Nucleophilic Aromatic Substitution of Benzyne

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1. Presentation By Aadil Ali Wani The Elimination-Addition Mechanism of Nucleophilic Aromatic Substitution : Benzyne

2. Cl NH 2 Aryl Halides Undergo Substitution When Treated With Very Strong Bases KNH 2 , NH 3 –33°C (52%)

3. 2 NH 3 –33°C Regiochemistry new substituent becomes attached to either the carbon that bore the leaving group or the carbon adjacent to it CH 3 CH 3 CH 3 B r NaNH 2 , NH + NH 2

4. + 2 Regiochemistry new substituent becomes attached to either the carbon that bore the leaving group or the carbon adjacent to it CH 3 CH 3 CH 3 NaNH 2 , NH 3 – 33° C NH B r NH 2

5. Regiochemistr y CH 3 NH 2 NaNH 2 , NH 3 – 33°C CH 3 CH 3 CH 3 NH 2 + + NH 2 NH 2

6. Same result using 14 C label * Cl KNH 2 , NH 3 – 33°C NH 2 * + * NH 2 (52% ) (48%)

7. Cl • •• • N H 2 • H H Mechanism Step 1 H H • • • – •• H

8. – • •• Cl • H Cl • • • H • N H 2 • H H H 2 •• Mechanism Step 1 H H • •• • • • •• – • • H N H H H compound formed in this step is called benzyne

9. Benzyne H H H H Benzyne has a strained triple bond. It cannot be isolated in this reaction, but is formed as a reactive intermediate.

10. • N H 2 • Mechanism Step 2 H H – •• H H

11. •• • N H 2 • N H 2 H H Mechanism Step 2 H H H – H – •• •• H H Angle strain is relieved. The two sp -hybridized ring carbons in benzyne become sp 2 hybridized in the resulting anion.

12. •• •• •• Mechanism Step 3 H H N H 2 H – H N H 2 H

13. N H 2 • H H N H 2 H • •• •• •• Mechanism Step 3 – • • •• H H H – H N H 2 H N H 2 H H

14. reaction of with NaOH Hydrolysis of Chlorobenzene 14 C labelin g * Cl indicates that the high- temperatur e NaOH , H 2 O 395°C chlorobenzen e O H goes via benzyne . * + * O H (43% ) (54%)

15. Diels-Alder Reactions of Benzyne

16. 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.

17. Mg, THF • • F •• F •• • • Other Routes to Benzyne B r Mg Br • • hea t •• + F Mg Br

18. Benzyne as a Dienophile Benzyne is a fairly reactive dienophile, and gives Diels-Alder adducts when generated in the presence of conjugated dienes.

19. + F Benzyne as a Dienophile B r Mg , THF heat (46%)