INTRODUCTION:
Formazans are compounds which contain the characteristic chain of atoms (-N=N-C=N-NH-) having wide range of applications in organic, inorganic and pharmaceutical chemistry and can be synthesized using different methods. Oxazacoronands called as crown formazan have recently been studied as potential chromogenic chelates for transition and post transition metals with excellent selectivity towards copper (II) and mercury (II) and were recommended as selective extractants for these metal cations1. Reduction of water-soluble tetrazolium salts by metabolically active eukaryotic and prokaryotic cells leads to precipitation of colored formazans. The reaction has been applied in a variety of biological assays including subcellular localization of oxidoreductases. It has also been used to test cell viability and to estimate cell culture growth2 .One class of formazan derivatives of so called diphenylthiocarbazone (dithizone) has been used as reagents for various heavy metals. Di-bete-napthylthiocarbazone (3-mercapto-7,5-di-beta-napthylformazan) has been used to detect traces of mercury and zinc in biological materials. Several formazans with substituted sulphonic acid group salts studied as dyestuffs. Formazans have been found to possess wide spectrum of biological activities such as antiviral3, antimicrobial4, antiinflamatory5, antifungal6, anticacer7, anti HIV8,9. Several formazans show promising antifertility10 and anticonvulsant activity11. This article is an attempt to discuss chemistry, methods of synthesis, biological and medicinal properties of formazan along with focus on some recent works in the field of formazans12.
Definition:
Formazans are compounds which contain the characteristic chain of atoms (-N=N-C=N-NH-). Their structure was first elucidated by Bamberger and Von Pechmann13, 14 who agreed to call them “Formazyl compound”
Nomenclature:
Difficulties in the nomenclature of these compounds have resulted from divergence in British, American and German practice. The two general structure for formazan are chemically indistinguishable (structure a, b).
Modern German usage is exemplified by Beilstein in which the hypothetical fundamental compound HN=N-CH=N-NH2 is termed as formazan. Although numbering may be applied arbitorily in either direction, this cannot lead to confusion. It may be noted that the oxa-aza system of nomenclature is applicable to formazan, the application of this system to aliphatic compound has not been approved by IUPAC committee on nomenclature. It would merely involve the replacement of long established term “formazyl” by “3-carba-pentaaza-1,3-diene”.the term “formazyl” can be applied to disubstituted radical of the type. Thus diformazan can be named without difficulty.
Tautomerism:
When the compound obtained by condensation of diazonium salt RN2+X- with phenylhydrazine R1NHN=CHR3 is compared with the compound derived from diazonium salt R1N2+X- and phenyl hydrazone R5NHN=CHR3 they are found to be identical in appearance, melting point, solubility and other properties. When these two compounds are made to undergo certain reactions each yield same single product. Von Pechmann15,16,17 therefore concluded that tautomerism is exhibited by formazans.
Stereochemistry:
The classical spatial arrangement of formazan molecule allows the existence of 4 possible structures due to geometrical isomerism about the two double bonds.
Synthesis of Formazans:
a) From diazonium salt (method A1):
The coupling of diazonium salt with aldehyde or glyoxylic acid arylhydrazone is carried out at alkaline pH, usually in the presence of caustic alkalies, pyridine, sodium acetate.
It had been shown by Von Pechmann that secondary phenyl hydrazine of the type
do not react with diazonium salt to give formazans, it appear therefore that imide hydrogen atom play essential part in the reaction.
b) By the action of diazonium salts on compounds containing active methylene or methane groups (method A2):
It has long been known that diazonium salts may be coupled with variety of compounds containing active methylene groups like aliphatic azo compounds,sulphonic acid derivatives of ethyldiazo acetate, benzene sulphonyl acetic acid, isoquinopthalone, beta-camphorylidenepropionic acid, unsaturated phenols, trichloro-beta-hydroxy-alpha-nitroparafins; the activation of which is usually due to carboxyl or nitro group on α-carbon atom.
c) From aryl hydrazines(method B):
Phenylhydrazine reacts with variety of compounds to form formazans like ethyl formate, ethyl orthoformate, ethyl nitrate, iminoethers, halogen hydrazides, dichloroacetanilide and diaminotetrazines.
d) By reduction of tetrazolium salts (method C):
Formazans can be prepared by the reduction of tetrazolium salts. Since there is no synthesis of tetrazolim salt other than through formazan, this method is of no value.
Agents for reduction of tetrazolium salts must be chosen with care because the formazan can be further reduced without difficulty, especially if it is somewhat soluble in reduction medium. Although a wide variety of substances will cause reduction at pH above 7, ammonium polysulphide, sodium amalgm, ascorbic acid in dil. NaOH18 have been used to prepare formazans.
e) By the modification of substituents already present in formazans (method D):
The hydrolysis of ester and nitrile substituents to the carboxylic acids19 and of N-acyl group to free amino group have been reported in particular cases. Nitro groups have been reduced to amino carboxylic acids20 have esterified through the silver salts19 and decarboxylation of C-carboxyl compounds has been described19,21. In C-nitroformazans the nitro group can be replaced by –NH2,-SH,-OH20. In C-chloroformazans chlorine has been replaced by –I, NH2,-OH,-SH22.
f) By the oxidation of diphenylcarbazides and diphenylthiocarbazides (method E):
Diphenylcarbazides and diphenylthiocarbazides and their ring substituted derivatives can be oxidized at alkaline pH to –OH and mercapto formazan23-32.
Perhydrol is effective oxidizing agent20.
g) Miscellaneous formazan synthesis (method G):
By the action of heat on tetrazan33 give rise to N-acylated formazan.
The condensation of phenylazoethane with isoamylnitrile in presence of HCl leads to 3-methyl-1,5-diphenylformazan34.
Aldehyde semicarbazone in which amine group is substituted with 2-arylradicals coupled with diazonium salt to give formazan like compounds35.
Physical Properties:
a) Formazans are weak acids and weak bases in nature
b) Both types of salts which can result are hydrolyzed by water in cold.
c) Many formzans give deep red solution with conc.aq. alkali and precipitate free
formazan upon dilution with water.
Reaction of formazans:
a) Acylation:
Formazan cannot be acylated very readily. Acetylation can be accomplished with acetic anhydride in presence of ZnCl236-38 and can be achieved in special cases by the use of acetic anhydride alone. C-hydroxyalkylformazans have been found to react with warm acetic anhydride to give O-acetyl derivatives only.
b)Oxidation:
Tetrazolium salts can be prepared by the oxidation of formazan with particular oxidizing agent; the use of more powerful ones (conc.HNO3) causes complete destruction of molecule. The guanazyls undergo special oxidative reaction with conc HNO3 to form disubstituted tetrazoles39.
c) Reduction:
Compounds of several types are produced by the reduction of formazans using various reducing agents like ammonium sulphide, sodium dithionite, hydrogen sulphide, zinc and dilute acids, zinc dust, stannous chloride and sodium amalgm. The relatively mild action of ammonium sulphide leads to a discharge of cola and reduction of azo group to hydrazo group40.
d) Action of acids:
Many formazans are readily decomposed by acids. They dissolve in cold H2SO4 to give characteristic intensely colored solution. Mineral acids act at slightly higher temp causing formazan to rearrange to benztriazines21,38.
e) Action of alkalies:
Alkalies do not easily cause breakup of formazan molecule and can therefore be used for hydrolysis of substituent group leaving basic structure unaffected.3-nitro-1,5 diphenylformazan is hydrolyzed in alkali condition to corresponding 3-hydroxyformazan which is oxidized rapidly to 5-hydroxy 2,3 diphenyl tetrazolium betain20,41.
Recent Work:
1-aryl-3-(3, 4-dimethoxy-6-nitro phenyl)-5-phenyl formazans had shown significant antiviral activity against tobacco mosaic virus and ranikhet disease virus. The substitution of ester in the aryl moiety makes formazan possess marked antiviral property. The halogen substituents at position 4 of phenyl ring at position 1 of formazans, 4-bromo substituent shows greater protection. In case of substitution of different
ester groups, all the compounds show high activity. Marked protection against virus infection was also observed with 2-ethoxy analogues as compared to 4-ethoxy analog42.
2-phenyl-3-substituted benzylaminoindoles and formazans have been combined so as to have molecules of enhanced antibacterial activity against S.aureus, S.Pyrogen, E.Coli, K.arogens and for antifungal activity against A.Niger43.
Formazan derivatives were synthesized by condensation of p–nitrobenzoylhydrazide with substituted aromatic aldehyde under microwave irradiation (2-3 min) and by conventional method (5-6 hr) to provide Schiff bases and these bases condensed with diazonium salt of 6-methoxy-2-aminobenzothiazole giving formazans44.
These compounds were screened for their antibacterial activity against Bacillus subtilis, Staphylococcus aureus and E.coli and antifungal activity against Candida albicans and Aspergillns niger by filter paper disc technique.
3-[20-(10-substituted phenyl-30-substituted indolyl formazan-40-yl) thiazol-40-yl]-2-(4-
chlorophenyl) indoles and 3-[20-(10-substituted phenyl-30-substituted indolyl formazan-40-yl) oxazol-40-yl]-2-(4-chlorophenyl) indoles had shown good anti inflammatory as well as analgesic activity. Oxazolyl formazans have shown a slightly better anti-inflammatory and analgesic activity than thiazolyl formazans45.
N-(substituted phenylimino)-N’-(4-(4-ethylpiperazin-1-yl) phenyl)benzamidine(formazans) were synthesized by coupling schiff base with appropriate aryl diazonium chloride in pyridine. The compounds were screened for antibacterial and antifungal activity46.
2-(4’-methoxyphenyl)-1-[3’-cyano-5’-(5’’’’’-chloro-3’’’’’-methyl-1’’’-phenylpyrazol-4’’-yl vinyl)-7’’,7’’-dimethyl-6’’,7’’-dihydrobenzo(b)thiophen-2’yl)-4-(2’’’’,4’’’’ dichlorophenyl]formazan were synthesized from substituted benzothiophene and assayed in vitro for antibacterial activity against B.megaterium, B.subtilis, E.coli and antifungal activity47.
The recent study have been shown that 1,5-diaryl-3-(3-indolyl) formazans exhibit antifertility activity. The maximum activity of 67% was observed with compound 6,followed by compound 3 and 7(60% activity)compound 5 was found to possess 50% activity. The result for 7 and 8 indicate that methoxy group at position 4(compound 7) results in better activity (60%) than at position 2(compound 8) The R=H compound showed little activity, but R=NO2 gave encouraging results (compound 3 and 5)48.
The formazans prepared by the condensation of the phenylhydrazone of 3,4-dimethoxy-6-nitro-veratraldehyde with the appropriate phenyl diazonium salts exhibit antiviral activity against the Ranikhet disease virus and vaccinia virus. The one of the compound prepared by this method namely 1-o-carboxyphenyl-3-[3’,4’-dimethoxy-6’-nitrophenyl]-5-phenylformazan evinced 100% protection against the Ranikhet disease virus.49
Other Applications of Formazans :
1) Dyestuffs50: Fichter and Schiess prepared several formazans with substituted sulphonic acid groups,as their sodium. or potassium salts and studied their potentialities as dyestuffs.
2) Metallic reagents51-one class of formazan derivatives of the so called diphenylthiocarbazone (dithizone) has been used as reagents for various heavy metals. .Di-bete-napthylthiocarbazone (3-mercapto-7,5 di-beta-napthylformazan)has been used to detect traces of mercury and zinc in biological materials.
3) Formazan of benzaldehyde and formazan of p-dimethyl aminobenzaldehyde showed good performance as corrosion inhibitor in HCl solution medium due to the presence of heteroatom and unsaturated bond that cause effective adsorption process leading to the formation of an insoluble protective surface film which suppresses the metal dissolution reaction52.
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Received on 20.11.2010 Modified on 10.12.2010
Accepted on 24.12.2010 © RJPT All right reserved
Research J. Pharm. and Tech. 4(4): April 2011; Page 510-514