Bromination of Acetanilide

O
NaBr, NaClO 2

HN

HN

EtOH, AcOH
Br
acetanilide

4-bromoacetanilide
mp 165-169 C

Adapted from: Luong et al J. Chem. Educ. 2012, 89, 1061.

Chemicals Required [CAS #]

Acetanilide [103-84-4]
Bleach (sodium hypochlorite) [7681-52-9]
Ethanol (95%) [64-17-5]
Sodium bromide [7647-15-6]
Sodium hydroxide [1310-73-2]
Sodium thiosulfate pentahydrate [10102-17-7]

Hazards
Sodium hypochlorite is an oxidizing agent and can release toxic fumes, and should be used in a fume hood. Sodium
hydroxide is caustic (causes severe burns), hygroscopic (readily absorbs water from the air) and deliquescent
(absorbs so much water from the air that it will dissolve into an aqueous solution). Containers of sodium hydroxide
must be closed immediately after use; any spilled pellets must be disposed of immediately before they can turn into
caustic liquid. Appropriate eye protection, gloves and lab coat should be worn in order to avoid burns, contact with
skin and eyes of the used chemicals.

Introduction
Bromination is a very useful electrophilic aromatic substitution reaction, because halogenated arenes (aromatic
hydrocarbons) can be used as building blocks to make larger compounds. Classically, they could be converted to
the corresponding aryllithium or Grignard reagent (by treating them with lithium or magnesium metal, respectively).
In recent decades, mild couplings using palladium or other transition metals have become widely used. The Nobel
Prize in Chemistry for 2010 was awarded to Ei-ichi Negishi, Akira Suzuki, and UDs own Richard Heck for the
development of their namesake reactions. As an example, a typical Heck coupling between an aryl bromide and
alkene is shown below:

Br
+

Pd catalyst

OMe

OMe

base

Halogens often behave as electrophiles in chemical reactions. An X2 molecule can be thought of as behaving like
+

X X (e.g. Br Br ). The net equivalent of X can be delivered to a nucleophile, with loss of an X leaving group.

For less reactive arenes, halogens do not readily add to the aromatic ring, and a Lewis acid catalyst such as FeX3
must be used (e.g. FeBr3 used with Br2). The Lewis acid helps to polarize the X2 molecule and make it more
electrophilic. However, sufficiently reactive aromatic rings such as phenols and anilines can react directly with Cl2
or Br2. In fact, they are so reactive that it can be hard to stop at a monohalogenated product. For example, reaction
of aniline with bromine would give 2,4,6-tribromophenol. However, conversion of the phenol or aniline to the
corresponding ester or amide attenuates the reactivity, because the electron-withdrawing carbonyl group makes the
: or :N a weaker electron-donating, and thus weaker activating, group. In your experiment, you will see that
acetanilide is reactive enough towards bromine that no catalyst is required, but unreactive enough that you can
isolate a monobrominated product.

Traditionally, a solution of acetic acid and molecular bromine (Br2) has been used to brominate aromatic systems.
Liquid bromine is a volatile (fuming) liquid capable of causing severe burns; concentrated acetic acid has a pungent

odor and also causes burns. This is a hazardous concoction to handle, so a green (environmentally friendly) way
of performing the same reaction was devised. This method involves the reaction of sodium hypochlorite (NaClO,
household bleach) under acidic conditions with sodium bromide to generate molecular bromine in situ (in the
reaction mixture). This is a redox reaction, where the bleach oxidizes bromide to bromine. The in situ generation of
Br2 is much safer than handling acidic solutions of Br2, since most of the bromine generated is consumed
immediately by the electrophilic aromatic substitution reaction. Any excess bromine that remains is reduced back to
bromide by the addition of the reducing agent sodium thiosulfate. Sodium hydroxide is also added at this point, to
decrease the solubility of your product and thus improve yield.

Procedure
Individual chemicals can be measured out at the balances (solids) or fume hoods (liquids) and then carried to your
fume hood. Your final product can be weighed on the balance. All other operations are to be carried out in the
fume hood.

In a 125 mL Erlenmeyer flask, dissolve 1.0 g acetanilide and 1.8 g NaBr in a mixture of 6 mL of 95% ethanol and 5
mL of acetic acid. Cool the resulting solution in an ice bath to at least 5C. Add 7 mL of 8.25% bleach (ca. 1.1 M in
NaClO). Allow the reaction to warm up to room temperature over 15 minutes, then cool the reaction in an ice bath.
Quench any unreacted bromine in the reaction mixture and precipitate your product by adding 1 g of sodium
thiosulfate and 1 g of sodium hydroxide. Make sure that both fully dissolve before recovering the precipitated
product by vacuum filtration using a Bchner funnel. Obtain a mass of the crude product.
Recrystallize your product from 50% aqueous ethanol. Be careful not to use too much solvent. Collect the product
by suction filtration, washing the crystals with a small amount of ice-cold 50% ethanol. Obtain the final mass of
product and show your product to your TA.

Post-Lab Questions:
1. Bromine is produced in a series of chemical steps:
+

i) H + Br + NaOCl HOBr (hypobromous acid) + NaCl

+

ii) H + Br + HOBr Br2 + H2O

Give the net balanced reaction equation for this sequence.

2. Based on the answer to #1, and the balanced reaction equation for the reaction of acetanilide with bromine, what
was the limiting reactant in this reaction? Use this to calculate your theoretical and percent yield.

3. If bromine were used in excess, dibromoacetanilide could be produced as a byproduct. What would be the
structure of the major dibrominated byproduct? Would the second bromination occur faster than the first, or slower?
Explain why.