Reactions In Microdroplets Research Articles

Ammonium Bicarbonate Significantly Accelerates the Microdroplet Reactions of Amines with Carbon Dioxide.

The reactions between amines and carbon dioxide (CO2) are among the most commonly used and important carbon fixation reactions at present. Microdroplets generated by electrospray ionization (ESI) have been proved to increase the conversion ratio (RC) of amines. In this work, we confirmed that the presence of ammonium bicarbonate (NH4HCO3) in ESI microdroplets significantly increased the RC of amines. The RC went up remarkably with the increase in the concentration of NH4HCO3 from 0.5 to 20 mM. The RC of N,N-dibutyl-1,3-propanediamine (DBPA) reached 93.7% under 20 mM NH4HCO3, which was significantly higher than previous reports. The rise in RC became insignificant when the concentration of NH4HCO3 was increased beyond 20 mM. Further investigations were made on the mechanism of the phenomenon. According to the results, it was suggested that NH4HCO3 decomposed into CO2 and formed microbubbles within the microdroplets of ESI. The microbubbles acted as direct internal CO2 sources. The conversion reactions occurred at the liquid-gas interface. The formation of CO2 microbubbles remarkably increased the total area of the interface, thus promoting the conversion reactions. 13C-labeled experiments confirmed that NH4HCO3 acted as an internal CO2 source. Factors that influenced the RC of the reaction were optimized. Pure water was proved to be the optimal solvent. Lower temperature of the mass spectrometer's entrance capillary was beneficial to the stabilization of the product carbamic acids. The sample flow rate of ESI was crucial to the RC. It determined the initial sizes of the microdroplet. Lower flow rates ensured higher RC of amines. The present work implied that NH4HCO3 could be a superior medium for CO2 capture and utilization. It might offer an alternative choice for future CO2 conversion research studies. In addition, our study also provided evidence that NH4HCO3 decomposed and generated microbubbles in the droplets during ESI. Attention should be paid to this when using NH4HCO3 as an additive in mass spectrometry-based analysis.

Accelerated photocatalytic [3+2] cycloaddition of phenols and olefins in nESI-MS

The photocatalytic [3+2] cycloadditions of phenols and olefins are normally limited by the relatively tedious process. Herein, based on accelerated microdroplet reactions, a nano-electrospray ionization (nESI) was constructed for online acceleration of photocatalytic [3+2] cycloaddition between phenols and olefins. As demonstrated, the high reaction rates were obtained by nESI tips with smaller orifice inner diameter and the electrode closed to the nESI tip. These were further confirmed by the calculations on the conversion ratios and apparent acceleration factors. Meanwhile, the important intermediates (especially short-lived radicals) were recorded by virtue of the online monitoring of nESI mass spectrometry (MS). Subsequently, the dynamic information of substrates, intermediates and products were examined. Therefore, the mechanism of photocatalytic [3+2] cycloaddition reactions between phenols and olefins was proposed. This work not only enlarges the application of microdroplet synthesis, but also would provide a possible perspective for accelerating photocatalytic reactions and mechanism examinations.

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

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.

The use of a commercial ESI Z-spray source for ambient ion soft landing and microdroplet reactivity experiments

In this study, the ability of an unmodified ESI Z-spray source to carry out ambient ion soft landing (AISL) and microdroplet reactions (MR) was tested. To this aim, heme proteins were ionized and landed onto the working area of multi-walled carbon nanotubes electrodes. The voltammetric and spectroscopic analyses of the modified electrodes evidenced a strong interaction of unfolded structures of the heme proteins with the carbon nanotubes surface.Moreover, the possibility to use the ESI Z-spray source to study microdroplet reactions was attempted by exploring the accelerated acid-catalyzed decomposition of carbohydrates. The study demonstrated that a commercial ESI Z-spray source can provide successful modifications of surfaces by AISL, and represents a suitable platform for the study of accelerated microdroplet reactions.

Microdroplet Mass Spectrometry Enables Extremely Accelerated Pepsin Digestion of Proteins.

In microdroplets, rates of chemical or biomolecular reactions can exceed those in the bulk phase by more than a million times. As electrospray ionization-based mass spectrometry (MS) involves the formation of charged microdroplets, reaction acceleration and online MS monitoring of reaction products can readily be performed at the same time. We investigated accelerated enzymatic reactions in microdroplets and focused on the proteolytic enzyme pepsin. Electrosonic spray ionization (ESSI) was utilized for developing the ultrarapid pepsin in-spray digestion of two different proteins, cytochrome c and RocC, at low pH values. The optimization of the protein digestion aimed at achieving maximum sequence coverage for the analyzed proteins. Furthermore, carefully designed control experiments allowed us to unambiguously prove that enzymatic protein cleavage almost exclusively occurs within the spray at a millisecond time scale and not prior to microdroplet generation.

Accelerated Metal-Free Hydration of Alkynes within Milliseconds in Microdroplets

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.

A Covalent Black Phosphorus/Metal–Organic Framework Hetero‐nanostructure for High‐Performance Flexible Supercapacitors

AbstractWe develop hetero‐nanostructured black phosphorus/metal‐organic framework hybrids formed by P‐O‐Co covalent bonding based on a designed droplet microfluidic strategy consisting of confined and ultrafast microdroplet reactions. The resulting hybrid exhibits large capacitance (1347 F g−1) in KOH electrolytes due to its large specific‐surface‐area (632.47 m2 g−1), well‐developed micro‐porosity (0.38 cm3 g−1), and engineered electroactivity. Furthermore, the proposed 3D printing method allows to construct all‐integrated solid‐state supercapacitor, which maintains interconnected porous network, good interfacial adhesion, and robust flexibility for short‐path diffusion and excessive accommodation of ions. Consequently, the fabricated flexible supercapacitor delivers ultrahigh volumetric energy density of 109.8 mWh cm−3, large capacitance of 506 F cm−3, and good long‐term stability of 12000 cycles.

Microdroplet Ultrafast Reactions Speed Antibody Characterization.

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.

Total Integration of the Sample Injection, Microdroplet Reaction, Phase Separation, Real‐Time Optical Detection, and Recovery of Diverse Silver–Gold Bimetallic Nanoalloys in a Continuous Process (Part. Part. Syst. Charact. 1/2021)

Total Integration of the Sample Injection, Microdroplet Reaction, Phase Separation, Real‐Time Optical Detection, and Recovery of Diverse Silver–Gold Bimetallic Nanoalloys in a Continuous Process (Part. Part. Syst. Charact. 1/2021)

Total Integration of the Sample Injection, Microdroplet Reaction, Phase Separation, Real‐Time Optical Detection, and Recovery of Diverse Silver–Gold Bimetallic Nanoalloys in a Continuous Process

AbstractMicrofluidic droplet generators have garnered great attention due to the uniformity, high‐throughput capability, and facile experimental setup. To maximize the potentials of droplet technology as a chemical/biological nanoliter‐scale reactor, the downstream processes such as separation of the aqueous and oil phase, real‐time monitoring of the products formed in droplets, and the final product recovery from the droplets is necessary. In this study, the droplet is utilized as a chemical reactor to synthesize a variety of Ag and Au bimetallic nanoalloys in a fully integrated microsystem including sample injection, a T‐junction droplet generator, droplet reaction, water–oil phase separation, real‐time UV–vis absorbance detection, and product recovery. The flow rate of the Ag nanoparticle (NP) solution and the HAuCl4 solution was tuned to generate different molar ratios of Ag and Au components. The in‐line UV–vis absorbance spectrometer displays a peak shift of the Ag/Au bimetallic alloys depending on the molar ratio of Ag/Au in the continuous process, enabling to judge the kind of the Ag/Au alloys in situ and collect a variety of Ag/Au nanoalloys. Thus, the desired nanomaterials can be obtained with minimal trial and error, saving time and cost.

Study of the Aniline and Acetone Condensation Reaction under Electrospray Ionization Conditions

The present paper deals with the study of condensation reaction of aniline with acetone under electrospray ionization (ESI) conditions . An experimental setup is described for conducting reactions under ESI conditions with a possibility of the accumulation of reaction products. The aniline and acetone condensation products were analyzed by gas chromatography–mass spectrometry. Spraying this mixture with high concentration of formic acid, results in the formation of N-phenylformamide, N,N'-diphenylmethaneimidamide, and 1,2-dihydro-2,2,4-trimethylquinoline; the last one is the only product of the reaction of aniline with acetone. Thus, the Schiff base formation reaction radically changes its direction. The results obtained using the proposed experimental setup open up new prospects both for studying chemical reactions in charged microdroplets and for the use of ESI as a preparative method for the synthesis of organic compounds.

Accelerated nucleophilic substitution reactions of dansyl chloride with aniline under ambient conditions via dual-tip reactive paper spray

Paper spray ionization (PSI) mass spectrometry (MS) is an emerging tool for ambient reaction monitoring via microdroplet reaction acceleration. PSI-MS was used to accelerate and monitor the time course of the reaction of dansyl chloride with aniline, in acetonitrile, to produce dansyl aniline. Three distinct PSI arrangements were explored in this study representing alternative approaches for sample loading and interaction; conventional single tip as well as two novel setups, a dual-tip and a co-axial arrangement were designed so as to limit any on-paper interaction between reagents. The effect on product abundance was investigated using these different paper configurations as it relates to the time course and distance of microdroplet travel. It was observed that product yield increases at a given distance and then decreases thereafter for all PSI configurations. The fluorescent property of the product (dansyl aniline) was used to visually inspect the reaction progress on the paper substrate during the spraying process. Amongst the variety of sample loading methods the novel dual-tip arrangement showed an increased product yield and microdroplet density, whilst avoiding any on-paper interaction between the reagents.

Development of Microdroplet Generation Method for Organic Solvents Used in Chemical Synthesis.

Recently, chemical operations with microfluidic devices, especially droplet-based operations, have attracted considerable attention because they can provide an isolated small-volume reaction field. However, analysis of these operations has been limited mostly to aqueous-phase reactions in water droplets due to device material restrictions. In this study, we have successfully demonstrated droplet formation of five common organic solvents frequently used in chemical synthesis by using a simple silicon/glass-based microfluidic device. When an immiscible liquid with surfactant was used as the continuous phase, the organic solvent formed droplets similar to water-in-oil droplets in the device. In contrast to conventional microfluidic devices composed of resins, which are susceptible to swelling in organic solvents, the developed microfluidic device did not undergo swelling owing to the high chemical resistance of the constituent materials. Therefore, the device has potential applications for various chemical reactions involving organic solvents. Furthermore, this droplet generation device enabled control of droplet size by adjusting the liquid flow rate. The droplet generation method proposed in this work will contribute to the study of organic reactions in microdroplets and will be useful for evaluating scaling effects in various chemical reactions.

Restricted intramolecular rotation of fluorescent molecular rotors at the periphery of aqueous microdroplets in oil

Fluorescent molecular rotor dyes, including Cy3, Cy5, and Alexa Fluor 555, dissolved in micron-sized aqueous droplets (microdroplets) in oil were excited, and the fluorescence intensity was recorded as function of time. We observed lengthening of the fluorescence lifetime of these dyes at the water–oil periphery, which extended several microns inward. This behavior shows that intramolecular rotation is restricted at and near the microdroplet interface. Lengthened lifetimes were observed in water microdroplets but not in microdroplets composed of organic solvents. This lifetime change was relatively insensitive to added glycerol up to 60%, suggesting that solution viscosity is not the dominant mechanism. These restricted intramolecular rotations at and near the microdroplet periphery are consistent with the reduced entropy observed in chemical reactions in microdroplets compared to the same reaction conditions in bulk solution and helps us further understand why microdroplet chemistry differs so markedly from bulk-phase chemistry.

A High-Throughput Screening Method for Determining the Optimized Synthesis Conditions of Quinoxaline Derivatives Using Microdroplet Reaction

Quinoxaline derivatives demonstrate many distinguished chemical, biological, and physical properties and have a wide application in dyes, electroluminescent material, organic semiconductors, biological agents, etc. However, the synthesis of quinoxaline still suffers from several drawbacks, for instance, longer reaction time, unsatisfactory yields, and use of metal catalysts. Here, utilizing microdroplet-assisted reaction, we demonstrate the successive synthesis of several important quinoxaline derivatives. For case studies of 1H-indeno [1, 2-b] quinoxaline and 3,5-dimethyl-2-phenylquinoxaline, the present microdroplet approach can complete in milliseconds and the conversion rate reached 90% without adding any catalyst, which is considerably quicker and higher than conversional bulk-phase reactions. When combined with MS detection, high-throughput screening of the optimal reaction conditions can be achieved. Several impacts of droplet volume, reaction flow rate, distance from the MS inlet, spray voltage, and flow rate of the auxiliary gas can be screened on-site quickly for enhanced reaction speed and yields. More importantly, this platform is capable to be used for the scaled-up microdroplet synthesis of quinoxaline diversities. Considering the facile, economic, and environmentally friendly features of the microdroplet approach, we sincerely hope that the current strategy can effectively promote the academic research and industrial fabrications of functional quinoxaline substances for chemical, biological, and pharmaceutical application developments.

Strong Electric Field Observed at the Interface of Aqueous Microdroplets

Chemical reactions in aqueous microdroplets often exhibit unusual kinetic and thermodynamic properties not observed in bulk solution. While an electric field has been implicated at the water interface, there has been no direct measurement in aqueous microdroplets, largely due to the lack of proper measurement tools. Herein, we employ newly developed stimulated Raman excited fluorescence microscopy to measure the electric field at the water-oil interface of microdroplets. As determined by the vibrational Stark effect of a nitrile-bearing fluorescent probe, the strength of the electric field is found to be on the order of 107 V/cm. This strong electric field aligns probe dipoles with respect to the interface. The formation of the electric field likely arises from charge separation caused by the adsorption of negative ions at the water-oil interface of microdroplets. We suggest that this strong electric field might account in part for the unique properties of chemical reactions reported in microdroplets.

Rapid generation of double-layer emulsion droplets based on microfluidic chip

In vitro compartmentalization (IVC) links genotype and phenotype by compartmentalizing individual genes (including expression system) or cells into a micro-droplet reaction region. Combined with fluorescence-activated cell sorting (FACS), it can detect and separate single droplets in ultra-high throughput. IVC-FACS screening method has been widely used in protein engineering, enzyme directed evolution, etc. However, it is difficult to control the homogeneity of droplet size by mechanical dispersion method in previous studies, which seriously affects the quantitative detection of droplets and reduces the efficiency and accuracy of this screening method. With the rapid development of microfluidic chip manufacturing technology, the microfluidic chip-based methods for droplet generation are becoming more efficient and controllable. In this study, firstly, the water-in-oil (W/O) single-layer droplet generation chip was used to prepare single-layer monodisperse W1/O droplets at a high generation frequency, and then the W1/O droplets were reinjected into water-in-oil-in-water (W/O/W) double-layer droplet generation chip to prepare uniform W1/O/W2 double-layer emulsion droplets. By optimizing the flow rate and ratio of the oil and water phases, a single-layer micro-droplet can be generated with a diameter range from 15.4 to 23.2 μm and remain stable for several days under normal incubation. Then the single-layer droplets were reinjected into the double emulsion generation chip. By adjusting the flow rate of drop phase, oil phase and water phase, the double-layer emulsion droplets with a diameter range from 30 to 100 μm at a rate of 1 000 droplets/s could be obtained. Escherichia coli embedded in the double-layer emulsion droplets could be cultured and induced for protein expression. This study lays a foundation for the establishment of a high-throughput screening method based on the droplet and flow cytometry.

Electrical Actuation of Hydrophobic Bilayer Membranes of Reduced Graphene Oxide and Agar for Inducing Chemical Reactions in Microdroplets

Systems capable of remote handling of liquids in individual microdroplets are of great importance for both technological applications and fundamental studies. Here, we demonstrate the fabrication o...

Quantum Mechanical Modeling of Reaction Rate Acceleration in Microdroplets.

Organic reactions in microdroplets can be orders of magnitude faster than their bulk counterparts. We hypothesize that solvation energy differences between bulk and interface play a key role in the intrinsic rate constant increase and test the hypothesis with explicit solvent calculations. We demonstrate for both the protonated phenylhydrazine reagent and the hydrazone transition state (TSB) that molecular orientations which place the charge sites at the surface confer high energy. A pathway in which this high-energy form transforms into a fully solvated TSB has a lower activation energy than bulk by some 59 kJ/mol, a result that is consistent with experimental rate acceleration studies.

Chemoselective N‐Alkylation of Indoles in Aqueous Microdroplets

AbstractMany reactions show much faster kinetics in microdroplets than in the bulk phase. Most reported reactions in microdroplets mirror the products found in bulk reactions. However, the unique environment of microdroplets allows different chemistry to occur. In this work, we present the first chemoselective N‐alkylation of indoles in aqueous microdroplets via a three‐component Mannich‐type reaction without using any catalyst. In sharp contrast, bulk reactions using the same reagents with a catalyst yield exclusively C‐alkylation products. The N‐alkylation yield is moderate in microdroplets, up to 53 %. We extended the scope of the microdroplet reaction and obtained a series of new functionalized indole aminals, which are likely to have biological activities. This work clearly indicates that microdroplet reactions can show reactivity quite different from that of bulk‐phase reactions, which holds great potential for developing novel reactivities in microdroplets.