SYNTHESIS OF ACETANILIDE 1
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Silverio, A. , Soriano, R. , Tan, J. , Tequillo, H. , Tolentino, M.
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University of Santo Tomas, Faculty of Pharmacy 1
ABSTRACT The experiment is performed to understand the chemical synthesis of acetanilide, a derivative of aniline. Acetanilide, produced from the nucleophilic acyl substitution of aniline and acetic anhydride, is synthesized and purified by recrystallization. Color Test and Azo-Dyestuff Test ar e performed in order to determine the purit y of the synthesized acetanilide. A series of color reactions were observed upon the addition of chemical reagents in both tests. The first part of the Color Test showed the transition of colors from dirty white precipitate to purple crystal in solution. The second part of the Color Test started from dirty white precipitate until it formed a green solution. Finally, the Azo-Dyestuff Test started as a brown solution and formed a yellow yellow precipitate in the end. To further check the purity, the melting point determination is done. After getting the average of the two trials, a temperature of 115 °C is obtained, close to the melting point of pure acetanilide which is 114 °C.
INTRODUCTION Acetanilide is also known as N phenylacetamide, acetanil or acetanilid, and was [1] formerly known by the trade name Antifebrin.
Figure 1. Chemical structure of Acetanilide.
Acetanilide was the first aniline derivative found to possess analgesic and antipyretic properties, and was quickly introduced into medical practice by A. Cahn and P. Hepp in 1886. [2] But its unacceptable toxic effects, the most alarming being cyanosis due to methemoglobinemia, prompted the search for less toxic aniline derivatives. In 1948, it was established that acetanilide is mostly metabolized to paracetamol in the human body and that it was the paracetamol that was responsible for the analgesic and antipyretic properties. [3] The observed methemoglobinemia after acetanilide administration was ascribed to the small proportion of acetanilide that is hydrolyzed to aniline anili ne in the body. Acetanilide is no longer used as a drug in its own right, although the success of its metabolite, paracetamol, is well known. Acetanilide is used as an inhibitor of hydrogen peroxide decomposition and is used to
stabilize cellulose ester varnishes. It has also found uses in the intermediation in the rubber accelerator synthesis, dyes and dye intermediate synthesis, and camphor synthesis. Acetanilide is used for the production of 4-acetamidobenzenesulfonyl chloride, a key intermediate for the manufacture of the sulfa [4] drugs. It is also a precursor in the synthesis of [5] penicillin and other pharmaceuticals. Acetanilide can be produced by reacting acetic anhydride with aniline through nucleophilic acyl substitution. Aniline, as an amine, serves as the nucleophile which gains a carbonyl group and loses a proton. Acetic anhydride serves as the electrophile and is the source of an acyl group to form an amide [6] which is acetanilide and a by-product, acetic acid.
Figure 2. Nucleophilic acyl substitution of aniline and acetic anhydride to produce acetanilide and acetic acid.
Recrystallization is a widely-used technique to purify a solid mixture. The desired product is isolated from its impurities by differences in solubility. Insoluble impurities and colored impurities can be removed from hot solvent through the use of filtration. Soluble impurities remain in the cold solvent after recrystallization. The desired product should be as soluble as possible in hot solvent and as insoluble as possible in cold solvent. [7]
EXPERIMENTAL A. Compounds Tested Aniline (ρ=1.02g/mL) is a toxic organic compound with the formula C6H5 NH2. Consisting of a phenyl group attached to an amino group, aniline is the most prototypical aromatic amine. Its main use is in the
manufacture of precursors to polyurethane and other industrial chemicals. Like most volatile amines, it possesses the odor of rotten fish. It ignites readily, burning with a smoky flame characteristic of [8] aromatic compounds.
Figure 3. Chemical Structure of Aniline.
Acetic Anhydride, (ρ=1.082g/mL) also known as ethanoic anhydride, is the chemical compound with the formula (CH3CO)2O. Commonly abbreviated as Ac2O, it is the simplest isolatable acid anhydride and is a widely used reagent in organic synthesis. It is a colorless liquid that smells strongly of acetic acid, [9] formed by its reaction with the moisture in the air.
Figure 4. Chemical structure of Acetic Anhydride.
B. Procedure 1. Reaction of Aniline and Acetic Anhydride 20 drops of aniline and 10mL of distilled water were placed in a hard glass test tube. 20 drops of acetic anhydride were added to the aniline solution and stirred for 5 minutes or until the solid, a white
precipitate formed. 10mL of water was added and the test tube was heated in a water bath. It was stirred occasionally until the entire solid dissolved. The test tube was set aside for 5 minutes to cool and chilled in an ice bath for 10 minutes. Using pre-weighed filter paper, the solution was filtered and the residue was collected. The residue was pressed to remove excess water using another filter paper. The sample was allowed to dry completely. The acetanilide was weighed and the % yield computed. The sample was stored in an amber bottle until next experiment period. 2. Color Test 0.5g of acetanilide was placed in a test tube and treated with 1mL of concentrated HCl. The solution was diluted with 12mL of water and was gently heated to boiling. The solution was cooled and divided into 2 equal parts: a) to one portion, 1mL of free aqueous calcium hypochlorite was added; b) to another portion, 1mL of 2% KMnO 4 solution was added. 3. Azo-Dyestuff Test 0.5g of acetanilide was boiled with 1mL of concentrated HCl in a water bath. The test tube was cooled and placed in an ice bath for 10 minutes. The solution was diluted with 5mL of distilled water. 4 drops of 10% KNO 2 was added and made alkaline with NaOH. A pinch amount of beta naphthol was added. The color reaction was observed. 4. Melting Point Determination The test substance was pulverized by means of a clean spatula. The reducing of size was done in a watch glass. The open end of a capillary tube was pushed into the powdered test substance. The powder was moved to the closed end of the capillary tube by tapping it on the table until the powdered test substance occupied 1-2 mm of the capillary tube end. The opposite end of the filled capillary tube was sealed. The capillary tube was attached to a thermometer using rubber bands by aligning the bulb of the thermometer to the closed end of the capillary tube. An oil bath was made by half filling a 100ml beaker with warm cooking coil. The oil bath was heated. The thermometer/ capillary tube assembly was placed in an oil bath. The surface level of the aspirin must be beneath the surface level of the oil bath. The beaker was placed on a hot pl ate and the oil was frequently stirred to distribute heat uniformly. The temperature at which the aspirin melts was
noted. The procedure was repeated twice and the results were averaged. The experimental result was compared with the accepted value.
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Trials Temperature ( C) o 112 C 1 o 118 C 2 115 oC Average Table 1. Results of Melting Point Determination.
On average, the synthesized compound has a melting point close to the theoretical melting point, which is o 114 C. The raw and derived data collected during the experiment is as follows: Sample Name: Acetanilide A. Mass of Aniline Figure 5. An illustration of the setup used in Melting Point Determination.
RESULTS AND DISCUSSION Synthesized acetanilide is an odorless solid chemical of leaf or flake-like appearance. It is obtained by mixing premeasured amounts of aniline and acetic anhydride. The first part of Color Test resulted in a transition of colors from dirty white precipitate to purple crystals in this order: Dirty white precipitate- clear, colorless solution brown ring- clear, colorless solution- clear, light pink solution- dark blue turbid solution- purple crystals in solution The second part of Color Test gave a transition from dirty white precipitate to green solution in this order: Dirty white precipitate- clear, colorless solution brown ring- clear, colorless solution- clear, light pink solution- yellow solution- green solution The Azo-Dyestuff Test likewise gave a transition from brown solution to yellow precipitate in this order: Brown solution- purple solution- white precipitateorange precipitate- yellow precipitate Melting point determination determines the purity of the synthesized compound by comparing the experimental melting point to the theoretical melting point.
)() ( B. Mole of Aniline
) ( C. Mass of Acetic Anhydride ) ( )( D. Mole of Acetic Anhydride ) ( The limiting reagent is Acetic Anhydride while the excess reagent is Aniline. E.
Theoretical Moles of Acetanilide
)( ) ( )( F. Theoretical Mass of Acetanilide ( ) G. Mass of Filter Paper: 1.5699g H. Mass of the Filter Paper and Acetanilide: 2.7294g I. Calculation of Percentage Recovery
The percentage yield is 80.93%.
CONCLUSION Acetanilide is an odorless powder with a leaf or flake-like appearance. It is synthesized via nucleophilic acyl substitution by reacting aniline and acetic anhydride. It produces purple crystals and a green solution when subjected to Color test and gives a yellow precipitate in Azo-Dyestuff Test. It has a o melting point of 114 C.
REFERENCES [1]
http://chemicalland21.com/lifescience/phar/ACET
ANILIDE.htm [2]
Cahn, A .; Hepp, P. (1886), "The antifebrin, a new antipyretic," Centralbl. Klin Med. 7:. 561-64. [3]
Brodie, B. B.; Axelrod, J. (1948),"The fate of acetanilide in man", J. Pharmacol. Exp. Ther.94 (1): 29 – 38. [5]
Ashford’s Dict ionary of Industrial Chemicals (3 ed.). 2011. p.33.
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[6]
Acetanilide, SIDS Initial Assessment Report, Geneva: United Nations Environment Programme, September 2003. [7]
http://wwwchem.uwimona.edu.jm/lab_manuals/c1
0expt23.html [8]
en.wikipedia.org/wiki/Aniline
[9]
en.wikipedia.org/wiki/Acetic_anhydride
