Pyridine relative reactivity

TABLE III-37. COMPARISON OF THE RELATIVE REACTIVITIES (WITH RESPECT TO BENZENE) OF VARIOUS PYRIDINE SUBSTRATES towards PHENYL AND 2-THIAZOLYL RADICALS AT 70 TO... 

Reaction of 4,6 l/2-di-0-isopropyhdenesucrose in pyridine—chloroform with 3.3 molar equivalents of benzoyl chloride at 0°C eventually produced 3/6 -di-O-benzoylsucrose (36%) as the major and 3/4/6 - and 3,3/6 -tribenzoates as the minor products. The relative reactivities of the hydroxyl groups toward benzoylation was HO-3 HO-6 > HO-4 > HO-3 (55). 

All these methods demonstrate that the 2-positions of pyridine, pyrimidine, and other azines are the most electron deficient in the ground state. However, considerably greater chemical reactivity toward nucleophiles at the 4-position is often observed in syntheses and is supported by kinetic studies. Electron deficiency in the ground state is related to the ability to stabilize the pair of electrons donated by the nucleophile in the transition state. However, it is not so directly related that it can explain the relative reactivity at different ring-positions. Certain factors which appear to affect positional selectivity are discussed in Section II, B. 

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. 

Halopyridines undergo self-quaternization on standing while the less reactive 2-halo isomers do not. However, more is involved here than the relative reactivity at the ring-positions. The reaction rate will depend on the relative riucleophilicity of the attack-ing pyridine-nitrogens (4-chloropyridine is more basic) and on the much lower steric hindrance at the 4-position. Related to this self-quatemization are the reactions of pyridine and picolines as nucleophiles with 4-chloro- and 2-chloro-3-nitropyridines. The 4-isomer (289) is. again the more reactive by 10-30-fold (Table VII, p. 276). 

The reactivity of pyridine relative to that of benzene has been measured using the competitive technique developed by Ingold and his schoool for corresponding studies of electrophilic aromatic substitution. The validity of the method applied to free-radical reactions has been discussed. Three sources of the phenyl radical have been used the results obtained are set out in Table II. 

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... 

Table IX shows the relative reactivities and the partial rate factors for the phenylation of pyridine, quinoline, and benzothiazole, which...

Nucleophilic reagents attack pyridine at the a-position to form an adduct that rearomatizes by dissociation (Scheme 1). Only very strong nucleophiles, e.g. NH2-, RLi, LAH, Na-NH3, react, and for the second step to afford a substitution product (5), conditions that favour hydride loss are required. Adducts formed with hydride ions (from LAH) or carbanions (from lithium alkyls) are relatively more stable than the others at low temperature, and dihydropyridines (6) can be obtained by careful neutralization. Fusion of a benzene ring to pyridine increases reactivity towards nucleophiles, and attack is now found at both a- and y-positions in quinoline (7) and at C-l in isoquinoline (8). This may be attributed to a smaller loss of aromaticity in forming the initial adduct than in pyridine, and thus a correspondingly decreased tendency to rearomatize is also observed. Acridine reacts even more easily, but nucleophilic attack is now limited to the y -position (9), as attachment of nucleophiles at ring junctions is very rare. 

Pyrazines (see Sections II, V,B,2, and D). Both 2-amino- and 2-methylpyrazine react with Mel to give isomers. The observed isomer ratios are very close to those predicted by considering relative reactivities of the appropriately 2- and 3-substituted pyridines.62 The observation159 that 2-aminopyrazine undergoes quaternization... 

Imidazo[4,5-b pyridines. Methyl chloride reacts with 78 at the nitrogen atom of the pyridine ring, but with 79 at the unsubstituted imidazole nitrogen atom.183 The Former result is surprising because it does not fit a prediction based on a consideration of the relative reactivities of pyridine and 1-methylimidazole.44... 

The C2-symmetric 2,6-bis(2-oxazolin-2-yl)pyridine (pybox) ligand was originally applied with Rh for enantioselective hydrosilylation of ketones [79], but Nishiyama, Itoh, and co-workers have used the chiral pybox ligands with Ru(II) as an effective cyclopropanation catalyst 31 [80]. The advantages in the use of this catalyst are the high enantiocontrol in product formation (>95 % ee) and the exceptional diastereocontrol for production of the trans-cyclopropane isomer (>92 8) in reactions of diazoacetates with monosubstituted olefins. Electronic influences from 4-substituents of pyridine in 31 affect relative reactivity (p = +1.53) and enantioselectivity, but not diastereoselectivity [81]. The disadvantage in the use of these catalysts, at least for synthetic purposes, is their sluggish reactivity. In fact, the stability of the intermediate metal carbene has allowed their isolation in two cases [82]. 

A DFT study of the reactivity of pyridine and the diazabenzenes towards electrophilic substitution, assuming frontier orbital control of the reactions, predicts their low reactivity as the HOMOs of these substrates are not n-orbitals.5 For pyridine-N-oxide, however, the HOMO is an aromatic orbital. DFT studies giving Fukui indices predict6 the preferred sites of electrophilic attack on pyrrole, furan, and thiophene and calculation of the local softness of the reactive sites rationalizes relative reactivities. 

The relative reactivities of pyridine, 3-picoline, and 3-ethylpyridine toward phenyllithium have been measured under various conditions by a competitive technique and found to be in the order 3-pico-line > pyridine > 3-ethylpyridine.252 By carrying out reactions using an equimolar mixture of pyridine and 3-picoline and a large excess of phenyllithium, it has been possible to obtain yields of the phenyl-pyridines of over 80%, provided short reaction times and low temperatures are used. It has also been shown that the low yields usually obtained in such reactions are due to the fact that the dihydropyridyl-lithium intermediates form by-products, probably by polymerization (the intermediate dihydropyridine is a ct s-butadiene-like system and, in the presence of a Ziegler-type catalyst, can be expected to polymerize readily). The a-complexes from 3-picoline and phenyllithium polymerize faster than that from pyridine and phenyllithium, but there is no selective removal of the isomeric dihydropicolyllithium intermediates to form by-products, both isomers undergoing side-reactions at virtually the same rate. 

Relative Reactivities of Pyridine, 3-Picoline, and 3-Ethylpyridine toward Phenyllithium ... 

Table 26 Relative Reactivities of Some Halogenothiazoles and Pyridines <79HC(34-i)i, p. 568 ...

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