Can one trillionth of a liter of water increase the rate of a chemical reaction by a million times?

Water is the most common but also the most magical substance. Even a "drop" of water, which is only one quadrillionth of a liter, can accelerate chemical reactions, and the catalytic effect it exhibits has amazed countless scientists. This is the frontier hotspot in the field of chemistry in recent years - water droplet research. At present, water droplets have shown great application potential in the fields of organic chemical synthesis, nitrogen and carbon fixation, etc., but the mechanism of accelerating reactions is unclear and even controversial.

Written by Lieutenant Nie, Liang Qiujiang, and Yang Jun (Department of Chemistry, University of Hong Kong)

01 Introduction

Water is a necessary substance for maintaining life. Water is also an indispensable raw material in industrial and agricultural production; in chemical laboratories, water is also an important solvent. In addition to the "large amount" of aqueous solution required above, water at the level of one quadrillionth of a liter (cubic micrometer) is also widely present in the natural environment, such as water vapor in the atmosphere. Surprisingly, with the deepening of chemical research in recent years, people have found that "water microdroplets" of such a small volume can increase the rate of some chemical reactions by about 10 times or even 1,000,000 times! Research on water microdroplets has quickly become a hot topic in the field of chemistry. When readers read this article, I believe that chemical laboratories around the world are actively promoting the research of droplet chemistry.

02The past and present of water droplet research

As the name implies, water droplets refer to very small water droplets with a diameter ranging from about 1 micron to 1000 microns; its physical composition involves a liquid phase composed of water molecules, a gas phase (usually air) surrounding the droplets, and a gas-water interface formed by the gas-liquid two phases. Although the study of droplets is relatively new in the field of chemical synthesis, water droplets are not uncommon in daily life and other scientific research. The ultrasonic humidifier used in the home is a good water droplet generator. Water is broken up into droplets with a diameter of 1-10 microns under high-frequency physical vibration. These water droplets diffuse in the air and increase the indoor air humidity. Water droplets are also widely present in clouds and fog in the atmosphere, and their physical and chemical properties are crucial for studying atmospheric reactions. For a long time, due to the small size, limited reactants that can be contained, and the need for sensitive measurement methods, water droplets have only recently emerged in the field of chemical synthesis.

The study of water droplets in the field of chemistry can be traced back to the 1970s. With the development of high-precision analytical measuring instruments, especially high-resolution mass spectrometers (such as ion cyclotron resonance, etc.), they have been gradually applied to the field of chemistry, and high-precision measurement of chemical reaction rates has become possible. As a pioneer in related research, American chemist John Brauman used a mass spectrometer to measure the reaction rate constants of a large number of organic molecules and found that the rates of many gas-phase reactions were much higher than those of the corresponding liquid-phase reactions. In the 1980s, electrospray ionization technology was born. It uses high voltage to ionize liquids into charged droplets, which can produce water droplets containing charged ions of specific reactants and can be directly sent to a mass spectrometer for analysis. Its inventor, American chemist John Fenn, also won the 2002 Nobel Prize in Chemistry.

With mass spectrometers as the center, the team of Professor Graham Cooks of Purdue University has been studying ion reactions since the 1990s, exploring their applications in medicine, biochemistry, and organic chemistry. During this period, they measured the reaction rates of various chemical reactions in water droplets, preliminarily showing the potential of water droplets in the field of chemical synthesis. In 2011, Professor Cooks' team and their collaborators creatively used the organic reaction of ketosteroids and Girard reagent T to clearly demonstrate the acceleration effect of water droplets for the first time [1]. Subsequently, Professor Cooks, Professor Richard Zare of Stanford University, and other scholars began to try to apply this feature to chemical synthesis: their research showed that the reaction rates of many chemical reactions in droplets are much greater than their corresponding rates in aqueous solutions, and the acceleration factor can reach the order of 10^6.

As research continues to deepen, the potential of droplet chemistry has been discovered by more and more scholars. After less than a decade of development, in-depth research has been carried out on the mechanism explanation, reaction type, potential applications and other aspects of water droplets accelerating chemical reactions. At the same time, the study of droplet chemistry has also promoted people's 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. By using 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 while improving the safety of reactions, making chemical synthesis cleaner, more efficient and safer.

03 “Water Droplet Catalysis” has achieved remarkable results

Studies have found that water droplets can significantly accelerate a wide range of chemical reactions. For example, addition-elimination reactions such as the reaction of Girard reagent T with carbonyl compounds such as ketosteroids to generate corresponding hydrazone compounds, Michael addition reactions, dehydration reactions, and Schiff base synthesis; redox reactions such as amines and sulfides; and a series of organic synthesis reactions such as Mannich condensation. The kinetics of protein folding and unfolding catalyzed by metal ions have also been found to be significantly accelerated in water droplets. Water droplets play a role similar to that of catalysts and active centers in these micro- and nanoscale chemical reactions, and have become a powerful tool for researchers to explore new chemical reaction pathways and study rapid microsynthesis.

Let's take a look at the huge potential of these droplets, which can accelerate organic synthesis and provide a new method for nitrogen fixation.

3.1 Organic chemical synthesis

Organic reactions, as the basis for building many key industrial products and materials, play a vital role in the production of modern human society. Among them, the oxidation of aldehydes to carboxylic acids is one of the most basic and common types of organic reactions, and is widely used in the production of cosmetics, plasticizers, fibers, biomass-derived compounds, and pharmaceuticals. It can be said that the oxidation reaction of compounds such as hydrocarbons and aldehydes is a 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 Cr(IV)-based Jones oxidant, Ag(I)-based Tollen reagent, Cu(II)-based Fehling oxidant, or permanganate oxidant. Under the demand for long-term and large-scale production, the high cost and environmental damage brought by these traditional methods cannot be ignored.

As a natural oxidant, oxygen has excellent properties such as environmental friendliness, low cost, easy availability, and high atomic utilization rate. How to use gaseous oxygen to oxidize aldehydes to produce carboxylic acids has been a hot topic explored by academia and industry for a long time.

In 2018, Zare’s team attempted to use oxygen in water droplets to oxidize a variety of aldehydes to generate corresponding carboxylic acids [2]. The experimental results showed that under the action of water-ethanol droplets and nickel acetate catalyst, the aliphatic, aromatic and heterocyclic aldehyde compounds tested could be oxidized by oxygen to form corresponding carboxylic acids within 30 minutes under mild conditions, with a yield of 62%-91%.

Taking aldehydes (which are important raw materials for the synthesis of fine chemicals such as fragrances, dyes and medicines) as an example, under the same temperature, pressure and other conditions, in the control experiment of bubbling oxygen bubbles into the reactant solution, the yield of the corresponding carboxylic acid was less than 1%, which was only 1/50 of that in the droplet experiment. By adjusting the diameter and number of layers of the metal grid placed at the electrospray nozzle, the study found that the reaction yield increased with the decrease in the droplet diameter, and reached a maximum value when the diameter was 3 microns. On the contrary, when the droplet diameter is too large, such as 90 microns, the oxidation reaction yield is less than 5%. The relationship between droplet diameter and yield proves that the accelerating effect of droplets on the oxidation reaction of these aldehydes occurs at the gas-liquid interface that envelops the droplets.

Although the application of water droplets in actual organic synthesis such as aldehyde oxidation still requires a lot of in-depth research, the excellent catalytic efficiency and oxidizing properties exhibited by the droplets have demonstrated their application prospects in the field of chemical synthesis.

3.2 Non-biological methods for synthesizing biomolecules

Regarding the origin of life, water droplet research has brought new insights. The basic theory of the origin of life holds that the basic biological molecules such as peptides and nucleotides that originally existed in the ocean are necessary conditions for the origin of life. Life on Earth originated from water. However, before the birth of life, the surface of the earth was covered by the ocean. Excessive water molecules in the environment may hinder the dehydration reaction between amino acids, thereby affecting the production of peptides. Protein synthesis in organisms depends on the catalytic functions of various biological enzymes. In the absence of enzymes, how amino acids were converted into simple peptide molecules by non-biological methods in a natural environment is a key issue in the study of the origin of life.

Scientists studied the reaction of glycine (Gly) and alanine (Ala) in water droplets[5]. The experiment used electrospray ionization to generate water droplets containing only glycine or alanine, which diffused into the mass spectrometer at the back end at room temperature and pressure. The researchers found that dipeptides (GlyGly or AlaAla) were formed in the diffusing water droplets. The authors of the paper believe that it is the air-water interface of the water droplets that provides the necessary "drying" conditions, overcoming the thermodynamic barriers of the amino acid dehydration reaction in the liquid phase, thereby promoting the condensation reaction of amino acids under mild and catalyst-free conditions.

This discovery means that in the early ocean environment, water droplets may have played a key role in the birth of life: through their special air-water interface, they created favorable conditions for the dehydration reaction of amino acids, thereby promoting 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 when generated in aqueous solution. They have been found to be synthesized in water droplets under mild conditions under the action of magnesium ion catalysts [6]. These discoveries have made people re-understand the role of water in the origin of life and have also provided new inspiration for future life science research.

3.3 Nitrogen and carbon fixation

Recent research results of droplet chemistry have also shown magical effects in the fields of nitrogen fixation and carbon sequestration.

1% of total emissions. A 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 community 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].

The mass spectrometer signal gradually disappeared, indicating that the water droplets not only provided H atoms for urea molecules as a H source in the reaction, but their inherent special properties were also the key factor driving the reaction.

04 Acceleration Mechanism: Knowing the cause but not the reason

Behind the amazing experimental phenomena, researchers have also tried to understand the physicochemical mechanism of water droplets accelerating chemical reactions 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. Although there has been some progress in the study of the microscopic mechanism of accelerating chemical reactions, it is still far from mature and there is currently some controversy.

4.1 Air-water interface and strong electric field

To truly understand why water droplets accelerate chemical reactions, we must grasp and construct a realistic physical and chemical system, involving water chemistry and interface science at the microscopic scale. By comparing water droplets with liquid water, we can find clues.

First, the most intuitive difference between water droplets and bulk water is the increase in area-to-volume ratio due to the reduction in liquid diameter, that is, the increase in the air-water interface area per unit volume of water. By changing the diameter of the water droplets in the experiment and observing the changes in the reaction rate, we can determine the effect of the air-water interface in the water droplets on the reaction.

Another important feature of water droplets is the double electric layer formed on their surface, and the strong electric field generated within the extremely thin 1-2 angstroms (1 angstrom = 10^(-10) meters) of the air-water interface. From basic knowledge of electrostatic fields, we know that electric charges will be affected by electric field forces in an 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 large enough, the chemical bonds in the molecules will be activated or even dissociated, and the charged ions may also be rearranged under the action of the electric field, thereby promoting the related chemical reactions. In other words, only when the electric field on the surface of the water droplets is strong enough, can the water droplets accelerate the reaction through 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 crucial for the study of the mechanism of water droplets accelerating chemical reactions.

Due to the particularity of the air-water interface of water droplets, there are many challenges in directly measuring the electric field strength on the surface of water droplets in experiments, such as spatial resolution, measurement sensitivity, and the disturbances introduced by the measurement to the system. It was not until 2020 that Zare from Stanford University and Min Wei's team from Columbia University collaborated to use stimulated Raman excitation fluorescence spectrometer (SREF) to measure the vibrational Stark effect and obtained that the electric field strength on the surface of water droplets was about 10^9 V/m[8] . In 2022, Professor Teresa Head-Gordon of the University of California, Berkeley, applied the reaction force field model ReaxFF/C-GeM to simulate the electric field distribution and changes of water droplets with a diameter of 80-160 angstroms through molecular dynamics [9] . Calculations found that the electric field on the surface of water droplets showed a Lorentz distribution with an average value of 1.6 ×10^9 V/m. The above experimental and theoretical results all indicate that there is an electric field of up to 10^9 V/m on the surface of water droplets, which is sufficient to activate or break chemical bonds. At the same time, Ruiz-López et al. from the French National Center for Scientific Research believe that the electrostatic potential fluctuation effect caused by the dynamic reconstruction of the solvent on the droplet surface should not be ignored [10].

Recently, Zhang Xinxing's team at Nankai University in China used the strong electric field generated at the water-air interface to experimentally achieve catalytic acceleration of the Menshutkin reaction[11] . In addition, they achieved dehalogenation reaction through ultrafast electron transfer generated by the electric field at the interface of water droplets [12].

Charged droplets can also act as natural micro-batteries to drive chemical reactions involving water.

Therefore, many scholars believe that the strong electric field at the interface of water droplets is one of the important factors that promote chemical reactions.

4.2 Origin of surface charge on water droplets

Although experimental and theoretical studies have given consistent electric field strength on the surface of water droplets, the establishment of the surface electric field is ultimately due to the double electric layer formed by the distribution of positive and negative charges on the surface of water droplets. The source and existence of these positive and negative charges are still controversial, mainly divided into two views: water molecule ionization and hydrogen bond charge transfer.

A recent QM/MM simulation based on second-order perturbation theory found that there is continuous non-uniform charge transfer between water molecules on the surface of water droplets. The charge transfer of a single interfacial water molecule can reach up to ±0.2 e, which is much higher than the previous estimate of the charge transfer probability, thus generating a large number of partially charged water radicals. Calculations of the reaction between important CI (Criegee intermediates) molecules in the atmosphere and water droplets show that interfacial charge transfer increases the reactivity of CI molecules and water molecules, greatly reduces the reaction activation energy, and promotes the rapid occurrence of the reaction [14].

4.3 Other mechanisms

In addition to the strong electric field present at the air-water interface of water droplets, there are other possible mechanisms for accelerating chemical reactions:

1) Lower dissolution energy. Theoretically, reactants only need to partially dissolve at the air-water interface when they dissolve in water droplets, thus reducing the energy barrier for complete dissolution of reactants.

2) Orderly arrangement of reactant molecules at the air-water interface. Both experimental and theoretical studies have pointed out that due to the electric field on the surface of water droplets, some reactant ions or intermediates will form an orderly arrangement along a specific direction. The orderly arrangement of reactant molecules will reduce the entropy of the initial state of the reaction and increase the Gibbs free energy accordingly, thereby reducing the free energy change of the overall reaction.

3) Rapid evaporation of water droplets. As the water droplets evaporate rapidly in the air, the concentration of reactants in the water droplet system will increase significantly, causing the chemical equilibrium to shift positively.

In short, the current development of the mechanism of water droplets accelerating chemical reactions mainly revolves around the role of the air-water interface. Of course, the existence form of the reactants in the water droplets, and the interaction between the water droplets and the reactants and products during the reaction process are also important factors affecting the reaction rate.

05Summary : Challenges and opportunities coexist

Although droplet chemistry has only been around for a decade, it has quickly become the focus of the chemical community. Its research scope has rapidly expanded from initial analysis and synthesis to multiple fields and disciplines such as biology, medicine, energy, and catalysis. Although water droplets have broad application prospects, their microscopic mechanism of action still needs in-depth research and exploration. In addition, although studies have found that water droplets can 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 groups and ketosteroids. For reactions of non-polar molecules, 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, where experiments show that most of the reactants remain. From an application perspective, the difficulty in producing small-volume 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 reaction yields may be the key factor in determining whether 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 huge challenge and a rare opportunity. We all look forward to more breakthroughs in the research and application of water droplet chemistry in the future.

References

[1] Girod, Marion, et al. "Accelerated bimolecular reactions in microdroplets studied by desorption electrospray ionization mass spectrometry." Chemical Science 2.3 (2011): 501-510.

[2] Yan, Xin, Yin-Hung Lai, and Richard N. Zare. "Preparative microdroplet synthesis of carboxylic acids from aerobic oxidation of aldehydes." Chemical science 9.23 (2018): 5207-5211.

[3] Lee, Jae Kyoo, et al. "Spontaneous generation of hydrogen peroxide from aqueous microdroplets." Proceedings of the National Academy of Sciences 116.39 (2019): 19294-19298.

[4]Dan Gao, et ak. "Aqueous microdroplets containing only ketones or aldehydes undergo Dakin and Baeyer–Villiger reactions." Chemical Science 10.48 (2019): 10974-10978.

[5] Holden, Dylan T., Nicolás M. Morato, and R. Graham Cooks. "Aqueous microdroplets enable abiotic synthesis and chain extension of unique peptide isomers from free amino acids." Proceedings of the National Academy of Sciences 119.42 (2022): e2212642119.

[6] Nam, Inho, Hong Gil Nam, and Richard N. Zare. "Abiotic synthesis of purine and pyrimidine ribonucleosides in aqueous microdroplets." Proceedings of the National Academy of Sciences 115.1 (2018): 36-40.

[7] Song, Xiaowei, Chanbasha Basheer, and Richard N. Zare. "Making ammonia from nitrogen and water microdroplets." Proceedings of the National Academy of Sciences 120.16 (2023): e2301206120.

[8] Xiong, Hanqing, et al. "Strong electric field observed at the interface of aqueous microdroplets." The journal of physical chemistry letters 11.17 (2020): 7423-7428.

[9] Hao, Hongxia, Itai Leven, and Teresa Head-Gordon. "Can electric fields drive chemistry for an aqueous microdroplet?." Nature communications 13.1 (2022): 280.

[10] Martins-Costa, Marilia TC, and Manuel F. Ruiz-López. "Electrostatics and chemical reactivity at the air–water interface." Journal of the American Chemical Society 145.2 (2023): 1400-1406.

[11] Song, Zhexuan, et al. "Harnessing the High Interfacial Electric Fields on Water Microdroplets to Accelerate Menshutkin Reactions." Journal of the American Chemical Society 145.48 (2023): 26003-26008.

[12] Zhu, Chenghui, et al. "High Electric Fields on Water Microdroplets Catalyze Spontaneous and Fast Reactions in Halogen-Bond Complexes." Journal of the American Chemical Society 145.39 (2023): 21207-21212.

[13] Ben-Amotz, Dor. "Electric buzz in a glass of pure water." Science 376.6595 (2022): 800-801.

[14] Liang, Qiujiang, Chongqin Zhu, and Jun Yang. "Water Charge Transfer Accelerates Criegee Intermediate Reaction with H2O–Radical Anion at the Aqueous Interface." Journal of the American Chemical Society 145.18 (2023): 10159-10166.

[15] Colussi, Agustín J. "Mechanism of Hydrogen Peroxide Formation on Sprayed Water Microdroplets." Journal of the American Chemical Society (2023).

[16] Gallo Jr, Adair, et al. "On the formation of hydrogen peroxide in water microdroplets." Chemical Science 13.9 (2022): 2574-2583.

This article is supported by the Science Popularization China Starry Sky Project

Produced by: China Association for Science and Technology Department of Science Popularization

Producer: China Science and Technology Press Co., Ltd., Beijing Zhongke Xinghe Culture Media Co., Ltd.

Special Tips

1. Go to the "Featured Column" at the bottom of the menu of the "Fanpu" WeChat public account to read a series of popular science articles on different topics.

2. Fanpu provides a function to search articles by month. Follow the official account and reply with the four-digit year + month, such as "1903", to get the article index for March 2019, and so on.

Copyright statement: Personal forwarding is welcome. Any form of media or organization is not allowed to reprint or excerpt without authorization. For reprint authorization, please contact the backstage of the "Fanpu" WeChat public account.