Pyridine, reactivity compared

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. 

In Table 8 rates of nucleophilic reactions with p-nitrophenyl acetate in water are collected. It should be kept in mind that relative reactivities vary with solvent. For example, in aqueous dioxane the relative reactivity of pyridine, as compared with acetate, towards acetic anhydride drops by many powers often as the solvent becomes less aqueous (Koskikallio, 1963). In 50 %, 25 %, 8 %, 2 %, and 0-4 % aqueous dioxane the ratio of pyridine reactivity to acetate reactivity is 14,0-34, 9-5 x 10 , 2-4 X 10 and < 3 x 10 , respectively. 

The same authors found that thieno[2,3-c - and - 3,2-c]pyridones (e.g., 58) yielded substitution products (59) when treated with hydrogen halides and hydrogen peroxide, or with nitric acid. The orientation of substitution and increased reactivity compared with the parent thieno-pyridine were ascribed to the +M effect of the hydroxy group in that tautomeric form however, it is clear that the same results would be expected from the pyridone tautomer. 

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. 

Substituted zinc 2-aminobenzenethiolates 92 form two different condensation products in different reaction media in 95% ethanol, they yield compound 96 and in pyridine compound 97 (see a similar case in Section III.A.2) (Scheme 45). However, when reacting as the free substituted 2-aminobenzenethiols in pyridine only compound 96 forms. The formation of different products in alcohol and pyridine may be due to an increased reactivity of zinc salts in pyridine as compared to alcohol (88MI1). 

The oxidation of both aliphatic and aromatic amines to nitriles by O2 or air in the presence of the Ru2Cl4(az-tpy)2 complex indicates that the conversion is strongly influenced by the alkyl chain length. The amines with shorter chain had lower conversions than those with longer chains. Further, the ruthenium terpyridine complex functionalized with azulenyl moiety at the 4-position of the central pyridine core provided a much higher catalytic reactivity compared with a series of ruthenium terpyridine complexes. The use of deuterated benzylamine demonstrated the importance of RuOH in the mechanism of the reaction." ... 

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... 

Thiophenes with electron-deficient groups were more reactive compared with electron-donating substituents. ortfar-Substitution had no detrimental effect on reactivity and sterically demanding substrates could be accessed in excellent yields (80-91%). Heteroaryl bromides, such as pyridine, pyrimidine, quinoline, thiophene, and furan, were viable substrates. Notably, benzoth-iophene, benzofuran, furan, and pyrrole derivatives could also be directly arylated. 

You will remember that in the last chapter, we said that the reactivity of pyridine was comparable to that of nitrobenzene. So it is not unexpected that 2- and 4-halopyridines can be substituted by nucleophiles (Figure 13.19). In this reaction, we have a resonance form that is particularly favored... 

These compounds are soluble in ether, are comparatively stable, and exhibit many of the reactions of Grignard reagents but are more reactive. Because of their greater reactivity, organohthium compounds can often be used where Grignard reagents fail thus they add to the azomethine linkage in pyridines or... 

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). 

These reactions iavolve mostly dimethyl and diethyl sulfate. CycHc sulfates are also reactive, and several have been compared by determining reaction rates with a substituted pyridine or with water (40). In both cases, 1,2-ethylene sulfate is more reactive than 1,3-propylene sulfate or dimethyl or diethyl sulfates. 

The precise numerical values of the calculated electron densities are unimportant, as the most important feature is the relative electron density thus, the electron density at the pyrazine carbon atom is similar to that at an a-position in pyridine and this is manifest in the comparable reactivities of these positions in the two rings. In the case of quinoxaline, electron densities at N-1 and C-2 are proportionately lower, with the highest electron density appearing at position 5(8), which is in line with the observation that electrophilic substitution occurs at this position. 

The reactivity of isoxazole toward quaternization is compared with those of pyridine-2-carbonitrile, pyridine and five other azoles in Table 6 (73AJC1949). Isoxazole is least reactive among the six azoles and times less reactive than pyridine. There is also a good correlation between the rate of quaternization and basicity of the azole. 

Krohnke observed that phenacylpyridinium betaines could be compared to 3-diketones based on their structure and reactivity, in particular, their ability to undergo Michael additions. Since 3-dicarbonyls are important components in the Hantzsch pyridine synthesis, application of these 3-dicarbonyl surrogates in a synthetic route to pyridine was investigated. Krohnke found that glacial acetic acid and ammonium acetate were the ideal conditions to promote the desired Michael addition. For example, N-phenacylpyridinium bromide 50 cleanly participates in a Michael addition with benzalacetophenone 51 to afford 2,4,6-triphenylpyridine 52 in 90% yield. 

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. 

---