Continuously Operated Hydroamination â Toward High Catalytic

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Continuously Operated Hydroamination – Towards High Catalytic Performance via Organic Solvent Nanofiltration in a membrane reactor Dennis Vogelsang, Jens Martin Dreimann, Dominik Wenzel, Ludmila Peeva, João Burgal, Andrew Guy Livingston, Arno Behr, and Andreas Johannes Vorholt Ind. Eng. Chem. Res., Just Accepted Manuscript • DOI: 10.1021/acs.iecr.7b03770 • Publication Date (Web): 23 Oct 2017 Downloaded from http://pubs.acs.org on October 28, 2017

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Industrial & Engineering Chemistry Research

Continuously Operated Hydroamination – Towards High Catalytic Performance via Organic Solvent Nanofiltration in a membrane reactor Dennis Vogelsang[a], Jens M. Dreimann[a], Dominik Wenzel[a], Ludmila Peeva[b], João da Silva Burgal[b], Andrew G. Livingston[b], Arno Behr[a], Andreas J. Vorholt*[a] a

Laboratory of chemical process development, Department of Bio- and Chemical Engineering, Technical University of

Dortmund, Emil-Figge-Straße 66, 44227 Dortmund, E-mail: [email protected] b

Department of Chemical Engineering, Imperial College of Science, Technology and Medicin, London SW7 2AZ (United

Kingdom)

Abstract: Still, the hydroamination of dienes to form allylic amines is a challenging task in a continuous operation. Herein, we present the performance of a membrane reactor by the implementation of a continuously operated hydroamination reaction of β-myrcene with morpholine. Via application of a poly-ether-ether-ketone (PEEK) membrane operation at elevated temperatures was possible in an integrated reaction/separation unit. First, the kinetics of the hydroamination reaction and relevant membrane characteristics were determined under optimised reaction conditions. Afterwards, these results were incorporated in a reactor/separator model to predict the process behaviour. With this, catalyst replenishment was adjusted resulting in stable continuous operation. In the end an increase of the turn-overnumber from 460 to 5135 compared to a batch process was achieved. The desired geranyl amines were obtained in very good yields higher than 80%, while an excellent conversion of β-myrcene above 93% was reached in a long-time stable process.

Introduction Approximately 80-90% of the overall chemical feedstock in chemical production processes is converted by the application of catalysts, only about 10% of these take advantage of homogeneous catalysis. The application of homogeneous catalysts, especially homogeneous transition-metal catalysts, provides several advantages over heterogeneous catalysts e.g. efficient adjustment of selectivity and a defined number of active centres.1,2 A frequently investigated homogeneous catalysed reaction with a high potential increase in value is the hydroamination. Formally, the hydroamination is an atom economic reaction to convert olefins e.g. 1,3-dienes into amines by adding secondary amines.3–5 In Scheme 1, a general hydroamination reaction of 1,3-dienes with a secondary amine is shown.

Scheme 1. Hydroamination reaction of 1,3-dienes with a secondary amine.

In principle, the hydroamination reaction can be carried out by base or metal catalysis.6,7 In literature, several metal catalysts are presented to perform a directed hydroamination of 1,3-dienes, such as La8, Bi 9, Au10 or Pd11–14 salts can be used. Among these palladium catalysts show highest activity, while tailor-made ligands are mostly required to control selectivity. In the last decades, a dominant increase of the utilization of renewable resources has occurred to create sustainable chemistry and to reduce the carbon footprint. Especially, β-myrcene is an important renewable model substrate, which is easily accessible by the pyrolysis of β-pinene in a large scale and does not compete with food production because βpinene can be obtained as a by-product in paper industries. An already proceeded industrial relevant application of βmyrcene is the Takasago process to produce (-)-menthol. Converting β-myrcene by lithium base catalysed hydroamination, geranyl amines are obtained as intermediates which are subsequently functionalised to (-)-menthol in four more steps.15 Beyond industry, several examples to utilize β-myrcene are presented in literature.16

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An innovative and sustainable approach for the production of geranyl amines is the palladium-catalysed hydroamination of β-myrcene with morpholine. Under optimised conditions the desired 1,4-adducts of the geranyl amines are obtained in yields higher than 90% by applying the bidentate ligand bis(diphenylphosphino)butane (DPPB) and the palladium trifluoroacetate precursor in toluene.17 Generally, the main drawback of homogeneous catalysis is the separation of the mostly expensive transition-metal catalyst. In situ or subsequent recycling of the active catalyst species is required to increase catalytic performance and to bridge the gap between academic research and industrial process. Different technologies for catalyst recovery are available for specific applications e.g. distillation, liquid-liquid two-phase systems or thermomorphic solvent systems (TMS). With a TMS system consisting of n-heptane and acetonitrile, 79% yield of the desired hydroamination products with 85% myrcene conversion were achieved in three consecutive batch runs.18 In ensuing recent studies, a scale-up of the hydroamination of β-myrcene with morpholine was achieved in a continuous flow Taylor-Couette-reactor. Using the thermomorphic solvent system n-heptane/dimethyl formamide (DMF) the palladium catalyst was recycled, while the desired hydroamination products were obtained with good yields of 80% over a period of 24 h. The main drawback of these approaches often depends on the specific, adapted design of the recovery method which strongly influences catalyst activity, e.g. choice of extraction solvents. In consequence, low stability of the catalyst system over time occurs. Still, an efficient catalyst recovery and therefore an increase of the turn-over number (TON) compared to batch operation is missing (c.f. Figure 1).19

Figure 1. Increase in catalyst activity for the hydroamination reaction of β-myrcene with morpholine.

Besides these separation techniques, organic solvent nanofiltration (OSN) is one of the most promising technology for the recovery of homogeneous transition metal catalysts without taking much influence on catalyst activity. In particular, the utilisation of OSN membranes is an elegant method to separate a catalyst system from the reaction mixture to increase the TON of homogeneous catalysts and increase economic feasibility of a process. Inherently, OSN is a promising technology for the recovery of transition metal catalysts, which is applicable in continuous flow and therefore, highly relevant for industrial processes. Recently, several reviews about OSN were published reporting wide range of applications and the elegant way to implement a separation method at molecular level.20–22 Despite its great potential the OSN applications still remain mainly at laboratory scale. Especially, in the field of homogeneous catalysis different challenges still remain before OSN could be established as standard separation unit for chemical production processes, e.g. large scale production of highly solvent and temperature stable membranes with good selectivity, and particularly improvement of membrane performance in terms of catalyst separation efficiency.23–26 Poly-ether-ether-ketone (PEEK, Figure 2) is a promising material for membranes with broad application spectrum.27 PEEK-membranes can easily be produced by casting on a porous support followed by phase inversion, forming a tailormade membrane with a desired molecular weight cut-off.26 In contrast to other solvent stable membranes e.g. polyimide or polybenzimidazol membranes, the PEEK membrane demonstrates negligible aging and excellent long-term stability even under the treatment of aggressive solvents for instance dimethyl formamide (DMF) and high temperatures over 140 °C .28

Figure 2. General structure of the poly-ether-ether-ketone (PEEK) membrane.

Implementation of the PEEK membrane widens the application of membrane processes as reaction/separation units in continuous manufacturing, thus increasing process efficiency and reducing waste production. It has been recently demonstrated that in a membrane reactor/separator unit catalyst turn-over numbers (TONs) of ~20,000 with conversions


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above 98% and low contamination of the product stream (~27 mg Pd per kg of product) could be achieved for palladium catalysed Heck coupling reaction. Stable process operation was demonstrated over 1,000 h.3,29 In this work, we demonstrate a continuous flow process for the sophisticated hydroamination of β-myrcene with morpholine performed in a membrane reactor/separator equipped with a PEEK-membrane. A steady-state conversion higher than 90% with equal selectivity is maintained for 60 hours. The desired geranyl amines were produced in a 100 g scale with Pd catalyst TON of 5135, more than ten times higher than a batch process.

Results and Discussion The following investigation is subdivided in three main sections detailing the development of continuous flow hydroamination of β-myrcene with morpholine in a poly-ether-ether-ketone (PEEK) membrane reactor/separator. In part one the reaction kinetics of the hydroamination and the competing isomerisation were determined. Afterwards, the performance of the membrane in terms of pure solvent flux and catalyst recovery was characterised in part two. Finally, based on these results the optimal continuous operation conditions were estimated and validated experimentally. Reaction kinetics The hydroamination reaction of 1,3-dienes requires a precise adjustment of reaction conditions to ensure selective production of the desirable allylic amines, especially in terms of catalyst composition. Herein, the applied model reaction is the hydroamination of β-myrcene with morpholine for which our research group has already presented an optimised catalyst system. It was demonstrated that 0.2 mol% Pd(tfa)2 and 0.8 mol% diphenylphosphino butane (DPPB) in toluene with 0.17 molL-1 concentration of β-myrcene and a ratio of β-myrcene to morpholine of 1:1, provides selective (selectivity over 90%) synthesis of the targeted products in very good yield and after 5 h and at 100 °C reaction temperature.17 Under non-optimised reaction conditions, the palladium-catalysed hydroamination of β-myrcene with morpholine offers a complex reaction network leading to terpenyl amines and several by-products, e.g. telomerization products, dimers and isomers of β-myrcene. However, under optimizied reaction conditions the desired hydroamination products can be selectively obtained as a mixture of 1,4-head- and tail-terpenyl amines 1 and as the only undesired byproducts a mixture of myrcene isomers 2. For simplicity, the yields of the double bond isomers of the terpenyl amines (TA) 1 and myrcene isomers 2 will be summed up in the following. An overview of the possible reaction pathways and variety of the desired terpenyl amines and the undesired by-products is given in Scheme 2.

Scheme 2. Reaction pathways of the hydroamination reaction of myrcene and morpholine. (r1=hydroamination, r2=isomerisation); For simplification only examples of double bond isomers are shown.

The selectivity of the hydroamination reaction of β-myrcene with morpholine can easily be controlled by the choice of optimised reaction conditions. Thus, the reaction network can be minimised to the desired hydroamination reaction r1 and the isomerisation of β-myrcene r2 as shown in Scheme 2. Consequently, the kinetics of the hydroamination network solely depends on the reaction rates r1 and r2, defined in equations (1) and (2).

r1 =k1 caMyrcbMor =

dTerpAmin


(1)


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r2 =k2 cMyr = d

dIsomers

= r1 r2

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(2)

(3)

Based on these two reaction rates, the kinetics of the hydroamination reaction depends on five unknown parameters, the reactions constants k1 and k2 and the unknown reactions orders a, b and c. For this simplified kinetic model the following assumptions were made: Solely the hydroamination and the isomerisation reaction are considered Both types of reactions are fast and irreversible Double bond isomers will be summed up to one fraction of terpenyl amines 1 and myrcene isomers 2 To determine the reaction rates and estimate the unknown reaction parameters, the formation of the product yields of the hydroamination of β-myrcene with morpholine was monitored over time using the optimised reagents composition17 and reaction temperatures of 90 °C, 100 °C and 120 °C in a 300 mL batch autoclave. The results are displayed in Figure 3.

Figure 3: Product yields of the hydroamination reaction monitored over time at 90 °C, 100 °C, 120 °C reaction temperature. Reaction conditions: c(β-myrcene)=c(morpholine)=0,17 molL-1, c(Pd(tfa)2)= 6.86·10-4 molL-1, Pd:DPPB=1:4, 500 rpm; TA = terpenyl amines, isomers = myrcene isomers; product yields were determined via GC-FID-analysis.

As expected, the reaction rate of the hydroamination reaction strongly depends on the reaction temperature but also the selectivity of the hydroamination reaction crucially depends on the reaction temperature. A temperature of 90 °C leads to the highest selectivity of 97% of the desired terpenyl amines 1, but the reaction is slower in comparison to 100 °C or 120 °C and reaches a maximum yield of 91% terpenyl amines 1 after 5 h reaction time. Apparently 100 °C reaction temperature is the best compromise achieving a maximum yield of 91% terpenyl amines 1 showing high selectivity of 94% within 2 h reaction time. Increasing the reaction temperature above 100 °C showed unexpected results. As demonstrated in Fig. 2 a reaction temperature of 120 °C resulted in a fast reaction with a maximum of 83% TA 1 yield after 1 h. Afterwards the yield of the terpenyl amines 1 decreased to 75% and the isomers 2 continuously increased up to 22%. This result strongly suggests that the hydroamination of β-myrcene with morpholine is a reversible reaction, in contrast to previously published research or a different active palladium species was generated at higher temperature, which leads to degradation of the terpenyl amines. Indeed, the decomposition of the terpenyl amines 1 was not carried out by retro-hydroamination reaction, because the initially applied β-myrcene was not reobtained, instead myrcene isomers could be observed. On the other hand, after reaching the maximum yield of terpenyl amines 1, the constitution and the resulting reactivity of the palladium species could be changed at 120 °C. The in-situ formed palladium catalyst species could cause the degradation of the terpenyl amines 1. These results contradict the previously stated assumption, but the decomposition of the hydroamination products 1 at a reaction temperature of 100 °C is comparably negligible so that the presented model is sufficient for the prediction of the process performance. Reversibility of the reaction will be an objective of a separate study and beyond the scopes of the current paper. The experimental data at all three temperatures were fitted to obtain the yields of the TA 1 and the isomers 2 as functions of time. The estimated reaction parameters at 100 °C are listed in Table 1.


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Table 1: Fitted parameters of determined reaction rates. reaction

EA [kJ/mol]

k0 [-]

r1

73.63

r2

100.56

ki [1/min]

a [-]

b [-]

c [-]

6.09·108

0.0425

0.647

0.647

-

10

0.0003

-

-

0.49

3.57·10

The determined reaction constants ki are functions of the reaction temperature and contain the activation energies EA and impact factors k0,i of the hydroamination and the isomerisation reactions. By application of an Arrhenius plot (Eq 4) these reaction parameters were also calculated. Using linearization as demonstrated in Figure 4. The calculated activation energies EA and impact factors k0,i of the hydroamination and the isomerisation reactions are also shown in Table 1.

= , ∙

,

(4)

The activation energy in the range of 74 kJmol-1 of the hydroamination reaction of β-myrcene with morpholine and of 100 kJmol-1 of the isomerisation of β-myrcene could be estimated. In general it is known that the activation energy of the hydroamination reaction is relatively high, especially, in the case of 1,3-dienes as substrates. Unfortunately and to the best of our knowledge, there is not an example reported in literature so far for the determination of the activation energy of a palladium/diphosphine catalysed hydroamination of branched 1,3-dienes with amines. However, the calculated activation energy of the hydroamination is a good agreement with the general tendency.

Figure 4: Arrhenius plot for the calculation of the activation energy EA and the impact factor k 0 of the hydroamination and isomerisation reaction.

Using the combined set of equations 1-4 with parameters in Table 1 the process of the hydroamination reaction of β-myrcene with morpholine could be predicted. The comparison of the plotted prediction and experimental data are illustrated Figure 5.



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Figure 5: Comparison of the predicted kinetics with experimental data; reaction conditions of the experiment: c(β-myrcene)=c(morpholine)=0.17 molL-1, c(Pd(tfa)2)= 6.86·10-4 molL-1, Pd:DPPB=1:4, T=100 °C,

500 rpm; TA = terpenyl amines, isomers = myrcene isomers; product

concentrations were determined via GC-FID-analysis.

It should be pointed out that the prediction of the kinetics of the hydroamination reaction matches very well with the experimental data up to a reaction time of 3 h. Beyond that, the concentration of the desired terpenyl amines 1 is slightly lower and the concentration of morpholine is significantly higher than the predicted concentrations. These results agree with the hypothesis that the hydroamination reaction of β-myrcene with morpholine is reversible for longer reaction and higher residence time. In case of a short reaction time and incomplete conversion of β-myrcene the kinetics of the hydroamination reaction could be reasonably modelled as irreversible. Membrane performance In order to select optimal operational parameters for the continuous membrane reactor/separator the crucial properties of the applied poly-ether-ether-ketone PEEK membrane were determined e.g. pure solvent flux and the rejection of the solutes. Detailed characterization of this membrane was published by da Silva Burgal et al.28, showing a nominal molecular weight cut-off in the range of 470 gmol-1. Having in mind that the palladium catalyst used for hydroamination has molecular weight of 106 gmol-1and the ligand of 426 gmol-1, it could be expected that the described PEEK membrane is suitable for organic solvent nanofiltration in the palladium catalysed hydroamination process. At first, the pure solvent flux was measured under specific reaction conditions. A characteristic pure solvent flux of 0.43 gm -2min-1 was affected under 10 bar pressure and a temperature of 100 °C. Subsequently, the specific rejections of the palladium and phosphorus compounds at different reaction temperatures were determined, which is presented in Figure 6. Therefore, similar to the reaction conditions a mixture of the precursor Pd(tfa)2 and the ligand DPPB was dissolved in toluene and the specific rejections were determined under continuous operation. Likewise, the rejections of substrate and the products were also determined (see supporting information).


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Figure 6: Rejection of palladium and phosphorus (mixture of Pd(tfa)2:DPPB=1:4, c(Pd(tfa)2)= 6.86·10-4 molL-1 in toluene) of the PEEK membrane at 90 °C, 100 °C and 120 °C reaction temperature under constant trans-membrane pressure of 10 bar.

Apparently, the rejection of the palladium species is independent of the applied temperature and within the range of 90%. The rejection of the phosphorus compound decreases with increasing of the temperature and reaches ~73% at 100 °C. Presumably, all palladium centres are occupied by ligand coordination at lower reaction temperatures resulting in higher molecular weight (MW of 958 gmol-1) than the free palladium catalyst and higher rejection of the palladium compared to the phosphorous ligand alone. With higher reaction temperature, the phosphorus rejection decreases. This could be an effect of a fast dynamic palladium complex ligand exchange that is more favoured at higher temperatures. Consequently, more DPPB ligand could permeate through the membrane. In particular, this issue has to be considered in a continuous process, in which a higher amount of the ligand has to be supplied in the feed to maintain the crucial ratio of ligand to palladium to maintain the selectivity and activity of the reaction. Continuous operation of the membrane reactor The reaction kinetics and rejection data were further used to develop a model describing a continuous reactor operation and optimise reactor operational parameters (see supporting information). The residence time of β-myrcene is crucial for the reactor efficiency. Based on the model prediction, a residence time of 4 h will provide highest conversion and selectivity. Moreover, the residence time of 4 h is a compromise of the feasibility between the adjusted feed stream and the resulting pressure in the system. Under an adjusted feed stream of 9.9 gh-1,a residence time of 4 h could be provided and the resulting pressure of 10 bar is in a feasible range. In this respect, it is necessary to mention that the applied residence time is only effective for the compounds with low rejection by the membrane. This corresponds to the intial target of the project that the palladium catalyst should be efficiently rejected and ideally, the β-myrcene is quantitatively converted to the terpenyl amines, which permeate through the membrane with less effort. All crucial reaction parameters (temperature, catalyst concentration in the feed stream, ratio of β-myrcene and morpholine) were taken into account during the experiment. The results of this first continuously operated hydroamination reaction of β-myrcene with morpholine are presented in Figure 7.



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Figure 7: Product yields in the permeate flux of the long-time continuous operated hydroamination reaction; reaction conditions containing the following

feed concentrations: interval I c(β-myrcene)=c(morpholine)=0.17 molL-1, c(Pd(tfa)2)= 6.86·10-5 molL-1, c(DPPB)=5.56·10-4 molL-1,

T=100 °C, 500 rpm, feed=9.9 gh-1; interval II c(β-myrcene)=c(morpholine)=0.17 molL-1, T=100 °C, 500 rpm, feed=9.9 gh-1; III = I; All product yields were determined via GC-FID-analysis.

The continuous operation in Figure 7 is subdivided in three intervals which differ in reaction conditions. In interval I, optimal reaction parameters of the hydroamination reaction were used. Over a period of 60 hours, the hydroamination reaction was performed in stable continuous operation. The desired terpenyl amines 1 were obtained in very good yields of 80% and excellent selectivity higher than 90%. Only the myrcene isomers 2 as by-products were observed in yields of 13%. Moreover, the permeate product solution contents less than 5 ppm palladium. These results demonstrate that the predicted reaction parameters excellently agree with the experimental data of the sensitive hydroamination reaction. By application of the PEEK membrane reactor, sustainability and economic feasibility can greatly be increased. However, to gain more insights in the reaction performance of the hydroamination reaction which is conducted in a membrane reactor, the catalyst system was omitted from the feed stream in interval II after 60 hours. As a result, both yields of terpenyl amines 1 and myrcene isomers 2 decrease steadily, but the selectivity of the desired terpenyl amines 1 remained nearly constant. The formation of traces of dimers 3 and telomers 4 as by-product could be observerd. These results suggest that the catalyst concentration decreases over time due to incomplete rejection by the membrane (Pd rejection ~90%, P rejection ~70%), but the activity and selectivity of the remaining catalyst complex nearly stays constant. On the other hand, the upcoming formation of by-products indicates a steady change of selectivity of the catalyst. The phosphorous rejection is less than the palladium rejection. Consequently, the amount of remained ligand decreases with time. As mentioned above, the palladium/phosphorous ratio is crucial reaction parameter for the selectivity of the hydroamination reaction. Summarizing, this is a good evidence for this approach. To investigate the robustness of this process, in interval III the initial feed composition was resumed. The yields of the desired terpenyl amines 1 gradually increased almost reaching the levels from interval I. Interestingly, the yields of the isomers 2 increased comparably slow and the resulting selectivity is higher than 90%. Conceivalby, the initial applied amount of ligand in interval III is more suitable for the reaction performance of the hydroamination reaction. In conclusion, the implementation of a PEEK membrane in a reactor to form one reaction separation unit is suitable to operate the hydroamination reaction continuously over days in a steady state, due to precise prediction of the point of operation using the previously described reaction/separation model. The comparison of experimental and calculated values can be found in the supporting information. The turn-over-number of the palladium catalyst as a characteristic value of a productivity of a process was increased up 5135, nearly twenty times higher compared to the batch process. The application of this unit leads to a dramatic increase of sustainability and process intensification.

Conclusions The hydroamination reaction of β-myrcene with morpholine was successfully implemented in a stable continuous flow process using a membrane reactor as integrated reaction and separation unit. The implementation was accomplished over three consecutive steps: determination of the reaction rates of the hydroamination reaction and optimal reaction conditions, characterization of the applied PEEK membrane in terms of specific rejections and pure solvent flux and finally, modelling the optimal reaction conditions of the hydroamination to establish a stable and selective process.


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Under optimal reaction conditions, 80% yield of the desired terpenyl amines 1 with a selectivity higher than 90% were generated in a 100 g scale over a period of 180 hours with marginal palladium pollution less than 5 ppm. This corresponds to a production capacity of 2.4 gh-1 of terpenyl amines 1, which is about 10 times higher than the productivity of comparable batch runs. Furthermore, the robustness of the process was demonstrated by deliberately introducing fluctuations in the feed composition after 60 hours of operation. Upon restoring the original feed composition the process gradually recovered its original steady state operation. In conclusion, the implementation of membrane reactor/ separator unit is highly suitable for continuously operated process of the sensitive palladium catalysed hydroamination reaction of β-myrcene with morpholine resulting in considerable increase of the catalyst turn-over-number from 460 to 5135 (as compared to batch operation).

Experimental Section All preparations were performed under a dry, oxygen free argon atmosphere using standard Schlenk techniques. Argon gas (99.998%) was purchased from AIR LIQUIDE Deutschland GmbH. The applied palladium precursor (97%) was purchased from ABCR GmbH & Co. KG. and the DPPB ligand (95%) from TCI GmbH. Toluene of >98% purity (dried prior application using molecular sieve) was used for the process. Morpholine was purchased from Alfa Aeser GmbH & Co. KG with a purity of 99%. Myrcene used was purchased from commercial suppliers and was of the highest purity available (90%, the major impurity are myrcene dimers). All received chemicals were used without further purification steps. 1H and 13C spectra were recorded on a Bruker model DPX500 spectrometer at room temperature. 1H and 13C NMR chemical shifts were reported on the d-scale (ppm) relative to Me4Si as an external standard. Precious metal and phosphorus content were measured by inductively coupled plasma optical emission spectrometry with an IRIS Intrepid ICP-OES spectrometer. Routine gas chromatographic analyses were done on a Agilent Technologies Inc. 7890b instrument equipped with an FI-detector and an HP5 capillary column (30 m, diameter 0.25 mm, film thickness 0.25 mm) in connection with an autosampler 7693 and an injector G4513a. GC-MS analyses were carried out with Agilent Technologies Inc. 5977a MSD mass spectrometer at 70 eV. General procedure for determination of the reaction rate The Hydroamination experiments were performed in a 300 mL autoclave from Parr Instrument Company. To determine the reaction rate Pd(CF3CO2)2 (45.6 mg, 0.14 mmol) and DPPB (232 mg, 0.54 mmol) were dissolved in anhydrous toluene (43.35 g, 50 ml). Then, β-myrcene (4.64 mg, 34 mmol) and morpholine (2.99 g, 34 mmol) were added and the mixture was treated by ultrasound for 20 minutes. Further 150 mL of the reaction mixture was transferred into the evacuated autoclave and charged with 5 bar of argon. Subsequently, the autoclave was heated to the desired temperature. After reaching the temperature, the reaction mixture was transferred into the stirred autoclave under a slightly higher pressure. In a defined frequency samples were taken and analysed via GC-FID. General procedure for continuous flow hydroamination reaction The hydroamination reaction in a continuous flow was performed in a 100 mL membrane reactor3 equipped with a polyether-ether-ketone (PEEK) membrane. A constant flow of feed was provided to the reactor by a HPLC pump. The equivalent flow of the mixture leaving the reactor as permeate was collected in a beaker glass. As feed Pd(CF3CO2)2 (13.68 mg, 0.042 mmol), DPPB as ligand (273,6 mg, 0.56 mmol), β-myrcene (2.387 g, 17.52 mmol) and morpholine (1.526 g, 17.52 mmol) were dissolved in 600 mL of anhydrous toluene and treated by ultrasound for several hours. The reaction mixture (in the membrane reactor) was continuously stirred at 500 rpm and maintained at 100 °C by heating the membrane reactor on a heating/stirring plate. . Samples of permeate and retentate were taken over time and the product distribution was measured via GC-FID analysis. General procedure for determination of the specific rejection Ri To determine separation efficiency, the so called rejection Ri is used, which measures feed concentration cF,I and the permeate concentration cp,I of component i: Ri =1-

cP,i cF,i

An Iris Intrepid ICP (Thermo Elemental) was used to determine of the palladium and phosphorous content in both phases. For this, 0.23 g of a sample was measured out in a Teflon cup and 2.5 mL nitric acid (65%) and 4 mL sulfuric acid (96%) were added. The digestion process was conducted in a MWS µPrep start-system microwave (MLS). Upon completion of the digestion process, the samples were treated with 2 ml distilled water and 1 mL of H2O2 (Fisher Scientific, Optima grade, phosphorous free). The prepared samples were allowed to rest for twelve hours before measurement. To examine the specific rejection Ri of the products of the hydroamination reaction, the GC-FID analysis was used.



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Purification and characterisation of the products The crude product mixture was purified via column chromatography (silica gel, cyclohexane : ethyl acetate 10:1) giving a mixture of E and Z isomers of the 1,3-head and tail terpenyl amines 1. 4-((3E/Z)-2-ethylidene-6-methylhepta-3,5-ien-1-yl)morpholine – 1: 1H-NMR (500 MHz, CDCl3): ppm(δ) = 1.57 (m, 6H), 1.72 (s, 3H), 2.04 (not resolved, m, 4H), 2.43 (t, 4H), 2.94 (s, 2H), 3.70 (t, 4H), 5.06 (t, 1H), 5.23 (t, 1H); 13C-NMR (125 MHz, CDCl3): ppm(δ) = 17.0, 18.2, 22.3, 26.9, 40.3, 54.2, 57.0, 67.6, 120.9, 124.6, 132.4, 139.9; MS: m/z (%)=223 (13), 208 (5), 193 (2), 178 (3), 166 (4), 154 (66), 140 (15), 124 (50), 108 (4), 100 (100); HR-MS: m/z C14H26ON [M+H]+ = 224.20093, ∆=0.18485 ppm. (E/Z)4-(3,7-diemethylocta-2,6-dien-1-yl)morpholine - 1: 1H-NMR (500 MHz, CDCl3): ppm(δ) = 1.62 (m, 6H), 1.68 (s, 3H), 2.06 (not resolved, m, 4H), 2.38 (t, 4H), 2.78 (s, 2H), 3.68 (t, 4H), 5.14 (t, 1H), 5.38 (t, 1H); 13C-NMR (125 MHz, CDCl3): ppm(δ) = 15.6, 17.5, 25.5, 26.3, 31.7, 53.5, 56.8, 67.2, 122.6, 124.4, 131.4, 136.4; MS: m/z (%)=223 (38), 208 (100), 193 (8), 178 (8), 166 (10), 152 (77), 138 (15), 122 (35), 108 (19), 100 (79); HR-MS: m/z C14H26ON [M+H]+ = 224.20078, ∆=-0.51625 ppm.

Supporting Information This manuscript is accompanied by a supporting information including rejections of all compounds, equations used for calculations of the reaction parameters, illustration of the general reactor/separation system and analytic measurements regardin to the membrane- and product characterisation.

Acknowledgements This work is part of the Sonderforschungsbereich/Transregio 63 “Integrated Chemical Processes in Liquid Multiphase Systems” (TRR63). The authors would like to thank the Deutsche Forschungsgemeinschaft (DFG) for financial support. Keywords: hydroamination • organic solvent nanofiltration • β-myrcene • modelling • continuous flow operation

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