Electrophilicity of the carbonyl carbon atom

Thus, the role of zinc in the dehydrogenation reaction is to promote deprotonation of the alcohol, thereby enhancing hydride transfer from the zinc alkoxide intermediate. Conversely, in the reverse hydrogenation reaction, its role is to enhance the electrophilicity of the carbonyl carbon atom. Alcohol dehydrogenases are exquisitely stereo specific and by binding their substrate via a three-point attachment site (Figure 12.7), they can distinguish between the two-methylene protons of the prochiral ethanol molecule. 

Amides react as electrophiles only with powerful nucleophiles such as HO-. Acid chlorides, on the other hand, react with even quite weak nucleophiles neutral ROH, for example. They are more reactive because the electron-withdrawing effect of the chlorine atom increases the electrophilicity of the carbonyl carbon atom. 

On the other hand, in -fluoroalkyl groups (with one uncompensated C-F dipole moment) fluorination usually reduces lipophilicity. Another important instance of fluorine substitution reducing lipophilicity is in compounds with a-fluorocarbonyl groups. In these fluorination can increase the electrophilicity of the carbonyl carbon atom to such an extent that the formation of stable, polar hydrates occurs this again reduces the lipophilicity significantly (Scheme 4.13). In a-fluorocar-boxylic acids and fluorinated phenols the lipophilicity is also reduced by the increased ionization constant which results from the negative inductive —la) effect of fluorine [16]. 

An acid catalyst increases the electrophilicity of the carbonyl carbon atom and decreases the basicity of the leaving group. 

Dialkyl carbonates can be made from the reaction of alcohols with phosgene, a highly toxic gas. The second chlorine atom of phosgene increases the electrophilicity of the carbonyl carbon atom. As in the reaction of an alcohol with an acid chloride, a base is required to neutralize the HCl by-product. 

Carbonyl compounds react with thiols, RSH, to form hemi-thioacetals and thioacetals, rather more readily than with ROH this reflects the greater nucleophilicity of sulphur compared with similarly situated oxygen. Thioacetals offer, with acetals, differential protection for the C=0 group as they are relatively stable to dilute acid they may, however, be decomposed readily by H20/HgCl2/CdC03. It is possible, using a thioacetal, to reverse the polarity of the carbonyl carbon atom in an aldehyde thereby converting this initially electrophilic centre into a nucleophilic one in the anion (31) ... 

Umpolung The reversal of polarity of the carbonyl carbon atom is termed umpolung (German for polarity reversal). Normally the carbonyl carbon atom of an aldehyde (or a ketone) is partially positive i.e., electrophilic and therefore it reacts with nucleophiles. When the aldehyde is converted to a dithiane by reaction with 1,3-propanedithiol and reacted with butyl lithium the same carbon now becomes negatively charged to react with electrophiles. This reversed polarity of the carbonyl carbon is termed umpolung which increases the versatility of the carbonyl group in synthesis. The sulphur atoms stabilize... 

Figure 3-8. The hydrolysis of a kinetically inert complex containing a monodentate amino acid ester co-ordinated through nitrogen. The only effect of the metal is a long-range polarisation which slightly increases the electrophilic character of the carbonyl carbon atom.

In this case, diethylenetriamine acts as a trinucleophile its interaction with amino enone 71 involves double nucleophilic addition at the /1-carbon, forming ammonia, and an attack at the carbonyl group, liberating water. The reaction takes place when the compound contains a polyfluoroalkyl substituent, not only enhancing the electrophilicity of the /1-carbon atom, but also stabilizing the imidazolidine ring. 

Depending on the origin of the nucleophile which will open the monomer, two distinct mechanisms can be envisioned for the metal-mediated ROP of cyclic esters (Scheme 6). Upon coordination of the incoming monomer to the metal center, the electrophilicity at the carbonyl carbon atom is greatly enhanced. This eventually facilitates attack of either an internal nucleophilic moiety—that is, an anionic active ligand initially attached to the metal complex which accordingly operates via a so-called coordination-insertion mechanism—or an external (exogenous)... 

With respect to this mechanism, the rate of hydrolysis is influenced by electrophilic properties of the carbonyl carbon atom (attached substituents attracting electrons increase the reactivity of this carbon), and by sterical hindrance, which prevents a smooth access of the hydroxyl ion and decreases the hydrolysis rate. If the ester molecule contains groups stabilizing the carbonyl group by conjugation, the rate of hydrolysis diminishes (benzoates esters of a,j -unsaturated acids). 

The continued reaction of the remaining aluminum hydride with the carboxylate salt requires higher temperatures and longer reaction times because the hydride ion must react with a carbonyl carbon atom of the carboxylate, which is less electrophilic than the carbonyl carbon atom of an ester. 

While the aromatic ring of methyl w-nitrobenzoate is also expected to be just as deficient in electron density as that of the para isomer, the positive charge on the ring never occupies the carbon atom adjacent to the carbonyl carbon atom (structure B). So, the electron deficiency (electrophilicity) at the carbonyl carbon atom is not as large as that of the para isomer. Thus, the reaction rate is not as large as that of the para isomer. 

Experimental evidence, obtained in protonation (3,6), acylation (1,4), and alkylation (1,4,7-9) reactions, always indicates a concurrence between electrophilic attack on the nitrogen atom and the -carbon atom in the enamine. Concerning the nucleophilic reactivity of the j3-carbon atom in enamines, Opitz and Griesinger (10) observed, in a study of salt formation, the following series of reactivities of the amine and carbonyl components pyrrolidine and hexamethylene imine s> piperidine > morpholine > cthyl-butylamine cyclopentanone s> cycloheptanone cyclooctanone > cyclohexanone monosubstituted acetaldehyde > disubstituted acetaldehyde. 

As we saw in A Preview of Carbonyl Compounds, the most general reaction of aldehydes and ketones is the nucleophilic addition reaction. A nucleophile, Nu-, approaches along the C=0 bond from an angle of about 75° to the plane of the carbonyl group and adds to the electrophilic C=0 carbon atom. At the same time, rehybridization of the carbonyl carbon from sp2 to sp3 occurs, an electron pair from the C=0 bond moves toward the electronegative oxygen atom, and a tetrahedral alkoxide ion intermediate is produced (Figure 19.1). 

One further comparison aromatic aldehydes, such as benzaldehyde, are less reactive in nucleophilic addition reactions than aliphatic aldehydes because the electron-donating resonance effect of the aromatic ring makes the carbonyl group less electrophilic. Comparing electrostatic potential maps of formaldehyde and benzaldehyde, for example, shows that the carbonyl carbon atom is less positive (less blue) in the aromatic aldehyde. 

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