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Bismuth nitrate pentahydrate-induced novel nitration of eugenol

Organic and Medicinal Chemistry Letters volume 1, Article number: 9 (2011) Cite this article

Abstract

Background

Eugenol, the main constituent of clove oil possesses a number of medicinal activities. To enhance the medicinal property, structural modification is required. On the other hand, bismuth nitrate pentahydrate has been established as an excellent eco-friendly nitrating agent for several classes of organic compounds.

Results

Bismuth nitrate pentahydrate-induced nitration of eugenol has been investigated very thoroughly. Twenty five different conditions have been studied. The microwave-induced solvent-free reaction has been identified as the best condition.

Conclusions

Spectral analyses confirm that 5-nitroeugenol is the sole product in all the cases. No oxidized or isomerized product could be detected.

Background

Syzygium aromaticum L., popularly known as clove, belongs to the plant family Myrtaceae, and has been used in folk medicine and dental treatment. Eugenol (4-allyl-2-methoxyphenol), the main component of clove oil, is an allyl chain-substituted guaiacol in the biosynthesized phenylpropanoid compound class derived from Syzygium aromaticum L. and widely used in medicine[1]. It is widely cultivated in India, Indonesia, Sri Lanka, Madagascar, and Brazil. In addition, it is commonly used in root canal and temporary fillings; it shows antibacterial activity, and helps in dental caries treatment and periodontal disease[2, 3]. Clove oil has been successfully used for some breath problems[3]. It is slightly soluble in water and soluble in organic solvents. A recent report[4] reveals the insecticidal effect of eugenol. Anti-inflammatory and antinociceptive activities of eugenol have also been reported[5]. Moreover, eugenol is reported to possess antioxidant and anticancer properties[6].

In order to study the biological activities of eugenol derivatives, nitration by conventional nitric acid-sulfuric acid or a nitronium tetrafluoborate method were performed. These reactions require a mixture of concentrated or fuming nitric acid with sulfuric acid leading to excessive use of hazardous chemicals[7]. Nitration of eugenol and its derivatives was reported using HNO3/H2SO4 [8] or by HNO3/Et2O[9]. In addition, difficult work-up procedure and low yield were also observed as a result of some other side reactions.

On the other hand, the usefulness of clay-mediated organic synthesis has been documented in a large number of publications which includes Michael addition [10], regioselective synthesis of carbazoles [11], selective hydrolysis of nucleosides [12], and Knoevenagel/hetero Diels-Alder reaction [13]. We have demonstrated the use of trivalent bismuth nitrate pentahydrate in organic synthesis. These experiments have resulted in various methods that include protection of carbonyl compounds [14], Michael reaction [15], nitration of aromatic systems [16], deprotection of oximes and hydrazones [17], and Paal-Knorr synthesis of pyrroles [18]. Our success in the bismuth nitrate-induced reaction has revealed [19] that this reagent acts as a Lewis acid.

We have been studying metal/metal salts-mediated reactions with the aim of developing several biologically active compounds; including anticancer polyaromatic compounds [20] and anticancer β-lactams [21]. Toward this goal, we also demonstrated that an effective bismuth nitrate-mediated nitration of polycyclic aromatic hydrocarbons. We reported the nitration of estrone with metal salts which exclusively depends on the nature of the solid surfaces [22]. Herein we report the direct nitration of eugenol using bismuth nitrate pentahydrate, an economical, easily available and eco-friendly salt. A comparison with various solvents, solid supports along with solvent-free condition has been carried out.

Results

In previous work we reported the nitration of estrone with different types of metal salts in the presence of solid surfaces under various conditions[22]. It has been clearly established that the nitration reaction induced by metal salts depend on the nature of the solid surface, nitrating agents, and reaction conditions. We have extensively studied the nitration of eugenol using various methods and solid surfaces (Figure 1). The results are summarized in Table 1.

Figure 1
figure1

Nitration of eugenol with bismuth nitrate on solid surface.

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Table 1 Bismuth nitrate-induced nitration of eugenol under different conditions
Full size table

Discussion

Bismuth nitrate pentahydrate is the metal nitrate used in this experimentation process, although the effect of many others such as CAN, Zn(NO3)2, Ca(NO3)2, LaNO3, NaNO3, and Cu(NO3)2 were also studied elsewhere. Bismuth nitrate pentahydrate was confirmed as the best nitrating agent among all others. Dry conditions and solvent-free methods along with commercial solvents without any purification were investigated in order to identify the best conditions for this reaction. Reactions were performed at high temperature using Dean-Stark water separator, traditional reflux, and conventional kitchen microwave-induced methods. Solid surfaces such as florisil, silica gel, molecular sieves, KSF clay, and neutral alumina were used as solid support in the reaction. It was discovered that silica gel is the best solid surface. In some cases (entries 2, 17 and 22), the reaction gave 100% yield of the product (4-allyl-2-methoxy-5-nitrophenol). Eugenol and bismuth nitrate along with KSF clay as solid support, under the conventional microwave and solvent-free condition produced 100% yield (entry 19). Quantitative yield was also observed under reflux in benzene with bismuth nitrate in presence of silica gel (entry 22). No reaction was observed when Bi(NO3)3 was used at room temperature even after 24 h (entries 11-15).

Conclusions

In conclusion, metal nitrate-induced nitration of eugenol has been successfully carried out under various conditions and the formation of a single product (4-allyl-2-methoxy-5-nitrophenol) has been observed in variable yields. The exploratory results described herein confirm that bismuth nitrate pentahydrate is the reagent of choice in the absence of any solvent under microwave-irradiation condition (entry 19). Importantly, in contrast with nitric acid-mediated method, these reactions mediated by bismuth nitrate have several important characteristics. For example, no isomerization of the alkene moiety has been observed, regioselectivity remains identical irrespective of the solid supports and conditions, no oxidation of the alkene/aromatic systems has been observed, and phenolic hydroxyl group has no influence on the regioselectivity of the reactions. On the basis of these important and selective observations, this method will find very useful applications in synthetic chemistry of electrophilic aromatic nitration reaction.

Methods

General

FT-IR spectra were registered on a Bruker IFS 55 Equinox FTIR spectrophotometer as KBr discs. 1H-NMR (600 MHz) and 13C-NMR (125 MHz) spectra were obtained at room temperature with Bruker-600 equipment using TMS as internal standard and CDCl3 as solvent. Analytical grade chemicals (Sigma-Aldrich Corporation) were used throughout the project. Deionized water was used for the preparation of all aqueous solutions.

General procedure for the nitration of Eugenol

In general, eugenol (1 mmol) and bismuth nitrate pentahydrate (1 eqv.) were mixed and the mixture was studied under different conditions varying the method, solid support and/or solvent as mentioned in Table 1. A representative experimental procedure (entry 2) is as follows: Eugenol (1 mmol) and silica gel (500 mg) was added to a suspension of bismuth nitrate pentahydrate (1 eqv.) in dry benzene (20 mL). The mixture was refluxed using Dean-Stark water separator for 2 h. The progress of the reaction was monitored by TLC. The reaction mixture was then repeatedly extracted (3 × 10 mL) with dichloromethane, washed with saturated solution of sodium bicarbonate, brine and water successively. The organic layer was dried over anhydrous sodium sulfate and concentrated to afford the crude product which was purified by column chromatography (silica gel, hexane/ethyl acetate).

4-Allyl-2-methoxy-5-nitrophenol

sticky mass; IR (KBr disc, cm-1): 2369, 1522, 1457, 1243, 1136, 1061, 941, 810 and 712; 1H NMR (CDCl3, 600 MHz) δ: 10.67 (s, 1 H), 7.45 (s, 1 H), 6.84 (s, 1 H), 5.89 (m, 1 H), 5.05 (m, 2 H), 3.83 (s, 3 H), 3.27 (d, 2 H, J = 1.1 Hz). 13C NMR (CDCl3, 125 MHz) δ: 149.86, 144.88, 135.94, 133.64, 132.46, 128.63, 127.43, 125.07, 56.70, 36.74.

References

  1. 1.

    dos Santos AL, Chierice GO, Riga AT, Alexander K, Matthews E: Thermal behavior and structural properties of plant-derived eugenyl acetate. J Therm Anal Calorim 2009, 97: 329–332. 10.1007/s10973-008-9753-0

    CAS  Article  Google Scholar 

  2. 2.

    Cai L, Wu CD: Compounds from Syzygium aromaticum possessing growth inhibitory activity against oral pathogens. J Nat Prod 1996, 59: 987–990. 10.1021/np960451q

    CAS  Article  Google Scholar 

  3. 3.

    Lee KG, Shibamoto T: Antioxidant property of aroma extract isolated from clove buds [ Syzygium aromaticum ]. Food Chem 2001, 74: 443–448. 10.1016/S0308-8146(01)00161-3

    CAS  Article  Google Scholar 

  4. 4.

    Han Q-x, Huang S-s: The bioactivity of eugenol against the red flour beetle Tribolium castaneum . Chongqing Shifan Daxue Xuebao, Ziran Kexueban 2009, 26: 16–19.

    CAS  Google Scholar 

  5. 5.

    Daniel AN, Sartoretto SM, Schmidt GC, Caparroz-Assef SM, Bersani-Amado CA, Cuman RKN: Anti-inflammatory and antinociceptive activities of eugenol essential oil in experimental animal models. Revista Brasileira de Farmacognosia 2009, 19: 212–217. 10.1590/S0102-695X2009000200006

    CAS  Article  Google Scholar 

  6. 6.

    Carrasco AH, Espinoza CL, Cardile V, Gallardo C, Cardona W, Lombardo L, Catalan MK, Cuellar FM, Russo A: Eugenol and its synthetic analogues inhibit cell growth of human cancer cells. Part 1. J Brazilian Chem Soc 2008, 19: 543–548. 10.1590/S0103-50532008000300024

    Article  Google Scholar 

  7. 7.

    Lunar L, Sicilia D, Rubio S, Perez-Bendito D, Nickel U: Degradation of photographic developers by Fenton's reagent: condition optimization and kinetics for metol oxidation. Water Res 2000, 34: 1791–1802. 10.1016/S0043-1354(99)00339-5

    CAS  Article  Google Scholar 

  8. 8.

    Clemo GR, Turnbull JH: Nitration of some derivatives of eugenol. J Chem Soc 1949, 1870–1871.

    Google Scholar 

  9. 9.

    Andersen L: Nitration of phenols with carbon-containing substituents. Suomen Kemistiseuran Tiedonantoja 1956, 65: 17–18.

    CAS  Google Scholar 

  10. 10.

    Chakrabarty M, Sarkar S: Novel clay-mediated, tandem addition-elimination-(Michael) addition reactions of indoles with 3-formylindole: an eco-friendly route to symmetrical and unsymmetrical triindolylmethanes. Tetrahedron Lett 2002, 43: 1351–1353. 10.1016/S0040-4039(01)02380-2

    CAS  Article  Google Scholar 

  11. 11.

    Chakrabarty M, Ghosh N, Harigaya Y: A clay-mediated, regioselective synthesis of 2-(aryl/alkylamino)thiazolo[4,5-c]carbazoles. Tetrahedron Lett 2004, 45: 4955–4957. 10.1016/j.tetlet.2004.04.129

    CAS  Article  Google Scholar 

  12. 12.

    Gurjar MK, Mondal D, Ravindranath SV, Chorghade MS: Clay-mediated selective hydrolysis of 5'-O-acetyl-2',3'-isopropylidene/cyclohexylidene nucleosides. Synth Commun 2006, 36: 2321–2327. 10.1080/00397910600639968

    CAS  Article  Google Scholar 

  13. 13.

    Ramesh E, Raghunathan R: Microwave-assisted K-10 montmorillonite clay-mediated Knoevenagel hetero-Diels-Alder reactions: a novel protocol for the synthesis of polycyclic pyrano[2,3,4-kl]xanthene derivatives. Synth Commun 2009, 39: 613–625. 10.1080/00397910802417825

    CAS  Article  Google Scholar 

  14. 14.

    Srivastava N, Dasgupta SK, Banik BK: A remarkable bismuth nitrate-catalyzed protection of carbonyl compounds. Tetrahedron Lett 2003, 44: 1191–1193. 10.1016/S0040-4039(02)02821-6

    CAS  Article  Google Scholar 

  15. 15.

    Srivastava N, Banik BK: Bismuth Nitrate-Catalyzed Versatile Michael Reactions. J Org Chem 2003, 68: 2109–2114. 10.1021/jo026550s

    CAS  Article  Google Scholar 

  16. 16.

    Banik BK, Samajdar S, Banik I, Ng SS, Hann J: Montmorillonite impregnated with bismuth nitrate: Microwave-assisted facile nitration of β-lactams. Heterocycles 2003, 61: 97–100. 10.3987/COM-03-S62

    CAS  Article  Google Scholar 

  17. 17.

    Banik BK, Adler D, Nguyen P, Srivastava N: A new bismuth nitrate-induced stereospecific glycosylation of alcohols. Heterocycles 2003, 61: 101–104. 10.3987/COM-03-S63

    CAS  Article  Google Scholar 

  18. 18.

    Rivera S, Bandyopadhyay D, Banik BK: Facile synthesis of N-substituted pyrroles via microwave-induced bismuth nitrate-catalyzed reaction. Tetrahedron Lett 2009, 50: 5445–5448. 10.1016/j.tetlet.2009.06.002

    CAS  Article  Google Scholar 

  19. 19.

    Banik BK, Reddy AT, Datta A, Mukhopadhyay C: Microwave-induced bismuth nitrate-catalyzed synthesis of dihydropyrimidones via Biginelli condensation under solventless conditions. Tetrahedron Lett 2007, 48: 7392–7394. 10.1016/j.tetlet.2007.08.007

    CAS  Article  Google Scholar 

  20. 20.

    Banik BK, Becker FF: Synthesis, electrophilic substitution and structure-activity relationship studies of polycyclic aromatic compounds towards the development of anticancer agents. Curr Med Chem 2001, 8: 1513–1533.

    CAS  Article  Google Scholar 

  21. 21.

    Banik I, Becker FF, Banik BK: Stereoselective Synthesis of β-Lactams with Polyaromatic Imines: Entry to New and Novel Anticancer Agents. J Med Chem 2003, 46: 12–15. 10.1021/jm0255825

    CAS  Article  Google Scholar 

  22. 22.

    Bose A, Sanjoto WP, Villarreal S, Aguilar H, Banik BK: Novel nitration of estrone by metal nitrates. Tetrahedron Lett 2007, 48: 3945–3947. 10.1016/j.tetlet.2007.04.050

    CAS  Article  Google Scholar 

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Acknowledgements

We gratefully acknowledge the funding support from National Cancer Institute (NIH/NCI-P20, Grant# 5P20CA138022-02).

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    1. Department of Chemistry, The University of Texas-Pan American, 1201, West University Drive, Edinburg, TX, 78539, USA

      Luis Canales, Debasish Bandyopadhyay & Bimal K Banik

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    1. Luis Canales
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    2. Debasish Bandyopadhyay
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    3. Bimal K Banik
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    Correspondence to Bimal K Banik.

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    The authors declare that they have no competing interests.

    Luis Canales, Debasish Bandyopadhyay contributed equally to this work.

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    Canales, L., Bandyopadhyay, D. & Banik, B.K. Bismuth nitrate pentahydrate-induced novel nitration of eugenol. Org Med Chem Lett 1, 9 (2011). https://doi.org/10.1186/2191-2858-1-9

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    Keywords

    • Nitration
    • Root Canal
    • Eugenol
    • Solid Support
    • Bismuth Nitrate