Carboxylic acid dimer synthon

A nice example of grinding-induced crystal engineering is the formation of a hydrogen bonded cocrystal between ferrocene dicarboxylic acid and 1,4-diazabicyclo [2.2.2] octane (DABCO). The ferrocene dicarboxylic acid exists in the solid as a hydrogen bonded dimer based on two repeats of the carboxylic acid dimer synthon (solid A). Grinding with DABCO (solid B) gives rise to a new solid, C, in which the carboxylic acid dimers have been broken and replaced by an acid-amine synthon, Figure 8.25.30... 

Supramolecular architectures based on the carboxylic acid dimer synthon... 

Figure 3 Both the carboxylic acid dimer synthon and the carboxylic acid—amide synthon—have the same graph set symbol R2,2(8), where R is for ring, 2,2 stands for the number of hydrogen-bond donor and acceptor atoms, and (8) is the number of atoms in the ring.

The structures of three cocrystals of caffeine having a 1 1 stoichiometry with various hydroxy-2-naphthoic acids have been reported [62], The anticipated imidazole-carboxylic acid supramolecular synthon was observed in caffeine cocrystals containing l-hydroxy-2-naphthoic acid and 3-hydroxy-2-naphthoic acid, while a hydrogen-bonded carboxylic acid dimer (and no hydroxyl-caffeine heterosynthon) was observed in the caffeine cocrystal with 6-hydroxy-2-naphthoic acid. 

A lot of information can be generated by analyzing the crystal packing in monocarboxylic acids and we confirm that the presence of centrosymmetric supramolecular synthon (i.e. the carboxylic acid dimer) affords centrosymmetric crystals. 

The archetypal self-complementary supramolecular synthons are carboxylic acid dimers, which form i (8) rings (Fig. la). Extension from the discrete zerodimensional dimer into one-, two- and three-dimensional structures can be facilitated by the incorporation of more than one carboxylic acid group into a molecule. Hence simple dicarboxylic acids such as terephthalic acid and isophthalic acid typically exhibit tape structures whereas tricarboxylic acids such as trimesic acid form sheet structures (Fig. 2). 

As stated, hydrogen bonds have been used to construct the majority of finite molecular assemblies. Thus, most synthons used to form finite assemblies in the solid state have been based on hydrogen bonds. Many such synthons have also been used to form networks.2 Examples include single-point hydrogen bonds based on phenols and imidazoles, as well as multi-point hydrogen bonds based on carboxylic acid dimers, pyridone dimers, urea dimers, cyanuric acid-melamine complexes, and pyridine-carboxylic acid complexes.2... 

The crystal structures of six 3,6-diaryl-l,2,4,5-tetrazines have been determined and their molecular packing has been compared to the supramolecular architecture observed in related carboxylic acid dimers. In the tetrazines, covalent N-N bonds are considered to replace the intermolecular O-H- - -O hydrogen bonds of the carboxylic acids. In the system investigated, the covalent six-membered ring of the tetrazine was an appropriate replacement for the carboxylic acid synthon. This apparent interplay between molecular and supramolecular units may have applications in the crystal engineering of new materials (Figure 1) <2003HCA1205>. 

Figure 4.16 The carboxylic acid dimer is used as a supramolecular synthon in two systems with different tectons (a) benzene-p-dicarboxylic acid (b) benzene-1,3,5-tricarboxylic acid.

Figure 5 Molecular packing diagrams of (a) a and (b) p forms of tetrolic acid which are carboxylic acid dimer and catemer synthon polymorphs.

It is well-known, that in most carboxylic acid crystal structures, the conformation of the carboxyl group is synplanar and that the most frequent and dominant interlink is the syn-syn centrosymmetric dimer synthon, II. This synthon is found in nearly a third of all crystalline carboxylic acids, with or without any other functionality being present in the molecule, signifying robustness.1211 Against such a background, the crystal structures of 1,4-cubane-... 

That the dimer synthon is found in as many as a third of all carboxylic acids is quite impressive, considering the very large variety of other functional groups that are present in the acids contained in the CSD. If, however, one were to consider only simple carboxylic adds - that is, with no other functionality present other than carboxyl and hydrocarbon residues - then the proportion of acids that contain dimer synthon II rises to around 85 %. Hence, the qualifier robust is justified in this case. 

Cocrystal systems are assembled through the association of individual molecules into fundamental building block units that are known as supramolecular synthons [13]. For example, one such synthon would be formed by hydrogen-bond interactions between a phenyl-carboxylic acid and a phenyl-amide, with the molecules being linked into a dimeric species through 0 H-N and O-H O hydrogen bonds [14], This mode of interaction can be illustrated using the synthon that would result from the dimerization of benzoic acid and benzamide ... 

The amide-carboxylic acid interaction forms one of the most studied supramolecular synthons. For example, the binary synthon formed by benzamide and benzoic acid arises by the hydrogen-bond interactions that cause the molecules to become linked into a dimeric species through O -- H-N and O-H O hydrogen bonds ... 

As part of a more extensive study of cocrystals formed by isonicotinamide with carboxylic acids, 1 1 products containing the dicarboxylic fumaric or succinic acids [59]. In the structures of these particular cocrystals, the typical discrete dimeric synthon was not observed, but instead effectively infinite assemblies of one-dimensional chains were found instead. In a subsequent work, cocrystals of isonicotinamide containing mixed fumaric/succinic acids were prepared using both solid-state grinding and solution crystallization [60]. A full physical characterization of the products demonstrated that the products consisted of a single cocrystal phase, and were not simple physical mixtures of two cocrystal components. Such solid solutions were proposed as yet another method whereby one might obtain even finer control over the physical properties of cocrystal systems proposed as drug substances. 

Figure 12.1. Aromatic carboxylic acids linked via synthon I (a) 1 forms centro-symmetric dimers, (b) 2 forms linear tapes, (c) 3 forms crinkled tapes and...

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