This PhD thesis is focused on the development of novel carbon(II) and carbon(0) catalysis for organic synthesis. More specifically, the major objective has been to explore and design non-toxic and effective catalysts based on: an unusual Bertrand carbene type, a so-called bis(dialkylamino)cyclopropenylidene (BAC), and the carbodicarbene (CDC) framework; the central carbon atom in these molecules is in the formal low-oxidation state ‘+II’ and ‘0’, respectively. These species may be used in base catalysis or as ligands in metal catalysis, and in the context of frustrated Lewis pair (FLP) or dual catalysis. Prior to catalysis studies, the Lewis basicity of such carbon-based compounds has been assessed with 11B NMR analysis using various boron-based Lewis acids. Boron binding has been detected in all cases with a BAC, thereby confirming its strongly nucleophilic character and decreased steric demand. In contrast, only few ate complexes have been identified with CDCs (or precursors thereof), which means that CDCs may be more suitable for FLP catalysis. A preliminary electrophile binding study with a BAC has provided interesting data, based on which unprecedented aldimine Umpolung may be developed in the future. In the context of organocatalysis, BAC-mediated C–C bond formations between various Michael acceptors and N-tosyl imines have been developed (aza-Morita–Baylis–Hillman chemistry). In addition, C–N or C–Hal bond formations between various Michael acceptors and azodicarboxylates or electrophilic halogen reagents have been developed. The characteristic features of these unprecedented BAC catalyses include low catalyst loading, mild reaction conditions, and broad substrate scopes. Importantly, several novel chiral BACs have been synthesized and characterized, and excellent results have been achieved in BAC-catalysed asymmetric aza-MBH reactions (ee up to 97%). To the best of our knowledge, these data represent the first highly enantioselective BAC catalysis; chiral N-heterocyclic carbenes (NHCs) have proved to be substantially less effective in this context (ee up to 38%). In the same line, BAC-catalysed asymmetric borylations and silylations of Michael acceptors have been developed (preliminary ee up to 69%). These results demonstrate the high potential of the newly developed chiral BACs in asymmetric organocatalysis. Meanwhile, several BAC–gallium and BAC–iron complexes have been synthesized and characterized. These novel complexes may be used in Lewis acid catalysis after appropriate activation of the corresponding metal sites. Finally, the exploration of the catalysis potential of various C(0) compounds, namely CDCs, is still under investigation.

This thesis focuses on the mechanistic investigation of catalytic carbon-carbon σ-bond hydrogenation of hydrocarbons using water as the convenient hydrogen source under neutral conditions by group 9 metalloporphyrins M(por)X. [With diagram] / The benzylic carbon-carbon bond of [2.2]paracyclophane (PCP) was catalytically hydrogenated to give 4,4’-dimethylbibenzyl up to 98% yield using water with 10 mol% M(ttp)X pre-catalyst (ttp = 5,10,15,20-tetratolylporphyrinato dianion, M = Rhᴵᴵᴵ and Irᴵᴵᴵ, X = Me, Bn and ⁱPr) at 200°C in C₆D₆. Deuterium labeling experiments using D₂O supported water as the hydrogen source. Preliminary screening with Coᴵᴵ(ttp) catalyst in polar DMF solvent at 220°C also yielded the hydrogenation product selectively. The role of DMF is proposed to promote the hydrolysis of cobalt(III) porphyrin benzyl intermediates and increase the solubility of H₂O.[With diagram] / Kinetic studies on the stoichiometric benzylic CCA of PCP with Rhᴵᴵ(tmp) metalloradical (tmp = 5,10,15,20-tetramesitylporphyrinato dianion) gave the rate law as rate = k[Rhᴵᴵ(tmp)]²[PCP]. The 2ⁿᵈ order dependence on Rhᴵᴵ(tmp) radical suggests a bi-metalloradical CCA mechanism via a four-centered transition state. [With diagram] / In the iridium catalyzed system, Irᴵᴵᴵ(ttp)H was found to have promoting role in the hydrogenation process. The bi-molecular reductive elimination between Irᴵᴵᴵ(ttp)H and the CCA intermediates speeded up the hydrogenation process. It is estimated that this process gave the hydrogenated alkyl fragment 3 times faster than hydrolysis of the CCA intermediates. [With diagram] / 本論文主要探討在中性反應條件下，利用水作為一個方便的氫來源，以第9族金屬卟啉，M(por)X，催化碳氫化合物中的碳碳單鍵加氫反應的反應機制。 / 在200°C及溶有10 mol% M(ttp)X (M = Rhᴵᴵᴵ 和 Irᴵᴵᴵ，X = Me，Bn和ⁱPr) 預催化劑的氘代苯中，利用水把[2.2]二聚對二甲苯的苄基碳碳鍵進行催化加氫，生成高達98%的4,4’-二甲基聯苄(下稱PCP)。利用氘代水的氘標記實驗支持了氫的來源為水。另一方面，經過以Coᴵᴵ(ttp)催化劑進行了初步篩選後，能在220°C及DMF極性溶濟中使加氫產物選擇性地生成。DMF的作用被提議為促進鈷卟啉苄基的水解及增加了水的溶解度。 / 在進行了Rhᴵᴵ(tmp)與PCP的當量苄基碳碳鍵活化動力學實驗後，得出速率方程rate = k[Rhᴵᴵ(tmp)]²[PCP]。Rhᴵᴵ(tmp)的二級反應級數反映了一個經由四中心過渡態的雙金屬自由基碳碳鍵活化反應機制。 / 在由銥催化的系統中，發現了Irᴵᴵᴵ(ttp)H在加氫過程中的促進作用。Irᴵᴵᴵ(ttp)H與碳碳鍵活化中間體的雙分子還原消除反應把加氫過程加快。根據估計，這個雙分子還原消除反應比碳碳鍵活化中間體的水解要快3倍。 / To, Ching Tat. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2015. / Includes bibliographical references. / Abstracts also in Chinese. / Title from PDF title page (viewed on 14, September, 2016). / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only.

Leung, Chi Yin. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2013. / Includes bibliographical references (leaves 81-89). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstracts also in Chinese.

The following thesis outlines work carried out during the last three years for the development and investigation of methodologies using amides as N- and O- acylating agents. Chapter 1 highlights the range of methodologies and protocols reported in the literature that use amides as precursors for the synthesis of both functionalised amides and esters. The introduction will highlight the range of catalysts and promoters used as well as the scope of the current methodologies. As well as this it will highlight the limitations of the methodologies so emphasising where the following research fits into these areas. Chapter 2 presents the development of a transamidation methodology using zirconocene dichloride as a catalyst. The scope with respect to functional group tolerance is presented as well as the investigations into the mechanism of the reaction. Chapter 3 builds on the research presented in Chapter 2 and details the development of a more catalytically active zirconocene transamidation methodology. By the addition of a catalytic additive the temperature or time required for the reaction to be carried out could be lowered. Investigations into the mechanism were also carried out highlighting the in situ formation of an active catalytic species. Chapter 4 details the development of an operationally simple methodology for the O-acylation of alcohols using amides. Using a catalytic amount scandium triflate the substrate scope of the reaction was explored with a proposed mechanism presented based on activation of the amide.

This thesis describes the development of a more economical catalytic system for the N-alkylation of amines by “borrowing hydrogen” and its application in the synthesis of a variety of amines including the dopamine agonist Piribedil and the antihistamine agents Antergan and Tripelennamine. <b>Chapter 2</b> describes the development of the ruthenium-catalysed N-alkylation of primary amines with primary alcohols by “borrowing hydrogen”. <b>Chapter 3</b> describes the application of the ruthenium-catalysed N-alkylation of secondary amines with primary alcohols by “borrowing hydrogen”. The ruthenium-catalysed synthesis of dimethylamines by “borrowing hydrogen” is also described and a mechanistic proposal for the N-alkylation of alcohols with amines has been proposed. <b>Chapter 4</b> describes the role of amines in pharmaceuticals and the ruthenium-catalysed synthesis of Piribedil, Antergan and Tripelennamine by “borrowing hydrogen”.

Two methods of C-H functionalisation of sp2 C-H bonds via ruthenium catalysis have been developed in this thesis. The first methodology is the preparation of meta-sulfonated heteroaromatics. Individual substrate optimisations were performed on various nitrogen containing heteroaromatics such as 2-phenylpyridine, 1-phenylpyrazole and benzo[h]quinoline. It was discovered that 2-phenylpyridine was the best substrate for C-H sulfonation with aryl sulfonyl chlorides and gave yields of 4 – 63% and provided functional handles allowing for further synthetic manipulations. The second methodology developed is a ruthenium(II) catalysed ortho-C-H acylation of heteroaromatics. Initial optimisation was performed on 2-phenylpyridine with ortho-toluoyl chloride for C-H acylation and it was found tricyclohexylphosphine was the best ligand for this reaction. Unfortunately, the scope of this reaction is limited, as only a couple of aryl acid chlorides were compatible for the acylation of 2-phenylpyridine. This methodology was then applied to 1-phenylpyrazole and demonstrated the first example of C-H acylation of 1-phenylpyrazole with acid chloride as the coupling partner. C-H acylation of 1-phenylpyrazole is more versatile than 2-phenylpyridine, as the reaction scope is much broader. Various aryl and alkyl acid chlorides were compatible for the acylation of 1-phenylpyrazole derivatives and gave yields of 4 – 91%. Sterically hindered acid chlorides provided the higher yields, which is indicative of a steric acceleration during the reductive elimination step. Ruthenium-substrate complexes were synthesised and employed in stoichiometric experiments under the meta-sulfonation and ortho-acylation conditions independently, to attempt to elucidate the mechanistic pathways of these two reactions. 1H NMR spectroscopy on the meta-sulfonations of 1-phenylpyrazole and benzo[h]quinoline complexes indicated the formation of sulfonated ruthenium-substrate complexes, where the sulfone is substituted para to the ruthenium-carbon bond. C-H activation of 1-phenylpyrazole with a ruthenium-phosphine complex was attempted, and found it was difficult to synthesise the C-H activated substrate-ruthenium complex in the presence of phosphine ligands.

Silver nanoparticles (sub 10 nm), supported on, or in, cellulose, have been demonstrated to be well stabilised and immobilised during application in a model continuous reaction: the reduction of 4-nitrophenol (4-NP) to 4-aminophenol with sodium borohydride. The production of these silver nanoparticles (NP), within the cellulose supports, was carried out by either in situ reduction of silver precursors absorbed into the preformed cellulose supports, or, by inclusion of ex situ synthesised NPs (prepared in DMSO solutions) in the dissolution of cellulose and trapping upon subsequent coagulation of cellulose. The effects of NP synthesis method (affecting particle size and agglomeration) and the cellulose morphology and porous structure were examined with respect to the catalytic activity of the materials. The in situ reduction of a silver salt with aqueous NaBH4 solutions (0.03 to 1.0 wt. %) led to tuneable Ag NP sizes with mean diameters of 5 to 11 nm (TEM) and metal loadings of 0.5-1.0 wt. %. The catalytic activity of these samples in the 4-NP reduction reaction (0.05 mM, 0.167 M NaBH4, 30 °C) was demonstrated to increase upon decreasing NP size: TOF values of 22–356 h-1, consistent with a Langmuir-Hinshelwood mechanism. The porous structure of these Ag-cellulose materials (0.2 to 294 m2 g-1) was demonstrated to be variable and dependent on drying treatments of the regenerated cellulose hydrogel. Thermal drying, freeze-drying and critical point drying resulted in materials with different bulk structure and porosity. In turn the different porosities resulted in extremely different catalyst activities, e.g. Ag-cellulose catalyst (0.3 mm disks) thin film, hydrogel and cryogel phases exhibited TOF values of 2, 12 and 178 h-1, respectively. In addition, the NP synthesis could be carried out in either the cellulose hydrogel or cryogel, which led to different extents of Ag NP catalyst stabilisation against agglomeration during the 4-NP reaction and catalyst recovery and recycling. The Ag NPs synthesised in the cryogel cellulose disks were observed to undergo agglomeration (TEM) after use in 4 repeat batch reductions, whilst those NPs synthesised in the hydrogel cellulose, prior to freeze-drying to the final cryogel catalyst material, did not exhibit any agglomeration upon 4 repeat reduction reactions. The ex situ reduction of Ag and Au NPs was carried out by the reduction of AgOAc and Au(OAc)3 by DMSO and variation of the NP synthesis parameters, such as time (10 min – 1h) and temperature (50 – 80 °C), allowed for control of the NP sizes (3 to 6 nm Ag NPs and 4 to 11 nm Au NPs, TEM). It was demonstrated that the addition of the polysaccharide starch (0.42 wt. % in DMSO) allowed for consistent Ag NP size (ca. 4 nm) to be achieved throughout the 8 h synthesis, the starch acting as both the reducing and capping agent, maintaining the small sizes and narrow particle size distributions of the NPs upon aging (72 h). A kinetic model with a bimolecular nucleation step was developed to describe this reduction of the silver acetate by the starch/DMSO system. However, contact of the NPs with solutions of imidazolium ILs, 1-Ethyl-3-methylimidazolium acetate (EmimOAc) and 1-Butyl-3-methylimidazolium chloride (BmimCl) in DMSO, used in the dissolution of cellulose, led to the oxidation of the Ag(0) and Au(0) NPs. Thus, when these NP solutions were mixed in cellulose solutions regeneration by phase inversion with the aim of preparing cellulose/NP composites led to materials with negligible metal loadings (AAS). This oxidation, of the metal NPS, was partially overcome by stabilisation of the starch capped Ag NPs by pre-treatment with cellulose (1:1 mixture of α and MC cellulose). However, the activity of the resulting Ag-cellulose catalyst (0.5 wt. % AAS, 6.7 nm TEM) was much lower than the Ag-cellulose catalysts prepared by in situ reduction of silver in the cellulose hydrogel, despite the comparable NP sizes. This was presumed to be a result of encapsulation of the Ag NPs by the cellulose, leading to a decrease in the accessible surface of the NPs. Finally, the use of Ag NP / cellulose composites, prepared by in situ reduction of silver in cellulose hydrogel beads (0.19 wt. %, 6.4 nm), were demonstrated in the continuous reduction of 4-NP in a packed bed reactor (τ’ 100 g s dm-3). The activation energies of the reactions of 4-NP catalysed by the Ag-cellulose catalyst materials were determined (3.2 to 9.4 kJ mol-1) from Arrhenius plots, which demonstrated that above 20 °C the reaction was likely subject to diffusion limitations in the cellulose beads. The high degree of stabilisation of the Ag NPs against agglomeration imparted by the cellulose support was demonstrated: the rate of reaction was observed to be constant over 120 h, treating 45 L of 4-NP solution, with the catalyst material after use demonstrating no significant leaching of silver, or agglomeration, of NPs (AAS, TEM).

Catalyst-Controlled Divergent C–H Functionalization of Unsymmetrical 2-Aryl Cyclic 1,3-Dicarbonyl Compounds with Alkynes and Alkenes A problem faced within the area of C–H functionalization is achieving siteselectivity when several similar C–H bonds are present within a given compound. One solution to this problem is the development of reactions that employ different catalytic systems to control the required selectivity. Herein, it is shown that such catalyst-controlled selectivity could be achieved on 2-aryl cyclic 1,3-dicarbonyl compounds where there exist two potential, non-adjacent sites for C–H functionalization. Examples demonstrate the palladium- and ruthenium-catalysed oxidative annulations of the 2-aryl cyclic 1,3-dicarbonyl substrates with alkynes, as well as with alkenes, where initial C–H bond cleavage occurs at one of two potential sites, depending on the catalyst used, which give unique products. 1,4-Rhodium(III) Migration in the One-Carbon Oxidative Annulations of 2-Arylphenols, Benzamides, and Benzoic Acids with 1,3-Enynes Oxidative annulations of 2-arylphenols, benzamides, and benzoic acids with alkynes and enynes are precedented and provide a range of heterocyclic products. However, in these examples, either the alkyne or enyne acts as a two-carbon annulation partner, reacting only across the alkynyl moiety. Herein, a more expansive scope of a previously published process in which 1,3-enynes, possessing allylic hydrogen atoms cis to the alkyne, undergo oxidative annulations with the three aforementioned classes of substrates as a one-carbon annulation partner is described. Proposed to occur via the 1,4-migration of a rhodium(III) species, annulated products were formed from a range of 1,3-enynes and substrates possessing a variety of functional groups.

Thesis. 1977. Sc.D.--Massachusetts Institute of Technology. Dept. of Materials Science and Engineering. / MICROFICHE COPY AVAILABLE IN ARCHIVES AND SCIENCE. / Vita. / Includes bibliographical references. / Sc.D.

In heterogeneous catalysis, the phase of a catalytic agent, which is responsible for reducing the activation energy of a reaction, is different from the phase of its reactants or substrates. Often, soluble catalysts are tightly associated with an inert carrier in order to artificially alter their phase. Applying this concept to biocatalysis yields a system in which enzyme molecules are immobilized on a solid support. This often serves to stabilize the enzyme, as well as enhance the recyclability of the enzyme since it is no longer soluble. In this dissertation, two methods of enzyme immobilization are evaluated: adsorption to a solid surface and whole-cell biocatalysis. The latter is then engineered for improved kinetics and functional activity using principles of synthetic biology. Adsorption of a protein to a solid surface is driven by the same thermodynamic factors that are responsible for the folding of a protein. Hydrophobic interactions, ionic interactions, covalent bonding, and weak forces all contribute to minimizing the free energy of a protein, which defines its secondary, tertiary, and quaternary structures. Upon introduction to a surface, these different forces rearrange across the surface of the substrate to minimize the free energy of the system. Many factors influence this behavior, including particle curvature, material properties of the surface, and the stability of the protein. In the preexisting body of work, much of the research performed regarding the effects of thermal stability on adsorption were performed using mutant proteins whose structures were intentionally altered for a range of stabilities. In Chapter 2, we evaluate the effects of thermal stability on adsorption behavior using naturally evolved enzymes from the AKR superfamily, namely AdhD and hAR. These enzymes were selected for their structural homology, but vastly different thermal stabilities. Using these proteins, we demonstrate that the previously held theories of thermostable protein adsorption behavior are not entirely applicable to naturally evolved proteins that are not artificially stabilized. We also propose a modification to the classic 4-state adsorption/desorption model by introducing new pathways and protein states based on our experiments. In addition to physisorption, whole-cell biocatalysis was explored as an enzyme immobilization platform. In general, this can be accomplished by cytosolic expression, periplasmic expression, or surface display. After weighing these options, we chose periplasmic expression in E. coli for our biocatalysts. As for the catalytic component, we selected carbonic anhydrase (CA), a class of Zn+2-binding metalloenzymes that are capable of catalyzing the reversible hydration of CO2. This enzyme was selected for the breadth of applications it can be used for, as well as its ubiquity in nature and extremely fast kinetics. Two isoforms were selected (Cab and Cam) for their respective benefits and were periplasmically expressed using 2 different leader peptides, which we discuss in Chapter 3. The enzyme loading in the periplasm, kinetics, thermal stability, and functional activity are all reported for the resulting whole-cell biocatalysts. We also describe a new method for the measurement of the operational stability of CA-based biocatalysts. Modifications to the whole-cell biocatalysts are described in Chapter 4 and Chapter 5. In Chapter 4, we demonstrate that expression of a viral envelope protein enhances the permeability of the outer membranes of E. coli cells. We characterize this improvement by measuring small-molecule permeance, whole-cell kinetics, and functional activity of the modified biocatalysts. We also quantify this enhancement by applying concepts of porous chemical catalysts to our whole-cells. In doing so, we show improvements in parameters such as the effectiveness factor, Thiele modulus, diffusivity, and permeability. Finally, in Chapter 5 we show enhancement of the functional activity of the whole-cell biocatalysts by displaying small peptides on the outer surfaces of the cells. The modified cells are shown to enhance precipitation of calcium carbonate, a common end product of carbon mineralization. Improved solid formation rates are also reported and possible explanations for these effects are discussed. Overall, this dissertation explores immobilization of enzymes to create heterogeneous biocatalysts. First, the effects of immobilization on enzyme structure, stability, and activity are shown for two different immobilization techniques: adsorption to a solid surface and periplasmic expression in E. coli cells. After characterization, engineering of the whole-cell biocatalysts for improved properties is presented. Finally, future directions for this work are discussed which would advance our understanding of heterogeneous biocatalysts, as well as enhance their utility.