19.10 ACETALS AND THEIR USE AS PROTECTING GROUPS
ACETALS AND THEIR USE AS PROTECTING GROUPS The preceding sections dealt with simple carbonyl-addition reactions—first, reversible additions (cyanohydrin formation and hydration); then, irreversible additions (hydride 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 Hydrolysis of Acetals When an aldehyde or ketone reacts with a large excess of an alcohol in the presence of a trace of strong acid, an acetal is formed.
O2N %
% CH i
AO
+ 2 CH3OH
H2SO4 (trace)
(solvent)
m-nitrobenzaldehyde
OCH3 " L O2N % % CH OCH3 i + H2O
(19.44)
m-nitrobenzaldehyde dimethyl acetal (76–85% yield)
CH3O
L
OCH3
+ 2CH3OH
H2SO4 (trace)
(solvent)
acetophenone
i
C
L L
O S %C % CH3 i
L
19.10
921
CH3
+ H2O
(19.45)
acetophenone dimethyl acetal (82% yield)
An acetal is a compound in which two ether oxygens are bound to the same carbon. In other words, acetals are the ethers of carbonyl hydrates, or gem-diols (Sec. 19.7). (Acetals derived from ketones 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 L OH groups within the same molecule. Hence, one equivalent of a 1,2- or 1,3-diol can react to form a cyclic acetal, in which the acetal group is part of a five- or six-membered ring, respectively.
cyclohexanone
HO% CH2 " + CH2 HO% ethylene glycol
O p-toluenesulfonic acid (Sec. 10.3A)
0
0
(O
O
cyclohexanone ethylene acetal (85% yield)
+ H2O
(19.46)
922
CHAPTER 19 • THE CHEMISTRY OF ALDEHYDES 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 benzene. (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 alcohol to the carbonyl group to give a hemiacetal—a compound with an L OR and L OH group on the same carbon (hemi = half; hemiacetal = half acetal). O S %C % + ROH
acid
OH " LCL " OR
(19.47a)
hemiacetal
Hemiacetal formation is completely analogous to acid-catalyzed hydration. (Write the stepwise mechanism of this reaction; see Problem 19.16a, p. 910.) The hemiacetal reacts further when the L OH group is protonated and water is lost to give a relatively stable carbocation, an a-alkoxy carbocation (Sec. 19.6). 3 OR 2 " LCL | " H2O 2 L H 3O L H 2
STUDY GUIDE LINK 19.6
Hemiacetal Protonation
3 OR 2 " LCL " 3 O|L H " H
SN1
|
3 OR 2 " %C %
OR 2 S 2 %C % + H2O 2
|
(19.47b)
a-alkoxy carbocation
+ H2O 2 2 Loss of water from the hemiacetal is an SN1 reaction analogous to the loss of water in the dehydration of an ordinary alcohol (Eq. 10.3b). The nucleophilic reaction of an alcohol molecule with the cation and deprotonation of the nucleophilic oxygen complete the mechanism. 3 OR 2 " + HOR 2 %C |% 2
3 OR 2 " LCL "| 3 OR " H
ROH 2 2
3 OR 2 " | L C L + ROH2 " 2 3 OR 2
(19.47c)
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 substitution 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 alcohols; 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 hydrolysis is the reverse of the mechanism of acetal formation. Hence, acetal hydrolysis, like hemiacetal formation, is acid-catalyzed.
19.10 ACETALS AND THEIR USE AS PROTECTING GROUPS
923
The formation of hemiacetals is catalyzed not only by acids 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 only by acids
catalyzed by acids and bases OH " LCL " OR
O S %C % + ROH
OR " L C L + H2O " OR
ROH
hemiacetal
(19.47d)
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). H3C L CH A O + C2H5OH solvent
OH " H3C L CH " OC2H5
(19.48)
(97% at equilibrium)
Five- and six-membered cyclic hemiacetals form spontaneously from the corresponding hydroxy aldehydes, and most are stable compounds that can be isolated. H
L
L
HO
O
HOCH2CH2CH2CH2CH A O 5-hydroxypentanal
(19.49)
a cyclic hemiacetal (94% at equilibrium)
H
L
L
HO HOCH2CH2CH2CH A O 4-hydroxybutanal
O
(19.50)
(89% at equilibrium)
You learned in Sec. 11.7 that intramolecular reactions which give six-membered or five-membered rings are faster than the corresponding intermolecular reactions. Such intramolecular reactions are also more favored thermodynamically—that is, they have larger equilibrium constants, because an intramolecular L OH group simply has a greater probability of reaction than an L OH group in a different molecule. The five- and six-carbon sugars are important biological examples of cyclic hemiacetals.
924
CHAPTER 19 • THE CHEMISTRY OF ALDEHYDES AND KETONES. CARBONYL-ADDITION REACTIONS
HOCH2 OH $ HO % %H HO L $ OH O
HOCH2 O $ HO % %H HO L $ " OH OH
(|)-glucose
a-(|)-glucopyranose (a cyclic form of glucose)
(19.51)
(This reaction and its stereochemistry are discussed in Sec. 27.2B.) Storage of Aldehydes as Acetals Some aldehydes are stored as acetals. Acetaldehyde, when treated with a trace of acid, readily forms a cyclic acetal called paraldehyde. Each molecule of paraldehyde is formed from three molecules of 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 3CH3CH A O
C
O
acid
H3C
CH3
C
O
H
O C
CH3
(19.52)
H
paraldehyde Formaldehyde can be stored as the acetal polymer paraformaldehyde, which precipitates from concentrated formaldehyde solutions.
CH2 L O
HO
n
H
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 CH3CH2CH2CH + (CH3)2CHOH
acid
(solvent)
19.25 Propose syntheses of each of the following acetals from carbonyl compounds and alcohols. (a) (b) O O O
O
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
L
O
+ C2H5OH
acid
(C7H14O2)
(excess)
(b)
CH3 " 0A O + HO L CH2 L C L CH2 L OH " CH3
acid
(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 determined 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 doesn’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 protecting group or protective group. Acetals are among the most commonly 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 LcL C L CH3 HO L CH2CH2 LcL C L CH3
(19.53)
Solution It might seem that the way to effect this conversion would be to convert the starting halide into the corresponding Grignard reagent, and then allow this reagent to react with ethylene oxide, 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 material 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.
926
CHAPTER 19 • THE CHEMISTRY OF ALDEHYDES AND KETONES. CARBONYL-ADDITION REACTIONS
introduction of the the protecting group
O S Br LcL C L CH3
HOCH2CH2OH p-toluenesulfonic acid (trace) (See Eq. 19.46)
formation of the Grignard reagent
CL L CH
O
O
c
Br L
Mg ether
3
protonolysis of the alkoxide and hydrolysis of the acetal (removal of the protecting group)
acetal protecting group; inert to Grignard reagents
c
BrMg L
O $$ H2C L CH2
CL L CH
O
O
CL L CH
O
3
BrMg|
_OCH CH 2 2
c
L
O
H2O, H3O|
3
O S HOCH2CH2OH + HOCH2CH2 LcL C L CH3
(19.54)
Notice in this synthesis that all steps following acetal formation involve basic or neutral conditions. 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 frequently 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 protecting 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
19.11
19.27 Outline a synthesis of the following compound from p-bromoacetophenone and any other reagents. O O S S H3C L C LcL C L CH3
REACTIONS OF ALDEHYDES AND KETONES WITH AMINES A. Reaction with Primary Amines and Other Monosubstituted Derivatives of Ammonia A primary amine is an organic derivative of ammonia in which only one ammonia hydrogen is replaced by an alkyl or aryl group. An imine is a nitrogen analog of an aldehyde or ketone in which the C A O group is replaced by a C A NR group, where R = alkyl, aryl, or H.
