Identifying the best rhodium-modified catalyst and the best reaction conditions with ChemSCAN for the synthesis of aroma compounds

Table of Contents

• Introduction
• Materials and Method
• Results and Discussion
• Conclusion

Introduction

In the perfumery industry, there is a constant need to provide compounds imparting novel organoleptic notes. Aldehydic notes, which represent one of the key organoleptic facets of the lily of the valley odor are of particular interest. 3-(cyclohex-1-en-1-yl)propanal derivatives represent compounds imparting note of the muguet-aldehydic olfactive family. However, access to these derivatives is cumbersome and requires Grignard reagents, radical chemistry, or pyrolysis, to deliver the desired compounds with low yield and/or selectivity.^[1]

The selective hydroformylation of 4,4-dimethyl-1-vinylcyclohexyl acetate could provide the desired 3-(cyclohex-1-en-1-yl)propanal derivative. During this study the hydroformylation of 4,4-dimethyl-1-vinylcyclohexyl acetate was investigated using a ChemSCAN to identify the most appropriate rhodium catalyst and best reaction conditions. Different ligands were evaluated in fast parallel experiments, allowing the selection of the most active and selective catalyst. Subsequent concurrent experiments enabled to find the best reaction conditions for the appropriate scalable synthesis of the desired fragrance.

H.E.L’s ChemSCAN is a bench-top advanced parallel screening platform, designed to accelerate process development. Controlled by H.E.L’s WinISO, it enables fully automated, high-throughput investigations. ChemSCAN allows researchers to efficiently investigate reactions conditions, and optimize processes with great precision and speed. By offering precise control over variables such as temperature, pressure, and mixing, ChemSCAN enables reproducible results and enhances overall productivity in chemical research and development.

The aim of this study was the identification of the most suitable rhodium catalysis and the ideal conditions using H.E.L’s ChemSCAN capabilities.

Materials and Method

For the catalytic test, a ChemSCAN was used within a fume hood. The substrate 4,4-dimethyl-1-vinylcyclohexyl acetate was provided by Firmenich International SA. Precatalysts and ligands solutions were prepared under an argon atmosphere using standard Schlenk techniques. The solvents were dried by conventional procedures and distilled under an argon atmosphere. The structure of products was confirmed by NMR measurements on Bruker AV 300, AV 400, or AV 500 MHz spectrometers. Gas chromatography was performed on an Agilent 7890 A Series equipped with an HP5 column (30 m x 0.25 mm ID, 0.25µm film) using tetradecane as the internal standard.

General hydroformylation procedure:

4,4-dimethyl-1-vinylcyclohexyl acetate, Ligand (in EtOAc) and Rh(acac)(CO)₂ (in EtOAc) were added to an autoclave (H.E.L. ChemSCAN). The autoclave was purged 3 times with 8 bar Argon and 4 times with 10 bar syngas (H₂:CO, 1:1) under stirring (500 rpm). The autoclave was then charged with 10 bar syngas and the reaction mixture was heated until the temperature raised to 5°C under the target value. The autoclave was then further pressurized with syngas to the target pressure, the stirring rate adjusted at 900 rpm and the temperature was set to final value. The hydroformylation was continued compensating the gas uptake with H₂:CO (1:1). After the indicated reaction time, the mixture was cooled to room temperature, the pressure released, and the autoclave was purged 5 times with 12 bar Argon. Product analysis was performed by gas chromatography using tetradecane as internal standard.

Results and Discussion

Scheme 1. Hydroformylation of 4,4-dimethyl-1-vinylcyclohexyl acetate.

The hydroformylation of 4,4-dimethyl-1-vinylcyclohexyl acetate was evaluated by parallel screening of several ligands (Scheme 1). Some results of the reaction outcome using different ligands are shown in Table 1. Full conversion and excellent selectivity were achieved when bidentate diphosphite ligand BiPhePhos was used. The rhodium-modified catalyst with bidentate diphosphine Xantphos-type ligands showed lower activity but still good selectivity towards the desired n-Aldehyde 1. Other more flexible bidentate diphosphine ligands like BISBI and DPEphos did not show a good performance.