Microwave-assisted Reductive Amination with Aqueous Ammonia

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Microwave-assisted Reductive Amination with Aqueous Ammonia: Sustainable Pathway using Recyclable Magnetic Nickel-based Nano-catalyst Maela Manzoli, Emanuela Calcio Gaudino, Giancarlo Cravotto, Silvia Tabasso, R. B. Nasir Baig, Evelina Colacino, and Rajender S. Varma ACS Sustainable Chem. Eng., Just Accepted Manuscript • DOI: 10.1021/ acssuschemeng.8b06054 • Publication Date (Web): 08 Feb 2019 Downloaded from http://pubs.acs.org on February 11, 2019

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ACS Sustainable Chemistry & Engineering

Microwave-assisted Reductive Amination with Aqueous Ammonia: Sustainable Pathway using Recyclable Magnetic Nickel-based Nano-catalyst Maela Manzoli, ǂ Emanuela Calcio Gaudino, ǂ Giancarlo Cravotto, ǂ * Silvia Tabasso, § R. B. Nasir Baig, ǁ Evelina Colacino,ǂ ,¥,† * Rajender S. Varma¶*

ǂ

Dipartimento di Scienza e Tecnologia del Farmaco and NIS - Centre for Nanostructured Interfaces and Surfaces, University of Turin, Via Giuria 9, 10125- Turin, Italy.

§

Dipartimento di Chimica, University of Turin, Via P. Giuria 7, 10125 Turin, Italy.

ǁ

Oak Ridge Institute for Science and Education, P. O. Box 117, Oak Ridge TN, 37831, USA

¥

Université de Montpellier, Institut des Biomolécules Max Mousseron (IBMM), UMR-5247 CNRS-UM-ENSCM, Place E. Bataillon, Campus Triolet cc1703, 34095 Montpellier Cedex 05 (France).

†

Institut Charles Gerhardt de Montpellier (ICGM), UMR-5253 CNRS-UM-ENSCM, Ecole Nationale Supérieure de Chimie de Montpellier, 8 Rue de l’Ecole Normale, 34296, Montpellier Cedex 05 (France).

¶

Regional Centre of Advanced Technologies and Materials, Department of Physical Chemistry, Faculty of Science, Palacky University, Šlechtitelů 27, 783 71 Olomouc, Czech Republic.

Corresponding Authors *E-mail: [email protected]; [email protected]; [email protected]

KEYWORDS: Microwave irradiation, reductive amination, silica-supported Ni catalyst, nanocatalysis, sustainable chemistry. 1 ACS Paragon Plus Environment

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ABSTRACT: The development of sustainable protocols for the reductive amination is a highly desirable pursuit in the domain of green synthesis. Magnetic nano-catalysts have found a unique niche in chemical synthesis in recent years as the recovery of expensive and/or toxic catalysts after their use are some of the salient features of these greener processes. Herein, we report the application of a recyclable nickel silica eggshell iron-based magnetic nanoparticles (Fe3O4@SiO2-Ni) for the expeditious microwave-assisted reductive amination of aryl aldehydes and ketones in aqueous ammonia; several desired primary amines were produced in good to excellent conversions. Extensive characterization of both, fresh and recycled Fe3O4@SiO2-Ni catalysts, showed that the Ni nanoparticles are highly dispersed on the silica shell and that the metal active phase is highly stable as the core-shell morphology is maintained after reaction, indeed the catalyst is recyclable up to six runs without deactivating. A synergic effect between the Ni nanoparticles and the silica support has been hypothesized wherein the Fe3O4@SiO2-Ni system worked as a bifunctional catalyst; support facilitates the activation of the substrate and the metal nanoparticles promote the subsequent imine hydrogenation.

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INTRODUCTION Nitrogen-containing compounds, especially primary amines, are useful building blocks for the synthesis of polymers, dyes, surfactants, pharmaceuticals, and agrochemicals. The synthesis of primary amines has been pursued recently via direct reductive amination of aldehydes using ammonia as nitrogen source. However, the transition metal-catalyzed reductive aminations have frequently been accompanied by unwanted side product(s) due to the reduction of aldehyde to an alcohol.1-3 The improvements in the sustainability aspects of the processes entails the use of heterogeneous catalysts under milder reaction conditions.1, 3-4 Noble metal catalysts such as Pd, Pt, and Rh have been applied in reductive amination reactions due to their excellent hydrogenation and dehydrogenation effectiveness.5-6 However, they are very expensive, and expectedly the development of alternative earth-abundant catalysts have been receiving increasing attention; Ni- and Co-containing catalysts have been exploited for the reductive amination reactions because of their selective activity.7-8 Sewell et al.9 investigated the amination of alcohols over Ni- or Co-catalysts supported on SiO2; a higher EtOH conversion was obtained for the Co-based catalyst compared to that of the Ni-based counterpart, although selectivity towards the formation of different amine species varied depending on the metal type. More specifically, the Co favored the production of the primary amine, while the Ni-based catalyst was more selective towards the formation of the secondary amine; both cases, however, entails the oxidation of EtOH first to the corresponding acetaldehyde. The amination of EtOH was recently reported by Park et al.10 over a Ni/Al2O3 (nickel loadings 5-25 wt%) catalytic system describing excellent catalytic performance over 90 h reaction under 190 °C, and EtOH/NH3/H2 molar ratio = 1/1/6. As the recyclability of the catalysts is a crucial issue in terms of sustainability, magnetic nanoparticles represent a breakthrough in the field of green synthesis.11 Among these, supported iron oxide nano-catalysts have been the focus of different catalytic applications 3 ACS Paragon Plus Environment


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because of their low cost and toxicity, ready availability, and environmentally benign nature.1213

Recently, a AuPd alloy nanocatalyst supported on Fe3O4 was employed for a one-pot

reduction of a nitro compound followed by reductive amination of the ensuing amine.14 The relentless demand for more sustainable processes requires an efficient and safer energy transfer that can be achieved via microwave (MW) dielectric heating. The advantages related to the use of MW in organic synthesis are well documented in literature;15-17 MW promote remarkable reduction of reaction time, improved yields and attain cleaner reactions compared to conventional thermal heating.18 MW irradiation is therefore a suitable tool to overcome the limitations encountered in challenging organic reactions,19 such as direct reductive amination in the presence of heterogeneous catalysts17 and gaseous reagents. Very recently, continuous flow strategy has been successfully applied to perform reductive amination reactions in the presence of gold20 or nickel21-23 heterogeneous nanocatalysts, thus increasing the throughput for more challenging transformations. The use of magnetically recoverable nanoparticles as eco-friendly catalysts for development of sustainable processes, coupled to enabling technologies, has grown at a rapid pace paving the pathway to a large panel of applications in organic synthesis. Indeed, nanosized magnetic materials have ideally bridged the gap between hetero- and homogeneous catalysis, capitalizing on the advantages of both of the systems, due to an exposed highly robust surface area that favours the contact between the reactants and the catalyst. Additionally, the quasihomogeneous catalytic attribute for an easy separation and isolation of nano-sized catalytic system from the reaction mixture simply using an external magnet, thus reducing the loss of catalysts while enhancing its recyclability.24-30 The naturally abundant and inexpensive ferrites have been widely investigated in view of their stability under harsh conditions, and low toxicity. Benign organic syntheses have been


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successfully accomplished in aqueous media, at room temperature or under MW activation, using various ferrite-supported metal-nanocatalysts namely Cu,31-34 Mn,35 Ni,12 Pd,36-39 and Ru40-43 via a post-synthetic functionalisation of the magnetic core by anchoring organic or inorganic capping agents, such as glutathione (GT),31, 33, 44-45 dopamine (DOPA)12, 32-33, 39, 42-43 or silica (SiO2)34, 36, 40-41. The versatility of the supported nano-ferrite metal-catalysts and their robustness during the synthesis has been demonstrated, with absence of leaching in most of the cases; subtle differences in the ligand-based activity has been observed.33 With the aim for a broad-based use of nano-ferrite metal-coated catalysts for more challenging transformations, we focused our attention on the reductive amination reaction of carbonyl compounds. Nickel was selected as metal of choice for nano-ferrite functionalization not only because of its potential inherent stability, activity, and reduced cost, but also its containment as no leaching was discernable, in view of any toxicity to humans.46 Herein, we report an efficient and heterogeneous catalytic system based on nickel-based silica eggshell iron-based magnetic nanoparticles (Fe3O4@SiO2-Ni) for an expeditious and quantitative reductive amination of aldehydes and ketones; amination reactions were performed in aqueous ammonia under MW irradiation conditions in the presence of molecular H2. The Fe3O4@SiO2-Ni catalyst can be easily recovered from the reaction mixture with a magnetic bar and reused. This process afforded excellent conversions for primary amines under milder reaction conditions and was also extended to some biomass-derived aldehydes as well. The characterization showed that the coexistence of Ni nanoparticles highly dispersed on the silica shell covering the Fe3O4 core played a crucial role on the selectivity to primary amines. EXPERIMENTAL SECTION



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Catalyst preparation Synthesis of magnetic silica-supported nickel catalyst was acheived using the sequential addition of reagents as depicted in Scheme 1. In-situ generation of magnetic nanoferrites Fe3O4 was performed by stirring the aqueous solution of Fe2(SO4)3 and FeSO4·7H2O at 50 °C for 1 h using ammonium hydroxide solution (pH adjusted to ~10 using 25 % NH4OH). After the hydrolysis, the reaction was brought down to room temperature followed by the addition of tetraethyl orthosilicate (TEOS). The reaction mixture was stirred for additional 24 hours at room temperature. To this suspension, NiCl2 was added and the pH of the solution was adjusted to 10 using NH4OH (25 %) and the mixture stirred for another 12 h (Scheme 1). The synthesized magnetic silica-supported Ni nanoparticles (Fe3O4@SiO2-Ni) were separated using an external magnet,25 washed with water, followed by acetone, and dried under vacuum at 50 °C for 12 h.

Ni FeSO4.7H2O + Fe2(SO4)3

Ni

Ni NH4OH / H2O

TEOS

NiCl2

1 h, 50 oC

24 h, rt

12 h, rt

Fe3O4

Ni

Ni Ni

Fe3O4@SiO2

Ni Ni

Fe3O4@SiO2-Ni

Scheme 1. Preparation of Fe3O4@SiO2-Ni Microwave-assisted reductive amination MW-promoted reactions were carried out in the SynthWAVE reactor (Milestone Srl, Italy; MLS GmbH, Germany), a multimode system that enables multiple gas inlet. This instrument, equipped with a high-pressure stainless-steel reaction chamber, can work up to a maximum of 300 °C temperature and 199 bar, enabling MW reactions both on small (mL; racks up to 15 or 22 tubes/samples simultaneously) and large scale (L). Moreover, integrated reactor sensors 6 ACS Paragon Plus Environment

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continuously monitor the internal pressure, temperature and power applied inside the reactor cavity during all reactions run, adjusting the applied MW power in real time to follow a predefined temperature profile. A sampling valve on the bottom of the reactor is directly connected to the cooling chamber. The GC-MS analyses were performed with an Agilent 6890 system (Agilent Technologies, USA) fitted with a mass detector Agilent Network 5973 using a 30 m long capillary column, i.d. of 0.25 mm and a film thickness of 0.25 m (MEGA-MS); collection of GC-MS spectra is available in SI (Figure SI-3). General Procedure for Fe3O4@SiO2 Ni catalyst recycling The Ni catalyst (Fe3O4@SiO2-Ni) magnetically removed from the crude mixture after the first run was washed twice with ethanol (3 mL), dried under vacuum at room temperature and reused in the next runs under the same optimized reaction conditions. The recycling experiments were performed using benzaldehyde (1 mmol) as substrate, according to the reaction procedure previously described. Benzylamine was obtained after the same work up protocols and the conversions of the recycling tests were determined by GC-MS. The catalyst structure and the Ni loading were also analyzed after recycling. Characterization techniques Transmission electron microscopy (TEM) and high resolution TEM (HR-TEM) measurements were performed using a side entry Jeol JEM 3010 (300 kV) microscope equipped with a LaB6 filament and fitted with X-ray EDS analysis by a Link ISIS 200 detector. For analyses, the powdered samples were deposited on a copper grid, coated with a porous carbon film. All digital micrographs were acquired by an Ultrascan 1000 camera and the images were processed by Gatan digital micrograph. A statistically representative number of particles was counted in order to obtain the Ni (more than 200) and Fe3O4 (more than 100) particle size distributions.



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The mean particle diameter (dm) was calculated as dm = Σdini/Σni, where ni was the number of particles of diameter di. Metal Specific Surface area (Ni SSA, m2/g) of supported metal particles (supposed to be spherical) was also determined on the basis of the particles size distribution, by the formula SSA=3niri2/(Niniri3) m2/g, where ri is the mean radius of the size class containing ni particles, and Ni the volumetric mass of Ni (8.9 g/cm3). On the basis of the amount of catalyst used in the catalytic tests (17.47 mg) and of the Ni loading (16.8 wt%, by ICP-OES), the theoretical metal area (Ni SA, m2) was also calculated. The calculations on both Ni SSA and theoretical Ni SA have been reported in the Supporting Information (Tables SI-1 and SI-2). X-ray powder diffraction (XRD) patterns were collected with a PW3050/60 X'Pert PRO MPD diffractometer from PANalytical working in Bragg–Brentano geometry, using as a source the high-powered ceramic tube PW3373/10 LFF with a Cu anode (λ = 0.541 Å) equipped with a Ni filter to attenuate Kβ. Scattered photons were collected by a real time multiple strip (RTMS) X'celerator detector. Data were collected in the 20° ≤ 2θ ≤ 90° angular range, with 0.02° 2θ steps. The samples were examined in their as-received form. For diffuse reflectance (DR) UV–Vis-NIR analysis, powders were placed in a quartz cell, allowing treatments in controlled atmosphere and temperature, but spectra were recorded only at room temperature (r.t.). DR UV–Vis-NIR spectra were run at r.t. on a Varian Cary 5000 spectrophotometer, working in the range of wavenumbers 190-2500 nm and are reported in the Kubelka-Munk function [f(R∞)=(1−R∞)2/2R∞; R∞ = reflectance of an “infinitely thick” layer of the sample. A PHI 5000 VersaProbe Scanning X-ray photoelectron spectrometer (XPS), with an Al k-alpha source at 1486.6 eV, was used in order to investigate the surface chemical composition. The spectra obtained from the XPS analysis have been corrected by referencing the C1s line to 284.5 eV. The total Ni contents were determined by ICP-OES with a Perkin Elmer Optima 7000


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(Perkin Elmer, Norwalk, CT, USA) spectrometer by standard addition; the Ni emission wavelength selected being 231.604 nm. RESULTS AND DISCUSSION Characterisation of the fresh catalyst A representative TEM image of the Fe3O4@SiO2-Ni catalyst is reported in Figure 1a which shows that the catalyst support has a core-shell morphology, schematised in the sketch shown in Figure 1b, in which the core is made up by Fe3O4 particles with globular shape and have a mean diameter of 11.5 ± 2.3 nm (Figure 1d). The HR-TEM image in Figure 1b shows the lattice fringes corresponding to an interplanar distance of 0.48 nm that can be attributed to the (111) plane of the Fe3O4 cubic phase (JCPDS file number 00-001-1111).

a

b

SiO2 Crystalline Fe3O4

Ni nanoparticles

5 nm

10 nm

c

60

d

40

50 30

n.p. [%]

40

n.p. [%]

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


30

20

20 10

10 0

0 0

1

2

3

4

Ni particle size [nm]

5

0

5

10

15

20

25

Fe3O4 particle diameter [nm]



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Figure 1. TEM image of the fresh Fe3O4@SiO2-Ni catalyst in which the presence of Ni nanoparticles is highlighted by black arrows (section a). HR-TEM image of the fresh Fe3O4@SiO2 catalyst and sketch showing the Fe3O4@SiO2 core-shell morphology of the catalyst along with the presence of supported Ni nanoparticles (section b). Ni and Fe3O4 particle size distributions (sections c and d, respectively). Instrumental magnification: 200000X (section a) and 400000X (section b).

The subsequent Ni insertion/deposition resulted in the presence of highly dispersed Ni nanoparticles (signalled by black harrows in Figure 1a) with average size of 1.9 ± 0.5 nm. Moreover, the results obtained by TEM and HR-TEM characterization pointed out the presence of nickel nanoparticles homogeneously distributed. Basing on the particles size distribution reported in Figure 1c, the metal specific surface area (SSA) was calculated and it was found to be Ni SSA of 141.1 m2/g (see Table 1).

Table 1. Ni average size, metal SSA and SA, and Fe3O4 average size obtained for the Fe3O4@SiO2-Ni catalyst. Fe3O4@SiO2-Ni catalyst Pretreatment

Ni average size

Ni SSA

Ni SA

Fe3O4 average size

(nm)

(m2/g)

(m2)a

(nm)

Fresh

1.9 ± 0.5

141.1

0.4

11.5 ± 2.3

After the first run

1.8 ± 0.3

167.1

0.5

12.5 ± 2.9

a

Calculated on the amount of catalyst used in the first run (3 mg Ni).

XRD measurements were carried out in order to check the nature of the crystallographic phases of the Fe3O4 core and the possible presence of crystalline Ni nanoparticles. The diffraction pattern of the fresh Fe3O4@SiO2-Ni catalyst (a line) is shown in Figure 2. The presence of peaks related to crystalline Ni in the cubic phase (JCPDS file number 00-001-1260) is put in


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evidence by the blue dashed lines. Indeed, the two weak peaks at 2 44.6 ° and at 2 52.3° are assigned to the (111) and (200) main peaks of cubic Ni. Crystalline Ni0 nanoparticles are supported on amorphous silica, conversely the Fe3O4 core is made up by crystalline magnetite in the cubic form (JCPDS file number 00-001-1111).

1500

1000

(b)

533

422 511

400

220

500

440

311

Cps

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(a)

0 20

30

40

50

60

70

80

90

2 Theta

Figure 2. XRD patterns of the fresh (a line) and used (b line) Fe3O4@SiO2-Ni catalyst.

Further insights on the presence of different Ni species can be obtained by DR UV-Vis-NIR analysis reported in Figure 3. The fresh Fe3O4@SiO2-Ni catalyst strongly absorbs at 35000 cm-1, and possesses a shoulder at 20900 cm-1, the former signal is due to charge-transfer transitions (CT) from O2- to isolated octahedral (Oh) Fe3+ ions, the latter to d-d transitions of Fe3+.47-48



40 35 30

Kubelka-Munk

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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25

15

20900

20 10

15 17800

10

5

6900

5 0 22500

0 50000

20000

17500

40000

15000

30000

20000

10000

-1

Wavenumbers [cm ]

Figure 3. DR UV-Vis spectrum of the Fe3O4@SiO2-Ni fresh catalyst. Inset: zoom on the 22500-15000 cm-1 region. However, the component at 20900 cm-1 could also be due to the presence of Ni2+ species. Bands in similar positions were assigned to Ni2+ in the octahedral arrangement49 and to Ni[O] in surface NiAl2O4-like spinel.50 Since no diffraction peaks related to the presence of the NiO phase were observed in the XRD pattern (Figure 2, a line) it should be reasonable to conclude that the NiO species are highly dispersed on the catalyst surface. In addition, a weak component at about 16950 cm-1 can be barely observed and could be assigned to Ni2þ ions in tetrahedral coordination caused by the presence of Ni species in the spinel-like structure of NiAl2O4.51 Finally, in the NIR region, the band at 6900 cm-1 is due to the presence of OH groups at the SiO2 surface. To further investigate the elemental composition and chemical states of the Fe3O4@SiO2-Ni fresh catalyst, X-ray photoelectron spectroscopy (XPS) analysis was performed. The fine-scan XPS of the Ni region is shown in Figure 4. The Ni 2p1/2 and Ni 2p3/2 signals of the fresh catalyst 12 ACS Paragon Plus Environment

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are observed at 873.4 and 855.7 eV, respectively. The appearance of satellite peaks (labelled sat. in Figure 4) implies the presence of a high spin divalent state of Ni2+ in the sample.52

Ni 2p3/2

Intensity (a.u.)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Ni 2p1/2 sat.

900

890

880

sat.

870

860

850

840

Binding Energy (eV)

Figure 4. Ni 2p XPS spectrum of the Fe3O4@SiO2-Ni fresh catalyst.

XPS measurements reveal that the oxidation state of Ni is 2+, in agreement with literature results on similar systems.53 The apparent inconsistency with the XRD results, which revealed the presence of Ni0 nanoparticles (Figure 2, a line) can be explained by considering that the catalyst was exposed to air. Even though the samples were cleaned by plasma etching before XPS analyses, exposure to air caused surface oxidation resulting in surface NiO formation, in agreement with the DR UV-Vis and XPS results. Moreover, the weak XPS C1s signal of the fresh catalyst can be deconvoluted into three peaks (Fig. SI-1, section a), with the main peak at 284.5 eV corresponding to the formation of C-C bonds and the two components at higher energy can be related to oxidized carbon species.54 The O1s XPS spectrum is reported in Figure SI-1, section 13 ACS Paragon Plus Environment


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b. The signal deconvolution put in evidence the presence of four peaks. The very weak component at higher energy can be related to the presence of organic C, whereas the main peak at 532 eV is due to the silica layer. The peaks at 530 eV is possibly due to surface metal carbonates and the component at 529.6 eV is ascribed to NiO. Microwave-assisted reductive amination The direct amination of aldehydes to primary amines in presence of aqueous ammonia has been recently explored in the presence of supported Ru, Mo or Pd catalysts1, 3, 55 However, the effective heterogeneous catalytic systems that enables a fast amination reaction under milder conditions4 (e.g., temperature < 150 °C, pressure < 50 bar, time < 12 hours), are still illusive. Heterogeneous catalysts often prevent metal leaching into reaction products, a feature of crucial importance when dealing with common pharmaceutical intermediates and precursors, such as primary amines. For this reason, our attempt was to combine the advantages of dielectric heating and those coming from the non-uniform heating at the surface of heterogeneous catalysts; the formation of “hot spots” by MW irradiation, ensuing non-equilibrium localized heating at the surface of the metal nanoparticles present on the magnetically recoverable nickel (Ni) catalyst,56 will culminate in a sustainable protocol for the synthesis of primary amines.27, 57

The synergistic combination of heterogenous catalysis and the alternative activation MW technique could help develop a sustainable protocol,57 affording good to excellent yields under mild reaction conditions. The multi-mode MW reactor used for the reductive amination was equipped with a pressure control system and a multiple position rack, suitable for multiple gas loading (both inert or reactive one) and parallel reaction runs (Figure 5a). Easy reaction scaleup (up to 10 mol scale) could be also achieved in the same reactor using different reaction vessels (maximum 1 L capability). Moreover, the MW reactor was equipped with a sampling


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valve (Figure 5b) directly connected to a cooling chamber (Figure 5b) that enables the recovery of aqueous ammonia used in excess. The recovered ammonia was re-condensed at low temperatures (SI-Video 2) and used directly for the subsequent reaction cycles.

(a)

(b)

Figure 5. a) MW multimode reactor used for the reductive amination reaction. b) Sampling tools on the bottom of the MW reactor directly connected to a cooling chamber for ammonia recovery.

Benzaldehyde was at first used as a model substrate to test the MW-assisted reductive amination under H2 pressure over magnetically recoverable Fe3O4@SiO2-Ni in the presence of aqueous ammonia (Scheme 2).

= Fe3O4 core

= SiO2 shell

Scheme 2. Nickel-catalyzed reductive amination reaction 15 ACS Paragon Plus Environment


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Benzylamine, a common industrial chemical intermediate, is usually produced by direct hydrogenation of benzonitrile using several solid metal catalysts.58 Since the price of benzonitrile is significantly higher than that of benzaldehyde (around ~2750 € and 1500 € t–1 bulk, respectively)59 the aim of this study was in the first instance to describe a sustainable process that would provide the highest benzylamine production starting from cheaper benzaldehyde, and finally to broaden the range of substrates to be efficiently converted to primary amines. As benzaldehyde is a naturally occurring substrate, some other biomassderived aldehydes were also tested, in order to overcome the shortage of aldehydes feedstocks from petrochemical industry, meeting the Green Chemistry requirement for renewable feedstocks. To achieve the best catalytic performance, the influence of critical reaction parameters (i.e. temperature, time, H2 pressure, and catalyst loading) on MW-assisted reductive amination of benzaldehyde was investigated (Table 2). Using the magnetically recoverable Fe3O4@SiO2Ni catalyst, the reactions were performed first on 1 mmol scale in aqueous ammonia solution at 95 °C under 20 bars of H2 pressure. Adopting a catalyst loading corresponding to the 10 wt % of Ni, in only 4 hours of MW irradiation, benzylamine was obtained at 98 % GC-MS conversion as the only reaction product (Table 2, entry 5) as the direct benzaldehyde hydrogenation was avoided over the Ni catalyst. It was demonstrated recently that unsaturated N-containing intermediates, i.e. primary imines adsorb on the Ni catalyst surface stronger than the aldehyde, and thus restrict hydrogenation of the aldehyde to the alcohol.59 The possibility to reduce the amount of metal while slightly increasing the temperature represents another sustainably important goal. Indeed, even better results (100 % GC-MS conversion) were obtained by increasing reaction temperature until 115 °C and by halving the catalyst loading


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(Table 2, entry 10). In this frame, we tried also to reduce the reaction time. Full conversion to benzylamine was achieved in only two hours of MW irradiation while keeping the Fe3O4@SiO2-Ni catalyst loading fixed at 5 wt. % of Ni and the H2 pressure at 20 bars (Table 2, entry 10). A number of attempts were finally carried out to cut down the applied H2 pressure, but unfortunately, when operating below 20 bars (Table 2, entries 13-15) it was not possible to reproduce the excellent result achieved under the optimized conditions (Table 2, entry 9). As mentioned before, in all reported reductive amination conditions (Table 2), benzylamine was the only detected product and neither aromatic ring hydrogenation nor toluene production was recorded. At the same time the formation of benzoic acid was not observed, contrarily to previously reports in the literature,59 due to a partial metal leaching from the Ni catalyst used (SiO2-Ni or Raney Ni). In order to demonstrate the synthetic utility of this protocol, gram-scale reactions were carried out under the optimized conditions (115 °C, 2 hours), by reacting benzaldehyde (10 mmol), in the presence of Fe3O4@SiO2-Ni catalyst under 20 bars of H2, in aqueous ammonia. The reaction proceeded well by generating benzylamine in an 89% isolated yield (Table 2, entry 10c), as anticipated from the results of previous smaller–scale trials (Table 1, entry 10). For the sake of comparison, the optimized MW-assisted reductive amination procedure (115 °C, 20 bar H2, aqueous ammonia solution), was repeated under conventional heating using a Parr device (40 mL scale). After a reaction time of 24 h, benzylamine yields dropped to 73% (Table 1, entry 10), compared to 100% after 120 min under MW irradiation (Table 2, entry 10). A blank experiment, without any catalyst, was also performed. The results showed that no reaction occurred in the absence of catalyst. Table 2. MW-assisted Reductive amination of benzaldehyde: optimization of reaction parameters.



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Reaction conditions Entry

a

Fe3O4@SiO2-Ni catalyst H2 pressure metal loading (wt%)

(bar)

Temp.

Time

Conversionsb

(°C)

(h)

(%)

1

2.5

4

34

2

5

4

75

3

5

2

52

4

5

1

40

5

10

4

98

6

10

2

78

7

10

1

55

8

2.5

4

47

9

5

4

100

10

5

2

100 (89)c (73)d

11

5

1

83

12

5

0.5

75

13

5

15

2

73

14

5

10

2

55

15

5

5

2

< 30

95

20

115

a

Reactions performed under MW irradiation on a 1 mmol scale of aldehydes, in the presence of Fe3O4@SiO2-Ni catalyst, H2 pressure using 750 L aqueous ammonia (25 wt %) and 75 L of ethanol. b Determined by GC-MS. c Reactions performed under MW irradiation on a 10 mmol scale. d Reaction performed under conventional heating in 12 h. Encouraged by these results, we decided to test a wide range of substrates in order to establish the scope and limitations of the optimized heterogeneous Ni-catalyzed reductive amination procedure. A broad range of aromatic aldehydes was reacted simultaneously (rack up to 22 samples) on 1 mmol scale under MW irradiation in the presence of the Fe3O4@SiO2-Ni catalyst to furnish the desired primary amines in good to excellent conversions (Table 3). It was noteworthy that a wide range of synthetically useful functional groups, including halides, ethers and nitro groups remained intact over the course of the MW-reductive amination of para- and


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ortho-substituted benzaldehydes enabling the full conversion to corresponding primary amines (Table 3). Slightly lower conversions (70 %) were recorded when p-(methylthio) benzaldehyde was used as starting material (Table 3, entry 5) causing also an unexpected change in the color of the catalyst (the catalyst color turned from dark brown to orange) presumably due to the partial Ni catalyst poisoning by sulfur as has been previously documented,60 together with no experimental evidence of the presence of sulfur oxidation by-products in the crude mixture. Unexpectedly, poor amination conversions (40% and 5%, respectively) were recorded for the bio-derived p-hydroxy benzaldehyde and vanillin (Table 3, entries 6 and 8), and no conversion for the o-hydroxy substituted substrate (Table 3, entry 7). These worse results were probably due to the competition on the catalyst surface between the imine intermediate and the hydroxyl group of the benzaldehyde structure, and in the case of o-hydroxy-substituted benzaldehyde (entry 7) the reaction might be completely inhibited by the formation of a stable six membered structure via a bridged hydrogen bonding between the hydroxyl and the carbonyl groups. Moreover, the occurrence of steric hindrance effects cannot be excluded in the case of the osubstituted benzaldehyde. It has been recently reported that batch reductive amination of benzaldehyde occurs on Ni and entails two distinct stages, with the formation of the benzylimine intermediate which is adsorbed on active sites of the Ni catalyst and then its gradually hydrogenation.59 However, the authors emphasized a crucial role of the Ni active sites in the reductive amination of benzaldehyde, without taking into consideration the possible influence of the support. With this in mind, we tested the reaction in the same experimental conditions with two other Ni catalysts having analogous core-shell morphology, in which the Fe3O4 core was surrounded by a shell layer made up by either glutathione (Fe3O4@GT-Ni) or dopamine (Fe3O4@DOPA-Ni)12 (Figure SI-2). We found that both catalysts showed no catalytic activity (data not shown), pointing out the role of the silica shell in the Fe3O4@SiO2Ni catalyst in terms of beneficial interaction with the substrate. Indeed, the inactivity of the



Page 20 of 40

glutathione and the dopamine-coated catalysts might be due to the presence of organic surface groups possibly playing a role in the catalytic pathway. However, in the case of Fe3O4@GTNi catalyst, the GC-MS analysis of the crude showed the presence of partial hydrolysis of peptide backbone, in basic medium61 or due to pH-dependent self elimination degradation mechanism of glutathione.62 It can be proposed that the competition between the imine intermediate and the hydroxyl group of benzaldheyde takes place on the silica support, possibly at the perimeter area close to the Ni nanoparticles, on which the hydrogen molecule is activated and the selective hydrogenation occurs. We also found that the MW reductive amination procedure (2 h MW irradiation at 115° under 20 bar of H2 pressure) enabled the full conversion of different (biomass-derived) alkenyl aldehydes (Table 3) in the presence of the magnetically recoverable Fe3O4@SiO2-Ni catalyst (5 wt%). Myrtenal (Table 3, entry 17) and various para-substituted cinnamaldehydes (Table 3, entries 18-20) were selectively aminated to the corresponding primary amines preserving their double bond in α position. Partial hydrogenation of alkenyl aldehydes to corresponding alkyl amines (Table 3, entries 17c/d-20c/d) was only detected by increasing reaction time up to 4 h at 115 °C (Table 3, entry 17c-20c) or raising temperature up to 150 °C in 2 h of MW irradiation (Table 2, entry 17d-20d). Noteworthy is that in this case the hydroxyl group present on the cinnamaldehyde phenyl ring (Table 3, entry 18) did not inhibit the Fe3O4@SiO2-Ni catalytic activity as observed previously for the phenolic aldehydes which provided unsatisfactory conversions (Table 3, entries 6, 7, 8). According to the sketch shown in Scheme 3, this is probably due to the increased distance between the aldehyde moiety and hydroxyl groups on the substrate, that does not prevent the interaction between the imine intermediate with the catalyst surface, an essential feature to produce the corresponding amine, although the strong interaction between the hydroxyl group and the silica support still persists.


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Scheme 3. Interaction among different substrates and the catalyst surface.

Table 3. Reductive MW-assisted amination of aldehydes. Entrya

Substrate

Product

Conversions (%)b

1

100

2

100

3

100

4

100

5

70



Page 22 of 40

6

40

7

0

8

5

9

100

10

100

11

100

12

100

13

100

14

100

15

100


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16

5

17

100 (23)c (45)d

18

100 (41)c (57)d

19

100 (40)c (59)d

20

100 (41)c (56)d

a

Reactions performed under MW irradiation (2 hours, 115°C) on a 1 mmol scale of aldehydes, in the presence of Fe3O4@SiO2-Ni catalyst (5 wt. % loading), H2 (20 bar), using 750 µL aqueous ammonia (25 wt %) and 75 µL of ethanol. b Determined by GC–MS. c Reactions performed under MW irradiation (4 hours, 115°C). d Reactions performed under MW irradiation (2 hours, 150°C) The applied catalytic system also exhibited excellent potential for the reductive amination of heteroaromatic aldehydes (Table 4). In particular, 2-furan-, 2-imidazole, 2-thiophene, 3pyridine, 3-indole carbaldehyde moieties were reductively aminated in aqueous ammonia in the presence of the Fe3O4@SiO2-Ni catalyst under H2 pressure (20 bar). All MW-assisted reactions proceeded efficiently and gave the desired amine products in good to excellent conversion (65-100%) under 3h of MW irradiation at 115 °C (Table 4, entries 1-7). Importantly, this protocol can be applied successfully to the biomass-derived furfural, with a 100% product conversion.

Table 4. Reductive MW-assisted amination of Heteroaromatic aldehydes 23 ACS Paragon Plus Environment


Entrya

Substrate

Products

Page 24 of 40

Conversions (%)b

1

100

2

100 (100)c

3

100 (100)c

4

65

5

100

6

100

7

100

a

Reactions performed under MW irradiation (3 hours, 115°C) on a 1 mmol scale of aldehydes, in the presence of Fe3O4@SiO2-Ni catalyst (5 wt. % loading), H2 (20 bar), using 750 µL aqueous ammonia (25 wt %) and 75 µL of ethanol. b Determined by GC– MS. c Reactions performed under MW irradiation (4 hours, 115°C) led to the corresponding bis-amino derivative. It is worth noting that the nitro group (Table 3 entries 14 and 20; Table 4 entries 2 and 3) were not hydrogenated at 115 °C up to three hours reaction. However, the corresponding bis-amino derivatives were obtained upon prolonged heating (Table 4 entries 2 and 3), which is in agreement with results obtained using similar catalysts for the hydrogenation of nitroaromatic in water.63


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In comparison with aldehydes, the reductive amination of ketones is more challenging because of their lower reactivity. Although the reaction conditions required additional optimization, encouraging results were obtained while exploring the case of acetophenone as benchmark substrate (Scheme 4). The Fe3O4@SiO2-Ni catalyst was still able to afford the secondary amine in 4 hours reaction when used at 10% wt. metal loading under MW irradiation at 150 °C (Table 5, entry 6). It has been reported for example that the reductive amination of acetophenone with ammonia required up to 20 h at 80 °C over Ru/ZrO24 or Pt-MoOx/TiO21 while double coated Fe3O4@SiO2-amine@ACF-Ni catalyst (ACF = 2-acetylfurane) was effective at room temperature.64 The reductive amination of different ketones is still under progress using the described magnetically recoverable Ni catalyst.

= SiO2 shell

= Fe3O4 core

Scheme 4. Benchmark for the reductive amination reaction of ketones.

Table 5. Screening of the conditions for MW-assisted acetophenone reductive amination. Reaction conditions Entrya

Ni loading

Temp.

Time

Conversions

(wt%)

(°C)

(h)

(%)b

1

5

115

4

Microwave-assisted Reductive Amination with Aqueous Ammonia

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