 E x p e r i m e n t 1 7

Synthesis of Benzilic Acid

Objectives
 To synthesize Benzilic acid using a solvent free Green Chemistry procedure
K. Tanaka and F. Toda, Chem. Rev., 2000, 100, 1045.
 To investigate a carbon skeleton rearrangement reaction.
 To assess the purity of the product by determining its melting point.
 To determine the molar mass of the product via titration with standardized NaOH.

In the Lab
 Students work in pairs

After Lab
 Complete the Chem21 assignment

Waste
 Place the fluted filter paper in regular trash.
 Place the aqueous filtrate down the sink with plenty of water.
 Place the first three titration solutions (KHP titrations) down the sink with plenty of
water.
 Place the last three titration solutions (Benzilic acid) in the waste container labeled
Lab 17 - Aqueous Ethanol Waste located in the Instructor’s hood.
Safety
 Students must wear goggles for this experiment.
Mechanism

Benzilic acid, although posing no threat itself, is a precursor and degradation product of a
chemical warfare agent called “BZ”. BZ’s IUPAC name is -hydroxy--
phenylbenzeneacetic acid-1-azabicyclo[2.2.2]oct-3-yl ester (see structure below).

This compound is a psychogenic agent that incapacitates O OH

its victim. Approximately 30 minutes after exposure, C C
disorientation and visual and auditory hallucinations O
begin to appear. After four hours and lasting four days, N
symptoms can include distended pupils, dry mouth, and
increased body temperature. Most of these symptoms are
the result of BZ’s action on the central and peripheral nervous system via its binding to
muscarinic acetylcholine receptors. Production of BZ began in the United States in 1962 at
Pine Bluff Arsenal in Arkansas. It was later weaponized in bomblets with a pyrotechnic
mixture which, when ignited, produced a solid aerosol of the high-melting BZ. Between
1988 and 1990, the BZ munitions were destroyed and no BZ munitions remain in the US
stockpile.

The evidence proving that this nerve agent was used in warfare rests upon the detection of
benzilic acid (the compound we will make in this lab) in soil and water samples. This can be
accomplished using various instruments/techniques such as GC (gas chromatography), MS
(mass spectrometry), NMR (nuclear magnetic resonance spectroscopy) and LC (liquid
chromatography). To date, only one allegation of its use has surfaced – this from Bosnian
refugees. However, no soil or water samples were available to substantiate their allegations.
 E x p e r i m e n t 1 7 • Benzilic acid 17
Today’s lab uses a “green chemistry” approach that uses fewer, and less expensive reagents
and solvents. Most other procedures use 95% Ethanol as the solvent and its removal requires
time and energy. In addition, these procedures use the more expensive KOH as the base.
Finally, these procedures use decolorizing carbon and celite in their purification schemes.
The “green” procedure, devised by K. Tanaka and F. Toda, uses only solid NaOH, water and
conc HCl to accomplish the same reaction in a shorter amount of time with similar yields.

Table of Physical Constants

Chemical Molecular Melting Boiling n 20
Chemical Name Density D
Formula Weight Point Point

Benzil C6H5COCOC6H5 210.23 94-95 1.23

Conc Hydrochloric
HCl 36.46 1.200
Acid
(C6H5)2C(OH)CO
Benzilic Acid 228.25 150-153
OH
Table 1
 E x p e r i m e n t 1 7 • Benzilic acid 17
13. Collect the crystals via vacuum
Day 1 – Making Benzilic acid
filtration and wash twice with 50 mL ice
1. Pack a melting point tube with the
cold water.
benzil from Lab 16. Leave 0.5 grams of
14. Spread the crystals out on a labeled,
the benzil in the labeled vial.
weighed watch glass and place
2. Place the rest of the
them in the drying oven for 30
benzil in a mortar.
minutes.
3. Wear Gloves!! Add
15. Weigh the product, record
an equivalent mass of ~½ inch the mass of the Benzilic Acid
NaOH to the mortar.
of water [Data Sheet].
4. Place the mortar on
16. Determine the melting
the counter top and use the
point [Data Sheet] of the
pestle to crush the NaOH
crystals and calculate the
pellets. Once they are
percent yield [Online Report
crushed, grind the two
Sheet].
solids to make an easy
flowing powder (~ 2
minutes).
Standardizing the NaOH
5. Transfer the powder to a 250 mL
solution
Erlenmeyer flask and place the flask in a
17. Obtain ~200 mL of a sodium
600 mL beaker that contains ½ inch of
hydroxide solution that is ~ 0.05 M in a
distilled water.
clean beaker. Label the beaker – either
6. Heat the flask at 100°C for 20 minutes.
mark on the beaker or write NaOH on a
7. At the end of 20 minutes, place the
piece of paper and set the beaker on top of
flask on the counter top and add to it 15
the paper.
mL of the boiling water from the 600 mL
beaker. 18. Obtain a clean buret and buret clamp.
8. Swirl to dissolve the solid. Filter the Make sure the stopcock on the buret is
solution through a fluted filter paper and closed.
rinse the flask / filter paper with an 19. Add ~ 5 mL of the NaOH solution
additional 5 mL of hot distilled water. (from Step 17) to the buret (rotate the
9. Cool the solution in an ice / water bath buret to wash down the sides with this
for 10 minutes. NaOH solution) and empty it into a beaker
10. Add conc HCl, with stirring / swirling, designated for waste.
until there is obvious crystal formation. 20. Repeat Step 19.
11. Check the pH with pH paper. If the 21. Fill the buret to the top with the NaOH
pH is greater than 2, add conc HCl until solution. Place the beaker containing the
the pH is 2 or less. waste NaOH under the stopcock and fully
12. Cool the solution in ice for 5 minutes. open the stopcock allowing ~1 mL of base
to exit. Repeat opening and closing the

4
 E x p e r i m e n t 1 7 • Benzilic acid 17
stopcock until no more air bubbles exit colorless solution to a persistent (for at
the tip of the buret. least 1 minute) light pink.
22. Obtain three 200 (or 28. Record the final volume
250 or 300) ml of base used [Data Sheet].
Erlenmeyer flasks. Tare Remove Air 29. Determine the Molarity
a weighing paper (make Bubble In of the NaOH solution
sure the balance is not Buret Tip. [Online Report Sheet].
fluctuating due to air 30. Repeat Steps 22 – 29 for
currents). Using a Flasks 2 & 3 – record the
spatula, place 0.3 - 0.4 g data.
Potassium hydrogen
31. Determine the average
phthalate (KHP) on the
Molarity of the NaOH
weighing paper and close
solution from the 3 Trials
the lid to the balance to
[Online Report Sheet].
minimize air currents.
Record exactly the mass
of KHP [Data Sheet].
23. Add the KHP, 100  5 ml of distilled Titrating Benzilic acid
water, and three drops of the 32. Accurately weigh (to three significant
phenolphthalein indicator to Flask 1. figures) approximately 0.2 g of Benzilic
24. Place a stir bar in the flask and place acid (obtain this from your Instructor
the flask on a stirring plate. while your Benzilic acid is drying in the
25. Adjust the buret so that it is directly oven) using weighing paper [Data Sheet].
above the flask and the stirring plate. 33. Place the weighed Benzilic acid into
26. Record the volume of three different 125 (or 250)
NaOH in the buret [Data mL Erlenmeyer flasks.
Sheet] and begin to slowly 34. Dissolve the acid in each
add the base to Flask 1. flask with 50 mL of 50%
27. As base drops onto the Light pink aqueous ethanol (the
acid solution, a pink color for 1 minute Benzilic acid does not need
appears that rapidly to completely dissolve since
disappears with stirring. it will dissolve as it is
As time passes, the color titrated).
remains longer – you 35. Add 3 drops of a
should add the base phenolphthalein indicator.
dropwise at this point. 36. Record the starting buret
Eventually, one drop of volume [Data Sheet].
base will change the 37. Titrate the Benzilic acid
solution to a light peach endpoint - the
5
 E x p e r i m e n t 1 7 • Benzilic acid 17
color change will be obvious, but not as
obvious as a colorless solution turning Lab Report
pink. Make sure the peach color persists
for 1 minute to allow any undissolved acid Once you have turned in your Instructor
to dissolve. Data Sheet, lab attendance will be entered
and you will have access to enter your lab
38. Record the final buret volume [Data
data online and begin the lab submission
Sheet].
process. Enter you lab data before exiting
39. Repeat Steps 36 – 38 for Flasks 2 & the lab - enter your data accurately to
3 – record the data. avoid penalty. The lab program will take
40. Calculate the molar mass of benzilic you in order to each calculation. Mouse
acid for each titration [Online Lab Sheet]. over the orange “TOL” link to see the
41. Determine the average molar mass of points and tolerances for each calculation.
Benzilic acid [Online Lab Sheet].
42. Turn in the Benzilic acid crystals in a
labeled vial with your lab data sheet.

Lab 17
Benzilic acid
Name:
Mass: g

6
 17
Synthesis of Benzilic Acid
Student Data Sheet

Mass of Benzil used g

Initial Volume Final Volume

KHP Mass (g)
NaOH (mL) NaOH (mL)
Titration 1
Titration 2
Titration 3

Initial Volume Final Volume

Benzilic Acid Mass (g)
NaOH (mL) NaOH (mL)
Titration 4
Titration 5
Titration 6

Total mass of Benzilic Acid produced g

Melting Point Range of Benzilic Acid ºC

Name:
Partner:
Synthesis of Benzilic Acid
Instructor Data Sheet
Mass of Benzil used g

Initial Volume Final Volume

KHP Mass (g)
NaOH (mL) NaOH (mL)
Titration 1
Titration 2
Titration 3

Initial Volume Final Volume

Benzilic Acid Mass (g)
NaOH (mL) NaOH (mL)
Titration 4
Titration 5
Titration 6

Total mass of Benzilic Acid produced g

Melting Point Range of Benzilic Acid ºC

7
 17
Post Lab Quiz (15pts)

At the beginning of the next lab period, you will have a quiz over the questions below. You
will be given the entire question and any structures on the in-class quiz. You may work
together prior to the in-class quiz to find the correct answers.

1 In this lab, a molecular rearrangement, specifically a 1,2-phenyl shift, occurs as shown in

the mechanism. While we have studied similar “shifts” last semester, the intermediate in
the reaction performed in this laboratory is different and the mechanism is different.
What are the names of the other two “shifts” and what intermediate is formed in these
reactions prior to the “shift”? Also, what is the “driving force” for these latter two
reactions (i.e. why does rearrangement even occur)?

2 In fact, this benzilic acid rearrangement is the oldest known molecular rearrangement;
discovered by Justus von Liebig in 1832. How might you synthesize benzilic acid
starting from benzene going through benzophenone and a cyanohydrin intermediate and
finally producing benzilic acid.

3 Assign oxidation numbers to the carbon atoms in Benzil and benzilic acid (see Lab 16
introduction for assigning oxidation numbers). According to your numbers, has an
oxidation or reduction (or neither) occurred?

O O OH O OH O
OH- H+
C C C C - C C
O OH

4 Binding studies on stereoisomers of 3-quinuclidinyl esters (BZ being one such ester) have
shown that it is the (R)-stereoisomer that has the greatest affinity for the muscarinic
acetylcholine receptors. Using a dash or wedge (the structure will be provided on the
quiz), show the R stereoisomer of BZ.

5 BZ’s IUPAC name is α-hydroxy-α-phenylbenzeneacetic acid-1-azabicyclo[2.2.2]oct-3-yl

ester. To what atom(s) do(es) the term “aza” refer? To what does the [2.2.2] refer?
Explain fully (hint: look up “bicyclo" in the McMurray text book).

8
 17
6 What aldehyde would you use to prepare the following compounds (these products are in
every way analogous to the benzaldehyde  benzoin  benzil  benzilic acid
reactions studied in Experiments 15 – 17).
OH OH
O
a) CH3O C COOH b) C COOH

OCH3
7 Give a mechanism for the following transformations (this mechanism is in every way
analogous to the benzil  benzilic acid mechanism seen in this very lab).

O O
OH COOH

1) HO-
2) H+

8 Alpha hydroxy acids (AHAs) have been marketed and used extensively in the past two
decades by older consumers. Use the Internet or resource book to determine why AHA
producers have enjoyed widespread financial success.

9 Another AHA that forms in milk as it sours and is produced in muscles and blood after
vigorous exercise is lactic acid, CH3CH(OH)COOH. The maximum number of
stereoisomers of a given substance is 2n where n is the # of stereogenic centers. What is
the maximum number of stereoisomers possible for lactic acid? Draw all stereoisomers
and label all stereogenic centers as “R” or “S”.