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Austin Goewert, Chem 213 Synthetic #3 FFR Bromination of Acetanilide Introduction Electrophilic aromatic substitution is an important practice in organic

chemistry because it can be used to add a wide range of functional groups to aromatic rings. One such addition is the bromination of acetanilide to form 4-bromoacetanilide. Acetanilide has many chemical and biological functions including: inhibitor in hydrogen peroxide, rubber accelerator, antiseptic, and precursor to penicillin.1 Bromination of acetanilide is important because the resulting 4bromoacetanilide is a precursor to anti-cancer agents, kinase inhibitors, and other important pharmaceutical compounds.2 Bromination of acetanilide occurs at the para position due to the amine substituent. This substituent provides resonance stabilization to the carbocations created by ortho and para addition. Since the amine provides steric hindrance at the ortho position, bromination of acetanilide occurs at the para position. A common method for brominating acetanilide involves liquid bromine in glacial acetic acid. 3 In order to avoid the potential hazards of liquid bromine, alternative methods have been developed. One method forms bromine in-situ from potassium bromate and hydrobromic acid. This method resulted in a 96% yield of 4-bromoacetanilide.3 A third method is the sodium tungstate catalyzed reaction of sodium perborate with potassium bromate. This method produced only a 86% yield, however it may be advantageous in some cases due to the low cost and availability of sodium perborate.4 This experiment uses the second method, in-situ bromine formation from potassium bromate and hydrobromic acid, to brominate acetanilide.
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Scheme 1. Mechanism of bromine formation via oxidation of bromide with bromate First, a bromide ion is oxidized by bromate (1). The two negatively charged oxygens on the resulting compound are then protonated (2). A hydroxide shift and the breaking of the Br-Br bond cause the molecule to split (3). The two resulting molecules are each protonated (4), and then reduced by a bromide ion (5). As BrH2O is reduced, water is expelled as a leaving group, and one equivalent Br2 is produced. Br2O2H2 separates via a hydroxide shift and breaking of the Br-Br bond (6). The two BrOH molecules produced are protonated (7), and then reduced by bromide (8), expelling water as a leaving group, and forming two more equivalents of Br2 (9).

Scheme 2. Mechanism of bromination of acetanilide First, bromine is attacked by electrons on the aromatic ring of acetanilide (1), forming a Br-Ar bond at the para position. The electrons forming the Br-Br bond are pushed onto the other bromine atom, forming a bromide ion (2). The 4-bromoacetanilide carbocation is deprotonated by the conjugate of acetic acid. The electron pair that was bound to the hydrogen reenters the ring, restoring aromaticity (3). The purpose of this experiment is to form 4-bromoacetanilide by bromination of acetanilide. The bromine will be formed in-situ from hydrobromic acid and potassium bromate via the mechanism described in Scheme 2. The product will be purified via recrystallization, and analyzed by melting point, 60 MHz 1H NMR, and IR.

Experimental 4-Bromoacetanilide. HBr (0.3mL, 2.6mmol) was added to potassium bromate (0.085g, 0.5mmol), acetanilide (0.2g, 1.5mmol), and glacial acetic acid (2mL). The mixture was stirred for 60 minutes at room temperature. After 60 minutes, the mixture was added to cold water (25mL), producing a cloudy white precipitate. The solid was removed by vacuum filtration and washed with 10% sodium thiosulfate (5mL) and cold water (5mL). Recrystallization (95% ethanol) afforded 4-bromoacetanilide as needle-like white crystals (0.2075g, 65.5%), mp 166168oC; 1H NMR (60MHz, DMSO) 10.027 (s, 1H), 7.498 (m, 4H), 2.027 (s, 3H); IR (ATR)

max (cm-1) 3288.7, 3255.6, 3183.3, 3111.3, 1664.6.


Results and Discussion The formation of 4-bromoacetanilide was accomplished by bromination of acetanilide via electrophilic aromatic substitution. The bromine was generated in-situ via oxidation of bromide with bromate. When HBr was added to the reaction mixture, an orange color resulted. This color change is consistent with Schatzs results (from which the procedure is adapted).3 The reaction was stirred for 60 minutes, whereas Schatz only stirred for 30 minutes. After 60 minutes, the mixture was poured into cold water to precipitate out the product. Due to its size, acetanilide is only slightly soluble in water.5 The other major byproducts of the reaction: water, acetic acid, and K+ are soluble in water, and thus remain in solution while the product precipitates out. Using cold water is important as the low temperature further decreases the solubility of the product. The solid product was collected via vacuum filtration, and recrystallized using 95% ethanol. The final product was needle-like white crystals. This is consistent with Schatzs observations.3 The melting point of the purified product was 166-168oC. This falls within the
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range of the literature value of 165-169oC for 4-bromoacetanilide. IR and NMR were used to clarify the identity of the product. IR analysis proves difficult as the predicted peaks for starting material and product are similar. The product will have an aromatic-bromine absorption that the starting material will not, however this absorption is in the fingerprint region and is difficult to observe. The IR obtained (Figure 1) shows the carboxyl group at 1664.6 cm-1, the aromatic-hydrogen bonds from 3111.33183.3 cm-1, and the nitrogen-hydrogen bond at 3288.7cm-1. Comparing literature spectrum for product and starting material shows subtle differences in the shape of the aromatic-hydrogen peaks; however the spectra are too similar for any conclusions to be made. The IR obtained matches the 4-bromoacetanilide spectrum published by N. Inst. of Adv. Ind. Sci. and Tech.6 60 MHz 1H NMR provides more differentiation between product and starting material. Bromination replaces one of the aromatic hydrogens on acetanilide, meaning the product has four aromatic hydrogens while the starting material has five. The NMR spectra obtained (Figure 2) shows the aromatic hydrogens as a four hydrogen peak at 7.498ppm, proving the presence of 4-bromoacetanilide. Additionally, the methyl hydrogens are observed as a three hydrogen singlet at 2.027ppm, and the amine hydrogen is observed as a one hydrogen singlet at 10.027ppm. A peak at 2.074ppm indicates contamination with acetone. This contamination is a result of unevaporated acetone in the NMR tube after cleaning. The solvent used was DMSO, and peaks indicating water in DMSO are present at 2.493 and 3.301ppm. Aside from the contaminate peak, Figure 2 matches the NMR for 4-bromoacetanilide published by N. Inst. of Adv. Ind. Sci. and Tech.6

Based on melting point, IR, and NMR data, it can be concluded that 4-bromoacetanilide was produced. The percent yield was 65.5%. Loss of product can mostly be attributed to residual solid left on glassware and on the Hirsch funnel. Additionally, it is likely some product did not precipitate out during the workup. It is also probable that small amount of product was lost to excess solvent during recrystallization. The reaction was not monitored by TLC, and so it is possible it did not go to completion. This is unlikely however, as the reaction was run for twice the time recommended by Schatz. Schatz produced >90% yield with only 30 minutes of reaction time.3 Although a 65.5% yield is less then desirable, ample solid was produced to run the required analyses and determine the identity of the product. The melting point, IR, and NMR obtained for this experiment prove that acetanilide was brominated to form 4-bromoacetanilide. The product produced was pure, however the NMR tube was not completely dry, and so acetone can be observed in the NMR in Figure 2. It is important to be certain glassware is completely dry before use. The primary loss of product was due to residual solid. In the future, a better effort should be made to rinse and remove all residual solid. If the experiment were run again, it may also prove beneficial to monitor the reaction by TLC to avoid speculation as to whether it went to completion. Overall, the experiment succeeded in producing 4-bromoacetanilide via bromination of acetanilide.

References 1. Lewis, R.J. Hawleys Cond. Chem. Dictionary, 14th ed.; John Wiley & Sons: Chichester, U.K., 2000 2. Yang, X.; Zhang, Y.; Ma, D.; Adv. Synth. Catal. 2012, 13, 2443-2446. 3. Schatz, P.F.; J. Chem. Ed. 1996, 73, 267. 4. Hanson, J.R.; Harpel, S.; Immaculada, C.; Rodriguez, M.; Rose, D.; J. Chem. Research. 1997, 11, 432-433. 5. Advanced Chem. Development. Solubility Data. 1994-2013 6. N. Inst. of Adv. Ind. Sci. and Tech. (Japan). Integrated Spectral Database System of Organic Compounds. 2013