medc 527 fall 20081 reaction mechanisms hydrolysis of esters … basic conditions h 2 o/oh - _ + __...
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MEDC 527 Fall 2008 1
Reaction Mechanisms
Hydrolysis of Esters … basic conditions
Me
O
OMe Me
O
O
H2O/OH-
_
Me
O
OMe Me
O
OHOMe Me
O
OOMe Me
O
O+
_ _
__
OH_
H
MeOH_
MEDC 527 Fall 2008 2
Reaction Mechanisms
Basic Hydrolysis of Esters
electronic and steric effects …… pG-Ph-COOEt …… CH3COOR
Order of Reactivity
G = -NO2
-Cl
-H
-CH3
-OMe
Order of Reactivity
R = -Me
-Et
-i-Pr
-t-Bu
MEDC 527 Fall 2008 3
Reaction Mechanisms
Hydrolysis of Esters … acidic conditions
Me
O
OMe Me
O
OH
H2O/H+
MeOH+
Me
O
OMe Me
OH
H2OOMe Me
OH
OHOMe Me
O
OHMe
O
OMe
_H+
MeOH
+H
+H2O
+
+
+
H
H
MEDC 527 Fall 2008 4
Reaction Mechanisms
Acidic Hydrolysis of Esters
electronic and steric effects …… pG-Ph-COOEt …… CH3COOR
Order of Reactivity
G = -NO2
-Cl
-H
-CH3
-OMe
Order of Reactivity
R = -Me
-Et
-i-Pr
-t-Bu
(G = NO2 < Cl < H < CH3 < OMe)
(R = Me > Et > I-Pr > t-Bu)
MEDC 527 Fall 2008 5
Reaction Mechanisms
Hydrolysis of Amides … basic conditions
Me
O
NH2 Me
O
O
H2O/OH-
NH4+
_
Me
O
NH2OHMe
O
ONH3 Me
O
OMe
O
NH2
_OH_
NH3
_
+
_
__NH4+
MEDC 527 Fall 2008 6
Reaction Mechanisms
Hydrolysis of Amides … acidic conditions
Me
O
NH2 Me
O
O
H2O/H+
NH4+
_
+Me
O
NH2H2OMe
O
OHNH3 Me
O
OHMe
O
NH2Me
O
NH2 Me
O
O
_H+NH4
+
_H2O +
+
+
H H_
_NH3
MEDC 527 Fall 2008 7
Reaction Mechanisms
Hydrolysis of other carboxylic acid derivatives
O
O
NH
O
O
O O
NH
O O
O O
O
O NH
O
NH
NH
O
lactone lactam anhydride imide carbonate carbamate urea
MEDC 527 Fall 2008 8
Reaction Mechanisms
Hydrolysis of drugs
S
NMe
Me N
MeN
O
MeO
OHN
O
O
N
SH
Ritonavir(HIV protease inhibitor)
N
MeO
OHN
H
S
NMe
Me N
Me
O
N
S
MEDC 527 Fall 2008 9
O
O
O O
Me
OH
O
O
MeO
OHNeocarzinostatin A
(anti-tumor)
Reaction Mechanisms
Hydrolysis of drugs
O
O
O
O
OH
O
Me
OHMeO
MEDC 527 Fall 2008 10
Reaction Mechanisms
Predict ‘metabolites’
O
COOC3H7
O
Et2N
OMe
O
O
Et2N
OMe
COOH
Propanidid (anesthetic){Ester > 3O Amide
electronic + steric effect}
MEDC 527 Fall 2008 11
Reaction Mechanisms
Predict ‘metabolites’
Cocaine
NMe
O
O
COOMeN
Me
O
O
COOH
MEDC 527 Fall 2008 12
Reaction Mechanisms
Predict ‘metabolites’
N
N
Me
OO
Me
HH N
N
MeH
OO
MeH
Hydrolysis of pilocarpine is much faster than that of isopilocarpine{Stereochemical effect}
> >
Pilocarpine Isopilocarpine
MEDC 527 Fall 2008 13
Electrophilic Aromatic Substitution
N N
N
S
NH
NH
O S
NH
N
NH
N
N NH
NN
N
Aromatic Structures ….. Examples
MEDC 527 Fall 2008 14
Electrophilic Aromatic Substitution
Definition of EAS and Examples
MEDC 527 Fall 2008 15
Electrophilic Aromatic Substitution
Mechanism
HONO2 + 2H2SO4 H3O + HSO4 + NO2++ -HONO2 + 2H2SO4 H3O + HSO4 + NO2++ -
HH NO2 H NO2 H NO2
H NO2
+
+
+++ NO2
+
NO2
MEDC 527 Fall 2008 16
Electrophilic Aromatic Substitution
Substituent Effects
• Activating/Deactivating groups
• Directors - o, p, and m
Types of Substituent Effects
CH3 CH3
SO3H
CH3
SO3H
CH3
SO3H
+ +
32 % 6 % 62%
sulfonation
MEDC 527 Fall 2008 17
Electrophilic Aromatic Substitution
Substituent Effects
Activating: o-, p- directorsStrongly activating
-NH2, -NHR, -NR2
-OHModerately activating
-OR-NHCOCH3
Weakly activating-Ph-R
Deactivating: m-directors-NO2, -N(CH3)3
+, -CN, -COOH, -COOR, -SO3H, -CHO, -COR
Deactivating: o-,p- directors-F, -Cl, -Br, -I
MEDC 527 Fall 2008 18
Electrophilic Aromatic Substitution
Theory of Reactivity
ArH + Y+ ArY + H+ , where Y = -COCH3, or –NO2, or –Cl, etc.
+
H Y
Y+
OMe
Y+
NO2
Y+
H Y
OMe
+
H Y
NO2
+
MEDC 527 Fall 2008 19
Electrophilic Aromatic Substitution
Theory of Orientation
CH3
H
O2N
CH3
HO2N
CH3
H
NO2
CH3
H
O2N
CH3
HO2N
CH3
H
NO2
CH3
H
O2N
CH3
HO2N
CH3
H
NO2
++ +
++ +
++ +
NO2
H
O2NNO2
H
O2NNO2
H
O2N
NO2
H
O2N
NO2
H
O2N
NO2
H
O2N
NO2
HO2N
NO2
HO2N
NO2
HO2N
++
+
+ +
+
+
+ +
o-, p- directors m- directors eD groups eW groups
MEDC 527 Fall 2008 20
Electrophilic Aromatic Substitution
Theory of Orientation … the anomalous effect of halogensNote: Y is the incoming electrophile
H YCl
H YCl
H YCl
H Y
Cl
H Y
Cl
H Y
Cl
H Y
Cl
H Y
Cl
H Y
Cl
H YCl
H Y
Cl
Ortho attack
Meta attack
Para attack
+
++
+
+
++
+
++
+
_ _ _
_ _ _
_ _ _
MEDC 527 Fall 2008 21
CH3
OH
NitrationCH3
OH
O2N
Electrophilic Aromatic Substitution
Net Effect of Substituents in Directing the Incoming Group
OH
CHOBromination
OH
CHO
Br
MEDC 527 Fall 2008 22
Electrophilic Aromatic Substitution
Net Effect of Substituents in Directing the Incoming Group
CH3
Cl
Nitration
CH3
Cl
NO2
CH3
Cl
NO2
42% 58%
+
Cl
Br
NitrationCl
Br
NO2
Cl
Br
NO2
Cl
Br
O2N
+ +
1 % 62% 37%
MEDC 527 Fall 2008 23
Electrophilic Aromatic Substitution
Relevance of EAS to Drugs
O
OH
MEDC 527 Fall 2008 24
NHNH
Et
O
O
OOxidative Metabolism
Phenobarbital
NHNH
Et
O
O
O
OH
Electrophilic Aromatic Substitution
Relevance of EAS to Drugs
NHNH
O
O
Ph
Oxidative Metabolism
Phenobarbital
NHNH
O
O
OH
Ph
MEDC 527 Fall 2008 25
Electrophilic Aromatic Substitution
Relevance of EAS to Drugs
N
H
N
NH
H
NH2
NH
Oxidative Metabolism
Phenformin
N
H
N
NH
H
NH2
NH
OH
N
Cl
Cl
NH
NH
Clonidine
Little Metabolism
MEDC 527 Fall 2008 26
Electrophilic Aromatic Substitution
Relevance of EAS to Drugs
CH3OH
OH
Estradiol
oxidative metabolism
CH3OH
OH
OH
Little Metabolism
SO2NH(C3H7)2
COOH
oxidative metabolism
Probenecid
MEDC 527 Fall 2008 27
Electrophilic Aromatic Substitution
Relevance of EAS to Drugs
O
OH
NH
CH3
CH3
Propanolol
oxidativemetabolism
O
OH
NH
CH3
CH3
OH
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