Vilsmeier Haack Adducts as Effective Reagents for Regioselective Nitration of Aromatic Compounds under Conventional and Non-Conventional Conditions

Nitration of aromatic Compounds is triggered by Vilsmeier-Haack reagent (DMF/POCl3) or (DMF/SOCl2) in the presence of KNO3 or NaNO2 under conventional and non-conventional conditions. The reactions afforded corresponding Nitro derivatives in very good yield with high regioselectivity. The results obtained in non-conventional methods (Micro wave irradiation, Grinding, Sonication) are comparable with those obtained under conventional conditions, but the reaction times of former conditions are substantially shorter than that of the latter.


Introduction
Over the years, Nitration of aromatic compounds has been an area of interest to chemists because Nitro arenes are useful intermediates in the synthesis of organometallic species and pharmaceutically important compounds [1][2][3].Direct methods of Nitration of aromatic compounds involve the use of hazardous acid mixture (HNO 3 and H 2 SO 4 ) that is highly toxic, corrosive, and pollutes to the environment, and metal ion catalysts are generally expensive.In view of this, there has been an upsurge in the design and execution of mild methods of Nitration of aromatic compounds [4][5][6][7][8][9][10][11][12][13][14][15][16][17].Over the past decade, our group has also been actively involved in designing a variety of eco friendly materials using micelle-forming surfactants as catalysts and unconventional energy sources (such as microwave irradiation and ultrasound) to assist Vilsmeier-Haack (VH) reactions [18][19][20] and Hunsdiecker reactions [21][22] .Dramatic rate accelerations followed by an increase in the product yield were observed in these reactions in all cases.Organic reactions performed under solvent-free conditions have gained much attention because of their enhanced selectivity, mild reaction conditions, and associated ease of manipulation.The recent reviews and publications in this field prove the im-portance of solvent-free organic synthesis [23][24][25][26][27][28] and highlights that this process is not only simple but also satisfies both economical and environmental demands by replacing the toxic solvents.

Results and Discussion
The VH reaction [29][30][31][32] is widely used for formylation.It can be applied to introduce an acetyl group on activated aromatic or hetero aromatic compounds, many other conversions can be achieved with this technology.It is one of the most versatile reactions in organic synthesis for the conversion of arenes to corresponding bromo derivatives.In general, (DMF/POCl 3 ) or (DMF/SOCl 2 ) are used to generate an iminium salt intermediate salt can be used in the synthesis of a large number of heterocyclic compounds.The VH reaction is a mild method known for the introduction of a formyl (-CHO) group to various activated aromatic and hetero aromatic compounds.Recently our group reported that Vilsmeier-Haack (VH) reagents could be effectively used in presence of KBr or NBS for bromination of arenes [20].Encouraged by this result, we tried to use VH reagent (DMF/SOCl 2 and DMF/POCl 3 ) in presence of KNO 3 and NaNO 2 for nitration reactions.Aromatic compounds such as phenols and amines underwent nitration treated with VH reagent (DMF/SOCl 2 and DMF/POCl 3 ) in presence of KNO 3 and NaNO 2 afforded good yields of products under stirred conditions at room temperature.In this study KNO 3 and NaNO 2 were used as reagents for the generation of nitronium ions.Under these conditions only nitro derivatives were obtained.Howwever, in the absence of KNO 3 and NaNO 2 formylated products could be obtained.We have analysed the products carefully to check this point.
To check the generality of the reaction an array of aromatic compounds were used as substrates as shown in Scheme 1.
An important note that, Nitration of aniline using (HNO 3 and H 2 SO 4 ) forms m-nitro aniline as major product, it is because aniline is a strong activating group forms anlilinium salt ( 6 5 3 ) with strong acid.But, using VHR and KNO 3 or NaNO 2 can afford o, p-nitro anilines as major products.

C H -NH 
The reaction rapidly afforded high yields of the corresponding Nitro derivatives.All the products were characterized by physical data (m.p/b.p), 1 H NMR, and mass spectra, with authentic samples and found to be satisfactory.To compare these results, aromatic compounds were treated with VH adduct (POCl 3 + DMF) in Acetonitrile under reflux conditions.When aromatic amines and Phenols were reacted with (POCl 3 + DMF) in the presence of KNO 3 or NaNO 2 , the reaction indicated corresponding Nitro derivatives.The reaction proceeded rapidly with (POCl 3 + DMF)/(KNO 3 or NaNO 2 ) over (SOCl 2 + DMF)/ (KNO 3 or NaNO 2 ) to afford high yields of the corresponding Nitro derivatives.Data summarized in Figures 1-4 and Tables 1 and 2    ) is released faster in the case of the (POCl 3 + DMF)/(KNO 3 or NaNO 2 ) system and is available for favorable Nitration over the (SOCl 2 + DMF)/(KNO 3 or NaNO 2 ) system.It is interesting to note that the reaction times under thermal conditions are too long even though the yields are fairly appreciative.However, the reaction times decreased substantially from several (14 to 15) hours to few minutes under solvent-free (mortar-pestle) grinding conditions followed by a fairly good increase in the prouct yield.This observation could be attributed to an increase in the fraction of activated species supplemented by the heat energy generated due to the friction in grinding process [23][24][25][26].By and large similar rate enhancements were observed in the case of ultrasonically assisted reactions.The observed rate accelerations could be explained due to cavitation, a physical process that creates, enlarges, and implodes gaseous and vaporous cavities in an ultrasonically assisted (irradiated) liquid.Cavitation induces very high local temperatures in the reaction mixture and enhances mass transfer [33][34][35].On the other hand in microwave irradiated reactions, the reaction times further reduced dramatically to only few seconds.The yields also enhanced from good to excellent showing the catalytic effect of non-conventional energy to activate the reactive species in this study.The observations are in accordance with the literature reports that the chemical reactions are accelerated because of selective absorption of microwave energy by polar molecules, nonpolar molecules being inert to the MW dielectric loss [27,28].

Conclusions
In summary, the authors developed a protocol for imi-nium Salt Vilsmeier-Haack Reagent (VHR) triggered aromatic irradiated, sonicated and mortar-pestle) not only reduced the reaction times but enhanced the yield of products from good to excellent.The present finding is more advantageous because the reactions are conducted with economically cheap and readily available reagents.The reactions occur under mild and under environmentally safe conditions with a simple work up at room temperature.

General Procedure for Preparation of Vilsmeier-Haack Reagent
The Vilsmeier Haack (VH) adduct is prepared afresh be-fore use from Oxychloride (POCl 3 or SOCl 2 ) and dimethyl formamide (DMF).To a chilled (at -5˚C) Oxychloride in acetonitrile (MeCN), calculated amount of dimethyl formamide (DMF) was slowly added drop wise, which resulted in slurry indicating the formation of VH reagent.The reagent thus obtained is stored under cold conditions.

General Procedure for Synthesis of Nitro Arenes under Solvent Phase Conditions Using VH Reagent (Thermal)
A centi molar (0.01mol) organic substrate, (phenols, anilines), 0.01 moles of KNO 3 or NaNO 2 and about 0.015 moles of VH reagent and solvent (MeCN) were taken in a previously cleaned in a Round bottom flask and stirred for about 12 to 15 hours at room temperature.After completion of the reaction, as confirmed by TLC, the reaction mixture is treated with 5% sodium thiosulphate solution, followed by the addition of ethyl acetate.The organic layer was separated, dried over Na 2 SO 4 and evaporated under vacuum, purified with column chromatography using pet-ether and ethyl acetate to get pure product.

General Procedure for Synthesis of Nitro Arenes under Solvent Phase Conditions Using VH Reagent (Sonication)
A centi molar (0.01 mol) organic substrate, (phenols, anilines), 0.01 moles of KNO 3 or NaNO 2 and about 0.015 moles of VH reagent and solvent (MeCN) were taken in a previously cleaned in conical flask at room temperature.
After completion of the reaction, as confirmed by TLC, the reaction mixture is further processed for isolation of product as detailed in earlier section.

General Procedure for Synthesis of Nitro Arenes under Solvent Free Conditions Using VH Reagent (Grinding)
A centi molar (0.01mol) organic substrate, (phenols, anilines), 0.01 moles of KNO 3 or NaNO 2 and about 0.015 moles of VH reagent in a previously cleaned in mortar grounded with a pestle.After completion of the reaction, as confirmed by TLC, the reaction mixture is further processed according to the above procedure to get pure product.

General Procedure for Microwave Assisted Vilsmeier-Haack Synthesis of Nitro Arenes under Solvent Free Conditions
A centimolar (0.01mol) organic substrate (phenols, ani-lines), 0.01 moles of KNO 3 or NaNO 2 and about 0.015 moles of VH reagent were taken in a previously cleaned 50 ml beaker.About 500 mg of silica gel were added to the contents and mixed thoroughly and placed in microwave oven (CEM-908010, bench mate model, 300W laboratory microwave reactor).After completion of the reaction, as checked by TLC, the reaction mixture is treated with 5% sodium thiosulphate solution, followed by the same procedure as detailed above to get pure product.

Scheme 1 .
Scheme 1. Nitration of aromatic compounds with VH reagents and KNO 3 /NaNO 2 under conventional and non-conventional conditions.