NEIGHBORING GROUP NEIGHBORING GROUP PARTICIPATIONPARTICIPATION

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Hydrolysis of EtS–CH2CH2 – Cl is 104 times faster than that ofCH3–CH2CH2–Cl. Why?

EtS

Cl

.. slow EtS

Cl

fast

OH2

..

EtS

OH

..

Neighboring Group Participation (Anchimeric asssitance)

Stereochemistry

Cl

Et2(HO)C

HMe

Et2C

HMe

HOOH

Cl

Et2C

HMe

O

Et2C

HMe

O

Et2C

HMe

-OOH

NaOH Retention

-OH

-OH

-OHInversion 1 Inversion 2

Neighboring Group Participation : Retention of configuration

Different types of NG

NGP by a cyclopropane, cyclobutane or a homoallyl group

O

OBs

H3C O

NaOAc

HOAc

OAc

OAc

100% trans

THE ACETOXY BROSYLATE GIVES 100% TRANSTHE ACETOXY BROSYLATE GIVES 100% TRANS

INTERMEDIATE IONINTERMEDIATE ION

OO

CH3

O

CH3

O+

+

Bridged ion,OAc attacksequally oneither side,but alwaysanti

O-Ac-

trans diacetate

Neighboring group participation

Q.

OH H2N

OH

CO2H

HNO2

OO

H

CO2H

S S

OH N2

OH

C

O

O HS O

OH

O

O

H

HR

Q. Which one will undergo SN1 solvolysis faster? Exaplain?

H3C CH

CH2Cl H3C CH

CH2

CH3

Cl

I II

δH

H

H3C Cl

H H

H3CTS

HCl

H

H

H3C

Sol OH

HH

+ Cl

Solvolysis products

phenonium ion

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

OTs OTs

I II

Participation of the π electrons of the double bond gives the ion III, which would be stabilized by delocalization of the positive charge.

I

OTs

HOAc

III

OAc

I undergoes 1011 times greater rate than II

Neighboring group participation: Summary

• Retention of configuration• Enhanced rate of reaction

C

C O

O

BrHH3C

C

C O

O

OHHH3C

C

CO

O

HO HCH3

conc. [OH-]4M

dilute[OH-]

0.1M(S)-config

(R)-config

(S)-config

inversion

retention

-Bromopropionate Ion

SN2

neither SN1 or SN2

-

-

-

Two different results!

inversion

(R)-config(S)-config

C

CO

O

HO HCH3

C

C O

O

BrHH3C

conc [OH-]OH

-

SN2

REACTION IN CONCENTRATED BASEREACTION IN CONCENTRATED BASEstraightforward SN2 displacement

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

(S)-config

C

C

O HCH3

O

C

C O

BrHH3C

OSN2

inversion-1dilute [OH-]

O H

C

C O

OHHH3C

O

inversion-2

(S)-config

SN2

REACTION IN DILUTE BASEREACTION IN DILUTE BASEneighboring group participation

Two inversionsgive a productwith retention.

In dilute basethe internal displacementhas a competingrate.

Important name reactions based on Nucleophilic substitution

Appel Reaction

A modern SN2 reaction: Mitsunobu reaction

Mechanism: First step involves neither the Nu nor the alcohol

Stable anion

Ph3P=O +

EtO2CN

NCO2Et

Ph3P:

EtO2CN

NCO2Et

Ph3P

O RH

EtO2CN

NCO2Et

Ph3P

H

O R+

O RPh3P

EtO2CN

NCO2Et

H+

Nu

R Nu

SN2

100%

H Nu

EtO2CN

NCO2Et

H

H

100% inversion

EtO N

N OEt

O

O

Diethyl azo dicarboxylate (DEAD)R OHR O Ph

O

DEAD +Ph3P

PhCOOH

Nitrogen nucleophile; Gabriel procedure of amine synthesis

Problems

State with reasons whether these reactions will be either SN1 or SN2.

SN2 due to carbonyl

SN1 Acid catalysis makes better LG, inversion unusual, but due to OH group hindrance

SN2 base catalysis makes better Nu, inversion usual

On-PrO

OH

OPr(c)

( + )_ ( + )_

OO

OHn-PrOH

H

(b)

( + )_ ( + )_

OBr

O

ON3

O

N3(a)

OH

OH

Br

Br

CO2Me

AKOH

H2O

O

O CO2H

A+ K2CO3, acetone

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

O

O CO2Me

Carbonate is good enough to remove H+

from ArOH1°, C=O adjacent, both go by SN2

How to choose between SN1 and SN2 when the choice is more subtle

Ester hydrolysis

Problems :

BrBr Br

1 10-6 10-14

Explain?

2) Rate of solvolysis in EtOH :

CH3CH2 Br Me2HCCH2 Br Me3CCH2 BrCH3CH2CH2 Br

relative rate 1 2.8X10-1 3.0X10-2 24.2X10-6

1) SN2 reaction by EtO- in EtOH:

Explain ?

Br Br

1 10-23

Explain ?

1-bromotriptycene

Rigid structure, cation empty p-orbitals are at right angles to orbitals of Ph

cc at bridge head, less stable, difficult to attain planarity due to rigidity

A)

A)B)

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?

I

S

Cl

H

II

S

H

Cl

S

OAc

H

Q.

• 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

O

CH3

OTs

O

O

CH3

III

OTs

O

O

O

O OAc

OAc

HOAc

OAc

OAc

OAc

OAcO

O(+)

AcOH

AcOH. .

(+)

s

s R

R

Q. Suggest a mechanism for the following reaction

PhN

Ph

O

O

Cl H2OPh N

H

O

O

O

Ph

CH3CN, heat

N

O

Ph

O

Ph

Cl

O

NPh

O

Ph

O

NPh

O

Ph

OH

Ph NH

O

O

O

Ph

Phase- transfer catalysis of the SN2 reaction between NaCN and an alkyl halide

Na+ CN-

RX

aq. phase (H2O)

organic phase (CH2Cl2)

Na+ CN -

Q + X -

Na+ X-

Q + CN -

Q + CN -

RX

Q + X -

RCN

+ +

+ +

aq. phase (H2O)

organic phase

RX RCN + X -

takes place rapidlyCN - +

QX = R4N + X -

such as (CH3CH2CH2 CH2)4 N+ X-

Here no reaction takes place as CN- can’t enter into the org. phase to react with RX

Here the PTC transports the CN- ion (Q CN-) into the org. phase

Nucleophilic NGPNucleophilic NGPCase IICase II

Consider the following:

CH3CH2 S CH

CH3

CH2OHHCl

CH3CH2 S CH

CH3

CH2Cl +CH3 CH

Cl

CH2 S CH2CH3

"normal" product "rearranged" product

Rationale:

CH3CH

S

CH2CH3

CH2

OH2+

NGP

Cl-

C CH3C

HH

H

S

CH2CH3

+

Cl-

episulfonium ion

products

An SN

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.

Mechanism of Gabriel amine synthesis

Arbuzov ReactionMichaelis-Arbuzov Reaction; Phosphorous nucleophiles