Nucleophilic Substitution at Carbonyl Carbon

Fox, J. M., Dmitrenko, O., Liao, L.-A., Bach, R. D. Computational Studies of Nucleophilic Substitution at Carbonyl Carbon the Sn2 Mechanism versus the Tetrahedral Intermediate in Organic Synthesis. J. Org. Chem. 2004, 69, 7317-7328. 

The photoelectron spectra of the compounds RCS2 CF3 (R = F, Cl, or CFs-S) have been analysed with reference to the spectra of the thioketones R2CS (R = F, Cl, or alkylthio) and through CNDO calculations the CFs-S group has a substituent effect comparable to that of chlorine. i A study of the reactions of the acid derivatives XCO SCl (X = F or Cl) has shown that nucleophilic substitution at carbonyl carbon is more rapid with the dichloro-compound (X = Cl), although the S—Q bonds in both compounds are of comparable reactivity some chemical conversions of the fluoro-compound are shown in Sicheme 32. 

Nucleophilic Substitution at Carbonyl Carbon 51 Table 3.3 Illustration of the 2x2 array performed in a parallel, phase transfer microreactor. 

Carbonyl reactions are extremely important in chemistry and biochemistry, yet they are often given short shrift in textbooks on physical organic chemistry, partly because the subject was historically developed by the study of nucleophilic substitution at saturated carbon, and partly because carbonyl reactions are often more difhcult to study. They are generally reversible under usual conditions and involve complicated multistep mechanisms and general acid/base catalysis. In thinking about carbonyl reactions, 1 find it helpful to consider the carbonyl group as a (very) stabilized carbenium ion, with an O substituent. Then one can immediately draw on everything one has learned about carbenium ion reactivity and see that the reactivity order for carbonyl compounds ... 

The mechanistic aspects of nucleophilic substitutions at saturated carbon and carbonyl centers were considered in Part A, Chapters 4 and 7, respectively. In this chapter we discuss some of the important synthetic transformations that involve these types of... 

When the reaction is allowed to proceed with protected carbonyl groups, the expected protected P-ketophosphonates resulting from a nucleophilic substitution at the carbon atom of a-chloroke-tones are isolated in reasonable yields (Scheme 7.16). 152-154 However, unprotected y-bromo-P-oxobutanoic ester or amides - undergo phosphonylation in satisfactory yields with sodium or potassium dialkyl phosphites in THF at 0°C. 

Nucleophilic Substitution at the Carbon Atom of the Carbonyl Group... 

Some nucleophilic substitutions at a carbonyl carbon are catalyzed by nucleophiles.There occur, in effect, two tetrahedral mechanisms ... 

Chapters 1 and 2 dealt with formation of new carbon-carbon bonds by reactions in which one carbon acts as the nucleophile and another as the electrophile. In this chapter we turn our attention to noncarbon nucleophiles. Nucleophilic substitution is used in a variety of interconversions of functional groups. We discuss substitution at both sp3 carbon and carbonyl groups. Substitution at saturated carbon usually involves the Sjv2 mechanism, whereas substitution at carbonyl groups usually occurs by addition-elimination. 

Most of the reported reactions consist of nucleophilic attack at the carbon atom of the carbonyl group, resulting in substitutions rather than ring openings. Thus, in a series of recent publications, it was shown that pyrrolotriazinones 29 could be easily converted to the corresponding fully aromatic chloro derivatives 30. These chloroimidates readily... 

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. 

According to the available experimental data, it is impossible to distinguish between these mechanisms, but the second mechanism seems to be preferred [Scheme (7)] for, according to this Scheme, the reaction of amine addition proceeding through a cyclic transition state is completed in one step, whereas for the reaction to occur according to Scheme (2) or (6) it is additionally necessary to transfer the proton. Then, it is probable that the different mechanisms [Schemes (3) and (5)] may precede formation of one and the same transition state [Scheme (7)]. Note finally that the mechanism of bifunctional catalysis [Scheme (7)] is extremely popular in different reactions of nucleophilic substitution at the saturated carbon atom and reactions with participation of a carbonyl group32>. 

The electrophile shown in step 2 is the proton. In almost all the reactions considered in this chapter the electrophilic attacking atom is either hydrogen or carbon. It may be noted that step 1 is exactly the same as step 1 of the tetrahedral mechanism of nucleophilic substitution at a carbonyl carbon (p. 331), and it might be expected that substitution would compete with addition. However, this is seldom the case. When A and B are H, R, or Ar, the substrate is an aldehyde or ketone and these almost never undergo substitution, owing to the extremely poor nature of H, R, and Ar as leaving groups. For carboxylic acids and their... 

Table 19.2 Nucleophilic Substitution Reactions at Carbonyl Carbons...

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