Hydroacylation
Organic reaction
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Hydroacylation is a type of organic reaction in which an electron-rich[1] unsaturated hydrocarbon inserts into a formyl C-H bond. With alkenes, the product is a ketone:
- RCHO + CH2=CHR' → RC(O)CH2CH2R'
With an alkyne instead, the reaction produces an α,β-unsaturated ketone.[2]
The reaction requires a metal catalyst or a radical initiator.[1] Even so, the reaction is difficult to engineer, as oxidizing aldehydes to acyl radicals occurs only at high electrochemical potential.[3] It is almost invariably practiced as an intramolecular reaction using homogeneous catalysts, often based on rhodium phosphines.
History
Hydroacylation first appeared in 1949, part of Kharasch's studies on peroxide effects.[3] Because chain transfer occurs very slowly,[4][5]: 21–22 the radical reaction required a very large excess of aldehyde and decarbonylation byproducts appeared in large quantity with dicarbonyl substrates.[3]
In the 1970s, metal-catalyzed hydroacylation was discovered for the synthesis of certain prostanoids.[6] The reaction required tin tetrachloride and a stoichiometric amount of Wilkinson's catalyst:
An equal amount of a cyclopropane was formed as the result of decarbonylation.
The first catalytic application involved cyclization of 4-pentenal to cyclopentanone using (again) Wilkinson's catalyst.[7] In this reaction the solvent was saturated with ethylene.
- CH2=CHCH2CH2CHO → (CH2)4CO
As of 2019, metal-catalyzed reactions continued to require rhodium catalysis.[3]
In the 1990s, studies on acyl radicals revealed that thiols or N-hydroxyphthalimide could catalyze rapid chain transfer, mostly removing the drawbacks of Kharasch's original radical reaction.[4][3][5]: 21–22 However, substrate scope remained limited. Modern work focuses on photoredox catalysis, and has produced mediocre-yielding catalysts that handle arbitrary substrates.[3]
Reaction mechanism
In the presence of a metal catalyst, hydroacylation begins with two oxidative additions: of the alkene and into the aldehydic carbon-hydrogen bond. The relative order of these two coordinations is unclear. The product is an acyl-metal hydride alkene complex. Then the alkene ligand undergoes migratory insertion into either the metal-acyl or the metal-hydride bonds. Finally, the resulting alkyl-acyl or beta-ketoalkyl-hydride complex undergoes reductive elimination.[2][5]
A competing side-reaction is decarbonylation of the intermediate acyl-metal hydride to give an alkane and a metal carbonyl:[5]
- R"C(O)-MLn-H → R"-M(CO)Ln-H → R"-H + M(CO)Ln
Asymmetric hydroacylation
Hydroacylation as an asymmetric reaction was demonstrated in the form of a kinetic resolution.[8][9] A true asymmetric synthesis was also described.[10][11] Both conversions employed rhodium catalysts and a chiral diphosphine ligand. In one application the ligand is Me-DuPhos:[12]
