Lecture 3

Solvent effectsRate of a reaction depends on the difference between the energy of the reactants & the energy of the TS in the r.d.s. of reaction

When an alkyl halide undergoes both SN1 and SN2 reactions, the SN2 reaction will be favored by a high concentration of a good (negatively charged) neocleophile in a polar aprotic solvent, whereas the SN1 reaction will be favoured by a poor (neutral) nucleophile in a polar protic solvent

Q. Which reaction will take place more rapidly?

CH3Br NH3

Et2O

CH3Br NH3

EtOH

CH3NH3

CH3NH3

Br

Br

+ +

+ +

DMF

H C

O

N

CH3

CH3

H3C S

O

CH3

DMSO

H3C

S

CH3

O

H3CS

H3CO

CH3

S

H3C

O

KCH3

SCH3

O

polar aprotic solvent

Effectiveness of different nucleophiles in SN2 reaction

Relative rates of reaction with MeBr in EtOH

PhS

PhO

Nucleophile pKa of HX Relative rate

6.4 5.0 x 107

10.0 2.0 x 103

HO

PhO

AcO

H2O

Nucleophile pKa of HX Relative rate

15.7 1.2 x 104

10.0

19.0 x 102

2.0 x 103

4.8

-1.7 1.0

Relative rates of reaction with MeBr in EtOH

Nucleophilic power towards saturated carbon

I > Br > Cl > F

RSe > RS > RO

R3P: > R3N:

Hard nucleophiles, soft nucleophiles

Hard nucleophiles X Soft nucleophiles Y

small large

charged neutral

basic ( HX weak acid ) not basic ( HY strong acid )

low-energy HOMO high-energy HOMO

like to attack C=O like to attack satd. carbon

such as RO, NH2, MeLi such as RS, I, R3P

Soft nucleophiles are rather large and flabbywith diffuse high-energy electrons

Hard nucleophiles are small with closely held electrons and high charge density

For hard nucleophiles reactions are dominated by electrostatic interactions

For soft nucleophiles reactions are dominated by HOMO-LUMO interactions

SN2 Inversion of configuarationSN1 ideally Racemization

Retention of configuaration :

SNi ( substitution nucleophilic internal)

However, it can’t be a simple SN2.

Problem :

Me

OHPh

H

Me

ClPh

H

SOCl2 + + HClSO2

Rate = K [ROH] [ SOCl2] SN2

SNi 1) R OH

fast R O S

O

Cl+ HCl

2)R O S

O

ClSlow O

S

ClO

R R Cl - SO2

SOCl2

ion pair

Retention

Me

OHPh

H

Me

ClPh

H

SOCl2

Py

Inversion

Neighbouring Group Participation :

“Retention” “Anchimeric asssitance”

In presence of , carboxylate will be produced.

Q. Hydrolysis of EtS–CH2CH2 – Cl is 10 4 times faster than that of EtO–CH2CH2–Cl. Explain?

HO

O

C Br

MeH

HO2C

C OH

MeH

1) OH

2) H

OH

OH

O2C

HMe

OH

H

O C

O

H

Me

HO2C

OH

MeH

O

O

C Br

MeH

Inversion Inversion

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

Q. Draw mechanism for the reactions and describe the stereochemistry of the product

O

ClBr

NO

H2N

CO2Et

OR

CO2Et

OR

+

1. PhNMe2, CH2Cl2

2. NaH, DMF

O

Ph

OTs OTs

NH

KOH

H2S

OH

Ph

S

N+(a)

(b)

Q. Predict the stereochemistry of these products. Are they single diastereomers, enantiomerically pure, or racemic, or something else ?

Q. Describe the stereochemistry of the products of these reactions.

Cl

S

O LiAlH4

HS

O

S

S

OH_( + )

(a)

(b)

enantiomerically pure

base

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

OBr

O

O

N3

n-PrOH

H

On-PrO

ON3

O

OH

OPr

O

OH

(a)

(b)

( + )_

(c)

( + )_ ( + )_