262 . . .

12 Nucleophilic Substitution Reactions of Haloalkanes and Related Compounds

of the intermediate carbenium ion and the polarity of the solvent; it also accounts for the
stereochemical evidence (see next sub-section).

Exercise 12.8 Draw a reaction profile for an SN1 mechanism (cf. Section 7.4).

12.4.2 Stereochemistry of the SN1 mechanism

If the SN1 reaction proceeds via a carbenium ion, the stereochemical outcome must be
quite different from that of the SN2 reaction because the central carbon of the intermedi-
ate is sp2 hybridized and planar (Scheme 12.5). The lobes of the vacant 2p orbital (LUMO)
are perpendicular to the plane of the carbenium ion and the HOMO of the nucleophile
may interact with either of the lobes. If the reaction site of substrate RY is a chiral centre,
and nucleophilic attack at the carbenium ion is equally possible from both sides, the
outcome must be the formation of racemic product regardless of the enantiomeric purity
of the substrate RY.
Experimentally, however, racemization is usually only partial because the nucle-
ofuge is still present as a counter-ion on the side of the carbenium ion from which it
departed. In other words, the carbenium ion initially exists as an ion pair (Scheme
12.5) and its counter-ion Y– inhibits nucleophilic capture from the side leading to
product with retention of configuration. The result is partial inversion of configura-
tion, the degree of which depends on the stability (lifetime) of the ion-pair and the
nature of the solvent.

Scheme 12.5
vacant 2p orbital
Stereochemistry of the SN1
reaction of a chiral substrate.
–
Nu Nu–
1
R
R1 R1 R1
+
_Y –
C Y C Nu C + C Nu
–
2 Y R2 2
R R2 H R H
H H

an enantiomer carbenium ion intermediate a mixture of enantiomers

(chiral) (achiral) racemic or partial inversion

Example 12.4 Complete the following substitution reactions.

I
(a) Br
+ H2O (b) + MeOH
H2O MeOH

Solution
(a) 2-Bromo-2-methylbutane is a tertiary alkyl bromide, and reacts by the SN1 mechanism in a
weakly nucleophilic solvent.
SN1
Br OH
+ 2 H2O + H3O+ + Br–
H2O
2-bromo-2-methylbutane 2-methylbutan-2-ol
 12.4 The SN1 Mechanism . . . 263

(b) Iodocyclohexane is a secondary halide with a good nucleofuge, and also reacts by the SN1
mechanism in a weakly nucleophilic solvent.
I SN1 OMe
+ MeOH + HI
MeOH

iodocyclohexane methoxycyclohexane

Note that HI, like HBr and HCl, dissociates extensively in MeOH:
HI + MeOH MeOH2+ + I–

Explain why the rate of hydrolysis of Me3CBr in water can be measured by monitoring the acidity Exercise 12.9
(pH) of the solution.

Complete the following equations for solvolytic substitution reactions. Exercise 12.10

Cl
(a) + AcOH (b) Br + EtOH
AcOH EtOH

12.4.3 Stability of carbenium ions

Any feature which stabilizes the intermediate carbenium ion in an SN1 reaction will also
Simple primary alkyl
stabilize the transition structure for its formation (see the Hammond postulate in Panel
and methyl cations are
7.2). Stabilities of alkyl cations decrease in the order 3° > 2° >> 1°, so the SN1 reactivity of too unstable to exist in
alkyl halides, for example, decreases in the same order. common solvents, so their
Stability of carbenium ions:
derivatives do not react by
the SN1 mechanism.
R R R H
+ + + +
C < C < C < C
R R R H H H H H A carbenium ion
intermediate sometimes
SN1 reactivity of RY: rearranges to a more
> >> stable ion which leads to
3º 2º 1º methyl
rearrangement products.
This complication will be
How is a carbenium ion centre stabilized by an alkyl substituent? Delocalization of the
discussed in Chapter 14
positive charge is the most likely explanation, and we can identify two possible mecha- in the context of acid-
nisms. On purely electrostatic grounds, we can expect a localized positive charge to catalysed reactions of
polarize adjacent bonds and thereby attract electron density through the σ bonds. This is alcohols.
the so-called inductive effect we have encountered previously (Sub-section 6.3.3). Since
the electrons around a carbon atom are more polarizable than those around a hydrogen
Electron-donating
atom, a C–C σ bond is more polarizable than a C–H bond, and better able to supply elec-
inductive effect:
tron density to the positive centre. Alkyl substituents, therefore, stabilize a carbenium
+
ion centre by acting as electron-donating groups (but note that this electron-donation
C C C
is purely a response to the strong electron-attracting effect of the carbenium ion cen-
tre). Consequently, as the H atoms of a methyl cation are successively replaced by alkyl
groups, the positive charge is increasingly dispersed into the alkyl groups, and the car-
benium ion is stabilized.
The second mechanism by which alkyl substituents stabilize carbenium ions is best
described by the molecular orbital theory of bonding. The vacant 2p AO of the carbenium
264 . . . 12 Nucleophilic Substitution Reactions of Haloalkanes and Related Compounds
Figure 12.3 Stabilization
of a carbenium ion by
hyperconjugation.
We encountered
hyperconjugation as
a contributor to the
stabilization of the
staggered conformation of
ethane in Sub-section 4.2.1.
Exercise 12.11
Exercise 12.12
This is the opposite of what
happens in nucleophilic
addition to a carbonyl
group (Section 8.2).
The highly congested
tri(t-butyl)methyl chloride,
(Me3C)3CCl, is a particularly
reactive SN1 substrate—it
is much more reactive than
t-butyl chloride.
hyperconjugation
vacant
bonding H 2p AO
energy
H
σ MO C C
H H C–H
H bonding
σ MO
vacant 2p AO
ethyl cation orbital interactions
centre is able to interact with the bonding σ orbital of an adjacent C–H bond of the sub-
stituent alkyl group when the orbitals are coplanar, as illustrated in Figure 12.3. Although
the interaction between the relatively low energy σ bonding MO and the vacant 2p AO
is not large, there is a transfer of some C–H σ bonding electron density into the vacant
2p orbital of the carbenium ion: the alkyl group acts as an electron-donating group. In
this way, the carbenium ion is stabilized by delocalization of positive charge from the
central sp2 carbon. This type of interaction, delocalization involving a σ orbital, is called
hyperconjugation.
Carbenium ions are more strongly stabilized by conjugation of the vacant p orbital with
adjacent π bonds or unshared electron pairs (see Chapter 5), so a compound which yields
a conjugatively stabilized carbenium ion will be a reactive SN1 substrate. For example,
rates of SN1 reactions increase in the order:
Cl
< Cl
< Cl < MeO Cl
Write resonance forms for allylic, benzylic, and 1-methoxyethyl cations formed during the reac-
tions of the substrates given above.
What are the organic products in the reaction of 1-chloro-1-methoxyethane in aqueous solution?
Write a mechanism for this reaction.
Electronic stabilization of a carbenium ion is not the only reason for the relatively
easy formation of tertiary carbenium ions by heterolysis: there is a steric reason as well.
The hybridization of the central carbon changes from sp3 to sp2 upon formation of a
carbenium ion by heterolysis of its precursor. Consequently, the bond angles around
the central carbon widen from about 109.5° to 120° so there is a relief of steric strain as
substituent alkyl groups are able to move further apart (Figure 12.4). This relief of steric
strain, which facilitates bond cleavage in the first step of the SN1 mechanism (steric
acceleration), is largest for a tertiary alkyl substrate.
sp3
relief of R sp2
R
steric strain +
120º
109.5º C
C Y
R
R Y
– R R
Figure 12.4 Relief of steric strain upon heterolysis in an SN1 reaction.
 12.4 The SN1 Mechanism . . . 265

Panel 12.3 The SN1 mechanism in biological substitution reactions

The SN1 mechanism occurs when a substrate has a good nucleofuge and gives a relatively stable carbenium ion
intermediate. The most commonly found good nucleofuges in nature are phosphate and diphosphate (also called
pyrophosphate), which are conjugate bases of strong acids (phosphoric and diphosphoric acid, respectively). The usual
abbreviation for diphosphate (pyrophosphate) as a substituent is PPO (or OPP): this polyprotic acid residue will dissoci-
ate and bear a charge (which is not usually indicated) according to the pH of its aqueous environment. Then, following
departure, diphosphate is represented as PPO– regardless of its actual charge which, again, will depend upon the pH.

O O O
diphosphoric acid
P phosphoric acid P P
HO OH HO O OH (pyrophosphoric acid)
OH (pK a1 = 2.1) OH OH (pK a1 =1.5)
(PPOH)

3-Methylbut-2-enyl (dimethylallyl) diphosphate is a precursor for the terpene class of natural products (also called
isoprenoids) which are built up from branched C5 (isoprene) subunits (see Chapter 24). In addition to having a good
nucleofuge, dimethylallyl diphosphate is a good substrate for the SN1 mechanism because the intermediate dimethyl-
allyl cation is resonance-stabilized. Nucleophilic centres which capture this intermediate in biological SN1 reactions
include the OH groups of alcohols, and electron-rich carbon residues.

– PPO– + +
OPP
SN1
3-methylbut-2-enyl
(dimethylallyl) diphosphate ROH

H+
RO
+
–H + +
OR OR
H

When the nucleophile is 3-methylbut-3-enyl diphosphate (an isomer of dimethylallyl diphosphate), the product immedi-
ately following deprotonation is geranyl diphosphate, the hydrolysis product of which is geraniol—a component of rose oil.

+ +
OPP OPP
3-methylbut-3-enyl H H
diphosphate

hydrolysis
– H+
OPP OH
geranyl diphosphate geraniol (in rose oil)

Geranyl diphosphate is similar in reactivity to its dimethylallyl analogue as an SN1 substrate and reacts in the same way
with a further molecule of the carbon nucleophile, 3-methylbut-3-enyl diphosphate. Deprotonation of the intermedi-
ate gives farnesyl diphosphate with the additional isoprene unit, and hydrolysis yields farnesol, which is found in lily
of the valley. Still higher members of this family of natural products are produced in a similar manner.

SN 1 and
depr otonation
OPP
+ OPP
– PPOH
farnesyl diphosphate
OPP

hydrolysis

OH
farnesol (in lily of the valley)
266 . . . 12 Nucleophilic Substitution Reactions of Haloalkanes and Related Compounds

Exercise 12.13 Which of each pair of haloalkanes is more reactive in an SN1 reaction?

Cl I Cl
Cl
(a) and (b) and

Br Br
Cl Cl
(c) and (d) and

12.5 Intramolecular Nucleophilic

Displacement: Neighbouring Group
Participation
The normal SN2 mechanism is intermolecular with a bimolecular transition structure.
But suppose the molecule with the nucleofuge also contains a nucleophilic group—
could the internal nucleophile compete with an intermolecular nucleophile?
See Section 14.5 for the
Following extended reaction in alkaline solution, trans-1-chloro-2-hydroxycyclohex-
chemistry of oxiranes ane yields trans-1,2-dihydroxycyclohexane, i.e. replacement of Cl by OH with reten-
(epoxides). tion of configuration. The most credible explanation of this stereochemical result is the
mechanism shown in Scheme 12.6 involving a bicyclic intermediate containing a three-
membered cyclic (oxirane) function. Isolation of the intermediate (cyclohexene oxide)
under less forcing conditions supports this mechanism.

+HO– +
HO HO OH
–
–Cl OH HO
Cl

intramolecular
– OH OH
OH O
HO– O +H+
+
–Cl–
–H+ OH OH
trans Cl Cl HO– trans products
(racemate)
intermolecular

Scheme 12.6 Nucleophilic displacement of chloride by an internal nucleophile and subsequent reaction.

*A single half-chair form The alkoxide, generated in a pre-equilibrium, displaces Cl– to give an oxirane in an
of the oxirane which has intramolecular nucleophilic displacement reaction. This is an example of neighbouring
appreciable conformational group participation (n.g.p.), and the oxirane then suffers ring opening by intermolecular
flexibility is shown in nucleophilic attack by HO–. The double substitution, each with inversion, accounts for
Scheme 12.6 and the time- the overall retention of configuration. Note, however, that the HO– can attack either of the
averaged structure has a
two electrophilic carbon atoms;* consequently, regardless of the enantiomeric purity of
mirror plane.
the reactant, the product must be racemic.
 12.5 Intramolecular Nucleophilic Displacement: Neighbouring Group Participation . . . 267

In contrast, the diastereoisomeric cis-1-chloro-2-hydroxycyclohexane (in which the The rate enhancement
internal nucleophile cannot reach the rear side of the C bearing the nucleofuge) yields the associated with
same product, trans-1,2-dihydroxycyclohexane, in a simple SN2 reaction (Scheme 12.7). neighbouring group
The rate constant for this reaction, however, is about 100 times smaller than the one for participation, as found
the trans diastereoisomer, and the product from enantiomerically enriched starting mate- for trans-1-chloro-2-
hydroxycyclohexane
rial would be optically active.
in alkaline solution,
is sometimes called
– anchimeric assistance.
OH

HO
Cl
OH
–Cl–
HO
trans

Cl
OH
cis

Scheme 12.7 Intermolecular nucleophilic displacement of chloride by hydroxide.

Neighbouring group participation may also be observed in SN1 reactions via carbenium
ion intermediates. The solvolysis of trans-1-acetoxy-2-bromocyclohexane in ethanoic
acid containing silver ethanoate is appreciably faster than expected, and the product is
trans-1,2-diacetoxycyclohexane, i.e. Br– has been replaced by ethanoate with retention of
configuration. The stereochemical outcome and the enhanced rate are classic evidence of
n.g.p. in a substitution reaction, and a reasonable mechanism is shown in Scheme 12.8.
The departure of the nucleofuge, Br–, is assisted by nucleophilic participation by the ace-
toxy group, then the bicyclic cationic intermediate is captured at either of the equivalent
electrophilic ring carbons to give the product.

Me Me Ag+ ions complex the Br

+
OAc OAc to form a more effective
O O AcOH O O
+ nucleofuge in the solvolysis
+ AcO– Ag+
–AgBr of an alkyl bromide. Note
OAc OAc also that the products are
Br AcO–
an equimolar mixture of
enantiomers (racemate)
due to the symmetry of
the intermediate even if
AcO OAc + AcO
the starting material is the
AcO OAc
trans Br tr ans products pure stereoisomer.
(racemate)

Scheme 12.8 Neighbouring group participation in the solvolysis of trans-1-acetoxy-2-bromocyclohexane in

ethanoic acid containing AcOAg.
Note that n.g.p. always
involves formation of a
The neighbouring acetoxy group in cis-1-acetoxy-2-bromocyclohexane is unable to cyclic intermediate, e.g.
approach the rear side of the C which bears the Br in either chair conformation, so the oxirane in Scheme
n.g.p. is not possible. Consequently, its substitution reaction under the same solvo- 12.6 and the resonance-
lytic conditions is much slower and gives predominantly inversion of configuration stabilized acetoxonium ion
(Scheme 12.9). in Scheme 12.8.
268 . . . 12 Nucleophilic Substitution Reactions of Haloalkanes and Related Compounds

Scheme 12.9 Br
Solvolysis of cis-1-acetoxy-2- AcOH
AcO + AcO– Ag+ AcO
bromocyclohexane in ethanoic –AgBr
H OAc
acid containing AcAg.
cis trans

Me

O O
Br
H

Exercise 12.14 If the solvolyses of enantiomerically enriched cis- and trans-1-acetoxy-2-bromocyclohexanes

were monitored in polarimeters, explain what you would expect to observe.

Internal nucleophilic groups able to participate as neighbouring groups are not limited
to those with lone pairs, as we shall see in Chapter 22. We shall also explore in more
detail in that chapter the formation of rearrangement products in reactions involving
neighbouring group participation.

12.6 Competition between SN1 and SN2

Mechanisms
Characteristic features of SN1 and SN2 mechanisms are compared in Table 12.1 which
we use below to summarize and review what we have covered so far about nucleophilic
substitution reactions at saturated carbon.
Simple primary alkyl substrates do not react by the SN1 mechanism because primary
alkyl cations are too unstable to form in solution, and tertiary alkyl substrates are too
sterically hindered to react by the SN2 mechanism. Between these, secondary alkyl sub-
strates may react by SN1 and/or SN2 mechanisms, depending on the reaction conditions.
One defining difference between the two mechanisms is that the nature of the nucleo-
phile and its concentration affect the rate of an SN2 reaction, but not of an SN1. So, good
nucleophiles favour the SN2 mechanism, whereas the SN1 mechanism is more likely in
weakly nucleophilic reaction conditions. Polar aprotic solvents are good for SN2 reac-
tions and, as they are usually only weakly nucleophilic, they will not compete effectively
with a nucleophilic solute. Polar protic solvents, such as water and lower alcohols and

Table 12.1 Comparison of SN1 and SN2 mechanisms

SN1 SN2
Rate-determining step unimolecular bimolecular
Rate law 1st order 2nd order
Mechanistic steps two steps one step
Intermediate carbenium ion none
Reactivity 3° > 2° >> 1°, methyl methyl > 1° > 2° >> 3°
(carbenium ion stability) (steric hindrance)
Effect of nucleophile none faster with better
Good solvent polar protic polar aprotic
Stereochemistry racemization/partial inversion inversion
 12.6 Competition between SN1 and SN2 Mechanisms . . . 269

carboxylic acids, are good for SN1 reactions because their polarity facilitates formation of
carbenium ion intermediates which are stabilized by solvation (electron-pair donation).
SN1 reactions in which the solvent is an active participant (a solvent molecule acts as
a nucleophile in the product-determining step) are called solvolytic reactions, or sol-
volyses (e.g. hydrolysis in water, methanolysis in methanol, etc.).
A second defining difference is that an SN2 mechanism involves complete inversion
of configuration at the reaction site, and often gives a high yield of a single product. In
contrast, the SN1 mechanism involves an achiral carbenium ion intermediate (initially
within an ion pair), even if the starting material is chiral at the reaction site. Consequently,
the product is always racemic to some degree (often a high degree) but with an excess of
inversion of configuration due to the departing nucleofuge inhibiting nucleophilic cap-
ture with retention. SN1 reactions may give a multiplicity of products, including alkenes
by elimination (see next chapter), which reduces their synthetic value.

Predict a mechanism for each of the following reactions and give structures of substitution prod- Example 12.5
ucts with stereochemistry where applicable.
Br
(a) Br + NaCN (b) + MeOH
MeOH MeOH

Br Cl
(c) + MeCO2Na (d) + HCO2H
DMSO HCO2H

Solution
(a) Reaction of a primary alkyl bromide with a good nucleophile proceeds by the SN2 mecha-
nism. Products are:
CN + NaBr
butanenitrile

(b) Solvolysis of a secondary alkyl bromide in methanol (no nucleophilic solute) proceeds by the
SN1 mechanism. The product is the largely racemic ether.
OMe OMe
+ + HBr
(S) (R)
2-methoxybutane

(c) Ethanoate (acetate) ion is usually a poor nucleophile in hydrogen-bonding solvents, but is
sufficiently good in the aprotic DMSO to give an SN2 reaction with a secondary alkyl bromide
with inversion of configuration.
OCOMe
+ NaBr
(S)-1-methylpropyl ethanoate

(d) Solvolysis of a tertiary (achiral) alkyl chloride in the highly polar and only moderately nucleo-
philic methanoic acid (formic acid) occurs by the SN1 mechanism.

+ HCl
OCHO
1,1-dimethylpropyl methanoate
270 . . . 12 Nucleophilic Substitution Reactions of Haloalkanes and Related Compounds

Exercise 12.15 Predict a mechanism for each of the following reactions and give structure(s) of substitution
product(s) with stereochemistry where applicable.

Br Br
(a) + MeOH (b) + NaSH
MeOH propanone

Br Br
(c) + HCO2H (d) + NaCN
HCO2H propanone
CH3 CH3

Summary

The C–Y bond of haloalkanes and related compounds RY is polar, and the partially positive (electrophilic) carbon
is susceptible to direct nucleophilic attack.

Nucleophilic attack occurs at the C from the side opposite to the C–Y bond by the SN2 mechanism, whereupon
the nucleofuge (leaving group, Y–) is displaced to give a substitution product with stereochemical inversion.

Being bimolecular, the single-step SN2 mechanism is subject to steric hindrance and the reactivity generally
decreases in the order methyl > 1° > 2° alkyl derivatives; 3° alkyl derivatives do not react by the SN2 mechanism.

Solvents have major effects upon the rate constant of a reaction when there is an appreciable difference in
polarity between reactant molecule(s) and the (rate-determining) transition structure. Polar aprotic solvents are
generally good for SN2 reactions with anionic nucleophiles.

The alternative SN1 mechanism occurs in polar but weakly nucleophilic/basic solution by initial unimolecular
heterolysis of the C–Y bond to give a carbenium ion intermediate which is trapped by a nucleophile (usually
the solvent) in the second step to complete the substitution; the more stable the intermediate carbenium ion,
the faster the reaction.

Reactivity by the SN1 mechanism decreases in the order, 3° > 2° for simple alkyl derivatives; allylic and benzylic
derivatives are particularly reactive whereas simple primary alkyl substrates do not react by the SN1 mechanism.

The rate constant of a reaction is appreciably enhanced in the event of neighbouring group participation by
an internal nucleophilic group; this involves intramolecular rate-determining formation of a cyclic intermediate
which is then trapped by external nucleophiles to give the final products.

Problems

12.1 Complete the following equations. Br

Cl + NaI (c) + Me2NH
(a)
propanone EtOH

Br
Cl + EtONa
(b) (d)
EtOH + EtSNa
EtOH
 Problems . . . 271

12.2 What is the main product in each of the Br

following substitution reactions?
(a)
H2O-EtOH and
(a) Br + NaCN
O reflux
Br

H2O-EtOH
(b) Br Br + 2 NaCN Br
reflux
(2 equiv.) (b)
and
NaHCO3 Br
(c) PhCH2Cl + PhNH2
H2O, 90_95 ºC Cl Cl

KOH
(d) PhCH2Br + (c)
and
N DMSO, rt
H O2N
CH2Cl
AcOH
(e) + AcONa
reflux (d) Br and
O2N Br
95% ethanol
(f ) 2 PhCH2Cl + Na2S
(2 equiv.) reflux 12.6 When benzyl and p-methoxybenzyl bromides
are heated in ethanol, the corresponding ethyl ethers
12.3 Draw the structure of the main product in each are formed. Which of the two bromides reacts faster, and
of the following reactions, and give its IUPAC name explain why?
including its R,S stereochemical designation.
H Br
12.7 What is the main product from each of the
(a) following dihalides in the reactions indicated?
+ NaCN
propanone
EtOH-H2O
Br (a) Cl Br + KCN
(1 equiv.) reflux
(b) + NaI
propanone
10% aq. Na2CO3
(c) + MeSNa (b)
EtOH Cl Cl reflux
H Cl

H Br
propanone
Br (c) Br CH2Br + Me2NH
(d) reflux
+ NaOEt
EtOH
12.8 Draw a free energy profile for the reaction
12.4 Which of each of the following will be the faster in ethanol given in Exercise 12.6(a), and show
SN2 reaction?
how the profile would be different for the reaction
(a) 1-Bromobutane or 2-bromobutane with sodium in water.
iodide in propanone.
(b) 2-Bromopentane or 2-iodopentane with sodium 12.9 Draw a free energy profile for the reaction of
cyanide in ethanol. iodomethane with dimethylamine, and use it to explain
(c) Ethanamine or 2-methylpropan-2-amine (t-butylamine) how a change from a less to a more polar solvent would
with 1-bromobutane. affect the rate constant of the reaction.
(d) Sodium ethoxide or sodium ethanoate (acetate) with
12.10 When 1,4-dibromobutane reacts with Na2S in
iodomethane.
ethanol, a product with the molecular formula C4H8S is
12.5 Which of each of the following pairs of obtained. Give the structure of the product by showing
haloalkanes will be the more reactive SN1 reactant, and how it is formed.
explain why?
272 . . . 12 Nucleophilic Substitution Reactions of Haloalkanes and Related Compounds

12.11 Explain the following reaction and comment 12.12 Give a mechanism for the following
on the outcome if the reactant had been a single reaction and indicate the stereochemistry of the
enantiomer. main product.
OMe OMe Cl
AcOH KOH
OH
AgOAc H2O, 20–30 ºC (Courtesy of the Royal
Br OAc
Society of Chemistry.)