Protons substrates/products

Ion 21 can either lose a proton or combine with chloride ion. If it loses a proton, the product is an unsaturated ketone the mechanism is similar to the tetrahedral mechanism of Chapter 10, but with the charges reversed. If it combines with chloride, the product is a 3-halo ketone, which can be isolated, so that the result is addition to the double bond (see 15-45). On the other hand, the p-halo ketone may, under the conditions of the reaction, lose HCl to give the unsaturated ketone, this time by an addition-elimination mechanism. In the case of unsymmetrical alkenes, the attacking ion prefers the position at which there are more hydrogens, following Markovnikov s rule (p. 984). Anhydrides and carboxylic acids (the latter with a proton acid such as anhydrous HF, H2SO4, or polyphosphoric acid as a catalyst) are sometimes used instead of acyl halides. With some substrates and catalysts double-bond migrations are occasionally encountered so that, for example, when 1 -methylcyclohexene was acylated with acetic anhydride and zinc chloride, the major product was 6-acetyl-1-methylcyclohexene. ... 

Axially chiral phosphoric acid 3 was chosen as a potential catalyst due to its unique characteristics (Fig. 2). (1) The phosphorus atom and its optically active ligand form a seven-membered ring which prevents free rotation around the P-0 bond and therefore fixes the conformation of Brpnsted acid 3. This structural feature cannot be found in analogous carboxylic or sulfonic acids. (2) Phosphate 3 with the appropriate acid ity should activate potential substrates via protonation and hence increase their electrophilicity. Subsequent attack of a nucleophile and related processes could result in the formation of enantioenriched products via steren-chemical communication between the cationic protonated substrate and the chiral phosphate anion. (3) Since the phosphoryl oxygen atom of Brpnsted acid 3 provides an additional Lewis basic site, chiral BINOL phosphate 3 might act as bifunctional catalyst. 

The first term of the rate law requires acid-catalyzed decomposition of the conjugated acid of the ester. This term predominates only under strongly acidic conditions. It has not been investigated in detail, but the major product of the acid catalyzed reaction is the corresponding hydroxylamine. The second term predominates under neutral to mildly acidic conditions. This term is consistent with uncatalyzed heterolysis of the N—O bond of the neutral ester to generate a heteroaryinitrenium ion. " The rate law is more complicated than that for reactive esters of carbocyclic hydroxylamines or hydroxamic acids that show pH-independent decomposition over a wide pH range. The kinetic behavior of the heterocyclic esters is caused by protonation of a pyridyl or imidazolyl N under mildly acidic conditions. The protonated substrates are not subject to spontaneous uncatalyzed decomposition, so decreases under acidic conditions until acid-catalyzed... 

Fig. 25. Optimized minimum with the substrate product in phenol form prior to (18a) and subsequent to (19a) protonation of the cofactor.

The simple treatment given above is based on the assumption that all proton dissociations are rapid compared to /ccat, that enzyme in only one state of protonation binds substrate, and that ES in only one state of protonation yields products. These assumptions are not always valid. It also assumes that both binding and dissociation of substrate are rapid, that is, to use Cleland s terminology the substrate is not "sticky." For a sticky substrate that dissociates more slowly than it reacts to form products (/c3 > /c2 Eq. 9-54), the values of pKlE will be lowered and pK1e of Eq. 9-53 will be raised by log (1 + k3 / /c2).65/66 In addition to the articles by Cleland, other detailed treatments of pH effects have been prepared by Brocklehurst and Dixon69 and Tipton and Dixon.70... 

This new general synthetic method utilizes the well-known S2Os2 /Ag1 redox system. The first step is the formation of the alkoxyl radical by Ag(II) electron transfer oxidation. The fast (3-scission gives the nucleophilic CH2OH radical which adds to the protonated substrate. As already seen, the intermediate is oxidized by S2Os2 /Ag2 species, affording the hydroxymethylated products. 

The values of the reaction constant, p, found in the Hammett correlations of 1/2 discussed above, are relatively small compared to other polarographic reaction constants . This has also been taken as an indication of electron transfer to the protonated substrate in which case a positively charged species is reduced to a neutral one with the consequence that stabilization of the reduction product by electron-withdrawing groups is of limited importance . 

While the abstraction of protons adjacent to the carbon-nitrogen double bond of imines/imine derivatives has been utilized for tiie regioselective generation of azaallyl anions (which are useful in asymmetric ketone synthesis), it competes with and often prevents the addition of nucleophiles to imines. For this reason, imine additions often involve azomethines (e.g. benzylidineanilines) which are not capable of enolization. Many potentially useful additions, however, involve substrates capable of proton abstraction. By avoiding in certain instances some of the structural features of imines/imine derivatives and the reaction conditions responsible for proton abstraction, products resulting from this serious side reaction can be minimized. 

Kinetic studies with calcineurin yielded a modest solvent isotope effect of 1.35, and a proton inventory and fractionation factor data that were most consistent with a mechanism involving a single proton transfer from a water molecule coordinated to a metal ion.136 No transphosphorylation products were found in the presence of alternate nucleophiles, consistent with direct phosphoryl transfer to a metal-coordinated water.137 No calcineurin-catalyzed oxygen exchange of 180 labeled water with phosphate could be detected.138 In a study using / NPP as the substrate, product inhibition studies found that both phosphate and p-nitrophenol are... 

Chemical interactions of CO2 with substrates, products or catalysts can also play a major role in defining rate and selectivity of a given reaction. This chemical influence must not necessarily be positive, making it even more important to remember that CO2 does not always provide an inert medium. For example, hydrogen carbonate and protons are generated in the presence of water (pH = 3), carbamic acids or carbamates are formed with basic N-H functionalities, and the coordination ability and reactivity towards various transition metal centers is well established [20]. One of the appealing prospects of the chemical reactivity of CO2 is its simultaneous use as solvent and Cj building block in metal-catalyzed processes. 

Experiments reported by Pollack and his coworkers allow the conclusion that the dienolate anion intermediate is approximately isoenergetic with the more unstable unconjugated enone substrate/product, as proposed by Knowles and Albery in their theory for understanding optimization of catalytic efficiency [9]. Thus, based on the value of the rate constant for proton abstraction from the unconjugated enone, 1.7 x 10 s Pollack and coworkers calculated that the value of the Glint for proton abstraction from carbon is 10 kcal mol, a modest reduction from that expected ( 13 kcal mol ) for the nonenzymatic reaction. 

This is a very common pattern in acid catalysis. In the first step the acid transfers a proton to the substrate, which in the second step transfers another proton, the product being formed either simultaneously or in a subsequent step. In basic catalysis (which also occurs with the iodination of acetone), the substrate molecule first transfers a proton to the basic catalyst, and in a second step accepts a proton at another position. 

In the various examples presented in this section, confining Zn(II) at the bottom of a hydrophobic cavity generated patterns highly reminiscent of hydrolytic enzymes control of the protonation state of bound water, substrate/product cavity binding, or pH-triggered host-guest ability. Nevertheless, functional models would require the presence in close vicinity of an activated water and a substrate molecule. This is precluded by the calix[6]arene cavity, as Zn(II) displays only one labile site, accessible via the large rim. To circumvent the problem, a new type of model has been developed, which is based on the resorcin[4]arene scaffold. Unlike... 

---