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Experiment 7 Lab Report...

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A Six-Step Conversion Synthesis of Aniline to 1-Bromo3-Chloro-5-Iodobenzene CHEM-245: Organic Chemistry Lab 2019

Submitted on December 10th,

Abstract: A six step conversion synthesis of aniline to 1-bromo-3-chloro-5-iodobenzene was performed, achieving a 6.8% overall yield. The chemistry for this synthesis involves first adding a protecting group on the amino group via acetylation, which activates the ring for electrophilic aromatic substitution using halogens and maintains its ortho/para directing factor. The protecting group was hydrolyzed and the amino group later deaminated to obtain product. Melting point, percent yield (for each step along with overall yield), a products for each step were obtained. IR/NMR data for each compound was given and analyzed to further determine the efficiency of the reaction. INTRODUCTION Figure 2. Six-Step Synthesis The goal of this synthesis was to obtain 1bromo-3-chloro-5-iodobenzene (7) from aniline (1). Aniline was used as the starting reactant instead of benzene, due to benzene being known as a toxic compound that is a carcinogen and neuronal toxin 1 and instead of nitrobenzene because the process of reducing the nitro group to an amino group requires extreme conditions, which is not ideal for an undergraduate laboratory setting. This overall shortens the synthesis steps from eight to six. The overall percent yield was evaluated by multiplying the yield for each step.

The amino group in aniline (1) is a very strong activating group along with being an ortho/para substitution director However, this strong

activating factor may lead to polysubstitution of the ring. In addition, the amino group can act as both a nucleophile and a base to react with other compounds. Hence, the amino group was acetylated, and acetanilide(2) was formed. The protecting group is still a ortho/para director, but is is relatively less activated for only monosubstitution to that place.

1 PubChem. Benzene. Accessed Dec. 8, 2017. https://pubchem.ncbi.nlm.nih.gov/compound/241#section=Top

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Figure 3. Mechanism for Acetylation

During the acetylation, H 2O is present to stabilize the dipolar intermediate formed. An initial amount of HCl is needed to solvate aniline before neural aniline is remade by sodium acetate. The aniline then acts as a nucleophile to attack acetic anhydride. Potential side reaction such as the forming of diacetanilide compound may have occurred but will not affect purity of the pure product since it is removed through recrystallization in methanol. The formation of acetanilide can be verified with the disappearance of the amine stretch and appearance of amide stretch in the infrared spectrum analysis and the appearance of amide hydrogen peak in the NMR spectrum.

Figure 4. Mechanism for Bromination

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Monobromination of acetanilide to form 4bromoacetanilide was possible because the amido group have a relatively weaker activating influence than the amino group present before acetylation. In this reaction, acetic acid not only solvated the bromide ion and the intermediate cation but also works as a base to abstract a proton from the intermediate and form the neutral product. The para isomer is expected to be the major product of the bromination. Due to steric hindrance of the bromide ion and the amido group, the formation of the ortho product is less likely to happen because the transition state would be very high in energy. Any ortho product will be removed when recrystallizing crude product in methanol. Para-isomer products have higher melting point and lower solubility when compared with ortho-isomer product because of the para-isomer symmetry which allows better crystal packing and higher lattice energy. The formation of 4-bromoacetanilide can be verified with the presence of a C-Br stretch in the infrared spectrum analysis.

Figure 5. Mechanism for Chlorination

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For monochlorination of 4-bromoacetanilide to 4-bromo-2-chloroacetanilide, Cl2 was produced in situ using HCl and NaClO3. The production of Cl2 is a oxidation-reduction reaction and it is a simple and safe method to form the Cl2 gas. Despite the presence of a bromide on the ring, which is electron withdrawing, the ring is still activated to react with the Cl2 gas, and the mechanism is a electronic aromatic substitution similar to the addition of the bromide one step before. However, the chlorine in this step is added to the ortho position. Although, the amide group this have major steric hindrance to the ortho position, chloride ion is smaller than bromide and hence, will have a easier time fitting in the ortho position. Formation of 4bromo-2-chloroacetanilide can be verified with the presence of a C-Cl stretch in the infrared spectrum analysis.

Figure 6. Mechanism for Amide Hydrolysis

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Now, the ring has two electron-withdrawing substituents (Cl- and Br-), which overpowers the electron-donating effect of the amide group, and cause the ring to be deactivated so that iodination cannot take place. Therefore, a stronger activating group was needed for iodination to take place; an amino group is a strong activator and could be gained by simply removing the protecting group from the amido group via acid-catalyzed hydrolysis. Ethanol as a

solvent, dissolved the solid 4-bromo-2chloroacetanilide and caused the mixture to be homogenous. However, ethanol can act as a nucleophile, which could lead to the side reaction forming ethyl acetate instead of acetic acid. The formation of 4-Bromo-2-chloroaniline is expected to cause a disappearance of amide stretch and appearance of amine stretch on the infrared spectra and the presence of amino hydrogen on the NMR image.

Figure 7. Mechanism of Iodination For iodination, ICl was used instead of I 2 because the bond in ICl is polarized and therefore have more positive electronic characteristics. Furthermore, ICl can hydrogen bond with acetic acid which will increase ICl’s electrophilic character. Acetic acid can also be a proton acceptor in the iodination reaction. Excess ICl was removed using bisulfite which causes a oxidation-reduction reaction to form the halide ion which was was later washed off with a lot of water. Formation of 4-Bromo-2-chloro6-iodoaniline would be represented by the appearance of a C-I stretch on the infrared spectra.

Figure 8. Mechanism of Deamination

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Ola’s is thought that a concerted reaction includes the leaving of the N 2 along with hydride transfer from ethanol, which forms both the final product, 1-Bromo-3-chloro-5-iodobenzene and the by-product of protonated acetaldehyde. The protonated acetaldehyde can react with ethanol to create hemiacetal, which can perform a hydride transfer to the carbocation and create ethyl acetate, as a second by-product. These byproducts can be removed via recrystallization of the crude product in methanol, but the percent yield of the pure product will be compromised. Formation of the 1-Bromo-3-chloro-5iodobenzene would be represented by the disappearance of the amine stretch in the infrared spectrum.

The last step was deamination where the amino group was replaced with a hydrogen. NaNO2 and H2SO4 forms nitrous acid which decomposes into NO+ (nitrosyl cation), which acts as an electrophile. NO+ is attacked by the ring to form diazonium ion. The mechanism is unclear, but it

There are many side reactions that are possible. Water and ethanol can both act as nucleophiles, and can attack the carbocation to form phenol and ethyl phenyl ether, respectively. Phenol can be removed through using NaOH, and ethyl phenyl ether can be removed using recrystallization. Another possible side reaction is halogen exchange of the other halogen substituents, which is possible because the diazonium ion is a very strong electron donating group, which is able to stabilize the intermediate complex formed when the nucleophile initially attacks the ring.

Figure 9. Mechanism of Halogen Exchange

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RESULTS Table 1. Percent Yield and Melting Point for Product Sample

Percent Yield (%)

Weight Obtained (g)

Theoretica l Yield (g)

Crude m.p (oC)

Pure m.p (oC)

Known Description meltin g point (oC)

Acetanilide

100%

9.36

4.89

111

114.0 115.8

113116

White crystals

4Bromoacetanilide

90%

7.63

7.82

167-170.4

167.9-168.7

168169

White flaky solid

4-Bromo-2chloroacetanilide

59%

5.3

8.95

147-147

149.0-150.0

151152

White granular crystals

4-Bromo-2chloroaniline

95%

4.1

4.34

66

69.0-70.8

70-71

Off-white flaky solid

4-Bromo-2-chloro- 42% 6-iodoaniline

2.82

6.65

94-97

96.5 - 97.0

96-98

Pinkish flaky solid

1-Bromo-3-chloro- 32% 5-iodobenzene

0.60

1.9

82-88

84.0 - 86.1

84-86

White, long needles

Overall Yield

1 × 0.9 × 0.59 × 0.95 × 0.42 x 0.32 = 6.8%

DISCUSSION

Despite the overall yield being 6.8%, the synthesis was relatively successful. The percent yield for each step varied between 32% - 100%, and specifically the first step of acetylation of amino group had the highest percent yield (100%) while the last step of deamination had the lowest yield (32%). Loss of product through transfers and recrystallization contributed to lowering the percent yield for each step, especially if the crude product was recrystallized in methanol where too much methanol could decrease the product and too much heat can evaporate the product. Melting point determination of each product confirmed the purity

of the products, and most were close and in the range of the known melting point, albeit some being slightly lower (i.e 4-bromo-2chloroacetanilide), which suggest the presence of minute impurities. Furthermore, the physical characteristics of product obtained when compared to the physical characteristics of the known products are similar, adding another layer of verification for the efficiency of the synthesis. By the process of acetylation, the IR spectrum will loss a N-H amine stretch, while gaining a N-H amide stretch (~3300 cm-1).

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yield for a synthesis in a laboratory settings. Overall, this synthesis experiments demonstrates how difficult it is to achieve high overall percent In conclusion, since this synthesis is

ANALYSIS OF SPECTRA DATA

Acetanilide (2) Structure

IR ● ● ● ● ● ●

NMR 3300 cm-1 → amide N-H stretch. 3000 cm-1 → aromatic C-H stretch 3000-2900 cm-1 → alkane C-H stretch 1700 cm-1 → amide C=O stretch 1500 cm-1→ aromatic C-C stretch 1300-1200 cm-1 → C-N stretch

By the process of acetylation, the IR spectrum will loss a N-H amine stretch, while gaining a N-H amide stretch (~3300 cm-1). There will also be an alkane C–H stretch (~3000 cm-1), and amide C=O stretch (~1700 cm-1) due to acetylation of amino group. In the NMR spectrum, HC ( 7.9 ppm) is most deshielded due

● ● ● ● ●

7.9 ppm → HC,1H, singlet 7.5 ppm → HA,,2H, doublet, J =8 Hz 7.3 ppm → HB,2H, triplet, J=7.75 Hz 7.0 ppm →HE, 1H, triplet, J=7.5 Hz 2.1 ppm → HD, 3H, singlet.

to the nitrogen it is directly bonded to and experience no splitting. HA (7.5 ppm) is a doublet that is slightly deshielded by N, and coupled to HB. HB (7.3 ppm) is a triplet coupled with HA and HE. HE (7.0 ppm) is a triplet coupled to HB. singlet HD (2.1 ppm) is a singlet that experience no splitting.

4-Bromoacetanilide (3) Structure

IR ● ● ● ● ● ● ● ●

NMR 3400-3250 cm-1→ N–H 3100-3000 cm-1 → aromatic C–H 3000-2850 cm-1→ alkane C–H 1690-1650 cm-1→ amide C=O 1600-1584 cm-1 → aromatic C–C 1250-1020 cm-1 → C–N 700-500 cm-1→ C–Br 825 cm-1 → para-substitution

By the process of bromination, there is an appearance of a C-Br stretch at ~700 cm-1 in the fingerprint region. HC (10.14 ppm) is a singlet, most deshielded due to amide with no neighbors.

● ● ● ●

10.14 ppm→HC, 1H, singlet, 7.57 ppm→HA, 2H, doublet. J = 8.5 Hz 7.46 ppm→HB, 2H, doublet, J = 8.5 Hz 2.00 ppm → HD, 3H, singlet

HA ( 7.57 ppm) is a doublet coupled with HB, but is more deshielded than HB due to neighboring the amide. HB (7.46 ppm) is a doublet coupled with HA. HD (2.00 ppm) has no neighbors.

4-Bromo-2-chloroacetanilide(4)

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Structure

IR

NMR 3400-3250 cm-1→ N–H 3100-3000 cm-1→ aromatic C–H 3000-2850 cm-1 → alkane C–H 1690-1650 cm-1 → amide C=O 1600-1584 cm-1 → aromatic C–C 1250-1020 cm-1 → C–N 700-500 cm-1 → C–Br 825 cm-1 → 1,2,4 substituent 800-600 cm-1 → C–Cl

● ● ● ● ● ● ● ● ●

By the process of chlorination, a C–Cl stretch in the fingerprint region will appear in the IR spectrum. HB (8.3 ppm) is a doublet, and is most deshielded due to adjacent Cl and Br and is coupled with HC. HE ( 7.59 ppm) is a singlet with no neighbors and is deshielded by nitrogen. H A

● ● ● ● ●

8.3 ppm → HB, 1H, doublet,J = 8.85 Hz 7.59 ppm → HE, 1H, singlet 7.57 ppm → HA,1H, doublet, J = 2.5 Hz 7.40 ppm → HC, 1H, doublet of doublet, J = 9.03, 2.5 Hz 2.2 ppm → HD, 3H, singlet

(7.57 ppm) is a doublet coupled with H C. HC (7.40 ppm) is doublet of doublet coupled with both HA and HB, and is a doublet of doublet because of benzene asymmetry. HD (2.2 ppm) is a singlet with no neighbors.

4-Bromo-2-chloroaniline (5) Structure

IR

NMR 3400-3250 cm-1 → amine N–H 3100-3000 cm-1 → aromatic C–H 1600-1584 cm-1 → aromatic C=C 1250-1020 cm-1 → amine C–N 700-500 cm-1 → C–Br 800-600 cm-1 → C–Cl 825 cm-1 → 1,2,4 substituent

● ● ● ● ● ● ●

By amide hydrolysis, there is a loss of N–H amide stretch, amide C=O, and alkane C–H stretch, and a gain of of N–H amine stretch (~3400 cm-1) . HB (7.37 ppm) is a doublet that is most deshielded due to being adjacent Cl and

7.37 ppm → HB, 1H, doublet, J = 2.5 Hz 7.15 ppm → HC, 1H, doublet of doublet, J = 8.50, 2.5 Hz 6.6 ppm → HA, 1H, doublet, J= 8.5 Hz 4.0 ppm →HD, 2H, singlet

● ● ● ●

Br, and coupled with H C. HC (7.15 ppm) is a doublet of doublet coupled with H A and H B. HA (6.6 ppm) is a doublet coupled with HC. HD (4.0 ppm) is a singlet with no neighbors.

4-Bromo-2-chloro-6-iodoaniline (6) Structure

IR ● ● ● ● ●

NMR 3400-3250 cm-1 → N–H 3100-3000 cm-1 → aromatic C–H 1600-1584 cm-1 → aromatic C–C 1250-1020 cm-1 → C–N 700-500 cm-1 → C–Br

● ● ●

7.7 ppm → HA,1H, doublet, J = 2.0 Hz 7.4 ppm → HB, 1H, doublet, J = 2.5 Hz 4.6 ppm → HC, 2H, singlet

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800-600 cm-1 → C–Cl 600-400 cm-1 → C–I 825 cm-1 → para-substitution

● ● ●

By iodination, there is an appearance of a C–I stretch in the fingerprint region (600-400 cm-1). HA (7.65 ppm) is a doublet, couple with HB and more deshielded than H B because Cl is more

electronegative that I. H B (7.48 ppm) is a doublet coupled with H A. HC (4.6 ppm) is a singlet with no neighbors.

1-Bromo-3-chloro-5-iodobenzene (7) Structure

IR ● ● ● ● ● ●

NMR 3100-3000 cm-1 → aromatic C–H 1600-1584 cm-1→ aromatic C–C 1250-1020 cm-1 → C–N 700-500 cm-1 → C–Br 800-600 cm-1 → C–Cl 600-400 cm-1 → C–I

● ● ●

7.75 ppm → HA, 1H, triplet, J = 1.5 Hz 7.65 ppm → H C, 1H, triplet, J = 1.6 Hz 7.48 ppm → HB, 1H, triplet, J = 1.75 Hz

By deamination, there is a loss of N–H amine stretch and C–N stretch. H A (7.75 ppm) is a triplet and is most deshielded because it is between Cl and Br, which are both more electronegative than I. H C (7.65 ppm) is a triplet, which is more deshielded than H B

because Cl is more electronegative than Br. H B (7.48 ppm) is a triplet, least deshielded because it is flanked by I and Br , the least electronegative of the three halogens on the ring. All the hydrogens couples each other.

EXPERIMENTAL SECTION

was added to mixture and stirred vigorously, before cooling in ice bath while stirring until crystal product precipitated. Solid was collected via vacuum filtration and washed with 5 mL of ice cold H2O and air dried. Obtained wet product (acetanilide) was white, crystalline solid (9.36 g, 191% - there was no time allowed for drying). Pure m.p 114-115 oC. l.v 113-116 oC. IR: 34003250 (N–H), 3100-3000 (aromatic C–H), 30002850 (alkane C–H), 1690-1650 (amide C=O), 1500-1400 (aromatic C–C), 1360-1180 cm-1 (C– N). 1H NMR (CDCl3): ẟ7.8 (s, 1H), 7.5 (d, 2H, J = 8.1 Hz), 7.3 (q, 2H, J = 7.7 Hz), 7.0 (t, 1H, J = 7.4 Hz), 2.1 (s, 3H).

General. For each product, percent yield and melting point of crude and pure samples were obtained. Second crop from recrystallization were combined with first crop if melting point difference was less than ~5%. For all second crop, H2O was added dropwise to filtrate until solid was present, then placed in ice water bath, then collected via vacuum filtration. A portion of each pure product was obtained, labeled, and given to TA for physical analysis. All IR spectrum was measured in cm-1. H1 NMR spectra was ran at 300 MHz. Legend: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, dd = doublet of doublet. l.v. = literature value Acetanilide. A mixture of aniline (3.37 g) and 0.4 M HCl (100 mL) was stirred and heated to 50 oC on a hot plate in a Erlenmeyer flask. Mixture was cooled while stirring at room temperature. Solution of sodium acetate (6 g) in H2O (20 mL) and 4.4 mL of acetic anhydride

4-Bromoacetanilide. A mixture of Br2 in acetic acid (4 mL) was slowly added to stirred mixture acetanilide (4.89 g) and acetic acid (15 mL). Reaction was mixed for 10 minutes after addition. Ice cold water (100 mL) was added slowly while stirring mixture. Sodium bisulfate (5 mL) was added dropwise to stop color from

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changing. Mixture cooled in ice bath before solid was collected via vacuum filtration and wash well with water to remove traces of color. A portion of crude product was collected for melting point determination, then remainder was recrystallized in 3-5 mL methanol per gram of product. Product obtained was white flaky solid (7.63 g, 90%). Pure m.p 167.9-168.7 oC. l.v 168169 oC. IR: 3400-3250 (N–H), 3100-3000 (aromatic C–H), 3000-2850 (sp 3 C–H), 16901650 (amide C=O), 1600-1584 (aromatic C–C), 1250-1020 (C–N), 700-500 cm-1 (C–Br). 1H NMR (DMSO-d6): ẟ 10.14 (s, 1H), 7.57 (d, 2H, J = 8.97 Hz), 7.46 (d, 2H, J = 8.95 Hz), 2.00 (s, 3H). 4-Bromo-2-Chloroacetanilide.4-bromoacetanilide (7.63 g) is added to stirred mixture of HCl (15 mL) and acetic acid (20 mL). Mixture was dissolved by heating and stirring. Mixture was cooled to 2 o C in ice water bath. Aqueous sodium chlorate was added dropwise over 5 minute period as color discharged. Mixture was stirred at room temperature for an hour, then solid was collected by vacuum filtration. Solid was washed with ice cold H 2O (~100 mL) to neutralize product, then recrystallized in methanol (3 mL per gram of product. Pure cooled in ice water bath before collected via vacuum filtration and washed in 1:1 cold methanol-water solution. Pure product was offwhite flaky solid (4.1 g, 95%). Pure m.p 69.070.8 oC. l.v. 70-71 oC. IR: 3400-3250 (N–H), 3100-3000 (aromatic C–H), 1600-1584 (aromatic C–C), 1250-1020 (C–N), 700-500 (C– Br), 800-600 cm-1 (C–Cl). 1H NMR (CDCl3): ẟ 7.37 (d, 1H, J = 2.3 Hz), 7.15 (dd, 1H, J = 8.50, 2.12 Hz), 6.6 (d, 1H, H = 8.85 Hz), 4.0 (s, 2H). 4-Brom...