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 OXFORD CHEMISTRY PRIMERS
Physical Chemistry Editor Founding/Organic Editor Inorganic Chemistry Editor Chemical Engineering Editor
RICHARD G. COMPTON STEPHEN G. DAVIES JOHN EVANS LYNN F. GLADDEN
University of Oxford University of Oxford University of Southampton University of Cambridge

| S. E. Thomas Organic synthesis: The roles ofboron and silicon R. H. S. Winterton Heat transfer
2 D. T. Davies Aromatic heterocyclic chemistry 51 N. C. Norman Periodicity and the s- and p-block elements
3 P.R. Jenkins Organometallic reagents in synthesis R. W. Cattrall Chemical sensors
4 M. Sainsbury Aromatic chemistry M. Bowker The Basis and applications of
5 L. M. Harwood Polar rearrangements heterogeneous catalysis
6 T. J. Donohoe Oxidation and reduction in organic synthesis M. C. Grossel Alicyclic chemistry
i J. H. Jones Amino acid and peptide synthesis Second edition J. M. Brown Molecular spectroscopy
8 C. J. Moody and G, H. Whitham Reactive intermediates G, J. Price Thermodynamics ofchemical processes
9 G. M. Hornby and J. M. Peach Foundations of organic chemistry A. G. Howard Aquatic environmental chemistry
10 R. Henderson The mechanisms ofreactions at transition metal sites A. O. S. Maczek Statistical thermodynamics
1] H. M. Cartwright Applications ofartificial G. A. Attard and C. J. Barnes Surfaces
intelligence in chemistry W. Clegg Crystal structure determination
M. Bochmann Organometallics 1; Complexes with transition M. Brouard Reaction dynamics
metal—carbon s-bonds
A. K. Brisdon Inorganic spectroscopic methods
M. Bochmann Organomertallics 2; Complexes with transition
metal—carbon p-bonds G. Proctor Stereoselectivity in organic synthesis
C. E. Housecroft Cluster molecules of the p-block elements C. M. A. Brett and A. M. O. Brett Electroanalysis
M. J. Winter Chemical bonding N. J. B. Green Quantum mechanics 2: The toolkit
R. S. Ward Bifunctional compounds D. M. P. Mingos Essentials of inorganic chemistry 2
S. K. Scott Oscillations, waves, and chaos in I. Fleming Pericyclic reactions
chemical kinetics N. S. Lawrence, J. D. Wadhawan & R. G. Compton Foundations of
T. P. Softley Atomic spectra physical chemistry: Worked examples
J, Mann Chemical aspects of biosynthesis J. R. Chipperfield Non-aqueous solvents
— B. G. Cox Modern liquid phase kinetics T. J. Mason Sonochemistry
A. Harrison Fractals in chemistry J. McCleverty Chemistry ofthe first-row transition metals
NY M. T. Weller Inorganic materials chemistry
NY
NON E. C, Constable Coordination chemistry of macrocyclic compounds
R. PR. Wayne Chemical instrumentation C. E. Housecroft The heavier d-block metals: Aspects of inorganic
D. E. Fenton Biocoordination chemistry and coordination chemistry
W. G. Richards and P. R. Scott Energy levels in atoms and P. D. Beer, P. A. Gale and D. K. Smith Supramolecular chemistry
molecules N. Kaltsoyannis and P. Scott Thefelements
M. J. Winter d-Block chemistry D. S. Sivia and S. G. Rawlings Foundations of science mathematics
D. M. P. Mingos Essentials of inorganic chemistry 1 S. Duckett and B. Gilbert Foundations ofspectroscopy
G. H. Grant and W. G. Richards Computational chemistry J. H. Atherton and K. J. Carpenter Process development:
S.A. Lee and G. E. Robinson Process development: Fine chemicals Physicochemical concepts
from grams to kilograms R. de Levie Acid—base equilibria and titrations
C. L. Willis and M. R. Wills Organic synthesis H. Maskill Structure and reactivity in organic chemistry
P. J. Hore Nuclear magnetic resonance D.S. Sivia and S. G. Rawlings Foundations ofscience
G. H. Whitham Organosulfur chemistry mathematics: Worked problems
A. C. Fisher Electrode dynamics J. Iggo NMR Spectroscopy in inorganic chemistry
G. D. Meakins Functional groups: Characteristics and P. Biggs Computers in chemistry
interconversions
D. J. Walton and P. Lorimer Polymers
A. J. Kirby Stereoelectronic effects
R. J. Davey and J. Garside From molecules to crystallizers
P. A. Cox Introduction to quantum theory and atomic structure
G, M. Hornby and J. M. Peach Foundations oforganic chemistry:
P. D. Bailey and K. M. Morgan Organonitrogen chemistry
Worked examples
C. E. Wayne and R. P. Wayne Photochemistry
M. J. T. Robinson Organic stereochemistry
C. P. Lawrence, A. Rodger, and R. G. Compton Foundations of
H. R.N. Jones Radiation heat transfer
physical chemistry
J. Saunders Top drugs—top synthetic routes
R. G. Compton and G. H. W. Sanders Electrode potentials
P. B. Whalley 7wo-phase flow and heat transfer M. J. Perkins Radical chemistry: The fundamentals
L. M. Harwood and T. D. W. Claridge /ntroduction to organic P. J. Hore, J. A. Jones, and S. Wimperis NMR: The toolkit
spectroscopy G. A. D. Ritchie and D. S. Stvia Foundations ofphysics
forchemists
C. E. Housecroft Metal-metal bonded carbonyl dimers and clusters M. J. Winter and J. Andrew Foundations ofinorganic chemistry
H. Maskill Mechanisms of organic reactions 95 J. Robertson Protecting group chemistry
P. C, Wilkins and R. G. Wilkins /norganic R. Whyman Applied organometallic chemistry and catalysis
chemistry in biology J. S. Ogden Introduction to molecular symmetry
J. H. Jones Core carbonyl chemistry 98 C. M. Dobson, A. J. Pratt, and J. A. Gerrard Bioorganic chemistry
N. J. B. Green Quantum mechanics 1; Foundations B. G. Davis and A. J. Fairbanks Carbohydrate Chemistry
I. S. Metcalfe Chemical reaction engineering: A first course
Foundations of
Organic Chemistry
Michael Hornby
Stowe School, Buckingham

Josephine Peach
Somerville College and the Dyson Pernns Laboratory, University of Oxford

OXFORD
UNIVERSITY PRESS
 OXFORD
UNIVERSITY PRESS

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First published 1993
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All rights reserved. No part of this publication may be reproduced,
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A catalogue record for this book is available from the British library
Library of Congress Cataloging in Publication Data
Hornby, G. Michael
Foundations of organic chemistry / G. Michael Hornby and Josephine M. Peach
(Oxford chemistry primers: 9)
1. Chemistry, Organic. I. Peach, Josephine M. II. Title.
III. Series.
QD253.H67 1993 547-—dc20 92-26902
ISBN: 978-0-19-855680-0
18
Printed in Great Britain by
CPI Antony Rowe,
Chippenham, Wiltshire
Series Editor’s Foreword
Students starting chemistry courses at university have a wide range of
backgrounds, and consequently each individual’s elementary knowledge of
the subject tends to be fragmented differently. Ideally all chemistry students
should start their university courses with the same elementary knowledge
base. This Oxford Chemistry Primer is designed to draw the subject together
to provide a concise introduction to organic chemistry. It should stimulate
young people reading chemistry at advanced level in school, and serve to
excite still further the student’s interest in the subject during the transitional
period between school and university.
This primer will be of interest to chemistry schoolteachers and all who
aspire to serve an apprenticeship in chemistry at university.
Stephen G. Davies
The Dyson Perrins Laboratory, University of Oxford

Preface

This book has been written to bridge the gap between organic chemistry at
school and at university, to stimulate the interest of advanced level chemists,
and to provide a foundation for undergraduates starting courses in chemistry
or biochemistry. The first three chapters lay the basis of the physical
chemistry needed and lead into the discussion of the reactions from a
mechanistic point of view. We have tried to keep the majority of the main text
within the A level syllabuses, with some extensions in the margins and in the
last chapter. It is not intended as, nor can it be, a comprehensive A level text.
By concentrating on mechanism we hope to emphasize the common threads
that hold the subject together.
We are most grateful to all those who have given us valuable criticism and
advice, in particular Dr Peter Carpenter (Roedean School), Dr John Nixon
(Haberdashers’ Aske’s School, Elstree), and Dr David Smith (Winchester
College). Dr Sydney Bailey (St Peter’s College, Oxford) has been a constant
source of help and inspiration to both of us since our own undergraduate
days. Colleagues at ICI Pharmaceuticals and Agrochemicals have generously
provided information on some of the commercially important compounds.
Finally we would like to thank Mrs Brenda Armstrong (Fellows’ Secretary at
Somerville College, Oxford) for her valiant efforts at deciphering not one but
two sets of chemical handwriting.
We would like to dedicate this book to Janet and to John, and to our
mutual goddaughters, Helen and Emma.

Buckingham G. M. Ef,
Oxford J.M. P.
September 1992
Contents
Molecules
Mechanisms
Acids and bases
Reactions with nucleophiles
Reactions with electrophiles
Reactions with radical intermediates
-&
WY
&
bh
uu
NIATaking it further
Further reading
Index
1 Molecules —
1.1. Introduction

Organic chemistry began as the chemistry of living things, like yeast,

moulds, mushrooms, willow trees, and whales. It is based on the
compounds of carbon, whose molecules are the essence of organic
: we ee e aes CH,OH
chemistry. From fuels through pain-killers and antibiotics to vitamins, they fh
fascinate us. How are they constructed? How can we make them? Why do GOH
they behave the way they do? What can we make from them? How do we Ss
make molecules which are going to affect biological systems in the way we H3C N
want, with minimal side-effects? Vitamin B6

OH
C,H,CH,CONH St He CH,

N / CH, CH,~ ~or" O Je 8

0 S H,
Penicillin G cove ll Muscarine

OCOCH; H, Myo TH, HL Me,

COOH Hwy be es Hy Hy He OM,

Aspirin Cetyl alcohol

Before we can begin to answer these questions we need to understand the The abbreviated way of drawing
ways in which atoms join together to form molecules. In later chapters we organic molecules is explained on
will explore the ways in which a molecule’s architecture affects its pp. 7 and
11.

chemistry, and how we exploit this to make new compounds.

1.2 Atoms

Chemical reactions are the result of bond breaking and bond making,
involving the most energetic, outer shell electrons of atoms. Before we can
discuss bonding we need to have some idea of how electrons are distributed
in separate atoms, particuiarly carbon atoms.
The electronic configuration of a carbon atom in its ground state, or
lowest energy state, is 1s*2s’2p*. The terms s and p describe the types of
orbital in which these electrons are found, an orbital simply showing the
probable distribution of electron density.
2 Molecules

s Atomic orbitals

or
Each s orbital can hold a pair of electrons and is spherically symmetrical.
The diagram shows the region in which an s electron is most likely to be found.

p Atomic orbitals
or In the same way the electron density in a p orbital is shown as two pears end
to end. p Orbitals are not spherically symmetrical and there are three of
them, of equal energy, mutually at right angles, in each main shell.

The electrons in a p orbital are most likely to be found somewhere within

the ‘double pear’ region. On average they will be further from the nucleus
than electrons in the corresponding s orbital.

1.3 Bonding

o Bonds

The simplest case is hydrogen, H,. The two singly occupied s orbitals on two
hydrogen atoms combine to form one bonding orbital in Hp.
Two atomic orbitals combine to form
two molecular orbitals, but only one is
occupied and bonding. OOF ca.
Bonds like these, where two half-filled orbitals on neighbouring atoms
combine to give a bonding molecular orbital with high electron density
between the two nuclei involved, are called sigma or o bonds. This is the
normal single bond.

Making four single bonds to carbon

If a carbon atom remained in its ground state in a molecule it could form
only two covalent bonds, using its two unpaired p electrons, and it would
still have only six electrons in its outer shell.
 Foundations of organic chemistry 3

It is energetically more favourable to promote one of the 2s electrons into

the vacant p orbital. The four half-filled orbitals can then combine with half-
filled orbitals on four other atoms (e.g. H) to form four equivalent covalent
bonds. The carbon atom makes four bonds and so will share eight electrons
in its outer shell (two electrons per bond). A < ‘ eh
gain the eight atomic orbitals com-
bine to form eight molecular orbitals,
of which four are occupied and bond-
ing.
In general n atomic orbitals com-
ONE 1s FOUR equivalent ‘hybrid’ orbitals bine to form n molecular orbitals, of
orbital (sometimes called sp?) which n/2 are occupied and bonding.

The energy for the promotion, about +400 kJ mol™’, is more than repaid by
the bond energy (see p. 10) from making four bonds instead of two.

Methane. In methane, CHy, the four equivalent half-filled orbitals on 2

carbon overlap with the half-filled s orbitals of four hydrogen atoms to give o Sess
four new bonding molecular orbitals, each containing a shared pair of » 109
electrons. We have made four new o bonds (see right). H 2 2
The shape of methane. Mutual repulsion of the electron pairs in these H
H
molecular orbitals or bonds leads to their pointing to the corners of a
tetrahedron. This is the geometry for maximum separation of electrons and
maximum bond angles (see p. 11). 7]

Making multiple bonds to carbon: 7 bonds

There are other ways in which the four half-filled orbitals of carbon can be
combined, allowing carbon to make double or triple bonds to another atom.

Double bonds. Three of the four half-filled orbitals are used to form three
equivalent ‘hybrid’ orbitals (called sp”) leaving one half-filled p orbital to
form one other bond.

—___’
ONE Is THREE equivalent ONE p
orbital ‘hybrid’ orbitals ( sp* ) orbital

In ethene, C)H,, each carbon atom makes three o bonds, using the three
(sp”) ‘hybrid’ orbitals.

sigma bonds: OF C—-C

4 Molecules

If the remaining half-filled p orbitals on the two carbon atoms are parallel,
they can combine to form a new bonding orbital: a 7 (pi) bond. The shared
electron pair is most likely to be found in the two sausage-shaped lobes on
either side of the line joining the two nuclei.

am Bonds are always associated with a o bond directly between the nuclei,
giving a ‘hamburger’ look to the electron density diagram.

in

Together the o and 7 bonds make a double bond between the two carbon
atoms.

The shape of ethene. The principle of mutual repulsion of electron pairs

helps to explain why the three atoms bonded to each carbon are in a trigonal
planar arrangement (flat, propeller-like), with bond angles of about 120°.
Ethene, C,H,, is a flat or planar molecule.

H H

This diagram shows each shared pair of electrons as a line but makes no
distinction between the o and 7 contributions to the double bond, which is
fundamental to an understanding of the reactions of ethene (see Chapter S,
p.58). We will consider the implications of 7 bonding on the shapes of
molecules later in this chapter (p. 12). Similar 7 bonds occur in the carbonyl
group, C=O, in aldehydes, ketones, esters, and so on. The geometry is
again planar with bond angles of about 120° (see left).

Triple bonds. Two of the half-filled orbitals on carbon form two equivalent
‘hybrid’ orbitals (called sp) leaving two half-filled p orbitals to form two 7
bonds.

ONE s TWO equivalent TWO p orbitals

orbital ‘hybrid'orbitals ( sp ) for two pi bonds
for two sigma bonds

Linear triple bonds in alkynes and nitriles are the result of the formation of
two m bonds using two mutually perpendicular p orbitals on each of the
 Foundations of organic chemistry 5
triple bonded atoms, with a o bond in the middle as before. So the two
aw bonds of the triple bond are in planes at right angles to each other. The distribution of the wm electron
density is cylindrically symmetrical in
these triple bonded molecules.

H—C=C—H CH;—C=N
an alkyne a nitrile

Delocalized 7 bonds

More than two adjacent p orbitals can combine to form a set of molecular , single conventional structure does
orbitals where the electron pairs are shared by more than two atoms. These not adequately describe the methan-
form ‘delocalized’ 7 bonds. The methanoate ion HCOO , for example, can oate ion. Instead of the ‘cloudy’
be drawn as either picture, the methanoate ion can be
‘ described using the two conventional
ye structures. Neither of these contribut-
Fe or HC ing structures actually exists but the
ye ‘ true structure of the methanoate ion
lies in between them. This method of
description is called ‘resonance’ and
is denoted by double-headed arrows
but is better represented by H—CK - where between the contributing structures,
e.g.
: H H
\ \ ”
C=@ —~,- C—O
O- J
shows the probable distribution of the two delocalized pairs of electrons Resonance structures differ only in
over the three atoms. This explains the observed equal C—O bond lengths. electron distribution; all the atoms
In the case of benzene, CeH¢, there are six p orbitals making three _ stay in the same places.
delocalized bonding orbitals, each holding a pair of electrons. These are Normal C-~O and C=O bond
usually summarized as a double ring doughnut of electron density. lengths are about 0.14 and 0.12 nm
respectively. Both carbon-to-oxygen
bonds in the methanoate ion have a
length in between these values: 0.13
nm.

The o bond framework of the molecule is shown as lines. The region of high
electron density is above and below the plane of the ring. In structural
formulae (see p. 7) benzene is represented as

either oS or or

in more
The structure of benzene, and the evidence for it, will be discussed
detail in Chapter 5 (see p.67). The delocalization in benzene can be
extended to other adjacent atoms. If delocalization is extended sufficiently
6 Molecules

the compounds become able to absorb light energy in the visible region;
they become coloured.
Compounds with a system of alternate
single and double bonds are said to
have conjugated double bonds.

The dye INDIGO

is obtained from a plant (an Indigofera ©

species). A colourless sugar derivative
is first isolated, which after hydrolysis Na*
is oxidized by air to the familiar blue 2 +
dye used for jeans. The dye is not 50; 2
stable and gradually fades.
Sunset Yellow FCF; E 110.

Bond polarization: dipoles

Pairs of electrons in covalent bonds are only shared equally by atoms of the
same element. The electron distribution is symmetrical.

Dissimilar nuclei will have a differing attraction for the shared pair which
results in an unsymmetrical distribution of electron density and a permanent
slight separation of charge, a dipole. This dipole can be measured, and for a
liquid its magnitude can be related to the solvent properties. H—Cl is
actually HCl _ because the chlorine has a greater attraction for the
shared pair than does the hydrogen. This gives a small separation of charge,
see the partial charges being shown as 5+ and 5—. The bond is said to be
polarized. The presence of nonbonded pairs on only one of the atoms may
6 is used to mean ‘a small amount of’; also contribute to this dipole.
Bo Wate raeer is (acura roe’ Chlorine is said to be more electronegative than hydrogen. Some other
charge and 8— a fractional negative se ae ?
Bees electronegativities are shown in Table 1.1.

Table 1.1 Electronegativities (Pauling scale)

lei G25 N 3.0 Oss F 4.0

12.5 Br 2.8 C13.0 F 4.0

The more electronegative of the two atoms in a dipole carries the 8—. The
bigger the difference in electronegativity of the two atoms, the bigger the
 Foundations of organic chemistry 7

dipole in a covalent bond between them. The molecule as a whole will have
a measurable dipole moment, unless the dipoles within it cancel each other
out by being arranged symmetrically.

H H b-
eee ae
Se) mor
cl
Ve \cl vyeet \
é- $-
clS— H
Permanent dipole No permanent dipole

Bond polarization: inductive effects

The effect of a permanent dipole may be felt some distance away in a
molecule, the dipole in one bond inducing a similar smaller dipole next door.
Thus C—C—C] is actually C€§C@ CI and there is an induced dipole in
the C—C bond. This can be written C——- C>>- Cl; NB it is not a dative
bond X —>Y. A methyl group attached to carbon also has an inductive
effect, H3C - C (see right).
Inductive effects are most useful in supplying a rule of thumb ‘explanation’
for differences in reactivity.

Structural formulae

Molecules are drawn using structural formulae, a kind of shorthand for the
full bonding diagram. Some examples will show how they are used; look at
the yellow dyes on p. 6 and these simpler molecules below.

H
|
Methane: CH, or ae C—

O
H Il H
\ “oy Gs
axe
Propanone: CH3COCH3 or
Ei oy \ le!
H H

It is common to see the structures of

H O alkyl groups drawn with apparent
\ 4 bond angles of 90°, but remember
Ethanoic acid: CH;COOH or H -¢ —C
that the carbons are tetrahedral with
H O=—H
angles of about 109°.

Each — represents one bond or a shared pair of electrons. The advantage is

that we can see at a glance exactly which atoms are joined and by how many
bonds, but we still have to remember details of type of bond (p. 2) and shape
of molecule, which are not always shown explicitly.
For larger molecules (like the yellow dyes) showing every bond is
cumbersome, and we usually restrict them to functional groups (see p. 8),
8 Molecules

grouping the other atoms together in such a way as to make the structure
clear.

H
Propanonitrile Ne —C=N_ would become CH3CH,C = N
\
H
or even CoH5CN

Stearic acid, from animal fat, is then CH3(CH2);6 COOH.

For complex compounds even this convention would take a good deal of
writing time, whilst drawing attention away from the functional groups
which are the bits that really influence the chemistry.

Hexane can be shown as -\7\_

~~ and cyclohexane as

Each corner or end represents a carbon atom and each line a bond.
Hydrogen atoms on carbon are not shown and we assume that each carbon
atom has the right number of hydrogens to give it four bonds altogether.
CH; CH; We have already shown, on p.5, the representation of the delocalized
system in benzene. So the structures on the left represent methylbenzene,
where one of the hydrogens on the ring has been replaced by a CH3; or
methyl group. The versatility of these shorthand forms can easily be
appreciated in the structures given below and the two yellow compounds on
CH; p. 6.
CH
or

NH,

O O O ¢g | N
CH; rT iI i pe

OH
Adenosine triphosphate (ATP)
H3C CH;

Menthol Functional groups

Name the functional group in

Compounds such as ethanol, CH;CH,OH, and propanol, CH;CH,CH,OH,
MENTHOL, which is extracted from have very similar chemical properties because the ‘business ends’ of their
plants of the mint family and is used in molecules, where reactions occur most readily, are identical. They both
sweets and toothpaste. have the group of atoms —CH,OH, a primary alcohol.
 Foundations of organic chemistry 9

In the same way, all carboxylic acids possess —-COOH as the business end
of their molecules. We have already come across several more of these OXETANOCIN is a natural product
functional groups. from a bacterium which is used clinic-
ally against HIV. It includes two prim-
Cc ary alcohol groups (~CH2OH), a
\ Za
bee) ‘cae —C=N four-membered ether ring, and a
e “i primary amine.
ketone alkene nitrile

Cc
\
—NH, H as —OH
(
HOCH),
primary amine secondary alcohol

Part of any organic course involves learning the structures of these

functional groups and some of the reactions associated with them. You will
find this material in your notes or in any standard textbook. Such an
approach tends to emphasize the differences in behaviour of the various
functional groups. In this book we are more concerned with drawing
together the common underlying themes involved in the structures of the
compounds and the mechanisms of their reactions.

Dot diagrams

Dot diagrams give a simple way of following the formation of ions or

molecules from atoms. You may be familar with this idea already. Outer
shell electrons are represented by dots (or asterisks). The formation of
sodium and chloride ions from their respective atoms would be shown as in
the diagram on the right.
The electron pairs on the chloride ion are indistinguishable from each
other. Covalent bonding in methane would be represented as

The use of such diagrams allows us to get the electron bookkeeping correct,
with the formation of the right number of bonds. The use of dots allows us
to keep track of electron pairs during the bond-making and -breaking in a
reaction (e.g. p.21). It also helps us to understand why some of the inter-
mediates of organic reactions are charged (see p.59).

H
H3C + CH; \ i
‘C—CHs -c30 You should try drawing dot diagrams
H3C CN for these two ions.
10 Molecules

Nonbonded pairs
H H If we draw a dot diagram for ammonia, we find that the outer shell of the
H:N: H:0: nitrogen atom contains a nonbonded (or lone) pair of electrons. The oxygen
H ee

atom in the water molecule similarly has two nonbonded pairs. The
ammonia water
molecular orbital picture for ammonia would have the nonbonded pair on
top.

In a full structural formula,

we would write

We can simply abbreviate this to :NH3. In practice, the nonbonded pairs are
often omitted in formulae such as NH3, which can make it difficult to see
which ions or molecules will act as bases (p. 33) or nucleophiles (p. 40) until
one is familiar with them.
COCCINELLIN is a ‘defence com- Nonbonded pairs can be used to form dative covalent bonds with other
pound’ exuded by ladybirds when atoms or molecules. The ‘type reaction’ is H3N: + BF3 going to H3N—>BF3;
attacked. where — represents the dative bond between N and B using the nonbonded
The central N atom in coccinellin pair on the nitrogen. This is an underlying theme in many organic reactions
has used its nonbonded pair to make involving polar mechanisms (e.g. p.41). Although we do not draw all
a dative bond to oxygen.
nonbonded pairs onto structural formulae even when they are needed, you
will have to remember where they are. Most nucleophiles have them.
“ny

1.4 Bond strengths and lengths

“CH;
Two factors influencing the strength of a bond are its type and the sizes of
the atoms involved. We define bond strength as the enthalpy change of the
process X—Y(.) > Xg) + Y(g). The term bond energy is often used for this.

Table 1.2

Bond Length(nm) Bondenergy(kJmol~') Type

O=-C 0.154 346 o
C=C 0.135 610 o+T
C0 0.143 358 o
C=O 0,122 736 o+t
(aldehyde)

Table 1.2 shows that o bonds are stronger than m bonds for C to C
connections. The 7 bond between C atoms is therefore the easier part of the
double bond to break and the chemistry of alkenes is dominated by this.
For carbon to oxygen double bonds the reverse appears to be true. This
could be one reason why there are more addition/ elimination reactions in
C=O chemistry than in C=C chemistry (see p. 49).
 Foundations of organic chemistry 11
Short bonds are usually strong ones. In the case of multiple bonds, the
attraction of two shared pairs for the two positive nuclei pulls them closer
together. The effect of atomic size on bond energy can be seen in the series
C—halogen. The smaller the halogen atom, the closer the bonding nuclei
can get to each other (Table 1.3).

Table 1.3

Bond __Length(nm) _ Bond energy (kJ/mol-')

Ci 0.138 452
CCl O77 339
C—Br 0.194 280
Cal 0.214 230

All other things being equal, one would expect the C—I bond to be the lodobutane is indeed hydrolysed
easiest of the four to break. It is the comparative difficulty of breaking C—F faster than chlorobutane, partly
and C—Cl bonds that has made chlorofluorocarbons (CFCs) a menace to because of the weakness of its C—|
the environment. Compounds such as CCI,F, linger for years in the bond (see also p. 41).

atmosphere and are unaffected by bacteria. There is evidence that they

It is their very lack of reactivity that
damage the ozone layer. They are now banned in the UK.
makes them so useful as refrigerants,
anaesthetics, and non-stick coatings.

1.5 Stereochemistry
Bond angles, molecular shapes
‘All electron pairs, being similarly charged, are mutually repulsive but
nonbonded pairs are more repulsive than others.’ All we need in order to
apply this principle to work out shapes is a knowledge of the number and
type of electron pairs around the atom of interest. Their distribution in
space will be such that they are all as far away from each other as possible.
Their mutual repulsion leads to the shape involving the maximum H
separation of electron pairs. Dot diagrams (p. 9) make good starting points.
Methane has four bonding pairs. Maximum separation is achieved by the H
four pairs taking up a tetrahedral arrangement with bond angles of 109.5°. In
the figure (right), thick lines —-_[ represent bonds that are coming out of
the page towards us, 1111: bonds that are going away from us into the page.
Lines of normal thickness — are bonds in the plane of the page.
|
wey Cca
109.5°

ig, H
The same distribution applies to ammonia (three bonding pairs, one H
nonbonded pair), though the greater repulsive effect of the nonbonded pair,
which stays closer to its parent nucleus than a bonded pair, reduces the bond
angle to 107°. The actual atoms in ammonia are arranged in a pyramid. The
angular structure of water can be rationalized in the same way with two
nonbonded pairs.
H oy H .
H:N?
Sty °
e/g ae N
H;O-
° ~ e
rae
-

H H 107° Hose!
ammonia water
12 Molecules

The two pairs of electrons in a double bond appear to be a little more

H H repulsive than a single pair, and they can be counted as one region of
\ /
Nar Oe electron density for shape purposes.
eae It is usually good enough to take these trigonal planar angles to be 120°.
The need for overlap of the two parallel p orbitals to make the 7 bond
means that the whole molecule is flat. Rotation around the central C=C
bond is difficult energetically because it involves breaking the 7m bond; the
overlap of the two p orbitals would be minimal if the two CH) ends were at
right angles (see p.4). The same trigonal planar carbon atoms are seen in
benzene, in methanal, and in carbocations (e.g. p. 45). BF; is also a trigonal
planar molecule.
H CHs te
C=0 C—CH, B—F
H CH; F
cl
The other shape we are likely to come across is the trigonal bipyramid
wiiceal
arrangement for which the classic example is gaseous PCls, where five pairs
of electrons are associated with the central atom. For overall maximum
Cl separation three pairs of electrons are in a trigonal planar arrangement with
the other two pairs at right angles to this plane. We will meet this shape
H again in the transition states for some nucleophilic substitution reactions
Be VS & (see p. 41).
HO ---- C----- Br The C—O and C—Br bonds are drawn dotted to show that they are
|
CH; neither completely made nor completely broken but in between, as one
might expect in a transition state. The carbon atom is not 5-valent!
Overall, this transition state must
have one whole negative charge (see
p. 28). Structural isomerism

There are several ways in which the same set of atoms can be joined
together to form different molecules. The simplest way is to join the atoms
in a different order. Compare
OF CH)
CHEF anid, and Chin 18
methoxymethane ethanol

and the three possible nitromethylbenzenes.

CH; CH; CH;

Pick out the carboxylic acid and ester
groups in ASPARTAME, a synthetic NO,
‘sweetener 150 times as sweet as
sugar. Draw out the structure show-
ing al/ the multiple bonds. NO}
NO)
HOOC

These are usually referred to as structural isomers or simply isomers. As

well as having different physical properties such as melting and boiling
points, these isomers are likely to have different chemical properties, very
different if the functional groups have been changed. For example, both
 Foundations of organic chemistry 13
CH3CH,COOH and CH3COOCH; are C3H,O>, but one is an acid and the
other an ester. ;

Stereoisomerism: geometric (cis/trans) isomerism

Stereoisomerism describes isomerism where two molecules have the same
atoms joined to each other in the same order but with a different
arrangement in space. Such isomers exist because they lack symmetry.
The first kind is called geometric or cis/ trans isomerism, with but-2-ene as H H
‘oY
an example. Written linearly, CH3;CH=CHCHs3, the molecule gives no hint Cae
Ti aX
of the two possibilities. But when the structure is drawn to show the shape, CH; CH;
one can either write it with both the hydrogens attached to carbon on the
same side of the double bond, the cis isomer, or on opposite sides, the trans
isomer.
There is restricted rotation about the C=C bond and the two isomers are H CH;
eae,
not interconvertible without breaking the 7 bond and rotating one end. This GC
0 \
is energetically unlikely. The two compounds have different physical CH; H
properties, such as boiling point, and slightly different chemical properties.
trans but-2-ene
One might think that
H CH, H H
\ / \ /
oC and G6
/ \ / \
H H H CH;

are also isomers, but because the molecule as a whole is flat one can simply
turn the left hand molecule over to get the right hand one. The key feature
for this isomerism is the presence of two different groups on each end of the
double bond. The conversion of one cis isomer into its trans relation is a
central] feature of human vision.

CH; CH, CH,

CH
all trans-retinal
11-cis-retinal

We can draw butane CH;CH,CH>CH; showing three dimensions to see if

a similar isomerism is possible. Remember that thick —««# bonds are coming
out of the page, 1111! bonds are going away from us, and normal lines — are
bonds in the plane of the paper.

H H H CH;
: cant s th the same as \o — (
CH3 45 gies: CH, H a
14 Molecules

In fact the easy rotation about the central single carbon to carbon o bond
means that the two drawings are of the same molecule, one end being
rotated relative to the other by 120°. It is much easier to see these three
dimensional shapes with molecular models, and it is well worth having
regular access to a set of them. It could be said that Watson and Crick won
their Nobel prize for playing with models of DNA.

ALANINE
COOH '! HOOC Stereoisomerism: optical isomerism
The second type of stereoisomerism is caused by a lack of symmetry in a
Ci, wae
Ye dst Eis: SS molecule’s structure so that the molecule and its mirror image are actually
HN Neu, Hic” NH)
A B different, like a left hand and a right hand. No amount of twiddling, with
models or on paper can make the mirror structures identical, without
In diagram B you can see that we
breaking bonds; they are nonsuperimposable. An example is the amino acid
have drawn the groups the ‘wrong’
way round:
alanine (2-aminopropanoic acid).
H3C— for methyl, —CH3; If we try to rotate molecule A, hoping to get molecule B by overlapping
HOOC— for carboxylic the central C atom, the COOH and the NH) groups, we are unsuccessful
acid, -COOH. because now the methyl (CH3) group is going into the paper instead of
The groups are not different at all, coming out. Confirm this for yourself using molecular models. The isomers
but just drawn backwards to emphas-
differ in the direction in which they rotate the plane of plane polarized light;
ize the atoms which are bonded
otherwise their physical properties are the same. They are identical in
together and the mirror-image re-
lationship of A to B. The amino group chemical reactivity except in cases where shape and symmetry are critical,
in diagram A is also reversed for the most notably in reactions with other optical isomers including enzymes (see
same reasons. p. 85). In simple cases we can recognize a molecule with optical isomers by
the presence of one or more asymmetric carbon atoms, that is, a carbon
atom bearing four different substituents. A few minutes spent playing with
drawings or models will show you that the mirror image is different. On the
Only one optical isomer of DOPA,
other hand a little twiddling of H
called .-DOPA, is effective in the
treatment of Parkinson’s disease.
Com,
Non,
+

HO NH
= COO”
should show that the presence of two identical substituents on the carbon
HO
atom rules out optical isomerism. A molecule possessing asymmetry leading
to optical isomerism is said to be chiral. Biological systems are often very
Only one isomer of MORPHINE
acts as an addictive but efficient selective about optical isomers. We can only metabolize amino acids shaped
painkiller. like B above. One optical isomer of limonene occurs in oranges, the other in
peppermint oil, and both in turpentine. The two isomers smell different!
HO

Limonene from lemons Limonene from oranges

or peppermint oil CH; H3C

How many asymmetric carbon atoms

are there in these molecules?
 Foundations of organic chemistry il)

1.6 Intermolecular attractions

There are a number of ways in which separate molecules can attract each
other. These affect physical properties such as melting point and boiling
point as well as solubility.

Dipole—dipole attractions
The permanent dipoles (see p.6) in molecules will attract each other,
following the general principle that opposite charges attract, e.g. propanone.
H3C
6+ 8- cH,
Ga Ona)
HC De CH3
:
This is a weak attraction (only a few kJ mol’; compare with the energy of
covalent bonds in Table 1.2). This weak attraction is enough to account for
the relative boiling points of propanone and butane, which have a similar c€=0
/
number of electrons altogether. Remember that in going from liquid to gas H3C
it is only those bonds between molecules that are broken. Propanone, b.p. 56°C
The attraction of molecules with permanent dipoles (polar molecules) for permanent dipole
fully charged ions helps to explain the solubility of compounds like sodium
chloride in water. The figure shows only one water molecule per ion for
simplicity. There will actually be seve.‘al clustered around each ion. Cc CH;
ice ac
Hy
Butane, b.p. 0°C
no permanent dipole

This is ion—dipole attraction.

Van der Waals forces

A second type of weak attraction occurs between molecules which do not

possess permanent dipoles. A rationale for this kind of attraction is that at
any instant the electrons around even a symmetrical molecule may be
unsymmetrically distributed, producing a temporary tiny dipole. This could
induce a similar dipole in a neighbouring molecule. All these interactions
give net attraction and are called van der Waals forces. The more electrons,
the better!
The more ‘contact’ the attracted molecules can have with each other the
stronger the forces are likely to be. The tiny dipoles can get close enough to
interact in molecules which can lie easily side by side. So straight chain
alkanes have higher boiling points than branched ones containing the same
number of atoms (see Table 1.4).
16 Molecules

Table 1.4

Compound b.p. °C)

pentane 26
2-methylbutane 18
2,2-dimethylpropane 10

These van der Waals forces, again worth only a few kJ mol’, are generally
weaker than dipole/ dipole attractions. They are important in the mainten-
ance of the coherence and fluidity of biological membranes. Phospholipid
molecules with long hydrocarbon side chains are held together by van der
Waals forces (see left).
They can also contribute to the tertiary structure of proteins. It is likely
that at the active sites of some enzymes the catalysed reaction is essentially
taking place in an organic medium, since all the water has been excluded.

Hydrogen bonding
A special case of dipole/dipole attraction involves hydrogen bonded to a
small highly electronegative atom (fluorine, oxygen, or nitrogen). This H
atom is attracted to another N, O, or F atom; this second atom must carry a
nonbonded electron pair. This is known as hydrogen bonding and is worth
10-40 kJ mol™?.
6+ H \
5+ H 0-H
e.g. water \
Wee = 26>

pe ge
The stronger the attractive inter- Hydrogen bonding is the strongest of the weak interactions and accounts for
actions between molecules in a liquid, the high boiling points of alcohols compared with alkanes or ethers
the more difficult it is for the mole- containing a similar number of electrons. Compare ethane (b.p. —89°C)
cules to escape from each other to H3C— CH; with methanol (b.p. 64°C):
form the vapour.

ot
CH, -O—CH;
\ RANE
O—H
b-— &

It also accounts for the solubility of alcohols and carboxylic acids (of
relatively low molecular mass) in water (see p. 17).
Hydrogen bonding is essential for the complementary base pairing which
holds together the double helix of DNA and forms the biochemical basis of
genetics.
Hydrogen bonding is vital in the maintenance of secondary structure, the
a-helices, and tertiary structure in proteins. It is involved in the binding of
substrate molecules to the active sites of most enzymes, e.g. chymotrypsin
(p.17). The substrate is bound in by both hydrogen bonding and van der
Waals attraction as shown.
 Foundations of organic chemistry 17

protein substrate with

tyrosine side-chain

van der Waals

attraction PARACETAMOL is a widely used
pain-killer. Draw diagrams to show
how a molecule of paracetamol could
hydrogen be involved in hydrogen bonding with
bonding
water molecules.
chymotrypsin H
binding site Nene

\|
1.7 Solubility O
HO
This has been mentioned already in this chapter. Substances will mix
completely, or a solute will dissolve in a solvent, as long as the sum of the
attractions between molecules after mixing is equal to or more than that
before. Where there is little change in the attractions during solution there
will be no barrier to the mixing. This is the basis of the ‘like dissolves like’
principle.
Short chain alcohols and carboxylic acids, which are hydrogen bonded
before mixing, will dissolve in water (also hydrogen bonded), with plenty of
hydrogen bonding after mixing.
Propanone, with dipole/ dipole attractions before mixing, will dissolve in CH; H §+
\ /
water because of the possibility of new hydrogen bonds after mixing (see C=0"-=---< F—@)
J+ 5- Se 26-
right). CH;
Compounds like hexane and benzene, whose molecules have no
permanent dipoles, can mix freely because both possess van der Waals
attractions before and after. But hexane, with van der Waals attractions,
will not dissolve in water because, if it did so, some of the hydrogen bonding
in the water would have to be sacrificed. Hexane molecules would physically
get in the way with no compensating new attractive forces to make up for
the loss. _ Before: hake

oe CH % & Ha y

Peg ae MyC~ cy, 25- &

on .
OH HC ~ oH, The hydrogen bonds being broken
26- ot &+ ‘
are worth about —30 kJ mo!~'. Form-
Om \ ing the extra new van der Waals
26- & CH,
attractive interactions, at about
Even for alcohols and carboxylic acids in water, a balance is struck between —4 kJ mol~', is not enough to make
the effects of the ‘soluble’ ends, —CH,OH (hydrogen bonding) and the the whole process energetically
CH; (interference with hydrogen bonding).
‘insoluble’ ends, —CH:—CH,— favourable.
Alcohols and carboxylic acids with short hydrocarbon side-chains do There is more to solubility than just
these enthalpy changes, but the
dissolve in water, but as the chain length increases they become less and less
necessary consideration of entropy is
soluble. The energy gain at the polar end is gradually outweighed by the loss beyond the scope of this book.
at the lengthening nonpolar end.
2 Mechanisms

2.1. Introduction

Organic reaction mechanisms are shorthand descriptions of how the starting

compounds are made into the products. Molecules with the same functional
groups usually react by similar mechanisms, and we can use mechanisms for
known reactions to predict how other molecules will behave under similar
conditions. Mechanisms are thus a connecting thread between similar
reactions and allow us to rationalize the products of a known reaction and to
predict the reactivity of other organic molecules.

Types of reaction
In this book we will be considering the mechanisms of three types of
reaction: substitution, addition, and elimination.

Substitution reactions involve exchanging one atom or group of atoms on

the organic molecule for another.
ég. CH, 4° Cy —- CHC! + HC
A chlorine has replaced one of the hydrogen atoms on the methane.

Addition reactions mean just that; one molecule adds onto another and
nothing is lost.
€.g. CH=CH, + Br2 ae CH2BrCH2Br

Elimination reactions involve the loss of a relatively small molecule from

the organic reactant.
e.g. CH3;CH,OH semis CH=CH, + H,O

Water has been eliminated from the alcohol. Remember that elimination is
the reverse of addition.

Heterolytic and homolytic bond breaking

Most reactions involve bond breaking as well as bond making. This can be
of two types, heterolysis and homolysis.
In heterolytic bond breaking the pair of electrons in the bond becomes
associated with only one of the atoms involved.
3 Yr Se Ke aE
The resulting fragments are likely to be charged. If so, they are ions.
In homolytic bond breaking each fragment retains one of the bonding pair
of electrons. These fragments are called radicals.
Dn 6 —_——— Xe BOY,
 Foundations of organic chemistry 19
2.2 Nucleophiles, electrophiles, radicals

It is useful to classify the chemicals with which organic molecules react.

Leaving acid/base and some redox reactions on one side for the time being,
we find that there are three types of reagent to deal with.

Most nucleophiles are molecules or ions with a nonbonded pair of

electrons (see p. 10), with which they can form a new dative bond. They are
‘electron rich’. Some examples are:

HO : OH :Br? 2CN: : NH; CH;CH)NH> CH3CH,OH

We can look at the reaction of the triphenylmethyl cation with hydroxide

ion, following the nonbonded pair.

pair

It is a common mistake to suppose that nucleophiles must be negatively

charged, forgetting that the critical thing that many of them have in
common is a nonbonded pair. Textbooks and papers do not help the
beginner by leaving them out most of the time, assuming that everyone
knows they are there. We shall do so ourselves in due course, but you need
to remember where the nonbonded pairs are when you write mechanisms.

Electrophiles represent the other side of the coin. They are molecules or
ions which are prepared to form a new covalent bond using a pair of CHs
electrons provided by another atom or molecule, often the organic reactant. ‘:Br * HOC
Some examples are shown in the margin. CH;
Sometimes the electrophiles, such as the three positively charged
examples, actually have an empty bonding orbital available at low enough
energy to accept the incoming pair of electrons. Uncharged electrophilic St 8
molecules are either polarized, e.g. HBr, or can be so readily, e.g. Bro. H—Br Br—— Br

The addition of a proton, H*, to an alkene will show how the first kind
operates. The 7 electron pair on the alkene is shown as asterisks (*) for
emphasis.

Nuc’ tut oc
/ 4 \ H
this pair forms
the new bond
20 Mechanisms

In other cases heterolytic bond breakage in the electrophile makes an

empty orbital available.

Ng
OGG wh es
~ : Ct 3 SBrl
‘

H shee x. oe

> Br:

The 7 electron pair forms a new bond to the hydrogen atom while the HBr
bond breaks heterolytically (see p. 18). The bromine atom of HBr becomes
a bromide ion, carrying both of the original shared pair of electrons.

A radical carries an unpaired electron. Radicals are usually written with a

dot to show these unpaired electrons.
It is worth drawing a full dot diagram for each of these to check the
electron bookkeeping, and to show that they are electron deficient.

i @lirs = -Br:
oe
atc

2.3 Drawing mechanisms using dot diagrams and curly

arrows

Curly arrows ~~‘ and fishhooks ( \ are the conventional ways of

depicting electron movements for pairs of electrons and single electrons
respectively. We use ~~ for ionic (or polar) reaction mechanisms, that is,
those involving nucleophiles and electrophiles. Bond breakage in these
reactions results in the bonding pair of electrons remaining associated with
only one of the atoms which were originally bonded so this is heterolytic
bond breakage.

yee - +
CHs
c+
Bree CH; —— Bis
N mara
CH; CH; CH3

The pair of electrons in the breaking C—Br bond go to the bromine atom,
forming a bromide ion. The positively charged carbon is short of electrons
(electron deficient). The C—Br bond has broken heterolytically.
Curly arrows ~— can be used for bond breaking, bond making, and for
both making and breaking together.

Examples: bond breaking H Le —» 4H ze AGI

ae
bond making PNY SH SS HN
+ as
both H,N:” “CH, Ce ee H3;N—CH; + Cl
 Foundations of organic chemistry 21
In each case a curly arrow must start from an electron pair, either a bonding
or nonbonded pair, and end on an atom or in a new bond.
We use (Y for radical reactions, where it represents the movement of a
single electron.

Ruste eye x Santee SoS ie + Br?

ee ee energy ee ee

or:

(aN ligh
s Br aE = Br°* 2. ° Br

In radical reactions bond breakage leaves one of the bonding electrons on

each of the originally bonded atoms. This is homolytic cleavage. Again,
(Y can be used for making as well as breaking bonds.
We can show both types, ionic and radical, using full dot diagrams. It is
probably a good idea to draw each mechanism in both ways until it becomes
familiar.
Here is a nucleophile in action.
Dot version:

Nee CH . sos feces

lee XOrS 3k ISIE (Cs Bes HO 7 GacH + SUB Tans
ee H ° ee H ee

By emphasizing the electron pairs involved with different coloured pens we

can follow what is going on. This is for our convenience; the four pairs in the
bromide ion outer shell are quite indistinguishable from each other.
Compare this with the shorthand curly arrow version.
Curly arrow version:
H
= CH a sCH3 as
HO: CBr ——> HO=C + ‘Br
ee
H H

You will frequently find such mechanisms drawn without the nonbonded
pair on the hydroxyl ion. This nonbonded pair is going to form the new
bond, a dative one, to carbon while the C—Br bond breaks heterolytically
with the bonding pair of electrons going off on the bromide ion as it leaves.
Curly arrows show electron pairs going places.
An electrophilic reaction is shown below. Notice the asterisk pairs.

H H In this reaction the right-hand carbon

Dot version: “c foe C Isl
fe . ee
Jl atom of ethene loses a half-share in
oe
u Ase HON ee Er50
ek
the asterisk pair of electrons. Since
is et panats formally it loses one electron from an
tes Br H
2K ok
uncharged state, the carbon must
4 IBBE become positively charged.
oo

The advantage of this method is that it helps us to see clearly why the right-
hand carbon atom in the carbocation carries a positive charge.
22 Mechanisms

Curly arrows are also used to relate Curly arrow version:

resonance structures to each other,
H H H
e.g. for the methanoate ion (see p. 5): Ny / \ / =
C=C —— Wi Caer + Br
H H / , \ | \
\ = \
iS £6 <= S =O Br
/,
Q) Ol ¢@
Br
and for benzene:
In the same way we can use either dot or fishhook versions of radical

Os
mechanisms, as for example in the reaction of methane with a chlorine
radical.
Dot version:

SCI SLB (G) 3isl pe Alok wictee donGereved etc

ee H ee af

Fishhook version:

H H
! SN
cl WRC“ H ee ke
H H
Curly arrow and fishhook mechanisms are simple descriptions. They need
to be based on real experimental evidence, such as kinetics, isolation of
intermediates and radioactive tracer experiments. Like all good theories
they must be firmly based on fact.

2.4 Introduction: equilibria and rates

For all chemical reactions there are two vital questions to be answered.

1. How much product can be made?

2. How fast will it be made?

‘How much’ is determined by the equilibrium constant for the reaction at

a particular temperature. This is related to what are called thermodynamic
factors (see p. 23).
‘How fast?’ is determined by the rate constant at a particular temperature
and what we call kinetic factors (see p. 24).
Organic chemists are interested in the answers to both questions because
they wish to obtain the maximum yield of a desired product, as fast as
possible. Some idea of how the bond breaking and bond making happens
would be useful. This is the heart of the reaction mechanism, which must fit
the observed facts about how much and how fast.
 Foundations of organic chemistry 23

How much can be made? Equilibrium and energy profiles

Equilibrium. Some reactions seem to go to completion. This means that
when the dust settles there are only products to be seen.
O
4 4
€.g. CH; —C ota H,0 a CH, —- Se + HCl

i OH
In other reactions both starting materials and products are there at the end.
The classic organic example is acid-catalysed esterification.

oe Ht 4
CH; = & + C)H;0H Ola ee + H,0

OH OC)Hs
In fact the reaction is still going on at the apparent end, but with equal
rate in each direction. There is no further change in concentration of
products or reactants once the reaction has reached this dynamic equili-
brium. The concentrations of products and reactants at this point are related
by the equilibrium constant, K,, which is constant at any particular
temperature. For this example

[CH;COOC)Hs] [H20]
K,=
[CH;COOH] [C)H;OH]
= 0.26 at 373K

The [ ]terms refer to concentrations in mol dm~?.

A high value of the equilibrium constant, K,, would show that there will
be a high proportion of products in the equilibrium mixture. A low value
would indicate a low proportion of products at equilibrium.
Energy profiles. A simplified energy profile for a reaction shows the
difference in energy between the reactants and products.
This reaction is thermodynamically
reactants Bees se ctee favourable.

energy energy
change

products

progress of reaction ——»

The ‘energy change’ for a reaction is related to its equilibrium constant by

the expression

Energy change = — R7InK

24 Mechanisms

where R is the gas constant (8.3 JK~'mol~*) and T is the temperature in

kelvin. We can see that a large energy drop (—) in going from reactants to
products will correspond to a high value of the equilibrium constant K
This good yield can only be realized if (greater than 1) and the reaction can give a good yield of product.
the reaction is fast enough (see next An energy increase (+), on the other hand
section).

products

energy energy
This reaction is thermodynamically change
unfavourable. reactants

progress of reaction =>

will give a low value of K (less than 1) and there will be a low proportion of
product in the equilibrium mixture.
In a special case there is no energy change. What do you think would be
the implications for equilibrium constant and yield of product in this case?

energy reactants products

progress of reaction =>

For many reactions in solution the enthalpy changes, AH, can act as a guide
to the energy changes and, hence, to where the equilibrium lies. But they
are only a rough guide.

How fast? Activation energy

Even reactions with large values of K are not instantaneous; they happen at
varying rates. What is involved in two molecules reacting?

1. They must meet or collide.

2. They must presumably approach each other lined up so that the bond
breaking and making process is made easy.

3. They must, between them, possess enough energy to get the reaction
started.
 Foundations of organic chemistry 25
A pen and its top can collide with each other from all directions.

BS

There is only one orientation which lets the top slip on, and they only stay
together if it is pushed on with enough energy.

[ere
—_—_—_> <—

For chemical reactions, the energy barrier is known as the activation energy,
E,. The height of the barrier determines how fast a thermodynamically
favourable reaction will go. Look at the reaction profiles below; the overall
energy change is the same in each case.

Note that the backward reaction, pro-

SLOW ducts —reactants, has a different
(and higher) activation energy in both
these cases.
FAST
energy energy

reactants

products products

progress of reaction => progress of reaction =>

A low value of E, will normally correspond to a rapid reaction, a high value

of E, to a slower one. A reaction may be extremely favourable in overall
energy terms, but very slow at low temperatures. For example, the
equilibrium constants for the oxidation of glucose or magnesium are both
large, but these substances are remarkably unreactive to oxygen at room
temperature. The reaction rates are very slow because the activation
energies are high.
There are two ways of speeding reactions up. Firstly we can heat the
reactants so that a higher proportion of them have the activation energy on
collision. This will give a higher proportion of successful collisions and
therefore a faster reaction. This can be seen on the Maxwell—Boltzmann
diagram (overleaf) which shows the distribution of kinetic energy in
molecules at two different temperatures.
26 Mechanisms

Maxwell—Boltzmann diagram to show Ty

l
the distribution of kinetic energy at
temperatures 7, and 75.

number of
molecules T
wo

kinetic energy —=—)>

You can see that at 7, the higher temperature, a higher proportion of

molecules has the activation energy, E,, or greater.
Secondly we can add a catalyst to the reaction mixture. The catalyst
provides an alternative reaction pathway, involving a different set of bond
breakings and makings, which has a lower activation energy. See p. 29.
Notice that the overall energy change and the equilibrium constant, K, are
unchanged. Looking back to the Maxwell—Boltzmann diagram above, we
can see that if we lower E, we will increase the proportion of molecules with
the activation energy or greater, without changing the temperature.
If we wish to oxidize glucose completely in the laboratory we can heat it in
air until it burns.
C6H 1206 a 60, = 6CO, + 6H20

However, every cell in our bodies can achieve this oxidation, at body
temperature, through a series of reactions, each one of which uses a specific
catalyst or enzyme. Another example is:
2H 702 a 2H20 ate Op

Both manganese(IV) oxide and the enzyme catalase in liver will make the
decomposition of hydrogen peroxide solution go faster, but catalase does it
about a million times faster than manganese(IV) oxide.

Kinetics and rate equations. Rate determining steps

Looking at kinetics shows us which factors influence the rates of chemical
reactions. We have already seen qualitatively how increasing temperature
can raise the rate of reaction by increasing the proportion of molecules with
enough energy to react—the activation energy (see p. 24). In the same way
reactant molecules are more likely to collide if there are more of them about
in a given volume. One would expect more concentrated reactants to react
faster. The exact dependence of the rate of a reaction on the concentration
of the reactants is found by experiment and is expressed in a rate equation.

A+B ——— C+D

k is the rate constant for the reaction. Initial rate is proportional to [A}‘[B)?’: Rate = A[A}‘[B)’
 Foundations of organic chemistry 27
Here x and y are powers that are found by experiment. They do not
necessarily bear any relationship to the balanced chemical equation at all, in
marked contrast to equilibrium constants.
Let us take as an example the reaction

CH3;COCH;
+I ——
CH)ICOCH;
+ HI

With acid catalysis the rate equation is found to be

Rate = k[CH3COCH
(aq) [H™ (aq)| Reaction rates are usually expressed
as rates of change of concentrations.
The iodine does not appear in the equation at all. With all the powers in we
would write

Rate = k[CH3COCHa(aq)] : [H* (aq) : [Toraqy]°

The reaction is then said to be first order with respect to propanone, first
order with respect to hydrogen ions, and zero order with respect to iodine. It
is second order (1 + 1 +0) overall, because the sum of all the powers in the
rate equation is 2.
The proportionality constant k in the rate equation is known as the rate
constant and is a characteristic of a particular reaction at a given
temperature.
The mathematical relationship between E,, the temperature 7, and the
rate constant k for a reaction is given by the Arrhenius equation:

k= Ae "RT (R=8.3JK~'mol”*)
The exponential factor, e£a’"’, is the
Increasing T makes E,/RT smaller and therefore e~ £a/®7 gets larger, and k fraction of molecules possessing at
gets larger. least the activation energy E,. This
For many reactions it is possible to devise experiments which allow us to corresponds to the area to the right of
deduce the experimental rate equation. What does it tell us? the E, vertical line on the diagram on
The actual sequence of bond breaking and making in the reaction is likely p. 26.
to take place in a number of stages, some fast and others slow. The slowest A is the frequency factor. It can be
expressed as the product PZ, where
stage will act as a bottle-neck for the reaction and dictates the overall rate,
P is a steric factor and Z is the total
so it is called the rate-determining step. number of collisions per second of the
The substances involved in or before the rate-determining step will appear reactant molecules.
in the rate equation for the reaction. You can now see how the Arrhen-
For example, the nitration of 1,3,5-trimethylbenzene has first order ius equation relates to our pen-and-
kinetics. top analogy at the beginning of the
section.

——S>>

CH3 4 CH; CH; ’ CH3

The rate is proportional to [HNOs3], but is independent of the concentration

of trimethylbenzene. These data fit a mechanism in which the formation of
28 Mechanisms

the nitronium ion, NO,*, from nitric acid is the slow or rate-determining
step. The rate of the slow step dictates the rate of reaction. Nitration is
discussed further on p. 70.
If we understand something of the kinetics and mechanism of a reaction,
we may be able to see how to increase the rate of a slow stage to give us
more of the desired product.

Intermediates and transition states

What exactly is the activation energy? What is happening at the top of the
energy hump? In the substitution reaction
CH;CH,CH,CH,Br+ OH 9 —» CH;CH,CH,CH,OH + Br _
the C—Br bond begins to break at the same time as the C—OH bond begins
to form.
energy
There comes a point when the C—Br bond is weakened and the new C—
OH bond is only partly formed. At this point we are poised on an energy
reactants
maximum from which it is downhill in any direction, either back to C—Br
and OH™ or on to C—OH and Br. The energy we have invested so far is
products
the activation energy, E,. We refer to this maximum energy (downhill either
progress of reaction [=> way) state as the transition state.

There is an overall charge of —1 on HH H

the transition state, which is shown

em gle Ree s,H 2
HO~ “CrBr —» | HO---- C----- Br — > HO-C + Br
with two partial negative charges (8—) |
C3H7 C3H, C3H7
in the diagram. See p.12 for the
shape of TS.
The TRANSITION STATE,
TS

Transition states cannot be detected. We presume they are there because of

the energy barrier.
You can create a model for this by partially inflating one of those
‘sausage’ balloons with separate panels as in (1).

1. reactant 2. ‘transition state’ 3. product

Now squeeze the air into the second panel. Part-way through this process
you will suddenly feel that the balloon is poised (2). A tiny extra squeeze
sends the air on into the next panel (3); a slight relaxation lets it back into
the first (1). This in-between position (2) is like the transition state. If you
let the balloon go, the air always goes to one end or the other. But the
balloon has got to go through the ‘transition state’ if the air is to be shifted
from one end to the other.
Now we can extend this idea to a balloon with three panels, the reaction
being to get the air from the left hand panel into the one on the right. You
 Foundations of organic chemistry 29

4. reactant 5. ‘intermediate’ 6. product

will have noticed that the reaction happens in two stages with the air-in-the-
middle (5) being an intermediate stage. Each step in squeezing the air across A catalysed reaction may involve an
will have a ‘transition state’ as before. On an energy profile it would look extra intermediate (or intermediates)
like this. in this way.

uncatalysed
transition state |
+
ve

transition state 2 catalysed

,

energy intermediate
reactants
energy
intermediate

reactants progress of reaction =——)>

products

progress of reaction SS

Each step has its own activation energy and its own transition state. Here the
first stage is rate-determining because E,, > E,2. The intermediate itself has
a finite existence, and can sometimes be detected or even isolated in the
absence of nucleophiles such as hydroxide ions. Here is an example.

OHO ia
= OH

CLO. e:

intermediate
(carbocation)
The carbocation is the intermediate. It has been isolated as a crystalline
chlorate (VII) salt. We shall see more of these carbocations in later chap- + =
C7 cio;
ters.

How far or how fast? Thermodynamic or kinetic control

So far in this section we have only asked two simple questions about our
reactions.
1. Is the reaction likely to go on thermodynamic (or energy) grounds?

2. If the answer to the first question is yes, will the reaction go at a

reasonable rate?
30 Mechanisms

Now suppose that there is more than one set of possible products. The
reaction of A+ B can go to give either C+ D or E+F as products. Which
will we get and why? Let us look at the reaction profiles.

energy AxB energy | AaB

E+F

progress of reaction progress of reaction

We should get the most energetically favourable products, E+F in this

case, if all the reactions have reached equilibrium. This would be
thermodynamic control. Even if the reactions were not at equilibrium the
activation energy for A+B going to E+ F is smaller than that for A+B
going to C+D. As a result the A+ B to E+ F reaction is also the faster.
A+B to E+F is favoured on both thermodynamic (energy) and kinetic
(rate) grounds.
Now we will look at another possibility. Suppose the activation energy for
A+B going to C+ D were less than that for A+ B going to E+ F. What
products would we get then?

energy A+B energy A+B

E+F

progress of reaction progress of reaction

Here the anaes controlled product at equilibrium ahve

be
mostly E + F, but the reaction rate to C + D will be faster (kinetic control).
Keeping the temperature down will give mostly C+D, because few
molecules will have enough energy for the E+F reaction. Raising the
temperature gives enough energy for both reactions and their reverse; that
is, they will be at equilibrium and we will get mostly E + F (thermodynamic
control). An example of this is the sulphonation of naphthalene.
 Foundations of organic chemistry 31

SO3H

conc. H2SO, eS Sulponation is useful because it intro-

duces the acidic SO3H group, which
= is easily converted by neutralization
IO into salts. e.g. SO3Na‘.
over
This means that the resulting mole-
SO3H
cules are more likely to be water-
conc. H»SO,4 ©
soluble (see p. 15). Many detergents
120°C
have long hydrocarbon tails with
—SO3 end-groups.
Which is the lower energy product? Which is produced by the faster
reaction? Check your understanding by working out the probable products
in the special case where the activation energies for the two possible
reactions are the same. You can assume that all the reactions involved are
reversible.

energy IN #8) energy en)

E+F

progress of reaction => progress of reaction =>

2.5 How do we get the products we want?

Chemists become quite subtle in the way they arrange for the desired
outcome, even with familiar reactions.

CH;CH,OH —* _ CH;CHO — CH,COOH

Look up the boiling points of ethanol,
Ethanol is readily oxidized to ethanal by heating with acidified potassium ethanal, and ethanoic acid, and see
chromate(VII). Ethanal is even more readily oxidized under the same why this works. Rationalize the
conditions. The problem is how to get a good yield of ethanal. The solution pattern in these boiling points (see
bid):
is to remove it from the mixture, by distillation, as soon as it is formed.
Plants and animals go one better by using, as catalysts, enzymes specific for
the first reaction but not the second. These are known as alcohol
dehydrogenases.
32 Mechanisms

Changing solvent can also lead to different products.

SUBSTITUTION OH
aqueous KOH CH3CHCH,CH;

Br
CH3;CHCH2CH3

hot alcoholic KOH CH3CH = CHCH;

ELIMINATION

We can prepare either the alcohol or the alkene by changing the conditions.
Look also at the two ways of brominating methylbenzene on p. 78.
3 Acids and bases
3.1 Introduction

The Brgnsted—Lowry theory states that acids are proton donors, and bases
proton acceptors. Chemists use the term ‘proton’ for the hydrogen ion, H*.
We will start by looking at acids and bases in water.

HClag) = H20q)
HzO"
(aq) + Cl (ag)
acid base

Hydrogen chloride forms ions, or dissociates, readily in water with each

HCI molecule donating its proton, H*, to water. The HCl acts as an acid, Hoo: 4H =entOH
the H,O as a base. The new O—H bond is formed using a nonbonded pair
on the oxygen of H2O; it is a dative bond.
Ammonia on the other hand acts as a base, whilst the water this time
behaves as an acid:
+ —

NH3(aq) + H2Oq) == = —NAiavag) + OH (a)

base acid

We use pairs of half arrows, ——, to represent equilibria. Acid/base

reactions are largely equilibria and are therefore under thermodynamic
control (see p. 29).

3.2 Equilibrium constants

A strong acid, such as HCl, is fully dissociated into its ions in water. The
equilibrium constant for this acid dissociation is very large, and the system
settles almost entirely on the right:
HCl + H,0 H,0* + Cl
Many organic acids, such as ethanoic acid, are weak acids. The
equilibrium constants are small, much less than 1, and remarkably little of
the acid donates its proton, H*, to water in aqueous solution.
~ +
CH3COOH (aq) + H20,) CH3COO (aq) t H30(aq)

The equilibrium lies towards the left. The acid dissociation equilibrium
constant is K,.

[CH;COOX (ag)] [H3O* (aap

Fag ae a i Sk ere
[CH;COOH (aq)]
= 1.7 x 107~> mol dm~? at 298K
34 Acids and bases

The calculation shows that, in ethanoic acid (0.1 mol dm~°), the hydrogen ion
pH = — logso[H30* (aq)]
concentration is only 1.3 x 10-3 mol dm7?. This corresponds to a pH of 2.9.
Hydrochloric acid of the same concentration has a pH of 1.0.
Most organic bases, like ammonia itself, are weak bases. We can write
equations, similar to those for acids, to show how they act as bases in water.
ae =
CH3COOH (aq) + H20,)
CyH5NH (a9) + H20q) C2H5NH3 (aq) ap OF (aq)
no. of moles: 0.1-x \
K, is the equilibrium constant for base action in water.
= “te
CH;,COO (aq) ot H30 (ag)

no. of moles: x x % [CoH5NH3* (aq)] [OH (aq)]

b= A
ee

[CoHsNHaqaq)]
[CH;COOH,.,)
It is often more convenient to look at bases from the other end of the
ee es ee tT ek equation, that is to consider the acid dissociation of their conjugate acids,
Owe x
the protonated forms.
Because x is very small, we can put ae +
C2HsNH3(aq) + H20q) = CoHsNHa(aq)_ + H3O0(aq)
Ko) ves VIRMO™. conjugate acid
0.1
Now use K, for the conjugate acid, C;H;NH;3°.
Thus x = 1.3x10° moldm”.

K [CoHsNHacaq)] [H30* (aqy]

a = Se

[CsHsNH3"* (aq)]

The relationship between K, and K, for any conjugate acid/base pair is

surprisingly simple. Multiply the expressions for K, and Ky, above, together
and cancel to arrive at

K,Kp = [H30* (aq)] [OH (aq)

= K,,, the ionic product of water

K,, has a value of 107!4mol? dm~° at 298 K.

For convenience K, and Ky are often used in the log form:

pK, = —logioK,
pKy = —logioKy

For a conjugate acid/base pair at 298K, pK, + pK, = 14. Large values of
either pK, or pK, correspond to weakness.
There is a useful consequence of this relationship. The conjugate base of
a strong acid will be a weak base.
ae *
HCl(aq) ap H20,q) H30(aq) + Cl (aq)

HCl is very strong acid; chloride ion, Cl, is a very weak base.
 Foundations of organic chemistry 35
+ _

HCN aq) op H20q) 7 30 (aq) TN (aq)

HCN is a fairly weak acid (K, = 4.9 x 107!° moldm~3). This makes cyanide
ion, CN”, a moderate base (K, = 2.0 x 107° mol dma*); Ethanol is a very
weak acid (K, = 10'*moldm~°), so ethoxide ion is strongly basic.
i = +
C2HsO0H (aq) ate H20q) ~~ C2H5O0 (aq) at H30 (aq)

3.3 Solubility
Many organic acids and bases are largely insoluble in water. Benzoic acid,
for example, is only slightly soluble in cold water. It is also a weak acid,
which means that only a small proportion of the dissolved benzoic acid will
ionize as an acid.

——— ie ot
C6HsCOOH (ag) + H20,q) er ee CeHsCOO (aq) + H30 (aq)

Addition of an alkali, like NaOH, will remove H30* from the system by SOLUBLE ASPIRIN is the sodium
neutralizing it to give water. The system will shift to the right to replace the __Salt of aspirin (see p. 1).
H30* and more undissolved benzoic acid will be able to go into solution. | Why is this more soluble than
Very shortly all the benzoic acid will dissolve in excess alkali to give sodium SP!"in itself?
benzoate in solution. OCOCH;
You might like to work through the similar argument which shows how
phenylamine, CsHsNHp, although relatively insoluble in water, dissolves COG
freely in hydrochloric acid.

3.4 Reactivity of bases as leaving groups and nucleophiles

We can now try to use the acidity of the acid HX to get an idea of the ability
of X~ as a leaving group in nucleophilic substitution, since both equations
have X~ on the right hand side.
cf =
HX + H,O === H30 + X

5 2 ss E
Ng ae ae —s Nu—c Fae a

Although the second is a kinetically controlled reaction whereas the first is a

thermodynamically controlled equilibrium, one can provide a guide to the
other. The best leaving groups are often the conjugate bases of strong acids.
Thus Br~ and Cl leave readily, CH3;COO less readily and OH, the base
corresponding to the very weak acid H,O, much less readily. This neatly
explains the idea of protonating alcohols, with strong acid, to make them
more open to nucleophilic attack; H,O, the base corresponding to the
strong acid H3O*, is a much better leaving group than OH . (The reaction
is explained in more detail on p. 44.)
36 =©Acids and bases

Action as a base involves electron Nitriles (e.g. CH3CN), on reaction with alkali, do not lose CN™ but are
pair donation to H*. Nucleophilic re- converted to salts of the corresponding carboxylic acids (e.g. CH;COO-
actions may involve electron pair Na*). This is because HCN is a weak acid, and CN” a poor leaving group.
donation to other atoms, such as
Nucleophilic addition to C=N is faster.
carbon. Can we relate base strength
to nucleophilic reactivity? Here are
Ethers, such as C;H3;—-O—C>Hs, are resistant to nucleophilic attack
some comparisons: because C,H;O, as the base corresponding to the very weak acid ethanol,
is an extremely poor leaving group.
Base strength: You will not be surprised to find also that the best nucleophiles are often
CzHs07 > OH~ > CN7> CI the bases corresponding to the weak acids. Thus OH”, CH3;0, CN, and
Nucleophilic reactivity: CH3COO «are all good nucleophiles.
CN- > CsH,0- > OH- > CI- This is a useful guide. It cannot be more than that because we are trying
The concepts are linked but are not
to compare two situations that are very different.
the same. Nucleophilic reactivity is
measured by the rate of reaction,
whereas base strength is measured by 3.5 Acid strengths compared
the equilibrium constant, Ky.
Acid strengths, recorded as K, and pK, values in aqueous solution, are
given in Table 3.1. These are found by experiment.

Table 3.1

Calculate the value of pK, for water

Acid K,(moldm~*) pK,
(this may not be as simple as it
seems!) Ethanol CH3CH,OH_ 1.3 x 107!° 15.9
Phenol CsH;0H Paci 9.9
Hydrogen cyanide HCN 4.9°« 1077” 9.3
Ethanoic acid CH;COOH __1.7x 1075 4.8
Methanoic acid HCOOH 6p Ome 3.8
Sulphuric acid H)SO, ~ 10° -3

Deduce which of the three OH groups

of ADRENALIN is the /east acidic. It is probably impossible to account for all the differences with a single
satisfying theory. This is largely because such an account would need more
data than we have available for even one case.
We can start by drawing an energy profile (see p. 23) for a generalized
example of an acid dissociation.
+ ats.

HX (aq) i H20q)
H30 (aq) + X(aq)

+ HX (aq) + H20q)

energy energy
change
+ =
H3O0(aq) + X(aq)

progress of reaction, ==)

 Foundations of organic chemistry 37
The energy change between reactants and products labelled in the diagram
is the crucial factor. The larger, and more negative, the value of the energy
difference, the higher the value of K,, and the stronger the acid. To
compare acid strengths, it is the energy differences between HX(aq) and
X"(aq) that we should be looking at. Anything which makes X™(aq) More
stable (that is of lower energy) will strengthen the acid. Anything which
makes HX (aq) less stable (that is of higher energy) will have the same effect.
There are three approaches we can use in trying to explain the different K,
values of organic compounds.
TENORMIN has CH, NH, and OH
1. The electronegativity of the atom carrying the negative charge in the anion groups. Which is the most acidic
X~. For most organic acids this is oxygen. Compounds without an hydrogen in the molecule? Tenormin
electronegative atom are not usually acidic, although they can be. The _'$ 4 drug used in the treatment of high
pK, for methane, for example, is 40; it is not acidic. plood pressure, angina, and = oe
heart rhythms. It acts selectively on
the heart.
2. Delocalization of the negative charge in the anion X” will stabilize the
anion relative to the parent acid. ay

3. Effects of solvent, or solvation effects, are important but hard to

quantify. HCl, for example, does not dissociate into ions much in the gas N
phase or in solution in methylbenzene, in spite of behaving as a very CH3
strong acid in water. OH

For most organic acids the energy change for dissociation in water is small
and positive. This means that the equilibrium constant, K,, is small and
certainly less than 1, as can be seen in Table 3.1. They are all weak acids.
We can now compare them and try to find reasons for their different K,
values, using the approaches listed above. As explanations they are not
fundamental but they do well as guides.
Let us start with ethanol, CH3;CH,OH, and ethanoic acid, CH;COOH.
Why should the latter be the better acid? Here the possibility of /!
delocalization in the ethanoate anion (right) makes it reasonably stable with N
respect to the parent ethanoic acid. A delocalized system involves greater O
stability, i.e. Jower energy, than expected from isolated single and double
bonds.
Such help from delocalization is not possible for the ethanol/ethoxide CH;CH, — O-
system.
In the same way phenol, CsH5OH, is a stronger acid than ethanol because
of the possibility of extended delocalization in the phenoxide ion.
Why is phenol a weaker acid than ethanoic? Here we use the idea that
delocalization is more effective for the anion which can delocalize the
charge over the most oxygen atoms. Ethanoic acid wins! In the same way
OH
\
H,0 + H7SO4 eae Oe emus + H30*

H,O0 + HSO3 —— = ake 4 H30*

38 Acids and bases

sulphuric acid is stronger than sulphurous acid because there are three
oxygens involved in the delocalization and not just two. Nitric and nitrous
acids can be compared similarly.

3.6 Base strengths compared

The pK, values for a number of organic bases are shown in Table 3.2.
Table 3.2
PHENTERMINE is a drug used to
suppress appetite. Do you think its Base pky
pKy is nearer 9 or 4?
Phenylamine Ce6H;sNH>2 9.4
NH) Ammonia NH3 4.8
Trimethylamine (CH3)3N 4.2
CH; CH3 Ethylamine CH3CH,NH, 3.4

The values for the various al/kylamines are very similar, and it seems likely
that solvent effects are important in creating the small differences that are
observed.
Phenylamine is notably weak because of the inclusion of the nonbonded
pair of electrons on the nitrogen in the delocalization. Making this pair of
electrons available for bonding to H* would involve loss of the extra
delocalization energy. Therefore phenylamine is a weak base.

3.7 Amino acids

Amino acids are the building blocks of proteins, compounds which have
major structural and catalytic roles in all living organisms.
+ = aE - + =
H3NCH,COO H,;NCHCOO H3;3NCHCOO

CH; CH2SCH3
glycine alanine methionine

They all have the H;N*CHCOO™ group containing both a protonated

amino group and a carboxylate anion. The structures shown above are
Uncharged structures, such as charged. Why?
H2NCH2COOH, are frequently shown
We need to start by looking at a model for each end separately; first,
in textbooks to emphasize the amino
and carboxylic acid functional groups.
CH3COOH.
- +
Nevertheless they mostly exist in their CH3COOH(aq) + HO faq) === CH COO),.f PHC.)
charged forms, with a very small
fraction of uncharged molecules at bee [CH3COO “(aq)] [H30*
(aq)
equilibrium.
[CH3COOH
caq)]
From the equation it is clear that for a given weak acid the ratio
[CH3COO “(aq)]/[CH3COOH(aq)] is very sensitive to the hydrogen ion
concentration, or pH.
 Foundations of organic chemistry 39

At a pH value exactly equal to the pK,, 4.78 for ethanoic acid, the base/ This argument can be demonstrated
acid ratio will be 1. If the pH drops by 2 units, caused by added acid, 99% easily using the log form of the equil-
will be in the —-COOH form. Likewise, if the pH rises by 2 units above the ibrium expression, known as the
Henderson equation.
pK,, to 6.78 in this case, 99% will be in the -COO™ form. So at pH 7 we
CH3COO,
can write itas —-COO-. pH = pK, + logio [cH3CO0 ool
The nitrogen end can be given the same treatment and you should work |CHyCOOH
cag)
through it for methylamine, CH3NH)y. It will be easier to consider it starting
At a pH 2 units below the pK, we have
from the conjugate acid, CH;NH3*, whose pK, value is 10.6. You will
discover that at pH values below 8.5, the compound is mostly in its
pK, = 2 =
protonated form, CH3NH;". This is therefore the predominant form at pH
ch
Now look at the amino acids shown on p. 38. If we start, theoretically, [CH3COOH
4g)
with one —NH) and one —COOH group as in H2N—CH,—COOH, we can
show that in aqueous solution around pH 7.0 they will exist as the doubly
charged structures, e.g. H3N*—CH,—COO, as shown. This is also the Thus logy {CtHICOO cea} =9
form that they take in the crystalline state. |CH3COOH (aa)]
We can now follow what happens to glycine, for example, as we change
the pH of its solution:
and so [CH3C00 aa] = a
[CH3COOH
(4)| 100
H3N*CH,COOH H3N*CH,COO”- H,NCH,COO-
You should work through the calcu-
low pH pH7 high pH lations for pH 6.78 in the same way.
acidic solution neutral alkaline solution.

The structure H,NCH,COOH is never the major species in aqueous + =

solution. HyN~ (4, COO
Several amino acids have acidic or basic side-chains which are also |
Hoey)
involved in acid/base equilibria as the pH is changed, e.g:
NH;*
s aspartate
+ =
HN. 4, —COOH H3N~ 4, e -COO H oN c“4 = COO

ie te =
| |

COOH COO coo

low pH eS eS high pH

valine

You should try drawing similar diagrams for the three amino acids in the + e
margin. H3N~ Gy -COO
At physiological pH, around 7, any free acid or amino ends in a protein l
will be charged. These charges are vital in maintaining the three CH,
dimensional structure of the protein. They can also be important in binding
the substrate to the enzyme, and in the catalytic action which follows. Quite
small changes in pH can alter the distribution of charge in the protein,
usually disastrously. Most of your enzymes only work well over a narrow pH
range, e.g. around pH 8 in the gut and mouth and around pH 2 in the
OH
tyrosine
stomach.
 4 Reactions with nucleophiles
4.1 Introduction: nucleophiles

Nucleophiles are ‘electron rich’ and have either nonbonded pairs of

electrons or 7 bonds. They can be anions or neutral molecules. Examples are

NUCLEOPHILIC ANIONS: [HG] unually wrinen as HO or OH

|:N=C:|~ usually writenasNC”orCN

NUCLEOPHILIC NEUTRAL MOLECULES: H,6, CH;OH, NH3, CH;CH,NH.

H,C=CH,, CHyCH=CH).

Nucleophiles can react with species which have either positive charge or low
electron density. This is the basis of many reactions, which begin with the
transfer of electron density from the more electron-rich atom (in the
nucleophile) to the more electron-deficient atom (in the electrophile). An
example is the reaction of ammonia with bromoethane.
H3N¢ ae H,C — br S007 HyN— ae Br
/
H3C CH,
Nucleophiles and bases
Nucleophiles are also bases (see pp.33 and 35) because they react with
protons, Ht. Ammonia can also act as a base:

i. g
HN? HCO = NI

Basicity and nucleophilicity are linked but are not the same.

Nucleophiles need electrophiles for reaction

A new bond can be formed as a nucleophilic reagent approaches an
electrophile. Many organic molecules contain electrophilic carbon atoms,
which are positively polarized because they are bonded to a more electro-
negative atom such as Cl, Br, or O (see p.6). The electrons in the C—X
bond are not evenly distributed between the two atoms and the electro-
a = 056 -
negative atom readily bears a full or partial negative charge, 8”. Examples
are the haloalkanes and carbonyl compounds. Evidence for this polarization
comes from the high boiling points of these compounds compared with
hydrocarbons of similar size and shape (see p. 15).
We shall divide these 8* carbon electrophiles into three groups and then
look at their reactions with nucleophiles,
 Foundations of organic chemistry 41
Group A. Haloalkanes, e.g. CH3CH2Br, CHsI.

Group B. Aldehydes and ketones, e.g. HC H3C

Lc —'@ C=O
H H3C

Group C. Esters, carboxylic acids and their derivatives, e.g.

H3C \ H3C H3C

3

C=O C=O C=O

Z / /
OCH; OH cl

4.2 Nucleopnilic substitution reactions of haloalkanes

Bromoethane and hydroxide ion
When bromoethane is warmed with aqueous KOH, ethanol is produced.
This is a nucleophilic substitution reaction.
The nucleophilic hydroxide ion approaches the 5* carbon atom of the
C—Br bond. The new HO—C bond forms at the same time as the old C—Br
breaks. We can draw this mechanism using dot diagrams to show how a pair
of electrons on the oxygen atom forms the new bond to carbon, while the
bromine atom goes off (as bromide ion) with the C—Br bond pair.
- H H = In this mechanism, the hydroxide ion
H: i SO —— HlOl2CeH 4 SRr: is written as HO™ so that the non-
bonded pair of electrons on oxygen is
placed near the 5* carbon of the
haloalkane.
HO} + CH3CH,Br —s HOCH,CH3 + Br

This is usually abbreviated to a ‘curly arrow’ diagram (see p. 20).

=~ Hy s,H =
HO 72s Cra — HO-¢ + Br The first arrow shows a pair of
electrons from the oxygen making a
H3C CH,
covalent bond to carbon. The carbon
Remember that curly arrows start at a pair of electrons: a nonbonded pair already has eight electrons (a pair in
each of four bonds) in its outer shell;
for OH™~ and the C—Br bond pair in bromoethane. We are dealing with
so if a new pair is brought in, a pair
electron pairs so these are heterolytic reactions (see p. 18). must be lost at the same time. The
This is a single-stage reaction going via a transition state (TS) (see p. 28). pair the carbon loses to the Br is
shown by the second arrow.

Overall this TS must have ONE

Hit (oe : - oo Hy
Eom Bis eratpeheBOareane asks — = HO-C* + Br WHOLE negative charge, because it
is made from two species which
CH3
H3C CH; together have one negative charge.
42 Reactions with nucleophiles

The shape of the transition state TS is a trigonal bipyramid (see p. 12). The
transition state TS is unstable and is at an energy maximum.

TS
A reaction is more likely to go if its
transition state is of relatively low
energy.

ener
ee CH3CH Br

+ HO
CH3;CH,0OH
an Bde

progress of reaction ————>

Energy profile for CH3CH2Br + KOH going to CH3CH2OH + KBr

General mechanism
Alkoxide and phenoxide ions also
All the reactions in this and the following five sections follow similar
react with haloalkanes.
mechanisms. If we write Nu: or Nu: for the nucleophile and X for the
Draw the mechanism for the forma-
tion of 2,4-D leaving group, the general mechanisms are:

H
a CcN
Nui osc &X —— Neate" ab
Oo COOH
or
Cl
from
Nui SCL — NO Oe sua

Gl The nucleophile’s nonbonded pair forms the new Nu—C bond at the same
time as the leaving group (X) goes off with the C—X bonding pair. We can
OH
now apply this general mechanism to many similar reactions.
Cl Hy
7 Cy Other haloalkanes with hydroxide ion or water
and Cl COOH

Many other haloalkanes react with aqueous hydroxide ion to give alcohols
Cl
in the same way as bromoethane. For example, iodomethane gives
methanol and 2-chloropropane gives propan—2-0l.
in the presence of NaOH. 2,4-D is a
selective weedkiller for broadleaved H
= H3C,< 3CH3 =
weeds in grassland. HO7 CrCl —- HO-C til
pe \
HC CH;
Overall: NaOH + (CH3)2CHCI — (CH3)2CHOH + NaCl

The reactions of these haloalkanes with pure water are much slower than
their reactions with aqueous NaOH or KOH. Water with its non-bonded
pairs of electrons on oxygen is also a nucleophile, but a weaker one than the
negatively charged hydroxyl ion (see p. 35). «
 Foundations of organic chemistry 43
Cyanide ion, CN~
Cyanide ion reacts with haloalkanes in the same way as OH:
H H
Bisa SH 3 Here again the cyanide ion is drawn
NG Za Ce Bi eae NG + Br the other way round as NC~ to put
TX \
H3C CH; the nonbonded pair on the carbon
atom of the cyanide ion near the 8+ C
Overall: KCN + CH3CH,Br a CH3CH2CN + KBr of the haloalkane.
A new C—C bond is made in the product, which is a nitrile. These nitriles
are particularly interesting because they can be elaborated into other
organic compounds. An example using iodomethane is shown below.

LiAlH, CH;CH,NH,

=
KCN
CH31 ———————» (CH,CN
nucleophilic
substitution In an organic hydrolysis reaction,
conc. acid O
hydrolysi
ydrolysis CH; ea
water is involved both as reagent and
as solvent; the organic molecule is
OH split.

In this way complex molecules can be built up.

Ammonia and the amines

Ammonia, NH3, and the amines, such as ethylamine, CH3CH,NHz, are

nucleophiles because of the nonbonded pair of electrons on nitrogen. They
react with haloalkanes by nucleophilic substitution reactions to give salts:
e-2,
H H
CH,CH, —N: pee CrBr == CILCIL ae
N= Br
Hee tla wed Hye i
H3C CH,

Overall: CH3CH,2NH>) +
aa = Draw the mechanism for the prepara-
CH3CH,Br = CH3CH2NH7CH»CH; Br
tion of GLYPHOSATE
+ a
(compare NH3 + HCl ae INISY EN
H
If you want the product amine and not the salt, you can either treat the
HOGG No ee Pe
product with a strong base to liberate the weaker base (the amine) from its
salt
+ ~

CH3CH2NH2CH2CH3 Br PeOn CH3CH2NHCH,CH3 + KBr + H,0 from (e

Hy
or use excess ethylamine. O
ote a
ll
2CH3CH2NH2 te CH3CH Br —————o- CH3CH2,NHCH2CH3 ac CH3CH2NH3 Br and Cl pee OH
CC OH
The amine product is still a nucleophile, and can react again with H
bromoethane. This can lead to mixtures of products which are difficult to Glyphosate is used to control couch
separate. (Write the equations for these reactions.) grass in cereals.
44 Reactions with nucleophiles

The natural aminoacid, glycine, can be made by a nucleophilic substitu-

tion reaction of ammonia with chloroethanoic acid. The mechanism is
essentially the same as that of ethylamine with bromoethane.
H H
H a + Sy H _—

H3N er: Cl Bae H;N—C ry a

\ =
COO= COO
Chloroethanoate ion Glycine
(aminoethanoic acid)

4.3 Changing the leaving group: substitution reactions of

alcohols
So far we have used several different nucleophiles (OH ,H2O, CN’, NH3
and amines) to react with the haloalkanes, in which the leaving group
displaced is a halide ion (Cl-, Br” or I"). These are good leaving groups,
but for the alcohols OH is a poor leaving group (see p. 35). So, if we want
to do nucleophilic substitution reactions on alcohols, we will need to go
through a reactive intermediate which has a better leaving group than OH,
In a solution acidic enough to proto- such as water, H,O. We can do this by protonating the —OH of the alcohol
nate the leaving group, many nucleo- to make —-OH,”*. Alcohols can be made into bromoalkanes by reaction with
philes will themselves be protonated. HBr, which is made from a mixture of KBr and concentrated H2SOx,.
For example, ammonia would be
+ =
converted into the ammonium ion, HBr Ss H + Br
which has no nonbonded pair of a +
electrons and is not a nucleophile. CH3CH,0H +H = CH3CH 20H)

+ +
NH; + H ——
———_ NH,
H H
Thus an amine cannot be made B
E
Se Pee
as gia a eo
_—
\
i + H,O
2

directly from the alcohol with NHs3,

H3C CH;
even in the presence of acid.

Overall: CH;CH,OH + HBr — > CH;CH,Br + H,0

Phosphorus pentachloride reacts with alcohols in a similar way via a reactive

intermediate, CH;CH,OPCl,.

CH3CH20H + PCls — CH3CH20PCl, + HCl

intermediate

GIScl Gl
- He a BH faCl -
Cl ~~~ C=0—P—Cl a Cle + O=P Tel
page| \ \
H3C Cl CH; Cl

Overall: CH3CH,0OH + PCls — CH3CH,Cl + POC]; + HCl

We can use these reactions in longer sequences to build up complex

molecules, especially as the alcohols themselves can be prepared by
reduction of aldehydes, ketones, or acid derivatives.
 Foundations of organic chemistry 45

4.4 Polymerization of cyclic ethers

In the three-membered ring cyclic ether, HyC—CH, , the bond angles in

the ring (about 60°) are smaller than the normal bond angles in an open-
chain ether (about 110°). This makes the small-ring ether unstable and
reactive. It can react with nucleophiles such as OH.

/
HoC—CH, —» H»C—CH,
7

But the product is also a nucleophile and can attack another molecule of the
cyclic ether, and so on until a polymer is built up:
HO—CH2—CH,—O —CH,—CH2—O—CHz . . . The repeating unit is This cyclic ether can also be polymer-
CH,OCH), an ether, so the polymer is called a polyether. Polyethers are __ ized using an acid catalyst. Draw the
used for making surfactants. mechanism for this.

4.5 Two-stage nucleophilic substitution: the carbocation

intermediate

In all the reactions so far, the nucleophilic substitution has taken place in a
single stage and the new bond to carbon is made at the same time as the
leaving group’s bond is broken.

ees ee A Aa ‘A ;
Nu-*C X — Nu---C---X — = Nu-—-C + X

transition state

This is one of the commonest mechanisms for nucleophilic substitution.

However, for some compounds there is a lower energy, two-stage pathway
in which the leaving group goes first and the nucleophile attacks the carbon
afterwards. A positively charged, planar intermediate is formed, called a
carbocation.

First stage: SS x ee any cig + Xx

ionization / Lg

planar, trigonal
carbocation

Second stage: > = é i AS

nucleophile
: : reacts = yy,7"®C tuneg? SN Nu == Nu or Nit
with cation from
either side | a
46 Reactions with nucleophiles

Compare this two-stage reaction profile with the single-stage one (p. 42).

energy

progress of reaction SSS

You can guess that the halocompounds which react by this two-stage
mechanism will be the ones which can ionize to give low-energy, stable
carbocations. One example is (CH3)3CBr, a crowded halide which gives a
cation that is stabilized by inductive effects. A second example is
(C6Hs)3CBr, which is also crowded and whose cation can be
stabilized by the benzene rings.
x 4
(CgHs)3CBr — > (CgHs)3C + Br

The delocalization in each benzene CoH HsC

Se i. 2 : £ .CcHs
ring has been extended to include the
HO* Ce =o HO—C
positive charge on the central C atom.
HsCg CeHs \
This increased delocalization stabil-
izes the ion.
Notice that in (CgHs)3CBr the halogen atom is not attached directly to a
benzene ring, but is on the carbon next to the ring. Compounds such as
chlorobenzene and bromobenzene, which have the halogen atom directly
attached to the benzene ring, are very unreactive towards nucleophiles in
marked contrast to the other halocompounds we have seen so far.

4.6 Competition between nucleophilic substitution and

elimination
All our nucleophiles so far have reacted with electrophilic carbon atoms in
the organic molecules. Nucleophiles may also act as bases and remove a
proton from the haloalkane, causing elimination of hydrogen halide instead
of substitution. The product will then be an alkene. Hence two different
products can be obtained from the same haloalkane, by substitution or
elimination. For example, with 2-bromopropane and KOH, substitution gives
the alcohol (OH behaves as a nucleophile):
 Foundations of organic chemistry 47
H H
Ee . $4CH3 =
HO / Aes —— HO= 7 + Br

H3C CH;
Overall: KOH + (CH3).CHBr — > (CH3)2CHOH + KBr

and elimination gives the alkene (OH behaves as a base):

H
CH; a
i ~CEBr -
CH

Hig cies HaGe

H H
Overall: KOH + (CH3)2CHBr — > CH;CH=CH, + H,O + KBr
In the elimination, the C—H bond electrons go to form the new C=C
double bond. Elimination is more important if the haloalkane is very
crowded (e.g. (CH3)3CCl) and if hot alcoholic KOH is used.

4.7 Reactions of nucleophiles with aldehydes and ketones

Introduction to nucleophilic addition reactions

Because the positively-polarized carbon of the carbonyl group is part of a
double bond to oxygen (see Table 1.2), this time we get nucleophilic
addition instead of the nucleophilic substitution of the haloalkanes. The
displaced electrons of the m bond can go to the electronegative oxygen atom
to make a relatively stable tetrahedral intermediate carrying a negative
charge.
se
ue NOPYS= A
Nimans G =? — Nu—C
Draw a transition state for this reaction.
Tetrahedral
intermediate

To complete the addition, this intermediate can be protonated on the —O7

(see next subsection). It may then go on to eliminate water to give an
‘addition—elimination’ product (see p. 49).
Hydride ion donors, NaBH, and LiAlH4. Aldehydes can be reduced to
primary alcohols, and ketones to secondary alcohols, by either NaBH, or
LiAIH,. These two reducing agents can be considered as sources of RASPBERRY KETONE
nucleophilic hydride ion, H_, which adds to the carbonyl group: O
I
oO C
™“CHe
Bete SCH;
H ACG
ceev re gC
\ HO
H3C H3C is used in synthetic raspberry flavour-
Tetrahedral ings. Draw the mechanism for the
intermediate
reduction of raspberry ketone by
NaBH, in ethanol.
48 Reactions with nucleophiles

The addition is completed by protonation.

Lithium tetrahydridoaluminate, LiAlHy, reacts violently with water and
alcohols, so protonation is carried out after the reduction is complete.

i)H
Overall: (CH3)2CO —_— (CH3)2CHOH
then ii) H"(ag)
with great care

Hydrogen cyanide. HCN will also add to carbonyl compounds. This

involves nucleophilic addition of CN” then protonation by undissociated
HCN or the solvent.
H ae:
Nem ‘c= nomen
Ss eee \
H3C CH;
intermediate

H,: ef
$40 ay $,0H CN
NC— - H TN —> Ne— S ar

CH; CH;

H
i
Overall: CH;CHO + HCN — Cha oT OH
CN

Notice that the cyanide ion used in the addition is regenerated at the end; it
is a catalyst and strictly it is the HCN which is used up.
The best reagents for this HCN addition are a mixture of HCN and KCN,
formed by addition of cold sulphuric acid to KCN. HCN is a weak acid (see
p. 33); by itself it produces a very low concentration of cyanide ions and so
the reaction rate would be slow. Excess KCN is needed to increase the
reaction rate by raising the cyanide ion concentration. Alternatively, a small
amount of a base, such as KOH, can be added to react with HCN to
increase the concentration of CN.
Note that these are overall additi»ns of HCN. Contrast the conditions
used with those for cyanide ion substitutions on p. 43.
Uses. The HCN addition product, with its new C—C bond, offers scope for
further synthesis (see p. 43).

H3C
\_-OH-

H3C
hydrolysis
Sees
aa . EL ~COOH
H3C

\ KCN
+ H,SO Nee Ort
C=O pee (Oz
/ 7 CN
H H

reduction \ OH

H
 Foundations of organic chemistry 49

Introduction to nucleophilic addition—elimination reactions

These reactions involve a group of nucleophiles that carry two hydrogen
atoms on a nucleophilic nitrogen atom (—NHz2). This means that the usual
carbonyl addition product can then eliminate water to give an unsaturated
product. These are called addition—elimination (or condensation) reactions.
Hydrazine, H2NNHp>. This is a good nucleophile. It is better than
ammonia, NHs3, probably because of the repulsion between the nonbonded The structure of hydrazine is
pairs of electrons on adjacent N atoms. One of the nucleophilic nitrogen
H H
atoms uses its nonbonded pair to add to the carbonyl group (in the same /
way as H” and CN’ did). A tetrahedral intermediate (a) is formed as usual. :N—N:
This intermediate gains a proton on the —O™ and loses a proton from the / SON
—NH,*— group to give an uncharged addition product (b). We shall call
H H
this process, (a) to (b), a ‘gain-and-loss’ of protons. The uncharged
intermediate (b) then eliminates water to give the final product, a
hydrazone, which has a C=N double bond.
H3C
3
H3C
on addition Ho, 220
. é re PE ee 5 NaC
NH, / H,N aN
HN 3 CH;

: (a)

Si elimination Rome mS OH
N=c x
+ H,0 nec = \ Predict the structure of the product of
CH,
4

H)N CH, H,N the reaction of hydrazine NH2NH2

a hydrazone (b) with LILY-OF-THE-VALLEY ALDE-
HYDE.
.
a).
Overall: H,NNH, “+ (CH3),CO ——— (CH3),C=NNH, Ga H,O CHO
H wee
The final elimination stage can be catalysed by acids, which protonate the
AE
—OH first. Compare this with the protonation of alcohols (p. 44).
These hydrazones are not always very easy to purify, so sometimes the CH,
2,4-dinitrophenylhydrazones are made instead because they are easier to This aldehyde is used in perfumery;
crystallize. The mechanism of the reaction with 2,4-dinitrophenylhydrazine the trans compound has no detect-
is similar to that for hydrazine. able smell.

Overall: CH;

NH) CH nee
HN + o=c ——~ HN CH3 + H,0
ae
‘ NO) CH; NO,
P 4 6 2

5 3 2 :
4 4

NO, NO,
50. Reactions with nucleophiles

Write out the full mechanism showing the three stages:

(i) nucleophilic addition;

(ii) ‘gain-and-loss’ of protons;

(iii) elimination of water.

H 20
Hydroxylamine, HONH)>. This also reacts with aldehydes and ketones by an
Cl cl addition—-elimination mechanism. The overall reaction for hydroxylamine
and propanone is:
joib jib
NH, =) 0=e Nv
— HO’
N=c st
+ H,O
7
|NH,OH HO CH; CH
H_ NOH Now draw out the mechanism; start by nucleophilic addition of the
N nonbonded pair to the carbonyl group.
G ao

Cl Cl
Uses. These reactions have all been used to make crystalline derivatives of
aldehydes and ketones; now they are used more often in syntheses. We have
exchanged a C=O for a C=NX group and made new C to N bonds. Many
This is part of the synthesis of
nitrogen-containing compounds (such as dichlobenil) can be made using this
DICHLOBENIL. CN
type of reaction.
@ Cl

4.8 Reactions of nucleophiles with esters, carboxylic acids,

and derivatives
Draw the mechanism for this reaction.
Dichlobenil is used to control weeds
Introduction
in apple and pear orchards; it inter-
Like the aldehydes and ketones, these compounds have the C=O
feres with the photosynthetic path-
group in their structures.
way.

Ketones and aldehydes Acids and derivatives

H3C H3C ne 3C eS
C=O C=0 C=O C=O C=O
/ / /f
H3C H OH OCH, Cl
(ketone) (aldehyde) (carboxylic (ester) (acyl
acid) chloride)

We can write a general structure CH3;COX for all of these compounds, where
only X changes. The main distinction between the left- and right-hand sets is
that for the right-hand set X is a possible leaving group (see p.35). These
can therefore undergo addition—elimination reactions re-forming the C=O
group.
The initial stage of the reaction is the same for all: the nucleophile adds to
the electron-deficient carbon of the °*C=O°" to give a tetrahedral
 Foundations of organic chemistry 51
intermediate. For the acid derivatives this can now go on directly to re-form An example is the conversion of an
the C=O group by eliminating X (often as X~ ion): e.g. ethyl ester into a methyl ester (a
transesterification reaction).
HC HC oe HC
=
Nie C=O
\ one
addition Nieuw
20 ; ‘4
elimination
3 CH;
‘c=o eg CO
aa oO
YA
xX
AMA G X
\ Nu
/ OGjH:
intermediate

Overall: Nu + CH;COX —*» CH,CONu + X BC

8 AO
H,co—c*_)
The overall result is a substitution of the nucleophile Nu for X. There are Coc,
two stages and the first addition stage is usually the slower, rate-determining
stage.

Relative reactivity of different derivatives

When we compare the reactivity of the various carboxylic acid derivatives,

RCOX, two factors operate in opposite directions.

1. The inductive effect of X. If X is more electronegative than C, this

Inductive effect:
\ ae 6C0
reduces the electron density on the C=O carbon atom even more, and
so would increase the likelihood of bond formation to nucleophiles.

2. The stabilization of the molecule by delocalization of a lone pair of

electrons on X with the C=O double bond. This will decrease the Delocalisation:
reactivity to nucleophiles, as the energy gap between the more stable
starting material and the transition state, which does not have this
delocalization, will probably be greater.

Note that the observed flat structure of the amide group, X = NHnp, with its
angles of about 120° around carbon and nitrogen, would be predicted from
this delocalization. This flat amide or peptide structure is very important in
maintaining the shapes of proteins and enzymes.

Now look at the balance of inductive effects and delocalization on the Esters and acids also have
reactivity of CH;COX.
4
a flat = system
1. Acyl halides (also called acid halides), e.g. X = Cl (CH3COCI). Here the o—

inductive effect of the electronegative halogen seems to dominate and O

these are very reactive to nucleophiles. 4
like the amides —-C
iN
N—
2. Esters and amides, e.g. X=OCH3 (CH3;COOCH3) and X=NH) vA
(CH3;CONH),). Here delocalization reduces the reactivity; for example,
NaBH, will reduce acyl halides, aldehydes, and ketones but not esters
and amides.

Let’s start off by looking at the most familiar reaction of esters, ester
hydrolysis, and its reverse, esterification.
52 Reactions with nucleophiles

Esters

Hydrolysis and esterification. Esters are hydrolysed to carboxylate salts

and alcohols when warmed in aqueous alkaline solution, e.g. for ethyl
ethanoate:
CH;COOCH)CH; + NaOH — +» CH,COO Na + CH,CH,OH
The standard addition-elimination mechanism outlined on p. 51 is followed,
ending with a proton exchange between the acid and the alkoxide ion.
Bie |Otto = ’
(i) Nucleophilic addition of HO to ne to give a tetrahedral inter-
mediate A.
HC, ce es

HO Ge= — + HO-C \ A
OCH,CH; OCH,CH;
(ii) Intermediate A re-forms the C=O bond with elimination of alkoxide
ion, CH3CH,0 .

Hs oO
oy) if
CH3 =

PYRETHRIN | is a natural insecticide \\ \

made by some chrysanthemum A e OCH,CH; O
species.
(iii) Proton exchange then occurs between the acid and alkoxide ion; since
O CH3CH,0 is a stronger base than CH3COO, this equilibrium lies
far over to the right causing the hydrolysis to be essentially irreversible.
CH; CHy
= / = tf
CH3CH 20 “—™“~H ie —C ~=_> CH3;CH20OH Se O-——=6¢
\ \

This is a very good way to hydrolyse esters, and it is used in the hydrolysis of
natural esters (fats) for soap production.
Esters can also be hydrolysed in aqueous acidic solution. The C=O group
is first protonated to make the carbonyl carbon even more electron-
H3C CH; deficient; this is necessary because water is a weaker nucleophile than OH.
It is an ester. Draw the structures of See if you can complete the mechanism for this.
the acid and the alcohol from which it
might be synthesized.
HC N H3C
% 4 +
ye = O. H —_— pe =OH

OCH,CH, OCH,CH3
Overall: H’ + CH;COOCH,CH; + H;0 as
CH,COOH + CH,CH,OH + H*
The proton is regenerated at the end so this is an acid-catalysed hydrolysis.
Since it is a reversible reaction, an equilibrium, we can also use it to prepare
esters. We still need the acid catalyst, in order to reach equilibrium faster,
but we must now start off with as /ittle water as possible so that as much ester
as possible is present at equilibrium.
Thus, if we choose the conditions carefully we can use the acid-catalysed
reaction for either ester hydrolysis or esterification.
 Foundations of organic chemistry 53

CH3;COOCH)CH; + HAO == CH;COOH + CH;CH,OH

ESTER HYDROLYSIS
+

Hand water i.e. aqueous acid

Benzene-1,4-dicarboxylic acid and
nas ESTERIFICATION. ethane-1,2-diol react together to give
H* no water i.e. conc. HSOg or dry HCl a polyester, terylene. Draw the re-
; ; : peating unit of terylene.
If there is no acid or base present, just ester and water, the reaction is so
slow that nothing appears to happen at all. COOH
The importance of these reactions can be seen from the wide range of
naturally occurring esters and from the number of biological catalysts, the
esterase enzymes, used by plants and animals for these processes.
Lithium tetrahydridoaluminate reduction of esters. This goes in several
stages, the aldehyde being an intermediate. The mechanism is a combin- COOH
ation of:

(i) typical addition—elimination of esters; with

(ii) nucleophilic addition to carbonyl (see p. 47).

We will use H™ for the LiAlH4.

Ge
=H3C 45 => 4g, elimination ees
uf ~
eel —o= eens H—-c* Hee + OCH,CH3
\
OCH,CH, OCH,CH; e

H3C H3C _ ee
i) 4H a Nc =o ve
addition H—-C $0
4 protonation H—-C = 4 + OH =
/ \ +H,0 \
H H H

Overall: CH3COOC2Hs + 4H ioe CH3;CH,0H ar C,H50H

Notice that NaBHy, which is less reactive than LiAlH,, does not normally
reduce either esters or acids but will reduce aldehydes and ketones.

Amides
Amides and peptides contain the same planar functional group (see p. 51). i
Many important natural products (proteins, enzymes, hormones, antibiotics) eee
and synthetic polymers (nylon) contain this group. Amides and peptides are
generally less reactive to nucleophiles than esters, but like esters they can be |
hydrolysed in either acidic or alkaline solution by nucleophilic addition— amide or peptide link
elimination mechanisms. q f
Overall: CH3CONH) + H20 + H —s CH;COOH + NH,

or CH,;CONH, + NaOH =—* CH;COO Na + NH;

54 Reactions with nucleophiles

Amides can be made by nucleophilic reaction of ammonia or amines on

acyl chlorides, acid anhydrides (see below), or esters, again by addition—
elimination mechanisms. Note that ammonia (a base) reacts with a
carboxylic acid to give a salt.
— +
CH,COOH + NH; —_— CH;COO NH,
Pick out the peptide link in the drug
Proteins are polymers of aminoacids, joined together by amide (peptide)
ZESTRIL, used in the treatment of
high blood pressure and heart failure. bonds.

Hooc Sy
H
N COOH

In the laboratory, these are usually hydrolysed back to a mixture of

aminoacids using acidic conditions because some of the natural aminoacids
are unstable in alkaline solution. In animals and plants, proteins are
Ce6Hs hydrolysed using natural catalysts, enzymes such as chymotrypsin. An
interesting aspect of enzyme-catalysed hydrolysis reactions is that these,
NH, too, use the standard mechanism:
Draw the structures of the two amino-
acids from which this peptide could
be made.
(i) nucleophilic addition to C=O to give a tetrahedral intermediate;

(ii) re-formation of the C=O group and elimination of a leaving group.

Acyl chlorides and anhydrides

These all have the group RCOX where X is Cl or OCOCH3. They are more
reactive towards nucleophiles than esters. Ethanoyl chloride, CH3;COCI,
ethanoy] chloride reacts almost explosively with cold aqueous NaOH (don’t do it!) and even
its reaction with water is violent. Anhydrides come in between the acyl
chlorides and the esters in reactivity.
O O Both families of compounds react readily by the standard addition-
I I elimination mechanism with nucleophiles such as water, alcohols, ammonia,
Cc Cc
IC” GO" Gre and amines. Work out the mechanisms for these two examples:
ethanoic anhydride
CsHsCOC! + CH;CH,OH —= CyHsCOOCH,CH; + HCl

O 4O NH 3CH3
H3C ae A
d O ats 2CH3NH = H3C — . +
a
O a ‘ NHCH3 =oz oe
4

CH3 CH;

You should be able to see why two molar equivalents of amine are used in
the second example.
Acid anhydrides can be made from acyl chlorides and anhydrous
carboxylate salts. Write out this mechanism, too.
 Foundations of organic chemistry 55

oo aS 4 Dee One of the intermediates in the syn-

i Gs + Na Ome. ate H€— € o + NaCl
thesis of the foliar fungicide CAPTAN
Cl CH3 — a
\
CH,

Overall: CH;COCI + CH;COO Na —®» CH,COOCOCH; + NaCl

Carboxylic acids
Nucleophiles are also bases and often react with carboxylic acids to form
salts. For example,
2 +
CH3;COOH + NaOH ——= CH;COO Na + H,O
This limits the reactivity of carboxylic acids with nucleophiles, because the \
O
resulting carboxylate anion is much less reactive to nucleophiles than esters
Predict the structure of the product
or acid anhydrides.
formed when this anhydride reacts
= at
CH3COOH at H,NCH»CH3 — > CH;COO H3NCH2CH3 with ammonia, and write the mechan-
ism.
Under forcing conditions amides can be made from carboxylic acids, e.g. in Captan is used against apple and
the polymerization to give nylon-6. pear scab. It reacts with other com-
pounds in the fungus to produce toxic
H,N(CH2)sCOOH gives ---- NH(CH2)sCONH(CH))sCONH(CH));CO ---- CSClo.

Carboxylic acids react with inorganic acid chlorides such as SOCI, or PCI,
to give organic acid chlorides; compare this with the conversion of alcohols
into haloalkanes (see p. 44).
dr
CH,COOH + SOC, —» CH;COCI + SO, + HCI

The reduction of acids by LiAlH, is similar to the reduction of esters (see

253).

Overall: CH3;CH,COOH + 4H — (CH3;CH2CH,0OH + H2,O0

4.9 Comparison of acid derivatives with aldehydes and

ketones

Aldehydes and ketones differ from the acid derivatives because they have
H, alkyl, or phenyl instead of a possible leaving group, X. They all undergo
addition first to give a tetrahedral intermediate. Now the best leaving group
in the case of the aldehydes and ketones is the nucleophile (—Nu) and its
loss simply reverses the addition. For example, for propanone with cold,
dilute OH “:
56 Reactions with nucleophiles

a ies " : Pee

The intermediate can exchange its HO” “c= (= HO=C then HOT Es ee Ge c=
—OH proton with water
/
H3C CH3 CH3 H3C
HC intermediate
20
H,O + HO-C*
4.10 Comparison of the reactivities of the different types of
HyC halocompound with nucleophiles

We will now compare the reactions of three groups of chlorocompounds

with aqueous OH and with HO.

Group I. Alkyl halides, including CH;3CH2CH?Cl and CgsH;sCH?2Cl.

Group II. Acyl halides, such as CH3;COCI.

H3C
iw get ZO
H,O + cae Group III. Phenyl and aryl halides, such as CgH;Cl, and haloethenes, such
H3C as H,C=CHCl.
Using this, work out what happens
when propanone is treated with cold, Group I. Here the Cl is attached to a carbon atom which carries only
dilute NaOH in H2"80. single bonds; notice that in Groups II and III the Cl is attached to a double-
bonded carbon atom. For Group I we therefore expect (and find) direct
displacement, and we look for addition and then elimination in Groups II
and III.

Group II. Addition of nucleophiles to C=O is very easy; the

C=O group is highly polarized and oxygen takes the pair of 7 electrons
from C=O and so bears the negative charge in the intermediate.

H3C
1G 30
3 se

Nu eG — Nu—C ae C=O +c.

Yo @ if
Cl Cl Nu
Tetrahedral intermediate

These Group II reactions are very fast.

Group III. Addition of nucleophiles to C=C is normally difficult; the

C=C group is ‘electron-rich’ and not very polarized. If addition did occur,
the negative charge would be on carbon, e.g. structure B.

HO Cl
 Foundations of organic chemistry 57
Presumably these intermediates are of high energy and are difficult to form,
because the Group III halides are essentially inert to OH~ under normal
conditions. Notice how the reactivity changes sharply according to whether
the Cl is directly attached to a benzene ring (Group III) or attached to a
carbon next to a benzene ring (Group I). _
The reactivities of the three groups, with variations according to precise
structure, are summarized in Table 4.1.

Table 4.1

Group II I Ill
Type Acyl halides Alkyl halides Aryl halides
Reaction withaq.OH™ Violent, almost Fast No reaction
explosive
Reaction with H,O0 Very fast Slow No reaction
 5 Reactions with electrophiles
5.1 Introduction

Electrophiles have centres of low electron density, which will accept an

electron pair to make a covalent bond. There are three types: positively
charged cations, neutral molecules, and radicals. The first two will be dealt
with here (see p. 75 for radicals).

Notice that the stable cations Na* Cations, e.g. H* from HCl, NO,* from HNO3. These cations can readily
and K* are not included because accept a pair of electrons to form new covalent bonds.
they do not easily accept extra elec-
trons to form covalent bonds. Neutral molecules, e.g. Brz, HBr. Some of these are easily polarized, such
as bromine, ®*Br—Br®~; the 8+ part is electrophilic. Others are
permanently polarized, e.g. hydrogen bromide (see p. 6), °*H—Br®.

We could also include as electrophiles all the organic molecules which react
with the nucleophilic reagents in Chapter 4, e.g. the polarized haloalkanes
and carbonyl compounds. To prevent repetition, we will follow the usual
convention in organic chemistry and classify the inorganic and small organic
species as the reagents. This can lead us into trouble when neither reactant
fits into the ‘reagent’ category!

Addition to double bonds

The electron-rich organic molecules in this chapter all have formal carbon—
carbon double bonds. The carbon-carbon double bond can be considered as
a o bond and a w bond. The electrons of the 7 bond are in a m7 molecular
orbital, made by combining two p atomic orbitals. This 7 orbital has its
average electron density further from the positive carbon nuclei than in a
single o bond. The electrons are more easily available to electrophiles.
The carbon-carbon double bond is weaker than two single bonds and so
electrophiles (generalized as E*) normally add to C=X. In the addition to
C=C, electrons are transferred from the double bond to E*, creating
positively charged intermediates.

7 ,
fe ) NS E ‘ss ~
E*

intermediate

A new C-—E bond is formed leaving the other carbon atom as an electron-
deficient carbocation, with only six electrons in its outer shell. This may be
clearer from a dot diagram taking ethene as our example.
 Foundations of organic chemistry 59

H, nisl H OH
a G ‘ Cc" os Hi 2s@y 3. Ga
H re H A EH
E eu %
8 electron C 6 electron C

The electrons of the 7 bond both go to form the new C—E bond, so this is a
heterolytic fission of the bond. The reaction can then be completed by
addition of an anion, X~.
+

PC = Ce Ge WE” Gece ECH, — CH,

+ Es
ECH) = CH) te x —_ ECH, ae CH)X

Overall: H,C=CH, + EX —— » ECH, — CH)X

Both steps involve the formation of new dative covalent bonds.

We shall see later that compounds like benzene follow the same first
addition stage, but then lose H* instead of gaining an anion.

5.2 Addition of hydrogen halides to alkenes

Ethene

When hydrobromic acid and ethene are mixed, oily drops of bromoethane
are formed.

H,C = CH) + HBr —> H3C — CH,Br

The electrophile is the proton, from the dissociation of HBr, a strong acid.
ot “
HBrvaq) Hoag) + Br(aq) If the HBr |is not dissociated, the
polarized H —Br molecule can act
The proton adds to the carbon-carbon double bond to form a new C—H as the electrophile to give the same
bond. The carbocation intermediate then adds the Br’ to give bromoethane, carbocation intermediate.
in which both C atoms now have eight outer shell electrons. For dot
diagrams this is:
vt
N
9) | Ose
ee,
Fin om
EG 0
H
ay
if H ee =
Ht carbocation intermediate wo—m
a

Or, using curly arrows (remember that the arrow begins at the electron pair
and goes to make a bond to the electron-deficient atom):

H H ie) | OR +

\ 7
pe~ a 4 Pa ‘N re \ pice
w emg
=
Guta
proeeeats
OD
H a H H H H HH
H ai
intermediate
60 Reactions with electrophiles

The reaction of ethene with HCI follows a similar mechanism (write it

out, using both types of diagram).
As the electrophile here is a proton, H”, the first addition to C=C is also
an acid-base reaction (see p. 33). HBr is the acid and ethene is the base.
Because alkenes are weak bases only strong acids protonate them
effectively, so that HCN (a weak acid) does not usually add to alkenes.

Propene
The initial addition of H* to propene can give two different carbocation
intermediates, one primary (P) and one secondary (S).

H H Z H
Either Sn eee eee ct
Primary carbocations have only one HC ) H Mm
C substituent attached to the C*, ea (P)
secondary have two, and tertiary (e.g.
(CH3)3C*) have three.
H H H Ay
ot ic N SS re=e4
7 vA \
H,C A H H3C H
H* (S)
The secondary carbocation (S) is more stable (of lower energy) than the
primary one (P) and. is formed faster in this first, rate-determining step of
the reaction. We assume that the transition state leading to the secondary
More stable (lower energy) intermed- carbocation is of lower energy than the corresponding one leading to the
iates are likely to be preceded by primary carbocation. Let’s consider two possible reasons for this: stereo-
lower energy transition states, since chemical and inductive.
the structure of a transition state is
probably similar to the structure of the Stereochemical effects. For a stable three-coordinate carbocation, the ideal
intermediate. angles around C* are about 120° (three electron pairs, as far away from
each other as possible). This keeps large substituents farther apart than the
109° (tetrahedral) bond angle of a 4-coordinate carbon. Thus the change
from four- to three-coordination favours the more stereochemically
crowded carbon; tertiary > secondary > primary for stability of carbo-
cations.

H3C G Hy
+

stability fe
|
CH;
|
CH,
|
H

Inductive effects. The electron-releasing inductive effect of an extra methyl

group (see p.7) helps to neutralize and stabilize the developing positive
charge on carbon. Tertiary carbocations with three methyl groups, such as
(CH3)3C*, are even more stable than secondary carbocations.
 Foundations of organic chemistry 61

H3C CH; H CH; F3C CH;

stability On a ee ea be

CH3 CH; CH;

In general, the more stable the intermediate, the lower its energy and the
more likely it is to be formed. Therefore the addition of HBr to propene
goes mostly via the more stable secondary carbocation (S) to give 2-
bromopropane, rather than via the less stable primary carbocation (P) to
give 1-bromopropane. In fact, the product is nearly all 2-bromopropane.
Br Draw the mechanism for the addition
CH=CH
= ae = nb zee of molecular HBr (not ionized) to
H3C* i : H3C~ ~CH, fear CH, propene.
H+ (S)
For propene and HCl, the 2-halopropane is again the major product.
If you want to predict which haloalkane will be formed by polar addition Try this idea for the addition of HBr to
1—pentene and to F3CCH=CH>.
of hydrogen halide to an unsymmetrical alkene (like propene), draw the
possible carbocation intermediates. Work out which you think is the more
stable; this intermediate should be formed more easily and lead to the major Markovnikov’s rule, which states that
product. ‘the more positive Y portion of the
reagent Y—Z goes to the carbon
atom of the C=C which already bears
the more H atoms’, is an empirical
5.3 Reactions of alkenes with sulphuric acid: hydration rule governing these additions, and
was used before the mechanisms
Ethene were understood.

Concentrated sulphuric acid (a strong acid) will protonate the double bond
of ethene just as HCl and HBr do.

H,SO AD =
CH,>=CH, 2s CH;—CH, HSO,
carbocation
intermediate

The HSO,~ anion traps the carbocation to give a hydrogensulphate ester,

which is easily hydrolysed by water.

H H
H\ 7
H “
Hat C—C+ / J HSO,
H = ‘
Hy% Cc—- Vo
OSO3H
C=C — a Gp
7 ) \ My re de MH
H H H H H ?
y a hydrogensulphate
Coso3H ester

: OSO3H Tag OH
C=C, — H
is C,.,
\ "
a ’ H
H H hydrolysis H

‘onc. H2SO,
Overall: CH,»=CH, + H2O Peers ae) (CHR CHOU

Overall this is a hydration reaction, in which water is added across a

multiple bond.
62 Reactions with electrophiles

Propene
The acid-catalysed hydration of propene gives propan-2-ol. First,
protonation gives the more stable, secondary carbocation (see p. 60) which
then forms the secondary alcohol. The mechanism is similar to the addition
of HBr.
H3C H3C OSO3H OH
GH=ca,
= 25 ‘tH — Cea aeee
— ag BS
e : H,C— 4 CH, H3C ~ yy CH3
H. a H7SO4
(0s
The hydration of ethene and of propene are of great industrial
importance, as the two alcohols are used on an enormous scale as solvents
and as chemical feedstock.

5.4 Addition of halogens to alkenes

Ethene

Bromine and chlorine molecules are easily polarized—by glass, water, or

other molecules, even by the high electron density of the C=C in the
alkenes themselves.
Stee Se oe
—>
Bre— Bre Br—Br BY — Bie be

The electron-deficient 6+ end can add to an alkene at the same time as

bromide ion is lost. The intermediate is a cyclic, three-membered ring
bromonium ion. This bromonium ion then reacts with bromide ion to
complete the overall addition of Br2 to the double bond.

Bromide does notionise sponta- H

neously; these mechanisms are writ- = Cc.
x 5 — H wo
& 7 ae H ve
—s- ~} oy
ten using whole bromide molecules.
H H Br 2 substitution Br
Br +: at carbon

Overall: H,C=CH) oh Bro aa CH,BrCH,Br

The formation of the bromonium ion intermediate can be understood if we

look at a possible carbocation which might be formed. This carbocation can
In the addition of HBr to alkenes, the stabilize itself by sharing a nonbonded pair from the newly bonded bromine
added H atom has no non-bonded atom, to form the three-membered ring bromonium ion.
pairs of electrons and so cannot form
a cyclic ion like the bromonium ion. H\ H A H H H H E
Do you think that Cl is more (or less) corte / arm2? Hee
c—cst %
totecH Ha
~c_c™s
likely than Br to form a cyclic ‘onium H ,) H * Br? my H ° Br:
\
he
ion during halogen addition to Br ee +
alkenes? possible carbocation bromonium ion
 Foundations of organic chemistry 63
The addition of bromine is the classical test for unsaturation. The brown Carefully draw this mechanism in 3-D
colour of bromine disappears almost immediately as the alkene is converted for the addition of Bra to cyclopent-
into the colourless dibromoalkane. ene, and show that the product con-
If water is used as solvent for the bromine (‘bromine water’) then H,O sists of only one geometric isomer. (If
you find this easy, show why two
can also trap the intermediate bromonium ion to give the bromohydrin,
stereoisomers are produced!)
CH,BrCH,OH (compound 2). If the bromine addition is carried out in a
solution containing a high concentration of NaCl, then the two nucleophiles
Br and Cl” compete for the intermediate and some CH,BrCH>Cl
(compound 3) will be formed as well as the dibromide (compound 1).
Br
/
H,C—CH, (1)
Sie /
Br OH
= Br H,0 /
H2C = CH, — H,C Wake aera H,C — CH, (2)
\ =

Br Br
at x Cl
Cl /
HC as CH) (3)

Be

The formation of compounds (2) and (3) is seen as evidence for the cationic
intermediate. What other product might be formed if sodium ethanoate
(CH3;CO,~ Na*) were present in the bromine solution?

Propene
In the addition of bromine to propene, the intermediate cation is not
symmetrical and more positive charge is on the secondary carbon atom than
on the primary carbon atom (carbocation stability: tertiary > secondary >
primary, see p. 60).
H3C, 5. ee A
CH,CH = CH, —— H=—C-C ane Br
44, ~ -<

Srl
pf
Br-=—Br
La
The nucleophiles attack the more positive carbon atom (6+).

pe ae Nu
H3C,,= \ =
fo hae —e aes
Ca, CH, Br
o+

Examples. Write the detailed mechanisms for the overall reactions.

Br, + CH;CH =CH, —* CH3CHBrCH2Br

Br2 + CH3;CH=CH) + H,0 —» CH;CHOHCH2Br + HBr

64 Reactions with electrophiles

Chlorine and fluorine

Chlorine also adds to alkenes by an electrophilic mechanism. Fluorine

reacts too violently to be useful; the initial formation of the stable C—F
bond is very exothermic.

5.5 Cationic polymerization of alkenes

Many alkenes can be polymerized by heating with an acid catalyst, HX, ora
Ziegler catalyst. The intermediate is an electron-deficient carbocation. This
A Ziegler catalyst is electron-deficient reacts with more of the electron-rich alkene to give another, longer
and can accept a pair of electrons carbocation, and so on, to form polymers, e.g. ethene to poly(ethene),
from the C=C ; bond to form acarbo- «)5)
polythene’.?
cation. A mixture of TiCl, and
Al(CH2CHs3)2Cl is an example of a +
Zeigler catalyst. CH ce OyCH)

SG c CH tc.
HC’ ~Cc* ‘7? = 4c
— Chr

Overall: n HjJC=CH, —»-+CH,—CH)7 sipoly(ethene)

If we start with propene, CH;CH=CH2, we keep forming secondary

(rather than primary) carbocations because secondary carbocations are
more stable (see p. 60).
oe we CH;
|
20H Bs H _CH
HC H3C “¥ HGS
H* |

CHs CH CH;
i
sD co2fN 2CH
HCH C.* H,C
H

ois CH; CH;

| |
orci Om GSH etc.
H3;C H . inh AC arly
CH Oia) a=
2 H2
Overall: n HyC=CHCH; ——» -~{CH,CHCH3)-- poly(propene)
 Foundations of organic chemistry 65
The repeating unit of poly(propene), ‘polypropylene’, is -CH,—CHCH;-.
In the same way phenylethene can be polymerized to poly(phenylethene),
‘polystyrene’, (CH,CHC,Hs),,, via the cations stabilized by delocalization
with the adjacent benzene ring (see p. 46).

CeHs CeHs CoHs

|

Overall: n H,C=CHCgH, ——» -{CH,CHC,Hs)q,— _ poly(phenylethene)

The structures of these alkene polymers can be predicted using the stability
of the cationic intermediates, in the same way as we predicted the
orientation of addition of HBr to propene (see p. 60). Draw the mechanism
and the product for the cationic polymerization of HyC=C(CH3)p.
The polymers no longer have alkene C=C bonds, so they are resistant to
attack by electrophiles like acids and KMnO,. They are generally inert, like
alkanes, as you would expect from their structural formulae. The reason
why so many of these plastics are not biodegradable is that their molecules
are not accepted as substrates by fungal or bacterial enzymes.

Rubber—a natural polyalkene.

Rubber is a natural polymer of 2-methylbuta-1,3-diene.
MONOMER POLYMER

H) H)
H,C NN 4 CH)
n Selec ee ‘c=c’%
if \ / N
H3C H H3C H n

Polymerization occurs in the plant to give rubber latex, a colloidal

suspension of rubber in water, which is collected by ‘tapping’ the rubber
tree. Synthetic rubber was first made from the diene monomer in 1955.
Rubber still has alkene double bonds and so it can be chemically modified.
Its reaction with sulphur to give a crosslinked, harder rubber is a process
called vulcanization.
66 Reactions with electrophiles

We are not giving details of these 5.6 Oxidation of alkenes

complex mechanisms (see further
reading for more information). Ozonolysis
The full mechanism for ozonolysis of alkenes is complicated. The stable
addition product (an ozonide) from ozone and ethene has a five-membered
ring; the double bond in ethene has been broken completely. The ozonide is
hydrolysed reductively (e.g. using Zn+H,O) to give the aldehyde,
methanal.
H H H H
\ ’ O03 H Tyo OS lil! Zn + H,O \
Cae —— HY? Cw — CSO. 20 Ee
/ \ / /
Two problems: H H O-O H H
ozonide
1. Deduce the structure of OLEIC
ACID (from olive oil) which gives
Ozonolysis of propene gives a 1: 1 mixture of ethanal and methanal.
CH3(CH2)7CHO and OHC(CH2)7COOH
after ozonolysis and _ reductive H3C H
ee a O3 he@y Sane Red Zn + HzO \
hydrolysis. a SSS HY? one lame + O=C

H H O= © H H
2. Deduce the structures of the pro- ozonide
ducts from treating LIMONENE with
first excess O3 and then Zn + H2O. Ozonolysis has been used to identify the substituents on each end of a C=C
bond; the two carbonyl compounds produced could be identified (for
example) from the melting points of their 2,4-dinitrophenylhydrazones (see
H3C p.49). In modern organic chemistry, ozonolysis is more likely to be used to
prepare aldehydes or ketones from alkenes.

Potassium manganate(VII)

Alkenes can be oxidized by potassium manganate(VII), KMnO,. When an

alkene is shaken with purple KMnQ,, the colour disappears; this can be
used as a test for alkenes (like the decolorization of bromine). The alkene is
oxidized to the 1,2 diol and the manganese is reduced, its oxidation state
going from +7 (purple KMnO,) to +4 (brown precipitate of MnO;).

For ethene: H,C=CH, — > H,C — CH)

/ Ni
HO OH
For phenylethene: Cg6Hs;CH=CH, = ——> CehicCh ee
/
HO OH
What is the change in the oxidation
state of Mn in going from KMnO, to
the cyclic intermediate below? Unfortunately, alcohols and diols are further oxidized by KMnQ, so that
this is not usually a good preparation of diols. Notice that in the
phenylethene reaction only the alkene group is oxidized, not the benzene
ring (see p. 74).
YS ote
Go ork
 Foundations of organic chemistry 67

5.7 Benzene and related compounds

The structure of benzene

Benzene, C¢Hg, has a planar structure which is drawn in several ways.

In the resonance description of its
structure, benzene can be considered
as a ‘hybrid’ of two contributing non-
delocalized forms—but remember
that neither of these two forms actually
exists.
H Nondelocalized Hexagon + circle

The C—H bonds are left out of the last three diagrams for clarity, as is usually
done for complex organic molecules. Don’t forget that if no substituent is
shown on a benzene ring, you must assume that there is a hydrogen atom
attached to each carbon, making C—C—H bond angles of 120°.
The actual shape of the benzene molecule is a flat, regular hexagon (from
the X-ray crystal structure analysis of the solid). The carbon-carbon bond
lengths are all the same (0.139 nm), a value in between normal double
(0.134 nm) and single (0.154 nm) bonds.
If each carbon atom in benzene makes single bonds to each carbon
neighbour and a third single bond to hydrogen, there will be one unused
outer shell electron left in a p orbital on each carbon (diagram A).
These six atomic orbitals can combine to form a new set of molecular
orbitals in which all six ring carbon atoms are involved. It is this lower-
energy arrangement of the remaining six electrons in their special set of
molecular orbitals which gives benzene (and other ‘aromatic’ compounds)
their characteristic properties, such as bond lengths, stability, and resistance
to reaction compared with alkenes. The six electrons are delocalized over
the six-carbon ring, with the electron density greatest above and below the
ring in a ‘double doughnut’ shape (diagram B). This structure is much more
stable than the theoretical ‘cyclohexatriene’ structure which would have
alternating double and single carbon-carbon bonds. Let’s look at the
evidence for this extra stability, compared with alkenes.
1. Thermochemistry. The enthalpy change on hydrogenation or on Remember that six atomic orbitals
combustion of benzene is less exothermic than ‘expected’ in terms of a combine to make six molecular
structure with three alkene C=C bonds. orbitals, of which three are bonding
orbitals and are occupied (see margin
on p. 3).
(i) Hydrogenation
CéHeoy + 3Hag) = CeHi2)
AH = —209.2 kJ mol?
‘expected’ value is —360.4 kJ mol”!

This can be shown on a diagram.

68 Reactions with electrophiles

Calculated value for

‘cyclohexatriene’ + 3H
(calculated from
3 cyclohexene + 3H9)

Observed value for

enthalpy benzene + 3H,
H AH
- 360
kJ mol!
kJ mol!

Cyclohexane

(ii) Combustion
Draw your own enthalpy diagram for CeHeay + 15/2 Or(g) = 6CO 2g) ate 3H20
the combustion. AH = —3313.8 kJ mol!
‘expected’ value is —3473.4 kJ mol!
These figures suggest that benzene is much more stable (of /ower energy)
than the theoretical ‘cyclohexatriene’ model, by about 150-160 kJ mol™?.
The delocalization energy contributes to this stabilization. Breaking the
bonds in benzene is more endothermic than it would be for cyclohexatriene;
the difference is used as a measure of the delocalization energy.
2. Low reactivity of benzene. If benzene is more stable than the alkenes,
we expect it to be less reactive (more energy needed for reaction). This is
true for a wide range of reactions. Here are some examples.

(i) Hydrogenation. Cyclohexene can be hydrogenated by hydrogen and a

Ni catalyst at room temperature and pressure; benzene requires 200°C
and 200 kP (see p. 78).

(ii) Bromination. No catalyst is need for the reaction of bromine with

alkenes, but bromination of benzene needs a metal bromide (see
p. 71). Both begin by an electrophilic addition reaction.

(iii) Polymerization. Phenylethene has both a benzene ring and an alkene

C=C, but when it is polymerized with acid or radicals only the alkene
C=C reacts (see pp. 65 and 81).

How do we draw benzene?

The two standard ways are the ‘nondelocalized’ and ‘hexagon + circle’
diagrams: on :
 Foundations of organic chemistry 69

either or

Nondelocalized Hexagon + circle

First of all, neither way is ‘right’ but both are useful. A ‘nondelocalized’ Only one 1,2 disubstituted CeH4Xo
diagram implies separate double and single carbon-carbon bonds; this is not &xiSts; that is
so, as all the carbon-carbon bond lengths are identical in benzene.
Nevertheless, these diagrams are useful for drawing mechanisms, and we x
will use them for mechanisms. In the hexagon + circle diagram, the circle
represents the six delocalized electrons in their set of molecular orbitals.
This shows the hexagonal symmetry of benzene but it is more difficult to use
when drawing mechanisms. Professional chemists often use the hexagon +
circle for speed but change to nondelocalized diagrams when drawing
mechanisms.

and
5.8 Electrophilic substitution of benzene

Benzene reacts with electrophiles through the high electron density

associated with the set of six delocalized electrons. This is similar to the way _ all represent the same compound.
in which alkenes react through their m-bond electrons. Both react first by
addition of the electrophile, but instead of completing the addition as the
alkenes do, the benzene intermediate loses a proton, H™, to give overall
substitution. In terms of energy, it is more worthwhile to regain the special
stability from delocalization than to make the extra bond and leave a diene.
Using ®°* E—X°®~ as a general electrophile:

18)

sO x
—_ ae

substitution addition
product product

The stability of the benzene system pulls these reactions towards overall
substitution rather than addition. The three electrophilic substitution
reactions we will look at in more detail are nitration (in which NO replaces
H), bromination (Br replaces H), and chlorination (Cl replaces H).
70 Reactions with electrophiles

Nitration

When benzene is warmed with a mixture of concentrated nitric acid and

concentrated sulphuric acid, nitrobenzene is formed.
NO)

Overall: + HNO; canned o + HO

The detailed equilibria are: The H,SO, does not appear in the equation. It acts as an acid catalyst and
H,SO, HSO4 the reaction is very slow without it. The electrophile is the electron-deficient
a2 SSS se ‘ ion NO,* (O=N =O). This is formed by mixing a very strong acid (e.g.
HNO} H»NO} H,SO,) with nitric acid.

HONO; === ehs088 NO, Overallin, 2H5SO,. .4.EINO - NO, 4. 4:0 + 2HSG,
We will now draw the mechanism of the substitution using a non-
H,O H,0* delocalized diagram for benzene. This makes it easy to compare this
+3 a he mechanism with the electrophilic addition to alkenes.
H)SO, HSO, +

NO,
ey >

addition
wunH

+
a
ary +

elimination

A
Compare:

Sseen Me E mae E
pene a ] py l
Ee addition Pe addition x7 ne
B
Intermediate cations A and B are formed by the initial addition of E*, but
notice that the positive charge in cation A can be delocalized using the two
remaining conjugated double bonds. This can be drawn as a ‘horseshoe’ to
Cation A:
show the delocalized electrons. Note that the ‘horseshoe’ delocalization
involves carbons 2 to 6 inclusive but not carbon I (which is saturated and
tetrahedral). The reaction is completed by loss of a proton to re-form the
fully delocalized benzene system.
+

mH 3 %

or ae
The structure of the nitro-group can Es NO> NO, NO;
be drawn as

cP" | x oy

which is also delocalized. Overall: Co5H6 ap HNO; CeHsNO> ote H,0

 Foundations of organic chemistry 71
Use of nitration reactions. Nitration is an important substitution reaction
because nitrocompounds are easily reduced to amines.
Pd catalyst
CeHsNO> oS 3H) ee CegHsNH>2 ors 2H20

The aromatic amines are very useful synthetic intermediates because a wide
variety of new functional groups can be introduced via diazotization (see
2.23): PARATHION is an aromatic nitro-
The explosive TNT (trinitrotoluene, or 2,4,6-trinitromethylbenzene) is COMPOUNd which isa broad spectrum
made by (careful!) nitration of methylbenzene. lnsecticie it meanics acctyicnolie
and acts as an inactivator of the
CHs enzyme acetylcholine esterase.

+ 3HNO, conc. H,SO,4 Be 5.7 0GDEES

O con OG)Hs

NO)
Polynitrocompounds are thermodynamically unstable chiefly because they
produce the very stable nitrogen molecule, N2, when they decompose.
NO,
Bromination

Ethene decolorizes a brown bromine solution rapidly to form colourless 1,2-

dibromethane by an addition reaction.

H,C=CH, + Br —®* _ BrCH)CH,Br

If you shake benzene with bromine solution, nothing happens. Bromine

needs to be much more highly polarized before it can react with the more
Why are FeBr3 and AICl3 described
stable aromatic compound. Bromine can be polarized or even ionized using
as ‘electron-deficient’? Would you
metal halides that are electron-deficient; e.g. FeBr3, AlBr3, AlCl;. These
expect either BBrs or NBrg to act as a
can accept a bromide ion from bromine to form a new ion pair containing catalyst for this reaction?
the very reactive electrophile, Br*.
a
Bry + FeBr3 == Br a + FeBr4

Bo \¢ Alby, SSB; a Alby,

Br* has only six electrons in its outer shell and will now react with the
benzene.

‘Br’ i rie aed

Sines
onan:
eto gil
AlGBicks <a e[ot Br sBr mie
seal Bret

+ Br -
Br Br
ee LE un H Ht

—_ eS
mS SF:
72 Reactions with electrophiles

Here again, the positive charge of intermediate cation C can be delocalized.

When all the equations are written out, we find that the metal
halide is regenerated at the end; formally, it is a catalyst to polarize the Br.

iy 4 Albee Se er Ales

CH 46 Bre ees OIC Br

CoH¢Br* ea CAB a NET

H 4 AlIBy === HBr 4+ AIBr

Overall: (Ash, Se Bry CcisBr + HBr

All these reactions are usually carried out away from bright light to avoid
radical reactions (see p. 78).

Chlorination

This follows a similar pathway to bromination and again needs a catalyst.

Usually FeCl, or AICI, are used with Cl.

Reactions of phenol and phenylamine

Halogenation of phenol, CsH;OH, and phenylamine, CgsH5NHy, is interest-
ing because these two aromatic compounds do not need a catalyst and both
form tri-substituted products. This suggests that phenol and phenylamine
are more reactive to electrophiles than benzene (which does need a catalyst
and forms a monosubstituted compound). Nevertheless, they all still follow
The positions at which the bromines
substitute in phenylamine are related a similar mechanism of addition-elimination rather than addition.
to the higher electron densities caused
by delocalization of the N nonbonded NH, NH)
pair.
+
Br Br
(:NHa NH + 3HBr

Dy 5
=

£) white precipitate

Why are phenol and phenylamine more reactive towards electrophiles

+ + than benzene? Since they are more reactive, we might expect them to have
NH) NH) higher electron density. In phenol and phenylamine, the nonbonded pairs of
electrons on the O or N atoms can be involved in the delocalized system and
=P € so raise the electron density in the benzene ring. This delocalization of the
nonbonded pair of electrons in phenoxide ion is responsible for the
increased acidity of phenols over alcohols (see p. 37). See also the related
Asimilar effect operates in phenol. effect on the basicity of phenylamine (p. 38)..
 Foundations of organic chemistry 73
Phenol reacts with chlorine to give the familiar antiseptic, TCP
(2,4,6-trichlorophenol). DIPRIVAN is a phenol which is a
OH fast-acting, injectable anaesthetic for
surgery.

+ 3Cly a OH
(CH3)2CH CH(CH3)2

Diazotization and diazo-coupling

One of the most important functional groups in the chemistry of aromatic

compounds is the amino group. This is because it can be converted into the
—N,"* group, a process called diazotization.

NaNO, + HCl —*= HNO, + NaCl

NH) ee
HNO, + HCI A
ee Cl” + 2H,0
0 to 5°

a diazonium salt

The —N.* group is weakly electrophilic and can react with very electron-
rich aromatic compounds such as phenols. This is the basis of the azo dye
industry, because the ‘aromatic ring-N=N-aromatic ring’ products are
brightly coloured, fast azo dyes. They are widely used in the printing
industry.
O Nat OH

N
fe N mame NII + NaCl Draw the two geometric isomers of
a
the dye.
Cl

Diazonium salt + sodium phenoxide — an azo dye

Work out the mechanism of this last reaction (it’s an electrophilic substitution
reaction on the phenoxide ion).
The —N,* of the diazonium salt also provides the best leaving group of
all, stable molecular nitrogen, Nz. Diazonium salts are also useful
compounds for further synthesis because many different groups can be
substituted for the N2*, e.g. cyanide.

UeA
N
N ; ven CN
Cl eekge +ON5. KCl
CuCN catalyst
74 Reactions with electrophiles

Conclusions: general mechanism

The general mechanism for the reaction of benzene with an electrophile E*

SOS
is
E+ E

delocalized
cationic intermediate

E
re S| “s Ht

re

The stable benzene molecule needs a reactive (unstable) electrophile, which

is often made in the reaction mixture, e.g. NO”.

HNO; + 2H,SO4 — » NO,* + H,0* + 2HSO,

5.9 Oxidation of benzene and related compounds with

KMnO,

Benzene is inert to KMnQ,. In special conditions it can even be used as a

solvent for KMnO,. Contrast this with the rapid oxidation of alkenes (see
p.66). Side-chains on benzene rings may be oxidized. Methylbenzene is
oxidized by KMnQ, to benzoic acid, but the benzene ring remains intact.

CH, COOH

+ 30 — a5 H20

5.10 Benzene compared with alkenes

Some points to note are:

1. Both are electron-rich and react with electrophiles.

2. The bonding in benzene is different from alkenes; evidence: C—C bond

lengths (see p. 67).
3. Benzene and related compounds are thermodynamically much more
stable than expected for a triene; evidence: heats of hydrogenation and
combustion (see p. 67).

4, Alkenes undergo addition reactions whereas benzene undergoes overall

substitution, evidence: see bromination (pp. 62 and 71).
5. Benzene and related compounds are more resistant to oxidation and
reduction; see KMnO, (p. 66) and catalytic hydrogenation (p. 78).
6 Reactions with radical
intermediates
6.1 Introduction

In Chapters 4 and 5 the reaction mechanisms all involved the transfer of

pairs of electrons. These are heterolytic reactions and often have charged
intermediates. In this chapter we will be looking at homolytic reactions
which involve radical intermediates. A radical has an odd unpaired electron,
and is normally uncharged. Radicals are electron-deficient in the sense that
the atom carrying the unpaired electron is one electron short of a stable
outer shell, such as carbon or chlorine with seven electrons instead of eight.
For drawing mechanisms involving single electron transfers we use fishhook
arrows (see p. 20).

Formation and reactions of radicals

In order to unpair two bonding electrons to make two radicals we need to
supply energy, usually as heat or light (often high-energy ultraviolet light).
The formation of radicals at the beginning of a reaction is called the
initiation. The reaction then continues by the propagation steps, in which a
radical reacts with a molecule to give another radical as one of the products.
The propagation steps can go on and on to make a chain reaction, until two
radicals combine to form a stable compound; this is the termination
reaction. We will now look at these three processes, initiation, propagation,
and termination, for the radical chlorination of methane.

6.2 Halogenation of hydrocarbons

The radical chlorination of methane

This is a chain reaction.

Initiation. Chlorine and methane are mixed and either irradiated with
ultraviolet light or left in sunlight, of which ultraviolet light forms a part.
The energy of the light is absorbed by the chlorine molecules, which split
homolytically to give two radicais. It is a photochemical reaction.

light —
Cle El ee CaCl

This is energetically easier than splitting the stronger H—CH3; bond of

methane.
76 Reactions with radical intermediates

Propagation. Each chlorine radical takes a hydrogen atom from methane

to produce HCl and a new radical “CH, in which the C atom has a share in
only 7 outer shell electrons.

CH, tcl ae CH CI

or eae 2 ‘a ange H,C’ + H-Cl

H H
or Tiere — , H:C° + Figen Gla
H H
The new methyl radical "CH; can then take a chlorine atom from Cl, to
make CH3Cl and another chlorine radical.
Ch t5CH, oe Cl._+, CHC

or Ge — Cl° + CI—CH,
This chlorine radical can go on to react with another molecule of methane,
and so on. Notice that in each of these propagation steps there is an odd
number of electrons on both sides of the equation.

Termination. The propagation chain is broken when any of the radicals

involved reacts to form only electron-paired compounds. Here the propa-
gation radicals are Cl’ and ‘CH3, so that the most likely chain termination
One of the key stages in the synthesis
reactions are combinations of these radicals.
of the herbicide PARAQUAT
+ ot Cl
ae Cl ee Ccl——Cl (the reverse of initiation)

Cl Cl
is the combination of two radicals. cl a ‘CH; —
Paraquat is used for cleaning cereal
stubble before direct drilling, as part
of ‘minimum cultivation’ to retain soil fe ‘Ch. — + H,C—CH,
structure. Paraquat is inactivated by
the soil.
Putting all the steps together:

Ny light s
Initation: Cl, — —2C!
Propagation: CHC) =e TCH re!

Cult+ CH; = Cl” & .CLGH,

Termination: e.g. 2CH;° —=— JnliCeles

light
OVERALL: Cly + CHy ee CH;C! + HCl
 Foundations of organic chemistry 77
We can also show this as a radical flow diagram. The central circle contains the chain-
carrying radicals in the propagation
CH;Cl ie CH, steps. The side arrows show which
starting materials go in and which
products go out at each propagation
step.
Ge "CH3 HCI
This is the major overall reaction if there are equimolar amounts of Cl and
CHg,. If there is more Cly, the reaction can go on to give CH,Cl,, CHCl,
and eventually CCl, as well as HCl. The propagation steps for CH>Cl are:

~e
A
‘a °

re — HC. + H-C
Cl

ae Pi oes
H»C—Cl —> H,C—Cl
° \

Write the corresponding steps for CHCl; and CCl,. Remember that the
termination steps are any combination of chain-carrying radicals. By
adjusting the relative amounts of CH, and Clo, you can make mostly CH3Cl,
CH2Cl,, CHCl;, or CCly. Draw radical flow diagrams for these, too.

Bromination of methane

The photochemical bromination of methane is a very similar radical

reaction. It starts with the homolytic splitting of the Br—Br bond to give
two bromine radicals. The propagation steps, involving Br and °CH;,
follow and the termination is a combination of two radicals. Draw the
mechanisms for the initiation, propagation, and termination steps for this
reaction, using fishhook arrows. Draw a radical flow diagram for this
reaction as well.

Halogenation of other hydrocarbons

Chlorination and bromination of methane are relatively simple because
methane has only one type of C—H bond. Propane, CH3;CH>2CHs, has
methyl C—H’s (six) and CH, C—H’s (two). Two different hydrocarbon
radicals can be formed, primary CH3CH,CH,’ and secondary CH; CHCH3.
The secondary CH; CHCH; radical is more easily formed because the CH)
C—H bonds are weaker thar. methyl C—H bonds; but there are three times On an industrial scale it is sometimes
as many methyl C—H bonds. These factors are closely balanced and worthwhile to separate these mixtures.
mixtures of products are often obtained.
In the photochemical chlorination of methylbenzene, C6HsCHs, the side-
chain radical CsHsCHz’ is much more stable and is more easily formed than
any of the ring radicals, such as the one shown in the margin. This is because
78 Reactions with radical intermediates

C.6Hs;CH,’ is stabilized by delocalization (we shall see this type of radical

again in the polymerization of phenylethene; see p. 81).

Overall: CH;CH, + Ch light

= CELCHLC! + AC

Conclusions

These radical reactions are very important because an inert hydrocarbon is

turned into a more reactive halocompound, allowing access to a wide range
Part of the synthesis of DICHLOBENIL of organic reactions.
(see p. 50) involves the radical chlor- The conditions for these homolytic reactions are quite distinct from
ination of a side-chain methyl group. heterolytic reactions. For example, we can brominate methylbenzene to
CH, give two different products by choosing different reaction conditions.
Cl Cll
+ 2Clo Homolytic substitution:
CH; CH)Br

4 Bry light + HBr

CHCl,
Cl Cl
+ 2HCI Heterolytic substitution:

CH, CH;

+ Bro BeBe + HBr

Br
NOLVADEX is used to treat breast
cancer.
Using structural formulae, draw the . :
equation for the reaction of Nolvadex 6.3 Reduction: catalytic hydrogenation
with hydrogen and a palladium cata-
lyst at room temperature. Alkenes can be reduced to alkanes by the addition of hydrogen in the
presence of a finely-divided transition metal catalyst, often Ni, Pd, or Pt.

CH;CH,
Xs Pd
€ CH;CH=CH, + H2 —- CH3CH2CH3
I] room temp.

Pd
C.H;sCH = CH a H) ee CeH5CH2CH3
room temp.

The mechanism of these reactions is not fully understood. Both alkene and
hydrogen are probably absorbed on the catalyst surface, and the H)
molecule is probably split into hydrogen atoms. The reaction is thus
CH3—N. heterogeneous (taking place in more than one phase, here gas + solid) and
CH; homolytic (H—H goes to 2H , bonding electrons shared evenly).
 Foundations of organic chemistry 79

This reaction is very important industrially, for example in the conversion

(‘hardening’) of oils into fats, such as the hydrogenation of palm oil for
margarine manufacture. Nickel catalysts, being relatively cheap and robust,
are commonly used. In research laboratories, where smaller amounts of
more delicate chemicals are used, the more expensive and more reactive Pd
or Pt catalysts are usually used.
Benzene rings are much more resistant to hydrogenation than alkenes
(see the phenylethene reaction) and usually need high pressure and high
temperature, even with more reactive catalysts. This is an important
difference (see p. 68).
Notice that the nucleophilic reducing agent LiAlH, does not react with
benzene or ethene.

6.4 Thecracking of hydrocarbons

The world’s major sources of hydrocarbons are coal and oil. Both contain a
wide range of hydrocarbons. Some of the most desirable hydrocarbons have
quite low relative molecular masses. The less useful, higher relative
molecular mass hydrocarbons can be ‘cracked’—that is, converted by Plant oils are possible renewable
heating into hydrocarbons of lower relative molecular mass. The heat fuels for the future. The methyl ester
energy causes homolytic breakage of the C—C bonds to give radicals, which of rape-seed oil has been tested as
react further to give alkanes and alkenes. an alternative tractor fuel, and palm
oil has been suggested as a future
car fuel.
heat °
e.g. CH3(CH, Cy - CHy(CH,)4CH3 —» 2 CH;(CH>),CH2

CH jh
CH3(CH2)4CH2 H Oe Saas CH3(CH?)4CH3 13 CH

\(CH,)3;CH, (CH,),CH:

heat
Overall: CH3(CH,)9CH; 9——= ~~CH3(CH),CH; + —CH3(CH,);CH=CH,

Hydrogen is a by-product of some

The high temperatures are needed because of the high C—C bond energy. cracking reactions, e.g.
Ethene, propene, and ethyne are all manufactured by the cracking of higher
hydrocarbons. Ci2H26 — Ci2H + Hy

6.5 Radical polymerization of alkenes

Ethene
Radicals will add to carbon-carbon double bonds to make new radicals. If
R’ represents a radical from the initiation step:
80 Reactions with radical intermediates

saan nearemcarei y
brie
ois?
Liem
R

The new radical can add to another alkene molecule, and so on to make a
polymer. For ethene these steps are:

FAN CCH —=— R._ CH

R H.C aint (ele
Hy
e le H, °

BX LCH) \/_ S$CHe = Se ca deat,

Gs HC
a HOG

H) J H> H> 2
ROH, ACA Cth WF aba RCH ACN CK CH gto,
H> H) Hy Hy Hy
R

Overall: nH,C=CH2 — —(CH2CH2}-

polyethene, or polythene

Propene
Propene is not a symmetrical alkene and R’ could add to either end of the
double bond to give two different radicals, one primary (P) and one
secondary (S):
7 ne R° x

CH3CH 7 CH) <= CH3CH = CH) = CH3CH = CH)

/ \
R R

(P) (S)

Usually reaction goes via the more stable radical, which is preceded by the
lower-energy transition state. The stabilities of alkyl radicals are in the
order
tertiary > se ondary > primary

€.g. (CH3)3C > (CH3))CH > CH,CH,

This is the same order as for carbocations. Both species are 3-coordinate
and electron-deficient, so some of the same influences may be operating
here, e.g. stereochemical and inductive effects (see p. 60). Polymerization
of propene goes through secondary radicals like (S) and so gives a regular
head-to-tail polymer. Here is the overall equation: you should write the
detailed mechanism.

R CH,
\
Poly(propene) is used to make ropes n CH,CH=CH, — —+ CH—CH,>—
and in light engineering. polypropene, or polypropylene
 Foundations of organic chemistry 81
Phenylethene
When a radical adds to phenylethene, the more stable radical intermediate
is the one where the carbon with the odd electron also carries the benzene
ring. This radical can be stabilized by delocalization over the ring.

H,
CH i. 26
HO4N AL °*R Hes ES R

—_—_—_

HORA
CH, ee e Ec ae
Adee HC<
e
psc. Ae
S Gc

— etc

H)
c
Overall: nCg.H;CH=CH, — Puc }
| Expanded polystyrene, used for
C6Hs thermal insulation and packaging, is
a honeycomb made using gaseous
The polymer produced is ‘polystyrene’. pentane during the polymerization.

Initiators for the manufacture of polyalkenes

All these polymerizations need an initiating radical R’. This is often made
by heating a compound with a weak bond which will break homolytically;
for example, a peroxide.

(CHs)3C — 0.) ie ibs (CHy)3C —O

O—C(CH;),
weak bond broken INITIATOR

By careful control of the conditions of the reaction—time, temperature,

pressure, concentration of monomer, nature and concentration of initiator—
polymers of predictable average relative molecular mass and physical
properties can be manufactured. The chemical inertness of these polymers
is the reason why they are so widely used, although this means that their
disposal is also a problem (see p. 65).
82. Reactions with radical intermediates

6.6 Enzyme-catalysed radical reactions

Most enzymic reactions are heterolytic, as they take place in aqueous

solution where they can take advantage of the solvation energy available for
charged or polarized species. Nevertheless, some enzymes do make use of
Higher animals and plants cannot radical reactions, and many of these take place within membranes where
make their own vitamin Byp; it is only
less water is available for solvation. For example an alkyl radical is involved
synthesized by micro-organisms such
in the reactions of vitamin B,,. Homolytic breakage of a cobalt-carbon
as anaerobic bacteria. Pernicious
anaemia is caused by impaired ab- bond (initiation) produces a —CH,’ radical, which subsequently takes a
sorption of vitamin B,2 from the ileum, hydrogen atom from another molecule to form a —CHs group and a second
and it can be cured by relatively large radical (propagation). This is part of a biochemical pathway for the
injections of the vitamin. oxidation of fatty acids. For another possible example, see p. 88.

6.7 Radical reactions in the gas phase

Here solvation is not possible and radical reactions often dominate, for
example in the atmosphere. The formation of photochemical ‘smog’ and the
formation and destruction of the ozone layer are all complex radical
processes.
? Taking it further
7.1 Introduction

You are now familiar with a good deal of factual functional group
chemistry, and when you have worked through the first six chapters of this
book you will have met many of the basic ideas that underpin organic
chemistry. These ideas help us to relate one aspect of the subject to another.
They allow us to thread the facts together, like beads on a necklace, holding
them together to make a satisfactory pattern. Such patterns should be
recognizable and memorable so that they can be extended and developed in
new and interesting ways.

Theories need evidence

Underpinning these patterns is a solid base of fact, that is, good, repeatable
experimental data. We need theories, but all good theories are firmly based
on facts. The mechanisms in Chapters 4 to 6 are descriptions of what
happens; in very few cases have we given you any of the experimental data Mechanisms cannot be ‘proved’; they
upon which they are based or explained the interpretation of the data (but are descriptions based on the best
see p.63). ‘How do you know that?’ and ‘How do you show that this available data. As new reliable data
appear, mechanisms are constantly
statement is true?’ are questions you will be asking more often in the future.
modified and updated.
It is in answering these questions that the armoury of techniques of the
modern organic chemist comes into play, from chemical kinetics to nuclear
magnetic resonance (NMR) spectroscopy and X-ray crystallography.

7.2 Mechanisms and molecular orbitals

We have considered most reactions in terms of an electrophile (6+, or

‘electron-deficient’), and a nucleophile (6—, having a nonbonded electron
pair or ‘electron-rich’), which might imply that the interaction between the
two is just the attraction of positive and negative charges. This would be an
over-simplification; it is clear that the electron pair concerned must go from
an orbital in the nucleophile towards an orbital in the electrophile. The
reaction therefore can also be seen as an interaction between two orbitals,
molecular or atomic, an occupied orbital in the nucleophile and an
unoccupied one in the electrophile. (Remember that each orbital can hold
only two electrons.) This interaction depends on the size, shape, and energy
levels of the two orbitals. Jf we are dealing with elements in the first short
period of the periodic table (Li-F) the size-and-shape match will probably
be quite good. Since electrons fill the lowest energy orbitals first, an
occupied orbital will normally be of lower energy than an unoccupied one.
We are therefore looking for a relatively high-energy occupied orbital to
interact with a relatively low-energy unoccupied orbital.
84 Taking it further

Nonbonded and 7 electron pairs occupy relatively high-energy orbitals,

and polar (or multiple) bonds such as C—Cl and C=O provide relatively
low-energy unoccupied orbitals. So most of our reactions involve the
combination of molecules with nonbonded pairs or 7 electrons, such as NH3
or ethene, with haloalkanes, carbonyl compounds, or even bromine
(permanent or temporary polarization). These are exactly the molecules we
have already classified as nucleophiles and electrophiles. So the two ways of
looking at these reactions do have common ground!

Orbitals and stereochemistry

Orbitals, which show the probable distribution of electron density, may
have directional properties; remember the three mutually perpendicular p
orbitals (see p.2). So for a successful interaction between two orbitals, we
also need to have their relative positions in space more or less correct: the
reagent has to be on the right ‘flight path’ to start bond formation. The study
of the stereochemistry of interacting molecular orbitals is called stereo-
electronics. We will look at two examples: first, nucleophilic substitution of
a haloalkane (see p. 41).
Stereochemistry of nucleophilic substitution. The nucleophile has a non-
bonded pair (high-energy filled orbital). The haloalkane has its lowest
energy unoccupied orbital at 180° to (that is, behind) the C—Br bond, so the
best flight path is for the nucleophile nonbonded pair to approach the back
of the C—Br bond.

What is the stereochemical relation-

ship between A and B in this substi-
tution reaction? (The energy profile of
This is how they are drawn in Chapter 4 with curly arrows.
this reaction looks like the second
diagram on p. 24.) >=

Ho copy = foe es Br |
\
This flight path has important stereochemical consequences if the halo-
alkane is optically active, because it throws the molecule ‘inside out’.
Stereochemistry of addition to carbonyl. As the second example, let’s look
at addition to the carbonyl group (see p. 47). We believe that nucleophiles
either \
attack the carbonyl carbon atom from a direction at right angles to the plane
of the carbonyl group and from slightly behind. This is where the lowest-
energy unoccupied orbital is located. Some of the experimental evidence
for this comes from collecting observations of many different X-ray crystal
structure analyses of compounds which include both a carbonyl group and a
nucleophile close together, and then looking for the most popular relative
positions. These results agree with modern theoretical calculations and with
the current molecular orbital picture of the carbonyl group. Now we can use
this idea to predict the outcome of a new reaction, or to help us to
understand the stereochemistry of other reactions.
 Foundations of organic chemistry 85
Enzymes can break the symmetry of simple molecules
When 1-deuterioethanal is reduced by NaBHy, an equimolar (1: 1) mixture
of the two optical isomers of 1-deuterioethanol is produced.

c=O0 — H3;C — CHDOH

It is equally likely that the H™ will approach the top or bottom face of the
molecule.

a
H
H3C Mago H3C 4 4
=O ==> c
O
1:1 ratio

ec ME
Make yourself some molecular
H tn. csLi H (© tay Aa models of these molecules to help
you to understand the stereo-
7 H chemistry of these reactions.
H

Two enzymes, liver alcohol dehydrogenase and yeast alcohol dehydro-

genase, will also catalyse the reduction of 1-deuterio-ethanal, but there is a
striking difference from the sodium borohydride reaction. Each enzymic
reaction produces only one optical isomer of 1-deuterioethanol.

OH
H;C.., enzyme H3Cy,,, 7
D= C— SS D= Ss only
H

The deuterioethanal is bound to the enzyme surface, so that the top and
bottom faces are not identical; the symmetry has been broken. The reducing
H is delivered from a nearby part of the enzyme surface. enzyme
surface

OH
Freya.
D&= q
H
86 Taking it further

Each enzyme breaks the symmetry of the original planar aldehyde, so

that a single, optically active isomer of the alcohol is made. This research
gives you an example of the use of isotopes to study the course of a reaction.
H and D are sufficiently different that there are two optical isomers of
CH3;CHDOH, but sufficiently similar that the chemical reactions of
CH3CHO and CH3CDO are almost exactly the same.

7.3 Using functional group chemistry

Having looked at the extensions of some theories, now let’s look at the
application of some familiar reactions on new molecules.

Benzocaine and Novocaine

The local anaesthetic Benzocaine is an ester—an ethyl ester of a

substituted benzoic acid.

O O CH 2 CH 3
II i H) ]
~ OCH2CH; N9-"No- NcHcHy
2:

Which of the two nitrogen atoms of

HN H)N
Novocaine is the more basic? (See
Benzocaine Novocaine
p. 38.)
Esters can be made from an acid and an alcohol (see p. 52) so Benzocaine
could be prepared from 4-aminobenzoic acid and ethanol. We need an acid
catalyst and dry conditions, such as dry HCl. The reactions will be:

O O
II Il
Ce Cy.
OCH,CH; aq.NaOH OCH,CH;
HOCH,CH;
————
+ + NaCl + H,O
dry HCI H3N H)N

Novocaine is a newer, related local anaesthetic. Work out the last stages
for a synthesis of Novocaine.

NH, O Luminol

Luminol is chemiluminescent. When it decomposes in the presence of

alkaline K3Fe(III)(CN)s and H2O;, it gives out energy in the form of
ultraviolet light. The hydrocarbon rubrene can absorb this light energy and
re-emit it by fluorescence, making the solution glow with a bright yellow
Luminol light. This type of reaction can be used in, ‘light sticks’; the reagents are
 Foundations of organic chemistry 87
mixed by breaking the barrier, between the two compartments when the
stick is bent.
Luminol can be made from benzene-1, 2-dicarboxylic anhydride in three
stages.
O NO,
3 li Storadll
; : mn conc.HNO3 + conc.H,SO, 4 3 Pon
(i) Oo —
5 ec / then HO 5 OH
6 \\ A i
9 O

NO, O NO, O
I Il
Cc e
és OH NH)NH) at 220° Se
11 — oe |

ee _NH
Il ll
Oo

NO, O NH) Fireflies produce their light by

ll ll enzymic oxidation of LUCIFERIN.

Ce NH Na ,S 70. ~ NH HO
(iii), oe
a29204

_NH oo NH
HI It
O

Luminol

Stage (i) is the nitration of an aromatic compound (see p. 70) followed by

the hydrolysis of an acid anhydride (see p. 54); the only difficulty is whether
the new nitro group substitutes at position 3 or 4. Draw these mechanisms
out.
Stage (ii) is the reaction of a carboxylic acid with an amine under forcing
conditions (220°C) to form an amide bond (see p. 55). This happens twice;
draw this mechanism, too.
Stage (iii) is the reduction of a nitro group to an amine. The reducing
agent Na2S,O, may be new to you; another possible reagent might have
been hydrogen with a palladium catalyst, but this breaks the N—N bond as
well.
You will notice how we have put each stage into its categories of reaction
type (e.g. reduction in stage (ili)) and functional group change (e.g. acid to
amide in stage (ii)). This is a very useful way to look at the chemistry of
complex molecules, but you learn to be careful of undesirable side-effects
on other functional groups (see stage (iii) ).

The structure of the whole molecule affects each functional group

We must remember that the rest of the molecule around a functional group
affects its chemistry. Our choice of reducing agent in the previous
subsection depended on other groups present in the molecule, and we can
88 Taking it further

see how the reactions of bromoethane and of 2-bromo-2-methylpropane

130) with NaOH differ (see p. 46).
O COOH
Pe N
CH3CH Br + NaOH a cm CH3CH,0H + NaBr

Cl
(CH3)3CBr + NaOH —— is (CH3)yC=CH, + NaBr + HzO
The biochemistry may alter too, even with quite subtle changes. The two
molecules 2,4-dichlorophenoxyethanoic acid (2,4-D) and 2,4-dichlorophen-
Cl oxybutanoic acid (2,4-DB) look very similar chemically but they are very
different to a plant.
2,4-D 2,4-D stimulates a fatal level of growth in broadleaved plants and is an
excellent weedkiller for narrow-leaved crops like wheat. 2,4-DB itself is
Hy Hy
inactive as a weedkiller, but some broadleaved plants metabolize it by
oxidation to 2,4-D—with fatal effects. Thus 2,4-DB is even more selective
O°. "ey “G00H
than 2,4-D.
cl $

7.4 Some current research projects

Cl
What sort of things are organic chemists busy investigating now? Three
2,4-DB examples follow; we make no apology for the biological slant to these
because this reflects the authors’ interests!

The biosynthesis of ethene: ripening fruit

If you want to make green tomatoes ripen faster, put a ripe tomato or apple
or banana with them. The ripe fruit gives off ethene which catalyses the
ripening process. We know how to make ethene from coal or oil or ethanol;
but how does a plant make ethene?
Ethene will also accelerate the forma-
tion of seed-heads from flowers; so a
Ethene in plants is made from the cyclic aminoacid A, which itself comes
bunch of carnations will last longer if from one of the common ‘essential’ amino acids, methionine:
they are not near a bowl of fruit. +

K NH; 4 in
4 \ enzyme H>C NH3 enzyme CH 2
Be ees YS 2 pre ee 4 "
tio coo HxC 2 ~COO™ 3 CH)
Methionine A

How do we know this? If the methionine has been prepared with a

radioactive ‘label’ (14C) at either C3 or C4, then this label appears both in
the aminoacid A and in the ethene. So the carbon atoms of the ethene are
derived from carbons 3 and 4 of methionine. But what is the stereo-
chemistry of the conversion of the amino acid A into ethene? Do the two cis
hydrogen atoms on the same side of ethene always come from the same side
of the ring of A? The answer is no—because the two deuterated versions of
A both give a ‘scrambled’ 1:1 mixture of dideuterioethenes (but
no CH,CD,).
The detailed enzyme mechanism is unknown, but it probably involves a
radical intermediate. Even less is known about how the ethene catalyses
ripening!
 Foundations of organic chemistry 89

H H
\ /
D ne) ND) H Sa
a a m
\. ABN \ Na D D What chemical reaction(s) could you
- Sie or f ie enzyme a use to differentiate between CH2CD2
H Coy D Cia ratio and CHDCHD? Which of the two
geometrical isomers of CHDCHD has
COOm COO 3 x C=C / H the larger dipole moment?
/ SS
H D

The taxols: synthesis of new anti-cancer agents

One of the most promising new drugs for the treatment of cancer of the
breast or colon is taxol. Taxol is extracted from the Pacific yew, and it takes
one mature tree to provide enough taxol for one patient. The tree is a slow-
growing North American evergreen which is becoming rare. Total synthesis
of taxol is difficult because of its complex stereochemistry. Several
companies are attempting to set up commercial tissue cultures of Pacific yew
bark cells to make taxol. A more wide-ranging approach to the problem is
to use a tissue-culture to produce compounds similar to taxol, in which the
plant cells have done much of the difficult chemistry. For example baccatin Make a list of the names and struct-
IV is comparatively abundant in English yew, and other related species have ures of all the functional groups in
Taxol.
yet to be scanned.

Taxol Baccatin IV

(0.01% in bark) (1% in leaf)

These and similar compounds can then be elaborated in the laboratory to

give a new range of potential anti-cancer drugs. The powerful combination What reactions would be needed to
of cell culture and organic synthesis is a flexible approach which may help to convert Baccatin IV into Taxol? List
save the lives both of the patients and of the Pacific yew. them as_ functional group _ inter-
conversions, e.g.
secondary alcohol oxidation ketone.
Tools for biochemistry and physiology: fluorescent indicators for calcium
ions
How does a heart beat? How does the beating of a diseased heart differ
from that of a healthy heart, and why? What is the molecular mechanism of
the contraction of a single heart cell? Changing the concentration of calcium
ions in the cell is one of the control mechanisms, and so a method is needed
to measure this inside the cell.
90 Taking it further

Methyl orange and other pH (proton) indicators show different colours

when they are bound to protons (in acid solution) and when they are not (in
alkaline solution).
+

Indicator Sa Indicator H
(alkaline solution) (acidic solution)
ORANGE RED

CH, CH;
_ 4%
N NYN Z Ns a
Ne
N
03S N CH3 0,8 N CH3
x

Calcium indicators will do the same with calcium ions, Ca*+. The most
sensitive indicators are fluorescent and show a different fluorescence colour
depending on whether they are bound to Ca’* or not. These indicators are
complex molecules with two overlapping parts: one to bind the Ca**+ and
one to give the fluorescence, e.g. INDO-1.

o0c” “y cae
ie 00C'«
Yas -N “coo ay te ide
' : ‘ : binding
; ' oO! O
aN EQ ‘ae eee ee S ewer:
INDO is a large organic molecule,
and yet it is soluble in water: why?
And to which atoms in INDO do you CH;
think the calcium ion binds? LC Pisin

skt

COO | INDO-1
fluorescence
Calcium ions are very important in
cells such as nerve cells and in the New and better indicators are being synthesized for Ca** as well as for
retina of the eye. Calcium ions are other biologically important ions such as Mg** and Zn?*, which will be very
also involved in the opening and valuable for medical research. The collaboration between the synthetic
closing of the stomata in leaves. ' organic chemists and the physiologists is crucial for progress.

7.5 Conclusion

Almost every section in this book could have been developed further, with
more sophisticated ideas and examples. From time to time you will have
glimpsed the depths and sensed their challenge, a challenge which we hope
you now feel ready to take up.
Further Reading
General A level chemistry: Atkins, P. W., Clugston, M. J., Frazer, M.
J., and Jones, R. A. Y. (1988). Chemistry: principles and applications.
Longman, London.
Undergraduate organic chemistry: Kemp, D. S. and Vellaccio, F.
(1980). Organic Chemistry. Worth, New York.
Biological Aspects: Stryer, L. (1988). Biochemistry. 3rd edn, Freeman,
New York.
Research topics in Chapter 7:
(a) Ethene: Adlington, R. M., Baldwin, J. E., and Rawlings, B. J.
(1983). J. Chem. Soc. Chem. Comm., 290.
(b) Taxol: Potier, P. (1992). Chem. Soc. Rev. 21, 113.
(c) INDO: Grynkiewicz, G., Poenie, M., and Tsien, R. Y. (1985). J.
Biol. Chem. 260, 3440.

Index

acid alkenes bromination 62,71, 77

anhydrides with nucleophiles 54 electrophilic addition 58-66 bromonium ion 62
chlorides, see acyl chlorides hydrogenation 78 Brgnsted—Lowry theory 33
conjugate 34 oxidation 66
dissociation 33 polymerization 64-5, 79-81 CFCs 11
strength 33-8 structure 4 carbocations 12, 29, 45-6, 58
strong/weak 33 alkyne structure 5 stability 60-1
activation energy 24-5 amide hydrolysis 53-4 carbonyl compounds, see aldehydes or
acyl chlorides with nucleophiles 51, 54-5 amines ketones
addition 18, 58 as nucleophiles 43-4, 54, 55 carboxylic acids
addition-elimination 49-50, 56 as weak bases 34, 38 addition/elimination 55
alcohols amino acid structure 38-9 esterification 53
elimination 18 Arrhenius equation 27 reduction 55
hydrogen bonding in 16, 17 asymmetric carbon 14 solubility 16-17
as nucleophiles 54 as weak acids 33
nucleophilic substitution 44 bases 33 see also acid
oxidation 31 as leaving groups 35-6 catalysis 26, 29
aldehydes as nucleophiles 35-6, 40 chain reactions, see radical reactions
addition—elimination 49-50 strength 38 chirality 14
enzymic reduction/stereochemistry benzene chlorination 64, 72,75
84-5 compared to alkenes 74 cis/trans isomerism 13-14
nucleophilic addition 47-8 electrophilic substitution 69-74 collision theory 24-5
reduction 47-8 reduction 68 condensation, see addition—elimination
structure 4 structure 5, 67-9 conjugated double bonds 6
alkanes boiling points and structures 15-16 cracking 79
cracking 79 bond curly arrows 20-2
radical substitution 75-8 angles 11-12
solubility 17 lengths and strengths 10-11
92 Index

dative covalency 10,59 reduction 47-8 radical 18

delocalization 5, 37-8, 62, 67-9 solubility 17 flow diagram 77
diazotization 73 structure 4 reactions 22, 75-82
dipole-dipole attraction 15 kinetic stability 80
dipoles 6, 16-17 control 29-31 rate
dot diagrams 9 energy of molecules 25-6 constant 27
dynamic equilibrium 23 kinetics 26-31 determining step 27-8
K,, 34 equations 26-8
electronegativity 6, 37, 60 reduction of
electrophiles 19,58 leaving groups 35-6, 50 acids 55
electrophilic lone pairs, see nonbonded pairs aldehydes 47
addition 58-66 alkenes and benzene 78-9
substitution 69-74 Markovnikov’s rule 61 esters 53
elimination 18, 46-7 Maxwell—Boltzmann diagram 26 nitriles 43, 48
energy molecular orbitals 2, 83 nitrocompounds 71, 87
barrier (activation energy) 25, 28 multiple bonds 3-5 resonance 5, 22,67
changes (RTInK) 23
profiles 23-5, 28-9 nitration 70, 87 sorbitals 2
equilibria 22-3, 33-5 nitriles shapes of molecules 3, 4, 11-12
esterification 52-3, 86 hydrolysis 36, 43, 48 drawing in3D 11
ester reduction 43, 48 sigma (a) bonds 2
hydrolysis 52 nonbonded pairs 10 solubility
reduction 53 nucleophiles 10, 19, 40 of acids and bases 35
nucleophilic factors affecting 16-17
fishhooks 20-1 addition 47-8 solvation 37
functional groups 8-9, 86-7 addition-elimination 49-55 stereoelectronics 84
reactivity 35-6 stereoisomerism 11-14
geometric isomerism 13-14 substitution 41-7 structural
formulae 7
haloalkanes isomers 12
elimination 32, 46-7 optical isomerism 14 substitution 18, 41, 69, 75
nucleophilic substitution 32, 41-7 order of reaction 27
stereochemistry of 84 oxidation of thermodynamic control 29-31
polarity 7 alcohols 31 transition states TS 12, 28-9, 42
halocompounds, comparative aldehydes 31
reactivity 56-7 alkenes 66 van der Waals forces 15-16
heterolysis 18, 41, 59 benzene compounds 74
homolysis 18,75 ozonolysis 66
hybrid orbitals 3
hydration 61 p orbitals 2
hydride ion donors (NaBHy, LiAlH,) 47, pH 34
53 and amino acid structure 38-9
hydrogen bonding 16-17 partial charges (8+ and 8—) 6
hydrogenation 78-9 phenol
hydrolysis 43 electrophilic substitution 72, 73
as a weak acid 37
inductive effect 7,37, 60-1 phenylamine
intermediates 9, 28-9, 45-6, 47 diazotization 73
intermolecular attractions 15-17 electrophilic substitution 72
ion—dipole attraction 15 as a weak base 38
isomerism 12-14 photochemical reactions 75-8
pi (a) bonds 4
K, and pK, 33, 34 polarization of bonds 6, 15, 19, 40
K, and pK, 34 polymerization 55, 64-5, 79
ketones cationic 64-5
addition-elimination 49-50 radical 79-81
intermolecular attraction 15 proton (H*) 33, 61
nucleophilic addition 47-8 protonation 44, 47
polarity 15
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SERIES EDITORS

STEPHEN G. DAVIES _ This series of short texts provides accessible accounts of a range of essential topics in
chemistry and chemical engineering, Written with the needs of the student in mind,
RICHARD G. O COMPTON
the Oxford Chemistry Primers offer just the right level of detail for undergraduate
[OHUN EVANS. Study, and will be invaluable as a source of material commonly presented in lecture
courses yet not adequately covered in existing texts. All the basic principles and facts
LVI GUADOEN ina particular area are presented in a clear and straightforward style, to produce
concise yet comprehensive accounts of topics covered in both core and
specialist courses.

Advanced school students and beginning undergraduates will find this book a read-
able and stimulating summary of the fundamentals of organic chemistry. The first
three chapters introduce some basic physical chemistry, and laythe groundwork
for the mechanistic organic chemistry covered later in the book. The importance of
bonding and mechanism are stressed throughout, and students are encouraged to
apply their chemical knowledge in new and unfamiliar situations in order to develop
and sustain their interest, A wide range of examples including natural products and
pharmaceuticals is included, with the final chapter exploring some new develop-
ments and providing an introduction to current research.

Michael Hornby is Senior Tutor at Stowe School, Buckingham.

Josephine Peach is a Fellow and Tutor in Organic Chemistry at Somerville
College, University of Oxford.

From some recent reviews

|have no hesitation in recommending this book as a study guide and revision aid.
Education in Chemistry
This is quite simply the best book for this.stage that |have ever seen.
School Science Review
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