1. NEIGHBORING GROUP
PARTICIPATION
WHEN YOU NEIGHBOR HELPS OUT

2. Neighboring Group Participation (Anchimeric asssitance)
Hydrolysis of EtS–CH2CH2 – Cl is 104 times faster than that ofCH3–CH2CH2–Cl. Why?
.. slow fast ..
EtS EtS
EtS
Cl Cl OH
..
OH2

3. Stereochemistry

4. 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

5. Different types of NG

6. NGP by a cyclopropane, cyclobutane or a homoallyl group

7. THE ACETOXY BROSYLATE GIVES 100% TRANS
H3C O
O OAc
NaOAc
HOAc
OBs OAc
100% trans

8. INTERMEDIATE ION
CH3 CH3
Bridged ion,
O OAc attacks
O + O
O equally on
+ either side,
but always
anti
- O-Ac
trans diacetate

9. Neighboring group participation
Q. H HNO2 H
O S S
O
CO2H O CO2H
OH H2N
H
R
HO O O H
O S H H
O
C
OH N2 O
O

10. Q. Which one will undergo SN1 solvolysis faster? Exaplain?
CH3
H3C C CH2Cl H3C 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

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

12. Neighboring group
participation: Summary
• Retention of configuration
• Enhanced rate of reaction

13. α-Bromopropionate Ion
H3C conc. [OH-] CH3
H C Br 4M
HO C H
C O O C
O- 0.1M O (R)-config
(S)-config
- inversion
dilute
[OH-] H3C
H C OH SN 2
C O
O- (S)-config
retention
Two different results! neither SN1 or SN2

14. REACTION IN CONCENTRATED BASE
straightforward SN2 displacement
-
H O H3C CH3
H C Br conc [OH-] HO C H
C O S N2 O C
inversion
O O
(S)-config (R)-config
SN2 ( rate = k[RBr] [OH] ) is favored by high [OH]

15. REACTION IN DILUTE BASE
neighboring group participation
H3C inversion-1 CH3
H C Br dilute [OH-] O C H
S N2 O H
C O C
O O
(S)-config inversion-2
SN2
In dilute base H3C
C OH
the internal
displacement
H
has a competing C O Two inversions
rate.
O give a product
with retention.
(S)-config

16. Important name reactions based
on Nucleophilic substitution

17. Appel Reaction

18. A modern SN2 reaction:
Mitsunobu reaction

19. O
PhCOOH
O
O N Et
Et N O
DEAD +Ph3P O
R O Ph
R OH Diethyl azo dicarboxylate (DEAD)
100% inversion
Mechanism: First step involves neither the Nu nor the alcohol
Ph3P: Ph3P Ph3P
N CO2Et N CO2Et
EtO2C N EtO2C N N CO2Et + O R
EtO2C N
H H
Stable anion O R
Ph3P=O H Nu
+ Nu H
100% Ph3P N CO2Et N CO2Et
R Nu O R + EtO2C N EtO2C N
H H
SN2

21. Nitrogen nucleophile; Gabriel procedure of amine synthesis

22. Problems

23. State with reasons whether these reactions will be either S N1 or SN2.
O O
(a) Br N3 N3
O O
SN2 due to carbonyl
O
O
n-PrOH
(b) OH
H
_
(+)
SN1 _
(+)
Acid catalysis makes better LG, inversion unusual, but due to OH group hindrance
OH
O
n-PrO
(c) OPr
SN2 _
(+) _
(+)
base catalysis makes better Nu, inversion usual

24. How to choose between SN1 and SN2 when the choice is more subtle
Q. The chemistry shown here is the first step in the manufacture of
Pfizer’s doxasolin (Cardura), a drug for hypertension. Draw the
mechanism of the reaction involved and comment on the bases used
OH O
CO2Me
+ Br
K2CO3, acetone
A
OH Br
O CO2Me
O
KOH
A
H2O
O CO2H
Carbonate is good enough to remove H+
from ArOH
1°, C=O adjacent, both go by SN2
Ester hydrolysis

25. Problems :
1) S N 2 reaction by EtO - in EtOH:
CH3CH2 Br CH3CH2CH2 Br Me2HCCH2 Br Me3CCH2 Br
Explain ?
relative rate 1 2.8X10-1 3.0X10-2
24.2X10-6
2) Rate of solvolysis in EtOH :
Br
Br Explain?
A) Br
cc at bridge head, less
stable, difficult to attain
planarity due to rigidity
1 10-6 10-14
Br Br
B) Explain ?
A) Rigid structure, cation empty
p-orbitals are at right angles
to π orbitals of Ph
1 10-23
1-bromotriptycene

26. Q. Which compound solvolyses faster in HOAc containing NaOAc
(I or II)?
The product is the same from either I or II. What is the structure
of the product?
S S
H Cl
Cl H
II
I
S
H
OAc

27. OTs OTs
CH3 CH3
Q. O
O
I II O
O
• Which compound solvolyses in HOAc faster ?
• Predict the stereochemistry in each case
• If I is optically active, is the product is also optically active?
OTs O OAc
O HOAc
O O OAc
AcOH
..
(+) OAc
s OAc R
O
s OAc O R OAc
(+)
AcOH

28. Q. Suggest a mechanism for the following reaction
O O
H2O O Ph
Ph Cl
N Ph N
CH3CN, heat H
Ph O
O
O O
O
Cl
Ph N Ph N
Ph N
O O Ph O
Ph Ph
OH
O
O Ph
Ph N
H
O

29. Phase- transfer catalysis of the SN2 reaction between NaCN and an alkyl halide
aq. phase (H2O) aq. phase (H2O)
Na CN
+ - Na+ CN - Na+ X-
+ +
+ -
Q X Q CN -
+
organic phase (CH2Cl2)
Q+X- Q + CN -
RX QX = R4N + X - + +
such as (CH3CH2CH2 CH2)4 N+ X- RCN RX
organic phase
Here no reaction takes Here the PTC transports
place as CN- can’t enter the CN- ion (Q CN-)
into the org. phase to into the org. phase
react with RX
CN - + RX RCN + X -
takes place rapidly

30. 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.

31. Mechanism of Gabriel amine synthesis

32. Arbuzov Reaction
Michaelis-Arbuzov Reaction; Phosphorous nucleophiles