Basicity of nitrogen heterocycles

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. 

However, pyridine and pyrrole are significantly less basic than either of their saturated analogues. The pyridinium cation has pATa 5.2, making pyridine a much weaker base than piperidine, whereas the pyrrolium cation (pATa - 3.8) can be considered a very strong acid, and thus pyrrole is not at all basic. 

Although the nitrogen atom in these systems carries a lone pair of electrons, these electrons are not able to accept a proton in the same way as a simple amine. The dramatic differences in basicity are a consequence of the Jt electron systems, to which the nitrogen contributes (see Section 2.9.6). 

Pyridine, like benzene, is an aromatic system with six jt electrons (see Section 11.3). The ring is planar, and the lone pair is held in an sp orbital. The increased s character of this orbital, compared with the sp orbital in piperidine, means that the lone pair electrons are held closer to the nitrogen and, consequently, are less available for protonation. This hybridization effect explains the lower basicity of pyridine compared with piperidine. Pyrrole is also aromatic, but there is a significant difference, in that both of the lone pair electrons are contributing to the six-jr-electron system. As part of the delocalized Jt electron system, the lone pairs are consequently not available for bonding to 

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These empirical relationships are intended to provide quantitative and conceptual frameworks for the rationalization of structural effects on the basicity of nitrogen heterocycles. 

We have just mentioned the protonation of aziridine, and you might imagine from what we said earlier about the comparative nucleophilicity and basicity of nitrogen heterocycles and their acyclic counterparts that aziridine will be even more nucleophilic than pyrrolidine, and about as basic. Well,... 

To determine the relative basicity of nitrogen heterocycles that are also aromatic, you must know whether the nitrogen lone pair is part of the aromatic 7t system. 

A precise treatment of the free energy change of protonation, expressed in terms of the partition functions and the various energy components, can be found in a discussion of the basic strengths of nitrogen heterocycles by Chalvet, O., Daudel, R., and Peradejordi, F., J. Chim. Phys. 59, 709 (1962). In their treatment, as in the present case, possible effects due to relative differences in molecular partition functions are neglected. 

It has long been observed that some aromatic nitrogen heterocyclic compounds aminate more easily than others. For instance, 1-methylbenzimidazole is aminated in a matter of a few minutes, whereas pyridine requires about 2 hr. In order to explain this, chemists in the U.S.S.R. have considered four factors they believe are most responsible for causing different rates of amination in aprotic solvents at elevated temperatures (heterogeneous conditions). They are (1) basicity of the heterocycle (2) positive charge on the carbon atom adjacent to the nitrogen (3) polarizability of the C=N bond and (4) ease of aromatization of the a-adduct (76CHE210). The first three pertain to the addition step of the Chichibabin reaction and the last factor depends upon the hydride-ion elimination step. 

Preparation of Pyrrolidine Derivatives. In a manner analogous to that described above, the use of appropriately functionalized nitrogen-centered nucleophiles allows the preparation of nitrogen heterocycles. Thus the 7V-benzoyl or 7V-phenylsulphonyl derivatives (6) of o -aminoketones, readily prepared from o -amino acids, react with 1 under basic conditions to give the 2,5-dihydro-pyrrole (7) (eq 6). Product 7 may be modified to provide variously substituted pyrroles. Use of homochiral ketone derivative 6 allows essentially complete retention of configuration to provide 7 as a single enantiomer. ... 

Donor atoms in the molecule may coordinate to the 14-electron ruthenium-catalytic species and, thereby, take up a vacant site. Basic nitrogen atoms have this effect, although there are exceptions. Nevertheless, metathesis reactions have proved very effective for the synthesis of nitrogen heterocycles, as this effect can be suppressed. One way to suppress this effect is by use of an electron-withdrawing protecting group, such as a sulfonamide, a carbamate or an amide (Scheme 8.75). Another way is to carry out the reaction in the presence of acid, so that it is the salt 8.278 with no lone pair, that cyclizes. The problem is less severe with less-basic amines, including anilines. ... 

Meot-Ner M (1979) Ion thermochemistry of low-volatility compounds in the gas phase. 2. Intrinsic basicities and hydrogen-bonded dimers of nitrogen heterocyclics and nucleic bases. J Am Chem Soc 101 2396-2403. doi 10.1021/ja00503a027... 

If nitrogen heterocycles have basic properties, the preparation of picrates, chloroplatinates, or the quaternization of the heterocyclic nitrogen with methyl iodide (see p. 326) is recommended this is true especially for pyridine-, pyrroline-, and quinoline-type bases. Tetraphenylboranates (111) are also suitable for the identification of nitrogen heterocycles. For their preparation see p. 331. The preparation of quinoline picrate is described on p. 330. 

The nitrogen of aHphatic and aromatic amines is alkylated rapidly by alkyl sulfates yielding the usual mixtures. Most tertiary amines and nitrogen heterocycles are converted to quaternary ammonium salts, unless the nitrogen is of very low basicity, eg, ia tn phenylamine. The position of dimethyl sulfate-produced methylation of several heterocycles with more than one heteroatom has been examined (22). Acyl cyanamides can be methylated (23). Metal cyanates are converted to methyl isocyanate or ethyl isocyanate ia high yields by heating the mixtures (24,25). 

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). 

Methylation of nitrogen at the 2 position also proves to be consistent with diuretic activity. Condensation of 160 with urea affords the heterocycle, 193. Treatment of this compound with methyl iodide and base effects alkylation on the more acidic ring nitrogen (194). Basic hydrolysis then gives the N-methylated aminosulfonamide (195). Condensation of this with chloroacetalde-... 

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. 

Furthermore, the strongly metallic character of selenium weakens the C-Se bond and thus favors reactions involving opening of the ring. The basicity of the three heterocycles is approximately in the same order, the nitrogen atom of selenazole and thiazole possessing much the same properties as the heteroatom of pyridine. Of the two carbon atoms ortho to nitrogen, that is, the 2-carbon and the 4-carbon, only the one in the 2-position is fairly active as a result of its interaction with selenium or sulfur. The 4- and 5-positions of thiazole and selenazole are more susceptible to electrophilic substitution than the 3- and 5-positions of pyridine. This is particularly true of the 5-position of selenazole. Thus it can be said that the 2- and 5-positions of the selenazoles and thiazoles... 

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