Nucleophiles, azide ion

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. ... 

The syntheses were effected by selective mesylation of one or two hydroxyl groups and displacement of each mesyloxy group by an azido group, which was reduced to amino. Although attempted SN2 displacement of cyclohexane substituents is often unsuccessful, the powerfully nucleophilic azide ion is usually able to displace an alkylsulfonoxy group, and this route has been exploited in several recent cyclitol syntheses. 

The rate constant kgaiv for solvolysis is assumed to reflect the stability and reactivity of (i.e., faster solvolysis gives a more stable cation, which, therefore, reacts more slowly with nucleophiles). The ratio kt /k , measured by product distribution studies, is a measure of selectivity with respect to the nucleophiles azide ion and water. The plot of log k oiv against log (kn/k ) is messy and rather confusing, containing regions of constant selectivity, RSP behavior, and possibly anti-RSP behavior. The present point is that the measures of reactivity and selectivity may affect the conclusions drawn. The role of solvent effects can be important in modifying RSP behavior. ... 

Nucleophilic azide ion displacements are enhanced by polar, aprotic solvents (e.g. DMSO) with which high yield, aryl halide displacement to form even mononitrophenyl azides can occur. Phase-transfer catalysis (permitting the use of less polar solvents) or ultrasonication (for activated primary halides) has also been used. Under such conditions, 8 2 inversion of configuration occurs and this has been observed also for alcohols under Mit-sunobu conditions (Triphenylphosphine, Diethyl Azodicarboxy-late, HN3). Retention is possible where a neighboring group is present. ... 

Al-Kazwini AT, O Neill P, Cundall RB, Adams GE, Junino A, Maignan J (1992) Direct Observation of the Reaction of the Quinone Methide from 5,6-Dihydroxy-indole with the Nucleophilic Azide Ion. Tetrahedron Lett 33 3045... 

At 100°C, /Ceq/fcrac = 2.3. If it is assuHied that ionization to p-nitrobenzoate ion completely randomizes the label, then /Cgq is a measure of the total ion-pair return, and k ac is a measure of the extent of racemization associated with this return. The greater rate of equilibration compared to racemization is indicative of ion-pair return with predominant retention of configuration. In the presence of added sodium azide (0.14 M), /Cgq is about the same, but k ac goes to zero. This means that the highly nucleophilic azide ion intercepts an intermediate that would return with racemization, but is not intercepting an intermediate that returns with retention of configuration. The intermediate that is more easily intercepted is the solvent-separated ion pair, and the intermediate that is difficult to intercept is the intimate ion pair. 

In the presence of. 06 M sodium azide, both 2-octanol and 2-octyl azide are formed with complete inversion of configuration. Clearly, in the presence of the very nucleophilic azide ion, the weakly nucleophilic dioxane cannot compete effectively, and the racemization pathway is eliminated. On the basis of these results and related kinetic studies, it was proposed that the rate-determining intermediate was the intimate ion pair, and that the displacement of the anion from the intimate ion pair occurred stereospecifically with inversion. " ... 

Coupling of (R)-IO and (R)-ll to (R)-12 is completed by the well-known Suzuki-Miyaura reaction where Pd(0) complex catalyzes the formation of the C-C bond (Sect. 6.3, Example 6.4). In the next step, the protecting group is eliminated and the C=C bond reduced by achiral Ir(I) complex to trans-(lR,4S)-14. It is important to note the wrong R configuration at the C(l) atom in this and the previous intermediate. Inversion of the configuration in (15,45)-15 is achieved by the Mitunobu reaction with diphenylphosphorylazide (dppa) as the source of nucleophilic azide ions in the presence of DBU. This reaction is the method of choice for the transformation of alcohols in many other functionalities, azides, esters, alkyl-aryl ethers, imides, sulfonamides, etc., and its mechanism is explained in considerable detail [21, 22]. 

The nucleophile, azide ion (N3 ), gives rise to stereospecific backside displacement of chloride, giving the azidoalkane product with the inverted configuration at the chiral carbon. 

Alkyl azides are unstable compounds, but they can be easily prepared by nucleophilic substitution of a halide by the very nucleophilic azide ion, (N3"). Reduction of azides yields amines. 

Additional evidence in favor of the intermediacy of a carbocation in the acid solvolysis of styrene oxides could be obtained from a trapping experiment. In order to increase the lifetime of the carbocation, it would be convenient to use a -MeO-sustituted styrene oxide as substrate and very little nucleophilic solvent. The trapping agent should be very reactive and much more nucleophile than the solvent, to avoid any undesirable competition reaction between both species. The highly nucleophile azide ion could be suitable to trap the intermediate which has sufficiently long lifetimes in aqueous solutions to be trapped by the reagent (Scheme 11.8). 

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