Base protonation mechanism

Electrochemical oxidation of [Co S2C2(CN)2 2]2 in THF produces initially monomeric [Co S2C2(CN)a 2], which quickly dimerizes to [Co S2C2(CN2 2]2 (Scheme 105). In DMSO this subsequent dimerization is only slight.1187 Further reduction to [Co(S2 C2 (CN)2 2 j3 is possible and weak acids are reduced to H2 by this ion. A metal-based protonation mechanism (Scheme 105) has been proposed.1197... 

Fig. 2 Schematic illustration of the three different mechanisms treated in this review. The base protonation mechanism treats protonation of 02 as well as all other sites of the pyrimidine ring...

The present methodology, using accurate QM models that treat only a rather small part of the active site, has met considerable success during the last few years. The authors of the present review have used the method mainly for metalloenzymes [18, 19, 20] but have also applied the methodology to ODCase [21]. That study treated the concerted reaction mechanism and the base protonation mechanism with 02 as protonation site. The present review includes those results but also presents significant extensions to the modeling of these mechanisms. In addition, results from investigations of other base protonation mechanisms, and the mechanism where the C-C bond is cleaved prior to protonation are also presented. 

This contribution reviews computational results for three classes of reaction mechanisms proposed for ODCase. Firstly, the mechanism that assumes protonation of C6 concerted with decarboxylation is described. Secondly, the base protonation mechanisms are reviewed. Finally, a shorter treatment is given of a reaction mechanism where the C-C bond is broken before the proton attaches to the base. All values in the review are obtained by the use of QM models of the active site. Effects of different residues on the reaction barrier are analyzed when going from small to large QM models. A QM/MM treatment is applied to each mechanism to see whether this treatment has any major effect on the calculated results. The goal of the review is to provide information regarding the activity of ODCase and to shed light on the requirements on QM models that are applied to enzymatic systems. 

So far all models used for the base protonation mechanism have given total barriers for decarboxylation of more than 40 kcal/mol. In all those models, the amino acids added were chosen mainly to affect the C-C bond strength, but a large fraction of the total barrier comes from the protonation cost. The next step is therefore to discuss models that focus on the region around 02 and include residues that might affect the proton affinity of 02. In the X-ray... 

The above results, using extended quantum mechanical models for the active site of ODCase, indicate that the base protonation mechanism has a decarboxylation barrier that is too high to be compatible with the experi-... 

The relative importance of the potential catalytic mechanisms depends on pH, which also determines the concentration of the other participating species such as water, hydronium ion, and hydroxide ion. At low pH, the general acid catalysis mechanism dominates, and comparison with analogous systems in which the intramolecular proton transfer is not available suggests that the intramolecular catalysis results in a 25- to 100-fold rate enhancement At neutral pH, the intramolecular general base catalysis mechanism begins to operate. It is estimated that the catalytic effect for this mechanism is a factor of about 10. Although the nucleophilic catalysis mechanism was not observed in the parent compound, it occurred in certain substituted derivatives. 

Addition of hydride ion from the catalyst gives the adsorbed dianion (15). The reaction is completed and product stereochemistry determined by protonation of these species from the solution prior to or concurrent with desorption. With the heteroannular enolate, (13a), both cis and trans adsorption can occur with nearly equal facility. When an angular methyl group is present trans adsorption (14b) predominates. Protonation of the latter species from the solution gives the cis product. Since the heteroannular enolate is formed by the reaction of A" -3-keto steroids with strong base " this mechanism satisfactorily accounts for the almost exclusive formation of the isomer on hydrogenation of these steroids in basic media. The optimum concentration of hydroxide ion in this reaction is about two to three times that of the substrate. 

Mechanism of Base-Catalyzed Hydration The base-catalyzed mechanism (Figure 17.5) is a two-step process in which the first step is rate-detennining. In step 1, the nucleophilic hydroxide ion attacks the carbonyl group, forming a bond to carbon. An alkoxide ion is the product of step 1. This alkoxide ion abstracts a proton from water in step 2, yielding the geminal diol. The second step, like all other proton transfers between oxygen that we have seen, is fast. 

Molecular orbital based molecular mechanical (MOMM) calculations have been carried out on 3H-2-benzazepinyl phosphonates.43 Similar calculations on 5//-dibenz[Z>,/]azepine lead to the prediction that there are two stable boat conformations for the seven-membered ring both of which are more stable than the planar form by 22.6 and 10.9 kJ moP, respectively the more stable conformer being the one in which the proton on nitrogen is exo lo the azepine... 

Proton transfers between oxygen and nitrogen acids and bases are usually extremely fast. In the thermodynamically favored direction, they are generally diffusion controlled. In fact, a normal acid is defined as one whose proton-transfer reactions are completely diffusion controlled, except when the conjugate acid of the base to which the proton is transferred has a pA value very close (differs by g2 pA units) to that of the acid. The normal acid-base reaction mechanism consists of three steps ... 

By contrast base-catalyzed mechanisms are generally fast, provided, of course, that one of the heteroatoms defining the tetrahedral intermediate has an ionizable proton. 

Clearly, in the related catalysts containing just simple bidentate phosphines, dipyridines, or bis-oxazolines the concerted, heterolytic transfer cannot take place in the same way, unless we invoke an alkoxide or other anion as the proton-receiving moiety. In Figure 4.28 we have presented a simplified scheme for the hydride/proton mechanism for hydrogen transfer using an external base. 

Note how the key interaction boosting the catalytic effect is the protonation of the carbonyl group on the TG. Such catalyst-substrate interaction increases the electrophilicity of the adjacent carbonyl carbon atom, making it more susceptible to nucleophilic attack. Compare this to the base-catalyzed mechanism where the base catalyst takes on a more direct route to activate the reaction, creating first an alkoxide ion that directly acts as a strong nucleophile (Figure 4). Ultimately, it is this crucial difference, i.e., the formation of a more electrophilic species (acid catalysis) v.s. that of a stronger nucleophile (base catalysis), that is responsible for the differences in catalytic activity. 

The mechanism shown in Scheme 3 envisions an association by hydrogen bonding between the catalyst and the carbonyl compound, followed by rate-determining attack of the nucleophile (HaO) and simultaneous transfer of the proton. The rate of this step will depend on the nature and concentration of HA, and the mechanism is consistent with general catalysis. It should be noted that the reverse process consists of a specific acid plus a general base catalysis. A possible general base catalysis mechanism is shown in Scheme 4. The reverse is a specific base plus a general acid catalysis. 

The interconversion of the carbonyl and enol tautomers is catalyzed by either acid or base and occurs rapidly under most circumstances. The process requires only the addition of a proton to either the carbon or the oxygen atom and the removal of a proton from the other atom. In the acid conditions mechanism the proton is added first, while the base conditions mechanism involves removal of the proton in the first step. These mechanisms are shown in Figures 20.1 and 20.2. 

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