PROTON, C-13, AND N-15 NUCLEAR MAGNETIC-RESONANCE AND CNDO-2 STUDIES ON THE TAUTOMERISM AND CONFORMATION OF AMILORIDE, A NOVEL ACYLGUANIDINE

The favored ground-state structures were determined for the novel acylguanidine diuretic, amiloride (2a.HCl), and its free base form (2a) using natural-abundance 1H, 13C, and 15N NMR techniques and CNDO/2 theoretical calculations. Amiloride was found to exist primarily in the acylamino tautomer form as planar conformer Fl, whereas free base 2a was shown to prefer the acylimino tautomer form as planar conformer Al (and/or A4). The conformational preference (i.e. as conformer Al or as conformer A4) of 2a was not established. The dynamic mechanism(s) for the experimentally observed rapid equilibration of the terminal amino groups in 2a and 2a-HCl and. when N-substituted. their substituents were explored by the CNDO/2 method. Of the six possible pathways considered for effecting N-10-N-11 interconversion in 2a, a novel mechanism involving a synchronous rotation around ø2 and ø3 (path F) was calculated to have the lowest barrier to interconversion. Experimental verification of this novel mechanism was attempted, but not found, by preparation of an appropriate model, 11, and subsequent determination of the ΔG≠ values (14.7-14.8 kcal/mol) for 11 and pyrazine analogues 4e and 4e-HC1 using the dynamic 13C NMR technique in Me2SO-d6-CD3OD. Based on the results of these studies, it is concluded that free base 2a is likely to undergo N-10-N-11 interconversion via simple ø3 rotation and/or ø2 rotation plus inversion. Accordingly, amiloride (2a-HCl) must equilibrate by a ø3 rotation mechanism. © 1979, American Chemical Society. All rights reserved.