With Azides

Sodium azide can substitute an azide group for the halogen atom of alkyl or acyl halides. 

A number of serious accidents have occurred due to spontaneous explosion of organic azides. Statements in the literature about the supposed stability of individual azides, particularly those of low molecular weight, should not be implicitly trusted (see, for example, Grundmann and Haldenwanger660). All operations with azides must be carried out with extreme care and with safety precautions similar to those used in work with peroxides, as described on page 306. Particular attention is directed also to the toxicity of hydrogen azide (hydrazoic acid). 

Rodionow, I. W. Matschinskaja, and W. M. Belikow in Synthesen organi-scher Verbindungen, VEB Verlag Technik, Berlin, 1959, Vol. 1, p. 120. 

Alkyl azides are usually prepared by warming alkyl iodides or bromides with an excess of sodium azide in an organic solvent.661 Glycol ethers are recommended as solvents for the simple alkyl azides (C3-C10).662 

Pentyl azide 662 A mixture of activated sodium azide663 (27 g), diethylene glycol monoethyl ether ( Carbitol ) (450 ml), and water (75 ml) is placed in a 1-1 three-necked flask fitted with a reflux condenser, thermometer, and stirrer the mixture is stirred while pure pentyl iodide (60 g) is added in one portion. The solid dissolves within a few minutes. Whilst being continuously stirred, the mixture is heated during 3 h to 95° and then kept at that temperature for 20 h. It is then cooled and poured in two portions into separate portions of ice-water (each 800 ml). The aqueous phases are separated and extracted twice with ether (200-ml batches). The ether solutions are united with the previous organic phases, and the ether is evaporated. The residue (42 g) is fractionated in a vacuum, giving the azide, b.p. 77-78°/112 mm, nD20 1.4266 (27.8 g, 81.4%). 

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The major disadvantage of solid-phase peptide synthesis is the fact that ail the by-products attached to the resin can only be removed at the final stages of synthesis. Another problem is the relatively low local concentration of peptide which can be obtained on the polymer, and this limits the turnover of all other educts. Preparation of large quantities (> 1 g) is therefore difficult. Thirdly, the racemization-safe methods for acid activation, e.g. with azides, are too mild (= slow) for solid-phase synthesis. For these reasons the convenient Menifield procedures are quite generally used for syntheses of small peptides, whereas for larger polypeptides many research groups adhere to classic solution methods and purification after each condensation step (F.M. Finn, 1976). 

Dipolar cycloaddition reactions with azides, imines, and nitrile oxides afford synthetic routes to nitrogen-containing heterocycles (25—30). 

CPB1457), whilst with azide ion the chloro compound (107) underwent ring opening and reclosure to give the 2-tetrazolyl-3-aminopyridine (108) (74CR(C)(278)l42l). 

Apparent nucleophilic attack on large, fully unsaturated rings may occur by way of attack on a valence tautomer, such as the reaction of oxepin with azide ion. Attack on the oxanorcaradiene valence tautomer leads to ring opening of the three-membered ring, and formation of 5-azido-6-hydroxy-l,3-cyclohexadiene (Section 5.17.2.2.4). 

The commonest of these for oxirane opening are amines and azide ion [amide ions promote isomerization to allylic alcohols (Section 5.05.3.2.2)]. Reaction with azide can be used in a sequence for converting oxiranes into aziridines (Scheme 49) and this has been employed in the synthesis of the heteroannulenes (57) and (58) (80CB3127, 79AG(E)962). 

Neopentyl (2,2-dimethylpropyl) systems are resistant to nucleo diilic substitution reactions. They are primary and do not form caibocation intermediates, but the /-butyl substituent efiTectively hinders back-side attack. The rate of reaction of neopent>i bromide with iodide ion is 470 times slower than that of n-butyl bromide. Usually, tiie ner rentyl system reacts with rearrangement to the /-pentyl system, aldiough use of good nucleophiles in polar aprotic solvents permits direct displacement to occur. Entry 2 shows that such a reaction with azide ion as the nucleophile proceeds with complete inversion of configuration. The primary beiuyl system in entry 3 exhibits high, but not complete, inversiotL This is attributed to racemization of the reactant by ionization and internal return. 

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. ... 

Consider these results with respect to the mechanisms outlined in Fig. 5.6 (p. 274). Delineate the types of substituted 1-arylethyl halides which react with azide ion according to each of these mechanisms on the basis of the data given above. 

Perfluoroisobutylene undergoes cycloadditions with azides only at elevated temperatures, the reaction can lead to subsequent loss of nitrogen [6] (equation 4) In another high-temperature reaction, chlorotrifluoroethylene undergoes cy cloaddition with the azomethineylide generated from the thermal electrocyclic nng opening of an azindine, a reaction that contributes to a good overall synthesis of 3,4-difluoropyrroles [7] (equation 5)... 

Chalcogen-nitrogen cations can be generated by the reactions of homopolyatomic chalcogen cations with azides. For example, the... 

Azides have been shown to react with itniniutn salts to give addition products. The same product is obtained if the iminium salt is treated with azide ion or if the enamine is treated with hydrazoic acid 14). The yields of the products were all very high (85-95 %). The interest in this reaction centers on the fact that the azides react with isonitriles to give substituted tetrazoles (83) 44). 

Is azide anion linear or bent Name a common neutral organic molecule that is isoelectronic (same number of valence electrons) with azide anion. Is this molecule linear or bent ... 

Seel and Nogradi were probably the first to suspect that the formulation of the thiol as azidodithiocarbonic acid was incorrect. In a study of the reaction of nitrosyl chloride with azides they found that... 

Properties attributed to the intermediate complex from reaction of 4-nitrofluorobenzene with azide ion were found later to be due to an artifact resulting from photolytic decomposition of the... 

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... 

Nitrile groups attached to the furazan and furoxan rings are susceptible to nucleophilic reagents. The nitrile group was easily reacted with azides (68USP3386968,... 

Diacetylenic lotsitch reagents with azides (THF, 15-18°C, 20 h) afford l-alkyl(aryl)-5-ethynyl-l,2,3-triazoles (94) in 48-70% yield(67ZOR2241). These... 

The 1-mesyloxy intermediate (6) was similarly prepared via the equatorial monobenzoate, and it reacted with azide ion by a single SN2 displacement, since no anchimeric effect was possible here. The scyllo... 

Finally the dimesyl derivative (7) was prepared in a similar manner. When it reacted with azide ion, configurational inversions were observed at positions 1, 2, and 3 (formula 7), owing in part to the anchimeric effect of the position 3 acetoxy group. The vibo or dl (145/23) configuration (same as in the starting material) was retained in the final product 10 (Y = NHAc), a derivative of 3,5-diamino-l,2,4-cyclo-hexanetriol (42). 

Azide synthesis (Section 24.6) A method for preparing amines by S 2 reaction of an alkyl halide with azide ion, followed by reduction. 

Curtius rearrangement (Section 24.6) The conversion of an acid chloride into an amine by reaction with azide ion, followed by heating with water. 

MO calculations were performed rarely for thiopyrans except for an MNDO study of 2 [84ZN(A)267], Charge distribution and orbital interaction concepts were explored in an interpretation of model reactions of thiopyrylium ions with azides giving 68 and the corresponding 3,5-unsub-stituted thiopyrans (84T3549) as well as for the equilibria between 1 and 2 or 167 and 168, respectively (92JOC4431). 

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