A comprehensive classification and nomenclature of carboxyl-carboxyl(ate) supramolecular motifs and related catemers: implications for biomolecular systems

Abstract

Carboxyl and carboxylate groups form important supramolecular motifs (synthons). Besides carboxyl cyclic dimers, carboxyl and carboxylate groups can associate through a single hydrogen bond. Carboxylic groups can further form polymeric-like catemer chains within crystals. To date, no exhaustive classification of these motifs has been established. In this work, 17 association types were identified (13 carboxyl-carboxyl and 4 carboxyl-carboxylate motifs) by taking into account the syn and anti carboxyl conformers, as well as the syn and anti lone pairs of the O atoms. From these data, a simple rule was derived stating that only eight distinct catemer motifs involving repetitive combinations of syn and anti carboxyl groups can be formed. Examples extracted from the Cambridge Structural Database (CSD) for all identified dimers and catemers are presented, as well as statistical data related to their occurrence and conformational preferences. The inter-carboxyl(ate) and carboxyl(ate)-water hydrogen-bond properties are described, stressing the occurrence of very short (strong) hydrogen bonds. The precise characterization and classification of these supramolecular motifs should be of interest in crystal engineering, pharmaceutical and also biomolecular sciences, where similar motifs occur in the form of pairs of Asp/Glu amino acids or motifs involving ligands bearing carboxyl(ate) groups. Hence, we present data emphasizing how the analysis of hydrogen-containing small molecules of high resolution can help understand structural aspects of larger and more complex biomolecular systems of lower resolution.

Keywords: biomolecular systems; crystal engineering; pharmaceuticals; supramolecular motifs.

Figure 1

Carboxyl(ate) groups (syn and anti conformers) and schematic structure of a catemeric chain. The syn and anti lone pairs of the three carboxyl(ate) O atoms are marked by double dots.

Figure 2

Geometric parameters used for separating the carboxyl syn and anti conformers. The syn conformers are defined by a θ value below 120° (marked by a blue dashed line on the histogram; θ corresponds to the O⋯O—H angle). The anti conformers are defined by a θ value greater than 120°. The histogram has been derived from an ensemble of low R-factor (R ≤ 0.05) carboxylic acid containing structures.

Figure 3

Three dicarboxylic acids with an anti carboxyl group involved in an intramolecular hydrogen bond, schematically displayed under the CSD most represented mono-anion dicarboxylic acid form.

Figure 4

All 17 possible carboxyl–carboxyl(ate) dimers with accompanying nomenclature. The cyclic dimer is represented in the top left box; the eight ‘carbonyl dimers’ involving a hydroxyl donor and a carbonyl acceptor group are represented in the top right box; the four ‘hydroxyl dimers’ involving a donor and acceptor hydroxyl group are represented in the central box (the two as-a and aa-s dimers not identified in the CSD are shaded); the four carboxyl–carboxylate dimers are represented in the bottom box.

Figure 5

Geometric parameters used for separating carboxyl–carboxylate dimers involving syn or anti lone pairs. The histogram has been drawn for a sub-ensemble of SS and SA dimers. The syn conformers are defined by a φ value below 130° marked by a blue dashed line on the histogram; φ corresponds to the O(H)⋯O⋯O angle. The anti conformers are defined by a φ value greater than 130°.

Figure 6

Histograms showing the distance distribution between the two O atoms involved in the interlinking hydrogen bond(s) for carboxyl–carboxyl(ate) dimer structures with low R-factors (R ≤ 0.05). The arrows mark the average values. (a) d(O⋯O) histogram for the two carboxyl⋯carboxyl hydrogen bonds of the cyclic dimers. (b) d(O⋯O) histogram for the non-cyclic carboxyl⋯carboxyl hydrogen bonds. All syn and anti conformers are taken into account. (c) d(O⋯O) histogram for the carboxyl⋯carboxylate hydrogen bonds (intramolecular hydrogen bonds are not considered). All syn and anti conformers are taken into account. (d) d(O⋯O) histogram for the carboxyl⋯carboxylate intramolecular hydrogen bond found in mono-anion dicarboxylic acids (see for instance Fig. 3 ▶).

Figure 7

Carboxyl–carboxyl dimers involving a syn conformer and the lone pair of a carbonyl group (‘carbonyl dimer’) along with their rotamer distribution around the interlinking hydrogen bond for structures with R ≤ 0.05. The C and O atoms not belonging to the interacting carboxyl groups are shown in light blue, F and Cl atoms are shown in yellow and green, respectively. (a) Antiplanar SS-S dimer (NAGVUM) and O1—O2—O3—O4 dihedral angle rotamer histogram. (b) Antiplanar SS-A dimer (CBUCDX01) and O1—O2—O3—O4 dihedral angle rotamer histogram. (c) Antiplanar and synplanar SA-S dimers (CLACET01 and ACETAC09) and O1—O2—C3—C4 dihedral angle rotamer histogram. (d) Antiplanar SA-A dimer (MALIAC12) and O1—O2—C3—C4 dihedral angle rotamer histogram.

Figure 8

Carboxyl–carboxyl dimers involving an anti conformer and the lone pair of a carbonyl group (‘carbonyl dimer’). The C and O atoms not belonging to the interacting carboxyl groups are shown in light blue, Cl and Ge atoms are shown in green and dark green, respectively. (a) AS-S dimer (WOKPOC). (b) AS-A dimer (NEWXAO). (c) AA-S dimer involving two fumaric acid molecules (KACNAD). (d) AA-A dimer (DMOXEA01).

Figure 9

Rare carboxyl–carboxyl dimers involving the lone pair of the hydroxyl group (‘hydroxyl dimers’). The C and O atoms not belonging to the interacting carboxyl groups are shown in light blue, N atoms are shown in magenta. The light blue spheres indicate that the molecule has been truncated for visualization purposes. (a) Antiplanar SS-A dimer (CACTUW; R = 0.04). Due to the size of the system, only the interacting fragments are shown. The unusually short carboxyl–Ow distance is given. The red asterisks mark the carboxyl groups involved in the ss-a dimer. (b) Antiplanar sa-s dimer (CAYJAO; R = 0.06). (c) Synplanar sa-s dimer involving two fumaric acid molecules (EMONAW; R = 0.11). The N-containing interacting molecule has been truncated due to its size.

Figure 10

The four carboxyl–carboxylate dimer types and their rotamer distribution around the interlinking hydrogen bond for structures with R ≤ 0.05. The C and O atoms not belonging to the interacting carboxyl or carboxylate groups are shown in light blue, N atoms are shown in magenta. (a) (Left) Antiplanar SS dimer involving two fumaric acid molecules (HUSSUJ). (Middle) Synplanar SS dimer (JEDPUE). An NH₄ ⁺ molecule links the carboxyl(ate) groups. The light blue spheres indicate that the molecule has been truncated for visualization purposes. (Right) O1—O2—O3—O4 dihedral angle rotamer histogram. (b) Antiplanar SA dimer involving two fumaric acid molecules (CLEMAS) and O1—O2—C3—C4 dihedral angle rotamer histogram. (c) Antiplanar AS dimer involving two fumaric acid molecules (SEGSAZ) and O1—O2—O3—O4 dihedral angle rotamer histogram. (d) Antiplanar AA dimer involving two fumaric acid molecules (BAHLEC) and C1—C2—C3—C4 dihedral angle rotamer histogram.

Figure 11

Histograms showing the distance distribution between the two O atoms directly involved in the carboxyl(ate)–water hydrogen bond. For clarity, only water molecules positioned in a 1 Å slice above and below the plane defined by the three heavy atoms of the carboxyl(ate) groups are considered. A cut-off of 2.2 Å for d(C=O⋯H—Ow) or d(C—OH⋯Ow) was used. (a) d(C—OH⋯Ow) histogram involving carboxyl groups. (b) d(C=O⋯Ow) histogram involving carboxylate groups. (c) d(C=O⋯Ow) histogram involving carbonyl O atoms of the carboxyl group.

Figure 12

Examples of the eight catemer types identified in the CSD. The C and O atoms not belonging to the interacting carboxyl groups are shown in light blue. The white and red dots mark the position of the connected carboxylic groups in the catemeric chain. The red asterisks mark the carboxyl groups used for naming the catemer. The light blue spheres indicate that the molecule has been truncated for visualization purposes. (a) SS-S homo-catemer (XONNET); (b) SA-S homo-catemer (ACETAC07); (c) AS-A homo-catemer (GIMRAW); (d) AA-A homo-catemer (DMOXBA01); (e) SS-A·AS-S hetero-catemer (ROZHEU); (f) SS-A·AA-S hetero-catemer (WOKPOC); (g) SA-A·AS-S hetero-catemer (MEKLOE). (h) SA-A·AA-S hetero-catemer (MALIAC12).