Synthesis of New Knoevenagel Derivative using Fe3O4 Magnetic Nanoparticals

Introduction

Today organic synthesis based on magnetic nanomaterial’s are found a major role in many fields including industrial procedure, biotechnology, environmental remediation, biomedicine, and particularly catalysis [1-2a-d]. Reactions were generally and mostly carried out in organic solvents, some time with aqueous [3]. Some case water also act as environmentally benign solvent [4]. The use of environmentally benign solvents like water [5] and absent of organic[6] methods from inexpensive as well as importance in synthetic point of view[7]. This methods  improve the rate  of many organic reactions. Thus carry out the Knoevenagel condensation in water  medium [8]. Application of Knoevenagel condensation reaction of in water aromatic aldehydes with ethyl cyanoacetate or malononitrile[9]. The separation and recycling of the catalyst is highly favorable because catalysts are very expensive.

Surface reform i. e. immobilization of functional group has been extensively studied [10] formation of new covalent bond on the targeted structure [11]. There are wide reports [12-13] immobilization also different kind like chelate forming organic reagents, some on polymers, naturally found compounds, metal salts and carbon and highly dispersed silica.  Immobilization of compounds depend on substitution reaction between the surface of the supporting material [14]. Among the different adsorbents, silica gel particularly restrained with various organic compounds [15-19] Conducting same reactions by using heterogeneous catalyst had reduced many drawbacks found in previously reported reactions. In this type of reactions, the catalyst can be recovered by filtration and it can be reuse for the next cycle. However, it is worthy to mention in spite of several advantages experienced practically in using of heterogeneous catalysts, due to the nanosized particles used, few limitations to the sustainability are observed [20-24].

Experimental

¹H NMR Spectra and ¹³C NMR spectra were recorded as δ values in ppm on instrument Brucker FT AC-400 MHz and 100 MHz (TMS Internal standard). IR spectra on a Perkin-Elmer 1605 FT-IR and absorptions recored in cm^-1 unit. Thermo Scientific Q-Exactive, Accela 1250 pump use for LCMS data.

Preparation of Ferrite (Fe₃O₄) magnetic nanoparticles:-

FeCl₃.6H₂O (Ferric Chloride Hexahydrate) (5.8 g, 0.022 mol) and FeCl₂.4H₂O (Ferrous Chloride Tetra hydrate) (2.1 g, 0.011 mol) were were dissolved in 150 mL of deionized H₂O in a round bottom flask (250 mL) at R.T. under constant stirring. Thereafter, 10 mL of aq. NH₃ solution (32%) was then added into mixture within 40 min with stirring. Finally the black precipitate solid was collected by magnetic decantation, washed with distilled water until solution becomes neutral, and then washed with ethanol two times. After the performed of procedure the magnetic nano materials have been characterized using an Infrared spectroscopy and the structure of magnetic catalysts was determined by X-ray diffraction (XRD) study. Scanning electron microscope (SEM) use for determine crystal size of catalyst.

General Procedure

We have carried out reaction of various substituted benzaldehyde with  active methylene compounds active (acyclic) and (cyclic) active methylene compounds (e.g. barbituric acid and thiobarbituric acid) in presence of ferrite heterogeneous catalyst as shown in scheme : 1.

Knoevenagel reactions of substituted benzaldehydes with active methylene compounds using  nano-ferrite as catalyst:

We have carried out Knoevenagel condensation reactions. In this various substituted benzaldehyde with active methylene compounds(cyclic and acyclic) use ferrite catalyst. (Scheme :1).

Scheme 1: Nano-ferrite catalysed Knoevenagel condensation. Click here to View figure

Results And Discussion

We have made efforts to improve a catalytic system that would overcome the limitations of the earlier reported Knoevenagel reactions. When initial study held, benzaldehyde (1a) and malononitrile (2a) used as a represented system. optimization was done  by Sequences of the experiments performed with a variety of reaction parameters, like type of catalyst, catalyst quantity, solvent, temperature and time (Table-1). Initially we have synthesized the paramount magnetically distinguishable catalysts, all MFe₂O₄ (M=Fe²⁺, Zn²⁺, Mn²⁺ and Ni²⁺) by screened for sample reaction. Apart from catalysts examined, Fe₃O₄ found to be the best, providing very good yields of the targeted product 3a (Table-1, entries 1-5). Then catalysts concentration study performed having  rang 10 to 20 mol% rises the yield of product 3a up to 94%, Further increase of catalyst concentration to 25 mol% did not improve the yield of 3a (Table-1, entries 5-8). As the solvent have an impact on the overall process, the effect of various solvents (Table-1, entries 5, 9-13,15) were examined; the best results was obtained with C₂H₅OH which afforded 3a in 94% yield (Table-1, entry 5). We have also made temperature study data 3a obtained good yield at reflux temperature for complete consumption of aldehyde (Table-1,entries 5,14). Reaction conditions optimized and  we have explore the substrate scope of the ferrite catalyzed Knoevenagel condensation of substituted aldehydes with acyclic active methylene compounds (malononitrile, ethyl cyanoacetate, ethyl acetoacetate) and cyclic active methylene compounds ( barbituric acid and thiobarbituric acid) for the synthesis of styrene derivatives having different functional groups. Thus, we have observed that electron good yield of products. Satisfyingly this protocol endured a range of common functional groups such as alkyl, ether, halogen and nitro groups irrespective of the place. Results of these reactions listed in Table-2.

Our aim is to make catalytic system more cheap, we have focused on the reusability of nano–Fe₃O₄ catalyst in this condensation reaction as shown in Table-3, the catalyst shown extraordinary activity in all three cycles. Reaction was monitored by TLC. Followed by touching the external magnet to wall of the round bottom flask and reaction mixture was decant in the small beaker. The catalyst was washed with ethanol (3×5 ml) and dried it for 1 hr at 120°C in oven, it is ready for next cycle. Catalyst were recycled three times without significant loss of catalytical activities.

Table 1: Optimization of Reaction Parametersa Click here to View table

Table 2: Substrate Study of Knoevenagel Producta. Click here to View table

Table 3: Substrate Study of Knoevenagel Producta Click here to View table

Table 4: Catalyst Recycle Study^a

Sr.No.	Run No.	Yield(%)b
1	1st	94
2	2nd	88
3	3rd	76
aReaction conditions: Benzaldehyde (1mmol), malononitrile (1mmol), ethanol(5 mL), bIsolated yield.

 

Figure 1: X-ray diffraction study of nano-ferrite catalyst Click here to View figure

Figure 2: Scanning Electron Microscope (SEM) images of nano-ferrite catalyst. Click here to View figure

Synthesis of styrene compounds

Benzaldehyde (1 mmol), malononitrile (1 mmol), Fe₃O₄ (20 mol %) in ethanol (5 ml) heated at reflux for 30 min. Reaction was monitored by Thin Layer Chromatography. The catalyst was recovered by simple magnetically decantation of reaction mixture by pouring in cold H₂O and the product were filtered and purified in aqueous ethanol. Recovered catalyst was washed with ethanol and dried in oven. The catalyst is ready for next cycle of the reaction.

Spectral Data of Selected Compounds

2-(4-chlorobenzylidene)malononitrile (3d).

FT-IR (KBr):3030, 2227, 1955, 1558, 779, 617 cm^-1.

¹H-NMR (CDCl₃,400 MHz)δ:7.880(d, J=8.4Hz, 2H), 7.760(s,1H), 7.545(d, J=8.4Hz, 2H).

¹³C NMR (CDCl₃,100 MHz)δ: 158.30, 141.18, 131.86, 130.09, 129.28, 113.45, 112.35, 83.37.

2-(2-chlorobenzylidene) malononitrile (3f).

Colour: Pale yellow, MP:96-98^°C. FT-IR (KBr): 3055, 2222, 1907, 1587, 756, 619 cm^-1

¹H NMR (Deuterated chloroform, 400 MHz) δ: 8.295(s, 1H), 8.205(d, J = 8.0Hz, 1H,), 7.576(d,J=3.6Hz, 2H), 7.495 –7.435 (m, 1H).

 ¹³CNMR (Deuterated chloroform, 100MHz)δ: 156.05, 136.35,    135.04, 130.72, 129.51, 129.07, 127.80, 113.22, 111.91, 85.81.

2-(2-nitrobenzylidene) malononitrile (3m).

Colour: Yellow M.P.: 140-142^°C

FT-IR(KBr): 3047, 2239, 1975, 1591, 1523, 1440 cm^-1.

 ¹H NMR(Deuterated chloroform, 400 MHz) δ: 8.474(s, 1H), 8.393 – 8.369(m, 1H), 7.931-7.891(m, 1H), 7.855-7.816(m, 2H).

 ¹³C NMR(Deuterated chloroform, 100 MHz) δ: 158.83, 146.80, 134.98, 133.44, 130.49, 126.72, 125.88, 112.24, 110.98, 88.55.

2-(3,4-dimethoxybenzylidene)malononitrile(3o).

Colour: Yellow, M.P: 142-144^°C,

FT-IR(KBr): 2933, 2833, 2218, 1909, 1467, 1251,1147 cm^-1,

¹H NMR(Deuterated chloroform, 400MHz) δ: 7.683 (t,J = 2.0 &12.0Hz, 2H,), 7.399(q, J=2.4 &6.0Hz, 1H), 7.283 (s,1H), 4.003 (s, 3H), 3.953 (s, 3H).,

 ¹³C NMR(Deuterated chloroform, 100 MHz) δ: 159.15, 154.28, 149.56, 128.22, 124.29, 114.42, 113.59, 111.10, 11, 0.78, 78.45, 56.34, 56.09.

(Z)-ethyl 2-cyano-3-(3,4-dimethoxybenzylidene)acrylate(3p).

Colour: Yellow, M.P: 156-158^°C,

FT-IR(KBr):3003, 2845, 2222, 1928, 1710, 1512, 1159, 1097 cm^-1.,

¹H NMR(Deuterated chloroform, 400 MHz) δ: 8.162 (s, 1H), 7.808 (s, 1H),7.482 (d,J = 7.6 Hz, 1H), 6.955 (d, J = 7.6 Hz, 1H), 4.377 (q, J = 7.2 Hz, 2H), 3.900(s,6H), 3.400(t, J= 7.2 Hz, 3H).,

 ¹³C NMR(Deuterated chloroform, 100 MHz) δ:163.11, 154.70, 153.68, 149.28, 127.89, 124.61, 116.36, 111.65, 110.95, 99.38, 62.46, 56.15, 56.05, 14.21.

5-benzylidenepyrimidine-2,4,6(1H,3H,5H)-trione(4a).

Colour: Yellow, M.P: 270-272^°C,

FT-IR(KBr): 3512, 3313,3074, 2845, 1880, 1701, 1581,1438.,

 ¹H NMR(Dimethyl sulfoxide-d_6, 400 MHz)δ: 11.735(bs,2H), 7.913(t, J =6.8 &1.6 Hz, 1H), 7.615 (t, J= 6.8 &7.6Hz, 1H),7.180(t,J= 7.6 Hz, 1H), 7.075(t, J=7.2 Hz, 1H), 7.015(d, J = 8.0Hz, 2H), 5.946(s,1H).,

 ¹³C NMR(Dimethyl sulfoxide-d_6, 100 MHz) δ:193.74, 173.30, 163.50,142.89, 136.64, 135.07, 133.89, 129.96, 129.63,128.61, 128.17, 126.99, 125.44, 96.35, 31.06.

5-(3-methoxybenzylidene)pyrimidine-2,4,6(1H,3H,5H)-trione(4h).

Colour: Brown, M.P: 268-270^°C,

FT-IR(KBr): 3518, 3458, 3007, 2828, 1938, 1660, 1570, 1444, 1163 cm^-1,

 ¹H NMR (Dimethyl sulfoxide -d_6, 400 MHz)δ: 11.407 (s,1H), 11.256(s,1H), 8.259 (s, 1H),7.845(t, J = 2.0Hz, 1H), 7.611(q,J = 0.8Hz&. 0.4Hz, 1H),7.395 (t, J=8.0Hz, 1H), 7.142–7.117(m,1H,) 3.797(s,3H).

, ¹³C NMR (Dimethyl sulfoxide-d_6, 100 MHz) δ: 163.87, 162.09, 159.08, 154.98, 150.64, 134.31, 129.59, 126.55, 119.74, 118.91, 118.07,55.68.

5-(2-chlorobenzylidene)-dihydro-2-thioxopyrimidine-4,6(1H,5H)  dione(4k).

Colour: Red, M.P: 234-236^°C,

FT-IR(KBr): 3633, 3388, 3076, 1718, 1583, 1215, 1049,725, 642 cm^-1,

 ¹H NMR(Dimethyl sulfoxide-d_6, 400 MHz) δ: 11.491(s,1H), 11.272(s,1H), 8.292,( s, 1H), 7.747 (t, J= 6.8 & 0.8 Hz, 1H), 7.556, (q, J= 1.2Hz & 6.8Hz, 1H), 7.497 – 7.456, (m, 1H), 7.392 – 7.352, (m,1H).,

 ¹³CNMR(Dimethyl sulfoxide-d_6, 100 MHz) δ: 163.12, 161.38, 150.69, 150.17, 133.64, 132.74, 132.44, 132.40, 129.35, 126.80, 122.26

9) 5-(3-methoxybenzylidene)-dihydro-2-thioxopyrimidine-4,6(1H,5H)-dione(4q).

Colour: Red, M.P: 236-238^°C,

FT-IR(KBr): 3485, 3070, 2904, 1944, 1701,1651, 1548, 1228, 1151, 1047 cm^-1., ¹HNMR(Dimethyl sulfoxide-d_6, 400 MHz)δ: 12.477(s,1 H), 12.357 (s,1H), 8.271(s,1H), 7.892(s,1H), 7.676 -7.657(d,1H, J=7.6Hz),7.430- 7.390(m,1H, J = 8.0Hz), 7.172-7.147, (m,1H), 3.803 (s, 3H).,

¹³C NMR(Dimethyl sulfoxide-d_6, 100MHz) δ: 179.02, 162.18, 159.94, 159.12, 155.88, 134.29, 129.68, 126.92, 119.80, 119.45, 118.31, 55.72.

10)  5-(3,4-dimethoxybenzylidene)-dihydro-2-thioxopyrimidine-4,6(1H,5H)-dione (4r).

Colour: Red, M.P: >290^°C,

FT-IR(KBr): 3506, 3386, 3083, 1946, 1662, 1583, 1220, 1159 cm^-1,

¹H NMR (Dimethyl sulfoxide-d_6, 400 MHz) δ: 12.403-12.300(d, 2H), 8.438(d, J= 1.6Hz, 1H), 8.275(s, 1H), 7.969 (t, J= 1.2 & 7.2 Hz, 1H), 7.157(q, J = 8.0 & 9.2 Hz, 1H), 3.830(s,6H),

¹³C NMR (Dimethyl sulfoxide -d_6, 100 MHz) δ: 191.86, 178.65, 162.76, 160.60, 156.97, 154.70, 154.66, 149.63, 148.35, 132.84, 130.09, 126.60, 125.91, 117.43, 115.79, 111.74, 111.69, 109.87, 56.42, 56.35, 55.98, 55.93.

Conclusion

We have carried out Knoevenagel reactions of various substituted aromatic aldehydes with cyclic and acyclic active methylene compounds resulting compounds form with good to significant  yields at refluxed temperature in presence of environmentally benign Fe₃O₄ as a nano catalyst. The ferrite catalyst was recycled upto three successive times. But  not in considerable loss in action. The present method displaces all other methods that used various homogeneous catalysts and performed compare with elevated temperature. FT-IR, ¹H NMR and ¹³C NMR spectroscopy, characterized structures of the synthesized compounds.

Acknowledgement

¹H NMR analysis for S. P. University, Pune  and SAIF Panjab    University, Panjab. UICT, KBC, NMU, Jalgaon for XRD and SEM and Principal , M.J. College,  Jalgaon for IR analysis, Principal, R. C. Patel College, Shirpur, for microbial screening. Also thank full to Principal, Jaihind Educational Trust’s Zulal Bhilajirao Patil College Dhule, Maharashtra, India  and Head, Chemistry Department, Jaihind Educational Trust’s Zulal Bhilajirao Patil College Dhule Maharashtra, India  for providing laboratory for carried this work.

Conflict of Interest

The authors declare that there is no conflict of interests concerning the publication of this article.

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