Influence of (S)-1-phenylethylamine para substitution on the resolution of (±)-1,4-benzodioxane-2-carboxylic acid: a crystallographic, theoretical and morphologic approach

The crystal structures of the salts of (S)- and (R)-1,4-benzodioxane-2-carboxylic acid with (S)-1-phenylethylamine and its p-methyl and p-nitro substituted analogues were determined in order to correlate the differences in solubility between diastereomeric salts with their solid state structures. A common characteristic of the six structures is the presence of hydrogen bond interactions, which always involve the ammonium group NH3+ and the carboxylic oxygens of three adjacent acid molecules with the formation of molecular chains in the direction of the binary screw crystallographic axis (unique axis in the monoclinic system and, in the orthorhombic space group, coincident with the direction of the shortest cell axis). A determinant factor for the high inter diastereomer solubility difference of the two pairs of p-methyl and p-nitro substituted amine salts seems, in the case of the p-methyl derivatives, to be the different mutual disposition of the acid and amine aromatic rings at the boundaries of the molecular chains and, for the p-nitro derivatives, the prevalence, in the same region, of the nitro groups or of the acid aromatic moieties. A morphologic study at SEM revealed some correlation between the crystal habit and solubility. Theoretical calculations, based on the LSER model, account for the observed solubilities in methanol.

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(S)-1,4-Benzodioxane-2-carboxyilic acidC9H8O4Ee = 99.8%[α]D25=-63.9 (c 1, CHCl3)Source of chirality: resolution with (S)-1-(p-nitrophenyl)ethylamine or (S)-1-(p-methylphenyl)ethylamine