N,N-二(对氟苄基)-N′-(2′,3′-二脱氧-3′-硫代胞苷)甲脒水解反应的理论研究

Theoretical Study on the Hydrolysis of N,N-Bis(p-fluorobenzyl)-N'-(2',3'-dideoxy-3'-thiacytidinyl)Formamidine

采用密度泛函理论方法B3LYP/6-31++G(d,p)//B3LYP/6-31G(d,p)和导体极化连续模型B3LYP/CPCM/6-31++G(d,p)方法对苯环对位上有F取代的N,N-二(对氟苄基)-N′-(2′,3′-二脱氧-3′-硫代胞苷)甲脒(FBFA-3TC)水解反应机理和溶剂效应进行了研究.考虑两条可能反应途径:水分子首先进攻CN双键的途径(PathA)和先进攻C—N单键的途径(PathB).计算结果表明,气相和水中两条途径的第一步都是速率控制步骤,PathA比PathB更有利.对优势途径PathA的第二步反应的进一步研究发现,中间体的羟基H原子转移到双键N比单键N更容易,从而形成2′,3′-二脱氧-3′-硫代胞苷(3TC)的最终水解产物.

Theoretical study on the hydrolysis mechanism of N,N-bis（p-fluorobenzyl）-N＇-（2＇,3＇-dideoxy-3＇-thiacytidinyl）formamidine（FBFA-3TC）was carried out at the B3LYP/6-31G（d,p）level.The solvent effect was evaluated using the conductor polarizable continuum model（CPCM）through the single point energy calculations at the B3LYP/6-31＋＋G（d,p）level.Two reaction pathways are considered.Path A is the addition of water molecule to the CN double bond in the amidine group in its first step and Path B is the attack of water mo-lecule to the C—N single bond in its first step.The calculated results indicate that the first step in both pathways is the rate-limiting process and Path A is more favorable than Path B in the gas phase and in water.The solvent effects are not distinct.It is also found that the second step in Path A proceeds preferably accor-ding to Channel a,in which the second H atom of water transfers to the N atom in double bond of the amidine group,leading to products the modified cytidine and N,N-dibenzyl formamide.