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Ratcheting synthesis

Nature Reviews Chemistry volume 8, pages 8–29 (2024)Cite this article

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Abstract

Synthetic chemistry has traditionally relied on reactions between reactants of high chemical potential and transformations that proceed energetically downhill to either a global or local minimum (thermodynamic or kinetic control). Catalysts can be used to manipulate kinetic control, lowering activation energies to influence reaction outcomes. However, such chemistry is still constrained by the shape of one-dimensional reaction coordinates. Coupling synthesis to an orthogonal energy input can allow ratcheting of chemical reaction outcomes, reminiscent of the ways that molecular machines ratchet random thermal motion to bias conformational dynamics. This fundamentally distinct approach to synthesis allows multi-dimensional potential energy surfaces to be navigated, enabling reaction outcomes that cannot be achieved under conventional kinetic or thermodynamic control. In this Review, we discuss how ratcheted synthesis is ubiquitous throughout biology and consider how chemists might harness ratchet mechanisms to accelerate catalysis, drive chemical reactions uphill and programme complex reaction sequences.

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Fig. 1: Ratcheting synthesis.
Fig. 2: Ratchets for synthesis (biology and artificial systems).
Fig. 3: Driven and spontaneous catalyst dynamics can accelerate the rate of catalysis.
Fig. 4: Ratchets in endergonic synthesis.
Fig. 5: Endergonic synthesis in synthetic methodology.
Fig. 6: Small-molecule machines for programmable synthesis.
Fig. 7: Oligonucleotide-based sequence-programmable synthesis.

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Acknowledgements

We thank the Engineering and Physical Sciences Research Council (EPSRC; grant number EP/P027067/1) and the European Research Council (ERC; advanced grant number 786630) for the funding. D.A.L. is a Royal Society Research Professor.

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  1. These authors contributed equally: Stefan Borsley, James M. Gallagher, Benjamin M. W. Roberts.

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  1. Department of Chemistry, University of Manchester, Manchester, UK

    Stefan Borsley, James M. Gallagher, David A. Leigh & Benjamin M. W. Roberts

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Correspondence to David A. Leigh.

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Glossary

Brownian ratchet

A mechanism for rectifying stochastic motion on an asymmetric potential energy surface in response to an energy input.

Catalytic resonance

The exploitation of periodic changes in binding energy to enhance the rate and control the outcome of heterogeneous catalysed reactions.

Catalyst dynamics

Consequential conformational changes in a catalyst that occur during the catalytic cycle.

Chemical engine cycle

Catalytic cycle for the fuel-to-waste reaction encompassing different chemical and orthogonal dynamic (for example, mechanical) states of a molecular ratchet.

Chemical fuels

The reactants in a fuel-to-waste reaction that release free energy that is transduced to drive an orthogonal nonequilibrium process, either continuously (via an information ratchet mechanism) or through pulsed or sequential operations (often via an energy ratchet mechanism). We find it helpful to use the term ‘fuel’ (as explained here14) to differentiate such reactants from the more typical use of chemical reagents to react directly with functional groups in the transformation to be powered.  

Endergonic synthesis

The synthesis of a molecule that, under the reaction conditions, has a more positive free-energy (higher chemical potential) than the starting materials.

Energy ratchets

Brownian ratchets that transition between two (or more) potential energy surfaces allowing a particle to relax directionally to a local minimum, driving the system away from the global equilibrium.

Fuel-to-waste reaction

The exergonic (that is, free-energy-releasing) conversion of chemical fuel into waste products that provides the chemical potential gradient necessary to drive chemical systems away from equilibrium.

Information ratchets

Brownian ratchets in which differences in the rate of an energy-dissipating process dependant on a stochastic process (for example, dynamics) kinetically drive the system out of equilibrium.

Kinetic asymmetry

The overall kinetic bias in a chemical engine cycle, characterized by the ratcheting constant, Kr, which represents the number of forward cycles divided by the number of backward cycles.

Kinetic gating

The kinetic bias in a process depending on the state of a ratchet, usually represented as a ratio of rates, corresponding to the relative activation energies.

Kinetic proofreading

Kinetic selection of incorrect products for removal, resulting in selectivities exceeding the native thermodynamic preference.

Markov process

A stochastic process in which the probability of an event does not depend on the history of events in the system.

Programmable synthesis

The translation of external inputs into a controlled sequence of reactions.

Ratcheted synthesis

The exploitation of a Brownian ratchet to control reaction pathways and outcomes.

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Borsley, S., Gallagher, J.M., Leigh, D.A. et al. Ratcheting synthesis. Nat Rev Chem 8, 8–29 (2024). https://doi.org/10.1038/s41570-023-00558-y

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