Substituent effects carbonyl groups

Studies of the stereochemical dependence of 1H chemical shifts in cyclobutanes, benzocyclobute-nes and /J-lactams have been collected463. In a number of cases the protons or proton groups are shielded if they are cis to vicinal halogen, hydroxy or phenyl substituents, due to a ring-current effect. Carbonyl groups, however, can give rise to deshielding effects. 

Table 20.1 summarizes the stabilizing effects of substituents on carbonyl groups to which they are attached. In addition to a qualitative ranking, quantitative estimates of the relative rates of hydrolysis of the various classes of acyl derivatives are given. A weakly stabilized carboxylic acid derivative reacts with water faster than does a more stabilized one. 

Acid chlorides, on the other hand, are more reactive toward addition than ketones since the inductive effect of the chlorine substituent increases carbonyl group reactivity and more than compensates for the small tt-donor effect of the chlorine. 

Carboxylic acids are weak acids and m the absence of electron attracting substituents have s of approximately 5 Carboxylic acids are much stronger acids than alcohols because of the electron withdrawing power of the carbonyl group (inductive effect) and its ability to delocalize negative charge m the carboxylate anion (resonance effect)... 

The negatively charged oxygen substituent is a powerful electron donor to the carbonyl group Resonance m carboxylate anions is more effective than resonance m carboxylic acids acyl chlorides anhydrides thioesters esters and amides... 

The electronic environment of an a-substituent on pyridine (319) approaches that of a substituent on the corresponding imino compound (320) and is intermediate between those of substituents on benzene and substituents attached to carbonyl groups (321, 322) (cf. discussion in Chapter 2.02). Substituents attached to certain positions in azole rings show similar properties to those of a- and y-substituents on pyridine. However, the azoles also possess one heteroatom which behaves as an electron source and which tends to oppose the effect of other heteroatom(s). 

Alkoxy-2,l-benzisoxazole-4,7-diones undergo ready nucleophilic displacement of the 3-alkoxy substituent, yielding 3-alkylamino and 3-dialkylamino derivatives with primary and secondary amines, respectively (67TL4313). In this instance the 4-carbonyl group apparently provides an activating effect. 

Substitution reactions by the ionization mechanism proceed very slowly on a-halo derivatives of ketones, aldehydes, acids, esters, nitriles, and related compounds. As discussed on p. 284, such substituents destabilize a carbocation intermediate. Substitution by the direct displacement mechanism, however, proceed especially readily in these systems. Table S.IS indicates some representative relative rate accelerations. Steric effects be responsible for part of the observed acceleration, since an sfp- caibon, such as in a carbonyl group, will provide less steric resistance to tiie incoming nucleophile than an alkyl group. The major effect is believed to be electronic. The adjacent n-LUMO of the carbonyl group can interact with the electnai density that is built up at the pentacoordinate carbon. This can be described in resonance terminology as a contribution flom an enolate-like stmeture to tiie transition state. In MO terminology,.the low-lying LUMO has a... 

Table 8.5. Substituent Effects on Carbonyl Group Stabilization...

Thus, reduction of the bicyclic derivatives 25 (RR = CH2 RR = CH=C(Ph)) affords the corresponding 26a-type products, while hydrogenation of 2-ethoxy-3-acetylpyridine gives, along with the carbonyl group reduction product, the imine isomer 26b (R = Me, R = Et). These results were explained by the so-called internal strain effect, e.g., by steric repulsion between the nitrogen and oxygen lone pair in rotationally restricted bicyclic derivatives or between the 2 and 3 substituents. 

It reveals that either the steric effect of the bulky N-substituent on the interaction of Ce(IV) ion and urea reductant, or the electron withdrawing effect of the vinyl group, will reduce the coordination of Ce(lV) ion with the carbonyl group, thus resulting in a decrease of the Rp. 

The mode of the diastcrcofacial selectivity is completely reversed in the case of reactions with A -methyl A-acyliminium precursors 4176. Now the nitrogen atom of the A-acyliminium ion is not able to chelate with the tin atom and the lower diastereoselectivity is explained by the less rigid nonchelation-controlled transition state 5. An electronic effect, such as n-iz attraction between the electron-deficient carbonyl group of the acyliminium ion and the electron-rich phenyl group of the phcnylthio substituent R, may account for the somewhat higher diastereoselectivity in the case of arylthio substituents R. 

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