Reactions at Carbonyl Carbon

When heated to 100-150°C, 7- and 6- (but not a-) alkoxyacyl chlorides (168) rearrange to give the alkyl y- or 5-chloro esters (170), respectively. Support for the proposed intermediate oxonium ion (169) is derived from 

Finally, the presence of a ) -ether or amine group in certain bicyclic P, y-unsaturated ketones alters the course of rearrangement of the latter group. This has been discussed by Cargill 0 al  

---

A logical extension of the Abramov- and Pudovik-type reactions at carbonyl carbon is the conjugate addition of the phosphorus reagents at distant sites of conjugated carbonyl and related systems. A wide range of such Michael addition reactions, many of significant practical... 

Table 19.2 Nucleophilic Substitution Reactions at Carbonyl Carbons...

In the following sections, we focus on condensation reactions at the a-carbon atom of esters. Reactions of these derivatives form carbon—carbon bonds and are useful in synthesis. Alkylation reactions using alkyl halides and reactions at carbonyl carbon atoms both occur with ester enolates. However, the reactions of enolates of acid derivatives differ somewhat from the reactions of enolates of aldehydes and ketones. For one thing, the a-hydrogen atoms of esters (pA 25) are less acidic than those of aldehydes and ketones (pif 20). Two resonance forms are written for aldehydes and ketones. The dipolar resonance form of a ketone has a positive charge on an electron-deficient carbonyl carbon atom. The contribution of this resonance form (2) to the resonance hybrid increases the acidity of the a-hydrogen atom as the result of inductive electron withdrawal. 

In many reactions at carbonyl groups, a key step is addition of a nucleophile, generating a tetracoordinate carbon atom. The overall course of the reaction is then determined ly the fate of this tetrahedral intermediate. 

When a Br nsted base functions catalytically by sharing an electron pair with a proton, it is acting as a general base catalyst, but when it shares the electron with an atom other than the proton it is (by definition) acting as a nucleophile. This other atom (electrophilic site) is usually carbon, but in organic chemistry it might also be, for example, phosphorus or silicon, whereas in inorganic chemistry it could be the central metal ion in a coordination complex. Here we consider nucleophilic reactions at unsaturated carbon, primarily at carbonyl carbon. Nucleophilic reactions of carboxylic acid derivatives have been well studied. These acyl transfer reactions can be represented by... 

Reactions at the carbon-nitrogen double bond of iminium salts are analogous to nucleophilic reactions at the carbonyl group of aldehydes and ketones. This is why free enamines do not react with nucleophilic reagents, whereas their salts can undergo such reactions. 

Attempts to use n values for one class of reactions (e.g., attack at saturated carbon) for another (e.g., attack at carbonyl carbon) are not entirely successful. Edwards proposed a two-term equation,15... 

A detailed kinetic study of the reaction of trialkyl phosphites (44) with benzil has been carried out (see Chapter 2 for the reactions of a-diketones with trialkyl phosphites). The reaction is first-order in both phosphite and benzil and the rate constant increases with the dielectric constant of the solvent. The authors propose initial attack of phosphite at carbonyl carbon (45), in opposition to the original suggestion by Ramirez, who proposed initial attack at carbonyl oxygen. 

The various reactions of aminophosphines with ketones have been discussed. Reaction of (52) with benzaldehyde presumably takes place by attack at carbonyl carbon followed by a proton shift. " The same site of initial attack is suggested for the reaction of pyruvate esters with (53), although in this case it is followed by rearrangement. 

The use of an anionic reagent for addition at carbonyl carbon rather than a fully esterified form of a trivalent phosphorus acid obviates a troublesome aspect of the Abramov reaction. Specifically no dealkylation step is required. Mechanistic investigations257 258 indicate that the reaction proceeds much as a simple "aldol"-type reaction in which the anionic phosphorus site adds directly to the carbonyl center. While the initial efforts concerned with the "Pudovik reaction"259 were directed toward the use of sodium salts of the simple dialkyl phosphites, as shown in Equation 3.17,260 266 with a, 5-unsaturated carbonyl systems (vide infra) competition between sites for addition can occur. Addition at the carbonyl carbon site is the kinetically favored route.267-270... 

For reaction of benzoyl chlorides in water, reactivity follows the electronreleasing ability of p-substituents, and there are striking differences in the micellar effects (Table 7). With electron-withdrawing substituents k+/k > 1, but its value progressively decreases with increasing electron release from a p-substituent. Thus an increase in electron release changes k+/k from values characteristic of a carbonyl addition reaction to values characteristic of SN reactions at saturated carbon. This classification also... 

Similar qualitative relationships between reaction mechanism and the stability of the putative reactive intermediates have been observed for a variety of organic reactions, including alkene-forming elimination reactions, and nucleophilic substitution at vinylic" and at carbonyl carbon. The nomenclature for reaction mechanisms has evolved through the years and we will adopt the International Union of Pure and Applied Chemistry (lUPAC) nomenclature and refer to stepwise substitution (SnI) as Dn + An (Scheme 2.1 A) and concerted bimolecular substitution (Sn2) as AnDn (Scheme 2.IB), except when we want to emphasize that the distinction in reaction mechanism is based solely upon the experimentally determined kinetic order of the reaction with respect to the nucleophile. 

The phenyl and carbonyl groups remain in the molecule but the Cl group is replaced by the NH2 group. We called the molecule of ammonia (NH3) the nucleophile and the chloride was called the leaving group. In this chapter we shall be looking at similar reactions at saturated carbon atoms, this sort of thing. 

Competition of a different kind occurs in reactions of esters and lactones since these compounds contain hydrogen atoms alpha to a carbonyl group and alpha to an ether function. A priori, abstraction of either type of hydrogen might be expected. In fact, reaction of phenanthrenequinone at 4358 A led in quantitative yield to products of reaction at the carbon atom alpha to the ether function (52,53) in ethyl acetate 132>, ethyl propionate 132>, and y-butyrolactonee) 110>. 

---