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Suggested

solutions for Chapter 21 21



PROBLEM 1
All you have to do is to spot the aromatic rings in these compounds. It may not
be as easy as you think and you should give some reasons for questionable
decisions.

I O CO2H

I O
H NH2 OH

HO I CO2H
OH O OH OH
I thyroxine: human hormone
regulating metabolic rate aklavinone:
tetracycline antibiotic
MeO OR
H
HO O
NHMe
MeO
MeO OR
O
colchicine: OH calistephin:
anti-cancer agent HO2C natural red flower pigment
from the autumn crocus OMe
NH CO2H

methoxatin: coenzyme from


bacteria living on methane
O CO2H
O

Purpose of the problem


Simple exercise in counting electrons with a few hidden tricks.

Suggested solution
Truly aromatic rings are marked with bold lines. Thyroxine has two
benzene ringsobviously aromaticand thats that. Aklavinone also
has two aromatic benzene rings and we might argue about ring 2. It has
four electrons as drawn, and you might think that you could push
electrons round from the OH groups to give ring 2 six electrons as well.
But if you try it, youll find you cant.


2 Solutions Manual to accompany Organic Chemistry 2e

I O CO2H

I O
H NH2 1 2 3 OH

HO I CO2H
OH O OH OH
I

Colchicine has one benzene ring and a seven-membered conjugated


ring with six electrons in double bonds (dont count the carbonyl
electrons as they are out of the ring). It perhaps looks more aromatic if
you delocalise the electrons and represent it as a zwitterion. Either
representation is fine.

MeO MeO
H H
NHMe NHMe
MeO MeO
MeO MeO
O O

OMe OMe

Methoxatin has one benzene ring and one pyrrole ring an example
of an aromatic compound with a five-membered ring. The six electrons
come from two double bonds and the lone pair on the nitrogen atom.
The middle ring is not aromaticeven if you try drawing other
delocalised structures, you can never get six electrons into this ring.

HO2C HO2C
NH CO2H NH CO2H

O CO2H O CO2H
O O


Solutions for Chapter 21 Electrophilic Aromatic Substitution 3

PROBLEM 2
First, as some revision, write out the detailed mechanism for these steps.

NO2
NO2
HNO3 + H2SO4 NO2

In a standard nitration reaction with, say, HNO3 and H2SO4, each of these
compounds forms a single nitration product. What is its structure? Explain
your answer with at least a partial mechanism.

CO2H
NHAc

Me O

Purpose of the problem


Revision of the basic nitration mechanism and extension to compounds
where selectivity is an issue.

Suggested solution
The basic mechanisms for the formation of NO2+ and its reaction with
benzene appear on p. 476 of the textbook. Benzoic acid has an electron-
withdrawing substituent so it reacts in the meta position. The second
compound is activated in all positions by the weakly electron donating
alkyl groups (all positions are either ortho or para to one of these
groups) but will react at one of the positions more remote from the
alkyl groups because of steric hindrance.

CO2H CO2H
O2N

NO2

The remaining two compounds have competing ortho,para-directing


substituents but in each case the one with the lone pair of electrons (N
or O) is a more powerful director than the simple alkyl group. In the
first case nitrogen directs ortho but in the second oxygen activates both
ortho and para and steric hindrance makes the para position marginally
more reactive.


4 Solutions Manual to accompany Organic Chemistry 2e

NHAc NHAc O2N


NO2 NO2

Me Me NO2 O O


PROBLEM 3
How reactive are the different sites in toluene? Nitration of toluene produces
the three possible products in the ratios shown. What would be the ratios if
all the sites were equally reactive? What is the actual relative reactivity of the
three sites? You could express this as x:y:1 or as a:b:c where a+b+c = 100.
Comment on the ratio you deduce

NO2
Me
Me Me Me +NO2
HNO3
+ +
H2SO4 NO2
59% yield 4% yield 37% yield

Purpose of the problem


A more quantitative assessment of relative reactivities.

Suggested solution
As there are two ortho and two meta sites, the ratio if all were equally
reactive would be 2:2:1 o:m:p. The observed reactivity is 30:2:37 or
15:1:18 or 43:3:54 depending on how you expressed it. The ortho and
para positions are roughly equally reactive because the methyl group is
electron-donating. The para is slightly more reactive than the ortho
because of steric hindrance. The meta position is an order of magnitude
less reactive because the intermediate is not stabilised by electron-
donation (-conjugation) from the methyl group.


Solutions for Chapter 21 Electrophilic Aromatic Substitution 5

reaction in the ortho position


Me Me
NO2
NO2
H

reaction in the meta position


Me Me Me

etc positive charge is


never adjacent to Me
NO2 NO2
NO2 H H

PROBLEM 4
Draw mechanisms for these reactions and explain the positions of
substitution.

OH OH OH
Br
HNO3 Br2

NO2 NO2

Cl Br
Br

Cl

AlCl3

Purpose of the problem


More advanced questions of orientation with more powerful electron-
donating groups.

Suggested solution
The OH group has a lone pair of electrons and dominates reactivity and
selectivity. Steric hindrance favours the para product in the first
reaction. The bromination has to occur ortho to the phenol as the para
position is blocked.


6 Solutions Manual to accompany Organic Chemistry 2e

OH OH OH OH OH
Br Br Br Br
H

NO2 H NO2 NO2 NO2 NO2


The second example has two Friedel-Crafts alkylations with tertiary


alkyl halides. The first occurs para to bromine, a deactivating but
ortho,para-directing group (see p. 489 in the textbook), preferring para
because of steric hindrance. The second is a cyclisationthe new ring
cannot stretch any further than the next atom.

Br Br
Br
Cl Cl
and repeat

AlCl3
Cl
Cl

PROBLEM 5
Nitration of these compounds gives products with the 1H NMR spectra shown.
Deduce the structures of the products and explain the position of substitution.
WARNING: do not decide the structure by saying where the nitro group ought
to go! Chemistry has many surprises and it is the evidence that counts.

NO2 H
? 7.77 (4H, d, J 10)
8.26 (4H, d, J 10)

Cl H
NO2 7.6 (1H, d, J 10)
? 8.1 (1H, dd, J 10,2)
Cl 8.3 (1H, d, J 2)

F H
NO2
? 7.15 (2H, dd, J 7,8)
8.19 (2H, dd, J 6,8)

Purpose of the problem


Revision of the relationship between NMR and substitution pattern.


Solutions for Chapter 21 Electrophilic Aromatic Substitution 7

Suggested solution
The first product has only eight hydrogens so two nitro groups must
have been added. The molecule is clearly symmetrical and the coupling
constant is right for neighbouring hydrogens so a substitution on each
ring must have occurred in the para position. Note that the hydrogen
next to the nitro group has the larger shift. We can deduce that each
benzene ring is an ortho,para-directing group on the other because the
intermediate cation is stabilised by conjugation.

H
NO2
NO2

H
O2N NO2 Vicinal (ortho) coupling
constants in benzene rings are
NO2 typically 8-10 Hz; meta coupling
7.77 H H 8.26 constants are typically <2 Hz: see p.
(4H, d, J 10) 295-6 o f the textbook.
(4H, d, J 10)

The hydrogen count reveals that the next two products are mono-
nitro compounds. There are two hydrogens ortho to nitro in the second
compound and one of them also has a typical ortho coupling to a
neighbouring hydrogen while the other has only a small coupling (2 Hz)
which must be a meta coupling. Substitution has occurred para to one
of the chlorines and ortho to the other. The chlorines are ortho,para-
directing thus activating all remaining positions so steric hindrance
must explain the site of nitration.

H 1H, d, J 2
H
Cl NO2 Cl Cl NO2
NO2
The idea that heteronuclear
Cl Cl H couplings leave unpaired coupling
Cl constants
1H, dd, J 10,2 in the 1H NMR spectrum
1H, d, J 10 H in the green box on p.
is explained
416 of the textbook.
The third compound has the extra complication of couplings to
fluorine. The coupling of 7 Hz shown by one hydrogen and 6 Hz shown
by the other must be to fluorine as they occur once only. The symmetry
of the compound and the typical ortho coupling between the hydrogens
(8 Hz) shows that para substitution must have occurred.


8 Solutions Manual to accompany Organic Chemistry 2e

F F F

H
NO2 H NO2
NO2 7.15 (2H, dd, J 7,8)
H
8.19 (2H, dd, J 6,8)

PROBLEM 6
Attempted Friedel-Crafts acylation of benzene with t-BuCOCl gives some of the
expected ketone A as a minor product, as well as some t-butylbenzene B, but
the major product is the substituted ketone C. Explain how these compounds
are formed and suggest the order in which the two substituents are added to
form compound C.

O
O
AlCl3
Cl + +
benzene

A B C O

Purpose of the problem


Detailed analysis of a revealing example of the Friedel-Crafts reaction.

Suggested solution
The expected reaction to give A is a simple Friedel-Crafts acylation with
the usual acylium ion intermediate.

O
O O
H
Cl A

Product B must arise from a t-butyl cation and the only way that
might be formes is by loss of carbon monoxide from the original
acylium ion. Such a reaction happens only when the resulting
carbocation is reasonably stable.

H
O
B


Solutions for Chapter 21 Electrophilic Aromatic Substitution 9

The main product C comes from the addition of both these


electrophiles, but which adds first? The ketone in A is deactivating and
meta directing but the t-butyl group in B is activating and para-
directing so it must be added first.

O
AlCl3
+
Cl

C O

That answers the question but you might like to go further. Both A
and C are formed by the alkylation of benzene as the first step. The
decomposition of the acylium ion is evidently faster than the acylation
of benzene. However, when B reacts further, it is mainly by acylation as
only a small amount of di-t-butyl benzene is formed. Evidently the
decomposition of the acylium ion is slower than the acylation of B! This
is not unreasonable as the t-butyl group accelerates electrophilic
attackbut it is a dramatic demonstration of that acceleration.

PROBLEM 7
Nitration of this heterocyclic compound with the usual HNO3/H2SO4 mixture
gives a single nitration product with the 1H NMR spectrum shown below.
Suggest which product is formed and why.

H
3.04 (2H, t, J 7 Hz)
3.68 (2H, t, J 7 Hz)
C8H8N2O2 6.45 (1H, d, J 8 Hz)
N 7.28 (1H, broad s)
H
7.81 (1H, d, J 1 Hz)
7.90 (1H, dd, J 8, 1 Hz)

Purpose of the problem


Revision of NMR and an attempt to convince you that the methods of
chapter 21 can be applied to molecules youve not met before.

Suggested solution
The two 2H triplets and the broad NH signal show that the heterocyclic
ring is intact. One nitro group has been added to the benzene ring. The
proton at 7.81 with only one small (meta) coupling must be between


10 Solutions Manual to accompany Organic Chemistry 2e

the nitro group and the other ring and is marked on the two possible
structures.

Ha

HNO3 O2N
or
H2SO4 O2N N
N N H
H H Hb

You could argue that NH is ortho,para directing and so the second


structure is more likely. But this is a risky argument as the reaction is
carried out in strong acid solution where the nitrogen will mostly be
protonated. It is safer to use the predicted H from tables. Here we get:

Proton ortho meta para predicted H
Ha NO2 = +0.95 CH2 = 0.14 NH = 0.25 7.73
Hb NO2 = +0.95 NH = 0.75 CH2 = 0.06 7.31

Theres not much difference but Ha at 7.73 is closer to the observed
7.81, so it looks as though the small amount of unprotonated amine
directs the reaction.

PROBLEM 8
What are the two possible isomeric products of this reaction? Which
structure do you expect to predominate? What would be the bromination
product from each?

MeO
A + B both C12H16O

Br2 Br2
OH
? ?

Purpose of the problem


Getting you to think about alternative products and possible reactions
on compounds that havent been made (yet).

Suggested solution
The reaction is a Friedel Crafts cyclisation, as you could have deduced
by the simple loss of water. The resulting cation could cyclise in two
ways, arbitrarily called A and B. Steric hindrance suggests that A would
be the more likely product.


Solutions for Chapter 21 Electrophilic Aromatic Substitution 11

MeO MeO MeO

MeO H
H A

OH2
MeO MeO
B

Bromination will go either ortho or para to the methoxy group: A has


two different positions ortho to the OMe, but the para position is
blocked. The least sterically hindered position gives a 1,2,4,5-
tetrasubstituted ring. B might give a mixture of ortho and para
substitution.

MeO
Br2 Br2
A B MeO + MeO
Br
Br Br


12 Solutions Manual to accompany Organic Chemistry 2e

PROBLEM 9
On p. 479 of the textbook we explain the formation of 2,4,6-tribromophenol
by bromination of phenol in water. It looks as though we can go no further as
all the ortho and para positions are brominated. But we can if we treat the
tribromo-compound with bromine in an organic solvent. Account for the
formation of the tetrabromo-compound.

OH OH O
Br2 Br Br Br2 Br Br

H2O, EtOH HOAc


NaOAc
Br Br
Br

The product is useful in brominations as it avoids using unpleasant Br2.


Suggest a mechansism for the following bromination and account for the
selectivity.

Br
O
CF3 Br CF3
Br
+
90%
NMe2 NMe2 yield
Br Br

Purpose of the problem


Exploration of interesting chemistry associated with electrophilic
substitution on benzene rings.

Suggested solution
Phenol is so reactive that the fourth bromine adds in the para position.
Now the molecule has a problem as there is no hydrogen on that carbon
to be lost. So the phenolic hydrogen is lost instead. It is surprising but
revealing that this loss of aromaticity is preferred to the alternative
bromination at the meta position.

H
OH O O
Br Br Br Br Br Br

Br Br Br Br
Br Br Br


Note that the meta directing
Solutions for Chapter 21 Electrophilic Aromatic Substitution 13
effect of the deactivating CF3 group
is irrelevant (see p. 491 of the
textbook).

In the second reaction, one of the reactive bromines in the para


position is transferred to the amine. It could have added ortho or para
to the NMe2 group but CF3 is small and NMe2 is large, because the two
methyl groups lie in the plane of the ring, so steric hindrance rules. The
other product is recovered tribromophenol.

OH
Br Br
O
Br Br

Br
+
Br Br
Br H Br
CF3
CF3 CF3

NMe2
NMe2 NMe2

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