Racemization and intramolecular nucleophilic substitution reactions of ibutilide.
The kinetics and mechanisms of the racemization and cyclization reactions of ibutilide are described. The cyclization reaction yields a bell-shaped rate-pH curve consistent with a change in rate-determining step. It is hypothesized that the hydroxyl group leaves to form a carbocation intermediate; this is followed by nucleophilic attack by the amine. This mechanism is supported by kinetic analysis, aniline trapping of carbocation intermediate, and observation of all four stereo-isomers of the resulting quaternary ammonium compound. Whereas racemization can also progress through the carbocation intermediate, a direct SN2 mechanism appears to be the major route for the racemization reaction.
Lambert
W J
WJ
Drug Delivery Research and Development Unit, Upjohn Company, Kalamazoo, MI 49001.
Timmer
P G
PG
Walters
R R
RR
Hsu
C Y
CY
D000889:Anti-Arrhythmia Agents / Q000737:chemistry*; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D015394:Molecular Structure; D000644:Quaternary Ammonium Compounds / Q000737:chemistry; D013237:Stereoisomerism; D013449:Sulfonamides / Q000737:chemistry*
D000889:Anti-Arrhythmia Agents; D000644:Quaternary Ammonium Compounds; D013449:Sulfonamides; C067192:ibutilide