Palladium-Catalyzed Carbonylation Reactions in Organic Synthesis

Palladium-catalysed carbonylation has emerged as a cornerstone technique in the assembly of carbonyl-containing compounds, enabling the direct incorporation of carbon monoxide into organic substrates. The versatility of this methodology spans the formation of esters, amides, ketones and lactones from simple feedstocks such as alkenes, alkyl halides and aryl partners. Mechanistically, these transformations proceed via formation of a palladium-carbonyl complex, migratory insertion of CO into a Pd–C bond and subsequent nucleophilic attack or reductive elimination. Advances in ligand design, catalyst activation and alternative CO sources have extended scope to challenging substrates, improved selectivity and lowered reaction pressures. Industrially, palladium carbonylations underpin bulk processes such as hydroesterification of ethylene and fine-chemical syntheses including late-stage functionalisation of pharmaceuticals. Contemporary research is focused on sustainable carbonylation protocols, asymmetric variants and cascade sequences that deliver complex motifs in a single operation, highlighting the central role of palladium catalysis in modern synthetic planning.

Research from Nature Portfolio

A rationally designed palladium complex bearing a bulky bis(phosphine) ligand has demonstrated exceptional activity in alkoxycarbonylation of sterically hindered alkenes. This system achieves record turnovers and outstanding selectivity for the transformation of tetra- and tri-substituted olefins into esters, even on industrial metrics for ethylene functionalisation. Such robustness has broadened the practical application of carbonylation in both commodity and fine-chemical production. In a complementary development, relay hydroaminocarbonylation employing a simple palladium catalyst and hydroxylamine hydrochloride as an ammonia equivalent enables sequential C–N bond formation and CO insertion. This one-pot protocol converts alkenes into primary amides via in situ generation of alkylamines, streamlining access to nitrogen-rich scaffolds under mild conditions. Earlier foundational work introduced a cooperative redox activation strategy in which carbon dioxide is reduced to CO and immediately engaged in palladium-catalysed carbonylative coupling. The dual role of the silane reagent in CO generation and transmetalation significantly reduces waste and expands the toolbox for C1 chemistry.

Palladium-Catalyzed Carbonylation Reactions in Organic Synthesis publication trend

The graph below shows the total number of articles in palladium-catalyzed carbonylation reactions in organic synthesis across all publications each year (not limited to Nature Index journals).

Technical terms

Carbonylation: A reaction in which carbon monoxide is inserted into a metal-carbon bond to form a carbonyl functional group.

Alkoxycarbonylation: The addition of an alcohol and carbon monoxide across an alkene, yielding an ester.

Hydroaminocarbonylation: A variant of carbonylation in which an amine or ammonia equivalent and CO combine with an alkene to form an amide.

Hemilabile ligand: A chelating ligand that possesses both strongly and weakly coordinating donor sites, enabling dynamic binding during catalysis.

Turnover number (TON): The number of substrate molecules converted per catalyst molecule before deactivation.

References

1. Highly active and efficient catalysts for alkoxycarbonylation of alkenes. Nature Communications (2017).
2. Cooperative catalytic methoxycarbonylation of alkenes: uncovering the role of palladium complexes with hemilabile ligands. Chemical Science (2018).
3. PdI2-Based Catalysis for Carbonylation Reactions: A Personal Account. Catalysts (2019).
4. Palladium-catalyzed enantioselective carbonylation reactions. Science China Chemistry (2022).
5. Cooperative redox activation for carbon dioxide conversion. Nature Communications (2016).
6. Palladium-catalyzed relay hydroaminocarbonylation of alkenes with hydroxylamine hydrochloride as an ammonia equivalent. Communications Chemistry (2019).