CATALYTIC ASYMMETRIC CHLOROFUNCTIONALIZATION REACTIONS: MECHANISTIC DISCOVERIES AND ADVANCEMENTS By Aritra Sarkar A DISSERTATION Submitted to Michigan State University in partial fulfillment of the requirement s for the degree of Chemistry Doctor of Philosophy 20 20 ii ABSTRACT CATALYTIC ASYMMETRIC CHLOROFUNCTIONALIZATION REACTIONS: MECHANISTIC DISCOVERIES AND ADVANCEMENTS By Aritra Sarkar This thesis presents the mechanistic exploration of various catalytic asym metric alkene halofunctionalization reactions. The mechanistic studies were focused on asymmetric halofunctionalization reactions that are catalyzed by the well - known, commercially available catalyst (DHQD) 2 PHAL. Chemical kinetics were a central part of th is investigation as the study entailed exploration of various kinetic properties , such as rate law equations, effects of isotopic substitution , and competition studies , to obtain key mechanistic insight s into these reactions . The kinetic studies were compl emented with computational modeling that led to the propos al of detailed catalytic models. Chapter 1 introduces the inherent mechanistic challenges in a successful catalytic asymmetric alkene halofunctionalization reaction and also serves as an introduct ion to the kinetic tools that will be utilized in the following chapters to investigate the mechanism of the reactions. Chapter 2 presents the mechanistic investigation of (DHQD) 2 PHAL catalyzed asymmetric chlorolactonization of alkene carboxylic acids and illustrates the mechanistic model of catalysis for this reaction. Chapter 3 presents the mechanistic investigation of DHQD) 2 PHAL catalyzed asymmetric chloroetherification of alkene amides reaction. Interestingly, despite being driven by the same cataly st and chlorine source, evidence s pointed to the two reaction s having dramatically divergent mechanistic picture s . iii ACKNOWLEDGEMENTS I am i ncredibl y grateful for the constant support from my friends and colleagues here at Michigan State University. Firs t and foremost, I want to thank my advisor Prof. Babak Borhan, without whom the work presented thesis would not be possible. I will be forever grateful for his constant support and his trust in my ability to steer this research in directions I found most e xciting. Babak is also an extraordinary mentor and teacher, and over the years, my interactions with him has greatly shaped how I communicate scientific endless guidance and unfaltering patience have allowed me to grow as a researcher and as a person. Few people have been as instrumental to my research projects as Dr. Dan Holmes and Dr. Li Xie at the Max T. Rogers facility at MSU. From early days of my projects to the last, Dan and Li has spent endless hours training me on various NMR instrum ents and helping me to get my kinetic experiments up and running . I have spent numerous hours with them, brainstorming about ideas, discussing projects and various NMR technique. I will always be in debt to Dan and Li for their incredible support as mento r s and friend s . I am grateful for the support provided by my committee members : Prof. Ned Jackson, Prof. William D. Wulff and Prof. Dan Jones. Ned has been my default go - to person whenever I am stuck on a mechanistic question or when I am out of ideas. The and forth were some of the most exciting moments of graduate research. Every week of w as it a fantastic opportunity to learn about new reactions and it also taught me how iv systematically comb through scientific literature in my early years of graduate school and allowed me to contribute to building the database of reactions. I am grateful f or the incredible support from my current and former lab mates at MSU. Dr. Chrysoula Vasileiou , Dr. Hadi Gholami, Dr. Roozbeh Yousefi, Dr. Kumar Ashtekar, Dr. Arvind Jaganathan, Dr. Nastaran Salehi Marzijarani , Dr. Bardia Soltanzadeh, Dr. Jun Zhang, Dr. Wei Sheng, Dr. Xingliang Ding and Dr. Calvin Grant were great mentors and friends whose support, e specially in my early years in graduate school, have helped me quickly learn and grow as a graduate researcher . I am also incredible grateful to Dan Steigerwald, Saeedeh Torabi Kohlbouni , Debarshi Chakraborty , Sophie Bedford and Emily Dzurka for being fant astic lab mates, collaborators, and friends. I also want to thank Aria Vahdani, Soham Maity , Ankush Chakraborty , Mehdi Moemeni , Rahele Esmatpour Salmani , Behrad Masoudi , Homa Sadeghzadeh , Jiaojiao Wang and Mitchell Maday; Ishita Chandra for being wonderful lab mates. I am also thankful to my friends at Michigan State University Dr. Jonathan Dannatt, Hailey Dannatt, Dr. Aliakbar Mohammadlou, Po - Jen Hsiao, Dr. Faezeh Habib Zadeh , Dr. Emiliano Deustua, Jonathan Yarranto n for their support . Last but not the le ast, I want to thank my wife, Dr. Grace Elizabeth (Gracielou) Klinger. She has been my single biggest source of inspiration . H er contagious positive energy and kindness has helped me push through the toughest days of graduate school. Without her continued love and support , the work presented in this thesis would simply not be possible. v T ABLE OF CONTENTS LIST OF TABLES ................................ ................................ ................................ ....... viii LIST OF FIGURES ................................ ................................ ................................ ......... x KEY TO SYMBOLS AND ABBREVIATIONS ................................ ................................ . xv Chapter 1. Catalytic asymmetric alkene halofunctionalization reaction and kinetic approaches for mechanistic studies ................................ ................................ ................ 1 1.1 Catalytic asymmetric halofunctionalization reaction ................................ . 1 1.2 Challenges in asymmetric stereoinduction: A non - trivial mechanism of addition ................................ ................................ ................................ ................. 4 1.3 Another mechanistic possibility: concerted addition pathway ................. 11 1.4 Role of the catalyst ................................ ................................ ................. 16 1.5 (DHQ D) 2 PHAL catalyzed asymmetric halofunctionalization reaction ..... 21 1.6 Kinetic studies ................................ ................................ ........................ 25 1.7 Reaction rate and the rate law equation ................................ ................. 25 1.8 Empirical rate law and order of components ................................ .......... 28 1.9 Reaction monitoring and kinetic measurements ................................ ..... 30 1.10 Kinetic analysis to find order of components ................................ ....... 34 1.10.1 Method of isolation ................................ ................................ ......... 35 1.10.2 Method of initial rate ................................ ................................ ....... 36 1.10.3 Method of reaction progress kinetic analysis (RPKA) .................... 39 1.10.4 Method of variable time normalized analysis (VTNA) ..................... 50 REFERENCES ................................ ................................ ................................ .......... 58 Chapter 2. Mechanism o f catalytic asymmetric chlorolactonization of alkene carboxylic acids ................................ ................................ ................................ ....... 65 2.1 Introduction ................................ ................................ ............................ 66 2.2 Kinetic studies ................................ ................................ ........................ 70 2.3 Resting state of the catalyst ................................ ................................ ... 78 2.4 Structural insight into the transition state 2 - B ................................ ......... 84 2.5 Evidence for concerted addition ( NAAA ) pathway ................................ .. 85 2.6 Quinuclidine - catalyzed TS for syn and anti chlorocyclization ................. 88 2.7 Modeling of the syn - addition TS for (DHQD) 2 PHAL catalyzed reactions 90 2.8 Summary ................................ ................................ ................................ 92 2.9 Experimental detail ................................ ................................ ................. 94 2.9.1 General remarks ................................ ................................ .............. 94 2.9.2 Kinetic studies ................................ ................................ .................. 95 2.9.2.i. Sample and NMR instrument preparation for kinetic studies .................. 95 2.9.2.ii. Reaction Progress Kinetic Analysis (RPKA) data collection and analysis ................................ ................................ ................................ ........................... 95 vi 2.9.2.iii. Kinetic experiments to determine rate equation ................................ .... 96 2.9.2.iv. Kinetic studies in presence of benzoic acid ................................ ........... 97 2.9.2.v. Kinetic studies in absence of benzoic acid ................................ ............. 99 2.9.2.vi. Comparison of rates of the reaction with and without benzoic acid ..... 100 2.9.2.vii. Discussion on the order of components in the rate law equation ....... 101 2.9.3 Kinetic models ................................ ................................ ................ 102 2.9.3.i. Model 1: In absence of benzoic acid ................................ ..................... 102 2.9.3.ii. Model 2: In presence of benzoic acid ................................ ................... 104 2.9.3.iii. Model 3: Alternative scenario of 1:1 alkene - catalyst being the reactive intermediate ................................ ................................ ................................ ...... 107 2.9.4 1 H NMR analysis of alkenoic acid 2 - 5 and its complexes with (DHQD) 2 PHAL and quinuclidine ................................ ................................ ........... 109 2.9.4.i. Sample and NMR instrument preparation for 1 H NMR studies ............. 109 2.9.4.ii. 1 H NMR of alkene 2 - 5 ................................ ................................ ........... 110 2.9.4.iii. 1 H NMR of alkene 2 - 5:quinuclidine (1:1) mixture ................................ . 111 2.9.4.iv. 1 H NMR of quinuclidine ................................ ................................ ....... 112 2.9.4.v. 1 H NMR of (DHQD) 2 PHAL and alkene 2 - 5 (1:2) ................................ ... 113 2.9.4.vi. 1 H NMR of 0.04 M (DHQD) 2 PHAL under various concentration of benzoic acid ................................ ................................ ................................ ................... 114 2.9.5 ROESY analysis of (DHQD) 2 PHAL:alkene 5 complex ................... 115 2.9.5.i. Sample and NMR instrument preparation for ROESY studies .............. 115 2.9.5.ii. Measuring intermolecular distances using ROESY analysis ................ 115 2.9.5.iii. Measuring intermolecular distances using ROESY analysis ............... 118 2.9.6 General procedure for kinetic isotopic effect studies ...................... 119 2.9.7 General procedure for the titration of (DHQD) 2 PHAL with alkene 1 121 2.9.8 X - Ray crystallography ................................ ................................ .... 123 2.9.9 General procedures for computational studies ............................... 124 REFERENCES ................................ ................................ ................................ ........ 125 Chapter 3. Mechanism of catalytic asymmetric chloroetherification of alkene amides ................................ ................................ ................................ ..... 133 3.1 Introduction ................................ ................................ .......................... 134 3.2 Kinetic studies ................................ ................................ ...................... 137 3.2.1 Order of alkene ................................ ................................ .............. 138 3.2.2 Order of DCDMH ................................ ................................ ............ 139 3.2.3 Product inhibition and catalyst binding ................................ ........... 142 3.2.4 Role of the nucleophile ................................ ................................ ... 144 3.2.5 Catalyst order ................................ ................................ ................. 146 3.2.6 Catalytic model ................................ ................................ ............... 147 3.3 Resting state of the catalyst ................................ ................................ . 150 3.4 Catalytic cycle for chloroetherification ................................ .................. 156 3.5 Investigation into the transition states ................................ .................. 158 3.6 Summary ................................ ................................ .............................. 160 3.7 Experimental det ail ................................ ................................ ............... 162 3.7.1 General remarks ................................ ................................ ............ 162 3.7.2 Kinetic Studies ................................ ................................ ............... 163 vii 3.7.2.i Experimental procedure ................................ ................................ ......... 163 3.7.2.ii Kinetic analysis protocols ................................ ................................ ...... 164 3.7.2.iii Measuring concentration of DCDMH and MCDMH .............................. 166 3.7.3 Kinetic analysis results ................................ ................................ ... 168 3.7.3.i Order of alkene 3 - 3 and DCDMH in 10 mol% (DHQD) 2 PHAL ............... 168 3.7.3.ii Same excess experiments ................................ ................................ .... 170 3.7.3.iii Order of (DHQD) 2 PHAL in the 2.5 - 10 mol% loading regime ................ 171 3.7.3.iv Order of methanol at 10 mol% (DHQD) 2 PHAL ................................ ..... 172 3.7.3.v Order of alkene 3 - 3 and DCDMH in 1 mol% (DHQD) 2 PHAL ................ 175 3.7.3.vi Order of (DHQD) 2 PHAL in the 2.5 - 10 mol% loading regime ................ 177 3.7.3.vii Order of methanol at 10 mol% (DHQD) 2 PHAL ................................ .... 178 3.7.3.viii Empirical rate laws in different ca talyst loading regime ...................... 179 3.7.3.ix Effect of additives ................................ ................................ ................. 180 3.7.3.x Kinetic isotopic effect studies ................................ ................................ 181 3.7.4 Kinetic model ................................ ................................ .................. 183 3.7.5 1 H NMR studies ................................ ................................ .............. 186 3.7.5.i 1 H NMR of DCDMH (Exp 1, Table 3.10) ................................ ................ 187 3.7.5.ii 1 H NMR of MCDMH (Exp 2, Table 3.10) ................................ ............... 188 3.7.5.iii 1 H NMR of DMH (Exp 3, Table 3.10) ................................ .................... 189 3.7.5.iv 1 H NMR of (DHQD) 2 PHAL (Exp 4, Table 3.10) ................................ .... 190 3.7.5.v 1 H NMR of DCDMH + (DHQD) 2 PHAL 1:1 mixture (Exp 5, Table 3.10) . 191 3.7.5.vi 1 H NMR of DCDMH + (DHQD) 2 PHAL 2:1 mixture (Exp 6, Table 3.10) 192 3.7.5.vii 1 H NMR of MCDMH + (DHQD) 2 PHAL 1:1 mixture (Exp 7, Table 3.10) ................................ ................................ ................................ ......................... 193 3.7.5.viii 1 H NMR of MCDMH + (DHQD) 2 PHAL 2:1 mixture (Exp 7, Table 3.10) ................................ ................................ ................................ ......................... 194 3.7.5.ix Spectra i - viii (Exp 1 - 8, Table 3.10) gem - dimethyl region ...................... 195 3.7.6 DOSY NMR studies ................................ ................................ ....... 196 3.7.6.i Sample preparation ................................ ................................ ............... 196 3.7.6.ii DOSY analysis ................................ ................................ ...................... 197 3.7.6.iii DOSY NMR spectra of DCDMH (Exp 1, Table 3.11) ........................... 198 3.7.6.iv DOSY NMR spectra of DCDMH - (DHQD) 2 PHAL (Exp 2, Table 3.11) ... 199 3.7.6.v DOSY NMR spectra of MCDMH (Exp 3, Table 3.11) ............................ 200 3.7.6.vi DOSY NMR spectra of MCDMH - (DHQD) 2 PHAL (Exp 4, Table 3.11) .. 201 3.7.6.vii DOSY analysis to determine bound ratio ................................ ............ 202 3.7.7 General procedure for computational stud ies ................................ . 205 REFERENCES ................................ ................................ ................................ ........ 206 viii L IST OF TABLES Table 1.1 Set of experiments for finding the order of components using method of isolation ................................ ................................ ................................ ................................ ...... 35 Table 1.2 Set of experiments for finding the order of A using method of initial kinetics . 37 Table 1.3 Set of different excess experiments for finding order of components using RPKA ................................ ................................ ................................ ................................ ...... 45 Table 1.4 Set of same excess experiments ................................ ................................ ... 48 Table 1.5 Set different experiments for finding order of components using VTNA ........ 52 Table 1.6 Set of 4 kinetic experiments for finding order of components using method of isolation ................................ ................................ ................................ ......................... 56 Table 2.1 1 H NMR analysis of alkenoic acid 2 - 5 and its complexes with (DHQD) 2 PHAL and quinuclidine at - 40 ºC in CDCl 3 . ................................ ................................ .............. 81 Table 2.2 RPKA studies in presence of benzoic acid as an additive ............................. 97 Table 2.3 RPKA studies in absence of benzoic acid ................................ ..................... 99 Table 2.4 ROESY correlations ................................ ................................ .................... 117 Table 3.1 DOSY NMR of chlorohydantoin - catalyst complexes ................................ ... 155 Table 3.2 Calibration curve table for a reaction using initial concentration of 0.08 M for DCDMH ................................ ................................ ................................ ....................... 167 Table 3.3 Different excess experiments for VTNA studies ................................ .......... 168 Table 3.4 Same excess experiments for VTNA studies ................................ .............. 170 Table 3.5 Experiments with different catalyst concentration ................................ ........ 171 Table 3.6 Experiments with different concentration of methanol ................................ . 172 Table 3.7 Different excess experiments for VTNA studies ................................ .......... 175 Table 3.8 Experiments with different catalyst concentration ................................ ........ 177 ix Table 3.9 Experiments with different catalyst concentration ................................ ........ 180 Table 3.10 Experiments with different catalyst concentration ................................ ...... 186 Table 3.11 Experiments with different catalyst concentration ................................ ...... 197 Table 3.12 Extracting the free - to - bound ratio from a biexponential fitting ................... 203 x L IST OF FIGURES Figure 1.1 Alkene halogenation reaction. ................................ ................................ ........ 2 Figure 1.2 Catalytic asymmetric halofunctionalization of alkene. ................................ .... 3 Figure 1.3 Mechanism of alkene halogenation. ................................ ............................... 5 Figure 1.4 Chall enges in catalytic asymmetric halofunctionalization via cyclic haliranium intermediate. ................................ ................................ ................................ ................... 6 Figure 1.5 Challenges in catalytic asymmetric halofunctionalization via a - halocarbenium pathway. ................................ ................................ ................................ .......................... 8 Figure 1.6 Challenges in catalyt ic asymmetric halofunctionalization. ............................ 10 Figure 1.7 A concerted addition pathway for halofunctionalization. ............................... 12 Figure 1.8 Halenium affinities. ................................ ................................ ....................... 13 Figure 1.9 Discovery of concerted NAAA addition pathway for chlorolactonization reaction. ................................ ................................ ................................ ........................ 15 Figure 1.1 0 Chiral lewis base catalyst system (type I). ................................ .................. 17 Figure 1.11 Chiral ion pairing catalyst system (type II). ................................ ................. 18 Figure 1.12 Substrate - catalyst hydrogen bonded complex (type III). ............................ 19 Figure 1.13 Substrate - catalyst Lewis acid - base complex (type IV). .............................. 20 Figure 1.14 (DHQD) 2 PHAL catalyzed asymmetric alkene chlorofunctionalization reaction. ................................ ................................ ................................ ................................ ...... 22 Figure 1.15 Prior mechanistic studies for dissecting the face selectivities. ................... 24 Figure 1.16 Different rate equation for different mechanistic models ............................ 27 Figure 1.17 Similar rate equation for different mechanistic models. .............................. 28 Figure 1.18 Reaction monitoring techniques. ................................ ................................ 30 xi Figure 1.19 Challenges in reaction monitoring of chlorolactonization of alkene carboxylic acids. ................................ ................................ ................................ ............................. 32 Figure 1.20 Challenges in reaction monitoring of chloroetherification of alkene amides. ................................ ................................ ................................ ................................ ...... 32 Figure 1.21 Challenges in reaction monitoring of chloroamidation of alkene amides. ... 34 Figure 1.22 Graphical analysis of rate law equation. ................................ ..................... 40 Figure 1.23 Kinetic profile of a second order reaction. ................................ .................. 41 Figure 1.24 RPKA analysis of rate law. ................................ ................................ ......... 42 Figure 1.25 RPKA analysis of rate law for a reaction of overall order of 1. ................... 43 Figure 1.26 Reacti on progress kinetic analysis of different excess experiments to find the order of components. ................................ ................................ ................................ .... 45 Figure 1.27 Reaction progress kinetic analysis of same excess experiments. .............. 48 Figure 1.28 Variable time normalized analysis of different excess experiment s to find order of components. ................................ ................................ ................................ .... 53 Figure 1.29 Variable time normalized analysis of different excess experiments using summation func tion. ................................ ................................ ................................ ...... 54 Figure 1.30 Time normalized analysis of same excess experiments. ........................... 56 Figure 2.1 Halocyclization reactions. ................................ ................................ ............. 67 Figure 2.2 Stereochemical outcomes of chlorolactonization reaction. ........................... 68 Figure 2.3 Chlorohydantoin effect on rate of chlorolactonization reaction. .................... 69 Figure 2.4 Catalytic cycle for chlorolactonization reaction. ................................ ............ 73 Figure 2.5 Competition studies on chlorolactonization reaction. ................................ ... 77 Figure 2.6 Conformational changes observed upon binding of 2 - 1 to (DHQD) 2 PHAL. .. 79 Figure 2.7 Structural investigation of resting complex using ROESY NMR. .................. 82 Figure 2.8 Prior work on concerted vs stepwise addition. ................................ ............. 87 Figure 2.9 Transition states for q uinuclidine catalyzed reaction. ................................ ... 89 xii Figure 2.10 Modeling of (DHQD) 2 PHAL catalyzed Transition states. ............................ 91 Figure 2.11 Different excess experiments to find order of alkene and DCDMH. ........... 97 Figure 2.12 Same excess experiment. ................................ ................................ .......... 98 Figure 2.13 Finding or der of catalyst. ................................ ................................ ............ 98 Figure 2.14 Different excess experiments to find order of alkene and DCDMH. ........... 99 Figure 2.15 Same excess experiment. ................................ ................................ ........ 100 Figure 2.16 Rate comparison with and without benzoic acid. ................................ ...... 100 Figure 2.17 Model 1: In absence of b enzoic acid. ................................ ....................... 102 Figure 2.18 Model 2: In presence of benzoic acid. ................................ ...................... 104 Figure 2.19 Model 2: Alternative scenario of 1:1 alkene - catalyst being reactive intermediate. ................................ ................................ ................................ ............... 107 Figure 2.20 ROESY reference distances. ................................ ................................ ... 117 Figure 2.21 Proton label for ROESY studies. ................................ .............................. 117 Figure 2.22 Kinetic isotopic effect studies. ................................ ................................ .. 119 Figure 2.23 Proton label for ROESY studies. ................................ .............................. 120 Figure 2.24 Proton label for ROESY studies. ................................ .............................. 120 Figure 2.25 Change in chemical shift of H b on titrating (DHQD) 2 PHAL with alkene 2 - 1. ................................ ................................ ................................ ................................ .... 122 Figure 2.26 Co - crystal of (DHQD) 2 PHAL with benzoic acid . ................................ ....... 123 Figure 3.1 (DHQD) 2 PHAL catalyzed chlorofunctionalization of alkene amides. .......... 134 Figure 3.2 Mechanistic study on catalytic chlorofunctionalization of alkene amides. .. 135 Fi gure 3.3 Kinetic experiments to determine order of alkene 3 - 3. ............................... 139 Figure 3.4 Finding order of DCDMH. ................................ ................................ ........... 140 Figure 3.5 Investigating product inhibition and catalyst deactivation. .......................... 143 xiii Figure 3.6 Investigating the role of nucleophile. ................................ .......................... 145 Figure 3 .7 Order of the catalyst (DHQD) 2 PHAL. ................................ ......................... 146 Figure 3.8 Catalytic model. ................................ ................................ .......................... 148 Figure 3.9 Investigating the resting state of the catalyst. ................................ ............. 151 Figure 3.10 NMR evidence towards supporting binding model. ................................ .. 152 Figure 3.11 Catalytic cycle for chlorofunc tionalization of alkene amides. .................... 156 Figure 3.12 Transition state calculations. ................................ ................................ .... 159 Figure 3.13 Eyring plot. ................................ ................................ ............................... 160 Figure 3 .14 Kinetic study procedures. ................................ ................................ ......... 165 Figure 3.15 Quantifying concentration of DCDMH. ................................ ..................... 167 Figure 3.16 Finding Order of alkene amides 3 - 3 at high catalyst loading. ................... 168 Figure 3.17 Finding order of DCDMH at high catalyst loading. ................................ ... 169 Figure 3.18 Same excess experiments. ................................ ................................ ...... 170 Figure 3.19 Order of catalyst (DHQD) 2 PHAL at high catalyst loading. ........................ 171 Figure 3.20 Concentration profiles used to find rate constants. ................................ .. 173 Figure 3.21 Rate profiles used to extract the rate constants. ................................ ...... 173 Figure 3.22 Finding order of methano l (nucleophile) at high catalyst loading. ............. 174 Figure 3.23 Finding order of alkene amide 3 - 3. ................................ ........................... 175 Figure 3.24 Finding order of DCDMH. ................................ ................................ ......... 176 Figure 3.25 Finding order of (DHQD) 2 PHAL at low catalyst loading. ........................... 177 Figure 3.26 Finding order of methanol (nucleophile) at low cat alyst loading. .............. 178 Figure 3.27 Effect of additive on chloroetherification. ................................ .................. 180 Figure 3.28 Kinetic isotopic effect study. ................................ ................................ ..... 181 xiv Figure 3.29 Kine tic model. ................................ ................................ ........................... 183 Figure 3.29 Chemical shift change of chlorohydantoins in presence of catalyst. ........ 195 xv K EY TO SYMBOLS AND ABBREVIATIONS Å Angstrom cm - 1 wavenumber h hour mg milligram g gram M molar ° C degree Celsius K kelvin mM millimolar mmol millimole µ L microliter mL milliliter L liter min minutes exp experiment conc. concentration rxn reaction eq equation ln natural logarithm kcal/mol kilocalorie per mole ppm parts per million xvi MS molecular sieve s dr diastereomeric ratio er enantiomeric ratio ee enantiomeric excess aq aqueous ZPE zero - point energy E difference in energy G difference in Gibbs free energy H difference in enthalpy S difference in entropy t difference in time xs excess k obs observed rate constant LA Lewis acid LB Lewis base cat catalyst Nuc nucleophile CHCl 3 chloroform CDCl 3 deuterated chloroform MeCN acetonitrile CD 3 CN deuterated acetonitrile MeOH methanol CD 3 OH deuterated methanol xvii CH 2 Cl 2 dichloromethane H 2 O water D 2 O deuterium oxide Et 2 O diethyl ether EtOH ethanol ROH alcohol Hex n - hexane n PrOH n - propanol nPrNO 2 1 - nitropropane THF tetrahydrofuran HCl hydrogen chloride HFIP 1,1,1,3,3,3 - hexafluoroisopropanol TFE 1,1,1 - trifluoroethanol Na 2 CO 3 Sodium carbonate NaHCO3 sodium bicarbonate NaOH sodium hydroxide K 2 CO 3 potassium carbonate Na 2 SO 3 sodium sulfite Na 2 S 2 O 3 sodium thiosulfate Na 2 SO 4 sodium sulfate CaH 2 calcium hydride (DHQD) 2 PHAL Hydroquinidine 1,4 - phthalazinediyl diether (DHQ) 2 PHAL Hydroquinine 1,4 - phthalazinediyl diether xviii NCS N - chlorosuccinimide NBS N - bromosuccinimide NIS N - iodosuccinimide DCDMH 1,3 - dichloro - 5,5 - dimethylhydantoin MCDMH 3 - chloro - 5,5 - dimethylhydantoin DMH 5,5 - dimethylhydantoin DCH 1,3 - dichlorohydantoin MCH 3 - chlorohydantoin DCDPH 1,3 - dichloro - 5,5 - diphenylhydantoin DBDMH 1,3 - dibromo - 5,5 - dimethylhydantoin HalA haleni um affinity NAAA nucleophile assisted alkene activation Ad E 3 termolecular electrophilic addition NMR nuclear magnetic resonance ROESY rotating frame overhauser effect spectroscopy COSY correlation spectroscopy HSQC heteronuclear quantum co herence HMBC heteronuclear multiple bond correlation NOE nuclear overhauser effect DOSY diffusion ordered spectroscopy IR infrared HPLC high performance liquid chromatography UV ultraviolet xix Vis visible HRMS high resolution mass spectrometry ESI electrospray ionization RPKA reaction progress kinetic analysis VTNA variable time normalized analysis rate of reaction KIE kinetic isotopic effect DFT density functional theory TS transition state H - bonding hydrog en bonding 1 Chapter 1. Catalytic asymmetric alkene halofunctionalization reaction and kinetic approaches for mechanistic studies Catalytic asymmetric alkene halofunctionalization reactions are a rapidly evolving area. Despite recent developments and the flurry of reports in this area, the mechanism for catalysis remains largely unexplored. This chapter aims to introduce the possible mechanistic scenarios for the uncatalyzed halofunctionalization reactions and illustrate the challenges in attaining catalyst - controlled selectivity in product formation. This was followed with a discussion on the working models for catalysis that have be en proposed in literature thus far. The second part of the Chapter 1 presents an introduction to various kinetic analysis protocols and tools that will be utilized throughout the thesis to explore the mechanism of the catalytic processes. 1.1 Catalytic asy mmetric halofunctionalization reaction Alkene halogenation are a well - known class of reactions that pertains to addition of halogen atoms to olefinic centers leading to the formation of organohalides ( Figu re 1. 1 ). The apparent familiarity of alkene halogenation reaction for anyone associated in the area of chemical sciences stems from its early incorporation into organic chemistry textbooks. 1 While, earliest reports of halogenation reactions dates back to the 19 th century, 2 currently, these halogenation reactions ar e some of the very first reactions taught to sophomore level undergraduate students. Perhaps the most commonly depicted mechanism for these addition reactions is where the alkene attacks the electrophilic halogen center (X) leading to the formation of a ca tionic haliranium intermediate, which in turn is captured by a nucleophile (Y) ( Figu re 1. 1 ). 3 If the nucleophile (Y) involved in the second step is a halide, the reaction is a dihalogenation reaction. However, one may also 2 envision a more generalized scenario, where the nucleophile is not restricted to a hali de, but can also be a nucleophile such as water, alcohol, carboxylic acids or amines. To encompass all these scenarios, a more generalized term coined for these reactions is the alkene halofunctionalization reaction. Figu re 1. 1 Alkene halogenation reaction . A classical depiction of electrophilic halogenation of alkene via a cyclic haliranium ion intermediate. The utility of halofunctionalization reactions stems from versatility, as not only this reaction allows one to quickly introduce multiple functional grou ps in an olefinic moiety, but the nature of the carbon - halogen bond enables introduction of other functional groups (substitution reactions, coupling reactions etc. 4 - 6 A catalytic asymmetric version of ha lofunctionalization would augment the utility of this reaction by providing an efficient means to rapidly access various chiral motifs. 7, 8 Despite the potential application of catalytic asymmetric halofunctionalization reactions, their appearance is surprisingly recent in modern literature. In 2010, Borhan and co - workers reporte d one of the very first, practical, catalytic asymmetric halofunctionalization reaction. 9 This reaction, which was catalyzed by an organocatalyst (DHQD) 2 PHAL, involved the chlorination and cyclization 1,1 - disubstituted alkene carboxylic acids ( Figure 1. 2 ) to generate chiral chlorolactones. Since this report, example of halofunctionalizations in the literature has burgeoned over 3 the last decade, 10 - 17 further underscoring the interest of the scientific community to find efficient ways to halofunctionalization simple olefins. Figure 1. 2 Catalytic asymmetric halofunctionalization of alkene . (a) A schematic depiction of catalytic asymmetric halofunctionali zation of alkene to make chiral organohalides. (b) Catalytic asymmetric chlorolactonization of alkene carboxylic acids . Despite the rapid growth in this emerging area of catalytic asymmetric halofunctionalization significant challenges remain, both in term s of rational catalyst design and in expanding the applicability and substrate scope. 10, 11 These challenges have prevailed in part due to the dearth in mechanistic insights into these catalytic asymmetric halofunctionalization process. While many of these reported catalytic asymmetric halofunctionalizations have put forth hypothesized working m odels, most of these models have little mechanistic support. A detailed mechanistic analysis of catalytic asymmetric halofunctionalization would not only illuminate the catalytic process, but also 4 could provide critical information that can potentially be leveraged to improve existing reactions or even design new asymmetric transformations. 1.2 Challenges in asymmetric stereoinduction: A non - trivial mechanism of addition The most simplistic mechanistic picture for halofunctionalization consists of a two - ste p addition of halenium and nucleophile to an olefin, via a three membered halonium (or haliranium) intermediate ( Figu re 1. 1 ), as proposed originally by Roberts and Kimb all, 3 and later experimentally supported by Olah. 18 - 20 While this interpretat ion is not incorrect, it often represents only a segment of the various mechanistic possibilities. While NMR studies by Olah and coworkers have shown evidence for the existence of these cyclic haliranium intermediates, significant evidences have also favor - halocarbenium ion intermediate 21 - 25 as shown in Figure 1. 3 , This is especially true for c hlorine due to its high electronegativity as compared to bromine and iodine. Studies have also shown that in the absence of any significant electronic bias in an olefinic center, the - halocarbenium ion can be in an equilibrium with its regioisomeric form, as well as with the cyclic halirenium form. Furthermore, Brown and coworkers have also demonstrated that these cyclic haliranium intermediates can engage in a halenium exchange equilibrium with unreacted olefins at a rate comparable to that of diffusion - controlled reaction the. 26 - 28 5 Figure 1. 3 Mechanism of alkene halogenation . Above is a depiction of the various outcomes of electrophilic halogenation of al kene and the fate of a classical cyclic haliranium ion intermediate Once all these pathways are taken into account, the overall mechanism of an olefin halofunctionalization process becomes far less trivial than what is often interpreted in a typical underg raduate textbook. The key challenges in attaining any form of selectivity (regio - , diastereo - , or enantioselectivity) in a halofunctionalization reaction thus lies in its unique mechanistic possibilities. To envision this better, consider a simplified scen ario of a catalytic asymmetric halofunctionalization reaction via the irreversible formation cyclic haliranium intermediate ( Figure 1. 4 a). Achievement of high enantiose lectivity will hinge manner in the first step. A high diastereoselectivity is also expected if this is the only mechanism, as the nucleophiles will presumably attack the haliranium intermediate from the opposite face of the halenium addition, leading to an anti - addition. But the regioselectivity of the nucleophile attack will either have to be controlled by the internal 6 bias of the alkene or the catalyst. This will lea d to a successful regio - and stereoselectivity in this simplified scenario for a catalystic asymmetric halofunctionalization reaction. If the possibility of an olefin to olefin halenium transfer is now factored in ( Figure 1. 4 b), one is suddenly faced with a precarious scenario where this rapid exchange completely scrambles the stereocenter set by the catalyst in cyclic haliranium intermediate, which in turn would lead to a complete or partial racemic product mixture. The prospect of this unfortunate outcome has been elegantly demonstrated by Denmark and co - workers. 29 They showed that by doping a process that involved a stereoselective, nucleophilic trapping of an in - situ generated chiral bromonium intermediates with external olefins led to a noticeable loss of the stereoselectivity, via olefin to olefin halenium trans fer. The results from their study immediately underscores the challenge posed by such olefin to olefin halenium transfer processes towards the development of a successful catalytic asymmetric halofunctionalization reaction. Figure 1. 4 Challenges in catalytic asymmetric halofunctionalization via cyclic haliranium intermediate . (a) Depiction of an ideal catalytic asymmetric halofunctionalization reaction via a cyclic haliranium intermediate. Note that so long as 7 controls the regioselectivity of addition in step 2, the catalyst only needs to control the face - selectivity of step 1. (b) Depicts an unwanted racemization pathway, that may rescind face - selectivity set by the catalyst. Now consider another simplistic scenario where the reaction is a two - step process via the irreversible for - halocarbenium ion intermediate ( Figure 1. 5 a). In this scenario, face selectivity in the addition of the halenium ion as well as the nucleophile has to be c atalyst controlled in order to obtain any enantioselectivity or diastereoselectivity. bias or by the catalyst. This scenario by itself is not trivial as now the cat alyst has to serve the purpose of a bifunctional catalyst controlling the selectivity of addition of both the nucleophile and the electrophile separately in both step 1 and step 2. Failure of the catalyst to control the selectivity both step 1 and step 2 s imultaneously would lead to a loss of diastereoselectivity as shown in Figure 1. 5 b and Figure 1. 5 c. 8 Figure 1. 5 Challenges in catalytic asymmetric halofunctionalization via a - halocarbenium pathway . (a) Depiction of an ideal catalytic asymmetric halofunctionalization reaction via - halocarbenium pathway. To selectively generate only one stereoisomer, the catalyst must exert selectivity in both step 1 and step 2. (b) Failure of catalyst to control fac e selectivity of nucleophile in step 2 will lead to a loss in diastereoselectivity. (c) Failure of catalyst to control face selectivity of the halenium in step 1 will lead to a mixture of diastereomer. Nonetheless, this model becomes exponentially more con voluted once the reversibility of the halenium addition step and the possibility of the simultaneous existence - halocarbenium regioisomers and cyclic haliranium intermediates are - halocarbenium regioisomer have co mparable lifetimes, one could potentially scramble the regioselectivity in the products. If the olefin - to - olefin halenium transfer is at play, even the face selectivity of the halenium would be lost. Thus, even if a catalyst exerts perfect selectivity in s tep 1 and step 2 of the addition, the rapid 9 equilibria between the different intermediates could lead to a complete loss of selectivity. Figure 1. 6 attempts to illustra te this loss of selectivity by considering all of these possibilities. 10 Figure 1. 6 Challenges in catalytic asymmetric halofunctionalization . (a) Depiction of an ideal catalytic asymmetric halofu nctionalization reaction via - halocarbenium pathway. (b ) Various pathways to lose all selectivity despite the catalyst successfully controlling 11 the face - selective delivery of both the halenium ( step 1) and nucleophile (step 2). The a bove exercise hopefully demonstrates how addition of these mechanistic possibilities to the classical halofunctionalization pathway (via a cyclic haliranium intermediate) can disproportionately increase the challenges in developing a successful catalytic a symmetric halofunctionalization reaction. 1.3 Another mechanistic possibility: concerted addition pathway The above mechanistic models for halofunctionalization focused on a stepwise electrophilic halenium, however, recent reports have shed light on the possibility of an alternative mechanistic scenario. Independent investigations by Borhan and co - workers as well as by Denmark and co - workers have provided strong experimental evidence i n favor of a one - step concerted A d E 3 - type addition mechanism ( Figure 1. 7 ). 30, 31 In this concerted addition pathway, the alkene engages both the electrophilic halenium ion as well as the nucleophile simultaneously. 12 Figure 1. 7 A concerted addition pathway for halofunctionalization . (a) Depiction of a concerted addition pathway for halofunctionalization of an alkene. (b) Uncatalyzed chlorolactonization reaction has been shown to take a concerted addition pathway for addition. The operation of this concerted addition pathway was perhaps first hinted at during the development of a para meter called halenium affinity, which as the name suggests provides a measure of the affinity of a species toward binding to a halenium ion (shown in Figure 1. 8 a). 32 Halenium affinity of a species can easily be calculated using relatively inex pensive density functional models and relates to the ground state enthalpic difference between the halogenated and the de - halogenated species. In a system with multiple Lewis basic centers competing for a halenium ion, halenium affinity calculation can acc urately predict the location of the halenium ion ( Figure 1. 8 b). Halenium affinities can also be calculated for species that at a glance might not appear as typical Lewis bases, such as alkenes, where the halogenated species would be either the cyclic haliranium or - halocarbenium ions. A few of these reported halenium affinity calculations 32 are shown in Figure 1. 8 c. 13 Figure 1. 8 Halenium affinities . (a) Depiction of a general definition for halenium affinity. (b) The halogenating ability of a species may be predicted based on halenium affinity calculation. Higher the halenium affinity of a d ehalogenated species, worse it is as a halogenating agent. (c) Shown are the reported halenium affinities of several species. The halenium affinity values (in kcal/mol) were calculated with density functionals B3LYP/6 - 31G* and in gas phase. Halenium affini ty calculation is a tool that enabled one to predict whether a halogenating agent would be thermodynamically potent to halogenate an alkene. However, attempting to directly apply halenium affinities to predict alkene reactivities led to some unanticipated results. For example, certain alkenes, such the one shown in Figure 1. 9 a, were predicted to be unreactive towards the used halogenating agents yet 14 they reacted readily. 30 Understanding this unusual reactivity led to a detailed investigation into the reactive conformations of these alkenes, which in - turn revealed a novel addition pathway via a concerted addition mechanism. For the chlorolactonization reaction, the reactive alkene precursor ( Figure 1. 9 c) was found to be in a biased conformation where the nucleophile (carboxylic acid) is positioned in a way where it is poised for a simultaneous attack on the alkene as it captures the halenium. This reactive precursor conformation of the alkene (often dubbed the nucleophile activated alkene) is often a few kcal/mol unit higher in energy as compared to the fully relaxed alkene. However, it does kinetically enable the alke ne to capture the halenium ion by simultaneously compensating the charge development on - rocess to enable the halogenation of an otherwise unreactive alkene led to the process being dubbed nucleophile - assisted alkene activation or NAAA. This concerted addition pathway in chlorolactonization reaction that was hinted at by halenium affinity calc ulations of the folded and the unfolded alkenes ( Figure 1. 9 b) were supported with various kinetic isotopic effect studies (not shown here). 30 It is important to note that while halenium affinity is a thermodynamic parameter, transition state of the reaction, as it lowers the activation energy barrier in the process. However, it has been shown that one may be able to factor in the effect of NAAA into halenium affinity calculations and thereby predict alkene reactivity, by measuring 15 halenium affinities of conformational minima in alkenes that well represent NAAA conformation of the concerted addition. 30 Figure 1. 9 Discovery of concerted NAAA addition pathway for chlorolactonization reaction . (a) Halenium predicted reactivity of chlorolactonization (b) Halenium affinity 16 cal culations that indicated a folded conformation of the alkene was necessary for effective halenium transfer from the halogen source to the alkene. (b) Depiction of the feasibility of the concerted pathway versus the stepwise addition pathway. To summarize, there are multiple possible pathways for alkene halofunctionalization. Evidences have shown the possibility of both stepwise and concerted addition pathways, as well as several unwanted pathways for isomerizations and racemizations. However, these studies have only explored either uncatalyzed reaction systems or reactions that are not asymmetric halofunctionalizations. The mechanism of the catalytic asymmetric halofunctionalization yet remains unexplored. Nonetheless, these detailed studies lay the foundati on for the rest of the chapters as we explore more of the catalytic asymmetric reaction systems. 1.4 Role of the catalyst To understand the catalytic version of an uncatalyzed reaction one must first probe the role served by the catalyst, specifically with regards to the stereoinduction in the product in an asymmetry catalysis. Denmark and co - workers have elegantly summarized a set of four plausible catalytic models to account for the role of the catalyst in various reported catalytic asymm etric halofunctionalization reactions. 10 While these models certainly do not cover every possible catalytic behavior, it represents a good starting framework to build more complex models, and are highlighted briefly. The catalytic models are as f ollows: Chiral L ewis base catalytic systems (type I ) . As the name suggests, in these systems the chiral catalyst has a chiral Lewis basic center that is halogenated first and in turn delivers the halenium ion over to the reacting alkenoic center in a stere oselective manner ( Figure 1. 10 a). Perhaps the simplest of the catalytic models, reactions that are 17 hypothesized to obey this model also represent some of the oldest/earl iest efforts towards catalytic asymmetric halofunctionalization reactions. 10 In reality, the catalysts in these models are chiral mediators for the halenium source rather than actual catalyst, as every example either uses stoichiometric or super - ( Figure 1. 10 b). 33 A reason for this could be that these chiral mediators could do not words, catalyst - halenium complexation do not lead to an activated halenium complex. Figure 1. 10 Chiral lewis base catalyst system (type I) . (a) Depicts the mechanism of halenium delivery for catalyst in type I model. (b) An example of a catalytic system hypothesized to be following a type I mechanistic model is one reported by Ishihara and co - workers. Chiral ion - pairing catalytic systems (ty pe II ): This is a variation of the first system, where the chiral catalyst and the halenium ion source forms a tight adduct, either through ion - pairing or a hydrogen bonded complex ( Figure 1. 11 ). This chiral adduct is now a more 18 potent halenium donor (as compared to the naked halenium source) and ferries the halenium to the reacting alkene center leading to the halofunctionalization. A majority of the reported catalytic asymmetric halofunctionalization reactions are hypothesized to follow this pathway; an example of this type is shown in Figure 1. 11 b. 34 Figure 1. 11 Chiral ion pairing catalyst system (type II) . (a) Depicts the mechanism of halenium delivery and stereoinduction for catalyst in type II model. (b) An example of a cataly tic system hypothesized to be following a type II mechanistic model is one reported by Denmark and co - workers. H ydrogen bond ed s ubstrate - catalyst complex (type III ): In both the type 1 and 2 systems, the catalyst creates a chiral halenium source, leading t o its facial discrimination in halenium delivery. In type 3 systems, the alkene substate is bound within the catalytic cavity via hydrogen bonding, this enables the incoming halogen source to stereo - differentiation between the two faces of the alkene ( Figure 1. 12 ). While the face - selectivity of the alkene is determined by its binding to the catalyst, the enhanced reactivity of 19 catalytic pathway over the background reaction, that is presumably arising from the activation of the halenium source is more difficult to rationalize. 10 To justify the reactivity of these catalytic systems, the catalyst - alkene complex is typically depicted to further pre - organize with the halenium source into ternary complexes leading to an activated complex. An example of a reaction hypothesized to follow this mechanism is reported by Nicolaou and co - workers is shown in Figure 1. 12 b. 35 Note that perhaps the success of these catalytic systems can be better explained in ma ny cases by invoking the possibility of a concerted (NAAA) pathway, where the catalyst - bound nucleophilic site of the alkene is more activated for a concerted addition. This will be explored further in chapter 2 for chlorolactonization reaction, another re action hypothesized to follow the same type III mechanistic model. Figure 1. 12 Substrate - catalyst hydrogen bonded complex (type III) . (a) Depicts the mechanism of halenium delivery and stereoin duction for catalyst in type III model. (b) An 20 example of a catalytic system hypothesized to be following a type III mechanistic model is one reported by Nicolaou and co - workers. Bound substrate via L ewis acid - base adduct (type IV ): Quite similar to type three systems, these are also heavily preorganized systems where the catalyst, alkene and the halenium source are arranged via Lewis acid - base interactions ( Figure 1. 12 ). The catalytic asymmetric halofunctionalization reactions reported by Burn and co - workers, for instance, are hypothesized to obey this model ( Figure 1. 13 ). 7, 36 Figure 1. 13 Substrate - catalyst Lewis acid - base complex (type I V ) . (a) Depicts the mechanism of halenium delivery and stereoinduction for catalyst in type III model. (b) An example of a catalytic system hypoth esized to be following a type IV mechanistic model is one reported by Burns and co - workers. A few cautionary notes, while the above models are elegant and logical from a chemical sense, they are mostly formulated based on preexisting knowledge of uncatalyz ed processes. The reactions that have been allotted to different models, are done so with only little, or in some cases no experimental investigations into the 21 - workers have also pointed this out for several reactions where the proposed mechanisms were found to have conflicting interpretations. 10 Furthermore, the models have been proposed with mostly a haliranium intermediate pathway in mind. 1.5 (DHQD) 2 PHAL catalyzed asymmetric halofunctionalization reaction With an exploration of the possible mechanism of addition in halofunctionalization and roles of catalyst for a catalytic asymmetric version, let us return to the (DHQD) 2 PHAL catalyzed halofunctionalizatio n reaction mentioned earlier in the chapter. (DHQD) 2 PHAL is a dimeric cinchona alkaloid that has found remarkable success in its role as chiral organocatalyst for various chlorofunctionalization reactions. Since the report of catalytic asymmetric chlorolac tonization ( Figure 1. 2 ) in 2010 by Borhan and co - workers, 9 a number of catalytic asymmetric chlorofunctionalization have been reported to have used (DHQD) 2 PHAL as the chiral catalyst. 37 - 43 These chlorofunctionalization reactions are typically categorized into two types based on the location of the nucleophile, 1) cyclization reactions where the nucleophile are tethered to the alkene or are intramolec ular ( Figure 1. 14 a), and 2) reactions that use external nucleophiles or are intermolecular ( Figure 1. 14 b). Examples of the former include chlorolactonization, 9 chlorocyclization of alkene amides, 37 chlorocyclization of alkene carbamates, 38 while some examples of the latter class are chloroetheri fications, 41 dichlorinations, 42 and chloroamidations. 43 22 Figure 1. 14 (DHQD) 2 PHAL catalyzed asymmetric alkene chlorofunctionalization reaction . Type I systems (a) Chlorolactonization of alkene carboxylic acids. (b) Chlorocyclization of alkene amides. (c) Chlorocyclization of alkene carbamates. Type II systems (d) chloroetherification of alkene amides. (e) Chloroamidation of alkene amides. (f) Dichlorination of alkene amides. (g) Catalyst and chlorine source utilized for these chlorofunctionalization reactions. Despite the success of (DHQD) 2 PHAL as a chiral catalyst for catalytic asymmetric chlorofunctionalization reactions, little is still known about the mechanism of the reaction. Based on a few preliminary investigations on the chlorolactonization reaction, 10 the model for (DHQD) 2 PHAL catalyzed reactions have been hypothesized to be that of type III ( Figure 1. 12 ), where the substrate is presumably sitting in the catalytic cavity, while t he chlorenium source delivers the halogen in a face selective manner. However, there is a lack of any rigorous investigations to rule out alternative mechanistic possibilities. 23 Investigations of the face selectivity of these reactions have also led to som e interesting revelations that are hard to explain with a single generalized mechanism. For instance, the alkene face selectivity of the nucleophile is completely different in the cyclization of alkene carboxylic acid (chlorolactonization) versus the cycli zation of alkene amides. 44, 45 Interestingly, the alkene carboxylic acid was found to undergo a syn - addition, which is difficult to explain with the classical mechanistic mod el of addition via a cyclic haliranium intermediate. However, the amide cyclization was found to proceed as an anti - addition ( Figure 1. 15 a). This difference is surprisi ng given the two reaction systems are driven by the same catalyst and similar chlorenium source, the only major difference between the two systems being the amide vs carboxylic acid serving as the nucleophile and polar protic vs non - polar solvent environme nt. Perhaps more interesting is the cyclization of alkene carbamate, 38, 45 where only a change from a polar protic to non - polar solvent changes the face selectivity of the nucleophile, leading to syn - addition in the former case and a nti - addition in the latter ( Figure 1. 15 b). In this case the polar protic conditions led to improved selectivity at lower temperatures while the non - polar conditions had improved selectivity at a more elevated temperature. Furthermore, all polar reactions were found to have severely enhanced rat e while most non - polar reactions were much slower. 24 Figure 1. 15 Prior mechanistic studies for dissecting the face selectivities . (a) Change in nucleophile face selectivity for chlorolactonization vs chlorocyclization of alkene amide. (b) Solvent dependent change in nucleophile face selectivity in chlorocyclization of alkene carbamates. These differences pointed to a non - trivial mechanistic scenario which needed a thorough mechan istic investigation. Some reasonable q uestions about the mechanism of these catalytic asymmetric halofunctionalization reactions may be: 1) What is the mechanism of addition ? 2) What role does the catalyst serves ? 3) H ow does the catalytic pathway lower the activ ation energy barrier? 4) How does is the asymmetric induction taking place? 5) Is the mechanism same for all of the reactions listed in Figure 1. 14 ? To answer these questions , we have conducted an in - depth mechanistic study using chemical kinetics as our primary tool for mechanistic exploration. The mechanism will be explored in the form of two catalytic asymmetric chlorofunctionalization reactions 1) Chlorolactonization react ion, which will be the subject of C hapter 2, 2) 25 Chloroetherification reaction, which will be the subject of C hapter 3. Kinetics is an integral , albeit not the only tool utilized for our mechanistic studies . T hus , the following sections of this chapter will discuss some of the early and recent kinetic techniques that are relevant to our investigations. 1.6 Kinetic studies Chemical kinetics is an area of study that measures and analyzes the temporal - concentration p rofile of reacting components for the reaction under study. 46 Often these studies are associated with divulging the empirical function linking the concentration of each reacting component to the reaction rate, also known as the rate law equation. The studies leading to a rate equation can provide critical information relating to the mechanism of the reaction under study. Although finding the rate law equation will be the primary goal of our mechanistic studies, the study of chemical kinetics encompass es numerous other tools for mechanistic investigation , including the effect of isotopic substituent on reaction rates (kinetic isotopic effects), 47 finding activation parameters 48 - 50 (Eyring plots), etc. As such, chemical kinetics has historically been an indispensable tool for mechanistic investigations . 51 In the following section, we will discuss how obtaining a rate law equation can allow for the development of mechanistic models. 1.7 Reaction rate and the rate law equation Kinetic experiments tha t measure the temporal change in concentration of various components in a reaction can provide one with the rate of the reaction. While detailed discussion on the definition of the rate of a reaction can be found in several advanced texts, 51 - 53 to accomplish a meaningful transition into kinetic studies in the following 26 section s, we will briefly introduce the idea of rate using a simple example. Consider a simple chemical transformation: rxn (1.0) For the above reac tion A, B, C and D are the chemical components while a, b, c and d are the stoichiometric coefficients of each component that allows a balanced chemical equation. The rate of the above reaction can be defined in terms of the concentration of the substrates and products as follows: eq (1.1) Where [A], [B], [C] and [D] are the concentration of the respective components at time t. Thus, rate of a reaction is defined by the concentration change of each component per unit time, normalized with their stoichiometry of consumption in the reaction. 51 - 53 The rate can often be represented as a function of the concentration of the various reacting components as shown in equation (1.2). eq (1.2) These functions f([A],[B]), are known as the rate law equation for representative reaction. The mathematical form of this rate function can be derived from the mechanistic model of the reaction , and conversely, the form of the rate equation function reflects the mechanistic model . This is demonstrated by using a simplified reaction (Rxn 2) in Figure 1. 16 , where one may notice how two different reaction mechanism for the same transformation yields different rate law equation s . Thus , experimentally determining th is mathematical form of the rate law can illuminate the mechanism of the reaction. 27 Figure 1. 16 Different rate equation for different mechanistic models . This figure depicts different mechanistic scenarios may lead to different rate equation for the same reaction. It is, however, important to note that the form of a rate equation is always not unique to a singular mechanism, in other words, multiple mechanistic scenarios can lead to the same form of rate equation. This is shown in Figure 1. 17 , despite the two - rate equation being different, they have similar form, that is the rate of the reaction is k obs [A][B]. Thus, it is often necessary to complement these kinetic studies with oth er investigations, such as kinetic isotopic effect studies, to establish a reaction mechanism with a greater degree of certainty. Nonetheless, determination of the rate law sets a stringent boundary conditions, often dramatically cutting the number of mech anistic possibilities to only a select few. 28 Figure 1. 17 Similar rate equation for different mechanistic models . This figure depicts how two different mechanistic scenarios could also lead to rate equation of similar form. 1.8 Empirical rate law and order of components An experimentally determined rate law, for a generic reaction such as the one in Rxn 1, is typically represented in the following form, eq (1.3) The k obs is the experimentally observed rate constant for the reaction. The powers each component of a reaction can have positive, negative, integer or non - inte ger values, and are unrelated to their stoichiometric coefficients in the reaction. When order of a component is zero (zeroth order), rate of the reaction has no concentration dependence on that component, when order of a component is one (first order), ra te of the reaction has linear dependence on that component and so on. The summation of the order of each 29 component represent the overall order of the reaction, for instance, if order of every component is zero (a rare occurrence) the overall reaction is a zero - order reaction. Determining the orders not only allows one to define the empirical rate equation but are via kinetic experiments for various chlorofunctionalization reactions will be a key part of the following chapters. Discussion on the zeroth, first and second order reactions, their mechanistic implications and case studies etc. can easily be found in any undergraduate 54, 55 as well as advanced texts 51 - 53 on re action kinetics and will not be discussed further. Note that the empirical rate law can have a different, more simplified linear form compared to the one derived from a proposed mechanistic model. However, the derived rate equation can always be reduced to its empirically determined form at certain concentration limits (also known as limiting form) or with certain reasonable approximations. To understand this, consider reaction model 2 in Figure 1. 16 . The rate law equation derived from the mechanistic model has the following form, eq (1.4) However, if k - 1 is insignificantly small under the reaction condition (due to large B or k 2 ), the above equation 1.4 can be approximated to the following form equation ( 1.5 ) similar to the generalized empirical rate equation. eq (1.5) Once the empirical rate law is determined using kinetic experiments, one may leverage the above fact to ensure that the proposed mechanism is correct, as the rate 30 law derived from the correct mechanistic model will conform with the experimental rate law. Despite the proven utility of chemical kinetics to determine reaction mechanism, it is often underutilized among synthetic organic chemist due to two reasons: 1 ) Challenges in reaction monitoring , 2 ) The often - cumbersome mathematics that are asso ciated with kinetic analysis to find the order of components. These two points will be addressed in the next section in more detail to illustrate how recent development has simplified kinetic measurements and kinetic analysis. 1.9 Reaction monitoring and kinetic measurements The first step towards any kinetic study is establishing a protocol for consistent measurement of the reaction progress for the reaction under study. This involves choosing the appropriate spectroscopic tools/instrumentation for quanti tative analysis, as well as a standard reaction condition that is suitable for the kinetic study. This step can often be deceptively challenging, and the challenges may be unique to each reaction system , as will be displayed with examples from our own stud ies. Figure 1. 18 Reaction monitoring techniques . (a) Reaction monitoring using a discontinuous assay. (b) Reaction monitoring using a continuous assay. 31 Perhaps the most common approach towards monitoring reaction progress is via measurement of the concentration decay and growth of the substrate and prod uct, respectively, over time. The measurements can be done using a discontinuous assay or a continuous assay method ( Figure 1. 18 ). 52 A discontinuous assay would involve direct extraction and analysis of reaction aliquots from benchtop reactions at des ignated time intervals. However, advent of modern spectroscopic tools now also allows for a continuous assay that allows for direct in - situ reaction monitoring of the concentration of each component (example NMR and React - IR spectroscopy). Both the discont inuous assay and the continuous assay methods have their own advantages and disadvantages. For instance, continuous in - situ reaction monitoring typically provides greater number of data points, which is especially convenient for fast reactions, and are les s prone to human error due to the entire experiment being in - situ once initiated. On the other hand, a discontinuous assay via time course sampling can provide greater flexibility for measurements as the reaction condition is not restricted to the instrume limitations (monitoring a reaction with no available deuterated analog of the solvent). Once a concentration - time profile is obtained from the kinetic measurements, one may either directly analyze to find properties of interest (order of component s, rate constants etc.) or convert the concentration - time profile to a rate - concentration profile for further analysis (discussed more in next section). Alternative to a concentration measurement, direct rate measurement can also be performed, using techni ques such a reaction calorimetry. This thesis will present kinetic studies of various (DHQD) 2 PHAL catalyzed asymmetric chlorofunctionalization reactions. The kinetic studies are the result of in - situ 32 reaction monitoring using NMR spectroscopy and, in some cases, react - IR. Reaction monitoring of each chlorofunctionalization reaction presented its own unique set of challenges. Some of these challenges and experimental techniques used to overcome them are discussed in the following paragraphs . Figure 1. 19 Challenges in reaction monitoring of chlorolactonization of alkene carboxylic acids . Challenges in reaction monitoring (shown in right box) is specifically for reaction monitoring using NMR Chlorolactonization of alkene carboxylic acids : T he original optimized reaction condition , 9 which involved a 1:1 mixture of chloroform:hexane was reoptimized to use only chloroform as the solvent, while maintaining a comparab le selectivity and yield ( Figure 1. 19 ) . This was done to easily monitor this reaction using 1 H NMR spectroscopy without involving any solvent suppression in the spectra . Figure 1. 20 Challenges in reaction monitoring of chloroetherification of alkene amides . Challenges in reaction monitoring (shown in right box) are for both for NMR and React - IR. Chloroetherification of alkene amides : Th e biggest challenge for chlorofunctionalization of any alkene amide 41 ( Figure 1. 20 ) system was found to be their fast rate. Chloroetherification reaction at room temp or even when lowered down to - 30 33 °C reaction went to completion in <30 min in most cases. Attempts to slow the reaction by lowering the catalyst loading did not yield helpful result (which ultimate presented an important mechanistic clue, discussed more in chapter 3). Attempts to slow reaction rate by l owering temperature further was also not feasible since l owering temperatu re below - 30 °C often lead to substrate (alkene amide) precipitation . This was exacerbated from the instrument limitations as the NMR and React - IR cooling systems used did not allow for maintaining a consistent temperature when temperature was lowered belo w - 30 °C. Lowering rate by lowering the overall reactant concentration was avoided due to the low starting concentration of reactants (40 mM). These problems were compounded by the fact that the reaction uses a solvent mixture of methanol - acetonitrile (3:7 ). Fortunately, deuterated versions of both solvents are cheap, commercially available, and miscible. However, the presence of multiple deuterium signals increased the time necessary for properly locking and shimming the samples at the beginning of the kin etic runs, leading to a loss of a significant number of data points at the start of the reaction. Further challenges included the slow relaxation of some of the protons of interest in these solvents (up to ~3 secs). React - IR is a good alternative for captu ring fast reaction processes due - IR as a means of reaction monitoring, however, presented its own set of challenges. For instance, the reaction lacked high intensity infrared active functional groups t hat changed during the course of the reaction. The change of alkene to chloroalkane was not directly visible in the IR, however, we were able to monitor and quantify (albeit with difficulty) the chlorinating agent and its byproduct. This although, not idea l did provide one of the first ways to monitor the chloroetherification reaction. Ultimately, screening substrate s led to a less reactive alkene 34 that further mitigated some of the problems by slow ing the reaction rate enough for reaction monitoring with NM R . The standard conditions and protocols for chloroetherification will be discussed further in the experimental section of Chapter 3. Figure 1. 21 Challenges in reaction monitoring of chloroamida tion of alkene amides . Challenges in reaction monitoring (shown in right box) are for both for NMR and React - IR. Chloroamidation of alkene amides : Monitoring catalytic asymmetric chloroamidation 43 reaction were accompanied with challenges similar to chloretherification due to its comparably fast rate ( Figure 1. 21 ). Si milar to chloroetherification, use of appropriate substrate allowed for reaction monitoring with NMR and react - IR. Monitoring the catalytic asymmetric chlorocyclization of alkene amides and alkene carbamates are perhaps more challenging due to their faster rate and their use of fluorinated alcoholic solvents which are not ideal for NMR use. Currently, efforts are underway in the Borhan lab to develop standard conditions appropriate for continuous reaction monitoring for the latter two reactions. 1.10 Kinetic analysis to find order of components Once a standard condition is established for reaction monitoring, the data is then subjected to kinetic analysis for extracting various kinetic properties of the reaction. As discussed before, determining the or der of each components can provide valuable information about the mechanism of a reaction. While determining order of a component is relatively simple (ex: using method of half - life) when there is only one component 35 involved in the reaction (rate law has t he form rate = k[A] n ), this is rarely the case for most organic reactions. Determining the order of each components when there are multiple components involved in the reaction can be especially tricky. Thus, various protocols are reported in the literature for treating of kinetic data to extract information relating to order of each components, some of which will be discussed in the following sections. 1.10.1 Method of isolation Method of isolation is a protocol well utilized in older literature to determi ne order of components. This technique involves an assay of varying the initial concentration of the particular reaction component whose order is of interest while maintaining saturation with every other reaction component. 53 This is explained with a simple example as follows. Consider the following reaction: rxn (2.0) ion 2 is as follows: eq (1.6) Table 1. 1 Set of experiments for finding the order of components using method of isolation Exp [A] (M) [B] (M) 1 1 10 2 2 10 3 10 1 4 10 2 To determine the order of A one may run a minimum two experiments (exp 1 and 2, Table 1. 1 ), with different concentration of A. For each of these experiments the equival ence of B is set to be at least 10 times (or more) than that of A. As the reaction progresses, both A and B are consumed, but the change in concentration of B is negligible 36 leading to B having a pseudo order (an approximately constant impact on rate). Thus , the above rate equation is reduced to rate being a function of A only. eq (1.7) Where, eq (1.8) Thus, by measuring the impact on rate for the two reaction with two different initial concentr ation of A (exp 1 and 2, Table 1. 1 ) one may deduce the order of A. Conversely, one can determine the order of B by saturating the reaction with A and measuring the impac t of two different initial concentration of B on the rate. While this method is relatively simple and intuitive, it has several obvious drawbacks. For example, it might not be feasible to drastically increase the concentration of components due to factors like precipitation. Furthermore, using this abnormal stoichiometry, which is often different from original reaction conditions, could change the mechanism of the reaction, yielding misleading results. 1.10.2 Method of initial rate Method of initial rate, a s the name suggests leverages on the change of rate at the very beginning of the reaction (t 0) with change in initial concentration of the reaction component to find its order. Let us consider the same last example to understand the method. rxn (2.0) Where the rate equation is as follows: eq (1.9) Based on equation 1.1, rate can be represented as, eq (1.10) 37 The (measurable) rate at the very beginning of the reaction when t 0 , that is the initial rate i , can be approximately represented in terms of the known initial concentration of the reaction components eq (1.11) Thus, if one were to estimate the order of A, one may run at least two experiments with different initial concentration of A, say A 1 and A 2 ( Table 1. 2 ), while maintaining an otherwise ide ntical reaction condition including the same initial concentration of B. The initial rate for the two system can be approximately defined as eq (1.1 2 ) eq (1.1 3 ) Table 1. 2 Set of experiments for finding the order of A using method of initial kinetics Exp [A] (M) [B] (M) 1 A 1 B 2 A 2 B Dividing the above two equation above leads to equation eq (1.1 4 ) Taking a log of both side and rearranging the above equation can easily reveal the eq (1.1 5 ) For the above equation, A 1 and A 2 are known as they represent the initial concentration of A ( Table 1. 2 ) . Thus, initial rates i , 1 and i,2 are the only values needed 38 The advantage of this method over the method of isolation is that the kinetic experiments can be performed under conditions that are relatively similar to the original reaction con ditions. Furthermore, as the measurements only rely on measurements of parameters under the initial reaction, a rigorous instrumental setup for continuous reaction monitoring to monitor the entire reaction profile is not entirely necessary. Unfortunately, this method is not without its disadvantages either. The first and rather more obvious disadvantage is that by focusing entirely on the initial conditions, one is discarding the kinetic information of the entire later part of the reaction. This is especial ly important for enzyme kinetics where drastic change in substrate concentration can often lead to a change in enzyme activity or even molecularity. By relying solely on this method, one may lose information on such late stage processes. There are other ki inactivation, 56 which one may complement with the initial rate measurements. However, these tests again require an instrumental setup for a complete kinetic profiling of the reaction. The second, less obvious disadvantage of this method stems from the challenges in the measurability of the initial rate. Initial rate, by definition, has to be measured from the small change in the concentration of a components, say dA with small change in time dt, when time is closes to zero (t 0). An approximation often used for cal culating these terms of A. eq (1.1 6 ) 39 As long we know the concentration of A at time t (A t ) one might think its easy to calculate the initial rate, while the reality is less trivial. For instance, the measured span of time (and concentration) will always be larger that of the ideal theoretical value. And since rate only decrease over time (in most reactions), the me asured initial rate will always be smaller than the actual initial rate. In fact, the measured initial rate is most likely not the initial rate at all but rather an average of a series early rate values. Perhaps more accurate approach for this is by plotti ng the concentration vs time profile of A vs t and then extracting the initial rate from the tangent of the plot at the origin (that is when A and t are both nearly zero). Nonetheless, accurate measurement of the curvature from the initial data points is n ot trivial. Early reaction events such as brief incubation periods, could contribute to the inaccurate estimation of the real initial rate. 52 1.10.3 Method of reaction progress kinetic analysis (RPKA) Reaction progress kinetic analysis or RPKA is a graphical kinetic analysis protocol that has found extensive following in the modern lite rature to solve various mechanistic problems. 57, 58 At its core, the philosophy of RPKA protocol is to analyze the measured kinetic profile(s) of a reaction (concentration vs time or rate vs time), and present it in a graphical form that allows for direct extraction of relevant kinetic information, such as order of components. To illustrate this in its simplest case let us consider the following reaction. rxn (3.0) The empirically measured rate equation for the above reaction will have the form, eq (1.1 7 ) 40 Figure 1. 22 Graphical analysis of rate law equation . (a) Plot of measured data (rate or concentration) against time. (b) Plot of rate against concentration. The straight line through the origin in this plot indicates first order in A, providing direct information on the nature of the rate law. For the above Figure 1. 22 , the left plot represe nts the measured data, that is, either a rate vs time or concentration vs time profile. While the plot by itself does not intuitively provide any information about, say the rate law of the reaction, replotting the same information in a rate vs concentratio n plot (also known as graphical rate equations), shows a linear relationship between rate and concentration of A. The linearity of this plot immediately and intuitively provides the user with a rate equation (Rate = k[A]) and this graphical analysis to fin d the rate equation would be a reaction progress kinetic analysis. For any RPKA study, there are really only two requirements: 1) one must have some means to be able to monitor a significant amount of reaction progress (preferably using a continuous assay) 2) One needs a computer equipped with a graphical software that supports basic data analysis functions such as curve - fitting (such as excel). Due to the over - simplicity of the above example and the fact that these plots are shown regularly in undergraduat e physical chemistry courses, the novelty of the approach will probably not be apparent unless we consider a more complex kinetic scenario. Thus, let us look at the RPKA analysis of the the following reaction. a. Measured data b . Graphical rate equation 41 (initial conc. of A, B, C, D are 2 M, 3M, 0M, 0M) rxn (4.0) We have illustrated that whenever we have a multicomponent reaction such as the one above ( r xn 4) obtaining the order of each component using the method of isolation or the method of initial rates involves several caveats. The nov elty of RPKA really stems from its simple and intuitive graphical approach to solving rate equations for multi - component reactions, while avoiding the compromises of the classical kinetic analysis approaches. Let us assume that the reaction has the followi ng rate equation, eq (1.1 8 ) Based on the above rate equation, rate has a first order dependence on the concentration of both A and B (overall second order). If we were to determine this relationship using RPKA, based on t he last example we could take the following steps. First measure the concentration - time profile, then plot this as a rate vs concentration for A or B ( Figure 1. 23 ). However, now the rate vs A or B would have a parabolic plot that fails to intuitively present the order of each components. Figure 1. 23 Kinetic profile of a second order reactio n . (a) Concentration vs time plot. (b) Rate vs concentration plot. Fitting functions generated from a second order rate law can be developed and used to establish that this reaction is a second order reaction but that would require a a. Concentration profile b. Rate profile 42 more complex mathemat ical analysis. The goal of RPKA is to present a simple and more visually intuitive approach for synthetic organic chemists. RPKA would suggest plotting the following functions instead would directly provide a meaningful information, - or - eq (1.19) The above function now presents a simple form where the left - hand side of the other component [B] or [A ] (right - hand side). Provided the order of both A and B is one, plotting either of these equations should be a straight line through the origin as shown in Figure 1. 24 . Conversely, the linear nature of the plot of Rate/[A] against B, determined through experiments will support a first order in both A and B. Figure 1. 24 RPKA analysis of rate law . (a) The rate axis has been normalized for the concentration effect of A leading to its displayed linearity. (b) The rate axis has been normalized for the concentration effect of B. Thus, the linearity in the above graphical r ate equation plot, directly informed us about the order of the reaction components A and B, and theoretically for this kinetic scenario, a single experiment is sufficient to deduce the order. A generalized approach to determine order for more complex cases using experiments known as different excess experiments will be discussed in the next section. This linearization approach (heavily inspired by the Lineweaver - Burk plot 59 ) laid a simple, direct insight into physical a. b. 43 parameters, such as orders of components, to establi sh the rate law equation. Furthermore, this approach does not require any unnatural saturation conditions and the order can be measured in terms of the entire span of the reaction and requires few experiments, thus negating the pitfalls of the method of is olation or the initial rates. (initial conc. of A, B, C, D are 2M, 3M, 0M, 0M) rxn (4.0) Another common scenario for r xn (4) is where the order of one of the components while B is zero. eq (1. 20 ) In this case, the above equation (1.20) would be reduced to the following Figure 1. 25 RPKA analysis of rate law for a reaction of overall order of 1 . (a) Since rate is independent of the concentration of B (zero order), removing the effect of A on rate lead to a function (rate/[A]) that does not change with the concentration of B. (b) The plot of rate against the concentration of A also generates a straight line through the origin, indicating a zero order effect of B and first order effect of A on rate. Thus, in the above case, the Rate/[A] function is a constant and should not change with [B]. Hence, plotting Rate/[A] against B would still yield a straight line but now the line would be horizontal or parallel to the axis of B, this is shown in Figure 1. 25 . And the b . a. 44 reverse would be true if order of A was zero and B was one. This again demonstrates how from the nature of this plot one can quickly extract the order. The RPKA technique is not restricted to integer orders (such as 0 or 1 as shown above), rather any value of order (positive, negative, integer or fraction) can be determined using RPKA in a similarly intuitive fashion and will be discussed in the following section. While a comprehensive review articulating the generalized approaches to kinetic analysis using RPKA 57, 58 is beyond the scope of this chapter, the following paragraph illustrates a few key approaches that will be utilized in the following chapters. Different excess experiments : To understand the generalized appr oach for finding the order of components, let us consider the following catalytic reaction (5), rxn (5.0) The reaction will have the following general rate equation, eq (1.21) Where, and eq (1.22) For the above rate equation, the composite rate constant is composed of rate constants from multiple elementary steps. To interrogate the general order of A an A is a constant throughout the entire reaction (provided A reacts only with B and vice versa). To determine the order of A and B using RPKA, we need to run a at least two experiments Table 1. 3 which presents a set of different excess exp eriments. 45 Table 1. 3 Set of different excess experiments for finding order of components using RPKA Exp [A] (M) [B] (M) xs (M) = B A 1 2 3 1 2 2 4 2 3 3 3 0 Figure 1. 26 Reaction progress kinetic analysis of different excess experiments to find the order of components . The figure (a) - (f) demonstrates how the curvature and overlay of the plots for experiment 1 and 2 (Table 1.3) changes with change in the order of A and B figure (e) and (f) revealing the correct values to be 1 for both. a. b. d. c. e. f. = 1 = 0 = 1 = 0.5 = 0 = 1 = 0.5 = 1 = 1 = 1 = 1 = 1 46 To understand how these different excess experiments can be leveraged to find the order, let us go back the gen eral rate equation (1.21). Similar to before, the rate expression can be rearranged to the following forms, - or - eq (1.23) Once again, the left - hand side (Rate/[A] or Rate/[B] function of concentration of one component B or A, only when raised to their respective If one conducts a set of two experiments with different excess of B (experiment 1 and 2, Table 1. 3 ), and plot of the above two functions should be linear, and overlay provided the correct values of . the investigator in the beginning, however, once a kinetic profile for the reaction is obtained experimentally (experiment 1, Table 1. 3 ), the data can be easily converted to the above form using a plotting software ( like excel) and the investigator may start their Once this is done, the ( unknown variables) can be changed manually until the two plot linearizes and overlays, which only occurs for the correct valu e of . This process of analysis is demonstrated in Figure 1. 26 , notice how the plots do not overlay for Figure 1. 26 a and Figure 1. 26 b, however both of the plot becomes linear and overlay when value for o be 1 in Figure 1. 26 e and Figure 1. 26 f . This indicates the correct power of both A and B are 1. Thus, one can see how only two kinetic experiments (different excess) provided the order of both A and B regardless of their value via analysis of overlay. The need for fewer experiments further adds to the appeal of using RPKA protocols fo r kinetic analysis. Of course, one may also complement or verify this further with a third different excess, 47 with a different value of A instead (experiment 3, Table 1. 3 ). It is also important to point out that the slope of these plots now directly represents the observed rate constants for these reactions, providing the user with another important parameter from the same set of experiments. Finally, one may also determi ne catalyst order in the same manner, by defining the term rate/[cat] and plotting it against the concentration of A or B. For experiments run under different concentration of the catalyst, the plots must overlay when using the correct order of the cataly st . entire rate equation in terms of either A or B as the excess is a constant. eq (1.24) eq (1.25) This means, while useful, it is not necessary to be able to individually monitor the concentration of both A and B, one may simply replace A or B by the other in terms of its excess as shown below. This further simplifies the experimental setup f or the above graphical analysis. - or - eq (1.26) Same excess experiments : Using RPKA one can also extract other valuable mechanistic information about a reaction, such as, the presen ce of catalyst deactivation or product inhibition. This can be done using a set of experiments called the same excess experiments. To understand this let us consider the same reaction (Rxn 5). One may run two experiments ( Table 1. 4 , exp 1 and 2) with the same excess (xs) values but different initial concentration of A and B. 48 Table 1. 4 Set of same excess experiments Exp [A] (M) [B] (M) Catalyst (M) xs = B A additive 1 2 3 0.1 1 - 2 3 4 0.1 1 - 3 2 3 0.1 1 C, 1 M Figure 1. 27 Reaction progress kinetic analysis of same excess experiments . (a) In this case, the overlay of experiment 1 and 2 (Table 1.4) indicate that there is no product inhibition or catalyst deactivation occurring. (b) The non - overlay of experiment 1 and 2 indicate either product inhibition or catalyst deactivation. (c) The overlay of experiment 3 with 1 indicate catalyst deactivation. (d) The overlay of experiment 3 with 2 indicate product inhibition. Figure 1. 27 presents the simulated plot of the experiments in Table 1. 4 . Notice that as the reaction progresses, the concentration of A and B in experiment 2 (3 and 4 M respectively), at some point of time, will match that of the reaction in experiment 1 (2 and 3 M respectively). In other words, they are essentially the same experiment with different initial points and their kinetic profil es are expected to overlay as shown in Figure 1. 27 a. a. b. c. d. 49 key differences between them. First the catalyst in experiment 2 has undergone a few turnovers, and second some product has been generated and is now present in the reaction mixture. If the profile of reaction 1 and 2 do not match or overlay, like the one shown in Figure 1. 27 b, it is the result of either catalyst deactivation or product inhibition from the generated product. The actual cause behind this can further be verified by running experiment 1 with the product (let us say, C, Table 1. 4 , experiment 3) added in as an additive from the beginning. If this new experiment (exp 3, Table 1. 4 ) has the same profile as experiment 1, as shown in Figure 1. 27 c, product has no influence on the rate and the difference is due to catalyst deactivation. However, if exp 3 is now overlays with experiment 2, as shown in Figure 1. 27 d, that would indicate the different between exp 1 and 2 arises from product inhibition. This demonstrates how these experiments are key to illuminating various off - cycle catalytic activities and will be used for studing ch lorofunctionalization reaction as well in later chapters. The above sections have briefly illustrated the power of RPKA studies to extract kinetic information with little compromise. To summarize the advantages this technique 1) Involves r elatively simple m athematical transformations 2) D oes not require advanced kinetic simulation software 3) Reactions can be studies under conditions similar to optimized conditions 4) Involves analysis of the entire kinetic profile There are, however, some disadvantages, for instance plots utilized for extracting information are completely based on visual analysis and there is no straight - forward way of determining the error in an overlay. 60 For reaction monitoring, 50 most often spectroscopic instruments are employed that directly generate a concentration profile. To create the above shown graphical rate equation plots, the concentration - time data needs to be converted into the rate. Rate is generally determined by taking a differential of these concentration - time profiles but doing so can sometime introduce noise and artifacts in the rate data and thereby in the graphical plots. To circumvent this, one may couple the instrument that d irectly monitors concentration (such as a react - IR or NMR) with another instrument that directly collects rate data (such as reaction calorimeter, which provides rate in the form of instantaneous heat flow). However, this will further complicate the instru mental setup, will increase the number of experiments necessary and doing so is not always feasible. Nonetheless, the advantages of RPKA arguably far outweigh the drawbacks as is demonstrated from its extensive implementation in both academia 61 - 66 and industry. 67 - 71 1.10.4 Method of variable time normalized analysis (VTNA) VTNA or variable time normalized analysis is a more recent iteration of the RPKA analysis that leverages on the same type of ex periments (different excess, same excess etc.) to find order of reaction components. 6 0, 72 - 74 However, instead of graphical rate plots it extracts the same information directly from the measured concentra tion - time profiles, with little graphical manipulation. This allows for circumventing the issues in analysis of rate profiles as discussed at the end of RPKA, as one may now directly conduct the analysis of orders from the measured concentration profile. T o understand the VTNA analysis, let us revisit the Rxn (5) rxn (5.0) The rate equation for which can be represented as, 51 eq (1.27) Following the footsteps of RPKA the above rate equation (1.27) could be rearranged to the following form leading to its analysis in the graphical form eq (1.28) The left side of above equation (1.28) is represented in terms of rate, which is a differenti al term and not often directly measured, rather it is generally derived from the differential of the concentration - time profile. To change it to a form where each variable is in the form of concentration or time (which can be directly measured in most scen ario), the above equation must be taken to its integral form. This was done as follows, eq (1.29) Notice that the equation (1.29) now appears in a relatively complex integral form, however, the integra tions need not be solved. The aim here is to reduce the integral rate equation to a form where effect of concentration of the various components are at the above eq uation, the left side is only a function of A as shown below, eq (1.30) Therefore, the right side of equation (1.29) by virtue of equality to the left side, is also just a function of A, eq (1.31) Plot of A vs time (t) for the two different excess experiments 1 and 2 ( Table 1. 5 ) will yield a non - overlaying plot as shown in Figure 1. 28 a, due to the effect of the concentration of B on the rate (provided order of B is not zero). Since the above integral 52 function (1.31) represents a function of only A, the two diffe rent excess experiments ( Table 1. 5 ) where only the initial concentration of B is varied should yield overlaying plots when plotted A vs f (A) or rather A vs B dt. However, this overlay will only occur when the B in B by the correct order of B. This is shown by the analysis of overlay by changing the value Figure 1. 28 b, Figure 1. 28 c, and Figure 1. 28 d the order of B is 1. Thus, if B dt is measurable, we will have another scenario of a reaction progress kinetic analysis whereby conducting a different excess experiment, allows for measuring the order of B by merely Figure 1. 28 . B dt is called the normalized time axis where the effect of the concentration of B has bee n normalized from the time axis. Table 1. 5 Set different experiments for finding order of components using VTNA Exp [A] (M) [B] (M) xs (M) = B A 1 2 3 1 2 2 4 2 53 Figure 1. 28 Variable time normalized analysis of different excess experiments to find order of components . (a) This plot represents a typical concentration vs time plot. F igure (b) - (d) demonstrates how the curvature and overlay of the tim e normalized plots the linearization of the plot is not general and stem fro m the fact that the order of A was chosen to be zero for the simulated plot. dt would be difficult to evaluate from its integral form, however, it can be simplified readily using the trapezoid approximation. This simplifies the equation 1.3 1 as follows eq (1.32) Now that the integral function above has been reduced to a summation function, it can be deduced readily if the concentration values of B and time is known. Since, the summation expression 1.32 is relatively large, it will be abbreviated as follows, eq (1.33) a. b. d. c. = 0 = 2 = 1 54 B t represents the time normalized axis and the overlay of plots for a s et of simulated different excess experiment is shown in Figure 1. 29 . Again, based on the overlay of plots in Figure 1. 29 d, one may conclude that the order of B is 1. (Note: the linearity of the plot in Figure 1. 29 d is not general. The linearity in th is plot stems from the fact that for the simulated kinetics, the order of A was kept as zero, and normalizing the time axis for the concentration effect of B gave the decay profile an overall zero order trend. A non - zero order of A will bring a curvature t o the plot, however, there will still be Figure 1. 29 Variable time normalized analysis of different excess experiments using summation function . The interpretation of the plots in this figure is identical to the last. The difference is that the time normalized axis for all plot is now a summation function (instead of integral) which can be derived more easily with plotting software like excel. F igu re (b) - (d) demonstrates how the curvature and overlay of the time normalized plots = 0 a. b. d. c. = 1 = 2 55 Thi s principle can be applied to any of the component as long as their concentration can be (directly or indirectly) measured. For instance, order of A can be determined by plotting A t against B or even C or D. This can also be extended for determining cat alyst order where instead of representing the time normalized axis as [cat] dt, it can simply be represented as [cat] t, since the concentration of the catalyst generally remains constant. Same excess experiments can also be conducted and analyzed using VTNA to determine the presence of product inhibition or catalyst deactivation. This is done by comparing and the concentration profiles of a set of same excess experiments. The concentration profile of two reactions for two same excess experiments (See exp 1 and experiment 2, Table 1. 6 ) will be offset at first based on how the starting time is chosen ( Figure 1. 30 a). To determine whether catalyst deactivation or product inhibition affected the concentration profile for experiment 1 and 2 ( Table 1. 6 ) one must shift the experiment 1 along the time axis until the start time for the experiment 1 fall along the profile for the experiment 2. This is shown in Figure 1. 30 b. By doing so, if the two concentration profile of exp 1 now follows that of exp 2, then there is no product inhibition or catalyst deactivation ( Figure 1. 30 b). Alternatively, Figure 1. 30 c and Figure 1. 30 d shows a scenario where time - shifting the concentration profile of exp 1 and 2 ( Table 1. 6 ) does not lead to an overlay of the two profiles. This difference now must arise from either product inhibition of catalyst deactivation. Conducting a third experiment (experiment 3, Table 1. 6 ) with identical conditions as exp 1 but with added product could now lead to one of two scenarios. If the profile of exp 3 continues to match profile of experiment 1 the difference 56 is due to catalyst deactivation. However, if the profile of exper iment 3 now matches that of experiment 2, then this indicated product inhibition, slowing the reaction down. Table 1. 6 Set of 4 kinetic experiments for finding order of components using method of isolation Exp [A] (M) [B] (M) Cat alyst (M) xs = B A additive 1 2 3 0.1 1 - 2 3 4 0.1 1 - 3 2 3 0.1 1 D, 1 M Figure 1. 30 Time normalized analysis of same excess experiments . (a) A set of same excess experiments to probe catalyst deactivation or product inhibition. (b) Shifting the experiment 1 (Table 1.6) along the time axis led to complete overlay indicating no catalyst a. b. e. f. d. c. 57 deactivation or product inhibition. (c) An alternative result for the same set of same excess experiment. (d) Shifting the experiment 1 along the time axis in this case did not lead to overlay indicating either catalyst deactivation or product inhibition. (e) A time shifted experiment 3 overlays with experiment 1 indicates catalyst deactivation. (f) A time shifted experiment 3 overlays with experiment 2 indicates product inhibition . The above RPKA/VTNA studies have hopefully demonstra ted how one may quickly extract kinetic information of a reaction using relatively few experiments. VTNA studies, being fundamentally similar to the previous graphical rate based RPKA studies, also have similar drawbacks, 60 however, it improves on the RPKA for experimental setups where direct measurement of rate is not possible. These RPKA and VTNA methods will be used rigorously in the successive chapters to deduce the rate law equati on and consequently, the mechanism and catalytic cycles of various (DHQD) 2 PHAL catalyzed asymmetric chlorofunctionalization reactions. 58 REFERENCES 59 REFERENCES 1. 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Y.; Reibarkh, M., Discovery of a Photoinduced Dark Catalytic Cycle Using in Situ LED - NMR Spectroscopy. J. Am. Chem. Soc. 2018, 140 (42), 13843 - 13853. 72. Bures, J., A Simple Graphical Method to Determine the Order in Cataly st. Angew. Chem. Int. Ed. 2016, 55 (6), 2028 - 2031. 73. Bures, J., Variable Time Normalization Analysis: General Graphical Elucidation of Reaction Orders from Concentration Profiles. Angew. Chem. Int. Ed. 2016, 55 (52), 16084 - 16087. 74. Bures, J., What is t he Order of a Reaction? Top. Catal. 2017, 60 (8), 631 - 633. 65 Chapter 2. Mechanism of catalytic asymmetric c hlorolactonization of alkene carboxylic acid s Electrophilic halofunctionalization reactions have undergone a resurgence sparked by recent discoveries in the field of catalytic asymmetric halocyclizations. To build mechanistic understanding of these asymmetric transformations, a toolbox of analytical methods has been deployed, addressing the roles of catalyst, electrophile (halenium do nor), and nucleophile in determining rates and stereopreferences. The test reaction, (DHQD) 2 PHAL - catalyzed chlorocyclization of 4 - aryl - 4 - pentenoic acids with 1,3 - dichloro - 5,5 - dimethylhydantoin (DCDMH), is revealed to be first order in catalyst and chlorenium ion donor and zero order in alkenoic acid substrate under synthetically relevant conditions. The simplest interpretation is that rapid substrate - catalyst binding precedes rate - limiting chlorenium attack, controlling the face selec - tivity of both chlorine attack and lactone closure. ROESY and DFT studies, aided by crystal structures of carboxylic acids bound by the catalyst, point to a plausible resting state of the catalyst - substrate complex predisposed for asymmetric chlorolactonization. As reve aled by our earlier labeling studies, these findings suggest modes of binding in the (DHQD)2PHAL - and enantioselection - determining events. Though a comprehensive modeling analysis is beyo nd the scope of reaction paths point to a one - step concerted process with the nucleophile playing a critical role in activating the olefin for concomitant electrophili c attack. 66 2.1 Introduction Electrophilic olefin halocyclizations ( Figure 2. 1 a ) are long - known workhorse organic transformations , 1 now returning to prominence as their catalytic asymmetric variants offer a powerful strategy for enlarging the chiral pool. 2 - 47 In early work on 4 - aryl - 4 - 2 PHAL, to be an efficient mediator for asymmetric chlorolactonization ( Figure 2. 1 b ) . 38, 48 Since then, reports from our own and other labs have confirmed the efficacy of cinchona alkaloid dimers in a range of asymmetric halofunctionalizations. 17 - 19, 22, 39 - 41, 49 - 52 With the growing list of examples, mechanistic insight into the catalytic activation and stereoinduction in these processes is necessary to support the design of new reactions and catalyst scaffolds. Taking (DHQD) 2 PHAL - catalyzed asymmetric chlorola ctonization of 4 - aryl - 4 - propenoic acid as a test reaction, we present here kinetic, spectroscopic, structural, and computational studies leading to a mechanistic model. 67 Figure 2. 1 Halocyclizatio n reactions . a. Generalized depiction of halocyclization reactions; b. Catalytic asymmetric chlorolactonization of 4 - aryl - 4 - pentenoic acid 2 - 1 mediated by (DHQD) 2 PHAL Our recent labeling and spectroscopic analyses 53, 54 revealed the absolute and relative face selectivities of Cl (electrophile) and O (nucleophile) addition across the double bond in 2 - 1 ( Figure 2. 2 ) as well as the rate and stereochemical effects of varying the chlorohydantoins (chlorenium ion donors) . 53, 54 The cumulative findings of this work led to the following conclusions: 1. Catalyst templated addition across the olefin 2 - 1 shows both a strong pro - R preference (>20:1) for chlorenium i on attachment at C - 6, and closure favoring the 5 R over the 5 S lactone by a factor of >10:1. The net result is predominant syn Cl, - bond in 2 - 1 - D , obviating the potential intermediacy of a 3 - membered cyclic chloronium ion ( Figure 2. 2 ). 68 Figure 2. 2 Stereochemical outcomes of chlorolactonization reaction . Summary of observed stereoselectivities with deuterated substrate analog 2 - 1 - D , highlighting the syn addition as the major product of the catalytic reaction 2. In principle, the two new bonds in the major product stereoisomer 2 - 2 - D could be formed stepwise, via a carbocation intermediate, or concertedly ( Figure 2. 2 ). 3. In either mechanistic case, the catalyst templates the ring closure. Catalyst binding, mainly via hydrogen bonding and van der Waals interactions, presumably limits the conformational choices of substrate 2 - 1 , guiding the enantioselective cyclization. 69 Ar HalA (Cl) a kcal/mol %yield %ee k Ar (s - 1 ) 4 - Me - C 6 H 4 274.3 86 88 1.6 x 10 - 6 C 6 H 5 273.8 78 88 2.1 x 10 - 6 2 - F - C 6 H 4 272.4 67 88 2.4 x 10 - 6 4 - CN - C 6 H 4 266.3 78 84 5.6 x 10 - 6 4 - NO 2 - C 6 H 4 265.2 71 86 7.4 x 10 - 6 a Calculated at the B3LYP/6 - 31G*/SM8 (CHCl 3 ) level of theory. Figure 2. 3 Chlorohydantoin effect on rate of chlorolactonization reaction . Electronic perturbation at the N 1 substituent of chlorohydantoins affecting the rate of chlorolactonization. The plot represents the linear variation of G = RTln( k Ar / k Ph ), relating experimentally determined rate constants ( k Ar ) with the theoretically calculated absolute HalA (Cl) value s. 4. As depicted in Figure 2. 3 , we have probed the effects of tuning the chlorenium source in our asymmetric chlorolactonization protocol. By preparing and studying a series of previously unknown N - aroylated N - chlorohydantoins, we have shown that N1 substituents inductively activate delivery of the N3 chlorine to the substrate during 70 the course of the chlorolactonization. The reaction rates of these elec tronically perturbed chlorinating agents vary as predicted by their HalA values (halenium affinity). 55 The transition state for chlorine transfer. Furthermore, chiral chlorohydantoins in these reactions d isplay classic match - mismatch behaviors. 54 These results indicate direct involvement of the chlorohydantoins in the rate and stereoselectivity - determining events in the asymmetric chlorocyclization. These preliminary mechanistic findings call for a full investigation of the reaction mechanism to identify the modes of interaction among the participants, and to map out the catalytic cycle of this (DHQD) 2 PHAL catalyzed asymmetric chlorolactonization. 2.2 Kinetic studies Kinetic investigation of multistep organic reaction s can provide key insights into reaction mechanisms by revealing the order of individual components in the rate - determining step (RDS). As articulated in recent years by Blackmond and co - workers, 56 - 59 Reaction Progress Kinetic Analysis (RPKA) explo its modern reaction monitoring methods and easily accessible fitting and graphing software to improve the ease and accuracy of analyses over classical approximation methods. A great advantage of RPKA is that it can probe practical reactions such as halofun ctionalization under their native conditions, unlike classical kinetic treatments that require e.g. the unbalanced concentrations used in pseudo first order studies. In this work, RPKA results place critical boundary conditions on the mechanisms proposed f or this asymmetric chlorolactonization. 71 In the original optimized reaction, 4 - phenyl - 4 - pentenoic acid 2 - 1 at 0.051 M concentration was cyclized in the presence of 0.056 M 1,3 - dichloro - 5,5 - diphenylhydantoin (DCDPH) as the chlorine source, along with 10 mol % (DHQD) 2 PHAL as the chiral catalyst. The highest enantioinduction was observed in a 1:1 chloroform:hexane mixture as solvent with benzoic acid as an additive at 0.051 M ( Figure 2. 1 b ). 38 To follow the kinetics of this reaction, NMR analysis proved optimal as the reagent and products displayed well - resolved peaks under the reaction conditions. The following modifications to the standard protocol were intro duced to simplify the mixture for kinetic studies: (i) deuterated chloroform was employed instead of 1:1 chloroform:hexane; (ii) 4 mol% of the catalyst was used to slow the reaction, enabling capture of the important early data points. This approach allowe d time for temperature equilibration in the probe measurement; (iii) 1,3 - dichloro - 5,5 - dimethylhydantoin (DCDMH) was employed since the originally used DCDPH results in the insoluble byproduct 1 - chloro - 5,5 - diphenylhydantoin, adversely affecting the spectra of the evolving reaction mixture. (iv) to reduce the complexity of the initial kinetic studies, benzoic acid was omitted, although, as described in the experimental section , and later in the manuscript, including benzoic acid was illuminating with respect to the order of the substrate. These adjustments for the kinetic studies led to only a 5% drop in ee and presumably do not qualitatively change the reaction mechanism. 72 A detailed RPKA analysis of the chlorolactonization reaction revealed the following results (see SI for detailed experimental analysis and a brief theoretical description of RPKA in the context of asymmetric halogenation): a) The asymmetric chlorolactonization is zero order in alkene carboxylic acid 2 - 1 . b) The reaction shows first order dependence with respect to the catalyst (DHQD) 2 PHAL and the chlorenium ion donor - DCDMH. c) The reaction does not suffer from any catalyst deactivation or product inhibition, as demo d) Addition of an external carboxylic acid such as benzoic acid or an inert alkenoic active site, retards the overall rate of the reac tion. The fact that the reaction is zeroth order in substrate 2 - 1 (4 - phenylpent - 4 - enoic acid) suggests that the catalyst is saturated, binding 2 - 1 rapidly to the basic quinuclidine moiety to form the strongly hydrogen - bonded acid - base adduct. As detailed further below, this resting state species is a 1:2 complex of (DHQD) 2 PHAL and 2 - 1. Quantum che mical modeling of the reaction components and their interactions finds that quinuclidine has a substantially stronger affinity for alkenoic acid 2 - 1 ( - 15.8 kcal/mol) than for DCDMH ( - 10.6 kcal/mol; see shaded box in Figure 2. 4 ). It is thus not surprising that alkene 2 - 1 outcompetes DCDMH for binding to the catalyst. NMR evidence further supports this conclusion: 1,3 - dichlorohydantoin with (DHQD) 2 PHAL shows splitting of th e CH 2 hydrogens into a diastereotopic pair, implying a complex formed with 73 the chiral catalyst. However, addition of 2 - 1 completely reverses this complexation, returning the hydantoin spectrum to that of uncomplexed reagent. 38 Figure 2. 4 Catalytic cycle for chlorolactonization reaction . Putative catalytic cycle for (DHQD) 2 PHAL catalyzed chlorolactonization of alkenoic acid 2 - 1 (in the absence of benzoic acid additive). Path A depicts a stepwise addition via a carbocationic intermediate 74 2 - A . Path B depicts a possible one step concerted addition to the a lkene 2 - 1 . NMR studies and computational modeling of the proposed intermediates and transition states are detailed in the following section. The top table insert displays calculated binding enthalpies of alkene 2 - 1 , DCDMH and quinuclidine (a truncated mode l for the catalyst). These pairwise association energies argue for the validity of the resting state. For clarity, only one alkenoic acid is shown bound to the catalyst, although experimental results indicate two molecules are bound at one time . Collisio n of suitable conformations of the resting state complex (DHQD) 2 PHAL - 2 - 1 with DCDMH results in chlorenium transfer to the alkene in a rate determining step (RDS, see SI for the detailed kinetic model that leads to the rate law and proposed catalytic cycle) . This process may follow either of two paths: (a) formation of a - chloromethyl carbenium ion intermediate 2 - A (Path A, Figure 2. 4 ), or (b) a concerted addition via transition state 2 - B , to directly access the products (Path B, Figure 2. 4 ). This latter Ad E 3 - type process is an example of nucleophile assisted alkene activation ( NAAA ). 60 In the absence of (DHQD) 2 PHAL or quinuclidine catalysts, the DCDMH and alkene 2 - 1 are essentially unreactive at - enantioselectivity by pro viding a chiral pocket, the catalyst must also activate the alkene or the DCDMH (or both). To promote the stepwise pathway leading to intermediate 2 - A , the catalyst must activate the DCDMH to form the proposed chlorocarbenium ion intermediate. Rapid cycliz ation, guided by the catalyst, would then afford the product. On the other hand, the concerted pathway via transition state 2 - B hinges on the activation of the alkene, irrespective of additional activation of the chlorenium source. In the case of stepwise cyclization, the cation closure (step three in Figure 2. 4 ) could not be rate limiting as this would predict a buildup of cation intermediate, which is not observed. Also, reversible formation of the carbocation should scramble the stereochemistry of the alkene =CHD site in deuterium labeled substrate 2 - 1 - D (see 75 Scheme 1), a process ruled out by the finding that recovered starting materials retain their stereochemical integrity. In the alternative event of a concerted addition via NAAA ( transition stat e 2 - B ), the concerted chlorenium ion attack and ring closure would directly form the chlorolactone product. In either case (Path A or B), the chlorenium ion delivery - determining step. The kinetic studi es also helped clarify the role of the benzoic acid additive, which marginally increases the enantioselectivity. We surmise that its presence aids in maintaining the rigidity of the C 2 - symmetric (DHQD) 2 PHAL catalyst (see next section for validation of this hypothesis by NMR and X - ray studies), and perhaps also aids in shuttling the protons required to neutralize the byproduct hydantoin anions, especially toward the end of the reaction when the concentration of 2 - 1 is low. Consistent with this idea, benzoic acid addition at an equimolar ratio to substrate lowers the rate of chlorolactonization (see SI for experimental details); presumably benzoic acid competes with 4 - phenylpent - 4 - enoic acid 2 - 1 ined support from RPKA studies with benzoic acid added, which raised the measured order of the alkene from zero to 0.5 in the rate equation. This change is expected due to the fact that alkene 2 - 1 has to compete with the benzoic acid for binding in the cat alyst, making its concentration relevant with respect to the rate. The following is the observed rate law in presence of benzoic acid: To further explore the proposed catalytic cycle, we resorted to c ompetition studies ( Figure 2. 5 ). Prior analysis of the catalytic asymmetric chlorolactonization methodology revealed that 4 - (4 - (trifluoromethyl)phenyl)pent - 4 - enoic acid 2 - 3 is one tenth as reactive 76 as 2 - 1 . 38 Nonetheless, the trifluoromethyl substituent should not interfere with binding, as other sterically comparable substrates behaved well under the same reaction conditions. If substrate 2 - 3 binds to the catalyst to form an unreactive analogue of the resting state , it should serve as a competitive inhibitor, decreasing the concentration of the reactive complex with substrate 2 - 1 . Indeed, as shown in Figure 2. 5 , the chlorolactonization of 2 - 1 was slowed dramatically (decreased by 58%) upon addition of one equivalent of 2 - 3 to a 1:1 mixture of 2 - 1 and DCDMH with 1.5 mol% catalyst. A similar competition study was performed between 4 - phenylpent - 4 - enoic acid 2 - 1 and 4 - (3 - nitrophenyl)pent - 4 - enoic acid 2 - 4 , known to be a slow substrate. With a 1:1:1 mixture of substrates 2 - 1 , 2 - 4 and DCDMH under 1.5 mol% catalyst loading, the rate of the chlorolactonization of 2 - 1 was decreased by 71% ( Figure 2. 5 ). At a 1:1 ratio of inhibitor 2 - 4 to substrate 2 - 1 , a 50% decrease in rate would suggest similar binding affinity of 2 - 4 and 2 - 1 with (DHQD) 2 PHAL; the larger observed inhibition suggests a stronger complexation with 2 - 4 . Perhaps this hints at the presence of weak aromatic stacking interaction contributing to the binding, which is expected to be stronger for 2 - 4 . Further evidence supporting the idea that chlorine delivery from the hydantoin to 2 - 1 is rate - determining may be found in the effects of structural variations in the hydantoin chlorenium donors. As noted earlier ( Figure 2. 3 ), the N 3 chlorine is activated when the N 1 substituent of DCDMH is an electron withdrawing group (EWG). As quantified by the HalA values, stronger EWGs on N 1 accelerate the reaction, consistent with chlorine delivery to 2 - 1 in the R DS. A related result is that chiral chlorohydantoins show match/mismatch effects in reaction, pointing to direct involvement of the chlorenium delivery reagent in the chlorocyclizations. 54 77 Figure 2. 5 Competition studies on chlorolactonization reaction . Rate of formation of product 2 - 2 in presence of alkenoic acids 2 - 3 and 2 - 4 . The reduced rates imply 2 - 3 and 2 - 4 are competitive inhibitors of the catalyst, presumably binding to the active site and retarding the binding of substrate 2 - 1 . To probe the involvement of the carboxylic acid moiety in the rate determining step, chlorocyclization of the deuterated 4 - phenylpent - 4 - enoic acid 2 - 1 - OD (RCO 2 D) was studied and compared to th e same reaction with unlabeled substrate 2 - 1 . An inverse isotope effect ( k H / k D = 0.82, see experimental sections for more detail ) was measured, suggesting that the carboxylate plays a direct role in the reaction. Considering Path A , the change from H to D should not lead to the observed KIE, as the electrophilic transfer of the chlorenium ion is ostensibly insensitive to the nature of the hydrogen - bonded 78 nucleophile. On the other hand, the concerted Path B via transition state 2 - B would quence of the increased acidity of 2 - 1 - OD vs 2 - 1 - OH . Overall, reaction progress kinetic analysis (RPKA), competition, reagent, and isotope studies find that (a) rate is first order in catalyst and in DCDMH, but zero order in substrate; (b) chlorenium donor ability and asymmetry characteristics affect reaction implication is that the rate - determining step involves chlorenium transfer and the protonation. 2.3 Resting state of the catalyst With the elementary steps of the catalytic cycle deduced from the kinetic findings, we undertook NMR and computational studies to gain structural insight into intermediates and transition states along the reac tion paths. Our first target in this process was the resting state (catalyst - substrate complex) of the catalytic cycle. A comprehensive conformational search of the free catalyst using molecular mechanics and density functional simulations revealed three l ow energy conformational orientations for the two sidechains on the phthalazine (see SI for computational details). These showed H a CCH b dihedral angles of roughly 80° and 170°, consistent with prior NMR and theoretical work. 61 - 63 Figure 2. 6 a shows a DFT - B3LYP/6 - 31G* (gas) minimized structure of (DHQD) 2 PHAL with a H a CCH b dihedral of 169.4°. This is consistent with the NMR of free (DHQD) 2 PHAL, where the H b resonance exhibits a ddd with three equivalent 9 Hz coupling constants. Dihedral angles between H b and the methylene protons in the 79 quinuclidine ring lead to the anticipated 9 Hz coupling. Thus, the third 9 Hz coupling of H b is ascribed to its interaction with H a , resulting from the anti orientation of the two protons. Figure 2. 6 Conformational changes observed upon binding of 2 - 1 to (DHQD) 2 PHAL . (a) represents the minimized structure of free (DHQD) 2 PHAL with H a CCH b dihedral angle ~170°, supported by the 9 Hz coupling of H b with H a . (b) 1 H NMR titration induces a change in the H b / H a coupling from 9 to <3 Hz with the addition of the alkenoic acid 2 - 1 . (c) The model depicts a minimized structure of the catalyst bound to two alkenoic acid 2 - 1 , where the two H a CCH b dihedral angle are 73.8° and 80.7°. The dihedral angles of the bound catalyst fit well with the observed smaller coupling constant for H a /H b . Computed binding free energies for complexation of the first and second alkenoic acids 2 - 1 , and for DCDMH with (DHQD) 2 PHAL are shown in the shaded box. b. H a H b Bound free minimized structure of (DHQD) 2 PHAL bound to 2 - 1 H a H b c. a. 80 Titration of (DHQD) 2 PHAL with substrate 2 - 1 a - H b coupling constant from 9 to <3 Hz, suggesting a conformation with an averaged H a CCH b dihedral angle close to 90° ( Figure 2. 6 b) . This geometry, as depicted in Figure 2. 6 c , also orients the quinuclidine N toward the chiral cleft of the catalyst. Furthermore, the 1:1 catalyst complex exhibits broad peaks which sharpen on addition of another equivalent of alkenoic acid suggesting that in the resting state , the catalyst binds two alkenes. Finally, conformational searching using the MMF F94 force field, followed up by B3LYP - D3/6 - 31G*/postSMD(CHCl 3 ) structural optimization of the (DHQD) 2 PHAL bound with two alkenoic acids found calculated binding free energies for the first and second molecules of 2 - 1 in (DHQD) 2 PHAL of - 14.6 and - 13.3 kcal/ mol, respectively. Among the lowest energy complex minima, the structure shown at right in Figure 2. 6 is used here as the resting state catalyst model; this structure h as H a CCH b dihedral angles of 73.8° and 80.7°, consistent with the <3 Hz coupling of H a with H b in the NMR of the fully saturated complex. Given the desymmetrization observed in the NMR of dichlorohydantoin interacting with the catalyst, one might expect t hat DCDMH binding would compete for the catalyst active site. However, for both the empty and singly occupied forms of the catalyst, the - 14.6 and - 13.3 kcal/mol binding energies of an additional acid substantially outcompete the - 5.7 kcal/mol binding free energy of a molecule of DCDMH. Interacting with the doubly occupied resting state , the association of DCDMH is even weaker, as shown by the free energy values in Figure 2. 6 c . 81 Table 2. 1 1 H NMR analysis of alkenoic acid 2 - 5 and its complexes with (DHQD) 2 PHAL and quinuclidine at - 40 ºC in CDCl 3 . Further structural data on the resting state complex were obtained from NMR studies of a 2:1 mixture of 4 - (4 - fluorophenyl)pent - 4 - enoic acid 2 - 5 and (DHQD) 2 PHAL in CDCl 3 carried out at - 40 °C. Carboxylic acid 2 - 5 was used as a substitute for 2 - 1 since its aromatic protons (ortho to fluorine) do not ov erlap with the aromatic protons of the catalyst. Table 2. 1 compares the 1 H NMR chemical shifts of the substrate with and without (DHQD) 2 PHAL present. It is notable th at the vinylic protons and also two methylene groups of the alkenoic acid 2 - 5 are shielded by ~0.5 ppm upon complexation with catalyst. We interpret this shielding as a combination of two effects: (a) deprotonation of the carb oxylic acid and (b) binding in the cleft of the catalyst. To distinguish these contributions, 1 H NMR spectra of 2 - 5 were taken with quinuclidine in CDCl 3 . There, it was the methylene group adjacent to the carboxylate moiety that showed the highest upfield Thus, acid - base complex formation does not account fully for the large shielding seen with the catalyst bound substrate. 82 To further probe the interactions between the s ubstrate and the catalyst, ROESY experiments using the methods described by Bodenhausen et al. 64 - 66 found correlations between protons of 2 - 5 and (DHQD) 2 PHAL offering further insights into bindin g. As depicted in Figure 2. 7 , ROESY correlations, leading to average distances are grouped into intramolecular and intermolecular correlations. The distances derived for the intramolecular interactions fit well with the minimized structure of the catalyst, illustrated in Figure 2. 6 . Probing intermolecular interactions, the OMe sidechains of the quinoline group (H n r and H t ) and phenyl protons (H k ). T his also matches well with the calculated resting state model, depicted in Figure 2. 6 c , where the calculated distances fall well within the ROESY measured values (H n /H t n /H r n /H k ROESY verified model for the resting state shown in Figure 2. 6 c illustrat es carboxylate binding to the protonated quinuclidine moiety, positioning the vinylic protons in the shielding regions of the quinoline rings, which leads to their observed upfield shifts. Figure 2. 7 Structural investigation of resting complex using ROESY NMR . Intramolecular and intermolecular ROESY correlations of 2 - 5 bound to (DHQD) 2 PHAL. The intramolecular correlations place the ethyl group near the phthalazine ring, whi le the methoxy shows close intermolecular relations with the substrate methylene units. These interactions are present in the lowest energy conformation of (DHQD)2PHAL . 83 As a C 2 symmetric cinchona alkaloid, (DHQD) 2 PHAL can potentially bind to two substrates at the same time (as depicted in Figure 2. 6 ). Consistent with this idea, when (DHQD) 2 PHAL is treated with only one equivalent of the alkenoic acid 2 - 1 , the 1 H NMR peak broadening at room temperature clearly suggests loss of structural symmetry due to partial occupancy of the substrate. The spectra sharpen up in the presence of two equivalents of 2 - 1 . These results support a picture in which (DHQD) 2 PHAL requires two subst rates (or other carboxylic acids) to maintain its conformational rigidity in the C 2 - symmetric anti - open form. On the other hand, addition of four equivalents of alkenoic acid to (DHQD) 2 PHAL resulted in an averaged spectrum for the substrates, indicating fast equilibrium (on the NMR time scale) between bound and free forms of the alkenoic acid, (see SI for NMRs of (DHQD) 2 PHAL with benzoic acid). To further e xplore the stoichiometry of complexation, (DHQD) 2 PHAL was treated with two equivalents of a 1:1 mixture of alkenoic acids 2 - 1 and 2 - 4 . This NMR experiment showed shielding behavior for both 2 - 1 and 2 - 4 similar to that seen in 2:1 substrate:catalyst mixture s with the individual substrates. If catalyst had only a single binding site, such mixtures should show more shielding of resonances of the more tightly bound alkenoic acid. Since the same degree of chemical shift is observed in the above case with the spe ctra being well - resolved, it appears that the catalyst binds both substrates in a 1:1:1 complex without competition. This 2:1 binding model is in accord with the reactivity results involving 2 - 1 , 2 - 3 , and 2 - 4 previously shown in Figure 2. 5 , and with the calculated binding energetics in Figure 2. 6 . As discussed further below, the 2:1 c omplex may undergo attack by the chlorenium ion donor on either of the two essentially 84 independently bound substrate molecules; it is thus the substrate for attack by the chlorenium ion donor. An alternative scenario might involve dissociation to an activ e 1:1 complex, with the catalytically incompetent 2:1 complex serving simply as an off - cycle reservoir. In this scenario, however, the initial rate would not be the same for two reactions with different starting concentrations, such as the different excess experiments carried out in this study. We would anticipate the reaction with a higher concentration of the starting alkene to have a smaller initial rate. This behavior is not observed (see Figure 2. 11 and the description of kinetic models in the experimental details ). Although we were unable to obtain crystals of the resting state itself, we were able to co - crystallize the catalyst (DHQD) 2 PHAL with benzoic acid. This crystal structure displayed essentially the conformation deduced from the NMR studies (see SI for crystal structure), with the two H a CCH b dihedral angle being 73.7° an d 77.6°. 2.4 Structural insight into the transition state 2 - B To understand the asymmetric induction achieved in the (DHQD) 2 PHAL - catalyzed chlorocyclization of 2 - 1 with DCDMH, a model of the interaction of the chlorenium ion donor with the resting state i s needed, which must entail both activation and asymmetric specificity. The combination of substrate 2 - 1 with DCDMH alone is essentially unreactive (at - 30 °C); a basic catalyst, such as quinuclidine or (DHQD) 2 PHAL is needed to promote the reaction. Also, as noted earlier, both rate and stereoselectivity are affected by electronic and stereochemical variations in the dichlorohydantoins used. Thus, the ring - forming reaction involves both the state of carboxylate deprotonation, and the identity of the chlorin e donor. 85 One path that might be envisioned is indirect chlorine transfer to substrate via a chlorinated (DHQD) 2 PHAL. This can be ruled out as it predicts that the enantioselectivity should be independent of the chlorenium ion source (hydantoin) as the N - c hloroquinuclidinium form of (DHQD) 2 PHAL would now serve as the active in situ generated halogenating reagent. Also, as assessed in terms of HalA (Cl) values, chlorenium ion transfer to the quinuclidine nitrogen in the catalyst would be strongly endothermi c ( HalA (Cl) 24.0 kcal/mol in CHCl 3 ), even when the stabilizing effects of tight ion pairing and solvation are included in the calculation. 2.5 Evidence for concerted addition ( NAAA ) pathway Without assistance, chlorenium transfer from DCDMH to the alkene would be unfavorable ( HalA (Cl) = 22.3 kcal/mol in CHCl 3 ) (see HalA values in Figure 2. 8 a ). Despite its low HalA , alkene 2 - 1 does slowly react with DCDMH. Howeve r, the rate is accelerated greatly in the presence of a basic catalyst such as quinuclidine. This strongly suggests that the catalyzed halocyclization of 2 - 1 proceeds via a nucleophilic activated alkene addition ( NAAA ) mechanism. Previous reports on chloro lactonization (summarized in Figure 2. 8 ) have noted that a low energy barrier pathway via concerted addition can be triggered when the substrate adopts conformations wi th the anionic carboxylate oxygen atom near the alkene moiety. This close proximity of the nucleophile sharply enhances the alkene halenium affinity, enabling capture of the chlorenium ion from its donor, as the nucleophile approach now stabilizes for the developing charge in the alkene sp 2 carbon. This view is verified further by the contrasting isotope effects seen in the uncatalyzed reactions of DCDMH with alkenes 2 - 1 and 2 - 6 ( Figure 2. 8 a ). Here, in 2 - 1 , replacement of the protons vicinal to the putative carbenium site with deuterium 86 showed no observable kinetic isotopic effect ( k H / k D = 1.0). 60 As depicted in Figure 2. 8 , 2 - TS - I illustrates the concerted transition state with bond distances that indicate a one - step, asynchronous addition of the chlorenium and the carboxylate to the olefin . In the case of 2 - 6 , the 4 - methoxy analog of 2 - 1 enough that the nucleophile - assisted pathway is unimportant; uncatalyzed reaction of 2 - 6 with DCDMH is much faster as compared to 2 - 1 . However, as expect ed for a stepwise pathway via a carbocationic intermediate, reaction of alkene 2 - 6 displayed a significant secondary kinetic isotopic effect (k H /k D = 1.2). In contrast to the concerted addition calculated for alkene 2 - 1 , 2 - TS - II depicts the attack to form the carbocation in the stepwise addition of the chlorenium ion to substrate 2 - 6 . The HalA (Cl) values of 2 - 1 and 2 - 6 (158.8 and 169.4 kcal/mol) differ by >10 kcal/mol, supporting the formation of a carbocation intermediate. The HalA (Cl) value of 2 - 6 close ly matches that of the hydrogen - bonded MCDMH anion (~173 kcal/mol), consistent with unassisted chlorenium capture by 2 - 6 to form the carbocation, an action too endothermic for olefin 2 - 1 without further activation. 87 Figure 2. 8 Prior work on concerted vs stepwise addition . (a) Evidence for concerted addition from HalA (Cl) calculations and KIE experiments. (b) Computationally modeling an uncatalyzed syn - co ncerted addition leading to chlorofunctionalization. (c) Computationally modeling an uncatalyzed syn - stepwise addition leading to chlorofunctionalization. The m - NO 2 analogue of 2 - 1 , alkene 2 - 3 , is intrinsically deactivated and unreactive towards DCDMH, hin ting that NAAA can only offer so much activation if there are strong 88 inherent factors retarding the intrinsic nucleophilicity of the alkene. Though it appears quite general for otherwise nonpolarized alkenes, the concerted NAAA mechanism evidently strikes a fine balance. With the experimental evidence firmly indicating concerted addition to the alkene 2 - 1 , transition states with quinuclidine as well as (DHQD) 2 PHAL as a catalyst were computationally modeled and analyzed in the following section. 2.6 Quinuclidine - catalyzed TS for syn and anti chlorocyclization For the quinuclidine catalyzed reaction, transition structures for the lowest energy syn and anti concerted addition pathways were identified and optimized. ( Figure 2. 9 ). In search of optimized structures, conformational analyses using the MMFF94 force field provided poses, which were further refined via B3LYP - D3/6 - 31G*/postSMD (CHCl 3 ) calculations. Though the developing negative charge on the hydantoin ring in the syn TS benefits from proximity to the partially positive protonated quinuclidine, that advantage is outweighed by the steric freedom of approach from the far side ( anti approach). In the CHCl 3 anti - addition pathway is found to be 0.7 kcal/mol lower in energy than its syn partner, a result consistent with experimental findings. Both structures show similar parameters, with the deve loping C - Cl and C - O bond lengths slightly longer in the anti (2.2, 2.6 Å) than in the syn case (2.1, 2.4 Å). All attempts to initiate chlorenium atom transfer from DCDMH to 2 - 1 were monotonically endothermic in conformations that did not place the nucleoph ilic carboxylate moiety nearby ( Figure 2. 9 ). This implies that a stable - chloromethyl carbenium ion intermediate is not a minimum along the reaction coordinate as would be expected for the stepwise mechanism. 89 Figure 2. 9 Transition states for quinuclidine catalyzed reaction . Transition states leading to syn and anti - addition for quinuclidine catalyzed chlorolactonization. Calculated using density functionals B3LYP - D3/6 - 31G* SM8 (CHCl 3 ) The experimentally observed syn : anti ratio for quinuclidine catalyzed chlorocyclization of 2 - 1 - D is 1:5. 53 This agrees with the discussion above, and also with the calculated difference in activation energies computed for the s yn and anti TS structures shown in Figure 2. 9 ( G = 0.7 kcal/mol). 90 2.7 Modeling of the syn - addition TS for (DHQD) 2 PHAL catalyzed reactions Having identified the lowest energy TS structures for quinuclidine - catalyzed chlorocyclization of 2 - 1 , we proceeded to model the syn structure into the optimized geometry of (DHQD) 2 PHAL, reoptimizing at the B3LYP - D3/6 - 31G* level of theory. The reader is re minded that the asymmetric catalyzed chlorolactonization of 2 - 1 - D favors the syn adduct 2 - 2 - D ( syn : anti ratio ~9:1). 53 The energy of activation (10.5 kcal/mol) and partial bond lengths (2.4 Å for C - O and 2.1 Å for C - Cl) for the lowest energy (DHQD) 2 PHAL catalyzed transition state were comparable to the quinuclid ine catalyzed addition ( Figure 2. 10 a). The acute H a CCH b dihedral angle of 61.7° in the TS effectively oriented the quinuclidine towards the center of the catalyst allowing for the alkenoic acid - - stacking with the phthalazine linker. This dihedral angle al so fits well with the NMR studies depicted in Figure 2. 6 for (DHQD) 2 PHAL bound to 2 - 1 . As illustrated in Figure 2. 10 a , the Re face of the alkene is now readily accessible by both the chlorenium ion donor and the quinuclidine - activated carboxylate nucleophile, the simultaneous addition of which leads to the experimentally observed major syn enantiomer. Computational searches for NAAA - type TS structures leading to the minor products were much less successful; those products may well arise via more complex stepwise paths, and further studies in this direction are deferred to a future detai led computational analysis. Prior studies have demonstrated that chlorolactonization using chiral chlorohydantoins exhibits matched - mismatched behavior when used with (DHQD) 2 PHAL ( Figure 2. 10 b, Table in direct involvement in the rate determining step as the chlorenium source. 91 Figure 2. 10 Modeling of (DHQD) 2 PHAL catalyzed Transition states . (a) Transition states for (DHQD) 2 PHAL catalyzed chloro - lactonization using DCDMH and the chiral chlorenium reagent . (b) The non - degeneracy of the two transition states confo rms with the previously reported matched - mismatched selectivity. Structures were calculated using the dispersion - corrected density functional method B3LYP - D3, with all optimizations carried out in SMD simulated CHCl 3 . This scheme is denoted B3LYP - D3/6 - 31G* /SMD (CHCl 3 ) . 92 To connect our computational results to these experimental findings, we reoptimized the (DHQD) 2 PHAL catalyzed transition state with the two enantiomers of the chiral hydantoin 2 - 8 and alkene 2 - 1 . Consistent with the experimental findings, the TS calculated with the ( R ) - 8 (mismatch) shows steric crowding of the isopropyl group with the quinuclidine moiety of (DHQD) 2 PHAL, presumably magnified as the hydantoin is approaching the resting state prior to reaching the TS. The ( S ) - congener (match), however, has a more relaxed approach, having the isopropyl group pointed in the opposite direction. This is also represented in the activation energies for each transition state, with the match TS having a slightly lower barrier ( G = 0.5 kcal/m ol). Owing to less steric conflict with the catalyst, the approach of ( S ) - 8 to the olefin is also more linear, avoiding the DCDMH distortion seen in the TS from the ( R ) isomer. 2.8 Summary Reaction progress kinetic analysis (RPKA) and competition studies r evealed the delivery of chlorenium ion to the olefin as a key feature of the rate determining step (RDS). These kinetic studies also define the order of each reagent and consequently the rate equation of this catalytic reaction both in the presence and abs ence of the benzoic acid: rate = k [(DHQD) 2 PHAL][DCDMH] . Moreover, these studies were conducted at concentrations relevant to the optimized standard protocol, obviating the need for extrapolations outside the range studied. The observed inverse isotope effe ct (acid catalysis) suggests that the alkene - COOD is more activated for DCDMH attack in transition state 2 - B than alkene - COOH. Between the kinetic results, ROESY NMR studies, X - ray structures, and DFT analysis, we propose a resting state model in which two molecules of substrate 2 - 1 occupy the binding pockets of (DHQD) 2 PHAL. In the 93 proposed catalytic cycle ( Figure 2. 4 ), the alkene face that is ultimately chlorinated is ex posed to solution, allowing collision with DCDMH. Ring closure is achieved when the backbone chain achieves a conformation placing C - 4 near the partially negatively charged carboxylate oxygen, activating the olefin for the concerted NAAA closure. The syn preference reflects the electrostatic attraction between the developing negative charge on the hydantoin and the positively charged quinuclidinium ion. These mechanistic investigations, coupled with our previously reported labeling studie s, suggest that the rate - determining and enantioselectivity - determining events occur together in the predominant pathway . Taken together, the experimental results were combined with an initial DFT analysis that provided structural insight into the resting state model and the corresponding transition state 2 - B . Overall, using the asymmetric chlorolactonization of 2 - 1 as a proof of principle, a toolbox of analytical techniques has been successfully optimized and applied to probe the nuances underlying the (DH QD) 2 PHAL catalyzed halofunctionalization of olefins. These mechanistic studies have established an optimal range of alkene HalA values over which concerted reactions dominate, firmly defining both relative and absolute stereochemical relationships. This co nceptual framework and set of tools for reaction assessment will serve as a guide, in a broad sense, to the emerging field of catalytic stereoselective halofunctionalizations of olefins. More specifically, the localized interactions identified in exploring these chlorolactonization reaction paths point the way to key features needed in the design of simplified organocatalysts. 94 2.9 Experimental detail 2.9.1 General remarks Unless otherwise mentioned, solvents were purified as follows. CHCl3 (amylene stabiliz ed) was purchased from Sigma Aldrich and incubated over 4Å MS for 48 h prior to use. Toluene and CH 2 Cl 2 were dried over CaH 2 whereas THF and Et 2 O were dried over sodium (dryness was monitored by colorization of benzophenone ketyl radical); they were freshl y distilled prior to use. NMR spectra were obtained using either a 500 MHz or 600 MHz Varian NMR spectrometer, or an Avance II Bruker 900 MHz instrument, and referenced using the residual 1H peak from the deuterated solvent. Infrared spectra were measured on a Nicolet IR/42 spectrometer FT - IR (thin film, NaCl cells). Waters 2795 (Alliance HT) instrument was used for HRMS (ESI) analysis with polyethylene glycol (PEG - 400 - 600) as a reference. Column chromatography was performed using Silicycle 60Å, 35 - 75 µm s ilica gel. Pre - coated 0.25 mm thick silica gel 60 F254 plates were used for analytical TLC and visualized using UV light, iodine, potassium permanganate stain, p - anisaldehyde stain or phosphomolybdic acid in EtOH stain. Halofunctionalization reactions wer e performed in the absence of light. 1,3 - Dichloro - 5,5 - dimethylhydantoin (DCDMH) and 3 - chloro - 5,5 - dimethylhydantoin (MCDMH) were re - crystallized prior to use. Alkenoic acids 2 - 1 , 2 - 3 , 2 - 4 , 2 - 5 , and 2 - 6 were prepared as described previously. 38, 67 All other commercially available reagents and solvents were used as received unless otherwise mentioned. 95 2.9.2 Kinetic studies 2.9.2.i. Sample and NMR instrument preparation for kinetic studies The probe of the NMR instrument was cooled to - 40 °C and allowed to equilibrate for 60 minutes. A stock solution of catalyst and internal standard (toluene, used when benzoic acid was not present) was prepared by dissolving (DHQD) 2 PHAL (16 mg, 0.0205 mmol) and benzoic acid (6 2 mg, 0.51 mmol) or toluene (47 mg, 0.51 mmol) in CDCl3 (2 mL). In two additional vials, stock solutions of DCDMH (67.1 mg, 0.34 mmol) and 4 - phenyl - 4 - pentenoic acid (60.4 mg, 0.34 mmol) 2 - 1 were prepared in CDCl 3 (1.5 mL). Kinetic experiments were then per formed as follows: To each NMR tube, 0.2 mL of the (DHQD) 2 PHAL + internal reference (benzoic acid or toluene) solution was added (4 mol% catalyst + 1 equiv. internal standard). The NMR tube solution was then frozen at - 78 °C, and the desired amounts of the 4 - phenyl - 4 - pentenoic acid 2 - 1 and the DCDMH stock solutions were added to the frozen NMR tube, allowing each to freeze in turn. While still frozen, the solution in the NMR tube was made up with CDCl 3 to 1 mL total volume. This frozen sample was inserted i nto the NMR instrument and after 2 min (when the frozen sample had melted at - 40 °C), the sample was ejected, very briefly shaken to homogenize the solution, and quickly reinserted into the NMR instrument. After locking and shimming the instrument and sett ing up the array experiment (six min after shaking the NMR tube), collection of kinetic data ensued either every five or every ten minutes over 10 h. 2.9.2.ii. Reaction Progress Kinetic Analysis (RPKA) data collection and analysis 04 M (Table 1) were chosen for the different conditions in both experiments were chosen to be close to the optimized conditions, which highlight the advantage of RPKA over c lassical kinetic methods.3 - 5 In the first set of 96 experiments, benzoic acid (1 equiv.) not only assumes the role of the additive, it was also used as the internal standard to normalize the integral values of the product and starting materials during the cou rse of the reaction. In the second set of experiments, toluene (1 equiv.) was used instead of benzoic acid as an internal standard. Based on the constant concentration of internal standard (benzoic acid or toluene), concentrations of the product 2, DCDMH and 4 - phenyl - 4 - pentenoic acid 2 - 1 at each data point were calculated. The AB quartet peak at 3.8 ppm (chloromethylene) was used to calculate the concentration of the product, while the resonances for the vinylic protons (s, 5.3 and 5.1 ppm) and methyl grou ps (s, 1.5 ppm) peaks were used to determine concentrations of 4 - phenylpent - 4 - enoic acid 2 - 1 and DCDMH, respectively. After fitting a sixth order polynomial function to the plot of product concentration vs. time, the rate at each data point was calculated via the first derivative of the fitted polynomial function. 2.9.2.iii. Kinetic experiments to determine rate equation Two sets of experiments (Set 1 and Set 2) were designed for RPKA studies (shown in Table 2. 2 and Table 2. 3 ). The first set of experiments were conducted in the presence of benzoic acid as an additive (as well as an internal standard), similar to reported optimized condition. 56 The second set of experiments were conducted in the absence of benzoic acid to measure the empirical rate law equation. 97 2.9.2.iv. Kinetic studies in presence of benzoic acid The following experiments shown in Table 2. 2 were conducted to determine the order of the alkene, catalyst and DCDMH in presence of benzoic acid, and also to determine the effect of any catalyst deactivation of produc t inhibition. Table 2. 2 RPKA studies in presence of benzoic acid as an additive Exp 2 - 1 (M) DCDMH (M) Benzoic acid (M) (DHQD) 2 PHAL (mol%) Excess (M) A 0.071 0.051 0.051 4 0.02 B 0.091 0.051 0.051 4 0.04 C 0.091 0.051 0.051 4 0.02 D 0.091 0.051 0.051 6 0.02 Figure 2. 11 Different excess experiments to find order of alkene and DCDMH . RPKA analysis of the order of alkene 2 - 1 and DCDMH from a set of different excess experiment s . The plots corresponding to the two experiments (A and B) overlay when alken e 2 - 1 and DCDMH are raised to the respective power of 0.5 and 1 98 Figure 2. 12 Same excess exper iment . Overlay of a set of same excess experiments (A and C) indicate that there is neither catalyst deactivation nor product inhibition contributing to the reaction kinetics Figure 2. 13 Finding order of catalyst . Overlay o f plots corresponding to a set of same excess experiments ( C and D), ran at different catalyst concentration when catalyst is raised to the power of 1.2, indicating that the catalyst is approximately first order 99 2.9.2.v. Kinetic studies in absence of benzoic acid The following experiments shown in Table 2. 3 were conducted to determine the order of the alkene, catalyst and DCDMH in presence of benzoic acid, and a lso to determine the effect of any catalyst deactivation of product inhibition. Table 2. 3 RPKA studies in absence of benzoic acid Exp 2 - 1 (M) DCDMH (M) Benzoic acid (M) (DHQD) 2 PHAL (mol%) Excess (M) E 0.071 0.051 0.051 4 0.02 F 0.091 0.051 0.051 4 0.04 G 0.091 0.051 0.051 4 0.02 Figure 2. 14 Different excess experiments to find order of alkene and DCDMH . RPKA analysis of the order of alkene 2 - 1 and DCDMH from a set of different excess experiment s . The plots corresponding to the two experiments ( E and F ) overlay when alken e 2 - 1 and DCDMH are raised to the respective power of 0 and 1 100 Figure 2. 15 Same excess experime nt . Overlay of a set of same excess experiments ( F and G ) indicate that there is neither catalyst deactivation nor product inhibition contributing to the reaction kinetics 2.9.2.vi. Comparison of rates of the reaction with and without benzoic acid The following plo ts shows rate effect of benzoic acid. Figure 2. 16 Rate comparison with and without benzoic acid . Overlay The rate profiles demonstrate the negative impact of benzoic acid on the rate of the chlorolactonization. Exp B (Table 2.2) is in presence of benzoic acid and is significantly slower than Exp F (Table 2.3) 101 2.9.2.vii. Discussion on the order of components in the rate law equation The zeroth order of alkene 2 - 1 in absence of the benzoic acid indicat es that the catalyst (DHQD) 2 PHAL is fully saturated with alkene 2 - 1 . This saturated acid - base complex reacts with the DCDMH leading to the rate determining step. The molecularity of DCDMH in the RDS, equally one from the rate law, indicates the collision o f one chlorinating agent with the saturated catalyst, leading to the product. In presence of benzoic acid, which in itself can form an acid - base complex with the catalyst, the alkene now must compete against the benzoic acid for catalyst binding. This comp eti tion will favor alkene binding at a higher alkene concentration (assuming similar binding affinities for both species) . Therefore, a higher concentration of alkene now leads to a greater concentration of the resting state complex, which ultimately resul ts in the overall rate equation exhibiting a positive dependence on the alkene 2 - 1 concentration (see next section for a detailed kinetic model). 102 2.9.3 Kinetic models 2.9.3.i. Model 1: In absence of benzoic acid Figure 2. 17 Model 1: In absence of benzoic acid. Reaction pathways in absence of benzoic acid. Acid - base equilibri a between catalyst and alkenoic acid 2 - 1 : - or - eq ( 2. 1) - or - - or - eq (2.2) Total concentration of the catalyst: eq ( 2. 3) Using eq ( 1 ) eq (2) and eq ( 3 ) - or - eq ( 2.4 ) Rate of product formation based on model above : eq ( 2.5 ) Using eq ( 2.2 ) and (2.4) to replace [ I 2 ] and [ C ] - or - eq ( 2.6 ) The above eq ( 2.6 ) represent s the derived rate law equation for the proposed catalytic cycle . Since we predict the resting state of the catalyst is I 2 based on corroborating data presented in the text , we may assume large equilibrium constant s for K 1 and K 2 driv e this 103 bindin g process. If K 1 and K 2 >> 1, K 1 K 2 [ 2 - 1 ] 2 will be the largest component in the denominator, and thus, the above rate law equation can be reduced to the following simplified form, which is in accord with the empirical rate law: since eq ( 2.7 ) 104 2.9.3.ii. Model 2: In presence of benzoic acid Figure 2. 18 Model 2: In presence of benzoic acid. Reaction pathways in presence of benzoic acid. Acid - base equilibri a between catalyst and alkenoic acid 2 - 1 : - or - eq ( 2.8 ) - or - - or - eq (2.9) Acid - base equilibri a between catalyst and benzoic acid : - or - eq ( 2.10 ) - or - - or - eq (2.11) Acid - base equilibri a between catalyst , benzoic acid and alkene 2 - 1 : - or - - or - eq ( 2.12 ) Total concentration of the catalyst: eq ( 2. 13) NMR and computational studies discussed in the text demonstrate that the catalyst has a strong affinity to bind to two carboxylic acids. This implies that the total catalyst 105 concentration [ C ] o approximately equals the summation of its various doubly acid bound states (resting states). Therefore, [ C ], I 1 and I 3 will be negligible and can be ignored. This enables the simplification of eq (2.13) to the following eq (2.14): Total concentration of the catalyst: eq ( 2. 14) Applying eq (2.9), eq (2.11) and eq (2.12) on eq (2.14), we have eq ( 2. 1 5 ) On rearranging that above eq (2.15) we have eq ( 2. 1 6 ) Rate of the reaction (or product formation) is a summation of the rate of two reactive resting states I 2 and I 5 reacting with DCDMH and leading to the product : eq ( 2. 1 7 ) Using eq ( 2.9 ), eq ( 2. 1 2 ) and eq ( 2. 1 7 ) we have, eq ( 2. 1 8 ) Using eq ( 2.16 ) and eq ( 2. 1 8 ) eq ( 2. 1 9 ) The above eq ( 2.19 ) represent s the derived rate law equation for chlorolactonization in presence of benzoic acid based on the proposed catalytic cycle. If K 1 K 2 , K 3 K 4 , and K 3 K 5 are comparable in magnitude, a reasonable assumption given that all of them represent a 1:2 binding of (DHQ D) 2 PHAL to carboxylic acid s (that assumes the binding affinity for substrate and benzoic acid is similar) , the denominator is no longer simplified as described for the case above (Model 1) . The presence of [ 2 - 1 ] in the denominator explains the observed fra ctional order of the alkenoic acid 2 - 1 (half order), and the presence of [ B ] 106 in the denominator explains the rate inhibitory effect of benzoic acid. Furthermore, this model also complies with the first order rate observed for DCDMH and the catalyst. 107 2.9.3.iii. Mode l 3: Alternative scenario of 1:1 alkene - catalyst being the reactive intermediate Figure 2. 19 Model 2: Alternative scenario of 1:1 alkene - catalyst being reactive intermediate. Reaction pathways for a scenario where 1:1 alkene - catalyst complex is the reactive intermediate. The following is a scenario where the 1:1 alkene - catalyst complex is the re active species in the catalytic cycle and the resting state 2:1 complex is an unreactive off - cycle species. Acid - base equilibria between catalyst and alkenoic acid 2 - 1 : - or - eq ( 2. 20) - or - - or - eq ( 2. 21) Total concentration of the catalyst: eq ( 2. 22) Using eq (20), eq (21) and eq (22) - or - eq ( 2. 23) Rate of product formation based on model above: eq ( 2. 24) Using eq ( 2. 20), eq ( 2. 23) and eq ( 2. 24) - or - eq ( 2. 25) Equation 2. 25 represent the rate law in this scenario. Note that the current scenario results in rate equation having a higher term for the alkene in the denominator. Since the 108 resting state has already been established to be I 2 , we may make similar assumptions of la rge equilibrium constants of K 1 and K 2 . Therefore, similar to model 1, it is reasonable to assume K 1 K 2 [ 2 - 1 ] 2 will be the large, and thus, the above rate law equation can be reduced to the following simplified form: eq ( 2 . 26) In this current scenario, rate would have an inverse dependence on alkene 2 - 1 . This is a result of higher alkene concentration driving the formation of inactive state I 2 . Since this behavior is not observed we may rule out this scenario. 109 2.9.4 1 H NMR analysis of alkenoic acid 2 - 5 and its complexes with (DHQD) 2 PHAL and quinuclidine 2.9.4.i. Sample and NMR instrument preparation for 1 H NMR studies The NMR probe was cooled to - Stock solutions of catalyst and diff erent substrates were prepared, and the desired volumes were calculated and added to the NMR tube. In all 1 H NMR studies, the volume in the NMR tube was adjusted to 1 mL by addition of CDCl 3 . 110 2.9.4.ii. 1 H NMR of alkene 2 - 5 111 2.9.4.iii. 1 H NMR of alkene 2 - 5:quinuclidine ( 1:1) mixture 112 2.9.4.iv. 1 H NMR of quinuclidine 113 2.9.4.v. 1 H NMR of (DHQD) 2 PHAL and alkene 2 - 5 (1:2) i (CHCl 3 ) 2 - 114 2.9.4.vi. 1 H NMR of 0.04 M (DHQD) 2 PHAL under various concentration of benzoic acid (DHQD) 2 PHAL :Benzoic (DHQD) 2 PHAL :Benzoic (DHQD) 2 PHAL 1,1,2,2 - tetrachloroethylene (internal standard) 115 2.9.5 ROESY analysis of (DHQD) 2 PHAL:alkene 5 complex 2.9.5.i. Sample and NMR instrument preparation for ROESY studies The 600 MHz NMR instrument was used for all ROESY studies. Prior to any ROESY experiments , the probe was cooled to - 20 º C (the lowest practical temperature on this instrument) and allowed to equilibrate for 2 h. Stock solutions of catalyst and substrate were prepared and the desired volumes of catalyst and substrate were calculated and added to the NMR tube. In all ROESY st udies, the solutions in the NMR tubes were equalized to 1 mL by addition of CDCl 3 . After preparing the sample, dissolved oxygen was removed from the sample via three cycles of f reeze - p ump - t haw degassing method. The NMR tube was sealed with Teflon tape and inserted in the NMR instrument. The sample was equilibrated in the NMR for 10 min. After tuning the 13 C and 1 H channels , locking and shimming the sample, PW 90 º was measured and used for the study. 2.9.5.ii. Measuring intermolecular distances using ROESY analysis T he intensity - ratio method (developed by Bodenhausen and Ernst and later used by Ammalahti) 64 - 66 was used to determine the inter - nuclear distances from the ROESY experiments. Several effects such a s HOHAHA type magnetization and the offset dependence of the spin - locked conditions can influence the intensities of ROESY cross peaks. ROESY cross peaks can be used to estimate the distances between selected protons by carefully adjusting the measurement conditions. To minimize undesired effects on the ROESY peaks, the spin - lock pulse was positioned at the far low side of the sp ectrum (3 , 599 Hz) and a moderate spin - lock field (5 , 758 Hz) was used. The following equations illustrate the method t o measure th e inter - atomic distance s . Eq (27) represents the estimated inter - nuclear distances between two nuclei i and j . 64 - 66 To apply this equation, correction factors based on eq (29) and eq (30) were 116 calculated. Two atom pairs at known, fixed distances were chosen as references to Figure 2. 20 , was assigned a 1.6 Å fixed distance to calculate the constant. To evaluate the accuracy of this eq (27) with the calculated constant. The result was then compared with its actual distance from the (DHQD) 2 PHAL crystal structure (2. 3 Å). This control experiment shows that this method is reliable within acceptable error margins. These calculations are sum marized in Table 2. 4 and were used to predict the catalyst conformation proposed for the resting state of substrate in the catalyst binding pocket. Distance between the two nuclei r ij is given by: eq (2 7 ) eq (2 8 ) eq (2 9 ) eq ( 30 ) eq ( 31 ) eq ( 32 ) Definition of terms: mix = mixing time a ij = intensity of the cross peak a ii = intensity of the diagonal peak 0 = offset frequency 117 Figure 2. 20 ROESY reference distances . Reference distances used for accurately deriving internuclear distances with ROESY analysis Table 2. 4 ROESY correlations ROESY Correlations (ppm) Cross peak intensity Diagonal peak intensity C ij C ii Distances (Å) Proton i Proton j q (2.80) p (3.11) 8.64 36.4 1.208 1.109 1.6 h (7.30) c (8.50) 3.56 135.5 1.086 1.017 2.3 r (2.40) n (3.67) 0.62 152.6 1.207 1.14 3.2 t (2.03) n (3.67) 0.77 133.7 1.238 1.169 3 n (3.67) k (6.85) 0.29 191.4 1.067 1.059 3.8 e (8.00) d (8.30) 3.24 100 1.106 1.044 2.2 v (1.69) d (8.30) 1.78 125 1.273 1.202 2.6 h (7.25) d (8.30) 0.65 135 1.078 1.017 3.1 d (8.30) y (0.94) 0.46 165 1.354 1.278 3.4 n (3.67) j (7.15) 0.97 191.4 1.075 1.059 3.1 Figure 2. 21 Proton label for ROESY studies . Proton labels in 1 H NMR of a 1:2 mixture of (DHQD) 2 PHAL and alken e 2 - 5 118 2.9.5.iii. Measuring intermolecular distances using ROESY analysis 119 2.9.6 General procedure for kinetic isotopic effect studies Sample and NMR instrument preparation were the same as that for RPKA kinetic studies. In these experiments [DCDMH] o = 0.056 M and [ 2 - 1 ] o = 0.051 M, were used in the presence of [ t oluene] o = 0.051 M. Catalyst loading was decreased to 1 mol% to monitor the reaction slowly and collect more data points. Concentration of the product was obtained from the concentration of the internal standard. Product concentration was plotted as a function of time and fitted to an exponential growth curve , utilizing the Excel solver tool using eq (33) , and was fitted to the observed data by varying t o (this accounts for the correct time of the reaction initiati on since time elapses from the actual initiation and the first data point acquired by NMR) , k , and [ P ] (extrapolated product concentration) . The completion criterion in Excel solver was a non - linear least squared regression error below 0.00002. Fitting curve equation: eq ( 33 ) Figure 2. 22 Kinetic isotopic effect studies . The figure depicts the kinetic effect of isotopic substitution of OH to OD in substrate 2 - 1 . 120 Figure 2. 23 Proton label for ROESY studies . Fit of eq ( 33) to the kinetic profile of product forma - 5, least squared error = 2.78 x 10 - 6 Figure 2. 24 Proton label for ROESY studies . Fit of eq ( 33 ) to the kinetic profile of product formation from alkene 1 - - 5 , least squared error = 1.17 x 10 - 5 Kinetic profile for alkene 2 - 1 Kinetic profile for alkene 2 - 1 - OD 121 2.9.7 General procedure for the titration of (DHQD) 2 PHAL with alkene 1 Samples for NMR were prepared using anhydrous CDCl 3 inside a dry - box under N 2 atmospher e. CDCl 3 containing 0.1 µL/g tetramethyl silane was stored over flame dried 3 Å molecular sieves for at least 1 day. T he substrate 2 - 1 was sublimed and the sublimator was opened inside a dry - box. (DHQD) 2 PHAL was dried under vacuum overnight. All glassware were dried in an oven at 160 °C, and cooled down during transfer to the dry - box under antechamber vacuum. The NMR tube caps were sealed using parafilm to slow down water diffusion and spectra were collected on an Avance II Bruker 900 MHz instrume nt. The peak profile for proton H b is shown below. Measurement of H a was not feasible over the given range of titration since aromatic resonances overlapped with H a at certain concentrations. 122 Figure 2. 25 Change in chemical shift of H b on titrating (DHQD) 2 PHAL with alkene 2 - 1 . The figure depicts the change in chemical shift of the proton in (DHQD) 2 PHAL when titrated with the alkene 2 - 1 . 2 - 1 :(DHQD) 2 PHAL 0:1 1:1 2:1 4:1 6:1 H b H b H b H b H b 123 2.9.8 X - Ray crystallography Cocrystal of (DHQD) 2 PHAL and benzoic acid was obtained by slow evaporation of a chloroform solution containing 1:2 ratio of (DHQD) 2 PHAL and benzoic acid in a capped NMR tube over three weeks. Figure 2. 26 Co - crystal of (DHQD) 2 PHAL with benzoic acid . The figure depicts the co - crystallized structure of (DHQD) 2 PHAL with benzoic acid. 124 2.9.9 General procedures for c omputational studies All computations were performed using Gaussia n 16. 68 Q uantum chemical modeling of reactant, complex, and transition state structures was performed at the B3LYP - D3/6 - 31G* lev el. 69 - 72 All species were fully optimized, with stationary points characterized by vibrational analysis to verify the presence of zero (for minima) and only one (for transition states) imaginary frequencies. At first, energetic contributions of polarizable continuum model of Cramer et al. 73 app lied after optimization as additive corrections to the calculated gas - phase enthalpies and free energies. This two - step method is denoted B3LYP - D3/6 - 31G*/postSMD(CHCl 3 ). However, in the co ntext of this project, where protons and chlorenium ions are potentially transferred, creating or destroying charged sites, we were concerned about structural and energetic differences between structures optimized in vacuum and those optimized in the simul ated CHCl 3 . For this reason, computations that involve uncatalyzed and quinuclidine - promoted reactions were rerun with optimization and vibrational analyses obtained at the B3LYP - D3/6 - 31G*/SMD(CHCl 3 ) level, in which both the D3 dispersion correction of Gri mme et al. 70 and the SMD solvation model were included in the optimization and vibrational an alyses. Ultimately, the structures and energies showed little change from the original approach, and conclusions were unchanged. 125 REFERENCES 126 REFERENCES 1. Cresswell, A. J.; Eey, S. T. C.; Denmark, S. E., Catalytic, Stereoselective Dihalogenation of Alkenes: Challenges and Opportunities. Angew. Chem. Int. Ed. 2015, 54 (52), 15642 - 15682. 2. 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Mechanism of catalytic asymmetric c hloroetherification of alkene amide s Catalytic asymmetric halofunctionalizations have proliferated over the last decade, yet mechanistic insights into these catalytic processes remain scarce. This article presents a novel mechanism, revealed via detailed kinetic analysis of (DHQD) 2 PHAL cata lyzed asymmetric chloroetherification. The rate of alkene amide 3 - 3 undergoing chloromethoxylation showed a first order dependence on the alkene and the methanol. The electrophilic chlorinating agent, DCDMH, showed zeroth order dependence, attributed to it s strong binding to and reaction with the catalyst, which only complexes alkene weakly. An inverse secondary kinetic isotopic effect at the site of ether formation pointed to a concerted Ad E 3 - type addition of the electrophile and nucleophile components to the alkene. Surprisingly, the catalyst was found to have a zeroth order effect on the reaction rate under the previously reported reaction conditions. This discovery enabled a 10 - fold drop in catalyst loading for the chloroetherification with essentially n o loss in efficacy or stereocontrol. The kinetic studies were complemented with spectroscopic investigations of reaction intermediates and quantum chemical modeling to further dissect the elementary steps involved in the catalysis. The findings for this ca talytic chloroetherification led to a unique kinetic model that contrasts with our prior reported mechanism of chlorolactonization activated by the same catalyst. Exposing this mechanistic diversity among seemingly similar catalytic asymmetric halofunction alizations underscores the value of such mechanistic investigations and their role in reaction discovery and optimization . 134 3.1 Introduction Over the last decade, catalytic asymmetric halofunctionalizations of alkenes have taken their place in the vast arse nal of asymmetric transformations. 1 - 10 As one would expect in a growing field, a variety of catalysts have shown efficacy for halofunctionalization of different families of olefinic substrates. Most of these catalysts work via Bronsted or Lewis acid/base reactivities, each presumably with unique mechanistic features. 5 Even with the same catalyst, the same mechanism o f action is not a foregone conclusion; reaction conditions and changes in substrate functional groups and structures may lead to varied mechanistic pathways. The story reported here highlights this point emphatically. Figu re 3. 1 (DHQD) 2 PHAL catalyzed chlorofunctionalization of alkene amides . Various examples of (DHQD) 2 PHAL catalyzed asymmetric chlorofunctionalizations of alkene amides demonstrating its broad applicability . Our initial discovery of the asymmetric chlorolactonization of alkene carboxylic acids, 11 catalyzed by the well - known cinchona alkaloid dimer (DHQD) 2 PHAL, 12 was followed by several halofunctionalization reactions of alkene amide substrates. Some recent examples include chlorocyclizations, chloroetherifications, chloroamidations and alkene amide dichlorinations ( Figu re 3. 1 ). 13 - 19 These reactions are broadly classified into 135 intramolecular and intermolecular cases, with the former requiring a nucleophile tethered to the olefin, while the latter involve exte rnal nucleophiles ( Figu re 3. 1 ). Despite the surge in catalytic chlorofunctionalization processes, there is a dearth of literature insight into their reaction mechanisms . This is most apparent for the intermolecular processes, arguably the more versatile and general of the category. Detailed herein is the discovery of a unique mechanism responsible for the asymmetric chloroetherification of alkene amides ( Figure 3. 2 b ), as revealed by kinetic, spectroscopic, and computational tools. Figure 3. 2 Mechanistic study on catalytic chlorofunctionalization of alkene amides . (a) Prior work on the mechanism of chlorolactonization. (b) Current work on mechanism of (DHQD) 2 PHAL catalyzed chloroetherification of alkene amides. 136 In a recent article we describe d the mechanism of chlorolactonization of alkene carboxylic acids, one of the first known catalytic asymmetric halofunctionalization reactions. 20 It is tempting to extrapolat e the mechanistic conclusions from that report to other transformations achieved by the same catalyst and chlorenium ion source, such as the chlorofunctionalization of alkene amides. Unfortunately, that logical extension fails, as the present account will show. The reaction conditions for chlorolactonization of alkene 3 - 1 differ from those of chlorofunctionalization of alkene amides in two key aspects: 1) the nature of the substrate (carboxylic acid vs amide), and 2) the nature of the solvent (non - polar in one case, polar protic in other). Notably, in a previous study, a similar difference was sufficient to invert the stereochemistry. 13, 21, 22 The following observations further differentiate the two systems, suggesting that differing mechanisms are to be expected: 1) Prior investigations have sh own that the face selectivity of nucleophile attachment in the chlorofunctionalization of 1,1 - disubstituted alkene amides is opposite to that in the analogous reaction with 1,1 - disubstituted alkene carboxylic acids. 13, 21, 22 2) Substrate scope studies have demonstra ted that the stereocontrol in chlorofunctionalizations of alkene amides is in general more robust in the face of structural variations than the corresponding chlorolactonizations of alkene carboxylic acids. 11, 14 - 19 3) As noted above, polar - protic solvents are optimal for alken e amide chlorofunctionalizations, whereas non - polar solvents are best for chlorolactonization. 4) Carboxylic acid substrates, with their inherently low p K a values, are strong binders of the basic (DHQD) 2 PHAL catalyst. This leads to the formation of a key subs trate - 137 catalyst complex at the start of chlorolactonization (the resting state). The alkene amide - catalyst complexation is not as strong. For instance, the B3LYP/6 - 31G* calculated gas - phase association energ y of N - methyl acetamide with trimethylamine is 6 - 7 kcal/mol weaker than that of acetic acid. With these differences in mind, an independent investigation into the mechanism of alkene amide chlorofunctionalizations was necessary. In this paper, we describe an extensive mechanistic study on the (DHQD) 2 PHAL catalyzed intermolecular chloroetherification of alkene amides ( Figure 3. 2 b ). A unique mechanistic picture has emerged from this investigation for alkene amide functio nalization that differs sharply from that of chlorolactonization. When run at typical catalyst concentrations, the process was found to exhibit a surprising, zero order dependence on the concentration of (DHQD) 2 PHAL. Only at catalyst concentrations an order of magnitude lower did a rate dependence emerge. The amide functional group plays a critical role in engaging the nucleophile for attack on the alkene while the chlorenium ion is first transferred to the catalyst, and then delivered to the alkene. All these observations are in contrast to the (DHQD) 2 PHAL catalyzed asymmetric chlorolactonization of alkene carboxylic acids. 20 Fortuitously, this investigat ion has revealed an improvement upon the original reported reaction condition, lowering the catalyst required by 10 - fold without impacting the reaction. 3.2 Kinetic studies Chemical kinetics has always been an indispensable tool for mechanistic investiga tions. Identifying a complete rate law for any reaction not only limits the number of mechanistic interpretations by setting stringent boundary conditions, but also often 138 provides critical information regarding the elementary steps involved in a catalytic process. In recent years, the use of kinetic studies has grown among organic chemists with the advent of various visual kinetic analysis protocols such as the Reaction Progress Kinetic Analysis (RPKA) and the Variable Time Normalized Analysis (VTNA) develo ped by Blackmond and Bures, respectively. 23 - 28 The popularity of these techniques stem from their highly intuitive nature, as well as their ease of execution and analysis even for organic chemists not adept in chemical kinetics. These protocols often work well with practically relevant reaction conditions, unlike more classical techniques that extrapolate from pseudo first order conditions, where large concentration imbalances are n eeded for analysis. We began our mechanistic study with a comprehensive investigation into the chloroetherification kinetics of alkene amide 3 - 3 . Using the VTNA protocol along with classical kinetic techniques, we established the order of each component, leading to a rate law for the reaction. The standard conditions for these experiments were 0.04 M alkene, 0.08 M DCDMH, 0.004 M (DHQD) 2 PHAL in 3:7 v:v methanol / acetonitrile at - 32 ° C. These conditions are nearly identical to those originally reported, and thus negligibly impact the enantioselectivity. Deuterated analogs of the solvents (methanol - d 4 and acetonitrile - d 3 ) were used to enable in situ reaction monitoring via NMR spectroscopy. 3.2.1 Order of alkene Two experiments, A and B, shown in Figure 3. 3 were executed at different concentrations of alkene with otherwise identical conditions. Analysis of these two experiments utilizing the standard VTNA protocol showed optimal overlay of their respective time - normalized plots when the alkene concentration carried an exponent of 1.1 ( Figure 3. 3 ). Thus, the rate of chloroetherification has a first - order dependence on the 139 alkene concentration, which is in contrast to the pre vious report for chlorolactonization. 20 In chlorolactonization, the observed zeroth order behavior in alkenoic acid 3 - 1 originated from the substrate saturating the catalyst resulting in a bound resting state. The observed first order dependence on alkene amide 3 - 3 for the chloroetherification reaction points to a different substrate - catalyst relationship where the catalyst is no longer saturated with the alkene. The justifica tion for this hypothesis is explored further in later sections. Exp 3 - 3 (M) DCDMH (M) (DHQD) 2 PHAL (M) excess (M) A 0.04 0.08 0.004 0.04 B 0.06 0.08 0.004 0.02 C 0.04 0.06 0.004 0.02 Figure 3. 3 Kinetic experiments to determine order of alkene 3 - 3 . (a) A set of different excess experiments analyzed using VTNA protocol to determine order of alkene 3 - 3 . 3.2.2 Order of DCDMH Unfortunately, direct determination of the ord er of DCDMH using experiments A and C ( Figure 3. 3 ) was less straightforward. DCDMH and its dechlorinated by - product, 1 - chloro - 5,5 - dimethylhydantoin (MCDMH), did not dis play unique NMR signals during the course of the reaction. Instead, a combined averaged peak for the two species (DCDMH and MCDMH) was observed. Thus, as chloroetherification progressed, the observed 140 averaged peak for the hydantoins moved upfield as the DC DMH:MCDMH ratio decreased ( Figure 3. 4 a ). This implied a dynamic equilibrium, presumably due to Cl/H exchange between DCDMH and MCDMH under the reaction conditions. In c ontrast, both forms are clearly observed under the chlorolactonization conditions. Figure 3. 4 Finding order of DCDMH . (a) DCDMH - MCDMH chlorine exchange resulted in averaged 1 H NMR spectra for both species. (b) Example of external calibration curves generated prior each experiment to enable quantification of DCDMH and MCDMH with reaction process. (c) A Jobs plot depicting a 1:1 equilibrium between DCDMH and MCDMH . (d) Finding order of DCDMH using VTNA protocols. a . b. d . c. 141 Evidently, this Cl/H exchange is triggered by the presence of a protic solvent; it is not observed when pure acetonitrile is used as the solvent. Addition of methan ol or fluorinated alcohols such as 1,1,1,3,3,3 - hexafluoro - 2 - propanol (HFIP) lead to immediate coalescence of the peaks. Jobs plot analysis of these two species under the reaction conditions confirmed the 1:1 H/Cl equilibration ( Figure 3. 4 c ). 29 Individual external calibration curves generated prior to each reaction from mixtures with known concentrations of DCDMH and MCDMH (an example shown in Figure 3. 4 b ), all owed quantification of DCDMH and MCDMH concentration during the course of the reaction. This ultimately provided the means to directly evaluate the order of DCDMH, which was found to be nearly zero ( Figure 3. 4 d ). eq ( 3.1 ) An important note here is that the rate equation evaluated thus far is in stark contrast to our recent report on chlorolactonization of alkene carboxylic acid . 20 In chlorolactonization, the rate was found to be first order with respect to the DCDMH and zero order with respect to alkene 3 - 1 . As previously mentioned, the zeroth orde r with respect to alkene 3 - 1 was a result of saturation kinetics, where 3 - 1 rapidly binds (DHQD) 2 PHAL to form a resting complex. This resting complex reacted with DCDMH in the rate determining step, thus exhibiting first order dependence on DCDMH and (DHQD) 2 PHAL. In chloroetherification of alkene amide 3 - 3 , the opposite order with respect to the components ( 3 - 3 and DCDMH) indicates that this is certainly no longer the case. The current rate equation could in fact be hinting at a reverse scenario where the DCDMH outcompetes alkene 3 - 3 for catalyst binding, leading to a saturation of available catalyst as a DCDMH - bound complex. 142 3.2.3 Product inhibition and catalyst binding Investigation into the presence of catalyst deactivation or product inhibition pr ovided further clues about the various binding equilibria operating along the reaction Figure 3. 5 a, Figure 3. 5 b ) revealed the byproduct MCDMH to be an inhibitor of the catalytic chloroetherification. This is yet another finding that directly contradicts the chlorolactonization rea ction mechanism, where no product inhibition was observed. More importantly, this reinforces the hypothesis that in chloroetherification of alkene amides, DCDMH binds more strongly than alkene 3 - 3 to (DHQD) 2 PHAL. And perhaps the MCDMH, impotent as a haloge nating agent but structurally similar to DCDMH, now competes with DCDMH for catalyst binding to form an inactive complex. To similarly probe whether amides (alkene substrate or product) show significant catalyst binding, the reaction was doped with 0.5 eq uivalent of 3 - 5 , the saturated analog of alkene amide 3 - 3 . Given their structural similarities, 3 - 5 should compete with alkene amide 3 - 3 and/or the reaction product for catalyst binding, provided that binding of 3 - 3 to catalyst is important to the kinetics . Under this scenario, unreactive 3 - 5 would siphon off some of the catalyst into an inactive off - cycle complex, acting as a competitive inhibitor and slowing the reaction. However, addition of a 0.5 equivalent (or 0.02 M) of 3 - 5 had no effect on the rate o f chloroetherification of alkene amide 3 - 3 ( Figure 3. 5 c ). This suggests little affinity of the catalyst for any of the amides, substrate 3 - 3 , product 3 - 4 , or additive 3 - 5 . Nonetheless, the amide functionality is essential to achieve high stereoselectivity in asymmet ric chlorofunctionalizations. 17, 18 What t hen is the role of the amide functional group in substrate 3 - 3 ? This question is explored further in a later section via computational studies. 143 The above studies led to the proposed equilibria shown in Figure 3. 5 d , illustrating that the total catalyst concentration is effectively shared between a DCDMH - bound active - resting - complex I 1 and an MCDMH bound inactive - resting - complex I 2 . The roles of complexes I 1 and I 2 are examined further in the later section using NMR. Exp 3 - 3 (M) DCDMH (M) (DHQD) 2 PHAL (M) MCDMH (M) B 0.0 6 0.08 0.004 - C 0.0 4 0.0 6 0.004 - D 0.04 0.06 0.004 0.02 Figure 3. 5 Investigating product inhibition and catalyst deactivation . (a) Same excess experiment s conducted to investigate catalyst deactivation of product inh ibition . (b) Experiment B, C and D demonstrates a small but noticeable product inhibition from the MCDMH by - product . (c) Addition of structurally similar alkane amide 3 - 5 to the reaction does not impact the reactivity, indicating amides do not compete for the catalyst b. c. a. d. 144 binding . (d) Binding model illustrating competitive binding of DCDMH and MCDMH to the catalyst to generate the active I 1 and inactive I 2 intermediate species respectively . 3.2.4 Role of the nucleophile The need to investigate the order of nucleophile stemmed from our prior investigations of uncatalyzed halofunctionalizations that indicated a critical role of the nucleophile in alkene chlorofunctionalizations. 30 Prior experimental findings found these alkene additions to occur via a low ba rrier Ad E 3 - type pathway in which the nucleophile and the chlorenium ion donor participate concertedly in preference to a stepwise addition ( Figure 3. 6 a ), a process dubbe d nucleophile assisted alkene activation (NAAA). 30 - 32 Although demonstrated for the uncatalyzed reaction, rigorous investigations into the NAAA pathway are lacking for the catalyzed halofunctionalization reactions. For the present reaction, a concerted rate - limiting addition involving the methanol nucleophile predicts a positive reaction order of the alcohol, whereas, zeroth order would indicate its involvement post formation of the high energy carbocation intermediate ( Figure 3. 6 a ). Methanol, the nucleophile in chloroether ification of alkene amides is present in large excess and is practically a constant, as it experiences negligible change in concentration during the course of the reaction. Thus, the order of the methanol in chloroetherification is determined under varying concentrations of methanol by pseudo first - order analysis. Plotting the rate constants ( k obs ) as a function of methanol concentration yields a linear relationship that indicates a first order dependence ( Figure 3. 6 b , see experimental section for detail ). The explicit presence of methanol in the rate further strengthens the idea that the concerted addition of the nucleophile via the NAAA pathway is operational here. eq ( 3. 2) 145 Figure 3. 6 Investigating the role of nucleophile . (a) Concerted vs. stepwise alkene chlorofunctionalization. A concerted pathway would involve simultaneous addition of nucleophile (NAAA), while a step wise addition usually involves the nucleophile post chlorenium addition. (b) Finding the pseudo - order of methanol from the rate constant. A first order dependence on methanol concentration supports concerted addition mechanism. (c) Inverse KIE on isotopic substitution center of nucleophilic attack supports a concerted addition pathway over a stepwise addition . Though it was explored over a range of relatively high concentrations, it could be argued t hat the observed positive effect of methanol concentration on rate could be an indirect consequence of a change in factors such as solvent polarity and hydrogen bonding. Independent evidence for the direct involvement of the nucleophile as expected in the NAAA pathway was obtained in the form of a kinetic isotopic effect (KIE) study. 33 Specifically, an inverse isotopic effect is anticipated for addition to the deuterated alkene analog 3 - 3 - D ( Figure 3. 6 c ) due to the sp 2 to sp 3 rehybridization during the nucleophilic a. b. c. 146 attack. Little isotopic effect would be expected for a stepwise pathway via a carbocationic or cyclic halonium intermediate, where the center of nucleophilic attack undergoes minimal change in hybridization ( Figure 3. 6 a ). In the event, competition experiments conducted with alkenes 3 - 3 and 3 - 3 - D resulted in a me asured inverse KIE value of 0.89 ( Figure 3. 6 c ). Thus, the observed inverse KIE combined with the first - order kinetics in methanol provides conclusive experimental eviden ce in support of concerted nucleophilic attack (NAAA pathway) in the catalyzed chloroetherification of alkene amide 3 - 3 . 3.2.5 Catalyst order With the order of alkene 3 - 3 , DCDMH , and methanol in hand, completing the empirical rate equation required the de termination of the order of the catalyst (DHQD) 2 PHAL. Three experiments with different catalyst loadings of 10 mol% (original condition, 0.004 M), 5 mol%, and 2.5 mol% were investigated while otherwise maintaining identical reaction conditions. Surprisingl y, this geometric drop in catalyst loading had little effect on the overall rate of the reaction. Analysis of the data using the VTNA protocol ( Figure 3. 7 a ) provided the following completed rate equation, where rate has a near - zero order (0. 15 ) dependence on catalyst: Figure 3. 7 Order of the catalyst (DHQD) 2 PHAL . (a) Catalyst order is nearly zero (0.15) in the range of 2.5 - 10 mol% catalyst loading. (b) Lowering the catalyst loading to much value eventually led to an observed first order in catalyst (range 0.25 - 1.0 mol%) . b. a . 147 eq ( 3. 3) Zero - order dependence of a catalyzed reaction rate on catalyst concentration is a rare occurrence. Often the most plausible explanation for such cases is that the rate determining step is outside the catalytic cycle. 34 - 37 Nonetheless, the first order dependence on alkene and nucleophile indicates that the slowest step for the entire reaction sequence likely precedes the catalytic cycle and involves only the alkene and the nucleophile (methanol , Figure 3. 6 ). This pre - catalytic step could be the association between the alkene and the nucleophile to slowly generate a reactive species, perhaps an NAAA - active conformation, which would be consistent with previous findings with 3.2.6 Catalytic model A mechanistic model of catal ysis that would fit the findings from the empirically derived rate equation (eq 3.3 ) is shown in Figure 3. 8 . This model proposes that alkene amide 3 slowly associates w ith the nucleophile (methanol) to form a reactive species I 3 in a precatalytic step. I 3 is then quickly siphoned off into the catalytic cycle by the active catalyst complex I 1 , the DCDMH - (DHQD) 2 PHAL bound species. I 1 likely contains an activated chlorenium, which is delivered to the activated alkene complex I 3 . This rapidly leads to the chlorofunctionalized product 3 - 4 along with MCDMH. MCDMH then returns to siphon off some of the catalyst to form an inactive complex I 2 , leading to the observed byproduct inhibition as an off - cycle path. The rate insensitivity to the catalyst concentration begged further examination of the catalyst loading to find the minimum catalyst necessary to maintain the efficiency of the reactio n. If a pre - catalytic step is slowly producing a reactive species I 3 that is instantaneously being siphoned off into a catalytic cycle, then at any given moment the 148 concentration of this reactive species I 3 is exceedingly small. Nonetheless, this would als o mean that further lowering catalyst concentration (and in turn I 1 ) should at some point lead to a small accumulation of I 3 , having insufficient I 1 needed for rapid consumption of all I 3 . Thus, at a certain lower limit of catalyst loading, the rate should gain a dependence on the catalyst concentration. In fact, this is exactly what was observed; as the catalyst loading was lowered below 1 mol% (0.0004 M), a clear dependence on the catalyst concentration became evident ( Figure 3. 7 b ). Lowering the concentration of the catalyst to this range also slightly improved the enantioselectivity of the reaction, allowing for a 10 - fold reduction from the previously reported condition s, and importantly, confirming that the reaction is not significantly diluted by background, non - catalyzed processes. Figure 3. 8 Catalytic model . A mechanistic scenario that explains the observed orders of each component, a slow precatalytic step is likely the cause of the observed zero order in catalyst . The order of every component (alkene, methanol, and DCDMH) was remeasured with 1 mol% catalyst, following the procedures described in pr evious sections (see SI for details ). This led to two distinct rate laws for the two catalyst concentration regimes: At higher catalyst loading of 2.5 - 10 mol% eq ( 3. 3) At lower cataly st loading of 0.25 - 1.0 mol% catalyst 149 eq ( 3. 4) At the lower catalyst loading, the rate now has a first order dependence on DCDMH as well (along with catalyst, alkene and nucleophile). The proposed catalytic cycle ( Figure 3. 8 ) does, however, connect the two seemingly disparate rate equations ( 3.3 and 3.4 ). A higher catalyst concentration (10 mol%, 0.00 4 M) drives the formation of I 1 , which quickly consumes I 3 as it is slowly generated from alkene amide 3 - 3 and methanol. The bottleneck for the overall process is the production of I 3 resulting in the observed first order kinetics of alkene 3 - 3 and methanol, and zero order in catalyst and DCDMH. On the other hand, a drastic cut in the catalyst loading (1 mol%) leads to a significant decline in the concentration of I 1 (due to the revers ibility of its formation). This results in an accumulation of I 3 whose consumption now depends on the available concentration of I 1 . Thus, now the rate displays a dependence on the concentration of both the catalyst and DCDMH, as amplifying the concentrati on of either species favors the formation of I 1 . This dependence disappears again once the concentration of I 1 exceeds I 3 at high catalyst concentrations. 38 The combination of the two rate expressions ( 3.3 and 3.4 ) along with the inhibition and KIE results presented in prior sections paint a completely novel mechanism for chloroetherification of alkene amides (as shown in Figure 3. 8 ). In the prior model for the chlorolactonization of alkene carboxylic acids, neither zero order catalyst, dual rate law, DCDMH binding of catalyst, nor MCDMH inhibition of reaction were se en . 20 Pr esumably due to the different solvent systems, (non - polar for chlorolactonization of 3 - 1 , polar protic for chlorofunctionalization of 3 - 3 ), the two reactions proceed by dramatically different 150 mechanistic pathways, despite their use of similar reagents. The following sections further investigate the key structural features of the intermediates involved in the reaction. 3.3 Resting state of the catalyst With kinetics providing insight into the elementary steps of the reaction sequence, further exploration of the nature of the resting state of the catalyst in the catalytic cycle was pursued via NMR spectroscopy. Based on kinetic data, (DHQD) 2 PHAL is predicted to have a strong affinity for both DCDMH and MCDMH, resulting in complexes I 1 and I 2 as the active and inactive resting state complexes, respectively ( Figure 3. 8 ). Putatively, (DHQD) 2 PHAL and DCDMH form a zwitterionic complex resulting from halogen bonding interaction ( Figure 3. 9 a the chlorenium ion donor. Halogen bond interactions are well - known in the literature with energies that span a range of 2 to 35 kcal/mol. 39 It is conceivable that such an interaction between the nucleophilic quinuclidine nitrogen atom in (DHQD) 2 PHAL and the low - lying * of N - Cl in DCDMH, aided by the presence of a polar protic solvent, results in the formation of an ion - pair. In fact, a prel iminary look via quantum chemical modeling into this interaction energy between quinuclidine (as a truncated model for the catalyst ) and DCDMH revealed a substantially exothermic process of - 7.6 kcal/mol ( Figure 3. 9 b ). The calculations were performed at the DFT - B3LYP/6 - 31G*/SM8 (acetonitrile) level. Likewise, MCDMH and quinuclidine formed a halogen bond, albeit weaker ( - 4.2 kcal/mol . see Figure 3. 9 b ). The lower affinity presumably reflects weaker electrophilicity of the monochloro reagent. Hydrogen bonding with the quinuclidine via the N - H of the MCDMH (see Figure 3. 9 b ) was found to be favored over halogen bonding ( - 7.8 kcal/mol) and is presumably the preferred mode of catalyst binding and inhibition. 151 Figure 3. 9 Investigating the resting state of the catalyst . (a) DCDMH - (DHQD) 2 PHAL complexation via halogen bonding to form charge separated intermediate I 1 , facilitated in alcoholic solvents. (b) Computational studies suggest significant binding affinity between quinuclidine (truncated catalyst) and chlorenium source DCDMH and MCDMH. Binding enthalpy calculated using DFT - B3LYP/6 - 31G*/SM8 (acetonitrile) supports the proposed binding model. (c) HalA (Cl) calculations further supports chloreni um transfer to quinuclidine nitrogen . Hydrogen bonding between DCDMH and the protic co - solvent can further facilitate the chlorenium transfer from DCDMH to quinuclidine ( Figure 3. 9 a ). Calculations indicate 152 that a hydrogen bonded 1 - chloro - 5,5 - dimethyl hydantoin anion has a much lower halenium ion affinity ( HalA (Cl) of 156.2 kcal/mol) than one lacking the hydrogen bonded me thanol ( 165.4 kcal/mol), when calculated using DFT - B3LYP/6 - 31G*/SM8 (acetonitrile) ( Figure 3. 9 c ). 40 In fact, under these conditions, the HalA (Cl) value of quinuclidine (156.0 kcal/mol) is comparable to that of the hydrogen bonded 1 - chloro - 5,5 - dimethyl hydantoin anion. This further supports the hypothesis that, in the polar setting of the chloroetherification reaction, it is feasible for DCDMH to transfer the chlorenium ion to the quinucli dine nitrogen of (DHQD) 2 PHAL . This chlorenium transfer to the catalyst nitrogen atom was disfavored in chlorolactonization presumably due to the non - polar solvent conditions which is also supported by prior HalA (Cl) calculatio n s . 31 Figure 3. 10 NMR evidence towards supporting binding model . Change in 1 H NMR chemical shifts of chlorohydantoins DCDMH and MCDMH in presence of catalyst (DHQD) 2 PHAL further support the binding model. The spectra were collected at room DCDMH MCDMH DMH B A C 153 (Fig temperature with concentration (DHQD) 2 PHAL at 0.04 M in acetonitrile - d 3 in 0.4 M HFIP (10 equiv) . The n to * donation from catalyst quinuclidine nitrogen to the N 1 - Cl in DCDMH is expected to partially or completely ionize the pair by weakening the N 1 - Cl bond in DCDMH. This should res ult in an increased negative charge density on DCDMH and positive charge density on the quinuclidine nitrogen atom, an effect that should be reflected in the NMR chemical shift of the res pective moieties. Thus, to investigate the (DHQD) 2 PHAL binding to DCDMH and MCDMH, various mixtures of these species were studied in a series of NMR experiments. The measurements were conducted at room temperature (25 ° C) to avoid catalyst precipitation un der stoichiometric conditions used for these studies. Methanol was replaced with HFIP (10 equivalents, 0.4 M) as a protic co - solvent with acetonitrile - d 3 . This was done to avoid DCDMH decomposition to MCDMH, which is prevalent with methanol at room tempera ture ( presumably due to its enhanced nucleophilicity ) . HFIP and other fluorinated alcohols have been effective as co - solvents in previous reported chlorofunctionalization reactions. 14, 18, 41 For these experiments, the 1 H NMR resonances of the methyl protons in samples of pure DCDMH, MCDMH , and their unchlorinated analog 5,5 - dimethylhydantoin (DMH) were measured as controls. The chemical shifts of these methyl protons in various (DHQD) 2 PHAL - DCDMH and (DHQD) 2 PHAL - MCDMH mixtures were then remeasured, and their changes were compared against th ese controls. Figure 3. 10 highlights some of the results (for the complete set see SI). The final conclusions are summarized as follows: 1) Addition of 1 equiv. (DHQD) 2 peaks upfield (peak A, Figure 3. 10 ). This large upfield shift suggests negative 154 charge build up on the hydantoin due to partial or complete de - chlorination at N1 by the nucleophilic nitrogen atom of the catalyst ( Figure 3. 10 ). 2) In the above 1:1 mixture, the DCDMH methyl groups (peak A) are split into two distinct resonances. This diastereotopic splitting indicates that the chlorenium source spends significant time in the chiral cavity. 3) In the 1:1 mixture, both catalyst and DCDMH resonances exhibit significant line broadening, hi nting at a dynamic process. Broadening of the catalyst peaks upon addition of DCDMH is also observed in the spectra from the actual reaction kinetics runs. In the mixture, (DHQD) 2 PHAL peaks are broadened to the point where most coupling constants were lost . 4) In a 2:1 DCDMH - (DHQD) 2 PHAL mixture, the DCDMH methyl proton (peak B) shift comes between that of free DCDMH and a 1:1 mixture. This suggests a rapid 1:1 binding exchange between DCDMH - (DHQD) 2 PHAL and the free DCDMH, resulting in an averaged chemical shif t for DCDMH. 5) The 1:1 and 2:1 mixtures of MCDMH and (DHQD) 2 PHAL display similar trends (upfield chemical shifts of the methyl resonances) along with the induced diastereotopic splitting of the two methyl peaks in MCDMH (1:1 mixture is shown in Figure 3. 10 , see experimental section for full spectra). The combined studies strongly suggest that the catalyst (DHQD) 2 PHAL undergoes reversible 1:1 binding with DCDMH and MCDMH to form the active and inactive resting state complex I 1 and I 2 respectively, (see Figure 3. 8 ) consistent with the kinetic findings. Unlike the chlorolactonization of alkene carboxylic acids, here the highly polar environment for chloroetherification of alkene amides evidently facilita tes formation of the 155 charge separated species present in the complexation of I 1 and I 2 . Furthermore, under the reaction conditions, where the concentrations of DCDMH and MCDMH are much higher than the that of catalyst, the total catalyst concentration can be assumed to be effectively shared entirely between I 1 and I 2 . Table 3. 1 DOSY NMR of chlorohydantoin - catalyst complexes composition 1 H NMR (ppm) DOSY coefficient a DCDMH 1.516 0.9375 DCDMH: (DHQD) 2 PHAL 1.343 (peak A) b 0.5625 MCDMH 1.440 0.5738 MCDMH: (DHQD) 2 PHAL 1.300 (peak C) b 0.4546 a DOSY coefficients were normalized against the solvent acetonitrile; b See SI for full DOSY spectra (all DOSY experiments were conducted at 0 ºC). Finally, the 1 H NMR studies were complemented with DOSY NMR experiments. Interaction between DCDMH and (DHQD) 2 PHAL should slow the diffusion of the smaller, lighter DCDMH resulting in a smaller diffusion coefficient approaching that of the (DHQD) 2 PHAL. In order to investigate the extent o f binding, DOSY experiments of DCDMH, MCDMH and their 1:1 mixture with (DHQD) 2 PHAL (see SI) with 10 equivalents of HFIP were conducted at 0 ° C in acetonitrile - d 3 . The diffusion coefficients for DCDMH and MCDMH obtained from a mono - exponential were normaliz ed against the diffusion of acetonitrile to compensate for interexperimental differences. 42 As expected, free DCDMH demonstrated a faster diffusion rate (0.9375) as compared to DCDMH in the presence of (DHQD) 2 PHAL (0.5625). This 40% drop in the relative rate of diffusion is indicative of DCDMH binding to the (DHQD) 2 PHAL. Consist ent with formation of I 1 and I 2 , a similar effect was observed on the diffusion coefficient of MCDMH ( Table 3. 1 ); the slow diffusion of MCDMH itself can be understood in terms of the known tendency of the lactam - type functionality found in MCDMH to self - associate into dimers. 43, 44 156 3.4 Catalytic cycle for chloroetherification Figure 3. 11 Catalytic cycle for chlorofunctionalization of alkene amides . Proposed catalytic cycle for (DHQD) 2 PHAL catalyzed chloroetherification. The inset in the top left corner presents the empirically estimated rate laws at high and low catalyst concentration 157 regimes. The catalytic cycle illustrates that how DCDMH and the MCDMH competes for catalyst binding, with the former leading to a productive intermediate I 1 in the catalytic cycle, while the later leads to an inactive species I 2 . Kinetic studies suggest that amide mediated methanol (nucleophile) activation of the alkene, to generate an NAAA active conformation I 3 is likely the slow precatalytic step. Evidence for concerted addition of the methanol is presented in the bottom right shaded box. To rationalize the combined results of the studies described above, we propose the catalytic c ycle illustrated in Figure 3. 11 . The reaction begins with alkene amide 3 and nucleophile, methanol, forming an activated species I 3 , in a pre - catalytic step as supporte d by the first order dependence of both species on the rate. I 3 is presumably an - The rapidly generated DCDMH - (DHQD) 2 PHAL complex I 1 (Step 1) siphons the nucleophile - activated alkene species I 3 ( Step 2 , Figure 3. 11 ) into the catalytic cycle , leading to the chlorofunctionalized product 3 - 4 . The first order rate dependenc e on methanol, and the observed inverse KIE ( Figure 3. 6 c ) support s an NAAA - type concerted addition of the nucleophile and chlorenium ion to the alkene amide 3 - 3 . This i s also in agreement with prior analyses of uncatalyzed chlorofunctionalization of alkene carboxylic a cids. 30 Instead of an uncomplexed DCDMH, I 1 is the effective chlorenium ion source, presumably the catalyst chlorinated at the quinuclidine nitrogen atom ( Figure 3. 11 ). Thus, in contradistinction to chlorolactonization of alkene carboxylic acids, which involves direct chlorenium ion transfer from DCDMH to the catalyst - bound alkene ce nter, 19, 20 the c hlorinated catalyst here plays the role of chlorenium ion delivery agent in chloroetherification of alkene amides. Consistent with this scenario, our prior studies of (DHQD) 2 PH AL - catalyzed chloroetherification found essentially identical enantioselectivities, regardless of chlorenium ion donor. 17 The by - product MCDMH exchange s chlorenium ion with DCDMH, and also acts as a weak competitive inhibitor to 158 the catalyst ( Figure 3. 11 ). The proposed catalytic model supports the variable dependence on the concentration of the catalyst, as depicted by the empirical rate laws shown in Figure 3. 11 shaded box . At high catalyst concentrations, formation of I 3 , via an e quilibrium outside of the catalytic cycle, is rate limiting. But at low catalyst concentrations, Step 2 is the RDS, and the rate shows the expected dependencies on catalyst and chlorenium source, along with the nucleophile and the starting material. 3.5 Investigation into the transition states While a full - scale computational investigation exploring the labyrinthine route to chloroetherification is beyond the scope of this paper, a few key preliminary findings can be presented to support the discussion. E xploring the possible reaction trajectories while imposing the boundary conditions set by the experimental results, led to the proposed transition state 3 - TS1 shown in Figure 3. 12 a . The calculations were performed at the B3LYP/6 - 31Gd* level, 45 - 48 finding an entha lpic barrier of 4.2 kcal/mol for passa ge over the transition state 3 - TS1 . Th is low barrier explains the fast rate of the chloroetherification of alkene amides (30 min to 2 hours at - 30 ° C, <1 min at room temp) relative to chlorolactonization (>12 h to completion at - 30 ° C). In 3 - TS1 , the amide functional group direct s the nucleophilic attack of methanol via hydrogen bonding, enabling the concerted addition pathway by pre - organizing the NAAA complex (in Figure 3. 12 a ). The concerted addition places the methanol 2.4 Å above the reacting alkenoic center. The chlorenium ion, now delivered by the quinuclidine nitrogen atom to the alkene, is nearly equidistant from the two centers at about 2.2 Å, while the aromatic ring is positioned away from the catalytic center, consist ent with the observed tolerance for various aryl substitutions in chlorofunctionalization of alkene amides. 15, 17 159 Figure 3. 12 Transition state calculations . (a) Computational investigation of the chlorofunctionalization step in (DHQD) 2 PHAL catalyzed chloroetherification reaction, revealed 3 - TS1 to be the most favored transition state. 3 - TS1 involved a (DHQD) 2 PHAL mediated chlo - renium transfer. (b) 3 - TS2 represents a low energy alternative transition state that is disfavored over 3 - TS1 , in 3 - TS2 chlorenium is directly transfer from DCDMH to alkene similar to prior mechanistic reports . An alternative pathway, where DCDMH transfers the chlorenium ion direct ly to the alkenoic center ( as in chlorolactonization) rather than via quinuclidine was also explored ( Figure 3. 12 b ). However, such transition states were disfavored by a minimum of 8 kcal/mol. Similarly, alternative transition states for pathways where the amide is not involved in directing the methanol or those that involved stepwise addition via carbenium or chloriranium ion intermediate s were disfavored over the propo sed 3 - TS1 . The above transition states were complemented with an experimental exploration into the activation energy barriers using Eryring plots ( Figure 3. 13 ). The re action was studied under a temperature range of - 36 to - 12 ° C. The low enthalpic barrier for the 1.7 Å 2.4 Å 2.2 Å 2.2 Å Explicit solvents used as hydrogen bond partners Quinuclidine - mediated chlorenium ion transfer Low enthalpic barrier H = 4.2 kcal/mol (favored) High enthalpic barrier H = 12.5 kcal/mol (disfavored) a. Transition state 1 ( 3 - TS1 ) b. Transition state 2 ( 3 - TS2 ) 2.2 Å 2 .1 Å 2.3 Å 1.7 Å 160 chloroetherification process ( - 7.28 kcal/mol) were in alignment with the computational findings. Entropy was found to be the predominant contributor to the ove rall free energy barrier further supporting the highly organized transition states displayed in Figure 3. 12 a. The selectivities were found to be negligibly impacted by in the temperature range studied for the eyring plot. T (°C) k obs ln(k/T) (kcal/mol) (kcal/mol) (kcal/mol) - 31.8 4.05E - 04 - 13.30 - 10.46 7.28 17.74 - 36.3 2.95E - 04 - 13.60 - 10.26 7.28 17.55 - 27.5 5.91E - 04 - 12.94 - 10.64 7.28 17.93 - 24.1 7.71E - 04 - 12.68 - 10.79 7.28 18.08 - 18.5 1.02E - 03 - 12.43 - 11.03 7.28 18.32 - 12.1 1.32E - 03 - 12.20 - 11.31 7.28 18.60 Figure 3. 13 Eyring plot . Dissecting the enthalpic vs entropic contribution for chloroetherification using an Eyring plot at 10 mol% catalyst loading. 3.6 Summary Detailed in this article is a comprehensive mechanistic investigation of (DHQD) 2 PHAL catalyzed chloroetherification of alkene amides. The study used a combination of modern kinetic techniques, NMR spectroscopy, isotope effects and computation s to reveal a novel mechanism of chloroetherification of a lkene amide system. The kinetic studies revealed rate to have a first order dependence on the concentration of alkene and a zeroth order dependence on the concentration of DCDMH 161 under the originally reported reaction condition. This behavior stems from the preferential binding of the DCDMH to the catalyst, resulting in the chlorinating reagent saturating the catalyst. The first order dependence on methanol and the observed inverse kinetic isotopic effect point to a concerted addition of the nucleophile for chloroetherification. Further exploration revealed a zeroth - order dependence in catalyst when the reactions were run under the prior reported conditions (10 mol% catalyst). The study has illustrated two distinct rate laws for the reaction under two differe nt catalyst loading regimes. These discoveries have demonstrated that reaction efficacy is preserved even after a 10 - fold lowering in catalyst loading, improving upon the original reported conditions. The study has also dissected out several on - and off - cy cle equilibria modulating the reactivity of the species involved in the reaction, such as inhibition by the by - product MCDMH. The spectroscopic and computational investigation found the chlorenium ion to take a completely novel route to reach the alkene fr om its source by shuttling via the quinuclidine moiety of the catalyst. Finally, the amide functional group appears to activate the methanol for its nucleophilic attack via hydrogen bonding. These mechanistic discoveries in (DHQD) 2 PHAL catalyzed chloroeth erification stand in contrast to the prior mechanistic report of chlorolactonization in almost every aspect. Furthermore, the mechanistic differences between these two ostensibly similar reactions encourage vigilance in extrapolating mechanistic conclusion s. Consistent with earlier findings of selectivity in version, 13 t hes e differences can be associated to the drastic changes in the nature o f solvent (polar protic vs non - polar) and substrate (alkene amide vs alkene carboxylic acid) functional groups in the two reactions. Though the greatest lesson of this work is to avoid facile generalization of mechanisms from one reaction to 162 another, we ho pe that the present account will prove valuable in analysis and reaction design, especially for the fast - growing family of (DHQD) 2 PHAL - catalyzed alkene amide chlorofunctionalizations, which are typically run under similar media and conditions. 3.7 Experimental detail 3.7.1 General remarks Unless otherwise mentioned, solvents were purified as follows. Molecular sieves (4 Å) were dried at 160 °C under 0.25 mtorr pressure prior to use. CHCl 3 (amylene stabilized) was purchased from Sigma Aldrich and inc ubated over 4 Å MS for 48 h prior to use. Toluene and CH 2 Cl 2 were dried over CaH 2 , whereas THF and Et 2 O were dried over sodium (dryness was monitored by colorization of benzophenone ketyl radical); all were freshly distilled prior to use. Deuterated solvents such as acetonitrile - d 3 , methanol - d 4 and CDCl 3 were purchased from Sigma Aldrich but were dried fur ther over 4 Å molecular sieves for 48 h prior to use . All NMR spectra were obtained using an autosampler - equipped Agilent 500 MHz NMR , Varian Inova 500 MHz NMR , and Varian Inova 600 MHz NMR instruments and referenced using the residual 1 H peak from the deu terated solvent . All kinetic experiments were run on the Varian Inova 500 MHz NMR and Varian Inova 600 MHz NMR instruments fitted with chillers. Infrared spectra were measured on a JASCO 6600 FT - IR fitted with an ATR probe. Waters 2795 (Alliance HT) instru ment was used for HRMS (ESI) analysis with polyethylene glycol (PEG - 400 - 600) as a reference. Column chromatography was performed using Silicycle 60Å, 35 - 75 µm silica gel. Pre - coated 0.25 mm thick silica gel 60 F254 plates were used for analytical TLC and visualized using UV light, iodine, potassium permanganate stain, p - anisaldehyde stain or phosphomolybdic acid in EtOH stain. 163 Chloro functionalization reactions were performed in the absence of light. 1,3 - Dichloro - 5,5 - dimethylhydantoin (DCDMH) and 3 - chloro - 5,5 - dimethylhydantoin (MCDMH) were recrystallized prior to use. Alkenoic amide 3 - 3 was prepared as described previously. 17 All other commercially available reagents and solvent s were used as received unless otherwise mentioned. 3.7.2 Kinetic Studies 3.7.2.i Experimental procedure The NMR probe was cooled to - 32 °C and allowed to equilibrate for at least for 1 hour prior to use. The volume of reaction mixture in each NMR experime nt was 0.8 mL after addition of all the substrates, reagents, catalyst, internal standard, additive or additional solvent. A 0.16 M stock solution of the internal standard, 1,1,2,2 - tetrachloroethane (TCE), was prepared by dissolving 34 µl (0.32 mmol) of TC E in 1966 µL of the solvent (deuterated methanol:acetonitrile, 3:7 v/v). From this solution, 0.2 mL was used for each experiment to attain the final molarity of 0.04 M. A 0.16 M stock solution of the alkene 3 - 3 , was prepared by dissolving 0.32 mmol (79.4 m g) of alkene in 2 mL of the solvent, from which an appropriate amount was used for each experiment. Similarly, a 0.016 M stock solution of the (DHQD) 2 PHAL was prepared by dissolving 0.032 mmol (24.9 mg) of the catalyst in 2 mL of the solvent, from which an appropriate amount was used for each experiment. The stock solution of DCDMH was prepared fresh in small batches before each experiment by dissolving 0.128 mmol (25.2 mg) of DCDMH in 0.4 mL of solvent, which was frozen immediately until use. From the stoc k solution, appropriate amounts of alkene, internal standard and catalyst were syringed into a dry NMR tube under nitrogen. This NMR tube was placed in the temperature equilibrated NMR and was subsequently tuned, locked and shimmed to collect a pre - reactio n 164 spectrum. Further spectral collection parameters for the kinetic study were set at this point. The sample was then ejected and immediately placed in - 78 ° C bath. The appropriate amount of DCDMH was then added from its thawed solution to start the reactio n. The entire mixture was shaken to homogeneity, wiped, and placed back in the - 32 °C NMR. The NMR was quickly locked and shimmed and the array of spectral collection was begun. The exact time of addition of the DCDMH to the reaction mixture was noted down in seconds and was marked as the start of the reaction. The time of each NMR spectrum collected during the experiment was normalized to this exact time of DCDMH addition to accurately define the starting point of every reaction. 3.7.2.ii Kinetic analysis protocols The spectra collected were analyzed using the MestReNova software package. Each spectrum was phased, and baseline corrected prior to integration. Figure 3. 14 a depicts an example of the concentration profile extracted from the spectral analysis of a kinetic experiment run under the standard condition. Vinylic proton of the alkene 3 - 3 (H a ) was chosen for analysis of its concentration, the corresponding proton for the product 3 - 4 (H b ) was used to calculate the product concentration ( Figure 3. 14 b). Figure 3. 14 b also depicts a pair of replicate experiments (Exp 1 and 2 are replicates) illustrating reproducibility of the obtained concentration profile. 165 Figure 3. 14 Kinetic study procedures . (a) Sample NMR spectra from kinetic study used to generate the concentration profile. (b) Concentration profile of alkene and product. In accord with the reaction progre ss kinetic analysis (RPKA) methods, 23, 24 experiments were conducted to establish the orders of the alkene and the DCDMH. T he amounts of DCDMH were chosen as 0.02 and 0.04 M ( Table 3. 3 ), with the alkene being the limiting substrate. Similarly, experiments were conducted to show the effect of any product inhibition or catalyst deactivation ( Table 3. 4 ). A set of experiments with varying concentrations of catalyst enabled the a. H a H b TCE b . 166 determination of catalyst reaction order ( Table 3. 5 ). The variable time normaliz ed analysis (VTNA) protocols were used to analyze the reaction kinetics . 26 - 28 Based on VTNA, visual overlay of the different datasets enables the determination of the order of each of these components. These plots will be shown in the followi ng sections. Methanol, being a solvent component, is expected to have a pseudo order impact on rate. The order of methanol was determined from the rate constant measurements from a series of reactions run with varying concentration of methanol. This proced ure will be discussed in more detail in following sections. Two sets of experiments were conducted to determine the order of the alkene, DCDMH and methanol. The first set was run with 10 mol% catalyst (DHQD) 2 PHAL and second set with 1 mol% (DHQD) 2 PHAL. In all studies, 0.04 (M) TCE was used as an internal standard. 3.7.2. iii Measuring concentration of DCDMH and MCDMH C oncentration s of the alkene 3 - 3 or the product 3 - 4 could be easily determined from peak integration against the internal standard (TCE) . Howev er, since DCDMH and MCDMH displayed a combined averaged peak ( Figure 3. 15 a, also discussed in the main text), measuring th eir concentration s required a separate approach . External calibration curves had to be generated prior to every experiment to quantify their con centrations ( Figure 3. 15 b). Each calibration curve related the averaged chemical shift of the methyl peaks of DCDMH and MCDMH at varying mole fraction ( X ) ratios totalin g 0.08 M for their combined concentration, measured under the corresponding reaction conditions. This allowed their actual concentrations to be determined from the observed chemical shift during the course of the reaction. A reasonable assumption here is t hat the total 167 concentration of DCDMH + MCDMH during the reaction course is the same as the initial concentration of DCDMH for that reaction. An example is shown below ( Figure 3. 15 ). Table 3. 2 Calibration curve table for a reaction using initial concentration of 0.08 M for DCDMH DCDMH (M) MCDMH (M) X DCDMH ppm) 0 0.08 0 1.3702 0.08 0 1 1.4531 0.04 0.04 0.5 1.4108 0.07 0.01 0.875 1.4403 0.06 0.02 0.75 1.4312 0.05 0.03 0.625 1.4224 Figure 3. 15 Quantifying concentration of DCDMH . (a) Displayed above is the change in chemical shift of the averaged methyl peak of DCDMH and MCDMH over the course of the reaction. (b) Example of a calibration curve used to quantify DCDMH and MCDM concentrations for the kinetic study . a . b. 168 3.7.3 Kinetic analysis results 3.7.3.i Order of alkene 3 - 3 and DCDMH in 10 mol% (DHQD) 2 PHAL The following experiments shown in Table 3. 3 were utilized to find the order of the alkene 3 - 3 and DCDMH using VTNA protocols. Table 3. 3 Different excess ex periments for VTNA studies Exp 3 - 3 (M) DCDMH (M) (DHQD) 2 PHAL (mol%) Excess (M) A 0.0 4 0.0 8 10 0.0 4 B 0.0 6 0.0 8 10 0.0 2 C 0.0 4 0.0 6 10 0.02 Figure 3. 16 Finding Order of alkene amides 3 - 3 at high catalyst loading . The plot represents the VTNA analysis of a pair of different excess experiments conducted to find the order of alkene 3 - 3 . The plots corresponding to experiments A and B overlay when the alkene term in the time - normalized axis is raised to the power of 1.1 , revealing it to be the correct order for the alkene . The time normalized ( x - axis) axis utilized for VTNA analysis represent the time integral form of the concentration of the respective species. 26 For the above case, it is represented by: eq ( 3. 5) 169 Figure 3. 17 Finding order of DCDMH at high catalyst loading . The plot represents the VTNA analysis of a pair of different excess experiments conducted to find the order DCDMH. The plots corresponding to experiments A and C overlay when th e DCDMH term in the time - normalized axis is raised to the power of 0.1, revealing it to be the order for DCDMH . The time normalized axis is represented by: eq ( 3. 6) 170 3.7.3.ii Same excess experiments The experiments in Table 3. 4 were utilized to determine the effect of product inhibition or catalyst deactivation usi ng VTNA protocols . Table 3. 4 Same excess experiments for VTNA studies Exp 3 - 3 (M) DCDMH (M) (DHQD) 2 PHAL (mol%) Excess (M) Additive (M) B 0.0 6 0.0 8 10 0.0 2 - C 0.0 4 0.0 6 10 0.02 - D 0.0 4 0.0 6 10 0.0 2 0.02, MCDMH Figure 3. 18 Same excess experiments . The above are a set of same - excess experiments. The non - overlay of the concentration vs time profiles of experiments B and C indicates either catalyst deactivation or product inhibition during the reaction course. Overlay of experiment D, which is identical to experiment C with the exception of the added MCDMH, indicates product inhibition by MCDMH . 171 3.7.3.iii Order of (DHQD) 2 PHAL in the 2.5 - 10 mol% loading regime The followi ng experiments in Table 3. 5 were utilized to determine the order of the catalyst using VTNA protocols. Table 3. 5 Experiments with different catalyst concentration Exp 3 - 3 (M) DCDMH (M) (DHQD) 2 PHAL (mM) Excess (M) A 0.0 4 0.0 8 4.0 (10.0 mol%) 0.0 4 E 0.0 4 0.0 8 2.0 (5.0 mol%) 0.0 4 F 0.0 4 0.0 8 1.0 (2.5 mol%) 0.0 4 Figure 3. 19 Order of catalyst (DHQD) 2 PHAL at high catalyst loading . The plot represents the VTNA analysis of a series of experiments with varying concentrations of the catalyst (DHQD 2 PHAL to find its order. The plots corresponding to experiments A, E, and F overlay when the catalyst term in the time - normalized axis is raised to the power of 0.15, revealing its order to be nearly zero . 172 3.7.3.iv Order of methanol at 10 mol% (DHQD) 2 PHAL For a general rate law equation, Rate = k obs [ 3 - 3 ] x [DCDMH] y where the [methanol] is much greater than [alkene] or [DCDMH], the order of the methanol will be included in the observed rate constant k obs = k 3 OH] z . To extract the order of methanol from the observed rate constant ( k obs ) the following steps were taken . 1) To determine the order of methanol a series of four kinetic experiments were run with different concentrations of methanol ( Table 3. 6 ). For each experiment different methanol - acetonitrile ratios were used while maintaining a constant total solvent volume of 0.8 mL. This held the concentration of the reaction components identical in each case (0.04 M alkene, 0.08 M DCDMH and 4.0 mM (DHQD) 2 PHAL). Table 3. 6 Experiments with different concentration of methanol Exp Methanol (M) k obs l n [ CH 3 OH ] ln( k obs ) 1 4.92 1.02E - 03 1.59 - 6.8 9 2 6.15 1.2 3 E - 03 1.8 2 - 6.6 9 3 8.62 1.72E - 03 2.15 - 6.36 4 9.8 5 1.93E - 03 2.2 9 - 6.2 5 2) The concentration profile for each of these experiments were fitted with a 6 th order polynomial. Rate was determined from the derivative of this 6 th order polynomial ( Figure 3. 20 shows the concentrat ion profile for experiment 2 of Table 3. 6 ). 173 Figure 3. 20 Concentration profiles used to find rate constants . An example of the concentration profile of alkene 3 - 3 fitted with a 6 th order polynomial, whic h will be subsequently used to determine rate as a function of reaction time . 3) Based on the rate equation, rate = k [ 3 - 3 ] x [DCDMH] y , rate is expected to be linear function of the variable [ 3 - 3 ] x [DCDMH] y . Thus, the slope of the rate vs [ 3 - 3 ] x [DCDMH] y plot is expected to yield the observed rate constant ( k obs ). The following is an example of such a plot with the slope of the linear fit used as the rate constant ( Figure 3. 21 ). Figure 3. 21 Rate profiles used to extract the rate constants . An example of rate vs [ 3 - 3 ] x [DCDMH] y plot used to extract the observed rate constant . 174 4) The order of methanol can now be obtained in two ways. First by plotting the concentration of methanol against the rate constant ( k obs ) ( Figure 3. 22 a ). A linear change of k obs with methanol would indicate a first order effect. Second , a log of the obtained rate constant against the log of the concentration of the methanol ( Figure 3. 22 b ). In this case the slope of the trend would indicate the methanol order. This was found to be 0.9. Figure 3. 22 Finding order of methanol (nucleophile) at high catalyst loading . (a) Plot of k obs vs CH 3 OH to find the order of methanol. (b) Plot of ln k obs vs ln[CH 3 OH] to fin d the order of methanol. a. b . 175 3.7.3.v Order of alkene 3 - 3 and DCDMH in 1 mol% (DHQD) 2 PHAL The following experiments shown in Table 3. 7 were utilized to find the order of the alkene 3 - 3 and DCDMH using VTNA protocols. Table 3. 7 Different excess experiments for VTNA studies Exp 3 - 3 (M) DCDMH (M) (DHQ D) 2 PHAL (mol%) Excess (M) G 0.0 4 0.0 8 1 0.0 4 H 0.0 6 0.0 8 1 0.0 2 I 0.0 4 0.0 6 1 0.02 Figure 3. 23 Finding order of alkene amide 3 - 3 . The plot represents the VTNA analysis of a pair of different excess experiments conducted to find the order of alkene 3 - 3 . The plots corresponding to experiments G and H overlay best when the alkene term in the time - normalized axis is raised to the power o f 0.9, which is taken to be the reaction order of the alkene . The time normalized axis is represented by: eq ( 3. 7) 176 Figure 3. 24 Finding order of DCDMH . The plot represents the VTNA analysis of a pair of different excess experiments conducted to find the order of DCDMH. The plots corresponding to experiments G and I overlay when the DCDMH term in the ti me - normalized axis is raised to the power of 0.8, which is taken to be the order of the DCDMH . The time normalized axis is represented by: eq ( 3. 8) 177 3.7.3.vi Order of (DHQD) 2 PHAL in the 2.5 - 10 mol% loading regime The following experiments in Table 3. 8 were utilized to determine the order of the catalyst using VTNA pr otocols. Table 3. 8 Experiments with different catalyst concentration Exp 3 - 3 (M) DCDMH (M) (DHQD) 2 PHAL (mM) Excess (M) G 0.0 4 0.0 8 0.4 (1.0 mol%) 0.0 4 J 0.0 4 0.0 8 0.2 (0.5 mol%) 0.0 4 K 0.0 4 0.0 8 0.1 (0.25 mol%) 0.0 4 Figure 3. 25 Finding order of (DHQD) 2 PHAL at low catalyst loading . The plot represents the VTNA analysis of a series of experiments with varying concentrations of the catalyst (DHQD) 2 PHAL to find its order. The plots corresponding to experiments G, J, and K overlay when the catalyst term in the time - normalized axis is raised to the power of 1.0 . 178 3.7.3.vii Order of methanol at 10 mol% (DHQD) 2 PHAL The order of methanol was determined using the same procedure as depicte d in Section iv. The following represents the final two plots leading to the order of methanol from k obs . Figure 3. 26 Finding order of methanol (nucleophile) at low catalyst loading . (a) Plot of k obs vs CH 3 OH to find the order of methanol. (b) Plot of ln k obs vs ln[CH 3 OH] to find the order of methanol. a. b. 179 3.7.3.viii Empirical rate laws in different catalyst loading regime The following represent the rate law equations at the two catalyst concentration regime: Rate l aw equation a t high catalyst loading of 2.5 - 10.0 mol% eq ( 3.9 ) Rate law equation at lower catalyst loading of 0.25 - 1.0 mol% catalyst eq ( 3.10 ) 180 3.7.3.ix Effect of additives To explore possible binding of amide to the catalyst (DHQD) 2 PHAL, the reaction was doped with 0.5 equivalent of alkane amide 3 - 5 (experiment L, Table 3. 9 ). This additive had a negligible impact of the kinetic profile of the reaction indicating that amides 3 - 3 or 3 - 5 do not competitively bind to the catalyst, in contrast to the behavior of MCDMH. Table 3. 9 Experiments with different catalyst concentration Exp 3 - 3 (M) DCDMH (M) (DHQD) 2 PHAL (mol%) Additive A 0.04 0.08 1 0 - L 0.04 0.08 10 0.02 (M) of 3 - 5 Figure 3. 27 Effect of additive on chloroetherification . Kinetic profiles of (DHQD) 2 PHAL catalyzed chloroetherification with and without the additive 3 - 5 . 181 3.7.3.x Kinetic isotopic effect studies The kinetic isotopic effect (KIE) of deuterium at the ether - forming carbon was measured using competition experiment protocols well - established in literature. 33 A ~1:1 mixture of alkene amide 3 - 3 and 3 - 3 - D (0.02 M, each) were subjected to the typical reaction conditions used for kinetic studies (0.08 M DCDMH, 4 mM or 0.4 mM (DHQD) 2 PHAL in a 3:7 mixture of methanol - acetonitrile at - 32 °C). To al low only partial conversion, the reaction was quenched after 30 min using saturated aqueous sodium thiosulfate. The aqueous layer was extracted with dichloromethane (2 mL x 3). The combined organic layer was evaporated to obtain the crude product. The crud e solid was passed through a short bed of silica with ethyl acetate - hexane (1:1) to filter out the catalyst and hydantoin by - products. This provided a mixture of products 3 - 4 and 3 - 4 - D , along with the unreacted alkene amides 3 - 3 and 3 - 3 - D . The pre - reaction and the post - reaction isotopic mixtures were analyzed using 1 H NMR to measure the change in isotopic composition using equation 3.11. TCE was used as internal standard and methanol - d 4 :acetonitrile - d 3 (3:7) was used as the NMR solvent of choice. Figure 3. 28 Kinetic isotopic effect study . Competition between isotopes of alkene amide 3 - 3 revealed an inverse kinetic isotopic effect on the (DHQD) 2 PHAL catalyzed chloroetherification reaction. 182 eq ( 3.11 ) Where F H , R f and R 0 are: eq ( 3.12 ) eq ( 3.13 ) eq ( 3.14 ) At high catalyst loading of 10.0 mol%: kinetic isotopic effect ( k H / k D ): 0.89 At low catalyst loading of 1.0 mol% kinetic isotopic effect ( k H / k D ): 0.87 183 3.7.4 Kinetic model The kinetic model for the proposed catalytic cycle is illustrated below: Figure 3. 29 Kinetic model. Reaction pathways for the proposed kinetic model. DCDMH - (DHQD) 2 PHAL binding equilibrium to form the active halogenating complex: - or - eq ( 3.15 ) MCDMH - (DHQD) 2 PHAL binding equilibrium to form the inactive complex: - or - eq ( 3.16 ) Total concentration of the catalyst: eq ( 3.17 ) Using eq ( 3.15 ) , eq ( 3.16 ) , and eq ( 3.17 ) - or - eq ( 3.18 ) Formation of I 3 is hypothesized to be a slow, reversible pre - catalytic step. This implies k 1 << k 2 or k 3 , which results in the rapid consumption of I 3 as it is form ed . Therefore, rather than a true equilibrium, the low concentration of I 3 is in a steady state. This leads to the following steady state approximation: eq ( 3.19 ) 184 Using equations ( 3.15 ) and ( 3.19 ) eq ( 3.20 ) Rearranging the above equation, we have, eq ( 3.21 ) Rate of product formation based on the proposed catalytic cycle is given by: eq ( 3.2 2 ) Using eq uations ( 3.21 ) and ( 3.15 ) to replace [ I 3 ] and [ I 1 ] eq ( 3.23 ) Substituting in eq ( 3.18 ) to eq ( 3.23 ) provides the final equation: eq ( 3.24 ) Equation ( 3.24 ) represents the rate law equation governing the proposed catalytic cycle. This equation is consistent with variation of empirical rate equations at differing concentration s of catalyst. Note that equation ( 3.24 ) has a denominator term for MCDMH, indicating that the presence of MCDMH slows down the reaction rate. This accounts for the inhibitory activity of MCDMH from its competitive binding to (DHQD) 2 PHAL. The denominator o f the derived rate equation ( 3.24 ) contains a catalyst concentration term. Thus, at a relatively high catalyst loading the k 3 K 1 [ C ] 0 [ D ] term becomes the dominant factor in the denominator. This reduces the above rate equation to the approximate form: eq ( 3.25 ) 185 This now explains the observed rates showing near zeroth order dependence on [ catalyst ] and [ DCDMH ] , but first order on [ methanol ] and [ alkene 3 - 3 ] at high [ catalyst ] . The reverse is true in the low catalyst regime , where the k 3 K 1 [ C ] 0 [ D ] term is now negligible, leading to a pparent first order dependence on [ catalyst ] and a positive order (0.8) for [ DCDMH ] . This reduces the above rate equation 3.24 to the approximate form: eq ( 3. 26 ) 186 3.7.5 1 H NMR studies 1 H NMR studies were conducted at 25 °C, in acetonitrile - d 3 (0.8 mL total volume) as the deuterated solvent with 0.04 M of the reagents or catalyst (DCDMH, MCDMH and (DHQD) 2 PHAL). A 0.16 M stock solution of the DCDMH, MCDMH and (DHQD) 2 PHAL was prepared by dissolving 0.32 mmol of each species in 2 mL of deuterated solvent. Appropriate volumes of reagents (0.2 mL aliquots for 0.04 M final concentration) from these stock solutions, were syringed into a clean, dry NMR tube under nitrogen. 0.32 mmol (or 34 µ L, equals 10 equiv. to mimic reaction conditions ) of 1,1,1,3,3, 3 - hexafluoroisopropanol (HFIP) was added to each sample directly using a gas tight micro syringe, as the protic additive (as a replacement for methanol). Total volume of each sample solution was adjusted to 0.8 mL by adding the appropriate amount of the de uterated solvent. Each spectrum was a result of 16 scan accumulating with 10 seconds of recycle delay. The spectra with mixed hydantoin and catalyst (Exp 5 - 8, Table 3. 10 ) were not labeled due to broadening of peaks. Table 3. 10 Experiments with different catalyst concentration Exp Hydantoin (M) HFIP (M) (DHQD) 2 PHAL (M) 1 0.04 M , DCDMH 0.4 - 2 0.04 M , M CDMH 0.4 - 3 0.04 M , DMH 0.4 - 4 - 0.4 0.04 5 0.04 M , DCDMH 0.4 0. 0 4 6 0.0 8 M , DCDMH 0.4 0. 0 4 7 0.04 M , M CDMH 0.4 0. 0 4 8 0.0 8 M , M CDMH 0.4 0. 0 4 187 3.7.5.i 1 H NMR of DCDMH (Exp 1, Table 3.10) HFIP (C - H) HFIP (O - H) DCDMH CH 3 CN 188 3.7.5.i i 1 H NMR of MCDMH (Exp 2, Table 3.10) MCDMH CH 3 CN HFIP (C - H) HFIP (O - H) 189 3.7.5.i ii 1 H NMR of DMH (Exp 3, Table 3.10) 190 3.7.5.i v 1 H NMR of (DHQD) 2 PHAL (Exp 4, Table 3.10) a b d e c f TCE HFIP h j k m n CH 3 CN 191 3.7.5. v 1 H NMR of DCDMH + (DHQD) 2 PHAL 1:1 mixture (Exp 5, Table 3.10) HFIP C H 3 CN TCE 192 3.7.5. v i 1 H NMR of DCDMH + (DHQD) 2 PHAL 2:1 mixture (Exp 6, Table 3.10) HFIP CH 3 CN TCE 193 3.7.5. vi i 1 H NMR of MCDMH + (DHQD) 2 PHAL 1:1 mixture (Exp 7, Table 3.10) HFIP CH 3 CN TCE 194 3.7.5. vii i 1 H NMR of MCDMH + (DHQD) 2 PHAL 2:1 mixture (Exp 7, Table 3.10) HFIP TCE CH 3 CN 195 3.7.5.i x Spectra i - viii (Exp 1 - 8, Table 3.10) gem - dimethyl region Figure 3. 30 Chemical shift change of chlorohydantoins in presence of catalyst . The above overlay of spectra demonstrates the change in chemical shift of the methyl protons of DCDMH and MCDMH with various equivalents of (DHQD) 2 PHAL indicat ing a reversible binding (Table 3.10 , Exp 1 - 8). Also note the doubling of the two methyl signals in the presence of the catalyst, indicates the diastereotopic environment experienced by them inside the chiral pocket . Exp 1 Exp 2 Exp 3 Exp 5 Exp 6 E xp 7 Exp 8 196 3.7.6 DOSY NMR studies 3.7.6.i Sample prepa ration DOSY NMR studies were conducted at 0 °C in acetonitrile - d 3 (0.8 mL total volume of the sample) as the deuterated solvent. The NMR probe was cooled to 0 °C and allowed to equilibrate for at least 1 h prior to use. S tock solution s (0.16 M) of DCDMH, M CDMH and (DHQD) 2 PHAL each were prepared by dissolving 0.32 mmol of each species in 2 mL of deuterated solvent. Appropriate volumes of reagents (0.2 mL for 0.04 M final concentration) from these stock solutions were syringed into a clean, dry NMR tube under nitrogen. 1,1,1,3,3,3 - hexafluoroisopropanol (HFIP , 0.32 mmol or 34 µ L ) was added to each sample directly using a gas tight micro syringe as the protic additive (as a replacement for methanol). Total volume of each sample was adjusted to 0.8 mL by add ing the appropriate amount of the deuterated solvent. The pulse sequence used for the DOSY experiment is dbppste_cc (Bipolar Pulse Pair Stimulated Echo with convection com pensation with 15 increments, gradient strength incremented from 2.4 to 56.6 G/cm). 49 Each spec trum was a collection of 16 scans, with 10 second recycle delay, 20 ms diffusio n delay, and 1.0 - 1.4 ms diffusion gradient length. Gradient strengths, diffusion delays , and gradient lengths were set such that the signal intensity of the spectrum with the hi ghest gradient power was 10 - 20% of that of the spectrum with the lowest gradient power. 197 3.7.6.ii DOSY analysis The DOSY NMRs were analyzed using MestReNova 12.0 and 14.1. The diffusion coefficients for the chlorohydantoins ( DCDMH and MCDMH ) were obtained from mono - exponential fits. The coefficients from the mono - exponential were normalized against the diffusion of acetonitrile , as an internal standard to compensate for interexperimental differences). 42 Table 3. 11 Experiments with different catalyst concentration Exp Chlorohydantoin (M) HFIP (M) (DHQ D) 2 PHAL (M) Gradient length (ms) Chlorohydantoin NMR 1 H NMR (ppm) DOSY coefficient* 1 0.04 M , DCDMH 0.4 - 1.0 1.516 0.9375 2 0.04 M , DCDMH 0.4 0.04 1.2 1.343 0.5625 3 0.04 M , MCDMH 0.4 - 1.4 1.440 0.5738 4 0.04 M , MCDMH 0.4 0.04 1.3 1.300 0.4546 * DOSY coefficients were normalized with respect to the solvent acetonitrile set to 1.0 198 3.7.6.iii DOSY NMR spectra of DCDMH (Exp 1, Table 3.11) 199 3.7.6.iv DOSY NMR spectra of DCDMH - (DHQD) 2 PHAL (Exp 2, Table 3.11) 200 3.7.6.v DOSY NMR spectra of MCDMH (Exp 3, Table 3.11) 201 3.7.6.vi DOSY NMR spectra of MCDMH - (DHQD) 2 PHAL (Exp 4, Table 3.11) 202 3.7.6.vii DOSY analysis to determine bound ratio Under the assumption that chlorohydantoins (DCDMH and MCDMH) exist in two states in p resence of the catalyst (DHQD) 2 PHAL (1:1 bound and an unbound state) , o ne may derive the approximate bound to unbound ratio of chlorohydantoin in these 1:1 chlorohydantoin:catalyst mixture s . This is done by fitting the average diffusion decay of the chlorohydantoin with a linear combination of two exponential s (eq 3.27) , one corresponding to the catalyst from the 1:1 complex and one corresponding to the ( S 0A and S 0B ) of the linear combination of these two exponentials approximately represents the free to bound ratio. A modified version of the Stejskal - Tanner equation, 50 which compensates for non - uniform pul se field gradients, was used in the single exponential DOSY analyses. The necessary calibrations and equations were implemented as provided by the instrument vendor, Varian - Resolution Diffusion - Ordered Spectroscopy (DOSY) Use Biexponential fitting of the decay of hydantoin peaks in the hydantoin - catalyst mixture was performed using a slight modification of the standard Stejskal - Tanner equatio n : eq ( 3. 27 ) S is the signal amplitude, S 0 is the echo amplitude for no diffusion, D is the diffusion coefficient, is the gradient pulse width, is the gyromagnetic ratio, g is the gradient amplitude, is the diffusion time corrected for the effects of finite gradient pulse width, and a and b are the fractional contribution from the two diffusing species. 203 Prior to DOSY coefficient calculation, 1.0 Hz line broadening, zero - filling to 64k data points, and Whittaker Smoother bas eline correction as employed in Mnova 14.1 were performed on all data. DOSY coefficients were calculated using the m aximum peak calculation for relevant peaks including a biexponential calculation for the reagent, chlorohydantoins (DCDMH and MCDMH). 51 The diffusion of the deuterated solvent, CD 3 CN, was used as an internal standard and diffusion values were adjusted to compensate for differences in CD 3 CN between experiments. The biexponential is calculated assumi ng that the reagent diffusion is a combination of diffusion as the free reagent and as that bound to the catalyst. The diffusion coefficients for the biexponential were set from the diffusion coefficient of the reagent without catalyst and the average of t he aromatic diffusion coefficients of the catalyst in the presence of the reagent. The relative ratios between the two exponentials were free variables, allowed to be determined by MNova. The resulting biexponential is a good fit giving the ratios of bound to free in Table 3. 12 . Table 3. 12 Extracting the free - to - bound ratio from a biexponential fitting Exp Chlorohydantoin ( M ) (DHQD) 2 PHAL ( M ) S 0A S 0B Free to bound ratio of chlor o hydantoins 1 0.04 M , DCDMH - - - 100:0 2 0.04 M , DCDMH 0.04 14.79 10.38 59:41 3 0.04 M , MCDMH - - - 100:0 4 0.04 M , MCDMH 0.04 26.26 31.14 46:54 T he biexponential coefficient ( S 0A and S 0B ) r epresents the bound vs. free ratio. Another interpretation could be that it's purely free reagent on top of only catalyst and a biexponential fit is not appropriate. This would make sense if both peaks were superimposed and had similar linewidths making deconvolution i mpossible. Since the data shows that the catalyst has much broader peaks than that of the reagent , indicating 204 slower dynamics (larger, slower moving molecules or assemblies have shorter T 2 time constants and broader peaks), the bound vs. free is the more credible model. The effect of the 1,1,1,3,3,3 - hexafluoroisopropanol (HFIP) was not addressed in these calculations. The HFIP is present in excess (10 equiv ) for all experiments and is assumed that its influence , if any, on binding and diffusion is averaged out. 205 3.7.7 General procedure for c omputational studies General remarks : All calculations presented in this article were performed using (Spartan 18; Wavefunction Inc.: Irvine, CA) software package. Density functional theory was used to optimize all structures at the B3LYP/6 - 31G* level. 45, 47, 48 Chlorohydantoin - quinuclidine binding enthalpies : Structures were optimized using d ensity functional theory at the B3LYP/6 - 31G* level in the gas phase. The optimized structures were then reoptimized using the SM8 polarizable continuum solvent model 40 with acetonitrile as the solvent. Vibrational analysis was performed to ensure the absence of imaginary frequencies for optimized minima. Binding enthalpies were calculated f rom the enthalpic differences of the respective bound and unbound species. (DHQD) 2 PHAL transition states and substrate - bound complexes : Both transition state and substrate - bound complex structures were optimized using d ensity functional theory at the B3LYP /6 - 31G* level in the gas phase. S tructural optimization was followed (transition structure , with a single imaginary frequency ) or a minimum (no imaginary frequency) . Exp licit solvent methanol molecules were utilized as hydrogen bond partners of DCDMH . Halenium affinity calculations : Structures used for halenium affinity calculations were optimized using d ensity functional theory at the B3LYP/6 - 31G* level in the gas phase. The optimized structures were then reoptimized using the SM8 model with acetonitrile as the solvent of choice. Vibrational analysis was performed to ensure the absence of imaginary frequencies for optimized minima. 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