Lab Report 8 - multi step synthesis PDF

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Report 8: Six-Step Synthesis: Aniline to 1-bromo-3-chloro-5-iodobenzene

Abstract In this paper, the six-step synthesis of 1-bromo-3-chloro-5-iodobenzene from aniline is reported. The synthesis demonstrates the use of an electron-donating group to activate the aromatic ring and direct halogen atoms onto the ring via electrophilic aromatic substitution. After all the desired substituents are placed around the ring, the electron-donating group is deaminated and replaced with a hydrogen atom. The experiment has six individual steps: 1) Acetylation, 2) Bromination, 3) Chlorination, 4) Amide Hydrolysis, 5) Iodination, 6) Deamination. In each step, a recrystallized product, melting point data, and yield data were collected to confirm the identity and quantity of the product. This synthesis can be performed successfully in an undergraduate laboratory using microscale techniques. Overall, this synthesis has the potential to produce high individual yields ranging from 62-96%. However, lower yields, less than 65% in each step, were observed because of human error and side reactions.

Introduction Many organic compounds are not readily available or naturally occurring and can be produced through multi-step syntheses. Electrophilic aromatic substitution is one of the most important reactions in synthetic organic chemistry. Such reactions are used for the synthesis of important intermediates that can be used as precursors for the production of pharmaceutical, agrochemical and industrial products. There are three fundamental components to an electrophilic aromatic substitution: 1) formation of the new σ bond with a strong electrophile by using pi electrons in the aromatic nucleophile, 2) removal of a proton by breaking the C-H σ bond, 3) reforming the C=C to restore the aromaticity. Once the pi electrons form a new σ bond with the electrophile, a resonance-stabilized carbocation is created called the sigma 1

complex. The formation of the carbocation is the rate-determining step in the reaction and aromaticity is regained by loss of a proton from the site of substitution. Substituents on the benzene ring can either donate electrons to the ring or have withdrawing abilities. Electron donating groups allow the substitution to occur faster than electron withdrawing groups because the electron donating groups delocalize positive charge on a carbocation, which increases carbocation stability. Substituents on the aromatic ring control the regiochemical course of the reaction. 1 In this experiment, a six-step synthesis is performed by converting aniline to 1-bromo-3-chloro-5iodobenzene (9). The preparation of 1-bromo-3-chloro-5-iodobenzene (9) uses important factors, such as the role of protecting groups, electrophilic substitution reactions, and substituent effects, in the multistep synthesis. 1-bromo-3-chloro-5-iodobenzene can be initiated from benzene; however, benzene is a carcinogen, so the experiment will begin with aniline (3). The series of reactions for the synthesis is outlined in Figure 1. Each step requires a short reaction time, and produces high individual yields ranging from 62-96%2.

Figure 1.1: Steps of Synthesis of 1-bromo-3-chloro-5iodobenzene from benzene The first step of the synthesis is acetylation, the conversion of aniline to acetanilide using sodium acetate and acetic anhydride (4). Acetylation is necessary to protect the amine to prevent unwanted reactions. The amino function on the aniline is an electron-donating group that activates the ring toward electrophilic aromatic substitution reactions. Electrophilic reagents or other functional groups may be present on the ring can react directly with the amino group. The amino group produces undesired trisubstitution of bromine in the next step of the synthesis. Acetylating the amino group to the acetamido group, CH3CONH–, forms a less powerful activating group because the resonance within the N-acetyl group of the amide competes with delocalization of the nonbonding electrons on the nitrogen into the ring. The acetamido group activates 2

the ring for the desired product of monobromination in the next step without a strong lewis acid catalyst. Water is used as a solvent to stabilize the positive and negative charges in solution. The reaction proceeds by a nucleophilic attack of acetic anhydride by the :NH2-. (See mechanism). Sodium acetate deprotonates the extra proton from aniline.

Mechanism1.1: Acetylation of aniline

The second step of the synthesis is bromination of acetanilide to 4-bromoacetanilide using bromine in glacial acetic acid (5). The reaction proceeds via electrophilic aromatic substitution mechanism (refer to mechanism 1.2) to form the monobromination product. Bromination of acetanilide uses the polar solvent of acetic acid. The acetic acid solvent removes the proton needed for electrophilic aromatic substitution and stabilizes the intermediate cation. Acetic 3

acid solvates the bromide ion. The acetamido group is an ortho/para director, so both the para, 4bromoacetanilide (95% major product) and ortho, 2-bromoacetanilde (5% minor product) are observed. The para position is favored because of its greater molecular symmetry, can stack better, and the steric bulk of the acetamido substituent hinders attack at the 2-position. The two isomers are separable with a single recrystallization in methanol. The para isomer has a higher melting point than the ortho isomer, 170 and 100 degrees Celsius respectively. Removal of excess Br is accomplished with the use of bisulfite: HSO3-- + Br2 + 3H2O = HSO4--- + 2Br-+ 2H3O+ Reduction: Br2+ 2e = 2Br-__ Oxidation: HSO3= HSO4__ + 2e__

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Mechanism 1.2: Para and Ortho Isomer Bromination of Acetanilide Mechanism 5

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The third step in the synthesis is chlorination of 4-bromoacetanilide to 4-bromo-2chloroacetanilide(6) using sodium chlorate, hydrochloric acid, and acetic acid. The reaction proceeds via electrophilic aromatic substitution mechanism with chlorine substitution occurring at the ortho position, according to Mechanism 1.3. 4-bromoacetanilide is slightly less reactive towards electrophilic aromatic substitution than acetanilide because the bromine substituent is an electron-withdrawing group; however, the ring is reactive enough for chlorination to proceed. Chlorination occurs in an acetic acid solvent, showing the same advantages as discussed in bromination. The formation of the 2-rather than the 3-chloro isomer demonstrates the more powerful directing effect of the acetamido group as compared to the bromine substituent. Chlorine is generated in situ by HCl and NaClO3 to avoid hazards and generate the gas with precision. An oxidation-reduction reaction occurs by which chlorine ion is oxidized to chlorine gas and chlorate is reduced to chlorine gas. Oxidation: 2 Cl- = Cl2 + 2 eReduction: 12 H3O+ + 2 ClO3 - + 10 e- = Cl2 + 18 H2O Overall: 5 Cl- + ClO3- + 6 H3O+ = 3 Cl2 + 9 H2O

Mechanism 1.3: Chlorination of 4-bromoacetanilide 7

The fourth step is the amide hydrolysis, 4-bromo-2-chloroacetanilide to 4-bromo-2-chloroaniline (7) using HCl, H2O and ethanol as the solvent. The acetamido group of 4-bromo-2-chloroacetanilide is the most powerful director of the three substituents on the aromatic ring, so further electrophilic substitution will preferentially occur at the 6-position of the molecule. However, hydrolysis is important to deprotect the amino group in preparation to add the weak electrophile, I+ at the 6-position. The amide group is less reactive than an amino group—the regeneration of the amino group allows reactivation of the aromatic ring that has been deactivated by the electron-withdrawing groups Br and Cl. The strong amino group allows iodination to occur by: 1) reactivating the ring for EAS at the ortho position and 2) removing the bulky acetyl group to prevent steric hindrance for iodination at the ortho position. The acid-catalyzed (HCl) hydrolysis mechanism takes place by protonating the carbonyl on the acetyl group, adding water to hydrolyze the bond, and protonating the amine to make it a good leaving group and separate it from the acetyl group. NaOH is added in the workup to deprotonate the positively charged aniline and remove excess Cl-.

Mechanism 1.4: Hydrolysis of 4-bromo-2chloroacetanilide

The fifth step is iodination of 4-bromo-2-chloroaniline to 4-bromo-2-chloro-6-iodoaniline (8) using the iodinating agent, iodine monochloride, ICl. Iodine is less electronegative than Bromine and chlorine; this makes elemental iodine (I2) a weak and unreactive electrophile. ICl is polarized to make the iodine atom electrophilic for aromatic substitution, adding a partial positive charge on the iodine and a partial 8

negative charge on the chlorine. The polarized ICl bond is stabilized by acetic acid. The iodine adds at the ortho 6-position to the aniline group via electrophilic aromatic substitution. Bisulfite is used as a reducing reagent to quench the reaction: Reduction: 2e- +ICl I-+ClOxidation: HSO3-HSO4-+2eI-Cl +HSO3-+ 3H2O  I- + Cl- + HSO4- + 2H3O+

Mechanism 1.5: Iodination of 4-bromo-2-chloroanilie

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The final step is deamination of 4-bromo-2-chloro-6-iodoaniline to 1-bromo-3-chloro-5iodobenzene (9) using sodium nitrite, sulfuric acid, and ethanol. The purpose of the amino group is to activate the aromatic ring and direct halogenation around the ring. After the fifth step of the synthesis, halogenation is completed as desired; therefore, the amino group can be removed via the deamination mechanism using nitrous acid (Mechanism 1.6). Nitrous acid is unstable, so it is generated using sodium nitrite and sulfuric acid. The reaction of NaNO2 and H2SO4 with the aniline group produces the diazonium ion. The diazo group may be replaced with a hydrogen atom using ethanol or hypophosphorous acid, H3PO2. This experiment uses ethanol because it works well with aromatic compounds containing halogen atoms. The mechanism for the diazo group may be replaced with a hydrogen atom is ill defined; a possible mechanism is shown below. Side reactions may be observed if the carbocation is attacked by water to form a phenol or ether forms if the oxygen in ethanol attacks at the carbocation. Ether and phenol formation are minor processes in the present reduction, and any ether that is produced is removed by recrystallization of the product. Halogen exchange may also occur if HCl was used instead of H2SO4, replacing the Br/I on the ring with Cl atoms.

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Mechanism 1.6: Deamination of 4-bromo-2-chloro-6iodoaniline

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Overall, the synthesis of 1-bromo-3-chloro-5-iodobenzene is unique because it uses a ring activating, electron-donating amino group to direct the three-halogen atoms (Br, Cl, I) on to the ring and later removes the amino group from the final product. The amino group is protected to force bromination to the desired para position and then chlorination to the ortho position, while producing only monobromination and monochlorination products. The protected group is hydrolyzed to reactivate the ring to allow a weak electrophile, iodine, to substitute at the 6-position. After all the halogen atoms are substituted the amino group is removed and replaced with a hydrogen atom. 3

Experimental Section Melting points were obtained using a corrected MelTemp apparatus. The NMR spectrum was provided—60 MHz in CDCl3 or DMSO-6 solution using tetramethylsilane (TMS) as an internal standard. The IR spectrum was provided and obtained on a Perkin-Elmer 710B Spectrophotometer in CCl4 solution. Acetanilide (4). A sample of aniline (density 1.02, 0.04 mol, 3.6 mL) was dissolved in a 100 mL of 0.4N hydrochloric acid in a 250-ml Erlenmeyer flask. The solution was stirred briskly to dissolve, heated to 50OC, and then subject to magnetic stirring. One portion of acetic anhydride (density 1.08, 4.4 mL) was added to the hot solution. After stirring, a prepared solution of 6.0 g of sodium acetate trihydrate dissolved in 20 mL of water was added to the hot solution. The reaction mixture was cooled and magnetic stirred until crystalline product completely precipitated. The acetanilide was collected by vacuum filtration. An additional 2 mL of acetic anhydride was added to the filtrate to ensure all the aniline was acetylated. Any precipitate was vacuum filtered and added to the first crop. 100% yield was observed with a wet product weight of 6.73 g. The melting temperature was measured to be 114.7-117.6OC for the final product (lit 113-115 C). IR  max (CCl4) 3330 (NH stretch, weak) 2800-3000 (C-H; aromatic), 1665 (C=O stretch), 1600 (C-H: aromatic, weak), 1540 (NH bending), 1500 (C-H: aromatic, weak), 750 and 690 (C-H bending, aromatic). 1H NMR (CDCl3)  7.81 ppm (singlet, 1H, H on nitrogen)  7.55 ppm (doublet, 2H; aromatic H ortho J ~ 6.06 Hz)  7.35 ppm (multiplet, 2H; aromatic H meta J = 7.71 Hz)  7.10 ppm (triplet 1H; para He J =6.63 Hz)  2.15 ppm (singlet 3H; CH3 group). Observations: Aniline is a yellow solution; after the solution is stirred and warmed with HCl and sodium acetate, the solution is white powdery precipitate. Recrystallized product appears large, white powdery crystals. Potential safety hazards include hydrochloric acid can cause skin irritation, wear gloves. 4-bromoacetanilide (5). From the acetanilide produced in the previous step, 5 mL of acetic acid was used for every 0.01 mole of acetanilide. The acetanilide, 5.40 g (0.040 mol), was dissolved in 20 mL of glacial acetic acid in a round bottom flask with a stir bar. 4 mL of bromine in glacial acetic acid was added to the stirred solution of acetanilide over a 1-2 minute period. The reaction mixture was stirred for another 10 minutes, forming a precipitate. 66 mL of ice-cold water was added with stirring and minimal aqueous sodium bisulfite solution should be added to discharge any color. The crude was vacuum filtered and washed well with water. The crude product was recrystallized in 20 mL of methanol. A second crop 13

was obtained by adding 4 mL of water to the dissolved filtrate and combined with crop one. 64% yield was observed with a weight of 5.47 g. The melting temperature was measured to be 164.2-166.3 OC for the crude product and 166.7-168.1 OC for the recrystallized product (lit 165-169 °C). IR  max (CCl4) 3330 (NH stretch, weak) 2900-3100(C-H; aromatic), 1725 (C=O stretch), 1600 (CH: aromatic, weak), 1540 (NH bending), 1500 (C-H: aromatic, weak), 825 (C-H bending) 1H NMR (DMSO-D6)  10.15 ppm (singlet,1 H, H on the nitrogen)  7.60 ppm (doublet, 2H; aromatic H meta to Br, J = 8.97 Hz)  7.45 ppm (doublet, 2H; aromatic H ortho to Br, J =8.95 Hz)  2.05 ppm (singlet 3H; CH3 group). Observations: Adding acetic acid results in a clear solution. After adding bromine, the solution turns brown orange color to bright orange precipitate. Adding cold water changes the mixture to a yellow color. Sodium bisulfite changes the solution to a cloudy white precipitate. The crude product is a white paste. When dissolved in methanol, solution is clear. The recrystallized product is a white, flaky crystal. Potential hazards include: bromine is a hazardous chemical that may cause serious chemical burns. The vapors should not be inhaled or avoid contact to skin. Glacial acetic acid is a corrosive liquid. 4-bromo-2-chloroacetanilide (6). 5.33 g (0.026 mol) of 4-bromoacetanilide was recovered from the previous step. 5.43 g of 4-bromoacetanilide was suspended in concentrated HCl (density 0.909, 11.7 mL) and glacial acetic acid (density 1.05, 14.2 mL) in an Erlenmeyer flask with a magnetic stir bar. The mixture was warmed gently until the mixture until the mixture becomes homogenous. The solution flask was placed in an ice bath and stirred until the temperature reached between 0O and 5OC. A solution of 1.42 g of sodium chlorate, NaClO3, dissolved in 3.6 mL of water was prepared and added dropwise to the cooled solution over a 5-minute period. A yellow precipitate forms and the reaction mixture was stirred at room temperature for one hour. The crude product was filtered and washed well with cold water. The crude product was recrystallized in 15 mL of boiling methanol and vacuum filtered. A second crop was obtained and combined with first crop. The yield was 50% with a product weight of 3.17 g. The melting temperature was measured to be 146.6-149.7 OC for the crude product and for the recrystallized product 148.7-150.1 OC (lit 151-152°C). IR  max (CCl4) 3250 (NH stretch, weak) 2800-3100(C-H; aromatic), 1700 (C=O stretch), 1600 (C-H: aromatic, weak), 1540 (NH bending), 1500 (C-H: aromatic, weak), 780 and 700 (C-H bending), 825 (C-H bending), 800 (C-Cl) 1 H NMR (CDCl3)  8.33 ppm (doublet, 1 H, aromatic H ortho to Cl, J= 11.23 Hz)  7.60 ppm (singlet, 1 H, H on the nitrogen)  7.56 ppm (doublet,1 H; aromatic H meta to Cl, J= 2.4 Hz)  7.42 (doublet of doublet, 1 H; aromatic H ortho to Cl, J=2.35, 2.14)  2.10 ppm (singlet 3H; CH3 group). Observations: Clear solution when 4-bromoacetanilide was suspended in concentrated HCl. A yellow precipitate formed immediately after adding NaClO3 and chlorine gas evolves. The reaction is exothermic, rise in temperature is observed. The crude product appears as a white/yellow paste. *Notes: all the acid (yellow ) in this product was not removed. The recrystallized product is a fine, powdery crystal white/yellow color. Potential hazards include: avoid exposure to chlorine gas released in the experiment. Perform experiment in the hood. Chlorine gas is toxic. 4-bromo-2-chloroaniline (7). 3.10 g (0.013 mol) of 4-bromo-2-chloroacetanilide was mixed with 5.6 mL of 95% ethanol and 3.6 mL of concentrated HCl in a 100 mL round-bottom flask. The reaction mixture was heated under reflux for 0.5 hr. Add the end of the reflux, 25 mL of hot water was added to the flask to dissolve the solids in the flask. If the solution is not clear, gravity filter any remnants. The hot solution was poured into a beaker containing 42 g of ice. 3.33 mL of 14 M NaOH was slowly added to reaction mixture while stirring until the mixture is basic. The solid was isolated by vacuum filtration (washed with cold water) and recrystallized in 4 mL of methanol per gram of crude product. A second crop was obtained and combined with crop one. The yield is 64% with a product weight of 1.65 g. The 14

melting temperature was measured to be 65.5-67.2 OC for the crude product and for the recrystallized product 69.7-71.2 OC (lit 70-72 OC). IR  max (CCl4) 3300, 3400 (NH stretch), 3050 (C-H; aromatic), 1600 (N-H2: bending, medium), 1540 (NH bending), 1500 (C-H: aromatic, weak), 780 (C-H bending), 825 (C-H bending, para), 800 (C-Cl) 1 H NMR (CDCl3)  7.38 ppm (doublet, 1 H ortho to Cl, J =4.1 Hz)  7.16 ppm (doublet of doublet, 1 H; aromatic H para to Cl, J = 2.16 Hz, 6.01 Hz)  6.63 ppm (doublet, 1 H; aromatic H meta to Cl, J =11.37 Hz)  4.02 ppm (singlet 2H; N-H2). Observations: Reflux –drips are seen down side of round bottom flask. 4-bromo-2-chloroacetanilide dissolves into solution during reflux and a white precipitate forms. A purple rim is seen in the precipitate showing signs of oxidation of the amine. The solution was clear after gravity filtration. The crude product is a brown, paper-like appearance. The crude product in methanol forms a clear solution. The first recrystallized crop is a brown/white crystalline and the second crop is a white crystalline. Potential hazards include direct exposure to HCl can cause skin irritation. 4-bromo-2-chloro-6-iodoaniline (8). 1.60 g (0.008 mol) of 4-bromo-2-chloroaniline was dissolved in 26 mL of glacial acetic acid and 6.5 mL of water in a round-bottom flask. 6.4 mL of iodine monochloride solution was added to reaction mixture over an 8-10 minute period. The mixture was stirred, heated (steam bath) to 85-90 C, and then cooled to 50OC. 10 mL of sodium bisulfite was added to precipitate out the crude product and 5 mL of water. The reaction mixture was cooled in ice, and the crude product was obtained via vacuum filtration. The product was washed with ice-cold 33 % aqueous acetic acid and with over 50 mL of water. Recrystallization was performed in...