Nucleophilic Addition of Alcohols Acetal Formation

Acetal formation is similar to the hydration reaction discussed in Section 19.5. kike water, alcohols are weak nucleophiles that add to aldehydes and ketones only slowly under neutral conditions. Under acidic conditions, however, the reactivity of the carbonyl group is increased by protonation, so addition of an alcohol occurs rapidly. 

A neutral carbonyl group is moderately electrophilic because of the polarity of the C-0 bond. 

A protonated carbonyl group is strongly electrophilic because of the positive charge on carbon. 

Because all the steps in acetal formation are reversible, the reaction can be driven either forward (from carbonyl compound to acetal) or backward (from acetal to carbonyl compound), depending on the conditions. I he forward reaction is favored by conditions that remove water from the medium and thus drive the equilibrium to the right. In practice, this is often done by distilling off water as it forms. The reverse reaction is favored by treating the acetal with a large excess of aqueous acid to drive the equilibrium to the left. 

Mechanism of acid-catalyzed acetal formation by reaction of an aldehyde or ketone with an alcohol. 

Aldehydes and ketones react reversibly with 2 equivalents of an alcohol in the presence of an acid catalyst to yield acetals, R2C (OR )2, sometimes cabled keta s if derived from a ketone. Cyclohexanone, for instance, reacts with methanol in the presence of HCI to give the corresponding dimethyl acetal. 

O Protonation of the carbonyl oxygen strongly polarizes the carbonyl group and. . .  

Protonated carbonyl group (strongly electrophilic and highly reactive toward nucleophiles) 

CHAPTER 19 Ald hydes and Ketones Nudeophllk Addition Reactions 

Neutral carbonyl group Protonated carbonyl group 

CHAPTER 19 U Aldehydes and Ketones Nucleophilic Addition Reactions 

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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. 

Stabilities of o -adducts derived from nucleophilic addition of alcohols and alkox-ide ions to azaaromatic compounds are varied to a great extent. A whole number of alkoxy adducts of 1,4-diazinium and 1,2,4-triazinium cations have been registered by NMR [114] however, attempts to isolate them failed. Contrary to that, treatment of 3-aryl-l,2,4-triazin-5-ones with primary or secondary alcohols in the presence of acetic anhydride results in the formation of rather stable 6-aIkoxy-l-acetyl-l,6-dihydro-l,2,4-triazin-5-ones (Scheme 38) [117, 140, 141],... 

Many of the most interesting and useful reactions of aldehydes and ketones involve trans formation of the initial product of nucleophilic addition to some other substance under the reaction conditions An example is the reaction of aldehydes with alcohols under con ditions of acid catalysis The expected product of nucleophilic addition of the alcohol to the carbonyl group is called a hemiacetal The product actually isolated however cor responds to reaction of one mole of the aldehyde with two moles of alcohol to give gem mal diethers known as acetals... 

The mechanism of acid-catalyzed esterification involves two stages. The first is formation of a tetrahedral intermediate by nucleophilic addition of the alcohol to the carbonyl group and is analogous to acid-catalyzed acetal and ketal formation of aldehydes and ketones. The second is dehydration of the tetrahedral intermediate. 

Significantly better results in addition of non-stabilized nucleophiles have come from hydrogenolysis reactions using formate as a hydride donor as shown in Scheme 8E.46. The racemic cyclic acetate and prochiral linear carbonates were reduced in good enantioselectivities by monophosphine ligands (/ )-MOP (16) and (Zf)-MOP-phen (17), respectively [195]. The chirality of the allylsilane can be efficiently transferred to the carbinol center of the homoallylic alcohol by the subsequent Lewis acid catalyzed carbonyl addition reaction 1196], The analogous... 

The survey in Figure 9.23 shows that N nucleophiles can react with carbonyl compounds in the following ways (1) An addition to the C=0 double bond followed by an SN1 reaction leads to the formation of AW-acetals (details Section 9.2.4). (2) An addition to the C=0 double bond is followed by an El reaction by which, amongst others, enamines are formed (details Section 9.3). (3) Imines are produced. We still need to discuss whether the reaction of O nucleophiles with carbonyl compounds also gives us two options—parallel to the two possibilities (1) and (2) mentioned above. According to Figure 9.12 alcohols and carbonyl compounds always afford 0,0-acetals—through an addition and an SN1 reaction (details Section 9.2.2). 

The mechanism of the formation of the tetrahydropyranyl ether (see Figure 23.1) is an acid-catalyzed addition of the alcohol to the double bond of the dihydropyran and is quite similar to the acid-catalyzed hydration of an alkene described in Section 11.3. Dihydropyran is especially reactive toward such an addition because the oxygen helps stabilize the carbocation that is initially produced in the reaction. The tetrahydropyranyl ether is inert toward bases and nucleophiles and serves to protect the alcohol from reagents with these properties. Although normal ethers are difficult to cleave, a tetrahydropyranyl ether is actually an acetal, and as such, it is readily cleaved under acidic conditions. (The mechanism for this cleavage is the reverse of that for acetal formation, shown in Figure 18.5 on page 776.)... 

CHAPTER 7 CHAPTER 8 CHAPTER 10 CHAPTER 11 CHAPTER 15 CHAPTER 17 CHAPTER 18 Acid-Catalyzed Dehydration of an Alcohol 313 Electrophilic Addition to Alkenes 330 Grignard Reactions 443 The Williamson Ether Synthesis 500 The Diels-Alder Reaction 684 Electrophilic Aromatic Substitution 757 Nucleophilic Additions to Carbonyl Groups 841 Formation of Imines 851 Formation of Acetals 856... 

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