Organic Chem II Lecture 5 6 SN and E Reactions

University of Science and Technology of Hanoi
Department of Fundamental and Applied Sciences
NUCLEOPHILIC SUBSTITUTION REACTIONS
Dr. Nguyen Duc Anh

Department of Fundamental and Applied Sciences (FAS)
nguyen-duc.anh@usth.edu.vn
0904888819
September 2019
Ionic substitution reactions Ionic substitution reactions Elimination reactions Elimination reactions The competitions
Organic halogenides
SN2 SN1 E2 E1
Organic halogenides
 
Alkyl halides  
An alkyl halide has a halogen atom bonded to
an sp3-hybridized (tetrahedral) carbon atom.
C X X = Cl, Br, I
Halogens are more
electronegative than carbon
The carbon–halogen bond length increases

and bond strength decreases as we go down
the periodic table
Organic halogenides
SN2 SN1 E2 E1
Organic halogenides
Types of halides
Alkyl halides (haloalkanes) sp3
C X
Prone to undergo Nucleophilic Substitutions (SN) and Elimination Reactions (E)
sp 2 sp2
Vinyl halides (Alkenyl halides) Aryl halides X
X
benzene or aromatic ring
sp
Different reactivity than alkyl halides, and do
Acetylenic halides (Alkynyl halides) X not undergo SN or E reactions
Organic halogenides
SN2 SN1 E2 E1
Ionic substitution reactions

In a nucleophilic substitution reaction a nucleophile
(Nu:) displaces a leaving group (LG) in the molecule
that undergoes the substitution (the substrate)
In nucleophilic substitution reactions the bond between the

substrate carbon and the leaving group undergoes heterolytic
bond cleavage. The unshared electron pair of the nucleophile
forms the new bond to the carbon atom.
Organic halogenides
SN2 SN1 E2 E1

Nucleophile
A nucleophile is a reagent that seeks a positive center
The nucleophile is always a Lewis base, and it may

be negatively charged or neutral. Any negative ion
or uncharged molecule with an unshared electron
pair is a potential nucleophile.
HO , CH3O , H2N (negative charge)
H2O, NH3 (neutral)

Organic halogenides
SN2 SN1 E2 E1

Leaving group
To be a good leaving group, the substituent must be able to leave as a relatively stable, weakly basic molecule or ion
e.g.: I⊖, Br⊖, Cl⊖, TsO⊖, MsO⊖, H2O, NH3
O
OTs = O S CH3 (Tosylate)
O
O
OMs = O S CH3 (Mesylate)
O
Organic halogenides
SN2 SN1 E2 E1
Nucleophiles ?
Substrates ?
Leaving groups ?
Organic halogenides
SN2 SN1 E2 E1
2 proposed mechanisms
+ The ionization mechanism (SN1, substitution-nucleophilic-
unimolecular)
+ The direct displacement mechanism (SN2, substitution-
nucleophilic-bimolecular)
+ Both can happen?
Organic halogenides
SN2 SN1 E2 E1

Ionic substitution reactions SN1 (stepwise mechanism)
Mechanism Step (1):
R (k 1 ) R
SN2 (concerted mechanism) R C Br R C + Br k1 << k2 and k3
Slow
R R
Step (2)
R R (k 2 ) R H
R R
    R C + H 2O R C O
HO C Br   HO C
R
HO C Br
R R fast R H
R Slow R R fast R
transition state (T.S.)
Step (3)
+ Br-
R H (k3) R
R C O + H 2O R C OH + H3O+
R = k[Nu][Substrate] R H fast
R
+ Bimolecular reactions R = k1[Substrate] + Unimolecular reactions
S stands for substitution S stands for substitution

N stands for nucleophilic N stands for nucleophilic
2 stands for bimolecular 1 stands for unimolecular
Organic halogenides
SN2 SN1 E2 E1

SN2 Ionic substitution reactions
H
H H
   
   
HO C Br HO C Br HO C
H H
H H
H H
+ Br-
Negative OH- brings an e- pair to C O–C bond partially formed; C–Br O–C bond formed; Br- departed.
Br begins to move away with an e- pair bond partially broken. Configuration of C inverted
Configuration of C begins to invert
Organic halogenides
SN2 SN1 E2 E1

Transition State Theory: Free Energy Diagrams
A reaction that proceeds with a negative free-energy change A reaction that proceeds with a positive free-energy change (absorbs
(releases energy to its surroundings) is said to be exergonic energy from its surroundings) is said to be endergonic
 Exergonic (ΔGo is negative)

 Thermodynamically
favorable process
• The reaction coordinate indicates the progress of the reaction, in terms of the conversion of reactants to products.
• The top of the energy curve corresponds to the transition state for the reaction.
• The free energy of activation (ΔG‡) for the reaction is the diffrence in energy between the reactants and the transition state.
• The free energy change for the reaction (ΔGo) is the diffrence in energy between the reactants and the products.
Organic halogenides
SN2 SN1 E2 E1

Inversion of configuration
The nucleophile approaches the substrate

carbon from the back side with respect to
the leaving group.
SN2 reactions always occur with

inversion of configuration.
Organic halogenides
SN2 SN1 E2 E1

The Reaction of tert-Butyl Chloride with Hydroxide Ion: An SN1 Reaction
 The rate of SN1 reactions depends only on concentration of

the alkyl halide and is independent on concentration of the CH3 CH3
Nu: CH3 C Br + H2O CH3 C OH + HBr
Rate = k[RX]
In other words, it is a first-order reaction CH3 CH3
 unimolecular nucleophilic substitution
In a multistep reaction, the rate of the

overall reaction is the same as the rate of k1 k2 k3
the SLOWEST step, known as the rate- Reactant Intermediate Intermediate Product
(slow) (fast) (fast)
determining step (r.d.s) 1 2
k1 << k2 or k3
Organic halogenides
SN2 SN1 E2 E1

The most important transition state (TS) for SN1 reactions is T.S. (1) of the rate-determining step (r.d.s.)
Organic halogenides
SN2 SN1 E2 E1

2 intermediates and 3 transition states (T.S.)

Organic halogenides
SN2 SN1 E2 E1

Carbocation
• Carbocations are trigonal planar
• The central carbon atom in a carbocation is electron

deficient; it has only six e⊖ in its valence shell
H3C • The p orbital of a carbocation contains no electrons, but it

C CH3 can accept an electron pair when the carbocation
H3C
undergoes further reaction
• General order of reactivity (towards SN1 reaction)
3o > 2o >> 1o > methyl
sp2-sp3 p bond • The more stable the carbocation formed, the faster the
SN1 reaction
Organic halogenides
SN2 SN1 E2 E1

Stability of carbocation
Positive inductive effect

Hyperconjugation effect
Hyperconjugation involves
electron delocalization (via partial
CH2 CH2 orbital overlap) from a filed
etc. bonding orbital to an adjacent

unfiled orbital
Resonance stabilization of allylic and benzylic cations Hyperconjugation effect

Organic halogenides
SN2 SN1 E2 E1

Stereochemistry of SN1
Because the carbocation formed in the first step of an SN1 reaction has a
trigonal planar structure, when it reacts with a nucleophile, it may do so
from either the front side or the back side
Ph Ph
Ph
CH3OH CH3OH
C CH3 C OCH3
With some cations, however, stereoisomeric products CH3 Br CH3 CH2CH3
arise from the two reaction possibilities. CH2CH3 CH2CH3
(S ) (trigonal planar) (R) and (S)
racemic mixture
A reaction that transforms an optically active compound
into a racemic form is said to proceed with racemization.
CH3OH
CH3OH
attack from left
attack from right
Racemization takes place whenever the reaction causes chiral
molecules to be converted to an achiral intermediate Ph Ph
CH3O CH3 CH3 OCH3

CH2CH3 CH2CH3
(R) (S )
(1 : 1)
Organic halogenides
SN2 SN1 E2 E1
Detailed mechanism ??
Organic halogenides
SN2 SN1 E2 E1

Factors Affecting to SN1 and SN2 Reactions
S N1
The structure of the substrate
The primary factor that determines the reactivity of organic
SN 2 substrates in an SN1reaction is the relative stability of the
carbocation that is formed.
● 3o > 2o >> 1o > methyl

The more stable the carbocation formed, the faster the SN1
+ Inductive effects
+ Resonance effects
+ Hyperconjugation effects
Hammond postulate
A steric effect is an effect on the relative rates caused by the space-

filing properties of those parts of a molecule attached at or near the
reacting site.
Steric hindrance is when the spatial arrangement of atoms or groups at
or near a reacting site of a molecule hinders or retards a reaction.
Organic halogenides
SN2 SN1 E2 E1

The solvents
Classification of solvents
Non-polar solvents
(e.g. hexane, benzene)
Polar protic solvents:
- The solvent involves Hydrogen bondings
between molecules
Solvents
Polar protic solvents - The solvents contains labile protons
(e.g. H2O, MeOH)
Polar aprotic solvents:
Polar solvents - The solvent does not contains H connected
with high electronegativity atoms  no H
Polar aprotic solvents bonding.
- The solvents non-contains labile protons
(e.g. DMSO, HMPA)
Organic halogenides
SN2 SN1 E2 E1

SN 2 SN 1
Favored by polar aprotic solvents Favored by polar protic solvents
- Protic solvents solvate anions  decrease nucleophilic activity Protic solvents, facilitate formation of a carbocation by forming
- Aprotic solvents solvate cations hydrogen bonds with the leaving group as it departs, thereby
lowering the energy of the transition state leading to a carbocation
Organic halogenides
SN2 SN1 E2 E1

Factors Affecting the Rates of SN1 and SN2 Reactions + Halogens: The presence of solvents changes
nucleophilicity and basicity of leaving groups
Nature of leaving groups
Leaving groups depart with the electron pair that was used to
Protic solvents
bond them to the substrate.
The best leaving groups are those that become either a relatively
Aprotic solvents
stable anion or a neutral molecule or a weaker basicity specie
when they depart
Increase of leaving ability
+ Strongly basic ions rarely act as leaving groups
In either an SN1 or SN2 reaction the leaving group begins to acquire a

negative charge as the transition state is reached
Organic halogenides
SN2 SN1 E2 E1

The concentration and reactivity of the nucleophile
+ The rate of an SN1 reaction is unaffected by either

the concentration or the identity of the R R
  R
nucleophile, because the nucleophile does not  
HO C Br   HO C
participate in the rate-determining step of an SN1 HO C Br
reaction.
R Slow fast R
R R R
+ The rate of an SN2 reaction depends on both the R
concentration and the identity of the attacking + Br-
nucleophile.
R = k[Nu][Substrate]
The rate of an SN2 reaction depends on the concentration

Organic halogenides
SN2 SN1 E2 E1

The relative strengths of nucleophiles can be correlated with three
structural features
The relative strength of a nucleophile (its nucleophilicity)

is measured in terms of the relative rate of its SN2 reaction
with a given substrate.
Strong nucleophile  higher reactivity

Organic halogenides
SN2 SN1 E2 E1

(2)The strength of the bond being formed to carbon;
Because the SN2 process is concerted, the strength of the
Other factors affected nucleophilicity partially formed new bond is reflected in the TS. A
stronger bond between the nucleophilic atom and carbon
(1) The solvation energy of the nucleophile; results in a more stable TS and a reduced activation
Strong solvation lowers the energy of an anionic energy.
nucleophile relative to the TS, in which the charge is
more diffuse, and results in an increased Ea. Viewed
from another perspective, the solvation shell must be
disrupted to attain the TS and this desolvation
contributes to the activation energy.
Organic halogenides
SN2 SN1 E2 E1

(3) The electronegativity of the attacking atom;
High electronegativity atom is unfavorable
(4) The polarizability of the attacking atom
Polarizability describes the ease of distortion

of the electron density of the nucleophile.
Again, because the SN2 process requires bond
formation by an electron pair from the
nucleophile, the more easily distorted the
attacking atom, the better its nucleophilicity.
Organic halogenides
SN2 SN1 E2 E1

(5) The steric bulk of the nucleophile.
A sterically congested nucleophile is less reactive than a less hindered one because of non-bonded repulsions
that develop in the TS. The trigonal bipyramidal geometry of the SN2 transition state is sterically more demanding
than the tetrahedral reactant so steric interactions increase as the TS is approached.
Organic halogenides
SN2 SN1 E2 E1

The Conjugated systems
- In protic solvents, SN1 substitution reactions of proceed more rapidly in the systems of allylic and benzylic cations than
in alkyl systems.
In aprotic solvents SN2 is also favorable in the presence of allylic and benzylic substrates in aprotic solvents since the TS
has been stabilized because of delocalized electrons
Organic halogenides
SN2 SN1 E2 E1

Neighboring-group participation.
When a molecule that can react by nucleophilic substitution also contains a substituent group that can act as a
nucleophile, it is often observed that the rate and stereochemistry of the nucleophilic substitution are strongly
affected. The involvement of nearby nucleophilic substituents in a substitution process is called neighboring-group
participation.
Rate of solvolysis of cis- and trans-2-acetoxycyclohexyl p-toluenesulfonate in ethanol

Organic halogenides
SN2 SN1 E2 E1

Organic halogenides
SN2 SN2 E2 E1
Chapter 6: 6.20; 6.21; 6.22; 6.24; 6.26; 6.27; 6.28, 6.48, 6.49, 6.50
ELIMINATION REACTIONS
Organic halogenides
SN2 SN2 E2 E1
Organic halogenides – Elimination reactions
Elimination reactions
Elimination reactions involve the removal of

another molecule from a reactant.
Elimination reactions can be classified

according to the structural relationship
between the proton and the leaving group.
Organic halogenides
SN2 SN2 E2 E1
In an elimination reaction the fragments of some molecule (YZ)
are removed (eliminated) from adjacent atoms of the reactant.
This elimination leads to the creation of a multiple bond
Dehydrohalogenation (-HX) and Dehydration (-H2O) are the main

types of elimination reactions
The hydrogen atom that is eliminated in

dehydrohalogenation is from the β carbon atom,
these reactions are often called β eliminations
Organic halogenides
SN2 SN2 E2 E1
Organic halogenides
SN2 SN2 E2 E1
 Substitution
Elimination reactions of alkyl halides are important H OCH3 H OCH3

C C C C + Br-
reactions that compete with substitution reactions. (acts as a
Br Nu )
 Elimination
e.g.
t
BuOK
I OtBu + H OCH3
C C (acts as a C C + CH3OH + Br-
t
BuOH
SN2: 15% E2: 85% H
Br base)
Organic halogenides
SN2 SN2 E2 E1
For alkyl halides, two mechanisms are especially important because

they are closely related to the SN2 and SN1 reactions. One mechanism,
called the E2 reaction, is bimolecular in the rate-determining step; the
other mechanism is the E1 reaction, which is unimolecular in the rate-
determining step
2-methylpropene 1-bromo-1,1-dimethylethane 2-methylpropene

1-bromo-1,1-dimethylethane
rate = k [1-bromo-1,1-dimethylethane]
rate = k [1-bromo-1,1-dimethylethane][OH-]
this reaction is an example of a E1 reaction.
this reaction is an example of a E2 reaction.
E stands for elimination
E stands for elimination
1 stands for unimolecular
2 stands for bimolecular
Organic halogenides
SN2 SN2 E2 E1
E2 Elimination reactions – Synthesis of alkenes
A widely used method for synthesizing alkenes is the

elimination of HX from adjacent atoms of an alkyl halide.
Heating the alkyl halide with a strong base causes the
reaction to take place.
Various strong bases have been used for dehydrohalogenations.

The most common used strong bases are conjugated bases of
alcohols
EtONa/EtOH t- BuOK/t- BuOH

Organic halogenides
SN2 SN2 E2 E1
The E2 mechanism
Organic halogenides
SN2 SN2 E1 E2
Stereochemistry of E2 reactions
E2 reactions must go by an anti elimination

This means that the hydrogen atom and halogen atom must Newman projection formula shows
be 180o (coplanar) with respect to each other!! the H and LG on opposite sides.
The five atoms involved in the transition state of an E2 reaction
(including thebase) must be coplanar, i.e., lie in the same plane
The geometry required here is similar to that of the SN2 reaction.

In the SN2 reaction, the nucleophile must push out the leaving
group from the opposite side. In the E2 reaction the electron
pair of the C - H bond pushes the leaving group away from the
opposite side as the base removes the hydrogen.
Why base attacks on the anti-coplanar H?

Organic halogenides
SN2 SN2 E2 E1
What about the purity of products in two reactions ?

Organic halogenides
SN2 SN2 E2 E1

Stereochemistry of E2 reactions Zaitsev’s rule:
In reactions of removal of hydrogen halides from alkyl halides or the
removal of water from alcohols, the hydrogen which is lost will come
from the more highly-branched b-carbon.
Kinetic control of product formation: An elimination occurs

to give the more stable, more highly substituted alkene.
- The preferential formation of one product because the free
energy of activation leading to its formation is lower than
that for another product
Organic halogenides
SN2 SN2 E2 E1

Carrying out dehydrohalogenations with a bulky base such as potassium tert-

butoxide (t-BuOK) in tert-butyl alcohol (t-BuOH) favors the formation of the
less substituted alkene
When an elimination yields the less substituted alkene, we say

that it follows the Hofmann rule Reasons?
Organic halogenides
SN2 SN2 E2 E1

Diastereomers (S,S – R, S)
CH3 Br CH3
Br
t-butyl t-butyl
C C C C
CH3 H
H
H H
CH3
KOH
ethanol KOH
heat What about this guy?
ethanol
???
heat
???
??? ???
CH3 CH3 H CH3
C C C C CH3 CH3 H CH3
H t-butyl CH3 t-butyl
Cis - isomer
(E)-isomer Trans - isomer
(Z)-isomer C C C C
H T-butyl CH3 t-butyl
Organic halogenides
SN2 SN2 E2 E1

E1 reactions
E1 elimination reaction is in competition with SN1
The initial step for both the substitution and the elimination
pathways is the formation of a tert-butyl cation as a
common intermediate. This is also the slowest step for both
reactions; thus both reactions exhibit fist-order kinetics and
are unimolecular in the rate-determining step.
Organic halogenides
SN2 SN2 E2 E1
E1 reactions - Mechanism
α carbon
β hydrogen
H H2O
H2O
Cl + H3O
slow
r.d.s. fast (E1 product)
fast H 2O
H H2O
O OH + H3O
H
(SN1 product)
Organic halogenides
SN2 SN2 E2 E1
Organic halogenides
SN2 SN2 E2 E1
Organic halogenides
SN2 SN2 E2 E1
Organic halogenides
The competition of SN2 and E2
The most significant of these in the SN2/E2 competition are the type of base that is applied and the structure of the substrate
In favor of the E2 elimination

- Strong base, non- or weak nucleophilicity
(slightly polarizable group)
- High steric hindrance base (bulky base)
- More substituent groups substrate
(primary < secondary < tertiary)
- Polar protic solvent
In favor of the SN2 Substitution
- Weak base, good nucleophile
(highly polarizable group)
- Small nucleophile
- Less substituent groups substrate
(tertiary < secondary < primary)
- Polar aprotic solvents
Organic halogenides
SN2 SN2 E2 E1
Organic halogenides
The competition - Temperature
Increasing the reaction temperature favors elimination

(E1 and E2) over substitution. elimination reactions
have greater free energies of activation than
substitution reactions because more bonding changes
occur during elimination. When higher temperature is
used, the proportion of molecules able to surmount the
energy of activation barrier for elimination increases
more than the proportion of molecules able to undergo
substitution, although the rate of both substitution and
elimination will be increased.
Organic halogenides
SN2 SN2 E2 E1
Organic halogenides
Organic halogenides
SN2 SN1 E2 E1
Organic halogenides
Organic halogenides
SN2 SN1 E2 E1
Organic halogenides
Organic halogenides
SN2 SN1 E2 E1
Organic halogenides
The rearrangement reactions
A rearrangement reaction is a broad class of

organic reactions where the carbon skeleton of a
molecule is rearranged to give a structural isomer
of the original molecule. Often a substituent moves
from one atom to another atom in the same
molecule.
Carbocation rearrangements are common in organic

chemistry and are defined as the movement of a
carbocation from an unstable state to a more stable
state through the use of various structural
reorganizational “shifts” within the molecule
Organic halogenides
SN2 SN1 E2 E1
Organic halogenides
The rearrangement reactions
Organic halogenides
SN2 SN1 E2 E1
Organic halogenides
The rearrangement of carbocation – Hydride shift
Hydride shift is the process of the two electron
hydrogen from the unimolecular substitution moves
over to the neighboring carbon.
Organic halogenides
SN2 SN1 E2 E1
Organic halogenides
Organic halogenides
SN2 SN1 E2 E1
Organic halogenides
Organic halogenides
SN2 SN1 E2 E1
Organic halogenides
The rearrangement of carbocation
Organic halogenides
SN2 SN1 E2 E1
Organic halogenides
The rearrangement of carbocation – Alkyl shift
Organic halogenides
SN2 SN1 E2 E1
Organic halogenides
The rearrangement of carbocation – Alkyl shift
Ring expansion in SN1 reaction

Organic halogenides
SN2 SN1 E2 E1
Organic halogenides
Chapter 6: 6.29; 6.31; 6.32; 6.33; 6.34; 6.36; 6.42; 6.43;

6.48; 6.52; 6.53
Organic halogenides
SN2 SN1 E2 E1
Organic halogenides
• End lec. 7

Organic Chem II Lecture 5 6 SN and E Reactions

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Organic Chem II Lecture 5 6 SN and E Reactions

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University of Science and Technology of Hanoi

Department of Fundamental and Applied Sciences

NUCLEOPHILIC SUBSTITUTION REACTIONS

Dr. Nguyen Duc Anh

The carbon–halogen bond length increases

Prone to undergo Nucleophilic Substitutions (SN) and Elimination Reactions (E)

Ionic substitution reactions

Ionic substitution reactions

In nucleophilic substitution reactions the bond between the

Ionic substitution reactions

Ionic substitution reactions

A nucleophile is a reagent that seeks a positive center

The nucleophile is always a Lewis base, and it may

HO , CH3O , H2N (negative charge)

H2O, NH3 (neutral)

Ionic substitution reactions

Ionic substitution reactions

e.g.: I⊖, Br⊖, Cl⊖, TsO⊖, MsO⊖, H2O, NH3

Ionic substitution reactions

Ionic substitution reactions

Ionic substitution reactions

Ionic substitution reactions

Ionic substitution reactions

+ Bimolecular reactions R = k1[Substrate] + Unimolecular reactions

S stands for substitution S stands for substitution

Ionic substitution reactions

Ionic substitution reactions

 Exergonic (ΔGo is negative)

Ionic substitution reactions

The nucleophile approaches the substrate

SN2 reactions always occur with

Ionic substitution reactions

 The rate of SN1 reactions depends only on concentration of

In a multistep reaction, the rate of the

Ionic substitution reactions

Ionic substitution reactions

2 intermediates and 3 transition states (T.S.)

Ionic substitution reactions

• The central carbon atom in a carbocation is electron

H3C • The p orbital of a carbocation contains no electrons, but it

• General order of reactivity (towards SN1 reaction)

3o > 2o >> 1o > methyl

Ionic substitution reactions

Positive inductive effect

CH2 CH2 orbital overlap) from a filed

etc. bonding orbital to an adjacent

Resonance stabilization of allylic and benzylic cations Hyperconjugation effect

Ionic substitution reactions

CH3O CH3 CH3 OCH3

Ionic substitution reactions

Ionic substitution reactions

● 3o > 2o >> 1o > methyl

A steric effect is an effect on the relative rates caused by the space-

Ionic substitution reactions

Ionic substitution reactions

Favored by polar aprotic solvents Favored by polar protic solvents

Ionic substitution reactions

In either an SN1 or SN2 reaction the leaving group begins to acquire a

Ionic substitution reactions

The concentration and reactivity of the nucleophile

+ The rate of an SN1 reaction is unaffected by either

The rate of an SN2 reaction depends on the concentration

Ionic substitution reactions