The document discusses different types of substitution reactions including nucleophilic substitution, electrophilic substitution, and free radical substitution. It provides details on the mechanisms, kinetics, stereochemistry and factors affecting the rate of nucleophilic substitution reactions SN1 and SN2. SN1 follows a unimolecular mechanism involving a carbocation intermediate while SN2 follows a bimolecular mechanism with a single concerted transition state. The document also discusses electrophilic aromatic substitution reactions and addition and elimination reactions of alkenes and alkynes.

1. Substitution Reactions
Nucleophilic Substitution
Electrophilic Substitution
Free radical Substitution

2. Nucleophilic Substitution Reaction
nucleophilic
substitution
Nucleophile
++ C NuC XNu
-
X-
leaving
group
C-L bond cleaved C-Nu bond formed

3. Types of Nucleophilic Substitution
SN1 : substitution nucleophilic unimolecular
SN2 : substitution nucleophilic bimolecular
SNi : substitution nucleophilic intramolecular
Points to be discussed for SN1 and SN2
Definition with examples
 Mechanism
Kinetics
Stereochemistry
Factors influencing the reaction rate

4. SN2 : Bimolecular nucleophilic
substitution
Examples

5. Mechanism
The nucleophile and the alkyl halide combine to form a
pentacoordinate transition state. This is the slow rate
determining step (r.d.s); it entails two species, R-X and
Nu . The dotted lines indicate partially formed orӨ
partially broken covalent bonds.
C Br
H
H
H
HO + C
H
H H
HO Br
δ- δ-
Transition state with
simultaneous bond breaking
and bond forming
C
H
H
H
HO + Br
-

6. Kinetics
 The reaction involves a transition state in which
both reactants R-X and OH-
are together
 Rate = k[RX][OH]
 The study of rates of reactions is called kinetics
 The rate is dependent of the concentration of
two species, i.e. the alkyl halide and NaOH.

7.  The transition state of an SN2 reaction has a planar arrangement of
the carbon atom and the remaining three groups
 Occurs with inversion of chiral center called Walden Inversion.
Stereochemistry
Tetrahedral Planar Transition state

8. SN1 : Unimolecular nucleophilic substitution
Example
Solvolysis of tert-butyl bromide to give tertiary butyl alcohol.
Mechanism
Step 1: the leaving group dissociates to form a
carbocation
C
CH3
CH3H3 C
+C
H3C
H3 C
Br
H3 C
slow, rate
determining
A carbocation intermediate;
carbon is trigonal planar
+ Br

9. Step 2: reaction of the carbocation (an electrophile) with water (a
nucleophile) gives an oxonium ion
Step 3: proton transfer completes the reaction
CH3 O
H H3 C
C
CH3
CH3
OCH3
H
C
CH3
CH3
CH3
O
H3 C
H
H3 C
H3 C
C
H3 C
O
CH3
H
fast
++ ++
+
++
+ fastC
H3 C
H3C
O
H3 C
O
CH3
H
OHO
CH3CH3
H
H
CH3
H3C
C
H3 C
H3C
HH
H
H
H
H H
H

10. Kinetics
 First order
 Rate-determining step is formation of carbocation
Rate = k [RX]
 Depends only on the concentration of the substrate
SN2SN1

11. Stereochemistry
Proceed with partial recemisation and some inversion
Recemisation : the nucleophile can attack from either face of the
planar carbocation intermediate
(R)-Enantiomer Planar carbocation
(achiral)
C
H
Cl
C6 H5
Cl
C+
C6 H5
H
Cl
CH3 OH-Cl
-
-H
+
+
A racemic mixture
Cl
C6H5 C6H5
C OCH3
H
CH3 O C
H
Cl
(R)-Enantiomer(S)-Enantiomer
Frequent complication: the Leaving Group will tend to block approach of the
nucleophile leading to more inversion than retention for the SN1

12. SN1 in reality: Formation of ion pair

13. Factors influencing the rate of the reaction
 Effect of Substituent
 Nature of the nucleophile
 Nature of the leaving group
 Solvent effect
Effect of substituents on SN reaction
 governed by electronic factors namely the relative stabilities of
carbocation intermediates
 relative rates: 3° > 2° > 1° > methyl
SN1 reactions

14. SN2 reactions
 governed by steric factors namely the relative ease of approach
of the nucleophile to the site of reaction
 relative rates: methyl > 1° > 2° > 3°
 The SN2 reaction is fastest with unhindered halides.

15. Nucleophile
 Nucleophile is a neutral or negatively charged Lewis base.
 Anions are usually more reactive than neutrals
 More basic nucleophiles react faster
 Better nucleophiles are lower in a column of the periodic
table
Order of nucleophilicity
NH2
-
> RO-
>OH-
>RNH-
> ArO-
>NH3
-
> pyridine > F-
>H2O
I-
>Br-
> Cl-
> F-
(in polar protic solvents)
F-
> Cl-
> Br-
> I-
( aprotic solvents)

16. Leaving group
 Stable anions that are weak bases are usually excellent
leaving groups and can delocalize charge

17. Protic solvent: a solvent that can form hydrogen bond (-OH, -NH)
 these solvents favor SN1 reactions; the greater the polarity of the
solvent, the easier it is to form carbocations in it
Aprotic solvent: does not contain an -OH group
 it is more difficult to form carbocations in aprotic solvents
 aprotic solvents favor SN2 reactions
Solvent effect

18. Solvent effect
Solvents that can donate hydrogen bonds (-OH or –NH)
slow SN2 reactions by associating with reactants
Energy is required to break interactions between reactant
and solvent
Polar aprotic solvents (NH, OH, SH) form weaker
interactions with substrate and permit faster reaction

19. Electrophilic Substitution
Chemical reactions in which an electrophile displaces a group in a
compound.
Electrophilic aromatic substitution
Electrophilic aliphatic substitution
R-X + E
+
R-E + X
+
electrophile displaces a functional group in aliphatic compounds
Mechanism
Substitution electrophilic unimolecular (SE1)
Step-1
R X R X+
Step-2 R YR Y+
Slow

20. Substitution electrophilic bimolecular (SE2)
C X
Y
C Y X+
SE2 (back)
Inversionof configuration
C X Y C
Y
X+
SE2 (front) Retention of configuration
Substitution electrophilic internal (SEi)
When the electrophile attacks from the front and a portion of it assists in the
removal of leaving group
C X Y C
Y
X+
SEi Retention of configuration
Z
Z

21. Nitrosation
 Secondary amines and mono-N-substituted amides (RCONHR’) undergo
N-nitrosation when treated with nitrous acid
 Nucleophiles Cl-
, SCN-
and thiourea catalyze the reaction
Aliphatic diazonium coupling
 Compounds containing active hydrogen (acidic C-H bond) couple with
diazonium salts in presence of base
Z-CH2-Z’ + ArN2
Z C
Z'
NHAr+
Z, Z’ = electron withdrawing groups such as NO2, CN, COOR, SO2R, COR
 Reaction proceeds through SE1 mechanism
R2N-NOR2NH + HONO

22. Electrophilic aromatic substitution
 Atom appended to the aromatic ring, usually hydrogen, is replaced by
an electrophile
Mechanism: Arenium Ion
E
H
:A-
E
H A+
Step-1
Step-2
slowE A
E
H
E
H
E
H
Arenium ions
The proton is removed by any of the bases

23. X2
,
FeX3
(x = Cl, Br)
X
HX
R
C
R
O
SO3H
NO2
HONO2
H2SO4
SO3
H2SO4
RCl, AlCl3
(R can rearrange)
RC Cl, AlCl3
O
H2O
HCl
HCl
+
+
+
+
Halogination
Nitration
sulfonation
Friedel-Crafts alkylation
Friedel-Crafts acylation

24. Substituent groups on a benzene ring affect electrophilic aromatic
substitution reactions in two ways:
1) Reactivity
activate (faster than benzene)
or deactivate (slower than benzene)
2) Orientation
ortho and para- direction
or meta-direction

25. -NH2, -NHR, -NR2
-OH
-OR
-NHCOCH3
-C6H5
-R
-H
-X
-CHO, -COR
-SO3H
-COOH, -COOR
-CN
-NR3
+
-NO2
increasingreactivity
ortho/para directors
meta directors

26. If there is more than one group on the benzene ring:
The group that is more activating (higher on “the list”) will direct the next
substitution.
Little or no substitution between groups that are meta- to each other.
CH3
OH
NHCOCH3
CH3
CHO
OCH3
Br2, Fe
HNO3, H2SO4
Cl2, Fe
CH3
OH
Br
NHCOCH3
CH3
NO2
CHO
OCH3
Cl
CHO
OCH3
Cl
+

27. Free Radical Substitution Reaction
Alkanes undergo substitution reactions with halogens such as fluorine,
bromine and chlorine in the presence of heat or light.
X=F, Cl, Br, I
CH4 + X2 CH3X + HX
hν
or heat
 Radical halogenation can yield a mixture of halogenated compounds
because all hydrogen atoms in an alkane are capable of substitution
Monosubstitution can be achieved by using a large excess of the alkane
 Bromine is less reactive but more selective than chlorine

28. The reaction mechanism has three distinct steps
Mechanism
Initiation
Propagation
Involves the production of free radicals in presence of light or heat
Involves the reaction of free radicals with molecules to produce free radicals
 A single chlorine radical can lead to thousands of chain propagation cycles

29. Termination
Involves the reaction of free radicals to produce a molecule
 Occasionally the reactive radical intermediates are quenched by reaction
pathways that do not generate new radicals
 The reaction of chlorine with methane requires constant irradiation to replace
radicals quenched in chain-terminating steps

30. 30
• Halogenation at an allylic carbon often results in a mixture of
products. Consider the following example:
• A mixture results because the reaction proceeds by way of a
resonance stabilized radical.
Radical Reactions
Radical Halogenation at an Allylic Carbon:

31. Reactivity

32. Stereochemistry
The alkyl radical having planar structure is attacked from both faces with
equal ease to form racemic mixture

33. Electrophilic Addition Reactions
Unsaturated hydrocarbon: contains one or more carbon-carbon
double or triple bonds undergo electrophilic addition reactions
The π electrons are less tightly held and acts as a source of electrons
(nucleophile).It reacts with electron deficient compounds (electrophile)
forming addition product

34. Addition reactions are exothermic (two stronger σ bonds formed in
expanse of one π bond)
Kinetics
Second order
Rate = [alkene] [E-Nu]

35. Stereochemistry
Two modes of addition is possible
Anti addition: E+
and Nu-
added from
same side
Syn addition: E+
and Nu-
added from
same side
Carbocations are planar -> attack from both sides possible!!

36. Bromination of alkene
Mechanism

37. CH3-CH=CH2 + HCl
CH3-CH=CH-CH3 + HCl CH3-CH-CH2-CH3
ClSymmetrical Symmetrical
Unsymmetrical
CH3-CH=CH2 + Br2 CH3-CH-CH2-Br
BrSymmetrical
only one possible product
CH3-CH2-CH2-Cl
Cl
CH3-CH-CH3
+
Two possible product
Markovnikov product
Markovnikov’S Rule:
In the ionic additions of an unsymmetrical reagent to a double bond,
the positive portion of the adding reagent attaches itself to a carbon
atom of the double bond so as to yield the MORE STABLE
CARBOCATION as an INTERMEDIATE
UnsymmetricalUnsymmetrical

38. H
H3C
H
H
H Cl
H
H3C
H
H
H
H
H3C
H
H
H Cl
H
H3C
H
H
Cl
H3C
H
H
H
Cl
HH
fabourable secondary carbocation
unstable primary carbocation
Markovnikov product
Addition is regioselective (regioselective reaction: a reaction in which
one direction of bond-forming or bond-breaking occurs in preference
to all other directions

39. Another example
Addition of HBr
Peroxide
(-O-O-)
Markovnikov product
Anti-Markovnikov product

40. In absence of peroxide (ionic mechanism)
Markovnikov product
In presence of peroxide (free radical mechanism)
Radical addition leads to the formation of the more stable radical, which
reacts with HBr to give product and a new bromo radical.
Anti-Markovnikov product

41. Carbocation rearrangement
favourable tertiary carbocation

42. Alkenes –Addition of halogens in water under basic conditions -> Epoxides
Alkenes –Addition of halogens in water -> Halo alcohol (halohydrin)
Alkenes –Addition of BH3 followed by oxidation-> Anti-Markovinkov addition of water

43. Alkynes –Addition of halides
HR
2HBr
H
H
H
Br
Br
R

44. Elimination Reactions
Nucleophilic substitution reaction there must be the possibility of
competing elimination reactions
The nucleophiles can attack the electrophilic site to give the
substitution product or they can act as bases giving the elimination
Elimination
Substitution

45. Substrate compound must have nucleophilic group as leaving group
Common leaving groups
X (Br, Cl, F), OH, OR, N3, N2
+
, OTs, NR3
+
, H2O+
, SR2
+
Elimination usually produce a new π-bond in the modified substrate
CH3-CH-CH2-L CH3-CH=CH2 + H+
+ L-
H
Leaving group
In some elimination a new sigma bond is produced instead of π-bond
Br
H
B
BH Br+ +
New σ-bond
π-bond in the product

46. Elimination reaction
 E1 (Elimination unimolecular) Reactions – one molecule (the substrate) in r.d.s.
 E2 (Elimination Bimolecular) Reactions -two molecules (the substrate and
base/nucleophile) in r.d.s.

47. E1 Mechanism
The first step of E1 and SN1 mechanisms is identical

48. Kinetics
First order
Rate = k [R-X]
Rate: R3CX > R2CHX > RCH2X
 More substituted halides react fastest
 Favored by weaker bases such as H2O and ROH
 Polar protic solvents that solvate the ionic intermediate
favours the E1 mechanism

49. Major product is according to Saytzeff rule
Thy hydrogen is removed from the β-carbon bonded to the lowest hydrogens
Two elimination productIntermediate carbocation
70%
30%
+
Thermodynamically stable product
Generally, the more substituted the alkene, the more stable it is.

50. Hofmann Elimination product (Less substituted alkene)
 When the base is bulky
 Steric hindrance at β-carbon
 When the leaving group is a pore leaving group such as F, NR3
+
and SR2
+
 When the alkyl halide contains one more double bonds
H3C C
CH3
CH3
H2
C
CH3
Br
CH3 CH3O H3C C
CH3
CH3
C
H
C
CH3
CH3
H3C
CH3
CH3
H2
C C
CH3
CH2+ +
12% 88%
Crowding at β-carbon
+
H2
C
H
C CH
CH3
CH3
Br
C
H
C
H
CH
CH3
CH3
H2
C C
H
C
CH3
CH
3
major product minor product
Poor leaving group
Contains one or more double bonds
CH3O+ +
30%70%
H3C
H2
C C
H
CH3
F
H3C
H2
C C
H
CH2 H3C C
H
C
H
CH3
H3C C
CH3
Br
H2
C CH3 +
20%80%
H3C C
CH3
Br
O H2C C
CH3
H2
C CH3 + H3C C
CH3
C
H
CH3
Bulky base

51. Elimination products: Hofmann VS. Saytzeff
Bulky bases increase the proportion of the less substituted alkene
(Hofmann product)
Bulky base (tertiary alkoxide)
The H’s on the less substituted β carbon are more sterically accessible to the
base than the H’s on the more substituted β carbon

52. Substitution versus elimination: SN1 Vs E1
C
H3C
H3C
H3C
Br slow
H2O, EtOH CH3
C
H3C C
H
H H
Br+
O
HH
CH3
C
H3C C
H
H H
O
H H
kelim
ksub
CH3
C
H3C C
H
H
H3O
C O
H3C
H3C
H3C
H
H H2O C O
H3C
H3C
H3C
H
64% SN1 product
37% E1 product
H3O
+
+
Step-1
Step-2
As E1 reaction involves the formation of carbocation intermediate,
rearrangement of the carbon skeleton can occur before the proton lost.

53. E2 Mechanism
Kinetics
Second order
Rate = k [R-X] [base]
R3CX > R2CHX > RCH2X
 Favored by strong base
 Favored by Polar aprotic solvent
Relative reactivities of alky halide in an E2 reaction

54. Stereochemistry of the E2 reaction
The leaving group and the H atom can be syn or anti to each other
Syn-elimination (substituents removed from same side)
Anti-elimination (substituents removed from opposite side)
Favored in E2 reaction

55. H3C
C
CH3
H3C
Br
H3CH2C O
H3C
C
CH2
CH3
100%
CH3CH2Br
H3CH2C O
H3CH2C O CH2CH3 99%
Substitution versus elimination: SN2 Vs E2
Because many good nucleophiles are also good bases, SN2 often competes
with E2 for those substrates that are good for SN2
H3C
C
CH3
H
Br H3CH2C O
H3C
C
CH3
H
OCH2CH3
H3C
C
CH2
H
21%
79%
substitution product elimination product
To promote E2 over SN2 we want to use strong bases that or non-nucleophilic.
elimination product
substitution product