Under the conditions of transfer hydrogenation utilizing chromatographically purified ortho-cyclometallated iridium C,O-benzoate precatalysts, enantioselective carbonyl crotylation and methallylation can be performed in the absence of stoichiometric metallic reagents and stoichiometric chiral modifiers. In the case of carbonyl crotylation, use of a preformed precatalyst rather than an in situ generated catalyst results in lower reaction temperatures, providing generally higher diastereoselectivity and yields. By utilizing a more reactive leaving group in chloride over acetate on our methallyl donor, the inherently shorter lifetime of the olefin π-complex is compensated for, giving our group’s first report of reactivity utilizing 1,1-disubstituted allyl donors. / text

Under the conditions of transfer hydrogenation employing ortho-cyclometallated iridium C,O-benzoate catalysts, two protocols of iterative chain elongation of 1,3-diols to furnish 1,3-polyols were developed. First, one-directional chain elongation employing mono-protected 1,3-diols as starting materials was achieved. In all cases, high levels of catalyst-directed enantioselectivity and diastereoselectivity were observed. Then, double asymmetric allylation of 1,n-glycols to deliver C₂-symmetric adducts with exceptional level of enantioselectivity was devised. Iterative two-directional elongation of 1,3-diols to furnish 1,3-polyols with high level of catalyst-directed diastereoselectivity was then achieved. Implementation of this methodology and other hydrogenative C-C bond formations proved to be effective means for the preparation of a known bryostatin A-ring fragment and the total synthesis of bryostatin 7. / text

This diploma thesis is a study of the potential of heat transfer enhancement in the process of hydrogenation refining of oil. The simulation of the process and the heat-hydraulic analysis of the heat exchanger network are performed using the software tools. Based on the obtained results and the results of the optimization study, a new heat exchanger is placed in the process and its parameters are subject to further calculations. The aim is to study the possibilities of heat transfer enhancement for the newly used heat exchanger and to discuss aspects connected with the use of selected software.

Ce travail traite de la synthèse énantiosélective de composés trifluorométhylés via l’étude de la réaction d’isomérisation rédox d’alcools allyliques trifluorométhylés catalysée par des complexes de ruthénium. Nous avons mis au point la réaction d’isomérisation rédox d’alcools allyliques secondaires β-trifluorométhylés. Une étude du mécanistique réactionnel a mis en évidence que l’étape cinétiquement déterminante de cette réaction pour les substrats β-trifluorométhylés est différente de celle décrite pour les substrats non fluorés, il s’agit de l’étape d’insertion. Cette observation nous a permis de mettre au point une réaction d’isomérisation rédox énantiospécifique permettant un transfert intramoléculaire de chiralité via un processus suprafacial. Cette méthode a été appliquée à la synthèse du (S)-CF3-citronellol. En parallèle, nous avons étudié la réaction tandem : isomérisation rédox – transfert d’hydrogène en partant d’alcools allyliques ou d’énones β-trifluorométhylées permettant l’accès aux alcools saturés correspondants. / This work deals with the enantioselective synthesis of trifluoromethylated compounds via the study of the ruthenium catalyzed redox isomerization reaction of trifluoromethylated allylic alcohols. We have developed optmized conditions for the redox isomerization of β-trifluoromethylated secondary allylic alcohols. A mechanistic study of the reaction revealed that the rate determining step for β-trifluoromethylated substrates is different from that described for the non-fluorinated substrates. This observation allowed us todevelop an enantiospecific redox isomerization reaction with a total transfer of chirality via a suprafacialintramolecular process. This methodology has been applied to thesynthesis of (S)-CF3-citronellol. In parallel, we have studied the tandem reaction : redox isomerization - transfer hydrogenation starting from β-trifluoromethylated allylic alcohols orenones, allowing access to the corresponding saturated alcohols.

The two projects described in this dissertation demonstrate the wide utility of noble metal N-heterocyclic carbene (NHC) complexes. The first project details the design of iridium NHC amino acid complexes for asymmetric transfer hydrogenation (ATH) of prochiral ketones. Iridium(I) bis-NHC complexes were found to undergo oxidative addition with a variety of alpha-amino acids, generating chiral iridium(III) complexes of the form Ir(NHC)2(aa)(H)(X) (aa = amino acid, X = halide). The complexes were screened for ATH of aryl and alkyl ketones, and optimization studies found enantioselectivity in this system was highly sensitive to the reaction temperature, NHC ligand, and amino acid. Incorporation of secondary amino acids was essential to enantioselectivity. Aryl ketones were reduced in high conversion and enantioselectivity when employing the Ir(IMe)2(L-Pro)(H)(I) catalyst in isopropyl alcohol, in some cases giving over 90% ee of the alcohol products. Density functional theory calculations were conducted in order to gain insight into the active catalytic species, and the results suggest that the high enantioselectivity of this system primarily arises from steric effects. The second project details the design of rhodium and iridium NHC piano-stool complexes featuring derivatized tetramethylcyclopentadienyl ligands (Cp*R, R = alkyl or aryl substituent) for antimicrobial applications. Complexes of the form (Cp*R)M(NHC)Cl2 (M = Rh or Ir) were synthesized by transmetallation of the NHC ligand using silver(I) oxide in the presence of the desired noble metal Cp*R dimer. The complexes were screened for biological activity against various bacteria, yeast, and fungi. Many of these compounds were highly active against Mycobacterium smegmatis, displaying minimum inhibitory concentrations (MICs) as low at 0.25 microgram per mL. Analysis of structure-activity relationships found that incorporation of the NHC ligand greatly enhances the antimicrobial properties of rhodium and iridium piano-stool complexes, more so than previously investigated diamine, amino acid, or beta-diketonato ligands. Cytotoxicity studies on one of the rhodium NHC complexes showed this compound was nontoxic towards mammalian cells at low concentrations, which strengthens the potential of these types of compounds as viable drug candidates. / Doctor of Philosophy / This dissertation describes two practical applications of a series of complexes featuring the noble metals rhodium and iridium. In all of these complexes, the metal center is bonded to one or two groups known as N-heterocyclic carbenes (NHCs). The most common structural variant of NHCs are five-membered rings. The metal is usually bonded to a carbon atom on these rings, which is flanked by two nitrogen atoms. Noble metal complexes containing NHCs are widely investigated in contemporary chemical literature for a variety of reactions, primarily because noble metals form exceptionally strong bonds with NHCs, making these complexes very stable. N-Heterocyclic carbene compounds are also fairly easy to synthesize and structurally modify, which allows fine-tuning for specific applications. The first project in this dissertation employed iridium NHC amino acid complexes for the selective production of alcohols, meaning only one structure of the alcohol product is favorably generated. This is an important transformation in the chemical and pharmaceutical industries, which often require the synthesis of highly pure products. These complexes were found to be quite successful for this application on a range of model substrates, in some cases generating as high as 95% of one alcohol product over the other. Product selectivity was found to depend on the specific structure of the NHC compound. The second project investigated the antimicrobial properties of rhodium and iridium NHC complexes. In recent years, the growing threat of antimicrobial resistance against traditional pharmaceuticals has led to an interest in the development of metal-based drugs, which may allow for metal-specific mechanisms of drug action that are not possible for commonly employed antimicrobial agents. These NHC complexes were screened for biological activity against various bacteria, yeast, and fungi. Many of the complexes displayed high activity against Mycobacterium smegmatis, comparable to those displayed by other clinical drugs such as ampicillin or streptomycin. These results were highly encouraging, as Mycobacterium smegmatis often serves as a model to study other mycobacteria.

This dissertation describes the design and synthesis of a series of half-sandwich amino acid complexes of the form), (aa = α-amino carboxylate), and their utility as asymmetric transfer hydrogenation catalysts of ketones. Variation of the metal center, the n-ring, and the aa was used to tune these systems for specific sets of ketones. Upon reaction with homochiral]s, the ligand environment in all of these complexes is pseudotetrahedral, leading to stereogenic metal ions (SM, RM). The addition of another stereogenic center from the amino acid ligand (the carbon, RC or SC;glycine) gives rise to two pairs of diastereomeric complexes. / Ph. D.

Thesis (PhD)--Stellenbosch University, 2015. / ENGLISH ABSTRACT: The synthesis of a range of siloxane functionalized Ru(arene)Cl(N,N) complexes allowing for the synthesis of novel MCM-41 and SBA-15 immobilized ruthenium(II) catalysts, is described in this thesis. Two distinctly different approaches were envisaged to achieve successful heterogenization of these siloxane functionalized complexes. Condensation of the siloxane functionalized complexes, C2.4-C2.6 (siloxane tether attached to imine nitrogen) and C3.5-C3.7 (siloxane tether via the arene ring), with the surface silanols of the synthesized silica support materials MCM-41 and SBA-15, afforded immobilized catalysts IC4.1-IC4.6 (siloxane tether attached to imine nitrogen) and IC4.7-IC4.12 (siloxane tether via the arene ring). Model and siloxane functionalized complexes C2.1-C2.6 were prepared by the reaction of diimine Schiff base ligands L2.1-L2.6 with the [Ru(p-cymene)2Cl2]2 dimer. A second, novel, approach involved the introduction of the siloxane tether on the arene ligand of the complex. Cationic arene functionalized Ru(arene)Cl(N,N) complexes, C3.1-C3.4, were prepared with varying N,N ligands including bipyridine and a range of diimine ligands, with either propyl or diisopropyl(phenyl) substituents at the imine nitrogen (greater steric bulk around the metal center). The reaction of these propanol functionalized complexes with 3-(triethoxysilyl)propyl isocyanate, afforded urethane linked siloxane functionalized complexes C3.5-C3.8, where the siloxane tether is attached to the arene ring of the complex. The complexes were fully characterized by FT-IR spectroscopy, NMR (1H and 13C) spectroscopy, ESI-MS analysis and microanalysis. Suitable crystals for the alcohol functionalized complex C3.1 were obtained and the resultant orange crystals were analyzed by single crystal XRD. The heterogenized catalysts, IC4.1-IC4.12, were characterized by smallangle powder X-ray diffraction, scanning and transmission electron microscopy (SEM and TEM), thermal gravimetric analysis (TGA), inductively coupled plasma optical emission spectroscopy (ICP-OES) and nitrogen adsorption/desorption (BET) surface analysis to name but a few. ICP-OES allowed for direct comparison of the model and immobilized systems during catalysis ensuring that the ruthenium loadings were kept constant. The application of the model complexes C2.1-C2.3 and C3.1-C3.3, as well as their immobilized counterparts, IC4.1-IC4.12, as catalyst precursors in the oxidative cleavage of alkenes (1-octene and styrene), were investigated. The proposed active species for the cleavage reactions was confirmed to be RuO4 (UV-Vis spectroscopy). In general it was observed that at lower conversions, aldehyde was formed as the major product. Increased reaction times resulted in the conversion of the formed aldehyde to the corresponding carboxylic acid. For the oxidative cleavage of 1-octene using the systems with the siloxane tether attached to the imine nitrogen, the immobilized systems outperformed the model systems in all regards. Higher conversions and selectivities of 1-octene towards heptaldehyde were obtained when using immobilized catalysts IC4.1-IC4.6, as compared to their non-immobilized model counterparts (C2.1-C2.3) at similar times. It was found that the immobilized catalysts could be used at ruthenium loadings as low as 0.05 mol %, compared to the model systems where 0.5 mol % ruthenium was required to give favorable results. Complete conversion of 1-octene could be achieved at almost half the time needed when using the model systems as catalyst precursors. The activity of the model systems seems to increase with the increase in steric bulk around the metal center. These model and immobilized systems were also found to cleave styrene affording benzaldehyde in almost quantitative yield in some case (shorter reaction times). The systems, with the siloxane tether via the arene ring, were found to be less active for the cleavage of 1-octene when compared to the above mentioned systems (siloxane tether attached to the imine nitrogen). The immobilized systems IC4.7-IC4.12 performed well compared to their model counterparts, but could not achieve the same conversions at the shorter reaction times as were the case for IC4.1-IC4.6. This lower activity was ascribed to the decreased stability of these systems in solution compared to the above mentioned systems with the tether attached to the imine nitrogen. This was confirmed by monitoring the conversion of the complex (catalyst precursor) to the active species in the absence of substrate (monitored by UV-Vis spectroscopy). It was observed that model complex C3.1 could not be detected in solution after 1 hour, compared to complex C2.2 which was detected in solution even after 24 hours. Experiments were carried out where MCM-41 was added to a solution of model complex C2.2 under typical cleavage reaction conditions. A dramatic increase in the conversion was achieved when compared to a reaction in the absence of MCM-41. An investigation into the effect of the support material on the formation of the expected active species was carried out using UV-Vis spectroscopy. The presence of the active species, RuO4, could be observed at shorter reaction times in the presence of MCM-41. This suggested that the silica support facilitates the formation of the active species from the complex during the reaction, therefore resulting in an increased activity. It was also observed that RuO4 is present in solution in reactions where the immobilized catalyst systems are used after very short reaction times, compared to the prolonged times required for this to occur as is the case for the model systems. Model and immobilized catalysts, C2.1-C2.3 and IC4.1-IC4.6, were also applied as catalysts for the transfer hydrogenation of various ketones. The immobilized systems could be recovered and reused for three consecutive runs before the catalysts became inactive (transfer hydrogenation of acetophenone). Moderate to good conversion were obtained using the immobilized systems, but were found to be less active their model counterparts C2.1-C2.3. / AFRIKAANSE OPSOMMING: Die sintese van `n reeks siloksaan gefunksioneerde Ru(areen)Cl(N,N) komplekse, wat die sintese van nuwe MCM-41 en SBA-15 geimmobiliseerede rutenium(II) katalisatore toelaat, word in hierdie tesis beskryf. Twee ooglopend verskillende metodes is voorgestel om die suksesvolle immobilisering van die siloksaan gefunksioneerde komplekse te bereik. Die kondensasie van die siloksaan gefunksioneerde komplekse, C2.4-C2.6 (siloksaan ketting geheg aan die imien stikstof) en C3.5-C3.7 (siloksaan ketting geheg aan die areen ligand), met die oppervlak silanol groepe van die silika materiale MCM-41 en SBA-15, laat die sintese van geimmobiliseerde katalisatore IC4.1-IC4.6 (siloksaan ketting geheg aan die imien stikstof) en IC4.7-IC4.12 (siloksaan ketting geheg aan die areen ligand) toe. Model en siloksaan gefunksioneerde komplekse C2.6-C2.6 is berei deur die reaksie tussen Schiff basis ligande, L2.1-L2.6, en die [Ru(p-simeen)2Cl2]2 dimeer. `n Tweede, nuwe benadering wat die sintese van komplekse met die siloksaan ketting geheg aan die areen ligand behels, is ook gevolg. Kationiese areen gefunksioneerde Ru(areen)Cl(N,N) komplekse, C3.1-C3.4, is berei deur die N,N ligande rondom die metaal sentrum te wissel vanaf bipiridien tot `n reeks diimien ligande met propiel of diisopropielfeniel substituente by die imien stikstof. Hierdie propanol gefunksioneerde komplekse is met 3-(triëtoksiesiliel)propiel-isosianaat gereageer om sodoende die uretaan gekoppelde siloksaan gefunksioneerde komplekse C3.5-C3.8 op te lewer. Al die komplekse is ten volle gekaraktariseer deur van FT-IR spektroskopie, KMR (1H and 13C) spektroskopie, ESI-MS analise en mikroanalise gebruik te maak. In die geval van model kompleks C3.1, is `n kristalstruktuurbepaling ook uitgevoer. Die heterogene katalisatore, IC4.1- IC4.12, is gekaraktariseer deur poeier X-straaldiffraksie, skandeer- en transmissieelektronmikroskopie, termogravimetriese analise (TGA), induktief gekoppelde plasma optiese emissie spektroskopie (IKP-OES) en BET oppervlak analises, om net `n paar te noem. IKP-OES het ons toegelaat om `n direkte vergelyking te tref tussen die model en geimmobiliseerde sisteme tydens die katalise reaksies. Model komplekse C2.1-C2.3 en C3.1-C3.3, sowel as hul geimmobiliseerde eweknieë IC4.1- IC4.12, is vir die oksidatiewe splyting van alkene (1-okteen en stireen) getoets. Die voorgestelde aktiewe spesie wat tydens hierdie reaksie gevorm word, RuO4, is bevestig deur van UV-Vis spektroskopie gebruik te maak. Oor die algemeen is dit gevind dat aldehied oorheersend gevorm word by laer omsetting. Wanneer die reaksietyd verleng is, is daar gevind dat die aldehied na die ooreenstemmende karboksielsuur omgeskakel is. Wanneer die geimmobiliseerde katalisatore gebruik is tydens die oksidatiewe splitsing van 1-okteen, het die sisteme, met die ketting geheg aan die imien stikstof, deurgangs beter as die model sisteme gevaar. Hoër omskakelings van 1-okteen en hoë selektiwiteite vir heptaldehied is behaal wanneer die geimobiliseerded katalisatore IC4.1-IC4.6 met die nie-geimmobiliseerde model sisteme (C2.1- C2.3) vergelyk is by dieselfde reaksietye. Die geimobiliseerde sisteme kon by rutenium beladings van so laag as 0.05 mol % gebruik word. Dit is in teenstelling met die model sisteme waar 0.5 mol % rutenium nodig was om die reaksie suksesvol te laat plaasvind. Die totale omskakeling van 1-okteen is bereik in die helfte van die tyd wat nodig was wanneer die model sisteme gebruik is. Dit is gevind dat die aktiwiteit van die model sisteme toeneem met `n toename in die steriese grootte van die ligand rondom die metaal. Beide die model en geimmobilseerde sisteme kon ook gebruik word vir die oksidatiewe splyting van stireen. Bensaldehied kon in kwantitiewe opbrengs gevorm word in sommige gevalle. `n Laer aktiwiteit vir die oksidatiewe splyting van 1-okteen is vir die sisteme waar die siloksaan ketting aan die areen ligand geheg is, waargeneem. Hoewel die geimmobiliseerde sisteme IC4.7-IC4.12 beter as hul model eweknieë gevaar het, kon die aktiwiteite wat met IC4.1-IC4.6 bereik is nie geewenaar word nie. Hierdie laer aktiwiteit is toegeskryf aan die verlaagde stabiliteit van dié sisteme in oplossing in vergelyking met IC4.1-IC4.6 (ketting geheg aan die imine stikstof). Die stabiliteit van beide sisteme is getoets deur die omskakeling van die model komplekse (C2.2 en C3.1; katalise voorgangers) na die aktiewe spesie te monitor (UV-Vis spektroskopie). Na 1 uur kon die model kompleks C3.1 nie meer in die oplossing waargeneem word nie. In teenstelling kon model kompleks C2.2 nog selfs na 24 uur in die oplossing bespeur word. Om die rol van die silika materiale tydens die reaksie te ondersoek, is `n eksperiment uitgevoer waar MCM-41 by `n oplossing van kompleks C2.2 gevoeg is. `n Toename in die omskakeling van 1-okteen is waargeneem in vergelyking met `n reaksie waar geen silika teenwoordig was nie. UV-Vis spektroskopie is gebruik om die invloed van die silika op die vorming van die aktiewe spesie te ondersoek. In eksperimente waar MCM-41 teenwoordig was, kon die aktiewe spesie, RuO4, by baie korter reaksietye waargeneem word. Dit wil blyk of die silika materiaal die vorming van die aktiewe spesie vanaf die kompleks aanhelp en sodoende `n toename in die spoed van die reaksie bewerkstellig. RuO4 kon ook by baie korter reaksietye waargeneem word wanneer die geimmobiliseerde sisteme gebruik is. Beide model en geimmobiliseerde sisteme, C2.1-C2.3 en IC4.1-IC4.6, is getoets vir die oordrag hidrogenering van verskilende ketone. Dit was moontlik om die geimmobiliseerde sisteme drie keer te herwin en vir daaropvolgende reaksies te gebruik. Vir die geimmobiliseerde sisteme kon egter slegs gemiddelde omskakelings verkryg word en het swakker gevaar as hul model ekwivalente sisteme, C2.1-C2.3.

<p>This thesis describes the use of kinetic isotope effects, linear free energy relationships and stereochamical studies to distinguish between different mechanistic alternatives and to obtain information about transition state structure.</p><p>In the first part fluorine and deuterium kinetic isotope effects were determined for the base promoted HF elimination from 4-fluoro-4-(4’-nitrophenyl)butane-2-on. During this work a new method for the determination of fluorine kinetic isotope effects was developed. The results from the study demonstrates that the reaction proceeds via an E1cB_ip mechanism.</p><p>In the second part the transition state structure for the S_N2 reaction between ethyl chloride and cyanide ion in DMSO was studied. Kinetic isotope effects for six different positions in the reacting system, both in cyanide and ethyl chloride, were determined. The experimental isotope effects were then compared with the theoretically predicted isotope effects. </p><p>The third part describes the use of Hammett type free-energy relationships and stereochemical evidence to study the mechanism of the copper catalysed alkene aziridination. The results from the study support a model that involves the simultaneous presence of two different copper nitrene intermediates. One which reacts non-stereospecifically via a radical intermediate and one which reacts stereospecifically via a concerted mechanism.</p><p>In the fourth part a mechanistic study of the Ru(aminoalcohol) catalysed transfer hydrogenation of acetophenone in isopropanol is described. Kinetic isotope effects were determined for both proton and hydride transfer. The observation of significant primary deuterium kinetic isotope effects for both proton and hydride transfer support a mechanism where the proton and hydride are transferred simultaneously in a concerted mechanism.</p>

<p>The development of new aza-bicyclic structures with potential applications as ligands synthesised <i>via</i> an aza-Diels-Alder cycloaddition has been studied. The studies are concerning the i) development of large scale aza-Diels-Alder reaction, ii) development of a fast and simple route to bicyclic diamine ligands, iii) development of new aza-Diels-Alder adducts from different dienes, iv) development and application of bicyclic N,P ligands for catalytic Michael additions and v) development of robotized asymmetric transfer hydrogenation reactions.</p><p>i) Development of large-scale aza-Diels-Alder reaction giving up to 110 g pure product, in ordinary laboratory equipment without the need of any flash chromatography.</p><p>ii) Development of a new synthetic route to bicyclic diamine ligands highly useful for asymmetric rearrangement of olefin oxides to allylic alcohols and thereby shortening the ligand synthesis dramatically and moreover providing with a faster access to those ligands.</p><p>iii) Expanding the scope of the aza-Diels-Alder reaction by the use of spirodienes and anthracene as dienes.</p><p>iv) Development and application of a new bidentate ligands for catalytic Michael addition to cyclic enones using 5 mol % ligand giving the product in 71 % ee.</p><p>v) Utilisation of Chemspeed ASW 2000 in catalytic transfer hydrogenation and solving of problems regarding use of highly air sensitive reactions in an automated environment.</p>

This thesis describes the use of kinetic isotope effects, linear free energy relationships and stereochamical studies to distinguish between different mechanistic alternatives and to obtain information about transition state structure. In the first part fluorine and deuterium kinetic isotope effects were determined for the base promoted HF elimination from 4-fluoro-4-(4’-nitrophenyl)butane-2-on. During this work a new method for the determination of fluorine kinetic isotope effects was developed. The results from the study demonstrates that the reaction proceeds via an E1cBip mechanism. In the second part the transition state structure for the SN2 reaction between ethyl chloride and cyanide ion in DMSO was studied. Kinetic isotope effects for six different positions in the reacting system, both in cyanide and ethyl chloride, were determined. The experimental isotope effects were then compared with the theoretically predicted isotope effects. The third part describes the use of Hammett type free-energy relationships and stereochemical evidence to study the mechanism of the copper catalysed alkene aziridination. The results from the study support a model that involves the simultaneous presence of two different copper nitrene intermediates. One which reacts non-stereospecifically via a radical intermediate and one which reacts stereospecifically via a concerted mechanism. In the fourth part a mechanistic study of the Ru(aminoalcohol) catalysed transfer hydrogenation of acetophenone in isopropanol is described. Kinetic isotope effects were determined for both proton and hydride transfer. The observation of significant primary deuterium kinetic isotope effects for both proton and hydride transfer support a mechanism where the proton and hydride are transferred simultaneously in a concerted mechanism.