Hemiacetals acid-catalyzed formation

Protonation of the aldehyde or ketone oxygen atom makes the carbonyl carbon more susceptible to nucleophilic attack. [The protonated alcohol results from reaction of the alcohol (present in excess) with the acid catalyst, e.g., gaseous (anhydrous) HCI.] 

An alcohol molecule adds to the carbon of the oxonlum cation. 

The transfer of a proton from the positive oxygen to another molecule of the alcohol leads to the hemiacetal. 

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The first of these, 7, has CH3OH as a leaving group and reverts back to the conjugate acid of ethanal. This is the reverse of acid-catalyzed hemiacetal formation ... 

Draw a mechanism for the acid-catalyzed cyclization of L-threose to give (3-L-threofuranose. (Hint You may want to first review the mechanism for acid-catalyzed hemiacetal formation, Mechanism 20.5.)... 

The reaction above is an example of acid-catalyzed acetal formation, in which the product is favored by the removal of water. The mechanism can be divided into two parts (1) formation of the hemiacetal and (2) formation of the acetal. Formation of the hemiacetal involves three mechanistic steps ... 

Steps 4-5 Conversion of hemiacetal to carbocation These steps are analogous to the formation of carbocations m acid catalyzed reactions of alcohols... 

In a study of the acid-catalyzed formation of the hemiacetal, Grunwald has shown that the data best fit a mechanism in which the three steps shown here are actually all concerted that is, the reaction is simultaneously catalyzed by acid and base, with water acting as the base ... 

SAMPLE SOLUTION (a) The reaction given is the acid-catalyzed esterification of methanol by benzoic anhydride. The tetrahedral intermediate is formed by addition of a molecule of methanol to one of the carbonyl groups of the anhydride. This reaction is analogous to the acid-catalyzed formation of a hemiacetal by reaction of methanol with an aldehyde or ketone. 

Formation of hemiacetals and acetals, as well as of hemiketals and ketals, is reversible under acidic conditions, as we already have noted for acid-catalyzed esterification. The reverse reaction is hydrolysis and the equilibrium for this reaction can be made favorable by having an excess of water present ... 

Exercise 15-16 Hemiacetal formation is catalyzed by both acids and bases, but acetal formation is catalyzed only by acids. Write the steps involved in the formation of 1-methoxyethanol from ethanal in methanol containing sodium methoxide ... 

Exercise 16-9 Write equations to show the steps involved in the following carbonyl-addition reactions (a) base-catalyzed addition of ethanol to ethanal to form the corresponding hemiacetal, 1-ethoxyethanol (b) formation of 1-ethoxyethanol from ethanol and ethanal, but under conditions of acid catalysis (c) formation of 1,1-diethoxyethane from 1-ethoxyethanol and ethanol with an acid catalyst and (d) formation of diethyl carbonate (CH3CH20)2C—0 from ethanol and carbonyl dichloride. 

We already have discussed additions of alcohols and, by analogy, thiols (RSH) to carbonyl compounds (see Section 15-4E). We will not repeat this discussion here except to point out that addition of water to the carbonyl group of an aldehyde is analogous to hemiacetal formation (Section 15-4E) and is catalyzed both by acids and bases ... 

Fig. 9.2. Base-catalyzed (top) and acid-catalyzed (bottom) hemiacetal formation from carbonyl compounds and alcohols.

There are many examples of acid catalyzed carbonyl addition reactions, such as formation of hydrates (R2C(OH)2), hemiacetals, hemiketals, cyanohydrins, bisulfite compounds, azomethines, oximes, hydrazones, etc. These important reactions are discussed in Vol. 11. 

A recent application of the furan-carbonyl photocycloaddition involved the synthesis of the mycotoxin asteltoxin (147)." Scheme 16 shows the synthetic procedure that began with the photoaddition of 3,4-dimethylfuran and p-benzyloxypropanal to furnish photoaldol (148), which was epoxidized with MCPBA to afford the functionalized product (149) in 50% overall yield. Hydrolysis (THF, 3N HCl) provided the monocyclic hemiacetal which was protected as its hydrazone (150). Chelation-controlled addition of ethylmagnesium bromide to the latent a-hydroxy aldehyde (150) and acetonide formation produced compound (151), which was transformed through routine operations to aldehyde (152). Chelation-controlled addition of the lithium salt of pentadienyl sulfoxide (153) followed by double 2,3-sigma-tropic rearrangement provided (154) as a 3 1 mixture of isomers (Scheme 17). Acid-catalyzed cyclization of (154) (CSA/CH2CI2) gave the bicyclic acetal (155), which was transformed in several steps to ( )-asteltoxin (147). ... 

Hemiacetal formation is catalyzed by both acid and base. The acid-catalyzed mechanism is identical to Mechanism 21.9, except that the reaction occurs in an intramolecular fashion, as shown for the acid-catalyzed cyclization of 5-hydroxypentanal to form a six-membered cyclic hemiacetal in Mechanism 21.11. 

In acidic media, polarized multiple bonds often undergo acid catalyzed addition, and a common mode of addition is the Ad 2. Deprotonation of the nucleophile by solvent gives the neutral compound. Common examples of this easily reversible Adg2 reaction are the formation of hydrates (NuH is H2O) and, if NuH is ROH, hemiacetals (from aldehydes) and hemiketals (from ketones). Usually this reaction favors reactants. 

The reaction undoubtedly proceeds through formation of the hemi-acetal, followed by acid-catalyzed etherification of the hemiacetal by excess alcohol. A possible mechanism is illustrated here. 

The overall reaction proceeds in two stages. The hemiacetal is formed in the hrst stage by nucleophilic addition of the alcohol to the carbonyl group. The mechanism of hemiacetal formation is exactly analogous to that of acid-catalyzed hydration of aldehydes and ketones (Section 17.6) ... 

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