The Critical Role of Tilted Cinchona Surface Species for

Subscriber access provided by HACETTEPE UNIVERSITESI KUTUPHANESI

Article

The critical role of tilted cinchona surface species for enantioselective hydrogenation Laura Rodríguez-García, Konrad Hungerbuehler, Alfons Baiker, and Fabian Meemken ACS Catal., Just Accepted Manuscript • Publication Date (Web): 24 Apr 2017 Downloaded from http://pubs.acs.org on April 24, 2017

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a free service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are accessible to all readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

ACS Catalysis is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 39 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

ACS Catalysis

The critical role of tilted enantioselective hydrogenation

cinchona

surface

species

for

Laura Rodríguez-García, Konrad Hungerbühler, Alfons Baiker, Fabian Meemken* Institute for Chemical and Bioengineering, Department of Chemistry and Applied Biosciences, ETH Zürich, Hönggerberg, HCI, CH-8093 Zürich, Switzerland * Corresponding author E-mail: [email protected]

Abstract On chirally-modified metal catalysts enantioselectivity is controlled by the molecular orientation of adsorbates at the chiral catalytic solid-liquid interface. To gain information on the surface coverage and to assess the enantioselecting ability of chiral modifiers depending on their molecular orientation we employed an operando spectroscopic technique using attenuated total reflection-IR and UV-Vis spectroscopies. Our study reveals that the enantiodifferentiation of the cinchona chiral modifier cinchonine varies significantly depending on its adsorption mode. In contrast to the prevailing mechanistic models, which imply that the most stable surface species is responsible for enantiodifferentiation, our results show that less stable cinchona species with a tilted aromatic ring anchor provide significantly stronger enantioselective control. As a consequence the so-called anchoring moiety of the chiral modifier exceeds the mere function of adsorptive anchoring and its molecular orientation has to be also taken into account in explaining the observed enantioselectivity of chirally-modified metals. Keywords: asymmetric hydrogenation – operando spectroscopy – IR spectroscopy – cinchonine – heterogeneous catalysis – solid-liquid interface – chirally-modified metals

1 ACS Paragon Plus Environment

ACS Catalysis 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

1.

Introduction

Controlling selectivity is a major goal in catalysis and will become increasingly important in the coming decades due to severe limitations on resources and more rigid environmental regulations.1,2 Imparting proper enantioselective control to solid catalysts for the efficient production of pure enantiomers has been proven particularly challenging. While the application of such heterogeneous asymmetric catalysts would offer promising technical advantages connected with the ease of separation, handling and re-use, their development has been hampered by a lack of understanding about the complex surface processes leading to enantiodifferentiation. In heterogeneous hydrogenation catalysis the selectivity is governed by the interactions at the catalytic solid interface and the resulting adsorption of the unsaturated reactant.3-5 The molecular orientation of adsorbates also plays a crucial role in asymmetric catalysis as the enantiospecific adsorption of the prochiral reactant determines the enantioselectivity.6-8 A practically very simple approach to transfer enantiocontrol to a conventional achiral hydrogenation catalyst is to modify the noble metal with a suitable organic chiral molecule, referred to as chiral modifier.9,10 Amongst various chiral organic compounds the naturally-occurring pseudo-enantiomers cinchonine (CN) and cinchonidine (CD) stand out as efficient chiral modifiers. Their addition in small amounts to the liquid reaction solution can lead to strong stereochemical control in heterogeneous hydrogenations on Pt and Pd catalysts.11-16 Despite the practical simplicity, the enantioselectivity-controlling process at the catalytic solidliquid interface, that is, the influence of the surface coverage and molecular orientation of the chiral modifier on the catalytic performance are still rather poorly understood, which impedes the development of chirally-modified metals for heterogeneous asymmetric catalysis.


Page 2 of 39

Page 3 of 39 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

ACS Catalysis

Quantum chemical calculations have become a powerful tool to investigate and predict the behavior of complex chemical systems, e.g. involving chiral intermolecular interactions on transition metal surfaces. In the field of chirally-modified metals calculations on diastereomeric surface complexes involving a prochiral reactant and a chiral modifier currently focus on the most stable adsorbed species of the chiral modifier, which is bound with its aromatic ring system parallel to the catalytic metal surface due to strong π-electron interaction.17-20 Nevertheless, to guide and refine such theoretical calculations comparison to experimental observations is inevitable. Microscopic techniques, such as scanning-tunneling microscopy (STM), are able to provide single-site information on molecular surface processes under model conditions. Today, surface scientists are able to visualize the complexation between a chiral molecule and a prochiral substrate on a single crystal surface with submolecular-level resolution.17,18 As those STM studies capture the formation of surface species at low surface coverage and under ultra-high vacuum, the relevance of such information to explain surface processes occurring on a polycrystalline catalyst during the hydrogenation in liquid-phase is uncertain, particularly in the light of the high parametric-sensitivity of heterogeneous asymmetric hydrogenation.9,21 The catalytic solid-liquid interface formed between a working catalyst in presence of a solvent can be probed during hydrogenation by vibrational spectroscopic techniques, such as attenuated total reflection-infrared (ATR-IR) spectroscopy,22 sum-frequency generation spectroscopy,23 or surface enhanced Raman spectroscopy,24 which provide information on molecular interactions. One of the major disadvantages of these established spectroscopic techniques is the lack of a quantitative description of the observed surface processes, because surface coverage as well as the orientation of the probed molecules on the noble metal contribute to the reflection 3 ACS Paragon Plus Environment

ACS Catalysis 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

spectrum.25-27 The surface coverage of various co-adsorbates at the catalytic solid-liquid interface under reaction conditions, and more importantly, even during the hydrogenation (operando) has not been accessible with existing techniques. While it has been observed that cinchona alkaloids can adopt various adsorption configurations at the catalytic solid-liquid interface,28-32 the specific contribution of differently adsorbed chiral modifier species to the overall observed enantioselectivity is unknown, which represents a major stumbling block for a more rational design of synthetic chiral modifiers. Measuring chiral active hydrogenation sites of a chirally-modified metal catalyst is further complicated by the inherent heterogeneity of the noble metal surface, and besides chirally-modified sites the catalyst may also host non-modified hydrogenation sites. These racemic sites may reduce the overall enantioselectivity significantly, depending on their fraction and intrinsic kinetics.33 Without information on the contribution of these non-modified racemic hydrogenation sites to the performance of the catalyst the intrinsic enantiodiscriminating ability of chirally-modified surface sites cannot be assessed on the macroscopic level. To gain information on the surface coverage and to assess the enantioselecting ability of chiral modifiers depending on their molecular orientation at the catalytic solid-liquid interface, we have refined our operando spectroscopic technique in two crucial aspects: By including time-resolved UV-Vis spectroscopic detection of the liquid phase we now can quantify the adsorption of the modifier at the catalytic solid-liquid interface and simultaneously determine the surface coverage-dependent molecular orientation of adsorbates, which is extracted from the ATR-IR spectrum. The second refinement concerns the surface-sensitive detection and its relationship to the macroscopically observed catalytic performance, which is a crucial aspect as IR spectroscopy is mute to chirality and enantioselectivity has to be determined ex situ using chiral separation, 4 ACS Paragon Plus Environment

Page 4 of 39

Page 5 of 39 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

ACS Catalysis

e.g. chiral gas or liquid chromatography. Insufficient fluid exchange at the powder catalyst particles deposited directly onto the spectroscopic probe window is the main barrier between spectroscopically detected and catalytically relevant surface processes. To reduce such mass transport limitations the ATR-IR spectroscopic detection of the catalytic interface was improved in terms of the preparation of the deposited catalyst sample and the cell geometry, particularly the fluid in- and outlet of the ATR-IR spectroscopic flow-through reactor. Ultimately, the quality of the operando spectroscopic detection could be improved significantly, which is now suitable to correlate the detected surface coverage of co-adsorbates to the obtained enantioselectivity. The experimental set-up of the operando spectroscopic recycle reactor system is schematically shown in Figure 1A, and detailed information is provided in the Methods section and in the Supporting Information. Using the asymmetric hydrogenation of 4-methoxy-6-methyl-2-pyrone (MeOPy) on CNmodified 5 wt.% Pd/TiO2 catalyst as a model reaction,13 we were able to identify four different CN surface species on the polycrystalline Pd catalyst. Each of the detected CN species predominates on the catalyst surface depending on the coverage and according to the measured correlations they all contribute differently to the overall enantiodiscrimination. In our recent operando spectroscopic study, the importance of a tilted cinchona surface species on the integral enantioselectivity of a CD-modified Pt catalyst was shown,22 but precisely the lack of quantitative surface information did not allow us to distinguish between the contributions of various co-existing species to the overall enantiomeric excess (ee). Astonishingly, and against the general contention in the literature,6,9,17-20,29,34-36 it is not the flat-lying, most strongly bound cinchona species, which is responsible for the very strong stereochemical control. Instead, a surface species with the quinoline ring anchor tilted along both its short and long axes provides


ACS Catalysis 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

the excellent enantiodiscrimination with an ee of up to 87% in the asymmetric hydrogenation of MeOPy on the Pd catalyst to the corresponding (R)-5,6-dihydropyrone.

2.

Experimental Section

2.1. Catalyst Preparation Preparation of a 5 wt.% Pd/TiO2 catalyst has been described elsewhere.13 The catalyst was reduced in a fixed-bed tubular reactor under flowing hydrogen for 30 min at room temperature prior to use. The dispersion of Pd was 0.5 based on the determination of the particle size distribution using TEM (see Supporting Information) and its relationship to the dispersion according to Bergeret and Gallezot.37

2.2. Hydrogenations Hydrogenations of MeOPy were performed in a 50 mL three-necked glass reactor at 298 K (controlled by a Mettler Toledo Easy Max 102) and at atmospheric pressure under a constant flow of H2. The general reaction procedure was the following: The catalyst was transferred to the reactor and reduced in situ in 5 mL of solvent under constant H2 flow for 15 min. The premodification was then initiated by addition of CN in 2 mL of solvent and let stir for 15 min. The reaction was started by addition of MeOPy in 3 ml solvent. The following reaction conditions were used for all hydrogenations unless stated otherwise: 10.0 +/- 0.1 mg of Pd/TiO2, 8.0 mM MeOPy, 10 ml of isopropanol, 298 K, under hydrogen flow, and mechanical stirring (750 rpm). Studies on additional co-adsorption of QN were conducted according to the same procedure except that CN solutions were prepared in 1 ml isopropanol and after pre-modification for 10 6 ACS Paragon Plus Environment

Page 6 of 39

Page 7 of 39 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

ACS Catalysis

min, 0.5 µmol QN in 1 ml isopropanol was added for the remaining 5 min, prior to the MeOPy hydrogenation. The conversion and enantioselectivity were determined by gas chromatography (GC) using a flame ionization detector and a chiral capillary column (CP-Chirasil-Dex CB, 25 m length, 0.25 mm internal diameter, 0.25 µm film thickness). The chiral modifier CN leads to the preferential formation of the (R)-enantiomer of the corresponding 5,6-dihydropyrone.13

2.3. Preparation of Pd/TiO2 Thin Films for ATR-IR Spectroscopy The catalyst layer preparation is a crucial aspect for obtaining reproducible results from the ATR-IR spectroscopic study. The form of preparation described below leads to an increase in catalyst layer homogeneity and better reproducibility of experiments compared to water-made catalyst layers. A slurry was prepared with Pd/TiO2 catalyst (4 mg) and 1,4-dioxane (2 mL), which was ultrasonicated for 15 min to obtain a well-mixed suspension. Subsequently, the entire amount of the slurry was placed on a ZnSe internal reflection element (IRE, bevel of 45°, 72 mm × 10 mm × 6 mm, Specac Ltd.), and 1,4-dioxane was evaporated at 353 K for 1 h. This procedure yielded a catalyst layer of 3.0 ± 0.1 mg. After the coated crystal was mounted in a flow-through cell, the catalyst layer was reduced by subjecting it to flowing solvent saturated with hydrogen at 298 K for 1 h prior to use at a flow rate of 1 ml min-1. The as-prepared catalyst layer adhered to the IRE such that no ablation of catalyst was observed over the course of several hours under flowthrough conditions.


ACS Catalysis 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

The control experiment in a conventional semi-batch reactor using dioxane-dried catalyst showed only a slight decrease in enantioselectivity of 5% to 82%, compared to the ee of 87% achieved in the hydrogenation using catalyst without such a drying treatment.

2.4. Operando Spectroscopic Measurements ATR-IR spectra were recorded on a Bruker vertex 70 spectrometer equipped with a liquid nitrogen cooled MCT detector. A home-built stainless steel flow-through cell with a height of 100 µm mounted on an ATR-IR attachment (OPTISPEC) was used for all measurements. The reactor cell design was improved with respect to the fluid in- and outlet by implementing a tilted slit geometry (see Supporting Information for old and novel cell design). The measurement temperature (298 K) was regulated by a thermostat (Haake N3 with external water cooling connection). The implementation of the ATR-IR spectroscopic reactor cell into a recycle reactor has been described in detail elsewhere.22 In addition, UV-Vis detection was installed in front of the ATR-IR spectroscopic cell for liquid phase concentration monitoring. UV-Vis spectroscopic measurements were performed at 254 and 285 nm wavelengths with a UV-900 Amersham Biosciences UV-Vis detector equipped with an 8 µL flow cell. The as-described reaction set-up has a volume of 2.9 ml. For each experiment, the progress of the CN concentration over time was monitored during the loaded catalyst experiment and, in addition, in blank mode (reference experiment with a blank crystal) at 25 °C. The experimental procedure was as follows: in situ reduction by subjecting it to flowing solvent saturated with hydrogen at 298 K for 1 h prior to use at a flow rate of 1 ml min-1, then the liquid flow velocity was adjusted to 9 ml min-1 for the modification and reaction runs. The IR spectra


Page 8 of 39

Page 9 of 39 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

ACS Catalysis

were acquired in rapid scan mode by co-adding 32 scans into one spectrum at a scanner velocity of 80 kHz, which resulted in a time-resolution of 4.09 s per spectrum. Acquisition of spectra and control over the recycle reactor (filling and flushing) was synchronized in rapid scan mode. The following rapid scan method was executed for every modification and consecutive hydrogenation run: acquisition of 5 spectra in filling mode (21 s), 222 spectra in recycle mode (15 min 8 s), 15 spectra in flushing mode (1 min 1 s). The chiral modification and the hydrogenation were initiated by admitting the stated CN concentration and 0.5 mM MeOPy to the recycle, respectively. CN concentrations were varied between 0.3 – 114.8 µM. The online UV-Vis spectroscopic detection also allowed to follow MeOPy conversion. To better compare TOF and enantioselectivity data, the recycle reactor was manually opened during the hydrogenation run upon reaching a similar level of MeOPy UV absorption corresponding to roughly 20% conversion.

2.5. Conventional Slurry Reactor vs. Operando Spectroscopic Set-up The observed discrepancy between the highest attainable ee in the conventional semi-batch slurry reactor (87%) with the one from the operando spectroscopic set-up (71%) can be traced back to the external mass transport experienced with the two different reactor systems. The excellent mixing of the reaction slurry achieved with magnetic stirring at the reactor bottom at 750 rpm provides an ee of 87%, while a top-mounted stirrer even at 1200 rpm only provided an ee of 70% in conventional semi-batch reactions. Therefore, we infer that the enantioselection achieved with the operando spectroscopic recycle reactor system reaching 71% ee under the best conditions is limited by the transport at the fixed-bed catalyst layer deposited in the flow-through reactor. Another important difference for the conventional semi-batch experiments is the 9 ACS Paragon Plus Environment

ACS Catalysis 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

presence of CN molecules throughout the reaction, while the CN solution in the operando study is removed before the start of the hydrogenation. The CN uptake was not assessed during conventional semi-batch hydrogenations. In order to calculate the CNads./Pdsurf. ratios from the initial CN liquid phase concentrations used in the QN experiments in Section 3.5, we assumed a Langmuir type adsorption isotherm to describe the measured dissolution – adsorption data points in Figure 1B.

3.

Results and Discussion

3.1. Chiral Modification of Pd with Cinchonine The catalytic performance and the required reaction conditions of the asymmetric hydrogenation of 4-methoxy-6-methyl-2-pyrone (MeOPy) on the Pd/TiO2 catalyst modified with cinchonine (CN) render it an ideal model reaction for an operando spectroscopic study. The absence of an enhanced hydrogenation rate in the presence of the chiral modifier and the high enantioselectivity obtained at atmospheric H2-pressure in the solvent isopropanol (iPrOH) at 25 °C

13

facilitate correlating catalytic performance with spectroscopic detection over a wide

range of surface coverages. In addition, the weak adsorption of the prochiral substrate MeOPy relative to the adsorption of CN permits to modify the catalyst prior to the hydrogenation and the consecutive asymmetric hydrogenation can be performed in the absence of dissolved CN without compromising the enantioselectivity. Such a sequential reaction procedure is beneficial for quantifying the adsorption processes at the iPrOH – Pd catalyst interface in a recycle reactor. Another decisive advantage of the chosen catalytic system concerns the nature of the solvent and the supported catalyst. We have shown that accumulation on the support material of the catalyst


Page 10 of 39

Page 11 of 39 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

ACS Catalysis

can obscure the sensitive detection of species bound to the catalytically active noble metal.22 While accumulation of CN onto the catalyst support also dominated the adsorption in the aprotic solvent toluene, essentially no adsorption onto TiO2 was detected at the iPrOH – Pd/TiO2 interface showing exclusively signals from Pd bound species (see Supporting Information Figure S1). First, we addressed the chiral modification process on the supported Pd catalyst to establish a better understanding of the molecular orientation of the quinoline (QN) ring anchor of CN depending on the surface coverage. To reveal the relationship between the dissolution-adsorption equilibrium and the molecular orientation of the chiral modifier we studied the adsorption of CN onto 3.0 ± 0.1 mg Pd/TiO2 by varying the initial CN concentration in the recycle reactor from 0.3 – 114.8 µM. The adsorption process at the catalytic solid-liquid interface is driven by the liquidphase concentration, but consecutive partial saturation of the adsorbed aromatic QN ring anchor of the chiral modifier can diminish the surface coverage. While dissolved CN from the liquid solution can replace partially saturated CN, the decrease in concentration due to hydrogenation of the chiral modifier leads to a discrepancy between the quantity of adsorbed modifier and the consumed amount measured in the liquid-phase. Based on our transient investigation (Section 3.3. Transient Analysis of Cinchonine Adsorption) a standard modification time of 15 min was chosen to compromise between adsorption and competitive hydrogenation. In Figure 1B, the dissolution-adsorption curve describes the relationship between the initial CN concentration and the resulting surface coverage (ϑCN) calculated from the molar ratio of CN uptake after 15 min (CNads.) and the surface Pd (Pdsurf.) of the deposited Pd/TiO2 catalyst mass (Pd dispersion is determined by TEM, see Supporting Information). The relative dissolution – adsorption equilibrium is well described by the measured values, but the accuracy of the absolute values of


ACS Catalysis 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

the surface coverage approaching saturation at ϑCN ≈ 7.1% is obviously limited not only by the experimental error of the in situ measurement but also by the heterogeneity of the noble metal catalyst. The standard deviation of the catalyst particle size distribution and hydrogenation of CN, which cannot be excluded completely under reaction conditions, represent the most significant factors of uncertainty in the reported ϑCN.

Figure 1. Determination of Pd surface coverage (ϑCN) as a function of CN uptake using UV-Vis spectroscopy and simultaneous monitoring of the CN orientation at the catalytic solid-liquid interface using ATR-IR spectroscopy in the presence of the solvent iPrOH and H2. (A) Schematic representation of the experimental operando spectroscopic set-up. (B) Relationship between the initial liquid-phase concentration of CN and the resulting surface coverage on the Pd catalyst surface. (C) and (D) Spectra 12 ACS Paragon Plus Environment

Page 12 of 39

Page 13 of 39 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

ACS Catalysis

showing adsorbed CN for various ϑCN. For the sake of comparison, the rescaled spectra of solid and dissolved CN are also included.

The molecular orientation of the chiral modifier at the catalytic solid-liquid interface depending on ϑCN is extracted from the IR spectroscopic data displayed in Figure 1C and 1D, which correspond to the highlighted experiments in Figure 1B. We focus on the orientation of the aromatic QN anchor with respect to the Pd surface, which is described by the relative signal intensities of the three highlighted vibrational modes. Particularly, the well isolated signals of the dipole moment changes corresponding to the aromatic CH in-plane stretches, labeled as (CH), and to the aromatic CC stretches oriented along the long axis of the QN ring, labeled as long(CC), provide valuable information about the tilting of chemisorbed CN with respect to the paramagnetic Pd surface. While previous studies on the adsorption of cinchona alkaloids28-30 onto noble metals had focused on the lower frequency region (< 1800 cm-1), in this study the adsorption of CN was also characterized including the vibrational mode at around 2962 cm-1 and its assignment to (CH) of chemisorbed QN of CN was confirmed using additional experiments, including the adsorbates QN, CN and CD as well as toluene as additional solvent and Pt/Al2O3 as Pt catalyst. The assignment of the vibrational modes of CN is summarized and compared to the literature values in the Supporting Information. At ϑCN ≈ 0.5% (purple spectrum) no (CC) ring vibrations signals were detected at the iPrOH – Pd/TiO2 interface. The presence of adsorbed chiral modifier, though, was observed by the appearance of the (CH2) mode of the quinuclidine moiety of CN detected at 1460 cm-1 28 and by the removal of other surface species detected at 1762 cm-1 and 1845 cm-1. These two broad bands have to originate from iPrOH decomposition on Pd, and we assign the modes at around 1762 cm-


ACS Catalysis 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

1

and 1845 cm-1 to adsorbed oxo propyl species on Pd(111)

Page 14 of 39

4

and three-fold bound CO on

Pd(111)38, respectively. Note that the absorption at 1762 cm-1 might also originate from CO adsorbed to the polycrystalline Pd catalyst, but the exact origin is neither important for the following analysis nor the conclusions. Nevertheless, at the iPrOH – Pd/TiO2 interface CN must adsorb competitively to these species. Due to the absence of (CC) ring modes, the QN moiety of the detected CN species has to be oriented parallel to the paramagnetic Pd

25

and at low

surface coverage the Pd surface is covered by such flat-lying cinchona species, which we designate as species I. In the high frequency region in Figure 1C, a minor feature was discernible at 2952 cm-1, which could be assigned to (CH) of chemisorbed QN of CN species I. Surface science studies have revealed that the CH bonds of an aromatic ring adsorbed parallel to Pt possess peculiar acidity and such C-H bonds were proposed to tilt away from the surface by up to 20° allowing for their spectroscopic detection even for nearly parallel adsorbed aromatic rings.39 An increase of the surface coverage led to the appearance of the QN signals at 2962 cm-1, and at around 1570 cm-1, but the latter mode was overlapping with the strong absorption centered around 1650 cm-1. Up to ϑCN ≈ 1.7% (blue spectrum) these absorption bands grew continuously and particularly the observation of the vibrational mode directed along the short axis indicates the accumulation of a CN surface species standing on its long QN axis, designated as species II. The broad absorption at around 1650 cm-1 most likely originates from both adsorbed cinchona species and species originating from adsorbed solvent or decomposition products of the solvent, and a clear distinction cannot be drawn unambiguously. We also recorded the adsorption of CN on the Pd/TiO2 catalyst using toluene as solvent and absorption in this region was less pronounced (compare Figure S1). Additionally, these spectra show the rapid saturation of the vinyl bond of CN, as its (C=C) stretch absorption mode at 1637 cm-1 was only detected on a


Page 15 of 39 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

ACS Catalysis

TiO2 layer, and completely absent in the presence of Pd/TiO2. The rapid hydrogenation of the vinyl bond is no surprise and catalytic studies involving C10,11-dihydrocinchonine or C10,11dihydrocinchonidine have confirmed that the vinyl bond does not impact the catalytic performance.40,41 We expect C10,11-dihydrocinchonine to be the predominant surface species and this cinchona species was shown to give rise to broad absorption at around 1630 cm-1.42 However, due to the insignificant role of the vinyl bond for enantioselection and to avoid confusion in the following discussion we continue to refer to CN as the surface modifier. Adsorption of species II was accompanied by a continuous removal of surface oxo propyl and CO species. Thereafter, further increase of CN coverage did not induce a significant decrease of the bands at 1762 cm-1 and 1845 cm-1, indicating that nearly all of these specific surface sites on the Pd catalyst were fully occupied by CN species II at around ϑCN ≈ 1.7%. Strikingly, an additional but slight increase of ϑCN to 1.9% (green spectrum) induced a remarkable spectral change in the region of the long(CC) mode. The broad absorption band peaking at 1498 cm-1 is considerably shifted with respect to the long(CC) mode of dissolution and solid-phase species at 1509 cm-1.22,28 The redshift by 11 cm-1 indicates the detection of a weaker aromatic CC bond and accordingly the band at 1498 cm-1 is assigned to a CN species with the QN moiety chemisorbed to Pd. The strong increase of the long(CC) mode relative to the other two detected modes of QN ((CH) and short(CC)) revealed a transition of the predominant configuration of chemisorbed CN, and the observed spectral changes characterize an additional tilting of the QN moiety along the short axis. It has to be stressed that the abrupt appearance of the absorption band at 1498 cm-1 had to be caused by a sudden transition of the predominant surface orientation of the chiral modifier as a result of a minor incremental increase of the surface coverage, that is, the signal contribution due to the additional accumulation on the surface is negligible. Note that it is in fact


ACS Catalysis 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

the complementary, quantitative UV spectroscopic measurement, which provides the necessary information to discriminate between signal contributions originating from surface coverage and from a change of the orientation of the molecular bond. Despite the acquisition of sample average data of the molecular surface processes by ATR-IR spectroscopy, we could narrow down the sudden transition to occur at around ϑCN ≈ 1.8% ± 0.1%, which marks the shift of the predominant adsorption configuration from surface species II with its QN moiety standing on the long axis to another CN surface species III with the QN moiety tilted along both axes. In Figure 1C and 1D, comparison of the spectra recorded at ϑCN ≈ 1.7% and ϑCN ≈ 1.9% clearly shows that the signal intensity of the in-plane (CH) mode did not increase significantly during the transition of orientation on the noble metal surface. On the contrary, in the spectrum recorded at ϑCN ≈ 2.6% it becomes evident that the Pd surface can still accommodate chemisorbed CN without further removal of oxo propyl and CO species, and the (CH) mode is the most suitable signal to follow additional accumulation of chemisorbed CN towards formation of a full monolayer with species III. Accumulation at the catalytic solid-liquid interface was found to cease using a high initial CN concentration of 86.5 µM at around ϑCN ≈ 7.1%, and saturation of the catalyst at this surface coverage was corroborated with an additional experiment using an even higher concentration of 114.8 µM (see Figure 1B). While the additional CN uptake did not lead to a significant increase of the (CH) mode, accumulation of CN at the catalytic solid-liquid interface was reflected in a substantial increase in the spectral region of the short(CC) and long(CC) modes. However, an additional absorption band was clearly discernible at 1509 cm-1, which does not originate from a Pd bound QN. Instead, the detected absorption can be better explained by the accumulation of another differently oriented CN species (species IV) and a different interaction must be 16 ACS Paragon Plus Environment

Page 16 of 39

Page 17 of 39 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

ACS Catalysis

responsible for the additional accumulation. From the additional broad absorption at around 2653 cm-1 belonging to the (N+H) mode of the protonated quinuclidine moiety 43,44 and the redshift in the (OH) stretch region we infer that the formation of hydrogen bonding at the CN-modified Pd catalyst – iPrOH interface is at the origin of additional accumulation. The CN species IV appears to form a second layer on top of the chemisorbed monolayer of species III interacting via the amine and the alcohol function of CN, while the QN moiety is directed away from the Pd surface.

3.2. Catalytic Performance of the Various Cinchonine Species The active species among the four cinchona surface species was identified by correlating the spectroscopic detection to the catalytic performance achieved in the consecutive hydrogenation on the as-prepared CN-modified catalyst. In Figure 2, each data set comprising ee, TOF and a surface coverage represents a separate experiment at a MeOPy conversion of 20 - 30%. The correlation of the operando spectroscopic data allowed to stake out four surface coverage regimes, each predominantly populated by one of the identified CN surface species I-IV.


ACS Catalysis 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

Figure 2. Correlation of CN surface coverage to the catalytic performance revealing four regimes (I-IV) each predominately covered by one of the identified CN surface species. Closed symbols refer to 15 min pre-modification time with various concentrations under otherwise standard reaction conditions (see Experimental Section), and open symbols refer to pre-modifications with 28.8 µM CN for 5 min and 30 min, respectively.

In regime I, insufficient enantiodifferentiation and very high catalytic activity is explained by partial surface coverage of the most stable flat-lying CN species I and the presence of remaining non-modified sites. At ϑCN above 0.5% the TOF was strongly reduced, indicating the absence of 18 ACS Paragon Plus Environment

Page 18 of 39

Page 19 of 39 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

ACS Catalysis

highly active non-modified sites. While the active hydrogenation sites appeared to be fully occupied by adsorbed CN, in this regime II the ee was only slightly increased remaining below 20% until ϑCN ≈ 1.7%. Thereafter, the sudden shift to regime III can be followed by the abrupt step of the IR signal at 1498 cm-1. Furthermore, the change to another catalytic surface regime at ϑCN ≈ 1.8% ± 0.1% is also evident by the sharp increase in the ee from below 20% to more than 50%, which has to originate from another surface process with stronger enantioselective control. Predominant control over the enantioselection by CN species III reaching the best ee of 71% was observed at roughly ϑCN ≈ 3.5%, which correlates well to the saturation of the (CH) band at around 4.4 mA. In surface regimes II and III, the TOF is barely affected by the chiral modifier coverage, which roughly triples in surface regime II before surface regime III is reached, rendering the role of additional accumulation of CN on the surface as blocking agent of remaining non-modified hydrogenation sites unlikely. Hence, the sharp increase in enantioselectivity within this relatively small coverage increment and its coincidence with the prevalence of the more weakly bound tilted CN species III strongly suggest that the change of the orientation of the adsorbed CN is the reason for the enhancement of ee. The correlation in Figure 2 is compelling experimental evidence that CN species III provides significantly improved stereochemical control compared to species I and II. Additional CN uptake above ϑCN ≈ 3.5% gave rise to a nearly linear increase of the absorption detected at 1498 cm-1. However, the absorption originates from the non-chemisorbed QN mode at 1509 cm-1 and due to the close vicinity of the vibrational modes accumulation of species IV was reflected in the absorption at 1498 cm-1. In regime IV, the enantioselectivity remained constant, but accumulation of hydrogen-bonded species IV had a detrimental effect on the catalytic turnover, indicating competitive adsorption between multilayer CN and the reactant


ACS Catalysis 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

MeOPy for chirally-modified surface sites. Regarding the stoichiometry of the identified surface sites, at full monolayer coverage of species III at ϑCN ≈ 3.5% one CN molecule would occupy a surface ensemble of approximately 30 Pd surface atoms, which is sterically feasible to accommodate a QN ring. At ϑCN ≈ 7.1% one hydrogen-bonded species IV would interact with exactly one chemisorbed species III, corresponding to a 1:1 stoichiometry at saturation of the catalyst.

3.3. Transient Analysis of Cinchonine Adsorption The transient data in Figure 3 provide insight into the adsorption kinetics of CN at the iPrOH – Pd/TiO2 interface and the competitive hydrogenation of adsorbed CN. Time-resolved monitoring of the chiral modification process under reaction conditions and evaluation of the enantioselecting ability in three separate experiments, each with a distinct pre-modification time, revealed the dynamic nature of the identified surface processes and substantiated the relevance of the presented correlation in Figure 2 as well as the crucial role of species III for strong enantioselective control. As depicted in Figure 3, the two IR modes obeyed different kinetics and in combination with the UV spectroscopic detection they provide sufficient information to distinguish between the four regimes during the chiral modification.


Page 20 of 39

Page 21 of 39 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

ACS Catalysis

Figure 3. Time-resolved ATR-IR and UV spectroscopic monitoring of the chiral modification of Pd/TiO2 in the presence of iPrOH and H2. Enantioselectivity was determined in three separate experiments each with a distinct modification time of 15 min, 62 min, and 62 min + 15 min (additional second admission of 14.4 µM CN after 62 min). The three vertical dashed lines correspond to the start of the consecutive hydrogenation yielding the depicted ee. The UV-Vis signal at 254 nm was used to follow the CN concentration in the liquid-phase.

Upon admission of 14.4 µM CN both IR modes increased rapidly within the first minutes due to the predominant formation of species II and then species III, and after about 10 min the initial liquid-phase concentration was decreased by almost 50%. As the chiral modifier adsorption approached an equilibrium the altered kinetics of the two IR modes indicated some accumulation of species IV. In accordance to the data presented in Figure 2, chiral modification for 15 min resulted in an absorbance of 3.9 mA at (CH) and an ee of 66%. In case the modification was continued, absorption at long(CC) began to decline after 15 min due to considerable CN hydrogenation. However, temporarily the surface coverage of surface species III remained constant as observed by the steady (CH) signal. Instead, hydrogenated surface CN appeared to be rapidly replaced and the consumption of CN was on the expense of CN accumulated in the 21 ACS Paragon Plus Environment

ACS Catalysis 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

multilayer reservoir (species IV) as well as on dissolved CN. Accordingly, the liquid-phase concentration of CN also decreased continuously ceasing at 4.3 µM after 35 min. Now, long(CC) dropped abruptly from 0.5 mA approaching 0.2 mA rapidly (scaled by x2 in Figure 3). This abrupt drop can be again explained by a change of the predominant orientation of the QN moiety and a transition back to regime II. The reversal of the predominant orientation was also reflected in the starting decline of the (CH) mode and the transient IR data correspond to the reported signal intensities in Figure 2. Indeed, the reaction performed after 62 min pre-modification time yielded only an ee of 32%, which is in good agreement to the correlation in Figure 2 showing an enantioselectivity of approximately 30% for absorbance values of 3.4 mA and 0.2 mA for the (CH) and long(CC) modes, respectively. Exposing the same Pd/TiO2 catalyst layer a second time to a fresh 14.4 µM CN solution after 62 min in the third experiment, additional CN uptake was observed, but the liquid-phase concentration decreased considerably slower compared to the first admission. The maximum absorption of (CH) was discernible after 5 min, indicating saturation of the surface with species III. In contrast, accumulation of species IV in the multilayer over the entire second modification run was followed by the continuous growth of long(CC). Particularly during the second chiral modification, the altering kinetics of the two IR modes clearly showed the transition from monoto multilayer formation. While the (CH) signal intensity only reached a maximum of 3.9 mA during the first modification, full surface coverage by species III was attainable in the second modification and after the additional 15 min the obtained ee of 71% is in excellent agreement to the detected absorbance of 4.4 mA.


Page 22 of 39

Page 23 of 39 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

ACS Catalysis

3.4. Co-Adsorption of the Prochiral Substrate Now we turn our attention to the co-adsorption of the substrate MeOPy. The IR spectra depicted in Figure 4 were recorded during the asymmetric hydrogenation at various CN surface coverages, but all surface spectra correspond to a MeOPy conversion between 20 - 30%. Prior to admission of the substrate solution, the recycle reactor was flushed with iPrOH to remove dissolved species, but no removal of adsorbed CN was observed. Two important findings emerge from the spectra in Figure 4 concerning the co-adsorption of the prochiral substrate to pre-adsorbed CN. The weak adsorption of MeOPy was confirmed under the chosen experimental conditions as no removal of chemisorbed CN could be detected in the presence of MeOPy. The absorption in the spectral region of long(CC) and short(CC) decreased slightly at ϑCN ≈ 2.6%, which, however, is associated to the removal of only hydrogen bonded species IV and the competitive adsorption to CN species IV was more clearly seen at ϑCN ≈ 7.1%.


ACS Catalysis 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

Figure 4. Co-adsorption of MeOPy on the CN-modified catalyst. Spectra collected at roughly 20% conversion during the MeOPy hydrogenation at various pre-modification surface coverages (ϑCN) under otherwise standard reaction conditions. For the sake of comparison the spectrum of MeOPy dissolved in iPrOH is included.

The second finding concerns the orientation of the prochiral substrate on the CN-modified Pd catalyst, which can be followed by the characteristic (CO) stretch absorption of the ester group. Comparison of the spectra recorded at ϑCN ≈ 1.7% and ϑCN ≈ 1.9% showed a remarkable difference in carbonyl absorption, which coincided with the “activation” of the more enantioselective surface process at around ϑCN ≈ 1.8%. At ϑCN ≤ 1.7% the ester group of the catalytically active MeOPy species appeared to be either oriented nearly parallel to the paramagnetic Pd surface because the carbonyl mode at around 1709 cm-1 was absent or considerably red-shifted to 1660 cm-1. On the contrary, the carbonyl absorption observed at ϑCN ≈ 1.9% at around 1709 cm-1 is likely to originate from a more upright orientation of the ester group of MeOPy on the Pd catalyst modified with CN species III, and it seems that the change of the adsorption geometry of CN is also reflected in the co-adsorption of the prochiral substrate. In such an orientation the unsaturated C=C bonds of the substrate can still interact with the catalyst surface, and the carbonyl bond could still engage in hydrogen-bonding with the chiral modifier. Although ultimately information on the molecular structure of the diastereomeric surface complex formed between the chiral modifier and the prochiral substrate is needed, a further investigation in this direction goes beyond the scope of this study. Notably, the increasing carbonyl absorption at higher ϑCN revealed that the substrate is also prone to accumulate in the multilayer regime as a spectator species and, indeed, the competitive adsorption between MeOPy and CN species IV is reflected in the lower hydrogenation activity (compare Figure 2).


Page 24 of 39

Page 25 of 39 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

ACS Catalysis

3.5. Co-Adsorption of Cinchonine and Quinoline To verify our hypothesis on the crucial role of the tilted cinchona species III for controlling enantioselectivity, we attempted to investigate the effect of tilting of the QN ring on the ee by an alternative way. By adding a third compound to the reaction slurry of a conventional semi-batch hydrogenation we aimed at triggering externally the same tilting of the QN moiety of CN on the surface. To emulate the required steric crowding on the catalyst surface at insufficient CN concentration we chose QN as the additional co-adsorbate due to its obvious resemblance of the QN ring anchor of CN and the absence of chiral information in this aromatic compound. As seen in Figure 5 at ϑCN = 0, sole addition of QN did not induce any enantioselection. However, addition of a constant amount of QN to the CN-modified catalyst increased the ee considerably, particularly over the catalytic surface regime II, which can be better followed by the incremental increase (∆ee) plotted on the right y-axis.

Figure 5. Influence of QN addition on enantioselectivity in a conventional semi-batch hydrogenation. Closed black circles refer to standard semi-batch hydrogenations with 15 min pre-modification with 25 ACS Paragon Plus Environment

ACS Catalysis 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

various CN concentrations. Closed blue circles refer to a second set of experiments involving premodification with various CN concentrations for 10 min and the addition of 0.5 µmol QN for the remaining 5 min. Open blue circles indicate the incremental ee increase due to the addition of QN plotted as ∆ee on the right y-axis.

Remarkably, in these semi-batch experiments the highest incremental increase of 12% ee was also observed at around ϑCN ≈ 1.8% where the transition from CN species II to species III was found to occur in the operando spectroscopic experiments.

3.6. Mechanistic implications The correlation of activity, enantioselectivity and surface coverage of various differently adsorbed cinchona surface species represents strong experimental evidence for the critical role of tilted surface CN species III shown in Figure 2 for enantioselective hydrogenation on Pd catalyst and against the important role of flat-lying chiral modifier species. Due to the rate deceleration with increasing modifier surface coverage, generally experienced in asymmetric C=C bond hydrogenation on chirally-modified Pd, it was possible to clearly distinguish between the catalytic regimes I and II, that is, when the contribution of racemic (non-modified) sites to the overall catalytic performance becomes negligible. Because of this clear distinction it was possible in this operando spectroscopic study to make the strong statement about the poor and high enantioselection of CN species adsorbed to the catalyst with the aromatic ring oriented flat and tilted, respectively. This experimental observation runs counter to the general contention in the literature and the prevailing mechanistic models.6,9,17-20,29,34-36 The flat-lying surface species, also referred to as –bound species, is the most strongly bound cinchona species on Pt or Pd metal catalysts, according to theoretical calculations20 and experimental observations28-30 26 ACS Paragon Plus Environment

Page 26 of 39

Page 27 of 39 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

ACS Catalysis

including this experimental work. Weaker bound tilted cinchona species have also been found in previous studies on Pt28,29 and Pd,30 but strong surface anchoring via parallel –bonding of the aromatic moiety has been considered favorable for enantioselection6,9,29,34-36 and theoretical studies have focused on the most strongly bound species.17-20 In the presented operando spectroscopic study we accomplished to distinguish between four different regimes depending on the chiral modifier surface coverage under reaction conditions and such a detection is a necessary prerequisite for assessing the enantiodifferentiating ability of differently bound chiral modifier surface species. These unprecedented experimental observations reveal that a cinchona species more weakly bound via a tilted aromatic QN moiety is in fact responsible for the very high enantioselectivity in the studied Pd-catalyzed reaction, and we have to discuss whether these mechanistic implications also hold true for other chirallymodified catalysts, that is, for catalytic systems involving other substrates, solvents, chiral modifiers and also Pt catalysts. Enantioselectivity has not been assigned experimentally to the adsorption mode of a chiral modifier under reaction conditions in any other reported study, and the discrimination of the enantioselectively active cinchona chiral modifier species required certain experimental conditions regarding the properties of the powder catalyst, the solvent and the substrate. A variation of the experimental conditions will change the spectroscopic detection and such an unambiguous discrimination may become impossible for other catalytic systems. The present finding of superior enantiodifferentiation of the weaker bound tilted cinchona species compared to the corresponding flat–lying species can therefore not be generalized for any cinchonamodified catalytic system, but it clearly demonstrates that the enantiodifferentiation strongly depends on the orientation of the adsorbed cinchona modifier and other experimental 27 ACS Paragon Plus Environment

ACS Catalysis 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

observations have to be evaluated in the light of the new mechanistic understanding, taking the high parametric sensitivity and complexity of chirally-modified metals into account.9,21 Regarding the transferability of these mechanistic implications to explain enantioselectivity on Pt catalysts we need to refer to our previous operando spectroscopic study, which focused on the asymmetric hydrogenation of the activated ketone ketopantolactone on CD-modified Pt catalyst in the solvent toluene.22 In this study, we were not able to quantify the surface coverage and could not clearly stake out surface regimes II and III. However, we also observed poor enantioselection at relatively low CD concentration when the most strongly bound CD surface species predominate on the surface.28,29 Notably, we found the highest enantioselection at saturation of the Pt catalyst surface with a similarly tilted CD species giving rise to broad absorption bands in the (CC) region, which cannot originate from a CD surface species with the QN ring adsorbed (nearly) parallel to the surface. In other words, besides the strong experimental evidence in favor of the tilted CN species as the enantiodifferentiating active species on Pd catalyst provided in this work, there is also experimental evidence based on operando spectroscopic characterization in favor of the weaker bound tilted CD species and in disfavor of the flat-lying species on Pt catalyst.22 The often observed rate acceleration of the chirally-modified over the non-modified hydrogenation of activated ketones on Pt catalyst45 makes the distinction between the different surface regimes discovered in this study more difficult. It may be argued that the globally observed poor enantioselection at low chiral modifier surface coverage does not originate from the poor enantioselection of the flat-lying species, but is merely the result of an insufficient and unknown number of chiral sites imparted by flat-lying chiral modifier species, which prompted us not to make a stronger statement in our publication in ref. 22. However, in addition to these


Page 28 of 39

Page 29 of 39 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

ACS Catalysis

two operando spectroscopic studies there are catalytic experiments involving the addition of QN to cinchona-modified hydrogenations, which further corroborate our hypothesis on the crucial role of surface species III. In this work in section 3.5 the beneficial effect of QN addition shifting the poor enantiodifferentiation of surface regime II to surface regime III was shown for the CNmodified Pd-catalyzed hydrogenation. In the past, particularly Margitfalvi and co-workers41,46,47 have observed the same behavior in several catalytic studies for CD-modified Pt-catalyzed hydrogenations involving alumina and silica supported Pt catalyst, as well as the model substrates ethyl pyruvate and methyl benzoylformate. For example, Tálas and Margitfalvi46 observed a tremendous improvement of more than 50% ee upon addition of 60 µM QN to the asymmetric hydrogenation of ethyl pyruvate in toluene at low CD concentration (6 µM CD), and no improvement was observed at 60 µM CD concentration (Figure 1 in ref. 46). For other chiral modifiers such as the simpler synthetic modifier 1-(1-naphthyl)ethylamine (NEA), there are no operando spectroscopic studies or catalytic studies embracing the effect of the surface arrangement of the aromatic anchoring unit on enantioselection. Surface science studies focus on NEA surface species strongly anchored to the single crystal surface with a flatlying aromatic ring and the observed prochiral ratios are in general on a low level (0 – 30%),1719,48

while the chiral modifier NEA can provide an ee of up to 82% in catalytic experiments

under optimized conditions.49 Nevertheless, it can only be speculated that the poor enantioselection observed at low NEA surface coverages is attributable to the flat surface orientation of the aromatic ring, because other factors associated to the differences between surface science conditions and catalytic conditions have to play a major role, too. While surface science studies have recently shown different enantioselectivity for the exo- and endo- surface conformers of NEA at different ketopantolactone to NEA ratios,48 it would be interesting to


ACS Catalysis 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

investigate microscopically how the surface orientation of the aromatic anchoring unit influences the enantioselection. In the light of the molecular-level insight provided by this operando spectroscopic study, the catalytic results by Margitfalvi et al.,46,47 by Blaser et al.41 and by us in this work involving various substrates, solvents and Pt as well as Pd catalysts serve as compelling experimental evidence for the crucial role of the cinchona surface species III for enantioselective hydrogenation on Pd and Pt catalysts and the tilted orientation of the more weakly bound aromatic ring anchor has to be taken into account in future mechanistic considerations. For future experimental and theoretical studies it could be fruitful to focus more strongly on the tilted cinchona species in Pt and Pd catalyzed asymmetric hydrogenation.

4.

Conclusions

Our operando spectroscopic study unveils the relationship between the molecular orientation and the enantiodifferentiating ability of adsorbed cinchona chiral modifier species on Pd catalyst. Particularly, it was shown that the enantiodifferentiation varies significantly depending on the adsorption mode of the QN moiety of CN. As a consequence the so-called anchoring moiety of the chiral modifier exceeds the mere function of adsorptive anchoring and its molecular orientation has to be also taken into account in explaining the observed enantioselectivity of chirally-modified metals. In contrast to the prevailing mechanistic models, which imply that the most stable surface species of cinchona chiral modifiers formed by flat (parallel to the surface) QN adsorption is responsible for enantiodifferentiation, our results show that less stable, tilted CN species can provide significantly stronger enantioselective control. Proper adjustment of the


Page 30 of 39

Page 31 of 39 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

ACS Catalysis

coverage-dependent adsorption mode of the chiral modifier is shown to strongly enhance the enantiodifferentiation and is therefore a crucial design parameter for such asymmetric catalytic systems. These unprecedented experimental observations bring about major mechanistic implications for a more rational design of these asymmetric catalytic systems. They not only reveal a crucial aspect on the molecular-level regarding the design of chirally-modified metals, but should also help to guide and refine quantum chemical calculations for investigating and predicting the behavior of such complex chemical systems.


ACS Catalysis 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

Author Information Corresponding Author: [email protected] Notes: The authors declare no competing financial interests.

Associated Content Supporting Information. Experimental details, IR spectra for CN adsorption on Pd/TiO2 and TiO2 from toluene and isopropanol, materials, dissolution-adsorption equilibrium curve, TEM images of the Pd/TiO2 catalyst, GC temperature program, calibration of the UV-Vis detector, ATR-IR spectroscopic cell design, CN and CD vibrational modes assignments, assignment of the vibrational mode at 2962 cm-1. This material is available free of charge via the Internet at http://pubs.acs.org

Acknowledgments We would like to thank Roland Walker for his technical support in manufacturing the spectroscopic reactor cell. We gratefully acknowledge the help of Dr. Frank Krumeich with the TEM measurements.

References (1) (2) (3) (4) (5) (6) (7) (8) (9) (10) (11) (12) (13) (14) (15)

Sheldon, R. A. Green Chem. 2016, 18, 3180-3183. Corma, A. Angew. Chem. Int. Ed. 2016, 55, 6112-6113. Loffreda, D.; Delbecq, F.; Vigne, F.; Sautet, P. J. Am. Chem. Soc. 2006, 128, 1316-1323. Dostert, K. H.; O'Brien, C. P.; Ivars-Barceló, F.; Schauermann, S.; Freund, H. J. J. Am. Chem. Soc. 2015, 137, 13496-13502. Marshall, S. T.; O'Brien, M.; Oetter, B.; Corpuz, A.; Richards, R. M.; Schwartz, D. K.; Medlin, J. W. Nat. Mater. 2010, 9, 853-858. Gellman, A. J.; Tysoe, W. T.; Zaera, F. Catal. Lett. 2015, 145, 220-232. Forster, M.; Raval, R. Chem. Commun. 2016, 52, 14075-14084. Ernst, K. H. Acc. Chem. Res. 2016, 49, 1182-1190. Baiker, A. Chem. Soc. Rev. 2015, 44, 7449-7464. Baiker, A. Catal. Today 2005, 100, 159-170. Orito, Y.; Imai, S.; Niwa, S.; Nguyengiahung J. Synth. Org. Chem. Jpn. 1979, 37, 173-174. Sutyinszki, M.; Szöri, K.; Felföldi, K.; Bartók, M. Catal. Commun. 2002, 3, 125-127. Huck, W. R.; Mallat, T.; Baiker, A. Catal. Lett. 2002, 80, 87-92. Szőllősi, G.; Hermán, B.; Felföldi, K.; Fülöp, F.; Bartók, M. Adv. Synth. Catal. 2008, 350, 28042814. Nitta, Y.; Watanabe, J.; Okuyama, T.; Sugimura, T. J. Catal. 2005, 236, 164-167. 32 ACS Paragon Plus Environment

Page 32 of 39

Page 33 of 39 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

ACS Catalysis

(16) (17)

(18) (19) (20) (21) (22) 73. (23) (24) (25) (26) (27) (28) (29) (30) (31) (32) (33) (34) (35) (36) 2679. (37) (38) (39) (40) (41) (42) (43) (44) (45) (46) (47) (48) 1765.

Zhan, E.; Chen, C.; Li, Y.; Shen, W. Catal. Sci. Technol. 2015, 5, 650-659. Demers-Carpentier, V.; Goubert, G.; Masini, F.; Lafleur-Lambert, R.; Dong, Y.; Lavoie, S.; Mahieu, G.; Boukouvalas, J.; Gao, H. L.; Rasmussen, A. M. H.; Ferrighi, L.; Pan, Y. X.; Hammer, B.; McBreen, P. H. Science 2011, 334, 776-780. Mahapatra, M.; Burkholder, L.; Garvey, M.; Bai, Y.; Saldin, D. K.; Tysoe, W. T. Nat. Commun. 2016, 7, 1-8. Lemay, J. C.; Dong, Y.; Groves, M. N.; Demers-Carpentier, V.; Goubert, G.; Lafleur-Lambert, R.; Boukouvalas, J.; Hammer, B.; McBreen, P. H. Surf. Sci. 2016, 646, 13-18. Schmidt, E.; Bucher, C.; Santarossa, G.; Mallat, T.; Gilmour, R.; Baiker, A. J. Catal. 2012, 289, 238-248. Blaser, H.-U.; Jalett, H.-P.; Garland, M.; Studer, M.; Thies, H.; Wirth-Tijani, A. J. Catal. 1998, 173, 282-294. Rodríguez-García, L.; Hungerbühler, K.; Baiker, A.; Meemken, F. Catal. Today 2017, 283, 66Wang, H. L.; Sapi, A.; Thompson, C. M.; Liu, F. D.; Zherebetskyy, D.; Krier, J. M.; Carl, L. M.; Cai, X. J.; Wang, L. W.; Somorjai, G. A. J. Am. Chem. Soc. 2014, 136, 10515-10520. Guan, S. L.; Donovan-Sheppard, O.; Reece, C.; Willock, D. J.; Wain, A. J.; Attard, G. A. ACS Catal. 2016, 6, 1822-1832. Greenler, R. G.; Snider, D. R.; Witt, D.; Sorbello, R. S. Surface Science 1982, 118, 415-428. Zaera, F. Chem. Soc. Rev. 2014, 43, 7624-7663. Kraack, J. P.; Kaech, A.; Hamm, P. J. Phys. Chem. C 2016, 120, 3350-3359. Ferri, D.; Bürgi, T. J. Am. Chem. Soc. 2001, 123, 12074-12084. Kubota, J.; Zaera, F. J. Am. Chem. Soc. 2001, 123, 11115-11116. Ferri, D.; Bürgi, T.; Baiker, A. J. Catal. 2002, 210, 160-170. Ma, Z.; Lee, I.; Zaera, F. J. Am. Chem. Soc. 2007, 129, 16083-16090. Motobayashi, K.; Tomioka, R.; Uchida, T.; Osawa, M. Chem. Lett. 2015, 44, 770-772. Garland, M.; Blaser, H. U. J. Am. Chem. Soc. 1990, 112, 7048-7050. Lavoie, S.; Laliberté, M.-A.; Temprano, I.; McBreen, P. H. J. Am. Chem. Soc. 2006, 128, 75887593. Meemken, F.; Maeda, N.; Hungerbühler, K.; Baiker, A. Angew. Chem. Int. Ed. 2012, 51, 82128216. Bonello, J. M.; Lindsay, R.; Santra, A. K.; Lambert, R. M. J. Phys. Chem. B 2002, 106, 2672Bergeret, G.; Gallezot, P. In Handbook of Heterogeneous Catalysis; Wiley-VCH Verlag GmbH & Co. KGaA, 2008, pg. 738. Bradshaw, A. M.; Hoffmann, F. M. Surf. Sci. 1978, 72, 513-535. Lavoie, S.; Mahieu, G.; McBreen, P. H. Angew. Chem. Int. Ed. 2006, 45, 7404-7407. Mameda, T.; Misaki, T.; Okamoto, Y.; Sugimura, T. React. Kinet. Mech. Cat. 2015, 114, 55-61. Blaser, H. U.; Jalett, H. P.; Wiehl, J. J. Mol. Catal. 1991, 68, 215-222. Chu, W.; LeBlanc, R. J.; Williams, C. T.; Kubota, J.; Zaera, F. J. Phys. Chem. B 2003, 107, 14365-14373. Matsuda, Y.; Ebata, T.; Mikami, N. J. Chem. Phys. 1999, 110, 8397-8407. Pretsch, E.; Bühlmann, P.; Badertscher, M. In Spektroskopische Daten zur Strukturaufklärung organischer Verbindungen; Springer Berlin Heidelberg: Berlin, Heidelberg, 2010, pg. 297. Blaser, H. U.; Jalett, H. P.; Monti, D. M.; Reber, J. F.; Wehrli, J. T. Stud. Surf. Sci. Catal. 1988, 41, 153-163. Tálas, E.; Margitfalvi, J. L. Catal. Commun. 2008, 9, 984-989. Margitfalvi, J. L.; Tálas, E. Catal. Commun. 2014, 46, 142-145. Dong, Y.; Svane, K.; Lemay, J.-C.; Groves, M. N.; McBreen, P. H. ACS Catal. 2017, 7, 1757-


ACS Catalysis 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

(49) 268.

Minder, B.; Schürch, M.; Mallat, T.; Baiker, A.; Heinz, T.; Pfaltz, A. J. Catal. 1996, 160, 261-


Page 34 of 39

Page 35 of 39 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

ACS Catalysis

ACS Paragon Plus Environment

ACS Catalysis 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


Page 36 of 39

Page 37 of 39 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

ACS Catalysis


ACS Catalysis 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


Page 38 of 39

Page 39 of 39 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

ACS Catalysis


The Critical Role of Tilted Cinchona Surface Species for

Recommend Documents