Electrophilic Attack on a Carbonyl Group

Simple orbital interaction theory is only partially informative in distinguishing the relative basicities (nucleophilicities) of carbonyl groups in different bonding environments. 

Basicity in the gas phase is measured by the proton affinity (PA) of the electron donor and in solution by the pAb. A solution basicity scale for aldehydes and ketones based on hydrogen bond acceptor ability has also been established [186]. Nucleophilicity could be measured in a similar manner, in the gas phase by the affinity for a particular Lewis acid (e.g., BF3) and in solution by the equilibrium constant for the complexation reaction. In Table 8.1 are collected the available data for a number of oxygen systems. It is clear from the data in Table 8.1 that the basicities of ethers and carbonyl compounds, as measured by PA and pAb, are similar. However, the nucleophilicity, as measured by the BF3 affinity, of ethers is greater than that of carbonyl compounds, the latter values being depressed by steric interactions. 

TABLE 8.1. Ionization Potentials (IP), Proton Affinities (PA), pAb Values, and BF3 Affinities 

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When a carbonyl group and an amino group are present within the same molecule, reaction with dichlorocarbene favours, somewhat unexpectedly, electrophilic attack on the carbonyl group [ 14, 15]. Although no confirmatory evidence is available, such a reaction pathway (Scheme 7.17) would explain the formation of the ring... 

In chapter 21 we emphasise that the most reliable method of controlling one chiral centre by another in open chain compounds is by Felkin-Anh orbital control of nucleophilic attack on a carbonyl group next to a chiral centre. We shall start this discussion with that method and follow with the next most reliable - Houk control of electrophilic attack on alkenes also next to a chiral centre. These are of course both 1,2-control and we shall deal with that before discussing 1,3-, 1,4- and remote control. 

Pyridine is too unreactive to suffer electrophilic attack by a carbonyl group. However, a form of electrophilic substitution occurs when picolinic and isonicotinic acids are decarboxylated in the presence of carbonyl compounds. These acids undergo decarboxylation in the zwitterionic forms (p. 319), and when decarboxylation occurs in the presence of carbonyl compounds, carbinols are formedi37-9, Jt is not certain whether the reaction proceeds by electrophilic attack by the carbonyl compound on the product of decarboxylation (process A) or whether the carbonyl compound is involved in the decarboxylation (process B), The reaction has preparative value . See also the discussion of the reactions of aminopyridines with aldehydes (p. 359). 

In reactions with azides, ketones are directly converted to 5-hydroxytriazolines. Ketone enolate 247, generated by treatment of norbornanone 246 with LDA at 0°C, adds readily to azides to provide hydroxytriazolines 248 in 67-93% yield. Interestingly, l-azido-3-iodopropane subjected to the reaction with enolate 247 gives tetracyclic triazoline derivative 251 in 94% yield. The reaction starts from an electrophilic attack of the azide on the ketone a-carbon atom. The following nucleophilic attack on the carbonyl group in intermediate 249 results in triazoline 250. The process is completed by nucleophilic substitution of the iodine atom to form the tetrahydrooxazine ring of product 251 (Scheme 35) <2004JOC1720>. 

This is formally the reverse of the BA1,1 cleavage of an ester, and is the only one-stage mechanism for ester formation available for the ionized carboxyl group. Numerous methods are, of course, available which involve initial electrophilic attack on the carboxylate group, followed by a displacement at the carbonyl carbon atom of the intermediate formed, which is often an anhydride. An example134 is the esterification of carboxylic acids in the presence ofp-toluenesulphonyl chloride in pyridine, viz-... 

The overall process of peptide bond scission is identical in all classes of peptidases and differences between the catalytic mechanisms are rather subtle. The attack on the carbonyl group of the peptide bond requires a nucleophilic agent, either oxygen or sulfur, in order to approach the slightly electrophilic carbonyl carbon atom. To remove a proton from the attacking nucleophile, general base catalysis will assist this process. Furthermore, some type of electrophilic action on the carbonyl oxygen increases the polarization of the C - O-bond. 

Diethylentriamine acts as a trinucleophile. Its interaction with amino enones includes double nucleophilic addition on atom C/J with elimination of ammonia and attack on the carbonyl group accompanying by loss of a molecule of water. Successful reaction is promoted by the presence of polufluoroalkyl substituents that not only increase the electrophility of atom C/J, but also stabilizes the imidazoline ring. 

Vinyltins. BusSnCI is commonly used as an electrophile to trap a-lithioimines, enolates of trimethylsilylacetic esters, and alkynyltrialkylborate salts. P,y-Epoxy ketones. The reaction of tin enolates with a-halo carbonyl compounds generally affords 1,4-dicarbonyl products. However, in the presence of BusSnBr and Bu4NBr the major pathway is switched to attack on the carbonyl group instead of on the o-carbon, resulting in 8, y-epoxy ketones. 

Step 1 Make a new bond between a nucleophile (arene ring) and an electrophile. The phenoxide ion reacts like an enolate anion it is a strong nucleophile. Nucleophilic attack of the phenoxide anion on a carbonyl group of carbon dioxide gives a substituted cyclohexadienone intermediate. 

There were very few reports of Schmidt reactions involving alkyl azides for almost 40 years after Boyer s papers appeared. Some papers described sequences that resembled the bona fide Schmidt reaction in that azides ultimately afforded lactams, but were thermally enacted and mechanistically distinct from the classical Schmidt reaction (see Section 7.5). hi the early 1990s, a series of disclosures finally established synthetically useful versions of the Schmidt reaction using various kinds of alkyl azides as the key substrates. The following discussion of this chemistry will concentrate first on those reactions in which the electrophilic partner is a carbonyl group or carbonyl equivalent. Later sections will describe processes in which an alkyl azide attacks a carbocation derived from an alkene, alcohol, or a related precursor. Finally, the ways in which these reactions have been used to construct natural products or other compounds of interest will conclude this chapter. 

Electrophilic attack on the carbonyl oxygen of the acetate ligand appears to be the route by which these reactions proceed. The attack is carried out by acetyl cations, methyl cations, or cation equivalents. As a result the acetate group is transformed into a ligand easily replaced by the solvent molecule. 

Because the carbon atom attached to the ring is positively polarized a carbonyl group behaves m much the same way as a trifluoromethyl group and destabilizes all the cyclo hexadienyl cation intermediates m electrophilic aromatic substitution reactions Attack at any nng position m benzaldehyde is slower than attack m benzene The intermediates for ortho and para substitution are particularly unstable because each has a resonance structure m which there is a positive charge on the carbon that bears the electron withdrawing substituent The intermediate for meta substitution avoids this unfavorable juxtaposition of positive charges is not as unstable and gives rise to most of the product... 

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