Transient modulation of catalysis by switching effectors in molecular cages

the news article:

Researchers at the Homogeneous, Supramolecular and Bio-inspired Catalysis group led by Prof. Joost Reek have devised a novel concept for catalysis which enables transient control during the course of a reaction. Their catalyst consists of a molecular cage that can bind different ‘effector’ guest molecules which affect the rate of the reaction, and importantly, can be switched using an orthogonal chemical reaction. The study, which has been presented in a paper in Angewandte Chemie, demonstrates for the first time how artificial catalytic systems can be used to emulate complex biochemical reaction networks.

Schematic overview of the effector-regulated cage catalysis now presented in Angewandte Chemie. The cyclization reaction of 3 to 4 can be modulated in situ by transient effector switching, using the orthogonal carbodiimide cycle to change the guest within C from phthalic acid to phthalic anhydride (depicted above), which can be displaced by alternative guest fumaronitrile, over the course of the cyclization of 3 to 4. Image: HIMS / ANIE.

The authors used the Pt₂L₄ molecular cage which catalyzes a cyclization reaction at the outside of the cage. The guest molecules that bind inside the cage alter the reaction rate that takes place outside the cage by changing the electronic properties of the metal.

Guest molecules can be generated by an independent diacid-catalyzed carbodiimide hydration cycle. The researchers demonstrate how the latter, orthogonal reaction influences the rate of the Pt-catalyzed cyclization reaction to different extents. The guest molecules, that act as effectors to the cyclization reaction, are transiently generated by the carbodiimide driven cycle and thus regulate transiently the turnover frequency of the catalyst.

This novel concept opens up a systems chemistry approach where multi-component supramolecular architectures can be used to modulate chemical conversions, for instance by biasing different reaction pathways, or introducing cooperative effects to amplify small changes.

More efficient and self-regulating chemistry

The novel concept can help introduce a paradigm shift in chemical production, which is currently based on stepwise synthesis routes using pure components in a controlled, isolated environment. In contrast, biochemical conversions in nature take place in very complex mixtures facilitating all relevant conversion steps. This involves supramolecular control over reaction networks and molecular feedback loops. Emulating such biochemical systems can not only enhance overall efficiencies but also introduce autocorrection features. The latter is very important, for example, in the sustainability transition where oil is replaced with bio- and waste-based feedstocks that often fluctuate in composition and quality. The envisioned self-regulating conversion systems will result in a much more stable conversion of such feedstocks.

Abstract, as published with the paper

The complexity of allosteric enzymatic regulation continues to inspire synthetic chemists seeking to emulate interconnected biological systems. In this work, a Pt₂L₄ cage capable of catalyzing the cyclization reaction of an alkynoic tosyl amide is orthogonally coupled to a diacid-catalyzed carbodiimide-hydration cycle. This new Pt-catalyzed cyclization reaction is demonstrated to exhibit electronic regulation by inclusion of different guest effectors. The orthogonal diacid-catalyzed carbodiimide hydration cycle produces transiently diverse guests that influence the rate of the Pt-catalyzed cyclization reaction to different extents. Further complexity can be introduced to the system through displacing the transiently-formed, weakly bound anhydride guest with the stronger binding fumaronitrile, affecting the catalytic rate to a larger extent for the duration of the orthogonal reaction cycle. The modulation of a Pt-catalyzed cyclization reaction can thus be regulated transiently over the course of the reaction—either up- or down-regulating the turnover frequency (TOF)—via coupling with a temporally controllable orthogonal process. This study demonstrates that principles of allosteric enzymatic regulation can also be applied to simple artificial systems.

Paper details

Zoe Ashbridge, Joost N. H. Reek: Transient Allosteric Regulation of Catalysis by Effector Switching in a Pt₂L₄ Cage. Angew. Chem. Int. Ed. 2025, e202500214 DOI: 10.1002/anie.202500214

prvious  Nature Synthesis paper:

The multifaceted roles of metal-organic cages in catalysis

In an invited review article in Nature Synthesis, postdoctoral research associate Dr Zoe Ashbridge and Prof. Joost Reek of the research group Homogeneous, Supramolecular and Bio-Inspired Catalysis describe the potential of metal-organic cages, in particular of the MnL2n type, in catalysis.

Cartoon depictions of the roles for caged catalysts in different functions played by MnL2n cages in the context of catalysed synthetic reactions: Protection of catalysts or substrates; Concentration enhancement of reactants or catalysts in confined space; and Activation or Preorganization of guests. Image: HIMS / Nature Synthesis.

With their review, Ashbridge and Reek highlight the multifaceted role of cage catalysts and advocate the use of these readily accessible, robust and versatile catalysts as an ubiquitous choice for mediating synthetic reactions. By summarising and listing the available literature, they demonstrate the potential of caged catalysts to provide unique reactivity and improved spatial and temporal control in a diverse range of catalytic processes, at times even emulating the highly complex nature of enzyme active sites.

Although their review focuses on M_nL_2n cage systems - including important concepts developed at their own research group - they expect that this potential also applies for other metal–organic and even purely organic cage architectures. Thus, with important advances in synthesis and application already demonstrated in recent years, it is very possible that metal–organic cages may soon assume a routine role in synthetic chemistry.

Zoe Ashbridge & Joost N. H. Reek: The multifaceted roles of M_nL_2n cages in catalysis. Nat. Synth. (2024). DOI: 10.1038/s44160-024-00606-5

From our Nature chemistry paper:

How supramolecular machinery can enhance the efficiency of dye-sensitized solar cells

The paper presents a sophisticated molecular design based on a pseudorotaxane with a neutral naphthalene diimide based ring. Solar cells with this type of molecular machine display a five times higher efficiency when compared to solar cells lacking the pseudorotaxane. Electron recombination is prevented because the moving rotaxane-ring establishes charge separation through a process of ‘ring launching’: electrons generated in the dye are transferred to the rotaxane ring that subsequently experiences a fast repulsion from the dye. Femtosecond TA studies carried out at the University of Twente provide direct evidence for this ring-launching mechanism. Light amperometry and electrochemical impedance spectroscopy under varying light intensities established that both preorganization and ring launching contributes to lowering recombination and a threefold extension to hole lifetimes, leading to a higher V_OC and 16 times increase in PCE in p-DSSC.

Abstract of the paper

Molecular photoelectrochemical devices are hampered by electron–hole recombination after photoinduced electron transfer, causing losses in power conversion efficiency. Inspired by natural photosynthesis, we demonstrate the use of supramolecular machinery as a strategy to inhibit recombination through an organization of molecular components that enables unbinding of the final electron acceptor upon reduction. We show that preorganization of a macrocyclic electron acceptor to a dye yields a pseudorotaxane that undergoes a fast (completed within ~50 ps) ‘ring-launching’ event upon electron transfer from the dye to the macrocycle, releasing the anionic macrocycle and thus reducing charge recombination. Implementing this system into p-type dye-sensitized solar cells yielded a 16-fold and 5-fold increase in power conversion efficiency compared to devices based on the two control dyes that are unable to facilitate pseudorotaxane formation. The active repulsion of the anionic macrocycle with concomitant reformation of a neutral pseudorotaxane complex circumvents recombination at both the semiconductor–electrolyte and semiconductor–dye interfaces, enabling a threefold enhancement in hole lifetime.

Publication details

T. Bouwens, T. M. A. Bakker, K. Zhu, J. Hasenack, M. Dieperink, A. M. Brouwer, A. Huijser, S. Mathew, J. N. H. Reek: A Bioinspired Strategy for Directional Charge Propagation in Photoelectrochemical Devices Using Supramolecular Machinery Nat. Chem. (2022). DOI: 10.1038/s41557-022-01068-y

Joost Reek finished his masters at the University of Nijmegen in 1991 and received his PhD in 1996 at the same university. His research was done in the group of Prof. R.J.M. Nolte, were he acquired expertise in the field of supramolecular chemistry and synthesis. He attended the group of Prof. M.J. Crossley in Sydney as a postdoctoral fellow in 1996, where he got experienced in porphyrin chemistry and dendrimers. In January 1998 he became lecturer (senior lecturer in 2003) in the group of Prof. P.W.M.N. van Leeuwen at the University of Amsterdam (UvA) were he got experienced with transition metal catalysis. Collaborative research activities with Van Leeuwen focused on transition metal catalysis, catalyst immobilization and dendritic transition metal catalysis. In this period he started his own successful new line of research on the border of transition metal catalysis and supramolecular chemistry, which has resulted in several patents, many papers in high impact journals and an appointment as full professor (chair supramolecular catalysis) at the UvA in 2006. In addition he founded InCatT (innovative catalyst technologies) as a spin-off company in 2009, to commercialize some of the supramolecular catalysts. He was scientific director of the Van ‘t Hoff Institute for Molecular Sciences (HIMS) of the UvA (122 fte) from 2013-2017 and Since 2016 he is the scientific director of NIOK (national school on catalysis). In 2017 he became distinguished faculty professor at the Faculty of Science of the University of Amsterdam

In 2005 he was elected a young member of Royal Netherlands Academy of Arts and Sciences (KNAW), and since 2015 he is elected full member of the KNAW. As a young member of the KNAW he visited high schools, organized meetings on interdisciplinary research topics and he took part in the committee judging the KNAW recognized research schools in the area of natural sciences. As a KNAW member his takes part in various committees including van ‘t Hoff committee and science domain KNAW, and he is the chair of KNAW section chemistry and he is board member of the NTW domain. In 2013 he was elected as a new member of the Royal Holland Society of Sciences and Humanities (KHMW), in 2018 he was honoree member of the Israel Chemical Society. In 2019 he became elected member of the European academy of science. He was member of the management team of the NRSCC (top research school catalysis), member of the board of the European journal of inorganic chemistry, and chair of the study group Coordination chemistry and homogeneous catalysis of NWO, board member of the KNCV (Royal Netherlands Chemical Society) and board member of the national BioSolarCell research program. He received numerous grants including a grant for talented young chemists, VICI grant (2002) and NWO TOP grants of the national research funding agency NWO, a large grant from economic affairs and in 2013 the ERC advanced grant. In 2023 he received an ERC synergy grant for exploring cage catalysis in the context of brain tumor treatment. On top of that Reek collaborates with numerous industries, and he was selected scientist for the CBBC consortium (collaborative program with industry). He was the coordinator of a successful European research training network and involved in other EU networks.

Joost Reek currently heads a research group of around 40 people, with 20 PhD students and 8 post-docs, working on various topics related to supramolecular chemistry and transition metal catalysis. So far, he has been (co-) supervisor of over 70 PhD students. With over 430 scientific papers published, his H-index is currently 82 (in 2010 he entered the top 1000 of most cited chemists in the world (643^th position), at the age of 43, in 2021 he still was in top 1000). He has (co)edited a book on dynamic combinatorial chemistry, a new field of science that is strongly inspired by natural selection events. Reek gave many invited lectures like the Troisième cycle (Switserland, 2007), the DSM-lecture at the ICOMC (Rennes, 2008) and the Erdtman Lecture in 2009, the molecular science frontier lecture of ICCAS (Chinese academy of science) in 2018, IFOC lectureship award (Japan 2018), and the Earl Muetterties lecture in Berkeley. In 2011 he was invited to a DoE workshop on CO₂ reduction, to advise the Department of Energy in US. In 2014 and 2016 he explained on television (De kennis van nu and toekomstmakers) one of his scientific dreams to the public. Current research program is focused on supramolecular catalysis for synthetic purposes, for application in living cells and solar fuels.

€10.6 million for innovative toolboxes to tackle brain cancer

Researchers at the Universities of Amsterdam and Leiden together with the Netherlands Cancer Institute (Amsterdam) and Oncode Institute (Utrecht) have received a €10.6 million ERC Synergy Grant to develop innovative therapeutic approaches to target glioblastoma, a deadly primary brain tumour for which no curing therapy is yet available. At the heart of the proposed method are enzyme-mimicking molecular catalysts capable of producing various types of anti-cancer drugs within the tumour tissue itself. According to Joost Reek, professor of Supramolecular Catalysis at the University of Amsterdam (UvA) and coordinator of the ‘Cat4CanCenter’ research, this new approach could potentially solve many of the difficulties associated with the current treatment of glioblastoma.