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

The Journal of Organic Chemistry
Tobin J DickersonKim D Janda

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 provi...Continue Reading

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Oct 31, 2002·Proceedings of the National Academy of Sciences of the United States of America·Tobin J Dickerson, Kim D Janda
Jun 20, 2003·Proceedings of the National Academy of Sciences of the United States of America·Tobin J Dickerson, Kim D Janda

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Citations

Nov 4, 2009·Chemical Communications : Chem Comm·Monika Raj, Vinod K Singh
Jul 15, 2005·Proceedings of the National Academy of Sciences of the United States of America·Andrew P BroganKim D Janda
Sep 27, 2006·Angewandte Chemie·Andrew P BroganKim D Janda
Nov 15, 2006·Angewandte Chemie·Yujiro Hayashi
May 13, 2010·Organic & Biomolecular Chemistry·Angel L Fuentes de ArribaJoaquín R Morán
Nov 15, 2017·Chemphyschem : a European Journal of Chemical Physics and Physical Chemistry·Pedro S Pereira da SilvaManuela Ramos Silva
Mar 26, 2008·Chemical Communications : Chem Comm·Andrew P BroganKim D Janda
Jun 16, 2010·The Journal of Organic Chemistry·Peter HammarFahmi Himo
Jun 6, 2006·The Journal of Organic Chemistry·Mathieu Lemay, William W Ogilvie
Oct 29, 2008·The Journal of Organic Chemistry·Michael C PirrungJianmei Wang
Nov 19, 2005·The Journal of Organic Chemistry·Xiyun Zhang, K N Houk

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