1. Reactions
Ionic reactions: Radical reactions:
Bond breaking and bond Bond breaking and bond making
making take place in a take place in a
heterolytic fashion homolytic fashion
-
R X R+ + X R X R. + X.

2. Ionic Reactions :
1) substitution :
Y + R X R Y + X
R = aliphatic as well as aromatic
2) elimination :
3) addition :
R1
R1 X H R1 XH
X + Y
R2 Y R2 Y
R2
X = O , NH

3. Nucleophilic Substitution

5. Nucleophilic Substitution
Y + R X R Y + X
R = aliphatic as well as aromatic
Nucleophile + Substrate Product + Leaving group

6. Nucleophilic Substitution
S N1 S N2
S: Substitution S: Substitution
N: Nucleophilic N: Nucleophilic
1: unimolecular 2: Bimolecular
leaving group goes first and nucleophile comes later
Y + C X C+ C Y + X
nucleophile attacks and leaving group goes simultaneously
Y + C X C Y + X

7. SN2
 reaction and mechanism
 kinetics
 stereochemistry
 substrate structure
 nucleophiles
 leaving groups
 solvents

8. SN2 reaction and mechanism

9. Synthetic Utility of the SN2 Reaction
A variety of functional groups can be prepared employing a good
nucleophile and an electrophile with a good leaving group:
9

11. SN2 reaction : Kinetics

12. The Rate Law of an SN2 Reaction
Obtained experimentally:
Rate law includes both
the alkyl halide and the
nucleophile, a second-
order process
12

13. SN2 reaction : Stereochemistry

14. SN2 MECHANISM
nucleophilic attack
R (R)-config
..
H O: ..
.. C : Br :
..
CH3
R
attacks H
back lobe
..
H O:
.. C
INVERSION CH3
(S)-config
H

15. Stereochemistry of SN2
Walden inversion
=>

17. THE INVERSION sp2
R 2p
HO C B
PROCESS
partial bonding
HO C Br
activated complex
CH3 H is trigonal planar (sp2 )
configuration
.. R sp3
is inverted
H O:
.. R
sp3
C : Br
Ea HO : C
CH3
H CH3
(R)-configuration
H
(S)-configuration

18. SN2 reaction : substrate
structure

19.  Less bulky
 Should stabilize the
transition state

20. SN2 Reaction: substrate structure
KI in Acetone at 25°
krel
CH3 Br 150
CH3 CH2 Br 1
CH3 CH Br 0.008
CH3
CH3
unreactive!
CH3 C Br
CH3

22. Relative rates of SN2 reactions of alkyl chlorides with the iodide ion
The rates are
given with
respect to
Alkyl chloride relative rate n-BuCl
Me Cl 200
0.02
Cl
Me 920
O Cl
O
Cl
1,00,000

23. O O
Nu- only SN2, no SN1
Hal Nu
R R
R = alkyl, aryl, OR'
Relative rates of SN2 reactions with iodide ion
O
Cl 1:500
Me Cl
C=O group stabilizes the T.S. by
Overlap of its π* orbital with full
P-orbital of the C-atom under attack
σ * of of the C-Cl +
+
π* of the C=O Cl π* of Cl
H the C=O H
H H
Nu Nu

24. SN2 reaction : Effect of Nucleophile

25.  The nucleophilicity may be
correlated with the availability of
the electron pairs and the ease with
which it is donated

26. Trends in Nuc. Strength
 Increases down Periodic Table, as
size and polarizability increase:
I- > Br- > Cl- >F-
 Of a conjugate acid-base pair, the
base is stronger:
OH- > H2O, NH2- > NH3

27. Polarizability and nucleophilicity - increased
polarizability makes for a better nucleophile
I- > Br- > Cl- >F-

28. Effect of Nucleophile :
The nucleophilicity may be correlated to its basicity as both involve the
availability of the electron pairs and the ease with which it is donated
rapid
CH3O + H3C I CH3OCH3 + I
very
CH3OH + H3C I
CH3OCH3 + HI
slow
Nucleophilicity of CH3O
> A negatively charged nucleophile is
CH3OH always stronger than its conjugate acid.
Stronger base weaker base
better nucleophile poorer nucleophile
HO > H2O
CH3O > CH3OH
H2N > NH3
The direct relationship between basicity and nucleophilicity
is maintained if the reaction occurs in the gas phase

29. SN2: Nucleophilic Strength
 Stronger nucleophiles react faster.
 Strong bases are strong nucleophiles, but
not all strong nucleophiles are basic.
=>

30. SN2 reaction : Effect of leaving group

31. •A good leaving group needs to be a
Stable anions that are weak bases
which can delocalize charge
31

32. The Leaving Group

33. Sulfonate Leaving Groups
O
R O S CH3 R OTs
O
para-Toluenesulfonate Tosylate
O
R O S Br R OBs
O
para-Bromobenzenesulfonate Brosylate

34. SN2 reaction : Effect of Solvent

35.  Solvent
Polar Solvent
nonpolar Solvent
Polar protic Solvent Polar aprotic Solvent
SN2 reaction prefers polar aprotic
solvent

36. Solvent Effects (1)
Polar protic solvents (O-H or N-H) reduce
the strength of the nucleophile.
Hydrogen bonds must be broken before
nucleophile can attack the carbon.
=>

37. Solvent Effects (2)
 Polar aprotic solvents (no O-H or N-H) do
not form hydrogen bonds with nucleophile
 Examples:
O
CH3 C N O
C CH3
acetonitrile H N C
CH3 H3C CH3 =>
dimethylformamide acetone
(DMF)

38. Marked effect on the rate of S N 2 reaction, when that transferred from
polar protic solvent to polar aprotic solvent.
solvent
Me I + N3-Na+ Me N3 + NaI
Rate in MeOH (ε = 33) 1
DMF (ε = 37) 4.5X104 DMF: HCONMe2
DMSO (ε = 46) 1X109 DMSO: Me2SO
• In MeOH both Na + and N 3 - are solvated.
• In DMF only Na + is solvated, but not N 3 -.
• So, unsolvated N 3 - is a much more powerful
nucleophile

39. SN1
 reaction and mechanism
 kinetics
 stereochemistry
 substrate structure
 nucleophiles
 leaving groups
 solvents

40. SN1: reaction and mechanism

41. Solvolysis of tert-Butyl Bromide
CH3 CH3
acetone
CH3 C CH3 + H2O CH3 C CH3 + H Br
Br OH
+ other products

42. SN1: Mechanism
carbocation
1935: Hughes & Ingold

43. SN1 reaction : Kinetics

44. SN1 Reaction: kinetics
 Thereactions follows first
order (unimolecular) kinetics
 Rate = k [R-Br]1

45. Reaction profile for SN1 reaction
slow fast
R LG LG + R R Nu
Nu
Rate = K[R-LG]

46. SN1 reaction : Stereochemistry

47. S N 1: Hydrolysis of t -butyl chloride by base proceed according
to
Rate = k 1 [ t -BuCl] or independent of [OH - ]
Me
HO Me
fast
Me
Me Me -
slow OH
Me Cl +
fast
Me Me - Me
Me OH
3 2 Me OH
sp sp Me
1. Halide undergoes slow ionization to yield the ion pair R + and Cl -
followed by first attack by – OH or solvent or nuleophile.
2. The energy necessary to effect the initial ionization is largely
recovered from the energy evolved through solvation of the
resultant ion-pair.

50. SN1 reaction : substrate
structure

51.  Stability of carbocation

52. CH3
CH3 C Br > CH3 CH Br > CH3-CH2-Br > CH3-Br
CH3
CH3
tertiary secondary primary
CH3
+ + +
CH3 CH CH3 CH 2 CH3
CH3 C+
CH3
CH3
tertiary secondary primary very unstable
carbocation carbocation carboc
carbocation carbocation
(very stable) (unstable)
three methyl two methyl one methyl no methyl
groups groups group groups

53. SN1 Reaction: substrate
structure
krel
CH3 Br no reaction
CH3 CH2 Br 1.00
CH3 CH Br
11.6
CH3
CH3
6
CH3 C Br
1.2 x 10
CH3
Solvolysis in water at 50°C

54. SN1 reaction : Effect of Nucleophile

55. Nucleophiles in SN1
 Since nucleophilic addition occurs after
formation of carbocation, reaction rate is
not normally affected by nature or
concentration of nucleophile (weak
nucleophile)

56. A protic solvent acts as both a
solvent and nucleophile in S N 1
reactions - solvolysis:
Water O
H H
abbreviations
O HOMe
Methanol H CH3
Ethanol O CH3 HOEt
H CH2
Acetic acid O HOAc
H C CH3
O
Formic acid O
H C H
O

57. SN1 reaction : Effect of leaving group

58. Leaving groups
 Leaving groups are the same as in S N2
reactions:

59. SN1 reaction : Effect of Solvent

60. Solvent effect
Increase in dielectric constant and/or ion-solvating
ability result in a marked increase in reaction rate
Dielectric constant (ε, at 25 C): H2O 79
EtOH 25

61.  Polar protic solvents favoring the SN1 reaction since it stabilizes
carbocation of the transition state
 Protic solvents disfavor the SN2 reaction by stabilizing the ground
state
Transfer from polar, protic to polar, aprotic solvents
can change the reaction mode from SN1  SN2

62. Things to remember

63. SN2 or SN1?
 Primary or methyl  Tertiary
 Strong nucleophile  Weak nucleophile
 Polar aprotic (may also be solvent)
solvent  Polar protic solvent,
 Rate = k [halide] silver salts
[Nuc]  Rate = k [halide]
 Inversion  Racemization
 No rearrangements  Rearranged products
=>

64.  Competition reaction in SN1

65. Rearrangements
 Carbocations can rearrange to form a
more stable carbocation.
 Hydride shift: H- on adjacent carbon bonds
with C+.
 Methyl shift: CH3- moves from adjacent
carbon if no H’s are available.
=>

66. Hydride Shift
Br H H
CH3 C C CH3 CH3 C C CH3
H CH3 H CH3
H H
CH3 C C CH3 CH3 C C CH3
H CH3 H CH3
H H Nuc
CH3 C C CH3 Nuc
CH3 C C CH3
=>
H CH3 H CH3

67. Methyl Shift
Br CH3 CH3
CH3 C C CH3 CH3 C C CH3
H CH3 H CH3
CH3 CH3
CH3 C C CH3 CH3 C C CH3
H CH3 H CH3
CH3 CH3 Nuc
Nuc
CH3 C C CH3 CH3 C C CH3 =>
H CH3 H CH3

68. Important substrates……..

69. Allylic and Benzylic compounds

70. Allylic and Benzylic compounds
Allylic and benzylic compounds are especially reactive in
SN1 reactions.
Even though they are primary substrates, they are more
reactive most other halides! They form resonance
stabilized carbocations.
CH2-Br CH2=CH-CH2-Br
benzyl bromide allyl bromide

71. +
+
CH2 CH2 etc
+
+
CH2 CH2 etc

72. Allylic and Benzylic compounds
Allylic and benzylic compounds are especially reactive in
SN2 reactions.
They are more reactive than typical primary compounds!
CH2-Br CH2=CH-CH2-Br
benzyl bromide allyl bromide

73. For S N 2: stabilisation of TS by conjugation with allylic π-bond
+ δ(-) +
+
δ(-) +
Br
Nu Nu
H
H
Br H
H Nu
Br δ(-) Nu δ(-)
T.S. T.S.

74. BENZYL ( GOOD FOR SN1 )
IS ALSO A GOOD SN2 SUBSTRATE
primary, but faster
than other primary
CH2 Br + NaI CH2 I + NaBr
I overlap in
the activated
H complex
lowers the
activation
energy
H
Br
critical
overlap

75. Vinyl and aryl halides

76. Vinyl and aryl halides do not undergo SN1 because:
76

77. Vinyl and aryl halides do not undergo SN2 because:
77

78. Cyclic systems

79. rigid bicyclic molecule.
You can’t have p orbitals on a -- You cannot form a
bridgehead position carbocation
at a bridgehead position.
X
Br +
cannot become
+ planar
“steric rigidity”
+

80. Problems :
1) S N 2 reaction by EtO - in EtOH:
CH3CH2 Br CH3CH2CH2 Br Me2HCCH2 Br Me3CCH2 Br
Explain ?
relative rate 1 2.8X10-1 3.0X10-2
24.2X10-6
2) Rate of solvolysis in EtOH :
Br
Br Explain?
A) Br
cc at bridge head, less
stable, difficult to attain
planarity due to rigidity
1 10-6 10-14
Br Br
B) Explain ?
A) Rigid structure, cation empty
p-orbitals are at right angles
to π orbitals of Ph
1 10-23
1-bromotriptycene