Chemoselective Hydrogenation Of Fragrance Precursor Using H-Cube® Continous Flow Reactor

H-Cube® Application Note

The following application note demonstrates how ThalesNano’s H-Cube® flow reactor proved to be a paradigm change for safe, fast, and easy to use hydrogen catalyst screening for Givaudan.

INTRODUCTION

Chemoselective hydrogenation of fragrance precursors opens up the way to a vast variety of new candidates for olfactory screening. Their chemical syntheses are not only making them cheaper but they are also saving the natural resources of such compounds. Using this method, novel, unique odor characteristics can be made that are not synthesized in nature. In the following application note we will introduce selective hydrogenation reactions that were in Givaudan’s research scope. Each of the presented molecules hereby fall under the groups of such odor substances that are of great importance from fragrance industrial perspectives. The studied compounds are mainly alkenols; unsaturated and cyclopropanated carbonyls (e.g. derivatives and precursors of Pashminol™, cis-Javanol, Melonal™ etc).

Alkenyl – Cyclopropanecarbinols

‘Substantivity’ is of great importance in fragrance chemistry. The term refers to the perfume materials’ persistence capability on the intended field of application such as skin, hair, garment, etc. One method of increasing the substantivity of a certain fragrance compound is to increase its molar mass in such a way that the transformation does not have a major impact on the molecule’s conformation. Therefore, the shape of the molecule, a factor of key importance for odor sensation, remains similar and its vapor pressure is decreased due to the elevated molar mass. Modified new substances may result in a longer-lasting effect with similar odor characteristics. A well-tried method for increasing substantivity is the cyclopropanation of alkene-related fragrance precursors. This type of transformation does not modify the conformation of the unsaturated functionalized terpenes that much as long as they are synthesized under stereospecific Simons–Smith conditions. Chemoselective hydrogenation of a partially cyclopropanated diene or polyene may pose a challenging task due to possible cyclopropane cleavage side reactions. This is what Givaudan’s chemists were faced with during Pashminol™ synthesis.

Table 1. demonstrates some selected results of catalyst screening in the selective hydrogenation of a Pashminol™ precursor. Schröder et al. found that, even though Raney Nickel and Pd/CaCO3 proved to be very efficient catalysts with a nearly quantitative substrate conversion and minor cyclopropane cleavage, the 5% Pt/C catalyst gave the best results for leaving the cyclopropyl moiety untouched.

Other substrates were also screened with similar catalysts and the most effective catalyst for a given substrate is listed in Table 2. Entry 7 was also tested with Pd/CaCO3and Pt/C catalysts, but it was only Raney Nickel that left the hydroxyl group untouched, avoiding deoxygenation.

EntryCatCart®T/pOccurance in product
Substrate (1)Cyclopropane cleavage (2)PashminolTM
110% Pd/C25 °C/1 bar3 %5 %73 %
25% Pd/Al2O325 °C/1 bar17 %15 %53 %
35% Pt/C25 °C/1 bar1 %0 %84 %
4Raney Nickel80 °C/1 bar2 %1 %87 %
55% Pd/CaCO325 °C/1 bar1 %1 %83 %

Table 1: Selected examples of catalyst screening in Pashminol™ synthesis

EntrySubstrateCatalystProduct
1Substrate 1Pd/CaCO3Product 1
2Substrate 2Product 2
3Substrate 3Product 3
4Substrate 4Product 4
5Substrate 5Product 5
6Substrate 6Product 6
7Substrate 7Raney NickelProduct 7
8Substrate 8Pt/CProduct 8

Table 2: Selective hydrogenation of alkenes in the presence of cyclopropylcarbinols or allyl alcohols.

Unsaturated Aldehydes

In case of unsaturated aldehydes, displayed in Table 3, Pt/CaCO3 and Pd/CaCO3 left the aldehyde function untouched. Raney Nickel caused a selective aldehyde function reduction under mild reaction conditions. However, at elevated pressures and temperatures the same catalystceased being selective anymore and triggered further saturation in the screened substance. Pd/C had a relatively unselective and drastic saturating effect on the dienal substrate (entry 4). During the hydrogenation of conjugated aldehydes in the H-Cube® flow reactor, Pd/CaCO3 proved to be an effective catalyst for selectively saturating the carbon-carbon double bond. Ru/C hadan unselective hydrogenation effect (entry 4). See below in Table 4.

EntrySubstrateCatalystProduct
1Substrate 1Pt/CaCO3Product 1
2Substrate 2Raney NickelProduct 2
3Substrate 3Raney Nickel (Higher T and p)Product 3
4Substrate 4Pd/CProduct 4
5Substrate 5Pd/CaCO3Product 5
6Substrate 6Pd/CProduct 6

Table 3: Selective hydrogenation of unsaturated aldehydes.

EntrySubstrateCatalystProduct
1Substrate 1Pt/CaCO3 (100 °C)Product 1
2Substrate 2Pt/CaCO3Product 2
3Substrate 3Pt/CaCO3Product 3
4Substrate 4Ru/C(90 °C/90 bar)Product 4

Table 4: Selective hydrogenation of conjugated aldehydes.

Unsaturated Ketones

In the case of using Pd/CaCO3 for the presented cyclopropylketone hydrogenation in Table 5 (entry 1) a cyclopropyl cleavage occurs first due to the neighboring group effect of the alkene, then the resulting alkene is reduced giving the saturated ketone. However in the case of using Raney Nickel with the same substrate (entry 2), the alkene hydrogenation occurs first, which makes the possible cyclopropylketone relatively inert against cleavage.

Quantitative Raney Nickel hydrogenation of cyclododeca-4,8-dienone gave the monoalkene with 46% selectivity, against 25% of substrate and 26% of cyclododecanone. Pd/C and Lindlar’s catalyst tested on the same substrate gave exclusively cyclododecanone. Reducing raspberry ketone’s benzene ring to the cyclohexanone moiety was achieved using Pd(OH)2/C (entry 5). Rh/Al2O3 yielded a complex product composition with the same substrate (entry 6).

EntrySubstrateCatalystProduct
1Substrate 1Pd/CaCO3Product 1
2Substrate 2Raney NickelProduct 2
3Substrate 3Raney NickelProduct 3
4Substrate 4Pd/CLindlarProduct 4
5Substrate 5Pd(OH)2 90 °CProduct 5
6Substrate 6Rh/Al2O3Product 6

Table 5: Selective hydrogenation of unsaturated ketones.

Alkenols

With alkenols, only Pd/C catalyst effected a complete conversion on the studied substrates using H-Cube®. It is worth noting that Pd/C did not trigger deoxygenation in the sensitive tertiary alcohols displayed in Table 6.

EntrySubstrateCatalystProduct
1Substrate 1Pd/CProduct 1
2Substrate 2Product 2
3Substrate 3Product 3
4Substrate 4Product 4
5Substrate 5Pd/CaCO3Product 5
6Substrate 6Product 6

Table 6: Selective hydrogenation of alkenols

SUMMARY

It was demonstrated that the H-Cube® flow reactor alongwith a wide range of supplemental CatCarts® proved to be a paradigm change for safe, fast and easy catalyst screening for the Flavour & Fragrance chemistry and facilitated Givaudan’s research challenges to be addressed. As aresult of their efforts they have succesfully developed avast number of selective hydrogenation reactions, whoseproducts are of great importance from commercial as-pects. In this demonstration the first generation hydroge-nation apparatus of ThalesNano, the H-Cube®, was used.The new generation version of this device, the H-CubePro, could also be used for this purpose. The Phoenix Flow Reactor, the new, high temperature flow reactor is also very useful for similar catalyst screening processes.

ACKNOWLEDGEMENTS

We would like to thank Dr. Fridtjof Schröder for presenting at our user group meeting, his constant help in our work and his friendship. Your contribution is highly valued!

REFERENCE

Brunner, G; Elmer, S; Schröder, F; Transition-Metal-Catalyzed Cyclopropanation of Nonactivated Alkenes in Dibromomethane with Triisobuthylaluminium; Eur. J. Org. Chem ; 2011; 4623-4633

LEGAL

Pashminol and Melonal are trademarks of GivaudanS.A. CatCart and H-Cube are registered trademarks of ThalesNano Inc. H-Cube Pro is a trademark ofThalesNano Inc.