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Quantum Chemical Studies of Enantioselective Organocatalytic Reactions

Peter Hammar

Department of Theoretical School of Biotechnology Royal Institute of Technology Stockholm 2008

Quantum Chemical Studies of Enantioselective Organocatalytic Reactions Licentiate thesis Department of Theoretical Chemistry Royal Institute of Technology Stockholm, Sweden

© Peter Hammar, 2008 ISBN 978-91-7178-934-1 ISSN 1654-2312 TRITA-BIO-Report 2008:6 Printed by Universitetsservice US AB, Stockholm

Abstract

Density Functional Theory is used in order to shed light on the reaction mechanisms and the origins of in enantioselective organocatalytic reactions. The reactions investigated are the dipeptide-catalyzed , the - catalyzed nitroaldol reaction and the prolinol derivative-catalyzed hydrophosphination reaction. We can justify the stereoselectivity in the reactions from the energies arising from different interactions in the transition states. The major contributions to the energy differences are found to be bond-type attractions and steric repulsions. This knowledge will be useful in the design of improved catalysts as well as general understanding of the basis of selection in other reactions.

iii

Contents

Preface...... v List of Abbreviations...... vi List of Included Papers...... vii 1. Introduction to Enantioselective ...... 1 1.1 ...... 1 1.2 Enantioselection ...... 2 1.3 Organocatalysis...... 3 2. Theoretical Methods ...... 5 2.1 Introduction to Quantum Chemistry and Density Functional Theory...... 5 2.2 Numerical Representation – Basis Sets ...... 6 2.3 The B3LYP Functional ...... 7 2.4 Solvation Model...... 7 2.5 Interpretation of the Energies...... 9 2.6 Scope of the Method ...... 10 3. Applications ...... 13 3.1 Peptide-Catalyzed Aldol Reaction...... 13 3.1.1 Stereoselectivity...... 14 3.1.2 Conclusion...... 16 3.2 Hydrophosphination of α-, β-Unsaturated Aldehydes...... 17 3.2.1 Stereoselectivity...... 18 3.2.2 Conclusion...... 18 3.3 Cinchona Thiourea-Catalyzed ...... 20 3.3.1 Mechanism ...... 21 3.3.2 Stereoselectivity...... 23 3.3.3 Conclusion...... 24 4. Summary and General Conclusions...... 25 References ...... 27 Acknowledgements ...... 31

Preface

This thesis aims at giving insight into the reaction mechanisms and enantioselectivity in three different organocatalytic systems. In recent years the field of organocatalysis has attracted wide interest and experienced a strong growth in research and development. By theoretical tools we can gain information in order to understand or verify predictions of the function of the catalyst. Thereby it is possible to refine the catalyst design, or possibly get ideas that can be brought over to other systems or of other reactions. The work in this thesis explores the application of quantum chemistry, i.e. the use of quantum mechanics to derive physical properties of chemical systems, to obtain insight into chemical processes such as reaction mechanism and stereoselection. The method of choice is Density Functional Theory with the B3LYP functional, since it is well-studied and provides excellent trade-off between accuracy and computational speed suitable for the systems studied. In the coming pages I will give a short introduction to the field of asymmetric organic catalysis (Chapter 1), briefly describe the method used (Chapter 2) and summarize the applications (Chapter 3). In the end I will draw some conclusions of my work (Chapter 4).

vi

List of Abbreviations

B3LYP Becke 3-parameter density functional Bn Benzyl CD Circular Dichroism CPCM Conductor-like Polarizable Continuum Model DFT Density Functional Theory ee HPLC High Performance Liquid Chromatography Me Methyl OTMS Tri-methyl-silyl-ether PES Potential Energy Surface Ph Phenyl QM/MM Quantum Mechanics/Molecular Mechanics R, S, Re, Si Descriptors of stereochemistry SCF Self-Consistent Field SCRF Self-Consistent Reaction Field THF Tetrahydrofuran ZPE Zero Point Energy

vii

List of Included Papers

I. Density Functional Theory Study of the Stereoselectivity in Small Peptide-Catalyzed Intermolecular Aldol Reactions. Peter Hammar , Armando Córdova and Fahmi Himo. Submitted. I have been responsible for the calculations as well as writing most of the manuscript. II. Enantioselective Organocatalytic Hydrophosphination of α,β-Unsaturated Aldehydes. Ismail Ibrahem, Ramon Rios, Jan Vesely, Peter Hammar , Lars Eriksson, Fahmi Himo, and Armando Córdova. Angew. Chem. Int. Ed. 2007, 46, 4507–4510 and Angew. Chem. 2007, 119, 4591 –4594. I have done the calculations in this report and prepared the text describing these results. III. Organocatalytic Asymmetric Addition of Phosphorus to α,β-Unsaturated Aldehydes: Mechanism and Scope. Ismail Ibrahem, Peter Hammar , Jan Vesely, Ramon Rios, Lars Eriksson and Armando Córdova. Submitted. I have done the calculations in and written the part of the manuscript dealing with the theoretical investigation. IV. Density Functional Theory Study of the Cinchona Thiourea-Catalyzed Henry reaction: Mechanism and Enantioselectivity. Peter Hammar , Tommaso Marcelli, Henk Hiemstra and Fahmi Himo. Adv. Synth. Catal. 2007, 349, 2537 – 2548. I have been responsible for the calculations and writing the manuscript.

Chapter 1

1. Introduction to Enantioselective Organocatalysis

1.1 Stereochemistry The structure of a is defined by the connectivity and orientation in space of its atoms. Substances which contain the same kinds and numbers of atoms, i.e. the same molecular formula, but where these do not have the same connectivity are called constitutional . with the same connectivity as defined by a two-dimensional map (Figure 1.1 A) but are different in the three dimensional space (Figure 1.1 B-D) are said to have different configuration and are called stereoisomers. Stereoisomers can be characterized by two relationships, enantiomerism and diastereomerism. If two molecules are they are mirror images of each other that cannot be superimposed by any rotation (structure B and C in Figure 1.1). have different connectivity in space. They are neither super-imposable on each other, nor are they mirror images (for example B and D or C and D in Figure 1.1). A common term for enantiomerism is , referring to the Greek word for hand ( χειρ ), since our hands practically are enantiomers. An equal mixture of two enantiomers is called a .

OH OH O O

OH OH A B C D Figure 1.1. A: Two-dimensional connectivity map of . B-D: three dimensional representations. B and C are enantiomers. Either of B and C are diastereomers relative to D. The molecule D is a special case since it is identical to its mirror image, and is called a meso-compound.

Constitutional isomers as well as diastereomers have physically different properties, such as for example melting point and different reactivity, and can be separated relatively easily. Enantiomers, on the other hand, have the same physical properties, except for interaction with polarized light. Classically enantiomers have been characterized by their , giving rise to the notion of optically active compounds. Optical rotation is the phenomenon of change in the plane of when linearly polarized light passes through a medium where one is in excess over the other. The linearly polarized light can be considered as an equal mixture of left and right circularly polarized light, which experience different refractive index in a medium comprising a non-racemic compound. This will shift the phase of the two components of the linearly polarized light, resulting in the optical rotation. Absorbance of circularly polarized light is also different depending on the chirality of the light and substance. This is used in the method called Circular Dichroism (CD), where the difference in absorbance of left and right circularly polarized light is measured for different frequencies.

2 Introduction to Enantioselective Organocatalysis

Enantiomers interact differently with other chiral species, something that is exploited in the most common way of determining the enantiomeric excess. This is the use of high performance liquid chromatography or gas chromatography, which rely on chemical non- bonding interactions with enantiomerically pure stationary phases. Determination of can be achieved for example by X-ray crystallography, by comparison between experimental and theoretically calculated CD-spectra or by transformation into a compound with a known configuration. The study of enantiomers dates back to the mid 19 th century when Pasteur discovered optical rotation of enantiomerically pure tartaric acid. 1

1.2 Enantioselection The main driving force for the development in stereochemistry, the study of and in particular chiral molecules, is its need in applications such as development of pharmaceuticals, molecular biology, flavours and other food additives and agricultural applications. Most large organic molecules in biological systems are chiral, including proteins and sugars. More importantly these molecules occur in only one enantiomer of which the specific configuration is required for correct interaction with other chiral molecules. In a few examples both enantiomers of a compound are naturally occurring, in which case the two stereoisomers most commonly have different biological activity. A few examples of this are aroma compounds such as carvone, found in caraway and spearmint. 2 The molecules from caraway and those from spearmint are enantiomers. They come from different plants and have completely different smells. is another example where R-limonene (one of the enantiomers) smells of orange while S-limonene (the other enantiomer) smells of lemon. The importance of understanding and controlling stereochemistry can also be stressed by examples of pharmaceuticals. is probably the most well-known case, where one enantiomer combats pregnancy sickness. Unfortunately the other enantiomer caused birth defects. 3 Another example is Naproxen, an anti-inflammatory drug. The R-enantiomer is 28 times less active than the S-enantiomer but more importantly the R-enantiomer is reported to be a liver toxin, hence the drug has to be enantiomerically pure. 4 In order to achieve enantioselectivity, i.e. to obtain preferentially one of the two enantiomers from a reaction, the environment has to be chiral and non-racemic, creating a diastereomeric relationship between the substrate-chiral environment complexes which will enable the selection. This can be accomplished either by separating the enantiomers from each other by purification involving some chiral element, or already in the synthesis of the chiral molecule from achiral reactants. This latter method involves enhancement of the reaction rate leading to one enantiomer of the product, and is often termed enantioselective catalysis. Synthesis of chiral compounds is commonly called asymmetric synthesis. Either the catalyst or the reaction medium has to be chiral and non-racemic to achieve chirality in the product. Another way of achieving single enantiomer substances is to synthetically modify natural products which are already enantiomerically pure.

Chapter 1 3

1.3 Organocatalysis Until recently there were two classes of catalysts that have been successful in asymmetric catalysis, namely transition metal complexes with chiral ligands and . Enzymes often suffer from not being stable under synthetic conditions and are difficult or expensive to obtain in large quantities needed for large scale synthesis. 5 They might also have a narrow substrate range and are hard to tune to the desired product. The metal catalysts commonly use the metal as a Lewis acid to bind electron rich segments of the substrate molecules. It is not uncommon that this binding is too strong, resulting in reduced catalytic turnover since the product remains bound to the catalyst. Also the price of metal catalysts is often high. A more serious problem of metal catalysis is that many metals are poisonous and require a lot of caution in order to handle toxic waste from chemical industry and expensive purification due to the strict requirements for pharmaceutical products. 6,7 The last decade a new class of catalysts has emerged as a powerful way of achieving enantioselective catalysis, namely the use of chiral organic compounds as catalysts. This field is termed asymmetric organocatalysis and is the subject of this thesis. Among the advantages of using organocatalysts are their inertness towards moisture and oxygen, feasible reaction conditions such as ambient temperature and a large solvent scope. They are also inexpensive and often more stable than enzymes or other biomolecular catalysts. 7 The absence of metals makes the organocatalytic approach particularly attractive for applications where poisonous metallic traces are unacceptable in the final products, such as the pharmaceutical and agrochemical industries. Organocatalysts can broadly be categorized into two classes, catalysts forming a covalent intermediate with the substrate, and catalysts hydrogen bonding the substrates. The former includes reactions where reactive iminium and intermediates are formed by condensation of carbonyls to catalysts. 8 Two of the reactions studied in this work are of this type. The catalyst of the last work in this thesis may be categorized into the latter class of organocatalysts where the reaction is catalyzed by protonation or hydrogen bond coordination of the substrates. 6 The concept of using asymmetric organic catalysts was in use already a century ago. A report of Breding and Fiske in 1912 where a small optical yield was obtained from addition of HCN to benzaldehyde is regarded as the first example of asymmetric organocatalysis. 9 Despite this long history the organocatalytic approach to enantioselective synthesis has largely been ignored, possibly due to the great success of organometallic catalysis. 10 Not until the last decade there has been an incredible growth of interest in this field. In the development of organocatalysts cinchona alkaloids and the (see Figure 1.2) are among the most well studied compounds, since they were early discovered to be promising in asymmetric catalysis. These compounds are the key players in the development of the catalysts used in the reactions studied in this thesis, and will be further discussed in connection with the applications considered in Chapter 3.

4 Introduction to Enantioselective Organocatalysis

OH

N

N

N COOH O H A B Figure 1.2. A: Quinidine, an example of a cinchona alkaloid. B: The amino acid proline.

Chapter 2

2. Theoretical Methods

2.1 Introduction to Quantum Chemistry and Density Functional Theory It is generally accepted that quantum mechanics, where physical observables are described as eigenvalues to mathematical operators, presently is the most accurate description of chemistry and chemical properties. This thesis deals with the feasibility of different reaction pathways. One way of addressing this is by considering their relative energy. Thus, the observable we are interested in is the energy (E), which is obtained as an eigenvalue to the Hamiltonian (H) operator, H Ψ = E Ψ, where Ψ is the wave function that completely determines the chemical system. This is the time-independent formulation of the Schrödinger equation, and in the context of the chemical reactions studied here the time dependence of the original equation is neglected. To describe the energy in this context, the Hamiltonian includes terms of kinetic energy of nuclei and electrons, the attraction between electrons and nuclei and the electron- electron and nucleus-nucleus repulsions. The first approximation to introduce at this point is what is known as the Born-Oppenheimer approximation, where the equation is separated in two parts, one concerning the electronic structure around spatially fixed nuclei, and one concerning the motion of the nuclei 11 . This is rationalized by the presumption that the nuclei and electrons are moving on considerably different timescales. What will be discussed in the following section concerns the electronic part. The electronic wave function is a function of the spin and spatial coordinates of each electron and the methods available for solving wave function problems are typically very time-consuming for achieving acceptable accuracy. In this work we have employed density functional theory (DFT), where the problem is stated in terms of the total electron density. DFT is currently the best method for addressing problems like the ones considered in this thesis, as judged by computational time versus accuracy, given the computational resources available. Hohenberg and Kohn showed that the electron density uniquely determines the external potential (in a molecular case the charges from the nuclei), which in turn determines the ground state so that the ground state is completely determined by the density. 12 The DFT approach results in a less demanding computational problem compared to wave function- based methods. It is further proven that there exists a functional of the density such that its minimum value corresponds to the ground state energy. In order to calculate the energy, we need to know the density. One of the most helpful things in the search for the density is the variational principle presented by Hohenberg and Kohn 12 , in which they show that the energy functional takes on its minimum value for the correct density, the value being the ground state energy. Finding the energy now reduces to minimizing a functional of the three-dimensional density function. The minimization procedure employed is referred to as a self-consistent field (SCF) method, outlined for DFT by Kohn and Sham 13 similar to the scheme used in the approximate wave function-based Hartree-Fock method 14 . Kohn and Sham formulated the problem in terms of a system of non-interacting particles, and added all discrepancies compared to the real system in one term in the equations. Since the problem is expressed in terms of independent particles, the wave function can be expressed as a product of functions of one electron each, commonly

6 Theoretical Methods

called orbitals. Having an orbital representation, one may use variational calculus with Lagrangian multipliers, which transforms the expression for the energy into an eigenvalue problem for a one-electron operator, to minimize the energy. This one-electron operator consists of the operators of the energy of one-particle motion, nuclei-electron attraction, the repulsion from the total density and one term including all corrections compared to the real system of interacting electrons. Since the latter two terms are themselves functionals of the density, the problem is solved iteratively until consistency is reached. Initially the orbitals are constructed as a guess, from which the first one-electron operator is computed. Then a new set of orbitals are taken as the solution vectors with lowest eigenvalues of the equation and used for updating the operator, and the procedure is repeated until convergence is reached.

2.2 Numerical Representation – Basis Sets The functional form of the one-electron function can be very complex, thus it is important to find an efficient way of representing it mathematically. Any function can be expressed as a linear combination of other functions spanning the same functional space (a complete set of basis functions), although possibly an infinite number of functions might be needed. In this way one can hope to find functions that are simpler to work with, so that although you need more of them it will be of good help. First we can note that we are studying functions of the spatial coordinates, which are practically limited in space, so that we can expect that a finite number of basis functions can be good enough. One popular choice of basis functions are atomic orbitals, i.e. the solutions to the one electron Schrödinger equation centred on the sites of the atomic nuclei are taken as basis functions. However, these functions have the computational drawback of having a radial part that decays exponentially, which is not very convenient for computing derivatives. The exponential part of these functions can in turn be expanded in a basis of Gaussian functions, which have defined analytical derivatives and are computationally efficient. Each basis function is thus consisting of a polynomial multiplied by a sum of Gaussian functions. A basis set constructed in this way is called a Gaussian type linear combination of atomic orbital basis set. The use of this type of basis set has proven to give good results in quantum chemical calculations, and is the one that is used in the work summarized in this thesis. We can note that these functions are all centred on atomic nuclei, and practically limited in space, since the Gaussian function quickly tends to zero by distance. In the projects summarized in this thesis two sets of basis functions have been used. In case of geometry optimizations the so-called 6-31G(d,p) basis set has been employed, where each core atomic orbital is expanded in terms of six Gaussians, and inner and outer components of the valence atomic orbitals are expressed by three and one Gaussian components, respectively. It also contains functions of higher orbital symmetry for both hydrogen (p) and other elements (d). This gives further freedom of displacing the electrons from their respective nuclear positions and one-electron orbitals, and is needed for expressing for example polarization of an atom. Energies are calculated using the larger and thus more accurate 6-311+G(2d,2p) basis set, having an extra function for the split valence, functions with a slower radial decay to represent a more diffuse electron distribution and additional polarization functions. The procedure of different basis sets is used since the computational cost is related to the number of basis functions used. The geometry optimizations are computationally demanding, but the geometries achieved from calculations using the smaller basis set are accurate enough. For the energies more basis functions are needed to reach the demanded accuracy. 15, 16

Chapter 2 7

2.3 The B3LYP Functional As mentioned above, the functional used in the Kohn-Sham formalism of DFT includes the operators of the energy of one-particle motion ( T), nuclei-electron attraction ( Vne ), the repulsion from the total density ( Vee ) and one term including all corrections compared to the real system of interacting electrons ( FXC ), as summarized in Equation 1. The latter term thus includes the difference to the real kinetic energy arising from the electron interaction and all non-classical corrections to the electron-electron interaction, such as exchange, correlation and self-interaction. The major problem still today is that these contributions are unknown.

E = T[ρ]+Vne [{z}, ρ]+Vee [ρ]+ FXC [ρ] (1) The functional employed in this thesis is called B3LYP, and its non-classical term consists of several parts that are fitted to experimental data using three parameters for their respective weight into the final result 17. B3LYP is the most used density functional in chemistry, with a performance that rates among the best in numerous studies 18 . The functional form includes an LDA exchange energy that depends on the density, so called local density approximation ( EX ), B 19 and also the density gradient with a functional form proposed by Becke (EX ) and one part HF consisting of the exchange energy as defined in the Hartree-Fock theory (EX ) and a VWN 20 correlation functional proposed by Vosko, Wilk and Nusair ( EC ) dependent of the LYP 21 density itself and one of the gradient, as proposed by Lee, Yang and Parr ( EC ) , as expressed in Equation 2. The values of a, b and c are 0.20, 0.72 and 0.81, respectively, which were actually optimized for the similar functional B3PW91. B3PW91 has a somewhat different expression for the correlation energy.

LDA HF B VWN LYP Fcorr = 1( − a)EX + aE X + bE X + 1( − c)EC + cE C (2) In the method outlined above the spin of the electrons has been neglected. In the systems studied in this thesis the electronic structure is so called closed shell, where all electrons are paired. As such there is no need for describing the spin, and a representation of the geometric distribution of each pair of electrons is enough. In a system of open shell structure, where the electrons of opposite spin are not always paired, the spin dependence can be expressed by using two densities, one for each spin. The electronic energy obtained by the method outlined above is according to quantum mechanics not the true ground state energy. The lowest energy a system can possess is referred to as the zero point energy (ZPE) and corresponds to the lowest vibrational energy that the system can adopt (which is not zero). This is calculated from the second derivatives of the energy with respect to nuclear displacements from the stationary points, which gives the vibrational energy from the harmonic approximation. This energy contribution is added to the electronic energy to get the ground state energy. The vibrational analysis is performed with the same basis set as is used for the geometry optimization.

2.4 Solvation Model The DFT calculations as expressed above give us the optimized molecular structures in vacuum or commonly labelled gas phase, corresponding to the geometry at 0 Kelvin being devoid of vibrations. This might be quite far from the reaction conditions of the experiment we are comparing to, and the optimal procedure would involve calculating the molecular properties in a condensed phase. However, calculation of molecular properties, such as molecular geometries and energies, at a microscopic level in a condensed phase is a great challenge mainly due to the number of involved molecules. There are two ways of

8 Theoretical Methods

approaching this problem, one being to treat all molecules in the solution explicitly, the other describing the solvent implicitly as a dielectric medium. 22 There are a couple of different models for an explicit treatment of solute-solvent interactions, which all share the principle of sampling a large number of (geometrical) configurations and from the properties of each of these configurations derive the entities of interest (such as ground state geometry or energy). Among these methods are Monte Carlo, where configurations are randomly generated, and molecular dynamics, where the configurations are generated from each other by following the gradient of the energy. The energies of the configurations are classically calculated using force fields parameterized in the nuclear coordinates. This method does not have the accuracy desired in this study, and there is no parameterization that accounts for bond breaking and bond formation. Thus it is not suitable for chemical reactions as the ones studied in this thesis. However, the methods can also be used by a quantum chemical calculation at each configuration, such as first-principle molecular dynamics, or a divided scheme with the central part of the system calculated by quantum chemistry and the bulk calculated with classical force fields, known as quantum mechanics/molecular mechanics (QM/MM) approach. These calculations are however not feasible, since they would require a huge amount of quantum calculations since many configurations have to be evaluated in order to get statistical data of the system. A conceptually different approach to the problem is using continuum models, where the solvent interaction is approximated with that of a dielectric continuum surrounding the quantum chemically modelled molecule. In this work the conductor-like polarizable continuum model (CPCM) 23 has been used, since it is one of the more accurate models. 24 A surface is constructed around the molecule as the outer part of intersecting spheres centred on the nuclei. The surface is then treated as a conductor, on which the charges from the molecule induce a polarization. The charge distribution from this polarized conductor in turn gives rise to an electric field that affects the electron density. The electronic structure is then iterated against this potential in what is called a self consistent reaction field (SCRF) method, until convergence of the new density function is reached. The polarizable continuum is expected to account for stabilization similar to that of interaction from solvent molecules, although it cannot describe any specific interactions such as hydrogen bonding. The CPCM model is defined by the dielectric constant, i.e. the permittivity of the solvent, and other parameters, such as solvent molecular size which determines the radii of the spheres defining the model surface. In the applications in this thesis the solvent interaction is calculated as the difference in electronic energy compared to that of an in vacuo calculation. The solvent effect is calculated with the same basis set as the geometry optimization. This interaction energy is added to the gas phase energy obtained from the calculation with larger basis set. It has been demonstrated that the geometry is not significantly altered if the molecules were to be optimized in within the SCRF solvent model. 17 In the case of the studies involving the dipeptide catalyst (Chapter 3.1) and the cinchona thiourea catalyst (Chapter 3.3) the UFF model has been used. This model uses radial parameters from the Universal Force Field method for building the cavity, treating hydrogen explicitly whereas many other schemes for cavity construction let the hydrogen atoms be included in the larger spheres from the heavier atoms. The explicit hydrogen description is of good use since in these studies there are several transition states involving a proton transfer, where the proton is no longer covered by the larger spheres. In the hydrophosphination study (Chapter 3.2) the United Atom Topological Model applied on

Chapter 2 9

atomic radii of the UFF force field, UA0, is used which is the default in the employed Gaussian ’03 program package 25 .

2.5 Interpretation of the Energies This thesis deals with considerations of mechanisms and stereoselectivity in catalyzed reactions. This section will briefly introduce how the calculated energies can be related to relevant measurements. The potential energy surface (PES) defines the energy of each geometrical setup. The calculations are used to retrieve the stationary points of the electronic energy landscape, although the real PES also includes the entropic factors, the zero point energy and solvent effects. We assume that the stationary points on the obtained PES after addition of the zero point and solvent corrections sufficiently closely resemble the desired ones. A stationary point can be either a minimum, which is the conformation that is statistically most occupied, or a first order saddle point (called transition state), that is the highest point of the minimum- energy path connecting two minima. The energies of these points are used to get an overview of the PES. According to Maxwell-Boltzmann statistics, the probability of any given geometry is related to its energy as the inverse exponent of the energy divided by the temperature and the Boltzmann constant, as expressed in Equation 3, where Z is the so-called partition function, which is the sum of the exponentials of all states (geometries).26

E − i N e k BT i = (3) N Z The PES is assumed to be populated according to the Boltzmann distribution, and the number of molecules that are at the transition state are related to the total number according to the inverse exponential of the energy difference divided by the temperature and the universal gas constant. In transition state theory a rate (k) is determined by this exponential energy difference (kB replaced by the universal gas constant R in a molar context) multiplied by a factor of the Boltzmann constant ( kB), the temperature (T) and divided by the Planck constant ( h) as expressed in Equation 4.11

‡ k T −∆E k = B e RT (4) h The energies referred to here are the free energies, whereas the ones calculated in this thesis correspond to the enthalpies, the difference being an additional entropic term in the free energy. This term is neglected here. In many of the studied reactions no accurate measurement of the kinetics has been performed, hence there is no estimate of the experimental barrier to compare to the theoretical one. It is still possible to determine whether the activation energies obtained are feasible under the experimental conditions. A rule of thumb is that a barrier of 18 kcal/mol corresponds to a reaction rate of 1 per second at room temperature, and every change of 1.4 kcal/mol will result in a 10-fold alteration in reaction rate (see Figure 2.1). More interesting is to compare the . According to the Curtin-Hammett principle the ratio of different products formed from rapidly interconverting intermediates is dependent on the difference of the absolute energies of the transition states, in accordance to their relative population 27 . Thus we can relate the stereoselectivity to the calculated enthalpies. The stereoselective outcome of a reaction is commonly expressed as enantiomeric excess ( ee ), the excess of one enantiomer over the other as a percentage of their sum (Equation 5, brackets

10 Theoretical Methods

denotes concentrations of the enantiomers). The ee as a function of the difference in transition state energy is depicted in Figure 2.1.

[R]− [S] ee = (5) R [][]R + S

10000 100.0%

90.0%

80.0% 1000 70.0%

60.0%

100 50.0%

40.0% Enantiomeric excess Enantiomeric Relative reaction rate reaction Relative 30.0% 10 20.0% Relative reaction rate, left axis 10.0% Enantiomeric excess, right axis 1 0.0% 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 Relative energy (kcal/mol)

Figure 2.1. The dependence of enantiomeric excess and relative reaction rate on the relative energy of two transition states at room temperature. The solid inverse exponential line depicts the enantiomeric excess for the linear scale on the right-hand side y-axis. The relative reaction rate (higher rate divided by lower rate) is expressed by the dashed line on a logarithmic scale (left axis).

2.6 Scope of the Method It should be noted that the formalism behind DFT is non-approximate for calculating the in vacuo molecular ground state. It is in two ways approximations come in. Firstly and most importantly the correct expression for the electronic interactions are unknown. The variational principle only holds true for the right functional, thus approximate functionals can give both higher and lower energies compared to the desired ground state. Secondly, the choice of basis set for expansion of the solution introduces a source of error. This error can be minimized by using a more complete set of functions.

Chapter 2 11

The parameters in the B3LYP functional are fitted for a test set of small molecules.17 The systems studied here only include elements up to the second row, hence the method can be assumed to be a good choice. A common way of assessing the accuracy of a functional is to evaluate the mean absolute error in calculated energies compared to the experimental values of heats of formations, i.e. the enthalpy change upon formation of a molecule into its standard state from the constituting elements in their standard state. A recent study comprising 633 organic molecules showed that this mean absolute error is 2.6 kcal/mol when some systematic errors are eliminated. 16 This is in line with earlier studies, that have shown an error in heats of formation of 2-4 kcal/mol.15, 28 More relevant to reaction barriers is the isomerization energy benchmark given by Tirando-Rives and Jorgensen 16 comparing 34 isomerization energies involving hydro-, nitrogen-containing and oxygen-containing molecules. This showed an average error of 2.2 kcal/mol (using the 6-31G+(d,p) basis set) and the error decreased upon increasing the basis set. However, a study by Kang and Musgrave comparing transition state barriers reports a mean absolute error of 3.3 kcal/mol for hydrogen abstraction reactions and 4.2 kcal/mol for non-hydrogen abstraction reactions. 29 Thus the reaction energies calculated in this work are expected to have an error of a few kilocalories per mole. For the energy difference of stereoisomers that are calculated to assess the enatio- and diastereoselectivities the relative errors are expected to be subject to even more substantial cancellation of errors, giving the sub-kcal/mol accuracy needed for these studies (1 kcal/mol energy difference corresponds to 70% enatiomeric excess at 25 °C as can be seen from Figure 1.1). This is best verified by the agreement of the calculated stereoselectivities with experimental ones as shown in the present thesis as well as in many other studies.30, 31 The calculated energy corresponds to the enthalpy, and entropic factors are neglected since the estimation provided by the calculations does not offer accuracy comparable to the electronic energy. In bimolecular reactions there are significant entropic contributions, but for the stereoselection and reaction pathway comparisons performed here the isomers of molecular complexes have similar binding and the differences in entropic energy are presumably small enough to be neglected. As noted above the stationary points are those of the electronic PES. The location of the stationary points of the true energy surface (including entropy, solvation and other corrections) could hypothetically differ, but this is expected not to be of importance and is not considered. A more severe problem in determining the shape of the PES is finding the global minimum, since the optimization method gives us a local minimum. In most cases there are several local minima and several saddle points. A major part of the practical effort in this thesis has been dealing with the search for the global minimum or the lowest transition state. This is best exemplified by the study of the dipeptide-catalyzed aldol reaction, where a multitude of transition states were optimized for the reaction leading to the same stereoisomer and a scheme of varying different geometrical parameters resulted in finding the globally preferred transition state. Since the uncertainties are of the same order of magnitude as the calculated energy differences for stereoselective transition states, we cannot expect to reproduce enantiomeric excesses to the percentage given by the experiments. However, the obtained values are indicating the energetic trend of the different geometric constraints, which in many cases can establish a rationale for the observed selectivity.

Chapter 3

3. Applications

The methods described in Chapter 1 above have been applied to three different organocatalytic reactions, namely the peptide-catalyzed aldol reaction, hydrophosphination of unsaturated aldehydes and the asymmetric Henry reaction. This chapter summarizes the results.

3.1 Peptide-Catalyzed Aldol Reaction One of the most important milestones in field of asymmetric organocatalysis is the discoveries of the intramolecular aldol reaction catalyzed by the amino acid proline. The discovery was made by Hajos and Parrish and Eder, Sauer and Wiechert 32 in the 1970’s, and has been used in the synthesis of steroids. 33 However, it was not until 2000 when List, Lerner and Barbas demonstrated that proline and its derivatives are highly enantioselective catalysts for the intermolecular asymmetric aldol reaction between and aldehydes that asymmetric enamine catalysis received an increased attention. 34 Córdova and co-workers demonstrated that also primary amino acids such as 35 and dipeptides of such amino acids 36, 37 are capable of catalyzing this reaction. The aldol reaction is an important reaction for forming -carbon bonds. The starting materials are two carbonyl compounds of which one must possess an α-proton. The catalysts, amino acids and peptides, are commercially available and economically attractive. This amino acid and peptide-catalyzed aldol reaction is also significant from the evolutionary point of view. It is believed that this reaction can be one of the reactions counting for the formation of the homochiral starting material needed for life to evolve. 38 Importantly, the small peptides, in contrast to the amino acids, catalyze the reaction stereoselectively also in water 37 , and can thus be regarded as the precursors to aldolase enzymes. 39 In case of proline, there have been several theoretical studies on the reaction mechanism 40 as well as stereoselectivity. 31 It is now established that the catalysis is performed via an enamine mechanism. 41 The mechanism and selectivity for the alanine-catalyzed aldol reaction between benzaldehyde and cyclohexanone was studied computationally by Bassan et al .42 Starting from this enamine mechanism we have in this study assessed the origins for stereoselectivity for the di-alanine-catalyzed reaction between benzaldehyde and cyclohexanone (Figure 3.1). This is done by locating and comparing the transition states for the stereointroducing C-C bond forming step.

14 Applications

O O HO H2O HN O Ph H

O HN

O O O HO HN O HN O

OH NH H2N Ph H

OH O H O Ph 2 H

Figure 3.1. Proposed mechanism for peptide-catalyzed aldol reaction.

3.1.1 Stereoselectivity The dipeptide differs from the amino acid in regard to its use as a catalyst in two important aspects. In the aldol reaction the amino acid is a bifunctional catalyst where the carboxyl group is donating a proton or at least a strong hydrogen bond and the nitrogen is involved in the enamine formation (see Figure 3.1). The dipeptide has another functional group, namely the amide group of the peptide bond, which is important in the transition state binding. The other difference, which is more of a modelling aspect, is that the dipeptide has a significantly larger conformational freedom. Practically this means that there are many transition state structures for the desired reaction. The preceding work by Bassan et al .42 on the alanine-catalyzed aldol reaction was a thorough study done by locating all possible transition states for the stereointroducing C-C bond forming step of the reaction. The primary amino acid has rotational freedom in the C-N bond, which is locked in the ring in the secondary amino acid proline. This gives catalytic access to both faces of the enamine, which is not the case in proline. In the case of the alanine-catalyzed reaction of benzaldehyde and cyclohexanone several geometry variations can be envisioned, all of which comprise the transition to the desired configuration of the product. The attack can be on the Si or Re-face of the enamine by the Si or Re-face of the aldehyde. The enamine can be syn or anti to the carboxyl group. The cyclohexene ring can adopt different conformations,

Chapter 3 15

as well as rotameric variations along the forming C-C bond. Including two ring conformations and two rotamers, it all together gives 32 unique transition states. In the case of the dipeptide the conformational freedom increases, since in addition to the factors just mentioned, the peptide itself can take on different conformations and the carboxylic moiety can reach further away from the amino residue than what is possible in the amino acid, hence a larger rotameric freedom along the C-C bond can be achieved with retained stabilization or protonation of the developing alkoxide. Instead of locating all transition states by all possible variations, we decided to explore each conformational variation by finding some representative transition states which have all conformations same except for the one investigated. Using this approach we have selected the lowest energy conformation by each variation and found the overall most accessible transition states for the different classes of configuration of the product. These transition states are shown in Figure 3.2. In respect to the factors mentioned above, we can draw some conclusions about the most accessible transition state. The transition state provides stabilization of the emerging alkoxide anion of the aldehyde by several hydrogen bonds from the catalyst. In the case of proline, where the only hydrogen bond donor present is the carboxylic acid, the proton is transferred to the carbonyl concertedly in the C-C bond forming transition state. In the transition state of Figure 3.2 A there are additionally two hydrogen bond donors, the terminal amine and the peptide amide. This provides efficient stabilization of the anion, which makes the proton transfer from the carboxyl group to form the alcohol of the product very asynchronous. For transition state A in Figure 3.2 a separate proton transfer transition state can be located in vacuo . The two transition states and the intermediate in-between lie within 0.3 kcal/mol for large basis set energy including zero point vibrational contributions. However when solvation is added the barrier for the proton transfer disappears, resulting in a concerted reaction in solution. While the amine offers the ability of enamine formation that is the basis for the catalysis in the reaction, the asymmetric electrostatic stabilization of the aldehyde by the hydrogen bond donors in the transition state makes the reaction stereoselective. The tridentate coordination in the optimal transition state offers a significant energetic stabilization. Lack of any of these hydrogen bonds results in a higher transition state energy. The face of attack is determined for the aldehyde by the steric repulsion between the two substrates. For catalyst conformations of reasonable energy, the attack by the opposite face of benzaldehyde would result in a strong repulsion between the two rings. The cyclohexene- enamine intermediate is preferentially attacked on the face that lacks the repulsion from the chiral residue of the first amino acid and provides stabilization from the terminal amine hydrogen bond, i.e. the anti enamine. In the optimal transition state the steric repulsions within the peptide backbone are minimal for offering additional two hydrogen bonds from the amide and the carboxyl groups. From the different possible ring twists of the cyclohexene in the transition state, the half-chair that will lead to the chair product is the most stable one in all comparisons we have made. Other rotamers of the substrates than the one are not preferred since that would result in loss of one or more of the hydrogen bonds and a less optimal catalyst conformation.

16 Applications

Figure 3.2. Transition states leading to the four stereoisomers. Energies in kcal/mol are given in the labels that also specify the product configuration of each transition state. Distances from hydrogen bond donor protons to the developing alkoxide are given in Å. Also the distances of the forming C-C bonds are given in bold grey (Å).

3.1.2 Conclusion Quite like the selectivity studies of proline and alanine, we find that the diastereoselectivity is a consequence of the interaction between the two substituents – the rings are energetically optimized to be apart from each other – and not directly dependent on the catalyst. While in proline the enantioselectivity is due to the conformationally constrain of fixing the carboxyl on one face of the enamine, the alanine offers selectivity based on avoidance of the sterics between the chiral residue of the amino acid and the substrate in the major transition state. This is also the case for the dialanine. The multidentate binding in the peptide may explain why selectivity is retained in water where it is not for the amino acids. The computational results are in good agreement of the experimental enantiomeric excess.

Chapter 3 17

3.2 Hydrophosphination of α-, β-Unsaturated Aldehydes Chiral compounds incorporating phosphorus are important for many chemical applications. In asymmetric metal catalysts it is common to use phosphines as ligands, whose chirality accounts for the asymmetry of the catalyst. Phosphines are also used as organocatalysts, and phosphonates are valueable precursors in the synthesis of pharmaceuticals.43 This work deals with an organocatalytic approach of enantioselective formation of phosphorus-carbon bonds.

In this work a prolinol derivative is used as catalyst, offering enamine-iminium catalysis. The residue breaking the symmetry in the pyrrolidine is a bulky substituent shielding one face of the iminium intermediate – in contrast to the bifunctional catalyst proline where the carboxyl residue takes part in the reaction and steer the stereochemistry by hydrogen bonding. In the computational model the bulky group is a di-phenyl-, (trimethyl-silyl-ether)-methyl (Ph 2OTMS). For the modelling the optimized reaction was used where the reactants are cinnamic aldehyde, the simplest aldehyde from the experimental substrate scope, and diphenyl phosphine, the only that showed enantiomeric excess. The reaction is illustrated in Figure 3.3. The reaction was performed in CHCl 3, as was used for the calculation of the solvent effect. Ph H2O Ph Ph Ph P N OTMS H O H + H H Ph

Ph Ph Ph Ph N OTMS Ph N H H OTMS Ph P Ph O H Ph H Ph P H O Ph + H 2 Ph Figure 3.3. Prolinol-catalyzed hydrophosphination.

In the computational study we have addressed the enatioselectivity of the reaction, thus focusing only on the stereointroducing phosphination transition state. The aldehyde adds to the prolinol and forms an iminium intermediate, which then reacts with the nucleophilic phosphine. We have investigated the conformational possibilities of the iminium intermediate, demonstrating that the E-trans - is lowest in energy among the E/Z -s-cis/trans -Z- isomers considered. However, the energy of the Z-trans -isomer has quite similar energy, 2.0

18 Applications

kcal/mol with solvation correction (3.5 kcal/mol in vacuo ), suggesting that it could possibly offer a relatively accessible transition state, see Figure 3.4.

Ph Ph

+ Ph + Ph N N OTMS OTMS H H

Ph Shielded Ph Si -face Shielded Re -face

Unshielded Unshielded Re -face Si -face

E-trans -iminium Z-trans -iminium

Figure 3.4. E-trans and Z-trans -iminium intermediates. Z-trans -iminium is 2 kcal/mol higher in energy including solvent correction.

3.2.1 Stereoselectivity Several transition states were optimized for the phosphine addition. The diphenylphosphine can be aligned corresponding to the three different rotamers of the product along the P-C bond. The different rotameric transition states are shown to lie relatively close in energy, the difference is due to the different interactions between the phenyls of the phosphine and the phenyl of the cinnamic iminium species. The transition state holding the lowest energy is the attack of the unshielded face of the E- trans -iminium (Figure 3.5, A), which also gives the same stereoisomer as the experimentally observed major product ( S). The located lowest lying transition state for the minor product ( R) (Figure 3.5, B) is 2.1 kcal/mol higher in energy (4.2 kcal/mol in gas phase) and corresponds to the attack on the unshielded face of the Z-trans -iminium. Thus the energy difference of the transition states correlates well with that of the iminium conformations, both being close to 2 kcal/mol. The attack on the shielded face of the preferred iminium (Figure 3.5, C) is slightly higher in energy, 2.4 kcal/mol in solvent (3.1 kcal/mol in gas phase), due to the steric repulsion from the bulky group.

3.2.2 Conclusion The shielding of one face of the cinnamic-pyrridinium intermediate is efficient, and our study indicates that the selectivity is dependent on the energy spacing of the different iminium conformations.

Chapter 3 19

Figure 3.5. Lowest lying transition states leading to S-product ( A) and R-product, B and C. Energies are given in kcal/mol and the distances of the forming P-C bonds are given in Å.

20 Applications

3.3 Cinchona Thiourea-Catalyzed Henry Reaction The Henry reaction, also called nitroaldol reaction, is the addition of nitro alkanes to ketones or aldehydes, discovered by Belgian chemist Louis Henry in 1895.44 The reaction is a powerful method of C-C bond formation, where the nitro group is useful for subsequent functionalization.45 The reaction introduces one or two new in the product molecule. An asymmetrically catalyzed reaction was presented by Shibasaki in 1992.46 Recently Marcelli et al . developed a cinchona-based organocatalyst for the Henry reaction. 47 The Cinchona alkaloids are well known and frequently used organic catalysts, since they are readily available and inexpensive natural products. They exist in two pseudoenantiomeric forms, quinine and quinidine, which provide a basis for creating one catalyst for each enantiomer of the product. The catalyst used in this study incorporates the quinuclidinium of the cinchona, a base that can deprotonate the nitromethane, coordinate the reacting species through hydrogen bonding and finally protonate the product. Also a thiourea moiety is used for coordination by strong hydrogen bonding. This work aims at explaining the reaction mechanism as well as rationalizing the enantioselectivity of this reaction.

N H OH MeNO2 N NO 2 OMe

N S H N H

N H N H N N H OMe OMe O N S H H N S N O O O H N H N N H N O H N H OMe Pathway B O O N S N H N O H O

Pathway A

Figure 3.6. The cinchona thiourea-catalyzed Henry reaction. Two possible pathways in regard to catalyst coordination have been studied.

Chapter 3 21

5 N 5 N H H N N OMe OBn

HN S HN S

HN HN CF3

CF3 1 2 Figure 3.7. The Chinchona-thiourea catalyst, small model 1 and larger model 2.

The binding geometry of the substrates and the rigidity of the catalyst minimize the number of transition states to consider, compared to the earlier studies. We have found two pathways similar to a related study by Papai and co-workers 45 and can also for the present reaction and catalyst confirm that both pathways are feasible. Several models have been considered, initially to reduce the computational effort. Additions to the model were made to verify its validity. Experimental verification of the computational model has also been carried out. The reaction was modelled with THF (dielectric constant ε = 7.6), the experimentally used solvent.

3.3.1 Mechanism The mechanism, which is illustrated in Figure 3.6, is considered as deprotonation of nitromethane, C-C bond formation and protonation of the product as well as regeneration of the catalyst. In our study we show that this is an energetically accessible mechanism. The nitromethane is converted into an activated nucleophile through deprotonation by the quinuclidine base without aid of solvent, also yielding quinuclidinium as a hydrogen bond donating site. As a second step the benzaldehyde is hydrogen bonded to the catalyst making it more susceptible for nucleophilic attack. The barrier for proton transfer is calculated to 10.8 kcal/mol including solvent correction (14.7 kcal/mol in vacuo ). For the C-C bond formation there is shown to be two coordination modes possible. In the first (Pathway A) the nitromethide is coordinated to the quinuclidinium through an ion pair interaction, while the benzaldehyde is hydrogen bonded to the thiourea. In the second (Pathway B) the nitromethide is bonded to the thiourea, while the aldehyde is coordinated to the quinuclidinium. The optimal transition states for the nucleophilic attack of the two pathways are shown in Figure 3.8. The energies of the transition states are similar, there is only a small preference of 1.6 (1.1) kcal/mol for Pathway A. Thus both mechanisms are energetically feasible, Pathway A have a total barrier of 12.5 kcal/mol (10.1) compared to the nitormethide-quinuclidinium ion pair. The ion pair is the lowest point along the reaction, being 2.7 kcal/mol (-4.4) more stable than the reactants separate. In case of Pathway B the former benzaldehyde carbonyl is protonated once the carbon-carbon bond is formed. In the in vacuo optimization the ion pair intermediate is not stable, but the proton is transferred after the C-C bond is formed. The product complex is very stable, -5.6

22 Applications

kcal/mol (-14.1) compared to the reactants, while the whole reaction is almost thermoneutral having a reaction energy of 1.2 kcal/mol (-0.7). The energies of the two reaction ways are summarized in Figure 3.9.

Figure 3.8. Preferred transition states for Patway A (left) and Pathway B (right), both leading to the S-product. Distances of hydrogen bond-like interactions and forming C-C bonds are given in Å, the relative energies of the two transition states are given in kcal/mol in the label.

CC bond forming TS Proton transfer TS 10.00

5.00

0.00

-5.00 Relative [kcal/mol] energy

-10.00 Pathway A, THF Pathway A, in vacuo Pathway B, THF Pathway B, in vacuo -15.00

Figure 3.9. Energy diagram for both pathways of the reaction, Pathway A is presented in a heavier line than Pathway B. The energies excluded solvent effect is given in dashed lines. Both pathways exhibit comparable energies.

Chapter 3 23

3.3.2 Stereoselectivity An enantiomeric excess of 73% at most was achieved in the experiment. This corresponds to an energy difference of ca 1 kcal/mol between the most accessible transition states for the different enantiomers. However, the selectivity is strongly dependent on the solvent, demonstrating that solvent interaction in the transition state might be of great importance. Computationally we reproduced the enantioselectivity for model 1 shown in Figure 3.7. The optimal transition states for Pathway A leading to the different conformations of the product are shown in Figure 3.10. The small energy differences are mainly due to steric interactions between the phenyl of benzaldehyde and either the methoxy group of the quinuclidinium or the phenyl of the thiourea.

Figure 3.10. Transition states for Pathway A leading to the different enantiomers of the product. Left (A) is the preferred transition state (S) , right (B) is the energetically most feasible transition state for the (R) -product.

To verify these calculations a larger model was constructed, catalyst 2 (Figure 3.7). In this model the CF 3 groups were added as well as a benzyloxy substituent replacing the methoxyl group of catalyst 1. The transition states were reoptimized for this model (Figure 3.11). Except a vinyl fragment in position 5 of catalyst 2 this catalyst resembles the catalyst used in the original paper by Marcelli et al .47 Despite higher experimental ee (89%), we could note that two transition states leading to different enantiomeric products carries very similar energies. The S-transition state is still favoured, but only by 0.2 (0.2 in vacuo ) kcal/mol. There is still a small preference for the pro-S transition state in the gas phase calculation.

24 Applications

Figure 3.11. Transition states leading to S and R-products using catalyst model 2. Distances in Å and relative energies in kcal/mol.

3.3.3 Conclusion There are no strong interactions that account for the selectivity, but rather weak steric interactions between the benzaldehyde phenyl and the catalyst that can be overcome by solvent interactions. We can demonstrate the trend of the selectivity, but fail to quantify it due to the strong solvent dependence of the reaction. It is beyond the scope of the CPCM method used in our study to account for the solvent interaction.

Chapter 4

4. Summary and General Conclusions

We have shown that the transition state enthalpy is a good descriptor for enantiomer differentiation. The selectivity in the investigated reactions is due to steric interactions between the catalyst and substrates as well as between the different substrate molecules in the transition states. The dipeptide study revealed that the side chain of the amino acid accounts for the steric interaction with the ketone, and intersubstrate steric repulsions are responsible for the diastereoselection. Although the molecular size was feasible for being studied with the selected method, the large flexibility of the catalyst-substrate complex implies a large space of feasible transition state structures to locate, which is a tedious work. In case of the Cinchona-project the selectivity arises from small steric effects. We can also note that the enantioselectivity presented is quite low and approaching the limits of the method. Also the solvent effects are significant in the experiment which is not computationally accessible with the selected solvent model. I find it unlikely that any other solvent model currently employable would be able to accurately address these differences. In the phosphination project the selectivity is, as expected, due to the asymmetric bulkiness of the catalyst. However for both the dipeptide catalyst and the prolinol-derivative catalyst there are competing transition states which are not directly hindered by the bulkiness of the chiral hindrance. Tuning the bulkiness of the chiral group would thus not necessarily improve the selectivity. Overall, addressing moderate enantioselectivity is difficult. Enantiomeric excesses of less than 90% is common in many experiments, representing a quite small energy difference of around 1.5 kcal/mol at room temperature, which challenges the accuracy of the method especially for systems with larger molecules. We can reproduce the trends in terms of which enantiomer is preferred, although the results might not be enough to quantify precisely the effect of the different contributions in a system where many factors together account for the stereochemical outcome of the reaction. These and other successful studies do however show that this is a feasible approach to address the stereoselectivity in organocatalysic reactions. It is of great help in understanding the mode of catalysis and selection which in turn will enable development of better catalysts as well as wider applications.

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Acknowledgements

Firstly I’d like to express my deep gratitude to my supervisor, Docent Fahmi Himo, who introduced me to the field of quantum chemistry and has consistently guided me through my studies. I’d also like to thank Professor Hans Ågren, head of the department. Secondly I’d like to thank my collaborators, Docent Armando Córdova and Dr. Tommaso Marcelli, who apart from providing me with interesting problems and rewarding scientific discussions also have been of great help in teaching me chemistry. Special thanks to Kathrin and Elias for fruitful discussions of all kinds. I’m also grateful to Emil and Prakash for the entertainment they have provided me as we have shared office at the department. It has also been a real delight to work with the rest of the catalysis group, Robin, Polina, Liao, Chen, Francesca, Sugata and Anna. I’m happy that Pawel has provided me with a lot of help during my course of work at the department, as have Emanuel and Laban. More important are probably all the lunch-breaks and other good times we have shared, making my work at the department pleasant. I’d also like to express my gratefulness to all the other people at the department for sharing many joyful moments! Special thanks also to everyone who have kindly helped me in the writing of this thesis, in particular Tommaso, Kathrin, Elias and surely my supervisor. Finally I’d like to thank Ji-Yeun and my family for constantly supporting me throughout my life. Thank you all! Tack! 고마워!