Cgapter 6

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www.chem.sc.edu/faculty/bryson/index.html
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CHEM 333
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Cgapter 6
synthesis
50
2
CHAPTER 6
Nucleophilic Substitution Elimination rxs of
Alkyl Halides Ionic rxs Organic
halides Nuecleophiles Leaving groups Mechanism
for SN2 Kinectics of Nu substitution -
SN2 Transition state theory Stereochemistry of
SN2 Rx of t-butyl chloride with (-)OH
SN1 Mechanism for SN1 Carbocations Stereochemistry
pf SN1 Factors affecting rates SN1/
SN2 Functional group transformations using SN2
Elimination rx of alkyl halides E2, E1 rx
Determing if SN1 or E1 is favored
3
Nucleophilic Substitution (alkylation, SN2)

rxs can compete
4
Haloalkane
sp3
Halogens are more electronegative than carbon
Attached to 1 carbon
2 carbons
3 carbons
1o chloride
2o bromide
3o iodide
(R carbon chain)
Ch. 6 - 6
5
methyl, 1o, 2o and 3o halides
Prone to undergo Nucleophilic Substitution (SN)
and Elimination Reactions (E)
Ch. 6 - 8
6
Nucleophilic Substitution Reactions
new covalent bond
Ch. 6 - 9
7
Timing of The Bond Breaking Making Process
Two types of mechanisms 1st type SN2 (concerted
mechanism)
R C or H
2nd type SN1 (stepwise mechanism)
by-products
Ch. 6 - 10
8
2nd type SN1 (stepwise mechanism)
slow
fast
fast
Ch. 6 - 11
9
Nucleophiles
unshared pair of e? seeks a positive (/ )
center e.g.
Ch. 6 - 12
10
Examples
Ch. 6 - 13
11
SN2
The rate(speed) of reaction is directly
proportional to the concentration of either
reactant. When the concentration of either
reactant is doubled, the rate of reaction doubles.
Rate dependant on CH3BrOH-
second order rx -
bimolecular
Ch. 6 - 14
12
A Mechanism for the SN2 Reaction
substitution nucleophilic bimolecular
second order rx -
SN2
Ch. 6 - 15
13
Free Energy Diagram of SN2 Reactions
exothermic
starting material
products
reaction coordinate
Ch. 6 - 16
14
Inversion of configuration
(inversion)
(R)
(S)
sense R -gt S (or S -gt R)
Ch. 6 - 17
15
Example
Nu? attacks from the BACK face.
Ch. 6 - 19
16
Example
Nu? attacks from the TOP face.
Ch. 6 - 18
17
The rate of SN1 reactions depends only on alkyl
halide Rate kRX first-order
reaction unimolecular nucleophilic substitution
Ch. 6 - 20
18
Rate-Determining Step
In a multistep reaction the rate of reaction is
the rate of the SLOWEST step
rate-determining step (r.d.s) For example
Ch. 6 - 21
19

• The opening A is much smaller than openings B and
  C

A
B
C
Ch. 6 - 22
20
SN2 Reactions, inversion of configuration
(R)
(S)
SN1 Rx multistep mechanism
Ch. 6 - 17
21
Ch. 6 - 23
22
Free Energy Diagram of SN1 Reactions
Ch. 6 - 24
23
slow r.d. step
(ionization of alkyl halide)
Ch. 6 - 25
24
Free Energy Diagram of SN1 Reactions
25
slow r.d. step
(ionization of alkyl halide)
fast
fast
Ch. 6 - 27
26
Free Energy Diagram of SN1 Reactions
Ch. 6 - 28
27
2 intermediates and 3 transition states (T.S.)
The most important t.s. for SN1 reactions is t.s.
(1) of the rate-determining step (r.d.s.)
Ch. 6 - 29
28
The Structure of Carbocations

• Carbocations are trigonal planar

The central carbon of carbocation is electron
deficient 6 valence shell e?
Empty p orbital is e(-) pair acceptor
Ch. 6 - 30
29
SN1 stereochem
Ch. 6 - 33
30
5050chance
(1 1)
Ch. 6 - 31
31
Example
racemic mixture ( 1 1 )
Ch. 6 - 32
32
The structure of the substrate The reactivity of
the nucleophile The effect of the solvent The
nature of the leaving group
Ch. 6 - 34
33
The Effect of Substrate Structure

• General order of reactivity (towards SN2
  reaction)
• Methyl gt 1o gtgt 2o gtgtgtgtgt 3o

Ch. 6 - 35
34
Compare
faster
slower
completely blocked see other RX
Ch. 6 - 36
35
Factors Affecting the Rates of SN1 and SN2 Rxs
The structure of the substrate The reactivity of
the nucleophile The effect of the solvent The
nature of the leaving group
Ch. 6 - 34
36
Reactivity of the Substrate in SN1 Reactions
Stability of cations 3o gt 2o gtgt 1o gt methyl
Ch. 6 - 38
37
allylic (benzylic) facilitates SN2
38
Resonance stabilization for allylic and benzylic
cations
Ch. 6 - 39
39
Effect of the Concentration Strength of the Nu
For SN1 reaction
Rate kRX Rate of SN1 rx - NOT affected by
concentration or identity of the Nu?
For SN2 reaction
Rate kNuRX Rate of SN2 reactions depends on
both identity concentration of the Nu?
Ch. 6 - 40
40
Relative strength of a Nu?
Nucleophilicities roughly parallels basicities if
comparing Nus with the same nucleophilic atom.
e.g. for O,
When the nucleophilic atoms are different,
nucleophilicities may not parallel basicities
Ch. 6 - 41
41
Relative strength of a Nu?
42
Identity of the Nu? The strength
(nucleophilicity) of a Nu? is a measure of its
SN2 reaction rate with a substrate
eg
Ch. 6 - 43
43
rx types
44
Relative strength of a Nu?
good
moderate
H3N,RNH2,R2NH,R3N,RSH,R2S
weak
45
Solvent Effects on SN2 and SN1 Reactions
Classification of solvents
Ch. 6 - 45
46
Best solvents for SN2 rxs are Polar Aprotic
solvents

• strong dipoles
• and no OH or NH groups

Ch. 6 - 46
47
Polar APROTIC solvents solvate cations
48
Polar PROTIC solvents solvate cations anions
49
SN2 tremendous acceleration in polar aprotic
solvent
MeOH 1
DMF 106
Ch. 6 - 49
50
SN1 Reactions Solvent effects are due to
stabilization of the transition state
Ch. 6 - 50
51
Leaving Groups
good leaving gp - stable or weakly basic w/ e(-)s
Ch. 6 - 51
52
Examples of the reactivity of some X?
Relative Rate
HO?, H2N?, RO? F? Cl? Br? I? TsO?
0 1 200 10,000 30,000 60,000
lt
lt
lt
lt
ltlt
Ch. 6 - 52
53
?
?
Ch. 6 - 53
54
Ch. 6 - 54
55
Ch. 6 - 55
56

• Examples

NaOEt, DMSO
NaSMe, DMSO
Ch. 6 - 56
57
Ch. 6 - 57
58

• Conjugate base of alcohols (alkoxide)

Li, K, Mg
R-O-H
(-)NH2, R(-)
Ch. 6 - 58
59
16 E2 Reaction, Mechanism
Rate ? CH3CHBrCH3EtO? Rate determining step
involves both the RX RO(-) A bimolecular
reaction
Ch. 6 - 59
60
All nucleophiles are potential bases all
bases are potential nucleophiles
SN2
E2
Substitution is competitive with elimination
Ch. 6 - 60
61
Primary ( Methyl) Substrate

• Unhindered small base/Nu?

But 1o with Hindered or bulky base/Nu?
Ch. 6 - 61
62
Secondary and Tertiary Substrate

• With a strong base (e.g. EtO?) favors E2

Ch. 6 - 62
63

• Substitution (SN) elimination (E) rxs can be
  competitive

Ch. 6 - 63
64

• E1 Unimolecular elimination (3o or 2o substrate)

Ch. 6 - 64
65
Mechanism of an E1 Reaction
slow r.d.s.
Ch. 6 - 65
66
Free Energy Diagram of E1 Reaction
Ch. 6 - 66
67
Free Energy Diagram of E1 Reaction
Ch. 6 - 67
68
Tertiary Halides SN1 vs. E1 E2
Ch. 6 - 68
69
2o substrate SN1 SN2 vs. E1 E2
If 2o chiral?
Ch. 6 - 69
70
Very fast
-
-
-
Hindered bases give mostly alkenes e.g. with
tBuO?
RCH2X
Mostly
-
-
Mostly SN2 with weak bases e.g. with CH3COO?
NC? Br(-)
Strong bases promote E2 e.g. with RO?, HO?
H2N? R?
RCO2H, H2O, MeOH, RSH, RSR possible Solvolysis
Strong bases promote E2 e.g. with RO?, HO?
H2N? R?
Very favorable with weak bases e.g. with
H2O MeOH
Always competes with SN1
-
Ch. 6 - 70
71
2o substrate
SN2
E2
SN2
(s)
E1/SN1
72
Guidelines for Substitution Elimination linked
to home page
H3C-X
Nu-
polar protic unimolecular
polar aprotic bimolecular
73
Relative strength of a Nu?
good
strong bases
moderate
H3N,RNH2,R2NH,R3N,RSH,R2S
weak
74
Summary Chapter 6
strong
75
2o substrateSN1 SN2 vs. E1 E2
Ch. 6 - 75
76
Rearrandement
77
Review Problems
SN2 with inversion
Intramolecular SN2
Ch.06- 73
78
Need SN2 rx at 2o site to control
stereochemistry But SN2 rxs give the inversion of
configurations how do you get the retention of
configuration?
D deuterium
Ch.06- 73
79
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Ch.06- 73
80
Chapters 6 7
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Cl? from top
SN1 with racemization
Ch. 6 - 74