Carbon–hydrogen bond activation


In organic chemistry and organometallic chemistry, carbon–hydrogen bond activation is a type of organic reaction in which a carbon–hydrogen bond is cleaved and replaced with a bond. Some authors further restrict the term C–H activation to reactions in which a C–H bond, one that is typically considered to be "unreactive", interacts with a transition metal center M, resulting in its cleavage and the generation of an organometallic species with an M–C bond. The organometallic intermediate resulting from this step could then undergo subsequent reactions with other reagents, either in situ or in a separate step, to produce the functionalized product.
The alternative term functionalization is used to describe any reaction that converts a relatively inert bond into a bond, irrespective of the reaction mechanism. In particular, this definition does not require the cleaved C–H bond to initially interact with the transition metal or for an organometallic intermediate to exist in the reaction mechanism. In contrast to the organometallic variety, this broadened type of C-H activation is widely employed industrially and in nature. This broader definition encompasses all reactions that would fall under the restricted definition of C–H activation given above. However, it also includes iron-catalyzed alkane C–H hydroxylation reactions that proceed through the oxygen rebound mechanism, in which an organometallic species is not believed to be involved in the mechanism. In other cases, organometallic species are indirectly involved. This occurs, for example, with Rh-catalyzed C–H insertion processes in which an electrophilic metal carbene species is generated and the hydrocarbon C–H bond inserts into the carbene carbon without direct interaction of the hydrocarbon with the metal. Other mechanistic possibilities not involving direct C–H bond cleavage by the metal include generation of arylmetal species by electrophilic aromatic substitution mechanism, cleavage of the C–H bond via hydrogen atom abstraction by an O- or N-centered radical, which may then go on to further react and undergo functionalization with or without forming an organometallic intermediate, and C–H deprotonation at the α-position of a π-system assisted by initial formation of a π-complex with an electrophilic metal to generate a nucleophilic organometallic species.
Often, when authors make the distinction between C–H functionalization and activation, they will restrict the latter to the narrow sense. However, it may be challenging to definitively demonstrate the involvement or non-involvement of an interaction between the C–H bond and the metal prior to cleavage of the bond. This article discusses C–H functionalization reactions in general but with a focus on C–H activation sensu stricto.

Classification

Mechanisms for C-H activation by metal centers can be classified into three general categories:
  • Oxidative addition, in which a low-valent metal center inserts into a carbon-hydrogen bond, which cleaves the bond and oxidizes the metal:
  • Electrophilic activation in which an electrophilic metal attacks the hydrocarbon, displacing a proton:
  • Sigma-bond metathesis, which proceeds through a "four-centered" transition state in which bonds break and form in a single step:

    Historic overview

The first C–H activation reaction is often attributed to Otto Dimroth, who in 1902, reported that benzene reacted with mercury acetate. Many electrophilic metal centers undergo this Friedel-Crafts-like reaction. Joseph Chatt observed the addition of C-H bonds of naphthalene by Ru complexes.
Chelation-assisted C-H activations are prevalent. Shunsuke Murahashi reported a cobalt-catalyzed chelation-assisted C-H functionalization of 2-phenylisoindolin-1-one from -N,1-diphenylmethanimine.
In 1969, A.E. Shilov reported that potassium tetrachloroplatinate induced isotope scrambling between methane and heavy water. The pathway was proposed to involve binding of methane to Pt. In 1972, the Shilov group was able to produce methanol and methyl chloride in a similar reaction involving a stoichiometric amount of potassium tetrachloroplatinate, catalytic potassium hexachloroplatinate, methane and water. Due to the fact that Shilov worked and published in the Soviet Union during the Cold War era, his work was largely ignored by Western scientists. This so-called Shilov system is today one of the few true catalytic systems for alkane functionalizations.
In some cases, discoveries in C-H activation were being made in conjunction with those of cross coupling. In 1969, Yuzo Fujiwara reported the synthesis of -1,2-diphenylethene from benzene and styrene with Pd2 and Cu2, a procedure very similar to that of cross coupling. On the category of oxidative addition, M. L. H. Green in 1970 reported on the photochemical insertion of tungsten in a benzene C–H bond and George M. Whitesides in 1979 was the first to carry out an intramolecular aliphatic C–H activation
The next breakthrough was reported independently by two research groups in 1982. R. G. Bergman reported the first transition metal-mediated intermolecular C–H activation of unactivated and completely saturated hydrocarbons by oxidative addition. Using a photochemical approach, photolysis of Cp*IrH2, where Cp* is a pentamethylcyclopentadienyl ligand, led to the coordinatively unsaturated species Cp*Ir which reacted via oxidative addition with cyclohexane and neopentane to form the corresponding complexes, Cp*IrHR, where R = cyclohexyl and neopentyl, respectively. W.A.G. Graham found that the same hydrocarbons react with Cp*Ir2 upon irradiation to afford the related complexes Cp*IrHR, where R = cyclohexyl and neopentyl, respectively. In the latter example, the reaction is presumed to proceed via the oxidative addition of alkane to a 16-electron iridium intermediate, Cp*Ir, formed by irradiation of Cp*Ir2.
The selective activation and functionalization of alkane C–H bonds was reported using a tungsten complex outfitted with pentamethylcyclopentadienyl, nitrosyl, allyl and neopentyl ligands, Cp*W.
In one example involving this system, the alkane pentane is selectively converted to the halocarbon 1-iodopentane. This transformation was achieved via the thermolysis of Cp*W in pentane at room temperature, resulting in elimination of neopentane by a pseudo-first-order process, generating an undetectable electronically and sterically unsaturated 16-electron intermediate that is coordinated by an η2-butadiene ligand. Subsequent intermolecular activation of a pentane solvent molecule then yields an 18-electron complex possessing an n-pentyl ligand. In a separate step, reaction with iodine at −60 °C liberates 1-iodopentane from the complex.

Mechanistic understanding

One approach to improving chemical reactions is the understanding of the underlying reaction mechanism. time-resolved spectroscopic techniques can be used to follow the dynamics of the chemical reaction. This technique requires a trigger for initiating the process, which is in most cases illumination of the compound. Photoinitiated reactions of transition metal complexes with alkanes serve as a powerful model systems for understanding the cleavage of the strong C-H bond.
In such systems, the sample is illuminated with UV-light, which excites the metal center, leading to ligand dissociation. This dissociation creates a highly reactive, electron deficient 16-electron intermediate, with a vacant coordination site. This species then binds to an alkane molecule, forming a σ-complex. In a third step, the metal atom inserts into the C-H bond, cleaving it and yielding the alkyl metal hydride.
The intermediates and their kinetics can be observed using time-resolved spectroscopic techniques. Time-resolved infrared spectroscopy is a rather convenient method to observe these intermediates. However, it is only limited to complexes which have IR-active ligands and is prone to correct assignments on the femtosecond timescale due to underlying vibrational cooling. To answer the question of difference in reactivity for distinct complexes, the electronic structure of those needs to be investigated. This can be achieved by X-ray absorption spectroscopy or resonant inelastic X-ray scattering. These methods have been used to follow the steps of C-H activation with orbital resolution and provide detailed insights into the responsible interactions for the C-H bond breaking.
Full characterization of the structure of methane bound to a metal center was reported by Girolami in 2023: isotopic perturbation of equilibrium studies involving deuterated isotopologs showed that methane binds to the metal center through a single M···H-C bridge; changes in the 1JCH coupling constants indicate clearly that the structure of the methane ligand is significantly perturbed relative to the free molecule.

Directed C-H activation

Directed-, chelation-assisted-, or "guided" C-H activation involves directing groups that influence regio- and stereochemistry. This is the most useful style of C-H activation in organic synthesis. N,N-dimethylbenzylamine undergoes cyclometalation readily by many transition metals. A semi-practical implementations involve weakly coordinating directing groups, as illustrated by the Murai reaction.
The mechanism for the Pd-catalyzed C-H activation reactions of 2-phenylpyridine involves a metallacycle intermediate. The intermediate is oxidized to form a PdIV species, followed by reductive elimination to form the C-O bond and release the product.

Borylation

Transforming C-H bonds into C-B bonds through borylation has been thoroughly investigated due to their utility in synthesis. John F. Hartwig reported a highly regioselective arene and alkane borylation catalyzed by a rhodium complex. In the case of alkanes, exclusive terminal functionalization was observed.
Later, ruthenium catalysts were discovered to have higher activity and functional group compatibility.
Other borylation catalysts have also been developed, including iridium-based catalysts, which activate C-H bonds with high compatibility.
For more information, consult borylation.