Organic Chemistry: Concepts and Applications - Headley Allan D. 2020

Addition Reactions Involving Carbonyls and Nitriles
9.5 Addition of Alcohols to Carbonyl Compounds

The mechanism for the addition of alcohols to the carbonyl functionality of aldehydes and ketones is similar to that of the addition of water to carbonyl compounds. Under acidic conditions, the reaction of an aldehyde with one mole of an alcohol gives a hemiacetal. The general reaction mechanism for the acid-catalyzed addition of an alcohol to an aldehyde is shown in Reaction (9-26).

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Note that these reactions are reversible and the equilibrium can be shifted in any direction by increasing the concentration of either the alcohol or the aldehyde in the presence of an acid. Reaction (9-27) shows the acid-catalyzed reaction of propanol with butanal.

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It is possible to have intramolecular hemiacetal formation in which the alcohol and aldehyde functionalities of a difunctional molecule react in an acidic medium, as shown in Reaction (9-28).

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The mechanism for the intramolecular acid-catalyzed addition reaction is similar to that of the intermolecular reaction in that the carbonyl oxygen is first protonated. The next step in the mechanism involves the intramolecular attack of the alcohol functionality on the electrophilic carbonyl carbon to form the protonated cyclic hemiacetal. The last step involves the regeneration of the proton catalyst and the cyclic hemiacetal as outlined in Reaction (9-29).

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Problem 9.5

Complete each of the following reactions by giving the structure of the hemiacetal product or the appropriate aldehyde and alcohol.

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An important intramolecular hemiacetal formation exists in biological science. Glucose and similar monosaccharaides contain both an aldehyde and alcohol functionalities, and in solution, these compounds form cyclic hemiacetals as shown in Reaction (9-30).

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Most monosaccharides exist as hemiacetals or hemiketals, which we will be covering in Chapter 20.

Problem 9.6

The open-chain structure of mannose is shown below. Give the most stable chair conformation of the six-member cyclic hemiacetal for mannose that would exist in aqueous solution.

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Hemiacetals, in the presence of an alcohol and in the presence of an acid catalyst, react to form acetals. In the first step of the reaction mechanism leading to the acetal formation, the hemiacetal is protonated as shown in Reaction (9-31) to produce a resonance-stabilized carbocation after loss of water.

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In the next step of the mechanism, the newly developed carbocation reacts with a molecule of the nucleophilic alcohol to produce a protonated acetal, which loses a proton to form the acetal, as shown in Reaction (9-32).

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Thus, the overall reaction of an aldehyde in the presence of excess alcohol and in an acidic medium results in the acetal that is reflected in the reaction of butanal with an excess of methanol in an acidic medium as shown in Reaction (9-33).

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Problem 9.7

Complete each of the following reactions by giving the structure of the acetal product or the appropriate aldehyde and alcohol.

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Similar addition reactions as those shown above involving aldehydes to form hemiacetals and acetals are possible for ketones. In this case, however, the products are known as hemiketals and ketals. The hemiketal formation of propanone and methanol is shown in Reaction (9-34).

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Hemiketals in the presence of an excess of an alcohol will react further to form ketals as shown below in the reaction of the hemiketal of propanone in the presence of another mole of methanol. In the first step of the mechanism, the hemiketal is protonated and water leaves to create a fairly stable resonance-stabilized carbocation as shown in Reaction (9-35).

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In the next step of the reaction mechanism, the carbocation reacts with another mole of methanol to form a protonated ketal, and after the loss of a proton in the final step, the ketal is formed as shown in Reaction (9-36).

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Problem 9.8

i. Give the ketal or acetal that would result from the reaction of each of the carbonyl compounds shown below in an acidic medium and in the presence of excess methanol.Image

ii. Which of the above molecules would you expect to be the most reactive? Explain your answer.

It is possible to use a diol instead of an excess of alcohol to react with a carbonyl compound to produce a ketal or acetal. 1,2-Ethanediol is one such molecule that has two alcohol functionalities and readily reacts with aldehydes or ketones in the presence of an acid to form cyclic acetals or ketals as shown in the example in Reaction (9-37).

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The importance of these types of reactions will be discussed in the next section.

Problem 9.9

Using arrow-pushing formulism to indicate electron movement, propose a reasonable mechanism for the reaction shown below.

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9.5.1 Ketals and Acetals as Protection Groups

For molecules that have more than one of the functional groups listed in Chapters 3 and 4, extreme care must be exercised if it is desired to have just one functional group that undergoes a specific reaction and not another functional group. For polyfunctional molecules, many times the reaction conditions that are suited for one functional group are also suitable for a reaction to occur not only at the desired functional group but also at other functional groups. We have seen in this chapter that alkenes and carbonyl compounds can undergo addition reaction. Thus, if a molecule has both alkene and carbonyl functionalities present, it becomes very difficult to carry out a reaction involving just one functionality without affecting another. A strategy that is often used in organic chemistry is to protect one of the functionalities from the reaction that can take place at another functional group. Once the reaction is complete, the protection group is removed to generate the original functional group. Since the addition reactions of alcohols to the carbonyl functionality form ketal and acetals are reversible reactions, alcohols are ideal to act as protecting groups for carbonyl groups. Thus, for a difunctional molecule that has a carbonyl functionality and another functionality, the carbonyl functionality can be converted to the ketal functionality, then a reaction can be carried out on another functionality on the same molecule. Once that reaction is complete, the protecting acetal or ketal can be removed to regenerate the original carbonyl functionality. The challenge is illustrated in the desired transformation shown in Reaction (9-38).

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In order to carry out the transformation shown in Reaction (9-38), the reaction needs to take place at the alkylbromide functional end and not at the carbonyl group. As we will see in the next section, there is a reaction that can transform an alkyl bromide to an alkene, but it involves the reaction with another molecule that has a carbonyl functionality. Thus, in order to carry out this transformation, the aldehyde functionality must be first protected before carrying out the reaction at the alkylbromide functionality. Once the reaction is complete, the protecting group is removed to generate the desired product. The strategy is illustrated in the sequence of reactions shown in Reaction (9-39).

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The first reaction to be carried out is the protection of the aldehyde to form an acetal. Once protected, specific reactions can occur involving the alkylbromide functionality to give the protected target molecule. The last reaction in this sequence of reactions involves the conversion of the protected target molecule to get the target molecule, as shown in Reaction (9-40).

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As you can imagine, the reaction of carbonyl compounds and dithiols should be very similar to that of diols. In fact, 1,2-ethanedithiol is sometimes used as a protecting group for carbonyl compounds. The reaction involving a 1,2-ethanedithiol and cyclohexanone to produce 1,3-dithiolanes is shown in Reaction (9-41), but ketals and acetals are used more often as protecting groups in organic synthesis.

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Problem 9.10

i. Give the ketal or acetal that would result from the reaction of each of the carbonyl compounds shown below with ethylene glycol (1,2-ethanediol) in the presence of an acid.Image

ii. Give the 1,3-dithiolane that would result from the reaction of each of the carbonyl compounds shown above with 1,2-ethanedithiol in the presence of an acid.