Nornicotine aqueous aldol reactions: Synthetic and theoretical investigations into the origins of catalysis

Tobin J. Dickerson, Timothy Lovell, Michael M. Meijler, Louis Noodleman, Kim D. Janda

Research output: Contribution to journalArticlepeer-review

71 Scopus citations

Abstract

The recent discovery that nornicotine 1, a minor nicotine metabolite, can catalyze the aldol reaction under physiologically relevant conditions has initiated research efforts into the potential chemical roles of nicotine metabolites. Herein, we disclose studies aimed at determining the origin and thus mechanism of the nornicotine-catalyzed aqueous aldol reaction. Conformationally constrained compounds designed to mimic the low-energy conformations of nornicotine were synthesized and tested for aldol catalysis; however, none showed rate enhancements on par with nornicotine. To further explore the mechanism of this process, a density functional theory (DFT) study was performed by using a variety of compounds previously tested for catalysis. These in silico studies have uncovered an unprecedented mechanistic subtlety of aqueous aldol reactions. Unlike the single transition state model observed for aldol reactions in organic solvent, the nornicotine-catalyzed reaction in water proceeds via a two-step mechanism in which a water molecule is utilized in both steps and a stable intermediate is generated. In total, these studies validate the proposed enamine-based mechanism of nornicotine-catalyzed aqueous aldol reactions and also provide the basis for future studies into the stereoelectronic nature of individual catalyst structures.

Original languageEnglish
Pages (from-to)6603-6609
Number of pages7
JournalJournal of Organic Chemistry
Volume69
Issue number20
DOIs
StatePublished - 1 Oct 2004
Externally publishedYes

ASJC Scopus subject areas

  • Organic Chemistry

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