Linear amino acids covalently supported on graphene sheet were employed as catalysts for asymmetric aldol reactions between cyclohexanone and aldehydes (aliphatic and/or aromatic) in a batch type reactor in the presence of water. The reactions were found to exhibit high yield as well as excellent ee value. Additionally, the catalysts were found to be truly heterogeneous and eco-friendly.
Recently, linear amino acids have been extensively investigated as effective homogenous catalysts in asymmetric aldol reactions between ketone and aldehyde in the presence of polar solvents [
Graphene sheet (supplied by Chengdu Organic Chemicals Co. Ltd.) were functionalized by modified Hummer and Offeman’s method [
Notably, new peaks were observed at around 1248, 1310, 930, and 1640 cm−1, which reveal the presence of (-C-O-C-), (C-N), (C-C), and acid amide groups, respectively. This entire process was repeated for preparing all other catalysts. Hereafter, the catalysts are referred to as catalyst A, B, C and D where A, B, C and D are L-alanine, L-serine, L-valine, and L-arginine covalently immobilized on graphene sheet respectively.
Scheme 1. A generalized scheme for covalently immobilizing amino acids on graphene sheet.
50 mg of catalyst, 10 mL distilled water, 3.3 equiv cyclohexanone and 1.0 equiv aldehyde were loaded to three necked batch reactor. The reaction mixture was stirred at 40˚C for 24 hours as shown in Scheme 2. The reaction was periodically monitored by TLC (Rf = 0.27 for 2-(hydroxy(phenyl)methyl) cyclohexanone in ethyl acetate/n-hexane solvent system). Finally, the mixture was extracted with ethyl acetate. Column chromatography on silica gel using ethyl acetate/n-hexane (1:9) gave pure aldol product while anti/syn was determined by 1H NMR analysis, and ee value was determined by Agilent 1100 HPLC with Daicel Chiralpak AS, OJ, and AD columns.
Remarkable improvement in the catalytic potential of linear amino acids has been attained by immobilizing them covalently on functionalized graphene. Therefore, a persistent struggle for developing new methodologies to synthesize chiral heterogeneous catalysts that could provide high % yield and ee value, is underway [
Catalysts A, B, C and D are capable of catalyzing the direct asymmetric aldol reactions in aqueous medium through enamine mechanism. The presence of water in the aldol reaction increases the rate of reaction in comparison to the reaction carried out under solvent free condition. An explanation to this effect is that the presence of water facilitates the hydrolytic detachment of amino acid from the resulting product of the aldol reaction [
These catalysts were also used for aldol reaction of cyclohexanone and m-nitrobenzaldehyde, affording both high % yield and % ee value as shown in
Experiments were extended further to study the catalytic efficiency of these catalysts for aldol reaction between cyclohexanone and 3-methylbutanal. Again the results were quite impressive both in terms of % yield and ee value as shown in
Scheme 2. Model reaction of cyclohexanone and benzaldehyde to 2-(hydroxy(phenyl) methyl) cyclohexanone, catalysed by L-alanine covalently immobilized on graphene.
3-methylbutanal generating 65% yield and 80% ee while in the presence of catalysts “B”, “C” and “D”, the same reaction resulted in (53% yield and 78% ee), (58% yield and 81% ee) and (44% yield and 56% ee).
The stereochemistry of the β-hydroxy group of the aldol adducts derived by L-linear amino acid supported on graphene sheet is R as demonstrated by chiral-phase HPLC analysis, optical rotation and compared with the literature [
Linear amino acid covalently immobilized on graphene sheet catalyzed asymmetric intermolecular aldol reaction of aldehyde and ketones through enamine route [
X: graphene sheet.
Scheme 3. Reaction route.
of the intermediate of the enamine catalytic cycle. These results provide clear evidence that acyclic amino acids covalently immobilized on graphene are remarkable chiral organo-catalysts, capable of catalyzing the direct asymmetric aldol reaction with excellent reactivity and stereoselectivity. Throughout the study, water was the only solvent. The catalysts showed good stability in solvent and recycled by simple filtration and used for five runs without coming across any loss in their catalytic efficiency.
Linear amino acids covalently supported on graphene sheet can function as remarkable heterogeneous organo- catalysts for the direct asymmetric aldol reactions between cyclohexanone and aldehydes with excellent reactivity and stereoselectivity. All these catalysts generated high yield as well as high ee value for m-nitrobenzalde- hyde in comparison with those for benzaldehyde and 3-methylbutanal. This improved efficiency of catalysts in the case of m-nitrobenzaldehyde most probably due to the presence of electron withdrawing group. In case of reaction between cyclohexanone and 3-methylbutanal, the catalysts manifest moderate % yield and ee value. All these findings provide sufficient evidence for the effectiveness of linear amino acids supported on graphene sheet as useful, eco-friendly and heterogeneous catalysts for direct asymmetric aldol reactions.
The authors greatly acknowledge the financial support of High Education Commission of Pakistan, Project No. 20-1897/NRPU/R&D/HEC/116806 and Project No: 20-1604/R&D/092198, under National Research Programme for Universities.