Speciation of Substituted Benzoic Acids in Solution: Evaluation of Spectroscopic and Computational Methods for the Identification of Associates and Their Role in Crystallization

Self-association of four benzoic acid derivatives 2-chloro-4-nitrobenzoic acid, 2-methyl- 4-nitrobenzoic acid, 3-hydroxybenzoic acid, and 2,6-dimethoxybenzoic acid in solution was investigated using spectroscopic measurements (Fourier transform infrared and H-1 and C-13 NMR spectroscopy) and molecular simulation methods. Based on the formation of hydrogen bonds, solvents can be divided into two groups: apolar solvents or solvents with a low hydrogen bond acceptor propensity, in which the benzoic acid derivatives form hydrogen-bonded dimers, and solvents with hydrogen bond acceptor propensity beta > 0.3, interacting with the carboxylic group of benzoic acid, thus screening its interaction in the formation of self-associates. The formation propensity and structure of self-associates stabilized by weak interactions, such as pi center dot center dot center dot pi stacking and CH3 center dot center dot center dot pi interactions, however, are determined by the substituents in the benzene ring. Despite all the studied compounds being polymorphic, in none of the cases, an unequivocal structural link between self-associates present in the solution and the crystal form was observed.

Automated summary

The self-association of four benzoic acid derivatives in solution was investigated, revealing that solvent type and substituents have an impact on the formation propensity and structure of self-associates. However, no clear structural link between self-associates in solution and crystal forms was observed.