Chemoselective Organoclick–Click Sequence

The copper‐catalyzed azide alkyne 1,3‐cycloaddition (CuAAC) reaction has received enormous attention as a powerful tool to form 1,4‐disubstituted‐1,2,3‐triazoles easily and conveniently. Particularly, an efficient protocol of the CuAAC reaction for regioselective double ligation through differentiating the reactivity of an azide or alkyne group is interesting for application in chemical biology, material science and pharmaceutical research. Herein, a simple competitive CuAAC reaction in water using miscibility difference of alkynes with water was discovered. Under conventional CuSO4‐NaAsc catalysts, the CuAAC reaction between a water‐insoluble alkyne and an organic azide furnished a wide range of triazole adducts primarily based on a hydrophobic effect in good‐to‐excellent yields even in the presence of a water‐soluble alkyne. This protocol provides environmentally friendly conditions for aqueous medium, easy and convenient access to triazoles without specially designed ligands for the activation and stabilization of the Cu catalyst and thus is applicable to various fields of chemistry.

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Nucleophilicity and Electrophilicity Parameters for Predicting Absolute Rate Constants of Highly Asynchronous 1,3-Dipolar Cycloadditions of Aryldiazomethanes

Jangra

Chen

Fuks

et al. 2018

J. Am. Chem. Soc.

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Kinetics of the reactions of aryldiazomethanes (ArCHN2) with benzhydrylium ions (Ar2CH+) have been measured photometrically in dichloromethane. The resulting second-order rate constants correlate linearly with the electrophilicities E of the benzhydrylium ions which allowed us to use the correlation lg k = s N(N + E) (eq 1) for determining the nucleophile-specific parameters N and s N of the diazo compounds. UV–vis spectroscopy was analogously employed to measure the rates of the 1,3-dipolar cycloadditions of these aryldiazomethanes with acceptor-substituted ethylenes of known electrophilicities E. The measured rate constants for the reactions of the diazoalkanes with highly electrophilic Michael acceptors (E > −11, for example 2-benzylidene Meldrum’s acid or 1,1-bis(phenylsulfonyl)ethylene) agreed with those calculated by eq 1 from the one-bond nucleophilicities N and s N of the diazo compounds and the one-bond electrophilicities of the dipolarophiles, indicating that the incremental approach of eq 1 may also be applied to predict the rates of highly asynchronous cycloadditions. Weaker electrophiles, e.g., methyl acrylate, react faster than calculated from E, N, and s N, and the ratio of experimental to calculated rate constants was suggested to be a measure for the energy of concert ΔG ‡ concert = RT ln(k 2 exptl/k 2 calcd). Quantum chemical calculations indicated that all products isolated from the reactions of the aryldiazomethanes with acceptor substituted ethylenes (Δ2-pyrazolines, cyclopropanes, and substituted ethylenes) arise from intermediate Δ1-pyrazolines, which are formed through concerted 1,3-dipolar cycloadditions with transition states, in which the C–N bond formation lags behind the C–C bond formation. The Gibbs activation energies for these cycloadditions calculated at the PCM(UA0,CH2Cl2)/(U)B3LYP-D3/6-31+G(d,p) level of theory agree within 5 kJ mol–1 with the experimental numbers showing the suitability of the applied polarizable continuum model (PCM) for considering solvation.

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Chemoselective Organoclick–Click Sequence

Cited by 4 publications

References 23 publications

[3+2]‐Cycloaddition for Fully Decorated Vinyl‐1,2,3‐Triazoles: Design, Synthesis and Applications

[3+2]‐Cycloaddition for Fully Decorated Vinyl‐1,2,3‐Triazoles: Design, Synthesis and Applications

Competitive CuAAC Reaction between Hydrophobic and Hydrophilic Alkynes with Azides in Water

Nucleophilicity and Electrophilicity Parameters for Predicting Absolute Rate Constants of Highly Asynchronous 1,3-Dipolar Cycloadditions of Aryldiazomethanes

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