L'activation de molécules inertes telles que les alcanes constitue l'un des défis les plus difficiles en catalyse, du fait de la grande stabilité de la liaison C-H. Pour répondre aux principes de la chimie verte, les méthodes de fonctionnalisation doivent respecter un certain nombre d'exigences, telles que l'utilisation de solvants et de réactifs non toxiques, la réduction des apports énergétiques, en association avec une activité élevée. Afin de satisfaire ces conditions, nous nous sommes dirigés vers l'utilisation d'un système enzymatique. En effet, les liaisons C-H non activées peuvent être fonctionnalisées en conditions douces par des monooxygénases, telles que les cytochromes P450, mais leur activité est relativement faible. Dans le but de disposer de cytochromes P450 plus actifs sur les alcanes, nous décrivons la fusion entre un membre de la famille des CYP153 et un partenaire donneur d'électrons. Cette protéine de fusion a été caractérisée, et ses propriétés catalytiques étudiées. Nous avons montré que la fusion augmente de manière considérable l'activité alcane hydroxylase. Nous avons, dans un second temps, continué d'exploiter le fort potentiel de ce biocatalyseur en tentant de réduire le volume de son site actif par mutagénèse dirigée, en vue de l'hydroxylation des alcanes gazeux, notamment le méthane. Enfin, différentes modifications des conditions réactionnelles nous ont permis d'atteindre une activité non égalée pour l'hydroxylation terminale de l'octane. / Activation of inert molecules such as alkanes is considered as one of the most difficult challenges in catalysis, due to the high stability of the C-H bond. To comply with the principles of green chemistry, functionalization methods must respect multiple requirements, such as the use of non-toxic solvents and reagents, in addition to reducing energy usage whilst maintaining maximal activity. To satisfy these conditions, we decided to focus on the use of an enzymatic system. Indeed, unactivated C-H bonds can be functionalized under mild conditions by monooxygenases, such as cytochrome P450s, but their activity is relatively limited. In order to have cytochrome P450s more active on alkanes, we describe the fusion between a member of the CYP153 family and an electron donor partner. This fusion protein has been characterized and its catalytic properties studied. We have shown that the fusion increases significantly the alkane hydroxylase activity. Our second step was to continue to exploit the potential of this biocatalyst by attempting to reduce the volume of its active site using site-directed mutagenesis for the hydroxylation of gaseous alkanes, including methane. Finally, various modifications of the reaction conditions allowed us to achieve the terminal hydroxylation of octane with a previously unequalled activity.

The selective transformation of carbon-carbon and carbon-hydrogen bonds represents an attractive approach and rapidly developing frontier in synthesis. Benefits include step and atom economy, as well as the ubiquitous presence in organic molecules. Advances to this exciting realm of synthesis are described in this thesis with an emphasis on the development of catalytic, selective reactions under mild conditions. Additionally some applications of the methodologies are demonstrated. In Chapter 1, the first examples of inter-and intramolecular enantioselective conjugate alkenylations employing organostannanes are reported. A chiral, cationic Rh(I)-diene complex catalyzed the enantioselective conjugate addition of alkenylstannanes to benzylidene Meldrum’s acids in moderate enantiomeric ratios and yields. Notably, the cationic and anhydrous conditions required for the asymmetric alkenylation are complementary to existing protocols employing other alkenylmetals. In Chapter 2, a domino, one-pot formation of tetracyclic ketones from benzylidene Meldrum’s acids using Sc(OTf)3 via a [1,5]-hydride shift/cyclization/Friedel-Crafts acylation sequence is described. Respectable yields were obtained in accord with the ability to convert to the spiro-intermediate, and considering the formation of three new bonds: one C-H and two C-C bonds. An intriguing carbon-carbon bond cleavage was also serendipitously discovered as part of a competing reaction pathway. In Chapter 3, the pursuit of novel C-H bond transformations led to the development of non-carbonyl-stabilized rhodium carbenoid Csp3-H insertions. This methodology enabled the rapid synthesis of N-fused indolines and related complex heterocycles from N-aziridinylimines. By using a rhodium carboxamidate catalyst, competing processes were minimized and C-H insertions were found to proceed in moderate to high yields. Also disclosed is an expedient total synthesis of (±)-cryptaustoline, a dibenzopyrrocoline alkaloid, which highlights the methodology. In Chapter 4, the Lewis acid promoted substitution of Meldrum’s acid discovered during the course of the domino reaction was explored in detail. The protocol transforms unstrained quaternary and tertiary benzylic Csp3-Csp3 bonds into Csp3-X bonds (X = C, N, H) and has even shown to be advantageous with regards to synthetic utility over the use of alternative leaving groups for substitutions at quaternary benzylic centers. This reaction has a broad scope both in terms of suitable substrates and nucleophiles with good to excellent yields obtained (typically >90%).

Atoms construct the molecules and molecules construct the material substances (with the exceptions as well, e.g.., metals, where atoms directly construct the material substances). Intermolecular interactions play an important role in most of the branches of sciences, ranging from material sciences to biological sciences. Van der Waals interactions are weak intermolecular interactions while hydrogen bonding varies in strength from weak to strong (1 to 40 kcal/mol). The present work focuses on applying some theoretical methods (ab initio and Atoms in Molecules theory) on these interactions to differentiate them with physically meaningful parameters such as hydrogen bond radii and atoms in molecules theory parameters. 1)Defining and calculating H-bond radii have been done using atoms in molecules theory approach which can explain ruling out the presence or absence of an H-bond in an intermolecular interaction. 2) A blue-shift of 200 cm-1 for a weakly bound complex is unprecedented. Our studies on weakly bound complexes showed the blue-shift of 200 cm-1 for H3C•••CIF and shift has been found to be purely from the mixing of normal modes and not because of an interaction. 3)Methane, a symmetric top molecule can act both as H-bond acceptor and donor. The present work shows that methane is rather a better H-bond acceptor than a donor and all the calculated parameters are in favor of this description. 4) Microwave spectrometer is an ultimate tool (at least at present) for structural characterization of the weakly bound complexes accurately. The rotational spectrum of the weakly bound isotopomer weakly bound complexes accurately. The rotational spectrum of the weakly bound isotopomer 13CC5H6•••Ar, which is a symmetric top and gives only “B” rotational constant. Moreover, the A rotational constant of the complex is the same as the rotational constant for 13CC5H6, which has no dipole moment. C2H2 molecule is an astrophysically important molecule as it is present in asymptotic giant branch and T-type stars (Teff<3000K). Due to its various infrared active vibrational modes, C2H2 is one of the most important sources in cool stars. The production of C2H2 infrared spectroscopic data at high temperature is therefore essential to trace back physical characteristics of these objects and to model the radiative transfer in their envelope. The databases such as “HITRAN”, do not have enough data available for stimulating high temperature spectra. Keeping all these objectives in mind, high temperature emission spectrum of acetylene has been recorded around 3µm region of acetylene.

Η εργασία αυτή αποτελεί τη διπλωματική εργασία που εκπονήθηκε στα πλαίσια του διατμηματικού μεταπτυχιακού προγράμματος “Ιατρική Χηµεία: Σχεδιασμός και Ανάπτυξη Φαρμακευτικών Προϊόντων” του Πανεπιστημίου Πατρών. Στη φύση, η καταλυτική οξείδωση οργανικών μορίων με υψηλή εκλεκτικότητα αποτελεί σημαντικό εργαλείο στη σύνθεση πολύπλοκων φυσικών προϊόντων και επιτυγχάνεται με εξειδικευμένα ένζυμα που έχουν ως βάση κυρίως το χαλκό και το σίδηρο. Αντικείμενο της εργασίας ήταν ο σχεδιασμός και ανάπτυξη πρωτότυπων καταλυτικών συστημάτων οξείδωσης αλειφατικών δεσμών C-H με βάση τον χαλκό που εν δυνάμει προσομοιάζουν τη λειτουργία των βιολογικών συστημάτων. Εξετάστηκε μεθοδικά η σχέση χαλκού-υποκαταστάτη με τις συνθήκες της αντίδρασης σε συνάρτηση με την τόπο-και χημειοεκλεκτικότητα της αντίδρασης. Τα βέλτιστα αποτελέσματα απόδοσης και εκλεκτικότητας στην οξείδωση του κυκλοεξανίου επιτυγχάνονται σε διαλύτη ακετονιτρίλιο ή ακετόνη με νιτρικό ή τριφλικό δισθενή χαλκό σε συνδυασμό με 1,10-φαινανθρολίνη ή 4-άμινο τριαζόλη. Συγκεκριμένα επετεύχθησαν αποδόσεις 25-35% και εκλεκτικότητες Α/Κ 13-32:1. Παράλληλα έγινε σύγκριση με τα state-of-the-art συστήματα που αναφέρονται στη σύγχρονη βιβλιογραφία. Οι εκλεκτικότητες που επετεύχθησαν σε αυτήν την έρευνα είναι οι υψηλότερες που έχουν αναφερθεί όχι μόνο για συστήματα με βάση το χαλκό αλλά και με άλλα μέταλλα. Αντίθετα, τα καταλυτικά αυτά συστήματα δεν φαίνεται να είναι αποτελεσματικά στις οξειδώσεις αλλυλικών και βενζυλικών δεσμών C-H. / This work is the final year’s thesis of the inter-departmental postgraduate program “Medicinal Chemistryː Design and Development of Pharmaceutical Products” of the University of Patras. Nature uses catalytic selective oxidation of C-H bonds in order to construct complex natural products by utilizing specialized enzymes mainly based on copper or iron. The aim of the work is the design and development of novel copper-based catalytic systems capable of C-H oxidation that could mimic the performance of the biological systems. The investigation focused on the interrelationships/dependencies between the type of copper ion and ligand with the reaction conditions in relation to the observed regio- and chemoselectivity. In the oxidation of cyclohexane the best results for yield and chemoselectivity were achieved using 1,10-phenanthroline or 4-amino-1,2,4-triazole as ligands, copper (II) triflate or nitrate as metal sources and acetone or acetonitrile as solvents. Reaction yields of 25-35% and A/K ratios of 13-32 : 1 where achieved and a comparison with state-of-the-art systems from the recent literature was also made. The A/K ratios obtained in this work are the highest reported not only for copper based systems but also for other metals. In contrast, these systems showed no catalytic activity with the weaker allylic or benzylic C-H bonds.

No description available.

The Dong research group is interested in harnessing the power of transition metal catalysis to transform simple molecules and reagents (such as carbon monoxide, hydrogen gas, olefins, and C–H and C–O bonds) into valuable products (such as functionalized heterocycles, chiral carbonyl compounds and natural products). This thesis will describe our continual effort to achieve this goal. Part I describes the Pd-catalyzed functionalization of sp2 and sp3 C–H bonds. Carbon monoxide is used as a stoichiometric reductant in the cyclization of diarylnitroalkenes to afford biologically relevant 3-arylindoles and other N-containing heterocycles with carbon dioxide as the only stoichiometric byproduct. Also, an aryl sulfoxide moiety is shown to direct the arylation of sp3 C–H bonds to afford beta-functionalized amides. Part II describes the Ru-catalyzed sp3 C–O bond activation of alkoxypyridines and related heterocycles. In this transformation, an O- to N-alkyl migratory rearrangement occurs to afford N-alkylated pyridones which are structures found in many natural products and pharmaceutical agents. Part III describes our pursuit of metal-catalyzed asymmetric synthesis. Readily available benzylic bromides are carbonylated with carbon monoxide in alcoholic solvent mixtures. The resulting medicinally relevant 2-arylpropionic esters are obtained with moderate to good enantioselectivities. Preliminary results for the asymmetric hydrogenation of gem-diarylethylenes and novel ligand development are also disclosed. Part IV describes our efforts towards the total synthesis of 6-deoxyerythronolide B. Our retrosynthetic analysis of the macrolide antibiotic involves disconnections at the lactone linkage and between C7 and C8. The two equally complex fragments were prepared via reliable aldol, hydroboration, crotylation and redox chemistry. Rather than the typical macrolactonization method to form the 14-membered ring, we propose an alternative strategy where we plan to cyclize with a metal-catalyzed ring-closing metathesis event. Currently, this step is under investigation by other members in the group.

The Dong research group is interested in harnessing the power of transition metal catalysis to transform simple molecules and reagents (such as carbon monoxide, hydrogen gas, olefins, and C–H and C–O bonds) into valuable products (such as functionalized heterocycles, chiral carbonyl compounds and natural products). This thesis will describe our continual effort to achieve this goal. Part I describes the Pd-catalyzed functionalization of sp2 and sp3 C–H bonds. Carbon monoxide is used as a stoichiometric reductant in the cyclization of diarylnitroalkenes to afford biologically relevant 3-arylindoles and other N-containing heterocycles with carbon dioxide as the only stoichiometric byproduct. Also, an aryl sulfoxide moiety is shown to direct the arylation of sp3 C–H bonds to afford beta-functionalized amides. Part II describes the Ru-catalyzed sp3 C–O bond activation of alkoxypyridines and related heterocycles. In this transformation, an O- to N-alkyl migratory rearrangement occurs to afford N-alkylated pyridones which are structures found in many natural products and pharmaceutical agents. Part III describes our pursuit of metal-catalyzed asymmetric synthesis. Readily available benzylic bromides are carbonylated with carbon monoxide in alcoholic solvent mixtures. The resulting medicinally relevant 2-arylpropionic esters are obtained with moderate to good enantioselectivities. Preliminary results for the asymmetric hydrogenation of gem-diarylethylenes and novel ligand development are also disclosed. Part IV describes our efforts towards the total synthesis of 6-deoxyerythronolide B. Our retrosynthetic analysis of the macrolide antibiotic involves disconnections at the lactone linkage and between C7 and C8. The two equally complex fragments were prepared via reliable aldol, hydroboration, crotylation and redox chemistry. Rather than the typical macrolactonization method to form the 14-membered ring, we propose an alternative strategy where we plan to cyclize with a metal-catalyzed ring-closing metathesis event. Currently, this step is under investigation by other members in the group.

The selective transformation of carbon-carbon and carbon-hydrogen bonds represents an attractive approach and rapidly developing frontier in synthesis. Benefits include step and atom economy, as well as the ubiquitous presence in organic molecules. Advances to this exciting realm of synthesis are described in this thesis with an emphasis on the development of catalytic, selective reactions under mild conditions. Additionally some applications of the methodologies are demonstrated. In Chapter 1, the first examples of inter-and intramolecular enantioselective conjugate alkenylations employing organostannanes are reported. A chiral, cationic Rh(I)-diene complex catalyzed the enantioselective conjugate addition of alkenylstannanes to benzylidene Meldrum’s acids in moderate enantiomeric ratios and yields. Notably, the cationic and anhydrous conditions required for the asymmetric alkenylation are complementary to existing protocols employing other alkenylmetals. In Chapter 2, a domino, one-pot formation of tetracyclic ketones from benzylidene Meldrum’s acids using Sc(OTf)3 via a [1,5]-hydride shift/cyclization/Friedel-Crafts acylation sequence is described. Respectable yields were obtained in accord with the ability to convert to the spiro-intermediate, and considering the formation of three new bonds: one C-H and two C-C bonds. An intriguing carbon-carbon bond cleavage was also serendipitously discovered as part of a competing reaction pathway. In Chapter 3, the pursuit of novel C-H bond transformations led to the development of non-carbonyl-stabilized rhodium carbenoid Csp3-H insertions. This methodology enabled the rapid synthesis of N-fused indolines and related complex heterocycles from N-aziridinylimines. By using a rhodium carboxamidate catalyst, competing processes were minimized and C-H insertions were found to proceed in moderate to high yields. Also disclosed is an expedient total synthesis of (±)-cryptaustoline, a dibenzopyrrocoline alkaloid, which highlights the methodology. In Chapter 4, the Lewis acid promoted substitution of Meldrum’s acid discovered during the course of the domino reaction was explored in detail. The protocol transforms unstrained quaternary and tertiary benzylic Csp3-Csp3 bonds into Csp3-X bonds (X = C, N, H) and has even shown to be advantageous with regards to synthetic utility over the use of alternative leaving groups for substitutions at quaternary benzylic centers. This reaction has a broad scope both in terms of suitable substrates and nucleophiles with good to excellent yields obtained (typically >90%).

No description available.

This thesis examines the interaction of hydrides of the group 13 metals aluminium and gallium with transition metal centres. Furthermore, a gallium-based system is developed which activates a wide range of E-H bonds, with the product of H₂ activation found to act as a catalyst for the reduction of CO₂ to a methanol derivative. Chapter 3 details the synthesis of a number of alane and gallane adducts of expanded-ring N-heterocyclic carbene (NHC) ligands, which are more strongly σ-donating and sterically shielding analogues of classical NHCs. These NHC adducts are found to be apposite for the formation of σ-alane and σ-gallane complexes at group 6 metal carbonyl fragments, which has allowed the characterisation of the first κ² σ-gallane complexes. The attempted formation of a terminally coordinated κ³ σ-alane complex leads instead to the isolation of a novel dinuclear cluster featuring both μ:κ¹,κ¹ and μ:κ²,κ² coordination to Mo(CO)₃ units. The work presented in Chapter 4 probes the interaction of the β-diketiminate stabilised gallane Dipp₂NacNacGaH₂ with transition metal carbonyls. Far from simply mimicking the chemistry of the alane congener Dipp₂NacNacAlH₂, which forms simple κ¹ and κ² σ-alane complexes, the gallane shows a marked propensity towards dehydrogenation and formation of direct M-Ga(I) bonds. This represents a rare mode of reactivity among group 13 hydrides, being unprecedented beyond boron chemistry, and provides a new route to M-Ga bond formation. Experimental and computational investigations of the mechanism suggest that initial Ga-H oxidative addition is facile, and is generally followed by rate-limiting loss of H₂. The reaction of Dipp2NacNacAlH2 with Co₂(CO)₂ is shown to yield an unusual alane complex which displays an unprecedented degree of Al-H activation in a σ-alane complex. Chapter 5 represents an extension of the work described in Chapter 5, investigating the interaction of Dipp₂NacNacMH₂ (M = Al, Ga) with cationic group 9 transition metal fragments supported by ancillary phosphine ligands. While attempts to isolate unsupported, cationic σ-alane complexes prove unsuccessful, Dipp₂NacNacGaH₂ readily binds to cationic rhodium and iridium centres, forming the first cationic σ-gallane complexes as well as cationic gallylene complexes resulting from complete Ga-H oxidative addition. The extent of Ga-H bond activation is shown to be markedly dependent on the nature of the phosphine co-ligands. In particular, a series of rhodium complexes is reported which represents snapshots of the oxidative addition process, from a Rh(I) σ-gallane complex to a Rh(III) gallylene dihydride, with two further complexes which are on the cusp of these two oxidation states. Described in Chapter 6 are the synthesis and reactivity studies of an ambiphilic system, Dipp₂NacNac′Ga(^tBu), featuring a three-coordinate gallium centre supported by a deprotonated NacNac ligand. The combination of this electrophilic gallium centre with the highly nucleophilic exocyclic alkene functionality facilitates the cooperative activation of protic, hydridic and apolar E-H bonds. Accordingly, molecules including H₂, NH₃, H₂S and SiH4 may be cleaved under mild conditions. Moreover, the hydride product of H₂ activation is shown to be a competent catalyst in conjunction with HBpin for the reduction of CO₂ to the methanol derivative MeOBpin.