Bach Robert D, Dmitrenko Olga, Thorpe Colin
Department of Chemistry and Biochemistry, University of Delaware, Newark, Delaware 19716, USA.
J Org Chem. 2008 Jan 4;73(1):12-21. doi: 10.1021/jo702051f. Epub 2007 Dec 4.
Both density functional theory (DFT) (B3LYP) and CCSD ab initio calculations were employed in a theoretical investigation of the mechanism of thiolate-disulfide exchange reactions. The reaction pathway for degenerate thiolate-disulfide exchange reactions with dimethyl disulfide has been shown to proceed through a SN2-like transition structure that is very close in energy to the corresponding trisulfur anionic intermediate ([delta-S-S-Sdelta(-)]). When relatively small substituents are involved, the level of theory must be increased to CCSD to make this rather subtle mechanistic distinction. With the more sterically hindered exchange reaction involving t-butyl mercaptide and di-t-butyl disulfide, the potential energy surface exhibits a distinct preference for the S(N)2 displacement pathway with an activation barrier of 9.8 kcal/mol. When corrections for solvent polarity are included (COSMO), an S(N)2 mechanism is also implicated in both polar and nonpolar solvents. DFT studies on thiolate-disulfide exchange, when the substituent is a model peptide, strongly support the intermediacy of a trisulfur intermediate that lies 10.7 kcal/mol below isolated reactants. A well depth of this magnitude should provide a sufficient lifetime of the intermediate to accommodate the requisite conformational adjustments that accompanies formation of the new disulfide bond.
密度泛函理论（DFT）（B3LYP）和耦合簇单双激发（CCSD）从头算计算方法均被用于硫醇盐 - 二硫化物交换反应机理的理论研究。与二甲基二硫化物发生的简并硫醇盐 - 二硫化物交换反应的反应途径已表明是通过一种类似于SN2的过渡结构进行的，该结构在能量上与相应的三硫阴离子中间体（[δ-S-S-Sδ(-)]）非常接近。当涉及相对较小的取代基时，理论水平必须提高到CCSD才能做出这种相当微妙的机理区分。对于涉及叔丁硫醇和二叔丁基二硫化物的空间位阻更大的交换反应，势能面表现出对S(N)2取代途径的明显偏好，其活化能垒为9.8千卡/摩尔。当包含溶剂极性校正（COSMO）时，在极性和非极性溶剂中也暗示了S(N)2机理。当取代基是模型肽时，对硫醇盐 - 二硫化物交换的DFT研究有力地支持了三硫中间体的中间体状态，该中间体比孤立的反应物低10.7千卡/摩尔。这种量级的阱深应该为中间体提供足够长的寿命，以适应伴随新二硫键形成所需的构象调整。
