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

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).

IMPACT SUMMARY
The proposed research has tremendous potential to impact different branches of industry, economy and society, with potential beneficiaries including petrochemical, agrochemical, specialty chemicals and pharmaceutical industries; on the societal side potential beneficiaries include public health and environment agencies, as well as individual councils and households.

INDUSTRIAL AND ECONOMIC IMPACT
The proposed research represents a paradigm shift in synthetic chemistry, with the potential to transform some existing laboratory and industrial processes. The energy- and solvent-efficiency of the proposed research, coupled with the ability of design derived from state-of-the-art computational methods, promise large reductions in the energy, solvent and waste involved in laboratory and industrial synthesis. In the short term (5-10 years), this could benefit a range of industries by reducing the costs of resources, and facilitating the fulfilling of environmental legislative requirements. The new methodologies developed in the proposed research could make industries increasingly sustainable and recognisable by the general public as environmentally benign. These economic and public relations benefits are expected to outweigh the financial investment in the development of industrial processes, particularly as most industries already employ large-scale milling technologies. A consortium of leading pharmaceutical companies have published the principal requirements for effective implementation of principles of Green Chemistry. The highest priority was given to an efficient and benign technology for the transformations of amides, which is one of the goals in our proposal.

SOCIETAL AND ACADEMIC IMPACT
The general adaptation, over a period of 5-10 years, of methods developed in the proposed research by both academia, as well as industry, will firstly lead to a reduction of energy and natural resources consumption. This will enable an overall improvement in the state of the environment, reduction of costs to the UK Environment Agency as well as the UK Health Protection Agency, as well as reduced costs associated with environmental care and pollution control imposed on local councils and households. The reduction in environmental impact of both industry and academia will trigger modifications to environmental legislature, making the UK a European and global leader in drafting such documents. The proposed research will increase the public awareness of economic and environmental aspects of academic and industrial research through training post-doctoral research associates who will be highly employable in a range of professions in industry, academia, government and education.

The reduction in use of industrial solvents (e.g. halogenated solvents such as chloroform, hydrocarbons such as hexanes and aromatics such as toluene) will particularly benefit the workforce involved in the chemical and pharmaceutical industries. In the long term (over 10 years), the goals of the proposed research are designed to lead to new materials and synthetic capabilities which will improve the lifestyle and standard of UK citizens, increase the impact of UK industries and benefit the UK economy. The improved solvent-, energy- and atom efficiency (i.e. the ability to convert starting materials into products with minimum amount of waste) will facilitate the availability of new drugs and advanced materials. The development of amide and Diels-Alder chemistries is extremely relevant in that context because of their importance in the synthesis of pharmaceuticals and self-healing polymers, respectively. The new computational and experimental approaches to molecular templating will lead to facile synthesis of complex molecular architectures for use as advanced medicines, interlocked structures for use in molecular electronics or molecular capsules for storage and transport of hydrogen fuel or waste carbon dioxide.