Graton Jérôme, Berthelot Michel, Gal Jean-François, Laurence Christian, Lebreton Jacques, Le Questel Jean-Yves, Maria Pierre-Charles, Robins Richard
Laboratoire de Spectrochimie et Modélisation (EA 1149, FR 2465), Université de Nantes, 2, rue de la Houssinière, BP 92208, 44322 Nantes Cedex 3, France.
J Org Chem. 2003 Oct 17;68(21):8208-21. doi: 10.1021/jo035018h.
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.
已通过傅里叶变换红外光谱法在四氯化碳中针对参考氢键供体4-氟苯酚测量了乙酰胆碱激动剂尼古丁和去甲烟碱以及模型吡啶、吡咯烷和N-甲基吡咯烷的氢键络合热力学。设计了各种方法来分别测量尼古丁和去甲烟碱中每个氮的氢键受体强度：络合化学计量的变化；与氮上的静电势以及3-取代吡啶、2-取代吡咯烷和2-取代N-甲基吡咯烷系列中的取代基常数的相关性；以及4-氟苯酚与氟化氢键合络合物之间的线性自由能关系。一致发现尼古丁和去甲烟碱有两个活性氢键受体位点，即吡啶氮和吡咯烷氮，并且约90%（对于尼古丁）和80%（对于去甲烟碱）的1:1氢键络合物是与吡啶氮形成的，尽管吡咯烷氮是尼古丁和去甲烟碱在水中的第一个质子化位点。尼古丁中吡咯烷氮的低氢键碱性主要由2-(3-吡啶基)取代基的诱导吸电子和空间效应来解释。络合异构化（AH...Nsp(2) <==> AH...Nsp(3)）的吉布斯自由能划分为焓和熵贡献表明，有利于吡啶氮的选择性是由熵驱动的。认识到尼古丁在氢键中的双功能性对于理解其在非质子介质中的亲脂性和分子识别很重要。当尼古丁和去甲烟碱在其sp(3)氮上被单质子化时，它们通过其sp(2)氮保持显著的氢键碱性，该碱性大于乙酰胆碱酯基的氢键碱性。
