Computer simulations based on density functional theory, molecular dy- namics and metadynamics methods have revealed the role of solvent in the kinetics and thermodynamics of aggregation of mABA molecules in aque- ous and organosulfur (DMSO) solutions.
DFT calculations with a continuum model to describe the solvation en- vironment were used to probe the potential energy surfaces of molecular clusters of meta-aminobenzoic acid, (mABA)n (n = 2-4), locate the low- lying energy structures of (mABA)n, and compute their Gibbs free energies in water and DMSO. Starting from many randomly generated candidate structures and by imposing the condition of minimum free energy in solu- tion for the isomers of (mABA)n, we proved that the structure of the most stable dimer and tetramer correspond to the classic carboxylic dimer π-π stacking synthon found in the crystalline form II of mABA. Consequently, the transfer of structural information from the solution- to the solid state- phase of mABA is not only related with the presence of stable carboxylic
acid dimers, as previously suggested, but also to higher-order prenucleation clusters (mABA)4, which could also direct the nucleation process towards the formation of the polymorphic form II of mABA.
MD simulations of mABA solutions show a significant solvent-dependent behavior for the aggregation of mABA molecules. In aqueous solutions, even at relatively low concentrations, mABA molecules spontaneously form H-bonded π-π stacking cluster. In organosulfur solutions, molecules of mABA are in a more solvated state and high concentrations of mABA are required to observe appreciable levels of mABA aggregation, but the forma- tion of the stable dimeric and tetrameric species predicted by the quantum mechanical continuum solvation calculations could not be observed during the MD simulation.
Free energy profiles for the mABA dimerisation computed using metady- namics simulations show that in DMSO there is a higher Gibbs activation energy associated with the diffusion and desolvation of mABA, which are necessary and pre-requisite steps for the aggregation of organic molecules from solution to occur. In particular, the formation of (mABA)2 in DMSO has an activation barrier that is twice the one in water, and much larger than the value of kT at 300 K. This rationalises the observed solvent- dependent aggregation behavior of mABA and agrees with the DFT cal- culations of the formation of microsolvated mABA clusters, mABA(S)n, reported in Chapter 3, which show that mABA-DMSO interaction is sub- stantially larger (up to 10 kcal.mol−1) than mABA-water interaction.
Chapter 5
Aggregation of
Meta-aminobenzoic Acid in
Water
Meta-aminobenzoic acid exists in water in both the nonionic (mABA) and zwitterionic (mABA±) forms. However, the constituent molecules of the polymorph that crystallises from aqueous solutions are zwitterionic. This chapter reports atomistic simulations of the events surrounding the early stage of crystal nucleation of meta-aminobenzoic acid from aqueous solu- tions. Density functional theory calculations were conducted to determine the low-lying energy conformers of meta-aminobenzoic acid dimers and to compute the Gibbs free energies in water of nonionic, (mABA)2, zwitte- rionic, (mABA±)2 and nonionic-zwitterionic, (mABA)(mABA±), species. Classical molecular dynamics simulations of mixed mABA-mABA± aque- ous solutions were carried out to examine the aggregation of meta-aminobenzoic acid. According to these simulations, the selective crystallisation of the
polymorph, with constituent molecules in the zwitterionic form, is driven by the formation of zwitterionic dimers in solution, which are thermody- namically more stable than (mABA)2 and (mABA)(mABA±) pairs. This work represents a paradigm of the role of molecular processes during the early stages of crystal nucleation in affecting polymorph selection during crystallisation from solution.
5.1
Introduction
The very strong polymorphic character of meta-aminobenzoic acid is re- lated to the manifold of inter-molecular interactions between meta-aminobenzoic acid molecules (hydrogen (H) bonding, π-π interactions and H-π interac- tions) but also to the ability of this molecule to exist in either of both the nonionic (mABA) and zwitterionic (mABA±) forms.113 The constituent molecules of the polymorphs denoted I, III and IV are zwitterionic, whereas in the polymorphs II and V they are nonionic:95,99 in II, mABA molecules interact through the O-H...O acid dimer of a R2
2(8) ring motif [Figure 5.1(a)]; in III, mABA± molecules form ionic N+-H...O− interactions in a R44(8) ring motif [Figure 5.1(b)]; in Form IV, two independent molecules form a linear C(7) chain through ionic N+-H...O− interactions [(Figure 5.1(c)]. The crystal structure of Form I has not been determined so far and the crystal structure of Form V shows disorder.95,99,156
The nature of the solvent can significantly control the formation of one specific polymorph over another.114,157 Form II preferentially crystallises from dimethyl sulfoxide (DMSO),99 where meta-aminobenzoic acid exists in the nonionic form.117,157 On the other hand, Form I preferentially crys-
tallises from aqueous environments,99 despite the values of the equilibrium constant KZ = [mABA±]/[mABA] for aminobenzoic acids are of the order of unity in water,97,98,158 implying a comparable distribution of mABA± and mABA molecules. The fundamental details of factors controlling the selection between zwitterionic and nonionic forms of meta aminobenzoic acid during crystal nucleation from aqueous solution are not known yet.117 This work aims to solve this conundrum by applying a combination of atomistic methods to follow the events surrounding the crystal nucleation of meta-aminobenzoic acid from aqueous solutions. Density functional theory (DFT) calculations have been used to determine the structure and energet- ics of formation in water of (mABA)2, (mABA)(mABA±) and (mABA±)2 dimers. Classical molecular dynamics (MD) simulations of mixed mABA- mABA±aqueous solutions have been conducted to quantify the aggregation of meta-aminobenzoic acid.
Figure 5.1: Crystal structure of the polymorphs of meta-aminobenzoic acid denoted II, III and IV: (a) (1x3x1) unit cell of Form II (neutral); (b) (1x2x2) unit cell of Form III (zwitterionic); (c) (2x2x1) unit cell of Form IV (zwit- terionic).95