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Non‐thermal plasma discharge produced in the wake of charged microdroplets is found to facilitate catalyst‐free radical mediated hydrazine cross‐coupling reactions without the use of external light source, heat, precious metal complex, or trapping agents. A plasma‐microdroplet fusion platform is utilized for introduction of hydrazine reagent that undergoes homolytic cleavage forming radical intermediate species. The non‐thermal plasma discharge that causes the cleavage originates from a chemically etched silica capillary. The coupling of the radical intermediates gives various products. Plasma‐microdroplet fusion occurs online in a programmable reaction platform allowing direct process optimization and product validation via mass spectrometry. The platform is applied herein with a variety of hydrazine substrates, enabling i) self‐coupling to form secondary amines with identical N‐substitutions, ii) cross‐coupling to afford secondary amine with different N‐substituents, iii) cross‐coupling followed by in situ dehydrogenation to give the corresponding aryl‐aldimines with two unique N‐substitutions, and iv) cascade heterocyclic carbazole derivatives formation. These unique reactions were made possible in the charged microdroplet environment through our ability to program conditions such as reagent concentration (i. e., flow rate), microdroplet reactivity (i. e., presence or absence of plasma), and reaction timescale (i. e., operational mode of the source). The selected program is implemented in a co‐axial spray format, which is found to be advantageous over the conventional one‐pot single emitter electrospray‐based microdroplet reactions. 

Direct infusion ionization methods provide the highest throughput strategy for mass spectrometry (MS) analysis of low-volume samples. But the trade-off includes matrix effects, which can significantly reduce analytical performance. Herein, we present a novel chemical approach to tackle a special type of matrix effect, namely type II isobaric overlap. We focus on detailed investigation of a nanodroplet-based esterification chemistry for differentiating isotopologue [M + 2] signal due to unsaturated fatty acid (FA) from the monoisotopic signal from a saturated FA. The method developed involves the online fusion of nonthermal plasma with charged nanodroplets, enabling selective esterification of saturated FAs. We discovered that unsaturated FAs undergo spontaneous intramolecular reaction via a novel mechanism based on a carbocation intermediate to afford a protonated lactone moiety (resonance stabilized cyclic carbonium ion), whose mass is the same as the original protonated unsaturated FA. Therefore, the monoisotopic signal from any saturated FA can be selectively shifted away from the mass-to-charge position where the isobaric interference occurs to enable effective characterization by MS. The mechanism governing the spontaneous intramolecular reactions for unsaturated FAs was validated with DFT calculations, experimentation with standards, and isotope labeling. This novel insight achieved via the ultrafast plasma-nanodroplet reaction environment provides a potentially useful synthetic pathway to achieve catalyst-free lactone preparation. Analytically, we believe the performance of direct infusion MS can be greatly enhanced by combining our approach with prior sample enrichment steps for applications in biomedicine and food safety. Also, combination with portable mass spectrometers can improve the efficiency of field studies since front-end separation is not possible under such conditions 

Three-dimensional (3D) dried blood spheroids form when whole blood is deposited onto hydrophobic paper and allowed to dry in ambient air. The adsorbed 3D dried blood spheroid present at the surface of the hydrophobic paper is observed to offer enhanced stability for labile analytes that would otherwise degrade if stored in the traditional two-dimensional (2D) dried blood spot method. The protective mechanism for the dried blood spheroid microsampling platform was studied using scanning electron microscopy (SEM), which revealed the presence of a passivation thin film at the surface of the spheroid that serves to stabilize the interior of the spheroid against environmental stressors. Through time-course experiments based on sequential SEM analyses, we discovered that the surface protective thin film forms through the self-assembly of red blood cells following the evaporation of water from the blood sample. The bridging mechanism of red blood cell aggregation is evident in our experiments, which leads to the distinct rouleau conformation of stacked red blood cells in less than 60 min after creating the blood spheroid. The stack of self-assembled red blood cells at the exterior of the spheroid subsequently lyse to afford the surface protective layer detected to be approximately 30 μm in thickness after three weeks of storage in ambient air. We applied this mechanistic insight to plasma and serum to enhance stability when stored under ambient conditions. In addition to physical characterization of these thin biofilms, we also used paper spray (PS) mass spectrometry (MS) to examine chemical changes that occur in the stored biofluid. For example, we present stability data for cocaine spiked in whole blood, plasma, and serum when stored under ambient conditions on hydrophilic and hydrophobic paper substrates. 

Positional isomers of alkenes are frequently transparent to the mass spectrometer and it is difficult to provide convincing data to support their presence. This work focuses on the development of a new reactive nano-electrospray ionization (nESI) platform that utilizes non-inert metal electrodes ( e.g. , Ir and Ru) for rapid detection of fatty acids by mass spectrometry (MS), with concomitant localization of the CC bond to differentiate fatty acid isomers. During the electrospray process, the electrical energy (direct current voltage) is harnessed for in situ oxide formation on the electrode surface via electro-oxidation. The as-formed surface oxides are found to facilitate in situ epoxide formation at the CC bond position and the products are analyzed by MS in real-time. This phenomenon has been applied to analyze isomers of unsaturated fatty acids from complex serum samples, without pre-treatment.