CHEM360 Lab Manual 2009/12 Experiment 17

Experiment 17 Date: 14th June

2018

Student Name: Helen Holy Espedido Student ID:

3330816

Title

Multi-step synthesis: Benzocaine

Purpose/Objective of Lab
The purpose of this experiment is to provide an example of how a multi-step

synthesis can

be used in order to prepare an organic compound, which is present in a

number of consumer

products. Benzocaine is a topical aesthetic that also acts as a sunburn preventative. It is

prepared by esterification of p-aminobenzoic acid, a vitamin B-complex factor necessary for

nucleic acid synthesis in some bacteria.

Introduction/Theory:

The structure of p-aminobenzoic acid (PABA) differs from the 20 naturally occurring a-amino
acids in that the amino group of PABA is attached to the 6 carbons. PABA is also classified as an
amino acid because it has both an amino group and a carboxylic group in the same molecule. As
an amino acid, PABA is physiologically active. It is incorporated by enzymes into folk acid
along with pteridine and glutamic acid. In the first step, p-toluidine is protected against oxidation
by acetylation with acetic anhydride. In the second step, the methyl group is oxidized by
CHEM360 Lab Manual 2009/12 Experiment 17

potassium permanganate to give p-acetamido benzoic acid. Hydrolysis of the acetamido group
regenerates the amine as p-aminobenzoic acid (PABA).
Benzocaine, ethyl 4-aminobenzoate, is found in medications used to ease the
pain of
wounds, burns and sunburn. It is also used in suppositories for hemorrhoid
sufferers. A
quick look around the shelves of any drug store would reveal the wide use of
this compound
in such products as Solarcainev ®, Lanacaine ® and Anivy ®. Benzocaine
may be prepared
from 4-nitrotoluene by the following five-step synthesis shown in Figure 17.1:

The approach that we will use involves the reduction of the nitro group
before the methyl
group is oxidized. The reagent used to bring about the reduction is a mixture
of tin and
hydrochloric acid. After the reduction is complete, the reaction mixture is
made basic and
CHEM360 Lab Manual 2009/12 Experiment 17

the product, 4-methylaniline, is extracted using a process called steam

distillation. Because
4-methylaniline contains two activating groups, CH 3 and NH2, it is very
susceptible to
oxidation. To prevent oxidation from occurring, the amine is immediately
converted to a salt
by dissolving it in aqueous acid.
Once 4-nitrotoluene has been converted to 4-methylaniline (in fact 4-
methylanilinium
chloride), the next step is to oxidize the methyl group. This cannot be done
directly,
however, as the highly activated aromatic ring would be destroyed under the
conditions
employed. Instead, the highly activating amino group is acetylated to give an
acetamido
group, CH3-(C=O)-NH-, which is much less activating. The product of this
reaction, 4'-
methyl acetanilide, is then oxidized to 4-acetamidobenzoic acid under
approximately neutral
conditions. The acetamido group is then hydrolyzed back to an amino group
and the
resulting 4-aminobenzoic acid is esterified to give the desired product.

The reduction of 4-nitrotoluene

The reduction of nitro compounds is the principal method of preparing
primary aromatic
amines. This reduction can be achieved through the use of hydrogen and a
suitable catalyst,
or by using a metal/acid combination such as tin and hydrochloric acid. A
variety of
nitrogen compounds is formed as the reduction proceeds, but under the
conditions used in
this experiment none of the intermediates can be isolated. The actual
product of the
reduction is the double salt, (C6H5NH3)2SnCl6, and the free amine is liberated
by treating this
double salt with base.

The acetylation of 4-methylaniline

This step is relatively straightforward and requires no detailed explanation

The oxidation of 4'-methylacetanilide

Although alkanes and aromatic hydrocarbons are generally very resistant to
oxidation, the
CHEM360 Lab Manual 2009/12 Experiment 17

carbon attached to the aromatic ring of an alkylaromatic hydrocarbon is

sufficiently activated
to be quite easily oxidized. While it is occasionally possible to obtain other
oxidation
products, an alkyl group is normally cleaved between the - and -carbons to
give the
corresponding aromatic carboxylic acid. In the oxidation of a methyl group,
the partially
oxidized intermediates, the alcohol and the aldehyde, are more easily
oxidized than the
methyl group, so that only under rather special conditions is it possible to
stop the oxidation
and isolate these intermediates. Thus, benzoic acid or some other aromatic
acid is the usual
product.
The oxidation is slow; in part because the starting material is not very
soluble, when the
reaction is complete, a large amount of solid manganese(IV) oxide and some
unreacted
permanganate ions are present. These substances may be reduced to water-
soluble
manganese(II) ions through the addition of an acidic solution of sodium
hydrogen sulfite.
The acidification also serves to convert the product from the soluble
potassium salt to the less soluble carboxylic acid and the latter then
crystallizes out of solution.

The hydrolysis of 4-acetamidobenzoic acid

The hydrolysis of an amide group is generally performed under acidic
conditions. At
elevated temperatures it is possible that, with the presence of the electron-
withdrawing
carboxyl group in the para position, some nucleophilic displacement could
occur. Once
produced, the free amine could also undergo some air oxidation.
The product of this reaction is an amino acid. In basic solutions, the amino
acid will be
converted to the water-soluble carboxylate salt, while in acidic solutions it
will be present as
the water-soluble amine salt (see Figure 17.2). Thus, care must be taken in
adjusting the pH
of the final solution so that 4-aminobenzoic acid itself is precipitated.
CHEM360 Lab Manual 2009/12 Experiment 17

The acid catalyzed esterification of a carboxylic acid is an equilibrium

reaction that
usually requires either a large excess of one of the reactants (usually the
alcohol) or the
removal of one of the products (usually water) in order for a good yield of
ester to be
obtained.
As the product of our reaction is quite soluble in ethanol, some of the latter
must be removed
from the reaction mixture before the product can be isolated.
CHEM360 Lab Manual 2009/12 Experiment 17

General Equation:
CHEM360 Lab Manual 2009/12 Experiment 17

Procedure:

Reference to Lab Manual:

Carmichael, Robert. Browne, Lois. Jaleel, Nyron. Shaw, Lawton. Law, David. Last, Arthur.

2017. CHEM 360 Lab Manual, Athabasca University, Canada, 156-161.

Table 15.1. Table of Reagents for Exp. 15

Reagent Formula M d mp bp Haz. Properties

wt.

Benzaldehyde C6H5CHO 106.1 1.044 -26 179.5

2

4-methylbenzaldehyde CH3C6H4CHO 120.1 1.019 204-

5 205
CHEM360 Lab Manual 2009/12 Experiment 17

4-methoxybenzaldehyde CH3OC6H4CHO 136.1 1.119 -1 248

5

trans-cinnamaldehyde C6H5CHCHCH 132.1 1.048 248

O 6

Acetone CH3COCH3 58.08 0.791 -94 56

Cyclopentanone C5H8 (=O) 84.12 0.951 -51 130-

131

Cyclohexanone C6H10 (=O) 98.15 0.947 -47 155

4-methylcyclohexanone CH3C6H9 (=O) 112.1 0.914 169-

7 171

Formaldehyde HCHO 30.03 1.083

Acetophenone C6H5COCH3 120.1 1.030 19-20 202

5

1-butanol CH3(CH2)3OH 74.12 0.810 -90 117.7

2-butanol C2H5CH(OH)C 74.12 0.807 99-100

H3

Methanol CH3OH 32.04 0.791 -98 64.7

Brady's Reagent Solution See hydrazine, 2,4-dinitrophenyl

2,4-dinitrophenyl (O2N)2C6H3NH 198.1

hydrazine NH2 4

Sulfuric acid, conc. (18 H2SO4 98.08 1.840

M)
CHEM360 Lab Manual 2009/12 Experiment 17

Ethanol, 95% CH3CH2OH 46.07 0.785 78.5

Tollen's Reagent Solution See ammonia + silver

nitrate

Schiff's Reagent Solution mixture of roseaniline hydrochloride and sulfur dioxide,

Toxic

Ammonium hydroxide NH4OH 35.05 0.90

Silver nitrate AgNO3, 0.3 M 169.8 4.352 212

7

Nitric acid HNO3 63.01

Sodium hydroxide NaOH, 3 M 40.00 ~1.00

Iodine in potassium I2 in KI
iodide

Experiment 15 Part A Results:

CHEM360 Lab Manual 2009/12 Experiment 17
CHEM360 Lab Manual 2009/12 Experiment 17

Experiment 15 Post Lab Questions:

1. Write a balanced equation for the reaction of acetaldehyde (i.e. ethanal) with
ammoniacal silver nitrate. Remember that this is a redox reaction.

2. Outline a systematic functional group test procedure that would enable you to
distinguish among hexanal, 2-hexanone, 3-hexanone, 2-hexanol, and cyclohexanol.
CHEM360 Lab Manual 2009/12 Experiment 17
CHEM360 Lab Manual 2009/12 Experiment 17

3. Aldehydes and ketones can also be easily distinguished by their infrared spectra and
their identity deduced from their 1H-NMR spectra. Explain why this is.

Aldehyde has a hydrogen (known as aldehydic hydrogen) which is highly deshielded [R-CHO]
The peak appears near 10 ppm, which is missing in ketones.

4. From the following results, identify the unknown compounds.

a) Compound A: 2,4-DNPH positive, Tollens Test positive, Schiff's test positive,

Iodoform negative (see Spectrum (A) next page).
Compound a
2,4-DNPH positive: A carbonyl compound is present (C=O) as it gives positive test with 2,4
DNP
Tollens Test positive: It shows That the aldehyde is oxidized to Carboxylic acids with reduction
of Silver ions to Silver so aldehyde is present Schiff's test positive: compound is an aldehyde
Iodoform negative: methyl ketone is absent

b) Compound B: 2,4-DNPH positive, Tollens Test negative, Schiff's test negative,

Iodoform positive (see Spectrum (B) next page).

Compound b
2,4-DNPH positive: A carbonyl compound is present (C=O) as it gives positive test with 2,4
DNP
CHEM360 Lab Manual 2009/12 Experiment 17

Tollens Test negative: It shows that aldehyde is not oxidized so aldehyde is absent. Schiff's test
negative: Again, it shows that the compound is not an aldehyde Iodoform positive: methyl
ketone present
CHEM360 Lab Manual 2009/12 Experiment 17

Spectrum (A): 1H-NMR, 400 MHz in CDCl3

Molecular Formula C8H8O2 ,  9.9 = 1H,  7.8 = 2H,  7.0 = 2H,  3.9 = 3H.

Spectrum (B): 1H-NMR, 90 MHz in CDCl3

Molecular Formula C8H8O ,  7.9 = 2H,  7.3-7.7 = 3H,  2.6 = 3H.

CHEM360 Lab Manual 2009/12 Experiment 17

Conclusion:
In this lab we have compared the reactivity of carboxyl group in aldehyde and

ketones by different tests i.e. Brady’s reagent, Schiff’s reagent, Iodoform test

and Tollen’s test. The experiment involves very sharp observational skill,

where we must observe any changes of color and forming or layers or

precipitate, this is because the product will determine the reliability of

unknown solution.

We were expecting the unknown solution will have any parallel similarities to

the other four compounds, which are cyclohexanone, 1- butanol, 2-butanol

and acetophenone. These four compounds do help in comparing the changes

to identify the unknown x and y. To obtain the right identification, we

compared the observation we took during experiment to the literature

sources. From that we conclude that the unknown X is ketone and unknown

Y is an aldehyde.