Addition to Hemiacetals

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... 

In addition to the silicon-based in situ activation of hemiacetal donors, there has been a significant body of work that uses electrophilic silicon activation of preformed C-l silyl hemiacetal donors [54—67]. However, this work is outside the scope of this discussion. 

Although addition of activated phosphoramidite to hemiacetals of manno-pyranoses under thermodynamic control has been reported to deliver exclusively a-phosphates in some cases,43 anomeric mixtures with preponderance of a-anomer have been reported in other examples.10,44 Since formation of phosphorotetrazolidite is a rate-limiting step of the process, initial activation of phosphoramidite followed by addition of nucleophilic hemiacetal should accelerate condensation and favour the formation of the thermodynamic a-product. Indeed, reaction of hemiacetal 101 with dibenzyl phosphorotetrazolidite assured exclusive a-selectivity of the resulting glycosyl phosphate 102.43 The accumulation in the reaction mixture of mildly acidic 1H-tetrazole, which is liberated upon reaction of tetrazolidite with hydroxylic component, could also favour predominant formation of the a-phosphate (Scheme 18, A). Conventional hydrogenolysis afforded the a-mannosyl phosphate 103. 

Intramolecular transannular OH-group addition to the C=0 bond yields bicyclic hemiacetals of erythromycin [90JCS(P1)1409 91JCS(P2)1481] and related polyfunctional macrocycles. 

Each anthocyanidin is involved in a series of equilibria giving rise to different forms, which exhibit their own properties including color. One- and two-dimensional NMR have been used to characterize the various forms of malvidin 3,5-diglucoside present in aqueous solution in the pH range 0.3 to 4.5 and to determine their molar fractions as a function of pH. In addition to the flavylium cation, two hemiacetal forms and both the cis and trans forms of chalcone were firmly identified. In a reexamination, the intricate pH-dependent set of chemical reactions involving synthetic flavylium compounds (e.g., 4 -hydroxyflavylium) was confirmed to be basically identical to those of natural anthocyanins (e.g., malvidin 3,5-diglucoside) in... 

From prior attempts at FruA-catalyzed DHAP additions to glyoxal or glutaric dialdehyde no product had been isolated, probably because the dialdehydes can cause cross-linking of the protein and thereby irreversibly destroy its enzymatic activity. On the other hand, hydroxylated aldehydes were assumed to form stable intramolecular hemiacetals in aqueous solution, which may mask the reactivity of free dialdehydes. Using the branched-chain glutaric dialdehyde 38 as a potential precursor to carbon-linked disaccharide mimetics (Scheme 2.2.5.14), we... 

Mechanism. The first step is the typical acid-catalysed addition to the carbonyl group. Then the alcohol nucleophile attacks the carbonyl carbon, and forms a tetrahedral intermediate. Intramolecular proton transfer from nitrogen and oxygen yields a hemiacetal tetrahedral intermediate. The hydroxyl group is protonated, followed by its leaving as water to form hemi-acetal, which reacts further to produce the more stable acetal. 

Zinc bisenolate 136 (Figure 11) is prepared by the transmetallation of propiophenone lithium enolate with 0.5 equivalents of ZnBr2 136 reacts with aldehydes, both aliphatic and aromatic, in a domino aldol reaction which mimics the action of aldolases167. The first aldol reaction between 136 and the aldehyde produces zinc aldolate 137, which then undergoes a second intramolecular aldol addition to adduct 138. Spontaneous hemiacetalization affords 139, where all large substituents occupy equatorial positions168. 

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 ... 

A typical reaction of aldehydes and ketones is addition to the C—O ji bond. Examples of addition reagents are H2 (resulting in reduction to the corresponding alcohol), ROH (to give a hemiacetal or hemiketal) and RM (yielding a metal alkoxide). Only the hydrogenation reaction produces an addition product for which there is any useful quantity of thermochemical data, however. Equation 34 represents an overall reaction of the carbonyl compound with a (hypothetical) reagent XY, an equation which includes any reaction, subsequent to an initial addition reaction, to form products for which there are sufficient data. 

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. 

In addition to the two furanose forms just shown, two more are possible. Instead of the reaction of the CH2OH group that was shown to form the cyclic hemiacetal, the other CH2OH group may add to the aldehyde carbonyl. 

Ketoacetals are available from the Lewis acid catalysed Michael addition of hemiacetal vinylogues to 3,4-dihydropyrans. The products are a source of hydroxy- and amino- acetals and hence give access to annulated tetrahydropyrans (95JCS(P 1)2103). 

H20 or alcohols as nucleophiles give low molecular weight compounds when they add to the C=0 double bond of carbonyl compounds. These addition products are called aldehyde or ketone hydrates (Section 9.1.1) and hemiacetals or hemiketals (Section 9.1.2), respectively, depending on whether they result from the addition to an aldehyde or a ketone. Today, one no longer distinguishes systematically between hemiacetals and hemiketals, but the expression hemiacetal is frequently used to cover both. 

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. 

Kinetic data on acetal formation and cleavage in alcohols are scarce although kinetic and thermodynamic data in the same experimental conditions are of great interest (Davis et al., 1975). It should be noted that under these conditions inequality (53) is inverted and that, therefore, the rate-limiting step corresponds to water addition to an alkoxycarbenium ion (Step 3) or hemiacetal cleavage (Step 4). Recent data by El-Alaoui (1979) on forward and reverse rates are in agreement with those expected the acetal formation rate is independent of water concentration for a series of substituted acetophenones. 

In the first proton-transfer step, ethanol acts as a base, removing a proton in the second it acts as an acid, donating a proton. Strong acids or strong bases (for example, HCl or NaOH) increase the rate of hemiacetal or hydrate formation because they allow these proton-transfer steps to occur before the addition to the carbonyl group. 

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. 

Nevertheless, two other cases of diastereoselection in cyclizations of type b have been recorded. In the first case, protodesilylation of rac-2 and subsequent hemiacetal formation precedes conjugate addition to give rac-326. Whereas the hemiacetal formation proceeds diastereo-selectively, the conjugate addition step finally affords a 1 1 partition of epimeric products. 

---