A Co-operative Bimetallic Approach for the Transformation of Lithiation

锂离子是构建大大小小分子的最佳工具之一。它的应用超越了化学，并跨越了其他学科，如生物化学和材料科学。它提供了一种有效的直接方法来打破惰性C-H键(在有机化合物中普遍存在)，并将它们转化为活性C-Li键，这些C-Li键可以用来制造人类维持日常生活质量所需的无数分子。有机锂工具在世界各地的学术实验室和许多精细化学品的制造中都有使用，特别是药物(据估计，95%的已制造药物在其制备过程中涉及有机锂工具)。作为最著名的有机锂工具，丁基锂在合成化学中几乎无处不在，其重要性也在继续升级，这一事实证明了化工公司FMC最近在印度海得拉巴和张家港(中国)开设了新的丁基锂工厂，以满足金砖四国(巴西-俄罗斯-印度-中国)新兴经济体快速扩张的制药业务。由于丁基锂可以破坏大量的碳氢键以及执行其他断键、成键任务，因此它被广泛用于药物开发。有机锂工具还用于制备其他特种化学品，如农用化学品、生物化学品、催化剂、染料和香水。如何完善C-H键的活化是世界上最紧迫的重大科学挑战之一，因为鉴于化石燃料的迅速枯竭，必须找到新的创新方法，将烷烃等廉价而丰富的原材料转化为珍贵的功能性有机化合物。尽管锂离子具有广泛的用途，但作为C-H键活化的一种直接形式，它受到了严重的限制。对其长期可持续性打上问号的一个主要限制是，它完全是一个化学计量过程。例如，需要一摩尔的有机锂工具来制造一摩尔的目标产品。此外，锂化通常需要能源浪费的低温条件以及大量昂贵和危险的乙醚溶剂。它也有许多固有的化学局限性，包括官能团的耐受性差，不能与弱酸性的C-H键反应，以及与后续过渡金属催化的成键反应不相容。将锂离子转化为亚化学计量比过程，最终将其发展为催化过程是本项目雄心勃勃的目标。例如，使用少至0.1摩尔或更少的有机锂工具来制造1摩尔的目标产品。为了实现这一目标，该项目将在双金属化学中开发一个新的概念，即协同逐步金属-金属协作性(基本上是两种金属在单独的分子中一个接一个地工作)，建立在PI最近开创的成功但完全不同的协同同步金属-金属协作性(基本上两种金属在同一分子中并行工作)的基础上。首先，将对锂锌协作性进行筛选。鉴于上文提到的一长串应用，开发催化锂化将是开创性的，具有直接的化学和经济效益以及间接的社会效益。在实现催化锂化的过程中，将出现一个有趣的、有用的新化学库，包括直接C-H键激活的改进方法、新的组合锂离子-Negishi偶联和其他组合锂离子-过渡金属键形成策略、具有高官能团耐受性的反应，以及使用更环保的溶剂和更温和的反应条件的“更绿色”过程。与现有有机锂工具无法打破的纽带也将使用新的钾基工具来打破。

Lithiation is one of best tools for building molecules big and small. Its application transcends chemistry and crosses over to other disciplines such as biochemistry and materials science. It offers an efficient direct way of breaking inert C-H bonds (ubiquitous in organic compounds) and transforming them into reactive C-Li bonds which in turn can be used to make a myriad of molecules, that mankind needs to sustain the quality of our daily lives. Organolithium tools find employment in academic laboratories worldwide and in the manufacture of many fine chemicals, in particular pharmaceuticals (it has been estimated that 95% of manufactured pharmaceuticals involve an organolithium tool in their preparation). The best known organolithium tool, butyllithium is near ubiquitous in synthetic chemistry, and its importance continues to escalate as evidenced by the fact that the chemical company FMC recently opened new butyllithium plants in Hyderabad (India) and Zhangjiagang (China) to service the rapidly expanding pharmaceutical business in the emerging BRIC (Brazil-Russia-India-China) economies. Because butyllithium can break numerous carbon-hydrogen bonds as well as performing other bond-breaking, bond-making tasks, it is widely used in drug development. Organolithium tools are also used to prepare other specialty chemicals such as agrochemicals, biochemicals, catalysts, dyes and perfumes. How to perfect C-H bond activation is one of the World's most pressing scientific grand challenges as new innovative ways must be found for converting cheap and abundant raw materials such as alkanes into precious functionalised organic compounds given the rapid depleting of fossil fuels. Despite its vast utility, lithiation, a direct form of C-H bond activation, suffers from severe limitations. A major limitation which puts a question mark against its long term sustainability is that it is exclusively a stoichiometric process. For example one mole of the organolithium tool is needed to make one mole of the target product. Moreover, lithiation often requires energy wasteful cryogenic conditions as well as ethereal solvents which are expensive and hazardous on a large scale. It also has many intrinsic chemical limitations including a poor tolerance of functional groups, a failure to react with weakly acidic C-H bonds, and incompatibility with subsequent transition metal catalysed bond-forming reactions.To transform lithiation into a substoichiometric process, ultimately developing it to a catalytic process is the ambitious goal of this project. For example, to use as little as 0.1 mole or less of the organolithium tool to make one mole of the target product. To reach this goal, the project will develop a new concept in bimetallic chemistry, synergistic stepwise metal - metal' co-operativity (basically two metals working one after the other in separate molecules) building on the successful, but wholly distinct foundation of synergic synchronised metal - metal' co-operativity (basically two metals working side-by-side in the same molecule) that the PI has recently pioneered. Initially a lithium-zinc co-operativity will be screened. Developing catalytic lithiation will be groundbreaking with direct chemical and economic benefits as well as indirect societal benefits given the long list of applications mentioned above. A library of interesting, useful new chemistry not currently possible in lithiation will emerge on the journey to achieving catalytic lithiation, including improved methods for direct C-H bond activation, new combined lithiation - Negishi coupling and other combined lithiation - transition metal bond forming strategies, reactions with high functional group tolerance, and "greener" processes using more environmentally friendly solvents and milder reaction conditions. Bonds impossible to break with existing organolithium tools will also be broken using new potassium based tools.