Insight into substituent effects on the hydrolysis of amidines by a microhydration model

Abstract

The hydrolysis of substituted amidines XN′=CH–N(Y)2 (X = alkyl, nucleoside, aryl; Y = methyl, benzyl) is studied by use of computational techniques. For each substituted system, two possible pathways, N′-Path and N-Path, are considered, in which the proton transfer to N′ and N, respectively, after the nucleophilic attack of H2O to C=N′ double bond. The geometry optimizations of the stationary states are carried out to map out the hydrolysis pathways at the density functional theory B3LYP/6-311+G(d,p) level. Single-point MP2 calculations (MP2/6-311++G(d,p)//B3LYP/6-311+G(d,p)) are performed to obtain more credible energy information. A microhydration surrounding is constructed to describe the effect of water molecules in the first hydration shell on the energy barrier from radial distribution functions, g(R). The bulk solvent effects are examined by using the conductor-like polarizable continuum model (CPCM). The calculated results indicate that the hydrolysis of N,N-disubstituted formamidines is more favored for Y = methyl than for Y = benzyl. Furthermore, for N′-substituted formamidines, the hydrolysis reactivity increases in the following order: X = aryl < X = nucleoside < X = alkyl. In addition, the substituent effects on the proton transfer manner after the nucleophilic attack of H2O to C=N′ double bond are discussed. The preference of proton transfer to N′ or N atom depends on the different nucleophilicity of each nitrogen atom bearing different substituents in the intermediate (IM). Our computational results are in agreement with the available experimental conclusion and will allow for a better understanding of the hydrolysis mechanism of amidines.