含氮药物分子中氮a-位碳氢键离解能的理论研究

本文利用G3B3 和CBS-Q高精度理论方法检验了一系列胺类有机化合物中α-碳氢键离解能的实验测量值，在此基础上筛选出(U)BHandH/6-311++G(2df, 2p)//(U)B3LYP/6-31G(d)方法，发现其可以准确快速的预测氮α-碳氢键离解能。运用该方法研究了若干含氮药物分子，发现氮α-碳氢键离解能随药物分子结构发生明显变化。为了阐明其变化规律，系统研究单取代和双取代基效应，并解释了不同取代基效应的来源。

Strength of C–H Bonds at Nitrogen α ‐Position:Implication for Metabolic Stability of Nitrogen‐containing Drug Molecules

The available experimental αC‐H BDEs of a variety of amine‐containing molecules were examined by using the G3B3 and CBS‐Q methods. The verified values were employed to benchmark and calibrate the density functional theory methods. It was found that the (U)BHandH/6‐311++G(2df, 2p)//(U)B3LYP/6‐31G(d) method was a fast and accurate method for calculating C–H BDEs at nitrogen α‐positions. By using the newly benchmarked BHandH method, the αC–H BDEs in a number of nitrogen‐containing drug molecules were calculated, where a dramatic variation of the αC–H BDEs was discovered. To understand this variation, the effects of mono‐ and double‐substitution at both carbon and nitrogen atoms on the αC‐H BDEs were systematically studied. The origin of the substitution effects was thoroughly discussed in terms of four categories of substituents.