Halogen substituents results

An extensive study of the amination of halopyridines has been carried out by den Hertog and co-workers.A comparison of their results with studies in inert solvents using primary and tertiary amines should permit some evaluation of the postulated factors. 2,4-Dichloropyridine in concentrated aqueous ammonia (180°, 5 hr) resulted in the formation of 4-amino- (60% yield) and 2-amino-chloropyridines (20% yield). Under similar conditions, only 4-substitution of 3,4,6-trichloro- and of 2,3,4,5-tetrabromo- and -tetrachloro-pyridines was observed. However, in these and the other polyhalo pyridines, the appreciable and unequal mutual activation by the halogen substituents needs to be emphasized. 

Halogenations of quinoline, isoquinoline, acridine, and phenanthridine will be discussed here. Reaction usually occurs in a homocyclic fused ring rather than in the 7r-deficient pyridine moiety, especially in acidic media. Relatively mild conditions suffice, but under more vigorous regimes radical involvement can result in heteroring halogenation. Substituents are able to modify reactivity and regiochemistry. 

Nitromethane has been used as a solvent for molecular bromination297. The bromination of polymethylbenzenes in nitromethane, acetic acid, and 1 1 mixtures of these solvents at 30 °C, showed that rates were much faster (about 330-fold) in nitromethane than in acetic acid. With nitromethane, in the bromine concentration range 0.01-0.02 M, the reaction was third-order in bromine. The relative deactivating effects of m-halogen substituents were measured in terms of the time taken for 10 % reaction to occur, and these values are given in Table 71 from which the relative reactivities in the different solvents are apparent the deactivating effects of the m-nitro substituent were obtained by comparison with the reactivity of chloromesitylene at different concentrations (0.035, 0.055 M) of reactants. The results for the nitro compounds were interpreted in the same way... 

Certain polar substituents at the 4-position of 2,5-DMA render the eompounds inaetive for example, the 4-COOH and 4-OH derivatives do not produee DOM-like effeets. On the other hand, 4-halogenated compounds result in relatively potent derivatives. The 4-fluoro derivative DOF is 4 times more potent than 2,5-DMA. whereas the 4-chloro (DOC) and 4-iodo (DOI) analogs are about 20 times more potent than 2,5-DMA. The most potent halogenated derivative is the 4-bromo analog DOB, which is about 40 times as potent as 2,5-DMA. 

The chloro- and bromo-cyclohexane inclusion compounds have been extensively examined by infrared (4000-30 cm-1) spectroscopy65-68 and by Raman (< 1000 cm-1) spectroscopy 69). In the canals both guests are found to exist exclusively in the chair conformation with an axial halogen substituent, while iodocyclohexane 65, 68,69) acj0pts both axial and equatorial conformations in the canal. These results should be contrasted with the familiar situation in the liquid phase where the equatorial arrangement is the lowest energy conformer and is present to the extent of about 65-70% at room temperature. 

Halogen substituents withdraw electron density from the aromatic nucleus but direct olp-through resonance effects. The result is that halobenzenes undergo nitration with more difficulty relative to benzene. The nitration of chlorobenzene with strong mixed acid gives a mixture of 2,4- and 2,6-isomeric dinitrochlorobenzenes in which the former predominates." The nitration of 2,4-dinitrochlorobenzene to 2,4,6-trinitrochlorobenzene (picryl chloride) requires an excess of fuming nitric acid in oleum at elevated temperature. Both are useful for the synthesis of other polynitroarylene explosives but only 2,4-dinitrochlorobenzene finds industrial importance (Sections 4.8.1.2 and 4.8.1.3). 

Halogen substituents are of course easy to introduce to heteroaromatic rings, and they also enhance the acidity of the ring protons. n-BuLi will, for example, lithiate the tetrafluoropyridine 179 at —60°C in ether ° but with pyridine itself it leads to addition/reoxidation products . Addition to the ring is the major product with 2-fluoropyridine 180, though some metaUation can be detected selectivity in favour of metaUation is complete with LDA in THF at —75 °C or with phenyUithium and catalytic -Pr2NH at —50°C (Scheme 90) . Similar results are obtained with quinolines . 

All these transformations are obtained in good yields and 5-bromo derivatives are often crystalline and easy to separate. By-products can be bromides or dibromides with halogen substituent at C-l and C-5, but the regioselectivity of photobromination at C-5 results from the easier formation of tertiary radicals. The a-bromination confirms the stereoselectivity of the substitution reaction with the preferential abstraction of axial H-5. 

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