Experiment for drug synthesis reaction

Experiments for Drug Synthesis Reaction are a compulsory course . It is the purpose to develop elementary technical ability of experimental synthesis for students.

The experiment for drug synthesis is a compulsory specialized course offered by  institutesand together with the reaction of drug synthesis .

The aim of this teaching material is to give undergraduates some practice in the experiments of drug synthesis, familiarize with and mastering the basic operation and influential factors of various typical unit reaction, training student’s working style and scientific attitude to combine theory with practice.

According to the requirements included the teaching program, 20 pharmaceuticals synthesis experiments was in the teaching material, including the common unit reaction approximately. Every experiment needs about 6 teaching hours. During the teaching course, the teacher can select the specific experiments on the basis of the teaching hours. In order to attract the students interest and save the expenditure, the textbook has selected some experiments, which are connected with each other, that is, the products of the former experiment will be used as the raw material of the next experiment. For the sake of enhancing the students specialized English level and the ability of reading specialized literature, the textbook is written in English.

On the account of hurry and the compilers limited level, there may be some errors in the book, and we will appreciate any comment or criticism made by readers.


 

Content

 

Chapter 1  Laboratory Notes  -------------------------------------------------------1

 

Chapter 2  Exercises on Basic Laboratory Operations----------------------------2

 

2.1 Apparatus for simple Distillation--------------------------------------------3

2.2 Vacuum distillation------------------------------------------------------------4

2.3 Refluxing-----------------------------------------------------------------------5

2.4 Gas Absorption Traps---------------------------------------------------------6

 

Chapter 3   General Remarks---------------------------------------------------------7

 

3.1  Preparation Before the laboratory-----------------------------------------7

3.2  Laboratory Directions-------------------------------------------------------8

3.3   In the laboratory------------------------------------------------------------9

 

Chapter 4   Experimental Parts -----------------------------------------------------11

Experiment 1  Preparation of Chalcone (Benzylideneacetophenone) ------11

Experiment 2  Preparation of Acetanilide---------------------------------------13

Experiment 3  Preparation of p-Nitro-acetanilide------------------------------15

Experiment 4  Preparation of 2,4-Dichloroacetanilide------------------------17

Experiment 5  Preparation of Furylacrylic acid (2-Furanacrylic acid) -----18

Experiment6 Preparation of tert-Butyl Chloride (Propane 2-chloro-2-methyl-) ------------------------------------------------------------------------20

Experiment 7  Preparation of n-Butyl Chloride (Butane, 1-chloro-)---------21

Experiment 8  Preparation of  Propanoyl Chloride---------------------------23

Experiment 9  Preparation of p-Nitro-benzoic acid (KMnO4)--------- ------25

Experiment 10  Preparation of p-Nitro-benzoic acid (Na2Cr2O7)- ----------26

Experiment 11  Preparation of Ethyl-4-nitro-benzoate------------------------28

Experiment 12  Preparation of Ethyl-4-amino-benzoate----------------------29

Experiment13  Preparation of Benzalaniline (Aniline, N-benzylidene-)----30

Experiment 14  Preparation of 4-Chloro-benzoic acid------------------------31

Experiment 15  Preparation of Di-phenyl carbinol (benzohydrol)------- ---32

Experiment 16  Preparation of Acetyl-salicylic acid---------------------------33

Experiment 17  Preparation of propiophenone---------------------------------35

Experiment 18  Preparation of acetophenone-----------------------------------37

Experiment 19  Preparation of m-Nirto-benzaldehyde------------------------39

Experiment 20  Preparation of p-Nitro-benzaldehyde-------------------------41

Experiment 21  Preparation of o-Chloro-toluene (Toluene, o-chloro-)------43

 

Chapter 5   Appendix-----------------------------------------------------------------46

 

5.1  Fire---------------------------------------------------------------------------46

5.2  Injuries and chemical burns-----------------------------------------------46

5.3  Cuts---------------------------------------------------------------------------47


 

Chapter 1   Laboratory Notes

 

All of the experiments are carried out on a scale that significantly reduces the hazards and the disposal problem. We should well aware of the fear many neophytes have of chemicals. Rather than hide the chemical hazards, the approach taken here is to try to identify them, especially those that students might not be aware of, and indicate how to cope with particular hazards and prevent them from becoming dangers.

  It is essential to have a suitable notebook in which to record directly the observations made during, and to assemble information that will aid in the performance of experiments. The use of spiral or loose-leaf notebooks for laboratory records is not satisfactory, and the recording of observations on loose sheets or scraps of paper is not permitted.

  Before you come to the laboratory, the following steps should be carried out:

 

1.1    Read the descriptive pages concerning the laboratory operations to be carried out (these are found immediately preceding each experiment). In your notebook, write a title and general statement of the process to be studied.

 

1.2    Read the laboratory directions for the entire experiment note particularly the     CAUTIONS and other warnings about handling materials, and think about the reasons for the procedure to be followed. In your notebook jot down any points that require special observation or reminders of specific details.

 

1.3    For each chemical to be used look up and record its properties and note any chemical or biological hazards it presents.

 

1.4    Write the names and formulas of the compounds to be used and, where chemical tests are to be made, write equations for the reactions.

 

Careful planning of laboratory work is essential. Effective use of laboratory time requires that you know in advance just what you are going to do in the laboratory. Instead of watching idly while a liquid is being heated for an hour or more, you can use periods when full attention is not required to conduct another experiment, to clean apparatus, or to prepare for subsequent work.

 

When you come to the laboratory, proceed as follows:

 

1.5   Arrange the apparatus for the experiment and secure the approval of the laboratory instructor for the setup.

 

1.6   Perform the experiment according to the laboratory directions and record observations directly in your notebook. When the exercise has been completed, dismantle the setup and immediately clean the glassware and apparatus.

 

After you have completed the laboratory and gone home.

 

1.7   Spend a few minutes to review what you have accomplished in the laboratory and reflect on how you could prepare better for the next laboratory period.

 

1.8   Fill out the report forms provided by the instructor.

 

1.9   Write answers to the questions assigned by the instructor. Make complete statements in answering the questions.

 

Chapter 2  Exercises on Basic Laboratory Operations

 

The first order of business is to check the equipment in your desk. After you have done so, the remainder of the period will be spent carrying out several very basic laboratory operations. These may seem trivial, but the point is to ensure that in the subsequent experiments you can focus on the new material.

The directions given here assume that you will be using an electrically heated mantle and controller. If you are not, small adjustments in the procedure will be required.

The main difficulty in using a heating mantle is its temperature lag. These devices require time to heat and cool; there is a natural (impatient) tendency to set the controller at too high a setting only to find that the flask is eventually overheated. It is a good practice to arrange the apparatus so that the heating mantle can be easily lowered or even removed if the situation calls for it.

 

2.1  Apparatus for simple Distillation

 

A simple distillation apparatus suitable for distillation of samples is shown in Figure 1.

 

         

Figure 1:  Apparatus for simple Distillation

 

The key part of this assembly is the distillation “head” shown in the center of the figure. This “head” is a single glass unit that contains a water-cooled condenser, an opening for a thermometer, and ground joints at both ends for attaching a boiling flask and receiver. A thermometer is held in place in the vertical arm of the distillation “head” by a special rubber connector at a height adjusted so that the top of the mercury bulb is even with the bottom of the opening of the side arm.

The distilled liquid is colleted in a clean, dry receiver, commonly a round-bottomed flask with its ground-glass joint mated to the lower joint of the distillation “head”. A distilling assembly must have an opening to the atmosphere to avoid development of a dangerously high pressure with the system when heat is applied. When a mated round-bottom flask is used as the receiver, the side arm on the distillation “head” becomes the opening, and this arm must not be sealed.

The distilling flask should be of such size that the material to be distilled occupies between one third and two third of the bulb. If the bulb is more than two-thirds filled, there is danger that some of the liquid may splash into the distillate. If the bulb is less than one-third filled, there will be an unnecessarily large loss resulting from the relatively large volume of vapor required to fill the flask. This loss is particularly serious with compounds of high molecular weight.

Whether a pure compound or a mixture is distilled, a small portion of liquid will always be left in the flask. The flask containing the material to be distilled should never be heated to dryness because the flask might crack.

Distillation procedure:

The proper method of carrying out a distillation is to supply just enough heat at the distilling flask so that the liquid distills regularly at a uniform rate. Insufficient supply of heat will stop the distillation temporarily, and the bulb of the thermometer will cool below the distilling temperature, resulting in erratic temperature readings. Overheating and unsteady application of heat can increase the opportunity for superheating the liquid and cause bumping. Even with proper heating, it is necessary to introduce one or two tiny boiling chips of a porous substance, or some other anti-bumping agent, into the liquid before heat is applied.

 

2.2  Vacuum distillation

 

Assembly for Distillation under diminished pressure An apparatus for moderate-scale vacuum distillation is shown in Figure 2. The purpose of the adapter is to reduce the chance of contamination of the distillation from frothing or violent bumping, both of which are more troublesome in vacuum distillation than in ordinary distillation. For very small-scale distillations, because one must minimize mechanical losses from holdup, the adapter left out and the sample is distilled slowly and carefully. The size of the boiler flask should be such that it is not quite half filled at the start of the distillation. It is preferable to use an oil bath or sand bath to ensure regular heating, but a heating mantle, used with care, will do the job. The bath temperature is usually 1525higher than that of the distilling liquid.

 

Figure 2.        Vacuum distillation

 

Boiling chips are frequently ineffective in vacuum distillation because of their limited air supply. Somewhat better are long wooden splints of the kind that can be purchased in any drugstore. These can be broken off to a size that will fit in the flask comfortably. The best procedure, although it is somewhat inconvenient, is to introduce a fine stream of air bubbles through a thin, flexible capillary tube. If the substance to be distilled is easily oxidized, argon or nitrogen should be substituted. A different approach that works quite well is to stir the boiling mixture rapidly with a magnetic stirrer.

 

2.3   Refluxing

 

In preparative organic work it is frequently necessary to maintain a reaction at an approximately constant temperature for a long period of time with a minimum of attention. The simplest procedure for reactions carried out in the solution is to boil the solution and condense the vapors so that they are return to the reaction flask (refluxing). The temperature in the flask remains nearly constant at approximately the boiling point of the solvent. This operation is so common and important that the principle and technique should be understood clearly

 

                      

Figure 3:         Reflux Assemblies

 

2.4    Gas Absorption Traps

 

In some organic preparations, noxious gases are liberated that must not be allowed to escape into the laboratory. Two common methods for trapping water-soluble gases are picture in Figure 4.

                  

Figure 4.     Gas Absorption Traps

 

The principal precaution to be observed in trapping gases by the inverted funnel method is to construct the apparatus so that a drop of pressure in the reaction flask will not suck, water back into water more than 1 or 2mm. If the possibility of sucking water back into the reaction flask poses a hazard, a safely flask should be connected between the reaction vessel and the trap.

 In the water-aspirator method, the flow of air sucked in by the aspirator is normally sufficient to overcome all but the most vigorous evolution of gas.

 

Chapter 3   General  Remarks

 

3.1  Preparation Before the laboratory

 

 For experiments dealing with syntheses and reactions, the advanced preparation of your notebook involves several in addition to those listed in section 12 for the exercises on separation and purification of organic compounds. You should review that material now.

The most important addition is a table of physical constants of the substances the manipulated. By collecting this information and having it available, you will be able to understand more readily the reasons for the particular procedure and will often be able to overcome independently and small difficulties that may arise in the course of the laboratory work. You should proceed in the following manner.

 

3.1.1 Read the descriptive pages concerning the laboratory operation to be carried out (these are found immediately preceding each experiment). In the notebook, write a title and general statement of the process to be studied.

 

3.1.2 Read the laboratory direction for the entire procedure and note particularly any cautions for handling materials.

To aid in understanding the reactions for the procedure, it is helpful to consult the textbook or lecture notes for a discussion of the particular class of compounds this is to be studied. Consideration should be given to important general principles, such as the law of mass action and the influence of solvents and catalysts on rate of reaction.

 

3.1.3 In your notebook, give a concise statement of the type of reaction that is to be carried out. Write balance equations using condensed structural formulas, for the main reaction or sequence of reactions involved in converting the starting materials to the final products. Along the reaction arrow indicate to the conditions used-temperature, solvent, catalyst (if any), and so forth.

 

3.1.4 Write balanced equations for significant side reactions that may divert an appreciable amount of the starting materials and lead to formulation of by-products that must be removed in the purification of the main product.

Write balanced equations for any test reactions that are used to test for completion of the reaction, to detect the presence of an impurity, to confirm the identity of the product by conversion to a derivative, and so on.

 

3.1.5  To make a table of the physical constants of all organic and inorganic substances that enter into the main and side reactions and produced in these reactions. The physical constants of common organic and inorganic compounds may be found in chemical handbooks.

Include in the table the weight (in grams) of each reactant and the number of moles, or fraction of a mole, actually used. From these data and the balanced equation for the main reaction, determine which starting material is the limiting factor and calculate the theoretical yield (in grams) based on this reactant.

For each of the reagents used and each of the products produced note any hazard that the material presents. The point here is both to provide the knowledge needed to perform the experiments in a prudent manner and to emphasize that one may not work with organic material in an innocent, mindless manner.

 

3.1.6  After you have prepared your notebook in accordance with the foregoing instruction, your instructor may ask to see it for preliminary approval before you start to perform the experiment. In certain experiments, you will be asked to arrange the apparatus for the experiment and have it approved by the instructor.

 

3.1.7 In laboratory work it is essential to make efficient use of the time assigned; you are expected to plan your laboratory schedule and to make preliminary preparations before coming to the laboratory.

Since many experiments require that the reactants be refluxed for several hours, you should plan to perform other laboratory work the operation of refluxing is being carried out.

 

3.2  Laboratory Directions

 

The laboratory directions given in this manual are deliberately detailed. In advanced work and research one frequently must follow directions that assume a general knowledge of manipulative technique and of the chemistry involved.

The ability to fill in experimental detail is an important part of being a good laboratory worker and you are advised, as you carry out the experiments in this manual, to ask yourself at each stage why a certain operation or reagent is used.

 

3.3   In the laboratory

 

Carry out the experiment according to the laboratory direction and promptly record your observations, in ink, directly in your notebook. Record the quantities of reagents such as addition and distillation. As you work, compare what you see happening with what you anticipated; record all discrepancies. Always observe and record the boiling point of a liquid preparation, and the melting point of a solid organic preparation, unless instructed not to for reasons of safety. Your instructor may also require that you obtain some spectroscopic proof of purity of your product such as an IR or NMR spectrum.

Record the actual yield and calculate the percentage yield as described in detail in the next section. Record any general observations and conclusions drawn from your experiment.

 

3.3.1  Calculation of Yields

 

The yield (sometimes called the actual yield) is the amount of the purified product actually obtained in the experiment. The theoretical yield (sometimes called the calculated yield) is the amount that could be obtained under theoretically ideal conditions; that is, the main reaction is assumed to proceed to completion without side reactions or mechanical losses, so that the starting materials are entirely converted into the desired product and no material is lost in isolation and purification.

The percentage yield (also called the percent yield) is obtained by comparing the actual yield with the theoretical yield, in the following manner.

 

                  Actual  yield

Percent yield  =                       × 100%

                Theoretical  yield

 

3.3.2   Samples and reports

 

At the conclusion of the experiment you will be required to submit the final substance prepared (along with samples of intermediates if a sequence of reactions was involved). Each preparation should be placed in an appropriate bottles for liquids) of suitable size, with the experiment number and the name of product, the melting or boiling point, as actually observed, your name, and the actual yield (in grams), and tare of the bottle included on the label, as follows.

Some form of report will also be required. At a minimum this could be your notebook with a final report page summarizing the observed and physical properties of the substance and giving the percentage yield. On the other hand, you could be asked to write a formal report that gives all of these data and discusses the chemistry involved.

Your instructor will examine your notebook (or report) and your product and may ask questions designed to test your knowledge of the fundamental principles involved in the experiment and your ability to make and apply generalizations of the chemistry. Your grade will depend on the quality and quantity of your product, your laboratory technique, and your notebook and report, as well as your understanding of the chemistry.


 

Chapter 4   Experimental Parts

 

Experiment 1   Preparation of Chalcone

                         (Benzylideneacetophenone)

 

[Experimental purpose]

 

Grasp Aldol condensation reaction mechanism and experimental process.

 

[Equation]

 

[Reagents]

 

Benzaldehyde            9.2g (0.09mol)

Acephenone             10.4g (0.09mol)

95% Alcohol             25ml

Sodium hydroxide        4.4g

 

[Procedure]

 

  A solution of 4.4g sodium hydroxide in 40ml of water, 25ml of 95 per cent alcohol and 10.4g of acetophenone are introduced into a 250ml three-necked flask which is supplied with an effective stirrer, a thermometer, a reflux condenser and a dropping funnel. The stirrer started and heal the solution to 20 on water bath, 9.2g of benzaldehyde is then added from the dropping funnel to the solution. The temperature of the mixture should be controlled between20 to 25. It is advantageous, though not essential, to inoculate the mixture with a little powdered benzalacetophenone after stirring for one-half hour. After 1.5 hours, the mixture becomes so thick that the stirring is no longer effective, and then filter on a large Buchner funnel, wash water until the washings are neutral to litmus. Dry in the air, the crude product weights about 13g. It can be purified by re-crystallization from 95 per cent alcohol and give light yellow material (m.p.55-56).

 

[Notes]

 

1.      If the temperature is too low, or the stirring too slow, the product separates as an oil, which later solidifies in large lumps. If the temperature is allowed to rise above 30, secondary reactions diminish both the yield and the purity of the product. The most favorable temperature is 25.

2.      In re-crystallizing benzalacetophenone, the alcohol should be saturated at 50o. If the solution is saturated above this temperature, the benzalacetophenone ends to separate as an oil. The solution should be allowed to cool gradually, and should finally be chilled in a freezing mixture.

 

 

[Methods of  Preparation]

 

  Benzalacetophenone can be prepared from benzaldehyde and acetophenone, by the use of either acid or alkaline condensing agents. The alkaline agents are superior and those generally used are a 30 per cent solution of sodium methoxide at low temperatures and alcoholic sodium hydroxide. Preliminary experiments showed that condensation with sodium methoxide requires a long time and gives a product  which is difficult to handle in large quantities.


Experiment 2   Preparation of Acetanilide

 

[Experimental Purpose]

 

To Understand acetylating agent and acetylation

 

[Equation]

 

 

[Reagents]

 

 Acetic anhydride       14ml

 Aniline               10ml

 Water                30ml

 

[Procedure]

 

  Place 10ml of aniline and 30ml of water in a 250ml three-necked equipped with a strirrer, thermometer, condenser and a dropping funnel. Stir the solution and drop in 14ml of acetic anhydride while the temperature is controlled below 40. After all the acetic anhydride has been added, stir further 30 minutes at room temperature and then allow to stand for 1 hour. Filter with suction, the residue is washed with cold water until free from acids (test the wash water) and drain well. Dry the crystals and weigh them.

 

[Notes]

 

1.      Because the product acetanilide is insoluble in water, it crystallizes out as the reaction proceeds. It is true that acetic anhydride reacts with water to yield acetic acid. However, the reaction with aniline is much more rapid than that with water because of the greater nucleophilicity of nitrogen as compared to oxygen. Nevertheless, you must make add acetate as soon as the anhydride dissolves in the reaction mixture.

2.      It is not uncommon for aniline to have decomposed somewhat on the shelf, yielding a dark colored impurity which you must remove or it will discolor the final product crystals. Adsorption of the impurity on decolorizing charcoal is effective.

 

[Questions]

 

1.      What should be done if the acetanilide is colored?

2.      why did wash with cold water until free from acids?


Experiment 3   Preparation of p-Nitro-acetanilide

 

[Experimental purpose]

 

 To understand nitrating agent, the ratio of nitrate isomeride and methods of separation

 

[Equation]

 

        

 

[Reagents]

 

         Acetanilide                      13.5g

         Glacial acetic acid                13.5ml

         Concentrated sulfuric acid           33ml

         Concentrated nitric acid (6568%)   6.9ml

         Alcohol (95%)                   130ml

Ice                             130g

 

[Procedure]

 

  Add 13.5g of finely powdered, dry acetanilide to 13.5ml of glacial acetic acid contained in a 250ml three-necked flask which is fitted with a thermometer, a mechanical stirrer and a dropping funnel. Introduce into the well-stirred mixture 33ml of concentrated sulfuric acid (note 1). The mixture becomes warm and a clear solution results. Surround the flash with a freezing mixture of ice and salt, and stir the solution mechanically. Support a dropping funnel containing a cold mixture of 6.9ml of concentrated nitric acid and 6ml concentrated sulfuric acid, over the beaker (note 2). When the temperature of the solution to 02, run in the acid mixture gradually while the temperature is maintained below 10. After all the mixed acid has been added, remove the flask from the freezing mixture, and allow it to stand at room temperature for 1hr. Pour the reaction mixture onto 130g of crushed ice, where by the crude nitro-acetanilide is at once precipitated. Allow to stand for 15minutess, filler with suction on a Buchner funnel, wash it thoroughly with cold water until free from acids (test the wash water), and drain well. Re-crystallize the pale yellow product from alcohol (of industrial spirit), filter at the pump, wash with a little cold alcohol and dry in the air upon filter paper (the yellow o-nitro-acetanilide remains in the filtrate). They yield of p-nitro-acetanilide, a colorless, crystalline solid of m.p.214 is 911g.

 

[Notes]

 

1.      When concentrated sulfuric acid is added into mixture, it will liberate a vast amount of heat. So the sulfuric acid must be added slowly to mixture.

2.      When we mix nitric acid with sulfuric acid, we must add sulfuric acid into nitric acid.

3.      In this reaction the temperature is kept below 10. The nitro-sulfuric acid must be added slowly to the acetanilide.

4.      In this reaction, therefore, the amino function must be protected from oxidation. The acetyl group function as a protecting group. A protecting group protects some part of a molecule from its environment and must be easy to put on the molecule, stable under the reaction conditions from which it protects the molecule, and easy to remove.

 

[Questions]

 

1.      What is the purpose of the glacial acetic acid?

2.      What is the other method to isolate o-nitro-acetanilide and p-nitro-acetanilide?

 

 


Experiment  4   Preparation of 2,4-Dichloroacetanilide

 

[Experimental purpose]

 

To grasp the kinds of halogenating agent and halogenating reaction

 

[Equation]

 

     

 

[Reagents]

 

   Acetanilide                   10g (0.074mol)

   Glacial acetic                  20ml

   Concentrated hydrochloric acid    35ml

   Sodium chlorate                5.5g  (it is dissolved in 15ml water )

 

[Procedure]

 

  Place acetanilide and glacial acetic in 250ml three-necked flask which equipped with a mechanical stirrer, thermometer and reflux condenser. Stir the mixture and add concentrated hydrochloric acid into the flask. Then cool the mixture with ice-water bath and drop in the sodium chlorate solution from the dropping funnel at such a rate that the internal temperature remains at about 2025. After that, continue stirring at this temperature for 1 hour. Filter with suction and the residue is washed with water until free from acid (test the wash water). The product can be re-crystallized by 80% methanol.

 

[Questions]

 

1.      What are by-products in this reaction?

2.      Can we select other chlorinating agent?


Experiment 5   Preparation of  Furylacrylic acid

                     (2-Furanacrylic acid)

 

[Experimental purpose]

 

To understand Knoevenagel reaction and condition

 

[Equation]

 

     

[Reagents]

 

        Furfural                       4.9g

        Malonic acid                   5.3g

        Pyridine                       2.5ml

Concentrated ammonia solution    about 10ml

Dilute hydrochloric acid (1:1)      right amount

 

[Procedure]

 

  Place 4.8g of freshly distilled furfural (note 1), 5.2g of dry malonic acid (note 2) and 25ml of dry pyridine (note 3) in a 100ml round-bottomed flask fitted with a reflux condenser. Heat the flask on a boiling-water bath for 2 hours. Cool the reaction mixture and dilute with 50ml of water, dissolve the acid by the addition of concentrated ammonia solution, filter the solution and wash the filter-paper with a little water. Add dilute hydrochloric acid (1:1), with stirring, to the combined filtrate and washings until acid below pH=3, and cool in ice bath for at least 1hour. Filter the furylacylic acid and wash it with a little water (15ml×2); it weighs 5g after drying and melts at 139140

 

[Notes]

 

1. Commercial furfural is subjected to a single distillation; b.p.160160.

2. Commercial malonic acid is dried at 100 for 2 hours and stored in a stopped bottle.

3. The pyridine, which may be a commercial grade, is dried over sticks of potassium hydroxide for a few hours and filtered.

4. [Re-crystallization]

A convenient procedure is to dissolve the acid in a slight excess of 50% alcohol, reflux the solution with charcoal (5g. per 100g. of acid) for 510 minutes, and filter through a fluted filter in a preheated funnel. Any solid material that separates toward the later stages is re-dissolved by the addition of a few drops of alcohol. The residue is thoroughly washed with boiling water. The hot solution is then diluted with cold water until crystals separate, heated to boiling, cooled slowly, and allowed to stand in a refrigerator several hours. When the mother liquors are used for subsequent batches, the usual loss (23%) by re-crystallization is more than halved.


Experiment 6   Preparation of tert-Butyl Chloride (Propane

              2-chloro-2-methyl-)

 

[Experimental purpose]

 

To understand chlorinating agent and reaction condition

 

[Equation]

 

        

[Reagents]

 

tert-Butyl alcohol                10g

Concentrated hydrochloric acid     33ml

5% NaHCO3 solution             50ml

 

[Procedure]

 

In a three-necked flask equipped with a stirrer, thermometer and condenser place 10g of tert-butyl alcohol, 33ml of concentrated hydrochloric acid. Stir the reaction mixture at room temperature for 1 hour. Stop stirring and it will form two distinct layers, discard the water layer and wash the oil layer with 24ml×2 of 5% sodium hydrogen carbonate solution. Dry the oil layer the anhydrous calcium chloride and then distil. Collect distillate at 5052, yield 85% (about 9.8g)

 

[Notes]

 

1.  As it is difficult to prepare tert-butyl alcohol free from water, 84g of the constant-boiling mixture of the alcohol and water can be used. This mixture boils at 80, contains 88.24 per cent alcohol when the distillation is carried out at 760mmHg., and can be readily obtained by distilling a sample of the dilute alcohol.

2.  The chloride is very slowly hydrolyzed by cold water.

3. It is suggested that calcium chloride be added to the saturation point after the tert-butyl alcohol and hydrochloric acid are mixed in order to salt out the tert-butyl chloride and to concentrate the hydrochloric acid.

Experiment 7   Preparation of n-Butyl Chloride (Butane,

               1-chloro-)

 

[Experimental purpose]

 

   To understand chlorinating agent and reaction condition

 

[Equation]

        

 

[Reagents]

 

n-Butyl alcohol                 3.7g (0.05mol)

Concentrated hydrochloric acid    8.7ml (0.1mol)

Anhydrous zinc chloride         13.6g

10%NaOH solution             8ml

 

[Procedure]

 

  In a 50ml round-bottomed, short-necked flask,13.6g of anhydrous zinc chloride is dissolved in 8.7ml of concentrated hydrochloric acid, the flask being cooled to prevent loss of hydrogen chloride(note 1). To this solution is added 3.7g of n-butyl alcohol. The flask is attached to a vertical, water-cooled reflux condenser (note 2), the top of which carries a thermometer and a goose-neck tube connected with an efficient downward condenser. To the end of the downward condenser is attached a 10ml flask which is connected to a 2.5ml flask by a bent tube. A tube from the second receiving vessel is connected with a gas-absorption trap (note 3) or to a funnel inverted over 8ml of 10 per cent sodium hydroxide solution in a 10ml beaker. Rubber stoppers are used throughout. Both the receiving vessels are cooled in a large ice-salt bath.

The flask is heated by an oil bath to 150 (bath temperature), at which temperature the solution starts to boil and butyl chloride begins to distil. After a few moments, it is necessary to control the temperature in the reflux condenser at 7580 by a very slow stream of water. The temperature of the oil bath is gradually raised to 155, and one hour from the time of initial boiling practically all the butyl chloride has distilled. If necessary, however, heating at 155 may be continued for ten to fifteen minutes longer and the temperature of the bath then raised to 160165, the reflux temperature not being allowed to get above 80. The distillate is washed with 10ml of cold water, 5ml of cold concentrated sulfuric acid, 10ml of water, and finally with 2.5ml of 10 per cent sodium carbonate solution. It is dried over o.1g of calcium chloride and distilled (note 4). The fraction boiling from 75.5to 77.5 weighs 3.5g. (7678 per cent of the theoretical amount).

 

[Notes]

 

The sticks of zinc chloride are crushed before being mixed with the acid, and then the mixture is agitated with frequent cooling under the water tap. After the initial heat of solution is over (about five minutes), and there is no further tendency for the mixture to heat up, the flask is closed with a rubber stopper which is wired on and the solution process completed by thirty minutes of mechanical shaking. If a few grams of zinc chloride remain, they will dissolve soon after the beginning of the reaction.

 

1.      Condenser provides sufficient refluxing to insure separation of the butyl chloride and the alcohol. When the reflux temperature reaches 75, a very slow stream of water is necessary to keep it within the desired range.

2.      The gas-absorption trap may be used.

3.      Distillation of the crude product was carried out through a column.


Experiment  8   Preparation of  Propanoyl Chloride

 

[Experimental purpose]

 

 To understand chlorinating agent and reaction condition

 

[Equation]

 

          

 

[Reagents]

 

Propionic acid             37.3ml (37g)

Phosphorus tri-chloride      17.5ml (27.4g)

Calcium chloride

 

[Procedure]

 

In a 100ml round-bottomed flask, 27.4g of phosphorus tri-chloride is poured on to 37g the propionic acid, and mixture is shaken several times. The flask is fitted a condenser which provided with a calcium chloride tube and a gas absorbent unit. Alternatively, it can be heated in the oil bath to 50 for 3 hours. Then it may be distilled of directly from the phosphorous acid, collect distillation cut at 7680.

 

[Notes]

 

  All instruments must be dry.

 

[Side reaction ]

 

          


Experiment 9   Preparation of p-Nitro-benzoic acid (KMnO4)

 

[Experimental Purpose]

 

To understand oxidizing agent and appliance

 

[Equation]

 

 

[Reagents]

 

p-Nitro-toluene               7.0g

KMnO4                      20g

Concentrated hydrochloric acid   10ml

Water                       120ml

 

[Procedure]

Successively place 7.0g of p-nitro-toluene, 100ml of water, 10g of potassium permanganate in a 250ml three-necked flask equipped with a mechanical stirrer, thermometer and reflux condenser.

Stirring is started and the mixture is heated to 80. After the mixture has been heated for 1 hour at this temperature, 5g of potassium permanganate is added. The mixture is stirred for a further 1 hour at 80. Then at this temperature another 5g of potassium permanganate is added. After a further 30minutes of heating, the temperature of the reaction mixture is gradually raised to gently reflux until all the color of potassium permanganate has disappeared. Cool the reaction mixture to room temperature, and filter with suction, the residue is washed once with about 20ml of water. The combined filtrates are acidified with 10ml of concentrated hydrochloric acid. Filter the precipitate with suction, wash twice with a small amount of cold water and press as dry as possible on the filter, the yield of p-nitro-benzoic acid is about 5g, m.p.238.


Experiment 10  Preparation of p-Nitro-benzoic acid (Na2Cr2O7)

 

[Experimental Purpose]

 

To understand oxidizing agent and appliance

 

[Equation]

 

 

[Reagents]

 

p-Nitro-toluene             6g

Na2Cr2O7.2H2O            18g

Concentrated sulfuric acid    28ml

Water                     40ml

5% Sulfuric acid            25ml

5% NaOH solution          50ml

15% Sulfuric acid           60ml

 

[Procedure]

 

Successively place 6g of p-nitro-toluene, 18g of sodium dichromate and 40ml of water in a 250ml three-necked flask equipped with a mechanical stirrer, thermometer and a dropping funnel. Stir the solution, then add 28ml of concentrated sulfuric acid from funnel during about 30 minutes to the well-stirred mixture (note 1). The heat of dilution of the acid causes the p-nitro-toluene to melt and oxidation takes place; if the reaction shows signs of becoming vigorous, the rate of addition must be reduced. When all the sulfuric acid has been introduced and the temperature of the mixture commences to all, attach a reflux condenser to the flask, and heat to gentle boiling for 1.5hours. Cool and pour the reaction mixture into 50ml of water. Transfer the solid to a beaker, add about 25ml of 5 per cent sulfuric acid, and digest on a water bath agitation for 10minutes (note 2). Then cool and filter again, transfer the solid to a beaker, break up any lumps of material and treat it with 5 per cent sodium hydroxide solution (note 3). Add about 0.3g of decolorizing carbon, warm to about 50 with stirring for 5minutes and filter with suction. Run the alkaline solution of sodium p-nitro-benzoate into about 60ml of well-stirred 15 per cent sulfuric acid. Do not add the acid to the alkaline solution. Filter the purified acid at the pump, wash it thoroughly with cold water and dry it. They yield p-nitro-benzoic, m.p.237238,is 56g .

 

[Notes]

 

1.      The heat of dilution of the sulfuric acid will cause the nitro-toluene to melt, and rapid oxidation will soon take place. The last half of the sulfuric acid must be added gradually, in order to prevent too violent a reaction

2.      In order to remove the chromium salts as completely as possible, the crude p-nitro-benzoic acid is warmed on the water bath and agitated with dilute (5%) sulfuric acid solution.

3.      In order to remove unchanged nitro-toluene. They can be recovered from the reaction mixture by steam distillation, but the value of the byproduct would not pay for the time spent in recovery.

 

[Question]

 

What should be done to get pure product?


Experiment 11   Preparation of Ethyl-4-nitro-benzoate

 

[Experimental purpose]

 

To study esterization reaction and grasp this reacting approach

 

[Equation]

 

      

 

[Reagents]

p-Nitro-benzoic acid               12g

Anhydrous alcohol                 52ml

Concentrated sulfuric acid            6ml

5% Sodium carbonate solution    about 50ml

 

[Procedure]

 

Successively place 12g of p-nitro-benzoic acid, 52ml of anhydrous alcohol and 6ml of concentrated sulfuric acid in a 250ml round-bottomed flask fitted with a reflux condenser. Heat the flask on a boiling-water bath for 2 hours. Then distil some quantity of alcohol (about 37ml) and pour the hot reaction mixture on to 120ml of cold water, with stirring. Write solid will precipitate. The solid is separated by suction filtration and washed with water. The product is suspended in 50ml of 5% aqueous sodium carbonate solution and stirred. After thorough mixing, the solid is collected on a filter, washed with water. Dry and weight. m.p. 56.

 

[Question]

 

What is the purpose of the concentrated sulfuric acid?


Experiment 12   Preparation of Ethyl-4-amino-benzoate

 

[Experimental purpose]

 

To study this approach and characteristic reduction reaction

[Equation]

 

     

 

[Reagents]

 

Ethyl-4-nitrobenzoate            6g

Iron powder                   15g

Glacial acetic acid                2.5ml

10% Sodium carbonate solution      35ml

95% Alcohol                     50ml

 

[Procedure]

 

In a 250ml round-bottomed flask place 15g of iron powder, 50ml of 95% alcohol and 2.5ml of glacial acetic. The flash is equipped with a reflux condenser and a heat a boiling-water bath for 10 minutes. Cool the reaction mixture slightly then add 6g of ethyl-4-nitro-benzoate and continue the heating under refluxing. After 2.5 hours, add 35ml of warmed 10% sodium carbonate solution slowly to the flask and stir well. Filter the solution while still hot and pour some water into it, cool and separate out the ethyl-4-amino-benzoate.

 

[Questions]

 

1.      What is the purpose of the glacial acetic acid? Why don’t use hydrochloric acid?

2.      To explain the separating mechanism of product.


Experiment 13   Preparation of Benzalaniline (Aniline,

                    N-benzylidene-)

 

[Experimental purpose]

 

Grasp the mechanism of Aldol condensation reaction and experimental process.

 

[Equation]

 

     

 

[Reagents]

 

Benzaldehyde (fresh)         1.6g (0.1mol)

Aniline                    9.3g (0.1mol)

95% Alcohol               16.5 ml

 

[Procedure]

 

In a 250ml three-necked round-bottomed flask provided with a mechanical stirrer, thermometer, reflux condenser and a dropping funnel place 10.6g of benzaldehyde, 9.3g of aniline is added with rapid stirring. After a few seconds a reaction occurs with evolution of heat and separation of water. The mixture is allowed to stir 60 minutes after all of the aniline is added. Then poured, with vigorous stirring, into 16.5ml of 95 per cent alcohol in a beaker. Crystallization begins in about five minutes, and the mixture is allowed to stand in ice water for 30 minutes. The almost solid mass is next transferred to a large funnel, filtered by suction, pressed out, and air-dried. The yield of pure benzalaniline melting at 52 is 1516g (8487 per cent of the theoretical amount).

 

[Notes]

 

1.      Removal of the alcohol by distillation at ordinary pressure gives a much darker product.

2.      If a product of high purity is desired, it may be obtained by re-crystallization from 85 per cent alcohol.

Experiment 14   Preparation of 4-Chloro-benzoic acid

 

[Experimental purpose]

 

To grasp oxidizing reaction and characteristic

 

[Equation]

        

[Reagents]

 

p-Chloro-toluene        12.6g

Potassium permanganate    17g

 

[Procedure]

 

Intimately mix 12.6g of p-chloro-toluene and 30ml of water in a 250ml three-necked flask fitted with a stirrer, condenser and a thermometer. Heat the solution to 75. Meanwhile, prepare a solution of 17g of potassium permanganate in 50ml of water, and drop the prepared solution to the flask. Control the dropping rate and make temperature not above 90. After all the solution has been added, stir well reflux over a period of 4 hours. Cool the mixture and add hydrochloric acid to pH=2.Filter the precipitated p-chlorobenzoic acid and re-crystallize from alcohol. The yield pure product, m.p.238240, is 8g.

 

[Notes]

 

 If the mixture is heated too rapidly the reaction may be violent at the outset; It can be controlled by laying wet towels upon the upper part of the flask.

 

 


Experiment 15   Preparation of Di-phenyl carbinol

(benzohydrol)

 

[Experimental purpose]

 

To study this approach and characteristic of reduction reaction

 

[Equation]

 

        

 [Reagents]

 

Diphenyl ketone     18.2g (0.1ml)

NaBH4             1.9g (0.05ml)

95% alcohol         100ml

 

[Procedure]

 

In a 250ml three-necked flask fitted with a mechanical stirrer, thermometer and reflux condenser place 18.2g of diphenyl ketone and 100ml of per cent alcohol. Heat the flask on water-bath. When the solid is dissolved absolutely, cool the reaction solution to room temperature. Then stir well and add 1.9g of sodium boro-hydride to the solution, not for one portion. The temperature should be controlled below 50 because the reaction is an exothermic reaction. After that, raise the temperature to refluxing for 1 hour. Then cool the mixture to room temperature and add 100ml of cold water. The excessive sodium boro-hydride will be resolved. Drop 10 per cent hydrochloric acid slowly until the reaction stop. Cool to room temperature and filter, wash the filtrate with and dry it. The product may be re-crystallized from petroleum ether (b.p.3060).

 

[Questions]

1.      What is the purpose of the 10% hydrochloric acid after reaction?

2.      Please you design another approach to prepare diphenyl carbinol.


Experiment 16   Preparation of Acetyl-salicylic acid

 

[Experimental purpose]

 

To study esterization reaction and grasp this reacting approach

 

[Equation]

 

     

[Reagents]

 

Salicylic acid       2.76g (0.02mol)

          Acetic anhydride      8ml (0.08mol)

Concentrated sulfuric acid

10% Sodium hydrogen carbonate solution

6M hydrochloric acid

Water

 

[Procedure]

 

Place 2.76g of salicylic acid, 80ml of acetic anhydride and 68 drops of concentrated sulfuric acid in a three-necked flask equipped with a stirrer, thermometer and reflux condenser. Stirring is started and the mixture is heated to 85on bath. After one hour, cool the reaction mixture to room temperature and 15ml of cold water is added slowly, with stirring, at such a rate that the temperature does not too high. The flask can be surrounded by a cold water bath if necessary. Cool the solution to room temperature the white crystal will appear. Collect the residue and wash it with 2530ml of cold water. Remove the crude product to a 250ml beaker, add 40ml of 10% sodium hydrogen carbonate solution when stirring well until there is not more CO2 gas release. Filler off the by-product and add 20ml of 6M hydrochloric acid into the filtrate slowly with stirring. A quantity of sediment will be precipitated, allow to precipitate thoroughly in an ice-water bath. Then filter the crystal at the pump, wash it with ice-water and dry it. The yield is 2.4g (67%), m.p.132135. Re-crystallization can use toluene or ethyl acetate.

 

[Question]

 

1.      What is the purpose of the concentrated sulfuric acid?

2.      What are the by-products? How do separate?


Experiment 17   Preparation of propiophenone

 

[Experimental purpose]

 

Grasp the mechanism of Friedel-Crafts acylation and experimental process.

 

[Equation]

 

      

 

[Reagents]

 

Benzene                      40ml

Propionyl chloride              13g 

AlCl3                         20.3g

Concentrated hydrochloric acid

10% NaOH solution

 

[Procedure]

 

In a 250ml three-necked flask with an efficient stirrer, a dropping funnel, and reflux condenser provided with a calcium chloride tube, place 40ml of sodium dried anhydrous A.R. benzene and 20.3g of finely powdered anhydrous aluminum chloride, stir the mixture for 10minutes. Then 13g of the propionyl chloride is added form the dropping funnel with water cooling at such a rate that the internal temperature always remains at about 2530. After that, raise the temperature slowly to 50, and continue stirring at this temperature for 2 hr. Cool to 20

The solution of reaction is carefully poured onto crushed ice and any aluminum hydroxide that may have separated out is brought into solution with a little concentrated hydrochloric acid. Then the organic layer is separated off in the separating funnel and the aqueous layer is extracted twice more with benzene. The combined extracts together with organic layer are carefully washed with water, 5% caustic soda solution, and again with water. After drying over anhydrous calcium chloride, the solvent is evaporated off and finally the propiophenone is distilled. The fraction boiling at approximately 92 at 11mmHg pressure is collected.

 

[Note]

Weigh AlCl3: Because of the fuming of aluminum chloride in moist air, you must weight it rapidly and put it into a tightly covered container immediately.


Experiment 18   Preparation of acetophenone

 

[Experimental purpose]

 

Grasp the mechanism of Friedel-Crafts acylation and experimental process.

 

[Equation]

    

[Reagents]

 

Benzene                      65ml

Anhydrous aluminum chloride     40g

Acetic anhydride               20.4g

Concentrated hydrochloric acid    75ml

Sodium hydroxide solution (5%)

 

[Procedure]

 

Connect a 500ml flask to a reflux condenser, dropping funnel and a trap for absorption of escaping hydrogen chloride

When the apparatus is assembled, disconnect the flask and put into it 40g of anhydrous aluminum chloride and 65ml of dry benzene. Join the flask to the condenser and during a period of about 10 minutes, add through the dropping funnel 20.4g of acetic anhydride. From time to time loosen the reactants clamp on the flask and shake the flask in order to mix the reactants thoroughly. If the heat of the reaction causes the benzene to boil, decrease the rate of addition of the acetic anhydride and, if necessary, bring a cooling bath up around the flask. After all of the acetic anhydride has been added and the vigor of the reaction has diminished, heat the flask on the steam bath for 20minutes. Then remove the steam bath, cool the flask in cold water, and pour its contents slowly into a beaker which contains 75ml of concentrated hydrochloric acid and about 150g of crushed ice. If any precipitate of basic aluminum salt remains after the mixture is well stirred, add enough hydrochloric acid to bring it into solution. The beaker now contains an acidic aqueous solution of aluminum chloride and an upper layer consisting of benzene and acetophenone.

By means of the separating funnel remove the upper layer and extract the aqueous layer with 20ml×2 of benzene. Combine the two solution and wash them twice with 200ml of water and then once with dilute sodium hydroxide solution (5%). Dry the solution over anhydrous magnesium sulfate, decant from the drying agent and distill the liquid. The acetophenone boils at 202. Yield 1620g.


Experiment 19   Preparation of m-Nirto-benzaldehyde

 

[Experimental purpose]

 

To understand nitrating reaction

 

[Equation]

 

         

 

[Reagents]

 

Benzaldehyde                  10g

Potassium nitrate                11g

Concentrated sulfuric acid         40ml

5% Solution carbonate solution     20ml

 

[Procedure]

 

Place a mixture of 11g potassium nitrate and 40ml of concentrated sulfuric acid in a 250ml three-necked flask at room temperature, fitted with a thermometer, a mechanical stirrer and a dropping funnel. Cool the mixture to 0 in an ice  salt bath, with effective stirring, and drop in 10g benzaldehyde at such a rate that the temperature remains at 05. Stir the mixture for 1.5hr. and then pour it onto crushed ice-water, the crude product is precipitated with stirring. Filter with suction on a funnel, wash it thoroughly with 20ml 5% aqueous sodium carbonate solution and ice water, press well and dry well. The yield of m-nitrobenzaldehyde,  m.p. 5658 is 11.8g (82.8%). The crude solid can be re-crystallized by benzene and petroleum.

 

 

 

[Note]

 

A small amount of an oily liquid passes through the filter; this material is a mixture of the ortho and meta isomers. If a very pure product is desired, this oil may be discarded; although some of the meta isomer will be lost. It is usually satisfactory to combine it with the solid material, the m-nitro acetal being obtained in a state of purity sufficient for most purposes in the final distillation.


Experiment 20  Preparation of p-Nitro-benzaldehyde

 

[Experimental purpose]

 

To grasp the demulcent oxidizing agent in oxidizing reaction

 

[Equation]

 

        

 

[Reagents]

 

p-Nitro-toluene                   6.3g

Acetic anhydride                  50ml

Concentrated sulfuric acid           10ml+2ml

Chromium trioxide                 12.5g

Acetic anhydride                    57ml

2% aqueous sodium carbonate solution   40ml

Ethanol                          2.5ml + 20ml

 

[Procedure]

 

(A)  p-Nitro-benzaldiacetate.

 

In a 250ml three-necked flask provide with a mechanical stirrer, dropping funnel, and thermometer, surrounded by an ice-salt bath, are place 50ml of acetic anhydride and 6.3g of p-nitro-toluene. To this solution is added slowly, with stirring, 10ml of concentrated sulfuric acid. When the mixture has cooled to 0, a solution of 12.5g of chromium trioxide in 57ml of acetic anhydride is added slowly, with stirring, at such a rate that the temperature does not exceed 10 and stirring is continued for 2hr. at 510 in ice-water bath after the addition is completed. The contents of the flask are poured into a beaker with 250g chipped ice, and water is added until the total volume is 750ml. The solid is separated by suction filtration and washed with water until the washings are colorless. The product is suspended in 40ml of 2% aqueous sodium carbonate solution and stirred. After thorough mixing, the solid is colleted on a filter, washed with water and finally with 2.5ml of ethanol.

 

(B)  p-Nitro-benzaldehyde

 

A mixture of crude p-nitro-benzaldiacetate, 20ml of water, 20ml of alcohol, and 2ml of concentrated sulfuric acid is refluxed for thirty minutes and filtered through a filter, and the filtrate is chilled in an ice bath. The crystals are separated by suction filtration, washed with cold water, and dried in a vacuum drying oven. The first crop weights 3.54g, m.p.106106.5. A second crop is obtained by diluting the filtrate with water.

 

[Notes]

 

1.      If the sulfuric acid is added too rapidly, charring occurs.

2.      It is essential that the temperature of the reaction mixture be maintained below 10. If the oxidant is added so rapidly that this temperature is exceeded, the yield is lowered considerably. With a good ice-salt bath, the time required for the addition is forty-five to sixty minutes.


Experiment 21   Preparation of o-Chloro-toluene (Toluene,

                   o-chloro-)

 

[Experimental purpose]

 

To understand diazo-reaction

 

[Equation]

 

 

[Reagents]

 

Copper sulfate     12.5g

Sodium chloride  3.25g

Sodium bisulfate  2.65g

Sodium hydroxide   1.75g

28% hydrochloride acid   20g

o-toluidine     4.28g

Sodium nitrite   2.8g

 

[ Procedure]

 

(A) preparation of Cuprous Chloride Solution (Note l)

A solution of 12.50 g. (0.05 moles) of crystallized copper sulfate and 3.25 g. (0.56 moles) of sodium chloride in 40ml. of hot water is prepared in a 0.12-L.flask. The flask is fitted with a mechanical stirrer, and an alkaline solution of sodium sulfite (2.65 g. of sodium bi-sulfite and 1.75 g. of sodium hydroxide in  20L. of water) is added during a period of five to ten minutes. The mixture is allowed to cool to room temperature and washed by decantation. The cuprous chloride is obtained as a white powder, which, however darkens on exposure to the air. The crude product is dissolved in 20g. of commercial 28 per cent hydrochloric acid (sp  gr. l.14) and the solution is used in the following preparation (Note 2).

(B- ) 0-Chlorotoluene.

In a 0.10-L. stone jar fitted with a mechanical stirrer are placed 20g. (17.55 cc.) of commercial 28 per cent hydrochloric acid (sp. gr. I.14) and 4.28 g. ( 4.27 cc., 0.04 moles) of o-toluidine. The mixture is cooled to 0by adding cracked ice (about l0g. is required) . The o-toluidine hydrochloride separates as a finely divided precipitate. The stirrer is started, and to the cold suspension is added a solution of 2.80 g. (0.04 moles) of sodium nitrite in 8.00 cc. of water the  diazotization is carried out at 0-5' and requires about fifteen minutes. Cracked ice is added from time to time to keep the temperature within the proper limits. The volume of the final solution is 50--80ml.

While the diazotization is being carried out the cuprous chloride solution (A) is cooled to 0'. The cold diazonium solution is now poured rapidly into the well-stirred cuprous chloride solution. The solution becomes very thick, owing to the separation of an addition product between the diazonium salt and the cuprous chloride. The cold mixture is allowed to warm up to room- temperature,  and stirring is continued for two and one-half to three hours at this temperature (Note 3) . When the temperature reaches about 15', the solid addition compound begins to break down with the formation of nitrogen and o-chlorotoluene. After the specified time the solution is placed on a steam bath and heated to 60" to complete the decomposition of the addition product. The o-chlorotoluene forms a layer on top of the copper salt solution. The water solution is drawn off through a siphon until only 5-6L remains. The remaining material is steam-distilled from a 12-l. round-bottomed flask (Note 4) until about 3.5-4L. is collected in the distillate. The 0-chlorotoluene layer is separated from the water, washed with cold concentrated sulfuric acid (Note 5) and then with water, and finally dried over calcium chloride. The product boiling at 155-158' weighs 375-400g. (74-79 per cent of the theoretical amount).

(C) p-Chloro-toluene.

p-Chloro-toluene is prepared in exactly the same way starting with p-toluidine. The yields are 70-79 per cent of the theoretical amount of a product which boils at 158-162and melts at 4--7.

 

[Notes]

 

l. The cuprous chloride solution prepared as described is more satisfactory and less expensive than one prepared by reducing cupric chloride with copper turnings.

2. If less cuprous chloride is used the yield is lowered. It seems desirable to use l mole of cuprous chloride (CuCl) to l mole of diazonium salt. Increasing the amount of cuprous chloride beyond this point does not improve the yield.

3. The literature directions usually call for mixing the diazonium solution and the cuprous chloride solution at about 30-40". This procedure gives a yield considerably lower than that obtained by mixing the solutions cold and allowing to warm up gradually. If the mixture obtained by adding the diazonium solution to the cuprous chloride solution is heated at once, the yield falls to 55-65 per cent.

4. The steam distillation can be conveniently carried out in the apparatus described on p. 479.

5. The treatment with sulfuric acid is necessary to remove cresol and a trace of azo compound that usually colors the crude product and cannot be removed by distillation.


 

Chapter 5   Appendix

 

In case of Accident

 

Always call or notify a laboratory instructor as soon as possible.

 

5.1   Fire

 

5.1.1  Burning Reagents: Immediately extinguish any gas burners in the vicinity. Fire extinguishers, charged with carbon dioxide or mono-ammonium phosphate powder under pressure, are available in various parts of the laboratory.

For burning oil use powdered sodium bicarbonate.

 

5.1.2  Burning clothing: Avoid running (which fans the flame) and take great care not to inhale the flame. Rolling on the floor is often the quickest and best method for extinguishing a fire on one’s own clothing. Smother the fire as quickly as possible using wet towels, laboratory coats, heavy (fire) blankets, or carbon dioxide extinguisher.

 

5.1.3  Treatment of Small Burns: Submerge the burned area in cold water until the pain subsides. Blot the area dry, gently, with sterile gauze and apply a dry gauze as a protective bandage. In some second or third degree burns in which blisters have formed or broken, or in which deep burns are encountered, see a physician as soon as possible.

 

5.1.4 Extensive Burns:

These require special treatment to avoid serious or fatal outcome---summon medical treatment at once. Combat the effects of shock by keeping the patient warm and quiet.

 

5.2  Injuries and chemical burns

 

5.2.1 Reagents in the eye

 

Wash immediately with a large amount of water, using the ordinary sink hose, eye-wash foundation, or eye-wash bottle---do not touch the eye. After the eye has been washed thoroughly for 15min, if any discomfort remains, see a physician.

 

5.2.2  Reagent on the skin

 

Acid ----Wash immediately with a large amount of water, then soak the burned part in sodium bicarbonate solution. Cover the burned area with a dressing bandage and see a physician.

Alkali---- Wash immediately with a large amount of water, then soak the burned area in 1% boric acid solution to neutralize the alkali. Cover the burned area with a dressing and see a physician.

Bromine---- Wash immediately with a large amount of water, then soak the burned area in 10% sodium thiosulfate or cover with a wet sodium thiosulfate dressing, for at least 3hr and see a physician.

Organic Substances ---- Most organic substances can be removed from the skin by washing immediately with ordinary ethanol, followed by washing with soap and warm water. If the skin is burned (as by phenol), soak the injured part in water for at least 3hr and see a physician.

 

5.3 Cuts

 

Wash the wound with sterile gauze, soap and water. Cover with a sterile dressing and keep dry.

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