NMR Studies of Drugs: Antipyrine and Analogs. I. Use of Achiral and Chiral Lanthanide Shift Reagents to Examine Hindered Rotation.

The 200 MHz ¹H NMR spectra of the analgesic, antipyrine, 1, have been studied in CDC1₃ 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, and with the chiral LSR, tris3-(heptafluoropropylhydroxymethylene)-(+)-camphorato]europium(III), Eu(HFC)₃, 3., Lanthanide-induced shift (LIS) magnitudes and broadening of selected signals are consistent with predominant LSR binding at the carbonyl oxygen with either 2 or 3. Of the different possible conformational regimes for the N-phenyl group of 1, our results appear to rule out a slow exchange limit (SEL) system with the N-phenyl coplanar with the heterocyclic ring. Perpendicular rings in an SEL regime can not be ruled out. A rapidly-rotating N-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) are determined from spectra with added LSR by extrapolation to zero molar ratios of LSR]:1]. Relative slopes in the plots of chemical shift versus LSR]:1] molar ratios are calculated for each proton signal of 1.