Equipe Chimie et Biochimie Théoriques, SRSMC, Nancy-University, CNRS, BP 70239, 54506 Vandoeuvre-lès-Nancy, France.
J Am Chem Soc. 2010 Feb 24;132(7):2410-6. doi: 10.1021/ja910350q.
The reactivity of alkyllithium-lithium-aminoalkoxide unimetallic superbases has been investigated. These systems are used for deprotonative lithiation of pyridine derivatives in apolar non-coordinating media with excellent regio- and chemoselectivity, in deep contrast with alkyllithium. With the aim of getting a better understanding of the chemistry behind these promising reagents, we have carried out a joint experimental and theoretical study of the metalation of 2-chloropyridine with combinations of nBuLi and (S)-(-)-N-methyl-2-pyrrolidinylmethoxide (LiPM). Nucleophilic addition or alpha-lithiation has been observed, depending on conditions (solvent, temperature, stoichiometry), while ortho-metalation was not detected. Theoretical calculations using Density Functional Theory (B3LYP/6-31G(d) method) have then been carried out in gas phase at 195 K to characterize the relevant chemical species (reactive aggregates, transition structures) and estimate free energies of activation and relative reaction rates. Solvent effects in hexane have been neglected according to previous calculations. The effect of coordinating solvents such as THF has been qualitatively discussed. A major achievement of the present work has been to demonstrate that chemoselectivity crucially depends on aggregate type: dimers systematically lead to nucleophilic addition, while tetramers lead to alpha-lithiation. Besides, the calculations predict dimers to be more reactive than tetramers, yet they are much less stable, so that the observed selectivity results from the combination of both properties. A simple procedure to evaluate the basicity of an organlithium compound has been proposed. It has allowed us to show that the nBuLi-LiPM tetramer has a significantly larger basicity than its corresponding dimer, which is not at all the case for nBuLi aggregates, thus explaining differences in selectivity. Solvent and temperature effects on nBuLi-LiPM reactivity have been analyzed. By increasing the temperature in hexane, or changing the solvent from hexane to THF, dimer concentration is expected to rise, and likewise the weight of nucleophilic addition rises, in agreement with the experimental findings.
已研究了烷基锂-锂-氨基醇盐单金属超强碱的反应性。这些系统用于在非配位极性介质中对吡啶衍生物进行去质子化锂化，具有出色的区域和化学选择性，与烷基锂形成鲜明对比。为了更好地了解这些有前途的试剂背后的化学原理，我们对 nBuLi 和（S）-（-）-N-甲基-2-吡咯烷甲醇（LiPM）的组合对 2-氯吡啶的金属化进行了实验和理论联合研究。根据条件（溶剂、温度、化学计量比）观察到亲核加成或α-锂化，而未检测到邻位金属化。然后，在 195 K 下使用密度泛函理论（B3LYP/6-31G(d)方法）在气相中进行理论计算，以表征相关化学物质（反应性聚集体、过渡态）并估计活化自由能和相对反应速率。根据先前的计算，忽略了在己烷中的溶剂效应。定性讨论了配位溶剂（如 THF）的影响。本工作的一个主要成就是证明化学选择性取决于聚集体类型：二聚体系统地导致亲核加成，而四聚体导致α-锂化。此外，计算预测二聚体比四聚体更具反应性，但它们的稳定性要低得多，因此观察到的选择性是这两种性质的组合。提出了一种评估有机锂化合物碱性的简单方法。它使我们能够表明 nBuLi-LiPM 四聚体的碱性明显大于其相应的二聚体，这与 nBuLi 聚集体的情况完全不同，从而解释了选择性的差异。分析了溶剂和温度对 nBuLi-LiPM 反应性的影响。通过在己烷中升高温度或从己烷改变溶剂为 THF，预计二聚体浓度会增加，亲核加成的比例也会增加，这与实验结果一致。
