Directed Covalent Assembly in the Solid State: towards Predictable Solvent-free Synthesis

拟议的研究是绿色化学的跨学科合作，它解决了全球对环境友好和高效的化学过程的日益增长的需求，这些化学过程可以减少化学工业对环境的影响，减缓自然资源的枯竭。这将通过将非传统的固态合成方法与动态共价化学的概念和最先进的计算方法相结合来实现，以开发一种无溶剂和原子经济的方法来合成高产量的分子目标。该项目基于新型固态合成技术和计算固态建模方法之间的持续发展和反馈。该研究计划的最终目标是开发以计算为导向的方法来生成小的非对称分子，以及以定量产量和最高原子效率指导复杂分子结构的合成，即几乎不产生浪费，能量消耗最少，不使用散装溶剂。小型非对称分子的有效合成对于需要清洁和成本效益的方法来制造这种前体的工业应用具有最高的相关性。计算指导有效构建大环分子结构的能力对于它们在储氢材料、先进药物和分子电子学中的相关性可能特别重要。提出研究的灵感来自该项目团队最近的发现，即可逆化学反应可以在无溶剂的研磨条件下进行催化热力学平衡，并且这种平衡的结果既可以计算解释，也不同于在常规溶液环境中获得的结果。特别是，可逆反应体系的固态热力学平衡可以偏向于单一产物，甚至在无溶剂和最小能量条件下导致其定量（100%）形成。项目团队在2011年提供了这一发现的原理证明报告。这一发现开启了一种新的可能性，以前从未在合成有机化学或固态化学的背景下探索过，利用固态的热力学平衡来实现环境友好，原子经济（即起始材料完全转化为所需产品，没有原子浪费），无溶剂和无废物的目标分子合成。拟议的项目将在四种不同类型的可逆键化学的背景下探索这种可能性，选择它们在工业产品中的重要性：二硫键、亚胺键、Diels-Alder偶联和酰胺键的形成。根据绿色化学工业圆桌会议（Green Chemistry Industrial Roundtable）的投票结果，后者代表了工业合成中绿色方法发展的最大挑战。最近首次报道了一种在良性条件下加强酰胺键热力学平衡的基于溶液的方法。化学。Soc. 2009, 131, 10003)，将为固态绿色合成酰胺的发展提供一个合适的起点。由于在拟议的研究中开发的新合成原理是通用的，因此成功可以随后转化为各种其他反应，其中一些由于高动力学反应障碍而尚未考虑（即认为缺乏可逆性）。

The proposed research is an interdisciplinary collaboration in Green Chemistry, which addresses the globally rising need for environmentally benign and efficient chemical processes which could reduce the environmental impact of the chemical industry and slow the depletion of natural resources. This will be done through combining the non-conventional methodologies of solid-state synthesis with concepts of Dynamic Covalent Chemistry and state-of-the-art computational methodologies to develop a solvent-free and atom-economic approach to the synthesis of molecular targets in high yield. The project is based on the continuous development and feedback between novel solid-state synthesis techniques and computational solid-state modelling approaches. The ultimate goal of the research programme is to develop computationally-directed methodologies to generate small non-symmetrical molecules, as well as direct the synthesis of complex molecular architectures in quantitative yields and with highest atom efficiency, i.e. generating almost no waste, with minimal energy expenditure and without using bulk solvents. The efficient synthesis of small non-symmetrical molecules is of highest relevance for industrial applications requiring clean and cost-efficient approaches to such precursors. The capability to computationally guide the efficient construction of macrocyclic molecular architectures may be of particular importance for their relevance in materials for hydrogen storage, advanced medicines and molecular electronics .The inspiration for the proposed research is this project team's recent discovery that reversible chemical reactions can undergo catalysed thermodynamic equilibration under the solvent-free conditions of milling, and that the outcome of such equilibration can be both computationally explained and different from the results obtained in conventional solution environments. In particular, solid-state thermodynamic equilibration of a reversible reaction system can be biased towards a single product and even lead to its quantitative (100%) formation under solvent-free and minimal energy conditions. The project team has provided the proof-of-principle report on this discovery in 2011. This discovery opens a new possibility, never before explored in the context of either synthetic organic chemistry or solid-state chemistry, to exploit thermodynamic equilibration in the solid state for an environmentally benign, atom-economic (i.e. the starting materials are fully converted to desired products, with no atom wasted), solvent- and waste-free synthesis of target molecules. The proposed project will explore this possibility in the context of four different types of reversible bond chemistries, selected for their importance in industrial products: the disulfide bond, the imine bond, Diels-Alder coupling and the formation of the amide bond. The latter represents the top challenge, as voted by a Green Chemistry Industrial Roundtable, in the development of Green methods for industrial synthesis. A solution-based method to enforce thermodynamic equilibration of amide bonds under benign conditions was first reported very recently (J. Am. Chem. Soc. 2009, 131, 10003) and will provide a suitable starting point for the development of green synthesis of amides in the solid state. As the new synthetic principles developed in the proposed research are generic, the successes could subsequently be translated into a variety of other reactions, some of them not yet considered due to high kinetic reaction barriers (i.e. a perceived lack of reversibility).