Can We Identify the Salt–Cocrystal Continuum State Using XPS?

X-ray photoelectron spectroscopy (XPS) is used to understand the nature of acid–base crystalline solids, to know whether the product is a salt (proton transfer, O–···H–N+) or a cocrystal (neutral adduct, O–H···N). The present study was carried out to explore if intermediate states of proton transfer from COOH to nitrogen (the proton resides between hydrogen bonded to O and N, O···H···N, quasi state) can be differentiated from a salt (complete proton transfer, N+–H··· O–) and cocrystal (no proton transfer, O–H···N) using N 1s XPS spectroscopy. The intermediate states of proton transfer arise when the pK a difference between the acid and the conjugate base is between −1 and 4, −1 < ΔpK a < 4, a situation common with COOH and pyridine functional groups present in drug molecules and pharmaceutically acceptable coformers. Complexes of pyridine N bases with aromatic COOH molecules in nine salts/cocrystals were cocrystallized, and their N 1s core binding energies in XPS spectra were measured. The proton state was analyzed by single-crystal X-ray diffraction for confirmation. Three new complexes were crystallized and analyzed by XPS spectra (without knowledge of their X-ray structures), to assess the predictive ability of XPS spectra in differentiating salt–cocrystal intermediate states against the extremities. The XPS results were subsequently confirmed by single-crystal X-ray data. Complexes of 3,5-dinitrobenzoic acid and isonicotinamide in 1:1 and 1:2 ratios exist as a salt and a salt–cocrystal continuum, respectively, as shown by the N 1s core binding energies. The proton states of the crystalline solids by XPS are in good agreement with the corresponding crystal structures. Other complexes, such as those of 3,5-dinitrobenzoic acid with 1,2-bis­(4-pyridyl)­ethylene, exhibit a salt–cocrystal continuum, maleic acids with 1,2-bis­(4-pyridyl)­ethylene and acridine are salts, 2-hydroxybenzoic acid and acridine is a salt, and the complex of 3,5-dinitrobenzoic acid and 3-hydroxypyridine is a salt and salt–cocrystal continuum, while fumaric acids with 1,2-bis­(4-pyridyl)­ethylene and acridine are cocrystals. Furthermore, three new acid–base complexes of 3,5-dinitrobenzoic acid with phenazine, 4-hydroxypyridine, and 4-cyanopyridine were studied initially by XPS and then confirmed by X-ray diffraction. In summary, since the N 1s binding energies cluster in a narrow range as cocrystals (398.7–398.9 eV) and salts (400.1–401.1 eV), it is clearly possible to differentiate b