Nucleophilic Substitution
Reactions
Nucleophilic substitution reaction is a class of organic reactions
where one nucleophile replaces another. It is very similar to the
normal displacement reactions where, a more reactive element
replaces a less reactive element from its salt solution. The group
which takes electron pair and displaced from the carbon is known
as “leaving group” and the molecule on which substitution takes
place is known as “substrate”. The leaving group leaves as a
neutral molecule or anion.
A nucleophile is any negative ion or any neutral
molecule that has at least one
unshared electron pair-General Reaction for
Nucleophilic Substitution of an Alkyl Halide by
Hydroxide Ion.
Kinetics of nucleophilic substitution
Reaction rate: how fast (or slow) reactants are converted into product (kinetics)
Reaction rates are dependent upon the concentration of the reactants. (reactions rely on
molecular collisions)
At a given temperature:
If [OH-] is doubled, then the reaction rate may be doubled
If [CH3-Br] is doubled, then the reaction rate may be doubled
A linear dependence of rate on the concentration of two reactants is called a second-
order reaction (molecularity)
Reaction rates (kinetic) can be expressed mathematically:
reaction rate = disappearance of reactants (or appearance of products)
For the disappearance of reactants:
rate = k [CH3Br] [OH-]
[CH3Br] = CH3Br concentration [OH-] = OH- concentration
k= constant (rate constant)
For the reaction above, product formation involves a collision between both
reactants, thus the rate of the reaction is dependent upon the concentration
of both.
Nucleophilic Substitution comes in two reaction types:
SN2 SN1
S= substitution S= substitution N=
N= nucleophilic nucleophilic 1=
2= biomolecular unimolecular
rate = k [R-X] [Nu:] rate = k [R-X]
The SN2 Reaction: Mechanism
It is a single step process consisting of one intermediate. It proceeds through the
backside (of the LG) attack of the incoming nucleophile to avoid repulsions,
leading to an intermediate, which is indicated using two dotted lines between
carbon – Nu and carbon-X. The two dotted lines in the intermediate indicate that
the C–X bond is broken and the C–Nu bond is formed simultaneously. And at the
end, C–X bond is completely broken and the C–Nu bond is completed formed.
Since it’s a backside attack of the nucleophile, the product will always have an
inverted configuration with the substrate. Therefore, the SN2 mechanism always
results in “inversion of configuration”. In case of t-butyl of chloride,
SN2 mechanism becomes increasingly difficult as the nucleophile will find it
difficult to attack from the backside due to the presence of bulky methyl.
Highly crowded substrates will be less reactive towards the SN2 mechanism. The order
of reactivity of 1°, 2°, 3° halides is as follows.
1° > 2° > 3° (steric hindrance). The rates of SN2 reactions are enhanced if polar aprotic
solvents such as DMF, DMSO, etc are used as reaction mediums.
Characteristics of Nucleophilic Substitution Bimolecular
Reaction
1. Sensitive to the steric effect.
2. A reaction occurs with inversion of a chiral center.
3. Methyl halides are more reactive, a primary compound next reactive,
secondary halides may react but tertiary halides are not reactive.
4. At C=C in the vinyl compound, there is no reaction.
5. The reaction between the negatively charged nucleophile with the
substrate will give a neutral product.
6. The reaction between the neutral nucleophile with the substrate will give
rise to the positively charged product.
7. A weak base (stable anions) are good leaving groups.
8. A few compounds such as alcohols, fluorides, ether, amines, do not
undergo SN2 reactions, and also if the leaving group is very small it prevents
the SN2 mechanism.
9. The solvents that are capable of donating hydrogen bond will slow down
the SN2 reaction because of association with the reactants.
The rate of an SN2 reaction depends upon 4 factors:
1. The nature of the substrate (the alkyl halide)
2. The power of the nucleophile
3. The ability of the leaving group to leave
4. The nature of the solvent
1. Consider the nature of the substrate
❑ Unhindered alkyl halides, those in which the back side of the α-carbon is not
blocked, will react fastest in SN2 reactions, that is:
Me° >> 1° >> 2° >> 3°
❑ While a methyl halides reacts quickly in SN2 reactions, a 3° does not react.
The back side of an α-carbon in a 3° alkyl halide is completely blocked.
H3C H3C
CH Br H3C C Br
H3 C Br H3 C CH2 Br
H3C H3C
methyl bromide ethyl bromide isopropyl bromide t-butyl bromide
❑ The α-carbon in vinyl and aryl halides, as in 3° carbocations, is completely
hindered and these alkyl halides do not undergo SN2 reactions.
H2C CH Br Br
vinyl bromide bromobenzene
Nu:- Nu:-
H2C CH Br Br
The overlapping p-orbitals that form the -bonds in vinyl and aryl halides
completely block the access of a nucleophile to the back side of the α-carbon.
2. Consider the nature of the nucleophile
Nucleophilicity
It is defined as the ability of the nucleophiles to denoted their lone pairs to a positive
center. It is a kinetic term which relates to the rate at which the nucleophile attacks the
substrates (R – LG). The nucleophilicity of different nucleophiles can be compared by
using the following factors.
The Basic Strength of Nucleophiles
• Nucleophilicity roughly parallels basicity when comparing nucleophiles that have the
same attacking atom
• Nucleophilicity usually increases going down a column of the periodic chart. Thus,
sulfur nucleophiles are more reactive than oxygen nucleophiles. I- > Br- > Cl-
• Negatively charges nucleophiles are usually more reactive than neutral nucleophiles.
• Nucleophiles having lone pairs on highly electronegative atoms are less nucleophilic
or weaker nucleophiles. SH- is better nucleophile than OH-
• Presence of electron-donating groups in the nucleophiles increases their
nucleophilicity RCOO- is better nucleophile than HCOO-
• Two nucleophiles having the same nucleophilic atom, the one which is charged
(negative) is more nucleophilic than the neutral one. OH- is better nucleophile than
H2O
2. Consider the nature of the nucleophile
Reactivity Nu:- Relative Reactivity
very weak HSO4-, H2PO4-, RCOOH < 0.01
increasing
weak ROH 1
HOH, NO3- 100
fair F- 500
Cl-, RCOO- 20 103
NH3, CH3SCH3 300 103
good N3-, Br- 600 103
OH-, CH3O- 2 106
very good CN-, HS-, RS-, (CH3)3P:, NH2- ,RMgX, I-, H- > 100 106
3. Consider the nature of the leaving group
➢ The leaving group usually has a negative charge
➢ Groups which best stabilize a negative charge are the best leaving groups, i.e., the weakest
bases are stable as anions and are the best leaving groups.
➢ Good leaving groups are the conjugate bases of strong acids
➢ Weak bases are readily identified. They have high pKb values.
pKb = 23 pKb = 22 pKb = 21 pKb = 11 pKb = -1.7 pKb = -2 pKb = -21
I- Br - Cl- F- HO- RO- H2N-
30,000 10,000 200 1 0 0 0
Increasing leaving ability
❑ Iodine (I) is a good leaving group because iodide (I-) is non-basic.
❑ The hydroxyl group (-OH) is a poor leaving group because hydroxide (OH-) is a strong
base.
4. Consider the nature of the solvent
There are 3 classes of organic solvents:
❑ Protic solvents, which contain –OH or –NH2 groups. Protic solvents slow down SN2
reactions.
❑ Polar aprotic solvents like acetone, which contain strong dipoles but no –OH or –
NH2 groups. Polar aprotic solvents speed up SN2 reactions.
❑ Non polar solvents, e.g., hydrocarbons. SN2 reactions are relatively slow in non-
polar solvents.
Protic solvents (e.g., H2O, MeOH, EtOH, CH3COOH, etc.) cluster around the Nu:-
(solvate it) and lower its energy (stabilize it) and reduce its reactivity via H-bonding.
H OR
+ -
A solvated anion (Nu:-) has reduced nucleophilicity,
- H OR reduced reactivity, and increased stability
RO H X:
- + A solvated nucleophile has difficulty hitting the -
carbon.
H OR
+ -
Solvent Effect for SN2 reactions
• Requires a polar, aprotic solvent…
• NO alcohols or amines
Polar, Aprotic Solvents
SN2 Conditions Summary
⚫ 1) Substrate (methyl > primary > secondary >> tertiary)
⚫ 2) Nucleophile (negative charge > neutral)
⚫ 3) leaving group (Y) (Y stabilizes a negative charge)
⚫ 4) solvent (needs to be polar and aprotic)
AN SN1 REACTION
• THE REACTION OF TERT-BUTYL
CHLORIDE WITH HYDROXIDE ION
1st Order Nucleophilic Substitution Reactions, i.e.,
SN1 reactions
CH3 CH3
rapid
3° Na+ Br-
H3C C Br + Na+ I- H3C C I +
CH3 CH3
❑ 3 alkyl halides are essentially inert to substitution by the SN2 mechanism
because of steric hindrance at the back side of the a-carbon.
❑ Despite this, 3 alkyl halides do undergo nucleophilic substitution reactions
quite rapidly , but by a different mechanism, i.e., the SN1 mechanism.
❑ SN1 = Substitution, Nucleophilic, 1st order (unimolecular).
❑ SN1 reactions obey 1st order kinetics, i.e., Rate = k[RX].
❑ The rate depends upon the concentration of only 1 reactant, the
alkyl halide-not the nucleophile
❑ The order of reactivity of substrates for SN1 reactions is the reverse of SN2
3 > 2 > 1 > vinyl > phenyl > Me°
R3C-Br R2HC-Br RH2C-Br CH2=CH-Br -Br H3C-Br
increasing rate of SN1 reactions
Mechanism of SN1 reactions
The mechanism of an SN1 reaction occurs in 2 steps:
Reaction steps:
1. the slower, rate-limiting dissociation of the alkyl halide forming a C+ intermediate
2. a rapid nucleophilic attack on the C+
Note that the nucleophile is not involved in the slower, rate-limiting step.
The Rate of SN1 reactions
The rate of an SN1 reaction depends upon 3 factors:
1. The nature of the substrate (the alkyl halide)
2. The ability of the leaving group to leave
3. The nature of the solvent
The rate is independent of the power of the nucleophile.
1. Consider the nature of the substrate
Highly substituted alkyl halides (substrates) form a more stable C+
more less
stable stable
CH3 CH3 CH3 H
H3C C+ H3C C+ H C+ H C+
CH3 H H H
tertiary > secondary > primary > methyl
3º 2º 1º
Stability of Carbocations
Alkyl groups are weak electron donors.
❑ They stabilize carbocations by donating electron density by induction (through
bonds)
CH3
Inductive effects:
Alkyl groups donate (shift) electron
H3C C+ density through sigma bonds to
electron deficient atoms.
This stabilizes the carbocation.
CH3
❑ They stabilize carbocations by hyperconjugation (by partial overlap of the alkyl C-to-H
bonds with the empty p-orbital of the carbocation).
vacant p orbital overlap (hyperconjugation)
of a carbocation
sp 2 Csp3-Hs
hybridized sigma bond
carbocation H orbital
..
+
C C H
H
HYPERCONJUGATION
Stability of Carbocations
❑Allyl and benzyl halides also react quickly by SN1
reactions because their carbocations are unusually
stable due to their resonance forms which delocalize
charge over an extended system
H2C CH +CH H2C+ HC CH2 H2C CH +CHR H2C+ HC CHR
2
1º allyl carbocation 2º allyl carbocation
2º benzylic
H H 1º benzylic H H
+ + H
C C C C +
H H H H C
R
+ +
Relative Stability of All Types of Carbocations
Increasing C+ stability and rate of SN1 reaction
+ +
C HR C H2
+ 1º benzylic
2º benzylic
C R2
3º C + 2º C + 1º C + H
3º benzylic
+
CH3 CH3 H + H C+
C+ > > CH2 CH > >
CH3 C+ > CH3 CH3 C+ H
> + +
CH3 H H vinyl C
phe nyl m e thyl C
+
+ +
CH2 CH CR2
CH2 CH CHR CH2 CH CH2
3º allylic 2º allylic 1º allylic
Note that 1° allylic and 1° benzylic C+’s are about as stable as 2°alkyl C+’s.
Note that 2° allylic and 2° benzylic C+’s are about as stable as 3° alkyl C+’s.
Note that 3° allylic and 3° benzlic C+’s are more stable than 3° alkyl C+’s
Note that phenyl and vinyl C+’s are unstable. Phenyl and vinyl halides do not
usually react by SN1 or SN2 reactions
Consider the nature of the Nucleophile
Involvement of the nucleophile in the SN1 reaction is after
the rate-limiting step. Thus, the nucleophile does not appear
in the rate expression. The nature of the nucleophile plays
no role in the rate of the SN1 reaction.
Consider the nature of the leaving group
➢ The nature of the leaving group has the same effect on both SN1 and SN2 reactions.
➢ The better the leaving group, the faster a C+ can form and hence the faster will be the SN1
reaction.
➢ The leaving group usually has a negative charge
➢ Groups which best stabilize a negative charge are the best leaving groups, i.e., the weakest bases
are stable as anions and are the best leaving groups.
➢ Weak bases are readily identified. They have high pKb values.
pKb = 23 pKb = 22 pKb = 21 pKb = 11 pKb = -1.7 pKb = -2 pKb = -21
I- Br - Cl- F- HO- RO- H2N-
30,000 10,000 200 1 0 0 0
Increasing leaving ability
❑ Iodine (I) is a good leaving group because iodide (I-) is non basic.
❑ The hydroxyl group (-OH) is a poor leaving group because hydroxide (OH-) is a
strong base.
Consider the nature of the solvent
❑ For SN1 reactions, the solvent affects the rate only if it influences the stability of the
charged transition state, i.e., the C+. The Nu:- is not involved in the rate determining step
so solvent effects on the Nu:- do not affect the rate of SN1 reactions.
❑ Polar solvents, both protic and aprotic, will solvate and stabilize the charged transition
state (C+ intermediate), lowering the activation energy and accelerating SN1 reactions.
❑ Nonpolar solvents do not lower the activation energy and thus make SN1 reactions
relatively slower
The relative rates of an SN1 reaction due to solvent effects are given
(CH3)3C-Cl + ROH → (CH3)3C-OR + HCl
H2O 20% EtOH (aq) 40% EtOH (aq) EtOH
100,000 14,000 100 1
reaction rate increases with polarity of solvent
