Gold-amine cooperative catalysis for reductions and reductive aminations using formic acid as hydrogen source

Journal Pre-proof Gold-Amine Cooperative Catalysis for Reductions and Reductive Aminations Using Formic Acid as Hydrogen Source Jhonatan Luiz Fiorio (Conceptualization) (Methodology) (Investigation) (Validation) (Writing - original draft), Thaylan Pinheiro ´ (Methodology) (Investigation) (Validation) (Writing - review Araujo and editing), Eduardo C.M. Barbosa (Methodology) (Investigation) (Validation) (Writing - review and editing), Jhon Quiroz, Pedro Henrique Cury Camargo (Conceptualization) (Resources) (Validation) (Supervision) (Funding acquisition) (Writing - review and editing), Matthias Rudolph (Methodology) (Validation) (Writing review and editing), A. Stephen K. Hashmi (Conceptualization) (Resources) (Writing - review and editing), Liane Marcia Rossi (Conceptualization) (Resources) (Validation) (Supervision) (Funding acquisition) (Project administration) (Writing - review and editing)

PII:

S0926-3373(20)30143-0

DOI:

https://doi.org/10.1016/j.apcatb.2020.118728

Reference:

APCATB 118728

To appear in:

Applied Catalysis B: Environmental

Received Date:

9 August 2019

Revised Date:

27 January 2020

Accepted Date:

3 February 2020

´ TP, Barbosa ECM, Quiroz J, Cury Camargo PH, Please cite this article as: Fiorio JL, Araujo Rudolph M, Hashmi ASK, Rossi LM, Gold-Amine Cooperative Catalysis for Reductions and Reductive Aminations Using Formic Acid as Hydrogen Source, Applied Catalysis B: Environmental (2020), doi: https://doi.org/10.1016/j.apcatb.2020.118728

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Gold-Amine Cooperative Catalysis for Reductions and Reductive Aminations Using Formic Acid as Hydrogen Source

Jhonatan Luiz Fiorio,a,b Thaylan Pinheiro Araújo,a Eduardo C. M. Barbosa,a Jhon Quiroz,a Pedro Henrique Cury Camargo,a Matthias Rudolph,b A. Stephen K. Hashmi,b Liane Marcia Rossia*

a

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Departamento de Química Fundamental, Instituto de Química, Universidade de São

Paulo, Av. Prof. Lineu Prestes, 748, 05508-000, São Paulo, SP, Brazil. b

Organisch-Chemisches Institut, Heidelberg University, Im Neuenheimer Feld 270,

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69120 Heidelberg,Germany

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* [email protected]

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amination, amine.

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Keywords: Gold nanoparticles; transfer hydrogenation; formic acid; alkyne; reductive

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Graphical abstract

Transfer hydrogenation via amine-assisted formate decomposition at the Au NPs interface is a cleaner, safer, more efficient and selective manner to access Z-alkynes and

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valuables amines.

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A gold catalyst assisted by amine was applied in transfer hydrogenation reactions; High reaction rate was obtained when using an appropriate amine; Mechanistic studies gave insights that the decomposition of Au-formate species is involved in the rate-determining step of the reaction; The catalyst could be reused up to five times without any significant loss of activity; Efficient and selective method to catalyze the semihydrogenation of alkynes and synthesis of valuables amines.

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HIGHLIGHTS

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ABSTRACT Selective hydrogenation of alkynes to alkenes and reductive amination are industrially important reactions to synthesize a variety of fine and bulk chemicals. We report herein on a green and convenient approach for Z-alkenes and secondary amines using gold catalyst and formic acid (FA) as a green reductant. Furthermore, we highlight that the key to successfully obtain high reaction rates is to use an appropriate amine, which acts

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cooperatively with the gold surface, to activate formic acid. Studies with deuteriumlabeled hydrogen donors gave insights that the decomposition of Au-formate species is involved in the rate-determining step. Moreover, various valuable secondary amines

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could be synthetized from readily available nitro and carbonyl compounds. This new strategy provides a cleaner, safer, more efficient and selective way to catalyze the

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synthesis of Z-alkenes and valuable amines.

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INTRODUCTION Catalytic hydrogenation constitutes one of the most fundamental methodologies in organic synthesis and in chemical industry, contributing to the production of numerous fine and bulk products.[1] In general, hydrogenation reactions are carried out by using molecular hydrogen as reductant. However, these reactions typically require high H2 pressure, which can lead to substrate over-reduction. Moreover, elaborate experimental setups are often required.[2] In this sense, an attractive alternative to the common use of

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molecular hydrogen is the utilization of inexpensive and readily available hydrogen donors, a strategy known as transfer hydrogenation (TH).[3][4][5]

Among the various hydrogen donors used in TH, formic acid (FA, HCOOH) has

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emerged as a green and bio-renewable hydrogen carrier which the additional advantage

of utilizing CO2.[3],[6] In fact, a significant number of protocols using FA as hydride

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source has emerged, employing either homogeneous or heterogeneous catalysts.[2]

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Recently, heterogeneous catalysts based on gold nanoparticles (Au NPs) in the presence of FA have shown promising catalytic properties in chemoselective reduction reactions.[7],[8],[9] Gold-based catalysts used in the TH reaction rely on Au NPs

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supported on titania[9],[10] or Au-NPore [11]. Furthermore, Vilhanova et al.[8] described Au NPs supported on silica as an active catalyst in transfer hydrogenations of

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N-heterocyclic compounds using FA/triethylamine as a hydrogen-donor mixture. The

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activity of the previously related system is attributed to the exceptionally small subnanometer gold particles. Despite these important achievements, little is known about how the addition of base (or N-containing ligands) affects the hydrogenation reactions using FA as H-source. Recently, we have shown that the adsorption of amines on a gold surface decreases the energy barrier for the dissociation of H2 as well as the transfer of the H-/H+ pair to the organic moiety.[12]

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In an effort to shed light on the structural influence of different amines on the catalytic activity of gold catalysts in TH reactions, we herein report a general study on the amine effect. The preparation and catalytic activity of well-controlled Au NPs supported on silica were monitored by adding different amines to Au NPs and by using FA as the Hsource. The catalyst systems were first explored towards the selective hydrogenation of alkynes and then to the synthesis of secondary amines via reductive amination of readily available nitro and carbonyl compounds. Au NPs in combination with amines were

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found to be an efficient and highly selective catalytic system for TH reactions with FA. Both the desired alkenes and secondary amines were obtained under mild conditions in

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moderate to excellent yields.

EXPERIMENTAL SECTION

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Materials: HAuCl4·3H2O (hydrogen tetrachloroaurate trihydrate, 48% in gold, Sigma– Aldrich), Na3C6H5O7 (Sodium citrate tribasic dehydrate, ≥ 99,0%, Sigma–Aldrich),

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C76H52O46 (Tannic acid, ≥ 99,9%, Sigma-Aldrich), TEOS (Tetraethyl orthosilicate, 98%, Sigma-Aldrich), APTES ((3-Aminopropyl)triethoxysilane, 99%, Sigma-Aldrich),

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NH4OH (Ammonium hydroxide, 28%, Mallinckrodt), Toluene (Mallinckrodt, 99,9%), K2CO3 (Potassium Carbonate, 99%, Synth Brazil), Ethanol (99%, Synth Brazil). Unless

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otherwise stated, all other reagents used for the support and catalysts preparation were

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of analytical grade and used as received. The Schlenk tube was thoroughly cleaned with aqua regia, pure water, and dried in an oven prior to use. Preparation

of

silica

(SiO2)

and

amino-functionalized

silica

(SiO2-NH2)

microspheres: Silica (SiO2) microparticles were prepared by following a modified Stöber methodology.[13] In a typical procedure, a premixed solution containing ammonium hydroxide (35mL), ethanol (75mL) and deionized water (15mL) was added

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to a TEOS solution in ethanol (25mL, 26%v/v) and kept under stirring for 2 h. Afterwards, the microspheres were isolated by centrifugation (7000 rpm, 10 min), washed twice with deionized water and once with ethanol. The sample were dried at 100 °C for 2 h and calcined at 600°C for 2 h. Later, SiO2 microspheres were functionalized with APTES using a previous reported procedure with minor adjusts.[14] Typically, 1g of SiO2 microspheres were added to 150 mL of dry toluene and sonicated for 30 min. Then, 1.5 mL of APTES was added dropwise to the mixture under stirring,

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at room temperature and kept that way for 2 h. Finally, the amino-functionalized solid (SiO2–NH2) was separated by centrifugation, washed once with toluene, twice with acetone, and dried at 80 °C for 20 h.

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Preparation of Au NPs supported on amino-functionalized silica (Au/SiO2-NH2): Gold (Au) nanoparticles were synthesized according to a method reported elsewhere

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with slight modifications.[15] Briefly, a freshly prepared aqueous solution of sodium

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citrate (150 mL, 2.2 mM) was placed in a 250 mL three-necked round-bottom flask and heated to 70°C. Then, tannic acid (0.1 mL, 2.5 mM) and K2CO3 (1 mL, 150 mM) were added to the solution under vigorous stirring. After 2 min, 1 mL of HAuCl4 (25 mM)

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was injected and the mixture maintained under stirring at 70°C for 7 min. Au/ SiO2-NH2 was prepared as follows: 0.1 g of SiO2-NH2 was added to the as-prepared

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Au nanoparticles suspension at room temperature. The mixture was sonicated for 30

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min and stirred for additional 1 h. Subsequently, the solid was isolated by centrifugation (7000 rpm, 10 min), washed three times with deionized water and dried under reduced pressure for 6 h. The final catalysts contain about 3.0 wt % of gold as determined by FAAS. Characterization techniques: TEM images were obtained using a Tecnai FEI G20 operated at 200 kV. Samples were prepared by drop casting an aqueous suspension of

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each particle in a carbon coated copper grid. Size distribution profile was determined by individually measuring the size of 200 nanoparticles from TEM images. HRTEM images were recorded on FEI TECNAI G² F20 HRTEM operated at 200 kV. SEM images were obtained using a JEOL microscope FEG-SEM JSM6330F operated at 5 kV. SEM samples were prepared by drop-casting an aqueous suspension of the particles onto a Si wafer, followed by drying under ambient conditions. X-ray diffractograms were obtained using a Bruker D2 Phaser equipment with a standard Cr/Co/Cu ceramic

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sealed tube (l ¼ 0.154060 nm). X-ray photoelectron spectroscopy (XPS) measurements were performed with an SPECSLAB II (Phoibos-Hsa 3500 150, 9 channeltrons) SPECS spectrometer, with Al Kα source (E = 1486.6 eV) operating at 12 kV, pass energy

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(Epass) = 40 eV, 0.1 eV energy step and acquisition time of 1 s per point. The samples

were placed on stainless steel sample-holders and were transferred to the XPS

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prechamber and held there for a 2 h in a vacuum atmosphere. The residual pressure

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inside the analysis chamber was ∼1 × 10−8 Torr. The binding energies (BE) of the Au 4f, C1s, O1s, Si2s and Si2p spectral peaks were referenced to the C 1s peak, at 284.5 eV, providing accuracy within ±0.2 eV. Metal content in the catalysts were measured by

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FAAS analysis, on a Shimadzu AA-6300 spectrophotometer using an Au hollow cathode lamp (Photron). Metal leaching into the supernatant solution was measured by

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inductively coupled plasma optical emission spectrometry measurements, performed on

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a Spectro Arcos ICP OES. GC analyses were carried out with a Shimadzu GC-2010 equipped with an RTx-5 column (30 m x 0.25 mm x 0.25 mm) and a FID detector. Method: Ti = 40 °C, Tf = 200 °C, 17 min, T FID and SPLIT = 200 ºC. Internal standard: biphenyl. General procedure for alkynes hydrogenation: A typical procedure for the hydrogenation of 3-butyn-1-ol is as follows: 0.5 mmol of alkyne, 5 mmol of formic

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acid, 3.2 mmol of amin-base, 2 mL of acetone were added to a modified oven-dried Schlenk tube. The Schlenk tube was evacuated and N2 was purged five times, leaving the vessel under inert atmosphere. The resulting mixture was vigorously stirred using a Teflon-coated magnetic stir bar and the temperature was maintained at 60 °C. After the desired time, the catalyst was removed by centrifugation and the products were analyzed by GC with an internal standard to determine the alkyne conversion and the selectivity for alkene.

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General procedure for reductive amination reactions: In a typical run, nitrobenzene (0.5 mmol), benzaldehyde (0.5 mmol), formic acid (7.5 mmol), amine-base (3.2 mmol), Au/SiO2 catalyst (25 mg), and tetrahydrofuran (THF, 2 mL) were added into a glass vial

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reactor equipped with a magnetic stirring bar. The resulting mixture was vigorously

stirred (1000 rpm) at 80 °C under a N2 atmosphere for a given reaction time. After the

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mixture was cooled to room temperature, conversion and yield were determined by 1H

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NMR spectroscopy using 1,3,5-trimethylbenzene as internal standard. Procedure for reductive amination of dinitro compounds: Dinitro compound (0.5 mmol), carbonyl compound (0.6 mmol), FA (15 mmol), amine-base (3.2 mmol)

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Au/SiO2 catalyst (25 mg), and tetrahydrofuran (THF, 2 mL) were charged in a glass vial reactor with a magnetic stirring bar. The mixture was vigorously stirred (1000 rpm) at

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80 °C under a N2 atmosphere. After the reaction was complete, the mixture was cooled

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to room temperature, conversion and yield were of the crude reaction mixture were determined by 1H NMR spectroscopy. Recycling experiment: For the recycle experiments, after each catalytic experiment under the above typical reaction conditions, the catalyst was recovered by centrifugation and washed three time prior to next reuse. The used catalyst was tested again under

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identical reaction conditions just by adding to the reactor a new amount of substrate, amine and formic acid. The product obtained after centrifugation was analyzed by GC. Determination of the isotopic effect: To investigate the isotope effect in the semihydrogenation of 3-butyn-1-ol, HCOOH was replaced by one of its deuterated counterparts. The reaction was performed under similar conditions in an oven-dried Schlenk tube under N2 atmosphere. After the desired time, the reactor was cooled down to room temperature and aliquots of the reaction mixture were collected. The products

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were analyzed by GC with an internal standard. kH and kD were determined from the

RESULTS AND DISCUSSION

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Catalyst preparation and characterization

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hydrogenation curves.

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We started our studies with the Au/SiO2-NH2 catalyst reported previously.[12] However, the new reaction conditions with FA instead of H2 caused metal leaching. The next step was the selection of other protocols for the preparation of the catalyst and the

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best results were obtained with Stöber silica as the support followed by the immobilization of pre-synthesized Au NPs at its surface (sol-immobilization method).

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SiO2 microspheres were prepared according to a previously reported method [10] and

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functionalized with amino-propyl groups [11]. A scanning electron microscopy image (Figure S1A, supporting information) shows that the support possesses controlled spherical morphology and a very uniform particle size distribution (mean diameter= 390 ± 20 nm, Figure S1B, supporting information). Transmission electron microscopy (TEM) images (Figure 1A and 1B) show that the Au NPs were uniformly deposited over the support surface without significant agglomeration. Figure 1C depicts a high-

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resolution transmission electron microscopy (HR-TEM) image of Au NPs, which displays lattice fringes assigned to the fcc {111} lattice spacings for Au (corresponding to 0.24 nm). The size distribution histogram for Au NPs (Figure 1D) shows a mean diameter of 4.5 ± 0.8 nm, which confirms that Au NPs maintain its high monodispersity

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profile even after immobilization on the support.

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Figure 1. TEM images of Au NPs supported onto SiO2-NH2 microspheres with low (A)

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and high (B) magnification. Inset: Zoomed-in image of an individual Au NP at the surface of the Au/SiO2-NH2 microspheres (the scale bar corresponds to 2 nm). (C) Phase-contrast HRTEM image of Au NPs showing lattice fringes assigned to fcc Au. (D) Histogram of size distribution for Au NPs obtained by measuring the diameter of 200 nanoparticles from TEM images.

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Further characterization by wide-angle powder X-ray diffraction (XRD) and X-ray photoelectron spectroscopy (XPS) are given in the SI (Figure S2 and S3). The SiO2NH2 XRD pattern displays only a broad reflection centered at about 22° characteristic of amorphous SiO2. The Au/SiO2-NH2 sample displays two additional peaks at 38.0°, 44.2° and broad reflections of lower intensity at around 64.4°and 77.3°, corresponding to (111), (200), (220), (311) crystal planes of metallic fcc Au structure (JCPDS 040783). The broadness of Au reflections is consistent with the obtention of small gold

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particles. The XPS spectrum of the Au (4f) core levels shows two intense photopeaks with maximum binding energy (BE) values of 83.2 and 86.8 eV ascribed to the Au 4f7/2 and 4f5/2 doublet, respectively. These BE values are consistent with the presence of gold

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Catalytic Selectivity and Activity

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considering the Au 4f, Si 2p and O 1s regions.

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species in the metallic state.[16] The surface gold atomic composition was estimated

The obtained material (Au/SiO2-NH2) was tested for the transfer hydrogenation of 3butyn-1-ol (1a) as a model substrate for alkyne hydrogenation using FA as the hydrogen

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source. Au/SiO2-NH2 itself performed poorly (5% conversion), but it produced exclusively the alkene 3-buten-1-ol (2a) as product (Figure 2A). A series of amines with

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increasing pKa values were examined as base to assist Au NPs in the hydrogenation

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process. Pyridine (L1) which was previously used with AuNPore catalyst,[17] did not affect the reactivity of Au/SiO2-NH2 catalyst. The catalyst in the presence of collidine (L2) or 1,4-diazabicyclo[2.2.2]octane (DABCO) (L3) was able to reach 7% and 11% conversion of 1a, respectively. Trimethylamine (L4) provided a significant increase in the catalytic activity, providing 43% of conversion of 1a. Among the amines tested, triethylamine (L5), tributylamine (L6) and quinuclidine (L7) significantly improved the

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catalytic activity of the Au NPs under the studied reaction conditions. Full conversion of 1a, without the formation of the over-reduced product, was observed using those bases. We noticed that the Au/SiO2-NH2 catalyst performance correlates well with the increase in the pKa value of the amines, in which those with high pKa values (>9) are able to assist Au NPs to perform the reaction. The kinetic data for the selective hydrogenation of 1a using L1, L5, L6 and L7 as promoter are presented in Figure 2B. Full conversion was obtained after 2 h of reaction, and >99% of 2a was obtained using

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L5, L6 or L7. Nevertheless, very low conversion of 1a was achieved without the addition of amines or using L1. Except L1, instead of decreasing the reaction rate, the

addition of a amine results in an improvement in the reaction rate (Figure 2C). The

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catalytic systems formed by adding L5, L6 or L7 showed similar reaction rate (0.869, 0.845 and 0.947 mmol gcat-1 min-1), though L7 furnished a slightly increase when

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compared to the others. The reaction performed without amine exhibited a reaction rate

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of 0.04 mmol gcat-1 min-1, demonstrating a base-accelerated catalytic reaction. This phenomenon has been previously described in heterogeneous catalyst systems composed of copper nanoparticles and phosphine ligands,[18] amine ligands and gold

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nanoparticles,[19] and palladium nanoparticles and N-heterocyclic carbenes.[20] It should be noted that in the absence of the catalyst, with the addition of amine and

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reducing agent, no reaction occurred, and the starting alkyne was quantitatively

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recovered. Due to the easy availability and cheapness, L6 was chosen as base for the optimization of common parameters such as the reducing agent:base molar ratio, temperature and solvent. The best catalytic activity was obtained by using a 5:2 reducing agent:base molar ratio, 60 ºC, and acetone as solvent (Table S1-S3). Next, in order to reach a deeper understanding of whether the active species is heterogeneous in nature or not, we performed a series of control experiments., such as:

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(1) the addition of Hg, which should result in the formation of a catalytically inactive amalgam. This led to an immediate inhibition of the reaction; (2) Hot filtration of the reaction suspension (Figure S4) to remove the insoluble heterogeneous catalyst which also led to the inhibition of the reaction; and (3) ICP OES analysis of the of the reaction medium which indicated that no undesired Au leaching occurred during the course of the catalytic hydrogenation (detection limit: 0.10 ppm). In order to demonstrate the stability and recyclability of the Au/SiO2-NH2 catalyst, we reused the catalyst for the

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model reaction up to five times after adding new portions of the amine in each reaction cycle. As shown in Figure 2C the catalyst is stable under the optimized reaction

conditions. After the fifth run, the product yield was still 96%. This formidable stability

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can be ascribed to the fact that only slight agglomeration of the Au NPs was observed after the recycling test (Figure S5A, supporting information), revealing that mostly Au

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NPs were still well-distributed and supported over the SiO2-NH2 surface, which could

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be further confirmed by the XRD results (Figure S5B, supporting information).

Figure 2. A) Screening of auxiliary amine-bases for 3-butyn-1-ol 1a hydrogenation with Au/SiO2-NH2 catalyst. B) Effect of the bases in the hydrogenation of 1a. C) Recycling experiments using the Au/SiO2-NH2 catalyst. Reaction conditions: 0.5 mmol

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of 1a, 25 mg of Au/SiO2-NH2, 5 mmol of formic acid, 3.2 mmol of amine, 2 mL of acetone, 60 °C, 2 h. Determined by GC using internal standard technique. In all cases no over-reduced alkane was formed, selectivity to alkene 2a >99%.

To gain further insights into the generality and limitations of the catalytic system on the selective hydrogenation of alkynes, we decided to extend our studies to various types of alkynes. As shown in Scheme 1, a variety of terminal and internal alkynes were readily

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hydrogenated to the desired alkenes in moderate to excellent yields without overreduction to alkanes. In the case of internal alkynes, cis-alkenes were obtained in perfect

diastereoselectivity. Phenylacetylene and 4-methoxy phenylacetylene were selectively

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hydrogenated to the corresponding styrene derivatives (2c and 2d) in yields of over 80%, without producing any poly- or oligomerization reactions of the substrates or

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obtained products. A series of allyl alcohols (2e-2m) could be obtained by the

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developed catalytic system in yields over 65%. This class of compounds has a widespread demand in the flavor, flagrance, and pharmaceutical industries.[21] Furthermore, the semireduction of aliphatic alkynes can be achieved under standard

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reaction conditions without the commonly known double bond isomerization (2n and 2o). The catalytic system could even selectively hydrogenate alkynes bearing an alkene

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moiety, reducing only the alkyne unit without any detectable concurrent reduction of the

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alkene moieties both in the parent and product molecules in a yield of over 70% (2p). Due to the steric hindrance of internal alkynes, an increase of the amount of reducing agent was necessary for better conversions if L6 was used as base. Notably, only (Z)alkenes (2q-2v) were formed from the hydrogenation of internal alkynes using L6 and L7.

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Reaction conditions: 0.5 mmol of 1a, 25 mg of Au/SiO2-NH2, 5 mmol of formic acid,

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Scheme 1. Gold-amine-catalyzed semi-hydrogenation of alkynes to alkenes with formic acid.a,b

3.2 mmol of amine, 2 mL of acetone, 60 °C. Conversion was determined by GC using

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internal standard technique. b Z/E ratio was determined by 1H NMR spectroscopy. c 7.5 mmol of formic acid.

To gain insights into the role of the different hydrogens in formic acid in the reaction pathway and rate determining steps, hydrogenation reactions were performed with deuterium-labeled formic acids HCOOD, DCOOH, and DCOOD. When comparing the

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rates of the hydrogenation reactions of 1a with HCOOH and D-labeled formic acids, a primary kinetic isotope effect (KIE) of 5.2 and 2.1 was observed on the formic (CH/CD) and the acidic (OH/OD) position, respectively, while a primary KIE of 5.5 was observed with the double isotopic substituted formic acid (HCOOH/DCOOD). Considering the similarity in the magnitude of the KIE measured with DCOOH and DCOOD, the decomposition of the Au-formate species could be suggested as the ratedetermining step, meaning that the H/D-C bond is broken in the rate determining step.

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Otherwise, the primary KIE measured with HCOOD is smaller but still kinetically relevant. The existence of a dependence of reaction conversion with amine pKa (shown

in Figure 2A) suggests that the nature of the auxiliary amine plays a crucial role to

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facilitate the O-H bond cleavage, acting as a proton scavenger.[9],[22],[23] Studies with

deuterium-labeled hydrogen donors suggest that the transfer of hydrogen atoms takes

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place in two separate hydrogen transfer steps.

On account of the above observations and the mechanism for Au-catalyzed

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semyhydrogenation of alkynes previously reported,[9],[8][24] a plausible catalytic cycle is proposed in Figure 5. Firstly, formic acid is deprotonated in the presence an auxiliary

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amine, such as triethylamine. The resulting formate anion and protonated amine may interact with the gold surface. It is expected that gold activates the formate, thus

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forming an Au-H- species under release of carbon dioxide (CO2 formation during the

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reaction was confirmed by bubbling the gas phase in a tube counting a solution of barium hydroxide, the solution first becomes cloudy, eventually a white precipitate is formed).[25],[26] Finally, the transfer of the two hydrogen atoms from these two different species (Au−H- and R3N+H) to the alkyne adsorbed to the Au-catalyst surface successively occur to produce the alkene products.[8],[9],[27][28]

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Figure 5. Possible mechanism for gold-catalyzed transfer hydrogenation of alkynes.

Due to the positive results for the transfer reduction of alkynes, we became interested in

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testing this heterogeneous catalytical system in a domino fashion by the reductive amination directly from nitro-compounds. Conventional reductive amination protocols

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are costly and usually give rise to over-alkylation or the formation of toxic byproducts. The reduction of nitroarenes using green and versatile FA is exceedingly attractive, as it

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represents a mild, one-step construction of higher amines from a mixture of cheaply available compounds.[29],[30],[31],[32] In a preliminary test, nitrobenzene (3a) was

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reacted with an equimolar amount and benzaldehyde (4a) with formic acid as reductant in the presence of Au/SiO2-NH2 catalyst (1 mol% Au loading, 0.5 mmol of

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nitrobenzene, 0.5 mmol of benzaldehyde, 5 mmol of formic acid, 3.2 mmol of L5, 2 mL of acetone, 60 °C, 6 h). The formation of the desired secondary amine was observed in 66% NMR yield. To further improve the yield, variation of solvent, amine, FA:amine ratio, and prolonging the reaction time (Supporting Information, Table S4, entries 1–8) resulted in a 90% NMR yield of N-benzylaniline (5a), the only side product observed during the reaction was the imine (N,1-diphenylmethanimine, 10% yield).

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Subsequently, we started to explore the scope and limitations of the reductive amination, which are summarized in Scheme 2. First, we explore the reductive amination of different aldehydes with nitrobenzene. Both electron-donating and electron-withdrawing substituent groups in the aromatic aldehydes could undergo reductive coupling to give the corresponding secondary amine products in good to excellent yields (Scheme 2, 5a–5e). For instance, the reaction of 4-chlorobenzaldehyde and 4-fluorobenzaldehyde with nitrobenzene resulted in the formation of the

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corresponding secondary amines in 89% and 92% yields, respectively (Scheme 2, 5d and 5e) and no dehalogenation of the chloride group was observed. The reaction of (hetero) aromatic aldehydes proceeded smoothly and furnished the desired products in

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most cases in moderate to good yields (up to 73 %, Scheme 2, 5g-5i). Next, the reductive amination of nitro compounds with substituents and benzaldehydes was also

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studied. The electronic effect on the aromatic ring was not significant, though a slightly

amine was up to 85%.

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decrease in the catalytic activity was noticed, and the yield of the desired secondary

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Scheme 2. Gold-amine-catalyzed reductive amination of nitro and carbonyl compounds formic acida

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Reaction conditions: 0.5 mmol of nitro compound, 0.5 mmol of carbonyl compound,

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25 mg of Au/SiO2-NH2, 5 mmol of formic acid, 3.2 mmol of amine, 2 mL of THF, 80

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°C, 12 h. Determined by 1H NMR spectroscopy using internal standard technique.

Finally, we were interested in demonstrating the usefulness of the developed catalytic

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system for the synthesis of bioactive compounds. Thus, we applied the system in the reductive amination of dinitrobenzene with carbonyl compounds (Scheme 3). As a

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specific synthetic application, we developed a formal synthesis of quinoxaline-derived

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molecules in a one-pot reaction, the N-heterocycles compounds were obtained up to 70% yield.

Scheme 3. Gold-amine-catalyzed reductive amination of dinitro and carbonyl compounds using formic acid.a

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Reaction conditions: substrates (0.5 mmol), Au/SiO2-NH2 (25 mg), 2 ml of THF, 15

mmol of formic acid, and 3.2 mmol of amine, 80 ºC.

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CONCLUSIONS

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In summary, we have successfully applied gold catalysis for the selective transfer hydrogenation of alkynes and reductive coupling of nitro and carbonyl compounds. By

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combining renewable formic acid as hydrogen source with the appropriate amine and the supported gold nanoparticles, a benign and sustainable method for the chemical

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synthesis of a range of alkenes and secondary amines was developed. The gold catalyst could be reused up to five times without any significant loss of activity. Regarding the

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mechanistic study, an amine-assisted formate decomposition at the Au NPs interface was proposed and supported by the primary kinetic isotope effects measured from the

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reactions with deuterium-labeled formic acids. The strategy developed herein provides a cleaner, safer, more efficient and selective manner to catalyze the semihydrogenation of alkynes and synthesis of valuables amines.

Jhonatan Luiz Fiorio: Conceptualization, Methodology, Investigation, Validation, Writing- Original draft preparation, Thaylan Pinheiro Araújo: Methodology, Investigation, Validation, Writing - Review & Editing. Eduardo C. M. Barbosa: Methodology, Investigation, Validation, Writing - Review & Editing. Jhon Quiroz: Methodology, Investigation, Validation, Writing - Review & Editing. Pedro

21

Henrique Cury Camargo: Conceptualization, Resources. Validation, Supervision, Funding acquisition, Writing - Review & Editing, Matthias Rudolph: Methodology, Validation, Writing - Review & Editing A. Stephen K. Hashmi: Conceptualization, Resources, Writing - Review & Editing , Liane Marcia Rossi: Conceptualization, Resources, Validation, Supervision, Funding acquisition, Project administration, Writing - Review & Editing.

Declaration of interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

ACKNOWLEDGEMENTS The authors are grateful to the Brazilian government agencies FAPESP (grant numbers

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2016/16738-7, 2015/21366-9 and 2015/26308-7), Serrapilheira Institute (grant number

Serra-1709-16900), CNPq, and CAPES for financial support. L. M. R and P.H.C.C. thank CNPq for the research fellowships. J.Q., T.P.A., and E.C.M.B. thank FAPESP for

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the fellowships (grant numbers 2016/17866-9, 2017/07564-8, and 2015/11452-5, respectively). J.L.F also thanks CAPES-DAAD-CNPQ for his scholarship (Grant

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