Abstract
Transition metal-catalysed C–H activation has emerged as an increasingly powerful platform for molecular syntheses, enabling applications to natural product syntheses, late-stage modification, pharmaceutical industries and material sciences, among others. This Primer summarizes representative best practices for the experimental set-up and data deposition for C–H activation, as well as discussing key developments including recent advances in asymmetric, photoinduced and electrocatalytic C–H activation. Likewise, strategies for applications of C–H activation towards the assembly of structurally complex (bio)polymers and drugs in academia and industry are discussed. In addition, current limitations in C–H activation and possible approaches for overcoming these shortcomings are reviewed.
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Acknowledgements
Generous support by the Deutsche Forschungsgemeinschaft (DFG) (SPP 1807 and Gottfried–Wilhelm–Leibniz prize to L.A.) and the Onassis Foundation (fellowship to N.K.) is gratefully acknowledged. The research leading to these results has received funding from the NMBP‐01–2016 Program of the European Union’s Horizon 2020 Framework Program H2020/2014–2020 under Grant Agreement No. 720996. This project has received funding from the European Union’s Horizon 2020 research and innovation programme under Marie Skłodowska-Curie Grant Agreement No. 860762. D.G.M. acknowledges the National Science Foundation (NSF) grant under the CCI Center for Selective C–H Functionalization (CHE-1700982). Z.E.W. and M.A.B. thank the Maurice Wilkins Centre for Molecular Biodiscovery for financial support. J.W.-D. thanks the CNRS (Centre National de la Recherche Scientifique), the Ministere de l’Education Nationale et de la Recherche France and the ANR-DFG programme, grant number Projet ANR-17-CE07-0049-01. This work was supported by a Grant in Aid for Specially Promoted Research by MEXT (No. 17H06091). M.J.J. thanks the Swedish Foundation for Strategic Environmental Research (Mistra; project Mistra SafeChem).
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Contributions
Introduction (T.R., N.K. and L.A.); Experimentation (T.R., N.K., L.A., M.J.J., N.C., J.K., S.C., B.P., L.L.S. and D.G.M.); Applications (D.G.M., J.W.-D., C.A.R., R.S., Z.E.W., M.A.B. and M.J.J.); Reproducibility and data deposition (T.R., N.K. and L.A.); Limitations and optimizations (T.R., N.K., J.W.-D., M.J.J. and L.A.); Outlook (T.R., N.K., L.L.S., M.J.J. and L.A.); Overview of the Primer (L.A.).
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Glossary
- Chemoselectivity
-
The preferential reaction of compounds at one out of two or more functional groups.
- Position selectivity
-
The preferential reaction of a compound at one out of two or more reaction sites.
- Directing groups
-
Lewis-basic functional groups that coordinate the transition metal complex and bring it in close proximity to a desired bond.
- σ-Bond metathesis
-
The simultaneous cleavage of two σ-bonds and the formation of two new σ-bonds via a concerted four-membered transition state.
- Density functional theory
-
A widely employed and versatile quantum mechanical modelling method for the investigation of electronic structures of many-body systems, in particular in computational chemistry.
- LUMO
-
The lowest-energy unoccupied molecular orbital (completely or partly vacant) of a molecular entity.
- HOMO
-
The highest-energy occupied molecular orbital (filled or partly filled) of a molecular entity.
- Chiral
-
Derived from the Ancient Greek word ‘cheir (χείρ)’, and based on the fact that the right and left hands are in a mirror image relationship with each other and do not overlap, a chiral molecule is one whose mirror image does not overlap itself, and therefore has an enantiomer.
- Relativistic effects
-
Corrections to the non-relativistic energy that originate from the movement of heavy atom inner shell electrons with velocities corresponding to a significant fraction of the velocity of light, that is, spin–orbit coupling.
- Molecular dynamics
-
A simulation procedure consisting of the computation of the motion of atoms in a molecule or of individual atoms or molecules in solids, liquids and gases, according to Newton’s laws of motion. The forces acting on the atoms, required to simulate their motions, are generally calculated using molecular mechanics force fields.
- Quantum mechanical
-
The treatment of a (molecular) system according to the laws of quantum mechanics.
- Prochiral
-
The property of an achiral molecule, which can be transformed into a chiral compound through a chemical transformation.
- Achiral
-
The absence of a stereogenic element.
- Post-translational modification
-
The (typically covalent) modification of proteins after their biosynthesis, usually catalysed by enzymes.
- Macrocyclization
-
The joining of two parts of a molecule to form a large ring with more than 12 atoms.
- Peptide stapling
-
The addition of a synthetic brace between two amino acids of a peptide to constrain its confirmation, often as an α-helix.
- High-throughput experimentation
-
A scientific method of conducting large numbers of experiments in parallel, typically employed in drug discovery.
- Process mass intensity
-
A green chemistry metrics, defined as the ratio of the total mass in a process or process step to the total mass of products.
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Rogge, T., Kaplaneris, N., Chatani, N. et al. C–H activation. Nat Rev Methods Primers 1, 43 (2021). https://doi.org/10.1038/s43586-021-00041-2
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DOI: https://doi.org/10.1038/s43586-021-00041-2
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