M 320 Laboratory Projects Spring, 2009 I. Enantioselective Reduction of Benzofuran-2-yl Methyl Ketone using Enzymes from arrots. Typically, the reduction of an unsymmetrical, achiral ketone with a hydride reducing agent (e.g. ab 4 ) results in the production of a racemic mixture of secondary alcohols. This is due to the hydride having equal access to both faces of the planar carbonyl group. owever, with a chiral reducing agent, a chiral alcohol can be obtained. Recently, biological organisms have been found to affect the reduction of a variety of prochiral ketones (upon reduction of the carbonyl group, a chiral center is formed) with remarkable enantioselectivity. This essentially mimics many of nature s synthetic processes. The most common microbial method is the reduction via microbes found in Baker s yeast. This method, although inexpensive, requires the use of large quantities of organic solvents. Recently, new plant sources of enzymes have been shown to affect the reduction of prochiral ketones in an environmentally friendly way. In this experiment, you will perform a reduction of benzofuran-2-yl methyl ketone using the enzymes found in carrots (Scheme 1). Although the setup is quite simple, the reaction may take several hours to complete. The reaction will be monitored by Thin Layer hromatography (TL). carrot fragments in 2 Scheme 1 The enantioselectivity of this reaction (+/- ratio) will be determined by using a chiral lanthanide shift reagent (LSR) with 1 MR spectroscopy and polarimetry. Since the (+) and (-) enantiomers have identical MR spectra, the chiral shift reagent can be used to form diastereomeric complexes of both enantiomers. These complexes will have proton signals with slightly different chemical shifts. areful integration of the methyl doublets will allow for the determination of the enantiomeric excess (e.e.) in this reduction. Tris [3-(heptafluoropropylhydroxymethylene)-(+)-camphorato] europium (III) is the shift reagent. For the MR experiment, only about 4 mg (0.004g) of chiral alcohol will be used in Dl 3. After the 1 MR spectrum is determined, add 0.5 mole equivalents of LSR so that the separation of methyl triplets is measurable. This will require the use of the analytical balances. What is the enantiomeric excess (e.e.) of this reaction? F 2 F 2 F 3 Eu (+)Eu(hfc) 3 3
II. Microwaves in rganic Synthesis: Preparation of various Biphenyls via a Pd(II) catalyzed Suzuki oupling. onventional organic reactions involve significant quantities of non-aqueous solvents and substantial heating times. Recently, the use of microwaves in organic synthesis has become more popular due to the lower amounts of solvent needed and dramatically shorter reaction times. Palladium catalysts are among the most commonly used in organic synthesis. A common reaction involves the coupling of an aryl halide and an aryl boronic acid to afford biphenyl compounds (a Suzuki coupling). In this reaction, the concept of a catalytic reaction cycle will be introduced as a new mechanistic thought process. The preparation of 4-acetylbiphenyl is shown below in Scheme 2. Br + () 2 B Pd(Ac) 2, a 2 3 tbu 3 Br, 2 o microwave, 160 Scheme 2
III. Mannich Reactions in Room Temperature Ionic Liquids (RTILs): An Advanced Undergraduate Project of Green hemistry and Structural Elucidation. An ideal solvent for an organic reaction is chemically and thermally stable, has a low vapor pressure, has a wide temperature range as a liquid, is non-toxic and recyclable. Additionally, this solvent should be able to dissolve a wide variety of organic and inorganic compounds so that reactions can be run homogeneously. A relatively new area in the field of organic chemistry involves the utilization of ionic liquids as solvents. These compounds have a great deal of potential as environmentally friendly replacements for organic solvents. Most of these liquids are ammonium or pyidinum salts with reasonably long alkyl groups attached as shown below in Fig.1. The anion is often BF 4 - (tetrafluoroborate). R + BF 4 R' disubstituted imidazolium salt Fig. 1. 5 11 BF 4 -pentylpyridinum tetrafluoroborate The project involves a synthesis of 3,5-dimethyl-2,6-diphenyl-4-piperidone (1) in a Mannich type reaction. The general reaction involves an ketone (in its enol form) an imine to form a β-ketoamine or a Mannich base (Scheme 3). These are very useful synthetic intermediates. First, you will be synthesizing 1-butyl-3-methylimidazolium tetrafluoroborate, [bmim] + BF 4 - (compound 2), as your ionic liquid (Scheme 4). This will be used as the solvent in the Mannich reaction (Scheme 3). 2 Scheme 3 + 4 Ac + [bmim][b 4 ] (2) 30 o Ph 1 Ph 3 Scheme 4 l + l abf 4 BF + 4 in 3 / under 3 4 9 in 2 3 4 9 2 [bmim][bf 4 ], 2
IV. Sharpless Asymmetric Dihydroxylation: Effect of Alkene Structure on Rates and Selectivity. The Sharpless asymmetric dihydroxylation is one of the most often utilized and most useful reactions of modern times. The significance of this reaction is that it incorporates 2 adjacent chirality centers in a molecule in a highly stereoselective fashion. This is significant as pharmaceutical companies must now often prepare medicines in their pure (+) or pure (-) forms. In this reaction, the oxidizing agent is s 4 complexed to an chiral amine ligand. This makes the oxidizing agent chiral and thus the syn addition of the two - groups will occur on a specific face of the alkene. Each group will choose a different alkene so we can compare differences in structure with the efficiency of the reaction (both reaction rate and enantioselectivity). The reaction is outlined in Scheme 5. The structure of the complex chiral ligand can be found in the lead reference. R s 4. R' R 3 R' (R 3 = single enantiomer of a chiral ligand) R s R 3 K 3 Fe() 6 K 2 3, 2 R R' (+ s 4. R 3 ) Scheme 5 + K 4 Fe() 6 + K 3.
V. Greening Wittig Reactions: Solvent-Free Synthesis of Ethyl trans innamate and Ethyl trans 3-(9-Anthryl)-2-Propenoate. The Wittig reaction is an extremely versatile method of synthesizing alkenes from aldehydes and ketones. In a Wittig reaction, a phosphorous ylide undergoes a nucleophilic addition to a ketone or aldehyde. Subsequent loss and precipitation of triphenylphosphine oxide drives the equilibrium to the product alkene (see Scheme 6 for an example). + 2 =P( 6 5 ) 3 2 + ( 6 5 ) 3 P Scheme 6 In this project, you will synthesize one of the title alkenes using an aromatic aldehyde (either benzaldehyde or 9-anthraldehyde) with (carbethoxymethylene)triphenylphosphorane (Scheme 7). What makes this reaction unique is that you will use no solvent to carry out the reaction. + Ph 3 P 2 3 2 3 benzaldehyde ylide (+ Z isomer) + Ph 3 P Scheme 7
VI. Independent Project For the sixth laboratory project, you have the opportunity to carry out an experiment that complements the previous five. This project should introduce a unique reaction and/or technique and present a challenge. In each issue of the Journal of hemical Education, there is a section entitled In the Laboratory. Typically there are two or three good advanced organic laboratory experiments each month but you certainly do not need to limit yourself to that journal. An abstract for your project is due on February 20, 2009. In this brief proposal, you should include the cover sheet from the link on our site that includes: I) ames of two students carrying out the work. II) III) IV) Title of the project. Reference of primary article used in proposal (attach a copy of the article including experimental sections). ovel techniques/reactions utilized in this project. V) Approximate timetable for project. VI) VII) hemicals needed: include ARS numbers of all chemicals that we need to purchase. If not available from ARS, use Aldrich. Equipment needed: includes glassware, dry ice, and gases (argon or nitrogen). If unavailable, supply a vendor. Upon approval, your chemicals will be ordered. The report for this laboratory project will be submitted in the form of a poster. Details on the make-up and design of the posters are forthcoming. The poster session will be held on Thursday, April 30, 2009.