Green approach to Palladium Cross-Coupling reactions and development of new methodologies based on highly abundant metals

Transition metal catalyzed cross-coupling reactions represent among the most versatile and useful tools in organic synthesis for the carbon-carbon (C-C) bond formation and have a prominent role in both the academic and pharmaceutical segments. Among them, palladium catalyzed cross-coupling reactions are currently the most versatile. In this thesis, the applications, impact and development of green palladium cross-coupling reactions are discussed. Specifically, we discuss the translation of the Twelve Principles of Green Chemistry and their applications in pharmaceutical organometallic chemistry to stimulate the development of cost-effective and sustainable catalytic processes for the synthesis of active pharmaceutical ingredients (API). The Heck-Cassar-Sonogashira (HCS) and the Suzuki-Miyaura (SM) protocols, using HEP/H2O as green mixture and sulfonated phosphine ligands, allowed to recycle and recover the catalyst, always guaranteeing high yields and fast conversion under mild conditions, with aryl iodides, bromides, triflates and chlorides. No catalyst leakage or metal contamination of the final product were observed during the HCS and SM reactions, respecting the very low limits for metal impurities in medicines established by the International Conference of Harmonization Guidelines Q3D (ICH Q3D). In addition, a deep understanding of the reaction mechanism is very important if the final target is to develop efficient protocols that can be applied at industrial level. Experimental and theoretical studies pointed out the presence of two catalytic cycles depending on the counterion, shedding light on the role of base in catalyst reduction and acetylene coordination in the HCS coupling. Finally, the development of a cross-coupling reaction to form aryldifluoronitriles in the presence of copper is discussed, highlighting the importance of inserting fluorine atoms within biological structures and the use of readily available metals such as copper as an alternative to palladium.

Bis-Alkoxycarbonylation And Difunctionalization Of Alkenes Employing Palladium(II) Or Nickel(II) Complexes As Catalysts

Section 1 is focused on the bis-alkoxycarbonylation reaction of olefins, catalyzed by aryl α-diimine/Pd(II) complexes, for the synthesis of succinic acid ester derivatives, important compounds in many industrial fields. The opening chapter (Chapter 1) of this thesis presents an overview of the basic chemistry of organopalladium compounds and carbonylation reactions, focusing on oxidative bis-alkoxycarbonylation processes. In Chapter 2 the results obtained in the bis-alkoxycarbonylation of 1,2-disubstituted olefins are reported. The reaction proceeds under very mild reaction conditions, using an aryl α-diimine/Pd(II) catalyst and p-benzoquinone as oxidant, in the presence of a suitable alcohol. This process proved to be very efficient, selective and diastereospecific and various 2,3-disubstituted succinic esters have been obtained in high yields. In Chapter 3 the first bis-alkoxycarbonylation reaction of acrylic esters and acrylic amides, leading to the synthesis of 2-alkoxycarbonyl and 2-carbamoyl succinates respectively, is reported. Remarkably, the utilized aryl α-diimine/Pd(II) catalyst is able to promote the carbonylation of both the β- and the generally non-reactive α- positions of these alkenes. The proposed catalytic cycle is supported by DFT calculations. Section 2 is mainly focused on the Ni-catalyzed difunctionalization of unactivated alkenes tethered to unstabilized ketones. This reaction allows for a wide range of pharmaceutically useful cyclic architectures to be obtained. Chapter 4 consists of an introduction to the difunctionalization reactions of unactivated olefins. In particular, intramolecular reactions will be discussed in detail. In Chapter 5 the results obtained from the Ni-catalyzed difunctionalization of unactivated alkenes tethered to unstabilized ketones are reported. The reaction proceeds through the formation of a zinc-enolate compound, followed by a cyclization/cross-coupling reaction, which takes place in the presence of a phosphine/Ni(II) complex and an (hetero)aryl electrophile, leading to different cyclic and bicyilc architectures. In Chapter 6, preliminary results concerning the anionic cyclization of zinc enolates tethered to unactivated alkenes are presented.

Photoredox Catalysis and Nucleophilic Organometallic Reagents – Application in Organic Synthesis

The main purpose of my PhD was the combination of the principles of transition metal catalysis with photoredox catalysis. We focused our attention on the development of novel dual catalytic protocols for the functionalization of carbonyl compounds through the generation of transient nucleophilic organometallic species. Specifically, we focused on the development of new methodologies combining photoredox catalysis with titanium and nickel in low oxidation state. Firstly, a Barbier-type allylation of aromatic and aliphatic aldehydes –catalytic in titanium– in the presence of a blue photon-absorbing dye was developed. Parallelly, we were pleased to observe that the developed methodology could also be extended to the propargylation of aldehydes under analogous conditions. After an extensive re–optimization of all the reaction parameters, we developed an enantioselective and diastereoselective pinacol coupling of aromatic aldehydes promoted by non-toxic, cheap and easy to synthetize titanium complexes. The key feature, that allows the complete (dia)stereocontrol played by titanium, is the employment of a red-absorbing organic dye. The tailored (photo)redox properties of the red-absorbing organic dye [nPr–DMQA+][BF4–] promote the selective reduction of Ti(IV) to Ti(III). Moreover, even if the major contribution in dual photoredox and nickel catalysis is devoted to the realization of cross-coupling-type reactions, we wanted to evaluate different possible scenarios. Our focus was on the possibility of exploiting intermediates arising from the oxidative addition of nickel complexes as transient nucleophilic species. The first topic considered regarded the possibility to perform allylation of aldehydes by dual photoredox and nickel catalysis. In the first instance, a non–stereocontrolled version of the reaction was presented. Finally, after a long series of drastic modification of the reaction conditions, a highly enantioselective variant of the protocol was also reported. All the reported methodologies are supported by careful photophysical analysis and, in some cases, computational modelling.

N-Heterocyclic carbene complexes of rhodium: structures, dynamics and catalysis

A series of imidazolium salts of the type [BocNHCH2CH2ImR]X (Boc = t-Bu carbamates; Im = imidazole) (R = Me, X = I, 1a; R = Bn, X = Br, 1b; R = Trityl, X = Cl, 1c) and [BnImR’]X (R’ = Me, X = Br, 1d; R’ = Bn, X = Br, 1e; R’ = Trityl, X = Cl, 1g; R’ = tBu, X = Br, 1h) bearing increasingly bulky substituents were synthetized and characterized. Subsequently, these precursors were employed in the synthesis of silver(I)-N-heterocyclic (NHC) complexes as transmetallating reagents for the preparation of rhodium(I) complexes [RhX(NBD)(NHC)] (NHC = 1-(2-NHBoc-ethyl)-3-R-imidazolin-2-ylidene; X = Cl; R = Me, 4a; R = Bn, 4b; R = Trityl, 4c; X = I, R = Me, 5a; NHC = 1-Bn-3-R’-imidazolin-2-ylidene; X = Cl; R’ = Me, 4d, R’ = Bn, 4e, R’ = Trityl, 4g; R’ = tBu, 4h). VT NMR studies of these complexes revealed a restricted rotation barriers about the metal-carbene bond. While the rotation barriers calculated for the complexes in which R = Me, Bn (4a,b,d,e and 5a) matched the experimental values, this was not true for the complexes 4c,g, bearing a trityl group for which the values are much smaller than the calculated ones. Energy barriers for 4c,g, derived from a line shape simulation, showed a strong dependence on the temperature while for 4h the rotational energy barrier is stopped at room temperature. The catalytic activity of the new rhodium compounds was investigated in the hydrosilylation of terminal alkynes and in the addition of phenylboronic acid to benzaldehyde. The imidazolium salts 1d,e were also employed in the synthesis of new iron(II)-NHC complexes. Finally, during a six-months stay at the University of York a new ligand derived from Norharman was prepared and employed in palladium-mediated cross-coupling.

The coupling between electron transfer and Protein/Solvent Dynamics in Photosynthetic Reaction Centers: Spectroscopic Studies in Amorphous Matrices

We investigated at the molecular level protein/solvent interactions and their relevance in protein function through the use of amorphous matrices at room temperature. As a model protein, we used the bacterial photosynthetic reaction center (RC) of Rhodobacter sphaeroides, a pigment protein complex which catalyzes the light-induced charge separation initiating the conversion of solar into chemical energy. The thermal fluctuations of the RC and its dielectric conformational relaxation following photoexcitation have been probed by analyzing the recombination kinetics of the primary charge-separated (P+QA-) state, using time resolved optical and EPR spectroscopies. We have shown that the RC dynamics coupled to this electron transfer process can be progressively inhibited at room temperature by decreasing the water content of RC films or of RC-trehalose glassy matrices. Extensive dehydration of the amorphous matrices inhibits RC relaxation and interconversion among conformational substates to an extent comparable to that attained at cryogenic temperatures in water-glycerol samples. An isopiestic method has been developed to finely tune the hydration level of the system. We have combined FTIR spectral analysis of the combination and association bands of residual water with differential light-minus-dark FTIR and high-field EPR spectroscopy to gain information on thermodynamics of water sorption, and on structure/dynamics of the residual water molecules, of protein residues and of RC cofactors. The following main conclusions were reached: (i) the RC dynamics is slaved to that of the hydration shell; (ii) in dehydrated trehalose glasses inhibition of protein dynamics is most likely mediated by residual water molecules simultaneously bound to protein residues and sugar molecules at the protein-matrix interface; (iii) the local environment of cofactors is not involved in the conformational dynamics which stabilizes the P+QA-; (iv) this conformational relaxation appears to be rather delocalized over several aminoacidic residues as well as water molecules weakly hydrogen-bonded to the RC.

The photosynthetic bacterial reaction center in native and artificial envirnoments: effects on light-induced electron transfer

In this thesis we focussed on the characterization of the reaction center (RC) protein purified from the photosynthetic bacterium Rhodobacter sphaeroides. In particular, we discussed the effects of native and artificial environment on the light-induced electron transfer processes. The native environment consist of the inner antenna LH1 complex that copurifies with the RC forming the so called core complex, and the lipid phase tightly associated with it. In parallel, we analyzed the role of saccharidic glassy matrices on the interplay between electron transfer processes and internal protein dynamics. As a different artificial matrix, we incorporated the RC protein in a layer-by-layer structure with a twofold aim: to check the behaviour of the protein in such an unusual environment and to test the response of the system to herbicides. By examining the RC in its native environment, we found that the light-induced charge separated state P+QB - is markedly stabilized (by about 40 meV) in the core complex as compared to the RC-only system over a physiological pH range. We also verified that, as compared to the average composition of the membrane, the core complex copurifies with a tightly bound lipid complement of about 90 phospholipid molecules per RC, which is strongly enriched in cardiolipin. In parallel, a large ubiquinone pool was found in association with the core complex, giving rise to a quinone concentration about ten times larger than the average one in the membrane. Moreover, this quinone pool is fully functional, i.e. it is promptly available at the QB site during multiple turnover excitation of the RC. The latter two observations suggest important heterogeneities and anisotropies in the native membranes which can in principle account for the stabilization of the charge separated state in the core complex. The thermodynamic and kinetic parameters obtained in the RC-LH1 complex are very close to those measured in intact membranes, indicating that the electron transfer properties of the RC in vivo are essentially determined by its local environment. The studies performed by incorporating the RC into saccharidic matrices evidenced the relevance of solvent-protein interactions and dynamical coupling in determining the kinetics of electron transfer processes. The usual approach when studying the interplay between internal motions and protein function consists in freezing the degrees of freedom of the protein at cryogenic temperature. We proved that the “trehalose approach” offers distinct advantages with respect to this traditional methodology. We showed, in fact, that the RC conformational dynamics, coupled to specific electron transfer processes, can be modulated by varying the hydration level of the trehalose matrix at room temperature, thus allowing to disentangle solvent from temperature effects. The comparison between different saccharidic matrices has revealed that the structural and dynamical protein-matrix coupling depends strongly upon the sugar. The analyses performed in RCs embedded in polyelectrolyte multilayers (PEM) structures have shown that the electron transfer from QA - to QB, a conformationally gated process extremely sensitive to the RC environment, can be strongly modulated by the hydration level of the matrix, confirming analogous results obtained for this electron transfer reaction in sugar matrices. We found that PEM-RCs are a very stable system, particularly suitable to study the thermodynamics and kinetics of herbicide binding to the QB site. These features make PEM-RC structures quite promising in the development of herbicide biosensors. The studies discussed in the present thesis have shown that, although the effects on electron transfer induced by the native and artificial environments tested are markedly different, they can be described on the basis of a common kinetic model which takes into account the static conformational heterogeneity of the RC and the interconversion between conformational substates. Interestingly, the same distribution of rate constants (i.e. a Gamma distribution function) can describe charge recombination processes in solutions of purified RC, in RC-LH1 complexes, in wet and dry RC-PEM structures and in glassy saccharidic matrices over a wide range of hydration levels. In conclusion, the results obtained for RCs in different physico-chemical environments emphasize the relevance of the structure/dynamics solvent/protein coupling in determining the energetics and the kinetics of electron transfer processes in a membrane protein complex.

Sulfanyl Radical Addition to Alkynes: Revisiting an Old Reaction to Enter the Novel Realms of Green Chemistry, Bioconjugation, and Material Chemistry

In the last decade considerable attention has been devoted to the rewarding use of Green Chemistry in various synthetic processes and applications. Green Chemistry is of special interest in the synthesis of expensive pharmaceutical products, where suitable adoption of “green” reagents and conditions is highly desirable. Our project especially focused in a search for new green radical processes which might also find useful applications in the industry. In particular, we have explored the possible adoption of green solvents in radical Thiol-Ene and Thiol-Yne coupling reactions, which to date have been normally performed in “ordinary” organic solvents such as benzene and toluene, with the primary aim of applying those coupling reactions to the construction of biological substrates. We have additionally tuned adequate reaction conditions which might enable achievement of highly functionalised materials and/or complex bioconjugation via homo/heterosequence. Furthermore, we have performed suitable theoretical studies to gain useful chemical information concerning mechanistic implications of the use of green solvents in the radical Thiol-Yne coupling reactions.

Regiocontrolled Synthesis of Pyrazole Derivatives Through 1,3-Dipolar Cycloaddition Reaction And Synthesis of Helicene-Thiourea based and Polymer Supported Soos's Catalyst for Asymmetric Synthesis

In first part we have developed a simple regiocontrolled protocol of 1,3-DC to get ring fused pyrazole derivatives. These pyrazole derivatives were synthesized using 1,3-DC between nitrile imine and various dipolarophiles such as alkynes, cyclic α,β-ketones, lactones, thiocatones and lactums. The reactions were found to be highly regiospecific. In second part we have discussed about helicene, its properties, synthesis and applications as asymmetric catalyst.Due to inherent chirality, herein we have made an attempt to synthesize the helicene-thiourea based catalyst for asymmetric catalysis. The synthesis involved formation of two key intermediates viz, bromo-phenanthrene 5 and a vinyl-naphthalene 10. The coupling of these two intermediates leads to formation of hexahelicene.

Radiative neutron capture cross section on 238U at the n_TOF CERN facility: a high precision measurement

The aim of this work is to provide a precise and accurate measurement of the 238U(n,gamma) reaction cross-section. This reaction is of fundamental importance for the design calculations of nuclear reactors, governing the behaviour of the reactor core. In particular, fast neutron reactors, which are experiencing a growing interest for their ability to burn radioactive waste, operate in the high energy region of the neutron spectrum. In this energy region inconsistencies between the existing measurements are present up to 15%, and the most recent evaluations disagree each other. In addition, the assessment of nuclear data uncertainty performed for innovative reactor systems shows that the uncertainty in the radiative capture cross-section of 238U should be further reduced to 1-3% in the energy region from 20 eV to 25 keV. To this purpose, addressed by the Nuclear Energy Agency as a priority nuclear data need, complementary experiments, one at the GELINA and two at the n_TOF facility, were scheduled within the ANDES project within the 7th Framework Project of the European Commission. The results of one of the 238U(n,gamma) measurement performed at the n_TOF CERN facility are presented in this work, carried out with a detection system constituted of two liquid scintillators. The very accurate cross section from this work is compared with the results obtained from the other measurement performed at the n_TOF facility, which exploit a different and complementary detection technique. The excellent agreement between the two data-sets points out that they can contribute to the reduction of the cross section uncertainty down to the required 1-3%.