Silica Sulfuric Acid/ NaNO2 as a Novel Heterogeneous System for the Nitration of Phenols under Mild Conditions

Nitrophenols can be obtained in moderate to high yields via nitrosation-oxidation of phenols with silica sulfuric acid, NaNO2 and wet SiO2 at room temperature. In situ generation of HNO2 and a radical cation mechanism via the nitrous acid catalyzed (NAC) pathway appear to be applicable to phenol nitration using these reagents.


Introduction
In several industrially important processes (e.g. nitration, nitrosation, etc.) a large excess of sulfuric acid is required because the water by-product slows the reaction down by diluting the acid. At the end of these processes, a large amount of "spent acid" is obtained which, in batch reactions, is usually neutralized and disposed of, while, in continuous processes, it has to be recycled by complex techniques. Also, the separation of the products from the acid is often a difficult and energy consuming process that habitually implies a basic aqueous work-up. Moreover, sulfuric acid is corrosive and is dangerous to transport and handle. Consequently, any reduction in the amount of sulfuric acid needed and/or any simplification in handling procedures would be highly convenient in terms of risk reduction, economic advantages and environment protection [1]. On the other hand, there is intense current research and general interest in heterogeneous systems because of the perceived opportunities such systems present for basic research and because of the unquestioned importance such systems have in industry and in developing technologies [2]. In continuation of our studies on the application of inorganic acidic salts we found that silica gel reacts with chlorosulfonic acid to give silica sulfuric acid (I). It is interesting to note that the reaction is easy and clean, not requiring any work-up procedure because the evolved HCl gas can be removed from the reaction vessel immediately (Scheme 1).

Scheme 1
We believed that the silica sulfuric acid (I) is a superior proton source to all of the reported acidic solid supports or acidic resins such as polystyrene sulfonic acid and Nafion-H [3] for running reactions under heterogeneous conditions. Therefore, we were interested in using this inorganic acidic resin (I) as a new sulfuric acid function immobilized on the surface of silica gel via covalent bonding for the insitu generation of HNO 2 when used in conjunction with NaNO 2 , wet SiO 2 .
The nitration of aromatic compounds may be achieved with many nitrating reagents and is a very useful reaction in organic synthesis. Nitration of the phenol as a special case has been studied using various nitrating agents under different conditions [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20]. Recently, in this connection we have reported the applications and mechanism of reaction of some hydrated metal nitrates and their dinitrogen tetroxide complex analogues for the nitration of phenols under various conditions [21]. We have also demonstrated that in situ formation of HNO 3 is a major factor for effective nitration of phenols with metal nitrates (containing covalent nitrato groups) [21a].
Our goal, in undertaking this line of work, was two-fold: a) to overcome the limitations and drawbacks of the reported methods such as: tedious work-up [12,14], strongly acidic media (H o~ -8) [7b], oxidation ability of the reagents and safety problems (storage, handling, use and also presence of toxic transition metal cations such as Cr +3 , Hg +2 , Cu +2 , etc., within molecular structure of the reagents) [22,23]; (b) moreover, high-yielding one-pot synthesis of nitrophenols using a novel combination of reagents are our main interest.
Very recently, we among many others, have demonstrated that heterogeneous reagent systems have many advantages such as simple experimental procedures, mild reaction conditions and minimization of chemical wastes as compared to their liquid phase counterparts. We have reported simple procedures for in situ generation of the nitrosonium ion (NO + ) under mild and heterogeneous conditions and also applications of it for different purposes [24]. Therefore, we decided to seek a heterogeneous system for the nitration of phenols, and we have investigated a number of different reaction conditions based upon the in situ generation of HNO 2 by the relatively strong solid inorganic acidic resin [silica sulfuric acid (I)] with sodium nitrite. We wish to report here a one-pot heterogeneous procedure for the nitration of phenols.

Results and Discussion
During the course of our studies on the utilization of NO + in functional groups transformations, we thought that phenol (1) must be converted in to the p-nitrosophenol selectively in CH 2 Cl 2 as solvent by silica sulfuric acid (I) [(2 eq), one equivalent of I was needed for oxidation step], NaNO 2 [(II), (1 eq)] and wet SiO 2 (50% w/w) via in situ generation of HNO 2 . On the other hand, we also thought that phenol nitrosation is rapid and yields almost entirely the para-isomer which can be readily converted to p-nitrophenol via a mild oxidation with HNO 3

Scheme 2
Different kinds of 4-substituted phenols (5) were also subjected to nitration reaction in the presence of silica sulfuric acid (I), NaNO 2 (II), and wet SiO 2 (50% w/w) in dichloromethane (Scheme 3). The nitration reactions were performed under mild and completely heterogeneous conditions at room temperature in moderate to excellent yields (Scheme 3, Table 1). The present nitration reactions can be readily carried out by placing the nitrating agents, phenols (1 or 5) and the solvent used in a reaction vessel and efficiently stirring the resultant heterogeneous mixture at room temperature. The mono nitrophenols can be obtained by simple filtration and then evaporation of the solvent. This method provides nitrated phenols directly, in short reaction times and good yields. In fact, a combination of sodium nitrite and silica sulfuric acid (I) can act as solid HNO 2 which can be readily weighed, handled and used for different purposes in the presence of moist SiO 2 [24]. A competitive reaction was performed between phenol and anisole. It was observed that exclusive phenol nitration proceeded, anisole remaining intact in the reaction mixtures after 24 hours (Scheme 4). Selective mononitration of 4,4 ' -dihydroxydiphenyl (5k) was also achieved by controlling the stoichiometry of reagents ( Although the reaction occurs without wet SiO 2 , the reaction times are very long, taking several days to go to completion. Therefore, we think that the wet SiO 2 acts as an effective heterogeneous surface for in situ generation of HNO 2 . It also makes work-up easy. This new system i.e. a combination of silica sulfuric acid (I) and sodium nitrite is similar to N 2 O 4 (N 2 O 4 ⇔ NO + NO 3 -) [30] as a nitrosating agent via in situ generation of HNO 2 (eq 1) and NO + (eq 2). Thus, on the basis of our observations, the previously reported results concerning the applications of N 2 O 4 [28, 29], metal nitrate dinitrogen tetroxide complexes [M(NO 3 ) m .nN 2 O 4 ] [20a], oxidation of HNO 2 with oxygen and production of N 2 O 4 (eq 3-6) [30], the very recent reported mechanism for nitration of phenols [31][32][33] and the products which are obtained, the following nitrous acid catalyzed mechanism (NAC) may be proposed (Scheme 5).

Conclusions
The cheapness and the availability of the reagents, easy and clean work-ups and good yields make this method attractive for large-scale operations. Moreover, a new feature here is the fact that the reaction is heterogeneous. This could be worthwhile in an industrial setting [20].

General
Chemicals were purchased from the Fluka, Merck and Aldrich chemical companies. Yields refer to isolated pure products. The nitration products were characterized by comparison of their spectral (IR, 1 H-NMR, 13 C-NMR), TLC and physical data with the authentic samples [7,21].
Preparation of silica sulfuric acid (I) [38] A 500 mL suction flask equipped with a constant-pressure dropping funnel and a gas inlet tube for conducting of HCl gas over an adsorbing solution (i.e. water) was used. It was charged with silica gel (60.0 g). Chlorosulfonic acid (23.3 g, 0.2 mol) was added dropwise over a period of 30 min at room temperature. HCl gas immediately evolved from the reaction vessel (Scheme 1). After the addition was completed the mixture was shaken for 30 min. A white solid of silica sulfuric acid (76.0 g, ~100%) was obtained.
A suspension of compound 5b (0.257 g, 2 mmol), I (1.25 g), wet SiO 2 (50% w/w, 0.2 g) and II (0.138 g, 2 mmol) in dichloromethane (10 mL) was stirred at room temperature for 1.5 hours (the progress of the reaction was monitored by TLC) and then filtered. Anhydrous Na 2 SO 4 (3 g) was added to the filtrate. After 15 minutes the resulting mixture was also filtered. Dichloromethane was removed by water bath (35-