Traditionally, scientists believed that water couldn’t be as effective as an organic solvent because of the idea that “like dissolves like.” Since many catalysts and reagents show sensitivity to moisture, water was often excluded as a potential solvent in favor of other substances.
However, recent research proves that water can be a very effective solvent for carrying out organic reactions. Water is also more environmentally friendly than many organic solvents such as ethanol, acetone, or benzene. Since the Montreal Protocol of 1987 began phasing out other ozone-depleting chemicals, organic chemists have been looking for greener alternatives for chemical reactions. Now, it appears that many organic transformations can be achieved either in water or on water without using harmful chemicals or volatile organic compounds (VOCs) as solvents.
Thanks to increased research and successful experiments, water may now become a better alternative for organic transformations in terms of enhanced reaction rates and less toxicity. It’s a paradigm shift for organic chemistry that can improve not only green chemistry approaches, but also the many applications of organic reactions like drug development.
What are in-water and on-water reactions?
In-water reactions involve chemical processes occurring in an aqueous medium. Also known as homogeneous systems, these reactions include pericyclic reactions, reactions of carbanion equivalent, reactions of carbocation equivalent, reactions of radicals and carbene, and oxidation-reduction reactions. In 1980, scientists reported the first successful instances of Diels-Alder cycloadditions in water that not only worked but exhibited dramatically enhanced reaction rates and selectivity compared to organic solvents.
A further boost to water as a solvent came from the concept of on-water reactions, introduced by Sharpless et. al to describe reactions of water-insoluble organic compounds that take place in aqueous suspensions (see Figure 1).
These on-water reactions, also called heterogeneous systems, take place at the interface of water and organic substances, often without requiring the organic compound to dissolve in water. Examples include Diels–Alder reactions, 1,3-Dipolar Cycloadditions, Claisen Rearrangement, Passerini, and Ugi reactions.
How do these reactions work? There are important distinctions between in-water and on-water (see Figure 2).
![Figure 2: Hydrogen bonding between water molecules (in-water) and substrate and water (on-water) facilitates the reaction. Source: [ref.]](https://cdn.prod.website-files.com/650867962272bf8f15c1034b/685edbe035f2c251e2101c7a_b09cf6b2.png)
The internal pressure indicates the energy required to form a cavity by reorienting interfacial water molecules, whereas the cohesive energy density pertains to the energy needed to create a cavity by completely disrupting water-water interactions. The internal pressure is the key factor for small solutes, while the cohesive energy density is more significant for larger solutes. This involves rearranging the water structure at the oil/H₂O interface.
When small, dilute solutes are present, the aqueous interface remains largely undisturbed because water molecules can rearrange themselves to prevent the loss of hydrogen bonds to the hydrophobic entity. According to the "iceberg model," the first layers of water around small, non-polar solutes form a clathrate or hydrogen-bonded cluster to avoid "wasting" hydrogen bonds on the solute. As the temperature rises, the "icy" shell structure around hydrophobic molecules breaks down before the bulk water structure does.
This shift from entropy-driven to enthalpy-driven behavior explains the high heat capacity of water during hydration. Additionally, various van der Waals interactions between water and solutes, as well as between solutes themselves, contribute to the enthalpy value.
As noted, increased reaction rates for Diels-Alder reactions were found during on-water experiments. The formation of hydrogen bonds between the dangling –OH groups and the lipophilic substrates contributes to catalyzing and increasing the rate of these reactions. These hydrogen bonds are stronger in the transition state than at the initial state of reaction.
During in-water reactions, when water surrounds small hydrophobic solutes, the hydrogen bonds within the clathrate structure must be broken to activate the substrates, which requires more energy. Consequently, an "H-bonding catalyst" effect is also suggested for small entities, but to a lesser extent due to this energy cost. This explains why the reaction is slower compared to its heterogeneous counterpart. However, the reaction is still accelerated because the energy needed to break the interfacial hydrogen bonds is lower than that required in bulk water.
Research spikes as green chemistry takes off
While initial experiments were completed decades ago, it’s only been in the last 10 to 15 years that the use of water as a solvent has substantially increased in organic transformations. We examined the CAS Content CollectionTM, the largest human-curated repository of scientific information, and found that it was only after 2010 that journal and patent publications notably accelerated (see Figure 3).
We also found that while journal publications experienced a steady increase, patent publications showed more volatility over time. Patent activity declined significantly between 2008-2018, which can be attributed to several possible factors: the global economic recession that constrained R&D investments, technical challenges in scaling laboratory successes to industrial applications, and the competitive emergence of alternative green chemistry approaches. However, since 2018, there has been a strong resurgence of patent activity, indicating renewed industrial confidence driven by technological advancements and expanded application potential.
We further analyzed key concepts in the literature of water-mediated organic reactions to better understand current research priorities (see Figure 4). This analysis confirms that oxidation, cyclization, and green chemistry are the leading areas of interest in this field.
The predominance of these topics, along with alkene synthesis and C-C bond formation reactions, suggests that researchers have prioritized developing fundamental reaction methodologies that can operate efficiently in water. The high ranking of green chemistry concepts confirms that environmental sustainability is a primary driver for research in this field.
Synthetic applications of aqueous solvents
Both in-water and on-water methodologies have demonstrated remarkable advantages with efficiency, selectivity, and potential rate acceleration. For example, the on-water Diels-Alder reaction was completed in just 10 minutes, compared to organic solvents that took hours. The ubiquity of this reaction across organic chemistry applications means that numerous organic synthesis types could be completed faster and with fewer toxic solvents.
Drug development and creating hydrogels for drug delivery are potential biomedical applications of the Diels-Alder reaction. The synthesis of polymers and even nanomaterials — which can also assist in drug delivery — are important applications of this reaction as well, and they can benefit from more efficient, safer methodologies.
Our analysis of the CAS Content Collection also revealed which reactions dominate the current literature, and while Diels-Alder is one of the leaders, we found that Suzuki Coupling and Sonogashira Coupling reactions are the most prevalent (see Figure 5).
Suzuki Coupling is critical for synthesizing complex compounds, such as pharmaceuticals and fine chemicals. Boronic acid has also been found to react efficiently in aqueous media due to its stability. Sonogashira Coupling is another important reaction for drug development. The dominance of these coupling reactions in the literature suggests there is interest in catalyst design for aqueous compatibility. It also means that drug development, among other organic applications, may be enhanced by using water as a solvent.
The future of water as a solvent
The standardization of sustainability metrics across chemical research and industrial sectors has elevated the importance of using water as a solvent. Increasingly stringent worldwide regulations governing solvent usage, especially within pharmaceutical production, are driving faster industry-wide implementation of aqueous synthetic approaches. The environmentally friendly nature of water, combined with its efficiency for these reactions, makes it a valuable alternative to other solvents and a key component of green chemistry efforts going forward.
In-water and on-water methodologies are poised to revolutionize the development of pharmaceutical ingredients and fine chemicals, including peptides, alkaloids, and complex heterocyclic compounds. These sustainable approaches will advance the synthesis of pharmaceutical compounds through improved asymmetric synthesis and catalysis techniques.
The benefits of this shift are multifaceted: accelerated development of life saving medications and critical compounds, improved reaction efficiency and selectivity in aqueous environments, and enhanced environmental sustainability. By utilizing water as nature's solvent instead of toxic organic solvents, these methodologies will significantly reduce environmental impact while maintaining or improving synthetic performance.
