Indian Journal of Chemistry Vol. 408, December 2001 , pp. 1 19 1 - 1 1 95

An efficient method for chemoselective nitration of phenols under mild and heterogeneous conditions

Mohammad Ali Zolfigol*, Elahe Madrakian & Ezat Ghaemi

Department of Chemistry, College of Science, University of Bu-Ali Sina, zip code 65 174, Hamadan, I.R. Iran, E-Mail: Zolfi@basu.ac.ir.

Fax: (+98) 8 1 1 8272404

Received 11 February 2000; accepted (revised) 23 July 2001

Nitrophenols can be obtained via nitrosation-oxidation of phenols with Mg(HS04h or NaHS04.H20, NaN02 and wet Si02 at room temperature in moderate to high yields. In situ generation of HN02 and radical cation mechanis_m via nitrous acid catalyzed (NAC) pathway appear to be applicable to phenol nitration using these reagents.

The nitration of aromatic compounds may be achieved with many nitrating reagents and is a very useful way in organic synthesis 1 . Also, nitro compounds find use in many industrial applications2.3

and para isomers are commonly the more commercially desirable products,e.g., p-nitrotoluene vs o-nitrotoluene or p-nitrophenol vs o-nitrophenol and production of 2-nitroestrone versus 4-nitroestrone is important from pharmaceutical point of view4 . Nitration of the phenol as a special case has been studied by various nitrating agents under different conditions4.1 5. Very recently, Rodrigues et al. reported that phenol can be nitrated by silica gel-supported acetyl nitrate with excellent ortho regioselectivity l6. Although a survey of the l iterature indicates the lack of entire selectivity of para nitration of phenol but almost selective ortho nitration of phenol was performed with N204 and pyridine derivatives carrying transferable nitro group or silica gel­supported acetyl nitrate6. 16. It is clear that, on the basis of the above facts there is a need for more regioselective control of nitration of aromatic compounds. Recently, in this connection we have reported the applications and mechanism of some hydrated metal nitrates and their dinitrogen tetroxide complex analogues for nitration of phenols under different conditions 17. We have also demonstrated that in situ formation of HN03 is a major factor for an effective nitration of phenols with metal nitrates (containing covalent nitrato groups ) 1 7a. 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,9. 1 1

strongly acidic media (Ho_8),4b oxidation ability of the reagents and safety problems (storage, handling, using and also presence of toxic transition metal cations such as Cr+3, Hg+2, Cu+2 , . . . within molecular structure of the reagents) 1 8.19, (b) moreover, constraining a reaction to the surface of solid habitually allows to use milder conditions and increases its reactivity2o. 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 'nitrosonium ion (NO+) under mild and heterogeneous conditions and also applications of it for different purposes21 . Therefore, we decided to seek a heterogeneous system for selective nitration of phenol, and we have investigated a number of different reaction conditions based upon the in situ generation of HN02 by relatively strong solid inorganic acidic salts [NaHS04.H20, Mg(HS04h. pka-2] and sodium nitrite. We wish to report here in one-pot heterogeneous procedure for 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 to the p-nitrosophenol selectively by Mg (HS04h (I) or NaHS04.H20 (II) [( 2 eq), one equivalent of I or II were needed for oxidation step], NaN02 [(III), ( 1 eq)]

1 192 INDIAN J CHEM., SEC B, DECEMBER 2001

and wet S i02 (50% wlw) in CH2Cl2 as usable solvent via il l situ generation of HN02. Since, phenol nitrosation is rapid and yields almost entirely the para isomer which can be readily converted to p-nitrophenol via mild oxidation with HN03,22 H202/Na2WO/3 etc. Therefore, we decided to produce p-nitrophenol via nitrosation-oxidation strategy22-24 in one pot reaction under mild and heterogeneous condition by addition of NaN03 (or other ionic metal nitrates) to the reaction mixture ( as a source for in situ generation of HN03 in the presence of I or II and wet Si02) after performing the nitrosation reaction (Scheme I, path a) . Whereas, in contrast to the reported procedures under aqueous media22-24 we observed that nitrosation and oxidation were occurring simultaneously without addition of any oxidant to the reaction mixture for the oxidation of nitrosophenol . Hence, in this reaction mono nitration has occurred and o-nitrophenol 4 and p-nitrophenol 2 were obtained (Scheme I, Table I , path b).

Different kinds of 4-substituted phenols 5 were also subjected to nitration reaction in the presence of inorganic acidic salts e. g. Mg(HS04h (I) or NaHS04.H20 (II), NaN02 (III), and wet Si02 (50% wlw) in dichloromethane (Scheme II). The nitration reactions were performed under mild and completely heterogeneous conditions at room temperature in moderate to excellent yields (Scheme II, Table I).

The present nitration reactions can be readily carried out by placing the nitrating agents, phenols (1 or 5) and the usable solvent in a reaction vessel and efficiently stirring the resultant heterogeneous mixture at room temperature. The mono nitrophenols can be obtained by simple filtration and evaporation of the solvent. This alternative method provides nitrated phenols directly, in short reaction times and good yields.

In fact, a combination of sodium nitrite and solid acids can act as solid HN02 which can be readily weighed, handled and used for different purposes in the presence of moist Si022 1 .

In order to show the chemoselectivity of this method a competitive reaction was performed between phenol and anisole. It was observed that exclusive phenol nitration proceeded whereas anisole remained intact in the reaction mixtures after 24 hr (Scheme III).

This method is also very mild as the hydrolysis product of 4-cyanophenol was not observed (Scheme

OH OH a ¢ N'N03.¢ OH

© l or II NO N02 III 2 3 OH OH

b ¢ ©rNO, + N02

3 4

Scheme I

IV, Entries 9 and 1 0) . Selective mononitration of 4,4'­dihydroxydiphenyl 51 was also achieved by controlling stoichiometry of reagents (Table I, Entries 25 and 26).

Although the reaction occurs without wet Si02 but, the reaction time period is very long and completed after several days. Therefore we think that the presence of wet S i02 will act as a media and will provide a heterogeneous effective surface area for in situ generation of HN02. I t also will make easy work­up. Meanwhile, nitration was not occurred in the absence of inorganic acidic salts (Table I, Entry 27).

This new system e.g. a combination of inorganic acidic salts I or II and sodium nitrite is similar to

N204 (N204 ¢:::> NO + N03 -)27 as a nitrosating agent via

+ in situ generation of HN02 (Eqn 1 ) and NO (Eqn 2). Therefore on the basis of our observations, the previously reported results concerning the applications of N204,25.26 metal nitrate dinitrogen tetroxide complexes [M(N03)m.nN204] , 17. oxidation of HN02 with oxygen and production of N204 (Eqn 3_6),27 very recent reported mechanism for nitration of phenols28. 29 and the products which are obtained, the following nitrous acid catalyzed mechanism (NAC) may be proposed (Scheme V).

In conclusion, the cheapness and the availability of the reagents, easy and clean work-up, and high yields make this method attractive for the large-scale operations. This simple procedure is highly selective and contamination by oxidation side-products is avoided. Moreover, the new element here is that the reaction is heterogeneous. This could be worthwhile in an industrial setting2o.

ZOLFIGOL et al. : AN EFFICIENT METHOD FOR CHEMOS ELECTIVE NITRATION OF PHENOLS 1 193

OH OH

� l or II �N02

• III

X X

5 6

5 a b c d e f g h j k

X F C l Br CN Ph CH) OCH) COCH) COOH CH2Ph NHOAc 4-HOC6H4-

Scheme II Table I-Mononitration of phenols to their corresponding nitro derivatives with a combination Mg(HS04h (I) or NaHS04.H20 (II),

NaN02 (III) and wet Si02 (50% w/w) in dichloromethane at room temperature.

Entry Substrate Product Reag.lSubst. (mrnole)" Time Yieldsb m.p. (0C) I II III (min) % Found Reported

1 3 I 1 0 3 1 1 l0- 1 13 1 157 4 4 1 44-45 447

2 1 3 1 0 33 1 10- 1 13 1 157 4 4 1 44-45 447

3 Sa 6a 45 65 73 73-744<: 4 Sa 6a 45 87 73 73-744<: 5 5b 6b 45 79 89 9 1 1 1 . 28

6 5b 6b 45 89 89 9 1 " . 28

7 5c 6c 60 82 87 84". 28

8 5c 6c 45 76 87 84". 28

9 5d 6d 1 80 83 140-142 1454<:· 28

10 5d 6d 1 80 92 140- 142 1454<:· 28

1 1 5e 6e 1 80 92 6 1 -63 66)1

12 5e 6e 1 80 95 61-63 6631

1 3 Sf 6f 1 80 75 29-3 1 3 1 1 1 . 28

1 4 Sf 6f 1 80 77 29-3 1 3 1 ". 28

15 5g 6g 45 79 54-56 28

16 5g 6g I 45 83 54-56 28

1 7 5h 6h 2 2 1 80 80 1 22- 124 123", 28

18 5h 6h 2 2 1 80 82 122- 124 1 23 " . 28

1 9 5 i 6i 2 2 180 80 1 80- 183 28

20 5i 6i 2 2 1 80 83 1 80- 183 28

2 1 5j 6j 2 2 1 80 9 1 6 1 -6 22 5j 6j 2 2 1 80 90 6 1-6 23 5k 6k 1 80 50 1 80 32

24 5k 6k 1 80 56 1 80 _32 25 51 61 40 70 180- 1 84 3 1 26 51 61 40 87 1 80- 1 84 _31

27 1 3, 4 24(h) NO ReactionC

a \'. et Si02 : substrate ( I ) (0.2 g : 1mmole) . bIsolated Yields. C Reaction was not occurred in the absence of inorganic acidic salts.

Experimental Section General. Chemicals were purchased from Fluka,

Merck and Aldrich chemical companies. Yields refer to isolated pure products. The nitration products were ·-:haracterized by comparison of their spectral (JR, IH_

NMR, 13C_NMR), TLC and physical data with the authentic samples4, 17 .

Mononitration of phenol (1) with NaHS04.H20 (II), NaN02 and wet Si02 : A typical procedure. A suspension of compound 1 0 .88 g, 0.02 mole), II

1 1 94 INDIAN J CHEM., SEC B, DECEMBER 2001

OH + �

HJ OH

�N02 c9J l or II $-N02 III

• +

X X

l or 5 7 J, 4 0r 6 8

100% 0%

Scheme III

OH OH OH

� _I_or_II_ •• &N02 + &N02

III � � eN CN

1 00%

Scheme IV

H+ + N02' --+ HN02 HN02 + 2H+ --+ NO+ + H30+ 2HN02 --+ N20) + H20 N20) --+ NO + N02 2N02 --+ N204 2NO --+ N202 + O2 --+ N204

COOH

0%

(eq 1 )

(eq 2)

(eq 3) (eq 4)

(eq 5) (eq 6)

c$J� ��c$J ��-N� OH [ OH (j l OH

X 'X X X I or S J' 4 or 6

Scheme V

(2.76 g, 0.02 mole), NaN02 ( 1 .38 g, 0.02 mole) and wet Si02 (50% w/w, 2 g) in CH2Ch (20 mL) was stirred magnetically at room temperature. The reaction was completed after 1 0 minutes and then filtered. The residue was washed with CH2Ch (2x lO mL). Anhydrous Na2S04 (5 g) was added to the filtrate. After 15 minutes the resulting mixture was also filtered. Dichloromethane was removed by water bath (35-40 0C) and simple distillation. Residue obtained was 4-nitrophenol 3 ( insoluble in /1-pantane) , l . 1 3 g (4 1 %), mp 1 1 0- 1 3 DC (lit7 mp

1 14DC). The n-pantane was evaporated by water bath (35-40 DC), 2-nitrophenol 4, 0.94 g, 33%, mp 44-45 DC (lit7 mp 44 DC) was also obtained (Table I, Scheme I).

Mononitration of 4-cyanophenol (5d) with NaHS04.H20 (II), NaN02 and wet Si02 : A typical procedure. A suspension of compound 5d (0.238 g, 2 mmole), II (0.276 g 2 mmole), wet Si02 (50% w/w, 0.2 g) and NaN02 (0. 1 38 g, 2 mmole) in dichloromethane (4 mL) was stirred at room temperature for 3 hr (the progress of the reaction was monitored by TLC) and then filtered. Anhydrous Na2S04 (5 g) was added to the filtrate. After 1 5 min the resulting mixture was also filtered. Dichloromethane was removed by simple distillation on water bath (35-40 DC). The yield was 0.299 g (92%) of crystalline pale yellow solid (6d), mp 1 40-42 °C (Lit.4c mp 1 45 °C) . IH-NMR (FT-90 MHz, CDCh, TMS) : 0 7.34 (d, I H), 7.77 (dd, 1 H), 8.48 (d, I H), 1 0.87 (b, I H) . IH-NMR spectra were identical with reference spectra4C.

Acknowledgement The authors gratefully acknowledge partial support

of this work by the Research Affair of Bu-Ali Sina University, Hamadan, I.R Iran.

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