Chapter 4 1

Organic Chemistry – Substitution and

Elimination
To learn many organic chemistry reactions, you must first understand substitution and elimination reactions.
Substitution reactions involve the substitution of a leaving group with a nucleophile. Elimination reactions
involve the loss of a proton and a leaving group to form a double bond. This chapter will cover the
mechanisms for these reactions, as well as strategies to determine whether substitution or elimination is
more likely.

1 Nucleophiles and Electrophiles

De ning Nucleophiles and Electrophiles

A nucleophile is an electron-rich species that tends to donate electron density to an electrophile.
An electrophile is an electron-poor species or compound that is susceptible to nucleophilic attack.
Neutral compounds and anions can function as nucleophiles, as long as they have excess electron
density in the form of a negative charge, lone pair, or even a pi bond. Electrophiles can be neutral
compounds or cations, but they must have a region that is electron deficient.

Common Nucleophiles Common Electrophiles

O LG
I Cl Br H O H S N C

(leaving group)

Common nucleophiles and electrophiles that are important to remember.

Periodic Table Trends

Nucleophile strength increases from right to left on the periodic table in both polar protic solvents
and polar aprotic solvents. This increase in nucleophilicity is due to decreasing electronegativity of
the atom. More electronegative atoms hold electrons more tightly, so they are less prone to
donating them in a nucleophilic attack.

In a polar protic solvent, nucleophile strength increases down a group. In polar protic solvents,
nucleophiles can be stabilized through interactions with electron-poor hydrogen atoms. A larger
atomic radius results in a weaker solvation shell and therefore, a more reactive nucleophile. Thus, the
larger the atomic radius of a nucleophile in a polar protic solvent, the stronger the nucleophile.
Common polar protic solvents include water, methanol, ethanol, acetic acid and ammonia

On the other hand, in a polar aprotic solvent, nucleophilicity decreases down a group. This is
because solvation effects are not as extreme in aprotic solvents due to a lack of hydrogen bond
donors. In polar aprotic solvents, nucleophilicity parallels basicity. Basicity decreases down a
group, so nucleophilicity in polar aprotic solvents decreases down a group. Common polar aprotic
solvents include acetone, DMSO, DCM and THF.
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Chapter 4 2

nucleophile strength nucleophile strength

in polar protic solvents in polar aprotic solvents

C N O F C N O F
Cl Cl
Br Br
I I

Nucleophile strength in polar protic and aprotic solvents.

Leaving Groups
Both substitution and elimination reactions involve the loss of a leaving group. Weak bases make
great leaving groups because they are stable on their own.
1
Common Leaving Groups
O
I Cl Br HO S O H2 O
O
Common leaving groups.

2 SN2 Reactions

The SN2 reaction is a second order nucleophilic substitution reaction. In an SN2 reaction, a
nucleophile attacks an electrophile and kicks out a leaving group. SN2 reactions are concerted,
meaning the nucleophilic attack and loss of a leaving group occur in the same step.

SN2 Reaction
R R
Nu LG Nu + LG
H
H HH

SN2 reaction mechanism.

Because SN2 reactions are concerted, they have a pentavalent transition state and a bimolecular
rate law. The transition state is pentavalent because it consists of the electrophile weakly
coordinated to both the nucleophile and the leaving group. The rate law, rate=k[nucleophile]
[electrophile], is considered bimolecular because the rate of an SN2 reaction is dependent on both
the concentration of the nucleophile and the concentration of the electrophile.

R
𝛿- 𝛿+ 𝛿-
Nu LG
H H

pentavalent transition state

Pentavalent transition state.

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Chapter 4 3

In an SN2 reaction, the nucleophile attacks the electrophile from the backside of the leaving group.
Thus, SN2 reactions are stereospeci c; if a nucleophile attacks a chiral center, inversion of
stereochemistry occurs.

H3C SN2 CH3

Br Cl Br + Cl
H H
H3CH2C CH2CH3

(R)-2-chlorobutane (S)-2-bromobutane

Stereospecificity of SN2 reactions.

Example 4.21:
Show the mechanism and final product of the following SN2 reactions:

Cl NaBr
A

Br
KCN
B

Solution:
Cl Br Br
A

Br CN
B CN

3 SN1 Reactions

The SN1 reaction is also a nucleophilic substitution reaction. Unlike SN2 reactions, the SN1 reaction
mechanism consists of separate steps and therefore, is not concerted. The first step of an SN1
reaction is carbocation intermediate formation via the loss of a leaving group. This is the slow
step or rate limiting step of the reaction. The next step is carbocation rearrangement, if possible. The
final step is nucleophilic attack of the carbocation. This reaction can only occur with secondary and
tertiary substrates because primary substrates would form a highly unstable primary carbocation
intermediate. SN1 reactions have a unimolecular rate law: rate=k[electrophile]. Notice the
nucleophile is not involved in the rate limiting step of the reaction, so it is not included in the rate
law.

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Chapter 4 4

SN1 Reaction

Nu
LG Nu
loss of a nucleophilic
leaving group attack

SN1 reaction mechanism.

It is important to look out for possible carbocation rearrangements in an SN1 reaction. Carbocations
can be stabilized by neighboring alkyl groups bonds via hyperconjugation. Therefore, the more
carbon atoms bound to the positively charged carbon, the more stable the carbocation. Resonance
delocalization also stabilizes carbocations.

H R R R
least C C C C most
stable H H H H H R R R stable
vinyl phenyl methyl 1° 2° 3° allyl benzyl

Least to most stable carbocation rearrangements based

on hyperconjugation and resonance delocalization.

Due to the carbocation intermediate, SN1 reactions are not stereospecific. Carbocations are sp2
hybridized and thus, have trigonal planar geometry. This means that the nucleophile can attack from
either the front or back side of the molecule, forming a racemic mixture (50/50 mixture of
enantiomers) if the product is chiral.

Example 4.31:
Show the mechanism and final product of the following SN1 reactions:

I NaCl
A

KI
B
Br

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Chapter 4 5

Solution:

I Cl Cl
A

H
I I
B
Br

4 Zaitsev and Hofmann Products

Elimination reactions produce alkenes. In an elimination reaction, a leaving group and a proton on an
adjacent carbon (beta proton) are removed to form a carbon-carbon pi bond.

LG

Formation of a carbon-carbon
pi bond.

Sometimes, more than one alkene product is possible in an elimination reaction. The Zaitsev
product refers to the more substituted alkene, and the Hofmann product refers to the less
substituted alkene. An alkene is more stable when it is bonded to more substituents. When a
non-sterically hindered base is used (such as methoxide or ethoxide), the Zaitsev product is favored
in an elimination reaction. The Hofmann product is favored if the base is large and sterically
hindered. Therefore, an elimination reaction with a bulky base such as tert-butoxide will favor the
Hofmann product:
Br
O O

bulky base H H small base

Hofmann Zaitsev
Product Product

Elimination reaction with a bulky v. small base.

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Chapter 4 6

Least to most stable alkenes

based on substitution.

5 E2 Reactions

E2 reactions are concerted, meaning beta proton removal, carbon-carbon pi bond formation, and
leaving group loss all occur in the same step. Because E2 reactions are concerted, they have a
bimolecular rate law. The rate law of an E2 reaction is rate=k[base][substrate].

E2 Reaction

H H R H
R
B
R H R
H LG

E2 reaction mechanism.

In an E2 reaction, the leaving group and the beta proton must be anti-periplanar or 180° apart. This
is essential because pi bond formation requires lateral overlap of unhybridized p orbitals. This is only
possible when the substituents lie within the same plane and are pointing in opposite directions.

E2 reactions are more complicated for cyclic compounds because they have restricted bond rotation.
For cyclohexane, E2 reactions only occur if the leaving group and beta proton are on adjacent axial
positions and are anti-periplanar to one another:

Br OH E2
H

Br
axial and
anti-periplanar

E2 reaction for a cyclic compound.

If the substrate for an E2 reaction has two protons on the relevant beta carbon, two stereoisomers
are possible: the E alkene, and the Z alkene. These reactions are stereoselective, meaning that if the
E alkene can be formed, it will be the major product. This is because the E alkene has less steric
hinderance and therefore, is more stable.

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E alkene (trans) Z alkene (cis)

major product minor product
Br
+

2 protons on relevant
beta carbon
Stereoselective E2 reaction.

If the substrate has only one proton on the relevant beta carbon, only one stereoisomer is possible.
This is known as a stereospeci c reaction. To identify the configuration of the product, start by
drawing a Newman Projection that looks down the bond where the carbon-carbon pi bond will form.
Rotate the Newman projection to put the proton and the leaving group on opposite sides of the
molecule, in the antiperiplanar position. Remove the proton and the leaving group, draw the double
bond, and maintain the configuration from the Newman projection to determine the product.
rotate back
antiperiplanar
carbon
H H
H H
Br H Br
Br

Stereospecific E2 reaction.

Example 4.51:
Show the mechanism and final product of the following E2 reactions:
O
NaOEt
A
Cl

I
NaOH
B

KOC(CH3)3
C
Br

Br
NaOMe
D

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Solution
O H O
A OEt

Cl

I Me
H I H I
B
Me H H
Me Me
Zaitsev Product

H O
C
Br Hofmann Product

Br
OMe
D H

6 E1 Reactions

E1 reactions are also elimination reactions. However, like SN1 reactions, they involve a multistep
mechanism with a carbocation intermediate. The unimolecular rate law of an E1 reaction is
rate=k[substrate].

The reaction begins with the loss of a leaving group from the substrate to form a carbocation
intermediate. This is the slow step or rate determining step of the reaction. If possible, carbocation
rearrangements then occur. Finally, a beta proton on the carbocation intermediate is removed by a
base and a C-C pi bond is formed. E1 reactions occur using weak bases such as H2O or alcohol.
Strong bases such as NaOH or NaOR will readily react with the substrate prior to the formation of a
carbocation intermediate— thus, strong bases favor E2 reactions over E1 reactions. Heat can be
added to the reaction to ensure that the E1 product is favored over the SN1 product.

E1 Reaction
OH2
Br
loss of a H
proton
leaving group removal

E1 reaction mechanism.

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Chapter 4 9

7 Acid Catalyzed Dehydration of Alcohols

The hydroxide ion (OH-) is a terrible leaving group because it is a strong base. Because OH- is not a
good leaving group, elimination of alcohols requires the use of concentrated acid such as H2SO4 and
heat. The Zaitsev product is always the major product of an acid catalyzed dehydration reaction.

The first step of acid catalyzed dehydration is protonation of the hydroxyl group to make it a good
leaving group (H2O). If the alcohol is secondary or tertiary, H2O leaves, forming a carbocation
intermediate. Finally, another molecule of alcohol grabs a proton from the molecule and a carbon-
carbon pi bond forms.

O Zaitsev
OH H O S O H OH2 Product
O
OH
H

Reaction mechanism of acid catalyzed dehydration of an alcohol.

If the alcohol is primary, an E2 reaction will occur rather than E1 (no carbocation intermediate forms).

8 Carbocation Rearrangements

Carbocation rearrangements are possible in SN1 and E1 reactions. An understanding of hydride shifts
and methyl shifts is important for success on the DAT. Carbocation rearrangements occur to make
a more stable carbocation intermediate. A methyl shift is the migration of a methyl group as well
as the electrons of the bond attaching the methyl group to the molecule itself. A hydride shift is the
migration of a hydride group, which is a hydrogen atom as well as the electrons of the bond
attaching the hydrogen to the molecule itself.

CH3
methyl shift H
R R
R
CH3 R
2° carbocation 3° carbocation
H
hydride shift H
R R
R
H R
A methyl (top) and a hydride (bottom) shift.

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Example 4.81:

OH
conc. H2SO4
A heat

NaOEt
B I

Solution:

O
OH H O S O H OH2
H ROH
O
A
H

H
OEt
B I

9 Determining Reaction Mechanisms

Selecting between SN2, SN1, E2, and E1

When given a starting material and reagent, it may be difficult to decide which mechanism is most
probable between SN2, SN1, E2, and E1. There are five different factors that you need to consider
when choosing a mechanism:

1. Degree of Substitution of the Substrate: SN2 does not occur with a tertiary substrate, but
E2 is possible. SN1/E1 are also possible with a tertiary substrate because a tertiary
substrate forms a stable carbocation intermediate. A primary substrate, on the other hand,
cannot form a carbocation, so SN1/E1 will not occur. Thus, SN2 and E2 are our only options
for primary substrates. All four mechanisms are possible with a secondary substrate, so we
cannot rule anything out.

2. Strength of the Base/Nucleophile: A negatively charged molecule is reactive and thus a

strong base/nucleophile. If the molecule is neutral and unreactive, it is a weak base/
nucleophile. For instance, hydroxide is a strong base/nucleophile, and water is a weak
base/nucleophile. A strong base/nucleophile will favor SN2/E2, and a weak base/
nucleophile will favor SN1/E1.

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Chapter 4 11

3. Steric Hindrance of the Base/Nucleophile: A sterically hindered molecule will almost

exclusively act as a base. For example, tert-butoxide will only perform E2.

4. Solvent Effects: Nucleophiles are more reactive in polar aprotic solvents but less reactive
in polar protic solvents. This is because polar protic solvents can stabilize anions via
hydrogen-bonding. The identity of the solvent is most useful when deciding between SN2
and E2. A polar protic solvent favors E2, and a polar aprotic solvent favors SN2.

5. Temperature: At low temperatures, nucleophilic substitution is more likely, and at high

temperatures, elimination is more likely. Elimination reactions are favored by heat when
there are competing substitution and elimination reactions.

Mechanism Flow Chart

Strong Base,
Weak Nucleophile
E2
NaH, DBN, DBU, LDA,
t-BuOK, Triethylamine,
Diisopropylethylamine

SN2/ E2
1o SN2 favored
Strong Base,
Strong Nucleophile 2o SN2/ E2
Substrate? E2 favored
RO-, HO-, MeO-, EtO-

3o E2
Reagent?

Weak Base, 1o or 2o SN2

Strong Nucleophile
Substrate?
I-, Br-, Cl-, RS-, HS-,
RSH, H2S 3o SN1

1o No Reaction
Weak Base,
Weak Nucleophile 2o Not
Substrate? Straightforward
H2O, MeOH, EtOH, ROH cold SN1
3o Temperature?
hot E1

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Guide to SN1, SN2, E1 and E2 Reactions

Primary Secondary Tertiary

Situation: Example:
Substrate Substrate Substrate
SN2 (polar aprotic
Non- Basic solvent)
Br-, I-, Cl-, H2S, RS-, HS- SN2 SN1
Nucleophile SN1 (polar protic
solvent)
Non- t-buOK, DBU, DBN,
Nucleophilic Diisopropylethylamine, E2
Base Triethylamine, LDA, NaH
Strong E2 and SN2
E2 only due to
nucleophile, RO-: HO-, MeO-, EtO- E2 (polar protic solvent)
steric hindrance
Strong base SN2 (polar aprotic solvent)
Weak SN1 and E1
ROH: HOH, MeOH,
nucleophile, Not straightforward Heat favors
EtOH
Weak base elimination

Regiochemical outcome Stereochemical outcome

Attack at the alpha position, kick

SN2 - Inversion of configuration (flip like an umbrella).
out leaving group in same step.

Nucleophilic attack of the - Since the carbocation intermediate is planar,

carbocation. Carbocation could be nucleophile can attack from either face with
SN1
where the leaving group was, or it equal probability. Produces a racemic mixture if
could have rearranged. the product is chiral.

- Stereoselective if there are 2 protons on the

Zaitsev Product: more substituted
appropriate beta carbon can form E or Z alkene,
alkene is favored if base is
but the major product is the E alkene.
unhindered.
E2 - Stereospecific if there is only 1 proton on the
appropriate beta carbon need to draw the
Hofmann Product: less substituted
Newman projection so that the leaving group
alkene is favored if base is bulky.
and hydrogen being pulled are antiperiplanar.

Zaitsev Product- more substituted - Stereoselective- E alkene will be favored over Z

E1
alkene is favored. (no antiperiplanar requirement).

Alcohols:
• Hydrohalic acid + alcohol: substitution products (SN1 or SN2).
• Concentrated acid + alcohol + heat: dehydration (E1 or E2).
◦ Elimination of 3°, 2° alcohol: E1, forms the Zaitsev product.
◦ Elimination of 1° alcohol: E2, forms the Zaitsev product.

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