Ketone protonation equilibria

The concentration of the ketone enolate is higher than that of the aldehyde enolate. This is true under thermodynamic control as the stability of an enolate increases with its degree of substitution. It is also true under kinetic control since enolization is an acid-base equilibrium, the increased enolate concentration reflects the higher acidity of the ketone protons. 

This principle can be extended to ketones whose enolates have less dramatic differences in stability. We said in Chapter 21 that, since enols and enolates are alkenes, the more substituents they carry the more stable they are. So, in principle, even additional alkyl groups can control enolate formation under thermodynamic control. Formation of the more stable enolate requires a mechanism for equilibration between the two enolates, and this must be proton transfer. If a proton source is available— and this can even be just excess ketone—an equilibrium mixture of the two enolates will form. The composition of this equilibium mixture depends very much on the ketone but, with 2-phenylcyclo-hexanone, conjugation ensures that only one enolate forms. The base is potassium hydride it s strong, but small, and can be used under conditions that permit enolate equilibration. 

Under equilibrium conditions (thermodynamic control), the allylic source adds to the polarized multiple bond (path AdN). However, the allylic source can also serve as a base and may deprotonate the sink, creating a mixture of sources and sinks and thus a messy statistical mixture of products. Clean products result if the source is just the deprotonated sink or if the sink has no acidic protons. With ketones, the equilibrium of the attack step favors the starting materials, and therefore the reaction goes to completion only if driven by a following elimination. In the next Adisj2 example, the source is the deprotonated sink. The product is an aldehyde-alcohol, or aldol, a name now used for the general process of an enol (acidic media) or enolate (basic) reacting with an aldehyde or ketone. 

Equilibrium among enolate anions is established when the ketone is in slight excess, a condition under which it is possible for proton-transfer reactions to occur between an enolate and an a-hydrogen of an unreacted ketone. Thus, equilibrium is established between alternative enolate anions. 

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. 

Enols are related to an aldehyde or a ketone by a proton transfer equilibrium known as keto-enol tautomerism (Tautomensm refers to an mterconversion between two struc tures that differ by the placement of an atom or a group)... 

Equilibrium between the various enolates of a ketone can be established by the presence of an excess of the ketone, which permits proton transfer. Equilibration is also favored by the presence of dissociating solvents such as HMPA. The composition of the equilibrium enolate mixture is usually more closely balanced than for kinetically... 

Eq. (4e)] is not reduced by metal-ammonia solutions so that the existence of this equilibrium cannot lead to further reduction of the saturated ketonic product only protonation on carbon can result in further reduction (see page 39). 

The equilibrium ratios of enolates for several ketone-enolate systems are also shown in Scheme 1.1. Equilibrium among the various enolates of a ketone can be established by the presence of an excess of ketone, which permits reversible proton transfer. Equilibration is also favored by the presence of dissociating additives such as HMPA. The composition of the equilibrium enolate mixture is usually more closely balanced than for 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 solvation, there can be exceptions. This factor, along with CH3/CH3 steric repulsion, presumably accounts for the stability of the less-substituted enolate from 3-methyl-2-butanone (Entry 3). 

Scheme 7.25 shows the role of quinone methide energy on the cation-quinone methide equilibrium. A high pKa value for this equilibrium is expected if the energy of the quinone methide approaches that of the carbocation. To construct this cycle, we used the Ka values that we determined for the protonated ketone (pKa — —0.9) and quinone methide (pKa = 6.6). This pKa difference requires that the keto form be more stable than the quinone methide by — 10.2kcal/mol. We obtained the calculated energy difference of lO.lkcal/mol from Hartree-Fock calculations using 6-31G and STO-3G basis sets, inset of Scheme 7.25. 

Attack by eCN is slow (rate-limiting), while proton transfer from HCN or a protic solvent, e.g. HzO, is rapid. The effect of the structure of the carbonyl compound on the position of equilibrium in cyanohydrin formation has already been referred to (p. 206) it is a preparative proposition with aldehydes, and with simple aliphatic and cyclic ketones, but is poor for ArCOR, and does not take place at all with ArCOAr. With ArCHO the benzoin reaction (p. 231) may compete with cyanohydrin formation with C=C—C=0, 1,4-addition may compete (cf. p. 200). 

Note that deuterium exchange of the -OH leads to incorporation of deuterium alpha to the carbonyl in the ketone form. This may happen, even if there is no evidence of any enol signals in the spectrum initially, i.e., it can occur even when the equilibrium is heavily in favour of the ketone. Aromatic protons of rings which bear two or more -OH groups are also prone to undergo slow exchange, as are nitrovinyl protons. 

Still another possibility in the base-catalyzed reactions of carbonyl compounds is alkylation or similar reaction at the oxygen atom. This is the predominant reaction of phenoxide ion, of course, but for enolates with less resonance stabilization it is exceptional and requires special conditions. Even phenolates react at carbon when the reagent is carbon dioxide, but this may be due merely to the instability of the alternative carbonic half ester. The association of enolate ions with a proton is evidently not very different from the association with metallic cations. Although the equilibrium mixture is about 92 % ketone, the sodium derivative of acetoacetic ester reacts with acetic acid in cold petroleum ether to give the enol. The Perkin ring closure reaction, which depends on C-alkylation, gives the alternative O-alkylation only when it is applied to the synthesis of a four membered ring ... 

Hydride transfer from [(bipy)2(CO)RuH]+ occurs in the hydrogenation of acetone when the reaction is carried out in buffered aqueous solutions (Eq. (21)) [39]. The kinetics of the reaction showed that it was a first-order in [(bipy)2(CO)RuH]+ and also first-order in acetone. The reaction proceeds faster at lower pH. The proposed mechanism involved general acid catalysis, with a fast pre-equilibrium protonation of the ketone followed by hydride transfer from [(biPy)2(CO)RuH]+. 

The TEAF system can be used to reduce ketones, certain alkenes and imines. With regard to the latter substrate, during our studies it was realized that 5 2 TEAF in some solvents was sufficiently acidic to protonate the imine (p K, ca. 6 in water). Iminium salts are much more reactive than imines due to inductive effects (cf. the Stacker reaction), and it was thus considered likely that an iminium salt was being reduced to an ammonium salt [54]. This explains why imines are not reduced in the IPA system which is neutral, and not acidic. When an iminium salt was pre-prepared by mixing equal amounts of an imine and acid, and used in the IPA system, the iminium was reduced, albeit with lower rate and moderate enantioselectivity. Quaternary iminium salts were also reduced to tertiary amines. Nevertheless, as other kinetic studies have indicated a pre-equilibrium with imine, it is possible that the proton formally sits on the catalyst and the iminium is formed during the catalytic cycle. It is, of course, possible that the mechanism of imine transfer hydrogenation is different to that of ketone reduction, and a metal-coordinated imine may be involved [55]. 

Enolization and ketonization kinetics and equilibrium constants have been reported for phenylacetylpyridines (85a), and their enol tautomers (85b), together with estimates of the stability of a third type of tautomer, the zwitterion (85c). The latter provides a nitrogen protonation route for the keto-enol tautomerization. The two alternative acid-catalysed routes for enolization, i.e. O- versus Af-protonation, are assessed in terms of pK differences, and of equilibrium proton-activating factors which measure the C-H acidifying effects of the binding of a proton catalyst at oxygen or at nitrogen. 

This is an equilibrium reaction, and it raises a couple of points. First, there are two a-positions in the ketone, so what about the COCH3-derived enolate anion The answer is that it is formed, but since the CH3 group is not chiral, proton removal and reprotonation have no consequence. Racemization only occurs where we have a chiral a-carbon carrying a hydrogen substituent. Second, the enolate anion resonance structure with charge on carbon is not planar, but roughly tetrahedral. If we reprotonate this, it must occur from just one side. Yes, but both enantiomeric forms of the carbanion will be produced, so we shall still get the racemic mixture. 

In the presence of excess monoalkylamine, carbonyl compounds in aqueous solution are in equilibrium with the corresponding imine. In most cases these imines cannot be isolated but they are reduced at a less negative potential than the carbonyl compound. Selective reduction of such equilibrium mixtures is a useful route to alkylamines from ketones in yields of 70-90%. The process fails with hindered ketones such as camphor and with bulky amines such as fert.-butyl amine. Overall the reaction has advantages of lower costs and simpler work-up compared to the use of cyanoborohydride reducing agents. In the electrochemical reaction, protonation of carbanion intermediates occurs from the more hindered side and where two isomeric products are fomied, the least hindered amine predominates [193]. 

O-Substituted oxime derivatives are synthetically useful in a wide variety of transformations. Hoffman and Butani have observed that reaction of a series of aldehydes and ketones with the potassium salt of Af,0-bis(trimethylsilyl)hydroxylamine 4a or 4b (a rapid equilibrium between 4a and its Af,N-bis(silylated) isomer 4b probably exists in solution) gave high yields of the corresponding oximate anion 5, formed via the Peterson-type reaction, together with the silyl ether 6. Anion 5 could be protonated to the oxime 7 or trapped in situ with a variety of electrophiles to give 0-substituted oxime derivatives (Scheme 6). 

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. 

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