Enols kinetically stable

For simple carbonyl compounds, the equilibrium between an aldehyde or a ketone and its corresponding enol is usually so shifted towards the keto form that the amount of enol at equilibrium can neither be measured nor detected by spectroscopy. Nevertheless, as recently emphasised by Hart (1979), this does not mean that the enol cannot exist free, not in equilibrium with ketones and aldehydes. Several examples of kinetically stable enols in the gas phase or in aprotic solvents have been reported. Broadly speaking, it appears that enols have relatively large life-times when they are prepared in proton-free media [e.g. the half-life of acetone enol was reported to be 14 s in acetonitrile (Laroff and Fischer, 1973 Blank et al., 1975) and 200 s in the gas phase (MacMillan et al., 1964)]. These life-times are related to an enhanced intramolecular rearrangement, indicated by the very high energies of activation (85 kcal mol-1 for acetaldehyde-vinyl alcohol tautomerization) which have been calculated (Bouma et al., 1977 Klopman and Andreozzi, 1979) It has therefore been possible to determine most of the spectroscopic properties of simple enols [ H nmr,l3C nmr (CIDNP technique), IR and microwave spectra of vinyl alcohol... 

We have established that enols are, in general, less stable than the keto form of the molecule. We might hope to see stable enols if we changed that situation by adding some feature to the molecule that stabilized the enol thermodynamically. Or we might try to create an enol that would revert only slowly to the keto form—in other words, it would be kinetically stable. We shall look at this type first. 

These kinetic lithium enolates are stable yM, SiNle3... 

Enolates are selectively formed by treating ketones with a strong base such as lithium diisopropylamide (LDA) [LiN(i-C3H7)2] and tetrahydrofuran (THE) at —78°C, NaH or alkoxide ion. LDA and THE at —78°C give less stable, i.e. less substituted, enolate (kinetic enolate) 3.5 from unsymmetrical ketone 3.4, whereas methoxide (CEisO ) forms the more stable, i.e. more substituted, enolate (thermodynamic enolate) 3.6 from unsymmetrical ketone 3.4. 

The discovery that sterically crowded -carbon enols are kinetically stable constitutes the milestone towards the elucidation of the electron transfer ability of enolates . Based on this, Schmittel and coworkers started an accurate examination of their redox aptitude, and how it could be reflected on their chemical reactivity. In particular, they pointed out how the predominance of ketones over enols in the neutral keto/enol equilibrium could be inverted upon one-electron oxidation. These findings opened up interesting possibilities for new synthetic procedures. Starting from available ketones, the small amount of enol present in equilibrium can be oxidized by suitable oxidants and the resulting radical cation can be trapped by nucleophiles. For example, l-(p-methoxyphenyl)propan-2-one, which has an enol [l-(p-methoxyphenyl)propen-2-ol] content of only about 0.0001% , reacts with tris(p-methoxyphenyl)aminium hexachloroantimonate in methanol to give the a-methoxyketone 76 °. Comparable yields are obtained with [Fe(phen)3](PFe)3. The products isolated in the reactions are consistent with the mechanism reported in equation 52. 

Van Horn and Masamune have shown that it is possible to prepare either boryl enolate stereoisomer from the same ketone by changing the steric demand of the dialkylboryl triflate (Scheme Evans et al. also carried out independent studies on the stereochemical course of these aldol reactions and demonstrated that dialkylboryl enolates were kinetically stable even at elevated temperatures. The results obtained from the Evans group also established that exceptionally high levels of aldol dia-stereoselection are governed by the stereochemistry of the dialkylboryl enolates (Table 1). 

These kinetic lithium enolates are stable in THF at -78 C for a short time but can be preserved at room temperature in the form of tl eir silyl ethers. 

A large part of carbonyl chemistry is concerned with enolization. Kinetic deprotonation of ketones suggests the following preference CH3CO >CH2CO >CHCO. On considering the carbanions as acid-base complexes it becomes clear that the primary complex is better stabilized than the secondary one, which is, in turn, more stable than the tertiary complex. 

The ketone is added to a large excess of a strong base at low temperature, usually LDA in THF at -78 °C. The more acidic and less sterically hindered proton is removed in a kineti-cally controlled reaction. The equilibrium with a thermodynamically more stable enolate (generally the one which is more stabilized by substituents) is only reached very slowly (H.O. House, 1977), and the kinetic enolates may be trapped and isolated as silyl enol ethers (J.K. Rasmussen, 1977 H.O. House, 1969). If, on the other hand, a weak acid is added to the solution, e.g. an excess of the non-ionized ketone or a non-nucleophilic alcohol such as cert-butanol, then the tautomeric enolate is preferentially formed (stabilized mostly by hyperconjugation effects). The rate of approach to equilibrium is particularly slow with lithium as the counterion and much faster with potassium or sodium. 

Potassium Amides. The strong, extremely soluble, stable, and nonnucleophilic potassium amide base (42), potassium hexamethyldisilazane [40949-94-8] (KHMDS), KN [Si(CH2]2, pX = 28, has been developed and commercialized. KHMDS, ideal for regio/stereospecific deprotonation and enolization reactions for less acidic compounds, is available in both THF and toluene solutions. It has demonstrated benefits for reactions involving kinetic enolates (43), alkylation and acylation (44), Wittig reaction (45), epoxidation (46), Ireland-Claison rearrangement (47,48), isomerization (49,50), Darzen reaction (51), Dieckmann condensation (52), cyclization (53), chain and ring expansion (54,55), and elimination (56). 

Protonation of the a-carbanion (50), which is formed both in the reduction of enones and ketol acetates, probably first affords the neutral enol and is followed by its ketonization. Zimmerman has discussed the stereochemistry of the ketonization of enols and has shown that in eertain cases steric factors may lead to kinetically controlled formation of the thermodynamically less stable ketone isomer. Steroidal unsaturated ketones and ketol acetates that could form epimeric products at the a-carbon atom appear to yield the thermodynamically stable isomers. In most of the cases reported, however, equilibration might have occurred during isolation of the products so that definitive conclusions are not possible. 

In the absence of steric factors e.g. 5 ), the attack is antiparallel (A) (to the adjacent axial bond) and gives the axially substituted chair form (12). In the presence of steric hindrance to attack in the preferred fashion, approach is parallel (P), from the opposite side, and the true kinetic product is the axially substituted boat form (13). This normally undergoes an immediate conformational flip to the equatorial chair form (14) which is isolated as the kinetic product. The effect of such factors is exemplified in the behavior of 3-ketones. Thus, kinetically controlled bromination of 5a-cholestan-3-one (enol acetate) yields the 2a-epimer, (15), which is also the stable form. The presence of a 5a-substituent counteracts the steric effect of the 10-methyl group and results in the formation of the unstable 2l5-(axial)halo ketone... 

Ketone imine anions can also be alkylated. The prediction of the regioselectivity of lithioenamine formation is somewhat more complex than for the case of kinetic ketone enolate formation. One of the complicating factors is that there are two imine stereoisomers, each of which can give rise to two regioisomeric imine anions. The isomers in which the nitrogen substituent R is syn to the double bond are the more stable.114... 

Write the structures of all possible enolates for each ketone. Indicate which you expect to be favored in a kinetically controlled deprotonation. Indicate which you would expect to be the most stable enolate. 

Kinetic enolates. Alkyllithium reagents have the advantage over lithium amides for deprotonation of ketones in that the co-product is a neutral alkane rather than an amine. This bulky lithium reagent is useful for selective abstraction of the less-hindered a-proton of ketones with generation of the less-stable enolate, as shown previously for a hindered lithium dialkylamide (LOBA,12,285). Thus reaction of benzyl methyl ketone (2) with 1 and ClSifCH,), at - 50° results mainly in the less-stable enolate (3), even though the benzylic protons are much more acidic than those of the methyl group, the less hindered ones. Mesityllithium shows... 

It should be noted here that a regioselective control may also be exerted by just controlling the experimental conditions. Thus, working under strictly kinetic conditions (low temperature, absence of oxygen and slow addition of the ketone to an excess of a solution of an aprotic base) the less substituted enolate of carvomenthone can also be selectively generated and may be then submitted to different kind of reactions. However, reversible reactions like the Michael addition would equilibrate the reaction mixture to the thermodynamically more stable enolate. 

Hydroxyaminobenzo-furan and -thiophene (32a X = O, S) are the unstable enam-ine tautomers of the corresponding oximes (32b). Kinetics of the tautomeric interconversions have been measured, yielding tautomeric constants the latter have been compared with the corresponding keto-enol constants. The enamines are ca 40 times less stable, relative to the oximes, than are the enols, relative to the ketones. The minor tautomers are ca 100 times more stable (relative to the major) for the benzothiophene system. 

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