Research Front: Advances in Carbon-Hydrogen Chemistry

March 2012

The aim this century is to “green” the chemical, agrochemical, and pharmaceutical industries by finding processes that produce high yields of products with little or no waste. One of the stumbling blocks to achieving this has been the lack of reactivity of carbon-hydrogen bonds which need to be severed in order to form new molecules.

In the past, this has required several steps using hazardous reagents, and with low overall yields. Now, however, better ways have been found to achieve this. Given the right catalyst, it is possible to form carbon-to-carbon bonds by activating carbon-hydrogen bonds, a process that is equivalent to oxidation:

C–H + C–H → C–C

The reaction, known as dehydrogenative cross-coupling, needs to be catalyzed, and there are three categories of agents which will perform this function—namely, transition metals, organic molecules, and enzymes. However, it is the first of these which is currently attracting the most attention.

A Growing Front

This aspect of C-H bond functionalization is the subject of a Thomson Reuters Research Front. These Fronts represent discrete areas of related research identified through citation analysis—specifically, analysis of papers that are frequently cited together, or “co-cited.” Each Front consists of a “core” of co-cited foundational papers along with the subsequent reports that have cited the core.

Current Research Front in Chemistry
Selected core papers and key reports for Research Front on carbon-hydrogen bond functionalization, ranked by citations
Rank Paper Citations
1 S.H. Cho, S.J. Hwang, S. Chang, "Palladium-catalyzed C-H functionalization of pyridine N-oxides: Highly selective alkenylation and direct arylation with unactivated arenes," J. Am. Chem. Soc., 130(29): 9254-6, 23 July 2008. [Korea Adv. Inst. Sci. & Tech., Taejon, South Korea] 160
2 D.H. Wang, et al., "Ligand-enabled reactivity and selectivity in a synthetically versatile aryl C-H olefination," Science, 327(5963): 315-9, 15 January 2010. [Scripps Res. Inst., La Jolla, CA] 73
3 S. Rakshit, F.W. Patureau, F. Glorius, "Pyrrole synthesis via allylic sp3 C-H activation of enamines followed by intermolecular coupling with unactivated alkynes," J. Am. Chem. Soc., 132(28): 9585-7, 21 July 2010. [U. Munster, Germany] 48
4 F.W. Patureau, F. Glorius, "RH catalyzed olefination and vinylation of unactivated acetanilides," J. Am. Chem. Soc., 132(29): 9982-3, 28 July 2010. [U. Munster, Germany] 37
5 F.W. Patureau, T. Besset, F. Glorius, "Rhodium-catalyzed oxidative olefination of C-H bonds in acetophones and benzamides," Angew. Chem. Int. Ed., 50(5): 1064-7, 2011. [U. Munster, Germany] 23
6 L. Ackermann, "Carboxylate-assisted transition-metal-catalyzed C-H bond functionalizations: Mechanism and scope," Chem. Rev., 111(3): 1315-45, March 2011. [U. Gottingen, Germany] 14
7 C.S. Yeung, V.M. Dong, "Catalytic dehydrogenerative cross-coupling; forming carbon-carbon bonds by oxidizing two carbon-hydrogen bonds," Chem. Rev., 111(3): 1215-92, March 2011. [U. Toronto, Canada] 13
8 T. Dröge, et al., "Palladium-catalyzed C-H bond functionalization of a metal-organic framework (MOF): Mild, selective, and efficient," Chem.-Eur. J., 17(43): 11974-7, 17 October 2011. [U. Munster, Germany] 1
SOURCE: InCites®, Essential Science Indicators, Thomson Reuters

The accompanying table presents a listing of papers selected from the 49 core papers underlying this Front, along with other key reports, ranked by total citations to date.

Another measure of the growth in this area is that a whole issue of Chemical Reviews was devoted to it in 2011.This included a notable review of 78 pages by Charles Yeung and Vy Dong (paper #7 in the table) along with another of 30 pages by Lutz Ackerman (#6). The former cites more than 500 references to work in this area, indicating just how important this line or research has become in the past few years. Exponential growth seems certain to continue.

Hydrogen storage in crystals that have enormous cavities might well play a role in the future use of this source of energy in vehicles.

By far the most-cited paper in this area is the 2008 one of Sukbok Chang and colleagues of the Korea Advanced Institute of Science and Technology, Daejon, Korea (#1). It describes how palladium acetate, along with silver carbonate, catalyzed the reaction of pyridine N-oxides and various alkenes to give yields as high as 90% of the alkylenated products. The paper also reports 24 reactions involving the N-oxides of phenyl substituted pyridine, quinoline, benzoquinoline, pyrazine and quinoxaline reacting with a variety of vinyl compounds, benzene, and di-substituted benzene. Yields were in the range of 50–80%.

Glorius Achievements

Frank Glorius of the University of Munster, Germany, is also an advocate of the palladium catalyzed route; witness his recent paper (#8) about the activation of benzene-type C-H bonds in what he describes as mild, selective, and efficient conditions. This paper has implications for energy use.

Hydrogen storage in crystals that have enormous cavities might well play a role in the future use of this source of energy in vehicles. Even here dehydrogenative cross-coupling is being used to modify the crystals, and in #8, Glorius reports what he describes as a "mild-mannered" addition of a phenyl group to a UMCM-type metal-organic framework using a palladium catalyst. (UMCM is short for University of Michigan Crystalline Material.) This is a zirconium carboxylate with enormous absorbing capacity, on account of its porous structure, and which is seen as a way of storing volatile materials like hydrogen gas.

However, Glorius’s work concerns another metal, rhodium, which is proving to be an equally efficient catalyst. Rhodium is used in the form of [(RhCp*Cl2)2] where Cp* is the pentamethylcyclopentadiene moiety and rhodium is Rh(III). Glorius reports the benefits which accrue from using it. Paper #3 reports the easy synthesis of pyrrole compounds using the catalyst and formed by the reaction of C-H bond activated enamines and unactivated alkynes. (Pyrroles are one of the most important classes of heterocycles found in biologically active compounds.)

More recently, in paper #5, Glorius reveals that [(RhCp*Cl2)2] can activate acetophenone and benzamides, both notably reluctant to form C-C bonds attaching groups to their aromatic ring moiety. In this paper he shows these compounds can react with olefins to give yields as high as 99%.

In #4 it is the olefination of acetanilides which highlights two other features: the lower amount of rhodium catalyst needed and its ability to promote reactions with electron-neutral olefins like ethylene and styrene.

Drug ManUfacture

That C-H activation can be effective in drug manufacture is demonstrated in the paper (#2) by Jin-Quan Yu and colleagues of the Scripps Research Institute, La Jolla, California. This highly cited work again centers on palladium(II) as the catalyst. The research involves phenylacetic acid and 3-phenylpropionic acid with specific C-H bonds targeted by a variety of olefins and using atmospheric oxygen as the oxidizing agent.

The generality of the reaction is demonstrated on a range of substituted acids, including some with fluorine and chlorines attached, and yields of up to 98% were recorded. This paper also reports that by adding amino acid ligands, another level of control was possible in that just one particular C-H bond on the benzene ring could be singled out for replacement with yields exceeding 99%.

Yu’s paper shows that it is possible to synthesize two highly active antibiotics, neocarzinostatin and kedarcidin, in a much more efficient and cleaner process than that currently used.

Dr. John Emsley is based at the Department of Chemistry, Cambridge University, U.K.

The data and citation records included in this report are from Thomson Reuters Web of ScienceTM. Web of ScienceTM is a registered trademark of Thomson Reuters. All rights reserved.