Hemiacetals, intermediate

You learned in Section 17 8 of the relationship among hemiacetals ketones and alcohols the for mation of phenol and acetone is simply an example of hemiacetal hydrolysis The formation of the hemiacetal intermediate is a key step in the synthetic procedure it is the step in which the aryl—oxygen bond is generated Can you suggest a reasonable mechanism for this step" ... 

The most widely used reagent for partial reduction of esters and lactones at the present time is diisobutylaluminum hydride (DiBAlH).83 By use of a controlled amount of the reagent at low temperature, partial reduction can be reliably achieved. The selectivity results from the relative stability of the hemiacetal intermediate that is formed. The aldehyde is not liberated until the hydrolytic workup and is therefore not... 

The mechanism proposed for the aldehyde dehydrogenases includes an enzyme-bound hemiacetal intermediate, possibly via a thioester bond with a cysteine (100). The specificity of the enzyme for aldehydes is quite broad. Apparent Km values for many aliphatic and aromatic aldehydes are in the micromolar range, with the highest reaction velocities observed for aldehydes with electron-with-drawing substituents on the a carbon for aliphatic aldehydes and in the para position for aromatics (99). 

The above dramatic dependence of regio- and stereoselectivity on the nature of the metal can be explained by the reaction mechanism shown in Scheme 11.49 (167). The nitrone cycloadditions of allylic alcohols are again magnesium-specific just like the nitrile oxide reactions described in Section 11.2.2. Magnesium ions accelerate the reaction through a metal ion-bound intramolecular cycloaddition path. On the other hand, zinc ions afford no such rate acceleration, but these ions catalyze the acetalization at the benzoyl carbonyl moiety of the nitrone to provide a hemiacetal intermediate. The subsequent intramolecular regio- and stereoselective cycloaddition reaction gives the observed products. 

The oxidative cyclization of an ortho-hydroxy-methoxy-substituted aromatic system giving a methylenedioxy group is also known to involve a cytochrome P-450-dependent mono-oxygenase. This enzyme hydroxylates the methyl to yield a formaldehyde hemiacetal intermediate, which can cyclize to the methylenedioxy bridge (the acetal of formaldehyde) by an ionic mechanism (Figure 2.21). 

F. W. Lichtenthaler, P. Jarglis, and K. Lorenz, Convenient one-pot conversion of alcohols into esters via hemiacetal intermediates, Synthesis, (1988) 790-792. 

For aryl aldehydes under polar, nonpolar, and protic conditions, it has been determined that the rate-determining step is second-order in aldehyde and first-order in DABCO and acrylate. On the basis of this reaction rate data, Tyler McQuade recently proposed the following mechanism involving the formation of a hemiacetal intermediate ... 

The aluminium alkoxide acts as a Lewis acid to coordinate with one molecule of the aldehyde, and to facilitate the addition of a second equivalent of aldehyde, generating a hemiacetal intermediate ... 

Primary alcohols react slowly giving dimeric ester, presumably via hemiacetal intermediates. 

Thus, the eight L-hexoses were obtained from the single precursor (-)-26 along with additional four D-hexoses through the five hemiacetal intermediates, 36,44,47, 50 and 53. 

Another support for this mechanism was found in the detailed kinetic analysis of the reaction of acrylates with aryl aldehyde, where the RDS is second order in aldehyde and first order in the catalyst and acrylate, a fact which is in accordance with the formation of a hemiacetal intermediate 19 (Scheme 5.5) [52]. This intermediate subsequently undergoes elimination and generates 21, with liberation of the catalyst leading either to the normal adduct 22 or, alternatively, to the diox-anone product 23. The formation of this byproduct is favored when O-R is a good leaving group and when the concentration in aldehyde is high. 

In examining the mechanism leading to the nucleophile-mediated conversion of an ester to a ketone, initial addition of a nucleophile to the carbonyl results in formation of a hemi-acetal intermediate. Subsequent collapse of the hemiacetal intermediate liberates a ketone and an alkoxide leaving group. This mechanistic sequence, illustrated in Scheme 7.19... 

The maximum reaction time required for any one of the substrates shown in the Table is 7 days. In reaction mixtures which contain lactones 4 and 5, minor amounts of the hemiacetal intermediates are present they are removed during the extraction at pH 13. After chromatographic separation from any unreacted diols, they can be readily converted to the corresponding lactones... 

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. 

Djerrassi and co-workers suggested a mechanism for the oxygen introduction step, which involved formation of a hemiacetal intermediate caused by the fission of the carbon-sulfur bond followed by attack with hydroxide ion, as illustrated in Scheme 13.14.161,162 The mechanism is supported by the preservation of chiral center when an optically active ethylenehemithio acetal was subjected to desulfurization to regenerate the ketone. 

In the synthesis of verrucarin J (55) by Fraser-Reid and coworkers [62], triol 109 was treated with pyridiniura dichromate (PDC) for 3 days, resulting in oxidative cleavage of the adjacent diol to the corresponding aldehyde and further oxidation of the presumed cyclic hemiacetal intermediate gave 55 in 50% yield (Scheme 37). 

Figure 26 (a) The oxidation of alcohols to aldehydes via an hemiacetal intermediate (b) The sterol side chain cleavage reaction via a diol note the formation of an O-based radical intermediate... 

The reductive acetylation of esters and lactones can be accomplished by treatment of the ester with a two-fold excess of DIBALH at -78°C followed by trapping of the resulting aluminum hemiacetal intermediate with acetic anhydride in the presence of pyridine and DMAP at low temperature. This transformation has been successfully applied to a wide range of esters and lactones, including sterically-... 

Because the conversion of primary diols into lactones is accomplished not only by oxidizing agents but also by catalytic dehydrogenation, it is likely that the reaction takes place stepwise via hemiacetal intermediates (equation 294) [355]. 

Well, you saw a diagram like this in the last chapter when we were discussing kinetic and thermodynamic products (p. 000) and you can probably also apply something of what you now know about the reactivity of carbonyl compounds towards nucleophiles to work out what is happening in this reaction between a carbonyl compound and an amine. The hydroxylamine first adds to the ketone to form an unstable intermediate such as a hemiacetal. intermediate formation... 

O-a-acyloxyalkyl ethers are also a useful prodrug type for compounds containing a phenol group. Such derivatives (58) are hydrolyzed by a sequential reaction involving formation of an unstable hemiacetal intermediate (59), as shown in Scheme 7. These kinds of ethers might be better prodrugs than normal phenol esters... 

When 2-methoxycyclopropyl ketones 1 were treated with aqueous acid, the bond between the functional groups was cleaved and <5-oxoaldehydes 2 were obtained in good yield.The formation of these products can be rationalized by the addition of water across the activated cyclopropane bond and elimination of methanol from the hemiacetal intermediate. Usually, the generation of the cyclopropane derivative from the alkyl 2-chloro-3-methoxypropyl ketone and the subsequent ring-opening reaction was performed without isolation of the cyclopropane. ... 

However, this sequence can be reversed. - Thus, the activated cyclopropane can be de-protonated by lithium diisopropylamide, reacted with an appropriate ketone and opened by various methods such as treatment with acid or desilylation with fluoride. Using this reaction sequence, y-lactones 52 with various substituents can be obtained by the intramolecular attack of the ketone oxygen on the siloxy-substituted carbon followed by oxidation with pyridinium chlorochromate. The cyclic hemiacetal intermediates 53 can be converted to the tetrahyd-rofuran derivatives 55 by deoxygenation with triethylsilane/boron trifluoride. 

---