1. MEDC 527 Fall 20081 Reaction Mechanisms Hydrolysis of Esters … basic conditions H 2 O/OH - _ + __ _ _ OH _ H MeOH _

2. MEDC 527 Fall 20082 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

3. MEDC 527 Fall 20083 Reaction Mechanisms Hydrolysis of Esters … acidic conditions H 2 O/H + MeOH + _ H + + H + H2OH2O + + + H H

4. MEDC 527 Fall 20084 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)

5. MEDC 527 Fall 20085 Reaction Mechanisms Hydrolysis of Amides … basic conditions H 2 O/OH - NH 4 + _ _ OH _ NH 3 _ + _ _ _ NH 4 +

6. MEDC 527 Fall 20086 Reaction Mechanisms Hydrolysis of Amides … acidic conditions H 2 O/H + NH 4 + _ + _ H + NH 4 + _ H2OH2O + + + HH _ _ NH 3

7. MEDC 527 Fall 20087 Reaction Mechanisms Hydrolysis of other carboxylic acid derivatives lactone lactam anhydride imide carbonate carbamate urea

8. MEDC 527 Fall 20088 Reaction Mechanisms Hydrolysis of drugs Ritonavir (HIV protease inhibitor)

9. MEDC 527 Fall 20089 Neocarzinostatin A (anti-tumor) Reaction Mechanisms Hydrolysis of drugs

10. MEDC 527 Fall 200810 Reaction Mechanisms Predict ‘metabolites’ Propanidid (anesthetic) {Ester > 3 O Amide electronic + steric effect}

11. MEDC 527 Fall 200811 Reaction Mechanisms Predict ‘metabolites’ Cocaine

12. MEDC 527 Fall 200812 Reaction Mechanisms Predict ‘metabolites’ Hydrolysis of pilocarpine is much faster than that of isopilocarpine {Stereochemical effect} > Pilocarpine Isopilocarpine

13. MEDC 527 Fall 200813 Electrophilic Aromatic Substitution Aromatic Structures ….. Examples

14. MEDC 527 Fall 200814 Electrophilic Aromatic Substitution Definition of EAS and Examples

15. MEDC 527 Fall 200815 Electrophilic Aromatic Substitution Mechanism + + + + + NO 2 +

16. MEDC 527 Fall 200816 Electrophilic Aromatic Substitution Substituent Effects Activating/Deactivating groups Directors - o, p, and m Types of Substituent Effects

17. MEDC 527 Fall 200817 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

18. MEDC 527 Fall 200818 Electrophilic Aromatic Substitution Theory of Reactivity ArH + Y + ArY + H +, where Y = -COCH 3, or –NO 2, or –Cl, etc. + + +

19. MEDC 527 Fall 200819 Electrophilic Aromatic Substitution Theory of Orientation + + + + + + + + + o-, p- directors m- directors eD groups eW groups

20. MEDC 527 Fall 200820 Electrophilic Aromatic Substitution Theory of Orientation … the anomalous effect of halogens Note: Y is the incoming electrophile Ortho attack Meta attack Para attack + + + + + + + + + + + ___ ___ ___

21. MEDC 527 Fall 200821 Electrophilic Aromatic Substitution Net Effect of Substituents in Directing the Incoming Group

22. MEDC 527 Fall 200822 Electrophilic Aromatic Substitution Net Effect of Substituents in Directing the Incoming Group 1 % 62% 37%

23. MEDC 527 Fall 200823 Electrophilic Aromatic Substitution Relevance of EAS to Drugs

24. MEDC 527 Fall 200824 Electrophilic Aromatic Substitution Relevance of EAS to Drugs

25. MEDC 527 Fall 200825 Electrophilic Aromatic Substitution Relevance of EAS to Drugs

26. MEDC 527 Fall 200826 Electrophilic Aromatic Substitution Relevance of EAS to Drugs

27. MEDC 527 Fall 200827 Electrophilic Aromatic Substitution Relevance of EAS to Drugs