Research Journal of Chemical Sciences ______________________________________________ ISSN 2231-606X Vol. 4(10), 54-57, October (2014) Res. J. Chem. Sci. International Science Congress Association 54 Hydroxylamine Hydrochloride as an effective Catalyst for Form amide derivative Synthesis and their DPPH scavenging activityAgarwal Deepali *, Agrwal Akansha, Bairagi Anamika and Kasana Virendra Kumar Organic Synthesis Laboratory, Department of Chemistry, CBSH, G.B. Pant University of Agriculture and Technology, Pantnagar U.S. Nagar 263 145, INDIAAvailableonline at: www.isca.in, www.isca.me Received 16th June 2014, revised 3th August 2014, accepted 12th October 2014 AbstractHydroxylamine hydrochloride offers simple, efficient, economical and environmentally benign method for amidation at room temperature. The reaction was carried out under neat condition affording most of the products in excellent yield. Plausible mechanism to explain the ability of hydroxylamine hydrochloride to enhance the rate of reaction is described. The method is superior as in this method less amount of formic acid is required and reaction proceeds at room temperature. Synthesized formamides were found to have significant radical scavenging effect on 2,2-diphenyl-1-picryl-hydrazyl radicals Keywords: Hydroxylamine hydrochloride, amidation, environmentally benign, room temperature, radical scavenging. Introduction Formylation of amines is required during the synthesis of a number of compounds used in medicinal and industrial fields. In the synthesis of medicinally important compounds such as 1,2 dihydroquinolines, substituted aryl imidazoles, cancer chemo-therapeutic compoundsand oxazolidinonesthe application of N-formylation is well documented1-4. Formamides are used as catalyst in the process such as allylation and hydrosilylation of carbonyls compounds5-6. They are important precursor in the synthesis of fungicides and herbicides. They are used as reagents for Vilsmeir formylation. Formamides are also used in the synthesis of formamidiens and isocyanide9-11. A number of catalysts such as ZnCl, iridium, ammonium formate, thiamine hydrochloride, guanidine derived ionic liquids, sulfated titanium oxide, sodium formate, sulfated tungstate, amberlite IR 120, melamine trisulfonic acid have been reported to catalyse N- formylation of amines12-21. Most of the reported methods of N-formylation methods have one or more disadvantages such as harsh reaction conditions and long reaction time, thermally unstable and toxic catalyst and tedious workup. So, it is desirable to develop mild, convenient and high yielding procedure using non toxic and inexpensive catalyst22-25. The present work is in continuation to our earlier work to develop new synthetic methods using environmentally benign and inexpensive catalysts26-27. We herein report a convenient and green approach for N-formylation of amines using hydroxylamine hydrochloride as a catalyst under neat condition. Synthesized N-formylated derivatives have been studied for their antioxidant activity viz., radical scavenging effect on DPPH28Material and Methods Synthesis: A mixture of aniline (1mmol), hydroxylamine hydrochloride (0.1 mmol) and formic acid (2 mmol) was taken in 100 ml round bottom flask and stirred at room temperature for 70 minutes. After completion of the reaction as indicated by TLC, 20 ml of EtOAc was added to the reaction mixture. The reaction mixture was then transferred to the separating funnel and washed with aq HCl (conc 5%), aq NaCO (conc 5%). Organic layer was separated, dried over anhydrous NaSO and concentrated to afford the compound without further purification (table-1, entry 4). DPPH radical scavenging activity: The DPPH free radical scavenging activity was determined according to the method described by Chen and Ho (1995).29 To the 5 ml 0.004% ethanolic solution of DPPH, varying amount (5, 10, 15, 20 and 25 l) of ethanolic solutions of formamide derivatives was added. The test solution was prepared in triplicate and placed in dark for 2 h. The absorbance at 517 was recorded at room temperature. The percent DPPH radical scavenging activity of compound was calculated using following equation: % DPPH radical scavenging activity = [1-(Absorbance of sample/ Absorbance of control)] × 100 BHT (butylated hydroxytoluene), ascorbic acid and gallic acid were used as a reference compounds. IC50 value (g of compound per ml) was calculated by interpolation from linear regression analysis. Research Journal of Chemical Sciences ___________________________________________________________ ISSN 2231-606XVol. 4(10), 54-57, October (2014) Res. J. Chem. Sci. International Science Congress Association 55 Table-1 N-formylation of amines (3a-g) with formic acid (2) using hydroxylamine hydrochloride under solvent free condition NH HO NH 1a-g3 a-gHydroxylamine hydrochloridertEntry Amine R Products Time (min) %Yield a 1 3a 4-CH 3 3a 330 76 2 3b 2-Cl 3b 60 93 3 3c 4-F 3c 90 80 4 3d H 3d 70 97 5 3e 3-COCH 3 3e 230 75 6 3f 2-OH 3f 200 95 7 3g 4-NO 2 3g 20 90 a Isolated yield Table-2 Comparison of hydroxylamine hydrochloride catalyzed N-formylation with other reported methods Entry Catalyst Temperature Amine: HCOOH Ref. 1 ZnCl 70°C 1:3 13 2 Ammonium formate Reflux - 15 3 Thiamine hydrochloride 80°C 1:4 16 4 Amberlite IR 320 Microwave 1:3 21 5 Melamine Trisulfonic acid 60°C 1:2 22 6 Hydroxylamine hydrochloride Rt 1:2 Present work Results and Discussion Syhthesis: N-formylation reaction afforded good to excellent (table-1, entry 1-7) involving hydroxylamine hydrochloride as a catalyst under solvent free condition. Superiority of our protocol in comparison to reported methods in literature may be established by comparing the results of our protocol with those of reported methods. The two important features of our method are requirement of fewer amounts of formic acid and low temperature (room temperature). The amine: formic acid ratio and temperature for reported methods using different catalysts are given in table-2. Perusal of table-2 clearly indicates that hydroxylamine hydrochloride as a catalyst is most efficient in terms of temperature, time and mole ratio of amine and formic acid.DPPH radical scavenging activity: DPPH is a stable free radical with an absorption maximum at 517 nm. When an antioxidant is present in the medium, it donates protons to DPPH radical which lowers the initial absorbance of DPPH solution. Figure-2 showed that with increasing the concentration of formamide derivatives, the DPPH free radical scavenging activity increases and attained constant value. Perusal of table-3 reveals that all the formamide derivatives with –H, CH, -Cl, -NO, -COCH, -F, -OH groups exhibit free radical scavenging activity as it is evident from their IC50 values. These compounds were found to exhibit activity, comparable with standards i.e. BHT, gallic acid and ascorbic acid. Figure-2 The effect of ethanolic solution of formamide derivatives on DPPH scavenging activity Research Journal of Chemical Sciences ___________________________________________________________ ISSN 2231-606XVol. 4(10), 54-57, October (2014) Res. J. Chem. Sci. International Science Congress Association 56 Table-3 Free radical scavenging activity of formamide derivatives and standards in the antioxidant activity evaluation assays Compounds DPPH (IC 50 ) g/ml 3a 3.05 3b 2.26 3c 2.87 3d 2.91 3e 3.2 3f 3.23 3g 2.4 BHT 1.47 Gallic acid 1.3 Ascorbic acid 1.3 Spectral Characterization data of selected compounds: N-(2-chlorophenyl)-formamide (3b): IR (KBr, cm-1): 3251, 2900, 1939, 1790, 1663, 1540; H NMR (CDCl, 300 MHz): ppm 7.04-7.7 (m, 4H, Ar), 8.38 (1s, 1H, NH), 8.70 (1s, 1H, CHO). N-(phenyl)-formamide (3d): IR (KBr, cm-1): 3408, 1586, 1394; H NMR (CDCl, 300 MHz): ppm 7.07-7.55 (m, 5H, Ar),8.39 (s, 1H, NH), 8.71 (s, 1H, CHO) N-(2-hydroxyphenyl)-formamide (3f): IR (KBr, cm-1): 3376, 3089, 2877, 1655, 1590, 1376, 1279; NMR (CDCl, 300 MHz): ppm 7.01-7.18 (m, 4H, Ar), 6.87 (s, 1H, OH), 7.26 (s, 1H, NH), 8.27 (s, 1H, CHO). N-(4-nitrophenyl)-formamide (3g): IR (KBr, cm-1): 3212, 3082, 1688, 1595; H NMR (CDCl, 300 MHz): ppm 7.2-7.7 (m, 4H, Ar), 8.22 (s, 1H, NH), 8.9 (s, 1H, CHO). Conclusion In conclusion, hydroxylamine hydrochlorideis an efficient catalyst for N-formylation of amines. Two salient features of our protocol are requirement of fewer amounts of formic acid and low temperature. The protocol provides simple, economical and environment friendly method for formamide synthesis. The results reveal that all the ethanolic solutions of synthesized formamide derivatives showed significant DPPH radical scavenging activity to produce broad spectrum of antioxidant potential to create effective defense system against free radical attack. Acknowledgement One of the authors Deepali Agarwal is sincerely thankful to DST, New Delhi for the award of Inspire Fellowship. Authors gratefully acknowledge to IICT Hyderabad for spectral analysis. 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