Research at the Yan Lab

 Reactive Microdroplet Mass Spectrometry and Its Applications

Reactive Microdroplet Mass Spectrometry

We develop microdroplet reactions that exhibit significant acceleration, often faster than corresponding bulk reactions by one or more orders of magnitude. We also integrate microdroplet reactions with mass spectrometry (reactive microdroplet mass spectrometry), providing a powerful toolset for unraveling reaction mechanisms and facilitating rapid small-scale synthesis by collecting microdroplets on a surface. One of our focuses includes the development of interfacial microreactors to accelerate electrochemical reactions, particularly those that are sluggish in bulk phases, such as electrooxidative cross-coupling reactions. The exceptional acceleration in the interfacial microreactor arises from the synergistic interplay of reactions occurring at the electrochemical solid/solution interface and the accelerating solution/air interface, a unique feature absent in conventional electrochemical cells. The interfacial microreactor can serve as an ion source and can be combined with a mass spectrometer, facilitating the capture of transient intermediates and shedding light on intricate reaction mechanisms. Expanding the horizons of reactive microdroplet mass spectrometry, we apply microdroplet reactions to biological tissues like brain tissues, facilitating real-time on-tissue biomolecular derivatization and characterization. Reactive microdroplet mass spectrometry offers invaluable chemical insights for mechanistic studies, rapid synthesis capabilities, and expands the range of analyzable molecules. 

References: Angew. Chem. Int. Ed., 2020, 59, 19862 –19867; Chem. Commun, 2021, 57, 3757– 3760; Anal. Bioanal. Chem. 2023, 415, 4197– 4208; Anal. Chem. 2023, 95, 18557–18563.  

In-Depth Structural Lipidomics at the Isomer Level

Altered lipid metabolism stands as a hallmark in numerous diseases. Understanding lipid composition is essential for studying lipid roles in physiology and pathology. We develop novel lipid reactions and integrate them into the ion source, coupled with tandem mass spectrometry, enabling the resolution of lipid structures at the isomer level, a feature unattainable with conventional methods. Our methodologies include the development of electro-epoxidation for unsaturated lipids, facilitating the analysis of C=C bond positional isomers. In real-time, the interfacial microreactor achieves electro-epoxidation, generating characteristic fragments crucial for pinpointing C=C bond locations in tandem mass spectrometry. Additionally, we have developed a divergent approach that combines voltage-dependent Co anodic corrosion with electro-epoxidation, thus achieving multi-isomer level lipid analysis. These analytical methods are instrumental in discovering lipid biomarkers for disease diagnosis and unveiling hidden structure-function relationships in lipid pathology.

References: Angew. Chem. Int. Ed., 2020, 59, 209-214; Anal. Chem. 2022, 94, 12750–12756; US Patent application number: US 62/924,889.

Isobaric Mass Tagging for Quantitative Lipidomics

Changes in lipid concentrations are associated with perturbation of the physiological environment within the biological system. Thus, knowing the concentrations of these lipids is significant in targeting biomarkers for early disease diagnosis, progression monitoring, and therapeutic response prediction. To overcome the challenge in lipid quantification, we have introduced the first lipid isobaric mass tagging strategy for accurate relative quantification of unsaturated lipids, utilizing aziridination chemistry coupled with tandem mass spectrometry. This tag labeling methodology allows accurate relative quantification of lipids in different biological samples in a single experimental run. The tandem mass spectrometry of tagged lipids can also produce characteristic fragments for lipid isomer characterization. The method has been applied to lipid analysis to identify potential lipid biomarkers for disease diagnosis such as Alzheimer's disease and colon cancer. 

References: Angew. Chem. Int. Ed., 2022, 61, e202207098; US Patent application number: US 63/171,846.

Electrolytic Transition Metal Catalysis

We found that picomole-scale anodic corrosion of transition metal electrodes (e.g. Pd) could generate exceptionally efficient cationic electrocatalysts without acid/base or additives. The superior catalytic activity of in situ formed electrolytic Pd over various neutral Pd catalysts is caused by a lack of coordinating anion which would result in highly active low-coordinate Pd species due to the high Lewis acidity of the Pd center. We further developed the integrated platform using electrolytic Pd coupled with mass spectrometry for online screening of electrochemical transition-metal catalysis, by which we discovered mild Pd-catalyzed Suzuki coupling/C–H arylation cascades and achieved late-stage functionalization of complex drug molecules. This opens new venues to mild electrocatalysis. Notably, this achievement has translated into the scalable synthesis of these reactions on a milligram scale within an electrochemical cell using the electrolytic Pd catalyst.  Given the high efficiency and capability of rapid electrocatalytic reaction screening, these novel catalysts and platforms promise to significantly impact transition metal electrocatalysis. 

Reference: J. Am. Chem. Soc. 2022, 144, 1306–1312.

We gratefully acknowledge the generous support of the following funding agencies for our research.