MEDC 527 Fall 20081 Reaction Mechanisms Hydrolysis of Esters … basic conditions H 2 O/OH - _ + __...
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Transcript of MEDC 527 Fall 20081 Reaction Mechanisms Hydrolysis of Esters … basic conditions H 2 O/OH - _ + __...
![Page 1: MEDC 527 Fall 20081 Reaction Mechanisms Hydrolysis of Esters … basic conditions H 2 O/OH - _ + __ _ _ OH _ H MeOH _.](https://reader035.fdocuments.us/reader035/viewer/2022062301/56649d705503460f94a523ea/html5/thumbnails/1.jpg)
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_
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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
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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
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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)
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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+
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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
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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
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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
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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
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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}
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MEDC 527 Fall 2008 11
Reaction Mechanisms
Predict ‘metabolites’
Cocaine
NMe
O
O
COOMeN
Me
O
O
COOH
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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
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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
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MEDC 527 Fall 2008 14
Electrophilic Aromatic Substitution
Definition of EAS and Examples
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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
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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
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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
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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
+
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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
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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
+
++
+
+
++
+
++
+
_ _ _
_ _ _
_ _ _
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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
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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%
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MEDC 527 Fall 2008 23
Electrophilic Aromatic Substitution
Relevance of EAS to Drugs
O
OH
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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
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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
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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
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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