SUBSTITUTION

REACTION
 Learning objectives
• Recognise, differentiate and explain the different
reaction substitution mechanism involving alkyl
halides and alcohols
• Recognize and explain substitution reaction
mechanism of amines
• Predict carbocation stability and rearrangement
products
• Illustrate the different reactions and mechanisms
using examples
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 Preparation of Alkyl halide
1. Addition of HX into Alkene
(Will be covered in alkene chemistry)
H X
+ H X C C

2. Free radical substitution

Alkanes reacts readily with Cl2 or Br2 in the presence of light
to give alkyl halide substitution products.
This involved radical mechanism.

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 h .
Initiation step Cl Cl 2Cl

H3C H H Cl
Step 1 +
+ .
.
Propagation steps Cl CH3
(repeating cycle) + Step 2 +
H3C Cl Cl Cl

. .
CH3 + CH3 H3C CH 3

Termination steps
. . Cl CH 3
Cl + CH3

. .
Cl + Cl Cl Cl

Overall reaction CH4 + Cl2 CH3Cl + HCl

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But this is not a good method as can produce mixture of
products.
This can be seen in case of alkanes made up of different type of
hydrogens
Cl
CH3CH2CH2CH3 + Cl2 CH3CH2CH2CH2Cl + CH3CH2CHCH3

30:70

+ Dichloro-, trichloro-, etc

In term of reactivity, the tertiary radical is more stable

than secondary radical followed by primary radical.
H R R
R C. R C . R C .
H H R
Primary < Secondary < Tertiary

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3. Allylic bromination of alkenes
Allylic position is position next to double bond.
Alkenes react with N-bromosuccinimide (NBS) in the presence
of light to give substitution product at allylic position.
The mechanism is by radical method as discussed above by
removal of one of the allylic hydrogen radicals by bromine
radical.
O

H H N Br Br O

Allylic O
+ N H
position
h
H H O

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4. Substitution of alcohols
This is a general method for preparing alkyl halides from
alcohols.
Many different ways have been developed in this preparation.
R OH + HX R X + H2O

The reactivity of different alcohol towards conversion to alkyl

halides is as follow:
H H R
R C OH R C OH R C OH
H R R

Reactivity

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 Reactions of Alkyl Halides

Substitution reaction
Substitution of the X group by a nucleophile (Nu-)

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 Kinetics of Nucleophilic substitution

The exact rate at which a reactant is converted to product is called

reaction rate and can be measured.
The reaction rate depend on the concentration of the reactants.
Consider the nucleophilic substitution below:

- -
OH + H3C Br HO CH 3 + Br

When the concentration of each reactant is double individually,

the reaction rate also double.
When the reaction depend of concentration of two species, this
is called second-order reaction, and rate equation is expressed
as:
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 Reaction rate = Rate of disappearance of reactant
= k  [RX]  [OH]

Where [RX] = CH3Br concentration

[OH-] = OH- concentration

k = A constant value

This is also called SN2 reaction – substitution nucleophilic

bimolecule.

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 SN2 reaction

This reaction occur with inversion of configuration

The reaction show second order kinetics with rate law:

Rate = k  [RX]  [Nu-]

The incoming nucleophile attacks the alkyl halide from

opposite direction of group that leaves.
As it come from one side and bond to the carbon, the
halide departs from the other side, thereby inverting the
stereochemical configuration. Example:
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 H3C H CH3 CH3
- H C -HO C Br - C H -
OH Br HO + Br
H3CH2C CH2CH3 CH2CH3

(S)-2-Bromobutane Transition state (R)-2-butanol

(partially formed (Stereochemistry at
C-OH& partially carbon is inverted)
broken C-Br bond)

The nucleophile approach from the backside of the reactant,

i.e. 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.
The SN2 reaction occurs in a single step involving both alkyl
halide and nucleophile.

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Steric effects in the SN2 reaction
•A hindered and bulky substrate would prevent easy approach
of the nucleophile, making bond formation difficult.
•Thus, this difficulty increases as the three substituents increase
in size.

CH3 CH3 CH3 H H

H2
H3C C Br H3C C C Br H3C C Br H3C C Br H C Br
CH3 CH3 H H H

Tertiary Neopentyl Secondary Primary Methyl

SN2 Reaction Reactivity Increase

Methyl halides are the most reactive substrates in SN2

reactions, followed by primary alkyl halides and the rest.
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 Nucleophile

Any species can act as a Nu if it has an unshared electron pair

(Lewis base)
If the nucleophile is negatively charged, the product is neutral.
If the nucleophile is neutral, the product is positively charged.
Neutral
- - -
Negatively charged Nu Nu + R Y R Nu + Y

Nu + R Y R Nu+ + Y-
Neutral Nu

Positively charged

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 Nucleophilicity is a measure of the affinity of Nu for a carbon
atom in the SN2 reaction.

SN2 reaction of bromoethane 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

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 The leaving group

In most SN2 reaction, the leaving group is expelled as a

negatively charge group.
The best leaving groups should be the weakest bases (anion
derived from the strongest acid).

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

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

Leaving group reactivity

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 The solvent

Protic solvents – those that contain –OH or –NH groups – are

worst solvents for SN2 reactions.
Polar aprotic solvents, which have strong dipoles but don’t
have –OH or –NH groups, are the best for SN2 reactions.

CH3CH2OH, H2O, DMSO, DMF, CH3CN

Solvent reactivity to SN2 reactions

Why?

N.B. DMSO = (CH3)2SO (dimethyl sulfoxide);

DMF = (CH3)2NCHO (dimethylformamide)
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 SN1 Reactions

In SN2 reactions, we have seen how the reactions being carried

out in an unhindered substrate, a negatively charged nucleophile
and a polar aprotic solvent.

The reaction of tertiary halide, such as (CH3)3CBr with H2O to

give 2-methyl-2-propanol, undergo by SN1 reaction.

SN1 reaction is substitution nucleophilic unimolecular reaction.

R Br + H2O R OH + HBr

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This is a first order kinetics and the rate depend only on the
alkyl halide concentration.

Rate = Rate of disappearance of alkyl halide

= k  [RX]

Where k = A constant value

[RX] = Concentration of alkyl halide

Many organic reactions occurs in many steps. One of the steps

is usually slower than the others and this is called rate
determining step.

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 H2O
CH3 CH3
C+
-
H3C C Br H3C + Br
CH3 CH3

Dissociation of alkyl halide in The intermediate carbocation

slow rate determining step to reacts with H2O in a fast step
give carbocation intermediate. to give protonated alcohol

H2O

CH3 CH3
H
H3C C O+
H3O+ + H3C C OH
H
CH3 CH3

Loss of proton from

intermediate then give
the alcohol product

In SN1 reaction, the leaving group dissociate first before the

nucleophile approaches. Two steps. 20
 Stereochemistry of SN1 reactions

This reaction occurs through the formation of carbocation.

Carbocations are planar, sp2-hybridized and achiral.
The symmetrical carbocation intermediate can react with
nucleophile equally well from either side.
This will lead to the formation of 50:50 mixture of
enantiomers – a racemic mixture. Example:

CH3 H3C CH3

H2O
Br C CH2CH3 H3CH2C C OH + HO C CH2CH3
CH2CH2CH3
Ethanol H3CH2CH2C CH2CH2CH3

50% 50%
(R)-3-Bromo-3-methylhexane (S)-3-Bromo-3-hexanol (R)-3-Bromo-3-hexanol

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 Characteristics of SN1 reactions
Substrate
The more stable the carbocation intermediate, the faster the SN1
reaction.
Thus the stability order of carbocation, 3o>2o>1o>-Me is still
valid.
To this list we must add the resonance stabilized allyl and benzyl
cations,
Benzylic means next to an aromatic ring.
H
H H CH 2+ H CH 3
H C H
H C+ H3C C+ C C+ H3C C+ H3C C+

H H H H CH 3 CH 3

Methyl Primary Allyl Benzyl Secondary Tertiary

Less stable Carbocation stability More stable

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 The leaving group
Good leaving groups (more stable anions) increase the reaction
rate by lowering the energy level of the transition state leading
to carbocation formation.
The same reactivity order as in SN2 also applies here.

OH-, NH-2, OR-, F-, Cl-, Br-, I-

Less reactive Leaving group reactivity More reactive

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The nucleophile
The nucleophile does not affect the reaction rate.
Reaction works well under neutral and acidic conditions.

The solvent
Solvent has effect on SN1 reaction.
This is due largely to stabilization and destabilization of the
transition state.
Polar solvents stabilize the carbocation intermediate by
solvation, thereby increases the reaction rate.

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 Reactions of alkyl halides

Grignard reagents formation

RX reacts with magnesium metal in ether or THF to yield RMgX
(alkylmagnesium 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

Br MgBr
Mg, Ether ROH
CH3CH2CH2CHCH3 CH3CH2CH2CHCH3 CH3CH2CH2CH2CH3

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 Organometallic coupling reaction

RX react with lithium metal to give alkyllithium reagent

which can further be reacted with copper(I) iodide to give
diorganocopper compound, LiR2Cu.
This will undergo coupling with another RX to give alkane
Li CuI -
CH3CH2Br CH3CH2Li (CH3CH2)2Cu Li+ + LiBr
Pentane Ether, 0oC
CH3CH2CH2CH2CH2Br

CH3CH2CH2CH2CH2 CH2CH3 + LiI + CH3Cu

I - CH 2CH 3
(CH3CH2)2Cu Li+
+ CH3CH2Cu + LiI

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 Reactions of Alcohol
• Dehydration to alkene
• Oxidation to aldehyde, ketone
• Substitution to form alkyl halide
• Reduction to alkane
• Esterification
• Tosylation
• Williamson synthesis of ether

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Summary Table

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 Reactions of alcohols: Conversion of alcohols to alkyl
halides

Tertiary alcohols are readily converted to alkyl halide by using HCl

or HBr at 0oC (SN1).

H
+O H CH3 H3C Cl
H3C O H H3C -
+ Cl
H Cl

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Primary and secondary alcohols can only be converted by using
SOCl2 or PBr3 (SN2).

O
SOCl2 SN2
HCl + RH2C O S Cl - RCH2Cl + SO2 + HCl
Cl
RCH2OH
PBr3 SN2
HBr + RH2C O PBr2 RCH2Br + HOPBr2
-
Br
 AMINES

Amines are organic derivatives of ammonia, NH3.

Amines contain nitrogen atom(s) with lone pair electrons,
thus making it basic and nucleophiles
Amines occur widely in plants and animals. Example

H
CH 3
N N
H3C CH 3 CH 3
N

Trimethylamine Nicotine (found in tobacco)

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Preparation of amine
Alkylation of ammonia or alkylamine with alkyl halide.
Depending on amines used, this will yield primary, secondary or tertiary
amines.
Ammonia and alkyl amines are good nucleophile in SN2 reaction.

SN2 reaction - NaOH

Ammonia NH3 + R X RNH3+ X RNH2 Primary

- Secondary
Primary RHN2 + R X R2NH2+ X R2NH

-
Secondary R2NH + R X R3NH+ X R3 N Tertiary

Tertiary - Quaternary ammonium salt

R3N + R X R4N+ X

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 However, these reactions don’t stop cleanly after single
alkylation has occurred.
The monoalkylated product often undergoes further reaction to
yield mixture of products. Example:

CH3(CH2)4CH2Br + NH3 CH3(CH2)4CH2NH2 + [CH3(CH2)4CH2]2NH

+ [CH3(CH2)4CH2]3N

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 Reactions of alkynes
Formation of acetylide anions and its alkylation
• Terminal alkynes are relatively acidic (pKa= 25) compared to terminal alkenes (pKa=44)
• Reacts with strong bases (eg NH2-) to form acetylide anions ( a nucleophile)
• The acetylide anions can react with primary alkyl bromides or alkyl iodides to form a new alkyne
• Best method to prepare a substituted alkyne from a simpler precursor

NaNH2 RCH2Br
HC CH HC C Na HC CCH2R
acetylene a terminal alkyne
NaNH2 RCH2Br
RC CH RC C Na RC CCH2R
a terminal alkyne an internal alkyne

i) NaNH2, NH3
CH3CH2CH2CH2C CH CH3CH2CH2CH2C CCH2CH2CH2CH3
ii) CH3(CH2)3Br, THF
 Williamson Ether Synthesis
• Alkoxide ion + 1 alkyl bromide (or tosylate)
• Example:
CH3 CH3

H3C OH + NaH H3C O

CH3 CH3

CH3 H CH3 H
SN 2
H3C O H3CH2C C Br H3C O C CH2CH3

CH3 H CH3 H

Overall:
NaH, CH3CH2CH2Br
(CH3)3COH (CH3)3COCH2CH2CH3
THF 35