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Stereoselective Synthesis of Alicylic Amines

S. David Jackson, K. F. Graham, K. T. Hindle, D. J. M. Williams, and S. Wuttke. WestCHEM, Department of Chemistry, University of Glasgow, Joseph Black Building, University Avenue, Glasgow, G12 8QQ, United Kingdom

Abstract: The liquid phase hydrogenation of para-alkylaromaticamines over 2.5 % wt Rh/SiO2 catalysts yields both cis and trans isomeric forms of para-alkylcyclohexylamines. Reaction temperature and solvent affect the cis/trans ratio of isomers. This ratio varies between 4.5 for methanol and 1.7 for 2,2,4-trimethylpentane equivalent to an increase in stereochemical excess from 63 to 82 %. Catalyst metal crystallite size, temperature and solvent also alter the rates of reaction. Using a combination of solvent and metal crystallite size, it is possible to increase yields of the desired cis isomer by 40-fold.

Keywords: Stereoselective hydrogenation, solvent, alicylic amines


Alicyclic amines such as 4-methylcyclohexylamine and 4-tert-butylcyclohexylamine are commonly used for the manufacture of pesticides, plasticisers, explosives, sweetening agents and as intermediates in the pharmaceutical industry. The current synthesis of alicyclic amines does not utilise a heterogeneously catalysed route. The advantages for industry include an enhanced throughput, improved product selectivity and a cleaner, greener chemical process.


The catalysts (2.5 % wt Rh/SiO2) were prepared by Johnson Matthey using supports supplied by Grace Davison. The hydrogenation of para-alkylaromaticamines was performed in a Büchi stirred tank batch reactor. Hydrogen pressure was set to 2 bar g and stirrer speed set at 1000 rpm. The autoclave was charged with 2 g of catalyst and 0.3 L of solvent. After an in-situ reduction of the catalyst, 4-methylaniline or 4-tert-butylaniline (0.0196 mol) was added.

Results and discussion

Higher reaction temperatures increase the rate of hydrogenation and decrease the cis/trans ratio of products in line with kinetic and thermodynamic expectations. As metal crystallite size increases so does Turn-Over Frequency (TOF). This unusual antipathetic particle size effect suggests hydrogenation is preferred at plane face/terrace sites rather than edge or corner sites. The rate of hydrogenation for both 4-methylaniline and 4-tert-butylaniline tends to zero at ~0.35nm (Figure 1).

The rate of 4-methylaniline and 4-tert-butylaniline hydrogenation has been monitored in polar primary and secondary alcohols and non-polar solvents. The reaction rates vary by an order of magnitude depending on the solvent used. The maximum reaction rate is achieved when using propan-2-ol. The ‘hydrogen-donor' characteristics of polar secondary alcohols provide an additional source of molecular hydrogen, an effect reported for alkene hydrogenations. The ratio of cis/trans isomers is proportional to the dielectric constant of the solvent (Figure 2). As dielectric constant increases the polarity of the solvent also increases. This affects the relative thermodynamic stability not of the final products but of the partially hydrogenated enamine and imine intermediates. The imines hydrogenate to the respective cis isomer. At higher reaction temperatures the cis/trans ratio of products tends towards the thermodynamic equilibrium of <1.


Using a combination of metal crystallite size, solvent and temperature it is possible to control catalyst activity and stereoselectivity independently. This allows the yield of the desired cis isomer to be enhanced 40-fold. Control of the catalytic chemistry provides the potential for developing a new industrial process for the production of alicyclic amines.