Proton transfer enol formation

The slow step m base catalyzed enolization is formation of the enolate ion The second step proton transfer from water to the enolate oxygen is very fast as are almost all proton transfers from one oxygen atom to another... 

Figure 12.11. Enolate formation and protonation in chain transfer...

The first step of the reaction path involves the addition of H2O2 to the Fe " resting state to form an iron-oxo derivative known as Compound I, which is formally two oxidation equivalents above the Fe state (Fig. 2). The well studied Compound I contains a Fe" = 0 structure and a n cation radical. In the second step. Compound I is reduced to Compound II with a Fe =0 structure. The reduction of the n cation radical by a phenol or enol is accompanied by an electron transfer to Compound I and a proton transfer to a distal basic group (B), probably His 42 (Fig. 3, step 1). The native state is regenerated on one-electron reduction of Compound II by a phenol or an enol. In this process, electron and proton transfers occur to the ferryl group with simultaneous reduction of Fe" to Fe (Fig. 3, steps 2-3) and formation of water as the leaving group (Fig. 3, step 4). 

OTHER EXAMPLES OF KINETIC ISOTOPE EFFECTS. The power of kinetic isotope effects in enzymol-ogy is well illustrated in the work of Rose ° and Knowles deahng with hydrogen effects in proton transfer to and from carbon. Abstraction of a proton from a tetrahedral carbon is a fundamental step in many enzyme-catalyzed reactions. Intramolecular proton transfer as well as partial loss (wash-out) migrating protons have provided important clues in mechanistic investigations. Enol and enediolate formation constitute several... 

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]. 

A crossed Claisen is die reaction of an ester enolate with an aldehyde or ketone to produce a /3-hydroxy ester. This works well because aldehydes and ketones are more reactive electrophiles than esters thus the ester enolate reacts faster with die aldehyde or ketone than it condenses with itself, avoiding product mixtures. Moreover, die aldehyde or ketone should not have a hydrogens so that proton transfer to die more basic ester enolate is avoided. This would lead to the formation of an aldehyde or ketone enolate in the mixture, and an aldol reaction would be a major competing reaction. 

The final proton transfer will be extremely fast, so the rate of formation of product is effectively shown in Equation 4.16, i.e. the rate of the addition of the enolate anion to another molecule of aldehyde ... 

The Morita-Baylis-Hillman (MBH) reaction is the formation of a-methylene-/ -hydroxycarbonyl compounds X by addition of aldehydes IX to a,/ -unsaturated carbonyl compounds VIII, for example vinyl ketones, acrylonitriles or acrylic esters (Scheme 6.58) [143-148]. For the reaction to occur the presence of catalytically active nucleophiles ( Nu , Scheme 6.58) is required. It is now commonly accepted that the MBH reaction is initiated by addition of the catalytically active nucleophile to the enone/enoate VIII. The resulting enolate adds to the aldehyde IX, establishing the new stereogenic center at the aldehydic carbonyl carbon atom. Formation of the product X is completed by proton transfer from the a-position of the carbonyl moiety to the alcoholate oxygen atom with concomitant elimination of the nucleophile. Thus Nu is available for the next catalytic cycle. 

A. C. Amyes, T. L. Formation and stability of enolates of acetamide and acetate anion an Eigen plot for proton transfer at y-carbonyl carbon./. Am. Chem. Soc. 2002, 124, 2957— 2968. 

On the other hand, in view of important analogies in kinetic behaviour between enol ketonisation and enol ether hydrolysis, the HA [HA,] terms cannot correspond to a concerted mechanism. Lienhard and Wang (1969) and this author (Dubois and Toullec, 1969b Toullec and Dubois, 1974) have pointed out that the rate-limiting step of enol ketonisation is closely similar to that of enol ether hydrolysis if the two-step mechanism for acid-catalysed enolisation is valid. The two reactions occur by rate-limiting proton transfer to the double bond with formation of either a hydroxycarbenium ion (19) or an alkoxycarbenium ion (20). However, in the latter reaction, in contrast to the... 

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. 

Kinetic enolate formation must occur at the methyl group of the ketohe followed by acylation with the lactone. Lactones are rather more electrophilic than noncyclic esters, but the control in this sequence is still remarkable, Notice how a stable enolate is formed by proton transfer within the first-fofmed product. 

The mechanistic proposal for the formation of these p-laclonc products is related to that for the formation of y-lactones (Scheme 17). Initial formation of the conjugate enamine Ila is followed by a proton transfer from oxygen to carbon thereby forming the enolate V. In an aldol-type reaction this enolate attacks the electrophilic ketone providing zwitte-rions VI. The subsequent cyclization to the lac tone 18 then liberates the NHC catalyst. 

Prior to 2001, when the first serious computational approaches to the problem appeared in print, four mechanistic proposals had been offered for understanding the Hajos-Parrish-Wiechert-Eder-Sauer reaction (Scheme 6.8). Hajos and Parrish proposed the first two mechanisms Mechanisms A and B. Mechanism A is a nucleophilic substitution reaction where the terminal enol attacks the carbinolamine center, displacing proUne. The other three mechanisms start from an enamine intermediate. Mechanism B invokes an enaminium intermediate, which undergoes C-C formation with proton transfer from the aminium group. Mechanism C, proposed by Agamii to account for the nonlinear proline result, has the proton transfer assisted by the second proline molecule. Lastly, Mechanism D, proffered by Jung, proposed that the proton transfer that accompanies C-C bond formation is facilitated by the carboxylic acid group of proline. 

The second mechanism. Reaction 6.32, proposes that water acts as a base to create acetone enolate anion. This enolate next adds to acetaldehyde through a TS that is 49.1 kcal mol above reactants. The final aldol product is obtained by proton transfer. While this mechanism require less energy than the first of Houk s mechanisms, it too is unlikely to be competitive, given its large barrier for formation of the acetone enolate. 

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