Hemiacetals, formation

9 Additions of Heteroatom Nucleophiles to Carbonyl Compounds and Subsequent Reactions 

What you have learned in Section 9.1.1 about electronic substituent effects explains why intermolecular hemiacetal formation from the electron-deficient carbonyl compounds methyl glyoxalate (A) and ninhydrin (B) take place quantitatively  

Five- or six-membered cyclic hemiketals, which are also referred to as lactols, can form from y- or 8-hydroxy kefones. However, hemiketals of this type are not necessarily more stable than the acyclic hydroxyketone isomers because ketones are less thermodynamically suitable to add nucleophiles than are aldehydes (Section 9.1.1). 

In order to understand certain reactions of lactols with nucleophiles, you must now familiarize yourself with the principle of microscopic reversibility. 

When a molecule A is converted to a molecule B through a certain mechanism—and it does not matter whether this mechanism comprises one or more elementary reactions—a conversion of product B back into the starting material A takes place through the very same mechanism. 

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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... 

FIGURE 25 3 Cyclic hemiacetal formation in 4 hydroxybutanal and 5 hydroxypentanal... 

Aldoses exist almost exclusively as their cyclic hemiacetals very little of the open chain form is present at equilibrium To understand their structures and chemical reac tions we need to be able to translate Fischer projections of carbohydrates into their cyclic hemiacetal forms Consider first cyclic hemiacetal formation m d erythrose To visualize furanose nng formation more clearly redraw the Fischer projection m a form more suited to cyclization being careful to maintain the stereochemistry at each chirality center... 

Hemiacetal formation between the carbonyl group and the C 4 hydroxyl yields the five membered furanose ring form The anomenc carbon is a new chirality center its hydroxyl group can be either cis or trans to the other hydroxyl groups of the molecule... 

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... 

During the discussion of hemiacetal formation in d ribose in the preceding section you may have noticed that aldopentoses have the potential of forming a six membered cyclic hemiacetal via addition of the C 5 hydroxyl to the carbonyl group This mode of ring closure leads to a and p pyranose forms... 

Furanose form (Section 25 6) Five membered nng ansing via cyclic hemiacetal formation between the carbonyl group and a hydroxyl group of a carbohydrate... 

Relaxation kinetics. In the course of a study of hemiacetal formation with a phenol nucleophile, an equation was given for the relaxation time in the system ... 

The pKj, value (2.43) of the hydration constant of the cyanidin was found to be lower than the pKj, values of glycosylated and acylated cyanidins, meaning lower resistance of the anthocyanidin to hydration. The stability of nonacylated 3,5-diglucosides was lower compared to the 3-glucoside because the 5 position markedly lowered the hydration constant due to decreased electron density of the pyrilium ring that favors nucleophilic attack by water, enhancing hemiacetal formation. ... 

Periodate oxidation followed by reduction and acid hydrolysis gave rise to glycerol and Xyl in a molar ratio of 88 12. However, when the polyol was reoxidized with periodate and reduced, acid hydrolysis gave rise to glycerol and Xyl in a molar ratio of 94 6, as expected. Interunit hemiacetal formation must have taken place during the initial periodate treatment inhibiting further oxidation. 

It can be assumed that, upon irradiation, tautomer 5-40-II reacts with the alkene 5-41 in a highly regioselective [2+2] cycloaddition to give the cyclobutane 5-42 as an intermediate. Subsequent retro-aldol-type reaction and hemiacetal formation produces 5-44 via 5-43. After addition of the Lewis acid (BF3-Et20), cyclization takes place to give the desired products. It should be noted that the excess of alkene must be removed under reduced pressure before addition of the Lewis acid in order to avoid polymerization. 

A solution of the ester (56) and the tetrahydropyranyl ether (57) was irradiated to form the intermediate compound (58), which would rearrange through a retro-aldol reaction and a hemiacetal formation route to the less strained six-membered heterocycle (59). The hemiacetal (59) could be converted to loganin (55) in several steps Z3>. 

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. 

Purists might criticize the avoidance of equilibrium arrows in the mechanisms shown. Some reactions, e.g. hemiacetal formation or acid-catalysed ester hydrolysis, are undoubtedly reversible, yet we have shown them as proceeding only in the forward direction. We believe it is more important to develop the skills for predicting a rational mechanism rather than remembering whether the reaction is reversible or not. Unless there is any specific comment regarding reversible reactions, we should concentrate on the reaction in the sense given in the question. 

As a result of hemiacetal formation, an additional chiral center arises at C-1, which can be present in both possible configurations (anomers) (see p.8). To emphasize this, the corresponding bonds are shown here using wavy lines. 

The formation of the products could be explained by hemiacetal formation followed by Prins cyclization and subsequent Ritter amidation. A tentative reaction mechanism to realize the cis selectivity is given in Fig. 20 and could be explained by assuming the formation of an (L )-oxocarbenium ion via a chair-like transition state, which has an increased stability relative to the open oxocarbenium ion owing to electron delocalization. The optimal geometry for this delocalization places the hydrogen atom at C4 in a pseudoaxial position, which favors equatorial attack of the nucleophiles. 

According to Hockett and Chandler, the hydrolysis of an acetylated nitrile (LIII) results in the formation of an acetylated aldehydo sugar (LIV). If this compound then undergoes ammonolysis at carbon atoms 2 or 3, the formation of diacetamides is to be expected, since hemiacetal formation involving the C2 or C3 hydroxyl group is unknown. The... 

EVIDENCE FOR HEMIACETAL FORMATION AS EXEMPLIFIED WITH GLUCOSE... 

The linear dextran has also been used in investigating the mechanism of the periodate oxidation of polysaccharides. The results support the proposal that inter-residue, hemiacetal formation is a general occurrence in the later stages of the oxidation.128... 

Possible factors influencing these results were that an almost equimolar (4R and 4S) equilibration had been caused by the strongly basic SDMA during the reduction of 156, but the hemiacetal formation from 157 to 158 proceeded more readily for the [(R)-phenylphosphinyl]pen-tofuranoses 158, because there is less steric congestion between the P-phenyl and the 2-and 3-hydroxyl groups in the precursors of 158. 

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