Journal of Flow Chemistry

, Volume 8, Issue 2, pp 81–88 | Cite as

Reductive aminations using a 3D printed supported metal(0) catalyst system

  • Charlotte Genet
  • Xuan Nguyen
  • Bita Bayatsarmadi
  • Mike D. Horne
  • James Gardiner
  • Christian H. Hornung
Full Paper


Additively manufactured catalytic static mixers were used for the intensified reductive amination of aldehydes and ketones inside a continuous flow reactor. This efficient synthesis method is enabled by the use of tubular reactors fitted with 3D printed metal static mixers which are coated with a catalytically active layer, either Pd or Ni. The 3D printing process allows for maximum design flexibility for the mixer scaffold and is compatible with a range of deposition methods including electroplating and metal cold spraying. Single- and multi-stage continuous flow processing yielded high to full conversion and has the potential to scale-up these operations without the need for manual handling of reactive imine intermediates.

The continuous flow reductive amination was performed in a tubular hydrogenation reactor, using nickel or palladium containing catalytic static mixers

Graphical Abstract


Heterogeneous catalysis Flow chemistry Hydrogenation Amines Palladium Nickel 


Functional amines are an important class of intermediates in the organic synthesis of pharmaceuticals and fine chemicals and have a broad range of applications [1]. The reductive amination of aldehydes and ketones is a practical and efficient method for the synthesis of these amines and a series of different catalysts and protocols have been used for this reaction. Often these protocols involve expensive, highly reactive or toxic reagents and catalysts such as sodium borohydride and other borane-based reductants, dihydropyridines, tin hydrides, ionic liquids and others [2, 3, 4, 5, 6, 7, 8, 9, 10]. Palladium(0) and nickel(0) bound to a metallic surface and employed in a continuous flow reactor setting present effective and versatile alternative catalysts for reductive aminations, addressing both laboratory scale research as well as manufacturing of kg or ton quantities for commercial use.

Flow chemistry reactor technology for heterogeneous catalysis has attracted a lot of attention over the past 15 years, and continuous flow hydrogenations were amongst the first reactions investigated in flow reactors [11, 12, 13, 14, 15, 16]. However, these flow hydrogenation systems all use cartridges or packed columns, which essentially are downscaled versions of industrial fixed bed reactors, adopted for laboratory synthesis. In contrast to these more conventional approaches, our group at CSIRO has devised a new approach using a tubular reactor geometry with 3D printed and catalytically active tube inserts termed Catalytic Static Mixers (CSMs). The catalytic metal(0) layer is deposited either by electroplating or cold spraying [17, 18, 19]. One immediate difference and defining advantage over packed bed systems is the significantly higher L/D ratio of the cylindrical reactor geometry which allows for a much improved control over the chemical process. In addition, our inserts are structured and regular, allowing for a predictable and tuneable flow field, thus minimising issues associated with flow maldistribution and pressure drop. Our mixer design can vary depending on flow conditions and fluid properties, and the choice of design can therefore be tailored to the needs of the chemical process. By using additive manufacturing methods, i.e. 3D metal printing, limitations of conventional subtractive metal forming techniques can be overcome, resulting in nearly complete freedom of design. The key advantage of the CSM technology over conventional solid phase Pd and Ni catalysts, is its unique combination of catalyst geometry and morphology. Other than powder or granular systems, CSMs contain a highly active catalyst layer with a strong metallurgical bond to its 3D printed substrate. As a result CSMs have a very low leaching profile [17, 18, 19], thus eliminating a range of complications associated with catalyst contamination of the product stream, which often plague industrial heterogeneous catalyst systems, such as e.g. Pd on carbon. In most of these cases labour and time intensive filtration processes to remove residual solid or soluble catalyst matter reduce overall efficiency of the process, while with CSMs these post-reaction operations can be completely avoided.

Herein we present a series of reductive aminations using the CSM technology, reacting several aldehydes and ketones with a range of primary and secondary amines to yield a series of functional amines. The heterogeneous catalytic reduction of the imine intermediate to the functional amine is performed on CSMs containing Pd(0) or Ni(0). The preceding condensation step can either also be performed in the CSM reactor or in a separate homogeneous tubular reactor situated before the CSM reactor in order to optimise conversion of the overall operation. All results were quantified in terms of conversion, turn-over frequency (TOF) and space time yield (STY).

Results and discussion

CSMs are static mixers, coated with a catalytically active layer, which can be fitted inside a tubular reactor geometry (see Fig. 1). The CSMs used in this work were prepared at CSIRO using a combination of additive manufacturing and metal deposition techniques. Three catalyst sets, containing 12 CSMs each were prepared for this work. The first set, Ni-CS-1, contained a total of 6.0 g Ni(0), the second set, Pd-EP-2, contained a total of 1.4 g Pd(0), and the third set, Pd-EP-3, contained a total of 2.3 g Pd(0). Nickel was deposited by cold spraying and palladium was deposited by electroplating. The scaffold material chosen for all sets was 316 L stainless steel. SEM images of Ni-CS-1 and Pd-EP-2 are presented in Fig. 2. The catalytic reactions were conducted in a tubular continuous flow reactor fitted with either one of the above CSM sets. Detailed description of the manufacture of the CSMs and of the catalytic flow reactor were reported in our previous work [17, 18, 19]. A series of aldehydes and ketones (benzaldehyde, 2-, 3- and 4-anisaldehyde, 5-methylfurfural, cinnamaldehyde, vanillin and 2-heptanone) were reacted with several amines (n-butylamine, aniline, allylamine, ethanolamine, α-methylbenzylamine, piperidine and morpholine) in a one-step procedure (see Scheme 1) to form the coupling products shown in Tables 1 and 2. Table 1 contains all reactions conducted with the Pd catalyst and Table 2 contains all reactions conducted on Ni. Here, L is the liquid flow rate, GN the normal gas flow rate, and G/L is the gas to liquid ratio inside the reactor. For most examples only one product was observed; where there were more than one, further details are given. All products are known literature compounds and references for each of them are provided in the tables.
Fig. 1

Catalytic Static Mixer fitted in steel tube with inner diameter of 6 mm; length of CSM: 150 mm

Fig. 2

SEM images of the surface of a Ni-CSM taken from the Ni-CS-1 set (left) and of a Pd-CSM taken from the Pd-CS-2 set (right)

Scheme 1

Reductive amination of aldehydes and ketones using a one-step procedure inside a CSM reactor

Table 1

Results (conversion, TOF, and STY) from reductive amination experiments using a Pd catalyst, Pd-EP-2, in a one-step procedure on the CSM reactor

All reactions were conducted at 120 °C, 20 bar reactor pressure, with a liquid flow rate of 1 mL/min, a normal gas flow rate of 54.4 mLN/min, a G/L of 4 and a carbonyl concentration of 0.5 M in ethyl acetate; literature references of the products are added for comparison

areduction of imine and alkene, see Scheme 2, conversion is based on reduction of both reactive moieties to the product 1.6 or 1.10; bmultiple products identified, see Fig. 3, conversion is based on desired product 1.7; cmultiple products identified, see Fig. 3, conversion is based on desired product 1.11

Table 2

Reaction conditions (reactor pressure, p, liquid flow rate, L, normal gas flow rate, GN, gas to liquid ratio inside the reactor, G/L) and results (conversion, TOF and STY) from reductive amination experiments using a Ni catalyst, Ni-CS-1, in a one-step procedure on the CSM reactor

All reactions were conducted at 120 °C and with a carbonyl concentration of 0.5 M in EtOAc, literature references of the products are added for comparison

During these experiments high catalytic activity was observed with reaction conversions of >90% for the majority of examples. Turn-over frequencies (TOF) were typically between 1 and 2 h−1 and space time yields (STY) were typically between 0.4 and 0.8 mol L−1 h−1. Details on the calculation of TOF and STY can be found in the supplementary information. Entries 1.7, 1.8, 1.9, 1.11 and 1.13 showed significantly lower conversions than the other reactions. In some of these cases, e.g. entries 1.8 and 1.9 the reactivity of the carbonyl-amine combination to form the reactive imine species was low, in others, e.g. entries 1.7 and 1.11, undesired side reactions lowered the overall conversion. These cases will be described in further detail below.

The synthesis of product 1.5 (reacting 5-methylfurfural with n-butyl amine) was further optimised by doubling the normal gas flow rate, GN, to 108.7 mLN/min and the gas to liquid ratio, G/L, to 8, which increased the conversion to 80%. This demonstrates the potential to further improve the reduction of the imine by increasing the hydrogen flow rate, an observation which is consistent with our previous work [17, 18, 19]. This however comes at the cost of using more hydrogen. Entry 1.6 used cinnamaldehyde as the carbonyl source and entry 1.10 used allylamine as the amine source; both of which also contain alkene moieties. These alkene moieties were also cleanly reduced to the corresponding alkane alongside the imine moieties (see Scheme 2).
Scheme 2

Reductive amination using Pd-CSMs and the following substrates: n-butylamine and cinnamaldehyde (entry 1.6), allylamine and benzaldehyde (entry 1.10)

In some cases we observed a side reaction, namely a double carbonyl addition yielding a tertiary amine, such as in entry 1.7 using vanillin or entry 1.11 using ethanolamine. In the case of vanillin only 21% of the starting material were converted to the desired secondary amine product while 64% were converted to the tertiary amine, 4,4′-((butylazanediyl)bis(methylene))bis(2-methoxyphenol). Also, 6% of unreduced imine were found (see Fig. 3). In the case of ethanolamine 44% were converted to the desired secondary amine product, 26% were converted to the tertiary amine, 2-(dibenzylamino)ethan-1-ol, and 30% were other unidentified side products (see Fig. 3).
Fig. 3

Selectivity of the Pd-CSMs for the reductive amination of the following substrates: n-butylamine and vanillin (entry 1.7), ethanolamine and benzaldehyde (entry 1.11); reaction with vanillin produced 64% of the tertiary amine side product shown on the top right; reaction with ethanolamine produced 26% of the tertiary amine side product shown on the bottom right; the conversion to the desired secondary amines was 21 and 44% respectively

When reactions were conducted using the nickel CSM set, Ni-CS-1, we observed a significantly lower activity compared to Pd, however this was not surprising and in accordance with our previous work [17, 18, 19]. After a short optimisation, we managed to also achieve high conversions with Ni using more forcing conditions, especially at higher GN and higher reactor pressure. Table 2 shows the optimised conditions for Ni and Fig. 4 shows a comparison between Ni and Pd for identical conditions. Further details on the optimisation process for the Ni catalyst can be found in the supplementary information.
Fig. 4

Comparison of catalyst performance for Pd and Ni CSMs under the following reaction conditions: TR = 120 °C, pR = 20 bar, L = 1 mL/min, GN = 54.4 mLN/min, G/L = 4, concentration of aldehyde = 0.5 M in ethyl acetate

Out of the examples in Table 2, entry 2.4 is particularly interesting, as it presents a facile one step synthesis route to benzylmorpholines, which are selective inhibitors of lung cytochrome P450 2A13, tested for the chemoprevention of lung cancer [30]. Another interesting example is the direct reductive amination of aryl aldehydes with anilines (entries 1.9 and 2.3), which are used e.g. as building blocks in the synthesis of dibenzazepines for use as antitumor agents [31]. Most commonly these reactions are conducted using expensive or toxic reagents and catalysts such as sodium borohydride and other borane-based reductants or tin hydrides [2, 3, 4, 6, 31].

As conversions in our CSM reactor for the less reactive amine, aniline (entry 1.9), and the less reactive ketone, 2-heptanone (entry 1.8), were significantly lower than for more reactive primary amines and aldehydes at identical conditions, we tried to optimise these reactions by transferring them into a two-step continuous flow process. This procedure included a first, homogeneous liquid phase step which was conducted in a tubular plug flow reactor, forming the imine intermediate under forcing conditions. The second step was then the reduction of this imine to the secondary amine product in the CSM reactor. By decoupling the two reaction steps and using a dedicated and individually tailored reactor set-up for each step, we managed to increase the overall conversion of these reductive amination sequences (see Fig. 5). Table 3 shows all examples that were conducted using this two-step procedure, either with a Pd or a Ni catalyst.
Fig. 5

Reductive amination using a two-step continuous flow procedure; step one was conducted in a tubular plug flow reactor at 140 °C; step two was conducted in the CSM reactor at 120 °C

Table 3

Results (conversion to imine intermediate and to amine product, TOF, and STY) from reductive amination experiments using a two-step procedure: step one forming the imine intermediate in a tubular liquid phase reactor, step two forming the amine product in the CSM reactor

All reactions were conducted at 120 °C, with a liquid flow rate of 1 mL/min, and a carbonyl concentration of 0.5 M in EtOAc, literature references of the reductive amination products are added for comparison

ain step one; bin step two

The two step procedure for the synthesis of N-benzylaniline using Pd-CSMs (entry 3.1) resulted in a greatly improved overall conversion (84%) when compared to the corresponding one step procedure (entry 1.9, 12%). The two step process allows for a high conversion to the imine intermediate in the tubular reactor (81%), which then leads to a high conversion to the desired secondary amine in the CSM reactor. A similar conversion could be achieved with Ni-CSMs at higher reactor pressure and higher G/L (entry 3.2). Likewise, the reductive amination of n-butylamine with 2-heptanone could be improved from 57% (entry 1.8) to 85% (entry 3.3) using the two step procedure. As in both cases, the rate limiting step is the formation of the imine, not the catalytic reduction, using a dedicated tubular reactor to increase the rate of the condensation reaction impacts greatly on the overall conversion of the reductive amination sequence. The reaction between 5-methylfurfural and n-butylamine (entry 3.4) was improved marginally compared to the one step procedure (entry 1.5).

In order to establish a meaningful yield, we scaled up the reductive amination of one example from Table 1, namely the reaction between benzaldehyde and n-butylamine using Pd-EP-3 (see entry 1.1), to 300 mL of stock solution, during an extended reactor runtime. This reaction was processed at a liquid flow rate of 0.5 mL/min and a gas flow rate of 195.3 mLN/min, resulting in a conversion of 96% to the desired amine product and a 93% yield based on mass recovery.

Catalyst leaching was investigated by submitting concentrated samples for ICP-OES which were also derived from a series of large scale runs, generally 1 L of product solution or more. The product stream from these steady state experiments contained on average 41 ppb Ni, 26 ppb Cr, 242 ppb Fe, 2 ppb Mo and 5 ppb Mn for the Ni catalyst, Ni-CS-1, and < 2 ppb Pd, 60 ppb Ni, 125 ppb Cr, 165 ppb Fe, 74 ppb Mo and 6 ppb Mn for the Pd catalyst, Pd-EP-3. These results show that both the Pd and the Ni catalysts have a very strong metallurgical bonding to the mixer substrate, and that the majority of the soluble metal was Fe, which is a contamination from the stainless steel reactor tubing and the CSM substrate. This data is consistent with our previous findings [17, 18, 19].


Herein we have demonstrated a new, facile approach for reductive aminations using an additively manufactured flow chemistry system. The metal(0) catalyst was supported on a 3D printed metal scaffold, which can be easily tailored to a specific reaction application. Flow chemistry reactors are characterised by efficient heat transfer and mixing and by linear scalability from laboratory to pilot to production, which is usually significantly more efficient and faster than a corresponding batch approach. The benefits resulting from the efficient heat and mass transfer often translate to a reduction or elimination of undesired side-products, which in turn leads to less need for purification and reduces waste and power consumption for a manufacturing process. The highly active catalyst layer of our system has a strong metallurgical bond to its 3D printed substrate which results in a very low leaching profile. This in turn eliminates complications associated with catalyst contamination of the product stream, meaning that time and labour intensive filtration steps can be avoided. The reductive aminations conducted on our catalytic flow reactor system reached high conversions to the desired functional amines for the majority of examples. Where the condensation to the imine intermediate was slow, we could improve the overall conversion by changing to a two-step flow procedure including an additional homogeneous liquid phase tubular flow reactor. This work showcases the efficiency and robustness of the CSM technology for the synthesis of functional amines, an important and widely used class of organic intermediates.

Experimental section

Continuous flow reductive amination – single step

A series of continuous flow experiments with hydrogen gas were conducted in the CSM reactor. For a typical single-step reductive amination reaction using Pd-CSMs the following protocol was employed:

Before first use of the CSMs (Pd-EP-2), they were activated inside the reactor by flowing hydrogen over them at 16 bar, 120 °C and a gas flow rate of 67.9 mLN/min. The activation was conducted for 60 min. After activation the reactor was flushed with solvent, ethyl acetate (EtOAc), using the liquid reagent pump. A substrate solution containing 1.64 g of n-butylamine and 2.38 g of benzaldehyde in 45 mL of EtOAc was prepared. Upon start-up of the reactor system, hydrogen gas was introduced, together with the washing solvent (EtOAc) to prime the reactor, and the parameters for the reaction were adjusted to the following: reactor pressure, pR = 20 bar, liquid flow rate, L = 1 ml/min, gas flow rate inside the reactor at reaction pressure, GR = 4 mL/min, normal gas flow rate measured by the hydrogen mass flow controller, GN = 54.4 mLN/min, gas to liquid ratio, G/L = 4, reactor temperature, TR = 120 °C. Note that the calculation of G/L is based on the gas flow rate at reactor pressure, GR, not the normal gas flow rate, GN. Once pressure and temperature had stabilised, the liquid feed was changed from solvent to stock solution, thus starting the reaction. After one residence time inside the reactor, the clear product, N-benzylbutan-1-amine in solvent, was collected at the outlet of the reactor and was then analysed by 1H-NMR and GC. Further details on analysis methods and reagents can be found in the supporting information.

Typically these reactions were performed on a 30 to 50 mL scale of substrate solution. In order to establish an isolated yield on a significant scale, we scaled up the reductive amination of benzaldehyde and n-butylamine to 300 mL, during an extended operation. This reaction was processed at a liquid flow rate of 0.5 mL/min and a gas flow rate of 195.3 mLN/min, resulting in a conversion of 96% to the desired amine product. After solvent removal the product was recovered with a 93% yield. Aside from the product, we only observed ~4% of unreduced imine intermediate; there was no aldehyde starting material left. GC-MS and 1H NMR of the product from this extended run can be found in the supporting information.

Continuous flow reductive amination – two-step

For a two-step continuous flow reductive amination, we performed the first step, the formation of the imine intermediate, on a Vapourtec R2/R4 tubular flow reactor, and the second step, the reduction, in the CSM reactor. The first step was typically carried out as follows:

Two reactant solutions were prepared, one containing 9.78 g of aniline in 100 mL of EtOAc, and the other containing 10.61 g of benzaldehyde in 100 mL of EtOAc. The two solutions were pumped with two HPLC pumps and continuously mixed in a T-piece before they were fed into a Vapourtec R2/R4 flow reactor set-up [32], consisting of four 1.0 mm ID perfluoroalkoxy alkane (PFA) reactor coil modules in series (10 mL each – total reactor volume: 40 mL). Both pump flow rates were set to 2.0 mL/min. This resulted in a total flow rate of 4.0 mL/min and a mean hydraulic residence time of 10 min inside the two PFA reactor coils (the mean hydraulic residence time is defined as ‘flow rate/reactor volume’). The reaction was conducted at 140 °C. The product, a transparent, faintly yellow solution, was collected at the reactor outlet, after passing through a 100 psi back pressure regulator. From this solution, the reaction conversion was determined by 1H NMR and GC. The second step was then conducted on the CSM reactor as described above, using the product solution from the first step without further purification.



The authors thank Winston Liew for ICP-OES measurements, Andrew Urban for cold-spraying of the nickel catalyst, Darren Fraser for 3D printing of the mixer substrates, John Tsanaktsidis, Oliver Hutt and Dayalan Gunasegaram for many helpful discussions and the Active Integrated Matter (AIM) Future Science Platform for financial support for Charlotte Genet.

Supplementary material

41981_2018_13_MOESM1_ESM.docx (4 mb)
ESM 1 (DOCX 4122 kb)


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Copyright information

© Akadémiai Kiadó 2018

Authors and Affiliations

  • Charlotte Genet
    • 1
  • Xuan Nguyen
    • 1
  • Bita Bayatsarmadi
    • 2
  • Mike D. Horne
    • 2
  • James Gardiner
    • 1
  • Christian H. Hornung
    • 1
  1. 1.CSIRO ManufacturingClayton SouthAustralia
  2. 2.CSIRO Minerals ResourcesClayton SouthAustralia

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