Raycroft Mark A R, Racine Karl É, Rowley Christopher N, Keillor Jeffrey W
Department of Chemistry and Biomolecular Sciences , University of Ottawa , Ottawa , ON K1N 6N5 , Canada.
Department of Chemistry , Memorial University of Newfoundland , St. John's , NL A1B 3X7 , Canada.
J Org Chem. 2018 Oct 5;83(19):11674-11685. doi: 10.1021/acs.joc.8b01638. Epub 2018 Sep 19.
A mechanistic study was undertaken to elucidate the reaction pathways for thiol addition to N-methylmaleimide in water. We used linear free energy relationships, solvent kinetic isotope effects (SKIEs), activation parameters, and ionic strength effects to probe the nature of the rate-limiting transition states. Calculations were also employed and assisted in illuminating three possible mechanistic pathways: (1) stepwise addition with rate-limiting nucleophilic attack, (2) stepwise addition with rate-limiting proton transfer, and (3) concerted addition with nucleophilic attack and proton transfer occurring concurrently. Alkyl thiolate addition exhibits β= 0.4, small negative Δ S values, prominent ionic strength effects, and no evidence of general acid catalysis, consistent with pathway 1. Aryl thiolate addition exhibited β = 1.0, large negative Δ S values, normal primary SKIEs, general acid catalysis, and negligible sensitivity to ionic strength, consistent with pathways 2 and 3. The experimental and computational data depict an energy surface where ground state effects, namely the energy of the alkyl/aryl thiolate, play a major role in shaping the governing pathway. Application of these findings to bioconjugation chemistry is also discussed.
开展了一项机理研究，以阐明在水中硫醇加成到N-甲基马来酰亚胺的反应途径。我们使用线性自由能关系、溶剂动力学同位素效应（SKIEs）、活化参数和离子强度效应来探究限速过渡态的性质。还进行了计算，有助于阐明三种可能的机理途径：（1）以限速亲核进攻进行分步加成，（2）以限速质子转移进行分步加成，以及（3）亲核进攻和质子转移同时发生的协同加成。烷基硫醇盐加成表现出β = 0.4、较小的负ΔS值、显著的离子强度效应，且没有一般酸催化的证据，这与途径1一致。芳基硫醇盐加成表现出β = 1.0、较大的负ΔS值、正常的一级SKIEs、一般酸催化，以及对离子强度的敏感性可忽略不计，这与途径2和3一致。实验和计算数据描绘了一个能量表面，其中基态效应，即烷基/芳基硫醇盐的能量，在塑造主导途径中起主要作用。还讨论了这些发现对生物共轭化学的应用。
