School of Chemistry - Theses

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Tailored Growth of WS2 for AFM Sensing Applications

Rokhsat, Eliza ( 2023-11)

Two-dimensional layered transition metal dichalcogenides (TMDs) such as MoS2, WS2, MoSe2, and WSe2 are garnering considerable attention for their potential in chemical sensing applications. This thesis investigates the influence of source sublimation temperature and source-to-substrate distance on the nucleation and growth kinetics of WS2. A novel approach is developed to fabricate highly luminescent WS2 monolayers, which exhibit adjustable composition, optical, morphological, and electrical properties. Incorporating these WS2 layers as sensing materials, surface potential measurements have revealed critical connections between intrinsic defects and the chemical sensing capabilities of the monolayers. The thesis also delves into the challenges that need to be addressed to harness TMD monolayers effectively as molecular sensing materials, potentially enriching our understanding of chemical sensors. Additionally, this study examines nanomechanical detection using microcantilevers, exploring the fundamental mechanisms, benefits, and drawbacks of both methods to provide a comprehensive view of their efficacy, rapid response times, and selectivity in molecular sensing.
Valence Tautomerism in Cobalt-Dioxolene Complexes: A Combined Computational and Experimental Study

Mohamed Zahir, Fathima Zahra ( 2023-12)

Switchable molecules afford potential applications for the advancement of functional materials in sensing and display to molecular memories. The ability to identify the occurrence of switching along with their precise properties computationally, before synthesis, is a significant advancement. This thesis presents a series of studies on a computational and experimental investigation of valence tautomeric (VT) behavior in cobalt-dioxolene complexes. Density functional theory (DFT) methods have been effectively utilized for the exploration of VT characteristics of neutral [Co(3,5-dbdiox)(3,5-dbsq)(N2L)] (3-5-dbdiox/ 3,5-dbsq- = 3,5-di-tert-butyldioxolene/semiquinonate; N2L = diimine ancillary ligand) family of VT complexes. Appropriate DFT methods are selected via a rigorous benchmarking process to explore various properties including electronic structure, electronic absorption spectral transitions, spin-state energetics, and the impact of ancillary ligands on the transition temperatures (T1/2) of the complexes. From this analysis, the extent of sigma donation and pi back bonding effects are quantified, which led to a simple model for the prediction of experimental T1/2 values of the complexes, by determining the lowest unoccupied molecular orbital (LUMO) energy of the corresponding diimine ligand. Understanding important concepts in VT equilibria requires an extensive and unified analysis of the existing molecules. The study presents a robust approach for the analysis of diverse cobalt-dioxolene complexes, which involves a quantitative DFT-based benchmark study with reliable quasi-experimental references. Around 50 different cobalt-dioxolene complexes are considered for this study that encompassed both cationic [Co(diox)(N4L)]+ and neutral [Co(diox)(sq)(N2L)] (diox = generic dioxolene, N2L/N4L = bidentate/tetradentate N-donor ancillary ligand) family of complexes. The best-performing method not only accurately captured the experimental behavior of all the reported complexes but also afforded the prediction of potential VT complexes. The predictions are verified by the synthesis and experimental investigation of three new complexes, two of which exhibit thermally-induced VT, while the third remains in the LS-CoIII-cat form across all temperatures, in agreement with the predictions. The study also enabled the elucidation of the origin of the solvent effects for VT equilibria, which has not been definitively known. The analysis revealed that VT transition temperatures in various solvents are modulated via solvent stabilization energy and change in dipole moment. The study presents the impact of valence tautomeric switching characteristics under temperature and pressure through a combined approach of computational and experimental investigations. Previously reported [Co(3,5-dbdiox)(Mentpa)][PF6].(toluene) (Mentpa = tris(2-pyridylmethyl)amine where n = 2 and 3, indicates methylation of the 6-position of the pyridine rings) are investigated by single crystal X-ray diffraction under temperature and pressure. The study showed that high pressure induces unique behavior in the complexes compared to the thermal counterparts. The thermally inactive HS-CoII-sq (high-spin CoII-semiquinonate) [Co(3,5-dbdiox)(Me3tpa)][PF6].(toluene) compound, displayed VT transition under applied pressure. Various computational approaches including quantum mechanochemical methods are utilized for rationalizing the experimental observations. Density functional theory calculations revealed that compression assists in overcoming the spin-state energy requirements. The best-performing DFT approaches identified for mononuclear neutral and cationic cobalt-dioxolene complexes are utilized for the investigation of VT characteristics of dinuclear cobalt-dioxolene complexes. Throughout the series of studies, it is identified that, regardless of the type of cobalt-dioxolene (mononuclear neutral, mononuclear cationic or dinuclear), thermal VT interconversions occur with experimental enthalpy change of 20 – 70 kJ mol-1. This criterion based on experimental enthalpy change, is utilized for understanding the thermal accessibility of the complexes, serving as a key parameter in identifying various transition profiles in dinuclear cobalt-dioxolene VT complexes. The study facilitates the identification of potential VT complexes with specific properties including transition temperature, sensitivity to the environment, and characteristics of the transition. This enables the in-silico design of VT complexes for a range of potential applications.
The Development of Methods to Install and Diversify Carbonyl Derivatives via Radical Intermediates

Guan, Xiaocong ( 2023-10)

Alkyl carboxylic acids play a crucial role as pharmacophores in drug molecules. The current method for obtaining alkyl carboxylic acids primarily limited to the hydroxylation of carboxylic acid derivatives. Therefore, developing innovative approaches to directly install carboxylic acid is very meaningful for pharmaceutical molecular synthesis. The most efficient way to incorporate this motif is through direct carboxylation of the substrate. Traditionally approach involves preparing highly reactive Grignard reagents from alkyl halides, which had limitations in terms of functional group tolerance. Previous work by the Polyzos group demonstrated that transition metals such as palladium could selectively activate C(sp3)-H bonds by forming palladacycle complexes with the assistance of directing groups. However, the insertion of CO2 into the palladacycle was found to be unfavourable. Therefore, CO2 surrogate was employed to explore direct C(sp3)-H carboxylation based on the palladacycle complex. Another approach to construct alkyl carboxylic acids is through the hydrocarboxylation of double-bond systems, which can be achieved by using umpolung strategy. Although reaction systems utilizing photochemistry and electrochemistry have been reported for the hydrocarboxylation of double bonds, these methods are specific to certain double bond system, and most electrochemical methods require sacrificial anodes to stabilize the carboxylic anion. Chapter 1 is a literature review, in which two direct carboxylic acid installation approaches, C(sp3)-H carboxylation and hydrocarboxylation of double bond systems, are introduced. The challenges of C(sp3)-H carboxylation and limitations of current hydrocarboxylation examples were highlighted. Next, the principles of photocatalysis, electrochemistry and continuous flow chemistry are discussed. Finally, the general objectives of this PhD thesis are subsequently elaborated. Chapter 2 explores direct C(sp3)-H carboxylation using carbon tetrabromide as a CO2 surrogate. This approach builds upon previous work by the Polyzos group on auxiliary-directed C(sp3)-H arylation through synergistic photoredox and palladium catalysis. To check the feasibility of this reaction design, the exploration was started with the palladacycle, which is the key intermediate for the previous arylation reaction. During the exploratory studies, both carboxylation and carbonylation product were obtained under the photoredox reaction system. Although the selectivity issue was eliminated by adopting a direct excitation of the palladacycle complex, which favours the annulation pathway, only moderate yield was obtained. Chapter 3 investigates the hydrocarboxylation of double bonds to access alkyl carboxylic acid construction. Electrochemical approach was employed to address the challenging reduction of the double bonds. Furthermore, due to the CO2 gas was employed as the carboxylation source, the continuous flow technology was incorporated to better manage the multiphase reaction, which could also potentially circumvent the decarboxylation issue by precisely control the residence time. Following optimization, the reaction exhibits excellent functional group tolerance and this hydrocarboxylation procedure broadly covers C=N, C=O, C=C systems. Mechanistic study indicates the carboxylic acids are primarily formed through the nucleophilic attack of the carbanion on the CO2. In Chapter 4, a chemoselective reduction procedure of carbonyl compounds in continuous flow was developed, based on the disparities observed in the primary byproducts during the hydrocarboxylation process of C=N and C=O bonds described in Chapter 3. The umpolung strategy, wherein the ketyl undergoes the radical polar crossover under specific flow-electrochemical conditions, is employed to solve the homocoupling issue in the carbonyl reduction process. Both aromatic or aliphatic ketones and aldehydes, are viably reduced to the corresponding alcohols in good to excellent yields with broad functional group tolerance. Quantitative deuterium incorporation indicates the radical polar crossover was effectively achieved. Chapter 5 provides detailed experimental procedures and spectroscopic data for all isolated compounds throughout the thesis.
Model chemistry relevant to the molybdenum copper active site of CO dehydrogenase

Gourlay, Craig (University of Melbourne, 2007)
Toward the synthesis and analysis of selenium-containing glucocorticoid prodrugs

Macdougall, Phoebe Eleanor. (University of Melbourne, 2007)
NMR studies of amyloid ab-peptide in membranes

Lau, Tong Lay (Crystal) (University of Melbourne, 2006)
Gas Phase Chemistry of Iranium Ions with Unsaturated Carbon-Carbon Bonds

Brydon, Samuel Charles ( 2023-10)

The study of cyclic iranium ions has developed rapidly over the last few decades as control of stereoselective outcomes during the electrophilic functionalisation of alkenes is mostly determined by the configurational stability of these species. Trace nucleophiles such as solvent, counter-ions, or unreacted alkene may cause decomposition or racemisation of these intermediates as the electrophilicity of both the heteroatom and endocyclic carbons make them susceptible to nucleophilic attack. Mass spectrometry (MS) thus offers an alternative means by which to isolate these charged species and study their bimolecular reactivity in the gas phase. Generation of these ions was achieved by electrospray ionisation of precursors containing a suitably basic group beta to the heteroatom, which upon protonation would fragment either in-source or following collision-induced dissociation of the pseudomolecular ion to give the heterocyclic three-membered ring. The multistage MS capabilities of a modified linear ion trap were utilised to isolate the iranium ion and observe its reactivity with neutral alkenes or alkynes. Changing the chalcogen (Ch) from sulfur to selenium to tellurium had a significant effect on the partitioning between attack at the heteroatom or ring-opening at carbon. Telluriranium ions underwent exclusive pi-ligand exchange with direct transfer of the tellurenium cation to the neutral reagent in a series of identity reactions, whilst all thiiranium ions studied only showed addition products from ring-opening by the neutral species. The reactivity of seleniranium ions towards alkenes partitioned between these two pathways with electron-donating groups on the heteroatom favouring the former, whilst the latter was promoted by electron-withdrawing groups. Computational studies into the pi-ligand exchange reaction revealed a Huckel pseudocoarctate transition state with a disconnection in the orbital array during the bond-breaking and bond-forming step. Extension to the haliranium ions showed kinetics of ion-molecule reactions with both cyclic and linear alkenes proceeding at the collision rate with iodiranium ions reacting dominantly via pi-ligand exchange, but bromiranium ions underwent carbocation-based fragmentation following ring-opening. Conjugation of the double bond to methyl esters suppressed heteroatom attack on iodiranium ions and only gave allylic stabilised oxocarbenium ions. The partitioning between these two reaction channels could be tuned by substituting inductively electron donating methyl groups onto the carbon-carbon double bond or entirely reverted to pi-ligand exchange by disrupting the conjugation with a methylene spacer enabling differentiation between three isomeric unsaturated methyl esters. Stability of the unsaturated irenium ions was examined by natural bond orbital theory to study (anti)aromaticity in these species. This approach revealed the antiaromatic nature of halirenium ions due to repulsion between the lone pairs and filled pi-orbital of the endocyclic double bond, and non-aromatic nature of the chalcogen irenium ions due to introduction of stabilising pi(C=C) - sigma*(Ch-R) hyperconjugative interactions. These species were generated in the gas phase for the first time by ion-molecule reactions of iranium ions with alkynes. The selenirenium ion structure assignment was strongly supported by cross-over experiments showing selenyl transfer to another alkyne, whilst the proposed iodirenium ion showed different reactivity to that of the open beta-iodovinyl cation produced upon reaction with phenylacetylene.
Effectively Benchmarking Density Functional Theory Methods for Models of Enzymatically Catalysed Reactions

Wappett, Dominique Ann ( 2023-09)

This thesis involves the analysis of the accuracy of quantum chemical methodology when applied to models of enzymatically catalysed reactions. My main aim is to test Density Functional Theory (DFT) methods, as these are regularly used in computational studies of enzyme mechanisms. This process also results in detailed assessment of high level Coupled Cluster approaches, as I seek to calculate reliable reference values against which DFT methods can be tested. Firstly, I assess a range of density functionals on the ENZYMES28 benchmark set, which contains models of five enzymes (four organic and one zinc-dependent), and make recommendations of methods that perform well. In the second project, I establish guidelines for effective benchmarking of enzymatically catalysed reactions---namely, that the level of theory of the reference values and size of the model systems in the test set should be carefully considered, as inadequate choices of both lead to unreliable benchmarking results. Thirdly, I use the insights from the first two projects to develop the MME55 set which represents 10 different metalloenzymes, as there is limited reliable and comprehensive benchmark data for bioinorganic systems. I use MME55 to benchmark DFT methods, and I compare these results to those from the ENZYMES28 set in the first project. While some recommendations are the same, other methods are notably less reliable for models containing transition metals. Finally, I investigate a new approach to improve the accuracy of DLPNO-CCSD(T) to see how it performs for calculating benchmark energies for enzyme models, and subsequently present updated reference values for the organic models from ENZYMES28 that reflect the recent improvements in Coupled Cluster methodology. From these results, I make recommendations of robust DFT methods that can be applied in future computational studies of enzyme mechanisms instead of functionals that are more popular than they are accurate, such as B3LYP. I also suggest methodology for reliable benchmarking that can be applied broadly to many types of test sets.
RAFT Polymerization of Acrylates and Acrylamides in Ionic Liquids; An Accelerated and Potentially Sustainable Process

Santha Kumar, Arunjunai Raja Shankar ( 2023-04)

Ionic liquids (ILs) are organic salts having asymmetric cations and anions that remain as liquid below 100 C. ILs have emerged as a new class of sustainable solvents for polymerisation processes because of their unique combination of properties such as low vapour pressure, high thermal and chemical stability, high conductivity, wide electrochemical window, ability to dissolve organic and inorganic solutes, low volatile organic content (VOC), and have tuneable solvent properties such as miscibility, melting point, viscosity, and hydrophilicity depending on the constituting cations and anions. The use of ILs as polymerization media not only increases the sustainability of the process but also increases the rate of polymerization. However, the role of IL and its influence on the polymerisation rate are still subject of investigation. This thesis addresses these issues by designing experiments to study the kinetics of RAFT polymerisation in different ILs, IL-organic binary solvents, and using different monomers and RAFT agents. The kinetics study revealed that the [BMIM][PF6] IL enhances the rate of RAFT polymerization of n-butyl methacrylate almost 10 times irrespective of its miscibility with the polymerization system. It is also revealed that only a small amount of IL is enough to increase the rate of polymerization. Deep eutectic solvent (DES), a subclass of ILs, made of choline chloride/urea was studied as a polymerization media for RAFT polymerization of 2-hydroxyethyl methacrylate and its copolymerization with methyl methacrylate. The kinetics of polymerisation was studied using a novel DSC methodology, which allowed the polymerisation to be monitored in real time. The data showed that the DES accelerated polymerisation as fast as bulk polymerisation but with more than 90% monomer conversion. The block copolymerisation yielded a spherical and a vesicular morphology of the copolymers demonstrating polymerisation-induced self-assembly in DES. Photoiniferter RAFT polymerisation is a slow but unique process to produce high chain-end fidelity polymers. [EMIM][EtSO4] IL was studied to accelerate the RAFT polymerization of N,N-dimethyl acrylamide under photoiniferter condition achieving more than 90% monomer conversion in less than 5 h. Synthesis of different polymer architecture such as chain extension and block copolymerization demonstrated the versatility and robustness of the process. A comparison was made with thermal initiated RAFT polymerisation which showed the high chain-end fidelity of photoiniferter RAFT polymerisation process in ILs.
Understanding the Impact of Core Polymer Architecture of pH-Responsive Nanoparticles on Intracellular Therapeutic Delivery

Samara Devage, Umeka Nayanathara ( 2023-07)

Advances in nanomedicine have enabled the development of stimuli-responsive polymeric nanoparticles with the potential for improving the efficiency of therapeutic delivery for the treatment of various diseases including cancer. pH-responsive nanoparticles that can respond to changes in the pH of intracellular microenvironments have generated particular interest in addressing specific biological barriers associated with intracellular drug delivery. These nanoparticles can be tailored with different functionalities such as charge-shifting polymers or acid-labile linkers, to effectively navigate biological barriers, allowing for site-specific drug delivery with increased drug circulation time and minimum side effects. In chapter 2, we report the design of a novel dual pH-responsive nanoparticle with tunable core architectures, based on either star or linear morphology, aiming to conquer the limitations associated with conventional pH-responsive systems for intracellular therapeutic delivery. Dual pH-responsive behaviour was achieved by combining both charge-shifting polymers and acid-labile linkages. Four-arm star and linear core polymers were designed by reversible addition-fragmentation chain transfer (RAFT) polymerization of charge-shifting monomers, 2-(diisopropylamino) ethyl methacrylate (DPAEMA) and 2-(diethylamino) ethyl methacrylate (DEAEMA) with 1:1 molar ratio, and hydrophobic anticancer drug, doxorubicin (Dox) was covalently conjugated to the polymer backbone via acid-labile hydrazone linkages. Dual pH-responsive nanoparticles with tunable core polymer architectures were engineered using a nanoprecipitation method by combining either star or linear polymer-Dox conjugates with an amphiphilic block copolymer, poly(2-(diethylamino)ethyl methacrylate)-b-poly(ethylene glycol) (PDEAEMA-b-PEG). The nanoparticles exhibited similar physicochemical properties regardless of the core architecture. Furthermore, both nanoparticles demonstrated dual pH-responsive behaviour, disassembling at pH 6.2-6.0 and releasing the drug in response to the acidic pH. The pH of disassembly could also be tuned by adjusting the ratio of DEAEMA and DPAEMA to 2:1 to design nanoparticles with a disassembly pH of approximately 6.6-6.4. This proof-of-concept design revealed the potential of these dual component systems to act as efficient drug delivery vehicles, opening up new opportunities to design more controlled drug delivery systems. In chapter 3, the dual pH-responsive system was optimized to understand the impact of core architecture of dual pH-responsive nanoparticles on intracellular drug release behaviour. The 2:1 system was used to explore the impact of architecture due to the similar pH of disassembly with previous work which had shown good endosomal escape capabilities. These nanoparticles disassembled when the pH was reduced below 6.6, and faster drug release was observed at acidic pH highlighting their potential to act as effective drug delivery vehicle. Interestingly, nanoparticles with linear polymer core displayed higher cellular association and higher toxicity in MCF-7 breast cancer cells (IC50 = 60 ng/mL) compared to nanoparticles containing the star polymer core architecture (IC50 > 1000 ng/mL). Furthermore, Langmuir-Blodgett experiments revealed that nanoparticle with linear polymer core exhibited significantly higher membrane interactions at endosomal pH, in a model endosomal membrane, compared to nanoparticle with star polymer core. These findings highlight that higher endosomal membrane interactions of nanoparticles with linear polymer core may facilitate improved cytosolic delivery of Dox leading to enhanced toxicity. This suggests that core polymer architecture can influence the intracellular drug release behaviour, and thus this study provides important insights into the design of optimized drug delivery systems. Endosomal escape is the major bottleneck for efficient intracellular delivery of therapeutics. Chapter 4 presents the application and optimization of the split luciferase endosomal escape quantification (SLEEQ) assay to investigate the endosomal escape capability of pH-responsive nanoparticles with tunable core compositions, for intracellular delivery of polypeptide cargoes. SLEEQ assay is based on split luciferase reporter system which consists of LgBiT protein, which is expressed in the cytosol and HiBiT peptide, which is attached to part of the nanoparticle core. HiBiT was attached to the nanoparticle core via cleavable disulfide linkage and non-cleavable carbonylacrylic functionalized thioether linkage. Endosomal escape is quantified by measuring the luminescent signal when they meet together in the cytosol. Nanoparticles with linear polymer core containing 2:1 ratio of DEAEMA:DPAEMA demonstrated five-fold higher endosomal escape with cleavable HiBiT-polymer conjugate compared to those with non-cleavable HiBiT-polymer conjugate. These results suggested that the presence of reducing agents, such as glutathione, in endosomal microenvironment directly impacted the higher endosomal escape observed for the nanoparticles with disulfide-linked HiBiT-polymer conjugates, owing to the potential instability of disulfide linkage within the endosomal microenvironment. These findings indicated that application of more stable linkage for conjugating HiBiT to the nanoparticle core would provide a better understanding of the endosomal escape efficiency of nanoparticles using the SLEEQ assay. However, further studies are required to understand the endosomal escape efficiency of nanoparticles with star polymer core. Together, this work highlights that the design of dual pH-responsive nanoparticles based on charge-shifting polymers and acid-labile linkers, and shows that even subtle changes to the nanoparticle core composition or architecture can have a significant impact on their biological interactions. A greater understanding of how nanoparticle structure influences intracellular therapeutic delivery will pave the way for the design of more efficient and effective drug delivery vehicles in the future.

School of Chemistry - Theses

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