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17.8 Acetal Formation 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 Recall Hydration of Aldehydes and Ketones

R • C O• •• R'

HOH

R •• •• HO C O H •• •• R' Alcohols Under Analogous Reaction with Aldehydes and Ketones R • C O• •• R'

R"OH

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

R •• •• Product is called R"O C O H •• •• an acetal. R'

ROH, H+

R •• •• R"O C O H Product is called •• •• a hemiacetal. R' Example

O + CH + 2CH3CH2OH

HCl

CH(OCH2CH3)2 + H2O

Benzaldehyde diethyl acetal (66%) Diols Form Cyclic Acetals

CH3(CH2)5CH + HOCH2CH2OH benzene p-toluenesulfonic acid

H2C CH2

O O O + H2O C

(81%) H (CH2)5CH3 In general:

Position of equilibrium is usually unfavorable for acetal formation from ketones.

Important exception: Cyclic acetals can be prepared from ketones. Example

C H CH CCH C6H5CH2CCH3 + HOCH2CH2OH benzene p-toluenesulfonic acid

H2C CH2

O O O + H2O (78%) C

C6H5CH2 CH3 Mechanism of Acetal Formation

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

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

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

R •• + • O • C O H H Mechanism

R •• •• O C O• + H H Mechanism

R •• •• O C O• + H H

•• O R •• H Mechanism

R •• •• O C O• •• H H + O R •• H Mechanism of Acetal Formation

Second stage is hemiacetal-to-acetal conversion involves carbocation chemistry Hemiacetal-to-acetal Stage

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

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

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

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

R R •• + O C+ O C •• ••

Carbocation is stabilized by delocalization of unshared electron pair of oxygen Hemiacetal-to-acetal Stage

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

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

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

R R •• •• O C O R •• •• •• H O + H Hydrolysis of Acetals

OR" O

+ R C R' + H2O C 2R"OH R R' OR" mechanism: reverse of acetal formation; hemiacetal is intermediate application: aldehydes and ketones can be "protected" as acetals. 17.9 Acetals as Protecting Groups Example

The conversion shown cannot be carried out directly... O

CH3CCH2CH2C CH

1. NaNH2 2. CH3I O

CH3CCH2CH2C CCH3 because the carbonyl group and the carbanion are incompatible functional groups.

O – CH3CCH2CH2C C: Strategy

1)1) protectprotect C=OC=O 2)2) alkylatealkylate 3)3) restorerestore C=OC=O Example: Protect O + CH3CCH2CH2C CH HOCH2CH2OH benzene p-toluenesulfonic acid

H2C CH2

O O C

CH2CH2C CH CH3 Example: Alkylate

H2C CH2

O O C

CH2CH2C CCH3 CH3

H2C CH2

1. NaNH2 O O 2. CH I 3 C

CH2CH2C CH CH3 Example: Deprotect

H2C CH2

O O H2O C HCl CH2CH2C CCH3 CH3

O + HOCH2CH2OH CH3CCH2CH2C CCH3 (96%)