Solvent- and functional-group-assisted tautomerism of 3-alkyl substituted 5-(2-pyridyl)-1,2,4-triazoles in DMSO-water.

The tautomerism of a series of 5-alkyl substituted 3-(2-pyridyl)-1,2,4-triazoles in DMSO- d 6 -containing water has been investigated by 1 H, 13 C and 15 N NMR spectroscopy. The populations of the three possible regioisomers in the tautomeric equilibrium (A [3-alkyl-5-(2-pyridyl)-1 H ], B [5-alkyl-3-(2-pyridyl)-1 H ] and C [5-alkyl-3-(2-pyridyl)-4 H ]) were determined. Isomers A (17-40%) and B (54-79%) are the major components and their ratio is insensitive to the substitution pattern, except for the unsubstituted and the methoxymethyl substituted derivatives. The isomer C (3-5%) has been fully characterised for the first time by NMR spectroscopy. Activation energies of tautomerisation (14.74-16.78 kcal mol -1 ) were determined by EXSY experiments, which also supported the involvement of water in the tautomerisation. Substituent effects on the 15 N chemical shifts are relatively small. The DFT study of the tautomerism in DMSO-water showed that both A/B and B/C interconversions are assisted by the pyridine substituent and catalysed by solvent molecules. The NH-A/NH-B tautomerisation takes place via a relayed quadruple proton transfer mediated by three water molecules in the hydrogen-bonded cyclic substructure of a triazole·4H 2 O complex. The equilibrium B ⇄ C involves three steps: NH-B transfer to the pyridyl nitrogen mediated by a water molecule in a 1 : 1 cyclic complex, rotamerisation to bring the pyridinium NH close to N4 of the triazole catalysed by complexation to a DMSO molecule and transfer of the NH from the pyridinium donor to the N4 acceptor via a 1 : 1 complex with a bridging water molecule. This mechanism of 1,3-prototropic shift in triazoles is unprecedented in the literature.