Basicity of heterocyclic amines

The basicity of heterocyclic amines varies over a wide range and reflects both the hybridization of the orbital of nitrogen containing the lone pair electrons and the effects of delocalization. Pyridine is a substantially weaker base than alkylamines such as piperidine. The electron pair of pyridine occupies an sp2-hybridized orbital and lies closer to the nucleus than the electron pair in the sp -hybridized orbital of alkylamines. As a result, pyridine is a weaker base (larger than an alkylamine. 

Tertiary amines catalyze the homopolymerization of epoxy resins in the presence of hydroxyl groups, a condition which generally exists since most commercial resins contain varying amounts of hydroxyl functionality (B-68MI11501). The efficiency of the catalyst depends on its basicity and steric requirements (B-67MI11501) in the way already discussed for amine-catalyzed isocyanate reactions. A number of heterocyclic amines have been used as catalytic curatives pyridine, pyrazine, iV,A-dimethylpiperazine, (V-methylmorpholine and DABCO. Mild heat is usually required to achieve optimum performance which, however, is limited due to the low molecular weight polymers obtained by this type of cure. 

Although the pKa or H0 values for several acids are known [10,11], the definition of strong acid is somewhat arbitrary, because the position of equilibrium (13) depends on the basicity of heterocyclic monomer. Because this basicity varies from rather low (e.g., cyclic acetals) to rather high (e.g., cyclic amines) no universal rule describing the behavior of particular protonic acids in ring-opening polymerization exists. 

Basicity of Heterocyclic Aromatic Amines (Section 23.5C) Heterocyclic aromatic amines are considerably weaker bases than aliphatic amines. 

The 1-azirine ring also undergoes a number of reactions in which the heterocycle plays the role of the nucleophile. Although the basicity of the nitrogen atom in the azirine ring is much lower than in simple aliphatic amines, this system can still function as a nucleophilic reagent. One example of this involves the acid-catalyzed hydrolysis of 1-azirines to a-aminoketones (200) which represents a well-established reaction. In fact, in many reactions of 1-azirines where acid catalysis is used, formation of a-aminoketones is difficult to avoid (67JA44S6). 

Esters of diphenylacetic acids with derivatives of ethanol-amine show mainly the antispasmodic component of the atropine complex of biologic activities. As such they find use in treatment of the resolution of various spastic conditions such as, for example, gastrointestinal spasms. The prototype in this series, adiphenine (47), is obtained by treatment of diphenyl acetyl chloride with diethylaminoethanol. A somewhat more complex basic side chain is accessible by an interesting rearrangement. Reductive amination of furfural (42) results in reduction of the heterocyclic ring as well and formation of the aminomethyltetrahydro-furan (43). Treatment of this ether with hydrogen bromide in acetic acid leads to the hydroxypiperidine (45), possibly by the intermediacy of a carbonium ion such as 44. Acylation of the alcohol with diphenylacetyl chloride gives piperidolate (46). ... 

Table 24.1 lists pXa values of some ammonium ions and indicates that there is a substantial range of amine basicities. Most simple alkylainines are similar in their base strength, with p/q/s for their ammonium ions in the narrow range 10 to 11. Aiylctmines, however, are considerably less basic than alkylamines, as are the heterocyclic amines pyridine and pyurole. 

Other common five-membered heterocyclic amines include imidazole and thiazole. Imidazole, a constituent of the amino acid histidine, has two nitrogens, only one of which is basic. Thiazole, the five-membered ring system on which the structure of thiamin (vitamin Bt) is based, also contains a basic nitrogen that is alkylated in thiamin to form a quaternary ammonium ion. 

The diazotization of heteroaromatic amines is basically analogous to that of aromatic amines. Among the five-membered systems the amino-azoles (pyrroles, diazoles, triazoles, tetrazoles, oxazoles, isooxazoles, thia-, selena-, and dithiazoles) have all been diazotized. In general, diazotization in dilute mineral acid is possible, but diazotization in concentrated sulfuric acid (nitrosylsulfuric acid, see Sec. 2.2) or in organic solvents using an ester of nitrous acid (ethyl or isopentyl nitrite) is often preferable. Amino derivatives of aromatic heterocycles without ring nitrogen (furan and thiophene) can also be diazotized. 

Cyclization to six-membered rings (Eq. 15) provided modest diastereoselectivity and required the use of bulkier PhMeSiH2 to prevent olefin hy-drosilylation. Propargyl and homopropargyl amines 94 afforded a variety of heterocycles (Scheme 21), if the catalyst was added slowly over the reaction course to diminish side reactions resulting from metal coordination to the basic amine [56]. The reaction procedure was extended to the diastereoselect-ive bicyclization of dienyne substrate 95, giving 96 as product in a cascade fashion (Eq. 16) [57]. 

The use of heterocyclic diazo components is particularly important in the preparation of blue disperse dyes. It is often difficult to prepare, diazotise and/or couple the highly electronegatively substituted diazo components of the benzene series needed to achieve blue hues, and feebly basic aminoheterocycles offer a convenient alternative. The small molecular size of these heterocyclic amines, compared with that of heavily substituted anilines, is another factor favouring their use. 

Table 3.19 lists examples of the preparation of nitrogen-containing heterocycles by RCM. As mentioned in Section 3.2.5.3, free amines can partly deactivate metathesis catalysts. With the highly reactive molybdenum catalyst 1 it is, however, possible to cyclize dienes containing a basic amino group. If the less reactive catalysts 2 or 3 are to be used, protonation or acylation of the amine can be used to reduce their nucleophilicity. This will generally lead to higher yields with smaller amounts of catalyst. 

Our discussions of the basicity of organic nitrogen compounds have concentrated predominantly on simple amines in which the nitrogen atom under consideration is part of an acyclic molecule. Many biologically important compounds, and especially drug molecules, are based upon systems in which nitrogen is part of a heterocycle. We shall consider the... 

The basicities of the simple heterocycles piperidine and pyrrolidine vary little from that of a secondary amine such as dimethylamine. pATa values for the conjugate bases of these three compounds are 11.1, 11.3, and 10.7 respectively. 

The relative basicity of an aromatic nitrogen heterocycle is dictated by the ring size, the presence of any other heteroatoms, and possible effects from substituents. It is potentially a rather more complex problem than with, say, simple amines, and should be approached logically and systematically. In practice, these examples do not present particularly difficult problems. 

For weakly basic amines, i.e. anilines with poly nitro groups, e.g. 2, 4,-dintro-6-bromoaniline, and also most heterocyclic amines, an alternative method must be adopted using nitrosylsulfuric acid. This diazotising medium can be made by dissolving sodium nitrite in concentrated sulfuric acid, but is also available preformed from chemical suppliers. The weakly basic amine is added gradually to the nitrosyl-sulfuric acid with cooling, and after reaction is complete the mixture is poured into ice and water to give a solution of the diazonium salt. 

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