Conformational Analysis and Derivation of Molecular Mechanics Parameters for Esters and Thioesters

The ab initio MP2 and DFT/B3LYP quantum chemical methods applying the 6-311++G** basis set are equally useful for the conformational analysis of simple esters and thioesters. Calculated equilibrium geometric values were close to the experimental ones for the cis methyl acetate and methyl thioformate. Barriers to the OC−X−C rotation in methyl acetate (X = O) and methyl thioacetate (X = S) were calculated at 11−13 kcal/mol with both methods. Both oxo- and thioesters favor the OC−X−C cis, planar form. Solvent effects were estimated by using the polarizable continuum dielectric method (PCM). The cis form was found as the prevailing conformation for both the oxo- and thioesters in chloroform, acetone, acetonitrile, and water. The trans CH3−CH2−CO structure (with cis OC−X−C ester moiety) is a transition state both in methyl propanoate and methyl thiopropanoate, and a basically cis arrangement is preferred for both esters as revealed from B3LYP/6-311++G** calculations. The potential curve for the rotation of the methyl-group of ethyl acetate shows double minima at φ = 87° and φ = 180°. Only the gauche methyl position (φ = 85°) corresponds to an energy minimum structure in ethyl thioacetate. Using the results of the conformational analyses, stretching, bending, torsion, and improper torsion (out-of-plane) parameters were derived for the −CH2−CH2−C(O)−S−CH2−CH2− thioester moiety. In compliance with parameters in the GROMACS force field and by accepting the united CH3 and CH2 atom models with zero net-charge for these groups, the derived parameters are useful in molecular modeling of unusual proteins containing an acylated cysteine side chain.