Experiment 5. Synthesis of Anthranilic Acid

C7H7NO2

Molecular Formula of Anthranilic Acid

2-aminobenzoic acid or o-aminobenzoic acid

IUPAC name of Anthranilic Acid

137.14 g/mol

molecular weight

precursor/ intermediate

USES OF ANTHRANILIC ACID:

1. It serves as a a.__________________ in the synthesis of various biologically active compounds, including the popular anti-inflammatory drug b._________________.

2. Anthranilic acid is considered as _______________________.

1.a. = ?

mefenamic acid

USES OF ANTHRANILIC ACID:

1. It serves as a a.__________________ in the synthesis of various biologically active compounds, including the popular anti-inflammatory drug b._________________.

2. Anthranilic acid is considered as _______________________.

1.b. = ?

uremic agent

USES OF ANTHRANILIC ACID:

1. It serves as a a.__________________ in the synthesis of various biologically active compounds, including the popular anti-inflammatory drug b._________________.

2. Anthranilic acid is considered as _______________________.

2 = ?

Mefenamic Acid

ANTHRANILIC ACID IS AN INTERMEDIATE IN THE SYNTHESIS OF:

1. A nonsteroidal anti-inflammatory drug (NSAID) used to treat pain, especially menstrual pain.

2. An antimycobacterial drug used to treat leprosy and other mycobacterial infections.

3. Antidepressants: Certain derivatives of anthranilic acid have been explored for their potential antidepressant activity.

4. Beyond its role as a pharmaceutical intermediate, anthranilic acid is also a precursor in the production of _________________________.

5. Its _____________________________________make it a valuable building block in organic synthesis.

1 = ?

Clofazimine

ANTHRANILIC ACID IS AN INTERMEDIATE IN THE SYNTHESIS OF:

1. A nonsteroidal anti-inflammatory drug (NSAID) used to treat pain, especially menstrual pain.

2. An antimycobacterial drug used to treat leprosy and other mycobacterial infections.

3. Antidepressants: Certain derivatives of anthranilic acid have been explored for their potential antidepressant activity.

4. Beyond its role as a pharmaceutical intermediate, anthranilic acid is also a precursor in the production of _________________________.

5. Its _____________________________________make it a valuable building block in organic synthesis.

2 = ?

Antidepressants

ANTHRANILIC ACID IS AN INTERMEDIATE IN THE SYNTHESIS OF:

1. A nonsteroidal anti-inflammatory drug (NSAID) used to treat pain, especially menstrual pain.

2. An antimycobacterial drug used to treat leprosy and other mycobacterial infections.

3. Certain derivatives of anthranilic acid have been explored for their potential antidepressant activity.

4. Beyond its role as a pharmaceutical intermediate, anthranilic acid is also a precursor in the production of _________________________.

5. Its _____________________________________make it a valuable building block in organic synthesis.

3 = ?

quinoline derivatives and azo dyes

ANTHRANILIC ACID IS AN INTERMEDIATE IN THE SYNTHESIS OF:

1. A nonsteroidal anti-inflammatory drug (NSAID) used to treat pain, especially menstrual pain.

2. An antimycobacterial drug used to treat leprosy and other mycobacterial infections.

3. Antidepressants: Certain derivatives of anthranilic acid have been explored for their potential antidepressant activity.

4. Beyond its role as a pharmaceutical intermediate, anthranilic acid is also a precursor in the production of _________________________.

5. Its _____________________________________make it a valuable building block in organic synthesis.

4 = ?

amino and carboxylic acid functionalities

ANTHRANILIC ACID IS AN INTERMEDIATE IN THE SYNTHESIS OF:

1. A nonsteroidal anti-inflammatory drug (NSAID) used to treat pain, especially menstrual pain.

2. An antimycobacterial drug used to treat leprosy and other mycobacterial infections.

3. Antidepressants: Certain derivatives of anthranilic acid have been explored for their potential antidepressant activity.

4. Beyond its role as a pharmaceutical intermediate, anthranilic acid is also a precursor in the production of _________________________.

5. Its _____________________________________make it a valuable building block in organic synthesis.

5 = ?

gastrointestinal tract

Anthranilic acid Absorption:

1. Anthranilic acid derivatives, when used as drugs, are typically well-absorbed via the ____________________ when administered orally.

2. However, anthranilic acid itself is not widely used in pharmacology in its _____

1 = ?

pure form

Anthranilic acid Absorption:

1. Anthranilic acid derivatives, when used as drugs, are typically well-absorbed via the ____________________ when administered orally.

2. However, anthranilic acid itself is not widely used in pharmacology in its _____

2 = ?

derivative and its pharmacological properties

Anthranilic acid Distribution:

1. Once absorbed, anthranilic acid derivatives distribute into various tissues, often depending on the specific _____________________________________.

2. Some derivatives, such as mefenamic acid, show good distribution in ____________________.

1 = ?

inflamed tissues

Anthranilic acid Distribution:

1. Once absorbed, anthranilic acid derivatives distribute into various tissues, often depending on the specific _____________________________________.

2. Some derivatives, such as mefenamic acid, show good distribution in ____________________.

2 = ?

conjugation reactions

Anthranilic acid Metabolism:

1. Anthranilic acid is metabolized primarily in the liver through _______________ (e.g., glucuronidation).

2. Its metabolism is closely related to that of other ________________________

3. It is involved in the biosynthesis of essential biomolecules, such as ________.

1 = ?

aromatic amino acids

Anthranilic acid Metabolism:

1. Anthranilic acid is metabolized primarily in the liver through _______________ (e.g., glucuronidation).

2. Its metabolism is closely related to that of other ________________________

3. It is involved in the biosynthesis of essential biomolecules, such as ________.

2 = ?

tryptophan

Anthranilic acid Metabolism:

1. Anthranilic acid is metabolized primarily in the liver through _______________ (e.g., glucuronidation).

2. Its metabolism is closely related to that of other ________________________

3. It is involved in the biosynthesis of essential biomolecules, such as ________.

3 = ?

kidneys

Anthranilic acid Excretion:

1. Anthranilic acid and its derivatives are typically excreted via the __________, primarily as conjugated metabolites.

2. The elimination _____ varies based on the specific derivative used in therapy.

1 = ?

half-life

Anthranilic acid Excretion:

1. Anthranilic acid and its derivatives are typically excreted via the __________, primarily as conjugated metabolites.

2. The elimination _____ varies based on the specific derivative used in therapy.

2 = ?

skin and eyes

Anthranilic acid Toxicology:

1. Anthranilic acid itself is not considered highly toxic but may cause irritation to the _________________________.

2. Certain derivatives, however, such as mefenamic acid, can cause __________

1 = ?

gastrointestinal irritation, kidney damage, and, in rare cases, hypersensitivity reactions

Anthranilic acid Toxicology:

1. Anthranilic acid itself is not considered highly toxic but may cause irritation to the _________________________.

2. Certain derivatives, however, such as mefenamic acid, can cause __________

2 = ?

hydrolysis

The synthesis of anthranilic acid typically involves the a._______ of phthalimide in the presence of a b.______________________________, followed by c.________. This reaction exemplifies d._________________ at an imide group, resulting in the formation of anthranilic acid.

a = ?

strong base, such as sodium hydroxide

The synthesis of anthranilic acid typically involves the a._______ of phthalimide in the presence of a b.______________________________, followed by c.________. This reaction exemplifies d._________________ at an imide group, resulting in the formation of anthranilic acid.

b = ?

hydrolysis

The synthesis of anthranilic acid typically involves the a._______ of phthalimide in the presence of a b.______________________________, followed by c.________. This reaction exemplifies d._________________ at an imide group, resulting in the formation of anthranilic acid.

c = ?

nucleophilic substitution

The synthesis of anthranilic acid typically involves the a._______ of phthalimide in the presence of a b.______________________________, followed by c.________. This reaction exemplifies d._________________ at an imide group, resulting in the formation of anthranilic acid.

d = ?

10 grams of phthalic anhydride and 2 grams of urea (or 8.88 mL of concentrated ammonia solution)

A. Preparation of Phthalimide

1. Mix ____________________________________ in a 250-mL Erlenmeyer flask and connect an air condenser.

2. Heat the flask in a ________________________ until the content melts, froth up and become solid.

3. Turn off the ______________ and allow to cool.

4. Upon cooling, ______________________.

5. Recrystallize using _____________ to obtain a white product.

6. Determine the melting point (___________)

7. TLC: ________________________

1 = ?

sand bath at 130-135°C

A. Preparation of Phthalimide

1. Mix ____________________________________ in a 250-mL Erlenmeyer flask and connect an air condenser.

2. Heat the flask in a ________________________ until the content melts, froth up and become solid.

3. Turn off the ______________ and allow to cool.

4. Upon cooling, ______________________.

5. Recrystallize using _____________ to obtain a white product.

6. Determine the melting point (___________)

7. TLC: ________________________

2 = ?

source of heat

A. Preparation of Phthalimide

1. Mix ____________________________________ in a 250-mL Erlenmeyer flask and connect an air condenser.

2. Heat the flask in a ________________________ until the content melts, froth up and become solid.

3. Turn off the ______________ and allow to cool.

4. Upon cooling, ______________________.

5. Recrystallize using _____________ to obtain a white product.

6. Determine the melting point (___________)

7. TLC: ________________________

3 = ?

disintegrate the solid

A. Preparation of Phthalimide

1. Mix ____________________________________ in a 250-mL Erlenmeyer flask and connect an air condenser.

2. Heat the flask in a ________________________ until the content melts, froth up and become solid.

3. Turn off the ______________ and allow to cool.

4. Upon cooling, ______________________.

5. Recrystallize using _____________ to obtain a white product.

6. Determine the melting point (___________)

7. TLC: ________________________

4 = ?

ethanol

A. Preparation of Phthalimide

1. Mix ____________________________________ in a 250-mL Erlenmeyer flask and connect an air condenser.

2. Heat the flask in a ________________________ until the content melts, froth up and become solid.

3. Turn off the ______________ and allow to cool.

4. Upon cooling, ______________________.

5. Recrystallize using _____________ to obtain a white product.

6. Determine the melting point (___________)

7. TLC: ________________________

5 = ?

232-235°C

A. Preparation of Phthalimide

1. Mix ____________________________________ in a 250-mL Erlenmeyer flask and connect an air condenser.

2. Heat the flask in a ________________________ until the content melts, froth up and become solid.

3. Turn off the ______________ and allow to cool.

4. Upon cooling, ______________________.

5. Recrystallize using _____________ to obtain a white product.

6. Determine the melting point (___________)

7. TLC: ________________________

6 = ?

Acetone: Hexane (1:3)

A. Preparation of Phthalimide

1. Mix ____________________________________ in a 250-mL Erlenmeyer flask and connect an air condenser.

2. Heat the flask in a ________________________ until the content melts, froth up and become solid.

3. Turn off the ______________ and allow to cool.

4. Upon cooling, ______________________.

5. Recrystallize using _____________ to obtain a white product.

6. Determine the melting point (___________)

7. TLC: ________________________

7 = ?

Phthalic Anhydride

This compound, when heated, is reactive towards nucleophiles. Its cyclic anhydride structure is particularly suited for reacting with nitrogen-containing nucleophiles

Ammonia or Urea

acts as the nitrogen source to form the imide linkage

Urea

solid alternative that allows better control over the reaction and avoids handling concentrated ammonia gas, which can be unpleasant or hazardous

130-135°C

The mixture is heated to ________, at which temperature phthalic anhydride melts and reacts with the ammonia (or urea).

Heating

necessary to promote the reaction between phthalic anhydride and the nitrogen source by making the reactants more mobile and reactive

phthalimide

The reaction of phthalic anhydride with ammonia (or the ammonia released by heating urea) results in the formation of

water and carbon dioxide

If urea is used in the reaction of phthalic anhydride the by-products are:

frothing

As the reaction proceeds, the formation of phthalimide and the release of by-products like CO₂ or water causes __________. Once the reaction completes, the product solidifies upon cooling.

Phthalimide

stable and solid compound, which facilitates easy isolation after cooling

impurities

The solid product is broken up and recrystallized from ethanol to purify the phthalimide. Recrystallization removes any __________ formed during the reaction.

7.5 grams of NaOH

Synthesis of Anthranilic Acid ]

1. Dissolve __________ in 40-mL distilled water.

2. Cool the mixture in an ice bath to about _________.

3. To the cooled solution, add _________________________.

4. Add ___________________________.

5. Add _________________.

6. Heat the solution for ____________________ until phthalimide dissolves.

7. Filter the solution and neutralize the solution with ____________ (Litmus: Blue to Blue or Red to Red).

8. Acidify with _______________________ (Use pH paper)

9. Filter the solid crystals of anthranilic acid and wash with ___________________.

10. Recrystallize using _________

11. If colored, add ______________ to decolorize.

12. Filter the recrystallized acid in a Buchner funnel and dry at _______________

13.TLC: __________________________

1 = ?

0°C

Synthesis of Anthranilic Acid ]

1. Dissolve __________ in 40-mL distilled water.

2. Cool the mixture in an ice bath to about _________.

3. To the cooled solution, add _________________________.

4. Add ___________________________.

5. Add _________________.

6. Heat the solution for ____________________ until phthalimide dissolves.

7. Filter the solution and neutralize the solution with ____________ (Litmus: Blue to Blue or Red to Red).

8. Acidify with _______________________ (Use pH paper)

9. Filter the solid crystals of anthranilic acid and wash with ___________________.

10. Recrystallize using _________

11. If colored, add ______________ to decolorize.

12. Filter the recrystallized acid in a Buchner funnel and dry at _______________

13.TLC: __________________________

2 = ?

10mL sodium hypochlorite solution

Synthesis of Anthranilic Acid ]

1. Dissolve __________ in 40-mL distilled water.

2. Cool the mixture in an ice bath to about _________.

3. To the cooled solution, add _________________________.

4. Add ___________________________.

5. Add _________________.

6. Heat the solution for ____________________ until phthalimide dissolves.

7. Filter the solution and neutralize the solution with ____________ (Litmus: Blue to Blue or Red to Red).

8. Acidify with _______________________ (Use pH paper)

9. Filter the solid crystals of anthranilic acid and wash with ___________________.

10. Recrystallize using _________

11. If colored, add ______________ to decolorize.

12. Filter the recrystallized acid in a Buchner funnel and dry at _______________

13.TLC: __________________________

3 = ?

6 grams of phthalimide

Synthesis of Anthranilic Acid ]

1. Dissolve __________ in 40-mL distilled water.

2. Cool the mixture in an ice bath to about _________.

3. To the cooled solution, add _________________________.

4. Add ___________________________.

5. Add _________________.

6. Heat the solution for ____________________ until phthalimide dissolves.

7. Filter the solution and neutralize the solution with ____________ (Litmus: Blue to Blue or Red to Red).

8. Acidify with _______________________ (Use pH paper)

9. Filter the solid crystals of anthranilic acid and wash with ___________________.

10. Recrystallize using _________

11. If colored, add ______________ to decolorize.

12. Filter the recrystallized acid in a Buchner funnel and dry at _______________

13.TLC: __________________________

4 = ?

20 mL 10% KOH

Synthesis of Anthranilic Acid ]

1. Dissolve __________ in 40-mL distilled water.

2. Cool the mixture in an ice bath to about _________.

3. To the cooled solution, add _________________________.

4. Add ___________________________.

5. Add _________________.

6. Heat the solution for ____________________ until phthalimide dissolves.

7. Filter the solution and neutralize the solution with ____________ (Litmus: Blue to Blue or Red to Red).

8. Acidify with _______________________ (Use pH paper)

9. Filter the solid crystals of anthranilic acid and wash with ___________________.

10. Recrystallize using _________

11. If colored, add ______________ to decolorize.

12. Filter the recrystallized acid in a Buchner funnel and dry at _______________

13.TLC: __________________________

5 = ?

5-10 minutes

Synthesis of Anthranilic Acid ]

1. Dissolve __________ in 40-mL distilled water.

2. Cool the mixture in an ice bath to about _________.

3. To the cooled solution, add _________________________.

4. Add ___________________________.

5. Add _________________.

6. Heat the solution for ____________________ until phthalimide dissolves.

7. Filter the solution and neutralize the solution with ____________ (Litmus: Blue to Blue or Red to Red).

8. Acidify with _______________________ (Use pH paper)

9. Filter the solid crystals of anthranilic acid and wash with ___________________.

10. Recrystallize using _________

11. If colored, add ______________ to decolorize.

12. Filter the recrystallized acid in a Buchner funnel and dry at _______________

13.TLC: __________________________

6 = ?

12M HCl

Synthesis of Anthranilic Acid ]

1. Dissolve __________ in 40-mL distilled water.

2. Cool the mixture in an ice bath to about _________.

3. To the cooled solution, add _________________________.

4. Add ___________________________.

5. Add _________________.

6. Heat the solution for ____________________ until phthalimide dissolves.

7. Filter the solution and neutralize the solution with ____________ (Litmus: Blue to Blue or Red to Red).

8. Acidify with _______________________ (Use pH paper)

9. Filter the solid crystals of anthranilic acid and wash with ___________________.

10. Recrystallize using _________

11. If colored, add ______________ to decolorize.

12. Filter the recrystallized acid in a Buchner funnel and dry at _______________

13.TLC: __________________________

7 = ?

glacial acetic acid to pH 3

Synthesis of Anthranilic Acid ]

1. Dissolve __________ in 40-mL distilled water.

2. Cool the mixture in an ice bath to about _________.

3. To the cooled solution, add _________________________.

4. Add ___________________________.

5. Add _________________.

6. Heat the solution for ____________________ until phthalimide dissolves.

7. Filter the solution and neutralize the solution with ____________ (Litmus: Blue to Blue or Red to Red).

8. Acidify with _______________________ (Use pH paper)

9. Filter the solid crystals of anthranilic acid and wash with ___________________.

10. Recrystallize using _________

11. If colored, add ______________ to decolorize.

12. Filter the recrystallized acid in a Buchner funnel and dry at _______________

13.TLC: __________________________

8 = ?

distilled water

Synthesis of Anthranilic Acid ]

1. Dissolve __________ in 40-mL distilled water.

2. Cool the mixture in an ice bath to about _________.

3. To the cooled solution, add _________________________.

4. Add ___________________________.

5. Add _________________.

6. Heat the solution for ____________________ until phthalimide dissolves.

7. Filter the solution and neutralize the solution with ____________ (Litmus: Blue to Blue or Red to Red).

8. Acidify with _______________________ (Use pH paper)

9. Filter the solid crystals of anthranilic acid and wash with ___________________.

10. Recrystallize using _________

11. If colored, add ______________ to decolorize.

12. Filter the recrystallized acid in a Buchner funnel and dry at _______________

13.TLC: __________________________

9 = ?

hot water

Synthesis of Anthranilic Acid ]

1. Dissolve __________ in 40-mL distilled water.

2. Cool the mixture in an ice bath to about _________.

3. To the cooled solution, add _________________________.

4. Add ___________________________.

5. Add _________________.

6. Heat the solution for ____________________ until phthalimide dissolves.

7. Filter the solution and neutralize the solution with ____________ (Litmus: Blue to Blue or Red to Red).

8. Acidify with _______________________ (Use pH paper)

9. Filter the solid crystals of anthranilic acid and wash with ___________________.

10. Recrystallize using _________

11. If colored, add ______________ to decolorize.

12. Filter the recrystallized acid in a Buchner funnel and dry at _______________

13.TLC: __________________________

10 = ?

activated charcoal

Synthesis of Anthranilic Acid ]

1. Dissolve __________ in 40-mL distilled water.

2. Cool the mixture in an ice bath to about _________.

3. To the cooled solution, add _________________________.

4. Add ___________________________.

5. Add _________________.

6. Heat the solution for ____________________ until phthalimide dissolves.

7. Filter the solution and neutralize the solution with ____________ (Litmus: Blue to Blue or Red to Red).

8. Acidify with _______________________ (Use pH paper)

9. Filter the solid crystals of anthranilic acid and wash with ___________________.

10. Recrystallize using _________

11. If colored, add ______________ to decolorize.

12. Filter the recrystallized acid in a Buchner funnel and dry at _______________

13.TLC: __________________________

11 = ?

100 C

Synthesis of Anthranilic Acid ]

1. Dissolve __________ in 40-mL distilled water.

2. Cool the mixture in an ice bath to about _________.

3. To the cooled solution, add _________________________.

4. Add ___________________________.

5. Add _________________.

6. Heat the solution for ____________________ until phthalimide dissolves.

7. Filter the solution and neutralize the solution with ____________ (Litmus: Blue to Blue or Red to Red).

8. Acidify with _______________________ (Use pH paper)

9. Filter the solid crystals of anthranilic acid and wash with ___________________.

10. Recrystallize using _________

11. If colored, add ______________ to decolorize.

12. Filter the recrystallized acid in a Buchner funnel and dry at _______________

13.TLC: __________________________

12 = ?

Ethanol: Chloroform 3:7

Synthesis of Anthranilic Acid ]

1. Dissolve __________ in 40-mL distilled water.

2. Cool the mixture in an ice bath to about _________.

3. To the cooled solution, add _________________________.

4. Add ___________________________.

5. Add _________________.

6. Heat the solution for ____________________ until phthalimide dissolves.

7. Filter the solution and neutralize the solution with ____________ (Litmus: Blue to Blue or Red to Red).

8. Acidify with _______________________ (Use pH paper)

9. Filter the solid crystals of anthranilic acid and wash with ___________________.

10. Recrystallize using _________

11. If colored, add ______________ to decolorize.

12. Filter the recrystallized acid in a Buchner funnel and dry at _______________

13.TLC: __________________________

13 = ?

bromine (Br₂)

SYNTHESIS of ANTHRANILIC ACID: Reaction Scheme

When a.___________ is added to the cold NaOH solution, it reacts to form b.____________ in situ which acts as the brominating agent needed for the Hofmann rearrangement.

a = ?

sodium hypobromite (NaOBr)

SYNTHESIS of ANTHRANILIC ACID: Reaction Scheme

When a.___________ is added to the cold NaOH solution, it reacts to form b.____________ in situ which acts as the brominating agent needed for the Hofmann rearrangement.

b = ?

Br2+2NaOH→NaBr+NaOBr+H2OBr2+2NaOH→NaBr+NaOBr+H2O

SYNTHESIS of ANTHRANILIC ACID: Reaction Scheme

The reaction is as follows:

10% potassium hydroxide (KOH)

SYNTHESIS of ANTHRANILIC ACID: Reaction Scheme

a. Adding ________________________ increases the basicity of the solution, which helps stabilize the intermediate and facilitates the rearrangement step.

b. This strongly basic environment supports the next stage of the reaction, where the N-bromo phthalimide undergoes the __________________________.

a = ?

Hofmann rearrangement

SYNTHESIS of ANTHRANILIC ACID: Reaction Scheme

a. Adding ________________________ increases the basicity of the solution, which helps stabilize the intermediate and facilitates the rearrangement step.

b. This strongly basic environment supports the next stage of the reaction, where the N-bromo phthalimide undergoes the __________________________.

b = ?

isocyanate intermediate

SYNTHESIS of ANTHRANILIC ACID: Reaction Scheme

a. The __________________ is reactive and quickly hydrolyzes in the aqueous solution to form anthranilic acid.

b. This occurs when __________________, leading to the formation of an amine (NH₂ group) and a carboxyl group (COOH) on the benzene ring.

a = ?

water attacks the isocyanate (hydrolysis)

SYNTHESIS of ANTHRANILIC ACID: Reaction Scheme

a. The __________________ is reactive and quickly hydrolyzes in the aqueous solution to form anthranilic acid.

b. This occurs when __________________, leading to the formation of an amine (NH₂ group) and a carboxyl group (COOH) on the benzene ring.

b = ?

neutralized with glacial acetic acid

SYNTHESIS of ANTHRANILIC ACID: Reaction Scheme

a. After heating, the reaction mixture is ________________________________.

b. This step _________________ on anthranilic acid, causing it to precipitate out of solution as a solid.

a = ?

protonates the amine group

SYNTHESIS of ANTHRANILIC ACID: Reaction Scheme

a. After heating, the reaction mixture is ________________________________.

b. This step _________________ on anthranilic acid, causing it to precipitate out of solution as a solid.

b = ?

water-soluble impurities

SYNTHESIS of ANTHRANILIC ACID: Reaction Scheme

The solid anthranilic acid is collected by filtration and washed with distilled water to remove any remaining _________________.