Single Site Surface Reactions: STM Studies
Thèse Yi Dong Doctorat en chimie Philosophiæ doctor (Ph.D.) Québec, Canada © Yi Dong, 2018Single Site Surface Reactions: STM Studies
Thèse
Yi Dong
Sous la direction de:
Résumé
La demande des composants chimiques énantiopurs dans le secteur pharmaceutique est une des forces qui motive la recherche dans la création des catalyseurs homochiraux à la surface. La catalyse hétérogène est une méthode prometteuse pour la fabrication des produits énantio-purs puisqu'elle porte des avantages tels que la facilité de la séparation des produits désirés, la réutilisation du catalyseur et l'adaptabilité dans diérentes conditions de la production en continu. La réaction d'Orito est un des exemples de la réaction hétérogène énantiosélective la plus réussie. Elle concerne l'hydrogénation de α-cétoesters sur des particules de platine modi- ées par le cinchona. Il est généralement accepté que des modi cateurs cinchona tels que la cinchonidine ou la cinchonine transfère la chiralité en formant des complexes bimoléculaires (complexes 1 :1) avec des réactifs prochiraux sur la surface. La compréhension de la catalyse asymétrique hétérogène au niveau fondamental est insu sante. Par contre, c'est aussi une zone fertile pour la découverte. Du progrès dans le domaine peut être réalisé par des travaux complémentaires en catalyse, en sciences des surfaces et en calcul théorique. Cette thèse décrit les études en science des surfaces inspirées par des rapports dans la littérature sur la réaction d'Orito.
En plus des alcaloïdes du cinchona, qui sont des produits naturels, certains nombres de molécules synthétiques sont également des modi cateurs chiraux pour la réaction d'Orito. En particulier, Baiker et ses collègues ont enquêté sur la performance du 1-(1-naphtyl)éthylamine (NEA) optiquement pur en tant que modi cateur chiral pour l'hydrogénation énantiosélective de cétopantolactone (KPL) en pantolactone sur le Pt/Al2O3.1 Une partie du travail décrit
dans cette thèse est l'étude des complexes formés par l'interaction de (R)-NEA et KPL sur la surface de monocristal Pt(111). Le microscope à eet tunnel (STM) est utilisé pour acquérir un grand nombre d'images des complexes KPL/(R)-NEA. Les mesures sont eectuées sur un large rapport de couverture de KPL à (R)-NEA sur la surface. Un algorithme est développé pour accélérer le comptage et la catégorisation de la forme du grand ensemble d'images STM des complexes. L'abondance de plusieurs complexes distincts qui impliquent toute une liaison hydrogène NH· · ·O est déterminée. La prochiralité de KPL dans ces complexes sont attribuées en référant des images STM simulées par théorie de la fonctionnelle de la densité (DFT). Le rapport prochiral global (pr) mesuré dans l'expérience de la surface est comparé au rapport énantiomérique (er) mesuré par Baiker et ses collègues.
Un autre algorithme est développé pour l'analyse des événements dynamiques des com-plexes diastéréomères individuels. Il est appliqué pour tester l'interconversion d'un état à l'autre état pendant la durée de vie de chaque complexe qui est observée par STM. Les ré-sultats sont présentés pour les complexes formés entre 2,2,2-tri uoroacetophenone (TFAP) et (R)-NEA sur le Pt(111). Les complexes TFAP/(R)-NEA montrent des événements dy-namiques qui sont décrits comme décomplexation, inversion prochirale sur site et migration intracomplexe. Les résultats sont discutés en référant les barrières énergétiques prédites par DFT pour l'hydrogénation et pour l'inversion prochirale sur site. Un rapport préliminaire présente les données quantitatives sur les interconversions des états aux états des complexes individuels des trois systèmes : TFAP/(R)-NEA, KPL/(R)-NEA et TFAP/8-Me-(R)-NEA. Le dernier modi cateur de la surface concerne la substitution d'un méthyle à l'hydrogène à la position 8 du groupe naphtyle du (R)-NEA.
Les observations sur les complexes KPL/(R)-NEA et TFAP/(R)-NEA sont résumés dans le contexte des données de science de surface précédemment publiées de notre groupe. La revue met l'accent sur le rôle des interactions secondaires, CH· · ·O et CF· · ·H, dans le contrôle stéréoscopique des molécules prochirales.
Abstract
The demand for enantiopure compounds in the pharmacological sectors is a strong driving force for research aimed at creating homochiral catalyst surfaces. Heterogeneous catalysts oer potential advantages over homogeneous catalysts including ease of separation of products from the catalyst and greater suitability for operations under continuous ow conditions. One of the most successful examples of a heterogeneous enantioselective reaction is known as the Orito reaction, the hydrogenation of α-ketoesters on cinchona modi ed platinum particles. It is believed that the cinchona modi ers operate chirality transfer by forming bimolecular surface complexes with prochiral reactants. At a fundamental level, heterogeneous asymmetric catalysis is a poorly understood area of surface chemistry. Hence, it is also a fertile area for discovery. Progress in the area can best be made by complementary work in catalysis, surface science and computation. This thesis describes surface science studies that were inspired by reports in the catalysis literature on the Orito reaction.
In addition to cinchona alkaloids, which are natural products, a number of synthetic molecules have been shown to be eective chiral modi ers for the Orito reaction. In particular, Baiker and co-workers explored the performance of optically pure 1-(1-naphtyl)-ethylamine (NEA) as a chiral modi er for the enantioselective hydrogenation of ketopantolactone (KPL) to pantolactone on Pt/Al2O3.1 A major part of the work described in this thesis deals with
the investigation of surface complexes formed through the interaction of (R)-NEA and KPL on single crystal Pt(111). Scanning tunnelling microscopy (STM) measurements were used to acquire a large number of images of KPL/(R)-NEA complexes. The measurements were performed over a wide ratio KPL to (R)-NEA surface coverage ratios. An algorithm was developed to enable accelerated counting and cataloguing of the large set of STM images of complexes. The relative abundances of multiple distinct complexation states, all involving NH·· ·O hydrogen bonding, were determined. The prochirality of KPL in these states was assigned by reference to density functional theory (DFT) simulated STM images. The overall prochiral ratio (pr) measured in the surface science experiment was compared to the enantiomeric ratio (er) measured by Baiker and co-workers.
An algorithm was developed to investigate uxional events in individual diastereomeric complexes. It was applied to examine state-to-state interconversion occurring during the
life-times of complexes, as observed using time-lapsed STM measurements. Results are presented for complexes formed by 2,2,2-tri uoroacetophenone (TFAP) interacting with (R)-NEA on Pt(111). The TFAP/(R)-NEA complexes show dynamic events that we describe as decom-plexation, on-site prochiral inversion and intracomplex migration. The results are discussed in relation to energy barriers predicted by DFT for hydrogenation and for on-site prochiral inversion. Quantitative data for state-to-state interconversion in single complexes are pre-sented for three systems: TFAP/(R)-NEA, KPL/(R)-NEA and for TFAP interacting with methyl-substituted (R)-NEA. A preliminary analysis of the data is presented.
The observations on KPL/(R)-NEA and TFAP/(R)-NEA complexes are reviewed within the context of previously published surface science data from our group. The review empha-sizes the role of secondary interactions, CH· · ·O and CF· · ·H bonding, in the stereocontrol of prochiral molecules.
Table des matières
Résumé iii
Abstract v
Table des matières vii
Liste des gures viii
Remerciements ix
Avant-propos x
1 Introduction 1
1.1 Chirality . . . 1
1.2 Production of single enantiomers . . . 2
1.3 Mechanistic studies in heterogeneous asymmetric hydrogenation catalysis . 5
2 Investigation Methods and Data Treatment 14
2.1 Scanning Tunnelling Microscope . . . 14
2.2 Density Functional Theory. . . 23
3 Structure and Dynamics of Individual Diastereomeric Complexes on Platinum: Surface Studies Related to Heterogeneous Enantioselective
Catalysis 25
3.1 Résumé . . . 26
3.2 Abstract . . . 27
3.3 Introduction. . . 28
3.4 Establishing the Adsorption Geometry of the Chiral Modi er (R)-NEA on
Pt(111) . . . 29
3.5 Three Representative Prochiral Molecules: Structures and H-Bonding
Prop-erties. . . 31
3.6 STM Images of Ensembles of (R)-NEA and TFAP on Pt(111) . . . 32
3.7 Distinguishing pro-S and pro-R Complexation Con gurations: Determining
the Prochiral Ratio (pr) . . . 35
3.8 Comparing an STM-Determined Prochiral Ratio (pr) with an Enantiomeric
Ratio (er) Measured under Practical Reaction Conditions . . . 36
3.9 Merging STM and DFT Data To Identify the Most Abundant Complexation
3.10 Time-Lapsed STM Study of Individual Fluxional TFAP-(R)-NEA Complexes 41
3.11 Attractive Stereodirecting Interactions: CH· · ·O and CF· · ·H Bonding . . . 42
3.12 Conclusions . . . 44
3.13 Acknowledgment . . . 45
4 STM Study of Ketopantolactone/(R)-1-(1-Naphthyl)ethylamine Com-plexes on Pt(111): Comparison of Prochiral and Enantiomeric Ratios and Examination of the Contribution of CH· · ·OC Bonding 46 4.1 Abstract . . . 47
4.2 Introduction. . . 48
4.3 Experimental Section. . . 53
4.4 Results. . . 54
4.5 Discussion . . . 61
5 Monitoring Interconversion Between Stereochemical States in Single Chirality-Transfer Complexes on a Platinum Surface 66 5.1 Résumé . . . 66 5.2 Abstract . . . 67 5.3 Introduction. . . 67 5.4 Results. . . 70 5.5 Discussion . . . 78 5.6 Methods . . . 81 5.7 Supplementary information . . . 82
6 Fluxional Chirality-Transfer Complexes on Pt(111) 83 6.1 Introduction. . . 83
6.2 TFAP/8-Me-(R)-NEA Complexes. . . 90
6.3 KPL/(R)-NEA Complexes . . . 94
6.4 Conclusion . . . 98
Liste des gures
1.1 (R)-(-)-carvone (left) and (S)-(+)-carvone (right). . . 1
1.2 Statistics on newly approved drugs. Proportion of enantiopure, racemic and
diastereomeric compounds in newly launched chiral synthetic drugs [3].. . . 3
1.3 Four examples of cinchona alkaloids: cinchonidine (CD) on top left, cinchonine (CN) on top right, quinine (QN) on bottom left and quinidine (QD) on bottom right. The dierence between derivatives shown on top and bottom is the functional group at position 6'. The dierence between derivatives shown to
the left and right is the handedness at C8 and C9 as marked in green. . . 4
1.4 The hydrogenation of a β-ketoester, methylactoacetate (MAA), on (R, R)-tartaric acid modi ed Raney Ni catalysts in tetrahydrofuran (THF) to yield (S) or (R)-methyl-3-hydroxybutyrate.26 α-amino acids (e.g. (S)-alanine, glutamic
acid) and D-glucose can also be used as chiral modi ers for this reaction.11,2731 5
1.5 Schematic representation of chemisorbed CD.53The speci c conformation shown,
the so-called open(3) conformation,53,59 is the one most often cited in
discus-sions of modi er-substrate interactions in the Orito reaction. . . 7
1.6 The α-ketoester, methyl pyruvate, is hydrogenated to (R)-methyl lactate over cinchonidine modi ed supported platinum catalysts. This, along with the hy-drogenation of ethyl pyruvate, is one of the best studied examples of the Orito
reaction. Methyl pyruvate can also be described as an activated ketone. . . 7
1.7 Asymmetric hydrogenation of isophorone on proline modi ed Pd/C catalyst to
produce (S)-TMCH. . . 9
1.8 A proposed model for the stereodirecting interactions between a chiral modi er and a prochiral molecule on a surface. The stacked squares on the left repre-sent the chiral modi er and the rectangular shape on the right reprerepre-sents the
substrate. A-D are H-bonding functional groups.38 . . . . 11
1.9 Schematic representation of four principal adsorption sites for benzene on an fcc (111) surface drawn with two layers. Maroon represents an atop site over a single atom. Green represents bridge sites involving two neighbor atoms. Blue represents hollow-hcp sites that show the same sequence as hcp stacking of the planes (ABAB). Orange represents hollow-fcc sites. The angles refer to rotation
with respect to close-packed rows. . . 12
1.10 STM image of 2,2,2-tri uoroacetophenone (TFAP) and (R)-NEA coadsorbed on the Pt(111) surface, acquired at room temperature. The white circle marks a TFAP molecule captured during a movement from left to right; the black triangle marks an observation plausibly due to the rotation the CF3CO group
of TFAP; the blue rectangle marks a (R)-NEA molecule moveing right and left
2.1 A particle (orange) with kinetic energy E strikes a barrier (grey) with height of
U and length L (U>E). . . 15
2.2 A and B show images of homochiral S and R TFPE dimers observed on Pt(111) surface at the start of STM experiments. Each monomer displays three small protrusions. C shows an STM image of dimer motifs observed after scanning for 10 minutes. A, B and C were acquired at 233 K. Tunnelling conditions: bias=1
V, current= 0.21 nA. A', B' and C' use colours to dierentiate the motifs' features. 16
2.3 Large scan (30 nm Ö 30 nm) STM image of TFPE on Pt(111) at 233 K. The interior grated part (20 nm Ö 20 nm) was scanned for ∼23 min before acquisition
of the whole image. Tunnelling conditions: bias=1 V, current=0.21 nA. . . 17
2.4 Overview of the data mining process.102 . . . . 18
2.5 Schematic representation of the image analysis method. From left to right: selection of data to analyze, image processing step, extracted information on
all molecules and the presentation of data patterns. . . 19
2.6 STM image of TFAP adsorbed on Pt(111) at 222 K. . . 19
2.7 Image recognition process. From left to right: a raw image to be recognized; two methods to improve the contrast; result of the recognition process; patterns
produced by the subsequent analysis process. . . 20
2.8 Analysis process by manual application of masks. Left: manual application of masks; Middle: extraction of the geometric shapes of complexation motifs;
Right: data patterns.. . . 21
2.9 Determining the prochirality of TFAP from the STM images and schematic illustration of the conventions used to de ne ϑ and ϕ for TFAP/(R)-NEA STM motifs (A), DFT calculated structures (C) and motifs replicated using image analysis masks (E). (A) STM image of a complex formed on Pt(111) at 254 K by TFAP binding to the exo-conformer of (R)-NEA. Tunnelling conditions: tunnel current = 0.220 nA, bias voltage = 1 V. (B) DFT-simulation of the STM image. (C) De nition of ϑ and ϕ for the DFT-calculated structure. (D) The alcohol product (R)-TFPE, formed by adding hydrogen atoms from the surface to TFAP. (E) Determining ϑ and ϕ using masks applied in the image analysis process. Parts (A-E) of this Figure are based on our previously published
work.42,108 . . . . 22
2.10 The STM data are plotted according to the position (ϑ) and orientation (ϕ) of TFAP relative to the modi er. The colour map on the right indicates the
number density at every point. . . 23
3.1 Determination of the adsorption geometry of (R)-(+)-1-(1-naphthyl)ethylamine ((R)-NEA) on Pt(111).42,49(a) STM image showing several (R)-NEA molecules
adsorbed on Pt(111) at 295 K. The red and blue squares highlight the observa-tion of two distinct STM motifs. The two motifs, shown separately in (b) and (c), are labeled 1 and 2, respectively. Tunneling conditions: T = 246 K; Vt = 1.0 V; it = 0.200 nA. (d, e) The two most stable DFT-calculated chemisorption geometries. The N atom is shown in blue, and the Pt atoms to which (R)-NEA is directly coordinated are shaded. (f, g) DFT-simulated STM motifs for the structures in (d) and (e), respectively. (h) RAIRS spectra of (R)-NEA on
3.2 Time-lapsed STM images of ensembles of TFAP and (R)-NEA on Pt(111). The overlaid geometric forms are used to guide the eye to examples of changes seen in consecutive frames measured at a rate of one per 52.6 s. Tunneling conditions: (a, b) T = 295 K; Vt = 1.0 V; it = 0.280 nA. (c, d) T = 261 K; Vt = 1.0 V; it
= 0.220 nA. . . 32
3.3 Determination of the prochiralities of TFAP, MTFP, and KPL complexed to (R)-NEA on Pt(111). (a1-a4) Example using a 1-TFAP complex..42,108(a1) The
measured STM motif (T = 262 K; Vt = 1.0 V; it = 0.220 nA). (a2) The cor-responding DFT-simulated motif. (a3) The DFT-calculated structure to which the motif is assigned. (a4) The product, (R)-2,2,2-tri uoro-1-phenylethanol, formed by adding hydrogen atoms from the surface to TFAP in the complex. (a5) Proxy drawing of the STM motif showing the parameters (ϑ, ϕ)STM used to specify its geometric shape. (b1-b4) Example using a 2-MTFP complex.46,108
Adapted from ref 46. (b1) The measured STM motif (T = 262 K; Vt = 1.0 V; it = 0.250 nA). (b2) The corresponding DFT-simulated motif. (b3) The DFT-calculated structure to which the motif is assigned. (b4) The methyl (R)-3,3,3-tri uoro-2-hydroxypropanoate product formed by adding hydrogen atoms from the surface to MTFP in the complex. (b5) Proxy drawing of the STM motif. (c1-c4) Example using a 2-KPL complex.52,121 (c1) The measured STM
motif (T = 247 K; Vt = 1.0 V; it = 0.220 nA). (c2) The corresponding DFT-simulated motif. (c3) The DFT-calculated structure to which the image is as-signed. (c4) The (R)-pantolactone product formed by adding hydrogen atoms
from the surface to KPL in the complex. (c5) Proxy drawing of the STM motif. 34
3.4 Comparison of prochiral ratio (pr) and enantiomeric ratio (er) data for KPL/(R)-NEA/Pt. (a) Literature er values reported for the enantioselective hydrogena-tion of KPL to pantolactone (PL) on (R)-NEA-modi ed Pt/Al2O3 catalysts in
acetic acid under 1 bar H2.34The gray region is used to indicate the range of
re-ported values. (b) (pr) values measured by counting the numbers of pro-R and pro-S KPL-(R)-NEA complexes observed in STM experiments.52 Reproduced
from ref 52. . . 37
3.5 Results of a systematic DFT search for the set of most stable 2-MTFP complexes.46
(A, B) The most stable chemisorption geometry found for MTFP on Pt(111), shown in pro-S and pro-R con gurations. (C) Sets of the most stable pro-S and pro-R complexes. Complexation energies (eV), calculated using the M06-L exchange-correlation functional, are indicated by the color scale. (D, E) The
two most stable complexes and their formation energies. Reproduced from ref 46. 39
3.6 Merging of STM and DFT data for TFAP-(R)-NEA so as to de ne the most abundant complexation structures. The STM data, measured in the 253-263 K range, are plotted according to the position (ϑSTM) and orientation (ϕSTM) of
TFAP relative to the modi er. The two parameters are de ned in Figure 3.1a5. The densities of data points are indicated by the vertical color scales. The triangles locate (ϑ, ϕ)DFT values describing the most stable DFT-calculated
structures. The colors of the triangles indicate the calculated complexation en-ergies, with reference to the horizontal color scale. Dierent-sized triangles are used to improve the visual clarity. pro-S and pro-R con gurations of complexed
3.7 Time-lapsed STM study of interconversion between 1-TFAP stereochemical states.51 (a) The six most abundant 1-TFAP STM motifs observed in STM
experiments at 253-260 K. The states are labeled to specify the (R)-NEA con-former, the prochirality of TFAP, and the angle ϑ (Figure 3.1a5) describing the position of the phenyl group of TFAP. (b) The corresponding DFT-calculated structures. Adapted from ref 108. (c) Consecutively acquired STM images of a single complex showing an on-site prochiral inversion event. (d) Consecutively acquired STM images of a single complex showing an intracomplex migration event. (e) Time-lapsed images of a single complex showing TFAP sampling all six of the abundant 1-TFAP states. The number of consecutive frames in which each motif was observed is indicated at the bottom left of each selected frame. Tunneling conditions: T = 254 K; Vt = 0.7 V; it = 0.220 nA. Acquisition time
per frame = 52.6 s.51 . . . . 41
3.8 Selected evidence for the contribution of secondary attractive non-covalent in-teractions to stereocontrol by (R)-NEA. (a, b) Two 1-TFAP states coupled by on-site prochiral inversion: the 1R100 state (a) is more abundant than the 1S100 state (b)42 and.108 (c, d) Schematic illustration of the STM-observed
distribu-tion of KPL around the ethylamine groups of 1 and 2, respectively. Adapted from ref 121. (e-h) The 2-MTFP structure (e) is assigned to the most abundant STM motif observed for MTFP-(R)-NEA complexes (f).46,108 A motif
corre-sponding to structure (g) is not observed in the STM experiments. Tunneling
conditions: Vt = 1.0 V; it = 0.200 nA. Adapted from ref 46.. . . 43
4.1 DFT-calculated most stable chemisorption structures of (R)-NEA and KPL on Pt(111). (A, B) (R)-NEA is presented in two dierent adsorption geometriess : an exo conformation ((R)-NEA-1) and an endo conformation ((R)-NEA-2). Adapted from ref 49. (C, D) : pro-S and pro-R adsorption con gurations of
KPL. Adapted from ref 121. . . 51
4.2 Illustration of the proposed relationship between the STM motif of a KPL/(R)-NEA complex and the molecular structure of the complex. (a) STM motif of a complex. Tunneling conditions : V = 1 V ; it= 0.22 nA ; T = 245 K. (b) The same motif as in (a) is labeled to indicate three protrusions arising from complexed KPL : 1 is the brightest protrusion and 3 the dimmest protrusion. The brightest protrusion, 1, is attributed to the dimethyl group, on the basis of DFT-simulated images.121 (c) DFT-calculated molecular and chemisorption
structure of a complex that is consistent with the STM motif. KPL is in a pro-R
con guration in the complex. Adapted from ref 121. . . 52
4.3 (A, B) Time-lapsed images of KPL/(R)-NEA on Pt(111) at 246 K. Blue and red squares are used to indicate (R)-NEA-1 and (R)-NEA-2, respectively. The arrow indicates the location of the ethylamine group of an (R)-NEA-2 molecule. The circle guides the eye to an apparent event where KPL moves from one (R)-NEA-1 to a near neighbor (R)-NEA-1. The two (R)-NEA-1 molecules are rotated with respect to each other by 120°due to the rotational symmetry of the surface (Figure 4.1A). Tunneling conditions : V = 1 V ; it = 0.22 nA ; frame rate of one frame per 52.6 s. (C) Relative surface coverages of the (R)-NEA conformers, as measured by counting from images acquired at eight dierent
4.4 (A-C) Large scan STM images (15 nm × 15 nm) for the coadsorption of (R)-NEA and KPL on Pt(111) at KPL to (R)-(R)-NEA ratios of approximately 0.2 (A), 0.8 (B), and 1.7 (C). (D-I) Selected images of complexes involving single (R)-NEA molecules. (J-L) Selected images of (KPL)2/((R)-NEA)2 complexes.
Tunneling conditions : V = 1 V ; it = 0.22 nA. The images were acquired at T
= 240 K, apart from (C), which was acquired at 244 K. . . 56
4.5 DFT-calculated complexes and complexation energies for structures where KPL
interacts uniquely with the naphthyl group of (R)-NEA. . . 57
4.6 Fraction of (R)-NEA-1 (blue) and (R)-NEA-2 (red) in complexes, relative to the total population of (R)-NEA-1 and (R)-NEA-2, respectively, as a function of the KPL to (R)-NEA ratio observed by STM. The fractions in 1 :1, 2 :1, and 3 :1 (KPL)n/(R)-NEA complexes are indicated by progressively lighter shades
of blue and red. The black line indicates the measured ratio of KPL to (R)-NEA
(right axis). The data were measured in the 237-250 K temperature range. . . . 58
4.7 (left) The ten most abundant STM motifs observed for KPL/(R)-NEA bimole-cular complexes on Pt(111). A schematic illustration of the STM motif is inclu-ded in each case. The naphthyl group of (R)-NEA is illustrated by blue and red ellipses for (R)-NEA-1 and (R)-NEA-2, respectively. A yellow ellipse is used to represent the ethylamine group. The three-protrusion STM motifs of KPL in the complexes (described in Figure 4.2) are represented in yellow (the methyl groups), gray (the CH2 group), and black (the ester moiety). The complexes
are labeled to specify, in sequence, the prochirality of KPL, the conformation of (R)-NEA, and the location of KPL to the right, top, or left of the ethylamine group. The label for the pro-R KPL/(R)-NEA-2 con guration (R)-2R2 is
dis-tinguished from that for the spatially overlapping con guration (R)-2R1 by the
subscript. (right) Schematic illustration of the ten most abundant STM motifs for KPL/(R)-NEA complexes. Tunneling conditions : V = 1 V ; it = 0.22 nA.
The images were acquired at 248 K. . . 59
4.8 Most abundant STM motifs observed for termolecular (KPL)2/(R)-NEA
com-plexes on Pt(111). The STM motifs are presented in order of decreasing abun-dance from left to right for the combined data on (R)-NEA-1 and (R)-NEA-2 complexes. Tunneling conditions : V = 1 V ; it = 0.22 nA. The images were
acquired in the 237-246 K temperature range. . . 60
4.9 Relative abundances of KPL/(R)-NEA complexation con gurations for ve ranges of KPL to (R)-NEA ratio. The dierent complexation con gurations are indicated by the color codes shown in the insets. The ranges of ratios are, from left to right in each case, approximately [<0.4], [0.4-0.7], [0.7-0.8], [0.8-1.2],
and [1.2-1.8]. The data were measured in the 237-250 K temperature range. . . 61
4.10 STM-determined prochiral ratios (pr) of KPL in complexes presented for ve dierent ranges of KPL to (R)-NEA ratio. The data are presented separately for KPL/(R)-NEA-1 complexes (left), KPL/(R)-NEA-2 complexes (middle), and all complexes (right). The ve ranges of KPL to (R)-NEA ratios are, from left to right in each case, approximately [<0.4], [0.4-0.7], [0.7-0.8], [0.8-1.2], and
4.11 (A) Literature data for the enatiomeric ratio (er) observed for the enantio-selective hydrogenation of KPL to pantolactone (PL) over (R)-NEA-modi ed Pt/Al2O3 in solvent at 1 bar of H2.34The shaded region is used to indicate that
a range of er values are reported in ref 34. (B) STM-determined prochiral ratio (pr) measured for KPL/(R)-NEA/Pt(111) at low to medium KPL :(R)-NEA
ratios. The STM data were measured in the 237-250 K temperature range. . . . 63
5.1 Determining the prochirality of TFAP from the STM image of a TFAP/(R)-NEA complex.42,108 a, STM image of a complex, labelled R100,
formed on Pt(111) by TFAP binding to the exo-conformer of (R)-NEA. (Vbias = 1.0 V ; it=0.220 nA ; T = 254 K). b, DFT simulation of the STM image. c, DFT-calculated complexation structure corresponding to the simulated image. Pt atoms are shaded to emphasize the coordination footprint of the complex. Colours are used to indicate H (white), C (grey), F (green), O (red) and N (blue) atoms. d, The alcohol product, (R)-TFPE, formed by adding hydrogen atoms from the surface to TFAP in R100. e, Notation used to label complexes.
The label R speci es the prochirality of TFAP in the complex.42,108. . . . 69
5.2 DFT-calculated structures of the adsorption conformers of (R)-NEA on Pt(111) that are assigned to the two observed STM motifs. a, exo-(R)-NEA ; b, endo-(R)-NEA. The structures and their assignment to STM
motifs are discussed in references 42 to 52.49,52 . . . . 70
5.3 Time-lapsed STM images of individual TFAP/exo-(R)-NEA com-plexes showing interconversion between complexation con gurations. a, Summary of STM data showing the six abundant STM motifs observed for TFAP/exo-(R)-NEA complexes at 254 K. b, DFT-calculated structures to which the STM motifs are assigned.108 c-e, Time-lapsed STM images of
com-plexes : consecutively acquired STM frames showing rst an S100 state and then an R100 state (c) ; consecutively acquired STM frames showing rst an S100 state and then an R60 state (d ; the blue arcs are guides to the eye) ; and a sequence of consecutively observed STM motifs for a single complex sho-wing interconversion between multiple preorganization states (e). The number of consecutive 30 × 30 nm2 frames in which each distinct motif was observed is
indicated at the bottom right of the frames. (Vbias = 0.70 V ; it = 0.220 nA ; acquisition time per frame = 52.6 s ; T=253 K (c) ; T = 260 K (d) ; T = 254 K
(e)).108 . . . . 72
5.4 Example of consecutive images of a TFAP/exo-(R)-NEA complex revealing TFAP movement beneath the STM tip. The images were acquired in the
5.5 Fluxional events speci c to individual TFAP/exo-(R)-NEA preorganization states. a, Histogram with bins corresponding to the number of complexes showing n events (on-site prochiral inversion or intra-complex migration) for a sample of 8,750 observations on 754 bimolecular complexes. b, Histogram showing the absolute number of observations (left axis) of on-site prochiral inversion (red), intra-complex migration (blue) and decomplexation events (green) of a given preorganization state i of TFAP/(R)-NEA. The vertical black lines indicate the state-speci c number of events observed relative to the population of the ith preorganization state (right axis). The vertical blue lines show the
rela-tive populations of the six preorganization states. c, Schematic depiction of the
preorganization states, using the labelling system de ned in Fig. 5.1e. . . 74
5.6 Fluxional events speci c to TFAP/endo-(R)-NEA preorganization states. a, Histogram with bins corresponding to the number of complexes sho-wing n events (on-site prochiral inversion or intra-complex migration) for a sample of 3860 observations on 501 bimolecular complexes. b, Histogram sho-wing the absolute number of observations (left-axis) of on-site prochiral inver-sion (red), intracomplex migration (blue) and decomplexation events (green) of a given preorganization state i of TFAP/(R)-NEA. The vertical black lines indicate the state-speci c number of events observed relative to the population of the ith preorganization state (right-axis). The vertical blue lines show the
relative populations of the ve preorganization states. c, Schematic depiction
of the preorganization states, using the labelling system de ned in Fig.5.1 . . . 74
5.7 Arrhenius plot for the STM determined rate of complexation con guration change in single TFAP/exo-(R)-NEA complexes on Pt(111). Both on-site pro-chiral inversion and intra-complex migration events are counted together. The Arrhenius equation was used to nd the best t as shown by the green dashed line (model). The best parameters are 0.75 eV for the activation energy and 1.3 x 1012 s-1 for the prefactor. The 1 standard deviation errors derived from the
t are 0.51 eV and 3.1 x 1013 s-1, respectively. . . . . 76
5.8 Test for possible STM tip-induced contributions to the observation of dynamic events. The histogram presents preorganization state-speci c data for dynamic events observed for TFAP/exo-(R)-NEA separated according to three rotatio-nally equivalent orientations of (R)-NEA on Pt(111). The data are presented as the total number of events (on-site prochiral inversion, intra-complex migra-tion and decomplexamigra-tion) for each state, normalized to the populamigra-tion of the state. The directions, labeled as the angles 10°, 70°and 130°, are relative to the fast-scan direction of the STM tip. There is a 10°oset between the fast-scan
axis and the closest close-packed direction of Pt(111). . . 77
5.9 Schematic depiction of the enantioselective hydrogenation of TFAP on (R)-NEA modi ed Pt and schematic depiction of competing reaction coordinates. a, Illustration of stereocontrol by chemisorbed exo-(R)-NEA of the conversion of TFAP to the alcohol product TFPE. For clarity, the diagram shows only the S30 and R30 preorganization states. These two states are directly coupled by on-site prochiral inversion. b, Indicative potential energy diagram for the conversion of S30 and R30 to TFPE and for on-site prochiral inversion between
6.1 Examples of complexation state changes observed for individual TFAP/(R)-NEA-2 complexes on Pt(111) at 254 K (a) and 258 K (b, c). (a) decomplexa-tion ; (b) on-site prochiral inversion ; (c) intra-complex migradecomplexa-tion. Tunneling
conditions : current = 0.22 nA, bias = 1 V. . . 84
6.2 Schematic depiction of the most abundant preorganization states for TFAP/NEA/Pt(111). The blue and red ovals are used to show NEA-1 and (R)-NEA-2, respectively.. The value of theta is presented in digits in the grey circle. It is de ned by the angle between the two green lines on the drawing
of TFAP/(R)-NEA-2 complexes. . . 84
6.3 Summary of the most abundant STM motifs observed for TFAP/(R)-NEA-2 complexes. The STM images are matched with DFT-calculated complexation structures. The labeling system for the complexation states is described in
Chap-ter 5. Tunneling conditions : current = 0.22 nA, bias = 1 V. . . 85
6.4 (a) Decomplexation events for (TFAP)n/(R)-NEA complexes (n=1,2,3). The
data combine observations for (R)-NEA-1 and (R)-NEA-2 complexes acquired in multiple experiments in the the 253 to 263 K temperature range. The his-togram shows the numbers of single decomplexation events from bimolecular, termolecular and tetramolecular complexes normalized to the total number of each type of complex. The black lines show the absolute numbers (right axis) of bimolecular, termolecular and tetramolecular complexes in the sample. (b) STM image of an (TFAP)2/(R)-NEA-1 complex. (c) STM image of an (TFAP)3
/(R)-NEA-2 complex. . . 86
6.5 State-speci c interconversion events in individual bimolecular TFAP/(R)-NEA-1 complexes (a) and TFAP/(R)-NEA-2 complexes (b). Data for the most abun-dant complexation con gurations are shown using the notation de ned in Fi-gures 5.1 and 6.2. The relative abundances of pro-R and pro-S complexes are shown in blue and brown, respectively, for each indicated (bottom axis) value of theta. The interconnecting lines show the percentage of the population of a speci c state that apparently moves to a dierent speci c state. For example, 12% of the population of 1S60 apparently interconvert to 1S30 over the course of experiments lasting 25 to 55 min and measured at a frame rate of one per
52.6 s. Lines for interconversion values below 5% are not shown.. . . 87
6.6 Absolute numbers of observed state-speci c interconversion events in individual bimolecular TFAP/(R)-NEA-1 complexes (a) and TFAP/(R)-NEA-2 complexes (b). Data for the most abundant complexation con gurations are shown using the notation de ned in Figures 5.1 and 6.2. The relative abundances (right axis) of pro-R and pro-S complexes are shown in blue and brown, respectively. The interconnecting lines show the population of a speci c state that apparently moves to a dierent speci c state. For example, 37 1S60 apparently interconvert to 1S30 over the course of experiments lasting 25 to 55 min and measured at a frame rate of one per 52.6 s. Lines for interconversion values below 5 are not
shown. . . 87
6.7 DFT calculation of TFAP/(R)-NEA complexation energies using the
optB88-vdW functional. This Figure is based on DFT data presented in reference 108. 89
6.8 DFT calculation of TFAP/(R)-NEA complexation energies using the M06-L
functional. This Figure is based on DFT data presented in reference 108.. . . . 89
6.9 The notation used to label DFT calculated TFAP/8-Me-(R)-NEA complexation
6.10 Histograms of the fraction of (A) (R)-NEA-1 and (B) TFAP/8-Me-(R)-NEA-2 bimolecular complexes showing n con guration changes events. The data are for samples of 3025 observations on 517 8-Me-(R)-NEA-2 complexes and 4467 observations on 701 8-Me-(R)-NEA-1 complexes. The data sample is from a set of experiments performed over 25 to 39 min. periods in the 232 to 254 K temperature range. Experimental conditions : current = 0.22 nA, bias =
1 V. . . 91
6.11 Complexation state-speci c numbers of decomplexation, on-site prochiral in-version and intra-complex migration events observed for TFAP/8-Me-(R)-NEA complexes. The data are for (a) samples of 4467 observations on 701 8-Me-(R)-NEA-1 complexes and (b) 3025 observations on 517 8-Me-(R)-NEA-2 com-plexes. The histogram shows the normalized percentage of observations (left-axis) of on-site prochiral inversion (red), intra-complex migration (grey) and decomplexation events (white) of a given preorganization state i. The vertical black lines indicate the relative abundance of the ith preorganization state
ob-served relative to the overall population of bimolecular complexes (right-axis). The labeling system for these most abundant complexation structures speci es the 8-Me-(R)-NEA conformer, 1 or 2, the prochirality of TFAP and (roughly) the anti-clockwise angular position of the phenyl group relative to the center of
the long axis of the naphthyl group of 8-Me-(R)-NEA. . . 92
6.12 State-speci c interconversion events observed for individual bimolecular TFAP/8-Me-(R)-NEA-1 (a) and TFAP/8-Me-(R)-NEA-2 (b) complexes. Data for the most abundant complexation con gurations are shown using the notation shown above in Figure 6.9. The relative abundances of pro-R and pro-S complexes are shown in blue and brown, respectively. The interconnecting lines show the per-centage of the population of a speci c state that apparently moves to a dierent speci c state. For example, 12% of the population of 1S60 apparently intercon-vert to 1S30 over the course of experiments lasting 25 to 39 min and measured
at a frame rate of one per 52.6 s. . . 93
6.13 Absolute numbers of observed state-speci c interconversion events observed for ensembles of individual bimolecular Me-(R)-NEA-1 (a) and TFAP/8-Me-(R)-NEA-2 (b) complexes. Data for the most abundant complexation con -gurations are shown using the notation shown above in Figure 6.9. The relative abundances of pro-R and pro-S complexes are shown in blue and brown, res-pectively. The interconnecting lines show the population of a speci c state that apparently moves to a dierent speci c state. For example, 9 molecules at 1S30 apparently interconvert to 1R30 over the course of experiments lasting 25 to 39
min and measured at a frame rate of one per 52.6 s. . . 93
6.14 Histograms of the fraction of KPL/(R)-NEA-1 (a) and KPL/(R)-NEA-2 (b) bimolecular complexes showing n complexation con guration change events. The data are for samples of 13556 observations on 618 (R)-NEA-2 complexes and 14833 observations on 679 (R)-NEA-1 complexes. The data sample is from a set of experiments performed over 38 to 60 min. periods in the 237 to 250 K
temperature range. Experimental conditions : current = 0.22 nA, bias = 1 V. . 94
6.15 Consecutive STM images of KPL/(R)-NEA acquired at 248 K. The number of consecutive 30 x 30 nm2 frames in which each distinct motif was observed is
indicated at the bottom right of the frames. Experimental conditions : current
6.16 (a) State-to-state interconversion events in individual KPL/(R)-NEA complexes observed in experiments performed at relatively low ratios of KPL to (R)-NEA on Pt(111) in the 237 to 250 K temperature range. The relative abundances of pro-R and pro-S complexes are shown in brown and blue, respectively. The interconnecting lines show the percentage of the population of a speci c state that apparently moves to a dierent speci c state. For example, 15% of the population of the 2F state apparently convert to the 2D state over the course of experiments lasting 38 to 60 min and measured at a frame rate of one per 52.6 s. (b) Schematic illustration of the most abundant complexes. The labeling system employs 1 and 2 to specify the exo- and endo-conformers of (R)-NEA,
respectively. . . 95
6.17 Absolute numbers of observed state-to-state interconversion events in individual KPL/(R)-NEA complexes observed in experiments performed at relatively low ratios of KPL to (R)-NEA on Pt(111) in the 237 to 250 K temperature range. The relative abundances of pro-R and pro-S complexes are shown in brown and blue, respectively. The interconnecting lines show the population of a speci c state that apparently moves to a dierent speci c state. For example, 45 KPL at 2F state apparently convert to the 2D state over the course of experiments lasting 38 to 60 min and measured at a frame rate of one per 52.6 s. The labeling system employs 1 and 2 to specify the exo- and endo-conformer of (R)-NEA,
respectively. . . 96
6.18 DFT calculated structures and complexation energies (Ecomp) of KPL/(R)-NEA
and hy-KPL/(R)-NEA bimolecular complexes. In hy-KPL the keto carbonyl is transformed to OH. The color of substrates in the left-hand panel indicates their complexation energy (Ecomp) as de ned by the color bar. Corresponding colors
of labels are used in order to assign complexation con gurations. Only structures corresponding to abundant complexes are shown. Calculated structures of KPL and hy-KPL on non-modi ed Pt(111) are shown in the right-hand side panels.
Remerciements
À ce moment particulier, je veux d'abord remercier à mon superviseur de recherche, Prof. Peter H. McBreen. Il a fourni une condition de recherche exceptionnelle en termes de matériel et environnement. Ainsi, son écoute, sa con ance et son soutien sont présents tous durant mes avancements d'études. En plus, les opportunités qu'il m'a accordées dans l'exploration de mes capacités depuis le début. Les anciens étudiants Vincent Dermers-Carpentier et Guillaume Goubert qui m'ont fait appris les techniques et leurs pensées inspirantes. Je tiens à remercier aussi aux autres membres du groupe Jean-Christian Lemay, Carole-Anne Fortin, Yang Zeng, Keramat Saeedi, Tianchi Zhang, Xueqin Zhang pour leur contribution et l'eort en vue de l'avancement du projet, leurs aides à la réparation des machines et leurs encouragements. Les étudiants d'été, Mireille Ouellet, Théophrase Lescot, Pierre-Jean-Simon Frenière, Ginnette N'guessan ont fait chacun une participation dans diérents aspects du projet.
Je voudrais remercier à nos collaborateurs sans qui l'étude ne sera pas si belle. Vincent Albert et Raphaël La eur-Lambert venant du groupe John Boukouvalas du département de chimie à l'Université Laval, pour la synthèse de molécule et les tests catalytiques et ses aides chaleureuses à propos de produit organique. Anton Rasmussen, Katrine Louise Svane et Mi-cheal N. Groves du groupe théorique supervisé par Prof. Bjørk Hammer dans le centre iNano et département de physiques et astronomie à l'université Aarhus au Danemark ont fourni leur excellent travail théorique.
Je voudrais aussi exprimer mes reconnaissances pour toutes les ressources nancières du département et les fonds pour la bourse CCVC, la bourse Paul-Antoine Giguère et la bourse CRSNG. En plus, tous sorts de supports au sein du département chimie. En particulier, je voudrais remercier l'excellent service des personnels du côté de soutien technique Sébastien, Jean et André et l'équipe d'administration Mélanie et Magali. Le travail de Pierre est aussi essentiel à la réussite des études.
Je me trouve chanceuse d'être née dans une famille avec bonnes ententes entre les membres et j'ai eu moins de frustration. Puis, le fait d'avoir un frère a fait une grande dié-rence dans ma vie. L'encouragement et la compréhension que lui et sa famille m'ont donnée sont uniques et précieux. Je les garde toujours au fond de mon coeur. Et je tiens à remercier Lei pour son accompagnement et son encouragement.
Avant-propos
The work presented here is the result of a collaboration of our group with the DFT group led by Prof. Bjørk Hammer in Aarhus University in Danemark and the organic chemistry group lead by Prof. Boukouvalas in Chemistry Department of Laval University.
Chapters 3-5 present three publications. Chapter 3 is a review article on our groups' study of diastereomeic complexes on Pt(111). It is based, in part, on data presented in more detail in chapters 4 and 5. Chapter 4 presents a comprehensive study of diastereomeric com-plexes formed as a function of the chiral modi er to prochiral substrate ratio on the surface. The measurements were performed with help from Jean-Christian Lemay. Chapter 5 presents dynamic observations on diastereomeric complexes. A part of the study described in Chapter 5 was performed by a previous student, Dr. Guillaume Goubert, with my collaboration. Dr. Goubert included a preliminary analysis of the data in his dissertation. Chapter 5 contains a substantial set of new data as well as a detailed presentation and analysis of the overall data. Chapter 6 consists of a preliminary analysis of the results of dynamic studies of three dierent substrate/modi er combinations. As concerns all of the data and analyses presented in chapters 3-6, I've actively participated in the experimental part from the design of experi-ments to the measurement of high quality STM data under a variety of conditions, taking into account the temperature range, image resolution and thermal drift. In addition to performing experiments, I signi cantly upgraded an analysis algorithm that was initiated by Dr. Goubert. The primary goal of the algorithm is the extraction of the dynamic behaviour of individual molecules. Much of the analysis of the data presented in this thesis refers to speci c complexa-tion con guracomplexa-tions between chiral modi er and prochiral molecules. Hence, a crucial step in the analysis involves the counting, through visual inspection, of STM motifs corresponding to dierent complexation con gurations. The algorithm provides a means to cross-check the results of counting. It is described in chapter 2.
Fellow graduate student Jean-Christian Lemay assisted in the STM experiments, in the presentation, discussion and analysis of data and the optimization and maintenance of the ins-truments. Summer students, Carole-Anne Fortin (now a master student), Ginnette N'Guessan and Pierre-Jean-Simon Frenière participated in the counting and categorization of some sets of STM data.
Chapitre 1
Introduction
1.1 Chirality
Figure 1.1 (R)-(-)-carvone (left) and (S)-(+)-carvone (right).
A chiral molecule has the special symmetry property that it cannot be superimposed onto its mirror image. For example, gure 1.1 shows a pair of carvone enantiomers. The carvone molecules possess one stereogenic centre. The carbon atom, C∗, at the stereogenic centre is
directly bonded to four dierent atoms or groups. The dierence between the stereoisomers lies in the spatial arrangement around the stereogenic centre, which results in their being non-superimposable and hence chiral. The Cahn-Ingold-Prelog (CIP) rules are used to specify the rotation direction, in terms of the priority of the three nearest atoms linked to the chiral centre (Fig. 1.1). In the simplest case, the higher the atomic number of the atom, the higher the priority is. The molecule is assigned R (rectus) if the rotation direction, in decreasing priority, is clockwise, or S (sinister) if the rotation direction is anticlockwise. Diastereoisomers (or diastereomers) are two or more molecules, which although they possess the same molecular formula and bond connectivity, are not related as mirror images. Examples are cis- and trans-isomers of a molecule. A molecule possessing two stereogenic centres can have up to four (22)
diastereomeric forms. The term achiral is used to describe structures which are not chiral. For example Pt(111) surface is achiral as it possesses planes of mirror symmetry. The Pt surface is rendered locally chiral, in the Orito reaction, though the adsorption of a chiral modi er molecule, typically a cinchona alkaloid.
While a pair of enantiomers have the same physical properties, apart from the sense of rotation of light, they dier in their interaction with chiral environments, such as living organisms. Notably, only one chiral con guration is found for essential building blocks of macromolecules such as peptide chains, RNA and DNA. Such homochiral structures are in all living organisms on our planet. Due to the chiral environment in the bio-organism, dierent enantiomers will trigger dierent biological or chemical responses. For example, (S)-Carvone smells like caraway while (R)-Carvone is like spearmint. In the pharmaceutical industry, the therapeutic eect of a drug is often due to a single enantiomer, since each enantiomer possesses its own pharmacological activity. The non-active enantiomer can have no, a similar or even a drastically dierent potency.2 Thus, high enantiopurity of active pharmaceutical ingredients
is required. This is also true in other industries, such as pesticides in agriculture and fragrance in cosmetic products. As a result there is intense research activity on enantiomer separation, enantioselectivity in chemical reactions and chirality-transfer mechanisms.
Enantiomeric excess (ee) or enantiomeric ratio (er) are measures of the enantiopurity of a mixture of enantiomers. They are calculated by equation 1.1and equation 1.2, respectively.
ee = (R − S)
(R + S) × 100% (1.1) er = R
(R + S) × 100% (1.2)
1.2 Production of single enantiomers
Since early 1980's, the proportion of single enantiomer drugs in the Food and Drug Administration (FDA) approval list increased dramatically [3]. In two decades, this fraction increased from nearly 30% to 90% (Fig. 1.2). Generally, the approaches for the production of enantiomerically enriched compounds can be divided in three categories: chiral pool, resolution and asymmetric synthesis.
Figure 1.2 Statistics on newly approved drugs. Proportion of enantiopure, racemic and diastereomeric compounds in newly launched chiral synthetic drugs [3].
1.2.1 Chiral pool synthesis
The chiral molecules in nature are available in a single enantiomeric form. The simplest way to produce enantiopure compounds is by using the available substance from nature (chiral pool). We can either directly use the extracted compounds as nal products or as precursors in enantioselective synthesis. However, limitations on the variety and quantity doesn't allow this approach to meet the increasing need.
1.2.2 Resolution
Based on its physical and/or chemical properties, a racemic mixture can be converted to an enantioenriched product by crystallization-based separation, chiral chromatography or kinetic resolution. The use of enzymes in the production process is also well developed.
1.2.3 Asymmetric catalysis
Asymmetric synthesis is de ned by the International Union of Pure and Applied Chem-istry (IUPAC) as the stereoselective synthesis of chiral compounds.4 The starting material
is achiral, which makes the process distinct from the separation methods described above. Recognizing the importance of asymmetric catalytic synthesis, the Nobel Prize in Chemistry in 2001 was awarded to Knowles, Noyori and Sharpless for their work using chiral catalysts in the production of single enantiomer drugs and chemicals. Asymmetric catalysis is usually di-vided into two sub-classes: homogeneous asymmetric catalysis and heterogeneous asymmetric catalysis. In homogeneous catalysis, the reactants and the catalyst coexist in a single phase, typically a liquid. One of the most important categories of homogeneous catalysts involves organometallic molecules, which are organic compounds with at least one metal atom con-stituent. For example, BINAP-metal catalysts are used to hydrogenate prochiral molecules
producing relatively high enantiomeric ratios. One inherent advantage, that of greater se-lectivity, of homogeneous catalysis over heterogeneous catalysis is due to their very nature: the former is characterized by a single kind of active site whereas the latter has a range of adsorption sites for the reactants. This single site nature of homogeneous catalysis facilitates the understanding of stereoselective reaction mechanisms and the rational design of better catalysts.5 The opposite is true for heterogeneous asymmetric catalysis. However, since
ho-mogeneous catalysis usually takes place in the liquid solution phase, a temperature limit is imposed. Besides, the removal and recycling of the catalyst upon reaction completion is an inherent challenge for this class of catalyst.69
Heterogeneous asymmetric catalysis
Figure 1.3 Four examples of cinchona alkaloids: cinchonidine (CD) on top left, cinchonine (CN) on top right, quinine (QN) on bottom left and quinidine (QD) on bottom right. The dierence between derivatives shown on top and bottom is the functional group at position 6'. The dierence between derivatives shown to the left and right is the handedness at C8 and C9 as marked in green.
Heterogeneous hydrogenation is the most widely applied catalytic method in the ne chemicals industry.10 The main advantage of using heterogeneous catalysts lies in the ease
of separation and recycling of the catalyst. The relative low cost of the catalyst, typically using a noble metal, makes this class of catalysis a promising way to perform chiral synthesis. However, despite the application of heterogeneous catalysis in many industrial processes, only a few asymmetric catalysts are found to yield both high ee and high reaction rate.5,11Two
well-known examples are the hydrogenation of activated ketones on platinum1217or palladium1820
by tartaric acid (Fig. 1.4).16,21,22For a limited number of substrates, these reactions show ee
values of over 90%.2225
Figure 1.4 The hydrogenation of a β-ketoester, methylactoacetate (MAA), on (R, R)-tartaric acid modi ed Raney Ni catalysts in tetrahydrofuran (THF) to yield (S) or (R)-methyl-3-hydroxybutyrate.26 α-amino acids (e.g. (S)-alanine,
glutamic acid) and D-glucose can also be used as chiral modi ers for this reaction.11,2731
1.3 Mechanistic studies in heterogeneous asymmetric
hydrogenation catalysis
The development of asymmetric catalysts prepared by chemisorbing a chiral modi er on a transition metal surface is at an early stage. In these systems, stereodirection results from subtle small energy dierences in the presence of strong chemisorption interactions. This makes it di cult to attempt a mechanism-based design of new heterogeneous asymmetric catalysts or to even rationally optimize existing processes. Yet, the potential combination of enhanced catalytic performance, ease of separation of products and reuse of the catalyst make the design of heterogeneous systems an active eld of research.
The studies described in the thesis is our mechanistic surface science work related to the asymmetric hydrogenation of α-ketoesters and activated ketones on cinchona-modi ed platinum catalysts. Orito and coworkers rst reported this reaction.12,13,15 Its signi cance
within an industrial context and the progress in mechanistic studies were described in recent papers.32,33 There is a wide consensus that it is a true heterogeneous reaction, and that
enantioselection is the result of the formation of 1:1 diastereomeric complexes between the chiral modi er and the prochiral molecule, both of which are chemisorbed on the metal surface. Hence the chemisorption properties of both the modi er and the substrate are fundamental parameters in the reaction, and these properties can be studied in most detail using surface science techniques. The bulk of the surface science work on the Orito reaction was carried out by the McBreen, Tysoe, Zaera and Lambert groups. Tysoe and co-workers focused on the palladium surface. McBreen and co-workers, and Lambert et al., focused on the platinum
surface. Zaera and co-workers focused on spectroscopic measurements in the presence of solvents. Recently, the Baiker group has carried out detailed spectroscopic studies coupled with simultaneous measurents of ee of Orito catalysts under working conditions (so-called operando measurements).34,35
The interpretation of surface science data is facilitated by the fact that in most cases it is possible to make correlations with literature measurements on actual catalytic performance. Since the Orito reaction has been the subject of hundreds of studies over a period of nearly forty years there is now a vast database available for such comparisons.
By comparing our surface science data3652 with the available database we are able to
rationalize many experimental observations on the Orito reaction.
1.3.1 Summary of widely accepted views on the Orito reaction
The Orito reaction, the enantioselective hydrogenation of ketone groups on cinchona modi ed platinum, is the most widely studied example of the application of chirally modi ed supported metal particle catalysts. As illustrated by a number of excellent reviews,5357 the
large database permits a wide, although incomplete, consensus on many details of the reaction and its mechanism:
i. The chiral induction occurs on the metal surface of the chemisorption layer. While this point forms the basis of the work described in this thesis, it is kept in mind that cinchona molecules are very eective asymmetric organocatalysts. Hence, in order to describe their operation at a metal surface it is necessary to blend concepts from the areas of chemisorption and organocatalysis.
ii. Recent studies reveal that it is an open question as to whether the modi er chemisorbs through the interaction of its aromatic group with the surface in a π-bonded con gura-tion. It is generally assumed that under optimal reaction conditions, the aromatic group lies at on the surface. However, some operando vibrational spectroscopy studies show evidence for tilted aromatic groups.58 We de ne optimal reaction conditions as those
Figure 1.5 Schematic representation of chemisorbed CD.53 The speci c
con-formation shown, the so-called open(3) concon-formation,53,59is the one most often
cited in discussions of modi er-substrate interactions in the Orito reaction.
iii. The chiral induction occurs through the formation of isolated modi er-substrate di-astereomeric complexes. This is described as a 1:1 interaction.
iv. It is generally assumed that the reaction is only e cient for intramolecularly activated ketones. The most widely studied substrates are the α-ketoesters where the ester group activates the prochiral keto group. As an example, the hydrogenation of methyl pyruvate (MP) to the α-hydroxy ester, (R)-methyl lactate (ML), is illustrated in scheme1.6.
Figure 1.6 The α-ketoester, methyl pyruvate, is hydrogenated to (R)-methyl lactate over cinchonidine modi ed supported platinum catalysts. This, along with the hydrogenation of ethyl pyruvate, is one of the best studied examples of the Orito reaction. Methyl pyruvate can also be described as an activated ketone.
v. By abstracting atomic hydrogen from the metal surface, the quaternary nitrogen in the quinuclidine group can be protonated in aprotic solvents, forming an ammonium centre.60
vi. Hydrogen bonding of the substrate (the prochiral molecule) to the ammonium centre plays a key role in the formation of the diastereomeric 1:1 complex. Methylation of the ammonium group leads to complete loss of enantioselection.
vii. In general, the absolute con guration at C8 and C9 determines the chirality of the
product. For example, CD or QN modi ed Pt yields (R)-product and CN or QD modi ed Pt yields (S)-product.61 Exceptions to this rule, of which there are a signi cant number
of examples, are described as cases of stereoinversion. Solvent and modi er substituent dependent stereoinversion have been reported.62
viii. Modi ed Pt is the best catalyst for the Orito reaction. Promising results have been obtained using Rh,63 Ir6467 and Pd68 catalysts. Interestingly, CD modi ed Pd leads to
the formation of (S)-hydroxy ester.
ix. Care must be taken to inhibit hydrogenation of the quinoline group under reaction conditions.69Studies on shape-controlled Pt nanoparticles show that the (111) surface is
preferable to the (100) surface in that hydrogenation of the aromatic anchoring group is slower on more compact face.70 There is very little evidence pointing towards enhanced
performance as the metal particle size is decreased.
x. The substitution of the OH group in CD with a methoxy group does not signi cantly aect the outcome of the reaction. In contrast, substitution using phenyl groups can lead to stereoinversion.
xi. There is now accumulated experimental evidence showing that the stereoselective hy-drogenation of α-ketoesters is e cient for cases where there are bulky alkyl groups at either the keto or ester groups of the substrate. These results rule out steric interaction with respect to the quinoline group as a primary stereodirecting force.
xii. Optimization of the reaction requires considerable tuning and the optimal conditions depend on the speci c type substrate used. An example of this speci city is that as compared to methyl pyruvate/cinchonidine system, approximately ves times greater concentration of modi er is required for the enantioselective hydrogenation of 2,2,2-tri uoroacetophenone (TFAP).
xiii. Large rate-accelerations are observed in the hydrogenation of α-ketoesters on cinchona modi ed Pt. That is, the rate of reaction is observed to be higher on the chirally modi ed surface than on the same catalyst without the modi er. Rate enhancement is not observed, or is negligible, for some substrates, notably α-phenyl ketones.
xiv. Although the reaction can be carried out at H2 pressures as low as 1 bar, the highest
enantioselectivities and reaction rates are achieved at higher hydrogen pressures. xv. The chiral modi er is described as creating a chiral pocket on the surface in which
asymmetric induction occurs. The conformational exibility of the quinuclidine moiety of cinchonas is important in determining the shape of the chiral pocket. Taking the example of cinchonidine (CD), it can be seen that at least three complex factors need to be taken into account in describing the chiral pocket. These are the non-covalent interaction of the quinuclidine moiety with the metal surface, the solvation of the quinuclidine moiety by the solution phase, and the induced- t between the modi er and the substrate taking into
account that both are chemisorbed on the surface. In certain cases, such as cinchonine (CN) there may also be a covalent interaction between the vinyl group of the quinuclidine moiety and the surface.
xvi. The reaction can take place in the absence of a solvent. However, a solvent is used in all practical applications. Furthermore, the choice of the solvent is an important parameter in the optimization procedure.
The mechanism of the Orito reaction is still under debate even though there is general agreement on most of the above points. The continuing debate is primarily due to the fact that the database is complex, displaying several examples of solvent and modi er substituent dependent stereoinversion, markedly dierent optimization conditions for dierent groups of substrates, varying degrees of rate enhancement eects for dierent groups of substrates, and possible surface modi cation through side-reactions. This makes it challenging to state a general mechanism for the reaction, or indeed to know if the reaction may be described in terms of a single mechanism. The lack of mechanistic understanding is widely acknowledged as a major impediment to the development of the eld of chirally-modi ed supported metal catalysis.
Figure 1.7 Asymmetric hydrogenation of isophorone on proline modi ed Pd/C catalyst to produce (S)-TMCH.
Furthermore, it is not always easy to determine if an asymmetric catalytic reaction is truly a heterogeneous reaction. For example, proline, an amino acid, is used in homogeneous asym-metric catalysis as chiral ligand,71 and also a potential chiral modi er in the Pt/C catalyzed
asymmetric hydrogenation of isopohrone to 3,3,5-trimethylcyclohexanone (TMCH), as shown in Fig. 1.7. However, the enantiodierntiation in the latter reaction72,73 was attributed by
Lambert et al. to a kinetic resolution process following a racemic hydrogenation process.74,75
More recent work by Baiker and coworkers76 found evidence, however, that chirality transfer
occurs on the surface, depending on the reaction conditions. This example highlights the im-portance mechanistic studies. Kobayashi et al. have reviewed the same question concerning asymmetric C-C coupling reactions involving chirally modi ed RhAg nanoparticles.77
1.3.2 Brief introduction to the study of activated ketones substrates coadsorbed with (R)-1-1-naphthylethylamine or its derivatives on platinum
In addition to cinchona alkaloids, which are natural products, a number of synthetic molecules have been shown to be reasonably active chiral modi ers for the Orito reaction. In particular, Baiker and co-workers studied 1-(1-naphtyl)-ethylamine (NEA), and an extensive range of N-alkylated secondary amines produced through the reductive amination of NEA.7881
In the hydrogenation of methyl pyruvate, the N-alkylated derivative is formed in-situ through reaction with the substrate and acts as the actual modi er. In contrast, reductive amination does not occur in-situ during the hydrogenation of TFAP or KPL on NEA modied Pt. The modi er used in our work is (R)-1-1-naphthylethylamine, (R)-NEA. It is preadsorbed on the surface in order to create chiral adsorption sites that will induce the prochiral substrate to preferentially adsorb with one enantioface pointing towards the surface.
The simpler structure of NEA has led to it being a molecule of choice for surface science studies of the chiral modi cation of Pt. Both NEA and protonated cinchonidine (CDH+)
possess an aromatic group, a stereogenic centre (several in the case of CDH+) and an amine,
H-bond donor, group. In the preferred low coverage adsorption geometry, the quinoline group of CDH+ is believed to anchor the molecule to Pt through a strong π-bonding interaction.
This con guration, in which the aromatic group is at-lying, is often believed to be the adsorption state responsible for eective enantioselection in the Orito reaction. Vibrational spectra acquired in in-situ and operando experiments show, however, that other adsorption geometries of cinchonidine, where the aromatic group is tilted away from the surface, may be populated at higher coverages. In the case of NEA, it is generally believed that adsorption involves π-bonding of the naphthyl group to the surface. However, on the basis of solvent phase studies, Zaera and co-workers provided evidence that bonding con gurations where NEA is attached to the surface solely via the amine group should also be considered.82
Several groups have studied the interaction of prochiral molecules with chemisorbed enan-tiopure NEA. Of particular relevance to the present study, Tysoe and co-workers83used TPD,
RAIRS, STM and DFT methods to study the chemisorption of (S)-NEA on Pd(111). Their STM, and RAIRS data shows strong parallels with our data for (R)-NEA on Pt(111). Further-more, they reported an STM and DFT study of complexes formed between methyl pyruvate and NEA on Pd(111).31,68,83
Figure 1.8 A proposed model for the stereodirecting interactions between a chiral modi er and a prochiral molecule on a surface. The stacked squares on the left represent the chiral modi er and the rectangular shape on the right represents the substrate. A-D are H-bonding functional groups.38
pr = pro − R
(pro − R + pro − S)× 100% (1.3) Figure 1.8 represents a schematic example of an 1:1 interaction model84 of complexes
formed by two H-bonding38 contacts. A and B are functional groups of the modi er (left). C
and D represent functional groups of prochiral substrate (right). Intermolecular interactions between A and C and between B and D, in combination with chemisorption interactions, in-duce a particular adsorption geometry in which the prochiral substrate exposes a "selected" enantioface to metal.38,42,85 Hydrogen dissociates spontaneously on Pt surface at room
tem-perature. Thus, the enantioface of the substrate which is exposed to the surface will be hydrogenated preferentially. The enantiomeric excess is directed by the intermolecular inter-actions of A· · ·C and B· · ·D. If the reaction is under purely thermodynamic control, then the enantiomeric ratio (er) should be equal to the prochiral ratio pr. The pr is de ned in Equation
1.3. However, the er may dier from the induced pr due to dierent kinetics for routes to (S) and (R)-products and due to the contribution of racemic reaction at non-modi ed sites.
Platinum was chosen for its ability to dissociate hydrogen into two hydrogen atoms. The highly symmetric fcc{111} surface is an ideal substrate: it is the closest-packed facet and has the highest thermodynamic stability.86For example, another low-index surface, Pt(100) shows
faster hydrogenation of the aromatic ring of alkaloids, which is not desirable. Therefore, our studies are performed using a Pt(111) surface. A schematic image shows the adsorption of the simple, symmetric benzene molecule on a fcc(111) surface.86 Considering the arrangement of
surface atoms and only the two top close-packed planes stacking in fcc (ABCABC), one can de ne four adsorption sites: atop, bridge, hollow-hcp and hollow-fcc. Prior to the hydrogena-tion reachydrogena-tion, the modi er will adsorb at speci c surface sites. This adsorphydrogena-tion geometry of the modi er will determine the creation of chiral sites and the possible intermolecular interactions with the prochiral substrate.
Figure 1.9 Schematic representation of four principal adsorption sites for ben-zene on an fcc (111) surface drawn with two layers. Maroon represents an atop site over a single atom. Green represents bridge sites involving two neighbor atoms. Blue represents hollow-hcp sites that show the same sequence as hcp stacking of the planes (ABAB). Orange represents hollow-fcc sites. The angles refer to rotation with respect to close-packed rows.
Choice of experimental condition
Experimental conditions need to be carefully tuned due to the complexity of the sys-tem. Data on abundant preorganization states, molecular diusion and the observation of intermediates45,87 are crucial in elucidation of the mechanism. Figure 1.10 shows examples
of molecular dynamics observed in an STM image of the TFAP/(R)-NEA/Pt(111) system acquired at room temperature. The image shows streaks due to rapidly diusing TFAP. The blue square shows an example where the chiral modi er moves during imaging. The white oval shows an example where the TFAP image is distorted due to movement while imaging. The black triangle shows a case where TFAP in a complex moves during imaging. Thus, the exper-iments reported in this thesis were done at temperatures below room temperature. We were aware that the substrate may undergo chemical changes as a function of temperature.40,45,87
The temperature chosen was as high as possible in order to mimic room temperature reaction conditions while also ensuring the acquisition of high quality images. Our STM experiments show that TFAP is stationary on Pt(111) at 223 K, rotational motion is observed at 242 K and translational motion sets in at approximately 249 K. The more stable conformer of modi- er, (R)-NEA-1, displays discrete rotational motion and limited discrete translational motion at 261 K.51 Our previous study also showed that TFAP could be half-hydrogenated and
experiments were taken between 253 - 263 K.
Figure 1.10 STM image of 2,2,2-tri uoroacetophenone (TFAP) and (R)-NEA coadsorbed on the Pt(111) surface, acquired at room temperature. The white circle marks a TFAP molecule captured during a movement from left to right; the black triangle marks an observation plausibly due to the rotation the CF3CO
group of TFAP; the blue rectangle marks a (R)-NEA molecule moveing right and left during image acquisition. Tunnelling conditions: current = 0.28nA, bias = 1.2V
One important feature in the present studies is the coexistence of multiple complexa-tion structures.42 In order to study the complexation states separately, su ciently detailed
experimental data are needed. Therefore, the control of experimental conditions and the categorization of experimental results are of primary importance in order to understand the chemistry on the surface. These points are discussed in detail in Chapter 2.
