From The Kiel University [Christian-Albrechts-Universität zu Kiel] (DE)
1.24.23
Organic chemists develop new catalyst to selectively activate carbon-hydrogen bonds
Prof. Dr. Manuel van Gemmeren
Otto Diels-Institut für Organische Chemie
Christian-Albrechts-Universität zu Kiel
+49 431 880 1707
vangemmeren@oc.uni-kiel.de
Substituted aromatics are among the most important building blocks for organic compounds such as drugs, cropprotecting agents, and many materials. The function of the molecules is determined by the spatial arrangement of the different building blocks, the substitution pattern. A research team from the Otto Diels Institute of Organic Chemistry at Kiel University has now presented a method in the journal Chem [below] to produce compounds with a particularly attractive but typically challenging to access substitution pattern, more efficiently than before. To enable the required activation of carbon-hydrogen (C-H) bonds, they developed a special palladium catalyst that can for the first time selectively approach a previously impossible position within molecules.
Graphical abstract
Closing a long-time research gap
With their new method, the scientists close a long-time research gap. “In principle, substituted aromatic compounds have three positions to which a catalyst can attach in order to induce a reaction – called ortho, meta and para. Depending on the position, different chemical products with fundamentally different properties are formed at the end,” says Manuel van Gemmeren, Professor of Organic Chemistry at Kiel University. For the ortho and para positions, it is already known how to allow catalysts to specifically attack there. Now, for the first time, Manuel van Gemmeren and his team can also selectively target the meta position directly. This allows them to produce meta-substituted benzyl ammonium species, which are versatile compounds for further elaboration in organic chemistry.
Normally, these compounds only appear in small amounts mixed with other products. “Until now, they had to be separated from each other with a lot of effort. Alternatively, you needed tedious synthetic routes to produce them in a targeted manner. Both cases resulted in unnecessary waste products,” explains van Gemmeren.
With the new method, meta-substituted benzyl ammonium compounds can now be produced much more efficiently. The research team around van Gemmeren used a principle that had not been described in the literature before: the palladium catalyst they designed can interact with charges in the molecule. This drastically changes the composition of the resulting products in favour of the substitution pattern that was previously difficult to produce. Calculations by colleagues at the Institute of Chemical Research of Catalonia (ICIQ), Spain, showed that charge interactions are indeed responsible for this.
Method also interesting for pharmaceutical or agricultural companies
These findings from basic research can also be of interest to pharmaceutical or agricultural companies that build up huge libraries of structurally related molecules to study their biological activity. “Wherever the largest possible variety of compounds is systematically examined, our method can be a helpful tool to close previous knowledge gaps,” says van Gemmeren.
The development of the new method is the result of many years of preliminary work that began at the University of Münster. Here van Gemmeren set up his own research group on the activation of C-H bonds via the Emmy Noether program of the German Research Foundation (DFG) before he came to Kiel University in 2022. In Kiel, he will also implement his ERC Starting Grant project “DULICAT”, from which the conceptual idea for the new method emerged. For this van Gemmeren had received funding of 1.8 million euros from the European Research Council (ERC).
Introduction to the main image:
The presence of multiple chemically different C–H bonds in organic molecules with only marginal differences in their stability and reactivity renders the control of regioselectivity one of the key challenges in the field of C–H activation and functionalization.
In this context, unbiased monosubstituted arenes are highly interesting because of the three competing positions (ortho, meta, and para; Scheme 1). Proximal ortho-C–H activation reactions have been well explored with the assistance of chelation control using Lewis-basic moieties on the substrate (path A). Alternatively, distal meta- and para-positions have been reached through the use of either a transient mediator (path B) or the analogous introduction of a traceless directing group (DG) in the middle position and its subsequent removal after metafunctionalization.
U-shaped (for meta, path C) and D-shaped (for para) templates can accommodate macrocyclic cyclophane-like transition states. Despite significant progress, these directed or template-assisted C–H activation methods suffer from the inherent limitations of requiring a covalent attachment of the transition metal to the often highly specialized structural motif of the DG. As a consequence, additional steps can become necessary to convert the DG into a desired simple organic functionality.In turn, non-directed methods, although delivering products starting from simple arenes, suffer from regioselectivity issues, especially for unbiased substrates.
To overcome these limitations, non-directed methods have been supplemented with weak non-covalent interactions between the substrate and the ligands of the catalyst, an approach that was first introduced for Ir-catalyzed C–H borylation reactions.
In 2017, the Yu group reported a bifunctional template with two distinct metal positions. One of these metal centers anchors the heterocyclic substrate through coordination and positions the substrate such that the other site can selectively engage in a meta-C–H activation and olefination (path D), an approach later extended by Xu, Jin, and co-workers to H-bonding interactions.
Inspired by the studies describing non-covalent interactions in Ir-catalyzed borylation chemistry,
we envisaged a charge-controlled meta-C–H activation using Pd catalysis, which would introduce a unique means of controlling regioselectivities in Pd-catalyzed C–H activation that to the best of our knowledge has not been described in the literature.
Scheme 1. Design of the charge-controlled site-selective C–H activation
Chem
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The Kiel University [ Christian-Albrechts-Universität zu Kiel ] (DE) was founded back in 1665. It is Schleswig-Holstein’s oldest, largest and best-known university, with over 26,000 students and around 3,000 members of staff. It is also the only fully-fledged university in the state. Seven Nobel prize winners have worked here. The CAU has been successfully taking part in the Excellence Initiative since 2006. The Cluster of Excellence The Future Ocean, which was established in cooperation with the GEOMAR [Helmholtz-Zentrum für Ozeanforschung Kiel](DE) in 2006, is internationally recognized. The second Cluster of Excellence “Inflammation at Interfaces” deals with chronic inflammatory diseases. The Kiel Institute for the World Economy is also affiliated with Kiel University. The university has a great reputation for its focus on public international law. The oldest public international law institution in Germany and Europe – the Walther Schuecking Institute for International Law – is based in Kiel.
History
The University of Kiel was founded under the name Christiana Albertina on 5 October 1665 by Christian Albert, Duke of Holstein-Gottorp. The citizens of the city of Kiel were initially quite sceptical about the upcoming influx of students, thinking that these could be “quite a pest with their gluttony, heavy drinking and their questionable character” (German: mit Fressen, Sauffen und allerley leichtfertigem Wesen sehr ärgerlich seyn). But those in the city who envisioned economic advantages of a university in the city won, and Kiel thus became the northernmost university in the German Holy Roman Empire.
After 1773, when Kiel had come under Danish rule, the university began to thrive, and when Kiel became part of Prussia in the year 1867, the university grew rapidly in size. The university opened one of the first botanical gardens in Germany (now the Alter Botanischer Garten Kiel), and Martin Gropius designed many of the new buildings needed to teach the growing number of students.
The Christiana Albertina was one of the first German universities to obey the Gleichschaltung in 1933 and agreed to remove many professors and students from the school, for instance Ferdinand Tönnies or Felix Jacoby. During World War II, the University of Kiel suffered heavy damage, therefore it was later rebuilt at a different location with only a few of the older buildings housing the medical school.
In 2019, it was announced it has banned full-face coverings in classrooms, citing the need for open communication that includes facial expressions and gestures.
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