Skip to Content
Merck
HomeApplicationsChemistry & SynthesisSynthetic MethodsC–H Functionalization

C–H Functionalization

C–H functionalization has been called the holy grail of synthetic organic chemistry.1   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.   

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

Featured Categories

3 Bottles of ReagentPlus® solvent grade products in various volumes.
Solvents

Your Solvent Source: Find the right fit with Supelco®, SigmaAldrich®, & SAFC® brands, covering analytical, lab, & biopharmaceutical uses. Order online.

Shop Products
Sample heterocyclic building blocks for organic synthesis
Organic Building Blocks

Find the basic components needed to drive your research forward in our portfolio of organic building blocks. Alkenesm alkanes, alkynes, arenes, allenes & more!

Shop Products
Sample heterocyclic building blocks for organic synthesis
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.

Shop Products
Three chemical structures are depicted on colored geometric backgrounds. On the left, a blue hexagon features “2-Bromo-4-fluoropyridine,” with its corresponding molecular structure showing a pyridine ring with bromine (Br) and fluorine (F) substituents. In the center, a yellow square displays “2,2-Difluoroethylamine,” alongside its molecular formula NH2CHF2. On the right, a purple pentagon presents “1,1,1-Trifluoro-3-methyl-2-butene-1-ol,” with its molecular structure illustrating multiple fluorine (F) atoms and an alcohol group (OH) attached to a branched carbon chain.
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.

Shop Products

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.

Document Search
Looking for More Specific Information?

Visit our document search for data sheets, certificates and technical documentation.

Find Documents
Featured Articles
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.
Baran Diversinates™
Rapidly diversify (hetero)aromatic scaffolds for chemical industry needs amid resource and time constraints, ensuring efficiency.
C–H Amination
Stanford's Du Bois group advances Rh-catalyzed C–H amination, producing heteroatom motifs in ring heterocycles.
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.
Related Services
SYNTHIA™ 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?