The seminal contributions by Sonogashira, Cassar and Heck in mid 1970s on Pd/Cu- and Pd-catalysed (copper-free) coupling of acetylenes with aryl or vinyl halides have evolved in myriad applications. Despite the enormous success both in academia and in industry, however, critical mechanistic questions of this cross-coupling process remain unresolved. In this study, experimental evidence and computational support is provided for the mechanism of copper-free Sonogashira cross-coupling reaction. In contrast to the consensus monometallic mechanism, the revealed pathway proceeds through a tandem Pd/Pd cycle linked via a multistep transmetallation process. This cycle is virtually identical to the Pd/Cu tandem mechanism of copper co-catalysed Sonogashira cross-couplings, but the role of Cu^I is played by a set of Pd^II species. Phosphine dissociation from the square-planar reactants to form transient three-coordinate Pd species initiates transmetallation and represents the rate-determining step of the process.

A novel bis(pyridyl-functionalized 1,2,3-triazol-5-ylidene)-palladium(II) complex [Pd(Py-tzNHC)₂]²⁺ catalyses the copper-, amine-, phosphine-, and additive-free aerobic Sonogashira alkynylation of (hetero)aryl bromides in water as the only reaction solvent. The catalysis proceeds along two connected Pd-cycles with homogeneous bis-carbene Pd⁰ and Pd^II species, as demonstrated by electrospray ionization mass spectrometry.

We report a copper-catalyzed cycloaddition of hydrogen azide (hydrazoic acid, HN₃) with terminal alkynes to form 4-substituted-1H-1,2,3-triazoles in a sustainable manner. Hydrazoic acid was formed in situ from sodium azide under acidic conditions to react with terminal alkynes in a copper-catalyzed reaction. Using polydentate N-donor chelating ligands and mild organic acids, the reactions were realized to proceed at room temperature under aerobic conditions in a methanol–water mixture and with 5 mol % catalyst loadings to afford 4-substituted-1,2,3-triazoles in high yields. This method is amenable on a wide range of alkyne substrates, including unprotected peptides, showing diverse functional group tolerance. It is applicable for late-stage functionalization synthetic strategies, as demonstrated in the synthesis of the triazole analogue of losartan. The preparation of orthogonally protected azahistidine from Fmoc-l-propargylglycine was realized on a gram scale. The hazardous nature of hydrazoic acid has been diminished as it forms in situ in <6% concentrations at which it is safe to handle. Reactions of distilled solutions of hydrazoic acid indicated its role as a reactive species in the copper-catalyzed reaction.

A robust, selective and highly efficient method for the preparation of 1,3,4-triaryl 1,2,3-triazolium salts has been developed. It features arylation of a click triazole with a diaryliodonium salt in the presence of a copper catalyst under neat conditions. The presence of pyridine functionality is tolerated, enabling the first access to key precursors of pyridyl-mesoionic carbene ligands. The method has been integrated into a one-pot protocol with a terminal alkyne, sodium azide, and diaryliodonium salt as staring compounds.

The cationic palladium(II) complex 1 of pyridyl-mesoionic carbene ligand catalyzes Markovnikov-selective intermolecular hydroamination between anilines and terminal alkynes into the corresponding imines. The reaction proceeds at room temperature, in the absence of additives, with exquisite selectivity and diverse functional group tolerance. The key intrinsic feature of the catalyst is the pyridine wingtip confined to the proximity of the alkynophilic metal active site, which mimics the function of enzyme-like architectures by assisting entropically favored proton transfers.

Modelling the correlation between molecular electrostatic potential and pKa on sets of carboxylic acids, phenols and anilines