NEIGHBORING GROUP

PARTICIPATION

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 Neighboring Group Participation (Anchimeric asssitance)

Hydrolysis of EtS–CH2CH2 – Cl is 104 times faster than that of EtO–CH2CH2–Cl. Why?

.. slow fast ..
EtS EtS
EtS
Cl Cl OH

..
OH2

Reaction of CH3COOH with

MeO reacts four times slower than
OSO2Ar OSO2Ar
Reaction of ROH with
Me
O
OSO2Ar OSO2Ar
Me
OMe
reacts 400 times faster than
Nucleophilic Neighboring Group Participation
Case I: Rationale
Rationale to explain enhanced rates of substitution for compounds 4 & 5:

OBs internal HCOOH

+ product
O displacement O -
OBs
CH3 CH3
cyclic oxonium ion

internal HCOOH product

OBs displacement +
O O
OBs -
CH3 CH3
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 6-
membered 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:

HCl
CH3 CH2 S CH CH2 OH CH3 CH2 S CH CH2 Cl + CH3 CH CH2 S CH2 CH3
CH3 CH3 Cl
"normal" product "rearranged" product
Rationale:

H Cl- H Cl- H
OH2
H3 C C H3 C H
CH2 + C C products
NGP +
S S
CH2 CH3 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.

 -Bromopropionate Ion

H3 C c o n c . [O H-] C H3
H C Br 4M
HO C H
C O O C
O- 0 .1 M O (R )-c o n fig
(S )-c o n fig
- in ve r s io n
d ilu t e
[O H -] H3 C
H C OH SN2

C O
O- (S )-c o n fig
r e t e n t io n
Two different results! neither SN1 or SN2
 REACTION IN CONCENTRATED BASE
straightforward SN2 displacement

-
H O H3C C H3
H C Br c o n c [O H -] HO C H
C O S N2 O C
in v e r s io n
O O
(S )-c o n fig (R )-c o n fig

SN2 ( rate = k[RBr] [OH] ) is favored by high [OH]

 REACTION IN DILUTE BASE
neighboring group participation

H3 C in ve r s io n -1 CH 3
H C Br d ilu t e [O H-] O C H
S N2 O H
C O C
O O
(S )-c o n fig in ve r s io n -2
S N2
In dilute base H3 C
C OH
the internal
displacement
H
has a competing C O Two inversions
rate.
O give a product
with retention.
(S )-c o n fig
 Neighboring Group Participation : Retention of configuration
Et2
Et2(HO)C C
NaOH HO
Cl OH Retention
Me Me
H H
Et2
C
-
OH -
O
OH
Et2 Et2 Me
C C
-
OH H
Inversion 1 Inversion 2
O -
Cl O OH
Me Me
H
H
Explanation
Explanation to
to account
account for
for the
the
acetolysis
acetolysis results
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.
NGP by a cyclopropane, cyclobutane or a homoallyl group

NGP by an aromatic ring

 Me
OH-
Et S Cl Two products
 Me Me
Et S Cl Et S
+

Non symmetrical episulfonium ion

Nu-

Nu Me
EtS
Nu
Me EtS
THE ACETOXY BROSYLATE GIVES 100% TRANS

H3C O

O O Ac
Na OAc

HOAc
OBs O Ac

1 0 0 % t ra n s
 INTERMEDIATE ION

CH3 CH3
Bridged ion,
O OAc attacks
O + O
O equally on
+ either side,
but always
anti

- O-Ac

trans diacetate
 OTs
OTs NaOAc OAc
OAc OAc
OAc Direct SN2
enantiopure trans-1,2-diacetate
enantiopure cis-isomer

OTs AcO path 1

OTs OAc
NGP O
O
OAc O O Me OAc
AcO Rapidly interconvertible
enantiopure trans-isomer
enantiomeric pair
path 2 Flip

enantiomeric
OAc product OAc
OAc OAc
Racemic mixture

* Enantiopure cis compound will lead enantiopure trans-compound

* Enantiopure trans compound will lead to racemic mixture
* Both the stereoisomer will lead to trans-1,2 diacetoxy cyclohexane compound

OAc OAc
OAc
OAc
(1S,2S)-cyclohexane-1,2-diyl diacetate
(1R,2R)-cyclohexane-1,2-diyl diacetate
 Neighboring group participation

Q. H HNO2
O S S H
O
CO2H O CO2H
OH H2N

H
R
H O O O H
O S H H
O
OH C
N2 O
O
 O O
NaNO2
OH OH
NH2 AcOH, 50C
OAc

What about the final stereochemistry

O O
SN2, NGP O SN2, AcO-
OH OH
O
N + OAc
N
-lactone Retention of configuration
 O
??
OH
NH2 O
Q. Which one will undergo SN1 solvolysis faster? Exaplain?

CH3

H 3C C CH2Cl H 3C C C Cl
I
H H H2
II

phenonium ion

δ
H H + Cl
H
H H H
Cl H
H3C Cl H3C H
TS H3C H
Sol OH

Solvolysis products
Q. Which compound solvolyses faster in HOAc? (I or II). Give the
structure of the product from I.
OTs OTs

I II


OTs
OAc

HOAc
I

III

Participation of the π electrons of the double bond gives the ion III, which
would be stabilized by delocalization of the positive charge.
I undergoes 1011 times greater rate than II
 Which reaction in each pair would be expected to be faster?

OTs

solvolysis in AcOH
TSo

PhS-(CH2)3-Cl and PhS-(CH2)4Cl solvolysis in MeOH

OTs OTs
solvolysis in AcOH

Ph Ph
PhO2C solvolysis in AcOH
Br Br
CO2Ph

Me3CCH2OTs Solvolysis in dil. NaOH

OTs
 OTs OTs

solvolysis in AcOH

anti syn

rate: 107 1
OTs
+
C +

syn syn

AcO
 AcOH
OTs Product
OTs

+
C

OAc
 OH OPh NMe2
DEAD, TPP DEAD, TPP
NMe2 NMe2 OH
PhOH PhOH

A B

Both A and B gave the same priduct when subjected to Mitsunobu conditions with phenol as nucleophile

H
H
OH DEAD, TPP
NO2
NO2
H

Explain the reaction

 PhOH

Me OPh
+
N
Me NMe2

common intermediate

OH OP+Ph3 OP+Ph3
TPP NO2

DEAD NO2
NO2 C NO2
H
O
H2O HO CHO
Br
O O O

Br +
hemiacetal
C
HO

+
O
HO CHO
O O O

OTs
C+
HO
hemiacetal

O+ OH

CHO