Dipodal Ferrocene Derivatives for Nanostructured Redox-Functionalised Surfaces

Self-assembled monolayers (SAMs) on solid surfaces are of great current interest in science and nanotechnology. This thesis describes the preparation of several symmetrically 1,1’-substituted ferrocene derivatives that contain anchoring groups suitable for chemisorption on gold and may give rise to SAMs with electrochemically switchable properties. The binding groups are isocyano (-NC), isothiocyanato (-NCS), phosphanyl (-PPh2), thioether (-SR) and thienyl. In the context of SAM fabrication, isothiocyanates and phosphanes are adsorbate systems which, surprisingly, have remained essentially unexplored. SAMs on gold have been fabricated with the adsorbates from solution and investigated primarily by X-ray photoelectron spectroscopy and near-edge X-ray absorption fine structure spectroscopy. The results of these analytical investigations are presented and discussed in matters of the film quality and possible binding modes. The quality of self-assembled monolayers fabricated from 1,1’-diisocyanoferrocene and 1,1’-diisothiocyanatoferrocene turned out to be superior to that of films based on the other adsorbate species investigated. Films of those absorbates as well as of dppf afforded well-defined SAMs of good quality. All other films of this study based on sulfur containing anchoring groups exhibit chemical inhomogeneity and low orientational order of the film constituents and therefore failed to give rise to well-defined SAMs. Surface coordination chemistry is naturally related to molecular coordination chemistry. Since all SAMs described in this thesis were prepared on gold (111) surfaces, the ferrocene-based ligands of this study have been investigated in their ability for complexation towards gold(I). The sulfur-based ferrocene ligands [fc(SR)2] failed to give stable gold(I) complexes. In contrast, 1,1’-diisocyanoferrocene (1) proved to be an excellent ligand for the complexation of gold(I). Several complexes were prepared and characterised utilising a series of gold(I) acetylides. These complexes show interesting structural motifs in the solid state, since intramolecular aurophilic interactions lead to a parallel orientation of the isocyano moieties, combined with an antiparallel alignment of neighbouring units. The reaction of 1 with the gold(I) acetylide [Au(C≡C–Fc)]n turned out to be very unusual, since the two chemically equivalent isocyano groups undergo a different reaction. One group shows an ordinary coordination and the other one undergoes an extraordinary 1,1-insertion into the Au-C bond. As a sideline of the research of this thesis several ferrocene derivatives have been tested for their suitability for potential surface reactions. Copper(I) mediated 1,3-dipolar cycloadditions of azidoferrocene derivatives with terminal alkynes appeared very promising in this context, but failed to a certain extent in terms of ‘click’ chemistry, since the formation of the triazoles depended on the strict exclusion of oxygen and moisture and yields were only moderate. Staudinger reactions between dppf and azidoferrocene derivatives were also tested. The nucleophilic additions of secondary amines to 1,1’-diisothiocyanatoferrocene led to the respective thiourea derivatives in quantitative yields.

1,3-Dipolar cycloadditions to unsymmetrical ketone-derived chiral stabilized azomethine ylides: strategies for the synthesis of highly substituted amino acids

We report herein, the first generation of unsymmetrical ketone-derived chiral stabilized azomethine ylides. Intrairiolecular and intermolecular cycloaddition strategies have been utilized to synthesize both an enantiornerically pure bicyclic proline derivative and an enantionierically pure beta-hydroxy-alpha-amino acid.

Azide 1,3-dipolar cycloadditions to N-propynoyl and N-propenoyl (5R)-5-phenylmorpholin-2-one: diastereocontrolled aziridine formation

N-Propynoyl (5R)-5-phenylmorpholin-2-one undergoes nonregioselective cycloaddition with aromatic azides to furnish mixtures of the corresponding triazoles, whereas N-propenoyl (5R)-5-phenylmorpholin-2-one reacts to furnish the corresponding diastereoisomerically pure aziridines in moderate to good yields, presumably via the intermediate triazolines.

Sequential ring-closing metathesis and nitrone cycloaddition on glucose-derived substrates: a divergent approach to analogues of spiroannulated carbanucleosides and conformationally locked nucleosides

The carbohydrate-derived substrate 3-C-allyl-1,2: 5,6-di-O-isopropylidene-alpha-D-allofuranose was judiciously manipulated for preparing suitable synthons, which could be converted to a variety of isoxazolidino-spirocycles and -tricycles through the application of ring-closing metathesis (RCM) and intramolecular nitrone cycloaddition (INC) reactions. Cleavage of the isoxazolidine rings of some of these derivatives by tranfer hydrogenolysis followed by coupling of the generated amino functionalities with 5-amino-4,6-dichloropyrimidine furnished the corresponding chloropyrimidine nucleosides, which were elaborated to spiroannulated carbanucleosides and conformationally locked bicyclo[2.2.1] heptane/ oxa-bicyclo[3.2.1]octane nucleosides. However, use of higher temperature for the cyclization of one of the chloropyrimidines led to the dimethylaminopurine analogue as a sole product, formed via nucleophilic displacement of the chloro group by dimethylamine generated from DMF.

The energy landscape for solvent dynamics in electron transfer reactions: A minimalist model

Energy fluctuations of a solute molecule embedded in a polar solvent are investigated to depict the energy landscape for solvation dynamics. The system is modeled by a charged molecule surrounded by two layers of solvent dipolar molecules with simple rotational dynamics. Individual solvent molecules are treated as simple dipoles that can point toward or away from the central charge (Ising spins). Single-spin-flip Monte Carlo kinetics simulations are carried out in a two-dimensional lattice for different central charges, radii of outer shell, and temperatures. By analyzing the density of states as a function of energy and temperatures, we have determined the existence of multiple freezing transitions. Each of them can be associated with the freezing of a different layer of the solvent. (C) 2002 American Institute of Physics.

Exploring the intrinsic polar [4?+?2+] cycloaddition reactivity of gaseous carbosulfonium and carboxonium ions

Gas-phase reactions of model carbosulfonium ions (CH3-S+?=?CH2; CH3CH2-S+?=?CH2 and Ph-S+?=?CH2) and an O-analogue carboxonium ion (CH3-O+?=?CH2) with acyclic (isoprene, 1,3-butadiene, methyl vinyl ketone) and cyclic (1,3-cyclohexadiene, thiophene, furan) conjugated dienes were systematically investigated by pentaquadrupole mass spectrometry. As corroborated by B3LYP/6-311?G(d,p) calculations, the carbosulfonium ions first react at large extents with the dienes forming adducts via simple addition. The nascent adducts, depending on their stability and internal energy, react further via two competitive channels: (1) in reactions with acyclic dienes via cyclization that yields formally [4?+?2+] cycloadducts, or (2) in reactions with the cyclic dienes via dissociation by HSR loss that yields methylenation (net CH+ transfer) products. In great contrast to its S-analogues, CH3-O+?=?CH2 (as well as C2H5-O+?=?CH2 and Ph-O+?=?CH2 in reactions with isoprene) forms little or no adduct and proton transfer is the dominant reaction channel. Isomerization to more acidic protonated aldehydes in the course of reaction seems to be the most plausible cause of the contrasting reactivity of carboxonium ions. The CH2?=?CH-O+?=?CH2 ion forms an abundant [4?+?2+] cycloadduct with isoprene, but similar to the behavior of such alpha,beta-unsaturated carboxonium ions in solution, seems to occur across the C?=?C bond. Copyright (c) 2012 John Wiley & Sons, Ltd.

Enantioselective Reactions Promoted by Organocatalytic Species From The Natural Chiral Pool

During the course of my Ph.D. in the laboratories directed by Prof. Alfredo Ricci at the Department of Organic Chemistry “A. Mangini” of the University of Bologna, I was involved in the study and the application of a number of organocatalytic systems, all coming from the natural chiral pool. The first part of this thesis will be devoted to new homogeneous organocatalytic reactions promoted by Cinchona alkaloid-based organocatalysts. Quinine based catalysts were found to be a very effective catalyst for Diels-Alder reactions involving 3-vinylindoles. Excellent results in terms of yields and enantioselectivities were achieved, outlining also a remarkable organocatalytic operational mode mimicking enzymatic catalysis. The same reaction with 2-vinylindoles showed a completely different behaviour resulting in an unusual resolution-type process. The asymmetric formal [3+2] cycloaddition with in situ generated N-carbamoyl nitrones using Cinchona-derived quaternary ammonium salts as versatile catalysts under phase transfer conditions, outlines another application in organocatalysis of this class of alkaloids. During the seven months stage in the Prof. Helma Wennemers’ group at the Department of Chemistry of the University of Basel (Switzerland) I have been involved in organocatalysis promoted by oligopeptides. My contribution regarded the 1,4-addition reaction of aldehydes to nitroolefins. In the work performed at the Department of Organic Chemistry “A. Mangini” of the University of Bologna, in collaboration with the ‘Institut Charles Gerhardt-Montpellier, of Montpellier (France) the possibility of performing for the first time heterogeneous organocatalysis by using a natural polysaccharide biopolymer as the source of chirality was disclosed. With chitosan, derived from deacetylation of chitin, a highly enantioselective heterogeneous organocatalytic aldol reaction could be performed. The use of an eco-friendly medium such as water, the recyclability of the catalytic specie and the renewable nature of the polysaccharide are assets of this new approach in organocatalysis and open interesting perspectives for the use of biopolymers.

Synthese von Carbolinen durch übergangsmetall-katalysierte [2+2+2]-Cycloaddition von Alkinen und Nitrilen: Ein neuer Weg zur Totalsynthese von Lavendamycin

Carboline sind eine große Gruppe von natürlich vorkommenden Alkaloiden, die eine tricyclische Pyrido[b]indol-Ringstruktur gemeinsam habe. Das breite Spektrum biologischer Eigenschaften dieser Verbindungsklasse macht sie zu einem interessanten Syntheseziel. Die größte Herausforderung in der Darstellung von Carbolinen ist die regioselektive Funktionalisierung an den aromatischen Positionen. Im Rahmen dieser Arbeit konnte ein A ABC-Zugang zu beta- und gamma-Carbolinen entwickelt werden, dessen Schlüsselschritt der Aufbau des Carbolin-Gerüsts durch eine übergangsmetall-katalysierte [2+2+2]-Cycloaddition von 1,6-Diin-Einheiten und Nitrilen ist. Die benötigten Diin-Einheiten wurden in wenigen Schritten ausgehend von 2-Iodanilin durch eine Reaktionssequenz aus Sonogashira-Reaktion mit terminalen Alkinen, N-Tosylierung und N-Ethinylierung mit Alkinyliodonium-Salzen synthetisiert. Eine flexible Funktionalisierung dieser Diine wurde durch palladium-katalysierte sp2-sp-Kreuzkupplungsreaktionen der terminalen Alkine mit Aryl- und Alkenylhalogeniden erreicht. Cp*RuCl- und [Rh(cod)2]BF4/BINAP-katalysierte [2+2+2]-Cycloadditionen der 1,6-Diine mit elektronenarmen Nitrilen lieferte in hoher Regioselektivität beta- oder gamma-Carboline. In Übereinstimmung mit literaturbekannten übergangsmetall-katalysierten [2+2+2]-Cycloadditionen konnte dabei eine starke Abhängigkeit von sterischen und elektronischen Faktoren beobachtet werden. Um das Potential dieser Methode zu demonstrieren, wurde der Einsatz der [2+2+2]-Cycloaddition in Totalsynthese von Lavendamycin untersucht. Lavendamycin, ein aus Bakterien stammendes Chinochinolin-substituiertes beta-Carbolin mit antimikrobieller und signifikanter Antitumor-Aktivität, wurde ausgehend von Hydrochinon und 2-Iodanilin in 14 Schritten und in einer Gesamtausbeute von 29% dargestellt.

Nuovi complessi alchinil tetrazolici di iridio(III) e renio(I): Sintesi, reattività e proprietà fotofisiche.

In this experimental thesis, two luminescent Ir(III) and Re(I) complexes which have a terminal alkynyl group on the tetrazole ligand were prepared. The aim was to use them as building blocks, in order to synthesize more complex structures. We explored two simple reactions: the first one was a coupling, for the formation of Ir(III)/Au(III) and Re(I)/Au(III) hetero binuclear complexes, and the second was a 1,3-dipolar Cu(I)-catalyzed “Click” cycloaddition, between the terminal alkyne and azide. The synthesized products were characterized through photophysical analysis, evaluating how the photoemissive properties of these substrates were affected by the formation of more complex structures. In questo lavoro di tesi sperimentale sono stati preparati due complessi luminescenti di Ir(III) e Re(I) che presentano un alchino terminale sul legante tetrazolico. Lo scopo è stato quello di utilizzarli come building blocks per la sintesi di strutture più complesse. Sono state esplorate due semplici reazioni: la prima di coupling, per la formazione di complessi etero binucleari Ir(III)/Au(III) e Re(I)/Au(III), e la seconda di “click”, ossia una cicloaddizione 1,3-dipolare Cu(I) catalizzata tra l’alchino terminale e un’azide. I prodotti sintetizzati sono stati caratterizzati attraverso analisi fotofisiche, valutando come le proprietà fotoemissive di questi substrati siano influenzate in seguito alla formazione di strutture più complesse.

Enantioselective 1,3-dipolar cycloadditions of azlactones and electrophilic alkenes catalyzed by dimeric BinapAuTFA complexes

Glycine-derived azlactones react with maleimides using (S)- or (R)-dimeric BinapAuTFA complexes affording the corresponding cycloadducts in good yields and high enantioselections (up to 99% ee). The intermediate carboxylic acids are treated with trimethylsilyldiazomethane and isolated as Δ¹-pyrroline methyl esters. These cycloadducts are transformed into exo-proline derivatives by reduction with NaBH3CN in acidic media. On the other hand, N-benzoylalanine-derived oxazolone reacts with tert-butyl acrylate providing the cycloadduct with the ester group at the 3-position with a trans-relative configuration with respect to the methyl ester group.

Asymmetric 1,3-Dipolar Cycloadditons of Stabilized Azomethine Ylides with Nitroalkenes

This review highlights the biological importance of many polysubstituted nitro-prolines and -pyrrolidines. Their preparation using asymmetric 1,3-dipolar cycloadditions of azomethine ylides with nitroalkenes using diastereoselective and enantioselective strategies is described remarking the scope and main features of each one.

1,3-Dipolar cycloadditions of azomethine imines

Azomethine imines are considered 1,3-dipoles of the aza-allyl type which are transient intermediates and should be generated in situ but can also be stable and isolable compounds. They react with electron-rich and electron-poor olefins as well as with acetylenic compounds and allenoates mainly by a [3 + 2] cycloaddition but they can also take part in [3 + 3], [4 + 3], [3 + 2 + 2] and [5 + 3] with different dipolarophiles. These 1,3-dipolar cycloadditions (1,3-DC) can be performed not only under thermal or microwave conditions but also using metallo- and organocatalytic systems. In recent years enantiocatalyzed 1,3-dipolar cycloadditions have been extensively considered and applied to the synthesis of a great variety of dinitrogenated heterocycles with biological activity. Acyclic azomethine imines derived from mono and disubstituted hydrazones could be generated by prototropy under heating or by using Lewis or Brønsted acids to give, after [3 + 2] cycloadditions, pyrazolidines and pyrazolines. Cyclic azomethine imines, incorporating a C–N bond in a ring, such as isoquinolinium imides are the most widely used dipoles in normal and inverse-electron demand 1,3-DC allowing the synthesis of tetrahydro-, dihydro- and unsaturated pyrazolo[1,5-a]isoquinolines in racemic and enantioenriched forms with interesting biological activity. Pyridinium and quinolinium imides give the corresponding pyrazolopyridines and indazolo[3,2-a]isoquinolines, respectively. In the case of cyclic azomethine imines with an N–N bond incorporated into a ring, N-alkylidene-3-oxo-pyrazolidinium ylides are the most popular stable and isolated dipoles able to form dinitrogen-fused saturated and unsaturated pyrazolopyrazolones as racemic or enantiomerically enriched compounds present in many pharmaceuticals, agrochemicals and other useful chemicals.

Mannich-Type reactions in the Gas-Phase: the addition of Enol Silanes to cyclic N-Acyliminium Ions

The intrinsic gas-phase reactivity of cyclic N-acyliminium ions in Mannich-type reactions with the parent enol silane, vinyloxytrimethylsilane, has been investigated by double- and triple-stage pentaquadrupole mass spectrometric experiments. Remarkably distinct reactivities are observed for cyclic N-acyliminium ions bearing either endocyclic or exocyclic carbonyl groups. NH-Acyliminium ions with endocyclic carbonyl groups locked in s-trans forms participate in a novel tandem N-acyliminium ion reaction:  the nascent adduct formed by simple addition is unstable and rearranges by intramolecular trimethylsilyl cation shift to the ring nitrogen, and an acetaldehyde enol molecule is eliminated. An NSi(CH3)3-acyliminium ion is formed, and this intermediate ion reacts with a second molecule of vinyloxytrimethylsilane by simple addition to form a stable acyclic adduct. N-Acyl and N,N-diacyliminium ions with endocyclic carbonyl groups, for which the s-cis conformation is favored, react distinctively by mono polar [4+ + 2] cycloaddition yielding stable, ressonance-stabilized cycloadducts. Product ions were isolated via mass-selection and structurally characterized by triple-stage mass spectrometric experiments. B3LYP/6-311G(d,p) calculations corroborate the proposed reaction mechanisms.

Synthesis of thioenol ether functionalized cyclooctyne and its orthogonal cycloaddition sequence

In this work, the synthesis of a new bifunctionalized cyclooctyne for a possible layer by layer surface functionalization is presented. The main objective is to find a more stable molecule than the literature known methyl enol ether substituted cyclooctyne. Accordingly, the two target functionalities are an internal alkyne group and a vinyl methyl sulfide group. The synthesis was achieved in 9 steps and consists first of all in the preparation of an aldehyde starting from 1,5-cyclooctadiene with a cyclopropanation reaction followed by a reduction and the SWERN oxidation to an aldehyde. The new functionality was introduced by exploiting the WITTIG reaction. For the alkyne group a bromination followed by a double elimination gave good results. The reactivity of the new molecule was tested using a sequential application of SPAAC and iEDDA reactions, comparing it with the cyclooctyne functionalized with a methyl enol ether. Concerning the comparison of both compounds the sulfur ether is significantly slower and therefore more stable. It will be tested in the future for surface functionalization from the KOERT group.

Fine Needle Aspiration Cytology In The Diagnosis Of Perioral Adverse Reactions To Cosmetic Dermal Fillers.

Facial cosmetic procedures are increasingly requested, and dermal filler materials have been widely used as a nonsurgical option since the 1980s. However, injectable fillers have been implicated in local adverse reactions. Therefore, the aim of this article was to describe the use of fine needle aspiration cytology (FNAC) in the diagnosis of foreign-body reactions to the perioral injection of dermal fillers. A 69-year-old woman presented with a painful nodule on her right nasolabial fold. Intraoral FNAC was performed, and cytologic smears were examined under optical and polarized light microscopy, showing birefringent microspheres, confirming the diagnosis of an adverse reaction caused by polymethyl methacrylate filler. FNAC is a less invasive method to confirm the diagnosis of adverse reactions caused by perioral cosmetic dermal fillers.