188. The kinetics and mechanism of heteroaromatic nitration. Part II. Pyrazole and imidazole

Austin, Michael W.; Blackborow, J. R.; Ridd, John H.; Smith, B. V.

doi:10.1039/jr9650001051

Cited by 29 publications

(9 citation statements)

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“…Nitration in the presence of mercuric chloride (6) gave slight improvement. Addition of sulfur trioxide to the nitrating mixture gave inferior results, in contrast to the improvement reported for the nitration of imidazole (7).…”

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confidence: 64%

“…Katritzky and others (8,9) have demonstrated that basic pyridines (pK, > + 1) are first protonated and then slowly nitrated, while weakly basic pyridines (pK, < -2.5) undergo nitration under mild conditions as free bases. Thus, the difficulty in nitrating 2-substituted imidazoles with nitric-sulfuric acid mixtures might be ascribed to the fact that the protonated species is being nitrated (7). 3 A procedure in which unprotonated basic resulting salt might be stable to the reaction conditions.…”

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confidence: 99%

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Nitration Studies on 2-Isopropylimidazole

Glass¹,

Blount²,

Butler³

et al. 1972

Can. J. Chem.

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The nitration of 2-isopropylimidazole has been studied under a variety of conditions involving nitration of the unprotonated imidazole, the imidazole anion, or an imidazole radical. From the reaction of nitronium tetrafluoroborate with 1-trimethylsilyl-2-isopropylimidazole there was isolated a dinitro compound the structure of which was shown by X-ray crystallography to be 1,4-dinitro-2-isopropylimidazole.

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confidence: 64%

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confidence: 99%

Nitration Studies on 2-Isopropylimidazole

Glass¹,

Blount²,

Butler³

et al. 1972

Can. J. Chem.

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“…Nitroimidazole (10) was synthesized from 7 using a mixture of H 2 SO 4 +SO 3 and neat red fuming nitric acid. 18 10 was then added to a mixture of 8 in nitrobenzene and refluxed at 140 °C open to the atmosphere overnight to provide NO 2 -Im-Ip-OMe (11) after precipitation from water. Compound 11 was reduced using Pd/C in the presence of hydrogen followed by Boc protection using a mixture of Boc 2 O and DMAP in DMF to provided the final dimer BocIm-Ip-OH (12) after saponification and precipitation (Scheme 1).…”

Section: Heterocycle Synthesismentioning

confidence: 99%

Programmable oligomers targeting 5′-GGGG-3′ in the minor groove of DNA and NF-κB binding inhibition

Chenoweth

Poposki

Marques

et al. 2007

Bioorganic & Medicinal Chemistry

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A series of hairpin oligomers containing benzimidazole (Bi) and imidazopyridine (Ip) rings were synthesized and screened to target 5′-WGGGGW-3′, a core sequence in the DNA binding site of NF-κB, a prolific transcription factor important in biology and disease. Five Bi and Ip containing oligomers bound to the 5′-WGGGGW-3′ site with high affinity. One of the oligomers (Im-Im-ImIm-γ-PyBi-PyBi-β-Dp) was able to inhibit DNA binding by the transcription factor NF-κB.

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“…For example, when nitrated with a mixture of nitric and sulfuric acids, imidazole always reacts as a cation, while the weaker base pyrazole does so only at the H 2 SO 4 concentrations above 90%. 28 Pyrazoles, due to their high activity and moderate strength as bases, undergo even the Friedel-Crafts acyla tion. In this case, in the presence of an equimolar amount of aluminum chloride, the latter binds to pyrazole to form a deactivated complex, so the reaction can be carried out in the presence of a catalytic amount of sulfuric acid.…”

Section: Methodsmentioning

confidence: 99%

Quantum chemical studies of azoles 2. Thermodynamic stability of neutral molecules and intermediates formed during electrophilic substitution of 1,2- and 1,3-azoles

2014

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The thermodynamic stability of 1,2 and 1,3 azole molecules, as well as of cationic and bipolar (carbenoid) intermediates in the gas phase and in aqueous solution formed by electro philic substitution (proton as a model electrophile) was compared based on the analysis of quantum chemical calculations performed at the DFT/B3LYP/6 31G(D) level of theory with zero point energy corrections. The differences in the chemical behavior of the isomeric 1,2 and 1,3 azole pairs, viz., pyrazole-imidazole, isoxazole-oxazole, and isothiazole-thiazole, were considered.Key words: 1,2 azoles, 1,3 azoles, electrophilic substitution, quantum chemical calcula tions, DFT/B3LYP/6 31G(D) method.In the previous communication, 1 we considered and discussed the results of quantum chemical calculations of 1,2 and 1,3 azoles, as well as of the intermediates that are formed via two alternative mechanisms of electrophilic substitution: the normal addition-elimination mechanism with the formation of intermediate cationic  complexes and the elimination-addition mechanism specific to azoles with the participation of ylide (carbene) intermedi ates. Such an ylide substitution is especially characteristic of 1,3 azoles; the corresponding experimental data is sum marized in the review. 2 The goal of the present work is to analyze the results of quantum chemical calculations reported previously 1 in or der to determine the relative thermodynamic stability of 1,2 and 1,3 azole molecules, as well as of cationic and bipolar (carbenoid) intermediates formed during electro philic substitution (proton as a model electrophile), and to consider the differences in the chemical behavior of isomeric 1,2 and 1,3 azole pairs: pyrazole-imidazole, isoxazole-oxazole, and isothiazole-thiazole. Structures 1-10, which characterize the transformation of the starting 1,3 and 1,2 azoles 1 and 6 into ylide substitution inter mediates 2-5 and 7-10, are shown in Scheme 1 and those related to the transformation of the same azoles 1 and 6 into the intermediates of the traditional addition-eli mination mechanism (cationic  complexes 11-16) are shown in Scheme 2. Quantum chemical methodIn the present work, we used the results of our quantum chemical calculations 1 done in terms of the density functional theory (DFT) using the B3LYP functional and the 6 31G(D) basis set with zero point energy corrections taking into account solvation effects using the overlapping sphere model (IEFPCM). 3 The appropriateness of this relatively simple DFT method with a modest basis set was justified in the work. 1 Thus, the results of calculations performed with this method for five membered heterocycles containing one heteroatom are in good agreement with the data obtained by ab initio Hartree-Fock and MP2 4,5 methods, which showed the relationship between the substrate selectivity and the ability of the heteroatom to delocalize a posi tive charge (N > O > S) and between the positional selectivity in the electrophilic substitution reaction of pyrrole, furan, and thio phene and the change in the st...

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188. The kinetics and mechanism of heteroaromatic nitration. Part II. Pyrazole and imidazole

Cited by 29 publications

References 0 publications

Nitration Studies on 2-Isopropylimidazole

Nitration Studies on 2-Isopropylimidazole

Programmable oligomers targeting 5′-GGGG-3′ in the minor groove of DNA and NF-κB binding inhibition

Quantum chemical studies of azoles 2. Thermodynamic stability of neutral molecules and intermediates formed during electrophilic substitution of 1,2- and 1,3-azoles

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