Oxygen Protonation

Beak and Siegel proposed the formation of a zwitterionic intermediate upon decarboxylation, which could provide rate acceleration through dipole-stabilization (see Fig. 6, structure 1) [7]. A related mechanism was put forth 20 years later when Lee and Houk proposed protonation at 04 instead of 02 (Fig. 6, structure 2) [27]. Quantum mechanical calculations on model systems (R=H in Fig. 6) were used by Lee and Houk to calculate and compare reaction energetics for these two pathways. It was shown that the activation enthalpy of the parent reaction was reduced from 44 kcal/mol in the gas phase to 22 kcal/mol with 02 protonation. The barrier was further reduced upon 04 protonation, to a value of 15.5 kcal/mol, indicating that 04 protonation is a viable strategy for catalysis. The preference for 04 protonation can be explained, at least in part, by examining the reasonable resonance structures of the decarboxylated intermediates (see Fig. 6). While every resonance structure for the 02 protonated intermediate involves charge separation, 04 protonation yields a stabilized neutral carbene. 

Additional density functional calculations on orotate derivatives by Singleton et al. indicated that the major factor favoring decarboxylation via 04 protonation is likely an inherent preference for 04 protonation in uracil derivatives, rather than strong selective stabilization of the 04-protonated decarboxylated product and the transition state for its formation [28]. The authors also compared experimental (in solution without enzyme present) and theoretical kinetic isotope effects, finding that those computed for the 04 protonation pathway matched best the experimentally determined values. It was also noted, though, that differences between isotope effects measured for the carboxylate carbon in the uncatalyzed [28] and enzyme-catalyzed [29] decarboxylations may indicate that the mechanisms in these two environments differ considerably. More recent isotope effect calculations performed by Phillips and Lee [30], however, indicate that protonation of either 04 or 02 is consistent with the reported experimental isotope effects for the ODCase-catalyzed reaction [31]. 

After the initial crystal structures of ODCase were reported, a modified 04 protonation mechanism was proposed [22]. In the original Lee-Houk proposal, the active-site residue Lys93 (yeast numbering, analogous to Lys72 in E, coli Fig. 4 and Table 2), which was experimentally shown to be catalyt-ically important, was assumed to be the species that protonated 04 [27, 32]. However, in the reported crystal structures this lysine does not reside near 04. It was therefore proposed that proton transfer from Lys93 to 04 might be mediated by an active site water molecule (see Fig. 7). The viability of this scenario has not yet been established, however. 

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Step 4 The oxygen protonated carbmolamme loses water to give a nitrogen stabilized carbocation CeHs H... 

Under conditions of acid catalysis the nucleophilic addition step follows protonation of the carbonyl oxygen Protonation increases the carbocat ion character of a carbonyl group and makes it more electrophilic... 

Protonation of this anion can occur either at the a carbon or at oxygen Protonation of the a carbon simply returns the anion to the starting aldehyde or ketone Protonation of oxygen as shown m step 2 of Figure 18 3 produces the enol... 

Protonation of carbonyl oxygen Protonation of amide nitrogen... 

Fig. 14.—Catalysis of glycosidic oxygen protonation by hydrated magnesium...

The cyclopropane acetals [10] and [11] also hydrolyze in aqueous sulfuric acid, but the reaction mechanisms for the two are not the same. Reaction of [10] involves pre-equilibrium oxygen protonation followed by rate-determining A1 ring opening, whereas that of [11] involves carbon protonation concurrent with... 

Fig. 9. Effect of the chain length of hydrocarbons on the adsorption enthalpy and rates of desorption. (A) Hydrocarbon in interaction with zeolite framework. Methyl groups interact with the framework oxygen protons exhibit an additional attractive force. (B) Heat of adsorption as a function of carbon number for zeolites MFI and FAU in the acidic and non-acidic form. (C) Relative desorption rates of a C12, Ci6, and C20 alkane compared to octane at 348 K. Values calculated from the linear extrapolation of the heat of adsorption values shown in (B).

The product ratio of 8K/9K is similar to that of the Lewis acid-mediated reaction of 4a-c. These products of the C2-C3 bond cleavage (8K and 9K) may be formed via alkylideneallyl cation intermediate, which is formed by the oxygen protonation of 4. Thus, the product ratio of 10/(8K + 9K) is controlled by the protonations at the olefinic carbon and at the acetal oxygen of 4. 

The reactions in a non-basic aprotic solvent CH2C12 provided solely 10, the product of carbon protonation, while those carried out in an acidic protic solvent HFIP give exclusively 8K, the product of oxygen protonation. The equilibrium protonation may be favored in a protic solvent having abundant protons available. In other basic solvents, the proton donor involved in the reaction should be the conjugate acid of the solvent, and many factors may delicately control the selectivity of the reaction. 

Infrared evidence on alkyluracyl salts supports oxygen protonation (Cook, 1966). The p/STj-value of the mono-cation is —3 38, according to Katritzky and Waring (1962), and —2 07, according to Antonovskii et al. (1972). 

The site of protonation of amino-substituted pyridazones [145] is not firmly established (Cookson and Cheeseman, 1972). Protonation on the ring nitrogen leading to a cation stabilized by amidinium-type resonance appears unlikely, since it would be expected to produce a bathochromic shift in the ultraviolet absorption. The reverse is observed and therefore oxygen protonation is more likely. 

Sydnones, which contain a cyclic ylid type structure [147], have one nitrogen and two possible oxygen protonation sites. Calculations quoted by Coulson (1952) show the largest negative ch urge on the carbonyl oxygen and protonation at that site has been observed by... 

Ultraviolet spectra of benzoic acid in sulphuric acid solutions, published by Hosoya and Nagakura (1961), show a considerable medium effect on the spectrum of the unprotonated acid, but a much smaller one in concentrated acid. The former is probably connected with a hydrogen-bonding interaction of benzoic acid with sulphuric acid which is believed to be responsible for a peculiarity in the activity coefficient behaviour of unprotonated benzoic acid in these solutions (see Liler, 1971, pp. 62 and 129). The absence of a pronounced medium effect on the spectra in >85% acid is consistent with dominant carbonyl oxygen protonation. In accordance with this, Raman spectra show the disappearance in concentrated sulphuric acid of the carbonyl stretching vibration at 1650 cm (Hosoya and Nagakura, 1961). Molecular orbital calculations on the structure of the carbonyl protonated benzoic acid have also been carried out (Hosoya and Nagakura, 1964). 

The implications of the above observations may be important, especially if similar trends are observed in pyranose anomers. For example, with respect to the mechanism of acid-catalyzed hydrolysis of pyranosides, endocyclic C-0 bond cleavage (preceeded by 05 protonation) may be assisted in P-anomers in which the Cl-01 bond is equatorial, since the 04-Cl bond may already be extended in these anomers. By a similar argument, exocyclic C-0 scission (preceeded by 01 protonation) may be assisted in the hydrolysis of a-pyranosides in which the Cl-01 is axial and extended, thus resembling the transition state. Post and Karplus have recently suggested that enzyme-catalyzed glycoside hydrolysis of P-pyranosides may indeed take place by ring oxygen protonation, followed by endocyclic C-0 bond scission. 

Initially, the reaction involves protonation of one of the oxygen atoms, followed by loss of this group as a neutral molecule and formation of a resonance-stabilized carbocation. If the oxygen protonated were that of the alkoxy group, then the product would merely be the protonated aldehyde, and the reaction becomes a reversal of hemiacetal formation. Only when the oxygen of the hydroxyl is protonated can the reaction lead to an acetal, and this requires nucleophilic attack of the second alcohol molecule on to the alternative resonance-stabilized carbocation. 

I OH2 HsC OH OEt an equilibrium loss of proton to solvent, then reprotonation from solvent the molecule may have any one of the three oxygens protonated... 

As the Connolly studies suggested (Sect. 3.5), protonated concave pyridines should be able to discriminate between small and large molecules. In a model reaction, a protonation reaction has therefore been examined. The protonation of nitronate ions 44 has been chosen [35] (Scheme 8). In these ions an intramolecular competition of carbon versus oxygen protonation leads to nitro (45) or flci-nitro (46) compounds. The latter ones may then be hydrolyzed by way of the Nef-reaction [36] to form carbonyl compounds 47. 

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