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Asymmetric Hydrogenation of #-Amino Ester Probed by FTIR Spectroscopy Long Zhang, Mehdi Lohrasbi, Uma Tumuluri, and Steven S. C. Chuang Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.6b00222 • Publication Date (Web): 22 Aug 2016 Downloaded from http://pubs.acs.org on August 24, 2016

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Organic Process Research & Development

Asymmetric Hydrogenation of α-Amino Ester Probed by FTIR Spectroscopy Long Zhang a, Mehdi Lohrasbi b, Uma Tumuluri b, and Steven S.C. Chuang a,* a

Department of Polymer Science, The University of Akron, Akron, OH 44325-3909

b

Department of Chemical and Biomolecular Engineering, The University of Akron, Akron, OH

44325-3906

ACS Paragon Plus Environment


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TOC Figure


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ABSTRACT

Asymmetric hydrogenation reaction of dehydro-α-amino acid (i.e., α-amino ester) over cinchonidine (CD) modified Pd catalyst has been studied by an array of in-situ infrared spectroscopic methods, including transmission, diffuse reflectance (DR), and attenuated total reflectance (ATR).

Transmission FTIR spectra probed the hydrogenation reaction process,

revealed OH---O and NH---N hydrogen bonding interactions between the adsorbed CD and during the reaction.

DR and ATR spectra of the hydrogenation reaction under different

conditions, which are consistent with but slightly different from the transmission spectra, evidenced the successful hydrogenation of the compound.

The incorporation of DR and

microfluidics flow-through design allowed us to investigate the adsorption of CD on the Pd surface efficiently.

The results revealed that the N-bonded CD on Pd surface in a tilted

configuration had increased abundance on the Pd surface with high coverage. These valuable insights provided an image of the reaction pathway to the prochiral structure (precursor state).

KEYWORDS: hydrogenation, asymmetric synthesis, chirally modified catalyst, FTIR spectroscopy, microfluidics



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INTRODUCTION Catalytic asymmetric synthesis plays an important role in pharmaceutical and natural products synthesis. Homogeneous asymmetric catalysis has been well developed over the past decades while heterogeneous asymmetric catalysis has not undergone similar development due to the difficulty in investigating the interactions among the catalyst, the reactant, and the chiral modifier under reaction conditions. Heterogeneous catalysis exhibits unique features including (i) easiness of product/catalyst separation and catalyst regeneration, (ii) good chemical and physical stability, and (iii) feasibility in continuous processes.1,

2

These features make it

meaningful to investigate the molecular interactions and reactions on the surface of heterogeneous catalysts. Fourier transform infrared (FTIR) spectroscopy is a versatile tool to provide insights into these interactions and reactions. There are three commonly used FTIR techniques – transmission, diffuse reflectance, and attenuated total reflectance (ATR). With proper design of in situ cells, these FTIR techniques can be used to probe the molecular interactions and reactions at the bulk and catalyst surface under reaction conditions. We choose catalytic asymmetric hydrogenation of dehydro-α-amino acid (i.e., α-amino ester), more specifically, methyl (Z)-2-acetamidobut-2-enoate, as a model reaction to investigate the molecular interactions between the chirally modified catalyst and the substrate. The overall reaction is illustrated in Scheme 1. The reasons to select dehydro-α-amino acid as a model molecule include (i) the high-purity enantiomers of the chiral compounds converted from this family of molecules provide building blocks for pharmaceutical industry, natural products synthesis, biomedical materials, and bio-compatible polymers, and (ii) the high conversion and enantioselectivity reported.3, 4 Among various methods to produce optically pure enantiomers,


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catalytic asymmetric hydrogenation, which is a major category of catalytic asymmetric synthesis, is an important and fundamental process to introduce α-hydrogen to the dehydro-α-amino acid.4, 5

Noble metals such as platinum, palladium, rhodium, are proven effective and efficient catalysts

for hydrogenation reactions generally.6-11 These catalysts are feasible and versatile for many reduction reactions under mild conditions. Horiuti and Polanyi12 first proposed the reaction mechanism of the catalytic hydrogenation over metal catalysts in 1934, which involves a hydrogen exchange process. This mechanism includes four steps: (i) the dissociation (activated adsorption) of hydrogen on the metal surface, (ii) the adsorption of the double-bond compound on the metal surface, (iii) the formation of the half-hydrogenated state via addition of hydrogen atom on the adsorbed compound, and (iv) the exchange of the hydrogen from and to carbon or the subsequent addition of hydrogen to reach the final hydrogenated products. Noble metals with chiral modifiers inherit the nature of bare noble metals for efficient hydrogenation while exhibiting a unique catalytic property in driving the hydrogenation products with optical activity.13-15 Pt or Pd catalysts modified with cinchonidine (CD) or its derivatives are among the most widely used heterogeneous catalysts for asymmetric hydrogenation.16-19 In this paper, we will present the results of FTIR studies, including the diffuse reflectance infrared Fourier Transform spectroscopic (DRIFTS) study of the adsorption of CD on the Pd/TiO2 surface incorporating the microfluidics concepts and the in-situ diffuse reflectance, ATR, and transmission IR studies on the catalytic asymmetric hydrogenation of methyl (Z)-2acetamidobut-2-enoate over cinchonidine-modified Pd/TiO2 catalyst.

Each of these in-situ

methods provides the specific information due to their different geometries.

DRIFTS

incorporated with microfluidic studies revealed that increasing CD coverage increased the fraction of N-bonded CD on the Pd catalyst surface. DRIFTS and ATR monitored the extent of



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hydrogenation near the interface while transmission IR provides insight into the role of hydrogen bonding in affecting the selectivity. The results will be discussed and compared to the literature.

Scheme 1. Reaction schematics and the structure of cinchonidine

H2 CD-Modified Catalyst Hydrogenation Reaction of Methyl (Z)-2-acetamidobut-2-enoate

Cinchonidine (CD)

EXPERIMENTAL SECTION Materials. Methyl (Z)-2-acetamidobut-2-enoate (AE, CiventiChem, U.S.A.), cinchonidine (CD, Sigma-Aldrich, U.S.A.), and dichloromethane (Sigma-Aldrich, U.S.A.) were used as received. 5 wt.% Pd/Al2O3, 5 wt.% Pd/TiO2, 5 wt.% Pt/Al2O3, 65 wt.% Ni/YSZ, and 5 wt.% Ni/ZnOx were prepared by the impregnation of corresponding metal salts on a support. The details of the preparation methods are described in our previous work. 20, 21 Autoclave. 0.1 mM AE and 0.01 mM CD were mixed with 5 wt.% of each catalyst mentioned above in CH2Cl2 (HPLC grade) in five separate vials. Another five vials of similar samples were prepared without CD. The vials were 4 mL in volume and each vial contained 2.5 mL of sample. Prior to the starting of the reaction, the vials were placed into a dry-ice bath and each sample was saturated with H2 by flowing pure H2 at dry ice temperature for 10 minutes and they were then placed into the autoclave. The autoclave was pressurized with pure H2 to 140 psi and allowed reaction for 12 hours at room temperature. The products were subjected to chromatography and mass spectroscopy characterizations.


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HPLC and MS Characterizations. High performance liquid chromatography (HPLC) was used to determine the enantioselectivity and enantiomeric excess (ee%) of the chiral product. A Shimadzu HPLC system equipped with a UV detector and a Phenomenex Chirex 3126 column (150 mm) was utilized. The reaction products were subjected to HPLC column at a flow rate of 1 mL/min. Electrospray ionization mass spectrometry (ESI-MS, Bruker Daltonics Esquire-LC Quadrupole-Ion-Trap Mass Spectrometer with Electrospray Ionization Source, positive mode with Na+ matrix) was employed to detect the product and the conversion of the reaction. (a)

1/2” Outlet

(b)

1/2”

Dome ZnSe Crystal

ZnSe Crystals

Inlet Reactant Catalyst

IR

O-ring Sample Germanium Crystal

IR

Metal Disk H2

(c)

Vent 4 x CaF2 Crystals

H2 Sample

1”

H2

IR IR 4 x O-rings Note: Section View Not Scaled Proportionally

Figure 1. Schematic drawings of the in-situ FTIR experimental apparatuses. (a) The attenuated total reflectance (ATR) flow-through cell with Ge crystal. A stainless-steel tube (not shown) with a few small holes was immersed into the liquid reactant to admit H2. (b) The diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS) cell. A dome was used to cover the sample



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for atmospheric control.

(c) The high-pressure transmission FTIR apparatus. Left: 3D

illustration (exploded view) of this apparatus; Right: Section view of this apparatus. FTIR Characterization.

In-situ Fourier transform infrared spectroscopy was applied to

monitor the progress of the reaction. A Thermo Nicolet 6700 FTIR spectrometer (MCT/B detector) with different accessories was used, including the homemade horizontal ATR flowthrough cell, Praying MantisTM DRIFTS reactor (Harrick Scientific), a novel DRIFTSmicrofluidics reactor, and a homemade high pressure transmission reactor. The spectra were collected at a resolution of 4.0 cm-1 with 10 co-added scans for each spectrum. These different accessories provided comprehensive insights in different aspects into the hydrogenation reaction of α-amino ester. (i) ATR reactor (Figure 1(a)): a piece of Germanium crystal was used as an internal reflectance element (IRE) for the multi-bounce horizontal ATR setup. The incident angle of the IR beam was 45°. A suspension of 60 mg 5 wt.% Pd/TiO2 mixed with 0.1 mmol CD in CH2Cl2 was drawn onto the Germanium surface with a pipette and dried in the air. The catalyst layer had a thickness of around 80 µm. 1 mL CH2Cl2 solution containing 1.0 mmol AE was admitted on top of the catalyst layer. The reactor was then covered and sealed by a homemade Alumina block with a gas inlet and a gas outlet. The gas inlet was connected to a tube with several small holes immersed in the liquid phase to allow the contact of the gas phase with the reactants. H2 was flown into the reactor through the inlet at a rate of 100 mL/min. The reaction temperature was 298 K. The whole reaction process was monitored by in-situ FTIR. (ii) DRIFTS reactor (Figure 1(b)): 25 mg of 5 wt.% Pd/TiO2 was mixed with 0.1 mmol CD and spread onto a stainless steel disk placed on top of the DRIFTS reactor. 1.0 mmol AE was casted on the dried catalyst layer. A dome with three ZnSe windows covered the metal disk to control the atmosphere. H2 was flown into the reactor at a rate of 100 mL/min after starting collecting


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IR spectra. The reaction temperature was 298 K. (iii) DRIFTS-microfluidics reactor (Figure 2): A microchannel was engraved on the surface of an Alumina block using a CNC machine. 5 wt.% Pd/TiO2 was coated on the surface of the microchannel. The microchannel was flushed with CH2Cl2 to make sure that the catalyst would not be removed by the liquid flow. The reactor was covered and sealed by a piece of circular CaF2 crystal and an O-ring. This reactor was utilized to investigate the adsorption of CD on the catalyst. CD dispersed in CH2Cl2 at various concentrations were slowly injected (1 mL/min) to the microchannel using a syringe pump and flushed with the same solvent. A spectrum was recorded after each injection. (iv) High pressure transmission reactor (Figure 1(c)): 25 mg of 5 wt.% Pd/TiO2 and 0.1 mmol of CD were suspended in CH2Cl2 and spread on a cylindrical CaF2 window followed by drying in the air. 1.0 mmol AE was casted on top of the catalyst layer and allowed drying in the air. The CaF2 window was then placed in the high pressure transmission cell perpendicular to the infrared beam path. The sample was sandwiched between this CaF2 window and another same piece. The reactor was pressurized by pure H2 to 100 psig. In-situ FTIR technique was used to monitor the changes in the spectra during the whole reaction process by continuously collecting infrared spectra. Circular Dichroism. A Jasco J-1500 circular dichroism spectrometer equipped with a UV detector was used along with a quartz cuvette. The pure AE and hydrogenated AE (collected from the DRIFTS reactor) were mixed with deionized water at v:v = 1:100. DFT Calculations.

The vibrational modes of AE and its hydrogenation product were

calculated using density functional theory (DFT). B3LYP hybrid functionals and 6-31G (d) basis set were applied. The calculations were conducted with Gaussian 09W software.



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RESULTS AND DISCUSSIONS Reactions in Autoclave.

The products from 5 different catalysts with and without CD

obtained from the autoclave were subjected to HPLC analysis. The HPLC results presented in Table 1 show that the conversion of the reactant ranged from 60.10% to 94.64% and the enantiomeric excess (ee%) increased significantly with CD-modified catalysts. The product from Pd/TiO2/CD catalyst was selected for further ESI-MS characterization. ESI-MS spectrum (see Supplementary Information, Figure S1) reported two major peaks at m/z = 182 and m/z = 180 (in association with a sodium ion). The mass of 182 (159 product + 23 Na+) represents the products of the hydrogenation reaction and the latter represents the reactant. The conversion calculated from ESI-MS spectrum was 90.7%.

These results proved the successful

hydrogenation and formation of enantiomers, providing proof-of-concept supports to the in-situ FTIR studies in the following sections. Table 1. Enantioselectivity and conversion of the hydrogenation reaction Sample 5 wt.% Pt/Al2O3 5 wt.% Pt/Al2O3 + CD 5 wt.% Pd/TiO2 5 wt.% Pd/TiO2 + CD 5 wt.% Pd/Al2O3 5 wt.% Pd/Al2O3 + CD 65 wt.% Ni/YSZ 65 wt.% Ni/YSZ + CD 5 wt.% Ni/ZnOx 5 wt.% Ni/ZnOx + CD

ee% 0.0 13.6 1.1 29.2 1.6 19.3 0.2 29.6 1.5 18.1

Conversion (%) 60.1 73.9 59.8 82.2 94.2 87.1 94.6 86.9 88.8 75.9

FTIR Study of the Adsorbed Cinchonidine on Pd Over the past ten years, a number of significant works were published on investigating the interactions between chiral modifiers and noble-metal catalysts. Baiker and his co-workers


22-27

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are among the pioneers of investigating the adsorption of cinchonidine (CD), a common chiral modifier, on catalyst surfaces. Their ATR-FTIR experiments and DFT computations uncovered the structures of the adsorbed CD on Pd or Pt surfaces. As proposed in their work, the adsorbed CD has three modes with different mechanisms – π-bonded (I), N lone pair bonded (II), and αhydrogen abstracted (III). Mode III is only observed on Pt surface due to the different electron configuration, while the other two modes exist on both Pd and Pt surfaces. Each mode exhibits characteristic infrared absorption bands and the abundance of these different modes is dependent on the surface coverage of CD. Here, we present our study of the adsorption of CD on Pd surface with DRIFTS.

The unique feature of our experiments is that we incorporated the

concepts of microfluidics into DRIFTS, which has never been reported. Thanks to its benefits, including small sampling quantities, precise control, low energy consumption, capability of combinatorial screening, and more, microfluidics has attracted many researchers in the disciplines of biology, biochemistry, pharmaceutical science, etc.

28-31

With our microfluidics-

DRIFTS prototype, we targeted to study the adsorbed species with various CD coverage on the Pd surface in an efficient manner. The great advantage of this design is the quick sampling without preparing new catalyst beds, which significantly reduces the time, resource and effort required. Using the syringe pump and the microfluidics has shortened the sample preparation time and simplified the sampling procedures. The diffuse reflectance spectra of the adsorbed CD on the catalyst at concentrations of 1 mM, 5mM, 10 mM, 25 mM and 50 mM are presented in Figure 2. The band assignments are listed in Table 2, with the help of the DFT calculation results reported by Kraynov et. al.26 Our results are in line with the reported data. The increasing absorbance at the marked vibration frequencies is well correlated to the concentration (or the surface coverage) of the CD. The ratio of the peak heights at 1452 cm-1 (Mode II) and



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1463 cm-1 (free CD) increased with CD coverage. This suggested that the concentration of the tilted CD configuration increased with CD coverage. Comparison of CD on TiO2 and Pd/TiO2 further revealed that N-bonded CD (Mode II) is mainly adsorbed on the Pd surface of Pd/TiO2 catalysts. (see Figure S2 in the Supplementary Information) Table 2. Vibrational frequencies of CD in solution and adsorbed on Pd/TiO2 Assignment CH2-Quinuclidine. Scissoring, free C-Quinuclidine, scissoring, adsorbed C-Quinuline, stretching, adsorbed C-Quinuline, stretching + H-Quinuline bending, free C-H-Quinuline, in-plane deformation, free


Wavenumber (cm-1) 1463 1452 1567 1590, 1508 1422

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(a) Screws 1” IR

Bracket O-ring CaF2 Window Engraved Microchannel

Outlet Syringe Pump (b)

H -1

1384

OH

1463 1452 1422

1508

1590 1567

1508 cm -1 1590 cm N Quinuline Ring

Quinuclidine Ring -1 1452 cm N -1 1463 cm

Absorbance (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


1600

CD Conc. 50 mM 25 mM 10 mM 5 mM 1 mM 1500 1400 -1 Wavenumber (cm )

1300

Figure 2. a) Photo and schematic drawing of the DRIFTS-microfluidics flow-through reactor. b) FTIR spectra of CD adsorption on 5 wt.% Pd/TiO2.

In-situ FTIR Studies In-situ spectroscopy or operando spectroscopy is a powerful tool to probe the molecular interactions during a reaction process. Researchers have reported in-situ spectroscopic studies on the asymmetric hydrogenation reactions involving chiral-modified catalysts. Meemken and coworkers

32-34

conducted operando spectroscopic studies on the asymmetric hydrogenation of

ketones over CD modified Pt/Al2O3 and Pt/C catalysts. Their work revealed the effect of support



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material of the noble metal on the spectroscopic analysis, the relationship between enantioselectivity and chiral modifier surface coverage, and the role of adsorbed CD and dissociated hydrogen on the enantioselection. They also pointed out the hydrogen bonding interactions during the reaction. Tan and Williams

35

applied in-situ ATR-IR spectroscopy to

investigate the effect of solvent on the adsorption of CD and the formation of alkenoic acid – CD complex in a reaction environment and concluded that the intermolecular interactions of the acid – CD complex, which were independent of the sequence of the adsorption of the two species, were the key in controlling preferential enantioselectivity. In this section, we report the results of our in-situ spectroscopic studies of the interactions involved in the asymmetric hydrogenation of α-amino ester on CD-modified Pd/TiO2. The in-situ FTIR spectra collected with ATR, DRIFTS, and transmission accessories and the intensity profiles of the C=C peak are shown in Figure 3. Figure 3(a) shows the spectra at the beginning and the end of the catalytic hydrogenation reaction. The reaction conditions are summarized in Table 3. In contrast to the ATR spectra, the DRIFTS and transmission spectra are consistent in the overall shape and peak locations but exhibit differences when viewed in detail. The similarity and difference will be discussed in a later section after presenting each set of the in-situ FTIR results. The DFT-calculated and experimental vibrational frequencies of the various vibrational modes in the reactant and the product are shown in Table 4. The scaling factors for each vibrational frequency has been calculated and appended to the corresponding calculated vibrational frequency. The scaling factor is defined by the ratio of the experimental vibrational frequency and the calculated one. It is a measurement of the accuracy of the DFT calculation results. These calculations provide a solid foundation for the FTIR spectra interpretation.


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(a)

(b) 0.1 Before Reaction After Reaction

0.0

ATR

ATR

log (1/SingleBeam) (a.u.)

-0.1 Absorbance (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


DRIFTS

-0.2

DRIFTS -0.3

-0.4

Transmission 2000

1800

1600

1400

Transmission

1200

-0.5

0

20

40

60

80

100

120

-1

Wavenumber (cm )

Time (min)

Figure 3. (a) IR spectra collected using ATR, DRIFTS, and transmission FTIR accessories. The spectra are displayed in log(1/SingleBeam Intensity). (b) C=C peak intensity profiles calculated from ATR, DRIFTS and transmission IR spectra. The catalyst used in these FTIR studies was 5 wt.% Pd/TiO2.

Table 3. Comparison of reaction conditions

T/K P / psig H2 Solvent AE / mmol CD / mmol Catalyst / mg

DRIFTS 298 0 Flow at 100 mL/min CH2Cl2, evaporated 1.0 0.1 25.0

ATR 298 0 Flow at 100 mL/min CH2Cl2 1.0 0.1 > 50.0


Transmission 298 100 Static, Pressurized CH2Cl2, evaporated 1.0 0.1 25.0


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Table 4. FTIR band assignments -1

Frequency (cm ) Vibrational Mode ν(C=C) ν(C=O) (O-C=O) ν(C=O) (N-C=O) + δ(C-N-H) δ(CH3), wagging δ(CH) (not chiral center) δ(CH2), twisting ν(C-N) (O=C-N) ν(C-N) (C=C-N) δ(CH) (chiral center)

Reactant Calculated Experimental (Factor) 1709 1705 (1.002) 1634 1656 (0.987)

Product Calculated Experimental (Factor) N/A N/A 1710 1824 (0.938)

1665

1689 (0.986)

1682

1795 (0.937)

1416, 1439

1439

Overlapped

1424

1374

1380 (0.996)

N/A

N/A

N/A 1351 1171 N/A

N/A 1336 (1.011) 1189 (0.985) N/A

Overlapped Overlapped N/A 1212

1376 1359 N/A 1213 (0.999)

Diffuse Reflectance. Diffuse reflectance (DR) technique is a practical FTIR technique widely applied in the studies of heterogeneous catalysis, especially the adsorption of species on the catalysts. This technique provides valuable information about the functional groups and their interactions at the top surface of a sample. In this study, we applied DRIFTS to the in-situ monitoring of the hydrogenation of α-amino ester with the Praying Mantis DRIFTS reactor. The DR spectra of the hydrogenation reaction from the starting point to 3 hours are shown in Figure 4 in the order of reaction time. These absorbance (difference) spectra are calculated from

A = log ( I / I 0 ) , where I and I0 are respectively the intensity of current single beam spectrum (a spectrum that is obtained directly from IR interferogram through Fourier transform) and that right at the beginning of the reaction. The absorption band at around 1685 cm-1 is attributed to the C=C stretching.36 The decrement in this band manifests the disappearing of the C=C bond during the reaction, and evidences the successful hydrogenation of α-amino ester. The circular


dichroism spectra of AE before and after the hydrogenation reaction are shown in Figure 5. The hydrogenated AE exhibited both positive and negative optical polarization, while the AE reactant gave a flat curve which implies no optical polarization.

This provides evidence for the

successful asymmetric hydrogenation of AE. C=C 180 min

Absorbance (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


120 min 80 min 60 min 50 min 40 min 30 min 20 min 10 min 0 min

1800

1700 1600 1500 Wavenumbers (cm-1)

1400

Figure 4. In-situ DRIFTS spectra during the hydrogenation reaction of AE over cinchonidinemodified 5 wt.% Pd/TiO2 catalyst. After reaction Before reaction

3.0 CD (mdeg)

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1.5 0.0 -1.5 -3.0

200

240 Wavelength (nm)

280

Figure 5. Circular dichroism spectra of the AE before and after hydrogenation over 5 wt.% Pd/TiO2 catalyst in DRIFTS reactor. Attenuated Total Reflectance. ATR is another commonly used FTIR sampling technique, which provides insights into the reactions from the interface between the IRE crystal and the bottom layer of the sample. The ATR-IR spectra of the asymmetric hydrogenation reaction are



shown in Figure 6. As the reaction went on, the band between 1600 cm-1 and 1700 cm-1 decreased. This indicates the disappearing of C=C bonds. The ATR-IR spectra exhibited much lower intensity and lower signal to noise ratio than those obtained from diffuse reflectance technique in our study. This is due to the use of Ge and the preparation procedure of the sample. Germanium has a refractive index of 4.0. The approximate depths of penetration at 1000 cm-1 at an incident angle of 45° is less than 0.7 µm.37 Since the catalyst layer was first coated on the Ge surface, a large proportion of the IR beam was absorbed by the catalyst layer, though limited amount of the AE and CD could diffuse through the catalyst layer, and then to the surface of the Ge crystal, sharing the rest of the incident IR beam. Regardless of the low intensity of IR spectra in this particular case, ATR-IR investigations provided evidence for the hydrogenation reaction. 0.001

30 min Absorbance (a.u.)

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80 min 1800

1700 1600 1500 Wavenumber (cm-1)

1400

Figure 6. In-situ ATR-FTIR spectra during the hydrogenation reaction of AE over 5 wt.% Pd/TiO2 catalyst. Transmission IR.

A high-pressure transmission FTIR reactor was built to study the

hydrogenation reaction at 100 psig. Figure 1(c) illustrates the design of the reactor. The sample was sandwiched between two ⌀10.0 mm cylindrical CaF2 windows, which are in between another two ⌀20.0 mm cylindrical CaF2 windows. The reactor is sealed with a few chemical-


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resistant O-rings. Figure 7 shows the 2D color map of the time-resolved FTIR spectra of the hydrogenation reaction with an inset figure of the 3D color map of the portion of the spectral range. The C=C stretching vibrational mode in AE, the O-C=O stretching and N-C=O stretching vibrational modes in the hydrogenated AE, are shown respectively in the figure and pointed to their corresponding vibrational frequencies. The decrease in the C=C band intensity (blue) and the increase in O-C=O and N-C=O band intensities (orange) imply the disappearing of the C=C bond in the reactant and the formation of hydrogenated AE.

The spectra evidenced the

hydrogenation reaction and, more importantly, revealed the feature of hydrogen bonding interactions during the reaction. The inset figure illustrates the significance of the hydrogen bonding interactions during the hydrogenation reaction. Both OH---O and NH---N hydrogen bonding were observed, from which the reaction pathway (precursor state) to the enantiomer can be proposed (Scheme 2). The reaction could proceed through three steps: (i) CD is adsorbed on the surface of the Pd catalyst which provides easier access for atomic hydrogen adsorbed on Pd surface to interact with CD and AE. The adsorbed CD through N-lone pair in a tilted configuration facilitates this kind of interaction. (ii) Hydrogen bonding (OH---O and NH---N) is formed between CD and AE, driving the reaction to an activating state in which a thermodynamically favored complex of CD-AE is formed for the production of a certain enantiomer. (iii) H2 disassociates from the Pd surface and attacks the C=C bond in the CD-AE complex adjacent to the Pd surface and produce one enantiomer.



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Figure 7.

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2D color map of the time-resolved transmission FTIR spectra during the

hydrogenation reaction of AE over 5 wt.% Pd/TiO2 catalyst. Inset: 3D color map of the timeresolved transmission FTIR spectra representing the hydrogen bonding.


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Scheme 2. Reaction pathway (precursor state) to form enantiomer during the hydrogenation reaction.

H

H H

H

N

N

H O

O

H

N

N Pd

Pd

Pd

O

N

O

Pd TiO2

TiO2 Adsorption of CD

O

+

Formation of H-Bond (Activating State)

H

Pd Particle 7.0 ±Size 2.0 nm H

50 nm

N

O

+

H O

H

N Pd

O

N

O

Pd TiO2

Formation of H-Bond (Activating State)

Comparison of Different FTIR Techniques.

The ATR, DRIFTS, and transmission IR

techniques provide consistent information for the same analytes but each technique has its unique characteristics. Comparing the spectra in Figure 3(a), the DRIFTS and transmission spectra are consistent in the overall shape while the ATR looks completely different. The change in the intensity of the C=C bond peak during the asymmetric hydrogenation in ATR, DRIFTS, and transmission spectra in Figure 3(b) shows that DRIFTS and ATR curves reach a plateau



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Page 22 of 29

after 60 min and 80 min, respectively, while the transmission curve implies active reaction even after 120 min. These differences are due to the natural of the optical paths of these three different techniques. DRIFTS and ATR primarily observe the surface interactions. After a certain time of reaction, the substances at the surface where IR beam can access have been mostly consumed, which explains why the plateaus appear. The ATR’s Ge crystal was coated with a dense layer of catalyst so that the amount of the reactant which diffused through the catalyst layer to the Ge crystal was limited. That accounts for the less significant change in the ATR profile and the low signal to noise ratio in the ATR spectra.

CONCLUSIONS In this paper, we explored the application, methodologies, and versatility of FTIR spectroscopy in heterogeneous catalytic asymmetric hydrogenation, especially for the catalytic asymmetric hydrogenation of α-dehydro amino acid over cinchonidine-modified Pd/TiO2 catalyst. Hydrogenation of the amino ester compound was evidenced by a decreased C=C vibrational peak.

Transmission IR allowed observation of the OH---O and NH---N hydrogen bonding

between cinchonidine (chiral modifier) and the amino ester. This hydrogen bonding could be essential to form prochiral complexes on or near the surface of Pd by contributing to the formation of a precursor state. The adsorption of cinchonidine on the Pd surface followed by such hydrogen bonding interactions facilitates a thermodynamically favored configuration to yield to the enantiodifference. The consistent but slightly different FTIR spectra from three different techniques help us monitor the reaction process and, more importantly, understand the surface chemistry of the catalytic asymmetric hydrogenation reactions over a heterogeneous catalyst.


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We incorporated DRIFTS with a flow-through microfluidic design which allowed us to observe the structure of the adsorbed CD under varying coverages. The results suggested increased tilted CD concentration with CD coverage on the Pd surface. This novel design could significantly reduce the effort and resources required to perform a series of FTIR analysis involving the variation of compositions and reaction conditions.

Associated Content Supporting Information The Supporting Information is available free of charge on the ACS Publications website at DOI: The ESI-MS spectrum of the hydrogenation product over CD-modified 5 wt.% Pd/TiO2, the IR spectrum of adsorbed CD on TiO2, and comparison of the adsorbed CD to free CD ratio on Pd/TiO2 and TiO2.

AUTHOR INFORMATION Corresponding Author *E-mail address: [email protected]. Present Addresses U. Tumuluri is currently at the Oak Ridge National Laboratory (Chemical Sciences Division, Oak Ridge National Laboratory, Oak Ridge, TN 37831) Funding Sources The authors are grateful to the financial support from the Faculty Research Initiative Fund of the University of Akron.



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Notes The authors declare no competing financial interest.

ACKNOWLEDGEMENT The authors thank Mr. Shijun Wang and Dr. Junfeng Wang for valuable discussions. The authors gratefully acknowledge Dr. Gang Cheng and Dr. Bin Cao for their generous help on HPLC characterization, Dr. Chrys Wesdemiotis for the assistance and valuable discussions on ESI-MS characterization and analysis, and Dr. Jie Zheng and Mr. Rundong Hu for their help on the circular dichroism characterization.

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