Brown Joseph S, Ruttinger Andrew W, Vaidya Akash J, Alabi Christopher A, Clancy Paulette
Robert F. Smith School of Chemical and Biomolecular Engineering, Cornell University, Ithaca, NY 14853, USA.
Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, MD 21218, USA.
Org Biomol Chem. 2020 Aug 19;18(32):6364-6377. doi: 10.1039/d0ob00726a.
The thiol-Michael addition is a popular, selective, high-yield "click" reaction utilized for applications ranging from small-molecule synthesis to polymer or surface modification. Here, we combined experimental and quantum mechanical modeling approaches using density functional theory (DFT) to examine the thiol-Michael reaction of N-allyl-N-acrylamide monomers used to prepare sequence-defined oligothioetheramides (oligoTEAs). Experimentally, the reaction was evaluated with two fluorous tagged thiols and several monomers at room temperature (22 °C and 40 °C). Using the Eyring equation, the activation energies (enthalpies) were calculated, observing a wide range of energy barriers ranging from 28 kJ mol-1 to 108 kJ mol-1 within the same alkene class. Computationally, DFT coupled with the Nudged Elastic Band method was used to calculate the entire reaction coordinate of each monomer reaction using the B97-D3 functional and a hybrid implicit-explicit methanol solvation approach. The thiol-Michael reaction is traditionally rate-limited by the propagation or chain-transfer steps. However, our test case with N-acrylamides and fluorous thiols revealed experimental and computational data produced satisfactory agreement only when we considered a previously unconsidered step that we termed "product decomplexation", which occurs as the product physically dissociates from other co-reactants after chain transfer. Five monomers were investigated to support this finding, capturing a range of functional groups varying in alkyl chain length (methyl to hexyl) and aromaticity (benzyl and ethylenephenyl). Increased substrate alkyl chain length increased activation energy, explained by the inductive effect. Aromatic ring-stacking configurations significantly impacted the activation energy and contributed to improved molecular packing density. Hydrogen-bonding between reactants increased the activation energy emphasizing the rate-limitation of the product decomplexation. Our findings begin to describe a new structure-kinetic relationship for thiol-Michael acceptors to enable further design of reactive monomers for synthetic polymers and biomaterials.
硫醇-迈克尔加成反应是一种常用的、选择性高、产率高的“点击”反应，应用范围从小分子合成到聚合物或表面改性。在这里，我们结合了实验和量子力学建模方法，使用密度泛函理论（DFT）来研究用于制备序列定义的寡硫醚酰胺（oligoTEA）的N-烯丙基-N-丙烯酰胺单体的硫醇-迈克尔反应。在实验中，使用两种含氟标记的硫醇和几种单体在室温（22℃和40℃）下对该反应进行了评估。使用艾林方程计算了活化能（焓），观察到在同一烯烃类别中，能垒范围从28 kJ mol-1到108 kJ mol-1。在计算方面，使用DFT结合推挤弹性带方法，采用B97-D3泛函和混合隐式-显式甲醇溶剂化方法计算每个单体反应的整个反应坐标。传统上，硫醇-迈克尔反应的速率受传播或链转移步骤限制。然而，我们用N-丙烯酰胺和含氟硫醇进行的测试案例表明，只有当我们考虑一个以前未被考虑的步骤（我们称之为“产物解络合”）时，实验和计算数据才会产生令人满意的一致性，该步骤发生在链转移后产物与其他共反应物物理分离时。研究了五种单体以支持这一发现，涵盖了一系列烷基链长度（从甲基到己基）和芳香性（苄基和乙烯基苯基）不同的官能团。底物烷基链长度的增加会增加活化能，这可以通过诱导效应来解释。芳香环堆积构型对活化能有显著影响，并有助于提高分子堆积密度。反应物之间的氢键增加了活化能，突出了产物解络合的速率限制。我们的研究结果开始描述硫醇-迈克尔受体的一种新的结构-动力学关系，以便能够进一步设计用于合成聚合物和生物材料的反应性单体。
