The Addition of Alcohols Hemiacetals and Acetals

The hemiacetal results by nucleophilic addition of an alcohol oxygen to the carbonyl carbon of an aldehyde or ketone. 

In this step the alcohol attacks the carbonyl carbon. 

In two intermolecular steps, a proton is removed from the positive oxygen and a proton is gained at the negative oxygen. 

Most simple sugars (Chapter 22) exist primarily in a cyclic hemiacetal form. Glucose is an example  

Whether the carbonyl reactant is an aldehyde or a ketone, the product with an —OH and an —OR group is called a hemiacetal. 

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For our present purposes, we are interested in the ways in which hemi-acetals, acetals, hemiketals, and ketals are formed. Hemiacetals and hemi-ketals can be regarded as products of the addition of alcohols to the carbonyl... 

Addition of Alcohols to Form Acetals (Section 16.7B) Formation of acetals is catalyzed by acid. Acetals are stable to water and aqueous base but are hydrolyzed in aqueous acid. Acetals are valuable as carbonyl-protecting groups. The mechanism for conversion of a hemiacetal to an acetal involves protonation of the OH group of the hemiacetal... 

Organic chemists originally used hemiketal and ketal for describing the products from alcohol addition to ketones and hemiacetal and acetal were used for the products from alcohol addition to aldehydes.The lUPAC system has dropped the hemiketal and ketal names in favor of using hemiacetal and acetal for the species formed from both aldehydes and ketones. We will not use hemiketal or ketal, but be alert, because one still sees these sensible terms occasionally. 

Further studies revealed that temperatures of 130°C and above are necessary for the formation of acetals from alcohols and added HCl has no influence. We believe that the reaction proceeds via enolether intermediates (Fig. 10, 17), which are generated by water elimination fi om the initially formed hemiacetals. This is supported by the observation of E, Z-mixtures of enolether intermediates 17 in the reaction mixture. In line with this postulate, reaction of complex 16 with benzyl alcohol (under neutral conditions), which lacks p-hydrogens and cannot form an enolether, did not yield benzylacetal rather, benzylbenzoate was quantitatively formed. Thus, formation of the acetal product likely takes place by the addition of alcohols to the C=C bond of the enolether (route b. Fig. 10). It is not clear at this... 

Aldehydes and ketones undergo reversible addition reactions with alcohols. The product of addition of one mole of alcohol to an aldehyde or ketone is referred to as a hemiacetal or hemiketal, respectively. Dehydration followed by addition of a second molecule of alcohol gives an acetal or ketal. This second phase of the process can be catalyzed only by acids, since a necessary step is elimination of hydroxide (as water) from the tetrahedral intermediate. There is no low-energy mechanism for base assistance of this... 

The equilibrium constants for addition of alcohols to carbonyl compounds to give hemiacetals or hemiketals show the same response to structural features as the hydration reaction. Equilibrium constants for addition of metiianoHb acetaldehyde in both water and chloroform solution are near 0.8 A/ . The comparable value for addition of water is about 0.02 The overall equilibrium constant for formation of the dimethyl acetal of... 

Hydroformylation of unsaturated amines offer a convenient synthetic access to cyclic AT.O-hemiacetals. If performed in the presence of alcohols or orthoesters AT,O-acetals are formed. With additional N-nucleophiles N,N-acetals are obtained. These compounds are synthetically attractive building blocks and were therefore used as a key step in the synthesis of various natural products [27,35]. Thus the synthesis of (+)-prosopinine starting from enantiopure (T)-scrinc leads to a cyclic N,O-acetal functionality with the required functionality for the attachment of the side chain (Scheme 6) [36]. 

The intermediate formed from this first nucleophilic addition is known as hemiacetal. When ketone is the starting material, the structure obtained is a hemiketal. Once the hemiacetal is formed, it is protonated and water is eliminated by the same mechanism described in the formation of imines with the only difference that oxygen donates a lone pair of electrons to force the removal of water rather than nitrogen (Following fig.). The resulting oxonium ion is extremely electrophilic and a second nucleophilic addition of alcohol to forms the acetal. 

The mechanism for acetal formation can be divided into two parts the addition of one equivalent of alcohol to form a hemiacetal, followed by the conversion of the hemiacetal to the acetal. A hemiacetal has a carbon atom bonded to one OH group and one OR group. 

A hemiacetal is formed by the addition of the nucleophilic alcohol molecule to the carbonyl group it is both an ether and an alcohol. With a few exceptions, hemi-acetals arc too unstable to be isolated. 

Aldehydes readily react with alcohols into hemiacetals and acetals. The first reaction involves simple addition, whereas water is liberated in the second reaction. The reactions are acid-catalyzed and reversible. Acid catalysis is, however, not a necessary condition for the reaction to proceed. Frequently, particularly in the case of aliphatic aldehydes, the reaction proceeds without a catalyst. If both alcohol and aldehyde are bifunctional reagents, it is possible that cyclic structures may form or that polymerization may occur. Whether or not one or the other of these reactions occur depends on the energy factors, steric accessibility of the reaction sites, and finally, as in all reversible reactions, on the position of the equilibrium according to the concentration of reagents and products in the solution. Starch, being a polyalcohol, also reacts with aldehydes. This subject was formerly reviewed by Roberts.1274... 

Evidence for the structure (CXXIII) of the hemiacetal is based on the extremely hindered nature of the derived aldehyde (CXXV) and carboxylic acid (CXXVII). Thus, the aldehyde exhibited a negative Cotton effect in methanol, which remained unchanged upon the addition of hydrochloric acid, indicating great resistance toward acetal formation. Attempts to prepare carbonyl derivatives of this aldehyde were unsuccessful. The acid CXXVII was prepared by oxidation of alcohol CXXIV with chromium trioxide in acetic acid. Comparison of the apparent dissociation constant of this acid (pX cs 9.45) with that for... 

Aldehydes and ketones undergo acid-catalyzed addition of water to form hydrates. Electron donation and bulky substituents decrease the percentage of hydrate present at equilibrium. Most hydrates are too unstable to be isolated. Acid-catalyzed addition of alcohol to aldehydes forms hemiacetals and acetals, and to ketones forms hemiketals... 

Aldehydes and ketones are prepared by the oxidation of primary and secondary alcohols, respectively. Aldehydes can be further oxidized to carboxylic acids, but ketones resist oxidation. Thus, aldehydes are oxidized by Tollens reagent (Ag" ) and Benedict s solution (Cu ), whereas ketones are not. A characteristic reaction of both aldehydes and ketones is the addition of hydrogen to the carbonyl double bond to form alcohols. In a reaction that is very important in sugar chemistry, an alcohol can add across the carbonyl group of an aldehyde to produce a hemiacetal. The substitution reaction of a second alcohol molecule with the hemiacetal produces an acetal. Ketones can undergo similar reactions to form hemiketals and ketals. 

The addition of a molecule of alcohol to the carbonyl group of an aldehyde or a ketone forms a hemiacetal (a half-acetal). This reaction is catalyzed by both acid and base Oxygen adds to the carbonyl carbon and hydrogen adds to the carbonyl oxygen ... 

In the presence of alcohols or amines, the aldehydes generated in the hydroformylaton reaction give acetals or imines. Depending on the hydroformylation catalyst used an additional acid catalyst is required. When the process is intramolecular, (i.e. when alcohols, amines or amides are present in the starting material), it is spontaneous and gives hemiacetals or imines, especially if five or six member rings can be formed [4b]. Moreover the presence... 

Many of the most interesting and useful reactions of aldehydes and ketones involve transformation of the initial product of nucleophilic addition to some other substance under the reaction conditions. An example is the acid-catalyzed addition of alcohols to aldehydes.The expected product, a hemiacetal, is not usually isolable, but reacts with an additional mole of the alcohol to give an acetal. 

The equilibrium constants for addition of alcohols to carbonyl compounds to give hemiacetals or hemiketals show the same response to structural features as do those for hydration reactions. The magnitude of the equilibrium constants is slightly smaller than for hydration. For example, whereas K for addition of water to acetaldehyde is 1.06, K s for addition of methanol and ethanol are 0.75 and 0.50 M respectively. The overall equilibrium constants for formation of the acetals are 0.03 and 0.0125 M , respectively. Because the position of the equilibrium does not favor product, the formation of acetals and ketals must be carried out in such a way as to compensate for the unfavorable equilibrium. One approach is to use a dehydrating reagent or azeotropic distillation so that the water that is formed is irreversibly removed, driving the reaction to completion ... 

Another addition reaction is the introduction of a molecule of water. The resulting hydrates are quite unstable but may serve as intermediates. Addition of alcohols, by extension, gives rise to the analogous hemiacetals. By further reaction with alcohol and removal of water, acetals are formed. The name acetal applies only to derivatives of aldehydes ketones form ketals. 

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