Aromatic amines basicity

Owiag to the lower basicity of the parent amines, aromatic amine oxides cannot be formed directiy by hydrogen peroxide oxidation. These compounds may be obtained by oxidation of the corresponding amine with a peracid perbenzoic, monoperphthaUc, and monopermaleic acids have been employed. 

Sulfonamides (R2NSO2R ) are prepared from an amine and sulfonyl chloride in the presence of pyridine or aqueous base. The sulfonamide is one of the most stable nitrogen protective groups. Arylsulfonamides are stable to alkaline hydrolysis, and to catalytic reduction they are cleaved by Na/NH3, Na/butanol, sodium naphthalenide, or sodium anthracenide, and by refluxing in acid (48% HBr/cat. phenol). Sulfonamides of less basic amines such as pyrroles and indoles are much easier to cleave than are those of the more basic alkyl amines. In fact, sulfonamides of the less basic amines (pyrroles, indoles, and imidazoles) can be cleaved by basic hydrolysis, which is almost impossible for the alkyl amines. Because of the inherent differences between the aromatic — NH group and simple aliphatic amines, the protection of these compounds (pyrroles, indoles, and imidazoles) will be described in a separate section. One appealing proj>erty of sulfonamides is that the derivatives are more crystalline than amides or carbamates. 

We mention Williams work briefly here because it may also explain Blangey s observations strongly basic primary amines unequivocally form 7V-nitrosoanilinium ions in strongly acidic media. In contrast to the rate-limiting deprotonations of the less basic aromatic and heteroaromatic nitrosoamine cations discussed in this section, the TV-nitroso cation of a strongly basic amine deprotonates extremely slowly. Therefore, the nitroso rearrangement, the Fischer-Hepp reaction, competes effectively with the 7V-deprotonation. 

In a new approach to the synthesis of phosphoramidates by the Todd-Atherton reaction, those from the more weakly basic amines, more particularly aromatic amines, have been obtained by... 

Figure 19. Multifunctional nature of quinine as a catalyst. The various parts of the molecule fill the following roles (a) hydrogen bond forming ligand forming with metals (b) basic amine (c) aliphatic hydrocarbon—bulk (d) handle to modify (e,f) epimers available few conformers (g) aromatic hydrocarbon—bulk, polarizable (h) handle to modify steric and polar influence.

The oxidation of nonfluorinated aromatic amines with free peracids (not acyl peroxides) proceeded best with the basic amines. The reaction did not pass through the azo stage of oxidation since azo compounds could not be converted under the reaction conditions and hydrazo compounds were oxidized to azo compounds. Under the reaction conditions, p-toluidine was converted only into p-nitrotoluene [31]. 

An additional modification in the above synthetic scheme is possible by introducing the aromatic diamine in the form of its trimethylsilyl derivative [72]. Monotrimethylsilyl-substituted amines are readily prepared from the free amine with hexamethyldisilazane or trimethylsilyl chloride in the presence of a tertiary amine [73, 74] whereas bis(trimethylsilyl)-substituted amines require more aggressive reagents, such as butyllithium in conjunction with trimethylsilyl chloride [75]. As illustrated in Scheme 19, monotrimethylsilyl-substituted amines react with acyl chlorides to form the corresponding amides and liberate trimethylsilyl chloride. Monotrimethylsilyl-substituted amines are reported to display increased reactivity with acyl chlorides [76], This is of great synthetic importance since the increased reactivity allows for reaction with low basicity amines. Bis(trimethylsilyl)-substituted amines, on the other hand, react with acyl chlorides to form the corresponding JV-trimethylsilyl amides, see Scheme 20. The JV-trimethylsilyl amides are much more soluble in common organic solvents. However, they are hydrolytically unstable and readily convert back to the free amides. 

Because of their basicity (lower than that of aliphatic amines), aromatic primary amines can be selectively nitrosated179 in the presence of aliphatic amines at low pH. An example is provided by the deamination of 3 -amino-3 -deoxyadenosine, although the yield of the product isolated, 3 -amino-3 -deoxyinosine, was180 only about 4%. Some 50% of the starting material remained unchanged, and hydrolysis released adenine (30%). 

Both 4-arylimino-2,6-dimethylpyran salts (167) and l-aryl-4-methoxy-2,6-dimethyl-pyridinium salts (168) result from the reaction of 4-methoxy-2,6-dimethylpyrylium salts with primary aromatic amines (78JCS(P1)1373). The ratio of the products varies with the basicity of the amine, the less basic amines giving mainly the pyran salt. The free iminopyrans (169), which have limited stability at room temperature, are readily obtained from the salts. 

Aromatic and heteroaromatic amines can be linked to insoluble supports using strategies similar to those used for aliphatic amines. Because of the lower basicities of aromatic amines, however, their /V-bcnzyl derivatives will usually be more susceptible to acidolytic cleavage than aliphatic /V-bcnzylamincs. For the same reason, N-acyl derivatives of aromatic amines will generally be more sensitive towards nucleophiles than the corresponding derivatives of aliphatic amines. 

In contrast to aliphatic amines, aromatic amines hardly react with C02 [21a] because of their poorer basicity. However, in the presence of suitable auxiliary bases (B) (such as amidines or penta-alkylguanidine superbases), carbamate salts (BH)02CNRAr (R = H, alkyl) can be generated in solution, as supported by spectroscopic and reactivity data [29]. It has been shown that even tributylamine may be effective if a suitable alkali metal salt is also present in solution in the latter case, the N-arylcarbamate has been isolated as an alkali salt (Equation 6.3)... 

The virtual screen was performed on nearly 50,000 compounds that were taken from a library of 1.6 million. Selection for docking required a structure to have a nonpolar aromatic ring and basic amine for matching the binding... 

Amines are weak bases. Alkylamines and ammonia are of comparable basicity, but aromatic amines are much weaker as a result of delocalization of the unshared electron pair on nitrogen to the ortho and para carbons of the aromatic ring. Amides are much weaker bases than amines because of delocalization of the unshared electron pair on nitrogen to the adjacent carbonyl oxygen. Amides are stronger Bronsted acids than amines because of the partial positive charge on the amide nitrogen and resonance in the amidate anion. 

For a discussion of the diazotization of weakly basic amines see Saunders, "Aromatic Diazo Compounds, Edward Arnold and Co., London, 1936. 

Sorption of amines on starch was recognized760 as early as 1910 in studies of the interactions between starch and piperidine. Experiments with starch and 1 -butylamine show extraordinarily high and fast adsorption. The equilibrium concentration of that amine reaches 1982 mg/g of starch, as compared to n-hexane (6 mg/g), ethyl acetate (27 mg/g), and ethanol (208 mg/ g). Desorption is, in fact, also significant, but is much lower than in the case of the other complexes just mentioned. Because of their basic properties, amines decompose their host molecule.674 Less-basic amines, such as aromatic trypoflavin761 and aliphatic amine salts,762 can be included into starch. 

The foimation of aromatic diazonium salts from aromatic primary amines is one of the oldest synthetic procedures in organic chemistry. Methods based on nitrosation of amine with nitrous acid in aqueous solution are die best known, but diere are variants which are of particular use widi weakly basic amines and for the isolation of diazonium salts fiom nonaqueous media. General reviews include a book by Saunders and AUen and a survey of preparative methods by Schank. There ate also reviews on the diazotization of heteroaromatic primary amines and on the diazotization of weakly basic amines in strongly acidic media. The diazotization process (Scheme 11) goes by way of a primary nitrosamine. 

Figure 7.13 The de novo design software Skelgen was used by Roche to fit fragments into a pharmacophore model that was obtained by merging the information of models 1 and 2. The best designed molecule is shown (EC50 = 0.2 nM Ki = 0.3 nM). The pharmacophore features are displayed as black, grey and white circles, representing basic amines, electron-rich regions and aromatic interaction centers, respectively.

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