Transcript Substitution and Elimination Reactions of Alkyl Halides

Substitution and Elimination
Reactions of Alkyl Halides
Substitution, Nucleophilic,
Bimolecular – SN2
Nuc :

C

X

Nuc
C

X
Nuc
transition state
Rate = k[Nuc: ][R-X]
Second Order Rate Kinetics
C
+ X
Reaction Profile for SN2
Reaction (Wade)
Stereochemistry of SN2 Reaction
Inversion of Configuration
CN
Br
+
(S)
KCN
+ KBr
(R)
Proof of Inversion of
Configuration at a Chiral Center
CH2
benzyl (Bz)
O
OCCH3
-OAc, acetate
OH
H
Bz
OTs
TsCl
H
Bz
CH3
(S)(-)
[]D = -33o
CH3
(S)
KOAc
SO2Cl
p-toluenesulfonyl chloride
(Ts-Cl)
O
CH3
CH3
RO-H
S O R
O
a tosylate (ROTs)
H
Bz
CH3
OH
(R)(+)
[]D = +33o
H2O
H
Bz
CH3
OAc
(R)
Acetate Approaches from 180o
Behind Leaving Group
Bz
AcO
OTs
H
CH3
(S)

AcO
Bz
CH3 H

OTs
Bz
AcO
(R)
H
CH3
OTs
Inversion on a Ring is often
more Obvious: Cis
Trans
Substrate Reactivity
Since the energy of the transition state is significant in determining
the rate of the reaction, a primary substrate will react more rapidly
than secondary (which is much more rapid than tertiary).
R
Rate: ~0
(CH3)3CBr
tertiary
Br + Cl
R
Cl + Br
6
1
500
40,000
(CH3)3CCH2Br
(CH3)2CHBr
CH3CH2Br
CH3Br
secondary
primary
methyl
neopentyl
2 x 10
1o > 2o >> 3o
Bulkiness of Substrate
Polar, Aprotic Solvents
Solvents should be able to "cage" the metal cation
O
CH3SCH3
DMSO
O
O
CH3CN
HCN(CH3)2 CH3CCH3
acetonitrile
acetone
DMF
Polar, protic solvents lower energy of nucleophile
by solvation
HOCH3
CH3OH
Br
CH3OH
HOCH3
Nucleophilicity
Nucleophile strength roughly parallels basicity
-
-
-
CH3 > NH2 > OH > F
-
Nucleophile strength increases going down a group
OH < SH
-
-
-
-
F < Cl < Br < I
NH3 < PH3
A base is always a stronger nucleophile than its conjugate acid
-
NH2 > NH3
-
OCH3 > CH3OH
Iodide vs. Fluoride as
Nucleophiles
Nucleophiles
(preferably non-basic)
basic
-
-
non-basic
-
-
-
-
-
HS > :P(CH 3)3 > CN > I > OCH3 > OH > Br > Cl > NH3 > OAc
-
Good Leaving Groups are
Weak Bases
C
LG bond is broken during RDS
Quality of leaving groups is crucial
Sulfonates are excellent leaving groups
O
SO
CH3
O
O
CH3SO
tosylate
O
mesylate
TsO-
MsO-
Common Leaving Groups
TsO- = MsO- > NH3- > I- > H 2O- = Br- > Cl- >> F-
Sulfonates are easily prepared from alcohols
O
CH3OH + ClSR
in pyridine
O
CH3OSR + HCl
O
O
tosylate R =
mesylate R = CH
CH3
3
SN2 and E2
SN2
H
R1 C
R2
Nuc:
C
H
Nuc
R1 C
R2
Br
C
+ Br
E2
H
R1 C
R2
C
B:
Br
rate = k[R-Br][B -]
R1
C
R2
C
+ B-H + Br
Bimolecular Elimination - E2
Nucleophile acts as Bronsted Base
Base:
H
C

C

C
Br
+ base-H
+ Br
-Elimination

Base
C
H
C

C


Br
SN2 Competes with E2
Depends on the Nature of the Nucleophile
CH3CO2
wk. base
Br
CH3CHCH3
CH3CH2O
str. base
Substitution
OAc
CH3CHCH3
100%
OEt
CH3CHCH3
20%
Elimination
CH2=CHCH3
0%
CH2=CHCH3
80%
SN2 Competes with E2
Depends on the Size of the Base
CH3CH2O
str. base
CH3CH2CH2CH2OEt
90%
CH3CH2CH=CH2
10%
CH3CH2CH2CH2Br
(CH3)3CO
str. bulky base
CH3CH2CH2CH2OtBu CH3CH2CH=CH2
85%
15%
SN2 Competes with E2
Depends on the Nature of the Substrate
CH3CH2CH2CH2Br
1o
(CH3)3CBr
3o
CN
str. nuc.; wk. base
CN
CH3CH2CH2CH2CN
100% SN2
CH2=C(CH3)2
100% E2
Stereochemistry of E2
rate = k[R-X][base]
second order rate kinetics
CH3O
H
C

C
C
Br
H on  carbon is anti to leaving group
C
+ CH3OH
+ Br
Anti-Coplanar Conformation
3(R),4(R) 3-Bromo-3,4dimethylhexane
CH2CH3
Br
CH3
NaOCH3
H
CH3
in CH 3OH
heat
CH2CH3
H and Br Anti-coplanar
orientation
CH3O
H
Me Et
C
C C
Et

Me (R) (R) Br
Me
C
Et
OCH3
H
Me
Et
Et
Me
Br
Me
Et
Me
Et
Et
Me
In a Cyclohexane,
Leaving Group must be Axial
KOC(CH3)3
OTs
in t-BuOH / 
+ KOTs
OTs
OTs
has no anti-coplanar H
H
OtBu
H
Zaitsev’s Rule
NaOCH3
in CH 3OH
Br
+
85%
15%
Zaitsev's Rule: In an elimination reaction, the
more highly substituted alkene (usually) predominates
More Stable Alkene
Predominates
Hyperconjugation
p bond associates with adjacent C-H s bond
1-butene
trans 2-butene
C
C
C
C
mono-substituted
disubstituted
With Bulky Base,
Hofmann Product Forms
Which will react more rapidly?
CH3
Cl
NaOEt in EtOH
heat
CH(CH3)2
Menthyl chloride
CH3
Cl
CH(CH3)2
Neomenthyl chloride
NaOEt in EtOH
heat
Reactive Conformations
Menthyl chloride
(CH3)2CH
Neomenthyl chloride
Cl
CH3
CH3
(CH3)2CH
Cl
stable
H
H
stable and reactive
flip
NaOEt
CH(CH3)2
CH3
CH3
CH(CH3)2
CH(CH3)2
H
NaOEt
Cl
reactive
CH3
E2 Reaction of
(R,R) 2-iodo-3-methylpentane
I
CH3CHCHCH2CH3
CH3
H
NaOCH2CH3
C
in ethanol 
C
CH3
CH3
(R,R)
CH2CH3
OR
CH3
CH2CH3
H
CH2=CHCHCH2CH3
C
OR
CH3
C
CH3
Stereochemistry is Important
reactive conformation
I
H
CH3
C
C
CH2CH3
CH3
OEt
(R,R)
I
H
H
CH3
CH3
CH3CH2
C=C
CH3
H
CH3CH2
H
CH3
E2 Reaction of a Vicinal
Dibromide using Zn dust or Iodide
Br
H
CH3
Br
H CH3
C
C
(R) (R)
Br
anti conformation
H
CH3
H
CH3
Br
Zn
HOAc
CH3
CH3
C
C
H
H
only cis forms
Unimolecular Substitution and
Elimination – SN1 and E1
CH3
CH3
C
Br
in warm CH 3OH
CH3
CH3
CH3
C
CH3
SN1
Rate = k[R-Br]
1st order rate kinetics
CH3
OCH3 +
C=CH2
CH3
+ HBr
E1
SN1 mechanism (Wade)
1st step is rate determining
Reaction Profiles (Wade)
SN1
SN2
Hammond’s Postulate
• Related species that are close in energy are close in
structure.
• In an endothermic reaction, the transition state is
similar to the product in structure and stability.
• In an exothermic reaction, the transition state is
similar to the reactant in structure and stability.
• i.e. the structure of the transition state resembles
the structure of the most stable species.
Endo- transition state looks like product
Exo- transition state looks like reactant
SN1 Transition State
SN1 Solvent Effects
CH3
CH3
C
Cl
ROH
react.:
1
CH3
C
OR + HCl
CH3
CH3
EtOH
CH3
40% H 2O / 60% EtOH
100
80% H 2O / 20% EtOH
14,000
H 2O
100,000
Transition state energy is lowered by polar protic solvents
Partial Racemization in SN1
Carbocation Stability
more highly substituted, lower energy
Carbocation Stability
CH3
CH3
C
H
> CH3
CH3
tertiary
>
C
= CH2=CH CH2 =
CH3
secondary = primary allylic
=
CH2 > CH3CH2
primary benzylic > primary
resonance stabilized
Carbocations can Rearrange
1,2-Hydride Shift
Br
CH3 C
H
H
C
CH3
CH3
H2O
H
CH3 C
H
OH
C
CH3 + HBr
CH3
Carbocations can Rearrange
1,2-Methide Shift
Hydride shift
H
2
o
Hydride
shift
H
o
3
Ring Expansion
a
a
c
c
b
b
2
o
2
o
Rings Contract, too
hydride
shift
a
b
H
ring
contraction
a
b
E1 Mechanism
E1 and SN1 Compete
b)
a)
OTs
CH3OH / 
CH3
+
Zaitsev
a) CH3OH
H
H
CH3
CH3
b) CH3OH
CH3
OCH3
CH3
Synthetic Chemist’s Nightmare
Br
CH3OH
CH3O
CH3O
CH3O
CH3O
Ring Expansion to a More
Stable 6-membered Ring
H
Br
via
hydride shift
c
CH3OH
b
H
a
b


c
a
via
ring expansion
hydride shift
Dehydration of Alcohols – E1
OH
H
H2SO4 (aq) cat.
+ H 2O
H
regenerated
H
O
HSO 4
or H2O
H
-H2O
H
Methide Shift is Faster than
Loss of H+
CH3
OH
CH3
CH3
CH3
CH3
H2SO4 (aq)
CH3
+
distill
major
minor
+ H2O
Provide a Mechanism
H
Br
OCH3
CH3O
H
OCH3
CH3OH, warm
+
+
+ HBr
(or CH3OH2)
H
Br
OCH3
CH3O
H
OCH3
CH3OH, warm
+
+
b)
H
a)
CH3OH a)
b)
Br
+ HBr
OCH3
(or CH3OH2)
ring expansion
(squiggly bond = both isomers)
CH3OH
H
hydride shift
H
CH3OH
H
OCH3
c)
Can R-X form a good LG?
No
Yes
no reaction classification of  carbon
o
3
1
o
o
2
nuc. hindered, strong base?
strong base?
nuc. a strong base?
Yes
E2
No
Yes
No
Yes
SN1*
E1
good nuc., nonbasic?
(some S N2) Yes
SN2 (slow S N2)
No
polar solvent?
E2
E2
No
good nuc., non-basic?
Yes
Yes
SN2
No
solvent polar? Yes
SN1*
E1
* SN1 is favored over E1 unless high temp. and trace amounts of base are used.
Give the Major Product &
Predict the Mechanism
OH
CH3
6M H2SO4
120 oC, distill
OH
CH3
6M H 2SO4
120 oC, distill
E1
CH3
NaNH2 in liq. NH 3
OTs
NaNH2 in liq. NH 3
OTs
E2
H
CH3
CH2CH3
OTs
KBr
in acetone, 20 oC
H
CH3
CH2CH3
OTs
KBr
in acetone, 20 oC
SN2
Br
CH3
CH2CH3
H
Br
1% AgNO3
in CH 3CH2OH
Br
1% AgNO3
in CH 3CH2OH
SN1
CH3CH2O
+ AgBr
Br
CH3CH2CH2OH
warm
Br
CH3CH2CH2OH
warm
SN1/E1
OCH2CH2CH3
+
CH3
Br
NaSCH2CH3
in CH 3CN
CH3
Br
NaSCH 2CH3
CH3
in CH 3CN
SN2
SCH2CH3
I
H2O
(phase transfer cat.)
I
OH
H2O
(phase transfer cat.)
SN1 (E1)
+
I
CH3
CH3
NaOCH2CH3
in refluxing ethanol
I
CH3
CH3
NaOCH2CH3
in refluxing ethanol
E2
CH3
CH3
NaOCH3
CH3CH2CH2CH2CH2Cl
in methanol, room temp.
NaOCH3
CH3CH2CH2CH2CH2Cl
in methanol, room temp.
SN2
O
Which Reacts More Rapidly in
E2 Reaction?
(CH3)2CH
I
A
(CH3)2CH
I
B
Cis Reacts more Rapidly
trans
I
reactive
I
(CH3)2CH
stable
CH(CH3)2
I
cis
(CH3)2CH
reactive & stable H
reacts more rapidly