Production 1-phenylethanol

Ligand Rh- Cat. L/Rh S/C Silane Silane/ Ketone Solvent TcmpTTimc (°C/h) Product 1 -phenylethanol (4) ... 

This is not a workable route, however, since the hydrogenation of acetophenone is not chemoselective and results in a mixture of products, 1-phenylethanol, ethyl benzene and ethyl cyclohexane, besides 1-cyclohexylethanol [11, 12]. The highest reported selectivity for TM 2.5b was 65 %, obtained with rhodium nanoparticles entrapped in boehmite nanofibers as catalyst [13]. 

In general, the hydrogenolysis product is also favored by an acidic medium, as illustrated in the hydrogenation over 5° palladium-on-carbon of acetophenone to the hydrogenation product phenylethanol and to the hydrogenolysis product ethylbenzene, with various additives present (S3). 

Acetophenone can react with formaldehyde to yield light-resistant resins which are used as additives in nitrocellulose paints. It is also used as a photoinitiator, and in the pharmaceuticals, perfumery, and pesticide industries (344). It can be hydrogenated to 1-phenylethanol which is used for the production of aromatic ester fragrances (345). Technical-grade acetophenone is available at 2.29/kg perfume-grade acetophenone was 6.50/kg in October 1994. 

Ethylbenzene Hydroperoxide Process. Figure 4 shows the process flow sheet for production of propylene oxide and styrene via the use of ethylbenzene hydroperoxide (EBHP). Liquid-phase oxidation of ethylbenzene with air or oxygen occurs at 206—275 kPa (30—40 psia) and 140—150°C, and 2—2.5 h are required for a 10—15% conversion to the hydroperoxide. Recycle of an inert gas, such as nitrogen, is used to control reactor temperature. Impurities ia the ethylbenzene, such as water, are controlled to minimize decomposition of the hydroperoxide product and are sometimes added to enhance product formation. Selectivity to by-products include 8—10% acetophenone, 5—7% 1-phenylethanol, and <1% organic acids. EBHP is concentrated to 30—35% by distillation. The overhead ethylbenzene is recycled back to the oxidation reactor (170—172). 

The coproduct 1-phenylethanol from the epoxidation reactor, along with acetophenone from the hydroperoxide reactor, is dehydrated to styrene in a vapor-phase reaction over a catalyst of siUca gel (184) or titanium dioxide (170,185) at 250—280°C and atmospheric pressure. This product is then distilled to recover purified styrene and to separate water and high boiling organics for disposal. Unreacted 1-phenylethanol is recycled to the dehydrator. 

The oxidation step is similar to the oxidation of cumene to cumene hydroperoxide that was developed earlier and is widely used in the production of phenol and acetone. It is carried out with air bubbling through the Hquid reaction mixture in a series of reactors with decreasing temperatures from 150 to 130°C, approximately. The epoxidation of ethylbenzene hydroperoxide to a-phenylethanol and propylene oxide is the key development in the process. 

Reactions of alcohols with sulfur tetrafluoride, because of decomposition and/or polymerization, usually do not give fluorinated products However, in the presence of a hydrogen fluoride scavenger like triethylamine or pyridine, even such sensitive substrates as benzylic alcohols [555], 2-phenylethanol, and 2-furylmethanol [554] can be fluorinated to give the expected fluoro derivatives (equation 73)... 

Treatment of perhydropyrido[2,l-c][l,4]oxazine-3,6-dione 232 with B2H6 yielded (—)-(2i )-[(2S)-hydroxymethyl)piperldin-1 -yl]-2-phenylethanol (233) (00T233). Reduction of ( )-(3i ,4i ,9aS)-4-methyl-3-phenylperhydropyr-ido[2,l-c][l,4]oxazin-3-ol (234) with NaBH4 yielded ring-opened product 235 (97JHC1813). 

Hydrogenation of styrene oxide over palladium in methanol 66 gives exclusively 2-phenylethanol, but in buffered alkaline methanol the product is l-phenylelhanol. If alcoholysis of the epoxide by the product is troublesome, the problem can be eliminated by portion-wise addition of the epoxide to the reaction, so as always to maintain a high catalyst-to-substrate ratio. The technique is general for reactions in which the product can attack the starting material in competition with the hydrogenation. 

When ionic liquids are used as replacements for organic solvents in processes with nonvolatile products, downstream processing may become complicated. This may apply to many biotransformations in which the better selectivity of the biocatalyst is used to transform more complex molecules. In such cases, product isolation can be achieved by, for example, extraction with supercritical CO2 [50]. Recently, membrane processes such as pervaporation and nanofiltration have been used. The use of pervaporation for less volatile compounds such as phenylethanol has been reported by Crespo and co-workers [51]. We have developed a separation process based on nanofiltration [52, 53] which is especially well suited for isolation of nonvolatile compounds such as carbohydrates or charged compounds. It may also be used for easy recovery and/or purification of ionic liquids. 

The research group of Backvall employed the Shvo s ruthenium complex (1) [21] for the racemization. This complex is activated by heat. For the KR they used p-chlorophenyl acetate as the acyl donor in combination with thermostable enzymes, such as CALB [20] (Figure 4.7). This was the first practical chemoenzymatic DKR affording acetylated sec-alcohols in high yields and excellent enantioselectivities. In the best case 100% conversion (92% isolated yield) with 99% ee was obtained. This method was subsequently applied to a variety of different substrates and it is employed (with a different ruthenium complex) by the Dutch company DSM for the large-scale production of (R)-phenylethanol [22]. 

The DKR of secondary alcohols can be efficiently performed via enzymatic acylation coupled with simultaneous racemization of the substrates. This method was first used by BackvaU for the resolution of 1-phenylethanol and 1-indanol [38]. Racemization of substrate 18 by a mthenium catalyst (Scheme 5.11) was combined with transesterification using various acyl donors and catalyzed by C.antarctica B Hpase. From aU the acyl donors studied, 4-chlorophenyl acetate was found to be the best. The desired product 19 was obtained in 80% yield and over 99% ee. 

The above-described reverse reaction (viz. the Fe-catalyzed dehydrogenation of alcohols to ketones/aldehydes) has been reported by Williams in 2009 (Table 9) [58]. In this reaction, the bicyclic complex 16 shows a sluggish activity, whereas the dehydrogenation of l-(4-methoxyphenyl)ethanol catalyzed by the phenylated complex 17 affords the corresponding ketone in 79% yield when 1 equiv. (relative to 17) of D2O as an additive was used. For this oxidation reaction, l-(4-methoxyphenyl) ethanol is more suitable than 1-phenylethanol and the reaction rate and the yield of product are higher. 

Although this chapter is directed toward ophthalmic products, it is largely applicable to parenteral and even nonsterile products (solutions, emulsions, and suspensions). The choice of preservative is limited to only a few chemicals that have been found, over the years, to be safe and effective for this purpose. These are benzalkonium chloride, thimerosal, methyl- and propylparaben, phenylethanol, chlorhexidine,... 

However, in the palladium-catalyzed addition of HSiCl3 to -substituted styrenes, the size of the substituent on the MOP ligand is crucial. While (R)-MeO-MOP/[Pd(//3-C3H5)Cl]2 yielded (R)-phenylethanol with poor enantioselectivity (14% ee),110 replacement of the methoxy group with hydrogen (H-MOP, (36d)) affords the same product with 93% ee (Equation (ll)) 111... 

Use of ferrocenylmonophosphine (fU-(A)-PPFA 5a for the same reaction improved the enantioselectivity.24,25,26 Here, the hydrosilylation product was oxidized into ( y)-l-phenylethanol 3 with 52% ee (entry 3). The ferrocenylmonophosphine 6 supported on Merrifield polystyrene resin has been also used for the hydrosilylation of styrene, though the enantioselectivity was lower (15% ee) (entry 4).27 Several chiral (/ -/V-sulfonylaminoalkyl)phosphines 7 were prepared from (A)-valinol and used for the asymmetric hydrosilylation of styrene.28 For styrene, phosphine 7a which contains methanesulfonyl group was most effective giving (asymmetric hydrosilylation (entries 6-9).29,29a... 

While Josiphos 41 also possessed an element of atom-centered chirality in the side chain, Reetz reported a new class of ferrocene-derived diphosphines which had planar chirality only ligands 42 and 43, which have C2- and C -symmetry, respectively.87 Rhodium(i)-complexes of ligands (—)-42 and (—)-43 were used in situ as catalysts (0.75 mol%) for the hydroboration of styrene with catecholborane 1 for 12 h in toluene at — 50 °C. The rhodium/ i-symmetric (—)-43 catalyst system was the more enantioselective of the two - ( -l-phenylethanol was afforded with 52% and 77% ee with diphosphines (—)-42 and (—)-43, respectively. In both cases, the regioselectivity was excellent (>99 1). With the same reaction time but using DME as solvent at lower temperature (—60 °C), the rhodium complex of 43 afforded the alcohol product with an optimum 84% ee. 

Extensive investigations in our laboratories on the deactivation of rhodium and iridium catalysts has shown there to be a number of different mechanisms involved. Both, rhodium and iridium catalysts are generally less stable at higher temperatures, and have more labile ligands than their ruthenium counterparts. All of the catalysts are affected by pH, but the ruthenium catalysts seem to be more readily deactivated by acid. Indeed, these reactions are often quenched with acetic acid, whilst stronger acids are used to quench the rhodium reactions. Each of the catalysts can be deactivated by product inhibition, the ruthenium catalyst with aromatic substrates such as phenylethanol, and the rhodium and iridium ones by bidentate chelating products. 

Figure 9.1 compares the synthesis of acetophenone by classic oxidation of 1-phenylethanol with stoichiometric amounts of chromium oxide and sulphuric acid, with an atom efficiency of 42%, with the heterogeneous catalytic oxidation with O2, with an atom efficiency of 87%, and with water as the only by-product. This is especially important if we consider the environmental unfriendliness of chromium salts the potential environmental impact of reactions can be expressed by the environmental quotient (EQ), where E is the E-factor (kg waste/kg product) and Q is the environmental unfriendliness quotient of the waste. If Q is... 

The chiral compounds (/ )- and (5)-bis(trifluoromethyl)phenylethanol are particularly useful synthetic intermediates for the pharmaceutical industry, as the alcohol functionality can be easily transformed without a loss of stereospecificity and biological activity, and the trifluoromethyl functionalities slow the degradation of the compound by human metabolism. A very efficient process was recently demonstrated for the production of the (5)-enantiomer at >99% ee through ketone reduction catalyzed by the commercially available isolated alcohol dehydrogenase enzyme from Rhodococcus erythropolis (Figure 9.1). The (7 )-enantiomer could be generated at >99% ee as well using the isolated ketone reductase enzyme KRED-101. 

Figure 9.1 Production of the (S)-bis-(trifluoromethyl)phenylethanol using alcohol dehydrogenase enzyme from R. erythropolis...

Ab initio MO calculations have been carried out for two carbocation-generating reactions the 6 nI reaction of protonated 1-phenylethanol (H2O leaving group) and the acid-catalysed hydration of styrene. Optimizations were done at the MP2/6-31G level. The 6 nI transition state lies half way between the reactant and the product with respect to the bond lengths, charge distribution, and secondary deuterium isotope effects. 

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