17.8 Acetal Formation 1

Compounds related to imines The Wittig reaction Some reactions of aldehydes and ketones progress beyond the nucleophilic addition stage Acetal formation Imine formation Enamine formation Compounds related to imines The Wittig reaction 22

Recall Hydration of Aldehydes and Ketones HOH C •• O • • HO H R R' 5

Alcohols Under Analogous Reaction with Aldehydes and Ketones R"OH C •• O • • R R' R"O H Product is called a hemiacetal. 5

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

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

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

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

Example O C6H5CH2CCH3 + HOCH2CH2OH H2C CH2 O O + H2O (78%) C C6H5CH2 benzene p-toluenesulfonic acid H2C CH2 O O + H2O (78%) C C6H5CH2 CH3 7

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

Mechanism H R + O • • R H O • • C O •• • • 10

Mechanism H R H O • • •• + C O O • • • • H R 10

Mechanism R H O • • •• + C O H 10

Mechanism R •• •• O C O • • + H H 10

Mechanism C O •• • • H + R O R H •• 10

Mechanism C O •• • • H R H + O •• R H 10

Mechanism of Acetal Formation Second stage is hemiacetal-to-acetal conversion involves carbocation chemistry 15

Hemiacetal-to-acetal Stage R + O • • C O •• • • H R 16

Hemiacetal-to-acetal Stage R O • • R H •• •• O + C O •• H 16

Hemiacetal-to-acetal Stage R H •• •• O + C O •• H 16

Hemiacetal-to-acetal Stage R O •• H • • •• O C + •• 16

Hemiacetal-to-acetal Stage •• R + R + O C •• Carbocation is stabilized by delocalization of unshared electron pair of oxygen 16

Hemiacetal-to-acetal Stage •• R + O •• H R • • 16

Hemiacetal-to-acetal Stage •• R + H 16

Hemiacetal-to-acetal Stage •• R + H O •• H R • • 16

Hemiacetal-to-acetal Stage •• R R •• H O + H 16

reverse of acetal formation; hemiacetal is intermediate Hydrolysis of Acetals OR" R R' C + H2O C R R' O 2R"OH + mechanism: reverse of acetal formation; hemiacetal is intermediate application: aldehydes and ketones can be "protected" as acetals. 26

17.9 Acetals as Protecting Groups 28

The conversion shown cannot be carried out directly... Example The conversion shown cannot be carried out directly... CH CH3CCH2CH2C O 1. NaNH2 2. CH3I CCH3 CH3CCH2CH2C O 29

because the carbonyl group and the carbanion are incompatible functional groups. CH3CCH2CH2C O – 31

Strategy 1) protect C=O 2) alkylate 3) restore C=O 32

Example: Protect O + CH3CCH2CH2C CH HOCH2CH2OH H2C CH2 O C CH2CH2C CH benzene p-toluenesulfonic acid H2C CH2 O C CH3 CH2CH2C CH 7

Example: Alkylate H2C CH2 O C CH2CH2C CCH3 CH3 H2C CH2 1. NaNH2 2. CH3I CH2CH2C CH 7

Example: Deprotect H2C CH2 O C CH3 CH2CH2C CCH3 H2O HCl CCH3 CH3CCH2CH2C O + HOCH2CH2OH (96%) 7