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The Ni/PPh 3 -catalyzed homocoupling of aryl chlorides in DMF using Zn as the stochiometric reducing agent is one of a general class of Ni-catalyzed processes, where the mechanism has been a matter of long-standing debate. This study re-evaluates prior conclusions and insights. NMR spectroscopy is used to identify [(PPh 3 ) 2 Ni II (Ar)Cl] as a key intermediate and to explore the indirect roles of using Zn as the reductant. The [ZnCl 2 ] coproduct is responsible for several features, including a sequential transmetalation pathway involving [ArZnCl]. [ZnCl 2 ] also abstracts halide from [(PPh 3 ) 2 NiCl 2 ] to generate [Ni II Cl(DMF) 5 ] + [ZnCl 3 (DMF)] - , and in doing so, affects the Ni II + Ni 0 ↔ 2 Ni I speciation. [ZnCl 2 ] thus acts as an accelerator and inhibitor, resulting in mildly sigmoidal reaction profiles. When the [ZnCl 2 ] concentration becomes too high or the phosphine ligand concentration too low, catalysis stalls. Turnover is restored by the addition of further phosphine ligand, or chloride ion. In the presence of an exogenous chloride ion, turnover is rapid, again proceeding via [(PPh 3 ) 2 Ni II (Ar)Cl] but via dinuclear metathesis. The generation of [ZnCl 3 (DMF)] - results in mutually antagonistic effects between [ZnCl 2 ] and [Cl] - such that turnover proceeds via one mechanism or the other, depending on which species is in excess. The intermediacy of [ArZnCl] suggests a solution to the long-standing anomaly that many other reductants were found to be much less effective than Zn in inducing turnover of Ni/PPh 3 catalyzed aryl chloride homocoupling in DMF. The use of DMAc as a solvent in place of DMF inhibits stalling through the steric inhibition of mixed metalate generation.

The kinetics of sulfur transfer from titanocene (poly)sulfides ( R Cp 2 TiS 5 , Cp 2 TiS 4 CMe 2 , Cp 2 Ti(SAr) 2 , Cp 2 TiCl(SAr)) to sulfenyl chlorides (S 2 Cl 2 , RSCl) have been investigated by a combination of stopped-flow UV-Vis/NMR reaction monitoring, titration assays, numerical kinetic modelling and KS-DFT calculations. The reactions are rapid, proceeding to completion over timescales of milliseconds to minutes, via a sequence of two S-S bond-forming steps ( k 1 , k 2 ). The archetypical polysulfides Cp 2 TiS 5 C(Me 2 TiS 4 C(Me 2 ) (2a) react with disulfur dichloride (S 2 Cl 2 ) through rate-limiting intermolecular S-S bond formation ( k 1 ) followed by a rapid intramolecular cyclization ( k 2 , with k 2 ≫ k 1 [RSCl]). The monofunctional sulfenyl chlorides (RSCl) studied herein react in two intermolecular S-S bond forming steps proceeding at similar rates ( k 1 ≈ k 2 ). Reactions of titanocene bisthiophenolates, Cp 2 Ti(SAr) 2 (5), with both mono- and di-functional sulfenyl chlorides result in rapid accumulation of the monothiophenolate, Cp 2 TiCl(SAr) (6) ( k 1 > k 2 ). Across the range of reactants studied, the rates are relatively insensitive to changes in temperature and in the electronics of the sulfenyl chloride, moderately sensitive to the electronics of the titanocene (poly)sulfide ( ρ (Ti-(SAr)) ≈ -2.0), and highly sensitive to the solvent polarity, with non-polar solvents (CS 2 , CCl 4 ) leading to the slowest rates. The combined sensitivities are the result of a concerted, polarized and late transition state for the rate-limiting S-S bond forming step, accompanied by a large entropic penalty. Each substitution step {[Ti]-SR' + Cl-SR → [Ti]-Cl + RS-SR'} proceeds via titanium-assisted Cl-S cleavage to generate a transient pentacoordinate complex, Cl-[Cp 2 TiX]-S(R')-SR, which then undergoes rapid Ti-S dissociation., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

The Cu-catalyzed azide-alkyne cycloaddition (CuAAC) reaction is used as a ligation tool throughout chemical and biological sciences. Despite the pervasiveness of CuAAC, there is a need to develop more efficient methods to form 1,4-triazole ligated products with low loadings of Cu. In this paper, we disclose a mechanistic model for the ynamine-azide (3 + 2) cycloadditions catalyzed by copper(II) acetate. Using multinuclear nuclear magnetic resonance spectroscopy, electron paramagnetic resonance spectroscopy, and high-performance liquid chromatography analyses, a dual catalytic cycle is identified. First, the formation of a diyne species via Glaser-Hay coupling of a terminal ynamine forms a Cu(I) species competent to catalyze an ynamine-azide (3 + 2) cycloaddition. Second, the benzimidazole unit of the ynamine structure has multiple roles: assisting C-H activation, Cu coordination, and the formation of a postreaction resting state Cu complex after completion of the (3 + 2) cycloaddition. Finally, reactivation of the Cu resting state complex is shown by the addition of isotopically labeled ynamine and azide substrates to form a labeled 1,4-triazole product. This work provides a mechanistic basis for the use of mixed valency binuclear catalytic Cu species in conjunction with Cu-coordinating alkynes to afford superior reactivity in CuAAC reactions. Additionally, these data show how the CuAAC reaction kinetics can be modulated by changes to the alkyne substrate, which then has a predictable effect on the reaction mechanism.