Substitution Of Imidazole Research Articles

Influence of the functionalization of imidazole on its CO2 uptake efficiency. A theoretical contribution

New capture and sequestration technologies have been proposed to mitigate CO2 emissions motivating the search for new materials such as MOF’s, ZIF’s and other porous solids. In this paper, the influence of the substitution of imidazole by different donor and acceptor groups on the CO2 uptake efficiency is analyzed. Imidazoles are important organic units of the ZIF’s.Geometries and energies of the different complexes have been optimized using the Density Functional (DFT) and Möller–Plesset (MP2) theories with cc-pVTZ and aug-cc-pVTZ atomic orbitals basis sets. For DFT calculations, the WB97XD functional, suitable for the description of dispersion forces and Van der Waals interactions, has been used. The preferred configurations of the substituted imidazoles are planar, favoring the CO2 approach to the sp2 type nitrogen. Binding energies are determined minimizing the basis set superposition error and taking into account the zero point energies. The interaction between imidazole and different greenhouse effect gases such as H2O, N2, CH4, NH3 and SO2 are also studied in order to demonstrate the selectivity of imidazole for CO2 capture. The imidazole molecules (or the ZIF’s) can then be used for selective separation of CO2 in gas mixture containing CO2, N2, and CH4 of industrial flues. However, it can be noticed that imidazoles are not adequate for gas mixture containing H2O and CO2 or NH3 and CO2. The behavior of imidazolates in dry or humid environments is predicted to be very different. The effect of the substitution of the imidazole hydrogens by one, two, or three active groups on the CO2 capture and storage is also analyzed. The selected groups are OH, CN, CH3, NH2, COH, Cl, CF3, OCH3 and C(CH3)3.

Novel metal chelating molecules with anticancer activity. Striking effect of the imidazole substitution of the histidine–pyridine–histidine system

Previously we have reported a metal chelating histidine–pyridine–histidine system possessing a trityl group on the histidine imidazole, namely HPH-2Trt, which induces apoptosis in human pancreatic adenocarcinoma AsPC-1 cells. Herein the influence of the imidazole substitution of HPH-2Trt was examined. Five related compounds, HPH-1Trt, HPH-2Bzl, HPH-1Bzl, HPH-2Me, and HPH-1Me were newly synthesized and screened for their activity against AsPC-1 and brain tumor cells U87 and U251. HPH-1Trt and HPH-2Trt were highly active among the tested HPH compounds. In vitro DNA cleavage assay showed both HPH-1Trt and HPH-2Trt completely disintegrate pUC19 DNA. The introduction of trityl group decisively potentiated the activity.

Spectroscopic insights on imidazole substituted phthalocyanine photosensitizers: Fluorescence properties, triplet state and singlet oxygen generation

Imidazole substituted metal phthalocyanine (Pc) complexes were synthesized. UV–vis absorption, steady state and time-resolved fluorescence, as well as laser flash photolysis were used to measure the photophysical and photosensitizing properties. All the imidazole–phthalocyanine conjugates show high ΦT (quantum yield of excited triplet formation), high ΦΔ (singlet oxygen formation yield, >0.50) and good fluorescence properties (quantum yield Φf>0.20 and lifetime τf>3.0 ns). Compared to the unsubstituted Pc, both α- and β-imidazole substitutions result in the remarkable decrease in Φf and τf, but the α-substitution is stronger. The imidazole substitution, on the other hand, causes the increase of ΦT, τT, and ΦΔ values. Magnesium phthalocyanine (MgPc) is more susceptible to the substitution than zinc phthalocyanine (ZnPc). The mechanism responsible for the result is suggested based on the involvement of intramolecular photoinduced electron transfer. The high ΦΔ and appropriate fluorescence properties make the Pcs good candidate for PDT photosensitizers.

One-step column purification of herpes simplex virus 1 helicase–primase subcomplex using C-terminally his-tagged UL5 subunit

A protocol for purification of the two-subunit complex of herpes simplex virus type 1 (HSV-1) helicase-primase by metal affinity chromatography is presented. In order to bind the enzyme complex consisting of UL5 and UL52 gene functions to the affinity column, the C-terminus of the UL5 gene of HSV-1 strain ANG was fused in-frame with a sequence encoding six histidines, resulting in a His6-tagged DNA helicase (UL5his) when expressed via recombinant baculovirus. In addition, hybridoma cell lines producing anti-UL5 IgG were generated for screening of DNA helicase expression. Initial purification trials revealed that the presence of low concentrations of imidazole in the wash buffers interfered with the binding of the helicase-primase subunit complex to the metal affinity resin. Alternative means, such as high salt, altered pH, and substitution of imidazole by histidine tetrapeptide (His4), were tested. From those, the addition of His4 in combination with an acidic pH turned out to be very efficient for the removal of protein contaminants from a Ni2+-NTA (nitrilotriacidic acid) affinity resin. By applying only one column step, the present protocol yields a helicase-primase preparation, which is suitable for inhibitor screening and further functional studies. The final preparation is free of interfering enzyme activities, and exerts each of the enzymatic functions described for a two subunit complex, i.e., DNA-dependent ATPase, DNA primase, and DNA helicase activities.

Low-Frequency Heme, Iron-Ligand, and Ligand Modes of Imidazole and Imidazolate Complexes of Iron Protoporphyrin and Microperoxidase in Aqueous Solution. An Analysis by Far-Infrared Difference Spectroscopy

FTIR difference spectroscopy, notably in the far-IR domain, is appealing for the analysis of hemoproteins, since it permits us to directly probe the properties of the heme and its ligands but also those of aminoacids remote from the heme. We recently set a thin path-length electrochemical cell with diamond windows allowing the far-IR analysis of proteins in aqueous solutions using FTIR difference spectroscopy (Berthomieu, C,; Marboutin, L.; Dupeyrat, F.; Bouyer, P. Biopolymers 2006 82, 363-367). In this study, we used this cell to identify redox-sensitive low-frequency IR modes of imidazole complexes of Fe-protoporphyrin IX and microperoxidase-8 and analyzed the pH dependence of these modes. The far-IR bands of the heme and the axial imidazole ligands were assigned using (15)N(2)-, and d(3)-imidazole isotopic substitution, as well as imidazole substitution by 4(5)-methylimidazole. Internal modes of the axial histidine and imidazole ligands were identified in the 670-580 cm(-1) region, which are sensitive to the iron coordination (five-coordinated high-spin heme or six-coordinated low-spin heme) and the protonation states of the axial ligands. We showed that deformation modes of the heme pyrroles dominate the 420-370 cm(-1) region of the difference spectra. These modes were highly sensitive to the coordination and redox states of the heme iron and the conformation of the tetrapyrrole. While no nu(as)(Fe-axial ligand) IR mode was detected in the difference spectra of the neutral imidazole complexes of Fe-protoporphyrin and microperoxidase, a new mode at 312 and 334 cm(-1) was found specific of the imidazolate complexes of Fe(3+)-protoporphyrin and Fe(3+)-microperoxidase-8, respectively. On the basis of isotope shifts observed upon ligand deuteration, this band was assigned to a mode mixing the asymmetric stretching of the axial bonds with an internal deformation of the imidazolate rings. These data set the bases for the analysis of the IR low-frequency modes of hemoproteins, and specifically the electronic properties of the heme axial histidine ligands.

Three-dimensional networks in the 1:2 organic salts 2,2′-biimidazolium bis(3-carboxy-4-hydroxybenzenesulfonate) and 2,2′-bibenzimidazolium bis(3-carboxy-4-hydroxybenzenesulfonate) trihydrate

The two title compounds of 2,2'-biimidazole (Bim) with 5-sulfosalicylic acid (5-H(2)SSA) and 2,2'-bibenzimidazole (Bbim) with 5-H(2)SSA are 1:2 organic salts, viz. C(6)H(8)N(4)(2+).2C(7)H(5)O(6)S(-), (I), and C(14)H(12)N(4)(2+).2C(7)H(5)O(6)S(-).3H(2)O, (II). The cation of compound (I) lies on a centre of inversion, whereas that of (II) lies on a twofold axis. Whilst compound (I) is anhydrous, three water molecules are incorporated into the crystal structure of (II). The substitution of imidazole H atoms by other chemical groups may favour the incorporation of water molecules into the crystal structure. In both compounds, the component cations and anions adopt a homogeneous arrangement, forming alternating cation and anion layers which run parallel to the (001) plane in (I) and to the (100) plane in (II). By a combination of N-H...O, O-H...O and C-H...O hydrogen bonds, the ions in both compounds are linked into three-dimensional networks. In addition, pi-pi interactions are observed between symmetry-related benzene rings of Bbim(2+) cations in (II).

Cisplatin mediates selective downstream hydrolytic cleavage of Met-(Gly) n-His segments ( n = 1,2) in methionine- and histidine-containing peptides: The role of ammine loss trans to the initial Pt-S(Met) anchor in facilitating amide hydrolysis

The pH- and time-dependent reactions of the antitumor drug cisplatin, cis-[PtCl 2(NH 3) 2], with the methionine- and histidine-containing pentapeptides Ac-Met-Gly-His-Gly-Gly-OH, Ac-Met-Gly-Gly-His-Gly-OH and Ac-Gly-Met-Gly-His-Gly-OH (Gly = glycyl, Met = l-methionyl, His = l-histidyl) at 313 K have been investigated by high performance liquid chromatography, mass spectrometry and nuclear magnetic resonance. Cisplatin mediates a rapid “downstream” hydrolytic cleavage of the Met-Gly amide bond in weakly acid solution (pH ⩽5) for all three peptides, leading to release of H-Gly-His-Gly-Gly-OH, H-Gly-Gly-His-Gly-OH and H-Gly-His-Gly-OH, respectively, and formation of κ 2 S, N M chelate complexes of the methionine-containing residuals Ac-Met-OH or Ac-Gly-Met-OH. An alternative reaction pathway affords tridentate κ 3 S, N M, N(imidazole) macrochelates of the original pentapeptide following ammine loss. The downstream cleavage pathway is competitive with the likewise cisplatin-mediated upstream cleavage of the Ac-Gly linkage in the pentapeptide Ac-Gly-Met-Gly-His-Gly-OH. This leads to formation of both the κ 3 S, N M, N G1 complex of H-Gly-Met-Gly-His-Gly-OH due to upstream cleavage and the analogous tridentate complex for H-Gly-Met-OH due to initial downstream loss of H-Gly-His-Gly-OH followed by upstream loss of acetic acid. As downstream cleavage is not observed for Ac-(Gly) 2-Met-(Gly) 2-OH under similar conditions, it may be concluded that rapid histidine imidazole substitution of the ammine ligand in trans-position to an anchoring methionine S atom must assist hydrolytic cleavage of the Met-Gly amide bond.

The enzymatic activation of coenzyme B12

The enzymatic "activation" of coenzyme B12 (5'-deoxyadenosylcobalamin, AdoCbl), in which homolysis of the carbon-cobalt bond of the coenzyme is catalyzed by some 10(9)- to 10(14)-fold, remains one of the outstanding problems in bioinorganic chemistry. Mechanisms which feature the enzymatic manipulation of the axial Co-N bond length have been investigated by theoretical and experimental methods. Classical mechanochemical triggering, in which steric compression of the long axial Co-N bond leads to increased upward folding of the corrin ring and stretching of the Co-C bond is found to be feasible by molecular modeling, but the strain induced in the Co-C bond seems to be too small to account for the observed catalytic power. The modeling study shows that the effect is a steric one which depends on the size of the axial nucleotide base, as substitution of imidazole (Im) for the normal 5,6-dimethylbenzimidazole (Bzm) axial base decreases the Co-C bond labilization considerably. An experimental test was thus devised using the coenzyme analog with Im in place of Bzm (Ado(Im)Cbl). Studies of the enzymatic activation of this analog by the B12-dependent ribonucleoside triphosphate reductase from Lactobacillus leichmannii coupled with studies of the non-enzymatic homolytic lability of the Co-C bond of Ado(Im)Cbl show that the enzyme is only slightly less efficient (3.8-fold, 0.8 kcal mol(-1)) at activating Ado(Im)Cbl than at activating AdoCbl itself. This suggests, in agreement with the modeling study, that mechanochemical triggering can make only a small contribution to the enzymatic activation of AdoCbl. Another possibility, electronic stabilization of the Co(II) homolysis product by compression of the axial Co-N bond, requires that enzymatic activation be sensitive to the basicity of the axial nucleotide. Preliminary studies of the enzymatic activation of a coenzyme analog with a 5-fluoroimidazole axial nucleotide suggest that the catalysis of Co-C bond homolysis may indeed be significantly slowed by the decrease in basicity.

Model studies of the histidine-tyrosine cross-link in cytochrome C oxidase reveal the flexible substituent effect of the imidazole moiety.

[reaction: see text] Experimental and theoretical studies were carried out to interrogate the effect of an imidazole substituent in each of the ortho, meta, and para positions on the pK(a), E degrees , and O-H BDE of phenol. The results reveal that imidazole substitution lowers the pK(a) of phenol and increases the E degrees of phenoxide due to its sigma-electron withdrawing ability (sigma(p)(-) = +0.21, sigma(m)(-) = +0.45) but decreases the O-H BDE and E degrees of phenol due to its pi-electron-donating ability (sigma(p)(+) = -0.45).

Crystal structures of copper(II) complexes with methyliminodiacetate ions and 1,10-phenanthroline or imidazole [Cu(Phen)H2O][Cu(Mida)2]·2H2O and [Cu(Mida)Im

Methyliminodiacetic acid (H2Mida) and imidazole react with copper(II) to form crystals of the square pyramidal complex [Cu(Mida)Im]. One N and two O atoms of the Mida ligand (Cu-N 2.010(1) A, Cu-O 1.955(1) A, and 1.978(1) A) and the imidazole N atom (1.950(1) A) lie at the base of the pyramid. The carboxyl O atom of the neighboring complex lies at the apical position (2.411(1) A); in this way the individual complexes are linked into infinite zigzag chains. Substitution of imidazole by 1,10-phenanthroline gave [Cu2(Mida)2(Phen)H2O]·2H2O crystals with two nonequivalent centrosymmetric octahedral anions [Cu(Mida)2]2− of face type (Cu-N 2.023 A and 2.028(2) A, Cu-Oax 2.579 A and 2.530(2) A, Cu-Obas 1.952 A and 1.936(2) A). The anions serve as bridges in chains between the [Cu(Phen)H2O]2+ cation fragments to which they are bonded by their axial carboxyl groups. The Cu atom of the cation has a [4+1] environment (with the H2O molecule lying on the axis of the pyramid, and with two N atoms of the ligand and two O atoms of the anions lying at the base).

Studies on kinetics and mechanism of imidazole substitution from cis-equatorial-[Cr(S-pdtra)(Him)]0 complex in acidic and alkaline aqueous solutions [S-pdtra = (S )-propylenediaminetriacetate] †

Aquation of the cis-equatorial-[Cr(S-pdtra)(Him)]0 complex [S-pdtra = (S)-propylenediaminetriacetate] has been studied within the pH range 0–14. Liberation of imidazole in acidic medium leads to the cis-eq-[Cr(S-pdtra)(H2O)]0 complex. Deprotonation of coordinated imidazole in alkaline solutions stimulates a reversible one-end dechelation of S-pdtra, which precedes substitution of imidazole; a characteristic bell-shaped kobsvs. [H+] dependence is observed. The values of ΔS ‡ = –52.8 J mol–1 K–1, ΔH ‡ = 84.2 kJ mol–1 and ΔV ‡ = –10.1 cm3 mol–1 for aquation in acidic medium are consistent with an Ia mechanism, whereas substitution of the imidazolate from the hydroxo complex with a tetradentate S-pdtra proceeds via an Id mechanism on the basis of ΔS ‡ = 49.6 J mol–1 K–1 and ΔH ‡ = 117.5 kJ mol–1. One-end dechelation of the S-pdtra ligand from the complex with imidazolate (pH > 13) is characterised by k298 = 6.43 × 10–3 s–1, ΔS ‡ = –57.2 J mol–1 K–1 and ΔH ‡ = 68.5 kJ mol–1.

Inhibition of nitric oxide synthase by 1-(2-trifluoromethylphenyl) imidazole (TRIM) in vitro: antinociceptive and cardiovascular effects.

1. The ability of a range of substituted imidazole compounds to inhibit mouse cerebellar neuronal nitric oxide synthase (nNOS), bovine aortic endothelial NOS (eNOS) and inducible NOS (iNOS) from lungs of endotoxin-pretreated rats was investigated. In each case the substrate (L-arginine) concentration employed was 120 nM. 2. 1-(2-Trifluoromethylphenyl) imidazole (TRIM) was a relatively potent inhibitor of nNOS and iNOS (IC50S of 28.2 microM and 27.0 microM respectively) but was a relatively weak inhibitor of eNOS (IC50, 1057.5 microM). The parent compound, imidazole, was a weak inhibitor of all three NOS isoforms (IC50S: nNOS, 290.6 microM; eNOS, 101.3 microM; iNOS, 616.0 microM). Substitution of imidazole with a phenyl group to yield I-phenylimidazole (PI) resulted in an isoform non-selective increase in inhibitory potency (IC50S: nNOS, 72.1 microM; eNOS, 86.9 microM; iNOS, 53.9 microM). Further substitution of the attached phenyl group resulted in an increase in nNOS and a decrease in eNOS inhibitory potency as in TRIM, 1-chlorophenylimidazole (CPI; IC50S: nNOS, 43.4 microM; eNOS, 392.3 microM; iNOS, 786.5 microM) and 1-(2,3,5,6-tetrafluorophenyl) imidazole (TETRA-FPI; IC50S; nNOS, 56.3 microM; eNOS, 559.6 microM; iNOS, 202.4 microM). 3. The ability of TRIM to inhibit mouse cerebellar nNOS activity in vitro was influenced by the concentration of L-arginine (0.12-10.0 microM) in the incubation medium. When mouse cerebellar nNOS was used as enzyme source a double reciprocal (Lineweaver-Burk) plot in the presence/absence of TRIM (50 microM) revealed a competitive inhibitory profile. The K(m) for L-arginine and the Ki for TRIM calculated from these data were 2.4 microM and 21.7 microM, respectively. The ability of TRIM to inhibit mouse cerebellar nNOS activity in vitro was unaffected by varying the time of exposure of the enzyme to TRIM from 0-60 min at 0 degree C. 4. TRIM exhibits potent antinociceptive activity in the mouse as evidenced by inhibition of acetic acid induced abdominal constrictions. The ED50 for TRIM following i.p. administration was 20 mg kg-1 (94.5 mumol kg-1). The antinociceptive effect of TRIM was reversed by pretreatment of animals with L-arginine (50 mg kg-1, i.p.) and was not accompanied by sedation, motor ataxia or behavioural changes (rearing, crossing, circling, dipping) as assessed by use of a box maze procedure. 5. L-NG nitro arginine methyl ester (L-NAME, 20 mg kg-1, i.v.) but not TRIM (0.5-20 mg kg-1, i.v.) increased mean arterial blood pressure (MAP) in the urethane-anaesthetized rat. 6. L-NAME (100 microM) potentiated the contractile response of the rabbit isolated aorta to phenylephrine (ED50; 0.084 +/- 0.01 microM in the presence and 0.25 +/- 0.05 microM in the absence of L-NAME; maximum response, 7.7 +/- 0.4 g in the presence and 5.6 +/- 0.5 g in the absence of L-NAME, n = 6, (P < 0.05) whilst TRIM (1-100 microM) was without effect. L-NAME (100 microM) but not TRIM (1-100 microM) also reduced carbachol-induced relaxation of the phenylephrine-precontracted rabbit aorta preparation. 7. L-NAME (50 microM) potentiated the vasoconstrictor effect of bolus-injected noradrenaline (10-1000 nmol) and reduced the vasodilator effect of carbachol (10 microM) added to the Krebs reservoir in the rat perfused mesentery preparation. L-NAME (50 microM) also reduced nitric oxide (NO) release (measured by chemiluminescence of nitrite in the Krebs perfusate) in response to noradrenaline (100 nmol; 53.8 +/- 4.0 pmol ml-1 in the presence and 84.8 +/- 8.0 pmol ml-1 in the absence of L-NAME, n = 15, P < 0.05) and carbachol (10 microM; 63.9 +/- 5.0 pmol ml-1 in the presence and 154.0 +/- 9.0 pmol ml-1 in the absence of L-NAME, n = 15, P < 0.05). TRIM (50 microM) did not affect either the vasoconstrictor response to noradrenaline or the vasodilator response to carbachol or the accompanying release of NO from the perfused rat mesentery.

Effect of the acyl group in the reaction of imidazole with acyl-substituted 4-nitrophenyl acetates in acetonitrile and in aqueous acetonitrile with a low water content

Reactions of imidazole with 4-nitrophenyl chloroacetate and dichloroacetate have been studied in acetonitrile and in 0.56 mol dm–3 water in acetonitrile. The second-order dependence, beside the first-order term in imidazole, is observed for all cases. The main interest was to study whether the first-order reaction in imidazole in aqueous acetonitrile is a general base-catalysed hydrolysis or a nucleophilic reaction of imidazole. The water isotope effects, steric effects by the 2-methyl substitution of imidazole, the effect of water in the reaction solution and the thermodynamic activation parameters were determined. Comparison of the results with those found previously for the reactions of imidazole with 4-nitrophenyl acetate and trifluoroacetate suggests that for 4-nitrophenyl chloroacetate and dichloroacetate the reaction first-order in imidazole represents a nucleophilic reaction and the reaction second-order in imidazole the general base-catalysed nucleophilic reaction of the amine. Accordingly, the change in the overall second-order reaction of 4-nitrophenyl acetates from a nucleophilic reaction of imidazole to the general base-catalysed hydrolysis needs a more electron-withdrawing acyl group than the dichloro substituted one.

Low-temperature crystallographic analyses of the binding of Hoechst 33258 to the double-helical DNA dodecamer C-G-C-G-A-A-T-T-C-G-C-G

The crystal structure of the complex of Hoechst 33258 and the DNA dodecamer C-G-C-G-A-A-T-T-C-G-C-G has been solved from X-ray data collected at three different low temperatures (0, -25, and -100 degrees C). Such temperatures have permitted collection of higher resolution data (2.0, 1.9, and 2.0 A, respectively) than with previous X-ray studies of the same complex. In all three cases, the drug is located in the narrow central A-A-T-T region of the minor groove. Data analyses at -25 and -100 degrees C (each with a 1:1 drug/DNA ratio in the crystallizing solution) suggest a unique orientation for the drug. In contrast, two orientations of the drug were found equally possible at 0 degrees C with a 2:1 drug/DNA ratio in solution. Dihedral angles between the rings of Hoechst 33258 appear to change in a temperature-dependent manner. The drug/DNA complex is stabilized by single or bifurcated hydrogen bonds between the two N-H hydrogen-bond donors in the benzimidazole rings of Hoechst and adenine N3 and thymine O2 acceptors in the minor groove. A general preference for AT regions is conferred by electrostatic potential and by narrowing of the walls of the groove. Local point-by-point AT specificity follows from close van der Waals contacts between ring hydrogen atoms in Hoechst 33258 and the C2 hydrogens of adenines. Replacement of one benzimidazole ring by purine in a longer chain analogue of Hoechst 33258 could make that particular site GC tolerant in the manner observed at imidazole substitution for pyrrole in lexitropsins.

ChemInform Abstract: General Base Catalysis in the Methanolysis of 4‐Nitrophenyl Acetates

The rates of the methanolysis of 4-nitrophenyl acetate, chloroacetate, and dichloroacetate have been measured in the presence of pyridines and imidazoles. Methyl substitution at the 2- and 6-positions in pyridine causes only a slight reduction in reactivity. A Bronsted β value of 0.48 has been evaluated for the catalysed methanolysis of 4-nitrophenyl chloroacetate by pyridines. The entropy of activation for the pyridine-catalysed methanolysis of 4-nitrophenyl dichloroacetate exhibits a substantial, negative value, –164 J mol–1 K–1. These results indicate that pyridine bases act as general base catalysts and not as nucleophiles in the methanolysis of 4-nitrophenyl acetates. Nucleophilic catalysis possibly occurs in the imidazole-catalysed methanolysis of 4-nitrophenyl acetate and chloroacetate. This suggestion is based on the steric effect caused by 2-methyl substitution of imidazole. The higher reactivity of imidazole as expected from the reactivity of pyridines confirms this conclusion.

General base catalysis in the methanolysis of 4-nitrophenyl acetates

The rates of the methanolysis of 4-nitrophenyl acetate, chloroacetate, and dichloroacetate have been measured in the presence of pyridines and imidazoles. Methyl substitution at the 2- and 6-positions in pyridine causes only a slight reduction in reactivity. A Brønsted β value of 0.48 has been evaluated for the catalysed methanolysis of 4-nitrophenyl chloroacetate by pyridines. The entropy of activation for the pyridine-catalysed methanolysis of 4-nitrophenyl dichloroacetate exhibits a substantial, negative value, –164 J mol–1 K–1. These results indicate that pyridine bases act as general base catalysts and not as nucleophiles in the methanolysis of 4-nitrophenyl acetates. Nucleophilic catalysis possibly occurs in the imidazole-catalysed methanolysis of 4-nitrophenyl acetate and chloroacetate. This suggestion is based on the steric effect caused by 2-methyl substitution of imidazole. The higher reactivity of imidazole as expected from the reactivity of pyridines confirms this conclusion.

Nucleophilic substitution of pentafluorobenzes with imidazole

The imidazole substitution of pentafluorobenzenes C 6F 5R: R = CN, NO 2, CO 2C 2H 5, CHO, I, Br, Cl, H) occurred mainly at the para -position to R and corresponding 1-(4′-R-tetrafluorophenyl)imidazoles were obtained in good yields. The reactivity varied markedly with the substituents: nitro- or cyanopentafluorobenzene easily reacted at ambient temperature without any bases; however, methyl- or methoxypentafluorobenzene failed to react even at 100°C in the presence of a strong base.

Kinetics and mechanism of the interactions of imidazole and benzimidazole withcis-diaquo(nitrilotriacetato)cobalt(III)

The kinetics of the anation ofcis-diaquo(nitrilotriacetato)cobalt(III) with imidazole (imz) and benzimidazole (bimz) have been studied in the pH range 6.10–7.10 and 5.60–6.85 respectively at μ = 0.1 M and in the temperature range 40–60°C. Both reactions produce the bisubstituted product but the entry of the first ligand is rate determining in each case. The pH dependence of rate shows that the neutral ligand reacts with both the acid and the base forms of the complex, the reactivity of the base form being slightly higher in each case. The pseudo first-order rate constants show a non-linear dependency on the concentration of incoming ligand at a particular pH. A pureD (dissociative) mechanism rather thanI d (dissociative interchange) is operative which is supported by previously reported results of imidazole substitution reactions.

Binding of an antitumor drug to DNA: Netropsin and C-G-C-G-A-A-T-T- BrC-G-C-G

The antitumor antibiotic netropsin has been co-crystallized with a double-helical B-DNA dodecanucleotide of sequence: C-G-C-G-A-A-T-T- BrC-G-C-G, and the structure of the complex has been solved by X-ray diffraction at a resolution of 2.2 Å. The structure has been refined independently by Jack-Levitt and Hendrickson-Konnert least-squares methods, leading to a final residual error of 0.257 by the Jack-Levitt approach (0.211 for two-sigma data) or 0.248 by the Hendrickson-Konnert approach, with no significant difference between refined structures. The netropsin molecule displaces the spine of hydration and fits snugly within the minor groove in the A-A-T-T center. It widens the groove slightly and bends the helix axis back by 8 °, but neither unwinds nor elongates the double helix. The drug molecule is held in place by amide NH hydrogen bonds that bridge adenine N-3 and thymine O-2 atoms, exactly as with the spine of hydration. The requirement of A · T base-pairs in the binding site arises because the N-2 amino group of guanine would demand impermissibly close contacts with netropsin. It is proposed that substitution of imidazole for pyrrole in netropsin should create a family of “lexitropsins” capable of reading G · C-containing base sequences.

Effect of imidazole substitution on the dimerization reaction of manganese(III) porphyrin in aqueous environments: Temperature jump study

Equilibrium constants for ligand binding and rate constants for a dimerization reaction in the presence of the ligand imidazole were determined for the manganese(III) porphyrin in 0.1M KNO 3. Imidazole binds to the manganese porphyrin in stepwise equilibria to form the diligated dimer (Mn PL) D and further to the di-imidazole monomer, Mn P 2. Analysis of temperature jump kinetic data, supported by spectrophotometric studies, showed that the phenomenon responsible for the relaxation is the dissociation of the ligated dimer. The mechanism proposed involves a self dissociation of the imidazole bound dimer and a ligand induced dimer dissociation viz: ▪ At 302°K, the rate constants evaluated are k 1 = 4.8 × 10 6 M −1 S −1, k −1 = 200 S −1 k 2 = 5.4 × 10 7M −1 S −1 and k −2 = 2500 M −1 S −1.