Chemistry 2312 Honors Organic Chemistry Laboratory

Tuesday, September 8, 2009 T. R. Hoye

Experiment 1. Ketone Reduction by Sodium Borohydride: Butyrophenone and Acetophenone

Introduction: The reduction of aldehydes, ketones, and esters is one of the fundamental transformations in organic synthesis. The resulting alcohol may be the desired final product, or it may be transformed into a leaving group for subsequent reactions like nucleophilic substitution or elimination. Since carbonyl reduction is so important to synthetic organic chemistry, a wide variety of reducing agents have been developed. Several of these reagents can be used to reduce all of the carbonyl groups of the above substrates to alcohols, but many hydride donors will only react with one class of compounds. For instance, lithium aluminum hydride (LiAlH4) will reduce, in most cases, aldehydes, ketones, and esters, but sodium cyanoborohydride (NaBH3CN) will only react with aldehydes at reasonable rates to give alcohols.
O R R' R OH R'

R = alkyl, aryl R' = OH, OR, H, R

R = alkyl, aryl R' = H, R

Experiment: In this experiment you will carry out the two reactions indicated in Scheme 1. Each is a reduction of a ketone substrate (acetophenone or butyrophenone) to the corresponding alcohol product (1a or 1b). Ask a TA for ~300 mg of either one of the ketones. Scheme 1
O Me NaBH4 MeOH < room temperature acetophpenone (1-phenylethanone; phenyl methyl ketone) H OH Me Me O NaBH4 EtOH room temperature Pr H OH

1a

butyrophenone (1-phenyl-1-butanone; phenyl propyl ketone)

1b

You will use NaBH4 as the hydride reducing agent. Find an appropriate literature precedent. That is, find a general or specific procedure to reduce a ketone to an alcohol and modify the procedure appropriately. The protocol can come from the primary literature or from a laboratory manual or general organic synthesis reference. Ask your TA if you are having trouble finding a suitable reference. If at all possible, you should follow the progress of each reaction you

perform in organic chemistry by thin-layer chromatography (TLC). In theory each of the four hydrides in NaBH4 is available to reduce a molecule of ketone. In other words, one mole of NaBH4 can reduce four moles of ketone. In practice, chemists often use at least two equivalents of hydride ion per ketone carbonyl group. Use ~300 mg (~0.3 g) of the starting ketone for your reduction and perform the reaction in methanol solution at a temperature below room (ambient) temperature. The concentration of your substrate should be ~0.25 M. You will need to devise a workup procedure. The product alcohol should be purified by simple flash column chromatography on silica gel. The product is somewhat volatile (bp ~180 C) and you might lose a significant portion of it if you place it under high vacuum or leave it on the rotary evaporator for an extended period (especially if the bath temperature is >ambient). Once you have successfully reduced your first ketone, repeat the reaction, using whichever of the two ketones you did not use in your first reduction reaction. Perform the reduction of the second substrate until you obtain an improved yield on your second attempt (I am guessing it will be the first retry because of the experience you gained from small mistakes made in the first reaction/workup/purification). Use ethanol as the reaction solvent and perform the reaction at room temperature. Spectral files of starting ketones: You should download and print a copy of the proton nmr (at both 300 and 500 MHz), carbon nmr (on a 300 MHz instrument), and gas chromatography/mass spectra of the starting acetophenone and of propiophenone (EtC(=O)Ph), a ketone related to butyrophenone. The NMR file names are: acetophenone_300; acetophenone_c13_300; acetophenone_500; acetophenone_c13_500. propiophenone_300; propiophenone_c13_300; propiophenone_500; propiophenone_c13_500. The GC-MS file names are: PP2-1D (for propiophenone) and AP-1.D (for acetophenone)which you will reach when you click on the following in order: C:, Hpchem, 1, Data, Horg2007, EXP1-Borohydride Red.

Include answers to the following questions at the end of your lab report for this experiment (Report #1): Questions: 1. What should the relative Rf values by TLC on silica gel be for the following three compounds: acetophenone, t-butyl phenyl ketone, 1-phenylethanol, and benzyl alcohol? Why? 2. What are the boiling points of 3-pentanone, 3-pentanol, and 1-pentanol? Which would your predict to have the longest and which the shortest retention time on a gc column coated with a 5%-phenyl silicone liquid phase (like the HP-5 column in our GC-MS instrument)? 3. Describe the concept of monitoring the reduction of a ketone to its alcohol by TLC and by GC. Include in your description the concept of co-spotting for TLC and co-injection with GC analyses. Discuss how you would deduce, from GC data, the half-life (t1/2) for the reaction. 4. How many unique carbon resonances do you expect to see in the 13C NMR spectrum of each of the ketones butyrophenone and 3-methylbutyrophenone? ... in each of the product alcohols 1b and 1-(3-methylphenyl)-1-butanol? 5. (a) What would the product of reduction of 1-tetralone be if you used the deuterated reducing agent NaBD4 in CH3OH solvent? (b) What would you obtain if you treated cyclohexanol (C6H12O) with an excess of deuterium oxide (D2O)? 6. Carefully draw each of the two enantiomers of alcohol 1b and of 2-phenyl-2-butanol and label each of the four structures as having the R or the S absolute configuration. 7. What is the chemical shift of the ortho protons on the phenyl ring in the 1H NMR spectrum of acetophenone? of 1-phenylethanol (1a)? Why are they further downfield in the ketone?