Tautomerism and NMR Spectroscopy of Heterocyclic Compounds

Tautomerism in heterocyclic systems—the reversible migration of protons accompanied by changes in bonding and electronic structure—constitutes a fundamental aspect of chemical behaviour that influences reactivity, molecular recognition and biological activity. In five-membered rings such as pyrazoles, imidazoles and indazoles, prototropic tautomerism interconverts NH and N–H positions, altering aromatic character and dipole moment. Larger heterocycles (pyridines, triazoles and thiosemicarbazides) exhibit analogous equilibria that are sensitive to solvent polarity, hydrogen-bonding partners and substituent effects. Nuclear magnetic resonance spectroscopy has emerged as the method of choice for probing tautomeric equilibria in solution and the solid state. High-resolution 1H and 13C NMR can resolve distinct chemical environments, while multinuclear (15N, 19F) experiments and two-dimensional correlation techniques afford definitive assignments of protonation sites and ring-current effects. Solid-state techniques, notably 13C cross-polarisation magic-angle spinning (CP-MAS) NMR, overcome line broadening due to rapid exchange and reveal coexisting tautomers in crystalline domains. Complemented by quantum-chemical calculations of chemical shifts and free-energy profiles, modern NMR studies delineate the interplay of intramolecular hydrogen bonding, substituent electronics and external media in steering tautomeric distributions. These insights underpin rational design of heterocyclic scaffolds for medicinal chemistry, materials science and catalysis, where a change in tautomeric form can dramatically alter binding selectivity, optical properties and redox behaviour.

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Tautomerism and NMR Spectroscopy of Heterocyclic Compounds publication trend

The graph below shows the total number of articles in tautomerism and nmr spectroscopy of heterocyclic compounds across all publications each year (not limited to Nature Index journals).

Technical terms

Tautomerism: The reversible migration of a proton accompanied by relocation of a double bond, leading to isomeric forms (tautomers) that differ in connectivity and electronic distribution.

Heterocyclic compound: An organic molecule featuring a ring structure containing at least one atom other than carbon (commonly nitrogen, oxygen or sulfur).

Nuclear magnetic resonance (NMR) spectroscopy: An analytical technique exploiting nuclear spin interactions in a magnetic field to provide detailed information on atomic environments and molecular structure.

Chemical shift: The resonant frequency of a nucleus in NMR relative to a standard, sensitive to electronic environment and used to distinguish functional groups and tautomers.

Cross-polarisation magic-angle spinning (CP-MAS): A solid-state NMR technique that enhances signal of low-sensitivity nuclei (e.g., 13C) by transferring polarization from abundant nuclei (1H) while spinning the sample at the magic angle to average out anisotropic interactions.

References

1. Experimental and computational studies of tautomerism pyridine carbonyl thiosemicarbazide derivatives. Structural Chemistry (2023).
2. Annular Tautomerism of 3(5)-Disubstituted-1H-pyrazoles with Ester and Amide Groups. Molecules (2019).
3. 13C CPMAS NMR as a Tool for Full Structural Description of 2-Phenyl Substituted Imidazoles That Overcomes the Effects of Fast Tautomerization. Molecules (2020).