Modulating Supramolecular Reactivity Using Covalent “Switches” on a Pyrazole Platform

Systematic co-crystallizations of halogen- methyl- and nitro-substituted pyrazoles with a library of 20 aromatic carboxylic acids have been carried out using melt and solution-based experiments. The solids resulting from all reactions were screened using infrared spectroscopy in order to determine if a reaction (co-crystal or salt) had taken place. The halogenated pyrazoles, including their dimethyl analogues, gave a supramolecular yield of 55–70%. Replacing a halogen atom (R-X, X = Cl, Br, I) with a nitro (R-NO2) group drops the success rate significantly to 10% due to the reduced charge on the basic nitrogen atom of the pyrazole. Eleven crystal structures were obtained: six were co-crystals and five were salts (including one hydrate). In all six co-crystals, dimeric pyrazole···acid assemblies were constructed via a combination of O–H---N­(pyz) and N–H---O hydrogen bonds corresponding to a 100% supramolecular yield. A variety of weaker halogen-bonds CN---I, I---I and X---O– connect dimers into infinite one-dimensional chains. In contrast, the salts displayed a variety of stoichiometries and a much wider range of noncovalent interactions, although a charge-assisted N+-H---O– hydrogen bond was present in all five structures. In general, the salts lack structural and stoichiometric predictability and stability as compared to the co-crystals. Furthermore, the overall electrostatic charge on the key binding sites on the pyrazole backbone can be modulated by using specific covalent switches, which in turn can increase (or decrease) the success rate for a reaction.