Carbon–hydrogen bond activation

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This article is about Organometallic pathways involving metal-carbon bonds. For other uses, see Hydrocarbon.

In

organometallic species with an M–C bond. The intermediate of this step (sometimes known as the C−H activation step) could then undergo subsequent reactions with other reagents, either in situ or in a separate step, to produce the functionalized product.[1]

The alternative term C−H functionalization is used to describe any reaction that converts a relatively inert C−H bond into a C−X bond, irrespective of the reaction mechanism (or with an agnostic attitude towards it). In particular, this definition does not require the cleaved C–H bond to initially interact with the transition metal in the reaction mechanism. 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 (e.g. cytochrome P450 enzymes and their synthetic analogues), in which a metal–carbon bond is not believed to be involved. Likewise, the ligand-based reactivity of many metal carbene species with hydrocarbons in which the carbene carbon inserts into a C–H bond, again without interaction of the hydrocarbon C–H bond with the metal, also falls under this category. Often, when authors make the distinction between C–H functionalization and C−H activation, they will restrict the latter to the narrow sense.

Classification

Mechanisms for C-H activations by metal centers can be classified into three general categories:

  • (i) Oxidative addition, in which a low-valent metal center inserts into a carbon-hydrogen bond, which cleaves the bond and oxidizes the metal:
LnM + RH → LnMR(H)
  • (ii) Electrophilic activation in which an electrophilic metal attacks the hydrocarbon, displacing a proton:
LnM+ + RH → LnMR + H+
  • (iii) Sigma-bond metathesis, which proceeds through a "four-centered" transition state in which bonds break and form in a single step:
LnMX + RH → LnMR + XH

Historic overview

The first C–H activation reaction is often attributed to

organomercury). Many electrophilic metal centers undergo this Friedel-Crafts-like reaction. Joseph Chatt observed the addition of C-H bonds of naphthalene by Ru(0) complexes.[2]

Chelation-assisted C-H activations are prevalent. Shunsuke Murahashi reported a cobalt-catalyzed chelation-assisted C-H functionalization of 2-phenylisoindolin-1-one from (E)-N,1-diphenylmethanimine.[3]

Cobalt-catalyzed C-H activation

In 1969,

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.[1][4]

In some cases, discoveries in C-H activation were being made in conjunction with those of

aliphatic C–H activation[7]

Fujiwara's palladium- and copper-catalyzed C-H functionalization

The next breakthrough was reported independently by two research groups in 1982.

pentamethylcyclopentadienyl ligand, led to the coordinatively unsaturated species Cp*Ir(PMe3) which reacted via oxidative addition with cyclohexane and neopentane to form the corresponding hydridoalkyl complexes, Cp*Ir(PMe3)HR, where R = cyclohexyl and neopentyl, respectively.[8] W.A.G. Graham found that the same hydrocarbons react with Cp*Ir(CO)2 upon irradiation to afford the related alkylhydrido complexes Cp*Ir(CO)HR, where R = cyclohexyl and neopentyl, respectively.[9]
In the latter example, the reaction is presumed to proceed via the oxidative addition of alkane to a 16-electron iridium(I) intermediate, Cp*Ir(CO), formed by irradiation of Cp*Ir(CO)2.

C–H activation by Bergman et al. (left) and Graham et al.

The selective activation and functionalization of alkane C–H bonds was reported using a

allyl and neopentyl ligands, Cp*W(NO)(η3-allyl)(CH2CMe3).[10]

C–H activation of pentane, as seen in Ledgzdins et al., J. Am. Chem. Soc. 2007; 129, 5372–3.
C–H activation of pentane, as seen in Ledgzdins et al., J. Am. Chem. Soc. 2007; 129, 5372–3.

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(NO)(η3-allyl)(CH2CMe3) 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

An important aspect of improving chemical reactions is the understanding of the underlying reaction mechanism. To answer this question for C-H activation, 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.[8][9]

Scheme for photoinduced C-H activation using a transition metal complex.

In such systems, the sample is illuminated with UV-light which excites an electron from the metal center to an unoccupied, antibonding ligand orbitals (

16-electron
intermediate, with a vacant coordination site. This species then binds to an alkane molecule, forming a σ-complex coordinating to a C-H bond. In a third step, the metal atom inserts into the C-H bond, cleaving it and yielding the C-H bond activated product.

The intermediates and their kinetics can be observed using different time-resolved spectroscopic techniques (e.g. TR-IR, TR-XAS, TR-RIXS). Time-resolved infrared spectroscopy (TR-IR) 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 (XAS) or resonant inelastic X-ray scattering (RIXS). These methods have been successfully 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.[11][12]

Full characterization of the structure of methane bound to a metal center was reported by Girolami in 2023: isotopic perturbation of equilibrium (IPE) 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.[13]

Directed C-H activation

Directed-, chelation-assisted-, or "guided" C-H activation involves

cyclometalation readily by many transition metals.[15] A semi-practical implementations involve weakly coordinating directing groups, as illustrated by the Murai reaction.[16]

Murai reaction; X = directing group.

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.[17]

Mechanism for Pd-catalyzed C-H activation

Borylation

Transforming C-H bonds into C-B bonds through borylation has been thoroughly investigated due to their utility in synthesis (i.e. for cross-coupling reactions). 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.[18]

Hartwig borylation
Hartwig borylation

Later, ruthenium catalysts were discovered to have higher activity and functional group compatibility.[19]

Ru catalyst based borylation
Ru catalyst based borylation

Other borylation catalysts have also been developed, including iridium-based catalysts, which successfully activate C-H bonds with high compatibility.[20][21][22]

For more information, consult borylation.

Natural gas

Main article: Methane functionalization

Naturally occurring methane is not utilized as a chemical feedstock, despite its abundance and low cost. Current technology makes prodigious use of methane by steam reforming to produce syngas, a mixture of carbon monoxide and hydrogen. This syngas is then used in Fischer-Tropsch reactions to make longer carbon chain products or methanol, one of the most important industrial chemical feedstocks.[23][24] An intriguing method to convert these hydrocarbons involves C-H activation. Roy A. Periana, for example, reported that complexes containing late transition metals, such as Pt, Pd, Au, and Hg, react with methane (CH4) in H2SO4 to yield methyl bisulfate.[25][26] The process has not however been implemented commercially.

C–H Bond activation Periana 1998
C–H Bond activation Periana 1998

Asymmetric C-H activations

Methyl phenyldiazoacetate is the precursor for asymmetric C-H activation viadonor-acceptor carbene using a chiral dirhodium catalyst.[27]

The total synthesis of lithospermic acid employs guided C-H functionalization late stage to a highly functionalized system. The directing group, a chiral nonracemic imine, is capable of performing an intramolecular alkylation, which allows for the rhodium-catalyzed conversion of imine to the dihydrobenzofuran.[28]

Key step in synthesis of lithospermic acid
Key step in synthesis of lithospermic acid

The total synthesis of calothrixin A and B features an intramolecular Pd-catalyzed cross coupling reaction via C-H activation, an example of a guided C-H activation. Cross coupling occurs between aryl C-I and C-H bonds to form a C-C bond.[29] The synthesis of a mescaline analogue employs the rhodium-catalyzed enantioselective annulation of an aryl imine via a C-H activation.[30]

See also

Older reviews

Pre-2004
  • Arndtsen, B. A.; Bergman, R. G.; Mobley, T. A.; Peterson, T. H. (1995). "Selective Intermolecular Carbon–Hydrogen Bond Activation by Synthetic Metal Complexes in Homogeneous Solution".
    doi:10.1021/ar00051a009
    .
  • Crabtree, R. H. (2001). "Alkane C–H activation and functionalization with homogeneous transition metal catalysts: a century of progress – a new millennium in prospect". J. Chem. Soc., Dalton Trans. 17 (17): 2437–2450.
    doi:10.1039/B103147N
    .
2004-7
2008-2011
2012-2015

Additional sources

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