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Abstract Electrospray deposition of copper salt‐containing microdroplets onto the liquid surface of an electrically grounded reaction mixture leads to the formation of Cu nanoclusters, which then catalyze the azide‐alkyne cycloaddition (AAC) reaction to form triazoles. This method of in situ nanocatalyst preparation provided 17 times higher catalytic activity compared to that in the conventional catalytic reaction. The gentle landing of the Cu‐containing droplets onto the liquid surface forms a thin film of catalyst which promotes the heterogeneous AAC reaction while showing diffusion‐controlled kinetics. UV‐vis spectral characterization confirms that the catalyst is comprised of Cu nanoclusters. This unique catalytic strategy was validated using several substrates and the corresponding products were confirmed by tandem mass spectrometry (MS/MS) analysis. 

Abstract The sulfur fluoride exchange (SuFEx) reaction is significant in drug discovery, materials science, and chemical biology. Conventionally, it involves installation of SO₂F followed by fluoride exchange by a catalyst. We report catalyst‐free Aza‐Michael addition to install SO₂F and then SuFEx reaction with amines, both occurring in concert, in microdroplets under ambient conditions. The microdroplet reaction is accelerated by a factor of ∼10⁴relative to the corresponding bulk reaction. We suggest that the superacidic microdroplet surface assists SuFEx reaction by protonating fluorine to create a good leaving group. The reaction scope was established by performing individual reactions in microdroplets of 18 amines in four solvents and confirmed using high‐throughput desorption electrospray ionization experiments. The study demonstrates the value of microdroplet‐assisted accelerated reactions in combination with high‐throughput experimentation for characterization of reaction scope. 

Abstract Late‐stage functionalization (LSF) of drug molecules is an approach to generate modified molecules that retain functional groups present in the active drugs. Here, we report a study that seeks to characterize the potential value of high‐throughput desorption electrospray ionization mass spectrometry (HT DESI‐MS) for small‐scale rapid LSF. In conventional route screening, HT‐based DESI‐MS provides contactless, rapid analysis, reliable and reproducible data, minimal sample requirement, and exceptional tolerance to high salt concentrations. Ezetimibe (E), an established hypertension drug, is targeted for modification by LSF. C−H alkenylation and azo‐click reactions are utilized to explore this approach to synthesis and analytical characterization. The effect of choice of reactant, stoichiometry, catalyst, and solvent are studied for both reactions using high throughput DESI‐MS experiments. Optimum conditions for the formation of LSF products are established with identification by tandem mass spectrometry (MS/MS).