Enols protonation

Polar solvents shift the keto enol equilibrium toward the enol form (174b). Thus the NMR spectrum in DMSO of 2-phenyl-A-2-thiazoline-4-one is composed of three main signals +10.7 ppm (enolic proton). 7.7 ppm (aromatic protons), and 6.2 ppm (olefinic proton) associated with the enol form and a small signal associated with less than 10% of the keto form. In acetone, equal amounts of keto and enol forms were found (104). In general, a-methylene protons of keto forms appear at approximately 3.5 to 4.3 ppm as an AB spectra or a singlet (386, 419). A coupling constant, Jab - 15.5 Hz, has been reported for 2-[(S-carboxymethyl)thioimidyl]-A-2-thiazoline-4-one 175 (Scheme 92) (419). This high J b value could be of some help in the discussion on the structure of 178 (p. 423). 

The proton transfer equilibrium that interconverts a carbonyl compound and its enol can be catalyzed by bases as well as by acids Figure 18 3 illustrates the roles of hydroxide ion and water m a base catalyzed enolization As m acid catalyzed enolization protons are transferred sequentially rather than m a single step First (step 1) the base abstracts a proton from the a carbon atom to yield an anion This anion is a resonance stabilized species Its negative charge is shared by the a carbon atom and the carbonyl oxygen... 

The mechanism of [3 + 2] reductive cycloadditions clearly is more complex than other aldehyde/alkyne couplings since additional bonds are formed in the process. The catalytic reductive [3 + 2] cycloaddition process likely proceeds via the intermediacy of metallacycle 29, followed by enolate protonation to afford vinyl nickel species 30, alkenyl addition to the aldehyde to afford nickel alkoxide 31, and reduction of the Ni(II) alkoxide 31 back to the catalytically active Ni(0) species by Et3B (Scheme 23). In an intramolecular case, metallacycle 29 was isolated, fully characterized, and illustrated to undergo [3 + 2] reductive cycloaddition upon exposure to methanol [45]. Related pathways have recently been described involving cobalt-catalyzed reductive cyclo additions of enones and allenes [46], suggesting that this novel mechanism may be general for a variety of metals and substrate combinations. 

Fig. 10 Proposed potential function for the enolic proton in 1,1,1,5,5,5-hexafluoropentane-2,4-dione...

Scheme 2.22 Synthesis of/ -allenic esters 65 by 1,6-cuprate addition to 2-en-4-ynoates 64 and regioselective enolate protonation.

In an asymmetric p-diketone there should be a preference by the enol proton for one of the carbonyls over the other and attempts have been made to determine which it is by C-nmr spectroscopy (Shapet ko et al., 1975 Lazaar and Bauer, 1983). With the additional help of O-nmr spectroscopy it has been possible to demonstrate convincingly that the enol group prefers the carbonyl with a p-group in the following order CF3 > Ph > Bu > Me (Geraldes et al., 1990). 

Reaction of aldehydes and ketones with iminoboranes has been widely investigated. Conditions for the [2 + 2]-cycloaddition between XBNR and R R"CO are relatively good stability of the iminoborane and lack of enolic protons in the oxo compound [Eq. (46)] 14, 19). Relatively less stable iminoboranes, but in some cases the stable ones too, may react with 0X0 compounds by a total opening of the B=N triple bond [Eq. (43)], presumably via a [2 + 2]-cycloaddition [Eq. (42)] (Section V,D). A relatively stable iminoborane and a ketone containing enolic protons may yield an open-chain product, probably through a six-membered cyclic transition state [Eq. (46b)] 19). 

Angular methylation at positions 8a, 9a and 14a has been carried out with the unsaturated keto steroids (16),158,159 (18), (20)160 and (21).161,162 The observed result is due to the presence of the double bond which controls the direction of enolization. Proton abstraction results in the formation of a conjugated dienolate anion which is alkylated from the less hindered side at the most electronegative carbon atom. 

A mole of an organometallic first reacts with the enol proton and a second mole (not necessarily the same reagent) adds exclusively to the carbonyl function, giving (3-hydroxydithioesters in good yields. After protection of the OH group the dithioester function can be used for formation of another carbon-carbon bond, and the starting 0-oxodithioesters can be viewed as a3df or synthetic equivalents [342]. 

Recent developments in enantioselective protonation of enolates and enols have been reviewed, illustrating the reactions utility in asymmetric synthesis of carbonyl compounds with pharmaceutical or other industrial applications.150 Enolate protonation may require use of an auxiliary in stoichiometric amount, but it is typically readily recoverable. In contrast, the chiral reagent is not consumed in protonation of enols, so a catalytic quantity may suffice. Another variant is the protonation of a complex of the enolate and the auxiliary by an achiral proton source. Differentiation of these three possibilities may be difficult, due to reversible proton exchange reactions. 

At pH values near neutral, a pH-independent rate of ketonization is frequently observed, which may be attributed to several different mechanisms (see section Mechanism of the Uncatalyzed Reaction ) carbon protonation of E by water or a concerted transfer of the enol proton to carbon through one or more solvent molecules, and carbon protonation of Ee by the proton, Equation (7). For pH << pAE, the right-hand expression becomes independent of cH . 

A stereoselective enolate protonation has been achieved by changing the counterion of the chiral alkoxide base employed the lithium alkoxide-generated enolate gives close to 90% of the /i-cpimcric ketone product, whereas the use of the potassium cation gives 99% a-epimer.293... 

Alkali metal counterion has been found to control the enolate protonation stereoselectivity.12 This remarkable phenomenon has been reported for lithium and potassium enolates of a norborneol derivative. 

Another example is the 1 1 1 complex of acetylacetone with the host 74 and a water molecule in which again the enol form was observed. In the case of the 2 2 complex of acetylacetone with (R,R)-(—Hra .s-4,5-bis(hydroxydiphcnylmcthyl)-2,2/-dimethyl-l,3-dioxacyclopentane 84 however, a crystal measured at room temperature showed a disordered enolic proton, i.e. the presence of two enol forms. The same complex measured at 100 K revealed the pure enol form for both symmetrically independent molecules of acetylacetone [83], The geometry of the enolic molecules resembled that obtained by gas-phase electron diffraction studies at room temperature [84],... 

NMR spectroscopy indicates that 3-acetyl-6,6-dimethyltetrahydrothiopyran-2,4-dione exists exclusively in a single enolic form 266 as does the derived enamine 267 <2003RJ0235> and a similar situation obtains for 4-acyltetrahydrothiopyran-3,5-diones for which the enolic proton resonates at ca. 618 <2003RJ01772>. 

Sulfhydryl protons usually exchange at a low rate so that at room temperature they are coupled to protons on adjacent carbon atoms (J —8 Hz). They do not exchange rapidly with hydroxyl, carboxylic, or enolic protons on the same or on other molecules thus, separate peaks are seen. However, exchange is rapid... 

This reaction is similar to the attack of an alkene on a halogen, resulting in addition of the halogen across the double bond. The pi bond of an enol is more reactive toward halogens, however, because the carbocation that results is stabilized by resonance with the enol —OH group. Loss of the enol proton converts the intermediate to the product, an a-haloketone. We can stop the acid-catalyzed reaction at the monohalo (or dihalo) product because the halogen-substituted enol intermediate is less stable than the unsubstituted enol. Therefore, under acid-catalyzed conditions, each successive halogenation becomes slower. 

Aldol condensations also take place under acidic conditions. The enol serves as a weak nucleophile to attack an activated (protonated) carbonyl group. As an example, consider the acid-catalyzed aldol condensation of acetaldehyde. The first step is formation of the enol by the acid-catalyzed keto-enol tautomerism, as discussed earlier. The enol attacks the protonated carbonyl of another acetaldehyde molecule. Loss of the enol proton gives the aldol product. 

The enol is stable it is delocalized. We can show the delocalization and explain why vitamin C is called ascorbic acid at the same time. The black enol proton is acidic because the anion is delocalized over the 1,3-dicarbonyl system. 

In the C-C bond-forming step, the same histidine is still there to remove the enol proton again and another histidine, in its protonated form, is placed to donate a proton to the oxygen atom of the ketone. You should see now why histidine, with a P-K h of about 7, is so useful to enzymes it can act either as an acid or as a base. 

The slow keto enol proton transfer means separate signals in the NMR spectrum for the tautomers. The second exchange (ii) is responsible for the line broadening and loss of multiplet structure of the NMR signal of the enol proton. The third type of proton motion, (iii), is not resolvable by NMR so that ways around this have been sought in order to obtain a time-averaged analysis of the proton s location in the cis enol. 

Table 1. Acetylacetone Variation of composition at equilibrium with solvent and the chemical shift of the enol proton, d(OHO)...

Another influence of the solvent on the keto enol equilibrium should be the hydrogen bonding propensity of the solvent itself. Hydrogen bond donors should interact better with the keto tautomer while hydrogen bond acceptors may possibly compete for the enol proton s attentions. The only purely donor solvent is CHC13 and this has slightly less enol than expected for its low e value. The purely acceptor solvents show more enol than expected. 

---