Post on 27-Oct-2014
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)
( + )_ ( + )_