CHM624 ADVANCED ORGANIC CHEMISTRY

LABORATORY EXPERIMENTS

Extracted from:

Harwood, L.M.; Moody, C.J.; Experimental Organic Chemistry: Principles and Practice, Blackwell Scientific Publications, 1989

LIST OF EXPERIMENTS 1. Peparation of 4-vinylbenzoic acid by a Wittig reaction in aqueous medium 2. 4-Bromobenzophenone by the Friedel-Crafts reaction 3. Oxidation of 4-tert-Butyl Cyclohexanol with PCC on a Silica Gel Substrate 4. Synthesis of flavone 5. Chemoselective Reduction of Methyl Acetoacetate using NaBH4 Note: The recommended experiments are experiments 1, 2 and 3 above. Duration: 7-8 weeks ASSESSMENT AND GRADING The laboratory sessions contribute 20% of the course grade. The marks for each experiment will be based on the followings:

A. Pre-laboratory preparations (assessed from the lab note books)

2 marks

B. Laboratory techniques (performance in the lab)

1 marks

C. Laboratory reports (all reports are individual work)

17 marks

Total 20 marks

A well written report should have the followings: 1. All laboratory reports must be typed and submitted one week after the experiments. 2. The cover page should contain the following information: Course name, Course code, number

and title of experiment, name of student, name of partners (for group work), name of lecturer, and date of experiment and date of submission of report.

3. The following marking scheme table must be included with the laboratory report. 4. Should the student fail to submit the week’s report, the student is given maximum of 3 marks

(for prelab and technique). Marks will also be deducted for late submission of report. 5. No report will be accepted (no marks given) from students who did not perform the week’s

experiment. 6. Students who missed any lab session (with medical certificate) will be graded based on the

remaining number of experiments. LABORATORY REPORT MARKING SCHEME

Full Mark(s)

Marks (to be filled by lecturer)

Objective of the Experiment 1.0

Introduction 2.0

Experimental Procedure 1.0

Results and Observations 2.0

Calculations 2.0

Discussion 5.0

Conclusion 1.0

Answers to Questions 2.0

References 1.0

Pre-laboratory preparations 2.0

Laboratory techniques 1.0

Total Marks 20

CHEMICALS REQUIRED Experiment 1: Peparation of 4-vinylbenzoic acid by a Wittig reaction in aqueous medium (Recommended Experiment) 1. Preparation of phosphonium salt

4-Bromomethylbenzoic acid (FW 215.1) 4.30 g (20 mmol) Triphenylphosphine (FW 262.3) 5.20 g (20 mmol) Acetone Diethyl ether

2. Preparation of 4-vinylbenzoic acid

Formaldehyde (37 wt % solution) (FW 30.0) 32 mL Sodium hydroxide pellets 2.5 g Ethanol Hydrochloric acid (concentrated)

Experiment 2: 4-Bromobenzophenone by the Friedel-Crafts reaction (Recommended Experiment)

Bromobenzene (FW 157.0) 2.0 mL, 3.0 g (19 mmol) Benzoyl chloride (FW 140.6) 3.3 mL, 4.0 g (30 mmol) Anhydrous aluminium chloride (FW 133.3) 4.0 g (30 mmol) Sodium hydroxide (10%) Diethyl ether

Light petroleum (60 - 80C) pH indicator paper

Experiment 3: Oxidation of 4-tert-Butyl Cyclohexanol with PCC on a Silica Gel Substrate (Recommended Experiment)

4-tert-butyl cyclohexanol (FW 156.27) 0.16 g (1.0 mmol) Pyridinium chlorochromate (FW 215.56) 0.43 g (2.00 mmol) Silica gel (230 – 400 mesh) 0.43 g (for synthesis) Dichloromethane Celite Saturated NaCl Anhydrous Na2SO4 Ethyl acetate Petroleum ether Silica gel (30 – 70 mesh) for filtering

Experiment 4: Synthesis of flavone 1. Preparation of 2-benzoyloxyacetophenone

2-Hydroxyacetophenone (FW 136.2) 2.46 mL, 2.72 g (20 mmol) Benzoyl chloride (FW 140.6) 3.48 mL, 4.22 g (30 mmol) Pyridine (FW 79.1) 5 mL Hydrochloric acid (3%)

Methanol 2. Preparation of ortho-hydroxydibenzoylmethane

Potassium hydroxide 0.85 g

*Important: Pulverize the KOH rapidly in mortar pre-heated to 100C Pyridine 8 mL *Important: Dry the pyridine over KOH Acetic acid solution (10%) 15 mL

3. Preparation of flavone

Glacial acetic acid 7 mL Sulfuric acid (concentrated) 0.25 mL

Light petroleum (bp 60 -80C) Experiment 5: Chemoselective Reduction of Methyl Acetoacetate using NaBH4

Methyl acetoacetate (FW 116.12)( 1.08 g/mL) 0.50 g (4.31 mmol) Sodium borohydride (FW 37.83) 0.20 g (5.17 mmol) Methanol 10 mL Dichloromethane Saturated ammonium chloride Anhydrous MgSO4 Ethyl acetate Petroleum ether Silica gel (230 – 400 mesh)

Experiment 1: Peparation of 4-vinylbenzoic acid by a Wittig reaction in aqueous medium (Recommended Experiment) This is an aqueous Wittig reaction in which the ylid is generated in the presence of a large excess of a reactive aldehyde. The ylid is stabilized by virtue of the electron withdrawing carboxylic acid group on the aromatic ring and resistant to hydrolysis. The phosphonium salt is prepared from 4-bromomethylbenzoic acid which, being nonvolatile, is relatively safe to handle, although it still has irritant properties. This starting material is available commercially.

HCHO, NaOH

H2O

PPH3, acetone

reflux

+

Br_

Time 3 h x 3 Equipments and instruments Magnetic stirrer Reflux apparatus Suction filtration IR Materials 1. Preparation of phosphonium salt

4-Bromomethylbenzoic acid (FW 215.1) 4.30 g (20 mmol) Triphenylphosphine (FW 262.3) 5.20 g (20 mmol) Acetone Diethyl ether

2. Preparation of 4-vinylbenzoic acid

Formaldehyde (37 wt % solution) (FW 30.0) 32 mL Sodium hydroxide pellets 2.5 g Ethanol Hydrochloric acid (concentrated)

Procedure 1. Preparation of 4-carboxybenzyltriphenylphosphonium bromide Dissolve the bromomethylbenzoic acid and the triphenylphosphine in 60 mL acetone in a 100 mL round bottomed flask and reflux the mixture for 45 min. After this time, cool the reaction mixture and filter off the precipitated phosphonium salt with suction. Wash the solid with diethyl ether (2 x 20 mL) on the sinter and dry it with suction. Record the yield and mp of the product which is sufficiently pure to use directly in the next stage. 2. Preparation of 4-vinylbenzoic acid Place 4-carboxybenzylphenylphosphonium bromide (3.76 g, 8 mmol), the aqueous formaldehyde and 15 mL water in a 250 mL Erlenmeyer flask equipped with a magnetic stirrer bar. Stir vigorously and a solution of the sodium hydroxide in 15 mL water over approximately 10 min. Stir the mixture for an additional 45 min and filter off the precipitate with suction, and wash it with water. Acidify the

combined filtrate and washings with concentrated hydrochloric acid and filter off the residual precipitate of crude product with suction. Recrystallize the product from aqueous ethanol and record the yield and mp of the material obtained. Analyze the purified material using NMR and IR spectroscopy. Problems 1. Assign the main absorptions in the IR spectrum of 4-vinylbenzoic acid. 2. Explain why it is possible to generate the ylid with aqueous sodium hydroxide in this experiment. 3. If an aldehyde other than formaldehyde were to be used, what would be the geometry at the

double bond in the major product? Why?

Experiment 2: 4-Bromobenzophenone by the Friedel-Crafts reaction (Recommended Experiment) The introduction of an acyl group into an aromatic ring is accomplished by an electrophilic

substitution by the acylium ion (RCO+) generated by the reaction between an acyl halide and aluminium chloride. In bromobenzene, the benzene is a deactivating and ortho, para-directing substituent. However, this reaction gives mainly the para-isomer, presumably ortho-substitution which might also be expected is sterically less favoured.

PhCOCl

AlCl3

Time 3 h x 2 Equipments and instruments Steam bath Rotary Evaporator IR Materials Bromobenzene (FW 157.0) 2.0 mL, 3.0 g (19 mmol) Benzoyl chloride (FW 140.6) 3.3 mL, 4.0 g (30 mmol) Anhydrous aluminium chloride (FW 133.3) 4.0 g (30 mmol) Sodium hydroxide (10%) Diethyl ether

Light petroleum (60 - 80C) pH indicator paper Procedure Place the bromobenzene and benzoyl chloride in a 50 mL Erlenmeyer flask. Add the aluminium chloride in three portions, shaking and stirring in between additions, and then heat the flask on a boiling water bath for 20 min. Cool, and pour the dark red liquid onto ice and wash out the remaining contents by careful addition of 10% NaOH to the flask. Make the combined solutions alkaline by the addition of 10% NaOH solution to dissolve any benzoic acid present and also aluminium salts. Extract with 2 x 25 mL of ether, dry the organic extract over MgSO4 and remove the ether on the rotary evaporator. 4-Bromobenzophenone remains and may be recrystallized from light petroleum to give a colourless solid. Record the yield and mp of the product. Analyze the purified material using NMR and IR spectroscopy.

Problems 1. Suggest syntheses of the following from benzene:

a) b) c)

Experiment 3: Oxidation of 4-tert-Butyl Cyclohexanol with PCC on a Silica Gel Substrate (Recommended Experiment) Oxidation reactions of alcohols greatly increase the synthetic usefulness of these compounds. Only primary and secondary alcohols can be easily oxidized with the former converted to aldehydes or carboxylic acids and the latter to the corresponding ketones. The strength and selectivity of oxidizing agents varies widely, the use of oxochromium(VI)-amine reagents is fundamental for a number of organic oxidative transformations. Pyridinium chlorochromate (PCC) is the most commonly used of these reagents, due to its availability, stability and versatility. Oxidation with PCC generally proceeds through a simple, one step reaction:

PCC, silica gel

DCM

Time 3 h x 2 Equipments and Instruments Pestle and mortar Magnetic stirrer Rotary evaporator IR Materials 4-tert-butyl cyclohexanol (FW 156.27) 0.16 g (1.0 mmol) Pyridinium chlorochromate (FW 215.56) 0.43 g (2.00 mmol) Silica gel (230 – 400 mesh) 0.43 g (for synthesis) Dichloromethane Celite Saturated NaCl Anhydrous Na2SO4 Ethyl acetate Petroleum ether Silica gel (30 – 70 mesh) for filtering Cautions PCC is an oxidizing agent! Handle with care! Wear gloves during the grinding process and do it under a hood. You do not want to oxidize your skin. Procedure Combine and grind PCC and silica gel (230 – 400 mesh) with a pestle and mortar to form a light orange powder. Add this powder to a 25 mL round bottomed flask along with 6 mL dichloromethane. While stirring, add the 4-tert-butyl cyclohexanol. Stir for additional 30 – 40 minutes. Test the reaction solution every five minutes with TLC (develop in iodine).

After the reaction has completed, dilute the reaction solution with 10 mL of ether and filter the solution through a pipet containing a cotton plug, 1 cm Celite, 3 cm silica gel (35 – 70 mesh). Concentrate the filtrate by blowing on it with N2 until it is a yellow oil. Then dilute with 5 mL of ether and transfer to a reaction tube. Extract with 2 x 5 mL of water and saturated NaCl solution. Dry over anhydrous Na2SO4 and transfer the organic layer to a tared 10 mL flask. Allow the solvent to evaporate overnight. Record the yield, melting point, NMR and IR data of the product. Problems 1. Would the final product have beenany different if you had used a stronger oxidizing agent such

as chromic acid? What would your products have been if you had been oxidizing the following compound with a) PCC, and b) chromic acid?

2. Given that PCC is only sparingly soluble in CH2Cl2 while cyclohexanol is miscible in CH2Cl2, suggest

a reason for the importance of grinding the PCC and silica gel to form a fine powder. (Hint: What basic physical property is changed by this?)

Experiment 4: Synthesis of flavone Nature abounds with bright colours. Some arise by light diffraction by the complex structure of the compounds but most colours in nature are by the absorption of certain wavelengths of visible light by organic compounds. Most red and blue flowers contain coloured glucosides called anthocynins. The colour imparted by an anthocynin is pH dependent. For an exmple, the red colour of roses and the blue of cornflowers are due to the same compound cyanin, which in its phenol form is red, and in its anionic form is blue. The nonsugar part of the glucoside is a type of flavylium salt. This term comes from the parent compound flavone, itself colourless, although the 3-hydroxy derivative, called flavonol, is yellow in colour (Latin flavus = yellow).

cyanin flavone flavonol

This project involves the 3-step synthesis of flavone from 2-hydroxyacetophenone, which is commercially available or can be prepared. The first stage is the benzoylation of the phenolic OH group with benzoyl chloride in pyridine to give 2-benzoyloxyacetophenone, which on heating in the presence of potassium hydroxide undergoes the Baker-Venkataraman rearrangement to give ortho-hydroxydibenzoylmethane in the second step. The final step involves cyclization of the ortho-hydroxydibenzoylmethane to flavone in the presence of acetic acid and sulfuric acids. After recrystallization, the flavone is obtained as colourless needles.

PhCOCl

C5H5N KON

AcOH

H2SO4

Time 3 h x 4 Equipments and instruments Steam bath Hot plate with magnetic stirrer Reflux apparatus Calcium chloride guard tube Suction filtration IR NMR

Materials 1. Preparation of 2-benzoyloxyacetophenone

2-Hydroxyacetophenone (FW 136.2) 2.46 mL, 2.72 g (20 mmol) Benzoyl chloride (FW 140.6) 3.48 mL, 4.22 g (30 mmol) Pyridine (FW 79.1) 5 mL Hydrochloric acid (3%) Methanol

2. Preparation of ortho-hydroxydibenzoylmethane

Potassium hydroxide 0.85 g

*Important: Pulverize the KOH rapidly in mortar pre-heated to 100C Pyridine 8 mL *Important: Dry the pyridine over KOH Acetic acid solution (10%) 15 mL

3. Preparation of flavone

Glacial acetic acid 7 mL Sulfuric acid (concentrated) 0.25 mL

Light petroleum (bp 60 -80C) Procedure 1. Preparation of 2-benzoyloxyacetophenone Dissolve the 2-hydroxyacetophenone in 5 mL pyridine (dried over KOH) in a 25 mL round bottomed flask. Add the benzoyl chloride, fit the flask with a calcium chloride guard tube and swirl the flask to ensure mixing of the reagents. The temperature of the reaction mixture rises spontaneously. Leave the reaction mixture for about 20 min or until no further heat is evolved. Then pour the mixture into a 250 mL beaker containing 120 mL hydrochloric acid (3%) and 40 g crushed ice with good stirring. Collect the product by suction filtration and wash it with 4 mL cold methanol and then 5 mL water. Dry the product by suction at the filter pump for 20 min, then recrystallize it from approximately 5 mL methanol. Record the yield, mp, and the IR and NMR (in CDCl3) spectra of the product after recrystallization. Record an IR spectrum of the starting 2-hydroxyacetophenone for comparison. 2. Preparation of ortho-hydroxydibenzoylmethane Dissolve 2.4 g (10 mmol) of the 2-benzoyloxyacetophenone in 8 mL pyridine (dried over KOH) in a 50

mL beaker. Warm the solution to 50C in hot water bath. Add the finely powdered potassium hydroxide and stir the mixture for 15 min using a glass rod. During this time a yellow precipitate of the potassium salt of the product forms. Cool the mixture to room temperature and add 15 mL of 10% acetic acid solution. Collect the product by suction filtration and dry it by suction at the filter pump for a few minutes. Record the yield and mp of the product, which is sufficiently pure for use in the next stage. 3. Peparation of flavone Dissolve 1.20 g (5 mmol) of the ortho-hydroxydibenzoylmethane in 7 mL glacial acetic acid in a 25 mL round bottomed flask. Swirl the solution and add 0.25 mL concentrated sulfuric acid. Fit the flask with a reflux condenser, add boiling chips and heat it for 1 h. Remove the boiling chip and pour the reaction mixture onto 40 g crushed ice contained in a 100 mL beaker with rapid stirring using a glass rod. When all the ice has melted, collect the crude product by suction filtration and wash with approximately 80 mL water until free from acid. Dry the product by suction at the filter pump and

then at 50C. Recrystallize the crude flavone from approximately 40 mL light petroleum. Record the yield, mp, and the IR and NMR (in CDCl3) spectra of the product after recrystallization. Problems 1. Discuss the mechanism of the Baker-Venkataraman rearrangement. 2. Assign the spectroscopic data for the starting 2-hydroxyacetophenone, its benzoylated derivative

and for flavone.

Experiment 5: Chemoselective Reduction of Methyl Acetoacetate using NaBH4

NaBH4, MeOH

0oC

Time 3 h x 3 Instruments Magnetic stirrer Rotary evaporator IR Materials

Methyl acetoacetate (FW 116.12)( 1.08 g/mL) 0.50 g (4.31 mmol) Sodium borohydride (FW 37.83) 0.20 g (5.17 mmol) Methanol 10 mL Dichloromethane Saturated ammonium chloride Anhydrous MgSO4 Ethyl acetate Petroleum ether Silica gel (230 – 400 mesh) Procedure

Methyl acetoacetate in methanol is cooled to 0C. NaBH4 is added in small portions over 5 minutes

and the mixture is stirred at 0C for an additional 30 min. The methanol is then removed under reduced pressure. The residue is diluted with dichloromethane and saturated NH4Cl, and extracted three times with dichloromethane. The combined organic layers are dried with anhydrous MgSO4 and concentrated under vacuum. The crude product is purified using column chromatography (ethyl/acetate petroleum ether as the solvent system). Perform TLC to identify the suitable solvent system. Record the yield, NMR and IR spectra of the product after purification via chromatography. Use HPLC to identify the ratio of the product’s isomers.