Hemiacetals nucleophilic addition

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 for formation of benzaldehyde diethyl acetal which proceeds m two stages is presented m Figure 17 9 The first stage (steps 1-3) involves formation of a hemiacetal m the second stage (steps 4-7) the hemiacetal is converted to the acetal Nucleophilic addition to the carbonyl group characterizes the first stage carbocation chemistry the second The key carbocation intermediate is stabilized by electron release from oxygen... 

Steps 1-3 Acid catalyzed nucleophilic addition of 1 mole of ethanol to the carbonyl group The details of these steps are analogous to the three steps of acid catalyzed hydration in Figure 17 7 The product of these three steps is a hemiacetal... 

Step 1 The peroxy acid adds to the carbonyl group of the ketone This step is a nucleophilic addition analogous to gem diol and hemiacetal formation... 

Aldoses incorporate two functional groups C=0 and OH which are capable of react mg with each other We saw m Section 17 8 that nucleophilic addition of an alcohol function to a carbonyl group gives a hemiacetal When the hydroxyl and carbonyl groups are part of the same molecule a cyclic hemiacetal results as illustrated m Figure 25 3 Cyclic hemiacetal formation is most common when the ring that results is five or SIX membered Five membered cyclic hemiacetals of carbohydrates are called furanose forms SIX membered ones are called pyranose forms The nng carbon that is derived... 

Hemiacetal (Section 17 8) Product of nucleophilic addition of one molecule of an alcohol to an aldehyde or a ketone Hemiacetals are compounds of the type... 

Nucleophilic addition of an alcohol to the carbonyl group initially yields a hydroxy ether called a hemiacetal, analogous to the gem diol formed by addition of water. HcmiacetaJs are formed reversibly, with the equilibrium normally favoring the carbonyl compound. In the presence of acid, however, a further reaction occurs. Protonation of the -OH group, followed by an El-like loss of water, leads to an oxonium ion, R2C=OR+, which undergoes a second nucleophilic addition of alcohol to yield the acetal. The mechanism is shown in Figure 19.12. 

Acetal and hemiacetal groups are particularly common in carbohydrate chemistry. Glucose, for instance, is a polyhydroxy aldehyde that undergoes an internal nucleophilic addition reaction and exists primarily as a cyclic hemiacetal. 

Glycolysis is a ten-step process that begins with isomerization of glucose from its cyclic hemiacetal form to its open-chain aldehyde form—a reverse nucleophilic addition reaction. The aldehyde then undergoes tautomerixa-tion to yield an enol, which undergoes yet another tautomerization to give the ketone fructose. 

We said in Section 19.10 that aldehydes and ketones undergo a rapid and reversible nucleophilic addition reaction with alcohols to form hemiacetals. 

If the carbonyl and the hydroxyl group are in the same molecule, an intramolecular nucleophilic addition can take place, leading to the formation of a cyclic hemiacetal. Five- and six-membered cyclic hemiacetals are relatively strain-free and particularly stable, and many carbohydrates therefore exist in an equilibrium between open-chain and cyclic forms. Glucose, for instance, exists in aqueous solution primarily in the six-membered, pyranose form resulting from intramolecular nucleophilic addition of the -OH group at C5 to the Cl carbonyl group (Figure 25.4). The name pyranose is derived from pyran, the name of the unsaturated six-membered cyclic ether. 

The hemiacetals obtained by nucleophilic addition of organometallic reagents to the carbonyl group of aldonolactones may be reduced to the corresponding C-glycosyl compounds. For example, treatment of 2,3,4,6-tetra-... 

Fig. 6.25. Simplified mechanism of two degradation reactions between peptides and reducing sugars occurring in solids, a) Maillard reaction between a side-chain amino (or amido) group showing the formation of an imine (Reaction a), followed by tautomerization to an enol (Reaction b) and ultimately to a ketone (Reaction c). Reaction c is known as the Amadori rearrangement (modified from [8]). b) Postulated mechanism of the reaction between a reducing sugar and a C-terminal serine. The postulated nucleophilic addition yields an hemiacetal (Reaction a) and is followed by cyclization (intramolecular condensation Reaction b). Two subsequent hydrolytic steps (Reactions c and d) yield a serine-sugar conjugate and the des-Ser-peptide...

This is a further example of a carbonyl-electrophile complex, and equivalent to the conjugate acid, so that the subsequent nucleophilic addition reaction parallels that in hemiacetal formation. Loss of the leaving group occurs first in an SNl-like process with the cation stabilized by the neighbouring oxygen an SN2-like process would be inhibited sterically. It is also possible to rationalize why base catalysis does not work. Base would simply remove a proton from the hydroxyl to initiate hemiacetal decomposition back to the aldehyde - what is needed is to transform the hydroxyl into a leaving group (see Section 6.1.4), hence the requirement for protonation. 

Cyclic hemiacetals are formed by intramolecular nucleophilic addition of a hydroxyl group to a carbonyl. 

The pyranose form arises by closure to a six-membered cyclic hemiacetal, with the C-5 hydroxyl group undergoing nucleophilic addition to the carbonyl. In the j8-pyranose form of D-xylose the anomeric hydroxyl group is up. 

Know the meaning of nucleophilic addition, hemiacetal and acetal, aldehyde hydrate, cyanohydrin. 

The reaction mechanism involves the nucleophilic addition of one molecule of alcohol to form a hemiacetal or hemiketal. Elimination of water occurs to form an oxonium ion and a second molecule of alcohol is then added ... 

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. 

Cyclopropanone ethyl hemiacetal is a molecule of considerable interest since its reactions appear to involve the formation of the labile cyclopropanone.7 It readily undergoes nucleophilic addition of Grignard reagents,4,5 azides,4 and amines5 to provide 1-substituted cyclopropanols in high yields. It has been reported that upon treatment with an equimolar amount of methylmagneslum iodide, the cyclopropanone ethyl hemiacetal is... 

In general, carbonyl compounds do not polymerize by themselves. It is only the exceptional reactivity of formaldehyde as an electrophile that allows repeated nucleophilic addition of hemiacetal intermediates. A more common way to polymerize carbonyl compounds is to use two different functional groups that react together by carbonyl substitution to form a stable functional group such as an amide or an ester. Nylon is just such a polymer. 

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