Download Nucleophilic Neighboring Group Participation Case I

Nucleophilic Neighboring Group Participation
Case I:
Consider the following data: R
OBs + HCOOH
SN2
conditions
R
O C H + BsOH
O
OBs
krelative ( 75o C )
1
CH3 (CH2 )2 CH2 OBs
l.00 (reference)
2
CH3 OCH2 CH2 OBs
0.10
3
CH3 OCH2 CH2 CH2 OBs
0.33
4
CH3 OCH2 CH2 CH2 CH2 OBs
461.0
5
CH3 O(CH2 )4 CH2 OBs
32.6
6
CH3 O(CH2 )5 CH2 OBs
1.13
Compound #
R
Nucleophilic Neighboring Group Participation
Case I: Rationale
Rationale to explain enhanced rates of substitution for compounds 4 & 5:
OBs
O
internal
displacement
+
O
CH3
CH3
HCOOH
product
HCOOH
product
-
OBs
cyclic oxonium ion
O
CH3
internal
OBs displacement
+
O
CH3
OBs-
cyclic oxonium ion
In addition to the available S N 2 pathway, a more favorable alternate pathway
for displacement of brosylate is possible for compounds 4 & 5. The internal
displacement pathway leads to the formation of relatively stable 5- and 6membered cyclic oxonium salts. As the chain length increases, the likelihood
of cyclic oxonium ion formation diminishes, and rates approach that of the
reference case where only S N 2 attack by HCOOH is possible.
Nucleophilic NGP
Case II
Consider the following:
CH3 CH2 S
CH CH2 OH
HCl
CH3 CH2 S
CH CH2 Cl + CH3 CH CH2 S
CH3
CH3
CH2 CH3
Cl
"normal" product
"rearranged" product
Rationale:
-
Cl
H
OH2
H3 C C
CH2 +
S
CH2 CH3
H
H3 C
NGP
Cl
C
-
C
H
H
products
+
S
CH2 CH3
episulfonium ion
An S N 1 pathway leading to a primary carbocationic intermediate is not as favorable as
a neighboring group participation (internal displacement) pathway leading to an
episulfonium ion intermediate.
Nucleophilic NGP
Case III
Consider the following:
(erythro)-3-iodo-2-butanol
(threo)-3-iodo-2-butanol
Rationale:
CH3
H
I
H
HCl
(erythro)-2-chloro-3-iodobutane (only product)
HCl
(threo)-2-chloro-3-iodobutane (only product)
I
HCl
H
OH
+
H2 O
OH2
H3 C
H3 C
I
CH3
H
(erythro reactant)
Cl
-
H
CH3
H3 C a
+
I
I
CH3
CH3
Cl
b H
b
a
H
H3 C
Cl -
H
H
H
H3 C
only one erythro product
Cl
Likewise, for threo reactant, only one threo product is obtained. In both erythro and
threo reactions, neighboring group participation by an iodonium ion intermediate
is more favorable than formation of an open carbocationic intermediate.
“Non-nucleophilic” NGP
Acetolysis of Phenyl tosylates
Consider the following:
H CH H C H
3
3
H
CH3 CH COOH
3
H
H
OTs
OAc
AcO
L-threo-3-phenyl2-butyl acetate (32%)
L-threo-3-phenyl2-butyl tosylate
CH3
H
OTs
H3 C
L-erythro-3-phenyl2-butyl tosylate
D-threo-3-phenyl2-butyl acetate (32%)
CH3
H
CH3 COOH
+
H
H
+
CH3
H3 C
H3 C
H
+
OAc
H3 C
L-erythro-3-phenyl2-butyl acetate
23%
alkenes
36%
alkenes
Possible explanations for the results
of the acetolysis reactions

Direct bimolecular nucleophilic attack at C-2
 Inconsistent

with the experimental data. Why?
Formation of a secondary carbocation at C-2
 Inconsistent
with the experimental data. Why?
Rapidly equilibrating secondary carbocations
to account for the acetolysis results?
The “Windshield-Wiper” Effect
CH3
H
H
H3 C
CH3 COOH
OTs
+
H
H3 C
L-erythro
(a)
CH3
H
H
H3 C
O C CH3
O
L-erythro
CH3
H
H
H3 C
+
CH3
H
CH3 COOH
(a)
(b)
(b)
H
H3 C
H3 C
CH3
C O
H
O
L-erythro
A rapidly equilibrating pair of secondary carbocations in which 1,2-phenyl shifts effectively prevent topside
attack by acetic acid.
Additional data concerning
acetolysis of phenyl tosylates
Fact One - Scrambling of a label
*
CH3
H
H
H3 C
OTs
L-erythro
*
CH3
H
CH3 COOH
H
H3 C
O C CH3
O
L-erythro
50%
H
H3 C
+
H3 C
*
CH3
H
C O
O
L-erythro
50%
Additional data concerning
acetolysis of phenyl tosylates
Fact Two - Substituent effects
Z
CH3
H
OTs
H
H3 C
As the electron-donating ability of substituent Z increases, the rate
of acetolysis increases.
7
k acetolys is (x10 )
Cl
H
CH 3
OCH3
0.39
2.39
19.0
228.0
Additional data concerning
acetolysis of phenyl tosylates
Fact Three - Formation of Spirane products
H
H
H2 O
Alcohols
+
OTs
H
H
H
H
HO
H
H
O
CH 3
H
-
OH /H 2 O
Alcohols
+
OTs
H
H3 C
H
H3 C
CH 3
H
Additional data concerning
acetolysis of phenyl tosylates
Fact Four - Unusual Kinetics
OTs
O
C
H
O
k1
HCOOH
OTs
O
C
O
HCOOH
k 1 = 1000 k 2
H
k2
Explanation to account for
the acetolysis results
Phenonium ion participation
Z
+
A phenonium ion: -electron donation from an
electron rich benzene  system leading to internal
displacement of the leaving group and formation of
a cyclopropyl spirane intermediate.
Alkyl Participation
 - bridged complexes
Consider the following reactions:
CH3
(CH3 )3 C CH2 OH
HBr
CH3 C CH2 CH3
Br
CH3
+
Ag
H2 O
(CH3 )3 C CH2 I
(only org. prod.)
CH3 C CH2 CH3 + AgI
OH
(only org. prod.)
Rationale
CH3
CH3
-1
CH3 C CH2
-I
I
slow
CH3
+
+
H3 C
H3 C
C CH2
I
(CH3 )2 C CH2 CH3
H2 O
-
Supporting evidence
H
H
H
B
B
H
H
H
B2 H6
H3 C
H3 C
CH3
Al
Al
CH3
Al2 (CH3 )6
CH3
CH3
alc. prod.
Corroborating evidence for alkyl participation
Observation:
H
H3 C
CHBr 3
(CH3 )3 C C* OH
KOH
D
optically active
H
C C
H3 C
+
H3 C
CH2
D
+ CH3 C
C C
CH3 H3 C
*
CHDCH 3
CH3
optically active
Preliminary explanation:
The above reaction generates carbocationic intermediates under strongly basic conditions.
In general:
-
-
CBr3 + H2 O
CHBr 3 + OH
-
-
ROH + OH
-
CBr3
-Br
H2 O + RO
-
CBr2 (an electrophilic carbene)
-
CBr2 + RORO C Br
+
R O C
ROCBr2
-Br-
-Br-
RO C Br
+
RO C +
+
R + O C
R
O C
Open carbocation possibility
H3 C
H3 C
H3 C
D
+O
H
C
-CO
H3 C
+
H3 C
D
H
H3 C
H3 C
rotation
+
D
H3 C
H3 C
1,2-Me
shift
1,2-Me
shift
CH3
CH3
H3 C
+
D
H
H3 C
-H
H3 C C
CH2
+
H3 C
H
D
H3 C
+
-H
2-butenes
+
H
+
2-butenes
CH3
D
H
+
H3 C
C
CH2
CH3
H
D
(S-enantiomer)
(R-enantiomer)
Racemic mixture- no optical activity
Methyl bridged intermediate
D
H3 C
+O
H3 C
H3 C
CH3
D
H

H3 C
H3 C
C
+

+
H
O C

+
-CO
CH3
CH3
H3 C
H3 C
+
D
H
-H
+
2-butenes + H3 C
C
CH2
D
H
(S-enantiomer)
Optically active
Even if the bridged pathway only competes with the open carbocation
pathway, one alkene enantiomer will still be produced in excess, and
there will be residual optical activity in the product.
Data for the solvolysis of cyclohexyl tosylates
Cons isder the following s olvolysis data:
H
*
CH 3
H
*
CH 3
OTs
H
(CH 3 )3 C
*
+
CH 3
-OTs
k ax
(CH 3 )3 C
optically active
(CH 3 )3 C
H
only alkene product
(racemic mixture)
H
*
CH 3
H
*
(CH 3 )3 C
CH 3
optically active
+
-OTs
k eq
(CH 3 )3 C
CH 3
TsO
(CH 3 )3 C
H
optically active
optically active
k ax ~
= 70-80k eq
H
*
Rationale for cyclohexyl tosylate solvolysis
Ordinarily, an axial leaving group, because it experiences more steric interactions, is solvolyzed 2 to 3
times faster than an equatorial leaving group. The greater rate of solvolysis (70-80 times as fast) for axial
tosylate relative to equatorial tosylate is suggestive of neighboring group participation.
H
H
*
CH3
(CH3 )3 C
+
(CH3 )3 C
TsO
H
CH3
E-1
-OTs
H
optically active
-H
H
H
*
*
CH3
CH3
+
(CH3 )3 C
(CH3 )3 C
optically active
optically active
+
Rationale for cyclohexyl tosylate solvolysis
cont’d.
-Hydrogen participation
H
H

OTs
*
CH3
OTs
(CH3 )3 C

(CH3 )3 C
optically active

H
*
CH3
+
-
-OTs
H
+
H
CH3
(CH3 )3 C
+
+
H
H
*
CH3
(CH3 )3 C
3o R
*
CH3
+
(CH3 )3 C
racemic alkene products
-H
+
Solvolysis of unsaturated tosylates
Consider the following observations:
a) (CH3 )2 C CH CH2 CH2 OTs
CH3 COOH

(CH3 )2 C CH CD2 CH2 OTs
CH3 COOH
b)
or

(CH3 )2 C CH CH2 CD2 OTs
(CH3 )2 C CH CH2 CH2 O
C CH3
O
(CH3 )2 C CH CD2 CH2 O
+
(CH3 )2 C CH CH2 CD2 O
C CH3
O
C CH3
O
both labelled products are obtained from
either labelled reactant
(CH3 )2 CHCH2 CH2 CH2 OTs
CH3 COOH

(CH3 )2 CHCH2 CH2 CH2 O C CH3
O
c)
(CH3 )2 C CH CH2 CH2 OTs
k
CH3 COOH

unsat'd.
>>
k
(CH3 )2 C CH CH2 CH2 O C CH3
O
s at'd.
Possible explanations for solvolysis of unsaturated tosylates
Possible explanation I:
+
Formation of (CH3 )2 C
CH CH2 CH2 ; Unlikely, this is a primary R
Possible explanation II:
(CH3 )2 C
.
O
CH3
CH CH2
CH2
+
+
C
OTs
CH2
CH
CH3
HO
C
CH3
CH2
The above explanation invokes the intermediacy of a tertiary carbocation formed with
-electron NGP; no primary carbocation is involved.Further, the above tertiary
carbocation can account for the scrambling observed with labelled reactants and for
the enhanced rate of solvolysis in the case of the unsaturated vs. saturated tosylate
reactants.
O
However:
CH2
a different set of solvolysis products
CH3 C OH
(CH3 )2 C CH
relative to those obtained from the
unsaturated tosylate reactants
CH2
Cl
Best explanation:
CH2
[ (CH ) C
3 2
CH
+
[ (CH ) C
]
3 2
CH2
3 2
CH
CH2
CH2
[ (CH ) C
CH2
CH
CH2
A homoallyl carbocation
+
]
+
]