Structure-Property Relationships and Charge Transport Modeling of Organic Molecular Materials

From the perspective of a new-generation opto-electronic technology based on organic semiconductors, a major objective is to achieve a deep and detailed knowledge of the structure-property relationships, in order to optimize the electronic, optical, and charge transport properties by tuning the chemical-physical characteristics of the compounds. The purpose of this dissertation is to contribute to such understanding, through suitable theoretical and computational studies. Precisely, the structural, electronic, optical, and charge transport characteristics of several promising organic materials recently synthesized are investigated by means of an integrated approach encompassing quantum-chemical calculations, molecular dynamics and kinetic Monte Carlo simulations. Particular care is addressed to the rationalization of optical and charge transport properties in terms of both intra- and intermolecular features. Moreover, a considerable part of this project involves the development of a home-made set of procedures and parts of software code required to assist the modeling of charge transport properties in the framework of the non-adiabatic hopping mechanism applied to organic crystalline materials. As a first part of my investigations, I mainly discuss the optical, electronic, and structural properties of several core-extended rylene derivatives, which can be regarded to as model compounds for graphene nanoribbons. Two families have been studied, consisting in bay-linked perylene bisimide oligomers and N-annulated rylenes. Beside rylene derivatives, my studies also concerned electronic and spectroscopic properties of tetracene diimides, quinoidal oligothiophenes, and oxygen doped picene. As an example of device application, I studied the structural characteristics governing the efficiency of resistive molecular memories based on a derivative of benzoquinone. Finally, as a second part of my investigations, I concentrate on the charge transport properties of perylene bisimides derivatives. Precisely, a comprehensive study of the structural and thermal effects on the charge transport of several core-twisted chlorinated and fluoro-alkylated perylene bisimide n-type semiconductors is presented.

Structure-property relations in polymers from renewable resources

The present research project focuses its attention on the study of structure-property relations in polymers from renewable sources (bio-based polymers) such as polymers microbially produced, i.e. polyhydrohyalkanoates (PHAs) or chemically synthesized using monomers from renewable sources, i.e. polyammide 11 (PA11). By means of a broad spectrum of experimental techniques, the influence of different modifications on bio-based polymers such as blending with other components, copolymerization with different co-monomers and introduction of branching to yield complex architectures have been investigated. The present work on PHAs focused on the study of the dependence of polymer properties on both the fermentation process conditions (e.g. bacterial strain and carbon substrate used) and the method adopted to recover PHAs from cells. Furthermore, a solvent-free method using an enzyme and chemicals in an aqueous medium, was developed in order to recover PHAs from cells. Such a method allowed to recover PHA granules in their amorphous state, i.e. in native form useful for specific applications (e.g. paper coating). In addition, a commercial PHA was used as polymeric matrix to develop biodegradable and bio-based composites for food packaging applications. Biodegradable, non-toxic, food contact plasticizers and low cost, widely available lignocellulosic fibers (wheat straw fibers) were incorporated in such a polymeric matrix, in order to decrease PHA brittleness and the polymer cost, respectively. As concerns the study of polyamide 11, both the rheological and the solid-state behavior of PA11 star samples with different arm number and length was studied. Introduction of arms in a polymer molecule allows to modulate melt viscosity behavior which is advantageous for industrial applications. Also, several important solid-state properties, in particular mechanical properties, are affected by the presence of branching. Given the importance of using ‘green’ synthetic strategies in polymer chemistry, novel poly(-amino esters), synthesized via enzymatic-catalyzed polymerization, have also been investigated in this work.

Tailoring, synthesis and structure-property relationships of 2,3-thienoimide based molecular materials

Organic molecular semiconductors are subject of intense research for their crucial role as key components of new generation low cost, flexible, and large area electronic devices such as displays, thin-film transistors, solar cells, sensors and logic circuits. In particular, small molecular thienoimide (TI) based materials are emerging as novel multifunctional materials combining a good processability together to ambipolar or n-type charge transport and electroluminescence at the solid state, thus enabling the fabrication of integrated devices like organic field effect transistors (OFETs) and light emitting transistor (OLETs). Given this peculiar combination of characteristics, they also constitute the ideal substrates for fundamental studies on the structure-property relationships in multifunctional molecular systems. In this scenario, this thesis work is focused on the synthesis of new thienoimide based materials with tunable optical, packing, morphology, charge transport and electroluminescence properties by following a fine molecular tailoring, thus optimizing their performances in device as well as investigating and enabling new applications. Investigation on their structure-property relationships has been carried out and in particular, the effect of different π-conjugated cores (heterocycles, length) and alkyl end chain (shape, length) changes have been studied, obtaining materials with enhanced electron transport capability end electroluminescence suitable for the realization of OFETs and single layer OLETs. Moreover, control on the polymorphic behaviour characterizing thienoimide materials has been reached by synthetic and post-synthetic methodologies, developing multifunctional materials from a single polymorphic compound. Finally, with the aim of synthesizing highly pure materials, simplifying the purification steps and avoiding organometallic residues, procedures based on direct arylation reactions replacing conventional cross-couplings have been investigated and applied to different classes of molecules, bearing thienoimidic core or ends, as well as thiophene and anthracene derivatives, validating this approach as a clean alternative for the synthesis of several molecular materials.

Effetti della viscoelasticità sulla misura dell’energia di adesione tra film di polietilene

Lo stretch film è una diffusa applicazione per imballaggio dei film in polietilene (PE), utilizzato per proteggere diversi prodotti di vari dimensioni e pesi. Una caratteristica fondamentale del film è la sua proprietà adesiva in virtù della quale il film può essere facilmente chiuso su se stesso. Tipicamente vengono scelti gradi lineari a bassa densità (LLDPE) con valori relativamente bassi di densità a causa delle loro buone prestazioni. Il mercato basa la scelta del materiale adesivo per tentativi piuttosto che in base alla conoscenza delle caratteristiche strutturali ottimali per l’applicazione. Come per i pressure sensitive adhesives, le proprietà adesive di film stretch in PE possono essere misurati mediante "peel testing". Esistono molti metodi standard internazionali ma i risultati di tali prove sono fortemente dipendenti dalla geometria di prova, sulla possibile deformazione plastica che si verificano nel peel arm(s), e la velocità e temperatura. Lo scopo del presente lavoro è quello di misurare l'energia di adesione Gc di film stretch di PE, su se stessi e su substrati diversi, sfruttando l'interpretazione della meccanica della frattura per tener conto dell'elevata flessibilità e deformabilità di tali film. Quindi, la dipendenza velocità/temperatura di Gc sarà studiata con riferimento diretto al comportamento viscoelastico lineare dei materiali utilizzati negli strati adesivi, per esplorare le relazioni struttura-proprietà che possono mettere in luce i meccanismi molecolari coinvolti nei processi di adesione e distacco. Nella presente caso, l’adesivo non è direttamente disponibile come materiale separato che può essere messo tra due superfici di prova e misurato per la determinazione delle sue proprietà. Il presupposto principale è che una parte, o fase, della complessa struttura semi-cristallina del PE possa funzionare come adesivo, e un importante risultato di questo studio può essere una migliore identificazione e caratterizzazione di questo "fase adesiva".

Simulation of Smart Materials

The aim of this thesis is the elucidation of structure-properties relationship of molecular semiconductors for electronic devices. This involves the use of a comprehensive set of simulation techniques, ranging from quantum-mechanical to numerical stochastic methods, and also the development of ad-hoc computational tools. In more detail, the research activity regarded two main topics: the study of electronic properties and structural behaviour of liquid crystalline (LC) materials based on functionalised oligo(p-phenyleneethynylene) (OPE), and the investigation on the electric field effect associated to OFET operation on pentacene thin film stability. In this dissertation, a novel family of substituted OPE liquid crystals with applications in stimuli-responsive materials is presented. In more detail, simulations can not only provide evidence for the characterization of the liquid crystalline phases of different OPEs, but elucidate the role of charge transfer states in donor-acceptor LCs containing an endohedral metallofullerene moiety. Such systems can be regarded as promising candidates for organic photovoltaics. Furthermore, exciton dynamics simulations are performed as a way to obtain additional information about the degree of order in OPE columnar phases. Finally, ab initio and molecular mechanics simulations are used to investigate the influence of an applied electric field on pentacene reactivity and stability. The reaction path of pentacene thermal dimerization in the presence of an external electric field is investigated; the results can be related to the fatigue effect observed in OFETs, that show significant performance degradation even in the absence of external agents. In addition to this, the effect of the gate voltage on a pentacene monolayer are simulated, and the results are then compared to X-ray diffraction measurements performed for the first time on operating OFETs.

Semi-synthetic bile acids as novel drug candidate in liver diseases: physico-chemical characterization and HPLC-ES-MS/MS methods for their quali-quantitative analysis in different experimental animal models

The physico-chemical characterization, structure-pharmacokinetic and metabolism studies of new semi synthetic analogues of natural bile acids (BAs) drug candidates have been performed. Recent studies discovered a role of BAs as agonists of FXR and TGR5 receptor, thus opening new therapeutic target for the treatment of liver diseases or metabolic disorders. Up to twenty new semisynthetic analogues have been synthesized and studied in order to find promising novel drugs candidates. In order to define the BAs structure-activity relationship, their main physico-chemical properties (solubility, detergency, lipophilicity and affinity with serum albumin) have been measured with validated analytical methodologies. Their metabolism and biodistribution has been studied in “bile fistula rat”, model where each BA is acutely administered through duodenal and femoral infusion and bile collected at different time interval allowing to define the relationship between structure and intestinal absorption and hepatic uptake ,metabolism and systemic spill-over. One of the studied analogues, 6α-ethyl-3α7α-dihydroxy-5β-cholanic acid, analogue of CDCA (INT 747, Obeticholic Acid (OCA)), recently under approval for the treatment of cholestatic liver diseases, requires additional studies to ensure its safety and lack of toxicity when administered to patients with a strong liver impairment. For this purpose, CCl4 inhalation to rat causing hepatic decompensation (cirrhosis) animal model has been developed and used to define the difference of OCA biodistribution in respect to control animals trying to define whether peripheral tissues might be also exposed as a result of toxic plasma levels of OCA, evaluating also the endogenous BAs biodistribution. An accurate and sensitive HPLC-ES-MS/MS method is developed to identify and quantify all BAs in biological matrices (bile, plasma, urine, liver, kidney, intestinal content and tissue) for which a sample pretreatment have been optimized.

Novel dual D3R/GSK-3β modulators: an innovative multitarget strategy for bipolar disorder

Among the psychiatric diseases, bipolar disorder (BD) is the sixth leading cause of disability with a prevalence up to 4 % worldwide. BD is a complex neuropsychiatric condition which alternates episodes of mania with symptoms of depression. Although the neurobiological pathways are not completely clarified, the dopamine (DA) hypothesis, recognized as the leading theory explaining the pathophysiology of the malady, states that the dramatically compromised homeostatic regulation of dopaminergic circuits leads to alternated changes in DA neurotransmission. Modulation of D2 and D3 receptors (D2/3R) through partial agonists represents the first-line therapeutic strategy for psychiatric diseases. Moreover, a deregulation of the enzyme glycogen synthase kinase-3β (GSK-3β) has been reported as peculiar feature of BD. In this scenario, the concomitant modulation of D3R and GSK-3β, by employing multitarget compounds, could offer promises to achieve an effective cure of this illness. In the light of these findings, we rationally envisaged the pharmacophoric model at the basis of the design of several D3R partial agonists, suitable to be exploited for the dual D3R/GSK-3β ligand design. Thus, synthetic efforts were addressed to develop a first set of hybrid molecules able to concurrently modulate the selected targets. For a chemical structure point of view, we employed different spacers to combine a substituted aryl-piperazine moiety, reported in previously discovered D3R modulators, with a pyrazole-based fragment, already identified in GSK-3β inhibitors. A fluorescent and a cellular functional assays were carried out to assess the activity of all synthetized compounds against GSK-3β and on D3R, respectively. Most of the derivatives proved to effectively modulate both GSK-3β and D3R with potencies in the low-µM and low-nM range, respectively. The consistent biological data allowed us to identify some lead candidates worth to be further modified with the aim to optimize their biological profile and to perform a structure-activity relationship (SAR) study.

Catalytic upgrading of carboxylic acids and esters to bio fuels and bio chemicals

The research activity was focused on the transformation of methyl propionate (MP) into methyl methacrylate (MMA), avoiding the use of formaldehyde (FAL) thanks to a one-pot strategy involving in situ methanol (MeOH) dehydrogenation over the same catalytic bed were the hydroxy-methylation/dehydration of MP with FAL occurs. The relevance of such research line is related to the availability of cheap renewable bio-glycerol from biodiesel production, from which MP can be obtained via a series of simple catalytic reactions. Moreover, the conventional MMA synthesis (Lucite process) suffers from safety issues related to the direct use of carcinogenic FAL and depends on non-renewable MP. During preliminary studies, ketonization of carboxylic acids and esters has been recognized as a detrimental reaction which hinders the selective synthesis of MMA at low temperature, together with H-transfer hydrogenation with FAL or MeOH as the H-donor at higher temperatures. Therefore, ketonization of propionic acid (PA) and MP was investigated over several catalysts (metal oxides and metal phosphates), to obtain a better understanding of the structure-activity relationship governing the reaction and to design a catalyst for MMA synthesis capable to promote the desired reaction while minimizing ketonization and H-transfer. However, ketonization possesses scientific and industrial value itself and represents a strategy for the upgrade of bio oils from fast pyrolysis of lignocellulosic materials, a robust and versatile technology capable to transform the most abundant biomass into liquid biofuels. The catalysts screening showed that ZrO2 and La2O3 are the best catalysts, while MgO possesses low ketonization activity, but still, H-transfer parasitic hydrogenation of MMA reduces its yield over all catalysts. Such study resulted in the design of Mg/Ga mixed oxides that showed enhanced dehydrogenating activity towards MeOH at low temperatures. It was found that the introduction of Ga not only minimize ketonization, but also modulates catalyst basicity reducing H-transfer hydrogenations.

Development and Detailed Characterization of Innovative, High-Performance Membrane Materials for CO2 Capture Processes

The scope of this dissertation is to study the transport phenomena of small molecules in polymers and membranes for gas separation applications, with particular attention to energy efficiency and environmental sustainability. This work seeks to contribute to the development of new competitive selective materials through the characterization of novel organic polymers such as CANALs and ROMPs, as well as through the combination of selective materials obtaining mixed matrix membranes (MMMs), to make membrane technologies competitive with the traditional ones. Kinetic and thermodynamic aspects of the transport properties were investigated in ideal and non-ideal scenarios, such as mixed-gas experiments. The information we gathered contributed to the development of the fundamental understanding related to phenomenon like CO2-induced plasticization and physical aging. Among the most significant results, ZIF-8/PPO MMMs provided materials whose permeability and selectivity were higher than those of the pure materials for He/CO2 separation. The CANALs featured norbornyl benzocyclobutene backbone and thereby introduced a third typology of ladder polymers in the gas separation field, expanding the structural diversity of microporous materials. CANALs have a completely hydrocarbon-based and non-polar rigid backbone, which makes them an ideal model system to investigate structure-property correlations. ROMPs were synthesized by means of the ring opening metathesis living polymerization, which allowed the formation of bottlebrush polymers. CF3-ROMP reveled to be ultrapermeable to CO2, with unprecedented plasticization resistance properties. Mixed-gas experiments in glassy polymer showed that solubility-selectivity controls the separation efficiency of materials in multicomponent conditions. Finally, it was determined that plasticization pressure in not an intrinsic property of a material and does not represent a state of the system, but rather comes from the contribution of solubility coefficient and diffusivity coefficient in the framework of the solution-diffusion model.

Non-ambient solid-state characterization of crystalline molecular organic semiconductors

The research project is focused on the investigation of the polymorphism of crystalline molecular material for organic semiconductor applications under non-ambient conditions, and the solid-state characterization and crystal structure determination of the different polymorphic forms. In particular, this research project has tackled the investigation and characterization of the polymorphism of perylene diimides (PDIs) derivatives at high temperatures and pressures, in particular N,N’-dialkyl-3,4,9,10-perylendiimide (PDI-Cn, with n = 5, 6, 7, 8). These molecules are characterized by excellent chemical, thermal, and photostability, high electron affinity, strong absorption in the visible region, low LUMO energies, good air stability, and good charge transport properties, which can be tuned via functionalization; these features make them promising n-type organic semiconductor materials for several applications such as OFETs, OPV cells, laser dye, sensors, bioimaging, etc. The thermal characterization of PDI-Cn was carried out by a combination of differential scanning calorimetry, variable temperature X-ray diffraction, hot-stage microscopy, and in the case of PDI-C5 also variable temperature Raman spectroscopy. Whereas crystal structure determination was carried out by both Single Crystal and Powder X-ray diffraction. Moreover, high-pressure polymorphism via pressure-dependent UV-Vis absorption spectroscopy and high-pressure Single Crystal X-ray diffraction was carried out in this project. A data-driven approach based on a combination of self-organizing maps (SOM) and principal component analysis (PCA) is also reported was used to classify different π-stacking arrangements of PDI derivatives into families of similar crystal packing. Besides the main project, in the framework of structure-property analysis under non-ambient conditions, the structural investigation of the water loss in Pt- and Pd- based vapochromic potassium/lithium salts upon temperature, and the investigation of structure-mechanical property relationships in polymorphs of a thienopyrrolyldione endcapped oligothiophene (C4-NT3N) are reported.

Design and characterization of polymorphs and co-crystals of organic molecular semiconductors

In the last decades, organic semiconductors have attracted attention due to their possible employment in solution-processed optoelectronic and electronic devices. One of the advantages of solution processing is the possibility to process into flexible substrates at low cost. Organic molecular materials tend to form polymorphs, which can exhibit very different properties. In most cases, the control of the crystal structure is decisive to maximize the performance of the final device. Although organic electronics have progressed a lot, n-type organic semiconductors still lag behind p-type, presenting challenges such as air instability and poor solubility. NDI derivatives are promising candidates for applications in organic electronics due to their characteristics. Recently, the structure-properties relationship and the polymorphism of these molecules have gained attention. In the first part of this thesis, NDI-C6 thermal behavior was extensively explored which revealed two different behaviors depending on the annealing process. This study allowed to define the stability ranking of the NDI-C6 bulk forms and to determine the crystal structure of Form γ at 54°C. Additionally, the polymorphic and thermal behavior of thin films of NDI-C6 was also explored. It was possible to isolate pure Form α, Form β, Form γ and a new metastable Form ε. It was also possible to determine the stability ranking of the phases in thin films. OFETs were fabricated having different polymorphs as active layer, unfortunately the performance was not ideal. During the second part of this thesis, core-chlorinated NDIs with fluoroalkyl chains were studied. Initially, the focus was on the polymorphism of CF3-NDI that revealed a solvate form with a very interesting molecular arrangement suggesting the possibility to form charge transfer co-crystals. In the last part of the thesis, the synthesis and characterization of CT co-crystal with different NDI derivatives, and acceptor and as donor BTBT and ditBu-BTBT were explored.

Anticancer drug discovery using artificial intelligence: an application in pharmacological activity prediction

Hematological cancers are a heterogeneous family of diseases that can be divided into leukemias, lymphomas, and myelomas, often called “liquid tumors”. Since they cannot be surgically removable, chemotherapy represents the mainstay of their treatment. However, it still faces several challenges like drug resistance and low response rate, and the need for new anticancer agents is compelling. The drug discovery process is long-term, costly, and prone to high failure rates. With the rapid expansion of biological and chemical "big data", some computational techniques such as machine learning tools have been increasingly employed to speed up and economize the whole process. Machine learning algorithms can create complex models with the aim to determine the biological activity of compounds against several targets, based on their chemical properties. These models are defined as multi-target Quantitative Structure-Activity Relationship (mt-QSAR) and can be used to virtually screen small and large chemical libraries for the identification of new molecules with anticancer activity. The aim of my Ph.D. project was to employ machine learning techniques to build an mt-QSAR classification model for the prediction of cytotoxic drugs simultaneously active against 43 hematological cancer cell lines. For this purpose, first, I constructed a large and diversified dataset of molecules extracted from the ChEMBL database. Then, I compared the performance of different ML classification algorithms, until Random Forest was identified as the one returning the best predictions. Finally, I used different approaches to maximize the performance of the model, which achieved an accuracy of 88% by correctly classifying 93% of inactive molecules and 72% of active molecules in a validation set. This model was further applied to the virtual screening of a small dataset of molecules tested in our laboratory, where it showed 100% accuracy in correctly classifying all molecules. This result is confirmed by our previous in vitro experiments.

Modelling the influence of diradical character and aggregation on conjugated molecular materials

Molecular materials are made by the assembly of specifically designed molecules to obtain bulk structures with desired solid-state properties, enabling the development of materials with tunable chemical and physical properties. These properties result from the interplay of intra-molecular constituents and weak intermolecular interactions. Thus, small changes in individual molecular and electronic structure can substantially change the properties of the material in bulk. The purpose of this dissertation is, thus, to discuss and to contribute to the structure-property relationships governing the electronic, optical and charge transport properties of organic molecular materials through theoretical and computational studies. In particular, the main focus is on the interplay of intra-molecular properties and inter-molecular interactions in organic molecular materials. In my three-years of research activity, I have focused on three major areas: 1) the investigation of isolated-molecule properties for the class of conjugated chromophores displaying diradical character which are building blocks for promising functional materials; 2) the determination of intra- and intermolecular parameters governing charge transport in molecular materials and, 3) the development and application of diabatization procedures for the analysis of exciton states in molecular aggregates. The properties of diradicaloids are extensively studied both regarding their ground state (diradical character, aromatic vs quinoidal structures, spin dynamics, etc.) and the low-lying singlet excited states including the elusive double-exciton state. The efficiency of charge transport, for specific classes of organic semiconductors (including diradicaloids), is investigated by combining the effects of intra-molecular reorganization energy, inter-molecular electronic coupling and crystal packing. Finally, protocols aimed at unravelling the nature of exciton states are introduced and applied to different molecular aggregates. The role of intermolecular interactions and charge transfer contributions in determining the exciton state character and in modulating the H- to J- aggregation is also highlighted.

Analyzing the dependence structure of microarray data: a copula–based approach

The main aim of this Ph.D. dissertation is the study of clustering dependent data by means of copula functions with particular emphasis on microarray data. Copula functions are a popular multivariate modeling tool in each field where the multivariate dependence is of great interest and their use in clustering has not been still investigated. The first part of this work contains the review of the literature of clustering methods, copula functions and microarray experiments. The attention focuses on the K–means (Hartigan, 1975; Hartigan and Wong, 1979), the hierarchical (Everitt, 1974) and the model–based (Fraley and Raftery, 1998, 1999, 2000, 2007) clustering techniques because their performance is compared. Then, the probabilistic interpretation of the Sklar’s theorem (Sklar’s, 1959), the estimation methods for copulas like the Inference for Margins (Joe and Xu, 1996) and the Archimedean and Elliptical copula families are presented. In the end, applications of clustering methods and copulas to the genetic and microarray experiments are highlighted. The second part contains the original contribution proposed. A simulation study is performed in order to evaluate the performance of the K–means and the hierarchical bottom–up clustering methods in identifying clusters according to the dependence structure of the data generating process. Different simulations are performed by varying different conditions (e.g., the kind of margins (distinct, overlapping and nested) and the value of the dependence parameter ) and the results are evaluated by means of different measures of performance. In light of the simulation results and of the limits of the two investigated clustering methods, a new clustering algorithm based on copula functions (‘CoClust’ in brief) is proposed. The basic idea, the iterative procedure of the CoClust and the description of the written R functions with their output are given. The CoClust algorithm is tested on simulated data (by varying the number of clusters, the copula models, the dependence parameter value and the degree of overlap of margins) and is compared with the performance of model–based clustering by using different measures of performance, like the percentage of well–identified number of clusters and the not rejection percentage of H0 on . It is shown that the CoClust algorithm allows to overcome all observed limits of the other investigated clustering techniques and is able to identify clusters according to the dependence structure of the data independently of the degree of overlap of margins and the strength of the dependence. The CoClust uses a criterion based on the maximized log–likelihood function of the copula and can virtually account for any possible dependence relationship between observations. Many peculiar characteristics are shown for the CoClust, e.g. its capability of identifying the true number of clusters and the fact that it does not require a starting classification. Finally, the CoClust algorithm is applied to the real microarray data of Hedenfalk et al. (2001) both to the gene expressions observed in three different cancer samples and to the columns (tumor samples) of the whole data matrix.

Rafael Moneo: la complessità del vuoto. Dalle matrici formali dell'opera di Oteiza e Chillida

The experience of void, essential to the production of forms and to make use them, can be considered as the base of the activities that attend to the formative processes. If void and matter constitutes the basic substances of architecture. Their role in the definition of form, the symbolic value and the constructive methods of it defines the quality of the space. This job inquires the character of space in the architecture of Moneo interpreting the meaning of the void in the Basque culture through the reading of the form matrices in the work of Jorge Oteiza and Eduardo Chillida. In the tie with the Basque culture a reading key is characterized by concurring to put in relation some of the theoretical principles expressed by Moneo on the relationship between place and time, in an unique and specific vision of the space. In the analysis of the process that determines the genesis of the architecture of Moneo emerges a trajectory whose direction is constructed on two pivos: on the one hand architecture like instrument of appropriation of the place, gushed from an acquaintance process who leans itself to the reading of the relations that define the place and of the resonances through which measuring it, on the other hand the architecture whose character is able to represent and to extend the time in which he is conceived, through the autonomy that is conferred to them from values. Following the trace characterized from this hypothesis, that is supported on the theories elaborated from Moneo, surveying deepens the reading of the principles that construct the sculptural work of Oteiza and Chillida, features from a search around the topic of the void and to its expression through the form. It is instrumental to the definition of a specific area that concurs to interpret the character of the space subtended to a vision of the place and the time, affine to the sensibility of Moneo and in some way not stranger to its cultural formation. The years of the academic formation, during which Moneo enters in contact with the Basque artistic culture, seem to be an important period in the birth of that knowledge that will leads him to the formulation of theories tied to the relationship between time, place and architecture. The values expressed through the experimental work of Oteiza and Chillida during years '50 are valid bases to the understanding of such relationships. In tracing a profile of the figures of Oteiza and Chillida, without the pretension that it is exhaustive for the reading of the complex historical period in which they are placed, but with the needs to put the work in a context, I want to be evidenced the important role carried out from the two artists from the Basque cultural area within which Moneo moves its first steps. The tie that approaches Moneo to the Basque culture following the personal trajectory of the formative experience interlaces to that one of important figures of the art and the Spanish architecture. One of the more meaningful relationships is born just during the years of his academic formation, from 1958 to the 1961, when he works like student in the professional office of the architect Francisco Sáenz de Oiza, who was teaching architectural design at the ETSAM. In these years many figures of Basque artists alternated at the professional office of Oiza that enjoys the important support of the manufacturer and maecenas Juan Huarte Beaumont, introduced to he from Oteiza. The tie between Huarte and Oteiza is solid and continuous in the years and it realizes in a contribution to many of the initiatives that makes of Oteiza a forwarder of the Basque culture. In the four years of collaboration with Oiza, Moneo has the opportunity to keep in contact with an atmosphere permeated by a constant search in the field of the plastic art and with figures directly connected to such atmosphere. It’s of a period of great intensity as in the production like in the promotion of the Basque art. The collective “Blanco y Negro”, than is held in 1959 at the Galería Darro to Madrid, is only one of the many times of an exhibition of the work of Oteiza and Chillida. The end of the Fifties is a period of international acknowledgment for Chillida that for Oteiza. The decade of the Fifties consecrates the hypotheses of a mythical past of the Basque people through the spread of the studies carried out in the antecedent years. The archaeological discoveries that join to a context already rich of signs of the prehistoric era, consolidate the knowledge of a strong cultural identity. Oteiza, like Chillida and other contemporary artists, believe in a cosmogonist conception belonging to the Basques, connected to their matriarchal mythological past. The void in its meaning of absence, in the Basque culture, thus as in various archaic and oriental religions, is equivalent to the spiritual fullness as essential condition to the revealing of essence. Retracing the archaic origins of the Basque culture emerges the deep meaning that the void assumes as key element in the religious interpretation of the passage from the life to the death. The symbology becomes rich of meaningful characters who derive from the fact that it is a chthonic cult. A representation of earth like place in which divine manifest itself but also like connection between divine and human, and this manipulation of the matter of which the earth it is composed is the tangible projection of the continuous search of the man towards God. The search of equilibrium between empty and full, that characterizes also the development of the form in architecture, in the Basque culture assumes therefore a peculiar value that returns like constant in great part of the plastic expressions, than in this context seem to be privileged regarding the other expressive forms. Oteiza and Chillida develop two original points of view in the representation of the void through the form. Both use of rigorous systems of rules sensitive to the physics principles and the characters of the matter. The last aim of the Oteiza’s construction is the void like limit of the knowledge, like border between known and unknown. It doesn’t means to reduce the sculptural object to an only allusive dimension because the void as physical and spiritual power is an active void, that possesses that value able to reveal the being through the trace of un-being. The void in its transcendental manifestation acts at the same time from universal and from particular, like in the atomic structure of the matter, in which on one side it constitutes the inner structure of every atom and on the other one it is necessary condition to the interaction between all the atoms. The void can be seen therefore as the action field that concurs the relations between the forms but is also the necessary condition to the same existence of the form. In the construction of Chillida the void represents that counterpart structuring the matter, inborn in it, the element in absence of which wouldn’t be variations neither distinctive characters to define the phenomenal variety of the world. The physics laws become the subject of the sculptural representation, the void are the instrument that concurs to catch up the equilibrium. Chillida dedicate himself to experience the space through the senses, to perceive of the qualities, to tell the physics laws which forge the matter in the form and the form arranges the places. From the artistic experience of the two sculptors they can be transposed, to the architectonic work of Moneo, those matrices on which they have constructed their original lyric expressions, where the void is absolute protagonist. An ambit is defined thus within which the matrices form them drafts from the work of Oteiza and Chillida can be traced in the definition of the process of birth and construction of the architecture of Moneo, but also in the relation that the architecture establishes with the place and in the time. The void becomes instrument to read the space constructed in its relationships that determine the proportions, rhythms, and relations. In this way the void concurs to interpret the architectonic space and to read the value of it, the quality of the spaces constructing it. This because it’s like an instrument of the composition, whose role is to maintain to the separation between the elements putting in evidence the field of relations. The void is that instrument that serves to characterize the elements that are with in the composition, related between each other, but distinguished. The meaning of the void therefore pushes the interpretation of the architectonic composition on the game of the relations between the elements that, independent and distinguished, strengthen themselves in their identity. On the one hand if void, as measurable reality, concurs all the dimensional changes quantifying the relationships between the parts, on the other hand its dialectic connotation concurs to search the equilibrium that regulated such variations. Equilibrium that therefore does not represent an obtained state applying criteria setting up from arbitrary rules but that depends from the intimate nature of the matter and its embodiment in the form. The production of a form, or a formal system that can be finalized to the construction of a building, is indissolubly tied to the technique that is based on the acquaintance of the formal vocation of the matter, and what it also can representing, meaning, expresses itself in characterizing the site. For Moneo, in fact, the space defined from the architecture is above all a site, because the essence of the site is based on the construction. When Moneo speaks about “birth of the idea of plan” like essential moment in the construction process of the architecture, it refers to a process whose complexity cannot be born other than from a deepened acquaintance of the site that leads to the comprehension of its specificity. Specificity arise from the infinite sum of relations, than for Moneo is the story of the oneness of a site, of its history, of the cultural identity and of the dimensional characters that that they are tied to it beyond that to the physical characteristics of the site. This vision is leaned to a solid made physical structure of perceptions, of distances, guideline and references that then make that the process is first of all acquaintance, appropriation. Appropriation that however does not happen for directed consequence because does not exist a relationship of cause and effect between place and architecture, thus as an univocal and exclusive way does not exist to arrive to a representation of an idea. An approach that, through the construction of the place where the architecture acquires its being, searches an expression of its sense of the truth. The proposal of a distinction for areas like space, matter, spirit and time, answering to the issues that scan the topics of the planning search of Moneo, concurs a more immediate reading of the systems subtended to the composition principles, through which is related the recurrent architectonic elements in its planning dictionary. From the dialectic between the opposites that is expressed in the duality of the form, through the definition of a complex element that can mediate between inside and outside as a real system of exchange, Moneo experiences the form development of the building deepening the relations that the volume establishes in the site. From time to time the invention of a system used to answer to the needs of the program and to resolve the dual character of the construction in an only gesture, involves a deep acquaintance of the professional practice. The technical aspect is the essential support to which the construction of the system is indissolubly tied. What therefore arouses interest is the search of the criteria and the way to construct that can reveal essential aspects of the being of the things. The constructive process demands, in fact, the acquaintance of the formative properties of the matter. Property from which the reflections gush on the relations that can be born around the architecture through the resonance produced from the forms. The void, in fact, through the form is in a position to constructing the site establishing a reciprocity relation. A reciprocity that is determined in the game between empty and full and of the forms between each other, regarding around, but also with regard to the subjective experience. The construction of a background used to amplify what is arranged on it and to clearly show the relations between the parts and at the same time able to tie itself with around opening the space of the vision, is a system that in the architecture of Moneo has one of its more effective applications in the use of the platform used like architectonic element. The spiritual force of this architectonic gesture is in the ability to define a place whose projecting intention is perceived and shared with who experience and has lived like some instrument to contact the cosmic forces, in a delicate process that lead to the equilibrium with them, but in completely physical way. The principles subtended to the construction of the form taken from the study of the void and the relations that it concurs, lead to express human values in the construction of the site. The validity of these principles however is tested from the time. The time is what Moneo considers as filter that every architecture is subordinate to and the survival of architecture, or any of its formal characters, reveals them the validity of the principles that have determined it. It manifests thus, in the tie between the spatial and spiritual dimension, between the material and the worldly dimension, the state of necessity that leads, in the construction of the architecture, to establish a contact with the forces of the universe and the intimate world, through a process that translate that necessity in elaboration of a formal system.