Synthesis, characterization and conformational studies of arylbenzylmaleimides

From the discoveries of Pasteur, stereochemistry has played an increasingly important role in the chemical sciences. In particular conformational study of molecules with axial chirality is object of intense research. Through Dynamic-NMR analysis and simulation of the spectra, the energy rotational barriers value of conformers are obtained. When this barrier is high sufficiently, atropisomeric stable compounds can be reached. They can be separated and used in stereo-synthesis and in packing processes. 3,4-bis-aryl maleimides, in which the aromatic groups are sufficiently bulky, generate atropisomeric stable configurations, that can be isolated at room temperature. The assignment of absolute configurations is performed through ECD analysis and comparison with computational calculations. The biological activities of maleimide derivatives widen the field of atropisomers application also in biological systems.

Synthesis and dynamic study of atropisomeric compounds containing boron-carbon bond

In this thesis we studied the stereodynamic behavior of 1,2-azaborines variously substituted on boron (7a, 7b, 13). Depending on the hindrance of the asymmetric aryl substituent the resulting conformations could be stereolabile or configurationally stable. Through dynamic NMR and lineshape simulation, the energy rotational barriers of the different conformers are obtained. When the barrier is higher than 22-23 kcal/mol stable atropisomers that are fisically separable could be obtained (case of compound 13) and the free activation energy barrier is determinable by kinetic analysis. Absolute configuration of two atropisomers were assigned by comparison between computational calculations and experimental ECD. Isosteric compound 21 is then synthesized in order to compare the rotational barrier around B-Caryl with the one around Cnaphth-Caryl bond.

Atropisomeric xanthines: Synthesis, stereodynamics and absolute configuration

During the thesis period a new class of atropisomeric xanthine derivatives has been studied. We decided to focus our attention on these purine bases because of their various biological activities, that could play an important role in the discovery of new bioactive atropisomers. The synthesized compounds bear an Aryl-N chiral axis in position 1 of the xanthine scaffold, around which the rotation is prevented by the presence of bulky ortho substituents. Through a retro synthetic analysis we synthesized three atropisomeric structures bearing in position 1 of the purine scaffold respectively an o-tolyl, o-nitrophenyl and a 1-naphthyl group. The conformational studies by DFT simulations showed that the interconversion energy barrier between the two available skewed conformations is higher enough to obtain thermally stable atropisomers. After the separation of the atropisomers, the experimental energy of interconversion was investigated by means of kinetic studies following the thermal racemization process using an enantioselective HPLC column. The absolute configuration of each atropisomer was assigned by experimental ECD analysis and TD-DFT simulations of the ECD spectra.

Synthesis, characterization and conformational studies of bis-phenothiazine-aryl-boranes

This thesis project presents a work based on the study of a particular class of amino-boranes, called bis-phenothiazine-aryl-boranes. The peculiarity of these compounds is the N-B-N chemical moiety and their complex conformational behaviour, due to the combination of steric hindrance and conjugation of the B-N bond. Our work is focused on two main products with different symmetry: bis-phenothiazine-2-methylnaphthyl-borane (2b) and bis-phenothiazine-anthracenyl-borane (2c). We firstly focused our attention on an effective way of synthesis, by optimizing both reaction conditions and purification. The products and co-products of interest were then characterized with NMR, mass spectroscopy and X-Ray diffraction on single crystals. The products were eventually analysed through conformational studies, by experimental techniques, such as dynamic NMR and EXSY, and by a theorical approach with DFT calculations.

Computational investigation of a stereoselective synthesis of atropisomeric hydrazides possessing an N–N stereogenic axis

Axially chiral substrates are an interesting and widely studied class of compounds as they can be found in bioactive natural products and are employed as functional materials or as ligands in asymmetric catalytic processes. One branch of this family is the well-known world of the atropisomers. Among them, atropisomeric compounds possessing an N–N stereogenic axis are one truthfully fascinating system but not completely understood yet. In this thesis, we computationally investigated the mechanism of the diastereoselective formation of the N – N chiral axis of a hydrazide under asymmetric phase transfer catalytic conditions. Moreover, during this study, torsional barriers have been calculated for both the reagent and the product at the density functional theory (DFT). These values turned out to suitably match the experimental values and observations. Finally, Electronic Circular Dichroism (ECD) spectra have been simulated in order to assign the chiral absolute configuration to the products.

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

The research performed in the framework of this Master Thesis has been directly inspired by the recent work of an organometallic research group led by Professor Maria Cristina Cassani on a topic related to the structures, dynamics and catalytic activity of N-heterocyclic carbene-amide rhodium(I) complexes1. A series of [BocNHCH2CH2ImR]X (R = Me, X = I, 1a’; R = Bz, X = Br, 1b’; R = trityl, X = Cl, 1c’) amide-functionalized imidazolium salts bearing increasingly bulky N-alkyl substituents were synthetized and characterized. Subsequently, these organic precursors were employed in the synthesis of silver(I) complexes as intermediate compounds on a way to rhodium(I) complexes [Rh(NBD)X(NHC)] (NHC = 1-(2-NHBoc-ethyl)-3-R-imidazolin-2-ylidene; X = Cl, R = Me (3a’), R = Bz (3b’), R = trityl (3c’); X = I, R = Me (4a’)). VT NMR studies of these complexes revealed a restricted rotation barriers about the metal-carbene bond. However, while the rotation barriers calculated for the complexes in which R = Me, Bz (3a’,b’ and 4a) matched the experimental values, this was not true in the trityl case 3c’, where the experimental value was very similar to that obtained for compound 3b’ and much smaller with respect to the calculated one. In addition, the energy barrier derived for 3c’ from line shape simulation showed a strong dependence on the temperature, while the barriers measured for 3a’,b’ did not show this effect. In view of these results and in order to establish the reasons for the previously found inconsistency between calculated and experimental thermodynamic data, the first objective of this master thesis was the preparation of a series of rhodium(I) complexes [Rh(NBD)X(NHC)] (NHC = 1-benzyl-3-R-imidazolin-2-ylidene; X = Cl, R = Me, Bz, trityl, tBu), containing the benzyl substituent as a chiral probe, followed by full characterization. The second objective of this work was to investigate the catalytic activity of the new rhodium compounds in the hydrosilylation of terminal alkynes for comparison purposes with the reported complexes. Another purpose of this work was to employ the prepared N-heterocyclic ligands in the synthesis of iron(II)-NHC complexes.

Beyond simple proton transfer processes: domino reactions between 4-substituted indoles and nitroethene as a new gateway to ergot alkaloids

The multimodal biology activity of ergot alkaloids is known by humankind since middle ages. Synthetically modified ergot alkaloids are used for the treatment of various medical conditions. Despite the great progress in organic syntheses, the total synthesis of ergot alkaloids remains a great challenge due to the complexity of their polycyclic structure with multiple stereogenic centres. This project has developed a new domino reaction between indoles bearing a Michael acceptor at the 4 position and nitroethene, leading to potential ergot alkaloid precursors in highly enantioenriched form. The reaction was optimised and applied to a large variety of substrate with good results. Even if unfortunately all attempts to further modify the obtained polycyclic structure failed, it was found a reaction able to produce the diastereoisomer of the polycyclic product in excellent yields. The compounds synthetized were characterized by NMR and ESIMS analysis confirming the structure and their enantiomeric excess was determined by chiral stationary phase HPLC. The mechanism of the reaction was evaluated by DFT calculations, showing the formation of a key bicoordinated nitronate intermediate, and fully accounting for the results observed with all substrates. The relative and absolute configuration of the adducts were determined by a combination of NMR, ECD and computational methods.

Aspetti meccanicistici della coordinazione di [(PPh3)3Ru(CO)(H2)] com Timina Acido Acetico

Ruthenium complexes have proved to exhibit antineoplastic activity related to the interaction of metal ion with DNA nucleobases. It is indeed of great interest to provide new insights on theses cutting-edge studies, such as the identification of distinct coordinative modes of DNA binding sites. During the investigation on the reaction between [(PPh3)3Ru(CO)(H)2], 1, and the Thymine Acetic Acid (THA) as model for nucleobases, we identified an unstable monohapto hydride acetate complex 2, which rapidly evolves into elusive intermediates whose nature was evidenced by NMR spectra and DFT calculations. We obtained crystals of [(PPh3)2Ru(CO)(k1-THA)(k2-THA)] 17, and [Ru(CO)(PPh3)2(k2-N,O)-[THA(A)];(k1-O)[THA(B)]2 18, phosphine ligands assuming cis conformation. The thesis deals on the analogue reactions of 1 with acetic acid by varying different parameters and operating conditions. The reaction yields to the hydride dihapto-acetate [(PPh3)2RuH(CO)(k2-Ac)] 8 through the related meridian monohapto, by releasing of phosphine ligand. However, the reaction yields a mixture of compounds, in which the dihapto hydride complex 8 is prevailing in any cases and does not provide any disclosure for the proposed mechanistic aspects. The reaction with two equivalents of acetic acid, affords the complex [(PPh3)2Ru(CO)(k1-Ac)(k2-Ac)] 11, exhibiting mutual trans:cis locations in 2:1 ratio for the phosphine. Such evidence agrees with the results obtained DFT calculations in vacuo, whereas it is in contrast with those obtained with the THA. Therefore we can inferred that the products obtained from the latter reaction is intermolecularly ruled by the hydrogen binding interactions between the functions [-NH•••(O)C-] in the two coordinated thymine ligands.

Synthesis, Characterization and Conformational Studies of Modified Carbazole-bis-aryl-boranes

During this project we have synthetized different compounds belonging to the class of amino-boranes for the study of bis-aryl-B=N system. We have decided to keep unchanged the aryl components and change only the amine to observe the effect of that on the B=N bond. The used amines are modified carbazoles with functional groups chosen to amplify or disempower the steric and the conjugation effect. We have found that the evaluation of steric barrier was possible studying the gearing aryls rotation around the C-B bonds, while the conjugation barrier is instead given by the energy needed to break the formal double bond B=N and allow the amine rotation. The work started with a proposed synthesis, improved for every reaction, then the products are characterized by NMR, fluorometric spectroscopy, mass spectrometry and X-Ray diffraction on single crystal. The following study on rotational energy barrier was possible theoretically through DFT calculation and experimentally with techniques like Dynamic NMR and EXSY. The fluorometric analysis was done for the study of the solvatochromic propriety of the products.

Determinazione delle barriere rotazionali di nuovi atropisomeri N-N: confronto tra metodi DFT e sperimentali.

Theoretical DFT calculations on rotational barriers of tetrasubstituted hydrazines were performed in order to synthesize new enantioenriched atropoisomers with chiral N-N axis. The molecules studied were chosen to be subsequently synthesized through asymmetric organocatalysis. New atropoisomers with chiral N-N axis were synthesized through organocatalysis methods via enamine or phase transfer. Cinchona alkaloid derivatives were used as catalysts. HPLC analyzes show that the three new synthesized molecules are atropoisomers at room temperature. Using an asymmetric procedure to synthesize the molecules studied, it was possible to generate enantiomeric excesses that remained unchanged for more than three weeks. The experimental rotational barrier of one of the three synthesized compounds was calculated. The experimental energy barrier at 25°C (ΔG^≠=25,7 kcal/mol) was lower than the DFT calculations and with a tendency to increase with temperature, due to a negative reaction entropy.

Synthesis and characterization of fluorescent atropoisomeric bis-arylboryl-carbazoles

This thesis project presents a work based on the study of bis-arylboryl-carbazoles a particular class of aminoboranes. The peculiarity of these compounds is the -B=N+ chemical moiety and their conformational behaviour coming from the combination of steric constrain and conjugation of the B-N bond. Our work is focused on three products: 9-(mesityl(naphthalen-1-yl)boraneyl)-9H-carbazole 1a, 9-(mesityl(2-methylnaphthalen-1-yl)boraneyl)-9H-carbazole 1b and 9-(anthracen-9-yl(mesityl)boraneyl)-9H-carbazole 1c. We firstly focused our attention on the synthesis optimizing conditions. Then the products were synthetized and characterized with NMR. The products were eventually analysed through conformational studies, by a theoretical approach with DFT calculations and by experimental techniques, such as standard kinetic and EXSY. In the end of this work the products were characterized through fluorescence studies both by DFT, TD-DFT calculations and experimentally by emission spectroscopy.

Sea organisms as a source of collagen-derived polymers for skin tissue engineering applications

Advanced therapies combating acute and chronic skin wounds are likely to be brought about using our knowledge of regenerative medicine coupled with appropriately tissue engineered skin substitutes. At the present time, there are no models of an artificial skin that completely replicate normal uninjured skin and they are usually accompanied by fibrotic reactions that result in the production of a scar. Natural biopolymers such as collagen have been a lot investigated as potential source of biomaterial for skin replacement in Tissue Engineering. Collagens are the most abundant high molecular weight proteins in both invertebrate and vertebrate organisms, including mammals, and possess mainly a structural role in connective tissues. From this, they have been elected as one of the key biological materials in tissue regeneration approaches, as skin tissue engineering. In addition, industry is constantly searching for new natural sources of collagen and upgraded methodologies for their production. The most common sources are skin and bone from bovine and porcine origin. However, these last carry high risk of bovine spongiform encephalopathy or transmissible spongiform encephalopathy and immunogenic responses. On the other hand, the increase of jellyfish has led us to consider this marine organism as potential collagen source for tissue engineering applications. In the present study, novel form of acid and pepsin soluble collagen were extracted from dried Rhopilema hispidum jellyfish species in an effort to obtain an alternative and safer collagen. We studied different methods of collagen purification (tissues and experimental procedures). The best collagen yield was obtained using pepsin extraction method (34.16 mg collagen/g of tissue). The isolated collagen was characterized by SDS-polyacrylamide gel electrophoresis and circular dichroism spectroscopy.

Towards the kinetic resolution of mechanically planar chiral rotaxanes

In this work, we reported the synthesis and characterization of two [2]rotaxanes endowed with a central ammonium group and two triazolium recognition stations on either side, acting as complexation sites for a dibenzo-24-crown-8 ether macrocycle. These mechanically interlocked architectures were obtained through the interlocking of a functionalized achiral macrocycle with Cs symmetry (where the symmetry element is a mirror plane corresponding to plane of the ring) and a C∞v symmetric axle (where a mirror plane and a C∞ principal axis are aligned along the axle length). We took advantage of the reversible acid/base triggered molecular shuttling of the ring between two lateral triazolium units to switch the rotaxanes between prochiral and mechanically planar chiral forms, which exists as two rapidly-interconverting co-conformers. We exploited the reactivity of the central amino group to attach an optically pure chiral substituent, with the goal of demonstrating the enantiomeric nature of the co-conformers and to obtain a non-zero diastereomeric excess in the resulting diastereomeric products through a dynamic kinetic resolution. To this end, two enantiopure reagents were chosen that could perform clean and fast reaction with amines: a sulfonyl chloride and an acyl chloride. Only the acyl chloride successfully produced an amide in high yield with the deprotonated rotaxane. The group added to the central amine station acted as a stopper against the shuttling of the macrocycle along the axis, thus preventing the fast interconversion of the two mechanically planar enantiomers. We analysed the results through static and dynamic NMR spectroscopic techniques by varying temperature and solvent used. Indeed, the presence of diastereomers was recorded alongside the configurational isomers resulting from the slow rotation of the CN-CO bond of the amide moiety, thus paving the way for a dynamic kinetic resolution.

Theoretical and experimental study on the role of benzoquinone in the Guerbet reaction catalyzed by a ruthenium complex

The benzoquinone was found as an effective co-catalyst in the ruthenium/NaOEt-catalyzed Guerbet reaction. The co-catalyst behavior has therefore been investigated through experimental and computational methods. The reaction products distribution shows that the reaction speed is improved by the benzoquinone supplement since the beginning of the process, having a minimal effect on the selectivity toward alcoholic species. DFT calculations were performed to investigate two hypotheses for the kinetic effects: i) a hydrogen storage mechanism or ii) a basic co-catalysis of 4-hydroxiphenolate. The most promising results were found for the latter hypothesis, where a new mixed mechanism for the aldol condensation step of the Guerbet process involves the hydroquinone (i.e. the reduced form of benzoquinone) as proton source instead of ethanol. This mechanism was found to be energetically more favorable than an aldol condensation in absence of additive, suggesting that the hydroquinone derived from benzoquinone could be the key species affecting the kinetics of the overall process. To verify this theoretical hypothesis, new phenol derivatives were tested as additives in the Guerbet reaction. The outcomes confirmed that an aromatic acid (stronger than ethanol) could improve the reaction kinetics. Lastly, theoretical products distributions were simulated and compared to the experimental one, using the DFT computations to build the kinetic models.

13C NMR of a single molecule magnet: analysis of pseudocontact shifts and residual dipolar couplings

Paramagnetic triple decker complexes of lanthanides are promising Single Molecule Magnets (SMMs), with many potential uses. Some of them show preferable relaxation behavior, which enables the recording of well resolved NMR spectra. These axially symmetric complexes are also strongly magnetically anisotropic, and this property can be described with the axial component of the magnetic susceptibility tensor, χa. For triple decker complexes with phthalocyanine based ligands, the Fermi˗contact contribution is small. Hence, together with the axial symmetry, the experimental chemical shifts in 1H and 13C NMR spectra can be modeled easily by considering pseudocontact and orbital shifts alone. This results in the determination of the χa value, which is also responsible for molecular alignment and consequently for the observation of residual dipolar couplings (RDCs). A detailed analysis of the experimental 1H-13C and 1H-1H couplings revealed that contributions from RDCs (positive and negative) and from dynamic frequency shifts (negative for all observed couplings) have to be considered. Whilst the pseudocontact shifts depend on the average positions of 1H and 13C nuclei relative to the lanthanide ions, the RDCs are related to the mobility of nuclei they correspond to. This phenomenon allows for the measurement of the internal mobility of the various groups in the SMMs.