Carbon–hydrogen bond activation

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Carbon–hydrogen bond activation (C–H activation), or C-H functionalization, is a type of reaction in which a carbon–hydrogen bond is cleaved and replaced with a carbon-X bond (where X is usually carbon, oxygen, or nitrogen).[1][2][3][4][5][6][7][8][9][10][11] The term is often restricted to reactions that involve organometallic complexes and transformations that proceed by coordination of a hydrocarbon to the inner-sphere of a metal, either via an intermediate “alkane or arene complex” or as a transition state leading to a "M−C" intermediate.[12][13][14] Important to this definition is the requirement that during the C–H cleavage event, the hydrocarbyl species remains associated in the inner-sphere and under the influence of “M”.

Representative image of C-H activation

Theoretical studies as well as experimental investigations indicate that C–H bonds, which are traditionally considered unreactive, can be cleaved by coordination. Much research has been devoted to the design and synthesis of new reagents and catalysts that can affect C–H activation. C-H activation chemistry has the potential to transform the chemical world through the development of novel synthetic methods. C-H activation could enable the conversion of cheap and abundant alkanes into valuable functionalized organic compounds and the efficient structural editing of already complex molecules (i.e. natural product synthesis).[15] The abundance of C-H bonds in organic molecules provides precedent for developing methods to convert C-H bonds into useful C-X bonds. Research leads to novel disconnections, drastically shortening synthetic routes.[16] There are applications of C-H activation in various fields, including materials science and pharmaceuticals. [16]

Challenges[edit]

Organic compounds often contain many carbon-hydrogen bonds. Hence, selective activation of a specific C-H bond poses a great challenge. The reactions must be regioselective and stereoselective. In addition, the reaction conditions need to be mild enough to tolerate additional functionality within the molecule.

Historic overview[edit]

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), but some scholars[who?] do not view this reaction as being true C–H activation. Many electrophilic metal centers undergo this reaction.

From a modern organometallic perspective, the first true C–H activation reaction was reported by Joseph Chatt in 1965[17] with insertion of a ruthenium atom ligated to dmpe in the C–H bond of naphthalene. 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(II). 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.[12]

On the other side of the spectrum, 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[18] and George M. Whitesides in 1979 was the first to carry out an intramolecular aliphatic C–H activation[19]

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.[20] 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.[21] 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 tungsten complex outfitted with pentamethylcyclopentadienyl, nitrosyl, allyl and neopentyl ligands, Cp*W(NO)(η3-allyl)(CH2CMe3).[22]

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 thermoloysis 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.

Arene C–H bonds can also be activated by metal complexes despite being fairly unreactive. One manifestation is found in the Murai olefin coupling.[23] In one reaction a ruthenium complex reacts with N,N-dimethylbenzylamine in a cyclometalation also involving C–H activation:[24]

Cyclometallation with a Substituted Benzylamine Chetcuti 2007


Scope[edit]

Overview[edit]

As mentioned previously, the challenge of C-H activation reactions is developing methods that will functionalize specific C-H bonds in the presence of other C-H bonds. The selectivity of these reactions can be explained through innate C-H activation or guided C-H activation. The figure depicts the two oxidation products possible, depending on the reagents used to functionalize a specific C-H bond. [25]

Guided vs. Innate C-H Activation


Selectivity of C-H activation[edit]

Electron density is a major factor in determining which C-H bond is most activated, and hence most reactive toward C-H functionalization reactions. Typically, the C-H bond that is most electron rich is the most reactive.The substitution of the carbon influences the electron density, such that tertiary carbons are the most electron rich and methyl is the least electron rich (most electron poor). The trend is as follows: tertiary>secondary>primary>methyl. For C-H bonds of equal substitution (i.e. two secondary carbons), the C-H bond that is furthest from an electron-withdrawing group is selectively activated, due to the greater electron density. Other factors that influence selectivity of C-H activation reactions include strain release and sterics. The C-H bond that relieves more strain is more activated. The more sterically accessible C-H bond is similarly selectively functionalized.

Selective C-H activation due to strain release

In the figure above, the axial C-H bond in cis-1,2-dimethylcyclohexane is selectively oxidized over the equitorial C-H bond. During oxidation, the axial methyl group becomes planar, decreasing the 1,3-diaxial interactions in the transition state, which stabilizes the transition state.[26]

An alkene C–H bond activation with a rhodium catalyst is demonstrated in the synthesis of this strained bicyclic enamine:[27]

C–H bond activation Yotphan 2008

Innate C-H activation[edit]

Innate C-H activation reactions are reactions that functionalize C-H bonds in the absence of directing forces, using only the natural reactivity of the molecule.[25] Inductive (through-bond) effects can explain the innate selectivity of a C-H bond in a molecule through the examination of the electronic nature of the bonds. The presence and proximity of electron-withdrawing groups (EWGs) or electron-donating groups (EDGs) influence if a C-H bond is electron rich or electron poor.[28] The reactivity trend for nonmetal insertion is tertiary>secondary>primary.[29]

Influence of inductive effects on selectivity of C-H bond activation

In the compound on the left in the figure, the tertiary position that is farther away from the electron-withdrawing OBz group, is more electron rich, and hence, is preferentially oxidized (C-H to C-O). Similarly, in compound on the right, the secondary methylene position that is most distal to the EWG is selectively oxidized.[28] Steric effects can also influence the selectivity of C-H bond activation. The presence of steric groups will decrease the rate of functionalizing a nearby C-H bond.

Steric Effects

In the oxidation of cyclohexane compound, the tertiary site on the ring is preferential over the tertiary site of the isopropyl substituent. The two methyl groups hinder the oxidation on the isopropyl group, making the less hindered cyclohexyl site more favorable.[28]

Guided C-H activation[edit]

Guided C-H activation reactions utilize external reagents or directing groups to exchange specific C-H bonds for C-X bonds.[25]

Guided Example 1

The figure demonstrates the use of a pyridine directing group to form a C-X halogen bond from a C-H bond via guided C-H activation. Pyridine derivatives are commonly used for ortho-selective C-H functionalization. Such reactions use palladium to catalyze sp2 C-H activation. A similar system uses pyridine to acetoxylate the C-H bond, forming a C-OAc bond, instead of a C-X halogen bond.[9]

Pd-catalyzed C-H activation reaction

The mechanism for the pyridine based Pd-catalyzed C-H activation reactions involves a catalytic cycle. In the cycle, the Pd ligand directs the molecule to interact with Pd to form a cyclic intermediate. The intermediate is oxidized to form a PdIV species, followed by reductive elimination to form the C-O bond and release the product.[9]

Pd-catalyzed mechanism for C-H activation

See Meta-selective C-H fuctionalization for more examples of directed C-H activation.

Reaction conditions[edit]

Many C–H bond activations proceed under rather harsh reaction conditions (high temperature, strongly acidic or basic conditions, strong oxidant, etc.), significantly limiting their utility. However, mild methods have been developed, significantly expanding the scope of these transformations.[30] Organocatalysis is another important approach to facilitating C-H activation.[31]

Case Study: Borylation[edit]

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). J.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.[32]

Hartwig borylation

Later, ruthenium catalysts were discovered to have higher activity and functional group compatibility.[33]

Ru catalyst based borylation

Other borylation catalysts have also been developed, including iridium-based catalysts, which successfully activate C-H bonds with high compatibility.[34][35]

For more information, consult borylation.

Applications[edit]

Natural gas[edit]

Natural gas is composed primarily of hydrocarbons methane and ethane. Although highly abundant, both methane and ethane are not well utilized due to the challenge of transporting and readily converting the hydrocarbons to useful products, such as methanol and ethanol. Prior technology involved a multistep process of converting the hydrocarbons to hydrogen gas and carbon monoxide, followed by the conversion to methanol, and so on.[36] More practical methods to convert these hydrocarbons involves C-H activation. 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.[37][38] The process has not however been implemented commercially.

C–H Bond Activation Periana 1998

Natural product synthesis[edit]

The development of methodology for C-H activation has impacted natural product synthesis significantly. Ideally, synthetic routes contain minimal steps, while maximizing yield. C-H activation has enabled researchers to activate C-H bonds in highly functionalized molecules.[39]

Example of synthesis of core leading to multiple natural products

The product in the above reaction is a common scaffold for multiple natural products, including hapalindole Q and ambiguine H. The core structure can be made through a C-C bond (blue bond in product) formation via C-H activation. The innate reactivity of the indole and enolate leads to the formation of the C-C bond to form the indole-carvone intermediate.[25]

(+)-Lithospermic acid via C-H activation[edit]

The total synthesis of lithospermic acid employs guided C-H functionalization late stage to a highly functionalized system. The directing group is a chiral nonracemic imine capable of intramolecular alkylation. The key step, in which C-H activation was utilized, is the conversion of imine to the dihydrobenzofuran using a rhodium catalyst (new bond formed in red).[40]

Key step in synthesis of lithospermic acid

Calothrixin A and B via C-H activation[edit]

The total synthesis of calothrixin A and B features an intramolecular Pd-catalyzed cross coupling reaction via C-H activation. The figure depicts the cross coupling between aryl C-I and C-H bonds to form a C-C bond (highlighted in red).[41]

Key step in total synthesis of Calothrixin A and B

See also[edit]

Additional Sources[edit]

References[edit]

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