CHE 232-002

C–C Bond-Forming Reactions We Know and Love

The essence of organic synthesis is forming C–C bonds. In a synthesis, you need to learn how to recognize when you have a structure that can be formed by a C–C bond-forming reaction. This table lists the C–C bond-forming reactions we have learned so far in CHE 230 and CHE 232.

Retrosynthesis is the process by which you figure out how to make a target from simpler starting materials. A retron is a substructure that can be made by a particular reaction. A disconnection breaks a target compound up into simpler starting materials. After you do a disconnection, you always need to check that the reaction works as desired in the forward direction.

Contents Sorted by Retron¹

• Alkyne alkylation
  • Retron: an alkyne.
  • Disconnect the bond between a C(sp) of the alkyne and an adjacent C(sp³), and add H to C(sp) and a leaving group to C(sp³). Use Br for the leaving group if C(sp³) is not stereogenic; use OTs (and invert the configuration!) if it is.
  • The forward reaction requires a strong base such as BuLi, LDA, or NaNH₂ to deprotonate the alkyne.
  • Does not work well for 2° alkyl halides/tosylates, not at all for 3° alkyl halides/tosylates.
  • If your electrophile is a tosylate, it is made from an alcohol of the same configuration.

• Cyanide alkylation
  • Retron: a nitrile or a carboxylic acid with an α-C(sp³).
  • Disconnect the bond between the C(sp) of the C≡N group or the carbonyl C of the CO₂H group and the α-carbon, and add a leaving group to the α-carbon. Use Br for the leaving group if the α-carbon is not stereogenic; use OTs (and invert the configuration!) if it is.
  • In the forward direction, simply add NaCN to the electrophile. If the carboxylic acid is desired, follow the NaCN reaction with aq. NaOH or aqueous acid.
  • Works so-so for 2° alkyl halides/tosylates, not at all for 3° alkyl halides/tosylates.
  • If your electrophile is a tosylate, it is made from an alcohol of the same configuration.

• Cyclopropanation
  • Retron: a cyclopropane. Two of the ring C atoms come from an alkene, the third from CHCl₃ or CH₂I₂.
  • Disconnection:
    • Identify a C of the ring that bears two H or two Cl atoms.
    • Disconnect the two bonds from that C to the other two C atoms of the ring.
    • Put a π bond between the two ring C atoms that are still connected to one another to get an alkene.
    • If the cyclopropane is cis or trans, the alkene must be the same.
  • The reagents for the forward reaction are CHCl₃ and aq. KOH to add a CCl₂ group, or CH₂I₂ and Zn(Cu) to add a CH₂ group.

• Diels–Alder reaction
  • Retron: a cyclohexane, cyclohexene, or 1,4-cyclohexadiene. Two of the ring C atoms come from a dienophile (alkene or alkyne), the other four from a 1,3-diene.
  • Disconnection:
    • Calling one double bond C(1)=C(2), number the ring atoms 1–6.
      • If the ring lacks a π bond, you can put it in retrosynthetically, later removing it in the forward direction by hydrogenation, dihydroxylation, hydroboration–oxidation, etc.
      • If the ring has two π bonds in a 1,4-relationship, the double bond that has electron-withdrawing groups attached should be labeled C(4)=C(5), and the other double bond should be C(1)=C(2).
    • Disconnect the C(3)–C(4) and C(5)–C(6) bonds.
    • Put an additional π bond at C(4)–C(5) to get the dienophile.
    • Put two additional π bonds at C(1)–C(6) and C(2)–C(3) and erase the C(1)–C(2) π bond to get the 1,3-diene.
    • If substituents at C(4) and C(5) were cis or trans, the C(4)=C(5) alkene must be the same.
    • If substituents at C(6) and C(3) were cis, they must both be "out" or both be "in" in the 1,3-diene. If they were trans, one must be "out" and the other "in".
  • Only heat is required to promote a Diels–Alder reaction. However, the reaction requires that the diene be electron-rich and the dienophile electron-poor. Some retrosynthetic steps may be required to bring your target to the stage where the Diels–Alder disconnection yields an electron-rich diene and an electron-poor dienophile.
  • Note that a 1,4-cyclohexadiene is also a retron for a Birch reduction of an arene with Li and liq. NH₃, but the Birch reduction does not make any new C–C bonds.

• Friedel–Crafts acylation
  • Retron: an aryl ketone, with the ketone attached directly to the aromatic ring
  • Disconnect the bond between the benzene ring and the ketone C, and add H to the C of the benzene ring and Cl to the carbonyl C.
  • The forward reaction requires excess AlCl₃.
  • Check that the reaction proceeds with the desired regioselectivity! If not, you may need to do the Friedel–Crafts reaction on an aromatic ring with different substituents, then convert those substituents to those in the target.

• Friedel–Crafts alkylation or acylation
  • Retron: a benzene ring with an alkyl substituent
  • Disconnect the bond between the benzene ring and the benzylic C(sp³), and add H to C(sp²) and Cl to C(sp³).
  • If the alkyl chloride is 2° or 3°, the forward reaction requires catalytic AlCl₃. However, if the alkyl chloride is 1°:
    • Replace the CH₂Cl group with C(=O)Cl.
    • The forward reaction requires excess AlCl₃, then H₂NNH₂, then KOH.
  • Check that the reaction proceeds with the desired regioselectivity! If not, you may need to do the Friedel–Crafts reaction on an aromatic ring with different substituents, then convert those substituents to those in the target.

• Cyanation of arenes
  • Retron: a benzene ring with a C≡N or CO₂H substituent
  • Disconnect the bond between the benzene ring and C≡N or CO₂H, and add NH₂ or NO₂ to C(sp²).
  • In the forward direction, the reaction sequence is: ArNO₂ + SnCl₂, HCl → ArNH₂ + NaNO₂, HCl → ArN₂⁺ + CuCN → ArCN + aq. NaOH → ArCO₂H.
  • Note that a benzoic acid, ArCO₂H, is also a retron for the KMnO₄ oxidation of an alkyl-substituted benzene, but this reaction does not make any new C–C bonds.

• Pd-catalyzed cross-coupling
  • Retron: a benzene ring with a C substituent (C may have any hybridization, but may not be C=O)
  • Disconnect the bond between the benzene ring and the benzylic C, and add Br to the benzene C and SnMe₃ to the former benzylic C.
    Other metal-containing groups can be used in place of SnMe₃:
    • For C(sp²), B(OH)₂ works well and is much safer.
    • For C(sp), use H and add Et₃N and cat. CuI.
    • For any kind of C, ZnCl often works well, as does MgBr, but these compounds are less tolerant of other functional groups or are more difficult to make.
  • In the forward direction, the reaction sequence is: ArBr + RSnMe₃ and cat. Pd(phosphine) → ArR.

• Grignard reagent addition to carbonyl compounds
  • Retron: an alcohol with no other heteroatom functionality nearby.
  • If two of the alkyl groups attached to the alcohol C are identical, disconnect them both, change the C–OH bond to a C=O bond, and add an OEt group to the carbonyl C atom; otherwise, disconnect just one of the alkyl groups attached to the OH-bearing C atom, and change the C–OH bond to a C=O bond. In either case, add MgBr to the C atom that was disconnected.
  • The Grignard reagent can be made from the alkyl halide in which the C–Mg bond is replaced with a C–Br bond.
  • In the forward direction, convert the alkyl bromide to the Grignard reagent by adding Mg, and then add the carbonyl compound.
  • Warning: The C atom that acquires the bond to Mg must not bear a heteroatom or be adjacent to a C that bears a heteroatom. If it is, choose another disconnection, or you may need to use a different reaction.

• Grignard reagent addition to nitriles
  • Retron: a ketone with no other heteroatom functionality nearby.
  • Disconnect the bond between the carbonyl C and the α-carbon, change the C=O bond to a C≡N bond, and add MgBr to the C atom that was disconnected.
  • The Grignard reagent can be made from the alkyl halide in which the C–Mg bond is replaced with a C–Br bond.
  • In the forward direction, convert the alkyl bromide to the Grignard reagent by adding Mg, and then add the nitrile.
  • Warning: The Mg-bearing C should not be attached to heteroatoms or adjacent to a C attached to heteroatoms. If it is, choose another disconnection, or you may need to use a different reaction.

• Grignard reagent addition to Weinreb amides
  • Retron: a ketone with no other heteroatom functionality nearby.
  • Disconnect the bond between the carbonyl C and the α-carbon, add N(Me)OMe to the carbonyl C, and add MgBr to the C atom that was disconnected.
  • The Grignard reagent can be made from the alkyl halide in which the C–Mg bond is replaced with a C–Br bond.
  • In the forward direction, convert the alkyl bromide to the Grignard reagent by adding Mg, and then add the Weinreb amide. The Weinreb amide can be made from a carboxylic acid via the acyl chloride or with DCC.
  • Warning: The Mg-bearing C should not be attached to heteroatoms or adjacent to a C attached to heteroatoms. If it is, choose another disconnection, or you may need to use a different reaction.

• Grignard reagent addition to CO₂
  • Retron: a carboxylic acid with no other heteroatom functionality nearby.
  • Disconnect the carbonyl C from the α-carbon, and add MgBr to the α-carbon.
  • The Grignard reagent can be made from the alkyl halide in which the C–Mg bond is replaced with a C–Br bond.
  • In the forward direction, convert the alkyl bromide to the Grignard reagent by adding Mg, and then add CO₂.
  • Warning: The Mg-bearing C should not be attached to heteroatoms or adjacent to a C attached to heteroatoms. If it is, choose another disconnection, or you may need to use a different reaction.

• Wittig reaction
  • Retron: an alkene or an α,β-unsaturated carbonyl compound.
  • Disconnect the C=C bond. If one of the disconnected C atoms is attached to a carbonyl C, add =PPh₃ to it, and add =O to the other C. Otherwise, add =PPh₃ to the less substituted C, and add =O to the more substituted C.
  • The P-containing compound (a phosphorane) can be made from an alkyl halide. Replace the =PPh₃ group with σ bonds to H and Br.
  • In the forward direction, add PPh₃ to the alkyl halide to make a phosphonium salt, add base to make the phosphorane, and add the carbonyl compound.
  • The product is predominantly cis (contrathermodynamic) unless the product alkene is conjugated to a carbonyl group.
  • A nitrile counts as an honorary carbonyl compound. The C(sp) of the nitrile is synthetically equivalent to a carbonyl C.

• Cyanohydrin formation
  • Retron: an α-hydroxy nitrile or carboxylic acid
  • Disconnect the bond between the C(sp) of the C≡N group or the C(sp²) of the CO₂H group, and convert C–OH to C=O.
  • In the forward direction, add NaCN to the carbonyl compound. If the carboxylic acid is desired, follow with aq. NaOH or aqueous acid.

• Alkylation of carbonyl compounds
  • Retron: a carbonyl compound with a C–C σ bond between the α- and β-C(sp³) atoms, and no OH or =O on the β-C(sp³) atom.
  • Disconnect the bond between the α- and β-carbon atoms, add an H to the α-carbon, and add a leaving group (usually Br, but OTs is best if the electrophilic C(sp³) is stereogenic) to the β-carbon.
  • If the electrophile is 2° and the carbonyl compound is a monocarbonyl, replace one of the H atoms on the α-carbon with a CO₂R group (R = Et or Me usually).
  • In the forward direction, add base (LDA for a monocarbonyl, NaOEt or NaOMe for a 1,3-dicarbonyl) to the starting carbonyl compound, and then add the electrophile. If it was necessary to retrosynthetically replace an H with CO₂R, follow it up with NaOH (to convert esters to acids) and then acidic H₂O and heat (to replace one CO₂H with H). If an ester is desired as the final product, follow these steps up with ROH and H⁺.
  • A nitrile counts as an honorary carbonyl compound. The C(sp) of the nitrile is synthetically equivalent to a carbonyl C.

• Aldol reaction
  • Retron: a β-hydroxy carbonyl compound.
  • Disconnect the bond between the α- and β-carbon atoms, add an H to the α-carbon, and change the β-C–OH bond to C=O.
  • In the forward direction, add LDA, and then add the ketone or aldehyde.
  • A nitrile counts as an honorary carbonyl compound. The C(sp) of the nitrile is synthetically equivalent to a carbonyl C.

• Aldol–dehydration reaction
  • Retron: an α,β-unsaturated carbonyl compound.
  • Disconnect the α- and β-carbon atoms, add two H atoms to the α-carbon, and add =O to the β-carbon.
  • In the forward direction, add base to the nucleophilic carbonyl compound, and then add the electrophile.
    • If the nucleophilic carbonyl compound is a simple ketone or aldehyde, use NaOR (R = H, Me, Et) as the base.
    • If the nucleophilic carbonyl compound is a 1,3-dicarbonyl compound, use a 2° amine (e.g., piperidine or pyrrolidine) as the base.
    • If the nucleophilic carbonyl compound is an acyl anhydride, use NaOAc as the base.
  • A nitrile counts as an honorary carbonyl compound. The C(sp) of the nitrile is synthetically equivalent to a carbonyl C.

• Claisen or Dieckmann condensation
  • Retron: a β-keto carbonyl compound with at least one H on the α-carbon.
  • Disconnect the bond between the α- and β-carbon atoms, add an H to the α-carbon, and add an OMe or OEt group to the β-carbon. If possible, a disconnection that gives two identical starting materials or a single starting material is better. Otherwise, after the disconnection, the carbonyl compound derived from the β-carbon should lack α-H atoms.
  • In the forward direction, heat the starting materials with a full equivalent of NaOMe or NaOEt.
  • A nitrile counts as an honorary carbonyl compound. The C(sp) of the nitrile is synthetically equivalent to a carbonyl C.

• Michael reaction
  • Retron: a 1,5-dicarbonyl compound (three C atoms between two carbonyl C atoms) with at least one H atom on C(2) or C(4).
  • There are two possible disconnections: between C(2) and C(3), and between C(4) and C(3). Essentially, you have to decide whether C(2) or C(4) will be the α-carbon of the nucleophile.
    • If C(2) or C(4) is attached to two carbonyl C atoms, then it is the α-carbon of the nucleophile.
    • If C(2) or C(4) is quaternary (lacks H atoms), then it is the α-carbon of the nucleophile.
  • Disconnect the bond between the α-carbon of the nucleophile and the adjacent C, and add an H atom to the α-carbon. Then remove an H atom from the α-carbon of the electrophile, and put a new π bond between the α- and β-carbon atoms of the electrophile.
  • If the α-carbon of the nucleophile bears two H atoms but only one carbonyl C, replace one of the H atoms on the α-carbon with a CO₂R group (R = Et or Me usually).
  • In the forward direction, combine the starting materials with a catalytic amount of weak base, e.g., NaOMe or NaOEt. If it was necessary to retrosynthetically replace an H with CO₂R, follow it up with NaOH (to convert esters to acids) and then acidic H₂O and heat (to replace one CO₂H with H). If an ester is desired as the final product, follow these steps up with ROH and H⁺.
  • A nitrile counts as an honorary carbonyl compound. The C(sp) of the nitrile is synthetically equivalent to a carbonyl C.

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