Essentials of Organic Chemistry

286 ELECTROPHILIC REACTIONS

Naturally, if the protonation step could lead to be almost entirely the result of tertiary carbocation
either a tertiary or a very unfavourable primary involvement.
carbocation, then we would expect the product to

H CH3 Cl− H Cl
H H CH3
H+
H CH3 H CH3 H CH3

favourable tertiary essentially
carbocation sole product

H CH3 H+ HH Cl− Cl H
2-methylpropene H CH3
CH3
H CH3
H CH3

highly unfavourable
primary carbocation

Long before any reaction mechanism had been by the presence of peroxides as radical initiators. This
deduced, Markovnikov’s rule had been utilized will be discussed further in Section 9.4.
to predict the regiochemistry for addition of HX
to an unsymmetrical alkene. Markovnikov’s rule The relative ease with which hydrogen halides
states that addition of HX across a carbon–carbon react with alkenes is in the order HI > HBr > HCl >
multiple bond proceeds in such a way that the HF. This is the same as their relative acidities
proton adds to the less-substituted carbon atom, (see Section 4.3.2) and indicates that protonation of
i.e. that already bearing the greater number of the alkene is the rate-limiting step for the addition
hydrogen atoms. Since we now know that carbocation reaction.
stability controls the regiochemistry of electrophilic
addition, it is recommended that the more favoured 8.1.2 Addition of halogens to alkenes
product be predicted simply from an inspection of
the possible carbocation intermediates. Alternatively, Halogens such as chlorine (Cl2) and bromine (Br2)
Markovnikov’s rule should be restated in mechanistic react readily with alkenes to produce 1,2-dihalogen
terms, in that the electrophile adds to the double derivatives. Although the halogen–halogen bond of
bond to form the more stable carbocation. In Cl2 and Br2 is non-polar, it becomes polarized as
some circumstances, this generalization has appeared it approaches the π electrons of the double bond.
incorrect, and so-called anti-Markovnikov addition The electrons in the halogen–halogen σ bond become
has been observed. Careful analysis of the reagents unequally shared, and are disturbed towards the atom
has shown that abnormal anti-Markovnikov addition furthest away from the polarizing double bond. As a
of HX is the result of a radical reaction brought about result, the dihalogen functions as an electrophile, in
much the same way as does HX.

Br d− d− Br Br
Br d+ d+ Br Br

CC Br Br
Br
π bond electrophilic addition lone pair of bromine atom Br
with loss of bromide interacts with resultant anti addition of two
p electrons cause carbocation giving cyclic rearside attack of bromine atoms
polarization of bromonium ion bromide nucleophile
dihalogen Br
Br
Br
or

Br

ELECTROPHILIC ADDITION TO UNSATURATED CARBON 287

As the reactants get closer, there is a flow of E
electrons from the π bond to the nearer halogen,
followed by departure of the further halogen as A X anti addition E Y
halide. This results in formation of a carbocation. X
In the next step, we see a significant difference
in mechanism when compared with the addition of BY A Nu
HX. Instead of the carbocation being quenched by Nu B
attack of nucleophile, there is formation of a cyclic
halonium ion. This is achieved by bonding of a E Nu
lone pair of electrons from the large halogen atom
to the carbocation, and it helps stabilize the cation by A syn addition E Nu
transferring the charge to the halogen. X

However, the bridging halogen atom now blocks BY AX
any further attack on the halogen-bonded face of the BY
original double bond, so that when a nucleophile
attacks it has to be from the opposite face. This means syn addition (Greek: syn = with). The observed
that there now has to be rearside attack to open the addition of halogen with anti stereochemistry is thus
cyclic halonium ion, in a process resembling an SN2 different from the simpler addition of HX, where the
mechanism (see Section 6.1). Of course, either car- initially formed carbocation may be attacked from
bon might be attacked by the nucleophile, but the either face by the nucleophile.
consequences are the same. The net result is forma-
tion of a 1,2-dihalo system, and, stereochemically, Bromine and chlorine both react via cyclic halo-
the halogen atoms have been inserted onto opposite nium cations, which we term bromonium and
faces of the double bond. This is described as anti chloronium cations respectively. Fluorine and iodine
addition (Greek: anti = against). are hardly ever used for halogenations; iodine is a
rather unreactive halogenating agent, whereas at the
A mechanism in which groups become attached to other extreme, fluorine is too vigorous to give con-
the same face of the double bond would be termed trollable reactions.

The stereochemical consequences of the elec-
trophilic addition of, say, bromine to certain alkenes
can be predicted as follows:

H3C H Br2 H3C Br H Note H H
H H3C Br H3C Br Br
H3C
H3C H H3C Br S pair of H3C H H
(Z)-but-2-ene S enantiomers ≡
H3C H H3C H Br
or H H3C
H
H3C Br H3C Br

H R
Br R
H3C H Br

Thus, (Z)-but-2-ene will react to give 2,3-dibromo- nucleophilic attack at the two possible centres.
butane as a pair of enantiomers, R,R and S,S, a Because of the symmetry in the molecules, it is only
result of the anti addition. A racemic product will necessary to consider one bromonium ion, since the
thus be formed, because there is equal probability of mirror image version is actually identical.

288 ELECTROPHILIC REACTIONS

Br2 Br H Note H H
H Br Br
pair of Br ≡
Br S enantiomers H
H S H
H
cyclohexene Br
Br H
or H
H
Br Br

R
R

Br
H

Similarly, cyclohexene will form 1,2-dibromo- When one considers bromination of (E)-but-2-ene,
cyclohexane as a racemic product, again R,R and the product turns out to be the meso R,S isomer, i.e.
S,S. Note that the three-membered ring of the a single product.
bromonium ion must be planar and can only be cis-
fused to the cyclohexane ring (see Section 3.5.2).

H3C H Br2 Br H3C HH
H CH3 H3C H Br H3C Br
S
(E)-but-2-ene Br ≡ rotate lower
H CH3 R group
or
H3C H H Br H3C H
Br CH3 Br

H CH3 H meso isomer
H3C Br H
Br H3C Br

R ≡
S

H Br H3C H rotate lower
CH3 Br group

note symmetry in molecules;
therefore, we have the meso isomer

Intriguingly, although there are going to be two pair of enantiomeric products results, due to the two
different and enantiomeric bromonium ions for an types of nucleophilic attack – try it!
unsymmetrical substrate such as (Z)-pent-2-ene, a

CH3 Br2 CH3 H3C H H3C H
H H Br Br

Br +
H3C H
H3C H H3C H Br H3C H Br
(Z)-pent-2-ene A B pair of
enantiomers
CH3 H3C H H3C H =
H Br Br

or Br +
H3C H
H3C H Br H3C H Br
enantiomeric C D
bromonium ions
A = D, and B = C

ELECTROPHILIC ADDITION TO UNSATURATED CARBON 289

For the HX additions above, we noted that, in alcohol (halohydrin), and overall we are seeing the
aqueous solution, water would be the most abundant electrophilic anti addition of X+ and HO−. This is
nucleophile, and the predominant product would sometimes considered as the addition of a hypohalous
thus be an alcohol derivative. A similar situation acid HOX, but is much more easily rationalized in
holds if we use aqueous bromine or chlorine, terms halogenation in the presence of water as the
for example. The product is going to be a halo predominant nucleophile.

d− Br Br2 Br water is the Br addition of HOBr
d+ Br H2O Br predominant
nucleophile Br
CC
Br Br OH
halo alcohol
OH (halohydrin)
OH2 H

One of the properties of halo alcohols formed is achieved by treatment with base, and an intra-
in this way is that they can be used to make molecular SN2 mechanism is involved (see Sec-
epoxides, three-membered oxygen heterocycles. This tion 6.3.2).

Cl HO− Cl an epoxide

HO O O
ethylene oxide
base removes proton intramolecular
from alcohol SN2 reaction
(not particularly
favourable)

Note that the bromination–hydroxylation sequence ideally set up for the SN2 reaction with the necessary
is going to produce anti addition, and the groups are rearside attack (see section 6.1).

Br2 Br NaOH Br
H2O O
cyclohexene O
H O
HO cyclohexene oxide

Br Br

cyclohexene; OH2 OH Br
half-chair conformation diaxial bromo alcohol HO
bromonium ion with planar
three-membered ring; Br preferred conformer
nucleophilic attack from water would be diequatorial

O
O

290 ELECTROPHILIC REACTIONS

In the synthesis of cyclohexene oxide from cyclo- O peroxyacetic acid
hexene shown, this does implicate the less favourable H3C
diaxial conformer in the epoxide-forming step. Cyclo-
hexene oxide contains a cis-fused ring system, the O OH
only arrangement possible, since the three-membered O
ring is necessarily planar (see Section 3.5.2).
cyclohexene cyclohexene oxide
Another method of making epoxides is the elec-
trophilic reaction of alkenes with a peroxy acid such polarized O–O bond in the peroxy acid. One could
as peroxyacetic acid (sometimes simply peracetic realistically suggest a potential carbocation inter-
acid). Thus, cyclohexene may be converted into the mediate, followed by nucleophilic attack of the
epoxide in a single reaction. hydroxyl oxygen, using as precedent the examples
seen above.
Mechanistically, this is an electrophilic attack
involving the π electron system of the alkene and the

a logical, but apparently incorrect mechanism:

H OH O
OO
OH
O
CH3

proposed cyclic mechanism

H OH the hydroxyl proton from
OO OO peroxyacetic acid actually ends
up in the acetic acid by-product
O CH3
CH3

However, since it is found that the hydroxyl proton Epoxides, like cyclic halonium ions, undergo
from peroxyacetic acid actually ends up in the acetic ring opening through rearside attack of nucleophiles
acid by-product, a messy-looking cyclic mechanism (see Section 6.3.2). Two mechanisms are shown,
has been proposed. This starts with the nucleophilic for both basic and acidic conditions. Under acidic
π bond attacking the peroxy acid oxygen, breaking conditions, protonation of the epoxide oxygen occurs
of the O–O bond to form a new carbonyl, with the first. The epoxidation–nucleophilic attack sequence
original carbonyl picking up the hydroxyl’s hydrogen. also adds substituents to the double bond in an
The remaining electrons from the hydroxyl are then anti sense.
used to bond to the electrophilic carbon from the
original double bond.

basic conditions acidic conditions
O
H OH HO H O H HO
O O
or
Nu Nu Nu Nu

Nu protonation of epoxide oxygen
precedes rearside nucleophilic attack
ring opening via rearside
nucleophilic attack

ELECTROPHILIC ADDITION TO UNSATURATED CARBON 291

Box 8.1

Halohydrins: biological activity of semi-synthetic corticosteroids

Corticosteroids are produced by the adrenal glands, and display two main types of biological activity.
Glucocorticoids are concerned with the synthesis of carbohydrate from protein and the deposition of glycogen
in the liver. They also play an important role in inflammatory processes. Mineralocorticoids are concerned with
the control of electrolyte balance, promoting the retention of Na+ and Cl−, and the excretion of K+. Synthetic
and semi-synthetic corticosteroid drugs are widely used in medicine. Glucocorticoids are primarily used for their
antirheumatic and anti-inflammatory activities, and mineralocorticoids are used to maintain electrolyte balance
where there is adrenal insufficiency.

The two groups of steroids share considerable structural similarity, and it is difficult to separate entirely the
two types of activity in one molecule. Extensive synthetic effort has been applied to optimize anti-inflammatory
activity, whilst minimizing the mineralocorticoid activity, which tends to produce undesirable side-effects. One
modification that has proved particularly successful has been to create 9α-halo-11β-hydroxy compounds. The 11β-
hydroxyl is present in all glucocorticoids and is known to be essential for activity; the introduction of the halogen
atom at position 9 was a major development in this group of drugs. Halogenation was achieved as shown below.

esterification with tosyl chloride base-catalysed nucleophile attacks at C-11;
to generate good leaving group E2 elimination C-9 is hindered by the C-10 methyl

HO 11 TsCl TsO AcO− H HO
9H H Br2

Br H

HH HH H H

bromination occurs from

11β-hydroxysteroid AcO less-hindered α face HO−
ring C of steroidal

system HO
H
HO HF AcO−
H OH

FH H base-catalysed Br H

intramolecular

acid-catalysed opening of epoxide SN2 gives epoxide 9α-bromo-
(favouring trans-fused ring system) 11β-hydroxysteroid

11 C D β-face CH3 R
9H CD
OH H unsaturated ketone in ring A and
A 10 H H O CH3 11 H appropriate R group are also
B required for corticosteroid activity
10 9

AB

F

α-face

steroidal ring system 9α-fluoro-11β-hydroxysteroid

Treatment of the 11β-hydroxysteroid with tosyl chloride produces a tosylate ester, providing a good leaving
group for a base-catalysed E2 elimination (see Section 6.4.1). The favoured product is the more-substituted 9,
11-alkene (see Section 6.4.1). A consideration of the steroid shape (see Box 3.19) shows that the 9α-proton and
the 11β-tosylate are both axial and, therefore, anti to each other; they are thus ideally positioned for an elimination

292 ELECTROPHILIC REACTIONS

reaction (see Section 6.4.1). Bromination of the alkene under aqueous alkaline conditions then leads to formation
of the bromohydrin. Interestingly, this reaction is quite stereospecific. Only one bromonium cation is formed,
because the upper face of the steroid is sterically hindered by the methyl groups and approach of the large bromine
molecule occurs from the lower less-hindered α-face. Ring opening by nucleophilic attack of hydroxide occurs
from the upper β-face, and at C-11, since the methyl groups, particularly that at C-10, again hinder attack at C-9.

The natural glucocorticoid is hydrocortisone (cortisol). Semi-synthetic 9α-bromohydrocortisone 21-acetate
was found to be less active as an anti-inflammatory agent than hydrocortisone 21-acetate by a factor of three,
and 9α-iodohydrocortisone 21-acetate was also less active by a factor of 10. However, 9α-fluorohydrocortisone
21-acetate (fludrocortisone acetate) was discovered to be about 11 times more active than hydrocortisone
acetate. Although the bromination sequence shown is equally applicable to chlorine and iodine compounds,
fluorine must be introduced indirectly by the β-epoxide formed by base treatment of the 9α-bromo-11β-hydroxy
analogue.

HO 11 OH HO OAc HO OAc HO OH

21 O O O
OH OH OH
O

OH

9H H H 1 H 16
10 H H Br H FH 2 FH

OOO O

hydrocortisone 9α-bromohydrocortisone fludrocortisone acetate betamethasone
(cortisol)
acetate (9α-fluorohydrocortisone

acetate)

The introduction of a 9α-fluoro substituent increases anti-inflammatory activity, but it increases mineralocor-
ticoid activity even more (300×). Fludrocortisone acetate is of little value as an anti-inflammatory, but it is
employed as a mineralocorticoid. On the other hand, additional modifications may be employed. Introduction
of a 1,2-double bond increases glucocorticoid activity over mineralocorticoid activity, and a 16-methyl group
reduces mineralocorticoid activity without affecting glucocorticoid activity. A combination of these three struc-
tural modifications gives valuable anti-inflammatory drugs, e.g. betamethasone, with hardly any mineralocorticoid
activity.

8.1.3 Electrophilic additions to alkynes the less-substituted carbon, a secondary vinyl cation
being preferred over a primary vinyl cation. Thus,
Electrophilic reactions of alkynes can readily be electrophilic addition of HX follows Markovnikov
predicted, based on the mechanisms outlined above orientation.
for alkenes. Of course, the main extension is that
addition will initially produce an alkene, which will The vinyl halide product is then able to react
then undergo further addition. with a further mole of HX, and the halide atom
already present influences the orientation of addition
Protonation of the alkyne is actually less favourable in this step. The second halide adds to the carbon that
than protonation of an alkene, because the result- already carries a halide. In the case of the second
ing vinyl cation is sp hybridized, having σ bonds addition of HX to RC≡CH, we can see that we
to just two substituents, a π bond, and a vacant are now considering the relative stabilities of tertiary
p orbital. A vinyl cation is thus less stable than and primary carbocations. The halide’s inductive
a comparable trigonal sp2-hybridized carbocation, effect actually destabilizes the tertiary carbocation.
since sp-hybridization brings bonding electrons closer Nevertheless, this is outweighed by a favourable
to carbon; it thus becomes less tolerant of posi- stabilization from the halide by overlap of lone pair
tive charge. Protonation, when it occurs, will be on electrons, helping to disperse the positive charge.

ELECTROPHILIC ADDITION TO UNSATURATED CARBON 293

secondary primary vinyl
cation
vinyl cation

H H H H
HBr not H

RH R R H R

H π bond
Br

Br

RH R H HBr R H RH RH
Br H H H Br H

Br H Br H Br H Br H

H H resonance stabilization main product is
HBr from bromine lone pair geminal dibromide

R H RH
Br H H

H Br H

primary carbocation inductive effect destabilizes
not favourable tertiary carbocation

In the case of electrophilic addition of HX to with a destabilizing inductive effect. The resonance
RC≡CR, it is possible to see even more clearly the contribution from the first halide atom still defines
role of the first halide atom. After addition of the first the position for the second protonation, and thus the
mole of HX, further protonation would give either nature of the major product, the gem-dihalide.
a secondary carbocation or the tertiary carbocation

H H RH both E and Z R H
R configurations Br R
HBr Br R are possible
H
RR R

Br H

RH Br RH R H
Br R R Br R
RH
Br H R Br H H

main product is Br H resonance stabilization
geminal dibromide from bromine lone pair
alternative secondary
carbocation; not favoured

Note also that, if 2 mol of HX add to an alkyne, Predicting the outcome of electrophilic additions to
it is of no consequence whether the first addition alkynes from an extension of alkene reactivity usually
produces an alkene with E or Z stereochemistry, works well, and can be applied to halogenations and
since the orientation of addition means the final hydrations. Hydration of an alkyne has a subtle twist,
product has no potential chiral centres. however; the product is a ketone! This can still be
rationalized quite readily, though.

294 ELECTROPHILIC REACTIONS

secondary

H H2SO4 vinyl cation RH H
H2O H RH
HO H HO H RH
RH R H H
enol
Hg2+ H OH
H2O
more stable
keto tautomer

Protonation of the alkyne produces the more later (see Section 10.1) as an important consideration
favourable secondary vinyl cation, which is then in the reactivity of many organic compounds. This
attacked by water, since water is the predominant reaction involves only one electrophilic addition, and,
nucleophile available. Loss of a proton from this although it does not occur readily using simply aque-
produces an enol, which is transformed into a more ous acid, it can be achieved by the use of mercuric
stable isomeric form, the ketone. This transforma- salts as catalyst. The mercuric ion may function as a
tion is termed tautomerism, and we shall meet it Lewis acid to facilitate formation of the vinyl cation.

Box 8.2

Electrophilic alkylation in steroid side-chain biosynthesis

Polyene macrolide drugs such as amphotericin and nystatin have useful antifungal activity but no antibacterial
action (see Box 7.14). Their activity is a result of binding to sterols in the eukaryotic cell membrane; they display
no antibacterial activity because bacterial cells do not contain sterol components. Binding to sterols modifies cell
wall permeability and leads to pores in the membrane and loss of essential cell components. Fungal cells are
also attacked in preference to mammalian cells, since the antibiotics bind much more strongly to ergosterol, the
major fungal sterol, than to cholesterol, the main animal sterol component. This selective action allows these
compounds to be used as drugs, though a limited amount of binding to cholesterol is responsible for side-effects
of the drugs.

H HH
HO
HH
HO ergosterol
(fungi)
cholesterol
(animals)

H H

HH HH
HO HO

stigmasterol sitosterol
(plants) (plants)

ELECTROPHILIC ADDITION TO UNSATURATED CARBON 295

A principal structural difference between ergosterol and cholesterol that affects binding to polyene drugs is the
extra methyl group on the side-chain in ergosterol. This extra methyl is known to be introduced in nature by an
electrophilic alkylation of a double-bond system, and it employs S-adenosylmethionine (SAM) as the electrophilic
agent. We have already met SAM as a biochemical alkylating agent through SN2 reactions (see Box 6.5). The
role of SAM in these electrophilic reactions is similar. It possesses a good leaving group in the neutral molecule
S-adenosylhomocysteine, and the methyl group can be donated to the alkene nucleophile in an electrophilic
addition.

electrophilic addition; Ad = adenosine
C-methylation using SAM
S-adenosyl- Ad
homocysteine
S CO2H second electrophilic Ad
NH2 addition involving SAM
Ad SAM S CO2H
H3C S CO2H H3C NH2

NH2 H 1,2-hydride shift followed
by loss of proton

H

e.g. lanosterol NADPH

NADPH

H

e.g. cholesterol NADPH dehydrogenation

dehydrogenation

e.g. sitosterol e.g. stigmasterol e.g. ergosterol

Cholesterol and ergosterol share a common biosynthetic pathway from squalene oxide as far as lanosterol
(see Box 6.12), but then subsequent modifications vary. Part of the route to cholesterol involves reduction of
the side-chain double bond, an enzymic process utilizing the hydride donor NADPH as reducing agent (see
Box 7.6). During ergosterol biosynthesis, the side-chain double bond is involved in an electrophilic reaction with
SAM, addition yielding the anticipated tertiary carbocation. This carbocation then undergoes a Wagner–Meerwein
1,2-hydride shift (see Section 6.4.2), an unexpected change, and subsequently loses a proton from the SAM-derived
methyl group to generate a new alkene. NADPH reduction of this double bond leads to the C-methylated side-
chain, as found in ergosterol, though further unsaturation needs to be introduced via an enzymic dehydrogenation
reaction.

Plant sterols such as stigmasterol typically contain an extra ethyl group when compared with cholesterol. Now
this is not introduced by an electrophilic ethylation process; instead, two successive electrophilic methylation
processes occur, both involving SAM as methyl donor. Indeed, it is a methylene derivative like that just seen in
ergosterol formation that can act as the alkene for further electrophilic alkylation. After proton loss, the product
has a side-chain with an ethylidene substituent; the side-chains of the common plant sterols stigmasterol and
sitosterol are then related by repeats of the reduction and dehydrogenation processes already seen in ergosterol
formation.

296 ELECTROPHILIC REACTIONS

8.1.4 Carbocation rearrangements As a simple example, note that the major products
obtained as a result of addition of HBr to the alkenes
Carbocations are highly reactive intermediates, and shown below are not always those initially expected.
are notorious for their ability to rearrange into more For the first alkene, protonation produces a particu-
stable variants. We have already met this concept larly favourable carbocation that is both tertiary and
when we considered carbocation rearrangements benzylic (see Section 6.2.1); this then accepts the bro-
as competing reactions during SN1 nucleophilic sub- mide nucleophile. In the second alkene, protonation
stitutions (see Section 6.4.2). Since carbocations are produces a secondary alkene, but hydride migration
also involved in electrophilic reactions, we must then leads to a more favourable benzylic carbocation.
expect that analogous rearrangements might occur As a result, the nucleophile becomes attached to a
in these. This is indeed the case. In Section 6.4.2, carbon that was not part of the original double bond.
we included examples of rearrangements in carboca- Further examples of carbocation rearrangements will
tions formed during electrophilic additions, because be met under electrophilic aromatic substitution (see
identical processes are involved, and it was more Section 8.4.1).
appropriate to consider these topics together, rather
than separately.

HBr

2-phenylbut-1-ene Br

formation of tertiary benzylic
carbocation favoured

HBr

HH Br

3-phenylprop-1-ene hydride migration produces
more favourable benzylic
formation of secondary carbocation
carbocation favoured

Rearrangements are an unexpected complication, on a terminal carbon atom; protonation of either
and it is sometimes difficult to predict when they C-2 or C-3 would produce an unfavourable primary
might occur. We need to look carefully at the carbocation.
structure of any proposed carbocation intermediate
and consider whether any such rearrangements are H HBr H resonance-stabilized Br−
probable. In most cases we shall only need to allylic cation
rationalize such transformations, and will not be 13
trying to predict their possible occurrence. 24 H

8.2 Electrophilic addition to buta-1,3-diene Br−
conjugated systems
HH
The first step in the reaction of HX with an alkene
is protonation to yield the more stable cation. If Br Br
we extend this principle to a conjugated diene, e.g. 1,2-addition
buta-1,3-diene, then we can see that the preferred 1,4-addition
carbocation will be produced if protonation occurs conjugate addition

ELECTROPHILIC ADDITION TO CONJUGATED SYSTEMS 297

At first glance, this appears to be a secondary system as in the 1,4-adduct is termed conjugate
carbocation, but on further examination one can see addition.
that it is also an allylic cation. Allylic carbocations
are stabilized by resonance, resulting in dispersal Now the allylic cation has two limiting structures,
of the positive charge (see Section 6.2.1). From one of which is a secondary carbocation and the
these two resonance forms, we can predict that both other a primary carbocation. We would expect
carbons 2 and 4 will be electron deficient. Now the secondary carbocation to contribute more than the
this has particular consequences when we consider primary carbocation, and this is usually reflected in
subsequent attack of the nucleophile X− on to the the proportions of the two products actually obtained
carbocation. There are two possible centres that from the reaction carried out at low temperatures.
may be attacked, resulting in two different products. Why the rider about low temperatures? Well, the
The products are the result of either 1,2-addition product ratio is different if the same reaction is carried
or 1,4-addition. The addition across the four-carbon out at higher temperatures, and typically the 1,2-
adduct now predominates.

HBr + kinetic control
−80˚C product ratio determined by
Br Br stability of carbocation
80% 20%

HBr + thermodynamic control
40˚C product ratio determined by
Br Br stability of product
20% 80%

1,2-adduct 1,4-adduct

At the higher temperature, the thermodynamic sta- that the reaction is reversible, so that the product can
bility of the product is the important consideration, lose halide to regenerate the allylic cation. Thus, the
with the 1,4-adduct, a disubstituted alkene, being product mixture from the lower temperature reaction
more stable than the 1,2-adduct, which is a monosub- is converted upon heating into the product mixture
stituted alkene. An essential part of the reasoning is corresponding to the higher temperature.

more favoured
secondary carbocation

heat

+

Br Br heat
80% 20%

low temperature + more stable
kinetic control disubstituted product

Br Br
20% 80%

high temperature
thermodynamic control

These concepts are termed kinetic control and importance of the carbocations, with the predominant
thermodynamic control. At the lower temperature, one reacting faster. At the higher temperature, the
the product ratio is determined by the relative product ratio is determined by the stability of the

298 ELECTROPHILIC REACTIONS

product, with the more stable one predominating. higher temperatures there is now sufficient energy
These products are, of course, the result of addition available to overcome both activation energies with
of just 1 mol of HX to the conjugated system. The ease, and, more importantly, the reverse reactions
second double bond could also react if further HX become feasible. We can also see that the less stable
were available, with regiochemistry now following 1,2-addition product will revert back to the allylic
the principles already established in Section 8.1. cation faster than the 1,4-addition product simply
because the energy barrier is that much less. The
The energy diagram for kinetic versus thermo- dominant equilibrium product will thus become the
dynamic control is shown in Figure 8.2. This may more stable material, i.e. the 1,4-addition product; we
be interpreted as follows. The 1,4-addition product now have thermodynamic control.
is of lower energy, i.e. more stable, than the 1,2-
addition product. The critical step, however, is the Similar observations emerge from addition of halo-
interaction of the bromide nucleophile with the allylic gens to butadiene. Thus, low-temperature bromina-
cation. The activation energy leading to the 1,2- tion gives predominantly the 1,2-adduct. At higher
addition product is lower than that leading to the temperatures, the 1,4-adduct is the main product, and
1,4-addition product. Therefore, at lower tempera- the mixture from the lower temperature reaction equi-
tures the 1,2-adduct is formed faster, and becomes the librates to the same product ratio. The 1,4-product is
dominant product. At the lower temperature, though, the thermodynamically more stable; it has the more-
there is insufficient energy available to overcome the substituted double bond, and the two large bromine
much larger energy barrier for the reverse reactions, atoms are further apart in this isomer. Mechanisms
so neither reaction is reversible. Both products are for formation and equilibration of the products can be
formed, but do not revert back to the allylic cation. written as shown, using bromonium cation intermedi-
Therefore, we have kinetic control: the product ratio ates. It is perhaps less easy to see why the 1,2-adduct
depends upon which product is formed faster. At should be the kinetically controlled product, until

activation energy for 1,4-addition
activation energy for 1,2-addition

Energy Br

H Br Br 1,2-addition

1,4-addition
Br

Reaction coordinate
Figure 8.2 Energy profile: 1,2 and 1,4 electrophilic addition to conjugated diene

CARBOCATIONS AS ELECTROPHILES 299

we consider that the bromonium cation is actually then use the same type of rationalization as with the
a stabilized carbocation (see Section 8.1.2). We can carbocation intermediates in HBr addition.

Br2 Br + Br Br
−15˚C Br
33% Br Br
67% 1,4-adduct Br Br
1,2-adduct

heat 60˚C

Br + Br Br
Br
Br Br Br
10% Br
1,2-adduct 90%
1,4-adduct

mechanisms for formation and
equilibration of 1,2- and 1,4-adducts

8.3 Carbocations as electrophiles is vulnerable to attack by another alkene molecule,
provided that the alkene concentration is sufficiently
As we have seen in Section 8.1, reaction of an alkene high. For example, protonation of styrene leads to
with an electrophile produces a carbocation that is a secondary carbocation that is favoured by being
subsequently attacked by a nucleophile. However, benzylic (see Section 6.2.1).
the carbocation is itself an electrophilic species, and

electrophilic formation of favoured
addition of alkene
secondary benzylic

H H H H HH carbocation
H H H
H+ H
H H HH H
Ph H H

styrene Ph Ph Ph Ph

favoured secondary Nu− electrophilic addition
benzylic carbocation −H+ of a further molecule

of styrene

Me Nu Me H

Ph Ph Ph Ph H
+ H

Me Ph Ph

Ph

etc. H
Ph Ph Ph
polymers

This carbocation now becomes the electrophile, second styrene molecule, the regiochemistry of attack
and may be attacked by the π electrons of a being the same as with the original protonation,

300 ELECTROPHILIC REACTIONS

i.e. giving the secondary benzylic carbocation. Now practice, the process is more useful for generating
this carbocation may suffer several fates. It may dimers and trimers than polymers, and industrial
be attacked by a nucleophilic species or, more polymers are usually produced by radical processes
likely, it may lose a proton to yield an alkene. (see Section 9.4.2).
Alternatively, it may act as the electrophile for
reaction with a further styrene molecule, generating Cationic polymerization is, of course, an inter-
yet another carbocation. It can be seen that this molecular electrophilic addition process. Intramolec-
type of process may then continue, giving polymeric ular electrophilic addition involving two double
products: polystyrene. The final carbocation will bonds in the same molecule may be used to generate a
be discharged most probably by loss of a proton. cyclic system. Thus, the trienone shown is converted
The process is termed cationic polymerization. In into a mixture of cyclic products when treated with
sulfuric acid.

protonation to favourable electrophilic addition to give proton loss generates more-
tertiary carbocation favourable tertiary carbocation substituted double bond and
favourable conjugated system

OO O O
H H2SO4 − H+

6,10-dimethyl- β-ionone
undeca-3,5,9-triene-2-one OO

alternative products not favoured
less-substituted double bond; not conjugated

This is easily rationalized by protonation of the The products are then formed by loss of a proton from
terminal alkene, yielding the preferred tertiary carbo- this carbocation, with a choice of protons that may
cation. The carbocation is then attacked by π elec- be lost, so that a mixture of products in varying pro-
trons from the neighbouring double bond, creating a portions results. β-Ionone is the predominant product.
new σ bond and a ring system. Note that this results This is the most substituted alkene, and has the added
in a favourable tertiary carbocation and a favourable stability conferred by extending conjugation with the
strain-free six-membered ring (see Section 3.3.2). unsaturated ketone (see Section 2.8).

Box 8.3

Electrophilic additions to carbocations in terpenoid and steroid biosynthesis

Terpenoids and steroids account for a huge group of natural products, and provide us with many useful materials,
including flavouring and perfumery agents, aromatherapy oils, some vitamins, steroidal hormones and a range
of drugs. Although spanning a vast range of chemical structures, these compounds all derive from two simple
precursors, dimethylallyl diphosphate and isopentenyl diphosphate.

CARBOCATIONS AS ELECTROPHILES 301

cation formation via electrophilic addition OPP = diphosphate
loss of leaving group giving tertiary cation
OO

OPP OPP OPP PP
H OOO
dimethylallyl diphosphate isopentenyl
DMAPP diphosphate (IPP) OO

– H+

OPP

resonance-stabilized OPP monoterpenes
allylic cation geranyl diphosphate (C10)

(GPP)

Dimethylallyl diphosphate is responsible for generating the carbocation. Loss of diphosphate as the leaving
group produces a resonance-stabilized allylic cation. An intermolecular electrophilic addition follows, with
isopentenyl diphosphate as the source of π electrons. Addition to the cationic species takes place at the terminal
carbon that is sterically less congested – at first glance, we appear to be invoking the less favourable resonance
form, but an alternative addition through the double bond onto the tertiary cation could be drawn. At this stage,
it is important to appreciate that these reactions are enzyme controlled, so that we can have two different species
reacting in a highly specific manner. The carbocation product is the more stable tertiary carbocation, as we might
predict, and this loses a proton to form the more-substituted alkene product, geranyl diphosphate.

electrophilic addition
giving tertiary cation

OPP resonance-stabilized OPP OPP
geranyl diphosphate allylic cation IPP H

– H+

sesquiterpenes OPP
(C15)

farnesyl diphosphate
(FPP)

An exactly analogous process can then occur, in which geranyl diphosphate provides the allylic cation, and a
further molecule of isopentenyl diphosphate adds on, giving farnesyl diphosphate; this can subsequently yield
geranylgeranyl diphosphate.

OPP allylic IPP – H+ OPP
cation

farnesyl diphosphate geranylgeranyl diphosphate
(GGPP)

diterpenes
(C20)

The compounds geranyl diphosphate, farnesyl diphosphate, and geranylgeranyl diphosphate are biochemical
precursors of monoterpenes, sesquiterpenes, and diterpenes respectively, and virtually all subsequent modifications
of these precursors involve initial formation of an allylic cation through loss of diphosphate as the leaving group.

The formation of cyclic terpenoids involves intramolecular electrophilic addition, and this can be exemplified
by the following monoterpene structures, again with all reactions being enzyme controlled.

302 ELECTROPHILIC REACTIONS

Box 8.3(continued)

Before cyclization can occur, however, there has to be a change in stereochemistry at the 2,3-double bond, from E
in geranyl diphosphate to Z, as in neryl diphosphate. It should be reasonably clear that geranyl diphosphate cannot
possibly cyclize to a six-membered ring, since the carbon atoms that need to bond are not close enough to each
other. The change in stereochemistry is achieved through allylic cations and linalyl diphosphate (see Box 6.4).

OPP = diphosphate single bond in LPP Z
allows rotation OPP
E OPP OPP
OPP
≡

geranyl PP linalyl PP neryl PP
(GPP) (LPP) (NPP)

OPP OPP OPP OPP

resonance-stabilized allylic cation resonance-stabilized allylic cation
(geranyl cation) (neryl cation)

Geranyl diphosphate ionizes to the resonance-stabilized geranyl carbocation, which, in nature, can recombine
with the diphosphate anion in two ways, either reverting to geranyl diphosphate or forming linalyl diphosphate. In
linalyl diphosphate, the original double bond from geranyl diphosphate has now become a single bond, and free
rotation is possible. Ionization of linalyl diphosphate then occurs, giving a resonance-stabilized neryl carbocation,
one form of which now has a Z double bond. Recombination of this with diphosphate leads to neryl diphosphate,
a geometric configurational isomer of geranyl diphosphate. It is normally very difficult to change the configuration
of a double bond. Nature achieves it easily in this allylic system via carbocation chemistry, and, in metabolic
processes, geranyl diphosphate can be isomerized through linalyl diphosphate to neryl diphosphate.

electrophilic addition
gives tertiary cation

OPP

NPP neryl cation menthyl / α-terpinyl
cation
protonation giving nucleophilic addition of

– H+ H2O tertiary cation hydroxyl forms new
heterocyclic ring

H
H+

limonene OH OH O
α-terpineol cineole

CARBOCATIONS AS ELECTROPHILES 303

Cyclization involves the neryl cation with electrophilic attack from the double bond giving the favoured
tertiary carbocation and a favourable six-membered ring. Loss of a proton from this cation results in formation of
limonene, actually the less-substituted alkene, so this where enzyme control takes over. Alternatively, discharge
of the cation by addition of water as a nucleophile leads to α-terpineol. By a similar sequence, α-terpineol may be
transformed into cineole. This requires generation of a carbocation by protonation of the double bond; the proton
is added so that the favoured tertiary cation is formed. Cineole formation then involves nucleophilic attack from
the alcohol group with generation of a further ring system, this time a heterocyclic ring. Limonene is a major
constituent of lemon oil, α-terpineol is found in pine oil, and cineole is the principal component of eucalyptus oil.

By far the most impressive example of electrophilic addition in natural product formation is in the biosynthesis
of steroids. The substrate squalene oxide is cyclized to lanosterol in a process catalysed by a single enzyme.
Lanosterol is then converted into the primary animal-steroid cholesterol. Squalene oxide comes from squalene,
which is itself formed through a combination of two molecules of farnesyl diphosphate.

squalene 2 × farnesyl PP
epoxidation
sequence of concerted
1,2-hydride and 1,2-methyl shifts

H H H

electrophilic HO
cyclizations loss of proton
gives alkene
HO H H
O HO lanosterol

squalene oxide H
H protosteryl cation

carbocation formation see below for
by protonation and further details
ring opening of
epoxide

cholesterol

protonation of epoxide electrophilic addition electrophilic addition
allows ring opening to gives tertiary cation gives tertiary cation
tertiary cation + six-membered ring + six-membered ring

O HO HO H
squalene oxide H HO

H H

electrophilic addition
gives secondary cation
+ six-membered ring

electrophilic addition
H H gives tertiary cation

+ five-membered

ring

H HO H
HO H

H
protosteryl cation

304 ELECTROPHILIC REACTIONS

Box 8.3(continued)

With squalene oxide suitably positioned and folded onto the enzyme surface, a series of electrophilic cyclizations
can be used to rationalize formation of the polycyclic structure. The cyclizations are carbocation-mediated and
proceed in a stepwise sequence. Thus, protonation of the epoxide group will allow opening of this ring and
generation of the preferred tertiary carbocation (see Box 6.12). This is suitably placed to allow electrophilic
addition to a double bond, formation of a six-membered ring and production of a new tertiary carbocation. This
process continues twice more, generating a new carbocation, until the protosteryl cation is formed. This is then
followed by a sequence of concerted Wagner–Meerwein migrations of methyls and hydrides leading to lanosterol.
It is not appropriate to discuss these migrations in this chapter, but this aspect is studied further in Box 6.12.

Note that the preferred tertiary carbocation (Markovnikov addition) is produced in all of the cyclizations, except
in one case, the third ring, which appears to be formed in an anti-Markovnikov sense. The latest studies now show
that the reaction as illustrated above is not quite correct. The third ring is first produced as a five-membered one,
reassuringly by Markovnikov addition via the predicted tertiary carbocation, and it is subsequently expanded to a
six-membered ring through a Wagner–Meerwein 1,2-alkyl shift. This should not be thought of as a complication;
simply note the formation of a biochemically important polycyclic ring system through a series of electrophilic
additions.

8.4 Electrophilic aromatic substitution be viewed as markedly different behaviour from
alkenes, but merely as an obvious consequence of
Electrophilic reactions with aromatic substrates aromatic stabilization dictating the fate of the initial
tend to result in substitution. This should not carbocation.

E E
E

electrophilic addition
Nu Nu

E E E electrophilic substitution
H
p electrons flow towards net result is
electrophile forming s bond H substitution
resultant carbocation loses
proton and regains
aromatic stability

However, there are differences, in that electrophilic and this leads to restoration of the aromatic π electron
attack on to an aromatic ring is energetically less system. The overall reaction is thus substitution.
favourable than attack on to an alkene. This is
because the initial addition reaction leading to E E E
carbocation formation uses up one of the p orbitals H H H
that normally contributes to the π electron system,
and thereby creates an sp3-hybridized centre. This resonance stabilization of arenium cation
means that the π electron delocalization characteristic
of an aromatic system is destroyed. However, there Because the initial electrophilic attack and carboca-
is also some good news: the carbocation generated tion formation results in loss of aromatic stabilization,
(an arenium cation) is resonance stabilized and is the electrophiles necessary for electrophilic aromatic
considerably more favourable than the corresponding substitution must be more reactive than those that
simple trigonal cation from an alkene. Accordingly, typically react with alkenes. Thus, chlorination or
the electrophilic addition can occur; but, rather than
reacting with a nucleophile, the cation loses a proton

ELECTROPHILIC AROMATIC SUBSTITUTION 305

bromination generally occurs only in the presence of The role of the Lewis acid AlCl3 in the chlorination
a Lewis acid, which allows a greater fraction of the
positive charge to develop on the electrophilic atom. of benzene is illustrated below; we can consider the
electrophilic species as Cl+.

Cl Cl AlCl3 complex dissociates to form other reagent combinations include
Cl+ as formal electrophile Br2 / AlBr3; Br2 / FeBr3

Cl Cl AlCl3 ≡ Cl AlCl4

Lewis acid polarizes H Cl AlCl3 dissociation of anion
halogen molecule Cl Cl AlCl3 produces chloride as base
to facilitate loss of proton
Cl Cl AlCl3

electrophilic attack from
p electrons onto complex

Cl

chlorobenzene

Nitration of an aromatic ring using nitric acid also loss of water and production of the nitronium ion as
requires the presence of sulfuric acid. Nitric acid is electrophile.
protonated by the stronger sulfuric acid, leading to

protonation from

strong acid

O H+ O − H2O O
N
HN HN
OO OO O

nitric acid H nitronium ion
as electrophile

O
H
O N NO2

NO

O

nitrobenzene

Aromatic sulfonation occurs with fuming sulfuric is present in concentrated sulfuric acid as a result of
acid, where the electrophile is sulfur trioxide. This the equilibrium shown.

OO OO etc.
S S
2H2SO4 SO3 + H3O + HSO4
OO

resonance structures predict the sulfur
atom in SO3 is electron deficient

306 ELECTROPHILIC REACTIONS

The product of electrophilic aromatic substitution to replace an SO3H group attached to an aromatic
is a sulfonic acid (see Section 7.13.1). Unusually, ring with hydrogen by heating the sulfonic acid with
sulfonation is found to be reversible; it is possible steam.

OO O O H+ SO3H
S HO O
O − H+
S S benzenesulfonic acid
O O

sulfur trioxide

8.4.1 Electrophilic alkylations: Friedel–Crafts electrophile is developed from either an alkyl halide
reactions or an acyl halide in the presence of a Lewis acid.
The alkylation reaction is mechanistically similar to
Particularly useful reactions result from Friedel– the halogenation process above, with the Lewis acid
Crafts alkylations and acylations, in which the increasing polarization in the alkyl halide.

complex dissociates to form
R+ as formal electrophile

R Cl AlCl3 R Cl AlCl3 R AlCl4

Lewis acid polarizes Cl AlCl3
halide molecule Cl AlCl3

H dissociation of anion
R produces chloride as base
to facilitate loss of proton
R

electrophilic attack from p
electrons onto carbocation

R

alkylbenzene

However, although we invoked a Lewis acid com- H3C Cl AlCl3 SN2 likely
plex to provide the halonium electrophile, there is
considerable evidence that, where appropriate, the H3C AlCl3 SN2 unlikely for
electrophile in Friedel–Crafts alkylations is actu- CH Cl stereochemical reasons
ally the dissociated carbocation itself. Of course, a
simple methyl or ethyl cation is unlikely to be formed, H3C
so there we should assume a Lewis acid complex as
the electrophilic species. On the other hand, if we can H3C Cl AlCl3 SN1 likely for
get a secondary or tertiary carbocation, then this is CH stereochemical reasons
probably what happens. There are good stereochem-
ical reasons why a secondary or tertiary complex H3C
cannot be attacked. Just as we saw with SN2 reac-
tions (see Section 6.1), if there is too much steric
hindrance, then the reaction becomes SN1 type.

ELECTROPHILIC AROMATIC SUBSTITUTION 307

Indeed, we can also achieve alkylation of an but using an aromatic substrate. Thus, an alkene in
aromatic ring by using any system that generates a strongly acidic conditions, or an appropriate alcohol
carbocation. In effect, we are paralleling the concept in acid, may be used to generate a carbocation and
of carbocations as electrophiles as in Section 8.3, achieve electrophilic substitution.

H
HF

carbocation generated by
protonation of alkene

HF

H
HCl

OH OH2

carbocation generated by
protonation of alcohol and
loss of leaving group

This involvement of carbocations actually limits the is used to generate what would be a primary carbo-
utility of Friedel–Crafts alkylations, because, as we cation, rearrangement to a secondary carbocation is
have already noted with carbocations, rearrange- likely to occur. Both types of cationic species can
ment reactions complicate the anticipated outcome then bond to the aromatic ring, and a mixture of iso-
(see Section 6.4.2). For instance, when a Lewis acid meric products is formed.

AlCl3 H H hydride shift converts unfavourable
Cl Cl AlCl3 primary into more favourable
secondary carbocation

HH H

primary secondary
carbocation carbocation

minor product major product

308 ELECTROPHILIC REACTIONS

To be really satisfactory, a Friedel–Crafts alkyla- starting material, with the consequence that di-, tri-,
tion requires one relatively stable secondary or ter- and poly-alkylated products also tend to be formed. It
tiary carbocation to be formed from the alkyl halide may be possible to minimize this if the starting mate-
by interaction with the Lewis acid, i.e. cases where rial is readily available, e.g. benzene, and can thus be
there is not going to be any chance of rearrangement. used in large excess.
Note also that we are unable to generate carboca-
tions from an aryl halide – aryl cations (also vinyl 8.4.2 Electrophilic acylations: Friedel–Crafts
cations, see Section 8.1.3) are unfavourable – so that reactions
we cannot use the Friedel–Crafts reaction to join aro-
matic groups. There is also one further difficulty, as In Friedel–Crafts acylations, an acyl halide, almost
we shall see below. This is the fact that introduc- always the chloride, in the presence of a Lewis acid
tion of an alkyl substituent on to an aromatic ring is employed to acylate an aromatic ring. The process
activates the ring towards further electrophilic sub- is initiated by polarization of the carbon–chlorine
stitution. The result is that the initial product from bond of the acyl chloride, resulting in formation of a
Friedel–Crafts alkylations is more reactive than the resonance-stabilized acylium ion.

lone pair can back-bond to
transfer charge to oxygen, thus
delocalizing positive charge

O AlCl3 O OO Cl AlCl3
R Cl R Cl AlCl3 CC
RR

resonance-stabilized
acylium ion

The acylium ion is now our electrophile, and aromatic complex must be decomposed by treatment with
substitution proceeds in the predicted manner. water, and the significant consequence is that the
Lewis acid has to be supplied in stoichiometric
The intermediate cation is subsequently deproto- amounts, in sharp contrast to Friedel–Crafts alky-
nated to yield the acylated product. However, this lations, where only catalytic amounts need to be
acyl derivative is actually a ketone, which can also used.
complex with the Lewis acid. Accordingly, the final

O Cl AlCl3
H
O dissociation of anion
C R produces chloride as base
R to facilitate loss of proton

electrophilic attack from p Cl AlCl3
electrons onto acylium ion
O AlCl3 O AlCl3
R AlCl3 R H2O O
R

acylbenzene Lewis acid complex ketone
(ketone)

ELECTROPHILIC AROMATIC SUBSTITUTION 309

A similar problem of complex formation may 8.4.3 Effect of substituents on electrophilic
be encountered if either amino or phenol groups aromatic substitution
are present in the substrate, and the reaction may
fail. Under such circumstances, these groups need Substituents already bonded to an aromatic ring influ-
to be blocked (protected) by making a suitable ence both the rate of electrophilic substitution and
derivative. Nevertheless, Friedel–Crafts acylations the position of any further substitution. The effect of
tend to work very well and with good yields, a particular substituent can be predicted by a con-
uncomplicated by multiple acylations, since the acyl sideration of the relative stability of the first-formed
group introduced deactivates the ring towards fur- arenium cation, formation of which constitutes the
ther electrophilic substitution. This contrasts with rate-limiting step. In general, substituents that are
Friedel–Crafts alkylations, where the alkyl sub- electron releasing activate the ring to further substi-
stituents introduced activate the ring towards further tution – they help to stabilize the arenium ion. Sub-
substitution (see Section 8.4.3). stituents that are electron withdrawing destabilize the
arenium ion, therefore, are deactivating and hinder
O O further substitution.
H3C Cl CH3
E E
AlCl3 H H

O X X
Cl
electron-withdrawing effect electron-donating effect
destabilizes carbocation stabilizes carbocation

O For the position of further substitution, we also need
to consider resonance forms of the arenium ion.

AlCl3 E E E
H H H
A useful extension of Friedel–Crafts acylation is
an intramolecular reaction leading to cyclic prod- resonance stabilization of arenium cation:
ucts. Thus, five- and six-membered rings are readily ortho and para positions are electron deficient
and efficiently created by use of an appropriate aryl
acyl chloride, as shown below. From these resonance forms we can deduce that posi-
tions ortho and para to the position of attack are elec-
O AlCl3 tron deficient. This means that any pre-existing sub-
Cl stituent will produce maximum effect if it is located
in any of these positions. We normally think in terms
O of the existing substituent directing the attack of the
1-hydrindanone electrophile to a position that optimizes the stability
(2,3-dihydroinden-1-one) of the arenium ion. Electron-releasing substituents are
thus ortho and para directing because they help to
Cl AlCl3 stabilize the arenium ion; electron-withdrawing sub-
O stituents destabilize the arenium ion more if they are
ortho or para, and, consequently, they are found to be
O meta directing. The observed electron-releasing and
1-tetralone electron-withdrawing properties of various groups are
summarized in Table 8.1, though to understand these

310 ELECTROPHILIC REACTIONS

Table 8.1 Directing effects of substituents in electrophilic aromatic substitution
Electron-releasing groups: ortho and para directors

Strong: NH2 OH O OR NR2

Moderate: O N SO2R O
C H C
NR OR
H
CF3 CCl3
Weak: –––R –––Ar

Electron-withdrawing groups: meta directors

Strong: O
N NR3

O

Moderate: d+ d− O d− O d− O d− O d− O d−
CN C d+ C d+ C d+ C d+ O d−

OR NH2 R H S
d+ OH

Halogens (σ withdrawers, π donors): ortho and para directors

–––F –––Cl –––Br –––I

fully we need to consider the properties in terms but is derived from overlap of σ orbitals with the
of both inductive effects and delocalization or aromatic π orbital system. Thus, with both ortho and
resonance effects. We must also appreciate that para addition there is one resonance form of the
the term ‘directing’ indicates the major product(s) arenium ion that is particularly favourable, in that the
formed, and not the exclusive product. Mixtures of positive charge is adjacent to the electron-donating
products are the norm. alkyl group, which thus helps to disperse the charge,
as with a carbocation (see Section 6.2.1). There is no
Stabilization of the arenium ion through electron- particularly favourable resonance form resulting from
donating effects is typical of alkyl substituents. This meta addition.
is not strictly an inductive effect (see Section 4.3.3),

inductive effect inductive effects
d−
CH3 CH3 OO RO d+ O
E E NC
CH3 CH3 H H
ortho E EE
H
E HH

toluene favourable unfavourable unfavourable
CH3
CH3 CH3 CH3
E
meta E E
E H H H

ELECTROPHILIC AROMATIC SUBSTITUTION 311

inductive effects

inductive effect d−
CH3 OO RO d+ O
CH3 CH3 CH3 NC
para

E H H H H H
E E E E E

favourable unfavourable unfavourable

Nitration of toluene gives approximately 59% partial positive charge. However, we must also realize
o-nitrotoluene, 37% p-nitrotoluene, and only 4% that toluene undergoes electrophilic substitution some
m-nitrotoluene. On the other hand, nitration of 25 times as readily as benzene because of the benefi-
nitrobenzene gives about 93% m-dinitrobenzene, 6% cial inductive effect, whereas nitrobenzene undergoes
o-dinitrobenzene, and 1% p-dinitrobenzene. Since nitration only about 10−4 times as readily as benzene
nitro is an electron-withdrawing group, those reso- because the inductive effect withdraws electrons from
nance forms stabilized by the presence of an alkyl the ring.
substituent are going to be seriously destabilized
when alkyl is replaced by an electron-withdrawing Groups that are particularly strong electron re-
group, and so meta substitution predominates. This leasers do not achieve this by an inductive effect,
can be appreciated even more readily when one looks but they have heteroatoms with lone pair electrons
at the representation of the nitro group or, say, an that are able to stabilize resonance structures by
ester group: the unfavourable resonance forms have transferring the charge to the heteroatom, i.e. an
the positive charge positioned adjacent to a full or electron-releasing resonance effect. An amino group
is typical of this type of substituent.

NH2 ortho NH2 NH2 resonance effect NH2
E E E E
H H NH2 H
E
H

aniline favourable

NH2 NH2 NH2 NH2

meta

E E E E NH2
H H H
NH2 NH2 NH2
para resonance effect
NH2

E H H H H
E E E E

favourable

It can be seen that lone pair donation creates for an amino group due to the heteroatom, but this
another favourable resonance form only when elec- effect is vastly overpowered by the resonance effect,
trophilic attack is ortho or para to the amino group. and an amino group is strongly activating and gives
There is a small electron-withdrawing inductive effect rise to ortho and para substitution. In fact, aniline

312 ELECTROPHILIC REACTIONS

reacts readily with bromine in water, without any the powerful activation provided by the phenol group.
need for a catalyst, giving 2,4,6-tribromoaniline in The activation is so great that all three positions are
nearly quantitative yield. The same is true for phenol, brominated.
which rapidly gives 2,4,6-tribromophenol, because of

NH2 Br2 Br NH2 OH Br2 Br OH
aniline Br phenol Br

H2O H2O

Br Br
2,4,6-tribromoaniline 2,4,6-tribromophenol

Groups such as amides and esters, where the two conflicting types of resonance behaviour in such
heteroatom is bonded to the aromatic ring, might molecules. These groups do activate the ring towards
be expected to behave similarly; this is true, but the electrophilic attack, and are ortho and para directing,
level of activation is markedly less than for amines but activation is considerably less than with simple
and phenols. We can understand this because of amino and phenolic groups.

O O OO

H R H R O R destabilizing O R
stabilizing N N stabilizing

destabilizing

H H H H
E E E E

For most substituents, electron-donating ones a very strong electron-withdrawing inductive effect
activate the ring towards electrophilic attack and and, consequently, significant deactivation towards
also direct ortho and para. Conversely, electron- electrophilic substitution. However, because there is
withdrawing substituents are deactivating and direct an electron-donating resonance effect we get ortho
substitution meta. This appears so straightforward and para substitution. This lone pair donation is not
a concept that we must have an exception; this is nearly as effective as with oxygen and nitrogen, how-
found with halogen substituents. Thus, chloroben- ever, because in the larger atom the orbitals are less
zene is nitrated about 50 times more slowly than able to overlap effectively. So we have the con-
benzene, but yields o- and p-nitro products. How- flicting trends, deactivation from a strong inductive
ever, the explanation is simple, and does not alter effect through σ bonds, but ortho and para directing
our reasoning. It turns out that, because of the because of a weak resonance effect through the π
high electronegativity of halogen atoms, we have bond system.

Cl Cl
E
strong electron- E weak electron-releasing H
withdrawing inductive resonance effect favours
effect deactivates ortho and para substitution

chlorobenzene

ELECTROPHILIC AROMATIC SUBSTITUTION 313

An understanding of electron-donating and elec- example, from the electrophilic substitution reactions
tron-withdrawing substituent effects is crucial to we have studied, there are two potential approaches
designing the synthesis of aromatic derivatives. For for the synthesis of m-nitroacetophenone:

acyl group is

O CH3 moderately O CH3
deactivating

CH3COCl HNO3

AlCl3 NO2
m-nitroacetophenone

NO2 NO2

HNO3 CH3COCl

AlCl3 CH3

nitro group is O
strongly deactivating;
this reaction fails

Only the first of these is effective, because strongly substitution reaction can be expected to yield a mix-
deactivating groups such as nitro almost completely ture of products that must be separated. In practice,
inhibit Friedel–Crafts acylation (or alkylation), and this problem can be minimal because of steric con-
the alternative sequence shown will fail at the second siderations. When the original substituent is large, or
step. Accordingly, the workable route inserts the less- the incoming substituent is large, the steric interac-
effective deactivating group, the acyl group, first, so tion will be considerably less with para substitution
that the second electrophilic substitution can proceed, than with ortho. Thus, both nitration of acetanilide
even though it tends to be fairly slow. and acylation of toluene give predominantly the para
product. Note that small amounts of the meta product
Although electron-donating substituents activate are inevitably formed as well as the ortho and para
the ring towards electrophilic attack, they are both products; these reactions are only regioselective.
ortho and para directing, and an electrophilic

ortho positions O O O O
hindered by large HN CH3 HN CH3
substituent HN CH3 HN CH3
HNO3 + NO2 +

acetanilide NO2 (19%) NO2
(acetamidobenzene) (79%) (2%)

approach of large CH3 O CH3 CH3 O CH3
electrophile Ph Cl + Ph +
hindered by Ph
substituent AlCl3 O Ph (7%) (1%) O
(92%)
toluene

314 ELECTROPHILIC REACTIONS

This is a good time to have another brief look and phenols. The rationalizations are essentially
at Sections 4.3.5 and 4.5.4, and compare how we identical.
used similar reasoning to consider the likely stability,
or otherwise, of anions and cations in order to The effect of heteroatoms on electrophilic aromatic
predict the acid–base properties of aromatic amines substitution, e.g. the reactions of pyridine, will be
considered separately in Chapter 11.

Box 8.4

Synthesis of ibuprofen

There are several approaches to the synthesis of the analgesic anti-inflammatory drug ibuprofen. Here is one that
employs a relatively simple sequence of reactions, beginning with a Friedel–Crafts acylation of isobutylbenzene.
The alkyl substituent is weakly electron releasing, and thus activates the ring towards electrophilic substitution.
It also directs further substitution to the ortho and para positions. As in most Friedel–Crafts acylations, the
para product predominates strongly over the ortho, a consequence of the relatively large size of the electrophilic
reagent (see Section 8.4.3). In this case, we also have a quite large alkyl substituent, again disfavouring the ortho
product. The subsequent steps are relatively straightforward. Sodium borohydride reduction of the ketone gives
an alcohol (see Section 7.5), then the alcohol is converted into a nitrile by successive nucleophilic substitution
reactions.

isobutylbenzene O O NaBH4 OH
CH3
H3C Cl CH3 HBr nucleophilic
AlCl3 borohydride substitution
reduction of
Friedel–Crafts ketone
acylation

CO2H H2SO4 CN NaCN Br
CH3
CH3 CH3
nucleophilic
ibuprofen acid-catalysed substitution
hydrolysis of nitrile

Note that a two-stage process is involved. Since hydroxide is a poor leaving group, nucleophilic substitution
requires acidic conditions to protonate the hydroxyl to provide a better leaving group (see Section 6.1.4). We
can formulate an SN1 conversion, since this would involve a favourable benzylic carbocation. HCN is a weak
acid (pKa 9.1), so it is not very effective in protonating the hydroxyl group. Thus, the two-stage process is used,
with displacement of hydroxyl via bromide, then subsequent displacement of bromide by cyanide, the latter step
usually being an SN2 process. Lastly, the nitrile group is hydrolysed to a carboxylic acid (see Box 7.9).

The starting material, isobutylbenzene, is readily available, but could be synthesized by exploiting another
Friedel–Crafts reaction.

O O Zn (Hg)
Cl HCl

AlCl3

Friedel–Crafts Clemmensen isobutylbenzene
acylation reduction of carbonyl

ELECTROPHILIC AROMATIC SUBSTITUTION 315

Friedel–Crafts rearrangement to
alkylation more favourable
tertiary carbocation
Cl AlCl3 Cl AlCl3
H

tert-butylbenzene

Note that a Friedel–Crafts alkylation is not a good idea. There is too much chance of rearrangement occurring,
since we are trying to generate the equivalent of a primary carbocation. We might expect that rearrangement of
the primary carbocation to a tertiary carbocation by hydride migration would occur, so that the product would
turn out to be tert-butylbenzene rather than isobutylbenzene. The approach then is to use Friedel–Crafts acylation,
then reduce the carbonyl group by an appropriate method, here a Clemmensen reduction (see below).

The substituents that can be introduced by elec- significantly the scope for this type of process. A
trophilic substitution appear somewhat limited, but few of these are shown below, though they will not
there exist standard chemical processes for converting be elaborated upon here.
these into other functional groups, thereby extending

Some useful functional group transformations

KMnO4 CO2H oxidation
CH3

NaOH

Sn NH2 reduction
NO2 HCl

O Zn (Hg) Clemmensen reduction
R HCl R

Cl2 CH2Cl photochemical halogenation
CH3

light

O I2 CO2H haloform reaction
CH3 NaOH

8.4.4 Electrophilic substitution on polycyclic compounds like benzene. We have briefly looked
aromatic compounds at the π electron systems and their aromatic sta-
tus in Chapter 2. In this short section, we wish to
Fused-ring cyclic hydrocarbons such as naphtha- demonstrate how the principles developed above for
lene and anthracene display the enhanced stabil- rationalizing the behaviour of benzene compounds
ity and reactivity associated with simple aromatic can be extended to the more complex ring systems.

316 ELECTROPHILIC REACTIONS

We observe that nitration of naphthalene using that Friedel–Crafts acylation with acetyl chlo-
nitric acid–sulfuric acid gives predominantly 1- ride–AlCl3 gives mainly 1-acetylnaphthalene.
nitronaphthalene (sometimes α-nitronaphthalene), and

81 HNO3 NO2 O CH3
72 H2SO4 1-nitronaphthalene
6 5 43 CH3COCl
AlCl3
naphthalene 1-acetylnaphthalene

This behaviour can readily be explained. Let us only one resonance structure has a benzene ring.
simply consider the resonance structures for the We know that a benzene ring has special stability
intermediate cation following attack of electrophile (see Section 2.9.1), so we can predict that the
at position 1 (α position) or at position 2 (β intermediate cation with more benzenoid resonance
position). On drawing these out, we find that two structures should be the more stable. This fits with
of the five structures retain a benzene ring if attack the observation that electrophilic substitution occurs
occurs at position 1. For attack at position 2, predominantly at position 1.

EE E E E E
HHHHH

1

two resonance structures
retain aromatic benzene ring

E H H H HH
2 E E E EE

only resonance
structure that retains
aromatic benzene ring

Using the same reasoning, it is not difficult to see substantially more than for a single naphthalene ring.
why anthracene becomes substituted on the central Anthracene undergoes aromatic substitution more
ring. The intermediate cation then benefits from the readily than naphthalene, and can frequently lead to
stability of two benzene rings, which is actually disubstitution, with both substituents on the central
ring.
78 9 1 Br
6 5 10 2 We can also rationalize how a substituent on
Br2 naphthalene will direct further substitution. If we
43 CCl4 have an activating group at position 1, electrophilic
attack will occur on the same ring and at positions
anthracene Br 2 or 4. Consideration of resonance structures shows
9,10-dibromoanthracene that the benzene ring can be retained whilst providing
favourable structures in which an electron-releasing
group minimizes the charge. Further, those groups

ELECTROPHILIC AROMATIC SUBSTITUTION 317

that are electron-releasing through lone pair donation, charge. This is shown in the case of para and
e.g. NH2 or OH, are ideally placed to delocalize ortho attack.

X = electron releasing substituent X XX
X

substituent at position 1 1
attack at position 4 4

E H H H
E E E
favourable favourable
X
substituent at position 1 X E X
attack at position 2 1E H E
H
2

favourable favourable

E EH EH EH
X X X X

substituent at position 2 1 favourable
attack at position 1 2

favourable

substituent at position 2 X X X
attack at position 4 EH EH
2
4

E

Should the activating substituent be at position are attached and hinder any further attack. Hence,
2, further substitution will be almost exclusively further electrophilic substitution occurs on the other
at position 1; this follows from consideration of ring whether the substituent is at C-1 or C-2. Further
resonance structures, where the 2-substituent has substitution occurs at positions 5 or 8, the positions
minimal effect if attack occurs at position 4. Of most susceptible to attack.
course, this would equate to meta attack, which we
know is unfavourable for an ortho and para director These trends are summarized below, though we
(see Section 8.4.3). recommend deducing the reactivity rather than com-
mitting it to memory.
Deactivating (electron-withdrawing) substituents
do just that: they deactivate the ring to which they

position of further electrophilic substitution

substituent activating substituent deactivating
X X

X X



9

Radical reactions

9.1 Formation of radicals AB A B heterolytic cleavage
ions
The ionization of HBr distributes the two electrons
of the single H–Br bond so that the electronegative AB A B homolytic cleavage
bromine accepts electrons whilst hydrogen loses radicals
electrons, and the resultant ions are thus H+ and Br−.
This process is termed heterolytic cleavage, in that Radicals may be generated in two general ways:
the two atoms of the bond suffer different fates and
that the two electrons are distributed unevenly. In • by homolysis of weak bonds;
marked contrast, it is possible for the two electrons • by reaction of molecules with other radicals.
of the single bond to be distributed evenly, so that
one electron becomes associated with each atom. Homolytic cleavage of most σ bonds may be achieved
This is termed homolytic cleavage, and it generates if the compound is subjected to a sufficiently high
radicals (often termed free radicals). A radical may temperature, typically about 200 ◦C. However, some
be defined as a high-energy species carrying an weak bonds will undergo homolysis at temperatures
unpaired electron. Note that, to indicate movement little above room temperature. Bonds of peroxy
of just one electron, we use a fish-hook curly and azo compounds fall in this category, and
arrow in mechanisms (see Section 5.2) rather than such compounds may be used to initiate a radical
the normal curly arrow, which denotes movement of process. Di-tert-butyl peroxide, dibenzoyl peroxide
two electrons.

O 100−130°C O
O O

di-tert-butyl peroxide tert-butoxyl radicals

O 60−80°C O O Ph
O Ph
Ph O O
Ph O
O benzoyloxyl radicals

dibenzoyl peroxide

O

CO2

O

benzoyloxyl radical phenyl radical

Essentials of Organic Chemistry Paul M Dewick
 2006 John Wiley & Sons, Ltd

320 RADICAL REACTIONS

and azoisobutyronitrile (AIBN) are good sources of is lost, and the phenyl radical is produced. This
radicals under typical reaction conditions. displacement is favoured by the inherent stability of
carbon dioxide.
At increased temperatures, the peroxide bond is
cleaved homolytically, giving radicals. Dibenzoyl Homolytic cleavage of diazo compounds such as
peroxide is a diacyl peroxide and cleaves rather AIBN is also driven by the stability of a neutral
more readily than the dialkyl peroxide, but further molecule, this time molecular nitrogen, and two alkyl
decomposition then occurs in which carbon dioxide radicals are produced.

N CN 60−80°C NN CN
NC N

NC

azoisobutyronitrile 2-cyano-2-propyl radical
(AIBN)

An alternative approach to homolytic cleavage is UV radiation. Thus, halogen molecules are easily
photolysis, the absorption of light energy, especially photolysed to generate halogen radicals.

homolytic cleavage of Cl Cl hn Cl Cl Cl Cl Cl
halogen molecules Cl Br
I seven electrons
hn in outer shell

Br Br Br

II hn hn is the accepted abbreviation for
I electromagnetic radiation

The halogen molecule is comprised of two halogen Radicals formed in one of these initiation reactions
atoms each with seven electrons in their outer shell. may themselves be the means of producing other
Sharing of the unpaired electrons creates a stable radicals, by reacting with another molecular species.
molecule in which each atom has now acquired an Abstraction of a hydrogen atom is a particularly
octet of electrons in its outer shell. By absorbing common reaction leading to a new radical.
energy, we have removed this stabilization and
effectively generated halogen atoms, which are our
radicals.

radical abstracts hydrogen atom,
generating a new radical

RO H Br RO H Br

instead of showing all the electron

movements, we could write the

mechanism like this: RO H Br RO H Br

Thus, abstraction of a hydrogen atom from HBr remaining electron from the bond now resides with
generates a bromine radical. Note that, for conve- the bromine in the form of a bromine radical. This
nience, we tend not to put in all of the electron move- is shown as a one-electron mechanism, and should
ment arrows. This simplifies the representation, but be compared with the analogous two-electron mech-
is more prone to errors if we do not count electrons. anisms that account for acidity and SN2 reactions. The
Our attacking radical has an unpaired electron, and it only difference is in the number of electrons involved,
abstracts the proton plus one of the electrons compris- which we indicate by the fish-hook or normal curly
ing the H–Br σ bond, i.e. a hydrogen atom, and the arrow.

STRUCTURE AND STABILITY OF RADICALS 321
hydrogen atom abstraction
Compare: RO H Br RO H Br
one-electron mechanism

two-electron mechanism R O H Br RO H Br proton removal − acidity

two-electron mechanism R O H3C Br RO CH3 Br SN2 reaction

Another possibility is that we can get radical on the other end of the double bond, and is now the
addition to an unsaturated molecule, e.g. an alkene. unpaired electron of the new radical. The original
Writing in all the electron movement arrows, we radical could potentially have attacked at either end
have one of the double bond π electrons being used of the double bond; the regiochemistry of addition is
to make the new σ bond with the original radical governed by the stability of the radical generated (see
species, whilst the second π electron becomes located below).

radical addition Br more favoured
to alkene tertiary radical

Br

Br

we could have written the mechanism in Br Br
either of these ways: Br
E E electrophilic addition
the first version is perhaps more commonly to alkene
used, in that it considers the radical as the
attacking species; a 2p orbital that is oriented at right angles to the
plane of the radical.
however, compare the second one with the
electrophilic addition mechanism

Note that if we choose not to put in all the CH3 H H planar structure with
curly arrows, we could write the mechanism in methyl radical H unpaired electron in
two ways: either considering the radical as the
attacking species or the double bond as the electron- p orbital
rich species. The first version is perhaps more
commonly used, but it is much more instructive to Although a radical is neutral, it is an electron-
compare the second one with an electrophilic addition deficient species that will be very reactive as it
mechanism (see Section 8.1). The rationalization attempts to pair off the odd electron. Because radicals
for the regiochemistry of addition parallels that of are electron deficient, electron-releasing groups such
carbocation stability (see Section 8.2). as alkyl groups tend to provide a stabilizing effect.
The more electron-releasing groups there are, the
9.2 Structure and stability of radicals more stable the radical. Thus, tertiary radicals are
more stable than secondary radicals, which in turn
Most radicals have a planar or nearly planar structure. are more stable than primary radicals.
Carbon is sp2 hybridized in the methyl radical, giving
three σ C–H bonds, and the single electron is held in

322 RADICAL REACTIONS

relative stabilities: overlap from σ bond into

RR R H singly occupied p orbital
HH H
methyl radical
>> >

RR RH HH C C
H
tertiary radical secondary radical primary radical
H

The order of stability is thus the same as with car- the radical (see Section 6.2.1). The similarity contin-
bocations, another electron-deficient species, and for ues, in that resonance delocalization also helps to
the same reason. There is favourable delocalization of stabilize a radical, so that the allyl radical and the
the unpaired electron through overlap of the σ C–H benzyl radical are more stable than an alkyl radical
(or C–C) bond into the singly occupied p orbital of (compare Section 6.2.1).

allyl radical stabilized by
resonance delocalization

benzyl radical stabilized by
resonance delocalization

Electron-donating functional groups, e.g. ethers, of this (compare carbanions, Section 10.4). It tran-
also stabilize radicals via their lone pair orbitals. spires that features that stabilize an anion, e.g. an
However, electron-withdrawing groups can also sta- electron-withdrawing group, features that stabilize a
bilize radicals, so that radicals next to carbonyl or carbocation, e.g. electron-donating groups, or features
nitrile are more stable than even tertiary alkyl radi- such as conjugation that may stabilize either, will all
cals. This is because these groups possess a π electron stabilize a radical.
system and the unpaired electron can take advantage
electron-withdrawing groups
electron-donating group

O O OO C C
R R radical adjacent to carbonyl N N
radical adjacent to ether
radical adjacent to nitrile

There is a significant difference between carboca- relates to the extra unpaired electron in the radical,
tions and radicals when we are thinking about sta- which has to occupy a higher energy orbital in the
bility, however. One of the more confusing aspects transition state.
relating to carbocations was their ability to rearrange,
either by migration of an alkyl group or of hydride, 9.3 Radical substitution reactions:
when a more stable system might be attained by this halogenation
means (see Section 6.4.2). We related this trend to the
enhanced stability of, say, a tertiary or allylic carbo- Halogenation reactions of alkanes provide good
cation over secondary or primary carbocations. Now, examples of radical processes, and may also be used
although we also find tertiary or allylic radicals are to illustrate the steps constituting a radical chain
more favourable than secondary or primary radicals, reaction. Alkanes react with chlorine in the presence
we do not encounter rearrangements with radicals, of light to give alkyl chlorides, e.g. for cyclohexane
even if the product radical is more stable. This comes the product is cyclohexyl chloride.
from an increased energy barrier to rearrangement in
radicals compared with carbocations, which in turn

RADICAL SUBSTITUTION REACTIONS: HALOGENATION 323

cyclohexane Cl2 Cl The initiation step is the light-induced formation
+ HCl of chlorine atoms as the radicals. Only a few
chlorine molecules will suffer this fate, but these
hn highly reactive radicals then rapidly interact with
the predominant molecules in the system, namely
cyclohexyl chloride cyclohexane.

Cl Cl hn Cl Cl

initiation step

H Cl H Cl

propagation steps

Cl Cl Cl
Cl

Cl Cl Cl Cl

termination steps

Cl
Cl

The chlorine radicals abstract hydrogen atoms from Finally, when we are running out of cyclohexane,
the cyclohexane substrate, producing new radicals, the process terminates by the interaction of two rad-
i.e. cyclohexyl radicals. These, in turn, cause further ical species, e.g. two chlorine atoms, two cyclohexyl
dissociation of chlorine molecules and the production radicals, or one of each species. The combination of
of more chlorine radicals. The cyclohexyl radical two chlorine atoms is probably the least likely of
reacts with a chlorine molecule rather than, say, the termination steps, since the Cl–Cl bond would
a further molecule of cyclohexane simply because be the weakest of those possible, and it was light-
bond energies dictate it is easier to achieve fission induced fission of this bond that started off the radical
of the Cl–Cl bond than the C–H bond. This reaction. Of course, once we have formed cyclo-
results in production of cyclohexyl chloride and a hexyl chloride, there is no reason why this should
further chlorine radical. The chlorine radical can not itself get drawn into the radical propagation steps,
now abstract hydrogen from another cyclohexane resulting in various dichlorocyclohexane products, or
substrate, and we get a repeat of the same reaction indeed polychlorinated compounds. Chlorination of
sequence, the so-called propagation steps of this an alkane will give many different products, even
chain reaction. During the propagation steps, one when the amount of chlorine used is limited to molar
radical is used to generate another, so that only ratios, and in the laboratory it is not going to be a
one initiation reaction is required to generate a large particularly useful process.
number of product molecules.

324 RADICAL REACTIONS

However, it is instructive to consider radical two different monochlorinated products, but not in
chlorination of alkanes just a little further, to equal amounts. There will also be other products
appreciate the mechanistic concepts. If we carry out containing more than one chlorine atom. A similar
light-induced chlorination of propane, then we obtain situation pertains if we chlorinate 2-methylpropane.

Cl

H3C CH3 Cl2 H3C Cl + H3C CH3 H3C H3C CH3
propane hn primary radical secondary radical

(43%) (57%)

CH3 Cl2 CH3 H3C Cl CH3 CH3
H3C CH3 hn Cl + H3C H3C CH3
2-methylpropane primary radical tertiary radical
H3C H3C CH3

(63%) (37%)

The proportion of each product formed can be appreciated that, even under conditions in which we
rationalized by considering a number of factors. can maximize monochlorination, it is highly desirable
First, the products from propane are the result of if there is no chance of forming isomers that have
generating either primary or secondary radicals. We to be separated. Substrates that meet these criteria
know that tertiary radicals are more favourable than include cyclohexane and 2,2-dimethylpropane.
secondary radicals, which in turn are more favourable
than primary radicals. It is also true that tertiary Bromine will also halogenate alkanes, but in this
C–H bonds are slightly weaker than secondary C–H case we find that bromine is considerably less reactive
bonds, which in turn are slightly weaker than primary than chlorine. As a result, the reaction becomes
C–H bonds. It is thus rather easier to break tertiary much more selective, and the product ratios are more
C–H bonds by the hydrogen abstraction reaction, distinctive. In fact, bromination of alkanes is so
followed by secondary C–H bonds, and then primary selective that it is a feasible laboratory process to
C–H bonds. On the other hand, there is a statistical make alkyl bromides from alkanes.
factor, in that there are six primary hydrogens in
propane and only two secondary ones, so it is Br2 Br
more likely that a primary C–H bond is attacked hn
by the very reactive radical. The net result of H3C CH3 H3C Br + H3C CH3
these two opposite trends is the slight excess of propane
the secondary halide product. With 2-methylpropane, (8%) (92%)
the statistical factor is even more pronounced (only
one tertiary hydrogen to nine primary hydrogens), CH3 Br2 CH3 H3C Br
and hence we get rather more primary product in
the reaction mixture, even though tertiary radicals H3C CH3 hn H3C Br + CH3
are the more stable and a tertiary C–H bond is H3C
the weakest. In fact, because the chlorine radical
is so reactive, the variation in bond strengths is 2-methylpropane (1%) (99%)
not an especially important factor. It can readily be
The product ratios for bromination of propane and
H3C CH3 Cl2 H3C CH3 2-methylpropane are quite different from those seen
H3C CH3 hn H3C CH2Cl above in the chlorination reaction, in that the
2,2-dimethylpropane more-favoured products by far are the secondary
and tertiary halides respectively. Abstraction of a
hydrogen atom by a bromine atom is now much more
difficult than with a chlorine atom. The favoured
product may be rationalized in terms of the relative
strength of the C–H bond being broken, and the

RADICAL SUBSTITUTION REACTIONS: HALOGENATION 325

relative stability of the radical produced, though this consequence; but, should the formation of the product
is an oversimplification and we ought to consider generate a chiral centre, we are going to get an
relative energies of transition states. equimolar mixture of both possible configurations,
i.e. formation of a racemic mixture. This outcome
9.3.1 Stereochemistry of radical reactions has already been noted when a carbocation, another
planar system, reacts to produce a chiral centre (see
The planarity of a radical (see Section 9.2) means Section 6.2).
that, when it reacts with a reagent, there is an equal
probability that it can form a new bond to either Thus, if we consider radical chlorination of butane,
side of the radical. In many cases this is of no we expect to get a mixture of products, including
the monochlorinated compounds 1-chlorobutane and
2-chlorobutane.

H3C CH3 Cl2 H3C CH2 + H3C CH3
butane hn H

Cl2 Cl2

H3C Cl H3C CH3
achiral Cl

racemic product

Et Et

H Me Cl Cl H
Et Me
radical can abstract Cl
chlorine atom from either
side of planar structure Et
Cl H
Cl Cl
Me
H Me

In the formation of 1-chlorobutane, an intermediate 9.3.2 Allylic and benzylic substitution:
primary radical is involved, and there are no stereo- halogenation reactions
chemical consequences. However, the secondary rad-
ical involved in 2-chlorobutane formation is planar, The selectivity of radical bromination reactions
and when it abstracts a chlorine atom from a chlo- depends, in part, on the increased stability of
rine molecule it can do so from either side with equal secondary or tertiary radical intermediates compared
probability. The result is formation of a racemic prod- with primary radicals. In Section 9.2 we noted
uct, (±)-2-chlorobutane. that allyl and benzyl radicals were especially

allylic position benzylic position
Br H H Br

allylic radical benzylic radical

326 RADICAL REACTIONS

stabilized by resonance delocalization; indeed, they with bromine to give the allylic bromide, plus
are even more stable than tertiary radicals. In the a further bromine atom to continue the chain
presence of a suitable initiator, bromine dissociates propagation steps. The symmetry in cyclohexene
to bromine atoms that will selectively abstract an means that the two resonance structures are identical.
allylic or a benzylic hydrogen from a suitable It does not matter which allylic radical picks up
substrate, generating the corresponding allyl and bromine, we get the same product. It is not difficult to
benzyl radicals. appreciate that a mixture of brominated products must
result if we start with a non-symmetrical substrate.
In the case of cyclohexene, this leads to a
resonance-stabilized allylic radical that then reacts

Br Br hn Br
Br

Br H HBr

resonance-stabilized
allylic radical

cyclohexene Br
Br Br Br

Br Br Br
Br
For example, radical allylic bromination of pent-
2-ene must produce a mixture of three products. of hydrogen from the terminal methyl gives an
There are two allylic positions in the substrate, and allylic radical for which the resonance structures are
either can suffer hydrogen abstraction. If hydrogen not equivalent, and hence two different brominated
is abstracted from the methylene, then the two products may be formed. The net result will be a
contributing resonance structures for the allylic mixture of all three products. If we want to exploit
radical are equivalent, and one product results allylic bromination, this means we must choose
when this captures a bromine atom. Abstraction the substrate carefully if we prefer to get a single
product.
H Br
equivalent resonance
pent-2-ene structures

Br Br
same product

Br H non-equivalent resonance
structures

different products
Br Br

RADICAL SUBSTITUTION REACTIONS: HALOGENATION 327

Of course, we have also seen that bromine can (see Section 8.1.2); further, it can add to a double
react with a double bond via electrophilic addition bond via a radical mechanism.

Br Br Br

Br Br Br

This could complicate an allylic bromination reaction, of bromine radicals, which can then abstract hydro-
and it is necessary to choose conditions that minimize gen from an allylic position on the substrate. The
any addition to the double bond. This is achieved chain reaction continues via a small concentration of
by carrying out the reaction in a solvent of low molecular bromine, which is generated by an ionic
polarity, e.g. CCl4, which suppresses the possibility mechanism from NBS and the HBr released as a con-
of the polar electrophilic addition, whilst keeping the sequence of the hydrogen abstraction. Accordingly,
concentration of bromine very low to suppress radical the broad overall reaction is just the same as if we
addition. were employing molecular bromine as the reagent.
The difference is in the use of NBS to maintain a
There is, however, a much better reagent than very low concentration of bromine. Under the condi-
bromine to brominate at an allylic position selec- tions used, i.e. in a non-polar solvent in which NBS
tively. This reagent is N-bromosuccinimide (NBS), is not very soluble, and with the very low concentra-
and it also reacts via a radical mechanism. The weak tion of bromine produced, there is almost exclusive
N–Br bond in NBS is susceptible to homolytic disso- allylic bromination and very little addition to the dou-
ciation initiated either by light or a chemical initiator, ble bond.
such as a peroxide. This produces a small amount

OO

hν N Br
N Br
HBr now reacts
or ROOR with NBS

OO HBr

N-bromosuccinimide Br H
(NBS)

allylic radical

generation of Br2 from HBr and NBS Br2 allows radical chain
(ionic mechanism) reaction to continue

O H Br OH OH Br Br O
N Br Br
NH NH
N Br

OO O O succinimide

protonation of carbonyl enol-like carbonyl
oxygen tautomer tautomer

A benzylic radical is generated if a compound dissociation energy for the C–H bonds of the aromatic
like toluene reacts with bromine or chlorine atoms. ring system is considerably more than that for the
Hydrogen abstraction occurs from the side-chain side-chain methyl, and relates to the stability of the
methyl, producing a resonance-stabilized radical. The radical produced.

328 RADICAL REACTIONS

Br Br hn Br Br
HBr
H Br

toluene benzyl radical stabilized by
resonance delocalization

Br Br Br Br

benzyl bromide Br CH3 CH3
H
The typical propagation steps now follow, although resonance
all halogenation proceeds in the side-chain; addition structures
to the ring would destroy the aromaticity and produce
a higher energy product. H Br

Benzyl chloride undergoes further chlorination no resonance
to give di- and tri-chloro derivatives, though it structures
is possible to control the extent of chlorination
by restricting the amount of chlorine used. As However, with the more reactive chlorine, chlorina-
indicated above, it is easier to mono-brominate than tion can occur at either position, though the major
it is to mono-chlorinate. The particular stabilization product is the benzylic halide. Benzylic bromina-
conferred on the benzylic radical by resonance is tion is also efficiently achieved by the use of N -
underlined by the reaction of ethylbenzene with bromosuccinimide as the halogenating species.
halogens.
9.4 Radical addition reactions:
CH3 Br CH3 addition of HBr to alkenes

Br2 The radical addition of halogen to an alkene has
been referred to briefly in Section 9.3.2. We saw
hn an example of bromination of the double bond in
cyclohexene as an unwanted side-reaction in some
CH3 Cl CH3 Cl allylic substitution reactions. The mechanism is quite
straightforward, and follows a sequence we should
Cl2 (44%) now be able to predict.
hn
More relevant to our consideration now is the
(56%) radical addition of hydrogen bromide to an alkene.
Radical formation is initiated usually by homolysis
Bromination occurs exclusively at the benzylic posi- of a peroxide, and the resultant alkoxyl radical may
tion, i.e. adjacent to the benzene ring. The radi- then abstract a hydrogen atom from HBr.
cal formed at this position is resonance stabilized,
whereas no such stabilization is available to the pri-
mary radical formed by abstraction of one of the
methyl hydrogens.

RADICAL ADDITION REACTIONS: ADDITION OF HBr TO ALKENES 329

RO OR heat OR radical initiation by
RO homolysis of a peroxide

RO H Br alkoxyl radical abstracts hydrogen
RO H Br from HBr, generating bromine atom

Br Br bromine atom adds to double bond,
producing more stable secondary radical

H

Br H Br Br secondary radical abstracts hydrogen
Br from HBr, generating bromine atom;

chain reaction continues

Br termination steps, supported by
Br Br Br formation of minor products

Br Br
Br Br

The bromine atom then adds to the alkene, generating The main product is thus the result of addition of HBr
a new carbon radical. In the case of propene, as to the alkene. Minor products detected are consistent
shown, the bromine atom bonds to the terminal with the proposed chain-termination steps.
carbon atom. In this way, the more stable secondary
radical is generated. This is preferred to the primary This looks quite logical and consistent with what
radical generated if the central carbon were attacked. we know about radical reactions. However, remind
The new secondary radical then abstracts hydrogen yourself of the addition of HBr to an alkene,
from a further molecule of HBr, giving another as we discussed under electrophilic reactions in
bromine atom that can continue the chain reaction. Section 8.1.1. There is a significant difference in the
nature of the product.

electrophilic addition of HBr

H Br H CH3 H Br major product;
H CH3 HBr H Br Markovnikov orientation
H CH3
HH HH
HH
more favourable
secondary carbocation

radical addition of HBr

Br

H CH3 HBr Br CH3 Br H major product;
anti-Markovnikov orientation
H H Br H CH3

H H radical HH HH
initiator

more favourable

secondary radical

330 RADICAL REACTIONS

Electrophilic addition of HBr to propene gives mechanism, because the radical propagation steps are
predominantly the so-called Markovnikov orienta- not favoured. The C–I bond is relatively weak, so
tion; Markovnikov’s rule states that addition of HX that addition of an iodine atom to the double bond
across a carbon–carbon multiple bond proceeds in is not favoured. On the other hand, the H–Cl bond
such a way that the proton adds to the less-substituted is relatively strong and hydrogen abstraction using a
carbon atom, i.e. that already bearing the greater radical is unfavourable. For many years, the addition
number of hydrogen atoms (see Section 8.1.1). We of HBr to an alkene seemed quite mysterious and
rationalized this in terms of formation of the more erratic, with Markovnikov or anti-Markovnikov ori-
favourable carbocation, which in the case of propene entation occurring apparently at random. Eventually,
is the secondary carbocation rather than the alterna- the problem was solved and traced to the purity of the
tive primary carbocation. compounds used. Impure reagents containing traces
of peroxides led to addition with anti-Markovnikov
Now, just the same sort of rationalization can orientation, and we can now see that this is the conse-
be applied to the radical addition, in that the quence of a radical reaction. Reagents free from per-
more favourable secondary radical is predominantly oxides react via the ionic electrophilic addition mech-
produced. This, in turn, leads to addition of HBr anism, and we thus get predominantly Markovnikov
in what is the anti-Markovnikov orientation. The orientation.
apparent difference is because the electrophile in
the ionic mechanism is a proton, and bromide 9.4.1 Radical addition of HBr to conjugated
then quenches the resultant cation. In the radical dienes
reaction, the attacking species is a bromine atom,
and a hydrogen atom is then used to quench the Radical addition of HBr to an alkene depends upon
radical. This is effectively a reverse sequence for the bromine atom adding in the first step so that
the addition process; but, nevertheless, the stability the more stable radical is formed. If we extend this
of the intermediate carbocation or radical is the principle to a conjugated diene, e.g. buta-1,3-diene,
defining feature. The terminologies Markovnikov or we can see that the preferred secondary radical will
anti-Markovnikov orientation may be confusing and be produced if halogenation occurs on the terminal
difficult to remember; consider the mechanism and it carbon atom. However, this new radical is also an
all makes sense. allylic radical, and an alternative resonance form
may be written.
This radical anti-Markovnikov addition of HX
to alkenes is restricted to HBr; both HI and
HCl add in a Markovnikov fashion by an ionic

radical addition of HBr electrophilic addition of HBr

Br HBr Br resonance-stabilized H H resonance-stabilized
allylic radical HBr allylic cation
13 radical
24 Br 13 H
initiator 24
HBr HBr Br−
buta-1,3-diene Br buta-1,3-diene Br−

Br HH

H H Br Br
1,2-addition 1,2-addition
1,4-addition 1,4-addition
conjugate addition conjugate addition

A hydrogen atom is abstracted from HBr in the structure is involved, we shall get different products,
following step of the chain reaction to produce the the results of 1,2- and 1,4-addition. The 1,4-addition
addition product. Depending upon which resonance is termed conjugate addition.

RADICAL ADDITION REACTIONS: ADDITION OF HBr TO ALKENES 331

This is comparable to the electrophilic addition 9.4.2 Radical polymerization of alkenes
of HBr to butadiene (see Section 8.2), though the
addition is in the reverse sense overall, in that Br The addition of a radical on to an alkene generates a
adds before H in the radical reaction, whereas H new radical, which potentially could add on to a fur-
adds before Br in the ionic mechanism. As with ther molecule of alkene, and so on, eventually giving
the electrophilic addition, we shall usually obtain a a polymer. This becomes an obvious extension of
mixture of the two products. the radical mechanisms we have already studied, and
is the basis for the production of many commercial
polymers.

O OR heat O OR
RO O RO O
initiation

O

RO R CO2

RR chain extension

R

R n HX termination

The radical initiator is usually a diacyl peroxide polymeric radical that consequently becomes an
(see Section 9.1) that dissociates to radicals that alkene. In this general fashion, polymers such as
in turn add on to the alkene. This starts the polyethylene (polythene), polyvinyl chloride (PVC),
chain reaction, which is terminated by hydrogen polystyrene, and polytetrafluoroethylene (PTFE) may
abstraction from some suitable substrate, e.g. another be manufactured.

ethylene polythene
Cl Cl Cl Cl Cl Cl
Cl
vinyl chloride polyvinyl chloride
Ph Ph Ph Ph Ph Ph
Ph
styrene polystyrene

332 RADICAL REACTIONS

F F FF FF FF FF FF F
F
F FF FF FF FF FF F
F polytetrafluoroethylene (PTFE; Teflon)
F

tetrafluoroethylene

We met a rather similar process, cationic polymer- above, and does not feature initiation, propagation
ization, under electrophilic reactions in Section 8.3. and termination steps. However, since it appears to
In practice, radical polymerization is more effective involve atomic hydrogen, it has much more in com-
than cationic polymerization, and industrial polymers mon with radical reactions than ionic ones, and we
are usually produced by radical processes. consider it here for convenience.

9.4.3 Addition of hydrogen to alkenes and The catalyst used is typically platinum, palladium,
alkynes: catalytic hydrogenation rhodium, or ruthenium, or sometimes an appropriate
derivative. Precise details of the reaction remain
The addition of hydrogen to carbon–carbon multi- vague, but we believe the catalyst surface binds to
ple bonds (reduction) may be achieved using gaseous both the substrate, e.g. an alkene, and hydrogen,
hydrogen in the presence of a finely divided noble weakening or breaking the π bond of the alkene
metal catalyst. This is termed catalytic hydrogena- and the σ bond of hydrogen. Sequential addition of
tion. It is not a radical reaction as we have seen hydrogen atoms to the alkene carbons then occurs and
generates the alkane, which is then released from the
surface.

HC H H H
HC C HC C

catalyst surface H C H
C C

hydrogen and alkene first hydrogen atom catalyst surface
bonded to catalyst bonds to alkene second hydrogen atom
bonds; alkane released
Catalytic hydrogenation delivers hydrogen to one HH
face of the alkene; the consequence is syn addition H2
of hydrogen. This is a departure from our usual Pt H H
observations with ionic mechanisms, where the
groups typically add to a double bond with anti syn addition of hydrogen
stereochemistry (see Section 8.1.2).
The stereochemical consequences of this are
illustrated in the following examples.

CH3 H2 H H syn addition from either side
CH3 CH3 of the double bond creates the
CH3 Pt same product
≡ H CH3

H CH3

1,2-dimethylcyclohexene cis-1,2-dimethylcyclohexane

RADICAL ADDITION OF OXYGEN: AUTOXIDATION REACTIONS 333

Ph CH3 H H
H3C Ph Ph CH3 Ph CH3
H2 R syn addition from either side of
Pd S + R the double bond creates a pair
S of enantiomers
H3C H Ph
H3C H Ph

trans-2,3-diphenylbut-2-ene (±)-2,3-diphenylbutane

Ph CH3 H2 H ≡ H syn addition from either side
Ph CH3 Pd Ph CH3 Ph CH3 of the double bond creates the
meso isomer
S R
R S

Ph H CH3 Ph H CH3

cis-2,3-diphenylbut-2-ene meso-2,3-diphenylbutane

Alkynes may also be hydrogenated, initially to 9.5 Radical addition of oxygen:
alkenes, and then further to alkanes. By suitable
modification of the catalyst, it has proved possible to autoxidation reactions
stop the reaction at the intermediate alkene. Typically,
platinum or palladium catalysts partially deactivated The slow spontaneous oxidation of compounds in the
(poisoned) with lead salts are found to be suitable for presence of oxygen is termed autoxidation (auto-
reduction of alkynes to alkenes. Again, syn addition oxidation). This radical process is responsible for
is observed. a variety of transformations, such as the drying of
paints and varnishes, the development of rancidity in
H3C CH3 H2 HH foodstuff fats and oils, the perishing of rubber, air
but-2-yne Pd−Pb oxidation of aldehydes to acids, and the formation of
H3C CH3 peroxides in ethers.
cis-but-2-ene
Unsaturated hydrocarbons undergo autoxidation
Isolated double and triple bonds are reduced because allylic hydrogens are readily abstracted by
readily, whereas conjugated alkenes and aromatic radicals (see Section 9.2). Molecular oxygen in its
systems are difficult to hydrogenate. Carbonyl double low-energy arrangement is a diradical, with only
bonds react only very slowly, if at all, so it is possible one bond between the atoms, and consequently an
to achieve selective reduction of C=C double bonds unpaired electron on each atom. Thus, oxygen can
in the presence of aromatic and carbonyl functions. abstract hydrogen atoms like other radicals, though
it is not a particularly good hydrogen abstractor.
OO Instead, sequences are initiated by light or by other
promoters that generate radicals, and oxygen is
CH3 H2 CH3 involved in the propagation steps.
Pd

(E)-4-phenylbut-3-en-2-one 4-phenylbutan-2-one

OO ≡ OO

oxygen as diradical

R OO ROO R formation of peroxyl radical
ROO HR peroxyl radical propagation step

ROOR

334 RADICAL REACTIONS

O OH Thus, the radical from the initiation reaction
abstracts hydrogen from the allylic position of
O2 cyclohexene, as we have seen previously, to give the
initiator resonance-stabilized radical (see Section 9.2).

cyclohexene 3-cyclohexenyl In the propagation steps, this radical then reacts
hydroperoxide with oxygen, producing a peroxyl radical, which then
abstracts hydrogen from a further molecule of the
The processes that occur when cyclohexene reacts substrate. The product is thus the hydroperoxide,
with oxygen in the presence of an initiator to give reaction having occurred at the allylic position of the
the allylic hydroperoxide exemplify this nicely. alkene. Two possible chain-termination steps might

RH RH resonance-stabilized
radical

OO OO

OO H O OH hydroperoxides easily dissociate
hydroperoxide further to generate radicals

RO OH RO OH

termination steps

OO OO

be the combination of two cyclohexenyl radicals peroxide
or the formation of a peroxide, as shown. The
hydroperoxide itself can easily dissociate to produce tend to be highly selective. They tend to abstract
radicals that may then initiate other chain reactions. hydrogen atoms most readily from tertiary, allylic
Peroxyl radicals are not particularly reactive, and thus and benzylic C–H bonds. These are systems with the
weakest bonds and that have maximum stabilization
in the radical produced.

Box 9.1

Autoxidation in fats and oils: the origins of rancidity

Oxygen-mediated autoxidation can occur with unsaturated acid components of fats and oils, which are esters of
fatty acids with glycerol (see Box 7.16). This leads initially to hydroperoxides that decompose further to produce

RADICAL ADDITION OF OXYGEN: AUTOXIDATION REACTIONS 335

low molecular weight carboxylic acids. These are the cause of rancidity, the unpleasant odour and taste associated
with badly stored fats. Linoleic acid is a typical unsaturated fatty acid component, and hydrogen abstraction will
occur from the methylene between the two non-conjugated double bonds. The radical thus produced benefits from
extensive delocalization, as shown by the resonance forms that can be drawn.

hydrogen abstraction occurs at
R methylene between double bonds

HH

CO2R´ H
conjugated
ester of linoleic acid double bonds

H resonance-stabilized H
radical
non-conjugated conjugated
double bonds CO2R´ double bonds

OO

H

CO2R´

O OH OO
hydroperoxide HH

CO2R´

However, the resonance forms in which the double bonds are conjugated are inherently more stable than
that with the unconjugated double bonds (see Section 9.2). Accordingly, the hydroperoxide subsequently formed
upon reaction with oxygen will have conjugated double bonds. Abstraction of a hydrogen atom to form the
hydroperoxide is part of the chain propagation process.

Fragmentation of the hydroperoxide can then lead to chain shortening, as illustrated.

H

O OH O OH O
oxidation

HO

O

Acidic products result from further oxidation of aldehydes (or ketones), again by a radical process. Oxidation
of an aldehyde to a carboxylic acid in the presence of air involves a peroxy acid (compare peroxyacetic acid,
Section 8.1.2). Finally, a reaction between the peroxy acid and a molecule of aldehyde yields two carboxylic
acid molecules; this is not a radical reaction, but is an example of a Baeyer–Villiger oxidation. Baeyer–Villiger