The molecular self-association of carboxylic acids in solution: testing the validity of the link hypothesis using a quantum mechanical continuum solvation approach

Abstract

According to the “link hypothesis” there is a connection between the solvent-dependent most stable self-associated groups of molecules and the building unit present in the polymorph that crystallizes from solution. We have tested this hypothesis by computing the Gibbs free energies for the molecular self-association in solution of three selected monocarboxylic acids that crystallize in different polymorphic forms and exhibit selective crystallization depending on the solvent: tetrolic acid (TTA), m-aminobenzoic acid (mABA) and m-hydroxybenzoic acid (mHBA). Calculations have been conducted at the density functional theory (M06-2X) level with the SMD polarizable continuum model to simulate aqueous and organic solutions. For all three systems we have found that the solvation environment significantly affects the stability of dimers. The most stable dimer in solution is the classic carboxylic acid dimer, and its stability decreases on going from nonpolar solvents, such as chloroform or acetonitrile, to aqueous and alcoholic solutions. However, whilst for TTA and mABA there is a link between the carboxylic dimer synthon in solution and the structural synthon packed in the metastable α-TTA polymorph, which crystallizes from chloroform, and in the crystal form-II of mABA, which crystallizes from acetonitrile, for mHBA the stabilization of the centrosymmetric carboxylic dimeric in acetonitrile and ethyl acetate does not correspond with recent experimental observations that the polymorph containing this structural unit (form I) is not the crystal form that nucleates preferentially from these solvents (Cryst. Growth Des., 2013, 13, 1140). Starting from the carboxylic dimer of TTA, the processes of trimerization and tetramerization of TTA from solution have been also modelled. The calculations suggest that the formation of tetramers in chloroform occurs from the self-association of the carboxylic acid dimers and not through the association of the TTA monomers and trimers. The free energy formation of the ionized forms of the mABA dimer (non-zwitterionic–zwitterionic and zwitterionic–zwitterionic) has been evaluated and, according to our results, zwitterionic–zwitterionic mABA dimers might be abundant in supersaturated aqueous and alcoholic solutions of m-aminobenzoic acid.