catalytic methods in asymmetric synthesis (advanced materials, techniques, and applications) ||...

CHAPTER 9

ASYMMETRIC CATALYTIC SYNTHESIS IN SUPERCRITICAL FLUIDS TOMOKO MATSUDA

9.1. Introduction 374 9.2. Basic properties of scCO 2 for the application in

organic synthesis 374 9.2.1. Advantages of organic synthesis in scCO 2 374 9.2.2. Reactors 376

9.3. Enzyme - mediated asymmetric synthesis 377 9.3.1. Lipase - catalyzed kinetic resolution of alcohols 378 9.3.2. Lipase and chemical catalysts - catalyzed kinetic resolution

and dynamic kinetic resolution of alcohols 379 9.3.3. Control of enantioselectivity of lipase - catalyzed

kinetic resolution 380 9.3.4. Alcohol dehydrogenase - catalyzed asymmetric reductions 383

9.4. Metal complexes - mediated asymmetric synthesis 383 9.4.1. Polymer - supported ( R,S ) - BINAPHOS - Rh(I) complex - catalyzed

olefi n hydroformylation 384 9.4.2. Hydrogenation of olefi n using aqueous/scCO 2 biphasic systems 385 9.4.3. Hydrogenation using IL and scCO 2 systems 385 9.4.4. Identifi cation of catalyst surface species for

platinum - catalyzed hydrogenation in supercritical ethane 386 9.4.5. Control of enantioselectivity of photoaddition by temperature

and pressure 387 9.5. Conclusions 388 References 388

373

Catalytic Methods in Asymmetric Synthesis: Advanced Materials, Techniques, and Applications, First Edition. Edited by Michelangelo Gruttadauria and Francesco Giacalone.© 2011 John Wiley & Sons, Inc. Published 2011 by John Wiley & Sons, Inc.

374 ASYMMETRIC CATALYTIC SYNTHESIS IN SUPERCRITICAL FLUIDS

9.1. INTRODUCTION

Green methods for asymmetric synthesis are increasing in importance as the demand for the use of chiral compounds grows. Such products are useful for a number of purposes, such as drug synthesis, where the majority of drug candidate molecules possess more than one chiral center. To synthesize them in environmentally friendly methods, green solvents and green catalysts are necessary. For these purposes, supercritical fl uids (fl uids above their critical points) have been used for organic synthesis [1] . Among supercritical fl uids, supercritical water (scH 2 O) and supercritical carbon dioxide (scCO 2 ) are con-sidered to be green because water and carbon dioxide exist naturally and abundantly. For asymmetric synthesis, carbon dioxide has been used due to the ambient critical temperature as shown in Table 9.1 and Figure 9.1 .

As catalysts for green asymmetric synthesis, both chemical and biological catalysts need to be developed because they are complementary to each other. They are used separately for most of the cases, but the methods of using both in one reaction, such as dynamic kinetic resolutions of racemates and using enzyme for resolution and metal catalysts for racemization, have become increasingly important. These reactions have also been conducted in scCO 2 .

Here, some representative reactions for asymmetric synthesis using scCO 2 by chemical catalysts and/or enzymes are shown. First, basic properties of scCO 2 are explained in Section 9.2 . Then, enzyme - mediated asymmetric syn-thesis is described in detail in Section 9.3 , and metal complexes - mediated asymmetric synthesis is introduced briefl y in Section 9.4 .

9.2. BASIC PROPERTIES OF SCCO 2 FOR THE APPLICATION IN ORGANIC SYNTHESIS

This section introduces the advantage of the use of scCO 2 for organic synthesis. The experimental apparatus are also explained briefl y here.

9.2.1. Advantages of Organic Synthesis in scCO 2

The properties of scCO 2 and the advantages of organic synthesis using scCO 2 are listed in Table 9.2 . scCO 2 is a high - density CO 2 solvent, so the use of scCO 2

TABLE 9.1. Critical Points of Some Materials Used for Organic Synthesis

Critical

Temperature ( ° C) Critical

Pressure (MPa) Critical

Density (g/mL)

CO 2 31 7.4 (73 atm) 0.47 Water 374 22 (218 atm) 0.32 Methanol 239 8.1 (80 atm) 0.27

BASIC PROPERTIES OF SCCO 2 FOR THE APPLICATION IN ORGANIC SYNTHESIS 375

FIGURE 9.1. (a) Phase diagram of carbon dioxide and image of each state; (b) tunability of the density of CO 2 by the temperature and pressure; (c) tunability of dielectric constant (closed square: 32 ° C; open square: 40 ° C; closed circle: 50 ° C; open circle: 60 ° C) [2] .

Temperature(oC)

Pressure(atm)

Supercritical�uid

Gas

LiquidSolid

160

80

0

-100 0 100

Critical point:31°C 73 atm (7.4 MPa)

Liquid

Gas

Supercritical �uidaround mark (near critical point and on the extension line of gas–liquid equilibrium line)

: one molecule

Supercritical �uid around mark

High density

Low density

Supercritical �uid around mark

*

***

***

***

**

Density(g/mL)

Pressure (MPa) Pressure (MPa)

Dielectric constant

3025201510500.0

0.2

0.4

0.6

0.8

1.0

3025201510501.0

1.1

1.2

1.3

1.4

1.5

1.6(b) (c)

(a)

makes feasible the development of a reaction using carbon dioxide as a reac-tant. The diffusivity of scCO 2 is high like a gas, which makes the reaction rate faster. The high solubilizing power of scCO 2 (like that of liquids) to dissolve hydrophobic substrate also leads to a higher reaction rate. Since scCO 2 is a hydrophobic solvent like perfl uorinated solvents (Fig. 9.1 c), a cosolvent may be necessary to dissolve hydrophilic substances. scCO 2 becomes a gas after the reaction pressure reaches 1 atm, so the separation of the product from the


solvent is easy, and an extraction process is not necessary. For the enzymatic process in aqueous media, the extraction of product and treatment of the wastewater contaminated with extraction solvent may be diffi cult, but the use of scCO 2 solves these problems. CO 2 exists naturally and abundantly, so there is no waste problem and no problem with existing traces of solvent in the product. Finally, the tunability of scCO 2 clearly distinguishes supercritical fl uids from conventional solvents. Its properties such as density, dielectric constant, diffusivity, viscosity, solubility, and so on, can be tuned by adjusting the pressure and temperature. For example, the density of scCO 2 can change from high (like a liquid) to low (like a gas) as shown in Figure 9.1 a,b by adjust-ing the pressure and temperature [2] . Therefore, solvent property can be adjusted to be suitable to the desired reactions by adjusting the pressure and temperature. In some cases, the selectivity of the reaction can be controlled by tuning the solvent property by adjusting the pressure and temperature. Moreover, with supercritical fl uids, solvent effects on the reaction can be examined without changing the kind of solvent. Therefore, continuous changes in the result — for example, enantioselectivity — can be expected, since the solvent properties can be changed continuously by manipulating the pressure and temperature.

9.2.2. Reactors

Both batch - and fl ow - type reactors have been used for asymmetric synthesis using scCO 2 . A representative fl ow reactor [3] is shown in Figure 9.2 . With fl ow reactors, the addition of a substrate to the column with a catalyst (chemical catalysts or enzymes) yields the product and CO 2 , which is a gas at ambient pressure. With the batch reactor, however, extraction of the product from the

TABLE 9.2. Advantages of Organic Synthesis in scCO 2

Properties of scCO 2 Advantages

High - density CO 2 Development of reaction using CO 2 as a reactant. High diffusivity High reaction rate. High solubilizing power

High substrate concentration to increase reaction rate.

Gas at ambient conditions

Easy separation of the product from the solvent.

CO 2 exists naturally No waste problem. No problem with existing traces of solvent in the product.

Tunability Control of selectivity by tuning the solvent properties. Examination of effect of solvent without changing the

kind of molecule.

ENZYME-MEDIATED ASYMMETRIC SYNTHESIS 377

FIGURE 9.2. Simplifi ed illustration of scCO 2 experimental apparatus.

Substratepump

CO2 pump

Catalyst in a reactor(chemical catalyst or enzyme, etc.)

Back pressure regulator

Product(chiral compounds, etc)

Substrate(racemic compounds etc.)

CO2P

P

Constant-temperature bath (higher than 31°C)

NO ORGANIC SOLVENT USEDFOR SYNTHESIS OF CHIRAL COMPOUNDS

(Immobilizedenzyme)

biocatalyst is necessary after depressurization, and an organic solvent may be used. Therefore, the fl ow type is superior to the batch type for achieving virtu-ally no solvent reaction. Moreover, the size of the reactors that use the fl ow process to generate an amount of product comparable with the corresponding batch reactors is smaller [4] , which is particularly attractive for a supercritical fl uid system.

9.3. ENZYME - MEDIATED ASYMMETRIC SYNTHESIS

The attraction of combining natural catalysts with a natural solvent has been the driving force behind a growing body of literature on the stability, activity, and specifi city of enzymes in scCO 2 [5] . Since the fi rst report on biotransforma-tions in supercritical fl uids in 1985 [6] , the benefi ts of using supercritical fl uids for biotransformations have been demonstrated, for example, in improved reaction rates, control of selectivities by pressure, and so on. The kind of bio-catalytic reaction in the majority of reports has been hydrolysis due to the high stability and ease in handling. Oxidation and reduction have accounted for the second largest number of studies of biocatalysis. Here are some examples presented for kinetic resolution of racemic alcohol through esterifi cation by lipase and asymmetric reduction.


9.3.1. Lipase - Catalyzed Kinetic Resolution of Alcohols

Heterogeneous, immobilized enzymes have been used for the synthesis of optically active compounds which have been virtually obtained without solvent using a fl ow reactor as shown in Figure 9.2 [3] . The use of the continuous fl ow reaction for the kinetic resolution of 1 - phenylethanol by lipase Novozyme 435 resulted in a completely organic solvent - free process and in a signifi cant improvement in the productivity for long periods of reaction times. The pro-ductivity of the optically active compounds, namely space – time yield, was improved by over 400 times compared to the corresponding batch reaction using scCO 2 . The reaction of 1 - phenylethanol and vinyl acetate, with the molar ratio of 1:0.5 at a fl ow rate of 0.70 mL/min, over the catalyst under 13 MPa of scCO 2 (1.5 mL/min), gave the corresponding acetate with 99.7% enantiomeric excess (ee) in 47% yield. The E value exceeds 1800 (Scheme 9.1 a). The use of a slight excess of vinyl acetate resulted in an increase in the chemical yield of optically active acetate from 47% to 50%, in which the unreacted alcohol with 98.8% ee was recovered quantitatively. Changing the CO 2 pressure from 8.9 to 20 MPa did not signifi cantly change the outcome of the reaction.

When the substrate specifi city of this system was investigated, it was found that aliphatic alcohols, 2 - undecanol, and 1 - tetralol were kinetically resolved with the Novozym catalyst to give a mixture of the corresponding optically active ( R ) - ester and unreacted ( S ) - alcohol (Scheme 9.1 b,c). This synthetic process is particularly useful for the large - scale production of optically active alcohols. The biocatalyst maintained its performance in terms of the reactivity and selectivity during 3 days of operation under supercriti-

SCHEME 9.1. Asymmetric enzymatic reactions using scCO 2 fl ow system.

Vinyl acetatescCO2

OH

Continuous kinetic resolution

O

O

Candida antarctica lipase B(Novozym 435)

OH

C9H19

OH

OH

C9H19

OAc

OAc

(R)

C9H19

OH

OH

(S)

E 112–137

E >1500

(R) (S)Vinyl acetate

scCO2

Novozym 435

Vinyl acetatescCO2

E >1000

(R) (S)

(a)

(b)

(c)Novozym 435


cal conditions (12.9 – 13 MPa at 42 ° C), and resulted in a quantitative transfor-mation of ( R / S ) - 1 - phenylethanol (221 g) to ( S ) - phenylethanol with 99% ee and the corresponding ( R ) - acetate with 99% ee using 1.73 g of the immobi-lized enzyme.

9.3.2. Lipase and Chemical Catalysts - Catalyzed Kinetic Resolution and Dynamic Kinetic Resolution of Alcohols

Enzymes and chemical catalysts are complementary to each other, so they are used together in an scCO 2 fl ow system. For example, the two - step reaction shown in Scheme 9.2 a was conducted successfully by linking two reactors in series [7] . The fi rst reactor was used for the metal - catalyzed hydrogenation of acetophenone and the second reactor for lipase catalyzed the kinetic resolu-tion of the resulting 1 - phenylethanol.

Using chemical catalysts and lipase together, dynamic kinetic resolution (DKR) was also successfully conducted in scCO 2 [8] . For the above - described kinetic resolution, the maximum conversion in the reaction is only 50%, and the product has to be separated from the reactants. However, in DKR, it is possible to convert the racemic reactant to product with 100% yield and 100% ee theoretically, because the reactant is racemized to replenish the faster reacting enantiomer at the expense of the slower reacting enantiomer. Continuous DKR processes in ionic liquid (IL)/scCO 2 biphasic systems

SCHEME 9.2. Asymmetric synthesis with lipase together with chemical catalysts using scCO 2 fl ow system: (a) hydrogenation of acetophenone over an achiral Pd catalyst to produce rac - 1 - phenylethanol (fi rst step) and the kinetic resolution of ( R / S ) - 1 - phenylethanol to produce ( R ) - acetate and ( S ) - alcohol (second step); (b) DKR of rac - 1 - phenylethanol by transesterfi cation with vinyl propionate catalyzed by the combined action of immobilized lipase (Novozym) and silica modifi ed with benzenosulphonic acid groups.

OH

Continuous one-pot reduction and kinetic resolution

O

O

Novozym 435, Pd catalyst,Vinyl acetate, scCO2

Vinyl propionate, scCO2, Ionic liquid

OH

Continuous dynamic kinetic resolution

O

O

Novozym 435Silica modified with benzenosulfonic acid 76% yield

91%–98% ee (R)

OHO

(a)

(b)

Heterogeneousacemization catalystr


were carried out by simultaneously using both immobilized lipase (Novozym 435) and silica modifi ed with benzenesulfonic acid (SCX) catalysts at 40 ° C and 10 MPa as shown in Scheme 9.2 b. SCX racemized ( S ) - 1 - phenylethanol effi ciently in different IL media ([emim][NTf 2 ], [btma][NTf 2 ], and [bmim][PF 6 ]), and lipase catalyzed the kinetic resolution of ( R / S ) - (1) - phenylethanol. Coating both chemical and enzymatic catalysts with ILs greatly improved the effi ciency of the process, providing a good yield (76%) of ( R ) - 1 - phenylethyl propionate product with excellent ee (ee = 91% – 98%) in continuous operation.

9.3.3. Control of Enantioselectivity of Lipase - Catalyzed Kinetic Resolution

One of the most prominent characteristics of scCO 2 is the tunability of the solvent properties. Its properties such as density can be tuned by adjusting the pressure and temperature [2] , so the property can be continuously changed. Here is an example of controlling the enantioselectivity of the lipase - catalyzed reaction by changing the pressure and temperature [9] .

The enantioselective acetylation of racemic 1 - ( p - chlorophenyl) - 2,2,2 - trifl uoroethanol with lipases and vinyl acetate in scCO 2 was examined in detail (Fig. 9.3 a), and it was found that the enantioselectivity of the reaction catalyzed by lipase Novozym can be controlled by adjusting the pressure and the temperature of the scCO 2 . First, various lipases were screened for the reaction (Table 9.3 ). In all but one case, the ( S ) - enantiomer reacted faster than the ( R ) - enantiomer, affording ( S ) - acetate and the remaining ( R ) - alcohol. The highest enantioselectivity ( E = 38) was obtained using Novozym at 9.1 MPa. Interestingly, the enantioselectivity was signifi cantly affected by pressure.

The effect of pressure on enantioselectivity was investigated in more detail by carrying out the esterifi cation at pressures ranging from 8 to 19 MPa and for different reaction times, while maintaining the temperature at 55 ° C. As shown in Figure 9.3 b, the E value decreased from 50 to 10 continuously when the pressure was changed from 8 to 19 MPa, regardless of the reaction time. The effect of pressure on enantioselectivity is indeed noteworthy, although the reason is not clear at present. When the pressure of scCO 2 was changed, there was no signifi cant change in the polarity evaluated as a dielectric constant and log P (at 50 ° C; 1.4 at 8 MPa and 1.9 at 11 MPa) [10] . On the other hand, the density of scCO 2 does change from 0.20 to 0.42 g/mL when the pressure is changed from 8 to 11 MPa at 55 ° C [2] . It was proposed that the large change in density could signifi cantly change the interaction between CO 2 and the enzyme by the formation of carbamates from CO 2 and the free amine groups on the surface of the enzyme. This can also occur by CO 2 adsorption on the enzyme and/or by CO 2 incorporation in the substrate - binding pocket of the enzyme, in analogy to the incorporation of organic molecules in enzymes. These interactions may gradually change the conformation of the enzyme in


FIGURE 9.3. Control of enantioselectivity of lipase - catalyzed kinetic resolution by pressure and temperature.

Novozym 435

Vinyl acetateCO2Ar = p-chlorophenyl

Ar

(a)OH OAc

CF3 Ar CF3

OH

Ar CF3

(R/S)

(S) (R)

(b)

Pressure, MPa

19171513119770

10

20

30

40

50

60 2 hours3 hours4 hours

E v

alue

(c)

Pressure, MPa

211917151311970

10

20

30

40

50

60

7031°C40°C60°C

E v

alue

(d) ln E = – (∆∆H‡ / R) (1/T) + (∆∆S‡ / R)

3.33.23.1

1/T × 10–3, K–1

3.02.0

2.5

3.0

3.5

4.0

In(E

)

∆∆H‡ = –11 kcal/mol ∆∆S‡ = –28 cal/K/mol


response to pressure, resulting in a continuous change in enantioselectivity. The effect of pressure on the enantioselective acetylation of the alcohol with vinyl acetate in scCO 2 by Novozym was also investigated at 31, 40, and 60 ° C (Fig. 9.3 c). As in the case at 55 ° C, the E value changed continuously according to the pressure. This is most probably due to the change of scCO 2 density, as described above. This explanation is in agreement with the observation that at lower temperatures (31 and 40 ° C), the decrease of the E value measured at pressures below 10 MPa is steeper, whereas at higher temperatures, the E values decrease more gradually. These changes correlate well with the change in density as shown in Figure 9.1 b [2] .

However, when E values obtained at the same density but at different temperatures were compared, a signifi cant temperature effect became evident. Therefore, the enantioselectivity is determined not only by density but also by temperature. In a reaction under ambient conditions, the enantioselectivity of a kinetic resolution is temperature dependent and obeys a modifi ed Eyring equation [11] . Sakai et al. provided the fi rst experimental evidence supporting the theory of the effect of temperature on stereochemistry [11b,c] . Here, we examine whether the theory is applicable to the reaction in scCO 2 . At a density of 0.75 g/mL (31 ° C at 9.5 MPa, 35 ° C at 11.2 MPa, 40 ° C at 13.2 MPa, 45 ° C at 15.3 MPa, 50 ° C at 17.5 MPa, 55 ° C at 19.6 MPa, and 60 ° C at 21.8 MPa), ln E was plotted against 1/T. As shown in Figure 9.3 d, the Eyring plot was found to be linear throughout this range and thus indicates the conformational stability of the transition state. The differences in enthalpy and entropy values calculated from the above graph are given in Figure 9.3 d.

TABLE 9.3. Screening of Lipases for Enantioselective Acetylation of 1 - ( p - Chlorophenyl) - 2,2,2 - trifl uoroethanol in scCO 2

Lipase

Low Pressure Conditions (9.1 MPa)

High Pressure Conditions (14.5 MPa)

Yield (%) E a Yield (%) E a

LPL ( Pseudomonas aeruginosa ) 52 12 38 16 AY ( Candida rugosa ) 8 1 b 2 2 AH ( Pseudomonas cepacia ) 3 29 0 – PS - D ( P. cepacia ) 0 – 0 – PS - C ( P. cepacia ) 43 8 22 17 Lipozyme ( Rhizomucor miehei ) 0 – 0 – Novozym 435 ( Candida antarctica ) 25 38 24 23

a Enantiomeric ratio, E value, was used to evaluate enantioselectivity. E = (VA/KA)/(VB/KB), where VA and KA, and VB and KB denote maximal velocities and Michaelis constants of the fast - and slow - reacting enantiomers, respectively. The ( S ) - enantiomer reacted faster than ( R ) - enantiomer. b In this case, the ( R ) - enantiomer reacted slightly faster than the ( S ) - enantiomer.

METAL COMPLEXES-MEDIATED ASYMMETRIC SYNTHESIS 383

9.3.4. Alcohol Dehydrogenase - Catalyzed Asymmetric Reductions

Most of the biocatalysts used in supercritical fl uids are hydrolytic enzymes such as lipases and proteases, and very few reports on the use of alcohol dehy-drogenases in supercritical fl uids have been published, despite the fact that they are an important class of enzymes for the asymmetric reduction of ketones to produce chiral alcohols. So far, alcohol dehydrogenases from Geotrichum candidum and horse liver dehydrogenase have been used in scCO 2 . The former was used for asymmetric synthesis, and the latter was used for reduction of butyraldehyde to butanol using fl uorinated coenzyme, nicotinamide adenine dinucleotide (NADH).

Asymmetric reduction was realized by using an immobilized cell of G. candidum NBRC 5767 in 10 MPa scCO 2 ; high activities and excellent enanti-oselectivities were observed for the asymmetric reduction of aromatic and cyclic ketones [12] . For example, 2 - fl uoroacetophenone was reduced to the ( S ) - alcohol in 81% yield with > 99% ee as shown in Figure 9.4 . The immobilized cell was also used in the fl ow system [12b,c] .

9.4. METAL COMPLEXES - MEDIATED ASYMMETRIC SYNTHESIS

Homogeneous and heterogeneous chemical catalysts have been used for asymmetric synthesis using supercritical fl uid as a solvent [1] . Biphasic systems,

FIGURE 9.4. scCO 2 as a solvent for reduction of ketone by fungus, G. candidum .

R R'

O

OH

NAD(P)H

O

FOH

R R'

OH

OH

OH OH

Geotrichum candidum NBRC 5767 (immobilized

on water-adsorbing polymer)scCO2(10 MPa, 35°C)

Yield 96%ee 96%(R)

Yield 61%ee >98%(S)

Yield 96%

NAD(P)+

Hydrogen donor

Substrate

X

X

Ho-Fm-Fp-Fo-Me

Yield (%)

5181531122

ee (%)

>99%(S)>99%(S)>99%(S) 97%(S)>99%(S)

Product

Product


scCO 2 /aqueous, or ILs are also being developed for the promotion of green chemistry. Some of the interesting examples are shown in this section.

9.4.1. Polymer - Supported ( R , S ) - BINAPHOS - R h ( I ) Complex - Catalyzed Olefi n Hydroformylation

Asymmetric hydroformylation of olefi ns was performed using an ( R , S ) - BINAPHOS - Rh(I) catalyst that is covalently anchored to a highly cross - linked polystyrene support (Fig. 9.5 ) [13] . The polymer - supported catalyst was appli-

FIGURE 9.5. Olefi n hydroformylation by polymer - supported chiral catalyst.

Product

R

R = Ph, C6F5, AcO, n-C6F13, Hex, Bu

Polymer-supported catalyst

H2/COscCO2

R

CHOH

(Stepwise injection of substrate under scCO2 �ow)

O PPh2P Rh(acac)

OO

O PPh2P

OO

Et

0.0075 0.0225

0.44 0.53

Reaction type Batch cis-2-Butene (S)-2-Methylbutanal 100:0 82 Injection to vapor-�ow 3,3,3-Tri�uoropropene (S)-2-Tri�uoromethylpropanal 95:5 90 column reactor

Sequential conversion

Cycle Ole<n Conv (%) Iso/normal ratio ee (%) 1st 49 82:18 2nd Vinyl acetate 5 70:30 3rd 1-Octene 47 21:79 734th 1-Hexene 40 21:79 60

7774

5th Styrene

Styrene

36 81:19 826th 2,3,4,5,6-Penta�uorostyrene 27 89:11 887th CF3(CF2)5CH=CH2 21 91:9 788th Styrene 54 80:20 80

Ole<n Iso/normal ratio ee (%)


cable to a continuous column reactor as well as to a batch reactor. Various olefi ns were injected and were successfully converted into the corresponding isoaldehydes with high enantioselectivity.

9.4.2. Hydrogenation of Olefi n Using Aqueous/ scCO 2 Biphasic Systems

Rh complex is also used in aqueous/scCO 2 biphasic systems, which allows the highly enantioselective hydrogenation of polar water - soluble substrates and effi cient recycling of the CO 2 - philic catalysts (Fig. 9.6 ) [14] . Chiral CO 2 - philic catalysts were effi ciently immobilized in scCO 2 as the stationary phase, while the polar substrates and products were contained in water as the mobile phase. Therefore, product separation and catalyst recycling were conducted without depressurization.

9.4.3. Hydrogenation Using IL and scCO 2 Systems

The IL/scCO 2 biphasic system has been used for the asymmetric hydrogena-tion of imine and olfi ne. The catalysts were immobilized in IL solution so

FIGURE 9.6. Hydrogenation of methyl 2 - acetamidoacrylate using aqueous/scCO 2 biphasic system.

HN

O

O

O

HN

O

O

Oconversion >99%ee >98%(R)

scCO2/aqueous biphasic catalytic system

(R,S)-3-H2F6-BINAPHOS

OPO

OP

C6F13

C6F13

H2scCO2/H2O[Rh(cod)2][BARF](R,S)-3-H2F6-BINAPHOS

aqueous phase to dissolve substrate and product

substrate in product out

scCO2 phase with H2/ [Rh]*


they were reused repeatedly without signifi cant loss of enantioselectivity or conversion. For example, chiral iridium - catalyzed hydrogenation of imines was conducted fi rst in scCO 2 in 1999 [15a] and then later using the IL/scCO 2 biphasic system [15b] as shown in Figure 9.7 . The biphasic system leads to activation, tuning, and immobilization of the catalyst. Moreover, the products are readily isolated from the catalyst solution by CO 2 extraction without cross - contamination of IL or catalyst.

The IL and scCO 2 were also used in symmetric hydrogenation of tiglic acid catalyzed by Ru(O 2 CMe) 2 (( R ) - tolBINAP) [16] . The reaction in wet IL ([bmim]PF 6 with added water, bmim: 1 - n - butyl - 3 - methylimidazolium) gave 2 - methylbutanoic acid with high enantioselectivity and conversion. The product was extracted with scCO 2 , giving a clean separation of product and catalyst.

9.4.4. Identifi cation of Catalyst Surface Species for Platinum - Catalyzed Hydrogenation in Supercritical Ethane

There have been successfully conducted studies for the analysis of catalysts species in supercritical ethane. In situ attenuated total refl ection infrared spectroscopy studies during the enantioselective hydrogenation of ethyl pyru-vate in supercritical ethane over a chirally modifi ed Pt/Al 2 O 3 catalyst show the preferential adsorption of ethyl pyruvate as cis - conformer and indicate a hydrogen bond interaction of this species with the coadsorbed modifi er cin-chonidine as shown in Scheme 9.3 [17] . The coadsorbed species interact via hydrogen bonding, forming a diastereomeric complex.

FIGURE 9.7. Iridium - catalyzed hydrogenation of imines using IL/scCO 2 biphasic system.

Ph

NPh

Ph

NHPh

(R)

scCO2 phase to dissolve substrate and product

substrate in product out

ionic liquid phase with Ir*-cat

IrPh2P N

OPF6

–

+

ionic liquid/CO2biphasic catalytic system

H2ionic liquid/CO2Ir*-cat


9.4.5. Control of Enantioselectivity of Photoaddition by Temperature and Pressure

The enantioselectivity of anti - Markovnikov photo addition of methanol to diphenylpropene was controlled by temperature and pressure of CO 2 (Scheme 9.4 ) [18] . The enantioselectivity is enhanced by increasing alcohol size and pressure. Interestingly, the pressure dependence of ee is discontinuous at the critical density, accompanying a big jump caused most probably by enhanced clustering of the alcohol.

SCHEME 9.3. Proposed model for ethyl pyruvate adsorption during enantioselective hydrogenation in scC 2 H 6 over Pt/Al 2 O 3 chirally modifi ed by CD (cinchonidine).

O

O

O

O

O

OH

Pt

O

H

OO

N+

NHO

H2

supercritical solventPt/Al2O3

(R)

SCHEME 9.4. Control of enantioselectivity of the photoaddition by pressure and temperature.

ROH

R = Me, Et, i-Pr

hu/Sens*

scCO2

Sens*

OR*

CO2R*

CO2R*

O

oo o

oO(

R* = 1,2:4,5-di-O-isopropylidene-a-D-fructopyranosyl)

Sudden jump ofoptical yieldat the criticaldensity


9.5. CONCLUSIONS

Some reactions for asymmetric synthesis using scCO 2 by chemical catalysts and/or enzymes are explained. These reactions may promote developing of green chemistry in the future.

REFERENCES

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