Theoretical study on the hydrolysis mechanism of N,N-dimethyl-N′-(2-oxo-1, 2-dihydro-pyrimidinyl)formamidine: Water-assisted mechanism and cluster-continuum model
✍ Scribed by Yong Wu; Lu Jin; Ying Xue; Dai Qian Xie; Chan Kyung Kim; Yong Guo; Guo Sen Yan
- Publisher
- John Wiley and Sons
- Year
- 2008
- Tongue
- English
- Weight
- 532 KB
- Volume
- 29
- Category
- Article
- ISSN
- 0192-8651
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✦ Synopsis
Abstract
The hydrolysis reaction of N,N‐dimethyl‐N′‐(2‐oxo‐1, 2‐dihydro‐pyrimidinyl)formamidine (DMPFA), a model compound of the antivirus drug amidine‐3TC (3TC = 2′, 3′‐dideoxy‐3′‐thiacytidine), is investigated by the hybrid density functional theory B3LYP/6‐31+G (d,p) method. The hydrolysis reaction of the title compound is predicted to undergo via two pathways, each of which is a stepwise process. Path A is the addition of H~2~O to the CN double bond in the amidine group to form a tetrahedral structure in its first step, and then the transfer of the H atom of hydroxyl leads to the corresponding products via four possible channels. Path B simultaneously involves the nucleophilic attack of H~2~O to the C atom of the CN bond and the proton transfer to the N atom of amino group leading to the cleavage of the CN single bond in the amidine group. The results indicate that path A is more favorable than path B in the gas phase. Moreover, to simulate the title reaction in aqueous solution, water‐assisted mechanism and the cluster‐continuum model, based on the SCRF/CPCM model, are taken into account in our work. The results indicate that it is rational for two water molecules served as a bridge to assist in the first step of path A and that cytosine rather than the cytosine‐substituted formamide should be released from the tetrahedral intermediate via s six‐membered cycle transition state (channel 2). Our calculations exhibit that the process toward the tetrahedral intermediate is the rate‐determining step both in the gas phase and in aqueous solution. © 2007 Wiley Periodicals, Inc. J Comput Chem, 2008