CHAPTER 6

NUCLEOPHILIC SUBSTITUTION
AT SATURATED CARBON
✓Recognize and explain nucleophilic substitution of
alkyl halides and alcohols
✓Recognize and explain amines, carboxylate, and
acetylide ions as nucleophiles
✓Predict carbocation stability and rearrangement
products
✓Illustrate the different reactions and mechanisms
using examples

2
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.

3
 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 CH3

Termination steps
. . Cl CH3
Cl + CH3

. .
Cl + Cl Cl Cl

Overall reaction CH4 + Cl2 CH3Cl + HCl

4
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 + CH3CH2CHCH 3

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. 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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Substitution reaction
Substitution of the X group by a nucleophile (Nu-) or
Elimination reaction of HX to yield an alkene.

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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 CH3 + 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.
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Example:

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.

Methyl halides are the most reactive substrates in S N2 reactions, followed by

primary alkyl halides and the rest. 12
 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 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

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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

DMSO = (CH3)2SO (dimethyl sulfoxide);

Solvent reactivity to SN2 reactions DMF = (CH3)2NCHO (dimethylformamide)

Protic solvent can H-bond to nucleophile, thus hinders

the nucleophile from attacking the substrate.

Nucleophile are less nucleophilic in protic solvents.

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17
 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
H3C C Br H3C C+
-
+ 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 CH2+ H CH3
H C H
H C+ H3C C+ C C+ H3C C+ H3C C+

H H H H CH3 CH3

Methyl Primary Allyl Benzyl Secondary Tertiary

Less stable Carbocation stability More stable 22

Resonance stabilization
 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 (water, methanol) stabilize the carbocation
intermediate by solvation, thereby increases the reaction
rate.

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26
27
 Alkyl Halides and
Nucleophilic Substitution

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Nucleophilic Substitution and Organic Synthesis.

• To carry out the synthesis of a particular compound, we must think backwards, and ask
ourselves the question: What starting material and reagents are needed to make it?
• If we are using nucleophilic substitution, we must determine what alkyl halide and what
nucleophile can be used to form a specific product.

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• To determine the two components needed for synthesis,
remember that the carbon atoms come from the organic
starting material, in this case, a 1° alkyl halide. The
functional group comes from the nucleophile, HO¯ in this
case. With these two components, we can “fill in the boxes”
to complete the synthesis.

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 Other reaction 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

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❑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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33
 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

• 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 SN 2
HBr + RH2C O PBr2 RCH2Br + HOPBr2
-
Br
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Mechanism of the reactions:
 Preparation of ethers : Williamson ether synthesis
• Lacking of O-H group, ether undergo few chemical reactions than alcohol
• Reaction is most successful using methyl halides and primary alkyl halides
• Alkoxide ion + 1 alkyl bromide
• Example:

CH3 CH3

H3C OH + NaH H3C O

CH3 CH3

Overall:
N aH , C H 3C H 2C H 2B r
(C H 3)3C O H (C H 3)3C O C H 2C H 2C H 3
THF
 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
CH3
N
N
H3C CH3 CH3
N

Trimethylamine Nicotine (found in tobacco)

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 Basicity of amines

• The chemistry of amines is dominated by the lone pair of

electrons on nitrogen atom. Hence they are both basic and
nucleophilic.
• Amines are stronger bases than alcohols, ethers or water.
• They reacts with acid to form acid-base salts and also react
with electrophiles in polar reactions.

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• When dissolved in water, an equilibrium is established in which water acts as an acid
and transfer a proton to amine.
• The most convenient way to measure basicity of an amine (RNH2) is to look at the
acidity of the corresponding ammonium ion (RNH3+).

RNH3+
+ H2O RNH2 + H3O+
Weaker base: Smaller pKa for ammonium ion
Stronger base: Larger pKa for ammonium ion

Amine pKa of ammonium ion

NH3 9.26
CH3CH2NH2 10.64
(CH3CH2)2NH 10.98
(CH3CH2)3N 10.76
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Preparation of amines

1. Reduction of nitriles, amides and nitro compounds

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2. 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 S N2 reaction.

S N 2 reaction - NaOH
Ammonia NH 3 + R X RNH 3 + X RNH 2 Primary

- Secondary
Primary RH 2 N + R X R 2 NH 2 + X R 2 NH

-
Secondary R 2 NH + R X R 3 NH + X R 3N Tertiary

Tertiary - Quaternary ammonium salt

R3N + R X R 4 N+ X

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

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 Substitution reaction using acetylide ions as
nucleophiles

• Deprotonate alkynes (acetylide ions) - excellent nucleophiles and can be combine with various
electrophiles.

• One of the simplest and yet most powerful reactions in terms of generating a diverse array of functional
groups is the SN2 reaction - nucleophile attacks a carbon with a good leaving group (alkyl halides).
• The “big barrier” to the SN2 is steric hindrance so the reaction works particularly well for methyl and
primary alkyl halides.
 Substitution reaction using carboxylate
ions as nucleophiles
Conversion of Carboxylic Acids into Esters by Alkylation

Carboxylic acids can be easily converted into their conjugate bases through deprotonation with a base,
such as sodium hydroxide. The resulting carboxylate can be alkylated using by an SN2 reaction with
either a methyl or primary halide. If a methyl ester is required, methyl iodide (CH3I) is a commonly used
reagent.
SUMMARY INVOLVING SUBSTITUTION REACTION WITH DIFFERENT
NUCLEOPHILES