Molecular ratchets

They force chemical reactions to run backwards, driving them energetically uphill. Molecular ratchets trap unstable molecules, spin molecular motors, and even generate electricity from light.

The chemical reactions we perform in the lab, whether they are under thermodynamic or kinetic control, form thermodynamically stable products. Nature, on the other hand, often operates away from thermodynamic equilibrium and carries out endergonic reactions. To perform endergonic reactions, nature pairs them with exergonic processes, leveraging the free energy released like a fuel. These reaction cycles are called molecular ratchets. They allow nature to develop specific structures and perform functions vital for life. Just like a mechanical ratchet permits movement solely in one direction, a molecular ratchet^1,2) is a chemical reaction cycle, where the components predominantly react in a single direction.

What does such a molecular ratchet look like? Considering the endergonic reaction converting A to B (Figure 1), B is not formed spontaneously. To produce B from A, an alternative reaction pathway driven by exergonic reactions must be used, forming a reaction cycle through intermediates A‘ and B‘. If there is a preference for A to convert into A‘ and for B‘ to convert into B, the reaction cycle acts as a molecular ratchet, enabling the formation of B through a pathway of A→A‘→B‘→B.³⁾ Ultimately, the endergonic reaction A→B is accomplished. Akin to nature using ATP hydrolysis to drive endergonic reactions or perform motion, the reactions A→A‘ and B‘→B are often driven by external stimuli such as concentration gradients, chemical fuels or light.

Recently, artificial molecular ratchets have gained interest, because they can both produce high-energy species and promote unidirectional motion within a structure.

In the following, we present examples of unidirectional motion, out-of-equilibrium structures, control of product distribution, and the generation of concentration gradients—one way nature stores energy—all achieved using molecular ratchets.

Ratchets propel molecular motion

Molecular motors exist in nature: one of the most commonly known motors is adenosin triphosphate (ATP) synthase, which uses H⁺ diffusion down an ion concentration gradient across a membrane to rotate its chiral structure unidirectionally and thereby drive endergonic formation of ATP from its diphosphate derivative ADP. Due to this example, chemists assumed that a molecular motor^4,5) had to be chiral to rotate unidirectionally, akin to a mechanical ratchet. Therefore, in 1997, Kelly and his group designed a ratchet-like molecular rotor R (Figure 2, white box).⁶⁾ However, despite its helically chiral structure, both clockwise and anticlockwise rotations are equally likely. Hence, molecular motors seem to need both: information about directionality of movement (e.g. a chiral input) and a driven reaction pathway to propel the reaction unidirectionally—such as the proton gradient used in ATP synthase.

The fact that the motor itself does not need to be chiral is shown by molecular motor M, designed by Leigh and his group,⁴⁾ which features two carboxylic acids on opposite sides of the rotary axis (Figure 2). The diacid-state of the motor can have two equally likely conformers, M-1 and M-4. The acid moieties of the motor can condense into a cyclic anhydride, which, again, exists in two equally likely conformers, M-2 and M-3. These four states form a reaction cycle. To obtain a molecular ratchet and unidirectional motion, the symmetry of the reaction cycle has to be broken. Two reactants achieve that: a chiral coupling reagent (S,S)-F for anhydride condensation and a chiral catalyst (S)-C for anhydride hydrolysis (Figure 2, grey box). M-1 reacts faster with (S,S)-F than M-4, while M-3 reacts faster with (S)-C than M-2, resulting in an anticlockwise rotation of the motor. Exchanging the reagents for their enantiomers, (R,R)-F and (R)-C, respectively, inverts the rotational direction of the molecular motor.

Ratchets perturb the thermodynamic equilibrium

Molecular ratchets control the flow of free energy from a fuel to an output, providing the ability to perform work—though they do not necessarily perform work themselves. Operating a chemical system out of thermodynamic equilibrium enables emergent behaviours. Nature demonstrates this nicely: polymerases and ribosomes proofread DNA and peptide sequences as they are synthesised, selecting the correct sequences and reducing error rates by several orders of magnitude. Ion pumps move ions to the correct positions, creating concentration gradients that are used, for example, in nerve impulses.

A molecular ratchet uses repetitive kinetic control to favour a ‘correct’ outcome more often than would be expected by chance. Carrying out a reaction more frequently at a specific location establishes spatial differentiation (i.e., concentration gradients), while selectively producing one species from a set of equally probable options permits the assembly of specific, complex structures.

For example, a molecular ratchet creates and sustains non-equilibrium states of A and B (Figure 1).^7,8) The ratchet drives A and B into a non-equilibrium state, as long as the reaction pathway A→A‘→B‘→B is faster than the equilibration between A and B.

von Krbek and her group recently used a ratchet mechanism to form a non-equilibrium distribution of Pd^II capsules (Figure 3).⁷⁾ Azobispyrazoles in the ligand backbones switch from their more stable E-states to their Z-states under UV light (Figure 3, grey box). In their respective E-states, triangle E-T is thermodynamically more stable than lantern E-L. When exposed to UV light, both E-T and E-L switch to their respective Z-states. However, transient Z-T rapidly transforms into Z-L. Under visible light, Z-L exclusively transforms into E-L, which gradually equilibrates to E-T. With constant exposure to white light or sunlight, this ratchet mechanism continuously operates, accumulating the out-of-equilibrium structure E-L. Hence, the system can convert solar energy into chemical energy and temporarily store it.

Moving a system out of thermodynamic equilibrium does not necessarily imply the accumulation of the thermodynamically less stable structure. Counterintuitively, overpopulating the more stable structure is also energetically uphill because the equilibrium distribution is the lowest free energy of the system. It is just Le Chatelier‘s principle: too much of the thermodynamic product causes the system to strive towards the less stable product.

Prins and his group used DNA to achieve such a non-equilibrium system⁸⁾—it accumulates the thermodynamically more stable double DNA strand BT (Figure 4). Purple and blue single DNA strands, P and B, both compete for template strand T to form PT and BT, respectively, with BT being thermodynamically favoured. If a competing fuel strand F is introduced, it quickly replaces P from PT to form FT (Figure 4, grey box). FT is selectively broken down by the enzyme uracil DNA glycosylase (UDG), converting F into a weaker-binding waste strand W with damaged ends. The damaged ends allow the formation of transient three-way complexes that exchange P and B more rapidly: less favoured PWT and the preferred BWT—which then releases W to form BT. As the driven ratcheted pathway is faster than passive P→B exchange, BT accumulates while the system is fuelled.

Ratchets driving reactivity

Molecular ratchets can drive non-ratcheted reactions. This is similar to ATP synthase, which uses its rotation to synthesise ATP from ADP, in a network of coupled reactions, in which the outcome of one reaction affects the outcome of another.^9,10)

Greenfield and his group achieved this within a dynamic library of imines,⁹⁾ where two amines a and b, and two aldehydes c and d form four imines E-1 – E-4 (Figure 5, left). In a dynamic library, the transimination of these four imine species is interconnected, because they are formed from the same four components. Imines E-1 and E-2 interconvert by exchanging amine a for amine b, with the equilibrium favouring E-1 in the presence of an excess of a. Because the imines are made from the same components, changing the population of one imine will influence the population of the others. For example, transimination of E-1 to E-2 binds b and releases a, which increases the amount of imine E-3. Under 405 nm light irradiation, E-1 and E-2 photoisomerise to 95% and 30% of their respective Z-states (Figure 5, right). Z-1 and Z-2 also undergo transimination, and Z-2 is rapidly removed from that equilibrium by photoisomerisation to the corresponding imine, E-2.

Hence, the photoirradiation operates via a ratchet mechanism populating E-2 and releasing a. In this dynamic reaction network, a photoresponsive ratchet mechanism propels a non-photoresponsive reaction: the excess of amine a, in turn, promotes the transimination of E-4 to E-3 (Figure 5, box, bottom right).

Ratchets generate concentration gradients

Nature uses concentration gradients across membranes to store chemical energy for rapid access. This energy is released by controlled equilibration of species across the membrane and used for various energy-demanding processes, e.g. ATP synthesis.

Some ratchet mechanisms create non-equilibrium concentration gradients in artificial systems,^11,12) thereby storing chemical energy similar to the way nature does it.

Pezzato and his group employed photoacidic merocyanine (MC) to induce a proton gradient.¹¹⁾ Visible light irradiation converts photoacid MC to spiropyran SP, releasing a proton (Figure 6). The process is reversed in the dark. Asymmetric irradiation of a reaction vessel containing a solution of MC separates the reactions MC → SP + H⁺ and SP + H⁺ → MC by diffusion—akin to nature employing membranes—thereby generating a concentration gradient via a molecular ratchet mechanism. When this MC solution is placed between two electrodes and exposed to asymmetric light irradiation (Figure 6, bottom), the charge gradient caused by accumulation of protons under irradiation induces open circuit voltages up to 240 mV, which can persist for hours under steady irradiation. The system performs similar to that of biological transmembrane proton pumps without the need for a membrane.

The ability of molecular ratchets to connect ‘unrelated’ chemical and physical phenomena (for example, linking a hydration reaction to directional movement or a capsule structure to irradiation) is an intriguing aspect for fundamental research and could be crucial for developing artificial bio-like technologies.

In a nutshell

Molecular ratchets are reaction cycles that predominantly proceed in one direction: they drive uphill chemical processes and unidirectional physical motion.

For example, molecular ratchets enrich products far from their equilibrium state or cause a molecule to rotate counterclockwise around its C–C single bond.

The fuel for these endergonic processes comes from exergonic reactions or external stimuli such as light.

This is von Krbek‘s third and final contribution to the article series Blickpunkt Synthese, which alternates between her and Alicia Casitas.

The authors

Benjamin Roberts has been a Liebig fellow and junior group leader at the University of Ulm since October 2025. His group designs non-equilibrium systems based on small molecules, supramolecular structures, and soft matter with emergent properties.

Larissa von Krbek is an Emmy Noether group leader at the University of Bonn. Since beginning her independent career in 2020, her team has been designing stimuli-responsive metallo-supramolecular structures, out-of-equilibrium systems, and photoswitches.

• ¹ S. Borsley, D. A. Leigh, B. M. W. Roberts, Angew. Chem. Int. Ed. 2024, 63, e202400495
• ² T. Sangchai, S. A. Shehimy, E. Penocchio, G. Ragazzon, Angew. Chem. Int. Ed. 2023, 62, e202309501
• ³ R. D. Astumian, Science 1997, 276, 917–922
• ⁴ S. Borsley, E. Kreidt, D. A. Leigh, B. M. W. Roberts, Nature 2022, 604, 80–85
• ⁵ M. Guentner, M. Schildhauer, S. Thumser et al., Nat. Commun. 2015, 6, 8406
• ⁶ T. R. Kelly, I. Tellitu, J. P. Sestelo, Angew. Chem. Int. Ed. Engl. 1997, 36, 1866–1868
• ⁷ L. P. Lara, B. Bädorf, M. J. Notheis et al., ChemRxiv 2025
• ⁸ B. M. W. Roberts, E. D. Grosso, E. Penocchio, F. Ricci, L. J. Prins, Nat. Nanotechnol. 2025, 20, 1449–1456
• ⁹ J. Wu, J. L. Greenfield, Chem 2025, 102579
• ¹⁰ M. Kathan, F. Eisenreich, C. Jurissek et al., Nat. Chem. 2018, 10, 1031–1036
• ¹¹ X. Dai, C. Berton, D. J. Kim, C. Pezzato, Chem. Sci. 2024, 15, 19745–19751
• ¹² C. M. E. Kriebisch, B. A. K. Kriebisch, G. Häfner et al., Angew. Chem. Int. Ed. 2025, 64, e202500243

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