Enolate ions kinetic control

A quite consistent relationship is found in these and related data. Conditions of kinetic control usually favor the less substituted enolate. The principal reason for this result is that removal of the less hindered hydrogen is faster, for steric reasons, than removal of more hindered protons. Removal of the less hindered proton leads to the less substituted enolate. Steric factors in ketone deprotonation can be accentuated by using more highly hindered bases. The most widely used base is the hexamethyldisilylamide ion, as a lithium or sodium salt. Even more hindered disilylamides such as hexaethyldisilylamide7 and bis(dimethylphenylsilyl)amide8 may be useful for specific cases. On the other hand, at equilibrium the more substituted enolate is usually the dominant species. The stability of carbon-carbon double bonds increases with increasing substitution, and this effect leads to the greater stability of the more substituted enolate. 

The E/Z stereoselection can be rationalized by assuming metal-centered pericyclic chairlike transition states 1 13,10 , 12 and 13. In this model proton transfer and metal ion transfer are assumed to occur simultaneously. When R is a bulky group, the nonbonded steric interaction between this group and the methyl group becomes strong and the Z-enolate will be the predominating isomer under kinetic control. 

The extent of kinetically controlled formation of the carboxonium ions 31 depends on the nature of R1 and Yy. The possible existence of 31 allows formation of acylated enols 32 (Y = R3CO), which are analogous with w-acylaminostyrene derivatives. As is known, the latter compounds easily undergo an intramolecular acid-catalyzed cyclization to isoquinolines (the Pictet-Gams reaction) (80T1279). 

Since alkylation is usually not reversible, the products are the result of kinetic control. However, iminium ions, CH2==N(CH3)2 , are stabilized electrophiles and reversibly add to enols to give the thermodynamically more stable C-alkylated product. 

The above rationalization is confirmed experimentally by the addition of methanol in mild acid to enol ether 71 (Fig. 3.20). Under these kinetically controlled conditions, a mixture of 74a and 75 was obtained in 76 24. This ratio corresponds to the energy difference of 0.70 kcal/mol for the transition state favoring the formation of 72a which is in complete agreement with the AMI [46] and 6.31G [47] calculation. This value is in agreement with that found by van Eikeren [45]. In addition, these calculations also show that the transition states are definitely late transition states and resemble the geometry of the oxocarbenium ion. 

If the electrophile is an alkyl halide, the enolate ion is alkylated. The less substituted a-carbon is alkylated when the reaction is under kinetic control, whereas the more substituted a-carbon is alkylated when the reaction is under thermodynamic control. 

When enolates are allowed to reach equilibrium, the composition of the mixture is usually more closely balanced than under kinetically controlled conditions. In general, the more highly substituted enolate is the preferred isomer, but if the alkyl groups are sufficiently branched as to interfere with the solvation of the enolate, there can be exceptions. Torsional and ring strain effects also come into play with cyclic ketones. The identity of the metal cation and the solvent, which are the major factors in determining the extent of ion pairing, also affect the position of the equilibrium. 

The use of /i-ketocstcrs and malonic ester enolates has largely been supplanted by the development of the newer procedures based on selective enolate formation that permit direct alkylation of ketone and ester enolates and avoid the hydrolysis and decarboxylation of ketoesters intermediates. Most enolate alkylations are carried out by deprotonating the ketone under conditions that are appropriate for kinetic or thermodynamic control. Enolates can also be prepared from silyl enol ethers and by reduction of enones (see Section 1.3). Alkylation also can be carried out using silyl enol ethers by reaction with fluoride ion.31 Tetraalkylammonium fluoride salts in anhydrous solvents are normally the... 

In base, as in acid, a./ -unsaturated ketones are hydrogenated in preference to the saturation of isolated double bonds. In basic solutions the product configuration obtained is markedly dependent on the amount of base present, particularly in very dilute systems. This indicates that the reaction proceeds by way of kinetically and thermodynamically controlled cnolatc formation. It is proposed that these enolates are very strongly or irreversibly adsorbed onto the catalyst surface and that the product configuration can best be explained by way of a hydride ion transfer from the catalyst, followed by protonation of the adsorbed species 7 by the solution28. 

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