Reactivity of the Carbonyl Group

There is another aspect to the question of the reactivity of the carbonyl group in r ck)hexanone. This has to do with the preference for approach of reactants from the axial ir equatorial direction. The chair conformation of cyclohexanone places the carbonyl coup in an unsynunetrical environment. It is observed that small nucleophiles prefer to roach the carbonyl group of cyclohexanone from the axial direction even though this is 1 more sterically restricted approach than from the equatorial side." How do the ctfcnaices in the C—C bonds (on the axial side) as opposed to the C—H bonds (on the equatorial side) influence the reactivity of cyclohexanone ... 

In a first step the reactivity of the carbonyl group is increased by protonation at the carbonyl oxygen. The peracid then adds to the cationic species 3 leading to the so-called Criegee intermediate 4 ... 

Acetal formation is similar to the hydration reaction discussed in Section 19.5. Like water, alcohols are weak nucleophiles that add to aldehydes and ketones only slowly under neutral conditions. Under acidic conditions, however, the reactivity of the carbonyl group is increased by protonation, so addition of an alcohol occurs rapidly. 

The aldehyde acid reactions have already been described generally in Chapter 2. There it was pointed out that a nucleophilic attack at a carbonyl group is particularly easy when this is attached to an aromatic ring that bears an electron withdrawing group at position 4. The reactivity of the carbonyl group is greatly increased in acid medium ... 

The reactivity of the carbonyl group is enhanced by resonance, which stabilizes the carboxylate ion (see Figure 9-16). This increased stability of the carboxylate ion means that it s easier for a hydrogen ion to leave the Ccirbox-ylic acid. Thus the resonance is one factor in accounting for the acidity of carboxylic acids. 

This provides a cyclic transition state in which hydrogen bonding can enhance the reactivity of the carbonyl group.119 120 Excellent yields of large-ring lactones are achieved by this method. 

The reactivity of the carbonyl group decreases with increasing size of R s and with electron donation by R. Electron-attracting R s increase the reactivity of 0=0. 

The carbonyl group of 2-phenylindolone (158 R = Ph) reacts to give the oxime,22,137 2,4-dinitrophenylhydrazone, and semicarbazone (204).49 With phenylmagnesium bromide it gives a compound identified as the indolenine (205).49 In this reaction the reactivity of the carbonyl group resembles that in isatogens (Section III,C). 

The relative reactivities of the carbonyl groups of 3,5-dioxoindolizidine (97) have been investigated (64CB1548). Hydrolysis occurs preferentially at the five-membered ring the reaction with stabilized phosphoranes proceeds as shown in Scheme 13. 

Uncatalyzed hydrolysis of a peptide linkage is very slow with f1/2 at neutral pH and 25°C of 300-600 years.189 Both acids and bases catalyze hydrolysis, but enzymes are needed for rapid digestion. The carbonyl group C=0 is highly polarized, with the resonance form C+-0 contributing substantially to its structure. An attack by a base will take place readily on the electrophilic carbon atom. While the reactivity of the carbonyl group in esters and amides is relatively low... 

Compared to carboxylic and carbonic acid derivatives, the less highly oxidized carbonyl compounds such as aldehydes and ketones are not so widespread in nature. That is not to say that they are unimportant. To the contrary. Aldehydes and ketones are of great importance both in biological chemistry and in synthetic organic chemistry. However, the high reactivity of the carbonyl group in these compounds enables them to function more as intermediates in metabolism or in synthesis than as end products. This fact will become evident as we discuss the chemistry of aldehydes and ketones. Especially important are the addition reactions of carbonyl groups, and this chapter is mostly concerned with this kind of reaction of aldehydes and ketones. 

Cyclopropenone undergoes many interesting reactions — one example is Diels-Alder addition, the product of which in methanol solution is a hemiketal. That the hemiketal is favored for the adduct, but not for cyclopropenone, indicates that the double bond of cyclopropenone has a considerable effect on the reactivity of the carbonyl group. 

This is a very general process for carbonyl compounds however, die elec-trophilic reactivity of the carbonyl group is very dependent on the groups attached to it. The reactivity is ranked ill the following order ... 

Enolates are important nucleophiles which react nicely with a variety of carbonyl compounds. In this case, the nucleophilic reactivity of the enolate and the electrophilic reactivity of the carbonyl group are well matched and a wide variety of products can be made. The type of enolate (ketone, ester, etc.) and the type of carbonyl electrophile (aldehyde, ketone, ester, etc.) determine the structure of the final product. Furthermore these reactions are often named according to the two partners that are reacted and the type of product produced from them. 

The structure of the complex (96) between benzaldehyde (95) and boron trifluoride (equation 15) was investigated by X-ray crystallography169. In 96, BF3 is in the anti position to the phenyl ring and this geometry remains also in solutions, as tested by the 19F-NMR spectrum in CD2CI2. An ab-initio study170 on interactions between formaldehyde and boron trihalides showed that these complexes (mainly donor-acceptor complexes) affect spectroscopic properties and the reactivity of the carbonyl group the polarization of the C=0 bond favours the attack of nucleophiles. 

Hence the reactivity of the carbonyl group and of the endo- and exo-hydrogens in (11), and the stereochemical consequences of such reactions (i.e. the stereo-isomeric nature of the product) are crucially dependent upon the conformation-ally fixed environment. Likewise the reactivity of the /i-orientated hydroxyl group and of the olefinic bond in cholesterol (14) is determined by the fixed conformational environment. 

According to the data obtained, such a reaction either does not proceed at all [4] or yields the corresponding f3-amino adduct 2 or 2-phenylbenzimidazole 4 [2], depending on the reaction conditions. These results were treated as a general feature of the interaction between 0-PDA and chalcones [2]. The impossibility of the formation of aromatic dihydrobenzodiazepine derivatives was explained by the essentially lower reactivity of the carbonyl group in chalcone molecules in comparison with that of the C = C bond. 

The electron withdrawing inductive effects of the fluorine substituents render the carboxonium ion 3 more electrophilic than carboxonium ion 2, and consequently it reacts with benzene. Thus, the electrophilic reactivity of the carbonyl group can be greatly enhanced by Brpnsted or Lewis acid solvation and by substitution with electron withdrawing groups. 

The t7 -correlation for carbonylic compounds suggested by Hart et al. (1967) can be applied to additional compounds thus, 2-pyrrolidone ( =l-3xl07 m—1 sec-1) (Szutka et al., 1965), asparagine in alkaline solution ( = 2-4x 107), acetylglycine and acetyl-alanine at pH = 9 (k 107 M-1 sec-1) (Braams, 1966) react at a rate practically equal to that of acetamide (k = 1-7 x 107 m-1 sec-1) (Hart et al., 1967). The ring closure seems to have little effect on the reactivity of the carbonylic group. 

Cross-coupling reactions of ArCOAr. Reaction of Yb(0) with diaryl ketones changes the reactivity of the carbonyl group from electrophilic to nucleophilic. Thus in the presence of this lanthanoid metal, diaryl ketones couple with other ketones, nitriles, and epoxides to give pinacols, a-hydroxy ketones, and 1,3-diols, respectively, via the intermediate a. 

Molecular orbitals explain the reactivity of the carbonyl group... 

When chelation is possible, this is the conformation to consider—the one with the carbonyl O and the other chelating atom almost eclipsing one another. It is the most populated because it is stabilized by the chelation, and it is also the most reactive, because the Lewis-acidic metal atom increases the reactivity of the carbonyl group. Attack is still along the less hindered pathway, but this now leads to the other face of the carbonyl group, and the stereochemical outcome is reversed. 

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