SYNTHESIS OF SCHIFF BASE DERIVATIVES

Transcription

1 MATERIALS Phenyl hydrazine hydrocholride, ethyl acetoacetate, dimethyl formamide, phosphoryl chloride, methanol, acetic acid, acetyl chloride, benzoyl chloride, 1,4- dioxane, calcium hydroxide, hydrochloric acid, 2-amino-1-methylbenzene, naphthalene-1-amine, antheacen-2-amine, 4-(phenyldiazenyl)aniline, 4-amino- 1,5-dimethyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one, toluene and ethanol. Dimethylformamide and 1,4-dioxane was distilled over calcium hydride before use. All of the reagents used for these studies were of analytical grade and procured from Sigma Aldrich or ACS chemicals. METHODS SYNTHESIS OF SCHIFF BASE DERIVATIVES A Schiff base is a nitrogen analog of an aldehyde or ketone in which the C=O group is replaced by C=N-R group. It is usually formed by condensation of an aldehyde or ketone with a primary amine according to following Scheme 2.1: Scheme 2.1 Formation of Schiff bases by condensation reaction Where R, may be an alkyl or an aryl group. Schiff bases that contain aryl substituents are substantially more stable and more readily synthesized, while those which contain alkyl substituents are relatively unstable. Schiff bases of aliphatic aldehydes are relatively unstable and readily polymerizable while those of aromatic aldehydes having effective conjugation are more stable [1-3]. The formation of a Schiff base from an aldehydes or ketones is a reversible reaction and generally takes place under acid or base catalysis, or upon heating as 39

2 shown in Scheme 2.2. Scheme 2.2 Reaction of Schiff base formation and its hydrolysis The formation is generally driven to the completion by separation of the product or removal of water, or both. Many Schiff bases can be hydrolyzed back to their aldehydes or ketones and amines by aqueous acid or base [4, 5]. The mechanism of Schiff base formation is another variation on the theme of neucleophilic addition to the carbonyl group. According to Scheme 2.3, the neucleophile is the amine. In the first part of the mechanism, the amine reacts with the aldehyde or ketone to give an unstable addition compound called carbinolamine. The carbinolamine loses water by either acid or base catalyzed pathways. Since the carbinolamine is an alcohol, it undergoes acid catalyzed dehydration. Typically the dehydration of the carbinolamine is the rate-determining step of Schiff base formation and that is why the reaction is catalyzed by acids. Yet the acid concentration cannot be too high because amines are basic compounds. If the amine is protonated and becomes non-neucleophilic, equilibrium is pulled to the 40

3 left and carbinolamine formation cannot occur. Therefore, many Schiff bases synthesis are best carried out at mild acidic condition [6, 7]. R 2 C OH N R ' H + R 2 C OH 2 N R ' H H (Acid-catalyzed dehydration) R C N R ' + H2 O R H R C N R ' + H 3 O + R Scheme 2.3 Mechanism for hydrolysis of Schiff base The dehydration of carbinolamines is also catalyzed by base. This reaction is somewhat analogous to the E 2 elimination of alkyl halides except that it is not a concerted reaction. It proceeds in two steps through an anionic intermediate [8]. The Schiff base formation is really a sequence of two types of reactions, i.e. addition followed by elimination. This synthesis is undertaken in three steps Step-1 Step-2 Synthesis of 3-methyl-1-phenyl-5-pyrazolone Synthesis of aldehyde/biketones from 3-methyl-1-phenyl-1Hpyrazol-5-ol 41

4 Step-3 Synthesis of Schiff base derivatives STEP-1: SYNTHESIS OF 3-METHYL-1-PHENYL-1H-PYRAZOL-5- OL (PMP) The preparation of 3-methyl-1-phenyl-1H-pyrazol-5-ol has been done using solid phenylhydrazine hydrochloride and ethyl acetoacetate [9]. The cyclization can be carried out by appropriate adoption of the experimental details given below (Scheme 2.4): Scheme 2.4 Synthesis of 3-methyl-1-phenyl-1H-pyrazol-5-ol(PMP) In a 50 ml conical flask, provided with 3cm reflux condenser, 7.3 g of phenylhydrazine hydrochloride, 9.3 g of crystallized sodium acetate and 6.5 g (6.4 ml) of redistilled ethyl acetoacetate were placed [10]. Add 10 ml of ethyl alcohol and reflux the mixture for one hour on a waterbath. Add 5 ml of 5% sodium carbonate solution, cool with ice for 10 minutes. Filter and wash with two 5 ml portion of ether. Recrystallize the crude product from toluene (15 ml) and wash the solid (after filtration). The yield of pure 3-methyl-1-phenyl-5-pyrazolone is 76%, m.p.127 C. 42

5 STEP-2: SYNTHESIS OF ALDEHYDE/BIKETONES The synthesis of 5-Hydroxy-3-methyl-1-phenyl-1H-pyrazole-4- carbaldehyde (PMFP), 1-(5-Hydroxy-3-methyl-1-phenyl-1H-pyrazole-4-yl) ethan-1-one(pmap) and (5-hydroxy-3-methyl-1-phenyl-1H-pyrazol-4- yl)(phenyl)methanone(pmbp) can be prepared by reaction of PMP with DMF, acetyl chloride and benzoyl chloride respectively [11-13]. Synthesis of PMFP As shown in Scheme 2.5, 5-Hydroxy-3-methyl-1-phenyl-1H-pyrazole-4- carbaldehyde was prepared by reaction of 3-methyl-1-phenyl-1H-pyrazol-5-ol with DMF in presence of POCl 3. 3-methyl-1-phenyl-1H-pyrazol-5-ol (8.7 g,0.05 mol) in DMF(10cm 3, 0.05 mol) was cooled to 0 C in an icebath. To this phosphoryl chloride (5.5 cm 3, 0.06 mol) was added dropwise to maintain the temperature between 10 to 20 C. After complete addition, the reaction mixture was heated on a steam bath for 1.5 hours and then poured in to 1 liter of ice water [14]. The resulting mixture was allowed to stand overnight and product was collected by filtration, washed with water and dried. Crystallisation was done from ethanol. Yellow compound PMFP was obtained with, yield 83%; M.P. 176 C. Scheme 2.5 Synthesis of PMFP 43

6 Synthesis of PMAP 3-methyl-1-phenyl-1H-pyrazol-5-ol (7.5 g) was dissolved in 80 ml of 1,4- dioxane by heating. Calcium hydroxide(12 g) was added followed by addition of acetyl chloride(5 ml) dropwise within one minute (Scheme 2.6) [15]. The temperature increased during the first few minutes and the reaction mixture became thick paste. The reaction mixture was refluxed for 30 minutes. Calcium complex of the desired ligand formed in the flask was decomposed by pouring the mixture in to dilute HCl (100 ml). An organic precipitate was formed slowly. It was filtered under suction washed with a little water and 1,4-dioxane, and recrystallised from a slightly acidified methanol-water mixture to destroy any undecomposed calcium complex. Scheme 2.6 Synthesis of PMAP 44

7 Synthesis of PMBP As shown in Scheme 2.7, 3-methyl-1-phenyl-1H-pyrazol-5-ol (7.5 g) was dissolved in 80 ml of 1,4-dioxane by heating. Calcium hydroxide(12 g) was added followed by addition of benzoyl chloride (5 ml) dropwise within one minute. The temperature increased during the first few minutes and the reaction mixture became thick paste. The reaction in mixture was refluxed for 30 minutes. Calcium complex of the desired ligand formed in the flask was decomposed by pouring the mixture in to diluted HCl (100 ml). An organic precipitates was formed slowly. It was filtered under suction washed with a little water and 1,4-dioxane, and recrystallised from a slightly acidified methanol-water mixture to destroy any undecomposed Calcium complex[16-18]. Scheme 2.7 Synthesis of PMBP 45

8 STEP-3: SYNTHESIS OF SCHIFF BASE DERIVATIVES The Schiff bases of PMFP, PMAP and PMBP are prepared with following five different amines.(i) 2-amino-1-methyl benzene, (ii) naphthalene-1 amine, (iii) anthracen-2-amine, (iv) 4-(phenyldiazenyl)aniline,(v) 4-amino-1,5 dimethyl-2- phenyl-1,2-dihydro-3h-pyrazol-3-one (i) 2-amino-1-methyl benzene (ii) NH 2 naphthalene-1-amine (iii) anthracen-2-amine 46

9 (iv) (v) 4-( phenyldiazenyl) aniline 4-amino-1,5 dimethyl-2-phenyl-1,2-dihydro-3h-pyrazol-3-one The reaction of synthesised aldehyde/biketone (PMFP, PMAP, PMBP) with above mention five amines can be done with condensation reaction. All aldehyde/biketone reacts with each amine and gives corresponding schiff bases as shown in Scheme

10 Scheme 2.8 Synthesis of schiff base derivatives Take 250 ml flat bottom flask, add 50 ml methanol and aldehyde/ biketone(0.05 mmol) and warm till dissolution. Take amine (0.05 mmol) in other beaker and dissolved in 30 ml methanol then add the amine solution in aldehyde/ biketone solution, add few drops of acetic acid and stir the reaction mixture on magnetic stirrer for 2 hours (Scheme 2.8)[19, 20]. 48

11 In case of PMBP derivatives, it takes 7 hours for the completion of reaction due to the hindrance of benzoyl group on 4 th position of pyrazol ring. All the compounds were dried and recrystallised by suitable solvents. The synthesis compounds were stored in the dark to protect from light interaction. The M.P. of the compounds was measured using TECH XT-5 melting point apparatus. Structures of all the synthesised schiff base compounds, its names, abbreviated names and code are given in the Table 2.1. ELEMENTAL ANALYSIS Quantitative analytical data are routinely reported for confirmation of the structure of new organic compounds; these data are extremely useful for structure determination of unknown compounds. A comparison of the found composition with the calculated values should indicate the identity and purity of the synthesized compound. If the differences are less than ±5% of the calculated values, the found values reflect relatively pure compound. If the differences are more than ±5% one should suggest possible contamination (water, unreacted reactant, etc.). The elemental analysis results together with spectral data (IR and NMR) represent convincing evidence that the compound you prepared is a targeted product. The elemental analyses were determined on Perkin-Elmer- 2400series (II). The elemental analysis results of all the compounds are shown in Table

12 Table 2.1: Name, structural formula and abbreviated names of the synthesised compound Code Name and structure of Schiff bases Abbreviated 1A Name PMFP-2A1MB 5-Methyl-2-phenyl-4-( o-tolylimino-methyl)- 2,4-dihydro-pyrazol-3-one 2A PMAP-2A1MB 5-Methyl-2-phenyl-4-(1- o-tolylimino-ethyl)- 2,4-dihydro-pyrazol-3-one 3A PMBP-2A1MB 5-Methyl-2-phenyl-4-(phenyl- o-tolylimino-methyl) -2,4-dihydro-pyrazol-3-one 50

13 Code Name and structure of schiff bases Abbreviated 1B Name PMFP-1NA 5-Methyl-4-(naphthalen-1-yliminomethyl)- 2-phenyl-2,4-dihydro-pyrazol-3-one 2B PMAP-1NA 5-Methyl-4-[1-(naphthalen-1-ylimino)-ethyl]- 2-phenyl-2,4-dihydro-pyrazol-3-one 3B PMBP-1NA 5-Methyl-4-[(naphthalen-1-ylimino)-phenyl-methyl]- 2-phenyl-2,4-dihydro-pyrazol-3-one 51

14 Code Name and structure of schiff bases Abbreviated 1C Name PMFP-2AA 4-(Anthracen-2-yliminomethyl)-5-methyl- 2-phenyl-2,4-dihydro-pyrazol-3-one 2C PMAP-2AA 4-[1-(Anthracen-2-ylimino)-ethyl]-5-methyl -2-phenyl-2,4-dihydro-pyrazol-3-one 3C PMBP-2AA 4-[(Anthracen-2-ylimino)-phenyl-methyl]-5-methyl- 2-phenyl-2,4-dihydro-pyrazol-3-one 52

15 Code Name and structure of schiff bases Abbreviated 1D Name PMFP-4AAP 4-[(1,5-Dimethyl-3-oxo-2-phenyl-pyrazolidin-4-ylimino)- methyl]-5-methyl-2-phenyl-2,4-dihydro-pyrazol-3-one 2D PMAP-4AAP 4-[1-(1,5-Dimethyl-3-oxo-2-phenyl-pyrazolidin-4-ylimino)- ethyl]-5-methyl-2-phenyl-2,4-dihydro-pyrazol-3-one 3D PMBP-4AAP 4-[(1,5-Dimethyl-3-oxo-2-phenyl-pyrazolidin-4-ylimino)- phenyl-methyl]-5-methyl-2-phenyl-2,4-dihydro-pyrazol-3-one 53

16 Code Name and structure of schiff bases Abbreviated 1E Name PMFP-4AAB 5-Methyl-2-phenyl-4-[(4-phenylazo-phenylimino)- methyl]-2,4-dihydro-pyrazol-3-one 2E PMAP-4AAB 5-Methyl-2-phenyl-4-[1-(4-phenylazo-phenylimino) -ethyl]-2,4-dihydro-pyrazol-3-one 3E PMBA-4AAB 5-Methyl-2-phenyl-4-[phenyl-(4-phenylazo-phenylimino)- methyl]-2,4-dihydro-pyrazol-3-one 54

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18 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ Code No. Abbreviated name Molecular Formula Table 2.2 Elemental analysis results Molecular weight % Yield M.P. ( C) Elemental analysis(%) Found and (calcd.) C H N O 1A PMFP-2A1MB C 18 H 17 N 3 O (74.20) 5.67(5.88) 14.67(14.42) 5.31(5.49) 2A PMAP-2A1MB C 19 H 19 N 3 O (74.73) 6.23(6.27) 13.67(13.76) 5.24 (5.24) 3A PMBP-2A1MB C 24 H 21 N 3 O (78.45) 5.89(5.76) 11.38(11.44) 4.22(4.35) 1B PMFP-1NA C 21 H 17 N 3 O (77.04) 4.74(5.23) 12.20(12.84) 4.75(4.89) 2B PMAP-1NA C 22 H 19 N 3 O (77.40) 5.54(5.61) 12.39(12.31) 4.32(4.69) 3B PMBP-1NA C 27 H 21 N 3 O (80.37) 5.23(5.27) 10.11(10.41) 3.97(3.97) 1C PMFP-1AA C 25 H 19 N 3 O (79.55) 5.07(5.07) 11.10(11.13) 4.21(4.24) 2C PMAP-1AA C 26 H 21 N 3 O (79.77) 5.06(5.41) 9.67(10.73) 4.09(4.29) 3C PMBP-1AA C 31 H 23 N 3 O (82.10) 4.98(5.11) 9.27(9.27) 3.02(3.53) 1D PMFP-4AAP C 22 H 23 N 5 O (68.20) 5.44(5.46) 17.76(18.08) 8.01(8.26) 2D PMAP-4AAP C 23 H 25 N 5 O (68.81) 6.12(5.77) 17.36(17.44) 7.93(7.97) 3D PMBP-4AAP C 28 H 27 N 5 O (72.55) 5.68(5.44) 15.04(15.11) 6.67(6.90) 1E PMFP-4AAB C 23 H 19 N 5 O (72.42) 5.02(5.02) 18.03(18.36) 4.19(4.19) 2E PMAP-4AAB C 24 H 21 N 5 O (72.89) 5.32(5.35) 17.51(17.71) 4.05(4.05) 3E PMBP-4AAB C 29 H 23 N 5 O (76.13) 5.07(5.07) 15.11(15.31) 3.41(3.50) ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 55

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