Evaluation of charge-assisted hydrogen bonds and weak intermolecular interaction in trimethoprim 2-aminobenzoate: a combined crystallographic and theoretical approach

Abstract

A comprehensive investigation of the weak non-covalent interactions within the crystal structure of trimethoprim 2-aminobenzoate (2,6-diamino-5-(3,4,5-trimethoxybenzyl)pyrimidin-1-ium 2-aminobenzoate) is presented. The protonation of trimethoprim and the deprotonation of 2-aminobenzoate were confirmed by NMR spectroscopy and a single-crystal X-ray diffraction study. Qualitative Hirshfeld surface analysis identified intermolecular H···H, O···H, and C···H contacts as the three primary interactions within the title salt. Fourteen molecular pairs (M1AA−M14AB) were extracted from the crystal packing of the title salt using the PIXEL method. These molecular dimers were further characterized using the QTAIM and DFT approaches. Seven intermolecular pairs (M1AA−M7BB) formed between like-charged species (i.e. +1···+1 or -1···-1) resulted in destabilization, with total energies (Etot) ranging from 67.2 to 200.1 kJ mol-1. Conversely, molecular pairs formed between oppositely charged species (i.e. +1···-1) exhibited stabilizing behavior, with interaction energies ranging from -133.7 to -449.7 kJ mol-1. Topological analysis of charge density revealed that two N–H···O hydrogen bonds between cation and anion displayed an intermediate character between shared and closed-shell interactions. Additionally, comparison with previously reported similar TMP salts (CSD ref. code: CESRUN, HURMOW and PARWUB) demonstrated 3D-isostructural packing features in the crystal structure of the title salt.