Organohalides: Nucleophilic Substitutions

and Eliminations

Dr Art Crossman

Learning Objectives: At the end of this topic we want to understand the

following concept:

Predict whether a reaction is likely to be SN1, SN2, E1, E1cB, or E2

 Organohalides or Haloalkanes
Compounds containing a halogen atom covalently bonded to an sp3 hybridized
carbon atom are named haloalkanes or, in the common system of nomenclature
alkyl halides. The general symbol for an alkyl halide is R-X where X may be F, Cl,
Br or I.

We are going to study two characteristics reactions of haloalkanes: Nucleophilic

substitution and β-Elimination. Haloalkanes are useful molecules because they
can be converted to alcohols, ethers, thiols, amines and alkenes and are thus
versatile molecules. Indeed, haloalkanes are often used as starting materials for
the synthesis of many useful compounds.
 Because all nucleophiles are also bases, nucleophilic substitution and base promoted β-
elimination are competing reactions. The ethoxide ion, for example, is both a
nucleophile and a base (see below).

OCH2CH3
as a nucleophile Nucleophilic
ethoxide ion attacks this carbon substitution
Br

+ CH3CH2O-Na+ H
a nucleophile and
a base
H
-elimination
as a base, ethoxide ion
attacks this hydrogen

β-Elimination reaction: The removal of atoms or groups of atoms from two

adjacent carbon atoms, e.g. the removal of H and X from an alkyl halide or H and
OH from an alcohol to form a carbon-carbon double bond.

We are going to study both of these reactions. Using them we can convert
haloalkanes to compounds with other functional groups including alcohols, ethers,
thiols, sulfides, amines, nitriles, alkenes and alkynes.
What are the SN2 and SN1 mechanisms for nucleophilic substituion?

On the basis of a wealth of experimental observations developed over a 70 year

period, chemists have proposed two limiting mechanisms for nucleophilic
substitutions. A fundamental difference between them is the timing of bond
breaking between carbon and the leaving group and of bond forming between
carbon and the nucleophile.

SN2 mechanism:
The two processes are concerted, meaning that bond breaking and bond forming
occur simultaneously. Thus, the departure of the leaving group is assisted by
the incoming nucleophile. This mechanism is designated SN2, where S stands
for Substitution, N for Nucleophilic and 2 for a bimolecular reaction. This type
of substitution reaction is classified as bimolecular because both the haloalkane
and the nucleophile are involved in the rate-determining step.

Rate law of the reaction: Rate=k[haloalkane][nucleophile]

The following is an SN2 mechanism for the reaction of hydroxide ion and
bromomethane to form methanol and bromide ion:

CH3Br + OH- CH3OH + Br


rate  k[CH 3 Br ][OH ]
The nucleophile attacks the reactive center from the side opposite the leaving
group; that is, an SN2 reaction involves a backside attack by the nucleophile.

note the inversion of

the reactive center
H H H
- -
C Br HO C Br + Br-
HO- + H
HO C
H
H H H
reactants H products
transition state with simultaneous
bond breaking and bond forming
 The SN2 Reaction is a concerted reaction

OH- + CH3-Br HO-CH3 + Br-

H Transition State [TS] ╪
Reaction energy diagram - - (highest energy state on
HO C Br reaction pathway)
Energy H H

ΔG╪ energy of activation

OH- + CH3-Br
o
ΔG energy of reaction
Initial
State
HO-CH3 + Br - Final
State

Reaction Coordinate
SN1 mechanism:
Bond breaking between carbon and the leaving group is completed before bond
forming with the nucleophile begins.
In the designation SN1, S stands for Substitution, N for Nucleophilic and 1 for a
unimolecular reaction. This type of substitution reaction is classified as
unimolecular because only the haloalkane is involved in the rate-
determining step.

Rate law of the reaction: Rate=k[haloalkane]

An SN1 reaction is illustrated by the solvolysis reaction of tert-butyl bromide in

methanol to form tert-butyl methyl ether.

Solvolysis definition: A nucleophilic substitution reaction in which the solvent is

the nucleophile.
Step 1: The ionization of a C-X bond forms a 3o carbocation intermediate

H3C CH3
slow, rate
determining
C Br C + Br-
H3C
H3C A carbocation intermediate
H3C CH3
Step 2: Reaction of the carbocation intermediate (an electrophile) with methanol (a nucleophile)
gives an oxonium ion. Attack by the nucleophile occurs with equal probability f rom either
face of the planar carbocation intermediate.

CH3 empty p H3C

CH3
orbitals fast
H3C CH3
CH3O C OCH3 + C O
O C
H CH3 H3C
H H H
H3C CH3 CH3 H3C

Step 3: Proton transfer f rom the oxonium ion to methanol (the solvent) completes the reaction and
gives tert-butyl methyl ether.
H3C H3C
CH3 H CH3 H
fast
C O + O C O +H O
H3C H3C
H CH3
H3C H3C CH3
 CH3 CH3
H3C
CH3OH + (CH3)3CBr C O C + Br-
CH3
H CH3
H3C CH3
+
CH3OH

Transition States (highest energy states on

reaction pathway)

[TS1] ╪
Energy

[TS2] ╪

ΔG╪ energy of activation

Me3C+

Me3C-Br
ΔG energy of reaction

Me3C-OCH3

Reaction Coordinate
Points to consider and remember.
1. If an SN1 reaction is carried out on a 2o haloalkane, a 2o carbocation is
formed as an intermediate. Recall, that a 2o carbocation can undergo a
rearrangement to form a more stable 3o carbocation and this will occur
before a nucleophile has a chance to attack.
2. If an SN1 reaction is carried out at a tetrahedral stereocenter, the major
product is a racemic mixture, because attack by the nucleophile occurs
with equal probability from either face of the planar carbocation
intermediate; the R and S enantiomers are formed in equal amounts and
the product is a racemic mixture.
What determines whether SN1 or SN2 predominates?
In answering this we consider the following:
1. What effect does the structure of the nucleophile have on the rate of
reaction?
2. What effect does the structure of the haloalkane have on the rate of
reaction?
3. What effect does the structure of the leaving group have on the rate of
reaction?
4. What is the role of the solvent?
A. Structure of the nucleophile
Relative nucleophilicity: The relative rates at Effectiveness Nucleophile
which a nucleophile reacts in a reference as a nucleophile
nucleophilic substitution reaction. We Br-, I-
can establish the relative nucleophilicities good CH3S-, RS-, -CN
for a series of nucleophiles by measuring HO-, CH3O-, RO-

Increasing nucleophilicity
the rate at which each displaces a
leaving group from a haloalkane. Cl-, F-
Because the nucleophile participates in the rate- O O
determining step in an SN2 reaction, the moderate CH3CO , RCO--
better the nucleophile, the more likely it is CH3SH, RSH, R2S
that the reaction will occur by that NH3, RNH2, R2NH, R3N
mechanism. The nucleophile does not
participate in the rate-determining step H2O
for an SN1 reaction. Thus, an SN1 poor CH3OH, ROH
O O
reaction can occur at approximately the
same rate with any of the common CH3COH, RCOH
nucleophiles, regardless of their relative
nucleophilicities.
The above table shows that
negatively charged species
are better nucleophiles than
neutral ones.
B. Structure of the haloalkane.
SN1 reactions are governed mainly by electronic factors, i.e. the relative stabilities of carbocation
intermediates. SN2 reactions, by contrast, are governed mainly by steric factors, and their
transition states are particularly sensitive to crowding about the site of reaction.
The distinction is as follows:
1. Relative stabilities of carbocations. As we’ve learned 3o carbocations are the most stable
whereas 1o carbocations are the least stable. Therefore, 3 o haloalkanes are most likely to
react by carbocation formation; 2o haloalkanes are less likely to react in this manner, and
methyl and 1o haloalkanes never react in this manner.
2. Steric hindrance. To complete a substitution reaction, the nucleophile must approach the
substitution center and begin to form a new covalent bond to it. The ease of approach to
a 1o haloalkanes is much easier than the same approach to a 3 o haloalkanes. Compare
ethyl bromide and tert-butyl bromide. 2o alkanes may react by either SN1 or an SN2
mechanism, depending on nucleophile and solvent.
less crowding; H3C more crowding; H3C
easier access to blocks access to
the backside of C Br the backside of C Br
H the haloalkane H C
the haloalkane 3
H H3C

SN1 Carbocation stability never by SN1

Goverened by
electronic factors R3CX R2CHX RCH2X CH3X
(3o) o
(2 ) o
(1 ) methyl
never by SN2 Access to the site of reaction SN2
Goverened by
steric f actors
C. The leaving group
In the transition state for nucleophilic substitution on a haloalkane, the halogen leaving
group develops a partial negative charge in both S N1 and SN2 reactions. The halogens
Cl-, Br- and I- make good leaving groups because their size and electronegativity help
stabilize the resulting negative charge. Thus, the ability of a group to function as a
leaving group is related to how stable it is as an anion. H 2O can act as a leaving group
if an –OH group of an alcohol is first protonated by an acid.

Rarely act as leaving groups

Greater ability to act as leaving group in nucleophilic substitution
O and -elimination reactions

I- > Br- > Cl- > H2O >> CH3CO- > HO- > CH3O- > NH2-
Greater stability of anion; greater strength of conjugate acid
D. The solvent
Solvents provide the medium in which reactants are dissolved and which nucleophilic
substitution reaction takes place. Common solvents for these reactions are divided into
two groups: protic and aprotic.

1. Protic solvents contain –OH groups and are hydrogen-bond donors. Each is able
to solvate both the anionic and cationic components of ionic compounds by electrostatic
interaction between its partially negatively charged oxygen(s) and the cation and
between its partially positively charged hydrogen and the anion. These same properties
aid in the ionization of C-X bonds to give an X - anion and a carbocation; thus, protic
solvents are good solvents in which to carry out S N1 reactions.

Protic Solvent Polarity of

Solvent These solvents favor SN1 reactions.
Water H 2O The greater the polarity of the solvent,
Formic acid HCOOH Increasing
the easier it is to form carbocations in it
Methanol CH3OH
Ethanol CH3CH2OH because both the carbocation and the
Acetic acid CH3COOH negatively charged leaving group can
be solvated.
R+ H

R-X O O
H 2O H

H H

X-
2. Aprotic solvents do not contain –OH groups and cannot function as hydrogen-bond
donors. They are unable to promote the formation of a carbocation because the leaving
group would be unsolvated. Therefore aprotic solvents cannot be used in S N1 reactions.
These solvents favour SN2 reactions because aprotic solvents are able to solvate only
cations and not anions.
Polarity of
Aprotic Solvent Solvent
O These solvents favor SN2 reactions.

Increasing
Acetone CH3CCH3 Although solvents at the top of this list are polar,
Dichloromethane CH2Cl2 formation of carbocations in them is far more
Diethyl ether (CH3CH2)2O difficult than in protic solvents because the anionic
leaving group cannot be solvated by these solvents.
R+

R-X O O C
acetone
C
X-
polar aprotic solvents, like acetone, can only solvate cations
effectively, making it unlikely for a leaving group to break
its bond to carbon and undergo an SN1 reaction

Na+
Na+OH- O O C a polar aprotic solvent, like acetone, will solvate the
acetone cation of an ion pair, but leave the anion "naked" and
C - thus a highly reactive nucleophile
OH
 SN1 versus SN2 Reactions of Haloalkanes continued

SN 2 SN 1
Substitution at a Inversion of configuration Racemization
Stereocenter The nucleophile attacks The carbocation intermediate is
the stereocenter from the planar, and attack by
the side opposite the leaving nucleophile occurs with
equal group. probability from either
side.
Examples: I H
H CN
+-
Na CN

SN 2 (S)-2-Iodooctane (R)-2-Methyloctanenitrile

H3C Br H3C OCH3 H3CO CH3

CH3OH +
SN 1
(R)-3-Bromo-3-methylhexane (R)-3-Methoxy-3-methylhexane (S)-3-Methoxy-3-methylhexane
What are the products of β-Eliminations?

We now study a type of β-elimination called dehydrohalogenation. In the presence of a strong

base, such as hydroxide ion or ethoxide ion, halogen can be removed from one carbon of
a haloalkane and hydrogen from an adjacent carbon to form a carbon-carbon double
bond. As the equation shows, we call the carbon bearing the halogen the α-carbon and
the adjacent carbon the β -carbon.

 
C C + CH3CH2O-Na+ C C + CH3CH2OH + Na+X-
CH3CH2OH
base
H X alkene
A haloalkane
Common strong bases used for β-eliminations are OH-, OR- and NH2-. Below are some
examples.


Br
+ t-BuO-K+

+ t-BuOH + Na+Br-
Br
CH3CH2O-Na+
+
CH3CH2OH
major product

Br
CH3O-Na+
+ CH2
CH3OH

major product

In the second and third examples, there are nonequivalent β-carbons, each
bearing a hydrogen, therefore, two alkenes are possible from each β -elimination.
In each case, the major product of these and most other β -elimination reactions is
the more substituted (and therefore the more stable) alkene. We say that each
reaction follows Saytsev’s rule.
Potassium t-butoxide (t-BuOK) DBN and DBU are what we call ‘big bulky’ bases and
want to pluck off a hydrogen and not attack carbon atoms in substitution reactions.

Clayden et.al. Organic Chemistry 2nd Edition

What are the E1 and E2 mechanisms for β-elimination?

There are two limiting mechanisms of β -elimination reactions. A fundamental difference

between them is the timing of the bond-breaking and bond-forming steps. Recall that we
made this same statement about the two limiting mechanisms for nucleophilic substitution
reactions.

At one extreme, breaking the C-X bond is complete before any reaction occurs with base to
lose a hydrogen and before the carbon-carbon double bond is formed. This mechanism is
designated E1, where E stands for elimination and 1 stands for a unimolecular reaction;
only one species , in this case the haloalkane, is involved in the rate-determining step. The
rate law for an E1 reaction has the same form as that for an S N1 reaction:
Rate=k[haloalkane]
The E1 mechanism is shown below:

Step 1: The ionization of a C-X bond forms a 3o carbocation intermediate

H3C CH3
slow, rate
determining
H3C
C Br C + Br-
H3C A carbocation intermediate
H3C CH3
Step 2: Proton transfer from the cabocation intermediate to methanol (which in this
instance is both the solvent and a reactant) gives the alkene:

H CH3 CH3
H
fast
O + H CH2 C CH3 O H + CH2 C CH3
H3C H3C

E2 Mechanism
At the other extreme is a concerted process. In an E2 reaction, E stands for
elimination, and 2 stands for bimolecular. Because the base removes a β-
hydrogen at the same time the C-X bond is broken to form a halide ion, the rate
law for the rate-determining step is dependent on both the haloalkane and the
base:
Rate=k[haloalkane][base]

The stronger the base, the more likely it is that the E2 mechanism will be in
operation.
In this E2 mechanism, proton transfer to the base, formation of the carbon-carbon double
bond, and the ejection of bromide ion occur simultaneously; that is, all bond-forming
and bond-breaking steps occur at the same time.

CH3

CH3CH2O- + H CH CH2 Br CH3CH2O H + CH3CH CH2 + Br-

For both E1 and E2 reactions, the major product is that formed in accordance with
Saytsev’s rule.
Anion-stabilizing groups allow another mechanism‒E1cB (cB for conjugate
Base)

An elimination catalysed by a strong base it looks like an E2

O OH O

KOH

Here is the mechanism generalized for other carbonyl compounds. The

elimination is unimolecular and the leaving group is not lost from the starting
molecule but from the conjugate base of the starting molecule.
O X Fast, reversible O X O
rate determining
deprotonation
step

stabilized anionic
H
Base intermediate

Note: ‒OH is never a leaving group in E2 reactions but it can be a leaving group
in E1cB reactions.
When do nucleophilic substitution and β-elimination compete?

Thus far we have considered two types of reactions of haloalkanes: nucleophilic substitution
and β-elimination. Many of the nucleophiles we have examined, for example hydroxide
ion and alkoxide ions, are also strong bases. Accordingly, nucleophilic substitution and
β-elimination often compete with each other, and the ratio of products formed by these
reactions depends on the relative rates of the two reactions:

nucleophilic
substitution
H C C Nu + X-

H C C X + Nu-

-elimination C C + H Nu + X-
SN1 versus E1 reactions
Reactions of secondary and tertiary haloalkanes in polar protic solvents give mixtures of
substitution and elimination products. In both reactions, Step 1 is the formation of a
carbocation intermediate. This step is then followed by either (1) the loss of a hydrogen
to give an alkene (E1) or (2) reaction with solvent to give substitution product (S N1). In
polar protic solvents, the products formed depend only on the structure of the particular
carbocation. For example, t-butyl chloride and t-butyl iodide in 80% aqueous ethanol
both react with solvent, giving the same mixture of substitution and elimination products:

CH3 CH3
E1
H2C C + H+
H3C C I
CH3
- CH3
-I CH3
CH3
H3C C SN1
CH3 H3C C OH + H+
H2O
-Cl-
CH3
H3C C Cl CH3
CH3
CH3 SN1
H3C C OCH2CH3 + H+
CH3CH2OH
CH3

Because iodide ion is a better leaving group than chloride ion, t-butyl iodide reacts
over 100 times faster than t-butyl chloride. Yet, the ratio of products is the same.
SN2 versus E2 reactions
It is easier to predict the ratio of substitution to elimination products for reactions of
haloalkanes with reagents that act as both nucleophiles and bases. The guiding
principles are as follows:
1. Branching at the α-carbon or β-carbon(s) increases steric hindrance about the α -
carbon and significantly retards SN2 reactions. By contrast, branching at the α-
carbon or β-carbon(s) increases the rate of E2 reactions because of the increased
stability of the alkene product.
2. The greater the nucleophilicity of the attacking reagent, the greater is the S N2 to E2
ratio. Conversely, the greater the basicity of the attacking reagent, the greater is
the E2 to SN2 ratio.

attack of base on a -hydrogen

by E2 is only slightly affected
by branching at the -carbon; R
alkene formation is accelerated R
H C 

C leaving group
SN2 attack of a nucleophile is impeded 
by branching at the - and -carbons R R
Clayden et.al. Organic Chemistry 2nd Edition
Problems: Tell whether each of the following reactions is likely to be S N1, SN2, E1,
E1cB, or E2, and predict the product of each:

Na+ OCH3
(a) Cl ?
CH3OH

Br

HCO2H / H2O
?
(b)

O
NaOH / Ethanol

OH
(c)
Answer for (a): Na+ OCH3
(a) Cl ?
CH3OH

Strategy:
Look carefully at the substrate, leaving group, nucleophile, and solvent. Then
decide which kind of reaction is likely to be favoured.

Solution:
A secondary, nonallylic substrate can undergo an SN2 reaction with a good
nucleophile in a polar aprotic solvent but will undergo an E2 reaction on
treatment with a strong base in a protic solvent. In this case, E2 reaction is
likely to predominate.

Na+ OCH3
Cl E2 reaction
CH3OH
Learning Objectives: At the end of this topic we want to understand the
following concept:

Predict whether a reaction is likely to be SN1, SN2, E1, E1cB, or E2