Chemistry 2312
Thursday, September 10, 2015
Honors Organic Chemistry Laboratory
T. R. Hoye
Experiment 1.
Ketone Reduction by Sodium Borohydride:
Propiophenone and 3-Chloroacetophenone
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 the "mild" reducing agent sodium
cyanoborohydride (NaBH3CN) will only react with aldehydes (the most reactive of the common
carbonyl-containing functional groups) at reasonable rates to give alcohols.
O
R
OH
R'
R
R = alkyl, aryl
R' = OH, OR, H, R
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 (propiophenone or 3-chloroacetophenone) to the
corresponding alcohol product (1a or 1b, respectively). Take ~300 mg of either one of the
ketones from the reagent bottle; each is a liquid at ambient temperature. Only use a clean and dry
disposable pipette to reach into any commercial (and community) bottle of a chemical, reagent,
or solvent in order to prevent contamination.
Scheme 1
O
O
H OH
NaBH 4
Me
Me
Me
EtOH
room temperature
propiophenone
(1-phenylpropan-1-one;
phenyl ethyl ketone)
H OH
NaBH 4
Cl
Cl
Me
MeOH
<room temperature
1a
3-chloroacetophenone
[1-(3-chlorophenyl)ethan-1-one]
1b
You will use NaBH4 as the hydride reducing agent. You should follow the progress of every
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 propiophenone as the substrate for your first reduction and
perform the reaction in ethanol at ambient (aka room) temperature. The initial concentration of
your substrate in the alcohol solvent should be ~0.25 M. You will need to devise a workup
procedure. Initial removal of the majority of the alcohol solvent on the rotary evaporator will aid
in a subsequent partitioning between water and diethyl ether in an extractive work-up. 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 propiophenone, repeat the reaction, using 3chloroacetophone as the substrate (aka staring material or reactant). Perform the reduction in
methanol solution at ca. 0 °C. Monitor reaction product by tlc, workup the reaction mixture, and
purify the product by flash chromatography. Repeat the experiment until the yield of purified
product from the second reaction is greater than that from the first (I am guessing it will be the
first try because of the experience you gained from small mistakes made in the first
reaction/workup/purification).
Spectral files of one of your 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 propiophenone (EtC(=O)Ph).
The NMR file names are:
propiophenone_300; propiophenone_c13_300; propiophenone_500; propiophenone_c13_500
(Grant: please check that these files are on the Varian 300 server).
The GC-MS file names are:
PP2-1.D (for propiophenone), which you will find when you click on the following folders, in
order: C:, Hpchem, 1, Data, Horg2013, EXP1-BorohydrideRed. (Grant: please check that this
files is there and that this is the correct path).
Include answers to the following questions at the end of your lab report for this experiment
(Report #1):
Questions:
1. What should be the relative retention factor (Rf) values by TLC on silica gel for the following
compounds: propiophenone, acetophenone, 1-phenylpropan-1-ol, and 3-phenylpropan-1-ol?
List them from highest Rf (least polar) to lowest Rf (most polar). Why?
2. What are the boiling points of cyclopentanol, cyclohexane, and cyclopentane at one
atmosphere of pressure? Which of these three would you 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 in 491 Kolthoff)?
3. How many unique carbon resonances do you expect to see in the 13C NMR spectrum of each
of the ketones 1-(3-methylphenyl)butan-1-one and 1-(4-chlorophenyl)-3-methyl-1-butanone?
... in each of the product alcohols arising from reduction of each of these ketones?
4. What is the chemical shift of the ortho protons on the phenyl ring in the 1H NMR spectrum of
propiophenone? … of 1-phenyl-1-propanol (1a)? Why are they further downfield (larger δ
value) in the ketone than they are in the alcohol?
5. Describe (briefly) the concept of monitoring the reduction of a ketone to its alcohol by TLC.
Include in your description the concept of co-spotting for TLC analysis. Discuss (briefly)
how you would deduce the half-life (t1/2) for the reaction by monitoring the reaction by GC.
[Hint: this involves taking aliquots of the reaction mixture and analyzing its contents over
time.]
6. What would the product of reduction of 1-tetralone (look up its structure) be if you used the
deuterated reducing agent NaBD4 in CH3OH solvent? Draw each of the two enantiomers of
this chiral molecule and label each as having the R or the S absolute configuration.
7. What would you obtain if you treated 2-hexanol (C6H14O) with an excess of deuterium oxide
(D2O)?