NMR studies of drugs: Antipyrine and analogs .1. Use of achiral and chiral lanthanide shift reagents to examine hindered rotation.

The 200 MHz H-1 NMR spectra of the analgesic, antipyrine, (1) under bar, have been studied in CDCl3 solution at ambient temperatures with the achiral lanthanide shift reagent (LSR) tris(6,6,7,7,8,8,8-heptafluoro-2,2-dimethyl-3,5-octanedionato)europium(III), Eu(FOD)(3), (2) under bar, and with the chiral LSR, tris[3-(heptafluoropropylhydroxymethylene)-(+)-camphorato]europium(III), Eu(HFC)(3), (3) under bar. Lanthanide-induced shift (LIS) magnitudes and broadening of selected signals are consistent with predominant LSR binding at the carbonyl oxygen with either (2) under bar or (3) under bar. Of the different possible conformational regimes for the (N) under bar-phenyl group of (1) under bar, our results appear to rule out a slow exchange limit (SEL) system with the (N) under bar-phenyl coplanar with the heterocyclic ring. Perpendicular rings in an SEL regime can not be ruled out, A rapidly-rotating (N) under bar-phenyl (fast exchange limit, FEL system) would also be consistent with observed results. Accurate chemical shifts for the aryl protons (overlapped in the 200 MHz spectrum of unshifted (1) under bar) are determined from spectra with added LSR by extrapolation to zero molar ratios of [LSR]:[(1) under bar]. Relative slopes in the plots of chemical shift versus [LSR]:[(1) under bar] molar ratios are calculated for each proton signal of (1) under bar.