Rate of enolization

It is worth noting that quantitative data on the rate of enolization could be obtained by polarimetry measurements since optically active thiazoline-5-ones are now available. 

The mechanism of enolization involves two separate proton transfer steps rather than a one step process m which a proton jumps from carbon to oxygen It is relatively slow m neutral media The rate of enolization is catalyzed by acids as shown by the mechanism m Figure 18 1 In aqueous acid a hydronium ion transfers a proton to the carbonyl oxygen m step 1 and a water molecule acts as a Brpnsted base to remove a proton from the a car bon atom m step 2 The second step is slower than the first The first step involves proton transfer between oxygens and the second is a proton transfer from carbon to oxygen... 

There have been numerous studies of the rates of deprotonation of carbonyl compounds. These data are of interest not only because they define the relationship between thermodynamic and kinetic acidity for these compounds, but also because they are necessary for understanding mechanisms of reactions in which enolates are involved as intermediates. Rates of enolate formation can be measured conveniently by following isotopic exchange using either deuterium or tritium ... 

Rates of enolization can be measured in several wt s. One method involves determining the rate of halogenation of the ketone. In the presence of a sufficient concentration of bromine or iodine, halogenation is much faster than enolu ation or its reverse and can therefore serve to measure the rate of enolization ... 

It is also possible to measme the rate of enolization by isotopic exchange. NMR spectroscopy provides a very convenient method for following hydrogen-deuterium exchange, and this is now the preferred method. Data for several ketones are given in... 

One of the general features of the reactivity of enolate anions is the sensitivity of both the reaction rate and the ratio of C- versus O-alkylation to the degree of aggregation of the enolate. For example, addition of HMPA fiequently increases the rate of enolate alkylation... 

OL Halogenation (Sections 18.2 and 18.3) Halogens react with aldehydes and ketones by substitution an a hydrogen is replaced by a halogen. Reaction occurs by electrophilic attack of the halogen on the carbon-carbon double bond of the enol form of the aldehyde or ketone. An acid catalyst increases the rate of enolization, which is the ratedetermining step. 

Crystalline triose reductone has been shown (56) by titration with strong base and with iodine, to exist in solution, for practical purposes, entirely as the enol form. In addition, the fact that it reduces exactly three molar equivalents of periodate to give quantitative yields of formic acid and of carbon dioxide indicates that it is also oxidized entirely in this form. However, nothing is known of the rate of enolization of tartronic dialdehyde and the possibility therefore remains that part of it may be oxidized in the dialdehydo form. If this were the case, the results of periodate oxidations would be dependent on the ratio of the rate of enolization of tartronic dialdehyde to the rate of its oxidation by periodate, since the oxidation of triose reductone is, again, for practical purposes, instantaneous. 

GL 4] [R 5] [P 5] The rate of the fluorination of y0-keto esters is usually correlated with the enol concentration or the rate of enol formation as this species is actually fluorinated [15, 16]. For the fluorination of ethyl 2-chloroacetoacetate in a micro reactor, much higher yields were found as expected from such relationships and as compared with conventional batch processing which has only low conversion. Obviously, the fluorinated metal surface of the micro channel promotes the enol formation. 

It should be noted that the rate of racemization (or the rate of hydrogen exchange in Section 10.1.1) is exactly the same as the rate of enolization, since the reprotonation reaction is fast. Hence, the rate is typical of a bimolecular process and depends upon two variables, the concentration of carbonyl compound and the concentration of acid (or base). 

A related mechanism can be drawn for acid-catalysed halogenation. Again, the halogen concentration does not figure in the rate equation, and the rate of enolization controls the rate of reaction. 

In acid solution the half-wave potentials for these processes are pH dependent. The overall reaction involves two electrons and is irreversible. Bond cleavage is believed to lead to the enol as shown in Scheme 5.4. Where, as with acetophenone, the ketone product is electroactive at more negative potentials, the wave height for ketone reduction is less than expected and is limited by the rate of enol to ketone tautomerism. This is because the enol is not electroactive. 

In 1989, Rebek and co-workers reported a simple system based on Kemp s triacid that served as a mimic of an enolizing enzyme [86]. This early mimic, however, had the enolizing substrate covalently attached to the triacid skeleton. In addition, the mimic did not possess any oxyanion hole functionalities. However, 2 years later the Rebek group reported a true enolizing catalyst that hosted a carboxylic acid as the oxyanion hole component (Scheme 4.8) [87]. The rate of enolization of the quinuclidone substrate was enhanced by a factor of 10 in the presence of 2.5 mM of the receptor (R = n-Pr). 

Rates of Enolization Reactions. For a better understanding of the transformation and oxidation reactions of reducing sugars, methods have been developed to measure the primary rates of enolization (18). One of these methods depends on the rate at which tritium ions are released from aldoses-2- to the solvent. This is measured by separation of the water-, sublimation, and radiochemical assay of the water as the reaction proceeds. The rate constant is calculated from the first-order equation ... 

Isbell and co-workers have now developed a more convenient method for measuring the primary rate of enolization that does not involve a primary isotope effect (25). The method (Scheme III) uses infrared absorption at 2.95 microns for measuring the amount of DOH formed by enolization of the deuterated sugar in alkaline D20. The rate constant, kH, is calculated from the usual first-order equation ... 

Rates of enolization of 4-oxophenylbutanoic acids, XC6H4COCH2CH2CO2H, have been measured in 75% acetic acid141 at 30 °C. A Hammett p value of —0.78 was found. Ortho substituents significantly enhance the rate H- and 13C-NMR suggest that this is because they twist the benzene ring out of conjugation with the carbonyl. 

Results of a study of electrostatic acceleration of enolization in cationic ketones have implications for enzymatic catalysis of enolization.136 Rate constants determined for water-, acetate- and hydroxide ion-catalysed enolizations of cationic ketones (79) (pK 11.13) and (80) (pK 11.90) have been compared with those for (81). It has been estimated that the inductive effects of the charged lings lower the p/y,s of (81) and (79) by 4.2 and 1.2 log units, respectively, whereas for (79) the electrostatic effect lowers the pAa by 6.3 log units, and enhances oh by 330-fold relative to a typical methyl ketone. The rate of enolization of (81) is enhanced 2.3 x 104-fold by the through-space electrostatic effect. 

Summing up the rates of these competing reaction paths, Equations (5-7), one obtains the total rate of enol ketonization, Equation (8). Note that vK refers exclusively to the forward reaction E —> K. 

The curves for log(kK/s ) and log(kK/s ) of acetophenone are parallel in the range pAT << PH << pAT and the vertical distance between them then equals pAtE = log(kK/s 1) — log /s-1). Most ketones are very weak bases, pAt < 0, so that the parameter does not affect the shape of the pH-rate profiles in the range pH > 1. Base catalysis of ketonization saturates at pH = pAr , while the rate of enolization continues to rise, so that the curves for kE and kK eventually cross at higher pH. At still higher pH, the rate constant kE exceeds that of kK = k o and kobs follows kK. The crossing point, for which kE = kK, lies at pH = pAT = 18.3 for acetophenone (Fig. 3), which is outside the accessible pH range when ionic strength I is limited to 0.1 m, but pA is readily calculated from Equation (2). 

The rates of ketonization are usually easier to determine (by flash photolysis) than the much slower rates of enolization that require laborious conventional methods such as measuring bromination kinetics and analysis of the reaction products. Thus the shape of the profile is conveniently explored by flash photolysis over a wide range of pH for kK, and only a single point on the lower curve is then required to determine the enolization constant Ke-... 

The rate of enolization is increased by heating or by base catalysis. The cis ring fusion in the product is more stable than the trans because there are not enough atoms in the six-membered ring to span trans-1,2 positions in the four-membered ring without excessive strain. 

In ammoniacal solutions of copper salts, the oxidation products are likely to contain nitrogen thus, hexoses give oxalic acid, imidazoles, hydrogen cyanide, and urea. Kinetic studies have been reported for the reaction of Cu(II) in the presence of ammonia with maltose, lactose, melibiose, and cellobiose.190 For the oxidation by tetraamminecopper(II) in ammoniacal and buffered media the rate of reaction is first order in disaccharide concentration, order one-half in ammonia concentration, but it is independent of Cu(II) concentration. The reaction rate is decreased by the addition of ammonium chloride, because of the common ion effect. These kinetics suggested mechanisms involving an intermediate enediolate ion, with the rate of reaction being equal to the rate of enolization.191 A similar mechanism has been proposed for the oxidation of D-fructose by a copper-pyridine complex in an excess of pyridine.192... 

Stoichiometric, irreversible formation of enolates from ketones or aldehydes is usually performed by addition of the carbonyl compound to a cold solution of LDA. Additives and the solvent can strongly influence the rate of enolate formation [23]. The use of organolithium compounds as bases for enolate formation is usually not a good idea, because these reagents will add to ketones quickly, even at low temperatures. Slightly less electrophilic carbonyl compounds, for example some methyl esters [75], can, however, be deprotonated by BuLi if the reactants are mixed at low temperatures (typically -78 °C), at which more metalation than addition is usually observed. A powerful lithiating reagent, which can sometimes be used to deproto-nate ketones at low temperatures, is tBuLi [76],... 

TABLE 2. Dissociation constants (left) of the aggregates (Kaggregate monomer) and rate of enolate with m-chlorobenzyl bromide compared to the enolate pKs (right) for a series of monomeric Li-Enolates (LiEn) in THF measured by UV-visible spectroscopy39lb... 

We have recently discovered at Michigan State University that the well-known photoenolization of ori/zo-alkyl ketones 87) involves two distinct rotamers 88>. The syw-triplet enolizes very rapidly (>109 sec-1), the anti-triplet so slowly ( 107 sec-1) that y-hydrogen abstraction can compete. The rate of enolization of the tfwfr -triplet is apparently determined by the necessary rotation into the syn conformation, since it is independent of substituents on the benzene ring and of the nature of the oriAo-alkyl group. 

Dioxocin 612, in LD30D-D20 underwent fast H/D exchange, but no detectable amount of the epimer 613 was formed during the exchange. Since protonation of the enolate 614 could lead to either of the epimers, the protonation should have been stereoselective by at least 100 times (detection limit <1%). The H/D exchange of 613 was actually very slow, and the solvolysis to give a methyl ester was much faster than the exchange. The rate of enolization of 612... 

The rate of enolate-carbonyl equilibration " is dependent on the forward and backward rates of proton exchange. Proton exchange from a carbon-based acid is known to be slower than that of a more electronegative atom donor (in particular, O and N atoms) . For a series of closely related molecules usually the more acidic a given molecule is, the faster the rate of proton transfer (high kreu note that thermodynamic and kinetic parameters are not related). For example, benzocyclobutanone (10) is less acidic and the rate of deprotonation is substantially slower (10 times) than the related benzocyclopentanone (12) due to its enolate (11) having unfavourable anti-aromatic character. Deprotonation of the simplest cyclobutanone (13) clearly does not lead to an unfavourable anti-aromatic enolate (14) . By assuming the internal strain of 14 is similar to that of 11, cyclobutanone (13) is evidently 10 " times more acidic than benzocyclopentanone (12). By the same vain, the more acidic propanone (15) has a faster rate of deprotonation (10 times) than the less acidic ethyl acetate (16) . ... 

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