Pyridine electron-deficient nature

Diazines (pyridazines, pyrimidines and pyrazines) undergo crosscoupling more readily than pyridines, due to the electron deficient nature of the heterocyclic ring. 4-Bromopyridazines bearing electron donating substituents in position 3 were found to couple readily with arylboronic acids in the presence of tetrakis(triphenylphosphane) palladium (7.10.).15... 

Pyridine is the prototypical electron-poor six-membered ring heterocycle. The aromaticity originally found in the benzene framework is maintained in pyridine via overlap with the unhybridized p orbital found on the sp hybridized nitrogen atom that is parallel to the Ji-system of the carbon framework. The resonance pictures, as well as, the natural atomic charges of pyridine (Fig. 4.2), predict its electron deficient nature. 

Cyclothiazomycin is 1 of 76 structurally distinct actinomycete thio-peptide antibiotics, can inhibit bacterial protein synthesis, and prevent the growth of gram-positive bacteria [38]. In 2011, Deiters and cowor-kers reported their work on the synthesis of the pyridine core of cyclothiazomycin based on ruthenium-catalyzed [2 + 2 + 2] cyclotri-merization as the key step (Scheme 3.17) [39]. The electron-deficient nature of the thiazole-bearing nitrile enables ruthenium catalysis under mild reaction conditions with excellent yields. Complete chemo and regioselectivity in the construction of the trisubstituted pyridine core were achieved by applying a temporary silyl tether. 

When the azomethine group is part of an electron-deficient ring, such as pyridine, pyrimidine or thiazole, the compounds exist as tetrazoles in the solid state, and at equilibrium with the azido form in solution . The equilibrium constants depend on the solvent, the nature of the substituents and the temperature . 2-Azido-4,6-dimethylpyrimidine (288a) thus exists in equilibrium with tetrazolo-pyrimidine (288b). Its chemical behaviour is, however, in accord with the azide structure 288a, including dipolar addition reactions and nitrene reactions . 

Due to the electrophilic nature of osmium tetroxide, electron-withdrawing groups connected to the alkene double bond retard the dihydroxylation. This is in contrast to the oxidation of alkenes by Potassium Permanganate, which preferentially attacks electron-deficient double bonds. However, in the presence of a tertiary amine such as pyridine, even the most electron-deficient alkenes can be osmylated by osmium tetroxide (eq 4). The more highly substituted double bonds are preferentially oxidized (eq 5). 

The reactivity of Cp2 with pyridine has been further examined by DPT calculations using B3LYP/6-31G. The reversible nature of the formation of thermodynamically unstable pyridinium difluoroylides (27) arising from the addition of Cp2 to pyridines has been unveiled. The DPT studies also revealed that the equilibrium position could be shifted by electronic effects, the more electron deficient the pyridine, the more shifted towards (27) the equilibrium. This trend has been supported experimentally by trapping such electron-poor ylides (27) with various activated dipolarophiles to give unstable cycloadducts (28) which, after dehydrofiuorination and oxidation, yield 3-fluoroindolizines (29). 

Since heteroaromatic compounds sometimes exhibit interesting physical properties and biological activities, construction of substituted heteroaromatics has drawn some attention. Heteroaromatics can be divided into two major categories. One is the tt-electron-sufhcient heteroaromatics, such as pyrrole, indole, furan, and thiophene those easily react with electrophiles. The other is the 7r-electron-deficient heteroaromatics, such as pyridine, quinoline, and isoquinoline those have the tendency to accept the nucleophilic attack on the aromatic ring. Reflecting the electronic nature of heteroaromatics, the TT-electron-deflcient ones are usually used as the electrophiles.t The rr-electron-sufficient heteroaromatics having simple structures, such as 2-iodofuran and 2-iodothio-phene, have also been utilized as the electrophiles. Not only the electronic nature of the heteroaromatics but also coordination of the heteroatom to the palladium complexes influence catalytic activity. This is another reason why the couphng reaction did not proceed efficiently in some cases. 

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