SN1, SN2, E1, E2

1
Chapter 11

• SN1, SN2, E1, E2
• Reactions of Alkyl Halides

2
Substitution Elimination Reactions
3
Substitution Elimination Reactions
Substitution
competing reactions
?-Elimination
nucleophile base
4
Substitution - nucleophilicity
?-
?
reaction rate is affected by all four.
5
Elimination - basicity
?
?
... reaction rate is affected by all four.
6
Substitution Elimination (nucleophilicity
basicity)
?-
?
?
?
7
Mechanisms

• Substitution
• Elimination

8
Types of Substitution

• Substitution, Nucleophilic, Bimolecular - SN2
• Substitution, Nucleophilic, Unimolecular - SN1
• Bimolecular or Unimolecular refers to the number
  of specie(s) present at the transition state, or
  ...
• describes the timing of bond breaking between
  carbon (on the substrate) and the leaving group
  and bond forming between carbon (on the
  substrate) and the nucleophile.

9
Substitution Reactions
involve configurational inversion at the
stereocenter.
10
Drawing Inversion
Show the SN2 reaction of OH- with
(R)-2-bromobutane.

CH3
Br
H
R
S
CH3CH2
OH-
11
a
SN1
-
inversion
racemic mixtures
b
carbocation intermediate


SN2
inversion
concerted
no intermediate
Review chapter 9 slides 53 - 57.
12
SN1 SN2
suggests that only atoms in S are involved in
the transition state.
says that the reaction rate is affected only by
S.
suggests that atoms in N S are involved in
the transition state.
says that the reaction rate is affected by both
N S.
13
a
SN1
-
b


SN2

Ratek


14
SN1 SN2
SN1
SN2


carbocation intermediate
concerted

15
Factors effecting Rates of SN2 SN1 Reactions
-CH3CH2Br Nu ? CH3CH2Nu Br-

• Structure of Substrate - steric effects.
• Structure of Nucleophile.
• Structure of Leaving Group.
• Solvent.

16
Substrate - SN2
concerted ...
back side attack ...
17
Substrate - SN2
1o
concerted ...
back side attack ...
18
Substrate - SN2
2o
concerted ...
back side attack ...
19
Substrate - SN2
3o
steric hindrance ...
20
Substrate - SN2 SN1
Relative reactivity
SN2
steric factors - reaction center neighbor.
2 x 106
4 x 105
500
lt1
1.2 x 106
12
1
lt1
SN1
electronic factors - carbocation stability.
1. Primary and methyl halides have less steric
hindrance, thus only SN2.
2. Tertiary halides (also, allylic or benzylic)
react via carbocation, thus SN1 exclusively.
3. 2o alkyl halides can react as SN1 or SN2,
depending on nucleophile and solvent.
21
Attacking Nucleophile
good
(Underlined nucleophiles are also strong bases)
moderate
poor
1. SN2 involves substrate and nucleophile in the
rate determining step (rds). Thus good
nucleophile lowers the ?G and therefore
increases the reaction rate.
2. SN1 does not involve the nucleophile in the
rate determining step. Thus nucleophile has no
effect on the reaction rate.
22
Polar aprotic
Polar protic
F-
F-
Nucleophilicity
Nucleophilicity
Cl-
Cl-
Br-
Br-
I-
I-
23
Species with higher electronegativity have
tightly held nonbonding electrons and therefore
less reactive towards forming new bonds.
Nucleophilicity
Nucleophilicity
Increase in size and polarizability.
24
Leaving group
strength of conjugate acid
stability of anion
Good
Poor
reactivity as a leaving group
1. Good leaving group increases rates of SN1
SN2.
2. The 1st three are such poor leaving group, no
substitutions are observed.
25
Solvents
Protic solvents
those that contain -OH or -NH groups worst
solvents for SN2 reactions.
Aprotic solvents
have strong dipoles but dont have -OH or -NH
groups. Best for SN2 reactions.
26
Protic Solvent
Common Solvents
polarity
Dielectric Constant
6 acetic acid
34 methanol
80
1. Contain OH group.
2. R is either CH3, CH3CH2 , or in general,
CnH2n1 .
3. Hydrogen bond with Nu, decreases its
reactivity, hinders SN2 .
4. Electrostatic interaction stabilizes
carbocation, facilitates SN1.
27
Aprotic Solvent
Common Solvents
Acetone
Diethyl ether
DMSO
DMF
HMPA
Dichloromethane
polarity
Dielectric Constant
4
30
48
21
9
38
1. Does not contain OH group.
2. DMSO, DMF, HMPA, acetone are polar aprotic,
remaining two are weakly polar aprotic.
3. Solvate but not H-bonding with Nu, thus good
for SN2.
28
Dielectric Constant
80
60
40
20
0
29
If the concentration of ethanol is halved, how
would it affect the rate of the reaction,
1. 3o alkyl halide, protic polar solvent, thus
expect SN1.
3. Halve CH3CH2OH will have no effect on the
rate .
30
If the concentration of ethanol is halved, how
would it affect the rate of the reaction,
1. 3o alkyl halide, aprotic polar solvent, most
likely mechanism is SN1.
3. Halve CH3CH2OH will reduce the rate.
4. See next slide for more explanation...
31
The carbocation is reduced due to
lower dielectric constant, thus slow down
the reaction.
The part of the reaction will not affect the rate
of the reaction since it is after the slow step.
32
Comment on the nucleophilic substitution
reaction,
1. Substrate 2-chlorobutane forms a 2o
carbocation.
2. Nucleophile Methanol is a weak nucleophile.
3. Leaving group Cl is a moderately leaving
group.
4. Solvent Methanol is a polar protic solvent,
favors carbocation formation.
Prediction SN1 mechanism.
Verification If predicted mechanism is correct,
one expects racemic mixture.
33
Comment on the nucleophilic substitution
reaction,
1. Substrate 1-Bromo-2-methlypropane forms
primary alkyl halide.
2. Nucleophile I- is a good nucleophile.
3. Leaving group Br- is a good leaving group.
4. Solvent DMSO is a polar aprotic solvent.
Prediction SN2 mechanism.
34
Comment on the nucleophilic substitution
reaction,
S
1. Substrate (S)-2-Bromobutane is a secondary
alkyl halide.
2. Nucleophile Methylsulfide ion, CH3S-, is a
good nucleophile.
3. Leaving group Br- is a good leaving group.
4. Solvent Acetone is a polar aprotic solvent.
Prediction SN2 mechanism.
Verification expect R product.
35
Write the product(s) and predict the mechanism for
1. Substrate A secondary alkyl halide, can be
SN1 or SN2.
2. Nucleophile Methanol is a poor nucleophile.
3. Leaving group Cl is a moderate leaving group.
4. Solvent Methanol is a polar protic solvent.
This eliminates SN2.
36
Limiting Mechanisms

• Substitution
• Elimination

37
Synthesis of Alkene
From halides - dehydrohalogenation (minus HX)
Elimination
From alcohol - dehydration (minus H2O)
Chapter 7 slide 5
38
Types of Elimination

• Elimination, Bimolecular - E2
• Elimination, Unimolecular - E1
• Bimolecular or Unimolecular refers to the number
  of specie(s) involved at the transition state.
• Bimolecular or Unimolecular describes the timing
  of bond breaking between carbon (on the
  substrate) and the leaving group and the
  formation of a double bond between the ? carbon
  and ? carbon.

39
Zaitsevs rule
Major
Major
Alkene having the greater number of
substituents on the double bond generally is the
major product.
40
E1 Mechanism
Reaction of 2-Bromo-2-methlypropane and methanol.
Step 1
same as SN1. E1 SN1 always occur in
conjunction with each other.
Step 2
41
E2 Mechanism
Reaction of 1-Bromopropane and sodium methoxide
in methanol.
1. Concerted.
2. H C H Br are anti periplanar.
42
Comment on the reaction mechanism of the reaction,
major
major
1. 2-Methylpropene is an E1 product.
2. Ethyl-t-butyl ether is a SN1 product.
3. Heat favors elimination(higher ?G) no heat
favors substitution (lower ?G).
4. E1and SN1 are always in competition of each
other.
43
Predict whether the reaction will proceed
predominately by E1 or E2 mechanism. Write the
major organic product.
1. NaOH is a strong base.
2. 3o alkyl halide - carbocation formation.
3. H2O is a polar solvent.
4. Heat suggests elimination.
Prediction E1
44
Predict whether the reaction will proceed
predominately by E1 or E2 mechanism. Write the
major organic product.
1. 3o alkyl halide - carbocation formation.
2. CH3CO2H is a weak polar solvent.
Prediction E1
45
Why
Elimination
?
non-Zaitsev
Zaitsev
co-planar elimination
46
Limiting Mechanisms

• Substitution
• Elimination

47
Flow Chart for Substitution and Elimination
yes
yes
yes
no
no
no
yes
yes
yes
no
no
no
no
yes
For E1 and/or E2, watch for anti periplanar.
48
Predict the mechanism and product(s) of
1. CH3OH is a poor attacking nucleophile.
2. CH3OH is a protic solvent, favors substitution.
3. 2o alkyl halide - carbocation formation.
4. I- is a good leaving group.
Prediction SN1 and/or E1. Possible products
49
Predict the mechanism and product(s) of
1. ?O- is a good attacking nucleophile.
2. ? O- is a strong base.
3. 1o alkyl halide - SN2.
4. I- is a good leaving group.
Prediction SN2. Possible products
50
Nucleophile
Substrate
Nucleophile
Substrate
51
1. The alkyl bromide starting material in each of
these reactions are classified as?
2. What type of solvent is being used?
3. The nucleophile in these reactions is?
4. The mechanism for these reactions is?
5. Which reaction is faster?
52
Answer
1. 1o alkyl bromide.
2. Aprotic solvent?
3. The nucleophile in these reactions is I-.
4. SN2
5. The second reaction is faster due to less
hindrance.
53
Reaction of bromomethane with sodium hydroxide in
water forms methanol. If sodium iodide is added
to the reaction mixture, the rate of methanol
formation is dramatically increased.
1. The mechanism involved in the reaction of
bromomethane with sodium hydroxide is SN1,
SN2, E1, or E2?
2. Write a reaction pathway that accounts for the
effect of added NaI.
3. Draw a reaction energy diagram showing the two
different energy pathways (i.e., before and
after adding sodium iodide). Indicate
structures for all energy minima in the diagram.
4. Explain why adding NaI increases the reaction
rate.
54
Reaction of bromomethane with sodium hydroxide in
water forms methanol. If sodium iodide is added
to the reaction mixture, the rate of methanol
formation is dramatically increased.
Answer
1. SN2
3.
4. Iodide is a better nucleophile than hydroxide,
so it is expected that reaction between CH3Br
and I- to proceed faster than the reaction
between CH3Br and OH-. CH3I is a more reactive
alkyl halide than CH3Br because I- is a
better leaving group than the Br-, so when
CH3I forms, it reacts with OH- faster than CH3Br
to form CH3OH. The overall result is faster
formation of CH3OH from CH3Br when NaI is
added.