Synthetic toolbox: C-H activation

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C-H activation

This page reproduces content from I. J. S. Fairlamb, Pd-catalysed Cross-couplings for the Pharmaceutical Sector and a Move to Cutting-edge C-H Bond Functionalization: Is Palladium Simply Too Precious?, in Green and Sustainable Medicinal Chemistry: Methods, Tools and Strategies for the 21st Century Pharmaceutical Industry, The Royal Society of Chemistry, 2016, ch. 11, pp. 129-139.. It is copyright to the Royal Society of Chemistry (RSC) and is reproduced here with their express permission. If you wish to reproduce it elsewhere you must obtain similar permission from the RSC.

Synthesis of organic molecules carrying a number of functionalities relies on the conversion of functional groups that display high reactivity, into the target functional groups. Carbon–hydrogen (C–H) bonds are not classically considered functional groups within the context of functionalisation. Therefore introduction of a new bond requires the presence of either a heteroatom on the carbon backbone, a leaving group or unsaturation.[1]

In the pharmaceutical industry new C–C and C–X (X= C, N, O) bonds are typically made by cross coupling reactions shown in Scheme 1. Of the methods highlighted, the Heck and Suzuki reactions are the most popular methods of C–C bond formation in the pharmaceutical industry, however as can be seen from Scheme 1, both systems require pre-functionalisation of one of the coupling partners with a halogen, while the other requires the presence of a terminal alkane (Heck) or a boronic acid (Suzuki).[2] Many synthetic intermediates do not lend themselves to the formation of terminal unsaturation, and boronic acids are synthesised from organometallic halides (e.g. Grignard reagents), which further adds to the complexity of what essentially is the formation of single bond. Aromatic and heteroaromatic groups are present in more than 75% of marketed pharmaceuticals, and their functionalisation represents a challenge to the synthetic community.  The recent developments in cross-coupling reactions catalysed by transition metals have enabled a range of methods for introducing aryl functionality, although their versatility is limited by the availability of aryl halides.[3]

The approach for the synthesis of new bonds via pre-functionalisation dictates the process of synthetic strategy; reactive sites are typically incorporated by a series of transformations and as a result the starting materials can be very different to the final product.  Thus, the direct conversion of C–H bonds of organic compounds into desired functional groups without pre-activation represents a crucial field in green synthetic chemistry.[5] Such transformations have the potential to provide clean and economic methods for the preparation of a wide variety of important chemicals directly from hydrocarbons. Moreover, with such tools in the synthetic chemist’s arsenal, new opportunities could present themselves that would have a significant impact on synthetic strategy.[5]  

The challenge to direct C–H functionalisation stems from the high bond dissociation energy of the C–H bonds of aromatics and alkanes (H–C6H5: 460 kJ/mol; H3C–H: 439 kJ/mol). [6] As such cleavage of these bonds requires high temperatures, the presence of strong oxidants and acidic or basic additives.[6] Such methods are incompatible for application with a significant number of functional groups, thus limiting their applicability. 

 

  1. K. Godula and D. Sames, C-H bond functionalization in complex organic synthesis, Science, 2006, 312, 67-72.
  2. J. S. Carey, D. Laffan, C. Thomson and M. T. Williams, Analysis of the reactions used for the preparation of drug candidate molecules, Org. Biomol. Chem., 2006, 4, 2337-2347.
  3. D. J. C. Constable, P. J. Dunn, J. D. Hayler, G. R. Humphrey, J. Johnnie L. Leazer, R. J. Linderman, K. Lorenz, J. Manley, B. A. Pearlman, A. Wells, A. Zaks and T. Y. Zhang, Key green chemistry research areas-a perspective from pharmaceutical manufacturers, Green Chem., 2007, 9, 411-420.
  4. I. J. S. Fairlamb, Pd-catalysed Cross-couplings for the Pharmaceutical Sector and a Move to Cutting-edge C-H Bond Functionalization: Is Palladium Simply Too Precious?, in Green and Sustainable Medicinal Chemistry: Methods, Tools and Strategies for the 21st Century Pharmaceutical Industry, The Royal Society of Chemistry, 2016, ch. 11, pp. 129-139.
  5. C. - J. Li and B. M. Trost, Green chemistry for chemical synthesis, PNAS, 2008, 105, 13197-13202.
  6. C. Jia, T. Kitamura and Y. Fujiwara, Catalytic Functionalization of Arenes and Alkanes via C−H Bond Activation, Acc. Chem. Res., 2001, 34, 633-639.