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Thursday, February 1, 2007
Rajender S. Varma
U. S. Environmental Protection Agency

Clean Chemical Synthesis in Water

Green or sustainable chemistry has now attained the status of a major scientific discipline (Green Chemistry: Theory and Practice, 1998, Oxford Press) and the studies in this area have led to the development of cleaner and relatively benign chemical processes with many new technologies being developed each year. Among them, much effort has been devoted to the use of nontraditional solvents for chemical synthesis. These unconventional media include solventless (Tanaka, Solvent-free Organic Synthesis, 2003, Wiley-VCH; Green Chem. 1999, 1, 43, ; ACS Symposium Series No. 767 , 2000, American Chemical Society, Washington DC, p 292; Pure Appl. Chem. 2001, 73, 193, Link), water (Chem. Rev. 2005, 105, 3095, ; Acc. Chem. Res. 2002, 35, 533. ; Organic Reactions in Aqueous Media, 1997, John Wiley & Sons; Org. Process Res. Dev. 2007, 11, 114. ), supercritical CO2 (Chemical Synthesis using Supercritical Fluids, 1999, Wiley-VCH), ionic liquids (Ionic Liquids in Synthesis, 2003, Wiley-VCH), and perfluorinated solvents (Tetrahedron 2002, 58, 3823. ). Water is commonly considered as a benign solvent in view of its non-toxicity and abundant natural occurrence, yet in the semiconductor industry, untreated wastewater contaminated with trace amounts of metals is a serious environmental problem. However, the use and release of “clean water” will have the least impact to the environment, and this article discusses the main advantages of using water as a reaction medium to develop cleaner chemical processes. Selected examples are provided.

1. Direct Utilization of Water-soluble Renewable Materials

Organic synthesis in aqueous media is rapidly gaining importance in view of the fact that the use of many toxic and volatile organic solvents, particularly chlorinated hydrocarbons, contributes to pollution. Consequently, it is highly desirable to develop environmentally benign processes that can be conducted in aqueous media. Furthermore, using water as a solvent offers many advantages, such as simple operation and high efficiency in many organic reactions that involve water-soluble substrates, reagents, and renewable materials, such as carbohydrates, without the necessary derivatizations. During the past two decades, many reactions that were conventionally believed to occur only in organic solvent have been developed to run in water. Since the seminal work on aqueous Diels-Alder reactions by Breslow (Acc. Chem. Res. 1991, 24, 159. ), there has been profound research activities in the development of organic reactions in aqueous medium (J. Am. Chem. Soc. 1999, 121, 6798. ), such as catalytic hydrogenation and hydroformylation, metal-mediated carbon-carbon bond formation, water-tolerant Lewis acid catalysis (Acc. Chem. Res. 2002, 35, 209, ; Acc. Chem. Res. 2002, 35, 533, ; Angew. Chem. Int. Ed. 2000, 39, 1256, ) including solid acids (Chem. Rev. 2002, 102, 3641. ), and transition metal-catalyzed carbon-carbon bond formations (Chem Commun. 2002, 268. ). These reactions provide the possibility of directly modifying water-soluble and renewable materials in water without the necessary protection-deprotection sequences that are commonly associated with conventional chemistry. This has the result of reducing the overall number of synthetic steps as exemplified in the higher carbon-sugar synthesis of (+)-3-deoxy-D-glycero-D-galacto-nonulosonic acid (KDN) from carbohydrate (J. Chem. Soc. Chem Commun. 1992, 747. )(Scheme 1).



Scheme 1

2. Catalyst Recycling and Efficient Product Isolation

Another potential opportunity for clean chemical synthesis in water is the development of high atom efficiency catalytic processes that can simplify catalyst recycling and product isolation. Ideally, the reactant and the product should have no or very little water-solubility. As a result, the product can be isolated by simple phase separations and the catalyst can be recycled readily. It is, therefore, possible to recycle the catalyst-bearing aqueous solution for an extended period of time without the need either to discharge it or to regenerate it, provided the low atom-efficiency processes which lead to the accumulation of unwanted materials in the solution can be avoided. Successful examples in this category include the aforementioned catalytic hydrogenations, hydroformylations, the Wacker oxidation, and some polymerization reactions.

Hydrogenation of both C-C unsaturated bonds and C-O double bonds in aqueous medium have been demonstrated using RuCl2(TPPMS)2 with sodium formate as the hydrogen donor (J. Mol. Catal. 1990, 58, 151, ; Organomet. Chem. 1989, 363, C19. ), including asymmetric hydrogenation processes (Tetrahedron Asymmetry, 1990, 1, 895. ) and a highly regio- and stereoselective hydrosilylation of terminal alkynes (Chem. Commun. 2003, 1668. ).

The hydroformylation process is one of the most successful industrial applications of aqueous medium catalysis, as attested by a series of patents describing the recovery of rhodium catalyst and the preparation of water-soluble sulfonated phosphane ligands. The optimized hydroformylation is the Ruhrchemie/Rhône-Poulenc process (Patent, DE-B 3431643, 1986) that uses HRh(CO)(tppts)3 as catalyst (Scheme 2). The product is separated from the catalyst solution by a simple phase separation, and the catalyst solution is recharged to the reactor for further reaction with a negligible loss of rhodium catalyst in the organic phase.



Scheme 2

The single site olefin polymerization reaction developed by Grubbs using water-soluble transition metal catalysts is particularly noteworthy (Science 2000, 287, 460. ).

3. Grignard-type Reactions via Catalytic Reaction of C-H Bonds

Carbon-carbon bond formation via C-H activation in water (Chem. Rev. 2005, 105, 3095. ) is another potential clean process that can have both high atom efficiency and easy recycling of the catalyst solution. These successful objective of obtaining a theoretical 100% atom efficiency for the Grignard-type reactions via C-H activation in water have been recognized by a Presidential Green Chemistry Challenge Award to Prof. Li. The initial investigation centered on the activation of the sp3 allylic C-H bond using ruthenium catalysts in air and water. The allylic C-H bond was activated via catalysis by RuCl2(PPh3)3, and the functional group of homoallyl alcohols was repositioned to give allyl alcohols. Subsequently, an aldol-type reaction was developed based on the allylic C-H activation in either water or ionic liquid (Org. Lett. 2003, 5, 657. ) (Scheme 3).



Scheme 3

The conventional methods employ a stoichiometric amount of organometallic reagents such as organolithium or organomagnesium for forming alkynylmetal reagents from alkynes or alkynyl halides in anhydrous organic solvents. An effective addition reaction of phenylacetylene to aldehydes in aqueous solution was developed via C-H activation catalyzed by a bimetallic Ru-In system (Green Chemistry, 2002, 4, 39. ). A highly efficient alkynylation of aldehydes was recently developed using silver-phosphine complexes as catalysts in water (Org. Lett. 2005, 7, 4395. ). Using a gold catalyst, an addition-cyclization sequence afforded isochromenes, common structural units in natural products which exhibit interesting antibiotic activities (Org. Lett. 2006, 8, 1953. ) (Scheme 4). Furthermore, catalytic conjugated addition of alkynes to unsaturated carbonyl compounds occurred (c and d) in water (Chem. Commun. 2004, 2362. ).



Scheme 4

A highly efficient A3-coupling (aldehyde-alkyne-amine) in water or under solvent-free conditions was described using a combination of RuCl3 and Cu(I) in catalytic amounts (Chem. Commun. 2002, 268. ), which was subsequently generalized using gold or silver catalysts without the need of co-catalyst or activator in water (J. Am. Chem. Soc. 2003, 125, 9584, ; Org. Lett. 2003, 5, 4473, ) (Scheme 5). An aqueous copper-mediated coupling of alkynes with N-acylimines and N-acyliminium ions to generate propargyl amide derivatives was also reported. (Tetrahedron Lett. 2002, 43, 5731. ). A multi-component coupling approach to β-lactams using N-alkyl hydroxylamines, aldehyde, and alkyne catalyzed by copper has been reported under mild conditions (Chem. Asian J. 2006, 203. ) (Scheme 5).



Scheme 5

4. The Use of Ultrasound and Microwave for Energy Efficiency

For many chemical processes, a major adverse effect to the environment is the consumption of energy for heating and cooling. To overcome such problems, it is highly desirable to develop efficient methods that utilize alternative energy sources such as ultrasound and microwave irradiation to facilitate chemical reaction. Ultrasonic irradiation enhances the chemical reaction and mass transfer via the process of acoustic cavitation (Synthetic Organic Sonochemistry, 1998, Plenum Press).

Ultrasound: In aqueous reaction media, the sonolysis of the O-H bond is a predominant phenomenon that occurs in the gas phase of the bubble, which generates hydrogen and hydroxyl radicals (Eq. 1).

Sonochemically generated oxidizing species such as hydroperoxyl radicals have been detected that originate from reaction of dioxygen with hydrogen (Advances in Sonochemistry 1993, 3, 17, Jai Press). This approach has potential application in the degradation of pollutants in water even at low concentrations and avoids the energy-intensive concentration efforts (Env. Sci. & Tech. 1992, 26, 1639) especially when used in conjunction with photocatalytic or electrochemical method (New J. Chem. 1995, 19, 989). Interfacial reactivity was apparent in the oxidation of hindered secondary amines (J. Am. Chem. Soc. 1992, 114, 3148. ). In presence of oxygen bubbling through the reaction mixture, stable nitroxides were produced as a result of hydroxyl radical abstraction of the hydrogen followed by the reaction of oxygen with nitrogen-centered radicals (Scheme 6).



Scheme 6

Sonication can greatly improve the rates and yields of organometallic reactions via enhancement of the electron transfer processes.

Organoclay assemblies bearing 3-aminopropyltriethoxysilane and surfactants in the clay interlayer have proven useful in several organic transformations, such as preparation of benzyl cyanides, thiocyanides, and alcohols from the corresponding benzyl halides and sodium cyanide, thiocyanide, and hydroxide, respectively (Green Chem. 1999, 1, 95. ). In this context, it is important to mention clay doped with 18-crown-6 as a recyclable phase transfer catalyst in nucleophilic substitution reactions that provided relatively improved yields of alkyl azides from alkyl bromides and sodium azide in aqueous medium (Synth. Commun. 1999, 29, 2823).

Further, it has been shown that alkyl halides and α-tosyloxyketones afforded the corresponding azide derivatives upon treatment with aqueous sodium azide (NaN3) under triphase catalysis or ultrasound irradiation conditions (Cat. Lett. 1998, 53, 225, ; Tetrahedron Lett. 1998, 39, 2915. ). Among the nucleophilic substitution reactions, a study has been conducted to explore the viability of ultrasound as a substitute for a phase-transfer catalyst (PTC) by comparing the results under various conditions, including triphase catalyst under classical (reflux) condition, triphase catalyst in conjunction with ultrasound irradiation at very low temperature, and finally, a two-phase catalyst-free system using only ultrasound irradiation (J. Mol. Cat. A Chemical 1999, 149, 153. ). In a typical example, the alkyl bromide or α-tosyloxyketone and aqueous NaN3 were admixed in the molar ratio 1:1.2 and refluxed with continuous stirring in the presence of organoclay material under classical conditions or under ultrasound irradiation with or without organoclay assembly (Scheme 7).





Scheme 7

Under the influence of ultrasound irradiation, it has been observed that a favorable acceleration in reaction rate occurred when compared to classical conditions (i.e. under reflux). The addition of catalytic amounts of surfactant-pillared clays further facilitated the reaction, thereby indicating a synergistic effect of ultrasound on the tri-phase catalyst system. However, the successful reaction with sonication in the absence of pillared clay indicates that ultrasound can indeed substitute for a phase transfer catalyst, thereby providing an attractive alternative for the nucleophilic substitution reactions (J. Mol. Cat. A Chemical 1999, 149, 153. ).

Microwave (MW) irradiation, an unconventional energy source, has been used for a variety of applications including organic synthesis (Microwaves in Organic Synthesis 2006, Wiley-VCH; Tetrahedron 2002, 58, 1235, ; Microwave Technology-Chemical Synthesis Applications, Kirk-Othmer Encyclopedia 2006, 5th Edn, Vol. 16, pp 538-594, John Wiley & Sons) wherein chemical reactions were accelerated because of selective absorption of microwave energy by polar compounds or intermediates, non-polar molecules being inert to the MW dielectric loss.

High-temperature aqueous reactions in continuous (CMR) and batch (MBR) microwave reactors have been explored and the technique has been used to conduct a variety of organic reactions in water. The advantages include less waste generation, safe handling, and low cost as demonstrated by Strauss in the following examples (Acc. Chem. Res. 2005, 38, 653. ).

In general, the hydrolysis of tertiary amides is difficult to achieve even at reflux conditions. A morpholinide derivative has been successfully hydrolyzed to afford 4-t-butylcyclopent-1-enoic acid (70%) in 10 min under microwave irradiation whereas only 40% product was obtained after 4 h reflux under classical conditions (J. Org. Chem. 1995, 60, 2456) (Scheme 8).



Scheme 8

Under optimized reaction conditions, specific product formation is achievable as has been demonstrated in the ortho-Claisen rearrangement of allyl phenyl ether or reaction of carvone in water (J. Org. Chem. 1997, 62, 2505. ). Heating of carvone in water at 210 °C afforded 8-hydroxy-p-menth-6-en-2-one in 10 minutes, whereas at 250 °C carvone isomerized to carvacrol in almost quantitative yield. In a batch reactor, upon heating in water, allyl phenyl ether delivered different products at various temperatures. The Claisen rearrangement product, 2-allylphenol (56%) is obtained at 200 °C, 2-(2-hydroxyprop-1-yl)phenol (37%) at 230 °C, and 2-methyl-2,3-dihydrofuran (72%) at 250 °C (J. Org. Chem. 1996, 61, 7355. ).

The Fischer indole synthesis of 2,3-dimethylindole (67%) has been accomplished in water from phenylhydrazine and butan-2-one at 220 °C within 30 minutes (Aus. J. Chem. 1998, 51, 703. ) thus circumventing the use of preformed hydrazone or any acid (Scheme 9).



Scheme 9

The conventional methods for decarboxylation of indole-2-carboxylic acid to indole are not environmentally benign as they often require the pyrolysis or thermolysis in quinoline or pyridine derivatives and in presence of various copper salts. The decarboxylation of indole-2-carboxylic acid occurred almost quantitatively in water at 255 °C within 20 minutes.

The formation of inorganic salts accounts for the major waste generation in the production of various pharmaceuticals and fine chemicals in view of the frequent neutralization of basic or acidic solutions. The MW protocols using high-temperature water as the reaction medium are especially attractive in this context because of the selectivity and usage of less of the acidic or basic agent that eventually reduces the requirement for neutralization (Aus. J. Chem. 1999, 52, 83. ).

Near critical water (NCW), generated in stainless steel pressure vessels or microwave-irradiated Teflon or glass reactors, has proven to be a useful green reaction medium for a variety of organic transformations. The properties of NCW can be fine tuned to attain selectivity for a desired molecule among several possible reaction products. With the increase in temperature and pressure, the dielectric constant and hydrogen bonding decreased and the water ionization and solubility of the organic molecules increased. These extreme changes in properties of NCW have been exploited in the synthesis of naturally occurring isocoumarins of medicinal interest that are normally obtained by aromatic substitution using activated methylene compounds in organic solvent in the presence of a base and stoichiometric amounts of copper catalyst. Pressurized hot water has proven to be an effective reaction medium for such reactions (Green Chem. 2003, 5, 174. ) with the added benefit of selectivity in the formation of 1 or 2 (Scheme 10).



Scheme 10

The approach has been further extended to the syntheses of nitrogen heterocycles where selective reduction, cyclodehydrations (Pfitzinger and Friedländer syntheses), Suzuki coupling, and ligand exchange reactions have been effected in water with potential recycling of the catalyst in aqueous medium (Green Chem. 2003, 5, 177. ).

In a similar approach, the synthesis of medicinally significant, 2-phenylbenzimidazole from 1,2-phenylenediamine and benzoic acid has been achieved in high temperature water (Scheme 11).



Scheme 11: Synthesis of 2-phenylbenzimidazole in water

The proper control of the reaction conditions provided high yields of the product and the solvation properties of water have been exploited by allowing the reaction product to crystallize out from the aqueous medium upon cooling (Green Chem. 2003, 5, 187. ).

Utilization of water as reaction medium (Chem Rev. 2005, 105, 3095, ; Angew Chem. Int. Ed. 2005, 44, 3275. ) in conjunction with microwave irradiation (Microwaves in Organic Synthesis, Chapter 8, 2006, pp 362-415, Wiley-VCH; Microwave Technology-Chemical Applications: Kirk-Othmer Encyclopedia of Chemical Technology, 2006, 5th Ed, Vol. 16, pp 538-594, John Wiley & Sons; “Advances in Green Chemistry: Chemical Syntheses Using Microwave Irradiation” AstraZeneca Research Foundation India, 2002, Bangalore, India; Angew. Chem. Int. Ed. 2004, 43, 6250. ) is one of the emerging non-conventional methods being recognized as a viable, environmentally benign alternative. Our group envisioned that the nucleophilic substitution reaction of alkyl halides with amines will be accelerated by microwave energy because of their polar nature. Indeed, a friendlier synthesis of tertiary amines is possible via direct N-alkylation of primary and secondary amines by alkyl halides that proceeds in basic water without any phase transfer reagent under microwave irradiation (Green Chem. 2004, 6, 219. ) (Scheme 12).



Scheme 12

The same nucleophilic substitution chemistry can be manipulated by means of microwaves to afford a variety of cyclic amines as building blocks in natural product syntheses via double N-alkylation of primary amines (Org. Lett. 2005, 7, 2409, ; Tetrahedron Lett. 2005, 46, 6011, ; J. Org. Chem. 2006, 71, 135, ) (Scheme 13). The protocol circumvents the difficulty associated with running multi-step reactions to assemble N-aryl azacycloalkanes and avoids the use of expensive metal catalysts in building aryl C-N bonds. Further, reactive functional groups such as carbonyl, ester, and hydroxyl etc., remained unaffected under these mild reaction conditions. The N-alkylation reaction has now been extended to hydrazines as well (Tetrahedron Lett. 2005, 46, 6011. ; J. Org. Chem. 2006, 71, 135, )







Scheme 13

It is noteworthy to mention that this reaction is not a homogeneous single phase system as neither reactant is soluble in aqueous alkaline reaction medium. The studies conducted by our group pointed out that the selective absorption of microwaves by polar molecules and intermediates in a multi-phase system could substitute as a phase transfer catalyst without using any phase transfer reagent, thereby providing the observed acceleration as has been observed for ultrasonic irradiation (Tetrahedron Lett. 1998, 39, 2915, ; Synth Commun. 1999, 29, 2823; J. Mol. Cat. A Chemical 1999, 149, 153, ).

The experimental observation is consistent with the mechanistic postulation wherein the polar transition state of the reaction is favored by microwave irradiation with respect to the dielectric polarization nature of microwave energy transfer (Chimica Oggi (Chemistry Today) 2006, 24, 36). In large scale experiments, the phase separation of the desired product in either solid or liquid form from the aqueous media can facilitate product purification by simple filtration or decantation instead of tedious column chromatography, distillation, or extraction processes which eventually reduces the usage of volatile organic solvent required for extraction or column chromatography.



Scheme 14

Microwave-assisted synthesis of azides, thiocyanates, and sulfones has been developed (Scheme 14) that has proved to be a useful alternative which avoids the use of environmentally detrimental volatile chlorinated hydrocarbons (J. Org. Chem. 2006, 71, 6697. ). All the reactions with these readily available halides or tosylates have shown significant increase in reactivity, thus reducing the reaction times with substantial improvement in the yields. Various functional groups such as ester, carboxylic acid, carbonyl, and hydroxyl were unaffected under the mild reaction conditions employed. This method involves simple experimental procedures and product isolation which avoid the use of phase-transfer catalysts, and is expected to contribute to the development of greener strategy for the preparation of various azides, thiocyanates, sulfones, and other useful compounds.

The acceleration of synthesis processes by microwave/ultrasonic irradiation to shorten the reaction time and eliminate or minimize side product formation is already finding acceptance in pharmaceutical industry (combinatorial chemistry) and polymer syntheses, and may pave the way towards the greener and more sustainable approach to chemical syntheses (Top. Curr. Chem. 2006, 266, pp 199-231, Springer-Verlag).

Conclusion

Green chemistry is a rapidly developing new field that provides us a proactive avenue for the sustainable development of future science and technologies. When designed properly, clean chemical technology can be developed in water as a reaction medium. The technologies generated from such green chemistry endeavors may often be cheaper and more profitable.

Acknowledgment

I thank Prof. C. J. Li, McGill University for his contribution and help.


Disclaimer

This article was authored by a U.S. Government employee as part of his official duties. In view of Section 105 of the Copyright Act (17 U.S.C. Section 105) the work is not subject to U.S. copyright protection. The views expressed in this article are those of the individual authors and do not necessarily reflect the views and policies of the U.S. Environmental Protection Agency. The use of trade names does not imply endorsement by the U.S. Government.

R. S. Varma, Org. Chem. Highlights 2007, February 1.
URL: http://www.organic-chemistry.org/Highlights/2007/01February.shtm