替马西泮醇解反应机理研究

Theoretical Study of the Alcoholysis Reaction Mechanism of Temazepam

大量镇静催眠药的滥用给食品安全带来了严重负面影响,时刻威胁着人们的身体健康和生命安全。本文采用B3LYP/6-311+G**和MP2/6-311+G**方法,研究了苯二氮类药物替马西泮(TMZ)在中性和酸性甲醇溶液中的醇解反应机理。结果显示,无论从热力学还是动力学上分析,TMZ分子在中性和酸性甲醇溶液中N1—C2键断裂开环降解反应(Path 2和Path 3)都很难发生;而中性甲醇溶液中断裂C3—N4键醇解开环降解反应(Path 1)从动力学上分析是可行的,反应涉及1个或2个显性甲醇溶剂分子参与反应,通过质子的受体与给体的酸碱催化作用促进反应的进行,液相能垒(ΔG≠)分别为85.7k J/mol和81.6k J/mol,应该为TMZ分子在甲醇溶液中醇解的优势反应路径。研究结果与实验观察一致。

Abuse of the large number sedative hypnotics has brought serious negative impacts to food safety, and also threatens people＇s health and life safety. In the present work, using temazepam （TMZ） as an example, we explore theoretically the alcoholysis of benzodiazepines in neutral and acidic methanol solvent by employing the B3LYP/6-311 ＋ G＊＊ and MP2/6-311 ＋ G＊＊ methods. The results indicated that the degradation reactions of TMZ by N1--C2 bond broken in neutral and acidic methanol solution （ Path 2 and Path 3 ） are difficult to process based on the analysis of kinetics and thermodynamics, while the degradation reaction of TMZ by C3--N4 bond broken （ Path 1 ） is feasible in neutral methanol solution according to the dynamic analysis. The reaction involves one （85.7kJ/mol （ △G≠ ） ） or two explicit solvent molecules （81.6 kJ/mol （ △G≠ ） ）, which act（s） as proton acceptor and donor to accelerate the reaction. Thus, Path 1 should be the dominated alcoholysis reaction path of TMZ in methanol solution, and the results are consistent with the experimental results.