REACTIONS OF ALKYL

HALIDES: NUCLEOPHILIC
SUBSTITUTIONS AND
ELIMINATIONS
NUCLEOPHILIC SUBSTITUTIONS AND
ELIMINATIONS
 The carbon–halogen bond in an alkyl halide is
polar and the carbon atom is electron-poor.
 Thus, alkyl halides are electrophiles, and much of
their chemistry involves polar reactions with
nucleophiles and bases.
NUCLEOPHILIC SUBSTITUTIONS AND
ELIMINATIONS
 Alkyl halides do one of two things when they
react with a nucleophile/base, such as hydroxide
ion: either they undergo substitution of the X
group by the nucleophile, or they undergo
elimination of HX to yield an alkene
WHY STUDY REACTIONS OF ALKYL
HALIDES?

 Nucleophilic substitution and base-induced

elimination are two of the most widely occurring
and versatile reaction types in organic chemistry,
both in the laboratory and in biological pathways
NUCLEOPHILIC SUBSTITUTION REACTIONS
 Nucleophilic substitution reactions:

 Any species, either neutral or negatively charged,

can act as a nucleophile as long as it has an
unshared pair of electrons; that is, as long as it is
a Lewis base.
NUCLEOPHILIC SUBSTITUTION REACTIONS

 If the nucleophile is negatively charged, the

product is neutral; if the nucleophile is neutral,
the product is positively charged
NUCLEOPHILIC SUBSTITUTION REACTIONS
 Nucleophilic substitutions occur by two major
pathways, named the SN1 reaction and the SN2
reaction
NUCLEOPHILIC SUBSTITUTION REACTIONS
 A wide array of substances can be prepared using
nucleophilic substitution reactions.
 The reaction of an acetylide anion with an alkyl
halide, for instance, is an SN2 reaction in which
the acetylide nucleophile displaces a halide
leaving group
NUCLEOPHILIC SUBSTITUTION REACTIONS
 Table 11.1 lists some nucleophiles and shows the
products of their reactions with bromomethane
NUCLEOPHILIC SUBSTITUTION REACTIONS
THE SN2 REACTION
 SN2 reaction—short for substitution, nucleophilic,
bimolecular
 Takes place in a single step without
intermediates when the incoming nucleophile
reacts with the alkyl halide (the substrate) from
a direction opposite the group that is displaced
(the leaving group).
 The SN2 reaction occurs when an electron pair on
the nucleophile Nu:- forces out the group X:-,
which takes with it the electron pair from the
former C-X bond.
RATES OF SN2 REACTIONS

 The rate is linearly dependent on the

concentrations of two species ( a second-order
reaction)
 If we double the concentration of OH-, the
frequency of encounter between the reaction
partners doubles and we find that the reaction
rate also doubles. Similarly, if we double the
concentration of CH3Br, the reaction rate again
doubles
STEREOCHEMISTRY OF SN2 REACTIONS
 As the nucleophile comes in on one side of the
substrate and bonds to the carbon, the halide
departs from the other side, thereby inverting the
stereochemical configuration
 This occurs through a transition state in which
the new Nu-C bond is partially forming at the
same time that the old C-X bond is partially
breaking and in which the negative charge is
shared by both the incoming nucleophile and the
outgoing halide ion.
 The transition state for this inversion has the
remaining three bonds to carbon in a planar
arrangement
STEREOCHEMISTRY OF SN2 REACTIONS
THE SUBSTRATE: STERIC EFFECTS IN SN2
REACTIONS
 Because the SN2 transition state involves partial
bond formation between the incoming nucleophile
and the alkyl halide carbon atom, a hindered,
bulky substrate should prevent easy approach of
the nucleophile, making bond formation difficult.
 The transition state for reaction of a sterically
hindered substrate, whose carbon atom is
“shielded” from approach of the incoming
nucleophile, is higher in energy and forms more
slowly than the corresponding transition state for
a less hindered substrate
THE SUBSTRATE: STERIC EFFECTS IN THE
SN2 REACTION
THE SUBSTRATE: STERIC EFFECTS IN THE
SN2 REACTION
 The difficulty of nucleophile approach increases
as the three substituents bonded to the halo-
substituted carbon atom increase in size.
 Methyl halides are by far the most reactive
substrates in SN2 reactions, followed by primary
alkyl halides such as ethyl and propyl.
 Alkyl branching at the reacting center, as in
isopropyl halides (2°), slows the reaction greatly,
and further branching, as in tert-butyl halides
(3°), effectively halts the reaction.
 Even branching one carbon removed from the
reacting center, as in 2,2-dimethylpropyl
(neopentyl) halides, greatly slows nucleophilic
displacement.
THE SUBSTRATE: STERIC EFFECTS IN THE
SN2 REACTION
THE SUBSTRATE: STERIC EFFECTS IN THE
SN2 REACTION
 As a result, SN2 reactions occur only at relatively
unhindered sites and are normally useful only
with methyl halides, primary halides, and a few
simple secondary halides
 Vinylic halides (R2C=CRX) and aryl halides are
unreactive toward SN2 displacement.
 This lack of reactivity is due to steric factors: the
incoming nucleophile would have to approach in
the plane of the carbon–carbon double bond and
burrow through part of the molecule to carry out
a backside displacement
THE SUBSTRATE: STERIC EFFECTS IN THE
SN2 REACTION
THE NUCLEOPHILE
 Negatively charged nucleophiles are usually
more reactive than neutral ones.
 As a result, SN2 reactions are often carried out
under basic conditions rather than neutral or
acidic conditions
THE LEAVING GROUP
 Because the leaving group is expelled with a
negative charge in most SN2 reactions, the best
leaving groups are those that best stabilize the
negative charge in the transition state.
 The greater the extent of charge stabilization by
the leaving group, the lower the energy of the
transition state and the more rapid the reaction
 Groups that best stabilize a negative charge are
also the weakest bases.
THE LEAVING GROUP
 Thus, weak bases such as Cl2, Br2, and tosylate
ion make good leaving groups, while strong bases
such as OH- and NH2- make poor leaving groups

 F-, HO-, RO-, and H2N- are not displaced by

nucleophiles. In other words, alkyl fluorides,
alcohols, ethers, and amines do not typically
undergo SN2 reactions.
THE SN1 REACTION
 Substitution, nucleophilic, unimolecular
 Occurs by spontaneous loss of the leaving group
before the incoming nucleophile approaches
 Loss of the leaving group gives a carbocation
intermediate, which then reacts with the
nucleophile in a second step to yield the
substitution product
 THE SN1 REACTION

A nucleophilic substitution reaction is occurring— a

halogen is replacing a hydroxyl group—yet the
reactivity order is backward
RATES OF SN1 REACTIONS
 Has a rate that depends only on the alkyl halide
concentration and is independent of the
nucleophile concentration.
 In other words, the reaction is a first-order
process
 The observation that SN1 reactions are
unimolecular means that the substrate
undergoes a spontaneous reaction without the
involvement of the nucleophile
RATES OF SN1 REACTIONS
STEREOCHEMISTRY OF SN1 REACTIONS
 Because an SN1 reaction occurs through a
carbocation intermediate, its stereochemical
outcome is different from that of an SN2 reaction.
 Carbocations are planar, sp2-hybridized

 The symmetrical intermediate carbocation can

react with a nucleophile equally well from either
side, leading to a racemic, 50:50 mixture of
enantiomers
STEREOCHEMISTRY OF SN1 REACTIONS
THE SUBSTRATE
 Since the rate-limiting step in an SN1 reaction is
the spontaneous, unimolecular dissociation of the
substrate to yield a carbocation, the reaction is
favored whenever a stabilized carbocation
intermediate is formed.
 The more stable the carbocation intermediate,
the faster the SN1 reaction
 The stability order of alkyl carbocations is
THE LEAVING GROUP
 The best leaving groups are those that are most
stable; that is, those that are the conjugate bases
of strong acids.
 An identical reactivity order is found for the SN1
reaction because the leaving group is directly
involved in the rate-limiting step.
 The SN1 reactivity order is

 The SN1 reaction is often carried out under acidic

conditions, neutral water is sometimes the
leaving group
THE NUCLEOPHILE
 The nature of the nucleophile plays a major role
in the SN2 reaction but does not affect an SN1
reaction.
 Because the SN1 reaction occurs through a rate-
limiting step in which the added nucleophile has
no part, the nucleophile can’t affect the reaction
rate.
 Furthermore, neutral nucleophiles are just as
effective as negatively charged ones, so SN1
reactions frequently occur under neutral or acidic
conditions.
ELIMINATION REACTIONS: ZAITSEV’S
RULE

 According to Zaitsev’s rule, formulated in 1875 by

the Russian chemist Alexander Zaitsev, base-
induced elimination reactions generally
(although not always) give the more stable
alkene product—that is, the alkene with more
alkyl substituents on the double-bond carbons
ELIMINATION REACTIONS: ZAITSEV’S
RULE
PREDICTING THE PRODUCT OF AN
ELIMINATION REACTION
 What products would you expect from
elimination reactions of the following alkyl
halides? Which product will be the major product
in each case?
ELIMINATION REACTIONS
 Elimination reactions can take place by different
mechanisms
 The most common mechanisms are the E1, E2,
and E1cB reactions which differ in the timing of
C-H and C-X bond-breaking
 All three mechanisms occur frequently in the
laboratory, but the E1cB mechanism
predominates in biological pathways
ELIMINATION REACTIONS
 In the E1 reaction, the C-X bond breaks first to
give a carbocation intermediate that undergoes
subsequent base abstraction of H+ to yield the
alkene
ELIMINATION REACTIONS
 In the E2 reaction, base-induced C-H bond
cleavage is simultaneous with C-X bond cleavage,
giving the alkene in a single step
ELIMINATION REACTIONS
 In the E1cB reaction (cB for “conjugate base”),
base abstraction of the proton occurs first, giving
a carbanion (R:-) intermediate. This anion, the
conjugate base of the reactant “acid,” then
undergoes loss of X- in a subsequent step to give
the alkene
THE E2 REACTION
 The E2 reaction (for elimination, bimolecular)
occurs when an alkyl halide is treated with a
strong base, such as hydroxide ion or alkoxide ion
(RO-).
 It is the most commonly occurring pathway for
elimination
 Like the SN2 reaction, the E2 reaction takes place
in one step without intermediates.
 As the base begins to abstract H+ from a carbon
next to the leaving group, the C-H bond begins to
break, a C=C bond begins to form, and the
leaving group begins to depart, taking with it the
electron pair from the C-X bond
 E2 reactions show second-order kinetics
THE E1 REACTION
 The SN1 reaction has a close analog called the E1
reaction (for elimination, unimolecular).
 E1 eliminations begin with the same
unimolecular dissociation to give a carbocation
that we saw in the SN1 reaction, but the
dissociation is followed by loss of H+ from the
adjacent carbon rather than by substitution.
 The E1 and SN1 reactions normally occur
together whenever an alkyl halide is treated in a
hydroxylic solvent with a nonbasic nucleophile.
THE E1 REACTION
 The best E1 substrates are also the best SN1
substrates, and mixtures of substitution and
elimination products are usually obtained
THE E1CB REACTION
 The E1cB reaction takes place through a
carbanion intermediate.
 Base-induced abstraction of a proton in a slow,
rate-limiting step gives an anion, which expels a
leaving group on the adjacent carbon.
 The reaction is particularly common in
substrates that have a poor leaving group, such
as -OH, two carbons removed from a carbonyl
group, HO-C-CH-C=O.
THE E1CB REACTION
 The poor leaving group disfavors the alternative
E1 and E2 possibilities, and the carbonyl group
makes the adjacent hydrogen unusually acidic by
resonance stabilization of the anion intermediate
A SUMMARY OF REACTIVITY: SN1, SN2, E1,
E1CB, AND E2
 SN1, SN2, E1, E1cB, E2—how can you predict
what will happen in any given case? Will
substitution or elimination occur? Will the
reaction be bimolecular or unimolecular? There
are no rigid answers to these questions, but it’s
possible to recognize some trends and make some
generalizations
 Primary alkyl halides: SN2 substitution occurs
if a nucleophile such as I-, Br-, RS-, NH3, or CN- is
used, E2 elimination occurs if a strong base such
as OH- or an alkoxide ion (RO-) is used, and E1cB
elimination occurs if the leaving group is two
carbons away from a carbonyl group
(HO-C-CH-C=O).
A SUMMARY OF REACTIVITY: SN1, SN2, E1,
E1CB, AND E2
 Secondary alkyl halides: SN2 substitution
occurs if a weakly basic nucleophile is used in a
polar aprotic solvent, E2 elimination
predominates if a strong base is used, and E1cB
elimination takes place if the leaving group is
two carbons away from a carbonyl group.
 Tertiary alkyl halides: E2 elimination occurs
when a base is used, but SN1 substitution and E1
elimination occur together under neutral
conditions, such as in pure ethanol or water.
E1cB elimination takes place if the leaving group
is two carbons away from a carbonyl group.