Enolate anions, kinetic derivatives

Anotheranalogy between the enolate anions derived from a,)3-unsatura ted ketones and the corresponding enamines is encountered in their alkylation reactions (57), which proceed by the kinetically controlled attack at the a-carbon atom. For instance, Stork and Birnbaum (51) found that the alkylation of the morpholine enamine of /J -octalone-2 (117) with methyl iodide gave the C-1 methylated derivative (118). 

Enolization of cationic ketones is accelerated by electrostatic stabilization of the enolate anion. Rate constants for water-, acetate-, and hydroxide ion-catalysed enolization of 2-acetyl- 1-methylpyridinium ion (94) have been measured13811 and compared with a 2-acetylthiazolium ion (95), a simple analogue of 2-acetylthiamine pyrophosphate.13811 For (94), qh = 1.9 x 102 M-1 s 1, about 1.1 x 106 times that for a typical methyl ketone such as acetone. Thermodynamically, it is >108 times more acidic (pAa values of 11.1 vs 19.3). These increases in kinetic and thermodynamic acidity are derived from through-bond and through-space effects, and the implications for enzymatic catalytic sites with proximal, protonatable nitrogen are discussed. The results for (94) suggest a pAa value of 8.8 for (95), a value that cannot be measured directly due to competing hydrolysis. 

Addition of a silylating reagent such as Me3SiCl to the reaction mixture traps the enolate anions and produces two silyl enol ethers in a ratio which reflects the ratio of the enolate anions. Thus if 2-methylcyclohexanone is added to the hindered base LDA at -78 °C and the mixture stirred for 1 hour at -78 °C and quenched with MeySiCl, then the major product is the silyl enol ether derived from the kinetic enolate. In contrast, heating 2-methylcyclohexanone, triethylamine, and Me3SiCl at 130 °C for 90 hours... 

The enolate anions are more reactive towards electrophiles when they are associated with non-coordinating quaternary ammonium cations than when they are associated with lithium cations. Thus, as illustrated in Equations Si3.4 and Si3.5, quaternary ammonium derivatives are preferred as counterions for kinetic enolates in order to prevent any isomerization to the thermodynamic enolate occurring before reaction with the added electrophile proceeds. 

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,... 

Trialkylsilyl halides show a great propensity to react with the oxygen rather than the carbon of enolate anions. Stork showed that 0-alkylation allows enolates to be trapped as the trialkylsilyl enol ether, which is most useful for kinetic enolates in which a lithium enolate (such as the kinetic enolate derived from 2-methyl-cyclohexanone and LDA) is reacted with trimethylsilyl chloride to give an isolable intermediate, 112. jjig enolate is trapped with high efficiency, and conversion to the enolate is readily accomplished by treatment with methyllithium, which generates the kinetic enolate (113) and the volatile trimethylsilane (Me3SiH). This... 

Enolate anions react as nucleophiles. They give nucleophilic acyl substitution reactions with acid derivatives. The condensation reaction of one ester with another is called a Claisen condensation and it generates a P-keto ester. A mixed Claisen condensation under thermodynamic conditions leads to a mixture of products, but kinetic control conditions can give a single product. 

What does all of this mean The reaction of 2-pentanone with LDA in THF at -78°C constitutes typical kinetic control conditions. Therefore, formation of the kinetic enolate and subsequent reaction with benzaldehyde to give 34 is predictable based on the kinetic versus thermodynamic control arguments. In various experiments, the reaction with an unsymmetrical ketone under what are termed thermodynamic conditions leads to products derived from the more substituted (thermodynamic) enolate anion. Thermodynamic control conditions typically use a base such as sodium methoxide or sodium amide in an alcohol solvent at reflux. The yields of this reaction are not always good, as when 2-butanone (37) reacts with NaOEt in ethanol for 1 day. Self-condensation at the more substituted carbon occurs to give the dehydrated aldol product 38 in 14% yield. Note that the second step uses aqueous acid and, under these conditions, elimination of water occurs. 

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. 

An ester enolate is formed by reaction with a strong base, and the resulting enolate anion can condense with an aldehyde, a ketone, or another ester. Ester enolates react with aldehydes or ketones to form p-hydroxy esters. Aldehyde or ketone enolate anions react with esters to form p-hydroxy esters, 1,3-diketones, or p-keto aldehydes 56,57,84,99,100,102,108,110,114,115. Enolate anions react as nucleophiles. They give nucleophilic acyl substitution reactions with acid derivatives. The condensation reaction of one ester with another is called a Claisen condensation and it generates a P-keto ester. A mixed Claisen condensation under thermodynamic conditions leads to a mixture of products, but kinetic control conditions can give a single product 52, 53, 54, 55, 59, 68, 69,98,99,101,125. 

While the addition-oxidation and the addition-protonation procedures are successful with ester enol-ates as well as more reactive carbon nucleophiles, the addition-acylation procedure requires more reactive anions and the addition of a polar aptotic solvent (HMPA has been used) to disfavor reversal of anion addition. Under these conditions, cyano-stabilized anions and ester enolates fail (simple alkylation of the carbanion) but cyanohydrin acetal anions are successful. The addition of the cyanohydrin acetal anion (71) to [(l,4-dimethoxynaphthalene)Cr(CO)3] occurs by kinetic control at C-P in THF-HMPA and leads to the a,p-diacetyl derivative (72) after methyl iodide addition, and hydrolysis of the cyanohydrin acetal (equation 50).84,124-126... 

Flash photolysis and laser flash photolysis are probably the most versatile of the methods in the above list they have been particularly useful in identifying very short-lived intermediates such as radicals, radical cations and anions, triplet states, carbenium ions and carbanions. They provide a wealth of structural, kinetic and thermodynamic information, and a simplified generic experimental arrangement of a system suitable for studying very fast and ultrafast processes is shown in Fig. 3.8. Examples of applications include the keton-isation of acetophenone enol in aqueous buffer solutions [35], kinetic and thermodynamic characterisation of the aminium radical cation and aminyl radical derived from N-phenyl-glycine [36] and phenylureas [37], and the first direct observation of a radical cation derived from an enol ether [38],... 

Metallation of the arylsulfinyl-N-methoxyacetimidate (49), which may be prepared in two steps from commercially available V-hydroxyacetimidate, followed by reaction with aldehydes provides adducts that after sequential desulfurization and hydrolysis may be converted into -hydroxy esters with 280% enantiomeric excess (Scheme 20). Thus, under kinetic conditions the reaction of the anion derived from (49) with aldehydes gives mixtures of the syn and anti products, (50) and (51) respectively, in nearly equal amounts. Under thermodynamic conditions, however, the more stable anti adducts (51) dominate, and after desulfurization and hydrolysis the P-hydroxy esters (53) are obtained in 75-94% enantiomeric excess. When the zinc enolate derived from (49) is condensed with aldehydes, the anti adducts (51) are again the major products and the p-hydroxy esters (53) can be isolated in 76-86% enantiomeric excess. On the other hand, the reaction of the zirconium enolate of (49), which is obtained by the addition of Cp2ZrCl2 to the corresponding lithium enolate, with aldehydes followed by desulfurization gives p-hy-... 

Regioselectivity in the context of substituted alkenyl anion has also been addressed. It is known that the base-induced fragmentation of tosylhydrazones (Shapiro reaction) derived from a-substituted ketones leads predominantly to the "kinetic" (cf. ketone enolates)... 

CB1981] and the same reaction of the related silyl enol ether (16) using polymer supported mandelic acid leads to (5)-mandelic acid in up to 94% e.e. [94TL2891]. Low temperature protonation of the anion derived from (17) produces mainly the cis product by kinetic control [94CB1495] and hydroboration of (18) gives the cis hydroxymethyl compound with high... 

The sites of deprotonation of a series of A -benzyl lactams have been determined. For five- and six-membered lactams, kinetic deprotonation occurred exclusively a to the carbonyl, while seven-and eight-membered lactams gave exclusively the products arising from deprotonation at the benzylic position. The alkylation of the anion derived from (121), however, gave an approximately 3 1 ratio of (122) to (123) (R = Bu", allyl and Bn) (Equation (5)) <87JA4405>. By contrast, the deprotonation of A -(BOC)caprylolactam with lithium hexamethyldisilazide in THF at — 78°C gave the expected enolate, which could be alkylated with iodomethane (81% yield) or phenylselenyl chloride (65% yield) <90SL63>. 

In a recent kinetic study, we investigated the ability of macrocyclic polyethers to activate enolates in the alkylation of deoxybenzoin with butyl derivatives nBuY (F=Br, I, OMes) catalyzed by crown ether 5 or cryptand 10 under EL- and SL-PTC conditions with strong bases (NaOH, KOH) (Eq. 10). The enolate reactivity increases up to 40 times, on going from crown ether 5 to cryptand 10 in line with the better anion activation realized by the latter. The regioselectivity of the reaction (0/C ratio) is also remarkably affected by the ligand. 

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