Heterogeneous organocatalysis: the proline case

Abstract

Asymmetric catalysis has allowed organic chemists to synthesize chiral molecules, such as amino acids, nucleic acids, sugars, and drugs. To achieve this, it is common to use a chiral catalyst to selectively accelerate the reaction. In the early days, it was believed that there were two main types of effective asymmetric catalysts: enzyme complexes and transition metal complexes. However, with the emergence of organocatalysis and the consequent introduction of a new category of highly effective asymmetric catalysts based solely on organic compounds, there was a revolution in the field of asymmetric catalysis. An excellent example of this innovation is l-proline, a fascinating molecule that demonstrates the transformative impact of organocatalysis. Organocatalysis presents itself as a simpler synthetic tool than other methodologies, however, despite being widely used in the research environment, it has not yet reached large-scale production. This gap occurs mainly due to the methodology working in a homogeneous phase together with the rest of the reagents involved. Although this does not present a problem on a laboratory scale, the recovery and reuse of the catalyst can be an obstacle in industrial processes. In recent years, with a view to some industrial uses, there has been an effort to make the immobilization (also called heterogenization) of organocatalysts possible. Such modified systems have broad catalytic applications in several organic transformations. Taking this into consideration, this review has the general objective of investigating the application of different supports in the immobilization of the classical organocatalyst l-proline, synthesized and characterized by three different methodologies, namely: impregnation, intercalation and grafting.

Fig. 1. The three pillars of asymmetric catalysis: biocatalysis, metal catalysis and organocatalysis.

Fig. 2. (A) Modes of action in proline catalysis. (B) Proline can activate carbonyls to make them more reactive and control reaction geometry – for example, in aldol reactions.

Fig. 3. Catalyst immobilization methods on solid supports.

Scheme 1. Methodology applied in the synthesis of MCM41-C catalyst.

Scheme 2. Aldol condensation between hydroxyacetone (2B) and different aldehydes (2A_1–5) catalyzed by l-proline or mesoporous material.

Fig. 4. Heterogeneous proline catalysts MCM41-Pro and MCM41-Pro(C) supported on mesoporous material.

Scheme 3. Reaction of 4-nitrobenzaldehyde (3A) with 2,2-dimethyl-1,3-dioxan-5-one (3B) used as standard model in the presence of MCM41-Pro.

Scheme 4. Synthesis of the MCM41-Pro(C) catalyst, exchange of the urea ligand for the new carbamate ligand.

Scheme 5. Preparation of the immobilized catalysts 5C₁ and 5C₂.

Scheme 6. Direct enantioselective α-aminoxylation of propanal (6A) catalyzed by resins 5C₁ and 5C₂.

Scheme 7. Synthetic route for SBA-15-APTES, Al-SBA-15-APTES, SBA-15-PYRRO, and Al-SBA-15-PYRRO.

Scheme 8. Test reaction for Knoevenagel reaction over different catalysts.

Scheme 9. Test reaction for one-pot deacetalization-Knoevenagel.

Scheme 10. Test reaction for one-pot deacetalization-Henry reaction.

Scheme 11. Test reaction from nitroaldol reaction.

Scheme 12. Test reaction from nitroaldol reaction.

Scheme 13. Synthetic route for the preparation of SSLP catalyst.

Scheme 14. (A) Test reaction between isatin, barbituric acid, malononitrile to form spirooxindole product. (B) Spirooxindole derivatives analogues.

Scheme 15. Proposed mechanism for the synthesis of spirooxindole derivatives using SSLP catalyst.

Scheme 16. Illustration of proline functionalized silica gel. (1) Overnight (2) ethyl chloroformate, triethylamine, CH₂Cl₂, 0 °C to rt, overnight (3) trifluoroacetic acid, CH₂Cl₂, rt.

Scheme 17. Illustration of the aldol reaction triggered by Si-LP (the catalyst was in a silica-packed chromatographic column eluted with dehydrated ethanol at rt and at atmospheric pressure at a flow rate of around 0.1 mL min⁻¹).

Scheme 18. Illustration of reaction to obtain mechanism considerations.

Scheme 19. Schematic diagram for the heterogenization of homogeneous linear chiral catalysts within the cavities of MOFs via in situ polymerization to afford chiral polymer/MOF composites (R) (taken from Dong, 2018).

Scheme 20. Test asymmetric direct aldol reaction.

Scheme 21. Preparation of the Pro/MWCNTs nanocatalyst.

Scheme 22. Schematic reaction tests for synthesis of 2-amino-3-cyano-4H-pyrans analogues 22C.

Scheme 23. Preparation of the magnetic nanocatalyst.

Scheme 24. Synthesis of 2,4,6-triarylpyridines analogues in the presence of LPSF nanocatalyst.

Scheme 25. Methodology for obtaining supported proline material.

Fig. 5. Supported asymmetric ionic liquid catalysis.

Scheme 26. Reagents and conditions for synthesis of supported ionic liquids.

Fig. 6. Catalytic systems studied.

Fig. 7. Reaction carried out using the systems (26C₁/bmimBF₄/pro) or (26C/4MBPBF₄/pro).

Scheme 27. Illustration of the preparation of the l-proline/GO hybrid. The red arrows demonstrate hydrogen bonds.

Scheme 28. Direct asymmetric aldol reaction between acetone and 2-nitrobenzaldehyde over different l-proline catalysts.

Scheme 29. Preparation of the catalyst via immobilization of the l-prolinate anion cationic polymer resin.

Scheme 30. Optimal condition for reaction with a series of aromatic aldehydes containing different substituent groups using 10 mol% [Amb]l-Prolinate in ethanol under reflux.

Scheme 31. Mechanistic proposal for the formation of 4H-pyrano[2,3-c]pyrazole using the [Amb]l-Prolinate catalyst. A = benzaldehyde; B = malononitrile and C = 3-methyl-1-phenyl-4,5-dihydro-1H-pyrazol-5-one.

Scheme 32. Preparation of silica-supported l-proline (SiO₂-l-proline).

Scheme 33. Benzylidene test reactions.

Scheme 34. Synthesis of heterogeneous catalyst-supported l-proline based on supramolecular interactions and free radical polymerization.

Scheme 35. Aldol reaction between acetone and 4-nitrobenzaldehyde catalyzed by different catalyst systems for 24 h in DMF (catalysts 10 mol%).

Scheme 36. Effect of solvents on reactions at 80 °C for 21 h (catalysts 20 mol%).

Scheme 37. Preparation pathway of graphene oxide GO/Fe₃O₄/l-proline nano hybrid.

Scheme 38. Test reaction for investigation of catalytic activity of GO/Fe₃O₄/l-pro for the synthesis of bis-pyrazole under various conditions.

Scheme 39. Synthesis of alcohol-functionalized ionic liquid [HEMIM][BF₄⁻].

Scheme 40. Synthesis of the organocatalyst IL-P immobilized in l-proline ionic liquid.

Scheme 41. Optimization of the Mannich reaction.

Scheme 42. Proposed mechanism for the transition state for Mannich reaction using organocatalyst IL-P.

Fig. 8. The schematic model of l-proline/MWCNTs.

Scheme 43. Aldol reaction of acetone and 4-nitrobenzaldehyde catalyzed by l-proline/MWCNTs.

Scheme 44. Proline immobilization by directly solvothermal method.

Scheme 45. Aldol reaction test.

Fig. 9. (a) The synthesis and structure of chiral [4 + 8] tetrameric cage CPOC-401-Pro. (b) The synthesis and structure of chiral [6 + 12] hexameric cage CPOC-302-Pro. Hydrogen atoms have been omitted for clarity (taken from Xu, 2022).

Scheme 46. Asymmetric aldol reactions catalyzed by chiral POCs.

Scheme 47. The schematic representation of aldol reaction between benzaldehyde and acetone.

Fig. 10. The schematic model of l-Pro LDHs (molar ratio of Mg/Al = 3 : 1).

Scheme 48. Preparation of spiroheterocycles through the Mannich reaction.

Fig. 11. Structural model of l-proline-intercalated LDHs.

Scheme 49. Test reaction using re-M_xAl-LDHs catalysts.

Fig. 12. Proposed catalytic cycle for the aldol condensation reaction with the Mannich pathway.