Acceptorless Amine Dehydrogenation and Transamination Using Pd

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Acceptorless amine dehydrogenation and transamination using Pd-doped hydrotalcites Diana Ainembabazi, Nan An, Jinesh C Manayil, Karen Wilson, Adam Fraser Lee, and Adelina M. Voutchkova-Kostal ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b03885 • Publication Date (Web): 20 Dec 2018 Downloaded from http://pubs.acs.org on December 20, 2018

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ACS Catalysis

Acceptorless amine dehydrogenation and transamination using Pd-doped hydrotalcites

Diana Ainembabazi,a Nan An,a Jinesh C. Manayil,b Karen Wilson,b Adam F. Lee*b and Adelina M. Voutchkova-Kostal*a a

Chemistry Department, The George Washington University, 800 22nd St NW, Washington, D.C.

20052, USA; bSchool of Science, RMIT University, Melbourne, VIC 3001, Australia

ABSTRACT

The acceptorless dehydrogenation of acyclic secondary amines is a highly desirable but still elusive catalytic process. Here we report the synthesis, characterization, and activity of Pd-doped hydrotalcites (Pd-HTs) for acceptorless dehydrogenation of both primary and secondary amines (cyclic and acyclic). These multifunctional catalysts comprise Brønsted basic and Lewis acidic surface sites that stabilize Pd in 0, 2+, and 4+ oxidation states. Pd speciation and corresponding catalytic performance is a strong function of metal loading. High activity is observed for the dehydrogenation of secondary aliphatic amines to imines, and N-heterocycles, such as indoline, 1,2,3,4-tetrahydroquinoline and piperidine, to aromatic compounds. Oxidative transamination of

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primary amines is achieved using low Pd loading (0.5 mol%), without the need for oxidants. The relative yields of secondary imines afforded are consistent with trends for calculated free energy of reaction, while yields for transamination products correspond to the electrophilicity of primary imine intermediates. Reversible amine dehydrogenation and imine hydrogenation determine the relative selectivity for secondary imine:amine products. Poisoning tests evidence that Pd-HTs operate heterogeneously, with negligible metal leaching. Catalysts retain over 90% of activity over six reuse cycles, but do suffer some selectivity loss, attributed to changes of Pd phases.

KEYWORDS acceptorless dehydrogenation, amines, amine dehydrogenation, transamination, Palladium, hydrotaclite, heterogeneous catalysis

INTRODUCTION Acceptorless dehydrogenation (AD), the removal of molecular hydrogen from organic substrates without use of a sacrificial acceptor, is a highly desirable, atom-economical route to activating substrates with concomitant hydrogen production.1-2 The development of efficient AD catalysts for various substrates affords an alternative to synthetic methods that necessitate toxic reagents and produce stoichiometric waste. Furthermore, catalysts for AD may also facilitate hydrogen storage in organic molecules, as microscopic reversibility generally dictates that catalysts active for dehydrogenation also facilitate hydrogenation under a hydrogen pressure. The development of catalysts for AD has received considerable attention for the production of alkenes from alkanes,3-5 and carbonyls from alcohols.6-9 Dehydrogenative coupling strategies have also been explored to afford long-chain alkanes,10 esters,8 amides,11 and secondary amines. However, in comparison to alcohols and alkanes, amines have received


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ACS Catalysis

significantly less attention as substrates for AD, with the exception of N-heterocycles, which have been exploited for hydrogen storage.12-13 In contrast to the AD of cyclic compounds, which can aromatize on dehydrogenation, AD of primary amines and acyclic secondary amines is thermodynamically challenging and efficient catalytic processes remain elusive. Imines are dehydrogenation products of secondary amines, and are valuable intermediates that can be modified at the imine carbon, α-carbon, or nitrogen to form an array of amines and N-heterocycles.14 Although aldimines can be prepared relatively easily via the condensation of aldehydes and primary amines, routes to ketimines require more arduous conditions, such as the use of metal halides to overcome the competing reverse reaction,15 or use of Grignard reagents and nitriles.16 Dehydrogenation of secondary amines could provide a valuable and atom-economical synthetic alternative to condensation routes. Existing methods for the dehydrogenation of secondary amines include Swern oxidation, which requires strong oxidants,17 or catalytic routes using milder oxidants such as of tert-butylhydroperoxide.18-20 Transfer hydrogenation of secondary amines with sacrificial hydrogen acceptors has also been explored.21 However, ultimately, methods that eliminate the need for oxidants or acceptors are highly desirable for mild synthetic conditions. Scheme 1. (a) Acceptorless dehydrogenation of secondary amines and (b) transamination of primary amines to secondary imines. H2

(a)

R1

N H

R2 Pd-LDH cat.

R1

H2 R1

(b)

NH2

Pd-LDH cat.

N

R2

NH3 R1

NH

R2-NH2


R1

N

R2

3

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Primary amine dehydrogenation is a synthetically useful route to secondary imines (Scheme 1b), sometimes referred to as oxidative transamination, but is a nascent field compared to well-established alcohol-amine coupling routes to imines (and amines). Oxidative transamination of primary amines to imines has been reported via photocatalytic routes22-23 or in the presence of oxidants (e.g. H2O2,24 AIBN,25 t-butyl hydroperoxide,26 TEMPO,27-28 or O229-30). Although it is highly desirable to eliminate the use of oxidants for this process, there are only three examples of homogeneous catalysts reported that are selective for secondary imine formation via transamination without oxidants (Scheme 2).31-33 However, due to the challenging nature of the reaction, catalytic activity is moderate (20-90 turnovers in 20-48 h31-33, Scheme 2). A few heterogeneous catalysts have also been reported for this process: Magyar et al reported that Cu(II) supported on molecular sieves facilitates the solventless selective coupling of imines;34-35 Torok et al reported that high loadings (1 g) of solid acidic K10 montmorillonite promoted oxidative transamination under microwave conditions,36 and Olah et al reported the use Pt/C, among other catalysts, also under microwave conditions37. However, in these examples the catalysts were not extensively characterized, and no activity for dehydrogenation of acyclic secondary amines was reported. Scheme 2. Comparable prior reports of imine-selective oxidative transamination of primary amines.


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ACS Catalysis

H2 R1

N H

R2 Cat

arene Cp* Bu

Ru O O

N N

N

Bu

Peris, 2011 >95% yield ~20 TON in 20h 150 oC

N R2P

N H Ru PR2 CO

Hunag, 2012 90% yield ~90 TON 115-160 oC

R1

N

R2

PF6

P Ru P NCMe Blacquarie, 2017 90% yield ~30 TON in 48 h 110 oC

Pt/C Pd-HT Olah, 2017 57% yield ~20 TON in 1 h 158 oC

This work 95% yield 190 TON in 24 h 140 oC

Inspired by elegant examples of homogeneous catalysts that exploit ligand cooperativity, and examples of supported Pd catalysts for the dehydrogenation of N-heterocycles under mild conditions, we sought to develop heterogeneous catalysts active for the AD of secondary amines and oxidative transamination of primary amines. Since ligand cooperativity facilitates lower energy pathways in homogeneous ruthenium catalysts,38 we explored whether basic sites on a support surface may afford analogous cooperativity with catalytically active metal centers. Pd was selected in the latter regard, as supported Pd catalysts have recently shown promising activity in the dehydrogenation of N-heterocycles.12-13, 37 We postulated that Pd on a support that affords both high metal dispersion and allows tuning of acid/base sites proximal to Pd could enhance activity for dehydrogenation of heterocycles, and even acyclic secondary amines. To this end, we targeted Pd-doped synthetic hydrotalcites (HTs) using the Mg6Al2CO3(OH)16·4(H2O) mineral. HTs are a sub-set of layered double hydroxide (LDHs)39 with a general formula of [M2+1xM

3+ nx(OH)2]x+(A )x/n.mH2O,

where M2+ and M3+ are alkaline earth and transition metal cations,

and An- represents interlayer anions. The surface acid/base,40 redox,41 and catalytic properties42 of HTs can be readily tuned, with minimal impact on morphology,39 rendering them an


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intriguing choice of supports to optimize the activity and stability of dispersed phases. The HT matrix can also support highly dispersed transition metals by incorporation in the cationic sheets or anionic interlayers. We recently developed a synthetic method that readily affords such dispersed species in HTs using co-precipitation under continuous flow conditions. This immobilization strategy is distinct from that previously employed to support Rh,43 Ru,44 Ag,45 Pd,46-48 Au,49 and Cu50 by post-synthetic wet deposition on prepared HTs, which typically results only in nanoparticles. Pd incorporation into cationic HT sheets has not previously been targeted to our knowledge. The Pd-HT catalyst reported here is distinct from previously described materials consisting of dispersed Pd on HT-derived phases. Choudary et al46 and Ruiz et al51 reported the formation of Pd0 nanoparticles (4-6 nm and 6-8 nm diameter respectively) formed by reducing Pd salts immobilized on HTs. Sivasanker et al52 and Ruiz et al53 reported immobilization of Pd salts on HTs by post-synthetic wet impregnation, but did not characterize the resulting catalysts. There are also two examples of dispersed Pd phases on mixed metal oxides (MMOs), derived by calcining HTs, both synthesized by wet impregnation. Chary et al54 reported the resulting formation of ~4 nm PdO nanoparticles, indicating a strong interaction with the MMO support, while Tan et al observed Pd0 nanoparticle formation following a mild alcohol reduction treatment.48 Here we describe the synthesis, characterization, and application of Pd-HTs that exhibit distinct physicochemical properties from previously described examples due to the use of a new, readily scalable process consisting of co-precipitation in a meso-scale continuous flow reactor, followed by aging. These materials exhibit unique catalytic activity for AD of secondary amines (Scheme 1a) and oxidative transamination of primary amines via dehydrogenation (Scheme 1b).


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ACS Catalysis

RESULTS AND DISCUSSION Synthesis and characterization of Pd-HTs Pd-HT catalysts with high (A) and low (B) Pd loadings were synthesized using meso-scale continuous flow precipitation, adapted from our previously reported protocol for flow synthesis of HTs55 (see ESI for details). A Pd-free Mg-Al HT control material (C) was also synthesized by the same method.55 We had previously prepared Pd-HTs by a traditional two-step coprecipitation and wet impregnation route in batch, but found poor reproducibility in the metal content of the resulting materials (standard deviations in Pd, Mg, and Al contents reaching 25 %). In contrast, the compositions of A, B, and C synthesized in flow were very reproducible, with standard deviations 2) palladium distinguishes them from literature examples.


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Figure 5. TEM images of (a) 5%Pd-HT (A) and (b) 0.5%Pd-HT (B) (50 nm scale bar); (c) TEM images of A (10 nm scale bar); (c) Particle size distribution of A (based on 500 particles).

Figure 6. Schematic of Pd species in (a) A and, (b) B Pd-HTs. Red and aqua spheres indicate interlayer carbonate anions and water respectively.


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Experimental determination of Pd dispersion by methods such as CO chemisorption is not viable for our catalysts since this approach requires that CO selectively titrates Pd metal (and not the support). Hydrotalcites are solid bases, and hence can bind weakly acidic CO molecules, hindering accurate dispersion measurements. Consequently, catalytic activity is quantitated based on the total Pd content, consistent with literature precedents.62-64 Our reported TONs therefore likely an underestimate the true catalyst performance. Secondary amine dehydrogenation The activity of A, B and C for AD of a model secondary amine, dibenzylamine, was explored under reflux in p-xylene for 24 h using 0.5 mol% Pd relative to the amine. Under these conditions, the high Pd loading catalyst, A, afforded 95 % imine, compared to 41 % for the lower loading B, and only a negligible yield for the bare support C (Table 1). The superior activity of A suggests that Pd0 may be the most active Pd phase for dehydrogenation. Identical results were obtained under an inert atmosphere, confirming that residual oxygen played no role in this reaction. The activity of A was higher than that of soluble Pd(OAc)2, which only afforded 72 % imine (Table 1, entry 4). The latter reaction mixture was examined by TEM post-reaction, with 4-8 nm Pd nanoparticles observed presumably due to in-situ reduction of the acetate complex (ESI Figure S4). Commercial Pd/C comprising 5 - 30 nm Pd0 NPs, afforded marginally lower yields and lower selectivity (entry 5), but exhibited significant variability in catalytic performance depending on the batch and manufacturer. We attribute this to the inconsistency observed in Pd speciation and particle size by TEM (see ESI Figure S-5). Table 1. Yields of (E)-N-benzylidene-1-phenylmethanamine from dehydrogenation of dibenzylamine using Pd catalysts.


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Yield % Entry

Catalyst

Conversion % Imine (1)

3 amine (2)

1

5% Pd-HT (A)

95 (±4)

0

>98

2

0.5% Pd-HT (B) 41 (±7)

0

58

3

Mg-Al HT (C)a 0

0

0

4

Pd(OAc)2

72 (±4)

3 (±2)

75

5

5% Pd/C

83 (±10) 9 (±4)

>98

Conditions: 1 mmol of benzylamine, 0.5 mol% Pd loading relative to substrate, 1 mL p-xylene, 24 h reflux at 140 C; yields determined using an internal standard by NMR and GC-FID.; yields reported as average of three experiments, with error reflecting the range; aFor C, the mass used was calculated to equal that used for 0.5%PdHT (B)

The broader applicability of A was subsequently explored for dehydrogenation of other secondary amines under the same conditions (Table 2). High yields were obtained for secondary benzylamines (80-93 %, entries 1-2), and some aliphatic amines (72 - 32 %, entry 5, 8, 9 and 12). However, sterics do influence dehydrogenation, with at least one methylene adjacent to the amine nitrogen required for good yields; dehydration of diisoproylamine (entry 11) afforded negligible product. AD was also performed on N-heterocycles (entries 3, 4, and 6). Indoline and 1,2,3,4tetrahydroquinoline were dehydrogenated with high yields (83 % and 72 % respectively) to the corresponding aromatic compounds indole and quinolone. For 1,2,3,4-tetrahydroquinoline this reaction requires the removal of two H2 equivalents, equating to 144 turnovers. Even piperidine, whose dehydrogenation is less thermodynamically favorable compared indoline and 1,2,3,4-


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ACS Catalysis

tetrahydroquinoline (see ESI Table S-5 for free energies of reaction), was dehydrogenated to form pyridine with a 45 % yield of pyridine in 24 h (135 turnovers for the three dehydrogenative steps). The activity of A for dehydrogenation of N-heterocycles is highly competitive with the most active iridium homogeneous catalyst, reported by Xiao et al (174 turnovers in 20 hours).65 A detailed comparison with reported catalysts is provided in ESI Figure S-7.65-67 Relative yields of the three heterocycles are consistent with computed free energies of their reactions (ΔGrxn, B3LYP/631G(d) of -11.29, -6.79 and 0.50 kcal/mol respectively for indoline, tetrahydroquinoline and piperidine, see ESI for computational details and Table S-5).

Table 2. Acceptorless dehydrogenation of secondary amines using 0.5 mol% catalyst A. Yield %

TON

1

95

190

2

80

160

3a

83

83

4a

72

144

5

72

144

6a

45

135

7

27*

54

8

60

120

Entry

substrate

product


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9

32

64

10

11

22

11

5

10

12

64

128

Conditions: 1 mmol of substrate, 0.5 mol% Pd loading cat A relative to substrate, 1 mL p-xylene, 24 h reflux at 140 C; yields determined using an internal standard by NMR and GC-FID. a 1 mol% Pd loading. *isolated yield

Oxidative Transamination Reactions with primary amines afford the selective formation of secondary imines via dehydrogenation to form a reactive aldimine, which undergoes nucleophilic attack by another amine to form the secondary imine and eliminate NH3 (Scheme 1b). Gases liberated during the reaction were identified as H2 and NH3 by splint test and GC-MS respectively. Using the same reaction conditions as for dehydrogenation of secondary amines (0.5 mol% Pd, 140 C), catalyst A afforded >90 % yield of the secondary imine in 24 h, with

Acceptorless Amine Dehydrogenation and Transamination Using Pd

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