Laboratory Experiment

pubs.acs.org/jchemeduc

A Multistep Synthesis Incorporating a Green Bromination of an

Aromatic Ring
Pascal Cardinal, Brandon Greer, Horace Luong,* and Yevgeniya Tyagunova
Department of Chemistry, University of Manitoba, Winnipeg, Manitoba R3T 2N2, Canada
*
S Supporting Information

ABSTRACT: Electrophilic aromatic substitution is a fundamental topic taught in the

undergraduate organic chemistry curriculum. A multistep synthesis that includes a safer
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and greener method for the bromination of an aromatic ring than traditional bromination
methods is described. This experiment is multifaceted and can be used to teach students
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about protecting groups, multistep synthesis, redox reactions/titrations, electrophilic

aromatic substitution, and nucleophilic acyl substitution.

KEYWORDS: Second-Year Undergraduate, Laboratory Instruction, Organic Chemistry, Hands-On Learning/Manipulatives,

Electrophilic Substitution, Green Chemistry, IR Spectroscopy, NMR Spectroscopy, Synthesis, Titration/Volumetric Analysis

E lectrophilic aromatic substitution (EAS) is a fundamental

concept in organic chemistry and is commonly used as the
topic of an experimental exercise at the undergraduate level.
These laboratory experiments enable the students to under-
stand the directive effects of substituted functional groups on an
aromatic ring.1 Quite often, traditional EAS reactions involve
dangerous chemicals and require disposal methods that are
expensive to the institution and hazardous to the environment.
In recent years, environmental concerns have directed
chemists to explore environmentally friendly methods in the
preparation of various compounds.2−5 Ideally, this entails the
development of procedures where reagents and products are
low in toxicity and volatility, thereby diminishing environ-
mental and health concerns during handling, use, storage, and
disposal.
Traditional undergraduate EAS reactions have required the
use of (or created as byproducts) harmful halocarbons: one
example being the synthesis of bromobenzene, a simple
halogenated aromatic ring. Typical procedures to generate
bromobenzene include electrophilic substitution of bromine
(from Br2) onto benzene via some metal Lewis acid catalyst
such as AlCl3, SbCl3, and SbCl4.6 The handling of liquid
bromine is a safety concern using these methods.
The organic synthesis chemical education community has
developed green methods that allow students to gain
experience in aromatic halogenation reactions without being
exposed to the hazards presented by traditional procedures.
One reagent that has shown promise in achieving this task is
pyridinium tribromide, which generates elemental bromine in
situ as the reaction progresses, avoiding the handling of liquid
bromine.7,8 However, a large quantity of waste is produced and
© 2012 American Chemical Society and
Division of Chemical Education, Inc.
product yields are appreciably affected by the temperature and
concentration dependences of the bromine-generating reagent.
A multistep synthesis of 4-bromoacetanilide from aniline is
presented (Scheme 1). In contrast to the old method of
Scheme 1. Synthesis of 4-Bromoacetanilide
brominating using bromine in acetic acid, the bromine used to
perform the bromination is generated in situ from an acidic
solution of sodium hypochlorite and sodium bromide. Both
reagents used to generate the bromine (sodium bromide and
sodium hypochlorite, which is found in bleach) are more
benign to handle than liquid bromine. The amine group of
aniline should be protected prior to bromination.9 This must be
done to minimize multisubstituted products. In using this
greener method, the amine group is protected for two reasons.
First, the protection helps minimize the production of
multisubstituted products. Second, even though it was reported
by Edgar and Falling10 that it is possible to selectively
monoiodinate phenol without the use of a protecting group
using conditions similar to what is proposed in this experiment,
the amine group on aniline is a safety concern when mixed with
Published: May 4, 2012
1061 dx.doi.org/10.1021/ed200579w | J. Chem. Educ. 2012, 89, 1061−1063
Journal of Chemical Education
sodium hypochlorite because dangerous chloramines can form.
Therefore, acetylating the amine group will also minimize safety
concerns.
The inspiration for the bromination reaction derived from
previous reports of iodination reactions using NaI and NaClO,
where high yields and selectivity were obtained.10,11 By using
the fundamentals of the iodination reactions, the reaction was
adopted for brominating conditions and the synthetic pathway
was controlled to avoid the aforementioned byproducts. The
new green method provides an efficient and safe way to prepare
a monosubstituted product and can easily be incorporated as a
preliminary reaction to further organic syntheses (e.g., amide
hydrolysis, metal-catalyzed coupling). The mechanism and
kinetics of generating the brominating species using the
conditions reported here is complicated but can be found in
the literature.12 Students who performed the bromination were
required to deduce which isomer was synthesized in the
bromination reaction and support their conclusion using data
collected (e.g., melting point and NMR spectroscopy).
■ CHEMICALS AND EQUIPMENT
All chemicals used were standard grade obtained from
commercial suppliers and used without further purification.
Bleach, used as a source of NaClO, was purchased from a local
grocery store. Melting points were measured using an
Electrothermal melting point apparatus. Infrared spectral data
were collected using a Bruker Alpha FT-IR spectrometer. 1H
and 13C NMR spectra were collected on a Bruker Advance 300
spectrometer (Bo = 9.4 T) with a Bruker 5 mm solutions probe,
using CDCl3 or acetone-d6 as a solvent.
■
EXPERIMENTAL PROCEDURE
Protecting Aniline
Aniline was reacted with acetic anhydride to yield acetanilide.
The reaction was quenched with a basic aqueous solution. The
product was made in 75% yield by an experienced chemist and
72% by students (34−91% from nine student trials).
Hypochlorite Concentration Determination in Bleach
The sodium hypochlorite concentration in bleach was
determined by a redox titration using sodium thiosulfate and
sodium iodide. The sodium hypochlorite concentration
advertised on the bleach bottle was 6% (about 0.8 M). The
actual concentration determined by titration was found to be
less than 3%. This discrepancy could be a function of how (and
how long) the bleach bottles have been stored.
Brominating Acetanilide
Acetanilide and sodium bromide were mixed in a solution of
acetic acid and ethanol and then cooled in an ice bath. The
appropriate amount of bleach was added to the cooled solution
such that there was about 5% mole excess of sodium
hypochlorite. Following a maximum reaction period of 25
min, the reaction was quenched with sodium thiosulfate and
sodium hydroxide. The addition of sodium thiosulfate and
sodium hydroxide precipitated the product. 4-Bromoacetanilide
is soluble in acetic acid, and by neutralizing the acetic acid with
sodium hydroxide, product recovery increased. The crude
product was recrystallized using 50% ethanol in relatively high
purity (experimental melting point of the product was found to
be 166−167 °C). The 4-bromoacetanilide was made in 88%
yield by an experienced chemist and 50% yield by students
1062
Laboratory Experiment
(29−73% from nine student trials; yields reported using
acetanilide as the limiting reagent).
■
HAZARDS
Acetic anhydride and acetic acid are corrosive and can cause
burns. Aniline is harmful if inhaled. Acetone, acetic acid,
ethanol, and acetic anhydride are flammable. Sodium
hypochlorite is an oxidizing agent and can release toxic fumes
and should be used in a fume hood. Appropriate eye protection,
gloves, and a lab coat should be worn in order to avoid
chemical burns and contact with eyes and skin.
■ RESULTS AND DISCUSSION
The experiment was incorporated into a second-year organic
chemistry laboratory program and can be completed over two
3-h laboratory periods. However, the experiment can be
shortened to one period by removing the bleach titration
step and consequently using a slight excess of sodium
hypochlorite (the solution will be tinted a faint brown−yellow
when a slight excess is available).
The technical skills emphasized in this experiment included
recrystallization, vacuum filtration, redox titration, recording
and analyzing IR spectra, melting point measurements,
preparing solutions, percent yield calculations, and NMR
spectral analysis. Numerous attempts were made to determine
appropriate thin-layer chromatography (TLC) conditions to
separate acetanilide and 4-bromoacetanilide; however, all
attempts failed. Two recent literature references mentioned
that they were able to separate the two by TLC.13 The authors
provided their TLC conditions for us to try, but the separation
proved to be unsuccessful.
It should be mentioned that using the procedure in this
paper, the student’s yield of 4-bromoacetanilide may not be as
high as previous syntheses (84%) that had used more
hazardous conditions.9 Overall yields for the greener experi-
ment are about 66% for an experienced chemist and 34% for
undergraduate students. The difference in overall yields
between the student’s and the experienced chemist’s experi-
ment may be due to a poor decision made on solvent volume
for the recrystallization of the final product. Students have a
tendency of using excess solvent, and therefore minimizing the
4-bromoacetanilide recovery.
One task in this experiment was to determine the volume of
bleach to use since the actual concentration of sodium
hypochlorite differed from the reported concentration. This
step in the procedure reviewed a laboratory technique
(titration) taught in the general chemistry curriculum. The
titration was an interesting aspect to the overall experiment
because it emphasized the relevance of a laboratory technique
taught elsewhere and brought an analytical technique into the
organic chemistry laboratory.
The students deduced the substitution pattern and purity of
the bromoacetanilide using melting point data and the supplied
1
H and 13C NMR spectra (available in the Supporting
Information). In typical student data, the melting point results
supported one isomer. Students recorded an IR spectrum,
which reveals functional group identity, but nothing about
purity or isomer identity can be confidently stated. The
undergraduate student would usually expect to observe two
doublets in the 1H NMR spectrum aromatic region for para-
substitution. Students normally expect the 1H NMR spectrum
to be a quintessential tool for solving structure; however, in this
dx.doi.org/10.1021/ed200579w | J. Chem. Educ. 2012, 89, 1061−1063
Journal of Chemical Education

■
Laboratory Experiment

situation, the 1H NMR spectrum is unreliable because of ACKNOWLEDGMENTS

second-order spin−spin coupling in the aromatic region (when
CDCl3 is used as the solvent). When using acetone-d6 as a
solvent, it is possible to resolve the doublets; however, the
acetyl CH3 resonance is hidden under the residual acetone
solvent signal in the 1H NMR spectrum. The bromoacetanilide
We would like to thank the CHEM 2220 students (winter 2010
and summer 2011 term) at the University of Manitoba for their
input concerning the experiment. As well, we would like to
thank Kirk Marat for use of the University of Manitoba NMR
facilities.

product is also soluble in acetone-d6 (unlike CDCl3), which
helps with the 13C NMR data acquisition. Therefore, to the
students’ surprise, the 13C NMR spectrum becomes important
in identifying the isomer. Substitution in ortho, meta, and para
positions are expected to give rise to six, six, and four
resonances in the aromatic region in the 13C NMR spectrum,
respectively. In the provided 13 C NMR spectrum of
bromoacetanilide, it is obvious that there are four aromatic
carbons. The exercise of examining the 13C NMR spectrum
allows students to see how chemical and magnetic equivalency
in NMR spectroscopy can be used to distinguish structural
isomers of organic compounds.
Many of the experiments at the second-year level are one-
step reactions. Because this reaction is composed of two steps
from aniline, it provides an opportunity to teach the students
how to calculate overall yields of a multistep synthesis (i.e., as
the product from the yield of each step).
The student assessment for this experiment was divided into
three parts: sample quality, laboratory report, and peer
evaluation. The quality of the sample was based on visual
inspection of the 4-bromoacetanilide sample; samples that were
white and crystalline and free of visible contaminants were
awarded full value. Students were organized into groups and
asked to produce a laboratory report containing all components
of a full report (questions and format available in the
Supporting Information). Peer evaluation, conducted according
to the percentage method,14 was deemed necessary for ensuring
everyone contributed to the project.
■
REFERENCES
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(accessed Apr 2012).

■ CONCLUSION
This article describes an easy and safe multistep reaction for
demonstrating the use of a protecting group, an electrophilic
aromatic substitution reaction, and how redox reactions can be
used in organic chemistry. The products are solids and,
therefore, are easy for the students to manipulate for
purification. A variety of laboratory techniques are exercised
in this experiment: recrystallization, redox titration, IR and
NMR spectroscopy, and vacuum filtration. This experiment
also reinforces lecture material regarding nucleophilic acyl
substitution, benzene-ring substituent directing effects, redox
reactions, multistep synthesis, and protecting groups. Addition-
ally, the procedure demonstrates to students that alternative
and safe pathways can be rationalized and developed that
accomplish an identical synthetic goal as traditional methods.

■
*
ASSOCIATED CONTENT
S Supporting Information

Instructor notes; student handouts; NMR spectra. This material

is available via the Internet at http://pubs.acs.org.

■ AUTHOR INFORMATION
Corresponding Author
*E-mail: luong@cc.umanitoba.ca.
Notes
The authors declare no competing financial interest.
1063 dx.doi.org/10.1021/ed200579w | J. Chem. Educ. 2012, 89, 1061−1063