Supramolecular Complexes of Sulfadiazine and Pyridines: Reconfigurable Exteriors and Chameleon-like Behavior of Tautomers at the Co-Crystal–Salt Boundary

Abstract

We apply crystal engineering principles to prepare organic cocrystals and salts of sulfadiazine and pyridines. Pyridines are molecular building blocks utilized in crystal engineering that can disrupt the hydrogen bonded (amidine) N−H•••N (pyrimidine) dimer within the parent sulfa drug (SD) crystals, while providing access to both co-crystals and salts. We have synthesized four co-crystals and three salts of sulfadiazine involving N,N-dimethyl-4aminopyridine, 4-aminopyridine, 4-picoline, 4,4′-bipyridine, (E)-1,2-bis(4pyridyl)ethylene, 1,2-bis( 4-pyridyl)acetylene, and 4-(pyridin-4-yl)piperazine. Single-crystal X-ray analyses reveal three hydrogen-bond motifs, namely, dyads, rings, and chains based involving either (amidine/aniline) N−H•••N (pyridine/ pyrimidine), (pyridinium) + N−H•••N − (amidide), (aniline/piperazine) N− H•••O 2 S (sulfoxide) interactions, or a combination thereof. The hydrogen-bond motifs are assigned as D 1 1 (2), R 2 2 (8), R 2 2 (20), C 2 2 (17), and C 2 2 (13) graph sets. An analysis of the Cambridge Structural Database (CSD) reveals that the S−N bond length is generally shorter in complexes based on an anionic SD, which is consistent with the sulfonamide possessing greater S N character. From an analysis of SD-based structures involving our work and the CSD, we present a heretofore not discussed role of tautomers at the co-crystal−salt boundary. Specifically, the ability of tautomeric forms of SDs to display reconfigurable exteriors, and thereby act as chameleons, enables SDs to accommodate different co-formers by assuming different geometries and adopting different regions along the co-crystal−salt boundary.

Pharmaceutical salts of ciprofloxacin with dicarboxylic acids

“…It has been shown that components with DpK a < À1 form mostly cocrystals, while systems with DpK a > 4 tend to form exclusively salts. This ''rule'' has been also adjusted to various drug/coformer pairs (Kathalikkattil et al, 2011;da Silva et al, 2013;Sanphui et al, 2013;Elacqua et al, 2013;Thomas et al, 2014), despite the fact that DpK a range between 0 and 3 remains hardly predictable. For ciprofloxacin (pK a = 8.74 for the piperazine fragment (Ross and Riley, 1990)) and coformers of interest, however, the DpK a values are considerably greater than 3 units, which strongly suggests proton transfer and salt formation to occur.…”

Crystal structure, Hirshfeld surface analysis, spectroscopic and biological studies on sulfamethazine and sulfaquinoxaline ternary complexes with 2,2′-biquinoline

“…materials, pharmaceuticals). In the case of sulfonamide metal complexes, inter and intramolecular hydrogen bonding, π•••π, and C-H•••π interactions have a great influence on the crystal lattice stabilization 1,3,5,8,17 . The Hirshfeld surface analysis is a powerful tool for visualizing and quantifying the contribution of such intermolecular interactions to supramolecular assemblies [18][19][20] .…”

Salt forms of sulfadiazine with alkali metal and organic cations

“…Conformationally, it is again an O atom that lies closest to the plane of the aniline ring, but in contrast to the SD anions, this O atom is anti to the pyrimidine ring. An expected small increase in S-N bond length is also seen for SDH 2 as compared to the SD anions (Elacqua et al, 2013;Buist et al, 2014). Another feature common in other structures with SDH 2 cations is a centrosymmetric R 2 2 (8) hydrogenbonded dimer of cations formed utilizing amide and pyrimidine N atoms (Buist et al, 2014).…”

“…Pan et al, 2013;Buist et al, 2014), as have studies of cocrystal phases featuring neutral SDH (e.g. Elacqua et al, 2013). Structures of the deprotonated Table 1 Experimental details.…”

“…Salt structures of SD with organic cations are also well known (e.g. Elacqua et al, 2013;Heren et al, 2006). Somewhat strangely, there are very few structural studies of s-block metal complexes of SD.…”