Enols and Enamines

Such slow rotation, coupled with a large preference for proton transfer to the carbon from the side flanked by the two oxygen atoms, accounts for the observed retention of configuration. Similar exchange experiments with 2-octyl phenyl sulfoxide indicate that the sulfinyl group has much less of an effect on the stereochemistry of an adjacent carbanion site, since ke/k —2.  

The study of the chemistry of carbonyl compounds has shown that they can act as carbon nucleophiles in the presence of acid catalysts as well as with bases. The nucleophilic reactivity of carbonyl compounds in acidic solution is due to the presence of the enol tautomer  

Enolization in acidic solution is catalyzed by O-protonation. Subsequent deprotonation at carbon gives the enol  

Like simple alkenes, enols are nucleophilic by virtue of their 7r-electrons. Enols are 

Fundamentals of Carbanion Chemistry, Academic Press, New York, 1965, pp. 85-105. 

In the absence of the carbonyl or similar stabilizing group, the onium salts are less acidic. The pA d sq of methyltriphenylphosphonium ion is estimated to be 22. Strong bases such as amide ion or the anion of DMSO are required to deprotonate alkylphos-phonium salts. 

Similar considerations apply to the sulfoxonium and sulfonium ylides, which are formed by deprotonation of the corresponding positively charged sulfur-containing cations. The additional electronegative oxygen atom in the sulfoxonium salts stabilizes these ylides considerably, relative to the sulfonium ylides.  

Carbonyl compounds can act as carbon nucleophiles in the presence of acid catalysts, as well as bases. The nucleophilic reactivity of carbonyl compounds in acidic solution is due to the presence of the enol tautomer. The equilibrium between carbonyl compounds and the corresponding enol can be acid- or base-catalyzed and can also occur by a concerted mechanism in which there is concurrent protonation and deprotonation. As we will see shortly, the equilibrium constant is quite small for monocarbonyl compounds, but the presence of the enol form permits reactions that do not occur from the carbonyl form. 

Like simple alkenes, ends are nucleophilic by virtue of their tt electrons. Enols are much more reactive than simple alkenes, however, because the hydroxy group participates as an electron donor during the reaction process. The oxygen is deprotonated and the strong C=0 bond is formed, providing a favorable energy contribution. 

Enols are not as reactive as enolate anions, however. This lower reactivity reflects the presence of the additional proton in the enol, which decreases the electron density of the enol relative to the enolate. In MO terminology, the —OH and —O donor substituents both raise the energy of the tt-HOMO, but the O group is the better donor. 

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 

Rates of enolization have usually been measured in one of two ways. One method involves measuring the rate of halogenation of the ketone. In the presence of a sufficient concentration of bromine or iodine, halogenation is much faster than enolization or its reverse and can therefore serve to measure the rate of enolization. 

The stability of the resulting neutral species is increased by substituent groups that can help to stabilize the electron-rich carbon. Phosphonium ions with acyhnethyl substituents, for example, are quite acidic. A series of aroyhnethyl phosphonimn ions have values of 4-7, with the precise value depending on the aryl substituents  

Similar considerations apply to the sulfonium and sulfoxonium ylides. These ylides are formed by deprotonation of the corresponding positively charged sulfur-containing 

The additional electronegative oxygen atom in the sulfoxonium salts stabilizes these yhdes considerably, relative to the sulfonium yhdes.  

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In addition to preparation of arylhydrazones from the carbonyl compounds and an arylhydrazine, the Japp-Klingemann reaction of arenediazonium ions with enolates and enamines is an important method for preparation of arylhydrazones. This method provides a route to monoarylhydrazones of a-dicarbonyl compounds from /3-keto acids and to the hydrazones of pyruvate esters from / -keto esters. Enamines also give rise to monoarylhydrazones of a-diketones. Indolization of these arylhydrazones provides the expected 2-acyI-or 2-alkoxycarbonyl-indoles (equations 95-97). 

Enzymologists have freely proposed enolate anions, enols, and enamines as intermediates for many years. Such intermediates have been demonstrated for some nonenzymatic acid- or base-catalyzed reactions, but how can enzymes form enolates at pH 7 without the use of strong acids or bases The microscopic pRa value of an a-hydrogen in a ketone or aldehyde is about 17-20.72 98"... 

A few other reactions were omitted because they did not fit into the current presentation (nitrile and alkyne chemistry, cyanohydrin formation, reductive amination, Mannich reaction, enol and enamine reactions). 

Arylation is possible by the addition of triplet aryl cations to neutral nucleophiles such as alkenes, alkynes, enols, and enamines (photo SN1 mechanism). For alkenes, the... 

It is of great interest to compare this last value with the keto-enol equilibrium constant obtained similarly for acetone = 0.35 x 10-8). Indeed, in many enzyme-catalysed reactions, aldolisation for example, enamine formation is not rate-limiting, and the rate is usually controlled by subsequent electrophilic additions. Consequently, the rate depends on enamine reactivity and on the enamine concentration at equilibrium. Therefore, if one wants to compare the two processes, via enol and via enamine, in order to explain why the enamine route is usually preferred, the difference in equilibrium constants for enol and enamine formation must be taken into account. Data on ketone to enol and ketone to enamine equilibrium constants show that the enamine and enol concentrations are of similar magnitude even for relatively small concentrations of primary amine. Thereafter, since the enamine is much more reactive than the enol for reactions with electrophilic reagents (in a ratio of 4-6 powers of ten for proton addition), it can be easily understood why the amine-catalysed pathway is energetically more favourable. 

Gilbert stark was bom in Brussels and became an assistant professor of chemistry at Harvard In 1948. Since 1953, Stork has been at Columbia University In New York. Sfnce the 1950s, he has pioneered new synthetic methods, among them many involving. enolates and enamines. 

A useful assortment of carbon-carbon bond forming reactions such as alkylation of enolates and enamines and carbon-oxygen bond forming reactions such as epoxidation with ylides have been described in this chapter. 

The enamine reaction provides an alternative method for selective alkylation and acylation of aldehydes and ketones. The enamine group is both a protecting group for carbonyl compounds and a directing or activating group for further elaboration. Note the relationship between enolates and enamines ... 

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