Decoding the Selective Formation of One over Eight Possible Products in a Pd-Catalyzed Multicomponent Reaction

Area of Science:

• Organometallic Chemistry
• Catalysis
• Reaction Mechanism

Background:

• Multicomponent reactions (MCRs) offer efficient synthetic routes.
• Palladium (Pd)-catalyzed reactions are vital in organic synthesis.
• Understanding reaction mechanisms is crucial for optimizing yields and selectivity.

Purpose of the Study:

• To comprehensively investigate the mechanism of a Pd-catalyzed MCR.
• To identify accessible products and competing pathways.
• To elucidate the role of reaction conditions and intermediates.

Main Methods:

• Density Functional Theory (DFT) calculations.
• Dual-level DLPNO-CCSD(T) computations.
• Experimental control experiments.

Main Results:

• Up to eight products are theoretically accessible, with three pathways dominating.
• A finely balanced competition between kinetic and thermodynamic factors governs product distribution.
• Cesium enolate aggregates were identified as the most probable nucleophiles.
• A relay mechanism was proposed for the major three-component product.

Conclusions:

• Subtle changes in base, solvent, and temperature significantly impact reactivity.
• The formation of E/Z isomers of cesium enolates explains the lack of asymmetric induction.
• Accurate identification of nucleophiles is critical in MCRs, especially under one-pot conditions.