Polymorphic Co-crystals from Polymorphic Co-crystal Formers: Competition between Carboxylic Acid···Pyridine and Phenol···Pyridine Hydrogen Bonds

The recent literature
has shown an increase in the number of co-crystals
reported to be polymorphic, with at least 45 such systems identified
thus far. The question of whether co-crystals, defined as any multicomponent
neutral molecular complex that forms a crystalline solid, are inherently
less prone to polymorphism than the individual components is shown
to be untrue in four sets of polymorphic co-crystals. The co-crystal
formers in this study, acridine, nicotinamide, 3-hydroxybenzoic acid,
2,4-dihydroxybenzoic acid, malonic acid, and pimelic acid, are all
polymorphic in their unimolecular states and are shown to be dimorphic
in the following combinations: (3-hydroxybenzoic acid)·(acridine)
[1­(I) and 1­(II)], (2,4-dihydroxybenzoic
acid)·(nicotinamide) [4­(I) and 4­(II)], (malonic acid)·(nicotinamide) [5­(I) and 5­(II)], and (pimelic acid)·(nicotinamide) [6­(I) and 6­(II)]. These co-crystals are assembled primarily
using carboxylic acid and phenol hydrogen bond donors that hydrogen
bond to pyridine N or amide carbonyl acceptors. Two different combinations
of donors and acceptors are primarily responsible for the formation
of polymorphs in 1 and 4, whereas conformational
differences within the malonic and pimelic acid molecules lead to
different packing arrangements using the same combination of hydrogen
bonded interactions in 5 and 6. The 1:2
co-crystal of (3-hydroxybenzoic acid)·(acridine)2 (2) displays both the phenol O–H···N
hydrogen bond observed in 1­(I) and the carboxylic acid
O–H···N hydrogen bond observed in 1­(II). In addition, a methanol solvate of (2,4-dihydroxybenzoic acid)·(nicotinamide)
(3) is reported. DFT calculations show that the carboxylic
acid···pyridine hydrogen bond is strongest and one
of co-crystallization’s most useful interactions.