Pyridine, reactivity compared benzene

From the relative reactivities, together with the isomer ratios for the phenylation of pyridine, it is possible to calculate the reactivity of each position in the pyridine ring compared with that of any one position in benzene (the partial rate factor). Thus, using the value of 1.04 for the relative reactivities obtained by Augood et al and the isomer ratios (2-, 58 3-, 28 4-, 14) obtained by Dannley and Gregg, the partial rate factors for the three positions in pyridine are 2-, 1.8 3-, 0.87 4-, 0.87. It is doubtful, however, whether much... 

Pyridines and azines. An -substituent in pyridine 597 is in an electronic environment approaching that of a substituent in the imino compound 598. Since the reactions of the carbonyl compounds 599 are better known than those of the imino compounds 598, the reactions of -substituted pyridines are compared with those of the analogous carbonyl compounds (see preceding section 3.2.3.1.1). However, the electron pull is much greater in carbonyl compounds than in pyridine -substituents on pyridine accordingly show reactivities intermediate between those of substituents on benzene and those attached to carbonyl groups. 

Simple HMO theory has been used to calculate Atj for several benzenoid hydrocarbons, substituted benzenes, and heterocycles. The resulting values are in qualitative agreement with reactivity trends. Scheme 9.3 gives some of the data. The less positive the number, the more reactive the position. Although there are some discrepancies between structural groups, within groups the Atj values correlate well with position selectivity. The most glaring discrepancy is the smaller activation hardness for deactivated compared with activated benzenes. In particular, benzaldehyde and benzoic acid have At values that are lower than that of benzene, which is counter to their relative reactivity. However, the preference for meta substitution of the deactivated benzenes is predicted correctly. The deactivation of pyridine, relative to benzene, is also not indicated by the At value. 

SeAt reactions proceed much more slowly with pyridine than with benzene. They usually demand drastic conditions and occur exclusively at the 3-position [47]. The reactivity of pyridine is comparable to that of nitrobenzene ( 10 relative to benzene). In S Ar reactions occuring in strongly acidic media (nitration, sulfonation), this reactivity is similar to that 1,3-dinitrobenzene (< 10" ). The basicity of the pyridine nitrogen is crucial in deciding whether the S Ar reactions in an acid medium involve the free pyridine base or the further deactivated pyridinium ion for instance, pyridines with a pX > 1 are nitrated via the protonated species, while in the case of pyridines with a pX > 2.5, the free base is involved. As expected, donor substituents increase the S Ar reactivity. 

SnAr reactions of pyridine proceed much more slowly than those of benzene they usually require drastic conditions and occur exclusively at the 3-position [80]. The relative reactivity of pyridine is comparable to that of nitrobenzene ( 10 rel. to benzene) in SnAr reactions operating in strongly acidic medium (nitration, sulfonation), the... 

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). 

The first generalization is illustrated by the behavior of the 2- and 4-vs. the 3-derivatives of pyridine, the second by the reactivity of 4- vs. 2-substituted pyridines, the third by the relation of 4- vs. 2-derivatives of pyrimidine, and the fourth by the appreciable reactivity of 3-substituted pyridines or 5-substituted pyrimidines compared to that of their benzene analogs. Various combinations of azine-nitrogens in other poly-azines supply further examples. Theoretical aspects of (1), (2) and (3) are discussed in Section II, B, 2. The effect involved in (4) is believed to be more the result of the inductive stabilization of an adjacent negative chaise in the transition state (cf. 251) than of the electron deficiency created in the ground state (cf. 252). The quantitative relation between inductive stabihzation and resonance stabilization is not precisely defined by available data. However, a... 

Relative reactivity wiU vary with the temperature chosen for comparison unless the temperature coefficients are identical. For example, the rate ratio of ethoxy-dechlorination of 4-chloro- vs. 2-chloro-pyridine is 2.9 at the experimental temperature (120°) but is 40 at the reference temperature (20°) used for comparing the calculated values. The ratio of the rate of reaction of 2-chloro-pyridine with ethoxide ion to that of its reaction with 2-chloronitro-benzene is 35 at 90° and 90 at 20°. The activation energy determines the temperature coefficient which is the slope of the line relating the reaction rate and teniperature. Comparisons of reactivity will of course vary with temperature if the activation energies are different and the lines are not parallel. The increase in the reaction rate with temperature will be greater the higher the activation energy. 

Nitration of pyridines in other than nitric or sulfuric acids is of little interest here because either no reaction or N-nitration takes place (see Section 2.05.2.10). However, pyridine 1-oxide is considerably more reactive and treatment with benzoyl nitrate ultimately leads to the 3-nitro derivative (Scheme 25) (60CPB28). Annelation of a benzene ring bestows greater reactivity on the 3-position in quinoline, compared with pyridine, and reaction with nitric acid in acetic anhydride furnishes the 3-nitro derivative (ca. 6%) (Scheme 26). This isomer has also been obtained, again at low yield (6-10%), by treatment of quinoline with tetranitratotitanium(IV) in carbon tetrachloride (74JCS(P1)1751>. Nitration of benzo analogues of pyridine occurs much more readily in the benzene ring, and Chapter 2.06 should be consulted for these reactions. 

A well understood case is that of quinoline reaction at position 2 is kinetically favored as compared with reaction at position 4, but the adduct from the latter is thermodynamically more stable. This situation, where the site of attack leading to the more stable adduct is the y position, is analogous with those regarding the formation of Meisenheimer adducts from benzene and pyridine derivatives and RCT nucleophiles. Presumably, with quinoline kinetic control favors the position that is more strongly influenced by the inductive effect of the heteroatom. The fact that position 2 of quinoline is the most reactive toward nucleophilic reagents is probably related to the lower 71-electron density at that position.123 However, the predominance of the C-4 adduct at equilibrium can be better justified by the atom localization energies for nucleophilic attachment at the different positions of quinoline. Moreover, both 7t-electron densities and atom localization energies indicate position 1 of isoquinoline to be the most favored one for nucleophilic addition. 

Aryl fluoroalkyl ethers have been prepared from the reaction, at room temperature in HMPA, of fluo-ro-substituted alkoxides with activated fluoro-,149 nitro-,149 and, at 150 °C, also chloro-arenes150,151 and some chloro-substituted pyrazines (equation 15), pyrimidines, quinolines,150,152 and pyridines.152 Disubstitution was observed in die presence of comparably activated leaving groups such as in 2,4- and 2,6-di-chloronitro- or cyano-benzenes, whereas regiospecific substitution took place at position 4 in 3,4-dichloronitro- or cyano-benzene and at position 2 in 2-fluoro-6-chlorocyanobenzene.151 Steric hindrance and the number of fluorine substituents in the alkoxide pose limits to the reactivity. Thus, tertiary alkoxides, or alkoxides containing more than four fluorine substituents, displace activated nitro and fluoro, but not chloro substituents.149,150 The secondary hexafluoro-2-propoxide anion does not react even with the more reactive nitro and fluoro derivatives.149... 

This gas-phase reaction provides the only method currently available for determining hydrogen-bonded pyridine free base. The method requires neither assumptions, extrapolations, nor approximations the p factor of the reaction is sufficiently small that the reactivities of the pyridine and benzene derivatives can be compared directly. The method was first introducted for determining the electrophilic reactivity of pyridine [62JCS4881 71JCS(B)2382] using 1-arylethyl acetates (9.109). Subsequent determinations used I-aryl-l-methylethyl acetates. (9.110) and i-arylethyl methyl carbonates (9.111) [79JCS(P2)228],... 

As a first approximation, the reactions of pyridines with electrophiles can be compared with those of trimethylamine and benzene. Thus, pyridine reacts easily at the nitrogen atom with reagents such as proton acids, Lewis acids, metal ions, and reactive halides to form salts, coordination compounds, complexes, and quaternary salts, respectively. Under much more vigorous conditions it reacts at ring carbons to form C-substitution products in nitration, sulfonation, and halogenation reactions. 

Positions marked BP have reactivity intermediate between benzene and pyridine and can be compared to the 3-position of pyridine. 

NH2- condensed pyridines (Skraup reaction) NH2-+N2 -+H, Cl, I, CN,... C02H->Br (Hunsdiecker reaction) Br-+H (Na/Hg) etc. As a matter of fact, the whole spectrum of aromatic reactivity can be transferred to indazoles substituted at the fused benzene ring. Compare, for example, the reactions described by Suschitzky et al. (68JCS(C)1937) for 2-azidonaphthalene (432) and for 5-azidoindazole (433). Pyrolysis of these compounds in a mixture of acetic and polyphosphoric acid yields (434) and (435), respectively. 

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