Final Report Summary - MODUCAT (New modular self-assembled homogeneous catalysts for asymmetric synthesis in water)
Project context and objectives
The need for sustainable, clean methods to produce fine chemicals for use as pharmaceutical intermediates or drugs, avoiding the production of large quantities of waste and toxic solvents, has received much attention during the last 20 years from both the academic and industrial world. Homogeneous catalysts, based on selected transition metals and tailored organic ligands, are considered as the most promising approach to producing large quantities of such important derivatives. By definition, a catalyst can bring about the transformation of large amounts of starting material (substrate) into the desired products without formally taking part in the reaction. As the interaction of drugs with living organisms often involves only one of the possible non-superimposable forms of a molecule (the so-called 'enantiomer'), this means that the catalysts used to produce such transformation must also select which enantiomer to give; in other words it must induce chirality into being an 'asymmetric catalyst'. A drawback in the application of such technology is the complicated synthetic protocols and the high costs of chirally-pure ligands and transition metals, together with the fact that these homogeneous catalysts (i.e. soluble in the reaction media) can be rarely recovered and reused, worsening their cost effectiveness.
Thus replacing conventional methods with new approaches involving asymmetric catalysis is mandatory so as to reduce considerable energy/material costs and the environmental impact of chemical manufacturing. The improvement of both efficiency and selectivity of traditional molecular chiral catalysts is a time-consuming and expensive procedure that may be bypassed by the development of innovative 'modular catalysts'. This project has therefore focused on this task.
The main objectives of the project are:
- to develop the modular assembly of a chiral catalyst consisting of two independent units, separately responsible for activity and enantioselectivity. Such units, assembled together by Coulombic and hydrophobic interactions, should form an innovative catalyst conjugating activity with enantioselectivity;
- to validate the project methodology in model catalytic asymmetric processes carried out in aqueous media. While the few known examples of modular catalysts find application in non-polar media, we proposed to use nanoparticles (NPs) functionalised with self-assembled monolayers (SAMs) of optically active charged molecules to bring about the modular approach in polar solvents. This will avoid the use of large quantities of often toxic organic solvents.
During the project we realised the idea of preparing a chiral modular catalyst for a given catalytic process - asymmetric transfer hydrogenation (ATH) of acetophenone (Acp) - based on the assembly of oppositely charged achiral catalytically active complexes and nanoscopic chiral units. Specifically designed charged nanoscopic objects (NPs and micelles) were assembled with organometallic catalysts in aqueous solutions by means of Coulombic (ES) and van der Waals (vdW) forces to give new entities the properties of both units. Such modular catalysts, being simply an ad-mixture of the two components, were shown to convert Acp into chiral 1-phenylethanol in water. Although the enantiomeric excess (ee) reached so far is moderate (up to 16 %), proof of concept was established, allowing us to extend the modular catalysis approach to aqueous media.
In the first part of the project, we studied gold NPs functionalised with thiolate SAMs. They were shown to be convenient models to study the assembly of oppositely charged nanoscopic objects and catalyst precursors. The aggregation of AuNPs, as a result of their complexation with the catalyst, was monitored by spectroscopic analyses such as UV-vis assisted titrations. This technique exploits the intensive surface plasmon resonance (SPR) band of AuNPs, giving information on the size of the NP/catalyst aggregates. Such information is important for properly designing the catalyst auxiliary group, which is responsible for binding with the NP. In this way, we demonstrated that only the catalysts bearing quaternary ammonium groups with long alkyl chains (C16) are able to form stable complexes with AuNPs having SAM derived from 11-mercaptoundecanoic acid (MUA) coupled with amino-acids. Analysis of the corresponding SPR band gives information on both the stability of the binary NP/catalyst aggregates and of their colloidal form in solution, which in turn helps to determine the applicable range of NP/catalyst ratios to be employed in the real catalytic system.
However some drawbacks of this approach emerged. First of all, it was not possible to use circular dichroism (CD), the common technique available for such studies, for measuring the transfer of chirality information from chiral NP to achiral catalyst in the complex formed. This was due to the presence of intensive SPR band and inter- and intra-band transitions in visible and near ultraviolet regions of the spectrum of the metal NPs. Another disadvantage of using NPs as a chiral additive is that the colloidal stability of the modular catalyst is significantly decreased by strong vdW attraction between NPs, due to their metallic nature. Ultimately, although the densely charged SAM of AuNPs is required to obtain high stability in water, it also prevents the substrate from approaching the chiral surface and the catalytic centre, thus inhibiting enantioselective catalysis. In conclusion, despite the NPs being convenient models for our studies, in order to develop the modular approach in water, they appeared to be inapplicable in real catalytic systems.
On this basis, in the second part of the project, we thought to use chiral micelles to replace NPs in the real catalytic systems. Micelles, although similar to NPs in their structure, have an empty space instead of a metal core. This difference is an advantage for modular catalysis because of the following:
- they should be able to store the hydrophobic substrate inside the micelle and enhance the interfacial substrate/reagents transfer;
- they should be able to re-assemble dynamically and so release the substrate directly to the chiral and catalytically active surface of the micellar catalyst;
- they should be stable in solution in a wide range of catalyst/micelle ratios, ionic strengths and pH ranges, since vdW forces between micelles are negligible compared to NPs;
- CD measurements can be used to read the chirality transfer information from the catalyst/micelle binary aggregates.
All these advantages make chiral micelles the most promising chiral additives to deliver chirality into an achiral catalyst without affecting its activity. In fact, this is the method used by biological systems working in living organisms. In our preliminary experiments we showed that replacing chiral NPs with chiral micelles gives, indeed, a modular catalyst, which is both active and enantioselective in ATH of Acp in water. Further optimisation is required to enhance the transfer of chirality information inside the binary catalyst-micelle and to improve the degree of chiral induction using a careful design of the micelles' structure. In conclusion, the results obtained so far prove unambiguously that the modular catalysis methodology can be achieved.
Main results
The work done in the project's incoming phase by the researcher has provided the validation for the applicability of the concept of modular catalysis for catalytic processes in water. This methodology provides a realistic approach for preparing binary catalysts in polar and aqueous media, thus moving the major drawback towards the application of modular catalysis to sustainable chemistry. The development of an innovative chemical approach for the design of catalytic systems for asymmetric synthesis is going to contribute to the development of sustainable chemistry, which is of potential interest to industrial applications in fine chemical manufacturing on a large scale, as it suggests an environmentally benign methodology based on the design of a new generation of inexpensive, less time-consuming, less laborious and environmentally friendly asymmetric catalysts.
In the returning phase, the researcher will carry on with the optimisation of chiral micelles to establish the adequate size, choice of auxiliary, etc. in order to increase the activity and chiral induction of the process.
The need for sustainable, clean methods to produce fine chemicals for use as pharmaceutical intermediates or drugs, avoiding the production of large quantities of waste and toxic solvents, has received much attention during the last 20 years from both the academic and industrial world. Homogeneous catalysts, based on selected transition metals and tailored organic ligands, are considered as the most promising approach to producing large quantities of such important derivatives. By definition, a catalyst can bring about the transformation of large amounts of starting material (substrate) into the desired products without formally taking part in the reaction. As the interaction of drugs with living organisms often involves only one of the possible non-superimposable forms of a molecule (the so-called 'enantiomer'), this means that the catalysts used to produce such transformation must also select which enantiomer to give; in other words it must induce chirality into being an 'asymmetric catalyst'. A drawback in the application of such technology is the complicated synthetic protocols and the high costs of chirally-pure ligands and transition metals, together with the fact that these homogeneous catalysts (i.e. soluble in the reaction media) can be rarely recovered and reused, worsening their cost effectiveness.
Thus replacing conventional methods with new approaches involving asymmetric catalysis is mandatory so as to reduce considerable energy/material costs and the environmental impact of chemical manufacturing. The improvement of both efficiency and selectivity of traditional molecular chiral catalysts is a time-consuming and expensive procedure that may be bypassed by the development of innovative 'modular catalysts'. This project has therefore focused on this task.
The main objectives of the project are:
- to develop the modular assembly of a chiral catalyst consisting of two independent units, separately responsible for activity and enantioselectivity. Such units, assembled together by Coulombic and hydrophobic interactions, should form an innovative catalyst conjugating activity with enantioselectivity;
- to validate the project methodology in model catalytic asymmetric processes carried out in aqueous media. While the few known examples of modular catalysts find application in non-polar media, we proposed to use nanoparticles (NPs) functionalised with self-assembled monolayers (SAMs) of optically active charged molecules to bring about the modular approach in polar solvents. This will avoid the use of large quantities of often toxic organic solvents.
During the project we realised the idea of preparing a chiral modular catalyst for a given catalytic process - asymmetric transfer hydrogenation (ATH) of acetophenone (Acp) - based on the assembly of oppositely charged achiral catalytically active complexes and nanoscopic chiral units. Specifically designed charged nanoscopic objects (NPs and micelles) were assembled with organometallic catalysts in aqueous solutions by means of Coulombic (ES) and van der Waals (vdW) forces to give new entities the properties of both units. Such modular catalysts, being simply an ad-mixture of the two components, were shown to convert Acp into chiral 1-phenylethanol in water. Although the enantiomeric excess (ee) reached so far is moderate (up to 16 %), proof of concept was established, allowing us to extend the modular catalysis approach to aqueous media.
In the first part of the project, we studied gold NPs functionalised with thiolate SAMs. They were shown to be convenient models to study the assembly of oppositely charged nanoscopic objects and catalyst precursors. The aggregation of AuNPs, as a result of their complexation with the catalyst, was monitored by spectroscopic analyses such as UV-vis assisted titrations. This technique exploits the intensive surface plasmon resonance (SPR) band of AuNPs, giving information on the size of the NP/catalyst aggregates. Such information is important for properly designing the catalyst auxiliary group, which is responsible for binding with the NP. In this way, we demonstrated that only the catalysts bearing quaternary ammonium groups with long alkyl chains (C16) are able to form stable complexes with AuNPs having SAM derived from 11-mercaptoundecanoic acid (MUA) coupled with amino-acids. Analysis of the corresponding SPR band gives information on both the stability of the binary NP/catalyst aggregates and of their colloidal form in solution, which in turn helps to determine the applicable range of NP/catalyst ratios to be employed in the real catalytic system.
However some drawbacks of this approach emerged. First of all, it was not possible to use circular dichroism (CD), the common technique available for such studies, for measuring the transfer of chirality information from chiral NP to achiral catalyst in the complex formed. This was due to the presence of intensive SPR band and inter- and intra-band transitions in visible and near ultraviolet regions of the spectrum of the metal NPs. Another disadvantage of using NPs as a chiral additive is that the colloidal stability of the modular catalyst is significantly decreased by strong vdW attraction between NPs, due to their metallic nature. Ultimately, although the densely charged SAM of AuNPs is required to obtain high stability in water, it also prevents the substrate from approaching the chiral surface and the catalytic centre, thus inhibiting enantioselective catalysis. In conclusion, despite the NPs being convenient models for our studies, in order to develop the modular approach in water, they appeared to be inapplicable in real catalytic systems.
On this basis, in the second part of the project, we thought to use chiral micelles to replace NPs in the real catalytic systems. Micelles, although similar to NPs in their structure, have an empty space instead of a metal core. This difference is an advantage for modular catalysis because of the following:
- they should be able to store the hydrophobic substrate inside the micelle and enhance the interfacial substrate/reagents transfer;
- they should be able to re-assemble dynamically and so release the substrate directly to the chiral and catalytically active surface of the micellar catalyst;
- they should be stable in solution in a wide range of catalyst/micelle ratios, ionic strengths and pH ranges, since vdW forces between micelles are negligible compared to NPs;
- CD measurements can be used to read the chirality transfer information from the catalyst/micelle binary aggregates.
All these advantages make chiral micelles the most promising chiral additives to deliver chirality into an achiral catalyst without affecting its activity. In fact, this is the method used by biological systems working in living organisms. In our preliminary experiments we showed that replacing chiral NPs with chiral micelles gives, indeed, a modular catalyst, which is both active and enantioselective in ATH of Acp in water. Further optimisation is required to enhance the transfer of chirality information inside the binary catalyst-micelle and to improve the degree of chiral induction using a careful design of the micelles' structure. In conclusion, the results obtained so far prove unambiguously that the modular catalysis methodology can be achieved.
Main results
The work done in the project's incoming phase by the researcher has provided the validation for the applicability of the concept of modular catalysis for catalytic processes in water. This methodology provides a realistic approach for preparing binary catalysts in polar and aqueous media, thus moving the major drawback towards the application of modular catalysis to sustainable chemistry. The development of an innovative chemical approach for the design of catalytic systems for asymmetric synthesis is going to contribute to the development of sustainable chemistry, which is of potential interest to industrial applications in fine chemical manufacturing on a large scale, as it suggests an environmentally benign methodology based on the design of a new generation of inexpensive, less time-consuming, less laborious and environmentally friendly asymmetric catalysts.
In the returning phase, the researcher will carry on with the optimisation of chiral micelles to establish the adequate size, choice of auxiliary, etc. in order to increase the activity and chiral induction of the process.