Formation of a Cyclic Hemiacetal

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. 

On the other hand, if ammonolysis first occurred at carbon atoms 4 or 5, the formation of a cyclic hemiacetal would be favored, and the possibility of obtaining a diacetamide would be correspondingly decreased. Such an explanation accounts for the formation of iV-acetyl-D-gluco-furanosylamine reported by Hockett and Chandler. Here, the first product of the reaction is a D-glucofuranose, which then condenses with acetamide. A similar explanation accounts for the results obtained by Brigl, Miihlschleger and Schinle with 2-thioethyl-3,4,5,6-tetrabenzoyl-oZde%do-D-glucose. 

In this example the oxygen of the hydroxy group acts as an intramolecular nucleophile. Recall from Section 8.13 that intramolecular reactions are favored by entropy. Therefore, the formation of a cyclic hemiacetal has a larger equilibrium constant than a comparable intermolecular reaction. This reaction is especially important in the area of carbohydrates (sugars) because sugars contain both carbonyl and hydroxy functional... 

Mechanism 23-1 Formation of a Cyclic Hemiacetal 1108 23-7 Anomers of Monosaccharides Mutarotation 1112 23-8 Reactions of Monosaccharides Side Reactions in Base 1114... 

Fig. 2-4. Formation of a cyclic hemiacetal. Rings are usually five- or six-membered.

Part of the reason for the stability of cyclic hemiacetals concerns entropy. Formation of an acyclic acetal involves a decrease in entropy (AS° negative) because two molecules are consumed for every one produced. This is not the case for formation of a cyclic hemiacetal. Since AG°= AH° -7AS°, a reaction with a negative AS° tends to have a more positive AG° in other words, it is less favourable. 

Hemiacetal formation is fundamental to the chemistry of carbohydrates (see Section 11.1). Glucose, for example, contains an aldehyde and several alcohol groups. The reaction of the aldehyde with one of the alcohols leads to the formation of a cyclic hemiacetal (even without acid catalysis) in an intramolecular reaction. 

Mono-enolisation of a 1,5-diketone, then the formation of a cyclic hemiacetal, and its dehydration, produces 4//-pyrans, which require only hydride abstraction to arrive at the pyrylium oxidation level. The diketones are often prepared in situ by the reaction of an aldehyde with two moles of a ketone (compare Hantzsch synthesis, 8.14.1.2) or of a ketone with a previously prepared conjugated ketone - a chalcone in the case of aromatic ketones/aldehydes. It is the excess chalcone that serves as the hydride acceptor in this approach. 

O. Winkelmann, C. Nather, U. Liining, Organocatalysis by bimacrocyclic NHC unexpected formation of a cyclic hemiacetal instead of a y-butyrolactone, Org. Biomol. Chem., 2009, 553-556. 

Formation of a Cyclic Hemiacetal Step 1 Protonation of the carbonyl. 

Hemiacetal formation is found in the aldopentoses, with formation of a cyclic hemiacetal using the C4-OH unit to generate a five-membered ring. Examination of d-ribose (14) reveals that the hydroxyl group on the next to last carbon attacks the acyl carbon of the aldehyde to form two possible furanose structures 33 or 34. In both cases, the cyclization product is shown in the same fundamental conformation as ribose, with hyperextended bonds to emphasize the bond that is formed and which atoms are involved. 

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