Intramolecular hemiacetal formation

Furanose. A sugar that contains a five-member ring as a result of intramolecular hemiacetal formation. 

Compound D immediately reacts further, as is typical for this type of compound (Figure 9.4). The result is an intramolecular addition of remaining OH group to the remaining C=0 double bond. Thus, the to (hemiacetal) B is produced. This second hemiacetal formation is more favorable entropically than the first one The number of molecules that can move about independently remains constant in the second hemiacetal formation (D —> B), whereas this number is reduced by a factor of one-half in the first hemiacetal formation (C — D). The second reaction of Figure 9.3 therefore drives the entire reaction to the product side. 

As can be seen from Figure 9.1, carbonyl compounds without electron-withdrawing a-sub-stituents do not react intermolecularly with alcohols to form hemiacetals to any significant extent. However, while for such carbonyl compounds there is too little driving force for hemi-acetalization to occur, the reaction is not drastically disfavored. This explains why this type of compound undergoes almost complete hemiacetal formation provided it takes place intramolecularly and leads to a nearly strain-free five- or six-membered cyclic hemiacetal— a so-called lactol (Figure 9.4). What makes the difference is that only in the intramolecular hemiacetal formation is no translational entropy lost (because the number of molecules moving about independently of each other does not decrease). 

Hemiacetal formation is reversible, and hemiacetals are stabilized by the same special structural features as those of hydrates. However, hemiacetals can also gain stability by being cyclic—when the carbonyl group and the attacking hydroxyl group are part of the same molecule. The reaction is now an intramolecular (within the same molecule) addition, as opposed to the intermolecular (between two molecules) ones we have considered so far. 

Entropy dominates equilibrium constants in the difference between inter- and intramolecular reactions. In Chapter 6 we explained that hcmiacetal formation is unfavourable because the C=0 double bond is more stable than two C-0 single bonds. This is clearly an enthalpy factor depending simply on bond strength. That entropy also plays a part can be clearly seen in favourable intramolecular hemiacetal formation of hydroxyaldehydes. The total number of carbon atoms in the two systems is the same, the bond strengths are the same and yet the equilibria favour the reagents (MeCHO + EtOH) in the inter- and the product (the cyclic hemiacetal) in the intramolecular case. 

In Scheme 139, three examples of unimolecular cyclization leading to uncondensed dioxocins by nucleophilic attack of an hydroxyl group at a carbonyl, a masked carbonyl or a carboxy acid are reported. 2-Hydroxy-l,5-dioxocin 708 was accidentally obtained in the attempt to oxidize the ether diol 707 to the corresponding dialdehyde derivative. Rather, oxidation occurred at one end of the molecule followed by intramolecular hemiacetal formation to yield 708 <2003JOC9166>. 

Hemiacetal formation is catalyzed by both acid and base. The acid-catalyzed mechanism is identical to Mechanism 21.9, except that the reaction occurs in an intramolecular fashion, as shown for the acid-catalyzed cyclization of 5-hydroxypentanal to form a six-membered cyclic hemiacetal in Mechanism 21.11. 

For (1 —> 4)-linked polysaccharides, intramolecular-hemiacetal formation may occur, to give five- or six-membered rings. Authors generally draw all their formulas of this type with one or other ring, although there is as yet no definite evidence as to which is correct, except possibly for oxycellu-loses. Some authors favor the five-membered, hemiacetal ring, because of... 

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. 

Allenylsilanes react with acetals, as they do with aldehydes, by addition, but a simple elimination step completes the substitution reaction (Scheme 48). Propargylsilanes likewise react with acetals in the presence of Lewis acids (Scheme 49). The reaction has en used intramolecularly (Scheme 50), where the first step is likely to be acetal or hemiacetal formation followed by ring closure, and in reactions at the anomeric position of sugars with high levels of axial attack giving allenes. ... 

Hemiacetal formation in sugars, shown for the intramolecular reaction of D-glucose. 

Most simple hemiacetals, like gem-6io s, are not isolable. However, the cyclic versions of these compounds often are. Consider combining the carbonyl and hydroxyl components of the hemiacetal reaction in Figure 16.37 within the same molecule (Fig. 16.38). Now hemiacetal formation is an intramolecular process. If the ring size is neither too large nor too small, the hemiacetals are often more stable than the open-chain molecules. 

Another example is intramolecular hemiacetal formation. If a relatively unstrained ring can be formed, compounds containing both a carbonyl group and a hydroxyl group exist in equilibrium with the cyclic hemiacetal (p. 783 Fig. 21.3). 

FIGURE 21.3 Cyclic hemiacetal formation involves an intramolecular hydroxyl group acting as a neighboring group on a ketone or aldehyde. 

You know already that carbonyl groups react with all manner of nucleophiles (Chapter 16). Hydration and hemiacetal formation are typical examples (Fig. 22.11). A hemiacetal could certainly be formed in an intramolecular reaction in which a hydroxyl group at one location in a molecule reacted with a carbonyl group at another location. Indeed, 4- and 5-hydroxy aldehydes exist mostly in the cyclic hemiacetal forms (p. 783). Figure 22.11 shows a typical reaction of this kind and makes the analogy to both hydration and intermolecular hemiacetal formation. 

FIGURE 22.11 Intramolecular hemiacetal formation is analogous to hydration and intermolecular hemiacetal formation. Cyclic hemiacetals having five or six atoms in the ring are easily made and are often more stable than their open forms. 

FIGURE 22.12 In an aldohexose, intramolecular hemiacetal formation results in either a furanose (five-membered ring) or a pyranose (six-membered ring). 

FIGURE 22.15 Intramolecular hemiacetal formation results in two C(l) stereoisomers called anomers shown in Fischer projection and as chair structures. The OC anomer has the OH on the anomeric carbon on the same side of the Rscher projection as the OH of the configurational carbon. The P anomer has the OH on the anomeric carbon on the opposite side of the OH of the configurational carbon. 

One new twist to a known reaction is intramolecular hemiacetal formation. Carbonyl groups react with nucleophiles in the addition reaction (Chapter 16). When the nucleophile is an alcohol, hemi-acetals are formed, but generally they are not favored at equilibrium. However, when a relatively strain-free ring can be formed in an intramolecular hemiacetal formation, the cyclic form can be favored. Such is the case for aldohexoses (and many other sugars), which exist mainly in the srx-membered pyranose forms (Fig. 22.12). 

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