Nicotine chemistry

Sheridan R P, R Ndakantan, J S Dixon and R Venkataraghavan 1986. The Ensemble Approach to Distanc Geometry Application to the Nicotinic Pharmacophore. Journal of Medicinal Chemistry 29 899-906. 

One interesting problem frequently recurring in heterocyclic chemistry, particularly with respect to nitrogen heterocycles, is tautomeric equilibria. Too many methods are available for the elucidation of equilibrium positions and tautomeric equilibrium constants (Kj) to adequately review the whole question here. However, the Hammett equation provides one independent method this method has the advantage that it can be used to predict the equilibrium position and to estimate the equilibrium constant, even in cases where the equilibrium position is so far to one side or the other that experimental determination of the concentration of the minor component is impossible. The entire method will be illustrated using nicotinic acid as an example but is, of course, completely general. 

The Hofmann-Loeffler-Freytag reaction has been described with A-chloro-as well as A-bromoamines—the former however usually give better yields. A-chlorinated primary amines react well in the presence of Fe-(II) ions. Just like the Barton reaction, the Hofmann-Loeffler-Freytag reaction has been applied mainly in steroid chemistry. An interesting example from alkaloid chemistry is the synthesis of nicotine 12 by Loeffler ... 

FIGURE 10.11 Interaction of pathways for degradation of pyridine-2-carboxylate, pyridine-3-carboxylate, and nicotine. (From Neilson, A.H. and Allard, A.-S., The Handbook of Environmental Chemistry, Springer, Heidelberg, 1998. With permission.)... 

Nearly all of the microbial and mammalian transformation studies with this group of alkaloids have been focused on nicotine. Microorganisms have been used to resolve racemic nicotine to make available unnatural (/ )-(+)-nicotine for biological evaluation. Highly significant work has detailed the mechanism of nicotine oxidation in mammals, and has resulted in the identification of reactive intermediates formed as the alkaloid is transformed by hepatic monooxygenases. The chemistry and pharmacology of the pyridine alkaloids is discussed by Strunz and Findlay in Volume 26 of this treatise. 

The acid-base chemistry of nicotine is now well known and investigations have shown that nicotine in tobacco smoke or in smokeless tobacco prodncts can exist in pH-dependent protonated or nnprotonated free-base forms. In tobacco smoke, only the free-base form can volatilize readily from the smoke particnlate matter to the gas phase, with rapid deposition in the respiratory tract. Using volatility-based analytical measurements, the fraction of nicotine present as the free-base form can be quantitatively determined. For smokeless tobacco products, the situation differs because the tobacco is placed directly in the oral cavity. Hence, the pH of smokeless tobacco prodncts can be measured directly to yield information on the fraction of nicotine available in the nnprotonated free-base form. It is important to characterize the fraction of total nicotine in its conjugate acid-base states as this dramatically affects nicotine bioavailability, because the protonated form is hydrophilic while the nnprotonated free-base form is lipophilic and thus readily diffuses across membranes (Armitage and Turner 1970 Schievelbein et al. 1973). As drug delivery rate and addiction potential are linked (Henningfield and Keenan 1993), increases in delivery rate due to increased free-base levels affect the addiction potential. 

Abstract For more than a half century, tobacco manufacturers have conducted sophisticated internal research to evaluate nicotine delivery, and modified their products to ensure availability of nicotine to smokers and to optimize its effects. Tobacco has proven to be a particularly effective vehicle for nicotine, enabling manipulation of smoke chemistry and of mechanisms of delivery, and providing sensory cues that critically inform patterns of smoking behavior as well as reinforce the impact of nicotine. A range of physical and chemical product design changes provide precise control over the quantity, form, and perception of nicotine dose, and support compensatory behavior, which is driven by the smoker s addiction to nicotine. Cigarette... 

Nicotinic acid and nicotinamide are precursors of the coenzymes NAD+ and NADP+, which play a vital role in oxidation-reduction reactions (see Box 7.6), and are the most important electron carriers in intermediary metabolism (see Section 15.1.1). We shall look further at the chemistry of NAD+ and NADP+ shortly (see Box 11.2), but note that, in these compounds, nicotinamide is bound to the rest of the molecule as an A-pyridinium salt. 

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