ORGANIC CHEMISTRY LABORATORY

SALAHADDIN UNIVERSITY
- COLLEGE OF EDUCATION
CHEMISTRY DEPARTMENT

A + B C
PRACTICAL ORGANIC PREPARATION

FOR THIRD STAGE STUDENTS

PREPARED BY:

Dr. FAROUQ E. HAWAIZ

LEC. MOHAMMED K. SAMAD

Ph Ph
N
2013
N H H N
2014
N
Ph Ph
 Contents
Exp. Subject Page
Safety and technique rules 2
Writing an Organic Chemistry Lab Report 4
How organic compounds React 6
A few words about curved arrow 7
1 Synthesis of an azo dye 8
2 Preparation of Benzocain 11
3 Preparation of methyl orange 13
4 Preparation of benzanilide 14
5 Aldol condensation Synthesis of dibenzalacetone 15
6 The benzoin condensation of benzaldehyde 19
7 Preparation of benzil 21
8 Synthesis of benzilic acid 23
9 Synthesis of dilantin 24
10 Preparation of succinic anhydride 26
11 Preparation of benzylidine-aniline (schiff base) 27
12 Preparation of ketoxime (benzophenone oxime) 28
13 Beckmmann rearrangement of an oxime 30
14 Preparation of 2-pyrazoline By one pot-synthesis 31
15 Preparation of dihydropyrimidinone By one pot three 32
components system
16 Preparation of phthalimide 34
17 Preparation of anthranilic acid 36
(hofmann rearrangement).
18 N-phenylanthranilic acid ( ullmann condensation). 38
19 Preparation of acridone 39
20 Preparation of anthraquinone 40
21 Preparation of sulphanilic acid 41
(p-aminobenzenesulphonic acid).

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 22 Preparation of acetanilide 42
23 Preparation of p-nitroacetanilide 43
24 Preparation of benzimidazole 45
25 Preparation of tetraphenylporphyrin 47
26 Preparation of o-lodobenzoic acid 48
(the sandmeyer reaction)
References 49

SAFETY AND TECHNIQUE RULES

Safety in the laboratory is extremely important. It is expected that you know
laboratory safety rules. It is important that if you feel uncomfortable with your
knowledge of these rule that you take the time to learn them. There is NO excuse for
not following safety rules.
1. Be attentive to instructions and follow them carefully.
2. If you ever have any questions about the procedure, apparatus, or chemicals it is
important that you ask the Instructor or Instructional assistant.
3. Do not perform any unauthorized experiments. Anyone found doing so faces
permanent expulsion from class.
4. Do not handle chemicals or materials not assigned to you or not called for in the
experiment.
5. Learn the location and proper use of the fire extinguisher,
6. Coats, books, etc., should be kept in the good place. Many of the chemicals used in
the lab can ruin or stain paper and clothing.
7. Never taste chemicals, nor pipet by mouth. Always use pipet bulbs or wheels.
8. Smell chemicals by fanning a little vapor towards you.
9. Experiments in which dangerous or obnoxious fumes are produced must be done
in the fume hood. Be sure to stop these reactions as soon as possible.
10.No eating, drinking or smoking in the lab.
11.Never point test tubes at yourself or others.
12.In the event of any injury, spill or glass breakage, inform the Instructor
immediately.
13.Goggles must be worn at all times when in the lab.
14.Chemicals may not be taken out of the lab.
15.Avoid unnecessary contact with ALL chemicals.
16.Do not leave lit burners unattended

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17.Every time you use a chemical read its label carefully. If any discrepancies inform
the instructor immediately.
18.All containers which contain a chemical or in which a reaction occurs must be
labeled.
19.When labeling a storage container include name and/or formula of chemical, any
appropriate warnings, concentration, date and your name.
20. NEVER place anything inside a reagent bottle, no spatulas, droppers, nor pipets.
If the reagent is a clumpy solid inform the IA. Proper technique is to "roll"
21.Containers from side to side to remove solids and to pour liquids into smaller
containers (such as a beaker) first.
22. NEVER return unused chemical (liquids or solids) back to the original container -
offer excess to another student or dispose of it appropriately.
23. Be conservative of reagents; place only the amount you need into a labeled
container (such as a beaker). Do not take the reagent bottles to your work area -
leave them where everyone can find them.
24.Use tap water to wash glassware - you should rinse with D.W- please be
conservative.
25. To dilute acids and bases, add the Acid (or Base) to the Water.
26. Dispose of liquids and solids appropriately, read the board, or your experimental
procedure for special instructions, otherwise dispose of liquids and soluble solids
down the sink with lots of water, insoluble Is materials (such as paper towels)
should be put in the waste basket. KEEP THE SINKS CLEAN
27. It is very important to keep the lab clean. Before you leave each time be sure to:
a) Return equipment to its proper place
b) Clean up your workspace with the sponge
c) Put away your lab ware
There is NO reason for a messy lab. Everything you need to keep your lab neat and
clean is available. Dirty counters, paper left in the sink or troughs, lab ware left
out, messes left under the fume hood, chemical spills left on the balance, are BAD
technique and as such will not be tolerated.
28.You may not be in the laboratory at any time other than your scheduled laboratory
period unless you have the permission of the instructor in charge as well as your
course instructor. Do not visit friends during their lab time and do not invite your
friends or family to visit you.

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 Writing an Organic Chemistry Lab Report

Components of a Laboratory Report

The following components should be contained for each experiment, along with any
additional material required by your instructor.

 Title and date

 Introduction (purpose, reaction)
 Physical data (including calculations)
 Data and observations
 Questions
 Discussion of results (conclusions)

Introduction

In a sentence or two, state the purpose of the experiment. If the experiment is a

preparative experiment, the introduction also includes the balanced equation for the
reaction.

In organic chemistry, there are different types of experiments: technique and

preparative. A technique experiment is one in which you are performing a technique
for the first time and studying its details, for example, distillation and extraction. A
preparative experiment is one in which a compound is synthesized from other
reagents.

Physical Data

List the molecular weight, melting point, boiling point, and hazards of all
pertinent chemicals used in the experiment. You can find this information in the
FLUKA Handbook of Chemistry and Physics. Or, you can find the information on the
Internet (see: Hazard and Physical Data for Compounds page). Chemfinder.com is
an excellent site to find this data. The physical data are most conveniently presented
in tabular form, although in a preparative experiment you may put the amounts of
reactants and products. In a preparative experiment, calculate the limiting reagent and
the theoretical yield of the product. Be sure to include your calculations for these
values.

4
Data and Observations

Your observations of the experiment as it progresses are important, new

information. Write these observations (color changes, appearance of crystals,
formation of an emulsion, boiling temperatures, test results, etc.) in your notebook as
you do the experiment. Also record the weights of reagents and products and tare
weights in this section.
In general, you do not need to re-write the Procedure section in these observations,
instead, you may state that “the procedure was carried out as planned” or “the
procedure was carried out as planned except . . . .” At times, however, you may have
to write the procedure out partially. For instance, if you state “the solution turned
green,” you will have to write out enough of the procedure so that your instructor will
know at what step in the reaction the solution turned green. As a guideline, consider
that from the procedure and data and observations sections, any chemist should be
able to duplicate your experiment. With this in mind, be thorough but include only
pertinent information.
Discussion of Results

This is the section in which you interpret the data obtained in the previous
section. For instance, indicate the amount of compound that you obtained and predict
the purity and identity of the compound was assessed. In a preparative experiment,
state the percent yield. Include and discuss instrument which are used in this
experiment. In this section, you can state whether or not the procedure was a good
method for making the desired compound; if not, try to make suggestions to improve
the method for future experimenters. Be sure to include a discussion of possible
sources of error, and how that error would affect the overall

COURSE OBJECTIVES
1. Solve complex reaction mechanisms.
2. Synthesize compounds starting with simple ingredients.
3. Determine the structure of organic compounds.
4. Name organic compounds based on their structure.

Scholars identify four distinct types of practical work:

1- Experiences, which are intended to give students a ‘feel’ for observable fact;
2- Exercises, which are designed to develop practical skills and techniques;
3- Demonstration, To develop a scientific argument or cause an impression; and

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4- Investigations, which give students the opportunity to tackle more open-ended
tasks like a problem-solving scientist

Notes
There are typical experiments in organic synthesis. You will encounter many observable
changes throughout these experiments. It is very important to record all the observations
accurately and in detail. Furthermore, when one makes an observation, it should be written
down immediately.
In order to avoid any excess of a reagent that could decompose or cause decomposition and
produce tar (byproduct), you need to weigh the quantities of solid reagent very carefully to
the accuracy of 0.05 g or better.
In all experiments you will have to calculate for yourself some of the amounts of
needed reagents. After you have calculated them, confirm your results with the instructor
before proceeding.
How organic compounds React
There are many millions of organic compounds. If you had to memorize how
each of them reacts, studying organic chemistry would be a horrendous experience.
Fortunately, organic compounds can be divided into families, and all the members of
a family react in similar ways. What determines the family an organic compound
belongs to is its functional group.
The functional group is a structural unit that acts as the center of reactivity of a
molecule. In essence, organic chemistry is about the interaction between electron-rich
atoms or molecules and electron-deficient atoms or molecules. It is these forces of
attraction that make chemical reactions happen. From this follows a very important
rule that determines the reactivity of organic compounds: Electron-rich atoms or
molecules are attracted to electron-deficient atoms or molecules. Each time you
study a new functional group, remember that the reactions it undergoes can be
explained by this very simple rule. Therefore, to understand how a functional group
reacts, you must first learn to recognize electron-deficient and electron-rich atoms and
molecules.
An electron-deficient atom or molecule is called an electrophile. An electrophile can
have an atom that can accept a pair of electrons, or it can have an atom with an
unpaired electron and, therefore, is in need of an electron to complete its octet. Thus,
an electrophile looks for electrons. Literally, “electrophile” means “electron loving”
(phile is the Greek suffix for “loving”).

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 An electron-rich atom or molecule is called a nucleophile. A nucleophile has a
pair of electrons it can share. Some nucleophiles are neutral and some are negatively
charged. Because a nucleophile has electrons to share and an electrophile is seeking
electrons, it should not be surprising that they attract each other. Thus, the preceding
rule can be restated as a nucleophile reacts with an electrophile.

Because an electrophile accepts a pair of electrons, it is sometimes called a Lewis

acid. Because a nucleophile has a pair of electrons to share, it is sometimes called a
Lewis base

A FEW WORDS ABOUT CURVED ARROWS

1. Make certain that the arrows are drawn in the direction of the electron flow and
never against the flow. This means that an arrow will always be drawn away from
a negative charge and/or toward a positive charge.

correct O incorrect O
O O
H3C C + Br
H3C Br H3C C + Br H3C Br

CH3 CH3
CH3 CH3

H3C O H H3C O H + H H3C O H H3C O H + H

H correct H
incorrect

2. Curved arrows are drawn to indicate the movement of electrons. Never use a
curved arrow to indicate the movement of an atom. For example, you can’t use an
arrow as a lasso to remove the proton, as shown here:

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 O H correct O O H incorrect O

C C C C
H3C CH3 H3C CH3 + H H3C CH3 H3C CH3 + H

3. The head of a curved arrow always points to at an atom or at a bond. Never draw
the head of the arrow pointing out into space.

O correct O incorrect
O O
C C
H3C OCH3 + OH H3C C OCH3 H3C OCH3 + OH H3C C OCH3
OH OH

4. A curved arrow starts at the electron source. It does not start at an atom. In the
following example, the arrow starts at the electrons of the pi bond, not at a carbon
atom:
H3CHC CHCH3 H Br H3CHC CHCH3 + Br
correct
H

H3CHC CHCH3 H Br H3CHC CHCH3 + Br

incorrect H

EXPERIMENT 1
SYNTHESIS OF AN AZO DYE
Background
Dyes play an indispensable role in human history since ancient time. Dyeing
processes are often considered as an important characteristic of a particular
civilisation or culture. Dyes are used in almost every commercial product such as
food, clothing, pigments and paints, etc.
There are many different classes of dyes in which azo dyes are certainly one of the
most important classes. About half of the dyes used in industry are azo dyes. Azo
dyes have the basic structure, Ar−N=N−Ar , where Ar and Ar’ are two aromatic
groups.

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 X N

N X

The unit containing the nitrogen-nitrogen double bond is called an azo group.
The nature of the aromatic substituents on both sides of the azo group controls the
colors of the azo compounds as well as the water-solubility of the dyes and how well
they
bind to a particular fabric. Conversion of a primary amino group to a diazonium
group requires a nitrosonium ion that is formed when water is eliminated from
protonated nitrous acid.

Mechanism of Azo Dye Formation

Azo dyes are formed by the coupling of an aryldiazonium salt with an aromatic
amine or a phenol. Aryl diazonium salts are prepared by treating an acidic solution
of an aryl amine with sodium nitrite:
Conversion of a primary amino group to a diazonium group requires a nitrosonium
ion that is formed when water is eliminated from protonated nitrous acid.

The group containing the nitrogen-nitrogen double bond is called an azo group. To
produce an azo dye, an aromatic amine is treated with nitrous acid to give a
diazonium ion intermediate. This process is called diazotization.

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 The diazonium ion is an electron deficient (electrophilic) intermediate. An
aromatic compound, suitably rich in electrons (nucleophilic) will add to it. The most
common used nucleophilic species are aromatic amines and phenols. The addition of
the amine or the phenol to the diazonium ion is called diazonium coupling reaction.

O
O H
N N H OH

N
N N
+ + N
H

H O
OH

There are several important steps in the experiment which have to be carried
out carefully. The benzenediazonium salt solution is unstable and prone to deteriorate
(decompose) upon standing at room temperature. The solution should always be kept
at below 10 °C and should be used as soon as it is generated. The alkaline naphthalen-
2-ol solution should be prepared prior to the preparation of the benzenediazonium salt
solution.
Procedure:

Step1: Formation of diazonium salt

5mmol of Aniline (or substituted aniline) dissolve by heating gently in a (4ml) of

3M hydrochloric acid. After most of the solid has dissolve the solution cool in an ice
bath to 0Co.While stirring, add slowly (5ml) of freshly prepared 1M of sodium nitrite
solution, in which the temperature remains below 10 Co. The solution keeps in the ice
bath and immediately proceeds to the next step.

Step2: Coupling process:

5mmol of phenol (or substituted phenol) dissolve in (10ml) of 1M sodium

hydroxide then cool with stirring in the ice bath and add slowly to the diazonium salt
solution. The mixture allowed to stir for 15min. until crystallization is completed. The
solid azo dye was collected by vacuum filteration, washed several times with water.

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 EXPERIMENT 2

PREPARATION OF BENZOCAINE
In this experiment, we will prepare Benzocaine ( is found in medications used
to ease the pain of wounds, burns and sunburn also it is one of the simpler local
anesthetics commonly used as a topical pain reliever. It is the active ingredient in
many over-the-counter analgesic ointments) from para-amino benzoic acid and
ethanol in the presence of conc. sulfuric acid. Benzocaine is an odorless, white crystal
with low water solubility. It is sensitive to light exposure and to temperatures above
30° C. As a drug, it has a low potency and low systemic toxicity.
Esterification of p-aminobenzoic acid change its pharmacological properties.
This illustrates the point that a relatively small change in structure can dramatically
alter the physiological and biological properties of the molecule. Pharmaceutical
companies frequently develop a new drug by making small alteration in the structure.

The effectiveness of each analog as a sunscreen will be assessed by measuring how

well it absorbs ultraviolet radiation from the sun (λ=300nm). Exposure to this
radiation can cause sunburn. Prolonged or severe exposure can cause skin cancer and
genetic mutation. Sunscreens work because they absorb UV radiation of the
appropriate wavelengths at the surface of the skin.

O O

OH
H2SO4 OCH2CH3
+ OH

H2N H2N

p-aminobenzoic acid ethanol Benzocaine

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Reaction mechanism:

O H H
O
H O O

C O S OH
H C
C H H
Ph O
O Ph O Ph O

pKa= 4.7 pKa= -9 pKa= -6

H3C CH2OH
H
H H O
O O
H Ph C O
Ph C O Ph C O H
H H H O
O O C2H5
C2H5 C2H5 H H3C CH2OH
C2H5 O H
pKa= 16
pKa= -2.4

H
O H O C2H5 O

C C2H5 C
H2O + C2H5
Ph O Ph O

Procedure:
1.20 g of p-amino benzoic acid and 12.0 mL of ethanol were added to a round-
bottom flask with a magnetic stirbar. The mixture was left to stir until the solid
dissolved. 1.0 mL of conc. Sulfuric acid was slowly added and the mixture was
allowed to genly boil under reflux for about 75 minutes.
After reaction, the mixture was allowed to cool and was transferred to a beaker
containing 30 mL of water. 10% sodium carbonate solution was added until gas was
no longer evolved and the pH was around 8.
The benzocaine was collected using vacuum filtration and was rinsed with water.

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 EXPERIMENT 3
PREPARATION OF METHYL ORANGE

Dyes are used to give colors to substances, especially fabrics. Chromopohores,

functional groups that absorb light, give color to these dyes. The most common
chromophores are azo, nitro, and carbonyl groups. Auxochromes, functional groups
that increase the intensity of the color, are also important parts of dyes. The most
common chromophores are hydroxyl, amino, sulfonate, and carboxylate groups.
In this experiment you will prepare methyl orange, an azo dye that forms beautiful
orange crystals and is used as an acid-base indicator. The anion form is yellow and
the acid form is red.
O
HO S N
O N N

Methyl orange
O
O
X O S N H HO S NH
O N N
O N N
Yellow, pH > 4.4
Red, pH < 3.1

Procedure:
Dissolve 0.010 mole of sulfanilic acid (anhydride) in about 50 ml of a solution of
sodium carbonate containing 0.010 to 0.0125 moles of sodium carbonate in a 125 ml
Erlenmeyer flask. Warm the mixture slightly to speed up dissolution. Test one drop of
the solution to make sure it is alkaline. If not, add a small amount (1-2 mL) sodium
carbonate solution and check the pH again. Then add 0.010 moles sodium nitrite and
cool to 25 °C (room temperature).
Put 40 g of ice in a 400 mL beaker and add enough hydrochloric acid of a 6M or a
12 M solution in order to provide a total of 0.030 mol HCl in your beaker. Add the
sulfanilate solution prepared above in a fine stream while stirring continuously. Keep
this solution cold in the ice bath at all times. It now contains your diazonium salt,

13
which will decompose if it becomes warm. It is only partially soluble in the aqueous
solution and will precipitate as a bluish-greenish solid.
Prepare a solution of N,N-dimethylaniline (0.010 mol) in 0.010 mol of acetic acid in a
25 ml Erlenmeyer flask.Now add the dimethylaniline acetate solution slowly with
constant stirring to thesuspension of the diazonium salt. A dull, reddish-purple mass
should appear.
Now, VERY SLOWLY add about 30 mL of 1.0 M sodium hydroxide solution
with constant stirring. Add the NaOH a few mL at a time. The addition should take 10
- 15 minutes. The reaction takes place best at about pH 7. Keep adding the NaOH
until the solutionbecomes basic (blue to litmus.)
At the end of the coupling reaction a yellow-orange or golden color should be
observed. The product will now be recrystallized from the reaction mixture. And
filtered by Buchner funnel.

EXPERIMENT 4
PREPARATION OF BENZANILIDE
O NH2 O

Cl N + HCl
H

A carbonyl group is a carbon double-bonded to an oxygen; an acyl group is a

carbonyl group attached to an alkyl or aryl group. Acyl halides, acid anhydrides,
esters, and amides are called carboxylic acid derivatives because they differ from a
carboxylic acid only in the nature of the group that has replaced the OH group of the
carboxylic acid. Cyclic esters are called lactones; cyclic amides are lactams. There
are symmetrical anhydrides and mixed anhydrides. Carbonyl compounds can be
placed in one of two classes. Class I carbonyl compounds contain a group that can be
replaced by another group; carboxylic acids and carboxylic acid derivatives belong to
this class. Class II carbonyl compounds do not contain a group that can be replaced by
another group; aldehydes and ketones belong to this class. The reactivity of carbonyl
compounds resides in the polarity of the carbonyl group; the carbonyl carbon has a
partial positive charge that is attractive to nucleophiles. Class I carbonyl compounds
undergo nucleophilic acyl substitution reactions: a nucleophile replaces the
substituent that was attached to the acyl group in the reactant. All Class I carbonyl
compounds react with nucleophiles in the same way: the nucleophile attacks the
carbonyl carbon, forming an unstable tetrahedral intermediate.

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Benzoylation is an important transformation in Organic Synthesis. Benzoylation is
often employed for the characterization and identification of aromatic amines
(primary and secondary).

Benzoylation has two important advantages over acetylation (a) benzoyl

chloride is so slowly hydrolyzed by water that it can be carried out freely in an
aqueous medium. (b)Benzoyl derivatives usually have a higher m.p., and are usually
much less soluble in most solvents, moreover all are insoluble in water. For
benzanilide preparation aniline is treated with benzoyl chloride in the presence of
sodium hydroxide solution.

Procedure:-

In Erlenmeyer flask place 2.6g (2.5ml0 of aniline and 25mlof aqueous 10% sodium
hydroxide solution. To this add 4.3g (3.5ml) of benzoyl chloride in small portions
with vigorous shaking for 1 min after every addition. Cork the flask and shake
vigorously for 10min. the reaction is exothermic and the flask becomes hot. Benzoyl
derivative may separate out as a white powder when the reaction is complete9Notes I
and II). Filter the solid on Buchner funnel at the pump. Wash several times with water
and drain. Recrystallize from boiling alcohol.

EXPERIMENT 5
ALDOL CONDENSATION
SYNTHESIS OF DIBENZALACETONE
Purpose - The objectives of this experiment are to learn aldol condensation mixture
of aldehydes and ketones, which used extensively in organic synthesis to form C-C
bonds and make bigger molecules.

Dibenzalacetone is a common ingredient in sunscreen. This is because

dibenzalacetone absorbs UV light and helps to protect the skin from the sun’s
damaging rays. The properties that are most valuable in a compound that is used in
sunscreen are the compound’s abilities to absorb, reflect, or even scatter the harmful
UV rays. Another importance is for the compound to not cause an allergic reaction on
a person’s skin.

15
Introduction
Like the Grignard reaction, the Aldol Condensation is an extremely useful
carbon-carbon bond-forming reaction in organic chemistry. Under the reaction
conditions in the experiment, two equivalents of aldehyde will react.
O
O O

aq. NaOH
+ Ar Ar
Ar H
R R
R R

The aldol condensation is a reaction that is named based on the type of product
formed when two aldehydes (or ketones), in the presence of dilute base, yields a
molecule having both alcohol and aldehyde functional groups. An example of the type
of base-catalyzed aldol condensation that you will perform is shown below.
O O
O
H -H2O
2
+ NaOH

Benzaldehyde Acetone Dibenzalacetone

These products are a β-hydroxyaldehyde (or a β-hydroxyketone). This reaction

is used extensively in organic synthesis to form C-C bonds and make bigger
molecules. In every case, the product results from the addition of one molecule of an
aldehyde (or ketone) to a second molecule in such a way that the a-carbon of the first
becomes attached to the carbonyl carbon of the second.

MECHANISM OF THE ALDOL CONDENSATION

The acidity of the alpha-carbon makes beta-dehydration of aldols an easy
reaction. (This is of course quite different than the chemistry of normal alcohols.)
This conjugated enone synthesis is catalyzed by both acids and bases. This shows the
mechanism of the experiment performed. The reaction proceeds by an aldol
condensation.

Step 1: First, an acid-base reaction.

Hydroxide functions as a base and removes the acidic α-hydrogen giving the reactive
enolate.

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 O O O
H
OH
H3C C H3C CH2 H3C CH2
H2
Step 2: The nucleophilic enolate attacks the aldehyde at the electrophilic carbonyl C
in a nucleophilic addition type process giving an intermediate alkoxide.
O O
O O

H3C CH2 + H
H3C

Step 3:

An acid-base reaction. The alkoxide deprotonates a water molecule creating

hydroxide and the β−hydroxyaldehydes or aldol product.

O O H O OH

OH
H3C H3C

B-Hydroxy ketone
(aldol product)

MECHANISM OF THE DEHYDRATION OF AN ALDOL PRODUCT

Step 1:

First, an acid-base reaction. Hydroxide functions as a base and removes an acidic α-

hydrogen giving the reactive enolate.
O OH
O OH
OH
H3C
H3C
H
reactive enolate

Step 2:

The electrons associated with the negative charge of the enolate are used to form the
C=C and displace the leaving group, regenerating hydroxide giving the conjugated
ketone.

17
 O OH O

H3C H3C

Dehydration generally occurs under slightly more vigorous conditions, such as

higher temperature, than the condensation reaction. Thus at higher temperature in
base the aldol reaction will go directly to the conjugated enone without any isolation
of the aldol intermediate

Notice that the aldehydes which aren’t contain an enolizable α-hydrogen, so

they cannot act as the nucleophilic species in the aldol reaction. Ketones, in general,
are less susceptible to nucleophilic attack than aldehydes, so in a reaction mixture
containing both an aldehyde and a ketone, the aldehyde will react faster with
nucleophiles. Thus, it is possible to perform a "crossed" aldol reaction in which the
enolate formed by abstraction of the alpha-hydrogen on the ketone attacks the
carbonyl of the aldehyde. Since we are working with conjugated aldehydes, the
resulting beta-hydroxyketones readily eliminate water to form enones. Under the
conditions used in this experiment (an excess of aldehyde), a "double condensation"
occurs by reaction on both sides of the ketone to give the products.

In the present case, the reaction—a mixed, or crossed aldol condensation

involving an aromatic aldehyde—is referred to as a Claisen-Schmidt condensation.
The Claisen-Schmidt condensation always involves dehydration of the product of the
mixed addition to yield a product in which the double bond (produced during
dehydration) is conjugated to both the aromatic ring and the carbonyl group.

Procedure:-

1- Mix 0.025 mole of benzaldehyde (MW =106 g/mole, density = 1.04 g/ml) with
0.0125 mole of acetone [ MW = 58.1, density = 0.790 g/ml.] in a 25 or 50-ml
conical flask. Set the flask (flask #1) aside.
2- In a 125 or 250-ml Erlenmeyer flask (flask #2) dissolve 2.5 g of sodium hydroxide
in 25ml of water, add 20 ml of ethanol, and cool this solution to 20oC.
3- Add half of the benzaldehyde-acetone solution (flask #1) to the sodium hydroxide
solution (flask #2) and swirl the mixture frequently for 15 minutes. The mixture
should turn cloudy within a couple of minutes of mixing and a yellow precipitate
should form.
4- After 15 minutes add the second half of the benzaldehyde-acetone mixture (flask
#1) to the basic mixture (flask #2). Rinse flask #1 with a little ethanol and add this
to the basic mixture (flask #2) also.

18
5- Continue swirling frequently for 30 minutes. Collect the yellow precipitate by
suction filtration in a Buchner funnel. Transfer the yellow solid to a large beaker
and add 300 ml of water. Stir this mixture to break up clumps of the product so the
water can dissolve the remaining sodium hydroxide; the dibenzalacetone is
insoluble in water. Collect the crude product by suction filtration on a Buchner
funnel using a fresh piece of filter paper.

EXPERIMENT 6
THE BENZOIN CONDENSATION OF BENZALDEHYDE

O O

H CN
H2O/EtOH OH
Benzoin

Aromatic aldehydes, in the presence of catalytic cyanide ion, dimerize to form

the corresponding _-hydroxyketone (acyloin). This reaction, which is reversible, is
known as the benzoin condensation. This “condensation” is a bit of a misnomer since
it is not actually a condensation reaction since no water or alcohol is produced but two
species do come together. Cyanide acts as a catalyst and has three different roles in
this process as shown in the mechanism below.
Addition of the cyanide ion to create a cyanohydrin effects an umpolung of the
normal carbonyl charge affinity, and the electrophilic aldehyde carbon becomes
nucleophilic after deprotonation:
O O
CN OH
O CN
H CN H H
H
H
OH

A strong base is now able to deprotonate at the former carbonyl C-atom

OH
OH OH
CN OH
OH CN CN
H CN
O
H H

A second equivalent of aldehyde reacts with this carbanion; elimination of the catalyst
regenerates the carbonyl compound at the end of the reaction:

19
 OH OH
OH
O
CN H H
+ H CN OH
CN O OH

Then
H
O
O O
OH

O CN OH OH
CN OH H H

The cyanide ion catalysis works only for aromatic aldehydes presumably
because the carbanion is stabilized not only by the cyano group but also by
delocalization into the aromatic ring. Of course one of the drawbacks with using
cyanide as a catalyst is the toxicity of cyanide or HCN. Care must be taken not only
with the handling of the cyanide but also with its disposal. If it is inadvertently poured
down a sink in which acid might be present then volatile and poisonous HCN is
produced.

Troubleshooting the Benzoin Condensation Reaction

The biggest problem with this experiment is trying to get the product to crystallize.
The crystallization procedure used here is referred to as solvent-pair crystallization.
Here, benzoin has a low solubility in water, high in ethanol, so as the water content
increases for an ethanol/water solution of benzoin, the benzoin (hopefully) begins to
precipitate. Often, however, the resulting reaction mixture is an oil, i.e., a supercooled
liquid. Besides scratching the side of the glass of the container with the mixture, there
are several other options that you may follow--sometimes a combination of the
following are necessary.
1- Scratch the walls of the container with a glass stir rod. Don't bear down on the
glass so much that you break the stir rod--shards of glass aren't the goal here.
2- Dip the stir rod into the mixture, let it air-dry until you see some small amount of
crystalline or powdery solid on the stir rod. Now, place the container in ice water,
and continue to scratch the walls of the container.

20
3- Try reducing the alcohol content of the mixture by letting it evaporate slowly
from an uncovered container between lab periods or boiling away with the aid of
some boiling chips.
4- Cool and add little more water, dropwise. This causes more oil to form. Be sure
you know which layer is the oil and which is the watery layer. Take the oil, add
just enough ethanol to redissolve the oil to give a homogeneous mixture, then try
scratching, cooling, add a little more water until the solution just becomes a little
cloudy, then let it stand uncovered.
Save your benzoin for next week’s lab.
Procedure:-

Place 0.5g of potassium cyanide (note) in a round bottomed flask, dissolve it in 5 ml

of water, add 10 ml of 95% ethanol and 5 ml of pure benzaldehyde, introduce a
boiling stone, attach a short condenser, and reflux the solution gently for 30 min.
Remove the flask, cool it in an ice bath, and, if no crystals appear within a few
minutes, withdraw a drop on the stirring rod and rub it against the neck of the flask to
induce crystallization. When crystallization is complete, collect the product and wash
it free of yellow mother liquor with a 1:1 mixture of 95% ethanol and water. Melting
point (134-135°C) .

EXPERIMENT 7
PREPARATION OF BENZIL
Benzoin can be oxidized to the a-diketone, benzil, very efficiently by nitric acid
or by copper(II) sulfate in pyridine. On oxidation with sodium dichromate in acetic
acid the yield is lower because some material is converted into benzaldehyde by
cleavage of the bond between two oxidized carbon atoms and activated by both
phenyl groups (a). Similarly, hydrobenzoin on oxidation with dichromate or
permanganate yields chiefly benzaldehyde and only a trace of benzyl

21
 Test for the Presence of Unoxidized Benzoin. Dissolve about 0.5 mg of crude
or purified benzil in 0.5 mL of 95% ethanol or methanol and add one drop of 10%
sodium hydroxide. If benzoin is present the solution soon acquires a purplish color
owing to a complex of benzil with a product of autoxidation of benzoin. If no color
develops in 2-3 min, an indication that the sample is free from benzoin, add a small
amount of benzoin, observe the observe the color that develops, and note that if the
test tube is stoppered and shaken vigorously the color momentarily disappears; when
the solution is then let stand, the color reappears.
Procedure:-
Heat a mixture of 4 g of benzoin and 14 mL of concentrated nitric acid on the
steam bath for 11 min. Carry out the reaction under a hood or use an aspirator tube
near the top of the flask to remove nitrogen oxides. Add 75 mL of water to the
reaction mixture, cool to room temperature, and swirl for a minute or two to coagulate
the precipitated product; collect and wash the yellow solid on a Hirsch funnel,
pressing the solid well on the filter to squeeze out the water. This crude product (dry
weight 3.7-3.9 g) need not be dried but can be crystallized at once from ethanol.
Dissolve the product in 10 mL of hot ethanol, add water dropwise to the cloud point,
and set aside to crystallize. Record the yield, crystalline form, color, and mp of the
purified benzil.

22
 EXPERIMENT 8
SYNTHESIS OF BENZILIC ACID
In this experiment, benzilic acid will be prepared by causing a rearrangement of the
1,2-diketone benzil. The rearrangement of benzil proceeds as follows:

The driving force for the reaction is provided by the formation of a stable
carboxylate salt (potassium benzilate). Once this salt is produced, acidification yields
benzilic acid. The reaction can generally be used to convert aromatic diketones into α-
hydroxyacids. Other compounds, however, also will undergo benzilic acid type of
rearrangement.

Reaction mechanism

23
Procedure:-

1) Add 3.0 g of benzil and 9.0 ml of 95% ethanol to a 50 ml flask and attach a reflux
condenser. Heat the mixture until the benzil is dissolved.
2) Add dropwise 7.5 ml of an aqueous potassium hydroxide solution downward
through the condenser into the flask. Gently reflux the mixture for 15 minutes with
swirling. After the mixture has dissolved and has been heated for a few minutes,
the mixture will turn blue-black in colour. As the reaction proceeds, the reaction
product will turn brown and the solid may, or may not, be completely dissolved.
At the end of the reaction, remove the flask and let it cool.
3) When the mixture is cooled, continue the cooling in an ice-water bath for an
additional 15 minutes, when crystallization should be complete. Crystallization is
complete when it appears that virtually the entire mixture is solidified. If this does
not occur in 15 minutes, allow the mixture to set overnight. Collect the crystals
using vacuum filtration and wash the crystals thoroughly with three 15 cm 3
portions of ice-cold 95% ethanol. The solvent should remove most of the colour
from the crystals.
4) Transfer the solid, which is mostly the potassium benzilate salt mix to dissolve the
remaining solid will not dissolve. If solid still remains in the flask, filter it.
5) With stirring, add dropwise 15 cm3 of 1 moldm-3 HCl to the solution of potassium
benzilate. The pH should be about 2; if it is higher than this add a few more drops
of acid and check the pH again. Allow the mixture to cool to room temperature
and then complete the cooling in an ice bath. Let the solid form in the ice bath for
at least 30 min, up to about 60 min. If solid has not formed after an hour, you can
store your sample until the next lab period.
6) Collect the benzilic acid by vacuum filtration. Wash the crystals with 30-40 mL of
water to remove salts. Dry the product and collect the soild.

EXPERIMENT 9
SYNTHESIS OF DILANTIN (PHENYTOIN)
Introduction
In 1838, the German chemist, Justus Liebig reported the discovery of dilantin.
It was not uncovered, however, until 100 years later that dilantin is an anticonvulsant.
This property is currently exploited in the treatment of epilepsy. Phenytoin has been
widely prescribed for the control of epilepsy since its introduction as a pharmaceutical
agent during 1950’s, and although superseded by a number of newer drugs, it remains

24
in use today in this role. The main structural challenge for the synthesis of this
compound is the construction of the hydantoin ring. This hydantoin ring can be
formed in a one-pot procedure starting from benzil. The procedure for this reaction is
a base catalysed addition of urea to benzil that is an interesting example of a benzilic
acid re-arrangement where the phenyl groups undergoes a 1,2-migration during
formation of the hydantoin ring.
O O
O
KOH
+ NH
EtOH HN
H2N NH2
O O

Reaction Mechanism

25
Procedure:-
Place the 0.005mol sample of crude benzil in a round-bottomed flask with 0.009mol of urea,
15mL of absolute ethanol and 0.0025mol sodium hydroxide. Add a boiling chip, attach
acondenser after wrapping the ground glass joint with Teflon tape, and heat the mixture on a
sand bath under reflux for 1.5 hour. Cool the reaction mixture before adding 10 mL of water.
(If the solution is not clear, remove the suspended solids by filtration.) Then, cautiously
acidify the clear solution with concentrated hydrochloric acid. Collect the product by
vacuum filtration and wash thoroughly with water. Recrystallize the product from ethanol,
weigh it dry and calculate the yield.

EXPERIMENT 10
PREPARATION OF SUCCINIC ANHYDRIDE
Dicarboxylic acids readily lose water when heated if they can form a cyclic
anhydride with a five- or a six-membered ring. Cyclic anhydrides are more easily
prepared if the dicarboxylic acid is heated in the presence of acetyl chloride or acetic
anhydride or if it is treated with a strong dehydrating agent such as P2O5.

Acetic anhydride can be prepared by the interaction of sodium acetate and acetyl
chloride or by the addition of acetic acid to ketone.
CH3COONa + CH3COCl (CH3CO)2O + NaCl

CH2CO + CH3COOH (CH3CO)2O

The anhydride of an acid also can be prepared by treatment of the acid with a
dehydrating agent, and in the case of a dibasic acid of the type of succinic acid this
direct method is only one applicable. This particular dehydration can be accomplished
by use of either acetic anhydride or acetyl chloride:

26
The reaction of the anhydride with aniline can be used for the identification of this
primary amine, since the product is a crystalline substance of sharp melting point

On treatment with acetyl chloride, succinanilic acid is crystallized to succinanil

Procedure:-
In a 125ml round bottomed flask fitted with a reflux condenser, place 15g of
succinic acid and 20ml of acetic anhydride. Heat to the boiling point, noting that the
crystals soon dissolve, and reflux gently for 15miutes. Let the solution cool for a time
undisturbed and observe the crystallization. Finally cool in ice, collect the crystals on
a dry suction funnel, and use several small portions of ether to rinse the reaction flask
and wash the crystalline anhydride. Test the product with cold sodium bicarbonate
solution for the presence of unchanged acid.

EXPERIMENT 11
PREPARATION OF BENZYLIDINE-ANILINE (SCHIFF BASE)
Aldehydes undergo condensation with primary amines with the elimination of
water to give compounds known as Schiff's Bases, which can also be used to
characterize aldehydes. Benzaldehyde for example condenses readily with aniline to
give benzylidene-aniline.
O H+ N
+ NH2 + H2O
H H
This product is called an imine or a Schiff base. The first stage of the
mechanism (Fig. 1) is a normal nucleophilic addition. The amine acts as the
nucleophile and the nitrogen atom is the nucleophilic center. The nitrogen uses its
lone pair of electrons to form a bond to the electrophilic carbonyl carbon.. The

27
nitrogen also gains a positive charge, but both these charges can be neutralized by the
transfer of a proton from.

Mechanism:

Procedure:-
Mix 0.01mol of benzaldehyde, 0.01mol of aniline and 5 drops of acetic acid in a
beaker, then place the beaker in water bath and stir the mixture gently with a glass
rod. (globules of water soon appear on the boiling layer). After 30 minutes place the
beaker in the ice water, and stir the contents well where upon solidification should
rapidly occur. Break up the solid material and transfer to the conical flask.

EXPERIMENT 12
PREPARATION OF KETOXIME (BENZOPHENONE OXIME)
OH
O N

NH2OH.HCl

Compounds of structure R2C=N-OH derived from condensation of aldehydes

or ketones with hydroxylamine. Oximes from aldehydes may be called aldoximes;
those from ketones may be called ketoximes. Where R1 is an organic side chain and

28
R2 is either hydrogen, forming an aldoxime, or another organic group, forming a
ketoxime. O-substituted oximes form a closely related family of compounds.
Amidoximes are oximes of hemiaminals with general structure RC(=NOH)(NRR').
Certain amidoximes react with benzenesulfonyl chloride to substituted ureas in the
Tiemann rearrangement. The term oxime dates back to the 19th century, a
condensation of the words oxygen and imide

Preparation
Oximes can be synthesized by condensation of an aldehyde or a ketone with
hydroxylamine. The condensation of aldehydes with hydroxylamine gives aldoxime,
and ketoxime is produced from ketones and hydroxylamine. Generally, oximes exist
as colorless crystals and are poorly soluble in water. Therefore, oximes can be used
for the identification of ketone or aldehyde.Oximes can also be obtained from reaction
of nitrites such as isoamyl nitrite with compounds containing an acidic hydrogen
atom. Examples are the reaction of ethyl acetoacetate and sodium nitrite in acetic
acid, the reaction of methyl ethyl ketone with ethyl nitrite in hydrochloric acid, and a
similar reaction with propiophenone, the reaction of phenacyl chloride, the reaction of
malononitrile with sodium nitrite in acetic acid.
Uses
In their largest application, an oxime in an intermediate in the industrial
production of caprolactam, a precursor to Nylon 6. About half of the world's supply of
cyclohexanone, more than a billion kilograms annually, is converted to the oxime. In
the presence of sulfuric acid catalyst, the oxime undergoes the Beckmann
rearrangement to give the cyclic amide caprolactam:

Procedure:-
In a flask provided with a reflux condenser dissolve 2.5 grams of
(benzophenone or 3-hydroxy benzaldehyde) in 25 ml. of alcohol, and add a solution
of 2.5 grams of hydroxylamine hydrochloride in 8 ml of water, to this add a solution
of 5 grams of sodium hydroxide in 8ml. of water, and heat the mixture on a water-
bath for an hour. Pour the product into about 100 ml of water, filter if necessary, and
add to the filtrate dilute sulphuric acid until the solution is just acidic to litmus paper.

29
After an hour filter off the benzophenoneoxime. Weigh the product when dry and
calculate the percentage yield. Benzophenoneoxime melts at 141°C.

Keep your product for next week.

EXPERIMENT 13
BECKMMANN REARRANGEMENT OF AN OXIME

The Beckmann rearrangement, named after the German chemist Ernst Otto
Beckmann (1853–1923), is an acid-catalyzed rearrangement of an oxime to an amide.
Cyclic oximes yield lactams.

This example reaction starting with cyclohexanone , forming the reaction intermediate
cyclohexanonoxime and resulting in caprolactam is one of the most important
applications of the Beckmann rearrangement, as caprolactam is the feedstock in the
production of Nylon 6.

The Beckmann solution consists of acetic acid, hydrochloric acid and acetic
anhydride, and was widely used to catalyze the rearrangement. Other acids, such as
sulfuric acid or polyphosphoric acid, can also be used. sulfuric acid is the most
commonly used acid for commercial lactam production due to its formation of an
ammonium sulfate by-product when neutralized with ammonia . Ammonium sulfate
is a common agricultural fertilizer providing nitrogen and sulfur

Reaction and Mechanism

Oxime generally have high barrier to inversion, and accordingly this reaction is
envisioned by protontion of the oxime hydroxyl, followed by migration of the
alkyl substituent “ trans to nitrogen”. The N-O bond is simulanesouly cleaved
with the expulsion of water.

30
Procedure:-
Dissolve (10 mmol) benzophenone oxime in ethanol (20 ml) which are charge
into a round-bottom flask equipped with a magnetic stirrer and condenser and sulfuric
acid (15 mmol) is add drop-wise to the mixture. The reaction is further react for 0.5 h
and then the resulted mixture is cool to room temperature. In order to achieve the
isolated yields, 20 mmol of sodium hydroxide is added to the resulted mixture to
neutralize the acid.

EXPERIMENT 14
PREPARATION OF 2-PYRAZOLINE
BY ONE POT-SYNTHESIS
Pyrazolines are well known nitrogen-containing heterocyclic compounds and
Several methods are employed in the synthesis of pyrazolines, including the
condensation of chalcones with hydrazine and hydrazine derivative under acidi or
basic conditions.Numerous pyrazolines have been found to possess important
bioactivities,
4

3 5

N NH
2 1

31
 Because of the applications of N-phenyl pyrazoline derivatives in heterocyclic
synthesis and medicine these compounds are prepared under basic-catalyzed. In this
procedure the hydrazination reaction involves initial nucleophilic attack at position β
of the chalcone nucleus and ring closer with nucleophilic attack to carbonyl position
of chalcone. The results shwed that the advantages of ultrasound procedures are good
yields, short reaction times, and mild conditions.

Procedure:-

1-Dissolve (10 mmol) Benzaldehyde in 15ml ethanol . 2- Add 10mmol of ethanolic

NaOH 3- Dissolve 10 mmol of acetophenone in 15 in ethanol, then add to the
mixture with stirring. 4- While stirring, add 10 mmol of phenylhydrizine .
5- Reflux for 1.5hr. 6- Cool and filtrate to get ppt.

EXPERIMENT 15
PREPARATION OF DIHYDROPYRIMIDINONE
BY ONE POT THREE COMPONENTS SYSTEM
Dihydropyrimidinone are a class of hetrocyclic compounds. Three-component
reactions have emerged as useful methods because the combination of three
components to generate new products in a single step is extremely economical, among
themulti-component reactions[1–5].The combination of an aldehyde 1, β-keto ester
2, and urea 3 under acid catalysis to give a dihydropyrimidinone 4, was first
reported by Pietro Biginelli in 1893.Referred to as the Biginelli reaction.
O O O Ar

H+ NH
Ar H + H2N NH2 H3C
1 3
+ H3C N O
O O H
4

H3C OCH2CH3
2

Important of one-pot three component reaction

32
 Multicomponent reactions have proved to be remarkably successful in
generating molecular complexity in a single synthetic operation. These processes
consist of two or more synthetic steps, thus reducing time and saving both energy and
raw materials.generation of highly diverse and complex product from easily available
strating materials.one-pot multi components contribute to the requirements of an
environmentally friendly process by reducing the number of synthetic steps, energy
consumption and waste production. The principles of green chemistry have been
introduced to eliminate or reduce the use of hazardous materials in chemical
processes.

Reaction mechanism
The reaction mechanism of the Biginelli reaction is a series of bimolecular
reactions leading to the desired dihydropyrimidinone.
There are two different routes for expression of the mechanism
Route A
According to a mechanism proposed by Sweet in 1973 the aldol condensation of
ethylacetoacetate 1 and the aryl aldehyde is the rate-limiting step leading to the
carbenium ion 2. The nucleophilic addition of urea gives the intermediate 4, which
quickly dehydrates to give the desired product 5.
O O Ar
O Ar O

Ar H H H
Et O Et O OH Et O O
H

O O O
1

-H2O
O
O O O O
Ar Ar Ar
H2N NH2 H
Et O N NH2 Et O Et O
H
-H
O O O

-H2O 3
2
4 O
Ar

Et O NH

N O
H

Route B this mechanism is superseded by Kappe in 1997.

33
 This mechanism begins with rate determining nucleophilic addition by the urea
to the aldehyde.The ensuing condensation step is catalyzed by the addition of acid,
resulting in the imine nitrogen. The β-ketoester then adds to the imine bond and
consequently the ring is closed by the nucleophilic attack by the amine onto the
carbonyl group. This final step ensues a second condensation and results in the
Biginelli compound.

R R
R O

HO NH H , -H2O H N
O H + H2 N NH2
H2N H2 N
O O
R O R

R' O N R' O NH
O O O
O H2O
H2N H2N N O
R' O
H

Procedure:-

A solution of acetylacetone (10 mmol), anisaldehyde (10mmol) and urea (13mmol),

in ethanol (20ml) was reflexed in the presence of conc. HCl (3 drops) for 1.5 hr. The
reaction mixture was then poured onto crushed ice and the solid product separated
was filtered to afford dihydropyrimidinone.
Or the mixture of 10 mmol of p-methoxybenzaldehyde, 10 mmol of ethyl cetoacetate,
13 mmol of urea and 1 ml Lemon Juice was stirring for 1.5 hours at slightly heating.
Then the reaction mixture was filtered, washed with water

EXPERIMENT 16
PREPARATION OF PHTHALIMIDE

Imide refers to any compound which contains the divalent radical "-
C(=O)NHC(=O)-". Imide compounds are derived from ammonia or primary amine,
where two hydrogen atoms are replaced by a bivalent acid group or two monovalent

34
acid groups, resulting in consisting of two carboxylic acid groups (or one dicarboxylic
acid). In other description, Imide is a compound derived from an acid anhydride by
replacing the oxygen with the =NH group. Imides are monomers to prepare
polyimides that contain repeating imide groups. Aromatic polyimides have better
resistance to high temperatures and corrosion than linear polyimides. Frequently, the
term of imide refers to the combined forms such as maleimides, phthalimides, and
succinimides which are used as plastic modifiers to improve heat-resistant,
antioxidant and antifoulant properties. They are used as intermediates for the
synthesis of cross-linking agents, pesticides, dyes, antiseptics and crystalline
adducting agents. They are also useful compounds in the synthesis of primary amines
and amino acids for the application in the field of medicine and biological research.
Phthalimide, derived from phthalic anhydride with ammonium hydroxide by heating,
is used in the synthesis of primary amines and amino acids. It is used to make
synthetic indigo and phthalocyanine pigments which have macrocyclic structure
showing striking coloring features like porphyrins (biopigments). Phthalimide has
isoindole moiety. Indole structure is a motif in nature. Prominent examples include
tryptophan (aromatic side chain amino acid), serotonin (neurotransmitter), auxin
(plant growth hormone), and indigo (plant colorant). The radical "=NH" is called
imido group. Phthalimides have served as starting materials and intermediates for the
synthesis of many types of alkaloids and pharmacophores. Recently, phthalimide and
some of its derivatives have proved to have important biological effects similar or
even higher than known pharmacological molecules and so their biological activity is
being a subject of biomedical research. On the other hand Schiff bases belong to a
widely used group of organic intermediates important for production of specially
chemicals like pharmaceuticals or rubber additive.

Phthalimides in organic synthesis

Phthalimides have a number of uses for example; they are used as nitrogen
protecting groups for amino acids.
O O
O
R
NH2 150 C
O
O + N
HO DMF
R O
O O
HO
They are also used in the Gabriel synthesis for the preparation of primary
amines using potassium phthalimide

35
 O
O
R
-KCl N2H2
N R NH2
NK + R Cl
DMF
O
O
Due to the acidity of “free” phthalimides (pKa = 9) potassium hydroxide can be
used to easily convert them to the corresponding potassium phthalimide salt. The
acidic hydrogen is removed from the phthalimide upon addition of base. This results
in the formation of a phthalimide anion which is a good nucleophile that can react
with alkyl halides to produce an intermediate N-alkylphthalimide. The N-
alkylphthalimide can then be hydrolyzed to the corresponding primary amine but this
can be a slow and difficult procedure. Alternatively, N-alkylphthalimides can be
treated with hydrazine (N2H4) to give the corresponding primary amine. Only primary
amines can be synthesized by this method and as a result the use of the Gabriel
Synthesis is limited to methyl and primary alkyl halides.

Procedure:-
A solution of aryl amine or ammonium carbonate (0.01 mole) in ethanol (20
ml) was added to a solution of phthalic anhydride (0.01 mole) and sodium acetate (
10 mole) in acetic acid (45 ml). Then the reaction mixture was refluxed for near about
1.5hrs. The reaction mixture was then cool to obtained solid product, washed with
water several times.

EXPERIMENT 17
PREPARATION OF ANTHRANILIC ACID
(HOFMANN REARRANGEMENT).
Anthranilic acid is an organic compound with the molecular formula C7H7NO2.
The molecule consists of a benzene ring, hence is classed as aromatic, with two
adjacent, or "ortho-" functional groups, a carboxylic acid and an amine. The
compound is consequently amphoteric, although it is not usually referred to as
an amino-acid.

Uses

Industrially, anthranilic acid is used as an intermediate for production

of dyes, pigments, and saccharin. It and its esters are used in preparing perfumes to
imitate jasmine and orange, pharmaceuticals (loop diuretics e.g. furosemide) and UV-

36
absorber as well as corrosion inhibitors for metals and mold inhibitors in soya sauce.
Anthranilic acid can be used in organic synthesis to generate the benzyne intermediate

Hofmann Rearrangement

Treatment of an amide with sodium hypobromite or sodium hypochlorite (or

with the halogen and alkali), results in the amine of one less carbon atom being
produced. The net result being the elimination of the carbonyl group. An example is

+ Br2 + NaOH CH3NH2 + CO2 + H2O

H3C NH2

The conversion of an amide into an amine in this way is termed the Hofmann reaction
or Hofmann rearrangement, this reaction is applicable for preparation of aromatic
amine, aryl- aliphatic and heterocyclic acid, another example for this reaction is the
preparation of anthranilic acid from phthalimide.
O
COOH COOH

NaOH NaOBr
NH
NH2
NH2

O O Anthranilic acid
phthalimide phthalimidic acid

Procedure:-
1- Prepare a solution of 7.5g sodium hydroxide in 40ml. of water in 250ml conical
flask and cool to 00C or below in bath of ice and salt
2- Add 2.1ml of bromine in one portion and stir until all the bromine has reacted.
3- Add 5gm of phthalimide in one portion to the cold sodium hypobromide, and
stir vigorously,
4- Then rapidly add a solution of 5.5g of NaOH in 20ml. of water. The solid will
dissolve and the temperature will rise, warm the reaction mixture in water bath
to 800C for 5min. filter if necessary and cool in ice bath.
5- Slowly add 15ml conc.HCl with stirring until the solution just neutral
6- Add (5-6)ml of glacial acetic acid to precipitate the anthranilic acid completely
7- Filter off the product and wash with a little cold water.

37
 EXPERIMENT 18
N-PHENYLANTHRANILIC ACID
( ULLMANN CONDENSATION).
A halogen atom directly attached to a benzene ring is usually unreactive, unless
it is activated by the nature and position of certain other substituent groups. It has
been shown by Ullmann, however, that halogen atoms normally of low reactivity will
condense with aromatic amines in the presence of an alkali carbonate (to absorb the
hydrogen halide formed) and a trace of copper powder or oxide to act as a catalyst.
This reaction, known as the Ullmann Condensation, is frequently used to prepare
substituted diphenylamines, it is exemplified in the following condensation of o-
chlorobenzoic acid with aniline to give N-phenylanthranilic acid or o-
carboxydiphenylamine.

NH2
COOH COOH
+

Cl N
H

Porcedure:-
Required: Aniline 15 ml, o-chlorobenzoic acid 4 g potassium carbonate, 4 g.;
powdered copper oxide, 0.2 g.
Prepare a mixture of 15 ml. of aniline, 4 g of o-chlorobenzoic acid, 4 g of
anhydrous potassium carbonate and 0.2 g. of copper oxide in a 250 ml. round-
bottomed flask fitted with an air-condenser, and then boil the mixture under reflux for
1.5 hours: the mixture tends to foam during the earlier part of the heating owing to the
evolution of carbon dioxide, and hence the large flask is used. When the heating has
been completed, fit the flask with a steam-distillation head, and steam-distil the crude
product until all the excess of aniline has been removed The residual solution now
contains the potassium .N-phenylanthranilate: add 2 g. of animal charcoal to this
solution, boil for about 5 minutes, and filter hot. Add dilute hydrochloric acid (1:1 by
volume) to the filtrate until no further precipitation occurs, and then cool in ice-water
with stirring. Filter off the N -phenylanthranilic acid at the pump, wash with water,
drain and dry.
.

38
 EXPERIMENT 19
PREPARATION OF ACRIDONE
Acridone (I) can be readily prepared by the cyclisation of N-phenylanthranilic
Acid, using sulphuric acid. Many substituted acridones may be similarly prepared.

O O
COOH

N N N
H H H
I II

Acridone is a highly stable, bright yellow compound, only slightly soluble in

most organic solvents. The colour and the chemical stability, i.e., the absence of many
normal properties of a ketone and of a secondary amine, indicate a marked
contribution by the polar form (II), which is confirmed by the infrared spectrum of
acridone.

Procedure:-

Required: N-Phenylanthranilic acid (4 g), sulphuric acid (10ml).

Prepare a mixture of 4 g. of N-phenylanthranilic acid and 10 ml. of
concentrated sulphuric acid in a conical flask, and heat it for 1.5 hours on a water
bath. Then pour the hot dark green solution slowly and cautiously into 200 ml. of
boiling water in a 500 ml. beaker, allowing the acid to run down the side of the beaker
to prevent "spattering". Then boil the mixture for 5 minutes, and filter it whilst hot
through a Buchner funnel, and wash the acridone on the filter with hot water. For
purification, transfer the acridone to a solution of 4 g. of hydrated sodium carbonate
in 50 ml. of water, boil the mixture for 5 minutes, and then filter it whilst hot: wash
the acridone with boiling water and dry thoroughly.

39
 EXPERIMENT 20
PREPARATION OF ANTHRAQUINONE
Anthracene is oxidised by chromium trioxide, CrO3, to anthraquinone. As the
reaction is carried out in solution, a solvent is required which will dissolve both the
anthracene and the chromium trioxide, and at the same time be unaffected by the
vigorous oxidizing action of the latter compound: acetic acid fulfills these conditions
admirably.
O

CrO3

O
Anthraquinone is of great technical importance, as many of its derivatives form
valuable dyes: notable among these are the hydroxyderivatives (alizarin), the amino-
derivatives (indanthrene) and the sulphonic acids.

Procedure:-
Required. Anthracene 1g, chromium trioxide 2 g, glacial acetic acid 15 ml.
Dissolve 1 g. of anthracene in 10 ml. of glacial acetic acid and place in 50 ml.
bolt-head flask fitted with a reflux water-condenser. Dissolve 2 g. of chromium
trioxide in 2 ml. of water and add 5 ml. of glacial acetic acid. Pour this solution down
the condenser, shake the contents of the flask and boil gently for 10 minutes. Cool and
pour the contents of the flask into about 20 ml. of cold water. Filter off the crude
anthraquinone at the pump, wash with water, drain well and dry. Purify by
recrystallisation from glacial acetic acid or by sublimation.

40
 EXPERIMENT 21
PREPARATION OF SULPHANILIC ACID
(P-AMINOBENZENESULPHONIC ACID).
Sulphonation of aromatic compounds take place by using either conc. Sulfuric
acid or oleum (fuming sulfuric acid. Benzene itself is sulphonated fairly slowly by hot
conc. H2SO4, but rapidly by oleum, and the rate is related to the latter SO3 content.
Therefore, probably the attacking electrophile is SO3.
Sulphanilic acid is a highly crystalline substance which, having a low solubility
in cold water, can be readily isolated. If aniline is treated with an excess of
concentrated sulphuric acid, aniline hydrogen sulphate is first formed, and then on
heating is converted into sulphanilic acid. This conversion into the sulphanilic acid is,
however, very slow with concentrated sulphuric acid.

If aniline is treated with excess conc. Sulfuric acid and the reaction mixture
which contains aniline hydrogen sulphate is heated at 180°C p-
aminobenzenesulphonic acid (sulfanilic acid) is formed. This conversion into the
sulfanilic acid is, however, very slow with conc. Sulfuric acid, If fuming sulphuric
acid is used, the sulphonation proceeds much more rapidly, but the aniline undergoes
a certain amount of charring and decomposition on the addition of the stronger acid.
It is best, therefore, first to add concentrated sulphuric acid to the aniline, and then to
add fuming sulphuric acid to the more resistant aniline hydrogen sulphate so formed:
under these conditions little decomposition occurs, and sulphonation proceeds readily
on heating.

Procedure:
Place (10 ml) of aniline in a 250-ml round bottom flask. Add slowly and
cautiously (20 ml) of concentrated sulfuric acid in small portions. Stir the flask gently
during the addition and keep it cool by immersing the flask in cold water. Heat the
mixture at 180-190°C(fume cupboard) for about 30min. the sulphonation is complete
when a test portion(2drops) is completely dissolved by 3-4ml 2N NaOH. Allow the
reaction mixture to cool to 50°C and pour it carefully, with stirring, into about 100ml

41
cold water or crushed ice. Upon cooling the sulfanilic acid separates as colorless
crystals. Filter the crystals and dry the product. The substance does not melt sharply.

EXPERIMENT 22
PREPARATION OF ACETANILIDE
Acetylation.
Compounds of the type ROH (alcohols and phenols), and also compounds of
the type RNH2 and R2NH (primary and secondary amines) can be directly acetylated,
the reactive H atom being replaced by the acetyl radical, -COCH3. Primary and
secondary amines similarly give acetyl derivatives of the type RNHCOCH3 and
R2NCOCH8 respectively, which can be regarded as mono-and di-substituted
derivatives of acetamide, H2NCOCH3.
O O O O
NH2 +H C NH C CH3 +
3 O CH3 H3C OH

Procedure:-
Safety Note: Aniline is toxic and can be absorbed through the skin. Measure in a fume
hood and wear gloves.
1. With a magnetic stirrer, add 60-mL water and 2.5-mL of concentrated
hydrochloric acid into a 150mL Erlenmeyer flask.
2. Add 2.5-mL aniline (density 1.02 g/mL) and stir to dissolve. Note any changes in
temperature.
3. To remove color, add 0.25 g decolorizing charcoal and heat the solution to 45-
50OC. Clarify the solution of aniline hydrochloride by filtering the carbon using
vacuum filtration.
4. In a separate container dissolve 4 g sodium acetate in 15 mL water and set aside.
5. Heat the aniline hydrochloride solution to 45-50oC on a hot plate.
Safety Note: Acetic anhydride is a lachrymator and reacts with water.

Look up the definition of lachrymator.

6. Once the temperature is 45-50OC, add 4-mL of acetic anhydride (density 1.08
g/mL). Note any temperature changes.
7. Immediately add the sodium acetate solution to the Erlenmeyer flask. Continue
stirring for 10 minutes.
Quality Note: A delay of the sodium acetate addition will allow the competing hydrolysis
reaction of the acetic anhydride into acetic acid and lower the product yield.

42
 8. After the 10 minute stir, cool the product with stirring in an ice bath. After 20
minutes in the ice bath, filter the crystals by vacuum and wash them with ice-cold
water. Dry the product for the next lab period. In the next lab, calculate the yield
for the nitration step.

EXPERIMENT 23
PREPARATION OF P-NITROACETANILIDE
O O
H2SO4
NH C CH3 + HNO3 O2N NH C CH3 + H2O

Aniline is highly activated towards electrophilic aromatic substitution.

However, aniline is also a base. Once protonated, the anilinium ion is formed which
is a strong deactivator and a meta director. This nitrogen basicity makes the direct
nitration of aniline impossible.

One solution to the problem is to use an acetyl group (CH3CO) to “protect” the
nitrogen atom during the nitration by converting the amine to an amide. After
nitration, the amide protecting group may be removed by hydrolysis
The aromatic nitration of acetanilide is an exothermic reaction ; the temperature
must be carefully controlled by chilling, stirring, and the slow addition of reagents.
Acetanilide is first dissolved in the solvent, glacial acetic acid, by warming. Glacial
acetic acid is used because it is a polar solvent capable of dissolving acetanilide and
the acetate ion is a poor nucleophile so no substitution is possible. After the solution
is cooled, sulfuric acid is added; however, even with cooling, the temperature of the
solution raises almost 40oC. Both the acetanilide solution and the nitrating solution (a
mixture of HNO3, and H2SO4) must be chilled to about 10oC before the reaction is
begun.
To prevent dinitration of the acetanilide, the nitrating mixture is added in small
portions to the acetanilide solution (and not vice versa) so that the concentration of
HNO3, is kept at a minimum. After all the HNO3, H2SO4 solution has been added, the
reaction mixture is allowed to warm slowly to room temperature. If the reaction
mixture has been kept excessively cold during the addition, there will be a relatively
large amount of unreacted HNO3 present, which may cause the temperature to rise
above room temperature. If this should happen, the mixture must be rechilled.

SAFETY NOTE 1: A mixture of concentrated nitric and sulfuric acids is used as the

43
nitrating mixture. Use extreme caution when preparing and using this mixture.
SAFETY NOTE 2: Nitro compounds are toxic and can be absorbed through the skin.
You may wish to wear disposable plastic gloves during portions of this experiment.

Physical Constants

Compound Mol. Wt Density b.p.(°C) m.p. (°C)

(g/mol) (g/mL)
Aniline 93.13 1.022 184 -6
Acetic anhydride 102.09 1.082 138-142 -73
Acetic acid 60.05 1.049 116-117 15-16
Sulfuric acid (conc. 36) 93.09 1.840 330 --
Acetanilide 135.17 solid -- 113-115
p-nitroacetanilide 180.16 solid -- 215-217
p-nitroaniline 138.13 solid -- 147-148
Procedure
Place 6.5 g of acetanilide in a 125-mL Erlenmeyer flask, add 10 mL of glacial
acetic acid (CAUTION: strong irritant), and warm the flask on a hot plate in a fume
hood until the acetanilide dissolves. Cool the flask in an ice bath to about 20oC; then
add 10 mL of cold, conc. sulfuric acid. The temperature of the mixture will rise to
about 60 oC. Chill the solution to about 10oC in an ice bath. (The solution will become
very viscous.) Mix 3.5 mL of conc. nitric acid and 5 mL of conc. sulfuric acid in a 50-
mL flask, and chill the flask in an ice bath. When both solutions are cold, slowly add
the HNO3, H2SO4 solution, 1 mL at a time, to the acetanilide solution. Keep the
reaction flask in an ice bath so that the temperature of the reaction mixture is
maintained between 10-20 oC. Stir the reaction mixture carefully after each addition.
The entire addition requires about 15 minutes
After the addition is completed, allow the reaction flask to stand at room temperature
for 30 minutes. Monitor the temperature; if it raises above 25 oC, chill the flask in an
ice bath. Should the rechilling be necessary, allow the flask to stand for 30 minutes or
more at room temperature after the rechilling. Pour the reaction mixture into a 250-
mL beaker containing 100 mL of water and 25 g of cracked ice. Using a large
Buchner funnel, filter the heavy lemon-yellow precipitate with vacuum. Press out as
much aqueous acid from the filter cake as possible with a spatula or clean cork while
suction is being applied (CAUTION: see Safety Note 2). The precipitate is
voluminous; use care in transferring it to the Buchner funnel or a substantial amount
of product will be lost. Transfer the filter cake to a clean 250-mL beaker, and add 100
mL of 15% aqueous disodium hydrogen phosphate. Stir the mixture to a paste-like

44
consistency and refilter using vacuum. Wash the beaker with two 30-mL portions of
cold water. Finally, wash the filter cake with an additional 50 mL of cold water. Press
the filter cake with a spatula or clean cork to remove as much water as possible, then
dry the solid overnight on a watch glass. Determine the yield and melting point.
The crude product can be purified by crystallization from 30-60 mL of 95% ethanol.
(The crude product dissolves very slowly, even with heating; avoid using an excess of
solvent.)

EXPERIMENT 24

PREPARATION OF BENZIMIDAZOLE
NH2 O N

+ H OH N
NH2 H

Imidazole is a five membered planar ring, which is soluble in water and other
polar solvents. It exists in two equivalent tautomeric forms because the hydrogen
atom can be located on either of the two nitrogen atoms. The compound is classified
as aromatic due to the presence of a sextet of π-electrons, consisting of a pair of
electrons from the protonated nitrogen atom and one from each of the remaining four
atoms of the ring. Some resonance structures of imidazole are shown below:

N N N N N

HN HN HN HN HN

Amphotericity
Imidazole is amphoteric, i.e. it can function as both an acid and as a base. As an
acid, the pKa of imidazole is 14.5, making it less acidic than carboxylic acids,
phenols, and imides, but slightly more acidic than alcohols. The acidic proton is
located on N-1. As a base, the pKa of the conjugate acid (cited above as pKBH + to

45
avoid confusion between the two) is approximately 7, making imidazole
approximately sixty times more basic than pyridine. The basic site is N-3

Pharmaceutical derivatives
The substituted imidazole derivatives are valuable in treatment of many
systemic fungal infections. Imidazoles belong to the class of Azole antifungals. The
imidzaoles include: (Ketoconazole, Miconazole, Clotrimazole).

Industrial applications
Imidazole has been used extensively as a corrosion inhibitor on certain
transition metals, such as copper. Preventing copper corrosion is important, especially
in aqueous systems, where the conductivity of the copper decreases due to corrosion.
Many compounds of industrial and technological importance contain imidazole
derivatives. The thermostable polybenzimidazole PBI contains imidazole fused to a
benzene ring and linked to a benzene, and acts as a fire retardant. Imidazole can also
be found in various compounds which are used for photography and electronics
Procedure:
Place 27g (0.25mol)of o-phenylenediamine in a 250ml round bottomed flask
and add 17.5g916ml,0.34mol) of 90% formic acid. Heat the mixture on a water bath
at 100°C for 2 hours. Cool, add 10% sodium hydroxide solution slowly, with constant
rotation of the flask, until the mixture is just alkaline to litmus. Filter off the crude
benzimidazole at the pump, wash with ice cold water, drain well and wash again with
25ml cold water. Dissolve the crude product in 400ml of boiling water, add 2g of
decolorizing carbon and digest for 15minutes. Filter rapidly at the pump through a
preheated Buchner funnel and flask. Cool the filtrate and dry at 100°C. The yield of
pure benzimidazole, m.p. 171-172C, is 25g (85%).

46
 EXPERIMENT 25
PREPARATION OF TETRAPHENYLPORPHYRIN

Porphyrins are macrocylic tetrapyrrole systems with conjugated double bonds

and various groups attached to the perimeter

Tetraphenylporphyrin abbreviated TPP or H2TPP, is a synthetic heterocyclic

compound that resembles naturally occurring porphyrins. Porphyrins are dyes and
cofactors found in hemoglobin and cytochromes and are related to
chlorophyll and vitamin B12. The study of naturally occurring porphyrins is
complicated by their low symmetry and the presence of polar substituents.
Tetraphenylporphyrin is hydrophobic, symmetrically substituted, and easily
synthesized. The compound is a dark purple solid that dissolves in nonpolar organic
solvents such as chloroform and benzene.

Tetraphenylporphyrin was first synthesized in 1935 by Rothemund, who caused

benzaldehyde and pyrrole to react in a sealed bomb at 150 °C for 24 h. Adler and
Longo modified the Rothemund method by allowing benzaldehyde and pyrrole to
react for 30 min in refluxing propionic acid.

Procedure:
Heat 40 mL of propanoic (propionic) acid to reflux. Once the propanoic acid
begins to reflux vigorously, add a mixture of 1.65 mL (15.75 mmol) of benzaldehyde
and 1.0 mL (14.4 mmol) of pyrrole by slowly pouring this solution down the reflux
condenser. Rinse the pyrrole and benzaldehyde down the condenser with 10 mL of
propanoic acid. Reflux the solution for 30 min and allow the flask to cool for a few
minutes. Filter the dark brown mixture through a medium porosity frit. Rinse the
mixture with a few mL of methanol until the washings are clear and purple crystals
remain on the frit. Allow the crystals to dry by pulling air through them for several
minutes.

47
 EXPERIMENT 26
PREPARATION OF O-LODOBENZOIC ACID
The Sandmeyer reaction is a versatile means of replacing the amine group of a
primary aromatic amine with a number of different substituents.

HBF4
F

CuCl
Cl

CuBr
Br

N+ N Cl KI
I

HCl H2O
0-5OC NaNO2 OH

NH2 H3PO2 H

CuCN CN

The diazonium salt is formed by the reaction of nitrous acid with the amine in
acid solution. Nitrous acid is not stable and must be prepared in situ; in strong acid it
dissociates to form nitroso ions, + NO, which attack the nitrogen of the amine. The
intermediate so formed loses a proton, rearranges, and finally loses water to form the
resonance-stabilized diazonium ion.

Procedure:
A 500-mL round-bottomed flask containing 13.7 g of anthranilic acid, 100 mL
of water, and 25 mL of concentrated hydrochloric acid is heated until the solid is
dissolved. The mixture is then cooled in ice. When the temperature reaches 0-5°C a
solution of 7.1 g of sodium nitrite is added slowly. After 5 min a solution of 17 g of
potassium iodide in 25 mL of water is added, when a brown complex partially
separates. The mixture is let stand without cooling for 5 min (under nitrogen) and then
warmed to 40°C, at which point a vigorous reaction ensues (gas evolution, separation
of a tan solid). After reacting for

48
10 min the mixture is heated on the steam bath for 10 min and then cooled in ice. A
pinch of sodium bisulfite is added to destroy any iodine present and the granular tan
product collected and washed with water. The still moist product is dissolved in 70
mL of 95% ethanol, 35 mL of hot water is added, and the brown solution is treated
with decolorizing charcoal, filtered, diluted at the boiling point with 35-40 mL of
water, and let stand. 2-Iodobenzoic acid separates in large, slightly yellow needles of
satisfactory purity (mp 164°C) for the experiment.

REFERENCES

1- Frederick G. M and Bernard C. S., "practical organic chemistry" 4th Ed.

Longman Inc., New York 1960
2- Bettelheim and Landesberg; "Laboratory Experiments For General, Organic
and Biochemistry" 4th Ed.
3- Vogel A. I., Furniss B.S., Hannaford A.J., Smith P.W.G., Tatchell A. R.,
“Vogel's Textbook of Practical Organic Chemistry”,5th Ed., Prentice Hall,
1996.
4- Paula Y.B., "Organic Chemistry" 6th Ed. McGraw-Hill 2007.

49