Andrew D. Bond

What is a co-crystal?

The term “co-crystal” is failing as a clear and consistent scientific descriptor. If it is to be retained, it should be used only as a synonym for “multi-component molecular crystal”.

Crystal engineering using 4,4′-bipyridyl with di- and tricarboxylic acids

Abstract The X-ray structures of four co-crystals of 4,4′-bipyridyl (Bipy) with two dicarboxylic acids and two tricarboxylic acids are described. A coupling (I) involving O–H⋯N and C–H⋯O interactions, previously seen in co-crystals of carboxylic acids with other heterocyclic bases, is again shown to be involved in the formation of supramolecular structures. Bipy with isophthalic acid, 1,4-naphthalenedicarboxylic acid and 1,3,5-cyclohexane-tricarboxylic acid forms 1:1 complexes. Tapes of acid:base components are formed via coupling I; these tapes extend to form supramolecular sheets via O–H⋯O and/or C–H⋯O interactions. With tricarballylic acid, a co-crystal with stoichiometry 3:2 (acid:base) is generated, with a four-acid-four-base cyclic motif (involving coupling I) as the elementary supramolecular unit. Two previously reported co-crystals of Bipy with trimesic acid and 2,5-di-n-hexylterephthalic acid are also discussed, as well as a CSD search for coupling I in mono-and poly-carboxylic acid/Bipy complexes.

Discovery of Potent and Selective Agonists for the Free Fatty Acid Receptor 1 (FFA1/GPR40), a Potential Target for the Treatment of Type II Diabetes

A series of 4-phenethynyldihydrocinnamic acid agonists of the free fatty acid receptor 1 (FFA(1)) has been discovered and explored. The preferred compound 20 (TUG-424, EC(50) = 32 nM) significantly increased glucose-stimulated insulin secretion at 100 nM and may serve to explore the role of FFA(1) in metabolic diseases such as diabetes or obesity.

On the crystal structures and melting point alternation of the n-alkyl carboxylic acids

The crystal structures of the complete series of n-alkyl carboxylic acids from hexanoic to pentadecanoic acid have been determined following in situ crystallisation. The structures reveal that the melting point alternation across the series is correlated with alternating crystal density. All even acids crystallise from the liquid as the C modification, while the odd acids exhibit a transition from the C′ to the C″ modification between undecanoic and tridecanoic acid. In each structure, molecules form hydrogen-bonded dimers arranged into bilayers, with a rectangular packing arrangement in the plane perpendicular to the dimer long axes. The packing density within bilayers is comparable in each case and the alternating crystal density can be attributed solely to alternating packing density between bilayers. The carboxyl groups are identically disposed in all structures, but adjacent dimers are offset to differing degrees parallel to their long axes to reduce in-plane O⋯O repulsions, giving rise to angles between n-alkyl chains. The extent of the lateral offset diminishes in general across the series as the n-alkyl chains exert an increasing driving force towards parallel alignment. The systematic alternation in the packing density between bilayers arises as a result of different orientations adopted by the terminal C–C bonds with respect to the methyl group interface. Several of the key structural features may be rationalised using a simple two-dimensional model that describes the packing of modified parallelograms and trapezoids, representing the even and odd acids, respectively. Extension of the model into three dimensions permits complete rationalisation of the structures.

Co-crystallisation of benzoic acid derivatives with N-containing bases in solution and by mechanical grinding: stoichiometric variants, polymorphism and twinning

Benzoic acid, salicylic acid and o-acetylsalicylic acid (aspirin) have been co-crystallised with diazabicyclo[2.2.2]octane (DABCO), piperazine, phenazine and 2-aminopyrimidine, using solution and solvent-drop grinding methods. Two of the resulting co-crystals, benzoic acid/DABCO (2 : 1) and benzoic acid/2-aminopyrimidine (2 : 1), form different polymorphs using the two distinct preparative techniques. In both systems, the polymorph obtained by grinding has a higher crystal density and packing coefficient than the polymorph obtained from solution. For benzoic acid/piperazine (2 : 1), salicylic acid/DABCO (2 : 1), salicylic acid/phenazine (2 : 1) and salicylic acid/N,N′-diacetylpiperazine (2 : 1) (derived from reaction between aspirin and piperazine), the same crystal form is obtained in bulk from solution and by solvent-drop grinding. For salicylic acid/N,N′-diacetylpiperazine (2 : 1), rapid cooling of an acetone solution produces single crystals of a different polymorph. Benzoic acid/2-aminopyrimidine also forms a 1 : 1 co-crystal from methanol solution on seeding with the material produced by grinding. For aspirin/DABCO (2 : 1), co-crystallisation was achieved only using solvent-drop grinding. Interactions between benzoic acid molecules in the co-crystals frequently resemble those in benzoic acid itself. For salicylic acid, two of the co-crystals have a layered structure in which the hydroxyl group is isolated within the layer, and the interlayer interactions also resemble those in benzoic acid. For aspirin, co-crystallisation with DABCO disrupts the layered structure and intermolecular interactions between acetyl groups. In benzoic acid/2-aminopyrimidine (2 : 1), insertion of base induces twinning based on two possibilities for the arrangement of adjacent hydrogen-bonded layers.

Templating and Selection in the Formation of Macrocycles Containing [{P(μ-NtBu)2}(μ-NH)]n Frameworks: Observation of Halide Ion Coordination

Amination of [ClP(micro-NtBu)](2) (1) using NH(3) in THF gives the cyclophospha(III)zane dimer [H(2)NP(micro-NtBu)](2) (2), in good yield. (31)P NMR spectroscopic studies of the reaction of 1 with 2 in THF/Et(3)N show that almost quantitative formation of the cyclic tetramer [[P(micro-NtBu)](2)(micro-NH)](4) (3) occurs. The remarkable selectivity of this reaction can (in part) be attributed to pre-organisation of 1 and 2, which prefer cis arrangements in the solid state and solution. The macrocycle 3 can be isolated in yields of 58-67 % using various reaction scales. The isolation of the major by-product of the reaction (ca. 0.5-1 % of samples of 3), the pentameric, host-guest complex [[P(micro-NtBu)(2)](2)(micro-NH)](5)(HCl).2 THF] (4.2 THF), gives a strong indication of the mechanism involved. In situ (31)P NMR spectroscopic studies support a stepwise condensation mechanism in which Cl(-) ions play an important role in templating and selection of 3 and 4. Amplification of the pentameric arrangement occurs in the presence of excess LiX (X=Cl, Br, I). In addition, the cyclisation reaction is solvent- and anion-dependent. The X-ray structures of 2 and 4.2 THF are reported.

Systematic study of spin crossover and structure in [Co(terpyRX)2](Y)2 systems (terpyRX = 4'-alkoxy-2,2':6',2''-terpyridine, X = 4, 8, 12, Y = BF4(-), ClO4(-), PF6(-), BPh4(-)).

A family of spin crossover cobalt(II) complexes of the type [Co(terpyRX)(2)](Y)(2) x nH(2)O (X = 4, 8, 12 and Y = BF(4)(-), ClO(4)(-), PF(6)(-), BPh(4)(-)) has been synthesized, whereby the alkyl chain length, RX, and counteranion, Y, have been systematically varied. The structural (single crystal X-ray diffraction) and electronic (magnetic susceptibility, electron paramagnetic resonance (EPR)) properties have been investigated within this family of compounds. Single crystal X-ray diffraction analysis of [Co(terpyR8)(2)](ClO(4))(2), [Co(terpyR8)(2)](BF(4))(2) x H(2)O, and [Co(terpyR4)(2)](PF(6))(2) x 3 H(2)O, at 123 K, revealed compressed octahedral low spin Co(II) environments and showed varying extents of disorder in the alkyl tail portions of the terpyRX ligands. The magnetic and EPR studies were focused on the BF(4)(-) family and, for polycrystalline solid samples, revealed that the spin transition onset temperature (from low to high spin) decreased as the alkyl chain lengthened. EPR studies of polycrystalline powder samples confirmed these results, showing signals only due to the low spin state at the temperatures seen in magnetic measurements. Further to this, simultaneous simulation of the EPR spectra of frozen solutions of [Co(terpyR8)(2)](BF(4))(2) x H(2)O, recorded at S-, X-, and Q-band frequencies, allowed accurate determination of the g and A values of the low spin ground state. The temperature dependence of the polycrystalline powder EPR spectra of this and the R4 and R12 complexes is explained in terms of Jahn-Teller effects using the warped Mexican hat potential energy surface model perturbed by the low symmetry of the ligands. While well recognized in Cu(II) systems, this is one of the few times this approach has been used for Co(II).

Single crystals of aspirin form II: crystallisation and stability

Single crystals of aspirin form II can be obtained by crystallisation of aspirin in the presence of aspirin anhydride in organic solvents such as acetonitrile or tetrahydrofuran. The crystals are stable under ambient conditions for months and do not show any phase transition on application of isotropic pressure up to 2.2 GPa.

Supramolecular architectures of cyclohexane-1, 3cis, 5cis-tricarboxylic acid in acid∶base complexes

Cyclohexane-1, 3cis, 5cis-tricarboxylic acid (CTA) has been co-crystallised with a range of organic bases containing one, two or more hydrogen bond acceptors. Various supramolecular acid motifs have been identified, including tapes, sheets and interpenetrating networks. Supramolecular zigzag tapes are observed in the 1∶1 co-crystal structure of CTA with acetonitrile (An) and in the 1∶1∶2 co-crystal with 1,10-phenanthroline (oPh) and methanol. In the 1∶1 co-crystal structures of CTA with 4,4′-bipyridyl (Bipy) and with 2-aminopyrimidine (APY), two types of linear supramolecular acid tapes are observed. Co-crystallisation with hexamethyltetramine (HMTA) in the molar ratio of 1∶1 results in supramolecular acid networks with pseudo-hexagonal grids, with HMTA located within the network cavities. Strong O–H⋯O and weak C–H⋯O hydrogen bonds are observed between CTA molecules in these structures.

Synthesis and characterization of a new layered compound of trimesic acid

The hydrothermal reaction between 1,3,5-benzenetricarboxylic acid (trimesic acid, H3BTC) and 1,2-bis(4-pyridyl)ethane (BPE), in the presence of cadmium(II) ions, results in the formation of a novel layered salt, in which the organic cations and water molecules occupy spaces between anionic layers of trimesic acid.