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2.4.1 Formation of acetamido/acetamidomethyl-pyridine cocrystals and salts

Infrared spectroscopy plays a vital role in screening the formation of cocrystal;

since the interaction between a N-heterocyclic compound and carboxylic acid show two broad stretches near 2450 cm^-1 and 1900 cm^-1, characteristic of O-H…N(py) hydrogen bonds.¹⁴ These stretches appeared in the vibrational spectra of all five compounds suggesting the presence of COOH….py intermolecular interactions. However, if the formation of a salt occurs it can be eliminated by looking at the conversion of the carbonyl to the carboxylate anion (COO^-). In the vibrational spectra of compounds 2SUB, 2SEB, 3SUC, and 3HBA the carbonyl stretch appears above 1670 cm^-1; whereas, in compound 2HG the carbonyl stretch is shifted to a lower wavenumber, below 1660

cm^-1 suggesting the presence of COO^- anions, Table 2.3. Furthermore, single-crystal structural determinations carried out on 2HG, 2SUB, 2SEB, 3SUC, and 3HBA confirmed the assignments made on the basis of the vibrational spectroscopy.

Table 2.3 Summary of IR data for compounds 2HG, 2SUB, 2SEB, 3SUC, and 3HBA

Compounds 2HG 2SUB 2SEB 3SUC 3HBA

Observed COOH/COO- Stretch (cm^-1) 1652 1691 1698 1707 1675

Product Salt Cocrystal Cocrystal Cocrystal Cocrystal

The distinction between cocrystal and salts can also be determined upon selective intermolecular distances and angles. In the crystal structures of 2SUB, 2SEB, 3SUC, and 3HBA each carboxylic acid contains distinctly different C-O bond distances corresponding to the C=O (1.217-1.224 Å) and C-O(H) (1.300-1.317 Å) covalent bonds.

Furthermore, the C-N-C endocyclic bond angle of the heterocyclic moieties fall in the range of 114.4^o-119.6^o, which is indicative of a non-ionized pyridine unit. In contrast, in the structure of 2HG the carboxylate C-O bond distances are more similar (1.27/1.23 Å).

In addition, the C-N-C endocyclic bond angle of the heterocyclic moiety is 121.1^o, which is typical for a pyridinium cation.¹⁴

2.4.2 Intermolecular interactions

The five crystal structures obtained exhibit similar primary trimeric supermolecules constructed through the expected intermolecular O-H…N synthon between the dicarboxylic acid and pyridine except for structure 3HBA. In addition to the primary hydrogen bonding within each trimer, the N-H moiety in each acetamido group is further involved in the formation of hydrogen bonds with a neighboring molecule; in all five structures the amide C=O moiety act as the hydrogen bond acceptor. Besides the primary interaction that takes place between the carboxylic acid or carboxylate and acetamido/acetamidomethylpyridine, four other types of motifs are possible in this series of compounds, Figure 2.21. The frequency of occurrence of each type of motif is summarized in Table 2.4.

Figure 2.21 Expected primary acid^…pyridine synthons (I). Three possible interactions involving the N-H hydrogen bond with the amide C=O (II), with the acid C=O (III), with the acid O-H (IV).

The binding motif in the crystal structure of 3HBA is different when compared to the other cocrystals mentioned above, in that the phenolic hydroxy group forms a hydrogen bond to the pyridyl-N, while the carboxylic acid forms a hydrogen bond with the amide (N-H) group on the ligand. This binding preference is not surprising based on the molecular electrostatic potential (MEP) charge calculation carried out indicating that the phenolic hydroxy group is a better donor when compare to the carboxylic acid.¹⁵ Moreover, there have been other similar cases of this interaction between phenolic hydroxy groups and isonicotinamide, where the phenol…pyridine interaction prevailed in the presence of COOH groups.¹⁶ This ‘low-yield’ adduct 3HBA provides more examples with acid…amide synthon III (Figure 2.21) without acid…pyridine recognition I (Figure 2.21). Furthermore, MEP charge calculations can be employed for assigning (and ranking) the relative hydrogen-bond donor/acceptor strengths across a wide range of chemical functionalities.

Overall, pyridine…carboxylic acid intermolecular interactions were observed approximately 90% of the time in this study. Thus this interaction may be employed in subsequent supramolecular synthetic strategies.

Table 2.4 Summary of structural motifs

A search for relevant pyridine…carboxylic acid cocrystals in the CSD⁷ revealed that this interaction occurs around 91% of the time, which was demonstrated in four out of the five structures herein. The self-complementarity of monoacetylated amides is generally a reliable motif with the combination of functionalities present. This intermolecular compability of the amide N-H and the amide C=O may therefore be employed in subsequent supramolecular synthetic strategies based upon a hierarchy of hydrogen bond interactions even in the presence of potentially competitive hydrogen bond acceptors.

2.4.4 Metal coordination abilities of acetamido/acetamidomethyl-pyridine moieties Single-crystal X-ray analysis of 1a-b, 2a, and 3a, has demonstrated that the self-complementary N-H…O=C intermolecular ligand…ligand hydrogen bond interaction is present. The O,O'-chelating anions employed, hexafluoro-2,4-pentanedionate and 1,3-diphenyl-1,3-propanedionate, occupy the four equatorial positions around the metal(II) ions, when the amide moiety is located further away from the equatorial plane as demonstrated by the meta- and para-substituted pyridine-based ligands, it gives the N-H moiety the structural freedom to select a hydrogen bond acceptor, the carbonyl moiety the preferred interaction site in each of the complexes, Figure 2.22.

Figure 2.22 Pictorial representation of the desired coordination chemistry around the M(II) centers after compound binds; as well as the possible hydrogen bond interactions.

The nature of the metal ion does not affect the resulting structure notably because in each case, the metal ion is ‘strapped into’ a fixed geometry dictated by the two anionic chelating ligands. The importance of using chelating ligands for controlling the coordination geometry, and thereby the structural role of the complex ion itself, is illustrated by a previously reported crystal structure of a five coordinate Cu(II) complex compromising of two 4-acetamidopyridine, two acetate ions and a water molecule in the first coordination sphere; in this case the amide…amide hydrogen bond is disrupted by the water molecule, and the result is a complex 3-D architecture.¹⁷

The self-complementary acetamido moiety has also been demonstrated in the preparation of a series of silver(I)-containing 2-D architectures,¹⁸ indicating that the particular supramolecular synthon is robust enough to organize relatively large complex ions into desired extended networks. A search of the CSD showed other examples of amido functional groups containing Ag(I) ions, where those structures also contained extended networks assembled via self-complementary N-H…O=C hydrogen bonds.¹⁹ Other examples include nicotinamide and isonicotinamide with Cu(II) ions to produce 2-D network and similar 2-2-D networks with open channels have been constructed from Ni(II), Cu(II) and Co(II).²⁰

The structures presented here support the idea that control at both the molecular and supramolecular level can be achieved by combining reliable supramolecular reagents

with coordination complexes where the coordination geometry is strictly controlled by the aid of suitable chelating ligands.