Organic Synthesis in Water
These include oxidations, reductions, carbon— carbon and carbon—heteroatom bond-forming reactions. All of these topics have been recently reviewed, 23 , 94 , 95 and therefore only several illustrative transformations that exhibit the on water reactivity enhancements will be covered in the section below. Transformations of acetylenes catalyzed by transition metals figure prominently in this field. Water appears to be an ideal solvent capable of supporting copper I acetylides in their reactive state, especially when they are formed in situ.
The copper I -catalyzed azide-alkyne cycloaddition CuAAC reaction is a striking example of the unique reactivity of copper I acetylides in water. When the acetylide is generated by the in situ reduction of a copper II salt or from copper metal in water with or without an organic co-solvent, as reported by the groups of Fokin and Sharpless, its reaction with organic azides cleanly proceeds in nearly quantitative yields, does not require any ligands, nor does the reaction mixture need to be protected from oxygen. In contrast, when the reaction is performed in organic solvents using copper I iodide as the catalyst, as reported independently by the group of Meldal, the addition of N -diisopropylethyl amine is required, and the reaction is plagued by the formation of oxidative coupling byproducts unless the alkyne is bound to a solid support Scheme The very broad scope, compatibility with most functional groups, exclusive regioselectivity, and operational simplicity have placed CuAAC among the most widely utilized click processes.
Another example of the aqueous transition metal-catalyzed alkyne chemistry is the aldehyde— alkyne—amine A 3 coupling reaction and its asymmetric variants, developed by Li and co-workers. In a subsequent report, the same authors described that the A 3 coupling could be catalyzed by gold salts Scheme The reaction was significantly faster in water than in dimethylformamide or toluene. Aromatic and aliphatic aldehydes and amines participated in the reaction, and nearly quantitative yields were obtained in most cases.
Different gold I and gold III salts, e. Another example of a gold-catalyzed on water synthesis of heterocycles from alkynes was reported by Che. The tricyclic pyrrolo[1,2- a ]quinolines were obtained from N -alkynyl anilines and alkynes in the presence of a Au I catalyst Scheme Several examples of the pyrrolo[1,2- a ]quinolines products illustrate the scope of the process.
A combination of Pd II and Cu I catalysts efficiently promoted the addition of terminal alkynes to ynones Scheme A one-pot rhodium-catalyzed hydrostannylation-conjugate addition reaction was developed by Li and Wu Scheme Bhattacharya and Sengupta described exceedingly facile on water Sonogashira reactions of aryl iodides and bromides. The reactions of aryl iodides were facilitated by the addition of diisopropylethylamine, and those of aryl bromides proceeded best in the presence of pyrrolidine. It is noteworthy that the addition of organic co-solvents e.
In another account of the on water Sonogashira reaction by Beletskaya and co-workers, diaryl alkynes, such as — , were synthesized from aryl iodides and phenylacetylene Scheme The inertness and relatively high solubility of boronic acids in water makes them particularly suitable reagents for aqueous transformations.
The boronic acid Mannich reaction, discovered by Petasis and co-workers, , and Suzuki-Miyaura couplings in aqueous solvents are well known. The aqueous Suzuki-Miyaura reactions are often performed at the elevated temperature and in the presence of water-soluble catalysts. The authors developed a highly-active water-soluble palladium catalyst based on the water-soluble phosphine and utilized it in Suzuki-Miyaura and Sonogashira coupling reactions.
Excellent substrate scope, both with respect to the halide and the boronic acid, was reported. These reactions proceeded as well in organic solvents. Highly efficient hydrosilylation of terminal alkynes - by triethyl silane was performed on water using a Pt catalyst Scheme Wang and Liao reported that the Doyle-Kirmse [2,3]-sigmatropic rearrangements of sulfonium ylides readily proceeded on water Scheme 54 in nearly quantitative yields in the presence of 0.
Allyl and propargyl sulfides readily participated in the reaction. Solid reactants were pre-dissolved in toluene before they were added to the reaction mixture. Afonso and coworkers demonstrated that selective intramolecular C-H insertion reactions of rhodium carbenes can be performed on water Scheme 55 using Rh II carboxylates if the substrate was sufficiently hydrophobic. Yorimitsu and co-workers developed an efficient Ni-catalyzed alkylation of aldehydes with alkylboranes on water Scheme Ketones were readily obtained on water at room temperature without a base additive.
Shinokubo and co-workers reported a three-component rhodium catalyzed coupling of aryl boronic acids with internal alkynes and acrylates. Substituted dienes Scheme 57 were obtained in good yields under the on water conditions, whereas the 1,4-addition of the boronic acid to the acrylate was observed in dioxane-water mixtures product , and the simple Heck-type products were isolated from the biphasic reactions performed in diisopropyl ether-water mixtures.
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Water soluble ligands did not affect the reaction. A general on water method for the direct arylation of thiazoles Table 15 was disclosed by Greaney and co-workers.
The reaction exhibited excellent substrate scope, as illustrated by the examples in Table Using the same on water protocol, thiazoles, benzoxazoles, benzimidazoles, and thiophenes - were arylated in good yields. A high-yielding and selective arylation of oxazoles was accomplished on water using Pd dppf Cl 2 catalyst Scheme The reaction was utilized in the synthesis of two oxazole-containing natural products, balsoxin and texaline.
A variety of diaryl sulfides were obtained in good yield Scheme Bergdahl and co-workers studied Wittig reactions of stabilized ylides Table 16 on water. Aldehydes containing both electron-donating and electron-withdrawing groups participated in the reaction. The addition of lithium chloride increased the yields while a surfactant, sodium dodecylsulfonate, had little effect on the outcome of the process.
Li and co-workers described an on water dehydrogenative coupling reaction.
Water in Organic Synthesis
The reaction of indoles with 1,4-benzoquinone readily occurred without a catalyst Scheme The reactants were insoluble in water and formed aqueous suspensions when the reaction mixtures were vigorously stirred. When the reaction was carried out in the presence of excess of indole, bis indolyl -1,4-quinones Scheme 63 were obtained in excellent yield.
A three-component coupling of aldehydes with propiolates to produce propargylic enol ethers Scheme 64 was reported by Tellado et al. One of the most remarkable on water processes was reported in by Guss and Rosenthal. The product bromohydrins cleanly separated from the water phase, while the succinimide by-product remains in it. A number of olefins were efficiently oxidized in this manner.
Guss and Rosenthal also showed that the corresponding epoxides could be accessed by heating the product bromohydrins in aqueous NaOH solution. The gradual addition of both peroxide and hyhdrobromic acid considerably increased the yield. Comparison with a commonly used organic solvent showed that reactions went much faster under on water conditions.
A variety of monobrominated products - were accessed by this method.
Organic Synthesis in Water
The same authors also studied benzylic brominations with N -bromosuccinimide. These Wohl— Ziegler-type reactions are normally performed in boiling carbon tetrachloride. However, Iskra and colleagues showed that these brominations could be accomplished on water with good to excellent yield Scheme For example, benzylmethylketone was selectively brominated at the benzylic carbon. However, the authors also reported that particularly activated aromatic substrates suffered from the competing aromatic bromination: The succinimide byproduct is soluble in water, whereas the brominated product forms a separate phase, making its separation easy.
Stavber and coworkers reported an example of bromination where a specific site selectivity Scheme 68 was achieved by performing the reaction in water. Water is a relatively red-ox inert molecule. In addition to being difficult to oxidize, it is supportive of a variety of chemical and electrochemical oxidants as well as transition metal catalysts. Hence it could be a useful solvent for oxidations and reductions of organic compounds. Indeed, aqueous organic oxidations and reductions are some of the oldest fields in catalysis, and their comprehensive coverage is well beyond the scope of the present review.
Accordingly, only a handful of recent examples which meet the on water criteria are mentioned below. For the additional coverage, the reader is referred to recent review literature. In a recent report, Malkov and Bourhani developed a catalyzed epoxidation of allylic alcohols with the in situ generated vanadium catalyst Scheme While these epoxidations also proceeded in toluene, the aqueous reactions were ligand-accelerated and only required a stoichiometric amount of the ligand with respect to vanadium.
Li and co-workers disclosed a catalyst-free on water oxidation of aromatic silyl enol ethers Several representative examples of the obtained products - illustrate the scope of this method. Tour and Price reported a unique way for functionalizing single walled carbon nanotubes in water Scheme Tris trimethylsilyl silane was used to reduce several organohalides , with 2-mercaptoethanol as co-catalyst under on water conditions Scheme Me 3 Si 3 SiH did not suffer from any side reactions with water.
This method was subsequently used in several radical transformations of both hydrophobic and hydrophilic substrates. The addition of 2-mercaptoethanol was required for the reactions of hydrophilic substrates. An efficient and chemoselective transfer hydrogenation reaction on water was reported by Xiao and coworkers Scheme The on water reactions were fast and high-yielding, and diversely substituted aryl and heteroaryl aldehydes — participated in the reaction.
The requirement for the heterogeneous on water conditions was demonstrated in a comparative study of aldehydes and The water-insoluble ester was readily and quantitatively reduced to the corresponding alcohol, whereas the carboxylate salt did not react at all. Reactions of aliphatic aldehydes were complicated by the competing aldol condensation. Therefore, enolizable aldehydes required slow addition to suppress this undesired pathway. Transfer hydrogenation reactions in water have been recently reviewed by Xiao.
To date, there is no unifying theory that could explain the effects of heterogeneous aqueous conditions on organic reactions. The possibility of the water—organic interface acting as a catalyst for the on water reactions is very enticing. Rate acceleration in homogeneous aqueous solution has been attributed to a variety of effects such as hydrophobic aggregation, 34 , 35 , cohesive energy density, - or destabilization of the reactants vs. An excellent review on the structure and properties of water, which helps rationalize rate enhancements observed for organic reactions in aqueous media, has been published recently.
Lubineau and Pirrung invoked the concept of cohesive energy density to explain the observed rate acceleration of heterogeneous aqueous reactions. Cohesive energy of a solvent is the energy required to remove a molecule from its nearest neighbors in the bulk, leading to the creation of a cavity, factored by the volume of the molecule removed. The cohesive energy of water corresponds to the internal pressure of ca.
The early experiments to test this theory were reported by Lubineau in and in the subsequent full account. Although hydrophobic effect and CED models may explain rate accelerations in some aqueous reactions, they require that organic reactants have certain solubility to enter the aqueous phase, however minute the amounts may be.
Additionally, an attempt to correlate the reaction rates with cohesive energy density of the solvent for a bimolecular reaction dimerization of cyclopentadiene, a negative volume of activation reaction and a unimolecular reaction dissociation of the dimer of triphenylmethyl radical, a positive volume of activation reaction failed, leading to the conclusion that the concept of cohesive pressure is useful only for reactions of neutral, non-polar molecules in non-polar solvents. In reactions involving polar molecules, or reactions in polar solvents, the contribution of cohesive pressure is simply negligibly small comparing to the solvation interactions.
The unique features of the water-organic interface can offer an alternative explanation of the reactivity of particularly hydrophobic organic substrates on water. Recently, Jung and Marcus proposed a model which suggests that interactions of hydrophobic organic molecules with water surface may be responsible for the rate enhancement observed on water. Simple kinetic considerations demonstrated that the reaction on water should be faster than reactions under homogeneous and neat conditions. The difference in solvation pattern in cases of on and in water conditions is shown in Scheme Cartoon representation of the differences in solvation patterns on water and in water.
Further DFT studies of the reaction between quadricyclane and DMAD demonstrated that there is an increase in the number of hydrogen bonds between the water surface and the reactants and the transition state shown as red dashed lines in Scheme The Jung-Marcus proposal is that these additional hydrogen bonds stabilize the transition state and therefore explain the experimentally observed rate acceleration. Energy calculation of each species under neat and on water conditions showed that the transition state of the on water reaction TSw, Scheme 78 is stabilized by 7. Based on these calculations, the authors also predicted that a reaction between quadricyclane and acetylene dicarboxylate would not show the on water effect.
This prediction has been confirmed experimentally.
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Performing organic reactions in water with substrates that are not soluble seems counterintuitive at first. We hope that this survey convinced the reader that attempting such heterogeneous reactions in water is a worthwhile endeavor. Apart from discovering new or improving existing organic transformations, it will surely give us a glimpse into the fascinating and still poorly understood world of water.
Like a growing child, organic synthesis on water still surprises us by most unexpected questions and observations. Freeing it from the stereotypes and constraints with which we grew up will propel it a prominent place in the arsenal of tools of synthetic organic chemists. Perhaps one day water will become the most used solvent in synthesis, and the ones that are considered common and conventional today will take an honorable place on the rare chemicals shelf. AC acknowledges a postdoctoral fellowship from Pfizer. National Center for Biotechnology Information , U.
Author manuscript; available in PMC Apr Arani Chanda and Valery V. The publisher's final edited version of this article is available at Chem Rev. See other articles in PMC that cite the published article. Introduction Water is the lingua franca of life on our planet and is the solvent of choice for Nature to carry out her syntheses.
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Open in a separate window. On Water Reactions 2. Table 1 Rate constants for the Diels—Alder reaction of 3 and 4 in different solvents. Table 3 Cycloaddition of enal 6 with diene 7. Table 4 Diels—Alder Reaction of 10 and 11 in different solvents. Cycloadditions of Azodicarboxylates Reactions of azodicarboxylates with unsaturated hydrocarbons are powerful C—N bond forming processes. Table 7 Solvent effects on the reaction of 57 with Claisen Rearrangement In , Gajewski, Ganem, Carpenter and co-workers reported a detailed experimental and mechanistic study of the rearrangement of chorismic acid to prephenic acid, an important step in the shikimic acid pathway.
Passerini and Ugi Reactions Multicomponent reactions provide rapid access to chemical diversity by combining several reactants into densely functionalized molecules. Nucleophilic opening of three-membered rings Nucleophilic openings of three-membered rings, such as epoxides and aziridines, are important and reliable methods for making carbon—heteroatom bonds because the competing elimination processes are stereoelectronically disfavored.
Nucleophilic substitution reactions An example of an efficient nucleophilic substitution reaction was reported by Finn, Sharpless and co-workers. Transformations Catalyzed by Transition Metals The stereotypical notion that organometallic reagents are not compatible with water stems from the extreme basicity and rapid hydrolysis of organolithium and organomagnesium compounds, the organometallic reagents on which most organic chemists have been educated. Table 15 Arylation of 2-phenylthiazole Bromination Reactions One of the most remarkable on water processes was reported in by Guss and Rosenthal.
Oxidations and reductions Water is a relatively red-ox inert molecule. Theoretical studies To date, there is no unifying theory that could explain the effects of heterogeneous aqueous conditions on organic reactions. Concluding remarks Performing organic reactions in water with substrates that are not soluble seems counterintuitive at first.
A Biography of Water. Baeyer A, Drewsen V. Head-Gordon T, Hura G. Kluwer Academic Publications; Boston: Shen YR, Ostroverkhov V. Organic reactions in aqueous media. Organic Synthesis in Water. Itami K, Yoshida JI. Angew Chem Int Ed.
Clean Technologies and Environmental Policy. Organic Reactions in Water: Principles, Strategies and Applications. Kobayashi S, Manabe K. Li CJ, Chen L. Dallinger D, Kappe CO. Nakamura K, Matsuda T. Hopff H, Rautenstrauch CW. Rideout DC, Breslow R. J Am Chem Soc. Structure and Reactivity in Aqueous Solution. Padwa A, Pearson WH, editors. Bergdahl and co-workers published the first report in the literature describing that Wittig reactions of stabilised and poorly water-soluble ylides with aldehydes are unexpectedly accelerated in an aqueous media Tetrahedron Lett.
Following an early report J. One example of a syn adduct from an E -silicon enolate and two examples of anti adducts from Z -silicon enolates are reported J. Taguchi and co-workers demonstrated that the intramolecular Diels-Alder reaction of 1,7,9-decatrienoate derivatives can be performed in an aqueous medium H 2 O - i PrOH 6: Methods for selective deprotection of functional groups are key tools for organic chemists. The following examples, performed in water, open new possibilities for the use of this challenging medium.
Deprotection of several acetates, alkyl ethers and acetals in aqueous media were recently reviewed Chem. Highlights , July Site Search any all words. Site Search any all words Main Categories. Bonifacio New University of Lisbon Organic Synthesis in Water Water plays an essential role in life processes, however its use as a solvent has been limited in organic synthesis. Allylations Using a recyclable electrochemical process up to five cycles with excellent yield , Zhang and co-workers Org.
Claisen Rearrangement In , Gajewski, Ganem, Carpenter and co-workers reported a detailed experimental and mechanistic study of the rearrangement of chorismic acid to prephenic acid, an important step in the shikimic acid pathway. It is also noteworthy that these reactions showed inverse temperature dependence. Several representative examples of the obtained products - illustrate the scope of this method. We hope that this survey convinced the reader that attempting such heterogeneous reactions in water is a worthwhile endeavor. Nucleophilic openings of other strained ring systems may also benefit from the on water conditions. The rate in methanol, a protic polar organic solvent, was intermediate, but closer to that in the hydrocarbon solution.
Wittig Reaction Bergdahl and co-workers published the first report in the literature describing that Wittig reactions of stabilised and poorly water-soluble ylides with aldehydes are unexpectedly accelerated in an aqueous media Tetrahedron Lett. Mannich-type Reactions Following an early report J.