Electrospray and Electrosonic Spray Ionization Mass Spectrometry (ESI-MS and ESSI-MS) have been widely used to report evidence that many chemical reactions in micro- and nano-droplets are dramatically accelerated by factors of ∼102 to 106 relative to macroscale bulk solutions. Despite electrospray's relative simplicity to both generate and detect reaction products in charged droplets using mass spectrometry, substantial complexity exists in how the electrospray process itself impacts the interpretation of the mechanism of these observed accelerated rates. ESI and ESSI are both coupled multi-phase processes, in which analytes in small charged droplets are transferred and detected as gas-phase ions with a mass spectrometer. As such, quantitative examination is needed to evaluate the impact of multiple experimental factors on the magnitude and mechanisms of reaction acceleration. These include: (1) evaporative concentration of reactants as a function of droplet size and initial concentration, (2) competition from gas-phase chemistry and reactions on experimental surfaces, (3) differences in ionization efficiency and ion transmission and (4) droplet charge. We examine (1-4) using numerical models, new ESI/ESSI-MS experimental data, and prior literature to assess the limitations of these approaches and the experimental best practices required to robustly interpret acceleration factors in micro- and nano-droplets produced by ESI and ESSI.

/pdf/a-critical-analysis-of-electrospray-techniques-for-the-23gzr5vll3.pdf

A critical analysis of electrospray techniques for the determination of accelerated rates and mechanisms of chemical reactions in droplets

Water serves as an inert environment for the dispersion and application of many kinds of herbicides. Viologen compounds, a type of widely used but highly toxic herbicide, are stable in bulk water, whose half-life can be up to 23 weeks in natural water, imposing a severe health risk to mammals. In this study, we present the striking results of the spontaneous and ultrafast reduction-induced degradation of three viologen compounds in water microdroplets and provide the concentration, time, temperature dependence, mechanism, and scale-up of the reactions. We postulate that the electrons existing at the air-water interface of the microdroplets due to the unique redox potential therein initiate the reduction, from which further degradation occurs. The host-guest complexation between cucurbit[7]uril and viologens only slightly changes the redox potential of viologens in the bulk but completely inhibits the reactions in microdroplets, adding to the uniqueness of the redox potentials at the air-water interfaces of microdroplets. Taken together, microdroplets might have been functioning as naturally occurring ubiquitous tiny electrochemical cells for a plethora of unique redox reactions that were thought to be impossible in the bulk water.

Spontaneous Reduction-Induced Degradation of Viologen Compounds in Water Microdroplets and Its Inhibition by Host-Guest Complexation.

Microdroplet chemistry is attracting increasing attention for accelerated reactions at the solution-air interface. We report herein a voltage-controlled interfacial microreactor that enables acceleration of electrochemical reactions which are not observed in bulk or conventional electrochemical cells. The microreactor is formed at the interface of the Taylor cone in an electrospray emitter with a large orifice, thus allowing continuous contact of the electrode and the reactants at/near the interface. As a proof-of-concept, electrooxidative C-H/N-H coupling and electrooxidation of benzyl alcohol were shown to be accelerated by more than an order of magnitude as compared to the corresponding bulk reactions. The new electrochemical microreactor has unique features that allow i) voltage-controlled acceleration of electrochemical reactions by voltage-dependent formation of the interfacial microreactor; ii) "reversible" electrochemical derivatization; and iii) in situ mechanistic study and capture of key radical intermediates when coupled with mass spectrometry.

Accelerating Electrochemical Reactions in a Voltage-Controlled Interfacial Microreactor.

Recently, microdroplet reactions have aroused much interest because the microdroplet provides a unique medium where organic reactions could be accelerated by a factor of 103 or more. However, microdroplet reactions of proteins have been rarely studied. We report the occurrence of multiple-step reactions of a large protein, specifically, the digestion, reduction, and deglycosylation of an intact antibody, which can take place in microseconds with high reaction yields in aqueous microdroplets at room temperature. As a result, fast structural characterization of a monoclonal antibody, essential for assessing its quality as a therapeutic drug, can be enabled. We found that the IgG1 antibody can be digested completely by the IdeS protease in aqueous microdroplets in 250 microseconds, a 7.5 million-fold improvement in speed in comparison to traditional digestion in bulk solution (>30 min). Strikingly, inclusion of the reductant tris(2-carboxyethyl)phosphine in the spray solution caused simultaneous antibody digestion and disulfide bond reduction. Digested and reduced antibody fragments were either collected or analyzed online by mass spectrometry. Further addition of PNGase F glycosylase into the spray solution led to antibody deglycosylation, thereby producing reduced and deglycosylated fragments of analytical importance. In addition, glycated fragments of IgG1 derived from glucose modification were identified rapidly with this ultrafast digestion/reduction technique. We suggest that microdroplets can serve as powerful microreactors for both exploring large-molecule reactions and speeding their structural analyses.

Microdroplet Ultrafast Reactions Speed Antibody Characterization.

Conversion of alkynes into ketones by hydration is one of the most fundamental organic addition reactions. Traditional methods for alkyne hydration suffer from usage of toxic and costly metals, excessive acids, harsh conditions, and long reaction times, bringing about an urgent desire to explore more efficient and green protocols to complete this transformation. A metal-free efficient protocol for the accelerated hydration of alkynes in microdroplets was successfully developed in this work to overcome these drawbacks. The hydration process was finished under room temperature using only 18 mol % sulfuric acid as the catalyst and acetonitrile as the solvent. Complete conversions were feasible on the low millisecond time scale in microdroplets for a wide range of alkynes bearing functional groups, including electron-withdrawing groups and electron-donating groups. This is in sharp contrast to trace amounts of ketones or none in 20 min in bulk phase. Compared to the bulk reaction under the same conditions, the reactions in microdroplets are accelerated by 4 to 5 orders of magnitude as seen by the increase in measured rate constants. Further, the accelerated microdroplet hydration can be scaled up to an acetophenone amount of 57.2 ± 0.1 mg min–¹ (3.43 ± 0.01 g h–¹) by using 2 mol L–¹ phenylacetylene sprayed at 300 μL min–¹. The microdroplet protocol offers several advantages including ultrahigh acceleration, complete conversion, mild reaction conditions (metal, light, and heat free), and minimal post purification, as well as a wide substrate scope, making it attractive for green and sustainable chemistry.

Accelerated Metal-Free Hydration of Alkynes within Milliseconds in Microdroplets

A closed system has been designed to perform microdroplet/thin film reactions with solvent recycling capabilities for gram-scale chemical synthesis. Claisen-Schmidt, Schiff base, Katritzky and Suzuki coupling reactions show acceleration factors relative to bulk of 15 to 7700 times in this droplet spray system. These values are much larger than those reported previously for the same reactions in microdroplet/thin film reaction systems. The solvent recycling mode of the new system significantly improves the reaction yield, especially for reactions with smaller reaction acceleration factors. The microdroplet/thin film reaction yield improved on recycling from 33% to 86% and from 32% to 72% for the Katritzky and Suzuki coupling reactions, respectively. The Claisen-Schmidt reaction was chosen to test the capability of this system in gram scale syntheses and rates of 3.18 g per h and an isolated yield of 87% were achieved.

/pdf/high-yield-gram-scale-organic-synthesis-using-accelerated-1ohde0v4ld.pdf

High-yield gram-scale organic synthesis using accelerated microdroplet/thin film reactions with solvent recycling

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.

Honggang Nie

Papers

High-yield gram-scale organic synthesis using accelerated microdroplet/thin film reactions with solvent recycling

Reaction Acceleration Promoted by Partial Solvation at the Gas/Solution Interface