Water is the lingua franca of life on our planet and is the solvent of choice for Nature to carry out her syntheses.1 In contrast, our methods of making complex organic molecules have taken us far away from the watery milieu of biosynthesis. Indeed, it is fair to say that most organic reactions commonly used both in academic laboratories and in industry fail in the presence of water or oxygen. As a direct consequence of our attempts to mimick Nature's way of making new chemical bonds, we learned to rely on highly reactive nucleophilic and electrophilic reagents to gain control of the chemical reactivity and to channel chemical reactions down a desired pathway. The requirement for the protection of all protic functional groups, such as alcohols and amines, is another corollary of our reliance on these energetic species. Nevertheless, chemical transformations in aqueous solvents are not new to organic chemists. On the contrary, they have attracted attention of scientists for many years: the first use of water for an organic reaction could be dated back to Wohler's synthesis of urea from ammonium cyanate.2 From a true organic synthesis perspective, the earliest example could be the synthesis of indigo by Baeyer and Drewsen in 1882 (Scheme 1).3 In their synthesis, a suspension of o-nitrobenzaldehyde 1 in aqueous acetone was treated with a solution of sodium hydroxide. The immediate formation of the characteristic blue color of indigo 2 ensued, and the product subsequently precipitated.



Scheme 1



Water possesses many unique physical and chemical properties: large temperature window in which it remains in the liquid state, extensive hydrogen bonding, high heat capacity, large dielectric constant, and optimum oxygen solubility to maintain aquatic life forms. These distinctive properties are the consequence of the unique structure of water.4,5 The structure and properties of water have been studied by scientists representing almost all fields of knowledge, and new theoretical models continue to emerge.6,7 Water is also known to enhance the rates and to affect the selectivity of a wide variety of organic reactions.8,9

In spite of these potential advantages, water is still not commonly used as a sole solvent for organic synthesis, at least in part because most organic compounds do not dissolve in water to a significant extent, and solubility is generally considered a prerequisite for reactivity: “corpora non agunt nisi soluta” (substances do not react unless dissolved). Consequently, in the many examples of “aqueous reactions” organic co-solvents are employed in order to increase the solubility of organic reactants in water.9,10 Alternatively, hydrophilicity of the reactants is increased by the introduction of polar functional groups, again to make the resulting compound at least partially water soluble.11 However, these manipulations tend to diminish and even negate the advantages of low cost, simplicity of reaction conditions, ease of workup, and product isolation that water has over traditional solvents. Therefore, the currently burgeoning field of organic synthesis in aqueous media encompasses a large family of reactions. The solubility of reacting species and products can range from complete to partial to practically none, so that reaction mixtures can be both homogeneous and heterogeneous. The amount of water can also range widely, from substoichiometric quantities to a large volume in which the reactants are suspended or dissolved. Several terms have been used in the literature to describe reactions in aqueous millieu. In water, in the presence of water, and on water are commonly found in the recent publications and are often used interchangeably to describe reactions that proceed under very different conditions.12,13 There is also a growing number of examples micellar catalysis in the presence of non-ionic surfactants, such as Triton X-100 and PTS (a tocopherol-based amphiphile).14-18

In this review, we attempt to survey organic transformations that benefit from being performed on water under the conditions defined by Sharpless and co-workers: when insoluble reactant(s) are stirred in aqueous emulsions or suspensions without the addition of any organic co-solvents. In many cases, it is impossible to ascertain whether the reaction is occuring in or on water, but as long as the reaction mixture remains heterogeneous and the overall process appears to benefit from it (either in terms of increased reaction rate or enhanced selectivity), it qualifies.

The ‘on water’ moniker reflects the defining attribute of these reactions: the lack of solubility of the reactant(s) in water. A considerable rate acceleration is often observed in reactions carried out under these conditions over those in organic solvents.19 Furthermore, in many cases a significant rate increase of on water reactions over reactions carried out neat indicates that rate acceleration is not merely a consequence of increased concentration of the reacting species. Naturally, the degree of on water acceleration varies between different reaction classes, and even when it is modest, there are other advantages to carrying out reactions in this manner. Firstly, water is an excellent heat sink due to its large heat capacity, making exothermic processes safer and more selective, especially when they are carried out on large scale. Secondly, reactions of water-insoluble substrates usually lead to the formation of water-insoluble products. In such cases, product isolation simply involves filtration of solid products (or phase separation in case of liquids). Finally, the growing list of examples wherein reactions performed on water are not only faster but also more selective (whether chemo-, regio-, or enantio-) underscores the significant potential for process intensification for reactions performed on water.

Although claims of the ecological advantages and “greenness” of water are almost invariably found in the opening paragraphs of reports describing aqueous reactions, they should be taken with a grain of salt. The low cost, relative abundance, and inherent safety of water notwithstanding, the environmental impact of a process is determined by many factors, such as the efficiency of the reaction in terms of atom economy,20 the nature of solvents used in the reaction workup, the residual concentration of regulated organic compounds and metal catalysts remaining in the aqueous waste, and the costs of its clean up or disposal.21,22 The mere finding that a process performs as well in water as it does in an organic solvent tells us little about its potential environmental impact.

The field of aqueous organic synthesis has been regularly and comprehensively reviewed.9,10,23-27 In addition, recent reviews focusing on microwave assisted organic synthesis in water,28 reactions in near-critical water,29 and biocatalysis in water30 have been published. Accordingly, these topics are not covered in the present review.

Organic Synthesis “On Water”

Sum-Frequency Vibrational Spectroscopy on Water Interfaces: Polar Orientation of Water Molecules at Interfaces

3.1.2. Huisgen [3 + 2] Cycloaddition Reaction 6313 3.1.3. Claisen Rearrangement 6315 3.2. Multicomponent Reactions 6316 3.3. Nucleophilic Ring-Opening Reactions 6316 3.4. Wittig Reaction 6318 3.5. Bioorthogonal Reactions 6318 4. Catalyzed Reactions 6319 4.1. Metal-Catalyzed Reactions 6319 4.1.1. Pericyclic Reactions 6320 4.1.2. Arylation Reactions 6321 4.1.3. Olefin Metathesis 6323 4.1.4. Mizoroki-Heck Reaction 6324 4.1.5. Suzuki Reaction 6325 4.1.6. Sonogashira Reaction 6327 4.1.7. Transfer Hydrogenation 6327 4.1.8. Lewis Acid Catalysis 6328 4.2. Organocatalyzed Reactions 6330 4.2.1. Pericyclic Reactions 6330 4.2.2. Michael Reaction 6331 4.2.3. Mannich Reaction 6332 4.2.4. Aldol Reaction 6333 5. Conclusion 6334 6. Supporting Information Available 6335 7. References 6335

Water: Nature’s Reaction Enforcer—Comparative Effects for Organic Synthesis “In-Water” and “On-Water”

The study of the interactions of salts and osmolytes with macromolecules in aqueous solution originated with experiments concerning protein precipitation more than 100 years ago. Today, these solutes are known to display recurring behavior for myriad biological and chemical processes. Such behavior depends both on the nature and concentration of the species in solution. Despite the generality of these effects, our understanding of the molecular-level details of ion and osmolyte specificity is still quite limited. Here, we review recent studies of the interactions between anions and urea with model macromolecular systems. A mechanism for specific ion effects is elucidated for aqueous systems containing charged and uncharged polymers, polypeptides, and proteins. The results clearly show that the effects of the anions are local and involve direct interactions with macromolecules and their first hydration shell. Also, a hydrogen-bonding mechanism is tested for the urea denaturation of proteins with some of these same systems. In that case, direct hydrogen bonding can be largely discounted as the key mechanism for urea stabilization of uncollapsed and/or unfolded structures.

/pdf/chemistry-of-hofmeister-anions-and-osmolytes-4bblt2re7s.pdf

Chemistry of Hofmeister anions and osmolytes.

Molecular structure of water at interfaces: wetting at the nanometer scale.

A phase-sensitive sum-frequency vibrational spectroscopic technique is developed to study interfacial water structure of water/quartz interfaces. Measurements allow deduction of both real and imaginary parts of the surface nonlinear spectral response, revealing an unprecedentedly detailed picture of the net polar orientations of the water species at the interface. The orientations of the icelike and liquidlike species appear to respond very differently to the bulk pH change indicating the existence of different surface sites on quartz with different deprotonation pK values.

New Information on Water Interfacial Structure Revealed by Phase-Sensitive Surface Spectroscopy

Phase-sensitive sum-frequency spectroscopy provides correct characterization of vibrational resonances of water-vapor interfaces and allows better identification of interfacial water species contributing to different parts of the spectra. Iodine ions emerging at an interface create a surface field that tends to reorient the more loosely bonded water molecules below the topmost layer.

Characterization of Vibrational Resonances of Water-Vapor Interfaces by Phase-Sensitive Sum-Frequency Spectroscopy

The first general phase-sensitive sum-frequency vibrational spectroscopy (SFVS) was described, which recovers the phase information lost in conventional SFVS measurements. Using a self-assembled monolayer, we demonstrated that this novel technique measures the absolute orientation of surface molecular moieties and is very powerful in resolving spectral features.

Victor Petrovich Ostroverkhov

Papers

Sum-Frequency Vibrational Spectroscopy on Water Interfaces: Polar Orientation of Water Molecules at Interfaces

New Information on Water Interfacial Structure Revealed by Phase-Sensitive Surface Spectroscopy

Characterization of Vibrational Resonances of Water-Vapor Interfaces by Phase-Sensitive Sum-Frequency Spectroscopy

Phase-Sensitive Sum-Frequency Vibrational Spectroscopy and Its Application to Studies of Interfacial Alkyl Chains

Vibrational spectra of water at water/alpha-quartz (0001) interface