Diisopropyl ether as solvent

We investigated lipase-catalyzed acylation of 1-phenylethanol in the presence of various additives, in particular an E. additive using diisopropyl ether as solvent. Enhanced enantioselectivity was obtained when a BEG-hased novel IE, i.e., imidazolium polyoxyethylene(lO) cetyl sulfate, was added at 3-10 mol% vs. substrate in the Burkholderia cepacia lipase (hpase PS-C) catalyzed transesterification using vinyl acetate in diisopropyl ether or a hexane solvent system. ... 

As shown in Scheme 6,2,6-dibromopyridine was treated with n-butyllithium at -78 °C to form the lidiio species 6 which was trapped widi DMF (dimethylformamide). The tetrahedral intermediate 7 was then inversely quenched into acid to form the aldehyde 8 in 51% yield. The inq)ortance of diisopropyl ether as solvent for the n-butyllithium reaction will be described in detail later. Side products formed in this reaction were die protonated... 

The (5)-cyanohydiin formation catalyzed by recombinant MeHNL adsorbed on cellulose in diisopropyl ether as solvent gave only moderate optical yields, but by using nitrocellulose as support, the enantioselectivity was high in most cases [14]. Table 7 shows that recombinant MeHNL exhibits a similar broad substrate range as (/ )-PaHNL from bitter almonds [14]. It catalyzes the cyanohydrin formation with aromatic and heterocyclic as well as with aliphatic aldehydes [14]. 

In non-polar solvents such as benzene, toluene, chlorobenzene and diisopropyl ether (called solvent set B), a mild acceleration is observed, and the reactions are slower than in hexane. A molecular complex (see below) is proposed to explain the results for the reactions in solvent set B. 

Under the same conditions, diisopropyl ether as the solvent was found to give the best results in terms of chemical yield and enantioselectivity. The absolute configuration of the stereogenic center of the major enantiomer was determined to be (J ) by chemical correlations with previously reported compounds [46]. An example of tin-lithium exchange followed by intramolecular carboHthiation of a carbon-carbon double bond as an efficient entry to the asymmetric synthesis of 3-hydroxy-pyrrolidines was reported by Hoppe et al. [47]. When the easily accessible enantioenriched stannane 173 was treated with n-butyUithium at low temperature, the five-membered heterocycle 174 was obtained in nearly quantitative yield and with excellent diastereo- and enantioselectivity (Scheme 10.57). 

There is considerable literature precedent with respect to the metallation of 2,6-dibromopyridine to form 6. The first report was from Gilman with THF as solvent, which described a rapid addition of the butyllithium in order to have an efficient reaction (J). Although feasible on smaller scale, this is not viable on multi-kilogram scale. This was followed by the report from Hohn which utilized diethylether 4), Holm reported that diethylether was a better solvent than THF, as the starting material was insoluble in this solvent, effectively mimicking the inverse addition developed by the Merck group. This report describes the use of diisopropyl ether as a more process friendly solvent than diethylether. Finally, a report from Peterson described the use of methylene chloride as the reaction solvent (5). With methylene chloride, the ring deprotonation was controlled as well. 

On the other hand, various ( l-cyanohydrins have been prepared using (5)-hydroxy-nitrile lyases from plants (Fig. 34). The (5)-cyanohydrins can be further converted to a-hydroxy acids by acid hydrolysis without racemization [107]. A recent example is the hydroxynitrile lyase from Manihot esculenta, which was cloned in E. coli and used as chiral catalyst for the synthesis of a broad range of optically active a-hydroxynitriles including keto-(5)-cyanohydrins using diisopropyl ether as organic solvent and HCN as cyanide source [112]. Compared to the enzymes from leaves, the overexpressed enzyme in E. coli showed higher enantioselectivity. 

Actinide ions form complex ions with a large number of organic substances (12). Their extractabiUty by these substances varies from element to element and depends markedly on oxidation state. A number of important separation procedures are based on this property. Solvents that behave in this way are thbutyl phosphate, diethyl ether [60-29-7J, ketones such as diisopropyl ketone [565-80-5] or methyl isobutyl ketone [108-10-17, and several glycol ether type solvents such as diethyl CeUosolve [629-14-1] (ethylene glycol diethyl ether) or dibutyl Carbitol [112-73-2] (diethylene glycol dibutyl ether). 

D/chloro-5-Cyclohexyl-2-Oxo-2,3-D/hydro 1 H-Benzo(fj-Diazepine-1,4 fa) Process Using Sodium Hypochlorite — 40 ml of a solution of sodium hypochlorite of 14.5 British chloro-metric degrees are added to a suspension of 5.4 grams of 7 chloro-5 cyclohexyl-2 oxo-2,3-dihydro 1 H-benzo(f)diazepine-1,4 in BO ml of methylene chloride. The mixture is stirred at room temperature for 15 minutes the solid dissolves rapidly. The organic iayer is decanted, washed with water, dried over anhydrous Sodium sulfate and the solvent evaporated under reduced pressure without exceeding a temperature of 30 C. The residue is taken up in a little diisopropyl ether and the crystals which form are dried. They are recrystallized as rapidly as possible from ethyl acetate. Colorless crystals are obtained (3.9 grams yield, B5%) MP < = 163°C, with decomposition. 

Ethers are relatively stable and unreactivc in many respects, but some ethers react slowly with the oxygen in air to give peroxides, compounds that contain an 0-0 bond. The peroxides from low-molecular-weight ethers such as diisopropyl ether and tetrahydrofuran arc explosive and extremely dangerous, even in tiny amounts. Ethers are very useful as solvents in the laboratory, but they must always be used cautiously and should not be stored for long periods of time. 

Method B The solution is poured into dil. aq NaHCO, and then extracted 5 times with CHC1,. In both procedures evaporation of the solvent in vacuo affords the product as an oil in virtually quantitative yield. On treatment with diisopropyl ether the methyl compounds (R2 = CH,) crystallize. 

Aqueous solutions are not suitable solvents for esterifications and transesterifications, and these reactions are carried out in organic solvents of low polarity [9-12]. However, enzymes are surrounded by a hydration shell or bound water that is required for the retention of structure and catalytic activity [13]. Polar hydrophilic solvents such as DMF, DMSO, acetone, and alcohols (log P<0, where P is the partition coefficient between octanol and water) are incompatible and lead to rapid denaturation. Common solvents for esterifications and transesterifications include alkanes (hexane/log P=3.5), aromatics (toluene/2.5, benzene/2), haloalkanes (CHCI3/2, CH2CI2/I.4), and ethers (diisopropyl ether/1.9, terf-butylmethyl ether/ 0.94, diethyl ether/0.85). Exceptionally stable enzymes such as Candida antarctica lipase B (CAL-B) have been used in more polar solvents (tetrahydrofuran/0.49, acetonitrile/—0.33). Room-temperature ionic liquids [14—17] and supercritical fluids [18] are also good media for a wide range of biotransformations. 

We initially tested Candida antarctica lipase using imidazolium salt as solvent because CAL was found to be the best enzyme to resolve our model substrate 5-phenyl-l-penten-3-ol (la) the acylation rate was strongly dependent on the anionic part of the solvents. The best results were recorded when [bmim][BF4] was employed as the solvent, and the reaction rate was nearly equal to that of the reference reaction in diisopropyl ether. The second choice of solvent was [bmim][PFg]. On the contrary, a significant drop in the reaction rate was obtained when the reaction was carried out in TFA salt or OTf salt. From these results, we concluded that BF4 salt and PFg salt were suitable solvents for the present lipase-catalyzed reaction. Acylation of la was accomplished by these four enzymes Candida antarctica lipase, lipase QL from Alcaligenes, Lipase PS from Burkholderia cepacia and Candida rugosa lipase. In contrast, no reaction took place when PPL or PLE was used as catalyst in this solvent system. These results were established in March 2000 but we encountered a serious problem in that the results were significantly dependent on the lot of the ILs that we prepared ourselves. The problem was very serious because sometimes the reaction did not proceed at all. So we attempted to purify the ILs and established a very successful procedure (Fig. 3) the salt was first washed with a mixed solvent of hexane and ethyl acetate (2 1 or 4 1), treated with activated charcoal and passed into activated alumina neutral type I as an acetone solution. It was evaporated and dried under reduced... 

Kinetics show that the reaction is pseudo-first order in the RX concentration and that there is a linear correlation in the rate of consumption of RX with the concentration of the catalyst. The need for a high rate of stirring indicates that, as discussed in Chapter 1, the base-initiated formation of the cobalt tetracarbonyl anion results from an interfacial exchange process. It is significant that, when preformed NaCo(CO)4 is used, the extractability of the anion by benzyltriethylammonium cation into diisopropyl ether is three times less efficient than it is into benzene or dichloromethane, but kinetic studies show that, in spite of the lower concentration of the anion in the ether, the rate of reaction with RX in that solvent is generally higher [3]. 

The characteristics of a support material are of great importance to the measured enzyme activity [79, 101]. Hydrophobic carriers have a low ability to attract water, thus leaving more available for the enzyme, hence Wehtje et al. [102, 103] have shown that celite is a suitable carrier for the PaHnl to yield an immobilized form of the enzyme. In contrast, controlled pore glass (CPG) and Sephadex G25 were found to be less well suited to enzyme support as, using these systems, cyanohydrin synthesis was significantly reduced (over 30%). Sephadex also promoted the spontaneous addition of HCN to benzaldehyde [102]. A series of batch experiments showed that if the solvent (diisopropyl ether) surrounding the immobilised PaHnl contained insufficient water (i. e. less than 2 %), it would be extracted from the enzyme preparation and consequently enzyme activity was lost [102]. These results were the basis for the production... 

The solubilities of water in a few different solvents at 25°C are as follows hexane 7 1/1 ethyl acetate 30 ml/1 diisopropyl ether 4 ml/1. Assume that the water activity is proportional to the water concentration in each solvent (in reality there are large deviations from this ideal behaviour). If you add 3.0 1 water to 1.00 ml of each dry solvent, which water activities will you get at equilibrium in a closed container without gas phase ... 

Figure 3.7 Catalytic activity of subtilisin in anhydrous organic solvents ( n-hexane, diisopropyl ether, T THF) as a function of the KCI content in the dry catalyst. The activity is expressed in terms of kat/Km of the transesterification reaction between N-acetyl-L-phenylalanine ethyl ester and n-propanol, used in concentrations of lOmM and 0.85 M, respectively [88].

Similar results were found by Griengl and co-workers [21] for HbHNL catalysis. Ethers, such as diisopropyl ether (DIPE) or tBME, were found to be the most suitable solvents. The transformation proceeds most efficiently at temperatures between 5 and 15 °C, and the formation of a stable emulsion seems to be of importance. A series of aldehydes were converted by this method (Figure 9.2). Compared to transformations in aqueous buffer medium [22], higher conversions and were achieved (Table 9.1) [21]. 

In general, ethers are low on the scale of chemical reactivity because the carbon-oxygen bond is not cleaved readily. For this reason ethers frequently are employed as inert solvents in organic synthesis. Particularly important in this connection are diethyl ether, diisopropyl ether, tetrahydrofuran, and 1,4-dioxane. The mono- and dialkyl ethers of 1,2-ethanediol, 3-oxa-l,5-pentanediol, and related substances are useful high-boiling solvents. Unfortunately, their trade names are not very rational. Abbreviated names are in... 

Initial preparative work with oxynitrilases in neutral aqueous solution [517, 518] was hampered by the fact that under these reaction conditions the enzymatic addition has to compete with a spontaneous chemical reaction which limits enantioselectivity. Major improvements in optical purity of cyanohydrins were achieved by conducting the addition under acidic conditions to suppress the uncatalyzed side reaction [519], or by switching to a water immiscible organic solvent as the reaction medium [520], preferably diisopropyl ether. For the latter case, the enzymes are readily immobilized by physical adsorption onto cellulose. A continuous process has been developed for chiral cyanohydrin synthesis using an enzyme membrane reactor [61]. Acetone cyanhydrin can replace the highly toxic hydrocyanic acid as the cyanide source [521], Inexpensive defatted almond meal has been found to be a convenient substitute for the purified (R)-oxynitrilase without sacrificing enantioselectivity [522-524], Similarly, lyophilized and powered Sorghum bicolor shoots have been successfully tested as an alternative source for the purified (S)-oxynitrilase [525],... 

E. C. 3.1.1.3) as the biocatalyst, the prochiral silanes 86 and 88 were transformed into the levorotatory isobutyrates (—)-87 and (—)-89, respectively (Scheme 20)73. The latter conversions were carried out in diisopropyl ether (with 86) and tetrahydrofuran (with 88) as solvent. The yields and enantiomeric purities obtained with the transesterifications of 86 and 88 with CCL and CVL are summarized in Table 4. The absolute configurations of the biotransformation products are unknown. 

At the end of the previous chapter, we discussed the medium dependence of the lipase-catalyzed synthesis of nifedipines, dihydropyridines with an aromatic substituent in the 4-position and often asymmetric ester derivatives in the 3- and 5-positions, which are active as calcium antagonists in cardiovascular therapy. At the Amano Company in Nagoya, Japan, lipase-catalyzed hydrolyses of methylene-oxypropionyl or -pivaloyl diesters with Amano PS (Pseudomonas sp.) lipase were found to yield varying enantiomeric excesses depending on the solvent in cyclohexane the different esters yielded half-esters with 88.8-91.4% e.e. (R)-specificity for a triple mutant ( FVL ) of Amano PS lipase, whereas the same transformation with the same enzyme in diisopropyl ether (DIPE) yielded between 68.1 and > 99% e.e. of the (S)-product (Chapter 12, Figure 12.10) (Hirose, 1992,1995). 

A tribenzoyl derivative was used by Decroix et al. [6] for the determination of glycerol. The preparation of the derivative was carried out directly in the sample as it does not require strictly anhydrous conditions. After performing the extraction with diisopropyl ether and after evaporating the solvent, the derivative dissolved in chloroform was injected. A detection limit of 1 pg of glycerol was reported. The low thermal stability of the derivative is a drawback. 

A mixture of 10 g (0.057 mol) of 3-phenyl-4-pentenoic acid (3), 9.1 g (0.11 mol) of NaHCOj and 200 mL of H,0 is stirred until a homogeneous solution is obtained. 200 mL of CHC13 arc added, the mixture is cooled in an ice bath, and 28.4 g (0.112 mol) of iodine are added. The mixture is stirred at OX for 6 h, and the organic phase is washed with 10% aq sodium thiosulfate until colorless, then with H,0 and brine. The organic layer is dried and the solvent is removed under reduced pressure. The crude cw-iodolactone is obtained as a semisolid yield 15.5-16.3 g (91-95%) d.r. (cis/trans) 77 23 (determined by H NMR) mp 75-90X. Direct recrystallization of this material (diisopropyl ether) affords 9.0-9.5 g (52-55%) of material with a cis/trans ratio of 98 2 mp 103-104X. Further recrystallization from diisopropyl ether gives (in two crops) 8.3-8.9 g (48-52%) of product with a purity of 98% mp 104 105 X. Additional product can be obtained from the mother liquors. 

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