Stabilizing Highly Reactive Aryl Carbanions in Water Microdroplets: Electrophilic -Substitution at the Air-Water Interface.

The fleeting existence of aryl carbanion intermediates in the bulk phase prevents their direct observation and spectroscopic measurement. In sharp contrast, we report the direct interception of such unstable species at the air-water interface of microdroplets. We observed the transformation of three types of aryl acids (benzoic, phenylsulfinic, and phenylboronic acids) into phenyl carbanion (Ph) in water microdroplets, as examined by mass spectrometry.

Revisiting the Enhanced Chemical Reactivity in Water Microdroplets: The Case of a Diels-Alder Reaction.

Often, chemical reactions are markedly accelerated in microdroplets compared with the corresponding bulk phase. While identifying the precise causative factors remains challenging, the interfacial electric field (IEF) and partial solvation are the two widely proposed factors, accounting for the acceleration or turning on of many reactions in microdroplets. In sharp contrast, this combined computational and experimental study demonstrates that these two critical factors have a negligible effect on promoting a model Diels-Alder (DA) reaction between cyclopentadiene and acrylonitrile in water microdroplets.

Transition-metal free, radical oxidation of 1,6-enyne cyclopropanation: synthesis of aza-bicyclo[4.1.0]heptane derivatives.

A straightforward transition-metal-free sustainable methodology for oxidative cyclopropanation of aza-1,6-enynes has been devised, enabling the synthesis of valuable, functionalized azabicyclo[4.1.0]heptane-2,4,5-triones, four bond formation in a single step under mild conditions.

Heavy Water Microdroplet Surface Enriches the Lighter Isotopologue Impurities.

Water microdroplets promote unusual chemical reactions at the air-water interface. However, the interfacial structure of water microdroplets and its potential influence on chemical processes are still enigmatic. Here, we present evidence of in-droplet fractionation of water isotopologues.

Water Microdroplets in Air: A Hitherto Unnoticed Natural Source of Nitrogen Oxides.

Water microdroplets are widespread in the atmosphere. We report a striking observation that micron-sized water droplets obtained from zero-volt spray sources (sonic spray, humidifier, spray bottle, steamer, etc.) spontaneously generate nitrogen oxides.

Carbocation Mechanism Revelation of Molecular Iodine-Mediated Dehydrogenative Aromatization of Substituted Cyclic Ketones to Phenols.

Dehydrogenative aromatization (DA) of cyclic ketones is central to the development of functionalized aromatic precursors and hydrogen transfer-related technologies. Traditional DA strategies require precious metals with oxidants and are typically performed at high temperatures (100-150 °C) to overcome the high energy barrier of aliphatic C-H bond activation. Recently, a mild alternative approach based on I has been proposed to realize DA on substituted unsaturated cyclic ketones under ambient conditions.

Mass Spectrometric Imaging of Anionic Phospholipids Desorbed from Human Hippocampal Sections: Discrimination between Temporal and Nontemporal Lobe Epilepsies.

Temporal lobe epilepsy (TLE) is one of the most common neurological disorders, often accompanied by hippocampal sclerosis. The molecular processes underlying this epileptogenesis are poorly understood. To examine the lipid profile, 39 fresh frozen sections of the human hippocampus obtained from epilepsy surgery for TLE ( = 14) and non-TLE (control group; = 25) patients were subjected to desorption electrospray ionization mass spectrometry imaging in the negative ion mode.

Spontaneous Generation of Aryl Carbocations from Phenols in Aqueous Microdroplets: Aromatic S1 Reactions at the Air-Water Interface.

Although phenol is stable in bulk water, we report an exceptional phenomenon in which phenol is spontaneously transformed into a phenyl carbocation (Ph) in water microdroplets. The high electric field at the air-water interface is proposed to break the phenolic Csp-OH bond, forming Ph, which remains in equilibrium with phenol as deciphered by mass spectrometry. We detected up to 70% conversion of phenol to Ph in aqueous microdroplets, although catalyst-free activation of the phenolic Csp-OH bond is challenging.

Mass Spectrometry Imaging of Lumpectomy Specimens Deciphers Diacylglycerols as Potent Biomarkers for the Diagnosis of Breast Cancer.

Detecting breast tumor markers with a fast turnaround time from frozen sections should foster intraoperative histopathology in breast-conserving surgery, reducing the need for a second operation. Hence, rapid label-free discrimination of the spatially resolved molecular makeup between cancer and adjacent normal breast tissue is of growing importance. We performed desorption electrospray ionization mass spectrometry imaging (DESI-MSI) of fresh-frozen excision specimens, including cancer and paired adjacent normal sections, obtained from the lumpectomy of 73 breast cancer patients.

Rapid Molecular Evaluation of Human Kidney Tissue Sections by In Situ Mass Spectrometry and Machine Learning to Classify the Nephrotic Syndrome.

Nephrotic syndrome (NS) is classified based on morphological changes of glomeruli in biopsied kidney tissues evaluated by time-consuming microscopy methods. In contrast, we employed desorption electrospray ionization mass spectrometry (DESI-MS) directly on renal biopsy specimens obtained from 37 NS patients to rapidly differentiate lipid profiles of three prevalent forms of NS: IgA nephropathy ( = 9), membranous glomerulonephritis ( = 7), and lupus nephritis ( = 8), along with other types of glomerular diseases ( = 13). As we noted molecular heterogeneity in regularly spaced renal tissue regions, multiple sections from each biopsy specimen were collected, providing a total of 973 samples for investigation.

Capturing Reactive Carbanions by Microdroplets.

Carbanions appear in many organic or biological reactions as fleeting intermediates, prohibiting direct observation or spectroscopic measurement. An aqueous environment is known to rapidly annihilate a carbanion species, reducing its lifetime to as short as picoseconds. We report that aqueous microdroplets can capture and stabilize reactive carbanion intermediates isolated from four classic organic reactions, aldol and Knoevenagel condensations, alkyne alkylation, and the Reimer-Tiemann reaction, enabling the detection of their carbanion intermediates by desorption electrospray ionization mass spectrometry.

Destabilized Carbocations Caged in Water Microdroplets: Isolation and Real-Time Detection of Carbonyl Cation Intermediates.

Over the last 50 years, proposals of α-carbonyl cation intermediates have been driven by chemical intuition and indirect evidence. Recently, wide interest in α-carbonyl cation chemistry has opened new gates to prepare α-functionalized carbonyl compounds. Though these intrinsically unstable carbocations are formed under forcing conditions (e.

Mapping Protein Structural Evolution upon Unfolding.

In the past, many intensive attempts failed to capture or underestimated the copopulated intermediate conformers from the protein folding/unfolding reaction. We report a promising approach to kinetically trap, resolve, and quantify protein conformers that evolve during unfolding in solution. We conducted acid-induced unfolding of three model proteins (cytochrome , myoglobin, and lysozyme), and the corresponding reaction aliquots upon decreasing the pH were electrosprayed for high field asymmetric waveform ion mobility spectrometry (FAIMS) measurements.

Mass Spectrometry Imaging Deciphers Dysregulated Lipid Metabolism in the Human Hippocampus Affected by Temporal Lobe Epilepsy.

Temporal lobe epilepsy (TLE) is the most prevalent form of human epilepsy, often accompanied by neurodegeneration in the hippocampus. Like other neurological diseases, TLE is expected to disrupt lipid homeostasis. However, the lipid architecture of the human TLE brain is relatively understudied, and the molecular mechanism of epileptogenesis is poorly understood.

Chemical analysis of the human brain by imaging mass spectrometry.

Analysis of the chemical makeup of the brain enables a deeper understanding of several neurological processes. Molecular imaging that deciphers the spatial distribution of neurochemicals with high specificity and sensitivity is an exciting avenue in this aspect. The past two decades have witnessed a significant surge of mass spectrometry imaging (MSI) that can simultaneously map the distribution of hundreds to thousands of biomolecules in the tissue specimen at a fairly high resolution, which is otherwise beyond the scope of other molecular imaging techniques.

Aqueous Microdroplets Capture Elusive Carbocations.

Carbocations are short-lived reactive intermediates in many organic and biological reactions that are difficult to observe. This field sprung to life with the discovery by Olah that a superacidic solution allowed the successful capture and nuclear magnetic resonance characterization of transient carbocations. We report here that water microdroplets can directly capture the fleeting carbocation from a reaction aliquot followed by its desorption to the gas phase for mass spectrometric detection.

Copper-induced spectroscopic and structural changes in short peptides derived from azurin.

The active sites of metalloproteins may be mimicked by designing peptides that bind to their respective metal ions. Studying the binding of protein ligands to metal ions along with the associated structural changes is important in understanding metal uptake, transport and electron transfer functions of proteins. Copper-binding metalloprotein azurin is a 128-residue electron transfer protein with a redox-active copper cofactor.

Empowering Clinical Diagnostics with Mass Spectrometry.

The unmet need for highly accurate methods of disease diagnosis poses new challenges for developments in laboratory medicine. Advances in mass spectrometry (MS)-based disease biomarker discoveries are continuously expanding the clinical diagnostic landscape. Although a number of MS-based diagnostics are already adopted in routine clinical practices, more are expected to undergo transition from bench to bedside in the near future.

Influence of Inlet Capillary Temperature on the Microdroplet Chemistry Studied by Mass Spectrometry.

Often, studies of microdroplet chemistry using electrospray ionization mass spectrometry (MS) either find a negligible effect of the heated inlet capillary of the mass spectrometer on the reaction rate or do not consider its effect. In this context, we studied two reactions in microdroplets, the Pomeranz-Fritsch synthesis of isoquinoline and the Combes quinoline synthesis. The reagents were electrosprayed with methanol and aqueous solutions forming small and large microdroplets at flow rates of 1 and 20 μL/min, respectively.

Early detection of unilateral ureteral obstruction by desorption electrospray ionization mass spectrometry.

Desorption electrospray ionization mass spectrometry (DESI-MS) is an emerging analytical tool for rapid in situ assessment of metabolomic profiles on tissue sections without tissue pretreatment or labeling. We applied DESI-MS to identify candidate metabolic biomarkers associated with kidney injury at the early stage. DESI-MS was performed on sections of kidneys from 80 mice over a time course following unilateral ureteral obstruction (UUO) and compared to sham controls.

Mechanistic insights of Cu(ii)-mediated ortho-C-H amination of arenes by capturing fleeting intermediates and theoretical calculations.

The capture of reactive intermediates empowers chemists to conjecture the detail of a chemical transformation. Here we explore the mechanism of a C-H amination by intercepting short-lived intermediates in real time using online mass spectrometry. Computational study unravels the favorable pathway of the proposed dual mechanism of the reaction.

1,4-Benzoquinone antimicrobial agents against and derived from scorpion venom.

Two 1,4-benzoquinone derivatives, found in the venom of the scorpion following exposure to air, have been isolated, characterized, synthesized, and assessed for antimicrobial activities. Initially a white, viscous liquid, the extracted venom colors within minutes under ambient conditions. From this colored mixture, two compounds, one red, the other blue, were isolated and purified using chromatography.

Assessment of Metabolic Signature for Cancer Diagnosis Using Desorption Electrospray Ionization Mass Spectrometric Imaging.

Metabolic reprogramming is a hallmark of tumor development. A technique that can map this complex biochemical shift by taking a snapshot of various metabolites in a tissue specimen (biopsy) is of high utility in the context of cancer diagnosis. Desorption electrospray ionization mass spectrometric imaging (DESI-MSI) is such a powerful and emerging analytical technique to simultaneously visualize the distributions of hundreds of metabolites, lipids, and other small molecules in the biological tissue.

Ambient ionization mass spectrometry imaging for disease diagnosis: Excitements and challenges.

Tissue analysis in histology is extremely important and also considered to be a gold standard to diagnose and prognosticate several diseases including cancer. Intraoperative evaluation of surgical margin of tumor also relies on frozen section histopathology, which is time consuming, challenging and often subjective. Recent development in the ambient ionization mass spectrometry imaging (MSI) technique has enabled us to simultaneously visualize hundreds to thousands of molecules (ion images) in the biopsy specimen, which are strikingly different and more powerful than the single optical tissue image analysis in conventional histopathology.