Carbonyl groups nucleophilic attack

When we come to reactions of amides we are at the bottom of the scale of reactivity. Because of the efficient delocalization of the nitrogen lone pair into the carbonyl group, nucleophilic attack on the carbonyl group is very difficult. In addition the leaving group (NH2, pkTaH about 35) is very bad indeed. 

Although somewhat less reactive than acid chlorides, anhydrides nonetheless readily react with most nucleophiles to form substitution products. Nucleophilic substitution reactions of anhydrides are no different than the reactions of other carboxylic acid derivatives, even though anhydrides contain two carbonyl groups. Nucleophilic attack occurs at one carbonyl group, while the second carbonyl becomes part of the leaving group. 

Likewise, when an electrophile attacks a carbonyl group, it will approach the carbonyl group so as to achieve the best overlap of its LUMO with the carbonyl s HOMO, the lone pair on oxygen (Fig. 4.42). The molecular orbitals are telling us what we already knew from the minor resonance form of the carbonyl group. Nucleophiles attack the 6+ end, and electrophiles attack the 6- end of the carbonyl group. The orientations of the orbitals tell us additional information on the position of attack. 

Much of the chemical reactivity of ketenes can be understood on the basis of the preference for nucleophilic attack at the carbonyl carbon in the ketene plane and electrophUic attack at C2, perpendicular to the ketene plane. As shown in Scheme 4.1, C2 is electron rich due to resonance donation from the carbonyl group. Nucleophilic attack at Ci in the plane preferentially occurs from the side of the less stericaUy demanding substituent, while electrophilic attack at C2 is less influenced by the steric effects of the substituents. 

Normally carbon-carbon double bonds are attacked by electrophiles a carbon-carbon double bond that is conjugated to a carbonyl group is attacked by nucleophiles... 

In these reactions (12-41-12-44), a carbonyl group is attacked by a hydroxide ion (or amide ion) giving an intermediate that undergoes cleavage to a carboxylic acid (or an amide). With respect to the leaving group, this is nucleophilic substitution at a carbonyl group and the mechanism is the tetrahedral one discussed in Chapter 10. 

Peptide aldehydes constitute a rather general example of protease inhibitors. The electrophilic carbonyl group is attacked reversibly by the cleaving nucleophile, forming a covalent acetal or thioacetal intermediate. With cysteine proteases the preferred inhibitors are strong electrophiles, for example ketones, chloromethyl ketones, epoxides, or vinyl sulfones. Many cysteine protease inhibitors form an enzyme-inhibitor complex irreversibly these are therefore denoted suicide-inhibitors . 

Nitriles can also be used as starting materials for the synthesis of ketones. Discussed in Chapter 21, nitriles are compounds containing the cyano (—C=N) functional group. Since nitrogen is more electronegative than carbon, the —C=N triple bond is polarized like the C=O bond of the carbonyl group. Nucleophiles can add to the — C = N triple bond by attacking the electrophilic carbon atom. 

When it is a n bond that is being broken rather than a a bond, only the n bond is broken and the O bond should be left in place. This is what commonly happens when an electrophilic carbonyl group is attacked by a nucleophile. Just as in the breaking of a a bond, start the arrow in the middle of the 7t bond and end by putting the arrowhead on the more electronegative atom, in this case oxygen rather than carbon. 

Oxidative insertion into the arylbromide, carbonylation, and nucleophilic attack on the carbonyl M. Mori et al Heterocycles, group with elimination of Pd(0) completes the catalytic cycle. No doubt the palladium has a 1979,12, 921. number (1-2) of phosphines complexed to it during the reaction and these keep the Pd(0) in solution between cycles. 

The electrophilicity of the carbonyl group of the ester functionality is a dominant feature of its chemistry and shields carbonyls from nucleophilic attack. However, its electrophilic properties must be considered as a major obstacle in any synthetic approach of stereoselective functionalization. This difficult task of protecting the carbonyl group can be achieved by highly stereoselective functionalization with very strong nucleophiles. This selective protection by functionalization with various blocking groups such as benzylidene, isopropylidene, and cyclohexylidene acetals is reported [27]. 

The first and last are rapid proton-transfer processes. The second is the nucleophilic addition step. The acid catalyst activates the carbonyl group toward attack by a weakly nucleophilic water molecule. Protonation of oxygen makes the carbonyl carbon of an aldehyde or a ketone much more electrophilic. Expressed in resonance terms, the protonated carbonyl has a greater degree of carbocation character than an unprotonated carbonyl. 

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