C–H Functionalizations by Palladium Carboxylates: The Acid Effect

Abstract

Finding optimal reaction conditions is usually complex, requires many experiments and is therefore demanding in terms of human, financial and environmental resources. This work provides a simple workflow for easier design of popular palladium catalyzed C-H functionalization reactions, where the active palladium catalysts contain carboxylate ligands. The key factor for optimizing reaction conditions is to find a balance between two opposing effects of the carboxylic acid in the reaction mixture; generation of more reactive palladium catalyst vs. deactivation of substrate by its protonation.

The Activating Effect of Strong Acid for Pd-Catalyzed Directed C–H Activation by Concerted Metalation-Deprotonation Mechanism

“…Since C–H activation is usually involved in the rate-determining step (RDS), [ 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 ] we hypothesized the relative free energy of transition states of C–H cleavage (ΔG TS ≠ ) can determine the reactivity. The CMD mechanism was chosen for C–H activation, which usually has the lowest barrier among the frequently proposed mechanisms [ 57 , 58 ].…”

“…Although impressive progress has been made, the scope of application of these strategies is still limited [ 36 , 37 ]. Using strong acid is also a widely used strategy to promote C–H activation; for example, palladium(II)-catalyzed ortho-selective C–H chlorination/bromination has demonstrated that proper strong acids (TFA, TfOH) could promote the reactivity of ortho-selective C–H bond cleavage ( Scheme 1 and Scheme 2 ) [ 25 , 26 , 27 , 28 , 29 , 30 , 38 , 39 , 40 ]. These experimental results showed that higher catalytic activity occurred in reactions with lower pKa value acids.…”

Relative Strength of Common Directing Groups in Palladium-Catalyzed Aromatic C−H Activation

“…A recent paper by Jiří Váňa et al. highlighted the effect of the carboxylates on different aspects controlling reactivity of the palladium-catalyzed C−H activation (Váňa et al., 2019). The authors concluded that TFA can replace acetic acid on the metal, which would change the reactivity of the catalyst by increasing the electrophilicity of the palladium atom.…”

Palladium‐catalyzed Aerobic Benzannulation of Pyrazoles with Alkynes

“…More importantly, the combination of carboxylic acids and carboxylate salts afforded consistently high yields, among which sodium acetate and acetic acid proved to be optimal (entries 5–7). Presumably, the buffer was beneficial to provide a balance among palladium acetate species throughout the reaction 9 . Solvent screening indicated that DMA was the optimal medium (entries 8–10).…”