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

这项拟议的研究是绿色化学的跨学科合作，旨在解决全球对环境友好和高效的化学过程日益增长的需求，这些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，以开发一种高产率合成分子靶标的无溶剂和原子经济的方法。该项目是基于新的固态合成技术和计算固态建模方法之间的不断发展和反馈。该研究方案的最终目标是开发以计算为导向的方法来产生小的非对称分子，以及以定量的产率和最高的原子效率来指导复杂分子结构的合成，即几乎不产生废物，能量消耗最少，并且不使用本体溶剂。小的非对称分子的有效合成对于需要清洁和经济高效地处理这类前体的工业应用具有最高的相关性。能够通过计算指导大环分子结构的有效构建可能是特别重要的，因为它们在储氢材料、先进药物和分子电子学中具有相关性。这项研究的灵感来自该项目组最近的发现，即在无溶剂的研磨条件下，可逆化学反应可以进行催化热力学平衡，并且这种平衡的结果可以通过计算解释，并且不同于在传统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能偏向于单一产物，甚至在无溶剂和最低能量的条件下导致其定量(100%)形成。项目组已于2011年提供了关于这一发现的原则证明报告。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，它利用固体中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，不浪费原子)、无溶剂和无废物地合成目标分子。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，这四种类型的可逆键化学因其在工业产品中的重要性而被选中：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投票表决的工业合成绿色方法发展中的最大挑战。最近首次报道了一种基于溶液的方法，在良性条件下加强酰胺键的热力学平衡(J.Am化学。SoC。10003)，并将为固体中酰胺的绿色合成提供一个合适的起点。由于拟议研究中开发的新合成原理是通用的，因此这些成功可能随后被转化为各种其他反应，其中一些由于高动力学反应障碍(即感觉到缺乏可逆性)而尚未被考虑。

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).