Water is the most common but also the most amazing substance. Even a "drop" of water, which is only one quadrillion of a liter, can accelerate chemical reactions, and the catalytic effect exhibited has left countless scientists dumbfounded. This is the frontier hot spot in the field of chemistry in recent years - the study of water droplets. At present, water droplets have shown great application potential in organic chemical synthesis, nitrogen and carbon fixation, etc., but the mechanism of their accelerated reaction is unclear and even controversial.
撰文 | 聂少尉、梁秋江、杨军（香港大学化学系）
01 Introduction
Water is essential for sustaining life. Water is also an indispensable raw material in industry and agricultural production, and an important solvent in chemical laboratories. In addition to the "large" aqueous solutions required above, quadrillionths (cubic microns) of water are also widely found in the natural environment, such as water vapor in the atmosphere. Surprisingly, in recent years, with the deepening of chemical research, it has been found that such a small volume of "water microdroplets" can increase the rate of some chemical reactions by about 10 times or even 1,000,000 times! As readers read this article, it is believed that chemical laboratories around the world are actively promoting the research of droplet chemistry.
02 The Past and Present of Water Droplet Research
As the name suggests, a water droplet is a very small water droplet with a diameter ranging from about 1 micron to 1000 microns, and its physical composition involves a liquid phase composed of water molecules, a gas phase (usually air) surrounded by the droplets, and a gas-water interface formed by the gas-liquid phase. Although droplet research is relatively new in the field of chemical synthesis, water droplets are not uncommon in everyday life and other scientific research. The ultrasonic humidifier used in the home is a good water droplet generator, the water is broken up into water droplets with a diameter of 1-10 microns under high-frequency physical vibrations, and these water droplets are diffused in the air to increase the humidity of the indoor air. Water droplets are also widely found in atmospheric clouds and fog, and their physicochemical properties are essential for studying atmospheric reactions. For a long time, water droplets have only recently made their mark in the field of chemical synthesis due to their small size, limited number of reactants, and the need for sensitive measurement methods.
The research of water droplets in the field of chemistry can be traced back to the 70s of the last century. With the development of high-precision analytical measuring instruments, especially high-resolution mass spectrometers (such as ion cyclotron resonance, etc.) are gradually applied to the field of chemistry, high-precision measurement of chemical reaction rate has been realized. As a pioneer in related research, American chemist John Brauman used mass spectrometry to measure the reaction rate constants of a large number of organic molecules, and found that the rate of many gas-phase reactions was much higher than that of the corresponding liquid-phase reactions. In the 80s, the American chemist John Fenn was awarded the Nobel Prize in Chemistry for the invention of electrospray ionization, which uses high voltage to ionize liquids into charged droplets, which can produce water droplets containing charged ions of specific reactants, which can be directly fed into a mass spectrometer for analysis.
Focusing on mass spectrometry, Professor Graham Cooks' team at Purdue University has been studying ionic reactions since the 90s of the last century, exploring their applications in the fields of medicine, biochemistry and organic chemistry. During this period, they measured the reaction rate of various chemical reactions in water droplets, which preliminarily showed the potential of water droplets in the field of chemical synthesis. In 2011, Prof. Cooks' team and his collaborators creatively demonstrated the accelerating effect of water droplets for the first time by creatively using the organic reaction of ketosin and Girard's reagent T [1]. Subsequently, Professor Cooks, Professor Richard Zare of Stanford University, and other scholars began to try to apply this property to chemical synthesis: their studies showed that many chemical reactions react at a rate much larger than their corresponding rate in aqueous solutions, with an acceleration rate of up to 10^6.
With the deepening of research, the potential of droplet chemistry has been discovered by more and more scholars. After less than ten years of development, in-depth research has been carried out on the mechanism explanation, reaction types, and potential applications of water droplet accelerated chemical reactions. At the same time, the study of droplet chemistry has also promoted the understanding of important issues such as nitrogen fixation, carbon dioxide conversion and the origin of life, and is expected to explore new reaction pathways and reduce the activation energy of reactions. Through the use of water droplets, the laboratory conditions required for some chemical reactions are changed from harsh high temperature and high pressure to normal temperature and pressure, which greatly reduces the energy consumption required for chemical reactions, improves the safety of the reaction, and makes chemical synthesis develop towards cleaner, more efficient and safer.
03 "Water droplet catalysis" has achieved remarkable results
It has been found that water droplets can greatly accelerate a wide variety of chemical reactions. For example, Girard reagent T and carbonyl compounds such as ketone steroids form corresponding hydrazone compounds, Michael addition reaction, dehydration reaction, Schiff base synthesis and other addition and elimination reactions, amine and sulfide and other redox reactions, and Mannich condensation and a series of organic synthesis reactions. Metal ion-catalyzed protein folding and unfolding kinetics have also been found to be significantly accelerated in water droplets. Water droplets play a role as catalysts and active centers in these micro-nanoscale chemical reactions, and have become a powerful tool for researchers to explore novel chemical reaction pathways and study rapid microsynthesis.
Let's take a look at the enormous application potential of these droplets by accelerating organic synthesis and providing novel methods for nitrogen fixation.
3.1 Organic chemical synthesis
Organic reactions play a vital role in the production of modern human society as the basis for the construction of many key industrial products and materials. Among them, the oxidation of aldehydes to form carboxylic acids is one of the most basic and common types of organic reactions, which are widely used in the production of cosmetics, plasticizers, fibers, biomass-derived compounds and pharmaceuticals. It can be said that the oxidation reaction of hydrocarbons, aldehydes and other compounds is the key method to turn primary raw materials into gold and obtain high value-added products. However, due to the relatively stable chemical properties of most aldehydes, the commonly used aldehyde oxidation methods in industry usually require the use of strong oxidants containing transition metals, such as Jones oxidant with Cr(IV) group, Tollen reagent with Ag(I) group, Fehling oxidant with Cu(II) group or permanganate oxidant. The high cost and environmental harm of these traditional methods cannot be ignored under the demand for long-term and large-scale production.
As a natural oxidant, oxygen has the excellent properties of environmental friendliness, cheap and easy to obtain, and high atomic utilization, and how to use gaseous oxygen to oxidize aldehydes to carboxylic acids has been a hot topic in academia and industry for a long time.
In 2018, Zare's team attempted to oxidize a variety of aldehydes in water droplets to generate corresponding carboxylic acids using oxygen [2]. The experimental results showed that the aliphatic, aromatic and heterocyclic aldehyde compounds tested could be oxidized by oxygen to form the corresponding carboxylic acids within 30 minutes under mild conditions under the action of water-ethanol droplets and nickel acetate catalyst, with a yield of 62%-91%.
It is an important raw material for the synthesis of fine chemicals such as spices, dyes and drugs), for example, under the same temperature, pressure and other conditions, in the control experiment of inflating oxygen bubbles into the reactant solution, the yield of the corresponding carboxylic acid is less than 1%, which is only 1/50 of the microdroplet experiment. By adjusting the diameter and number of layers of the metal grid placed at the electrospray nozzle, it was found that the reaction yield increased with the decrease of the droplet diameter and reached a maximum value at a diameter of 3 μm. Conversely, when the droplet diameter is too large as 90 μm, the oxidation yield is less than 5%. The relationship between droplet diameter and yield proves that the acceleration of the oxidation of these aldehydes occurs at the gas-liquid interface that encapsulates the droplets.
Although there is still a lot of in-depth research on the actual organic synthesis of aldehydes and other organic synthesis of water droplets, the excellent catalytic efficiency and oxidation properties of water droplets have demonstrated their application prospects in the field of chemical synthesis.
3.2 Non-biological methods for the synthesis of biomolecules
On the question of the origin of life, water droplet research has brought new insights. The basic theory of the origin of life holds that the basic biomolecules such as peptides and nucleotides that originally existed in the ocean were necessary conditions for the origin of life. Life on Earth originated in water, however, before the birth of life, the Earth's surface was covered by oceans, and too many water molecules in the environment may hinder the dehydration reaction between amino acids, thus affecting the production of peptides. Protein synthesis in living organisms depends on the catalytic functions of various biological enzymes, and how amino acids can be transformed into simple peptide molecules by abiotic methods in the natural environment is a key issue in the study of the origin of life.
Scientists have studied the reaction of glycine (Gly) and alanine (Ala) in water droplets [5]. The experiment produced water droplets containing only glycine or alanine by electrospray ionization and diffused into the back-end mass spectrometer at room temperature and pressure, and the researchers found that a dipeptide (GlyGly or AlaAla) was formed within the water droplets in the diffusion. According to the authors, it is the gas-water interface of water droplets that provides the necessary "drying" conditions to overcome the thermodynamic obstacle to the dehydration of amino acids in the liquid phase, thereby facilitating the condensation of amino acids under mild and catalyst-free conditions.
This discovery implies that in the early marine environment, water droplets may have played a key role in the birth of life: through their special air-water interface, favorable conditions were created for the dehydration reaction of amino acids, thus facilitating the further synthesis of proteins necessary for the birth of life. In addition, nucleotides, as the basic building blocks of RNA synthesis, are also endothermic in aqueous solutions, and they have been found to be synthesized in water droplets under mild conditions under magnesium ion catalysts [6]. These discoveries have led to a new understanding of the role of water in the origin of life, and also provided new enlightenment for future life science research.
3.3 Nitrogen and carbon sequestration
Recent research results in droplet chemistry have also shown miraculous effects in the fields of nitrogen fixation and carbon sequestration. Nitrogen fixation refers to the transfer of molecules
1% of total emissions. The green and efficient nitrogen fixation method that can be applied on a large scale has long been an urgent expectation of the entire human society. In this regard, recent achievements in the chemical field are expected to provide a "water droplet" version of the solution.
In April 2023, researchers discovered a method to convert nitrogen and water into ammonia at room temperature and pressure [7]. Experiments through ultra
The gradual disappearance of the mass spectrometer signal indicates that the water droplets not only provide the H atom of the urea molecule as the H source in the reaction, but also the special properties of the water droplet are the key factors driving the reaction.
04 Acceleration mechanism: I don't know why I know what it is
Behind the surprising experimental phenomena, researchers have also tried to understand the physicochemical mechanism of accelerated chemical reactions of water droplets from various perspectives, and have proposed a variety of models and conjectures. However, the micro-nano spatial scale of water droplets and the time scale of ultrafast reactions pose new challenges to experimental and computational methods, and although the study of the microscopic mechanism of accelerated chemical reactions has made some progress, it is still far from mature, and there is some controversy at present.
4.1 Gas-water interface and strong electric field
In order to truly understand the reasons why water droplets accelerate chemical reactions, we must grasp and construct a realistic physicochemical system, involving water chemistry and interface science at the microscopic scale. By comparing water droplets with liquid water, we can find clues.
First of all, the most intuitive difference between water droplets and bulk water is the increase in the area-to-volume ratio due to the decrease in the diameter of the liquid, that is, the increase in the area of the gas-water interface corresponding to the unit volume of water. The effect of the gas-water interface in the water droplets on the reaction can be determined by changing the diameter of the water droplets and observing the change in the reaction rate.
Another important feature of water droplets is the formation of an electric double layer on their surface and the resulting strong electric field within the extremely thin 1-2 angstroms (1 angstroms = 10^(-10) m) at the air-water interface. From the basic knowledge of the electrostatic field, it can be seen that the charge is affected by the electric field force in the electric field, and the magnitude of the force is proportional to the strength of the electric field. When the electric field strength of the environment is strong enough, the chemical bonds in the molecule will be reconstituted or even dissociated, and the charged ions may also be rearranged under the action of the electric field, thus promoting the progress of related chemical reactions. In other words, it is only when the electric field on the surface of the water droplet is strong enough that the water droplet is likely to accelerate the reaction by the action of the electric field. Therefore, the experimental measurement and theoretical calculation of the electric field strength on the surface of water droplets are of great importance for the study of the mechanism of accelerated chemical reactions of water droplets.
Due to the particularity of the gas-water interface of water droplets, there are many challenges in directly measuring the electric field strength on the surface of water droplets, such as spatial resolution, measurement sensitivity, and measurement of disturbances introduced into the system. Until 2020, the team of Zare at Stanford University and Min Wei at Columbia University used stimulated Raman excitation fluorescence spectroscopy (SREF) to measure the vibrating Stark effect, and the electric field intensity on the surface of the water droplets was about 10^9 V/m [8]. In 2022, Professor Teresa Head-Gordon of the University of California, Berkeley, used the reactive force field model ReaxFF/C-GeM to simulate the electric field distribution and variation of water droplets with a diameter of 80-160 angstroms by molecular dynamics [9]. The electric field on the surface of the water droplets showed a Lorentz distribution, with an average value of 1.6 ×10^9 V/m. The above experimental and theoretical results have shown that there is an electric field of up to 10^9 V/m on the surface of the water droplets, which is sufficient to activate or break the chemical bonds. At the same time, Ruiz-López et al. argued that the electrostatic potential fluctuation effect caused by the dynamic reconstruction of the solvent on the surface of the droplets should not be ignored [10].
Recently, Zhang Xinxing's team at Nankai University in mainland China experimentally accelerated the Menshutkin reaction by using the strong electric field generated at the water-air interface [11], and they achieved dehalogenation through ultrafast electron transfer generated by the electric field at the interface of water droplets [12].
Charged droplets can also act as natural miniature batteries to drive chemical reactions containing water. Recently, Fan Fengru class at Xiamen University
and eventually ethanol is generated. Therefore, many scholars believe that the strong electric field at the interface of water droplets is one of the important factors that promote the occurrence of chemical reactions.
4.2 Sources of surface charge of water droplets
Although experimental and theoretical studies have given consistent surface electric field strengths for water droplets, the establishment of the surface electric field is ultimately due to the formation of an electric double layer due to the distribution of positive and negative charges on the surface of water droplets. The source and form of these positive and negative charges are still controversial, which are mainly divided into two views: ionization of water molecules and charge transfer of hydrogen bonds.
A recent QM/MM simulation based on the second-order perturbation theory found that there is a continuous non-uniform charge transfer between water molecules on the surface of water droplets, and the charge migration of water molecules at a single interface can reach up to ±0.2 e, which is much higher than the previous estimation of charge transfer probability, resulting in a large number of partially charged water radicals. Reaction calculations of important CI (Criegee intermediates) molecules and water droplets in the atmosphere show that the interfacial charge transfer increases the reactivity of CI molecules and water molecules, greatly reduces the activation energy of the reaction, and promotes the rapid occurrence of the reaction [14].
4.3 Other Mechanisms
In addition to the strong electric field present at the gas-water interface of water droplets, there are other possible mechanisms that accelerate chemical reactions:
1) Lower dissolution energy. It is theorized that reactants only need to be partially dissolved at the gas-water interface when they occur in water droplets, thus reducing the energy barrier for complete dissolution of reactants.
2) The orderly arrangement of reactant molecules at the gas-water interface. Both experimental and theoretical studies have shown that due to the electric field on the surface of water droplets, some reactant ions or intermediates will form an orderly arrangement in a specific direction. The orderly arrangement of reactant molecules reduces the entropy of the initial state of the reaction and increases the Gibbs free energy accordingly, thereby reducing the change in the free energy of the overall reaction.
3) Rapid evaporation of water droplets. With the rapid evaporation of water droplets in the air, the concentration of reactants in the water droplet system increases significantly, resulting in a positive shift in the chemical equilibrium.
In short, the mechanism of the accelerated chemical reaction of water droplets is mainly based on the role of the gas-water interface. Of course, factors such as the form of reactants in water droplets and the interaction between water droplets and reactant products during the reaction process are also important reasons for the reaction rate.
05 Summary: Challenges and opportunities coexist
Droplet chemistry has only been around for more than a decade, but it has quickly become the focus of the chemical community. The scope of his research has rapidly expanded from the initial analysis and synthesis to many fields and disciplines such as biology, medicine, energy, and catalysis. Although the application of water droplets is promising, its microscopic mechanism still needs to be further studied and explored. In addition, while water droplets have been found to accelerate a variety of chemical reactions under mild conditions, most of these reactions are acid/base catalyzed, or the reactants contain polar functional groups such as amino and ketone steroids. For the reactions of non-polar molecules, the water droplets do not show a significant acceleration effect, such as the Diels–Alder reaction of the non-polar molecule 3,5-hexadienyl acrylate ester, and experiments show that most of the reactants remain. In terms of application, the difficulty of generating small volumes of water droplets on a large scale is also one of the obstacles to its practical application.
In the future, how to efficiently prepare charged water droplets and improve the reaction yield may be the key factors that determine whether the droplet synthesis chemistry can truly achieve large-scale clean and efficient industrial production of compounds. For scientists around the world, the development of droplet chemistry is both a great challenge and a rare opportunity. We look forward to more breakthroughs in the research and application of water droplet chemistry in the future."
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