17.8 Acetal Formation

1. 17.8Acetal Formation

2. Some reactions of aldehydes and ketones progressbeyond the nucleophilic addition stage Acetal formation Imine formation Enamine formation Compounds related to imines The Wittig reaction

3. R O C •• •• R' HOH R •• •• HO O H C •• •• R' Recall Hydration of Aldehydes and Ketones

4. R O C •• •• R' R"OH R •• •• R"O O H C •• •• R' Alcohols Under Analogous Reactionwith Aldehydes and Ketones Product is called a hemiacetal.

5. R •• •• R"O O H C •• •• R' R •• •• R"O O H C •• •• R' Hemiacetal reacts further in acid to yield an acetal Product is called an acetal. ROH, H+ Product is called a hemiacetal.

6. O CH CH(OCH2CH3)2 Example + 2CH3CH2OH HCl + H2O Benzaldehyde diethyl acetal (66%)

7. O H2C CH2 O O C (CH2)5CH3 H Diols Form Cyclic Acetals + CH3(CH2)5CH HOCH2CH2OH benzene p-toluenesulfonic acid + H2O (81%)

8. In general: Position of equilibrium is usually unfavorablefor acetal formation from ketones. Important exception: Cyclic acetals can be prepared from ketones.

9. O Example C6H5CH2CCH3 + HOCH2CH2OH benzene p-toluenesulfonic acid H2C CH2 O + O H2O (78%) C CH3 C6H5CH2

10. Mechanism of Acetal Formation First stage is analogous to hydration andleads to hemiacetal acid-catalyzed nucleophilic addition of alcohol to C=O

11. H R •• O O H C O •• •• •• •• + H R Mechanism

12. R O •• •• H Mechanism H •• + O O C •• •• H R

13. R O •• •• H Mechanism •• + O C H

14. Mechanism R •• •• O O C •• + H H

15. R •• •• O O C •• + H H •• O •• R H Mechanism

16. R •• •• O O C •• •• H Mechanism H + O •• R H

17. Mechanism of Acetal Formation Second stage is hemiacetal-to-acetal conversion involves carbocation chemistry

18. H R •• •• O H O O C •• •• + •• H R Hemiacetal-to-acetal Stage

19. H O •• •• R Hemiacetal-to-acetal Stage R H •• •• + O O C •• H

20. Hemiacetal-to-acetal Stage R H •• •• + O O C •• H

21. H •• O •• H Hemiacetal-to-acetal Stage R •• O + C ••

22. R •• O + C •• Hemiacetal-to-acetal Stage R + O C •• Carbocation is stabilized by delocalizationof unshared electron pair of oxygen

23. R R •• •• O + C O •• •• H Hemiacetal-to-acetal Stage

24. R R •• •• + O O C •• H Hemiacetal-to-acetal Stage

25. R R •• •• + R O O C •• •• H O •• H Hemiacetal-to-acetal Stage

26. R R •• •• O O C •• •• Hemiacetal-to-acetal Stage R •• H O + H

27. OR" O + C 2R"OH R C R' + H2O R R' OR" Hydrolysis of Acetals mechanism: reverse of acetal formation;hemiacetal is intermediate application: aldehydes and ketones can be "protected" as acetals.

28. 17.9Acetals as Protecting Groups

29. O CH CH3CCH2CH2C O CCH3 CH3CCH2CH2C Example The conversion shown cannot be carried outdirectly... 1. NaNH22. CH3I

30. O C: CH3CCH2CH2C because the carbonyl group and thecarbanion are incompatible functionalgroups. –

31. Strategy 1) protect C=O 2) alkylate 3) restore C=O

32. O CH H2C CH2 O O C CH CH3 Example: Protect + HOCH2CH2OH CH3CCH2CH2C benzene p-toluenesulfonic acid CH2CH2C

33. H2C CH2 O O C CH2CH2C CCH3 CH3 H2C CH2 O O C CH CH3 Example: Alkylate 1. NaNH22. CH3I CH2CH2C

34. H2C CH2 O O C CH2CH2C CCH3 CH3 O CCH3 CH3CCH2CH2C Example: Deprotect H2O HCl + HOCH2CH2OH (96%)