©@e@¢

- 2 @©@@@¢

oee.
- © 002 eee
>

©@e@

@@
e

fo

-
°
e

oy
e
.

.
.

-
MICHAEL COOK
PHILIPPA CRANWELL

WORKB 4 OKS IN CHEMISTRY

ORGANIC
CHEMISTRY
WORKBOOKS IN CHEMISTRY
ORGANIC CHEMISTRY
 Periodic table of the elements
Group
1 2 13 4 165 6 IW

1
1 s-block H
Period

flock

Lanthanides 6

Actinides = 7
 ‘
WORKB®OKS IN CHEMISTRY

ORGANIC
CHEMISTRY
Michael Cook
University of Hertfordshire

Philippa Cranwell
University of Reading

Series editor
Elizabeth Page
University of Reading

OXFORD
UNIVERSITY PRESS
 OXFORD
UNIVERSITY PRESS
Great Clarendon Street, Oxford, OX2 6DP,
United Kingdom
Oxford University Press is a department of the University of Oxford.
It furthers the University’s objective of excellence in research, scholarship,
and education by publishing worldwide. Oxford is a registered trade mark of
Oxford University Press in the UK and in certain other countries
© M Cook& P Cranwell 2017
‘The moral rights of the authors have been asserted.
Impression: 1
Allrights reserved. No part of this publication may be reproduced, stored in
aretrieval system, or transmitted, in any form or by any means, without the
prior permission in writing of Oxford University Press, or as expressly permitted
by law, by licence or under terms agreed with the appropriate reprographics
rights organization. Enquiries concerning reproduction outside the scope of the
above should be sent to the Rights Department, Oxford University Press, at the
address above
You must not circulate this work in any other form
and you must impose this same condition on any acquirer
Published in the United States of America by Oxford University Press
198 Madison Avenue, New York, NY 10016, United States of America
British Library Cataloguing in Publication Data
Data available
ISBN 978-0-19-10-7264-2
Printed in Great Britain by
Bell & Bain Ltd., Glasgow
Links to third party websites are provided by Oxford in good faith and
for information only. Oxford disclaims any responsibility for the materials
contained in any third party website referenced in this work.
Overview of contents

Preface vii

1.1. Drawing organic structures 1

1.2 Naming organic structures 4
1.3 Orbital overlap and bonding 8
1.4. Orbital hybridization 4
1.5 Double bond equivalents 15
1.6 Polarity 18
1.7 Aromaticity Pai |
1.8 Resonance 24
1.9 Tautomerism 28
1.10 Synoptic questions 30

2.1 What is isomerism? 32

2.2 Constitutional isomerism 32
2.3 Configurational isomerism 35
2.4 — Cis/trans isomerism 36
2.5 Optical isomerism (chirality) 39
2.6 Synoptic questions 45

3.1. Electrophiles and nucleophiles 47

3.2 Lewis acids and bases 49
3.3 Syl and S,2 51
3.4 The impact of pK, on leaving group ability 56
3.5 Synoptic questions 61

4.1 Synthesis of alkene via elimination (E2, E1, and E1cB) 62

5.1 Electrophilic addition 67

(QUEEN sooverview oF contents

6.1 Electrophilic aromatic substitution i

6.2 Effects of directing groups on S-Ar 74
6.3. Nucleophilic aromatic substitution 79
6.4. Azo coupling 82
6.5 — Synoptic questions 85

7.1. Structure and bonding 87

7.2 Reactions with nucleophiles 91
7.3 Reactions with reducing agents 94
7.4 Carboxylic acids 97
7.5 Acyl chlorides 100
7.6 Esters 103
7.7. Amides 106
7.8 Synoptic questions 109

Synoptic questions 111

Answers 113
Appendix 1 Acidity constants 116
Appendix 2 Electronegativity values for common elements vane
Appendix 3 Common functional groups in decreasing order of seniority,
according to IUPAC 118
Index 119
Preface

Welcome to the Workbooks in Chemistry

The Workbooks in Chemistry have been designed to offer additional support to help you make
the transition from school to university-level chemistry. They will also be useful if you are study-
ing for related degrees, such as biochemistry, food science, or pharmacy.

Introduction to the Workbooks

The Workbooks cover the three traditional areas of chemistry: inorganic, organic and physi-
cal. They are designed to complement your first year chemistry modules and to supplement,
but not replace, your course text book and lecture notes. You may want to use the Workbooks
as self-test guides as you carry out a specific topic, or you may find them useful when you
have finished a topic as you prepare for end of semester tests and exams. When preparing
for tests and exams, students often use practice questions, but model answers are not always
available. This is because there is usually more than one correct way to answer a question and
your lecturers will want to give you credit for your problem-solving approach and working, as
well as having obtained the correct answer. These Workbooks will give you guidance on good
practice and a logical approach to problem solving, with plenty of hints and tips on how to
avoid typical pitfalls.

Structure of the Workbooks

Each of the three Workbooks is divided into chapters covering the different topics that appear
in typical first year chemistry courses. As external examiners and assessors at different UK and
international universities, we realize that every chemistry programme is slightly different, so
you may find that some topics are covered in more depth than you require, or that there are
topics missing from your particular course. If this is the case, we would be interested in hearing
your views! However, we are confident that the topics covered are representative, and that most
first year students will meet them at some point.
Each chapter is divided into sections, and each section starts with a brief introduction to
the theory behind the concepts to put the subsequent problems in context. If you need to, you
should refer to your lecture notes and text books at this point to fully revise the theory.
Following the outline introduction to each topic, there are a series of worked examples, which
are typical of the problems you might be asked to solve in workshops or exams. These examples
contain fully worked solutions that are designed to give you the scaffolding upon which to base
any future answers, and sometimes provide you with hints about how to approach these types
of question and how to avoid common errors.
After the worked examples relating to a topic, you will find further questions of a similar type
for you to practise. The numerical or ‘short’ answers to these problems can be found at the end
of the book, whilst fully worked solutions are available on the Online Resource Centre. At the
end of each book is a bank of synoptic questions, also with worked solutions on the Online
Resource Centre. Synoptic questions encourage you to draw on concepts from multiple topics,
helping you to use your broader chemical knowledge to solve problems.
You can find the series website at www.oxfordtextbooks.co.uk/orc/chemworkbooks.
(QT prerace

How to use the Workbooks

You will probably refer to these Workbooks at different times during your first year course, but
we envisage they will be most useful when preparing for examinations after you have done
some initial revision.
Itis a good idea to use the introductions to the topics to check your understanding and refresh
your memory. The next step is to follow through the worked examples, or try them out yourself.
The hints will give you guidance on how to tackle the problem—for example, reminding you
of points you may need to use from different areas of chemistry.

> Hint If you find it difficult to rotate the molecule so that the lowest priority group is facing away
from you, then leave is where it is, assign the stereochemical configuration, and reverse the an-
swer at the end (i.e. (R) goes to (S), (S) goes to (R))—you'll end up with the correct isomer that way!

The comments will typically relate to the worked solutions and might explain why a unit con-
version has been used, for example, or give some background explanation for the maths used
in the solution. The comments are designed to help you avoid the typical mistakes students
make when approaching each particular type of problem. It is to be hoped that by being aware
of these pitfalls you will be able to overcome them.

S Note that inverting all the

stereocenters in a chiral molecule gives
the enantiomer, unless the compound
is meso. By contrast, inverting some,
but not all, of the stereocenters gives a
diastereomer.

When you are happy you have mastered the worked examples, try the questions. To check
your answers go to the back of the book, and to check your working look for the fully worked
solutions at www.oxfordtextbooks.co.uk/orc/chemworkbooks.
The synoptic questions can be used as a final revision tool when you are confident with your
understanding of the individual topics and want some final practice before the exam or test.
Again, you will find answers at the back of the book and full solutions online.

Final comments
We hope you find these workbooks helpful in reinforcing your understanding of key concepts
in chemistry and providing tips and techniques that will stay with you for the rest of your chem-
istry degree course. If you have any feedback on the Workbooks—such as aspects you found
particularly helpful or areas you felt were missing—please get in touch with us via the Online
Resource Centre. Go to www.oxfordtextbooks.co.uk/orc/chemworkbooks.
 Foundations

1.1 Drawing organic structures

Organic chemistry involves the study of molecules containing carbon, which make up the ma-
jority of biological matter. Due to the ability of carbon to bond so that it forms long chains, the
complexity of organic molecules can be very challenging. You may be familiar with the con-
densed formula or structural formulae often used to display organic molecules in introductory Ss Note: you may hear the word
chemistry courses. However, in specialized organic chemistry we will almost always use skel- ‘catenation’ used to describe the way that
etal formulae in order to quickly represent complex structures in a simple manner, and you will carbon atoms form chains.
need to be able to understand what these mean.
To draw a skeletal structure: S Methods of representing propan-2-ol,
also known as ‘isopropyl alcohol’:
« All hydrogen atoms that are bonded to carbon are not drawn—there are simply too many to
Molecular formula: C;H,O;
bother! Condensed formula: (CH,),CHOH;
¢ Chains of carbon atoms are simply drawn as zig-zags in which each connecting point Structural formula:
represents a carbon atom, with bonded hydrogen atoms.
« Double and triple bonds are represented as two or three lines between connecting points,

ee
respectively.

ads
=z
=

z
« ‘Heteroatoms, such as N, O, P, S, and the halogens, are written using their atomic symbol,

a
as normal.

Skeletal formula:

Worked example 1.1A OH

Convert the structural formula of 4-aminobutan-2-one into the skeletal formula.

D this ‘zig-zagging’ comes from the

Hon 109.5° bond angle found in tetrahedral

H-G-G-6-6—
carbon atoms. The bond angles for
NH,
carbon atoms with double or triple
H H H bonds are slightly different—for more
4-aminobutan-2-one information, see the section on orbital
hybridization (section 1.4).

S You may sometimes be asked to draw

Lewis structures. These are the same as
skeletal structures, but include dots to
First, we do not need to draw any of the hydrogen atoms that are bonded to carbon. We will represent lone pairs of electrons.

leave the hydrogen atoms of the amine (—NH,), as this is a functional group and the hydrogen
(e)
atoms are more likely to be important to its reactivity. Now, we will redraw the carbon chain as
AA
skeletal structure Lewis structure
(GP: rounpations

zig-zags, with each ‘point’ representing a carbon atom, while leaving the O and N heteroatoms
labelled. The skeletal structure should now be complete.

A 9 B a Remove H tl Redraw C o
H-C—C—C—C—NH, ———_»> C—C-—C—C—NH, ————»
‘i iy i chain NH2

4-aminobutan-2-one
Note that this final ‘point’
represents CH,

Worked example 1.1B

Methyl tert-butyl ether, or MTBE, is an organic solvent that is sometimes used as an alter-
native to diethyl ether, and also as an additive to unleaded petrol. Its condensed formula is
CH,OC(CH,),. Draw out its structural and skeletal formulae.

You will not often be asked to draw the structural formulae of organic compounds, but it is use-
ful here as an intermediate step between the molecular and skeletal formulae. Working from
left to right along the carbon chain, drawing bonds at right-angles, we will arrive at the struc-
tural formula shown below. Care must be taken to ensure that the three methyl groups (CH;)
are drawn attached to the same carbon atom. From this point we can convert to the skeletal
formula using the method in Worked example 1.1A. Note that the tert-butyl group, C(CH;),, can
be represented flat on the page, or in ‘3D: Both options are shown, but representing skeletal
structures in 3D will be very important when covering later topics.

>) Dashes and Wedges: In order to represent 3D structures on the page, ‘dashes’ and ‘wedges’
can be used to show that a bond is pointing away from, or towards the viewer, respectively.

b This dashed line shows that 'e' is

me i y_ Pointing away from us
C, ‘a’, and 'b' form a plane, aw ve
with 'd' above it, and 'e' below Cu
This wedge shows that 'd' is pointing
towards us

H
1
H—-C—H
H | H
I I
BCG @ne Gu
Hl oa
H-C-H k
H No SE No a

structural formula ‘Flat' skeletal formula "3D' skeletal formula

We can see from this example the level of complexity involved in drawing the full structural
formula of a relatively simple molecule. Drawing the molecule as a skeletal formula reduces the
image to a simple representation, while losing no structural information.
 1.1 DRAWING ORGANIC STRUCTURES [EID

© Question 1.1
Draw the structural formulae of the following compounds from their condensed formulae.
(a) CH,CH,CH,CH(CH,),
(b) CH,CHCH,OH
(c) CH,CH,CCCH,
(d) (CH,),CCH,CH,CH,OH
> Hint Be sure to look at the number of hydrogen atoms each carbon is bonded to—it may give
you an idea as to whether a double or triple bond might be present.

© auestion 1.2
Convert the following structural formulae into skeletal formulae.

H
1
H 62%"
1 1 I "
(a) H-¢-C—e-c—H (d) Cy C
roan of H~ Sc7~H
H H H H I
H
but-2-ene
cyclohexa-1,3,5-triene
(or benzene’)

(b)
i
H—-C—H (e)
1
H HOH

a. ae
rote

H H HH

2-methoxybutane (or ‘glycolonitrile’)

(c) (f)
H H HH HH H H fe} HH
ct oo oo toroid Io
H—N—C—C—C—C—N—-H BESO A|
1 ot
H H HH H HH H H

butane-1,4-diamine ethyl! butyrate

(or 'putrescine’) (smells like pineapple!) 5 Ramsembantarakeesrewitine

bond angles on alkenes and alkynes;

> Hint Take care when looking at double bonds—ensure that you draw the substituents in the C=C bonds give 120° angles with their
correct positions relative to each other. This will crop up in stereochemistry, which is covered in substituents, while C=C give bond
Chapter 2. angles of 180°. The reasons for this are
explained in section 1.4.
(RET 1 rounpations

>) There are a number of ‘trivial’ names 1.2 Naming organic structures
which are still used by chemists today,
but don’t follow IUPAC rules. You will In order to be able to know the structure of a molecule from its name, a set of rules for naming
come across these names often, and organic compounds, ‘nomenclature, has been laid out by the International Union of Pure and
include: acetone, formaldehyde, toluene, Applied Chemistry (IUPAC). This means that if you know the IUPAC name of a molecule, you
etc. Whilst these are useful for simplifying should be able to draw it. This is a great idea in principle, but can get complicated very easily.
the naming of molecules, there is no
In this workbook we will introduce the key concepts of chemical nomenclature and provide a
consistent methodology used so they
general method for naming organic molecules, but be warned—there are plenty of exceptions
need to be learnt individually.
that you will come across!

pn Hoh HH Naming alkanes

acetone formaldehyde toluene
In order to name alkanes using IUPAC nomenclature you must:

1. Identify the parent hydrocarbon chain. This will be the longest continuous carbon chain.
Please note that when the numbering
is conducted in this manner, you will
If there are no branches on the chain, this molecule will simply be named according to
sometimes see the positions described the number of carbon atoms in the chain (methyl, ethyl, etc.), followed by -ane. This is
as ‘locants’. the root name. In the case of cyclic alkanes, cyclo- is included before the root name, e.g.
cyclopropane, cyclopentane, etc.
S Please note, if there is more than one 2. Ifthere is branching present, number the carbon atoms in the chain, ensuring the first alkyl
identical substituent, the prefixes di-, tri-, substituent (branch) in the chain has as low a number as possible. This is the first point of
tetra-, etc., are used—this additional prefix difference rule.
does not affect the alphabetical ordering
of multiple substituents. For example 3. Number and name the alkyl substituents on the chain. This will become a prefix on the
ethyl- would be placed before dimethyl- parent hydrocarbon’s name. If there are multiple substituents to be added to the beginning
in an IUPAC name. of a name, then this is done in alphabetical order.

Worked example 1.2A

Name the following alkane according to IUPAC nomenclature.

First we have to identify and number the parent hydrocarbon chain. This is not always easy to
do, and can be hidden within a complex framework—so be careful! We must also ensure that
the first branch has the lowest possible number on the parent hydrocarbon chain. Numbering
along the chain gives us two possible arrangements, one of which has the first alkyl substituent
with a lower number, so is the correct numbering when naming the compound.
o

Cy

wo

correct
 1.2 NAMING ORGANIC STRUCTURES [EID
This allows us to see that the parent hydrocarbon chain is eight carbon atoms long, so the
name of the molecule will end -octane. Now we must deal with the alkyl substituents, or
‘branches: The substituent at carbon 2 (or C2) is —CH,, giving a 2-methyl- prefix, while C5 has
a —C,H,, or a 5-ethyl- prefix. We can now add these substituents in alphabetical order to the
beginning of the parent hydrocarbon name to give 5-ethyl-2-methyloctane.

Naming compounds with one functional group

When naming organic molecules with a single functional group we must modify our approach
slightly. Now, when naming an organic molecule we must:

1. Identify the functional group present. This will give the molecule either a prefix or suffix,
and in the latter case, will replace the -ane on the end of the root name. Where possible, it
is typical to use the suffix, rather than prefix. Some common examples of functional group
nomenclature are shown below:

Class: alcohols aldehydes ketones carboxylic acids alkyl halides

Structure: R—-OH
R
A, H R R' R OH R~~

Suffix: -ol -al -one -oic acid _—

F (fluoro-)
Cl (chloro-
Prefix: hydroxy- oxo-* oxo" —_ x Br ani
| (iodo-)
*rarely encountered

2. Identify the longest hydrocarbon chain to which the functional group is attached. We
now know the root name, and the suffix/prefix to be added to it. For example:

H~ A ~OH iAvon 7 i Soe i

mWAn
methanoic acid ethanoic acid propanoic acid butanoic acid
or or or or
"formic acid’ ‘acetic acid’ *propionoic acid’ "butyric acid’

3) To make matters more confusing, this is not the case for alkyl halides, alkenes or alkynes, for
which the parent hydrocarbon chain is the longest continuous carbon chain, as for the naming of
alkanes. For instance:

3 4

Poe’ poe,
gf gy? 4 gta?

2-ethylpentan-1-ol 3-(chloromethyl)hexane

NOT NOT

3-(hydroxymethyl)hexane 1-chloro-2-ethylpentane

In 2-ethylpentan-1-ol, the parent hydrocarbon chain is the longest continuous carbon chain which
the functional group (—OH) is attached to. However, in 3-(chloromethy|)hexane, as it contains a
(1 rounpations

halogen functional group the parent hydrocarbon chain is the longest continuous chain anywhere in
the molecule. The halogen-containing chloromethy! substituent is added as a prefix onto the name.
This should not crop-up too often, but is important to be aware of.

3. Number the parent hydrocarbon chain so that the functional group present has the lowest
possible number. Any alkyl substituents on the molecule may then be numbered according
to this functional group. For instance:

cl

1 4
i 2a" s

4-methylhexan-3-one 2-chloro-4-methylpentane

NOT NOT

3-methylhexan-4-one 4-chloro-2-methylpentane

Worked example 1.2B

Use the information provided in the IUPAC name to draw out 4-ethyl-5-methylheptan-2-one.

In order to draw out this molecule, we have to extract structural information from the IUPAC
name in a methodical manner. We can work backwards throughout the name to get all the
information we need.

1. The suffix 2-one tells us that this is a ketone at C2.

2. The root name heptan- tells us that the parent hydrocarbon chain is seven carbon atoms long.
3. The prefix 4-ethyl-5-methy] tells us that there are ethyl and methyl substituents at the C4
and C5 positions, respectively.

Using these three pieces of information we can now start to draw out the target molecule.
A good approach to this would be to draw out the parent hydrocarbon chain, number it, then
place the functional group and alkyl substituents in the positions identified. Firstly, we can
draw the seven-carbon chain, then number it from left to right. At the C2 position, we can now
add our ketone functional group. Now we can add the ethyl group to position C4, and the me-
thyl group to position C5. This gives us the structure 4-ethyl-5-methylheptan-2-one.

4-ethy|-5-methylheptan-2-one 4-ethyl-5-methylheptan-2-one

(7)

a. ~~.
——_> —_>>
1234587
draw carbon chain number carbon atoms add functional group
and substituents

Naming compounds with more than one functional group

If a molecule has more than one functional group, there is an important decision to be
made—which functional group dictates the suffix of the IUPAC name? In order to decide
this, IUPAC have prioritized certain functional groups over others, with higher priority
 1.2 NAMING ORGANIC STRUCTURES

functional groups dictating both the suffix (where appropriate) and the parent hydrocarbon >} The prioritization of functional groups
chain. IUPAC call this the ‘seniority’ of the group. The seniority of functional groups is laid _'s important in deciding the suffix of the
out in Appendix3. molecule name. Without prioritization
there would be many different names that
could be given to the same molecule. For
instance, in the molecule below, IUPAC
Worked example 1 -2C dictates that alcohols are given priority
over amine groups, therefore the correct
Isoleucine is an essential amino acid, meaning that humans cannot produce it themselves and _ IUPAC name is 3-aminopropan-1-ol.
must acquire it in their food. It has the IUPAC name 2-amino-3-methylpentanoic acid. Using
this information, draw isoleucine. HN “~-™on

3-aminopropan-1-ol

or
We were told in the question that isoleucine has the alternative IUPAC name of 2-amino-
3-methylpentanoic acid, which contains all the information we need to draw the structure out. HO” ~~,
We can break down the name into three parts as in Worked example 1.2B:
3-hydroxypropanyl amine
1. The suffix, -oic acid, tells us that this is a carboxylic acid. As carboxylic acids can only lie on
terminal carbon atoms, this is by definition the C1 position.

2. The root name is pentan-, so the parent hydrocarbon chain is five atoms long.
3. The prefixes tell us the character and position of the substituents. 2-amino tells us that
there is an amine group at the C2 position, while 3-methy] tells us that there is a methyl
group at the C3 position.

Using this information, we can draw out the parent hydrocarbon chain, number the carbon
atoms, then add the functional groups and substituents in the correct positions. The process is
shown below:

2-amino-3-methylpentanoic acid

9
Wm —_
1 3 5 SES
2° 4 HO
NH

draw and number parent add functional groups isoleucine

hydrocarbon chain and substituents

@ Question 1.3
Determine the IUPAC name for the following molecules.

(a) (b) (c) °

wwe ae A,
ZA

OH
(d) (e)
Br OH
AK
> Hint Use the nomenclature tables in Appendix 3 to help you if any functional groups are unfamiliar to you, and be careful to identify priority
when more than one functional group is present.
 GE : rounpations

@ Question 1.4
Draw the structures of the following molecules from the information provided in their
TUPAC name.

(a) 4-ethyl-6,6-dimethyloctane.
(b) 1,1-dimethylcyclopropane.
(c) 1,3-dichloropentane.
(d) 2-propyn-1-ol.
(e) 1-methyl-4-(1-methylethyl)benzene (trivial name: ‘cymene’).
(f) 3,7-dimethylocta-1,6-dien-3-ol.

> Hint When numbering -ene and -yne functional groups, the numbering is conducted from the
first carbon atom of the functional group. For instance, in pent-1-ene, the double bond is between
C1 and C2, and in pent-2-ene the double bond is between C2 and C3.

D3,7-dimethylocta-1,6-dien-3-ol, or ZA—oww 2S”

‘linalool’, is a popular perfume to add to pent-1-ene pent-2-ene
shampoos and bubble-bath. It smells (trans)
floral and spicy.

S When we talk about orbitals being

‘in-phase’ or ‘out-of-phase’, we mean
that the wave-like part of the orbital
is either constructively overlapping or 1.3 Orbital overlap and bonding
destructively overlapping, respectively.
Atoms consist of a nucleus, containing protons and neutrons, surrounded by electrons. You
For more information on this, see
Chapter 4 in Burrows et al. (2013).
should be aware at this point that these electrons are contained in atomic orbitals (AOs), des-
ignated s, p, d, and f, that can sit in different shells. In organic chemistry, we mainly concern
out-of-phase ourselves with s and p orbitals, which have characteristic sphere and dumb-bell shapes, respec-

COvo®
_—0" - LUMO
tively. In order to form a molecule, atoms must allow their AOs to overlap and form molecular
orbitals, that bond the atoms to each other. The combination of two AOs results in the production
of two molecular orbitals, one that is lower in energy than the constituent AOs (bonding), and
one that is higher in energy (anti-bonding). Bonding orbitals are formed when AOs overlap in-

o ce phase, while anti-bonding orbitals are formed when they combine out of phase. The behaviour
Energy

a 2p of electrons in these orbitals is described by molecular orbital (MO) theory, which we will touch
Nn
no]

upon here. The overlap of an s orbital with either an s or p orbital leads to the formation of ao
(sigma) bonding and a o* anti-bonding MO. If a p orbital overlaps with another p orbital, two
“4b o-HOMO types of bonds can be formed. ‘Head on’ overlap of the p orbitals leads to the formation of ao
bonding and a o* anti-bonding MO, whereas a ‘side on’ overlap leads to the formation of a x (pi)
eO-2@ bonding and a x* anti-bonding MO. These bonds are weaker because the orbitals do not overlap
in-phase so well. An example MO diagram is shown in Figure 1.1, which shows the ‘head-on’ overlap of
two 2p to form a o-bonding orbital and a o*-anti-bonding orbital. A pair of electrons sits in the
Figure 1.1 MO diagram showing the
overlap of two 2p orbitals to form a
o-bonding orbital, so a o-bond is formed. In the MO diagram we can see the Highest Occupied
o-bond. The shapes of the orbitals Molecular Orbital (HOMO), which is the highest energy orbital with electrons in. The lowest en-
involved are included. ergy orbital without electrons in is called the Lowest Unoccupied Molecular Orbital (LUMO).

Bond order
If either a o or x bonding MO contains a pair of electrons, then a bond is formed. If a pair of elec-
trons is added to the anti-bonding MO, then the corresponding bonding MO breaks. The number
of bonds shared between two atoms, or the ‘bond order, can be calculated using equation 1.1:

bonding electrons —anti-bonding electrons

Bond order = (1)
2
 1.3 ORBITAL OVERLAP AND BONDING [ES

where ‘bonding electrons, and ‘anti-bonding electrons’ refers to the number of electrons in
bonding and anti-bonding orbitals, respectively. This value must always be zero or a positive
integer, so if your answer is negative, something has gone wrong! We can see that if we would
add a pair of electrons to the o bonding orbital in Figure 1.1, we would have to occupy the
LUMO—the o* anti-bonding orbital (Figure 1.2). This would ‘break’ the o-bond, and reduce
the bond order to zero. This will be very important when mechanisms are covered later in the
workbook.

out-of-phase

bonding electrons — anti-bonding electrons

Bond order =
Energy

ny
+f o- HOMO ° is

eC:d
in-phase

Figure 1.2 Adding a pair of electrons into the o* anti-bonding MO reduces the bond order to zero,
breaking the o bond.

Worked example 1.3A

Show on an MO diagram what molecular orbitals are formed (if any) from the constituent AOs
of H,. Calculate the bond order.

This is the simplest possible scenario when drawing these MO diagrams, but care still needs to
be taken. First, we must identify what orbital the valence electron of hydrogen is in—namely the
1s orbital. We can then draw the MO diagram, showing the energy level of the 1s orbital for each
hydrogen atom—this will be the same in each atom. We can then add an electron into each of
these orbitals, completing the electronic arrangement for atomic H.

H H

Energy

sf 41s
(GET 1 rounpations

S There are three important rules to We can now draw the molecular orbitals of H, in the centre of the diagram. The combination
remember when adding electrons to MO of the constituent 1s orbitals will result in two new MOs—a o bonding orbital, and a o* anti-
diagrams: bonding orbital. The bonding orbital is lower in energy than the anti-bonding orbital, and the
¢ The Aufbau principle, which means 1s orbitals. To complete the MO diagram, fill the orbitals from bottom to top with the electrons
that you start filling the lowest energy from the constituent orbitals. This will demonstrate that a o-bond is being filled.
orbitals first.
© The Pauli exclusion principle, which H Hy H
states that each orbital may only
contain two electrons, of opposite spin. Energy
e Hund’s Rule, which states that when
there are orbitals which are equal in
energy (degenerate), electrons are
added one at a time to each orbital,
before pairing.

Finally, to calculate the bond order, simply use the equation given previously. In this case, we
can see from the diagram that there are two electrons in bonding orbitals, and no electrons in
anti-bonding orbitals. So:

bond order = (number of electrons in bonding orbitals—number of electrons in anti-bonding orbitals) /; 2

bond order = (2-0)/2 = 1 i.e. anewsingle bond.

Worked example 1.3B

Draw the MOs arising from the overlap of a 2s orbital with another 2s orbital.

We know from the introductory paragraph that when s orbitals overlap with s orbitals they form
o-bonds. This is also the case when a 2s orbital overlaps with another 2s orbital while in-phase.
However, we must be careful to remember that when two new AOs combine they produce two
MOs as a result. The other orbital formed is a o* anti-bonding orbital, resulting from the out-of-
phase combination of the two 2s orbitals. This can be depicted on an MO diagram, which nicely
shows the energy levels of the bonding and anti-bonding orbitals:

2s — 2s overlap

out-of-phase

ve
Energy

in-phase

Note that in this case we have drawn the 2s orbitals as being equivalent in energy—this is not
always the case, especially if the two atoms are different. However, even if the 2s orbitals are not
 1.4 ORBITAL HYBRIDIZATION (REEDS

equal in energy, the bonding orbital formed will be lower in energy than the constituent AOs. S You may have wondered why some
It is also the case that the anti-bonding orbital formed will be higher in energy than both of the orbitals are shaded, while others are not.
two constituent AOs. This shading designates a difference
in the sign of the wavefunction of the
In future work, unless instructed, we will simply depict the resulting MOs pictorially, without
orbitals—one orbital is plus, the other
an energy level diagram. This will help simplify diagrams as the examples used become more
is minus. A deep understanding of
complex in later chapters. We can show the MOs for in-phase or out-of-phase 2s orbital overlap wavefunctions is not yet necessary, but
more clearly in this way: you will need to know that for orbitals to
be ‘in-phase’, their shading, i.e. the sign
2s 2s o of their wavefunction, must be the same.

CLD > ©)
in-phase bonding orbital

C@-0®e
out-of-phase anti-bonding orbital

Ss The MO theory section of this

@ Question 1.5 workbook is restricted to the key
concepts which are necessary for use in
Show on an MO diagram what molecular orbitals are formed (if any) from the overlap of organic chemistry. More information and
constituent AOs of He,, and calculate the bond order. questions on MO theory can be found in
Clayden et al. (2012) and the Workbooks
in Chemistry: Physical Chemistry book in
this series
(?) Question 1.6
Draw the MOs arising from:

(a) The head-on overlap of a 2p orbital with another 2p orbital.

(b) The side-on overlap of a 2p orbital with another 2p orbital.

1.4 Orbital hybridization

The AOs, s, p, d, and f, are useful for describing the ground state of atoms, but often cannot ex-
plain the geometry of bonds in molecules, which arise from the overlap of these individual AOs.
In order to explain observed deviations in the bond angles expected from AOs, Linus Pauling
introduced the idea of ‘hybrid’ orbitals, which are the result of the mixing, or ‘hybridization, of
AOs. In this hybridization process, AOs combine to form an equal number of hybrid orbitals,
which are equivalent in energy, or ‘degenerate, shown in Figure 1.3. These hybrid orbitals have
some of the character of each of the AOs that hybridized to form them. Although all elements
are theoretically able to hybridize, in organic chemistry we mainly concern ourselves with the
hybridization of carbon, especially for introductory courses. The valence electrons in carbon sit
in the 2s and 2p orbitals, and these can hybridize to form sp, sp’, or sp* hybrid orbitals, depend-
ing on the bonding of the atom. The hybridization of one s and three p orbitals gives rise to sp*
orbitals; sp? orbitals arise from one s and two p orbitals, and sp orbitals arise from one s and
one p orbital. These hybrid orbitals retain some of the character of their constituent orbitals. An Ss Further information on the reasons.
overview of these hybridization processes is provided in Figure 1.3. These hybrid orbitals can for orbital hybridization can be found in
overlap ‘head-on’ with s, p, and other hybrid orbitals to form o bonding orbitals. Clayden et al. (2012).
(GREP 1 rounpations

second-shell orbitals of carbon in its four hybridization states

25 %s,
75 %p

‘et +—
rs I
1 1
rrr?
: cwtt+4
' \
' \

5[oy 3
oy
fr '
' a!
' \
\
' '
12s 4h '
unhybridized atomic carbon sphybridized carbon

a tn
2p
i
Pat +
1
' 33 % s, 66 %p >
a nn) By
3; 2: 50%s,50%p
wi}
at + 4 wy
| an)

uy
|
!
ag +
'
1

sp7hybridized carbon sp hybridized carbon

>) Note that electrons will spread evenly
throughout orbitals of equivalent energy, Figure 1.3 MO diagrams showing the energy levels and shapes of carbon in its various stages of
according to Hund’s rule. hybridization. The percentages of s and p character are inlaid.

It is straightforward to identify the hybridization of carbon atoms in a molecule, as long as

they possess a full valence shell and are uncharged, which is most commonly the case.

S Note that in these images we have « Ifthe carbon atom contains four o (single) bonds, and no x (double) bonds then it is sp*
shown the AOs of the constituent atoms. hybridized, and will be tetrahedral, e.g. the carbon atom in methane.
Looking at the molecule as a whole, these
AOs will overlap and form MOs (bonds),
it is just useful to see them in this state to
understand the resulting geometry of the a sp’ orbitals
molecule. 1
Coy

Onc
methane atomic orbitals

S Note that in this case, the sp? orbitals « Ifthe carbon atom contains three o-bonds, and one n-bond then it is sp* hybridized, and
are perpendicular to the p-orbital, i.e. will be trigonal planar, e.g. the carbon atoms in ethene.
the p-orbital points vertical, and the sp*
orbitals 90° to it p orbitals

H H
pac, > sp? orbitals
H H

ethene atomic orbitals

 1.4 ORBITAL HYBRIDIZATION [REFS

« Ifthe carbon atom contains two o-bonds, and two n-bonds then it is sp hybridized, and will Ss Note that a molecule is able to rotate
be linear, e.g. the carbon atoms in ethyne. around a single bond, however, when you
have r-bonds, this rotation cannot occur.
This is very important in stereochemistry,
p orbitals
covered in Chapter 2.

H-C=C-H @) ~ @)
\/
sp orbitals

ethyne atomic orbitals

Hybridization can also occur in other elements, such as oxygen and nitrogen. Similar to
carbon, whether the atom contains a double bond or triple bond is a good indicator that it
is likely to be sp? or sp hybridized. Atoms which are not carbon are more likely to possess
vacant orbitals or lone pairs of electrons, and in this case, we have to decide which orbital any
lone pairs of non-bonding electrons will reside in. If the lone pair is not conjugated, then it
will likely reside in a hybridized orbital. For conjugated lone pairs of electrons, they will sit in
p-orbitals in order to provide better overlap with any conjugated n electrons. For instance, the
nitrogen atom in an amine is sp* hybridized, whereas the nitrogen atom in an amide group is
sp’ hybridized.

Worked example 1.4A

Label the carbon atoms in the following molecule as sp, sp’, or sp* hybrids.

Zybe
{e)

NH,
(S)-2-Amino-4-pentynoic acid

(S)-2-Amino-4-pentynoic acid, also known as L-propargylglycine, contains five carbon atoms,

numbered 1-5 from the carboxylic acid.

NH,

Looking at the structure of the molecule, we are able to divide these carbon atoms into three
groups: those with only single bonds; those containing a double bond; and those containing
a triple bond. Carbons 2 and 3 contain only o-bonds, thus they are sp* hybridized. Carbon 1
contains a double bond, consisting of one x-bond and one o-bond, as well as two additional
o-bonds, thus it is sp* hybridized. Finally, carbons 4 and 5 are triple bonded to one-another, so
both have two o-bonds and two r-bonds, and are sp hybridized.
(EIN + rounpations

Worked example 1.4B

What is the hybridization state of the carbon atoms in propadiene? Draw the AOs, showing the
overlap that will occur to form MOs (bonds).

H,C=C=CH,
propadiene

First, we will identify the hybridization state of the carbon atoms present. The outer two carbon
atoms have three o-bonds and one m-bond each. Thus, they are sp* hybridized. The central
carbon may look a little unusual, but looking at the molecular orbitals present will lead you to
the correct hybrid state. It is in possession of two 6-bonds and two n-bonds, and is therefore sp
hybridized.
Next, we are asked to draw the AOs involved in the bonding of propadiene. Using the knowl-
edge of the hybridization states from the first part, we now simply need to draw the characteris-
tic shapes of sp’ and sp hybridized carbons in the order that they are in pentadiene.

H,C=C=CH,

sp? sp sp?

We must think about the orientation of these AOs a bit more carefully. In order to have good
enough orbital overlap to form a m-bond, p-orbitals must be aligned with one another. To
achieve this, we must rotate one of the outer sp? hybridized carbon atoms so that the p-orbital
is in-line with the p-orbital of the central sp hybridized carbon atom, i.e. facing the viewer.

H,C=C=CH, H,C=C=CH,

JAN JIN
sp’
Finally, we can move the orbitals closer to show the sites of overlap, and include the two or-
bitals of the hydrogen atoms attached to the outer carbon atoms. Here, dashed lines are used to
show how the p-orbitals would overlap to form a n-bond.

H,C=C=CH,
 1.5 DOUBLE BOND EQUIVALENTS [EES

© Question 1.7
Label all carbon atoms in the following molecules as sp, sp’, or sp* hybridized.

°
(a) “NZ (b) News
cl

(c) (a)
O H,C=C=NH

(e) (f)

> Hint The hybridization state of a carbon is reflected in its geometry. Bond angles may help you
to identify what kind of hybrid carbon you are looking at—especially for sp hybrids!

@ Question 1.8
Label all non-hydrogen or carbon atoms in the following molecules as sp, sp’, or sp*
hybridized.
9
(a) a (b) >A,
OH

(c) (a)

\Lsn
> Hint Nitrogen and oxygen atoms that don’t possess any n-bonding can still be sp? hybridized
if they are adjacent to a -bond (conjugated). This does not happen for saturated carbon atoms
as they do not possess a lone pair of electrons.

1.5 Double bond equivalents

When we are trying to determine the structure of a molecule from its molecular formula, it is
useful to be able to know the number of n-bonds and cyclic structures in the molecule. This can
be achieved by calculation of the double bond equivalents, also called the ‘degree of unsatura-
tion’ in some textbooks. The formula for calculating this is shown in equation 1.2:

Double bond equivalents (DBEs) = C— ae oan G2)

Where C= number of carbon atoms, H = number of hydrogen atoms and halogen atoms, and
N= number of nitrogen atoms.
(ETS + rounpations

>) The calculation of DBEs using Remember when using this equation that the number of DBEs includes all z-bonds, so covers
equation 1.2 will be incorrect for carbonyl groups, carboxylic acids, etc., as well as alkenes and alkynes.
molecular formulae containing atoms in
higher valence states, such as N(V), P(V),
and P(VII), so don’t be surprised if this
formula does not work for every molecule.
Worked example 1.5A

Calculate the number of double bond equivalents in benzene, C,H,.

Inorder to calculate the numberof DBEs, we need to identify

the C, H, and Ntermsin equation 1.2.
Cis the number of carbon atoms, and looking back at the molecular formula in the question we
can equate this to six. H is the number of hydrogen and halogen atoms. There are no halogens
present, and six hydrogen atoms. Therefore the H value is also six. There are no nitrogen atoms in
benzene, so the N term is equal to zero. We can now put these values into equation 1.2:

>) The molecular formula of benzene

was known long before its structure Double bond equivalents = C— a+ mae

-aiitia
was determined. In addition to Kekulé’s
structure, there were conflicting
structures proposed by chemists 2
including Adolf Claus and James Dewar. =6- 3+0+1
Kekulé’s structure is now used to depict =4
benzene, but be aware that due to
electron delocalization (aromaticity), it So, benzene has four DBEs. If we draw out benzene using the Kekulé-type structure, we can
does not tell the whole story. This will be count that it has three n-bonds. Benzene is also cyclic, which is equal to one DBE. These obser-
covered later in the chapter. vations account for the four DBEs calculated.

a
Kekulé
0
Dewar
&
Claus
Oo
benzene

Worked example 1.5B

Capsaicin is a naturally occurring mucosal irritant present in chilli peppers—it makes them
spicy! Using the molecular formula provided, calculate the number of DBEs, then identify
them on the structure.

wot
OH

RAW 0%

fe}
Capsaicin
(C4gH27NO3)

We can take the C, H, and N values from the molecular formula given above, equal to 18, 27, and
1, respectively. If we put these into equation 1.2 we get:

ppes=c- £4 Nay
2° 2
18. 22) 2 4
=18— 13.5+ 0.5+1
=6
 1.5 DOUBLE BOND EQUIVALENTS

So capsaicin has six DBEs. Now we need to identify them on the molecule. The number of DBEs
is equal to the number of 1-bonds plus the number of cyclic structures. Looking at capsaicin
we can see five n-bonds—four alkene groups and one carbonyl group. There is also one six-
membered ring on the right hand side of the molecule. This accounts for the sixth DBE.

4 OH

a“
a 5 2 0
oO

@ Question 1.9
Calculate the number of double bond equivalents from the following molecular formulae.

(a) C,H,O
(b) C,H,,0,
(c) C,H;NO
(d) C,H,CL,
(e) C,H,,0, (fluorescein, a fluorescent dye)
(f) CH,,CIN,O
(g) C,HF,O,
(h) C,.H,,N,(porphine, a metal-binding ligand present in many proteins)
> Hint Don’t forget that the H term in the DBE equation counts hydrogen and halogen atoms.

© Question 1.10
Tosyl chloride is commonly used to add a tosyl- protecting group to amines and alcohols.
By simply counting, we can see that the number of DBEs is 6.

tosyl chloride
(C7H,CIO,S)

However, using equation 1.2, the number of DBEs appears to be 4:

; 8 0
tosyl chloride DBEs =7— ae iad alae

Which value is correct, and why?

(QE 1 rounpations

1.6 Polarity
errr FF
In bonds between two different chemical elements, the electrons aren’t always equally at-
c-C C-N C-O C-F
+e + +> tracted to each atom. They can be drawn towards certain elements more than others, de-
pending on that element's electronegativity (y). More electronegative elements are able to
Figure 1.4 Polar bonds between draw electrons in bonds towards them from less electronegative elements, resulting in a
carbon (y: 2.5) and nitrogen (x: 3.0),
oxygen (x: 3.5), and fluorine (y: 4.0). The
slight negative charge (5-) at their end of the bond, and a slight positive charge (5*) on the
C—C bond is apolar due to the equal other. This creates a dipole and is indicated by a crossed arrow pointing from the 5* end to
electronegativity of the carbon atoms. the 5- (Figure 1.4). The electronegativity of elements is available through electronegativity
tables but generally increases in magnitude as you go across a period and decreases as you
S The arrow notation used here is the go down a group on the periodic table. Please note that those elements with electronegativ-
most commonly used. However, you
ity lower than carbon (x: 2.5) are often referred to as electropositive, and ‘push’ electrons
will also see a non-crossed arrow used
towards carbon.
to indicate polarity, which points from
& to 5*. This is actually what IUPAC says So, bonds can have polarity, but we must be aware that molecules also have an overall mo-
chemists should use, but at the time of lecular polarity, or dipole moment, which depends on the polarity of the bonds within the
writing, it has not been widely adopted. molecule and their arrangement in space. For instance, the C—C] bond is polar, which results
in dichloromethane having overall polarity. However, due to the arrangement of C—Cl bonds
errr FF in tetrachloromethane, it has no molecular polarity (Figure 1.5). A dipole moment has both
c-C C-N C-O C-F
magnitude and direction, determined by the arrangement of polar bonds within the molecule.
<—_— < <— Lone pairs of electrons residing on atoms also contribute to polarity.

dichloromethane tetrachloromethane

cl cl
dipole ai | I

ci Na ge” <a

no dipole moment

Figure 1.5 Polar bonds can cause a molecule to have an overall dipole moment, as in
dichoromethane. However, if these bonds oppose each other, as in tetrachloromethane, they can
cancel each other out, leaving the molecule with no dipole moment.

Worked example 1.6A

Despite having similar structures, formaldehyde has a high dipole moment, while carbon diox-
ide has no dipole moment. Explain this observation.

Le}
le} tl
n CG
mao nl
H H fe)

formaldehyde carbon dioxide

(polar) (nonpolar)

In order to understand the overall polarity of the molecules, we must look at the polarity of the
bonds present. Formaldehyde possesses C—H and C=O bonds. Carbon and hydrogen have
similar electronegativities (x: 2.5 and 2.2, respectively), so their bond is not considered to be
 1.6 POLARITY (ECS

polar. The electronegativity of oxygen is greater than carbon (x: 3.5 and 2.5, respectively), so Daithough we have said here that
the carbonyl group is polar, with a & charge on the oxygen. The polarity of this bond gives for- the C—H bond is not polar, there is still
maldehyde an overall dipole moment. Carbon dioxide possesses two polar carbonyl groups. a slight difference in electronegativity
between carbon and hydrogen. This
However, these directly oppose each other symmetrically. This means that overall, carbon
slight dipole on the C—H bond may not
dioxide is not polar.
be noticeable in some cases, but in alkyl
substituents the 5 charge can build up
on carbon atoms through multiple C—H

“it" dipole
a
d'¢ i
bonds, making the charge much more
significant. This means that overall,
alkyl groups are electron donating by
gq moment tt | nocdipole
induction.

3t
H
eo te- ot
The inductive effect aie ile
Polarization across a bond can have a knock-on effect along a chain of atoms, ‘pulling’ or R
‘pushing’ electron density along o-bonds. This effect diminishes along a chain of atoms
the further you get from the polar bond. This is called the inductive effect (Figure 1.6).
Atoms or groups which ‘pull’ electron density along o-bonds are called ‘electron with- >) For more information on pK,, see
drawing, and designated ‘—/’. Atoms which ‘push’ electron density along o-bonds are Chapter 3, section 3.4.
called ‘electron donating’ or ‘electron releasing, and designated ‘+’. This inductive effect
can serve to modulate the pK, of organic acids, and stabilize charge. This is especially a 3st
important when dealing with carbocations, where the presence of +] groups can greatly
improve stability. FO
855*

Figure 1.6 An electronegative fluorine

Worked example 1.6B atom is able to draw electron density
through o- bonds. This is known as the
Acetic acid has a pK, of 4.75, while 2-chloroacetic acid is more acidic, with a pK, of 2.85. Explain inductive effect.
this difference in acidity.
Would you expect 2,2-dichloroacetic acid to have a higher or lower pK,? >) Electron withdrawal and donation
can also occur through a m system, as.
Le} Le} described by the mesomeric effect. See
section 1.8 for details.
JR trea
HO HO

acetic acid 2-chloroacetic acid

pK,: 4.75 pK,: 2.85

fe}
cl
wo
cl

2,2-dichloroacetic acid
pK,: ?

In order to answer this question we need to know what factors affect the pK, of organic
acids. The more stable the conjugate base (the molecule after deprotonation), the more
readily it will dissociate from its proton, and the lower the pK, will be. For uncharged mol-
ecules like those above, the stability of the conjugate base is determined by its ability to
GET: rounpations

stabilize the resulting charge. So, when we compare the conjugate base of acetic acid to that
of 2-chloroacetic acid we need to look at what factors could affect the stability of the nega-
tive charge on the oxygen atom. 2-chloroacetic acid has a chlorine atom at the o-position.
Chlorine is more electronegative than carbon, so will draw electron density towards itself
through o-bonds. This effect can continue through to the oxygen atom, reducing the nega-
tive charge residing on that atom through induction. This stabilization is enough to cause
S It is important to note that charge can this increase in acidity, and associated reduction in pK,,. It should be noted that the methyl
also be stabilized by resonance, which is group on acetic acid actually serves as a +/ substituent, so destabilizes the charge on the
covered in section 1.8. conjugate base of acetic acid.

SL Ja
9 Le}

acid HO HO

acetic acid 2-chloroacetic acid

pK,: 4.75 pK,: 2.85

5; ° °
conjugate base }
ic} a +1 effect Jet -I effect
fe} fe)

less stable more stable

Now, having justified increased acidity due to inductive effects in the first part of this ques-
tion we can try to make a prediction about the acidity of 2,2-dichloroacetic acid. The inductive
effect is increased in the presence of additional -J groups. This means that an additional chlo-
rine atom will serve to further draw electron density away from the charged oxygen atom, stabi-
lizing the conjugate base of 2,2-dichloroacetic acid, so it is likely to be more acidic, and have a
lower pK,. This is the case, as the literature reports that 2,2-dichloroacetic acid has a pK, of 1.35.

© auestion 1.11
Are the following molecules polar or nonpolar?

(a) CF,
(b) HCN
(c) BCI,
(d) so,
(e) (CH,),SO
» Hint Revisit VSEPR theory for help deciding the geometry of these molecules. Then decide if
there is any symmetry that might affect the polarity of the molecules.

@ auestion 1.12
Which of the following charged molecules would you expect to be more stable?

(a)
° °
al ~ eo or yoke

cl

A B
 1.7 aRomaTiciTY (RS

(b)

A “ we
@

A B

©
fe} fo}

H Ave or 2 oe

A B

(d)
(2)
LS or “No

A B

1.7 Aromaticity
We have seen in section 1.3 that p-orbitals can overlap side-on to form m-bonds. If two or more
of these m-bonds are adjacent to each other in an organic molecule, and their p-orbitals are
in the same plane, they are said to be conjugated. This is also the case for electrons lying in
adjacent p-orbitals, such as a lone pair in an sp* hybridized oxygen atom. The electrons within
conjugated systems can delocalize over this extended n-system, providing additional stability
to conjugated systems.
Molecules that contain a planar, conjugated ring of sp* hybridized atoms with a delocalized
electron cloud in their x-system are said to be aromatic. The delocalized m-electrons in an aro- D You will come across some
matic m-system do not behave like electrons in a non-aromatic system, and will not undergo compounds that are anti-aromatic. These
the same chemical reactions. In order for a cyclic system to be aromatic it must be planar, con- molecules should not be confused with
non-aromatic compounds. Anti-aromatic
tain sp* hybridized atoms in its ring so that all p-orbitals are parallel, and will satisfy Hiickel’s
molecules possess a conjugated ring
tule. Hiickel’s rule states that in order to be aromatic, a planar conjugated ring must contain with 4n m-electrons, where n is a positive,
(4n + 2) n-electrons, where n is zero, or a positive integer (Figure 1.7). It is important to note, non-zero, integer. This anti-aromaticity
however, that Hiickel’s rule is not always effective for predicting the aromaticity of molecules is destabilizing, and often occurs in
containing more than one ring. reactive, short-lived, molecules.

planar

CO: ring conjugated

6 1 -electrons (n=1)
aromatic

benzene

Figure 1.7 Using Hiickel’s rule to determine aromaticity. Benzene is planar and possesses a fully
conjugated ring, which contains 6 m-electrons (n = 1). Benzene obeys Hiickel’s rule, so is considered
aromatic.
(EI 1 rounpations

Worked example 1.7A

Using Hiickel’s rule, why is furan aromatic, while cyclopentadiene is not?

Solution
In order to answer this question, we must ensure that we appreciate the three key elements of
Hiickel’s rule—namely that the molecule must be planar, the ring must be fully conjugated, and
the m-system must contain (4n + 2) electrons. Looking at furan and cyclopentadiene, we can
see that the only difference in their composition is whether there is an oxygen or carbon atom
5 This example illustrates that the at the one, or five, position, respectively. The oxygen atom in furan possesses two lone pairs of
hybridization state of heteroatoms can electrons, and adopts an sp’ hybridization state. This means that one pair of electrons is sitting
change in order to make a compound ina p-orbital, in the same plane as the two adjacent z-bonds, making the ring fully conjugated.
aromatic. Oxygen atoms in, for instance,
This gives the conjugated ring six -electrons in total, satisfying Hiickel’s rule, and making furan
an alcohol are sp? hybridized, but in
aromatic.
furan adopt an sp? hybridization in order
to complete the m-system. This can also Cyclopentadiene does not possess a fully conjugated ring due to the carbon atom at the
happen for other heteroatoms, such as 5-position containing no lone pairs of electrons. Additionally, the t-bonds of cyclopentadiene
nitrogen and sulfur. only contain 4 electrons (n = 0.5, which is not an integer), so it is non-aromatic.

planar planar
oO0 By
as ring conjugated
6 x -electrons (n=1)
QO ring not fully conjugated
4x -electrons
aromatic Non-aromatic

furan cyclopentadiene

Worked example 1.7B

Cyclooctatetraene consists of eight sp* hybridized carbon atoms in a ring, possessing four
«-bonds. It is conjugated and cyclic, however, it is non-aromatic and non-anti-aromatic. Why is
cyclooctatetraene non-aromatic? And why is it not anti-aromatic?

O
cyclooctatetraene

Solution.
While it may look like cyclooctatetraene is aromatic on first glance, in order to assign it so we
must make sure that it obeys Hiickel’s rule. The four conjugated -bonds in this molecule con-
tain eight m-electrons. Trying to put this into Hiickel’s rule gives us n= 1.5, which is not an inte-
ger. This means that cyclooctatetraene is non-aromatic.
There is, however, an additional subtlety within this question—why is cyclooctatetraene not
anti-aromatic? For compounds to be anti-aromatic they must possess a planar conjugated
 1.7 aRomaTicITY (PES

ring, containing 4n 1-electrons. Cyclooctatetraene is cyclic, conjugated, and does contain

An m-electrons (n = 2). Cyclooctatetraene is, however, not planar, so cannot be anti-aromatic.
The reason for cyclooctatetraene not adopting a planar conformation, despite its constituent
carbon atoms all being sp* hybridized is that the ideal bond angle inside an octagon is 135°,
whereas the ideal bond angle on an sp* hybridized atom is 120°. This leads to the molecule
adopting a non-planar ‘tub’ conformation due to ring strain.

© Question 1.13
Are the following molecules aromatic, non-aromatic, or anti-aromatic?

(a) Cr (b)

toluene cycloheptatriene

©) A (a) Co
cyclopropene
styrene

(e) (f)
cyclobutadiene
naphthalene

(9) (h) O Se
cyclodecapentaene biphenyl

> Hint Always consider:

© Does the ring only contain sp* hybridized atoms?
Is the ring planar?
* Then, for monocyclic systems, does this ring obey Hiickel’s rule?

> Hint For bicyclic molecules, Hiickel’s rule does not necessarily apply. It may help to consider
the conformation of each ring, and hybridization state of each atom in the ring to determine aro-
maticity for these compounds.
GEEZ: rounpations

@ auestion 1.14
Are the following heterocyclic compounds aromatic, non-aromatic, or anti-aromatic?

HH 2“ ~o
() O (b) &
FA
pyran
pyrrole

Cc2N A
@

©) @
HN S
1,2,3-Triazole
pyrylium cation

e s$
(e) aoe Gy) c a
dihydro-1,3-oxazine Cont

> Hint Think about the hybridization state of the heteroatoms in each of these molecules—do
they contain the p-orbitals necessary to form a delocalized m-system?

1.8 Resonance
There are times, like in aromaticity, where electrons aren’t simply localized to a single
orbital, but are able to occupy numerous different positions on a molecule, this is known
as resonance. We are able to visualize this by drawing different Lewis structures of the
same compound, but in reality the electron distribution is an average of all the different
forms. This effect can help to distribute charge over a molecule, increasing its stability.
For instance, the sulfate (2-) anion has several resonance forms (Figure 1.8), which help to
stabilize it. The increased stability of this anion through resonance is one of the reasons
that sulfuric acid has such a low pK,. We can draw different resonance forms by showing
the motion of electrons using curly arrows, and link the different resonance forms using a
double-headed arrow. Generally, the more resonance structures you can draw for a mol-
ecule, the more stable it will be.

These curly arrows indicate movement of electrons

fe) i fe) © Le} fe) ©

ic) Uf el QoOn8>
ll — dL
o-s+o ~<—. o-s=0 =<—~ — oreo
$ 5 A 0° 0°
sulfate H
this arrow indicates
resonance

Figure 1.8 Resonance structures of the sulfate anion.

 1.8 RESONANCE [PSD

>) Sometimes you will see the resonance forms of a molecule combined into a ‘resonance hybrid’
structure. This shows the resonating electrons averaged as a dotted line across the molecule. For
instance, in the formate anion:

Sig,
Not all resonance structures are of equal stability, and those that are more stable have a
greater contribution to the resonance hybrid. The first thought when assigning stability should
be whether the molecule satisfies the octet rule, and then stabilizing effects such as electro-
negativity can be considered.

The mesomeric effect

The resonance, or delocalization, of electrons through z-bonds or p-orbitals in a molecule
can serve to donate or withdraw electron density, which can, in turn, affect the stability
or reactivity of a molecule. This is called the mesomeric (or resonance) effect, and groups
which donate electron density through the mesomeric effect are designated +M, and those
which withdraw electron density are -M (Figure 1.9). Remember that the actual distribution
of electrons is an average of these resonance forms, and there is permanent polarization via
this process. So, for neutral molecules, while you will usually draw the uncharged species,
the charged resonance structure does make a contribution to the resonance hybrid, and
therefore the polarity.

Figure 1.9 Some examples of -/V and + functional groups.

Worked example 1.8A

Draw all the possible resonance structures of 3-methylphenol, also known as m-cresol. What
does this imply for the hybridization of oxygen?

> OH:

m-cresol
(QE Ut rounpations

Solution

We can use some steps for drawing out resonance structures in a methodical manner. Firstly,
we will show the movement of a pair of electrons using a double-headed curly arrow. Then, we
must consider if there needs to be any further movement of electrons (usually from m-bonds)
so that no atoms possess more than eight electrons, in accordance with the octet rule. Finally,
we need to assign any charge on the molecule. We can draw out the first resonance structure for
phenol by moving a pair of electrons from the oxygen atom to form a n-bond with the adjacent
carbon atom. This would leave that carbon pentavalent (which we must never do!), with ten
electrons in its outer shell. So, we must move a pair of electrons from that carbon atom’s other
>) Aromatic rings, such as that found in «-bond onto the neighbouring C2 position. This process would leave oxygen with a positive
phenol, are particularly good at stabilizing
charge, having been made to share an electron with the carbon at position 1, and the carbon
charge through resonance. This is one
at position 2 with a negative charge, having ‘gained’ an electron from the previously-shared
reason why phenol is so acidic—the
phenolate anion is stabilized through «-bond. We can continue this process around the aromatic ring to give 2 additional resonance
resonance, which weakens the O—H structures. As a lone pair on the oxygen is able to conjugate with the n system, the oxygen atom.
bond. must be sp” hybridized.

ao OH OH OH

Worked example 1.8B

Acetone has a pK, of 19.2, whereas the hydrogen atom at the 3-position of acetylacetone has a
pK, of 9.0. Explain this difference in acidity.

propan-2-one pentane-2,4-dione
"acetone" “acetylacetone”
pKa: 19.2 pKa: 9.0

The pK, of organic molecules is related to the stability of the conjugate base, as discussed in
Worked example 1.6B. If we draw out the conjugate base of acetone and acetylacetone, we can
then try to rationalize which is likely to be more stable.

Le} Le} Le}

conjugate ° ° le)

= Ase BAK
 1.8 RESONANCE [PTA

Now, we know from sections 1.6 and 1.8 that the main contributors to stability are inductive
effects and resonance. As in Worked example 1.6B, there is likely to be a contribution from the
inductive effect, due to electron withdrawal by the oxygen atom of the carbonyl groups. How-
ever, resonance effects are typically more stabilizing than inductive effects, so we must consider
these as well. We shall first draw out all possible resonance structures of acetone and acetyl-
acetone. This gives us two resonance structures for acetone, and three for acetylacetone. This
means that the conjugate base of acetylacetone is more stable than that for acetone, so acetyl-
acetone has a lower pK,,. It should be noted, also, that resonance forms which leave a negative
charge on an electronegative atom are particularly stable.

acetone Ch oh

a5) more stable

©: ()

tae
conjugate 9
> i?)
KR
>
A 9 9

more stable

@ Question 1.15
Draw all possible resonance structures of the following molecules.

fo}
(a) n (b) °
SC. 8
o ~o o™
carbonate anion ethyl acetate

NH,
(c) (d) Co

aniline

a s

(e) Ago (p a N J N —.
HO H H

glyoxylic acid N,N'-diethylthiourea

> Hint Be systematic, starting at a pair of non-bonded electrons moving to create a new x-bond.
Then, move electrons from m-bonds to new orbitals to ensure that there are no pentavalent spe-
cies created. Finally, decide if the movement of electrons has created any charged atoms. It will
also help to draw these as Lewis structures, displaying the lone pairs of electrons as dots.
QE i rounpations

© auestion 1.16
In each case, identify the most stable resonance structure (the ‘major contributor’) for the
following molecules. Justify your choices.

» Ae Bek
()

oy a
(b) o2P=0°
is <> ene)
o=P—0
° On
i. ii.

(c) NOX) <—__»> AZ

i. ii.

éy
(a) n=c0 <> N=c-0°

> Hint First consider whether the resonance structure satisfies the octet rule, then whether it has
fewer charged species, and finally, if there is any charge, how stable the ions are.

1.9 Tautomerism
Tautomerism describes the interconversion of two compounds by a shift of a double bond and
hydrogen atom (or proton). This may look at first like resonance is occurring, but tautomerism
actually describes an equilibrium between two distinct species that are constitutional isomers.
As a result, we are able to shift the equilibrium using factors such as pH. The most commonly
encountered form of tautomerism is keto-enol tautomerism, which describes the interconver-
sion of an aldehyde or ketone possessing o-hydrogen atoms to an enol. In order to speed up this
tautomerism, an acid or base catalyst can be used.

Worked example 1.9A

Draw the tautomeric forms of butanone.

First, we must draw on our knowledge of chemical nomenclature to draw out butanone. The
prefix butan- means that the parent hydrocarbon chain is four carbon atoms long, while the
 1.9 TAUTOMERISM [IPED

suffix -one means that this is a ketone. Drawing out butanone based on this knowledge will give
us the following structure:

a
butanone

Nowwe need to think about what tautomers could be formed. As butanone contains a ketone with
a-hydrogens, it is able to convert into an enol. However, there are o.-hydrogens at both the 1 and 3
position, so there will be two possible enols formed by tautomerism. We can now draw them out
by using the electrons in each C—H bond to form a z-bond with the carbon of the ketone, forming
an -ene group, and moving the hydrogen proton onto the oxygen, to form an alcohol.

OH

A
° ZA
SNA Enol forms
H H 2
1 2 SQ a

Keto- form : TK

n.b. equilibria arrows used

Worked example 1.9B

‘The use of a base can catalyse the tautomerization of acetone (propanone) to its enol form.
Provide a mechanism for this transformation.

This is one of the first mechanisms we've had to draw in this workbook, so we shall try to take
care. First, the base will extract an a-hydrogen by donating a pair of electrons into the C—H o*
anti-bonding orbital, which breaks the C—H o-bond, and forms a bond between the hydrogen
and base (1). The pair of electrons in the C—H o0-bond are now able to form a 1-bond with the
carbon of the ketone by donating a pair of electrons into the n* orbital of the C=O bond (2). This
results in the formation of an -ene group. The m-bond of the carbonyl has been broken, and the
pair of electrons must reside on the oxygen atom, so that the carbon does not exceed the octet
rule (3). We can now draw this using curly arrows:

°
3 © 9° ©
Ae) 2 = A +BH
H

B J enolate form
1

B=Base
QED: rounpations

This has formed the enolate, which is electronically identical to the enol, but is missing a hy-
drogen nucleus (proton) to convert it into the enol. Some tautomerizations only proceed to this
enolate, but we have been asked to draw the enol, so we shall assume that the conditions are
such that a proton could be extracted from either the protonated base, or solvent.

sv
@

fe) OH

QOS K

@ auestion 1.17
Draw all possible tautomeric forms of the following molecules.

le}
ia ° (b)
2 °
biacetyl
acetaldehyde

° ce l ®e \
(c)

> Hint Look for o-hydrogen atoms by the keto- or imine group. These will be removed to form
the ene- tautomer.

© auestion 1.18
Provide a mechanism for the acid catalysed tautomerization of acetone.

1.10 Synoptic questions

© Question 1.19
3,4,4,5-Tetramethylcyclohexa-2,5-dienone has the trivial name ‘penguinone, due to its
resemblance to the flightless seabird which shares its name.

(a) Draw penguinone.

(b) Identify whether penguinone is aromatic or not.
(c) Draw all possible resonance structures of penguinone.
 1.10 SYNOPTIC QUESTIONS [ETE

© Question 1.20
‘Michael addition’ is a useful way of forming C—C bonds between a nucleophile and an
a,B-unsaturated carbonyl compound. An example of a Michael addition is shown below.

Noe ° °
9 9 base B
Se x ———

Compound ‘A’ can undergo Michael addition with the «,B-unsaturated ketone ‘B’ if it is first
treated with a base to generate the reactive species X. Draw the structure of X and show any
resonance forms.

References
Burrows, A., Holman, J., Parsons, A., Pilling, G., and Price, G. (2013) Chemistry’, 2nd edn (Oxford University
Press, Oxford).
Clayden, J., Greeves, N., and Warren, S. (2012) Organic Chemistry, 2nd edn (Oxford University Press, Oxford).
 lsomerism

2.1 What is isomerism?

Isomerism describes the different ways that you can arrange the atoms in a molecule with a
fixed formula. This arrangement of atoms can take the form of constitutional (structural) isom-
erism, where the atoms are joined in a different order, or stereoisomerism, where the atoms are
arranged differently in space. Stereoisomerism is subdivided into conformational isomerism
and configurational isomerism. Two conformational isomers can be converted into each other
(interconverted) by rotation around single bonds, whereas configurational isomers cannot be
interconverted without breaking a bond.

SD Conformational isomerism is not

included in this workbook, but extra 2.2 Constitutional isomerism
information can be found in Chapter 18 of
Burrows et al. (2013). Two molecules that share the same molecular formula but have atoms bonded in a different
order are called constitutional isomers. For instance, if we take butan-1-ol, 2-methylpropan-
1-ol, 2-methylpropan-2-ol, and 1-methoxypropane, whose structures are shown in Figure 2.1,
and count the number of carbon, hydrogen, and oxygen atoms in these molecules, we obtain
the same molecular formula, C,H,,O0. However, it’s clear that these molecules are not identical,
>) Note that two constitutional isomers and even possess different functional groups. Constitutional isomers can have different con-
may be a combination of chain, nections in their carbon chains (chain isomerism), different placement of identical functional
positional, and functional group isomers. groups on that carbon skeleton (positional isomerism), or different functional groups entirely
(functional group isomerism). The relationship between the aforementioned butan-1-ol iso-
mers is shown in Figure 2.1.

Positional isomers Functional group isomers

—_ TT ee I

Ho pa " HON 72m

2-methylpropan-1-ol | 2-methylpropan-2-ol —_ butan-1-ol 1-methoxypropane
a |

Chain isomers
Figure 2.1 Relationships between positional isomers, chain isomers, and functional group isomers.
 2.2 CONSTITUTIONAL ISOMERISM [EZR

Worked example 2.1A

3-methylbutanal, also known as isovaleraldehyde, is commonly used in the production of pesti-

cides. Which of the compounds below are constitutional isomers of 3-methylbutanal?

we w~0wk ak
pent-1-en-3-ol 3-methylbutan-1-ol 3-methylbut-2-enal

0.
yu “No ‘o
2-ethoxypropane butanal 2-methyltetrahydrofuran

First of all, it is necessary to count the number of carbon, oxygen, and hydrogen atoms present
in 3-methylbutanal. It may help to redraw the molecule with all atoms included. This allows
identification of the molecular formula of 3-methylbutanal as C;H,,O.

H
HoH c:5
HG H:10
H oO
07°S¢- GS-4
PAS,
HH H Molecular formula: C5;H190

This question can be answered by simply counting the numbers of each atom present in is- Ss Double bond equivalents = C — (H/2)
ovaleraldehyde, and comparing the molecular formula to each other molecule. However, by + (N/2) +1, where C = number of carbon
first identifying the number of double bond equivalents in 3-methylbutanal, we can identify atoms, H = number of hydrogen atoms
pica A 23 “ e and halogen atoms, and N = number of
constitutional isomers quickly: 3-methylbutanal contains one double bond, on the aldehyde a 7
a mene 7 a + nitrogen atoms. See Chapter 1, section
functional group, so the constitutional isomers of 3-methylbutanal will contain one double
1.5 for further help.
bond equivalent. Only three molecules of the six contain one double bond equivalent, namely
pent-1-en-3-ol, butanal, and 2-methyltetrahydrofuran.
The number of carbon and heteroatoms may then be counted to identify the correct consti-
tutional isomers. Butanal can then be dismissed as it contains only four carbon atoms, leaving
pent-1-en-3-ol and 2-methyltetrahydrofuran as the constitutional isomers of 3-methylbutanal.

Worked example 2.1B

For compounds A-F, identify which pairs of compounds are isomers, then assign whether they
are chain, positional, or functional group isomers of each other.

‘ HN

A B c

4 H

D E F
GET 2 isomerism

First, the molecular formula of compounds A-F must be identified by counting the number
of carbon, hydrogen, and nitrogen atoms in each molecule. Those compounds with identical
molecular formulae must be isomers of each other. This allows the identification of the pairs of
constitutional isomers: A and E (C;H,,N), B and F (C,H,,N), and C and D (C,H,,N).
Now, the pairs of isomers can be compared, and the nature of their isomerism identified. A
contains a branched carbon-chain, whilst E has a straight carbon side-chain, therefore they are
chain isomers. B has the methyl group at the 3-position on the cyclic piperidine ring, whilst in
F it is bonded at the 2-position. The difference in the position of these groups makes the two
molecules positional isomers. Finally, C contains a primary amine functional group, whereas
in molecule D the nitrogen atom is within the secondary amine group. These two molecules are
therefore functional group isomers.

yore . 4° 2°
H Branched: H.N
1 H

H :
2 c D
|
Chain isomers Positional isomers Functional group isomers

© auestion 2.1
Draw and name all six possible constitutional isomers of 1-chloropentane (C,H,,Cl).

a7 ~~

1-chloropentane

© question 2.2
Identify whether the following pairs of molecules are chain, positional, functional group
isomers, or a combination of the three. Think carefully about the definitions of each!

m 4A wma —€ —>-€

(b) is and ey

(c) and roreN

H
(a) HN wx and ANN
 2.3 CONFIGURATIONAL ISOMERISM [SEES

2.3 Configurational isomerism

Configurational isomers are a type of stereoisomers, so they have the same molecular formula
and order of atoms, but have those atoms arranged differently in space. Configurational iso-
mers cannot be interconverted without having to break at least one chemical bond. Configu-
rational isomerism is further subdivided into cis/trans isomerism (E/Z isomerism) and optical
isomerism (chirality), shown in Figure 2.2.

Configurational isomerism

cis/trans isomerism Optical isomerism

re \=/ CH C2Hs
any, a OXNH,

Trans (E) Cis (Z) R s

Figure 2.2 The term ‘configurational isomerism’ covers both cis/trans isomerism and optical
isomerism, examples of which are shown.

Assigning the stereochemical configuration of isomers:

the Cahn-Ingold-Prelog system
In order to assign the stereochemical configuration of isomers, you will first need to be able to pri-
oritize groups according to the Cahn-Ingold-Prelog (CIP) system. Making sure that you are familiar
with this system will greatly speed-up your problem solving. The CIP system allocates each group
around a stereocentre a number (priority), with the relative positions of these numbers allowing
the assignment of stereochemical configuration. Briefly, the CIP system is applied as follows:

1. The atomic number of atoms closest to the stereocentre determines priority, with the
largest given highest priority, and so on.

e.g.

Order of priority by the CIP system: R-SH > R-OH > R-NH, >R-CH, > R—-H

Atomic number of first bonded atom: 16 (S) 8 (0) 7 (N) 6 (C) 1 (H)

2. Ifthe atoms have the same atomic number, then the atomic number of the next atom away
from the stereocentre is examined. If no difference is seen then continue to move away
from the stereocentre until a difference is found.

eg.
OH
Order of priority by the CIP system: e—/ > no a ca R / > R-CH,

3. Ifthe substituent contains a double or triple bond, then it is treated as being bonded to that
atom twice, or three times, respectively, e.g. C(H)=CH, is prioritized over CH,CH, S In the rare case that you might be
assigning priority to two different isotopes
eg. of the same element (which would
Order of priority by the CIP system: R—== > RY > EN therefore have the same atomic number)
you give priority to the atom with the
highest atomic weight. For example, H
fe} fe} and D have the same atomic number, but
Furthermore: Jk > J > R\ D has a larger atomic weight. So in this
R OH R OH case D would be prioritized over H.
QED 2 somerism

cis 2.4 Cis/trans isomerism

x N trans
Cis/trans isomers arise when rotation is restricted at a particular point in a molecule, most
R, R R H F , F
\ — ( ) ( commonly due to a carbon-carbon double bond. This restricted rotation allows groups posi-
tioned either side of the double bond to either sit adjacent to each other (cis), or opposite each
H H H R
other (trans), as shown in Figure 2.3. For disubstituted alkenes, the cis/trans system can easily
Figure 2.3 Example cis and trans isomers _ be applied by eye. However, for tri- and tetra-substituted alkenes, the relative priority of the two
of a general alkene. substituents on each side of the stereocentre must be assigned using CIP rules. When this sys-
tem is used, the isomers are assigned the letters (Z) or (£), instead of cis or trans, respectively.
S The (Z) and (E) notations are taken To assign E/Z isomers you need to look for the relative positions of the highest priority groups
from German—Zusammen (Z) means on either side of the double bond. If the highest priority groups either side of the double bond
‘together’, and Entgegen (E) means are adjacent to each other, the isomer is (Z) and vice-versa.
‘opposite’.

Worked example 2.2A

Identify whether the following three molecules are cis or trans isomers.

~
NH

‘NH,

(a) We need to look carefully at the relative position of the ethyl and methyl groups either side
of the double bond. Rotation cannot occur around this double bond, and the structure
provided shows us that these groups sit on opposite sides of the double bond. This
molecule is therefore the trans isomer of pent-3-ene.

+f
trans

(b) Itis important with any kind of stereoisomer firstly to identify the point(s) at which the
stereoisomerism arises (the stereocentre). In this example, there are two double bonds,
and therefore two points in the molecule at which no rotation is possible.The carbonyl
group (C=O) does not have any substituents attached to the oxygen atom, so cannot give
rise to cis/trans isomers. However, the carbon-carbon double bond has two different
substituents attached to either carbon atom, and can give rise to cis/trans isomers. This
is the stereocentre we need to assign. Looking at the double bond, we can see that the
methyl group on one side of the double bond and the carbonyl group on the other are
adjacent to each other. This is, therefore, the cis isomer.

cis

ore
rs

H H

(c) This question requires us to look at the cis/trans isomerism arising from restricted rotation
around a ring, but we follow the same principles as for double bonds to assign which
isomer is present. The two amine groups attached to the cyclohexane ring are on opposite
 2.4 CIS/TRANS ISOMERISM (IEA

sides of the ring to each other—one sits ‘up’ from the plane (the wedge), the other ‘down’
(the dashes). This means that this is the trans isomer.

1!) rotate 90°

NH, H.N trans

NH — "Tt NH,

Worked example 2.2B

For the following molecules, identify whether they are E or Z isomers.

(a) For the left-hand side of this molecule, assigning the priority of the substituents is easy— Ss This molecule may have looked as if it
hydrogen has the lowest atomic number of any element, so will be lower priority than were trans (E), because the methyl groups
any other element, according to the CIP rules. The right-hand side of the molecule looks were on opposite sides, but remember
that the stereochemistry is assigned
slightly more difficult. But as with all questions regarding the assignment of priority,
based on the priority of the groups using
assignment is simple if the CIP rules are systematically applied. Here, we have to assign
CIP, rather than their similarity.
priority to —OH or —CH,. Oxygen has an atomic number of eight compared to carbon’s
six, and therefore takes priority. This puts the two groups with the highest priority adjacent
to each other—this is, therefore, a (Z) isomer.

LHS | RHS
2H! 2

1’: +
on 1
¢

(b) Assignment of the left-hand side of this molecule requires the use of point 2 of the CIP
rules outlined previously. As we travel away from the stereocentre, the first atom met is
carbon in both cases. We need to move further along bonds in order to assign priority. One
of the substituents is a methyl group, with a carbon atom bonded to three hydrogen atoms.
The other is an ethyl group, and bears a carbon atom bonded to two hydrogen atoms and
one carbon atom. Carbon has a higher atomic number than hydrogen, so the ethyl group
takes priority. The right-hand side of this molecule is simply assigned based on atomic
number, with the carbon atom of the ethyl group taking priority over the hydrogen atom.
The highest priority groups are adjacent to each other, so this is the (Z) isomer.
QED 2 isomerism

(c) The left-hand side of this molecule requires us to assign priority to either an ethyl group
or an ethynyl substituent. Although both of the closest carbon atoms are bonded to an
additional carbon atom, the ethynyl group has a carbon-carbon triple bond, so is treated
as if it were bonded to three carbon atoms, rather than the single carbon in the ethyl group.
The ethynyl group is therefore higher priority, according to the CIP rules. The amine group
on the right-hand side has a higher priority as nitrogen has a higher atomic number than
carbon. The two highest priority groups are opposite each other, so this is the (EZ) isomer.

2 1

@ Question 2.3
Rank the following groups in order of their priority according to the CIP rules.

(a) —H —NH, —CH, —OH

(b) “AS > —CH, TH

(c) —CH, Sei —H —NH,

(d) —NH, —cN —NMe, —No,

> Hint Ensure you are familiar with the CIP system before you begin, and systematically apply
them in the order shown in section 2.3. Extra information is available in Burrows et al. (2013) and
Clayden et al. (2012) if you need help.

@ Question 2.4
Identify if the following molecules are cis or trans isomers.

OH ;
Ph NC
(a) =/ (b) Ve (c) OH (d)
Et

> Hint In disubstituted rings, the relative positions of the two substituents does not affect whether
an isomer is cis or trans. Just treat them as you would a 1,2-disubstituted system.
 2.5 OPTICAL ISOMERISM (CHIRALITY) (SESS

@ Question 2.5
Use the CIP system to assign the following molecules as either (£) or (Z) isomers.

OH °
SH NH, O NH.
() 1S () yon © \= @ \=
UY
HN

> Hint If you cannot assign priority on the first atom away from the double bond, then move to
the second, third, etc., until priority can be assigned.

2.5 Optical isomerism (chirality)

Amolecule with a non-superimposable mirror image is said to be chiral. In the majority of cases
that you will encounter in organic chemistry, this chirality arises at a carbon atom bonded to
four different chemical groups. This type of isomerism is often termed optical isomerism as
these molecules have the ability to rotate plane-polarized light. Figure 2.4 shows a chiral com-
pound, X, and its mirror image, Y. If we imagine turningY 180° horizontally, we get out a struc-
ture which is not superimposable on the original molecule, X. X is, therefore, chiral.

A ' ae 180° fotation d d

Ce —_—_> Y= -
c i : as c xs f= Ns

x | ¥ x Y
Non-superimposable mirror images
S You may see optical isomers
Figure 2.4 X is a chiral molecule, as its mirror image is not superimposable on itself.
designated as (+)- and (-)- or d- and /-.
These prefixes pertain to the direction
‘The two chiral stereoisomers arising from a single stereocentre are designated as either (R) _*hat plane polarized light is rotated, and
or (S). In order to assign chiral molecules as either (R) or (S), you must firstly prioritize the are not covered in this workbook. Nout
A 2 may also see molecules assigned as D-
substituents around the stereocentre according to the CIP system. Then, the molecule must be eco f
5 : 5 or L-, which is a slightly more complex
rotated so that the lowest priority substituent (most commonly hydrogen) is facing away from method of assigning chirality (usually to
the viewer. Now, if the priority of the substituents decreases clockwise around the molecule, the —_ amino acids) based on a separate set of
isomer is (R), if the priority decreases anticlockwise, then it is (S). rules called the CORN rules.

OH Assign priority OH Rotate OH ic

woknty ——— 77 wa 2 4 Aw i!)
\ aa

NH Assign priority NH, Rotate rf NH, ‘

———_—_—_—— ———_» :3 oe ‘ig
Kou 4 wom Ht (Ss)
‘ 1°
GED 2 isomerism

OH a OH
hs enantiomers (R)
——_—__—_>

OH " OH
= diastereomers
(s) <——_—_—_—> (S)
(R) (S)
OH OH

OH OH
(V4 meso A(R)
(R) = > (Ss)
OH OH

| rotatd 180° Identical

J OH

Figure 2.5 The relationship between enantiomers, diastereoisomers, and meso compounds.

>) Note that inverting all the A chiral molecule can also exist as a non-superimposable mirror image of itself: an enanti-
stereocenters in a chiral molecule gives omer. However, ifa chiral molecule contains more than one stereocentre giving rise to chirality,
the enantiomer, unless the compound it can be related to stereoisomers with different (R)/(S) configurations that are not mirror im-
is meso. By contrast, inverting some,
ages. These compounds are said to be diastereomers (or diastereoisomers). In specific cases, a
but not all, of the stereocenters gives a
diastereomer can have a configuration such that it is imposable on its own mirror image, and
diastereomer.
is therefore not chiral! In this case it is said to be a meso compound. The relationship between
chiral isomers is shown in Figure 2.5.

Worked example 2.3A

Assign the following chiral molecules as either the (R) or (S) enantiomers.

NH,
(a) Neen (b) Hom ORE iG)
NH,
aN

Solution

(a) Ifwe follow the same logic used in the explanatory paragraph at the start of this section,
then we will always arrive at the correct answer. First, we must assign priority to the
substituents using the CIP system. This puts the amine group as the highest priority,
 2.5 OPTICAL ISOMERISM (CHIRALITY) (PTI

the ethenyl group second, the methyl group third, and the hydrogen atom fourth. If you
require more practice assigning priority using the CIP system, then revisit section 2.4.
The lowest priority substituent, i.e. the hydrogen atom, is already facing away from the
viewer, so no rotation of the molecule is necessary. The substituents are now ordered in an
anticlockwise fashion, so the isomer is (S).

NH, Assign priority NH, Assign (R)/(S)

WS a SS H 4
2 3

(b) In this molecule, the hydrogen atom has not been drawn out for you, but it is still there.
However, you may find it helpful to redraw the structure with the atom included. Assigning
priority using the CIP system puts the groups in the following order:

3 2
COOH
HOo~
H.N H
4 1

Before we are able to assign whether this stereoisomer is R or S, we need to make sure the
lowest priority group is facing away from us. Rotating the molecule 180° horizontally, then
making an assignment allows us to identify this as the R enantiomer.

(c) This molecule may look a bit different from those we have previously assigned, but there is
still a stereocentre which gives rise to chirality in the molecule. Assigning priority is a little
difficult, due to the ring, but it is still possible if we follow the CIP system. The assignment
of priority must be done with careful consideration of the relative positions of the C—C
double bonds. In this case, hydrogen is lowest priority, followed by the left-hand side of
the ring, then the right, and finally the C-—CH,)CH, substituent. The lowest priority group
is facing the viewer, so the molecule is rotated 180° horizontally. The order of priority now
decreases in a clockwise fashion, so the molecule is the (R) enantiomer.
GED 2 isomerism

Worked example 2.3B

Are the following pairs of stereoisomers enantiomers, diastereomers or meso?

(a) OH
HN HO.,, NH,
NH, and
OH HN

tl ww NH2
(b)
OH and OH

NH,

o 9
& ° and
“a ° Oo

ae X

(a) This set of questions can be answered using two different methods. Either you can redraw
the molecules in order to see if they are mirror images of each other, or you can assign the
stereochemical configuration and work out their relationship from there. If we redraw the
molecule on the right-hand side so that the carbon backbone mirrors the molecule on the
left, we find that these isomers are not mirror images of each other due to the chiral centres,
but are still non-superimposable. This means that the molecules are diastereomers.

OH OH
HON2) boa HN ANH 2

OH OH

You may have difficulty rearranging molecules in this fashion, particularly as the complex-
ity of the molecules you are trying to assign increases. Another method of working out re-
lationships between these stereoisomers is to assign the stereochemical configuration to
each chiral centre first. If all stereocentres are inverted, the isomers are enantiomers; if
some—but not all—of the stereocentres are inverted, they are diastereomers. This will al-
ways be a good strategy in questions of this type.
First of all, we assign the stereochemical configuration to the two chiral centres on each
isomer using the CIP system covered in Worked example 2.6A. This gives us (R,R) for the
isomer on the left, and (S,R) for the isomer on the right. As only one of the two stereocentres
has been inverted, these are diastereomers.

OH OH
HN (R) Ho.,, AB NH,
(R) NE (s}
OH
HN
 2.5 OPTICAL ISOMERISM (CHIRALITY) (NPEN

(b) Firstly, assign the stereochemical configuration of the two isomers shown in this question.
This gives us (R,R) for the left-hand molecule, and (S,S) for the right. As both stereocentres
have been inverted, these are enantiomers. Furthermore, simply rotating the molecule on
the right hand side 180° anticlockwise gives us a non-superimposable mirror image of the
compound on the left.

fo)
5 (S\NH
'S)

OH
OH
(R) “NH, oy
°

(c) Again, assign the stereochemical configuration of each stereocentre first. Notice how
the configuration of each stereocentre has not changed, giving (R,S) in each instance.
The molecule is, therefore, meso. If we rotate the molecules 180° vertically, they are
superimposable.

= ~
HO~{R)(S" OH Sie
B4 / \ rotate x
oO and ° Oo — ° oO

ee X oot on

For future questions, you can use a quick trick to help you identify meso compounds: they
all contain at least one plane of symmetry (Figure 2.6). This plane of symmetry is what al-
lows them to be superimposable on their mirror image. Remember that C—C bonds can
rotate, barring steric effects, so sometimes you may have to change the orientation of a mol-
ecule to notice this symmetry.

ye HO;
oho
Ho Tos

Erythritol

Figure 2.6 Symmetry in meso compounds.

GET 2 isomerism

@ Question 2.6
Find and mark all chiral centres in the following molecules.

Br

(a) (b) (c)

OH O
(d) HO (e) (f)
OH
‘OH

> Hint Remember that for a carbon atom to be chiral it must be bonded to four different groups.

@ Question 2.7
Assign the following molecules as either the (R) or (S) isomers.

Br Ph O SiMe;
(a)
NH,

(d) NH coon (@)

> Hint If you find it difficult to rotate the molecule so that the lowest priority group is facing away
from you, then leave is where it is, assign the stereochemical configuration, and reverse the an-
swer at the end (i.e. (R) goes to (S), (S) goes to (R))—you’ll end up with the correct isomer that way!
 2.6 SYNOPTIC questions [IPERS

@ Question 2.8
Are the following pairs of compounds enantiomers, diastereomers, meso, or not stereoisomers at all?

° A
° and
7 on
° 3O- OH and
a

OH

i OH
oe SH and 4S ALNg, (4) SY and Oh
: ‘OH

(e) OH (f) Me HN.

; q 4 and 0. .

a
te)

> Hint If you are confident that you can rotate these compounds to try and mirror each other, you should reach an answer. If you are unsure,
however, assigning the stereochemical configuration of the chiral centres will lead you to a correct answer.

2.6 Synoptic questions

@ Question 2.9

(a) You are provided with an unknown colourless liquid. Elemental analysis shows
that this sample has the molecular formula C,H,Br. It is your task to identify this
compound. Firstly, draw all possible constitutional isomers of this sample.
(b) You now place this sample into a polarimeter. You find that the optical rotation
equals +4.5°. Draw and name the two compounds that this sample could be.
(c) Treating these compounds with a strong base can lead to an E2 elimination of
the bromine atom. This reaction could also potentially eliminate three different
hydrogen atoms, leading to three different products. Draw and name these
products.
> Hint In (a) calculating the number of double bond equivalents will help! In (c) you may strug-
gle with this question if you have not covered elimination reactions before. Don’t worry if you
haven't yet!
GED 2 isomerism

© auestion 2.10
Pseudoephedrine is a commercially available decongestant. You are provided with a
sample of the dextrorotatory (+) enantiomer of pseudoephedrine, shown below. You
measure the optical activity of this sample and find that (+)-pseudoephedrine has a spe-
cific rotation of +52°.

(a) Assign the stereochemical configuration of the two stereogenic centres of

(+)-pseudoephedrine.
(b) You obtain a different, unknown, stereoisomer of pseudoephedrine, ‘X; and
measure its optical activity. You find that this stereoisomer has a specific rotation of
—52°. What is the relationship of X to (+)-pseudoephedrine?
(c) Draw the structure of X.

References
Burrows, A., Holman, J., Parsons, A., Pilling, G., and Price, G. (2013) Chemistry’, 2nd edn (Oxford University
Press, Oxford).
Clayden, J., Greeves, N., and Warren, S. (2012) Organic Chemistry, 2nd edn (Oxford University Press,
Oxford).
Nucleophilic substitution

3.1 Electrophiles and nucleophiles

What is an electrophile?
An electrophile is a neutral or positively charged species with an empty orbital (or an ener-
getically accessible anti-bonding orbital) which can accept electrons. Lewis acids, e.g. AIC], and
BCL, can also be considered electrophiles as they have an empty orbital that can accept an >) For more information on Lewis acids
electron pair. and bases, see section 3.2.

S Accurly arrow denotes the movement

What is a nucleophile? of electrons.

A nucleophile contains a pair of electrons that can be used to form a new chemical bond. S The electrons that are donated can
Nucleophiles act as electron donors. When we draw a reaction mechanism we always draw the either be in the form of a lone pair or a
electrons flowing from the nucleophile to the electrophile. formal negative charge.

Worked example 3.1A

In the reaction below, which molecule is the electrophile and which molecule is the
nucleophile?

4“ H.e-H
ob: + SSp-ch = — > }!
H 9, ci” By
a7 er

The water molecule contains two lone pairs of electrons which can be donated. Boron trichlo-
ride contains an empty p orbital perpendicular to the plane of the molecule, which can accept
electrons. If we look at the product, the oxygen has become positively charged and therefore
must have donated a pair of electrons. By contrast, the boron has become negatively charged
and therefore must have accepted a pair of electrons. This means that in this case water is a
nucleophile, as it has donated a pair of electrons, and the boron species is an electrophile, as it
has accepted a pair of electrons.
(REA s nucteopnitic susstiTuTION

Arrow denotes
electron movement
1
Ho?
oO: Z Empty p
H°7 _-° orbital 6
BS? a New bond formed
a oltre by donation
Nucleophile
B -
cl>B-cl ci? cl of lone pair on O

6
cl cl

Electrophile

Worked example 3.1B

In the reaction below, which molecule is the electrophile and which molecule is the
nucleophile?

S A tosylate/tosyl group is a para- If we look at the reaction carefully we can see that the tosylate and bromide have swapped
toluenesulfonyl group. It is an extremely positions in the products when compared to the reactants. This therefore implies that the
good leaving group so is commonly used bromine must have used its electrons to displace the tosyl group, forming a new bond between
in nucleophilic substitution reactions.
the carbon and bromine.
We also know that sodium bromide, NaBr, exists as an ionic solid and can therefore be present
~~?

aon
as Na‘ and Br~ ions. Bromide (Br-) has a negative charge which can be donated; it is therefore
likely to act as a nucleophile. Consequently, iso-butyl tosylate will be the electrophile.
More specifically, the C—O o* orbital is the electrophile, as this is the lowest energy unoc-
cupied molecular orbital (LUMO). The tosylate leaves as a negatively charged salt; formally the
Dd) For more information on leaving positively-charged sodium will be associated with it, generating the products shown.
groups, see section 3.4 and Clayden
etal. (2012). C—O o* orbital

S A nucleophile must attack an

electrophile. Two electrophiles or two Y
nucleophiles cannot react together! ® a
Na + On 5 —————> Br + Nao...
4S 4S.
HOMO and LUMO are discussed oo oo
further in Chapter 1.
° Electrophile
Nucleophile
 3.2 LEWIS ACIDS AND BASES [PTR

(?) Question 3.1

Suggest which compound is likely to be an electrophile, and which a nucleophile, in the following series.

BF; AICI, HS MeOH NaOH H,0

> Hint Consider the HOMO and LUMO in each case.

@ Question 3.2
Suggest which species is likely to be the electrophile, and which the nucleophile, in the
reaction below. Suggest structures for the products.

H,0 a
O @ ———— x

OU
(?) Question 3.3
For each step depicted, which species is the electrophile and which is the nucleophile?

ety
Br +Br
9° )
} *r

> Hint The curly arrows provide a valuable clue.

3.2 Lewis acids and bases

What is an acid and a base?
There are two different types of acids and bases: Bronsted acids/bases and Lewis acids/bases.
Bronsted acids and bases are those that you have, most likely, encountered previously.
A Bronsted acid is defined as a molecule that can donate a proton; a Bronsted base is a molecule
that can accept a proton. Acids and bases always occur in pairs therefore if an acid is present,
there will also be a conjugate base (Figure 3.1).

(>) {>} @
HCl + HO cl + H,0

acid base conjugate conjugate

base acid

Figure 3.1 An example of a Bronsted acid and base reaction.

(RED 3 nucteopniic susstitution

< eo @
BF, + NH; === 5.B-—NH,
acid base adduct
Figure 3.2 An example of a Lewis acid and base reaction.

By contrast, a Lewis acid is an electron pair acceptor and a Lewis base is an electron pair
donor. A Lewis acid can also be thought of as an electrophile and a Lewis base as a nucleophile
(Figure 3.2).
As mentioned earlier, acids and bases always occur in pairs. An example of this is shown in
the reaction in Figure 3.1. HCl has reacted with HO“ to produce Cl and H,0*. HCl is the acid; it
loses a proton to H,0 to form CI, the conjugate base of HCl. Conversely, H,O is the base: it gains
a proton from HCl to form H,0*, its conjugate acid.

Worked example 3.2A

For the following examples, determine whether the following compounds are Bronsted acids/
bases or Lewis acids/bases.

HCI NEt, Et,0 BCI,

HClis a Bronsted acid because it can act as a proton donor. NEt, is a Lewis base as it has a lone
pair on the nitrogen which can be donated. Et,O, diethyl ether, is a Lewis base because it has
Jone pairs on oxygen that it can donate. Finally, BCI, is a Lewis acid because it can accept an
electron pair into its empty p orbital.

Worked example 3.2B

Identify the acid and conjugate base pairs for each of the following reactions.

0 é °
2 + OH =—_——_ 2 6 + H,0 ro
OH 0

N I
HH’ \H + HO = ® + S [2]

In reaction 1, the acid is acetic acid as it loses a proton to become acetate, the conjugate base.
The base is hydroxide as it gains the proton to become water, the conjugate acid.

Le} Le}
pe # Onn = 2 6 + H,0
OH [e}

acid base conjugate conjugate

base acid
 33 s1anDs2 (EE

In reaction 2, ammonia is the base: it accepts a proton to form ammonium, the conjugate
acid. Water is the acid: it loses a proton to form hydroxide, the conjugate base.

H
oN, ee e! °
H7-TH + H,0 => SNA
HON H i HO
H
H
base acid conjugate conjugate
acid base

(?) Question 3.4

Are the following compounds Lewis or Bronsted acids or bases?

AICI, HS FeCl, HPO,

@ Question 3.5
Identify the acid/base pairs for each of the following reactions.

NNO, nm Son ————— NJNO2 a H,O 1]

°

iS)
! LF
Sic x ey > [2]
FO CF

> Hint Follow the protons in each scheme.

3.3 S,1 and S,2

What are S,1 and S,2?
Sy1 and S,2 are two classes of reaction that describe the nucleophilic substitution, or replace- >) Nucleophilic substitution is different
ment, of one functional group at a saturated carbon centre by another. They are defined ac- _to aromatic substitution. Aromatic
cording to the molecularity (the number of species required) of the rate-determining step _SUbStitution is discussed in Chapter 6.
(RDS), or the slow step. A general scheme is shown in Figure 3.3.

The S,1 reaction

Rate = k, [substrate]
An Sy] reaction is independent of the concentration of the incoming nucleophile and is related
solely to the ability of the leaving group to leave. In an S,1 reaction a discrete positive charge
is formed on a carbon. The key point to remember is that the intermediate carbocation in an

nue + Ye —>+> \* + x
x Nu
Figure 3.3 A general substitution reaction.
(RED s nucteopnitic susstitution

<) RDS R _ R Nu Nu
ve —_——_> aA => R' R" >
R R'~@~R" R
R'
sp* hybridized sp? hybridized Empty p Racemic product
carbon centre carbon centre orbital perpendicular due to planar
to the C-R bonds intermediate

Planar intermediate
Figure 3.4 The S,1 reaction.

S For a reminder about hybridization, S,1 reaction needs to be stable. S,1 reactions can only occur at tertiary or secondary centres
see Chapter 1, section 1.4. because the resultant carbocation needs to be stabilized, either by hyperconjugation (through
space) or inductively (through bonds) (Figure 3.4).
S For more information, see Chapter 19 Hyperconjugation involves the overlap of o bond (e.g. a C—H or a C—C) with the empty,
of Burrows et al. (2013). hybridized p orbital present on the carbocation. The inductive effect is where electrons are at-
tracted to the carbocation through the C—C o bond directly attached to the carbocationic car-
bon centre, Figure 3.5.

+ Inductive effect Hyperconjugation

Electrons partially donated from Delocalization of electrons

the C—C o bond by side-on overlap of orbitals

Nemo
7c C., 'H
R 0 Oo
Empty H
p orbital

Figure 3.5 The inductive effect and hyperconjugation.

Worked example 3.3A

Suggest a mechanism for the following reaction.

OH HBr Br

S Under acidic conditions HO-is never ‘The first thing to notice is that the reaction is under acidic conditions so the oxygen will be pro-
a leaving group! tonated to give an oxonium species (a positively charged oxygen), that can then leave, generat-
ing a tertiary carbocation. This cation is attacked by the bromide anion, generating a new C—Br
bond.
 3.3 s,1ANDS,2 (REE

" Br°! OH now activated as a

leaving group

Oxonium ion . 0 .
Tertiary carbocation

Worked example 3.3B

Draw a mechanism for the following reaction. Suggest what will happen to the stereochemical
configuration of the carbon marked with an asterisk.

NaOH he
—_————> Et

In this example, iodide is the leaving group. This iodine resides on a tertiary carbon therefore 5) For more information about
the mechanism must be S,1, not S,2; when the iodide leaves a stable carbocation is generated. enantiomers and stereochemistry,
The cation formed has sp? hybridization and therefore has an empty p orbital. This p orbital can see Chapter 2.

be attacked by the nucleophile from either above (pathway a), or below (pathway b) the plane,
leading to two different products. These products are enantiomers.

Benzylic carbocation
(sp? hybridization)
uv
>

’
'
'
1 Et
1
1
| rate acceleration
1 due to cation OH
'
' stabilization by
'. conjugation
QZ 3 nucteoPuitic suBstituTION

@ Question 3.6
Provide a mechanism for the following transformation, assuming it undergoes an S,1-type
reaction pathway. Suggest the stereochemical configuration at the carbon labelled with an
asterisk.

tBu KI, acetone, tBu

reflux
NCI ——_————__> ATI

& Hint Draw the mechanism first and then consider the stereochemical implications.

(?) Question 3.7

Provide a mechanism and product for the following transformation. Suggest the stereo-
chemical configuration at the carbon labelled with an asterisk.

ie)

A loan EtSH
‘* —_> x

> Hint Draw the mechanism first and then consider the stereochemical implications.

The S,2 reaction

Rate = k, [substrate][nucleophile]
An S,2 reaction is a bimolecular reaction that is dependent on both the concentration of the in-
coming nucleophile and the ability of the leaving group to leave. If the concentration of the incom-
ing nucleophile is increased, the reaction rate will increase; if the concentration of the substrate
in increased, the reaction rate will increase. The key points to remember are that there is no inter-
S For a full orbital explanation of this mediate in an S,2 reaction and the reaction is concerted, S,2 reactions can only occur at primary
reaction, see Clayden et al. (2012). or secondary centres and S,2 reactions are stereospecific due to orbital constraints (Figure 3.6).

R R + R
Nue pe'TS eq ik ob’
ue hy
Nu~ SR" + x
H R' H H

sp? hybridized transition sp? hybridized

carbon centre state carbon centre;
(pseudo penta- inversion of
valent carbon) configuration
Figure 3.6 The S,2 reaction.

Worked example 3.3C

Provide a mechanism for the following transformation.

NaCl
nn _ OTs —> nl
 3.3 S,1ANDS,2 (ESN

The carbon that connects to the leaving group is primary, therefore the mechanism must be S,2. If Sr ‘or a refresher on chirality, see
it were S,1, an unstable primary carbocation would be generated. The mechanism involves attack Chapter 2, section 2.5.
of the nucleophile onto the C to which the leaving group is bonded. The nucleophile (Cl) makes
the new C—Cl bond at the same time as the C—O bond breaks; the process is concerted. More spe-
cifically, the incoming nucleophile attacks the C—O o* orbital, which leads to cleavage of the corre- Sr or a refresher on bonding and
sponding C—O o bond. It is due to the concerted nature of this reaction that in the transition state anti-bonding orbitals, see Chapter 1,
both the incoming nucleophile and leaving group are drawn carrying a partial negative charge. section 1.3.

This symbol indicates siseemicewien

= oseis 7
that this species is a ' |
transition state 1 C—O o* orbital
1 1
° ~ 1 f
r
fs ©Cl- 1)OTs an a

a 2. :‘
Wn Lots —_ —_ 6 7 On,
5 1 s

ci® cl °

Worked example 3.3D

Provide a mechanism for the following transformation, assuming the reaction undergoes an
Sy2-type reaction pathway. Suggest the stereochemical configuration of the product.

Et NaCN Et
ap ab
Me* Br Me CN
H H

We are going to go through this example in two parts; in the first part we will look at the mecha-
nism and in the second part we will look at the stereochemical implications of the mechanism.
It is often useful to break up challenging questions into smaller steps in order to avoid con-
fusion. In cases like this, trying to imagine the 3D positioning of groups whilst working out a
mechanism could be tough.
The first thing to notice here is that the carbon centre at which the substitution occurs is
secondary; this means that it can undergo either S,1 or S,2 substitution pathways. However,
in the question we have been told that it reacts via an $,2 mechanism therefore that is all we
consider. In an S,2 mechanism, the leaving group is displaced by the incoming nucleophile in a
synchronous process. The mechanism is the same as in the previous example; the nucleophile
attacks the C—Br o* orbital, generating the transition state shown, where the incoming nucleo-
phile and leaving group both have a partial negative charge. Finally, the leaving group is fully
displaced and the product is produced.

t
Et Et Et
() (-)
NC _ neater _ N oo he
ae Me H
QED 3 Nucteopuitic suBsTiTuTION

Now that we have ascertained the reaction pathway, we can start to consider the stereochem-
ical configuration of the product. In an S,2 reaction, inversion of the original stereocentre is
observed. This is due to the concerted nature of the reaction and that only one reaction pathway
can be followed due to orbital constraints. The incoming nucleophile attacks the C—Br o* orbital
generating the transition state shown. In this case, the methyl group in the starting material was
>, Be careful—even if the starting
at the back, therefore in the transition state the methyl group remains at the back as the nucleo-
material has an (R)-configuration, the
phile has attacked in a trajectory between the methyl and hydrogen. Once the bromide has left,
product will not necessarily be of an
(S)-configuration. You need to invoke the the resulting product has been inverted, rather like an umbrella being blown inside out. The
Cahn-Ingold-Prelog rules—see Chapter 2, final task is to determine the absolute configuration of the starting material and product. In this
section 2.3 for more information. case the starting material has (R) configuration and the product (S).

Et (—)
Et rea
= Et
NC > ™ oe z al —- Ee
Me’ Br : NC Me
H = Me H H
(R) (S)

[?) Question 3.8

Provide a mechanism for the following transformation.

HBr
re ——_——_—_—_—_— ro

@ Question 3.9
Provide a mechanism for the following transformation, assuming the reaction follows an
S,2 pathway. Suggest the stereochemical configuration of the carbon labelled with an
asterisk.

OTs OAc
—_——— 5

> Hint Draw the mechanism first and then consider the stereochemical implications.

3.4 The impact of pK, on leaving group ability

What is pK,?
pK, is the strength of an acid and is a measure of to what extent an acid is dissociated (Figure 3.7).
In theory, all compounds that contain a C—H o bond can act as an acid by donating that proton
to a suitable base. There are many factors that can affect the acidity of an organic compound;
the strength of the HA bond, the electronegativity of A, the stability of A’ compared to HA, and
the solvent that the compound is in. When stating a pK, value, the solvent in which the value
was calculated is often given. Usually the solvent is water or DMSO (dimethylsulfoxide). pK,
values generally lie between -10 and 50, although there are some compounds with pK, values
that lie outside this range. If a compound has a low pK, value it is a strong acid and the proton
can be removed easily. If the pK, value is high, however, the proton cannot be removed easily
and its conjugate base is therefore strong.
 3.4 THE IMPACT OF pK, ON LEAVING GROUP ABILITY

HA + B
Figure 3.7 An acid/base equilibrium.

We can determine if a proton can be removed easily by inspecting the C—H bond in question:

e Aweaker H—A bond means the proton can be removed more easily so the pK, is lower.
This is not usually a limiting factor in pK, values.
e Placing the negative charge of the anion on, or near, an electronegative atom e.g. oxygen is
also stabilizing. In the case of ethanol, an alcohol, removal of the alcohol proton leads to an
alkoxide which is stabilized by the electronegative oxygen. However, in the case of ethane,
removal of a proton leads to a carbon-based anion (a carbanion) which is extremely unstable.
e The more stable the conjugate base, the more acidic the proton. Conjugate bases can be
stabilized by a variety of means. If an anion can be distributed over a greater number of
atoms it is more stable because each atom ‘sees’ less of the negative charge, leading to a
lower pK, value. This is known as resonance.
e Finally, hybridization is another important factor. The more s character an orbital has, the
greater the degree of stability offered to the anion because of the spherical shape of the s orbital. S For more information about resonance,
see Chapter 1, section 1.8.
It should be noted that compounds with a low pK, are excellent acids but very poor bases.
The relationship between anion stability and pK, in some selected compounds is shown in S For a further explanation of this
Figure 3.8. reaction, see Clayden et al. (2012).

° ° @ Acetic acid
Ay qq = AA,9 = oH pK, 4.8

H °} lo) Ethanol S When discussing pK, values of

“Sot == Ot pK, 17 amines you need to take care because
amines are amphoteric (can act as
lo) Ethane acids or bases). The pK,,, value of an
“nu . wo + OH pK, ca. 48 amine refers to the parent acid (the
protonated species) e.g. with ammonia,
Figure 3.8 A comparison of pK, and anion stability for some selected compounds. NH,, pK,,, refers to NH,*. However, in
ammonia the N—H bond can be broken
to generate NH... To avoid confusion, if
How is pK, related to leaving group ability? the structure is not drawn we will use the
term pK,,,, which simply means the pK,
Generally speaking, if the pK, of the conjugate acid of a leaving group is low, then it is a better of the conjugate acid. For example with
leaving group. A list of approximate pK, values is given in Table 3.1. The asterisk denotes the ammonia, the pK,,, is 9 (NH,*) and the pK,
acidic proton. is 33 (NH,).

Table 3.1 Useful approximate pK, values.

pK, pK, pK, pK,

OH* fe} ‘i
ae 5 or a rr 19 WN 33

Oo H* H*
‘ 25 42
NOH 17 A
A ‘OH* 5

H fe) fe)
l@® 7
a 9 ar 18 Yon 25 NH 48
QE) 3 NucteoPuitic suBstiTuTION

Worked example 3.4A

Compare the acidity of the following protons marked with an asterisk. Suggest reasons for their
differing acidities.

OH*

\ 0H"

Ethanol Phenol

In this example both compounds contain an alcohol functional group. In the first example,
ethanol, removal of the proton generates a negative charge on oxygen. This leads to some
stabilization due to the electronegativity of oxygen therefore the proton is reasonably acidic;
however, the negative charge is completely localized on the oxygen atom.

® °
NJ OH* —_> H + NTO

Ethanol
pK, 17

S For a refresher on resonance In the second example, phenol, removal of the proton generates a negative charge on oxygen
stabilization, see Chapter 1, section 1.8. which can be distributed into the benzene ring due to resonance stabilization. This is an ex-
tremely effective way of stabilizing a negative charge and is reflected in the pK, values; the pK,
of ethanol is approximately 17 and that of a phenol is 12, ie. phenol is more acidic and will lose
its proton more readily as the conjugate base is more stable. Additionally, more stabilization is
offered because the carbon atoms in phenol are sp’, therefore they have increased s character
so are better able to stabilize a negative charge.

OH 0°
@
_~* H +

Phenol
pK, 12

Overall the series is as follows:

OH

< \JOH

pK, value 12 17

ee eee
Increasing acidity
(increasing anion stability)

Increasing basicity
(decreasing anion stability)
 3.4 THE IMPACT OF pK, ON LEAVING GROUP ABILITY [EZ

Worked example 3.4B

Suggest which of the following molecules has the highest pK,, i.e. is the least acidic.

In this case we have a proton in three different hybridization states: sp’, sp?, and sp. When we
remove the proton indicated we will generate the corresponding sp*, sp’, or sp anion. These
have different relative stabilities due to the amount of s character present in the orbital: as s
character increases, the anion is held closer to the nucleus so the electrons are more tightly
held and are therefore more stabilized, resulting in a lower energy species. This is reflected in S In chemistry, generally speaking, the
the pK,,. As s character increases, i.e. as we travel from sp* to sp? to sp, anion stability increases —_ [ower in energy something is, the more
and pK, decreases. stable it is.

A as aN

pK, value 25 43 51

Increasing acidity
(increasing anion stability)

Increasing basicity
(decreasing anion stability)

Worked example 3.4C

Taking into account the stability of the anion, suggest which of these leaving groups will be the
best.

)
fe)
AP

we or NO,
QED 3 Nucteopuitic suBsTiTuTION

The pK, of the alkoxide is approximately 17, the sulfonate -3, and the p-nitro phenol 8. The
compound with the lowest pK, is the best leaving group and is more able to stabilize a nega-
tive charge, therefore the sulfonate is the best leaving group and the alcohol the worst. This is
utilized within organic chemistry. as a sulfonate is often used as a leaving group in substitution
and elimination reactions.
If we did not know the pK, values for each, it is possible to compare the compounds in order
to predict which would be the better leaving group. In all examples the anion is on oxygen so it is
stabilized by the electronegativity of oxygen, therefore we need to inspect each molecule more
closely to see if there are likely to be any differences in stability, and therefore pK,,.
If we compare the sulfonate and the phenoxide with the ethoxide, respectively, the anion
can undergo resonance stabilization in the phenoxide and sulfonate whereas it cannot in the
ethoxide. This means that these anions are both more stable than the ethoxide. Comparing
the phenoxide and sulfonate, the anion in the sulfonate is strongly stabilized by the electron-
withdrawing SO, group. In the phenoxide the anion can resonate around the benzene ring into
the nitro group, but this is not as stabilizing because the nitro group is further away so the elec-
tron-withdrawing effect is weaker.

fe) [S) [e)

=>,

ell
(o) 07S) 9 [e) oye)

@ Question 3.10
Whyis there such a difference in pK,,, values of the following: butylamine (pK,,, 10.7); dibu-
tylamine (pK,,, 11.3); and tributylamine (pK,,, 9.9)?

n-Bu
n-Buy # I
aa n-Bu7 ~n-Bu n-Bu7’n-Bu
Butylamine Dibutylamine Tributylamine

s) Be careful—the values given are pK, > Hint Consider hydrogen-bonding with the solvent and the inductive effect of the alkyl chains.
not pK,!

© auestion 3.11
Which of the following compounds will have the lower pK,?

fe}
 3.5 SYNOPTIC QUESTIONS [TUN

3.5 Synoptic questions

© auestion 3.12
What is the most likely mechanistic pathway for the following reaction? Suggest the stereo-
chemical configuration of the product.

NaN,

AT
@ Question 3.13
What is the product of the following reaction? Draw the curved arrow mechanism and de-
termine the stereochemical configuration of the product.

Br
NaOH
OH

© question 3.14
Consider the following reaction. What would happen to the rate if:
(a) the substrate concentration was doubled?
(b) the nucleophile concentration was halved?

Nal I
cl
acetone
OY eo

[?) Question 3.15

What products could be made under the reaction conditions shown?

Np, NaCN
—_>

References
Burrows, A., Holman, J., Parsons, A., Pilling, G., and Price, G. (2013) Chemistry’, 2nd edn (Oxford University
Press, Oxford).
Clayden, J., Greeves, N., and Warren, S. (2012) Organic Chemistry, 2nd edn (Oxford University Press,
Oxford).
 Elimination reactions

4.1 Synthesis of alkene via elimination

(E2, E1, and E1cB)
In elimination reactions, a base (nucleophile) removes a hydrogen nucleus (proton), resulting
in the formation of an alkene with loss of a leaving group. This process can occur by three mech-
anisms, E2, El, and ElcB. The mechanism of elimination is dependent on factors including the
solvent, nature of nucleophile, and the nature of the eliminating species. Elimination reactions
often compete with substitution reactons. In this chapter we will look at the major products
of elimination reactions, but be aware that in practice some of these experiments would yield
several impurities, including substitution products.
> Depending on the nature of
the nucleophile, either elimination
or substitution can occur. Bulky E2 eliminations
nucleophiles, strong bases, and high
temperatures favour elimination over E2 elimination is so-named because it is a bimolecular elimination, involving a concerted
substitution, as does increasing the mechanism where a base removes a proton, with concomitant displacement of a leaving group
concentration of base. and the formation of a m-bond. A mechanism is shown in Figure 4.1. Both the base and the
reagent are included in the rate equation, making the process second-order, like S,2 reactions.
>) E2 eliminations prefer to yield a more
The reaction proceeds via an antiperiplanar conformation, as the mechanism requires the
substituted alkene (Zaitsev product), as
they are more stable, but steric hindrance movement of electrons from a C—H o-bond, to the C—LG o*-anti-bonding orbital, resulting
when using bulky bases can force the in the breakage of the C—LG bond, and the formation of a C—C m-bond. The E2 mechanism
process to yield a less substituted alkene is favoured if a strong base (e.g. an alkoxide or lithium diisopropylamide (LDA)) is used with
(Hofmann product). reagents where the leaving group sits in a primary or secondary position.

| Antiperiplanar \ B a"
H.R? RI R?
i conformation |

|' H 4°
w e “Y
R* ——_—_
_
S The diagram showing the 3 4 i

Re Rn Re LG R2 RS
antiperiplanar conformation in Figure 4.1 f n ?
is called a Newman projection. This type ! LG i

of projection demonstrates the relative

position of substituents on two adjacent Figure 4.1 A general mechanism for an E2 elimination. The reagent takes an antiperiplanar
atoms, and is drawn as if you are looking conformation in order to allow the movement of electrons into the o* anti-bonding orbital, yielding a
down the length of the bond. stereospecific product. A strong base is typically used.

E1 eliminations
£6) E1 eliminations are regioselective El eliminations are unimolecular, with only the concentration of the molecule undergoing
for the more substituted alkene (Zaitsev elimination contributing to the rate equation. E1 eliminations, like S,1 reactions, involve two
product). steps: the leaving group leaves (rate determining), then the proton is removed, forming an
alkene (Figure 4.2). Unlike E2 reactions this process does not require an antiperiplanar con-
formation, however steric effects can lead to these reactions being stereoselective; usually E
 4.1 SYNTHESIS OF ALKENE VIA ELIMINATION (E2, E1, AND E1cB) (EES

3 1 1 3
H 7 R4 slow " RS R2 Re 3 e R R? R°
3 x > Pe a or Bi Hk ——qx© =~ or an
R! R2 LG R' R? Rt H <1 Rt R 2 R 4 R' R*
B:JA
carbocation intermediate

Figure 4.2 The mechanism of an E1 elimination. The carbocation intermediate is planar and sp?
hybridized, allowing elimination from either side of the vacant p-orbital, which potentially yields both
the E and Z products. During the elimination step, the C—H o-bond must be aligned with the vacant
p-orbital of the cation.

alkenes are favoured due to this effect. E1 reactions typically occur when the structure of a rea-
gent means that the carbocation formed sits on a tertiary or secondary position, and where the
carbocation intermediate may be stabilized by surrounding substituents. El reactions require
a good leaving group and a weaker base (e.g. water or an alcohol), or no base at all!

E1cB eliminations
The ElcB mechanism is a two-step process that proceeds with the formation of a carbanion,
and subsequent displacement of a leaving group (Figure 4.3). The reactions are first order with
respect to the conjugate base. ElcB occurs when a a molecule with a poor leaving group is
treated with a strong base, and is only possible when the carbanion formed is stabilized by an
electron-withdrawing group (commonly a carbonyl). As in El reactions, the ElcB elimination is
regioselective based on steric effects, often yielding a major E product.

i contributor
major

foo
Y

Sen
Bim

“fee — [Bo —
H
—_—>
co GE a OH ©0 Son fe)

resonance stabilization

Figure 4.3 The mechanism for an E1cB elimination. The carbanion intermediate is stabilized by an
electron withdrawing group—in this case, a carbonyl.

Worked example 4.1A

The reaction below yields a single product through an elimination reaction. What is the SD The alkoxide and corresponding
product, and by which mechanism is it formed? alcohol conditions used for this reaction
are very common conditions for
Br NaOEt elimination reactions. Please note that if
2 the alkoxide and leaving group are not
EtOH sterically hindered, then S,2 reactions
may occur.

If we look at the reaction conditions, then we can note two things. First, a pretty strong alkoxide
base is used, which would favour the E2 mechanism, and second the leaving group (Br) is in
a secondary position. This means that were the reaction to proceed via an El mechanism, the
carbocation would be secondary, which is not very stable in the absence of electron donating
groups. These point to the likely mechanism being E2.
OO 4 evimination REACTIONS

Now, when trying to decide the likely product, we need to identify which protons could be
eliminated. These must be adjacent to the leaving group, giving us three possible protons to
choose from.

Br

XK,
H H 3
1 2

Eliminating proton 1 would lead to a trisubstituted alkene, whilst eliminating 2 or 3 would give
a disubstituted alkene. Zaitsev’s rule states that alkenes of higher substitution are more stable,
so eliminating proton 1 is preferable. Therefore the product would be:

anne
NaO
A major

Worked example 4.1B

Heating 3-iodo-3-phenylpropanoic acid in water yields two products, (£)-3-phenylprop-

2-enoic acid (cinnamic acid) and (Z)-3-phenylprop-2-enoic acid.

mE te OD
] fe) fe)
H,0

[e) OH
3-iodo-3-phenylpropanoic acid cinnamic acid (Z)-3-phenylprop-2-enoic acid

(a) Provide a mechanism for this reaction, explaining why two stereoisomers are formed.
(b) This reaction is stereoselective. Which do you expect to be the major product, and why?

(a) In 3-iodo-3-phenylpropanoic acid, iodine is a good leaving group and is located in a

position that yields a carbocation which can be stabilized by resonance from the phenyl
group. The only reagent is water, which is a polar protic solvent. These conditions favour
the El elimination mechanism. This reaction mechanism will proceed with formation of
S Note that even if there was only
onewabstracisibile:profontadiacent ttie a carbocation by the iodine atom leaving as iodide (I-). This carbocation is free to rotate
carbocation we would still synthesize around the C—C bond, so the electrons in either of the two adjacent C—H bonds to be
two products, as the C—H can align with eliminated can align with either lobe of the vacant p-orbital of the carbocation. This yields
either lobe of the carbocation’s p-orbital. two potential products when the proton is abstracted during the elimination step.

I ° ° i}
® path 1 NS
OH ——~> on > OH

Leh lie S
fe) OH
 4.1 SYNTHESIS OF ALKENE VIA ELIMINATION (E2, E1, AND E1cB) (ESN

(b) El reactions are stereoselective due to steric interaction between adjacent substituents on
the carbocation intermediate. If we draw Newman projections of the two intermediates we
can make a judgement about which is less sterically favourable.

H H

HOOC cen H tiien

H COOH
path 1 path 2

The major bulky groups in these projections are the phenyl and carboxylic acid groups.
This means that there is more steric hindrance in path 2, which aligns the groups with each
other. Thus, path 1 is more favourable, making the E stereoisomer, cinnamic acid, the major
product.

(?) Question 4.1

What is the likely outcome of the following reactions?

cl
(a) tBuONa

‘BuOH

(b) oa EtOH
Br

H,SO,
AS
(c)

a OTs NaO!Pr
—_>
(a) CY 'PrOH

OH
(e) Et,N
o.® ——>
(>) DMSO

> Hint When approaching these questions, try to look at the choice of base and the nature of the
leaving group. A strong base will often give E2 reactions, whilst a good leaving group that results
in the formation of a relatively stable carbocation will favour E1.
OD 4 evimination REACTIONS

(?) Question 4.2

How many different alkenes could be formed from the E2 elimination of the compound
below?

{e)

@ Question 4.3
In the laboratory, you stir a solution of (2-bromo-2-methylpropyl)cyclohexane in ethanol
at room temperature for 24 h. This yields a minor fraction (25%) of alkene products, but also
a major product (75%) which is not an alkene.
Br
sbeh Major product Alkenes
RT - 75% v 25%
(2-bromo-2-
methylpropyl)cyclohexane

(a) Draw the structure of the alkenes produced from this reaction.
(b) Predict the structure of the major product.
(c) Without changing or adding any reagents, suggest how you may increase the yield
of alkenes.
 Reactions of unsaturated
compounds
5.1 Electrophilic addition
In general, electrophilic addition reactions occur between an electrophile and an alkene,
though other groups possessing m-bonds may also react in this way. Electrophilic addition re-
sults in the t-bond breaking with the formation of two new o-bonds, with the electrophile ‘add-
ing’ to the alkene to form a new, larger, molecule. An example electrophilic addition is shown
in Figure 5.1, in which hydrogen bromide ‘adds’ to an alkene n-bond. Common reagents which
undergo electrophilic addition to alkenes are hydrogen halides, alcohols, and water. Acid cata-
lysts are often used which act as an electrophile, reacting with the alkene in the first instance to
form a carbocation, which is then attacked by a nucleophile.

H Br
/—\. 4 HBr > » {
R R
R R

Mechanism } :
' Lf Br }
~ r H Br. H 4
' a — 7 —_> \X '
' R R R R R R '
t '

Figure 5.1 An alkene undergoes electrophilic addition when treated with hydrogen bromide.

Regioselectivity in electrophilic addition

As the carbocation formed during electrophilic addition could reside at either carbon of the
m-bond, electrophilic additions are regioselective, giving a major product which has the more
stable carbocation in its transition state. For instance, electrophilic addition to propene gives a

—>) Markovnikov’s rule is used to predict the regioselectivity of electrophilic additions. In essence
it states that when the general electrophile ‘HX’ undergoes addition to an alkene, then the proton
is added to the carbon atom with the most hydrogen atoms. While this is often the case, it is not
always true. Products which adhere to this rule are often called the ‘Markovnikov’ product, whilst
those which don’t are called ‘anti-Markovnikov’. Anti-Markovnikov products are often seen in
radical-mediated reactions.

eo HBr HBr Br
<> —_——>
HOOH aS
Anti-Markovnikov Markovnikov
QUE C5 REAcTIONs OF UNSATURATED COMPOUNDS

‘
'
'
1 '
1 '
'
'

A eK
'
1
1
'
: more '
major '
: stable '
product '
'
1
1
1
ox 1
'
'
1 o™ > ~-* '
1 '
'
less minor '
1
stable product 1

Figure 5.2 The stability of the carbocation intermediate dictates the regioselectivity of electrophilic
addition.

major product which goes through the secondary carbocation transition state, which is more
stable than the primary (Figure 5.2).

Halogen addition reactions

*) The term ‘vicinal’ means that the Electrophilic addition reactions occur between alkenes and diatomic halogen molecules
functional groups are bonded to carbon (Br,, CL,, or I,), to form a vicinal dihalide. In this reaction, the electron density of the alkene
atoms adjacent to each other. ‘Geminal’ m-bond induces a dipole on the halogen molecule, making it electrophilic. The reaction mecha-
means that they are bonded to the same
nism is shown in Figure 5.3. Movement of electrons from the z-bond into the o* anti-bonding
carbon atom.
orbital results in the o-bond breaking, and the formation of a new o-bond between the halogen
and both carbon atoms, and a negatively-charged halide ion. The positively charged intermedi-
ate is known as a halonium ion, and is attacked in the manner ofa nucleophilic addition to yield
a product with two new vicinal halide groups.

S A non-nucleophilic solvent, like “Bromonium"

dichloromethane, must be used for this

FS
reaction. If this reaction is conducted @
Br Br
in the presence of water, it can attack
the halonium intermediate, giving a
At R R
‘halohydrin’, which has a halogen and
hydroxyl group vicinal to each other. Bo
addition from either
side possible
Figure 5.3 Treatment of an alkene with bromine results in a dibrominated product via electrophilic
addition.

Worked example 5.1A

What is the major product for the following reaction?

+ HBr
 5.1 ELECTROPHILIC ADDITION [RR

In this chapter we learn that hydrogen halides undergo electrophilic addition to alkenes, of
which this question is an example. The first step of this reaction involves the attack of the nucle-
ophilic alkene to the electrophilic proton of the hydrogen bromide. This could result in carboca-
tions I or II. lis more stable as it has the greater number of alkyl substituents, so the reaction will
proceed primarily via this intermediate. The bromide ion formed from the initial step can then

5
add to the carbocation formed to give 1-bromo-1-methylcyclopentane as the major product.

Dy H F
{
— more a
major product

i}
less stable

Worked example 5.1B

Two equivalents of styrene undergo electrophilic addition with ethylene glycol (ethan-1,2-diol)
in the presence of sulfuric acid. What is the major product?

Ss
H,SO,

We know that this is an electrophilic addition reaction, so first of all we will identify the elec-
trophile and nucleophile. The nucleophile must be electron-rich, and reactive, so styrene is a
good candidate. Styrene is electron-rich at the aromatic phenyl ring and vinyl double bond.
However, the aromaticity of the ring means that it will not undergo electrophilic addition at
that point, which would destroy the aromatic n-system. Styrene is therefore nucleophilic at the
vinyl double bond. The electrophile, in the first instance, will be a proton from the sulfuric acid
catalyst, since ethylene glycol is a weaker acid. If we draw out the first addition step, we have
*) Aromatic molecules will undergo
two possible carbocation intermediates, one at the primary position, and one at the secondary electrophilic aromatic substitution, rather
position. As discussed previously, the secondary carbocation is more stable due to +/ effects than addition, but this requires additional
from the alkyl substituents, but also, in this case, the phenyl ring is able to add extra stabilization _ reagents. See Chapter 6 for more
through resonance. information.

9 pe eeeeee cence ec ee eee ec ee seer eens sees ,

no=k-o=i X © : resonance stabilization :
Il ' ‘
=
: o~<~> <x ~6

;
i ee ®
ee
:
intermediate
5 REACTIONS OF UNSATURATED COMPOUNDS

At this point, the nucleophilic ethylene glycol is able to add to the carbocation intermediate,
followed by the loss ofa proton to yield an ether group between the two reagents and restore the
acid catalyst. This would lead to a racemic mixture of products, since the ethylene glycol is able
to add to either lobe of the carbocation’s p-orbital.

“™, BN °
® Ho on ® OH ie ~~ on
— —

We must resist the temptation to finish here, because we've been told that two equivalents
of styrene have been used, so there is still some reagent to react with the alcohol we’ve just
formed. This will proceed as an electrophilic addition, just like last time. The major product
drawn here has no stereochemistry defined, but would be a racemic mixture of the four possible
diastereoisomers/enantiomers.

L in~w -Ht
— al §~0 —_ ow?
H

major
product

(?) Question 5.1

Predict the major product for the following reactions, assuming no side-reactions, and
comment on its stereochemistry. Include a mechanism for each reaction.

(a) H,0, H,SO,

ZOGo_EE

HBr
(b) Sy ——_—_—4©+

[e)

(c) [ 0. MeOH, HCI

aaa _.. =

Br2, H2O
@ Ag
> Hint Remember to think about resonance and inductive effects on the carbocation inter-
mediate that may be stabilizing or destabilizing.
> Hint Ensure that you are careful with stereochemistry—review your answers to ensure
that you have included all possible stereoisomers in your answers. Each carbocation
p-orbital can be attacked by a nucleophile from either lobe.
5.1 ELECTROPHILIC ADDITION
 Aromatic chemistry

6.1 Electrophilic aromatic substitution

What is electrophilic aromatic substitution?
Electrophilic aromatic substitution (S,Ar) is where a functional group on an aromatic ring, usu-
ally a proton, is replaced by an electrophile.
In order to undergo reaction with the electrophile, the aromatic ring must be electron-
rich. This is because the mechanism requires the cloud of electrons on the benzene ring to
attack the electrophile; if the ring were electron-deficient, it would not be able to do this as
readily (Figure 6.1). The mechanism proceeds via a carbocation intermediate, also known as
S For more information about the Wheland intermediate. This intermediate can then lose a proton, restoring the aromaticity.
electrophiles, see Chapter 3, section 3.1.
H
a ® H E

OY "—~
rearomatization
(J
Wheland
intermediate

Figure 6.1 Electrophilic aromatic substitution general scheme.

Worked example 6.1A

Provide a mechanism for the following reaction. Suggest why nitration only occurs once.

O HNO3, H2SO,
Sa
RT or 0°C NO,

The overall reaction shows one of the protons on the benzene ring has been replaced by an
NO, group. In order for this reaction to work, we need to generate a species that can act as a
source of NO,; we need to consider formation of an active electrophile. Reaction of nitric acid
(HNO,) with sulfuric acid (H,SO,) generates a nitronium ion (NO,,). In this sequence, nitric
acid is protonated and a water molecule is subsequently eliminated.
®
H 5 Q
a H,SO, ¥\ l@ -H,0 ® 2.0
Vine (e) H o’ zo NW
HO” ~O 26 {°% i)
nitronium ion
 6.1 ELECTROPHILIC AROMATIC SUBSTITUTION

With the electrophile prepared, the S,Ar step can be considered. The pi-cloud of the benzene
ring can attack the nitronium ion, a very strong electrophile, to generate the Wheland (carbo-
cation) intermediate. The high-energy carbocation is no longer aromatic, so a proton leaves in
order to regain aromaticity.

ot — oF — oO
et H

Le) H

Finally, the reason that the ring is only nitrated once is because the nitro group is strongly elec-
tron withdrawing, therefore it deactivates the ring, preventing it from attacking other electro-
philes. If you recall from earlier, S,Ar requires an electron-rich substrate. It is possible to nitrate
the ring again but it requires extremely forcing conditions: fuming HNO,, concentrated H,SO,,
and heating to 100 °C!

Worked example 6.1B

Provide a mechanism for the following reaction.

There are two aspects in this question that will help you to answer it: the first is that the group
added to the benzene ring is almost the same as that over the arrow, but without the Cl. The
second is that there is an acyl chloride and a Lewis acid (AICI,). These two pieces of information S For a refresher on Lewis acids, see
point to a Friedel-Crafts type mechanism. Chapter 3, section 3.2.
The first step is coordination of the Lewis acidic aluminium species to the chloride, followed
by a lone pair on the carbonyl oxygen eliminating AICI, to generate a highly reactive acylium
ion. Once we have generated the acylium ion, we are in a familiar S,Ar mechanism; the ion is
attacked by the benzene ring generating the Wheland carbocation intermediate before the ring
undergoes rearomatization, providing the final product.

AICI;
i)
AICI,
cl ©
4 : —— ) ——_—_—_> AY ® + AICI,

[e) . -
acylium ion

® H Oo [e]
ia ® rearomatization
—$— > ~~ po. eo —
 6 AROMATIC CHEMISTRY

[?) Question 6.1

Suggest a mechanism for the reaction below.

Br, FeBr3 Br
SSEEUU coe

> Hint FeBr, acts in a similar manner to AICl,.

@ Question 6.2
Suggest a mechanism for the reaction below.

MP
H,SO, Sy
OH

> Hint This mechanism starts by protonation of one molecule of sulfuric acid by another, then
loss of a molecule of water.

(?) Question 6.3

Suggest a mechanism for the reaction below.

Ac
AICI,
>) For more information about directing
and activating effects, see Clayden et al.
(2012).

6.2 Effects of directing groups on S,Ar

What is a directing group?
Once a benzene ring is substituted, different positions will be favoured to be reactive. A directing
group is a functional group that can guide a reagent to react at a specific position on a molecule.
para In terms of electrophilic aromatic substitution, S,Ar, the position that undergoes substitution
depends upon the other ring substituents. If a substituent is electron donating, then the ortho
S Inductively means electron donation/
and para positions will be activated in relation to the donating substituent. If a substituent is
withdrawal through o bonds, and
mesomerically means electron donation/ electron-withdrawing, the positions substituted are meta in relation to that substituent.
withdrawal through x bonds. This is Some examples of functional groups that have an effect on the position of substitution are
covered in Chapter 1, sections 1.6 and 1.8. shown in Figure 6.2.
 6.2 EFFECTS OF DIRECTING GROUPS ON S,AR

Me | OH CF; NO,

Activating yes no yes no no

o EDG EWG EWG EWG EWG

T nla EDG EDG nla EWG

Position
. olp olp olp m m
functionalized (sterics
favour p)

Figure 6.2 The directing effects of some commonly encountered substituents. EWG means ‘electron
withdrawing group’ and EDG means ‘electron donating group’.

Worked example 6.2A

Suggest where the following molecules will undergo electrophilic aromatic substitution. >) The nitro group is drawn as shown.

Oo, y2o
NO, OH io)
It is important that you learn to draw it
out like this as it is commonly drawn
incorrectly in exams!

If we consider the first example, nitrobenzene, the nitro group is strongly deactivating in
both a o and x manner (inductively and mesomerically respectively), because it pulls elec-
tron density towards itself. There are two implications of this deactivating effect: first, there
is less electron density on the ring at the ortho and para positions (with respect to the nitro
group) due to the mesomeric (1) electron withdrawing nature of the nitro group, therefore
any electrophile will preferentially add at the meta position. Second, when considering any
resonance forms of the Wheland intermediate, we need to look at possible locations of the
positive charge.
If we follow Pathway A, where the electrophile adds para with respect to the nitro group, there
is a resonance form where the positive charge can be located on the carbon directly adjacent to
the nitro group; an extremely unfavourable interaction. This is also true if the electrophile adds
ortho to the nitro group. However, if the electrophile adds meta to the nitro group (Pathway B),
the positive charge generated cannot be located directly adjacent to the nitro group and the
intermediate generated is therefore much more stable. Both of these effects (the electron
withdrawing nature of the nitro group and the more stable carbocation intermediate) lead to
preferential formation of the meta product.
 6 AROMATIC CHEMISTRY

NO, NO, very unstable when the

NO, @ ~«---- positive charge is
Pathway A adjacent to the nitro group
=

°
Pathway B E cE

yy
NO, NO, NO,
<__\_> on <_—__> @®

: -E E E
meta substitution;
the only product

The second example we need to consider is phenol. In phenol, the OH is electron withdraw-
ing through the o bonds due to the electronegativity of oxygen (inductive effect), but electron
donating through the x bonds (mesomeric effect). However, the dominant effect is the 7 elec-
tron donation, therefore the OH group can be considered an activating group. As with the first
example, there are two things to consider. First, the electron-inducing nature of the OH group
S For a refresher on resonance, see means that the ortho and para positions are electron-rich compared to the meta position so
Chapter 1, section 1.8. these positions are likely to attack an electrophile.
Second, we need to consider the intermediate carbocation species. Both meta or para attack
onto an electrophile look plausible as resonance allows the positive charge to be moved around
the ring, which is stabilizing. We therefore need to look into these possibilities in more detail.
If we follow Pathway A, where the electrophile attacks meta to the OH, the positive charge is
never located adjacent an oxygen which we may consider to be a more favourable interaction.
However, if we follow Pathway B, where the positive charge can be adjacent the oxygen, one of
the oxygen lone-pairs can be used to stabilize the positive charge by m resonance, as shown.
This is also true if the phenol attacks in the ortho position. Overall, addition of an electrophile to
phenol will either be ortho or para to the OH group.

cannot be stabilized
by lone-pair
on oxygen
,
OH OH OH OH i
Pathway A “4
=~, 9 <> @

E E E
®
®E Pathway B Favourable
Hy interaction

.
OH ‘OH 0® a
So) |Z
Se

<—_—— <> <>

@

E E E

or ortho
product (due to
similar reasons)
 6.2 EFFECTS OF DIRECTING GROUPS ON S,AR

Worked example 6.2B

Suggest a mechanism for the following reaction. Account for the two products.

[e)
Me
A [e) Me oO
cl
al +

AICI,
Me

There are three clues in this question that will help you to determine the mechanism of this
reaction.

1. Both AICI, and an acyl chloride are present. Both of these things are required for a Friedel-
Crafts reaction, suggesting an S,Ar mechanism.
2. The methyl group is an electron-donating group so the benzene ring is electron-rich, giving
further evidence towards an S,Ar mechanism.
3. There are two products; one where the acyl group is added ortho and one where the acyl
group is added para to the methyl group. This final piece of evidence suggests that an S,Ar
reaction pathway has been followed.

Acetyl chloride is not a strong enough electrophile to undergo S,Ar without some help. In
this case, the AICI, activates the starting material by coordinating to the chlorine which allows
generation of an acylium ion. This acylium species is now electrophilic enough to react with the
aromatic ring.

[e)
A:
&
ve
4
Sig “O°
Gie a Z ue 8 + AICI,

AICI
AICI, © Acylium
ion

The reason there are two products is because the methyl group is electron inducing and, if
S Sometimes it can be helpful to
we ignore any steric effects, the ring can be acylated either ortho or para to the methyl group.
think of the ortho and para positions as
Once the Wheland cation has been generated by attack of the aromatic ring, it can be placed
having a slight negative charge due to
on the carbon adjacent to the methyl group; a stabilizing interaction. In this case, we can as- hyperconjugation and inductive effects.
sume that both the ortho and para products are formed with equal probability as no ratio has For further information about these
been given. effects, see Clayden et al. (2012).
6 AROMATIC CHEMISTRY

para ortho meta

——_—_—_ ® or or °

vA} 3
i
Cation cannot be
Cation can be inductively inductively
stabilized by methyl group stabilized by
ara methyl group
~ © x

ic)

e Oo

[e) [e)

@ Question 6.4
Suggest why there are differences in how many times the bromine is substituted onto the
rings in the examples below.

NH,
NH,
Br. Br Br
————z_-

AcOH
Br

fe)
fo) pe
Jk NH
i
Br
—]—>

AcOH, 0 °C

Br

> Hint Consider mesomeric and inductive effects.

 6.3 NUCLEOPHILIC AROMATIC SUBSTITUTION

@ Question 6.5
Suggest which of these reactions will proceed more quickly and why. Suggest a mechanism
for each.

NO, NO,
AICI, Clp
>

cl

OMe OMe
AICI, Clp
>

Cl

> Hint Consider mesomeric and inductive effects.

@ Question 6.6
Suggest the product or products of the reaction below. Which position is most likely to be
substituted?

OMe
HNO3, H,SO,
SP

OMe

6.3 Nucleophilic aromatic substitution

What is nucleophilic aromatic substitution?
Nucleophilic aromatic substitution (S,Ar) is where a group on an aromatic ring is replaced by a
nucleophile. It is the opposite of an electrophilic aromatic substitution, in that the ring acts as
an electrophile rather than a nucleophile. This reaction requires a nucleophile to attack the aro-
matic ring, to generate an anion (Figure 6.3). The aromatic ring therefore must be electron-poor
to both facilitate attack by the nucleophile, and also to stabilize the negative charge that is gen-
S For a refresher on nucleophiles, see
erated in the intermediate. In this reaction, the functional group or atom that is replaced must
Chapter 3, section 3.1.
be a good leaving group (LG); H is rarely substituted. Common leaving groups are FE, Cl, Br, and
I. It is important that you do not confuse this type of reaction with S,2 substitution. S,2 substitu- >) For a refresher on what makes a good
tion cannot occur at an sp’ carbon; S,Ar follows an addition-elimination mechanistic pathway. _ leaving group, see Chapter 3, section 3.4.

LG LG Nu Nu
ie [e 9 i?
(>) ———_> ——__—>

= Rearomatization
EWG EWG EWG

Figure 6.3 Nucleophilic aromatic substitution mechanism.

QED c aromatic cHemistrY

Cl OH
NaOH
>
NO, NO,

tl MeTA.
‘oO —<>
© cl
OH
x——~> 06
cl
OH
<_—_>
cl

©
OH

OH

NO, NO, NO, NO,

Figure 6.4 Unsuccessful S,Ar.

As stated earlier, this reaction works best if the aromatic ring is electron-poor and the result-
ing LG anion can be stabilized. If we consider the reaction in Figure 6.4, on initial inspection it
looks feasible because the aromatic ring is electron-poor and the chloride atom is a good leav-
ing group. However, this reaction is unlikely to take place readily because the anion generated
cannot be stabilized onto the nitro group, i.e. the anion generated cannot be placed directly on
the adjacent carbon atom.

Worked example 6.3A

Draw the mechanism for the following reaction.

cl OH
NaOH

In this example, there is again a chlorine atom and a nitro group on the ring. The first thing to do
is to look and see which has been replaced; in this example it is the chlorine, which is what we
would expect as chlorine is a better leaving group than NO.,,. The next thing to do is inspect the
relationship of the substituents. In this example the nitro group is para to the chlorine which
will be substituted. This is of benefit as the negative charge generated in the intermediate can be
stabilized through resonance onto the nitro group and the reaction therefore proceeds.

6 ™N? HO Cl on
HO ‘>
> i —_»>
® |
© UNS rd ) si,
 6.3 NUCLEOPHILIC AROMATIC SUBSTITUTION [SETI

Worked example 6.3B

Is the following reaction likely to occur?

cl CN
NaCN

The first thing to check is the substituents on the ring; in this case there is a chlorine and a
ketone. The chloride is a good leaving group, so can be substituted, and the ketone is elec-
tronically withdrawing hence the ring is electron-poor. Thus far, the conditions required for
a S,Ar reaction have been fulfilled. The next step is to check the relationship between the
leaving group and the EWG. If we attack the ring with the nucleophile, an anion is generated.
However, this anion cannot be resonance stabilized by the ketone, so this reaction is unlikely
to happen.

(?) Question 6.7

Suggest a mechanism for the reaction below. Why are two equivalents of the amine
required?

cl oO EtN QO
2 equiv. Et,NH
OH OH
SS

CN CN

> Hint Think pK,!

QED c aromatic cHEmistRY

(?) Question 6.8

Suggest why only one chlorine is substituted in the reaction below.

oY
cl

C Hs eo
C .

S CN
SsCN

> Hint Consider resonance.

@ Question 6.9
Suggest a mechanism for the reaction below.

NO, NO,
cl CuCN NC
>_>

6.4 Azo coupling

What is azo coupling?
Azo coupling is when an aromatic diazonium-containing compound is joined to another aro-
matic compound. The mechanism involves attack of the diazonium group (R-N,* ) by another
aromatic ring therefore the nucleophile must be electron-rich to enable attack of the diazonium
species (Figure 6.5). Often the product azo species are brightly coloured and are known as azo-
dyes, e.g. methyl orange indicator.
The same rules apply as for electrophilic aromatic substitution; whether the substituents on
the donating species are electron withdrawing or donating will affect where the substitution oc-
curs. The diazonium salts are commonly made by treating the corresponding aniline (aromatic
amine) with nitrous acid (NaNO,/HCI) or sodium nitrite (NaNO,).

R R
@-2N A /- A
Nyq 4 S. > not —> Ns AX

diazonium azo compound

species

Figure 6.5 Representative azo-coupling of a diazonium salt and an aromatic ring.

 6.4 AZO COUPLING [FE

Worked example 6.4A

Suggest a mechanism for the following reaction.

tok tO
G4 —@
In this question the first thing to do is to inspect the functional groups on the aromatic ring <) In this example the inductivity of OH
and consider any electronic effects they may have. In this case there is a hydroxyl group anda —_ dominates that of OMe. The reasons
methoxy group, both of which are ortho/para directing. Both of these groups render the ring _ fF this are beyond the scope of this
electron-rich so it is able to act as a nucleophile and attack the azo-species. rex ooKe
In this example the lone-pair on the oxygen is used to push electron density into the ring,
generating an oxonium intermediate. This intermediate then loses a proton to recover aroma-
ticity, a highly favourable process.

7 oO” H

H
@o” OH
i Ns O Ns 1@
—_> N —__> N
OMe in} H
N®

OMe OMe

Worked example 6.4B

Suggest a mechanism for the following reaction.

N
Wl
Oo OH N® H cr NO,

HO
NO,

In this example there are again two directing groups; the hydroxyl group is electron donating,
therefore activates the ortho and para positions towards nucleophilic attack. The aldehyde
is electron-withdrawing so deactivates the ortho and para positions, but the meta position is
QZ c aromatic cHEmIsTRY

unaffected. However, the hydroxyl group is an extremely strong donor therefore the deactiva-
tion effect from the aldehyde is over-ridden. As in the previous example, the oxygen lone-pair
is used to push electron density onto the ring and then to attack the electrophile, generating an
oxonium intermediate. This intermediate then loses a proton to regain aromaticity. Attack para
rather than ortho is most likely due to steric reasons: the OH group is interfering with approach
of the diazonium species.

-
ie] G9 oy

H NO 2

Ns ° N
a H > Ns
N
SNe HO

NO,

(?) Question 6.10

Suggest a mechanism for the following reaction.

OH NMo Ra CF;

r NO. 2 : Ney

CF;

> Hint Look at the product and then work backwards.

© auestion 6.11
Suggest a mechanism for the following reaction.

M ion
N®
HO eee Ns
“OO * HO N
HO
HO’
NO,
 6.5 SYNOPTIC QUESTIONS [EES

[?) Question 6.12

Suggest a mechanism for the following reaction. Why does substitution occur in the posi-
tion indicated?

O NNe
il

rd
O
@ + OPh Ns
N

OH OH
OPh

> Hint Consider resonance.

6.5 Synoptic questions

(?) Question 6.13

Suggest the possible product(s) from the following reaction and provide a mechanism.
Suggest which product is least likely and why.

HNO3, H,SO,
SS

Br

© Question 6.14
Is the reaction below likely to occur? Give reasons for your answer.

| OMe
NaOMe

@ Question 6.15
How would you synthesize the following molecule, starting from benzene?
QED c aromatic cHEmistRY

(?) Question 6.16

Suggest which synthetic approach would undergo faster reaction.

Pathway A

OH OH

@ + —_—_—_—_—__ > 2N
Ns N
~N

Pathway B

NsSN® 70 2N
OH
+ —_—> N

Br OMe OMe

References
Clayden, J., Greeves, N., and Warren, S. (2012) Organic Chemistry, 2nd edn (Oxford University Press, Oxford).
Carbonyl chemistry

7.1 Structure and bonding

What is the carbonyl group?
In its simplest form, the carbonyl group is a carbon to oxygen double bond (Figure 7.1). Both
the carbon and oxygen are sp” hybridized because they are joined by a double bond, and are
therefore planar. >) For a refresher on hybridization, see
Chapter 1, section 1.4.

Jk — Rew
R R EZ

3 o-bonds
120°
1 n-bond
per carbon

Figure 7.1 The carbonyl group.

A neutral carbon atom must have four bonds, therefore the nature of the other substituents
at the central carbon atom will dictate what type of carbonyl group it is and also its reactivity
profile.
There are numerous functional groups that contain a carbonyl moiety. Some of the groups
that you are most likely to encounter are shown in Figure 7.2.
If we consider the electronic structure of the carbon-oxygen double bond, we know that oxy-
gen is an electronegative element therefore the double bond is polarized towards the oxygen;
there is a larger orbital coefficient (i.e. more electron density) on the oxygen in the 2-bonding

A L 4tR™ A o ’
1 1 ' ' ’ t 1

woh H! RS Rv ~ot wee

aldehyde ketone ester amide

ROB
es “8 fd ===> .

ht ;
R'% “Cl; R* “OH; Ri an

acid chloride carboxylic acid anhydride

acid

Figure 7.2 Carbonyl-containing functional groups.

QE 7 carsonvi cHEMIsTRY

R Larger 1* orbital
& on carbon
R LUMO

R fy Lone pairs
Energy R A> HOMO
(non-bonding)

= 2 Larger x orbital
_ on oxygen

Figure 7.3 The relevant molecular orbitals of the carbonyl group.

>, For a refresher on bonding and anti- orbital (Figure 7.3). When considering the anti-bonding orbital (1*) the opposite is true; the
bonding, see Chapter 1, section 1.3. larger anti-bonding lobe is on the carbon. The lone pairs on oxygen are also important and are
known as non-bonding. They are useful because they are the HOMO, i.e. the most available pair
of electrons.
Consideration of the HOMO and LUMO orbitals is extremely important when discussing the
reactivity of the carbonyl group; nucleophiles attack the carbonyl group at the z* orbital (the
LUMO), i.e. at the central carbon atom, and electrophiles are attacked by the oxygen lone pairs
(HOMO) (Figure 7.4).

E°

5-O ' ok,

dt : bt
eh : R R
Nu>

nucleophiles electrophiles
attack the x* orbital are attacked by the
lone pair

Figure 7.4 Reactivity modes of the carbonyl group.

Worked example 7.1A

Name the carbonyl groups in the following compounds:

° fe)
A [e} fe} wo ly fe)

OH sae
SEN
H HH NH,

muscone aspirin ampicillin

 7.1 STRUCTURE AND BONDING [EER

In order to answer this question, you need to look at the carbon of the C=O and see what is £) A y-lactam ring contains five atoms
either side of it. In muscone there is only a ketone; the central carbon atom has acarbon on _and a 6-lactam ring contains six atoms
either side. In aspirin there are two carbonyl groups, both of which are flanked by one oxygen in total.
and one carbon. In this case we now need to look and see what is bonded to the oxygen. If the
oxygen is bonded to a hydrogen, making an OH group, the functional group is a carboxylic acid.
If the oxygen is bonded to another carbon atom, the functional group is an ester. Finally, in
ampicillin there are three C=O containing moieties; in one the central carbon is bonded to an
oxygen and a carbon, and in the other two the central carbon is bonded to a carbon and a nitro-
gen. The first oxygen-connected moiety is a carboxylic acid, for reasons discussed previously.
The nitrogen containing moieties are both amides; however, if an amide is contained within a
ring, it is referred to as a lactam. In this case it is a B-lactam because the amide-containing ring
has four atoms.

Carboxylic
acid \
Lactam

Carboxylic
acid

Worked example 7.1B

By comparing the structures of an aldehyde, a ketone, an ester, and an amide, which do you think
has the largest partial positive charge on carbon and why? How will this affect the reactivity?

ie) fe) fe) fe]

A H Bor of N -

The aldehyde and ketone are both flanked by atoms which do not have any lone pairs of elec-
trons (C and H) whereas in the ester and amide one of the flanking atoms has a lone pair of
electrons. The lone pair of electrons on both the oxygen and the nitrogen can be donated into
the carbonyl group, therefore increasing the electron density on the central carbon. This means
that the central carbon is less reactive towards nucleophiles because it is less 6+. We can now
make a judgement that the aldehyde and ketone are more reactive than the ester and the amide.
Looking more closely at the aldehyde and the ketone, we can see that the aldehyde has an
adjacent carbon and a hydrogen, and the ketone has two carbons. This makes a large differ-
ence to their comparable reactivity. The alkyl chains on the ketone are important, first because
they are able to inductively push electron density towards the central carbon atom (known S For more information about the
as hyperconjugation), and second because they are sterically large and hinder any incoming hyperconjugation effect of alkyl chains
nucleophile. and ketones, see Clayden et al. (2012).
OED 7 carsonvi cHEMisTRY

s) For a refresher on the inductive The aldehyde only has one alkyl chain that is able to offer this induction effect, therefore the
effect, see Chapter 1, section 1.6. stabilization of the 5+ charge is lower, so the aldehyde is more reactive towards nucleophiles
because the central carbon is slightly more 5+ than that of the ketone. Additionally, the steric
bulk of one H and one alkyl chain is less than that of two alkyl chains.

[e) ie)

A, AR
> For a more detailed explanation, see We now need to compare the reactivity of the ester and the amide, both of which are less
Clayden et al. (2012). reactive than the ketone and aldehyde due to the lone pairs on the adjacent heteroatoms
(O and N). The ester contains an adjacent oxygen and the amide an adjacent nitrogen; both
electronegative elements. Oxygen is more electronegative than nitrogen and therefore less
able to donate its lone pair of electrons into the carbonyl group so the amide has a smaller
5+ charge on the central carbon compared to the ester. If we compare the energy of the lone
pairs on O and N we can see why this is: the oxygen lone pair is lower in energy due to the
electronegativity of oxygen, therefore orbital overlap with the high-energy n* orbital of the
C=0 bond is less likely. This means that when comparing esters and amides, esters are more
reactive.

9°
; ° fo)

7s ROY RON
Av UR : BL UR <> SUR

The final reactivity series is therefore (most reactive first) aldehyde > ketone > ester > amide.

@ Question 7.1
Do you think that cyclopropanone (shown below) is very stable to nucleophiles? Give some
reasons to support your argument.

fe}

A
& Hint Consider the bond angles.

(?) Question 7.2

Which carbonyl group in the series below do you think will have the largest partial positive
charge on carbon and why?

ce) oO 9

Ace, AD weer,

> Hint Consider inductive effects.

 7.2 REACTIONS WITH NUCLEOPHILES [NETS

[?) Question 7.3

We usually depict the ester group as shown below with the C—C and O—C bonds aligned
with each other. Suggest four reasons for why this is the correct way of drawing the ester
group.

{e)

ror
aligned with
each other

7.2 Reactions with nucleophiles

Where does the nucleophile react?
As discussed earlier in the chapter (Figure 7.3), a carbonyl group has a larger orbital coefficient
on oxygen in the z-bonding orbital. When considering the anti-bonding orbital, the n*, the op-
posite is true; the larger anti-bonding lobe is on the carbon. The lone pair of electrons on the
oxygen are the HOMO, and the z* anti-bonding orbital is the LUMO. These are the most impor-
tant orbitals when discussing the reactivity of the carbonyl group with both nucleophiles and
electrophiles.
Nucleophiles contain either a negative charge or a readily available pair of electrons that can
be donated. A nucleophile always has to react with a lowest energy empty orbital, the LUMO
(Figure 7.5). In the case of a carbonyl group, the lowest energy empty orbital is the m*, which
has its largest orbital coefficient on the carbon. Once the carbonyl group has been attacked, the
hybridization of the central carbon changes from sp? to sp* and therefore the shape changes
from trigonal planar to tetrahedral. The angle of attack by the nucleophile is 107° in relation
to the C=O bond and corresponds to the location of the x* orbital. This angle is known as the
Biirgi-Dunitz angle or Biirgi-Dunitz trajectory.
If there is a leaving group on the carbonyl, e.g. Cl, the anionic oxygen generated from the >) Similar to other chemistry discussed
nucleophilic addition can eliminate the leaving group to reform the C=O bond, therefore re- _in this book, the ability of the leaving
generating an sp? hybridized carbon (Figure 7.6). This may be the final product, or, depending _9"OUP to leave is related to the pK, of the
parent acid. For more information, see
upon the reaction conditions, it is possible for this newly formed carbonyl group to react further ‘
Chapter 3, section 3.4.
with another nucleophile.

| ° n* (LUMO)
° i Nu \ “
o> Nu oO l4

J: : OS
Ag ax R

Nu sp? hybridised sp* hybridised

C centre C centre
(triognal planar) (tetrahedral)

Figure 7.5 Nucleophile reactivity general scheme.

OED 7 carsonvi cHEmistRY

sp? hybridized sp2 hybridized

C centre S C centre sometimes

‘ oS Nu 2°) -LG \o reacts again yy O°

3 a eae,
Nu sp® hybridized
C centre

Figure 7.6 Nucleophile reaction with a leaving group.

s For a more information, see Clayden Alternatively, if the incoming nucleophile has a free electron pair after it has attacked the
et al. (2012). C=O, this electron pair can be used to eliminate water (Figure 7.7). Examples of elements
which commonly do this are oxygen, to generate an oxonium species that can undergo further
reaction, or nitrogen to generate imines (or enamines) as shown. Usually these reactions re-
quire an acid catalyst.

@ He
ul
® fe 1 ® ®
af +H R—NH OH R{NH OH, _—H20 Ae 5 A =
A p< . ” N° NT
y) iminium imine

RNH,
Figure 7.7 Imine formation resulting from elimination of water.

Worked example 7.2A

Suggest the mechanism of the following reaction.

NaCN then
[e) H* w/up H OH

AA, wee

The key to answering this question is first to identify the nucleophile and use it to attack the
electrophile (LUMO, C=O n*). NaCN, sodium cyanide, is an ionic solid which exists as a so-
dium cation and a cyanide anion. The cyanide anion can act as a nucleophile because it has
a discrete negative charge and will attack the C=O n*, generating a tetrahedral oxy-anion that
can be quenched upon work-up to generate a cyanohydrin.
 7.2 REACTIONS WITH NUCLEOPHILES [NEES

H° wiup H OH

SIP ne Ne woo
——+>

tetrahedral cyanohydrin
intermediate

Worked example 7.2B

Suggest a mechanism for the following reaction, assuming there are at least two equivalents
of ethyl magnesium bromide present. Suggest why no intermediate X is isolated if only one
equivalent of nucleophile was used.

fe NV MgBr 6
Prd k ——_—_——_—_—_> x —_——

oS then Ht

S Organomagnesium species like the

For the magnesium species the carbon can be thought of as carrying a negative charge. one shown are called ‘Grignard reagents’
The negative charge is a nucleophile and will therefore attack the low-lying n* orbital and are very useful. You will learn more
about them at a later stage in your degree
of the C=O bond, generating an oxy-anion. Due to the leaving group on the carbonyl
course. For more information, see Clayden
carbon (OEt), the negative charge generated will eliminate ethoxide, to make a ketone which et al. (2012).
is more reactive than the starting ester (see section 7.1). This ketone then undergoes nu-
cleophilic attack to generate a final alkoxide species that cannot eliminate anything. This > Elimination is only possible if the pK,,,
is because the leaving group has to be a carbanion, having a higher pK,,, than the alkoxide of the eliminated species is low. Ethoxide
species (48 in the case of the carbanion versus 17 for the ethoxide), and is therefore a very can be eliminated because ethanol,
unfavoured process. the protonated species, has a pK, of
approximately 17. However, to eliminate
If only one equivalent of the magnesium species were added we would most likely end up
an alkyl chain would give a species with a
with a 1:1 mixture of starting ester and tertiary alcohol. This is because the ketone intermediate pK, of around 48. For a recap relating pK,
is more reactive than the ester starting material so the magnesium reagent will react with the to leaving group ability, see Chapter 3,
ketone more readily than the ester. section 3.4.

Good leaving
group
D
D

Oy

Pa!
oS So » HO
ae es
No oo,
More reactive than
the starting ester
EI 7 carsonvi cHEMisTRY

@ Question 7.4
Suggest a mechanism and the product of the following reaction.

fe}
NaOH
Cl ae x

> Hint Consider the most reactive part of the substrate.

[?) Question 7.5

Suggest a mechanism for the following reaction.

“HoT ON Le:

> Hint The acid coordinates to the lone pair on the oxygen so the carbonyl is more activated.
The reaction releases one molecule of water as a by-product and proceeds via an oxonium ion
(oxygen with a positive charge).

@ Question 7.6
Suggest a mechanism for the following reaction.

9 \ NH, |
————
~ H* cat. ~~

7.3 Reactions with reducing agents

Where does the reducing agent react?
s) For more information, see Clayden There are many different levels of oxidation state for carbon atoms ranging from the car-
et al. (2012). bon dioxide oxidation level to the alkane oxidation level (Table 7.1). The oxidation level at
which a particular carbon resides is related to the degree of saturation and the number of
bonds it has to heteroatoms (i.e. an atom that is not C or H).
If X is O, the number of oxidation states with a carbonyl group present is quite large. The
defined reactivity of the carbonyl group means that we are able to access most of these oxida-
tion states reasonably easily. In this section we discuss common ways of reducing the carbonyl
group, i.e. reducing the number of bonds that the central carbon has to a heteroatom.
> Do not confuse these reagents with There are a range of methods to reduce a carbonyl group but the most simple ones usually
sodium hydride (NaH) which is not a provide a source of hydride, H,, that acts as a nucleophile and adds to the central carbon atom.
reducing agent but a strong base. Some common hydride-containing reducing agents are sodium borohydride (NaBH,), sodium
cyanoborohydride (NaCNBH,), and lithium aluminium hydride (LiAIH,). There are two others
which you may also encounter, diisobutylaluminium hydride (DIBALH) and borane (BH,), but
 7.3 REACTIONS WITH REDUCING AGENTS [EES

Table 7.1 The various oxidation levels of carbon. X denotes a heteroatom.

Oxdstion
Level
Alkane Alcohol Aldehyde Carpowiie
acid
Capen
dioxide

No of bonds 0 1 2 3 4
to heteroatoms

<

<

<
MX x A x, ar

<
Xx Xx

cS AY Py Ay

\
Table 7.2 General reactivity guide for different hydride-containing reducing agents.

Increasing reactivity (from left to right)

aldehyde __ketone ester amide carboxylic acid
Increasing NaCNBH, | maybe maybe x x x
reactivity (from NaBH, SA: v x x x

ees aa v v v x x
DIBALH v v v v v
LiAIH, v v v v v

Smith, M. B. (2013) March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 7th edn (John
Wiley & Sons Inc., Hoboken, Nv).

these reagents are slightly more advanced as they are require the hydride ion to be generated
first through reaction of the substrate or solvent with the reducing agent.
The reducing agent that you use is important as they all react slightly differently. In the series
above, sodium cyanoborohydride can be considered the mildest reducing agent and lithium
aluminium hydride the strongest. The implication of this is that different reducing agents are
best for different functional groups (Table 7.2). It is even possible to reduce one carbonyl-
containing functional group in the presence of another, provided you choose an appropriate
hydride source.

Worked example 7.3A

Suggest a mechanism for the following transformation.

LiAIH, then
fo) H* wiup HOH
AV XY
EDI 7 carsonvi cHEMisTRY

*) Although this is a ketone, it is at the Lithium aluminium hydride (LiAIH,) is a very reactive source of hydride. The hydride ion at-
aldehyde oxidation level. tacks the carbonyl to give the reduced product; the oxidation level of the central carbon has
changed from the aldehyde to the alcohol oxidation level.
In this example, all that you need to appreciate is that a hydride is present and it will react in
much the same way as a nucleophile because it has a negative charge (HOMO) which can react
with the C=O n* orbital (LUMO).

Al coordinates to
Precoordination oxy-anion because it
of lithium (>) has a vacant p orbital
7 avails ‘
® ® ‘
Li-, Li.5— . 4o

A oe BSE
H. O-AIH; H* workup
Be
H OH

Worked example 7.3B

Suggest a mechanism for the following transformation.

BH, then
° H* w/up

>) Warning: This is a very simplified When there is not hydride already present as H’, e.g. in the case of DIBALH and borane (BH,),
version of this reaction mechanism! the hydride has to be generated. This is achieved by coordination of the substrate to the reduc-
ing agent to form the active hydride species. In this example, the lone pair on the oxygen of
the carbonyl group acts as a Lewis base, and can be donated into the empty p orbital on the
boron generating a boronate species—the active reducing species. The hydride species re-
quired for reduction has now been generated and the hydride can be delivered to the carbonyl
group intramolecularly, which is favourable. Additionally, boronate ester formation activates
the carbonyl group (by acting as a Lewis acid) and the oxygen now has a positive charge so the
t orbital is polarized and can undergo reduction much more easily. Acidic work-up provides
the alcohol product.

Empty p orbital

“OH
H
i HH
..
V4

“O° BH, 0°
BO 7H H,B—O H H* w/up HO H
AL aS" —
ee.

boronate
 7.4 CARBOXYLIC ACIDS

[?) Question 7.7

In the molecule shown below, suggest which carbonyl group would be reduced first by
using NaBH, and why.

> Hint Consider electron-density at the reactive centre.

(?) Question 7.8

What will be the product from one equivalent of DIBALH in this reaction? Provide the
mechanism.

1 equiv. DIBALH,
fe) hexane, —78 °C

A~RKw ,

(?) Question 7.9

Suggest a mechanism for the following reaction.

o BH;
Nw No
H H

> Hint Consider the lone pairs on nitrogen.

7.4 Carboxylic acids

What is a carboxylic acid?
Carboxylic acids are a class of carbonyl compounds that contain a carboxyl group. The terminal S For a refresher on pK,, see Chapter 3,
proton is reasonably acidic and has a pK, of approximately 5, therefore it can be removed fairly __ section 3.4.
easily.
When the proton has been removed and the acid is in the salt form, it is referred to as the
‘carboxylate’ A carboxylate is not a very good nucleophile because the negative charge is spread
over three atoms and is more diffuse (Figure 7.8).

How are they prepared?

Carboxylic acids can be prepared in a variety of ways. The most common are ester hydrolysis,
amide hydrolysis, and by the oxidation of primary alcohols.
OEE 7 carsonvi cHEMisTRY

° o® °
R OH R [e) R [e) R [e}

carboxylic carboxylate negative charge

acid effectively
spread over 3 atoms

Figure 7.8 Resonance structures of a carboxylate species.

How do they react?

>: For a refresher on reduction, see Carboxylic acids are reasonably versatile and can be used to prepare a variety of other functional
section 7.3. groups. They can be converted into esters, acid chlorides, alcohols, and can also be alkylated at
carbon to generate branched carboxylic acids.

Worked example 7.4A

Suggest a mechanism for the following reaction.

aq. NaOH fo)

then Ht w/up
oN ————+, ‘OH

Solution
Sodium hydroxide is an ionic compound and in aqueous media exists as a sodium cation and
a hydroxide anion. The hydroxide anion is nucleophilic enough to attack the ester at the 5+ car-
bonyl carbon, generating the tetrahedral intermediate shown. Once the tetrahedral intermedi-
ate has been made, the anion can regenerate the sp? carbonyl group by eliminating ethoxide.
The reason it has been drawn as a carboxylate rather than a carboxylic acid is because the pK,
of hydroxide is 15 and that of a carboxylic acid 5, therefore the hydroxide ion will deprotonate
the carboxylic acid as soon as it is formed because it generates a more stable anion. Only upon
work-up with a strong acid, e.g. aq. HCI, will the carboxylate be protonated to generate the de-
sired carboxylic acid product.

fesson ae ne 8
Ca
.
a
— ia
:
1
O9™

*
° ©O OH fo) 6 °
te _ >. O . “™~N —__ >. ca —OH on

°
OH tetrahedral H+
intermediate wi/up

(e)

OH
 7.4 CARBOXYLIC ACIDS [EER

Worked example 7.4B

Suggest a mechanism for the following reaction.

EtOH, °
cat. conc. H,SO,
OH a o7N

This reaction is known as a Fischer esterification and is the opposite of the other example S This reaction is under acidic conditions
discussed previously. The first step is protonation of the carbonyl group which activates it therefore under no circumstances can
by causing an even bigger dipole so the 8+ charge on carbon is enhanced. This then allows hydroxide (HO) be eliminated. It must be
the ethanol to attack to generate the intermediate I. Switching protons to generate a new eliminated as water.
oxonium species leads to intermediate II, which can eliminate water. Finally, deprotonation
of intermediate III leads to the product. It is important to notice that all of the reaction steps
are reversible therefore the whole system is in equilibrium.

carbonyl group
activated
®@ H by protonation

° ZH ee HO. OH H Rte
__ yt
“—~N
OH =
——~— ‘ OH ee
———~ o% <—~ tH
fo)
a H
HOV -
oe 1

@ o H

ors -Ht
ee.
— on™

(?) Question 7.10

Suggest a mechanism for the following reaction.

(e) soci, °
paws —> + SO, + HCI
OH cl
ETON 7 carsonvi cHEMIsTRY

© question 7.11
Suggest a mechanism for the following reaction.

NaH
9 then EtBr °
AHL
OH ow ~

> Hint What is NaH?

© question 7.12
Suggest a mechanism for the following reaction. Do you think the hydrolysis of an amide is
easier or harder than that of an ester? Give some reasons for your choice.

fe) conc. HCI fo) oD

rwN a atl yak + H3N
N OH
H

> Hint Consider electronegativities.

7.5 Acyl chlorides

What is an acyl chloride?
Acyl chlorides are a class of carbonyl compounds where the central carbonyl carbon is bonded
to a chlorine atom and another carbon. Acyl chlorides are extremely reactive and are used to
generate a variety of other functional groups. Acyl chlorides are very prone to hydrolysis to the
corresponding carboxylic acid. This is because the chlorine atom is electronegative, therefore
pulls electron density towards itself, making the carbonyl carbon atom have an increased 6+
charge. Chlorine is also a good leaving group, and leaves as chloride (Cl’). There is not much
overlap between the chlorine lone-pairs and the carbonyl 7* orbital due to a large difference
in orbital sizes so resonance forms are not so important. Acyl bromides exist but they are less
widely used because they are extremely reactive.
S when naming branches from the The naming of acyl chlorides is similar to that for carboxylic acids. For example benzoic
longest alkyl chain, the C=O carbon is C1. acid in the acyl chloride form becomes benzoyl chloride and ethanoic acid, ethanoyl chloride
(Figure 7.9). If there are substituents present, the carbonyl carbon is C1.

[e) [e)
9 [e)
OH cl ye AR
OH Cl

benzoic acid benzoyl chloride ethanoic acid ethanoyl chloride

peut
Cl

5-methylhexanoyl chloride

Figure 7.9 Some acyl chlorides you might encounter.

 7.5 ACYLCHLORIDES [ETSI

How are they prepared?

Acid chlorides are most often prepared from the corresponding carboxylic acid. Most often
SOCL, oxalyl chloride ((CICO),) or PCI, are used. There are other reagents available, for ex-
ample Ghosez’ reagent (1-chloro-N,N,2-trimethyl-1-propenylamine), but these are beyond the
scope of this book.

How do they react?

Acyl chlorides react with most nucleophiles. They are commonly used to prepare ketones,
esters, amides, and acid anhydrides.

Worked example 7.5A

Suggest a mechanism for the following reaction.

PCI, (phosphorus pentachloride) is a common reagent for this transformation. It has a trigonal
bipyramidal structure so the central phosphorus can be easily attacked generating an oxonium
intermediate (an oxygen with a positive charge), which can then be attacked by the chloride.
Finally, the tetrahedral intermediate falls apart eliminating phosphoryl chloride and the acid
chloride. The driving force for this reaction is the formation of a very strong P=O bond.

cl
I
Cl
cil> 1cl cl, Cl cl (ei Vi
cl Poel Pcl

JK —_
a:AQ _ 1" 7 Antares — A,

oI

Worked example 7.5B

Suggest a mechanism for the following reaction.

yh 9 EtMgBr

yh °
ET 7 carsonvi cHEmistRY

The Grignard reagent is an excellent nucleophile and will readily attack the acid chloride. We
don’t have to worry about over-addition to form the tertiary alcohol because the ketone product
is much less reactive that the starting material.

82]
—~
tetrahedral
intermediate

© auestion 7.13
Suggest a mechanism for the reaction below.

Q
fe)
————
“| . ao *

© question 7.14
Suggest a mechanism for the reaction below.

[e) fe) [S)

(c) @ UN
Cl te Oe N Se a N
a
(excess)

© question 7.15
Suggest the most likely product and a mechanism for the reaction below.

fe)
er Et,N
Gl + [> ——> x
 7.6 ESTERS (ETN

7.6 Esters
What is an ester?
Esters are a class of carbonyl compounds that contain a carbonyl where the central carbonyl
carbon is bonded to the two oxygen atoms and another carbon atom (Figure 7.10). Esters are im-
portant compounds within the flavourings and fragrances industries because they usually smell
pleasant. Butyl butanoate, for example, smells like pear drops. An important thing to note about
esters is their nomenclature. Their names are in two parts: the alkyl chain attached to the O is
named first, and then the left-hand section (as drawn) up to, and including, the carbonyl group.

a "butyl"
a
ANAK
e+“

“butanoate"
Figure 7.10 Naming of esters.

How are they prepared?

Esters can be made by a variety of methods but the ones you are most likely to encounter are
from the reaction of an alcohol with an acid chloride, a carboxylic acid (see section 7.4) or an
acid anhydride. When faced with the problem of how to make an ester, the best approach is to
imagine cutting the molecule in half across the C—O single bond and then considering which
starting materials are most appropriate (Figure 7.11).

Cleave across
here
, °
Oo 4

WAN

Figure 7.11 Cleavage of the ester bond.

Formation from an acid chloride and alcohol usually requires a weak base for two reasons: to
remove any HCl by-product which might lead to further undesirable reactions, and to remove
the proton from the alcohol once it has attacked the carbonyl group, generating the tetrahe-
dral intermediate (Figure 7.12). This method is generally quite a fast way of making ester com-
pounds but one drawback is the availability and stability of the starting acid chloride; they can
be expensive and are hydrolysed to generate a carboxylic acid if not stored correctly.

Et,N
° (pKay = 10) °
nv + Hos N =~ nv + Et,NeHCl
cl ons
Figure 7.12 Ester formation from an acid chloride and an alcohol.

Preparation from an acid anhydride usually requires slightly more forcing conditions than
with an acid chloride because of the reduced reactivity of the anhydride compared to the acid
chloride (Figure 7.13). Again, a base is present and is required to remove the proton from the
alcohol when it attacks the carbonyl group. When using anhydrides, it is necessary to determine
which end the nucleophile will attack otherwise you generate the wrong product!
OORT 7 carsonvi cHEMIsTRY

S
| ZB Sal
N ° fl °
Ho NN Za * Ae
(pKa = 5) fo)
Figure 7.13 Ester formation from an acid anhydride and an alcohol.

An alternative route, known as the Fischer synthesis, uses a carboxylic acid in the presence of
an acid catalyst (Figure 7.14). The acid activates the carbonyl group by protonation of the car-
bonly oxygen (for a full mechanism, see Worked example 7.6B). This reaction is in equilibrium
therefore it is best to ensure that the water by-product is removed by using a Dean and Stark
apparatus to force the equilibrium position to favour the products, or an excess of the alcohol.

[e)
fe) H,SO,, PhMe nw
nw + 47 OS oN +O
OH
Figure 7.14 Ester formation from a carboxylic acid and an alcohol.

How do they react?

Esters can react to form carboxylic acids (as discussed in section 7.4). They can also be used to
generate tertiary alcohols by addition of a good nucleophile, for example a Grignard reagent.

Worked example 7.6A

Suggest a mechanism for the following transformation.

Solution

s) If the base used is triethylamine, The reaction shown is a common way of preparing esters. Acid chlorides are extremely reactive
pathway 2 is less likely to occur due to therefore the reaction will proceed readily. Pyridine has two roles: one is to neutralize the HCl
steric reasons. produced during the reaction by forming a salt (pathway 1), and the other is to activate the acid
chloride (pathway 2).
Pyridine is not a strong enough base to deprotonate the alcohol therefore this is not a mecha-
nistic option! As with all reactions where there is addition into a carbonyl group, a tetrahedral
intermediate will be formed which, in this case, can eliminate chloride to generate the ester
shown.
 7.6 EsTERS [RTPI

Pathway1:

tetrahedral intermediate

eo 6A 6
[e) pane ( oc ° ol cl

Abe —_—_ ye — 7 —_ pe A + | =
s i 0 Z
HO Su

ZA

Pathway 2:

oN N
| | H He
\ A 4 @N_cl
s
Nw activated iN + |
| species Nt ZA
ZA \ |

Worked example 7.6B

Suggest a mechanism for the following transformation.

[e}

In this reaction the diol has been converted into a carbonate: a carbonyl group with two flanking
oxygen atoms. The mechanism for this is similar to that in the previous example; the triethylamine
will attack the phosgene (COCL,) to generate an activated intermediate which can then in turn be
attacked by the alcohol to form the ester. This process will happen twice. In terms of the order of
events, the primary alcohol probably will attack the phosgene first due to steric reasons, then the
secondary alcohol will attack to close the ring due to its close proximity to the acyl chloride.

Ag oe — ~~ OH 4H
uls
cig on and

OH
QUETSN 7 carsonvi CHEMISTRY

© question 7.16
Suggest a mechanism for the following reaction. What are the roles of pyridine?

_~
f fe)
N
cl o7
OH
O,N “—“- O,N

© question 7.17
Acetylsalicylic acid is a pro-drug for aspirin (salicylic acid). Suggest which bond is hydro-
lysed once it is in the stomach? Suggest a mechanism for this transformation.

© auestion 7.18
Will the following reaction form an ester? Give reasons for your answer.

9 NaOH °
MM OH —_—_—_—_—_> o~

~~
OH

7.7 Amides
What is an amide?
S In chemistry we refer to these Amides are a class of carbonyl compounds that contain a carbonyl group in which the car-
compounds as amides but in biochemistry bonyl carbon is also bonded to a nitrogen and another carbon atom. Amides are important
and chemical biology, where multiple compounds biologically because the amide bond is present in peptides and proteins.
amino acids are joined together, these
Amides are more resistant to attack than esters because the nitrogen lone pairs can delocal-
bonds are often referred to as peptides.
ize more effectively into the carbonyl group due to better orbital overlap, and because it is less
electronegative than oxygen. The implication of this is that the central carbon atom is less elec-
trophilic and the oxygen atom is more nucleophilic (Figure 7.15). An important thing to note
about amides is their nomenclature. Their names are in two parts, similar to an ester: the alkyl
chain attached to the nitrogen is named first, then the longest continuous carbon chain includ-
ing the carbonyl group of the amide.
 7.7 AMIDES 107

fo) Fe) t fe) ethyl oO

f
Bu N as < - NJN a ' pap N “—— as i —.

H H ' r , H L
: butyl
!
f
' N-ethylbutanamide N,N-diethylbutanamide

Figure 7.15 Structure and nomenclature of amides.

How are they prepared?

Amides can be prepared in a number of ways but the ones you are most likely to encounter in
your first years of university are reactions between an amine and an ester or an acid chloride.
They can also be made by reaction between an amine and a carboxylic acid but this usually re-
quires a coupling agent which is beyond the scope of this book. Mechanistically there is nothing
too new with their preparation compared to the esters and acid chlorides discussed previously.

How do they react?

Amides react in much the same way as esters, but often need more forcing conditions due to S Weinreb amide
the increased stability of the amide functionality. They can be hydrolysed to give a carbox-
ylic acid and an amine, and reduced to give an amine. Reaction with Grignard reagents can
be sluggish and give poor yields. There is one exception to this however; a Weinreb amide
(N-methyl-N-methoxy amide) can be used to generate ketones from an amide in excellent
yields and selectivity.

Worked example 7.7A

Suggest a mechanism for the following reaction:

When looking at this reaction, we can treat it the same as the other carbonyl reactions we have £) Remember, pK,,, is the PK, value
met. The acyl chloride is highly electrophilic at the carbonyl carbon due to the electronega- for the protonated parent species. For a
tivity of the chlorine, so is highly reactive towards nucleophiles, and chlorine is an excellent refresher, see Chapter 3, section 3.4.

leaving group (leaving as Cl’). The amine is a good nucleophile because the nitrogen contains
a lone-pair which can attack the C=O n* orbital, generating a tetrahedral intermediate which
can then eliminate chloride. The reason that chloride is eliminated and not the amine is be-
cause of their respective pK,,, values. The pK,,, of chloride (i.e. HCl) is —8 but that of the amine
(i.e. RNH,) is approximately 36. This means that the chloride anion is more stable, because it
has a lower pK,,,, therefore is the preferred leaving group. For this reaction to work the amine
must be in excess because one molecule of HCI is released which will make a salt with the
amine present.
OORT 7 carsonvi cHEMIsTRY

¢
ge — Aa Hed

=e |H ) ok x ) + AA}
aan cl I Y

Worked example 7.7B

Suggest a mechanism for the following reaction.

NaOH, H,0
° reflux [e) Lv
nH N 420 Pw N + H2N
H then H* w/up OH

Hydrolysis of an amide requires much more forcing conditions than for an ester therefore this
reaction must be undertaken at reflux. The hydroxide ion attacks the 6+ carbonyl carbon to
generate the tetrahedral intermediate. This then collapses to eliminate the amine as the anion.
The pK, of an amine is approximately 32 and that of water is 15.7, therefore the amine anion
formed deprotonates the water present. The newly formed carboxylic acid is deprotonated and
therefore cannot react any further due to delocalization of the negative charge, which renders
the carbonyl group unreactive towards nucleophiles.

.) -
H

+
!
Kr

on
ets
— OK — r1, OH
A
H
tetrahedral :
intermediate NaOH Protonated upon
acidic work-up
so can be
oO washed into the
aqueous phase
 7.8 SYNOPTIC QUESTIONS [ETE

© Question 7.19
Suggest a mechanism for the reduction below.

fe)
LiAIH, Na
N a

> Hint Consider resonance.

© Question 7.20
Suggest a mechanism for the reaction below.

ote a oY
© Question 7.21
Suggest the mechanism for conversion of the Weinreb amide shown below to a ketone.
How would you make the Weinreb amide?

LY MsgBr
ae OMe eee
N

7.8 Synoptic questions

@ Question 7.22
Suggest the major product of the reaction shown.
QUEEN 7 carsonvi cHEMIsTRY

© Question 7.23
Give reagents and conditions for steps A and C. Suggest mechanisms for steps A and C.

(e} fo} PMB-TCA fe)

Ph3CBF,
5 ——= ee ee ea pmpo. ~_ 1 pe 1
N N puso ~_JL yw
OMe OMe

© auestion 7.24
Suggest a mechanism for the hydrolysis of the B-lactam ring in ampicillin.

H H
WN =H Es HH OH
i H,0 i
09 “70 a o KANN
H “=O
H
HO CoH

© Question 7.25
Which of the following ketones would you expect to be reduced most quickly by NaBH,
and why?

O2N MeO

References
Clayden, J., Greeves, N., and Warren, S. (2012) Organic Chemistry, 2nd edn (Oxford University Press,
Oxford).
Synoptic questions

$1

m-CPBA, CHCl
OEt reflux, 4.5 days
od Xx
¢ 92%
oo ac |

'm-CPBA = bia
oO!
‘ O__

The following relate to the reaction scheme shown.

(a) Showing your working, is the alkene (E) or (Z)?

(b) What is the hybridization of the C marked with an asterisk?
(c) Predict the product of the reaction with m-CPBA and provide a mechanism.

$2
°

°
Step A Step B Step C
H SS a col x SS
0.
Te OMe
fo) [e)
fe)
AICl3, heat

The following relate to the reaction scheme shown.

(a) Provide reagents, conditions, and a full mechanism for step A.

(b) What is the name of the reaction in step B? Draw a full mechanism for formation of X, fully
justifying any regioselectivity.
(c) Give reagents, conditions, and a full mechanism for conversion of X to the product in step C.

$3

z fo)
@,2N HOT on
N Ns
or _— ee a KOH,
Ee 140 °C
F F
QUEEN synoptic questions
The following relate to the reaction scheme shown.

(a) Draw the mechanism for the azo coupling step.

(b) Suggest the structure of X and provide a mechanism for its formation.
(c) Starting from 1-fluoro-4-nitrobenzene, suggest a route for synthesis of the starting
diazonium species A. (Hint: It will take two steps.)

$4
(25,3S)-2-bromo-3-methylpentane reacts with lithium diisopropylamide (LDA) to yield two
major products.

(a) Draw the structure of (2S,3S)-2-bromo-3-methylpentane.

(b) Predict the structure of the two products, providing mechanisms for each reaction.

$5
Hydroboration-oxidation can be used to form alcohols from alkenes. The process is shown
below.

BH; H,0,

(a) Step 1 is an electrophilic addition. Which reagent is the nucleophile, and which is the
electrophile?
(b) Is the molecule synthesized the Markovnikov or anti-Markovnikov product?
(c) Suggest which reagents may be used to synthesize the tertiary alcohol below from this
alkene. Provide a mechanism.

ad
S6
En route to synthesizing diphenhydramine derivatives, you conduct the two-step reaction
below.

fe) owt
‘

i. NaBH, 2-bromoethanol
oO”

——————— xX —_—_—>
ii. Ht w/up TsOH

p-Toluenesulfonic acid
(TsOH)

(a) Predict the product from the first step of the reaction.
(b) Provide a mechanism for the second step.
Answers

Final answers to questions posed in the text (where they can be given) are presented here. You can find full solutions to
every question featured in the book in the Workbooks in Chemistry Online Resource Centre. Go to http://www.oxfordtext-
books.co.uk/orc/chemworkbooks/.

CHAPTER 1 Question 1.10 CHAPTER 2

6 DBEs; S(VI) invalidates equation 1.2.
Question 1.3 Question 2.2
(a) 3-methylpentane Question 1.11 (a) Positional isomers
(b) 4-ethyl-5-methylhept-1-ene (a) Nonpolar (b) Chain isomers
(c) Propanoic acid (b) Polar (c) Functional group isomers
(d) 3-methylcyclohexan-1-ol (c) Nonpolar (d) Chain and functional group
(e) 4-bromopentan-2-ol (d) Polar isomers
(f) 1,2-dichlorobenzene, or (e) Polar
ortho-dichlorobenzene Question 2.3
Question 1.12 (a) —OH>—NH,>—CH,>—H
Question 1.5 (a) B (b) —C=CH >—C(H)=CH, >
Bond order: 0 (b) A —CH,>—H
(c) A (c) —NH,>—Et>—CH,>—H
Question 1.6 (d) B (d) —NO,>—NMe, >
(a) ao bonding MO anda o* —NH,>—CN
anti-bonding MO will Question 1.13
be formed (a) Aromatic Question 2.4
(b) ambonding MO anda n* (b) Non-aromatic (a) Trans
anti-bonding MO will (c) Non-aromatic (b) Cis
be formed (d) Aromatic (c) Cis
(e) Aromatic (d) Trans
Question 1.7 (f) Anti-aromatic
(a) C1, C2: sp3; C3, C4: sp? (g) Non-aromatic Question 2.5
(b) Cl: sp’; C2: sp’; C3, C4: sp (h) Aromatic (a) 2)
(c) C1, C2: sp’; C3, C4: sp* (b) (Z)
(d) Cl: sp; C2: sp? Question 1.14 (c) (E)
(e) Phenyl group at C3 of propyne: (a) Aromatic
(d) (Z)
6 x sp’. C3 of propyne: sp*; C1, C2 (b) Non-aromatic
of propyne: sp (c) Aromatic Question 2.7
(f) All C atoms sp? hybridized (d) Aromatic (a) (S)
(e) Non-aromatic (b) (R)
Question 1.8 (f) Aromatic (c) (R)
(a) O:sp* hybridized (d) (S)
(b) O/N: sp? hybridized Question 1.16 (e) (R)
(c) N:sp hybridized (a) A
() (S)
(d) N: sp’ hybridized (b) A
(c) B Question 2.8
n9
Questio1. (d) B (a) Enantiomers
(a) 1 (b) Not stereoisomers
Synoptic question 1.19 (c) Meso
(b) 1
(a) N/A (d) Enantiomers
(c) 2
(b) Non-aromatic Diastereomers
(d) 4 (e)
(e) 15 (c) N/A (f) Diastereomers
(f) 0 Synoptic question 1.20
(g) 1 ‘X’ is the enolate of ‘A’
(h) 16
WEEE answers

Synoptic question 2.9 (b) They are enantiomers (c) El

(a) 1-bromobutane, 2-bromobutane, (c) N/A (d) E2
1-bromo-2-methylpropane, (e) ElcB
2-bromo-2-methylpropane. CHAPTER 4
(b) (R)-2-bromobutane; Question 4.2
4
(S)-2-bromobutane Question 4.1
(a) E2
Synoptic question 2.10 (b) El
(a) Both (s)
Appendix 1
Acidity constants

Values of pK, quoted at 298 K in water except when otherwise noted.

Acid Formula pK,*

Hydriodic acid HI -10
Hydrobromic acid HBr -9
Hydrochloric acid HCI ae
Sulfuric acid H,SO, -3
Perchloric acid HCIO, -1.6
Nitric acid HNO, -1.4
Trichloroethanoic acid CCI,CO,H 0.66T
lodic acid HIO, 0.78
Oxalic acid (CO,H), 1.25
Phosphonic acid (phosphorous acid) H,PO, 1.3f
Dichloroethanoic acid CI,CHCO,H 1.35
Sulfurous acid H,SO, 1.85
Chlorous acid HCIO, 1.94
Hydrogensulfate ion HSO,- 199.
Phosphoric acid H,PO, 2.16
Chloroethanoic acid CICH,CO,H 2.87
Bromoethanoic acid BrCH,CO,H 2.90
Hydrofluoric acid HF 3.20
Nitrous acid HNO, 3.25
Methanoic acid HCO,H 3.75
Hydrogenoxalate ion HO,CCO,- 3.81
Benzoic acid C,H,CO,H 4.20
Ethanoic acid CH,CO,H 4.76
Phenylammonium ion PhNH,* 4.87
Propanoic acid CH,CH,CO,H 4.87
Pyridinium ion C;H;NH* 5.23
Carbonic acid H,CO, 6.35
Hydrogen sulfide H,S 7.05
Hydrogensulfite ion HSO,- ye
Dihydrogenphosphate ion H,PO,- T21
Hypochlorous acid HCIO (or HOC)) 7.40
Hydrazinium ion NH,NH,* 8.1
Hypobromous acid HBrO (or HOBr) 8.55
Pentane-2,4-dione MeCOCH,COMe 9.0
Hydrocyanic acid HCN 9.21
Ammonium ion NH,* 9.25
Boric acid H,BO, (or B(OH),) 9.27T
Trimethylammonium ion Me,NH* 9.80
Silicic acid H,SiO, 9.9

(continued)
QUEEN rrenvix 1

Acid Formula pK,*

Phenol C,H,OH 9.99
Hydrogencarbonate ion HCO, 10.33
Ethylammonium ion EtNH,* 10.65
Methylammonium ion MeNH,* 10.66
Triethylammonium ion Et,NH* 10.75
Hydrogen peroxide H,0, 11.62
Hydrogenphosphate ion HPO,?- 12.32
Water H,O 14.00
Methanol MeOH 15.5
Hydrogensulfide ion HS- 19
Propan-2-one MeCOMe 20
Ethyne C,H, 25
Hydrogen H, 35
Ammonia NH, 38
Benzene CH, 43
Ethene C,H, 44

Ethane C,H, 50
* Values below —2 and above 18 are approximations.
+ 293 K.
$303 K.
Sources
Haynes, W.M. (ed.) (2015-16). CRC handbook of chemistry and physics, 96th edn. CRC Press, Boca Raton, Florida.
Smith, M.B. and March, J. (2007). March’s advanced organic chemistry: reactions, mechanisms, and structure, 6th edn.
Wiley-Interscience, New York.
 Appendix 2
Electronegativity values for common elements
Sooo s

Li
0.98

Na
0.93

0.82

Cs
0.79
Appendix 3
Common functional groups in decreasing order of seniority,
according to IUPAC

Functional Group Structure Prefix Suffix

Radicals R° - -yl

Anions RO - -ide

Cations R® = -ylium

°
Carboxylic acids 3k Carboxy- -oic acid
R OH

[e)
Esters J _R' Alkoxy-oxo- -oate
R [e)

O°
Acid halides JL X=¢h Br Halo-oxo- -oyl halide
R xX

[e)
Amides awe Amino-oxo- -amide
H

ZN
Nitriles ae Cyano- -nitrile

fe)
Aldehydes | Oxo- -al
R

[eo]
Ketones eR Oxo- -one

OH
Alcohols Hydroxy- -ol
R R'

SH
Thiols Sulfanyl- -thiol
R R'

NH,
Amines Amino- -amine
R R'

-R"
N
Imines | Imino- -imine
R R'

Alkene ROW - -ene

Alkyne R—=~R' - -yne

Index

Page numbers in bold type refer to sidenotes. Bronsted acids/bases 49, 50 ElcB elimination 62, 63
Page numbers italics refer to figures. Biirgi-Dunitz angle 91 E2elimination 62, 63
butanone 28-9 unimolecular elimination 62
1-chloropentane 34 enantiomers 40-1, 42-3, 53
2-chloroacetic acid 19, 20 Cc esters 87, 90,91, 103-6
2,2-dichloroacetic acid 19-20 ethylene glycol 69-70
3-methylbutanal 33 Cahn-Ingold-Prelog (CIP) system 35,
37-8
3-methylphenol 25-6 F
capsaicin 16-17
carbonyl groups 87-91 Fischer esterification/synthesis 99, 104
A reactions with nucleophiles 91-4 formaldehyde 4, 18-19
acetic acid 19 reactions with reducing Friedel-Crafts mechanisms 73
acetone 4, 26-7, 29-30 agents 94-7 functional group isomers 32, 34
acetylacetone 26-7 see also acid/acyl chlorides, amides, functional groups 5-7, 8, 118
acetylsalicylic acid 106 carboxylic acids, esters geminal functional groups 68
carboxylic acids 5, 87, 97-100
acid anhydrides 87 vicinal functional groups 68
catenation 1
preparation of esters 103-4 furan 22
chain isomers 32, 34
acid/acyl chlorides 87, 100-2
chiral molecules 39-41
preparation ofesters 103
see also optical isomers G
acidity constants 115-16
cis/trans isomers 35, 36-8 geminal functional groups 68
addition reactions
condensed formulae 1 Grignard reagents 93, 102, 104
electrophilic addition 67-70
configurational isomers 32, 35
halogen addition 68-9
conformational isomers 32
Michael addition 31
constitutional isomers 32-4
alcohols 5
CORN rules 39 halogen addition 68-9
aldehydes 5, 87, 89,90
cyclohexene 71 halohydrins 68
alkyl halides 5
cyclooctatetraene 22-3 highest occupied molecular orbitals
amides 87,90, 106-9
cyclopentadiene 22 (HOMOs) 8, 88
amines 57
cyclopropanone 90 Hiickel’s rule 21, 22
amino acids 7 Hund’srule 10
ampicillin 88, 89, 110
hybrid orbitals 11-14
anti-aromatic molecules 21 D
hydride-containing reducing agents 94-5
anti-bonding orbitals 8 di-iso-butylaluminium hydride hyperconjugation 52
aromatic molecules/rings 21-3, 26 (DIBAIH) 94, 96
azo coupling 82-4 diastereomers 40, 42-3
electrophilic substitution 72-8 diazonium salts 82
nucleophilic substitution 79-82 dichloromethane 18, 68 in-phase orbitals 8
arrow notation 18 dipole moments 18 inductive effect 19-20, 74
aspirin 88,89 directing groups 74-9 isoleucine 7
atomic orbitals 8 double bond equivalents 15-17 isomers 32-43
Aufbau principle 10 chain isomers 32,34
azo coupling 82-4 cis/transisomers 35, 36-8
configurational isomers 32, 35
E/Zisomers 36 conformational isomers 32
El elimination 62-3, 65 constitutional isomers 32-4
benzene 16 ElcB elimination 62, 63 diastereomers 40, 42-3
benzoic acid 100 E2 elimination 62, 63 E/Zisomers 36
bimolecular elimination 62 electronegativity values 117 enantiomers 40-1, 42-3,53
bond angles 1,3 electrophiles 47-8 functional group isomers 32, 34
bond orders 8-9 electrophilic addition 67-70 mesoisomers 40, 42-3
bonding orbitals 8 electrophilic substitution 72-8 optical isomers 35, 39-43
borane 94,96 elimination reactions 62-5 positional isomers 32, 34
borohydride 94 bimolecular elimination 62 (R)/(S) isomers 39, 40-1
boron trichloride 47 El elimination 62-3, 65 stereoisomers 32,35
isotopes 35 s
TUPAC nomenclature/notation 4-7,
18, 118 Newman projections 62 skeletal formulae 1-2
nitro group 75 Sy1 nucleophilic substitution 51-3
K nomenclature S,2 nucleophilic substitution 51, 54-6, 63
see IUPAC nomenclature sodium bromide 48
Kekuleé’s structure 16 nucleophiles 47-8 sodium cyanide 92
keto-enol tautomerism 28 reactions with carbonyl sodium cyanoborohydride 94, 95
ketones 5, 29, 87, 89 groups 91-4 sodium hydroxide 98
nucleophilic substitution 51-6 sp hybridized carbon atoms 14
L aromatic molecules 79-82 stereocentres 35, 40
Sy1 nucleophilic substitution 51-3 stereoisomers 32,35
L-propargylglycine 13
S,2 nucleophilic substitution 51, structural formulae 1
lactams 87,89
54-6, 63 substitution reactions
lactones 87
electrophilic substitution 72-8
leaving groups 57
Lewis acids/bases 49,50
oO nucleophilic substitution 51-6
sulfate anion 24
Lewis structures 1 optical isomers (chirality) 35, 39-43
linalool 8 orbitals T
lithium aluminium hydride 94, 95, 96 see atomic orbitals, molecular
locants 4 orbitals tautomerism 28-30
lowest unoccupied molecular orbitals out-of-phase orbitals 8 keto-enol tautomerism 28
(LUMOs) 8, 88 tert-butyl group 2
P tetrachloromethane 18
toluene 4
Pauli exclusion principle 10 tosyl chloride 17
Markovnikov’s rule 67 penguinone 30 tosylate/tosyl group 48
meso isomers 40, 42-3 phosgene 105 triethylamine 104, 105
mesomeric effect 25,74 phosphorous pentachloride 101 trivialnames 4
methyl tert-butyl ether (MTBE) 2 pK, values 19-20, 26-7, 56-60
Michael addition 31 polar bonds 18 U
molecular formulae 1 polarity
molecular orbitals 8-14 unimolecular elimination 62
see molecular polarity
anti-bonding orbitals 8 positional isomers 32, 34
bonding orbitals 8
Vv
propadiene 14
highest occupied molecular pseudoephedrine 46 vicinal functional groups 68
orbitals 8,88
pyridine 104
hybrid orbitals 11-14 Ww
in-phase orbitals 8
Wheland intermediates 72,73
lowest unoccupied molecular orbitals 8,
Weinreb amide 107, 109
88 (R)/(S) isomers 39, 40-1
out-of-phase orbitals 8 reducing agents 94-7
z
molecular polarity 18-20 regioselectivity 67-8
muscone 88, 89 resonance 24-7 Zaitsev’srule 64