Ketone deprotonation

Despite a very unfavorable proton transfer using (35) as an EGB, condensation of acetophenone with an aromatic aldehyde took place within a matter of hours. The reaction led to Q , 8-unsaturated ketones, which underwent the Michael addition with a second equivalent of deprotonated ketone. Scheme 30, [80, 81]. The EGB was generated ex situ. 

The para positions of A,A-dimethylanihne, diphenylamine, phenol, and anisole are electron-rich and accordingly attack 2-alkylthio-l,3-dithiolium cations at C-2, yielding various 2-aryl-1,3-dithiolium cations. A similar reaction occurs with 2,6-bis(/er/-butyl)phenol and with 2-naphthol, and by subsequent deprotonation ketones such as 174 and 175 are obtained. ... 

Enolsilylation Magnesium hexamethyldisilazide, which is prepared electro-chemically with a Mg anode, deprotonates ketones. An ensuing silylation delivers the silyl enol ethers. 

EnoUzation. Phenylmanganese chloride deprotonates ketones in the presence of a catalytic amount of an amine. Quenching with an anhydride gives enol esters. 

A summary of the outcomes observed when various bases are used to deprotonate ketones or 1,3-diketones. 

Figure 4.94 C-Tritiomethylation of a-deprotonated ketones and esters at high specific activities...

Ketones, in which one alkyl group R is sterically demanding, only give the trans-enolate on deprotonation with LDA at —12°C (W.A. Kleschick, 1977, see p. 60f.). Ketones also enolize regioseiectively towards the less substituted carbon, and stereoselectively to the trans-enolate, if the enolates are formed by a bulky base and trapped with dialkyl boron triflates, R2BOSO2CF3, at low temperatures (D A. Evans, 1979). Both types of trans-enolates can be applied in stereoselective aldol reactions (see p. 60f.). 

The high nucleophilicity of sulfur atoms is preserved, even if it is bound to electron withdrawing carbonyl groups. Thiocarboxylales, for example, substitute bromine, e.g. of a-bromo ketones. In the presence of bases the or-acylthio ketones deprotonate and rearrange to episulfides. After desulfurization with triphenylphosphine, 1,3-diketones are formed in good yield. Thiolactams react in the same way, and A. Eschenmoser (1970) has used this sequence in his vitamin B]2 synthesis (p. 261). 

The cationic intermediate is simply the protonated form (conjugate acid) of the a halo ketone Deprotonation of the cationic intermediate gives the products... 

In general the equilibrium represented by the sum of steps 1 to 3 is unfavorable (Two ester carbonyl groups are more stable than one ester plus one ketone carbonyl) However because the p keto ester is deprotonated under the reaction conditions the equilibrium represented by the sum of steps 1 to 4 does he to the side of products On subsequent acidification (step 5) the anion of the p keto ester is converted to its neutral form and isolated... 

Section 21 10 It is possible to generate ester enolates by deprotonation provided that the base used is very strong Lithium diisopropylamide (LDA) is often used for this purpose It also converts ketones quantitatively to their enolates... 

The dianions derived from furan- and thiophene-carboxylic acids by deprotonation with LDA have been reacted with various electrophiles (Scheme 64). The oxygen dianions reacted efficiently with aldehydes and ketones but not so efficiently with alkyl halides or epoxides. The sulfur dianions reacted with allyl bromide, a reaction which failed in the case of the dianions derived from furancarboxylic acids, and are therefore judged to be the softer nucleophiles (81JCS(Pl)1125,80TL505l). 

The tautomeric 2-hydroxypyrroles undergo base-catalyzed reactions probably through deprotonation to the ambident conjugate base (Scheme 71). 2-Hydroxyfurans (e.g. 178) similarly exist in ketonic forms (179) and (180), the most favoured tautomer being the conjugated 2(5//)-furanone (180)... 

Another technique is to measure the rate of halogenation of the carbonyl compound. Ketones and aldehydes in their carbonyl forms do not react rapidly with the halogens, but the enolate is rapidly attacked. The rate of halogenation is therefore a measure of the rate of deprotonation. 

Structural effects on the rates of deprotonation of ketones have also been studied using veiy strong bases under conditions where complete conversion to the enolate occurs. In solvents such as THF or DME, bases such as lithium di-/-propylamide (LDA) and potassium hexamethyldisilylamide (KHMDS) give solutions of the enolates in relative proportions that reflect the relative rates of removal of the different protons in the carbonyl compound (kinetic control). The least hindered proton is removed most rapidly under these... 

A number of studies of the acid-catalyzed mechanism of enolization have been done. The case of cyclohexanone is illustrative. The reaction is catalyzed by various carboxylic acids and substituted ammonium ions. The effectiveness of these proton donors as catalysts correlates with their pK values. When plotted according to the Bronsted catalysis law (Section 4.8), the value of the slope a is 0.74. When deuterium or tritium is introduced in the a position, there is a marked decrease in the rate of acid-catalyzed enolization h/ d 5. This kinetic isotope effect indicates that the C—H bond cleavage is part of the rate-determining step. The generally accepted mechanism for acid-catalyzed enolization pictures the rate-determining step as deprotonation of the protonated ketone ... 

Solutions of unstable enols of simple ketones and aldehydes can also be generated in water by addition of a solution of the enolate to water. The initial protonation takes place on oxygen, generating the enol, which is then ketonized at a rate that depends on the solution pH. The ketonization exhibits both acid and base catalysis. Acid catalysis involves C-protonation with concerted 0-deprotonation. 

Fluorinatedytides have also been added tofluoroalkylketones however, this olefination procedure may be accompanied by considerable side reactions resulting from deprotonation of the fluoroalkyl ketones In most cases, the yields are not better than 30% [39]... 

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