Real Enolates

Common reagents such as lithium diisopropylamide (LDA see Chapter 11, Problem 5) react with carbonyl compounds to yield lithium enolate salts and diisopropylamine, e.g., for reaction with cyclohexanone. 

Enolate chemistry is often the chemistry of the enolate salts. 

Compare the geometries of the cyclohexanone enolate and the cyclohexanone lithium enolate. Do both molecules show delocalized structures, or is the bonding in one of them more localized For comparison, examine the geometries of 1-hydroxycyclohexene md cyclohexanone. 

Compare atomic charges for the enolate anion and the lithium salt. Are there major differences, in particular, for the oxygen and the a carbon Also compare the highest-occupied molecular orbital (HOMO) in the two molecules. This identifies the most nucleophilic sites, that is, the most likely sites for attack by electrophiles. Are the two orbitals similar or do they differ substantially Elaborate. 

Do changes in geometries, charges and size and shape of the HOMO between the enolate anion and its lithium salt suggest differences in reactivities If so, what differences are to be expected  

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In spite of the fact that the only a-protons with respect to the carbonyl group in the tricyclic y-keto esters 231 are at bridgehead positions and thus no real enolates can be formed [118], compounds 231 with R = OR could easily and selectively be deprotonated at C-7, and the resulting lithium derivative then substituted with various electrophiles (Scheme 66). 

It IS important to recognize that an enol is a real substance capable of mdepen dent existence An enol is not a resonance form of a carbonyl compound the two are constitutional isomers of each other... 

In the first step an S03 molecule is inserted into the ester binding and a mixed anhydride of the sulfuric acid (I) is formed. The anhydride is in a very fast equilibrium with its cyclic enol form (II), whose double bonding is attacked by a second molecule of sulfur trioxide in a fast electrophilic addition (III and IV). In the second slower step, the a-sulfonated anhydride is rearranged into the ester sulfonate and releases one molecule of S03, which in turn sulfonates a new molecule of the fatty acid ester. The real sulfonation agent of the acid ester is not the sulfur trioxide but the initially formed sulfonated anhydride. In their detailed analysis of the different steps and intermediates of the sulfonation reaction, Schmid et al. showed that the mechanism presented by Smith and Stirton [31] is the correct one. 

Alternatively one can make use of No Barrier Theory (NBT), which allows calculation of the free energy of activation for such reactions with no need for an empirical intrinsic barrier. This approach treats a real chemical reaction as a result of several simple processes for each of which the energy would be a quadratic function of a suitable reaction coordinate. This allows interpolation of the reaction hypersurface a search for the lowest saddle point gives the free energy of activation. This method has been applied to enolate formation, ketene hydration, carbonyl hydration, decarboxylation, and the addition of water to carbocations. ... 

Anionic domino processes are the most often encountered domino reactions in the chemical literature. The well-known Robinson annulation, double Michael reaction, Pictet-Spengler cyclization, reductive amination, etc., all fall into this category. The primary step in this process is the attack of either an anion (e. g., a carban-ion, an enolate, or an alkoxide) or a pseudo anion as an uncharged nucleophile (e. g., an amine, or an alcohol) onto an electrophilic center. A bond formation takes place with the creation of a new real or pseudo-anionic functionality, which can undergo further transformations. The sequence can then be terminated either by the addition of a proton or by the elimination of an X group. 

Nor can there be any question of real tautomerism in the case of phenol. In its chemical properties phenol resembles the aliphatic enols in all respects. We need only recall the agreement in the acid character, the production of colour with ferric chloride, and the reactions with halogens, nitrous acid, and aromatic diazo-compounds (coupling), caused by the activity of the double bond and proceeding in the same way in phenols and aliphatic enols. The enol nature of phenol provides valuable support for the conception of the constitution of benzene as expressed in the Kekule-Thiele formula, since it is an expression of the tendency of the ring to maintain the aromatic state of lowest energy. In this connexion the hypothetical keto-form of phenol (A)—not yet obtained—would be of interest in comparison with... 

No real clinical advantage over less expensive agents (e.g., albuterol, metaproter-enol)... 

It should be emphasized that, in many cases, these equations are oversimplified. In many of the reported examples, the produced enolate is used in situ, and its real structure and nature of the counterion (Mg or Li) are obscured. 

Having got the idea, you might not want to be bothered with the rehydration step as it is easy to see the hidden carbonyl group where the alkene is and the half of the molecule with the carbonyl group must be the enolate in real life. Most people just disconnect the alkene and write... 

The problem of unnatural polarity also arises in making C-C disconnections for the synthesis of 1,4-difunctionalised compounds. If we start with 1,4-diketones 1, disconnection in the middle of the molecule gives a synthon with natural polarity 2, represented in real life by an enolate 4, and one of unnatural polarity, the a2 synthon 3 represented by some reagent of the kind we met in chapter 6 such as an a-haloketone 5. 

This section will give an outline of catalytic organic transformations where lanthanide alkoxides are, in particular, used as precatalysts. It must be assumed that other precatalysts underlie in situ formation of catalytically active Ln-O(alkoxide) moieties [229]. For example, in reactions involving ketones or aldehydes as substrates, enolate intermediates often act as the real active catalyst component. Many reactions are conducted in alcoholic solutions like MeOH or tBuOH or ethylene glycol [5]. Alcohols are often needed as proton source and their steric bulk can influence the product selectivities [230]. 

It is important that you appreciate one key difference between the enolate and enol forms the enolate is a delocalized system, with negative charge carried on both C and 0—we use a double-headed conjugation arrow to connect these two representations, But for the proton to move from C to 0 in the enol form requires o bonds to break and form, and this is a real equilibrium, which must be represented by equilibrium arrows. 

A real example comes in the acylation (Chapter 28) of the enolate from the keto-acetal above and alongside. The molecule is folded downwards and the enolate is essentially planar. Addition presumably occurs entirely from the outside, though the final stereochemistry of the product is controlled thermodynamically because of reversible cnolization of the product whatever the explanation, the black ester group prefers the outside. 

In earlier chapters we revealed how some reactive intermediates can be prepared, usually under special conditions rather different from those of the reaction under study, as a reassurance that some of these unlikely looking species can have real existence. Intermediates of this kind include the carboca-tion in the S l reaction (Chapter 17), the cations and anions in electrophilic (Chapter 22) and nucleophilic (Chapter 23) aromatic substitutions, and the enols and enolates in various reactions of carbonyl compounds (Chapters 21 and 26-29). We have also used labelling in this chapter to show that symmetrical intermediates are probably involved in, for example, nucleophilic aromatic substitution with a benzyne intermediate (Chapter 23). 

In the gas phase the free energy of protonation of A,N-dimethylvinylamine (equation 48) is — 220.0 kcal mol-1 64. As discussed in Section II.A.4, protonation occurs at Cp, as shown506 112,113. The free energies of protonation of methyl vinyl ether and methyl vinyl sulfide are —198.8 and —198.6 kcal mol-1, respectively these substances also are protonated at C/14. Far more basic than any of these is the enolate of acetaldehyde (vinyloxide-) for which C-protonation is accompanied by AG°(g) = —359 kcal mol-1 115. Thus, the gas-phase reactivity order is enolates > enamines en-olethers enols vinyl sulfides. (For the present purpose, we ignore the real, but smaller, differences in reactivity between enols, their ethers and vinyl sulfides.)... 

The most striking effect among the TSs listed in Table 15 was the destabilization imparted by the enolate Z-methyl group of the boat 163 (4.5 kcalmoG ) compared to the corresponding chair 162 arrangement. Like in the aldol reaction, this fact was clearly due to the interaction between the Z-methyl group and the substituent at the B heteroatom in the boat TS, and it is likely to increase in real cases where the substituent at B is not H but... 

In general, ketones are predicted to metalate via the open dimer pathway whereas imine metallations proceed more readily via monomers. By contrast, increased steric demands of the substrates promote the monomer pathways. It is reasonable to ascribe this to a decrease in congestion in monomers relative to open dimers. Indeed, for metalla-tion of imine 2 with LDA in THF (4 must be a real species) the rate behavior was consistent with the mechanism specified by M-1. When 2 2 TMEDA-LDA complex 1 was used for deprotonation of 3, a solvent-free open dimer proved to be a plausible reactive intermediate (Sch. 5) [28]. Accordingly, the rate of imine metalation depends strongly on the solvent and substrate used [29]. Kinetic evidence obtained in the enolization experiment with sterically demanding ester 5 showed disolvated LDA monomers to be the reactive form, providing the first direct support for Ireland s hypothesis of cyclic transition state... 

Enol siiyl ethers undergo Pd-catalyzed coupling with aromatic bromides in the presence of tributyltin fluoride, which converts the enol silyl ethers into the stannyl ethers or a-stannyl ketones regarded as real active species chemoselective a-arylation of terminal ketones is possible (equation 110). ... 

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