Topic 7:

NUCLEOPHILIC
SUBSTITUTION AT
SATURATED CARBONS

1
 Learning Objectives

1. Recognize and explain nucleophilic substitution of alkyl

halides and alcohols.

2. Recognize and explain amines, carboxylate, and

acetylide ions as nucleophiles.

3. Predict carbocation stability and rearrangement

products.

4. Illustrate the different reactions and mechanisms using

examples.

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Nucleophilic substitution reaction of RX
• Substitution of the X group by a nucleophile (Nu-)

Nu + C X C Nu + X

• Two types: SN1 and SN2

• Four effects:

1) Substrate 2) Nucleophile 3) Leaving group 4) Solvent

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 Nucleophilic substitution reaction of RX
Type SN2 SN1
Name Substitution Nucleophilic Substitution Nucleophilic
Bimolecular Unimolecular

Kinetic Second order reaction First order reaction

Rate = Rate =

Mechanism 1 step 2 steps

(X remove and Nu- (X remove and Nu-
attack at the same time) attack at different step)
- -
- -

Stereochemistry
of product

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 Nucleophilic substitution reaction of RX
Effect SN2 SN1
Substrate (RX) Steric hindrance Carbocation

Nucleophile

Leaving group Best LG is the weakest base

(X) I- > Br - > Cl- > F-

Solvent
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 Effect of substrate
• A hindered and bulky substrate would prevent easy approach
of the nucleophile, the slower the SN2 reaction.

• Thus, this difficulty increases as the three substituents

increase in size.

• Examples :

CH3 CH3 H CH3 H H

H3C C Br H3C C C Br H3C C Br H3C C Br H C Br
CH3 CH3 H H H H

RX : Tertiary Primary Secondary Primary Methyl

Steric decreases

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 Effect of substrate
• The more stable the carbocation intermediate, the faster the
SN1 reaction.

• Examples :

H CH2
H H H CH3
H C H
H C H3C C C C H3C C H3C C

H H H H CH3 CH3

C+ : Methyl Primary Primary Primary Secondary Tertiary

(Allyl) (Benzyl)

Stability increases

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 Substrate – carbocation rearrangement
• Rearrangement can be through:

1. Alkyl shift 2. Hydride shift

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 Effect of nucleophile
• Nucleophilicity (nucleophile strength) is a measure of the
affinity of Nu for a carbon atom that bonded to X. reaction.

• In the SN2 reaction, strong nucleophiles are favored.

• Example: SN2 reaction of bromomethane in aqueous ethanol

H3C Br + Nu H3C Nu + Br

Nu = H2O CH3CO2− NH3 Cl− OH− I− CN−

1 500 700 1000 16,000 100,000 125,000

increasing reactivity

• The nucleophile does not affect the reaction rate in SN1

reaction.
• Reaction works well under neutral and acidic conditions.
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 Effect of leaving group
• In the SN2 and SN1 reactions, the LG (X) is expelled as a
negatively charge group – same effect.

• The best LGs should be the weakest bases (anion derived

from the strongest acid; more stable anion).

OH−, NH2−, OR−, F−, Cl−, Br−, I− , TosO−

<< 1 1 200 10,000 30,000 60,000

Leaving group reactivity

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 Effect of solvent
• Polar aprotic solvents which have strong dipoles but don’t
have –OH @ –NH groups, so cannot form hydrogen bond :
are the best solvents for SN2 reaction.

CH3CH2OH, H2O, DMSO, DMF, CH3CN

Solvent reactivity to SN2 reactions

• Polar protic solvents that contain –OH R

O
-
@ –NH : worst solvents for SN2
reaction. H +

.....
- + + -
R O H ..... Nu ..... H O R
• Protic solvent can form H-bond to

.....
H +
nucleophile, thus hinders the
O -
nucleophile from attacking the
R
substrate.

• Nucleophile are less nucleophilic in protic solvents.

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 Effect of solvent
• Polar protic solvents favor SN1 reaction.

• Protic solvent facilitate formation of a carbocation by forming H-

bond with the LG as it departs – lowering the energy of the
transition state leading to a carbocation.

R
R R
O R
O R C
O
-
H R
H
.....

R H +
.....

.....
R +
R C X ..... H O R - - + + -
....... X ..... H O R
R C R O H ..... X ..... H O R
.....

R
.....

.....
H R
H H +
O
O O -
R
R R

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 SN2 mechanism

• The nucleophile approach from the backside of the reactant,

180o away from the departing group X.

• This causes the stereochemistry of the substrate to invert,

much like an umbrella turning inside out in the wind.
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SN1 mechanism

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 Nucleophilic substitution reaction of RX
Summary of factors that determine the SN2 and SN1 mechanisms

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 Other substitution reaction of alkyl halides
1. Substitution of alkyl halide with ammonia/amines

• Ammonia, 1°, 2° @ 3° amines reacts with 1° RX to

produce new 1°, 2° @ 3° RNH2 @ salt.

i) RX
RNH2 R NH
ii) NaOH
R

SN2 NaOH
Ammonia NH3 + RX RNH3+ X- RNH2 (1°)

SN2 NaOH
2 amine R2NH + RX R3NH+ X- R3N (3°)

3 amine SN2
R3N + RX R4N+ X- (4° ammonium salt)

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 Other substitution reaction of alkyl halides
Mechanism :

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 Other substitution reaction of alkyl halides
2. Substitution of alkyl halide with terminal alkynes

• Terminal hydrogen of alkynes are relatively acidic (pKa =

25).
• Terminal hydrogen can react with strong bases to form
acetylide anions.
• The acetylide anions can react with 1° RBr @ RI to form a
new alkyne.

i) NaNH2
RC CH RC CR
ii) RX

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 Other substitution reaction of alkyl halides
Mechanism :

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 Other substitution reaction of alkyl halides
3. Substitution of alkyl halide with alcohols (Williamson
Ether Synthesis)

• Reaction between alkoxide ion and 1 RX.

• Alkoxide ion can be prepared from alcohol and base.

i) NaH
ROH ROR
ii) RX

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 Substitution reaction of alkane
Substitution of alkane with X2

• X2 : Cl2 or Br2
• Reaction proceed in the presence of light.
• Involve radical mechanism.

H X
+ light
X X + H X

H R R
Reactivity of radical: R C . R C . R C .
H H R
Primary < Secondary < Tertiary

• not a good method - can produce mixture of products.

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 Substitution reaction of alkane
Example :

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 Substitution reaction of alkane
Mechanism :

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 Substitution reaction of Grignard reagent
Substitution of Grignard reagent with acid

• RX reacts with magnesium metal in dry ether @ THF to yield

RMgX (alkyl magnesium halides) = Grignard reagent.

• All 1o, 2o and 3o RX react readily.

• Can be used for conversion of RX to alkane by treatment

with weak acids such as H2O, ROH, RCOOH and RNH2.

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 Substitution reaction of alcohol
1. Substitution of alcohols with HX

SN1
R OH + HX R X + H2O

• Reactivity of alcohol :

Mechanism : H3C OH H3C Cl

HCl

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 Substitution reaction of alcohol
2. Substitution of alcohols with SOCl2 or PBr3

• 1° and 2° alcohols can be converted to alkyl halides.

SOCl2
RCH2OH RCH2Cl + SO2 + HCl
SN2

PBr3
RCH2OH RCH2Br + POBr + HBr
SN2

Cl O
SN2
C O S Cl Cl C + SO2 + Cl-
SOCl2 H H

Mechanism : C OH
H
PBr3
Br SN2
C O P Br C + Br2PO-
Br
H H

Br 26