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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 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). 

Abstract The kinetics of organic reactions of different types in microvolumes (droplets, thin films, and sealed tubes) show effects of gas/solution interfacial area, reaction molecularity and solvent polarity. Partial solvation at the gas/solution interface is a major contributor to the 10⁴‐fold reaction acceleration seen in bimolecular but not unimolecular reactions in microdroplets. Reaction acceleration can be used to manipulate selectivity by solvent choice. 

Abstract Palladium‐catalyzed Suzuki‐Miyaura (SM) coupling is widely utilized in the construction of carbon‐carbon bonds. In this study, nanoelectrospray ionization mass spectrometry (nanoESI‐MS) is applied to simultaneously monitor precatalysts, catalytic intermediates, reagents, and products of the SM cross‐coupling reaction of 3‐Br‐5‐Ph‐pyridine and phenylboronic acid. A set of Pd cluster ions related to the monoligated Pd (0) active catalyst is detected, and its deconvoluted isotopic distribution reveals contributions from two neutral molecules. One is assigned to the generally accepted Pd(0) active catalyst, seen in MS as the protonated molecule, while the other is tentatively assigned to an oxidized catalyst which was found to increase as the reaction proceeds. Oxidative stress testing of a synthetic model catalyst 1,5‐cyclooctadiene Pd XPhos (COD−Pd‐XPhos) performed using FeCl₃supported this assignment. The formation and conversion of the oxidative addition intermediate during the catalytic cycle was monitored to provide information on the progress of the transmetalation step. 

Abstract To disentangle the factors controlling the rates of accelerated reactions in droplets, we used mass spectrometry to study the Katritzky transamination in levitated Leidenfrost droplets of different yet constant volumes over a range of concentrations while holding concentration constant by adding back the evaporated solvent. The set of concentration and droplet volume data indicates that the reaction rate in the surface region is much higher than that in the interior. These same effects of concentration and volume were also seen in bulk solutions. Three pyrylium reagents with different surface activity showed differences in transamination reactivity. The conclusion is drawn that reactions with surface‐active reactants are subject to greater acceleration, as seen particularly at lower concentrations in systems of higher surface‐to‐volume ratios. These results highlight the key role that air‐solution interfaces play in Katritzky reaction acceleration. They are also consistent with the view that reaction‐increased rate constant is at least in part due to limited solvation of reagents at the interface. 

Abstract The sulfotransferase (SULT) 2B1b, which catalyzes the sulfonation of 3β‐hydroxysteroids, has been identified as a potential target for prostate cancer treatment. However, a major limitation for SULT2B1b‐targeted drug discovery is the lack of robust assays compatible with high‐throughput screening and inconsistency in reported kinetic data. For this reason, we developed a novel label‐free assay based on high‐throughput (>1 Hz) desorption electrospray ionization mass spectrometry (DESI‐MS) for the direct quantitation of the sulfoconjugated product (CV<10 %; <1 ng analyte). The performance of this DESI‐based assay was compared against a new fluorometric coupled‐enzyme method that we also developed. Both methodologies provided consistent kinetic data for the reaction of SULT2B1b with its major substrates, indicating the affinity trend pregnenolone>DHEA>cholesterol, for both the phospho‐mimetic and wild‐type SULT2B1b forms. The novel DESI‐MS assay developed here is likely generalizable to other drug discovery efforts and is particularly promising for identification of SULT2B1b inhibitors with potential as prostate cancer therapeutics.