Carbonyl enolization

The first three chapters discuss fundamental bonding theory, stereochemistry, and conformation, respectively. Chapter 4 discusses the means of study and description of reaction mechanisms. Chapter 9 focuses on aromaticity and aromatic stabilization and can be used at an earlier stage of a course if an instructor desires to do so. The other chapters discuss specific mechanistic types, including nucleophilic substitution, polar additions and eliminations, carbon acids and enolates, carbonyl chemistry, aromatic substitution, concerted reactions, free-radical reactions, and photochemistry. 

Enolized carbonyl compounds can be regarded as belonging to the general class of olefins... 

Two reports are available on the rearrangement of mixed vinyl phosphite esters to produce phosphonate diesters in moderate yield.94 95 In both instances, the vinyl phosphite esters were prepared by reaction of the dialkyl phosphorous chloride with highly enolized carbonyl compounds. The mixed ester products undergo thermal rearrangement to the phosphonate diesters (Figure 6.25). 

A reaction involving phosphorus trichloride providing a free phosphonic acid apparently involves an enolized carbonyl compound as the species attacking the phosphorus.96 Methyl aromatic ketones thus provide access to the vinylicphosphonic acids (Figure 6.26). 

As long as nucleophilic addition of the preformed enolate to the second carbonyl component is rapid and the carbonyl electrophile is added after the enolate is formed, the product is predictable and is not a mixture. The rule of thumb to ensure success is that the carbonyl electrophile should be more reactive than the carbonyl compound from which the enolate is derived. If this condition is met, the carbonyl electrophile can have a protons and the structural possibilities are increased tremendously. Typical enolate-carbonyl pairs that have been condensed by this methodology include the following ... 

As hydroxyl groups are usually present in the molecules of steroids, it is the preparation of esters of these groups and of the enolized carbonyl group with different acylating... 

The rate of enolate-carbonyl equilibration " is dependent on the forward and backward rates of proton exchange. Proton exchange from a carbon-based acid is known to be slower than that of a more electronegative atom donor (in particular, O and N atoms) . For a series of closely related molecules usually the more acidic a given molecule is, the faster the rate of proton transfer (high kreu note that thermodynamic and kinetic parameters are not related). For example, benzocyclobutanone (10) is less acidic and the rate of deprotonation is substantially slower (10 times) than the related benzocyclopentanone (12) due to its enolate (11) having unfavourable anti-aromatic character. Deprotonation of the simplest cyclobutanone (13) clearly does not lead to an unfavourable anti-aromatic enolate (14) . By assuming the internal strain of 14 is similar to that of 11, cyclobutanone (13) is evidently 10 " times more acidic than benzocyclopentanone (12). By the same vain, the more acidic propanone (15) has a faster rate of deprotonation (10 times) than the less acidic ethyl acetate (16) . ... 

The addition of trimethylsilylmethyllithium to enolizable ketones generally gives significant amounts of the enolized carbonyl compound. Johnson and Tait have shown that when the lithium anion is converted to tile cerium reagent it gives high yields of the addition product. For example, a-tetralone (151) reacts with trimethylsilylmethyllithium to give after protonation an 1 1 mixture of the desired exocyclic... 

Although boron enolates are usually more stereoselective in aldol reactions than lithium enolates, the latter are more readily prepared (e.g., using LDA). To obtain synthetically useful levels of aldol stereoselectivities with lithium enolates, the (E)-(O)- and (Z)-(0)-enolates must be available with high selectivity (> 95 5), and the non-enolized carbonyl group Rmust be large (Table 6.3). ... 

The mechanism of the Mannich reaction has been extensively investigated. The reaction can proceed under both acidic and basic conditions, but acidic conditions are more common. Under acidic conditions the first step is the reaction of the amine component with the protonated non-enolizable carbonyl compound to give a hemiaminal, which after proton transfer loses a molecule of water to give the electrophilic iminium ion.°° This iminium ion then reacts with the enolized carbonyl compound (nucleophile) at its a-carbon in an aldol-type reaction to give rise to the Mannich base. 

Only a limited number of formulae are possible for hasubanonine. The aromatic nucleus in the basic morphine skeleton must have methoxyl groups at positions 3 and 4, or (less likely) 2 and 1 it seems probable that the methine base is not a true phenol but contains a readily enolized carbonyl group (this would account for the fact that the methine does not show the expected intense diazo-reaction characteristic of phenols). 

As with the mono-ketones, coupling between groups on opposite sides of the carbonyl carbon is usually not observed. Similarly, coupling across the enolized carbonyl group (-C(OH)=CH) is not observed. 

In an important experiment, Mukaiyama and coworkers enolized carbonyl compounds under much milder conditions (low temperatures) with dialkylboryl triflate and a sterically hindered tertiary amine base such as 2,6-lutidine (2,6-dimethylpyridine) or diisopropylethylamine (DPEA).95-97 Less-hindered bases led to formation of a stable borane-amide complex (Lewis acid-Lewis base) and prevented the reaction with the carbonyl compound. Masamune et al,98 and Evans et a/.99100 carried out a study to investigate the reasons for the selective enolate formation. They showed that it depends on the boron ligand, base, solvent and the group attached to the carbonyl moiety. Ketones give (Z)-enolates with often excellent selectivity, whereas r-butyl thiolates give selectively the ( )-enolates (equations 32 and 33).100 101 Evans suggests that reactions with 9-BBN triflate are often under thermodynamic control.15 In equation... 

The Claisen condensation is the main method for synthesizing 1,3-dicarbonyl compounds. Analyze this reaction on the basis of its similarities to the aldol condensation (Section 18-5) It is an enolate + carbonyl process, so bond formation occurs between the a-carbon of one carbonyl compound (which may be cither an ester or a ketone) and the carbonyl carbon of another (an ester). Note the limitation Under the conditions given, the reaction works only when the 1,3-dicarbonyl product still possesses a hydrogen on the carbon between the two carbonyl groups. Dcprotnnation of this acidic H by excess base allows the equilibrium to shift to the product. 

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