Synthon formation in inclusion compounds of Phenylsuccinic acid

Abstract

The effect of chirality was investigated on selected physico-chemical properties by designing, synthesizing and analysing a series of racemic multicomponent crystals and their chiral counterparts. Eleven new crystalline materials were synthesised by combining phenylsuccinic acid (racemate or the S-enantiomer), a dicarboxylic acid, with primary or aromatic amines (aniline, pyridine, 4-picoline, 2,4-lutidine, 3,4-lutidine and 3,5-lutidine) and a drug pyrazine carboxamide (PCA). The carboxylic acids were combined with the amines to ensure the formation of the multicomponent crystals via acid-base heterosynthons. The varied positions of the functional groups on the aromatic amines gave rise to fine tune the packing of the crystals. The multicomponent crystals formed were examined by differential scanning calorimetry, thermogravimetric analysis, powder and single crystal X-ray diffraction. Fourier transform infrared spectroscopy was also performed for the complete characterisation of the new compounds. Ten out of the eleven novel compounds afforded multicomponent crystals with the expected composition, i.e. both the acid and the base were included in the crystal. These crystallisations resulted in a variety of different crystal forms, such as a true salt ([(R,S)-PSA-][ANI+]), a salt solvate ([(S)-PSA2-][2ANI+]·ANI), solvates ((R,S)-PSA·2PYR, (R,S)-PSA·2(4PIC), (R,S)-PSA·2(2,4LUT), (R,S)-PSA·2(3,4LUT) and 2(S-PSA)·4(3,4LUT)), co-crystal salts ([(R,S)-PSA2-]2[3,5LUT+]·2(R,S)-PSA and 2[(S)-PSA2-]4[3,5LUT+]·4 (S)-PSA) and a co-crystal (R,S)-PSA‧PCA. In these crystals, the phenylsuccinic acid showed great conformational variety. The analysis of the crystal packing (Z and related parameters, void analysis, etc.) highlighted the complexity of the packing of the multicomponent crystals and the significant differences between the racemic multicomponent crystals and their chiral counterparts. The acid-base heterosynthon, depicted as 𝑅22(7), was formed between the carboxylic acid and the pyridine moiety only in five of the multicomponent crystals. Interestingly, in the co-crystal of (R,S)-PSA‧PCA the carboxylic acid formed hydrogen bonds via the amide functional group of the PCA instead of via the nitrogen atom in the aromatic ring. The occurrence of the 𝑅22(7) synthon was investigated with the aid of the Cambridge Structural Database and the statistical analysis showed that the heterosynthon is formed only in 25-30% of the cases. It was also concluded that formation of the 𝑅22(7) synthon is less expected when crystallising enantiopure crystals because the limitations of the packing of chiral compounds adds an extra constraint to the packing of the crystal.