Organic reactions in which the H in a C–H bond is substituted
This article is about Organometallic pathways involving metal-carbon bonds. For other uses, see
Hydrocarbon.
In
organic chemistry and
organometallic chemistry, carbon–hydrogen bond activation (C−H activation) is a type of
organic reaction in which a
carbon–hydrogen bond is
cleaved and replaced with a C−X bond (X ≠ H is typically a main group element, like
carbon,
oxygen, or
nitrogen). 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 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
Otto Dimroth, who in 1902, reported that
benzene reacted with
mercury(II) acetate (See:
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]
In some cases, discoveries in C-H activation were being made in conjunction with those of
cross coupling. In 1969,[5] Yuzo Fujiwara reported the synthesis of (E)-1,2-diphenylethene from
benzene and
styrene with Pd(OAc)2 and Cu(OAc)2, 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 (as a Cp2WH2 complex) in a
benzene C–H bond[6] and
George M. Whitesides in 1979 was the first to carry out an
intramolecularaliphatic C–H activation[7]
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*Ir(PMe3)H2, where Cp* is a
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.
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(NO)(η3-allyl)(CH2CMe3).[10]
In one example involving this system, the alkane
pentane is selectively converted to the
halocarbon1-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]
In such systems, the sample is illuminated with UV-light which excites an electron from the metal center to an unoccupied, antibonding ligand orbitals (
MLCT), leading to ligand dissociation. This 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 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
directing groups that influence regio- and stereochemistry.[14] This is the most useful style of C-H activation in organic synthesis.
N,N-dimethylbenzylamine undergoes
cyclometalation readily by many transition metals.[15] A semi-practical implementations involve weakly coordinating directing groups, as illustrated by the
Murai reaction.[16]
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]
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]
Later, ruthenium catalysts were discovered to have higher activity and functional group compatibility.[19]
Other borylation catalysts have also been developed, including iridium-based catalysts, which successfully activate C-H bonds with high compatibility.[20][21][22]
Naturally occurringmethane 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.
Asymmetric C-H activations
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]
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]
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