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Computer-aided molecular design of solvents for accelerated reaction kinetics

Nature Chemistry volume 5, pages 952–957 (2013)Cite this article

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Abstract

Solvents can significantly alter the rates and selectivity of liquid-phase organic reactions, often hindering the development of new synthetic routes or, if chosen wisely, facilitating routes by improving rates and selectivities. To address this challenge, a systematic methodology is proposed that quickly identifies improved reaction solvents by combining quantum mechanical computations of the reaction rate constant in a few solvents with a computer-aided molecular design (CAMD) procedure. The approach allows the identification of a high-performance solvent within a very large set of possible molecules. The validity of our CAMD approach is demonstrated through application to a classical nucleophilic substitution reaction for the study of solvent effects, the Menschutkin reaction. The results were validated successfully by in situ kinetic experiments. A space of 1,341 solvents was explored in silico, but required quantum-mechanical calculations of the rate constant in only nine solvents, and uncovered a solvent that increases the rate constant by 40%.

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Figure 1: CAMD algorithm illustrated with a Menschutkin reaction.
Figure 2: Comparison of QM-calculated and experimental rate constants in several solvents.
Figure 3: Time evolution of product concentration in different solvents.

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Acknowledgements

The authors acknowledge funding from the Engineering and Physical Sciences Research Council (EPSRC) (EP/E016340, EP/J003840/1, EP/J014958/1), funding from EPSRC and Syngenta Cooperative Awards in Science and Engineering (CASE) award, access to computational resources and support from the High Performance Computing Cluster at Imperial College London. We are thankful to D. Blackmond for valuable discussions.

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Authors and Affiliations

  1. Department of Chemical Engineering, Centre for Process Systems Engineering, Imperial College London, London, SW7 2AZ, UK

    Heiko Struebing, Zara Ganase, Panagiotis G. Karamertzanis, Eirini Siougkrou, Amparo Galindo & Claire S. Adjiman

  2. Department of Chemistry, Imperial College London, London, SW7 2AZ, UK

    Peter Haycock & Alan Armstrong

  3. Process Studies Group, Syngenta, Jealott's Hill International Research Centre, Bracknell, RG42 6EY, Berkshire, UK

    Patrick M. Piccione

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Contributions

H.S. contributed to the QM-CAMD methodological development and carried out all computations, with the help of P.G.K. and E.S. Z.G. performed and analysed all the experiments, with the help of P.H. for the NMR measurements. P.M.P. provided input for the interpretation of the kinetic data. A.A., A.G. and C.S.A. designed the methodology, supervised the project and prepared the manuscript. All authors edited the manuscript.

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Correspondence to Claire S. Adjiman.

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Struebing, H., Ganase, Z., Karamertzanis, P. et al. Computer-aided molecular design of solvents for accelerated reaction kinetics. Nature Chem 5, 952–957 (2013). https://doi.org/10.1038/nchem.1755

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