Carbonyl compound-nucleophile reaction mechanism

The mechanism of the Mannich reaction has been extensively investigated. The reaction can proceed under both acidic and basic conditions, but acidic conditions are more common. Under acidic conditions the first step is the reaction of the amine component with the protonated non-enolizable carbonyl compound to give a hemiaminal, which after proton transfer loses a molecule of water to give the electrophilic iminium ion.°° This iminium ion then reacts with the enolized carbonyl compound (nucleophile) at its a-carbon in an aldol-type reaction to give rise to the Mannich base. 

The mechanism of the cycloaddition reaction of benzaldehyde 2a with Danishefsky s diene 3a catalyzed by aluminum complexes has been investigated theoretically using semi-empirical calculations [14]. It was found that the reaction proceeds as a step-wise cycloaddition reaction with the first step being a nucleophilic-like attack of Danishefsky s diene 2a on the coordinated carbonyl compound leading to an aldol-like intermediate which is stabilized by interaction of the cation with the oxygen atom of the Lewis acid. The next step is the ring-closure step, giving the cycloaddition product. 

As with the reduction of carbonyl compounds discussed in the previous section, we ll defer a detailed treatment of the mechanism of Grignard reactions until Chapter 19. For the moment, it s sufficient to note that Grignard reagents act as nucleophilic carbon anions, or carbanions ( R ), and that the addition of a Grignard reagent to a carbonyl compound is analogous to the addition of hydride ion. The intermediate is an alkoxide ion, which is protonated by addition of F O"1 in a second step. 

Both in the laboratory and in living organisms, the reactions of carbonyl compounds take place by one of four general mechanisms nucleophilic addition, nucleophilic acyl substitution, alpha substitution, and carbonyl condensation. These... 

Nucleophilic addition of an alcohol to the carbonyl group initially yields a hydroxy ether called a hemiacetal, analogous to the gem diol formed by addition of water. HcmiacetaJs are formed reversibly, with the equilibrium normally favoring the carbonyl compound. In the presence of acid, however, a further reaction occurs. Protonation of the -OH group, followed by an El-like loss of water, leads to an oxonium ion, R2C=OR+, which undergoes a second nucleophilic addition of alcohol to yield the acetal. The mechanism is shown in Figure 19.12. 

Lewis acids, particularly the boron trifluroride diethyl ether complex, are used to promote the reaction between allyl(trialkyl)- and allyl(triaryl)stannanes and aldehydes and ketones52-54. The mechanism of these Lewis acid promoted reactions may involve coordination of the Lewis acid to the carbonyl compound so increasing its reactivity towards nucleophilic attack, or in situ transmetalation of the allyl(trialkyl)stannane by the Lewis acid to generate a more reactive allylmetal reagent. Which pathway operates in any particular case depends on the order of mixing of the reagents, the Lewis acid, temperature, solvent etc.55- 58. 

Ab initio molecular orbital calculations are being used to study the reactions of anionic nucleophiles with carbonyl compounds in the gas phase. A rich variety of energy surfaces is found as shown here for reactions of hydroxide ion with methyl formate and formaldehyde, chloride ion with formyl and acetyl chloride, and fluoride ion with formyl fluoride. Extension of these investigations to determine the influence of solvation on the energy profiles is also underway the statistical mechanics approach is outlined and illustrated by results from Monte Carlo simulations for the addition of hydroxide ion to formaldehyde in water. 

The importance of displacement reactions on carbonyl compounds in chemistry and biochemistry has resulted in numerous mechanistic studies. In solution, there is general acceptance of the following mechanism for addition of anionic nucleophiles which features a tetrahedral intermediate, 1, and is designated (1). However, recent experimental (2 10) and theoretical (11-17)... 

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 ... 

Although the reaction of ketones and other carbonyl compounds with electrophiles such as bromine leads to substitution rather than addition, the mechanism of the reaction is closely related to electrophilic additions to alkenes. An enol, enolate, or enolate equivalent derived from the carbonyl compound is the nucleophile, and the electrophilic attack by the halogen is analogous to that on alkenes. The reaction is completed by restoration of the carbonyl bond, rather than by addition of a nucleophile. The acid- and base-catalyzed halogenation of ketones, which is discussed briefly in Section 6.4 of Part A, provide the most-studied examples of the reaction from a mechanistic perspective. 

Dithiophosphoric acids, (RO)2PS2H, have been used for the thionation of carbonyl groups in certain aldehydes, ketones, amides, esters, thio-carboxylates and other organics.163 The mechanism for this reaction proceeds via a reversible nucleophilic attack of the thioacid on the carbonyl compound, which can then rearrange by way of a four-membered PSCO cyclic intermediate into the desired C=S containing molecule and thiophosphoric acid (Equation 81).163... 

Since nucleophilic addition to a metal-coordinated alkene generates a cr-metal species bonded to an -hybridized carbon, facile 3-H elimination may then ensue. An important example of pertinence to this mechanism is the Wacker reaction, in which alkenes are converted into carbonyl compounds by the oxidative addition of water (Equation (108)), typically in the presence of a Pd(n) catalyst and a stoichiometric reoxidant.399 When an alcohol is employed as the nucleophile instead, the reaction produces a vinyl or allylic ether as the product, thus accomplishing an etherification process. 

While a large number of studies have been reported for conjugate addition and Sn2 alkylation reactions, the mechanisms of many important organocopper-promoted reactions have not been discussed. These include substitution on sp carbons, acylation with acyl halides [168], additions to carbonyl compounds, oxidative couplings [169], nucleophilic opening of electrophilic cyclopropanes [170], and the Kocienski reaction [171]. The chemistry of organocopper(II) species has rarely been studied experimentally [172-174], nor theoretically, save for some trapping experiments on the reaction of alkyl radicals with Cu(I) species in aqueous solution [175]. 

Although at first glance the behaviour of some of these carbonyl compounds towards nucleophiles might seem anomalous, closer consideration shows there is a logical explanation for the reactions observed. Furthermore, if we understand the underlying mechanisms, these reactions become predictable. 

The aldol reaction as formulated above involves two molecules of the starting substrate. However, by a consideration of the mechanism, one can see that different carbonyl compounds might be used as nucleophile or electrophile. This would be termed a mixed aldol reaction or crossed aldol reaction. However, if one merely reacted, say, two aldehydes together under basic conditions, one would get a... 

The Michael reaction involves conjugate addition of a nucleophile onto an a,P-unsaturated carbonyl compound, or similar system. Such reactions take place in nature as well, and some can be potentially dangerous to us. For example, the a,P-unsaturated ester ethyl acrylate is a cancer suspect agent. This electrophile can react with biological nucleophiles and, in so doing, bind irreversibly to the nucleophile, rendering it unable to carry out its normal functions. A particularly important enzyme that can act as a nucleophile is DNA polymerase, which is responsible for the synthesis of strands of DNA, especially as part of a DNA repair mechanism (see Section 14.2.2). The nucleophilic centre is a thiol grouping, and this may react with ethyl acrylate as shown. 

This chapter on electrophilic amination using O-substituted hydroxylamines 1-5 and oximes 7 is focused on the various methods that have been reported for the amination of carbon nucleophiles. Synthetic aspects and applications of the methods for C—N bond formation are accompanied by a brief discussion of the reaction mechanisms. The preparation of O-substituted hydroxylamines and oximes has not been considered in detail. This review covers the literature up to August 2007 and is partly based on reviews on the electrophilic amination of carbanions and a-amination of carbonyl compounds. ... 

Lithium Enolates. The control of mixed aldol additions between aldehydes and ketones that present several possible sites for enolization is a challenging problem. Such reactions are normally carried out by complete conversion of the carbonyl compound that is to serve as the nucleophile to an enolate, silyl enol ether, or imine anion. The reactive nucleophile is then allowed to react with the second reaction component. As long as the addition step is faster than proton transfer, or other mechanisms of interconversion of the nucleophilic and electrophilic components, the adduct will have the desired... 

The intracellular nucleophile glutathione (GSH y-Glu-Cys-Gly) acts as a protective mechanism against electrophilic insults and may be present at concentrations of up to 10 mM [26]. The reaction of glutathione with a non-polar compound bearing an electrophilic carbon, nitrogen or sulfur atom may be mediated enzymatically by glutathione-S-transferase (GST), with typical substrates being species such as arene oxides, quinones and a,P-unsaturated carbonyl compounds. 

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