Les travaux de cette thèse présentent la synthèse par une polymérisation RAFT en miniémulsion de nanoparticules fluorescentes (NPFs) polymères à coeur BODIPY copolymérisé au styrène et à couronne hydrophile biocompatible et fonctionnalisable à base de poly(oxyde d'éthylène) et de poly(acide acrylique). Les propriétés de fluorescence de ces NPFs ont été étudiées par spectroscopie de fluorescence stationnaire et résolue en temps. L'élaboration de la synthèse de ce type de NPFs, et la mise au point d'un procédé "one-pot" sont présentés dans un premier temps. Ensuite, les propriétés spectroscopiques de ces NPFs sont étudiées, notamment l'influence de la concentration en monomères de BODIPY au coeur des NPFs pouvant mener à la formation d'agrégats peu ou pas fluorescents. Les propriétés spectroscopiques (longueur d'onde d'émission de fluorescence et rendement quantique) du coeur des NPFs ont été modulées. Cela est rendu possible en réalisant la synthèse de monomères de BODIPY portant des groupements aromatiques encombrés, ou présentant différentes fonctions polymérisables. La couronne hydrophile des NPFs a également été modifiée afin d'obtenir différentes répartitions des unités acide acrylique et oxyde d'éthylène dans les chaînes de copolymères en surface. Ces nouvelles NPFs sont également synthétisées par un procédé "one-pot". Enfin, des molécules à fonctions amine (fluorophores, protéines) ont été introduites dans la couronne hydrophile de ces diverses NPFs par une chimie de couplage peptidique sur les fonctions acides carboxyliques. Des nano-senseurs de pH ratiométriques ont ainsi pu être élaborés. / This PhD work presents the synthesis of fluorescent nanoparticles (FNP) via a RAFT miniemulsion polymerisation and the analysis of their fluorescence properties. The core of the FNPs is a copolymer of styrene and a BODIPY monomer, and the shell, which is biocompatible and functionnalisable, is made of poly(ethylene oxyde) and poly(acrylic acid). First of all, the synthesis' optimisation of those FNPs is presented, and to the development of a one-pot process. Then, the fluorescence properties of those FNPs are studied, especially the impact of the BODIPY monomer concentration on the formation of non or weakly fluorescent aggregates. In order to change the FNP's spectroscopics properties (fluorescent quantum yield and emission wavelength), novel fluorescent BODIPY monomers have been synthesized. Those monomers presents either some bulky aromatics substituants, either variable polymerisable functions. The FNPS's hydrophilic shell has also been modified to get different distributions of the acrylic acid and ethylene oxyde units in the polymer chains of the FNPs' surface. Those new FNPs are also synthesized via a one-pot process. At last, molecules bearing an amine function (fluorescent dyes, proteins) have been grafted onto the differents FNPs' shell via a peptid coupling reaction on the carboxylic acid functions. As such, some pH ratiometric nano-sensors have been developped.

Les travaux réalisés durant ces années de doctorat ont été axés sur la conception de fluorophores pour diverses applications en fluorescence ou dispositifs de conversion d’énergie. Ainsi, plusieurs composés de la famille des Bodipys et triazatruxène ont été synthétisés, caractérisés et étudiés. En fonction des modifications structurales apportées à ces molécules, il est possible d’obtenir un panel de composés possédant une gamme d’absorption et d’émission pouvant s’étendre de 500 à 800 nm. La modulation de ses propriétés optiques a un intérêt dans un grand nombre d’applications. Ainsi, divers Bodipys ont été synthétisés en vue d’une éventuelle application pour le marquage biologique ou bien servant de support à l’étude du transfert d’énergie intramoléculaire. Le fort pouvoir absorbant de ces composés a été mis à contribution pour la réalisation de cellules solaires organiques originales et performantes. / The work undertaken during this PhD was focused on the design of fluorophores for several applications in fluorescence or energy conversion device. Several compounds from the Bodipy and Triazatruxene families were synthesized, characterized and studied. By structural modifications brought to these molecules, it was possible to obtain a panel of compounds those posses a range of absorption and emission properties which extend from 500 to 800 nm. The modulation of these optical properties has an interest in a large number of applications and field of research. Several Bodipys were synthesized for potential application in biological labeling and specific energy transfer processes. The strong absorption power and dedicated redox properties of these compounds was exploited for the preparation of solar

Organic solar cell (OSC) has been an active research field over the past decades, due to their intrinsic advantages, such as low consumption of materials and energy, the applicability on flexible substrates and the degradability of the organic components. Compared with the solution processing technology using polymers as electron donor materials, small molecule vacuum deposition is regarded as a promising fabrication method, avoiding the use of toxic aromatic solvents and guaranteeing constant batch-to-batch performance. Moreover, it is much easier to realize multi-junction tandem solar cells (TSCs) by thermal deposition, and the leading power conversion efficiency (PCE) of 13.2% was achieved using three different absorbers by vacuum deposition (“Heliatek sets new organic photovoltaic world record efficiency of 13.2%” 2016). In this dissertation, novel electron donor materials are synthesized based on the molecular skeleton of a famous chromophore, boron dipyrromethene (BODIPY), and chemical modifications are carried out to tune the intense absorption bands of these dyes to near infrared (NIR, λ>750,nm) region. Efficient small molecule NIR absorbers are highly required for TSCs, because they can construct a complementary absorption over the visible and NIR spectral region in cooperation with a wide bandgap material. Three β-fused aza-BODIPY molecules with heterocyclic substituents on α-positions are prepared using organolithium reagents and phthalonitrile as the starting materials. The organolithium reagents, namely N-methylpyrrole, N-methylindole and 2-trimethylsilylthiophene, are used instead of commonly used Grignard reagents. Moreover, three corresponding aza-BODIPY derivatives are obtained by replacing one fluorine atom in the BF_{2} moiety by a cyano group. UV-vis absorption spectra reveal that all these materials are strong NIR absorbers, and their abortion in solid state cover a wide range from 600 to 1000,nm. OSCs with these aza-BODIPY donors give a best PCE of 3.0%, which is a reasonable value for the NIR devices with the maximum and the onset of the EQE spectrum around 850 and 950,nm respectively. A series of furan-fused BODIPYs with a electron withdrawing CF_{3} group on the meso-C are synthesized, and the photophysical/electrochemical properties can be tuned easily by the electronic properties of the substituents on the peripheral aromatic rings. The most promising candidate gives a high PCE of 6.1% in a single junction OSC with a J_{sc} of 13.3,mA/cm^{2}, a V_{oc} of 0.73,V, and a FF of 62.7%. A serial connected TSC is fabricated using this BODIPY as the low bandgap donor and a “green” donor, and its EQE spectrum covers a wide range from 400 to 900,nm. The PCE reaches 9.9% with a J_{sc} of 9.9,mA/cm^{2}, a V_{oc} of 1.70,V, and a FF of 59.0%. Based on the general structure of furan-fused BODIPY, alkyl or fluorinated alkyl substituents with larger volume is introduced on either peripheral aromatic rings or the meso-C. The variations that caused by these substituents on the photophysical and electrochemical properties are negligible. The investigations on the OSCs demonstrate that the introduction of these alkyl chain substituents have positive influence on the PCE values, which benefit mainly from the increased photocurrent. However, there is no positive relationship between the device performance and the volume of the alkyl chain substituents. BODIPY molecules have been demonstrated as efficient and promising NIR electron donor materials for vacuum-deposited OSCs. Taking advantages of facile molecular modification, oustanding photophysical behaviors and tunable electrochemical properties, this series of dyes are also intereting for other semiconductor devices.

1 Abstract This work aims at showing synthesis and potential use of water-soluble fluorescent probes based on BODIPY. The preparation of probes containing bioorthogonal mono- and heterobifunctional functional groups was demonstrated. Ground work was done at the optimisation of reliable, scalable and fast sulfonation of BODIPY in 2,6-positions. A protocol for handling sulfonated BODIPY has been established; especially for the exchange of counterions. In counterion se- lection, their relation to synthetic pathway and biocompatibility were taken into consideration. The second part of the work shows series of water-soluble fluorescent probes, into which can be easily introduced bioactive or bioorthogonal functional groups. This can be used for click chemistry in connection with turn off/on probes or fluorescent sensing of molecules or ions. All this can be done in aqueous solution without organic solvents, which is relevant for biochemical, analytical and imaging applications. Keywords BODIPY, bifunctional, water-soluble, fluorescent probe, solubilization, biocompa- tible probes, bioorthogonal reaction, BODIPY sulfonation

Résumé Ce travail de thèse en cotutelle a été réalisé à l’Institut de Chimie Moléculaire de l’Université de Bourgogne (France) ainsi qu’au département de Chimie de l’Université de Sherbrooke (Québec). Ces travaux sont consacrés à la modification de la structure des BODIPY en vue d'une application in vivo pour l'imagerie bimodale optique/TEP ou TEMP. Ces modifications concernent l'hydrosolubilisation des fluorophores, mais aussi le décalage des domaines d’absorption et d’émission vers la fenêtre thérapeutique, zone dans laquelle la lumière est moins atténuée par les tissus biologiques. Des solutions permettant la bioconjugaison des fluorophores sur un dérivé de la bombésine, peptide permettant de cibler des récepteurs membranaires surexprimés dans certains types de cellules cancéreuses, sont également présentées. Enfin, une stratégie d’introduction d’un radioélément sur le BODIPY est décrite. Elle implique l’introduction sur l’atome de bore d’un groupe partant permettant sa radiofluoration. Différents dérivés de BODIPY ont également été utilisés pour la construction d’édifices multichromophoriques à transfert d’énergie. Ces travaux sont décrits dans la seconde partie de cette thèse. Ils comprennent notamment des études photophysiques permettant de mettre en évidence le transfert d’énergie photoinduit donneur-accepteur entre différents chromophores Dans les différents système élaborés, de type BODIPY-pophyrine et BODIPY-corolle, le BODIPY est alternativement donneur, ou accepteur d’énergie.

Visualizing proteins in living cells without perturbing biological function remains a key challenge in chemical biology. A chemical approach to this problem is the synthesis of small molecule fluorophores that react specifically with a protein of interest (POI). We have developed a site-specific labelling method based on a Fluorogenic Addition Reaction (FlARe). The FlARe probe’s fluorescence is quenched until it undergoes thiol addition with a small, genetically encoded dicysteine peptide tag fused to the POI. Recent blue coumarin probes were shown to be highly selective for target proteins over other cellular thiols; however, fluorogens that can label in the red and green channels of the fluorescence microscope are more desirable for cellular imaging, as red light is lower in energy and therefore less photo-toxic. In the work presented herein, we use DFT calculations to guide the design of red-shifted, PeT-quenched BODIPY based dimaleimide fluorogens. Driven by the preliminary results of a FlARe probe (YC29) that emitted in the red channel, we attempted to prepare the hit compound through a new synthetic approach to further evaluate kinetics and in cellulo labelling. Given the time available, this compound was unable to be synthesized through an SNAr or Pd-catalyzed approach. Alternatives probes lacking the red-shifting substituent were synthesized and evaluated in vitro and in cellulo. The fluorescent enhancement and reaction kinetics of these probes were evaluated in detail, in order to determine the suitability of their application to cellular labelling. A green-BODIPY fluorogen was synthesized that exhibits suitable kinetics for labelling and a dramatic fluorescent enhancement of ~800-fold upon tagging. This probe was successfully applied to the specific, fluorescent labelling of a nuclear histone protein in cellulo.

Chapter 2 In solution, py(mi)ridinols 1.33, 1.34 and 1.35 are 2-, 5- and 28-fold more reactive antioxidants, respectively, than α-TOH (the most potent lipid-soluble antioxidant in nature). In order to develop a highly-reactive fluorescent indicator of lipid peroxidation in cells, we sought to couple these antioxidants with boron-dipyrro- methene (BODIPY) dyes, such that the resulting conjugates will display a significant fluorecence enhancement upon oxidation. This chapter details efforts towards the synthesis of these compounds. Chapter 3 Lipoxygenases are a family of important enzymes that catalyze the dioxygenation of arachidonic acid to yield a variety of potent lipid mediators that have been implicated in the pathogenesis of numerous degenerative conditions. We have undertaken a preliminary study of the effect of replacing the unsaturation in the related polyunsaturated lipid linoleic acid with cyclopropane rings on both the oxidizability of the lipid, as well as lipoxygenase’s ability to utilize it as a substrate. We anticipate that these analogs will be useful in co-crystallization studies with the enzyme that will provide unique insight into substrate acquisition, binding and the necessary conformation for catalysis. / Thesis (Master, Chemistry) -- Queen's University, 2011-11-10 16:15:05.643

Résumé Ce travail de thèse en cotutelle a été réalisé à l’Institut de Chimie Moléculaire de l’Université de Bourgogne (France) ainsi qu’au département de Chimie de l’Université de Sherbrooke (Québec). Ces travaux sont consacrés à la modification de la structure des BODIPY en vue d'une application in vivo pour l'imagerie bimodale optique/TEP ou TEMP. Ces modifications concernent l'hydrosolubilisation des fluorophores, mais aussi le décalage des domaines d’absorption et d’émission vers la fenêtre thérapeutique, zone dans laquelle la lumière est moins atténuée par les tissus biologiques. Des solutions permettant la bioconjugaison des fluorophores sur un dérivé de la bombésine, peptide permettant de cibler des récepteurs membranaires surexprimés dans certains types de cellules cancéreuses, sont également présentées. Enfin, une stratégie d’introduction d’un radioélément sur le BODIPY est décrite. Elle implique l’introduction sur l’atome de bore d’un groupe partant permettant sa radiofluoration. Différents dérivés de BODIPY ont également été utilisés pour la construction d’édifices multichromophoriques à transfert d’énergie. Ces travaux sont décrits dans la seconde partie de cette thèse. Ils comprennent notamment des études photophysiques permettant de mettre en évidence le transfert d’énergie photoinduit donneur-accepteur entre différents chromophores Dans les différents système élaborés, de type BODIPY-pophyrine et BODIPY-corolle, le BODIPY est alternativement donneur, ou accepteur d’énergie.

The main thrust of this thesis is the development of new triarylborane containing luminescent molecules as well as utilizing triarylboron center as a receptor for the selective detection of biologically, environmentally and industrially important anions such as fluoride and cyanide in aqueous and non-aqueous solutions. The thesis contains nine chapters. The contents of each chapter are described below. Chapter 1 The first chapter is an introduction to the theme of the thesis and presents a general review on the techniques, theories and photochemistry relevant to the present work with emphasis on photochemistry of triarylboranes and their importance in the field of anion sensor chemistry. A review on various boron based luminophores is also presented. Chapter 2 The second chapter deals with the general experimental techniques and synthetic procedures utilized in this work. Chapter 3 This chapter deals with the synthesis of boryl-BODIPY dyads (1-8) in which triarylborane acts as anion receptor and BODIPY as a signalling unit. The absorption spectra of all boryl-BODIPY dyads shows similar pattern. However, the fluorescence spectra of 1, 2, 3, 6 and 7 shows dual emission bands whereas 4, 5 and 8 exhibit a single emission band. These interesting photophysical properties of boryl-BODIPYs (1-8) depends on the dihedral angle between two chromophores and partial energy transfer from donor (triarylborane) to acceptor (BODIPY) unit. The energy transfer efficiency of compounds 4, 5 and 8 is higher (close to 100%) compared to other series of boryl-BODIPYs (1-3, 6 and 7), due to the orthogonal arrangement of chromophores with high dihedral angles. To better understand photophysical properties and energy transfer process, anion binding studies were carried out since triarylborane acts as receptor for fluoride and cyanide ions. Anion binding studies of boryl-BODIPYs were (1-5) carried out in dichloromethane solutions and using tetrabutylammonium salt of fluoride/cyanide. All boryl-BODIPY dyads (1-5) were sensitive and selective sensor of fluoride, whereas the presence of only excess amounts (20 equv or more amounts) of cyanide made any changes in absorption and emission spectra. Other anions even above 100 eq were unable to cause any change. The quenching efficiency of compounds 4 and 5 was found to be more than that of other boryl-BODIPYs (1 and 3). The binding of fluoride with boryl-BODIPY (1-5) was entirely reversible; addition of BF3•Et2O to the fluoride adducts of compounds (1-5) regenerated the parent compounds. Chapter 4 In chapter 3, it was established that linear boryl-BODIPY dyads (1-8) show dual/single fluorescence bands depending on the dihedral angle between triarylborane and BODIPY unit. This Chapter describes the synthesis of three new “V” shaped boryl-BODIPY dyads (9, 10 and 11) their optical properties, Compound 9-11 are structurally similar differing only in the number of methyl substituents on the BODIPY moiety which were found to play major role in determining their optical behavior. The dyads show rare forms of multiple channel emission characteristics arising from different extents of electronic energy transfer (EET) processes between the two covalently linked fluorescent chromophores (triarylborane and BODIPY units). Owing to the presence of Lewis acidic triarylborane moiety, the dyads function as highly selective and sensitive fluoride sensors with vastly different response behavior. Upon binding of fluoride to the tricoordinate borane centre, dyad 9 shows gradual quenching of its BODIPY dominated emission due to the cessation of (borane to BODIPY) EET process. Dyad 10 shows ratiometric changes in its emission behavior upon addition of fluoride. Dyad 11 forms fluoride induced nanoaggregates which result in fast and effective quenching of its emission intensity upon addition of even small quantities of analyte (i.e. 0.1 equivalent of fluoride). When the solution is allowed to stand, disaggregation of the molecules results in partial recovery of the initial fluorescence bands. Thus, small structural alterations in these three structurally close dyads (9-11) result in exceptionally versatile and unique photophysical behavior and remarkably diverse responses towards a single analyte i.e. fluoride anion. Chapter 5 This chapter deals with intermolecular charge transfer (ICT) process in borane containing donor-acceptor triads and tetrads to realize colorimetric response for small anions such as fluoride and cyanide. Triad 12 and tetrad 13 incorporating –B(Mes)2, BDY (borondipyrromethene), and TPA (triphenylamine) were synthesized. Introduction of two dissimilar acceptors (triarylborane and BODIPY) on a single donor (TPA) resulted in two distinct ICT process (amine to borane and amine to BDY). The absorption and emission properties of new triad and tetrad are highly dependent on individual building units. The nature of electronic communication among the individual fluorophore units has been comprehensively investigated and compared with building units. Compounds 12 and 13 showed chromogenic and fluorogenic response towards small anions such as fluoride and cyanide. Chapter 6 In the previous chapter, it was demonstrated that although triphenylamine-triarylborane-BODIPY donor-acceptor conjugates show colorimetric response towards fluoride and cyanide. They could not distinguish these two interfering anions. To overcome the anion interference peripherally triarylborane decorated porphyrin (14) and its Zn(II) complex (15) were designed and synthesized and this forms the subject matter of this Chapter. Compound 15 contains two different Lewis acidic binding sites (Zn(II) and boron centre). Unlike all previously known triarylborane based sensors, the optical responses of 15 towards fluoride and cyanide are distinctively different thus enabling the discrimination of these two interfering anions. Metalloporphyrin 15 shows a multiple channel fluorogenic response towards fluoride and cyanide and also a selective visual colorimetric response towards cyanide. By comparison with model systems and from detailed photophysical studies on 14 and 15, it was concluded that the preferential binding of fluoride occurs at the peripheral borane moieties resulting in the cessation of the EET (electronic energy transfer) process from triarylborane to porphyrin core and with negligible negative cooperative effects. On the other hand, cyanide binding occurs at the Zn(II) core leading to drastic changes in its absorption behavior which can be followed by the naked eye. Such changes are not observed when the boryl substituent is absent (e.g. tetraphenyl-Zn(II)-porphyrin or TPP). The conjugates 14 and 15 showed reversible binding interaction towards CN and F and they are capable of extracting fluoride from aqueous media. Chapter 7 This Chapter deals with the design of a sensor which can detect fluoride colorimetrically in aqueous medium. Detecting fluoride in aqueous solution is an important area of current research owing to both positive and negative health and environmental effects associated with the fluoride ion. Although numerous fluoride sensors are reported, the colorimetric sensing (visual detection without the need of costly equipment and complicated analytical of fluoride at recommended levels 0.7 ppm) has not realized. Here we report the design, optical and fluoride sensing ability of two new water soluble Lewis acidic triarylborane-triarylamine conjugates 16 and 17 (containing one or two ammonium cations (-C6H4-NMe3). Compound 17 shows selective colorimetric response for aqueous inorganic fluoride at as low a level as 0.1 ppm Chapter 8 The synthesis and optical properties of four new triarylborane–dipyrromethane (TAB– DPM) conjugates (19a–d) containing dual binding sites (hydrogen bond donor and Lewis acid) have been reported. The new compounds exhibit a selective fluorogenic response towards the F− ion. The NMR titrations show that the fluoride ions bind to the TAB–DPM conjugates via the Lewis acidic triarylborane centre in preference to the hydrogen bond donor (dipyrromethane) units. Chapter 9 A new triarylborane-aza-BODIPY conjugate is reported (22). The conjugate molecule consists of two blue emissive dimesitylarylborane moiety and a NIR (near infra-red) emissive aza-BOIDPY core and shows panchromatic absorption spanning over ~300-800 nm region. The presence of two different fluorophore units in the conjugate leads to a broad dual-emissive feature covering a large part of visible and NIR region. DFT computational studies suggest limited electronic communication between the individual fluorophore units which may be responsible for the intriguing optical features of the conjugate molecule. Further, the broadband emissive conjugate can act as a selective sensor for fluoride anion as a result of fluorescence quenching response in both visible as well as in NIR spectral region.

Les travaux présentés dans ce manuscrit portent sur la synthèse et l’étude des propriétés spectroscopiques de systèmes multichromophoriques à base de Bodipy, fluorophore choisi pour ses propriétés émissives remarquables (&#61541-&#61472-et élevés, ) et pour son aptitude à donner et accepter les électrons. Notre objectif est de contrôler sa luminescence par association à un ou plusieurs chromophores de nature variée et répondant à des stimuli déterminés. L’exposé est divisé en quatre chapitres, dont le premier rappelle les méthodes de synthèse et de fonctionnalisation du noyau et détaille leur influence sur les propriétés de fluorescence. Le second chapitre présente le contrôle des propriétés d’émission intrinsèques par extension de conjugaison, au moyen d’une nouvelle réaction de type Knœvenagel. Les résultats spectroscopiques y sont notamment étudiés par modélisation quantique (DFT). Ensuite, nous démontrons qu’il est possible de contrôler la fluorescence par désagrégation de fluorophores greffés, en milieu aqueux par ajout de surfactant et par chélation d’anions. Le troisième chapitre est consacré à la modulation de la fluorescence par changement de l’état « rédox » du partenaire (électrofluorochromisme). A cet effet, deux chromophores ont été employés : la s-tétrazine et le ferrocène. Enfin, nous terminons notre étude par un quatrième chapitre qui aborde la photomodulation des propriétés émissives du Bodipy par couplage à diverses entités photochromes : les azobenzènes, les aniles et les photochromes à cyclisation péricyclique. Nous y détaillons les difficultés synthétiques rencontrées au cours de notre étude. / This work deals with the synthesis and the study of multichromophoric systems, based on Bodipy which is known for its oustanding emission properties (high &#61541- and values, ) and for both, its donating and withdrawing electronic characteristics. Our goal is to couple the fluorophore to other(s) chromophore(s) sensitive to a specific stimulus, to modulate the Bodipy’s emission. The first part, a bibliographic report, focuses on the various ways to functionalize the Bodipy core and discusses their influence on its spectroscopic properties. The second section aims at describing, first, the emission shift by extension of the core conjugation via a new Knœvenagel type reaction. DFT calculations will support experimental facts. It also focuses on external modulation factors such as disaggregation of Bodipy in aqueous media and anion chelation. The third chapter is fully devoted to the possibility of controlling the fluorescence properties by modification of the counter-chromophore “redox” state (so called electrofluorochromism). To that, two chromophores are used: the s-tetrazine and the ferrocene. Final section gathers the preliminary results of coupling reaction of photochromic species with Bodipy, in order to photocommutate its photophysics properties. Synthetic issues are largely discussed so as to highlight some general synthetic pathways that one needs to follow to succeed.