Azide anion, nucleophile addition

A kinetic distinction between the operation of the SN1 and SN2 modes can often be made by observing the effect on the overall reaction rate of adding a competing nucleophile, e.g. azide anion, N3e. The total nucleophile concentration is thus increased, and for the SN2 mode where [Nu ] appears in the rate equation, this will result in an increased reaction rate due to the increased [Nut]. By contrast, for the Stfl mode [Nut] does not appear in the rate equation, i.e. is not involved in the rate-limiting step, and addition of N3e will thus be without significant effect on the observed reaction rate, though it will naturally influence the composition of the product. 

Fig. 1 for stepwise solvolysis of R-X is due to the increase in ks (s ), with decreasing stability of the carbocation intermediate, relative to the constant value of az (M s ) for the diffusion-limited addition of azide anion. The lifetime for the carbocation intermediate eventually becomes so short that essentially no azide ion adduct forms by diffusion-controlled trapping, because addition of solvent to R occurs faster than escape of the carbocation from the solvent cage followed by addition of azide ion (k Now, the nucleophile adduct must form through a... 

Azide ion is a modest leaving group in An + Dn nucleophilic substitution reactions, and at the same time a potent nucleophile for addition to the carbocation reaction intermediate. Consequently, ring-substituted benzaldehyde g m-diazides (X-2-N3) undergo solvolysis in water in reactions that are subject to strong common-ion inhibition by added azide ion from reversible trapping of an o -azido carbocation intermediate (X-2 ) by diffusion controlled addition of azide anion (Scheme... 

Only the azide anion amongst the multitude of possible nitrogen nucleophiles had reported utility in alkynyliodonium salt addition chemistry at the inception of this project. Therefore, extension of this chemistry to amines and amide derivatives occupied our attention at the outset. The requirement for a soft, polarizable nucleophile limited our options, and screening a primary amine as well as some common amide derivatives in the prototype transformation 35 + 36 - 38 led to the first sense that this goal was achievable (Scheme 6).5a c In fact, the common amine protecting group tosyl proved to be the most effective modulator of amine nucleophilicity in this assay. Interestingly, amide pKa does not... 

These questions were addressed in studies of the reactions ofp-1 and / -Me-1 + in aqueous solution. The quinone methide p-1 was generated by photoheterolysis of neutral 4-hydroxybenzyl acetate in water, and ks = 3.3 s 1 determined for addition of water.52 The O-methylated quinone methide / -Me-l+ was generated as an intermediate of solvolysis of neutral precursors in water,128 and ks = 2.5 x 108 s 1 for addition of water was determined by using the diffusion-limited rate of nucleophile addition of azide anion to / -Me-l+ as a clock for the slower addition reaction of solvent.135,138 These data show that methylation ofp-1 causes an enormous 6 x 107-fold increase in the reactivity of the electrophile with solvent water.52... 

The electron-deficient double bond in lH-pentafluoropropene reacts easily with nucleophiles such as azide anion to form primarily an addition product l-azido-l,2,3,3,3-pentafluoropropane. In the basic medium, unsaturated l-azido-2,3,3,3-tetrafluoropropene is also formed, either by elimination of hydrogen fluoride from the addition product, or by direct displacement of fluorine by SN2 mechanism [90]. 

However, reaction of acyclic dienamines with hydrazoic acid gives a mixture of products derived by 1,2-, 1,4- and 3,4 + 1,2-addition of HN3 to the diene system. In this case C-protonation is followed immediately by addition of the strongly nucleophilic azide anion, so that equilibrium of the C-protonated enamines cannot occur3c. Treatment of the morpholine dienamine of isophorone with trichloroacetic acid in boiling benzene resulted in decarboxylation and the 1,4-addition of a proton and the trichloromethyl anion. Basic hydrolysis of the adduct gave dienoic acid 54 (Scheme 4). 

Inductive electron-withdrawal by the azido group, perhaps reinforced by the weak conjugative ( —K) effect, should activate nucleophilic addition (Ad ) reactions of olefins conjugated to the azido substituent. The only data available in this area concerns the addition in a dipolar aprotic medium of azide ion to picryl azide (18), in which the nucleophile is directed to the C(d position of the aromatic ring with the formation of the benzenide anion (19) . Although activation is predominantly due to the nitro groups, the inductive... 

Aqueous cationic micelles speed and anionic micelles inhibit bi-molecular reactions of anionic nucleophiles. Both cationic and anionic micelles speed reactions of nonionic nucleophiles. Second-order rate constants in the micelles can be calculated by estimating the concentration of each reactant in the micelles, which are treated as a distinct reaction medium, that is, as a pseudophase. These second-order rate constants are similar to those in water except for aromatic nucleophilic substitution by azide ion, which is much faster than predicted. Ionic micelles generally inhibit spontaneous hydrolyses. But a charge effect also occurs, and for hydrolyses of anhydrides, diaryl carbonates, chloroformates, and acyl and sulfonyl chlorides and SN hydrolyses, reactions are faster in cationic than in anionic micelles if bond making is dominant. This behavior is also observed in water addition to carbocations. If bond breaking is dominant, the reaction is faster in anionic micelles. Zwitterionic sulfobetaine and cationic micelles behave similarly. 

The data in Tables I and II, together with extensive additional evidence, allow several generalizations to be made about micellar effects upon bi-molecular reactions (5). First, overall rate constants follow the distribution of both reactants between water and micelles. Second, second-order rate constants for reactions of nonionic nucleophiles are lower in micelles than in water. Third, second-order rate constants for reactions of anionic nucleophiles are similar in water and micelles except for some reactions of azide ion (37). 

The strong association of I with small and hard anions leads only to a small and difflcult-to-measure (53) rate decrease of nucleophilic aromatic substitution (52, 53). Addition of the host II, however, to the SN2 reactions A and B (Scheme II) produced remarkable rate enhancements (Table II), which showed a Michaelis-Menten-type dependence on ratio of nucleophile and catalyst concentrations. The catalytic effect of the host was ascribed to a desolvation of the azide anion, which was used in all cases. This situation is similar to the rationalization of corresponding micelle-catalyzed substitutions (55, 56). Another important factor is the stabilization of the transition states,... 

RCON3 RNH2). The azide may be synthesized via an addition-elimination in which the azide anion cts as a nucleophile upon an acid chloride. 

Nucleophilic additions of inorganic anions to carbonyl groups also proceed efficiently under PTC conditions. Syntheses of acyl azides, acyl cyanides, cyanohydrin derivatives, and the Reissert compounds belong to this category of reactions ... 

In addition to the usual substitution reactions directly on the nitrogen atom of the amino or amido group, there are (as noted earlier, e.g.. Table 7.7) substitution reactions with other nucleophiles that can be converted to the amino (or substituted amino) group. These include incorporation of the azido function (produced by, e.g., a nucleophilic substitution reaction of azide anion [Ns"] on an alkyl halide) and its subsequent reduction (with lithium aluminum hydride, LiALH,) (Equation 10.60) or triphenylphosphine [( 5115)3 ] (Equation 10.61) to the corresponding amine, as well as a similar displacement reaction with isocyanate (0=C=N ) (Equation... 

Reaction of 6,7-dialkynyl-l,3-dimethylpteridine-2,4-(lH,3H)-diones 3.832 with sodium azide in DMF at room temperature produced [l,2,3]triazolo[l, 5, l,2]-pyrido[4,3-g ]-pteridine-8,10(9fi,llH)-diones 3.833 together with the isomers 3.834 (Scheme 3.107) [337]. The mechanism involves 1,3-dipolar cycloaddition of azide ion to the triple bond followed by intramolecular nucleophilic addition of the intermediate 1,2,3-triazole N-anion to the second triple bond. 

To account for the catalytic activity of catalyst 45d, several experimental data led the authors to privilege a Brpnsted acid/base catalysis over a nucleophilic catalysis. In particular, the full protonation of catalyst 45d observed by simply adding HN3 lends strong support to this point of view. The protonated catalyst 45d would promote the nucleophilic addition of azide counter anion to ketene followed by an enantioselective protonation of the resulting enolate 57 (Scheme 3.27). 

The effect of a substituent may be substantially modified by fast, concurrent, reversible addition of the nucleophile to an electrophilic center in the substituent. Ortho- and para-CS.0 and pam-CN groups have been found by Miller and co-workers to have a much reduced activating effect on the displacement of halogen in 2-nitrohaloben-zenes with methoxide ion [reversible formation of hemiacetal (143) and imido ester anions (144)] than with azide ion (less interaction) or thiocyanate (little, if any, interaction). Formation of 0-acyl derivatives of 0x0 derivatives or of A-oxides, hydrogen bonding to these moieties, and ionization of substituents are other examples of reversible and often relatively complete modifications under reaction conditions. If the interaction is irreversible, such as hydrolysis of a... 

Because of resonance stabilization of the anion, a tet-nazolyl moiety is often employed successfully as a bioisosteric replacement for a carboxy group. An example in this subclass is provided by azosemide (27). Benzonitrile analogue is prepared by phosphorus oxychloride dehydration of the corresponding benzamide. Next, a nucleophilic aromatic displacement reaction of the fluorine atom leads to The synthesis concludes with the 1,3-dipolar addition of azide to the nitrile liinction to produce the diuretic azosemi de (27). ... 

The value of = 1 X 10 s for the first-order rate constant for collapse of an ion pair between Me-4 and pentaflourobenzoate ion is larger than the second-order rate constant rcoo = 5x10 M s reported for the bimolecular addition of alkane carboxylates to Me-4. This second-order rate constant is limited by the rate constant for formation of an ion pair between Me-4 and a carboxylate ion. The larger barrier to encounter-limited reactions of carboxylate ions compared with the diffusion-limited reactions of anions such as azide ion, = 5 X 10 represents the barrier to desolvation of nucleophile that must precede formation of an ion pair between Me-4 and a carboxylate ion (Scheme 13). ... 

Sodium azide also adds to olefins of this t3rpe to give w-triazoles in fairly good yields. A mechanism involving nucleophilic displacement of the substituent X by azide, followed by cyclization of the vinyl azide in the presence of azide ions, has been suggested. An alternative mechanism involves conjugate addition of azide to the double bond, cyclization of the resulting anion, and aromatization. 

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