Acqua: solvente elettivo in Organocatalisi e Biocatalisi

Water is a safe, harmless, and environmentally benign solvent. From an eco-sustainable chemistry perspective, the use of water instead of organic solvent is preferred to decrease environmental contamination. Moreover, water has unique physical and chemical properties, such as high dielectric constant and high cohesive energy density compared to most organic solvents. The different interactions between water and substrates, make water an interesting candidate as a solvent or co-solvent from an industrial and laboratory perspective. In this regard, organic reactions in aqueous media are of current interest. In addition, from practical and synthetic standpoints, a great advantage of using water is immediately evident, since it does not require any preliminary drying process. This thesis was found on this aspect of chemical research, with particular attention to the mechanisms which control organo and bio-catalysis outcome. The first part of the study was focused on the aldol reaction. In particular, for the first time it has been analyzed for the first time the stereoselectivity of the condensation reaction between 3-pyridincarbaldehyde and the cyclohexanone, catalyzed by morpholine and 4-tertbutyldimethylsiloxyproline, using water as sole solvent. This interest has resulted in countless works appeared in the literature concerning the use of proline derivatives as effective catalysts in organic aqueous environment. These studies showed good enantio and diastereoselectivities but they did not present an in depth study of the reaction mechanism. The analysis of the products diastereomeric ratios through the Eyring equation allowed to compare the activation parameters (ΔΔH≠ and ΔΔS≠) of the diastereomeric reaction paths, and to compare the different type of catalysis. While morpholine showed constant diasteromeric ratio at all temperatures, the O(TBS)-L-proline, showed a non-linear Eyring diagram, with two linear trends and the presence of an inversion temperature (Tinv) at 53 ° C, which denotes the presence of solvation effects by water. A pH-dependent study allowed to identify two different reaction mechanisms, and in the case of O(TBS)-L-proline, to ensure the formation of an enaminic species, as a keyelement in the stereoselective process. Moreover, it has been studied the possibility of using the 6- aminopenicillanic acid (6-APA) as amino acid-type catalyst for aldol condensation between cyclohexanone and aromatic aldehydes. A detailed analysis of the catalyst regarding its behavior in different organic solvents and pH, allowed to prove its potential as a candidate for green catalysis. Best results were obtained in neat conditions, where 6-APA proved to be an effective catalyst in terms of yields. The catalyst performance in terms of enantio- and diastereo-selectivity, was impaired by the competition between two different catalytic mechanisms: one via imine-enamine mechanism and one via a Bronsted-acid catalysis. The last part of the thesis was dedicated to the enzymatic catalysis, with particular attention to the use of an enzyme belonging to the class of alcohol dehydrogenase, the Horse Liver Alcohol Dehydrogenase (HLADH) which was selected and used in the enantioselective reduction of aldehydes to enantiopure arylpropylic alcohols. This enzyme has showed an excellent responsiveness to this type of aldehydes and a good tolerance toward organic solvents. Moreover, the fast keto-enolic equilibrium of this class of aldehydes that induce the stereocentre racemization, allows the dynamic-kinetic resolution (DKR) to give the enantiopure alcohol. By analyzing the different reaction parameters, especially the pH and the amount of enzyme, and adding a small percentage of organic solvent, it was possible to control all the parameters involved in the reaction. The excellent enatioselectivity of HLADH along with the DKR of arylpropionic aldehydes, allowed to obtain the corresponding alcohols in quantitative yields and with an optical purity ranging from 64% to >99%.

Synthetic and mechanistic investigation of new radical processes: reaction of organic azides with group-XIII Lewis acids

Dichloroindium hydride revealed to be a valid alternative to tributyltin hydride for radical reduction of organic (alkyl, aryl, acyl, solfonyl) azides. The new approach entails mild reaction conditions and provides high yields of the corresponding amines and amides, also showing high degrees of selectivity. The system dichloroindium hydride / azides can be utilised in fivemembered ring closures of g-azidonitriles, as a new source of aminyl radicals for the attractive synthesis of interesting amidine compounds in the absence of both toxic reagents and tedious purification procedures. Allylindium dichloride seems a good substitute for dichloroindium hydride for generation of indium centred radicals under photolytic conditions, since it allows allylation of electrophilic azides (e.g. phenylsulfonyl azide) and halogen or ester δ-substituted azides, the latter through a 1,5-H transfer rearrangement mechanism. Evidences of the radical nature of the reactions mechanism were provided by ESR spectroscopy, furthermore the same technique, allowed to discover that the reaction of azides with indium trichloride and other group XIII Lewis acids, in particular gallium trichloride, gives rise to strongly coloured, persistent paramagnetic species, whose structure is consistent with the radical cation of the head-to-tail dimer of the aniline corresponding to the starting azide.

New materials for electrochemiluminescence

The study of electrochemiluminescence (ECL) involves photophysical and electrochemical aspects. Excited states are populated by an electrical stimulus. The most important applications are in the diagnostic field where a number of different biologically-relevant molecules (e.g. proteins and nucleic acids) can be recognized and quantified with a sensitivity and specificity previously not reachable. As a matter of fact the electrochemistry, differently to the classic techniques as fluorescence and chemiluminescence, allows to control the excited state generation spatially and temporally. The two research visits into A. J. Bard electrochemistry laboratories were priceless. Dr. Bard has been one of ECL pioneers, the first to introduce the technique and the one who discovered in 1972 the surprising emission of Ru(bpy)3 2+. I consider necessary to thank by now my supervisors Massimo and Francesco for their help and for giving me the great opportunity to know this unique science man that made me feel enthusiastic. I will never be grateful enough… Considering that the experimental techniques of ECL did not changed significantly in these last years the most convenient research direction has been the developing of materials with new or improved properties. In Chapter I the basics concepts and mechanisms of ECL are introduced so that the successive experiments can be easily understood. In the final paragraph the scopes of the thesis are briefly described. In Chapter II by starting from ECL experimental apparatus of Dr. Bard’s laboratories the design, assembly and preliminary tests of the new Bologna instrument are carefully described. The instrument assembly required to work hard but resulted in the introduction of the new technique in our labs by allowing the continuation of the ECL studies began in Texas. In Chapter III are described the results of electrochemical and ECL studies performed on new synthesized Ru(II) complexes containing tetrazolate based ligands. ECL emission has been investigated in solution and in solid thin films. The effect of the chemical protonation of the tetrazolate ring on ECL emission has been also investigated evidencing the possibility of a catalytic effect (generation of molecular hydrogen) of one of the complexes in organic media. Finally, after a series of preliminary studies on ECL emission in acqueous buffers, the direct interaction with calf thymus DNA of some complexes has been tested by ECL and photoluminescence (PL) titration. In Chapter IV different Ir(III) complexes have been characterized electrochemically and photophysically (ECL and PL). Some complexes were already well-known in literature for their high quantum efficiency whereas the remaining were new synthesized compounds containing tetrazolate based ligands analogous to those investigated in Chapt. III. During the tests on a halogenated complex was unexpectedly evidenced the possibility to follow the kinetics of an electro-induced chemical reaction by using ECL signal. In the last chapter (V) the possibility to use mono-use silicon chips electrodes as ECL analitycal devices is under investigation. The chapter begins by describing the chip structure and materials then a signal reproducibility study and geometry optimization is carried on by using two different complexes. In the following paragraphs is reported in detail the synthesis of an ECL label based on Ru(bpy)3 2+ and the chip functionalization by using a lipoic acid SAM and the same label. After some preliminary characterizations (mass spectroscopy TOF) has been demonstrated that by mean of a simple and fast ECL measurement it’s possible to confirm the presence of the coupling product SAM-label into the chip with a very high sensitivity. No signal was detected from the same system by using photoluminescence.

New routes to enantioenriched substances through small organic molecules

In this thesis we will disclose the results obtained from the diastereoisomeric salt formation (n salt, p salt and p1,n1 salt) between non-racemic trans-chrysanthemic acid (trans-ChA) and pure enantiomers of threo-2-dimethylamino-1-phenyl-1,3-propanediol (DMPP). The occurrence of p1,n1 salt formation can have profound effects on enantiomer separation of scalemic (non-racemic) mixtures. This phenomenon when accompanied by substrate self-association impedes the complete recovery of the major enantiomer through formation of an inescapable racemate cage. A synthetic sequence for the asymmetric synthesis of bicyclo[3.2.0]heptanones and bicyclo[3.2.0]hept-3-en-6-ones through a cycloaddition strategy is reported. The fundamental step is a [2+2]-cycloaddition of an enantiopure amide derived from the reaction between a set of acids and an oxazolidinone as the chiral auxiliary. The inter- and intramolecular cycloaddition of in situ-generated keteniminium salts gives bicycles with a good enantioselection. A key intermediate of Iloprost, a chemically stable and biologically active mimic of prostacyclin PGI2 is synthesized following a ‘green approach’. An example of simple optical resolution of this racemic intermediate involving the diastereoisomeric salt formation is described.

Transformations of bridging ligands in diiron complexes: unconventional routes to new functionalized multisite bound organic frames

The main scope of this Ph.D. thesis has concerned the possible transformations of bridging ligands in diiron complexes, in order to explore unconventional routes to the synthesis of new functionalized multisite bound organic frames. The results achieved during the Ph.D. can be summarized in the following points: 1) We have extended the assembling between small unsaturated molecules and bridging carbyne ligands in diiron complexes to other species. In particular, we have investigated the coupling between olefins and thiocarbyne, leading to the synthesis of thioallylidene bridging diiron complexes. Then, we have extended the study to the coupling between olefins and aminocarbyne. This result shows that the coupling between activated olefins and heteroatom substituted bridging carbynes has a general character. 2) As we have shown, the coupling of bridging alkylidyne ligands with alkynes and alkenes provides excellent routes to the synthesis of bridging C3 hydrocarbyl ligands. As a possible extension of these results we have examined the synthesis of C4 bridging frames through the combination of bridging alkylidynes with allenes. Also in this case the reaction has a general character. 3) Diiron complexes bearing bridging functionalized C3 organic frames display the presence of donor atoms, such as N and S, potentially able to coordinate unsaturated metal fragments. Thus, we have studied the possibility for these systems to act as ‘organometallic ligands’, in particular towards Pd and Rh. 4) The possibility of releasing the organic frame from the bridging coordination appears particularly appealing in the direction of a metal-assisted organic synthesis. Within this field, we have investigated the possibility of involving the C3 bridging ligand in cycloaddition reactions with alkynes, with the aim of generating variously functionalized five-membered cycles. The [3+2] cyclization does not lead to the complete release of the organic fragment but rather it produces its transformation into a cyclopentadienyl ring, which remains coordinated to one Fe atom. This result introduces a new approach to the formation of polyfunctionalised ferrocenes. 5) Furthermore, I have spent a research period of about six months at the Department of Inorganic Chemistry of the Barcelona University, under the supervision of Prof. Concepción López, with the aim of studying the chemistry of polydentate ferrocenyl ligands and their use in organometallic synthesis.

Microwave-Mediated Hetero Diels-Alder reaction: Synthesis of biologically active compounds

Heterocyclic compounds represent almost two-thirds of all the known organic compounds: they are widely distributed in nature and play a key role in a huge number of biologically important molecules including some of the most significant for human beings. A powerful tool for the synthesis of such compounds is the hetero Diels-Alder reaction (HDA), that involve a [4+2] cycloaddition reaction between heterodienes and suitable dienophiles. Among heterodienes to be used in such six-membered heterocyclic construction strategy, 3-trialkylsilyloxy-2-aza-1,3-dienes (Fig 1) has been demonstrated particularly attractive. In this thesis work, HDA reactions between 2-azadienes and carbonylic and/or olefinic dienophiles, are described. Moreover, substitution of conventional heating by the corresponding dielectric heating as been explored in the frame of Microwave-Assisted-Organic-Synthesis (MAOS) which constitutes an up-to-grade research field of great interest both from an academic and industrial point of view. Reaction of the azadiene 1 (Fig 1) will be described using as dienophiles carbonyl compounds as aldehyde and ketones. The six-membered adducts thus obtained (Scheme 1) have been elaborated to biologically active compounds like 1,3-aminols which constitutes the scaffold for a wide range of drugs (Prozac®, Duloxetine, Venlafaxine) with large applications in the treatment of severe diseases of nervous central system (NCS). Scheme 1 The reaction provides the formation of three new stereogenic centres (C-2; C-5; C-6). The diastereoselective outcome of these reactions has been deeply investigated by the use of various combination of achiral and chiral azadienes and aliphatic, aromatic or heteroaromatic aldehydes. The same approach, basically, has been used in the synthesis of piperidin-2-one scaffold substituting the carbonyl dienophile with an electron poor olefin. Scheme 2 As a matter of fact, this scaffold is present in a very large number of natural substances and, more interesting, is a required scaffold for an huge variety of biologically active compounds. Activated olefins bearing one or two sulfone groups, were choose as dienophiles both for the intrinsic characteristic flexibility of the “sulfone group” which may be easily removed or elaborated to more complex decorations of the heterocyclic ring, and for the electron poor property of this dienophiles which makes the resulting HDA reaction of the type “normal electron demand”. Synthesis of natural compounds like racemic (±)-Anabasine (alkaloid of Tobacco’s leaves) and (R)- and (S)-Conhydrine (alkaloid of Conium Maculatum’s seeds and leaves) and its congeners, are described (Fig 2).

Chemical characterization of atmospheric secondary organic aerosol of biogenic and anthropogenic origin

The main objective of this thesis was the chemical characterization of synthetic secondary organic aerosol (SOA) produced from atmospherically relevant anthropogenic and biogenic VOCs during reaction chamber experiments. In parallel, the resulting chemical features of these laboratory-SOA were used to interpret the composition of ambient samples of atmospheric fine particulate matter collected at several sites in Europe, in order to determine the fraction of ambient aerosol organic mass accounted for by biogenic and anthropogenic SOA.

Innovative Homogeneous and Heterogeneous Systems for Electrochemically Generated Luminescence Investigations: Towards One-Dimensional ECL

My research PhD work is focused on the Electrochemically Generated Luminescence (ECL) investigation of several different homogeneous and heterogeneous systems. ECL is a redox induced emission, a process whereby species, generated at electrodes, undergo a high-energy electron transfer reaction to form excited states that emit light. Since its first application, the ECL technique has become a very powerful analytical tool and has widely been used in biosensor transduction. ECL presents an intrinsically low noise and high sensitivity; moreover, the electrochemical generation of the excited state prevents scattering of the light source: for all these characteristics, it is an elective technique for ultrasensitive immunoassay detection. The majority of ECL systems involve species in solution where the emission occurs in the diffusion layer near to the electrode surface. However, over the past few years, an intense research has been focused on the ECL generated from species constrained on the electrode surface. The aim of my work is to study the behavior of ECL-generating molecular systems upon the progressive increase of their spatial constraints, that is, passing from isolated species in solution, to fluorophores embedded within a polymeric film and, finally, to patterned surfaces bearing “one-dimensional” emitting spots. In order to describe these trends, I use different “dimensions” to indicate the different classes of compounds. My thesis was mostly developed in the electrochemistry group of Bologna with the supervision of Prof Francesco Paolucci and Dr Massimo Marcaccio. With their help and also thanks to their long experience in the molecular and supramolecular ECL fields and in the surface investigations using scanning probe microscopy techniques, I was able to obtain the results herein described. Moreover, during my research work, I have established a new collaboration with the group of Nanobiotechnology of Prof. Robert Forster (Dublin City University) where I spent a research period. Prof. Forster has a broad experience in the biomedical field, especially he focuses his research on film surfaces biosensor based on the ECL transduction. This thesis can be divided into three sections described as follows: (i) in the fist section, homogeneous molecular and supramolecular ECL-active systems, either organic or inorganic species (i.e., corannulene, dendrimers and iridium metal complex), are described. Driving force for this kind of studies includes the search for new luminophores that display on one hand higher ECL efficiencies and on the other simple mechanisms for modulating intensity and energy of their emission in view of their effective use in bioconjugation applications. (ii) in the second section, the investigation of some heterogeneous ECL systems is reported. Redox polymers comprising inorganic luminophores were described. In such a context, a new conducting platform, based on carbon nanotubes, was developed aimed to accomplish both the binding of a biological molecule and its electronic wiring to the electrode. This is an essential step for the ECL application in the field of biosensors. (iii) in the third section, different patterns were produced on the electrode surface using a Scanning Electrochemical Microscopy. I developed a new methods for locally functionalizing an inert surface and reacting this surface with a luminescent probe. In this way, I successfully obtained a locally ECL active platform for multi-array application.

Advanced SPM studies on the growth of ultrathin films of organic semiconductors at metal and dielectric interfaces

Many studies on the morphology, molecular orientation, device performance, substrate nature and growth parameter dependence have been carried out since the proposal of Sexithiophene (6T) for organic electronics [ ] However, these studies were mostly performed on films thicker than 20nm and without specifically addressing the relationship between morphology and molecular orientation within the nano and micro structures of ultrathin films of 0-3 monolayers. In 2004, the observation that in OFETs only the first few monolayers at the interface in contact with the gate insulator contribute to the charge transport [ ], underlined the importance to study submonolayer films and their evolution up to a few monolayers of thickness with appropriate experimental techniques. We present here a detailed Non-contact Atomic Force Microscopy and Scanning Tunneling Microscopy study on various substrates aiming at the investigation of growth mechanisms. Most reported similar studies are performed on ideal metals in UHV. However it is important to investigate the details of organic film growth on less ideal and even technological surfaces and device testpatterns. The present work addresses the growth of ultra thin organic films in-situ and quasi real-time by NC-AFM. An organic effusion cell is installed to evaporate the organic material directly onto the SPM sample scanning stage.

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.

Study of thiabendazole resistance and volatile organic compounds production of Penicillium expansum strains

The years of excessive use of thiabendazole to control Penicillium expansum has induced the development of resistance. Sensitivity of fourty eight strains collected from orchards and packinghouses in Emilia Romagna to pure and commercial TBZ was determined in vitro on TBZ amended medium (400μg/mL). Out of 48 strains, 35 were thiabendazole-sensitive (S) and 13 were thiabendazole-resistant (R). Microtiter assay adapted to P. expansum, showed EC50 values ranging from 54 to 320 μg/mL for ten TBZ-resistant strains. At the highest dose (50 μg/mL), resistant strains growth was not inhibited and the reported MICs value were >1000 μg/mL. Therefore, preliminary screening combined with microtiter assay, can be a good strategy to test susceptibility to TBZ. Mutations in the β-tubulin gene were studied on amino acid sequences from residue 167 to residue 357 of 10 P. expansum strains. Mutation at codon 198 was associated with TBZ-resistance. However, its absence in 3 resistant strains can be explained by the involvement of other mechanisms. Moreover, a P. expansum strain LB8/99 showed good antifungal effect against some fungal pathogens through double petri dish assay. It inhibited both mycelium growth and conidia germination of B. cinerea, C. acutatum, and M. laxa, and reduced significantly by 53% and 18% respectively P. expansum. Three major VOCS: geosmin, phenethyl alcolhol (PEA) and an unknown substance were identified by GC-MS analysis. Consistent fumigation of fungal pathogens with PEA (1230 mg/mL), inhibited both conidia germination and mycelium growth of all pathogens, except conidia germination of P. expansum that was reduced by 90% with respect to control. While, the concentration of PEA produced naturally by LB8/99 was ineffective in controlling the pathogens and seemed to have a synergic or additive effect with the other VOCS. Investigations to study the biofumigant effect of LB8/99 on other commodities like seeds and seedlings are in progress.

Design, Synthesis and Characterization of N-Containing Organic Compounds

The needed of new intermediates/products for screening in the fields of drug discovery and material science is the driving force behind the development of new methodologies and technologies. Organic scaffolds are privileged targets for this scouting. Among them a priority place must be attributed to those including nitrogen functionalities in their scaffolds. It comes out that new methodologies, allowing the introduction of the nitrogen atom for the synthesis of an established target or for the curiosity driven researches, will always be welcome. The target of this PhD Thesis’ work is framed within this goal. Accordingly, Chapter 1 reports the preparation of new N-Heteroarylmethyl 3-carboxy-5-hydroxy piperidine scaffold, as potential and selective α-glucosidase inhibitors. The proposed reversible uncompetitive mechanism of inhibition makes them attractive as interesting candidate for drug development. Chapter 2 is more environmentally method-driven research. Eco-friendly studies on the synthesis of enantiomerically pure 1,4-dihydropyridines using “solid” ammonia (magnesium nitride) is reported via classical Hantzch method. Chapter 3 and Chapter 4 may be targeted as the core of the Thesis’s research work. Chapter 3 reports the studies addressed to the synthesis of N-containing heterocycles by using N-trialkylsilylimine/hetero-Diels–Alder (HAD) approach. New eco-friendly methodology as MAOS (Microwave Assisted Organic Synthesis) has been used as witness of our interest to a sustainable chemistry. Theoretical calculations were adopted to fully clarify the reaction mechanism. Chapter 4 is dedicated to picture the most recent studies performed on the application of N-Metallo-ketene imines (metallo= Si, Sn, Al), relatively new intermediates which are becoming very popular, in the preparation of highly functionalized N-containing derivatives, accordingly to the Thesis’ target. Derivatives obtained are designed in such a way that they could be of interest in the field of drug and new material chemistry.

Elemetary processes of radiation damage in organic molecules of biological interest

It was observed in the ‘80s that the radiation damage on biological systems strongly depends on processes occurring at the microscopic level, involving the elementary constituents of biological cells. Since then, lot of attention has been paid to study elementary processes of photo- and ion-chemistry of isolated organic molecule of biological interest. This work fits in this framework and aims to study the radiation damage mechanisms induced by different types of radiations on simple halogenated biomolecules used as radiosensitizers in radiotherapy. The research is focused on the photofragmentation of halogenated pyrimidine molecules (5Br-pyrimidine, 2Br-pyrimidine and 2Cl-pyrimidine) in the VUV range and on the 12C4+ ion-impact fragmentation of the 5Br-uracil and its homogeneous and hydrated clusters. Although halogen substituted pyrimidines have similar structure to the pyrimidine molecule, their photodissociation dynamics is quite different. These targets have been chosen with the purpose of investigating the effect of the specific halogen atom and site of halogenation on the fragmentation dynamics. Theoretical and experimental studies have highlighted that the site of halogenation and the type of halogen atom, lead either to the preferential breaking of the pyrimidinic ring or to the release of halogen/hydrogen radicals. The two processes can subsequently trigger different mechanisms of biological damage. To understand the effect of the environment on the fragmentation dynamic of the single molecule, the ion-induced fragmentation of homogenous and hydrated clusters of 5Br-uracil have been studied and compared to similar studies on the isolated molecule. The results show that the “protective effect” of the environment on the single molecule hold in the homogeneous clusters, but not in the hydrated clusters, where several hydrated fragments have been observed. This indicates that the presence of water molecules can inhibit some fragmentation channels and promote the keto-enol tautomerization, which is very important in the mutagenesis of the DNA.

Structure, Dynamics and Reactivity in the Organic Solid State: Anthracene Derivatives and Charge Transfer Crystals

The work presented in this thesis tackles some important points concerning the collective properties of two typical categories of molecular crystals, i.e., anthracene derivatives and charge transfer crystals. Anthracene derivatives have constituted the class of materials from which systematical investigations of crystal-to-crystal photodimerization reactions started, developed and have been the subject of a new awakening in the recent years. In this work some of these compounds, namely, 9-cyanoanthacene, 9-anthacenecarboxylic acid and 9-methylanthracene, have been selected as model systems for a phenomenological approach to some key properties of the solid state, investigated by spectroscopic methods. The present results show that, on the basis of the solid state organization and the chemical nature of each compound, photo-reaction dynamics and kinetics display distinctive behaviors, which allows for a classification of the various processes in topochemical, non topochemical, reversible or topophysical. The second part of the thesis was focused on charge transfer crystals, binary systems formed by stoichiometric combinations of the charge donating perylene (D) and the charge accepting tetracyano-quinodimethane (A), this latter also in its fluorinated derivatives. The work was focused on the growth of single crystals, some of which not yet reported in the literature, by PVT technique. Structural and spectroscopic characterizations have been performed, with the aim of determining the degree of charge transfer between donor and acceptor in the co-crystals. An interesting outcome of the systematic search performed in this work is the definition of the experimental conditions which drive the crystal growth of the binary systems either towards the low (1:1) or the high ratio (3:1 or 3:2) stoichiometries.