Voltammetric Study of Nitro Radical Anion Generated from Some Nitrofuran Compounds of Pharmacological Significance

The electrochemical behavior of 2‐(5‐amino‐ 1,3,4‐oxadiazolyl)‐5‐nitrofuran (NF359) and its comparison with well‐known drugs such as nifurtimox (NFX) and nitrofurazone (NFZ) in protic, mixed and aprotic media by cyclic voltammetry, tast and differential pulse polarography was studied. All the compounds were electrochemically reducible in all media being the reduction of the nitrofuran group the main voltammetric signal. The one‐electron reduction couple due to the nitro radical anion formation was visualized in mixed (for NF359 and NFZ) and aprotic media (for all compounds). By applying a cyclic voltammetric methodology we have calculated the decay constants (k₂) of the corresponding nitro radical anions in mixed and aprotic media. In mixed medium data fit well with a disproportionation reaction of the nitro radical anion but in aprotic medium fit better with a dimerization reaction. Also, considering cyclic voltammetric measurements in aprotic media we have estimated the reduction potential of the RNO₂/RNO₂^.? couple in aqueous medium, pH 7 (E¹₇ values) finding very good correlation with E¹₇ values obtained by pulse radiolysis. Furthermore we have calculated the equilibrium constants from the electron transfer from nitro radical anion to oxygen (k_O2) finding that nitro radical anion from NF359 is thermodynamically favored to react with oxygen in respect to both NFZ and NFX.     

Nitroradical Anion Formation from some Iodo‐Substituted Nitroimidazoles

The electrochemical behavior of iodo nitroimidazole derivatives such as 1‐methyl‐4‐iodo‐5‐nitroimidazole (M‐I‐NIm) and 1‐methyl‐2,4‐diiodo‐5‐nitroimidazole (M‐I₂‐NIm) and the parent compound 1‐methyl‐5‐nitroimidazole (M‐NIm), was studied in protic, mixed and non‐aqueous media. The electrochemical study was carried out using Differential Pulse Polarography (DPP), Cyclic Voltammetry (CV), Differential Pulse Voltammetry (DPV) and coulometry and as working electrodes mercury and glassy carbon were used. As can be expected, in all media, the effect of introduce iodo as substituent in the nitroimidazole ring produced a decrease of the energy requirements of the nitro group reduction. Certainly, this fact can be explained by the electron withdrawing character of the iodo substituent that acts diminishing the electronic density on the nitro group thus facilitating their reduction. In all the studied media the reduction of M‐NIm produced a detectable signal for a nitro radical anion derivative. In the case of M‐I‐NIm the nitro radical anion was only detectable in both mixed and non‐aqueous media. On the other hand the nitro radical anion for the M‐I₂‐NIm was detected only in non‐aqueous medium. When glassy carbon electrode was used as the working electrode in a mixed medium a detectable nitro radical anion derivative appeared for all compounds, thus permitting an adequate comparison between them. The obtained values of k₂ for M‐NIm, M‐I‐NIm and M‐I₂‐NIm in non‐aqueous medium were 5.81×10², 132×10² and 1100×10² M^?1 s^?1, respectively. From the obtained k₂ and t_1/2 values in this medium, it is concluded that there is a direct dependence between the presence of iodo substitution in the nitroimidazole ring with the stability of the nitro radical anion.     

Nucleophilic substitution studies on nitroimidazoles,and applications to the synthesis of biologically active compounds

The rationalization of the synthesis of substituted analogs of megazol, a biologically active 5‐nitroimidazole at position 4 of the imidazole ring, had led to the study of intermediate steps. The methylation by diazomethane of 2,4‐(5)dihalogeno‐5‐(4)nitroimidazole is regioselective leading to 2,4‐dihalogeno‐1‐methyl‐5‐nitroimidazole 2. On this compound 2 , hard nucleophiles such as cyanide, methoxide or hydride anions react only with the halogen at the 2 position; whereas soft nucleophiles such as amine, thiol or trifluoromethyl anion from an organocopper species react only with the halogen at postion 4 in the intermediate 3b or compound 4b.     

Analysis of the substituent effect on the reactivity modulation during self-protonation processes in 2-nitrophenols

A voltammetric and spectroelectrochemical ESR study of the reduction processes of five substituted 4-R-2-nitrophenols (R = -H, -OCH(3), -CH(3), -CN, -CF(3)) in acetonitrile was performed. In the potential range considered here (-0.2 to -2.5 V vs Fc+/Fc), two reduction signals (Ic and IIc) were detected; the first one was associated with the formation of the corresponding hydroxylamine via a self-protonation pathway. The voltammetric analysis at the first reduction signal showed that there are differences in the reduction pathway for each substituted 4-R-2-nitrophenol, being the E1/2 values determined by the inductive effect of the substituent in the meta position with respect to the nitro group, while the electron-transfer kinetics was determined by the protonation rate (k(1)+ ) of the anion radical electrogenerated. However, at potential values near the first reduction peak, no ESR signal was recorded from stable radical species, indicating the instability of the radical species in solution. Nevertheless, an intense ESR spectrum generated at the second reduction peak was detected for all compounds, indicating the monoelectronic reduction of the corresponding deprotonated 4-R-2-nitrophenols. The spin-coupling hyperfine structures revealed differences in the chemical nature of the electrogenerated radical; meanwhile, the -CF(3) and -CN substituents induced the formation of a dianion radical structure, and the -H, -CH(3), and -OCH(3) substituents provoked the formation of an anion radical structure due to protonation by acetonitrile molecules of the initially electrogenerated dianion radical. This behavior was confirmed by analyzing the ESR spectra in deuterated acetonitrile and by performing quantum chemical calculations of the spin densities at each site of the electrogenerated anionic radicals.     

Photolabile Protecting Groups for Nucleosides: Mechanistic Studies of the 2‐(2‐Nitrophenyl)ethyl Group

The photochemistry of several 2‐(2‐nitrophenyl)ethyl‐caged compounds including caged thymidine nucleosides was studied by nanosecond laser flash photolysis and stationary illumination experiments with quantitative HPLC analysis for quantum yields and product distribution. Effects of solvent basicity and acidity were investigated by varying the H₂O content and HCl concentration, respectively, in MeCN/H₂O mixtures. For all compounds 1 – 7 investigated, intramolecular H abstraction by the nitro group from the exocyclic α‐position with respect to the aryl moiety was found to be the primary process. The protolytic dissociation equilibrium of the resulting aci‐nitro compound was kinetically characterized in the 0.1 – 10 μs time region. In general, two reaction channels compete for the aci‐nitro compound and its anion: β‐elimination of the caged compound occurs from the anion, while from the undissociated aci‐nitro compound, a nitrosobenzene derivative is formed with no release of the caged compound. The yield ratio of these two reaction channels can be controlled through shifts in the protolytic dissociation equilibrium of the aci‐nitro compound. In solutions with either low basicity (H₂O‐free MeCN) or high acidity (higher concentration of HCl in H₂O/MeCN), two as yet unidentified products are formed, each one specifically for one of the mentioned conditions.     

Routes to N‐vinyl‐nitroimidazoles and N‐vinyl‐deazapurines

The preparations of 4‐ and 5‐nitro‐1‐vinylimidazole ( 2 and 7 ) are described. Selective reduction of the nitro group using Fe/dil.HCl is achieved for the 4‐nitro derivative but this is not effective when ethoxymethylenemalononitrile is used to trap the amine. For 5‐nitroimidazole studies the N‐vinyl substituent is kept masked as a 2‐chloroethyl group, which remains unchanged during catalytic reduction of the nitro function (Pd/C), and is revealed by HCl elimination at a later stage. In this way, the 1‐deazapurine 13 and the tricyclic derivative 14 have been prepared.     

6‐Methoxy‐2‐oxo‐1,2‐dihydroquinoline‐3,4‐dicarbonitriles,A Red Compound Class with Solvent and pH Independent Green Fluorescence Maxima

The sodium p‐toluenesulfinate mediated reaction of potassium cyanide with 4‐chlorocarbostyrils 8 , 16 , 18 , and 23 gave in all cases the highly fluorescent and stable 6‐methoxy‐2‐oxoquinoline‐3,4‐dicarbonitrile 9 (λ_exc 460 nm and λ_em 545 nm). This is remarkable, because starting carbostyrils 8 , 16 , 18 , and 23 had a chloro substituent, a nitro substituent, an acetylamino substituent, or a piperidinyl substituent in position 3. Hence, we observed not only a substitution of the 4‐chloro and expected 3‐chloro substituents by the cyanide nucleophile but also an exchange of a nitro substituent, an acetylamino substituent, and a piperidinyl substituent in position 3. The multistep insertion of substituents leading to 8 , 16 , 18 , and 23 started from 4‐hydroxy‐6‐methoxyquinolone 4 , easily obtained from p‐anisidine and malonic acid. Substitutions in position 3 gave 4‐hydroxy‐3‐nitro and 3‐chloro intermediates, which were converted to 3,4‐dichlorocarbostyril 8 and 4‐chloro‐3‐nitrocarbostyril 16 . Reduction of the 3‐nitro intermediate led to the 3‐acetylamino analog and subsequent chlorination led to 3‐acetylamino‐4‐chlorocarbostyril 18 . 4‐Chloro‐3‐piperidinylcarbostyril 23 was obtained from intermediate 3,3‐dichloroquinolinedione by subsequent amination, reduction and chlorination. Further, 3‐acetylamino‐4‐chlorocarbostyril 18 gave with lithium p‐toluenesulfinate highly fluorescent 3‐amino‐6‐methoxy‐4‐p‐tolylsulfonylquinolone 19 .     

Solvation Dependences of Isotropic Hyperfine Interaction Constants and out-of-Plane Distortions of ortho-Substituted Nitrobenzene Radical Anions

For a number of ortho-substituted nitrobenzene radical anions (RAs) generated in DMF and its binary mixtures with water, it is shown that for radical anions with a substituent of minor effective volume in one ortho position to the nitro group, the dependences of the isotropic hyperfine interaction (ihfi) constants on the mole fraction of water are S-like and dictated by the medium composition and the concerted out-of-plane rotational and pyramidal distortions of the nitro group of the radical anion. The S-like shape of the solvation dependences of the ihfi constants is dictated by the dominant rotational distortions of the nitro group. For most radical anions with two ortho substituents or with one ortho substituent with a large effective volume, the S-like dependences are not observed, and the values of the nitrogen ihfi constants depend on the dominant pyramidal distortion of the nitro group. For the 2-tert-butylnitrobenzene radical anion in water, the nitrogen ihfi constant is a_N=25.62 G, which is typical of nitroaliphatic radical anions. This effect is explained based on the pyramidal structure of the nitro group in the case of its large rotation angles.     

Structural studies and antileishmanial activity of 2‐acetylpyridine and 2‐benzoylpyridine nitroimidazole‐derived hydrazones

Three imidazole hydrazone compounds, namely 2‐(4‐nitro‐1H‐imidazol‐1‐yl)‐N′‐[1‐(pyridin‐2‐yl)ethylidene]acetohydrazide, C₁₂H₁₂N₆O₃, ( 1 ), 2‐(2‐nitro‐1H‐imidazol‐1‐yl)‐N′‐[1‐(pyridin‐2‐yl)ethylidene]acetohydrazide, C₁₂H₁₂N₆O₃, ( 2 ), and 2‐(2‐nitro‐1H‐imidazol‐1‐yl)‐N′‐[(phenyl)(pyridin‐2‐yl)methylidene]acetohydrazide, C₁₇H₁₄N₆O₃, ( 3 ), were obtained and fully characterized, including their crystal structure determinations. While all the compounds proved not to be cytotoxic to J774.A1 macrophage cells, ( 1 ) and ( 3 ) exhibited activity against Leishmania chagasi, whereas ( 2 ) was revealed to be inactive. Since both ( 1 ) and ( 3 ) exhibited antileishmanial effects, while ( 2 ) was devoid of activity, the presence of the acetyl or benzoyl groups was possibly not a determining factor in the observed antiprotozoal activity. In contrast, since ( 1 ) and ( 3 ) are 4‐nitroimidazole derivatives and ( 2 ) is a 2‐nitroimidazole‐derived compound, the presence of the 4‐nitro group probably favours antileishmanial activity over the 2‐nitro group. The results suggested that further investigations on compounds ( 1 ) and ( 3 ) as bioreducible antileishmanial prodrug candidates are called for.     

ESR and electrochemical study of 5-nitroindazole derivatives with antiprotozoal activity

The electrochemistry of 3-alkoxy- and 3-hydroxy-1-[omega-(dialkylamino)alkyl]-5-nitroindazole derivatives were characterized using cyclic voltammetry in DMSO. The nitro reduction process was studied and this was affected by the acid moieties present in these compounds. A nitro anion self-protonation process was observed. This phenomenon was studied by cyclic voltammetry in presence of increasing amount of NaOH. The reactivity of the nitro anion radical of these derivatives with glutathione was also studied by cyclic voltammetry. The oxidizing effect of glutathione is supported by the parallel decrease of the anodic peak current and increase of the cathodic peak in the cyclic voltammograms, corresponding to the wave of the nitro anion radical from uncharged species with the addition of glutathione. Nitro anion radicals obtained by electrolytic reduction of these derivatives were measured and analyzed in DMSO using electron spin resonance spectroscopy.     

Cyclic Voltammetric Study of Some Anti‐Chagas‐Active 1,4‐Dioxidoquinoxalin‐2‐yl Ketone Derivatives

The electrochemical properties of 24 1,4‐dioxidoquinoxalin‐2‐yl ketone derivatives with varying degrees of anti‐Chagas activity were investigated in the aprotic solvent dimethylformamide (DMF) by cyclic voltammetry and first‐derivative cyclic voltammetry. For this group of compounds, the first reduction in DMF was either reversible or quasireversible and consistent with reduction of the N‐oxide functionality to form the radical anion. The second reduction process for these compounds was irreversible under the conditions used. The reduction potentials correlated well with molecular structure. Substitution in the 3‐, 6‐, and 7‐ positions of the quinoxaline ring by electron‐withdrawing substituents directly affected the ease of reduction and improved the biological activities of these compounds, whereas substitution by electron‐donating groups had the opposite effect. The electrochemical results, when combined with previous work on their mechanism of action against Chagas disease and their measured anti‐Chagas activities, indicated that the quinoxaline 1,4‐dioxide system serves as a promising starting point for chemical modifications aimed at improving the T. cruzi activity via a possible bioreduction mechanism.     

Nitro radical anion formation from nitrofuryl substituted 1,4-dihydropyridine derivatives in mixed and non-aqueous media

Three new nitrofuryl substituted 1,4-dihydropyridine derivatives were electrochemically tested in the scope of newly found compounds useful as chemotherapeutic alternative to the Chagas' disease. All the compounds were capable to produce nitro radical anions sufficiently stabilized in the time window of the cyclic voltammetric experiment. In order to quantify the stability of the nitro radical anion we have calculated the decay constant, k2. Furthermore, from the voltammetric results, some parameters of biological significance as E7(1) (indicative of in vivo nitro radical anion formation) and KO2 (thermodynamic indicator of oxygen redox cycling) have been calculated. From the comparison of E7(1), KO2 and k2 values between the studied nitrofuryl 1,4-DHP derivatives and well-known current drugs an auspicious activity for one of the studied compounds i.e. FDHP2, can be expected.     

Colorless to Purple–Red Switching Electrochromic Anthraquinone Imides with Broad Visible/Near‐IR Absorptions in the Radical Anion State: Simulation‐Aided Molecular Design

The large redshift of near‐infrared (NIR) absorptions of nitro‐substituted anthraquinone imide (Nitro‐AQI) radical anions, relative to other AQI derivatives, is rationalized based on quantum chemical calculations. Calculations reveal that the delocalization effects of electronegative substitution in the radical anion states is dramatically enhanced, thus leading to a significant decrease in the HOMO–LUMO band gap in the radical anion states. Based on this understanding, an AQI derivative with an even stronger electron‐withdrawing dicyanovinyl (di‐CN) substituent was designed and prepared. The resulting molecule, di‐CN‐AQI, displays no absorption in the Vis/NIR region in the neutral state, but absorbs intensively in the range of λ=700–1000 (λ_max≈860 nm) and λ=1100–1800 nm (λ_max≈1400 nm) upon one‐electron reduction; this is accompanied by a transition from a highly transmissive colorless solution to one that is purple–red. The relationship between calculated radical anionic HOMO–LUMO gaps and the electron‐withdrawing capacity of the substituents is also determined by employing Hammett parameter, which could serve as a theoretical tool for further molecular design.     

Aerobic and Electrochemical Oxidative Cross‐Dehydrogenative‐Coupling (CDC) Reaction in an Imidazolium‐Based Ionic Liquid

The ionic liquid 1‐butyl‐3‐methylimidazolium tetrafluoroborate [BMIm][BF₄] has demonstrated high efficiency when applied as a solvent in the oxidative nitro‐Mannich carbon? carbon bond formation. The copper‐catalyzed cross‐dehydrogenative coupling (CDC) between N‐phenyltetrahydroisoquinoline and nitromethane in [BMIm][BF₄] occurred with high yield under the described reaction conditions. Both the ionic liquid and copper catalyst were recycled nine times with almost no lost of activity. The electrochemical behavior of the tertiary amine substrate and β‐nitroamine product was investigated employing [BMIm][BF₄] as electrolyte solvent. The potentiostatic electrolysis in ionic liquid afforded the desired product with a high yield. This result and the cyclic voltammetric investigation provide a better understanding of the reaction mechanism, which involves radical and iminium cation intermediates.     

The Reactivity of the Nitrate Radical (•NO3) in Aqueous and Organic Solutions

Rate constants for the nitrate (^•NO₃) radical reaction with alcohols, alkanes, alkenes, and several aromatic compounds were measured in aqueous and tert‐butanol solution for comparison to aqueous and acetonitrile values from the literature. The measured trends provide insight into the reactions of the ^•NO₃ radical in various media. The reaction with alcohols primarily consists of hydrogen‐atom abstraction from the alpha‐hydroxy position and is faster in solvents of lower polarity where the diffusivity of the radical is greater. Alkenes react faster than alkanes, and their rate constants are also faster in nonpolar solution. The situation is reversed for the nitrate radical reaction with the aromatic compounds, where the rate constants in tert‐butanol are slower. This is attributed to the need to solvate the NO₃⁻ anion and corresponding tropylium cation produced by the ^•NO₃ radical electron transfer reaction. A linear correlation was found between measured rate constants in water and acetonitrile, which can be used to estimate aqueous nitrate radical rate constants for compounds having low water solubility.     

SPECTROSCOPIC STUDIES OF CUTANEOUS PHOTOSENSITIZING AGENTS—VI. IDENTIFICATION OF THE FREE RADICALS GENERATED DURING THE PHOTOLYSIS OF MUSK AMBRETTE, MUSK XYLENE AND MUSK KETONE

Musk ambrette (4-tert-butyl-3-methoxy-2,5-dinitrotoluene), a common component of perfumes, soaps, and some food flavorings, can cause cutaneous photosensitization reactions including photoallergy. These may be mediated through free radicals formed during photolysis. When musk ambrette was photolyzed under nitrogen in basic methanol, two distinct nitro anion radicals were identified by electron spin resonance. One radical was centered on a nitro group in the plane of the aromatic ring, while the other was centered on a nitro group twisted out of the plane of the ring due to steric hindrance by bulky substituents on either side of the group: the two radicals appeared to interconvert and maintain an equilibrium concentration ratio. Two closely related compounds which are also used in perfumes, but have not been reported to cause photosensitizing reactions, also produced free radicals during photolysis. Musk xylene (2,4,6-trinitro-1,3-dimethyl-5-tert-butylbenzene) generated two nitro anion radicals, both of which were centered on twisted nitro groups, while musk ketone (3,5-dinitro-2,6-dimethyl-4-tert-butylacetophenone) produced only one nitro anion radical, which is also twisted. Athough these nitro anion radicals are probably the first step in the photolysis of these nitroarornatic molecules, it seems likely that in vivo they will undergo further reduction to produce more reactive species including the corresponding nitroso and hydroxylamine derivatives. In addition, autoxidation of the nitro anion radical intermediate forms superoxide.     

Isolation of a Neutral Boron‐Containing Radical Stabilized by a Cyclic (Alkyl)(Amino)Carbene

Utilizing a cyclic (alkyl)(amino)carbene (CAAC) as a ligand, neutral CAAC‐stabilized radicals containing a boryl functionality could be prepared by reduction of the corresponding haloborane adducts. The radical species with a duryl substituent was fully characterized by single‐crystal X‐ray structural analysis, EPR spectroscopy, and DFT calculations. Compared to known neutral boryl radicals, the isolated radical species showed larger spin density on the boron atom. Furthermore, the compound that was isolated is extraordinarily stable to high temperatures under inert conditions, both in solution and in the solid state. Electrochemical investigations of the radical suggest the possibility to generate a stable formal boryl anion species.     

Functionalization of Quinazolin‐4‐Ones Part 2#: Reactivity of 2‐Amino‐3, 4, 5, or 6‐Nitrobenzoic Acids with Triphenylphosphine Thiocyanate,Alkyl Isothiocyanates,and Further Derivatization Reactions

2‐amino‐3, 4, 5, or 6‐nitrobenzoic acids were reacted with PPh₃(SCN)₂ and alkyl isothiocyanates to give 5, 6, 7, or 8‐nitro‐2‐thioxo‐3‐substituted quinazolin‐4‐ones, respectively. The position of the nitro group was found to have significant influence on the outcome of the reactions. Similarly, the nature of the substituent at position 8 (NO₂, NH₂, NH(C═O)CH₃) in 8‐substituted‐2‐methylthio quinazolin‐4‐ones was also found to significantly influence their reactivity towards morpholine. A selection of the products were also tested for in vitro antibacterial activity but little activity was observed.     

4‐Amino derivatives of 7‐nitro‐2,1,3‐benzoxadiazole: the effect of the amino moiety on the structure of fluorophores

The crystal structures of three 4‐amino derivatives of 7‐nitro‐2,1,3‐benzoxa­diazole with increasing substituent ring size, viz. 7‐nitro‐4‐(pyrrolidin‐1‐yl)‐2,1,3‐benzoxa­diazole, C₁₀H₁₀N₄O₃, 7‐nitro‐4‐(piperidin‐1‐yl)‐2,1,3‐benzoxa­diazole, C₁₁H₁₂N₄O₃, and 4‐(azepan‐1‐yl)‐7‐nitro‐2,1,3‐benzoxa­diazole, C₁₂H₁₄N₄O₃, have been determined in order to understand their photophysical behaviour. All three were found to crystallize in centrosymmetric space groups. There is considerable electron delocalization compared with the parent compound, although the five‐membered oxa­diazole ring apparently does not participate in this. The length of the C—N bond between the amino N atom and the 7‐nitro­benzoxa­diazole system is found to be shorter than in similar compounds, as is the C—N_nitro bond. In each structure, the nitro group lies in the plane of the benzoxa­diazole unit.