In the Laboratory
Microscale Synthesis of Chiral Alcohols via Asymmetric Catalytic Transfer Hydrogenation Christine M. Peeters* and Rik Deliever Teaching Support Unit, Faculty of Bioscience Engineering, Katholieke Universiteit Leuven, Kasteelpark Arenberg 21, 3001 Leuven, Belgium; *
[email protected] Dirk De Vos Centre for Surface Chemistry and Catalysis, Faculty of Bioscience Engineering, Katholieke Universiteit Leuven, Kasteelpark Arenberg 23, 3001 Leuven, Belgium
In 1849 Louis Pasteur discovered that tartaric acid exists in two forms with opposite optical rotation. This started the study of chirality and has had far reaching implications in organic chemistry and biochemistry. In the late 1950s, the sedative and antiemetic drug thalidomide, taken during pregnancy, was sold as a racemic mixture. Later it was found that one of the enantiomers caused stunted limb development. In response to this tragedy, new methodologies were needed to produce pure enantiomers. Separation of enantiomers via crystallization or preparative chromatography, enzymatic or microbial transformations, or enantioselective synthesis are the main approaches to produce pure enantiomers. The most attractive variant of the latter approach uses enantioselective chemocatalysts rather than chiral stoichiometric reagents or auxiliaries. While the cost of the expensive reagents or auxiliaries impedes large-scale application, the cost of a catalyst can be kept within reasonable limits if the total turnover number is high. In the classical case of enantioselective catalysis, diastereomers are formed when the prochiral substrate, for example, a ketone or an olefin, forms a complex via one of its two enantiotopic faces with the chiral, enantioselective catalyst. Each diastereomeric intermediate reacts further to give either of the two enantiomeric products. In contrast to the enantiomeric products, the two diastereomeric intermediates have different energies, and this may mean that they are also formed in different ratios. Alternatively, the two diastereomeric intermediates may react at different rates, and this can as well be the cause of the enantioselectivity. The latter situation has for instance been encountered in some Rh-catalyzed enantioselective hydrogenations (1). Among the various transformations of prochiral compounds to chiral products by enantioselective catalysis (2), the reduction of ketones to chiral alcohols is one of the most successful transformations (3). Palmer reviewed the asymmetric reduction of C=O and C=N bonds by transfer hydrogenation, in which an organic molecule is used as the reductant, rather than pressurized H2 (4). This type of hydrogenation emerged as a powerful system because of its practical simplicity, mild reaction conditions, relatively non-hazardous reagents, and high selectivity. The efficiency of organometallic catalysts for the enantioselective reduction of ketones to secondary alcohols via transfer hydrogenation has been considerably improved (5). For the enantioselective hydrogenation of ketones, heterogeneous catalysts have been proposed as well, as they offer advantages such as easier handling and separation (6). The pivotal role of catalytic asymmetric synthesis in organic chemistry was recognized by the 2001 Nobel Prize in Chemistry that was shared by William Knowles, Ryoji Noyori, and Barry Sharpless for their contributions to this area (7).
As enantiomers can elicit different responses in biological systems, reliable methods are needed to analyze enantiopurity. The specific properties of cyclodextrins make this family of compounds suitable for applications in drug delivery and food technology, but also in organic synthesis and chromatography (8). The role of cyclodextrins in chiral chromatography was summarized by Juvancz (9) and Schneiderman (10). Method developments, applications, and ancillary techniques of chiral GC separations were reviewed by Schurig (11). Because of the relevance of chiral compounds and separations in life sciences, it is important to introduce these topics in organic lab for students in chemistry and biochemical engineering. Related projects involving stereochemistry have been published in this Journal. The reduction of ketones and aldehydes by Baker’s yeast is a common project demonstrating the use of a biocatalyst for introducing chirality into a molecule (12–15). Other projects emphasize the synthesis, isolation, and further characterization of enantiomers (16–21). Hanson (22) presented an attractive project for the enantioselective epoxidation using Jacobsen’s catalyst, but this project requires five 4-hour lab sessions. Nichols and Taylor described the synthesis of chiral catalysts followed by an asymmetric dihydroxylation of alkenes, but for this project the students need six 3-hour periods (23). Asymmetric reduction of ketones mediated by a cyclodextrin followed by GC using a chiral stationary phase within a short lab period was presented by Lipkowitz (24). Here we describe the microscale synthesis of chiral alcohols via asymmetric catalytic transfer hydrogenation of ketones and the subsequent GC analysis. This experiment (3–4 hours) fits into an advanced undergraduate laboratory. Experimental Procedures Since 2000, reduction of ketones followed by GC analysis has been part of our organic chemistry lab. This project is executed by 10 groups of 2–3 students and lasts 3–4 hours. Reduction of acetophenone with NaBH4 is used as a reference (Scheme I). In addition, substituted acetophenones were available, with Cl–, CH3–, or CH3O– groups in the ortho, meta, or para positions. Initially, we performed the stereoselective reduction of acetophenone using NaBH4 and a cyclodextrin auxiliary, as described by Lipkowitz (24). However, the enantioselectivity was low. Currently we apply catalytic asymmetric transfer hydrogenation as described in a patent from Zeneca (25). 2-Propanol is used as a hydrogen donor; the catalytic transfer hydrogenation (CATHy) catalysts are prepared in situ by combining a chiral bidentate nitrogen ligand with a Rh(III) metal complex containing a substituted cyclopentadienyl ligand (Scheme II).
© Division of Chemical Education • www.JCE.DivCHED.org • Vol. 86 No. 1 January 2009 • Journal of Chemical Education
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In the Laboratory OH CH3 O
CH3 NaBH4
Chirasil-DEX-CB column (Chrompack) was used for the chiral separation. Further details are given in the online material. Using the chromatograms the enantiomer excess (ee), conversion (conv), and turnover frequency (TOF) can be calculated
(R )-1-phenylethanol
ee 100%
OH CH3
(S )-1-phenylethanol
NH2
Cl
Cl
OH á
Rh
Rh Cl
Cl
conv 100%
R S R S K
amount t conv substrate TOF 100% amount t time catalyst
Scheme I. Reduction of acetophenone with NaBH4.
2
R S R S
where R, S, and K are the peak areas of the major enantiomer, (R)-1-arylethanol, the minor enantiomer, (S)-1-arylethanol, and the ketone substrate, respectively. Hazards
O 2
H2N Rh Cl
á 2HCl
Scheme II. Reaction between a chiral bidentate nitrogen ligand and a Rh(III) metal complex containing a substituted cyclopentadienyl ligand to generate the catalytic transfer hydrogenation (CATHy) catalysts in situ.
Catalyst Preparation The catalyst kit was purchased from STREM and contains (1S,2R)-(−)-cis-1-amino-2-indanol as chiral bidentate nitrogen ligand and pentamethylcyclopentadienylrhodium(III) chloride dimer as metal complex. The CATHy catalyst solution was prepared in small quantities by the technician as described in example 3 of the patent (25). Only the quantity needed for the synthesis was given to the students so that the effective costs were low. A detailed description of the preparation is given in the online material. Ketone Reduction The NaBH4 reduction, in the presence or in the absence of β-cyclodextrin, was adapted from Lipkowitz (24) and the catalytic asymmetric transfer hydrogenation from the information provided in the patent (25). Detailed descriptions are given in the online material. GC Analysis Sample preparation was as described by Lipkowitz (24), but methylene chloride was replaced by diethyl ether as a solvent. A 88
The components of the CATHy catalyst solution, acetophenone, 2-propanol, and most of the substituted acetophenones are harmful or irritant by inhalation and in contact with the skin or eyes. KOH is corrosive and may cause serious burns. It is harmful by ingestion, inhalation, and in contact with skin. NaBH4 is flammable and toxic and can produce hydrogen gas. Diethyl ether is flammable and harmful by ingestion, inhalation, or through skin contact. Students should have adequate eye protection, wear gloves, and work in well-ventilated fume hoods during sample preparations. Results and Discussion Examples of chromatograms of the hydrogenation with NaBH4 and the enantioselective hydrogenation with CATHy catalyst solution are presented in Figure 1. The hydrogenation of acetophenone results in (R)-(+)-1-phenylethanol and (S )-(−)-1-phenylethanol. Both compounds are commercially available and the first eluting enantiomer was identified as the (R)-enantiomer. As expected, the reduction of the various acetophenones with NaBH4 resulted in high conversions (typically greater than 90%) and low ee’s (typically within experimental error of zero). Although reduction in the presence of cyclodextrin has been presented as an asymmetric reduction method for ketones (24), the ee’s we obtained for this reduction were quite low for various acetophenones, ranging from 1–20% ee. The average ee and conversion for NaBH4 and Rh-catalyzed reduction of acetophenone and substituted acetophenones are summarized in Table 1. As the average ee for the reduction with NaBH4 is generally smaller than or comparable to the standard deviation, it can be safely assumed that the reaction is truly non-enantioselective. The Cl–, CH3–, and CH3O– substituent groups did not affect the enantioselectivity, nor the conversion, except for 4′-chloroacetophenone. For this compound the conversion was lower. The Zeneca proprietary catalysts for asymmetric catalytic transfer hydrogenation (trade name CATHy) are attractive be-
Journal of Chemical Education • Vol. 86 No. 1 January 2009 • www.JCE.DivCHED.org • © Division of Chemical Education
In the Laboratory A
B O
CH3
(R)-3b-methoxyphenylethanol
Cl
O
Detector Response
Detector Response
(S)-3b-methoxyphenylethanol
CH3
(R)-2b-chlorophenylethanol (S)-2b-chlorophenylethanol
OCH3
0
5
10
15
0
20
5
10
15
20
Time / min
Time / min
Figure 1. Chromatogram of the hydrogenation of (A) 3’-methoxyacetophenone with NaBH4 and (B) the enantioselective hydrogenation of 2′-chloroacetophenone with CATHy.
cause they are easy to synthesize, very selective, and active in mild reaction conditions. High enantioselectivity was observed for catalytic reduction of all ketones (Table 1), but conversion within the 60 min reaction time was much lower than for the reduction by NaBH4. For acetophenone a significant conversion increase with reaction time was observed. The effect of a range of substituents in ortho, meta, and para on the asymmetric reduction of acetophenones mediated by cyclodextrin was investigated (26). The substitution generally resulted in higher enantioselectivity indicating stronger host–guest interaction and a more pronounced control over
the access to the carbonyl group. These substituent effects were less pronounced in the asymmetric catalytic hydrogenation as performed by the students (Table 1). CH3– and CH3O– substituents slightly reduced ee compared to the hydrogenation of acetophenone, but no clear effect of the substituent position was observed. Chlorine in the meta or para position had no influence on the ee value, but Cl in the ortho position decreased the enantioselectivity. Comparison of conversion between the different substituted acetophenones was not possible because this conversion clearly depended upon the catalyst solution that was used.
Table 1. Enantiomeric Excess (ee) and Conversion (Conv) for Reduction of Acetophenone and Substituted Acetophenones Using NaBH4 or Rh-Catalyst NaBH4 ee (%)
Conv (%)
Rh-catalyst ee (%)
Conv (%)
No. of reactions
Reaction Timea/min
acetophenone
