SUBSTITUTION

REACTIONS
 Timing of The Bond Breaking & Bond Making Process

Two types of mechanisms

1st type: SN2 (concerted mechanism)

R
R −
R
−
δ+ δ− δ δ
HO C Br HO C Br HO C
R R
R R
R R
transition state (T.S.)
+ Br-
 2nd type: SN1 (stepwise mechanism)
Step (1):
R (k1) R
R C Br slow R C + Br
R r.d.s. R
k1 << k2 and k3
Step (2)
R (k2) R H
R C + H 2O R C O
fas H
R t R
Step (3)
R H (k3) R
+
R C O + H 2O +
R C OH H3O
fas
R H R
t
 Nucleophiles
A reagent that seeks a positive center
Has an unshared pair of e⊖
e.g.:

HO , CH3O , H2N (negative charge)

H2O, NH3 (neutral)

+ −
This is the positive δ δ
center that the C X
Nu⊖ seeks
Examples:

H H H H
HO + C C + Cl
CH3 Cl CH3 OH
(Nu ) (substrate) (product) (L.G.)

H H H H

H
O
H
+ C C H + Cl
CH3 Cl CH3 O
(Nu ) (substrate) H (L.G.)

H H
(product)
C + H3O
CH3 OH
 Leaving Groups
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
 Kinetics of a Nucleophilic Substitution
Reaction: An SN2 Reaction

HO + CH3 Br HO CH3 + Br
-
Rate = k[CH3Br][OH ]
The rate of the substitution reaction is linearly
dependent on the concentration of OH⊖ and CH3Br
Overall, a second-order reaction ⇒ bimolecular
 Example:
60oC
HO + Cl CH3 H2O
HO CH3 + Cl

Initial rate
[OH ]t=0
⊖
[CH3Cl]t=0 Result
mole L-1, s-1
1.0 M 0.0010 M 4.9 × 10-7
1.0 M 0.0020 M 9.8 × 10-7 Doubled
2.0 M 0.0010 M 9.8 × 10-7 Doubled
2.0 M 0.0020 M 19.6 × 10-7 Quadrupled
 A Mechanism for the SN2 Reaction
H
H −
H
+ − −
δ δ δ δ
HO C Br HO C Br HO C
H H
H H
H H
transition state (T.S.)
negative OH ⊖ + Br-
brings an e⊖ pair O–C bond partially
formed; C–Br O–C bond
to δ+ C; δ– Br formed; Br
begins to move bond partially ⊖

broken. departed.
away with an e⊖ Configuration
pair Configuration of C
begins to invert of C inverted
Free Energy Diagram of SN2 Reactions

T.S.
ΔG = free energy of
Free Energy

ΔG activation
HO- + CH3Br ΔGo = free energy
change
ΔGo
CH3OH + Br-
Reaction Coordinate

Exergonic (ΔGo is negative)

Thermodynamically favorable process
 8.The Stereochemistry of SN2 Reactions
Inversion of configuration

CH3
HO + C Br (inversion)
H
CH2CH3
(R)
CH3
HO C + Br
H
(S) CH2CH3
Example:
Nu attacks from the TOP face.
⊖

CH3 I +
OCH3

(inversion of configuration)

CH3 OCH3
+I
Example:

Nu attacks from the BACK face.

⊖

+ CN + Br
Br (inversion of
CN
configuration)
 The Reaction of tert-Butyl Bromide
with H2O: An SN1 Reaction
CH3 CH3
CH3 C Br + H2O CH3 C OH + HBr
CH3 CH3
The rate of SN1 reactions depends only on
concentration of the alkyl halide and is
independent on concentration of the Nu⊖
Rate = k[RX]
In other words, it is a first-order reaction
⇒ unimolecular nucleophilic substitution
 step 1
Br

Step (2)

CH3 (k2) CH3 H

CH3 C + H2O fast
CH3 C O
CH3 CH3 H
Step (2)

CH3 (k2) CH3 H

CH3 C + H2O fast CH3 C O
CH3 CH3 H

Step (3)

CH3 H (k3) CH3

CH3 C O + H2O fast CH3 C OH
CH3 H CH3
+
+ H 3O
Step (2)

CH3 (k2) CH3 H

CH3 C + H2O fast CH3 C O
CH3 CH3 H
k1 << k2 and k3
Step (3)

CH3 H (k3) CH3

CH3 C O + H2O fast CH3 C OH
CH3 H CH3
+ H3O+
 Free Energy Diagram of SN1 Reactions

T.S. (1)
T.S. (2)
Free Energy

T.S. (3)
(CH3)3C
+ Br-
ΔG1 (CH3)3C -OH2
+ Br-
(CH3)3CBr intermediate (CH3)3C-OH
+ H2O -
+ Br
Reaction Coordinate
 Carbocations
The Structure of Carbocations
Carbocations are trigonal
planar
The central carbon atom
in a carbocation is
electron deficient; it has
H3C only six e in its valence
shell
⊖

C CH3 The p orbital of a

H3C carbocation contains no
electrons, but it can
accept an electron pair
when the carbocation
undergoes further
reaction
The Relative Stabilities of Carbocations

General order of reactivity (towards SN1 reaction)

3o > 2o >> 1o > methyl
The more stable the carbocation formed, the faster the SN1
reaction
Stability of cations
most stable (positive inductive effect)
R R R H
> > >
C C C C
R R R H H H H H
Resonance stabilization of allylic and benzylic cations

CH2 CH2
etc.
 12. The Stereochemistry of SN1 Reactions
Ph Ph Ph
CH3OH CH3OH
C CH3 C OCH3
CH3 Br
CH2CH3 CH3 CH2CH3 CH2CH3
(S) (trigonal planar) (R) and (S)
racemic mixture

CH3OH CH3OH
attack from left 50:50 attack from right
chance
Ph Ph

CH3O CH3 CH3 OCH3

CH2CH3 (1 : 1) CH2CH3
(R) (S)
 Example: racemic mixture
( 1 : 1 )
(R) H2O (R) (S)
+
(SN1)
Br OH OH
(one enantiomer)
attack from H2O
slow TOP face
r.d.s. H2O
H2O O
H H

H2O attack from O

(carbocation) BOTTOM face H H
 Example:

I OMe Me
t
Bu Me MeOH tBu Me +tBu OMe

MeOH
slow Me H MeOH
r.d.s. O
t
Bu Me
MeOH
Me
⊕ CH3
t t H
Bu ⊕ Bu O
MeOH Me
trigonal planar
 Factors Affecting the Rates of
SN1 and SN2 Reactions
The structure of the substrate
The concentration and reactivity of the nucleophile (for SN2 reactions only)
The effect of the solvent
The nature of the leaving group
 13A. The Effect of the Structure of the Substrate

General order of reactivity (towards SN2 reaction)

Methyl > 1 > 2 >> 3 > vinyl or aryl
o o o

DO NOT undergo
SN2 reactions
 For example:

R B r + HO R OH + B r
Relative
Rate CH3 CH3
(toward
CH3 Br CH3CH2 Br CH3CH Br CH3 C CH2Br CH3 C Br
CH3 CH3 CH3
s SN2)
methyl neopentyl
1o
2 o
3o
500 1 <1
2 × 10 6
4 × 104
Most reactive Least reactive
 Note NO SN2 reaction on sp2 or sp carbons

e.g. sp
H I 2

+ Nu No reaction
H H
sp
2
I
+ Nu No reaction
s
p
I + Nu No reaction
Reactivity of the Substrate in SN1 Reactions

General order of reactivity (towards SN1 reaction)

3o > 2o >> 1o > methyl
The more stable the carbocation formed, the faster the SN1 reaction
Stability of cations

most stable (positive inductive effect)

R R R H
> > >
C C C C
R R R H H H H H

Allylic halides and benzylic halides also undergo SN1 reactions at reasonable rates

I
Br
an allylic bromide a benzylic iodide
Resonance stabilization for allylic and benzylic cations

CH2 CH2
etc.
The Effect of the Concentration & Strength of the Nucleophile

For SN1 reaction

Recall: Rate = k[RX]

The Nu⊖ does NOT participate in the r.d.s.

Rate of SN1 reactions are NOT affected by either the concentration or the

identity of the Nu⊖

For SN2 reaction

Recall: Rate = k[RX][nu]

The rate of SN2 reactions depends on both the concentration and the identity

of the attacking Nu⊖

 Identity of the Nu⊖
The relative strength of a Nu⊖ (its nucleophilicity) is measured in terms of the
relative rate of its SN2 reaction with a given substrate

rapid
-
CH3O + CH3I CH3OCH3 + I
⊖
Good Nu

Very
slow
-
CH3OH + CH3I CH3OCH3 + I
⊖
Poor Nu
The relative strength of a Nu⊖ can be correlated with 3 structural
features
A negatively charged Nu⊖ is always a more reactive Nu⊖ than its
conjugated acid
e.g. HO⊖ is a better Nu⊖ than H2O and RO⊖ is better than
ROH
In a group of Nu⊖s in which the
nucleophilic atom is the same, nucleophilicities parallel
basicities
e.g. for O compounds,
RO⊖ > HO⊖ >> RCO2⊖ > ROH > H2O
When the nucleophilic atoms are different, then nucleophilicities
may not parallel basicities
e.g. in protic solvents HS⊖, CN⊖, and I⊖ are all weaker bases
than HO⊖, yet they are stronger Nu⊖s than HO⊖
HS⊖ > CN⊖ > I⊖ > HO⊖
 SN2 Reactions in Polar Aprotic Solvents
The best solvents for SN2 reactions are
Polar aprotic solvents, which have strong dipoles but
do not have OH or NH groups
Examples

O
CH3 O
O
H N P NMe
S Me2N NMe2 2
CH3 CH3 CH3 CH3CN
(DMSO) (DMF) (HMPA) (Acetonitrile)
 Polar aprotic solvents tend to solvate metal cations
rather than nucleophilic anions, and this results in
“naked” anions of the Nu⊖ and makes the e⊖ pair of
the Nu⊖ more available
DMSO
CH3O Na CH3O + DMSO Na
"naked anion"
 Tremendous acceleration in SN2 reactions with polar
aprotic solvent

CH3Br + NaI CH3I + NaBr

Solvent Relative Rate

MeOH 1

DMF
106
 Halide Nucleophilicity in Protic Solvents
I⊖ > Br⊖ > Cl⊖ > F⊖

OR
RO δ + + OR
δ H
H H
δ+ δ+
RO H F -
H OR RO H I-
δ+ δ+
H H
RO OR H
OR
(strongly solvated) (weakly solvated)
Thus, I⊖ is a stronger Nu⊖ in protic solvents, as
its e⊖ pair is more available to attack the
substrate in the SN2 reaction.
Halide Nucleophilicity in Polar Aprotic Solvents (e.g. in DMSO)
F⊖ > Cl⊖ > Br⊖ > I⊖
Polar aprotic solvents do not solvate
anions but solvate the cations
The “naked” anions act as the Nu⊖
Since F⊖ is smaller in size and the
charge per surface area is larger than
I⊖, the nucleophilicity of F⊖ in this
environment is greater than I⊖
Solvent Effects on SN1 Reactions: The Ionizing
Ability of the Solvent
Solvent plays an important role in SN1 reactions but the
reasons are different from those in SN2 reactions
Solvent effects in SN1 reactions are due largely to
stabilization or destabilization of the transition state
In Sn1 ,the main factor is carbocation stability, while in
Sn2, it is steric hinderance.
Polar protic solvents stabilize the development
of the polar transition state and thus accelerate
this rate-determining step (r.d.s.):

δ+ OR
H
CH3 H3C +
slow δ δ−
CH3 C Cl CH3 C Cl
r.d.s.
CH3 δ− CH3 δ+
R O H
H OR
CH3
Cl- + CH3 C
CH3
 The Nature of the Leaving Group

The better a species can stabilize a negative charge, the better

the LG in an SN2 reaction
SN1 Reaction:

+
slow δ δ−
C X C X C + X
r.d.s.
SN2 Reaction:

− −
slow δ δ
C X Nu C X Nu C +X
r.d.s.

Nu:
 Examples of the reactivity of some X⊖:

CH3O + CH3–X → CH3–OCH3 + X

Relative Rate:

Best X⊖
Worst X ⊖

OH, << < < < <

NH2, F 
Cl 
Br 
I 
TsO
RO
~0 1 200 10,000 30,000 60,000

☞ Note: Normally R–F, R–OH, R–NH2, R–OR’ do not undergo SN2 reactions.