Experiment: Reduction of a Cyclic Ketone
When organic molecules undergo oxidation or reduction reactions, the following pattern is noted.
In the oxidized molecule, the number of oxygen atoms increase or the number of
hydrogen atoms decrease.
In the reduced molecule, the number of hydrogen atoms increase, or the number of
oxygen atoms decrease.
For example:
+ H2
catalyst
reduction
O
KMnO4
PCC
OH
H
O
oxidation
OH
In this experiment you will be adding hydrogens to the C=O of a ketone using sodium
borohydride, NaBH4. This inorganic compound is very useful for reducing a variety of organic
compounds and is also extensively used in the bleaching of wood pulp used for production of
white paper products.
The mechanism for the reduction reaction is shown below with a sample ketone (different from
the one you will be reacting).
BH3
H
O-
H
H3CH2C
H - Cl
H
OH
O
H3C
H
BH3
OH
H - Cl
OH
H
The first step involves the addition of the nucleophile, H-, to the positively polarized carbon atom
of the C=O. The second hydrogen adds to the alkoxide (RO-) as an H+ from the acid added in
the second step of the procedure.
According to molecular orbital theory, the H- comes into the C=O at an angle of 107o. For the
simple ketone show above, there is an equal probability of the addition occurring above or below
the C=O, so both enantiomers are formed in equal amounts. However, when 4-tbutylcyclohexanone undergoes reduction with NaBH4, the reaction you will perform, the
alcohols are not formed in equal amounts.
O
OH
1. NaBH4
+
OH
2. H2O, HCl
trans-4-t-butylcyclohexanol
cis-4-t-butylcyclohexanol
At room temperature, the bulky t-butyl group on the ring keeps the molecules essentially
“locked” into the conformations shown.
You will be performing this reaction and then analyzing the ratio of products via NMR. The
NMR spectra of the alcohols are complicated, but the hydrogen on the carbon bearing the alcohol
group is different for each enantiomer. The chemical shift for the hydrogen on the trans
molecule is at 3.5 ppm and at 4.0 ppm for the cis molecule.
You can use the integration values for these signals to get the trans:cis ratio of the products. In
the final post-lab analysis, you will be asked to look at the structure of the reactant ketone and
use it explain the trans:cis ratio you observed.
In this reaction the addition of H- in the first step is exothermic. According to the Hammond
Postulate, the transition state for this step must resemble the reactant. Therefore, the product
mixture formed is a result of kinetics (the speed of each reaction) rather than the thermodynamic
stability of the final products. To understand the product ratio you need to examine the three
dimensional structure of the cyclic ketone. Look at the location of the hydrogens in the axial
positions on the cyclohexane ring and predict whether it would be easier for the small
nucleophile (BH4-) to react above or below the molecule. Think about which pathway would
have a lower activation energy, and why.
 Pre-lab Preparation
Before coming to lab, you need to complete the following:
1. Look up the relevant physical constants for 4-t-butylcyclohexanone and the cis and trans
isomers of 4-t-butylcyclohexanol.
2. What is the relationship between the two isomers formed in the reduction of 4-tbutylcyclohexanone?
3. Classify the following reactions as oxidation or reduction.
O
a.
O
OH
b.
O
OH
O
O
c.
OH
H
4. Explain what would happen if:
a. you added the NaBH4 quickly.
b. you added 3M HCl quickly to the reaction mixture.
c. you did not let the reaction mixture cool before you added ether to it in the separatory
funnel.
Experimental Procedure
! Safety Considerations
! Wear gloves and work in the hood with sodium borohydride. Take care not to spill the powder
and keep it away from water. Contact with water causes the formation of flammable hydrogen
gas.
! 4-t-butylcyclohexanone and 4-t-butylcyclohexanol can be irritating to the skin and eyes.
Avoid skin contact and inhalation.
Work in pairs.
1.
Weigh 0.50 g of 4-t-butylcyclohexanone on waxed weighing paper. Add this to a clean
50 mL beaker.
2.
Add 5 mL 95% ethanol to the beaker containing 4-t-butylcyclohexanone. Gently swirl to
dissolve.
3.
Wear gloves when working with NaBH4. Obtain one of the premeasured vials of 0.40
g sodium borohydride (NaBH4), a micro-spoon spatula, and a large plastic weigh boat.
Work inside a hood. Place your beaker containing the 4-t-butylcyclohexanone solution
on the large, plastic weigh boat, which will serve as a tray to contain any spills. Add the
NaBH4 to the beaker slowly and swirl the beaker after each scoop of NaBH4. Once all of
the NaBH4 has been added, cover the beaker with a small watch glass and then let it sit
for 20 minutes at room temperature, swirling occasionally. The NaBH4 quantity is in
excess, so a small amount left sticking to the sides of the glassware is fine.
4.
Replace the cap on the vial and return it where you found it (for reuse in future labs).
Traces of NaBH4 on spatulas and any spills of the solid MUST be collected. To do this,
use water to rinse traces of NaBH4 into one of your large beakers. When the experiment
is complete, transfer the waste from your beaker to the larger NaBH4 beaker in the front
hood.
5.
After 20 minutes, measure 3 mL of water. Add the water using a pipet to wash down any
solid clinging to the sides of the beaker. Swirl the contents.
6.
In a clean graduated cylinder measure 2 mL of 3M HCl. This next step – acidification must be carried out very slowly. Use a pipet to add the 3M HCl one drop at a time.
After adding 2 mL of 3M HCl, let the beaker sit (open) and wait for the bubbling to
subside. Check the pH with pH paper. When the pH is 6-7 the NaBH4 has been fully
reacted and is no longer hazardous. If the pH still tests basic (greater than pH = 7), add
additional 3M HCl dropwise.
7.
Fill a beaker with ice and then place your beaker on the ice to cool. Make sure the beaker
is cool before adding ether in the next step.
8.
Add 5 mL of diethyl ether to the beaker and then swirl. Allow the solids to settle to the
bottom of the beaker. Carefully decant the liquid (both layers) into a 50 mL separatory
funnel, leaving the unwanted solid (and a small amount of liquid) behind. Rinse the
remaining solid with 2 mL ether and decant the liquid into the separatory funnel, leaving
any remaining solid in the beaker.
9.
Extract the liquids in your separatory funnel and then separate the layers. Set the ether
layer aside. Pour the aqueous layer back into the separatory funnel and extract with a
second 5 mL portion of ether. Combine the two ether layers in the separatory funnel and
then wash the combined ether layers with two 5 mL portions of water. Shake the
separatory funnel well to make sure the ethanol goes into the aqueous layer. The
aqueous layer MUST be placed in the appropriate waste container in the hood at the
front. Do not pour down the drain.
10.
Dry the ether layer over anhydrous magnesium sulfate in an Erlenmeyer flask. Use
enough of the drying agent to ensure all the water is removed (about 3-4 scoops). Cork
the flask, and let it sit for 5 minutes.
11.
Filter the drying agent from your flask by gravity using a fluted filter paper. Filter into a
50 mL Erlenmeyer flask with a 24/40 joint. Cork the 24/40 jointed flask before carrying
the flask outside of the hood to the rotary evaporator. Use a rotary evaporator (rotovap)
to remove the ether. This should take about 5 minutes at room temperature at full
vacuum. Do not evaporate to dryness as this will make it very difficult to scrape out the
solid.
12.
Once the sample is concentrated and most of the ether has been removed, turn off the
rotovap, remove the flask, quickly cork it, and take it back to your hood. Obtain one of
the warm (70oC) glass petri dishes from the oven on the cart. It will be hot, so hold the
hot petri dish with a paper towel. In your hood, immediately pour the liquid (product)
into the warm petri dish. As it cools, a solid should form. Once your product starts to
solidify, you can speed up the evaporation of the remaining solvent with a gentle stream
of air using the air nozzle and a hose.
13.
Run an IR of the solid using the IR on the right, which has the correct apparatus for
compressing the solid onto the plate. Use the instructions next to the IR for details about
how to obtain an IR of a solid. If the IR shows that the reduction was successful (there is
no carbonyl stretch), your sample can be used for the NMR analysis.
14.
Combine your product with another group’s product for NMR analysis. Weigh out
approximately 110 mg an then add it to one of the vials with a 1 mL mark, which will be
set out for you. Add NMR solvent CDCl3-0.5%TMS to the 1 mL mark and then use a
small stir rod to mix (do not shake it).
15.
If the sample looks clear, transfer it by pipette to an NMR tube. If the sample looks
cloudy or if you can see any solids, you must first filter the sample using a syringe filter.
Draw up the sample into the syringe (without any filter or needle attached). Place the
syringe filter on the open end and twist it to attach. Obtain a second vial with a 1 mL
mark and filter your product into the new, clean vial. Apply a small amount of pressure
to the syringe plunger to push the sample through the filter and into the clean vial. If you
no longer have 1 mL of volume, add CDCl3 to fill the vial to the 1 mL mark.
16.
Have the lab instructor help you run the NMR. Note that 20 scans will be needed to
obtain sufficient signal from this dilute sample. Once the scans are complete, use the
roller on the mouse to increase the height of the peaks and then integrate only the peaks
in the 3 – 5 ppm region, which will give you the trans:cis ratio for your solid.
 Post-Lab and Report Requirements
1.
Analyze your IR spectrum and explain whether the desired products were formed.
2.
Use the integration for the H’s on the carbon bearing the OH and calculate the trans:cis
ratio of the alcohols. Show/explain your work.
3.
Refer to the three dimensional structure of the reactants and products and explain this
ratio.
4.
Write a mechanism showing the formation of the major stereoisomer. Be sure to show
the direction of attack to form the correct major stereoisomer.
5.
Explain why when the reduction is performed with L-selectride, the trans:cis ratio is
1:20.
L-selectride