Reaction Mechanisms Hydrolysis of Esters basic conditions H
Reaction Mechanisms Hydrolysis of Esters … basic conditions H 2 O/OH_ OH _ _ MEDC 527 Fall 2008 _ Me. OH + _ H 1
Reaction Mechanisms Basic Hydrolysis of Esters electronic and steric effects …… p. G-Ph-COOEt …… CH 3 COOR Order of Reactivity G= R= -NO 2 -Cl -H -CH 3 -OMe MEDC 527 Fall 2008 -Me -Et -i-Pr -t-Bu 2
Reaction Mechanisms Hydrolysis of Esters … acidic conditions H 2 O/H+ H + + H Me. OH + H 2 O + _ + + MEDC 527 Fall 2008 + Me. OH H 3 H
Reaction Mechanisms Acidic Hydrolysis of Esters electronic and steric effects …… p. G-Ph-COOEt (G = NO 2 < Cl < H < CH 3 < OMe) …… CH 3 COOR (R = Me > Et > I-Pr > t-Bu) Order of Reactivity G= R= -NO 2 -Cl -H -CH 3 -OMe MEDC 527 Fall 2008 -Me -Et -i-Pr -t-Bu 4
Reaction Mechanisms Hydrolysis of Amides … basic conditions H 2 O/OH_ _ OH _ NH 4+ _ _ + MEDC 527 Fall 2008 _ NH 3 +NH _ 4 5
Reaction Mechanisms Hydrolysis of Amides … acidic conditions H 2 O/H+ _ H+ + H H 2 O NH 4+ _ + MEDC 527 Fall 2008 _ _ NH + 3 H +NH _ 4 + 6
Reaction Mechanisms Hydrolysis of other carboxylic acid derivatives lactone lactam anhydride imide MEDC 527 Fall 2008 carbonate carbamate urea 7
Reaction Mechanisms Hydrolysis of drugs Ritonavir (HIV protease inhibitor) MEDC 527 Fall 2008 8
Reaction Mechanisms Hydrolysis of drugs Neocarzinostatin A (anti-tumor) MEDC 527 Fall 2008 9
Reaction Mechanisms Predict ‘metabolites’ Propanidid (anesthetic) {Ester > 3 O Amide electronic + steric effect} MEDC 527 Fall 2008 10
Reaction Mechanisms Predict ‘metabolites’ Cocaine MEDC 527 Fall 2008 11
Reaction Mechanisms Predict ‘metabolites’ >> Pilocarpine Isopilocarpine Hydrolysis of pilocarpine is much faster than that of isopilocarpine {Stereochemical effect} MEDC 527 Fall 2008 12
Electrophilic Aromatic Substitution Aromatic Structures …. . Examples MEDC 527 Fall 2008 13
Electrophilic Aromatic Substitution Definition of EAS and Examples MEDC 527 Fall 2008 14
Electrophilic Aromatic Substitution Mechanism + NO 2+ + + MEDC 527 Fall 2008 15
Electrophilic Aromatic Substitution Substituent Effects Types of Substituent Effects • Activating/Deactivating groups • Directors - o, p, and m MEDC 527 Fall 2008 16
Electrophilic Aromatic Substitution Substituent Effects Activating: o-, p- directors Strongly activating -NH 2, -NHR, -NR 2 -OH Moderately activating -OR -NHCOCH 3 Weakly activating -Ph -R Deactivating: m-directors -NO 2, -N(CH 3)3+, -CN, -COOH, -COOR, -SO 3 H, -CHO, -COR Deactivating: o-, p- directors -F, -Cl, -Br, -I MEDC 527 Fall 2008 17
Electrophilic Aromatic Substitution Theory of Reactivity Ar. H + Y+ Ar. Y + + H+ , where Y = -COCH 3, or –NO 2, or –Cl, etc. + MEDC 527 Fall 2008 + 18
Electrophilic Aromatic Substitution Theory of Orientation + + + + + o-, p- directors e. D groups m- directors e. W groups MEDC 527 Fall 2008 19
Electrophilic Aromatic Substitution Theory of Orientation … the anomalous effect of halogens Note: Y is the incoming electrophile _ _ _ + Ortho attack + + Meta attack _ Para attack + + _ + + + _ MEDC 527 Fall 2008 _ _ 20
Electrophilic Aromatic Substitution Net Effect of Substituents in Directing the Incoming Group MEDC 527 Fall 2008 21
Electrophilic Aromatic Substitution Net Effect of Substituents in Directing the Incoming Group 1% MEDC 527 Fall 2008 62% 37% 22
Electrophilic Aromatic Substitution Relevance of EAS to Drugs MEDC 527 Fall 2008 23
Electrophilic Aromatic Substitution Relevance of EAS to Drugs MEDC 527 Fall 2008 24
Electrophilic Aromatic Substitution Relevance of EAS to Drugs MEDC 527 Fall 2008 25
Electrophilic Aromatic Substitution Relevance of EAS to Drugs MEDC 527 Fall 2008 26
Electrophilic Aromatic Substitution Relevance of EAS to Drugs MEDC 527 Fall 2008 27
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