number of developments in polymer mechanochemistry recently being applied to mechanically gated photoswitching, 52 photochemically gated chain scission,53 mechanically triggered molecular release,10 and mechanically gated polymer degradation.49,50 For cyclobutane compound 12, the CoGEF calculation predicts C–C bond cleavage at a location peripheral to the four-membered ring that is inconsistent with the reported reactivity. Each of the four-membered-ring mechanophores for which CoGEF correctly predicts a formal cycloelimination reaction exhibits a 1,2-disubstitution pattern for the positions of polymer attachment. In contrast, cinnamamide dimer 12 was reported to have a 1,3-disubstitution geometry on the cyclobutane ring.41,42 The available experimental data are insufficient to confirm the structure of the dimer in question, but the photodimerization of cinnamic acid and related derivatives has been shown to produce the head-to-head dimer corresponding to the 1,2-disubstituted cyclobutane.54,55 CoGEF calculations performed on alternative head-to-head dimer 12′ predict a formal cycloelimination reaction upon mechanical elongation, in agreement with the computational results for other 1,2disubstituted cyclobutane mechanophores. Based on this evaluation, we speculate that the fluorogenic mechanochemical activity previously observed for the cinnamamide dimer mechanophore may originate from reaction of the 1,2-disubstituted compound 12′. Additionally, the CoGEF calculation performed on head-to-tail coumarin dimer 13 predicts scission of the C–O bond adjacent to the pulling position, rather than the experimentally 12 observed retro-[2+2] cycloaddition reaction. Compared to head-to-head coumarin dimer 14, the head-to-tail dimer was demonstrated to be significantly less reactive. 43 Although the number of compounds that have been reported in the literature to exhibit non-productive reactivity under mechanical force is relatively limited, the ability to accurately identify this type of behavior in negative controls is critical to validate the CoGEF method as a reliable predictive tool. Two such examples are available in this class of mechanochemical reactions. The mechanochemical reactivity of cis and trans disubstituted 1,3-cyclobutanedione molecules Con1 and Con2 was investigated by Sijbesma and coworkers and both molecules were found to undergo non-specific bond scission under ultrasound-induced mechanical force rather than formal cycloelimination. 51 Consistent with these experimental observations, CoGEF calculations predict C–C bond scission peripheral to the cyclobutanedione core. Intriguingly, both benzylic C–C bonds cleave simultaneously in the CoGEF calculations to form a product consistent with the structure of 1,3-dimethylbicyclo[1.1.0]butane-2,4-dione for both the cis and trans cyclobutanedione stereoisomers. These results further reinforce the apparent regiochemical constraints for mechanochemical activation of four-membered-ring compounds and point to the privileged mechanochemical reactivity derived from 1,2-disubstitution. 1.3.2 Retro-[4+2] Cycloaddition Reactions Mechanically activated formal retro-[4+2] cycloaddition reactions have also been demonstrated for a variety of mechanophores (Chart 1.2). Within this category, retro-Diels– Alder reactions are prominent transformations that have garnered significant attention for applications including stress sensing52,56,57 and triggered small molecule release.9,10 CoGEF 13 calculations successfully reproduce the reported experimental mechanochemical reactivity for 13 of the 18 structures in this category (Table 1.2). CoGEF calculations performed on mechanophores 33–37 result in C–C, C–O, or C–S bond rupture that is inconsistent with the reported cycloelimination reactions. The mechanochemical reaction of oxanorbornadiene mechanophore 33 was achieved under compression in crosslinked elastomers resulting in the release of a small molecule furan derivative.9 Mechanical activation of 33 was hypothesized to proceed via a unique “flex activation” mechanism whereby force-induced bond-bending motions promote the desired retro-[4+2] cycloaddition reaction. Other computational studies have suggested that this reaction manifold is less sensitive to external mechanical perturbation and that a significant thermal component is still required for activation under relatively large forces. 20 Poor orientational alignment between the scissile bonds and the direction of applied force along the reaction coordinate results in weak mechanochemical coupling in these systems, and mechanical force alone is insufficient for activation. The formal retro-Diels–Alder reaction Chart 1.2 Structures Associated with Formal Retro-[4+2] Cycloaddition Reactions 14 Table 1.2 CoGEF Results for Formal Retro-[4+2] Cycloaddition Reactions§ Structure Resulta 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 Con3 Con4 Con5                   Fmax (nN) 6.2 6.0 5.8 2.9 6.5 4.1 4.0 3.9 4.8 4.1 4.0 4.0 3.8 4.6 3.9 6.0 6.0 6.0 Emax (kJ/mol) 676 693 736 295 772 306 372 230 504 285 264 245 284 396 243 843 832 650 Ref. 9,58 59 60 61 62 63,64 56 65 65 65,66 67 10 68 52 53 56 63 65 §B3LYP/6-31G* level of DFT. aConsistency between CoGEF prediction and reported experimental reactivity. of phenyltriazolinedione–anthracene adduct 34 was also investigated experimentally in crosslinked elastomers under tension where mechanical activation is expected to proceed via force-induced planarization.59 In addition to mechanical strain, simultaneous heating was required to achieve activation on the order of ~1% at 125 °C, indicating a relatively low level of mechanochemical reactivity. The reaction of 35 was recently reported to produce singlet oxygen under mechanical stress via a similar planarization process, 60 although it is important to note that control experiments to rule out thermal activation were not presented. For these flex-activated mechanophores, proper consideration of the thermal energy is critical in order to accurately model their reactivity. CoGEF calculations performed on compound 36 predict C–S bond scission instead of a retro-[4+2] cycloaddition reaction. Characterization data suggest that the bis-hetero-Diels–Alder 15 adduct investigated was symmetric,69 although the reported structure of 36 differs in the configuration of each adduct.61 Nevertheless, CoGEF calculations performed on simple models of individual hetero-Diels–Alder adducts comprising all of the different possible regio- and stereoisomers result in the same C–S bond scission (Figure 1.2). We cautiously Figure 1.2 CoGEF results for four possible isomers of a hetero-Diels–Alder adduct corresponding to the reactive subunits of reported mechanophore 36. All isomers are predicted to undergo C–S bond scission rather than the formal retro-[4+2] cycloaddition reaction. 16 note that additional experimental investigation is warranted to confirm the mechanochemical reactivity of the hetero-Diels–Alder adduct(s) represented by compound 36, as well as compound 35. The mechanochemical cycloreversion of 1,2,3-triazoles has been the subject of debate in the mechanochemistry literature.19,70 This transformation has piqued interest due to the ubiquitous use of azide–alkyne cycloaddition “click” chemistry. 71 Blank and coworkers previously demonstrated that the CoGEF method predicts a retro-[4+2] cycloaddition reaction for some 1,2,3-triazoles, although the reactivity is highly sensitive to pulling geometry.33 For triazoles derived from terminal alkynes, the cycloreversion reaction is only predicted for the 1,5-regioisomer, whereas non-specific bond scission adjacent to the triazole ring is expected for the 1,4-regioisomer accessed through the popular copper-catalyzed72,73 cycloaddition reaction. Stauch and Dreuw further demonstrated that even for 1,5-substitued 1,2,3-triazoles, cycloreversion competes with rupture of the C–N bond at the location of polymer attachment on the triazole ring because the forces associated with both processes are similar.74 Experimentally, the cycloreversion reaction of a 1,5-disubstituted 1,2,3-triazole was investigated using atomic force microscopy (AFM) methods leading to inconclusive results. 75 In another AFM study, the mechanochemical cycloreversion reaction of the strain-promoted azide–alkyne cycloaddition product 37 was probed, which suggested that cycloreversion of the triazole was achieved at the single molecule level as deduced through a series of subsequent labeling experiments.62 Nevertheless, the methods employed in the study did not permit conclusive chemical analysis of the reaction products. The CoGEF calculation for 17 compound 37 predicts C–O bond scission in the tether and not the cycloreversion reaction, similar to the results of previous computational studies on this scaffold. 33 Three molecules have been studied experimentally that serve as negative controls for this category of formal retro-[4+2] cycloaddition reactions. In contrast to mechanophores 38 and 39 that reveal fluorescent anthracene derivatives upon mechanochemical activation, anthracene–maleimide Diels–Alder adducts Con3 and Con4 with distal pulling geometries do not undergo a retro-[4+2] cycloaddition reaction under force.56,63 CoGEF calculations are consistent with these experimental results, predicting C– C bond scission at a terminal position in the tether groups instead of cycloelimination. In addition, Stevenson and De Bo elegantly illustrated the impact of both regiochemistry and stereochemistry on the mechanochemical reactivity of furan–maleimide adducts. 65 Compound Con5 with exo stereochemistry and a distal pulling position relative to the furan–maleimide junction was demonstrated to be mechanically inert under ultrasoundinduced elongational force due to poor alignment of the scissile bonds with the force vector. This behavior is accurately captured by the CoGEF calculation for this substrate, which predicts C–C bond rupture adjacent to the terminal pulling position rather than the retro[4+2] cycloaddition reaction observed in the CoGEF calculations for experimentally verified mechanophores 40–42. In addition, the calculated values of Fmax for these three furan–maleimide mechanophores are also consistent with their experimentally determined reactivity. For example, proximal–endo isomer 40 exhibited the lowest threshold molecular weight while distal–endo isomer 41 had the highest threshold molecular weight of the mechanochemically active adducts. The calculated values of Fmax for mechanophores 40 and 41 are 3.9 nN and 4.8 nN, respectively. 18 1.3.3 Retro-[4+4] Cycloaddition Reactions Anthracene dimers 48 and 49 have been reported to undergo a formal retro-[4+4] cycloaddition reaction under mechanical compression in polymeric materials to generate fluorescent anthracene moieties (Chart 1.3).76,77 CoGEF calculations do not predict the anticipated cycloelimination reaction for either compound, instead suggesting unproductive C–C or C–N bond scission near the pulling point (Table 1.3). However, Chart 1.3 Structures Associated with Formal Retro-[4+4] Cycloaddition Reactions Table 1.3 CoGEF Results for Formal Retro-[4+4] Cycloaddition Reactions§ Structure Resulta 48 48′ 49 49′  b  b §B3LYP/6-31G* Fmax (nN) 6.9 2.3 5.8 2.2 Emax (kJ/mol) 844 140 557 167 Ref. 76 77 - level of DFT. aConsistency between CoGEF prediction and reported experimental reactivity. bStructural revision results in CoGEF prediction matching expected reactivity. 19 unlike the bond elongation process typically operative in the activation of other mechanophores, we envisioned that the structure of these adducts may be uniquely susceptible to mechanical activation through compression-induced planarization. Modified CoGEF calculations were performed on 48 and 49 in which two carbon atoms in opposing phenyl rings were brought closer together in a typical series of constrained geometry calculations at the B3LYP/6-31G* level of theory. For both compounds, this alternative CoGEF model does indeed predict the formal retro-[4+4] cycloaddition reaction to generate a pair of anthracene products (Figure 1.3). These results may suggest that typical CoGEF calculations do not properly reflect the mode of mechanical activation for anthracene dimer mechanophores. However, it is important to note that the unconventional constrained geometry calculations were designed specifically to emulate the geometric distortions that are anticipated to occur for the anthracene dimers under compressive stress. We caution against applying these alternative methods broadly because they do not represent a realistic mode of mechanical activation for most mechanophores. Based on the regiochemical effects observed for other classes of mechanophores, we were also curious to investigate the impact of regiochemistry on the predicted mechanochemical reactivity of the anthracene dimer. The photodimerization of anthracene derivatives typically produces the head-to-tail isomer selectively; however, the head-to-head configuration is also accessible under certain conditions.78,79 The typical CoGEF operation performed on alternative head-to-head dimers 48′ and 49′ predicts the desired cycloelimination reactions. Although mechanistic interpretations should again be treated with caution, the CoGEF simulations performed on the anthracene dimer indicate that the 20 Figure 1.3 CoGEF calculations performed in an alternative compression mode for head-to-tail anthracene dimer mechanophores (A) 48 and (B) 49. The distance between carbon atoms labeled with a blue dot was decreased incrementally starting from the force-free equilibrium geometry. At each step, the geometry was optimized at the B3LYP/6-31G* level of DFT. Both molecules are predicted to undergo a formal retro-[4+4] cycloaddition reaction upon simulated compression. The transformation proceeds through an apparent stepwise pathway suggesting an intermediate with diradical character. 21 cycloelimination reaction does not proceed via a concerted retro-[4+4] cycloaddition reaction. Instead, the calculations suggest a stepwise reaction involving sequential, discrete bond-breaking events before ultimately generating the two anthracene products. This behavior is observed for both the head-to-tail and head-to-head dimers regardless of the simulated mode of mechanical activation. 1.3.4 2π Electrocyclic Ring-Opening Reactions Since first reported by Craig and coworkers in 2009,12 the mechanochemical 2π electrocyclic ring-opening reaction of gem-dihalocyclopropane (gDHC) mechanophores to generate 2,3-dihaloalkenes has been studied extensively. In addition to cyclopropanes, the mechanochemical reactivity of three-membered heterocycles including epoxides 80,81 and aziridines82 has also been explored (Chart 1.4). Unlike most of the mechanophores presented above that undergo cycloelimination reactions, mechanophores that undergo electrocyclic ring-opening reactions are non-scissile, allowing for the incorporation of many reactive units per polymer chain, thus enabling a greater degree of activation per stretching event.83 CoGEF calculations successfully predict a 2π electrocyclic ring-opening Chart 1.4 Structures Associated with Formal 2π Electrocyclic Ring-Opening Reactions 22 reaction that is consistent with the determined experimental behavior for 16 of the 19 structures in this category (Table 1.4). Table 1.4 CoGEF Results for Formal 2π Electrocyclic Ring-Opening Reactions§ Structure Resulta 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 Con6                    Fmax (nN) 3.6 3.3 3.5 3.2 3.3 3.7 3.6 5.7 3.8 3.4 3.2 3.7 5.2 3.8 5.4 5.6 6.4 6.2 6.2 Emax (kJ/mol) 216 184 262 183 164 180 166 448 205 190 148 202 557 340 300 416 729 549 607 Ref. 84,85 84,85 86 86 87 13,84,85,88 89 8 12,84,87 87 90 90 12,91 12,91 82 82 80 81 80 §B3LYP/6-31G* level of DFT. aConsistency between CoGEF prediction and reported experimental reactivity. CoGEF calculations correctly predict the C–C bond cleavage and concerted halide migration to form a 2,3-dihaloalkene product consistent with the anticipated 2π electrocyclic ring-opening reaction of gDHCs with only one exception, as noted below. The halide anti to the outwardly rotating alkyl substituents is the preferred leaving group for the thermal electrocyclic ring-opening reaction according to the Woodward–Hoffman– DePuy (WHD) rules.92–94 For gem-bromochlorocyclopropanes (gBCC) 50 and 51, CoGEF calculations follow the WHD predicted pathways and occur with migration of chlorine and bromine, respectively, which are anti to the alkyl substituents in each case. These results 23 are consistent with experiments for the mechanical activation of a copolymer containing each gBCC isomer, which proceeded to form both the chlorine and bromine migration products.85 On the other hand, CoGEF calculations predict chlorine migration for both gem-chlorofluorocyclopropane (gCFC) mechanophores 52 and 53, which contradicts the WHD rules, but again is consistent with experimental findings. 86 In this case, radical trapping experiments indicate that syn-Cl isomer 52 reacts via a mechanism involving a transition state with considerable diradicaloid character, similar to the isomerization reaction of gem-difluorocyclopropane (gDFC) mechanophores (vide infra). The value of Fmax calculated for syn-Cl gCFC 52 is approximately 0.3 nN larger than the Fmax for antiCl gCFC 53, which also agrees with the relative reactivity of the two mechanophores observed from SMFS experiments.86 Finally, we note that CoGEF calculations performed on mechanophores 56 and 57 successfully predict the expected 2π electrocyclic ringopening reactions accompanied by chlorine migration; however, the corresponding 2,3dichloroalkene products in these cases are thermally unstable and undergo subsequent elimination of HCl in the laboratory,8,89 which is not captured in the simulations, as expected. The diversity of structural variations for the gDHC mechanophores provides an opportunity to compare the results of CoGEF calculations to experimentally determined structure–property relationships. For example, comparing mechanophores 58, 59, and 60 reveals the impact of a so-called lever-arm effect 87 that has been demonstrated to reduce the force required for ring-opening by providing more efficient force transfer to the mechanophore. SMFS experiments confirm that a polynorbornene backbone attached to the gem-dichlorocycloproprane (gDCC) mechanophore (59) or the addition of an E-alkene 24 substituent (60) lowers the force required to promote the mechanochemical ring-opening reaction from approximately 1.3 nN for 58 to 0.9 and 0.8 nN for 59 and 60, respectively.87,90 The results of CoGEF calculations are consistent with these experimentally determined trends in reactivity. The CoGEF calculation performed on cis-gDCC mechanophore 58 with simple alkyl substituents predicts an Fmax value of 3.8 nN. Modifying the tethers to include terminal cyclopentyl groups that mimic the structure of a polynorbornene backbone lowers the calculated value of Fmax to 3.4 nN for 59, while incorporation of an E-alkene adjacent to the gDCC results in a calculated Fmax of 3.2 nN for 60. The incorporation of a Z-alkene substituent is less effective than the E-alkene, requiring a force of approximately 1.2 nN to achieve the ring-opening reaction in SMFS experiments. 90 The relative impact of the Z-alkene is also accurately reflected in the CoGEF calculation with a predicted Fmax value of 3.7 nN for 61, just below the calculated value of Fmax for dialkyl substituted mechanophore 58. The CoGEF calculation performed on trans-gDCC mechanophore 62 does not predict a 2π electrocyclic ring-opening reaction with concurrent halide migration to generate a 2,3-dichloroalkene product. Instead, the predicted transformation mirrors the CoGEF results for the gDFC mechanophores described below, indicating cleavage of the central C–C bond to form a product consistent with a transient diradical species. Although the mechanochemical reaction of cis and trans gDCC isomers was previously demonstrated to occur with nearly equal probability under ultrasonication conditions, 12 SMFS measurements revealed substantially different plateau forces of 1.3 nN and 2.3 nN for cisgDCC and trans-gDCC, respectively.91 Despite the different reaction pathways predicted by CoGEF, the calculated values of Fmax reflect the impact of cis and trans stereochemistry 25 on the gDCC mechanophore observed in SMFS experiments. The value of Fmax calculated for the electrocyclic ring-opening reaction of cis-gDCC mechanophore 63 is 3.8 nN, while the Fmax value predicted for the reaction of trans-gDCC analog 62 is 5.2 nN. The significantly larger force measured for the reaction of the trans-gDCC mechanophore is consistent with an electrocyclic ring-opening reaction that proceeds via a formally symmetry-forbidden conrotatory pathway.91 Alternatively, the CoGEF results for 62 suggest another intriguing mechanistic possibility, in analogy to the reactivity observed for gDFC mechanophores.95 That is, isomerization of the trans-gDCC into the cis isomer via a transient mechanical force and subsequent reaction via the expected electrocyclic ringopening pathway would ultimately furnish the 2,3-dichloroalkene product. To the best of our knowledge, this hypothesis has not been tested experimentally. The mechanochemical ring-opening reaction of epoxides to generate carbonyl ylide intermediates has been demonstrated for mechanophores 66 and 67, although the reactivity is low.80,81 SMFS measurements have revealed that the rate of ring-opening for even the most mechanochemically reactive allylic epoxide 67 is very slow under significantly large forces of approximately 2.5 nN,81 suggesting that ring-opening likely competes with nonspecific bond scission in the polymer backbone. CoGEF calculations performed on these epoxide mechanophores fail to reproduce the ring-opening behavior and instead predict C– C bond scission adjacent to the pulling point. The mechanochemical ring-opening reaction of epoxidized polybutadiene has also been characterized by SMFS measurements, which did not reveal any evidence for epoxide ring-opening at forces up to 2.5 nN. 80 Again, the cyclopentyl groups of structure 66 reflect a polynorbornene backbone, which has been suggested to provide more efficient force transduction compared to polybutadiene. 87 26 Similar to the other epoxides, the CoGEF calculation performed on Con6 does not predict a ring-opening reaction, which in this case is consistent with the experimental observation that epoxidized polybutadiene is mechanochemically inactive. 1.3.5 4π Electrocyclic Ring-Opening Reactions In 2007, Moore and coworkers described the mechanochemical 4π electrocyclic ringopening reaction of benzocyclobutene.11 Remarkably, both the cis and trans 1,2disubstituted benzocyclobutenes were demonstrated to undergo formal disrotatory and conrotatory electrocyclic ring-opening reactions, respectively, to generate identical E,Eortho-quinodimethide intermediates. For the formally symmetry-forbidden disrotatory electrocyclic ring-opening reaction of the cis-isomer, FMPES calculations suggest that mechanical force reduces the activation barrier of the concerted pathway, which becomes barrierless at sufficiently high forces.22 Six benzocyclobutene congeners have been investigated experimentally that differ in the substitution and stereochemistry at the positions of polymer attachment (Chart 1.5). CoGEF calculations predict a formal 4π electrocyclic ring-opening reaction for all six benzocyclobutene compounds reported in the literature (Table 1.5). 27 Chart 1.5 Structures Associated with Formal 4π Electrocyclic Ring-Opening Reactions Table 1.5 CoGEF Results for Formal 4π Electrocyclic Ring-Opening Reactions§ Fmax Emax Ref. (nN) (kJ/mol)  68 3.7 282 96  69 4.1 186 91  70 4.1 211 11,97  71 3.1 244 96  72 3.7 367 91  73 3.0 310 11,97 §B3LYP/6-31G* level of DFT. aConsistency between CoGEF prediction and reported experimental reactivity. Structure Resulta The CoGEF calculations performed on cis and trans 1,2-disubstitued benzocyclobutenes result in the formation of the same ortho-quinodimethide products, consistent with experimental measurements. The simulated ring-opening reactions of 68– 71 are consistent with a synchronous transformation in which the breaking and reformation of bonds occurs over a single elongation step in the CoGEF profile. On the other hand, the CoGEF calculations performed on mechanophores 72 and 73 appear to proceed through a highly asynchronous ring-opening process, which could suggest the formation of significant diradicaloid character prior to formation of the ortho-quinodimethide product. This behavior is not consistent with orbital symmetry arguments as the predicted ringopening reaction of other cis-disubstituted benzocyclobutenes 68 and 71 occurs 28 synchronously, so the origin of these qualitative differences in the CoGEF profiles is unclear. The impact of cis and trans stereochemistry of the pulling positions on the fourmembered-ring follows the same trends as the cyclobutane and gem-dichlorocyclopropane mechanophores presented above. The predicted Fmax is lower for cis-isomer 72 compared to the corresponding trans-isomer 69, with calculated values of 3.7 and 4.1 nN, respectively. This trend is also consistent with the relative forces measured experimentally using SMFS.91 Similar to the lever arm effect observed for gem-dichlorocyclopropanes,90 the E-alkene substituent of cis-disubstituted benzocyclobutene 71 results in a lower calculated Fmax value of 3.1 nN compared to cis-dialkyl substituted analog 72 with a calculated Fmax of 3.7 nN, which is again consistent with the relative forces measured by SMFS.96 29 1.3.6 6π Electrocyclic Ring-Opening Reactions Spiropyran97 and naphthopyran98 undergo a 6π electrocyclic ring-opening reaction under mechanical force to generate colored merocyanine dyes (Chart 1.6). The mechanochromic behavior of these mechanophores makes them particularly useful as molecular force probes for visual stress sensing applications. The mechanochemical reactivity of a variety of spiropyran and naphthopyran structures has been studied experimentally, providing insight into structure–mechanochemical activity relationships. Chart 1.6 Structures Associated with Formal 6π Electrocyclic Ring-Opening Reactions CoGEF calculations successfully predict the expected 6π electrocyclic ring-opening reaction for 16 out of 18 reported structures in this class (Table 1.6). 30 Table 1.6 CoGEF Results for Formal 6π Electrocyclic Ring-Opening Reactions§ Structure Resulta 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 Con7 Con8                   Fmax (nN) 4.4 2.7 2.6 2.0 3.5 3.2 5.9 5.7 4.8 4.3 4.4 4.1 3.7 3.7 3.9 4.1, 4.6 6.0 6.0 Emax (kJ/mol) 381 165 150 74 271 248 536 567 386 418 483 370 348 334 332 652, 740 716 650 Ref. 4,97,99,100 59,99–101 102 103 101,104 101 105 104 104 98 106 106 106 106 106 7 98 98 §B3LYP/6-31G* level of DFT. aConsistency between CoGEF prediction and reported experimental reactivity. Spiropyran is one of the most widely studied mechanophores in the literature. Similar to the gDHC mechanophores, the mechanochemical reactivity of a number of different spiropyran mechanophores with varying connectivity and substitution has been investigated using different experimental techniques enabling the elucidation of important structure–activity relationships. The two most commonly employed spiropyran mechanophores, 74 and 75, vary in the position of polymer attachment on the indoline portion of the molecule resulting in different mechanochemical activity in SMFS experiments.99 Attachment at the indoline nitrogen for mechanophore 75 leads to a greater mechanical advantage compared to 74, which is manifested in different plateau forces of 0.24 and 0.26 nN, respectively. The Fmax values calculated from CoGEF are qualitatively consistent with this trend in reactivity; however, as discussed in greater detail below, the 31 Fmax value of 4.4 nN calculated for mechanophore 74 is unexpectedly large compared to the Fmax value of 2.7 nN calculated for spiropyran 75. Notably, spirothiopyran 77 is predicted to have one of the lowest predicted values of Fmax (2.0 nN) of any mechanophore studied, although the force required for this ring-opening reaction has not been measured experimentally. The effect of electronic substitution on the mechanochemical reactivity of spiropyran has also been recently studied using SMFS. 101 The force required for ring opening was shown to vary depending on the nature of the substituent para to the oxygen on the benzopyran portion of the molecule following a classic Hammett relationship. The plateau forces measured for the ring-opening reaction of mechanophores 78, 79, and 75 were 0.41, 0.36, and 0.24 nN, respectively, indicating enhanced stabilization of negative charge in the transition state as the electron withdrawing power of the substituent increases going from hydrogen to bromine to a nitro group. The values of Fmax calculated for 78 (R = H), 79 (R = Br), and 75 (R = NO2) are 3.5, 3.2, and 2.7 nN, respectively, which are in agreement with the trend in reactivity determined from SMFS experiments. Spiropyran mechanophores 80 and 81 with pulling positions para to the pyran oxygen on the benzopyran fragment of the molecule are both predicted to undergo cleavage of the spiro C–N bond instead of the expected C–O bond. The C–N bond scission appears to be heterolytic in nature and occurs with predicted Fmax values of 5.9 nN (80) and 5.7 nN (81), which are significantly higher than values of Fmax computed for the ring-opening reaction of other spiropyran mechanophores. A prior investigation of the effects of regiochemistry on the mechanochemical activation of spiropyran in bulk materials revealed that para-substituted mechanophore 81 is significantly less sensitive to mechanical force 32 than analogous mechanophores with polymer attachment at the ortho and meta positions (78 and 82, respectively).104 Interestingly, CoGEF calculations predict the expected C–O bond cleavage reaction leading to merocyanine formation for structure 81 when the pulling point is changed to a hydrogen atom at either the meta or ortho position on the benzopyran portion of the molecule, indicating that the computed reactivity is affected strongly by the pulling geometry and not purely electronic factors (Figure 1.4). We further note that the computed visible absorption spectrum of the product resulting from C–N bond cleavage of spiropyran 81 is similar to that of the merocyanine species resulting from the expected 6π electrocyclic ring-opening reaction, possibly confounding the interpretation of colorimetric analyses if this competing reaction pathway is indeed experimentally accessible. Similar to the regiochemical effects discussed above for spiropyran and other classes of mechanophores, the mechanochemical activity of naphthopyran is highly dependent upon the positions of polymer attachment. While naphthopyrans 83–88 are mechanochemically active, regioisomers Con7 and Con8 do not undergo electrocyclic ring-opening reactions in polymeric materials under tension. 98 This behavior is accurately 33 Figure 1.4 Investigation of regiochemical effects on the predicted mechanochemical reactivity of spiropyran 81. (A) Changing the pulling position results in the anticipated scission of the C–O pyran bond leading to formation of the merocyanine. (B) Electrostatic potential map of the product predicted by CoGEF (parapulling) indicating heterolytic fragmentation of the C–N bond. (C) CoGEF profiles associated with the schemes in panel A. (D, E) Visible absorption spectra calculated at the B3LYP/6-31G* level of TD-DFT for the product resulting from C–N bond scission, and the expected merocyanine species. 34 reproduced in the CoGEF calculations, which predict C–C bond scission adjacent to the pulling point for both control molecules. The regioisomer-specific mechanochemical reactivity of naphthopyran 83 was previously attributed to better alignment between the labile C–O pyran bond and the direction of the applied force, which was quantified by a specific angle denoted here as the force–bond angle.98 The angle between the C–O pyran bond and the external force vector at maximum extension was calculated from molecular models to be relatively narrow for mechanophore 83, whereas the angle is substantially wider for the two unreactive naphthopyran regioisomers Con7 and Con8. While proper orientation between the external force vector and the labile bond in a mechanophore is a critical parameter that influences mechanochemical coupling, in general we find no correlation between force–bond angle and mechanochemical activity when analyzed broadly across the entire library of mechanophores and control structures (Figure 1.5). Figure 1.5 Summary of (A) Emax values and (B) force–bond angles determined using the CoGEF method for each mechanochemical reaction class. The CoGEF results for control structures are universally indistinguishable from the mechanophores when quantitative metrics Emax and force–bond angle are compared, indicating that these metrics are poor predictors of mechanochemical reactivity. Data from calculations that are inconsistent with experimentally determined reactivity are excluded. 35 Another notable example in this reaction class is bis-naphthopyran mechanophore 89, which contains two separate reactive sites and exhibits force-dependent changes in visible absorption due to distinctly colored merocyanine products resulting from the ringopening reaction of either one or both pyrans. 7 While the CoGEF calculation performed on bis-naphthopyran 89 predicts that both pyrans successfully undergo the anticipated ringopening reactions under force, the geometry constraints imposed by the CoGEF method necessitate a sequential ring-opening process upon molecular extension. Experiments indicate, however, that both rings open in tandem under ultrasound-induced mechanical elongation. Multiple chain scission reactions have been observed for cyclic polymers during a single high-strain-rate extensional event that suggest potentially important dynamic effects under ultrasonication conditions,107 which are not accurately captured by the CoGEF method. 1.3.7 Homolytic Reactions In a seminal report by Moore and coworkers in 2005, the mechanochemical site- specific chain scission of polymers containing mechanophore 90 with a mechanically weak azo group near the chain midpoint was demonstrated to occur through the putative homolytic expulsion of nitrogen.108 A number of diverse mechanophores have since been developed that react via radical pathways (Chart 1.7). For example, this category includes mechanochromic mechanophores 94–97 that generate colored stable free radicals under mechanical force,6,109–111 and ladderenes 98 and 99 that unzip to generate semiconducting polyacetylene.15,112 CoGEF calculations successfully predict the expected homolytic bond 36 Chart 1.7 Structures Associated with Homolytic Reactions H2N NC Me H3C tBu tBu R3 N N Me CN O N CH3 H3C 90 O O 91 O NH2 R3 O O CN CN O O NC R3 tBu tBu R2 OMe 95 F F H3C 96 97 H3C CH3 CH3 F F F 102 CH3 F F SiMe3 R3 SiMe3 O H3C CH3 SiMe3 107 N N Ph N Ph Ph R3 O O N 109 R3 F F F H H H H H H 99 CH3 O R2 = O O CH3 R3 = O H3C O R H H H R2 2 S O 111 N OMe O O O S O CF3 S 113 H3CO H F F F F F O F OCH3 O S N O O O R1 CF3 O CH3 O O O O 112 H3CO CH3 S H 106 O 1 S R CH3 101 O H3CO CH3 H H H H H OCH3 F CH3 O 100 R1 O 110 CH3 S MeO Ph Bn N R1 S R2 N 108' O Ph N N N 108 Ph R1 = 105 N Ph F O R3 Ph H3CO F CH3 103 R2 98 F 104 H3C H H H3C R3 R2 H H H H H H O S NC R3 94 S O R2 S 93 92 R2 R3 MeO CH3 N S R2 S S H3CO O 114 scission reactions for 23 out of 25 experimentally studied mechanophores in this class (Table 1.7). In addition to transformations involving simple homolytic bond scission, CoGEF calculations also successfully capture the mechanochemical behavior of more complex, multistep reactions. In many cases, CoGEF calculations accurately reproduce computations performed using more sophisticated approaches. According to FMPES calculations, the unzipping reaction of ladderene and ladderane mechanophores 98–100 proceeds via a mechanism that involves two transient diradical transition states. 15,112 The complex stepwise unzipping reaction of these mechanophores is successfully captured by CoGEF calculations. While the mechanochemical reaction mechanism of benzoladderene 101 has not been confirmed experimentally, we include it in this category in the context of other ladderene structures.113 Notably, the CoGEF calculation performed on 37 Table 1.7 CoGEF Results for Homolytic Reactions§ Structure 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 108′ 109 110 111 112 113 114 Resulta                    b       §B3LYP/6-31G* Fmax (nN) 3.7 5.2 2.0 3.6 3.5 4.5 4.3 4.4 3.2, 3.9 4.2, 4.0 4.2, 3.9 3.3 4.8 3.4 4.9 4.2 3.4 3.5, 2.6, 3.5 5.1 4.3 4.7 4.3 4.3 4.3 4.6 6.1 Emax (kJ/mol) 366 230 114 271 169 294 326 287 236, 239 451, 346 511, 326 245 466 292 771 455 409 348, 521, 617 536 258 369 472 227 625 626 611 Ref. 108,114 115 116 117 6,118 109 110 111 15,112 112 112 113 91,95,119 91,95,119,120 119 121 121 122 123 124 125 126 127 114 114 aConsistency level of DFT. between CoGEF prediction and reported experimental reactivity. bStructural revision results in CoGEF prediction matching expected reactivity. benzoladderene 101 predicts that the ring-opening reaction occurs through a stepwise mechanism similar to the other ladderene mechanophores. In contrast to the electrocyclic ring-opening reactions of other gDHCs described above, gem-difluorocyclopropane (gDFC) mechanophores 102 and 103 undergo homolytic bond scission leading to a transient diradical intermediate under force.95 As an interesting example, the CoGEF calculation performed on a representative dimer structure 104 predicts sequential ringopening reactions of the cis followed by the trans disubstituted gDFC groups to generate 38 an apparent tetraradical species, which subsequently disproportionates to form two identical 3,3-difluoroalkene radicals. This reactivity predicted by CoGEF is consistent with experimental characterization of reaction products by 1H and 19F NMR spectroscopy following ultrasound-induced mechanochemical activation and reproduces the results from AISMD simulations.119 Similarly, the mechanochemical reaction of perfluorocyclobutane mechanophores 105 and 106 has been demonstrated to proceed via a stepwise mechanism with a diradical intermediate,121 which is accurately reflected in the CoGEF calculations performed on these two structures. In another interesting example, the ring-opening reaction of vinyl-addition polynorbornene surrogate 107 is predicted to occur in a stepwise fashion to produce the ROMP-type polynorbornene repeat unit structure observed experimentally.122 The CoGEF calculation performed on triphenylimidazole dimer 108 predicts bond scission that differs from the anticipated reaction. Compound 108 was reported to undergo homolytic cleavage of the central C–N bond to generate a pair of stable triphenylimidazolyl radicals under force.123 Instead, CoGEF calculations predict fragmentation of a C–N bond in one of the imidazole rings. While the imidazole dimer containing a central C–N linkage is expected to be the major product of oxidative coupling, this species exists in equilibrium with other isomers.123 Performing the CoGEF calculation on isomer 108′ comprising a structure in which the imidazole rings are coupled via a central C–C bond results in the expected homolytic cleavage producing two identical triphenylimidazolyl radicals consistent with the experimentally observed behavior. The CoGEF calculations performed on compounds 109–113 predict homolytic bond scission that is consistent with the reported reactivity of these compounds, although we note that the products of these 39 mechanochemical transformations have not been fully characterized. The CoGEF calculation performed on 114, however, predicts scission of the C–O bond in a terminal ester group, rather than the anticipated C–O bond of the benzyl ether moiety. In fact, the reactivity of benzyl phenyl ether 114 was found to be surprisingly low.114 Poor mechanochemical coupling was attributed to contraction of the molecule as the benzyl carbon atom rehybridizes from sp3 to sp2 upon formation of the benzyl radical. In that scenario, the CoGEF process may bias the reaction along a trajectory that does not correspond to the global minimum energy force-coupled pathway. 1.3.8 Heterolytic Reactions Mechanochemical reactions that involve heterolytic fragmentation of covalent bonds to generate charged species are less common.128–132 Nevertheless, several mechanophores have been reported in the literature to undergo heterolytic covalent bond cleavage under mechanical force (Chart 1.8). The CoGEF calculations performed on models of all such structures successfully reproduce the experimentally demonstrated reactivity (Table 1.8). Notably, a series of N-heterocyclic carbene precursors (115–117) Chart 1.8 Structures Associated with Heterolytic Reactions 40 was recently discovered that undergoes selective C–C bond scission under mechanical force via three concomitant dissociation pathways. 132 CoGEF calculations predict the heterolytic fragmentation of all three compounds; however, experiments demonstrated that the proportion of heterolytic fragmentation diminishes with decreasing fluorination of the aryl group, favoring a concerted mechanism for mechanophores 116 and 117 with a less polarized scissile bond. Table 1.8 CoGEF Results for Heterolytic Reactions§ Structure Resulta 115 116 117 118 119 120       Fmax (nN) 5.2 5.5 5.8 5.6 3.7 4.6 Emax (kJ/mol) 388 438 499 507 266 368 Ref. 132 132 132 128,129 130 131,133 §B3LYP/6-31G* level of DFT. aConsistency between CoGEF prediction and reported experimental reactivity. Poly(o-phthalaldehyde) undergoes a mechanically triggered unzipping reaction above its ceiling temperature to generate o-phthalaldehyde monomers.128,129 The proposed mechanism, which is supported by AISMD simulations, involves mechanochemical chain cleavage via an initial heterolytic bond scission event followed by a depolymerization cascade.128 The CoGEF calculation performed on model structure 118, which represents a short repeating unit segment of poly(o-phthalaldehyde), predicts the simultaneous cleavage of three C–O bonds along the oligomer backbone including one central linking bond and two internal bonds on adjacent monomer units. The chemical transformation predicted by the CoGEF method is consistent with heterolytic fragmentation and two concurrent ring- 41 opening reactions to generate two new aldehyde functional groups, with an oxocarbenium ion and an oxyanion localized on the separate portions. These results are in excellent agreement with the prior mechanistic findings for mechanically initiated depolymerization of poly(o-phthalaldehyde). Triarylsulfonium compound 119 was reported to undergo heterolytic scission of the central polarized C–S bond to afford a phenyl cation, which was demonstrated experimentally through trapping experiments.130 The CoGEF calculation performed on mechanophore 119 predicts the rupture of the anticipated C–S bond that is consistent with the reported mechanochemical behavior. In addition, rhodamine mechanophore 120 undergoes a force-induced ring-opening reaction that leads to a change in color and fluorescence in polymeric materials.131,133 Although the mechanism has not been studied in detail, the C–N bond is presumed to cleave heterolytically, possibly with assistance from the diethylamine substituent para to the developing carbocation. The CoGEF calculation performed on mechanophore 120 predicts the selective scission of the anticipated central C–N bond. However, in the absence of a polarizable continuum model to simulate a polar solvent environment, a [1,3]-sigmatropic rearrangement is predicted to occur, resulting in the formation of a new oxygen-containing five-membered ring bearing an exocyclic C–N double bond. When the CoGEF calculation is repeated with a polar solvent model, heterolytic cleavage of the central C–N bond is observed without any rearrangement (see Appendix A for details). 42 1.3.9 Fmax as a reliable descriptor of mechanochemical reactivity Calculated values of Fmax are reliable and consistent indicators of the relative mechanochemical reactivity of mechanophores, as demonstrated above for various reactions within each formal mechanistic category. The value of Fmax from each successful CoGEF calculation across every reaction class is illustrated in Figure 1.6. For mechanophores where the predicted reactivity from the CoGEF calculation agrees with experimental results, the values of Fmax range from the lowest of 2.0 nN for spirothiopyran Figure 1.6 Summary of Fmax values calculated by the CoGEF method across all mechanistic categories. Data from calculations that are inconsistent with reported experimental reactivity are excluded. 77 and diaryldisulfide 92 to the highest of 5.9 nN for trans-cyclobutane 2. Notably, there is a clear distinction between the values of Fmax calculated for each mechanophore and the values of Fmax associated with bond scission in the negative controls, which in every case are ≥ 6.0 nN. In contrast, the CoGEF results for control structures are universally 43 indistinguishable from the mechanophores when alternative quantitative metrics Emax and force–bond angle are compared (Figure 1.5). While the values of Emax generally exhibit a positive correlation with Fmax, there is no such correlation with force–bond angle (Figure 1.7). It is worth reiterating, however, that the magnitude of Emax values from CoGEF calculations is highly variable, whereas Fmax is a more robust predictor of mechanochemical activity. We mention in passing that the use of unrestricted calculations (Figure 1.8) and dispersion corrections (Figure 1.9) appears to have minimal influence on the results of CoGEF calculations. Figure 1.7 Relationship between calculated values of (A) Emax and (B) force–bond angle with the calculated values of Fmax determined with the CoGEF method at the B3LYP/6-31G* level of DFT. There is a positive correlation between the values of Emax and Fmax, while there is no apparent correlation between force–bond angle and values of Fmax. 44 Figure 1.8 CoGEF calculations performed using unrestricted DFT (UB3LYP/6-31G*) on representative mechanophores for which CoGEF calculations at the B3LYP/6-31G* level of DFT predict reactions that are inconsistent with the reported experimental behavior. Use of the UB3LYP functional has minimal influence on the results of the CoGEF simulations. The same chemical transformations are predicted in each case. 45 Figure 1.9 Comparison of CoGEF calculations performed on representative mechanophores at the B3LYP/631G* level of DFT and using a dispersion-corrected functional (B3LYP-D3/6-31G*). Use of the dispersioncorrected B3LYP-D3 functional has minimal influence on the results of the CoGEF simulations. The same chemical transformations are predicted in each case. 46 Calculated values of Fmax obtained from CoGEF calculations also correlate well with the mechanochemical reactivity of different mechanophores determined experimentally (Figure 1.10). While systematic studies of structure–reactivity relationships using threshold molecular weight as a quantitative metric are limited to substituted cyclobutanes36 and furan–maleimide Diels–Alder adducts, 65 there is a positive correlation between the calculated values of Fmax and the experimentally measured threshold molecular weight for these mechanophores (Figure 1.10A). Mechanochemical reactivity is more accurately quantified using SMFS, which has been performed consistently on a relatively large number of mechanophores including spiropyrans, 99,101 benzocyclobutenes,91,96 and cyclopropanes.86,87,90,91 Again, there is a positive correlation between the values of Fmax calculated using CoGEF and the forces measured experimentally using SMFS (Figure 1.10B). As mentioned previously, spiropyran mechanophore 74 is a notable exception to this trend with an anomalously high calculated Figure 1.10 Values of Fmax from CoGEF calculations compared to experimentally determined values of (A) threshold molecular weight obtained from rates of ultra-sound induced mechanochemical activation, and (B) forces determined from single molecule force spectroscopy (SMFS) measurements. 47 Fmax value of 4.4 nN compared to the exceptionally low measured force of 0.26 nN. 99 The rupture forces calculated with the CoGEF method are consistently greater than forces determined from experiments, in part because thermal effects are neglected. 19 In addition, the forces measured using SMFS are dependent upon the loading velocity, with all of the forces considered here measured with a loading velocity of 300 nm/s. Nevertheless, the relationship between calculated values of Fmax and experimentally determined forces demonstrates that the CoGEF method is able to reliably predict the relative mechanochemical activity of mechanophores, further reinforcing the qualitative trends in reactivity highlighted above. 1.4 Conclusions The constrained geometries simulate external force (CoGEF) method is an operationally simple and highly accessible quantum chemistry technique that enables prediction of mechanochemical reactivity. In this study, we apply the CoGEF method systematically to every covalent mechanophore reported in the literature and compare the predicted reactivity against the experimentally determined behavior. CoGEF calculations are also performed on molecules that have been determined to be mechanochemically inactive as negative controls. Out of the 128 structures investigated with reactions that span eight distinct mechanistic categories, CoGEF calculations performed at the B3LYP/6-31G* level of DFT predict mechanochemical transformations that are consistent with the reported experimental reactivity for 112 molecules, including every negative control. In total, this corresponds to a success rate of 88%; however, analysis suggests that the accuracy of the CoGEF method is likely even higher. In some cases, for example, 48 computational results combined with experimental characterization data indicate that revision of prior structural assignments may be merited or that additional experiments are needed to substantiate the reported reactivity. The utility of the CoGEF method is revealed not only in its general ability to accurately predict covalent bond transformations, but also in quantitative comparisons of mechanochemical reactivity. We demonstrate that the maximum force predicted for bond rupture in CoGEF calculations is correlated with forces measured using single molecule force spectroscopy, suggesting that the CoGEF method is a reliable predictor of the relative activity of mechanophores. On the other hand, some notable limitations of the CoGEF method are revealed. The inability to account for thermal effects as a static quantum chemistry method manifests in limitations for calculating the mechanochemical reactivity of “flex activated” mechanophores, for instance, where proper consideration of the contribution from thermal energy to the overall activation is essential. Additionally, the inherent geometric constraints imposed by CoGEF can obscure dynamic effects, such as those that may be involved in some specific reactions under high strain rate conditions, or possibly bias reactions by stretching molecules along trajectories that do not correspond to global minimum energy force-coupled pathways. Nevertheless, the ability of the CoGEF method to reproduce more sophisticated computations as well as accurately predict remarkable transformations, like those that formally violate classical orbital-symmetry rules or proceed in a complex stepwise process, suggest that the technique is capable of providing important insight into mechanochemical reactions beyond identifying scissile bonds. Our results demonstrate that despite its simplicity, which is an enabling feature for 49 practitioners of experimental polymer mechanochemistry, the CoGEF method is a powerful tool for predicting and understanding mechanochemical reactivity. 1.5 Experimental Details 1.5.1 General methods CoGEF calculations were performed using Spartan ′18 Parallel Suite according to previously reported methods.24,36 A guide to running CoGEF calculations in Spartan can be found in Appendix B. Chemical structures were composed in ChemDraw, saved as .mol files, and then imported into Spartan. Structures were truncated to include tethers that accurately reflect the structure of the molecules used in the experimental studies. Ground state energies were calculated using DFT at the B3LYP/6-31G* level of theory in vacuum, unless specified otherwise. For the three mechanophores in the heterolytic category, CoGEF calculations were also performed using a polarizable continuum model (dielectric constant of 37) to simulate a polar solvent. Starting from the equilibrium geometry of the unconstrained molecule (relative energy = 0 kJ/mol), the distance between the terminal anchor atoms of the truncated structure was increased in increments of 0.05 Å and the energy was minimized at each step. This operation was carried out automatically using the Energy Profile calculation in Spartan. Calculations were run until a chemical transformation was predicted to occur, as evidenced by the rupture and reorganization of one or more covalent bonds. In some cases, an initial equilibrium conformer calculation was performed using Molecular Mechanics (MMFF) before performing the steps outlined above. The maximum number of geometry optimization cycles was increased beyond the default value using the GEOMETRYCYCLE option to ensure convergence at each step in the CoGEF profile. 50 1.5.2 Determination of Fmax The maximum force predicted for each mechanochemical transformation was calculated from the slope between contiguous points in the energy–displacement curve. In most cases, Fmax coincides with the displacement immediately prior to a discontinuity in the relative energy profile. The value of Fmax is thus calculated from the slope between the two data points preceding the abrupt attenuation in energy. More rarely, a continuous change in energy is observed that approaches an apparent plateau value at long displacements. In these cases, Fmax occurs at the inflection point in the CoGEF curve. The value of the slope is divided by the Avogadro constant and adjusted to provide force in units of nJ/m (nN). 1.5.3 Determination of Emax The maximum energy relative to the energy of the unconstrained molecule at equilibrium is reported as Emax. The value of Emax is determined from the CoGEF curve at the displacement corresponding to Fmax. Typically, this means that Emax represents the highest relative energy on the CoGEF curve; however, for instances in which the CoGEF profile exhibits a sigmoidal shape and/or a discontinuity is absent, Emax corresponds to the relative energy at the inflection point. 1.5.4 Determination of Force–Bond Angle Force–bond angles were calculated according to the previously described method using structural models from CoGEF calculations at the displacement corresponding to Fmax.98 The external force vector was approximated using the coordinates of the two terminal atoms that define the distance constraint in the CoGEF calculation. 51 1.6 References (1) Beyer, M. K.; Clausen-Schaumann, H. Mechanochemistry: The mechanical activation of covalent bonds. Chem. Rev. 2005, 105, 2921–2948. (2) Caruso, M. M.; Davis, D. A.; Shen, Q.; Odom, S. A.; Sottos, N. R.; White, S. R.; Moore, J. S. Mechanically-Induced Chemical Changes in Polymeric Materials. Chem. Rev. 2009, 109, 5755–5798. (3) Li, J.; Nagamani, C.; Moore, J. S. Polymer Mechanochemistry: From Destructive to Productive. Acc. Chem. Res. 2015, 48, 2181–2190. (4) Davis, D. A.; Hamilton, A.; Yang, J. L.; Cremar, L. D.; Van Gough, D.; Potisek, S. L.; Ong, M. T.; Braun, P. V.; Martinez, T. J.; White, S. R.; Moore, J. S.; Sottos, N. R. Force-induced activation of covalent bonds in mechanoresponsive polymeric materials. Nature 2009, 459, 68–72. (5) Chen, Y. L.; Spiering, A. J. H.; Karthikeyan, S.; Peters, G. W. M.; Meijer, E. W.; Sijbesma, R. P. Mechanically induced chemiluminescence from polymers incorporating a 1,2-dioxetane unit in the main chain. Nat. Chem. 2012, 4, 559–562. (6) Imato, K.; Irie, A.; Kosuge, T.; Ohishi, T.; Nishihara, M.; Takahara, A.; Otsuka, H. Mechanophores with a Reversible Radical System and Freezing-Induced Mechanochemistry in Polymer Solutions and Gels. Angew. Chem. Int. Ed. 2015, 54, 6168–6172. (7) McFadden, M. E.; Robb, M. J. Force-Dependent Multicolor Mechanochromism from a Single Mechanophore. J. Am. Chem. Soc. 2019, 141, 11388–11392. 52 (8) Diesendruck, C. E.; Steinberg, B. D.; Sugai, N.; Silberstein, M. N.; Sottos, N. R.; White, S. R.; Braun, P. V.; Moore, J. S. Proton-Coupled Mechanochemical Transduction: A Mechanogenerated Add. J. Am. Chem. Soc. 2012, 134, 12446– 12449. (9) Larsen, M. B.; Boydston, A. J. “Flex-Activated” Mechanophores: Using Polymer Mechanochemistry To Direct Bond Bending Activation. J. Am. Chem. Soc. 2013, 135, 8189–8192. (10) Hu, X.; Zeng, T.; Husic, C. C.; Robb, M. J. Mechanically Triggered Small Molecule Release from a Masked Furfuryl Carbonate. J. Am. Chem. Soc. 2019, 141, 15018–15023. (11) Hickenboth, C. R.; Moore, J. S.; White, S. R.; Sottos, N. R.; Baudry, J.; Wilson, S. R. Biasing reaction pathways with mechanical force. Nature 2007, 446, 423–427. (12) Lenhardt, J. M.; Black, A. L.; Craig, S. L. gem-Dichlorocyclopropanes as Abundant and Efficient Mechanophores in Polybutadiene Copolymers under Mechanical Stress. J. Am. Chem. Soc. 2009, 131, 10818–10819. (13) Ramirez, A. L. B.; Kean, Z. S.; Orlicki, J. A.; Champhekar, M.; Elsakr, S. M.; Krause, W. E.; Craig, S. L. Mechanochemical strengthening of a synthetic polymer in response to typically destructive shear forces. Nat. Chem. 2013, 5, 757–761. (14) Robb, M. J.; Moore, J. S. A Retro-Staudinger Cycloaddition: Mechanochemical Cycloelimination of a beta-Lactam Mechanophore. J. Am. Chem. Soc. 2015, 137, 10946–10949. (15) Chen, Z. X.; Mercer, J. A. M.; Zhu, X. L.; Romaniuk, J. A. H.; Pfattner, R.; Cegelski, L.; Martinez, T. J.; Burns, N. Z.; Xia, Y. Mechanochemical unzipping of 53 insulating polyladderene to semiconducting polyacetylene. Science 2017, 357, 475–478. (16) Piermattei, A.; Karthikeyan, S.; Sijbesma, R. P. Activating catalysts with mechanical force. Nat. Chem. 2009, 1, 133–137. (17) Michael, P.; Binder, W. H. A Mechanochemically Triggered “Click” Catalyst. Angew. Chem. Int. Ed. 2015, 54, 13918–13922. (18) Ribas-Arino, J.; Shiga, M.; Marx, D. Understanding Covalent Mechanochemistry. Angew. Chem. Int. Ed. 2009, 48, 4190–4193. (19) Stauch, T.; Dreuw, A. Advances in Quantum Mechanochemistry: Electronic Structure Methods and Force Analysis. Chem. Rev. 2016, 116, 14137–14180. (20) Roessler, A. G.; Zimmerman, P. M. Examining the Ways to Bend and Break Reaction Pathways Using Mechanochemistry. J. Phys. Chem. C 2018, 122, 6996– 7004. (21) Ribas-Arino, J.; Marx, D. Covalent Mechanochemistry: Theoretical Concepts and Computational Tools with Applications to Molecular Nanomechanics. Chem. Rev. 2012, 112, 5412–5487. (22) Ong, M. T.; Leiding, J.; Tao, H. L.; Virshup, A. M.; Martinez, T. J. First Principles Dynamics and Minimum Energy Pathways for Mechanochemical Ring Opening of Cyclobutene. J. Am. Chem. Soc. 2009, 131, 6377–6379. (23) Wolinski, K.; Baker, J. Theoretical predictions of enforced structural changes in molecules. Mol. Phys. 2009, 107, 2403–2417. (24) Beyer, M. K. The mechanical strength of a covalent bond calculated by density functional theory. J. Chem. Phys. 2000, 112, 7307–7312. 54 (25) Kersey, F. R.; Yount, W. C.; Craig, S. L. Single-Molecule Force Spectroscopy of Bimolecular Reactions: System Homology in the Mechanical Activation of Ligand Substitution Reactions. J. Am. Chem. Soc. 2006, 128, 3886–3887. (26) Paulusse, J. M. J.; Sijbesma, R. P. Selectivity of mechanochemical chain scission in mixed palladium(II) and platinum(II) coordination polymers. Chem. Commun. 2008, 2008, 4416–4418. (27) Di Giannantonio, M.; Ayer, M. A.; Verde-Sesto, E.; Lattuada, M.; Weder, C.; Fromm, K. M. Triggered Metal Ion Release and Oxidation: Ferrocene as a Mechanophore in Polymers. Angew. Chem. Int. Ed. 2018, 57, 11445–11450. (28) Sha, Y.; Zhang, Y. D.; Xu, E. H.; Wang, Z.; Zhu, T. Y.; Craig, S. L.; Tang, C. B. Quantitative and Mechanistic Mechanochemistry in Ferrocene Dissociation. ACS Macro Lett. 2018, 7, 1174–1179. (29) Sagara, Y.; Karman, M.; Verde-Sesto, E.; Matsuo, K.; Kim, Y.; Tamaoki, N.; Weder, C. Rotaxanes as Mechanochromic Fluorescent Force Transducers in Polymers. J. Am. Chem. Soc. 2018, 140, 1584–1587. (30) Sagara, Y.; Karman, M.; Seki, A.; Pannipara, M.; Tamaoki, N.; Weder, C. Rotaxane-Based Mechanophores Enable Polymers with Mechanically Switchable White Photoluminescence. ACS Cent. Sci. 2019, 5, 874–881. (31) Li, Z. A.; Toivola, R.; Ding, F. Z.; Yang, J.; Lai, P. N.; Howie, T.; Georgeson, G.; Jang, S. H.; Li, X. S.; Flinn, B. D.; Jen, A. K. Y. Highly Sensitive Built-In Strain Sensors for Polymer Composites: Fluorescence Turn-On Response through Mechanochemical Activation. Adv. Mater. 2016, 28, 6592–6597. 55 (32) Iozzi, M. F.; Helgaker, T.; Uggerud, E. Assessment of theoretical methods for the determination of the mechanochemical strength of covalent bonds. Mol. Phys. 2009, 107, 2537–2546. (33) Jacobs, M. J.; Schneider, G.; Blank, K. G. Mechanical Reversibility of StrainPromoted Azide–Alkyne Cycloaddition Reactions. Angew. Chem. Int. Ed. 2016, 55, 2899–2902. (34) Kryger, M. J.; Ong, M. T.; Odom, S. A.; Sottos, N. R.; White, S. R.; Martinez, T. J.; Moore, J. S. Masked Cyanoacrylates Unveiled by Mechanical Force. J. Am. Chem. Soc. 2010, 132, 4558–4559. (35) Lin, Y.; Chang, C.-C.; Craig, S. L. Mechanical generation of isocyanate by mechanically induced retro [2 + 2] cycloaddition of a 1,2-diazetidinone mechanophore. Org. Chem. Front. 2019, 6, 1052–1057. (36) Kryger, M. J.; Munaretto, A. M.; Moore, J. S. Structure-Mechanochemical Activity Relationships for Cyclobutane Mechanophores. J. Am. Chem. Soc. 2011, 133, 18992–18998. (37) Li, M.; Zhang, H.; Gao, F.; Tang, Z.; Zeng, D.; Pan, Y.; Su, P.; Ruan, Y.; Xu, Y.; Weng, W. A cyclic cinnamate dimer mechanophore for multimodal stress responsive and mechanically adaptable polymeric materials. Polym. Chem. 2019, 10, 905–910. (38) Zhang, H.; Li, X.; Lin, Y. J.; Gao, F.; Tang, Z.; Su, P. F.; Zhang, W. K.; Xu, Y. Z.; Weng, W. G.; Boulatov, R. Multi-modal mechanophores based on cinnamate dimers. Nat Commun 2017, 8, 1174. 56 (39) Pill, M. F.; Holz, K.; Preusske, N.; Berger, F.; Clausen-Schaumann, H.; Luning, U.; Beyer, M. K. Mechanochemical Cycloreversion of Cyclobutane Observed at the Single Molecule Level. Chem-Eur J 2016, 22, 12034–12039. (40) Wang, J. P.; Kouznetsova, T. B.; Boulatov, R.; Craig, S. L. Mechanical gating of a mechanochemical reaction cascade. Nat. Commun. 2016, 7, 13433. (41) Nofen, E. M.; Zimmer, N.; Dasgupta, A.; Gunckel, R.; Koo, B.; Chattopadhyay, A.; Dai, L. Stress-Sensing Thermoset Polymer Network via Grafted Cinnamoyl/Cyclobutane Mechanophore Units in Epoxy. Polym. Chem. 2016, 7, 7249–7259. (42) Gunckel, R.; Koo, B.; Xu, Y.; Pauley, B.; Hall, A.; Chattopadhyay, A.; Dai, L. L. Grafted Cinnamoyl-based Mechanophores for Self-Sensing and Photochemical Healing Capabilities in Epoxy. ACS Appl. Polym. Mater. 2020, DOI: 10.1021/acsapm.0c00599. (43) Zhang, Y.; Lund, E.; Gossweiler, G. R.; Lee, B.; Niu, Z.; Khripin, C.; Munch, E.; Couty, M.; Craig, S. L. Molecular Damage Detection in an Elastomer Nanocomposite with a Coumarin Dimer Mechanophore. Macromol. Rapid Commun. 2020, DOI: 10.1002/marc.202000359. (44) Kean, Z. S.; Gossweiler, G. R.; Kouznetsova, T. B.; Hewage, G. B.; Craig, S. L. A coumarin dimer probe of mechanochemical scission efficiency in the sonochemical activation of chain-centered mechanophore polymers. Chem. Commun. 2015, 51, 9157–9160. (45) Yang, J.; Horst, M.; Werby, S. H.; Cegelski, L.; Burns, N. Z.; Xia, Y. Bicyclohexene-peri-naphthalenes: Scalable Synthesis, Diverse Functionalization, 57 Efficient Polymerization, and Facile Mechanoactivation of Their Polymers. J. Am. Chem. Soc. 2020, DOI: 10.1021/jacs.0c06454. (46) Kean, Z. S.; Ramirez, A. L. B.; Yan, Y. F.; Craig, S. L. Bicyclo[3.2.0]heptane Mechanophores for the Non-scissile and Photochemically Reversible Generation of Reactive Bis-enones. J. Am. Chem. Soc. 2012, 134, 12939–12942. (47) Kean, Z. S.; Niu, Z. B.; Hewage, G. B.; Rheingold, A. L.; Craig, S. L. StressResponsive Polymers Containing Cyclobutane Core Mechanophores: Reactivity and Mechanistic Insights. J. Am. Chem. Soc. 2013, 135, 13598–13604. (48) Bowser, B. H.; Ho, C.-H.; Craig, S. L. High Mechanophore Content, StressRelieving Copolymers Synthesized via RAFT Polymerization. Macromolecules 2019, 52, 9032–9038. (49) Lin, Y.; Kouznetsova, T. B.; Craig, S. L. Mechanically Gated Degradable Polymers. J. Am. Chem. Soc. 2020, 142, 2105–2109. (50) Hsu, T.-G.; Zhou, J.; Su, H.-W.; Schrage, B. R.; Ziegler, C. J.; Wang, J. A Polymer with “Locked” Degradability: Superior Backbone Stability and Accessible Degradability Enabled by Mechanophore Installation. J. Am. Chem. Soc. 2020, 142, 2100–2104. (51) Groote, R.; Szyja, B. M.; Leibfarth, F. A.; Hawker, C. J.; Doltsinis, N. L.; Sijbesma, R. P. Strain-Induced Strengthening of the Weakest Link: The Importance of Intermediate Geometry for the Outcome of Mechanochemical Reactions. Macromolecules 2014, 47, 1187–1192. 58 (52) Hu, X. R.; McFadden, M. E.; Barber, R. W.; Robb, M. J. Mechanochemical Regulation of a Photochemical Reaction. J. Am. Chem. Soc. 2018, 140, 14073– 14077. (53) Kida, J.; Imato, K.; Goseki, R.; Aoki, D.; Morimoto, M.; Otsuka, H. The photoregulation of a mechanochemical polymer scission. Nat. Commun. 2018, 9, 3504. (54) Bernstein, H. I.; Quimby, W. C. The Photochemical Dimerization of transCinnamic Acid. J. Am. Chem. Soc. 1943, 65, 1845–1846. (55) Ishigami, T.; Murata, T.; Endo, T. The Solution Photodimerization of (E)-pNitrocinnamates. Bull. Chem. Soc. Jpn. 1976, 49, 3578–3583. (56) Gostl, R.; Sijbesma, R. P. pi-extended anthracenes as sensitive probes for mechanical stress. Chem. Sci. 2016, 7, 370–375. (57) P. Kabb, C.; S. O’Bryan, C.; D. Morley, C.; E. Angelini, T.; S. Sumerlin, B. Anthracene-based mechanophores for compression-activated fluorescence in polymeric networks. Chem. Sci. 2019, 10, 7702–7708. (58) Larsen, M. B.; Boydston, A. J. Successive Mechanochemical Activation and Small Molecule Release in an Elastomeric Material. J. Am. Chem. Soc. 2014, 136, 1276– 1279. (59) Gossweiler, G. R.; Hewage, G. B.; Soriano, G.; Wang, Q. M.; Welshofer, G. W.; Zhao, X. H.; Craig, S. L. Mechanochemical Activation of Covalent Bonds in Polymers with Full and Repeatable Macroscopic Shape Recovery. ACS Macro Lett. 2014, 3, 216–219. 59 (60) Turksoy, A.; Yildiz, D.; Aydonat, S.; Beduk, T.; Canyurt, M.; Baytekin, B.; U. Akkaya, E. Mechanochemical generation of singlet oxygen. RSC Adv. 2020, 10, 9182–9186. (61) Wang, Z.; Ma, Z.; Zhang, Z.; Wu, F.; Jiang, H.; Jia, X. Mechanical activation of a dithioester derivative-based retro RAFT-HDA reaction. Polym. Chem. 2014, 5, 6893–6897. (62) Khanal, A.; Long, F.; Cao, B.; Shahbazian-Yassar, R.; Fang, S. Y. Evidence of Splitting 1,2,3-Triazole into an Alkyne and Azide by Low Mechanical Force in the Presence of Other Covalent Bonds. Chem. Eur. J. 2016, 22, 9760–9767. (63) Konda, S. S. M.; Brantley, J. N.; Varghese, B. T.; Wiggins, K. M.; Bielawski, C. W.; Makarov, D. E. Molecular Catch Bonds and the Anti-Hammond Effect in Polymer Mechanochemistry. J. Am. Chem. Soc. 2013, 135, 12722–12729. (64) Li, J.; Shiraki, T.; Hu, B.; Wright, R. A. E.; Zhao, B.; Moore, J. S. Mechanophore Activation at Heterointerfaces. J. Am. Chem. Soc. 2014, 136, 15925–15928. (65) Stevenson, R.; De Bo, G. Controlling Reactivity by Geometry in Retro-Diels-Alder Reactions under Tension. J. Am. Chem. Soc. 2017, 139, 16768–16771. (66) Zhang, M.; De Bo, G. Impact of a Mechanical Bond on the Activation of a Mechanophore. J. Am. Chem. Soc. 2018, 140, 12724–12727. (67) Duan, H. Y.; Wang, Y. X.; Wang, L. J.; Min, Y. Q.; Zhang, X. H.; Du, B. Y. An Investigation of the Selective Chain Scission at Centered Diels-Alder Mechanophore under Ultrasonication. Macromolecules 2017, 50, 1353–1361. (68) Lyu, B.; Cha, W.; Mao, T.; Wu, Y.; Qian, H.; Zhou, Y.; Chen, X.; Zhang, S.; Liu, L.; Yang, G.; Lu, Z.; Zhu, Q.; Ma, H. Surface Confined Retro Diels–Alder 60 Reaction Driven by the Swelling of Weak Polyelectrolytes. ACS Appl. Mater. Interfaces 2015, 7, 6254–6259. (69) Inglis, A. J.; Sinnwell, S.; Stenzel, M. H.; Barner‐Kowollik, C. Ultrafast Click Conjugation of Macromolecular Building Blocks at Ambient Temperature. Angew. Chem. Int. Ed. 2009, 48, 2411–2414. (70) Krupicka, M.; Dopieralski, P.; Marx, D. Unclicking the Click: Metal-Assisted Mechanochemical Cycloreversion of Triazoles Is Possible. Angew. Chem. Int. Ed. 2017, 56, 7745–7749. (71) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Click Chemistry: Diverse Chemical Function from a Few Good Reactions. Angew. Chem. Int. Ed. 2001, 40, 2004– 2021. (72) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B. A Stepwise Huisgen Cycloaddition Process: Copper(I)-Catalyzed Regioselective “Ligation” of Azides and Terminal Alkynes. Angew. Chem. Int. Ed. 2002, 41, 2596–2599. (73) Tornoe, C. W.; Christensen, C.; Meldal, M. Peptidotriazoles on Solid Phase: [1,2,3]-Triazoles by Regiospecific Copper(I)-Catalyzed 1,3-Dipolar Cycloadditions of Terminal Alkynes to Azides. J. Org. Chem. 2002, 67, 3057– 3064. (74) Stauch, T.; Dreuw, A. Force-induced retro-click reaction of triazoles competes with adjacent single-bond rupture. Chem. Sci. 2017, 8, 5567–5575. (75) Schütze, D.; Holz, K.; Müller, J.; Beyer, M. K.; Lüning, U.; Hartke, B. Pinpointing Mechanochemical Bond Rupture by Embedding the Mechanophore into a Macrocycle. Angew. Chem. Int. Ed. 2015, 54, 2556–2559. 61 (76) Kan, L.; Cheng, H.; Li, B.; Zhang, X.; Wang, Q.; Wei, H.; Ma, N. Anthracene dimer crosslinked polyurethanes as mechanoluminescent polymeric materials. New J. Chem. 2019, 43, 2658–2664. (77) Song, Y.-K.; Lee, K.-H.; Hong, W.-S.; Cho, S.-Y.; Yu, H.-C.; Chung, C.-M. Fluorescence sensing of microcracks based on cycloreversion of a dimeric anthracene moiety. J. Mater. Chem. 2011, 22, 1380–1386. (78) Wu, D.-Y.; Zhang, L.-P.; Wu, L.-Z.; Wang, B.; Tung, C.-H. Water-in-oil microemulsions as microreactors to control the regioselectivity in the photocycloaddition of 9-substituted anthracenes. Tetrahedron Lett. 2002, 43, 1281–1283. (79) Becker, H. Dieter. Unimolecular photochemistry of anthracenes. Chem. Rev. 1993, 93, 145–172. (80) Klukovich, H. M.; Kean, Z. S.; Ramirez, A. L. B.; Lenhardt, J. M.; Lin, J. X.; Hu, X. Q.; Craig, S. L. Tension Trapping of Carbonyl Ylides Facilitated by a Change in Polymer Backbone. J. Am. Chem. Soc. 2012, 134, 9577–9580. (81) Barbee, M. H.; Wang, J.; Kouznetsova, T.; Lu, M.; Craig, S. L. Mechanochemical Ring-Opening of Allylic Epoxides. Macromolecules 2019, 52, 6234–6240. (82) Jung, S.; Yoon, H. J. Mechanical Force Induces Ylide-Free Cycloaddition of Nonscissible Aziridines. Angew. Chem. Int. Ed. 2020, 59, 4883–4887. (83) Bowser, B.; L Craig, S. Empowering mechanochemistry with multi-mechanophore polymer architectures. Polym. Chem. 2018, 9, 3583–3593. (84) Lenhardt, J. M.; Black, A. L.; Beiermann, B. A.; Steinberg, B. D.; Rahman, F.; Samborski, T.; Elsakr, J.; Moore, J. S.; Sottos, N. R.; Craig, S. L. Characterizing 62 the mechanochemically active domains in gem-dihalocyclopropanated polybutadiene under compression and tension. J. Mater. Chem. 2011, 21, 8454– 8459. (85) Black, A. L.; Orlicki, J. A.; Craig, S. L. Mechanochemically triggered bond formation in solid-state polymers. J. Mater. Chem. 2011, 21, 8460–8465. (86) Wang, J. P.; Kouznetsova, T. B.; Craig, S. L. Reactivity and Mechanism of a Mechanically Activated anti-Woodward-Hoffmann-DePuy Reaction. J. Am. Chem. Soc. 2015, 137, 11554–11557. (87) Klukovich, H. M.; Kouznetsova, T. B.; Kean, Z. S.; Lenhardt, J. M.; Craig, S. L. A backbone lever-arm effect enhances polymer mechanochemistry. Nat. Chem. 2013, 5, 110–114. (88) Wu, D.; Lenhardt, J. M.; Black, A. L.; Akhremitchev, B. B.; Craig, S. L. Molecular Stress Relief through a Force-Induced Irreversible Extension in Polymer Contour Length. J. Am. Chem. Soc. 2010, 132, 15936–15938. (89) Lin, Y.; Kouznetsova, T. B.; Craig, S. L. A Latent Mechanoacid for Time-Stamped Mechanochromism and Chemical Signaling in Polymeric Materials. J. Am. Chem. Soc. 2020, 142, 99–103. (90) Wang, J. P.; Kouznetsova, T. B.; Kean, Z. S.; Fan, L.; Mar, B. D.; Martinez, T. J.; Craig, S. L. A Remote Stereochemical Lever Arm Effect in Polymer Mechanochemistry. J. Am. Chem. Soc. 2014, 136, 15162–15165. (91) Wang, J. P.; Kouznetsova, T. B.; Niu, Z. B.; Ong, M. T.; Klukovich, H.; Rheingold, A. L.; Martinez, T. J.; Craig, S. L. Inducing and quantifying forbidden 63 reactivity with single-molecule polymer mechanochemistry. Nat. Chem. 2015, 7, 323–327. (92) Woodward, R. B.; Hoffmann, R. Stereochemistry of Electrocyclic Reactions. J. Am. Chem. Soc. 1965, 87, 395–397. (93) DePuy, C. H.; Schnack, L. G.; Hausser, J. W.; Wiedemann, W. Chemistry of Cyclopropanols. III. The Mechanism of the Solvolysis of Cyclopropyl Tosylates. J. Am. Chem. Soc. 1965, 87, 4006–4006. (94) DePuy, C. H.; Schnack, L. G.; Hausser, J. W. Chemistry of Cyclopropanols. IV. The Solvolysis of Cycopropyl Tosylates1,2. J. Am. Chem. Soc. 1966, 88, 3343– 3346. (95) Lenhardt, J. M.; Ong, M. T.; Choe, R.; Evenhuis, C. R.; Martinez, T. J.; Craig, S. L. Trapping a Diradical Transition State by Mechanochemical Polymer Extension. Science 2010, 329, 1057–1060. (96) Wang, J. P.; Kouznetsova, T. B.; Niu, Z. B.; Rheingold, A. L.; Craig, S. L. Accelerating a Mechanically Driven anti-Woodward-Hoffmann Ring Opening with a Polymer Lever Arm Effect. J. Org. Chem. 2015, 80, 11895–11898. (97) Potisek, S. L.; Davis, D. A.; Sottos, N. R.; White, S. R.; Moore, J. S. Mechanophore-Linked Addition Polymers. J. Am. Chem. Soc. 2007, 129, 13808– 13809. (98) Robb, M. J.; Kim, T. A.; Halmes, A. J.; White, S. R.; Sottos, N. R.; Moore, J. S. Regioisomer-Specific Mechanochromism of Naphthopyran in Polymeric Materials. J. Am. Chem. Soc. 2016, 138, 12328–12331. 64 (99) Gossweiler, G. R.; Kouznetsova, T. B.; Craig, S. L. Force-Rate Characterization of Two Spiropyran-Based Molecular Force Probes. J. Am. Chem. Soc. 2015, 137, 6148–6151. (100) Kim, T. A.; Robb, M. J.; Moore, J. S.; White, S. R.; Sottos, N. R. Mechanical Reactivity of Two Different Spiropyran Mechanophores in Polydimethylsiloxane. Macromolecules 2018. (101) Barbee, M. H.; Kouznetsova, T. B.; Barrett, S. L.; Gossweiler, G. R.; Lin, Y.; Rastogi, S. K.; Brittain, W. J.; Craig, S. L. Substituent effects and mechanism in a mechanochemical reaction. J. Am. Chem. Soc. 2018, 140, 12746–12750. (102) O’Bryan, G.; Wong, B. M.; McElhanon, J. R. Stress Sensing in Polycaprolactone Films via an Embedded Photochromic Compound. ACS Appl. Mater. Interfaces 2010, 2, 1594–1600. (103) Zhang, H.; Gao, F.; Cao, X. D.; Li, Y. Q.; Xu, Y. Z.; Weng, W. G.; Boulatov, R. Mechanochromism and Mechanical-Force-Triggered Cross-Linking from a Single Reactive Moiety Incorporated into Polymer Chains. Angew. Chem. Int. Ed. 2016, 55, 3040–3044. (104) Lin, Y. J.; Barbee, M. H.; Chang, C. C.; Craig, S. L. Regiochemical Effects on Mechanophore Activation in Bulk Materials. J. Am. Chem. Soc. 2018, 140, 15969– 15975. (105) Peterson, G. I.; Larsen, M. B.; Ganter, M. A.; Storti, D. W.; Boydston, A. J. 3D Printed Mechanochromic Materials. ACS Appl. Mater. Interfaces 2015, 7, 577– 583. 65 (106) Versaw, B. A.; McFadden, M. E.; Husic, C. C.; Robb, M. J. Designing Naphthopyran Mechanophores with Tunable Mechanochromic Behavior. Chem. Sci. 2020, 11, 4525–4530. (107) Lin, Y.; Zhang, Y.; Wang, Z.; Craig, S. L. Dynamic Memory Effects in the Mechanochemistry of Cyclic Polymers. J. Am. Chem. Soc. 2019, 141, 10943– 10947. (108) Berkowski, K. L.; Potisek, S. L.; Hickenboth, C. R.; Moore, J. S. Ultrasoundinduced site-specific cleavage of azo-functionalized poly(ethylene glycol). Macromolecules 2005, 38, 8975–8978. (109) Sumi, T.; Goseki, R.; Otsuka, H. Tetraarylsuccinonitriles as mechanochromophores to generate highly stable luminescent carbon-centered radicals. Chem. Commun. 2017, 53, 11885–11888. (110) Sakai, H.; Sumi, T.; Aoki, D.; Goseki, R.; Otsuka, H. Thermally Stable RadicalType Mechanochromic Polymers Based on Difluorenylsuccinonitrile. ACS Macro Lett. 2018, 7, 1359–1363. (111) Ishizuki, K.; Oka, H.; Aoki, D.; Goseki, R.; Otsuka, H. Mechanochromic Polymers That Turn Green Upon the Dissociation of Diarylbibenzothiophenonyl: The Missing Piece toward Rainbow Mechanochromism. Chem. Eur. J. 2018, 24, 3170– 3173. (112) Chen, Z.; Zhu, X.; Yang, J.; Mercer, J. A. M.; Burns, N. Z.; Martinez, T. J.; Xia, Y. The cascade unzipping of ladderane reveals dynamic effects in mechanochemistry. Nat. Chem. 2020, 12, 302–309. 66 (113) Yang, J. H.; Horst, M.; Romaniuk, J. A. H.; Jin, Z. X.; Cegelski, L.; Xia, Y. Benzoladderene Mechanophores: Synthesis, Polymerization, and Mechanochemical Transformation. J. Am. Chem. Soc. 2019, 141, 6479–6483. (114) Lee, B.; Niu, Z. B.; Wang, J. P.; Slebodnick, C.; Craig, S. L. Relative Mechanical Strengths of Weak Bonds in Sonochemical Polymer Mechanochemistry. J. Am. Chem. Soc. 2015, 137, 10826–10832. (115) Encina, M. V.; Lissi, E.; Sarasúa, M.; Gargallo, L.; Radic, D. Ultrasonic degradation of polyvinylpyrrolidone: Effect of peroxide linkages. J. Polym. Sci. B Polym. Lett. Ed. 1980, 18, 757–760. (116) Luzuriaga, A. R. de; Matxain, J. M.; Ruipérez, F.; Martin, R.; Asua, J. M.; Cabanero, G.; Odriozola, I. Transient mechanochromism in epoxy vitrimer composites containing aromatic disulfide crosslinks. J. Mater. Chem. C 2016, 4, 6220–6223. (117) Li, Y. C.; Nese, A.; Matyjaszewski, K.; Sheiko, S. S. Molecular Tensile Machines: Anti-Arrhenius Cleavage of Disulfide Bonds. Macromolecules 2013, 46, 7196– 7201. (118) Imato, K.; Kanehara, T.; Ohishi, T.; Nishihara, M.; Yajima, H.; Ito, M.; Takahara, A.; Otsuka, H. Mechanochromic Dynamic Covalent Elastomers: Quantitative Stress Evaluation and Autonomous Recovery. ACS Macro Lett. 2015, 4, 1307– 1311. (119) Lenhardt, J. M.; Ogle, J. W.; Ong, M. T.; Choe, R.; Martinez, T. J.; Craig, S. L. Reactive Cross-Talk between Adjacent Tension-Trapped Transition States. J. Am. Chem. Soc. 2011, 133, 3222–3225. 67 (120) Wang, J.; Kouznetsova, T. B.; Craig, S. L. Single-molecule Observation of a Mechanically Activated Cis-to-Trans Cyclopropane Isomerization. J. Am. Chem. Soc. 2016, 138, 10410–10412. (121) Klukovich, H. M.; Kean, Z. S.; Iacono, S. T.; Craig, S. L. Mechanically Induced Scission and Subsequent Thermal Remending of Perfluorocyclobutane Polymers. J. Am. Chem. Soc. 2011, 133, 17882–17888. (122) Lee, D. C.; Kensy, V. K.; Maroon, C. R.; Long, B. K.; Boydston, A. J. The Intrinsic Mechanochemical Reactivity of Vinyl‐Addition Polynorbornene. Angew. Chem. Int. Ed. 2019, 58, 5639–5642. (123) Verstraeten, F.; Gostl, R.; Sijbesma, R. P. Stress-induced colouration and crosslinking of polymeric materials by mechanochemical formation of triphenylimidazolyl radicals. Chem. Commun. 2016, 52, 8608–8611. (124) Karman, M.; Verde-Sesto, E.; Weder, C. Mechanochemical Activation of Polymer-Embedded Photoluminescent Benzoxazole Moieties. ACS Macro Lett. 2018, 7, 1028–1033. (125) Karman, M.; Verde-Sesto, E.; Weder, C.; Simon, Y. C. Mechanochemical Fluorescence Switching in Polymers Containing Dithiomaleimide Moieties. ACS Macro Lett. 2018, 7, 1099–1104. (126) Gordon, M. B.; Wang, S.; Knappe, G. A.; Wagner, N. J.; Epps, T. H.; Kloxin, C. J. Force-induced cleavage of a labile bond for enhanced mechanochemical crosslinking. Polym. Chem. 2017, 8, 6485–6489. (127) Nagamani, C.; Liu, H. Y.; Moore, J. S. Mechanogeneration of Acid from Oxime Sulfonates. J. Am. Chem. Soc. 2016, 138, 2540–2543. 68 (128) Diesendruck, C. E.; Peterson, G. I.; Kulik, H. J.; Kaitz, J. A.; Mar, B. D.; May, P. A.; White, S. R.; Martinez, T. J.; Boydston, A. J.; Moore, J. S. Mechanically triggered heterolytic unzipping of a low-ceiling-temperature polymer. Nat. Chem. 2014, 6, 624–629. (129) Peterson, G. I.; Boydston, A. J. Kinetic Analysis of Mechanochemical Chain Scission of Linear Poly(phthalaldehyde). Macromol. Rapid Commun. 2014, 35, 1611–1164. (130) Shiraki, T.; Diesendruck, C. E.; Moore, J. S. The mechanochemical production of phenyl cations through heterolytic bond scission. Faraday Discuss 2014, 170, 385–394. (131) Wang, Z.; Ma, Z.; Wang, Y.; Xu, Z.; Luo, Y.; Wei, Y.; Jia, X. A Novel Mechanochromic and Photochromic Polymer Film: When Rhodamine Joins Polyurethane. Adv. Mater. 2015, 27, 6469–6474. (132) Nixon, R.; De Bo, G. Three concomitant C–C dissociation pathways during the mechanical activation of an N-heterocyclic carbene precursor. Nat. Chem. 2020, DOI: 10.1038/s41557-020-0509-1. (133) Wang, T.; Zhang, N.; Dai, J.; Li, Z.; Bai, W.; Bai, R. Novel Reversible Mechanochromic Elastomer with High Sensitivity: Bond Scission and BendingInduced Multicolor Switching. ACS Appl. Mater. Interfaces 2017, 9, 11874– 11881. 69 Chapter 2 COMPUTATIONAL INVESTIGATION OF STRUCTURE–ACTIVITY RELATIONSHIPS OF 2-FURYLCARBINOL DERIVATIVES FOR MOLECULAR RELEASE 2.1 Introduction 2.1.1 Mechanically triggered molecular release Polymers that release functional molecules in response to mechanical force are desirable for a range of applications, including catalysis, sensing, self-healing, and drug delivery.1–3 To this end, various approaches have been reported, including physically entrapped payloads in a polymeric matrix,4 dissociation of supramolecular assemblies,5,6 and the use of fluid-filled microcapsules7 or vascular networks8 that release a payload after being ruptured. Recently, the use of mechanical force as an external stimulus to promote covalent chemical transformations has emerged as an attractive strategy for molecular release.9 Through this approach, force is transduced via polymer chains to mechanically sensitive molecules known as mechanophores, which respond in a chemoselective manner to promote a productive chemical reaction.10,11 Moore and Craig have reported gemdichlorocyclopropane mechanophores that undergo mechanochemical rearrangements that result in the release of HCl.12,13 Boydston has developed an oxanorbornadiene mechanophore to release a benzyl furfuryl ether via a mechanically induced cycloreversion reaction.14 Göstl and Herrmann developed a release platform that relies on the mechanochemical cleavage of a disulfide moiety and subsequent 5-exo-trig cyclization to release an alcohol attached via a β-carbonate linker.15 Recently, several groups have reported the mechanically triggered release of gases, including CO 16,17 and singlet O2.18 70 2.1.2 Mechanically triggered release from a latent furylcarbinol derivative Working to develop a general platform capable of releasing a wide range of cargo molecules from a single mechanophore core, we took inspiration from Gillies and coworkers, who reported the development of a thermal trigger for the depolymerization of self-immolative polymers (Scheme 2.1), whereby the thermal cycloreversion reaction of a furan–maleimide adduct reveals an unstable furfuryl carbonate. 19 The decomposition of this furfuryl carbonate motif initiates the depolymerization of a covalently linked polymer chain. Scheme 2.1 Thermally triggered depolymerization via a latent furfuryl carbonate developed by Gillies and coworkers Our strategy relied on a mechanically triggered cascade reaction in which a mechanochemical retro-cycloaddition reaction unveils an unstable furylcarbinol derivative that subsequently decomposes under mild conditions to release its molecular payload (Scheme 2.2).20 This modular approach to molecular release facilitates the use of a wide range of functional cargo molecules and enables independent modulation of the mechanochemical retro-cycloaddition reaction and the thermal decomposition release reaction. 71 Scheme 2.2 Mechanically triggered small molecule release based on a latent furfuryl carbonate The proposed mechanism for molecular release involves the formation of a furfuryl cation intermediately upon decomposition of the metastable furfurylcarbinol derivative (Scheme 2.3 Thermal decomposition/release reaction from a furfuryl carbonate via a furfuryl cation intermediate). We hypothesized that the stability of this furfuryl cation species could be turned through electronic properties of the furan. Scheme 2.3 Thermal decomposition/release reaction from a furfuryl carbonate via a furfuryl cation intermediate The work presented here focuses on the kinetics of this thermal decomposition reaction, which we probe using computational methods to develop key structure–activity relationships for this class of molecules. While these relationships could be developed through synthesis and experimentation, a computational investigation enables predictions of reactivity without expending laboratory resources and time. Additionally, the highly reactive substrates proposed to achieve rapid molecular release are not expected to be easily isolable. This makes unambiguous characterization of their experimental reactivity more difficult. Here, we describe a method for estimating transition state energies for the thermal decomposition reaction of furfuryl carbonates and related compounds. Using this method, we develop initial structure–activity relationships for this class of compounds. 72 2.2 Methods The primary intent of this work was to develop a workflow to accurately estimate the relative activation barriers (ΔG‡) for the thermal decomposition of a range of furfuryl carbonates and related compounds using density functional theory (DFT). Additionally, we aimed to create a relatively simple and intuitive method that could be implemented by chemists who do not have substantial computational background. Finally, we used computational techniques that enabled the use of a desktop computer without the need for high performance computing. All calculations presented here were run on a desktop computer using Spartan’18/Spartan’20 Parallel Suite software. 21 The calculated geometries for all compounds presented in this chapter can be found in Appendix C. A step-by-step guide for conducting a simple transition state calculation in the Spartan software can be found in Appendix D. For the initial work, we chose to focus on a simple furfuryl carbonate structure, although other payloads are examined later. For most compounds, our model structures included a simplified leaving group (e.g., methyl carbonate) for the sake of computational expediency. Similarly, we did not consider the effect of a protic solvent environment. Although these simplifications may reduce the accuracy of absolute activation energy values, we anticipate that relative reactivity trends will hold. 2.2.1 Initial transition state guess Transition state geometry optimization methods require a starting geometry that is close to the actual transition state. To provide an initial transition state guess for subsequent 73 transition state optimization calculations, we chose to employ a relaxed scan across the proposed reaction coordinate for the fragmentation. In our system, we expected this coordinate to involve the stretching of the C–O bond linking the carbonate oxygen to the α-position of the furan (Scheme 2.4). Scheme 2.4 An unsubstituted furfuryl carbonate showing the bond-breaking mode of interest O a O O O Cargo We extended the length of this C–O bond in a stepwise fashion, calculating the equilibrium geometry of the molecule at each step. Starting from the equilibrium geometry of the furfuryl carbonate, we extended the relaxed scan to 1.5 Å beyond the equilibrium C–O bond length. As shown in Figure 2.1, we tested a range of functionals and basis sets for these relaxed scan calculations. Figure 2.1 Relaxed scans across several levels of theory for a simple furfuryl carbonate, elongating the C–O bond that is expected to break in the decomposition/release reaction. Most methods show an increasing trend with no clear energy maximum. However, HF methods in a polar dielectric constant continuum produce a clear energy maximum at ~2.2 Å. Note that the sharp energy drop-offs below 2 Å for the HF methods correspond to conformational changes. 74 In a relaxed scan across a reaction coordinate, we expect to find an energy maximum corresponding to an approximate transition state structure. With the widely used B3LYP functional across a range of small basis sets, we do not observe a maximum in the energy profile. Instead, we see continuously increasing profiles that do not suggest a transition state along this coordinate. Other DFT functionals including ωB97X-D and M06-2X show similar increasing energy trends (the sharp energy drop-offs in some of these profiles correspond to conformational changes in the molecule, not transition states). Moving away from DFT functionals, we tested Hartree–Fock (HF) methods. Both 6-31G* and 6-31+G* basis sets yielded similar energy profiles to the DFT methods. However, implementation of a polarizable continuum model to simulate a polar solvent (ε = 37.22) resulted in reaction coordinate profiles with an obvious energy maximum. The incorporation of this uniform dielectric did not improve the performance of the B3LYP functional. Based on these results, we chose to implement HF/6-31+G* (polar) for our initial calculations. 2.2.2 Transition state geometry optimization To further refine our transition state structure, we used the transition state geometry optimization method within Spartan’18 to calculate an optimized transition state geometry for our molecule of interest. The maximum energy geometry from the relaxed scan calculations served as our starting transition state guess. We again employed the HF/631+G* level of theory for these calculations. We found that the results of these calculations result in a structure with a C–O bond length typically less than 0.03 Å different from the result of our initial relaxed scan. 75 2.2.3 Transition state energy calculation using constrained geometry optimization A transition state exists at a first-order saddle point on the potential energy surface such that it is a maximum along only one reaction coordinate and a minimum for all others. In transition state calculations, this is identified by finding the point where a single eigenvector (reaction coordinate) has a negative eigenvalue in the Hessian matrix of the potential energy surface. When evaluating a transition state calculation, we expect a valid transition state to exhibit a single negative vibrational frequency corresponding to the bond breaking/bond forming coordinate of interest. In our system, we found that molecular geometries calculated from the transition state search at the HF/6-31+G* level of theory exhibited several small negative vibrational frequencies (> –50 cm -1) in addition to the primary C–O bond breaking mode (< –250 cm-1). To further refine the structure and eliminate these unwanted vibrational modes, we implemented a constrained equilibrium geometry calculation as the final step in the transition state search. We constrained the elongated C–O bond length from the initial transition state optimization and relaxed the remainder of the molecule. Hoping to achieve accurate predictions for the transition state energy, we moved away from HF methods. We opted for the M06-2X functional, which is well suited for this application and is widely used to derive kinetic parameters.22 Other widely used functionals like B3LYP have been shown to yield inaccurate results for kinetics applications, especially those involving diffuse electron systems.23 A larger basis set was chosen to enable more accurate transition state energy calculations. The 6-311+G(d,p) basis set (also represented as 6-311+G**) was selected for its expanded orbital representation and incorporation of diffuse functions, as 76 we are probing a developing anion and non-equilibrium, long-range electronic interactions. Calculations at this level of theory were performed with a (99,590) Lebedev integration grid for higher precision with the M06-2X functional. The difference in Gibbs free energy between the optimized transition state geometry (G‡) and the equilibrium geometry of the starting material (G0) was used to calculate the activation energy (ΔG‡). 2.3 Results and discussion 2.3.1 Effects of substitution at the 5- and α-positions of a furfuryl carbonate We began our computational investigation with a series of furfuryl carbonates based on the thermal depolymerization trigger reported by Gillies (Figure 2.2). 19 The simplest furfuryl carbonate 1 consists of a methyl carbonate linked to the 2-position of an otherwise unsubstituted furan by a methylene group. We found the activation energy at room temperature for the decomposition of this compound to be 29.4 kcal/mol. The Eyring equation (eq. 1) tells us that the corresponding half-life of decomposition for this molecule is predicted to be >10 years at room temperature, much too slow for our intended applications. ‡ 𝑘= 𝑒 (1) 77 We next incorporated a methyl substituent at the 5-position of the furan to model the effect of the polymer tether point that we anticipated for our polymer-bound platform. This methyl group in furfuryl carbonate 2 lowers the activation energy to 25.8 kcal/mol. Hoping to achieve an even lower activation barrier to achieve rapid release at room temperature, we proposed the addition of an additional methyl substituent at the α-position of the furan (furfuryl carbonate 3), which we expected to stabilize the developing carbocation at this atom. This substituent results in a pronounced decrease in activation energy to 22.0 kcal/mol, corresponding to a half-life of <1 h at room temperature. Figure 2.2 Calculated activation energy values (M06-2X/6-311+G**) for the decomposition of furfuryl carbonates 1–3. The addition of methyl substituents at the 5- and α-positions of the furan result in a reduced activation barrier. 2.3.2 Role of the payload identity in transition state calculations For the sake of computation expediency, we chose a simple payload motif by using a methyl carbonate leaving group. If we instead use phenyl carbonate 4 to stimulate the release of a phenol, we calculate an activation energy of 19.3 kcal/mol (Chart 2.1 78 Comparison of the activation barrier for release of an alkyl alcohol and a phenol). Although a simplified cargo molecule may reduce the accuracy of the absolute activation energy values, we anticipate the predicted reactivity trends to hold. Additionally, we found that the use of the larger phenolic cargo led to significantly longer computation times (DFT typically scales as ~N3 for N atoms in the molecule) and identifying a transition state became more difficult due to the inclusion of additional possible vibrational modes. As a result, we chose to continue with the simplified payload motif. Chart 2.1 Comparison of the activation barrier for release of an alkyl alcohol and a phenol 2.3.3 Experimental validation of predicted furfuryl carbonate decomposition kinetics Our computational results suggest that an unsubstituted 2-furfuryl carbonate will exhibit high stability at room temperature, while the addition of substitution at the 2- and α-positions greatly increases the reactivity. To evaluate this experimentally, we synthesized model compound M1 and M3 corresponding to structures 1 and 3 shown above, respectively (Chart 2.2). A hydroxycoumarin (7-hydroxy-4-methylcoumarin) cargo was used for these model compounds. Both compounds were incubated in 3:1 (v/v) acetonitriled3:MeOH at room temperature and monitored by 1H NMR to measure the half-life of hydroxycoumarin release. Compound M1 exhibits a very slow half-life of 17 days, while furfuryl carbonate M3 reacts with a significantly shorter half-life of 79 min. 79 Chart 2.2 Experimentally determined half-lives of hydroxycoumarin release for two furfuryl carbonates Although the absolute activation energies do not perfectly match the computed values, we note that the trend in reactivity is consistent. Sonication experiments investigating the mechanically triggered release of hydroxycoumarin (measured by fluorescence spectroscopy) exhibited a thermal release half-life of 46 min from polymer-bound furfuryl carbonate P3 (Chart 2.3). Chart 2.3 Experimental half-life of polymer-tethered furfuryl carbonate with an α-methyl group 2.3.4 Release of an aniline cargo from a simple furfuryl carbamate We found that methyl substitution at both the 2- and α-positions of the furan motif of a furfuryl carbonate enabled efficient release of an alcohol cargo, with experimental results supporting the computational conclusions. However, when this platform was used to release an amine (Scheme 2.5), the experimental rate of release was extremely slow, occurring with a half-life of 240 days.24 Consistent with this long half-life, transition state calculations predict a high activation energy for furfuryl carbamate 5 of 28.9 kcal/mol, nearly 7 kcal/mol higher than for analogous furfuryl carbonate 3. 80 Scheme 2.5 Release of an amine cargo molecule from a furfuryl carbamate 2.3.5 Modulating the rate of release through additional furan substitution Given that the first-generation release platform did not enable efficient release of non-phenolic cargo molecules, we sought to improve the kinetics of the furfuryl carbonate decomposition reaction. Noting that stabilization of the developing furfuryl cation through the addition of an α-methyl substituent led to a substantial decrease in the activation energy, we proposed further stabilization of the furfuryl cation through the addition of electron donating substituents to the 3-position of the furan. We envisioned an electron-rich furan could better stabilize the cation forming during the transition state, thus lowering the activation barrier of release. To achieve the greatest improvement in activation energy, we coupled these proposed substituents with the 2-methyl and α-methyl substituents previously described. Our transition state calculations predict that all four proposed electron-donating substituents result in a reduced activation energy relative to furfuryl carbonate 3 (Figure 2.3). The addition of a 3-methyl substituent (compound 6) lowered the activation energy to 20.3 kcal/mol, while a 3-phenyl group (compound 7) further reduced this value to 19.0 kcal/mol. The more strongly electron donating 3-phenoxy group in furfuryl carbonate 8 dropped the activation energy to 18.3 kcal/mol, and the 3-methoxy substituent (compound 9) exhibited the lowest activation barrier at 16.1 kcal/mol. These results suggest that the incorporation of an electron-donating substituent at the 3-position 81 of a furfuryl carbonate can significantly attenuate the activation barrier for decomposition, enabling more rapid payload release. Figure 2.3 Calculated activation energy values (M06-2X/6-311+G**) for the decomposition of furfuryl carbonates with varying substitution at the 3-position of the furan. Increasingly electron donating substituents at this position result in a decreasing trend in activation energy. Although the 3-methoxyfurfuryl carbonate was shown to exhibit the highest reactivity, we chose to pursue 3-phenoxyfurfuryl carbonate 8 for its more facile synthesis. Before conducting laboratory experiments, we dove deeper into the structure–activity relationships of these substituted furfuryl carbonates to better understand the tunability of the release rate through varied furfuryl carbonate substitution. We investigated a series of furfuryl carbonates with varied substitution at the 3- and α-positions of the furan (Figure 2.4). This series demonstrated that modulating only these two substituents enabled tunable activation energies ranging from 18.3 kcal/mol to 25.8 kcal/mol for the release an alcoholic cargo. Furfuryl carbonate 3 with only an α-methyl substitution and compound 10 with only 82 the 3-phenoxy group are predicted to have similar activation barriers (22.0 and 21.5 kcal/mol, respectively) as determined computationally. Experimentally, we observe that the 3-phenoxy/α-H furfuryl carbonate (corresponding the compound 10) decomposes much faster.24 With a furfuryl carbonate with 3-phenoxy and α-methyl groups (corresponding to compound 8), we observed instantaneous release of hydroxycoumarin at room temperature in laboratory experiments. Figure 2.4 Calculated activation energy values (M06-2X/6-311+G**) for the decomposition of a series of furfuryl carbonates with varied substitution at the 3- and α-positions of the furan. An α-methyl group and a 3-phenoxy substituent both lead to reductions in the predicted activation barrier. 2.3.6 Improved release of an amine cargo with a 3-phenoxy furfuryl carbonate Analogous to our exploration of the alcoholic cargo, we next investigated the impact of a 3-phenoxy substituent and an α-methyl group on the release of an amine using our transition state method (Figure 2.5). Without either substitution as illustrated in furfuryl carbamate 11, these calculations predict a high activation barrier of 33.4 kcal/mol. Addition 83 of the α-methyl substituent in furfuryl carbamate 5 lowers the transition state energy to 28.9 kcal/mol. Experimentally, an analogous furfuryl carbamate with an aminocoumarin cargo exhibited a release half-life of 240 days.24 The presence of a 3-phenoxy group without the α-methyl group present (compound 12) results in an activation energy of 28.2 kcal/mol. Although our calculations predict a minimal decrease in the energy barrier, we observe a substantial reduction in the experimental half-life of cargo release to 6.5 days. 24 (This is consistent with the unexpected experimental results of the 3-phenoxy/α-methyl furfuryl carbonate described in Section 2.3.5. We are uncertain of the origin of this discrepancy between computational and experimental results.) Finally, compound 13 with both substituents is predicted to have an activation barrier of 23.8 kcal/mol. Consistent with this predicted reduction in the activation energy, the experimental half-life of amine release from an analogous furfuryl carbamate is shown to be 41 min. Figure 2.5 Calculated activation energy values (M06-2X/6-311+G**) for the decomposition of a series of furfuryl carbamates with varied substitution at the 3- and α-positions of the furan. An α-methyl group and a 3-phenoxy substituent both lead to reductions in the predicted activation barrier. 84 2.3.7 Release of additional functional cargo molecules With the development of the efficient 3-phenoxy/α-methyl furylcarbinol platform, we sought to investigate the release of a range of additional cargo molecules. We first looked at the release of a carboxylic acid from a furfuryl ester (Chart 2.4). We predicted the activation barrier for release of this cargo to be higher than that for alcohol release, as the ester substrate no longer has the added anion delocalization afforded by the carbonate. With only the α-methyl substitution, our transition state calculations predict a high activation energy of 27.4 kcal/mol for furfuryl ester 14. The addition of the 3-phenoxy group in compound 15 lowers this value to 22.5 kcal/mol, within the range of rapid release at room temperature. Chart 2.4 Activation energies of release for two furfuryl esters capable of carboxylic acid release Experimentally, the release of a carboxylic acid was shown to occur with a half-life of 28 h. We did not exhaustively evaluate a wide scope of molecular payloads using our computational methods, but we experimentally demonstrated that the 3-phenoxy/α-methyl furylcarbinol platform achieves rapid molecular release rates for a wide range of cargo molecules (Chart 2.5). 85 Chart 2.5 Experimental half-lives of release for a broad range of cargo molecules from a 3-phenoxy substituted furfurylcarbinol derivative Although not studied experimentally, we evaluated the release of a thiol from this platform (Chart 2.6). Furfuryl thiocarbonate 16 is predicted to have an extremely low activation energy of 14.9 kcal/mol. Chart 2.6 Activation energy of thiol release from a 3-phenoxy substituted furfuryl thiocarbonate 2.3.8 Geometry considerations for the improved release rate from the 3-phenoxy furylcarbinol platform We designed the 3-phenoxy substituted furfuryl carbonate with the intent of stabilizing the resulting furfuryl cation through greater electron density afforded by an electron-donating substituent. This effect likely plays a substantial role in lowering the activation energy relative to an unsubstituted furfuryl carbonate, but we note that the equilibrium conformation of these substrates may also contribute to the reduced activation barrier. In furfuryl carbonates 2 and 3 with no substitution at the 3-position of the furan, we see that the furan and carbonate are planar (Figure 2.6). We found that the dihedral 86 angle (φ) between these two elements is 0.0° for compound 2 and 2.6° for compound 3 with an α-methyl substituent. This planarity likely allows for stabilization of the furfuryl carbonate through conjugation of these two portions of the molecule. However, when a 3phenoxy substituent is added to the furan, the furfuryl carbonate adopts a conformation that places the carbonate group out of the plane of the furan. For furfuryl carbonate 10, we calculate a dihedral angle of –116.4° and for furfuryl carbonate 8 with both 3-phenoxy and α-methyl substituents, we see a dihedral angle of 111.1°. We propose that the lack of planarity observed for the 3-phenoxy substituted furfuryl carbonates plays a role in reducing the activation barrier for decomposition through destabilization of the starting material relative to the unsubstituted analogs. 87 Figure 2.6 Computed structures and dihedral angles (φ) for a series of furfuryl carbonates with varied substitution at the 3- and α-positions of the furan. The presence of a 3-phenoxy group breaks the planarity between the furan and the carbonate, which likely disrupts electron delocalization, leading to lower stability of the 3-phenoxy substrates. 2.3.9 Effect of electron-withdrawing substituents on the furan Through the addition of electron donating positions at the 3-position on the furan component of a furfuryl carbonate, we were able to achieve rapid cargo release at room temperature. To further explore the structure–activity relationships of this class of compounds, we chose to investigate two modified furfuryl carbonates that incorporate electron withdrawing substituents at the 3-position of the furan motif (Chart 2.7). We 88 anticipated these substitutions would lead to higher activation barriers, and thus slower cargo release. This effect might be desirable to control the decomposition of highly reactive species (e.g., furfuryl thiocarbonates, see Section 2.3.7) or in highly polar, protic environments (e.g., aqueous solutions). 3-bromofurfuryl carbonate 17 is predicted to have an activation barrier of 25.0 kcal/mol, which is 3 kcal/mol higher than furfuryl carbonate 3 with no substitution at this position. A 3-cyano group (compound 18) results in a very high activation barrier of 32.6 kcal/mol. Chart 2.7 Activation energies of release for furfuryl carbonates with electron-withdrawing substituents Me O O Br O O Me OMe 17 DG‡ = 25.0 kcal/mol O O CN OMe 18 DG‡ = 32.6 kcal/mol Thus, we have shown that it is possible to generate furfuryl carbonates that are inert, highly reactive, or anywhere in between through judicious substitutions to the 3- and α-positions Figure 2.7 Comparison of computationally derived activation energy values and reactivities for a series of furfuryl carbonates with varied substitution at the 3- and α-positions. 89 of the furan (Figure 2.7). We anticipate this will enable the development of highly tunable molecular release platforms for a wide range of cargo molecules and environments. 2.3.10 Effect of an α-tethered alcohol Through laboratory experiments, we found that a protic solvent environment is necessary to achieve efficient, clean cargo release from furfuryl carbonates. Functionality of this platform in aprotic environments would enable its utility for a wider range of applications, including in bulk polymeric materials. To overcome this limitation, we proposed the incorporation of a tethered alcohol directly onto the furfuryl carbonate to provide a local polar, protic environment.25 This work is described in detail in Chapter 3. When a primary alcohol is tethered to the α-position of the furfuryl carbonate, we observed a marked reduction in the activation barrier of release. Our calculations suggest that furfuryl carbonate 19 will have an activation energy of 18.1 kcal/mol, a significant reduction compared to compound 3 containing an α-methyl substitution (ΔG‡ = 22.0 kcal/mol). As described in Chapter 3, our DFT calculations suggest that this effect is facilitated by an intramolecular hydrogen bonding interaction between the tethered alcohol and the carbonate leaving group. To further probe the effect of the proposed hydrogen bonding stabilization of the carbonate leaving group, we investigated two additional furfuryl carbonates with tethered groups unable to participate in hydrogen bonding (Figure 2.8). We first looked at a butyl chain at the α-position (compound 20). The decomposition of this compound is predicted to have an activation energy of 23.5 kcal/mol. The increase in this transition state energy compared to the α-methyl substituted substrate 3 may be due to 90 the destabilization of the highly polar transition state in the presence of the added non-polar alkyl chain. We also calculated the activation energy for release from furfuryl carbonate 21 with a tethered methyl ether, which is predicted to be 23.4 kcal/mol. This suggests that the presence of a tethered oxygen atom alone is insufficient to stabilize the release reaction, and that the hydrogen bond enabled by the alcohol moiety is necessary to achieve the reduction in activation energy. Figure 2.8 Calculated activation energy values (M06-2X/6-311+G**) for the decomposition of a series of furfuryl carbonates with varied substitution at the α-positions of the furan. A tethered primary alcohol at this position leads to a significant reduction in the activation barrier. 91 2.3.11 Release from pyrrole-linked carbonates The primary focus of our work is on molecular release from furfuryl carbonates due to the well-studied nature of the furan–maleimide Diels–Alder adduct used for the development of a mechanophore platform. However, we envisioned that a similar release platform could be derived from an alternative heterocyclic diene. We turned our attention to pyrrole compounds, which we expected to exhibit improved release over furfuryl carbonates due to the greater electron donation from the pyrrole nitrogen compared to the furan oxygen. Additionally, the ability functionalize the pyrrole nitrogen would enable the synthesis of a unique Diels–Alder adduct mechanophore with a symmetric pulling position. Figure 2.9 Calculated activation energy values (M06-2X/6-311+G**) for the decomposition of a series of pyrrolyl carbonates with varied substitution. N-functionalization leads to a reduction in the activation barrier. Isoindole 27 exhibits an extremely low barrier to decomposition. 92 We first calculated transition state energies for release from a series of pyrrolyl carbonates to evaluate the reactivity of this class of compounds (Figure 2.9). Pyrrolyl carbonate 22 with no substitution on the nitrogen (N–H) is expected to have an activation energy of 20.9 kcal/mol. Adding a methyl substituent to the nitrogen (N–Me) as in compound 23 lowers this barrier to 19.2 kcal/mol. An N-methyl pyrrole without an αmethyl group (compound 24) is predicted to have an activation energy of 20.8 kcal/mol. If the N–Me group is substituted for an N–Ph substitution (compound 25), we see that the addition of this aromatic group lowers the activation energy of 16.8 kcal/mol. While the activation energy values for this class of molecules are promising, forming Diels–Alder adducts with pyrrolic compounds can be difficult. 26 However, the use isoindoles as dienes in Diels–Alder reactions has been reported. 27 We found the predicted activation energy for release from N-methyl isoindole 26 to be 15.5 kcal/mol. Unfortunately, we were unable to identify a transition state for an N-aryl isoindole carbonate. 2.3.12 Release from a 5-aryloxyfurfuryl carbonate In 2021, our group reported a modified furfuryl carbonate-based release platform that employs a 5-aryloxy substituent that simultaneously serves as a polymer tether point on the furan as well as providing electron donation to facilitate the desired release reaction (Chart 2.8 A 5-aryloxy furfuryl carbonate).28 It was shown that the synthesis of this modified release platform was significantly more efficient than the 3-phenoxy platform described in detail above. However, attempts to calculate the transition state energy for the decomposition of furfuryl carbonate 27 were unsuccessful. 93 Chart 2.8 A 5-aryloxy furfuryl carbonate O O O O OMe 27 Working under the assumption that the release mechanism for the 5-aryloxy system is similar to that proposed for other furfuryl carbonates, we were unable to identify a transition state corresponding to the simple bond breaking mode of the α C–O bond. This result may indicate a distinct mode of reactivity for the 5-aryloxy system, which is consistent with unexpected reaction products observed experimentally. 28 The mechanism of this decomposition reaction was not elucidated computationally or experimentally. 2.4 Conclusions Through the development of a simple workflow for predicting the activation energy associated with the decomposition of 2-furylcarbinol derivatives, we have begun to elucidate key structure–activity relationships for this class of compounds. These relationships will enable tunable platforms for thermally and mechanically triggered small molecule release that rely on this thermal decomposition reaction. Using this method, we identified a library of 2-furylcarbinol derivatives that exhibit activation energy values spanning from 15.5 kcal/mol to 29.4 kcal/mol for the release of an alcohol cargo molecule. These values correspond to release half-lives ranging from near-instantaneous to over a decade. In addition to identifying electronic factors that effect the rate of molecular release, we also demonstrated how molecular configuration as dictated by steric repulsion can modulate the predicted molecular release behavior. We hope that these results and this computational method further the development of predictable and highly tunable platforms for molecular release across a wide range of applications. 94 2.5 References (1) Swager, T. M. Sensor Technologies Empowered by Materials and Molecular Innovations. Angew. Chem. Int. Ed. 2018, 57, 4248–4257. (2) Roth, M. E.; Green, O.; Gnaim, S.; Shabat, D. Dendritic, Oligomeric, and Polymeric Self-Immolative Molecular Amplification. Chem. Rev. 2016, 116, 1309–1352. (3) Patrick, J. F.; Robb, M. J.; Sottos, N. R.; Moore, J. S.; White, S. R. Polymers with autonomous life-cycle control. Nature 2016, 540, 363–370. (4) Lee, K. Y.; Peters, M. C.; Mooney, D. J. Controlled Drug Delivery from Polymers by Mechanical Signals. Advanced Materials 2001, 13, 837–839. (5) Huo, S.; Zhao, P.; Shi, Z.; Zou, M.; Yang, X.; Warszawik, E.; Loznik, M.; Göstl, R.; Herrmann, A. Mechanochemical bond scission for the activation of drugs. Nat. Chem. 2021, 13, 131–139. (6) Küng, R.; Pausch, T.; Rasch, D.; Göstl, R.; Schmidt, B. M. Mechanochemical Release of Non-Covalently Bound Guests from a Polymer-Decorated Supramolecular Cage. Angewandte Chemie International Edition 2021, 60, 13626– 13630. (7) White, S. R.; Sottos, N. R.; Geubelle, P. H.; Moore, J. S.; Kessler, M. R.; Sriram, S. R.; Brown, E. N.; Viswanathan, S. Autonomic healing of polymer composites. Nature 2001, 409, 794–797. (8) Toohey, K. S.; Sottos, N. R.; Lewis, J. A.; Moore, J. S.; White, S. R. Self-healing materials with microvascular networks. Nature Mater 2007, 6, 581–585. 95 (9) Versaw, B. A.; Zeng, T.; Hu, X.; Robb, M. J. Harnessing the Power of Force: Development of Mechanophores for Molecular Release. J. Am. Chem. Soc. 2021, 143, 21461–21473. (10) Beyer, M. K.; Clausen-Schaumann, H. Mechanochemistry: The Mechanical Activation of Covalent Bonds. Chem. Rev. 2005, 105, 2921–2948. (11) Caruso, M. M.; Davis, D. A.; Shen, Q.; Odom, S. A.; Sottos, N. R.; White, S. R.; Moore, J. S. Mechanically-Induced Chemical Changes in Polymeric Materials. Chem. Rev. 2009, 109, 5755–5798. (12) Lin, Y.; Kouznetsova, T. B.; Craig, S. L. A Latent Mechanoacid for Time-Stamped Mechanochromism and Chemical Signaling in Polymeric Materials. J. Am. Chem. Soc. 2020, 142, 99–103. (13) Diesendruck, C. E.; Steinberg, B. D.; Sugai, N.; Silberstein, M. N.; Sottos, N. R.; White, S. R.; Braun, P. V.; Moore, J. S. Proton-Coupled Mechanochemical Transduction: A Mechanogenerated Acid. J. Am. Chem. Soc. 2012, 134, 12446– 12449. (14) Larsen, M. B.; Boydston, A. J. “Flex-Activated” Mechanophores: Using Polymer Mechanochemistry To Direct Bond Bending Activation. J. Am. Chem. Soc. 2013, 135, 8189–8192. (15) Shi, Z.; Song, Q.; Göstl, R.; Herrmann, A. Mechanochemical activation of disulfidebased multifunctional polymers for theranostic drug release. Chem. Sci. 2021, 12, 1668–1674. 96 (16) Sun, Y.; Neary, W. J.; Burke, Z. P.; Qian, H.; Zhu, L.; Moore, J. S. Mechanically Triggered Carbon Monoxide Release with Turn-On Aggregation-Induced Emission. J. Am. Chem. Soc. 2022, 144, 1125–1129. (17) Nijem, S.; Song, Y.; Schwarz, R.; E. Diesendruck, C. Flex-activated CO mechanochemical production for mechanical damage detection. Polymer Chemistry 2022, 13, 3986–3990. (18) Turksoy, A.; Yildiz, D.; Aydonat, S.; Beduk, T.; Canyurt, M.; Baytekin, B.; U. Akkaya, E. Mechanochemical generation of singlet oxygen. RSC Adv. 2020, 10, 9182–9186. (19) Fan, B.; Trant, J. F.; Hemery, G.; Sandre, O.; Gillies, E. R. Thermo-responsive selfimmolative nanoassemblies: direct and indirect triggering. Chem. Commun. 2017, 53, 12068–12071. (20) Hu, X.; Zeng, T.; Husic, C. C.; Robb, M. J. Mechanically Triggered Small Molecule Release from a Masked Furfuryl Carbonate. J. Am. Chem. Soc. 2019, 141, 15018– 15023. (21) Shao, Y.; Molnar, L. F.; Jung, Y.; Kussmann, J.; Ochsenfeld, C.; Brown, S. T.; Gilbert, A. T. B.; Slipchenko, L. V.; Levchenko, S. V.; O’Neill, D. P.; Jr, R. A. D.; Lochan, R. C.; Wang, T.; Beran, G. J. O.; Besley, N. A.; Herbert, J. M.; Lin, C. Y.; Voorhis, T. V.; Chien, S. H.; Sodt, A.; Steele, R. P.; Rassolov, V. A.; Maslen, P. E.; Korambath, P. P.; et al. Advances in methods and algorithms in a modern quantum chemistry program package. Phys. Chem. Chem. Phys. 2006, 8, 3172–3191. (22) Walker, M.; Harvey, A. J. A.; Sen, A.; Dessent, C. E. H. Performance of M06, M062X, and M06-HF Density Functionals for Conformationally Flexible Anionic 97 Clusters: M06 Functionals Perform Better than B3LYP for a Model System with Dispersion and Ionic Hydrogen-Bonding Interactions. J. Phys. Chem. A 2013, 117, 12590–12600. (23) Goerigk, L.; Grimme, S. A thorough benchmark of density functional methods for general main group thermochemistry, kinetics, and noncovalent interactions. Phys Chem Chem Phys 2011, 13, 6670–6688. (24) Hu, X.; Zeng, T.; Husic, C. C.; Robb, M. J. Mechanically Triggered Release of Functionally Diverse Molecular Payloads from Masked 2-Furylcarbinol Derivatives. ACS Cent. Sci. 2021, 7, 1216–1224. (25) Husic, C. C.; Hu, X.; Robb, M. J. Incorporation of a Tethered Alcohol Enables Efficient Mechanically Triggered Release in Aprotic Environments. ACS Macro Lett. 2022, 11, 948–953. (26) Kamimura, A.; Nakano, T. Use of the Diels−Alder Adduct of Pyrrole in Organic Synthesis. Formal Racemic Synthesis of Tamiflu. J. Org. Chem. 2010, 75, 3133– 3136. (27) Lin, C.; Zhen, L.; Cheng, Y.; Du, H.-J.; Zhao, H.; Wen, X.; Kong, L.-Y.; Xu, Q.-L.; Sun, H. Visible-Light Induced Isoindoles Formation To Trigger Intermolecular Diels–Alder Reactions in the Presence of Air. Org. Lett. 2015, 17, 2684–2687. (28) Zeng, T.; Hu, X.; Robb, M. J. 5-Aryloxy substitution enables efficient mechanically triggered release from a synthetically accessible masked 2-furylcarbinol mechanophore. Chem. Commun. 2021, 57, 11173–11176. 98 Chapter 3 INCORPORATION OF A TETHERED ALCOHOL ENABLES EFFICIENT MECHANICALLY TRIGGERED RELEASE IN APROTIC ENVIRONMENTS 3.1 Introduction Polymers that release functional small molecules upon external stimulation are desirable for a range of applications including sensing, catalysis, and drug delivery. 1,2 Mechanical force is an appealing stimulus that can be applied with spatial and temporal control and benefits from a variety of activation methods including tension, compression, and shear in solid materials;3 high intensity focused ultrasound;4,5 and solution-phase ultrasonication.6 In polymer mechanochemistry, stress-responsive molecules known as mechanophores are designed to undergo specific and productive chemical transformations in response to mechanical force, which is transduced by covalently bound polymer chains.7–9 A growing number of mechanophore platforms have been developed in recent years for mechanically triggered release.10 For example, Moore and Craig have developed gem-dichlorocyclopropane mechanophores that generate HCl upon mechanochemical activation.11,12 Moore and coworkers also recently reported a novel fluorogenic norborn-2en-7-one mechanophore that releases carbon monoxide gas. 13 Flex-activation strategies have been used by Boydston and coworkers to enable the release of a furan small molecule from an oxanorbornadiene mechanophore14 and to generate N-heterocyclic carbenes from a carbodiimide motif.15 This concept was also extended recently by Diesendruck and coworkers for CO release.16 In a more modular design, Herrmann and Göstl have developed a mechanophore platform that relies on the mechanochemical cleavage of a 99 disulfide unit that initiates an intramolecular cyclization reaction to release a cargo molecule bound through a carbonate linkage.17–19 In 2019, our group introduced a platform for mechanically triggered molecular release based on an unstable furfuryl carbonate masked as a mechanochemically active Diels–Alder adduct (Scheme 3.1a).20 This general design strategy relies on the decomposition of a latent 2-furylcarbinol derivative,21,22 which is gated by a mechanochemical retro-Diels–Alder reaction. Decoupling the mechanochemical activation step from 2-furylcarbinol decomposition provides for a highly modular system that we have further developed to enable the mechanically triggered release of functionally diverse molecular payloads including alcohols, amines, carboxylic acids, and sulfonic acids. 23,24 Notably, a polar protic environment is typically required for clean and efficient fragmentation of the latent 2-furylcarbinol derivative, which decomposes via a putative furfuryl cation intermediate. While this constraint does not pose a challenge for potential Scheme 3.1 A Tethered Alcohol Facilitates Mechanically Triggered Release in Aprotic Environments 100 biological applications in aqueous media, for instance, it limits the applicability of the mechanophore in a broader range of environments. Here we describe the design of a unique mechanophore scaffold that incorporates a tethered primary alcohol on the masked furfuryl carbonate to facilitate the efficient mechanically triggered release of small molecules in an aprotic environment (Scheme 3.1b). We hypothesized that the tethered alcohol would supplant the role of the protic additive – either methanol or water – in our previous studies by both stabilizing the polar transition state and serving as a nucleophile to intercept the furfuryl cation intermediate. We describe the computationally supported design and reactivity of this tethered furfuryl carbonate and demonstrate significantly enhanced molecular release upon ultrasoundinduced mechanochemical activation of the mechanophore under aprotic conditions in comparison to the original mechanophore design. 3.2 Results and Discussion 3.2.1 Computational investigation of the tethered alcohol substrate We first investigated the influence of the tethered alcohol on the decomposition reaction of the furfuryl carbonate scaffold using density functional theory (DFT). Activation energies for carbonate fragmentation were calculated for models FC1 and FC2 at the M06-2X/6-311+G** level of theory using a polarizable continuum model to simulate a polar solvent environment (Figure 3.1, see Section 3.4.5 for details). The reaction barrier is reduced by 3.9 kcal/mol for furfuryl carbonate FC2 incorporating the tethered alcohol motif in comparison to α-methyl derivative FC1, suggesting an increased rate of fragmentation leading to cargo release. The calculated geometry of transition state structure 101 Figure 3.1 Density functional theory (DFT) calculations performed on furfuryl carbonate models FC1 and FC2 at the M06-2X/6-311+G** level of theory using a polarizable continuum model to simulate a polar solvent environment. These results demonstrate a significantly reduced activation energy for FC2 incorporating a tethered primary alcohol. The computed structure of FC2‡ exhibits an apparent hydrogen bonding interaction suggesting stabilization of the transition state leading to carbonate fragmentation. FC2‡ indicates an intramolecular hydrogen bond between the tethered primary alcohol and the carbonyl oxygen of the carbonate, which is proposed to stabilize the developing negative charge on the carbonate leaving group. Read de Alaniz and coworkers have previously demonstrated that Brønsted acid facilitates the thermal decomposition of more stable furfuryl carbamates.25 The prior role of the protic additive in the decomposition of similar 2-furylcarbinol derivatives has not been explicitly studied, but based on these computational results, it may be reasonable to assume a similar activation manifold. Additional calculations using the constrained geometries simulate external force (CoGEF) method26,27 predict that mechanical activation of a furan–maleimide Diels–Alder adduct corresponding to FC2 generates the expected furfuryl carbonate via a formal retro-[4+2] cycloaddition reaction at a force of 4.2 nN (Figure 3.2), which is comparable to rupture forces determined for other experimentally validated furan–maleimide mechanophores. 27,28 102 Figure 3.2 DFT calculations performed on a truncated Diels–Alder adduct using the constrained geometries simulate external force (CoGEF) method at the B3LYP/6-31G* level of theory. The rupture force (Fmax) is calculated to be 4.2 nN, and the calculations predict the formation of the expected furan and maleimide products via a formal retro-Diels–Alder reaction upon elongation. 3.2.2 Mechanophore synthesis Encouraged by the computational predictions, we set out to synthesize a small molecule Diels–Alder adduct incorporating a masked furfuryl carbonate endowed with a tethered primary alcohol (Scheme 3.2). Two-fold lithiation of furfuryl alcohol followed by the addition of TBS-protected 4-hydroxybutanal generated diol 1 containing a TBSprotected tethered alcohol and a secondary alcohol for cargo attachment. Following esterification of the primary alcohol with α-bromoisobutyryl bromide, furan 2 was subjected to a [4+2] cycloaddition reaction with 2-hydroxyethylmaleimide to produce an isomeric mixture of Diels–Alder adducts from which endo diastereomer (±)-3 was isolated 103 Scheme 3.2 Synthesis of a Masked Furfuryl Carbonate with a Tethered Primary Alcohol and a Hydroxycoumarin Payload O Br Br HO O 1. n-BuLi, THF, 20 °C HO Me Me Et3N OH O OTBS O 2. TBSO 1 THF, 20 °C to rt 49% O Br DCM 0 °C to rt 79% OH O O OTBS Me Me OH 2 Me O Me R O O O Br H O Me Me O O pyridine O R' O Me R Me Me O O H O O O O Me N Cl DCM, 0 °C to rt O O O Br H O Me Me Me Me NEt3 DCM, 0 °C to rt N O O H Br Br (±)-6 (R = Me, R' = OTBS, 53%) (±)-7 (R = Br, R' = OTBS, 45%) Me Me NEt3 DCM, 0 °C to rt Hf(OTf)4 MeOH, rt 98% (±)-4 (R = Me, 38%) (±)-5 (R = Br, 50%) Br H O N O O H OH Me Cl OTBS OH O O Me Me or O OH O THF, rt 30% O O (±)-8 (R = Br, R' = OH) N O O (±)-3 OTBS by reverse phase chromatography. Selective esterification of the primary alcohol with αbromoisobutyryl bromide afforded adduct (±)-5 followed by installation of a hydroxycoumarin payload via reaction with the chloroformate to give carbonate (±)-7. Deprotection of the tethered alcohol was accomplished using catalytic Hf(OTf) 429 to provide bis-initiator (±)-8. We note that typical conditions employing tetrabutylammonium fluoride to remove the TBS group resulted in some undesired release of hydroxycoumarin. 3.2.3 Small molecule decompisition model experiment We next investigated the thermal reactivity of small molecule Diels–Alder adduct (±)-8 in pure acetonitrile to experimentally evaluate the impact of the tethered alcohol on the decomposition reaction of the latent furfuryl carbonate in the absence of any protic additive. A solution of (±)-8 in anhydrous acetonitrile-d3 was heated at 50 °C to promote the thermal retro-[4+2] cycloaddition reaction and the resulting mixture was analyzed by 104 Figure 3.3 Characterization of the reactivity of small molecule (±)-8 in acetonitrile (4.4 mM) at 50 °C. The thermally induced retro-Diels–Alder/decarboxylation reaction cascade is anticipated to proceed via a furfuryl cation intermediate, which is intercepted through intramolecular ether formation by the tethered alcohol. 1H NMR spectra (acetonitrile-d3, 400 MHz) demonstrate clean conversion of (±)-8 to the hydroxycoumarin, maleimide, and cyclic ether products. 1 H NMR spectroscopy and LCMS (Figure 3.3 and Figure 3.4). Upon full conversion of (±)-8 after 14 days, the major 1H NMR resonances in the crude reaction mixture match the spectra of hydroxycoumarin 9, maleimide ester 10, and cyclic ether 11. Formation of cyclic ether 11 is consistent with the expected decomposition pathway for the latent furfuryl carbonate in which the tethered alcohol undergoes an intramolecular cyclization reaction with the furfuryl cation intermediate. 105 Figure 3.4 Characterization of the thermal decomposition reaction of small molecule model (±)-8 in acetonitrile-d3 at 50 °C using HPLC with a UV detector (λ = 230 nm). HPLC chromatograms of (a) starting material (±)-8, and (b) the crude reaction mixture after 14 days in comparison to the HPLC chromatograms of analytical samples of (c) hydroxycoumarin 9, (d) maleimide 10, and (e) cyclic ether 11. The identity of the compound producing the small peak at ~8.7 min was not determined. 106 Figure 3.5 Characterization of the release of hydroxycoumarin 9 from the thermal decomposition reaction of (±)-8 in acetonitrile-d3 at 50 °C for 14 d using HPLC with a UV detector (λ = 320 nm). A 75% yield of hydroxycoumarin release was determined using an internal standard of 3-cyano-7-hydroxy-4methylcoumarin (3.73 mM). Both 1H NMR and LCMS results indicate relatively clean conversion of (±)-8 to these three anticipated products, releasing the hydroxycoumarin cargo in 75% yield as determined by HPLC measurements (Figure 3.5). In direct contrast, treatment of the analogous Diels– Alder adduct 12 derived from the α-methyl substituted furfuryl carbonate20 under similar conditions results in a complex mixture of products with hydroxycoumarin 9 ultimately being generated in a significantly lower yield of 37% (Figure 3.6–Figure 3.8). While the decomposition pathway for the α-methyl furfuryl carbonate under these conditions is not known, we speculate that adventitious water or another protic source may play a role in hydroxycoumarin formation. 107 12 Figure 3.6 1H NMR spectra (acetonitrile-d3, 400 MHz) before and after heating the indicated Diels–Alder adduct 1220 at 50 °C for 20 days. Initial concentration of substrate was 5.9 mM. Compound 12 was used as the bis-initiator to synthesize PMA-Me. 108 Figure 3.7 Characterization of the thermal decomposition reaction (acetonitrile-d3, 50 °C, 20 d) of the bisinitiator Diels–Alder adduct 12 containing an α-methyl carbonate. The HPLC chromatogram (λ=230 nm) of the crude reaction mixture shows formation of hydroxycoumarin 9 and maleimide ester 10, in addition to a number of unidentified products. Figure 3.8 Characterization of the release of hydroxycoumarin 9 from the thermal decomposition reaction (acetonitrile-d3, 50 °C, 20 d)) of the bis-initiator Diels–Alder adduct 12 containing an αmethyl carbonate, using HPLC with a UV detector (λ = 320 nm). A 37% yield of hydroxycoumarin release was determined using an internal standard of 3-cyano-7-hydroxy-4methylcoumarin (3.73 mM). 109 Diels–Alder adduct (±)-8 exhibits similar thermal stability as our original α-methyl analogue,23 undergoing ~4% retro-Diels–Alder reaction after 14 days at room temperature in acetonitrile as anticipated for simple endo furan–maleimide adducts (Figure 3.9). These results confirm the predicted reactivity of the furfuryl carbonate scaffold incorporating a tethered alcohol and highlight the substantially improved release performance in aprotic environments. Figure 3.9 1H NMR spectra (acetonitrile-d3, 400 MHz) of model compound (±)-8 acquired after 13 days in solution at room temperature. Approximately 4% retro-[4+2] cycloaddition is observed based on the integrated signals corresponding to starting material (±)-8 (5.35 ppm), maleimide 10 (6.76 ppm), and furfuryl ether 11 (6.42 ppm). 3.2.4 Mechanophore incorporation into poly(methyl acrylate) polymers We next synthesized a series of poly(methyl acrylate) (PMA) polymers containing the furan–maleimide Diels–Alder adducts for solution-phase ultrasonication experiments to evaluate their mechanochemical reactivity. Solvodynamic shear generated with 110 ultrasonication results in rapid chain elongation with mechanical force maximized near the center of the polymer.30 Therefore, polymers containing chain-centered Diels–Alder adducts incorporating the masked furfuryl carbonate with a tethered alcohol (PMA-OH) and the α-methyl derivative (PMA-Me) were prepared along with a chain-end control polymer (PMA-Control) derived from the adduct with a tethered alcohol (Chart 3.1). Chart 3.1 Poly(methyl acrylate) (PMA) Polymers Containing a Masked Furfuryl Carbonate Mechanophore with a Hydroxycoumarin Payload Polymers were synthesized via controlled radical polymerization using Cu wire/Me 6TREN in dimethyl sulfoxide from the corresponding Diels–Alder initiators bearing α-bromoester functional groups.20,31 Bis-initiator (±)-8 with a tethered primary alcohol was initially employed in the synthesis of PMA-OH; however, some undesired release of the hydroxycoumarin cargo occurred during polymerization in the presence of the Me 6TREN ligand, likely through activation of the alcohol toward intramolecular carbonate substitution. Instead, polymerization from TBS-protected bis-initiator (±)-7 followed by removal of the TBS protecting group using an ion exchange resin (Amberlyst 15) 32 afforded PMA-OH (Mn = 86 kDa, Ð = 1.10) (Figure 3.10 and Figure 3.11, see Section 3.4.2 for details). A similar polymerization procedure20 was used to prepare PMA-Me (Mn = 92 kDa, Ð = 1.10) allowing for the direct comparison of mechanochemical behavior and 111 the influence of the tethered alcohol as well as PMA-Control (Mn = 87 kDa, Ð = 1.16) to confirm the mechanical origin of reactivity. Figure 3.10 1H NMR spectra (CDCl3, 400 MHz) of bis-initiator (±)-7, PMA-OTBS, and PMA-OH showing successful removal of the TBS protecting group, as suggested by the nearly complete disappearance of the singlet at 0.05 ppm. Downfield signals corresponding to the chain-centered mechanophore remain intact after the deprotection reaction and no signals for release hydroxycoumarin are present. 112 Figure 3.11 Characterization of the crude deprotection reaction of PMA-OTBS using analytical gel permeation chromatography monitored with a UV detector (λ=320 nm). No small molecule peak corresponding to hydroxycoumarin 9 is observed in the crude deprotection reaction, indicating survival of the carbonate motif. The polymer peaks for PMA-OTBS and PMA-OH are nearly identical, indicating the polymer backbone is unaffected by the deprotection conditions. Figure 3.12 GPC traces (refractive index response) for the three polymers used in this study: PMA-OH (Mn = 86 kDa, Ð = 1.10), PMA-Me (Mn = 92 kDa, Ð = 1.10), and PMA-control (Mn = 87 kDa, Ð = 1.16). 113 3.2.5 Characterization of mechanochemical reactivity The mechanically triggered release of hydroxycoumarin 9 from dilute solutions of PMA-OH and PMA-Me in pure acetonitrile was evaluated using pulsed ultrasonication (1 s on/2 s off, 6–9 °C, 20 kHz, 15.5W/cm2). Aliquots were removed from solution over the course of the experiment and the generation of hydroxycoumarin 9 was monitored using HPLC equipped with a UV detector. Samples from sonicated solutions of PMA-OH and PMA-Me were incubated at room temperature for 72 h and 120 h, respectively, to allow for nearly complete decomposition of the unmasked furfuryl carbonate prior to quantifying the release of hydroxycoumarin using an internal standard (see Section 3.4.4 for details). As illustrated in Figure 3.13a, release of hydroxycoumarin is much more efficient from PMA-OH compared to PMA-Me under these conditions in the absence of any protic additive. Figure 3.13 Characterization of mechanically triggered release in acetonitrile. (a) Release of hydroxycoumarin 9 from polymers (2 mg/mL in acetonitrile) subjected to ultrasound-induced mechanochemical activation for various durations of sonication. Samples were subsequently incubated at rt for 72 h (PMA-OH) or 120 h (PMA-Me) and release was quantified using HPLC. (b) Time-dependent generation of hydroxycoumarin 9 from the unmasked furfuryl carbonate during incubation at rt as monitored by HPLC immediately following 120 min of ultrasonication. Error bars represent standard deviation from three replicate experiments. 114 Consistent with the small molecule reactivity described above, fitting the sonication timedependent release data to a first-order rate expression highlights the improved release efficiency attributed to the tethered alcohol. The extent of release is projected to plateau at 85% from PMA-OH, while the release of hydroxycoumarin from PMA-Me under these conditions is only projected to reach ~53% at full conversion (Figure 3.14 and Figure 3.15). Negligible release was observed upon ultrasonication of chain-end functionalized control polymer PMA-control under the same conditions, confirming that the release of hydroxycoumarin occurs from the unmasked furfuryl carbonate only upon mechanochemical activation of the furan–maleimide mechanophore. Figure 3.14 Release of hydroxycoumarin 9 from PMA-OH as a function of sonication time (2 mg/mL polymer in MeCN) as quantified by HPLC analysis. Aliquots were removed from the sonicated solution and incubated at room temperature for 72 h prior to measurement. Error bars represent standard deviation from three replicate experiments. Fitting the data to a first-order rate expression gives a projected maximum release of ~85%. 115 Figure 3.15 Release of hydroxycoumarin 9 from PMA-Me as a function of sonication time (2 mg/mL polymer in MeCN) monitored using HPLC. Aliquots were removed from the sonicated solution and incubated at room temperature for 120 h prior to measurement. Error bars represent standard deviation from three replicate experiments. Fitting the data to a first-order rate expression gives a projected maximum release of ~53%. To more clearly elucidate the difference in cargo release kinetics enabled by the tethered alcohol as predicted by the computational study, an aliquot from each polymer solution was characterized by HPLC at regular time intervals starting immediately after 120 min of ultrasonication (Figure 3.13b). These data were fitted to a first-order rate expression to determine relative release kinetics in pure acetonitrile from PMA-OH and PMA-Me. The similar size of each polymer is expected to result in comparable mechanophore conversion upon exposure to ultrasonication for the same amount of time. Therefore, differences in hydroxycoumarin release result nearly exclusively from differences in the decomposition reactions of each mechanically revealed furfuryl carbonate species. As anticipated, release of hydroxycoumarin from PMA-OH is significantly faster (t1/2 = 11 h) compared to PMA-Me (t1/2 = 39 h), suggesting that the tethered alcohol facilitates furfuryl carbonate decomposition under these aprotic solvent conditions (Figure 3.16 and Figure 3.17). The release of hydroxycoumarin from PMA-OH 116 plateaus at 70% of full release following 120 min of ultrasonication. In contrast, the release of hydroxycoumarin from PMA-Me is projected to plateau at only 45% of the theoretical maximum value, emphasizing the environmental limitations of molecular release from that system. These results demonstrate the enhanced payload release in aprotic environments enabled by a tethered alcohol motif on the masked furfuryl carbonate, fostering opportunities for mechanically triggered molecular release in diverse environments. Figure 3.16 Release of hydroxycoumarin 9 from PMA-OH as a function of incubation time at room temperature following 120 min ultrasonication (2 mg/mL in MeCN) monitored using HPLC. Error bars represent standard deviation from three replicate experiments. Fitting the data to a first-order rate expression provides a reaction half-life of ~11 h. 117 Figure 3.17 Release of hydroxycoumarin 9 from PMA-Me as a function of incubation time at room temperature following 120 min ultrasonication (2 mg/mL in MeCN) monitored using HPLC. Error bars represent standard deviation from three replicate experiments. Fitting the data to a first-order rate expression provides a reaction half-life of ~39 h. Figure 3.18 Characterization of PMA-OH by gel permeation chromatography (GPC) during the course of 120 min ultrasonication. (a) GPC traces as a function of ultrasonication time monitored with a refractive index (RI) detector. (b) Mn as a function of ultrasonication time showing a steady decrease in molecular weight as a result of ultrasound-induced mechanochemical activation. 118 3.3 Conclusion In summary, we have designed a masked furfuryl carbonate mechanophore endowed with a tethered alcohol motif that significantly enhances mechanically triggered molecular release in aprotic environments, overcoming a limitation of previous systems. Experiments demonstrate that a tethered primary alcohol incorporated onto a secondary furfuryl carbonate promotes clean decomposition in pure acetonitrile. Ultrasound-induced mechanochemical activation of the furan–maleimide mechanophore results in the release of a hydroxycoumarin cargo molecule with improved efficiency and faster release kinetics compared to the original α-methyl derivative. Density functional calculations suggest a favorable intramolecular hydrogen bonding interaction between the tethered alcohol and the carbonyl oxygen of the carbonate that reduces the activation barrier for furfuryl carbonate decomposition leading to cargo release. This study broadens the scope of mechanically triggered release from masked 2-furylcarbinol mechanophores, which will be useful for the implementation of this strategy in a wider range of environments including bulk polymeric materials. 3.4 Experimental 3.4.1 General experimental details and methods Reagents from commercial sources were used without further purification unless otherwise stated. Methyl acrylate was passed through a short plug of basic alumina to remove inhibitor immediately prior to use. Copper wire was cleaned prior to use by soaking in 1 M HCl for 5 min, and rinsed consecutively with deionized water, acetone, and DCM and 119 then dried. Dry THF, DCM, and MeCN were obtained from a Pure Process Technology solvent purification system. All reactions were performed under a N 2 atmosphere unless specified otherwise. Silica column chromatography was performed on a Biotage Isolera system using SiliCycle SiliaSep HP flash cartridges. Preparatory reverse phase chromatography was performed with an Agilent 1100 Series high-performance liquid chromatography (HPLC) system using an Agilent Eclipse C18 column (990967-202). NMR spectra were recorded using a 400 MHz Bruker Avance III HD with Prodigy Cryoprobe, a 400 MHz Bruker Avance Neo, or Varian Inova 500 MHz spectrometers. All 1 H NMR spectra are reported in parts per million (ppm) and were measured relative to the signals for residual chloroform (7.26 ppm), dichloromethane (5.32 ppm), or acetonitrile (1.94 ppm) in deuterated solvent. All 13C NMR spectra were measured in deuterated solvents and are reported in ppm relative to the signals for CDCl 3 (77.16 ppm), CD2Cl2 (53.84 ppm), or acetonitrile-d3 (1.32 ppm). Multiplicity and qualifier abbreviations are as follows: s = singlet, d = doublet, t = triplet, q = quartet, dd = doublet of doublets, td = triplet of doublets, ABq = AB quartet, m = multiplet, br = broad. High resolution mass spectra (HRMS) were obtained from an Agilent 6230 series time-offlight mass spectrometer equipped with an Agilent G1958 Jet Stream Electrospray Ionization Source. Analytical gel permeation chromatography (GPC) was performed using an Agilent 1260 series pump equipped with two Agilent PLgel MIXED-B columns (7.5 x 300 mm), an Agilent 1200 series diode array detector, a Wyatt 18-angle DAWN HELEOS light 120 scattering detector, and an Optilab rEX differential refractive index detector. The mobile phase was THF at a flow rate of 1 mL/min. Molecular weights and molecular weight distributions were calculated by light scattering using a dn/dc value of 0.062 mL/g (25 °C) for poly(methyl acrylate). Analytical high-performance liquid chromatography (HPLC) measurements were performed with an Agilent Eclipse Plus C18 column (959961-902) using a singlewavelength UV-vis detector. Ultrasound experiments were performed in a sound abating enclosure using a 500-watt Vibra Cell 505 liquid processor (20 kHz) equipped with a 0.5-inch diameter solid probe (part #630-0217), sonochemical adapter (part #830-00014), and a Suslick reaction vessel made by the Caltech glass shop (analogous to vessel #830-00014 from Sonics and Materials). 3.4.2 Synthetic details 4-((tert-butyldimethylsilyl)oxy)-1-(5-(hydroxymethyl)furan-2-yl)butan-1-ol (1). A flame-dried 500 mL two-neck flask equipped with a stir bar was charged with furfuryl alcohol (1.43 mL, 16.5 mmol) and THF (120 mL). The solution was cooled to −20 °C with an ice/brine bath before adding n-butyllithium (2.5 M in hexanes, 13.9 mL, 34.7 mmol) dropwise via an addition funnel. The reaction mixture was allowed to stir at −20 °C for 1 h before adding 4-((tert-butyldimethylsilyl)oxy)butanal33 (7.35 g, 36.3 mmol) 121 dropwise. The reaction was allowed to slowly warm to room temperature overnight. The reaction was quenched by the slow addition of sat. NaHCO3 (100 mL). The mixture was then extracted with EtOAc (3x150 mL), and the combined organic extracts were washed consecutively with water (200 mL) and brine (200 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (25–50% EtOAc/hexanes) to provide the title compound as an orange oil (2.45 g, 49%). R f = 0.35 (50% EtOAc/hexanes). HRMS (ESI, m/z): calcd for [C15H28O4SiNa]+ (M+Na)+, 323.1649; found, 323.1654. 1 H NMR (500 MHz, MeCN) δ: 6.18 (d, J = 3.1 Hz, 1H), 6.14 (d, J = 3.1 Hz, 1H), 4.56 (dd, J = 7.7, 5.9 Hz, 2H), 3.54 (t, J = 6.3 Hz, 2H), 1.80 (m, 2H), 1.53 (m, 2H), 0.89 (s, 9H), 0.05 (s, 6H) ppm. 13 C{1H} NMR (101 MHz, MeCN) δ: 158.4, 155.1, 108.6, 107.0, 67.7, 63.7, 57.2, 33.1, 29.8, 26.3, 18.9, −5.1 ppm. (5-(4-((tert-butyldimethylsilyl)oxy)-1-hydroxybutyl)furan-2-yl)methyl 2-bromo-2methylpropanoate (2). A flame-dried 50 mL two-neck flask equipped with a stir bar was charged with compound 1 (0.650 g, 2.16 mmol) and DCM (17 mL). The solution was cooled to 0 °C, and triethylamine (0.603 mL, 4.33 mmol) was added to the reaction flask. A solution of α-bromoisobutyryl bromide (0.267 mL, 2.16 mmol) in DCM (12 mL) was added slowly via an addition funnel. The reaction was stirred at 0 °C for 2 h, and 122 quenched with the addition of water (10 mL). The mixture was extracted with DCM (3 x 30 mL), and then dried with Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (10–30% EtOAc/hexanes) to yield the title compound as a pale yellow oil (0.766 g, 79%). R f = 0.80 (50% EtOAc/hexanes). HRMS (ESI, m/z): calcd for [C19H33BrO5SiNa]+ (M+Na)+, 471.1173; found, 471.1189. 1 H NMR (400 MHz, CDCl3) δ: 6.38 (d, J = 3.2 Hz, 1H), 6.22 (d, J = 3.3 Hz, 1H), 5.12 (s, 2H), 4.71 (dd, J = 7.9, 4.8 Hz, 1H), 3.69 (m, 2H), 3.30 (br, 1H, -OH), 1.96 (m, 2H), 1.92 (s, 6H), 1.66 (m, 2H), 0.90 (s, 9H), 0.08 (s, 6H) ppm. 13 C{1H} NMR (101 MHz, CDCl3) δ: 171.5, 158.3, 148.0, 111.8, 106.7, 67.9, 63.5, 59.8, 55.8, 33.5, 30.9, 29.0, 26.1, 18.5, −5.2 ppm. (7-(4-((tert-butyldimethylsilyl)oxy)-1-hydroxybutyl)-2-(2-hydroxyethyl)-1,3-dioxo1,2,3,3a,7,7a-hexahydro-4H-4,7-epoxyisoindol-4-yl)methyl 2-bromo-2methylpropanoate ((±)-3). A 25 mL round-bottom flask equipped with a stir bar was charged with furan 2 (2.00 g, 4.45 mmol), N-(2-hydroxyethyl)maleimide34 (1.26 g, 8.90 mmol), and THF (7 mL). The reaction was stirred at room temperature for 7 days, and then concentrated under reduced pressure. The crude reaction mixture was separated by 123 column chromatography (60–100% EtOAc/hexanes). The four diastereomeric products of the Diels–Alder reaction were separated by reverse phase chromatography (85% MeCN/H2O) to yield the desired endo isomer as a foamy white solid (0.788 g, 30%). R f = 0.18 (50% EtOAc/hexanes). HRMS (ESI, m/z): calcd for [C25H40BrO8SiH]+ (M+H)+, 590.1780; found, 590.1806. 1 H NMR (500 MHz, MeCN) δ: 6.35 (s, 2H), 4.90 (d, J = 12.5 Hz, 1H), 4.67 (d, J = 12.5 Hz, 1H), 4.22 (dd, J = 10.3, 2.4 Hz, 1H), 3.91 (d, J = 7.7 Hz, 1H), 3.72 (m, 2H), 3.66 (m, 2H), 3.55 (m, 3H), 3.44 (s, 1H, -OH), 1.94 (m, 6H), 1.89 (m, 1H), 1.78 (m, 2H), 1.63 (m, 1H), 0.90 (s, 9H), 0.08 (m, 6H) ppm. 13 C{1H} NMR (101 MHz, MeCN) δ: 175.9, 175.2, 171.3, 136.2, 134.7, 94.9, 89.4, 69.5, 63.5, 60.7, 55.6, 49.4, 47.5, 41.5, 30.8, 30.8, 30.5, 29.5, 26.1, 18.4, −5.2, −5.3 ppm. 2-((3aS,4S,7R,7aR)-4-(((2-bromo-2-methylpropanoyl)oxy)methyl)-7-(4-((tertbutyldimethylsilyl)oxy)-1-hydroxybutyl)-1,3-dioxo-1,3,3a,4,7,7a-hexahydro-2H-4,7epoxyisoindol-2-yl)ethyl pivalate ((±)-4). A flame-dried 10 mL two-neck flask was charged with Diels–Alder adduct (±)-3 (70.0 mg, 0.119 mmol), triethylamine (63.0 μL, 0.462 mmol), DMAP (1.00 mg, 0.008 mmol), and DCM (5 mL). The solution was cooled 124 to 0 °C, and pivaloyl chloride (16.0 μL, 0.130 mmol) was added dropwise. The reaction was allowed to warm to room temperature. After 26 h, the reaction was diluted with DCM (20 mL), and washed with sat. NH4Cl (10 mL), water (10 mL), and brine (10 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude reaction mixture was purified by column chromatography (20–50% EtOAc/hexanes) to yield the title compound as a colorless oil (40.3 mg, 50%). R f = 0. 72 (50% EtOAc/hexanes). HRMS (ESI, m/z): calcd for [C30H48BrNO9SiH]+ (M+H)+, 674.2355; found, 674.2348. 1 H NMR (400 MHz, CDCl3) δ: 6.34 (s, 2H), 4.90 (d, J = 12.5 Hz, 1H), 4.65 (d, J = 12.5 Hz, 1H), 4.21 (dd, J = 10.3, 2.5 Hz, 1H), 4.09 (m, 2H), 3.87 (d, J = 7.8 Hz, 1H), 3.72 (m, 2H), 3.59 (m, 2H), 3.50 (d, J = 7.8 Hz, 1H), 1.94 (m, 6H), 1.90 (m, 1H), 1.77 (m, 2H), 1.62 (m, 1H), 1.16 (s, 9H), 0.90 (s, 9H), 0.07 (m, 6H) ppm. 13 C{1H} NMR (101 MHz, CDCl3) δ: 178.3, 174.8, 174.2, 171.2, 136.2, 134.7, 94.7, 89.3, 69.5, 63.5, 63.5, 61.0, 55.6, 49.4, 47.5, 38.8, 37.9, 30.8, 30.8, 30.5, 29.5, 27.3, 26.1, 18.4, −5.2 ppm. ((3aS,4S,7R,7aR)-2-(2-((2-bromo-2-methylpropanoyl)oxy)ethyl)-7-(4-((tertbutyldimethylsilyl)oxy)-1-hydroxybutyl)-1,3-dioxo-1,2,3,3a,7,7a-hexahydro-4H-4,7- 125 epoxyisoindol-4-yl)methyl 2-bromo-2-methylpropanoate ((±)-5). A flame-dried 25 mL two-neck flask was charged with compound (±)-3 (0.150 g, 0.254 mmol) and DCM (10 mL). The reaction mixture was then cooled to 0 °C, followed by the sequential dropwise addition of triethylamine (42.5 μL, 0.305 mmol) and then α-bromoisobutyryl bromide (34.5 μL, 0.279 mmol) via microsyringe. After 18 h, the crude reaction mixture was diluted with DCM (50 mL) and then washed consecutively with sat. NH 4Cl (20 mL) and brine (20 mL). The organic layer was then dried with Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (20– 40% EtOAc/hexanes) to yield the title compound as a viscous colorless oil (0.144 g, 38%). Rf = 0.81 (50% EtOAc/hexanes). HRMS (ESI, m/z): calcd for [C29H45Br2NO9SiH]+ (M+H)+, 738.1304; found, 738.1324. 1 H NMR (400 MHz, CD2Cl2) δ: 6.38 (ABq, JAB = 5.7 Hz, 2H), 4.87 (d, J = 12.6 Hz, 1H), 4.66 (d, J = 12.4 Hz, 1H), 4.19 (m, 2H), 4.15 (m, 1H), 3.83 (d, J = 7.7 Hz, 1H), 3.70 (m, 2H), 3.64 (m, 2H), 3.52 (d, J = 7.7 Hz, 1H), 3.16 (d, J = 6.0 Hz, 1H), 1.94 (s, 6H), 1.91 (m, 1H), 1.89 (s, 6H), 1.76 (m, 2H), 1.61 (m, 1H), 0.90 (s, 9H), 0.08 (m, 6H) ppm. 13 C{1H} NMR (101 MHz, CDCl3) δ: 175.0, 174.5, 171.7, 171.4, 136.7, 134.9, 95.1, 89.6, 69.9, 63.7, 62.9, 56.3, 56.2, 49.5, 47.8, 37.7, 30.9, 30.9, 30.6, 30.1, 29.8, 26.1, 18.6, −5.3 ppm. 126 2-((3aS,4S,7R,7aR)-4-(((2-bromo-2-methylpropanoyl)oxy)methyl)-7-(4-((tertbutyldimethylsilyl)oxy)-1-((((4-methyl-2-oxo-2H-chromen-7yl)oxy)carbonyl)oxy)butyl)-1,3-dioxo-1,3,3a,4,7,7a-hexahydro-2H-4,7-epoxyisoindol2-yl)ethyl pivalate ((±)-6). A flame-dried 8 mL septum-capped vial was charged with compound (±)-4 (25.8 mg, .0382 mmol), pyridine (12.0 μL, 0.145 mmol), and DCM (0.5 mL). A solution of coumarin chloroformate20 (36.0 mg, 0.153 mmol) in DCM (1 mL) was added dropwise to the reaction mixture. The reaction was monitored by TLC, and after 19 h the crude mixture was filtered through a short plug of Celite to remove the insoluble bisarylcarbonate. The crude product was purified by column chromatography (30–60% EtOAc/hexanes) to yield the title compound as sticky white solid (17.7 mg, 53% yield). Rf = 0.57 (50% EtOAc/hexanes). HRMS (ESI, m/z): calcd for [C41H54BrNO13SiH]+ (M+H)+, 876.2621; found, 876.2647. 1 H NMR (400 MHz, CDCl3) δ: 7.61 (d, J = 8.7 Hz, 1H), 7.25 (m, 1H), 7.21 (dd, J = 8.7, 2.3 Hz, 1H), 6.47 (d, J = 5.8 Hz, 1H), 6.41 (d, J = 5.7 Hz, 1H), 6.28 (q, J = 1.3 Hz, 1H), 5.46 (dd, J = 10.0, 3.1 Hz, 1H), 4.95 (d, J = 12.6 Hz, 1H), 4.67 (d, J = 12.6 Hz, 1H), 4.12 (t, J = 5.2 Hz, 2H), 3.70 (m, 2H), 3.59 (m, 4H), 2.44 (d, J = 1.3 Hz, 3H), 2.24 (m, 1H), 1.94 (m, 6H), 1.88 (m, 1H), 1.73 (m, 2H), 1.16 (s, 9H), 0.89 (s, 9H), 0.06 (s, 6H) ppm. 127 13 C{1H} NMR (101 MHz, CDCl3) δ: 178.4, 173.5, 173.4, 171.2, 160.5, 154.3, 153.4, 152.7, 151.9, 135.6, 135.1, 125.6, 118.2, 117.5, 114.9, 110.0, 92.6, 89.3, 63.2, 62.4, 61.0, 55.4, 49.2, 48.7, 38.8, 38.2, 30.8, 30.8, 28.7, 27.3, 26.8, 26.1, 18.9, 18.5, −5.2 ppm. ((3aS,4S,7R,7aR)-2-(2-((2-bromo-2-methylpropanoyl)oxy)ethyl)-7-(4-((tertbutyldimethylsilyl)oxy)-1-((((4-methyl-2-oxo-2H-chromen-7yl)oxy)carbonyl)oxy)butyl)-1,3-dioxo-1,2,3,3a,7,7a-hexahydro-4H-4,7-epoxyisoindol4-yl)methyl 2-bromo-2-methylpropanoate ((±)-7). An oven-dried 8 mL vial equipped with a stir bar and septum cap was charged with (±)-5 (0.141 g, 0.191 mmol), pyridine (95.3 μL, 1.163 mmol), and DCM (0.5 mL). The reaction mixture was cooled to 0 °C and a solution of coumarin chloroformate20 (0.270 g, 1.144 mmol) in DCM (5 mL) was added dropwise. The reaction was allowed to slowly warm to room temperature and stir for 2 days. The reaction mixture was then diluted with DCM (50 mL) and washed consecutively with water (20 mL) and brine (20 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude mixture was taken up in EtOAc (5 mL) and filtered through a short plug of Celite to remove the insoluble bisarylcarbonate byproduct. The crude product was purified by column chromatography 128 (25–50% EtOAc/hexanes) to yield the title compound as a colorless oil (81.6 mg, 45%). Rf = 0.75 (50% EtOAc/hexanes). HRMS (ESI, m/z): calcd for [C40H51Br2NO13SiH]+ (M+H)+, 940.1570; found, 940.1586. 1 H NMR (400 MHz, CDCl3) δ: 7.61 (d, J = 8.7 Hz, 1H), 7.26 (m, 1H), 7.21 (dd, J = 8.7, 2.4 Hz, 1H), 6.52 (d, J = 5.7 Hz, 1H), 6.45 (d, J = 5.7 Hz, 1H), 6.28 (d, J = 1.3 Hz, 1H), 5.46 (dd, J = 10.0, 3.2 Hz, 1H), 4.95 (d, J = 12.6 Hz, 1H), 4.67 (d, J = 12.5 Hz, 1H), 4.23 (t, J = 5.2 Hz, 2H), 3.71 (m, 4H), 3.59 (m, 2H), 2.44 (d, J = 1.3 Hz, 3H), 2.23 (m, 1H), 1.94 (d, J = 1.8 Hz, 6H), 1.90 (s, 6H), 1.85 (m, 1 H), 1.73 (m, 2H), 0.89 (s, 9H), 0.06 (s, 6H) ppm. 13 C{1H} NMR (101 MHz, CDCl3) δ: 173.5, 173.4, 171.5, 171.2, 160.5, 154.3, 153.4, 152.7, 151.9, 135.8, 135.2, 125.6, 118.2, 117.5, 114.8, 110.0, 92.6, 89.4, 68.1, 63.1, 62.5, 62.4, 55.7, 55.4, 49.2, 48.8, 37.7, 30.8, 28.7, 26.8, 26.1, 18.9, 18.5, −5.2 ppm. ((3aS,4S,7R,7aR)-2-(2-((2-bromo-2-methylpropanoyl)oxy)ethyl)-7-(4-hydroxy-1((((4-methyl-2-oxo-2H-chromen-7-yl)oxy)carbonyl)oxy)butyl)-1,3-dioxo1,2,3,3a,7,7a-hexahydro-4H-4,7-epoxyisoindol-4-yl)methyl 2-bromo-2methylpropanoate ((±)-8). Compound (±)-7 (0.020 g, 0.0212 mmol) was suspended in MeOH (1.5 mL) in an oven-dried vial equipped with a stir bar and septum cap. A solution 129 of Hf(OTf)4 (0.8 mg, 0.0011 mmol) in MeOH (150 μL) was then added to the mixture. After stirring for 11 h, the reaction mixture became clear indicating full conversion of starting material, at which point the mixture was concentrated under reduced pressure. The crude product was purified by reverse phase chromatography (95% MeCN/H 2O) to provide the title compound as a foamy white solid (17.0 mg, 98%). R f = 0.36 (50% EtOAc/hexanes). HRMS (ESI, m/z): calcd for [C34H37Br2NO13H]+ (M+H)+, 826.0705; found, 826.0721. 1 H NMR (400 MHz, CDCl3) δ: 7.63 (d, J = 8.7 Hz, 1H), 7.37 (d, J = 2.3 Hz, 1H), 7.29 (dd, J = 8.7, 2.3 Hz, 1H), 6.60 (d, J = 5.8 Hz, 1H), 6.46 (d, J = 5.8 Hz, 1H), 6.28 (d, J = 1.3 Hz, 1H), 5.38 (dd, J = 9.7, 3.4 Hz, 1H), 4.89 (d, J = 12.7 Hz, 1H), 4.72 (d, J = 12.7 Hz, 1H), 4.23 (m, 2H), 3.68 (m, 6H), 2.45 (d, J = 1.3 Hz, 3H), 1.96 (s, 6H), 1.83 (m, 4H), 1.80 (m, 6H). 13 C{1H} NMR (101 MHz, CDCl3) δ: 173.6, 173.6, 171.5, 171.2, 160.6, 154.3, 153.6, 153.4, 152.0, 135.5, 134.8, 125.6, 118.3, 117.9, 114.8, 110.5, 91.7, 89.7, 63.0, 62.6, 62.3, 55.7, 55.5, 50.8, 49.1, 37.8, 30.8, 30.8, 30.8, 28.4, 27.5, 18.9 ppm. Maleimide 10 was prepared according to the literature.35 130 (5-(4-((tert-butyldimethylsilyl)oxy)-1-(((4-methyl-2-oxo-2H-chromen-7yl)carbamoyl)oxy)butyl)furan-2-yl)methyl 2-bromo-2-methylpropanoate (S1). A flame-dried 25 mL two-necked flask was charged with compound 2 (0.150 g, 0334 mmol), coumarin isocyanate23 (0.134 g, 0.667 mmol), and DCM (10 mL). The mixture was then cooled to 0 °C, and DMAP (4.0 mg, 0.033 mmol) was added and the reaction was allowed to warm slowly to rt. After stirring for 18 h, the reaction mixture was diluted with DCM (50 mL) and washed consecutively with water (2 x 30 mL) and brine (30 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (20–60% EtOAc/hexanes) to provide the title compound as a foamy white solid (0.167 g, 77% yield) Rf = 0.79 (50% EtOAc/hexanes). HRMS (ESI, m/z): calcd for [C30H40BrNO8SiNa]+ (M+Na)+, 672.1599; found, 672.1610. 1 H NMR (400 MHz, CDCl3) δ: 7.51 (d, J = 8.7 Hz, 1H), 7.41 (d, J = 2.2 Hz, 1H), 7.34 (dd, J = 8.7, 2.2 Hz, 1H), 6.86 (s, 1H), 6.40 (d, J = 3.3 Hz, 1H), 6.37 (d, J = 3.2 Hz, 1H), 6.19 (d, J = 1.3 Hz, 1H), 5.85 (t, J = 7.2 Hz, 1H), 5.14 (ABq, JAB = 13.2 Hz, 2H), 3.64, (td, J = 6.3, 1.4 Hz, 2H), 2.40 (d, J = 1.3 Hz, 3H), 2.07 (q, J = 7.6 Hz, 2H), 1.92 (d, J = 2.0 Hz, 6H), 1.56 (m, 2H), 1.56 (s, 3H), 0.89 (s, 9H), 0.04 (s, 6H) ppm. 131 13 C{1H} NMR (101 MHz, CDCl3) δ: 171.4, 161.1, 154.6, 153.2, 152.3, 152.2, 149.1, 141.4, 125.5, 115.7, 114.4, 113.4, 111.7, 110.0, 106.0, 70.3, 62.6, 59.7, 55.7, 30.8, 29.3, 28.7, 25.4, 18.7, 18.5, −5.2 ppm. (5-(tetrahydrofuran-2-yl)furan-2-yl)methyl 2-bromo-2-methylpropanoate (11). Compound S1 (0.010 g, 0.0153 mmol) was dissolved in MeCN (1 mL) in a small vial. A solution of Hf(OTf)4 (0.5 mg, 0.6 μmol) in MeCN (250 μL) was added dropwise. After 5 h, the reaction mixture was concentrated under reduced pressure. The reaction mixture was purified by column chromatography (10–50% EtOAc/hexanes) to provide the title compound as a colorless oil (1.4 mg, 29% yield). R f = 0.52 (20% EtOAc/hexanes). HRMS (ESI, m/z): calcd for [C13H17BrO4Na]+ (M+Na)+, 339.0203; found, 339.0206. 1 H NMR (400 MHz, CDCl3) δ: 6.37 (d, J = 3.2 Hz, 1H), 6.25 (d, J = 3.1 Hz, 1H), 5.13 (s, 2H), 4.90 (t, J = 6.7 Hz, 1H), 3.99 (m, 1H), 3.88 (m, 1H), 2.20 (m, 1H), 2.08 (m, 2H), 1.98 (m, 1H), 1.93 (s, 6H) ppm. 13 C{1H} NMR (101 MHz, CDCl3) δ: 171.5, 156.3, 148.6, 111.7, 107.7, 74.0, 68.5, 59.9, 55.8, 33.5, 30.9, 30.5, 26.0 ppm. Synthesis of poly(methyl acrylate) containing a chain-centered mechanophore with a TBS-protected tethered alcohol (PMA-OTBS). A 10 mL Schlenk flask with a stir bar 132 was charged with bis-initiator (±)-7 (10.6 mg, 11.3 μmol), DMSO (1.51 mL), copper wire (1 cm length, 20 gauge), and methyl acrylate (1.51 mL, 17 mmol). The flask was sealed, the solution was deoxygenated with five freeze-pump-thaw cycles, and then backfilled with nitrogen. The flask was warmed to rt, and Me6TREN (6.0 μL, 23 μmol) was then added via microsyringe. After stirring at rt for 87 min, the flask was opened to air and the solution was diluted with DCM. The polymer solution as precipitated into cold methanol (x3) and the isolated material was dried under vacuum to yield 0.839 g of polymer. Mn = 88 kDa, Ð = 1.10. Synthesis of poly(methyl acrylate) containing a chain-centered mechanophore with a tethered primary alcohol (PMA-OH). An oven-dried 8 mL vial was charged with PMA-OTBS (0.316 g) and MeCN (20 mL). Amberlyst-15 resin beads (0.275 g) were added, and the reaction was allowed to proceed under air at rt for 17 h. The mixture was filtered to recover the resin beads and the polymer solution was concentrated under reduced pressure. The polymer was then dissolved into DCM, precipitated into hexanes, and centrifuged to recover the polymer as a pellet. The polymer was then dried under vacuum to provide PMA-OH (0.255 g, 81%). Mn = 86 kDa, Ð = 1.10. Synthesis of poly(methyl acrylate) control polymer containing a mechanophore with a TBS-protected tethered alcohol at the chain end (PMA-control-OTBS). A 10 mL Schlenk flask with a stir bar was charged with bis-initiator (±)-6 (8.9 mg, 10.1 μmol), DMSO (1.36 mL), copper wire (1 cm length, 20 gauge), and methyl acrylate (1.36 mL, 133 15 mmol). The flask was sealed, the solution was deoxygenated with five freeze-pumpthaw cycles, and then backfilled with nitrogen. The flask was warmed to rt, and Me6TREN (5.0 μL, 19.5 μmol) was then added via microsyringe. After stirring at rt for 79 min, the flask was opened to air and the solution was diluted with DCM. The polymer solution was precipitated into cold methanol (x3) and the isolated material was dried under vacuum to yield 0.683 g of polymer. Mn = 85 kDa, Ð = 1.17. Synthesis of poly(methyl acrylate) control polymer containing a mechanophore with a tethered primary alcohol at the chain end (PMA-control). An oven-dried 8 mL septum-capped vial was charged with PMA-control-OTBS (0.200 g) and MeCN (15 mL). Amberlyst-15 resin beads (0.150 g) were added, and the reaction was allowed to proceed under air at rt for 10 h. The mixture was filtered to recover the resin beads and the polymer solution was concentrated under reduced pressure. The polymer was then dissolved into DCM, precipitated into hexanes, and centrifuged to recover the polymer as a pellet. The polymer was then dried under vacuum to provide PMA-control (0.171 g, 86%). Mn = 87 kDa, Ð = 1.16. Synthesis of poly(methyl acrylate) containing a chain-centered mechanophore with an α-methyl carbonate (PMA-Me). Polymer PMA-Me was synthesized according to the previously reported procedure.20 Mn = 92 kDa, Ð = 1.10. 134 3.4.3 General procedure for ultrasonication experiments An oven-dried sonication vessel was fitted with rubber septa, placed onto the sonication probe, and allowed to cool under a stream of dry argon. The vessel was charged with a solution of the polymer in anhydrous acetonitrile (2.0 mg/mL, 15 mL) and submerged in an ice bath. The solution was sparged with argon for 20 min prior to sonication and for the duration of the sonication experiment. Pulsed ultrasound (1 s on/2 s off, 30% amplitude, 20 kHz, 15.5 W/cm2) was then applied to the system. Aliquots (1 mL) were removed at 0, 20, 40, 60, 80, 100, and 120 min (sonication “on” time) and 14 μL of a 0.50 mM solution of 3-cyano-7-hydroxy-4-methylcoumarin internal standard in anhydrous MeCN was added. Samples were filtered through a 0.45 μm syringe filter prior to analysis by GPC and HPLC. Ultrasonic intensity was calibrated using the method described by Berkowski et al.6 3.4.4 Characterization of molecular release by HPLC Calculation of Relative Response Factors (RRF). A standard solution with known concentrations of the internal standard (IS) molecule (3-cyano-7-hydroxy-4methylcoumarin) and the small molecule analyte (7-hydroxy-4-methylcoumarin 9) was prepared and analyzed by HPLC equipped with a UV detector (λ = 320 nm). The RRF is calculated from the HPLC results of the standard solution using eq 1 and was determined to be 1.41. RRF = = / (1) 135 Determination of the concentration of released hydroxycoumarin cargo from polymers after ultrasound-induced mechanical activation. Aliquots were removed during ultrasonication experiments and 3-cyano-7-hydroxy-4-methylcoumarin (7.0 μM) was added as the internal standard. The solution was then kept at room temperature and analyzed by HPLC at various time intervals (HPLC conditions: 30:70 MeCN/water + 0.1% AcOH, 2 mL/min, λ = 320 nm). The concentration of hydroxycoumarin (analyte) in the solution was calculated using eq 2: concentration of analyte = ∗ ∗ concentration of IS (2) 136 Figure 3.19 Representative HPLC chromatograms for the analysis of mechanically triggered release of hydroxycoumarin 9 from PMA-OH containing a chain-centered mechanophore with a tethered alcohol. HPLC conditions: 30:70 MeCN/water + 0.1% AcOH, isocratic, 2 mL/min, λ = 320 nm. Table 3.1 Release of hydroxycoumarin payload from PMA-OH monitored by HPLCa a Sonication time (min) Payload peak area 0 20 40 60 80 100 120 1.1 11.1 18.0 22.4 26.6 29.8 31.9 Trial 1 IS Released peak payload, area calcd (μM) 10.8 0.503 9.3 5.89 9.4 9.45 9.3 11.9 9.4 14.0 9.6 15.3 9.3 16.9 Payload peak area 1.0 10.6 17.1 22.5 26.8 30.6 32.1 Each sample incubated at rt for 72 h prior to characterization Trial 2 IS Released peak payload, area calcd (μM) 11.3 0.437 10.0 5.23 9.5 8.88 9.7 11.4 9.6 13.8 9.3 16.2 8.9 17.8 Payload peak area 1.0 11.3 21.0 24.3 28.3 32.3 38.2 Trial 3 IS Released peak payload, area calcd (μM) 11.7 0.422 10.1 5.52 11.6 8.93 10.2 11.8 10.1 13.8 10.6 15.0 11.3 16.7 137 Table 3.2 Release of hydroxycoumarin payload from PMA-Me monitored by HPLC a a Sonication time (min) Payload peak area 0 20 40 60 80 100 120 2.3 5.7 9.1 11.2 12.9 14.6 17.1 Trial 1 IS Released peak payload, area calcd (μM) 9.8 1.16 7.7 3.65 8.1 5.54 7.8 7.09 7.9 8.06 7.3 9.87 8.7 9.70 Payload peak area 1.3 5.0 7.7 10.3 12.8 15.0 20.5 Trial 2 IS Released peak payload, area calcd (μM) 10 0.642 10.3 2.40 7.9 4.81 8.0 6.35 7.9 8.00 7.7 9.61 10.7 9.45 Payload peak area 1.5 5.4 8.0 10.2 13.0 13.7 18.7 Trial 3 IS Released peak payload, area calcd (μM) 10.6 0.698 9.4 2.83 10.5 3.76 8.1 6.21 8.8 7.29 8.7 7.77 10.3 8.96 Each sample incubated at rt for 120 h prior to characterization Table 3.3 Release of hydroxycoumarin payload from PMA-control monitored by HPLC a a Sonication time (min) Payload peak area 0 20 40 60 80 100 120 0 2.49 8.59 2.08 4.68 4.66 2.19 Trial 1 IS Released peak payload, area calcd (μM) 8.93 0 9.27 0.133 7.90 0.536 9.01 0.114 7.76 0.298 9.13 0.252 8.52 1.27 Payload peak area 0 0.677 0 1.69 1.08 1.25 1.45 Trial 2 IS Released peak payload, area calcd (μM) 9.00 0 9.72 0.344 10.1 0 9.10 0.092 9.37 0.566 8.72 0.708 9.65 0.740 Payload peak area 0.113 0.123 0.367 0.764 0.710 1.15 1.10 Trial 3 IS Released peak payload, area calcd (μM) 10.8 0.051 9.07 0.067 9.58 0.189 7.98 0.473 8.07 0.434 8.53 0.666 8.93 0.606 Each sample incubated at rt for 72 h prior to characterization Table 3.4 Release of hydroxycoumarin payload from PMA-OH after 120 min ultrasonication monitored by HPLC Time postsonication (h) Payload peak area 1 3 6 12 18 24 36 48 72 96 120 5.3 9.6 14.6 21.7 28.0 30.5 34.0 33.3 33.8 34.7 34.4 Trial 1 IS Released peak payload, area calcd (μM) 12.1 2.16 11.9 3.98 12.1 5.95 11.5 9.31 12.3 11.2 11.7 12.9 11.6 14.5 10.9 15.1 10.5 15.9 10.6 16.2 10.2 16.6 Payload peak area 5.0 9.9 15.5 22.0 26.9 31.3 32.8 31.7 33.2 35.8 34.8 Trial 2 IS Released peak payload, area calcd (μM) 12.0 2.06 11.6 4.21 11.5 6.65 13.4 8.10 11.6 11.4 11.1 13.9 10.6 15.3 9.9 15.8 10.1 16.2 10.9 16.2 10.5 16.4 Payload peak area 6.6 11.6 16.7 22.9 26.7 28.5 44.5 33.2 46.6 34.4 34.5 Trial 3 IS Released peak payload, area calcd (μM) 12.4 2.63 11.6 4.93 11.7 7.04 11.3 10.0 11.3 11.7 11.1 12.7 16.1 13.6 11.2 14.6 14.2 16.2 9.9 17.1 9.8 17.4 138 Table 3.5 Release of hydroxycoumarin payload from PMA-Me after 120 min ultrasonication monitored by HPLC Time postsonication (h) Payload peak area 1 3 6 12 18 24 36 48 72 96 120 4.6 6 6.3 10.4 8.7 9.8 11.7 13.3 16 17.3 17.1 Trial 1 IS Released peak payload, area calcd (μM) 12.3 1.85 13.2 2.24 11.7 2.66 15.3 3.35 11.3 3.80 11.1 4.36 10.3 5.61 9.9 6.63 10.5 7.52 10.4 8.21 8.70 9.70 Payload peak area 2.4 3.3 5 7 5.2 9.1 12.2 13.4 14 15 20.5 Trial 2 IS Released peak payload, area calcd (μM) 12.5 0.947 12.6 1.29 12.7 1.94 11.7 2.95 6.8 3.77 10.4 4.31 10.4 5.79 12.1 5.46 9.9 6.98 10.2 7.26 10.7 9.45 Payload peak area 3.5 4.5 5.5 7.1 8.4 10.2 11.5 14.1 18.0 15.6 18.7 Trial 3 IS Released peak payload, area calcd (μM) 11 1.57 10.9 2.04 11.2 2.42 11.2 3.13 11.0 3.77 10.7 4.70 10.5 5.40 11.4 6.10 12.5 7.11 10.4 7.40 10.3 8.96 Table 3.6 Release of hydroxycoumarin payload from PMA-control after 120 min ultrasonication monitored by HPLC Time postsonication (h) Payload peak area 1 3 6 12 18 24 36 48 72 96 120 0.523 1.40 0.246 1.53 1.04 0.468 0.886 0.821 1.32 1.37 1.07 Trial 1 IS Released peak payload, area calcd (μM) 12.1 0.213 11.5 0.597 9.80 0.124 11.8 0.639 10.7 0.480 10.0 0.231 9.95 0.439 9.52 0.425 9.49 0.686 12.0 0.561 11.5 0.459 Payload peak area 0.278 0.511 0.601 0.973 1.022 1.24 1.23 1.08 1.18 1.40 1.35 Trial 2 IS Released peak payload, area calcd (μM) 11.4 0.121 11.2 0.225 11.8 0.251 10.4 0.463 10.5 0.479 10.6 0.578 9.42 0.642 10.5 0.506 10.8 0.540 11.5 0.600 10.6 0.630 Payload peak area 0.682 1.06 1.13 1.06 1.47 0.886 1.38 1.53 1.10 1.04 1.85 Trial 3 IS Released peak payload, area calcd (μM) 11.8 0.285 11.3 0.463 11.3 0.491 10.3 0.507 10.7 0.677 10.1 0.432 9.40 0.724 10.1 0.748 10.8 0.503 10.1 0.508 9.39 0.972 139 3.4.5 DFT calculations CoGEF calculations. CoGEF calculations were performed using Spartan ′18 Parallel Suite according to previously reported methods. 36,37 Ground state energies were calculated using DFT at the B3LYP/6-31G* level of theory. Starting from the equilibrium geometry of the unconstrained molecule (relative energy = 0 kJ/mol), the distance between the terminal methyl groups of the truncated structure was increased in increments of 0.05 Å and the energy was minimized at each step. The maximum force associated with the retro-Diels–Alder reaction was calculated from the slope of the curve immediately prior to bond cleavage. Calculation of Activation Energies. Activation energies for model furfuryl carbonate compounds were calculated using Spartan ′18 Parallel Suite following our previous methods.20 All calculations were run with a solvent dielectric constant of 37.22. Equilibrium geometries and corresponding energies of each furfuryl carbonate or carbamate reactant were calculated at the M06-2X/6-311+G** level of theory with a fine integration grid (99,590). Transition state geometries were approximated using an initial energy profile at the HF/6-31+G* level of theory by lengthening the C‒O bond involved in the desired fragmentation reaction. The energy maximum from each profile was then chosen as the starting point for a transition state geometry optimization, which was conducted at the same level of theory. Subsequent geometry optimizations were performed at the M06-2X/6-311+G** level of theory and the optimized structures were subjected to a final energy and frequency calculation at the M06-2X/6-311+G** level of 140 theory using a fine integration grid (99,590). Each structure returned a single imaginary vibrational frequency corresponding to the expected bond-breaking mode. Optimized geometry coordinates determined for reactants: FC1 C C C C O C O C O O C C C H H H H H H H H H H H H 0.625870 -0.637531 -0.958334 0.141027 1.112139 0.489080 -0.676679 -0.838989 -1.929208 -0.120637 -2.251437 1.709154 1.534882 -1.267337 -1.876857 0.643752 -3.160018 -2.420655 -1.442508 1.532383 1.923473 2.572651 1.031381 1.814767 2.449632 0.060233 -0.421937 -0.466695 -0.011012 0.314046 0.196547 -0.235035 0.275808 -0.255985 1.085376 0.195065 -0.601630 0.347566 -0.711777 -0.792916 1.260760 -0.334074 1.270945 -0.055861 -1.666656 -0.420230 -0.292093 0.101527 1.403443 -0.245416 -3.079388 -2.982456 -1.578856 -0.934275 -1.827252 0.504506 1.232016 2.450477 2.982270 2.979217 4.308507 0.937563 -4.218350 -3.809040 -1.118582 0.698978 4.579274 4.304919 4.993306 0.776346 1.991323 0.347233 -5.152617 -4.238781 -4.146337 Gibbs free energy: -650.852643 hartrees FC2 C C C C O 0.681912 1.118496 0.924384 0.377291 0.221891 -3.279260 -3.184708 -1.817554 -1.189522 -2.062461 -0.070842 1.210410 1.614734 0.547284 -0.484780 141 C C C O C O O C C C O H H H H H H H H H H H H H H H H 0.608892 -0.029486 1.104177 -0.473257 -1.262991 -1.578488 -1.635465 -2.434362 1.366160 0.140190 -0.463559 1.527026 1.155431 0.998837 1.199438 -0.422764 -0.886162 0.841351 2.007171 -2.584174 -3.382537 -1.945968 1.696554 2.181588 0.438287 -0.598927 -0.890937 -4.390273 0.218496 1.076656 0.774845 1.839184 2.254522 2.342564 3.409968 0.813688 1.070049 2.334608 -3.991515 -1.369413 -5.300606 -4.162190 -4.568195 0.198319 2.129363 0.892345 3.602204 3.193465 4.256857 -0.218009 1.467104 1.076220 0.270531 2.312718 -1.053715 0.267593 -0.302322 1.523858 1.422291 2.634313 0.387201 2.692085 -1.786496 -2.664280 -2.411545 1.798614 2.568268 -0.599623 -1.944182 -1.365977 -0.409409 -0.170949 0.283948 3.750043 2.202326 2.212272 -1.944162 -2.107192 -3.713499 -2.542321 -1.543947 Gibbs free energy: -804.621845 hartrees Optimized geometry coordinates determined for transition states: FC1‡ C C C C O C O C O O C C 0.073604 -0.869568 -1.385115 -0.737277 0.160097 -0.847487 0.581266 0.270574 1.183177 -0.706692 0.929207 0.953177 -0.834324 -1.766528 -1.320899 -0.135217 0.143795 0.729874 -0.098879 0.178566 -0.316826 0.808274 -0.050229 -0.744765 -2.979311 -2.596366 -1.370519 -1.071603 -2.074375 0.015097 1.385189 2.584081 3.475021 2.988891 4.853305 -4.165913 142 C H H H H H H H H H H H H -0.295783 -1.136816 -2.143208 -1.637803 0.920061 1.743875 -0.023924 0.772576 0.756368 2.000866 0.661026 -0.210336 -1.011866 2.103570 -2.651513 -1.784077 0.502012 1.023505 -0.518718 -0.480650 -1.593836 0.182168 -0.742062 2.146153 2.493176 2.727429 -0.005012 -3.151222 -0.755986 0.720133 5.044726 5.401374 5.162460 -4.822418 -4.709369 -3.856617 -0.523101 1.006863 -0.555329 Gibbs free energy: -650.817542 hartrees FC2‡ C C C C O C C C O C O O C C C O H H H H H H H H H H H H 1.119523 -0.202107 -0.926940 -0.012958 1.242541 2.355076 -0.178387 0.858802 -0.061072 -0.656860 -0.673044 -1.191153 -1.313211 0.498253 -0.807079 -0.823774 -0.574442 -1.990818 2.113460 3.057405 2.836125 -1.209925 0.901775 1.837352 -1.222959 -2.364373 -0.817155 0.429613 -3.362485 -3.685325 -2.492753 -1.504728 -2.061892 -4.177092 -0.138613 0.679563 0.689892 1.808986 2.341800 2.416344 3.612103 0.853330 1.616522 2.869974 -4.668386 -2.340475 -5.210479 -3.787195 -4.136221 0.190370 1.666073 0.211029 3.872516 3.546177 4.362235 -0.120639 0.226211 0.457523 0.314258 -0.005767 -0.051461 0.231569 -0.242889 -0.931535 1.673383 1.713124 2.962015 0.777551 3.102388 -2.421835 -2.641026 -1.975381 0.696753 0.421184 0.472375 0.971805 -0.748268 -0.293890 -0.470351 -0.831800 4.154407 2.821080 2.486153 -2.915540 143 H H H H 1.319464 -0.923703 -1.667688 -0.951741 1.402455 1.820781 1.012168 2.713963 -2.889259 -3.706725 -2.331623 -1.024427 Gibbs free energy: -804.592990 hartrees 3.5 References (1) Ghanem, M. A.; Basu, A.; Behrou, R.; Boechler, N.; Boydston, A. J.; Craig, S. L.; Lin, Y.; Lynde, B. E.; Nelson, A.; Shen, H.; Storti, D. W. The role of polymer mechanochemistry in responsive materials and additive manufacturing. Nat Rev Mater 2021, 6, 84–98. (2) Zhang, Y.; Yu, J.; Bomba, H. N.; Zhu, Y.; Gu, Z. Mechanical Force-Triggered Drug Delivery. Chem. Rev. 2016, 116, 12536–12563. (3) Davis, D. A.; Hamilton, A.; Yang, J.; Cremar, L. D.; Van Gough, D.; Potisek, S. L.; Ong, M. T.; Braun, P. V.; Martínez, T. J.; White, S. R.; Moore, J. S.; Sottos, N. R. Force-induced activation of covalent bonds in mechanoresponsive polymeric materials. Nature 2009, 459, 68–72. (4) Kim, G.; Lau, V. M.; Halmes, A. J.; Oelze, M. L.; Moore, J. S.; Li, K. C. Highintensity focused ultrasound-induced mechanochemical transduction in synthetic elastomers. Proc. Natl. Acad. Sci. USA 2019, 116, 10214–10222. (5) Kim, G.; Wu, Q.; Chu, J. L.; Smith, E. J.; Oelze, M. L.; Moore, J. S.; Li, K. C. Ultrasound controlled mechanophore activation in hydrogels for cancer therapy. Proc. Natl. Acad. Sci. U.S.A. 2022, 119, e2109791119. 144 (6) Berkowski, K. L.; Potisek, S. L.; Hickenboth, C. R.; Moore, J. S. UltrasoundInduced Site-Specific Cleavage of Azo-Functionalized Poly(ethylene glycol). Macromolecules 2005, 38, 8975–8978. (7) Beyer, M. K.; Clausen-Schaumann, H. Mechanochemistry: The Mechanical Activation of Covalent Bonds. Chem. Rev. 2005, 105, 2921–2948. (8) Caruso, M. M.; Davis, D. A.; Shen, Q.; Odom, S. A.; Sottos, N. R.; White, S. R.; Moore, J. S. Mechanically-Induced Chemical Changes in Polymeric Materials. Chem. Rev. 2009, 109, 5755–5798. (9) Li, J.; Nagamani, C.; Moore, J. S. Polymer Mechanochemistry: From Destructive to Productive. Acc. Chem. Res. 2015, 48, 2181–2190. (10) Versaw, B. A.; Zeng, T.; Hu, X.; Robb, M. J. Harnessing the Power of Force: Development of Mechanophores for Molecular Release. J. Am. Chem. Soc. 2021, 143, 21461–21473. (11) Lin, Y.; Kouznetsova, T. B.; Craig, S. L. A Latent Mechanoacid for Time-Stamped Mechanochromism and Chemical Signaling in Polymeric Materials. J. Am. Chem. Soc. 2020, 142, 99–103. (12) Diesendruck, C. E.; Steinberg, B. D.; Sugai, N.; Silberstein, M. N.; Sottos, N. R.; White, S. R.; Braun, P. V.; Moore, J. S. Proton-Coupled Mechanochemical Transduction: A Mechanogenerated Acid. J. Am. Chem. Soc. 2012, 134, 12446– 12449. (13) Sun, Y.; Neary, W. J.; Burke, Z. P.; Qian, H.; Zhu, L.; Moore, J. S. Mechanically Triggered Carbon Monoxide Release with Turn-On Aggregation-Induced Emission. J. Am. Chem. Soc. 2022, 144, 1125–1129. 145 (14) Larsen, M. B.; Boydston, A. J. “Flex-Activated” Mechanophores: Using Polymer Mechanochemistry To Direct Bond Bending Activation. J. Am. Chem. Soc. 2013, 135, 8189–8192. (15) Shen, H.; Larsen, M. B.; Roessler, A.; Zimmerman, P.; Boydston, A. J. Mechanochemical Release of N-heterocyclic Carbenes from Flex-Activated Mechanophores. Angew. Chem. Int. Ed. 2021, 60, 13559–13563. (16) Nijem, S.; Song, Y.; Schwarz, R.; Diesendruck, C. E. Flex-activated CO Mechanochemical Production for Mechanical Damage Detection. Polym. Chem. 2022, DOI: 10.1039/D2PY00503D. (17) Huo, S.; Zhao, P.; Shi, Z.; Zou, M.; Yang, X.; Warszawik, E.; Loznik, M.; Göstl, R.; Herrmann, A. Mechanochemical bond scission for the activation of drugs. Nat. Chem. 2021, 13, 131–139. (18) Shi, Z.; Song, Q.; Göstl, R.; Herrmann, A. Mechanochemical activation of disulfidebased multifunctional polymers for theranostic drug release. Chem. Sci. 2021, 12, 1668–1674. (19) Shi, Z.; Song, Q.; G, östl R.; Herrmann, A. The Mechanochemical Release of Naphthalimide Fluorophores from β-Carbonate and β-Carbamate DisulfideCentered Polymers. CCS Chemistry 2021, 3, 2333–2344. (20) Hu, X.; Zeng, T.; Husic, C. C.; Robb, M. J. Mechanically Triggered Small Molecule Release from a Masked Furfuryl Carbonate. J. Am. Chem. Soc. 2019, 141, 15018– 15023. 146 (21) Fan, B.; Trant, J. F.; Hemery, G.; Sandre, O.; Gillies, E. R. Thermo-responsive selfimmolative nanoassemblies: direct and indirect triggering. Chem. Commun. 2017, 53, 12068–12071. (22) Taimoory, S. M.; Sadraei, S. I.; Fayoumi, R. A.; Nasri, S.; Revington, M.; Trant, J. F. Preparation and Characterization of a Small Library of Thermally-Labile EndCaps for Variable-Temperature Triggering of Self-Immolative Polymers. J. Org. Chem. 2018, 83, 4427–4440. (23) Hu, X.; Zeng, T.; Husic, C. C.; Robb, M. J. Mechanically Triggered Release of Functionally Diverse Molecular Payloads from Masked 2-Furylcarbinol Derivatives. ACS Cent. Sci. 2021, 7, 1216–1224. (24) Zeng, T.; Hu, X.; Robb, M. J. 5-Aryloxy substitution enables efficient mechanically triggered release from a synthetically accessible masked 2-furylcarbinol mechanophore. Chem. Commun. 2021, 57, 11173–11176. (25) Nichol, M. F.; Clark, K. D.; Dolinski, N. D.; Alaniz, J. R. de. Multi-stimuli responsive trigger for temporally controlled depolymerization of self-immolative polymers. Polym. Chem. 2019, 10, 4914–4919. (26) Beyer, M. K. The mechanical strength of a covalent bond calculated by density functional theory. J. Chem. Phys. 2000, 112, 7307–7312. (27) Klein, I. M.; Husic, C. C.; Kovács, D. P.; Choquette, N. J.; Robb, M. J. Validation of the CoGEF Method as a Predictive Tool for Polymer Mechanochemistry. J. Am. Chem. Soc. 2020, 142, 16364–16381. (28) Stevenson, R.; De Bo, G. Controlling Reactivity by Geometry in Retro-Diels–Alder Reactions under Tension. J. Am. Chem. Soc. 2017, 139, 16768–16771. 147 (29) Zheng, X.-A.; Kong, R.; Huang, H.-S.; Wei, J.-Y.; Chen, J.-Z.; Gong, S.-S.; Sun, Q. Hafnium Triflate as a Highly Potent Catalyst for Regio- and ChemoselectiveDeprotection of Silyl Ethers. Synthesis 2019, 51, 944–952. (30) May, P. A.; Moore, J. S. Polymer mechanochemistry: techniques to generate molecular force via elongational flows. Chem. Soc. Rev. 2013, 42, 7497–7506. (31) Nguyen, N. H.; Rosen, B. M.; Lligadas, G.; Percec, V. Surface-Dependent Kinetics of Cu(0)-Wire-Catalyzed Single-Electron Transfer Living Radical Polymerization of Methyl Acrylate in DMSO at 25 °C. Macromolecules 2009, 42, 2379–2386. (32) Bunce, R. A.; Hertzler, D. V. A selective method for oxygen deprotection in bistrimethylsilylated terminal alkynols. J. Org. Chem. 1986, 51, 3451–3453. (33) Asano, K.; Matsubara, S. Asymmetric Catalytic Cycloetherification Mediated by Bifunctional Organocatalysts. J. Am. Chem. Soc. 2011, 133, 16711–16713. (34) Heo, Y.; Sodano, H. A. Self-Healing Polyurethanes with Shape Recovery. Advanced Functional Materials 2014, 24, 5261–5268. (35) Deng, G.; Chen, Y. A Novel Way To Synthesize Star Polymers in One Pot by ATRP of N -[2-(2-Bromoisobutyryloxy)ethyl]maleimide and Styrene. Macromolecules 2004, 37, 18–26. (36) Beyer, M. K. The mechanical strength of a covalent bond calculated by density functional theory. J. Chem. Phys. 2000, 112, 7307–7312. (37) Klein, I. M.; Husic, C. C.; Kovács, D. P.; Choquette, N. J.; Robb, M. J. Validation of the CoGEF Method as a Predictive Tool for Polymer Mechanochemistry. J. Am. Chem. Soc. 2020, 142, 16364–16381. 148 Appendix A SUMMARIES OF INDIVIDUAL CoGEF CALCULATIONS PRESENTED IN CHAPTER 1 A summary of the results of each individual CoGEF calculation from Chapter 1 is presented on the pages below. All calculations were performed using DFT at the B3LYP/631G* level of theory in vacuum, unless specified otherwise. A reaction scheme depicts the structure of the truncated molecule and the product(s) predicted from the CoGEF calculation. Atoms colored blue indicate the anchor positions (i.e., pulling points) for defining the distance constraint and bonds that are predicted to cleave are colored red. Representative images of computed structures at critical points in the CoGEF profile are included that depict the force-free equilibrium geometry as well as the structure(s) immediately before and after bond cleavage events. The length of the distance constraint is included below each computed structure and the corresponding positions on the CoGEF curve are denoted. Electrostatic potential maps are included for the products predicted by CoGEF calculations in the heterolytic category. The calculated values of Fmax, Emax, and force–bond angle are tabulated for each calculation. Note that the former bonds persist as artifacts in Spartan after a reaction is predicted to occur. For references to the primary literature describing the experimental reactivity of each compound, refer to the tables in Chapter 1. 149 O O H 3C H H CoGEF O O O O CH 3 O O O + O O O O O H 3C O CH 3 O 1 Compound 1 (ii) (i) Equilibrium Geometry 13.344 Å (ii) Immediately Prior to Bond Cleavage (iii) (i) 20.294 Å (iii) Immediately After Bond Cleavage Summary of CoGEF Results Fmax 4.6 nN Emax 460 kJ/mol Force-Bond Angle 4° 20.344 Å 150 O O H 3C H H O O CoGEF O O O CH3 O H 3C O O + O O O O 2 O CH 3 O Compound 2 (ii) (i) Equilibrium Geometry 16.382 Å (ii) Immediately Prior to Bond Cleavage (iii) 21.232 Å (i) (iii) Immediately After Bond Cleavage Summary of CoGEF Results Fmax 5.9 nN Emax 746 kJ/mol Force-Bond Angle 25° 21.282 Å 151 O O H 3C N H O O O O O CH 3 CoGEF O H 3C O N O + O O O O 3 O CH 3 O Compound 3 (i) Equilibrium Geometry (ii) 14.479 Å (ii) Immediately Prior to Bond Cleavage (iii) (i) 19.979 Å (iii) Immediately After Bond Cleavage 20.029 Å Summary of CoGEF Results Fmax 4.0 nN Emax 335 kJ/mol Force-Bond Angle 7.1° 152 O H 3C O N H O O O O O CH 3 CoGEF O O H 3C O O N O + O O 4 O CH 3 O Compound 4 (ii) (i) Equilibrium Geometry 16.271 Å (ii) Immediately Prior to Bond Cleavage (iii) (i) 20.321 Å (iii) Immediately After Bond Cleavage Summary of CoGEF Results Fmax 4.8 nN Emax 426 kJ/mol Force-Bond Angle 20° 20.371 Å 153 O H3C O N N O O O O O CH3 CoGEF O H 3C O 5 O O N + N O O O O (i) Equilibrium Geometry 13.303 Å (ii) Immediately Prior to Bond Cleavage (iii) (i) 19.553 Å (iii) Immediately After Bond Cleavage Summary of CoGEF Results 3.4 nN Emax 285 kJ/mol Force-Bond angle 7.3° CH 3 Compound 5 (ii) Fmax O 19.603 Å 154 O H 3C O N N O O O O O CH 3 O CoGEF H 3C O 6 O N O + N O O O (ii) (i) Equilibrium Geometry 14.667 Å (i) (ii) Immediately Prior to First Bond Cleavage (v) 20.417 Å (iii) Immediately After First Bond Cleavage Summary of CoGEF Results Fmax 5.0 nN Emax 444 kJ/mol Force-Bond Angle CH 3 O (iv) (iii) O Compound 6 20.467 Å (iv) Immediately Prior to Second Bond Cleavage 27° 20.817 (iv) Immediately After Second Bond Cleavage 20.867 Å 155 O CoGEF H 3C O H H 7 O O O O O H3C H H CH 3 CH 3 O O O Compound 7 (i) Equilibrium Geometry (iv) (ii) 6.295 Å (iii) (ii) Immediately Prior to First Bond Cleavage (v) (i) 10.045 Å (iii) Immediately After First Bond Cleavage Summary of CoGEF Results Fmax 4.5 nN Emax 413 kJ/mol Force-Bond Angle 4.3° 10.095 Å (iv) Immediately Before Second Bond Cleavage 10.645 Å (v) Immediately After Second Bond Cleavage 10.695 Å 156 O O O H3C O O O CH 3 H H MeO CoGEF H H 8 O CH3 H 3C + O OMe O O O MeO MeO O Compound 8 (i) Equilibrium Geometry (ii) (iv) 14.256 Å (iii) (i) (ii) Immediately Prior to First Bond Cleavage (v) 19.006 Å (iii) Immediately After First Bond Cleavage Summary of CoGEF Results Fmax 5.0 nN Emax 417 kJ/mol Force-Bond Angle 30° 19.056 Å (iv) Immediately Prior to Second Bond Cleavage 20.106 (v) Immediately After Second Bond Cleavage 20.156 Å 157 O O O O H3C O CH 3 H H MeO H 3C O O CoGEF O CH3 MeO O + OMe O H H 9 O O OMe Compound 9 (i) Equilibrium Geometry (ii) 10.962 Å (ii) Immediately Prior to First Bond Cleavage (iii) (i) 18.162 Å (iii) Immediately After First Bond Cleavage Summary of CoGEF Results Fmax 2.5 nN Emax 253 kJ/mol Force-Bond Angle 6.9° 18.212 Å 158 O H 3C H H N H O O N H CH 3 CoGEF H 3C N H O H 3C + N H H H MeO MeO 10 OMe OMe Compound 10 (i) Equilibrium Geometry (ii) 5.759 Å (ii) Immediately Prior to First Bond Cleavage (iii) (i) Summary of CoGEF Results Fmax 4.4 nN Emax 364 kJ/mol Force-Bond Angle 10.259 Å (iii) Immediately After First Bond Cleavage 2.7° 10.309 Å 159 O H 3C H H O O O O H CH 3 H3C CoGEF H3C O O O H H Cl Cl H3C O CH 3 CoGEF O H O O Cl Cl Cl Cl Compound 11 11 (ii) (i) Equilibrium Geometry (iv) 9.485 Å (ii) Immediately Prior to First Bond Cleavage (i) (iii) (v) 12.885 Å (iii) Immediately After First Bond Cleavage Summary of CoGEF Results cyclobutane gDCC Fmax 4.7 nN 3.8 nN Emax 395 kJ/mol 291 kJ/mol 12.935 Å Force-Bond Angle 2.1° 0.4° (iv) Immediately Before Second Bond Cleavage 22.885 Å (v) Immediately After Second Bond Cleavage 22.935 Å 160 HN H H H 3C CH3 O H N O HN CoGEF + CH3 O O HN CH3 H H 12 Compound 12 (i) Equilibrium Geometry (ii) (iii) 7.497 Å (ii) Immediately Prior to Bond Cleavage (i) 11.397 Å (iii) Immediately After Bond Cleavage Summary of CoGEF Results Fmax 5.9 nN Emax 498 kJ/mol Force-Bond Angle 44° 11.5447 Å 161 H 3C NH HN H H CH 3 O O H 3C CoGEF O NH HN + CH 3 O H H Compound 12' 12' (ii) (i) Equilibrium Geometry 7.519 Å (ii) Immediately Prior to Bond Cleavage (iii) (i) 10.319 Å Summary of CoGEF Results Fmax 4.4 nN Emax 359 kJ/mol Force-Bond Angle (iii) Immediately After Bond Cleavage 2.2° 10.369 Å 162 O O H H O O CH 3 CoGEF O H3C H H O O 2 O O 13 (ii) CH3 (i) Equilibrium Geometry 7.484 Å (ii) Immediately Prior to First Bond Cleavage (iii) 17.484 Å (i) (iii) Immediately After First Bond Cleavage Summary of CoGEF Results Fmax 6.3 nN Emax 658 kJ/mol Force-Bond Angle 28° 17.534 Å Compound 13 163 O H H O O O O O CoGEF 2 H3C H H O 14 O CH3 O (iv) CH3 (i) Equilibrium Geometry 13.066 Å (ii) (ii) Immediately Prior to First Bond Cleavage (iii) (i) (v) 15.866 Å (iii) Immediately After First Bond Cleavage Summary of CoGEF Results Fmax 5.6 nN Emax 633 kJ/mol Force-Bond Angle 15.916 Å (iv) Immediately Before Second Bond Cleavage 26° 18.216 Å (v) Immediately After Second Bond Cleavage 18.266 Å Compound 14 164 O H H O O H3 C O O O CoGEF O 15 O CH 3 MeMe O O O O O CH3 H3C O O + H 3C O O O (iv) (i) Compound 15 (i) Equilibrium Geometry (ii) Immediately Prior to First Bond Cleavage (iii) (v) 25.907 Å (iii) Immediately After First Bond Cleavage Summary of CoGEF Results Fmax 5.9 nN Emax 1017 kJ/mol Force-Bond Angle CH 3 O 20.607 Å (ii) O 25.957 Å (iv) Immediately Before Second Bond Cleavage 29° 29.407 Å (v) Immediately After Second Bond Cleavage 29.457 Å 165 CH 3 H3C CH 3 H H H CoGEF H H 3C 16 Compound 16 (i) Equilibrium Geometry (ii) Immediately Prior to First Bond Cleavage (iii) Immediately After First Bond Cleavage 6.366 Å 10.066 Å 10.116 Å (v) Immediately Prior to Second Bond Cleavage (vi) Immediately After Second Bond Cleavage 12.216 Å 12.266 Å (iv) Summary of CoGEF Results (ii) Fmax 3.3 nN Emax 244 kJ/mol Force-Bond Angle (iii) (i) (v) 0.0° 166 CH3 H3C CH3 H H H CoGEF H H3C NMe2 NMe2 17 Compound 17 (i) Equilibrium Geometry (ii) Immediately Prior to First Bond Cleavage (iii) Immediately After First Bond Cleavage 6.351 Å 10.051 Å 10.101 Å (v) Immediately Prior to Second Bond Cleavage (vi) Immediately After Second Bond Cleavage 11.351 Å 11.401 Å (iv) (ii) Summary of CoGEF Results (iii) Fmax 3.3 nN Emax 241 kJ/mol Force-Bond Angle (i) (v) 1.0° 167 CH3 H3C CH3 H H H CoGEF H H3C O N Me O O N Me O Compound 18 18 (i) Equilibrium Geometry (ii) Immediately Prior to First Bond Cleavage (iii) Immediately After First Bond Cleavage 6.319 Å 10.069 Å 10.119 Å (v) Immediately Prior to Second Bond Cleavage (vi) Immediately After Second Bond Cleavage 12.569 Å 12.619 Å (iv) (ii) Summary of CoGEF Results (iii) (i) Fmax 3.3 nN Emax 244 kJ/mol Force-Bond Angle (v) 0.2° 168 CH 3 H3C CH 3 H H H CoGEF H H 3C OMe OMe OMe OMe 19 Compound 19 (i) Equilibrium Geometry (ii) Immediately Prior to First Bond Cleavage (iii) Immediately After First Bond Cleavage 6.325 Å 10.025 Å 10.075 Å (v) Immediately Prior to Second Bond Cleavage (vi) Immediately After Second Bond Cleavage 11.325 Å 11.375 Å (iv) (ii) Summary of CoGEF Results (iii) (i) (v) Fmax 3.3 nN Emax 236 kJ/mol Force-Bond Angle 1.2° 169 O H O H3C H H O O H 20 O CoGEF O O O O CH 3 H 3C O O O CH3 Compound 20 (ii) (i) Equilibrium Geometry 18.900 Å (i) Immediately Prior to Bond Cleavage (iii) (i) Summary of CoGEF Results Fmax 5.5 nN Emax 692 kJ/mol Force-Bond Angle 22.550 Å (iii) Immediately After Bond Cleavage 16° 22.600 Å 170 O H3C O O H H O O O O H H CH 3 CoGEF O H3C O O O O O O O CH3 O 21 Compound 21 (ii) (i) Equilibrium Geometry (iii) 4.462 Å (ii) Immediately Prior to First Bond Cleavage (i) (iv) 20.662 Å (iii) Immediately After First Bond Cleavage Summary of CoGEF Results Fmax 5.2 nN Emax 562 kJ/mol Force-Bond Angle 17° 20.712 Å (iv) Immediately After Second Bond Cleavage 20.762 Å 171 O H 3C O O H H O O O O O H H CH 3 CoGEF O O H3C O O O O O O 22 (ii) Compound 22 (i) Equilibrium Geometry 13.678 Å (ii) Immediately Prior to Bond Cleavage (iii) (i) 20.328 Å (iii) Immediately After Bond Cleavage Summary of CoGEF Results Fmax 4.6 nN Emax 469 kJ/mol Force-Bond Angle CH 3 4.9° 20.378 Å 172 O H3C O Br Br O O Br O H O O H O CH 3 CoGEF O O O H 3C O O Br O CH3 O O 23 (i) Equilibrium Geometry Compound 23 (ii) 12.604 Å (ii) Immediately Prior to First Bond Cleavage (iii) (i) Summary of CoGEF Results Fmax 3.6 nN Emax 332 kJ/mol Force-Bond Angle 19.654 Å (iii) Immediately After First Bond Cleavage 6.2° 19.704 Å 173 O O H 3C N H O O H O O O H O CH 3 CoGEF O O O H 3C O N O O CH3 O O 24 Compound 24 (i) Equilibrium Geometry (ii) 15.909 Å (ii) Immediately Prior to Bond Cleavage (iii) (i) 19.909 Å (iii) Immediately After Bond Cleavage Summary of CoGEF Results Fmax 4.0 nN Emax 313 kJ/mol Force-Bond Angle 8.5° 20.009 Å 174 O O H3C OMe CH3 H H OMe CoGEF H3C H 3C 25 Compound 25 (i) Equilibrium Geometry (iv) (ii) (iii) 3.052 Å (ii) Immediately Prior to First Bond Cleavage (v) (i) 4.902 Å (iii) Immediately After First Bond Cleavage Summary of CoGEF Results Fmax 3.8 nN Emax 302 kJ/mol Force-Bond Angle 7.1° 4.952 Å (iv) Immediately Prior to Second Bond Cleavage 5.552 Å (v) Immediately After Second Bond Cleavage 5.602 Å 175 O H 3C OMe CH 3 H H CoGEF CH 3 CH3 OMe O Compound 26 26 (i) Equilibrium Geometry (ii) 3.057 Å (ii) Immediately Prior to Bond Cleavage (iii) (i) 5.457 Å (iii) Immediately After Bond Cleavage Summary of CoGEF Results Fmax 3.5 nN Emax 278 kJ/mol Force-Bond Angle 3.1° 5.507 Å 176 O H3C OMe CH3 H H CH 3 CoGEF H 3C OMe O Compound 27 27 (iv) (i) Equilibrium Geometry (ii) 3.051 Å (iii) (ii) Immediately Prior to First Bond Cleavage (v) (i) 4.901 Å (iii) Immediately After First Bond Cleavage Summary of CoGEF Results Fmax 3.7 nN Emax 306 kJ/mol Force-Bond Angle 7.3° 4.951 Å (iv) Immediately Prior to Second Bond Cleavage 5.551 Å (v) Immediately After Second Bond Cleavage 5.601 Å 177 O H3C H H O O O H CH3 CoGEF O H O O CH3 O CH3 O O Me Me O O Me Me 28 Compound 28 (i) Equilibrium Geometry (ii) 6.476 Å (iii) (ii) Immediately Prior to Bond Cleavage (i) 10.026 Å Summary of CoGEF Results Fmax 4.4 nN Emax 345 kJ/mol Force-Bond Angle (iii) Immediately After Bond Cleavage 4.6 ° 10.076 Å 178 H 3C CH3 H H O CoGEF O CH3 O 29 CH3 O Compound 29 (i) Equilibrium Geometry (iv) (ii) 3.769 Å (ii) Immediately Prior to First Bond Cleavage (iii) (v) 5.119 Å (i) (iii) Immediately After First Bond Cleavage Summary of CoGEF Results Fmax 5.4 nN Emax 331 kJ/mol Force-Bond Angle 5.169 Å (iv) Immediately Prior to Second Bond Cleavage 24° 5.719 Å (v) Immediately After Second Bond Cleavage 5.769 Å 179 O N H3C O H O 30 O N CoGEF + O CH3 H3 C O O C O CH3 O O Compound 30 (ii) (i) Equilibrium Geometry (iii) 11.759 Å (ii) Immediately Prior to Bond Cleavage (i) 15.359 Å Summary of CoGEF Results Fmax 3.5 nN Emax 284 kJ/mol Force-Bond Angle (iii) Immediately After Bond Cleavage 9.3° 15.409 Å 180 O Ph H 3C O O O C Ph N N CoGEF O 31 O O N H3C CH3 O Ph + Ph N O O Compound 31 (ii) (i) Equilibrium Geometry (i) (iii) 14.018 Å (ii) Immediately Prior to Bond Cleavage Summary of CoGEF Results 3.6 nN Emax 260 kJ/mol Force-Bond Angle CH3 O O O Fmax O 25.418 Å (iii) Immediately After Bond Cleavage 34° 25.468 Å 181 O H 3C O O CH3 O O CoGEF H 3C O O O O O O O 32 Compound 32 (ii) (i) Equilibrium Geometry (i) 18.153 Å (iii) (ii) Immediately Prior to Bond Cleavage Summary of CoGEF Results Fmax 4.4 nN Emax 495 kJ/mol Force-Bond Angle 15° 24.203 Å (iii) Immediately After Bond Cleavage 24.253 Å 182 O H 3C O Me Me O Con1 O C O C Me CoGEF O CH3 Me + O CH3 O H3C Compound Con1 (ii) (i) Equilibrium Geometry (iii) 18.385 Å (ii) Immediately Prior to Bond Cleavage (i) 24.235 Å (iii) Immediately After Bond Cleavage Summary of CoGEF Results Fmax 6.3 nN Emax 947 kJ/mol Force-Bond Angle 43° 24.305 Å 183 O O Me Me O Con2 H 3C O C Me CoGEF O CH 3 O C Me + O H 3C O CH 3 (ii) (i) Equilibrium Geometry (iii) 19.350 Å (ii) Immediately Prior to Bond Cleavage (i) 24.200 Å (iii) Immediately After Bond Cleavage Summary of CoGEF Results Fmax 6.4 nN Emax 959 kJ/mol Force-Bond Angle 42° 24.250 Å Compound 184 O O O O H 3C O 33 CH 3 CoGEF O O O O O + O O CH3 H3C Compound 33 (ii) (i) Equilibrium Geometry (iii) 12.509 Å (ii) Immediately Prior to Bond Cleavage (i) 16.109 Å (iii) Immediately After Bond Cleavage Summary of CoGEF Results Fmax 6.2 nN Emax 676 kJ/mol Force-Bond Angle 78° 16.159 Å 185 O H 3C O O Ph N O O O CH3 N N CoGEF N N Ph N + O O 34 O O O CH3 CH3 Compound 34 O (ii) (i) Equilibrium Geometry (iii) 15.358 Å (ii) Immediately Prior to Bond Cleavage (i) 20.008 Å (iii) Immediately After Bond Cleavage Summary of CoGEF Results Fmax 6.0 nN Emax 693 kJ/mol Force-Bond Angle 85° 20.058 Å 186 O O CH3 O CoGEF O O O O H3C O O + O 3 O2 CH3 35 H 3C Compound 35 (ii) (i) Equilibrium Geometry (iii) 19.243 Å (ii) Immediately Prior to Bond Cleavage (i) Summary of CoGEF Results Fmax 5.8 nN Emax 736 kJ/mol Force-Bond Angle 66° 24.193 Å (iii) Immediately After Bond Cleavage 24.243 Å 187 H3C S O O O N O CH 3 O S Me S O O CoGEF H3C S 36 N O Me + S Compound 36 (i) Equilibrium Geometry 13.209 Å (iii) (ii) Immediately Prior to Bond Cleavage (i) 26.959 Å (iii) Immediately After Bond Cleavage Summary of CoGEF Results Emax 295 kJ/mol Force-Bond Angle S N (ii) 2.9 nN S Me N Fmax CH3 S 32° 27.009 Å Me 188 H 3C O N N N CoGEF 37 O O H N H3 C O N3 + O H N O CH 3 CH 3 Compound 37 (ii) (i) Equilibrium Geometry (iii) 15.627 Å (ii) Immediately Prior to Bond Cleavage (i) 19.777 Å (iii) Immediately After Bond Cleavage Summary of CoGEF Results Fmax 6.5 nN Emax 772 kJ/mol Force/Bond angle 8.9° 19.827 Å 189 CH3 O O N O O O CoGEF O CH3 O O + O H 3C CH3 O N O O 38 Compound 38 (i) Equilibrium Geometry (ii) 10.918 Å (iii) (ii) Immediately Prior to Bond Cleavage (i) Summary of CoGEF Results Fmax 4.1 nN Emax 306 kJ/mol Force/Bond angle 14.668Å (iii) Immediately After Bond Cleavage 25° 14.718 Å 190 O CH 3 O O N O CoGEF O O + O H 3C H 3C O 39 N O O O (ii) Compound 39 (i) Equilibrium Geometry 14.542 Å (ii) Immediately Prior to Bond Cleavage (iii) (i) Summary of CoGEF Results Fmax 4.0 nN Emax 372 kJ/mol Force-Bond Angle 26° CH3 O 21.842 Å (iii) Immediately After Bond Cleavage 21.892 Å 191 O CH3 H O O H 3C O O CH 3 O H3 C N O O CoGEF O O O + N H O O O Compound 40 40 (ii) (i) Equilibrium Geometry 13.422 Å (ii) Immediately Prior to Bond Cleavage (iii) (i) 15.922 Å Summary of CoGEF Results Fmax 3.9 nN Emax 230 kJ/mol Force-Bond Angle (iii) Immediately After Bond Cleavage 26° 15.972 Å 192 O H3C H 3C O H O O O O CH 3 O CoGEF N H3C O + N O H O O O O 41 O Compound 41 (i) Equilibrium Geometry (ii) 10.731 Å (ii) Immediately Prior to Bond Cleavage (iii) (i) 17.381 Å (iii) Immediately After Bond Cleavage Summary of CoGEF Results Fmax 4.8 nN Emax 504 kJ/mol Force-Bond Angle 6.8° 17.431 Å 193 O CH3 O H 3C O O H O CH 3 O CoGEF O H3 C N O O O O + N H O O O 42 Compound 42 (ii) (i) Equilibrium Geometry (iii) 12.433 Å (i) (ii) Immediately Prior to Bond Cleavage 15.933Å (iii) Immediately After Bond Cleavage Summary of CoGEF Results Fmax 4.1 nN Emax 285 kJ/mol Force-Bond Angle 22° 15.983 Å 194 O CH 3 O H O O N O O CH3 CoGEF H 3C O H3C O O O + O N O O H O 43 Compound 43 (i) Equilibrium Geometry (ii) 11.874 Å (ii) Immediately Prior to Bond Cleavage (iii) 14.474 Å (i) (iii) Immediately After Bond Cleavage Summary of CoGEF Results Fmax 4.0 nN Emax 264 kJ/mol Force-Bond Angle 21° 14.524 Å 195 O CH3 H3 C O O H O O O Me O O CoGEF H3 C N H O O O CH3 O O Me O O + O O CH3 N O O 44 O CH3 Compound 44 (i) Equilibrium Geometry (ii) 13.491 Å (ii) Immediately Prior to Bond Cleavage (iii) (i) 15.991 Å Summary of CoGEF Results Fmax 4.0 nN Emax 245 kJ/mol Force-Bond Angle (iii) Immediately After Bond Cleavage 26° 16.041 Å 196 CH3 O O CH3 O F O N H CoGEF O F H O O O N + O O CH3 O Compound 45 O CH3 45 (ii) (i) Equilibrium Geometry 11.583 Å (ii) Immediately Prior to Bond Cleavage (iii) (i) 16.383 Å (iii) Immediately After Bond Cleavage Summary of CoGEF Results Fmax 3.8 nN Emax 284 kJ/mol Force-Bond Angle 21° 16.433 Å 197 O O O O H N O O O CoGEF O Me H Me N S S O CH 3 S + H3 C H 3C O Me Me S O H3 C O 46 (ii) Compound 46 (i) Equilibrium Geometry (iii) 17.075 Å (ii) Immediately Prior to Bond Cleavage (i) Summary of CoGEF Results Fmax 4.6 nN Emax 396 kJ/mol Force-Bond Angle 20.325 Å (iii) Immediately After Bond Cleavage 26° 20.375 Å 198 O H 3C O O N O H F F F H F O F F Me O S O F F F O H 3C F O O CoGEF + Me N O O O Me CH3 F S F Me O CH3 47 Compound 47 (i) Equilibrium Geometry (ii) 12.087 Å (ii) Immediately Prior to Bond Cleavage (iii) (i) Summary of CoGEF Results Fmax 3.9 nN Emax 243 kJ/mol Force-Bond Angle 15.987 Å (iii) Immediately After Bond Cleavage 25° 16.037 Å 199 O Me O O Me O O CoGEF + N O O H 3C N O O O O O Con3 CH 3 O H3C O O O Compound (ii) (i) Equilibrium Geometry (iii) 16.84 Å (ii) Immediately Prior to Bond Cleavage (i) Summary of CoGEF Results Fmax 6.0 nN Emax 843 kJ/mol Force-Bond Angle 29° 25.49 Å (iii) Immediately After Bond Cleavage 25.54 Å CH 3 200 CH 3 O H3C O O O CH 3 O O N CoGEF O O CH 3 O O + O N Con4 O Compound (i) Equilibrium Geometry (ii) (iii) 16.321 Å (ii) Immediately Prior to Bond Cleavage (i) Summary of CoGEF Results Fmax 6.0 nN Emax 832 kJ/mol Force-Bond Angle 15° 20.821 Å (iii) Immediately After Bond Cleavage 20.871 Å 201 H 3C O O O H O O O CH 3 O O O CoGEF N O H O O CH 3 Con5 + CH 3 O N O Compound (i) Equilibrium Geometry (ii) (iii) 13.761 Å (ii) Immediately Prior to Bond Cleavage 18.361 Å (i) (iii) Immediately After Bond Cleavage 18.411 Å Summary of CoGEF Results Fmax 6.0 nN Emax 650 kJ/mol Force-Bond Angle 39° 202 O H3C NH O CoGEF O O + HN CH3 O O HN CH3 O HN O CH3 48 Compound 48 (ii) (i) Equilibrium Geometry (iii) 15.288 Å (ii) Immediately Prior to Bond Cleavage (i) 18.738 Å (iii) Immediately After Bond Cleavage Summary of CoGEF Results Fmax 6.9 nN Emax 844 kJ/mol Force-Bond Angle 53° 18.788 Å 203 O H 3C NH O CoGEF O O H 3C NH O + O O HN CH 3 HN O 48' CH3 Compound 48' (i) Equilibrium Geometry (iv) (ii) (i) (v) 11.492 Å (iii) (ii) Immediately Prior to First Bond Cleavage 13.642 Å (iii) Immediately After First Bond Cleavage Summary of CoGEF Results Fmax 2.3 nN Emax 140 kJ/mol Force-Bond Angle 5.7° 13.692 Å (iv) Immediately Prior to Second Bond Cleavage 14.892 Å (v) Immediately After Second Bond Cleavage 14.942 Å 204 CH3 O O CoGEF H 3C O O O O CH3 49 + O CH3 O Compound 49 (ii) (i) Equilibrium Geometry (iii) 10.728 Å (ii) Immediately Prior to Bond Cleavage (i) 13.128 Å (iii) Immediately After Bond Cleavage Summary of CoGEF Results Fmax 5.8 nN Emax 557 kJ/mol Force-Bond Angle 57.8° 13.178 Å 205 H3C O O CoGEF O H3C O O + O CH3 O O CH3 49' (ii) (i) (i) Equilibrium Geometry Compound 49' (iv) (iii) 6.033 Å (ii) Immediately Prior to First Bond Cleavage (v) 8.983 Å (iii) Immediately After First Bond Cleavage Summary of CoGEF Results Fmax 2.2 nN Emax 167 kJ/mol Force-Bond Angle 0.5° 9.033 Å (iv) Immediately Prior to Second Bond Cleavage 10.083 Å (v) Immediately After Second Bond Cleavage 10.133 Å 206 Cl H3C Br CoGEF CH 3 50 Br H3C CH3 Cl Compound 50 (ii) (i) Equilibrium Geometry 7.809 Å (ii) Immediately Prior to Bond Cleavage (i) (iii) 10.359 Å (iii) Immediately After Bond Cleavage Summary of CoGEF Results Fmax 3.6 nN Emax 216 kJ/mol Force-Bond Angle 0.1° 10.359 Å 207 Br Cl H3C 51 CoGEF CH3 Cl H 3C CH3 Br (i) Equilibrium Geometry Compound 51 (ii) 7.824 Å (ii) Immediately Prior to Bond Cleavage (i) (iii) 10.174 Å (iii) Immediately After Bond Cleavage Summary of CoGEF Results Fmax 3.3 nN Emax 184 kJ/mol Force-Bond Angle 0.1° 10.224 Å 208 F Cl H 3C 52 CoGEF CH3 (ii) F H 3C CH 3 Compound 52 Cl (i) Equilibrium Geometry 7.776 Å (ii) Immediately Prior to Bond Cleavage (i) 10.176 Å (iii) Immediately After Bond Cleavage (iii) 10.226 Å Summary of CoGEF Results Fmax 3.5 nN Emax 262 kJ/mol Force-Bond Angle 0.0° 209 F Cl H3C 53 Cl CoGEF H3C CH3 CH 3 F (ii) Compound 53 (i) Equilibrium Geometry 7.816Å (ii) Immediately Prior to Bond Cleavage (iii) 10.566 Å (i) (iii) Immediately After Bond Cleavage 10.616Å Summary of CoGEF Results Fmax 3.2 nN Emax 183 kJ/mol Force-Bond Angle 0.1° 210 Br Br H 3C 54 CoGEF CH3 Br H 3C CH3 Br Compound 54 (i) Equilibrium Geometry (ii) 10.675 Å (ii) Immediately Prior to Bond Cleavage (i) (iii) 12.575 Å (iii) Immediately After Bond Cleavage Summary of CoGEF Results Fmax 3.3 nN Emax 164 kJ/mol Force-Bond Angle 0.3° 12.625 Å 211 H 3C 55 Br CoGEF Br Br CH3 (ii) H3C CH 3 Br Compound 55 (i) Equilibrium Geometry 6.081 Å (ii) Immediately Prior to Bond Cleavage (i) (iii) 7.531 Å (iii) Immediately After Bond Cleavage 7.581 Å Summary of CoGEF Results Fmax 3.7 nN Emax 180 kJ/mol Force-Bond Angle 0.1° 212 H 3C Cl Cl OCH3 CH3 56 (ii) Cl CoGEF H3C OCH3 CH 3 Cl Compound 56 (i) Equilibrium Geometry 5.971 Å (ii) Immediately Prior to Bond Cleavage (i) (iii) 7.421 Å (iii) Immediately After Bond Cleavage Summary of CoGEF Results Fmax 3.6 nN Emax 166 kJ/mol Force-Bond Angle 3.8° 7.471 Å 213 Cl Cl Cl CoGEF H 3C Cl CH 3 H 3C CH3 Compound 57 57 (ii) (i) Equilibrium Geometry 8.972 Å (ii) Immediately Prior to Bond Cleavage (iii) (i) 12.272 Å (iii) Immediately After Bond Cleavage Summary of CoGEF Results Fmax 5.7 nN Emax 448 kJ/mol Force-Bond Angle 31° 12.322 Å 214 H3C Cl CoGEF Cl Cl H3C CH 3 58 CH 3 Cl Compound 58 (ii) (i) Equilibrium Geometry 6.079 Å (ii) Immediately Prior to Bond Cleavage (i) 7.629 Å (iii) (iii) Immediately After Bond Cleavage 7.679 Å Summary of CoGEF Results Fmax 3.8 nN Emax 205 kJ/mol Force-Bond Angle 0.0° 215 Cl Cl H 3C CoGEF CH3 59 Cl H 3C CH3 Cl Compound 59 (ii) (i) Equilibrium Geometry 10.746 Å (ii) Immediately Prior to Bond Cleavage (i) 12.696 Å (iii) Summary of CoGEF Results Fmax 3.4 nN Emax 190 kJ/mol Force-Bond Angle 0.4° (iii) Immediately After Bond Cleavage 12.746 Å 216 Cl Cl H 3C CoGEF CH 3 60 Cl H 3C CH 3 Cl (i) Equilibrium Geometry (ii) 6.904 Å (ii) Immediately Prior to Bond Cleavage (i) (iii) 8.604 Å (iii) Immediately After Bond Cleavage 8.654 Å Summary of CoGEF Results Fmax 3.2 nN Emax 148 kJ/mol Force-Bond Angle 9.0° Compound 60 217 CH3 Cl Cl CoGEF Cl CH3 61 CH3 CH3 Cl Compound 61 (i) Equilibrium Geometry (ii) 6.787 Å (ii) Immediately Prior to Bond Cleavage (i) (iii) 8.537 Å (iii) Immediately After Bond Cleavage 8.587 Å Summary of CoGEF Results Fmax 3.7 nN Emax 202 kJ/mol Force-Bond Angle 3.9° 218 Cl H3 C Cl Cl CH3 CoGEF H3C 62 Cl CH3 Compound 62 (i) Equilibrium Geometry (ii) (iii) 13.974 Å (ii) Immediately Prior to Bond Cleavage (i) 21.174 Å (iii) Immediately After Bond Cleavage Summary of CoGEF Results Fmax 5.2 nN Emax 557 kJ/mol Force-Bond Angle 20° 21.224 Å 219 H 3C Cl Cl CH3 Cl CoGEF 63 H3 C Cl CH3 Compound 63 (i) Equilibrium Geometry (ii) 11.037 Å (i) Immediately Prior to Bond Cleavage 15.337 Å (iii) (i) (ii) Immediately After Bond Cleavage 15.387 Å Summary of CoGEF Results Fmax 3.8 nN Emax 340 kJ/mol Force/Bond angle 0.1° 220 H3C O H 3C CoGEF H3C N H3C O O O H H 64 CH 3 O O N O O H3C O CH3 O or H3 C O O O N O H H CH 3 O H (i) Equilibrium Geometry (ii) 8.232 Å (ii) Immediately Prior to Bond Cleavage (iii) (i) 9.982 Å Summary of CoGEF Results Fmax 5.4 nN Emax 300 kJ/mol Force-Bond Angle (iii) Immediately After Bond Cleavage 22° 10.032 Å Compound 64 221 H 3C H 3C O CoGEF H3C N H3C O O O H H 65 CH3 O H 3C O O or N O H O H3C O H O CH3 O O H N H O O CH3 Compound 65 (i) Equilibrium Geometry (ii) (iii) 7.37 Å (ii) Immediately Prior to Bond Cleavage (i) Summary of CoGEF Results Fmax 5.6 nN Emax 416 kJ/mol Force-Bond Angle 10.22 Å (iii) Immediately After Bond Cleavage 0.1° 10.27 Å 222 O H 3C 66 CoGEF CH3 H3C O CH3 (ii) Compound 66 (i) Equilibrium Geometry (iii) 8.113 Å (ii) Immediately Prior to Bond Cleavage (i) 14.113 Å (iii) Immediately After Bond Cleavage Summary of CoGEF Results Fmax 6.4 nN Emax 729 kJ/mol Force-Bond Angle 0.8° 14.163 Å 223 O H3C CoGEF CH 3 67 H3C O CH 3 Compound 67 (ii) (i) Equilibrium Geometry (iii) 7.555 Å (ii) Immediately Prior to Bond Cleavage 11.005 Å (i) (iii) Immediately After Bond Cleavage Summary of CoGEF Results Fmax 6.2 nN Emax 549 kJ/mol Force-Bond Angle 1.5° 11.055 Å 224 O H 3C CoGEF CH3 67 H 3C O CH3 Compound 60 polar solvent (i) Equilibrium Geometry (ii) (iii) 6.606 Å (ii) Immediately Prior to Bond Cleavage 10.956 Å (iii) Immediately After Bond Cleavage (i) 11.006 Å Summary of CoGEF Results Fmax 6.1 nN Emax 529 kJ/mol Force-Bond Angle 1.6° 225 CoGEF O H3C CH 3 H3C O CH3 Con6 Compound (ii) (i) Equilibrium Geometry (iii) 5.523 Å (ii) Immediately Prior to Bond Cleavage 8.573 Å (iii) Immediately After Bond Cleavage (i) 8.623 Å Summary of CoGEF Results Fmax 6.2 nN Emax 607 kJ/mol Force-Bond Angle 0.0° 226 CH3 CoGEF H3C CH 3 CH 3 Compound 68 68 (ii) (i) Equilibrium Geometry 7.067 Å (ii) Immediately Prior to Bond Cleavage (iii) (i) 10.167 Å (iii) Immediately After Bond Cleavage Summary of CoGEF Results Fmax 3.7 nN Emax 282 kJ/mol Force/Bond angle 3.2° 10.217 Å 227 H3C CH3 H 3C CH 3 CoGEF 69 Compound 69 (ii) (i) Equilibrium Geometry 6.463 Å (iii) (ii) Immediately Prior to Bond Cleavage (i) 7.663 Å (iii) Immediately After Bond Cleavage Summary of CoGEF Results Fmax 4.1 nN Emax 186 kJ/mol Force/Bond angle 17° 7.713 Å 228 H H O O O O H 3C CH3 CoGEF H 3C O O O O CH 3 Compound 70 70 (i) Equilibrium Geometry (ii) 7.936 Å (ii) Immediately Prior to Bond Cleavage (iii) (i) 9.636 Å (iii) Immediately After Bond Cleavage Summary of CoGEF Results Fmax 4.1 nN Emax 211 kJ/mol Force-Bond Angle 25° 9.686 Å 229 H 3C CH3 CoGEF H3C CH3 71 Compound 71 (i) Equilibrium Geometry (ii) 7.011 Å (ii) Immediately Prior to Bond Cleavage (iii) (i) 10.161 Å (iii) Immediately After Bond Cleavage Summary of CoGEF Results Fmax 3.1 nN Emax 244 kJ/mol Force-Bond Angle 2.8° 10.211 Å 230 H 3C CH 3 H3 C CH3 CoGEF Compound 72 72 (i) Equilibrium Geometry 6.123 Å (iii) (ii) Prior to Bond Cleavage (iv) (ii) (i) 7.273 Å (iii) After Bond Cleavage Summary of CoGEF Results Fmax 3.7 nN Emax 367 kJ/mol Force/Bond angle 0.0° 8.123 (iv) After Formation of Double Bonds 8.573 Å 231 H 3C CH3 OH HO O O CoGEF H3 C O O O O CH3 Compound 73 73 (i) Equilibrium Geometry (ii) 6.275 Å (ii) Immediately Prior to Bond Cleavage (iii) (iv) (i) 9.425 Å (iii) Immediately After Bond Cleavage Summary of CoGEF Results Fmax 3.0 nN Emax 310 kJ/mol Force-Bond Angle 9.475 Å (iv) After Formation of Double Bonds 0.0° 10.225 Å 232 H3 C O O Me Me N O Me 74 NO 2 CoGEF H3C O O O O Me CH3 (ii) NO 2 Me N Me O O CH 3 O Compound 74 (i) Equilibrium Geometry 6.048 Å (ii) Immediately Prior to Bond Cleavage (iii) (i) 16.648 Å (iii) Immediately After Bond Cleavage Summary of CoGEF Results Fmax 4.4 nN Emax 381 kJ/mol Force-Bond Angle 14° 16.698 Å 233 H3 C O O Me Me N O Me 74 NO 2 polar solvent O O CoGEF CH3 (ii) Me H3C O O NO 2 Me N Me O O CH 3 O Compound 74 (polar (i) Equilibrium Geometry 7.920 Å (ii) Immediately Prior to Bond Cleavage (i) (iii) 16.470 Å (iii) Immediately After Bond Cleavage Summary of CoGEF Results Fmax 4.0 nN Emax 325 kJ/mol Force-Bond Angle 14° 16.520 Å 234 Me Me Me N O NO2 CoGEF NO 2 Me N O O CH3 O CH 3 O O O O CH 3 O 75 O Compound 75 CH3 (i) Equilibrium Geometry (ii) (iii) 11.600 Å (ii) Immediately Prior to Bond Cleavage (i) 14.500 Å Summary of CoGEF Results Fmax 2.7 nN Emax 165 kJ/mol Force-Bond Angle (iii) Immediately After Bond Cleavage 29° 14.550 Å 235 Me Me Me N O NO2 CoGEF NO2 Me N O O O O O CH 3 O O 76 O CH 3 O H3C CH 3 Compound 76 (i) Equilibrium Geometry (ii) 11.322 Å (iii) (ii) Immediately Prior to Bond Cleavage (i) Summary of CoGEF Results Fmax 2.6 nN Emax 150 kJ/mol Force-Bond Angle 15.922 Å (iii) Immediately After Bond Cleavage 27° 15.972 Å 236 Me Me Me N S O H 3C NO 2 N O S CH 3 NH O O O NH CoGEF NO2 Me O 77 O HN CH 3 O NH Compound 77 H3 C (i) Equilibrium Geometry (ii) 14.303 Å (i) (iii) Summary of CoGEF Results Fmax 2.0 nN Emax 74 kJ/mol Force-Bond Angle (ii) Immediately Prior to Bond Cleavage 18.803 Å (iii) Immediately After Bond Cleavage 31° 18.853 Å 237 Me Me Me CoGEF N O Me N O O CH3 O O O O CH3 O CH3 O 78 O CH3 (ii) Compound 78 (i) Equilibrium Geometry 7.625 Å (ii) Immediately Prior to Bond Cleavage (iii) (i) 14.975 Å (iii) Immediately After Bond Cleavage Summary of CoGEF Results Fmax 3.5 nN Emax 271 kJ/mol Force-Bond Angle 28° 15.025 Å 238 Br Me Me Me N O Br CoGEF Me N O CH 3 O O CH3 O O O O CH 3 O O CH 3 79 Compound 79 (i) Equilibrium Geometry (ii) (iii) 8.544 Å (ii) Immediately Prior to Bond Cleavage (i) 14.844 Å (iii) Immediately After Bond Cleavage Summary of CoGEF Results Fmax 3.2 nN Emax 248 kJ/mol Force-Bond Angle 27° 14.894 Å 239 Me Me Me Me CoGEF N O N O CH 3 H3C O CH3 O O 80 H3C (ii) O Compound 80 (i) Equilibrium Geometry (iii) 11.447 Å (ii) Immediately Prior to Bond Cleavage (i) 16.897 Å (iii) Immediately After Bond Cleavage Summary of CoGEF Results Fmax 5.9 nN Emax 536 kJ/mol Force-Bond Angle 47° 16.947 Å 240 Me Me O N O O Me Me O CH3 CoGEF CH3 O N O 81 O O O CH 3 O Compound 81 CH3 (ii) (i) Equilibrium Geometry (iii) 11.638 Å (ii) Immediately Prior to Bond Cleavage (i) 18.188 Å (iii) Immediately After Bond Cleavage Summary of CoGEF Results Fmax 5.7 nN Emax 567 kJ/mol Force-Bond Angle 49° 18.238 Å 241 Me Me Me O O O O CoGEF N O Me N O CH3 O 82 CH 3 O O H 3C O Compound 82 CH 3 (i) Equilibrium Geometry (ii) (iii) 12.787 Å (ii) Immediately Prior to Bond Cleavage (i) Summary of CoGEF Results Fmax 4.8 nN Emax 386 kJ/mol Force-Bond Angle 18.687 Å (iii) Immediately After Bond Cleavage 35° 18.737 Å 242 CoGEF O O O H 3C O O O O 83 O O H3C CH3 O O O CH3 Compound 83 (i) Equilibrium Geometry (ii) 13.325 Å (ii) Immediately Prior to Bond Cleavage (iii) (i) 19.925 Å (iii) Immediately After Bond Cleavage Summary of CoGEF Results Fmax 4.3 nN Emax 418 kJ/mol Force-Bond Angle 29° 19.975 Å 243 F CoGEF O O H 3C F O O O O O O O 84 H3C O O CH3 O CH3 Compound 84 (ii) (i) Equilibrium Geometry 13.160 Å (ii) Immediately Prior to Bond Cleavage (iii) (i) Summary of CoGEF Results Fmax 4.4 nN Emax 483 kJ/mol Force-Bond Angle 20.110 Å (iii) Immediately After Bond Cleavage 26° 20.160 Å 244 CoGEF O O O H 3C H 3C O O O 85 O O O O CH3 (ii) CH3Compound 85 (i) Equilibrium Geometry 13.153 Å (iii) (ii) Immediately Prior to Bond Cleavage (i) 17.503 Å Summary of CoGEF Results Fmax 4.1 nN Emax 370 kJ/mol Force-Bond Angle (iii) Immediately After Bond Cleavage 29° 17.553 Å 245 N CoGEF O O O H 3C O O O O O 86 O H3C O O CH3 O CH3 N Compound 86 (i) Equilibrium Geometry (ii) (iii) 11.651 Å (ii) Immediately Prior to Bond Cleavage (i) Summary of CoGEF Results Fmax 3.7 nN Emax 348 kJ/mol Force-Bond Angle 19.601 Å (iii) Immediately After Bond Cleavage 30° 19.651 Å 246 N CoGEF F O O O O O H 3C O O 87 O O F H3C O O CH3 O CH3 N Compound 87 (i) Equilibrium Geometry (ii) 11.190 Å (iii) (ii) Immediately Prior to Bond Cleavage (i) Summary of CoGEF Results Fmax 3.7 nN Emax 334 kJ/mol Force-Bond Angle 19.590 Å (iii) Immediately After Bond Cleavage 33° 19.640 Å 247 N CoGEF O O O H3 C O 88 O O H 3C O O O CH3 O CH 3 N Compound 88 (i) Equilibrium Geometry (ii) 13.054 Å (ii) Immediately Prior to Bond Cleavage (iii) (i) 17.354 Å Summary of CoGEF Results Fmax 3.9 nN Emax 332 kJ/mol Force-Bond Angle (iii) Immediately After Bond Cleavage 30° 17.404 Å 248 F O O H 3C F S O CoGEF O O F O O CH3 F S CoGEF O H3 C F O F S O O 89 O O O Compound 89 (i) Equilibrium Geometry (ii) 4.159 Å (ii) Immediately Prior to First Bond Cleavage (iii) (i) (v) 20.659 Å (iii) Immediately After Bond First Cleavage Summary of CoGEF Results (S,S) Fmax 4.1 nN (first) 4.6 nN (second) Emax 652 kJ/mol (first) 740 kJ/mol (second) Force-Bond Angle 20.709 Å (iv) Immediately Prior to Second Bond Cleavage 25° (first), 27° (second) The results presented here correspond to the (S,S)-isomer of compound 82. The CoGEF results for the (R,S)-isomer are similar: 24.009 Å (v) Immediately After Bond Second Cleavage Summary of CoGEF Results (R,S) Fmax 4.1 nN (first) 4.5 nN (second) Emax 644 kJ/mol (first) 727 kJ/mol (second) Force-Bond Angle CH3 O CH3 O (iv) O O H 3C 24° (first), 26° (second) 24.059 Å 249 H 3C H 3C O O O O O O CoGEF O O O O O CH 3 O Con7 CH 3 (ii) Compound (i) Equilibrium Geometry (iii) 16.735 Å (ii) Immediately Prior to Bond Cleavage (i) Summary of CoGEF Results Fmax 6.0 nN Emax 716 kJ/mol Force-Bond Angle 24.685 Å (iii) Immediately After Bond Cleavage 63° 24.735 Å 250 O O H 3C H 3C O O O O CoGEF O O O Con8 O O CH3 O CH 3 (i) Equilibrium Geometry (ii) (iii) 21.141 Å (ii) Immediately Prior to Bond Cleavage (i) Summary of CoGEF Results Fmax 6.0 nN Emax 650 kJ/mol Force-Bond Angle 25.091 Å (iii) Immediately After Bond Cleavage 56° 25.141 Å Compound 251 NC Me H3C N CH3 N CoGEF 2 Me CN H3C CN + N2 Me 90 Compound 90 (ii) (i) Equilibrium Geometry (iii) 4.452 Å (ii) Immediately Prior to Bond Cleavage (i) 9.652 Å (iii) Immediately After Bond Cleavage 9.702 Å Summary of CoGEF Results Fmax 3.7 nN Emax 140 kJ/mol Force-Bond Angle 29° 252 O N H3 C O 91 O CoGEF CH3 N CH3 O H 3C O + N O O N O Compound 91 (i) Equilibrium Geometry (ii) 5.818 Å (iii) (ii) Immediately Prior to Bond Cleavage (i) 7.068 Å (iii) Immediately After Bond Cleavage Summary of CoGEF Results Fmax 5.2 nN Emax 230 kJ/mol Force-Bond Angle 28° 7.118 Å 253 H2 N S CoGEF S S NH 2 H2N 92 NH 2 + S Compound 92 (i) Equilibrium Geometry 9.023 Å (ii) (ii) Immediately Prior to Bond Cleavage (iii) 13.923 Å (iii) Immediately After Bond Cleavage (i) 13.973 Å Summary of CoGEF Results Fmax 2.0 nN Emax 114 kJ/mol Force-Bond Angle 45° 254 O H 3C O S S 93 O CH3 O CoGEF H3C O O O S + S O CH 3 Compound 93 (i) Equilibrium Geometry (ii) (iii) 11.920 Å (ii) Immediately Prior to Bond Cleavage (i) 15.920 Å (iii) Immediately After Bond Cleavage Summary of CoGEF Results Fmax 3.6 nN Emax 271 kJ/mol Force-Bond Angle 29° 15.970 Å 255 H 3C O tBu O tBu O O tBu CoGEF O tBu O CH3 + O tBu tBu O tBu O O CH3 94 O tBu O CH 3 Compound 94 (i) Equilibrium Geometry (ii) (iii) 16.559 Å (ii) Immediately Prior to Bond Cleavage (i) Summary of CoGEF Results Fmax 3.5 nN Emax 169 kJ/mol Force-Bond Angle 44° 18.209 Å (iii) Immediately After Bond Cleavage 18.259 Å 256 H 3C O NC H3 CO H3CO OCH3 CH3 CN CoGEF CN O 95 O + O CH3 NC CH3 OCH3 Compound 95 (ii) (i) Equilibrium Geometry (iii) 16.700 Å (ii) Immediately Prior to Bond Cleavage (i) Summary of CoGEF Results Fmax 4.5 nN Emax 294 kJ/mol Force-Bond Angle 41° 18.750 Å (iii) Immediately After Bond Cleavage 18.800Å 257 O H3C O CoGEF NC CN 96 NC O H 3C + O CH 3 O O CN O O CH 3 Compound 96 (i) Equilibrium Geometry (ii) 15.307 Å (iii) (ii) Immediately Prior to Bond Cleavage (i) 17.507 Å (iii) Immediately After Bond Cleavage Summary of CoGEF Results Fmax 4.3 nN Emax 326 kJ/mol Force-Bond Angle 46° 17.557 Å 258 H3C O H3C O O CoGEF S S + O S O O S O O 97 CH3 CH3 Compound 97 (ii) (i) Equilibrium Geometry 11.109 Å (ii) Immediately Prior to Bond Cleavage (iii) (i) Summary of CoGEF Results Fmax 4.4 nN Emax 287 kJ/mol Force-Bond Angle 41° 18.659 Å (iii) Immediately After Bond Cleavage 18.709 Å 259 H3C CH3 CH 3 H H H H H H H H CoGEF CoGEF CH3 CH 3 H H H H H 3C Compound 98 98 (iv) Immediately Prior to Second Bond Cleavage (i) Equilibrium Geometry (vii) Immediately After Third Bond Cleavage 6.269 Å 10.169 Å 15.269 Å (ii) Immediately Prior to First Bond Cleavage (v) Immediately After Second Bond Cleavage (viii) Immediately After Fourth Bond Cleavage 15.319 Å 10.019 Å 10.219 Å (iii) Immediately After First Bond Cleavage (vi) Immediately Prior to Third Bond Cleavage 10.069 Å 15.219 Å (vi) (ii) (iii) (vii) (iv) (i) Summary of CoGEF Results (v) (viii) Fmax 3.2 nN (first) 3.9 nN (second) Emax 236 kJ/mol (first) 239 kJ/mol (second) Force-Bond Angle 0.1° (first), 4.4° (second) 260 O H3 C H H CH 3 O O O H H H O CH3 O CoGEF H H H O H H CH 3 CoGEF H 3C O O HO H O 99 O CH 3 Compound 99 (i) Equilibrium Geometry (iv) Immediately Prior to Second Bond Cleavage (vii) Immediately After Third Bond Cleavage 10.304 Å 13.754 Å 17.604 Å (ii) Immediately Prior to First Bond Cleavage (v) Immediately After Second Bond Cleavage (viii) Immediately After Fourth Bond Cleavage 12.554 Å 13.804 Å 17.654 Å (iii) Immediately After First Bond Cleavage (vi) Immediately Prior to Third Bond Cleavage 12.604 Å 17.554 Å (iv) (iii) (vi) (ii) (vii) Summary of CoGEF Results (i) (v) Fmax 4.2 nN 4.0 nN Emax 451 kJ/mol 346 kJ/mol Force-Bond Angle (viii) 0.2° (first) 3.4° (second) 261 O H3 C H H O O H H H CH 3 O O O CH3 H H H CoGEF O H H CoGEF CH3 H3C O O O HO H O Compound 100 100 (i) Equilibrium Geometry (iv) Immediately Prior to Second Bond Cleavage (vii) Immediately After Third Bond Cleavage 10.308 Å 14.208 Å 17.558 Å (ii) Immediately Prior to First Bond Cleavage (v) Immediately After Second Bond Cleavage (viii) Immediately After Fourth Bond Cleavage 17.708 Å 12.458 Å 14.258 Å (iii) Immediately After First Bond Cleavage (vi) Immediately Prior to Third Bond Cleavage 12.508 Å 17.508 Å (iv) Summary of CoGEF Results (iii) (vi) (ii) (vii) Fmax 4.2 nN (first) 3.9 nN (second) Emax 511 kJ/mol (first) 326 kJ/mol (second) Force-Bond Angle (i) (v) CH 3 (viii) 0.5° (first) 4.0° (second) 262 H3C CH3 H H H3C CoGEF H H CH3 Compound 101 (ii) (i) Equilibrium Geometry (iv) (iii) 6.368 Å (ii) Immediately Prior to First Bond Cleavage (i) (v) 10.018 Å (iii) Immediately After First Bond Cleavage Summary of CoGEF Results Fmax 3.1 nN Emax 207 kJ/mol Force-Bond Angle 10.068 Å (iv) Immediately Prior to Second Bond Cleavage 0.1° 10.218 Å (v) Immediately After Second Bond Cleavage 10.268 Å 263 H3 C F F CH3 CoGEF H3C F F CH3 102 Compound 102 (i) Equilibrium Geometry (ii) 12.504 Å (iii) (ii) Immediately Prior to Bond Cleavage 18.704 Å (i) (iii) Immediately After Bond Cleavage 18.754 Å Summary of CoGEF Results Fmax 4.8 nN Emax 466 kJ/mol Force-Bond Angle 21° 264 H3 C F F CoGEF CH3 H3C F F CH3 103 Compound (i) Equilibrium Geometry 14.312 Å (ii) Immediately Prior to Bond Cleavage (ii) (iii) (i) 17.912 Å (iii) Immediately After Bond Cleavage 17.962 Å Summary of CoGEF Results Fmax 3.4 nN Emax 292 kJ/mol Force-Bond Angle 0.0° 265 F F H H3C CoGEF F H F F F F 104 F CoGEF F F F H H CH 3 CH3 CH 3 CoGEF F F F 2 H3C CH3 CH3 Compound (i) Equilibrium Geometry (iv) Immediately Prior to Second Bond Cleavage 10.904 Å 14.604 Å (ii) Immediately Prior to First Bond Cleavage (v) Immediately After Second Bond Cleavage 13.104 Å 14.654 Å (iii) Immediately After First Bond Cleavage (vi) Immediately Prior to Disproportionation 13.154 Å 15.404 Å (vi) (vii) Immediately After Disproportionation (v) (iv) (vii) (iii) (ii) 15.454 Å Summary of CoGEF Results (i) Fmax 4.9 nN Emax 771 kJ/mol Force-Bond Angle 1.3° 266 F F H 3C F F O O 105 O F F CoGEF F F O H3C CH3 O F O F O F CoGEF F F F O F O CH3 O CH3 Compound (iv) (i) Equilibrium Geometry (ii) (iii) (v) 15.764 Å (ii) Immediately Prior to First Bond Cleavage (i) 18.214 Å (iii) Immediately After First Bond Cleavage Summary of CoGEF Results Fmax 4.2 nN Emax 455 kJ/mol Force-Bond Angle 17° 18.264 Å (iv) Immediately Before Second Bond Cleavage 19.514 Å (v) Immediately After Second Bond Cleavage 19.562 Å 267 F F H 3C F O F O 106 O F F CoGEF F O CH3 F H 3C O F O F O F F F F O CoGEF F O CH3 O CH3 Compound (i) Equilibrium Geometry (iv) (ii) 14.522 Å (iii) (v) (ii) Immediately Prior to First Bond Cleavage (i) 17.772 Å (iii) Immediately After First Bond Cleavage Summary of CoGEF Results Fmax 3.4 nN Emax 409 kJ/mol Force-Bond Angle 5.9° 17.822 Å (iv) Immediately Before Second Bond Cleavage 18.922 Å (v) Immediately After Second Bond Cleavage 18.972 Å 268 SiMe3 H 3C CH3 SiMe3 SiMe3 CoGEF H3C CH3 SiMe3 SiMe3 H3C CH3 Si CH3 SiMe3 CoGEF H3 C SiMe3 SiMe3 CoGEF CH 3 H3 C CH 3 CH3 Si CH3 Si CH 3 H3C CH3 H C SiMe3 107 3 Compound 107 (i) Equilibrium Geometry (ii) Immediately Prior to First Bond Cleavage (iii) Immediately After First Bond Cleavage (iv) Immediately Prior to Second Bond Cleavage 8.084 Å 10.534 Å 10.584 Å 13.234 Å (v) Immediately After Second Bond Cleavage (vi) Immediately Prior to Third Bond Cleavage (vii) Immediately After Third Bond Cleavage 13.284 Å 17.734 Å 17.784 Å (vi) Summary of CoGEF Results (iv) (ii) (v) (iii) (i) (vii) Fmax 3.5 nN (first) 2.6 nN (second) 3.5 nN (third) Emax 348 kJ/mol (first) 521 kJ/mol (second) 617 kJ/mol (third) Force-Bond Angle 7.5° (first) 16° (second) 7.0° (third) 269 CH3 O N CH3 N O O H 3C N N CoGEF + N HN N O N 108 CH3 Compound 108 (ii) (i) Equilibrium Geometry (iii) 15.861 Å (ii) Immediately Prior to Bond Cleavage (i) Summary of CoGEF Results Fmax 5.1 nN Emax 536 kJ/mol Force-Bond Angle 20.261 Å (iii) Immediately After Bond Cleavage 43° 20.311 Å 270 N N CH 3 N O O H 3C O N H3C N CH 3 N CoGEF + O N N 108' Compound 108' (ii) (iii) (i) (i) Equilibrium Geometry 16.537 Å (ii) Immediately Prior to Bond Cleavage Summary of CoGEF Results Fmax 4.3 nN Emax 258 kJ/mol Force-Bond Angle 18.537 Å (iii) Immediately After Bond Cleavage 40° 18.587 Å 271 H 3C O H 3C O O O CoGEF N O O H 3C O O N + H 3C O O 109 Compound 109 (ii) (i) Equilibrium Geometry 11.66 Å (iii) (ii) Immediately Prior to Bond Cleavage (i) 15.41 Å Summary of CoGEF Results Fmax 4.7 nN Emax 369 kJ/mol Force-Bond Angle (iii) Immediately After Bond Cleavage 15° 15.46 Å 272 O S N O S O O O CoGEF CH3 O O O H3C N 110 O S O S O + H3 C CH3 O CH2 Compound 110 (ii) (i) Equilibrium Geometry (iii) 15.926 Å (ii) Immediately Prior to Bond Cleavage (i) 19.076 Å Summary of CoGEF Results Fmax 4.3 nN Emax 472 kJ/mol Force-Bond Angle (iii) Immediately After Bond Cleavage 24° 19.126 Å 273 Me H3C O S S O Me O S 111 Me CoGEF CH 3 H3C O O S S Me S + O O CH3 O Compound 111 (i) Equilibrium Geometry (ii) (iii) 8.199 Å (ii) Immediately Prior to Bond Cleavage (i) 9.699 Å (iii) Immediately After Bond Cleavage Summary of CoGEF Results Fmax 4.3 nN Emax 227 kJ/mol Force-Bond Angle 35° 9.749 Å 274 O O H 3C O O O N O CF3 S O 112 O S N O O O O CF3 O O H 3C CoGEF CH3 O O N CF3 O + O S O O S N O O O CF3 O CH3 Compound 112 (i) Equilibrium Geometry 26.482 Å (ii) Immediately Prior to Bond Cleavage 38.432 Å (iii) Immediately After Bond Cleavage 38.482 Å (ii) Summary of CoGEF Results (iii) Fmax 4.3 nN Emax 625 kJ/mol Force-Bond Angle (i) 28° 275 Compound 113 (iii) (i) Equilibrium Geometry 12.527 Å (ii) At Fmax (ii) (iv) 14.677 Å (iii) Immediately Prior to Bond Cleavage 15.877 Å (i) (iv) Immediately After Bond Cleavage 15.927 Å Summary of CoGEF Results Fmax 4.6 nN Emax 626 kJ/mol Force-Bond Angle 20° 276 O OCH 3 O O CoGEF CH 2 H 3C O 114 OCH3 + H3CO O O O Compound 114 (i) Equilibrium Geometry (ii) 15.877 Å (ii) Immediately Prior to Bond Cleavage (iii) 19.227 Å (iii) Immediately After Bond Cleavage (i) 19.277 Å Summary of CoGEF Results Fmax 6.1 nN Emax 611 kJ/mol Force-Bond Angle 37° 277 Me Me N H H3C N O Me Me F Me F O Me Me F CH3 N CoGEF H 3C F N O Me Me F + Me O F Me 115 F F Compound 115 Me (ii) (i) Equilibrium Geometry (iii) 13.275 Å (ii) Immediately Prior to Bond Cleavage (i) Summary of CoGEF Results Fmax 5.2 nN Emax 388 kJ/mol Force-Bond Angle 17.025 Å 13° (iii) Immediately After Bond Cleavage 17.075 Å CH3 278 Me Me N H H3C N O Me Me F Me F O Me Me F CH3 polar solvent F N CoGEF H 3C N O Me Me F Me O F Me 115 F + CH3 F Me (ii) (iii) Compound 115 (polar (i) Equilibrium Geometry 13.275 Å (ii) Immediately Prior to Bond Cleavage (i) Summary of CoGEF Results Fmax 5.2 nN Emax 391 kJ/mol Force-Bond Angle 13° 17.075 Å (iii) Immediately After Bond Cleavage 17.125 Å 279 Me Me N H H3C N O Me Me Me F O Me Me CH3 N CoGEF H 3C F N O Me Me F + Me CH3 F Me 116 O Me Compound 116 (i) Equilibrium Geometry (ii) 12.940 Å (iii) (ii) Immediately Prior to Bond Cleavage (i) Summary of CoGEF Results Fmax 5.5 nN Emax 438 kJ/mol Force-Bond Angle 13° 17.140 Å (iii) Immediately After Bond Cleavage 17.190 Å 280 Me Me N H H3C N O Me Me Me F O Me Me CH3 N CoGEF polar solvent F H 3C N O Me Me F + Me CH3 F Me 116 O Me Compound 116 (ii) (i) Equilibrium Geometry 12.940 Å (ii) Immediately Prior to Bond Cleavage (iii) (i) Summary of CoGEF Results Fmax 5.5 nN Emax 458 kJ/mol Force-Bond Angle 17.240 Å (iii) Immediately After Bond Cleavage 12° 17.290 Å 281 Me Me N H H3C N O Me Me Me F O CH3 Me Me N CoGEF H 3C N O Me Me F + O CH3 Me 117 Me Me Compound 117 (ii) (i) Equilibrium Geometry (iii) 13.522 Å (ii) Immediately Prior to Bond Cleavage (i) Summary of CoGEF Results Fmax 5.8 nN Emax 499 kJ/mol Force-Bond Angle 14° 17.322 Å (iii) Immediately After Bond Cleavage 17.372 Å 282 Me Me N H H3C N O Me Me Me F O CH3 Me Me N CoGEF polar solvent H 3C N O Me Me F + O CH3 Me 117 Me Me Compound 117 (i) Equilibrium Geometry (ii) 13.522 Å (ii) Immediately Prior to Bond Cleavage (iii) (i) Summary of CoGEF Results Fmax 5.8 nN Emax 517 kJ/mol Force-Bond Angle 17.422 Å (iii) Immediately After Bond Cleavage 14° 17.472 Å 283 Me Me Me O O O O O Me O Me CoGEF Me O O O O Me O + O Me O 118 O Compound 118 (i) Equilibrium Geometry (ii) (iii) 10.099 Å (ii) Immediately Prior to Bond Cleavage (i) 15.599 Å (iii) Immediately After Bond Cleavage Summary of CoGEF Results Fmax 5.6 nN Emax 507 kJ/mol Force-Bond Angle 32° 15.649 Å 284 Me Me Me O O O O O Me O Me CoGEF Me polar solvent O O O O Me O Me O O + O 118 Compound 118 (polar (ii) (i) Equilibrium Geometry 10.099 Å (iii) (ii) Immediately Prior to Bond Cleavage (i) 15.299 Å (iii) Immediately After Bond Cleavage Summary of CoGEF Results Fmax 4.9 nN Emax 395 kJ/mol Force-Bond Angle 33° 15.349 Å t CoGEF S O H3C Bu O 119 O O CH 3 S O H 3C O + O t Bu O CH 3 Compound 119 285 (i) Equilibrium Geometry (ii) (iii) 13.405 Å (ii) Immediately Prior to Bond Cleavage (i) Summary of CoGEF Results 17.605 Å Fmax 3.7 nN Emax 266 kJ/mol Force-Bond Angle (iii) Immediately After Bond Cleavage 17° 17.655 Å tBu H3C CoGEF S O O 119 O O polar solvent CH 3 (ii) S O H 3C O + O tBu (i) Equilibrium Geometry O CH 3 Compound 110 (polar 286 (iii) 13.405 Å (i) (ii) Immediately Prior to Bond Cleavage 17.705 Å Summary of CoGEF Results Fmax 3.9 nN Emax 292 kJ/mol Force-Bond Angle (iii) Immediately After Bond Cleavage 18° 17.755 Å H 3C H N O Et N O CoGEF Et H 3C H N O Et N O Et O O N 120 O O O H N O CH 3 N O O (ii) (i) Equilibrium Geometry H N CH 3 Compound 120 287 9.989 Å (ii) Immediately Prior to Bond Cleavage (i) (iii) Summary of CoGEF Results 19.089 Å Fmax 4.6 nN Emax 368 kJ/mol Force-Bond Angle (iii) Immediately After Bond Cleavage 32° 19.139 Å H3C H N O Et N O Et CoGEF O N 120 O O O H N polar solvent H 3C H N O Et N O O N CH3 Et O H N O CH3 O Compound 120 (polar (ii) 288 (i) Equilibrium Geometry (iii) 14.019 Å (ii) Immediately Prior to Bond Cleavage (i) Summary of CoGEF Results Fmax 4.3 nN Emax 345 kJ/mol Force-Bond Angle 19.019 Å (iii) Immediately After Bond Cleavage 32° 19.069 Å 289 Appendix B A GUIDE FOR IMPLEMENTING THE CONSTRAINED GEOMETRIES SIMULATE EXTERNAL FORCE (CoGEF) METHOD IN SPARTAN This appendix will walk through the setup of a calculation using the constrained geometries simulate external force (CoGEF) method1 to evaluate the mechanochemical reactivity of a prototypical furan–maleimide mechanophore. This method is described more fully in Chapter 1. The screen captures used for this guide are from Spartan’18 Parallel Suite software. Setting up the calculation Building and importing the molecule The first step is to construct your molecule of interest in ChemDraw. You can save the structure in the MDL Molfile (*.mol) format or as ChemDraw file (*.cdx). Here, we are using an exo furan–maleimide adduct as an example. We have chosen methoxy pulling positions were used, but other polymer attachment motifs (e.g., acetoxy) may be more appropriate for your application. 1 Beyer, M. K. J. Chem. Phys. 2000, 112, 7307. 290 After opening the Spartan program, select File > Open. Change the file type to “All Files” and select your structure file. If you opened a .cdx file, your structure will automatically open in the 2D editor. If you are working from a .mol file, click the 2D Edit button if you wish to use the 2D editor. This workspace is the easiest way to check that your structure was imported properly. In particular, check that the molecule depicted has retained the desired stereochemistry, as this can be scrambled upon importing. If the structure is incorrect, use the structure drawing tools in the top left-hand corner to edit the 2D structure. When you are satisfied with the 2D structure, click the icon to enter the 3D view. Equilibrium conformer search and pre-stretching of the molecule We will first run a quick Equilibrium Conformer search to obtain a coarse optimization of the molecule. Click the Calculations button . Select the following options: Calculate: Equilibrium Conformer with Molecular Mechanics MMFF. 291 Once this calculation has finished, click the 3D Edit button . In order obtain a smooth energy profile, we will straighten out the molecule before running the CoGEF calculation to avoid large conformational changes upon elongation. This can be accomplished by rotating bonds, especially those associated with floppy alkyl tethers. To do this, click select a bond you wish to rotate around, then Alt+left click will allow you to rotate the bond with the mouse. When you are done, click the icon to return to the 3D Viewer. 292 Equilibrium Geometry Calculation The structure is now ready for the Equilibrium Geometry calculation. Click the Calculations button . Select the following options: Calculate: Equilibrium Geometry at Ground state in Gas with Density Functional B3LYP 6-31G* Hit Submit. A dialogue box will confirm that the task has started. A dialogue box will appear to inform you when the Equilibrium Geometry calculation has completed. When you accept the message, you may notice your structure changes slightly to represent the optimized geometry. Save this file. Running the CoGEF energy profile calculation Starting from the optimized structure found in the previous step, select the Constrain Distance icon click the two pulling position atoms on your molecule. They should become highlighted. 293 In the lower right-hand corner of the window, click the icon. A constraint line should appear between your two pulling position atoms. Now, select the “Profile” check box. Two boxes with the same distance will appear. These should reflect the linear distance between the two pulling positions. Be sure to leave the starting bond length as it is, but adjust the second to reflect the desired final separation of the pulled atoms. We typically pull 4–7 Å using a step size of 20 steps/Å resulting in the following common values: constraint (final) – constraint (initial) number of steps 4Å 81 5Å 101 6Å 121 7Å 141 294 On the Diels-Alder example, the equilibrium distance between the two pulling atoms was 10.751 Å and a profile length of 7 Å (10.751 Å + 7 Å, 141 steps) was used for the simulation: Once the constraint parameters are set, click the Calculations button. Set the parameters to: Calculate: Energy Profile at Ground state in Gas with Density Functional B3LYP 6-31G* Click Submit. A dialogue box will appear to confirm that the calculations have started. This process may take a while, depending on the size of your molecule. Do not close Spartan while this simulation is running. You can click the Status button to check the progress of the simulation. A new dialogue box will appear once the calculations are completed. Note: if your molecule has a large number of atoms that may not affect the overall mechanochemical behavior, it may be beneficial to truncate or simplify this portion of your molecule when running an initial CoGEF simulation. Eliminating extraneous atoms will greatly reduce the run time of the simulation (DFT typically scales as ~N3 for N atoms). For example, a CoGEF calculation for fulgide 1 took nearly 8 days, while the CoGEF calculation for fulgide 2 was completed in about three days. 295 O O O N O H O O H O O O H N O O H O O O O fulgide 1 O fulgide 2 Analyzing the results Once the calculations are completed, you will be prompted to open the newly generated file, which should have the suffix “_Prof” in the filename. Use the slider in the lower left-hand corner to see the progression of the geometry profile. Use this slider to ensure that the desired bonds are broken. Note here that the two lengthened (broken) bonds correspond to the bonds broken during the expected retro-[4+2] reaction: 296 If you wish to create an image (*.png) of the 3D structure, you can do so by selecting File > Save Image As. Be sure the slider is returned to the initial position before completing the following steps. Open the spreadsheet window by clicking the icon. Click “Add” and go to the “Molecule List” tab. Select “Relative Energy (kJ/mol)” from the list. You should see the relative energy values fill in the first column of the spreadsheet. On the 3D molecule viewer, click the line between the two constrained atoms. Then, with the spreadsheet window still open, click the icon in the lower right-hand corner. This will fill in the constraint profile values in the second column of the spreadsheet. 297 Thes values can be used to plot the energy profile and calculate force values. The maximum force immediately prior to bond cleavage is the estimated rupture force, Fmax. Relative energy Constraint (Å) Displacement (Å) 𝑙 (from Spartan) 𝐷 =𝑙−𝑙 Force (nN) (kJ/mol) 𝐸 (from Spartan) 𝐹= 𝐸 𝐷 −𝐸 10 × −𝐷 𝑁 Extending a calculation If the initial energy profile did not elongate the molecule enough to see a bond cleavage event, you may need to extend the calculation. In the CoGEF_Prof file, use the slider to view the final structure of the profile you previously ran. Right-click somewhere within the molecule boundaries and select “Copy.” Click the New Build icon and paste the final structure from the previous simulation. Select the Constrain Distance icon molecule. and click on the existing constraint line on the 298 Define a new profile using the Profile prompt in the lower right-hand corner. The beginning distance for this extension should reflect the final constraint distance from the first energy profile. Enter the new final bond length and the appropriate number of steps. Click the Calculations button to set up an Energy Profile calculation as done previous. Appending calculations After your extended calculation is finished, make a copy of the CoGEF file that includes the first portion of the calculation and save this with a distinct name. In this copied file, go to File > Append Molecules. Select the filename of the extended profile that you wish to append. Check that the process worked properly by using the slider in the lower left-hand corner to view the full profile. 299 Appendix C ATOMIC COORDINATES FOR MOLECULES DISCUSSED IN CHAPTER 2 The atomic coordinates for all numbered compounds discussed in Chapter 2 can be found below. Compounds labeled X are starting material geometries and those labeled X‡ represent the optimized transition state geometries. All final geometries were calculated at the M06-2X/6-311+G** level of theory. 1 C C C C O C O C O O C H H H H H H H H -0.30396 0.00000 1.00287 0.00000 1.03423 0.00000 -0.26122 0.00000 -1.08887 0.00000 -0.93827 0.00000 0.10058 0.00000 -0.31573 0.00000 0.74507 0.00000 -1.46640 0.00000 0.46337 0.00000 -0.82526 0.00000 1.84626 0.00000 1.89988 0.00000 -1.56375 0.88795 -1.56375 -0.88795 -0.09954 0.89360 1.43404 0.00000 -0.09954 -0.89360 -3.85119 -3.50022 -2.06139 -1.66423 -2.73727 -0.33776 0.64377 1.90905 2.69882 2.26377 4.10858 -4.79398 -4.17224 -1.41916 -0.21628 -0.21628 4.37535 4.59531 4.37535 1‡ C C C C O C O C O O C H H H H H H H H 0.80709 -0.29859 -1.02080 -0.31815 0.81391 -0.55877 0.53420 0.18522 0.86314 -0.64877 0.53760 1.63484 -0.53154 -1.94896 0.03819 -1.49075 0.74155 1.17264 -0.51207 -0.52524 -1.35165 -0.94134 0.12086 0.34974 0.88069 -0.16159 0.35641 -0.18734 1.24110 0.32812 -0.47480 -2.14123 -1.34093 1.75728 0.74927 1.39828 -0.20646 0.14884 -3.62548 -3.57537 -2.45389 -1.88459 -2.63625 -0.76700 0.87916 1.98118 3.04170 2.17748 4.33081 -4.31756 -4.27104 -2.07269 -0.55531 -0.23553 4.38365 5.03431 4.56642 300 2 C C C C O C O C O O C C H H H H H H H H H H 0.01933 0.00000 -3.09819 1.30718 0.00000 -2.67446 1.27156 0.00000 -1.23426 -0.03946 0.00000 -0.89900 -0.81499 0.00000 -2.01416 -0.78286 0.00000 0.39127 0.20452 0.00000 1.42536 -0.27583 0.00000 2.66730 0.74329 0.00000 3.51059 -1.44307 0.00000 2.96349 0.38977 0.00000 4.90396 -0.62782 0.00000 -4.43481 2.18076 0.00000 -3.30744 2.10589 0.00000 -0.55156 -1.41398 0.88772 0.48250 -1.41398 -0.88772 0.48250 -0.18615 0.89353 5.14165 1.33414 0.00000 5.43998 -0.18615 -0.89353 5.14165 0.13918 0.00000 -5.20865 -1.25566 -0.88468 -4.56385 -1.25566 0.88468 -4.56385 2‡ C C C C O C O C O O C C H H H H H H H H H H -0.08931 0.86422 1.47322 0.87119 -0.09416 1.05936 -0.32498 -0.20519 -1.05334 0.54810 -0.99920 -1.04241 1.07088 2.26419 1.89747 0.60601 -0.00809 -1.73766 -1.24797 -0.93386 -2.06551 -0.85297 -0.45722 -1.44283 -1.14942 0.00691 0.40710 0.72182 -0.11264 0.48080 -0.03701 1.40778 0.55945 -0.22150 -2.25949 -1.68907 0.46448 1.69533 0.44069 0.03213 1.62002 -0.99799 -0.22438 0.75504 -2.97806 -2.77539 -1.55472 -1.06896 -1.96784 0.09410 1.49807 2.61631 3.55512 2.90664 4.85045 -4.08335 -3.44861 -1.05495 0.72644 0.21833 5.28969 5.45065 4.79920 -4.83767 -3.70013 -4.53533 301 3‡ 3 C C C C O C O C O O C C C H H H H H H H H H H H H 0.62587 -0.63753 -0.95833 0.14103 1.11214 0.48908 -0.67668 -0.83899 -1.92921 -0.12064 -2.25144 1.70915 1.53488 -1.26734 -1.87686 0.64375 -3.16002 -2.42066 -1.44251 1.53238 1.92347 2.57265 1.03138 1.81477 2.44963 0.06023 -0.42194 -0.46670 -0.01101 0.31405 0.19655 -0.23504 0.27581 -0.25599 1.08538 0.19507 -0.60163 0.34757 -0.71178 -0.79292 1.26076 -0.33407 1.27095 -0.05586 -1.66666 -0.42023 -0.29209 0.10153 1.40344 -0.24542 -3.07939 -2.98246 -1.57886 -0.93428 -1.82725 0.50451 1.23202 2.45048 2.98227 2.97922 4.30851 0.93756 -4.21835 -3.80904 -1.11858 0.69898 4.57927 4.30492 4.99331 0.77635 1.99132 0.34723 -5.15262 -4.23878 -4.14634 C C C C O C O C O O C C C H H H H H H H H H H H H 0.07360 -0.86957 -1.38512 -0.73728 0.16010 -0.84749 0.58127 0.27057 1.18318 -0.70669 0.92921 0.95318 -0.29578 -1.13682 -2.14321 -1.63780 0.92006 1.74388 -0.02392 0.77258 0.75637 2.00087 0.66103 -0.21034 -1.01187 -0.83432 -1.76653 -1.32090 -0.13522 0.14380 0.72987 -0.09888 0.17857 -0.31683 0.80827 -0.05023 -0.74477 2.10357 -2.65151 -1.78408 0.50201 1.02351 -0.51872 -0.48065 -1.59384 0.18217 -0.74206 2.14615 2.49318 2.72743 -2.97931 -2.59637 -1.37052 -1.07160 -2.07438 0.01510 1.38519 2.58408 3.47502 2.98889 4.85331 -4.16591 -0.00501 -3.15122 -0.75599 0.72013 5.04473 5.40137 5.16246 -4.82242 -4.70937 -3.85662 -0.52310 1.00686 -0.55533 302 4 C C C C O C C C O C O O C C C C C C H H H H H H H H H H H H H H 0.00480 0.86995 0.91587 0.07700 -0.48493 -0.48491 -0.33977 -0.02707 0.40326 -0.11551 0.72952 -1.14881 0.35040 -0.60013 -0.92167 -0.29227 0.66192 0.98999 1.41162 1.49257 -0.02625 -1.57049 -0.22796 -1.40504 1.04405 -0.34335 -0.56605 -1.07370 -1.66273 -0.54457 1.15442 1.72986 -0.49497 -1.38937 -1.12289 -0.08107 0.31361 -0.23485 0.69221 2.17618 0.10153 0.23532 -0.34500 0.77556 -0.35701 -1.26913 -1.30533 -0.44190 0.46260 0.51154 -2.14891 -1.63574 -0.94582 -0.34419 0.77751 0.54033 2.32051 2.69606 2.59650 -1.93415 -2.01199 -0.47626 1.13364 1.20547 -4.62192 -4.08349 -2.66879 -2.46255 -3.63457 -5.99988 -1.25327 -1.36158 -0.16682 1.04562 1.91077 1.32867 3.25822 3.68948 5.04267 5.93744 5.47946 4.12656 -4.62522 -1.91622 -6.68615 -6.05578 -6.32029 -1.06291 -1.51370 -0.45655 -2.21163 2.97666 5.39654 6.99046 6.17290 3.74588 4‡ C C C C O C C C O C O O C C C C C C H H H H H H H H H H H H H H 0.07164 -0.72442 -1.29174 -0.81966 0.02213 0.91964 -1.04698 -0.69969 0.46646 0.09540 1.06884 -0.94898 0.79796 0.28683 0.07307 0.36771 0.87901 1.09668 -0.86430 -1.97026 0.88215 0.56651 1.95357 -1.79986 0.24291 -0.67501 -1.49710 0.06448 -0.32317 0.20154 1.11101 1.49364 -0.32544 -1.41718 -1.17247 0.05918 0.56144 0.00699 0.78331 2.21702 0.03134 0.08928 -0.43534 0.52127 -0.43981 -1.59200 -1.62123 -0.50499 0.64428 0.68123 -2.27293 -1.79829 -0.80462 0.92791 0.16230 0.37481 2.44986 2.50879 2.78473 -2.45032 -2.51817 -0.53113 1.51472 1.56548 -4.59647 -4.31407 -3.05546 -2.63707 -3.59941 -5.76237 -1.46840 -1.33851 -0.18012 1.02483 1.87262 1.49604 3.23115 3.81402 5.18988 5.96919 5.36937 3.99501 -4.95465 -2.49498 -6.48625 -6.23181 -5.44380 -0.80445 -1.83161 -0.29055 -1.83550 3.19011 5.65146 7.03957 5.97191 3.51031 303 5 C C C C O C C C O C O N C H H H H H H H H H H H H H -0.14632 0.14926 0.22382 -0.03889 -0.26377 -0.35502 -0.12309 0.85105 0.18266 -0.30892 -1.03437 0.10425 -0.31621 0.30098 0.43890 -1.36053 0.36376 -0.22695 -1.14491 1.87406 0.75582 0.62934 0.69914 -0.01651 0.16160 -1.39913 0.75383 -0.56713 -0.89808 0.25045 1.26392 1.70180 0.61461 1.72028 -0.59323 -0.70176 0.12807 -1.83601 -2.18130 -1.22713 -1.85623 2.12790 2.52350 1.17521 0.91542 1.40511 1.95073 2.62066 -2.45925 -1.40802 -3.11836 -2.30502 -3.19103 -3.11736 -1.71705 -1.04999 -1.92816 -4.31512 0.39790 0.78017 1.10656 2.36282 2.88141 2.94772 4.29464 -3.95723 -1.27253 -4.28518 -4.27193 -5.26030 0.64260 0.56499 1.84195 0.20524 2.42329 5.00309 4.56855 4.34494 5‡ C C C C O C C C O C O N C H H H H H H H H H H H H H -0.03743 -1.15630 -1.62172 -0.76999 0.20095 0.88456 -0.75597 0.06975 0.45865 0.16216 -0.78699 1.01319 0.63152 -1.56553 -2.47544 0.87473 1.90433 0.57923 -1.58741 1.03144 0.19908 -0.48234 1.59822 0.47455 1.44213 -0.28536 0.81019 -0.00044 -0.09796 0.66428 1.21096 1.28343 0.91142 1.97173 -0.78851 -1.02684 -0.52134 -1.90539 -2.49840 -0.45242 -0.64743 2.37498 0.96124 0.88071 0.51085 2.07998 1.77624 2.91434 -2.45817 -1.71836 -3.14232 -3.09277 -3.14227 -3.18806 -1.87131 -1.08602 -1.89266 -4.19788 0.27955 0.89723 1.03894 2.26363 2.89453 2.91503 4.18473 -4.07717 -1.50283 -4.24077 -3.97543 -5.16157 0.84613 0.39840 1.95932 0.78635 2.30633 4.92987 4.52412 4.11181 304 6 C C C C O C C C O C C O O C H H H H H H H H H H H H H H 0.83635 -0.21321 -0.49561 0.41283 1.22599 1.59539 -1.57606 0.69258 -0.48925 0.99691 -0.29981 0.75857 -1.47411 -1.44017 -0.73607 1.18375 1.53104 2.65049 -1.28962 -2.49450 -1.79369 1.52314 1.17476 1.89402 0.16934 -1.04780 -2.47180 -0.82344 0.76372 -0.08037 -0.67042 -0.13194 0.74513 1.65425 -1.66206 -0.31331 0.14402 -1.75200 0.53624 0.58614 0.87222 1.33063 -0.26265 1.57677 2.69494 1.37239 -2.66730 -1.39623 -1.69253 0.33935 -1.82632 -2.08129 -2.40715 0.54738 1.55526 2.22515 -2.81110 -2.98254 -1.69976 -0.84583 -1.51001 -3.72667 -1.39133 0.60670 1.32675 0.99431 2.58196 3.15751 3.09898 4.46036 -3.90964 -4.73236 -3.40042 -3.75689 -1.71153 -1.91804 -0.32338 0.87910 2.06806 0.46750 0.71900 5.10767 4.71423 4.53736 6‡ C C C C O C C C O C C O O C H H H H H H H H H H H H H H -0.88510 0.20802 1.04388 0.40453 -0.78073 -2.08584 2.34746 0.68820 -0.41199 2.00620 -0.77620 -0.57485 -1.46782 -1.92704 0.38328 -2.04309 -2.98899 -2.13804 3.14702 2.60472 2.28958 0.07222 1.94235 2.73338 2.35499 -1.08840 -2.44478 -2.61296 0.74339 0.01199 -0.13941 0.52873 1.05877 1.21892 -0.86583 0.72912 -0.79113 0.40940 -0.45936 0.60422 -1.46264 -1.18781 -0.36670 0.89385 0.82029 2.30934 -0.21860 -1.21333 -1.73093 1.46128 0.48502 1.14669 -0.58163 -0.97695 -2.08701 -0.33969 -2.64474 -3.04915 -1.92435 -0.88396 -1.35395 -3.36922 -1.89083 0.46674 1.38911 1.07147 2.56205 3.14534 3.17884 4.50201 -4.04430 -4.40685 -2.90208 -3.33406 -1.52549 -2.89039 -1.22556 0.97666 2.15484 0.71088 0.78726 5.16640 4.82862 4.50471 305 7 C C C C O C O C O C C O O C C C C C C C H H H H H H H H H H H H H H H H -1.65507 -1.62190 -0.88046 -0.50533 -0.98348 -2.26153 -0.64845 0.28876 -0.65814 1.04506 -0.17194 0.96760 -1.15581 -0.79398 0.32345 1.18573 2.14872 2.25313 1.38245 0.41610 -2.06448 -2.76252 -2.99214 -1.49549 0.97141 0.35295 1.63002 1.72570 -1.70721 -0.42999 -0.02928 1.11428 2.82148 3.00493 1.45440 -0.26894 1.99658 0.74874 -0.04700 0.75997 2.01451 3.27648 -1.39086 0.57312 0.63842 -0.74188 1.03710 1.36219 1.02304 1.43505 -1.82258 -0.96163 -1.50262 -2.87766 -3.72479 -3.20292 0.42592 3.12866 3.63065 4.04618 1.41798 -1.58327 -0.78903 -0.80949 1.36192 2.46155 0.77100 0.11019 -0.83423 -3.28754 -4.79864 -3.84510 -1.32755 -1.86004 -0.92613 0.09875 -0.14531 -1.77166 -1.02222 1.33849 2.44583 1.38754 3.61715 3.83840 4.50527 5.83360 -1.90023 -2.57090 -3.42260 -3.59974 -2.91448 -2.06454 -2.78936 -2.72739 -1.04091 -1.88934 1.44971 1.35468 2.30620 0.53637 6.41648 5.81943 6.23458 -2.43365 -3.94748 -4.26307 -3.04235 -1.52355 7‡ C C C C O C O C O C C O O C C C C C C C H H H H H H H H H H H H H H H H -1.27368 -0.64710 0.25389 0.13698 -0.82591 -2.31235 1.10592 0.71444 -0.66549 1.90704 -0.64381 0.08337 -1.56859 -1.62051 1.06703 2.04658 2.03311 1.04994 0.07591 0.07916 -0.81972 -2.59369 -3.19293 -1.93302 0.54640 1.81037 2.06301 2.77924 -2.40517 -1.86419 -0.66768 2.79903 2.79272 1.04325 -0.68732 -0.66625 1.87420 0.76815 0.34572 1.22387 2.15733 2.76473 -0.68056 1.27755 0.31411 0.46349 0.72577 1.58581 0.08032 0.46259 -1.51466 -1.36308 -2.21921 -3.19865 -3.33001 -2.48333 0.33218 2.42076 2.76824 3.78706 2.19066 -0.56450 0.49234 0.90923 -0.14352 1.52114 0.26282 -0.59157 -2.11756 -3.86092 -4.09420 -2.56628 -1.34475 -1.86352 -0.86267 0.21278 -0.12013 -1.91005 -0.88091 1.47657 2.64882 1.83444 3.85464 4.34638 4.62208 5.99693 -2.00423 -2.97145 -4.07005 -4.18382 -3.19633 -2.09177 -2.83415 -2.90338 -1.26392 -1.97435 2.03642 1.49070 2.91077 1.34283 6.44451 6.09492 6.48895 -2.85867 -4.83577 -5.04114 -3.28148 -1.30916 306 8 C C C C O C O C C C C C C C O C O O C C H H H H H H H H H H H H H H H H 0.33540 0.23620 -0.45764 -0.73207 -0.24994 0.92415 -0.81573 0.07073 -0.33455 0.48945 1.71279 2.10192 1.28567 -1.39205 -0.32675 -0.67781 0.39942 -1.78488 0.18932 -2.13177 0.60007 1.70673 1.35691 0.16025 -1.28884 0.17357 2.35299 3.04974 1.59383 -2.06048 -0.17344 1.16227 -0.52576 -1.43954 -2.61872 -2.89146 -0.39409 -1.56517 -1.24826 0.08132 0.60524 -0.02343 -2.14637 -2.38063 -3.32886 -3.61439 -2.96042 -2.01677 -1.71610 1.02654 1.86386 3.07992 3.68914 3.55398 5.02591 0.34956 -2.53165 0.72789 -0.90725 0.38830 -3.82525 -4.35114 -3.18492 -1.50156 -0.97644 1.67908 5.66181 5.36365 5.01641 -0.22204 1.10665 -0.32453 -3.18552 -2.50619 -1.29352 -1.30961 -2.47269 -4.49668 -0.32556 0.70503 1.64228 2.72270 2.87135 1.92739 0.83712 -0.37406 0.16531 0.57298 1.04820 0.51814 1.53197 0.76480 -2.81771 -4.36938 -4.96348 -5.16009 1.51078 3.45215 3.71575 2.03215 0.10879 -0.93943 0.72544 1.87625 2.35358 1.38516 1.37960 0.36701 8‡ C C C C O C C O C O O C O C C C C C C C H H H H H H H H H H H H H H H H 1.60947 0.58281 0.31277 1.19966 1.98475 2.33625 1.33953 0.03661 -0.46033 -0.03837 -1.24280 -0.54468 -0.61964 -1.34774 -0.73805 -1.48991 -2.82570 -3.41589 -2.67374 2.56664 0.09726 1.93285 3.39916 2.23458 0.79623 -0.11243 -1.63252 -0.23977 0.30154 -1.03038 -3.40669 -4.45469 -3.10731 2.40912 2.87479 3.36659 0.91993 1.52066 0.66393 -0.40086 -0.22267 1.31859 -1.53123 -2.82060 -3.74259 -3.69100 -4.61099 -4.70382 0.76489 1.95793 3.10838 4.27735 4.27874 3.10931 1.93296 -2.37079 2.44710 2.25522 1.44487 0.54424 -1.49575 -4.49844 -4.65576 -5.69201 3.08197 5.18535 5.19133 3.10805 1.00979 -3.31726 -2.54088 -1.82595 -2.17316 -1.48926 -0.39755 -0.46659 -1.58540 -3.40038 0.33913 -0.48551 0.24696 1.54029 -0.12143 2.40997 0.55387 0.60232 1.08174 1.15490 0.75658 0.28358 0.20141 0.27462 -1.75028 -3.78046 -3.18217 -4.16402 1.27569 3.38680 2.46231 2.06433 1.38959 1.52768 0.81718 -0.02560 -0.16514 0.78610 -0.75589 0.78780 307 9 C C C C O C O C C O C C O O C H H H H H H H H H H H H H H -0.79964 0.24976 0.95474 0.29072 -0.78843 -1.89415 2.06367 2.62956 0.45912 -0.55478 1.83204 -0.96412 -0.58887 -1.86576 -2.41357 0.48623 -1.78784 -2.86832 -1.86313 2.91440 3.51329 1.92386 0.22321 2.02951 1.88517 2.59544 -1.62096 -3.11936 -2.92180 0.75582 -0.04492 -0.28549 0.38970 1.02592 1.35818 -1.03484 -1.59802 0.55224 -0.29341 0.15909 0.07810 1.04789 -0.79743 -0.53341 -0.41202 1.06078 1.02440 2.44847 -0.81143 -2.14513 -2.28251 1.58237 -0.89241 0.33487 0.76224 -0.54111 -1.33794 0.42999 -2.43192 -2.75671 -1.52697 -0.54593 -1.10820 -3.23492 -1.33845 -2.51939 0.91499 1.55262 1.42752 2.75948 3.37113 3.18718 4.48874 -3.74243 -4.27734 -2.87048 -3.17444 -3.22238 -2.20059 -2.99641 1.18841 1.22086 2.50212 0.93375 5.23588 4.67264 4.49123 9‡ C C C C O C O C C O C C O O C H H H H H H H H H H H H H H -0.72096 0.32257 1.03599 0.38813 -0.70068 -1.80983 2.12272 2.66353 0.58278 -0.66033 1.84700 -1.09025 -0.80450 -1.96164 -2.50326 0.53235 -1.71217 -2.78004 -1.76553 2.94874 3.53925 1.93043 0.02719 2.15217 1.72329 2.63345 -1.70914 -3.16639 -3.06485 0.86122 0.02501 -0.14970 0.60570 1.21448 1.41520 -0.86997 -1.57742 0.78191 -0.56615 0.36502 -0.20477 0.81293 -1.11523 -0.80908 -0.39569 1.05268 1.11309 2.50658 -0.87185 -2.10136 -2.29042 1.59514 -0.63268 0.40723 1.07007 -0.73217 -1.63548 0.12571 -2.48077 -2.78576 -1.57459 -0.59772 -1.19409 -3.31818 -1.34532 -2.46962 0.77070 1.59136 1.43931 2.73852 3.36324 3.25300 4.53915 -3.75546 -4.33967 -2.91783 -3.31609 -3.25153 -2.09846 -2.85002 1.22441 1.13025 2.51945 1.14892 5.28314 4.78470 4.50899 308 10 C C C C O C O C C C C C C C O C O O C H H H H H H H H H H H H H H -0.01260 -0.23516 0.36789 0.91942 0.67635 -0.36334 0.41284 -0.08769 0.43286 -0.05086 -1.04550 -1.56017 -1.08974 1.63231 0.69734 0.74307 -0.24386 1.54526 -0.33222 -0.75353 -0.91895 -0.97904 0.53794 1.20988 0.35717 -1.41619 -2.33781 -1.49307 2.41076 2.07431 0.57497 -1.19223 -0.48039 -0.71797 -1.76005 -1.38183 -0.15152 0.26187 -0.47148 -2.15599 -1.63616 -2.17122 -1.72530 -0.75062 -0.23092 -0.67107 0.75127 1.71347 1.92162 2.74594 1.45388 3.08285 -2.67874 -1.32311 0.42566 -0.33235 -2.92390 -2.13821 -0.39977 0.52423 -0.26557 1.31241 0.17663 3.59555 3.74080 2.17962 -3.65067 -2.80568 -1.56649 -1.73336 -3.01099 -5.07180 -0.44165 0.73873 1.91294 3.13748 3.19061 2.00630 0.77112 -0.80947 -0.26162 1.05216 1.37460 1.81993 2.76842 -3.02983 -5.46196 -5.16684 -5.67307 1.85101 4.05266 4.14636 2.03587 -0.14889 -1.32702 0.00345 3.08621 2.85189 3.35959 10‡ C C C C O C O O C O O C O C O C O O C H H H H H H H H H H H H H H 1.47983 0.81681 1.10465 1.92782 2.14278 1.58373 2.43909 1.23328 0.07453 -0.07210 -0.84258 -1.33403 0.76224 -0.31866 -0.13678 -1.21684 -2.45151 -2.61160 -1.54343 0.21845 2.62741 1.22041 0.99428 3.24470 2.35745 -1.25744 -2.13598 -1.53244 0.83383 -1.08863 -3.28846 -3.57317 -1.65766 0.35577 0.97295 0.19810 -0.85388 -0.72517 0.69585 -1.94137 -3.51758 -3.45419 -2.39408 -4.24706 -2.26794 0.39889 1.23260 2.20404 3.01039 2.83897 1.85144 1.03388 1.86650 0.88021 -0.13608 1.58518 -2.50959 -1.93365 -1.37443 -2.15026 -3.14050 2.31759 3.77454 3.47003 1.70785 0.25101 -2.57038 -1.53791 -0.39388 -0.79218 -2.14981 -4.00725 -0.10449 -0.39017 0.15120 0.98589 -0.02874 1.64004 0.87731 1.15494 2.12674 2.47604 1.85569 0.88568 0.53093 -1.60994 -4.27172 -4.61462 -4.22112 -0.54934 0.97336 2.25657 0.91025 2.26319 2.59420 3.23336 2.12928 0.40742 -0.21055 309 11 C C C C O C C O C N O C H H H H H H H H H H H 0.19022 -0.90683 -1.63723 -0.92917 0.18555 1.33197 -1.14436 -0.16014 -0.17271 0.78527 -0.96796 0.97128 -1.16205 -2.56325 2.27802 1.21204 1.37973 -1.03062 -2.14548 1.41244 1.24132 1.77284 0.05911 2.43507 3.03060 1.99970 0.85707 1.10827 2.93250 -0.53902 -0.84466 -2.11663 -2.32161 -2.95781 -3.62710 4.07533 2.09407 2.76700 4.00059 2.41913 -1.23859 -0.63976 -1.56292 -4.37464 -3.54908 -3.94754 -1.73503 -1.19952 -0.51581 -0.68616 -1.43024 -2.54445 -0.24425 0.76171 1.21629 2.13362 0.83475 2.74312 -1.28316 0.03007 -2.02376 -2.72210 -3.50758 -1.07450 0.17614 2.35350 1.99465 3.47404 3.24866 11‡ C C C C O C C O C N O C H H H H H H H H H H H -0.02706 -1.01645 -1.63549 -1.00399 -0.01155 0.95107 -1.18263 0.19826 0.13252 0.82658 -0.50838 1.09129 -1.23667 -2.45140 1.96546 0.84572 0.78422 -0.67831 -2.02431 1.51008 1.69420 1.62409 0.15277 2.44582 3.02621 1.98099 0.80321 1.12771 3.03215 -0.50671 -0.80548 -2.02800 -2.30614 -2.93569 -3.67950 4.08066 2.03296 2.76656 4.11499 2.63386 -1.30598 -0.75767 -1.61279 -4.21847 -3.67055 -4.21816 -2.01952 -1.23772 -0.55633 -0.95547 -1.85683 -2.95932 -0.58285 1.12696 1.51603 2.68149 0.95551 3.07307 -1.19155 0.14931 -2.65352 -2.97578 -3.96292 -1.10682 0.04676 2.94477 2.33396 4.02373 3.20702 310 12 C C C C O C C O C N O C O C C C C C C H H H H H H H H H H H H H H H -1.21756 -1.24933 -1.30464 -1.30383 -1.25861 -1.15927 -1.34372 -0.02929 0.09222 1.33756 -0.82737 1.70563 -1.41779 -0.36406 0.91534 1.92309 1.66081 0.37302 -0.64329 -1.23187 -1.13412 -2.03351 -0.26530 -1.62105 -2.06135 2.03144 1.60601 2.74191 1.07571 1.12634 2.92091 2.45042 0.15605 -1.65051 2.86944 2.33254 0.91361 0.68324 1.88296 4.26519 -0.55612 -0.77610 -1.86837 -1.98976 -2.63419 -3.11186 -0.05104 -0.21228 0.27044 0.03195 -0.68067 -1.16200 -0.92931 2.86741 4.95351 4.49145 4.41926 -1.39320 -0.47571 -1.31336 -4.05792 -2.98163 -3.14247 0.81965 0.40764 -0.86042 -1.71901 -1.29287 -0.44039 0.80632 0.60736 -0.72782 -1.37663 -0.94209 -1.52812 -2.07539 -2.86155 -3.34687 -3.09231 -4.19294 1.56878 2.44577 2.19076 3.12399 4.28927 4.52413 3.60655 1.74302 -0.09835 -1.55665 -1.55058 -0.88623 -2.34650 -3.06694 -3.65705 -4.49621 -5.08314 1.28138 2.92911 5.00870 5.42818 3.77244 12‡ C C C C O C C O C N O C O C C C C C C H H H H H H H H H H H H H H H -1.39628 -0.82062 -0.71994 -1.25777 -1.65619 -1.76015 -1.36161 0.40537 0.45766 1.63902 -0.43536 1.74802 -0.20373 0.18139 1.52784 1.92103 0.97362 -0.37530 -0.78368 -0.51666 -1.47977 -2.83657 -1.24807 -1.17756 -1.96377 2.21961 1.55230 2.76419 1.04766 2.24359 2.97002 1.28500 -1.11463 -1.82866 2.49873 1.88773 0.52812 0.37567 1.62559 3.91177 -0.72863 -0.78704 -1.86005 -2.02774 -2.71824 -3.02899 -0.49425 -0.27147 -0.37410 -0.20335 0.06687 0.16299 -0.01076 2.37221 4.52004 3.99363 4.27899 -1.70256 -0.68263 -1.20610 -4.02037 -3.00989 -2.85100 -0.58423 -0.28047 0.19975 0.36785 0.05192 -0.22226 0.86833 0.51844 -0.76376 -1.19668 -0.46540 -1.57737 -2.68640 -3.40390 -4.09567 -3.48472 -5.14196 1.19269 2.51950 2.82703 4.15220 5.13601 4.79979 3.48096 1.78191 0.39207 -0.63309 -1.35752 -1.14614 -2.47389 -4.17116 -4.73303 -5.53371 -5.96428 2.04145 4.41188 6.16511 5.56474 3.19883 311 13 C C C C O C C O C N O C C O C C C C C C H H H H H H H H H H H H H H H H H 2.61427 2.02021 1.29308 1.49297 2.31263 3.48965 1.05110 0.14848 -1.13753 -1.84957 -1.58415 -3.26837 2.19981 0.59855 -0.43785 -0.86905 -1.92835 -2.55380 -2.11291 -1.05488 2.08105 3.67054 3.01976 4.44773 0.51776 -1.38206 -3.44307 -3.63533 -3.81747 2.71029 2.91456 1.82130 -0.36958 -2.26371 -3.37693 -2.59503 -0.72413 1.25187 1.38659 0.16590 -0.62137 0.03868 2.13956 -1.99670 -1.95947 -1.62629 -1.52839 -1.45118 -1.21803 -2.90148 -0.20661 0.59791 0.39195 1.14222 2.09668 2.28792 1.53972 2.23824 3.06484 2.38030 1.65593 -2.40503 -1.69391 -0.23816 -1.20876 -1.97081 -2.49522 -2.97788 -3.89646 -0.35266 0.98140 2.68296 3.02259 1.68317 -0.70164 0.51102 0.71710 -0.36783 -1.23843 -1.50791 -0.72151 -1.85131 -1.59561 -2.72989 -0.47590 -2.69958 -1.13208 1.83306 2.25800 3.56633 4.06182 3.26037 1.95477 1.44100 1.17050 -0.96253 -2.46424 -1.71079 0.13727 -3.60808 -2.24935 -3.72385 -2.12999 -2.00675 -0.31145 -1.36795 4.17499 5.07990 3.65048 1.32020 0.41985 13‡ C C C C O C C O C N O C C O C C C C C C H H H H H H H H H H H H H H H H H 2.73567 1.74531 0.90390 1.43130 2.56374 3.91546 0.96488 -0.36735 -1.34882 -2.33262 -1.46899 -3.35104 1.82125 -0.20106 -0.70900 -0.63520 -1.18177 -1.78370 -1.84609 -1.30883 1.65268 3.93421 3.87600 4.83151 0.15517 -2.07596 -3.91857 -4.03299 -2.92664 2.40071 2.51940 1.21075 -0.16084 -1.13437 -2.20690 -2.31869 -1.35252 1.17754 1.39616 0.26563 -0.58480 0.01354 1.98709 -1.79447 -1.20461 -2.03398 -1.63070 -3.10820 -2.56271 -2.67820 -0.03174 0.94639 0.71688 1.66250 2.81124 3.01808 2.07927 2.25595 2.90764 2.22919 1.42231 -2.25100 -0.88015 -2.93825 -2.03406 -3.41811 -2.10458 -3.19326 -3.42275 -0.18508 1.49844 3.54392 3.90869 2.21617 -0.13507 0.79086 0.70612 -0.25944 -0.77079 -0.51481 -0.75917 -2.23943 -2.36281 -3.24195 -1.75049 -3.69258 -1.59304 1.39166 2.25164 3.61575 4.48013 3.97340 2.59672 1.72130 1.43438 0.06529 -1.57911 -0.32749 -0.20288 -3.86539 -2.84094 -4.35739 -4.22793 -2.31528 -0.92294 -2.09860 3.98349 5.55004 4.64999 2.20009 0.64667 312 14 C C C C O C C C O C O C H H H H H H H H H H H H -0.09327 0.35665 0.37471 -0.06826 -0.35580 -0.34094 -0.29241 0.53534 0.08560 -0.46286 -1.25793 0.04232 0.64359 0.67407 -0.09063 -1.38990 0.27084 -1.35453 0.33924 0.26798 1.59745 1.12482 -0.43502 -0.17108 0.67671 -0.60123 -0.98531 0.09305 1.11160 1.64336 0.37849 1.55315 -0.82894 -1.05883 -0.31137 -2.34026 -1.19986 -1.93071 1.17791 1.94801 2.54014 0.56285 1.72573 2.45236 1.34801 -2.27762 -2.51259 -3.16466 -2.70568 -2.65981 -1.27140 -0.58323 -1.43646 -3.80563 0.86688 1.36916 1.54903 2.75273 3.26764 3.34375 -3.51025 -0.84883 -4.75847 -3.82951 -3.68200 1.04741 2.42777 0.81230 1.22210 3.46662 4.30461 2.66126 14‡ C C C C O C C C O C O C H H H H H H H H H H H H -0.32657 1.04954 1.54696 0.45128 -0.69165 -1.39828 0.31859 1.47923 -0.08829 -0.75776 -1.18260 -1.01026 1.60300 2.57882 -0.96292 -2.08625 -1.96666 -0.66718 1.24691 1.64428 2.38727 -0.05942 -1.70264 -1.40540 0.63274 0.54377 0.66261 0.82918 0.80251 0.57812 0.96941 1.19889 -1.13967 -1.19736 -0.21645 -2.60590 0.40838 0.63576 0.42525 -0.24002 1.51099 1.20324 0.85109 2.28245 0.72557 -3.03665 -2.58650 -3.23742 -2.61694 -2.71764 -1.41463 -0.57997 -1.34734 -3.63542 0.79489 1.68385 1.38667 2.47038 3.10192 2.99691 -3.63283 -1.09785 -4.62085 -3.41094 -3.63044 1.17890 2.68843 1.73167 1.31357 3.32075 3.83754 2.19938 313 15 C C C C O C C O C C C C C C C O C O C H H H H H H H H H H H H H H H H -1.54132 -1.54872 -0.82696 -0.42433 -0.86586 -2.10847 0.36344 -0.63491 0.31725 1.19732 2.13639 2.20075 1.31358 0.37020 1.09272 -0.57632 -0.09773 1.05951 -1.17429 -2.00457 -1.31882 -2.61838 -2.82412 1.06710 1.15690 2.82226 2.93443 1.35483 -0.32735 1.76901 1.67789 0.38232 -1.54134 -0.77352 -2.00889 1.98158 0.67659 -0.01857 0.89738 2.12566 3.21472 0.84317 -1.37081 -1.93804 -1.19375 -1.86507 -3.25398 -3.98258 -3.33026 -0.47331 1.06062 1.60113 1.91558 1.75117 0.25402 3.93854 2.96462 3.68155 1.67804 -0.11160 -1.28782 -3.76582 -5.06562 -3.87912 -0.65941 -0.42287 -1.29731 0.76096 2.25512 2.31545 -1.30994 -1.68188 -0.65612 0.26094 -0.13822 -1.91087 1.51857 -0.58354 -1.40360 -2.18263 -2.96498 -2.96740 -2.17494 -1.39228 1.72400 2.60749 3.73764 3.88095 4.77061 -2.56360 -2.12475 -2.84025 -1.23031 1.52675 -2.18153 -3.57427 -3.57815 -2.16635 -0.77062 0.88712 2.64226 1.79301 5.04715 5.64632 4.35341 15‡ C C C C O C C O C C C C C C C O C O C H H H H H H H H H H H H H H H H -1.15262 -0.58752 0.24185 0.14923 -0.73159 -2.10479 0.69211 1.00607 1.02249 1.94937 1.98405 1.10142 0.17999 0.13444 1.80790 -0.81519 -0.85164 -0.09565 -1.91122 -0.75590 -1.65054 -2.37605 -3.00440 0.56590 2.62479 2.70308 1.13293 -0.50598 -0.57203 2.72742 1.92875 1.64546 -1.56975 -2.06269 -2.84971 1.84250 0.64001 0.28907 1.30336 2.24830 2.72041 1.48797 -0.79388 -1.70805 -1.53449 -2.46670 -3.54463 -3.69625 -2.77144 0.64900 0.75727 1.35157 2.26843 0.82970 0.09585 3.69820 2.27155 2.86613 2.47381 -0.68717 -2.34939 -4.26718 -4.53480 -2.86631 0.95803 0.81655 -0.40773 -0.12500 1.53117 0.65416 -1.32747 -1.67534 -0.58875 0.36307 -0.12772 -2.04441 1.62889 -0.43318 -1.49368 -2.50939 -3.54289 -3.54505 -2.51154 -1.47132 2.14304 2.88547 4.02013 4.36531 4.97969 -2.59060 -2.22002 -2.99782 -1.44230 2.06061 -2.48330 -4.34472 -4.35171 -2.51217 -0.65503 1.63261 3.21106 1.94042 5.38651 5.79822 4.45337 314 16 C C C C O C C O C C S O C O C C C C C C H H H H H H H H H H H H H H H H -1.87952 -1.77944 -1.40812 -1.31488 -1.59488 -2.22964 -0.93022 0.46646 -1.76001 1.37481 0.79719 2.52734 2.39865 -1.24096 -0.04525 1.15218 2.31366 2.28308 1.07576 -0.09250 -1.94950 -2.42080 -1.41284 -3.12334 -1.00801 -2.80793 -1.41851 -1.66993 2.18417 3.04697 2.85057 1.17930 3.24745 3.19116 1.03934 -1.04181 1.57207 0.21806 -0.20156 0.91015 2.00093 2.61304 1.10646 1.53366 2.14898 1.05678 -0.04167 1.38641 -0.42343 -1.50030 -1.87237 -1.20464 -1.66860 -2.78589 -3.44856 -2.99540 -0.40615 2.14210 3.32931 3.15988 0.13116 1.84545 2.24430 3.11463 -1.12775 -0.88565 0.48012 -0.33420 -1.14677 -3.13721 -4.32033 -3.49302 -2.79122 -2.85554 -1.53995 -0.76490 -1.53356 -3.78981 0.65293 0.65679 1.37982 1.51042 2.78682 1.40612 3.53755 -1.14997 -0.56146 -0.79741 -0.18320 0.64562 0.86000 0.25880 -3.71832 -4.75311 -3.90272 -3.48075 1.13775 1.38049 2.41142 0.88082 4.34002 2.79609 3.93952 -1.44193 -0.35930 1.12096 1.50303 0.41816 16‡ C C C C O C C O C C S O C O C C C C C C H H H H H H H H H H H H H H H H 1.59546 0.77239 0.44477 1.10098 1.79726 2.26881 1.10228 -0.40443 2.17719 -1.20045 -0.71290 -2.22162 -2.09474 -0.37599 -0.73625 -2.08795 -2.47406 -1.51458 -0.16132 0.23859 0.45109 2.01398 1.95510 3.35196 0.68751 3.09185 1.92393 2.36336 -1.89745 -3.02886 -2.13870 -2.81455 -3.52730 -1.81981 0.58800 1.28644 2.23514 2.15489 0.78224 0.10600 1.02729 3.38762 -1.25546 -1.37808 -1.81411 -2.38294 -3.82299 -2.42980 -4.93473 0.16852 0.85643 1.04621 1.68259 2.11926 1.91486 1.27493 2.97633 4.30396 3.47336 3.24903 -1.89529 -1.86807 -2.81803 -1.16691 -5.85129 -4.49233 -5.14762 0.69989 1.83829 2.61520 2.24687 1.09874 -1.11917 -0.02697 0.09158 -0.91962 -1.66647 -1.76122 -1.26331 -2.47282 -2.13205 -2.53163 -1.54003 -3.19563 -1.89900 0.95391 2.11242 2.35300 3.53036 4.44046 4.17773 3.00854 0.59293 -1.23225 -2.80373 -1.74121 -0.49068 -1.53193 -2.46684 -2.98825 -1.34426 -1.56308 -2.96398 1.62758 3.73204 5.35418 4.88678 2.79263 315 17 C C C C O C C Br O C C O O C H H H H H H H H H H H -0.59430 -0.25298 0.39725 0.41285 -0.19370 -1.28775 0.93507 1.09549 -0.22457 1.71783 -0.00823 -1.14943 1.04552 -1.08697 -0.43427 -1.54881 -2.20104 -0.64411 1.54490 2.58354 1.09018 2.06610 -0.38789 -0.77962 -2.09507 2.77314 2.39455 1.12746 0.82101 1.82846 3.96442 -0.33480 0.07501 -1.12210 0.07079 -2.41536 -2.97189 -2.98703 -4.38089 2.93820 4.63950 3.67096 4.49353 -0.94268 0.66531 0.66507 -0.81753 -4.57025 -4.92256 -4.66230 0.93351 2.19219 2.04562 0.72494 0.03992 0.38396 -0.04472 3.43264 -0.43852 -1.28178 -0.66184 -1.04005 -0.53684 -1.31627 3.10539 1.19783 -0.13832 -0.32216 0.62451 -0.98542 -1.94715 -1.80924 -2.12987 -0.42267 -1.60567 17‡ C C C C O C C Br O C C O O C H H H H H H H H H H H -0.32113 -0.42200 0.14701 0.57803 0.26360 -0.72911 1.16171 0.28830 -0.60082 1.70395 -0.33517 -1.42748 0.74255 -1.22525 -0.85358 -1.19891 -1.43059 0.14644 1.47828 2.70907 1.10067 1.79717 -0.46567 -0.92359 -2.18348 2.89990 2.19190 0.94413 0.94221 2.16659 4.27432 -0.04499 -0.49079 -1.20064 0.20638 -2.43785 -3.20699 -2.97991 -4.61890 2.54315 4.75511 4.24803 4.85096 -0.94017 0.62878 0.92397 -0.72886 -4.90701 -4.96187 -5.05746 1.01317 2.19606 1.92948 0.60439 0.06568 0.65495 -0.16679 3.09788 -0.79766 -1.51929 -0.77595 -1.08467 -0.52039 -1.07777 3.11924 1.51025 -0.18203 0.34723 0.35593 -1.38948 -2.07303 -2.06745 -1.80523 -0.08741 -1.34709 316 18 C C C C O C C N C O C C O O C H H H H H H H H H H H -3.08129 -2.49027 -1.08033 -0.93005 -2.12821 -4.48144 -0.06788 0.70963 0.24239 1.34049 0.03690 2.55638 3.43342 2.80328 4.80581 -2.97267 -4.80242 -4.57868 -5.13346 0.44583 0.92369 -0.81959 -0.14336 5.10806 5.37512 4.92865 0.40048 0.29836 0.11851 0.12861 0.29627 0.59004 -0.02310 -0.12859 0.01526 -0.34705 -1.02699 0.03290 -0.38993 0.65352 -0.06272 0.33858 -0.24573 1.51054 0.65033 0.99408 -1.07126 -0.75103 -2.00543 -0.50852 -0.48591 1.01876 0.47619 1.68702 1.43083 0.07474 -0.50506 0.02621 2.41733 3.26022 -0.84591 0.00246 -1.93364 -0.39717 0.49626 -1.39823 0.21615 2.65025 -0.59918 -0.55321 0.89651 -1.28815 -2.56643 -2.54954 -1.48535 -0.73053 1.03804 0.18017 18‡ C C C C O C C N C O C C O O C H H H H H H H H H H H -2.66757 -2.99996 -2.04229 -1.16383 -1.59067 -3.30062 -1.98123 -1.95226 -0.02782 1.64383 0.50400 2.51728 3.49390 2.58719 4.52113 -3.83170 -3.63422 -2.57334 -4.15165 0.40260 1.55847 -0.03510 0.35963 5.07405 5.18480 4.10536 0.88437 -0.28036 -1.22020 -0.59985 0.69249 2.21662 -2.57358 -3.66196 -0.99291 -0.14131 -2.36653 0.41221 1.04000 0.45181 1.70028 -0.41234 2.44313 2.97534 2.23475 -0.26705 -2.34448 -2.91005 -2.89650 0.99268 2.13955 2.48390 0.38848 1.07167 0.69904 -0.20221 -0.35648 0.36313 1.14098 1.50774 -0.87549 0.59063 -0.89873 -0.12534 0.61620 -1.36034 -0.11724 1.74495 -0.65257 0.66022 1.04011 -1.55839 -1.16609 -1.68747 0.04093 -0.73654 0.62524 -0.75243 317 19 C C C C O C C C O C O O C C C O H H H H H H H H H H H H H H H H 0.68191 1.11850 0.92438 0.37729 0.22189 0.60889 -0.02949 1.10418 -0.47326 -1.26299 -1.57849 -1.63547 -2.43436 1.36616 0.14019 -0.46356 1.52703 1.15543 0.99884 1.19944 -0.42276 -0.88616 0.84135 2.00717 -2.58417 -3.38254 -1.94597 1.69655 2.18159 0.43829 -0.59893 -0.89094 -3.27926 -3.18471 -1.81755 -1.18952 -2.06246 -4.39027 0.21850 1.07666 0.77485 1.83918 2.25452 2.34256 3.40997 0.81369 1.07005 2.33461 -3.99152 -1.36941 -5.30061 -4.16219 -4.56820 0.19832 2.12936 0.89235 3.60220 3.19347 4.25686 -0.21801 1.46710 1.07622 0.27053 2.31272 -0.07084 1.21041 1.61473 0.54728 -0.48478 -1.05372 0.26759 -0.30232 1.52386 1.42229 2.63431 0.38720 2.69209 -1.78650 -2.66428 -2.41155 1.79861 2.56827 -0.59962 -1.94418 -1.36598 -0.40941 -0.17095 0.28395 3.75004 2.20233 2.21227 -1.94416 -2.10719 -3.71350 -2.54232 -1.54395 19‡ C C C C O C C C O C O O C C C O H H H H H H H H H H H H H H H H 1.11952 -0.20211 -0.92694 -0.01296 1.24254 2.35508 -0.17839 0.85880 -0.06107 -0.65686 -0.67304 -1.19115 -1.31321 0.49825 -0.80708 -0.82377 -0.57444 -1.99082 2.11346 3.05741 2.83613 -1.20993 0.90178 1.83735 -1.22296 -2.36437 -0.81716 0.42961 1.31946 -0.92370 -1.66769 -0.95174 -3.36249 -3.68533 -2.49275 -1.50473 -2.06189 -4.17709 -0.13861 0.67956 0.68989 1.80899 2.34180 2.41634 3.61210 0.85333 1.61652 2.86997 -4.66839 -2.34048 -5.21048 -3.78720 -4.13622 0.19037 1.66607 0.21103 3.87252 3.54618 4.36224 -0.12064 1.40246 1.82078 1.01217 2.71396 0.22621 0.45752 0.31426 -0.00577 -0.05146 0.23157 -0.24289 -0.93154 1.67338 1.71312 2.96202 0.77755 3.10239 -2.42184 -2.64103 -1.97538 0.69675 0.42118 0.47238 0.97181 -0.74827 -0.29389 -0.47035 -0.83180 4.15441 2.82108 2.48615 -2.91554 -2.88926 -3.70673 -2.33162 -1.02443 318 20 C C C C O C C C C C O C O O C O C H H H H H H H H H H H H H H H H H H 1.71579 2.60022 2.26166 1.19562 0.85354 1.52190 0.38909 0.51436 -0.02767 -1.40783 0.87484 0.00234 0.61914 -1.15473 -0.19239 -2.27972 -3.55252 3.39373 2.74680 2.26290 1.63555 0.52438 -0.65576 -0.03897 1.56514 0.64622 -0.06398 -1.79251 -1.36911 0.46483 -1.02771 -0.56070 -4.03013 -4.16429 -3.47003 -1.95509 -0.94277 0.08500 -0.37735 -1.62032 -3.28277 0.16580 1.67397 2.48714 2.04627 -0.49177 -0.63707 -1.22522 -0.29872 -1.45807 2.03483 1.51528 -0.93098 1.03966 -3.41897 -4.08565 -3.36079 -0.12628 1.93790 1.92260 2.41656 3.53925 2.72866 1.04086 -1.93961 -2.11018 -0.51117 2.11320 1.54805 0.47775 -2.22055 -2.41839 -1.47510 -0.77647 -1.22343 -2.85744 0.34637 0.52061 -0.66062 -1.11574 1.55532 2.54762 3.56381 2.53319 4.72655 -0.00086 -0.32769 -3.14896 -1.34031 -3.64427 -2.12526 -3.29571 0.22229 1.42433 0.69394 -1.51771 -0.36614 -1.88450 -1.56029 5.44444 4.47463 5.11912 -1.11262 0.57296 -0.67312 20‡ C C C C O C C C C C O C O O C O C H H H H H H H H H H H H H H H H H H 1.86727 2.76231 2.34418 1.20740 0.93631 1.77910 0.37391 0.46375 -0.27901 -1.69631 1.17832 0.25225 0.74263 -0.95945 -0.22293 -2.37197 -3.67074 3.60721 2.79940 2.56718 1.88526 0.80614 -0.55209 -0.00105 1.50674 0.26967 -0.29720 -2.22251 -1.69023 0.34550 -0.90070 -0.79956 -4.29343 -4.11081 -3.62654 -1.98106 -0.94991 0.10729 -0.32545 -1.61753 -3.34684 0.27311 1.72470 2.55802 2.07431 -0.46781 -0.67016 -1.11876 -0.51079 -1.38649 1.97947 1.44023 -0.98125 1.08087 -3.49469 -4.08650 -3.49502 -0.23891 1.88858 2.04042 2.52877 3.59507 2.76954 1.08886 -1.70046 -2.18299 -0.49073 2.08417 1.37201 0.43995 -2.28106 -2.49282 -1.67400 -1.01020 -1.39926 -2.84341 -0.07056 0.24164 -0.82544 -1.07664 1.77934 2.62415 3.81982 2.47764 4.83580 0.16191 0.01787 -3.16172 -1.56671 -3.57900 -2.04640 -3.31674 0.17016 1.21308 0.29144 -1.77023 -0.48280 -1.74263 -1.56525 5.70877 4.52520 5.06900 -0.61388 1.01185 -0.42893 319 21 C C C C O C C C O C O O C C C C H H H H H H H H H H H H H H H H H H -0.04411 0.27772 0.42937 0.18685 -0.10598 -0.33017 0.19602 0.17070 1.42126 1.41041 2.59920 0.48016 2.75236 -1.18281 -1.20598 -2.55834 0.39064 0.67836 0.37894 -0.24980 -1.33778 -0.64254 0.40100 0.96601 2.60706 3.76875 2.03598 -1.96301 -1.42877 -0.96274 -0.41935 -2.56151 -2.80492 -3.35298 3.48625 3.04906 1.62390 1.30140 2.42817 4.82691 0.02522 -1.21061 0.03794 -0.68113 -0.57534 -1.32053 -1.29809 -1.42745 -2.69861 -2.91962 3.66698 0.93577 5.06987 5.57953 4.86327 0.01201 -2.07542 -1.13168 -2.36371 -1.09894 -0.93611 -1.48849 -0.56847 -3.55763 -2.63736 -3.83146 -2.08138 -3.00426 0.42674 1.67199 1.57842 0.28438 -0.42629 -0.14496 -0.47743 0.41011 -1.26914 -2.38694 -2.96520 -2.81091 -4.19764 1.08504 1.93184 2.60528 2.54890 2.37165 -0.93967 0.63852 -0.56548 -1.17773 -0.21870 1.15852 -4.02503 -4.52385 -4.93398 0.31708 1.71772 1.29755 2.69153 3.20609 3.26256 1.85904 21‡ C C C C O C C C O C O O C C C C H H H H H H H H H H H H H H H H H H -0.12394 0.32004 0.42450 0.02970 -0.29980 -0.42463 -0.05434 0.05437 1.82388 1.73854 2.92945 0.75355 2.93813 -1.32110 -1.28239 -2.63222 0.53560 0.74316 0.19955 -0.23459 -1.47067 -0.55058 0.36667 0.79472 2.68759 3.95163 2.23123 -2.07441 -1.62237 -0.98298 -0.51215 -2.59374 -2.93392 -3.40848 3.61232 3.21577 1.81859 1.42983 2.55362 4.94621 0.18884 -1.07766 0.10664 -0.63861 -0.72510 -1.24773 -1.54372 -1.43666 -2.79308 -3.15466 3.87312 1.15326 5.13061 5.71456 4.99410 0.15222 -1.86734 -0.98733 -2.57582 -1.49107 -1.16853 -1.45614 -0.66075 -3.56052 -2.77183 -4.12609 -2.40848 -3.19860 0.44063 1.68693 1.64078 0.37141 -0.35065 -0.12548 -0.25585 0.50926 -1.29480 -2.31916 -2.98722 -2.73584 -4.15578 1.10792 1.80961 2.42428 2.51385 2.42964 -1.00265 0.62133 -0.43644 -1.21986 -0.17558 1.30682 -3.90743 -4.54806 -4.89677 0.31303 1.81880 1.08889 2.58736 2.92122 3.16394 1.65587 320 22 C C C C N C C O C O O C H H H H H H H H H H H -0.96136 0.35557 1.02498 0.09347 -1.10698 0.21671 1.54788 0.06297 -0.36624 -0.65705 -0.42949 -0.88788 -1.79968 0.78761 2.06695 -1.97015 -0.61055 2.36908 1.59334 1.65990 -0.21292 -0.87931 -1.89685 3.35936 3.66285 2.43476 1.42524 2.00483 -0.05179 -0.48462 -0.62435 -1.87924 -2.58015 -2.23838 -3.57826 3.99111 4.65155 2.30518 1.50107 -0.43308 -0.12416 -1.57227 -0.07681 -4.29359 -3.69528 -3.70396 -0.18406 -0.44729 -0.71507 -0.60161 -0.28279 -0.76286 -1.34570 0.57429 0.63774 -0.29973 1.91379 2.15578 0.06276 -0.45134 -0.96558 -0.13297 -1.36502 -0.72362 -1.40346 -2.35133 1.68757 3.23536 1.76512 22‡ C C C C N C C O C O O C H H H H H H H H H H H -0.97391 0.39800 1.04555 0.06170 -1.15986 0.16823 1.43581 0.12860 -0.29507 -0.67025 -0.30301 -0.76656 -1.80864 0.84801 2.10843 -2.05722 -0.74844 2.30764 1.42421 1.49583 -0.13821 -0.70097 -1.79986 3.42178 3.69346 2.48196 1.48309 2.11123 0.10286 -0.53133 -0.63432 -1.83203 -2.54076 -2.31913 -3.65952 4.08725 4.66635 2.31979 1.64263 -0.44242 -0.05292 -1.59430 -0.42193 -4.35405 -3.87238 -3.75532 -0.46033 -0.51483 -0.74663 -0.84036 -0.65296 -1.04005 -1.47806 0.92911 0.97584 0.04320 2.25317 2.41236 -0.30158 -0.39780 -0.84399 -0.65912 -1.23767 -1.03395 -1.24563 -2.56743 1.85336 3.47739 2.07598 321 23 C C C C N C C O C O O C C H H H H H H H H H H H H H -0.15487 0.61572 0.87417 0.24283 -0.37992 -1.17576 0.23341 0.20551 -0.27104 -0.18622 -0.71401 -0.67737 1.46078 -0.56839 0.95250 1.44832 -0.58315 -2.05517 -1.49803 -0.67691 -0.10597 -0.53545 -1.73350 2.36247 1.41950 1.50056 -0.49536 0.64392 0.89307 -0.10050 -0.94121 -2.11120 -0.37327 0.92268 0.95165 2.19468 0.01199 2.39863 -1.14386 -1.02763 1.22877 1.70327 -2.82091 -1.81874 -2.58880 -0.90694 1.79476 3.45630 2.13727 -0.57908 -1.32362 -2.10587 -3.39480 -3.32852 -1.95295 -1.23375 -2.11987 -1.77382 0.23763 0.88715 2.12636 2.57967 2.73846 3.91434 0.70358 -4.23749 -4.17061 -1.52935 -1.19478 -1.19792 -2.69686 0.51709 4.61815 4.11554 3.96687 0.45845 1.77905 0.18836 23‡ C C C C N C C O C O O C C H H H H H H H H H H H H H -0.43600 0.88151 1.60480 0.72377 -0.52497 -1.73738 0.93908 0.22771 -0.36483 -0.88217 -0.50527 -1.57268 2.30292 -1.30422 1.24244 2.65319 -1.62412 -1.92948 -2.56541 0.18013 -0.90691 -1.90889 -2.42955 2.94118 2.24851 2.74667 -0.52852 -0.17707 -0.18701 -0.56239 -0.75826 -1.11718 -0.71205 1.08855 0.93297 2.10763 -0.10508 2.04000 -0.67768 -0.62529 0.05339 0.03683 -2.10406 -0.37805 -1.13127 -1.22631 1.69689 3.05337 1.36901 0.05515 -0.47264 -1.67091 -3.20899 -3.53210 -2.34500 -1.31427 -1.89414 -1.16771 0.05913 0.82497 1.94012 2.40622 2.58424 3.65364 0.64624 -3.84443 -4.52172 -2.21644 -0.71884 -0.38937 -1.87254 0.63798 4.44624 3.86180 3.58461 0.15439 1.71376 0.51221 322 24 C C C C N C C O C O O C H H H H H H H H H H H -0.58610 0.00000 3.36365 -1.83361 0.00000 2.78396 -1.64151 0.00000 1.37268 -0.28152 0.00000 1.15201 0.35334 0.00000 2.36507 1.79581 0.00000 2.55855 0.50989 0.00000 -0.11445 -0.43502 0.00000 -1.19067 0.09436 0.00000 -2.41074 -0.89068 0.00000 -3.29551 1.27241 0.00000 -2.66318 -0.48127 0.00000 -4.67300 -0.27879 0.00000 4.39804 -2.77570 0.00000 3.31025 -2.40093 0.00000 0.60668 2.24073 -0.89026 2.11053 1.99939 0.00000 3.62741 2.24073 0.89026 2.11053 1.14684 -0.88603 -0.19453 1.14684 0.88603 -0.19453 0.10388 -0.89338 -4.88776 -1.40297 0.00000 -5.24722 0.10388 0.89338 -4.88776 24‡ C C C C N C C O C O O C H H H H H H H H H H H -0.33267 -1.52725 -1.52477 -0.32239 0.37702 1.66738 0.12631 -0.46743 -0.08412 -0.47787 0.55560 -0.10152 0.03907 -2.28347 -2.28116 1.58886 1.93980 2.42391 1.15892 -0.42840 0.98385 -0.49876 -0.53091 -0.39923 0.33925 1.03179 0.72167 -0.17125 -0.76573 1.14813 -0.30966 -0.01564 -0.95945 0.96701 -0.72532 -1.06675 0.34860 1.70163 -1.30734 -1.45362 0.01434 1.01767 1.92769 -0.68804 -1.56442 0.20865 3.31662 3.27220 2.07163 1.40102 2.20921 1.87863 0.16008 -1.18117 -2.36133 -3.26445 -2.72463 -4.62149 4.08058 4.04069 1.68972 0.93620 2.67553 1.79454 -0.13562 -0.34434 -4.71998 -5.18823 -4.98541 323 25 C C C C N C C O C O O C C C C C C C H H H H H H H H H H H H H H H -0.44996 -0.42126 -0.20967 -0.11749 -0.27029 0.23028 1.64448 0.12091 -0.05268 -0.09194 -0.18008 -0.37413 -0.26388 0.65177 0.65865 -0.23462 -1.14919 -1.17440 -0.60865 -0.54842 -0.11774 -0.49161 1.73712 1.87275 2.35897 0.48020 -0.45401 -1.28882 1.35571 1.37036 -0.22136 -1.85559 -1.90541 3.10225 3.61731 2.52740 1.38336 1.73858 -0.01887 -0.41332 -0.01290 -1.14546 -1.15701 -2.21061 -3.46243 0.86634 1.08725 0.24261 -0.82376 -1.03533 -0.18508 3.56847 4.65606 2.57122 -0.73268 -0.38819 -1.42317 0.29122 -3.66938 -4.20794 -3.42410 1.90778 0.41246 -1.48466 -1.85482 -0.32257 -0.69815 0.57226 1.46582 0.70840 -0.61552 1.12165 0.71640 2.56437 3.23889 4.44269 2.45933 3.14057 -1.74449 -2.77052 -3.87601 -3.94910 -2.92046 -1.81914 -1.65807 0.83523 2.53954 0.72632 -0.37111 1.05988 1.14637 3.78332 2.35525 3.72989 -2.69032 -4.67528 -4.80759 -2.97981 -1.03062 25‡ C C C C N C C O C O O C C C C C C C H H H H H H H H H H H H H H H -0.49800 -0.03060 0.72496 0.72981 -0.03497 1.26570 2.15025 -0.43541 -0.83930 -1.93486 0.08783 -0.29478 -0.37207 0.60569 0.27759 -1.01537 -1.98561 -1.66579 -1.12286 -0.22665 1.23223 1.33955 3.16042 2.18548 1.83821 -0.44086 0.52763 -1.21022 1.60614 1.03233 -1.26615 -2.98966 -2.40066 2.97156 3.87198 3.13971 1.80221 1.74180 0.65418 0.73984 -0.13509 -1.29055 -1.78627 -1.99677 -3.30767 0.53681 -0.12508 -1.31333 -1.82272 -1.14780 0.03707 3.13340 4.93244 3.51666 -0.24169 0.97094 -0.21879 1.52389 -3.95391 -3.67951 -3.27301 0.28958 -1.83796 -2.75064 -1.54861 0.56730 -0.84587 0.11366 1.02815 0.60615 -0.55919 1.20594 2.39374 2.10807 1.75732 2.00827 1.04362 0.63032 -1.25669 -1.99041 -2.63549 -2.54603 -1.80922 -1.15526 -1.71227 0.12332 1.90387 0.60181 2.03527 2.90808 3.08256 1.49688 0.02079 0.03979 -2.04866 -3.20923 -3.04652 -1.73263 -0.56014 324 26 C C C C C C C N C C C O C O C O H H H H H H H H H H H H H -0.33248 -0.97923 -1.05593 -0.47554 0.17575 0.23674 -0.38403 0.29505 0.64298 0.58911 -0.85882 0.28065 0.01535 1.14044 1.01767 -1.06863 -0.29796 -1.41544 -1.54783 0.72581 1.18588 1.21046 1.12162 -0.33801 -1.59091 -1.30343 0.33424 2.01892 0.65760 2.75232 3.07024 2.16318 0.87727 0.55835 1.52583 -0.25454 -1.20816 -0.75100 -2.54751 -0.48501 -0.38719 -0.63578 -0.53567 -0.77842 -0.90706 3.50456 4.05521 2.41662 1.29024 -1.37810 -3.05843 -2.47918 -3.10437 0.27241 -1.47331 -0.05614 -0.65473 -1.79163 -3.45566 -2.21874 -1.19663 -1.38257 -2.62488 -3.66549 -0.57009 -1.28053 -2.50964 -0.78249 0.80943 1.71274 2.98983 3.68502 5.09589 3.44348 -4.23536 -2.09680 -0.26345 -4.60450 -3.19928 -1.51426 0.16597 -0.64084 1.09024 0.94058 5.54040 5.49755 5.27005 26‡ C C C C C C C N C C C O C O C O H H H H H H H H H H H H H -0.36423 -1.00785 -1.13067 -0.59435 0.05482 0.16683 -0.54966 0.13512 0.49177 0.42406 -0.97496 0.52896 0.29257 1.36694 1.21041 -0.73688 -0.29322 -1.41073 -1.62429 0.65926 1.02531 0.99812 1.00204 -0.51128 -1.64018 -1.08055 0.39429 2.15311 1.01521 2.77016 3.05249 2.10230 0.82154 0.54199 1.52766 -0.36887 -1.31107 -0.80239 -2.67094 -0.60825 -0.20531 -0.51485 -0.25221 -0.55301 -0.98748 3.55163 4.04591 2.33239 1.30638 -1.39699 -3.17080 -2.63510 -3.20414 0.11935 -1.62383 0.02855 -0.27884 -1.61626 -3.39963 -2.16595 -1.17717 -1.41788 -2.65066 -3.65366 -0.64042 -1.40731 -2.58211 -0.96166 0.66366 1.81934 3.04201 3.83168 5.21983 3.50635 -4.14701 -2.00339 -0.23952 -4.59379 -3.30963 -1.73816 -0.03813 -0.79164 1.11168 1.02400 5.64947 5.68779 5.36192 325 27 C C C C C C O C C C C O C O C O O C C H H H H H H H H H H H H H H -0.68682 0.00495 0.94731 1.19272 0.48123 -0.45848 0.74403 0.28488 -0.48050 -0.58215 0.12180 0.66464 0.42253 -0.16213 0.02287 -0.56495 0.62649 -0.45290 -0.27199 -1.41458 1.50326 1.92670 -0.99196 -0.90612 -1.11172 1.50061 -0.01103 0.59587 -0.97899 -0.91974 0.61951 -0.60864 -1.05669 0.99220 -0.12775 -0.72446 -0.22475 0.88550 1.50274 1.43350 0.71867 -0.38923 -0.58599 0.40995 1.22410 0.80234 -0.20712 -0.04481 -1.04540 0.86336 -1.01801 -0.69490 1.47557 -1.58878 -0.68273 2.37238 -0.98620 -1.37082 0.84678 1.77560 -1.05654 -1.90231 -0.11524 -1.16666 0.08390 -1.45489 -4.67432 -5.13879 -4.29528 -3.02123 -2.59038 -3.39854 -1.33388 -0.29411 -0.15259 1.27576 1.85388 0.89434 3.25766 4.08393 5.39266 6.02617 5.90332 7.45944 -6.50711 -5.31754 -4.64312 -2.36779 -3.03310 -0.94156 1.79148 3.43139 3.50198 7.75073 7.80593 7.85092 -6.92290 -7.19277 -6.45456 *a transition state geometry for compound 27 was not identified 326 Appendix D A GUIDE FOR SIMPLE TRANSITION STATE CALCULATIONS USING SPARTAN This appendix will walk through the setup of a transition state calculation for a furfuryl carbonate using the method described in Chapter 2. This workflow is applicable to systems beyond the decomposition of furfuryl carbonates, and places where deviations from this workflow may be required are noted throughout. The screen captures used for this guide are from Spartan’20 Parallel Suite software. Introduction The goal of these calculations is to determine the activation energy for a chemical transformation of interest. The activation energy (ΔG‡) is defined as the difference in energy between the starting material (G = G0) and the transition state (G = G‡), so we must find optimized geometries for both species. In this example, we will find the activation energy for the decomposition of a simple furfuryl carbonate. Our proposed mechanism involves the cleavage of a C–O bond highlighted below. Starting material geometry calculation We will begin by finding the optimized energy of the starting material, which will allow us to find G0 as well as provide a starting place for the subsequent transition state search. 327 Begin by opening the ChemDraw file in Spartan. Ensure the structure is correct, as importing these files (especially those with stereocenters) can sometimes corrupt the structure. Equilibrium conformer search The first step is to run a quick equilibrium conformer search on the molecule as a starting place to find the optimized geometry. To do this, click the Calculations icon in the top toolbar. Select “Equilibrium Conformer” with “Molecular Mechanics” and “MMFF” as the level of theory. Press “Submit” to begin the calculation. This should only take a few moments. 328 Once this initial calculation is completed, save the resulting structure as a new file to begin the equilibrium geometry calculation. Equilibrium geometry optimization Once again, select the Calculations button in the top toolbar. Now, we will want to run this calculation at the final level of theory desired for our transition state calculation. Ideally, this will use an appropriate functional for transition state searches, and will implement a large basis set for the most accurate results. In this example, we have chosen to use the M06-2X functional. The 6-311+G** [also represented as 6-311+G(d,p)] was chosen for its expanded orbitals and diffuse functions, since we are dealing with the formation of a carbonate anion. We have chosen to use the “Polar Solvent” option to better represent experimental conditions. We have chosen to compute “IR” to calculate thermodynamic parameters. We have selected the FINEGRID “Option” to select a large Lebedev integration grid for more precise results. The Lebedev grid is defined by (x,y) where x is the number of radial shells and y is the number of radial points. Below are the Lebedev grid options in Spartan. Note that larger grids will result in slower computation times (from: https://downloads.wavefun.com/FAQ/Energy_FAQs.html). SG-1 and SG-0: small grids tuned for 6-31G* basis set SMALL GRID: Spartan default for most DFT functionals EMLGRID: (50,194) BIGGRID: (70,302) VERYBIGGRID: (100,434) FINEGRID: (99,590) HUGEGRID: (250,947) 329 We have also used the GEOMETRYCYCLE option to ensure convergence of the calculation. This option defines the maximum number of iterations Spartan will attempt before failing the calculation. This is not always necessary, especially for a simple equilibrium geometry calculation. However, including it does not hurt anything, as the calculation will finish once it converges regardless of the value entered here. Using GEOMETRYCYCLE=1000 is sufficient for most applications. Note that the “Options” are space delimited, so using FINEGRID and GEOMETRYCYCLE options should be entered as: FINEGRID GEOMETRYCYCLE=1000. Be sure the “Options” box is checked. Once this calculation is completed, we can check the results by selecting the “Output” icon in the top toolbar. Click “IR Table” to see a list of calculated IR peaks/vibrational modes. 330 Check that the lowest value in this table is a positive value. If there is a negative frequency, you have not found an optimized geometry. Re-run the equilibrium conformer and equilibrium geometry calculations. Here, we see that the lowest frequency is 31 cm -1, so we are good to go. In the same window, now click on “Thermodynamic Properties at 298.15 K.” The value we want is “Gibbs Energy.” DO NOT use the “Energy” value listed in the top table. You have now found the value of G0 for your molecule! 331 Transition state geometry search and optimization Now that we have found G0, we must calculate G‡, which is a more involved process. Finding an initial transition state guess through a “relaxed scan” Before we can use the transition state optimization algorithm built into Spartan, we must first find an initial “guess” that is close to the actual geometry of the transition state. Otherwise, our calculation will just collapse to the starting material geometry. Since we are probing a bond breaking event, we will elongate the bond of interest and equilibrate (“relax”) the molecule at each step. Evaluating the energy values along this profile will allow us to find a decent guess for the transition state. Starting from the optimized geometry of the starting material, save a new copy to use for this next step. We will begin by performing an “Energy Profile” calculation as we extend the C–O bond of interest. Begin by clicking the Constrain Distance icon in the top toolbar. Now click the bond of interest, which should become highlighted. In the lower right of the window, click the open lock icon . Select the “Profile” checkbox. We can now define the parameters for the elongation profile. Leave the starting bond length the same, but change the final bond length to an appropriate value for the 332 transformation of interest. For furfuryl carbonate decomposition, a scan of 1.5 Å over 20 steps is sufficient. Other substrates may require more precision or more elongation. Here, we are extending the bond from 1.428 Å to 2.928 Å over 20 steps. Next, click the Calculations icon . Select “Energy Profile” from the drop-down menu. Now, select the level of theory and solvent conditions to best match your system. Here, we are using the “Polar Solvent” option to best match our experimental conditions. We have selected Hartree-Fock/6-31+G* (HF/6-31+G*) as the level of theory based on testing of various HF and DFT methods. This may require some testing for different substrates, depending on the results of this relaxed scan. Ideally, this step should be performed at a low level of theory with a small basis set. Once the profile calculations are completed, we can view the results. First, click the constrained bond. Then, click the yellow and red button in the far bottom right of the page. 333 Click the “Spreadsheet” icon to show the spreadsheet that should already have the constraint values listed in a column labeled ‘Constraint(Con1).” Click the empty column to the right, then press the “Add” button. Under the “Molecule List” tab, select “Δ Energy (kJ/mol).” This should populate the empty column with relative energy values. 334 We can visualize this data by clicking the Plots icon window that appears, click the Add button in the top toolbar. In the . Set “X Axis” to “Constraint(Con1)” and “Y Axis” to “Δ Energy (kJ/mol).” Click “Create” and you should now see the energy vs. constraint plot. 335 Ideally, this plot rises in energy, has a clear maximum, and then falls again. If the plot looks different from this, you may need to extend the energy profile or use a different method/basis set. The plot above shows an ideal energy profile. Use the arrows or slider on the bottom left of the Spartan window to identify the structure associated with the highest energy in the profile. 336 Right-click this structure and copy it to a new Spartan window. Ensure that the bond length of the elongated bond is the same as the high energy structure from the energy profile. Save this new document as we move to the transition state optimization step. Transition state optimization With this high energy structure as our initial guess, we can now use the Transition State Geometry method built into Spartan. Remove the bond constraint on the copied structure by clicking the constrained bond and then clicking the closed lock button in the lower right of the window. The lock icon should switch from closed to open, and the constraint marker should disappear from the structure. 337 Click the Calculations button in the top toolbar to open the Calculations window. Select “Transition State Geometry” from the drop-down menu. Again, we are selecting “Polar Solvent” for our example. We are continuing with a low level of theory (HF/631+G*), as we found this to work well for this system. You may choose to use a higher level of theory for your calculations. Optimization of this procedure will require trial and error, and can be revisited after evaluating the final transition state geometry. Once this calculation is completed, check that the bond length of the bond of interest is similar to the initial transition state guess. If the input structure is too far from a transition state, the Transition State Geometry calculation may collapse back to the equilibrium geometry. Here, we see that the C–O bond length is still much longer than expected for a typical equilibrium bond. 338 Save this structure as a new file before moving to the final step. Constrained equilibrium geometry and transition state energy calculation For the final step, we will transition to a higher level of theory to provide more accurate energy values for our transition state geometry. We will also use a constrained geometry equilibration to relax portions of the molecule not involved in the transition state of interest. We will begin by once again constraining the bond of interest. Click the bond of interest, then click the Constrain Distance button , and then the open lock button in the lower right of the Spartan window. Once the bond is constrained, click the Calculations icon in the top toolbar. Select “Equilibrium Geometry” from the drop-down menu. Choose the same solvent conditions as before. We will need to select the same level of theory as for our initial Equilibrium Geometry calculation for the starting material. In our example, that was M06-2X/6311+G**. As we did for that starting material calculation, we will select “IR” and use the FINEGRID and GEOMETRYCYCLE=1000 options. We must also select the “Subject To: Constrains” box in order to keep our molecule from equilibrating to the starting material. 339 Run this calculation. Note that this will be the longest calculation in the workflow. For a simple furfuryl carbonate like our example, this may take 2–3 hours. Once the calculation is complete, click the Output button in the top toolbar and open “IR Table.” Here, the lowest value should be a negative frequency. Here, we see –287 cm -1. If there is no negative frequency, you have not found a transition state. Check that the result of your calculation using the Transition State Geometry method did not collapse to the equilibrium geometry. If your structure collapsed during the last (constrained) Equilibrium Geometry step, you likely did not select the “Subject To: Constraints” box in the Calculations window. If you see more than one negative frequency, you have not found a first-order transition 340 state. Often, we will see one large negative frequency accompanied by several smaller negative frequencies. This is an indication that your transition state geometry needs further optimization. If you see multiple large negative frequencies, you may be barking up the wrong tree with the predicted transition state. If you see one very small negative frequency (0 cm-1 > ν ≳ –50 cm-1), it likely does not correspond to the transition state of interest. For furfuryl carbonate decomposition, we typically find ν < –250 cm-1. If you see a single large negative frequency value, congratulations! You have found a transition state. To verify we have found the transition state of interest, click the Spectra icon in the top toolbar. In the window that appears, click the Add button Calculated” from the list of spectra. A calculated IR spectrum should appear. and select “IR 341 Click the Tables icon on the right side of the Spectra window. You should now see the list of calculated frequency values. Click the negative frequency to visualize the vibrational mode on the molecular structure. You should see the Spartan structure moving! Convince yourself that the vibrational mode you see corresponds to the desired transition state. For the C–O bond cleavage event for the furfuryl carbonate we studied, we see that the single negative frequency corresponds to a stretching mode of the C–O bond of interest. If you have undesired additional negative frequency values, this is a good way to understand where they are coming from. Small negative frequencies often arise from small perturbations in the molecule such as methyl rotors or large-scale gentle bending modes. Once you have identified these undesired vibrational modes, you can adjust those portions of the molecule and re-run the constrained equilibrium geometry calculation. For a methyl 342 rotor, spinning the offending methyl group and re-equilibrating is often successful. For large-scale bending motions, a slight rotation around a bond at the center of the bend may solve this problem. If you are satisfied that you have identified a valid first-order transition state, you can find the energy of this species by clicking the Output icon and extracting the Gibbs energy value from the “Thermodynamic Properties at 298.15 K” tab. This value is G‡. Now that you have found both G0 and G‡, you can calculate ΔG‡: ∆𝐺 ‡ = 𝐺 ‡ − 𝐺 The energy values provided by Spartan have units of hartrees, so multiple the value of ΔG‡ by 627.5 to derive the activation energy in units of kcal/mol. You have now successfully calculated the activation energy for your chemical transformation! 343 Appendix E SPECTRA RELEVANT TO CHAPTER 3: INCORPORATION OF A TETHERED ALCOHOL ENABLES EFFICIENT MECHANICALLY TRIGGERED RELEASE IN APROTIC ENVIRONMENTS 344 VIII. 1 H and 1 3 C NMR Spectra 345 346 347 348 349 350 351 352 353 354 355 356 357 358 359 360 361 362 363