2- benzimidazole, theoretical

Fig. 1 Micellar effects upon reaction of p-nitrophenyl diphenyl phosphate with benzimidazolide ion (solid points) open points are for reaction in the absence of benzimidazole , 10 4 M benzimidazole, pH 10.7 , 1.2 x 10-4 M benzimidazole, pH 11 O, pH 10.7, and 11 respectively. The solid lines are theoretical. (Reprinted by permission of the American Chemical Society)...

The reaction of iV-(2,4-dinitrophenyl)amino acids with base in aqueous dioxane has been shown to give benzimidazole iV-oxides (7). The rate-determining step is likely to be formation of an iV-alkylidene-2-nitrosoaniline intermediate (6), which is followed by rapid cyclization and decarboxylation.19 The loss of carbon dioxide from perbenzoate anions has been investigated by mass spectrometry and electronic structure calculations. The results, including isotopic labelling experiments, support a mechanism involving initial intramolecular nucleophilic attack at either the ortho- or ipso-ring positions. They also indicate that epoxides may be intermediates en route to the phenoxide products.20 There has also been a theoretical study of the formation of trichlorinated dibenzo-/ -dioxins by reaction of 2,4,5-trichlorophenolate ions with 2,4-dichlorophenol.21... 

We have carried out a theoretical study on the related cases of imidazoles (126) and benzimidazoles (127) [128],... 

Methoxy-2-[(3,5-dimethyl-4-nitro-2-pyridinyl)methylthio]-lH-benzimidazole(50 g, 0.145 mole) was dissolved in methanol and heated to 45°C. A solution of sodium methoxide (50 g, 0.925 mole) in methanol (150 ml) was added dropwise over a period of 3 hours at 45°-60°C. Stirring was continued for another 2 hours and then methanol was distilled off under reduced pressure. To the cooled residue was added water (200 ml) followed by concentrated HCI (65 ml) until the pH of the mixture was 7.5. The reaction mixture was extracted with dichloromethane and the dichloromethane layer was washed with water (2 times 100 ml). The dichloromethane layer was dried over sodium sulfate and concentrated to yield the product as an amber color syrup. Yield was 40.1 gm, about 83.8% of theoretical. A solid sample was obtained by trituration of the syrup several times with petroleum ether. Melting point was 87°-90°C. 

HCI gas was bubbled into a cooled solution of 5-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridinyl)methylthiol]-lH-benzimidazole (50 g) in dichloromethane (250 ml) until no more precipitation was observed. The reaction mixture was warmed to 40°C and again cooled to 10°C. The solid was filtered under suction and washed with dichloromethane to yield the product (49 g) as a cream colored fine granular solid. Yield was 88.2% of theoretical. Melting point 144°-148°C. 

To a solution of 5-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridinyl)methylthio]-lH-benzimidazole (32.9 g, 0.1 mole) in dichloromethane (200 ml) was added phthalic anhydride (20 g, 0.135 mole) and cooled in an ice salt bath. This was followed by addition of sodium carbonate (18 g, 0.17 mole) and water (20 ml). Hydrogen peroxide (12 ml, 45%, 0.16 mm mole) was added dropwise at -5°-0°C and the reaction mixture was stirred at the same temperature. When the reaction was complete as indicated by TLC, water (200 ml) was added, cooling bath was removed and the reaction mixture was stirred for 10 mins. The organic layer was separated and washed with 5% sodium carbonate solution. The separated dichloromethane solution was charcoalised and filtered through celite. The filtrate was concentrated to 100 ml and ethyl acetate 100 ml was added thereto. The separated solid was filtered, washed with ethyl acetate and dried in vacuum oven to yield 28.20 g of omeprazole. Yield 82.4% of theoretical. Melting point was 158°-160°C (dec.). 

Table 3.70 Experimental and theoretical characteristics of the UV spectra of benzimidazole and 5 (6)-nitrobenzimidazole...

Semi-empirical LCAO calculations for all azoles, introducing cr-electrons, indicate that charges are weak except those on NH nitrogen atoms, and that the cr-dipolar moments are close to those of lone pairs. It is therefore inappropriate to take cr-polarity into account in the approximations used in 7r-calculations for these heterocycles. A number of other quantum mechanical calculations have been applied to reactions of imidazoles (80AHC 27)241), while the nucleophilic substitution reactions at C-2 of benzimidazoles, and diazo coupling at C-2 of uncondensed imidazoles have been discussed from theoretical points of view. 

Comparisons have been made among benzimidazole, benzoxazole and benzoselenazole using MO calculations and PE spectra. The theoretical calculations agree with the observed relative band intensities for the He(I) and He(II) spectra (78MI40600). Application to imidazoles of He(I) PE spectroscopy demonstrates that the lone pair levels are heavily localized on nitrogen, while the other MOs of the valency shell are strongly delocalized (73T2173). 

AMI semiempirical calculations have shown that, as far as tautomerism is concerned, there is a structural relationship between jS-dicarbonyl compounds and NH-pyrazoles, and in a wide variety of NH-pyrazoles studied " the most stable tautomer was found to be that having the largest single-bond character between the C(3)—C(4) bond. The problem of proton transfer in NH-pyrazole crystals has been subjected to a detailed theoretical study, while a study of the tautomerism of 2-aryl and 2-heteroaryl derivatives of benzimidazole has indicated that tautomerism takes place by the intermolecular relay of protons between stacked molecules. The first report of the stable co-existence of two different histidine tautomers in one peptide crystal structure has appeared. Ab initio calculations have been used to study the tautomerism of both histamine and pyrazolo[3,4-i/]pyridazine in the gas phase and in aqueous solution, and a theoretical study of the NH tautomerism in free-base porphyrin has been undertaken. ... 

Values of x/gj plotted according to data in Ref. 43) and molecular weights according to data in Ref.43) (a) 4 poly(amide benzimidazole) in sulfuric acid 44) ( ) 5 poly(p-phenylene-1,3,4-oxadiazole) in sulfuric acid43) (v). The curve corresponds to theory as in Ref. 1). A and B are theoretical values for kinetically rigid Gaussian coils with strong (A) and weak (B) hydro-dynamic interactions 4 3)... 

The benzimidazole is dissolved in 750 cc. of boiling water in a 1500-cc. beaker. The solution is digested for fifteen minutes with about 2 g. of decolorizing carbon (Norite) and filtered rapidly through a well-heated filter (Note 4). The filtrate is cooled to 10-15°, S lid the benzimidazole is filtered and washed with 50 cc. of cold water. The white (Note 5) product is dried at 100°. The melting point is 170-172°, and the 5deld is 49-50.5 g. (83-85 per cent of the theoretical) (Notes 6 and 7). 

The yield is not greatly affected if the amount of formic acid is decreased almost to the theoretical, but a safe excess is recommended to insure utilization of the o-phenylenediamine. Formic acid of considerably less than 90 per cent concentration will form benzimidazole good yields were obtained with 40 per cent acid. 

The crude benzimidazole, if dried at 100°, weighs 57.5-59 g. (97-99 per cent of the theoretical), melts at 167-168°, and is yellow tinged. This discoloration is hard to remove and persists after two crystallizations (Note 5). 

Imidazoles and benzimidazoles unsubstituted on nitrogen exhibit fast prototropic tautomerism which leads to equilibrium mixtures of unsymmetrically substituted compounds, for example, 4(5)-substituted imidazoles, 4(7)- or 5(6)-substituted benzimidazoles. The proton exchange is an intermolecular process (which may involve a protic solvent), and is so fast on the NMR time scale that only one species is usually apparent in the spectrum. iV-Substituted azoles cannot exhibit such tautomerism, and strongly acidic media also inhibit proton exchange. Much work since the mid-1980s has focussed on determination of the proportions of isomers in tautomeric mixtures, with theoretical studies applied to the gas phase (and solution), and solid state studies are also receiving considerable attention. Extrapolation of the results of gas phase and solid state studies to solution, though, can only be less than perfect. 

This is theoretically the simplest way to obtain 1,2,4,6-thiatriazines, if sequences such as -S = N —C = N —C = N— are available on a preparative scale. However, the only known examples are the extremely unstable A -sulfinyl derivatives of ring-fixed biguanides, e.g. A-sulfinyl-benzimidazoles. 

Prilosec, Rapinex, Zegerid) and its S-isomer, esomeprazole (Nexium), lansoprazole (Prevacid), rabeprazole (Aciphex), and pantoprazole (Protonix). These drugs have different substitutions on their pyridine and/or benzimidazole groups but are remarkably similar in their pharmacological properties. Omeprazole is a racemic mixture of R- and S-isomers the S-isomer, esomeprazole (S-omeprazole), is eliminated less rapidly than R-omeprazole, which theoretically provides a therapeutic advantage because of the increased half-life. Despite claims to the contrary, all proton-pump inhibitors have equivalent efficacy at comparable doses. 

Very few theoretical studies concern these systems. An example using TD-DFT and the localized density matrix (LDM) method approaches to calculate the electronic spectra of 2-(2 -pyridyl)benzimidazole (111) and its boron and beryllium derivatives 112-114 has been reported recently (10THE(955)7). 

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