Scheme 2 Individual sequences simulated in this study; (a) substitution by an amine nucleophile (b) elimination of water to form the imine and (c) deprotonation.
All calculations were performed using DFT method implemented in the Gaussian G09. [59] All structures were optimized using hybrid meta exchange-correlation functionals, M06-2X with a 6-311+G(d,p) basis set.[60, 61] The reaction mechanism associated with SB formation was studied in the gasphase following the mechanism described in Scheme 2. In this model, a methylamine molecule acts as both the nucleophile and base in the reaction. Two explicitly modelled water molecules provide additional stabilization and facilitate proton transfer steps. The vibrational frequency calculations were performed to confirm all transition states (TS). TSs are characterized by having a single imaginary frequency and minima having none. The rate determining barrier were subsequently determined. Additional substrate properties (MWT and clogP) were obtained using the Chemaxon JChem.[62]
The correlation between independent and dependent variables was assessed using linear regression. The data was partitioned into a training (M=14) and test set (N=8) and a QMM was fitted using the RDS barrier and the logP using multiple linear regression. All statistical analyses were performed in Statistica 12.[63]