1. Dr. Wolf's CHM 201 & 20212-1 Chapter 12 (Part b) Aryl Halides

2. Dr. Wolf's CHM 201 & 20212-2 Aryl Halides Aryl halides are halides in which the halogen is attached directly to an aromatic ring. Carbon-halogen bonds in aryl halides are shorter and stronger than carbon-halogen bonds in alkyl halides.

3. Dr. Wolf's CHM 201 & 20212-3 Table 23.1: C—H and C—Cl Bond Dissociation Energies of Selected Compounds CH 3 CH 2 X H2CH2CH2CH2C CHX X sp 3 sp 2 X = H 410 (98) 452 (108) 469 (112) X = Cl 339 (81) 368 (88) 406 (97) Bond Energy: kJ/mol (kcal/mol)

4. Dr. Wolf's CHM 201 & 20212-4 Aryl Halides Aryl halides are halides in which the halogen is attached directly to an aromatic ring. Carbon-halogen bonds in aryl halides are shorter and stronger than carbon-halogen bonds in alkyl halides. Because the carbon-halogen bond is stronger, aryl halides react more slowly than alkyl halides when carbon-halogen bond breaking is rate determining.

5. Dr. Wolf's CHM 201 & 20212-5 Physical Properties of Aryl Halides resemble alkyl halides all are essentially insoluble in water less polar than alkyl halides Cl  1.7 D Cl  2.2 D

6. Dr. Wolf's CHM 201 & 20212-6 Reactions of Aryl Halides Electrophilic Aromatic Substitution (Chapter 12a) Formation of aryl Grignard reagents (Chapter 14) We have not yet seen any nucleophilic substitution reactions of aryl halides. Nucleophilic substitution on chlorobenzene occurs so slowly that forcing conditions are required.

7. Dr. Wolf's CHM 201 & 20212-7 Example ClOH 1.NaOH, H 2 O 370°C 2. H + (97%)

8. Dr. Wolf's CHM 201 & 20212-8 Reasons for Low Reactivity S N 1 not reasonable because: 1)C—Cl bond is strong; therefore, ionization to a carbocation is a high-energy process 2) aryl cations are less stable than alkyl cations Cl + + Cl –

9. Dr. Wolf's CHM 201 & 20212-9 Reasons for Low Reactivity S N 2 not reasonable because ring blocks attack of nucleophile from side opposite bond to leaving group

10. Dr. Wolf's CHM 201 & 20212-10 Nucleophilic Substitution in Nitro-Substituted Aryl Halides

11. Dr. Wolf's CHM 201 & 20212-11 nitro-substituted aryl halides do undergo nucleophilic aromatic substitution readily But...Cl NO 2 + NaOCH 3 CH 3 OH 85°C OCH 3 NO 2 + NaCl (92%)

12. Dr. Wolf's CHM 201 & 20212-12 especially when nitro group is ortho and/or para to leaving group Effect of nitro group is cumulative Cl1.0Cl NO 2 7 x 10 10 Cl NO 2 O2NO2NO2NO2N 2.4 x 10 15 Cl NO 2 too fast to measure

13. Dr. Wolf's CHM 201 & 20212-13 follows second-order rate law: rate = k[aryl halide][nucleophile] inference: both the aryl halide and the nucleophile are involved in rate-determining step Kinetics

14. Dr. Wolf's CHM 201 & 20212-14 Effect of leaving group unusual order: F > Cl > Br > I X NO 2 X Relative Rate* F Cl Br I 312 1.0 0.8 0.4 *NaOCH 3, CH 3 OH, 50°C

15. Dr. Wolf's CHM 201 & 20212-15 bimolecular rate-determining step in which nucleophile attacks aryl halide rate-determining step precedes carbon-halogen bond cleavage rate-determining transition state is stabilized by electron-withdrawing groups (such as NO 2 ) General Conclusions About Mechanism

16. Dr. Wolf's CHM 201 & 20212-16 The Addition-Elimination Mechanism of Nucleophilic Aromatic Substitution

17. Dr. Wolf's CHM 201 & 20212-17 Two step mechanism: Step 1) nucleophile attacks aryl halide and bonds to the carbon that bears the halogen (slow: aromaticity of ring lost in this step) Step 2) intermediate formed in first step loses halide (fast: aromaticity of ring restored in this step) Addition-Elimination Mechanism

18. Dr. Wolf's CHM 201 & 20212-18 ReactionF NO 2 + NaOCH 3 CH 3 OH 85°C OCH 3 NO 2 + NaF (93%)

19. Dr. Wolf's CHM 201 & 20212-19 Mechanism OCH 3 – NO 2 F H H H H bimolecular consistent with second- order kinetics; first order in aryl halide, first order in nucleophile Step 1

20. Dr. Wolf's CHM 201 & 20212-20 Mechanismslow OCH 3 – NO 2 F H H H H NO 2 F H H H H – OCH 3 Step 1

21. Dr. Wolf's CHM 201 & 20212-21 Mechanism NO 2 F H H H H – OCH 3 intermediate is negatively charged formed faster when ring bears electron- withdrawing groups such as NO 2

22. Dr. Wolf's CHM 201 & 20212-22 Stabilization of Rate-Determining Intermediate by Nitro Group N F H H H H OCH 3 OO + – –

23. Dr. Wolf's CHM 201 & 20212-23 Stabilization of Rate-Determining Intermediate by Nitro Group N F H H H H OCH 3 OO + – – N F H H H H OCH 3 OO + – –

24. Dr. Wolf's CHM 201 & 20212-24 Mechanism NO 2 F H H H H – OCH 3 Step 2

25. Dr. Wolf's CHM 201 & 20212-25 Mechanism fast OCH 3 NO 2 H H H H F H H H H – OCH 3 F – Step 2

26. Dr. Wolf's CHM 201 & 20212-26 carbon-halogen bond breaking does not occur until after the rate-determining step electronegative F stabilizes negatively charged intermediate Leaving Group Effects F > Cl > Br > I is unusual, but consistent with mechanism

27. Dr. Wolf's CHM 201 & 20212-27 Related Nucleophilic Aromatic Substitution Reactions

28. Dr. Wolf's CHM 201 & 20212-28 Example: Hexafluorobenzene FFF F F F NaOCH 3 CH 3 OH 65°C F OCH 3 F F F F (72%) Six fluorine substituents stabilize negatively charged intermediate formed in rate-determining step and increase rate of nucleophilic aromatic substitution.

29. Dr. Wolf's CHM 201 & 20212-29 Example: 2-Chloropyridine NaOCH 3 CH 3 OH 2-Chloropyridine reacts 230,000,000 times faster than chlorobenzene under these conditions. Cl N OCH 3 N 50°C

30. Dr. Wolf's CHM 201 & 20212-30 Example: 2-Chloropyridine Nitrogen is more electronegative than carbon, stabilizes the anionic intermediate, and increases the rate at which it is formed. Cl N OCH 3 –

31. Dr. Wolf's CHM 201 & 20212-31 Example: 2-Chloropyridine Nitrogen is more electronegative than carbon, stabilizes the anionic intermediate, and increases the rate at which it is formed. Cl N OCH 3 – Cl N –

32. Dr. Wolf's CHM 201 & 20212-32 Descriptive Passage The Elimination-Addition Mechanism of Nucleophilic Aromatic Substitution: Benzyne

33. Dr. Wolf's CHM 201 & 20212-33 Aryl Halides Undergo Substitution When Treated With Very Strong Bases Cl NH 2 KNH 2, NH 3 –33°C (52%)

34. Dr. Wolf's CHM 201 & 20212-34 CH 3 NH 2 new substituent becomes attached to either the carbon that bore the leaving group or the carbon adjacent to it Regiochemistry + NaNH 2, NH 3 –33°C CH 3 Br NH 2

35. Dr. Wolf's CHM 201 & 20212-35 new substituent becomes attached to either the carbon that bore the leaving group or the carbon adjacent to it Regiochemistry CH 3 Br + NaNH 2, NH 3 –33°C CH 3 NH 2 CH 3 NH 2

36. Dr. Wolf's CHM 201 & 20212-36 Regiochemistry + NaNH 2, NH 3 –33°C CH 3 NH 2 CH 3 NH 2 CH 3 Cl + NH 2

37. Dr. Wolf's CHM 201 & 20212-37 Same result using 14 C label Cl * KNH 2, NH 3 –33°C NH 2 * + * (48%)(52%)

38. Dr. Wolf's CHM 201 & 20212-38 Mechanism NH2NH2NH2NH2 – Step 1 HH H H Cl H

39. Dr. Wolf's CHM 201 & 20212-39 Mechanism NH2NH2NH2NH2 – Step 1 HH H H Cl H HHH H NH2NH2NH2NH2 H Cl – compound formed in this step is called benzyne

40. Dr. Wolf's CHM 201 & 20212-40 Benzyne HHH H Benzyne has a strained triple bond. It cannot be isolated in this reaction, but is formed as a reactive intermediate.

41. Dr. Wolf's CHM 201 & 20212-41 Mechanism NH2NH2NH2NH2 – Step 2 HHH H

42. Dr. Wolf's CHM 201 & 20212-42 Mechanism NH2NH2NH2NH2 – Step 2 HHH H HHH H NH2NH2NH2NH2 – Angle strain is relieved. The two sp-hybridized ring carbons in benzyne become sp 2 hybridized in the resulting anion.

43. Dr. Wolf's CHM 201 & 20212-43 Mechanism Step 3 HHH H NH2NH2NH2NH2 – NH2NH2NH2NH2 H

44. Dr. Wolf's CHM 201 & 20212-44 Mechanism NH2NH2NH2NH2 – Step 3 HHH H NH2NH2NH2NH2 – NH2NH2NH2NH2 H H HHH H NH2NH2NH2NH2

45. Dr. Wolf's CHM 201 & 20212-45 Hydrolysis of Chlorobenzene Cl * NaOH, H 2 O 395°C OHOHOHOH * + OHOHOHOH* (54%)(43%) 14 C labeling indicates that the high- temperature reaction of chlorobenzene with NaOH goes via benzyne.

46. Dr. Wolf's CHM 201 & 20212-46 Diels-Alder Reactions of Benzyne

47. Dr. Wolf's CHM 201 & 20212-47 Other Routes to Benzyne Benzyne can be prepared as a reactive intermediate by methods other than treatment of chlorobenzene with strong bases. Another method involves loss of fluoride ion from the Grignard reagent of 1-bromo-2- fluorobenzene.

48. Dr. Wolf's CHM 201 & 20212-48 Other Routes to Benzyne BrF Mg, THF heat MgBr F FMgBr +

49. Dr. Wolf's CHM 201 & 20212-49 Benzyne as a Dienophile Benzyne is a fairly reactive dienophile, and gives Diels-Alder adducts when generated in the presence of conjugated dienes.

50. Dr. Wolf's CHM 201 & 20212-50 Benzyne as a Dienophile Br F Mg, THF heat + (46%)

51. Dr. Wolf's CHM 201 & 20212-51 End of Chapter 12 (part b)