An ab initio molecular orbital study of intramolecular hydrogen bonding in ortho-substituted arylamides: Implications for the parameterization of molecular mechanics force fields

The aromatic oligoamide (arylamide) foldamer class, characterized by the repetitive aromatic-amide pattern, is one of the most intensively studied foldamer families. In this article, the potential energy profiles with regard to torsional motions around the two types of aromatic-amide bonds (C _a-C_p and C_a-N) are obtained at the B3LYP/6-311G(d,p) level of theory. The effect of ortho substituents with different hydrogen bonding abilities (OCH₃ vs. SCH₃) on the torsional potential profiles is analyzed in detail. There are several findings that have implications in foldamer design. The ortho-SCH₃ substituent on the benzene ring produces a much more flexible arylamide backbone with respect to the OCH₃ substituent, as it restricts the C _a-C_p torsion to a lesser extent. Interestingly, the rigidifying effect of the ortho-SCH₃ substituent on the C _a-N torsion is very similar to that of the OCH₃ substituent on the same linkage type. In addition, the SCH₃ substituent prefers a perpendicular orientation with respect to the benzene ring to the in-plane one. It is also found that reparameterization of the corresponding torsional parameters, sometimes specific to the ortho substituent type, in the general amber force field is necessary for an accurate description of the backbone torsions in arylamides. Six sets of partial charge/torsional parameters for each linkage (C_a-C_p or C _a-N)/substituent (OCH₃ or SCH₃) combination are obtained based on the ab initio torsional profiles. Initial assessments of these parameters show good agreement with the ab initio results.