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In situ1D NMR spectroscopic reaction monitoring allows detailed investigation of chemical kinetics and mechanism. Concentration versus time data are derived from a time series of NMR spectra. Each spectrum in the series is obtained by Fourier transform of the corresponding FID. When the spectrometer outputs FIDs recorded from multiple scans, the spectra benefit from an increase in signal-to-noise (S/N). However, this reduces the number of FIDs and, thus, kinetic data points. We report a simple alternative in which the same number of scans is acquired by the spectrometer, but each scan is saved independently. Signal averaging is then conducted by postacquisition processing. This leads to an increase in both the S/N and the number of kinetic data points and can avoid “overaveraging” effects. The entire series of single-scan FIDs spanning the reaction lifetime can be summed to yield a “total reaction spectrum” in which intermediates can be identified. The method can be applied in coherence with phase cycling to minimize spectral distortion during solvent signal suppression. Overall, the approach simplifies the preacquisition parameters to the estimation of the reaction duration and T1maxand then the selection of the pulse angle, θ, and scan repetition time, τR, without the need to set the signal averaging before the experiment.

The Ni/PPh3-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 [(PPh3)2NiII(Ar)Cl] as a key intermediate and to explore the indirect roles of using Zn as the reductant. The [ZnCl2] coproduct is responsible for several features, including a sequential transmetalation pathway involving [ArZnCl]. [ZnCl2] also abstracts halide from [(PPh3)2NiCl2] to generate [NiIICl(DMF)5]+[ZnCl3(DMF)]−, and in doing so, affects the NiII+ Ni0↔ 2 NiIspeciation. [ZnCl2] thus acts as an accelerator and inhibitor, resulting in mildly sigmoidal reaction profiles. When the [ZnCl2] 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 [(PPh3)2NiII(Ar)Cl] but via dinuclear metathesis. The generation of [ZnCl3(DMF)]−results in mutually antagonistic effects between [ZnCl2] 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/PPh3catalyzed 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 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.