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burgh and a collaboration between Shel don's group in Delft and Seddon in Bel fast have shown that hydrolases such as Candida antarctica lipase and thermoly sin efficiently catalyze the formation of amides, esters, and peracids in ionic liq uids," Roberts continues. 'The enzymes are perfectly stable in solvents such as l-butyl-3-methylimidazolium hexafluo rophosphate, and the commercial po tential of the protocol is demonstrated by the preparation of aspartame." Erbeldinger points out that thermolysin-catalyzed synthesis of Z-aspartame several types of organic reactions, such in an organic solvent such as ethyl ace as transesterification and perhydrolysis, tate is well known. "We used it as a mod in the ionic liquids [bmim] [PF6] or el reaction to replace organic solvents [bmim][BF4] [Org. Lett., 2, 4189 with an ionic liquid," he tells C&EN. (2000)]. The work was carried out by The Pittsburgh team synthesized Z-as professor of organic chemistry Roger A. partame by the reaction of carbobenzoxySheldon, associate professor of organic L-aspartate and L-phenylalanine methyl chemistry Fred van Rantwijk, and Ph.D. ester. Ζ is a protecting group that is later student Rute Madeira Lau of Delft Uni removed. By using [bmim] [PF6] contain versity of Technology, the Netherlands, ing 5% by volume of water, the group ob and chemistry professor Kenneth R. tained an aspartame yield of 95%, which is Seddon of Queen's University of Belfast similar to that reported for enzymatic as (QUB), in Northern Ireland. partame synthesis in organic solvents "Twenty years ago, the use of en with low water content. zymes in organic synthesis and the em "We observed a competitive rate of ployment of ionic liquids as solvents reaction in the ionic liquid compared were both regarded as orphan tech with that in the organic solvent," Er niques," remarks Stanley M. Roberts, beldinger says. "In addition, the en professor of chemistry at the University zyme, which normally requires immobi of Liverpool, in England. "Great strides lization, exhibited excellent stability in have been made in recent times so that the ionic liquid." both areas have gained in popularity The team isolated the product by and maturity. rinsing the ionic liquid with deionized "Erbeldinger and colleagues in Pitts- water. "We are currently optimizing the
NEW HORIZONS FOR IONIC LIQUIDS
Green 'designer solvents' find additional effective uses, now for enzyme catalysis and in classic organic syntheses Michael Freemantle C&EN London
R
oom-temperature ionic liquids are good solvents for a wide range of organic, inorganic, and polymeric compounds. Typically con sisting of nitrogen-containing organic cations and inorganic anions, they are easy to recycle, nonflammable, and have no detectable vapor pressure. Many chemists view these "designer solvents" as potential replacements for volatile organic compounds traditionally used as industrial solvents. Recent research now shows that it is possible to carry out enzyme-catalyzed reactions and other types of biotransfor mations in ionic liquids. In addition, conventional ionic liquids are opening up new lines of chemistry for classic or ganic reactions, and new types of ionic liquids may be useful as surfactants and in electrochemical processes. The discovery of enzyme activity in room-temperature ionic liquids is likely to give a further boost to research into the use of these environmentally benign solvents. Last month, chemical engineers at the University of Pittsburgh reported the first example of an enzymatic synthesis in a room-temperature ionic liquid. The group synthesized Z-aspartame, a precur sor to the artificial sweetener aspartame, by the reaction of two amino acid deriva tives catalyzed by thermolysin, a proteo lytic enzyme. The reaction was carried out using the ionic liquid l-butyl-3-methylimidazolium hexafluorophosphate— [bmim] [PF6]—as a solvent [Biotechnol. Prog., 16,1129 (2000)]. The authors are research associate Markus Erbeldinger, Ph.D. student Anita J. Mesiano, and pro fessor of chemical and petroleum engi neering Alan J. Russell. In parallel work, chemists in Europe have shown that a hydrolytic enzyme, Candida antarctica lipase, can catalyze
Enzyme catalyzes synthesis in ionic liquid \ 0 / ~
CH
C — O —CHo
2—0--C—NH—CH—C02H CH2 C0 2 H
Carbobenzoxy-L-aspartate L-Phenylalanine methyl ester Thermolysin
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Ionic liquid
CH 2 — O — C — N H — C H — C —NH—CH — C ~ O — CH3 + H 2 0
Protecting group (Z)
CH2 COoH
Z-Aspartame
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method of recycling the ionic liquid," From left: Sheldon, Lau, and Erbeldinger says. "Possibilities include van Rantwijk extracting the product into supercritical or liquid carbon dioxide." The team is also investigating the in- monia to yield ethyl fluence of reaction parameters such as octanamide and on water concentration and ionic liquid the reaction of octanocomposition on the synthesis. "In addi- ic acid with ammonia tion, we are now looking into the ability to yield octanamide. of lipases to make polyesters in ionic liq- They obtained a quanuids," Erbeldinger says. titative conversion for Whereas the Pittsburgh group used the octanoic acid reacan ionic liquid containing a small tion in [bmim] [BFJ. amount of water, Sheldon and coworkThe researchers ers used ionic liquids that did not con- also investigated the tain water. epoxidation of cyclo"We are looking for enzyme-cata- hexene by peroctanoic lyzed reactions that, for one reason or acid in ionic liquids. another, do not work in water or in stan- The acid was generated in situ by the dard organic solvents but can be carried lipase-catalyzed perhydrolysis of octanoic out in room-temperature ionic liquids," acid with aqueous hydrogen peroxide. Sheldon tells C&EN. "We have initially The yield of peroctanoic acid was 83%. concentrated on reactions catalyzed by 'These enzyme-catalyzed reactions lipases and have shown that they per- go at least as well in ionic liquids as in form well in ionic liquids in the total ab- the optimum organic solvents and in sence of water." some cases even better; for example, Lipases are widely used in industry with the ammoniolysis of a carboxylic to catalyze esterifications and trans- acid," Sheldon says. esterifications, he points out. They are 'We are now looking at the use of othused, for example, in the synthesis of er enzymes that catalyze important reacpharmaceutical and agrochemical inter- tions in organic synthesis such as hydrolmediates, in the petrochemical indus- ysis, oxidation, and C-C bond formation," try, and in the manufacture of flavors, he continues. "These include hydrolasfragrances, and health care products. In es—for example, amidases, proteases, transesterifications, an ester reacts with and glycosidases; redox enzymes such as an alcohol to form a new ester and the peroxidases; and enzymes that catalyze alcohol from the original ester. C-C bond formation such as aldolases. Sheldon's group studied the trans- We also intend to look further into the efesterification of ethyl butanoate with bu- fect of the structure of the ionic liquid, tan-l-ol in anhydrous [bmim] [PF6] and particularly the nature of the anion on the anhydrous [bmim][BF4] using C. ant- activity, enantioselectivity, and stability of arctica lipase as a catalyst. The butyl es- the enzyme and on its solubility in the ter was formed in 81% yield in both ionic ionic liquid." liquids. In ionic liquids containing 10% The group suggests that ionic liquids by volume of water, the yield of the es- could have added benefits for performter dropped to 62%, owing to the forma- ing biotransformations with highly potion of butanoic acid. The researchers lar substrates, carbohydrates for examalso obtained an 81% yield for the transesterification of ethyl octanoate with butan-1-ol in anhydrous Peroctanoic acid is generated [bmim][PF6]. Lower yields were in situ for epoxidation obtained in [bmim] [BFJ. "We wanted to compare the performance of two different types of ionic liquids," Sheldon exCyclohexene plains. 'We achieved better yields for the transesterification with [bmim] [PF6], which is hydrophoCH3(CH2)6COH CH3(CH2)6COOH bic, than with [bmim] [BFJ, Peroctanoic acid Octanoic acid which is hydrophilic." Sheldon and colleagues carHp0 2 Enzyme ried out similar studies on the reaction of ethyl octanoate and am2 2 JANUARY 1, 2001 C&EN
pie, that are sparingly soluble in common organic solvents. In July of last year, a British group, consisting of biochemical engineering lecturer Gary J. Lye and colleagues at University College London (UCL) and Seddon and coworkers at QUB, reported the first example of a biotransformation in an ionic liquid system. The group showed that Rhodococcus R312, a whole-cell biocatalyst that facilitates the transformation of nitriles to amides, could be used for the conversion of 1,3-dicyanobenzene to 3-cyanobenzamide and 3-cyanobenzoic acid in the two-phase water-[bmim] [PF6] system [Biotechnol. Bioeng., 69,227 (2000)]. "This result is not only surprising, but is one of the more exciting results that we have seen recently," Seddon comments. 'The work was mainly carried out at University College. Our role at QUB was to advise on the details of the ionic liquids." Lye explains that Rhodococcus is a bacterium that contains the nitrile hydratase enzyme. However, unlike the reactions reported by Erbeldinger's and Sheldon's groups, the enzyme is not active in [bmim][PF 6 ]. The ionic ^— liquid acts as a reservoir for the substrate. 'The cells remain in the aqueous phase, which is where the reaction takes place," Lye tells C&EN. 'The ionic liquid is used to dissolve concentrations of substrate above the aqueous solubility limit, which then partitions into the aqueous phase. "The results indicate improved catalytic stability compared to the use of organic solvents, and there are hints that ionic liquids may alter the selec-
tivity of the transformation," he continues. "Colleagues at UCL and elsewhere have spent the past decade developing guidelines for the selection of biocompatible solvents and understanding how whole-cell biocatalysts respond to exposure to such solvents. Our work shows that ionic liquids represent an interesting new alternative." Lye adds that the UCL group is now concentrating on two areas of research on the use of room-temperature ionic liquids as replacements for organic solvents in multiphase bioprocess operations. "At a fundamental level, we want to determine if there is a relationship between the structure of the ionic liquid and the selectivity of the biocatalyst— that is, will the ionic liquid alter the mechanism of enzyme-catalyzed transformations? We also want to understand the kinetics of the reaction as a basis for scaling up these processes," he says. In the same paper, Lye, Seddon, and their coworkers report the use of [bmim] [PF6] for the liquid-liquid extraction of the polyketide antibiotic erythromycin-Afrom an aqueous phase. As the authors point out, polyketides are a large and diverse class of naturally occurring compounds exhibiting antimicrobial, anticancer, and immunosuppressant effects. Liquid-liquid extraction is widely used industrially for the recovery and purification of antibiotics. Ethyl or butyl acetate are the most commonly used solvents for extraction. The researchers found that the magnitude of the erythromycin partition coefficients over the pH range of 5 to 9 for the two-phase water-[bmim] [PF6] system is similar to that for the water-butyl acetate system. The team concludes from its work on two-phase biotransformation processes and on the liquid-liquid extraction of antibiotics that ionic liquids might be suitable for a range of multiphase bioprocess operations. "The replacement of organic solvents with these ionic liquids would enable major process design and economic constraints associated with toxicity and flammability of organic solvents to be overcome," the group suggests. Two years ago, QUB's Seddon made a prediction: "It now looks as though there is no significant area of organic synthesis that cannot be performed in an ionic liquid," he told C&EN (C&EN, Jan. 4,1999, page 23). Judging from the spate of papers on the topic that have appeared since
then, it looks as if his prediction is and disposal problems because strong coming true. And the papers still keep acids such as hydrofluoric acid are usually employed for the diazotization. appearing. "We have shown that the ionic liquid For example, in a paper just published in the Journal of Fluorine Chemistryversion of this chemistry is quite conve[107, 31 (2001)], chemistry professor nient, and that the yields are near quanKenneth K. Laali and postdoctoral re- titative in most cases," he continues. search chemist Volker J. Gettwert at 'Workup procedures are simple and the Kent State University, in Kent, Ohio, ionic liquid solvent can be recycled sevshow that a range of room-temperature eral times." In another recent paper, the same ionic liquids are suitable solvents for replacing diazonium groups by fluorine in a two chemists report their exploratory studies on the utility of ionic liquids as process known as fluorodediazoniation. Laali and Gettwert investigated the solvents for the electrophilic nitration of Balz-Schiemann reaction, which is a aromatic compounds \J. Org. Chern., classical process for the regiospecific published Dec. 14 ASAP, http://pubs. introduction of fluorine into aromatic acs.org/journals/joceah]. "We conducted a survey using varicompounds via diazonium salts. They tested the utility of ionic liquids contain- ous nitrating agents to determine the ing [bmim] and l-ethyl-3-methylimid- potential of using imidazolium salts with azolium [emim] cations with [BFJ, different counterions as solvents for nitration," Laali says. "We identified sev[PF6], and other anions. "The Balz-Schiemann reaction is eral ionic liquids and nitrating systems practiced on an industrial scale," Laali as promising for arene nitration." Ionic liquid nitration is potentially a tells C&EN. "However, it suffers from lack of reproducibility, and the yields useful alternative to classical nitration are variable depending on the substrate. routes, he points out, because it is easiThere are also environmental concerns er to isolate the products and recover
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TREND/CONSUMPTION ANALYSIS & REPORTING
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science/technology the ionic liquid solvent. The method also avoids problems associated with neutralization of the large quantities of strong acid, such as concentrated nitric acid, that are needed in the classical routes. "From our perspective, because room-temperature ionic liquids have low nucleophilicity counterions, they provide unique environments for ex ploring ionic reactions involving elec tron-deficient intermediates, particular ly carbocations and onium ions, as they
could become more long-lived in these media," Laali says. "Another angle is to increase the Lewis acidity of the imidazolium cation core so it can function as both solvent and Lewis acid in certain acid-catalyzed reactions. "We are revisiting classical reactions that are fundamentally and industrially important in the hope of improving their yields and chemo- and regioselectivity, and to carry out these processes under environmentally more acceptable condi tions," he adds.
Call for Papers •
D e a d l i n e - M a r c h 3 1 , 2001
2001 Eastern Analytical Symposium Sept. 30 - Oct. 4,2001 Atlantic City, NJ The Eastern Analytical Symposium is the sec ond largest meeting in the United States dedicated to the needs of analytical chemists and those in the allied sciences. Please help us to make the 2001 EAS the best ever-be a part of the program by con tributing your own papers for inclusion in the oral or poster sessions. To submit a contributed paper for the 2001 EAS Technical Program, you should submit a 200-to 250-word abstract of the proposed paper, indicating your preference for either oral or poster format, to EAS Program Committee, at the address shown below. Preliminary abstracts can also be submitted by FAX to 610-485-9467, at our web site (http://www.easorg/), or via e-mail (
[email protected]). Please submit each pre liminary abstract only one time and only use one method to submit it. Regardless of the method of submission, please include the following information on your abstract: • Title of the Presentation • Complete names, mailing addresses, telephone numbers, and fax numbers for all authors • If the presentation is intended for the undergrad uate research symposium, please indicate it clearly on the abstract and also please indicate which author is the student and which author is the faculty advisor • Your preference for oral or poster format • Approximately six keywords that can be used to categorize the subject matter of your presentation If you have questions concerning the submission of presentations for the 2001 EAS please contact us at:
Eastern Analytical Symposium P.O. Box 633 Montchanin, DE 19710-0633 USA http://www.eas.opg email:
[email protected] EAS Hotline: 1-810-485-4833 EA8Faxline: 1-810-485-8487
EAS - Educating Analytical Scientists for over 40 years.
2 4 JANUARY 1, 2001 C&EN
R
^N^N^^(CF2)nCF3
PF6"
\=J Fluorous ionic liquid surfactants R = methyl or n-butyl η = 5 or 7
In France, chemists Virginie Le Boulaire and René Grée at the National Center for Scientific Research's (CNRS) Synthesis & Activation of Biomolecules Laboratory, in Rennes Beaulieu, have studied Wittig reactions in [bmim] [BF4] [Chem. Commun., 2000,2195]. The Wittig reaction is one between a phosphorus ylide and an aldehyde or ketone to give an alkene. Le Boulaire and Grée point out that it is one of the most popular methods for forming carbon-carbon double bonds, and in most cases it gives excellent stereocontrol. The French team reports that the reaction of aldehydes, such as benzaldehyde, and stabilized phosphorus ylides, such as (C6H5)3P=CHCOCH3, for example, are easily performed in [bmim][BFJ. They note that the ionic salt is an attractive solvent for Wittig reactions because it allows easier separation of alkenes from the problematic byproduct (C 6 H 5 ) 3 P=0 and efficient reuse of the solvent. Chemistry professor George W. Kabalka and postdoctoral research chemist Rama R. Malladi at the University of Tennessee, Knoxville, have demonstrated that ionic liquids are excellent solvents in which to carry out reductions using trialkylboranes [Chem. Commun., 2000,2191]. Kabalka and Malladi show that ionic liquids such as [bmim] [BFJ and [emim] [PF6] enhance the rate of organoboron-mediated reductions of aliphatic and aromatic aldehydes—for example, the reduction of benzaldehyde to benzyl alcohol. They point out that separation of the products from the ionic liquid and recycling of the solvent are both straightforward. The versatility of ionic liquids is not just restricted to their use as solvents for classical organic reactions. Assistant professor James H. Davis Jr. and coworkers at the University of South Alabama have synthesized ionic liquids from imidazolium cations with appended fluorous tails. The group demonstrates that these fluorinated ionic liquids function as surfactants when add-
ed to conventional ionic tive. LIPs can be pre liquids and facilitate the pared under relatively Polyammonium phosphates are liquids emulsification of perfluomild conditions and at room temperature rocarbons with ionic liq could provide a medi uid phases [Chem. Com um for green chemistry 4PO4 3 2 PO43mun. ,2000,2051]. applications because ρ(ΟΗ 2 ) 4 -η C|_,3 "We've shown in our they are easily and safe :N+ +N paper that, in terms of ly generated, relative s / L-(CH2)4—Ι Χ ° Η 3 bulk properties, ionic liq ly unreactive, and yet uids respond to surfac highly conducting. tants in much the same "Although viscous, way that conventional LIPs seem to be excel -l 2 P04 solvents do," Davis tells lent candidates as non C&EN. 'We've doped in aqueous solvent media 2P0 4 to a conventional ionic for the performance of liquid a second ionic liq organic electrochemical uid with a long fluorous processes, in addition to tail. The solution has a their potential applica hUC^ -ΌΗ3 markedly decreased tions for electrochemi N+ +N surface tension relative ^CH3 cal storage cells," he to a conventional ionic adds. "We are continu liquid. In the absence of ing to investigate both the surfactant, conven the potential of LIPs as tional ionic liquids and perfluorocar- aqueous media," Engel explains. "Pre media for electrochemical processes bons don't mix at all." viously prepared hexafluorophosphate and the syntheses of other easily pre Davis suggests that the results could ionic liquids are water insoluble, and pared, water-inert, and water-insoluble be useful in the development of biphasic the ionic liquids prepared with tetra- ionic liquids based on phosphorusreaction systems based on two environ chloroaluminate anions are water reac centered anions."^ mentally friendly solvent technologies: ionic liquids and perfluorocarbons. Ionic liquids are also potentially use ful in electrochemical applications, such as electrolytes in batteries (C&EN, May 15, 2000, page 37). Chemistry and bio chemistry professor Robert Engel and his students at Queens College of the City University of New York have syn thesized a new class of room-tempera ture ionic liquids that might be suitable candidates for such applications. Engel's team included graduate stu dents Sharon I. Lall and JaimeLee Iolani Cohen and undergraduates Danny Mancheno, Steve Castro, and Valbona Behaj. "Much of our effort here is done with undergraduates, and a significant portion of our support comes through the Alliance for Minority Participation," Engel tells C&EN. 'The alliance is our part of a federally funded program for support of members of underrepresented groups in the sciences." The group converted a novel series of solid polyammonium halide salts, previously synthesized in Engel's labo ratory, into nonaqueous room-tempera ONLINE CYLINDER ture ionic liquids simply by replacing the halide ions with phosphate ions INVENTORY CONTROL [Chem. Commun., 2000, 2413]. 'These new nonaqueous ionic liq uids, which we call liquid ionic phos - Scott Specialty Gases — phates, or LIPs, are water soluble and are not degraded by dissolution in
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