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Influence of Microemulsions on Enantioselective Synthesis of (R)-Cyclopent-2-enol Catalyzed by Vitamin B12 Bharathi Nuthakki,† James M. Bobbitt,† and James F. Rusling*,†,§ Department of Chemistry, U-3060, 55 North EagleVille Road, UniVersity of Connecticut, Storrs, Connecticut 06269, and Department of Pharmacology, UniVersity of Connecticut Health Center, Farmington, Connecticut 06032 ReceiVed January 3, 2006. In Final Form: March 22, 2006 The influence of microemulsions on the vitamin B12-catalyzed enantioselective isomerization of 1,2-epoxycyclopentane (1) to form (R)-cyclopent-2-enol (2) has been examined. The reaction was initiated by a reduction of vitamin B12 to the CoI form by Zn/NH4Cl. The largest enantiomeric excess (e.e.) in the products was 52% for (R)-2 obtained in a bicontinuous sodium dodecyl sulfate (SDS) microemulsion. A water-in-oil SDS microemulsion gave a poorer percent e.e. probably because of limited catalyst utilization in the water droplets. The influence of the pH of the water phase, the amount of water, and the concentration of vitamin B12 on the enantioselectivity and yield of the reaction was also explored. Results suggest that factors such as higher water content and bicontinuous fluid structure facilitated efficient intermixing of catalyst with reactant to form a key organocobalt intermediate, thus improving enantioselectivity.
Introduction Microemulsions are optically clear, thermodynamically stable, nanostructured fluids made from oil, water, surfactant, and often a cosurfactant.1 Bicontinuous microemulsions have continuous water and oil phases in a dynamic, intimately mixed network with surfactant residing at the oil/water interfaces. We have explored these fluids as less toxic, less expensive alternatives to organic solvents for mediated and direct electrochemical reactions.2,3 High dissolving power for reactants of unlike solubility, enhancement of reaction rates by controlling reduction potentials of mediators, possible reaction pathway control, and recycling of microemulsion components make microemulsions attractive reaction media. The influence of microemulsions on stereoselectivity for practical synthetic targets such as pharmaceuticals or their precursors is relatively unexplored. Recently, Adam et al.4 reported chemoselective and diastereoselective chemical peroxidation of allylic alcohol mesitylol in microemulsions. Under suitable reaction conditions with an optimized microemulsion composition, ∼97% chemoselectivity and 92% threo diastereoselective peroxidation was obtained. In the present paper, we describe the first study of the influence of microemulsion on the stereoselective synthesis of an allylic alcohol in an isomerization reaction catalyzed by vitamin B12a. Vitamin B12 is a natural, nontoxic, chiral cobalt corrin catalyst whose applications in organic synthesis have been investigated extensively.5-7 In 1988, Scheffold et al.8 used vitamin B12 to * Corresponding author. E-mail:
[email protected]. † University of Connecticut. § University of Connecticut Health Center. (1) (a) Bourrel, M.; Schechter, R. S. In Microemulsions and Related systems; Marcel Dekker: New York, 1988. (b) Friberg, S. AdV. Colloid Interface Sci. 1990, 32, 167-182. (2) Zhou, D.-L.; Gao, J.; Rusling, J. F. J. Am. Chem. Soc. 1995, 117, 11271134. (3) (a) Rusling, J. F. In Reactions and Synthesis in Surfactant Systems; Texter, J., Ed.; Marcel Dekker: New York,, 2001; pp 323-335. (b) Rusling, J. F. Interfacial Kinetics and Mass Transport. In Encyclopedia of Electrochemistry; Calvo, E., Ed.; Marcel Dekker: New York, 2003; Vol. 2, p 418. (c) Rusling, J. F., Campbell, C. C. In Encyclopedia of Electrochemistry; Hubbard, A., Ed.; Marcel Dekker: New York, 2002; p 1754. (4) Nardello, V.; Caron, L.; Aubry, J.-M.; Bouttemy, S.; Wirth, T.; SahaMoller Chantu, R.; Adam, W. J. Am. Chem. Soc. 2004, 126, 10692-10700.
Scheme 1. Isomerization of 1,2-epoxycyclopentane (1) Catalyzed by Vitamin B12
catalyze the enantioselective isomerization of achiral epoxides to optically active allylic alcohols in protic polar solvents. Chiral allylic alcohols are valuable building blocks in the synthesis of natural products such as prostaglandin precursors, carbovir, lasiol, faranal, and numerous drugs.9 Chiral lithium amide-mediated rearrangement of epoxides to form optically active allylic alcohols has been investigated.10 Such methods often require chiral reagents in large excess, and the regioselectivity of the lithiation depends on the choice of base, solvent, and substrate. Andersson et al.11 recently reported a lithium diamide-catalyzed isomerization of epoxides to allylic alcohols with enhanced enantioselectivity and reactivity and improved generality of the substrates. Our choice to explore the enantioselectivity of the vitamin B12-catalyzed isomerization of 1,2-epoxycyclopentane (1) to cyclopent-2-enol (2) (Scheme 1) in bicontinuous microemulsions has its origin in detailed mechanistic studies carried out by Scheffold in 1988.8,12 In methanol ( ≈ 28.5), isomerization of 1 in the presence of 1-3 mol % of hydroxocobalamin hydrochloride (vitamin B12a), metallic Zn, and NH4Cl under argon gave (R)-cyclopent-2-enol (2; yield: 64%, enantiomeric excess [e.e.]: 62%). Cyclopentanone (3; yield: 5.5%), cyclopentanol (5) Dolphin, D., Ed. Vitamin B12; Wiley: New York, 1982; Vol. 1. (6) (a) Scheffold, R.; Abrecht, S.; Orlinski, R.; Ruf, H.-R.; Stamouli, P.; Tinembart, O.; Walder, L.; Weymuth, Ch. Pure Appl. Chem. 1987, 59, 363-372. (b) Scheffold, R. In Modern Synthetic Methods; Scheffold, R., Ed.; Wiley: New York, 1983; Vol. 3, p 355. (7) Schneider, Z.; Stroinski, A. In ComprehensiVe B12; de Gruyter, W., Ed.; Berlin: New York, 1987. (8) Scheffold, R.; Su, H.; Walder, L.; Zang, Z.-D. HelV. Chim. Acta 1988, 71, 1073-1078. (9) O’Brien, P. J. Chem. Soc., Perkin Trans. 1 1998, 1439-1457. (10) Crandall, J. K.; Apparu, M. Org. React. 1983, 29, 345-443. (11) Bertilsson, S. K.; Soedergren, M. J.; Andersson, P. G. J. Org. Chem. 2002, 67, 1567-1573. (12) Bonhoˆte, P.; Scheffold, R. HelV. Chim. Acta. 1991, 74, 1425-1444.
10.1021/la0600191 CCC: $33.50 © 2006 American Chemical Society Published on Web 05/06/2006
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Table 1. Composition of Microemulsions microemulsion composition
structure
ref
1. CTAB/tetradecane/1-butanol/watera pH 7.0 2. CTAB/tetradecane/1-butanol/watera pH 4.0 3. CTAB/tetradecane/1-butanol/watera pH 10.0 4. SDS/ tetradecane/1-butanol/watera 5. SDS/ tetradecane/1-octanol/watera 6. DDAB/ n-hexane/water (wt % 36/ 54 /10)
bicontinuous bicontinuous bicontinuous bicontinuous W/O bicontinuous
14 14 14 14 14 15
a
wt % 17.5/12.5/35/35.
(4; yield: 0.5%), and cyclopentene (5; yield: 30%) were generated as byproducts (Scheme 1). Parameters such as the dielectric constant of the solvent, the pH of the solution, temperature, and irradiation with light influenced the rate of isomerization of the epoxide. Of these parameters, the dielectric constant () of the solvent most strongly influenced the e.e. of the reaction. Mixtures of dioxane and methanol in 4:1 ratio ( ≈ 9) provided the largest e.e. of 76.5%, while, in water ( ≈ 71), the e.e. was lowest at 45%.12 The rate constant of the isomerization of epoxide 1 to 2 and 3 was found to decrease with a decrease in the pH of the solution accompanied by improved enantioselectivity. Our interest in this reaction focused on possible control of the polarity of reaction environment by microemulsion properties to control enantioselectivity. Vitamin B12s is polar and highly water soluble. Since organic reactant is distributed toward the oil phase, we expected that this reaction occurs mainly in the water phase, but could involve cross-interface transport of the reactant. Bicontinuous microemulsions, by virtue of their high interfacial areas and relatively unrestricted mass transport in oil and water phases, can provide benefits in reaction rates when the key steps of the reaction involve reactants in different phases.2,13 As a first step, we sought to understand the effect of the bicontinuous microemulsion composition, structure, and acidity of the water phase on the enantioselectivity of the isomerization. One example of a water-in-oil (W/O) microemulsion was also included. In this paper, we present findings that suggest that the enantioselectivity of the reaction in scheme 1 can be controlled to some extent by controlling microemulsion properties and structure. Experimental Section Chemicals and Solutions. Vitamin B12a was obtained from Sigma. Compound 1, cyclohexanol, n-butanol, n-octanol, sodium dodecyl sulfate (SDS), cetyltrimethylammonium bromide (CTAB, 99%), zinc, and ammonium chloride were obtained from Aldrich. Didodecyldimethylammonium bromide (DDAB) was obtained from Acros. Tetradecane (99%) was obtained from Aldrich. Water purified with a Barnstead Nanopure system had specific resistance of >15 MΩ cm. Previously characterized microemulsions of 17.5% surfactant/ 12.5% tetradecane/35% water/35% n-alcohol14 and the threecomponent microemulsion 36% DDAB/54% n-hexane/10% water15 were prepared by mixing components by weight and stirring (Table 1). All other chemicals were analytical grade. The enantiomeric mixture of (R)- and (S)-cyclopent-2-enol was synthesized and purified according to the procedure reported by Scheffold.12 Isomerization of 1. To 20 mL of microemulsion in a 100 mL round-bottomed flask completely covered with aluminum foil to eliminate light, 0.1 g (70 µmol) of vitamin B12a and 0.4 g (7.5 mmol) of NH4Cl were added and stirred under an atmosphere of argon. Once these materials dissolved, 1 g (1.5 mmol) of Zn powder was added. After several minutes, 0.6 g (7 mmol) of 1 was added. The flask was flushed with argon and sealed to maintain an inert (13) (a) Vaze, A.; Parizo, M.; Rusling, J. F. Langmuir 2004, 20, 1094310948. (b) Vaze, A.; Parizo, M.; Rusling, J. F. Faraday Discuss. 2005, 265-274. (14) Ceglie, A.; Das, P. K.; Lindman, B. Colloids Surf. 1987, 28, 29-40. (15) Chen, S. J.; Evans, D. F.; Ninham, B. W.; Mitchell, D. J.; Blum, F. D.; Pickup, S. J. Phys. Chem. 1986, 90, 842-847.
atmosphere. The reaction was carried out in the dark, with constant stirring for a period of 7 days at room temperature. The oil/water (O/W) distribution of 1 was studied after equilibrating in tetradecane/water overnight at room temperature. The amount of epoxide in the tetradecane layer was determined by gas chromatography (GC). The amount of 1 in the water layer was analyzed by GC after extracting three times with fresh tetradecane. The O/W distribution coefficient obtained for 1 was 5.7. Instrumentation. A Hewlett-Packard (HP) 6890 gas chromatograph (GC) equipped with a flame ionization detector (FID) and a 5% phenyl methyl dioxane column (Hewlett-Packard, HP-19091J413; 30 m × 0.35 µm × 0.25 mm) was used for quantification. Helium carrier gas was used at a constant pressure of 14.2 psi, and the oven temperature was programmed from 32 °C to 220 °C at 8 °C per minute. Detector temperature was 300 °C, and injector temperature was 250 °C. The HP GC-mass spectrometer (MS) was equipped with a 5890 GC and a DB-1 methyl silicone (12 m × 0.22 mm × 330 µm) column. An HP 5970 mass selective detector with electron impact ionization and a quadrupole mass analyzer were used. Chiral GC analysis was performed on a β-dextran column (Supelco, BETA DEX 325 capillary column; 30 m × 0.35 µ × 0.25 mm) with the temperature programmed from 40 °C at the rate of 1 °C/min up to 220 °C. The carrier gas helium was at 12 psi, the FID detector temperature was 300 °C, and the injector temperature was 205 °C. Analysis of Products. The reaction mixture was collected after 7 days and eluted by gravity on a silica column (silica gel 60, 0.0630.200 mm) with ether as the solvent. This procedure traps surfactant on the column. The eluted reaction mixture containing mostly reactants and products was analyzed by GC-MS and quantified using GC with flame ionization detection (FID) using cyclohexanol as an internal standard. Peaks were assigned on the basis of the MS fragmentation pattern and the retention times of the standards in GC-MS, GC-FID, and chiral GC-FID. Cyclopentene was not determined due to losses resulting from its volatility. GC retention times on the chiral GC phase were tR ) 26.6 min for (S)-2 and tR ) 26.9 min for (R)-2 baseline separated. Retention times on the GC normal phase: 1 at tR ) 2.3, 2 at tR ) 2.6, 3 at tR ) 2.8, 4 at tR ) 3, and cyclohexanol at tR ) 4.4 min
Results Isomerization of 1 by vitamin B12a was carried out in various microemulsions, as shown in Table 1. The focus in all these experiments was to observe the influence of microemulsion structure and composition on the enantioselectivity of the reaction in Scheme 1. The bicontinuous CTAB and SDS microemulsions 1-4 were chosen so as to all have the same relative fractions of components. Microemulsion 5 substitutes octanol for butanol, converting the fluid to a W/O system featuring water droplets. The DDAB microemulsion 6 was chosen because this doublechain surfactant allows the formation of bicontinuous microemulsions with low water content.15 The product yields and stereoselectivity for each microemulsion are given in Table 2. In all of the bicontinuous SDS or CTAB microemulsions, allylic alcohol (R)-2 was the major product found (yield: av 60%) with less than 10% of the side products 3 and 4. Cyclopentene 5 (yield: 30% in methanol),12 the volatile side product of the reaction, was not quantified. This may have contributed to some of the lower mass balances (50-80%). The results are in general agreement with those reported by Scheffold in methanol.12 The best e.e. of 52% was found for the bicontinuous SDS microemulsion (Table 2, entry 4) at a yield of 58% (R)-2. The yield and percent e.e. were significantly smaller for the O/W SDS microemulsion (Table 2, entry 5). The best bicontinuous CTAB microemulsion was that at the neutral pH water phase, with an e.e. of 44% and 63% yield (Table 2, entry 1). The four-component bicontinuous microemulsions of CTAB and SDS seem to be the more suitable for the synthesis of (R)-2.
EnantioselectiVe Synthesis of (R)-Cyclopent-2-enol
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Table 2. Vitamin B12-Catalyzed Isomerization of 1 in Microemulsionsa
1 2 3 4 5 6 7 a
microemulsion
vit. B12a [µmoles]
1 [mmol]
% e.e.
(R)-2
CTAB/tetradecane/n-butanol/water, pH 7.0 CTAB/tetradecane/n-butanol/water, pH 4.0 CTAB/tetradecane/n-butanol/water, pH 10.0 SDS/tetradecane/n-butanol/water SDS/tetradecane/n-octanol/water (W/O) DDAB/n-hexane/water SDS/tetradecane/n-butanol/water
70 70 70 70 70 7 7
7 7 7 7 7 0.7 0.7
45 ( 0 40 ( 0 42 ( 3 52 ( 2 42 ( 3 0(0 40 ( 13
63 ( 21 58 ( 9 60 ( 5 58 ( 3 38 ( 16 28 20 ( 10
% yield 3 2(2 6(4 1(2 1(0 5(3 13 1 ( 0.5
4
mass balance %
1(1 1(1 2(1 4(0 1(2 4 2(3
79 ( 9 67 ( 11 68 ( 9 64 ( 5 54 ( 5 85 30 ( 6
The average of 2 reactions with an average deviation. 1: 1,2-epoxycyclopentane; 2: 2-cyclopentene-1-ol; 3: cyclopentanone; 4: cyclopentanol.
Table 3. Enantioselectivity in an SDS/Tetradecane/n-Butanol/ Water Microemulsion with Different Amounts of Catalyst vitamin B12a [µmol]
1 [mmol]
% e.e.
70 140 210 280 350
7 7 7 7 7
52 ( 2 41 ( 11 48 ( 3 35 ( 3 39 ( 14
In the three-component bicontinuous DDAB microemulsion, the solubility of vitamin B12a, which is water soluble but not oil soluble, is very low. With 7 µmol of the catalyst and 0.7 mmol of epoxide, no enantioselectivity was seen in this system (Table 2, entry 6). However, the four-component bicontinuous microemulsion of SDS/tetradecane/n-butanol/water (17.5/12.5/35/35), with the same amount of catalyst and epoxide but with more water, gave an e.e of 40% but a low yield (Table 2, entry 7). This suggests that the activity of the catalyst is influenced by the amount of water available in the microemulsion. The structure of a four-component microemulsion is partly determined by the chain length of the alcohol.16 Replacing n-butanol with n-octanol in the SDS/tetradecane/n-alcohol/water microemulsion changes its structure from a bicontinuous network of oil and water to microdroplets of water surrounded by oil (W/O).14,16 This may result in a decreased interaction of vitamin B12a (which is now segregated in the water droplets) with 1, which resides mainly in the oil phase. Accordingly, a decrease in e.e. from 52 to 40% was observed upon changing the cosurfactant of SDS/tetradecane/n-butanol/water to n-octanol, and the yield decreased as well. A decrease in the rate of isomerization of 1 under acidic conditions in methanol showed slight improvement in percent e.e.12 Hence, we carried out the reaction in CTAB bicontinuous microemulsions containing water phase with the pH adjusted to acidic and alkaline pH to see if an effect of pH on enantioselectivity could be observed. However, no improvement of the e.e. was found at acidic or alkaline pH in CTAB microemulsions (Table 2, entries 2 and 3). A series of reactions were carried out in the SDS/tetradecane/ water/n-butanol microemulsion with increasing amounts of the vitamin B12 catalyst while the initial concentration of 1 was kept constant. A slight decreasing trend in percent e.e. was observed with increased catalyst concentration (Table 3). However, these results suggest that the enantioselectivity of the reaction is not influenced very much by the amount of catalyst.
Discussion Reaction Pathway. We can interpret the results obtained in the light of the mechanistic aspects of the epoxide isomerization established by Scheffold.12 Due emphasis needs to be placed on (16) Ceglie, A.; Das, K. P.; Lindman, B. J. Colloid Interface Sci. 1987, 115, 115-120.
Scheme 2. Pathway for Isomerization of Cyclic Epoxide 1 to Chiral Alcohol by Cobalt Corrin Vitamin B12 via Organocobalt Intermediate 6
the effect of the composition and dynamics of the microemulsions that host the reaction. As a background, we begin with an overview of the reaction mechanism put forth by Scheffold,8,12 then summarize studies on catalysis by vitamin B12 in microemulsions.2,17 In methanol, the isomerization (Scheme 1) is known to proceed in two steps. In the first step, the CoII corrin complex vitamin B12r, obtained by one electron reduction of the CoIII form of vitamin B12a, is reduced by NH4Cl/Zn to the CoI form of vitamin B12s [CoIL]. This chiral, four-coordinate CoIL is a strong nucleophile. The epoxide ring of 1 is opened in a proton-assisted SN2-type displacement of the epoxide oxygen by CoIL. Cob(I)alamin reacts from its upper (β) side and displaces the O atom of the epoxide at one of the two enantiomeric C atoms with inversion of configuration to yield a mixture of intermediate diastereoisomers: the (1R,2R)- and (1S,2S)-(2-hydroxycyclopentyl) cob(III)alamins (Scheme 2).12 Reductive elimination leads to allylic alcohol and cob(I)alamin. Assuming that C substituents at the C atom bound to Co(III) in 6 are directed toward the (less hindered) “southern” hemisphere of the β side of vitamin B12, the reductive elimination leading to (R)-allylic alcohol ((R)-2) should occur from the diastereoisomer in which the hydrocarbon chain bearing the (R)-2 carbon is oriented toward the “eastern” hemisphere β side of vitamin B12. On the basis of this view, the ratio of diastereomeric organocobalt complexes was predicted8,12 to be 4:1 R/S based on the known stereochemistry of alkylation of CoI derivatives of vitamin B12 by epoxides such as epoxypropane.18,19 This cobalt alkylation to give 6 is the key step that determines the enantioselectivity of the reaction, since the absolute configuration of the hydroxy-substituted carbon atom in the product is fixed by the structure of the organocobalt intermediate 6. In the second step, the intermediate 6 decomposes to give (R)-2, recycled CoIL, protons, and 3, 4, and 5 as side products. In previous work,12 enantioselectivity was strongly influenced (17) Zhou, D.-L.; Carrero, H.; Rusling, J. F. Langmuir. 1990, 12, 3067-3074. (18) Dixon, R. M.; Golding, B. T.; Howarth, O. W.; Murphy, J. L. J. Chem. Soc., Chem. Commun. 1983, 243-245. (19) (a) Fountoulakis, M.; Re´tey, J.; Hull, W. E.; Zagalak, B. In Vitamin B12, Proceedings of the 3rd European Symposium, Zu¨rich, Switzerland, 1979; W. de Gruyter: Berlin, New York, 1979. (b) Kra¨utler, B.; Caderas, Ch. HelV. Chim. Acta, 1984, 67, 1891.
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by the dielectric constant of the solvent. The highest e.e. of 76% was obtained in a mixture of dioxane and methanol ( ) 9), while the lowest e.e. of 45% was obtained in water ( ) 71). It is reasonable to expect the same mechanism to hold for catalysis of the isomerization by vitamin B12a in microemulsions. Catalysis by Vitamin B12 in Microemulsions. Over the past decade, we have investigated electrochemical dehalogenation,2 cyclization,20 and cyclopropanation21 catalyzed by vitamin B12a in microemulsions. By tuning the composition of the microemulsion, enhanced reaction rates and control of pathways could be achieved by controlling the formal potential of the catalyst and the polarity of the reaction site, respectively.2 In the present work, we explored the effect of low availability of water, microemulsion structure, acidity, and catalyst concentration on the enantioselectivity and yields of the reaction in Scheme 1. Results suggest that the enantioselectivity of the reaction is influenced by structural and compositional changes in the microemulsion. Such changes influence the availability of vitamin B12a, the polarity and chemical nature of the reaction site, and key interactions with the reactant, which in turn influences the enantioselectivity by impacting the mechanism illustrated by Scheme 2. Specific results are discussed below. Influence of Water Content. When the reaction was carried out in the ternary bicontinuous microemulsion DDAB/hexane/ water with 10% water using 7 µmol of vitamin B12a, a complete lack of enantioselectivity for the allylic alcohol was found (Table 2, entry 6). In contrast, a four-component bicontinuous microemulsion of SDS/ tetradecane/n-butanol/water with the same amount of the catalyst and epoxide gave an e.e. of 40% of (R)-2 (Table 2, entry 7). Vitamin B12 is highly water soluble and resides almost exclusively in the water phases of microemulsions. Furthermore, the reactive Co(I) form has negligible interactions with charged surfactant headgroups.2,22 The measured O/W distribution coefficient obtained for 1 was 5.7, suggesting that only ∼15% of the reactant resides in the water phase at equilibrium. Hence, the reaction between the catalyst and the epoxide may be occurring predominantly in the water phase of the microemulsion, with reactant supplied by the transfer across the interface from the oil phase. Simultaneous recycling of the catalyst and partitioning of cyclopentene oxide from the oil to the water phase must occur for the reaction to proceed at a reasonable rate. Thus, the supply of reactant in the water phase or at the interface could be a limiting factor. Such a phenomenon was documented earlier for electrocatalytic reactions in W/O microemulsions having vitamin B12 sequestered in water droplets.22 The solubility of vitamin B12 in the DDAB/hexane/ water microemulsion was poor due to the low amount of water. However, the fact that the same amount of catalyst in SDS/ tetradecane/n-butanol/water with 35% of water gave an e.e. of 40% (Table 2, entry 7) suggests that the amount of water available is a significant factor for enantioselectivity. The decrease in water content in the ternary system may affect the availability of B12a to form the diastereomeric organocobalt complex (6), as well as efficient recycling of the catalyst following its decomposition, thus decreasing the overall reaction selectivity. Another factor that could be important and difficult to distinguish from the influence of water is the role of cosurfactant. Cosurfactants are nonionic amphiphilic molecules added to (20) (a) Gao, J.; Rusling, J. F.; Zhou, D.-L. J. Org. Chem. 1996, 61, 59725977. (b) Gao, J.; Rusling, J. F. J. Org. Chem. 1998, 63, 218-219. (c) Gao, J.; Njue, C. K.; Mbindyo J. K. N.; Rusling, J. F. J. Electroanal. Chem. 1999, 464, 31-38. (21) Njue, C. K.; Nuthakki, B.; Vaze, A.; Bobbitt, J. M.; Rusling, J. F. Electrochem. Commun. 2001, 3, 733-736. (22) Owlia, A.; Wang, Z.; Rusling, J. F. J. Am. Chem. Soc. 1989, 111, 50915098.
Nuthakki et al.
stabilize microemulsions, and alcohols are most commonly used.1,23 Texter et al.24 showed that, with partitioning of the cosurfactant between oil, water, and the interface, there is modification in surfactant packing and an increase in the interfacial dielectric constant. As a result, there is an increase in the polar or charged solute permeability within the interfacial region. Overall, addition of a cosurfactant improves interfacial fluidity and mixing of reactants in different microphases in quaternary fluids such as SDS/tetradecane/n-butanol/water microemulsions. This may be a factor in the improved enantioselectivity of the reaction in the SDS/tetradecane/n-butanol/water microemulsions, as opposed to the DDAB system with no cosurfactant. Enantioselectivity in Quaternary Bicontinuous Microemulsions. The best operating conditions for the enantioselective synthesis were found in quaternary bicontinuous microemulsions. These microemulsions feature relatively high water content (35%), good water/oil balance (Table 1), and good solubility of vitamin B12. These factors facilitate a better intermixing of catalyst and reactant. SDS/tetradecane/n-butanol/water with 70 µmol catalyst and 7 mmol epoxide gave the highest e.e. of 52%, followed by CTAB/tetradecane/n-butanol/water with 45% (Table 2, entries 1 and 4). The rate constant of isomerization of epoxide to 2 and 3 in methanol decreased with a decrease in the pH of the solution accompanied by improved enantioselectivity.8 To assess the effect of acidity on selectivity in microemulsions, the reaction was carried out in a CTAB/n-butanol/tetradecane/water system with the water-phase pH adjusted to acidic (pH 4) and basic (pH 10) conditions. While we realize that these pH values will not be exact in the final water phase, they can provide more acidic and more basic water phases in the microemulsions than a neutral water phase. The e.e. values of (R)-2 obtained in theses fluids were 40% (acidic) and 42% (basic) (Table 2, entries 2 and 3). Hence, there was no measurable influence of acidity of the water phase on the e.e. of the reaction in the microemulsions used. Effect of Microemulsion Structure. Changing the cosurfactant from n-butanol to n-octanol in (SDS/tetradecane/n-butanol/ water) changes the structure of the microemulsion from bicontinuous to W/O.14 Previous studies on mediated electrochemical synthesis in microemulsions indicated that the rates of electrochemical reduction of alkyl bromides, including trans1,2-dibromocyclohexane (DBCH) by vitamin B12a in a bicontinuous microemulsion of DDAB/dodecane/water (wt % 21:40: 39), were comparable to rates in homogeneous solvents.2 In addition, in DDAB/dodecane/water microemulsions, the reduction rate of DBCH by vitamin B12 was 40-fold larger than that in W/O microemulsions of aerosol-OT (AOT)/water/isooctane. Effective intermixing of the phases in bicontinuous systems with their larger O/W interfacial areas was an important factor in enhancing the observed kinetics. In the present work, the observed decrease in e.e. from 52 to 42% upon changing the microemulsion from bicontinuous to W/O may be an effect of decreased intermixing of the catalyst that is now confined in the water droplet surrounded by the substrate in the oil phase (Table 2, entries 4 and 5). The effect is not as striking as that in the case of DBCH, probably because of the nature of the substrate, its partial partitioning into water, and the slowness of the reaction, which leaves a lot of time for partitioning. (DBCH resides exclusively in the oil phase while ∼15% of 1 partitions into the water phase.) (23) Valiente, M.; A Ä lvarez. Colloids Surf., A. 2001, 183-185, 235-246. (24) (a) Garcia, E.; Song, S.; Oppenheimer, L. E.; Antalek, B.; Williams, A. J.; Texter, J. Langmuir 1993, 9, 2782-2785. (b) Antalek, B.; Williams, A. J.; Texter, J. Langmuir 1994, 10, 4459-4467. (c) Garcia, E.; Song, S.; Oppenheimer, L. E.; Antalek, B.; Williams, A. J.; Texter, J. Colloids Surf., A 1995, 94, 131-136.
EnantioselectiVe Synthesis of (R)-Cyclopent-2-enol
Concentration of Vitamin B12a. The enantioselectivity of the reaction in microemulsions did not depend strongly on the catalyst concentration (Table 3). The best operating conditions for the synthesis were 70 µmol of vitamin B12 and 7 mmol of the epoxide. Results in methanol also indicated that the e.e. was not substantially affected by catalyst concentration.8 This is not surprising given the fact that the enantioselectivity of the reaction is solely determined by the ratio of the diastereomeric mixture of the intermediates (1R,2R)- and (1S,2S)-CoIII-(2-hydroxycyclopentyl)cobalamins (∼4:1 in methanol). Factors such as availability, efficient reactant intermixing, and recycling of catalyst seem to be of greater importance than the amount of catalyst present in the microemulsion. Summary. The Vitamin B12a-catalyzed isomerization of 1 in the presence of Zn and NH4Cl was influenced by microemulsion structure. (R)-2 was obtained with the largest e.e of 52% in the bicontinuous fluid SDS/tetradecane/water/n-butanol. Factors such
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as higher water content and bicontinuous structure facilitated efficient intermixing of the catalyst with the reactant and improved enantioselectivity. This study shows that changes in microemulsion composition and structure influence the enantioselectivity of a reaction, and represents an initial step toward optimization of microemulsions as solvents for enantioselective syntheses. Further studies are required to understand the specific roles of factors such as interfacial transport effects or the possible adsorption of reactants or intermediates at O/W interfaces. Acknowledgment. The authors thank Christian Bruckner of the University of Connecticut for guidance in the synthesis of 2-cyclopentene-1-ol and James Stuart of the University of Connecticut for assistance with gas chromatography. This work was supported by Grant No. CTS-0335345 from NSF. LA0600191
