Experiment (1):

Nitration of Methyl Benzoate

Electrophilic Aromatic Substitution

Objectives of the Experiment:

The purpose of this experiment is to synthesize methyl nitrobenzoate from methyl

benzoate using concentrated HNO3, and concentrated H2SO4 via an electrophilic aromatic
substitution reaction. Later, the emerged product would be used to generate Nitro Benzoic
Acid by means of hydrolysis.

Background:

Aromatic systems such as the benzene ring have enhanced resistance toward reactions due
to the stability that resonance gives to the aromatic ring. Addition reactions are highly
unlikely as they would destroy the conjugated aromatic system. Substitutions can occur
and the best reagent to use should have electrophilic properties as the aromatic ring is rich
in electrons.

There are five reactions that are normally presented when discussing electrophilic
aromatic substitution reactions. They include:

1. Nitration using concentrated nitric acid and concentrated sulfuric acid to generate
the nitronium ion electrophile (which will be done in this experiment).
2. Halogenation using a halogen and a Lewis acid to generate the halonium ion
electrophile, such as Chlorination and Bromination.
3. Sulfonation using sulfur trioxide as the electrophile. This is the only neutral
electrophile in this series of reactions and this reaction is reversible.
4. Friedel-Crafts alkylation using some source of a carbocation as the electrophile.
This reaction will be done next week and will use an alcohol and concentrated
sulfuric acid to generate the carbocation.
5. Friedel-Crafts acylation using an acyl halide and a Lewis acid to generate the
acylium ion electrophile.

21
Nitration Reaction:
O O
N
HNO3 + H2SO4

Nitrating Mixture

22
Substituent Effects in EAS Reactions (Activating and Deactivating Substituents):

To fully understand the concept of activating and deactivating groups, you need to
consider the following examples:
NO2
HNO3 + H2SO4

Nitrating Mixture

CH3 CH3 CH3 CH3

HNO3 + H2SO4 NO2

Nitrating Mixture NO2

NO2

Major Major Minor

Nitration of toluene is much faster than the nitration of benzene; we can say that the
methyl group activates the aromatic ring towards nitration.
From the nitration of toluene, we found that the major products are p-nitrotoluene and o-
nitrotoluene; and only a small amount of m-nitrotoluene is formed. We say the methyl
group is an ortho, para director for electrophilic substitutions.
Generally, A substituent (-X) is said to be an ortho-para director if it directs an
incoming electrophile to positions ortho and/or para to itself. On the other hand, any given
substituent (-X) is said to be a meta director if it directs an incoming electrophile to
position meta to itself. Please refer to the following scheme:

23
Methyl benzoate is an aromatic compound structurally related to benzene. The aromatic
ring, being electron rich, reacts with electrophiles. One common electrophile used in these
reactions is (NO2+).This ion is not stable, so it must be made in the reaction flask that
contains the aromatic compound (methyl benzoate, in this case). This can be done by
treating nitric acid with sulfuric acid, as shown in the equation below. (Sulfuric Acid
protonates Nitric Acid acting as a weak base to form the Electrophilic Nitronium Ion,
which is added to the resonance disrupted Benzene ring replacing a Proton.
To keep the aromatic ring (which is especially stable, and therefore favorable) in the
product, the electrophile substitutes for one of the hydrogens on the ring, rather than
adding, like it does with alkenes. So which hydrogen on the ring is replaced? That's
determined by the group that already is attached to the ring at the start of the reaction. In
the case of methyl benzoate, the properties of the carbonyl group attached to the ring
direct substitution to the meta position. (You should confirm this by confirming the
identity of your final product.

Reactions involved in this experiment:

Step-1

HNO3 2 H2SO4 O N O 2 HSO4 H3O

Nitronium ion

CO2Me CO2Me
HNO3

H2SO4 NO2

Methyl Benzoate Methyl-3-nitrobenzoate

MW 136.15 g/mol MW 181.15 g/mol
bp 198-199°C mp 78-80°C

Step-2

O O O O Na O OH
C CH3 C C
NaOH H

NO2 NO2 NO2

24
Precautions & Safety Notes (before you begin):

In the experiment that will be done today, a substituted aromatic ring is used which will
lead to meta-nitration of the ring. The substituent chosen will moderate the reaction to
avoid di- and tri- substitution of the ring which could lead to explosive products.
Trinitrobenzene is explosive. It is best not to heat the reaction too high or too long to
avoid further undesired substitution.

Also note that this reaction often shows a delayed start. It is best to be patient. If the
mixture is heated highly or longer than directed, an uncontrolled reaction may ensue. And,
if the reaction is quickly quenched in an ice bath, it may be permanently stopped. If brown
fumes start to form, the reaction may be proceeding too quickly and should be moderated.

Concentrated nitric acid and concentrated sulfuric acid pose a hazard when being handled.
Gloves must be worn and care must be used. If any of the acid mixture gets on the skin,
it must be immediately washed with large amounts of cold water. Immediately wash the
affected area with water if you suspect that acid may be on your skin. Nitric acid destroys
proteins and if some of it (either as liquid or vapors) gets on the skin, the skin cells will
die over a few hours to days leaving an orange patch on the surface. This generally wears
off in a few days. This reaction usually goes well if care is exercised. The final product is
a crystalline solid with a low melting point.

Methanol is toxic and must be used in well-ventilated space only. All materials must be
discarded in the containers provided

Experimental Procedure:

1. Add 5 mL of concentrated sulfuric acid directly to a 50-mL Erlenmeyer flask

containing a stir bar. (If you don't have a very clean Erlenmeyer, do not wash now! The
water will do more harm than any residue that may be present.)
2. Set an ice bath on a stir plate and cool the solution in an ice bath. Turn the stirrer on.
3. Measure out 1.00 mL of methyl benzoate via syringe from the reagent bottle, and inject
it directly from the syringe into the cooled, stirring sulfuric acid solution.
4. Measure about 1.0 mL of concentrated nitric acid, add to 1ml of concentrated sulfuric
acid, the accuracy does not need to be high, cool, then add the nitric acid/sulphuric acid
mixture dropwise, by you dropper, over 3-4 minutes, to the methyl benzoate/sulfuric acid
solution, which should still be kept cold in the ice bath and being continuously stirred.
After completion stir for 5 more min.

25
5. Remove the cold bath and let the mixture stand at room temperature for 20 minutes,
with continuous stirring.
Note: (Use extreme care to avoid adding any additional water to the reaction mixtures.
Water must be kept to a minimum so as to enhance the reactivity of the nitrating mixture.
Water is a stronger base than HNO3, which is basic relative to H2SO4; thus, it would
interfere with the protonation of the Nitric Acid, hence the formation of the Nitronium ion.
The reaction temperature must be kept low to prevent the excessive formation of the
Dinitration products.
6. Pour the reaction mixture over about 20 ml of crushed ice in a 100 ml beaker, stirring as
you pour. Add another 10 ml of ice-cold water to the original Erlenmeyer, Swirl the water
around in the Erlenmeyer so that as much as possible of the original solution has a chance
to go into the water Pour the aqueous solution from the Erlenmeyer into the beaker.
Chill the mixture completely on an ice bath until crystallization of product is complete.
7. Collect the crystals by vacuum filtration. (Try to get the ice to melt first!) To remove
the strong acid impurities, add 2-3 ml of cooled distilled water, stir the product and wash
with water in the filter funnel (carefully avoiding disturbing the filter paper), and remove
the water by turning on the vacuum. Repeat this wash procedure (three times). Drain
thoroughly under vacuum for 2-3 minutes. Dry a small amount on a filter paper and
determine the melting point; use the remainder of the product for the next step without
any further purification or drying
8. Put your product in small round bottom flask and add 10 ml of methanol. Dissolve the
crystals and add 10 ml of 50% sod hydroxide solution (NaOH) stir and reflux for 20
minutes.
9. Cool using ice bath then add conc. HCl to the solution drop wise until precipitate
formed, observe the formation of the solid, to insure complete precipitation of the product
check the pH of the solution, pH should be around 4.Cool using ice bath.
10. Collect the product by vacuum filtration, don’t rinse with water, Dry and find the
mass, and melting point.

26
IR Spectrum of m-Nitro Methylbenzoate using KBr disk:

27
 Experiment (1): Nitration of Methyl Benzoate
Electrophilic Aromatic Substitution
LAB. REPORT
Group Members & University ID's: Section: Encircle as appropriate
UM UE MM ME TM
TE WM WE RM RE

Date: ( / /201 )

Objectives of the Experiment:

 To synthesize 3- nitro Methyl Benzoate.

 To prepare 3-nitro Benzoic Acid.
 To learn

Results:

Step-1)

CO2Me CO2Me
HNO3

H2SO4 NO2

Methyl Benzoate Methyl-3-nitrobenzoate

MW 136.15 g/mol MW 181.15 g/mol
bp 198-199°C mp 78-80°C
A

Melting Point = --------------------------------Cο

Mass collected (Practical) = ------------------g.

Mass expected (Theoretical) = ---------------g.

Percentage Yield = ----------------------------%

28
Step-2)

NaOH/H2O/Methanol

HCl/H2O

Melting Point = --------------------------------Cο

Molecular Weight = ---------------------g/mole

Mass collected (Practical) = ------------------g.

Mass expected (Theoretical) = ---------------g.

Percentage Yield = ----------------------------%

29
Show your calculations for the percentage yield for compounds (A and C):

30
Post-Lab Questions:
1) Using a resonance argument, show why phenol is an ortho para director?

2) Write the equation of step number 8 of the experimental procedure.

What kind of reaction is this?

3) Write the equation of step number 9 of the experimental procedure.

What kind of reaction is this?

End of Report Instructor's Signature: -----------------------

31
 Experiment (2) PART :A
Friedel-Crafts Alkylation Reaction
Preparation of 1,4-Di-t-Butyl-2,5-Dimethoxybenzene

Objectives of the Experiment:

Throughout this experiment the student will be introduced to the Friedel-Crafts alkylation
reaction, another one of the important electrophilic aromatic substitution reactions. The
experiment uses concentrated sulfuric acid to generate an unstable carbocation.

Background:

Friedel-Crafts alkylation reactions of aromatic compounds are considered to be specific

example of Electrophilic Aromatic Substitution, where the reactions leads to C-C bond
formation (substitution of an aromatic ring with an alkyl group).

The alkyl groups can be substituted on aromatic rings by using acid catalysis, such as:
H2SO4, H3PO4, and HF, or lewis acids such as AlCl3 and BF3.

This reaction occurs in three steps: formation of the electrophile, followed by nucleophilic
attack of the arene, and re-aromatization of the ring. The overall reaction and its
mechanism are given in the figures below.

The general reaction for Friedel-Crafts alkylation of benzene.

32
 The general mechanism for Friedel-Crafts alkylation of benzene.

In the first step (generation of electrophile), the chloride has an affinity for the metal
(which has an empty p orbital) thus facilitating the formation of electrophile. In the second
step, the arene attacks the electrophile forming a resonance-stabilized intermediate. In the
third and final step, there is an equilibrium, which generates the chloride as a base. It pulls
off a proton to regenerate the aromatic product. These reactions are known to be
extremely exothermic due to the reactivity of the Lewis Acid.

In this experiment we will perform an alkylation reaction of activated benzene molecule

(1,4-dimethoxybenzene) with a tertiary alcohol (t-butyl alcohol) in the presence of sulfuric
acid as the Lewis acid catalyst to prepare 1,4-di-t-butyl-2,5-dimethoxybenzene as seen in
the equation below.

33
Limitations of Friedel-Crafts reaction:

1. It can only produce a product in good yield if the starting material is at least as
reactive as benzene. If the benzene ring has deactivating groups attached, then little
or no product is formed.

2. The product is more reactive than the starting material. Alkyl groups activate the
ring, so addition of a second or third alkyl group is a faster reaction than the initial
reaction. So poly-alkylated products are often obtained.

3. The third limitation is the carbocation re-arrangement.

In this experiment, by choosing tert-butyl alcohol, rearrangement of the carbocation is not

a factor as the tertiary carbocation that is generated will not rearrange. The activity of the
benzene ring is enhanced by the addition of two methoxy groups. The bulky tert-butyl
groups stop the polyaddition at disubstitution.

Precautions & Safety Notes

 Be careful when handling the acetic and sulfuric acid.

 Make sure to use a clean spatula, filter flask, and reaction tube.
 Make sure to return the top (cap) to the reagent bottles.
 Consult your instructor for waste disposal.

34
Experimental Procedure:

1- Place 1,4-dimethoxybenzene (0.300 g, 2.2 mmoles) and acetic acid (1 mL) in a

suitable test tube or vial (not micro-scale) and, if needed, gently warm to dissolve.
2- Add pre-melted t-butyl alcohol (0.5 mL) to this tube and cool the entire mixture in
an ice bath.
3- Carefully add concentrated sulfuric acid (1 mL) drop wise via a glass pipette
(perform this step under the fume cupboard), mixing the solution with a glass rod
after each drop. A solid product may be visible at this point, but in order to
complete the reaction, remove the reaction vessel from the ice-bath, allow it to
warm to room temperature, and let it stand for 10 minutes.
4- After this 10 minutes time, re-cool the tube in ice in order to induce complete
crystallization. At this point, very carefully add distilled water (5 mL) drop wise to
the mixture in the reaction vessel, stirring after the addition of each drop.
5- Filter off the product using a Buchner funnel and pre-weighted filter paper and
wash the solid with ice-cold water. You could also further wash the crystals in the
Buchner funnel with cold methanol to purify it.
6- Put in an oven to allow the product to dry.
7- Record the mass and melting point of the crude product and determine the
percentage yield. If needed, recrystallize the product in the minimum amount of hot
methanol, and determine the mass, melting point and percent yield of the purified
product.
8- Further structural investigation such as (IR, NMR, etc..) could be requested by the
lab. Instructor, thus the students should ask the lab. Instructor if this step is required
or not.

35
 Experiment (2 PART A): Friedel-Crafts Alkylation Reaction
Preparation of 1,4-Di-t-Butyl-2,5-Dimethoxybenzene
LAB. REPORT
Group Members & University ID's: Section: Encircle as appropriate
UM UE MM ME TM
TE WM WE RM RE

Date: ( / /201 )

Objectives of the Experiment:

Results:

YOUR PRODUCT

Melting Point Cο
Mass collected (Practical) g
Moles or mmoles (practical)
Mass expected (Theoretical) g
Moles or mmoles (Theoretical)
Percentage Yield (%) %

38
Show your calculations for the percentage yield:

Comments and conclusions:(Give short comment about each of the followings: product's purity,
percentage yield, sources of errors, possible sample loss….etc).

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39
Post-Lab Questions:
1. If an ethyl groups (instead of t-butyl groups) is to be introduced using ethanol in a similar
reaction scheme, would the reaction work as well?

2. In our experiment, two t-butyl groups are ultimately introduced. Draw the structure
obtained after the first substitution. Why do you think you did not stop after just a single
alkylation? In other words, why were you able to add two t-butyls, not just one?

3. What would the product have been if cyclohexanol had been substituted for t-butyl alcohol
in this experiment? Draw the structure.

4. What would the product of the reaction have been if 1,3-dimethoxybenzene had been
substituted for 1,4-dimethoxybenzene in this experiment? Draw the structure.

40
 5. Could you suggest one side product that may be produced by doing this experiment.
Draw the structure.

6. Draw an arrow pushing mechanism for the reaction given in this experiment.

End of Report Instructor's Signature: -----------------------

41
 Expe:riment (2 PART B):
.. .

_;�ynthe.s.isof a_llet_erocycle:
2""Anj111:h-4��-�tl.ip1.etl1.ylpyri�idine

Heterocyclic compounds can be synthesized in two main ways. The heterocyclic ring can be
assembled from nonheterocyclic precursors (either acyclic or carbocyclic). Alternativel'y, an
easily available heterocycle (pyridine, thiophene, or furan, for example) can be structurally
modified and built up to a more complex heterocycle via substitution, addition, condensa­
tion, or other reaction types.
This experiment demonstrates the first of these two types of heterocycle syntheses.
2-Amino-4,6-dirnethylpyrimidine will be prepared from acyclic precursors. The overall
reaction is

NaOAc

guanidinc carbonate 2,4-pcnt.ancdione

(acetyl.ac:tonc)

2-amino-4,6-dimcthylpYrimidinc

The relationship among benzene, pyridine, and pyrimidine is shown by the following
structures.

0 0
bcnz.enc
(bp 8Cl°C)
N
pyridine
(bp 115°C)
-l I
N:)

N
pyrimidine
(bp 124 °C)
 /;;/!;: : � � ' . · �- � : �:. � - � : f : � : 1¥ �,�r�� · .· ocy(}le:
���2 PARTT BT���t���s.· o.f:. -���e.tet::
:-�---�F_';\ ::, ·. ,: ·.<. , : · . : ··?-<�m-!nt),-,:4:,�:-lh�et�-yfpynrrnd:nte
::::J·?tr>· · '-:�1f:if :.�:, · _ _ · - , · : ·-:·JdA1e_ttF;)'>::<)t'.t ,. :· •· · · · · · ·
Group Members & University ID's: Section: Encircle as appropriate
UM UE MM
TE WM WE

Date: ( I /201 )

Reagent Molecular Weight Grams Moles

Guanidine carbonate

2,4-Pentanedione

The· yield-limiting reagent is-----------------------,:---'-----

Theoretical yield of 2-ammo-4,6-dimethylpyrimidine: _________ mol

---------""

Actual yield: _________ g

Percentage yield: _________ %

The observed mp is _________ . The literature mp value for 2-arnino-4,6-dimethylpyrimidine is_.

151-153 ° C.
 Experiment (3):
Diel's-Alder Reaction
Anthracene with Maleic Anhydride

Objectives of the Experiment:

The purpose of this experiment is to synthesize 9,10-dihydroanthracene-9,10-α, β-succinic

anhydride utilizing an important cycloaddition reaction called Diels-Alder reaction. This
reaction will be carried out between anthracene and maleic anhydride to form what is
known as an (Adduct). Afterward, the adduct will be, purified and characterized using
traditional methods such as melting point determination and infrared-spectrum analysis.

Background:

The Diels-Alder reaction is a member of a class of reactions called cycloadditions. The

reaction involves three π bonds, two from the diene and one from the dienophile in a
concerted reaction to form a six-membered ring. Since the reaction involves four π
electrons in the diene and two π electrons from the dienophile, it is sometimes referred to
as a (4 + 2) cycloaddition reaction.

A diene is the 4-π-electron component. It is electron-rich, like a nucleophile in a Lewis

acid-base reaction. Simple dienes like are sufficiently electron-rich to react, but electron-
releasing groups such as alkyl groups (-R) or alkoxy groups (-OR) enhance a diene's
reactivity. On the other hand, the 2-π-electron component is called a dienophile (lover of
dienes). Good dienophiles contain relatively electron-poor double bonds or triple bonds; at
least one strongly electron-withdrawing group (W) is needed. See the figure that follows.

42
Because the reaction is concerted-that is, bond breaking and bond forming take place in
the same step the stereochemistry of the reactants and the symmetry of their molecular
orbitals control the stereochemistry of the products. Using well-chosen reactants, we can
control the stereochemistry of a Diels-Alder product at up to four carbon atoms.

In this experiment, maleic anhydride is used as the dienophile. Maleic anhydride is an

excellent dienophile because two strongly electron-withdrawing groups are attached to the
double bond. The diene is anthracene, which is commonly thought of as an aromatic
compound, and not as a diene. However, in polynuclear aromatic compounds like
anthracene, each individual ring may not be as well stabilized as an isolated benzene ring.
Anthracene has only 14 π electrons, compared with 18 needed for three fully independent
aromatic rings.

When anthracene's center ring reacts as a diene, the product has two fully aromatic rings,
each with six pi electrons, as shown below:

43
The reaction is carried out in xylene as a medium for the reaction, which is actually a
mixture of the three dimethylbenzenes, for three reasons. First, the 140 Cᵒ boiling point
provides a good reaction temperature. Second, the xylene mixture does not freeze when it
is cooled in ice water. Third, the reactants are more soluble in xylene than is the product,
which crystallizes.

The product is a relatively stable anhydride. Although anhydrides react with water and air,
this one reacts slowly and is easily isolated and characterized before much hydrolysis
occurs. There are several possible ways to name the product, but 9,10-
dihydroanthracene-9,10-α, β-succinic anhydride is probably the simplest.

Precautions & Safety Notes

 Anthracene is irritating. Maleic anhydride is toxic and corrosive.

 Xylene is flammable and irritating. Keep away from flames or other heat sources.
Use a fume hood.
 Protect your eyes, skin using goggles and safety clothing.
 Avoid inhaling and ingesting these compounds.
 Wash your hands thoroughly with soap or detergent before leaving the laboratory.
 Before conducting this procedure, you must review the reflux technique.

Experimental Procedure:
Conduct this reaction in a fume hood.

1- Weigh out 0.80 g of anthracene and 0.40 g of maleic anhydride and transfer the
reagents into a 50-ml round bottom flask containing a stir bar. Record both masses
to the nearest 0.01 g.

2- Add 10 ml of xylene to the round bottom flask and boiling chips. Caution: Xylene
is flammable, keep away from open flames and hot plates.

3- Set up a reflux apparatus as shown in the next page, making sure to clamp the flask
and condenser securely. Remember to grease the joints to prevent the glass from
sticking. Note: Maleic anhydride is water sensitive and the drying tube will help
prevent water in the air from entering the flask.

44
4- Heat the reaction mixture using a heating mantle to reflux (~180°C) for
approximately 30 minutes.

5- While waiting, prepare two ice water baths using two 250 ml beakers.

6- Obtain approximately 5 ml of xylene in the 100 ml beaker. Place the beaker in the
ice water bath to cool.

7- After 30 minutes, let the reaction flask warm to room temperature. Wait at least 15
minutes for the flask to warm to room temperature. Then, place the flask in the
second ice water bath for 10 minutes. You should observe crystallization at this
point.

8- Collect the solid.

a. Weigh the filter paper and record the mass to the nearest 0.01 g.
b. Set up a vacuum filtration with the Büchner funnel.
c. Filter the solid and wash the solid with ~5 mL of cold xylene.
d. Place the filter paper containing the solid on a watch glass to dry the solid.

9- Weigh the filter paper and dried product. Record the mass to the nearest 0.01 g.
10- Measure the melting point for your product. The sample should be completely
dried before taking a melting temperature.

45
Optional: Purifying your product:
For recrystallization, place the product in a 50-ml conical flask. Add 5-10 ml of xylene.
Heat the mixture gently on a hot plate until the xylene boils. Gradually add more xylene
until all the product dissolves or until no more appears to be dissolving. Do not exceed 15
ml total volume of xylene to dissolve the crystals. Allow the solution to cool to room
temperature. Then cool the solution in an ice bath for 5 min. If necessary, scratch the
bottom of the flask with a glass rod to induce crystallization. Collect the crystallized solid
by vacuum filtration, using a Buchner funnel. Rinse the crystals with 3 ml of ice-cold
xylene. Spread the product crystals thinly over a clean watch glass. Allow the crystals to
dry for about half an hour. Weigh the product and record the mass. Place the product in a
labeled product vial. Measure the melting points for both the crude product and the re-
crystallized product.

Reagents and Properties:

Substance Molar Mass m.p (Cᵒ) b.p (Cᵒ)

(g/mol)

Anthracene 178.23 216-218

maleic anhydride 98.06 54-56 200

Xylene (density 0.86) 106.17 137-144

9,10-dihydroanthracene-9,10- α, β-succinicanhydride 276.29 262-264

46
 Experiment (3): Diel's-Alder Reaction
(Anthracene with Maleic Anhydride)
LAB. REPORT
Group Members & University ID's: Section: Encircle as appropriate
UM UE MM ME TM
TE WM WE RM RE

Date: ( / /201 )

Objectives of the Experiment:

Results:

YOUR PRODUCT

Melting Point range Cο

Mass collected (Practical) g
Moles or mmoles (practical)
Mass expected (Theoretical) g
Moles or mmoles (Theoretical)
Percentage Yield (%) %

47
Show your calculations for the percentage yield:

Comments and conclusions:(Give short comment about each of the followings: product's purity,
percentage yield, sources of errors, possible sample loss….etc).

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48
Post-Lab Questions:
1- Define the terms diene and dienophile as they apply to the Diels-Alder reaction.

2- What are the products for the following Diel's Alder reactions:

49
 3- Recrystallizing an anhydride (such as the product of this reaction) from water or from an
alcohol is rarely a good idea. Explain why.

4- The product of this reaction can be hydrolyzed by water. Show the product of hydrolysis.

End of Report Instructor's Signature: -----------------------

50
 Experiment (4):
Five Membered Heterocyclic Compounds Containing Two Heteroatoms
Synthesis of 3-Methylpyrazol-5-one

Objectives of the Experiment:

Throughout this experiment, the students are expected to familiarize the different azoles
nuclei, especially the pyrazole and pyrazol-5-one nuclei, their properties, importance and
methods of preparation. In addition to that, the students are to prepare a Pyrazolone
nucleus called 3-Methylpyrazol-5-one using ethylacetoacetate and hydrazine hydrate
employing a reaction class called cyclocondensation.

Background:

Azole suffixed is used for five membered heterocycles containing two or more
heteroatoms; where at least one of them is nitrogen. They may contain two nitrogens e.g.
pyrazole and imidazole or one nitrogen and one oxygen such as oxazole and isoxazole or
one nitrogen and one sulfur e.g. thiazole and isothiazole. So these structures may be seen
as derivatives of pyrrole, furan and thiophene (see figure below):

Aromatic five-membered heterocycles

Pyrazoles:
Pyrazole (see figure) is a colorless solid with a melting point of 70 Cᵒ and a boiling point
of 185 Cᵒ. The higher the boiling point is due to its ability to form intermolecular
hydrogen bonding between dimmers (two pyrazole molecules).

51
Pyrazole exists in two tautomeric forms which shows that position 3 and 5 are equivalent
and thus pyrazole able to form only two c-alkyl derivatives i.e. 3- and 4-substituted
derivatives.

In comparison to pyrrole, pyrazole is more stable and more basic in nature. Chemically, it
is more aromatic than thiophene and electrophilic substitution takes place at C-4 than any
other nuclear carbon atom within its structure.

Pyrazole Reactivity:

1- Able to form salts when reacted with inorganic acids such as HCl, and this is due to
its basic character.

2- Could be acetylated by replacement of amino hydrogen.

3- Able to perform Electrophilic Substitution reaction i.e. Nitration, sulphonation,

halogenation…etc.

52
 4- Resistant to oxidation, because it is more aromatic and stable, but its side chain
could be easily oxidized.
5- Resistant to reduction except its N-phenyl derivative which may be reduced by
sodium in ethanol. On the other hand, pyrazole itself could be reduced in the
presence of proper catalyst i.e. H2.
6- Able to react with alkylhalides to form a quaternary salt which on boiling with
potassium hydroxide (KOH) will decompose into substituted hydrazine.

Preparing the pyrazole nucleus:

Many methods described in the literature for the synthesis of pyrazole nucleus, however
we will focus in this experiment on only one method called the “Knorr pyrazole
synthesis”, where in this reaction hydrazine or substituted hydrazine is to be reacted
with 1,3-dicarbonyl compounds to provide the pyrazole or pyrazolone ring system
according to the following reaction scheme:

53
Pyrazolones:

Pyrazolones are heteroaromatic five-membered ring compounds containing two bonded

nitrogen atoms and carbonyl group in their structure. Pyrazolone is named pyrazol-5-one,
its empirical formula C3H4N2O and represented by the structure below:

Pyrazolone can be considered as intermediate compound for synthesis of various cyclic

compounds of high biological activity such as anticancer, antiinflammatory, antifungal,
antipyretic, antitubercular, antihypertensive, antiviral and antimicrobial (see figure below).

In general pyrazolones are yellow solids with high melting points and moderate solubility
in water, alkaline and acidic solutions. They react with aldehydes in alcoholic basic
medium and with bromine to give high biologically active compounds.

In today’s experiment we will synthesize a pyrazolone nucleus called 3-Methylpyrazol-

5-one by the mean of cyclocondensation reaction of hydrazine hydrate with the β-
ketoester ethylacetoacetate (EAA). The reaction involves condensation of hydrazine with

54
EAA that leads to hydrazone formation followed by cyclisation and ring closure (See
below the reaction equation and the mechanism scheme).
Equation for the reaction:

Mechanism:

55
Precautions & Safety Notes

 This experiment should be carried-out under the fume cupboard.

 Gloves, Lab coat, eye goggles and face mask should be worn.
 Ethylacetoacetate (EAA) is irritant to skin and eyes, hazardous in case of ingestion
or inhalation.
 Hydrazine hydrate is extremely hazardous in case of skin contact (corrosive,
irritant), eye contact (irritant) and ingestion or inhalation. Very hazardous in case of
skin contact (sensitizer, permeator).

Experimental Procedure:

1- Place 6.5 g of ethylacetoacetate (EAA) in a 250-ml conical flask, then stir

magnetically.
2- In a second 250-ml conical flask, prepare a solution composed of 2.5 g (0.5 mol) of
hydrazine hydrate in 4 ml absolute ethanol.
3- Add the contents of the second flask over the first in slow, dropwise addition
allowing sufficient time for mixing. The temperature rises during this addition
which should be regulated so that a temperature of about 60 Cο is maintained (use
thermometer).
4- Once the addition is complete, a crystalline deposit will separate.
5- Keep stirring for further 1 hour at room temperature.
6- Cool the reaction mixture in an ice bath to complete the crystallization.
7- Filter the product using vacuum filtration using pre-weighted filter paper.
8- Wash the product with ice-cold ethanol while filtration.
9- Allow to dry using oven.
10- Perform an infrared (IR) analysis if required by the instructor.

Reagents and Properties:

Substance Molar Density m.p (Cᵒ) b.p (Cᵒ)

Mass (g/cm3)
(g/mol)
Ethylacetoacetate (EAA) 130.16 1.021 - 180.8
Hydrazine hydrate 50.06 1.029 - 113.5
Absolute Ethanol 46.07 - - 87.37
3-Methylpyrazole-5-one 98.103 1.107 220-224 -

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 Experiment (4):
Five Membered Heterocyclic Compounds Containing
Two Heteroatoms
Synthesis of 3-Methylpyrazol-5-one
LAB. REPORT
Group Members & University ID's: Section: Encircle as appropriate
UM UE MM ME TM
TE WM WE RM RE

Date: ( / /201 )

Objectives of the Experiment:

Results:

YOUR PRODUCT

Melting Point range Cο

Mass collected (Practical) g
Moles or mmoles (practical)
Mass expected (Theoretical) g
Moles or mmoles (Theoretical)
Percentage Yield (%) %

57
Show your calculations for the percentage yield:

Comments and conclusions:(Give short comment about each of the followings: product's purity,
percentage yield, sources of errors, possible sample loss….etc).

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58
Post-Lab Questions:

Suggest a product for the following reactions:

O O

O NH2-NH2

O O

CH3 CH3NH-NH2

End of Report Instructor's Signature: -----------------------

59
 Experiment (5):
Synthesis of Acetanilide

Objectives of the Experiment:

To synthesize acetanilide, an amide, through a Nucleophilic Acyl Substitution

(Addition/elimination) reaction between aniline and acetic anhydride, then to purify the
crude product by crystallization.

Background:
A number of the acetylated derivatives of aromatic amines such as anilines and phenols
are pharmacologically important, where some of these compounds exhibit a distinct
analgesic activity as seen in the following cases:

Primary amines react readily upon warming with acetic anhydride to yield a mono
acetylated derivative as seen in the following equation:

Amines such as aniline are considered to be more weakly basic than the corresponding
amides, thus making them (amines) more susceptible to oxidation (gain of oxygen or
losing a proton) than the amides.

The electron pair on the amidic nitrogen is less likely to be delocalized into the aromatic
ring; hence amide is stabilized by resonance involving the non-bonding pair of electrons
on the nitrogen atom and the strong electron-withdrawing carbonyl group as seen below:

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Amides have the highest melting and boiling points of all covalent organic compounds
because of the very strong dipole–dipole secondary attractions, a result of interaction
between the carbonyl group and the non-bonded electron pair of nitrogen.

In synthetic chemistry we usually convert amine into amide in case we intended to protect
the amine group from subsequent reaction effect such as oxidation, then afterward we
hydrolyze the amidic bond to retrieve the amine again.

The acetylating of aniline is a typical nucleophilic acyl substitution reaction; the

nucleophilic amine group in aniline will attack the carbonyl carbon of acetic anhydride to
give the corresponding acetanilide. Acetic acid during this procedure will be used as
catalyst, where it does not react with aniline or interfere with our reactants.

The mechanism of the reaction could be described as follow:

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In this experiment, purification of acetanilide is done by recrystallizing acetanilide in
water as a recrystallizing solvent. Generally, when choosing the proper recrystallizing
solvent you should take into account the following characteristics:

1. The impure crystals should have low solubility in the chosen solvent at room
temperature.
2. The impure crystals should have high solubility in the chosen solvent when
heated to boiling.
3. The impure crystals should not react with the solvent.
4. The solvent should boil at temperature below the solid melting point.
5. The solvent should moderately be volatile so crystals dried readily.
6. The solvent should be non-toxic, non-flammable, and inexpensive

Precautions & Safety Notes

 Acetic Anhydride causes irritation of tissue, especially the nasal passages.
 Aniline is toxic, can be absorbed through the skin.
 Gloves, Lab coat, eye goggles and face mask should be worn.
 Waste Disposal (Organics to be disposed in the safety can in the fume hood).

Experimental Procedure:

1- Place 5 ml of aniline, 8 ml of glacial acetic acid and 8 ml of acetic anhydride in 50

ml round-bottom flask (Don’t forget to add boiling stones, also you should be
careful when handling the RBF since the reaction is exothermic).
2- Assemble the reflux apparatus and heat to boiling using heating mantle for about
10 minutes.
3- Remove the round-bottom flask and cool it under running tap-water.
4- Pour the contents of RBF into a beaker containing 30 ml of iced-water and stir well
to enhance precipitation of acetanilide.
5- Filter using vacuum filtration, wash with iced-water.
6- Recrystallize acetanilide by the following procedure:
a- Place the impure crystals in 250 ml conical flask, and then add 50 ml of water
and boil.
b- Cool the conical flask for a while then add charcoal to do Decolorization.
c- Boil again, the filter to remove charcoal.
d- Take the filtrate and cool it slowly first using tap-water then ice bath to induce
the second crystallization of pure acetanilide.
7- Dry your product and determine the mass, melting point and the percentage yield.
8- Analyze your product using FT-IR machine.

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IR Spectrum of Acetanilide using KBr disk:

63
Reagents and Properties:

Substance Molar Mass Density m.p (Cᵒ) b.p (Cᵒ)

(g/mol) (g/ml)

Aniline 93.13 1.02 184.13

Acetic anhydride 102.09 1.082 139.8

Acetic Acid 60.05 1.049 118-119

Acetanilide 135.16 114.3

64
 Experiment (5):
Synthesis of Acetanilide
LAB. REPORT
Group Members & University ID's: Section: Encircle as appropriate
UM UE MM ME TM
TE WM WE RM RE

Date: ( / /201 )

Objectives of the Experiment:

Results:

YOUR PRODUCT

Melting Point range Cο

Mass collected (Practical) g
Moles or mmoles (practical)
Mass expected (Theoretical) g
Moles or mmoles (Theoretical)
Percentage Yield (%) %

65
Show your calculations for the percentage yield:

Comments and conclusions:(Give short comment about each of the followings: product's purity,
percentage yield, sources of errors, possible sample loss….etc).

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66
Post-Lab Questions:

1- Impure acetanilide was dissolved in hot water. The solution was filtered hot and the
beaker of solution was immediately placed in an ice-water bath instead being
allowed to cool slowly. What will be the result of cooling the solution in this
manner?

2- 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. Taking into consideration this information,
describe using equations how could you do nitration of aniline at the para
position?

End of Report Instructor's Signature: -----------------------

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