Iodination of Salicylamide
Electrophilic Aromatic Substitution
Aromatic compounds are unusually stable because of the delocalization of their electrons. Given that the cloud is so stable, aromatic compounds (like benzene and its
derivatives) do not undergo electrophilic addition reactions as simple alkenes do.
Br
Br2
alkene
(rapid reaction)
Br
Br2
no reaction
benzene
However, the electrons of aromatic compounds are strongly attracted to powerful
electrophiles. When such electrophiles are attacked by the cloud, the result is a positively
charged reactive intermediate known as a sigma () complex.
E
E
H
complex
If the complex subsequently reacts with a nucleophilic species, the result would be
an addition product, but a loss of aromaticity. This type of reaction does not occur in
aromatic systems. Instead, a proton (H+) is removed from the sigma complex by a base in
order to reform the stable aromatic system. The resulting product is classified as a
substitution product since the electrophile substituted for a hydrogen on the ring. This type
of reaction is known as an electrophilic aromatic substitution.
Nuc
E
E
H
Nuc
X
E
H
E
Base
complex
As shown in the figure below, the sigma complex intermediate is a resonancestabilized carbocation. The various resonance contributors show that the positive charge is
more greatly concentrated on certain carbon atoms.
E
H
E
H
E
H
Lab Documentation, p.2
The delocalization of the positive charge on the sigma complex means that
substituents on the ring will affect the reactivity of the ring toward electrophilic aromatic
substituion. In fact, substituents affect the ring’s reactivity in a couple of ways. First,
electron donating substituents make the ring more susceptible to attack since the resulting
sigma complex would be more stable (donating electrons to a carbocation increases its
stability) and, therefore easier to form. As you can imagine, electron withdrawing
substituents have the opposite effect. In addition, the electronic nature of a substituent also
determines where on the ring, relative to the position of the substituent, that an electrophile
will attach. These latter effects are termed directing effects, and substituents are grouped
according to whether they are ortho, para directors (typically electron donators) or meta
directors (typically electron withdrawers).
In this experiment, we will study the directing effects of a pair of substituents on a
single aromatic ring. Salicylamide (see structure below), is a component of some analgesics.
The hydroxyl group on the ring is a strongly activating, electron donating substituent, while
the amide group is electron withdrawing.
OH
O
OH
NH2
O
NH2
I
I
Salicylamide
The electrophile that we will use is formed from the reaction of sodium hypochlorite
(NaOCl, bleach) with iodide ion. The I+ ion formed in this reaction is a strong electrophile
that reacts quickly in an electrophilic aromatic substitution reaction.
NaOCl
+
NaI
I
Determining Substitution Patterns using IR
The advent of modern technology such as FT-NMR and the recent advances in mass
spectrometry have relegated infrared spectroscopy to the task of functional group
identification in organic compounds. While this is an important piece of information in
organic structural determinations, IR can also provide a wealth of additional information
about an organic compound. Unfortunately, this information remains largely untapped
because it is buried in the nuances of what is known as the “fingerprint region” of the IR
spectrum.
In this experiment, you will be introduced to the use of the fingerprint region of the
IR spectrum to determine the substitution pattern of aromatic rings. The spectral region
between 700 – 900 cm-1 contains a great deal of useful information for this task. As the
following table demonstrates, IR enables us to easily differentiate a variety of substitution
patterns on aromatic rings. Given that your job in this lab is to determine where on the ring
the iodine substitution occurs, you should find IR a very useful technique!
Your Tasks: 1) Predict the product of the electrophilic iodination of salicylamide (see
Question #1 at the end of the lab), 2) synthesize and purify (recrystallize) the
product, 3) collect an IR spectrum, interpret it, and determine if your prediction
is correct (see Question #5 at the end of the lab).
Lab Documentation, p.3
Fingerprint Infrared Absorptions for Substituted Aromatics
Ring substitution pattern*
Monosubstituted
Expected peaks (cm-1)
770 – 715 (strong)
1,2-Disubstituted
770 – 730 (strong)
1,3-Disubstituted
820 – 760 (strong)
1,4-Disubstituted
870 – 800 (strong)
1,2,3-Trisubstituted
790 – 750 (strong)
1,2,4-Trisubstituted
850 – 800 (strong)
1,3,5-Trisubstituted
910 – 830 (strong)
Substitution Pattern Example
*The numbers here apply to substitution patterns, not nomenclature.
Experimental Procedure
CAUTION: Use caution when handling the materials used in this experiment. Wear gloves
and appropriate eye protection at all times during this procedure. Salicylamide and sodium
iodide are irritants. Sodium hypochlorite and hydrochloric acid are irritants and are
corrosive.
Measure out ~1.0 g of salicylamide and record the mass to the nearest 0.1 g. Place
the salicylamide into a 100-mL round-bottom flask. Dissolve the salicylamide in 20 mL of
absolute ethanol, warming the flask with your hand to speed up the dissolution.
Once the salicylamide is completely dissolved, add 1.2 g of sodium iodide (NaI) to
the reaction mixture, stirring with a glass stirring rod until the solution is homogeneous.
Place the 100-mL round-bottom containing the reaction mixture into an ice bath.
(Think about thermal contact!! Ice bath means ice AND water.)
When the reaction is cooled to 0 ˚C (about 5 minutes), remove the reaction vessel
from the ice bath and quickly add 9.2 mL of 6% (w/v) sodium hypochlorite solution (ultra
strength household bleach). Swirl the flask vigorously to completely mix the contents. The
solution will change colors from the initial clear reaction mixture to a dark red-brown to
increasingly lighter shades of yellow. When the solution reaches a faint, pale yellow color,
the reaction is complete. (Typically, this takes less than five minutes.) Allow the reaction
vessel to sit on the benchtop undisturbed for 10 minutes.
Add 10 mL of a previously prepared solution of 10% (w/v) sodium thiosulfate to the
reaction solution and swirl the flask until the contents are thoroughly mixed. Next, acidify
Lab Documentation, p.4
the reaction solution by slowly adding 10% HCl. Monitor the acidity of the solution using
litmus paper. You will notice a white solid beginning to form in the reaction vessel. At this
point, the pH of the solution is near the desired acidity. Continue adding 10% HCl, but
carefully monitor the acidity.
Once the mixture is acidic, filter using vacuum filtration and a Büchner funnel.
Collect the precipitate from the filter paper and recrystallize from 95% ethanol. (After the
recrystallization mixture has cooled to room temperature, place it an ice bath for ~15 minutes
to complete crystallization.) Filter using vacuum filtration and allow the crystals to remain
on the funnel with air being drawn over them for 20 minutes to speed up the drying process.
Once your product is dry, weigh it and collect an IR spectrum using the
SMARTPerformer ATR accessory on the spectrophotometer. (Ask your TA for help with
the latter.) Be sure to carefully label all peaks between 700 – 900 cm-1 on your spectrum.
Experimental Record
Mass of salicylamide used
Moles of salicylamide used
Moles of sodium iodide used
Moles of sodium hypochlorite used
Mass of recrystallized product
Questions
1. Use your knowledge of electrophilic aromatic substitution and the directing effects of
substituents on an aromatic ring to answer the following questions.
A. What are the possible sites of iodination of the salicylamide ring? Briefly explain.
B. Predict the most likely site of iodination of the salicylamide ring and explain your
prediction.
2. What is the limiting reagent in this procedure for the iodination of salicylamide?
g
Lab Documentation, p.5
3. Calculate the theoretical and percent yield of iodinated salicylamide (product) assuming a
monoiodination reaction. (Show your calculations.)
4. The IR spectrum of salicylamide, your starting material, is shown below.
A. Identify the significant absorbances in the functional group region of the spectrum
(above 1400 cm-1) and correlate each to the structure of salicylamide.
B. Identify the peak in the fingerprint region that is indicative of the substitution pattern
of the aromatic ring of salicylamide.
5. Using the information you collected on the compound that you synthesized, draw the
structure of the product. Explain how the data you collected confirms the structure
you’ve proposed.
Lab Documentation, p.6
Instructor's Notes for A Green, Guided-Inquiry Based Electrophilic Aromatic
Substitution for the Organic Chemistry Laboratory
Students can do this experiment in pairs or individually. The information provided
for materials is per experimental set up.
Materials
1. Salicylamide – [65-45-2] – We purchase 99% from Sigma-Aldrich. Need ~1 g per set
up.
CAUTION: Salicylamide is an irritant. Always wear gloves and appropriate eye
protection when handling.
2. Ethanol – [64-17-5] – Need 20 mL of absolute ethanol per set up and ~20 mL of 95%
ethanol (for recrystallization) per set up.
3. Sodium iodide – [7681-82-5] – Need 1.2 g per set up.
CAUTION: Sodium iodide is an irritant. Always wear gloves and appropriate eye
protection when handling.
4. Sodium hypochlorite (6%) – We buy generic ultra strength household bleach from a local
grocery store. Works very well. Need ~10 mL per set up.
CAUTION: Sodium hypochlorite is corrosive and an irritant. Always wear gloves and
appropriate eye protection when handling.
5. Sodium thiosulfate (10%) – Dissolve 1.0 g Na2S2O3 [7772-98-7] in water to a final
volume of 10 mL. Need 10 mL per set up.
6. Hydrochloric acid (10%) – Carefully add 2.6 mL of concentrated HCl (38%) to 5.0 mL of
water. Dilute to a final volume of 10 mL. (CAUTION: The solution will get hot during
the addition. Take care to add the acid to the water.) Need ~10 mL per set up.
CAUTION: Hydrochloric acid is corrosive and an irritant. Always wear gloves and
appropriate eye protection when handling.
Notes on the Experimental Procedure
The initial dissolution of salicylamide in ethanol is not as fast as students expect/want it to
be. We instruct them to gently swirl the flask while warming it in their hands. The solid will
completely dissolve in 5 minutes or less.
While acidifying the reaction mixture after the reaction is complete, we instruct the students
to add 10% HCl until they see a white precipitate begin to form. They can do this addition
fairly rapidly. Once the precipitate begins to form, caution them to carefully monitor the pH
of the solution with litmus paper and to slowly add the acid until the solution is acidic.
Lab Documentation, p.7
We instruct students to leave the recrystallized product on the Büchner funnel with air being
drawn across it for ~20 minutes. This sufficiently dries the compound for use in collecting
an IR spectrum.
We use an attenuated total reflectance accessory on our ThermoNicolet Avatar 370 FT-IR.
The students get excellent results that are easy to interpret. To insure adaptability of this
procedure, we prepared a KBr pellet of the product while developing this lab and found the
spectra to be of equal quality in the fingerprint region of the spectrum.
Given that only the 4-iodo and 5-iodo isomers of salicylamide are known compounds, we
chose not to use melting point for identification of the product. With no melting point for 3iodosalicylamide (it is not in the literature), identification of the product becomes fairly
straightforward (less critical analysis of data required). Thus, we chose not to provide
melting point data. However, the data is provided in the table below for any instructor who
might wish to use it.
Name
Salicylamide
Structure
OH
Melting Point (˚C)
140 - 144
O
2
NH2
1
4-Iodosalicylamide
OH
206
O
NH2
I
5-Iodosalicylamide
OH
O
228
NH2
I
Answers to Post-Lab Questions
1. A. The amide is a meta-director and the hydroxyl group is an ortho,para-director. On
salicylamide, both groups direct to the position ortho to the hydroxyl and the position
para to the hydroxyl.
B. Students typically predict that the para (#5) position will be the preferred site for
substitution by the iodine. The usual explanation is that the size of the iodine
prevents it from substituting at position (#3) next to the hydroxyl. (While it is
possible for the iodine to substitute at the #3 position, it does not in this reaction.
Thus, we accept this prediction and explanation.)
2. The limiting reagent is salicylamide – 7.3 mmoles.
Lab Documentation, p.8
3. The theoretical yield, assuming 1.0 g of salicylamide:
1.0 g (
)
1 mole
1 mole (iodosalicylamide) 263.03g
salicylamide (iodosalicylamide) = 1.9g (iodosalicylamide)
1 mole
137.14 g
1 mole (salicylamide)
4. A. 3397 cm-1 – NH stretch, 3191 cm-1 – OH stretch, 1671 cm-1 – C=O stretch, 1630 cm-1 –
NH bend, 1591 & 1493 cm-1 – aromatic ring stretch.
B. The strong peak at 750 cm-1 indicates the 1,2-substitution pattern of salicylamide.