Equilibration of carbonyl compounds

Evidence for equilibration of carbonyl compounds with enols... 

EVIDENCE FOR THE EQUILIBRATION OF CARBONYL COMPOUNDS WITH ENOLS... 

Systematics are also available for the 8 0-values of the compounds in queshon [56[ carboxyl and carbonyl functions in isotopic equilibrium with the surrounding water are, due to equilibrium isotope effects, enriched in 0 relative to this water by 19 and by 25 to 28%o, respectively. From here, the 8 0-values of natural alcohols, mostly descendants of carbonyl compounds, will have (maximally) similar 8 0-values, provided the precursors have attained isotopic equilibrium with water and their reduction has not been faster than their equilibration. Alcohols from addihon of water to C=C double bonds or from exchange of halogen functions by OH groups, typical for synthetic alcohols, will have 8 0-values close to or even below that of the water, due to kinetic isotope effects. The few available results [246, 289, 290] seem to confirm this expectation. The 8 0-values of natural (and also synthetic) esters and lactones can be, especially in the carbonyl group, extremely high (up to 50%o), probably as a consequence of an intramolecular kinetic isotope effect on the activation of the carboxyl function. 

Keto enol equilibration is a property of carbonyl compounds that contain a proton on their a carbon and normally favors the keto form (Table 20.1). Simple aldehydes and ketones exist almost entirely in their keto forms acetaldehyde contains less than 1 ppm of its enol, and acetone contains 100 times less than that. The enol content of acetic acid and methyl acetate is even smaller because their keto isomers are stabilized by electron release from OH and OCH3, respectively, to C=0 the enols are not. 

The most commonly used protected derivatives of aldehydes and ketones are 1,3-dioxolanes and 1,3-oxathiolanes. They are obtained from the carbonyl compounds and 1,2-ethanediol or 2-mercaptoethanol, respectively, in aprotic solvents and in the presence of catalysts, e.g. BF, (L.F. Fieser, 1954 G.E. Wilson, Jr., 1968), and water scavengers, e.g. orthoesters (P. Doyle. 1965). Acid-catalyzed exchange dioxolanation with dioxolanes of low boiling ketones, e.g. acetone, which are distilled during the reaction, can also be applied (H. J. Dauben, Jr., 1954). Selective monoketalization of diketones is often used with good success (C. Mercier, 1973). Even from diketones with two keto groups of very similar reactivity monoketals may be obtained by repeated acid-catalyzed equilibration (W.S. Johnson, 1962 A.G. Hortmann, 1969). Most aldehydes are easily converted into acetals. The ketalization of ketones is more difficult for sterical reasons and often requires long reaction times at elevated temperatures. a, -Unsaturated ketones react more slowly than saturated ketones. 2-Mercaptoethanol is more reactive than 1,2-ethanediol (J. Romo, 1951 C. Djerassi, 1952 G.E. Wilson, Jr., 1968). 

A carbonyl compound with a hydrogen atom on its a carbon rapidly equilibrates with its corresponding enol (Section 8.4). This rapid interconversion between two substances is a special kind of isomerism known as keto-enol tautomerism, from the Greek Canto, meaning "the same," and meros, meaning "part." The individual isomers are called tautomers. 

Further, the two forms can also equilibrate via the open-chain carbonyl form of the sugar, so that the single isomers in solution are rapidly transformed into the equilibrium mixture (see Box 7.1). Since there are two anomeric forms, and these are often in equilibrium via the acyclic carbonyl compound. 

These observations emphasize the fact that gem-diols are usually unstable and decompose to carbonyl compounds. However, it can be demonstrated that hydrate formation does occur by exchange labelling of simple aldehyde or ketone substrates with 0-labelled water. Thus, after equilibrating acetone with labelled water, isotopic oxygen can be detected in the ketone s carbonyl group. 

Aldol reactions have also been used as a means of macrocychzation in total synthesis and were quite successful in some cases. However, over a broader spectrum of substrates, the results are unpredictable at best and yields and stereochemical outcome vary greatly. The predominant reasons are difficulties in selective enolate formation in multi-carbonyl compounds, competing and equilibrating retro-aldolizations—especially with polyketides, which often possess several aldol moieties—and intermolecular instead of intramolecular reaction preference. Whereas most of these drawbacks may be overcome, substrate-independent stereocontrol plays a crucial role. At least one new stereocenter is formed during a macroaldolization, and because of the folding constraints involved, its configuration cannot be adequately predicted. Therefore, this can be useful in special cases but with the current possibilities is not the method of choice for a general diversity-oriented synthesis. 

Many examples of equilibrations at C-C double bonds [mediated by Pd(ll) or via radical intermediates], at base-labile positions (e.g., a to carbonyl, cyano or sulfone groups, see the examples mentioned in Section 4.3.4.2.2.2.), of alcohols (via the corresponding carbonyl compound). at nitrogen, at sulfur (in sulfoxides), are known287. 

In this section, reactions of zinc dienolates with carbonyl compounds, imines and conjugated enones will be considered all of these reactions have been proved to be reversible, and, hence, conditions favouring either kinetic or thermodynamic control will drive the reaction towards the formation of different regioisomers. Generally, equilibrating conditions lead to attack at the position of 190, as a thermodynamically more stable conjugated carbonyl or carboxylic compound is formed on the other hand, kinetic control leads to attack at the electron richer a-position. 

The authors of this book are not aware of any case, in which a primary allylic alcohol suffers an oxidative transposition with PCC. Such case would be most unlikely, because it would involve an equilibrating pair of allylic chromate ester, in which the less stable minor one would evolve to a carbonyl compound. 

The oxidation of 1,4- and 1,5-diols with many oxidants leads to intermediate hydroxycarbonyl compounds that equilibrate with lactols, which are transformed in situ into lactones. This side reaction is very uncommon during Swern oxidations, due to the sequential nature of alcohol activation versus base-induced transformation of the activated alcohol into a carbonyl compound. Thus, during the oxidation of a diol, normally when the first alcohol is transformed into an aldehyde or ketone, the second alcohol is already protected by activation, resulting in the impossibility of formation of a lactol that could lead to a lactone. 

At the beginning of the 20th century, Meerwein,1 Ponndorf2 and Verley3 showed that alcohols and carbonyl compounds can equilibrate as in Equation below under the action of Al3+ alkoxides. 

In the reservoir model , which was confirmed by Noyori and coworkers as the prototype case of catalytic asymmetric organozinc additions to carbonyl compounds in the presence of (-)-3-exo-(dimethylamino)isoborncol (DAIB) yielding chiral benzyl alkanols with a higher ee than that of the added DAIB [17,18], there is a reversible equilibration between monomers and dimers. It is assumed that the monomers r and s are the catalysts and that the heterochiral dimers [r s] are of higher thermodynamic stability than their homochiral ([rr] and [s s]) analogues ... 

The mixture of a carbonyl compound, ammonia and hydrogen cyanide equilibrates into aminonitrile 1 and cyanohydrine 2, the product ratio being pH-dependent. 

The nucleophilic reaction of the cyanide ion on the carbonyl group is facilitated by protonat-ing the latter to a carboxonium ion. The addition of acid promotes the formation of cyanohydrins, but mainly for a thermodynamic reason. Under acidic conditions cyanohydrins equilibrate with the carbonyl compound and HCN. Under basic conditions they are in equilibrium with the same carbonyl compound and NaCN or KCN. The first reaction has a smaller equilibrium constant than the second, that is, the cyanohydrin is favored. So when cyanohydrins are formed under acidic or neutral (see Figure 9.8) instead of basic conditions, the reversal of the reaction is suppressed. 

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