MEDC 527 Fall Reaction Mechanisms Hydrolysis of Esters … basic conditions H 2 O/OH - _ + __ _ _ OH _ H MeOH _

MEDC 527 Fall Reaction Mechanisms Basic Hydrolysis of Esters electronic and steric effects …… pG-Ph-COOEt …… CH 3 COOR Order of Reactivity G = -NO 2 -Cl -H -CH 3 -OMe Order of Reactivity R = -Me -Et -i-Pr -t-Bu

MEDC 527 Fall Reaction Mechanisms Hydrolysis of Esters … acidic conditions H 2 O/H + MeOH + _ H + + H + H2OH2O H H

MEDC 527 Fall Reaction Mechanisms Acidic Hydrolysis of Esters electronic and steric effects …… pG-Ph-COOEt …… CH 3 COOR Order of Reactivity G = -NO 2 -Cl -H -CH 3 -OMe Order of Reactivity R = -Me -Et -i-Pr -t-Bu (G = NO 2 < Cl < H < CH 3 < OMe) (R = Me > Et > I-Pr > t-Bu)

MEDC 527 Fall Reaction Mechanisms Hydrolysis of Amides … basic conditions H 2 O/OH - NH 4 + _ _ OH _ NH 3 _ + _ _ _ NH 4 +

MEDC 527 Fall Reaction Mechanisms Hydrolysis of Amides … acidic conditions H 2 O/H + NH 4 + _ + _ H + NH 4 + _ H2OH2O HH _ _ NH 3

MEDC 527 Fall Reaction Mechanisms Hydrolysis of other carboxylic acid derivatives lactone lactam anhydride imide carbonate carbamate urea

MEDC 527 Fall Reaction Mechanisms Hydrolysis of drugs Ritonavir (HIV protease inhibitor)

MEDC 527 Fall Neocarzinostatin A (anti-tumor) Reaction Mechanisms Hydrolysis of drugs

MEDC 527 Fall Reaction Mechanisms Predict ‘metabolites’ Propanidid (anesthetic) {Ester > 3 O Amide electronic + steric effect}

MEDC 527 Fall Reaction Mechanisms Predict ‘metabolites’ Cocaine

MEDC 527 Fall Reaction Mechanisms Predict ‘metabolites’ Hydrolysis of pilocarpine is much faster than that of isopilocarpine {Stereochemical effect} > Pilocarpine Isopilocarpine

MEDC 527 Fall Electrophilic Aromatic Substitution Aromatic Structures ….. Examples

MEDC 527 Fall Electrophilic Aromatic Substitution Definition of EAS and Examples

MEDC 527 Fall Electrophilic Aromatic Substitution Mechanism NO 2 +

MEDC 527 Fall Electrophilic Aromatic Substitution Substituent Effects Activating/Deactivating groups Directors - o, p, and m Types of Substituent Effects

MEDC 527 Fall 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 Electrophilic Aromatic Substitution Theory of Reactivity ArH + Y + ArY + H +, where Y = -COCH 3, or –NO 2, or –Cl, etc

MEDC 527 Fall Electrophilic Aromatic Substitution Theory of Orientation o-, p- directors m- directors eD groups eW groups

MEDC 527 Fall 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 Electrophilic Aromatic Substitution Net Effect of Substituents in Directing the Incoming Group

MEDC 527 Fall Electrophilic Aromatic Substitution Net Effect of Substituents in Directing the Incoming Group 1 % 62% 37%

MEDC 527 Fall Electrophilic Aromatic Substitution Relevance of EAS to Drugs

MEDC 527 Fall Electrophilic Aromatic Substitution Relevance of EAS to Drugs

MEDC 527 Fall Electrophilic Aromatic Substitution Relevance of EAS to Drugs

MEDC 527 Fall Electrophilic Aromatic Substitution Relevance of EAS to Drugs

MEDC 527 Fall Electrophilic Aromatic Substitution Relevance of EAS to Drugs