The enol intermediate

It was shown that an enol intermediate was initially formed in the decarboxylation of l -ketoacids and presumably in the decarboxylation of malonic acids. It was found that the rate of decarboxylation of a,a-dimethylacetoacetic acid equalled the rate of disappearance of added bromine or iodine. Yet the reaction was zero order in the halogen . Qualitative rate studies in bicyclic systems support the need for orbital overlap in the transition state between the developing p-orbital on the carbon atom bearing the carboxyl group and the p-orbital on the i -carbonyl carbon atom . It was also demonstrated that the keto, not the enol form, of p ketoacids is responsible for decarboxylation of the free acids from the observa-tion that the rate of decarboxylation of a,a-dimethylacetoacetic acid k cid = 12.1 xlO sec ) is greater than that of acetoacetic acid (fcacw = 2.68x10 sec ) in water at 18 °C. Enolization is not possible for the former acid, but is permissible for the latter. Presumably this conclusion can be extended to malonic acids. 

A considerable amount of data are available relating to the effect of substituents upon the rate of decarboxylation. Unfortunately, rates or activation parameters are usually not given individually for the free acid and the anion. As indicated previously, caution must be used in the interpretation of these overall rate coefficients. A number of years ago, Bernoulli et reported an extensive study of the 

There appears to be an appreciable resonance interaction between the phenyl group and the developing enol system in the transition state as evidenced by the large acceleration in rate in the comparison of phenylmalonic and malonic acid. A Taft plot °- for the alkyl-substituted malonic acids (exclusive of the allyl-substituted acids, but including benzylmalonic acid) gives a p value of about + 2.0 0.3 Since the plot covers a small range of a values, the p value is only 

RATE COEFFICIENTS FOR THE DECOMPOSITION OF SUBSTITUTED MALONIC ACIDS IN 

In octanoic acid solvent, alkyl substitution of malonic acids causes a small decrease in AG and thus an increase in rate as seen from Table 47. This is in contrast to the alkyl substituent effect in water (Table 46). The enthalpy of activation is clearly more favorable for decarboxylation of alkyl malonic acids than malonic acid in octanoic acid. Both Ai/ and AG are less favorable for decarboxylation of malonic acid in octanoic acid compared to water. This is expected on the basis of either the concerted (2) or the zwitterion mechanism (3) and (4). Association of the carboxyl groups of malonic acid with the octanoic acid solvent would thwart the attainment of the concerted transition state. Also generation of the zwitterion would be suppressed in octanoic acid. It is clear that additional work is required 

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The enol intermediate subsequently tautomerizes to acetic acid... 

FIGURE 19.13 (a) A mechanism for the fructose-l,6-bisphosphate aldolase reaction. The Schlff base formed between the substrate carbonyl and an active-site lysine acts as an electron sink, Increasing the acidity of the /3-hydroxyl group and facilitating cleavage as shown. (B) In class II aldolases, an active-site Zn stabilizes the enolate Intermediate, leading to polarization of the substrate carbonyl group. 

Step conversion of 6 to 7 via an enol intermediate. It is important to note that this initial hypothesis was made with little supporting evidence. Amamath s data was inconsistent with the formation of the enol intermediate, thus the mechanism was revised to the version illustrated below. 

Some evidence for this mode of decarboxylation of the free acid has been obtained by trapping the enol intermediate (48). (3y-Unsaturated acids (49) probably also decarboxylate by an analogous pathway ... 

Diethyl malonate has been proposed for use as a proton source in these cyclization reactions [124], It is not a sufficiently strong acid to protonate the radical-anion rapidly. However it irreversibly protonates the enol intermediate generated after carbon-caibon bond formation. In one case, control of stereochemistry in favour of the traHS-sunstituted five membered ring 39 was achieved by the addition of cerium(Ill) ions [124],... 

By means of in situ NMR spectroscopy combined with deuterium incorporation experiments, van Leeuwen has elucidated the mechanism of termination by protonolysis, showing that the fl-chelates are in equilibrium with their enolate form by a p-H elimination/hydride migration process (Scheme 7.19). The enolate intermediates are regioselectively protonated at the C2 carbon atom by either MeOH or H2O to give Pd-OMe or Pd-OH and keto terminated copolymer. The enolate formation has been reported to be rate determining in the chain transfer [19]. 

Kim, Chin, and co-workers have described a highly interesting oxyanion hole mimic that transforms L-amino acids to D-amino acids [97]. The mechanism involves stabilization of the enolate intermediate by an internal hydrogen bond array generated by urea group (Scheme 4.14). In the presence of an external base, such as triethylamine, the receptors readily promote the epimerization of a-amino acids, favoring the D-amino acids due to unfavorable steric interactions in the receptor-L-amino acid complex. These receptors can also be viewed as chiral mimics of pyridoxal phosphate [98]. 

For example, in one pathway H-atom elimination reactions generate the enol intermediate, which eventually rearranges to 2-butanone. In a second competing reaction pathway, H-atom addition results in direct hydrogenation to the saturated alcohol 2-butanol. 

The high diastereoselectivity observed with benzylic halides has been explained by postulating an interaction between the aromatic ring of the halide and the conjugated double bonds of the enolate intermediate. One face of the enolate is shielded by the benzene ring of the phenyl-ethanamine moiety, thus hindering electrophilic attack. 

Satoh and coworkers further investigated this reaction and found that, in some cases, magnesium /3-oxido carbenoids gave better results. Trapping of the enolate intermediates with several electrophiles was successfully carried out and a new method for the synthesis of one-carbon expanded cyclic a,a-disubstituted ketones from lower cyclic ketones was realized. An example using 1,4-cyclohexanedione mono ethylene ketal (195) as a representative cyclic ketone is shown in Table 15. ... 

Quenching this reaction with deuteriomethanol gave 2-methylcycloheptanone having deuterium at the 2-position (199 E = D) in 75% yield with 95% deuterium incorporation. Aldehydes and benzoyl chloride gave the desired products in 60-70% yields. Alkylation of the enolate intermediate (198) was successfully carried out with alkyl halides in the presence of HMPA in good yields. The reaction with ethyl chloroformate and chlorotri-ethylsilane gave enol carbonate (200) and sUyl enol ether (201) in 74 and 75% yield, respectively. 

PLATE 5 Loop movement in the active site of yeast enolase. Lfpper left closed conformation (PDB 2AL1) superimposed upon the open conformation (PDB 1P43). Upper right view from the back. Lower left A quantum chemical soccer ball model for yeast enolase illustrated on the enol-intermediate and calculated at the TPSS(MARI-J COSMO)/SV(P) level of theory. Lower right view from the back... 

Since photoexcitation greatly enhances the reactivity of acetylenes, formation of the enol intermediate becomes faster than its rearrangement to ketone. As a result, the intermediate acetophenone enol in the hydration of phenylacetylene could be directly observed 42... 

As outlined in Scheme 4, the ultimate goal of the three-component coupling synthesis is the organometallic-aided conjugate addition of an cj side-chain unit to an 0-protected (J )-4-hydroxy-2-cyclopentenone, followed by electrophilic trapping of the enolate intermediate by an oc... 

An interesting use is made of addition to a double bond by glutathione-dependent cis-tmns isomerases.76 One of them converts maleate to fumarate with a turnover number of 300 s"1. Similar enzymes, which participate in bacterial breakdown of aromatic compounds (Fig. 25-7), isomerize maleylacetoacetate and maleylpyruvate to the corresponding fumaryl derivatives (Eq. 13-20). The - SH group of bound glutathione is thought to add to the double bond. Rotation can then occur in the enolic intermediate. Thiocyanate ion catalyzes the isomerization of maleic acid nonenzy-matically, presumably by a similar mechanism. 

Sugars behave as weak acids (pK - 12) and at high pH ionisation occurs. Ionisation in its turn induces enolisation of the aldehydo and keto functions in sugars and via these enolate intermediates sugars are mutually interconverted. The enolate intermediates not only reconvert to... 

The products are formed from the enolate intermediate by proton transfer to either carbon or oxygen. If the proton adds to oxygen the enol is formed, which is unstable with respect to the ketone and ultimately will rearrange ... 

The enolate intermediate (figure 15.26) reacts with oxygen to produce a cycloperoxide intermediate that decomposes into glycerate-3-phosphate and glyco-late-2-phosphate (figure 15.27). 

Pedersen350 showed that a,a-dimethylacetoacetic acid cannot enolize decarboxylates readily and thus concluded that the keto tautomers of /3-oxo acids are kinetically unstable. The enol intermediate formed in the decarboxylation of /3-oxo acids has been trapped by reaction with bromine3S1 and has also been detected spectrophotometrically in the decarboxylation of a,a-dimethyloxaloacetic acid,341 oxaloacetic acid352 and fluorooxaloacetic acid.342... 

The two distinct bond-forming steps in tandem vicinal difunctionalization have been studied extensively. The first step consists of a nucleophilic addition to a ir-system the nucleophile is almost invariably an organometal. 1,4-Addition to an a, -unsaturated carbonyl substrate concomitantly generates a new cr-bond at the (3-carbon and an enolate ion. The second step constitutes C-functionalization of the enolate intermediate, forming a new o -bond between the nucleophilic a-carbon of the enolate and an electrophilic reagent. 

Enones with a pendant aldehyde, RC(=0)-CH=CH-(CH2)2-CH0, have been cyclized via an intramolecular MBH reaction in a study of the influence of Michael acceptor stereochemistry on yield.164 Using triphenylphosphine as catalyst, the Z-isomer consistently gave 2.5-8.5 times higher yield of the product (55), using reaction times of 1-3 days. It is unclear whether this is due to the relative accessibility of the /3-positions of the isomers to the nucleophilic catalyst, or differential stability in the enolate intermediates. 

No strong acids, bases or high temperatures are needed as the enolate intermediate regenerates the reagent 2 so only catalytic weak base is needed. 

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