Intermolecular Mechanisms of Proton Transfer in Amidines

Free rotation about the C—N bond in acyclic amidines can place the hydrogen attached to the N(sp3) in a very accessible position to the lone pair of the N(sp2), producing intramolecular hydrogen bonding that enables proton migration. 

In contrast, in cyclic amidines free rotation does not occur, and conformational changes of the ring system cannot lead to intramolecular hydrogen bonding. Only intermolecular proton transfer is possible. Confirming this interpretation is the observation that in cyclic amidines a concentration dependence is observed on the rates of tautomerism, whereas in acyclic systems the proton transfer is independent of concentration. 

Despite the wide belief that hydrogen transfer between electronegative atoms, such as N or O, is a very fast process and that the presence of individual tautomers cannot, therefore, be detected on the NMR time scale, it is possible to slow down this equilibration rate by carefully controlling structural factors in a series of DHP. 

The steric environment of substituents adjacent to the amidine fragment of dihydropyrimidines (particularly the bulkiness of substituents at the neighboring sp3-hybridized carbon atom) also affects tautomeric exchange. [An analogous situation was found in the dihydro-1,3,5-triazine series (Section VIII,C).] Further investigations are necessary to clarify the mechanisms, particularly 15N-NMR studies of the annular tautomerism of dihydropyrimidines, the chemical shift data of which enable calculation of the electron 

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