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Synthesis of 3-Substituted Coumarins by the Knoevenagel Condensation Reaction
 

Synthesis of 3-Substituted Coumarins by the Knoevenagel Condensation Reaction

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    Synthesis of 3-Substituted Coumarins by the Knoevenagel Condensation Reaction Synthesis of 3-Substituted Coumarins by the Knoevenagel Condensation Reaction Presentation Transcript

    • Synthesis of 3-Substituted Coumarins by the Knoevenagel Condensation Reaction BY: MARIAM ISRAIEL Mentor: Dr. Kenneth Yamaguchi New Jersey City University (NJCU) Chemistry Department Experimental Protocol The Knoevenagel condensation reaction is an organic reaction named after Emil Knoevenagel. It is a modification of the Aldol condensation. The microwave irradiation-assisted and thermal solvent-free Knoevenagel condensations of aromatic ketones with malononitrile catalyzed by NH4OAc or silica gel, and the uncatalyzed Knoevenagel condensations in refluxing water have been investigated. The preparation of heterocyclic compounds under solvent - free conditions offers several key advantages and represents an important class of compounds with elevated biological activity and industrial importance . The microwave - assisted synthesis of a series of 3-Substituted Coumarins via the condensation of a series of 2-hydroxyaldehydes and dimethylmalonate on silica gel was explored . ■ 2-Hydroxyaldehyde (3mmol), dimethyl malonate (3mmol), ammonium acetate (231 mg, 3mmol) and silica gel or basic alumina (3g) are mixed thoroughly in a mortar. ■ The reaction mixture is placed in a beaker and irradiated in a microwave. ■ The progress of the reaction is monitored by TLC using petroleum ether-CH 2 Cl 2 (30:70). ■ The mixture is then extracted into methylene chloride (3×30-ml) then filtered and washed with water, the organic phase is removed under reduced pressure by rotary evaporation. Further purification by column chromatography on silica gel gives the desired product. Crystallization can be carried out in ethanol. Reactions Background Abstract ► All yields are based on pure products 1 2 4 3 5 7 9 6 8 10 Results Infrared Spectroscopy (IR) Results for Products: The Pechmann condensation is a synthesis of coumarins, starting from a phenol and a carboxylic acid or esters containing a β-carbonyl group. The condensation is performed under acidic conditions. The mechanism involves an esterification/ transesterification followed by attack of the activated carbonyl ortho to the oxygen to generate the new ring. The final step is a dehydration, as seen following an Aldol condensations. Active hydrogen compounds condense with aldehydes and ketones. Known as Knoevenagel condensations, these aldol-like condensations are catalyzed by weak bases such as amines. With simple phenols, the conditions are harsh, although yields may still be good Reaction Mechanism Chemical Formula: C 11 H 7 BrO 3 Molecular Weight = 267.075 Chemical Formula: C 12 H 9 BrO 3 Molecular Weight = 281.102 Chemical Formula: C 11 H 8 O 3 Molecular Weight = 188.179 Chemical Formula: C 12 H 10 O 3 Molecular Weig ht = 202.206 Chemical Formula: C 15 H 12 O 3 Molecular Weight = 240.253 Chemical Formula: C 16 H 14 O 3 Molecular Weight = 254.280 Chemical Formula: C 12 H 10 O 3 Molecular Weight = 202.206 Chemical Formula: C 13 H 14 O 3 Molecular Weight = 216.232 Chemical Formula: C 12 H 10 O 4 Molecular Weight = 218.205 Chemical Formula: C 12 H 10 O 4 Molecular Weight = 232.23 H1NMR and 13CNMR Spectrums of products 4 Result were confirmed using: ► GC-MS ► 1 HNMR ► 13 CNMR ► Infrared Spectroscopy (IR) ● Prep-Plates 30:70 (petroleum ether-CH2Cl2) ● Crystallization (ethanol) ● Flash Chromatography ● Long Column (Fraction Collection) ● Sep Packing (Fraction Collection) Purification Methods 1 HNMR for products and Reactants Conclusion References ■ Silverstein, R. "Spectrometric Identification of Organic Compounds" 6th Edition. ■ NIST Chemistry WebBook: http://srdata.nist.gov/gateway. ■ Fryhle, Craig and TW Graham Solomons. Organic Chemistry. 8th ed. New York: Wiley & Sons ■ http:// www.umich.edu "A Generalized Knoevenagel Condensation" ■ Aldrich Catalog ■ Spectral Database for Organic Compounds (SDBS) ■ ChemFinder: http:// cambridge soft.com ■ Pubchem:http://pubchem.nbci.nlm.nih.gov The reactions were carried out under atmospheric pressure in an a closed vessel adapted to Synthwave 402 microwave monomode reactor (Prolabo). All the compounds were identified by GC/MS, IR, NMR and gave satisfactory results in comparison with authentic samples. The Knoevenagel condensations between aldehydes and malononitrile in dry media catalyzed by silica gel and ammonium acetate (NH4OAc) basic alumina have been studied. In summary, the method describes a noticeable improvement in reactions conditions for the coumarin synthesis by the Knoevenagel condensation and takes advantage of both solvent free conditions reaction and microwave activation. 42.6% yield 71.3% yield 52.8% yield 49.2% yield 50.2% yield Results Products Dimethyl malonate Aldehyde 39.4% yield 65.3% yield 54.8% yield 44.9% yield 43.6% yield Results Products Diethyl malonate Aldehyde C=O (1700 cm -1 ) (1740.38 cm -1 ) C=C (1650 cm -1 ) (1655.66 cm -1 ) C  O (1100 cm -1 ) (1120.32cm -1 ) C=O (1700 cm -1 ) (1750.11 cm -1 ) C=C (1650 cm -1 ) (1651.64 cm -1 ) C  Br (650 cm -1 ) (655.36cm -1 ) C  O (1100 cm -1 ) (1110.81cm -1 ) C=O (1700 cm -1 ) (1772.1 cm -1 ) C=C (1650 cm -1 ) (1652.7 cm -1 ) C  Br (650 cm -1 ) (651.60cm -1 ) C  O (1100 cm -1 ) (1109.80cm -1 ) Infrared Frequencies Structure C=O (1700 cm -1 ) (1760.46 cm -1 ) C=C (1650 cm -1 ) (1650.34 cm -1 ) C  O (1100 cm -1 ) (1120.55cm -1 ) C=O (1700 cm -1 ) (1760.38 cm -1 ) C=C (1650 cm -1 ) (1650.68 cm -1 ) C  O (1100 cm -1 ) (1120.36cm -1 ) C=O (1700 cm -1 ) (1740.36 cm -1 ) C=C (1650 cm -1 ) (1655.69 cm -1 ) C  O (1100 cm -1 ) (1110.18cm -1 ) Infrared Frequencies Structure C=O (1700 cm-1) (1720.72 cm-1) C=C (1650 cm-1) (1653.34 cm-1) CO (1100 cm-1) (1120.36cm-1 and 1125.68) C=O (1700 cm-1) (1725.50 cm-1) C=C (1650 cm-1) (1653.80 cm-1) CO (1100 cm-1) (1125.56cm-1 and 1128.50) C=O (1700 cm -1 ) (1735.24 cm -1 ) C=C (1650 cm -1 ) (1655.63 cm -1 ) C  O (1100 cm -1 ) (1120.39cm -1 ) C=O (1700 cm -1 ) (1730.80 cm -1 ) C=C (1650 cm -1 ) (1660.79 cm -1 ) C  O (1100 cm -1 ) (1135.33cm -1 ) Infrared Frequencies Structure 7.99(1H, d, J=2.3, H-5), 7.50(1H, dd, J=8.7 and 2.3, H-7), 7.34(1H, d, J=8.7, H-8), 2.67(3H), s, CH3 acetyl), 2.55(3H, s, C2-CH3), and 2.45(3H, s, C6-CH3). methyl 2-methoxy-1-naphthoate 7.39(1H, dd, J=8.2 and 1.1, H-8), 7.37(1H, ddd, J=8.4, 7.1 and 1.1, H-6), 2.63(3H, s, CH3 acetyl), and 2.52(3H, s, C2-CH3). 4-acetyl-3-methoxyisocoumarin 7.72(1H, dd, J=8.8 and 2.4, H-7), 7.29(1H, d, J=8.8, H-8), 3.823(3H) 3-butyryl-4-hydroxycoumarin 10.40 s (1H), 8.44 d(1H), 7.74 d(2H), 7.66 s (1H), 7.45 s (1H), 7.30 s(1H), 3.983 (3H) ethyl 2-methoxy-1-naphthoate 7.79-7.78(Ar), 7.686 (Ar), 7.57-7.44(Ar), 3.823(3H), 1.550 s(2H) 7-methoxy-3-phenyl-4-chromanone 8.29(1H, d,J=2.5, H-5), 7.72(1H, dd, J=8.8 and 2.4, H-7), 7.29(1H, d, J=8.8, H-8), 2.53(3H, s, CH3 acetyl), and 2.86(3H, s, C2-CH3). 5-hydroxy-2-phenyl-4-chromanone 8.14(1H, dd, J=8.4 and 1.6, H-5), 7.64(1H, ddd, J=7.1, 8.2 and 1.6, H-7), 7.39(1H, dd, J=8.2 and 1.1, H-8), 7.37(1H, ddd, J=8.4, 7.1 and 1.1, H-6), 2.63(3H, s, CH3 acetyl), and 2.52(3H, s, C2-CH3). 5-Hydroxy-2-ethyl-1,4-naphthoquinone 8.30(1H, d,J=2.4, H-5), 7.67(1H, dd, J=8.8 and 2.4, H-7), 7.38(1H, d, J=8.8, H-8), 7.36(3H, s, CH3 acetyl), and 2.729(3H, s, C2-CH3). 5-Hydroxy-2-methyl-1,4-naphthoquinone 8.30(1H, d,J=2.4, H-5), 7.76(1H, dd, J=8.8 and 2.4, H-7), 7.33(1H, d, J=8.8, H-8), 2.64(3H, s, CH3 acetyl), and 2.53(3H, s, C2-CH3). 3-probyl-6-bromocoumarine 3.37(3H), 3.47(3H), 5.46(NH), 5.49 (1H), 7.42-7.25 (Ar) 3-acetyl-6-bromocoumarine 3.375 t(3H), 3.398d(2H). Dimethylmalonate 9.966s(1H), 7.440 (Ar,d) , 7.37 (Ar,d), 3.18, (Ar,d), 3.852 s(1H) 2-Hydrovy-5-methylbenzaldehyde 9.850s(1H), 7.540 d(2H)Ar, 7.41 d(2H)Ar, 7.089 d(2H)Ar 2-Hydroxy-4-methoxybenzaldehyde 4.206 d(2H), 3.361 d(2H), 1.285 d(2H). Diethylmalonate 13.12s (1H), 10.725s(1H)Ar, 8.254t(3H)Ar, 7.903 d(2H)Ar, 7.738 d(2H)Ar, 7.540 d(2H)Ar, 7.41 d(2H)Ar, 7.089 d(2H)Ar. 2-Hydroxy-1-napthaldehyde 6.944 (t), 7.005 (Ar, t), 7.473 (Ar,t), 9.858 d(2H), 1.999t(1H) Salicyaldehyde 10.92 s(1H), 9.84 d(2H), 7.66 (Ar, t) ,7.600 (Ar,d) ,7.856t(3H) 4-Bromobenzaldehyde