University of KwaZulu-Natal

School of Chemistry & Physics (Durban)

CHEM 320

Practical Manual

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No of Weeks Experiments Techniques Date to hand report

2 Exp 1: Isolation of eugenol and acetyleugenol

from cloves Extraction of natural products. Separation & characterisation

Gr 1 and 3 Start of next practical

2 Exp 2: Transformation of cholesterol to

cholestenone Crystallisation Stereochemistry

Gr 2 and 4 Start of next practical

1

Spectroscopy Workshop

2

Exp 3: Preparation of 2-Acetylcyclohexanone

Enamine synthesis Use of Dean & Stark

apparatus Distillation under reduced

pressure

Gr 3 and 5 Start of next practical

2 Exp 4: Preparation of 5,5-

dimethylcyclohexane-1,3-dione (dimedone)

Michael reaction Crystallisation

TLC

Gr 1 and 4 Start of next practical

1 Exp 5: Preparation of Camphor Addition, Mixing,

Purification by Sublimation

Gr 2 Start of next practical

1 Exp 6: Synthesis of 7,7-

dichlorobicyclo[4.1.0]heptane – Phase transfer catalysis

Phase transfer catalysis, Vacuum distillation

Gr 5 Start of next practical

Timetable for the practical sessions:

Week

1 2 3 4 5 6 7 8 9 10 11

Exp1 G1 G1 G2 G2 * G3 G3 G4 G4 G5 G5

Exp2 G2 G2 G3 G3 * G4 G4 G5 G5 G1 G1

Exp3 G3 G3 G4 G4 * G5 G5 G1 G1 G2 G2

Exp4 G4 G4 G5 G5 * G1 G1 G2 G2 G3 G3

Exp5 G5 G1 * G2 G3 G4

Exp6 G5 G1 * G2 G3 G4 * Spectroscopy workshop. In a lecture venue (to be announced)

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Contents ___________________________________________________

Introduction ................................................................................................................................................................ 3

Skills and Techniques ............................................................................................................................................. 3

Administration of Experiments ............................................................................................................................... 3

Pre-lab Questions .................................................................................................................................................... 3

Demonstrators and Technicians .............................................................................................................................. 3

Practical Reports and Samples................................................................................................................................. 4

Plagiarism ............................................................................................................................................................... 4

Locker Contents ...................................................................................................................................................... 4

Useful References .................................................................................................................................................... 4

Due Performance Certificate and Exemptions.......................................................................................................... 5

Treating Accident Cases ............................................................................................................................................. 6

(1) Fire ...................................................................................................................................................... 6

(2) Electrical .............................................................................................................................................. 6

(3) Chemical Poisoning (Oral) ................................................................................................................... 6

(4) Gassing ................................................................................................................................................ 7

(5) Corrosive Chemicals Spilt on Skin or Mucous Membranes ................................................................... 7

(6) Cuts and Grazes ................................................................................................................................... 7

(7) Eye Injuries .......................................................................................................................................... 7

Laboratory Rules ......................................................................................................................................................... 8

Experiment 1 .............................................................................................................................................................. 9

The Isolation of Eugenol and Acetyleugenol from Cloves ........................................................................................ 9

Experiment 2 .............................................................................................................................................................12

Transformation of Cholesterol to Cholestenone ......................................................................................................12

Experiment 3 .............................................................................................................................................................14

Preparation of 2-Acetylcyclohexanone ....................................................................................................................14

Experiment 4 .............................................................................................................................................................16

Preparation of 5,5-dimethylcyclohexane-1,3-dione (dimedone) ...............................................................................16

Experiment 5 .............................................................................................................................................................18

Preparation of Camphor .........................................................................................................................................18

Experiment 6 .............................................................................................................................................................20

Synthesis of 7,7-dichlorobicyclo[4.1.0]heptane – Phase transfer catalysis ...............................................................20

Appendix ...................................................................................................................................................................23

Occupational Safety Information ............................................................................................................................23

Safety Precautions and Regulations ........................................................................................................................26

Hazards and Precautions .......................................................................................................................................26

Guidelines for Writing Practical Reports ....................................................................................................................28

Model Report .............................................................................................................................................................32

Crystallisation and what to do if no crystals are formed ..............................................................................................37

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Introduction

______________________________________________________________________________

Skills and Techniques These experiments are designed to expose you to modern research methods in organic chemistry. The experiments have been carefully chosen to illustrate many of the synthetic manipulations used by modern-day organic chemists. Most of the experiments compliment the theory you will be covering in lectures. The experiments to be carried out involve the synthesis of a variety of organic compounds. You will be learning new techniques for setting up and monitoring reactions, as well as purifying and characterising products. These are described in more detail in the following section. You will perform a number of functional group manipulations including converting a ketone to an enamine; hydrazine to a hydrazone; anhydride to dicarboxylic acid; ester to carboxylic acid. You will be performing the following types of reactions, inter alia, Diels-Alder, Michael addition, condensations, acylation of an enamine, hydrolysis of anhydrides and esters, decarboxylation and oxidation. You will learn to do the following: perform reactions under anhydrous conditions; use a Dean and Stark apparatus to separate water from a reaction mixture; perform distillations at atmospheric pressure and under reduced pressure; comparison of an experimental boiling point with a literature value; recrystallizations; measure the melting point of a solid product and compare the experimental value with the theoretical value. You will learn to use-thin layer chromatography (TLC) to assess the purity of a sample and follow the progress of your reaction. You will learn how to separate mixtures of compounds using column chromatography. You will learn to characterise your products using modern spectroscopic methods including NMR, GC-MS and IR.

Administration of Experiments A timetable is included in this manual. This timetable will inform you of the day you will be performing each experiment. It will also tell you which day each report is due. Any other notices pertaining to the practical course will be displayed in the display cabinet outside the Laboratory. Make sure you read the relevant experiment before coming into the laboratory. The more time you waste in the lab, the more likely you are to rush critical steps and spoil your results.

Pre-lab Questions

Various questions precede each experimental method in this manual. It is compulsory to answer the pre-lab questions before the practical. You will be required to hand these answers in at the start of each practical. You will not be permitted to do the experimental work if you have failed to answer these questions. Your answers to these questions will form an important part of each practical report, i.e. you will be asked questions to probe whether you understand the practical. Your answers will be graded and the marks added to the marks you attain for the practical report.

Demonstrators and Technicians You will be conducting these practicals in the Synthetic Laboratories. There are laboratory technicians in each laboratory. You should consult them if you have any queries concerning chemicals and glassware. The demonstrators are present to give you advice concerning your

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practical work (e.g. setting up glassware for reactions, useful tips for recrystallization and distillation etc.).

Practical Reports and Samples The presentation of your experimental data in the form of a detailed report is a crucial part of any scientific endeavour. The report must provide all the information needed such that the reader understands the nature and purpose of the practical work and if necessary could readily repeat the experiment and obtain the same results. Practice makes perfect! You will be required to write regular reports on your experimental work whether you obtain a job in chemical industry or decide to carry on with postgraduate study in chemistry. The more effort you put in the easier writing good quality practical reports will become. The exercise will teach you to express yourself clearly, precisely and accurately, very important abilities in any scientific pursuit. Using textbooks and other reference sources to obtain information pertinent to your practical work will teach you to become more resourceful. You will be required to write 2 practical reports only. You should familiarise yourself with the format required for your practical reports by looking at the model report, as well as consulting the guidelines for writing effective practical reports, both included in this manual. Any queries regarding practical reports should be directed to the lecturer responsible for marking that experiment. Practical reports and attached, labelled samples for each experiment must be handed in to the technician in charge before or on the due date. Late submissions will be penalised (10% subtracted for each day overdue). NOTE: - Ensure you have received a receipt for you report. All samples prepared during each practical session must be submitted in a sample vial labelled with your experiment number and name and attached to a cover sheet in which you report the melting point and the yield. The purity and quality of your product(s) will be carefully looked at. Report marks will be posted on the SMS system on a weekly basis. You are encouraged to discuss the reports with the demonstrator of that experiment or lecturer in charge to find out where you could improve your report-writing technique. It is impossible to write detailed comments on everybody’s reports.

Plagiarism

The copying of any work will be taken very seriously, and will be forwarded to the University Authorities for disciplinary action.

Locker Contents Please report any breakages to the laboratory technician. In case of negligence, broken or misplaced glassware will be charged to your account.

Useful References

The following references are available in the UKZN libraries. You are strongly encouraged to consult these references for additional information pertaining to these practicals e.g. information on distillation, recrystallization, TLC, column chromatography etc. In addition, there are numerous general organic chemistry textbooks including the prescribed textbooks available on short loan. You

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are encouraged to consult these books for useful information pertaining to the theoretical component of these practicals (e.g. mechanism of reaction). 1. C. F. Wilcox and M. F. Wilcox, Experimental Organic Chemistry, A Small-Scale Approach,

second edition, Prentice-Hall, Englewood Cliffs, 1988. 2. J. S. Nimitz, Experiments in Organic Chemistry, From Microscale to Macroscale, Prentice

Hall, Englewood Cliffs, 1991. 3. L. M. Harwood and C. J. Moody, Experimental Organic Chemistry: Principles and Practice,

Blackwell Scientific Publications, Oxford, 1989. 4. H. Hart, Organic Chemistry, A Short Course, seventh edition, Houghton Mifflin, Boston,

1987. 5. R. Stock and C. B. F. Rice, Chromatographic Methods, third edition, Chapman and Hall,

Norwich, 1974. 6. R. Hamilton, S. Hamilton, Thin Layer Chromatography, Wiley, Chichester, 1987. 7. R. Keese, R. K. Müller, T. P. Toube, Fundamentals of Preparative Organic Chemistry, Ellis

Horwood, Chichester, 1982.

Due Performance Certificate and Exemptions

The laboratory course comprises five practicals and one spectroscopy workshop. You are required to attend and hand in reports for 80% of the practicals. If you do not meet this requirement, you will be refused a DP certificate and will not be allowed to write the examinations. You will only be exempt from a laboratory session if you produce a physician’s certificate. You should present your medical certificate to the lecturer in charge who will make a copy and keep it on record, you will also be provided a receipt acknowledging the certificate. The missed practical will be omitted when calculating your practical mark.

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Treating Accident Cases

Safety in the laboratory is not a matter that can be affected solely by the application of a number of hard-and-fast rules; it also requires the co-operation and interest of all staff members, demonstrators and students. Common sense, recognition of potential hazards, and confidence in reacting in a situation are essential to ensure the successful application of safety measures.

(1) Fire

The fire should be smothered using a fire blanket, laboratory coat, or other clothing. If the skin burn is severe, little else should be done except removing the patient to hospital. Invariably, treatment for shock is necessary. The patient should be kept warm and relaxed. All tight clothing should be loosened and sips of water can be given.

(2) Electrical Turn off the current before attempting to rescue any person in contact with a live circuit. If this is not possible, use rubber gloves or dry woollen material to protect the hands and make sure that you stand on a dry surface before attempting to drag the person off. The person should be treated for shock or burns where necessary.

(3) Chemical Poisoning (Oral) The first thing is to wash the mouth with water many times and drink large quantities of water or milk. These act as diluting agents. If the poison is an aqueous solution of a heavy metal compound, e.g., lead, mercury, or cadmium, the patient should drink milk since these metal ions will bind to proteins contained in the milk rendering them unavailable for free absorption in the gut, thereby protecting enzymes and other proteins in the blood. Generally, if the poison is known, references must be made to the appropriate chart and the necessary treatment given. It is very

RISK MANAGEMENT X 7133/7265 CAMPUS HEALTH CLINIC X 7338

Be aware of the location of the nearest fire extinguisher, eyewash, fire blanket, safety shower and first aid kit, and know how to use them.

First Aid gloves are positioned at both eyewash stands - It is policy that gloves be

worn at all times by any person attending to an injured individual.

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important that you know where such a chart (e.g., Laboratory First Aid Chart by the British Drug Houses Limited) is displayed in the laboratory.

(4) Gassing

If the gas is not known, the patient should be removed to fresh air and all clothing loosened. Do not give the patient anything to drink. It is essential to ascertain quickly that the tongue has not fallen back to block the throat. The patient must be placed in such a position that this cannot happen. Oxygen should be administered only by a skilled person and artificial respiration should be given only when breathing has stopped. As with all serious accidents, the case should be attended to by a trained person as soon as possible.

(5) Corrosive Chemicals Spilt on Skin or Mucous Membranes Remove the contaminated clothing and wash the eyes or skin thoroughly with flowing water.

(6) Cuts and Grazes There is always the danger of small pieces of glass remaining in the wound. It is therefore desirable to have the wound attended to by a skilled person.

(7) Eye Injuries It is unwise for an unskilled person to attempt to remove a foreign body, particularly small pieces of glass, from the eye. Alkali splashed in the eye is generally more dangerous than acid, except in the case of the very dangerous ACETIC ACID, and washing must be immediate and very thorough. Do not stand by, but plunge the person's head under the nearest cold water tap and ensure the eye is OPEN whilst washing. Usually the patient is concerned and afraid to use the eye bath efficiently. The rubber hose or plastic tubing attached to the sink tap is more effective as an eye washer than a normal tap. Even if the patient feels confident that the eye has sustained no damage, the patient must see a DOCTOR. Alternatively, special plastic spray bottles are available for eye irrigation. One is housed near the melting point apparatus and the other is located above the gas-isolating valve. NEVER ATTEMPT AN EYE WASH WITH ANY LIQUID OTHER THAN WATER.

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Laboratory Rules 1. Safety glasses and laboratory coats to be worn at all times in the laboratory. 2. No open shoes, sandals or slops to be worn in the laboratory. 3. No eating, drinking and smoking in the laboratory. 4. Never inhale, taste or sniff chemicals and handle all chemicals with great care. 5. No experimental work to be carried out outside of the allocated practical sessions. 6. All solvent residues except acetone are to be discarded into residue bottles provided in the

fumehood and not down the sink. Acetone must be discarded into the acetone residue bottles. 7. All broken glassware must be given to a technician. Do not discard broken glassware into

dustbins. 8. All sinks must be kept free of cotton wool, filter paper, micropipettes and Pasteur pipettes. 9. All solid waste, e.g. MgSO4, CaCl2, silica gel etc., must be discarded into a container marked

“solid waste”. 10. Attend to spills immediately. 11. Disconnect your heater-stirrer and tidy up your bench at the end of each practical session. 12. Always wash your hands before leaving the laboratory. 13. Always ask a demonstrator or lecturer if in doubt about anything concerning the practical.

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Experiment 1

The Isolation of Eugenol and Acetyleugenol from Cloves ________________________________________________________________________________

OHOMe

O

O

OMeEugenol Eugenol acetate Caryophyllene

Time Requirement: Two afternoons

Procedure Weigh out approximately 20 grams of uncrushed cloves and place them in a 250 ml round bottom flask. Add about 100 ml of water and several boiling chips and let the flask stand while you assemble the rest of the equipment. Set the flask for distillation using a distillation head, thermometer, condenser, receiver, adapter and a Bunsen burner. Place a suitable Erlenmeyer flask to collect the distillate. Heat the flask and rapidly distil about 50 ml of the water. Then add a further 50 ml of hot water to the distillation flask and rapidly distil a further 50 ml. Record the temperature of the distillation. Transfer the distillate to a separating funnel. Wash the Erlenmeyer with 15 ml of dichloromethane and add this dichloromethane to the separating funnel. Shake the contents of the separating funnel gently, allow the layers to separate, and remove the bottom layer containing the eugenol. Add another 15 ml to the separating funnel and repeat the extraction. Dry the combined dichloromethane layer using anhydrous sodium sulfate. Weigh a round bottom flask and filter into it the dichloromethane solution using gravity filtration (small filter paper or a glass wool plug) to remove the sodium sulphate. Remove the dichloromethane using a rotary evaporator. (Your demonstrator will demonstrate the use of the rotary evaporator to you). Be careful not to overheat the flask as eugenol is volatile and can easily be lost. Record the weight of your recovered clove oil. Calculate the % weight recovery based on the starting weight of cloves you used. Use some of the product (label) for the thin layer chromatography (TLC) and gas chromatography (GC) parts of the experiments.

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(A) Separation of Acetyleugenol from Cloves Redissolve 1 gram of clove oil in 20 ml of dichloromethane and pour into a separating funnel. Add 20 ml of 10% NaOH to the extract in the separating funnel. Shake and vent three times and allow to separate. Drain out the lower dichloromethane layer into the 50 ml Erlenmeyer flask. Repeat the dichloromethane extraction twice more (2 x 20mls), before drying the combined dichloromethane fractions with sodium sulphate. Combine the sodium hydroxide layers and pour them into a separate beaker for use in the next section. Weigh a round bottom flask and filter into it the dichloromethane solution using a gravity filtration (small filter paper or a glass wool plug) to remove the sodium sulfate. Evaporate the dichloromethane, using a rotary evaporator. Record the weight of your recovered acetyleugenol. Calculate the % weight recovery based on the amount clove oil used. Save and label it for further study using TLC, GC and IR. (Stop here on Day 1). (B) Separation of eugenol from cloves Take the aqueous NAOH extract saved from the previous separation and add 6-8 ml of 6M HCl to the extract adjust the pH = 1. It may take more than 20 ml but test with litmus paper (blue to red). Transfer the acidified extract to a separating funnel. Add 20 ml of dichloromethane, shake and vent, and allow the layers to separate. Allow the dichoromethane lower layer to drain into the 50 ml Erlenmeyer flask and add sodium sulphate to dry. Weigh a round bottom flask and filter into it the dichloromethane solution using a gravity filtration (small filter paper or a glass wool plug) to remove the sodium sulfate. Evaporate the dichloromethane using a rotary evaporator. Record the weight of your recovered eugenol. Calculate the % weight recovery based on the amount clove oil used. Save and label it for further study using TLC, GC and IR. Each group is expected to obtain a 1H NMR and GC-MS spectrum of eugenol (1 sample per group); include a copy of each in your report.

1. Assign the various resonances in the NMR spectrum. 2. How many different 13C NMR signals would you expect in the 13C NMR spectrum of

eugenol (ignore spin coupling). 3. Assign the major fragments of the mass spectrum of eugenol and propose the mechanism of

their formation. (C) Thin-layer chromatography of eugenol, acetyleugenol and clove oil Add 5 ml of 2:1 hexane/dichloromethane developing solvent into a 250 ml beaker. Take a TLC strip and using a thin capillary tube spot apply the clove oil, acetyleugenol and the eugenol. (Note draw a pencil mark across the strip 1 cm from the bottom of the strip. Allow for a 20-30 minutes developing time, mark the solvent front. Take the strips out of the solvent and allow it to dry for 5 minutes. Prepare another strip. Place one strip near a UV lamp and mark spots that appear above the spotting line and calculate RF values. Place the other strip in the iodine tank and mark the spots that appear. Compare the two results. Turn in the TLC plates attached to the lab report. (D) Infrared spectrum of acetyleugenol and eugenol. Obtain the infrared spectrum of acetyleugenol. As it is a liquid you should be able to do this using the NaCl crystal disks. Wash the IR card with two pipettes full of acetone found in the instrument

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room. Make sure the NaCl disks are dry before applying a drop of eugenol. Include the two IR spectra in your lab report.

1. Assign the major peaks. 2. Is there evidence of dichloromethane in your spectrum?

(E) Gas chromatography of clove oil, acetyleugenol and eugenol

Inject 50-µL of clove oil onto the gas chromatography column and obtain the chromatogram. Repeat the injections with acetyleugenol and then eugenol. Compare the chromatograms obtained. Was it possible to separate eugenol from acetyleugenol? Is there any correlation between this result and the result from TLC plates? Determine the retention times of the components. Calculate the percentage composition of the eugenol sample.

Prelab Questions 1. There are many types of distillation including simple distillation, fractional distillation, distillation

under reduced pressure, short path distillation and steam distillation.

(a) Distillation is a method for purifying volatile liquids. Explain how the impurities are separated from the desired product.

(b) Describe each of the above-mentioned forms of distillation. (c) For each type of distillation, state the boiling point difference required between the various

components to achieve separation. (d) What are the factors that help one decide which the most suitable type of distillation to

perform is? The temperature of the distillation is about 100ºC, the boiling point of water. Explain why eugenol is removed from the flask during the steam distillation.

2. The material recovered in the steam distillation contains mostly eugenol but it also has other

components such as caryophyllene. Look up the properties of phenols such as eugenol and suggest a chemical method for separating eugenol and caryophyllene.

3. How can information from analytical gas chromatography be used to purify the different

components of clove oil? How would this procedure compare to the use of column chromatography?

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Experiment 2

Transformation of Cholesterol to Cholestenone (Fieser 1963)

2

3

4

510

1

67

89

14

13

1211

HO

Cholesterol (1)

19

18

15

16

1720

21 22

23

2425

26

27

Br2HOAc HO

BrBr

2

Cr(VI)

OBr

Br

3

Zn

O

4

Introduction This experiment illustrates the transformation of a sensitive group (a double bond) to an unreactive group (a vicinal dibromide) that would not react during the transformation of cholesterol (1) to cholest-5-en-3-one (4). If the double bond is not protected in this way, it will isomerise during the oxidation to the 4-ene derivative. After the oxidation step, the double bond is regenerated by the treatment of the dibromide with zinc dust.

Time Requirement Two afternoons

Caution Bromine is extremely poisonous, and all reaction where bromine is used, should be carried out in a fume cupboard.

Procedure Weigh 2.9 g (7.5 mmol) cholesterol (1) in a 100 ml Erlenmeyer flask and add 25 ml ether. Stir the solution until the cholesterol is dissolved (heat slightly on a water bath if necessary). Add 14 ml of a solution of buffered bromine in acetic acid drop wise over a period of 5-10 minutes. (Bromine solution: 4.5 g bromine and 0.5 g sodium acetate in 50 ml acetic acid). Within a few minutes the cholesterol dibromide will start crystallising. Chill the mixture in an ice bath, collect the dibromide (2) in a Büchner funnel and wash it several times with 3 ml portions of acetic acid. Transfer the moist dibromide to a 250 ml beaker, pulverise it to smooth paste (use a glass rod) and add 40 ml acetic acid. Stir the suspension with a glass rod and heat it in a water bath until the temperature is 45 oC. Stir the mixture and add a solution of sodium dichromate (0.9 g) and concentrated sulfuric acid (0.6 ml, 12 drops) in water (1.5 ml) and acetic acid (30 ml) at such a tempo that the temperature does not rise above 55 oC. Keep the temperature at 45 oC and stir the mixture until the suspended solid is dissolved. Cool the mixture in an ice bath for 10 minutes. Stir

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the resultant suspension with a glass rod and add 8 ml water drop wise. Collect the product (3) in a Büchner funnel and wash it several times with 3 ml methanol portions until the filtrate is clear. (Stop here on Day 1). Transfer the moist 5, 6-dibromocholestan-3-one (3) to a 100 ml Erlenmeyer flask and add 40 ml ether and 0.5 ml (10 drops) acetic acid. Stir the solution in an ice bath until the temperature has decreased to 15 oC. Add 0,6 g zinc dust to the stirred solution. Keep the temperature of the mixture at 15-20 oC. Add two further portions of 0,6 g zinc dust. When the reaction has subsided, let the temperature rise to 20-25 oC and stir the mixture for 10 minutes. Add 1 ml pyridine to the reaction mixture to precipitate the zinc bromide. Filter the solution and wash the reaction flask with 10 to 20ml ether. Add to the precipitate and filter. Pour the filtrate into a separating funnel, add 10ml of water, shake the contents of the funnel gently, allow solution in funnel to separate and remove the aqueous layer. Repeat using 10ml water. Then to the organic layer in the funnel, add 10ml of 5% sodium bicarbonate, shake the funnel, allow solution to separate and remove aqueous layer. Repeat. Dry the organic layer over anhydrous sodium sulfate. Filter the ether solution and remove the solvent on the rotary evaporator. The product is heat sensitive – be careful not to heat it after the solvent has been removed. Crystallise the product from acetone. Determine the yield and melting point of the product. Obtain the 1H and the 13C NMR spectra of cholesterol and compare it with the NMR spectrum of your product (1 sample per group) with the help of a demonstrator. Assign as many of the peaks as possible in the spectra.

Pre-lab Questions 1. Draw cholesterol in a 3D-like fashion using chair or half-chair conformations, clearly showing the

axial and equatorial positions of the hydrogens and the methyl groups. 2. Why is the (5R,6R)-dibromide 2 less stable than the corresponding (5S,6S)-dibromo derivative of

cholesterol? (Hint: Consider the 3D structures of the two compounds). 3. Why is the dehalogenation of (5R,6R)-dibromide 2 easier than dehalogenation of the

corresponding (5S,6S)-dibromo derivative of cholesterol? (Hint: Reaction has an E2 mechanism). 4. Why can both the (5R,6R) and (5S,6S)-dibromo derivatives of cholesterol be easily

dehydrohalogenated (-HBr)? 5. If cholestenone (4) is treated with acid or base, an isomeric compound is formed. What is the

structure of this compound? Write a mechanism for both the acid- and base-catalysed reactions.

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Experiment 3

Preparation of 2-Acetylcyclohexanone

_____________________________________________________________________________

ONH

p-TsOH

N 1. Ac2O2. H3O+

O

Me

O

Time Requirement: Two afternoons

Procedure

Place cyclohexanone (5.0 ml), pyrrolidine (4.0 ml), toluene-4-sulfonic acid (0.1 g), three boiling chips, and 40 ml of toluene in a 100 ml round bottomed flask. Fit the Dean and Stark apparatus to the flask, and fit the reflux condenser (protected with a calcium chloride drying tube) to the top of the Dean and Stark apparatus (see below). Heat the flask, using a heating mantle so that the toluene refluxes vigorously (vapour should condense well up the condenser), and the water that is formed in the reaction collects in the trap. Maintain the solution at reflux until the condensation of water has stopped (between 30 – 60 minutes). Prepare a solution of acetic anhydride (4.5 ml, CAUTION - lachrymator, work as quickly and carefully as possible and do not touch your face with contaminated fingers) in 10 ml toluene.

Dean-Stark distillation

Allow the solution to cool somewhat, remove the Dean and Stark apparatus, fit the still head and thermometer, and reassemble the condenser with a receiver and receiver flask for distillation.

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Continue to heat the flask and distil off the remaining pyrrolidine and water. Continue the distillation until the temperature at the still head reaches 108-110ºC. Remove the heat and allow the flask, which contains a toluene solution of the enamine, to cool to room temperature. Remove the still head etc., and add the acetic anhydride solution whilst stirring. Stir the resulting mixture for 15 minutes and then stopper the flask and store it safely until your next practical session. Add 5 ml of water to the flask, fit a reflux condenser, and heat the mixture under reflux for 30 minutes (start timing once the solution is boiling). Transfer the mixture to a separating funnel containing 10 ml of water. Shake the funnel, separate the layers, and wash the organic layer successively with 3 X 10 ml hydrochloric acid (3M), and finally with 10 ml water. Dry the organic layer over MgSO4. Filter off the drying agent, and transfer the solution to a distillation set (see below), and distil off the toluene (b.p. 110ºC, 760 mmHg). Transfer the residue to a very small round-bottomed flask and attach a short-path condenser. Remember to preweigh a couple of receiver flasks. Flame distil the product under reduced pressure (vacuum) using the bench vacuum (use anti-bumping granules to stir your solution). A very rough estimate of the expected boiling point of the desired product using the vacuum in the laboratory is >110ºC. Record the temperature range (e.g. 115-122ºC) of each fraction. (The presence of impurities may mean you get more than one product distilling across). Record the mass of the distilled product(s).NOTE: % yield should be based on cyclohexanone.

To vacuum line

Pre-lab Questions 1. Research the potential toxicity of each of the reagents you will be using in this practical. 2. You will make use of a piece of apparatus known as a Dean and Stark trap in this experiment.

(a) What is a Dean and Stark trap? Draw a sketch of a typical Dean and Stark trap. (b) Explain why it is necessary to use this piece of apparatus in this experiment. What function

does the Dean and Stark trap perform? (c) Read up about azeotropic distillation. Water readily forms azeotropes with some organic

solvents. What is an azeotrope? What is the nature of the solvent (toluene) interaction with water?

(d) Discuss the significance of azeotropes in this experiment. (e) Describe another method that accomplishes the removal of water from a reaction mixture.

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Experiment 4

Preparation of 5, 5-dimethylcyclohexane-1, 3-dione (dimedone) _______________________________________________________________________

Me

Me

Me

O+

CO2Et

CO2EtNaOEt

Me Me

O O

CO2Et Me Me

O O

(i) aq. KOH(ii) H 3O+

Time Requirement: Two afternoons

Procedure All apparatus must be thoroughly dried in a hot (>120ºC) oven before use. Working as quickly and carefully as possible, add sodium (1.15 g, this will be supplied to you) to 30 ml of absolute ethanol in a 100 ml round bottomed flask fitted with a Claisen adapter (or double neck flask), a reflux condenser carrying a CaCl2 drying tube, and an addition funnel (see below). Add diethyl propanedioate (8.5 ml) from the addition funnel over 5 minutes followed by 5 ml absolute ethanol (do not heat reaction mixture at this stage). Add 4-methylpent-3-en-2-one (6.0 ml, CAUTION - lachrymator, work as quickly and carefully as possible and do not touch your face with contaminated fingers) over 5 minutes and then reflux the mixture gently for 45 minutes using a heating mantle (only start timing once the solution is boiling). Do not forget to add a few boiling stones to your reaction mixture.

During this time, dissolve potassium hydroxide (6.3 g) in 25 ml distilled water (100ml beaker). Add this through the addition funnel and continue refluxing for a further 45 minutes. Allow the mixture to cool, remove the adapter, reflux condenser, and addition funnel and stopper the flask and store it safely until your next practical afternoon.

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Arrange the apparatus for distillation. Distil off approximately 70% (by volume) of the ethanol-water mixture, cool the residue in ice and extract with 25 ml ether (separating funnel). Keep the aqueous layer. Return the aqueous layer to the reaction flask, acidify it to pH 1 with concentrated hydrochloric acid and reflux for 15 minutes (only start timing once the solution starts boiling). Allow the mixture to cool in an ice-water bath until crystallisation is complete (i.e. you have a reasonable amount of crystals) before filtering off the crude product under suction. Wash the crude product on the sinter with 25 ml distilled water and 25 ml light petroleum (60-80ºC), drying the product with suction after each washing. Record the mass of dry, crude material. Record the melting point of the crude product. (Set point = 139ºC). Recrystallize approximately 1 g from aqueous acetone. Record the melting point of the purified product (147 - 150°C). Run a TLC in a solution of Ether:Ethyl acetate (80 : 20), spotting the starting materials alongside your recrystallised product on the same plate. To prepare a spotting solution, dissolve a very small amount (a few small crystals) in 0.5 ml of acetone on a clean watch glass. Use a micropipette to apply this mixture to the TLC plate. To assess the success of the purification, run a TLC of the impure product alongside the recrystallised product on the same plate. View your plate under a UV lamp. Include the TLC plates in your report. Discuss the TLC results.

Pre-lab Questions 1. Research the potential toxicity of each of the reagents you will be using in this practical. 2. Crystalline compounds are easy to handle, their purity is readily assessed and they are often

easier to identify than liquids or oils. Crystals can be obtained in one of three ways: from the melted solid on cooling, by sublimation or crystallization from a supersaturated solution. The last method is by far the most common in the organic laboratory.

(a) Recrystallization is a method for purifying solid organic compounds. Describe the general

plan for the purification of an organic compound by recrystallization. Your answer must include a flow diagram of the recrystallization process. Clearly explain how the impurities are separated from the desired product. Bear in mind that certain impurities will be soluble and others insoluble in the solvent one uses for the recrystallization. (Note: certain authors use the terms crystallization and recrystallization interchangeably).

(b) What are the factors that one has to consider when choosing the ideal solvent system for a recrystallization? Describe how one tests the suitability of a chosen solvent. Suggest solvents for recrystallization of the most common classes of organic compounds, namely, hydrocarbons, ethers, halides, carbonyl compounds, alcohols, acids and salts.

(c) If a suitable recrystallization solvent cannot be found, then you may have to use a mixed solvent system. Describe how one performs a recrystallization using a mixed solvent system.

(d) In some cases the solution of your organic compound will be strongly coloured by impurities. This is not a problem provided that the coloured impurities remain in solution. Describe a method that serves to remove insoluble coloured impurities from your product.

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-20-

Experiment 6

Synthesis of 7,7-dichlorobicyclo[4.1.0]heptane – Phase transfer catalysis

________________________________________________________________________________

1 2

H

H

NaOH, H2O, CHCl3

[C6H5CH2N(CH2CH3)3]Cl Cl

ClH

H

In this practical a classical phase transfer catalytic reaction is demonstrated to generate a carbene. At the same time it illustrates the use of vacuum distillation.

Time Requirement: One afternoon

Procedure To a 100ml quickfit conical flask add 2g (0.025 mol) of cyclohexene, 10ml (0.13 mol) of chloroform, and 0.2g of benzyl triethylammonium chloride. Place 10ml of 50% aqueous sodium hydroxide in the addition funnel. Add a reflux condenser and a dropping funnel to the two neck flask. Add approximately 1ml of the aqueous sodium hydroxide solution from the addition funnel into the reaction flask. [Caution: Avoid skin contact with 50% aqueous NaOH. Wash any NaOH from your skin or clothes with copious amounts of water.] Warm the solution on a heater/stirrer unit and stir the solution to mix (use a magnetic stirrer). It is important to keep the two phases well mixed during the reaction. Over the next 20 minutes add 9 ml the sodium hydroxide in small portions, with stirring, to the refluxing reaction mixture. Continue to reflux the reaction mixture for 40 minutes after the addition is complete. Cool the solution and add slowly, with swirling, 15ml of a saturated brine solution and then 15ml of hexane to the reaction mixture. Transfer the mixture to a separating funnel. Separate and discard the lower aqueous layer. Wash the organic layer twice with 25ml portions of water, and dry the cloudy organic layer with anhydrous magnesium sulphate. Decant the organic layer off and remove the solvents from the dry organic layer using a rotary evaporator. Dispose the distillate in the waste container that is provided. Transfer the higher-boiling liquid residue to a small-scale distillation apparatus and distil the product. The product is distilled under reduced pressure (bp = 96oC at 35 Torr) or at atmospheric pressure (bp = 198oC with only slight decomposition). Weigh the purified product and calculate the percent yield. The collected product

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-22-

CH2 N CH2

CH2

CH2

CH3

CH3

CH3 ClOH

ClCH2 N CH2

CH2

CH2

CH3

CH3

CH3 OH

1 2 Note that complex 2 is transported from the water layer to the surface of the chloroform layer. The reaction can then proceed at the water/chloroform interface. The complex is also slightly soluble in the chloroform and will also react in the chloroform layer. The mechanism of carbine formation is:

OH

3 4

HCCl

ClCl SN2 Cl

CCl

H2O+ + Cl

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Appendix

Occupational Safety Information

________________________________________________________________________________ Please read the following sections containing vital safety information. Be aware of the potential hazards of each experiment and the procedures to adopt in the event of an accident. The best way to avoid accidents is to be well prepared for an experiment and to think about what you are doing at all times while conducting an experiment. ________________________________________________________________________________ EMPLOYEES’ DUTIES IN TERMS OF THE OCCUPATIONAL HEALTH AND SAFETY ACT NO 85 OF 1993 The Legislature has amended the Former Machinery and Occupational Safety Act No. 6 of 1983, by the new Act as mentioned above. The new Act imposes duties on the employer and the employee, and also imposes personal liability on the employee for non-compliance with the Act. Note that in the University context the new Act defines students as employees. Provisions in the Regulations Contained in the Act. General Administrative Regulations. Regulations 6 and 16. Regulation No 6: General Duties of Employees. 6. Subject to the provisions of Section 38(1) (m), (n) and (o) of the Act, and without derogating

from any other specific duty imposed on an employee by the Act or the regulations, every employee shall -

(a) carry out any lawful order given to him and shall obey the safety rules and procedures

laid down by his employer or by anyone authorised thereto by his employer, in accordance with or for the proper observance of the provisions of the Act or the regulations or in the interests of safety; and

(b) where a situation which is unsafe at or near his workplace comes to his attention, as

soon as possible report such situation to a safety representative or to his employer. Regulation No 16: Offences and Penalties. 16. Any person who - (a) contravenes or fails to comply with any provision of regulations .... 6 ..... (b) ........ shall be guilty of an offence and be liable on conviction to a fine not

exceeding R5 000 or to imprisonment for a period not exceeding six months and, in the case of a continuous offence, to an additional fine of R100 for each day on which the offence continues or to additional imprisonment of one day for each day on which the offence continues: Provided that the period of such additional imprisonment shall in no case exceed 90 days.

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THE OCCUPATIONAL HEALTH AND SAFETY ACT NO 85 OF 1993, PROVISIONS APPLICABLE TO “EMPLOYEE” Provisions in the Act. Sections 14, 15 and 38. Section 14: General Duties of Employees at Work. 14. Every employee shall at work - (a) take reasonable care for the health and safety of him-/herself and of other persons

who may be affected by acts or omissions; (b) as regards any duty or requirement imposed on his employer or any other person by

this Act, co-operate with such employer or person to enable that duty or requirement to be performed or complied with;

(c) carry out any lawful order given to him, and obey the health and safety rules and

procedures laid down by his employer or by anyone authorised thereto by his employer, in the interest of health or safety;

(d) if any situation which is unsafe or unhealthy comes to his attention, as soon as

practicable report such situation to a health and safety representative or to his employer; and

(e) if he is involved in any incident which may affect his health or which caused an injury

to himself, report such incident to his employer or to anyone authorised thereto by the employer, or to his health and safety representative, as soon as practicable but not later than the end of the particular shift during which the incident occurred, unless the circumstances were such that the reporting of the incident was not possible, in which case he shall report the incident as soon as practicable thereafter.

Section 15: Duty not to Interfere with, Damage or Misuse Things. 15. No person shall intentionally or recklessly interfere with, damage or misuse anything, which

is provided in the interest of health or safety. Section 38: Offences, Penalties and Special Orders of Court. 38 (1) Any person who - (a) contravenes or fails to comply with a provision of section ...... 14, 15 ...... ; (n) tampers with or misuses any safety equipment installed or provided to any person by

an employer or user; (o) fails to use any safety equipment at a workplace or in the course of his employment or

in connection with the use of plant or machinery, which was provided to him by an employer or such a user;

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(p) wilfully or recklessly does anything at a workplace or in connection with the use of

plant or machinery which threatens the health or safety of any person, shall be guilty of an offence and on conviction be liable to a fine not exceeding R50 000 or to imprisonment for a period not exceeding one year or to both such fine and such imprisonment.

Regulation No 10: Offences and Penalties. (1) 10. Any person who contravenes or fails to comply with a provision of regulation ....3, 4 .......

shall be guilty of an offence and liable on conviction to a fine not exceeding R5 000 or to imprisonment for a period not exceeding six months, and, in the case of a continuous offence, with an additional fine of R100 or additional imprisonment of one day for each day on which an offence continues: Provided that the period of such additional imprisonment shall in no case exceed 90 days.

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Safety Precautions and Regulations Safety in the laboratory is not a matter that can be effected solely by the application of a number of hard-and-fast rules; it also requires the co-operation and interest of all staff members, demonstrators and students. Common sense, recognition of potential hazards, and confidence in reacting in a situation are essential to ensure the successful application of safety measures.

Hazards and Precautions It is essential that you read through this section to ensure your own safety and good health. (1) All accidents must be reported immediately to the staff member in charge or, in his/her

absence, to a demonstrator. (2) If, as a result of an accident, you need treatment, the first aid facilities in the laboratory may

be used. In more serious cases, the CAMPUS HEALTH CENTER (telephone 5208) should be called.

(3) Be aware of the location of the nearest fire extinguisher, eyewash, fire blanket and first aid

kit, and know how to use them. (4) WASTE DISPOSAL: No liquids should be put into waste bins. Never pour organic

solvents (most of them flammable) down the drain. They may collect in the pipes (they either float on or sink in water), forming a potential explosive hazard. Pour all organic solvents into the residue bottles provided in the laboratory.

(5) Materials should never be put into an unlabelled container. (6) TOXIC MATERIALS:

Metals. The use of mercury is commonplace in a laboratory and safety precautions with this hazardous material should never be neglected, as its vapour is extremely toxic. Compounds of heavy metals (lead, cadmium, mercury, bismuth, and silver) and many transition metals (chromium, manganese, nickel, rhodium, palladium, ruthenium, osmium, molybdenum, and tungsten) should be viewed as hazardous. They typically lead to irreversible nerve cell damage, protein denaturation, and DNA mutation, the latter leading to cancer.

Organic Compounds. The vapours of many common solvents such as benzene, carbon disulfide, acetone and ethers are toxic and in some cases explosive. These vapours must be kept down to a minimum either by working in the fume hoods (where the vapours will be pumped out) or in a well-ventilated room. Benzene is highly flammable and forms an explosive mixture with air. If swallowed or breathed for any length of time it may be lethal. Carbon disulfide is so flammable that it can be ignited by a steam pipe. Ethers, in particular the common solvent diethyl ether, form explosive mixtures with air and may form explosive peroxides on storing.

(7) EYES: Injury to eyes is a very common laboratory hazard. THE WEARING OF

SAFETY GLASSES, WHICH IS OBLIGATORY, IS DESIGNED TO PREVENT FLYING OBJECTS OR SPLASHING LIQUIDS FROM INJURING THE EYE, OR

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TO PREVENT THE EFFECT OF ULTRAVIOLET RADIATION. SAFETY GLASSES MUST BE WORN AT ALL TIMES WHILE YOU ARE AT THE BENCH. You may be fined up to R 10.00 each time for not wearing your glasses!

(8) ACID SPLASHES: Acid or alkali splashes on the skin and clothing should immediately be

washed with large quantities of water. (9) FLAMES: When clothing or a hand covered in a flammable liquid catches alight, remember

that smothering the flames is a better way of putting out the fire than dousing with water. Throw a laboratory coat or other clothing over the flames.

(10) WASH BOTTLES: These should never be misused. The wash bottle may not contain

innocent water but a dangerous corrosive liquid, e.g., HCl. (11) PIPETTING DANGEROUS LIQUIDS: Never use your mouth to pipette liquids, always

use a pro-pipette. (12) DILUTING CONCENTRATED ACID: Always pour a concentrated ACID solution

INTO WATER slowly, with continuous stirring. (13) SMELLING VAPOURS: Smell a substance by WAFTING its odour gently towards

your face, wearing safety glasses. (14) HEATING TEST TUBES: (i) The test tube must NOT be more that 1/4 full. (ii) Set

the flame on LOW (± 4 cm high). (iii) Point it away from yourself and pass it gently back and forward through the flame. (iv) Never point the tube at your neighbour. (v) NEVER KEEP IT STATIONARY IN THE FLAME ! the liquid will boil violently and splash out of the tube.

(15) NEVER HEAT A GRADUATED (MEASURING) CYLINDER ! it will crack since it is made of soda glass, not Pyrex.

(16) NEVER HEAT A VOLUMETRIC FLASK ! the flask will distort and its calibrated volume will be rendered inaccurate.

(17) BE SENSIBLE, NEAT AND TIDY! It is important that you are at all times aware of the

dangers in the laboratory and that you think of these while you do your experiments. (i) Always use the correct equipment for the job at hand and ensure adequate support

(e.g. clamping) for all parts of the apparatus. (ii) Be careful not to contaminate reagents ! they may be incompatible and react

explosively! (iii) Return all reagents to where you found them. Other students will also need them.

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Guidelines for Writing Practical Reports This following information is intended to provide guidelines that will help you to write organic chemistry practical reports that represent scholarly work of a high standard. Students often make significant mistakes again and again merely because they know no better. This document is intended to pinpoint some of these common errors and ways to correct them. These guidelines can make the transition from practical ‘write-ups’ to project reports and even theses a smooth one.

Use these guidelines to help you decide content and presentation of practical reports. You should include all the following sections in your practical report in the order given. A model report consistent with these guidelines is included in this handout. It is strongly recommended that you read the model report as well as Chapter 6 (pp. 407-428) of Harwood and Moody before you begin writing your first practical report.

Title This should be explanatory and descriptive, but should also be short and concise.

Introduction Assume the reader has very little or no background knowledge of the organic chemistry contained in the practical. You should therefore introduce the reader to the subject matter (theory) of the practical work e.g. the type of reactions, explain the usefulness of this type of reaction, functional group, product etc. to organic chemistry. The introduction should also contain a concise account of the theory relevant to the practical, e.g. if you are doing an aldol condensation then you should discuss the general reaction and its usefulness (advantages and limitations) in organic chemistry. Illustrate the ideas you are conveying with diagrams and reaction schemes (see the model report). This section should conclude with a clear statement of the aim(s) (purpose and objectives) of the experiment. Give a reaction scheme to illustrate the aims.

Results Results should include percentage yield, melting point or boiling point (whichever is appropriate), and a physical description of the product(s). The latter descriptions should be in terms of the physical state of the product i.e. crystalline, solid, gum, oil, liquid; the colour of the product e.g. colourless, white, yellow, orange etc. Crystalline samples can be classified further according to the shape of the crystals e.g. amorphous (lacking a well-defined shape), plates or needle-like. In the chemical literature one often reads descriptions like white needle-like crystals, viscous yellow liquid, pale yellow gum, or colourless amorphous solid. Include thin layer chromatography (TLC) results (Rf values and solvent systems). Calculations must be written out in full. Units must be used throughout the results section and must appear in your final answer. Your final answer should contain the same number of significant figures as the value/quantity in the calculation possessing the smallest number of significant figures. For example: 0.0360 mol and 5.0010 g contain three and five significant figures respectively. Therefore if you use these values in a calculation you would quote your final answer to three significant figures. Percentage yields should always be quoted to two significant figures e.g. 63%, not 62.7%. It is preferable to minimise the number of decimal places in a value. For example, 0.00365 mol should be written as 3.65 mmol. Volumes must never be quoted to more than two decimal places, e.g. 12.83 ml, not 12.835 ml. When calculating percentage yields of products always include calculations of the number of moles of each reagent (ignore solvents) and then taking the stoichiometric relationship between the reagents/starting materials of the reaction into

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account, determine which is the limiting reagent (see the model report). The theoretical amount of product produced is determined (limited) by the amount of the limiting reagent. When the limiting reagent is used up, the reaction necessarily stops no matter how much of the other reagents remain. Therefore a little thought is necessary to determine which reagents are being used in excess in the reaction and which is the limiting reagent before calculating the theoretical amount of product. Always state which is the limiting reagent. The actual yield is the ratio of the amount of product to the limiting reagent obtained after isolation and purification (read pages 415-416 of Harwood and Moody). Percentage yield = [amount of pure product (moles)/theoretical amount of product (moles)] x 100

Melting points should always be reported as a temperature range from when the sample started melting till the entire sample had melted, e.g. mp 89.5-91.0°C. If you are working with a known compound then you should always compare your melting point with a literature value, e.g. mp. 89.5-91.0°C (lit.ref. number 90.5-91.0°C.). Temperatures must never be quoted to more than one decimal place, e.g. 90.5°C, not 90.51°C. Boiling points should be reported in the same manner. Boiling points should be accompanied by the pressure at which the distillation was carried out. The vacuum pressure in the Mudie laboratory is approximately 20 mmHg. Each literature citation in the body of the text must be marked by a numerical superscript and the references themselves grouped together in numerical order at the end of the report. Thus the superscripted numbers refer the reader to the list of references at the end of the report, i.e. these superscripted numbers should correlate with the numbers assigned to the full references given at the end of the practical report. References should be numbered in sequence throughout the report (see the referencing system used in the model report). Assign the 1H nuclear magnetic resonance (NMR) and infrared (IR) spectra in the results section.

Discussion This is perhaps the most important part of the write-up. It should be thorough but succinct (short and to the point) and it should follow the sequence of your results but not be a re-statement of them. Your analysis of the results should be one of assessment of their significance, of their accuracy and of their importance to the theory. State whether you obtained the desired product, quote the percentage yield and comment on the yield you obtained. You must compare your melting (boiling) points with literature values. Remember, agreement between these data and literature values or lack thereof allows you to make statements regarding the purity of your product. The presence of impurities in your sample tends to lower melting (boiling) points. Thin layer chromatography (TLC) is also a powerful method for assessing the purity of a product. Therefore you should also discuss the implications of your TLC results. Discuss significant experimental procedures, e.g. distillation, recrystallization etc. and describe the usefulness of these experimental techniques. Show the mechanism of the reaction carried out in diagrammatic form. In addition you have to describe the mechanism in the text (see the model report). This is intended for you to gain fluency in the language of organic chemistry. You should describe the reactions performed and any unusual instrument (e.g. polarimeter), experimental procedure or apparatus (e.g. Dean-Stark water separator) and describe its usefulness. If the reaction had to be performed under anhydrous conditions explain why this was necessary. Also record any observations (e.g. colour changes, temperature fluctuations, emulsions etc.) made during the experiment. Only reasonable conclusions should be drawn, with experimental support being given at all times. Suggest reasons for low yields of product(s); give specific reasons and do not attribute poor yields to ‘human error’. Explanations for reactions that did not go as planned are just as important as those for ‘successful’ reactions. You should also discuss your reasons for any deviation from the original experimental procedure. Suggest an alternative method(s) to synthesise the product and compare this method with the one

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you used in the practical. This comparison can be in terms of overall yield of product, number of steps to reach the target molecule, availability and cost of starting materials etc.

Conclusion This section should be a brief recapitulation of the most significant results of your practical work. Always think of your conclusion in relation to your stated aims. Therefore the opening sentence of the conclusion should state whether or not you prepared the desired product (see the model report). You should make a final statement concerning the purity of your product as evidenced by TLC and melting (boiling) point results.

Experimental This section should contain complete details of the laboratory operations that you carried out. It should be written in the past tense, passive voice (e.g. “the crude product was distilled”) and should be consistent in style throughout. It is especially important to consult the model report and conform to the accepted style for reporting your experimental procedure. Do not copy the experimental method verbatim from the practical manual. Always specify the mass or volume and number of moles of a reagent in parentheses after the name of the reagent. You must use systematic (IUPAC) nomenclature to name the products you prepare. Always ask yourself the question: If somebody were to follow my experimental procedure exactly, would they get exactly the same results I did?

References You must always record in your report all references that you used to perform the experiment and write the practical report. Of particular importance are the literature sources of the physical properties of known compounds. The observed value must never be simply stated without including the literature data for comparison. At points in the write-up where you have drawn on a specific authority, e.g. the ‘textbook value’ of some physical property, cites the reference using a superscripted number at the point you use it. References should be indicated in the main body of the text using numerical superscripts and then listed in numerical order at the end of the report. For purposes of consistency it is preferable if everybody adopts the following referencing styles. Citing a book: The following example illustrates the preferred style for referencing a book: L. M. Harwood and C. J. Moody, Experimental Organic Chemistry: Principles and Practice, Blackwell Scientific Publications, Oxford, 1989, 415-418. Note that both the publishing company and the city where the book was published are included. You should underline the title of the book if you are writing your report by hand. If there is more than one edition of the book then you need to specify the edition from which you obtained information. You insert the edition number (e.g. 2nd edition, 3rd edition etc.) between the title and the publisher. Use inclusive pagination i.e. state the first and last page number of the article or chapter.

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Citing a journal article: The following example illustrates the format for citing a journal article adopted by the Royal Society of Chemistry in Britain:

G. Pattenden and G. M. Robertson, Tetrahedron Lett., 1986, 27, 399-402.

General Comments You should write straightforward, legible prose using grammatically correct sentences, not notes. Use the third person, passive past tense. In other words, “the experiment was carried out” and not “I carried out the experiment”. Spelling mistakes, untidy-handwriting and illegibility create a very bad impression and detract from the scientific content of your report. It is preferable to type your reports using a word processing package. If you decide to do so then fully justify the text (i.e. straight right side margin). Do a spell check on your report when finished. Most articles in journals are written in very plain style. It is a challenge to avoid writing in a boring way, but it is worth trying. You can make the report more interesting by judicious choice of bold, italics and underline functions. Spread your work out; it always improves presentation. Mark each section clearly with bold headings. Remember that ‘data’ is plural. If you use a book or a journal article do not waste your time (and our time) by copying out whole paragraphs from it; rather give concise, relevant information only and always supply the reference. Read your practical write-up through when you have finished writing it to check for errors. Reflect that if you find your report difficult to read, then the examiner is likely to find it doubly so!

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Model Report ________________________________________________________________________________

Preparation of E-1,2-diphenylethene (trans-Stilbene)

Introduction The Wittig reaction dates back to 1953 when Wittig and Geissler1 found that the reaction of benzophenone (4) with methylenetriphenylphosphorane (3) gave 1,1-diphenylethylene (5) and triphenylphosphine oxide (6) in almost quantitative yield; the phosphorane had been prepared from triphenylmethylphosphonium bromide (1) and phenyllithium (2) (Scheme 1). This discovery led in the following years to the development of a new method for the synthesis of olefins from aldehydes and ketones which, under the name Wittig reaction, soon attained importance in preparative organic chemistry.

CH3Ph3P n +Br_

+ LiPh CH2Ph3P + PhH + LiBr1 2 3

CH2Ph3P3

+ Ph2C O4

Ph2C CH2

5OPh3P

6+

Scheme 1

The Wittig reaction is useful because it constitutes another method for forming carbon-carbon bonds but it is particularly important because it gives alkenes in which there is no ambiguity about the position of the alkene double bond; it is a completely regioselective reaction2 (Scheme 2).

OCH2Ph3P

+ _+

CH2

+ OPh3P

7 Scheme 2

The Wittig reaction is particularly useful for the synthesis of alkenes that are difficult to obtain by other means. For example, an attempt to synthesise the methylenecyclohexane product (7) by the following route gives the thermodynamically more stable alkene, namely, 1-methyl-1-cyclohexene (8) (Scheme 3)2.

O+ CH3 MgBr H3O+

OH CH3CH3

H3O+ + H2Odehydration step

7

CH2

little or noobserved

8

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Scheme 3 Another advantage of the Wittig reaction is that it is carried out in alkaline medium and usually under very mild conditions. Consequently it is the only method available for the preparation of sensitive olefins such as carotenoids, methylene steroids, and other natural products1. The aim of this experiment was to employ the Wittig reaction to synthesise 1,2-diphenylethene (13) from benzaldehyde (12) and a phosphorus ylid. The phosphorus ylid was prepared from benzyl bromide (9) and triphenylphosphine (10) (Scheme 4).

CH2PhPh3Pn Br

11

PhCH2Br + Ph3P9 10

1. NaOH2. PhCHO

12PhCH CHPh

13OPh3P +

Scheme 4

As can be seen in Scheme 4 the preparation of 1,2-diphenylethene (13) is a two step process. The first step involves the preparation of the phosphorus ylid. This is achieved by reacting benzyl bromide with triphenylphosphine. The intermediate triphenylphosphonium bromide salt (11) is deprotonated using sodium hydroxide under phase transfer conditions to form the phosphorus ylid. The phosphorus ylid is isolated prior to reaction with benzaldehyde. This Wittig reaction is not totally stereoselective (i.e. a mixture of E and Z isomers is formed) but treatment of the product mixture with a trace of iodine causes isomerization of the Z-1,2-diphenylethene to the sterically preferred E-isomer3.

Results Preparation of benzyltriphenylphosphonium bromide

Br

C 7H 7Br

+P

C 15H 15P

A cetone∆

P+

Br_

C 25H 22BrP

Benzyl bromide Triphenylphosphine volume: 2.40 ml mass: 5.20 g density: 1.438 g.ml-1 MW: 262.29 g.mol-1 MW: 171.04 g.mol-1 amount: 19.8 mmol amount: 20.2 mmol melting point: 79-81°C

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Benzyl bromide and triphenylphosphine react in a 1:1 stoichiometric ratio therefore triphenylphosphine is clearly the limiting reagent in this reaction. Therefore the maximum amount of benzyltriphenylphosphonium bromide that can be formed is 19.8 mmol. Benzyltriphenylphosphonium bromide mass: 5.49 g MW: 433.33 g.mol-1 amount: 12.7 mmol melting point: 294.0-295.5°C Percentage yield = actual amount of product/theoretical amount of product x 100 = 12.7 mmol/19.8 mmol x 100 = 64% Wittig reaction between benzyltriphenylphosphonium bromide and benzaldehyde

PPh3Phn

PPh3Phn NaOH

H2O+ Br_

PPh3Phn

+ H

O

C7H6ONaOH / H2O

CH2Cl2

C14H12

Benzyltriphenylphosphonium bromide Benzaldehyde mass: 5.34 g volume: 2.00 ml MW: 433.33 g.mol-1 density: 1.044 g.ml-1 amount: 12.3 mmol MW: 106.12 g.mol-1 amount: 19.7 mmol Benzyltriphenylphosphonium bromide and benzaldehyde react in a 1:1 stoichiometric ratio therefore benzyltriphenylphosphonium bromide is clearly the limiting reagent in this reaction. Therefore the maximum amount of E-1,2-diphenylethene that can be formed is 12.3 mmol. E-1,2-Diphenylethene mass: 0.62 g MW: 180.25 g.mol-1 amount: 3.44 mmol melting point: 122.5-123.0°C Percentage yield = actual amount of product/theoretical amount of product x 100 = 3.44 mmol/12.3 mmol x 100 = 28%

Discussion Stilbene was prepared in a two step process from benzyl bromide and benzaldehyde. The first step involved the nucleophilic substitution of the bromine atom of benzyl bromide (9) with triphenylphosphine (10) (Scheme 5). This reaction was straightforward although caution had to exercise working with the lachrymator benzyl bromide. Benzyltriphenylphosphonium bromide (14) was obtained in a satisfactory 64% yield. A melting point of 294-295°C was obtained which

compares favourably with the literature value 295-298°C5(a). This salt was then treated with an aqueous sodium hydroxide solution to effect deprotonation of the salt at the carbon atom alpha to the phosphorus atom to form the active ylid (15). The ylid once

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generated was reacted in situ with benzaldehyde (12). Carbon-carbon bond formation was effected by attack of the ylid carbanion on the electrophilic carbonyl carbon atom of benzaldehyde (12). This reaction forms a charged intermediate known as a dipolar betaine (16). The negatively charged oxygen atom then forms a bond with the electrophilic phosphorus atom to form the neutral heterocyclic oxaphosphetane intermediate (17). This compound is unstable and a cyclic movement of electrons serves to form 1,2-diphenylethene (13) and the by-product triphenylphosphine oxide (18). The thermodynamic driving force for the latter reaction is the tremendously strong phosphorus-oxygen double bond that is formed. 1,2-Diphenylethene was obtained in a low 28%

yield. More encouraging was the fact that it had a melting point 122.5-123.0°C that is in very close agreement with the literature value for E-1,2-diphenylethene 122-124°C5(b).

BrH H

+ PPh3Acetone D:

H HPPh3+Br_

NaOHCH2Cl2 / H20

PPh3H

+

_H

O

C - C bondFormation

OPPh3

HH Ph

Ph....

.._

+

unstable intermediate

O

P

HH Ph

PhPh

Ph

Ph

H

H

+OP PhPhPh

+..

..

..

..

16 12 15

17

9 10 14

Scheme 5 As was mentioned in the introduction it is known that this Wittig reaction is not totally stereoselective. Presumably the stilbene that was prepared exists as a mixture of E and Z isomers. Isomerization of the Z-isomer to the E-isomer can be brought about by treatment of the product mixture with a trace of iodine. However this procedure was not carried out. Water and dichloromethane were added to aid separation of the two layers in the separating funnel during the isolation of diphenylethene. It is usually the case when working with mixtures of aqueous

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solutions and chlorinated solvents such as dichloromethane that the aqueous phase is less dense and as a result constitutes the upper layer. However the sodium hydroxide solution used in this experiment was so concentrated that its density was greater than that of the organic phase and thus it constituted the lower layer in the separation. The dichloromethane solution was treated with hot petroleum ether to precipitate the by-product, triphenylphosphine oxide (Ph3P=O). The product stilbene is sufficiently non-polar to remain dissolved and it was thus possible to separate the two organic products by filtering off the Ph3PO and allowing the organic solution to cool whereupon the desired product, stilbene, crystallised out. Unfortunately a significant amount of product was lost when adding the hot petroleum ether to the dichloromethane solution. The low yield of stilbene is largely attributable to this spillage. Using the Wittig reaction to prepare stilbene is almost certainly easier (fewer synthetic steps) and less sensitive to atmospheric moisture and oxygen than preparing stilbene by means of a Grignard reaction between benzyl magnesium bromide and benzaldehyde. Grignard reagents are very labile and therefore air and moisture sensitive. In addition a second step would be needed to dehydrate the resulting alcohol to form the alkene (see Scheme 3). One could also conceive preparing stilbene using carbonyl condensation chemistry, for example via the Knoevenagel reaction4 (Scheme 6).

CO2EtH H

NaOHdeprotonation

H H

O

.._

[- H20]Ph

O

HEtO2CPh

_Na+

H3O+

Heatdehydration

O OEtNaOH / H2OHeatHydrolysis of Ester

O ONa+

H3O+

HeatDecarboxylation

Scheme 6

Conclusion Stilbene was prepared in two steps in 11% overall yield by means of a Wittig reaction between benzyl bromide and benzaldehyde. This low yield is certainly not a poor reflection on the Wittig reaction. Exercising greater care during the isolation of the stilbene would undoubtedly improve the yield of the product. Isomerization of the small amount of Z-alkene to the thermodynamically more stable E-isomer would be easy enough to achieve by treating the reaction mixture with a trace of

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molecular iodine3. The product was shown to be pure after recrystallization by a single spot present on a thin layer chromatogram. There was close agreement between the recorded melting points of the products and the corresponding literature values.

Experimental Preparation of benzyltriphenylphosphonium bromide3 Benzyl bromide (2.40 ml, 20.2 mmol) was added dropwise to a solution of triphenylphosphine (5.20 g, 19.8 mmol) in acetone (60 ml). The resulting solution was stirred under reflux (with a drying tube) for 45 min. The solution was cooled to 0°C and the resulting precipitate was filtered off and washed with diethyl ether (2 x 20 ml) to afford benzyltriphenylphosphonium bromide as a fine white solid (5.49 g, 12.7 mmol, 63%; m.p. 294.0-295.0°C, lit.5(a) 295-298°C). Preparation of E-1,2-diphenylethene3 Sodium hydroxide (50 g) was dissolved in distilled water (75 ml). Benzaldehyde (5.00 ml) was treated with aqueous potassium carbonate (10%, 30 ml). The resulting mixture was stirred vigorously. The resulting solution was decanted into a large test tube and the layers allowed to separate. Benzyltriphenylphosphonium bromide (5.34 g, 12.3 mmol) was added to a solution of benzaldehyde (2.00 ml, 19.7 mmol) and dichloromethane (15 ml) in the sodium hydroxide solution prepared above. The Erlenmeyer flask was plugged with cotton wool to prevent contamination and spillage and stirred vigorously for 30 min. The resulting mixture was diluted with distilled water (15 ml) and extracted with dichloromethane (2 x 20 ml). The combined organic extracts were dried (MgSO4) and filtered. The solvent was evaporated until a volume of ca. 10 ml remained and then the resulting mixture was triturated with hot petroleum ether (75 ml). This caused the precipitation of a white solid, triphenylphosphine oxide (2.20 g, 7.91 mmol) which was removed by filtration. The filtrate was left at room temperature overnight and stilbene was obtained as white, needle-like crystals (0.62 g, 3.44 mmol, 17%; m.p. 122.5-123.0°C, lit.5(b) 122-124°C).

References 1. G. Wittig and B. Geisller, Annalen, 1953, 44, 580. 2. G. M. Loudon, Organic Chemistry, 2nd edition, Benjamin/Cummings, Menlo Park, 1988, 800-

803. 3. L. M. Harwood and C. J. Moody, Experimental Organic Chemistry: Principles and Practice,

Blackwell Scientific Publications, Oxford, 1989, 585-588. 4. J. McMurry, Organic Chemistry, 2nd edition, Brooks/Cole, Pacific Grove, 1988, 832-833. 5. (a) Aldrich Catalogue Handbook of Fine Chemicals, Midrand, 1996-1997, 165; (b) Aldrich

Catalogue Handbook of Fine Chemicals, Midrand, 1996-1997, 1348.

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Crystallisation and what to do if no crystals are formed

Having filtered your hot solution into a suitable container, cover the flask with a watch glass to prevent contamination by atmospheric dust, and then set it aside so that the solution can cool slowly. The rate of cooling determines the size of crystals, rapid cooling favouring the formation of lots of small crystals, and slow cooling encouraging the growth of fewer, but much larger, crystals. A convenient compromise between speed of crystallisation and crystal quality is to allow the hot solution to cool to room temperature by placing the flask on a surface such as glass or cork that dies not conduct the heat away too quickly. The rate of crystallisation is usually greatest at about 50°C below the melting point of the substance, and maximum formation of crystals occurs at about 100°C below the melting point. Once the crystals have formed, it is usually a good idea to cool the solution from room temperature to about 0°C by placing the flask in an ice bath. This will ensure that the maximum amount of crystals is obtained. It is not usually good practice to cool the solution below 0°C because this results in condensation of water vapour into the solution unless special precautions are taken. What do you do when no crystallisation occurs after cooling the solution to room temperature? You should attempt to induce crystallisation by one of the following methods. Add a seed crystal, which was saved from the original mixture before dissolution. This will provide a nucleus on which other crystals can grow. If this fails, try scratching the side of the flask with a glass rod. This is thought to produce micro-fragments of glass which then serve as nuclei to induce crystallisation. If this fails, try cooling the flask in an acetone-solid CO2 bath, and then scratch the side of the flask as it warms to room temperature. If the substance still refuses to crystallise, it probably means that you have too much solvent; the excess solvent should be boiled off (hood - check for flames in the vicinity), and the reduced volume of solution should be set aside again until crystallisation occurs. Another problem that may be encountered in crystallisation is the separation of the substance as an oil rather than as crystals. This is known as oiling out, and usually occurs when the compound is very impure or when it has a melting point that is lower than the boiling point of the solvent. Even if the oil eventually solidifies, the compound will not be pure, and the material should be redissolved by heating the solution. You may need to add a little more solvent at this stage, or more good solvent if mixed solvents are being used. Indeed, crystallisation from a slightly more dilute solution may prevent oiling out. Slower cooling favours the formation of crystals rather than oils. If the compound completely refuses to crystallise, the chances are that it is too impure, and it should be purified by some other means such as chromatography.

University of KwaZulu-Natal

School of Chemistry & Physics (Durban)

CHEM 320

Practical Manual