NMR studies of the conformational interconversion of butaclamol in solution.
1H NMR experiments at 300 MHz have been carried out to determine the identity and study the interconversion of two conformations of butaclamol in solution. The hydrochloride salt in DMSO exists as an equilibrium mixture of two conformations, which differ in their stereochemistry about the ring junction that contains the single nitrogen atom in butaclamol. The trans form has a relative population of 80% and the cis I form 20%. In CDCl3 only the trans form is observed, while in CDCl3-DMSO mixtures, both forms are detected in a ratio (trans:cis I) that decreases as the percentage of CDCl3 decreases. For the free base in either CD2Cl2 or DMSO, only a single set of resonances is observed at room temperature, but as temperature is lowered, peaks from methine protons H4a and H13b near the ring junction broaden and (for samples in CD2Cl2) eventually split into two resonances corresponding to the cis and trans forms. It is suggested that nitrogen inversion is the dynamic process responsible for the interconversion of the two forms. Line shape analysis as a function of temperature yielded an energy barrier of 9.6 +/- 0.5 kcal/mol for the interconversion, in good agreement with values obtained from saturation transfer experiments. In the hydrochloride salt, the barrier in DMSO was somewhat higher, i.e., 17.3 +/- 0.9 kcal/mol, as determined by saturation transfer and variable-temperature measurements.
Casarotto
M G
MG
School of Pharmaceutical Chemistry, Victorian College of Pharmacy Ltd., Parkville, Australia.
Craik
D J
DJ
Lloyd
E J
EJ
D002069:Butaclamol / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D012996:Solutions; D013237:Stereoisomerism
D012996:Solutions; D002069:Butaclamol