Reactions In Microdroplets Research Articles

"On-Droplet" Chemistry: The Cycloaddition of Diethyl Azodicarboxylate and Quadricyclane.

Sharpless and co-workers previously studied the [2σ+2σ+2π] cycloaddition of diethyl azodicarboxylate (DEAD) and quadricyclane and reported that the addition of water to the neat reagents caused an acceleration in the reaction rate, giving birth to what has been called "on-water" chemistry. We have examined the same reaction in aqueous microdroplets (ca. 5 μm diameter) and find that the cycloaddition reaction is accelerated even further (by a factor of 102 ) compared to that of the "on-water" reaction reported previously. The trends of acceleration in solvents other than water demonstrated by Sharpless and colleagues were replicated in the corresponding microdroplet experiments. We also find that DEAD reacts with itself to form a variety of hydrazine carboxylates and intercept intermediates of this reaction in microdroplets to validate a mechanism proposed herein. We suggest that "on-droplet" chemistry, similar to "on-water" chemistry, may be a general process of synthetic interest.

Abiotic production of sugar phosphates and uridine ribonucleoside in aqueous microdroplets

Phosphorylation is an essential chemical reaction for life. This reaction generates fundamental cell components, including building blocks for RNA and DNA, phospholipids for cell walls, and adenosine triphosphate (ATP) for energy storage. However, phosphorylation reactions are thermodynamically unfavorable in solution. Consequently, a long-standing question in prebiotic chemistry is how abiotic phosphorylation occurs in biological compounds. We find that the phosphorylation of various sugars to form sugar-1-phosphates can proceed spontaneously in aqueous microdroplets containing a simple mixture of sugars and phosphoric acid. The yield for d-ribose-1-phosphate reached over 6% at room temperature, giving a ΔG value of -1.1 kcal/mol, much lower than the +5.4 kcal/mol for the reaction in bulk solution. The temperature dependence of the product yield for the phosphorylation in microdroplets revealed a negative enthalpy change (ΔH = -0.9 kcal/mol) and a negligible change of entropy (ΔS = 0.0007 kcal/mol·K). Thus, the spontaneous phosphorylation reaction in microdroplets occurred by overcoming the entropic hurdle of the reaction encountered in bulk solution. Moreover, uridine, a pyrimidine ribonucleoside, is generated in aqueous microdroplets containing d-ribose, phosphoric acid, and uracil, which suggests the possibility that microdroplets could serve as a prebiotic synthetic pathway for ribonucleosides.

Reaction Acceleration in Thin Films with Continuous Product Deposition for Organic Synthesis.

Thin film formats are used to study the Claisen-Schmidt base-catalyzed condensation of 6-hydroxy-1-indanone with substituted benzaldehydes and to compare the reaction acceleration relative to the bulk. Relative acceleration factors initially exceeded 103 and were on the order of 102 at steady state, although the confined volume reaction was not electrostatically driven. Substituent effects were muted compared to those in the corresponding bulk and microdroplet reactions and it is concluded that the rate-limiting step at steady state is reagent transport to the interface. Conditions were found that allowed product deposition from the thin film to occur continuously as the reaction mixture was added and as the solvent evaporated. Yields of 74 % and production rates of 98 mg h-1 were reached in a very simple experimental system that could be multiplexed to greater scales.

Reaction Acceleration in Thin Films with Continuous Product Deposition for Organic Synthesis

AbstractThin film formats are used to study the Claisen–Schmidt base‐catalyzed condensation of 6‐hydroxy‐1‐indanone with substituted benzaldehydes and to compare the reaction acceleration relative to the bulk. Relative acceleration factors initially exceeded 103 and were on the order of 102 at steady state, although the confined volume reaction was not electrostatically driven. Substituent effects were muted compared to those in the corresponding bulk and microdroplet reactions and it is concluded that the rate‐limiting step at steady state is reagent transport to the interface. Conditions were found that allowed product deposition from the thin film to occur continuously as the reaction mixture was added and as the solvent evaporated. Yields of 74 % and production rates of 98 mg h−1 were reached in a very simple experimental system that could be multiplexed to greater scales.

Two-Phase Reactions in Microdroplets without the Use of Phase-Transfer Catalysts.

Many important chemical transformations occur in two-phase reactions, which are widely used in chemical, pharmaceutical, and polymer manufacturing. We present an efficient method for performing two-phase reactions in microdroplets sheared by sheath gas without using a phase-transfer catalyst. This avoids disadvantages such as thermal instability, high cost, and, especially, the need to separate and recycle the catalysts. We show that various alcohols can be oxidized to the corresponding aldehydes and ketones within milliseconds in moderate to good yields (50-75 %). The scale-up of the present method was achieved at an isolated rate of 1.2 mg min-1 for the synthesis of 4-nitrobenzylaldehyde from 4-nitrobenzyl alcohol in the presence of sodium hypochlorite. The biphasic nature of this process, which avoids use of a phase-transfer catalyst, greatly enhances synthetic effectiveness.

Two‐Phase Reactions in Microdroplets without the Use of Phase‐Transfer Catalysts

AbstractMany important chemical transformations occur in two‐phase reactions, which are widely used in chemical, pharmaceutical, and polymer manufacturing. We present an efficient method for performing two‐phase reactions in microdroplets sheared by sheath gas without using a phase‐transfer catalyst. This avoids disadvantages such as thermal instability, high cost, and, especially, the need to separate and recycle the catalysts. We show that various alcohols can be oxidized to the corresponding aldehydes and ketones within milliseconds in moderate to good yields (50–75 %). The scale‐up of the present method was achieved at an isolated rate of 1.2 mg min−1 for the synthesis of 4‐nitrobenzylaldehyde from 4‐nitrobenzyl alcohol in the presence of sodium hypochlorite. The biphasic nature of this process, which avoids use of a phase‐transfer catalyst, greatly enhances synthetic effectiveness.

Nickel-Decorated Fe3O4 Nanoparticles as Recyclable Magnetic Self-Stirring Nanocatalysts for Microreactions

We presented the first exploration of the easily prepared nickel-decorated magnetic Fe3O4 nanoparticles as recyclable nanosized magnetic self-stirring catalysts for microdroplet reactions. The cross-linked polymer poly(cyclotriphosphazene-co-4,4′-sulfonyldiphenol) (PZS) was used as the intermediary to link Fe3O4 and anchored nickel nanodots. On the basis of the charming magnetic feathers of Fe3O4 and the fine catalysis activity of Ni, the Fe3O4@PZS-Ni nanoparticles could not only self-stir or make the reactants move along the tiny channels with the help of the external rotating magnetic field but also exhibit high catalysis activity and convenient recyclability. The Fe3O4@PZS-Ni nanoparticles have the merits of small size, good suspension, easy fabrication, and most importantly, superior flexibility and adaptability to any shape of the microreactors or nanoreactors; thus, they may bring new inspiration for self-stirring catalytic reactions in micro/nanochips or micro/nanobiological tubules or tissues.

Can all bulk-phase reactions be accelerated in microdroplets?

Recent studies have shown that microdroplet reactions are markedly accelerated compared to the corresponding bulk-phase reactions. This raises the question whether all reactions can be sped up by this means. We present a counter example, and we show that the reaction mechanism in microdroplets can differ sharply from that in bulk, especially because of the distinct microdroplet surface environment. This analysis helps to guide us how to choose and control reactions in microdroplets and provides a possible perspective on utilizing microdroplet chemistry to scale up synthesis.

ChemInform Abstract: Organic Reactions in Microdroplets: Reaction Acceleration Revealed by Mass Spectrometry

AbstractReview: [77 refs.

Chitosan nanoparticles synthesis caught in action using microdroplet reactions.

The ionic gelation process for the synthesis of chitosan nanoparticles was carried out in microdroplet reactions. The synthesis could be stopped instantaneously at different time points by fast dilution of the reaction mixture with DI water. Using this simple technique, the effect of temperature and reactant concentrations on the size and distribution of the nanoparticles formed, as a function of time, could be investigated by DLS and SEM. Results obtained indicated very early (1–5 s) nucleation of the particles followed by growth. The concentration of reactants, reaction temperature as well as time, were found to (severally and collectively) determine the size of nanoparticles and their distribution. Nanoparticles obtained at 4 °C were smaller (60–80 nm) with narrower size distribution. Simulation experiments using Comsol software showed that at 4 °C ‘droplet synthesis’ of nanoparticles gets miniaturised to ‘droplet-core synthesis’, which is being reported for the first time.

Acceleration of reaction in charged microdroplets.

Using high-resolution mass spectrometry, we have studied the synthesis of isoquinoline in a charged electrospray droplet and the complexation between cytochrome c and maltose in a fused droplet to investigate the feasibility of droplets to drive reactions (both covalent and noncovalent interactions) at a faster rate than that observed in conventional bulk solution. In both the cases we found marked acceleration of reaction, by a factor of a million or more in the former and a factor of a thousand or more in the latter. We believe that carrying out reactions in microdroplets (about 1–15 μm in diameter corresponding to 0·5 pl – 2 nl) is a general method for increasing reaction rates. The mechanism is not presently established but droplet evaporation and droplet confinement of reagents appear to be two important factors among others. In the case of fused water droplets, evaporation has been shown to be almost negligible during the flight time from where droplet fusion occurs and the droplets enter the heated capillary inlet of the mass spectrometer. This suggests that (1) evaporation is not responsible for the acceleration process in aqueous droplet fusion and (2) the droplet–air interface may play a significant role in accelerating the reaction. We argue that this ‘microdroplet chemistry’ could be a remarkable alternative to accelerate slow and difficult reactions, and in conjunction with mass spectrometry, it may provide a new arena to study chemical and biochemical reactions in a confined environment.

External control of reactions in microdroplets.

Scale reduction of chemical reactions enables novel screening and synthesis approaches that facilitate a highly parallelized and combinatorial exploration of chemical space. Droplet-based microfluidics have evolved as a powerful platform to allow many chemical reactions within small volumes that each can be controlled and manipulated. A significant technical challenge is the ability to change the concentration of reactants inside a droplet. Here we describe a strategy that relies on the use of reactants that are soluble in both oil and water and allow a passive, diffusive exchange of reactants between the oil and aqueous phases to externally control composition of the droplets. We demonstrate the applicability of our approach by externally changing the pH inside microdroplets without the need for physical manipulation or droplet merging.

Multistage Reactive Transmission-Mode Desorption Electrospray Ionization Mass Spectrometry.

Elucidating reaction mechanisms is important for advancing many areas of science such as catalyst development. It is often difficult to probe fast reactions at ambient conditions with high temporal resolution. In addition, systems involving reagents that cross-react require analytical methods that can minimize interaction time and specify their order of introduction into the reacting system. Here, we explore the utility of transmission mode desorption electrospray ionization (TM-DESI) for reaction monitoring by directing a microdroplet spray towards a series of meshes with micrometer-sized openings coated with reagents, an approach we call multistage reactive TM-DESI (TM (n) -DESI, where n refers to the number of meshes; n = 2 in this report). Various stages of the reaction are initiated at each mesh surface, generating intermediates and products in microdroplet reaction vessels traveling towards the mass spectrometer. Using this method, we investigated the reactivity of iron porphyrin catalytic hydroxylation of propranolol and other substrates. Our experimental results indicate that TM (n) -DESI provides the ability to spatially separate reagents and control their order of introduction into the reacting system, thereby minimizing unwanted reactions that lead to catalyst deactivation and degradation products. In addition, comparison with DESI-MS analyses (the Zare and Latour laboratories published results suggesting accessible reaction times <1 ms) of the reduction of dichlorophenolindophenol by L-ascorbic acid suggest that TM (1) -DESI can access reaction times less than 1 ms. Multiple meshes allow sequential stages of desorption/ionization per MS scan, increasing the number of analytes and reactions that can be characterized in a single experiment.

Chemical Reaction in Microdroplets with Different Sizes Containing CdSe/ZnS Quantum Dot and Organic Dye

We report a real time method to monitor the chemical reaction in microdroplets, which contain an organic dye, 5(6)carboxynaphthofluorescein and a CdSe/ZnS quantum dot using fluorescence spectra. Especially, the relationship between the droplet diameter and the reaction rate of the two reagents was investigated by changing an inlet flow rate. key words: Microfluidic Device, Fluorescence Spectroscopy, Real-Time Monitoring, Semiconductor Quantum Dot, Fluorescence Energy Transfer

Visualizing millisecond chaotic mixing dynamics in microdroplets: A direct comparison of experiment and simulation.

In order to fully explore and utilize the advantages of droplet-based microfluidics, fast, sensitive, and quantitative measurements are indispensable for the diagnosis of biochemical reactions in microdroplets. Here, we report an optical detection technique using two-photon fluorescence lifetime imaging microscopy, with an aligning-summing and non-fitting division method, to depict two-dimensional (2D) maps of mixing dynamics by chaotic advection in microdroplets with high temporal and spatial resolution. The mixing patterns of two dye solutions inside droplets were quantitatively and accurately measured. The mixing efficiency in a serpentine droplet mixer was also quantified and compared with the simulation data. The mapped chaotic mixing dynamics agree well with the numerical simulation and theoretical prediction. This quantitative characterization is potentially applicable to the real-time kinetic study of biological and chemical reactions in droplet-based microfluidic systems.

Accelerated bimolecular reactions in microdroplets studied by desorption electrospray ionization mass spectrometry

Functional group derivatization reactions occur in the course of microdroplet/surface collisions in the ambient ionization process of desorption electrospray ionization (DESI). The unique environment in the microdroplet causes rate enhancements of as much as several orders of magnitude in typical bimolecular reactions that proceed through either cationic or anionic intermediates. The environment in the evaporating charged microdroplet differs from that of the bulk: (i) the pH of the solution moves towards the extremes, (ii) the concentrations of the reagents increase, (iii) the relative surface area increases and (iv) collision frequencies increase. The rates of acid-catalyzed reactions, such as the reaction of Girard T reagent with ketosteroids, increase with decreasing pH in positively-charged microdroplets compared to the bulk solution rates. Similarly, the increased pH in evaporating negatively-charged microdroplets contributes to an increase in the rates of base-catalyzed Michael reactions over those recorded under bulk solution conditions. The amount of product formed depends on the reaction time and the droplet size. Nanoelectrospray ionization generates larger droplets than the secondary droplets of DESI so it does not show significant product formation in the analysis period and can be used to analyze products of the DESI experiments. When secondary microdroplets (ca. 1 micron diameter) are generated either by spraying a homogeneous solution of both reagents against an inert surface (reactive DESI) or when a solution of Girard T reagent is sprayed against a solid surface bearing the ketosteroid significant amounts of product are generated. In the case of the Michael reaction with cinnamic acid an alternative dehydrogenated reaction product is formed under microdroplet conditions. Some parallels between the phenomenon reported here and the rate acceleration seen in sonochemistry are noted. The potential value of mass spectrometry in establishing conditions that enhance reaction rates is also indicated. It is possible that these observations will assist in the selection of reaction conditions involving the use of charged microdroplets to enhance the rates of ordinary bulk chemical reactions, especially those involving strong steric hindrance.

ChemInform Abstract: Suzuki—Miyaura Coupling Reactions in Aqueous Microdroplets with Catalytically Active Fluorous Interfaces.

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Preparation of Two-dimensionally Ordered Microbeads Structure Dispensed with an Ink-jet and Its Application to ELISA

In order to the increase sensitivity of enzyme-linked immunosorbent assay (ELISA) using micro-droplet reaction system formed by ink-jet, we employed small dots of two-dimensionally well-ordered structure of polystyrene (PS) microbeads (710 +/- 25 microm in diameter) formed on the surface of polydimethyl siloxane (PDMS). An aqueous suspension of polystyrene microbeads (5 microm) was ejected on the PDMS plate with ink-jet. The PS beads were automatically assembled by capillary force accompanied with solvent evaporation. The evaporation rate was controlled by ambient relative humidity. The assembled beads were solidly immobilized on the surface of PDMS surface. The dots of well-ordered structure were stable against vigorous washing. ELISA using the structure as a reaction location was three times more sensitive than the material without the structure due to the increase of the surface area and consequent increase of the amount of antibody.

Simultaneous measurement of reactions in microdroplets filled by concentration gradients

This work describes a technology for performing and monitoring simultaneously several reactions confined in strings of microdroplets having identical volumes but different composition, and travelling with the same speed in parallel channels of a microfluidic device. This technology, called parallel microdroplets technology (PmicroD), uses an inverted optical microscope and a charge-coupled device (CCD) camera to collect images and analyze them so as to report on the reactions occurring in these microdroplets. A concentration gradient of one reactant is created in the microfluidic device. In each channel, a different concentration of this reactant is mixed with a fixed amount of a second reactant. Using planar flow-focusing methodology, these mixtures are confined in microdroplets of pL size which travel in oil as continuous medium, avoiding laminar dispersion. By analyzing the images of parallel strings of microdroplets, the time courses of several reactions with different reagent compositions are investigated simultaneously. In order to design the microfluidic device that consists in a complex network of channels having well-defined geometries and restricted positions, the theoretical concept of equivalent channels (i.e. channels having identical hydraulic resistance) is exploited and developed. As a demonstration of the PmicroD technology, an enzyme activity assay was carried out and the steady-state kinetic constants were determined.

Suzuki–Miyaura coupling reactions in aqueous microdroplets with catalytically active fluorous interfaces

Using microfluidic techniques and a novel fluorous-tagged palladium catalyst, we generated droplet reactors with catalytically active walls and used these compartments for small molecule synthesis.