Nitrogen heterocycles electron-deficient

The chemistry of highly electron deficient nitrogen heterocycles containing carbonyl groups is covered by Ana M. Costero of the University of Valencia, Spain, in the first overview of this interesting chemistry. 

Those heterocyclic systems attacked by complex metal hydrides are required to be relatively electron deficient. Nitrogen heterocycles in which the heteroatom contributes a single electron to the n system are considered electron deficient (e.g., 1). However, systems where the nitrogen atom contributes two electrons are considered electron rich (e.g., 2) and are not normally attacked by metal hydrides. Aromatic species that contain both a pyridine-like (1) and a pyrrole-like (2) heteroatom (e.g., 3) exhibit be-... 

The oxidative desulfurisation of 1,2,4-triazole thiones is a type of reaction common to other electron-deficient nitrogen heterocycles nitric acid is the oxidant in the example below. The process involves loss of sulfur dioxide from an intermediate sulfinic acid. ... 

An interesting intermediate 30 was proposed to result from the sequential addition of pyridine to tetrachlorocyclopropene (31). Compound 30 represents an alkyl nitrogen ylide with two 1-chloroalkyl pyridinium moieties in the same molecule. Pyridines with electron-withdrawing groups and heterocycles with an electron-deficient nitrogen, for example, pyridine-3-carbaldehyde or quinoline, react with 31 to yield the corresponding mono-substituted products 32a and 32b (83JOC2629) (Scheme 8). 

As sulfones are known to be readily displaced from electron deficient nitrogen-containing heterocycles, Bessard noted significant rate enhancements as well as improved yields in the displacement of the chloride on pyrimidine 49 by alcohols, through the use of sodium methylsulfinate as a catalyst <00T4739>. The production of trialkoxypyrimidines 51 as potential herbicides, presumably formed from the displacement of methysulfinate from intermediate 50 by the various alcohols, required a less than a stoichiometric amount of sodium methylsulfinate (typically 0.10-0.25 equivalents). 

Pteridinamines, -ones and pteridinethiones show tautomeric features which are similar to those of other 7r-electron deficient A-heterocycles. The pteridinamines show a marked preference for the amino 3,5 (X = NH) rather than the iminohydro 4,6 (X = NH) form, but, with few exceptions, hydroxy and sulfanyl pteridines show a strong preference for tautomers 4,6 (X = O or S) in which the mobile proton is situated at the adjacent ring nitrogen atom. 

No simple electrophilic substitution, for example nitrosation, nitration, sulfonation or halogenation of a C—H bond, has so far been recorded in the pteridine series. The strong 7T-electron deficiency of this nitrogen heterocycle opposes such electrophilic attack, which would require a high-energy transition state of low stability. 

An interesting method for the substitution of a hydrogen atom in rr-electron deficient heterocycles was reported some years ago, in the possibility of homolytic aromatic displacement (74AHC(16)123). The nucleophilic character of radicals and the important role of polar factors in this type of substitution are the essentials for a successful reaction with six-membered nitrogen heterocycles in general. No paper has yet been published describing homolytic substitution reactions of pteridines with nucleophilic radicals such as alkyl, carbamoyl, a-oxyalkyl and a-A-alkyl radicals or with amino radical cations. 

Pyridine is a jt-electron-deficient heterocycle. Due to the electronegativity of the nitrogen atom, the a and y positions bear a partial positive charge, making the C(2), C(4), and C(6) positions prone to nucleophilic attacks. A similar trend occurs in the context of palladium chemistry. The a and y positions of halopyridines are more susceptible to the oxidative addition to Pd(0) relative to simple carbocyclic aryl halides. Even a- and y-chloropyridines are viable electrophilic substrates for Pd-catalyzed reactions under standard conditions. 

Due to the electronegativity of the two nitrogen atoms, pyrimidine is a deactivated, rc-electron-deficient heterocycle. Its chemical behavior is comparable to that of 1,3-dinitrobenzene or 3-nitropyridine. One or more electron-donating substituents on the pyrimidine ring is required for electrophilic substitution to occur. In contrast, nucleophilic displacement takes place on pyrimidine more readily than pyridine. The trend also translates to palladium chemistry 4-chloropyrimidine oxidatively adds to Pd(0) more readily than does 2-chloropyridine. 

As written, the reaction is endothermic by ca 30 kJmoD. Pyrrole and pyridine are both 6-71 nitrogen-containing heterocycles. However, the former is electron-rich while the latter is electron-deficient and so conjugative stabilization mechanisms are different for the two species. Furthermore, the former can form one more hydrogen bond per molecule than the latter, a feature that may account for pyrrole-2-carboxaldehyde being a solid while pyridine-2-carboxaldehyde is a liquid. We wonder if either difference accounts for the profound lack of thermoneutrality for the above reaction. 

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