Merck
CN
HomeApplicationsChemistry & SynthesisSynthetic MethodsC–H Functionalization

C–H Functionalization

C–H functionalization has been called1 the holy grail of synthetic organic chemistry. Recent efforts across organic chemistry, organometallics, and catalysis have made serious inroads in both understanding the reactivity of C–H bonds and developing robust reactions taking advantage of this insight, suggesting that the time is right to widely introduce these tactics to the

retrosynthetic lexicon.2-11 The reliable and predictable conversion of a C–H into a C–C, C–N, C–O, or C–X bond in a selective and controlled way is beneficial in terms of step economy and waste reduction.

Novel methods for C–H activation extend the number of sites that can be targeted in a given molecule, increasing the opportunity to elaborate it into a more complex product. In addition, it allows for completely different kinds of chemical bonds to be targeted in organic synthesis, particularly with high chemoselectivity. Combined with traditional functional-group chemistry, C–H functionalization considerably streamlines chemical synthesis for the construction of complex natural products and pharmaceutical compounds. While clearly there are advantages to the application of C–H functionalization logic,12 many curricula for organic chemistry have not yet been updated to reflect this approach and further information can be found in the C-H Functionalization Manual.

Slide 1 of 5
  • A simple selectivity principle is covalent attachment of the C–H activating species to the substrate, with the geometry constraints inherent in the resultant intramolecular process limiting the potential C–H bonds to be activated.

    Figure 1.General Strategy for Directed C–H Functionalization

  • Selectivity in Ir-Catalyzed C–H Borylation.

    Figure 2.Undirected Sp2: Borylation

  • Undirected C–H Arylation of Heteroarenes

    Figure 3.Undirected Sp2: Direct Arylation

  • Amine Tolerant Undirected C–H Hydroxylation

    Figure 4.Undirected C–H Hydroxylation

  • Based Reactivity

    Figure 5.Based Reactivity

Related Technical Articles

  • Baran Diversinates™
    The synthesis of heteroaromatic and aromatic compounds is at the heart of the chemical industry. The ever-growing demand for new chemical entities, coupled with dwindling resources and time constraints allotted to any given research project, a rapid way to diversify (hetero)aromatic scaffolds is needed.
  • C–H Amination
    The Du Bois group at Stanford University has made substantial progress within the field of Rh-catalyzed C–H amination via oxidative cyclization of carbamate, sulfamate, sulfamide, urea, and guanidine substrates to give 1,2- and 1,3-heteroatom motifs masked in the form of 5- and 6-membered ring heterocycles.
  • Jørgensen’s Organocatalysts
    Professor Karl Anker Jørgensen and his group have developed ethers which serve as excellent chiral organocatalysts in the direct asymmetric α-functionalization of aldehydes.
  • MCAT- 53™ Catalyst for Ruthenium Formation
    A recyclable, ligand-free ruthenium catalyst for C–H activation reactions and concomitant C–C bond formation in the presence of water.
  • Palau’Chlor®: Easily and Selectively Functionalize Lead Compounds
    Aryl chlorides are commonly used in cross-coupling reactions and can serve as key intermediates towards the synthesis of pharmaceutical drug candidates and natural products.
  • See All
Related Applications
Reaction Design & Optimization
Chemical reaction design and optimization in organic synthesis aims to precisely alter reaction parameters to achieve optimum results in finding pathways to target molecules.
Cross-Coupling
Cross-coupling is a common reaction in organic chemistry for the creation of C-C, C-N, and C-O bonds with the aid of a metal catalyst.
Fluorination
Fluorination is the introduction of fluorine to a compound via electrophilic fluorination, nucleophilic fluorination, difluoromethylation, trifluoromethylation, or perfluoroalkylation.
Metathesis
Olefin metathesis involves an organic reaction that redistributes fragments of alkenes (olefins) by cleavage and transformation of carbon-carbon double bonds.
Related Product Categories
C–H Activation Catalysts
Our unparalleled portfolio of C–H activation catalysts, auxiliaries, and oxidants provide reliable and predictable conversions of C–H bonds to C–C, C–N, C–O or C–X bonds.
Fluorinated Building Blocks
With a vast offering of fluorinated building blocks, such as, trifluoromethyl, difluoromethyl, triflate, and pentafluorosulfanyl substituents for your toolkit, we make it even easier to discover your target compounds.
Halogenated Heterocycles
Shop our diverse portfolio of halogenated heterocycles for use in a vast array of synthetic protocols, including lithiation and palladium catalyzed cross-coupling methodologies.
Heterocyclic Building Blocks
We’re proud to offer a comprehensive portfolio of heterocyclic building blocks, one of the largest and most diverse families of molecular fragments used in organic synthesis.
Organic Building Blocks
Find the basic components needed to drive your research forward in our portfolio of organic building blocks which include Alkanes, Alkenes, Alkynes, Allenes, Arenes, Arsenic Compounds, Baran Functionalized Building Blocks, Baran Hindered Amines, Building Blocks and Chiral Small Molecules from Liverpool ChiroChem, Building Blocks for SuFEx: The Next Click Reaction, Carbenium Salts, an Carbonyl Compounds.
Solvents
Browse through our comprehensive range of solvents offered under three portfolio brands for your various applications: Supelco® for analytical methods, Sigma-Aldrich® for classic research and production, and SAFC® for biopharmaceutical and pharmaceutical applications. Order online.
Related Services
Synthia™ Organic Retrosynthesis Software
Our custom cell culture product design experts can offer advice and support as you scale your bioprocess from clinical to commercial supply, assisting with liquid products, dry powder products, selection of raw materials, quality testing, flexible product packaging, and product documentation.

References

1.
Arndtsen BA, Bergman RG, Mobley TA, Peterson TH. 1995. Selective Intermolecular Carbon-Hydrogen Bond Activation by Synthetic Metal Complexes in Homogeneous Solution. Acc. Chem. Res.. 28(3):154-162. https://doi.org/10.1021/ar00051a009
2.
He J, Wasa M, Chan KSL, Shao Q, Yu J. 2017. Palladium-Catalyzed Transformations of Alkyl C?H Bonds. Chem. Rev.. 117(13):8754-8786. https://doi.org/10.1021/acs.chemrev.6b00622
3.
Wang D, Weinstein AB, White PB, Stahl SS. 2018. Ligand-Promoted Palladium-Catalyzed Aerobic Oxidation Reactions. Chem. Rev.. 118(5):2636-2679. https://doi.org/10.1021/acs.chemrev.7b00334
4.
Davies HML, Morton D. 2016. Recent Advances in C?H Functionalization. J. Org. Chem.. 81(2):343-350. https://doi.org/10.1021/acs.joc.5b02818
5.
Upp DM, Lewis JC. 2017. Selective C?H bond functionalization using repurposed or artificial metalloenzymes. Current Opinion in Chemical Biology. 3748-55. https://doi.org/10.1016/j.cbpa.2016.12.027
6.
Cernak T, Dykstra KD, Tyagarajan S, Vachal P, Krska SW. The medicinal chemist's toolbox for late stage functionalization of drug-like molecules. Chem. Soc. Rev.. 45(3):546-576. https://doi.org/10.1039/c5cs00628g
7.
Yamaguchi J, Yamaguchi AD, Itami K. 2012. C?H Bond Functionalization: Emerging Synthetic Tools for Natural Products and Pharmaceuticals. Angew. Chem. Int. Ed.. 51(36):8960-9009. https://doi.org/10.1002/anie.201201666
8.
Lyons TW, Sanford MS. 2010. Palladium-Catalyzed Ligand-Directed C?H Functionalization Reactions. Chem. Rev.. 110(2):1147-1169. https://doi.org/10.1021/cr900184e
9.
Wencel-Delord J, Dröge T, Liu F, Glorius F. 2011. Towards mild metal-catalyzed C?H bond activation. Chem. Soc. Rev.. 40(9):4740. https://doi.org/10.1039/c1cs15083a
10.
Arockiam PB, Bruneau C, Dixneuf PH. 2012. Ruthenium(II)-Catalyzed C?H Bond Activation and Functionalization. Chem. Rev.. 112(11):5879-5918. https://doi.org/10.1021/cr300153j
11.
Engle KM, Mei T, Wasa M, Yu J. 2012. Weak Coordination as a Powerful Means for Developing Broadly Useful C?H Functionalization Reactions. Acc. Chem. Res.. 45(6):788-802. https://doi.org/10.1021/ar200185g
12.
Gutekunst WR, Baran PS. 2011. C?H functionalization logic in total synthesis. Chem. Soc. Rev.. 40(4):1976. https://doi.org/10.1039/c0cs00182a
Sign In To Continue

To continue reading please sign in or create an account.

Don't Have An Account?