Carbonyl-oxygen exchange

Carbonyl oxygen exchange was found during the cupric ion-catalyzed hydrolysis of DL-phenylalanine ethyl ester-carbonyl-O18 at pH 7.3 (11). This indicates that an additional intermediate is formed in this reaction. A mechanism (II) consistent with both the kinetic evidence and the oxygen-exchange evidence is given below. 

Application of the principle of stereoelectronic control to the hydrolysis of esters under basic conditions leads to the following predictions Z esters are allowed to undergo carbonyl-oxygen exchange but E esters cannot. 

Further experimental evidence supporting the principle of stereoelectronic control in the cleavage of hemi-orthoamide tetrahedral intermediates has been obtained from studies on the carbonyl-oxygen exchange during the basic hydrolysis of amides, and from the hydrolysis of imidate salts. These experiments are described next. 

Carbonyl-oxygen exchange concurrent with hydrolysis in amides... 

Carbonyl-oxygen exchange has been observed in the course of the basic hydrolysis of primary amides (23, 24). The exchange, observed by using Relabeling (0 = occurs vi a a tetrahedral hemi-orthoamide intermediate... 

The fact that there is carbonyl-oxygen exchange in primary and secondary amides is in accord with the principle of stereoelectronic control but it does not constitute a proof since these experimental results can be explained without the use of this principle. 

The rates of hydrolysis and carbonyl-oxygen exchange of 0-labeled N-benzyl-N-methylamides 34 (R=H, CD3 and CD2CH3) were carefully measured at several temperatures in 83 0 (18). The activation parameters, found by plotting... 

A similar conclusion can be reached with N — H lactams (37, R=H). Such lactams should give intermediate 38 (R=H). Again, 38 can only yield either 37 (R=H) or 39 (R=H). Unlabeled lactam 37 (R=H) can be obtained only via conformer 40 (R=H). Thus, as in the case of N-alkyl lactams, N-H lactams will undergo carbonyl-oxygen exchange only if the conformational change... 

Lactams 41 and 42 have also been studied (17). Concurrent carbonyl-oxygen exchange upon hydrolysis was not observed with B-lactam 41. The B-lactam 42 is hydrolyzed at a considerably slower rate than the B-lactam 41 and contrary to 41, 42 does undergo concurrent carbonyl-oxygen exchange. 

The mixture of ester and amine plus amide and alcohol products obtained from the imidate ion 54 (R=CHg ) and 55 (R=CgH-]i ) can also be explained. These ions could exist in the anti form only. However, this would be surprising on the basis of the steric argument discussed previously. Also, the results obtained from the carbonyl-oxygen exchange in tertiary amides definitely show that conformational change can easily compete with the breakdown at room temperature only when R=H in tertiary amide (RCONRj1). Thus,... 

Concurrent carbonyl-oxygen exchange and hydrolysis in esters... 

In previous studies, i,e. concurrent carbonyl-oxygen exchange in the hydrolysis of esters, acid hydrolysis of orthoesters and oxidation of acetals by ozone, the configuration of the tetrahedral intermediate was determined by the application of the principle of stereoelectronic control. There could be some ambiguity in these experiments as the theory of stereoelectronic control is used to predict both the stereochemistry of the tetrahedral intermediate as well as its breakdown. The oxidation cleavage of vinyl orthoesters can therefore be considered a more powerful experimental technique in that respect because the configuration of the hemi-orthoester... 

The rates of hydrolysis and carbonyl-oxygen exchange carried out at 27°C with potassium hydroxide (1.5 N) on labeled N-benzyl-M-methyl derivatives of formamide (21 ), acetamide (22), and propionantide (23) have been reported (14). 

Comparison of the activation parameters for carbonyl-oxygen exchange and for hydrolysis shows that, for the formamide, the rate of exchange is only slightly lower than that of hydrolysis, whereas in the case of acetamide and propionamide, the exchange occurs at a significantly lower rate. 

Labeled N-methylpiperidone (37, R=CH 3) and 0-labeled piperidone (37. R=H) have been studied (31) and it was found that basic hydrolysis (1 N, NaOH) at room temperature occurs readily but no carbonyl-oxygen exchange was observed. These results show clearly that the conformational change 38 40 (R=H or CH ) cannot compete with the breakdown of 38 to yield the hydrolysis product 38 (R=H or CHj). Again, these results are consistent only if the principle of stereoelectronic control is taken into consideration indeed, if it is neglected, 37 should give directly 40 as well as 38. 

These results can be explained by postulating that the tetrahedral intermediates can freely rotate prior to the cleavage even if they can break down with stereoelectronic control. This postulate is supported by the important carbonyl-oxygen exchange observed in the course of the basic hydrolysis of... 

Abstract This chapter emphasises on the important aspects of steric and stereo-electronic effects and their control on the conformational and reactivity profiles. The conformational effects in ethane, butane, cyclohexane, variously substituted cyclohexanes, and cis- and tra/ ,v-decalin systems allow a thorough understanding. Application of these effects to E2 and ElcB reactions followed by anomeric effect and mutarotation is discussed. The conformational effects in acetal-forming processes and their reactivity profile, carbonyl oxygen exchange in esters, and hydrolysis of orthoesters have been discussed. The application of anomeric effect in 1,4-elimination reactions, including the preservation of the geometry of the newly created double bond, is elaborated. Finally, a brief discussion on the conformational profile of thioacetals and azaacetals is presented. 

Keywords Conformational profile Steric effect E2 reaction Elcb reaction Anomeric effect Mutarotation Acetal hydrolysis Acetal formation Carbonyl oxygen exchange in esters Ozonation of acetals Orthoester and hydrolysis Numerical value of anomeric effect Relative energy of acetals 1,4-elimination Mono and dithoacetals Mono and diazaacetals... 

Consider all possible ways and arguments to demonstrate that it is fairly unlikely that a y-lactone will entertain carbonyl oxygen exchange when... 

This mechanistic proposal has extensive experimental support Imine 16 has been trapped and localized, and enzyme-catalyzed hydrogen/deuterium (H/D) exchange at C3 and C4 of DXP as well as carbonyl oxygen exchange has been detected. Acyl transfer to the C4 hydroxyl (18 to 19) as well as transfer of oxygen from DXP to nascent ThiS-COOH (21 to 22) has been demonstrated. Intermediate 22 has been trapped and detected by mass spectrometric analysis and the reaction product 14 has been fully characterized. Thiazole synthase complexed with ThiS-COOH has been structurally characterized and the DXP imine 16 has been modeled into the active site revealing key catalytic residues. ... 

Fig. 3.22. Energy profiles (in kcal/mol) and structures of intermediates and transition states for competing hydrolysis and carbonyl oxygen exchange for methyl acetate and hydroxide ion in the gas phase. Adapted from J. Am. Chem. Soc., 122, 1522 (2000), by permission of the American Chemical Society.

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