Arrow Lab

Organometallic Chemistry and Catalysis · Catalytic cycles

C–H activation and functionalization

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What you'll learn

  • Classify a metal-mediated C–H cleavage as oxidative addition, σ-bond metathesis or concerted metalation–deprotonation from the metal's d-electron count and the ligands present.
  • Draw concerted metalation–deprotonation steps and the palladium cycles of direct arylation, directed acetoxylation and oxidative olefination with exact oxidation states.
  • Use directing groups and palladacycle ring size to predict which C–H bond a palladium or ruthenium catalyst functionalizes.
  • Predict the site of iridium-catalyzed C–H borylation from sterics and contrast it with electrophilic aromatic substitution and acidity-controlled CMD.
  • Interpret isotope-effect and labelling data to locate the rate-determining step of a C–H functionalization cycle.

Free lesson

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Turning a C–H bond into a functional group

C–H bonds are strong (about 439 kJ/mol in methane and 473 kJ/mol in benzene), nonpolar and very weakly acidic, so classical reagents ignore them. A transition metal can cleave a C–H bond to give a metal–carbon bond, M–R, and that M–R bond then undergoes the familiar steps of catalysis: reductive elimination, insertion or transmetalation. The overall result replaces H with a new group, for example benzene and 4-bromotoluene giving 4-methylbiphenyl (shown) without any organometallic reagent. The prefunctionalization step of a cross-coupling (making the boronic acid or Grignard reagent) disappears, and the only by-product is HX, taken up by the base, instead of the boron, tin or magnesium waste of an organometallic partner. The two problems every method must solve are reactivity (breaking the strong bond) and selectivity (choosing one C–H bond among many).

Three ways a metal breaks a C–H bond

Oxidative addition needs an electron-rich, low-valent late metal with two d electrons to spare. Photolysis of Cp*Ir(PMe₃)H₂ releases H₂ and gives the 16-electron Ir(I) fragment Cp*Ir(PMe₃), which adds a C–H bond of cyclohexane (shown) to give Cp*Ir(PMe₃)(H)(C₆H₁₁): iridium goes from Ir(I), d⁸ to Ir(III), d⁶, and from 16 to 18 electrons. These fragments prefer primary over secondary C–H bonds, the opposite of radicals, and benzene over alkanes, because M–aryl bonds are much stronger than M–alkyl bonds: the selectivity follows the M–C bond formed, not the C–H bond broken. Cationic Pt(II) methyl complexes behave the same way: benzene adds to give a Pt(IV) methyl phenyl hydride, which eliminates methane. σ-Bond metathesis is the route for d⁰ metals, which have no d electrons to give: Cp*₂Lu–CH₃ exchanges its methyl with methane, and Cp*₂Sc–CH₃ turns benzene into Cp*₂Sc–C₆H₅ and methane, through a four-centre transition state in which the moving hydrogen sits between the two carbons; the oxidation state stays +3. Concerted metalation–deprotonation (CMD) is the route for Pd(II), Rh(III), Ru(II) and Ir(III) carboxylates: the M–C bond forms while a carboxylate bound to the same metal removes the proton, and the oxidation state does not change.

Concerted metalation–deprotonation

In the Fagnou direct arylation, Pd(0) adds an aryl bromide, pivalate replaces bromide on Ar–Pd(II), and the bound pivalate removes a benzene proton as palladium bonds to the same carbon. Reductive elimination then forms the biaryl and returns Pd(0). Pivalic acid (shown) is used in catalytic amounts: pivalate carries the proton from the arene to insoluble K₂CO₃ and is regenerated. Because the arene does not attack palladium as a nucleophile, CMD does not follow the rules of electrophilic aromatic substitution. Its rate tracks C–H acidity and the strength of the new Pd–C bond: pentafluorobenzene reacts faster than benzene, a C–H flanked by fluorines reacts first, and thiophenes react at the α-carbon next to sulfur. A large primary kinetic isotope effect (kH/kD of about 4–6) shows that the C–H bond breaks in the rate-determining step.

Directing groups and palladacycles

A Lewis-basic group (a pyridine or quinoline nitrogen, an amide or ketone oxygen, an oxime ether nitrogen) binds the metal and holds it next to one C–H bond. Cleavage is fastest when it closes a five-membered metallacycle (six-membered with anilides such as acetanilide, whose amide oxygen sits one atom further from the ring): 2-phenylpyridine (shown) is palladated at an ortho carbon of the phenyl ring, and 8-methylquinoline at its methyl group, an sp³ C–H bond. Where two ortho positions are available, the less hindered one reacts. The palladacycle can be oxidized by PhI(OAc)₂ to Pd(IV), which forms the C–O bond by reductive elimination and returns to Pd(II): a Pd(II)/Pd(IV) cycle, with no Pd(0). Alternatively, an alkene inserts into the Pd–C bond and β-hydride elimination releases a cinnamate (the Fujiwara–Moritani or oxidative Heck reaction); this leaves Pd(0), so an oxidant such as benzoquinone, Cu(OAc)₂ or O₂ must turn it back into Pd(II). Ruthenium does the same with ketones: in the Murai reaction a ketone oxygen directs ortho C–H oxidative addition to Ru(0), an alkene inserts into Ru–H, and C–C reductive elimination is the rate-determining step.

Iridium-catalyzed borylation: steric control

With [Ir(OMe)(cod)]₂, 4,4′-di-tert-butyl-2,2′-bipyridine (dtbpy) and B₂pin₂, arenes are converted into aryl pinacol boronates at room temperature. The active species is Ir(dtbpy)(Bpin)₃, Ir(III), d⁶. It adds an arene C–H bond to give Ir(V), d⁴, reductively eliminates Ar–Bpin, adds B₂pin₂ and eliminates H–Bpin to return to Ir(dtbpy)(Bpin)₃. The site is chosen by sterics, not electronics: C–H bonds next to a substituent are avoided, so 1,3-dichlorobenzene gives only the 3,5-dichlorophenyl boronate (shown), and toluene gives a roughly statistical 2 : 1 mixture of meta and para products with almost no ortho product. Oxidation of the boronate then gives meta-substituted phenols that electrophilic substitution cannot make.

Shilov platinum chemistry and rhodium carbenes

In the Shilov system, PtCl₄²⁻ (Pt(II)) activates methane to give a Pt(II)–CH₃ species, PtCl₆²⁻ oxidizes it to Pt(IV)–CH₃, and water or chloride attacks the methyl carbon in an SN2 step, releasing CH₃OH or CH₃Cl and Pt(II). The stoichiometric Pt(IV) oxidant is the practical problem. Dirhodium(II) carboxylates take a different path: they decompose α-diazo carbonyl compounds, with loss of N₂, to electrophilic rhodium carbenes, which insert into an unactivated C–H bond in one concerted step. In chains, the insertion favours the C–H bond five atoms away (a 1,5-insertion), giving cyclopentanones, and prefers a methylene over a methyl C–H bond: methyl 2-diazo-3-oxoheptanoate gives methyl 2-methyl-5-oxocyclopentane-1-carboxylate (shown).

What to carry forward

Match the C–H cleavage mode to the metal: electron-rich low-valent metals oxidatively add C–H bonds, d⁰ metals use σ-bond metathesis, and Pd(II), Rh(III) and Ru(II) carboxylates use concerted metalation–deprotonation without changing oxidation state. Selectivity comes from acidity and M–C bond strength in CMD, from five-membered metallacycles with directing groups, and from sterics in iridium borylation. Track oxidation states round each cycle: Pd(0)/Pd(II) for direct arylation, Pd(II)/Pd(IV) with PhI(OAc)₂, Pd(II)/Pd(0) plus an oxidant for oxidative olefination, Ir(III)/Ir(V) for borylation.

Practice problems (40)

Free to practice with an account.

Draw the mechanism 8

Directing groups and palladacycles

  • Amide-directed ortho-olefination of acetanilide (Fujiwara–Moritani)Draw the amide-directed ortho C–H palladation of acetanilide, syn insertion of n-butyl acrylate, syn β-hydride elimination and release of Pd(0), and explain why an oxidant is required.
  • Cyclopalladation of 8-methylquinoline at an sp³ C–H bondDraw nitrogen coordination and the acetate-assisted concerted metalation–deprotonation that cyclopalladates the methyl group of 8-methylquinoline.
  • Pd(II)/Pd(IV) ortho-acetoxylation of 2-phenylpyridineDraw the oxidation of a cyclopalladated 2-phenylpyridine by PhI(OAc)₂ to palladium(IV), the C–O reductive elimination and the release of the ortho-acetoxylated product with regeneration of Pd(OAc)₂.

Concerted metalation–deprotonation

  • Direct arylation of benzene with 4-bromotoluene by concerted metalation–deprotonationDraw the Pd(0)/Pd(II) direct arylation of benzene: oxidative addition, bromide-to-pivalate exchange, pivalate-assisted concerted metalation–deprotonation and C–C reductive elimination.
  • C5-selective direct arylation of 2-methylthiopheneDraw the Pd(0)/Pd(II) direct arylation of 2-methylthiophene with 4-bromoacetophenone and explain why acetate-assisted CMD selects the C5–H bond.

Borylation and other catalytic C–H reactions

  • Murai ortho-alkylation of acetophenone with triethoxyvinylsilaneDraw the ketone-directed ortho C–H oxidative addition to ruthenium(0), insertion of a vinylsilane into the Ru–H bond and C–C reductive elimination of the Murai reaction.
  • Rhodium carbene 1,5-C–H insertion to a cyclopentanoneDraw formation of a rhodium carbene from an α-diazo-β-keto ester and its concerted 1,5-insertion into a methylene C–H bond to form a cyclopentanone.

Breaking C–H bonds at metals

  • Benzene C–H activation by a cationic platinum(II) methyl complexDraw benzene C–H oxidative addition to a cationic platinum(II) methyl complex and the reductive elimination of methane, tracking Pt(II) → Pt(IV) → Pt(II).

Predict the product 7

Borylation and other catalytic C–H reactions

  • Borylation of 1,3-dichlorobenzenePredict the single product of iridium-catalyzed borylation of a 1,3-disubstituted arene from steric control.
  • Murai reaction of 3-methylacetophenonePredict the site of ketone-directed ruthenium ortho-alkylation in a meta-substituted aryl ketone.

Concerted metalation–deprotonation

  • Where does CMD arylate 1,3-difluorobenzene?Predict the site of CMD direct arylation in a fluoroarene from C–H acidity rather than sterics or electrophilic-substitution rules.

Breaking C–H bonds at metals

  • Which C–H bond of propane does iridium attack?Predict the primary-over-secondary C–H selectivity of oxidative addition at an electron-rich metal fragment.
  • Cp*₂Sc–CH₃ in benzenePredict the products of σ-bond metathesis between a scandium methyl and benzene from the transition-state geometry.

Directing groups and palladacycles

  • sp³ C–H acetoxylation directed by an oxime etherPredict the site of oxime-directed sp³ C–H acetoxylation from the size of the palladacycle formed.
  • Acetoxylation of 2-(3-methylphenyl)pyridinePredict which ortho C–H bond is acetoxylated when a directing group has two inequivalent ortho positions.

Classify 3

Concerted metalation–deprotonation

  • Recognize concerted metalation–deprotonationDistinguish concerted metalation–deprotonation from oxidative addition, electrophilic substitution and σ-bond metathesis by their bond changes.

Breaking C–H bonds at metals

  • How does a lutetium methyl exchange with methane?Classify the methyl–methane exchange of a d⁰ lanthanide complex as σ-bond metathesis.

Directing groups and palladacycles

  • Which compound cyclopalladates?Recognize a substrate whose donor atom can direct palladium to an ortho C–H bond through a five-membered palladacycle.

Compare 5

Borylation and other catalytic C–H reactions

  • Order the borylation cycleSequence the oxidative additions and reductive eliminations of the Ir(III)/Ir(V) borylation cycle.
  • Toluene: borylation versus nitrationContrast the steric selectivity of iridium borylation with the electronic selectivity of electrophilic aromatic substitution on toluene.

Breaking C–H bonds at metals

  • Rank C–H bond strengthsRank benzylic, tertiary, methane and aryl C–H bonds by bond dissociation energy and relate the order to metal selectivity.

Concerted metalation–deprotonation

  • Order the direct-arylation cycleSequence the elementary steps of a Pd(0)/Pd(II) direct-arylation cycle starting from Pd(0).

Directing groups and palladacycles

  • Two palladium cycles comparedContrast the Pd(II)/Pd(IV) cycle of PhI(OAc)₂ acetoxylation with the Pd(0)/Pd(II) cycle of direct arylation.

Calculate 6

Borylation and other catalytic C–H reactions

  • Atom economy of arene borylationCalculate the atom economy of iridium-catalyzed borylation of benzene when both boron atoms of B₂pin₂ are used.
  • d count of the iridium(V) intermediateFind the d-electron count of the seven-coordinate iridium aryl hydride in the borylation cycle.

Concerted metalation–deprotonation

  • Kinetic isotope effect in direct arylationCalculate a kinetic isotope effect from parallel rate constants and use it to place C–H cleavage in the rate-determining step.

Breaking C–H bonds at metals

  • d count after alkane oxidative additionFind the d-electron count of the iridium alkyl hydride formed by alkane C–H oxidative addition.
  • Electron count of Cp*₂Sc–CH₃Count the valence electrons of a bent-metallocene scandium methyl complex and relate the result to its reactivity.

Directing groups and palladacycles

  • Size of the 8-methylquinoline palladacycleCount the ring size of the palladacycle formed by sp³ C–H activation of 8-methylquinoline.

Find the error 1

  • Find the error in a direct-arylation mechanismIdentify an unjustified Pd(IV) hydride in a proposed C–H cleavage step and replace it with concerted metalation–deprotonation.

Interpret the evidence 2

Concerted metalation–deprotonation

  • Electron-poor arenes react fasterInterpret the reactivity of electron-poor arenes as evidence for CMD rather than electrophilic aromatic substitution.

Borylation and other catalytic C–H reactions

  • What deuterium scrambling revealsUse H/D scrambling between substrates to locate the rate-determining step of the Murai reaction.

Work backward 1

  • Which arene gives this boronate?Work backwards from a 1,3,5-substituted aryl boronate to the arene that iridium borylation converts into it selectively.

Plan a synthesis 1

  • Make 3,5-dichlorophenolPlan a route to a meta-substituted phenol using iridium-catalyzed C–H borylation followed by oxidation.

Explain why 6

Breaking C–H bonds at metals

  • Why does benzene beat alkanes?Explain why oxidative addition of an arene C–H bond is favoured over an alkane C–H bond even though the arene C–H bond is stronger.
  • Why no oxidative addition at scandium(III)?Explain why a d⁰ metal alkyl cannot activate C–H bonds by oxidative addition.
  • The σ-bond-metathesis transition stateDescribe the geometry and bookkeeping of the four-centre transition state of σ-bond metathesis.

Directing groups and palladacycles

  • Why does oxidative olefination need benzoquinone?Explain why a Pd(II)-catalyzed C–H olefination requires a stoichiometric oxidant.

Concerted metalation–deprotonation

  • Why add pivalic acid?Explain the role of catalytic pivalic acid in palladium-catalyzed direct arylation.

Borylation and other catalytic C–H reactions

  • The job of PtCl₆²⁻ in the Shilov systemExplain the role of the stoichiometric Pt(IV) oxidant in Shilov methane oxidation.

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