Enolate salts, carbonation

The Reformatsky reaction has been applied to the synthesis of fused pyranones and provides an example of selective isomer formation by careful choice of substrate. Hydroxy-methylenecyclohexanone (315) and methyl bromoacetate give 5,6,7,8-tetrahydro-l-benzopyran-2-one (316) through alkylation at the hydroxymethylene carbon atom (54JA6388). However, the benzoyl derivative (317) is unable to form an enolate salt and alkylation occurs at the carbonyl carbon atom, leading to 5,6,7,8-tetrahydro-2-benzopyran-3-one (318) (45HCA771). 

Furthermore, if the carbonyl compound has a hydrogen located on the carbon next to the carbonyl group, the Grignarji reagent can behave as a base and remove this hydrogen as a proton. The result is that the compound becomes an enolate salt and RMgX becomes RH. 

The Kolbe-Schmitt reaction is related to enzymatic carboxylations as of D-ribulose 1,5-diphosphate with carbon dioxide, a key step in photosynthesis (Section 20-9). The overall result is C—C bond formation by addition of C02 to an enolate salt or its enamine equivalent. 

HSAB is particularly useful for assessing the reactivity of ambident nucleophiles or electrophiles, and numerous examples of chemoselective reactions given throughout this book can be explained with the HSAB principle. Hard electrophiles, for example alkyl triflates, alkyl sulfates, trialkyloxonium salts, electron-poor car-benes, or the intermediate alkoxyphosphonium salts formed from alcohols during the Mitsunobu reaction, tend to alkylate ambident nucleophiles at the hardest atom. Amides, enolates, or phenolates, for example, will often be alkylated at oxygen by hard electrophiles whereas softer electrophiles, such as alkyl iodides or electron-poor alkenes, will preferentially attack amides at nitrogen and enolates at carbon. 

Why the thienyl- and furyllithium compounds attack the iodine atom instead of the p-carbon atom of alkynyliodonium ions is not entirely clear. However, they are much harder nucleophiles than the enolate salts of /Ldicarbonyl compounds and might prefer the harder iodonium center3. The much higher basicity of the heteroaryllithium reagents might also facilitate the formation of iodate ions and the displacement of alkynyllithiums from such intermediates. 

The enolate salts of simple ketones react with aryllead reagents, but the reaction is of little practical value. Indeed, only trisubstituted a-carbon atoms are reactive. The case of the potassium enolate of cyclohexanone derivatives is significant no reaction with cyclohexanone enolate (78), 36% with the mixture of enolates of 2-methylcyclohexanone (79), and 75% in the case of 2,6-dimethyl cyclohexanone enolate (80). ... 

Diisopropylamine has a pK of about 36, showing that it is much less acidic than a typical ketone or aldehyde. By virtue of its two isopropyl groups, LDA is a bulky reagent. It does not easily attack a carbon atom or add to a carbonyl group. Thus, it is a powerful base, but not a strong nucleophile. When LDA reacts with a ketone, it abstracts the a proton to form the lithium salt of the enolate. We will see that these lithium enolate salts are very useful in synthesis. 

A new synthesis of aldehydes with 2-methyl-2-thiazoline has the advantage of releasing the aldehydes from the thiazolidine intermediate under neutral conditions . Acetylene derivatives can be obtained from aldehydes via dibromomethylene compounds Novel reactions of alkynes with cationoid electrophiles have been published. -Diketones and 2-ketoalkoximes can be obtained by this reaction from acid chlorides and aliphatic nitro compounds respectively Addition of aldehydes to activated carbon-carbon double bonds occurs smoothly in the presence of cyanide ions as catalysts . Poly- -carbonyl compounds have been prepared by condensation of two anions, whereby the enolate salt of a y8-keto ester condenses as an electrophilic anion with strong nucleophiles such as the dianion of benzoylacetone. ... 

Alkylation of enamines with epoxides or acetoxybromoalkanes provided intermediates for cyclic enol ethers (668) and branched chain sugars were obtained by enamine alkylation (669). Sodium enolates of vinylogous amides underwent carbon and nitrogen methylation (570), while vicinal endiamines formed bis-quaternary amonium salts (647). Reactions of enamines with a cyclopropenyl cation gave alkylated imonium products (57/), and 2-benzylidene-3-methylbenzothiazoline was shown to undergo enamine alkylation and acylation (572). A cyclic enamine was alkylated with methylbromoacetate and the product reduced with sodium borohydride to the key intermediate in a synthesis of the quebrachamine skeleton (57i). 

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. 

The proposed intramolecular solvation is not the only feature differentiating between the polystyryl and polymethyl methacrylate salts. The former are classified as the salts of carbanions, whereas the latter are ambident salts having the character of allylic enolates with the cation interacting with the partially negatively charged carbon and oxygen atoms. The degree to which the one or the other interaction is favored is affected by the size of the cation. 

In the presence of a strong base, the ot carbon of a carboxylic ester can condense with the carbonyl carbon of an aldehyde or ketone to give a P-hydroxy ester, which may or may not be dehydrated to the a,P-unsaturated ester. This reaction is sometimes called the Claisen reaction,an unfortunate usage since that name is more firmly connected to 10-118. In a modem example of how the reaction is used, addition of tert-butyl acetate to LDA in hexane at -78°C gives the lithium salt of ferf-butyl acetate, " (12-21) an enolate anion. Subsequent reaction a ketone provides a simple rapid alternative to the Reformatsky reaction (16-31) as a means of preparing P-hydroxy erf-butyl esters. It is also possible for the a carbon of an aldehyde or ketone to add to the carbonyl carbon of a carboxylic ester, but this is a different reaction (10-119) involving nucleophilic substitution and not addition to a C=0 bond. It can, however, be a side reaction if the aldehyde or ketone has an a hydrogen. 

In contrast, the acid-catalyzed hydration of arylbenzoylacetylenes differs markedly from the hydration of a-unsaturated ketones. Hydration of unsaturated ketones has been shown to proceed via a 1,4-addition mechanism where protonation occurs on oxygen to give an oxonium salt, followed by attack of water at the 0-carbon to give a hydroxy enol. The rate-limiting step has been shown to be the protonation of the hydroxy enol (27) ... 

Besides the allylation reactions, imines can also undergo enol silyl ether addition as with carbonyl compounds. Carbon-carbon bond formation involving the addition of resonance-stabilized nucleophiles such as enols and enolates or enol ethers to iminium salt or imine can be referred to as a Mannich reaction, and this is one of the most important classes of reactions in organic synthesis.104... 

Whilst azo compounds prepared from diazonium salts and phenolic or keto-enol coupling components are often depicted in the hydroxyazo form (4.11), an alternative tautomeric structure can be drawn for such compounds (Scheme 4.19). This ketohydrazone tautomer (4.21) can, in cases where the azo and hydroxy groups are located on adjacent carbon atoms, exhibit hydrogen bonding between the two groups as shown. Similar pairs of structures, but without hydrogen bonding, can be drawn for p-hydroxyazo compounds. 

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