Predicting and Understanding Binding Affinities of Synthetic Anion Receptors

Anion receptors are molecules that can recognise and bind anions. They have applications in organocatalysis, anion sensing and the removal of anions from wastewater. Some anion receptors are also able to transport anions across cell membranes and show promise for the treatment of diseases such as cystic fibrosis and cancer. As such, it is of interest to develop computational methods that can reliably predict the physicochemical properties and anion binding affinities of these molecules. However, efforts to computationally model these molecules are hampered by the sheer size of typical receptors, making them too expensive to treat using accurate quantum chemical methods. Whilst efficient approximations such as local-correlation methods have been developed, the broader accuracy of these methods, particularly in their application to ionic non-covalent systems remains unclear. To address this gap, this thesis has carried out an extensive validation of local-correlation methods, and economical density functional theory (DFT) methods for receptors with different binding motifs. Additionally, multiscale models have also been examined with the view to extending the scope of these methods to model very large anion receptors. DFT methods giving good agreement with highly accurate calculations at a fraction of the cost were identified. The use of semiempirical methods combined with DFT in a multiscale model for calculating anion binding affinities lead to unexpectedly large errors with modest savings of computational time, while some "three-fold corrected" methods show promise in reducing the cost of geometry optimisations of large receptors. These validated protocols were subsequently applied to investigate the structure-binding relationships of a wide range of dual-hydrogen bonding receptors. Notably, different receptor motifs were found to have different conformational preferences, which could explain why experimentally, thioureas, thiosquaramides and croconamides show weaker chloride binding affinities than would be expected based on their acidity. The results suggest that pre-organising anion receptors in the conformer that facilitates hydrogen bond formation could be a promising strategy for the development of anion receptors. It is envisaged that these findings will aid in the design and screening of novel anion receptors with increased binding affinity and selectivity

Theoretical Studies of OME-synthesis and Ammonia SCR in Zeolite Catalysis

Die Emissionen globaler und lokaler Schadstoffe sind ein wachsendes Problem im Hinblick auf den Klimawandel und die öffentlich Gesundheit. Treibhausgase bestehen zu mehr als 80% aus Kohlendioxid. Die Verwendung von Oxymethylendimethylethern (OMEs) als Kraftstoffe oder Kraftstoffadditive im Transportsektor hat den Vorteil geringerer CO$_2$- und Stickoxidemissionen (NO$_x$) ohne dass der Motor angepasst werden muss. NO$_x$-Emissionen, die zur lokalen Verschmutzung beitragen, können auch durch Abgasnachbehandlung reduziert werden. $\\$ Auf Dichtefunktionaltheorie (DFT) basierende Berechnungen werden oft zur Modellierung von Katalysatoren verwendet. In dieser Arbeit habe ich die Genauigkeit von DFT für säurekatalysierte Reactionen (Methanol zu Olefinen) un Redoxreaktionen (selektive katalytische Reduktion) in Bezug auf übergeordnete Methoden getested. Clustermodelle wurden verwendet, um einen Hohlraum des Zeolithen innerhalb des Chabazitgerüsts zu modellieren, indem 46 tetraedische Atome aus der periodischen Struktur extrahiert wurden. Die mittleren absoluten Fehler der DFT hängen von der verwendeten Funktion ab, die im Vergleich zu DLPNO-CCSD(T)-Berechnungen zwischen 10 und 40 kJ/mol für MTO-Reaktionen und zwischen 20 und 50 kJ/mol für SCR-Reaktionen variieren. $\\$ In dieser Arbeit habe ich die Reaktionsmechanismen für die Synthese von Polyoxymethylenether (POME) und die selektive katalysche Reduktion, die eine Abgasnachbehandlung ist, von NO$_x$-Gasen zu molekularem Stickstoff und Wasser unter Verwendung theoretischer Methoden wie der Dichtefunktionaltheorie, Möller-Plesset-Störungstheorie zweiter Ordnung (MP2) und "domain-based local pair natural orbital coupled cluster with single, double and perturbative triple excitations" (DLPNO-CCSD(T)) untersucht. Die Untersuchungen zeigten, dass für die OME-Synthese unter Verwendung des H-BEA-Zeolithen die Trioxanringöffnung mit einem Übergangszustand von 60 kJ/mol, der ratebestimmende Schritt ist. Es wurde gefunden, dass die OME-Synthese in der homogenen Katalyse während des Initiationsschritts ein ähnliches Gibbs-Profil der freien Energie aufweist, welches der OME-Protonierung entspricht und auf der Acidität des Katalysators basiert. Für die SCR wurden Reaktionsmechanismen untersucht, die auf dem schnellen SCR-Zyklus und dem NO-Aktivierungszyklus basieren, Hierzu habe ich den Cu-SSZ-13-Zeolith untersucht und gefunden, dass der geschwindigkeitsbestimmende Schritt die NO-Oxidation mit Übergangszuständen nahe 300 kJ/mol ist. Strukturen im NO-Aktivierungszyklus haben einen Multireferenzcharakter gezeigt und erfordern wahrscheinlich die Verwendung von CAS-Methoden (Complete Active Space)

Computational modelling of solvent effects

This thesis is concerned with developing theoretical benchmarks and computational procedures that would facilitate robust descriptions of solvent effects on molecular properties and chemical reactions. This advancement will enable chemists to design more effective chemical reagents, drug molecules and materials, thereby reducing the need for extensive experimental trial-and-error. Towards this end, this thesis has developed theoretical benchmarks to evaluate the performance of lower-cost and approximate methods in predicting solute-solvent interaction energies. This includes the generation of high-level calculations of solute-solvent interactions and proton transfer reaction energies in very large water clusters (up to 160 water molecules) at a variety of solute-solvent configurations. This differs from previous studies, which mostly focused on small solvated clusters (1-6 solvent molecules) at equilibrium geometries. These theoretical benchmarks were then used to assess the performance of a range of contemporary density functional theory methods and hybrid quantum mechanics/molecular mechanics (QM/MM) approximations of these methods. A surprising finding was that significantly larger than expected QM region size (solute plus 40 or more water molecules) was needed before the QM/MM models converged to within 5.7 kJ mol-1 of the direct QM result. To address this limitation, an important contribution of this thesis is the development of efficient strategies based on charge-shift analysis and electrostatically embedded fragment methods to accelerate the convergence of the QM/MM models with respect to QM region size. Of particular note, the QM region selection based on atomic charges significantly reduced the errors in QM/MM models even when a low-level embedding potential was used. Finally, these findings culminated in developing a dual-Hamiltonian approach that may be used to systematically improve the accuracy of force field explicit solvent simulations of barriers of organic reactions. It is envisaged that these developments will directly contribute to the development of a systematic framework for improving computational simulations of solution-phase processes

AB INITIO MODELING OF THE SELECTIVITY AND REACTIVITY OF BOTH THERMAL AND LIGHT MEDIATED ORGANIC AND ORGANOMETALLIC TRANSFORMATIONS

The mechanism of a reaction is the collection of events that take place that lead to the products of a chemical transformation. Though there are some events in a chemical reaction that can be observed by experiment, such long-lived intermediates, many of the events are too short lived to be measured. Due to these restrictions and the advancements in the development of moderately scaling computational tools, it is becoming commonplace to use quantum mechanical software packages to model the mechanism of a reaction. Here, I used quantum mechanical calculations alongside experimental evidence provided by multiple collaborators to understand the reactivity of both heat- and light-mediated organic transformations. In chapter 2, I investigated the role of electron donor-acceptor complexes in the generation of alkyl and acyl radicals in the presence of visible light. In addition, the pathways to the experimentally observed products, alkyl and acyl thioethers, were modeled. The lowest energy pathway to product, post-radical generation, was radical addition to the radical electron donor-acceptor complex. For a photoredox-catalyzed method to cyclopropanes from a novel halomethyl radical precursor (Chapter 3), computations strongly supported a redox-neutral reductive radical/polar crossover mechanism over radical pathways, consistent with experimental trends. Investigation of the isomerization of cinnamyl chloride to cyclopropane via a commonly used photoredox catalyst (Chapter 4) revealed that the reaction was mediated via dexter energy transfer between photocatalyst and substrate over the more commonly proposed electron transfer, affording diastereoselective product formation. A dual nickel/photoredox-catalyzed coupling of sulfinate salts and aryl halides gave a mixture of aryl sulfide and aryl sulfone products (Chapter 5), suggesting that disproportionation of sulfone radical was leading to the formation of thiyl radical. Modeling the product determining steps indicated that the product distribution was controlled by radical addition of the thiyl radical to the nickel(II) species versus reductive elimination of the sulfone bound to the nickel(III) catalyst. A bicyclo[1.1.1]pentane diborylated with pinacolboryl groups, one at the arm and head position, was found to have reactivity only at the bridgehead position (Chapter 6). Calculations of a hydrozone coupling reaction performed by the Qin group found that the reactivity was due to the unique hybridization of the bridgehead position as well as increased steric interactions at the arm position. Finally, a sulfoxide synthesized from a sulfinate salt could be activated with Grignard reagent, affording coupling of the substituents originally bound to the sulfoxide. DFT calculations validated the role of the sulfurane intermediate acting as a mediator to the coupled product

Computational and experimental investigation of elemental sulfur and polysulfide

Petroleum processing results in the generation of significant quantities of elemental sulfur (S8), leading to a surplus of sulfur worldwide. Despite its abundance and low cost, the use of sulfur in value-added organic compound synthesis is limited due to its unpredictable and misunderstood reactivity. This dissertation aims to address this issue by tackling it from two angles. Firstly, by utilizing Density Functional Theory (DFT) calculations, the reactivity of sulfur in the presence of nucleophiles is studied. This facilitates the identification of organic polysulfide intermediates that can be generated under different conditions, as well as the corresponding reactivity for each type of nucleophile. This computational study begins with a benchmarking of numerous DFT functionals against experimental data and high-accuracy ab initio computations to determine the best functional(s) for studying elemental sulfur and polysulfides in organic reactions. Using the best DFT method, the mechanism of monosulfide formation from cyanide and phosphines is explained. At the end of this computational study, the mechanism of 2-aminothiophene formation via the Gewald reaction is elucidated. Secondly, attempts are made to synthesize sulfur-based organic compounds using elemental sulfur or compounds with a sulfur source through the utilization of boron, imine, and aryne chemistry. In summary, this dissertation aims to expand the use of sulfur in organic chemistry by providing an understanding to predict its reactivity with nucleophiles, as well as demonstrating its potential for the low-cost synthesis of valuable sulfur-based organic compounds

Synthesis, crystal structures and molecular modelling of rare earth complexes with bis(2-pyridylmethyl)amine and its derivatives : a quantum chemical investigation of ligand conformational space, complex intramolecular rearrangement and stability

Limited research has been performed on the coordination behaviour of hybrid aliphatic and heterocyclic polyamines with trivalent rare earth elements. The rare earth coordination properties of several Nalkylated derivatives of the tridentate ligand bis(2-pyridylmethyl)amine (DPA, HL1) backbone - involving the rare earth elements Y, La-Nd, Sm, Eu and Tb-Lu - have been investigated in this study However, the structural and energetic characteristics of DPA coordination with rare earth elements (REE) have not been studied thus far. Potential applications of DPA-based rare earth complexes are primarily dependent on their electronic and magnetic characteristics, which are affected weakly by the coordination environment, where potential applications may include use as Lanthanide Shift Reagents (LSR), Luminescence probes and small-molecule magnets (SMM). A systematic conformational search of DPA was carried out in this study in order to identify the global minimum conformer and for comparison of the free and coordinated geometries, using the M06(D3) functional belonging to the Density Functional Theory (DFT) family of model chemistries. An understanding of the aforementioned would play an important role in analysis of bulk characterization and the prediction of the reactivity of DPA. Final geometries and electronic energies were obtained from the ‘domain based local pair natural orbital’ (DLPNO)-Møller-Plesset and -coupled cluster theoretical methods, as follows: DLPNO-CCSD(T0)/aug-cc-pVQZ//DLPNO-MP2/aug-cc-pVTZ. Fifteen Single-crystal X-ray diffractometer (SC-XRD) crystal structures of mononuclear rare earth chloride coordination complexes with DPA (RE = La-Nd, Sm, Eu, Tb-Lu and Y) were obtained and geometrically analysed in this study. Three isostructural series of constitutional isomers were identified, consisting of one series of nine-coordinate molecule (M1) and two series of eight-coordinate ion pairs (M2 and M3). This conformational diversity is most likely due the flexible nature of the DPA backbone, as well as the additional stability gained from reduced coordination spheres as a function of decreasing rare earth ionic radii across the lanthanide series (Lanthanide contraction). A Quantum Theory of Atoms-in-Molecules (QTAIM) topological analysis was performed in order to identify and characterise potential hydrogen bonding interactions in H-optimised crystal structures. The crystal structures of five dinuclear (RE = Tb-Tm) and two tetranuclear (RE = Yb and Lu) rare earth chloride complexes with DPA have also been structurally analysed. Furthermore, one mononuclear (RE = Dy), two dinuclear complexes (RE = Dy and Lu) with EtDPA, and one mononuclear complex with the DPA-derivative HL4 (RE = Dy) were structurally characterised. A DFT study of the theoretical interconversion of one real- and two hypothetical- mononuclear lanthanum containing isostructural series (cf. aforementioned crystal structures) was undertaken in order to gain a deeper understanding of the processes involved, in terms of the participating minimum energy paths (MEPs), intermediates and transition states – as determined via the Nudged-Elastic Band (NEB) procedure. This hypothesis is supported by the well-known conformational lability of rare earth complexes, due to the weak/minor covalency of their coordination bonds. An attempt was made to determine the respective energies of one real- and two hypothetical diamagnetic or ‘closed-shell’ constitutional isomers containing the rare earth ions La3+(M1), Y3+(M2) and Lu3+ (M3). It was assumed that the most stable isomers have a greater probability of being observed as the asymmetric unit of the complex crystal structure – assuming weak contributions of lattice or intermolecular interactions towards the geometry of the asymmetric unit

Transition Metal Computational Catalysis: Mechanistic Approaches and Development of Novel Performance Metrics

Computational catalysis is an ever-growing field, thanks in part to the incredible progression of computational power and the efficiency offered by our current methodologies. Additionally, the accuracy of computation and the emergence of new methods that can decompose energetics and sterics into quantitative descriptors has allowed for researchers to begin to identify important structure-function relationships that predict the properties of unexplored subspaces within the overall chemical space. Catalytic descriptors have been used frequently in data driven high-throughput computational screenings. With the use of machine learning, a large portion of the chemical space an be predicted in matter of minutes or hours, instead of months and years. Herein, a full story of quantitative descriptors and computational catalysis is presented, where we have focused on developed metrics for understanding the underlying nature of dative bonding in main-group complexes and extended this into transition metal complexes. Additionally, the complexities of various catalytic reactions (hydrogen atom abstraction, aziridination, epoxidation and ring-opening metathesis polymerization) have been studied in depth to highlight the key features that lead to increased and decreased catalytic efficiency