high-throughput experimentation as a tool in catalyst design for the reductive amination of...

Applied Catalysis A: General 254 (2003) 77–84

High-throughput experimentation as a tool in catalystdesign for the reductive amination of benzaldehyde

Silvia Gomeza, Joop A. Petersa, Jan C. van der Waala,b, Thomas Maschmeyera,∗a Laboratory of Applied Organic Chemistry and Catalysis, DelftChemTech, Delft University of Technology,

Julianalaan 136, 2628 BL Delft, The Netherlandsb Avantium Technologies BV, Zekeringstraat 29, 1014 BV, P.O. Box 2915, 1000 CX Amsterdam, The Netherlands

Received 15 August 2002; accepted 25 November 2002

Abstract

A combinatorial library of 24 carbon-supported noble metal catalysts is screened for reductive amination of benzaldehydein the presence of ammonia. Gas chromatography is used to rapidly quantify the product yields and selectivities obtainedwith the different candidates. The results show that the catalytic activity is strongly influenced by, both, the nature of thesupport and the nature of the metal. The activity is higher when the parent support, SX1G, has been treated by oxidationand subsequent sodium-exchange. With regard to the metal, the activity decreases in the order of Ru, Pd, Pt. Surprisingly,Ru-based catalysts, which do not rank among the most commonly used for reductive amination processes, show the highestactivity. The selectivity to a particular amine is controlled essentially by the nature of the metal. Benzylamine is the majorproduct obtained over Ru-based catalysts, while dibenzylamine is formed preferentially over Pd-based catalysts. Conventionalmethods are in complete agreement with the trends observed by high-throughput techniques. Consequently, high-throughputexperimentation allows the discovery of new catalysts for a given reaction by shortening considerably the catalyst optimisationtime.© 2003 Elsevier Science B.V. All rights reserved.

Keywords: Benzaldehyde; High-throughput screening; Reductive amination; Selectivity; Supported catalysts

1. Introduction

The reduction of benzaldehyde with hydrogen inthe presence of ammonia results in the formation of amixture of primary and secondary amines, due to thehigh reactivity of the partially hydrogenated interme-diate dibenzylimine (DBI). As long as benzaldehyde ispresent in the reaction mixture, any benzylamine (BA)formed is converted into dibenzylimine. Dibenzylim-ine is subsequently hydrogenated to dibenzylamine

∗ Corresponding author. Tel.:+31-15-2785029;fax: +31-15-2781415.E-mail address: [email protected] (T. Maschmeyer).

(DBA) or undergoes a transimination reaction withammonia to yield benzylimine and benzylamine afterwhich benzylimine is also converted to benzylamine(seeScheme 1) [1]. In addition, direct hydrogenationof the starting compound, benzaldehyde, results inthe formation of benzyl alcohol and/or toluene. Bothbenzylamine and dibenzylamine are industrially in-teresting compounds used in rubber compounding, ascorrosion inhibitors and as intermediates in pharma-ceuticals. Improving the selectivity of the process toeither 100% BA or 100% DBA is, consequently, veryattractive.

Obviously, the selectivity towards either BA orDBA can partly be controlled by the molar ratio of

0926-860X/$ – see front matter © 2003 Elsevier Science B.V. All rights reserved.doi:10.1016/S0926-860X(03)00278-3

78 S. Gomez et al. / Applied Catalysis A: General 254 (2003) 77–84

Scheme 1. Reaction mechanism for the reductive amination of benzaldehyde.

benzaldehyde and ammonia chosen for the reaction.Furthermore, the choice of the catalyst is an importantparameter in this respect. It is generally assumed thatthe conversion of the reaction and the composition ofthe final product are mainly determined by the metalcomponent of the catalyst[2–5]. Raney nickel hasproved to be very suitable for the reductive aminationof benzaldehyde in the presence of ammonia[6,7].However, it has relevant disadvantages such as thelow selectivity for either BA or DBA, its fragility, itslack of safety, and the elevated temperatures and pres-sures that it requires. Lately, more resistant supportedor unsupported noble metals have been suggestedas alternative catalysts for this process, which allowmilder conditions and result in high yields and purities[8,9].

The support can also affect catalytic activity andselectivity. One of the most significant advantagesof activated carbon as a support is its susceptibil-ity to be modified by oxidative treatments to obtaindifferent amounts of oxygenated surface groups, andconsequently, different acidities and hydrophilicities[1,10–12].

The optimisation of the heterogeneous catalysts fora given transformation is mostly achieved by the sys-tematic variation of the catalytically active metals andof the nature of the support. In a traditional optimisa-tion process, the catalysts are tested and re-tested foractivity until no further improvements are found by us-ing laborious, time-consuming and often one-at-a-timemethods. In addition, this type of research is usu-ally carried out by different workers, rendering precisecomparisons a difficult task.

High-throughput experimentation has shown to bean exceptionally fast developing field in catalysis since

the end of the 1990s. It allows the simultaneous screen-ing of a large number of catalytic formulations withaccuracy, in a minimum of time and more efficientlythan with conventional methods[13–15]. Since the re-ductive amination of benzaldehyde with ammonia inthe presence of a supported metal catalyst is governedby an extensive amount of parameters, it is an idealsystem for evaluation by high-throughput procedures.

In this paper, we present the results of a high-throughput screening of a library of 24 composition-ally and structurally different carbon-supported noblemetal catalysts for this reaction, summarising about150 experiments. In every set of 24 experiments, eachcatalyst was tested three times and the same set waschecked for reproducibility by repeating the experi-ments with a different location of the catalysts in themultireactor array.

2. Experimental

Benzaldehyde was purchased from Fluka ChemieAG (Buchs, Switzerland). Benzylamine, dibenzyla-mine, Pd(NH3)4Cl2·H2O, Pt(NH3)4Cl2·xH2O, RuCl3·2.5H2O, SnCl4·5H2O and BiONO3 were obtainedfrom Aldrich (Milwaukee, USA). (NH4)2S2O8 wasobtained from Merck KGaA (Darmstadt, Germany).The steam-activated peat-based carbon SX1G was agift from Norit NV (Amersfoort, The Netherlands).

2.1. Carbons preparation

SX1G (10 g) was added to a saturated solutionof (NH4)2S2O8 (175 ml) in 1 M aqueous H2SO4.After stirring at room temperature for 22 h, the

S. Gomez et al. / Applied Catalysis A: General 254 (2003) 77–84 79

carbon was filtered off, washed until the filtratewas free of sulphate (as tested with BaCl2) anddried overnight under ambient conditions and 3 h at80◦C. The carbon treated in this way was denoted asSX1GNS.

SX1G (10 g) was refluxed in 65% nitric acid(200 ml) for 3 h. Subsequently, the carbon was fil-tered off and washed with water until the pH ofthe filtrate reached a value of 5.5. The carbonwas dried as described above and was denoted asSX1GN65.

2.2. Catalysts preparation

Five weight percent of Pd/C, Pt/C and Ru/C cata-lysts were prepared by incipient wetness impregnationof carbon (0.95 g) with Pd(NH3)4Cl2·H2O (127 mg),Pt(NH3)4Cl2·xH2O (82 mg) or RuCl3·2.5H2O(110 mg) in water (2 ml). After drying overnight atroom temperature and 3 h at 80◦C, the catalysts werereduced in a 10% H2/N2 flow for 2 h at different tem-peratures and passivated at room temperature witha slowly increasing O2 concentration. A Pd cata-lyst based on SX1GNS and reduced at 150◦C wasdenoted as Pd/SX1GNS150.

A sodium-exchanged catalyst was prepared by ex-change of the carboxylic acid protons of the catalystwith 0.05 M NaOH. This type of catalyst is encodedfor example as Pd/NaSX1GNS150.

Sn-promoted catalysts were prepared by deposi-tion of 1 wt.% Sn on 5 wt.% Pd or Pt/C by addingslowly (0.8 ml/min), and under a N2 atmosphere, anaqueous solution of SnCl4·5H2O (138 mg/30 ml wa-ter) to the catalyst suspension (3.8 g/50 ml water).The pH of the suspension was increased to 8.5 us-ing 1 M NaOH. The suspension obtained was filteredoff, the catalyst was washed till neutral and dried inair, first overnight at room temperature and then 3 hat 120◦C.

Bi-promoted catalysts were prepared by depositionof 1 wt.% Bi on the 5 wt.% Pd/C catalysts. An acidicsolution of BiONO3 (28 mg/30 ml water) was slowlyadded (0.8 ml/min) to an aqueous suspension of thecatalyst (2 g/50 ml water) and glucose (9 g), under N2and at 40◦C. After depositing Bi, the suspension wasfiltered, the catalyst was washed till neutral and driedin air overnight at room temperature and then 3 h at120◦C.

2.3. Reaction testing with a conventionalautoclave

A 6.6 M ammonia solution in methanol (23 ml)was introduced into a 160 ml Parr 4842 autoclave,made of Hastelloy C276. Methanol (57 ml), the cat-alyst (0.017 g) and benzaldehyde (1 g) were added.The reaction mixture was heated to the desired tem-perature under a N2 atmosphere, and after 1 h, theH2 pressure was applied. The experiments were per-formed at 90◦C and 40 bar H2. Samples taken duringthe reaction were analysed with a Varian Star 3400gas chromatograph (CP Sil-5 CB column) applying atemperature gradient from 50 to 300◦C. Experimentsfor which the deviation to the mass balance, after totalconversion, was more than 10% were not considered.

2.4. Reaction testing with the 24-autoclave array highpressure unit

In a typical experiment, a suspension of the catalyst(0.85 mg) in methanol (1.5 ml) was dispensed manu-ally in each of the 24 tubes. A 6.6 M ammonia solutionin methanol (575�l) and benzaldehyde (24�l) weresubsequently added.

Hydrogenation experiments were performed in ahigh-pressure multireactor system, consisting of 24parallel reactors (12 mm internal diameter, 70 mmheight). The reactors were heated uniformly in a steelheater block and pressure was applied to each indi-vidual reactor by means of a gas manifold to ensureidentical pressures over all reactors. The whole as-sembly was agitated by an orbital shaker. The heaterblock was prior heated to 90◦C under a N2 atmo-sphere and, after 1 h, a pressure of 30 bar H2 wasapplied. Samples taken after the reaction were anal-ysed on a UNICAM Pro GC that was modified byapplying a double CP-Sil-5B column configurationand back flush techniques to separate all major prod-ucts in under 6 min with an average error of under 3%as determined by calibration. Two internal standards(1-hexanol in the long column, and 1-hexadecanolin the short one) were used for quantification. Eachcatalyst was evaluated six times to check the repro-ducibility of the measurements, including the place-ment of the catalysts at different locations in the arraymicroreactor. The values for the activities are the av-erage of the results from the different experiments.


The deviation of each result from the average lies onthe range between 0 and 10% of the average value.

3. Results and discussion

3.1. The library of catalysts

The library of 24 catalysts applied in this studywas constructed from four different steam-activatedpeat-based carbons. The parent catalyst support,SX1G, was treated with (NH4)2S2O8 (SX1GNS) and65% HNO3 (SX1GN65) to evaluate the effect of car-boxylic surface groups on the course of the reaction.Furthermore, a sodium-exchanged form of SX1GNSwas included in order to gain additional insight intothe influence of the modification of the surface acidcharacteristics of the catalysts (NaSX1GNS).

The noble metals selected for this study were Pd,Pt, and Ru. Carbon-supported Pd and Pt catalysts rankamong those most commonly used for reductive am-ination processes[2,4]. Ru has been employed to amuch lesser extent. Only a single report on the use ofa commercial Ru/C catalyst for the synthesis of DBAis found in the patent literature[8]. The catalysts ofchoice in the present work contain 5 wt.% of eitherPd, Pt or Ru.

It has been shown previously that Sn-promotion hasan activating effect for the hydrogenation of carbonyland nitrile compounds[16,17]. Bi is usually addedin catalytic systems for the oxidation of alcohols, es-pecially when the catalysts are based on Pd[18,19].Therefore, a subset of catalysts was prepared by ad-dition of either 1 wt.% Sn or 1 wt.% Bi to test theirability as promoters in the reductive amination of ben-zaldehyde with ammonia.

3.2. Activity of the catalysts

The reactions were carried out in an array of 24autoclaves of 3 ml working volume under 30 bar H2 at90◦C. Each of the reactor vessels contained a molarratio ammonia/benzaldehyde of 16, methanol was usedas the solvent. The large excess of ammonia shouldbring about a high selectivity towards BA, therebyhighlighting any catalyst selectivity towards DBA.

A gas chromatograph (with a double CP-Sil-5Bcolumn configuration using back flush techniques)

was used to separate all products in under 6 mintime.

The conversion in the reductive amination is notstraightforward due to the intermediate DBI. Com-plete conversion of benzaldehyde into DBI cannot bedefined as 100% conversion, since it is not a finalproduct, but the starting compound for BA and DBA.Therefore, in an attempt to quantify the activity of thecatalysts, the following parameter has been defined:

activity = [DBI] + [BA] + 2[DBA]

[benzaldehyde]0(1)

where [benzaldehyde]0 is the initial concentration ofbenzaldehyde.

This activity parameter is related to the total amountof hydrogen consumed at a particular stage of the re-action. It is calculated taking into account that, for theformation of BA and DBI, one equivalent of hydrogenis required, whereas the formation of DBA requirestwo equivalents. With this equation, complete conver-sion of benzaldehyde into DBI corresponds with ac-tivity 0.5, whereas complete conversion of DBI to BAand/or DBA corresponds with activity 1.

From the results of the reductive amination ofbenzaldehyde with ammonia after 3 h of reaction(Fig. 1a), it is possible to observe that the activity ofthe catalysts is higher when SX1G has been treated byoxidation, which increases the total amount of acidicsites on the support. This is not unexpected, as theoxidative treatments on the support allow for a higherdegree of metal dispersion during the impregnationand reduction processes. The active metal surfacearea and the percentage of metal dispersion were de-termined for Pd/SX1G150 and Pd/SX1GNS150 byvolumetric CO chemisorption. The Pd surface areasobtained were 1.4 and 5.4 m2/g, respectively, whilethe Pd dispersions were 6 and 24%, respectively.The increase in the activity after oxidative treatmentswould be consistent with the equilibria involved inthe process being acid-catalysed, as suggested byHeinen et al.[1]. This would mean that the conden-sation steps of the reaction also occur on the catalyticsurface, however, the relative extent of the reactionstaking place at the surface of the catalyst and those inthe liquid phase is still a matter of discussion[20–25].

When the acidic support SX1GNS is sodium-exchanged, the resulting conversions appear to beslightly higher than with the unexchanged support.


Fig. 1. Activities of the 24 catalysts after 3 h of reaction (a) and 21 h of reaction (b).


Table 1Composition of the reaction mixture after 21 h whenRu/SX1GNS350, Ru/NaSX1GNS350 and Pd/NaSX1GNS150 areused as catalysts

Catalyst BA (mol%) DBA (mol%) DBI (mol%)

Ru/SX1GNS350 66 6 28Ru/NaSX1GNS350 65 6 29Pd/NaSX1GNS150 0 34 66

Currently, experiments are being carried out withdifferent cation-exchanges to shed some light on thisissue.

Platinum-based catalysts show little activity evenwhen the supports are treated by oxidation. Mostlikely, this may be ascribed to the inhibition byamines, which has been noted in the literature[26–30].Palladium-based catalysts exhibit higher activitiesbut, surprisingly, the ones that display the highestactivity are the ruthenium-based catalysts.

These results confirm that both the nature of themetal and the nature of the support greatly determinethe activity of the catalysts. However, the activity ofthe catalysts appears, at least in the present study, notto be affected to a large extent by the presence ofadditives.

From conversions after 21 h (Fig. 1b), NaSX1GNSis firmly established as the most convenient supportfor higher activities. Ru-based catalysts are likewiseconfirmed as the most active compounds for the reduc-tive amination of benzaldehyde, whereas the Pt-basedcatalysts display the lowest activity. A comparison ofthe data after 3 and 21 h shows that, under the con-ditions applied, the reaction slows down considerablyupon prolonged reaction times, but the various trendsremain the same.

3.3. Selectivity of the catalysts

The composition of the reaction mixture after 21 hof reaction in the most interesting catalysts found isrepresented inTable 1.

In the case of the Ru catalysts, BA is the predom-inant product formed from DBI. When using Pd cat-alysts, DBI has started to convert to DBA and no BAis observed but the conversion is not high enough toconclude whether DBA will be the only product ob-tained from the reaction.

Table 2Comparison between the activity parameters after 3 and 21 h ofreaction for some of the catalysts tested

Catalyst Activity after 3 h Activity after 21 h

Pd/SX1G150 0.08 0.17Pd/NaSX1GNS150 0.41 0.57Pd/SX1GNS65150 0.37 0.42Pd/SX1GNS150 0.29 0.31Ru/NaSX1GNS350 0.51 0.78Ru/SX1GNS350 0.47 0.68

The conversions after 21 h are higher when BA isthe final product obtained. This indicates that eitherthe Ru catalysts are more active than the Pd catalysts(comparing catalysts with modified supports) or thatthe formation of DBA is more affected by the prob-lems of hydrogen mass transfer limitation than the for-mation of BA.

The results furnish evidence that the support merelyhelps to increase the metal dispersion and contributesto the selectivity in a much lesser degree than themetal.

3.4. Validation of the results by conventionalmethods

High-throughput techniques are very valuable in apreliminary stage of the screening of large librariesof catalysts. However, the key-experiments must berepeated with conventional set-up, so as to allowindependent validation by other laboratories. Addi-tionally, in the current case, the protocol presents aspecific drawback: mass transfer limitation cannot beconsidered to be negligible in the miniature reactorvessels and the unexpected slowing down of the reac-tion upon prolonged reaction time might indicate thatthis actually occurred (Table 2).

Therefore, the most promising and the worst cat-alysts as selected from the high-speed approachwere re-investigated in more detail by conventionalmethods using a 160 ml Parr autoclave and rigorousstirring.

Fig. 2ashows the concentrations of BA, DBA andDBI as a function of time in a reaction using a conven-tional autoclave and with Ru/SX1GNS350 as the cata-lyst. This figure confirms the selectivity of the catalysttowards BA as the sole final product. No side-products


Fig. 2. Concentrations of benzylamine (BA (�)), dibenzylamine(DBA (�)) and dibenzylimine (DBI (�)) as a function oftime when Ru/SX1GNS350 (a); Pd/NaSX1GNS150 (b); andPt/SX1GNS150 (c) are used as catalysts in a conventional auto-clave.

are present. The discovery of the Ru-modified cata-lysts for the reductive amination of benzaldehyde isof great importance as they allow the synthesis of BAin mild conditions, with complete conversion of ben-zaldehyde, in a short reaction time and with high se-lectivity.

Experiments were also performed with the conven-tional autoclave that confirm the selectivity of thePd-catalysts with a modified support towards the sec-ondary amine (Fig. 2b).

Pt/SX1GNS150 was tested as well under identicalconditions.Fig. 2cdemonstrates the poor activity ex-hibited by this catalyst.

Consequently, the trends observed with the high-throughput techniques are in complete agreement withthe results obtained from a conventional autoclave.From Fig. 2a and b, it can be concluded that the Rucatalyst is slightly less active than the Pd catalyst. Thisindicates that the formation of the BA is somehow lessmass transfer-limited than the formation of the DBAin the set-up used for the high-throughput procedure.The difference between the results with the parallelsystem and the conventional autoclave is merely dueto the fact that, with the parallel autoclave set-up, partof the catalyst remains at the bottom of the reactorvessels due to poor stirring. Hence, only a part of thecatalyst is in suspension and the conversions obtainedare lower, whilst selectivities should be largely unaf-fected. Experiments carried out with the conventionalautoclave and different loadings of catalyst showedthat the conversion was proportional to the catalystamount used in the reaction and, that selectivities werenot affected. In the case of the Ru catalyst, the conver-sion to BA is complete with the conventional autoclaveafter about 2 h, the composition of the reaction mix-ture being 98% BA and 2% DBA. In the case of thehigh-throughput analysis, after 21 h, the compositionof the reaction mixture is still 66% BA, 6% DBA and28% DBI. Certainly, only 66% BA has been formed,but this may be ascribed to the fact that the reaction isincomplete. The selectivity is for both methods sim-ilar; the essential difference between the two set-upsis that higher conversions are achieved with the con-ventional autoclave because of rigorous stirring. Thesame holds for the Pd-based catalyst, with which, inthe parallel set-up, DBI has started to convert to DBA,although the conversion is even lower because the for-mation of DBA is more affected by the problems ofmass transfer limitation than the formation of BA. Asstated above, the performance of the Pt catalyst is alsocomparable with both methods because, even with theconventional autoclave, under the same conditions em-ployed for the other two previous catalysts, completeconversion of DBI is not achieved.

This indicates that in small autoclaves efficient stir-ring is essential to obtain results that are compara-ble with up-scaled experiments. This prompted us tomodify the equipment for testing catalysts for hydro-genations by parallel reactions. The orbital stirringwas replaced by magnetic stirring at 1400 rpm. Thekey-experiments were repeated using this set-up and


now the results were identical with those obtained withthe conventional autoclaves.

4. Conclusion

The high-throughput approach allows the screen-ing of 24 structurally and compositionally differentcatalysts in the reductive amination of benzaldehyde,which is a complex reaction due to the possible for-mation of different amines and other side-products.Comparisons are feasible and conclusions can bedrawn regarding the relationship between the proper-ties of the catalyst and its performance in the reaction.The type of metal appears to be decisive for the cat-alytic activity and selectivity whereas the effect ofthe support is only significant for the activity. Fur-thermore, Ru catalysts on a modified support havebeen identified as new and very effective catalystsfor the reaction tested displaying high conversionsand selectivities towards benzylamine. Scaling up ofthe experiments confirmed the trends observed in theminiature reactors. This work emphasises again thepossibilities that high-throughput experimentation canopen in the discovery and optimisation of new gener-ations of catalysts. Even though the equipment usedinitially was sub-optimal, Ru/C was discovered as ahighly reactive and selective catalyst for the reductiveamination of benzaldehyde.

Acknowledgements

Ing. J. Groen from the Delft University of Technol-ogy is acknowledged for performing the volumetricCO chemisorption measurements. Thanks are also dueto Norit N.V. for providing the parent activated carbonSX1G and to Mr. E. Wurtz for making the set-up forthe reduction of catalysts available.

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