DEPARTMENT OF PURE AND APPLIED CHEMISTRY Visayas State University, Baybay, Leyte CHEM126 Organic Chemistry II Laboratory Report
Name Course/Yr Group No
: Mark Ryan R. Tripole : BS Chemistry II : 2
Date Performed Date Submitted Score
: 01/20/2015 : 01/29/2015
Experiment No. 8 The Preparation of Acetanilide
I. Introduction Acetanilide, a compound also known by its IUPAC name as either N-phenylacetamide or Nphenylethanamide, is an odorless solid chemical that has either a leaf or a flake like appearance. The crystals of acetanilide are white in color and it is only sparingly soluble in water, but more or less soluble in other solvents like diethyl ether, ethanol, benzene and acetone. Looking at the past applications in the compound, acetanilide was considered to be the first aniline derivative that was found to possess analgesic as well as anti-inflammatory properties and because of this was included as a stable in medical practice under the trade name Antifebrin. But then it was found to cause a condition known as cyanosis (characterized by the purple coloration of the skin due to the tissues near the surface having low oxygen saturation) and was discontinued and less favored over much less toxic aniline derivatives such as phenacetin (which was also eventually found to be potentially carcinogenic). In its own right, acetanilide is not an analgesic, but is rather metabolized in the body into acetaminophen, also well known as Paracetamol. Acetanilide also found its way into photography in its experimental use as photographic developers. Eventually, the commercial usage of acetanilide has died down and most of its usage is involved with organic synthesis, being a precursor in the synthesis of penicillin and a host of other pharmaceuticals. Its closest use in today’s commercial spectrum is as an inhibitor that slows the decomposition of drug-store hydrogen peroxide solutions. The synthesis of acetanilide comes about by the acylation of aniline with carboxylic acids or their derivatives to give an amide product. Though there are quite a number of methods into the synthesis of the compound, the most common laboratory procedure that is popularly used in introductory organic chemistry courses is through the acylation of aniline with acetic anhydride. The objective of the experiment was to gain familiarization of the laboratory process in the synthesis of acetanilide, as well as gain familiarization of the mechanisms behind the process of acylation (defined as the process of adding an acyl group to a compound). Another objective of this experiment would be to obtain adequate knowledge into the basic ideas and concepts behind each particular portion of the experiment and why certain steps are involved.
II. Results Shown in the succeeding pages are the results based on the experiment, the data obtained through the performance of the procedure and related calculations.
Page 1 of 12
Calculation of number of moles of acetanilide produced to determine limiting reagent: Aniline No. of moles of acetanilide =20 grams aniline x
1 mol aniline x 93.12 grams aniline
1 mol acetanilide 1 mol aniline
No. of moles of acetanilide = 0.214 moles Acetic Anhydride No. of moles of acetanilide = 26 grams acetic x anhydride
1 mol acetic anhydride 102.09 g acetic anhydride
x
1 mol acetanilide 1 mol acetic anhydride
No. of moles of acetanilide = 0.253 moles Since it is the aniline that produces the smaller amount of the acetanilide, then it is the limiting reagent that will determine the amount of the final product.
Page 2 of 12
Calculation for theoretical yield for acetanilide: Theoretical yield = 0.214 mol acetanilide
x
135.16 grams acetanilide 1 mol acetanilide
Theoretical yield = 28.92 grams acetanilide Calculation of percentage yield based on actual yield: Actual yield = 4.5 grams Percentage yield =
Actual yield Theoretical yield
x
100%
Percentage yield =
4.5 grams 28.92 grams
x
100%
Percentage yield =
15.15 %
Further elaboration on the results shall be given in the next section of this laboratory report.
III. Discussion Shown below is a simple schematic diagram of the experimental procedure performed.
Page 3 of 12
The reaction as shown in the procedure is characteristic of an addition of an acyl group to a compound. For this particular reaction, the acylating group is the acetic anhydride and the aniline is the compound to be added to. The general equation for the reaction is shown below:
As shown in the general equation above, an acyl group from the acetic anhydride is added to the aniline, while the other component goes on to form acetic acid in solution. This reaction first goes through a series of steps before arriving at the final products. The first step of the procedure was to prepare a solution of aniline in water and hydrochloric acid. Because of the fact that aniline is only sparingly soluble in water, adding it without an acid will not facilitate the acylation reaction as it is supposed to happen in the later step because the aniline is not adequately dissolved. The hydrochloric acid helps in this step by making the aniline more water soluble through the protonation of the amino group. A simple mechanism of this protonation is shown below:
This mixture of aniline hydrochloride was then heated up to 60°C on a hot plate basically to allow for a complete reaction and the acetanilide product to remain dissolved in solution. The next step of the procedure was to take the reaction beaker off the heat, then the addition of the acetic anhydride to the aniline hydrochloride solution, which was then followed by the addition of a solution of sodium acetate. The first part of the mechanism would be the deprotonation of the aniline hydrochloride back to its original aniline form. The mechanism for deprotonation is shown below:
Page 4 of 12
Once the aniline has been reformed in this step, the amino group then goes on to initiate a nucleophilic attack on the reactive sites of the acetic anhydride, which is at one of the partially positive carbonyl carbons. The mechanism for this part of the reaction is shown below:
As shown in the mechanism above, the first step in the mechanism comes in the form of a nucleophilic attack. What essentially forms in this step is a tetrahedral intermediate that is pretty unstable and thus results in the reformation of the carbon to oxygen double bond and the expulsion of the other acetate group. It would be wise to take note in this portion of the mechanism that there are counter ions that balance out these charges on the intermediates. The more important is that the protonated acetanilide intermediate is balanced out by the chloride ions in solution. This brings in the next step of the mechanism, which is the deprotonation of the protonated intermediate. In its protonated form, the compound is more or less a hydrochloride salt which is soluble in water. This is the main reason why the precipitation of product does not happen immediately. The sodium acetate solution is added to provide excess acetate ions that will facilitate the deprotonation of this intermediate, releasing it from its hydrochloride salt form and allowing the acetanilide final product to precipitate out of solution. The mechanism for this final step of the reaction is shown in the next page.
Page 5 of 12
After the addition of the sodium acetate solution, the precipitation of the acetanilide out of solution came almost immediately. The reaction beaker was then cooled in an ice bath and the product allowed to further crystallize with the aid of vigorous stirring. The product was then collected through vacuum filtration and left to dry for two days, after which the product was then weighed and its melting point determined using a Thomas Hoover Apparatus. POSSIBLE SIDE REACTIONS The only side reaction of particular note for this reaction would be the hydrolysis of the acetic anhydride in the presence of the excess of water. It itself, acetic anhydride is already pretty unstable a compound and readily reactions. A simple diagram of this is shown below: 0
But considering it’s usage as the acylating agent in this procedure, acetic anhydride is found to have a relatively low rate of hydrolysis, low enough to allow for the acetylation of amines to be carried out in aqueous solutions.
Page 6 of 12
THE YIELD For the experiment the group had obtained a final yield of 4.5 grams which amounted to around a percentage yield of 15%, way off mark from the expected 14-16 grams that could be obtained based on the proportions of the chemicals used. One can only speculate as to the reason behind this, but the most probable one could be the quality of the chemicals used. Looking back at the experiment, the aniline and the acetic anhydride were obviously “old” stock and may have already lost their efficiency as chemicals. And for one thing, the procedure didn’t exactly call for extremely specific conditions, which is why this is the only reason I can think of for the extremely low yield. Moreoever, we had not exactly applied the usage of decolorizing charcoal for this experiment, which is an explanation for the off white or close to tan color of the acetanilide product in the end. This may be of minor importance, but another possible factor could have been that the crystals were not allowed to fully form in solution and was put through vacuum filtration quite soon. A much higher yield could have possible been obtained if more time was allowed for the acetanilide to precipitate out of solution. The possibility of side reactions is quite low, considering the only one of prime importance would be the hydrolysis of the acetic anhydride (which as already explained before has a low rate of hydrolysis in water).
IV. Conclusion
Page 7 of 12
V. Answers to Questions 1. Although ethyl phenylacetate reacts readily with ammonia and with methylamine to yield the corresponding amide, the reaction of ethyl phenylacetate with t-butylamine is so slow and the yield so small that it is essentially useless in the laboratory. Suggest a reason for the failure of the aminolysis with t-butylamine. (Hint: What is the mechanism of aminolysis?)
One reason that seems pretty obvious at first glance would essentially be the issue of sterics, meaning that the t-butyl group on the amine is a relatively bulky group and making it essentially add to a big molecule like the ethyl phenylacetate would result in an extremely slow reaction with little to no yield. (NOT SURE ABOUT THIS ANSWER PA MGA KATOKAYO) 2. Write equations for the synthesis of the following amides (a) benzanilide (b) N-tbutylphenylacetamide (c) succinimide. A. BENZANILIDE
Page 8 of 12
B. N-T-BUTYLPHENYLACETAMIDE
C. SUCCINIMIDE
3. What is the function of the sodium acetate used in the preparation of acetanilide according to the procedure given? Write the equation for the preparation of acetanilide as you have actually performed through the experiment (not the equation on the report form). Include all reactants and indicate the role of sodium acetate. The main function of the sodium acetate in the mechanism is to be a source of and excess of the basic acetate ions that will help in deprotonating the water soluble hydrochloride salt of the acetanilide. Initially, the acetanilide product is protonated and remains dissolved in the solution. Once the product is deprotonated by the acetate ions and is no longer a hydrochloride salt, its solubility in water is essentially decreased and it crystallized out of solution. The reaction equation including all the reactants is shown in the succeeding page.
Page 9 of 12
Page 10 of 12
4. Acetyl chloride and ketones may be used to acetylate aniline but both reagents offer certain disadvantages. Suggest possible disadvantages to the use of each. Do these reagents offer any obvious advantages? In reference to the acetyl chloride, the one disadvantage that would be fairly obvious would be its reactivity. In general acyl chlorides are very reactive compounds and they react vigorously. So there might be somewhat of a relative danger in handling them, especially due to the fact that they react readily with water. As for the ketones, I’m guessing that the reaction would more or less favor the nucleophilic addition of the aniline to the carbonyl ketone forming an imine. As for the advantages, one could possible be that the reactions with aniline and acetyl chloride would be non-reversible with a good yield, overall more efficient in a sense. And given the reactivity of the compounds, the reactions could very well happen at room temperature, no heating required. 5. For persons sensitive to aspirin, 4-hydrocetanilide is often prescribed as an analgesic. Suggest a synthesis leading to the preparation of this pharmaceutical product beginning with phenol. STEP 1 – Nitration of Phenol
STEP 2 – Reduction of nitro group to an amine
STEP 3 – Formation of amide (4-hydroxyacetanilide or Paracetamol)
Page 11 of 12
VI. References
“Acetanilide” http://www.chemistrylearner.com/acetanilide.html “Acetanilide” http://en.wikipedia.org/wiki/Acetanilide “Acetanilide” http://www.britannica.com/EBchecked/topic/3210/acetanilide “Succinic Acid” http://en.wikipedia.org/wiki/Succinic_acid “562 - Organic Synthesis” www.orgsyn.org/demo.aspx?prep=cv2p0562 “The preparation of acetanilide from aniline.” wwwchem.uwimona.edu.jm/lab_manuals/c10expt23.html “Synthesis of acetanilide” http://fd.valenciacollege.edu/file/vprasadpermaul/Example%20of%20Lab%20Notebook%20%20Barnett%202012.pdf “Amide synthesis” http://www.organic-chemistry.org/synthesis/C1N/amides.shtm “Preparation of Acetanilide” http://sites.psu.edu/lburns/wp-content/uploads/sites/3465/2013/04/ch.6-formalreport.pdf “Preparation of Organic Compounds - Unit 10” http://ncert.nic.in/ncerts/l/lelm110.pdf “Preparation of Acetanilide” http://www.studymode.com/essays/Preparation-Of-Acetanilide-1265917.html “Benzanilide” www.orgsyn.org/demo.aspx?prep=CV1P0082 “Paracetamol” en.wikipedia.org/wiki/Paracetamol “Paracetamol” http://www.rsc.org/learnchemistry/content/filerepository/CMP/00/000/047/Paracetamol_web.pdf
Page 12 of 12
