Aldehydes hemiacetal formation

Generating Haworth formulas to show stereochemistry m furanose forms of higher aldoses is slightly more complicated and requires an additional operation Furanose forms of D ribose are frequently encountered building blocks m biologically important organic molecules They result from hemiacetal formation between the aldehyde group and the C 4 hydroxyl... 

Initially, the reaction involves protonation of one of the oxygen atoms, followed by loss of this group as a neutral molecule and formation of a resonance-stabilized carbocation. If the oxygen protonated were that of the alkoxy group, then the product would merely be the protonated aldehyde, and the reaction becomes a reversal of hemiacetal formation. Only when the oxygen of the hydroxyl is protonated can the reaction lead to an acetal, and this requires nucleophilic attack of the second alcohol molecule on to the alternative resonance-stabilized carbocation. 

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. 

The position of equilibrium in acetal and hemiacetal formation is rather sensitive to steric hindrance. Large groups in either the aldehyde or the alcohol tend to make the reaction less favorable. Table 15-3 shows some typical conversions in acetal formation when 1 mole of aldehyde is allowed to come to equilibrium with 5 moles of alcohol. For ketones, the equilibria are still less favorable than for aldehydes, and to obtain reasonable conversion the water must be removed as it is formed. 

We already have discussed additions of alcohols and, by analogy, thiols (RSH) to carbonyl compounds (see Section 15-4E). We will not repeat this discussion here except to point out that addition of water to the carbonyl group of an aldehyde is analogous to hemiacetal formation (Section 15-4E) and is catalyzed both by acids and bases ... 

Detailed studies of the periodate oxidation of dextran and inulin (4-6) have shown evidence for the occurrence of hemiacetal structures formed by reaction of aldehydes with hydroxyl groups of either the same unit (intra-residual) or a neighbouring unit (inter-residual). Inter-residual hemiacetal formation reduces the number of diol struc-... 

In alcohol solution a carbonyl compound is in equilibrium with the acetal and hemiacetal forms. While for aldehydes these species are important, and sometimes predominate, for ketones they are usually present in smaller amounts. For this reason, most of the available data on equilibria deal with aldehydes, and only a few of them with ketones. Reports on acetal formation by Davis et al. (1975), Guthrie (1975), Machacek and Sterba (1976), Kavalek et al. (1976), Toullec and Alaya (1978) and Wiberg and Squires (1979), as well as ones on hemiacetal formation by Guthrie (1975) and Crampton (1975), have been published in the last few years. 

Peroxymonosulfuric acid (Caro s acid, H2S05) and its salts may be used to oxidize aldehydes. Although early results were poor compared with the use of organic peracids, good yields of esters have been obtained when reactions are carried out in the presence of alcohols.225 Unsaturated and aromatic aldehydes undergo analogous reactions. It is believed that hemiacetal formation occurs in these reactions, and that it is this species which is oxidized, rather than the aldehyde. 

The stereochemistry of the alkene product in Wittig reactions is thought to be influenced by the reversibility of formation of the isomeric threo and erythro oxaphosphetanes (or betaines) which undergo stereospecific loss of triphenyl-phosphine oxide to give the trans (E) and cis (Z) alkenes, respectively (Scheme 4). Factors that enhance the reversibility of this initial step favour the threo intermediate and hence the (E) alkene. Stabilized phosphoranes give a predominance of the (E) alkene while non-stabilized phosphoranes give the (Z) alkene. In general, stabilized phosphoranes react readily with aldehydes (see Protocol 4) while non-stabilized phosphoranes will react with aldehydes, hemiacetals (see Protocol 5) and ketones.2,3... 

Higher aldehydes, for example acetaldehyde or n-butyraldehyde, have much less tendency to polymerize compared to formaldehyde [5, 6]. Reasons have been given in thermodynamic terms by referring to the lower enthalpy of polymerization (about —7 kcal mole" ) as compared to formaldehydes (—12 kcal mole" ), which results in ceiling temperatures of —40°C. In terms of reactivity, aliphatic aldehydes undergo hydration and hemiacetal formation to an extent of about 50%. 

Hydration and Hemiacetal Formation. There is considerable evidence which indicates that when an aldehyde is dissolved in water or alcohols... 

Since a hemiacetal is formed so easily from a carbonyl compound and alcohol, it is not surprising to find that carbohydrates (polyhydroxy derivatives of aldehydes and ketones) frequently exist as cyclic structures in which a hemiacetal linkage is formed intramolccularly. Furthermore, since hemiacetal formation is a reversible process, many carbohydrates exhibit the phenomenon of mutarotation. The liberation of the free aldehyde (V) from the internal hemiacetal of the sugar (IV) destroys the optical activity of the hemiacetal carbon atom (in this case carbon 1), and reformation results in the formation of an equilibrium mixture of two diastereoisomers. 

There has been particular interest in 2-nitrofurans bearing a 5-carbonyl substituent, especially the aldehyde and its derivatives. Laviron and co-workers noted hydration and hemiacetal formation when 5-nitrofuran-... 

Compound XXXII is an aldehyde-hemiacetal phenylhydrazone XXXIII is a hemiacetal-aWehydo phenylhydrazone and XXXIV is a so-called hemialdal structure. Of them, only XXXIII is suited to formation of a formazan. The successful formazan reaction furnishes proof of the predominance of this hemiacetal-oZde do phenylhydrazone structure. On these grounds, it is safe to assume that, to the oxidized polysaccharides themselves, this aldehyde-hemiacetal structure (or the hydrate form) is to be assigned. 

The overall reaction proceeds in two stages. The hemiacetal is formed in the hrst stage by nucleophilic addition of the alcohol to the carbonyl group. The mechanism of hemiacetal formation is exactly analogous to that of acid-catalyzed hydration of aldehydes and ketones (Section 17.6) ... 

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. 

The reaction in water at pH 7 required either 24 h at room temperature or 12 h at the boiling point.1290 These observations were later confirmed by reaction of aliphatic aldehydes with starch over the temperature interval from room temperature to below the gelatinization temperature.1303 The properties of the products obtained under identical reaction conditions were dependent on the starch variety. Aromatic aldehydes reacted with difficulty under these conditions, as the reactions lasted up to one week at 37 °C.1303 The reaction may be performed without any catalyst, however, it required heating in a sealed tube at 160 °C for 3 h.1304 At lower temperatures, an extended heating time was required and the proportions of water, formaldehyde and starch also affected the outcome of this reaction. As expected for this reversible reaction, an increase in water content shifted the reaction in favor of the reactants. An excess of formaldehyde stopped the reaction at the stage of hemiacetal formation. 

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. ... 

In some cases subsequent reactions of the primary aldehyde function with other functions already present in the substrate are observed, such as hemiacetal formation in hydroformylation of methallyl alcohol16 (Table 7). 

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