Acid-catalysed enolisation

The acid terms of the general rate law are currently interpreted as corresponding to mechanism (10), originally suggested by Pedersen (1934). 

The inverse kinetic solvent isotope effects, corresponding to the replacement of H20 by DjO, strongly supports the two-step mechanism (Reitz, 1937 MacTigue and Sime, 1967 Toullec and Dubois, 1974). For example, the isotope effect kH)0 /kDi0+ = 0.54 0.03 observed for acetone enolisation results from opposite effects on the pre-equilibrium C hId/ hIh = 0.37) and on the rate coefficient of the rate-limiting step (k o/k o = 1.45). 

Plots of the logarithms of the individual catalytic rate coefficients kHAi, as defined in (12), against p/irHA, give linear Bronsted relationships (13) with a 

Data for the primary kinetic isotope effect, corresponding to the replacement of the simple aldehyde or ketone by the fully tr-deuterated compound, are roughly in agreement with transition state models in which the proton is not far from being half-transferred. For example, the value observed [6.5 (Hine et al., 1972) 6.7 (Toullec and Dubois, 1974)] for fully dissociated acid-catalysed enolisation of acetone are close to the theoretical maximum value which can be calculated for half proton transfer. 

Very recently (R. A. Cox et al., 1979), the variations of the enolisation rate coefficient as a function of sulphuric acid concentration (up to 60% w/w) were examined by means of the excess acidity method . According to this, the ratio / (7 = [YH+]/[Y]) between the concentrations of a protonated substrate YH+ and the corresponding free form Y in concentrated acid solutions can be expressed as (15), where [H+] is the acid concentration and X an empirical 

---

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... 

Acid-catalysed hydrogen-deuterium exchange in norcamphor has also been investigated by Werstiuk and Banerjee (1977) (DOAc—D20—DC1 medium). It was observed that exo-deuteron addition to the enol is also preferred, but with a slightly smaller selectivity (x 190). This would mean that, if torsional factors cause preferential base-catalysed exo-exchange, they also occur for acid-catalysed keto-enol tautomerism. However, the absence of important torsional strain effects on the rate constants of acid-catalysed enolisation of cyclic and bicyclic ketones contradicts this assumption. 

Obviously, these results cannot be explained by a very enol-like transition state. This does not mean that enol stability does not affect reactivity, but that it probably does so to a lesser extent than at first expected. Such a conclusion runs counter to the first assertions and to what is usually assumed (see e.g. Lamaty, 1976), but is in agreement with the data cited above concerning Bronsted a-exponents. Indeed, the a-value of 0.74 observed for acid-catalysed enolisation of cyclohexanone (Lienhard and Wang, 1969) corresponds to a relatively early transition state since the Bronsted / for base-promoted proton abstraction from the hydroxycarbenium ion intermediate [see eqn (3)] equals 1 — 0.74, or 0.26. As pointed out above, some data on the stereochemistry of ketonisation were accounted for by assuming an enol-like transition state. Clearly, these interpretations need to be re-examined. 

Kinetic and thermodynamic data for acid-catalysed enolisation of cycloalkanones 104 H0./dm3 mol-1 s-1 AH /kcal mol 1... 

A great number of data on inductive effects in the aliphatic series have been reported. Broadly speaking, results are in agreement with what is expected from the anionic and cationic characters of the transition states an electron-withdrawing substituent increases the rate of the base-promoted ionisation, whereas it retards that of acid-catalysed enolisation. For instance, a bromine atom at the exposition modifies the rate constants of acetate and HCl-catalysed bromination of acetone in water by factors of 4400 and 1/6.5, respectively (R. A. Cox and Warkentin, 1972 Watson and Yates, 1932). 

This can be cyclised in refluxing 62% HBr to an adamantane derivative, the dione 125. The mechanism of this cyclisation is by no means obvious, but with the hint that the alkene 124 is an intermediate and that the stereochemistry of the ester can change by acid-catalysed enolisation, you might see what is going on. 

Fig. 24. Acid-catalysed enolisation of acetone O, carboxylic acids, pyridinium ions and oxonium ion , primary and secondary amines [3].

Enono (32) is synthesised from (34) which we discussed on page 366. After methylation, acid-catalysed opening of the three-memberod ring gives (35) in which the new methyl group (Me ) has equilibrated to the equatorial position by enolisation. 

Current understanding of the reaction suggests that an unprecedented mechanism is operating. Unlike in classical Lewis acid catalysed reactions [28], the metal complex does not activate the carbonyl moiety but is understood to enhance the degree of enolisation and thus create the necessary nucleophilic enol structure for reaction with the fluorinating agent [29]. 

Over the past two decades, intramolecular catalysed enolisation or ionisation of carbonyl compounds, in which a catalytic acidic or basic site is suitably placed to assist the ionisation or the enolisation, has been extensively studied. 

Data for aliphatic aldehyde enolisation are very scarce, probably because the enolisation process is often complicated by oxidation and hydration. Nevertheless, the rate constants for base- and acid-catalysed iodination of R R2CHCHO were determined in aqueous chloroacetic acid-chloroacetate ion buffers (Talvik and Hiidmaa, 1968). The results in Table 4 show that alkyl groups R1 and R2 increase the acid-catalysed reactivity in agreement with hyperconjugative and/or inductive effects. This contrasts with aliphatic ketones for which steric interactions are important and even sometimes dominant. Data for base-catalysis are more difficult to interpret since a second a methyl group, from propionaldehyde to isobutyraldehyde, increases the chloroacetate-catalysed rate constant. This might result from a decrease of the a(C—H) bond-promoted hyperconjugative stabilisation of the carbonyl compound... 

Thioketones (6) can be obtained by the acid-catalysed reaction of ketones with hydrogen sulfide (Scheme 2). The course of the reaction is dependent on the reaction temperature, the nature of the solvent, the concentration of the ketone and the stability of the thioketone (6), especially in relation to enolisation. This appears to be the most generally useful preparative route to thioketones, and many simple aliphatic derivatives are obtained by performing the reaction in ethanol at low temperature (-80°C to -55°C). The gem-dithiol (9) may also be converted into the thioketone (6) by heating it at approximately 200°C in the presence of a basic catalyst (Scheme 2). Reasonably stable thioketones, e.g. aromatic and heterocyclic derivatives like (10) and (11), can be prepared by heating the corresponding ketones with phosphorus pentasulfide in boiling toluene, pyridine or xylene (see Chapter 2, p. 21) (Scheme 3). 

Step of a general acid-catalysed reaction is general base catalysed. There is a simple relationship between values of the Bronsted coefficients a and p for the forward and reverse reactions respectively, and this may be derived using the example of enolisation of acetone (Equation 36). The equilibrium constant for the formation of enolate ion is given by the equation (= so that the Bronsted relationships... 

Kinetic data exist for all these oxidants and some are given in Table 12. The important features are (i) Ce(IV) perchlorate forms 1 1 complexes with ketones with spectroscopically determined formation constants in good agreement with kinetic values (ii) only Co(III) fails to give an appreciable primary kinetic isotope effect (Ir(IV) has yet to be examined in this respect) (/ ) the acidity dependence for Co(III) oxidation is characteristic of the oxidant and iv) in some cases [Co(III) Ce(IV) perchlorate , Mn(III) sulphate ] the rate of disappearance of ketone considerably exceeds the corresponding rate of enolisation however, with Mn(ril) pyrophosphate and Ir(IV) the rates of the two processes are identical and with Ce(IV) sulphate and V(V) the rate of enolisation of ketone exceeds its rate of oxidation. (The opposite has been stated for Ce(IV) sulphate , but this was based on an erroneous value for k(enolisation) for cyclohexanone The oxidation of acetophenone by Mn(III) acetate in acetic acid is a crucial step in the Mn(II)-catalysed autoxidation of this substrate. The rate of autoxidation equals that of enolisation, determined by isotopic exchange , under these conditions, and evidently Mn(III) attacks the enolic form. 

Oxidation of benzoin, PhCH(OH)COPh (above) yields benzil, PhCOCOPh (133), and this, in common with non-enolisable 1,2-diketones in general, undergoes base-catalysed rearrangement to yield the anion of an a-hydroxy acid, benzilate anion, Ph2C(0H)C02e (134). This is, almost certainly, the first molecular rearrangement to be recognised as such. The rate equation is found to be,... 

A clue is in the presence of HBr, which could catalyse the enolisation of the acid bromide. 

These reactions can also be catalysed by acid. Try your hand at enolising acetone in acid solution and then using the enol to attack another molecule of acetone, still in acid. ... 

Enolisation is an example of a reaction which is catalysed both by acids and by bases. Studies in buffered solutions have shown that eqn (3) (Bell, 1959, 1973)... 

Comparison of the overall rate constants (when ionisation occurs along two competitive paths) or of the rate constants (when there is only one enolisation site) with that of a parent unsubstituted methyl ketone, e.g. acetone or acetophenone, shows that an alkyl group usually decreases ketone reactivity under conditions of base catalysis. This is in agreement with a small electron-repelling inductive effect which makes the carbanion ion less stable (e.g. the halogenation rate constant decreases by a factor of 6.5 on going from acetophenone to propiophenone when the reaction is catalysed by acetate ion [acetic acid-water 75 25 at 25°CI (Evans and Gordon, 1938). However, the factor is very small and could be explained by steric effects as well. 

---