Enolate anions, kinetic protonation

In a reaction under kinetic control, the composition of the product mixture is determined by the relative rates of formation of each product. No equilibrium among possible alternative structures is set up. In the case of formation of enolate anions, kinetic control refers to the relative rates of removal of the alternative a-hydrogens. The less hindered a-hydrogen is removed more rapidly thus, the major product is the less substituted enolate anion. Because a slight excess of base is used, there is no ketone to serve as a proton donor and the less stable enolate anion cannot equilibrate with a more stable one. 

Each act of proton abstraction from the a carbon converts a chiral molecule to an achi ral enol or enolate ion The sp hybridized carbon that is the chirality center m the start mg ketone becomes sp hybridized m the enol or enolate Careful kinetic studies have established that the rate of loss of optical activity of sec butyl phenyl ketone is equal to Its rate of hydrogen-deuterium exchange its rate of brommation and its rate of lodma tion In each case the rate determining step is conversion of the starting ketone to the enol or enolate anion... 

By analogy with the kinetic protonation of steroidal zl -enolate anions with weak acids such as acetic acid, which proceeds at the C-4 atom, since the maximum negative charge resides at this position (54,55), the kinetic protonation of the -dienamines with weak acids also occurs at this... 

These enzymes do not catalyze any proton exchange at C-3 of pyruvate or at C-2 of an acyl-CoA unless the biotin is first carboxylated. This suggested that removal of the proton to the biotin oxygen and carboxylation might be synchronous. However, 13C and 2H kinetic isotope effects and studies of 3H exchange66 support the existence of a discrete enolate anion intermediate as shown in Eq. 14-11.165/67 This mechanism is also consistent with the observation that propionyl-CoA... 

Whatever the explanation, the effect of acids is less marked than the selectivffy in alkaline solutions, where a attack is largely suppressed. The effect of alkali may depend upon the formation and selective reduction of enolate anions. The A2 4-dienolate anion, which is the major product of kinetically-controlled enolisation by bases (see p. 156) is seen from a molecular model to have a somewhat "folded conformation of the A/B ring system (ii). The convex / -face of the A/B ring system and the absence of an axial 2jS-proton should favour approach to the catalyst from this direction, whereas the a-face of the A -bond is severely hindered by the axial hydrogens at C(7) and C<9>. 

This compound has some similarities to the enol form of a carbonyl compound, and it is called an enamine. As this reaction is performed under reversible conditions, the thermodynamic isomer is always formed, i.e. the double bond is formed on the most highly substituted side. These compounds are of great synthetic importance. Furthermore, their use complements the use of the anions formed from carbonyl compounds. This is because enolate anions are usually produced under strongly basic, i.e. irreversible, conditions, and so the proton that is normally removed is the kinetically favoured one. Hence, the hydrogen atom that is removed in the formation of the enolate anion may be different from the one that is eliminated under thermodynamic conditions prevalent in the formation of the carbon/carbon double bond of the enamine. 

The a-protons that are less sierically hindered are most rapidly removed by a bulky base. Thus, addition of an unsymmetrical ketone to an excess of lithium diisopropy-lamide (LDA) gives the enolate anion on the less substituted side as the result of kinetic control. 2-Methylcyclohe anone has been specifically benzylated in the (3-position in this manner [4],... 

Each act of proton abstraction from the a-carbon atom converts a chiral molecule to an achiral enol or enolate anion. Careful kinetic studies have established that the rate of loss... 

The high values of the pK s of carbon acid substrates and the associated instability of enolate anion intermediates in nonenzymatic reactions first led to the expectation that these intermediates could not be rendered kinetically competent in enzymatic reactions [3]. As a result, the expectation was that these reactions must be concerted, thereby avoiding the problem of how an active site might provide sufficient, significant stabilization of the intermediates. However, the weight of the experimental evidence now is that enzymes that abstract protons from carbon acids are able to sufficiently stabilize enolate anion intermediates so that they can be kinetically competent. 

X 10 if the enolate anion intermediate were not stabilized in the active site this value is 10 -fold less than the observed value for the kcat, 500 s. Recall that an enolate anion is necessarily on the reaction coordinate, so the value of AG° must be reduced for the enolate anion to be kinetically competent irrespective of whether AG int can be reduced. Thus, the active site of mandelate racemase must decrease AG° from the value predicted from the values of the substrate carbon acid and the active site base in solution. The obvious strategy to accomplish this reduction is preferential stabilization of the enolate anion intermediate relative to the carbon acid substrate, the increased negative charge on (or proton affinity of) the carbonyl/carboxylate oxygen of the enolate anion intermediate provides a convenient handle for enhanced electrostatic or hydrogen bonding interactions with the active site. 

Although not a subject of this chapter, Toney and coworkers have quantitated the reaction coordinate of a PLP-dependent L-alanrne racemase [15]. Despite the expectation that the cofactor provides resonance stabilization of the carbanion/enolate anion (quinonoid) intermediate derived by abstraction of the a-proton, the spectroscopic and kinetic analyses for the wild type racemase at steady-state provided no evidence for the intermediate in the reaction catalyzed by the wild type enzyme. Indeed, Toney had previously demonstrated that a kinetically competent quinonoid intermediate accumulates in the impaired R219E mutant [16] Arg 219 is hydrogen-bonded to the pyridine nitrogen of the cofactor. For the wild type racemase, the derived transition state energies for conversion of the bound enantiomers of alanine,... 

A quantitative understanding of how enzymes catalyze rapid proton abstraction from weakly acidic carbon acids is necessarily achieved by dissecting the effect of active site structure on the values of AG°, the thermodynamic barrier, and AG int, the intrinsic kinetic barrier for formation of the enolate anion intermediate. The structural strategies by which AG° for formation of the enolate anion is reduced sufficiently such that these can be kinetically competent are now understood. In divalent metal ion-independent reactions, e.g., TIM, KSI, and ECH, the intermediate is stabilized by enhanced hydrogen bonding interactions with weakly acidic hydrogen bond donors in divalent metal-dependent reactions, e.g., MR and enolase, the intermediate is stabilized primarily by enhanced electrostatic interactions with... 

Under basic conditions, only two stereoisomers 153 and 155 were produced in ca. 2 1 ratio, respectively. It is considered that the result reflects a kinetic controlled cyclization. An enolate anion corresponding to [E] is produced via a half chair-like transition state [TS1] from [Dl], and then rapid protonation of the enolate from the top face provides 153 as a major product. Through a half chair-like transition state [TS2] from [D2], another enolate anion corresponding to [FI] is produced. This enolate is rapidly protonated from the bottom face and then epimerization of the C4 stereochemistry leads to 155. In each transition state, it is also considered that the transition state [TS1] (having no 1, 3-diaxiaI interaction) is more stable than the transition state [TS2] (having a 1, 3-diaxiaI interaction of two methyl groups). 

Enolate anions with extended conjugation can be formed by proton abstraction of a,p-unsaturated carbonyl compounds (1.9). Kinetically controlled alkylation of the delocalized anion takes place at the a-carbon atom to give the p,7-unsaturated compound directly. A similar course is followed in the kinetically controlled protonation of such anions. 

The idea of kinetic versus thermodynamic control can be illustrated by discussing briefly the formation of enolate anions from unsymmetrical ketones. A more complete discussion of this topic is given in Chapter 7 and in Part B, Chapter 1. Any ketone with more than one type of a-proton can give rise to at least two enolates when a proton is abstracted. Many studies, particularly those of House,have shown that the ratio of the two possible enolates depends on the reaction conditions. If the base is very strong, such as the triphenylmethyl anion, and there are no hydroxylic solvents present, enolate 6 is the major product. When equilibrium is established between 5 and 6 by making enolate formation reversible by using a hydroxylic solvent, however, the dominant enolate is 5. Thus, 6 is the product of kinetic control... 

Removal of the middle proton leads to a resonance-stabilized enolate anion with three resonance structures, as shown. Removal of the methyl proton leads to an enolate anion with only two resonance contributors. The middle proton is significantly more acidic and will deprotonate to give the enolate shown. If LDA is used, the kinetic enolate is the one derived from removal of the more acidic proton, which is the same enolate anion. 

The a-proton of an aldehyde or ketone is less acidic as more carbon substituents are added. As more electron-withdrawing groups are added, the a-proton becomes more acidic, so a 1,3-diketone is more acidic than a ketone. The more acidic proton of an unsymmetrical ketone is the one attached to the less substituted carbon atom 8,12,13,14,22,23,28,30, 77,81,86,89,93. Enolate anions react as nucleophiles. They give nucleophilic acyl addition reactions with aldehydes and ketones. The condensation reaction of an aldehyde or ketone enolate with another aldehyde or ketone is called an aldol condensation. Selfcondensation of symmetrical aldehydes or ketones leads to a single product under thermodynamic conditions. Condensation between two different carbonyl compounds gives a mixture of products under thermodynamic conditions, but can give a single product under kinetic control conditions 5, 9, 11, 15, 16, 17, 18,19,20,21,23,29,30,31,32,33,34,40,41,42,43,44,45,46,49,91, 92, 94,102,114,115,123,134. 

---