The radical and organometallic methylation of nicotine and nicotine n-oxide

2-Methylnicotine is a major product in the reaction of nicotine with methyllithium and methyl radical, in addition to the previously reported 4- and 6-methylnicotines. The reaction of nicotine N-oxide with methylmagnesium bromide furnishes both 2- and 6-methylnicotine.     

Interaction of nicotine with magnesium aluminum silicate at different pHs: characterization of flocculate size, zeta potential and nicotine adsorption behavior

The purposes of this study were to prepare dispersions in various ratios of nicotine (NCT) and magnesium aluminum silicate (MAS) at different pHs and to investigate interaction of NCT with MAS by characterizing microscopic morphology, particle size and zeta potential of MAS-NCT flocculates. Moreover, the NCT adsorption onto MAS at different pHs were also investigated. At basic medium, incorporating NCT into MAS dispersion brought about a small decrease in the zeta potential of MAS, leading to a loose flocculate formation of MAS. This is likely to be due to an adsorption of unionized form of NCT onto MAS via intermolecular hydrogen bonding. The lower zeta potential, denser matrix structure and larger size of the flocculates was found at neutral and acidic media because the protonated species of NCT could interact with the negatively charged MAS by electrostatic force. In addition the flocculates formed at pH 4 possibly possessed a higher density than those formed at pH 7, suggesting that the diprotonated species of NCT at pH 4 caused stronger interaction with MAS. The adsorption isotherms of NCT onto MAS at different pHs can be described not only using the Langmuir model, but also using the Freundlich model. The higher affinity of NCT adsorption onto MAS at neutral and acidic media was found. However, the adsorption capacity to form NCT monolayer reduced with decreasing the pH of the dispersions because of an adsorption of hydronium ions and a decrease in surface area of adsorption site by flocculation. These findings suggested that the flocculation of MAS dispersion could be induced by incorporation of NCT. The characteristics, such as particle size and zeta potential, of the NCT-MAS flocculates and the adsorption isotherms of NCT onto MAS were depended upon pH of dispersion, in which the different charged species of NCT were formed.     

First-principles calculation of pKa for cocaine, nicotine, neurotransmitters, and anilines in aqueous solution

The absolute pKa values of 24 representative amine compounds, including cocaine, nicotine, 10 neurotransmitters, and 12 anilines, in aqueous solution were calculated by performing first-principles electronic structure calculations that account for the solvent effects using four different solvation models, i.e., the surface and volume polarization for electrostatic interaction (SVPE) model, the standard polarizable continuum model (PCM), the integral equation formalism for the polarizable continuum model (IEFPCM), and the conductor-like screening solvation model (COSMO). Within the examined computational methods, the calculations using the SVPE model lead to the absolute pKa values with the smallest root-mean-square-deviation (rmsd) value (1.18). When the SVPE model was replaced by the PCM, IEFPCM, and COSMO, the rmsd value of the calculated absolute pKa values became 3.21, 2.72, and 3.08, respectively. All types of calculated pKa values linearly correlate with the experimental pKa values very well. With the empirical corrections using the linear correlation relationships, the theoretical pKa values are much closer to the corresponding experimental data and the rmsd values become 0.51-0.83. The smallest rmsd value (0.51) is also associated with the SVPE model. All of the results suggest that the first-principles electronic structure calculations using the SVPE model are a reliable approach to the pKa prediction for the amine compounds.     

Serum proteomic analysis during nicotine self-administration, extinction and relapse in rats

Nicotine dependence is known to induce long‐term neural adaptations in brain. The purpose of this study was to verify whether specific protein patterns related to nicotine self‐administration states could also be detected in a peripheral tissue. A serum proteomic analysis was performed by 2‐DE on samples taken at six time points: N, naïve; P, priming; S, self‐administration; W, withdrawal; E, extinction; R, relapse. After image analysis, spot volume values were submitted to a principal component analysis and relevant comparisons were selected. In N versus S; S versus W; E versus R; S versus R and S versus E comparisons a clear separation between groups could be observed, suggesting that each self‐administration state correlates with a specific protein expression pattern. Partial least squares discriminant analysis was adopted to rank proteins by the contribution to the overall separation. A number of spots were identified; among them, C reactive protein and haemopexin displayed a significant reduction after nicotine administration; two haemopexin isoforms were decreased in the S state and antithrombin III was increased in the E phase. This study showed that specific protein patterns related to the nicotine self‐administration states exist in serum. Further development of this approach may provide biomarkers to assess dependence states of drug‐taking individuals.     

Pyrylium colors from nicotine

Summary The colored substance given by nicotine under special oxidizing conditions and subsequent treatment of the resulting product with concentrated sulfuric acid proved to be pyrido-pyrylium sulfate.

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Zusammenfassung Der Farbstoff, der sich unter speziellen Oxydationsbedingungen und nachfolgender Behandlung des resultierenden Produktes mit konz. Schwefelsäure aus Nikotin bildet, erwies sich als Pyridopyrylium-Sulfat.

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Eesumen El colorante formado de nicotina, usando condiciones especiales de oxidación y tratamento con acido sulfurico concentrado del producto resultando, se revela ser el sulfato de un compuesto de tipo pyrido-pyrylium.

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Résumé La substance colorée obtenue par oxydation de la nicotine dans des conditions particulières et traitement ultérieur du produit résultant par l'acide sulfurique concentré s'est avérée être le sulfate de pyrido-pyrylium.

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Dedicated to ProfessorHans Lieb on occasion of his 70th birthday. Further details of this proof of structure will be published in an appropriate journal on organic chemistry.     

The nicotinic pharmacophore: thermodynamics of the hydrogen-bonding complexation of nicotine, nornicotine, and models

The thermodynamics of the hydrogen-bonding complexation of the acetylcholine agonists nicotine and nornicotine and of model pyridines, pyrrolidines, and N-methylpyrrolidines has been measured in CCl(4) by FTIR spectrometry toward a reference hydrogen-bond donor, 4-fluorophenol. Various methods are devised for measuring separately the hydrogen-bond acceptor strength of each nitrogen of nicotine and nornicotine: variation of the stoichiometry of complexation; correlations with electrostatic potentials on nitrogens and with substituent constants in the series of 3-substituted pyridines, 2-substituted pyrrolidines, and 2-substituted N-methylpyrrolidines; and linear free energy relationships between 4-fluorophenol and hydrogen fluoride hydrogen-bonded complexes. It is consistently found that nicotine and nornicotine have two active hydrogen-bond acceptor sites, the pyridine and pyrrolidine nitrogens, and that ca. 90% (for nicotine) and 80% (for nornicotine) of the 1:1 hydrogen-bonded complexes are formed to the pyridine nitrogen, although the pyrrolidine nitrogen is the first protonation site of nicotine and nornicotine in water. The low hydrogen-bond basicity of the pyrrolidine nitrogen in nicotine is mainly explained by the inductive electron-withdrawing and steric effects of the 2-(3-pyridyl) substituent. The partition of the Gibbs energy of the isomerism of complexation (AH...Nsp(2) <==> AH...Nsp(3)) into enthalpic and entropic contributions shows that the selectivity in favor of the pyridine nitrogen is driven by entropy. It is important to recognize the bifunctionality of nicotine in hydrogen bonding for understanding its lipophilicity and molecular recognition in non protonic media. When monoprotonated on their sp(3) nitrogen, nicotine and nornicotine keep, through their sp(2) nitrogen, a significant hydrogen-bond basicity which is greater than that of the ester group of acetylcholine.     

烟碱样品前处理及分析方法研究进展

烟碱是评价烟草及其制品的感官品质及内在质量的重要指标,同时也是监测食品、环境及人体中尼古丁暴露程度的关键因素。烟碱所在基质复杂,样品多样,针对不同检测环境及要求选择合适高效的分析方法对成功测定烟碱含量至关重要。该文介绍了测定烟草及生物样品中烟碱含量的样品前处理技术（固相/液相微萃取技术和分子印迹法）和常用的检测方法（分光光度法、液相色谱法、气相色谱法、毛细管电泳法、电化学法）,评述了每种方法的适用范围、应用实例和研究进展,并讨论了各种检测方法的灵敏度、准确性和检测效率等。     

High-performance liquid chromatographic determination of pyridostigmine bromide, nicotine, and their metabolites in rat plasma and urine

This study reports on the development of a rapid and simple method for the determination of the antinerve agent drug pyridostigmine bromide (3-dimethylaminocarbonyloxy-N-methyl pyridinium bromide) (PB), its metabolite N-methyl-3-hydroxypyridinium bromide, nicotine (S-1-methyl-5-(3-pyridyl)-2-pyrrolidine), and its metabolites nornicotine (2-(3-pyridyl)pyrrolidine) and cotinine (S-1-methyl-5-(3-pyridyl)-2-pyrrolidone) in rat plasma and urine. The compounds are extracted and eluted by methanol and acetonitrile using C18 Sep-Pak cartridges and separated using high-performance liquid chromatography by a gradient of methanol, acetonitrile, and water (pH 3.2) at a flow rate of 0.8 mL/min in a period of 14 min. UV detection was at 260 nm for nicotine and its metabolites and at 280 nm for PB and its metabolite. The limits of detection ranged between 20 and 70 ng/mL, and the limits of quantitation were 50-100 ng/mL. The average percent recovery of five spiked plasma samples were 85.7 +/- 7.3%, 80.4 +/- 5.8%, 78.9 +/- 5.4%, 76.7 +/- 6.4%, and 79.7 +/- 5.7% and for urine were 85.9 +/- 5.9%, 75.5 +/- 6.9%, 82.6 +/- 7.9%, 73.6 +/- 5.9%, and 77.7 +/- 6.3% for nicotine, nornicotine, cotinine, PB, and N-methyl-3-hydroxypyridinium bromide, respectively. The calibration curves for standard solutions of the compounds of peak areas and concentration are linear for a range between 100 and 1,000 ng/mL. This method is applied in order to analyze the previously mentioned chemicals and metabolites following their oral administration in rats.     

Hydrogen-bond interactions of nicotine and acetylcholine salts: a combined crystallographic, spectroscopic, thermodynamic and theoretical study

The hydrogen-bond (HB) interactions of the monocharged active forms of nicotine and acetylcholine (ACh) have been compared theoretically by using density functional theory (DFT) calculations and experimentally on the basis of crystallographic observations and the measurement of equilibrium constants in solution. The 2,4,6-trinitrophenolate (picrate) counterion was used to determine the experimental HB basicity of the cations despite its potential multisite HB acceptor properties. The preferred HB interaction site of the ammonium picrate salts was determined from a survey of crystallographic data found in the Cambridge Structural Database (CSD) and is supported by theoretical calculations. Two distinct classes of ammonium groups were characterised depending on the absence (quaternary ammonium) or presence (tertiary, secondary and primary ammoniums) of an N(+)HO hydrogen bond linking the two ions. The crystal structure of nicotinium picrate was determined and compared with that of ACh. This analysis revealed the peculiar behaviour of the ammonium moiety of nicotinic acetylcholine receptor (nAChR) ligands towards the picrate anion. Dedicated methods have been developed to separate the individual contributions of the anion and cation accepting sites to the overall HB basicity of the ion pairs measured in solution. The HB basicities of the picrate anions associated with the two different ammonium classes were determined in dichloromethane solution by using several model ion pairs with non-basic ammonium cations. The experimental and theoretical studies performed on the nicotine and ACh cations consistently show the significant HB ability of the acceptor site of nAChR agonists in their charged form. Both the greater HB basicity of the pyridinic nitrogen over the carbonyl oxygen and the greater HB acidity of the N(+)H unit relative to N(+)CH could contribute to the higher affinity for nAChRs of nicotine-like ligands relative to ACh-like ligands.     

Determination of gas phase nicotine and 3-ethenylpyridine,and particulate phase nicotine in environmental tobacco smoke with a collection bed – capillary gas chromatography system

A combined sampling and analysis technique for the determination of gas phase nicotine and 3-ethenylpyridine, and of particulate phase nicotine in environmental tobacco smoke with capillary gas chromatography is reported. The major advantage of the technique is that all of the collected particulate phase material is analyzed by thermal desorption of the collected material rather than by analysis of only a fraction of the sample extracted from the collection medium. A Teflon filter microtube is used to collect particulate phase nicotine. This microtube is follwed by a small Tenax sorbent bed to collect gas phase nicotine and 3-ethenylpyridine. After sampling, the Teflon filter is transferred to a clean glass tube and the tube becomes an insert for a modified packed column injector port where the material collected on the filter is heat desorbed to a cold capillary tubing trap. Gas phase nicotine and 3-ethenylpyridine are also transferred from the Tenax to the GC column by thermal desorption from the Tenax sorbent bed. Gas phase nicotine and 3-ethenylpyridine, and particulate phase nicotine are each determined by GC analysis of the desorbed material. Nicotine and 3-ethenylpyridine are quantitated by the use of external standards. This technique is straightforward and can be used for semi-real time determination of both gas and particulate phase compounds in environmental tobacco smoke. The results obtained by this technique compare well with those obtained by sampling with annular diffusion denuders.     

Formamidines as α-amino carbanion precursors. The synthesis of 2-arylpiperidines, -pyrrolidines,and nicotine analogs

Metallation of the $\text{t}$-butyl formamidines of benzyl or picolinyl amines followed by alkylation with α,ω -dihaloalkanes gives the title compounds after hydrazinolysis.     

Experimental observation of the transition between gas-phase and aqueous solution structures for acetylcholine, nicotine, and muscarine ions

Structural information on acetylcholine and its two agonists, nicotine, and muscarine has been obtained from the interpretation of infrared spectra recorded in the gas-phase or in low pH aqueous solutions. Simulated IR spectra have been obtained using explicit water molecules or a polarization continuum model. The conformational space of the very flexible acetylcholine ions is modified by the presence of the solvent. Distances between its pharmacophoric groups cover a lower range in hydrated species than in isolated species. A clear signature of the shift of protonation site in nicotine ions is provided by the striking change of their infrared spectrum induced by hydration. On the contrary, structures of muscarine ions are only slightly influenced by the presence of water.     

Quantitative analysis of nicotine in several cigarette brands,available in Iran

Summary The Nicotine content of seven brands of cigarettes, currently used in Iran, namely products O, Z, S, H, T, B & A has been measured. The percent of nicotine in various products has an increasing order of O>Z>S>H>T>B>A. Product O with the lowest amount of nicotine is known to be the least popular and A&B with relative high percent ages of nicotine are known to be the most popular cigarettes. The low protein and high sugar levels of some products, which improves the taste and burning quality, also accounts for higher popularity.     

The determination of nicotine and cotinine in plasma

A method to determine plasma nicotine and cotinine simultaneously is described. After a simple extraction procedure, the amounts of nicotine and cotinine present in a sample are determined by gas chromatography using nitrogen-sensitive detection and a fused silica capillary column. The method has been demonstrated to detect nicotine and cotinine plasma concentrations within 1 and 9 ng/ml, respectively. The accuracy and precision of the method was demonstrated using spiked calf and human sera. Data are presented for the direct comparison of the present method with other methods of determination for plasma nicotine and cotinine.     

The application of thin-layer chromatography and phosphorimetry for the rapid determination of nicotine,nornicotine, and anabasine in tobacco

Tobacco is ground and extracted with chloroform, and thin-layer chromatography is used to separate the 3 major tobacco alkaloids—nicotine, nornicotine and anabasine. Each of the alkaloids is quantitatively removed by scraping the spot into a container and dissolving in ethanol-sulfuric acid. A small volume of the ethanol solution is then measured phosphorimetrically. Excellent recoveries of each of the tobacco alkaloids were obtained; the relative standard deviation of analysis was 6% or less for all analyses. The total time for analysis of the 3 alkaloids was less than 90 min. This method is considerably faster and more accurate than previous methods.     

Simultaneous analysis of buprenorphine,methadone, cocaine,opiates and nicotine metabolites in sweat by liquid chromatography tandem mass spectrometry

A liquid chromatography tandem mass spectrometry method for buprenorphine (BUP), norbuprenorphine (NBUP), methadone, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP), cocaine, benzoylecgonine, ecgonine methyl ester (EME), morphine, codeine, 6-acetylmorphine, heroin, 6-acetylcodeine, cotinine, and trans-3′-hydroxycotinine quantification in sweat was developed and comprehensively validated. Sweat patches were mixed with 6 mL acetate buffer at pH 4.5, and supernatant extracted with Strata-XC-cartridges. Reverse-phase separation was achieved with a gradient mobile phase of 0.1% formic acid and acetonitrile in 15 min. Quantification was achieved by multiple reaction monitoring of two transitions per compound. The assay was a linear 1–1,000 ng/patch, except EME 5–1,000 ng/patch. Intra-, inter-day and total imprecision were <10.1%CV, analytical recovery 87.2–107.7%, extraction efficiency 35.3–160.9%, and process efficiency 25.5–91.7%. Ion suppression was detected for EME (−63.3%) and EDDP (−60.4%), and enhancement for NBUP (42.6%). Deuterated internal standards compensated for these effects. No carryover was detected, and all analytes were stable for 24 h at 22 °C, 72 h at 4 °C, and after three freeze/thaw cycles. The method was applied to weekly sweat patches from an opioid-dependent BUP-maintained pregnant woman; 75.0% of sweat patches were positive for BUP, 93.8% for cocaine, 37.5% for opiates, 6.3% for methadone and all for tobacco biomarkers. This method permits a fast and simultaneous quantification of 14 drugs and metabolites in sweat patches, with good selectivity and sensitivity.