Enolate anions, from amides

Similarly, the amide ion could be used to abstract a proton from a ketone to produce an enolate anion (see Section 10.2) in an essentially irreversible reaction, since the difference in acidities of the ketone and ammonia is so marked. However, if the base chosen were ethoxide, then enolate anion formation would... 

Note that we can write a similar resonance picture for esters, and we shall actually need to invoke this when we discuss enolate anions (see Section 10.7). However, electron donation from oxygen is not as effective as from the less electronegative nitrogen. We shall also see that this resonance effect in amides has other consequences, such as increased acidity of the amide hydrogens (see Section 10.7) and stereochemical aspects of peptides and proteins (see Section 13.3). In addition, the amide derivatives have... 

These compounds ionize and act as sources of hydride and amide ions respectively, which are able to remove a-protons from carbonyl compounds. These ions are actually the conjugate bases of hydrogen and ammonia respectively, compounds that are very weak acids indeed. What becomes important here is that enolate anion formation becomes essentially irreversible the enolate anion formed is insufficiently basic to be able to remove... 

Whereas the pATa for the a-protons of aldehydes and ketones is in the region 17-19, for esters such as ethyl acetate it is about 25. This difference must relate to the presence of the second oxygen in the ester, since resonance stabilization in the enolate anion should be the same. To explain this difference, overlap of the non-carbonyl oxygen lone pair is invoked. Because this introduces charge separation, it is a form of resonance stabilization that can occur only in the neutral ester, not in the enolate anion. It thus stabilizes the neutral ester, reduces carbonyl character, and there is less tendency to lose a proton from the a-carbon to produce the enolate. Note that this is not a new concept we used the same reasoning to explain why amides were not basic like amines (see Section 4.5.4). 

It is important to distinguish tautomerism from resonance, a term used to indicate that the properties of a given molecule cannot be represented by a single valence structure but can be represented as a hybrid of two or more structures in which all the nuclei remain in the same places. Only bonding electrons move to convert one resonance form into another. Examples are the enolate anion, which can be thought of as a hybrid of structures A and B, and the amide linkage, which can be represented by a similar pair of resonance forms. 

Their stability at low temperature means that lithium enolates are usually preferred, but sodium and potassium enolates can also be formed by abstraction of a proton by strong bases. The increased separation of the metal cation from the enolate anion with the larger alkali metals leads to more reactive but less stable enolates. Typical very strong Na and K bases include the hydrides (NaH, KH) or amide anions derived from ammonia (NaNH2, KNH2) or... 

Since most of the synthetically useful enolate anions described in the previous section are prepared by the reactions of enolizable substrates with alkali metal amide bases, it is appropriate to note a few structures of these amide bases. The common bases in synthetic organic chemistry include LDA and LHMDS. The structures of both of these bases are known as the THF solvates.Both of these compounds form bis-solvated dimers corresponding to structure (201). The diethyl ether solvate of LHMDS also forms a bis-solvated dimer (202).Sodium hexamethyldisilazide crystallizes as an unaggregated monomer from benzene solution.Two different cryst line forms of KHMDS are known as the polymeric dioxane solvate (203), ° and the unsolvated dimer (204). ... 

Alkylation or acylation of ketones, sulfides, and amines. This reagent generally reacts with alcohols or carboxylic acids to form 2,2,2-trifluoroethyl ethers or esters in satisfactory yields, except in the case of alcohols prone to dehydration. The reaction of these ethers provides a simple synthesis of unsymmetrical sulfides (equation I). A similar reaction can be used for preparation of secondary amines or amides (equation II). Enolate anions (generated from silyl enol ethers with KF) can be alkylated or acylated with a or b (equation III). Use of Grignard reagents in this type of coupling results in mediocre yields. 

The diacid corresponding to 114 is callosobruchic acid (115), and forms part of the copulation release pheromone of the azuki bean weevil, Callosobruchus chinensis Both chiral isomers have been synthesized by Mori et al. from methyl geranate epoxide (123). After scission of the epoxide group, the iodide 124 was made conventionally, then the chiral group was introduced using the Evans (R)- or (5)-prolinol propionamide enolate anion (125) (made with lithium diethylamide in tetrahydrofuran on the amide). Removal of the proline group... 

When acetone reacts with NaOEt in ethanol to form enolate anion 27, it is a reversible acid-base reaction. Therefore, unreacted ketone or aldehyde always remains in the reaction, and this fact allows self-condensation to occur. Is it possible to choose a base that will generate the enolate anion, but the equilibrium is pushed far to the right (toward the enolate anion product) If such a base is available, self-condensation is much less of a problem, which is particularly important for mixed aldol condensation reactions. As chemists experimented to find such a base, it was discovered that amide bases (RaNr), derived from secondary amines (R2NH) accomplished this goal. 

What does all of this mean The reaction of 2-pentanone with LDA in THF at -78°C constitutes typical kinetic control conditions. Therefore, formation of the kinetic enolate and subsequent reaction with benzaldehyde to give 34 is predictable based on the kinetic versus thermodynamic control arguments. In various experiments, the reaction with an unsymmetrical ketone under what are termed thermodynamic conditions leads to products derived from the more substituted (thermodynamic) enolate anion. Thermodynamic control conditions typically use a base such as sodium methoxide or sodium amide in an alcohol solvent at reflux. The yields of this reaction are not always good, as when 2-butanone (37) reacts with NaOEt in ethanol for 1 day. Self-condensation at the more substituted carbon occurs to give the dehydrated aldol product 38 in 14% yield. Note that the second step uses aqueous acid and, under these conditions, elimination of water occurs. 

Both processes provide an experimentally simple means for the introduction of a C2 or C3 fragment. However, they still require reaction temperatures of 140-200 °C and suffer from the restricted availability of orthoesters and amide acetals, respectively. A more general solution is offered by the methodology developed by Ireland et al. [9]. Deprotonation of an allyl ester 8 and immediate 0-silylation of the enolate 9 furnishes a silyl ketene acetal 10, which is less prone to undergo unwanted side reactions, as compared to the enolate anion itself,but which still rearranges easily to the silyl ester 11 at temperatures often below 60 °C (Scheme 3). 

Fig. 15 The IRMPD spectrum (solid black lines) of the Ci anion from AlaPhe compared to the computed IR spectra (blue dotted lines) for putative structures deprotonated at (a) the C-terminal amide, (b) the a-carbon, (c) the N-terminus, and (d) the C-terminal amide with enol-imine tautomerization. Reprinted from Grzetic and Oomens [37], Copyright 2012, with permission from Elsevier...

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