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19.10 Acetals and Their Use As Protecting Groups 921

19.10 Acetals and Their Use As Protecting Groups 921

19_BRCLoudon_pgs5-0.qxd 12/9/08 11:41 AM Page 921

19.10 AND THEIR USE AS PROTECTING GROUPS 921

19.10 ACETALS AND THEIR USE AS PROTECTING GROUPS

The preceding sections dealt with simple carbonyl-addition reactions—first, reversible additions ( formation and hydration); then, irreversible additions ( reduction and addition of Grignard reagents). This and the following sections consider some reactions that begin as additions but involve other types of mechanistic steps.

A. Preparation and of Acetals When an or reacts with a large excess of an in the presence of a trace of strong , an is formed.

OCH3

O2N CH A O H2SO4 O2N "CH OCH3 (trace) L % % 2CH3OH % % H2O (19.44) i + (solvent) i +

m-nitrobenzaldehyde m-nitrobenzaldehyde dimethyl acetal (76–85% yield)

O CH O OCH

S 3 3 L C L C H2SO4 L CH3 (trace) CH3 % % 2CH3OH H2O (19.45) i + (solvent) i + acetophenone acetophenone dimethyl acetal (82% yield)

An acetal is a compound in which two are bound to the same . In other words, acetals are the of carbonyl hydrates, or gem- (Sec. 19.7). (Acetals derived from were once called ketals, but this name is no longer used.) Notice that two equivalents of alcohol are consumed in each of the preceding reactions. However, 1,2- and 1,3-diols contain two OH groups within the same molecule. Hence, one equivalent of a 1,2- or 1,3- can react Lto form a cyclic acetal, in which the acetal group is part of a five- or six-membered ring, respectively.

O 0 O HO 0 CH p-toluenesulfonic % 2 acid (Sec. 10.3A) ( O H2O (19.46) + "CH2 + HO % cyclohexanone cyclohexanone ethylene acetal glycol (85% yield) 19_BRCLoudon_pgs5-0.qxd 12/9/08 11:41 AM Page 922

922 CHAPTER 19 • THE CHEMISTRY OF AND KETONES. CARBONYL-ADDITION REACTIONS

The formation of acetals is reversible. The reaction is driven to the right either by the use of excess alcohol as the solvent or by removal of the water by-product, or both. This strategy is another application of Le Châtelier’s principle. In Eq. 19.46, for example, the water can be removed as an azeotrope with . (The benzene–water azeotrope is a mixture of benzene and water that has a lower boiling point than either benzene or water alone.) The first step in the mechanism of acetal formation is acid-catalyzed addition of the alco- hol to the to give a —a compound with an OR and OH group on the same carbon (hemi half; hemiacetal half acetal). L L = = O OH S acid C ROH "C (19.47a) LL % + % "OR hemiacetal

Hemiacetal formation is completely analogous to acid-catalyzed hydration. (Write the step- wise mechanism of this reaction; see Problem 19.16a, p. 910.) The hemiacetal reacts further when the OH group is protonated and water is lost to give a relatively stable carbocation, an a-alkoxyL carbocation (Sec. 19.6).

OR OR OR OR| S 3 2 3 2 SN1 3 2 2 "C "C "CHC 2O (19.47b) LL LL + 2 | % | % % % H2O H ""O H O| H a-alkoxy carbocation 2 2 L 3 L 3 L 2 "H

H2O + 2 Loss of water from the hemiacetal2 is an S 1 reaction analogous to the loss of water in the de- STUDY GUIDE LINK 19.6 N Hemiacetal hydration of an ordinary alcohol (Eq. 10.3b). The nucleophilic reaction of an alcohol molecule Protonation with the cation and of the nucleophilic complete the mechanism.

OR OR OR 3 2 3 2 ROH 3 2 "C HOR "C 2 "C RO|H2 (19.47c) LL 2 LL % | % ++2 2 "OR| "OR 2 3 3 "H 2 As we have just shown, the mechanism for acetal formation is really a combination of other familiar mechanisms. It involves an acid-catalyzed carbonyl addition followed by a substitu-

tion that occurs by the SN1 mechanism. Because the formation of acetals is reversible, acetals in the presence of acid and excess water are transformed rapidly back into the corresponding carbonyl compounds and ; this process is called acetal hydrolysis. (A hydrolysis is a cleavage reaction involving water.) As expected from the principle of microscopic reversibility, the mechanism of acetal hydroly- sis is the reverse of the mechanism of acetal formation. Hence, acetal hydrolysis, like hemiac- etal formation, is acid-catalyzed. 19_BRCLoudon_pgs5-0.qxd 12/9/08 11:41 AM Page 923

19.10 ACETALS AND THEIR USE AS PROTECTING GROUPS 923

The formation of is catalyzed not only by but by bases as well (Problem 19.16b, p. 910). However, the conversion of hemiacetals into acetals is catalyzed only by acids (Eqs. 19.47b and c). This is why acetal formation, which is a combination of the two reactions, is catalyzed by acids but not by bases.

catalyzed by catalyzed acids and bases only by acids

O OH OR S ROH C ROH"C "C H2O (19.47d) LL LL % ++ % "OR "OR hemiacetal acetal

As expected from the principle of microscopic reversibility, the hydrolysis of hemiacetals to aldehydes and ketones is also catalyzed by bases, but the hydrolysis of acetals to hemiacetals is catalyzed only by acids. Hence, acetals are stable in basic and neutral solution. Hemiacetals, the intermediates in acetal formation (Eq. 19.47a), in most cases cannot be isolated because they react further to yield acetals (in alcohol solution under acidic conditions) or decompose to aldehydes or ketones and an alcohol. Simple aldehydes, however, form appreciable amounts of hemiacetals in alcohol solution, just as they form appreciable amounts of hydrates in water (see Table 19.2).

OH

H3C CHA O C2H5OH H3C" CH (19.48) L + solvent L "OC2H5 (97% at equilibrium) Five- and six-membered cyclic hemiacetals form spontaneously from the corresponding hy- droxy aldehydes, and most are stable compounds that can be isolated. HO H L LO HOCH2CH2CH2CH2CHA O (19.49) 5-hydroxypentanal a cyclic hemiacetal (94% at equilibrium) HO H

L LO HOCH2CH2CH2CHA O (19.50)

4-hydroxybutanal (89% at equilibrium)

You learned in Sec. 11.7 that intramolecular reactions which give six-membered or five-mem- bered rings are faster than the corresponding intermolecular reactions. Such intramolecular re- actions are also more favored thermodynamically—that is, they have larger equilibrium con- stants, because an intramolecular OH group simply has a greater probability of reaction than an OH group in a different Lmolecule. The five-L and six-carbon sugars are important biological examples of cyclic hemiacetals. 19_BRCLoudon_pgs5-0.qxd 12/9/08 11:41 AM Page 924

924 CHAPTER 19 • THE CHEMISTRY OF ALDEHYDES AND KETONES. CARBONYL-ADDITION REACTIONS

HOCH HOCH 2 OH 2 O HO HO $ $ (19.51) HO% H HO% H L $OH % L $OH % O "OH ( )- a-( )-glucopyranose | (a cyclic| form of glucose) (This reaction and its stereochemistry are discussed in Sec. 27.2B.)

Storage of Aldehydes as Acetals Some aldehydes are stored as acetals. ,when treated with a trace of acid,readily forms acyclicacetalcalledparaldehyde.Eachmoleculeofparaldehydeisformedfromthreemoleculesof acetaldehyde.(Notice that an alcohol is not involved in formation of paraldehyde.) Paraldehyde,with a boiling point of 125 C,is a particularly convenient way to store acetaldehyde,which itself boils near room temperature.Upon° heating with a trace of acid,acetaldehyde can be distilled from a sample of paraldehyde.(See Problem 19.60, p. 944.)

H CH3 C acid O O 3CH3CHA O (19.52) H3C C C CH3 O H H paraldehyde

Formaldehyde can be stored as the acetal paraformaldehyde, which precipitates from con- centrated solutions. HO CH OH 2 n L paraformaldehyde (An alcohol is not involved in paraformaldehyde formation.) Because it is a solid, paraformaldehyde is a useful form in which to store formaldehyde, itself a gas. Formaldehyde is liberated from paraformaldehyde by heating.

PROBLEMS 19.24 Write the structure of the product formed in each of the following reactions. (a) acid A O CH3CH2OH + (solvent) (b) O S acid CH3CH2CH2CH (CH3)2CHOH + (solvent) 19.25 Propose syntheses of each of the following acetals from carbonyl compounds and alcohols. (a) O (b) O

O O 19_BRCLoudon_pgs5-0.qxd 12/9/08 11:41 AM Page 925

19.10 ACETALS AND THEIR USE AS PROTECTING GROUPS 925

19.26 Suggest a structure for the acetal product of each reaction. (a) HO H

L LO acid C2H5OH (C7H14O2) + (excess)

(b) CH3 acid A O HO CH2 "C CH2 OH 0 + LLL L "CH3 (excess)

B. Protecting Groups A common tactic of organic synthesis is the use of protecting groups. The method is illustrated by the following analogy. Suppose you and a friend haven’t been invited to a party but are de- termined to attend it anyway. To avoid recognition and confrontation, you wear a disguise, which might be a wig, a false mustache, or even more drastic accoutrements. Your friend does- n’t bother with such deception. The host recognizes your friend and insists that he leave the party, but, because you are not recognized, you avoid such a confrontation and can remain to enjoy the evening, removing your disguise only after the party is over. Now, suppose two groups in a molecule, A and B, are both known to react with a certain reagent, but we want to let only group A react and leave group B unaffected. The solution to this problem is to disguise, or protect, group B in such a way that it cannot react. After group A is allowed to react, the disguise of group B is removed. The “chemical disguise” used with group B is called a or protective group. Acetals are among the most com- monly used protecting groups for aldehydes and ketones. Study Problem 19.4 illustrates the use of an acetal as a protecting group.

Study Problem 19.4 Propose a sequence of reactions for carrying out the following conversion. O O S S ? Br CCH3 HO CH2CH2 C CH3 (19.53) LcL L L LcL L

Solution It might seem that the way to effect this conversion would be to convert the starting halide into the corresponding , and then allow this reagent to react with ethylene , followed by dilute aqueous acid (Sec. 11.4C). However, Grignard reagents also react with ketones (Sec. 19.9). Hence, the Grignard reagent derived from one molecule of the starting mater- ial would react with the carbonyl group of another molecule, and thus the ketone group would not survive this reaction. However, the ketone can be protected as an acetal, which does not react with Grignard reagents. (An acetal is a type of ether, and ethers are unaffected by Grignard reagents.) The following synthesis incorporates this strategy. 19_BRCLoudon_pgs5-0.qxd 12/9/08 11:41 AM Page 926

926 CHAPTER 19 • THE CHEMISTRY OF ALDEHYDES AND KETONES. CARBONYL-ADDITION REACTIONS

introduction of the formation of the the protecting group Grignard reagent O S OO HOCH2CH2OH Mg Br C CH3 C p-toluenesulfonic L CH ether LcL L acid (trace) 3 (See Eq. 19.46) Br LcL acetal protecting group; protonolysis of the alkoxide inert to Grignard reagents and hydrolysis of the acetal (removal of the protecting group)

O OO OO H2C$ CH2 H2O, H3O| C L C L CH3 L CH3

BrMg BrMg OCH CH LcL |_ 2 2LcL O S HOCH2CH2OH HOCH2CH2 C CH3 (19.54) + LcL L Notice in this synthesis that all steps following acetal formation involve basic or neutral condi- tions. Acid can be used only when destruction of the acetal is desired. Although any acetal group can in principle be used, the five-membered cyclic acetal is fre- quently employed as a protecting group because it forms very rapidly (proximity effect; Sec. 11.7) and it introduces relatively little steric congestion into the protected molecule.

A number of reagents that react with carbonyl groups also react with other functional groups. Acetals are commonly used to protect the carbonyl groups of aldehydes and ketones from basic, nucleophilic reagents. Once the protection is no longer needed, the acetal protect- ing group is easily removed, and the carbonyl group re-exposed, by treatment with dilute aqueous acid. Because acetals are unstable in acid, they do not protect carbonyl groups under acidic conditions.

PROBLEM 19.27 Outline a synthesis of the following compound from p-bromoacetophenone and any other reagents. O O S S H3C C C CH3 L LcL L

19.11 REACTIONS OF ALDEHYDES AND KETONES WITH

A. Reaction with Primary Amines and Other Monosubstituted Derivatives of A primary is an organic derivative of ammonia in which only one ammonia is replaced by an or aryl group. An is a analog of an aldehyde or ketone in which the CAO group is replaced by a CANR group, where R alkyl, aryl, or H. =

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