Enolates mechanisms

Reactions 33 and 35 constitute the two principal reactions of alkyl hydroperoxides with metal complexes and are the most common pathway for catalysis of LPOs (2). Both manganese and cobalt are especially effective in these reactions. There is extensive evidence that the oxidation of intermediate ketones is enhanced by a manganese catalyst, probably through an enol mechanism (34,96,183—185). 

Several years ago, there was much debate concerning the mechanism of the Darzens condensation.2.3 The debate concerned whether the reaction employed an enolate or a carbene intermediate. In recent years, significant evidence that supports the enolate mechanism has been obtained, wherein the stabilized carbanion (11) of the halide (10) is condensed with the electrophile (12) to give diastereomeric aldolate products (13,14), which subsequently cyclize via an internal Sn2 reaction to give the corresponding oxirane (15 or 16). The intermediate aldolates have been isolated for both a-fluoro- and a-chloroesters 10. 

On the basis of the nature of CO adsorption and of the nature of chain initiator intermediates, popular mechanistic proposals include the carbide mechanism,1-2 wherein CO adsorbs dissociatively and the carbide (C ) is the chain initiator intermediate, and the enolic mechanism,3 involving molecular adsorption of CO and the formation of an oxygen intermediate, the enol (HC OH). 

Racemizations in the crystalline state have a long history. It is known that L-a-amino acids slowly racemize in the solid state [62]. As this also happens in solid proteins the implications are manifold, not only in pure chemistry but also in biochemistry, nutrition, food technology, and geology. Therefore, techniques have been developed to determine the dl ratio of amino acids down to 0.1% and inversion rate constants have been determined under acid hydrolysis conditions [63]. One could think of very slow deamination and readdition of the amine or an enolization mechanism. However, such reactions can also be induced by photolysis or radiolysis from natural sources [64]. 

Reports in the literature that isolate any of these processes are rare and often require unusual conditions. For example, in addition to the oxazoI-5(4//)-one studies described above, Kemp and Rebek[27l were able to use kinetic isotope effects to distinguish the enolization mechanism from oxazol-5(4//)-one formation in a simple peptide coupling experiment. a-2H-Labeled Bz-L-Leu-OH and Z-Gly-Phe-OH were prepared and coupling reactions to H-Gly-OEt were carried out. In cases where oxazol-5(4//)-one formation is rate-determining, such as with Bz- L-Leu-OH, the isotope effect kHlkD is equal to 1 because the a-proton is not removed until after this rate-determining step. In contrast, enolization requires the direct removal of the a-proton, and the isotope effect measured for this mechanism was as high as 2.9 with Z-Gly-Phe-OH. Therefore, a measurement of the isotope... 

The relationship between the structure of the tertiary amine and the intrinsic rate of racemization was clear. This effect has been studied before by Williams,[32 among others. Two families of bases were compared trialkylamines and 4-alkylmorpholines. The trends were most clearly expressed in the experiments using Boc-Ser(OBzl)-NCA. The rate was decreased within each family as the steric bulk of the amine was increased. This result was consistent with the direct enolization mechanism that requires a close approach of the tertiary amine for the abstraction of the a-proton. The rate was much lower with 4-alkyl-morpholines than with trialkylamines because of the decreased basicity of the former (triethylamine and 4-ethylmorpholine have similar structures TEA is actually more hindered). The most favorable results with respect to racemization were obtained when a weak base was combined with a sterically hindered substituent, as with 4-cyclohexylmorpholine. In the case of Boc-Phe-NCA, the same trends were seen, except that racemization by the 4-alkylmorpholines was so slow that the differences within that family were not significant. 

Griffiths and Gutsche (23) recently studied the interconversion of deuterated mandelaldehyde dimer and 2-hydroxyacetophenone in pyridine to obtain information concerning the glyceraldehyde-dihydroxy-acetone rearrangement. Their results support an enolization mechanism requiring a base and an acid catalyst. They found a deuterium isotope effect of ca. 1.3 for the transformation of the aldehyde to the ketone. When they corrected this for the apparently differing amounts of the aldehyde form in equilibrium with the proteo dimer and the deuterio dimer, they obtained a value of 3.9. By the Swain-Schaad equation (26) ... 

Scheme /V. Enolate mechanism for reaction of sugars with oxygen Dubourg and Naffa Mechanism (32)...

Two free-radical chain reactions, in addition to the ionic enolate mechanism, seem reasonable for the oxidation of the sugars by oxygen. With an aldose-2-f one of the free-radical mechanisms would yield non-labeled formic acid and the next lower aldonic acid the other would yield labeled formic acid and the same aldonic acid. 

In the case of the optically active acids, racemization is postulated as the result of the enolization mechanism ... 

The extent of racemization of peptide aldehydes exposed to silica gel has been determined as a function of time (Table 3).b0 The amount of racemization increases in the order Z-Cys(Bzl)-H > Z-Phe-H > Z-Leu-H > Z-Arg(N02)-HJ5 The unusually small amount of racemization observed with Z-Arg(N02)-H is probably due to its cyclic carbinol amine structure, which prevents racemization through a keto-enol mechanism. More racemization is seen in aldehydes possessing side chains such as Z-Cys(Bzl)-H that favor enolsJ15 ... 

Ah initio methods have been used to compare enzyme-catalysed enolization mechanisms.130 Acid- and base-catalysed stepwise mechanisms have been compared with the concerted reaction the latter is favoured by several hydrogen-bonding interactions. 

The hydrogenation of the carbonyl group can, in principle, proceed in two ways (Scheme 9) by the addition of adsorbed hydrogen to the C=0 bond (ketonic mechanism), or by the addition of adsorbed hydrogen to the C=C bond of the enol form (enolic mechanism). Deuteration appears to be a good method to distinguish the two mechanisms the ketonic mechanism would give rise to a C(l)—D bond, whereas the enolic mechanism... 

The reaction was rationalized by a ruthenium enolate mechanism (Fig. 4). Water served as a nucleophile and added to alkynes then the intermediate isomerized to give a ruthenium enolate, which then underwent addition to a-vinyl ketone followed by protonation to afford the 1,5-diketone. During the reaction, no ketone resulting from the hydration of the alkynes was found, which showed that the conjugate addition is faster than protonation of the ruthenium enolate in this aqueous reaction. 

Notice that in drawing this mechanism It is not necessary to locate the negative charge on the carbon atom. You should always draw enolate mechanisms using the better oxyanion structure. 

Figure 3-12 1,2-Enolization Mechanism of the Browning Reaction. Source From D.T. Hurst, Recent Developments in the Study of Nonenzymic Browning and Its Inhibition by Sulphur Dioxide, BFMIRA Scientific and Technical Surveys, No. 75, Leatherhead, England, 1972.

Enzymes thus far found to catalyze isomerization or epimerization by oxidation and reduction require the cofactor NAD, which is often very tightly bound, not being removed by dialysis, but only by treatment with charcoal. Enzymes for which a keto-enol mechanism has been suggested do not usually involve NAD. The two mechanisms should also be distinguishable by the nonoccurrence or occurrence, respectively, of hydrogen exchange with the solvent. 

Supporting evidence for the mechanism comes from the observation that the bromination and iodination proceed at the same rates. The deuterium exchange is also comparable in absolute rate. Very extensive work with the optically active sec-butyl phenyl ketone, C2H5—CH(CH3)COC6H6, has shown that the acid-catalyzed iodination, bromination, and inversion have identical rates. The base-catalyzed, OD, rates of deuteration and inversion have also been shown to be equal. If the enol and enolate ion can be considered to be planar about the a carbon atom, then these results provide very strong support for the slow enolization step. In fact it is difficult to find any other reasonable interpretation of the data. The enol mechanism is also compatible with the well-known susceptibility of H atoms, in the alpha position to one or more C==0 groups, to substitution reactions. 

The Amadori rearrangement has some features of the Lobry de Bruyn-Alberda van Ekenstein transformation, as can be seen from the ammono analogy to sugar enolization formulated in Part 2 of this Section. Both reactions occur in basic media, and each doubtless involves 1,2-enolization of the sugar. However, the Amadori rearrangement proceeds by acceptance of a proton from the acid catalyst, whereas the Lobry de Bruyn Alberda van Ekenstein transformation proceeds by delivery of a proton to the base catalyst. Aside from what may be argued as to the enolization mechanism, there are other important differences. 

P cm 21.8 Show in detail how the enolization mechanism accounts for the following facts (a) the rate constants for acid-catalyzed hydrogen-deuterium exchange and bromination of acetone are identical (b) the rate constants for acid-catalyzed racemization and iodination of phenyl rec- tyl ketone are identical. 

B Reactivity of Enols Mechanism of Alpha-Substitution Reactions... 

In addition to hydroperoxide decomposition and peroxy-radical reduction, manganese-ion catalysts have a pronounced tendency to promote the rapid oxidation of carbonyl-containing intermediates via enol mechanisms [49, 52-56] ... 

The use of manganese-ion catalysis frequently results in increased production of formic acid. This is probably the result of increased rate of production and a decrease in the relative rate of attack on formic acid [57, 58]. Part of the increased production would be the result of an enol mechanism for the oxidation of methyl ketones. For example, the manganese-ion catalyzed oxidation of methyl ethyl ketone (MEK) gives increased amounts of formic and propionic acids at the expense of acetic acid. 

There is evidence that the enol mechanism of manganese-ion catalyzed oxidation of carbonyl compounds is also active to some extent in the oxidation of... 

In the absence of oxygen, these radicals can be trapped by addition to olefins. Co , on the other hand, generates primarily acyl radicals from aldehydes i.e., the cobalt catalyzed reaction does not proceed through the enol mechanism. 

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