Substrates secondary

Entry 4 shows that reaction of a secondary 2-octyl system with the moderately good nucleophile acetate ion occurs wifii complete inversion. The results cited in entry 5 serve to illustrate the importance of solvation of ion-pair intermediates in reactions of secondary substrates. The data show fiiat partial racemization occurs in aqueous dioxane but that an added nucleophile (azide ion) results in complete inversion, both in the product resulting from reaction with azide ion and in the alcohol resulting from reaction with water. The alcohol of retained configuration is attributed to an intermediate oxonium ion resulting from reaction of the ion pair with the dioxane solvent. This would react until water to give product of retained configuratioiL When azide ion is present, dioxane does not efiTectively conqiete for tiie ion-p intermediate, and all of the alcohol arises from tiie inversion mechanism. ... 

Although this is a secondary substrate, complete shielding from backside attack by nucleophiles leads to S l solvolysis without solvent participation. The correspond-... 

Steric hindrance raises the energy of the Sjv-2 transition state, increasing AG- and decreasing the reaction rate (Figure 11.7a). As a result, SN2 reactions are best for methyl and primary substrates. Secondary substrates react slowly, and tertiary substrates do not react by an S -2 mechanism. 

The reaction of an alkyl halide or los3 late with a nucleophiJe/base results eithe in substitution or in diminution. Nucleophilic substitutions are of two types S 2 reactions and SN1 reactions, in the SN2 reaction, the entering nucleophih approaches the halide from a direction 180° away from the leaving group, result ing in an umbrella-like inversion of configuration at the carbon atom. The reaction is kinetically second-order and is strongly inhibited by increasing stork bulk of the reactants. Thus, S 2 reactions are favored for primary and secondary substrates. 

To sum up, primary and secondary substrates generally react by the Sn2 mechanism and tertiary by the SnI mechanism. However, tertiary substrates seldom undergo nucleophilic substitution at all. Elimination is always a possible side reaction of nucleophilic substitutions (wherever a P hydrogen is present), and with tertiary substrates it usually predominates. With a few exceptions, nucleophilic substitutions at a tertiary carbon have little or no preparative value. However, tertiary substrates that can react by the SET mechanism (e.g., /i-N02C6H4CMe2Cl) give very good yields of substitution products when treated with a variety of nucleophiles. ... 

Yet another approach uses electrolysis conditions with the alkyl chloride, Pe(CO)s and a nickel catalyst, and gives the ketone directly, in one step. In the first stage of methods 1, 2, and 3, primary bromides, iodides, and tosylates and secondary tosylates can be used. The second stage of the first four methods requires more active substrates, such as primary iodides or tosylates or benzylic halides. Method 5 has been applied to primary and secondary substrates. 

Finally we learned that if we analyze the first factor (substrate), we will find two effects at play electroiucs and sterics. We saw that Sn2 reactions require primary or secondary substrates because of sterics—it is too crowded for the nucleophile to attack a tertiary substrate. On the other hand, SnI reactions did not have a problem with sterics, but electronics was a bigger issue. Tertiary was the best, because the alkyl groups were needed to stabilize the carbocation. 

When the reageht fuhotiohs exclusively as a nucleophile (ahd hot as a base), ohiy substitutioh reactions occur (not elimination). The substrate determines which mechahism operates. 3 2 predominates for primary substrates, and 3 1 predominates for tertiary substrates. For secondary substrates, both 3 2 ahd 3 1 cah occur, although 3 2 is generally favored (especially when a polar aprotic solvent is used). 

For secondary substrates, E2 predominates, because E2 is not stericaiiy hindered, whiie 3 2 exhibits some steric hindrance. 

Our next step is to identify the substrate. In this case, the substrate is 3-bromopentane, which is a secondary substrate, and therefore, we expect E2 and Sn2 mechanisms to operate ... 

The E2 pathway is expected to provide the major product, because the Sn2 pathway is more sensitive to steric hindrance provided by secondary substrates. 

The proposed mechanism for the functionality of MnP involves the oxidation of manganous ions Mn2+ to Mn3+, which is then chelated with organic acids. The chelated Mn3+ diffuses freely from the active site of the enzyme and can oxidize secondary substrates [25],... 

Ionization of the secondary substrates such as 1-cyclobutylethanol, cyclobutylphenylmethanol, and cyclobutylcyclopropylmethanol, in all cases,... 

In general terms then, the Sn2 reaction is only important for primary and secondary substrates, and the rate of reaction for primary substrates is considerably greater than that for secondary substrates. Should a reaction be attempted with tertiary substrates, one does not usually get substitution, but alternative side-reactions occur (see Section 6.4). 

As we have just seen, SnI reactions are highly favoured at tertiary carbon, and very much disfavoured at primary carbon. This is in marked contrast to Sn2 reactions, which are highly favoured at primary carbon and not at tertiary carbon. With Sn2 reactions, consideration of steric hindrance rationalized the results observed. This leads to the generalizations for nucleophilic substitutions shown in Table 6.8, with secondary substrates being able to participate in either type of process. 

Nucleophilic Substitution at Benzyl Derivatives. The sharp break from a stepwise to a concerted mechanism that is observed for nucleophilic substitution of azide ion at X-l-Y (Figs. 2.2 and 2.5) is blurred for nucleophilic substitution at the primary 4-methoxybenzyl derivatives (4-MeO,H)-3-Y. For example, the secondary substrate (4-MeO)-l-Cl reacts exclusively by a stepwise mechanism through the liberated carbocation intermediate (4-MeO)-T, which shows a moderately large selectivity toward azide ion ( az/ s = 100 in 50 50 (v/v) water/ trifluoroethanol). The removal of an a-Me group from (4-MeO)-l-Cl to give (4-MeO,H)-3-Cl increases the barrier to ionization of the substrate in the stepwise reaction relative to that for the concerted bimolecular substitution of azide ion. The result is that both of these mechanisms are observed concurrently for nucleophilic substitution of azide ion at (4-MeO,H)-3-Cl in water/acetone solvents. These concurrent stepwise and concerted nucleophilic substitution reactions of azide ion with (4-MeO,H)-3-Cl show that there is no sharp borderline between mechanisms for substitution at primary benzylic carbon, but instead a region of overlap where both mechanisms are observed. 

Use of other methods has contributed further to the emerging picture of solvolysis of most secondary systems as being solvent-assisted. For example, the solvolysis rate acceleration on substituting a-hydrogen by CH3 in 2-adamantyl bromide is 107 5, much larger than that found for other secondary—tertiary pairs such as isopropyl-/-butyl. In molecules less hindered than 2-adamantyl, the secondary substrate is accelerated by nucleophilic attack of solvent.100 Rate accelerations and product distributions found on adding azide ion to solvolysis mixtures (Problem 4) also provide confirmatory evidence for these conclu-... 

It can therefore be concluded that the sites of secondary substrate recognition of the enzyme which impose a strain on the substrate and cause a geometrical distortion of the tetrahedral intermediate, are an obligatory part of the catalytic action of carboxypeptidase A which takes place under stere-oelectronically controlled conditions. 

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