Aniline isomerization

DIAZOTISATION OF ANILINE. PHENOL, IODOBENZENE AND BENZENE PROM ANILINE. ISOMERISM OF THE DIAZO-COMPOUNDS... 

This reaction sequence is much less prone to difficulties with isomerizations since the pyridine-like carbons of dipyrromethenes do not add protons. Yields are often low, however, since the intermediates do not survive the high temperatures. The more reactive, faster but less reliable system is certainly provided by the dipyrromethanes, in which the reactivity of the pyrrole units is comparable to activated benzene derivatives such as phenol or aniline. The situation is comparable with that found in peptide synthesis where the slow azide method gives cleaner products than the fast DCC-promoted condensations (see p. 234). 

Anilines react with ct-haloacetophenones to give 2-arylindoles. In a typical procedure an W-phenacylaniline is heated with a tw o-fold excess of the aniline hydrobromide to 200-250°C[1]. The mechanism of the reaction was the subject of considerable investigation in the 1940s[2]. A crucial aspect of the reaction seems to be the formation of an imine of the acetophenone which can isomerize to an aldimine intermediate. This intermediate apparently undergoes cyclization more rapidly (path bl -> b2) than its precursor (Scheme 7.3). Only with very reactive rings, e.g, 3,5-dimethoxyaniline, has the alternative cydiz-ation (path al a2) to a 3-arylindole been observed and then only under modified reaction conditions[3],... 

Maleic anhydride and the two diacid isomers were first prepared in the 1830s (1) but commercial manufacture did not begin until a century later. In 1933 the National Aniline and Chemical Co., Inc., installed a process for maleic anhydride based on benzene oxidation using a vanadium oxide catalyst (2). Maleic acid was available commercially ia 1928 and fumaric acid production began in 1932 by acid-catalyzed isomerization of maleic acid. 

Amidation. Reaction of maleic anhydride or its isomeric acids with ammonia [7664-41-7] (qv), primary amines (qv), and secondary amines produces mono- or diamides. The monoamide derivative from the reaction of ammonia and maleic anhydride is called maleamic acid [557-24-4] (8). Another monoamide derivative formed from the reaction of aniline [62-53-3] and maleic anhydride is maleanilic acid [555-59-9] (9). 

Phenazine mono-N-oxides have also been prepared from nitrobenzene derivatives. Condensation of nitrobenzene with aniline using dry NaOH at 120-130 °C results in modest yields of phenazine 5-oxide, although the precise mechanism of this reaction is not well understood (57HC(ll)l) with unsymmetrical substrates it is not possible to predict which of the isomeric fV-oxides will be produced. Nitrosobenzene derivatives also function as a source of phenazine mono-fV-oxides thus, if 4-chloronitrosobenzene is treated with sulfuric acid in acetic acid at 20 °C the fV-oxide is formed (Scheme 21). 

The impurities present in aromatic nitro compounds depend on the aromatic portion of the molecule. Thus, benzene, phenols or anilines are probable impurities in nitrobenzene, nitrophenols and nitroanilines, respectively. Purification should be carried out accordingly. Isomeric compounds are likely to remain as impurities after the preliminary purifications to remove basic and acidic contaminants. For example, o-nitrophenol may be found in samples ofp-nitrophenol. Usually, the ri-nitro compounds are more steam volatile than the p-nitro isomers, and can be separated in this way. Polynitro impurities in mononitro compounds can be readily removed because of their relatively lower solubilities in solvents. With acidic or basic nitro compounds which cannot be separated in the above manner, advantage may be taken of their differences in pK values (see Chapter 1). The compounds can thus be purified by preliminary extractions with several sets of aqueous buffers... 

The /neta-substituted anilines provide one or two isomeric products depending on the nature of the substituents (vide infra). 

The Hegedus indole synthesis involves one of the earlier (formal) examples of olefin hydroamination. An ortho-vinyl or ortho-nllyl aniline derivative 1 is treated with palladium(II) to deliver an intermediate resulting from alkene aminopalladation. Subsequent reduction and/or isomerization steps then provide the indoline or indole unit 2, respectively. 

Azcpincs under acid conditions reportedly117-225 yield aniline derivatives although ring contraction to pyridines is more usual. Thus, highly substituted 3//-azepines, e.g. 28, with a vacant 7-position, formed by cycloaddition of 2//-azirines with cyclopentadienones, on heating in acetic acid isomerize rapidly to the correspondingly substituted anilines 29.117... 

Allylmagnesium bromide, 41, 49 reaction with acrolein, 41, 49 5-Allyl-l,2,3,4,5-pentachlorocyclopen-tadiene, 43, 92 Allyltriphenyltin, 41, 31 reaction with phenyllithium, 41, 30 Aluminum chloride, as catalyst, for isomerization, 42, 9 for nuclear bromination and chlorination of aromatic aldehydes and ketones, 40, 9 as Friedel-Crafts catalyst, 41, 1 Amidation, of aniline with maleic anhydride, 41, 93... 

When HCl salts of arylalkylamines are heated at 200-300°C, migration occurs. This is called the Hofmann-Martius reaction. It is an intermolecular reaction, since crossing is found. For example, methylanilinium bromide gave not only the normal products o- and p-toluidine but also aniline and di- and trimethylanilines." As would be expected for an intermolecular process, there is isomerization when R is primary. 

The scope and mechanism of the isomerization of arylamines to methyl-substituted aromatic heterocycles have been studied. Aniline, toluidines, naphthylamines and m-phenylenediamine all gave the corresponding ortho-methyl-substituted aza-aromatics when exposed to high NHj pressure and elevated temperature in the presence of acid catalysts, e.g., zeolites. The yiel of pyridines formed by this process range from low to moderate <95JC(155)268>. 

The hydrogenation of 4-alkyl substituted anilines results in the production to two possible isomeric forms, cis and trans, and both of these isomers have two possible conformations in the chair configuration of the cyclohexyl ring. However experimentally it has been found that one cis and one trans conformer dominate. The dominant isomers are shown in Figure 1. 

The benzyl 1,2,4-thiadiazolium salt 59 can be isomerized to the 5-imino-l,2,4-thiadiazolidine 60 when treated with a strong base like potassium /-butoxide (Equation 17) <1997ZOR1728>. If the 2-substituent is replaced with a tosylmethyl group and the 5-position substituent is a diphenylamino in place of an aniline such as compound 61, then a rearrangement occurs to give an imidazole 62 (Equation 18) <1997ZOR1728>. 

Closely related to the 1,3,2-dithiazolyl radicals are the isomeric 1,2,3-dithiazolyl radicals. The benzo-fused derivatives were originally prepared by Herz in 192276 from the reaction of aniline and its derivatives with an excess of S2C12 (Scheme 10). Almost invariably the aromatic ring becomes substituted by chlorine para to the amine N atom. 

The stability of o-sulfonylbenzonitrile oxides and their thiophene analogs probably depends on electronic factors. The same factors do not prevent dimerization, as can be seen from data concerning several differently substituted nitrile oxides of the thiophene series (103). Sterically stabilized 3-thiophenecarbonitrile oxides 18 (R = R1 = R2 = Me R = R2 = Me, R1 = i -Pr), when boiled in benzene or toluene, isomerized to isocyanates (isolated as ureas on reaction with aniline) while nitrile oxides 18 with electron-withdrawing substituents (R1 and/or R2 = SOiMe, Br) dimerized to form furoxans 19. 

N-Heterocyclization.1 Anilines react with 1,3-propanediol in diglyme in the presence of RuC1,-3H20 complexed with Bu,P to give quinolines in 50-60% yield (isolated). Two isomeric quinolines are formed in a similar reaction with an un-symmetrical 1,3-diol. 

A highly substantive bluish red bis(sulphatoethylsulphone) structure (7.73) has been patented recently [29]. In a kinetic study using the t.l.c. double-scanning method, the condensation reactions between the bis(aminochlorotriazine) dye Cl Reactive Red 120 (7.48 X = Cl) and the two isomeric sulphatoethylsulphone anilines 7.38 and 7.39 to yield the two corresponding bis(sulphatoethylsulphone) isomeric dyes were compared. The rate constant of the reaction between Red 120 and the meta isomer 7.39 was about ten times as large as that for the para isomer 7.38 [64]. 

The reactions of anilines (R =4-MeO and 3-C1) and diethyl acetylmalonate in nitrobenzene at 230-235°C for 1-2 hr gave 2,4-dihydroxy-3-acetyl-quinolines (667, R = 6-MeO and 7-C1). In the case of 3-chloroaniline, a mixture of the isomeric 5- and 7-chloroquinolines was obtained (46JA324). The 7-chloroquinoline was the major isomer. 

Similar experiments reveal that ionized N-heterocycles such as pyridines eliminate HCN, rather than HNC148. This distinction offers a potentially useful means of distinguishing between isomeric anilines and pyridines. 

Wiener H (1948a) Relation of the physical properties of the isomeric alkanes to molecular structure. Surface tension, specific dispersion, and critical solution temperature in aniline. J. Phys. Chem. 52 1082-1089. 

Interestingly, the three isomeric aminopyridine molecular ions display ion chemistry similar to aniline molecular ions, i.e., metastable HNC loss, [222] instead of HCN loss which should also be possible due to the pyridine core of the molecule (Fig. 6.56b). 

The experimental procedure can be varied by the use of reagents which will give biguanides in situ and thus form the required triazine. Examples include 493, 554) the interaction of arylamines (e.g. p-chloro-aniline hydrochloride) and cyanoguanidine, followed by acetone and hydrochloric acid. Acetone may be replaced by its bisulphite compound, by diethyl acetal or by isopropenyl acetate, but p-chlorophenylbiguanide fails to condense 113) with acetone diethyl acetal at 130°. Under the correct acid conditions, the isomeric p-chloroanilino-triazine (CXXV) is not formed on the other hand, the free p-chlorophenylbiguanide base did not react with acetone in the absence of a catalyst. 

Structures have been determined for [Fe(gmi)3](BF4)2 (gmi = MeN=CHCF[=NMe), the iron(II) tris-diazabutadiene-cage complex of (79) generated from cyclohexanedione rather than from biacetyl, and [Fe(apmi)3][Fe(CN)5(N0)] 4F[20, where apmi is the Schiff base from 2-acetylpyridine and methylamine. Rate constants for mer fac isomerization of [Fe(apmi)3] " were estimated indirectly from base hydrolysis kinetics, studied for this and other Schiff base complexes in methanol-water mixtures. The attenuation by the —CH2— spacer of substituent effects on rate constants for base hydrolysis of complexes [Fe(sb)3] has been assessed for pairs of Schiff base complexes derived from substituted benzylamines and their aniline analogues. It is generally believed that iron(II) Schiff base complexes are formed by a template mechanism on the Fe " ", but isolation of a precursor in which two molecules of Schiff base and one molecule of 2-acetylpyridine are coordinated to Fe + suggests that Schiff base formation in the presence of this ion probably occurs by attack of the amine at coordinated, and thereby activated, ketone rather than by a true template reaction. ... 

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