Stereochemistry proton transfer

The mechanism includes two single electron transfers (steps 1 and 3) and two proton transfers (steps 2 and 4) Experimental evidence indicates that step 2 is rate determining and it is believed that the observed trans stereochemistry reflects the dis tribution of the two stereoisomeric alkenyl radical intermediates formed in this step... 

The stereochemistry of conjugate reduction is established by the proton transfer to the (3-carbon. In the well-studied case of A1,9-2-octalones, the ring junction is usually trans,213... 

Another important family of elimination reactions has as the common mechanistic feature cyclic transition states in which an intramolecular proton transfer accompanies elimination to form a new carbon-carbon double bond. Scheme 6.16 depicts examples of the most important of these reaction types. These reactions are thermally activated unimolecular reactions that normally do not involve acidic or basic catalysts. There is, however, a wide variation in the temperature at which elimination proceeds at a convenient rate. The cyclic transition states dictate that elimination occurs with syn stereochemistry. At least in a formal sense, all the reactions can proceed by a concerted mechanism. The reactions, as a group, are referred to as thermal syn eliminations. 

There may be two proton transfers in the carbonic anhydrase II-catalyzed mechanism of CO2 hydration that are important in catalysis, and both of these transfers are affected by the active-site zinc ion. The first (intramolecular) proton transfer may actually be a tautomerization between the intermediate and product forms of the bicarbonate anion (Fig. 28). This is believed to be a necessary step in the carbonic anhydrase II mechanism, due to a consideration of the reverse reaction. The cou-lombic attraction between bicarbonate and zinc is optimal when both oxygens of the delocalized anion face zinc, that is, when the bicarbonate anion is oriented with syn stereochemistry toward zinc (this is analogous to a syn-oriented carboxylate-zinc interaction see Fig. 28a). This energetically favorable interaction probably dominates the initial recognition of bicarbonate, but the tautomerization of zinc-bound bicarbonate is subsequently required for turnover in the reverse reaction (Fig. 28b). 

More recently, Apeloig and Nakash have studied diastereoselectivity in the reaction of (E)-5 with p-methoxyphenol53. In both benzene and THF, the stereochemistry of the products was independent of the phenol concentration. The syn/anti ratios of the addition products were 90 10 in benzene and 20 80 in THF. They have suggested that intramolecular proton transfer after rotation of the Si—Si bond of the phenol-coordinated intermediate is responsible for the formation of the anti-addition rather than intermolecular proton transfer. This must be a special case due to much slower (by a factor of 109-1012) rates of addition of phenol to (E)-5. Since phenolic oxygen is definitely less basic than alkyl alcoholic oxygen, coordination of oxygen in the zwitterionic intermediate in the reaction of (E)-5 with phenol must be loose and hence the intermediates should have much chance of rotation around the Si—Si bond. 

We now propose that the proton transfer process could be occurring via an intramolecular 4-centered transition state between the newly formed silyl ketal (Figure 10). A similar 4-centered transition state has been previously proposed by Sommer and Fujimoto to explain retention of the stereochemistry at an asymmetric silicon center during the exchange of alkoxide groups (Scheme 37).34 Brook and co-workers also proposed a 4-centered transition state for the thermal rearrangement of (3-ketosilanes (Scheme 38).35... 

In the case of 1-phenylpropyne a vinyl cation is suggested as intermediate. The kinetic law is rate = k3 [—C=C—] [HC1]2. The second order dependence on HC1 is explained by assuming that proton transfer to the triple bond results in the anion hydrogen dichloride, HClJ. The product distribution and the stereochemistry, under kinetic control, have been explained by assuming that a cw-oriented intimate ion-pair, 14 is initially formed which, following Scheme 2, may either collapse to cis chloride, undergo anion displacement by acetic acid to form tram acetate or a randomly oriented (solvent separated) ion-pair 15 which gives racemic material. 

The most promising direction for enzyme modeling is to synthetically mimick the nature of the binding site and the active site in terms of the close similarity of catalytic groups, stereochemistry, interatomic distances and the mechanism of the action of the enzyme. Mimicking of the proton-transfer relay proposed for the mechanism of the action of chymotrypsin is a brilliant example of such work (D Souza and Bender, 1987 and references therein). The miniature organic model of chymotrypsin built on the basis of cyclodextrin and the mechanism of hydrolysis m-tert-butylphenyl acetate is presented in Fig. 6.9. 

The kinetics of proton transfer from the C-2a position of 2-(l-methoxybenzyl)thiazolium salts was studied for the p-H and /)-NMeJ derivatives by H NMR spectroscopy. The study was carried out by mixing the salts rapidly with sodium hydroxide in a stopped-flow instmment and monitoring the progress of enamine formation and decomposition in the visible region of the spectmm. Under these conditions the thiazolium ring opened, the H NMR spectrum of the product being consistent with both as- and /ra r-stereochemistry about the newly formed enamine bond (Scheme 23) <1997JA2356>. 

In the first reaction there are two nucleophilic substitutions and you must decide which nucleophile attacks first. The amine is a better nucleophile than the alcohol and the cyclization occurs because it is an equilibrium with two equal leaving groups (both alcohols) but one (EtOH) goes away when it leaves while the other is attached and cannot escape. The second reaction is more straightforward. The product is used to control the stereochemistry of new molecules as you will see in Chapter 45. For the first time we are using shorthand mechanisms. Note the double-headed arrow on the carbonyl group and the omission of proton transfer steps. If you drew the full mechanism, you did a better job. If you removed the amide (NH) proton before reaction with the acid chloride in the second step you also did a better job. 

Ireland s deprotonation model is widely used to rationalize the stereochemistry with various ethyl ketones and bases. " In the absence of additives that solvate the lithium cation such as HMPA, proton transfer occurs via a chair-hke closed transition state. Under these conditions, the (Z)-enolate is disfavored because of the 1,3-diaxial interaction between the Me and the i-Pr group on nitrogen. As the steric requirement of the R group increases, so does the A strain between the R and Me groups in forming the double bond, thus destabilizing the ( )-(0)- relative to the (Z)-(0)-enolate (Table 6.2). 

The reaction of dichlorocarbene with p-hydroxyalkyl selenides is believed to take place selectively on the selenium atom, thus producing the corresponding p-hydroxyalkyldichloromethylenesele-nonium ylide (40 Scheme 197). This, after an intramolecular proton transfer leading to (41 Scheme 197), which probably occurs in a six-membered transition state, collapses selectively to die epoxide or to the carbonyl compound depending upon the substitution pattern around the substituted carbon. The regiochemistry of Ae latter reaction depends upon the stereochemistry of the starting material, and die regioisomeric ratio without doubt reflects the ratio of the two conformers (43 and 44 Scheme 197)... 

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