Phản ứng hóa học của

ankyl halogenua: Phản

ứng thế nucleophil và
tách loại
TS. Trần Thượng Quảng
Bộ Môn Hóa Hữu cơ
Viện Kỹ Thuật Hóa học
HUST
Ankyl halogenua phản ứng với tác
nhân nucleophil và bazơ
 Liên kết C-X phân cực
 Tác nhân nucleophil sẽ thay thế
nguyên tử halogen trong liên kết C-X

2
Ankyl halogenua phản ứng với tác
nhân nucleophil và bazơ
 Các nucleophil có tính bazơ mạnh
theo Brønsted gây ra phản ứng tách
loại

3
Phản ứng thế vs. Phản ứng tách
loại

4
8.11The Nature of Substitution
 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 .

5
Substitution Mechanisms
 SN1
 Two steps with carbocation intermediate
 Occurs in 3°, allyl, benzyl

 SN2
 Concerted mechanism - without intermediate
 Occurs in primary, secondary

6
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
7
Kinetics of Nucleophilic Substitution

Rate = d[CH3Br]/dt = k[CH3Br][OH-1]

This reaction is second order: two

concentrations appear in the rate law
SN2: Substitution Nucleophilic 2nd order
8
8.12 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) 9
SN2
Process

10
 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

11
12
13
8.13 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)

14
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 S N2
15
reactions.
Steric Effect in SN2

16
Steric Hindrance Raises
Transition State Energy
Very hindered

 Steric effects destabilize transition states

 Severe steric effects can also destabilize
ground state
17
Order of Reactivity in SN2
 The more alkyl groups connected to the reacting
carbon, the slower the reaction

18
Vinyl and Aryl Halides:

19
Order of Reactivity in SN2

DMF
R Br + Cl -1
R Cl + Br-1

Br Br Br Br

ethyl propyl isobutyl neopentyl

1.0 0.69 0.33 0.000006

20
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
 See Table 8.2 for an illustrative list

21
For example:
Br C N
+ CN-1 + Br-1

CH2 Cl + H2 O CH2 OH2 + Cl-1

22
23
Relative Reactivity of Nucleophiles
 Depends on reaction and conditions
 More basic nucleophiles react faster (for similar
structures. See Table 8.3)
 Better nucleophiles are lower in a column of the
periodic table
 Anions are usually more reactive than neutrals

24
25
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
26
The Leaving Group

27
Poor Leaving Groups
 If a group is very basic or very small, it does not
undergo nucleophilic substitution.

28
Converting a poor LG to a good LG:

29
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

30
Some Polar Aprotic Solvents
O
H3C CH3
H3C S N CH3

CH3 O P N
dimethylsulfoxide
(DMSO) CH3 N CH3
H3C CH3
O N
hexamethylphosphoramide
C CH3
H (HMPT)
dimethylformamide
(DMF)

31
32
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

33
Prob. 8.8 Arrange in order of SN2
reactivity

34
8.14 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:

35
SN1 Reactivity:

36
SN1 Energy Diagram

37
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.
 See Figure 11.9 – the same step is rate-
determining in both directions)

38
SN1 Energy Diagram

39
40
Stereochemistry of SN1 Reaction
 The planar carbocation intermediate leads to loss of chirality
 Product is racemic or has some inversion

41
42
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:

43
Effects of Ion Pair Formation

44
8.15 Characteristics of the SN1
Reaction
 Tertiary alkyl halides are the most reactive
simple halides by this mechanism
Controlled by stability of carbocation

45
Relative Reactivity of Halides:

46
Delocalized Carbocations
 Delocalization of cationic charge
enhances stability
 Primary allyl is more stable than
primary alkyl
 Primary benzyl is more stable than
allyl
47
Allylic and Benzylic Halides
 Allylic and benzylic intermediates stabilized by
delocalization of charge (See Figure 11-13)
 Primary allylic and benzylic are also more
reactive in the SN2 mechanism

48
49
Relative SN1 rates (formolysis):
RCl + HCOO-1

Cl Cl
1.0 3550

Cl
Cl
0.5
5670

50
Formation of the allylic cation:

Cl

Cl

51
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

52
Nucleophiles in SN1

 Since nucleophilic addition occurs after

formation of carbocation, reaction rate is not
normally affected by nature or concentration of
nucleophile

53
54
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

55
Polar Solvents Promote
Ionization
 Polar, protic and unreactive Lewis base solvents
facilitate formation of R+
 Solvent polarity is measured as dielectric polarization
(P) (Table 11-3)

56
Effect of Solvent

57
Solvent Polarity

58
Effects of Solvent on Energies
 Polar solvent stabilizes transition state and
intermediate more than reactant and product

59
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)
60
Prob. 8.9 Arrange in order of SN1
reactivity

61
Problem 8.10: SN1 or SN2?

62
Problem 8.11: SN1 or SN2?

63
Biological Substitution Reactions

64
Biological Substitution Reactions

65
Biological Substitution Reactions

66
8.16 Alkyl Halides: Elimination
 Elimination is an alternative pathway to substitution
 Elimination is formally the opposite of addition, and
generates an alkene
 It can compete with substitution and decrease yield,
especially for SN1 processes

67
Zaitsev’s Rule for Elimination
Reactions (1875)
 In the elimination of HX from an alkyl halide, the more
highly substituted alkene product predominates

68
Mechanisms of Elimination
Reactions
 Ingold nomenclature: E – “elimination”
 E1 (1st order): X- leaves first to generate a
carbocation
 a base abstracts a proton from the carbocation
 E2 (2nd order): Concerted transfer of a proton to a
base and departure of leaving group
 E1cb : Carbanion intermediate is formed in the
rate-determining step

69
E1 mechanism: starts out like SN1

70
E2 mechanism: concerted

71
E1cb: common in biochemical reactions

72
8.17 The E2 Reaction
Mechanism
 A proton is transferred to base as leaving
group begins to depart
 Transition state combines leaving of X and
transfer of H
 Product alkene forms stereospecifically

73
74
E2 Reaction Kinetics
 One step (concerted): rate law
dependent on base and alkyl halide
 Rate = k[R-X][B]
 Reaction goes faster with stronger
base, better leaving group

75
Kinetic Isotope Effect
 Substitute deuterium for hydrogen at α
position
 Effect on rate is kinetic isotope effect
(kH/kD = deuterium isotope effect)
 Rate is reduced in E2 reaction
 Heavier isotope bond is slower to break
 Shows C-H bond is broken in or before rate-
limiting step

76
kH/kD

77
Geometry of Elimination – E2
 Antiperiplanar allows orbital overlap and
minimizes steric interactions

78
E2 Stereochemistry

79
Comparison of SN2 and E2:

80
Predicting Product
 E2 is stereospecific
 Meso-1,2-dibromo-1,2-diphenylethane with base gives cis 1,2-
diphenyl-1-bromoethene
 RR or SS 1,2-dibromo-1,2-diphenylethane gives trans 1,2-diphenyl-
1-bromoethene

81
Anti periplanar geometry

82
8.18 Elimination From
Cyclohexanes
 Abstracted proton and leaving group
should align trans-diaxial to be anti
periplanar (app) in approaching transition
state (see Figures 11-19 and 11-20)
 Equatorial groups are cannot be in proper
alignment

83
Elimination From Cyclohexanes

84
Axial vs. Equatorial Leaving Groups

85
86
8.19 The E1 Reaction
 Competes with SN1 and E2 at 3° centers
 Rate = k [RX]

87
88
Stereochemistry of E1 Reactions

 E1 is not stereospecific and there is no

requirement for alignment
 Product has Zaitsev orientation because the step
that controls product formation is loss of proton
after formation of carbocation

89
Comparing E1 and E2
 Strong base is needed for E2 but not
for E1
 E2 is stereospecifc, E1 is not
 E1 gives Zaitsev orientation; E2 may
not due to stereospecificity
 E1 is favored in protic solvents;
competes with SN1
90
Comparing E1 and E2

91
E1cb:

92
A biochemical example (from fat
biosynthesis):

93
Reactivity Summary: SN1, SN2, E1, E2

94
General Pattern by Substrate

95
Primary alkyl halides (SN2 vs E2)

96
Secondary alkyl halides (SN2 vs E2)

97
Tertiary alkyl halides (SN1/E1 vs E2)

98
Prac. Problem

99
Answers

100
Problem 8.12

101
Problem 8.13: This halide does not
undergo SN1 or SN2 reactions. Why?

102
It also fails to eliminate HBr under
basic conditions. Why?

103