One-Pot Four Component Reaction for the Synthesis of Formazans in an Environmentally Benign Procedure Mediated by KHSO 4 Pranab

A microwave mediated solvent free one pot synthesis of formazans is developed using the solid acid, KHSO4. The products were obtained in a short reaction time in high yield. This study was undertaken to find an alternative and green method for the synthesis of formazans in the absence of corrosive mineral acids, buffered solutions and volatile organic compounds (VOCs).


Introduction
Formazans were first reported by Von Pechmann [1] and by Bamberger [2].They are intense coloured dyes characterized by their prominent π-π* transitions and these transitions are sensitive to the nature of the substituent present in the phenyl rings, nature of the organic solvents in solution and the acidity and basicity of the medium [3]- [5].Extensive studies have been carried out relating to their structure evaluation, photochromatic transitions, tautomer formation, redox potential and organometallic chemistry [6].Formazans also find extensive use in analytical chemistry [7] [8] and their photochemical and thermochemical properties have been investigated [9].Formazans are reported to exhibit a wide spectrum of biological activities and notable among them are antiviral [10] [11], antimicrobial [12] [13], anti inflammatory, analgesic [14] antifungal [15] properties.Synthetic methods for their preparation have been reviewed by Nineham earlier [16].Their synthesis is based on two general procedures.The first is the reaction of aryldiazonium salts with phenylhydrazones of aldehydes in basic medium and the second type is based on coupling of aryldiazonium ions with active methylene groups followed by Japp Klingermann rearrangement [17].However, these methods gave multiple products.Further to obtain the formazans in satisfactory yield strict control of pH of the medium is necessary.Newer methods of synthesis are reported and notable among them are the use of solid-liquid phase transfer catalysts [18]- [21], liquid-liquid systems and crown ethers [22], methods reported by Tezcan et al. [23]- [26] and a green method using solid Lewis acid namely nano BF 3 -SiO 2 [27].The commonly used method of synthesis involves three steps namely preparation of the aldehydehydrazones and the diazonium ions separately before reacting both in a suitable medium to give the formazan.This multiplicity of steps decreases the yield.Further diazotization is the key step and it requires the use of strong mineral acids and low temperature.The reaction conditions are stringent and require fine control of temperature as well as pH.High cost of starting materials, use of corrosive mineral acids and volatile organic solvents makes the procedures unacceptable from the standpoint of green and sustainable chemistry.Further in some instances autocatalytic side reactions tend to lower the yield due to multiple products formation [27].In some reported synthetic methods, alkali was used to accelerate the reaction which again makes the procedure unacceptable.While the only solvent free protocol reported by Bamoniri et al. [28] appears to be an improvement over other procedures; however, the use of NaOH and BF 3 -etherate in this method, prompts us to look for alternative green procedures which concomitantly result in high yields of the target product.It has already been reported that diazocoupling reactions could be conveniently carried in a one pot solvent free procedure using KHSO 4 with microwave as the promoter in a green synthetic protocol [29].The reported results encouraged us to extend this protocol and examined its applicability to the synthesis of formazans in a one pot solvent free four component reaction using this acidic salt.

Results and Discussion
We first examined the possibility by carrying out a one pot solvent free synthesis of formazans by mixing 4-nitroaniline, benzaldehyde and phenylhydrazine, NaNO 2 , KHSO 4 and 2 mL of deionized water.The mixture was ground to a fine homogeneous product.Gradual development of an intense red colour during grinding lead us to conclude that the reaction could be performed by grinding only however on examining the product in prepared silicagel plates using petroleum ether (60 -80): ethylacetate (9:1) as the eluent revealed only partial conversion.In order to drive the reaction to completion, the homogeneous mixture obtained after grinding, was subjected to microwave irradiation at 350 Watt power.Higher wattage of microwave was avoided as a precautionary measure against possible explosion because of the proven explosive proclivities of diazonium ions which are formed as the transient intermediate.Complete conversion to the formazan was observed after one minute of exposure.Encouraged by the results, we extended the reaction to the synthesis of a variety of formazans by using several combinations of aromatic aldehydes, aromatic amines and phenylhydrazone and in all cases yields were high and the products could be recovered in a simple work up procedure.The four component solvent free synthesis of formazans is shown in Scheme 1 and their physical characteristics summarized in Table 1.
A comparative study of the present methods to a few other procedures reported in literature is summarized in Table 2. Comparison reveals the superiority and better environmental acceptability of the one pot microwave mediated solvent free synthesis of formazans using cheap and easily available KHSO 4 .
Microwave mediated one pot solvent free synthesis of Formazans using KHSO 4 .

Conclusion
In all the previously reported synthesis of formazan, either the aldehyde phenylhydrazones or the diazonium ions or both were prepared separately and brought into reaction in a suitable medium.In this work, the possibility of a one pot procedure in the absence of any organic solvent or added coupling agents was explored.The use of moist KHSO 4 resulted in a one pot environmentally benign synthesis of formazans in high yield and in a very short reaction time.Further, delicate control of temperature as well as pH was not necessary making the procedure suitable for industrial application for large scale environmentally benign production of formazans dyes.

General
Chemicals were purchased from Loba chieme (India) and purified by procedures reported in literature [32].
Formazans obtained were confirmed by comparing their melting points with those reported in literature.Melting points were recorded in open capillaries and are uncorrected.Products were purified by repeated column chromatography.UV-vis spectra were recorded in UV-1800 Shimadzu UV spectrophotometer, IR spectra were recorded in KBr pellets in a Perkin Elmer FT-IR 1600 spectrophotometer and 1 H and 13 C NMR were recorded in Bruker Bio Spin 300MHz spectrometer using CDCl 3 as solvent and TMS as internal standard.Mass spectra of new compounds were recorded in Micromass QTOF ESI-MS instrument (model HAB273) and Microwave irradiation of reaction mixture was performed in reactor procured from Catalyst™ (India).

Figure 1 .
Figure 1.UV max of formazan (entry 10) before and after oxidation in ethanol solution.

Figure 2 .
Figure 2. UV max of formazan (entry 17) before and after oxidation in ethanol solution.

Table 1 .
Physical characteristics of formazans obtained by a four component solid phase reaction using KHSO 4 .

Table 2 .
Comparison of different methods of the synthesis of formazans.

Table 3 .
Shift in the π-π* electronic transitions before and after oxidation of formazans.