Phenyls to Painkillers: The Synthesis of an Analgesic from Aniline

Arvind Narayan
Section 216-133
GSI: Luke Peterson
Fall 2013

Introduction:
Anilines are pharmacologically important compounds because when acetylated, they act in a
chemically similar manner to painkillers [4]. Acetylation is used to reduce the severity of the
reaction between amines and other oxidizing agents. Acetylated anilines work by exhibiting
analgesic behavior and by working on the central nervous system. Tylenol and Aspirin are the
most common and commercially available acetylated anilines [4]. The purpose of this lab was to
utilize the acetylation reaction to prepare an unknown analgesic. Throughout the experiment,
several key identification tests were used to pinpoint the unknown product. The secondary
purpose of this lab was to become familiarized with the process of recrystallization.
Recrystallization is an extremely common technique used for purifying a compound.
Recrystallization uses the fact that impure solutions will contain two different compounds,
termed compound A and compound B, with two unique solubility products [5]. A very small
amount of hot solvent is added until the solution is saturated. The solution is then allowed to cool
[2]
. Since the solubility product of the impurity, Compound B, is never reached, because the
relative concentration of the impurity is extremely low, only the pure Compound A crystalizes.
The identification tests that are used are The Bielstein test, melting point, thin layer
chromatography, and an IR spectrum. The Bielstein test is useful for identifying compounds with
halogens. If the flame contains a quick burst of blue or green, then that is a positive marker for a
halogen[1]. Using this test helps to narrow the list of potential compounds for the unknown. A
thin layer chromatography (TLC) plate is used to compare two solutions. By co-spotting one
solution with another, you can effectively see the purity of the substance [2]. TLC is also often
used for separating mixtures. This can show if there are multiple different compounds in the test
solution.
IR spectroscopy is a technique that identifies bond energies by showing where energy is
absorbed in the molecule. A peak is created on the screen at certain frequencies indicating that a
certain bond exists in the molecule. Each IR spec contains two distinct regions. The fingerprint
region contains wavelengths in the 1450 600 cm -1 region and is hard to read. Therefore, only
energies higher than 1550 cm -1 are used when determining what bonds are in the molecule [3].
Each bond has its own energy so a table of known energies is used to identify the bonds in the
molecule.
Melting point is the best indicator of compounds. Melting a compound involved breaking the
intermolecular bonds that hold the substance in its solid form. This is something that is unique to
each compound because they contain distinctive ratios of atoms and bonds. By placing a sample
inside a Mel-temp and watching it melt, you can definitively conclude what substance something
is from a list of known substances. This is the last test that was used to figure out the unknown
compound.

The lab was done for two weeks on two different compounds. The first week it was run with
known aniline and the purpose was to become familiar with the reaction and with the
identification tests. The second week the lab was run with the exact same procedure but with
unknown aniline and the purpose was to identify the starting compound.

Reaction Scheme:

Experimental Section:
n-phenylacetamide. A 250 mL beaker was filled with an unknown analine (500 mg) and
dissolved in water (14 mL). Concentrated hydrochloric acid (0.45 mL , 37 wt%) was added to
the solution. Acetic anhydride (0.6 mL) was added to the aniline hydrochloride. A solution of
sodium acetate (530 mg, 6.46 mmol) and water was immediately added. The solution instantly
turned white and became homogeneous slurry. The solution was mixed and placed on an ice
bath. After the collection of crystals in the beaker, the solution was scooped onto filter paper and
solid product was collected using vacuum filtration. Ethanol (95 %) was heated and added drop
wise until all solid product was dissolved. Recrystallization of the crude product was carried out
by vacuum filtration. IR (film) 3265, 2963, 1645, 1587 cm -1. TLC Rf .685 (3:1 hexanes/ethyl
acetate)
aniline. The exact same procedure was carried out for the acetylation of aniline. IR 3442, 3360,
3035, 1619 cm-1 . TLC Rf .1625 (3:1 hexanes/ethyl acetate).

Results and Discussion:

The aniline used in the reaction was unknown solution #954. The actual amount of aniline that
was used was .5162 g. The aniline was a translucent red liquid. During the initial mixing process
the aniline and the water did not mix. Two layers were created. Bubbles of aniline formed on the
bottom of the beaker used for mixing the two liquids. The concentrated HCl helped dissolve the
aniline, a weak base, by creating a more acidic environment. There was a quick cloud of white
smoke that appeared when the concentrated HCL was added. Once all reagents has been added, a
white precipitate immediately formed. The solution was mixed to help all the reagents come in
contact to increase the yield of product. Once the slurry mix was sufficiently mixed, vacuum

filtration was used to remove excess liquid. What was left in the filter paper was the crude
product. The crude product was red-pink in color and very soft. It had a chalk-like texture. There
was no detectable odor. The crude product had a mass of .7055 g.
The reaction has a stoichiometric reactant to product ratio of 1:1. Therefore how many moles of
aniline were used is how many moles of product should have been formed. This is used to help
calculate theoretical yield.
The molar mass of aniline is 93.13 g, therefore the moles aniline used is

= .0054

mol aniline and thus .0054 mol product. If the steps are reversed and we use .0054 mol product
.7055 g products we get a molar mass of

. Using the fact

that the only difference between the aniline in the first part and the substituted aniline in the
second part is the added group, subtracting out the mass of aniline will give the mass of the
added group. This equals
.
The Bielstein test showed that there is no halogen present. The melting point of the recrystallized
product was between 75 C and 77 C. The TLC plate had the crystal and the unknown starting
liquid cospotted on the same plate. The solution that was used in the running phase was 75%
Hexanes and 25% ethyl acetate. The Rf value for the unknown was .685 and the Rf value for the
unknown was .143. The relatively high Rf value for the unknown shows that it is non-polar
because the running phase as also non-polar. The co spot worked to show that the compounds
were pure. The IR spectrum (attached) shows that there is an added peak at 1644 cm-1. This is the
C=O that was added in the acetylation process.

Conclusion
Using all of this information together, I conclude that the unknown compound is m-anisidine. Manisidine has a melting point of 80 C - 82 C and the functional O-methyl group has a mass of
32.042. The discrepancy between the actual and the calculated can be explained by any residual
water that was left in the product when it was placed on the scale. The IR spectra profile of manisidine found on chemexpr.com shows similar peaks to the IR spectra collected in lab.

References
1. Beilstein, F. "Ueber Den Nachweis Von Chlor, Brom Und Jod in Organischen
Substanzen."Zeitschrift Fr Analytische Chemie 12.1 (1873): 95. Print.
2. Leonard, J., B. Lygo, and Garry Procter. Advanced Practical Organic Chemistry. London:
Blackie, 1995. Print
3. Reusch, William. "Infrared Spectroscopy." Infrared Spectroscopy. Michigan State University
Department of Chemistry, 5 May 2013. Web. 26 Sept. 2013
4. Thomas Kahl, Kai-Wilfrid Schrder, F. R. Lawrence, W. J. Marshall, Hartmut Hke, Rudolf
Jckh "Aniline" in Ullmann's Encyclopedia of Industrial Chemistry 2007; John Wiley &
Sons: New
5. Eppley, Hilary J. Recrystallization of M(acac)3 Complexes. DePaw University and
Ionicviper.com, 03 Apr. 2009. Web. 28 Sept. 2013.