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

拟议的研究是绿色化学领域的跨学科合作，旨在满足全球对环境友好和高效化学工艺的日益增长的需求，这些工艺可以减少化学工业对环境的影响，减缓自然资源的枯竭。这将通过将固态合成的非常规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，以开发无溶剂和原子经济的方法来以高产率合成分子靶。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计算指导的方法来生成小的非对称分子，以及指导复杂分子结构的定量合成，并具有最高的原子效率，即几乎不产生废物，具有最小的能量消耗，并且不使用散装溶剂。小的非对称分子的有效合成对于需要清洁和成本有效的方法来制备这种前体的工业应用具有最高的相关性。通过计算指导大环分子结构的有效构建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。拟议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条件下进行催化热力学平衡，并且这种平衡的结果可以通过计算来解释，并且与传统溶液环境中获得的结果不同。特别是，可逆反应体系的固态热力学平衡可能偏向单一产物，甚至导致其在无溶剂和最小能量条件下定量（100%）形成。项目小组在2011年提供了关于这一发现的原理证明报告。这一发现开辟了一种新的可能性，以前从未在合成有机化学或固态化学的背景下探索过，以利用固态中的热力学平衡用于环境友好的，原子经济的（即起始材料完全转化为所需的产物，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，这些化学因其在工业产品中的重要性而被选择：二硫键，亚胺键，Diels-Alder偶联和酰胺键的形成。后者代表了绿色化学工业圆桌会议在开发工业合成的绿色方法方面的最大挑战。最近首次报道了在良性条件下加强酰胺键的热力学平衡的基于溶液的方法（J. Am. 2009，131，10003），并且将为固态酰胺的绿色合成的开发提供合适的起点。由于拟议研究中开发的新合成原理是通用的，因此这些成功随后可以转化为各种其他反应，其中一些反应由于动力学反应障碍高（即感知到缺乏可逆性）而尚未考虑。

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).