Transition state protonation

The most common type of biocatalytic reactions is proton transfer (115). Nearly, every enzymatic reaction involves one or more proton-coupled steps. Transition-state proton bridging and intramolecular proton transfer (general acid-base catalysis) are important strategies to accelerate substrate conversion processes. Moreover, proton transfer also plays a fundamental role in bioenergetics (116). 

The acidic cleavage of the Boc group is most probably proceeded by the protonation of the carbamate carbonyl with subsequent elimination of isobutene, either by an open or, more likely, by a cyclic transition state. Protonation leads to the liberated anoine or the annmonium salt, respectively (Scheme 35). The byproduct isobutene is either protonated to give the stable carbenium ion, or generates the tcrt-butyl trifluoroacetate, both of which act as terf-butylating agents, especially, when nucleophilic amino acid side chains are present in the molecule (vide infra). 

Carbocationic mechanisms. Ono and Mori [4], and others [5, 23], favored carbocationic mechanisms. According to Ono and Mori, surface methoxyls such as an Al-bridged silylmethyl ether may function as free methyl cations, which adds to the C-H of DME to form a pentavalent carbonium transition state. Proton loss completes the reaction, a net electrophilic substitution at a a-bond, analogous... 

So-called low-barrier hydrogen bonds [1] may also play a role in catalysis effected by hydrolases, but their catalytic role is less secure [2-5] relative to the role of transition state proton bridges. It is indeed ironic that while the structural origins of catalytically-questionable LBHBs can be determined with certainty, the structural origins of catalytically-critical TSPBs are elusive. The implications of the latter point will be the topic of the final section of this chapter where we examine several cases in which the results of solvent isotope effect studies that may have been interpreted in the context of the hydrolase chemistry, in fact reflect rate-limiting product release or conformational isomerization of the enzyme. 

The magnitude of the effect for the elimination reactions indicates a high degree of bond formation between the base and the proton in the transition state. Proton transfer is extensive in the ammonium compound and the proton is just more than half transferred to the base for the sulphonium salt. These... 

M. Nagaoka, Y. Okuno, and T. Yamabe,/. Am. Chem. Soc., 113,769 (1991). The Chemical Reaction Molecular Dynamics Method and the Dynamic Transition State Proton Transfer Reaction in the Formamidine and Water Solvent System. 

Therefore, if a single transition-state proton contributes to the solvent isotope effect,"fc will be linear function of n if two protons contribute, the dependence will be quadratic if three protons contribute, cubic, etc. In practice, even the most carefully collected data in the proton inventory experiments can distinguish... 

Nagaoka M, Okuno Y, Yamabe T (1991) The chemical reaction molecular dynamics method and the dynamic transition state proton transfer reaction in formamidine and water solvent system. J Am Chem Soc 113(3) 769-778... 

The effect of aromatic substrates on the formation of N02" is shown in the considerably increased substrate selectivity over that obtained with NO2+ salts. On the basis of the experimental data it is suggested that in these nitrations a weaker nitrating species than NO2+ must be involved in the primary interaction with the aromatic substrates. This incipient nitronium ion then attaches itself to the aromatics in a step giving high substrate selectivity. Whether the incipient nitronium ion is the nitracidium ion (H2NO3+), protonated acetyl nitrate (CH3COO—HN02 ) or probably a transition state of any of those unstable species to N02, in which water is loosened, but not yet completely eliminated, is difficult to say and no direct physical evidence is available. 

For electrophilic substitutions in general, and leaving aside theories which have only historical interest, two general processes have to be considered. In the first, the 5 3 process, a transition state is involved which is formed from the aromatic compound, the electrophile (E+), and the base (B) needed to remove the proton ... 

At one time a form of 8 2 mechanism was favoured for electrophilic substitution in which in the transition state bonding between carbon and the electrophile and severance of the proton had proceeded to the... 

The picture of the process of substitution by the nitronium ion emerging from the facts discussed above is that of a two-stage process, the first step in which is rate-determining and which leads to a relatively stable intermediate. In the second step, which is relatively fast, the proton is lost. The transition state leading to the relatively stable intermediate is so constructed that in it the carbon-hydrogen bond which is finally broken is but little changed from its original condition. 

Streitwieser pointed out that the eorrelation whieh exists between relative rates of reaetion in deuterodeprotonation, nitration, and ehlorination, and equilibrium eonstants for protonation in hydrofluorie aeid amongst polynuelear hydroearbons (ef. 6.2.3) constitutes a relationship of the Hammett type. The standard reaetion is here the protonation equilibrium (for whieh p is unity by definition). For eon-venience he seleeted the i-position of naphthalene, rather than a position in benzene as the referenee position (for whieh o is zero by definition), and by this means was able to evaluate /) -values for the substitutions mentioned, and cr -values for positions in a number of hydroearbons. The p -values (for protonation equilibria, i for deuterodeprotonation, 0-47 for nitration, 0-26 and for ehlorination, 0-64) are taken to indieate how elosely the transition states of these reaetions resemble a cr-eomplex. 

Because adjacent bonds are eclipsed when the H—C—C—X unit is syn coplanar a transition state with this geometry is less stable than one that has an anti coplanar rela tionship between the proton and the leaving group... 

Dehydrohalogenation of alkyl halides (Sections 5 14-5 16) Strong bases cause a proton and a halide to be lost from adjacent carbons of an alkyl halide to yield an alkene Regioselectivity is in accord with the Zaitsev rule The order of halide reactivity is I > Br > Cl > F A concerted E2 reaction pathway is followed carbocations are not involved and rearrangements do not occur An anti coplanar arrangement of the proton being removed and the halide being lost characterizes the transition state... 

The transition state involves the carbonyl oxygen of one carboxyl group—the one that stays behind—acting as a proton acceptor toward the hydroxyl group of the carboxyl that IS lost Carbon-carbon bond cleavage leads to the enol form of acetic acid along with a molecule of carbon dioxide... 

Alkyl groups under nonacidic conditions sterically deflect nucleophiles from C, but under acidic conditions this steric effect is to some extent offset by an electronic one the protonated oxirane opens by transition states (Scheme 40) which are even more 5Nl-like than the borderline Sn2 one of the unprotonated oxirane. Thus electronic factors favor cleavage at the more substituted carbon, which can better support a partial positive charge the steric factor is still operative, however, and even under acidic conditions the major product usually results from Cp attack. 

Successive introduction of two methyl groups at ring carbon increases the hydrolysis rate by a factor of 10 in each step, indicating cation formation in the transition state as in acetal hydrolysis. Equilibrium protonation before hydrolysis becomes evident from an increasing rate of hydrolysis with a decreasing pH value (Table 3). Below pH 3 no further increase of rate is observed, so that protonation is assumed to be complete. 

The enzyme provides a general base, a His residue, that can accept the proton from the hydroxyl group of the reactive Ser thus facilitating formation of the covalent tetrahedral transition state. This His residue is part of a catalytic triad consisting of three side chains from Asp, His, and Ser, tvhich are close to each other in the active site, although they are far apart in the amino acid sequence of the polypeptide chain (Figure 11.6). 

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