4 Major organic reactions

4.1 Substitution Reactions

4.1.1 Introduction
 Substitution requires that a "leaving group", which is
also a Lewis base, departs from the reacting molecule.
 A nucleophile is a reactant that can be expected to
participate as a Lewis base in a substitution reaction.

1
4.1.2 SN2 and SN1 mechanism

2
 Kinetics of Nucleophilic Substitution
• Rate is the change in concentration with time
• Depends on concentration(s), temperature,
inherent nature of reaction (energy of activation
• A rate law describes the relationship between the
concentration of reactants and the overall rate of
the reaction
• A rate constant (k) is the proportionality factor
between concentration and rate

3
 Kinetics of Nucleophilic Substitution

This reaction is second order: two

concentrations appear in the rate law
SN2: Substitution Nucleophilic 2nd order

4
 The SN2 Reaction
• Reaction occurs with inversion at reacting center
• Follows second order reaction kinetics
• Ingold nomenclature to describe rate-determining
step:
• S=substitution
• N (subscript) = nucleophilic
• 2 = both nucleophile and substrate in rate-
determining step (bimolecular)

5
SN2 Process

6
 SN2 Transition State
• The transition state of an SN2 reaction has a
planar arrangement of the carbon atom and the
remaining three groups
• Hybridization is sp2

7
 Characteristics of the SN2 Reaction

• Sensitive to steric effects

• Methyl halides are most reactive
• Primary are next most reactive
• Unhindered secondary halides react under some
conditions
• Tertiary are unreactive by this path
• No reaction at C=C (vinyl or aryl halides)

8
Steric Effects on SN2 Reactions

 The carbon atom in (a) bromomethane is readily

accessible resulting in a fast SN2 reaction.
 The carbon atoms in (b) bromoethane (primary), (c) 2-
bromopropane (secondary), and (d) 2-bromo-2-
methylpropane (tertiary) are successively more
hindered, resulting in successively slower SN2
reactions. 9
 Order of Reactivity in SN2
• The more alkyl groups connected to the reacting
carbon, the slower the reaction.

10
 Vinyl and Aryl Halides:

4.1.3 Factors affecting SN2

a. The Nucleophile
 Neutral or negatively charged Lewis base
 Reaction increases coordination (adds a new bond) at
the nucleophile
 Neutral nucleophile acquires positive charge
 Anionic nucleophile becomes neutral 11
 …cont

Forexample:

12
13
 Relative Reactivity of Nucleophiles
• Depends on reaction and conditions
• More basic nucleophiles react faster (for similar
structures.
• Better nucleophiles are lower in a column of the
periodic table
• Anions are usually more reactive than neutrals

14
…cont

15
 The Leaving Group
• A good leaving group reduces the energy of
activation of a reaction
• Stable anions that are weak bases (conjugate
bases of strong acids) are usually excellent
leaving groups
• Stronger bases (conjugate bases of weaker acids)
are usually poorer leaving groups

16
…cont

17
 Poor Leaving Groups
• If a group is very basic or very small, it does not
undergo nucleophilic substitution.

18
Converting a poor LG to a good LG:

19
 The Solvent
• Protic solvents (which can donate hydrogen bonds; -OH
or –NH) slow SN2 reactions by associating with reactants
(anions).
• Energy is required to break interactions between reactant
and solvent
• Polar aprotic solvents (no NH, OH, SH) form weaker
interactions with substrate and permit faster reaction

20
Some Polar Aprotic Solvents

21
…cont

22
 Summary of SN2 Characteristics
• Substrate: CH3->1o>2o>>3o (Steric effect)
• Nucleophile: Strong, basic nucleophiles favor the
reaction
• Leaving Groups: Good leaving groups (weak
bases) favor the reaction
• Solvent: Aprotic solvents favor the reaction;
• protic reactions slow it down by solvating the
nucleophile
• Stereochemistry: 100% inversion

23
Prob. 5.1 Arrange in order of SN2 reactivity

24
 The SN1 Reaction
• Tertiary alkyl halides react rapidly in protic
solvents by a mechanism that involves departure
of the leaving group prior to the addition of the
nucleophile.
• Reaction occurs in two distinct steps, while SN2
occurs in one step (concerted).
• Rate-determining step is formation of carbocation:

25
SN1 Reactivity:

26
 Rate-Limiting Step
• The overall rate of a reaction is controlled by the
rate of the slowest step
• The rate depends on the concentration of the
species and the rate constant of the step
• The step with the largest energy of activation is
the rate-limiting or rate-determining step.

27
SN1 Energy Diagram

28
SN1 reaction mechanisms

29
 Stereochemistry of SN1 Reaction
• The planar carbocation intermediate leads to loss
of chirality
• Product is racemic or has some inversion

30
 Stereochemistry of SN1 Reaction
• Carbocation is usually biased to react on side
opposite leaving group because it is
unsymmetrically solvated
• The second step may occur with the carbocation
loosely associated with leaving group.
• The result is racemization with some inversion:

31
Effects of Ion Pair Formation

32
 Characteristics of the SN1 Reaction
• Tertiary alkyl halides are the most reactive simple
halides by this mechanism
• Controlled by stability of carbocation

33
Relative Reactivity of Halides:

34
 Delocalized Carbocations
• Delocalization of cationic charge enhances
stability
• Primary allyl is more stable than primary alkyl
• Primary benzyl is more stable than allyl
Allelic and Benzylic Halides
Allylic and benzylic intermediates stabilized by
delocalization of charge
Primary allylic and benzylic are also more
reactive in the SN2 mechanism

35
…cont

36
Factor affecting SN1reaction
• Effect of Leaving Group on SN1
 Critically dependent on leaving group
Reactivity: the larger halides ions are better leaving
groups
In acid, OH of an alcohol is protonated and leaving
group is H2O, which is still less reactive than halide
p-Toluensulfonate (TosO-) is an excellent leaving group

37
 Nucleophiles in SN1
• Since nucleophilic addition occurs after formation
of carbocation, reaction rate is not normally
affected by nature or concentration of
nucleophile.

38
…cont

39
Solvent Is Critical in SN1
• The solvent stabilizes the carbocation, and also
stabilizes the associated transition state.
• This controls the rate of the reaction.

Solvation of a carbocation by water

40
 Polar Solvents Promote Ionization
• Polar, protic and unreactive Lewis base solvents
facilitate formation of R+
• Solvent polarity is measured as dielectric
polarization (P)

41
Solvent Polarity

42
 Effects of Solvent on Energies
• Polar solvent stabilizes transition state and
intermediate more than reactant and product.

43
 Summary of SN1 Characteristics
• Substrate: Benzylic~allylic>3o >2o
• Nucleophile: Does not affect reaction (although
strong bases promote elimination)
• Leaving Groups: Good leaving groups (weak
bases) favor the reaction
• Solvent: Polar solvents favor the reaction by
stabilizing the carbocation.
• Stereochemistry: racemization (with some
inversion)

44
Prob. 5.2. Arrange in order of SN1 reactivity

45
Practice Problem 5.3: SN1 or SN2?

46
 4.1.4 Applications of Substitution Reactions
 A real world application of nucleophilic
substitution reactions is the use of these
substitution reactions to combat antibiotic drug
resistance in modern medicine.
• Scientists rearrange the structure of the antibiotic
through substitution while keeping the drug’s
effectiveness, allowing it to work and not be
recognized by the bacteria.

47
4.2 Elimination reactions
• 4.2.1 Introduction
• Elimination reactions are commonly known by
the kind of atoms or groups of atoms leaving the
molecule.
• The removal of a hydrogen atom and a halogen
atom, for example, is known as
dehydrohalogenation; when both leaving atoms
are halogens, the reaction is known as
dehalogenation.

48
 …cont
• Dehydrohalogenation (-HX) and Dehydration (-
H2O) are the main types of elimination reactions.

49
 E2 mechanism
• This reaction is done in strong base at high
concentration, such as 1 M NaOH in water.

50
 Kinetics of an E2 reaction
• The reactions are second order (bimolecular
reactions).
• Rate = k [R-Br]1[Base]1

51
 Stereochemistry of reactants
• E2 reactions must go by an anti elimination
• This means that the hydrogen atom and halogen
atom must be 180o (coplanar) with respect to
each other!!
• This is the cis isomer. The trans isomer does not
react by an E2 reaction.

52
 Orientation of elimination:
regiochemistry/Zaitsev’s Rule
• In reactions of removal of hydrogen halides from
alkyl halides or the removal of water from
alcohols, the hydrogen which is lost will come
from the more highly-branched beta -carbon.

53
 E1 mechanism
• This reaction is done in strong base at low
concentration, such as 0.01 M NaOH in water.

54
 E1 Reactions
• These reactions proceed under neutral conditions
where a polar solvent helps to stabilize the
carbocation intermediate.
• This solvent also acts as a weak base and removes
a proton in the fast step.
• These types of reactions are referred to as
solvolysis reactions.

55
 …cont
• tertiary substrates go by E1 in polar solvents, with
little or no base present!
• typical polar solvents are water, ethanol, methanol
and acetic acid
• These polar solvents help stabilize carbocations
• E1 reactions also occur in a low concentration of
base (i.e. 0.01M NaOH).

56
Kinetics of an E1 reaction
• E1 reactions follow first order (unimolecular)
kinetics:

The solvent helps to stabilize the carbocation,

but it doesn’t appear in the rate law!!

57
…cont

58
Orientation of elimination
• E1 reactions faithfully follow Zaitsev’s rule!
• This means that the major product should be the
product that is the most highly substituted.
• Stereochemistry of products
• E1 reactions usually give the thermodynamically
most stable product as the major product.
• This usually means that the largest groups should
be on opposite sides of the double bond.

59
 Dehydration of Alcohols (acid assisted E1)
• Acid assisted reactions are always E1

60
Mechanism of Dehydration

61
Rearrangements in dehydration reactions

62
…cont

63
 Comparison of E2 / E1
• E1 reactions occur under essentially neutral
conditions with polar solvents, such as water,
ethyl alcohol or acetic acid.
• E1 reactions can also occur with strong bases, but
only at low concentration, about 0.01 to 0.1 M or
below.
• E2 reactions require strong base in high
concentration, about 1 M or above.

64
 …cont
• E1 is a stepwise mechanism (two or more)
• Carbocation intermediate!
• E2 is a concerted mechanism (one step)
No intermediate!
• E1 reactions may give rearranged products
• E2 reactions don’t give rearrangement
• Alcohol dehydration reactions are E1

65
Hofmann Elimination……Bulky leaving groups
-- …..
• This give the anti-Zaitsev product (least
substituted product is formed)!

66
Elimination with bulky bases
• Non-bulky bases, such as hydroxide and ethoxide,
give Zaitsev products.

• Bulky bases, such as potassium tert-butoxide,

give larger amounts of the least substituted alkene
(Hoffmann) than with simple bases.

67
Comparing Ordinary and Bulky Bases

68
4.2.5 Applications of Elimination Reactions
• Elimination reaction is a type of reaction is mainly
used to transform saturated compounds (organic
compounds which contain single carbon-carbon
bonds) to unsaturated compounds (compounds
which feature double or triple carbon-carbon
bonds).
• Besides, it is an important method for the
preparation of alkenes.

69
4.3 Addition Reactions
• An electrophile, an electron-poor species, combines with
a nucleophile, an electron-rich species
• An electrophile is a Lewis acid
• A nucleophile is a Lewis base
• The combination is indicated with a curved arrow from
nucleophile to electrophile.

70
 MECHANISM

Intermediate

71
ENERGY PROFILE

72
Addition of Hydrogen Halides

73
MARKOVNIKOV RULE

74
Mechanism (Markovnikov)

Secondary C+

Major product
75
Mechanism (anti-Markovnikov)

Primary carbocation

Minor!

76
Addition of Sulfuric Acid to an Alkene

77
ALKYL HYDROGEN SULFATES

78
Mechanism of Hydration

79
Addition of Bromine to an Alkene

80
Halohydrin Formation

81
Free Radical Addition of HBr to Alkenes (anti-Markovnikov!)

82
ADDITION OF HBr

Markovnikov
Addition

Anti-Markovnikov
Addition
83
STABILITY OF CARBON RADICAL INTERMEDIATES
• Radicals are electron-deficient just like
carbocations and have the same stability order.

and they are stabilized by resonance and / or hyperconjugation.

84
 Michael addition
• Michael reaction: the nucleophilic addition of an enolate
anion to an alpa, bata-unsaturated carbonyl compound.

85
 …cont
• The double bond of an a,b-unsaturated carbonyl
compound is activated for attack by nucleophile.

More positive carbon

86
Mechanism: Michael Reaction

87
…cont

88
 …cont
NaOH or KOH.

Step 1:
First, an acid-base reaction. Hydroxide functions as a
base and removes the acidic α-hydrogen giving the
reactive enolate. mechanism of the Michael addition
Step 2:
The nucleophilic enolate attacks the conjugated ketone
at the electrophilic alkene C in a nucleophilic addition
type process with the electrons being pushed through to
the electronegative O, giving an intermediate enolate.
Step 3:
An acid-base reaction. The enolate deprotonates a
water molecule recreating hydroxide and the more
favourable carbonyl group.

89
 4.3.6 Other Reactions of Double Bonds
• 4.3.6.1 Ozonization
• Ozone (O3) is the triatomic form of oxygen.
• It is a neutral but polar molecule that can be
represented as a hybrid of its two most stable
Lewis structures.

90
 Reaction mechanisms
• The gaseous ozone is first passed through the
desired alkene solution in either methanol or
dichloromethane.

91
 …cont
• Ozonides undergo hydrolysis in water, giving carbonyl
compounds.

 Two aldehydes, two ketones, or one aldehyde and one

ketone may be formed.

92
problems

93
 4.3.6.2 Diels-Alder reaction

• A particular kind of conjugate addition reaction earned

the Nobel Prize in chemistry for Otto Diels and Kurt
Alder of the University of Kiel (Germany) in 1950.
• The Diels–Alder reaction is the conjugate addition of an
alkene to a diene.
• Using 1,3-butadiene as a typical diene, the Diels–Alder
reaction may be represented by the general equation:

94
 …cont
• The Diels–Alder cycloaddition is one example of
a pericyclic reaction.
• A pericyclic reaction is a one-step reaction that
proceeds through a cyclic transition state.

95
 …cont
• The Diels–Alder reaction is stereospecific.
• Substituents that are cis in the dienophile remain cis in
the product; substituents that are trans in the dienophile
remain trans in the product.

96
 Questions
• What combination of diene and dienophile would you
choose in order to prepare each of the following
compounds?

To deduce the identity of the diene and dienophile that lead to a

particular Diels–Alder adduct, we use curved arrows in the reverse
fashion to “undo” the cyclohexene derivative. Start with the
component of the double bond in the six-membered ring, and move
electrons in pairs.

97
 4.3.6.3 Glycol formation
• Hydroxylation of Alkenes

98
 Mechanism for Glycol Formation

Higher yields of the diol are obtained with osmium tetroxide

99
 4.3.6.4 Addition polymerization
• Most of the ethylene is converted to polyethylene, a high-
molecular-weight polymer of ethylene.
• Polyethylene cannot be prepared by cationic
polymerization, but is the simplest example of a polymer
that is produced on a large scale by free-radical
polymerization.
• In the free-radical polymerization of ethylene, ethylene is
heated at high pressure in the presence of oxygen or a
peroxide.

100
…cont

101
 4.4 Rearrangement reactions
• 4.4.1 Migration to electron deficient carbon.
• Wagner-Meerwien Rearrangement
The generation of a carbocation followed by the
[1,2]-shift of an adjacent carbon-carbon bond to
generate a new carbocation is known as the
Wagner-Meerwein rearrangement.

102
…cont

103
4.4.2 Migration to electron deficient oxygen.
The Bayaer-Villiger Oxidation

• The reaction of ketones with peroxy acids is both novel

and synthetically useful.
• An oxygen from the peroxy acid is inserted between the
carbonyl group and one of the attached carbons of the
ketone to give an ester.
• Reactions of this type were first described by Adolf von
Baeyer and Victor Villiger in 1899 and are known as
Baeyer–Villiger oxidations.

104
…cont

105
 4.4.3 Migration to electron deficient nitrogen
Hofmann Rearrangement
On treatment with bromine in basic solution,
amides of the type undergo an interesting reaction
that leads to amines.
This reaction was discovered by the nineteenth
century German chemist August W. Hofmann and
is called the Hofmann rearrangement.

106
…cont

107
…cont

108
 Beckmann Rearrangement
• The acid-catalyzed conversion of an oxime into
an amide is known as Beckmann rearrangement:

109
…cont

110
…cont

111
 problems
Q. Shaw the mechanisms of the following reaction
in Beck man rearrangement.
a.

112