Chapter 6

Ionic Reactions:

Nucleophilic Substitution
And
Elimination
of Alkyl Halides
In this chapter we will consider:

What groups can be replaced (i.e., substituted) or

eliminated?

The various mechanisms by which such processes

occur.

The conditions that can promote such reactions.

6.0
Alkyl Halides
Haloalkane (alkyl halide): a compound containing a
halogen atom covalently bonded to an sp3 hybridized
carbon.
The C-X bond is polarized because of the greater
electronegativity of the halogen.
The carbon atom bears a partial positive charge, the
halogen atom a partial negative charge.
The general symbol for an alkyl halide is R-X.

6.1
 A haloalkane
R X (an alkyl halide)

-F Fluoro- Fluoride

-Cl Chloro- Chloride

-Br Bromo- Bromide

-I Iodo- Iodide

6.1
Alkyl halides are classified as primary (1o), secondary
(2o), or tertiary (3o) according to the number of carbon
groups (R) directly bonded to the carbon bearing the
halogen atom.

6.1
6.1
Vinylic and Phenyl Halides
In these compounds, the carbon is sp2 hybridized.

H
H C
C
H
C6H5 Ph

6.1
Several polyhaloalkanes are common solvents and are
generally referred to by their common or trivial names.

CHX3 CH2Cl2
Trihalomethane Dichloromethane
(Haloform) (Methylene chloride)

CHCl3 CH3CCl3
Trichloromethane 1,1,1-Trichloroethane
(Chloroform) (Methyl chloroform)

CHI3 CCl2 CHCl

Triiodomethane Trichloroethylene
(Iodoform) (Trichlor)

6.1
Physical Properties of Organic Halides

Most alkyl and aryl halides have very low solubilities in

water.
CH2Cl2, CHCl3 (chloroform), CCl4 are used as solvents
for nonpolar and moderately polar compounds.
CHCl3 and CCl4 have a cumulative toxicity and are
carcinogenic.
CH3I (bp 42oC) is the only monohalomethane that is a
liquid at room temperature and 1 atm pressure.

6.1
Nucleophilic Substitution Reactions
In a nucleophilic substitution reaction a nucleophile
(Nu:) displaces a leaving group (LG) in the molecule
that undergoes the substitution (the substrate).

LG .. LG

Substrate Leaving group

The nucleophile is always a Lewis base, and it may be

negatively charged or neutral

The leaving group is always a species that takes a pair

of electrons with it when it departs.

6.2
A characteristic reaction of alkyl halides is nucleophilic
substitution where a nucleophile with an unshared pair
of electrons replaces the halogen.

6.2
6.2
 The timing of the bond and bond making steps is
fundamental to a discussion of the mechanism of a
reaction.

Simultaneous Bond Breaking and Bond Making:

OR

Bond Breaking precedes Bond Making:

6.2
Nucleophiles
A nucleophile is a reagent that seeks a positive center.
Any negative ion or uncharged molecule with an
unshared electron pair is a potential nucleophiles.
The polarity of the carbon-halogen bond determines
the reactivity pattern.

6.3
Nucleophilic substitution by a negatively charged
nucleophile results directly in a neutral product.

Nucleophilic substitution by a neutral nucleophile

results initially in a positively charged product.

6.3
6.3
Leaving Groups
L represents a generic leaving group.
A good leaving group produces a stable anion or
neutral molecule.
Generally, the anions (conjugate bases) of strong acids
are good leaving groups.
Halide ions are among the best and most important
leaving groups.

6.4
Poor leaving groups can be turned into good leaving
groups by protonation.

6.4
Kinetics of a Nucleophilic Substitution Reaction
A chemical reaction can be analyzed in terms of:

The extent to which it takes place – how completely the

reactants are converted into products after equilibrium
is reached. This analysis is based on the
thermodynamic parameters.

The rate of the reaction – how fast the reactants are

converted to products. The kinetics of the reaction
means the rate of the reaction.

6.5
An SN2 Reaction
Initial Rate Measurement:

The rate of the reaction can be determined

experimentally by measuring the rate at which CH3Cl
or OH ion disappears from the solution or the rate at
which CH3OH or Cl ion appears in solution.

6.5
The rate of the reaction doubles when the concentration
of either reactant is doubled.

Rate = k[CH3Cl][OH ]
k: rate constant

A reaction rate that shows a kinetic dependence on the

concentrations of two reactants, each to the first power,
is called second order.

6.5
 Rate = k[CH3Cl][OH ]
k: rate constant

The reaction is termed bimolecular, meaning that two

species are involved in the step whose rate is being
measured, and given the symbol SN2.

S = substitution
N = nucleophilic
2 = bimolecular (two species are involved
in the rate-determining step)
6.5
A Mechanism for the SN2 Reaction

The nucleophile attacks the carbon on the side opposite

the leaving group.
As overlap develops between the orbital with the
electron pair of the nucleophile and the antibonding
orbital of the substrate, the bond between the carbon
and the leaving group weakens.
6.6
The backside attack by the nucleophile results in an
inversion of absolute configuration at the carbon center
that is called a Walden inversion.
The Walden inversion is a key characteristic of the SN2
mechanism.

* *
Nu + C L Nu C + L

6.6
The Hughes-Ingold mechanism for the SN2 reaction
involves only one step.
The SN2 reaction is a concerted reaction.

6.6
Transition State Theory:
Free-Energy Diagrams

Exergonic: a reaction that proceeds with a negative

free-energy change.
Endergonic: a reaction that proceeds with a positive
free-energy change.

DGo = -RT lnKeq

R: Gas constant (8.314 J K-1)
T: Absolute temperature in kelvins
6.7
 DGo = -RT lnKeq
-DGo
lnKeq =
RT
-(-100 kJ mol-1)
lnKeq = = 36.1
0.00831 kJ K-1 mol-1 x 333 K

Keq = 5.0 x 1015

An equilibrium constant as large as this means that the

reaction goes to completion.
The thermodynamic analysis only examines the relative
free energies of the starting and product states.
6.7
Free-Energy Diagram for an SN2 Reaction:

6.7
Free-Energy Diagram: a plot of the free energy of the
reacting particles (y-axis) against the reaction
coordinate (x-axis).
The reaction coordinate indicates the progress of the
reaction, in terms of the conversion of reactants to
products.
The top of the energy hill corresponds to the transition
state.

The DG++ is the free energy of activation which measures

the change in free energy between the starting state
and the transition state.
Highly exergonic reactions generally have smaller free
energy of activation.
6.7
Highly endergonic reactions generally have larger free
energy of activation.

+
+

6.7
6.7
6.7
6.7
For many reactions taking place near room
temperature, a 10oC increase in temperature will cause
the reaction rate to double.

6.7
Relationship between the Rate Constant and DG +
+

+
k= koe-DG + /RT
ko: the collision frequency at temperature T

ko = 6.2 x 1012 s-1 at 25oC

+
e +/RT
-DG is the fraction of collisions sufficiently energized
to reach the top of the reaction barrier.

Generally speaking, if a reaction has a DG++ less than 84

kJ mol-1, it will take place readily at room temperature
or below.

6.7
6.7
The Stereochemistry of SN2 Reactions
The nucleophile approaches the substrate carbon from
the back side with respect to the leaving group.

The stereochemistry of the SN2 reaction was elucidated

in studies on substrates with stereocenters.

6.8
6.8
SN2 reactions always occur with inversion of configuration.

6.8
Mechanism for the Reaction:

6.8
The Reaction of (CH3)3CCl with Water:
SN1 Reaction

The reaction rate depends on the concentration of tert-

butyl chloride, but shows no dependence on the
concentration of hydroxide ion.

6.9
The reaction rate depends on the concentration of tert-
butyl chloride, but shows no dependence on the
concentration of hydroxide ion.

Rate = k[(CH3)3CCl]
k: rate constant

A reaction rate that depends on the concentration of

only one reactant is called first-order or unimolecular.
The symbol is SN1.
6.9
Multi-Step Reactions and the Rate-Determining Step:
Many reactions in organic chemistry involve a
sequence of steps, each with an energy barrier linking
starting and product states. Each step proceeds with a
unique rate constant.
The slow step is called the rate-limiting step or the rate-
determining step.

k1 << k2 or k3

6.9
6.9
A Mechanism for the SN1 Reaction
(CH3)3CCl + 2 H2O (CH3)3COH + H3O + Cl

H3C CH3
H2O
H3C C Cl H3C C + Cl
slow
H3C CH3

CH3 H3C
fast
H3C C + O H H3C C O H
CH3 H H3C H

H3C H3C
fast
H3C C O H + O H H3C C O + H O H
H3C H H H3C H H
6.10
6.10
6.10
DG

6.10
Heterolytic cleavage of the C-Cl bond generates a
carbocation which is a high energy chemical species.
In the gas phase, the free energy of activation for the
bond heterolysis of an R-Cl compound is hundreds of
kJ/mol.
In solution phase, solvation stabilizes both the
carbocation and chloride anion through charge-dipole
interactions.

6.10
Carbocations
Early in the last century, carbocations began to be
postulated as intermediates in many organic reactions.
In the early 1960s, George Olah and others developed
methods to directly observe carbocations by NMR.
Carbocations are trivalent carbon species with a
positive charge.

6.11
The Nobel Prize in Chemistry 1994:

George A. Olah
(1927 - 2017)

"for his contribution to carbocation chemistry"

6.11
The Relative Stabilities of Carbocations:
Tertiary carbocations are the most stable, and the
methyl carbocation is the least stable.

3o > 2o > 1o > Methyl

6.11
Hyperconjugation:
Hyperconjugation involves electron delocalization from
a filled bonding orbital to an adjacent unfilled orbital.
Interaction of the sigma electrons in the C-H bond of
the methyl group with the empty p-orbital of the
carbocation disperses and stabilizes the positive charge.

6.11
Any time a charge can be dispersed or delocalized by
hyperconjugation, inductive effects, or resonance, a
system will be stabilized.

6.11
The Stereochemistry of SN1 Reactions
Because carbocations have trigonal planar geometry,
they possess a plane of symmetry and are achiral.
A carbocation can react with a nucleophile from either
the front side or the back side.

6.12
Racemization: transformation of an optically active
compound into a racemic mixture.

The SN1 reaction of an optically active substrate

necessarily produces a racemic form of a chiral
product.

6.12
Mechanism:

6.12
6.12
Solvolysis:
Solvolysis: a nucleophilic substitution in which the
nucleophile is a molecule of the solvent.

solvolysis = solvent + lysis

Hydrolysis
Methanolysis

6.12
Mechanism:

6.12
Factors Affecting the Rates of SN1 and
SN2 Reactions
The SN1 and SN2 are always potentially competitive
pathways for any nucleophilic substitution reaction.

However, because of structural, electronic, and other

factors, one pathway usually dominates.

solvent
Nu + C X C Nu + X

6.13
 solvent
Nu + C X C Nu + X

The structure of the substrate.

The concentration and reactivity of the nucleophile.

The effect of the solvent.

The nature of the leaving group.

6.13
Structure of the Haloalkanes:
SN1 reactions:
Governed by electronic factors, namely the relative
stabilities of carbocation intermediates.
relative rates: 3o > 2o >> 1o > methyl

SN2 reactions:
Governed by steric factors, namely the relative ease
of approach of the nucleophile to the site of
reaction.
relative rates: methyl > 1o > 2o >> 3o (unreactive)

6.13
6.13
Steric Hindrance:
The slowdown in the rate of the SN2 reaction with
increasing alkyl substituent around the reaction center
is attributed to a steric effect.

6.13
SN1 Reactions:
The primary factor that determines the reactivity of
RX compounds in the SN1 reaction is the stability of the
carbocation intermediate.
The only organic compounds that undergo reaction by
SN1 path at a reasonable rate are those that are capable
of forming relatively stable carbocations.

3o > 2o > 1o > Methyl

6.13
Effect of electronic and steric factors in competition
between SN1 and SN2 reactions:

6.13
The Hammond-Leffler Postulate:
The structure of a transition state resembles the stable
species that is nearest it in free energy.
In a highly endergonic step, the transition state
resembles the products of that step in structure.
In a highly exergonic step, the transition state
resembles the reactants in structure.

6.13
The structure of a transition state resembles the stable
species that is nearest it in free energy.

6.13
Concentration and Strength of the Nucleophile:
A change in the concentration of the nucleophile will
affect the rate of an SN2 reaction but will have no effect
on an SN1 reaction.
Nucleophilicity: a kinetic property measured by the rate
at which a Nu attacks a reference compound under a
standard set of experimental conditions
for example, the rate at which a set of nucleophiles
displaces bromide ion from bromoethane in ethanol
at 25oC

CH3CH2Br + Nu CH3CH2Nu + Br

6.13
6.13
Relative Nucleophilicity:
A negatively charged nucleophile is always a more
reactive nucleophile than its conjugate acid.

OH > H2O, RO > ROH

In a group of nucleophiles in which the nucleophilic atom
is the same, nucleophilicities parallel basicities.

RO > HO >> RCO2 > ROH > H2O

When the nucleophilic atoms are different, nucleophilicities

may not parallel basicities.

6.13
Solvent Effects in SN2 and SN1 Reactions:
Solvents provide the medium in which reactants are
dissolved and in which nucleophilic substitution
reactions take place.
Common solvents are divided into two groups;
protic and aprotic.
Protic solvent: a solvent whose molecules have a
hydrogen atom attached to a strongly electronegative
element such as oxygen or nitrogen.
Aprotic solvent: a solvent whose molecules do not
have a hydrogen atom attached to a strongly
electronegative element such as oxygen or nitrogen.

6.13
Protic solvent: a solvent whose molecules have a
hydrogen atom attached to a strongly electronegative
element such as oxygen or nitrogen.

6.13
An aprotic solvent does not have hydrogen atoms that
are capable of hydrogen bonding.
Many aprotic solvents are nonpolar, or have low
polarity and do not dissolve ionic materials.
Polar, aprotic solvents are often used alone or as co-
solvent for SN2 reactions.

6.13
SN2 reactions are favored by polar aprotic solvents
(e.g., acetone, DMF, DMSO).

Minimizing the solvent’s interaction with the

nucleophile in SN2 reactions.

SN1 reactions are favored by polar protic solvents

(e.g., EtOH, MeOH, H2O).

Facilitating ionization of the leaving group

and stabilizing ionic intermediates by solvents
in SN1 reactions.

6.13
The polar aprotic solvents dissolve ionic materials
and selectively interact with cations through dipole-
charge interactions.
Aprotic solvents do not solvate anions to any
appreciable extent.

6.13
Because anions are weakly solvated, and because
there is little cation-anion association in polar aprotic
solvents, the term “naked anions” is often used to
describe the state of anions in these solvents.
Naked anions are highly reactive both as nucleophiles
and bases.
The rates of SN2 reactions generally are vastly
increased when they are carried out in polar aprotic
solvents. The increase in rate can be as large as
millionfold.

Nucleophilicity in Aprotic Solvents:

6.13
A protic solvent has at least one hydrogen atom
capable of participating in a hydrogen bond.
Protic solvents facilitate formation of a carbocation
by forming hydrogen bonds with the leaving group as
it departs, thereby lowering the energy of the
transition state leading to a carbocation.

6.13
Dielectric constant: a measure of a solvent’s ability to
insulate opposite charges from each other. It is an
indication of the solvent’s polarity.

6.13
In a polar aprotic solvent, the nucleophile is less
unencumbered by solvent molecules.
Hydrogen bonding with a protic solvent encumbers a
nucleophile and hinders its reactivity in a substitution
reaction.

6.13
 Hydrogen bonds to a small nucleophilic atom are
stronger than those to larger nucleophilic atoms.
Larger atoms have greater polarizability.

Nucleophilicity in Protic Solvents:

6.13
The Nature of the Leaving Group:
The best leaving groups are those that become either
a relatively stable anion or a neutral molecule when
they depart.

6.13
 Leaving group ability influences the rates of both the
SN1 and SN2 reactions through the developing anion
character of the leaving group in the transition states.
Stable anions are weak bases ---- the anions of strong
acids.
Leaving group ability: I > Br > Cl >> F
Base strength: F >> Cl > Br > I
The typical relative reactivities of R-X compounds in
SN2 reactions differ greatly because of the different
leaving group abilities of the halides.

R-I R-Br R-Cl R-F

30,000 10,000 200 1
6.13
Another important class of good leaving groups are the
sulfonate esters, R-O3SR’, that produce stable sulfonate
anions in nucleophilic substitution reactions.

Tosylate (TsO )

Trifluoromethanesulfonate
(TfO )

6.13
Strongly basic ions rarely act as leaving groups.

Very powerful bases such as hydride and alkanide ions

virtually never act as leaving groups.

6.13
Poor leaving groups sometimes can be chemically
modified to turn into better leaving groups.

Protonation of the hydroxyl function of an alcohol is an

example.

6.13
6.13
Organic Synthesis: Functional Group
Transformation Using SN2 Reactions
Functional Group Transformation: conversion of one
functional group into another.
The SN2 reaction is often used to convert alkyl halides
into other functional groups.
Vinylic and aryl halides do not react readily by either
SN1 or SN2 mechanisms.

6.14
6.14
As in all SN2 reactions, the syntheses proceed with
inversion at a stereocenter.

6.14
Biological Methylation:
Methylation: the reaction transferring a methyl
group to a nucleophile.

6.14
 (SAM)

Sulfonium group

6.14
(SAM) 6.14
Elimination Reactions of Alkyl Halides
In an elimination reaction, the atoms or groups Y and
Z are lost from adjacent carbons forming a multiple
bond.

Dehydrohalogenation:

- HX
C C C C
H X
6.15
Examples:

6.15
The reaction is described as a b-elimination or 1,2-
elimination indicating the positions of the lost atoms or
groups.

6.15
Bases Used in Dehydrohalogenation:

Typical bases are potassium hydroxide in ethanol (to

solubilize the alkyl halide) or sodium ethoxide in
ethanol.
Potassium tert-butoxide is another oxygen base that is
often used in dehydrohalogenation reactions.

CH3
KOH NaOEt KO C CH3
CH3

6.15
Alkoxide bases can be prepared from the rapid redox
reaction of the anhydrous alcohol with an alkali metal.

6.15
Sodium alkoxides also may be prepared by reacting
alcohols with the strong base sodium hydride.

6.15
 H H H

Hydride Hydrogen Proton

6.15
Mechanisms of b-Elimination:
There are two limiting mechanisms for b-elimination
reactions.

E1 mechanism: at one extreme, breaking of the C-X

bond is complete before reaction with base breaks the
C-H bond.
only R-X is involved in the rate-determining step.

E2 mechanism: at the other extreme, breaking of the C-

X and C-H bonds is concerted.
both R-X and base are involved in the rate-
determining step.

6.15
The E2 Mechanism
The mechanism proposed for the E2 reaction is based
on the observed second order rate expression.

C2H5O + CH3CHBrCH3 CH3CH=CH2 + C2H5OH + Br

Rate = k[CH3CHBrCH3][C2H5O ]

6.16
 A one-step mechanism; all bond-breaking and bond-
forming steps are concerted.

C2H5O + CH3CHBrCH3 CH3CH=CH2 + C2H5OH + Br

+ C2H5OH + Br

6.16
The hydrogen atom being removed and the leaving
group are in the same plane.

6.16
The E1 Mechanism
The reaction of tert-butyl chloride in the mixed solvent
of 80% ethanol-20% water at 25oC yields a product
mixture from two competing reaction paths:
substitution and elimination.

6.17
The rate of formation of isobutylene is given by:
Rate = ke[tert-butyl chloride]

The rate of formation of SN1 products is given by:

Rate = ks[tert-butyl chloride]

ke / ks = 17 / 83
These two competing reactions have the same rate-
determining step: bond heterolysis to produce the tert-
butyl carbocation.

6.17
After the rate-determining step, two competing modes
of reaction between the tert-butyl carbocation and
water/ethanol (acting as nucleophile/base) lead to
substitution and elimination products.

SN1 reaction

6.17
Mechanism for the E1 Reaction:

(CH3)3CCl + H2O (CH3)2C=CH2 + H3O + Cl

6.17
6.17
Summary of E1 versus E2 Reactions:

6.17
Substitution versus Elimination
Many nucleophiles are also strong bases (OH- and RO-)
and SN and E reactions often compete.
The ratio of SN/E products depends on the relative
rates of the two reactions.

Nucleophilic
H C C Nu + X
substitution

H C C X + Nu
b-Elimination H Nu
C C +
X

6.18
SN2 versus E2 Reactions:
It is considerably easier to predict the ratio of SN2 to
E2 products.

6.18
Because the rate expressions for the substitution and
elimination reactions both depend on the
concentrations of the substrate and the
nucleophile/base, the competition between the paths
cannot be changed by varying the concentration of
either reactant.

Rate = ksub[RX][Nu ]
Rate = kelim[RX][Nu ]

However, this competition does very much depend on

the structure of R-X and choice of base.

6.18
The reaction of primary alkyl halides with unhindered
alkoxide bases favors substitution.

Secondary alkyl halides react with alkoxide bases to

give mostly alkenes.

6.18
Tertiary alkyl halides do not react by the SN2 reaction.

The observed substitution product probably comes

from a competing SN1 reaction.

6.18
Increasing the reaction temperature favors elimination
(E1 and E2) over substitution.

Elimination reactions are entropically favored over

substitution.

DGo = DHo - T DSo

An increase in temperature further enhances the

entropy effect.

6.18
Sterically hindered bases promote elimination.

6.18
Weak bases promote substitution.

6.18
 SN1 versus E1 Reactions:
Reactions of 2o and 3o haloalkanes in polar protic solvents
give mixtures of substitution and elimination products.

CH3
-I E1
H 3C C I (CH3)2C=CH2
CH3
CH3 CH3
SN1
H3C C H3C C OH
H2O
CH3 CH3
CH3
CH3
H3C C Cl SN1
- Cl H3C C OCH2CH3
CH3 CH3CH2OH
CH3

6.18
Overall Summary

6.19