Reactions In Microdroplets Research Articles

Microdroplet synthesis of azo compounds with simple microfluidics-based pH control.

Conventional solution-phase synthesis of azo compounds is complicated by the need for precise pH and temperature control, high concentrations of pH control reagents, and by-product removal. In this work, we exploited the advantages of microdroplet chemistry to realize the simple and highly efficient synthesis of an azo compound using microfluidics-based pH control. Owing to the small size of microdroplets, heat exchange between a microdroplet and its environment is extremely fast. Furthermore, chemical reactions in microdroplets occur rapidly due to the short diffusion distance and vortex flow. Formation of the azo compound reached completion in less than 3 s at room temperature, compared with 1 h at 0 °C under conventional conditions. pH control was simple, and the pH control reagent concentration could be reduced to less than one-tenth of that used in the conventional method. No by-products were generated, and thus this procedure did not require a recrystallization step. The time course of the chemical reaction was elucidated by observing the growth of azo compound microcrystals in droplets at various locations along the channel corresponding to different mixing times.

Reaction of chloroauric acid with histidine in microdroplets yields a catalytic Au-(His)2 complex.

An aqueous solution containing histidine (His, 100 μM) and chloroauric acid (HAuCl4, 10 μM) is electrosprayed (−4.5 kV) from a capillary (50 μm in diameter) with N2 nebulizing gas (120 psi). The resulting microdroplets entered a mass spectrometer with a 2 cm flight path. The mass spectrum recorded in negative ion mode showed several peaks including the Au5 nanocluster with the major one being [Au + 2His–2H]−, which is a catalytically active species. The reaction time was less 1 ms, and the yield of [Au + 2His–2H]− was 76%. In contrast, the bulk reaction for the same concentration run at room temperature for 2 h did not produce this species but instead formed Au10 nanocluster. When a solution of water and acetonitrile (1 : 1) containing indoline (100 mM) and the phenylacetylene (200 mM) as well as histidine and chloroauric acid at the same concentrations as above was electrosprayed, the mass spectrum showed the formation of the intermediate [Au + 2His + phenylacetylene + H]+. Upon collecting the microdroplets, the 4-methyl-4,6-diphenyl-1,2-dihydro-4H-pyrrolo[3,2,1-ij] quinolone product was observed by 1H nuclear magnetic resonance and liquid chromatography with a yield of 44%. The microdroplet synthesis using the Au–(His)2 complex as a catalyst was scaled up using room-temperature ultrasonic nebulization to produce the product at the rate of 35 mg min−1, which is semi-preparative and demonstrates the promise of using microdroplet reactions for chemical synthesis.

Diels-Alder Reactions in Water Are Determined by Microsolvation.

Nanoconfined aqueous environments and the recent advent of accelerated chemistry in microdroplets are increasingly being investigated for catalysis. The mechanisms underlying the enhanced reactivity in alternate solvent environments and whether the enhanced reactivity due to nanoconfinement is a universal phenomenon are not fully understood. Here, we use ab initio molecular dynamics simulations to characterize the free energy of a retro-Diels-Alder reaction in bulk water at very different densities and in water nanoconfined by parallel graphene sheets. We find that the broadly different global solvation environments accelerate the reactions to a similar degree with respect to the gas-phase reaction, with activation free energies that do not differ by more than kbT from each other. The reason for the same acceleration factor in the extremely different solvation environments is that it is the microsolvation of the dienophile's carbonyl group that governs the transition-state stabilization and mechanism, which is not significantly disrupted by either the lower density in bulk water or the strong nanoconfinement conditions used here. Our results also suggest that significant acceleration of Diels-Alder reactions in microdroplets or on-water conditions cannot arise from local microsolvation when water is present but instead must come from highly altered reaction environments that drastically change the reaction mechanisms.

Droplet Imbibition Enables Nonequilibrium Interfacial Reactions in Charged Microdroplets.

A droplet imbibition experiment is proposed to study interfacial effects, which appears to be the main factor influencing reaction acceleration in charged microdroplets produced by electrospray ionization (ESI). One reagent is deposited onto the surface of rapidly moving microdroplets containing the second reagent to be reacted. In this manner, reactions are hindered from reaching equilibrium and monitored in real time by mass spectrometry. We demonstrated this phenomenon using Katritzky chemistry, which is known to proceed either by the solvent-stabilized 2H-pyran intermediate or via the surface-active pseudobase intermediate. Comparisons with reactions performed using ESI show obvious surface effects in favor of the droplet imbibition experiment. By keeping reactant mole ratio constant, it was demonstrated that similar interfacial effects observed in the droplet imbibition experiment can be reached by allowing ESI microdroplets containing premixed reagents to traverse a distance >16 mm. At such spray distance, molecular diffusion and droplet lifetime become comparable allowing reactants to be enriched at droplet surface. Reactions were also conducted in rapid mixing, theta capillary-based droplets, which showed markedly reduced yields compared with the interfacial droplet imbibition experiment.

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. We also varied the inlet capillary temperature from 100 to 350 °C. Contrary to the view that the inlet temperature has little to no influence on the reaction rate, we found that the Pomeranz-Fritsch reaction was markedly accelerated for both solvents and for both droplet sizes on increasing the temperature, whereas the Combes synthesis showed the opposite behavior. We propose that these strikingly different behaviors result from a competition of two effects, the evaporative cooling versus the heating of ejected bare ions from the droplet, both taking place inside the heated inlet. This finding suggests that these phenomena must be taken into account while interpreting the microdroplet reactions studied by electrospray or a similar kind of ambient ionization MS.

Scale-up of microdroplet reactions by heated ultrasonic nebulization.

Dramatically higher rates for a variety of chemical reactions have been reported in microdroplets compared with those in the liquid bulk phase. However, the scale-up of microdroplet chemical synthesis has remained a major challenge to the practical application of microdroplet chemistry. Heated ultrasonic nebulization (HUN) was found as a new way for scaling up chemical synthesis in microdroplets. Four reactions were examined, a base-catalyzed Claisen-Schmidt condensation, an oximation reaction from a ketone, a two-phase oxidation reaction without the use of a phase-transfer-catalyst, and an Eschenmoser coupling reaction. These reactions show acceleration of one to three orders of magnitude (122, 23, 6536, and 62) in HUN microdroplets compared to the same reactions in bulk solution. Then, using the present method, the scale-up of the reactions was achieved at an isolated rate of 19 mg min-1 for the product of the Claisen-Schmidt condensation, 21 mg min-1 for the synthesis of benzophenone oxime from benzophenone, 31 mg min-1 for the synthesis of 4-methoxybenzaldehyde from 4-methoxybenzyl alcohol, and 40 mg min-1 for the enaminone product of the Eschenmoser coupling reaction.

Accelerated crystallization and encapsulation for the synthesis of water- and oxygen-resistant perovskite nanoparticles in micro-droplets.

Water- and oxygen-resistant perovskite nanoparticles (PC-PNPs) were synthesized in milliseconds via a single-step microdroplet reaction. It was found through kinetics studies that the synthesis was accomplished within 100 ms in microdroplet reactors, with ejection at ∼1.5 m s-1. Being small-sized, stable, less toxic and biocompatible, PC-PNPs were feasible for cell or in vivo imaging, and selective sensing for Fe3+ and Cys, which will inspire further expanded studies of perovskite materials.

Selective Synthesis in Microdroplets of 2-Phenyl-2,3-dihydrophthalazine-1,4-dione from Phenyl Hydrazine with Phthalic Anhydride or Phthalic Acid.

Pyridazine derivatives are privileged structures because of their potential biological and optical properties. Traditional synthetic methods usually require acid or base as a catalyst under reflux conditions with reaction times ranging from hours to a few days or require microwave assistance to induce the reaction. Herein, this work presents the accelerated synthesis of a pyridazine derivative, 2-phenyl-2,3-dihydrophthalazine-1,4-dione (PDHP), in electrosprayed microdroplets containing an equimolar mixture of phenyl hydrazine and phthalic anhydride or phthalic acid. This reaction occurred on the submillisecond timescale with good yield (over 90 % with the choice of solvent) without using an external catalyst at room temperature. In sharp contrast to the bulk reaction of obtaining a mixture of two products, the reaction in confined microdroplets yields only the important six-membered heterocyclic product PDHP. Results indicated that surface reactions in microdroplets with low pH values cause selectivity, acceleration, and high yields.

Reactive Laser Ablation Electrospray Ionization Time-Resolved Mass Spectrometry of Click Reactions.

Reactions in confined compartments like charged microdroplets are of increasing interest, notably because of their substantially increased reaction rates. When combined with ambient ionization mass spectrometry (MS), reactions in charged microdroplets can be used to improve the detection of analytes or to study the molecular details of the reactions in real time. Here, we introduce a reactive laser ablation electrospray ionization (reactive LAESI) time-resolved mass spectrometry (TRMS) method to perform and study reactions in charged microdroplets. We demonstrate this approach with a class of reactions new to reactive ambient ionization MS: so-called click chemistry reactions. Click reactions are high-yielding reactions with a high atom efficiency, and are currently drawing significant attention from fields ranging from bioconjugation to polymer modification. Although click reactions are typically at least moderately fast (time scale of minutes to a few hours), in a reactive LAESI approach a substantial increase of reaction time is required for these reactions to occur. This increase was achieved using microdroplet chemistry and followed by MS using the insertion of a reaction tube—up to 1 m in length—between the LAESI source and the MS inlet, leading to near complete conversions due to significantly extended microdroplet lifetime. This novel approach allowed for the collection of kinetic data for a model (strain-promoted) click reaction between a substituted tetrazine and a strained alkyne and showed in addition excellent instrument stability, improved sensitivity, and applicability to other click reactions. Finally, the methodology was also demonstrated in a mass spectrometry imaging setting to show its feasibility in future imaging experiments.

Enhancement of reaction rate in small-sized droplets: A combined analytical and simulation study.

Several recent mass spectrometry experiments reveal a marked enhancement of the reaction rate of organic reactions in microdroplets. This enhancement has been tentatively attributed to the accumulation of excess charge on a surface, which in turn can give rise to a lowering of activation energy of the reaction. Here we model the reactions in droplets as a three-step process: (i) diffusion of a reactant from the core of the droplet to the surface, (ii) search by diffusion of the reactant on the surface to find a reactive partner, and finally (iii) the intrinsic reaction leading to bond breaking and product formation. We obtain analytic expressions for the mean search time (MST) to find a target located on the surface by a reactant in both two- and three-dimensional droplets. Analytical results show quantitative agreement with Brownian dynamics simulations. We find, as also reported earlier, that the MST varies as R2/D, where R is the radius of the droplet and D is the diffusion constant of the molecules in the droplet medium. We also find that a hydronium ion in the vicinity can substantially weaken the bond and hence lowers the activation barrier. We observe a similar facilitation of bond breaking in the presence of a static dipolar electric field along any of the three Cartesian axes. If the intrinsic reaction is faster compared to the mean search time involved, it becomes primarily a diffusion-controlled process; otherwise the reaction cannot be accelerated in the droplet medium. The air-droplet interface provides a different environment compared to the interior of the droplet. Hence, we might also expect a completely different mechanism and products in the case of droplet reactions.

Microdroplet Chemistry: Difference of Organic Reactions between Bulk Solution and Aqueous Microdroplets

Recent applications of microdroplet reactions are noted as reaction acceleration in confined environments and possible future scale-up synthesis compare to that of bulk phase reactions. Microdroplet reactions overcome the thermodynamic and kinetic challenges in an aqueous solution. Due to the microdroplet’s distinctive surface environment, the chemistry in Microdroplets significantly differs from that in the bulk solution.

Bifunctional nanoscale magnetic chains with high saturation magnetization and catalytic activity

The conventional stirring method cannot be employed for chip-on-lab reactions such as microfluidic and microdroplet reactions as well as nanoscale reactions. Therefore, it is necessary to design a nanoscale magnetic stirrer with a high magnetic response towards the external magnetic field. In this work, one dimentional core@shell structured Fe-Fe2O3@poly(cyclotriphosphazene-co-4,4′-sulfonyldiphenol) magnetic nanochains modified by nickel hydroxide (denoted as Fe-Fe2O3@PZS@Ni(OH)2 NCs) as nanoscale magnetic stirrer and recyclable self-mixing nanocatalysts are successfully prepared through three steps: synthesis of Fe-Fe2O3 nanochains (NCs) with high saturation magnetization, coating with poly (cyclotriphosphazene-co-4,4′-sulfonyldiphenol) (PZS), and nickel hydroxide’s anchoring on the surface of Fe-Fe2O3@PZS NCs. The cross-linked polymer PZS is used to protect Fe-Fe2O3 NCs from chemical corrosion and as a platform for subsequent immobilization of nickel hydroxide. Characterization results show that the Fe-Fe2O3@PZS@Ni(OH)2 NCs own chainlike structure and high saturation magnetization of 103 emu g−1 at room temperature, exhibiting high magnetic response to the external rotating magnetic field. In the macro-reaction system for 4-nitrophenol (4-NP) reduction, the as-prepared Fe-Fe2O3@PZS@Ni(OH)2 NCs show an apparent rate constant of about 0.60 min−1. Furthermore, the Fe-Fe2O3@PZS@Ni(OH)2 catalyst is reused ten times while no obvious loss of catalytic activity was observed. In the micro-reaction system, the Fe-Fe2O3@PZS@Ni(OH)2 NCs also display good magnetic response and favorable catalytic activity for the hydrogenation of methylene blue. These results indicate that the bifunctional Fe-Fe2O3@PZS@Ni(OH)2 NCs with high saturation magnetization have great potential as excellent nanocatalysts and as promising nanoscale magnetic stirrers.

Accelerated multi-reagent copper catalysed coupling reactions in micro droplets and thin films

Electrospray (ES) and paper spray (PS) mass spectrometry were used to create confined liquid volumes in which accelerated air and water sensitive, heterogeneous, copper catalysed C–O and C–N coupling reactions occur.

Preparative microdroplet synthesis of carboxylic acids from aerobic oxidation of aldehydes.

Single liquid-phase and liquid-liquid phase reactions in microdroplets have shown much faster kinetics than that in the bulk phase. This work extends the scope of microdroplet reactions to gas-liquid reactions and achieves preparative synthesis. We report highly efficient aerobic oxidation of aldehydes to carboxylic acids in microdroplets. Molecular oxygen plays two roles: (1) as the sheath gas to shear the aldehyde solution into microdroplets, and (2) as the sole oxidant. The dramatic increase of the surface-area-to-volume ratio of microdroplets compared to bulk solution, and the efficient mixing of gas and liquid phases using spray nozzles allow effective mass transfer between aldehydes and molecular oxygen. The addition of catalytic nickel(ii) acetate is shown to accelerate further microdroplet reactions of this kind. We show that aliphatic, aromatic, and heterocyclic aldehydes can be oxidized to the corresponding carboxylic acids in a mixture of water and ethanol using the nickel(ii) acetate catalyst, in moderate to excellent yields (62-91%). The microdroplet synthesis is scaled up to make it preparative. For example, aerobic oxidation of 4-tert-butylbenzaldehyde to 4-tert-butylbenzoic acid was achieved at a rate of 10.5 mg min-1 with an isolated product yield of 66%.

Optimizing Chemical Reactions with Deep Reinforcement Learning.

Deep reinforcement learning was employed to optimize chemical reactions. Our model iteratively records the results of a chemical reaction and chooses new experimental conditions to improve the reaction outcome. This model outperformed a state-of-the-art blackbox optimization algorithm by using 71% fewer steps on both simulations and real reactions. Furthermore, we introduced an efficient exploration strategy by drawing the reaction conditions from certain probability distributions, which resulted in an improvement on regret from 0.062 to 0.039 compared with a deterministic policy. Combining the efficient exploration policy with accelerated microdroplet reactions, optimal reaction conditions were determined in 30 min for the four reactions considered, and a better understanding of the factors that control microdroplet reactions was reached. Moreover, our model showed a better performance after training on reactions with similar or even dissimilar underlying mechanisms, which demonstrates its learning ability.

Microdroplets rev up reactions

Electrospray ionization (ESI) is best known as a way to introduce chemical compounds and mixtures into mass spectrometers. The machines apply a voltage to a stream of liquid containing a sample, creating an aerosol of charged, microsized droplets that then fly into the detector for analysis. But what ESI might one day be just as well-known for is as a tool to accelerate chemical reactions, enabling scientists to test out catalysts, reagents, and conditions faster and more efficiently. Under the right conditions, the microdroplets generated by ESI can serve as reaction vessels. Chemists don’t yet know exactly why the tiny droplets accelerate the reaction of chemical reagents contained within, but they do know the microdroplets sometimes even allow chemical transformations to proceed that wouldn’t normally occur in bulk solutions—in flasks and other larger vessels. R. Graham Cooks’s group at Purdue University stumbled upon microdroplet reaction acceleration while trying to analyze

Exploring Chemistry in Microcompartments Using Guided Droplet Collisions in a Branched Quadrupole Trap Coupled to a Single Droplet, Paper Spray Mass Spectrometer.

Recent studies suggest that reactions in aqueous microcompartments can occur at significantly different rates than those in the bulk. Most studies have used electrospray to generate a polydisperse source of highly charged microdroplets, leading to multiple confounding factors potentially influencing reaction rates (e.g., evaporation, charge, and size). Thus, the underlying mechanism for the observed enhancement remains unclear. We present a new type of electrodynamic balance-the branched quadrupole trap (BQT)-which can be used to study reactions in microdroplets in a controlled environment. The BQT allows for condensed phase chemical reactions to be initiated by colliding droplets with different reactants and levitating the merged droplet indefinitely. The performance of the BQT is characterized in several ways. Sub-millisecond mixing times as fast as ∼400 μs are measured for low velocity (∼0.1 m/s) collisions of droplets with <40 μm diameters. The reaction of o-phthalaldehyde (OPA) with alanine in the presence of dithiolthreitol is measured using both fluorescence spectroscopy and single droplet paper spray mass spectrometry. The bimolecular rate constant for reaction of alanine with OPA is found to be 84 ± 10 and 67 ± 6 M-1 s-1 in a 30 μm radius droplet and bulk solution, respectively, which demonstrates that bimolecular reaction rate coefficients can be quantified using merged microdroplets and that merged droplets can be used to study rate enhancements due to compartmentalization. Products of the reaction of OPA with alanine are detected in single droplets using paper spray mass spectrometry. We demonstrate that single droplets with <100 pg of analyte can easily be studied using single droplet mass spectrometry.

“On‐Droplet” Chemistry: The Cycloaddition of Diethyl Azodicarboxylate and Quadricyclane

AbstractSharpless 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.

"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.