Issue 13, 2019

Tautomer selection through solvate formation: the case of 5-hydroxynicotinic acid

Abstract

The importance of controlling the crystallization of molecules in specific conformations for the production of crystalline organic materials with highly reproducible physicochemical properties has long been recognized. Using 5-hydroxynicotinic acid (5HNA) as a model the following two questions were addressed in this work: (i) is it possible to promote the crystallization of a tautomeric form dominant in a specific solvent through solvate formation? (ii) Does that form persist if the memory of solvation is erased through thermal desolvation? Single crystal X-ray diffraction (SCXRD) analysis indicated that the crystallization of 5HNA from water and dimethyl sulfoxide do indeed lead to a monohydrate, 5HNA·H2O, and a monosolvate, 5HNA·DMSO, respectively, where the tautomeric form preferred in solution is preserved (zwitterionic in H2O and neutral in DMSO). Subsequent differential scanning calorimetry (DSC), thermogravimetry (TG), powder X-ray diffraction (PXRD), and diffuse reflectance infrared Fourier transform (DRIFT) spectroscopy studies indicated that: (i) albeit upon thermal desolvation different solid forms are initially produced, their structures converge over time to that of the 5HNA starting material, hence to a crystal lattice consisting of the same tautomer; (ii) this tautomer corresponds to a zwitterion. The hydrate and solvate forms showed very distinct solvent loss behaviors at 298 K: 5HNA·H2O did not undergo dehydration even when kept under a reduced pressure, while 5HNA·DMSO was only stable for long periods of time if stored in a closed vial. A thermodynamic analysis based on DSC and Calvet drop microcalorimetry results allowed to rationalize these observations indicating that: (i) 5HNA·H2O is predicted to spontaneously lose water, even for a relative humidity of 100%, hence its robustness is most certainly of kinetical origin; (ii) 5HNA·DMSO is thermodynamically stable when a saturation DMSO pressure can be established over the sample, but becomes unstable when exposed to an atmosphere where the solvent is absent. The kinetically easier desolvation of 5HNA·DMSO compared to 5HNA·H2O may be related to the fact that water is isolated in the crystal lattice (isolated site hydrate) while DMSO is placed in channels (channel solvate).

Graphical abstract: Tautomer selection through solvate formation: the case of 5-hydroxynicotinic acid

Supplementary files

Article information

Article type
Paper
Submitted
13 Dec. 2018
Accepted
08 Marts 2019
First published
08 Marts 2019

CrystEngComm, 2019,21, 2220-2233

Tautomer selection through solvate formation: the case of 5-hydroxynicotinic acid

A. Joseph, J. S. Rodrigues Alves, C. E. S. Bernardes, M. F. M. Piedade and M. E. Minas da Piedade, CrystEngComm, 2019, 21, 2220 DOI: 10.1039/C8CE02108B

To request permission to reproduce material from this article, please go to the Copyright Clearance Center request page.

If you are an author contributing to an RSC publication, you do not need to request permission provided correct acknowledgement is given.

If you are the author of this article, you do not need to request permission to reproduce figures and diagrams provided correct acknowledgement is given. If you want to reproduce the whole article in a third-party publication (excluding your thesis/dissertation for which permission is not required) please go to the Copyright Clearance Center request page.

Read more about how to correctly acknowledge RSC content.

Social activity

Spotlight

Advertisements