Colorimetric Determination of Some N-Substituted Phenothiazine Derivatives Using 2-Iodoxybenzoate

Abstract

A new, sensitive colorimetric method has been described for the quantitative determination of six N-substituted phenothiazines. the method depends on the formation of stable phenothiazine free radical by the use of 2-iodoxybenzoate as chromogenic reagent. the drug in 50% sulphuric acid is treated with reagent (5×10^?4 M). the produced red or purple color possesses characteristic absorption maximum for each of the drugs tested. Beer's law is obeyed over the concentration range 2-30 μg.ml^?1 with apparent molar absorptivities ranging from 9.4-12.4×10^?3 for the studied phenothiazine derivatives. the average % recovery is 99.5±0.96 - 101.6±1.01. the method was applied successfully to the microdetermination of promazine. HCl, chlorpromazine, HCl, promethazine. HCl, perphenazine, levomepromazine HCl and mesoridazine besylate either in pure form or incorporated in their representative pharmaceutical preparations. the stoichiometry of the reaction was assumed and a reaction mechanism was suggested. the precision of the assay was comparable with the official ones.     

A theoretical study on the structure and properties of phenothiazine derivatives and their radical cations

Semiempirical CNDO, AM1, PM3 and ab initio HF/STO-3G, HF/3-21G(d), and HF/6-31(d) methods were employed in the geometry optimization of the phenothiazine and the corresponding radical cation. The results obtained from the PM3 performances were as good as those from the ab initio calculations in the structure optimization of both phenothiazine and phenothiazine radical cation. The PM3 method was used to optimize the structures of a series of N-substituted phenothiazine derivatives and their radical cations. The PM3-optimized results were then analyzed with the ab initio calculation at the 6-311G(d,p) level, which yielded the total energy, frontier molecular orbitals, dipole moments, and charge and spin density distributions of the phenothiazine derivatives and their radical cations.     

A mechanistic study on the disproportionation and oxidative degradation of phenothiazine derivatives by manganese(III) complexes in phosphate acidic media

The oxidative degradation of phenothiazine derivatives (PTZ) by manganese(III) was studied in the presence of a large excess of manganese(III)-pyrophosphate (P₂O₇ ²⁻), phosphate (PO₄ ³⁻), and H⁺ ions using UV–vis. spectroscopy. The first irreversible step is a fast reaction between phenothiazine and manganese pyrophosphate leading to the complete conversion to a stable phenothiazine radical. In the second step, the cation radical is oxidized by manganese to a dication, which subsequently hydrolyzes to phenothiazine 5-oxide. The reaction rate is controlled by the coordination and stability of manganese(III) ion influenced by the reduction potential of these ions and their strong ability to oxidize many reducing agents. The cation radical might also be transformed to the final product in another competing reaction. The final product, phenothiazine 5-oxide, is also formed via a disproportionation reaction. The kinetics of the second step of the oxidative degradation could be studied in acidic phosphate media due to the large difference in the rates of the first and further processes. Linear dependences of the pseudo-first-order rate constants (k _obs) on [Mn^III] with a significant non-zero intercept were established for the degradation of phenothiazine radicals. The rate is dependent on [H⁺] and independent of [PTZ] within the excess concentration range of the manganese(III) complexes used in the isolation method. The kinetics of the disproportionation of the phenothiazine radical have been studied independently from the further oxidative degradation process in acidic sulphate media. The rate is inversely dependent on [PTZ^+.], dependent on [H⁺], and increases slightly with decreasing H⁺ concentration. Mechanistic consequences of all these results are discussed.     

Spectrophotometric Determination of Certain Phenothiazines and Their Dosage Forms Using Bromophenol Blue

Abstract

A simple and rapid spectrophotometric method for the determination of seven phenothiazine derivatives has been performed either in pure form or in their dosage forms. The method is based upon the interaction of the drug in dry chloroform with bromophenol blue in the same solvent to produce a stable yellow ion-pair complex which absorbs at 410 nm, with high apparent molar absorptivity. Beer's Law is obeyed in the concentration range 1?10 ugml^?1 for the studied compounds. The mean recoveries range from 99.80±0.74 to 100.50±1.33. The proposed method is applied for the analysis of the studied compounds in their commercial preparations. Results are in good agreement with those obtained by official methods.     

Cation-radical oxidation step in the nitration of phenothiazine with nitric acid

A phenothiazine cation radical, which was isolated preparatively in the form of the perchlorate in the reaction of phenothiazine with the minimum amount of nitric acid in aqueous perchloric acid, is formed initially in the nitration of phenothiazine with nitric acid to give 3-nitrophenothiazine S-oxide. The perchlorate is also converted to the nitro compound by nitration. During nitration the phenothiazine cation radical is oxidized to the phenazthioniuin cation, the perchlorate of which was also isolated preparatively in the reaction of phenothiazine with HNO₃ in amounts that were twice the amount required for the formation of the phenothiazine cation radical. This is followed by the formation of the nitro derivative, which involves the reaction of the phenazthionium cation with the nitrite anion of nitrous acid. The resulting 3-nitrophenothiazine is then converted to the final product.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1214–1216, September, 1981.     

Spectrophotometric Analysis of some Phenothiazine Neuroleptics using Chloramine-T

ABSTRACT

A sensitive and selective spectrophotometric method has been developed for the determination of six phenothiazine neuroleptics. The method is based on the interaction of the drugs with chloramine-T in sulphuric acid medium to yield a red, reddish-violet, orange or greenish-blue intermediate with maximum absorption at 500-636 nm. Beer's law is obeyed over the range 5-125 μg ml^?1 of the drugs. The apparent molar absorptivities were found to be in the range 1.04x10³ to 5.46x10³ 1.mol^?1cm^?1. The investigated drugs were assayed in tablets and injections. The mean percentage recoveries were 97.65-101.75 and the relative standard deviations were found to be less than 2%.     

Dye-sensitized photooxidation of phenothiazine : An ESR study

The dye-sensitized or direct-light induced photooxidation of phenothiazine yielded phenothiazine nitroxide (1) and phenothiazanyl (2) radical depending on the reaction conditions. A singlet oxygen mechanism is suggested.     

Synthesis and Crystallographic Study of1,6‐bis‐(N‐phenothiazinyl)‐2,4‐hexadiyne

1,6‐bis‐(N‐phenothiazinyl)‐2,4‐hexadiyne (I) was synthesized in high yield by oxidative coupling of N‐propargyl phenothiazine. Grown from methylene chloride‐hexane solution, I is a monoclinic crystal, space group C2/c a=14.9500(18) Å; b=13.5512(15) Å; c=12.0116(10) Å; β=102.628(9)° Å; V=2374.6(4) ų. The intermolecular distances and arrangement of I in the unit cell preclude the usual diacetylene reactivity. Nevertheless, heating of I at 145°C results in decomposition of I to phenothiazine and a dark brown solid. In addition, cation‐radicals of I were prepared by oxidation with nitrosonium tetrafluoroborate and iodine to give stable ion‐radical salts.     

Inhibition of acrylic acid polymerization by phenothiazine and p-methoxyphenol

The major features of polymerization induction periods for acrylic acid inhibited with phenothiazine and p-methoxyphenol have been characterized at 100°C, including duration of the induction periods, and rates of inhibitor disappearance, molecular oxygen absorption, and peroxide formation. Surprisingly, thermally produced radicals react more rapidly with phenothiazine than with oxygen since there is no detectable oxygen absorption or peroxide for mation during phenothiazine-induced induction periods. Thus, phenothiazine has been used to estimate the thermal rate of radical formation. Phenothiazine's effectiveness as an inhibitor is not directly affected by oxygen, although it does undergo oxygen-promoted, noninhibition-related side reactions. p-Methoxyphenol, on the other hand, depends entirely on the presence of oxygen to function as an inhibitor. Compared with equivalent concentrations of p-methoxyphenol, induction periods obtained with phenothiazine are very long, and the rate of inhibitor disappearance is slower by at least an order of magnitude. The characteristics of p-methoxyphenol inhibition reflect a greater radical flux deriving from the significant rates of oligomeric peroxide formation and decomposition which we measured during p-methoxyphenol-induced induction periods at 100°C. MEHQ is an effective inhibitor at ambient temperatures in part because of the greater stability of the peroxides at these lower temperatures.     

Electrochemical C–H/N–H cross-coupling of 2-phenylindolizines with phenothiazines to synthesize novel N-aryl phenothiazine derivatives

A facile and elegant method for synthesis of novel N–aryl phenothiazine derivatives from 2-phenylindolizines and phenothiazines through direct electrochemical oxidation has been developed. This approach was performed smoothly at room temperature without external oxidant and catalyst. Cyclic voltammetry and in situ FTIR techniques were applied to analyze the cross-coupling process of phenothiazines and 2-phenylindolizines, which helped to select the appropriate reaction potential. Under the optimized conditions, a broad range of substrates were well tolerated, affording the desired products in moderate to excellent isolated yields (up to 91%) with high regioselectivity. Meanwhile, a plausible mechanism involving a radical pathway has been proposed.     

The influence of structure and conformation on electronic interactions of 4′-nitro-10-phenylphenothiazine

The crystal structure of 4′-nitro-10-phenylphenothiazine, 1 , has been determined by the single crystal x-ray diffraction studies and consists of two independent molecules in the asymmetric cell unit with a pseudo-center of symmetry. The crystal belongs to the monoclinic System with the space group P2₁/c. The central ring of the phenothiazine ring system is in a boat conformation and the 4′-nitro substituent is in a boat-axial conformation with respect to the central ring of phenothiazine. Compound 1 is the first reported 10-aryl phenothiazine in which the 10-phenyl ring is perpendicular to the plane bisecting the dihedral angle of the phenothiazine nucleus. This geometry allows for resonance interaction between the lone pair of electrons on N₁₀ and the 4′-nitro-10-phenyl ring which influences both the spectral properties and structure of the phenothiazine tricyclic ring. The correlation between the x-ray structure and ¹³C nmr spectral properties of 1 is discussed. The uv/vis and esr studies of the radical cation of 1 indicate that the 10-aryl ring is twisted with respect to the phenothiazine ring.     

Ion radicals. XIII. Spectroscopic and cryoscopic characterization of ions and ion radicals from phenothiazine and N-methylphenothiazine in sulfuric acid solutions

The formation and interconversion of the N-methylphenothiazine cation radical and the N-methylphenothiazine dication from both N-methylphenothiazine and N-methylphenothiazine S-oxide in sulfuric acid solutions have been demonstrated with e.s.r. and absorption spectroscopy. Cryoscopic measurements have shown that in slightly aqueous sulfuric acid N-methylphenothiazine S-oxide is converted to the N-methylphenothiazine dication and, analogously, phenothiazine 5-oxide is converted to the protonated phenazathionium ion (the phenothiazine dication).     

Photochemistry of cation radicals in solution : photoinduced oxidation by the phenothiazine cation radical

Irradiation of phenothiazine cation radical, Ph^.+, with 1,1-diphenylethylene, DPE, causes its reduction to Ph and oxidation of DPE. Cyclodimeric products are formed from DPE^.+.     

吩噻嗪和吩噁嗪氧化中间体的共振喇曼光谱研究

本文对吩噻嗪和吩噁嗪的单电子氧化产生的两种氧化态的亚稳态正离子进行了共振喇曼光谱研究。随着吩噻嗪的p电子逐步失去, 结构变形振动δ_(CNC)和δ_(CSC)的喇曼频移显著地增大, 环C=C伸缩振动区域的喇曼峰数目明显变多。由此推断, 随着吩噻嗪正离子氧化态的增高, 正离子转变成平面共轭结构。     

An ESR study of photochemical reactions of Co2(CO)6(PBu3)2 with quinones and phenothiazine

The photochemical reactions of Co₂(CO)₆(PBu₃)₂ with various quinones and phenothiazine were studied by ESR. The results indicate that the photolysis of Co₂(CO)₆(PBu₃)₂ in the presence of o-quinones led to the observation of an ESR spectrum, showing a broad 8 or 12 groups of hyperfine lines due to interaction with cobalt (Co, 1 = 7/2). The results show that with o-quinones the cobalt radical adducts are formed via metal chelation to the carbonyl oxygens. However, when Co₂(CO)₆(PBu₃)₂ was irradiated in the presence of p-quinones, only the para-semiquinone radicals were observed. The photolysis of Co₂(CO)₆(PBu₃)₂ with phenothiazine in toluene yields phenothiazine radical. The sixteen and eighteen electrons rule have been used to account for these observations.     

THE SYNTHESIS AND PROPERTIES OF DI/1,4 - PHENOTHIAZINE/

Abstract

The structure determination of the poly/1,4- phenothiazine/ is still difficult because of their very slight solubility in the organic solvents and low degree of crystallinity.     

Post-column oxidative derivatization for the liquid chromatographic determination of phenothiazines

A first post-column chemical derivatization method for the liquid chromatographic determination of phenothiazines is presented. Peroxyacetic acid is introduced as a derivatizing agent for phenothiazines, yielding the colored radical cations or fluorescent sulfoxides, depending on reaction conditions. Both reaction products were successfully employed for the detection of the phenothiazines after their liquid chromatographic separation. The fluorescence spectroscopic detection of the sulfoxides proved to be the more robust and sensitive method. Limits of detection ranged from 4 nM for triflupromazine and trimeprazine to 300 nM for phenothiazine for the fluorescence spectroscopic detection of the sulfoxide and from 0.3 μM for phenothiazine and triflupromazine to 2 μM for trifluperazine for the UV–Vis spectroscopic detection of the radical cation. The calibration functions for the fluorimetric sulfoxide determination ranged from two to more than three decades, starting at the limit of quantification.     

Fluorimetric Determination of Certain Phenothiazine Derivatives Using Eosin

Abstract

Eosin reacts with phenothiazine derivatives in dichloroethane to give intense fluorescent compounds having their excitation maximum at 318 nm and emission maxima at 450, 460 and 465 nm for prochlorperazine dimaleate, thiethylperazine dihydrochloride and trifluoperazine dihydrochloride, respectively. Under the optimum conditions, samples of 1-10 μg ml^?1 could be determined rapidly with coefficient of variation less than 1.8 %. This fluorescence reaction was also applied successfully to the determination of phenothiazine drugs in some pharmaceutical preparations.     

Spectrophotometric determination of cerium(IV) using a phenothiazine derivative.

A simple, rapid and sensitive spectrophotometric method has been proposed for the determination of cerium(IV) using a phenothiazine derivative, propionyl promazine phosphate (PPP). This method is based on the formation of a red-colored radical cation upon a reaction of PPP with cerium(IV) in a phosphoric acid medium having maximum absorbance at 513 nm. Beer's law is valid over the concentration range of 1-11 microg/ml with a Sandell's sensitivity value of 16.14 ng/cm2. The proposed method has been successfully applied to the analysis of magnesium-base cerium alloys and synthetic mixtures corresponding to various cerium alloys. Other phenothiazine derivatives viz. butaperazine dimaleate and propericiazine were also used for the determination of cerium(IV).     

Remarkable structure deformation in phenothiazine trimer radical cation

[structure: see text] A trimeric phenothiazine and its radical cation were prepared, and their structures were elucidated. In contrast to a largely twisted structure in the neutral species, the radical cation had a unique structure deformation that allowed charge-transfer-type conjugation from the outer phenothiazine rings to the central phenothiazine radical cation.