1. 9-1 Chapter 9 Nucleophilic Substitution &  -Elimination 1. Nucleophilic Aliphatic Substitution 2. Solvents for Nucleophilic Substitution Reactions 3. Mechanisms of Nucleophilic aliphatic substitution 4. Evidence of S n 1 / S n 2 Mechanisms 5. Analysis of some Nucleophilic Substitution Rx’s 6.  -Elimination 7.  -Elimination mechanism 8. Evidence for E1 and E2 9. Substitution vs Elimination

2. 9-2 substitution  - elimination rxs can compete leads to by-products (additional products) 4

3. 9-3 Product(s) s Leaving group - stable with pair of e’ s, weak B: 9 Nucleophilic Substitution Nu: + R 3 C-X R 3 C-Nu + X: (-) conditions Reactions with Lewis :Bases / :Nucleophiles Conditions - solvent, temperature, etc

4. 9-4 Nucleophilic Substitution (see Table 9.1 for more examples) Rx: (Chap 7) 4

5. 9-5 Nucleophilic Substitution examples Table 9.1 continued 2

6. 9-6 Nucleophilic Substitution examples Table 9.1 continued amine alcohol ether (after -H + ) 6

7. 9-7 A PROTIC 2. Solvents PROTIC [H + ] NON-POLAR dielectric constant ≥ 15 ≤ 5

8. 9-8 A PROTIC PROTIC [H + ] NON-POLAR dielectric constant ≥ 15 ≤ 5 DMSO 48.9 acetonitrile 37.5 DMF 36.7 acetone 20.7 dichloromethane 9.1 diethyl ether 4.3 toluene 2.3 hexane 1.9 2. Solvents of reaction (rx)

9. 9-9 water 79 formic acid 59 methanol 33 ethanol 24 acetic acid 6.2 A PROTIC 2. Solvents PROTIC [H + ] NON-POLAR dielectric constant ≥ 15 ≤ 5

10. 9-10 3. Substitution Mechanisms Difference: timing of bond-breaking and making One simultaneous breaking & making; [S N 2] Other, break then make bonds stepwise; [S N 1] 2 limiting mechanisms for substitution (S N 2, S N 1) 5

11. 9-11 CHOBr H H H  t.s. simultaneous bond breaking and making Mechanism - S N 2 sp 2 3

12. 9-12 + other products [important!] Mechanism - S N 1 4

13. 9-13 S N reactions Reactant structure have on mechanism/rate? Structure of Nu: have on mechanism/rate? Leaving group have on rate? What effect does the: What is: The stereochemical course of S N reaction? The role of the solvent? When or why: Does rearrangement occur? 5

14. 9-14 Kinetics/Nucleophilicity Kinetics/Nucleophilicity :Nucleophilicity - kinetic, speed of rxn. time Nu: C X H H H C Nu H H H + X (-)  +  - Nu: or B: H B-H + :Basicity - equilibrium Nucleophiles are also bases  :Nucleophilicity and :Basicity have correlations 4

15. 9-15 Reaction rate depends on [RX] unimolecular rx rate = k[(CH 3 ) 3 CBr] k - rate constant 1 st order kinetics / stepwise Kinetics - S N 1 4

16. 9-16 both reactants in rate limiting step bimolecular reaction rate = k[ CH 3 Br ][ - OH ] 2 nd order kinetics CHOBr H H H  kinetics - S N 2

17. 9-17 rx profile: t.s. 1 t.s. 2 SM products prog of rx HH R+R+ SN1SN1 E t.s. SM products prog of rx HH SN2SN2 2

18. 9-18 substitution S N 1 or S N 2? OR 2

19. 9-19 S N 1 or S N 2 with a 2 o RX is  on nucleophile nucleopilicity moderate strong weak strong bases

20. 9-20 substitution S N 1 or S N 2? OR √

21. 9-21 A PROTIC 2. Solvents PROTIC [H + ] NON-POLAR dielectric constant ≥ 15 ≤ 5 E + - Nu E+E+ - Nu polar 3

22. 9-22 Solvents effects on Nu: - ProticAprotic The greater the the solvent’s dielectric constant, the better ions of opposite charge are separated. Polar and Nonpolar Solvents E + - Nu E+E+ - Nu polar 2

23. 9-23 POLAR APROTIC solvents effective in solvating cations but poorly solvate anions, e.g.: Solvents effects on Nu: - The freer the Nucleophile’s e (-) s the greater its Nucleophilicity 2

24. 9-24 APROTIC solvents solvate cations F - “free” of Na + 3

25. 9-25 A PROTIC PROTIC [H + ] NON-POLAR dielectric constant ≥ 15 ≤ 5 DMSO 48.9 acetonitrile 37.5 DMF 36.7 acetone 20.7 solvents of S N 2 rx

26. 9-26 PROTIC solvents solvate cations & anions e.g. CH 3 OH 2

27. 9-27 S N 1rx  on separating charges (+/-) in t.s. C CH 3 3 H 3 CCl Br (-) in solvent C CH 3 3 H 3 CBr rx rate THF* - 0.05 Acetone - 0.5 H 2 O - 4x10 3 *dielectric constant 7 protic polar solvents separate cations & anions 4

28. 9-28 water 79 formic acid 59 methanol 33 ethanol 24 A PROTIC 2. Solvents PROTIC [H + ] NON-POLAR dielectric constant ≥ 15 ≤ 5

29. 9-29 Stereochemistry S N 1 4

30. 9-30 Stereochemistry S N 2 - Stereochemistry S N 2 - inversion C CH 3 Br D H I C H 3 C I D H + Br acetone S R inversion of configuration S->R & R->S BUT... C CH 3 Br D H I  -  - t.s. backside attack, 5

31. 9-31 S N 2 product is clearly inverted but substituent priorities changed S rotation product S backside attack, inversion of configuration 2

32. 9-32 Structure of RX Structure of RX R 3 CX R 2 CHX RCH 2 X CH 3 X Reactivities for S N 1 and S N 2 opposite increasing stability of carbocation SN1SN1 SN2SN2 decreasing steric hindrance governed by steric factors governed by electronic factors 5

33. 9-33 S N 2 sterics - 1 o :Nu (-) 3 o backside blocked  S N 1 :Nu (-) 6

34. 9-34 S N 2 sterics S N 2 sterics :Nu (-) 3 o backside blocked  S N 1 5

35. 9-35 hard to form easy to form RX - Carbocations (S N 1) RX - Carbocations (S N 1)  3 o R-X reacts by R + (S N 1) 3

36. 9-36 (S N 1) Other Cations (S N 1) Other Cations allylic & benzylic cation - resonance stabilized - delocalizated (+) charge [S N 1] 1 o allylic ≈ 2 o alkyl

37. 9-37 2 o & 3 o allylic cations are even more sable (S N 1) Other Cations allylic & benzylic cation - resonance stabilized - delocalizated + charge [S N 1] 1 o allylic

38. 9-38 mech. What is the effect of resonance on S N 1? same write either SN1SN1 rx 6

39. 9-39 (S N 1) Other Cations (S N 1) Other Cations allylic & benzylic cation - resonance stabilized - delocalizated ( + ) - charge [S N 1] or hybrid 4

40. 9-40 allylic (benzylic) facilitates S N 2 2

41. 9-41 Leaving group X - gains e (-) s (Lewis base ) - less basic or more stable with e (-) s better leaving gp. e.g. (-) OH vs (-) Cl Nu: + R-X Nu R X Nu-R+ :X  strong base “neutral”  a s leaving gp Cl (-) > > > (-) OH 8

42. 9-42 I (-) > Br (-) > Cl (-) ~ H 2 O > F (-) > AcO (-) > HO (-) > RO (-) > R 2 N (-) good leaving gp. stability of group with e (-) s special cases not leaving gp. Leaving group

43. 9-43 Which of the given substrates would undergo S N 2 substitution? Product(s)? Reason? strong bases: (-) OH, (-) OCH 3 ; (-) NH 2 even stronger!  not leaving groups 3

44. 9-44 Other concerns - Rearrangements S N 1 yes (R+); S N 2 no 6

45. 9-45 Summary of S N Rx’s Alkyl Halide CH 3 X methyl S N 2S N 1 S N 1 does not occur. methyl cation too unstable SN2SN2 R 2 CHX secondary S N 1 favored with poor nucleophiles. S N 2 favored in with good nucleophiles RCH 2 X primaryNo S N 1, 1° cations rarely observed SN2SN2 Tertiary R 3 CX S N 2 does not occur; steric hindrance S N 1 - ease of formation of 3 o carbocations stereocenter substitution inversionracemization 4

46. 9-46 polar protic unimolecular Guidelines for Substitution & Elimination H 3 C-X SN2SN2SN2SN2 weakweak S N 1 & E1 SN2SN2SN2SN2 Nu: - B: - polar aprotic bimolecular S N 1 & E1 weakweak B: - Nu: - med. B: good SN2SN2SN2SN2 Nu: - inversion racemic rearrange 8

47. 9-47 S N 1/S N 2 Problems Predict: products, and show (arrows) the mechanism. SN2SN2 SN1SN1 11

48. 9-48 a reaction in which a small molecule (HCl, HBr, HI, or HOH) is eliminated.  -Elimination

49. 9-49 E2: concerted break/make bonds bimolecular, rate  [R-X] [ B: or (Nu:)] E1: break bond, then make  bond unimolecular, rate  [ R-X ] 2 limiting mechanisms for  -elimination rx s  -Elimination

50. 9-50 Zaitsev rule: major  -elimination product = the more stable alkene (more substituted).  -elimination a a a b b b

51. 9-51 Mechanisms (2) timing of bond breaking/making differs E2

52. 9-52 E1 Mechanisms (2) timing of bond breaking/making differs E2

53. 9-53 ionization, rate determining step (same as S N 1) E1 mechanism HH SM product progress of reaction R+R+ Eact t.s. 1 t.s. 2 3

54. 9-54 E2 mechanism one-step mechanism; concerted bond-breaking and bond-forming t.s. SM products prog of rx HH 2

55. 9-55 Stereoselectivity of E2 E2 most favorable (lowest Ea) - H and X are anti and coplanar 1

56. 9-56 Stereoselectivity of E2 CC H H H R Bu t O - X H CC X - H H H R Bu t O H E2 most favorable (lowest Ea) - H and X are anti and coplanar

57. 9-57 Regioselectivity of E1/E2 E1: major product is the more stable alkene E2: the major product is usually the more stable alkene, but  on orientation of H and X (1.) (2.) *also S N 1 products how? 4

58. 9-58 Stereochemistry of E1 (1.) (2.) 3

59. 9-59 Stereochemistry of E2 The only anti-coplanar H to X arrangement forces formation of less stable olefin (2.)

60. 9-60 E2 branching hinders S N 2 SN2SN2 6

61. 9-61 S N vs E Many nucleophiles are also strong bases (OH - and RO - ), thus S N and E reactions often compete.

62. 9-62 Guidelines for Substitution & Elimination H 3 C-X SN2SN2SN2SN2 E2 strong bulky ( t BuO - ) weakweak S N 1 & E1 weakweak B: - Nu: - E2 strong B: med. B: good SN2SN2SN2SN2 E2 strong B: - Nu: - SN2SN2SN2SN2 Nu: - B: - polar protic unimolecular polar aprotic bimolecular Nu: - inversion stereochem racemic rearrange 11