Photosensitizers in Medicine, Environment, and Security
Tebello Nyokong • Vefa Ahsen Editors
Photosensitizers in Medicine, Environment, and Security
Editors Tebello Nyokong Department of Chemistry Rhodes University Grahamstown South Africa
[email protected] Vefa Ahsen Department of Chemistry Gebze Institute of Technology PO Box 141 41400 Gebze, Kocaeli Turkey
[email protected] ISBN 978-90-481-3870-8 e-ISBN 978-90-481-3872-2 DOI 10.1007/978-90-481-3872-2 Springer Dordrecht Heidelberg London New York Library of Congress Control Number: 2011941751 © Springer Science+Business Media B.V. 2012 No part of this work may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, microfilming, recording or otherwise, without written permission from the Publisher, with the exception of any material supplied specifically for the purpose of being entered and executed on a computer system, for exclusive use by the purchaser of the work. Printed on acid-free paper Springer is part of Springer Science+Business Media (www.springer.com)
Preface
Photosensitizers, in broad a meaning, included molecules interacting with light and having their properties modified under light irradiation. These properties proved to be useful in a wide range of applications, mainly in medical field but as well to solve some environmental problems, security issues, energy generation and modern synthetic methods. The book addresses the synthesis of the photosensitizers with a focus on tetrapyrrolic derivatives, their photochemistry and photophysics, and their use in environmental control, safety, solar energy and medicine. It discusses to common structure which are beneficial to these applications. In particular, tetrapyrrolic derivatives are currently being investigated as potential photosensitisers for applications to solve a wide variety of above cited real world problems. Metalloporphyrins and related metallophthalocyanines have a wide variety of applications due to their diverse chemical, structural, electronic and optical properties. As a result of their bright blue, green to violet colors and excellent fastness to light, traditional uses of metallophthalocynines are as dyes and pigments since nearly one century. In the last decades, their use in high technologic fields was developed as their properties have been found to be matching those required for several modernworld issues. This induced great developments in the design and synthetic method of these derivatives, possibly assisted by theoretical chemistry. Their photochemical and photophysical characterization have therefore a huge importance. High triplet state quantum yields, and long triplet lifetimes as well as high singlet oxygen quantum yields are required for efficient photosensitization, and these criteria may be fulfilled by the incorporation of diamagnetic metals such as zinc, aluminum or silicon into the macrocycle. For medical applications, and especially for treatment of cancer by photodynamic therapy, both metalloporphyrins and related metallophthalocyanines show promise as photosensitisers. PDT uses a combination of a photosensitizing drug and light in the presence of molecular oxygen to obtain a therapeutic effect based on selective cell destruction by the local generation of singlet oxygen, particular in aqueous media. Recently new type of materials – semiconductor quantum dots (QDs) – have became available for use in PDT, because of their considerably higher molar extinction v
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Preface
coefficients than that of any organic molecules. Unfortunately, QDs show very low singlet oxygen quantum yields. Based on this observation, QDs are now being combined with photosensitisers for possible application in PDT. This is the new way of treating cancer through “combination therapy”. In environmental applications, the photosensitisers are employed for water purification and treatment of waste. There is also an increasing demand for more sustainable processes for production of “fine” chemicals without the formation of undesirable toxic wastes, this is the so called “green” chemistry. The MPc complexes are being employed as catalysts for both formation of “fine” chemicals and for treatment of water. For use in photocatalysis (photosensitization), metalloporphyrins and metallophthalocyanines complexes containing non-transition metal ions are employed. For security applications photosensitisers are explored in the protection of lightsensitive elements such as optical sensors, human eyes and other light sensitive material from sudden and intense light sources. This application is based on a property referred to as optical limiting. When light interacts with light-sensitive material or elements, damage may occur if a protective devise is not available. This application has become of importance in warfare, where in many cases laser weapons are used as threats, especially for civil pilots on landing approach or in the army. In solar energy generation, new affordable photovoltaic solar cells that can be used to provide electricity independent from an installed grid is an attractive way of a sustainable supply with electricity. A word to thank the authors who participated and the referees who made a precious contribution to the quality of the book? Tebello Nyokong Vefa Ahsen
Contents
1
Design and Conception of Photosensitisers .......................................... Fabienne Dumoulin
2
Recent Developments of Synthetic Techniques for Porphyrins, Phthalocyanines and Related Systems ....................... Ayşe Gül Gürek and Catherine Hirel
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47
3
The Contribution of Theoretical Chemistry to the Drug Design in Photodynamic Therapy ..................................... 121 Angelo D. Quartarolo, Nino Russo, Emilia Sicilia, and Carlo Adamo
4
Photochemical and Photophysical Characterization ........................... 135 Mahmut Durmuş
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Sensitization of Singlet Oxygen Formation in Aqueous Media ................................................................................... 267 Nina Kuznetsova
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The Use of Phthalocyanines and Related Complexes in Photodynamic Therapy .................................................. 315 Rodica-Mariana Ion
7
Combination Therapy: Complexing of QDs with Tetrapyrrols and Other Dyes......................................................... 351 Vladimir Maslov, Anna Orlova, and Alexander Baranov
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Exogenously Induced Endogenous Photosensitizers............................ 391 Gesine Heuck and Norbert Lange
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Photocatalytic Degradation of Pollutants with Emphasis on Phthalocyanines and Related Complexes ........................................ 433 Alexander B. Sorokin
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Photosensitisation and Photocatalysis for Synthetic Purposes ............................................................................ 469 Lucia Tonucci, Alessandro Cortese, Mario Bressan, Primiano D’Ambrosio, and Nicola d’Alessandro
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Photosensitizers in Solar Energy Conversion ....................................... 527 Katja Willinger and Mukundan Thelakkat
12
Chromophores for Optical Power Limiting.......................................... 619 Yann Bretonnière and Chantal Andraud
Index ................................................................................................................. 655
Contributors
Carlo Adamo Laboratoire d’Electrochimie, Chimie des Interfaces et Modélisation pour l’Energie, CNRS UMR 7575, Ecole Nationale Supérieure de Chimie de Paris – Chimie Paristech, 11 rue P. et M. Curie, F-75231 Paris Cedex 05, France,
[email protected] Chantal Andraud Laboratoire de Chimie de l’ENS Lyon, UMR 5182 CNRS-ENS Lyon, Université de Lyon, 46 allée d’Italie, 69364 Lyon, France,
[email protected] Alexander Baranov St. Petersburg State University of Information Technologies, Mechanics and Optics, Kronverksky pr. 49, St. Petersburg 197101, Russia,
[email protected] Mario Bressan Department of Science, University “G.D’Annunzio” of Chieti and Pescara, Viale Pindaro, 42, Pescara, Italy,
[email protected] Yann Bretonnière Laboratoire de Chimie de l’ENS Lyon, UMR 5182 CNRS-ENS Lyon, Université de Lyon, 46 allée d’Italie, 69364 Lyon, France,
[email protected] Alessandro Cortese Department of Science, University “G.D’Annunzio” of Chieti and Pescara, Viale Pindaro, 42, Pescara, Italy,
[email protected] Nicola d’Alessandro Department of Science, University “G.D’Annunzio” of Chieti and Pescara, Viale Pindaro, 42, Pescara, Italy,
[email protected] Primiano D’Ambrosio Department of Science, University “G.D’Annunzio” of Chieti and Pescara, Viale Pindaro, 42, Pescara, Italy,
[email protected] Fabienne Dumoulin Chemistry Department, Gebze Institute of Technology, PO Box 141, 41400 Gebze, Kocaeli, Turkey,
[email protected] Mahmut Durmuş Chemistry Department, Gebze Institute of Technology, PO Box 141, 41400 Gebze, Kocaeli, Turkey,
[email protected] Ayşe Gül Gürek Chemistry Department, Gebze Institute of Technology, PO Box 141, 41400 Gebze, Kocaeli, Turkey,
[email protected] ix
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Contributors
Gesine Heuck School of Pharmaceutical Sciences, University of Lausanne, University of Geneva, 30, Quai Ernest Ansermet, CH – 1211 Geneva 4, Switzerland,
[email protected] Catherine Hirel Chemistry Department, Gebze Institute of Technology, PO Box 141, 41400 Gebze, Kocaeli, Turkey,
[email protected] Rodica-Mariana Ion Analytical Department, National Institute of R&D for Chemistry and Petrochemistry – ICECHIM, 202 Splaiul Independentei, Bucharest 060021, Romania Faculty of Materials Engineering, Mecathronics and Robotics, Valahia University, 013200 Targoviste, Romania,
[email protected] Nina Kuznetsova Federal State Unitary Enterprise “State Scientific Centre “Organic Intermediates and Dyes Institute” (FSUE“SSC”NIOPIK)”, B. Sadovaya str., 1, block 4, Moscow 123995, Russia,
[email protected] Norbert Lange School of Pharmaceutical Sciences, University of Lausanne, University of Geneva, 30, Quai Ernest, Ansermet, CH – 1211 Geneva 4, Switzerland,
[email protected] Vladimir Maslov Center of Information Optical Technologies, Saint-Petersburg State University of Information Technologies, Mechanics and Optics Saint-Petersburg, st. Petersburg 197101, Russia,
[email protected];
[email protected] Anna Orlova St. Petersburg State University of Information Technologies, Mechanics and Optics, Kronverksky pr. 49, St. Petersburg 197101, Russia,
[email protected] Angelo D. Quartarolo Dipartimento di Chimica and Centro di Calcolo ad Alte Prestazioni per Elaborazioni, Parallele e Distribuite-Centro d’Eccellenza MIUR, Universita’ della Calabria, I-87030 Arcavacata di Rende (CS), Italy,
[email protected] Nino Russo Dipartimento di Chimica, Università della Calabria, Via P. Bucci cubo 14c, I-87036 Rende, Italy,
[email protected] Emilia Sicilia Dipartimento di Chimica and Centro di Calcolo ad Alte Prestazioni per Elaborazioni, Parallele e Distribuite-Centro d’Eccellenza MIUR, Universita’ della Calabria, I-87030 Arcavacata di Rende (CS), Italy,
[email protected] Alexander B. Sorokin Institut de Recherches sur la Catalyse et l’Environement de Lyon – IRCELYON, UMR 5256, Université Lyon 1, 2, Avenue Albert Einstein, 69626 Villeurbanne Cedex, France,
[email protected] Mukundan Thelakkat Applied Functional Polymers, NW II, Room 363, University of Bayreuth, 95440 Bayreuth, Germany,
[email protected] Lucia Tonucci Department of Science, University “G.D’Annunzio” of Chieti and Pescara, Viale Pindaro, 42, Pescara, Italy,
[email protected] Katja Willinger Applied Functional Polymers, B6, Room 12, University of Bayreuth, 95440 Bayreuth, Germany,
[email protected] Abbreviations
Abs ADMA ADPA AIP AIST AK ALA ALA 5-ALA ALAD ALAS Al-TSPc AOP AP ARN AT ATO ATR-FTIR AZO BAT BBB BCC BHDC [bmim]BF4 [bmim]PF6 BNCT BPD-MA CaspACE
CB
Absorber Antracene-9,10-bis-methylmalonate Anthracenedipropionic acid Acute intermittent porphyria Advanced industrial science and technology Actinic keratosis 5-aminolevulinic acid Aminolevulinic acid 5-amino levulinic acid ALA–dehydratase ALA-synthetase AlOH-tetrasulfophthalocyanine Advanced Oxidation Processes Apurinic/apyrimidinic sites in DNA on RNA Acid ribonucleic Adenine thiamine Antimony doped tin oxide Attenuated total reflectance - fourier transform infrared (spectroscopy) Aluminium doped zinc oxide Brain adjacent to tumour Blood brain barrier Basal cell carcinoma Benzyl-n-hexadecyldimethyl ammonium chloride 1-Butyl-3-methylimidazolium fluoride-boron trifluoride 1-Butyl-3-methylimidazolium fluoride-hexafluorophosphate Boron-neutron capture therapy Benzoporphyrin derivative monoacid In Situ Marker that provides fluorogenic substrates and inhibitors that allow quantitative measurement of Caspase-1 and Caspase-3 protease activities Conduction band xi
xii
CDCA CEL Chle6 CLSM 1-ClNP CNV COPO 2-CP 3-CP 4-CP CSF CTAC CuP d.r. DBU DCA DCA DCC DCP DCQ DDQ DFO DFT DMAE DME DMF DMF DMPO DMPO DMSO DNA DPA DPBF DSC DTPA DTPC e.e. EDOT EDTA EDTA EMIB(CN)4 [emim]AlCl4 EPR EPR
Abbreviations
Chenodeoxycholic acid Cremophore EL Chlorin e6 Confocal laser scanning microscopy 1-chloronaphthalene Choroidal neovascularization Coproporphyrinogen III oxidase 2-chlorophenol 3-chlorophenol 4-chlorophenol Blood-cerebrospinal fluid Cetyltrimethylammonium chloride Copper [5,10,15,20-tetra(4-tertbutylphenyl)]porphyrin Diastereoselectivity ratio 1,8-Diazabicyclo[5.4.0]undec-7-ene 9,10-Dicyanoanthracene Deoxycholic acid N,N’-dicyclohexylcarbodiimide 2,4-dichlorophenol 2,6-dichloro-1,4-benzoquinone 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone Deferoxamine Density functional theory Dimethylamino ethanol Dimethyl ether N,N-Dimethylformamide N,N¢-dimethylformamide 5,5-dimethyl-1-pyrroline-1-oxide 5,5-dimethyl-1-pyrroline-N-oxide Dimethylsulfoxide Deoxyribonucleic acid 1-decylphosphonic acid 1,3-diphenylisobenzofuran Dye-sensitized solar cell Diethylenediaminepentaacetic acid Di-(N,N-trimethylammoniumpropylene)-3,4,9,10-perylenebiscarboximide Enantiomeric excess 3,4-ethylenedioxythiophene Ethylenediaminetetra-acetate Ethylenediaminetetraacetic acid 1-ethyl-3-methylimidazolium tetracyanoborate 1-Ethyl-3-methylimidazolium chloride-aluminium(III) chloride Electron paramagnetic resonance Enhanced permeability and retention
Abbreviations
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Er:YAG Et2S Et2SO EtAc EtOH FC FCS FDA FePcS FeTPPS FRET FTO GABA GC GC-MS GIT Gly GZO H2P H2Pc H2TCP H376 HDMA HMDS HOMO HONb HPD HpD HPPH HTM i-Pr2NEt IL ISC ITO LC LDH L-DSC LOX LSR-SF-SR LUMO MAL MB MBP MBR MC
Erbium:yttrium-aluminum-garnet Diethyl sulfide Diethyl sulfoxide Ethyl acetate Ethanol Ferrochelatase Fetal calf serum American Food and Drug Administration Iron tetrasulfophthalocyanine Iron tetrasulfophenylporphyrin Fluorescence (or Förster) resonance energy transfer Fluorinated tin oxide g -amino butyric acid Guanine cytosine Gas chromatography coupled with mass-spectrometry Gastro intestinal tract Glycine Gallium doped zinc oxide Metal free [5,10,15,20-tetra(4-tertbutylphenyl)]porphyrin Metal free phthalocyanine Tetracarboxyphenylporphyrin Oral squamous cell carcinoma-derived cells n-hexadecylmalonic acid Hexamethyldisilazane Highest Occupied Molecular Orbital N-hydroxy-5- norbornene-2,3-dicarboximide Hematoporphyrin Hematoporphyrin derivative (2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide-a) Hole transport material N,N-Diisopropylethylamine Ionic liquid Inter-system crossing Indium tin oxide Ligand centred Lactate dehydrogenase hydrogen Liquid-state dye-sensitized solar cell Human melanoma cells Transplantable sarcoma in rat induced by Rous sarcoma virus strain Lowest Unoccupied Molecular Orbital 5-ALA methylester Methylene blue Maltose binding protein Mitochondrial benzodiazepine receptor Metal entered
xiv
MC540 2-ME MEM MLA MLCT MPA MPc MPc MPcS MPcS4 MPcSn MSA MTCP mTHPC MTT MV MW nBCC [NBupy]AlCl4 NC-TPP NLS NMP 1 O2 3 O2 O/W OCPc OEP ORL P3HT P3TAA PACT PAH PAN PBG PBGD PBGS PBS Pc Pc4 PCNA PCP PD PDT PEDOT
Abbreviations
Merocyanine 540 2-mercaptoethanol Eagle’s minimal essential medium Methyl aminolevulinate Metal-to-ligand charge transfer 3-mercaptopropionic acid Metal phthalocyanine complex Metal phthalocyanine Metal tetrasulfophthalocyanine Tetrasulfonated metallophthalocyanines Metal sulfophthalocyanine obtained by sulfonation, n = 2,3 Methanesulfonic acid Meso-tetra(4-carboxyphenyl)porphine Meso-tetra-phenyl-chlorine Methylthiazol tetrazolium bromide Methylviologen Microwave Nodular basal cell carcinoma N-Butylpyridinium-aluminium(III) chloride N-Confused tetraphenylporphyrin Nuclear localization sequence 1-Methyl-2-pyrrolidinone Singlet oxygen Ground state oxygen Oil in water Octacarboxyphthalocyanine Octaethylporphyrin Oto-rhino-laryngology Poly(3-hexylthiophene) Poly(3-thiophenylacetic acid) Photodynamic antimicrobial chemotherapy Polycyclic aromatic hydrocarbon 1-(2-pyridylazo)-2-naphthol Porphobilinogen Porphobilinogen deaminase Porphobilinogen-synthase Phosphate buffer solution Phthalocyanine HOSiPcOSi(CH3)2(CH2)3N(CH3)2 – Si-phthalocyanine with long axial ligand applicable in PDT Proliferating Cell Nuclear Antigen Pentachlorophenol Fluorescence photodetection Photodynamic therapy Poly(3,4-ethylenedioxythiophene)
Abbreviations
PEG PET PGMEA PI PMII POM PPGIX PPIX PROTO PS PVP Py QD r.t. RB RB RCPV RhB ROS RPE SA SCC SCWO SDS S-DSC SMCC SnET2 spiro-OMeTAD SRB STV TAPc TAPP TBAB TBADT tBP TCO TCP TCPc TEMP TEMPO TEWL Tf TfR TGA
xv
Polyethylene glycol Photo-induced electron transfer Propylene glycol methyl ether acetate Propidium iodide 1-propyl-3-methylimidazolium iodide Polyoxometallated metal complexes Protoporphyrinogen IX Protoporphyrin IX Protoporphyrin IX oxidase Photosensitizer Poly(vinylpyridine) Pyridine Quantum Dot Room temperature Rose bengal dye Rose Bengal Research center for photovoltaics Rhodamine B Reactive oxygen species Retinal pigment epithelium Salicylic acid Squamous cell carcinoma Supercritical water oxidation Sodium dodecylsulfate Solid-state dye-sensitized solar cell Succinimidyl-4-(N-maleimidomethyl) cyclohexane-1-carboxylate Tin ethyl etiopurpurin 2,2¢,7,7¢-tetrakis(N,N-di-p-methoxyphenylamine)-9,9¢spirobifluorene Sulforhodamine B Streptavidin Tetraaminophthalocyanine Meso-tetra(p-trimethylaminophenyl)porphine Tetrabutylammonium bromide Tetrabutylammonium decatungstate 4-tert-butylpyridine Transparent conducting oxide 2,4,6-trichlorophenol Tetracarboxyphthalocyanine 2,2,6,6-tetramethyl-4-piperidone 2,2,6,6-tetramethyl-4-piperidone-N-oxyl Transepidermal water loss Transferrin Transferrin receptor Thioglycolic acid
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THF TMGT TOC TOF TON TOPO TPA TPA TPD TPP TPPA TPPS TSPc TSPP TX UP UROD UROS UV Vis WAO Zn-Tmtppa tF tT Fd FF FT FD
Abbreviations
Tetrahydrofuran 1,1,3,3- N,N,N¢,N¢-Tetramethyl-guanidinium trifluoroacetate Total organic carbon Turnover frequency Turnover number Trioctylphosphine oxide Two-photon absorption Thiopropionic acid Triphenyldiamine Tetraphenylporphyrin Tetrapyridinoporphyrazine 5,10,15,20-tetra-p-sulphonato-phenyl-porphyrin Tetrasulfophthalocyanine Meso-tetra(4-sulfonatophenyl)porphine Triton X-100 Human epidermal keratinocytes Uroporphyrinogen III decarboxylase Uroporphyrinogen III synthase Ultraviolet Visible Wet air oxidation Zn-tetramethyl-tetra-2,3-pyridinoporphyrazine Fluorescence lifetime Triplet lifetime Photodegradation quantum yield Fluorescence quantum yield Triplet quantum yield Singlet oxygen quantum yield
Chapter 1
Design and Conception of Photosensitisers Fabienne Dumoulin
Abstract This chapter resumes the general strategies and the last progresses in the design of photosensitisers, with chosen examples, many of them being extracted for the last 5 years literature.
1.1 1.1.1
Introduction Some Definitions
Let’s start with some definitions. This chapter deals with the design, the conception of photosensitisers. The design of a molecule consists in defining a molecular structure that will be synthesised. Designed molecules aim at exhibiting properties for specific utilisations in a more or less fundamental and/or applicative extend. The design of a molecule requires a minimum of knowledge about these targeted properties and/or applications, and a good dialogue with the concerned people. The design is thus a multidisciplinary process, at the interface of several fields [1, 2]. While designing molecular structures, eventual synthetic limitations should be kept in mind, as it is always easier to imagine, to draw a molecule on paper, than to make it. “Design”, “conception” are words implying a conscientious, volunteer demarche … but the contribution of random, serendipity shouldn’t be forgotten! Two roots are easily identified in the word “photosensitiser”: photo means in Greek light, and the Latin word “sensus” means perception, deals with what is likely
F. Dumoulin (*) Chemistry Department, Gebze Institute of Technology, PO Box 141, 41400 Gebze, Kocaeli, Turkey e-mail:
[email protected] T. Nyokong and V. Ahsen (eds.), Photosensitizers in Medicine, Environment, and Security, DOI 10.1007/978-90-481-3872-2_1, © Springer Science+Business Media B.V. 2012
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F. Dumoulin
to feel, to detect, to be affected by external effects, with variable perception threshold of the intensity of these effects. The basic meaning of photosensitiser is “something affected by light”. This definition is in our case restricted to photodynamic events, to the cases in which the interaction between the photosensitiser and the light occurs in combination with a third partner: oxygen, converted into singlet oxygen. On a strictly photophysical point of view, a photosensitiser is a molecule which upon irradiation at appropriate wavelengths is converted into its excited singlet state. When turning back to its electronic ground state, energy can be transferred via an inter-system crossing to oxygen which is in turn excited into its singlet radical form: singlet oxygen (Type II photosensitisation). Other reactive oxygen species (ROS) can be generated as well by direct electronic transfer from the excited photosensitiser to the molecule (Type I photosensitisation). Most of the photosensitisation reactions are Type II processes, on which will be focus along this chapter. As the events of photodynamic processes are known at an electronic level, the help of theoretical chemistry may be invaluable while designing photosensitisers, see relevant chapter of this book [3, 4].
1.1.2
Different Types of Photodynamic Actions
The singlet oxygen generated during a Type II photodynamic process [5] can be used in different applications, not only in medical fields, but as well for environmental or synthetic purposes. Medical applications Besides the most-known use for cancer treatment, photodynamic therapy is used in the treatment of age-related macular degeneration. Internal Photodynamic Antimicrobial Chemotherapy (PACT) is successfully used to clean and heal infected wounds. At an external level it is used to disinfect surfaces requiring complete aseptisation, such as hospital working places, including surgery-devoted devices. A very large majority of the photosensitisers are for these medical applications. Antimicrobial comprises antibacterial, antiviral [6, 7] and antifungi effects, for blood sterilisation [8, 9]. The number of reviews dealing with the state-of-the-art of the development of photosensitisers at regular intervals highlights the last improvements of the technique [10–13]. Environmental applications Photodynamic processes can be used for water-remediation and pollutants remediations. In the first case it another antimicrobial use, when in pollutants remediation the singlet oxygen is used to oxidize pollutants into environmental safe derivatives. This later issue will be detail in another section of this book (see relevant chapter of this book).
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Design and Conception of Photosensitisers
3
Synthetic applications The oxidative effects of photodynamically generated singlet oxygen can be used for synthetic purposes in oxidation reactions, a topic described later on in the book (see relevant chapter of this book).
1.1.3
Required Properties of Photosensitisers
The required properties of photosensitisers are frequently listed in reviews devoted to this topic [14–17]. A good generation of singlet oxygen, quantified by its quantum yield and lifetime, is the first desired for Type II photosensitisation. The mechanisms from energy and transition point of view are detailed in another chapter. The second important issue is the localisation of the photosensitiser selectively at its action site, as the singlet oxygen is generated and active at the immediate surrounding of the photosensitiser. The targeted application may imply specific features for the photosensitiser: absorption in the biological therapeutic window (at wavelengths not absorbed by the biological molecules such as heme proteins), in the near infra-red region of the electromagnetic spectrum [18, 19], and/or appropriate amphiphilicity [17]. Water-solubility is required for uses in aqueous media, and more especially medical and biological applications, with different chemical possibilities depending on the nature of the photosensitiser [20]. Cationic structures are needed for antibacterial PDT (quaternized substituted porphyrins or phthalocyanines, phenothiazinium, poly-L-lysine/chlorin e6 conjugate [21, 22]).
1.2
1.2.1
Presentation of the Different Types and Generations of Photosensitisers The Different Types of Photosensitisers
Tetrapyrrole-based structures The most represented class of photosensitisers is based on a tetrapyrrolic structure, with a strong occurence of porphyrins (1) and phthalocyanines (2) [23, 24]. Chlorins (3), bacteriochlorins (4), and other related tetrapyrrolic derivatives as porphycenes (5), texaphyrins (6), are being used as well in a less important extend. Expanded structures are reported with still scarce investigations [25]. BODIPY (for boron-dipyrromethene) (7), firstly developed for its fluorescence [26, 27] and other optical properties, is now extremely promising as photosensitiser [28]. Its aza derivatives proved to have excellent tunable singlet oxygen generation properties [29].
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ALA The approved and widely used 5-Aminolevulinic acid (ALA) (8) is actually a precursor of the photosensitising molecule: protoporphyrin IX [30]. ALA is a precursor at the basic stage of the haem biosynthesis, protoporphyriIX being the last step between haem. The photosensitiser is then formed in situ using the cell-available enzymatic sources. Some modifications of its structure were designed to produce more efficient derivatives. Phenothiazinium (9) Methylene blue is historically the first member of this category of compounds. It was firstly used in malaria treatment in the nineteenth century. These intrinsically cationic derivatives are especially suitable for antibacterial treatment. Hypericin (10) This chromophore of naphthodianthrone type is extracted from St John’s wort, and remains only partially studied, either from its chemistry (derivatized structures are uncommon) or physiological effects. Besides its curative use as photosensitiser, it is employed as well as a fluorescence marquor for cancer cells, for which hypericin has a high affinity [31]. N N NH
N M
N
N
N
HN
N
2
N H
R
N
N H N
HN
N
3
N
H N
4
N
R N
N
CI – + H3N
N
O
R
R
6
F
7
N H N
5 OH O
OH
OH O
OH
HO HO
R OH
B
1.2.2
NH
R
R
NH
N HN
N
N
1
R
NH
N
N
O
F
8
S
+
9
10
The Different Generations of Photosensitisers
Another way to classify the photosensitisers has a more historical perspective. The first developed photosensitisers, hematoporphyrin derivatives (HpD) and its purified fraction Photofrin® exhibited several drawbacks that immediately induced a need for new molecules [32]. They are commonly designated as the first generation of photosensitisers. Following the development of new strategies, so-called second and third-generation of photosensitisers have been developed.
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Design and Conception of Photosensitisers
5
Second generation photosensitisers are mainly tetrapyrrolic derivatives based on porphyrins and phthalocyanines. They are well-defined and characterized. A major representative is the clinically used Verteporfin, known as well as Visudyne. The third generation defines photosensitisers targeting the tumours, as for example antibody-specific derivatives. If no new photosensitising structures are being developed as far as we know, needs lie more in the optimization of the existing ones’ properties. Several photosensitisers have been clinically approved in the last decades and are commercially available [13, 33].
1.3
Why New Photosensitisers?
It seems that interrogations about the need for new photosensitisers rise in the last years. The talk given by Professor David A. Russell (University of East Anglia, UK) during the 2008 edition of the International Symposium on Photodynamic Therapy and Photodiagnosis in clinical practice (Bressanone-Brixen, Italy, 7th edition, 7–11 October 2008) was entitled “Do we need any more new photosensitisers for PDT?” If chemists produce numerous new structures at a quite important rythme, the fact is that their biological evaluation doesn’t follow the same tempo, as the procedures are much more time-consuming. In addition, many researches at a biological and clinical stage are performed with already approved photosensitisers, in order to shorter the time of procedure approval if the case arise. This is another point that may the work of chemists maybe less performant. Each design of new structures doesn’t benefit form biological results of relevant structures, and anyway most of the new photosensitisers will never have their biological activity studied, due to a lack of suitable laboratories. The need for new structures was nevertheless obvious since the development of the first hematoporphyrin derivative [34]. This can lead us to one more definition: The efficacy of a photosensitiser, on an application point of view. There is a direct relationship, even if not always known, between the structure of a molecule, its properties and from these properties the use that can be made of this molecule, in a word, its applications (Fig. 1.1). Depending on the researcher/team/background, etc… the diagram goes one way or the other one in the process [35]. Two strategies are exploited, and can be developed following different ways for the design of new photosensitisers: – The photophysical and photochemical optimization of the singlet oxygen generation, the active species of photodynamic process – The selective accumulation of the photosensitiser in the targeted tissues or against the targeted pathogens (case of aPDT)
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Applications
Properties
Structure Fig. 1.1 Structure, properties and applications relationships
1.4
Strategies to Design Photosensitisers
1.4.1
Several Working Axes
The most commonly developed strategies to improve a photosensitiser’s efficacy are presented in Fig. 1.2. Some of these strategies can be combined.
1.4.2
Optimization of Photophysical and Photochemical Properties
Two orientations lead the optimization of the photophysical properties of a photosensitiser: a better generation of singlet oxygen, the active species in a photodynamic process, and the use of excitation wavelengths within the therapeutic window. 1.4.2.1
Optimization of the Singlet Oxygen Generation
The electronic events leading to the generation of singlet oxygen via an intersystem crossing between the photosensitiser and oxygen at its fundamental electronic state can be optimized thanks to several modifications. The quantification of the efficacy of the event is made by the measurement of the singlet oxygene quantum yield and lifetimes. In addition, other physical and biophysical parameters relieving of physics field [36], such as the optimization of light source for better light penetration for example must be cited but won’t be further detailed as they are outside the scope of this chapter devoted to the role of chemists. Incorporation of Heavy Atoms The basic properties of the photosensitising structures can be tailored mainly by the incorporation of heavy atoms [37, 38]. This positive effect [39] increasing the
1
Design and Conception of Photosensitisers
7
Fig. 1.2 Strategies to improve photosensitisers’ properties and efficacy
ISC has been demonstrated in vitro on a wide range of pyrrolic and non-pyrrolic photosensitisers [40]. The effect of the introduction of halogens atoms on photosensitisers such as 5,10,15,20-tetrakis(3-hydroxyphenyl)porphyrin has been extensively studied [41] and widely utilized to optimize their photophysical and photochemical properties thanks to a more efficient intersystem crossing. A library of halogenated bacteriochlorins has been constituted for systematic investigation purposes [42]. Ng and coll. aimed at increasing the efficacy of silicon phthalocyanines by incorporating halogens atoms. Two octahalogenated silicon phthalocyanines bearing axial PEG [43, 44] were designed and prepared (11, 12), one octabrominated and the other one octachlorinated, whereas the analogous octaiodo derivative couldn’t be obtained. A second axially glucose-substituted with PEG spacer were prepared under their halogenated or non-halogenated form. In order to balance the aggregative effect of the chlorine atoms in aqueous media but to benefit from its heavy effect, only two chlorines were introduced on phthalocyanine (13). Following these results confirming the positive effect of the presence of chlorine atoms, the diaxially diisopropylidene galactose-substituted phthalocyanine (14) [45, 46], the corresponding chlorinated derivatives (15–17) were designed and prepared [47].
8
F. Dumoulin Me
Me O n
O n O
Cl
Br
Cl O
Cl
Br O
Br
Cl
N
O Cl
Br
n: 550 or 750
Me
O
O
O
Si
N
13
O
OO
O
OO
O
O
Cl
O N
N
N
N
Si
N
N
N
N
N
Si
N
O
O
O
O
N
15
Cl
Si
N
N
N
N N
Cl Cl
O
O
Cl Cl
O O
O OO
OO
14
N
O
O OO
N
O
O
O O
Cl
O N N
N
N
N
N
O
Cl Cl
N N
OO
O
O O
Cl
N N
O
OO
O
O
Cl
O
N
N
O
O
O O
N N
O
O O
n
12
O
O O
Me
11
O
O O
N
Br
On
O
Br
O
O
N
Si
N
O
Br
Cl
N
N N
N N
Cl
O
N
N
N
N N
Cl
Cl
N Si
N
N
Si N
O
O Cl
N
N
N
O Br
N
N
OO
16
17
Chemistry of BODIPY allows versatile modifications [48]. Similar attempts were conducted on BODIPY dyes [49], with the preparation of a rather complete series of BODIPY derivatives (18–22) bearing one, two or three iodine atoms at various positions, designed to investigate fine tuning of the expected properties.
I
I
I N
N
I
I N
N
B
B
18
19
NaO3S
N
N
SO3Na
B
20 COOH
I
I N
N B
21
I
I N
N B
22
Same effects were observed for the iodinated hypericin (23), designed with the same purpose to benefit of this heavy atom effect [50].
1
Design and Conception of Photosensitisers
9
OH
O
OH
OH
O
OH
I HO HO I
23 Heavy metals such as platin and palladium are introduced on photosensitisers to successfully enhance their photophysical properties. Two examples are currently at an advanced clinical trials stage: The palladium(II) complex of bacteriopheophorbide : TOOKAD (24) designed by Salomon and Scherz [51–53] and the tin complex of etiopurin (25). O
EtOOC
H N
N
H N Cl N Sn
Pd N
N
H
N Cl N H
HOOC
MeOOC H O
24
25
Following this strategy, platin and palladium were introduced on pyrrolidine-fused chlorins (26 and 27), with a significant increase of the singlet oxygen generation [54]. F
F
F
F
F
F
F
F N
F
N F
N
F
Pt F
N
F
F
F
F
F
F
F
F N
F N
F
F
F
F
N F
N
F
Pd F
N
F
F N F
F
F
F
F
F F
F
F
26
27
F
10
F. Dumoulin
In our case, we played with the central metal of phthalocyanines. Aware of the good water-solubilising effect of glycerol, we compare in a preliminary study the properties of two sets of solketal substitued phthalocyanines metalated by platinum and zinc (28–31, M: Zn or Pt) [55].
O
O
O
O
O O
O
O
O
N
M
N
N
N N O
O
O
28
N
N M
N
O O
O O
O
N
O
O
O
N
N N
O
N
O O
O O O O
29
O O O
N M
N O O
O N
O
N
N
O
O O
N
N
N
O O
N
N
N
O
O O
O
O O
N
O O N
M
N O
N
N
O
O
O
O O
N
O
O
O
O
O
O O
N N
O
O
O
O O O
O
30
O
O O
O O
31
More rare photosensitisers such as chalcogenapyrylium dyes [56] have been designed as well with similar approach.
Inhibition of Aggregation Aggregation quenches the electronic transferts required to generate the singlet oxygen and has therefore a negative effect on a photophysical point of view. This stacking tendency is particularly problematic with phthalocyanines, far more aggregating than other photosensitisers [57]. A common aggregation-lowering effect is provided by bulky substituents, which sterically prevent the stacking of the photosensitisers. This avoids or limits the undesirable quenching of the electronic events. The design of the octatbutylthio substituted Zn(II) phthalocyanine 32 compared with the analoguous substituted by thiooctyl chains proved to be pertinent towards this aim, with the expected benefits in terms of photophysical properties [58].
S
S S
S N N
N Zn
N N
N N
N S
S S
S
32
1
Design and Conception of Photosensitisers
11
Axial substitution of center metals or pseudo-metals has a similar effect: aluminium and silicon phthalocyanines are known to exhibit an enhanced efficacy due to a low aggregation. Non-peripherally substituted phthalocyanines are less aggregated than corresponding ones, due to the intercalating effect of the substituents between the macrocycles [59].
1.4.2.2
Shifting of the Absorption Toward the Therapeutic Window
Due to numerous biologic components absorbing at various wavelengths, ideal photosensitisers are excited by the small range wavelengths in the near-infra region of the visible spectrum, avoiding undesired interactions between the light and biological chromophores. Excitation at such wavelengths offers in addition the advantage to penetrate more deeply the tissues. This range of wavelengths is called the therapeutic irradiation window (Fig. 1.3). Some photosensitisers have this property directly from their structure, when others can be modified to have their maximum absorption wavelength suitably shifted. Usual methods are the extension of the electronic delocalisation via an extended conjugation, or the nature and eventually position of the substituents. One must keep in mind anyway that red-light excitation can yet have negative effects for some cancers (ORL and oesophageal for example) when there is a risk to damage fine organ’s wall. In this case, photosensitisers are excited by green light to avoid such undesirable effects.
Fig. 1.3 Reprinted from Ref. [19] with kind permission of John Wiley & Sons, Inc.
12
F. Dumoulin
Extension of Conjugation On BODIPY, variation of extended conjugation at the 4-pyrrolic position was investigated through a series (33–41) designed to combined fine-tuned conjugation extension combined with tailored amphiphilicity [49]. COOMe
SO3H
COOH
COOnBu
CHO N
N
N
N
B F F
B F F
33
34
B F
N
N B
F
F
38
N
N
B
F
F
35
N
B F
F
F
37 COOMe
N
MeOOC
N
N
BuOn OC
B
B F
N
36
COOMe
COOMe
MeOOC
N
N
N
F F
F
N
F
40
39
COOnBu N B F
41
The extension of the chromophoric system of chlorin by exocyclic substituted double bond induced a bathochromic shift up to 60 nm in the case of 42, and 20 nm for 43, depending on the extension of the electronic delocalisation [60].
N
N
N
N Ni
Ni N
N
N
42
N
43
BODIPY-porphyrin [61] fused conjugate 44 were thus designed with an astonishing combining effect of the two chromophores.
F
F B N NH N
N HN
44
N
1
Design and Conception of Photosensitisers
13
Three BODIPY derivatives (45–47) combining water-solubility and absorption in the therapeutic window thanks to extended conjugation were designed [62], all including bromine heavy atoms and PEG chains. O
O
O O
O O
O
O
O
O
O
O O O
O
O
O
O O
O
O
Me
Me
O O
Br
Br
N
O
N B F
Me
Me
F
Br
Br
N B
Br
Br
N F
45
O
O
F O
O
O
O Br
O
O
O
O
O
O
Me N F
O
O O
O
O
O
F
O
O
O O
N B
O
O O
Br
Br
O
O
O Me
O
O
O
O
O
O
O
O
O
O
46
O O O
O O
O
O
O
O
O
47
On tetrapyrrolic photosensitisors, the extension of the electronic delocalisation can be induced by the addition of a second fused macrocycle. The preparation of fused bi and trinuclear phthalocyanines 48 and 49 shifted their respective absorption to the near infra red as often desired [63, 64] and previously reported [65] (Fig. 1.4). RO
N RO
N H
RO N
RO
N
N
H N
N
N
N
RO
OR
RO
N
N OR
RO
HN
NH
N
N
OR
RO
OR
N
OR
N H
RO N
RO
N N
N OR
N
OR
H N
N
OR
48
RO
N
OR
N
N
N HN
NH N
RO
N
OR
RO
N
OR
N
N
RO
N OR R:
HN
NH N
OR N
OR
49
Modification of Substituents: Nature and Position The substitution pattern of porphyrins and phthalocyanines is easily tunable. In the case of phthalocyanines, the nature and number of substituents (axial and/or macrocyclic: tetra, octa, peripheral, non-peripheral) has a direct important effect on the photophysical properties of the molecule. These parameters are discussed in the relevant chapter of this book and numerous publications [66, 67].
14
F. Dumoulin
Fig. 1.4 Reprinted from Ref. [63] with kind permission of John Wiley & Sons, Inc.
The mono carboxy phthalocyanine 50 (X: CH) and azaphthalocyanine 51 (X: N) were designed with several of these parameters in mind, the design being very well detailed along the manuscript [68]. It combines as said above the aggregation inhibition effect of the bulky tBu groups, a red-shifting effect of the thioether link [69], and in addition further functionalization opportunities.
S
S X
S
X N
X N
N
N X S
N
Zn
N
N X
N X
S X
X
COOH
S
50 X: C 51 X: N
Still for phthalocyanines, same substituents positioned on the non-peripheral position instead of the peripheral ones induce the desired bathochromic shift of 20–50 nm [59].
1
Design and Conception of Photosensitisers
1.4.2.3
15
Photosensitisers for New Excitation Modes
Two-Photon Excitation Recently, the generation of singlet oxygen by a two-photon absorption (TPA) process raised interest, with potential advantages still under investigation [70], with a likely long-term medical use. The main expected advantage is the overcoming of the limited penetration of one photon absorption. The design of relevant photosensitisers depends on the TPA based on different mechanisms [71]. The concerned structures are thus very different. The structures combine cores known to have good TPA properties (52–56 among others) and bearing water-solubilizing groups [72]. –
CH3SO4
H3C(OH2CH2C)3O
Br
Br
O(CH2CH2O)3CH3
N
N
HO3S
Br
Br
O(CH2CH2O)3CH3
52
–
CH3SO4 S
S
SO3K
H3C(OH2CH2C)3O
OMe
+
N+
MeO
53
54
–
CH3SO4 N
+
Br
Br
–
CH3SO4
S
+
S Br
N I
N N
–
N
+
I
–
Br
N+
55
56
Ruthenium complexes proved to be excellent TPA agent and 1O2 generator. Thus the complex below was designed to offered several of the required properties: membrane crossing thanks to suitable ethylene glycol substitution, the photosensitising core being a tri 5-fluorene-1,10-phenanthroline Ru(II) complex (57) [73]. O O O
O O
O O O
N
2
N
N Ru
N O O O
O
N
2 PF6
O
N O O
O
O
O O
O O
O
O O
57
16
F. Dumoulin
1O 2
PUNP
Vis
IR laser
Tumor cell
Drug + SiO2 Antibody
Fig. 1.5 Reprinted from Ref. [76] with kind permission of The American Chemical Society
Mediated Excitation by Upconversion A promising development of nanotechnology in PDT is the use of upconverting nanoparticles, made of lanthanides [74, 75]. Based on the conversion of lowerenergy light to higher-energy light through excitation with multiple photons, they offer the enormous advantages to be excited by infrared wavelengths, a desired property as it fit the biological window and avoid light-interaction with biological absorbing components. PUNP (photon upconverting nanoparticles) have the other required facilities. Its design is explained in the figure taken out of the paper (Fig. 1.5) [76]. Such nanoparticles, by being excited with different wavelengths, solve partially the problem of the tissues-light low penetration [77, 78]. The range of the application of these nanosystems seems to be infinite. This is obviously due to their striking tailorability. Recently, the development of porphyrin-nanosensors made possible the following of intracellular reactive oxygen species [79]. Immobilization of porphyrins on carbon nanotubes has been very recently described [80]. This is one example among the tenth newly described every year.
X-Ray Excitation Since the description of the feasible luminescence generation by X-ray on porphyrins [81], together with singlet oxygen generation, excitation by low dose irradiations is being developed [82].
1
Design and Conception of Photosensitisers
1.4.3
17
Optimization of Biological Parameters
It is important to have the photosensitiser accumulated in a maximum extend on its action site, that is to say on the cancer or bacterial cells. This implies, at the organism level, the in vivo targeting of an injected photosensitiser to the concerned organ (when local topical application for some reasons are not possible or preferred). At a local level, it implies the recognition of the cells to destroy (cancer cells among healthy ones), then a good cell uptake, which means a good membrane crossing of the photosensitiser. An optimized intracellular localization improved the PDT efficacy and thus intracellular targeting may be envisageable. Different strategies have been developed to answer one or more of these issues. In addition, the stability of the photosensitiser inside the organism must be balanced: long enough to reach its target but not too long to avoid poisonuous accumulative issues [15].
1.4.3.1
Optimized Membrane Crossing
Cell membranes are self-assembled structures made of amphiphilic components. Their crossing is therefore easier for amphiphilic molecules. Amphiphilic structures are obtained by introducing two types of substituents on a same molecule, one type being hydrophilic, the other one hydrophobic. The amphiphilic balance of the molecule can be tailored by the nature and number of each of these substituents, and easily combined with other features. Three silicon (IV) phthalocyanines (58–60) having asymmetric axial substitution (one diisopropylidene galactose facing one alkyl chain of various lengths) have been designed to be compared with the symmetrically substituted by two galactose (15) [46]. The design of this series is based on two points: the presence of carbohydrates supposed to be attracted by the highly metabolically active tumour zone, and the amphiphilicity favouring the cell uptake.
OO O O O
O
O
N
N N
Si
N
N
Si
N
O O OO
N
N
O
15
Si
N
O OO
N
O
58
Si
N
N O
O O
N
N N
N
N
O O
N
N N
N
N
N
N N
N N
N
O
O
N
N
O OO
O O
59
O OO
O O
60
N
N
18
F. Dumoulin
In the case of ALA (9), it has been demonstrated that several esterified derivatives have a better cell uptake and thus required less administration. This lead to the design of a rather complete set of ALA esters in order to investigate the influence of the nature of the added part (61–69 ) [30, 83]
Cl H3N
O OH
9 Cl H3N
O
Cl H3N
O
61
O O
Cl H3N
O
O
O
Cl H3N
O
O
O
Cl H3N
O
O
O O
64
O O
O
67
Cl H3N
O
63
O
O
66
Cl H3N
O
62
O
O
65
Cl H3N
O
Cl H3N
O O
O
68
O
69
From mixtures of sulfophthalocyanines (70–74) in the 1980s to the powerful porphyrazine (76) in 2009. The design through several years of photosensitising sulfonated phthalocyanines by van Lier and co-workers is a very good illustration of the design process (Fig. 1.6). Since the PDT properties of zinc (II) sulfophthalocyanines are known [84], and more especially of the adjacent di derivative, it was thought to be possibly because of it amphiphilic nature [85]. A next step was the design of other amphiphilic sulfophthalocyanines, this time with three sulfo units facing one alkyl moiety of various lengths (75) [86]. The following step was the modification of the macrocyclic structure, with the introduction of an annulated benzene ring likely to improve its absorption window and modify the amphiphilic balance again of the molecule (76) [87].
1.4.3.2
Targeting Photosensitiser-Conjugates: The Two Levels of the Design Process
In addition to the required photophysical and solubility properties, the photosensitiser bears a functional group suitable for grafting to targeting moiety. Two designing processes occur in this case: the design of the photosensitiser-targeting agent conjugate, and the design of the photosensitiser under a “graftable” form, with the appropriate functionalisation. The third aspect consisting of the eventual design of the activated targeting moiety isn’t our purpose and won’t be much evokated here.
Design of the Conjugates: Choice of the Targeting Moieties [88] Cancers have characteristic features that are likely to be targeted, presented hereafter and detailed in specific paragraphs afterwards.
1
Design and Conception of Photosensitisers
19 SO3Na
SO3Na
Step 1 A first design: water soluble sulfophthalocyanines Preparation of the different sulfonated Zn(II) phthalocyanines
N
N N Zn
N
N
NaO3S
SO3Na
Di opposite
71
N
72 SO3Na
SO3Na N
NaO3S
N
N
N
Di adjacent
Zn
N N
N
N N
N
N
N Zn
N
N
N SO3Na
N
N
N
N N
N
N
N
N NaO3S
SO3Na
NaO3S
SO3Na
Tri
Tetra
73
74
R
NaO3S
Step 3 Design of more versatile structures with similar amphiphilicity: 4 sulfo and 1 alkyl chain
N Zn
N
N
N
70
N
N Zn
N
Mono
Step2 Determination of the best one Hypothesis: its suitable amphiphilicity
N
N
N
N N
N Zn
N N
Synthetic strategy: coupling of aklynes to the monoiodo
N N
N NaO3S
SO3Na
75
R NaO3S
Step 4 Design of molecule with a better activation window Addition of an annulated benzene ring
N N
N Zn
N N
N N
N NaO3S
76
SO3Na
Fig. 1.6 Multi steps design leading to the porphyrazine 76 with optimized properties and PDT results
20
F. Dumoulin
The rapid development of the continuously dividing cells required high energy, leading to highly active metabolism needing the development of hypervascularisation to bring the required energy and nutriments. Targeting this vasculature system is an exploited mean to eradicate tumour [89, 90]. These two points, the elevated needs in nutriments and energy and the development of neovasculature to carry them are related but will be treated in two different parts. The conjugation of photosensitisers with cancer cells specific antigenic determinant is called photoimmunotherapy, and considered as one of the way to explore to improve photodynamic treatments [91, 92]. This strategy was mainly developed on tetrapyrrolic photosensitiser the number of targeting units grafted on a photosensitiser is an important part of the design, as well as the choice of the other units in case of asymmetrical substitution.
Design of the Functionalised Photosensitiser: Molecular Design and Synthetic Strategies Chemical Derivatizations Several activated functions are commonly used to graft the photosensitiser to the targeting moieties: COOH [93], –N=C=S [94–96], triple bond [97], amine [97], SO3H [98]. These groups react easily with functions present on proteins (case of antibodies), carbohydrates, vitamines or any azido derivatives via a click reaction. Eventuel presence of a spacer to maximize interactions. The presence of a spacer is commonly supposed to be desirable to avoid steric hindrance between the photosensitiser core and the target. Efficacy related to the nature and length of the spacer are routinely investigated (see examples below). Photoimmunotherapy The antibody has generally several reactive functions that can be chemically used for the covalent coupling with the photosensitiser. It depends on its aminoacid composition and on the accessibility of the active residues.
1.4.3.3
The Different Cancer Targeting Strategies
As said above, the biological level of targeting can be various: at a macroscale, the tumour system is targeted. The targeting is based on the high metabolism of the tumour and can be directed against the elevated energy and nutriments (vitamins) required by prolifering cells, or the hyper vasculature developed by the tumour. At a more local scale, the cancer cells can be differentiated from the healthy ones thanks to receptors specifically expressed by the proliferating cells. Then at an intracellular level, uptake into specific organelle is likely to improve the efficacy of the treatment.
1
Design and Conception of Photosensitisers
21
Targeting of the High Metabolism of Tumour Folic acid (77), as a vitamin (B9), is highly demanded by prolifering cells. This is the reason why cancer cells generally overexpress folate receptors [99]. Photosensitiser covalently binded to folic acid is therefore a potentially efficient cancer targeting conjugate. The folate-porphyrin conjugate 79 was designed for this purpose [100, 101], with a short spacer. On a synthetic point of view, the design of the coupling intermediate 78 includes the presence of the spacer and of a activate function for the amide bond creation, the folic acid being activated as well by the DCC-HONb method.
OMe
HO
O
O
N H
O
NH OH
NH OH
N N
N
NH2
O
MeO N
N
HN
NH2
N
77 OMe
78 OMe
O NH
N O
MeO N
HO
HN
HO
H N
HN
O
O
N H
N N
N N
NH2
79 OMe
In the case of folate-porphyrin conjugates 80 and 81, the folic acid moiety is derivatized and grafted on a N-hydroxysuccinimide activated carboxyporphyrin. The design of the two conjugates includes, in addition to the targeting effect of the folate, an investigation of the nature of the spacer, more or less hydrophilic [102, 103].
22
F. Dumoulin
OH
H2N
O O
N
N N
OH
N H
HN
N
O
NH
NH
N
O
NH
NH
N
N H
O
N HN
80
OH
H2N
O O
N
N N
N H
N
OH HN
O
O
N H
O
N HN
81
Biotin, another vitamin known as well as the B8 or H vitamin, is readily uptaken by dividing cells. This lead to the design of the biotine-conjugated aluminum phthalocyanine 82, using a cadaverine spacer [104]. This photosensitiser benefits as well from the modification of its amphiphilicity compared to the corresponding trisulfonated one, used without modification for the grafting of the biotin moieties. O N H
HN S O O N OH N N N O HN H
NH H S H
H N
H HN
H NH O
SO3H N
Al
N
H S
N N H N S O O
O
82
Carbohydrates, as the first and quickest available energy resource of cells, can be used as a substituent of photosensitisers with the same aim: taking advantage of the high metabolism of the prolifering cells to have carbohydrate-photosensitiser
1
Design and Conception of Photosensitisers
23
conjugates internalised by energy demanding cells. The reasons enounced by authors to design and prepare carbohydrates-functionalized photosensitisers are numerous and therefore the object of an entire section of the chapter. Endocrine receptors are overexpressed in tumour. In a steroid-receptor based approach, estradiol-photosensitiser conjugates have been designed and prepared. van Lier et al. prepared a series of several Zn(II) phthalocyanine monoconjugates (83–86) with small structural variations likely to modify the efficacy of the conjugate, and three sulfonates groups for the water-solubility [105]. The syntheses based on a Pd catalyzed coupling of the estradiol moieties was prealably optimized on organosolubles derivatives [106]. The biological activities of both the water-soluble and lipopihilic derivatives were compared. OH
OH SO3Na
N NaO3S
N N
N Zn N
SO3Na
O
O
N
N
N
N
NaO3S
N
N
N Zn N
SO3Na
N N N
SO3Na
83
84 SO3Na
O N NaO3S
N
N
N
N
Zn
OH
N
N
N
SO3Na
85
SO3Na O
N NaO3S
N N
N Zn N
N
OH
N N
SO3Na
86
Other conjugates with a porphyrin photosensitiser core have been designed as well [107, 108].
24
F. Dumoulin
Targeting of the Cancer Neoangiogenic System Angiogenic systems exhibit marquors that are extremely concentrated in tumour growing neovasculature. In this case, photosensitiser can be conjugated to antiangiogenic antibody directed against marker of angiogenesis. A commonly used antibody for such purposes is the antibody L19, specific to the EDB domain of fibronectin, a marker of angiogenesis. Bis(triethanolamine)Sn(IV) chlorin e6 has been conjugated to L19 (compound 87), via small modification of the photosensitiser [109]. H3C
COOH CH2COOH N
H3C N
Sn
CONH
2+
N
LP19 CH3
N CH2CH3
H 3C
87
With the same strategy, the antiangiogenic antibody L19, expressed in small immunoprotein (SIP) format, has been conjugated to different porphyrins (88–90), designed following different criteria: [110] – cationic substituents ensuring the water-solubility of the conjugate, – one SMCC (succinimidyl-4-(N-maleimidomethyl) cyclohexane-1-carboxylate) group, chosen as it reacts specifically with thiol functions and can advantageously used for covalent coupling with cysteine containing proteins, – spacer of different length. N N
O NH
O
N
NH
N
N N
N
HN
HN
O
HN
N
O
3I
N
O N H
N
N O
3I
N
89
88 N
O O NH
N
HN
HN
O
O
HN N
O
O
O
O
O
O
HN N O
3I
N
90
Neuropilin-1 is a receptor expressed by endothelial cells, thus very present in cancer neovasculature systems. It can be targeted by photosensitiser to enhance their accumulation in a tumour asphyxia strategy. This receptor is recognised by peptides
1
Design and Conception of Photosensitisers
25
exhibiting unfortunately an excessive degradation by peptidases [111]. A first neuropilin-targeted photosensitiser 91 was designed, made of a photosensitiser core: monocarboxylic tetraphenyl chlorin, covalently linked via an amide bond to a spacer bearing the targeting peptide.
N NH
HN N O
H N
ATWLPPR
O
91
A second step of this neuropilin tarteging strategy, aiming at overcoming the peptidase degradation, was the design of three pseudopeptides, more stable towards peptidases, and conjugated with the same photosensitiser [112]. It is interesting to note that for this series, the main point of the design process is the one of the targeting moiety which isn’t a “native” biomolecule, the photosensitiser itself remaining unmodified. Targeting of Cancer Receptors: Photoimmunotherapy Cancer cells may express specific receptors at their surface. Bombesine is a peptide recognised by a gastrin-releasing peptide receptor [98]. In the case of prostate cancer, this receptor is early expressed and its presence was correlated with elevated tumor aggressiveness, making its targeting judicious. This lead to the design of the photosensitiser 92 conjugating several features: good photopgysical and photochemical properties thanks to an aluminum phthalocyanine core, water-solubility provided by the presence of three sulfonates, a good intereaction with the receptor thanks to a spacer limiting steric hindrance from the phthalocyanine core. −O S 3 NH2
O
N −O S 3
N N
N OH Al N N
N
H N
O S N H O
O N H
O
N
SO3−
H N O
O N H NH
H N O
O N H
H N
O N H
O N
NH
H N
O NH2
O S
92
In order to target ovarian cancer, a photoimmunoconjugate was designed: chlorin e6 was conjugated with a poly Lys residue activated thereafter by a pyridyldithiopropionic acid N-hydroxysuccinimide ester and subsequently coupled with OC-125F (ab8)2, leading to the desired cationic conjugate [113–115]. Similar anionic derivatives with water-solubility provided by succinyl groups instead of the amino are reported.
26
F. Dumoulin
Other monoclonal antibodies have been used for photoimmunotherapy, conjugated to NCS functionalized porphyrins 93 and 94, which have different water-solubilizing patterns [116]. NCS
HO
NCS
OH
N
NH
CI
HN
N
N HN
N
OH
HO
OH
HO
N
NH N
CI
N
CI
93
94
Intracellular Targeting The intracellular repartition of the internalized photosensitiser has an effect as well of the overall PDT efficacy [117–120]. Maximum damaging of DNA is expected to considerably enhance PDT efficacy. It is therefore important in such strategy to concentrate the photosensitiser into the cell nuclei. As retinoic acid receptor are among the nuclear receptors, porphyrins retinamides conjugates (96–99) were designed, with two different retinoic acids (of cis and trans configuration), both grafted by an amide function on the mono aminoporphyrin 95 and the presence or not of a hydrophilic spacer [119].
N
N
HN
HN
NH N
95
N
H N
NH2 NH N
HN
H N
NH N
O
O
96
97 NH
N
N
HN
H O N
O O
98 NH N
N
H O N
O O
N H
HN
99
O
O
H N O
N H
O
O
H N O
1
Design and Conception of Photosensitisers
27
Selective DNA-binding properties of the polyamines derivatives lead to the design of spermine and spermidine conjugates to porphyrin and protoporphyrin IX, with an aliphatic spacer, see the structure of the spermidine-porphyrin 100 [120].
NH2
N
N
NH
O
NH2
N H O
HN
N
100
Targeting of nucleoporins, proteins controlling the nuclear pore-complex can be achieved by derivatization with nuclear localization sequence (NLS). Several constructs made of these peptidique sequence and chlorin e6 conjugated with polyLys residus have been designed for this purpose [118]. Mitochondria is another organelle that can be advantageously targeted. Porphyrins bearing mitochondria localization sequence have thus been designed (101) [121].
NH N
O
N N H
HN
O O
N H
O
MSVLTPLLLRGLTGSARRLPVPRAKIHSL
O 5
O
101
Besides the use of this labelled photosensitisers, derivatization with lipophilic cation is a mitochondria targeting means, due to the high potential of the mitochondria membrane [122], among which triphenylphosphine based cationic (102) [123], guanine (103) and biguanine (104) [121] porphyrins.
NH
N O
N
HN
P
NH N
102
NH2 NH2
N N H
HN
103
N
NH2
CI
NH N
NH2
N N H
HN
104
NH2
CI
28
F. Dumoulin
1.4.3.4
Case of Carbohydrates Substitution
The strong increase of carbohydrate substituted photosensitisers is quite recent and concerns the tetrapyrrolic ones. As far as we could find out, no carbohydrate-BODIPY derivative has been designed to be used as a photosensitiser, nor phenothiazinium derivatives. In addition to the use of carbohydrates as biocompatible water-solubilizing substituents, two targeting approaches cohabit that lead to the design of carbohydratesubstituted photosensitisers: The first one is once again based on the highly active metabolism of cancer cells. Carbohydrates being an available source of energy easily metabolisable, prolifering cells are likely to uptake any glycoconjugates, including carbohydrate-decorated photosensitisers. The carbohydrates have the role of a hook. The second approach is based on the expression by cancer cells of specific lectines recognised by the corresponding carbohydrates following an interaction highly specific, comparable to an antigen-antibody interaction. This approach aims at being more selective. In both cases, the uptake is enhanced by the carbohydrates transporters overexpressed by cancer cells [124]. For these reasons, several glycoconjugates of chlorins (see 105–107) [125, 126], porphyrins (see 108–111) [126–128] and phthalocyanines [119–137] are reported. Systematic variations of the number (105–107) [125], of the position [138] and of the nature (108–111) [127] of the carbohydrates have been studied. The introduction of a spacer between the macrocycle and the carbohydrates was envisaged to study its potential effect [128]. OH
OH HO HO
OH
OH HO HO
HO HO
O
O NH
OH
N
O
N
HO
HO HO
OH OH
HO HO
O NH
N
O NH
OH
N
HN
HN
N
OH HO HO
OH
105 Sugar
Sugar O :
OH
O OH
107
HO
O
O HO
HO
OH OH
N
O
HO
O OH
OH
108
HN
O
HN
OH HO HO
O
106
O
N
/
O
Sugar
O OH
OH
OH
OH HO HO
OH
OH
HO
OH HO HO
O
109
O NH
N
Sugar
O HO
O
O
O OH
HO
O OH
OH
OH
110
111
Sugar
Given the promising results of tetra non-peripherally substituted glycerol Zn phthalocyanines [139], we designed four monocarbohydrate functionalized derivatives
1
Design and Conception of Photosensitisers
29
(112–115). The design aims at still benefiting from the water-solubilizing effect of three glycerols, the fourth substituent being a clicked carbohydrate of different nature at the extremity of a spacer in order to maximize potential interaction with lectine without inhibition due to the steric hindrance of the phthalocyanine macrocycle [129]. OH HO
O
OH
O
O N
N N
N
O
O
O
O
N
N Zn N HO
N
N N O
N
HO
O
OH
HO
AcO
OAc
O O
:
AcO AcO
AcO
O
O OAc
AcO AcO
O OAc
AcO
112
1.4.3.5
OAc
O
113
OAc OAc O
114
AcO AcO
O
OAc
OAc
O
O
O AcO OAc
OAc
O
115
Antimicrobial Photosensitisers
The negative character of the bacterial membrane requires cationic photosensitisers. Their electrostatic interactions ensure of maximized damages by the singlet oxygen. Besides cationic charges, amphiphilic structures optimize the cell penetration. Antimicrobial photosensitisers are used for different applications: blood sterilisation, treatment of infected wounds [140], cleaning of surfaces and materials requiring to be aseptised, waste waters remediation [141]. Phenotiazinium and related derivatives, due to their intrinsic cationic nature, are widely used [142–144]. Since the methylene blue (116) and Nile blue (117) basic structures, the design of optimized photosensitisers followed the strategies enounced previously: – Introduction of heavy atoms: halogens, sulfur [145], – Introduction of hydrophobic chains to enhance the amphiphilicity of a basically highly hydrophilic molecule: DO15 (118) and series with chains variations [146] – conjugation with peptides [147] Me
Me N
N Me2N
S
NMe2
Et2N
O
Methylene blue
Nile blue
116
117
N NH2
Me Me
N Et
S
DO15
N Et
Me Me
118
Many cationic porphyrins and phthalocyanines have been designed and prepared. Several parameters have been studied in a more or less systematic way with the design of series, as for example the charge effect [148] and the nature of the central metal in phthalocyanines: Zn, Ga [149].
30
F. Dumoulin
Recently, cationic prophycene (119) [150] proved to be of potential use in antimicrobial PDT. Br
Br N
N
N H N
N H N
MeO
N
119
1.4.4
Br
Bi and Multicomponents Photosensitisers
This part deals with covalent combinations of two or more active molecules having at least one photosensitiser component. The combination of several properties leads to molecules exhibiting, in addition to the photosensitising ability itself, either other therapeutic effects or imaging properties. One could think that photosensitisers bearing targeting moiety may have taken place here instead of in the previous part. This would have been another way to consider these conjugates, reasonable as well. 1.4.4.1
Combination of Two Photosensitisers
Two ALA-phthalocyanine [151] conjugates were designed to hopefully benefit synergically from their respective effects. As the tetra symmetrically substituted 120 was aggregated in water, the asymmetric derivative 121 has been designed. The menthol substituents, thanks to their bulkiness successfully lowered the aggregation and are expected in addition to improve cell uptake, menthol being a known additive of formulations [152]. O
O
NH3+, CF3SO2−
O(CH2)2O
+H N 3
O(H2C)2O
CF3SOO 2
O
N
N Zn
N
N
O
N
NH3+, CF3SO2−
O(CH2)2O
O(H2C)2O
+H N 3
N N
N O
O NH3 CF3SO2
N Zn
N
N N
N
O
N
N N
CF3SO2−
O(CH2)2O
O
O
O
O O
120
121
Radachlorin is a patented mixture of two photosensitisers, chlorin e6 and purpurine. The effect of this combination is currently under investigation [153].
1
Design and Conception of Photosensitisers
1.4.4.2
31
Combination of Photosensitisers with Other Anticancer Agents
The conjugates of SiPc and cis-platin (122 and 123) [154] were designed following previous conclusions about the synergic effect of PDT and chemotherapy [114], aiming at a “win-win” cooperation, with a nucleus targeting effect thanks to the DNA binding of the cis-platin. H3N NH3 Pt N CI
2+
NH3 N Pt NH3 CI
O
O N
N
N N
2+
Si
N N
N
N
N
N
N
Si
N
N N
N
N O
CI H3N Pt N H3N
CI
N Pt H3N NH3
122
O
123
Conjugates of ruthenium complex and porphyrin were designed following similar idea, and are schematically represented Fig. 1.7 [155].
N N
O
HN
O N N
N H
NH
N
N NH
N
HN
NH
O : ruthenium-based metal fragment N
N
Fig. 1.7 Conjugates of porphyrin and ruthenium complex
N O
32
1.4.4.3
F. Dumoulin
Combination of Photosensitisers with Imaging Agents
This later is increasing exponentially since the last years [156, 157]. This has the following advantages: – Visualisation of the photosensitiser, usually possible thanks to its intrinsic fluorescence, – Follow and monitor the response to the photodynamic treatment The incorporation of radioactive atom to photosensitiser is used to couple imaging and PDT [158]. A covalent amphiphilic combination (124) of a two-photon tumour imaging (a ruthenium complex) and a photosensitiser agent (a porphyrin) was recently obtained [159].
2+ O N N
N
Ru N
NH
NH
N
O N
N
HN
N
124
1.4.4.4
Dual PDT and BNCT Agents
Boron-neutron capture therapy is a tumour treatment based on tumour irradiation with low energy neutrons, inducing the irradiation site production of two cytotoxic species: 4He 2+ and 7Li3+, causing irreversible damage to tissue via ionization processes [160]. The rapid development of the chemistry of carboranyl chemistry extended the range of BNCT agents [161]. The interest of combining this technique with PDT for complete tumour eradication is growing in the last years, leading to the design of several dual BNCT-photosensitiser molecules. Red absorbing photosensitisers are once again prefered during the design of such dual agents. Therefore the chosen photosensitiser core is chlorin, tetrabenzoporphyrin [162, 163] and phthalocyanine [164, 165]. When the exhibition of water-solubility enters the design process, these designed dual agents exhibit the required hydrophily thanks to partial deboronation into ionic derivatives. Reported phthalocyanines bear a various number of boronated units [166, 167]. Their design was based on the synthetic possibilities offered by suitable synthetic pathways and commercially available boronated derivatives. The aim being a dual
1
Design and Conception of Photosensitisers
33
agent, we can note that all the described boronated phthalocyanines are metalated by a Zn. In the case of chlorin derivatives, two molecules offer a good example of the choices made during the design. Tetra boronated derivatives (127–128) [168, 169] focus on a high boron charge when 129 takes advantage of the exceptional photophysical properties of chlorin e6 core but is substituted by only one boronated unit [170]. K
H K
F
S
F
N F
S
F F
F NH N
H
N
N
F F
NH
HN
NH
HN
F
HN
F
N
2
F
F F S
H
125
N
N
F F
F
S
K HH
MeOOC
MeOOC
O
NH N N N
O
O
K
126
127
Recently, it was evidenced that carboranyl including photosensitisers exhibit a higher PDT efficiency than comparable non-carboranyl photosensitisers. This was the case of chlorin [171] and porphyrins [172, 173].
1.4.5
Beyond the Molecular Level. Design of Nanosystems
The exponential interest for nanoparticles in biological [174] and medical fields [175] early reached the photodynamic therapy [176, 177]. We will explain here briefly the impact it has for the design of photosensitiser, as well as the two levels of design occuring during the conception of photosensitising nanoparticles: the design of the nanoobject itself, and the design of the photosensitiser intended to be included in the nanoobject. The purpose of this part isn’t to be exhaustive but to give the reader an idea of the new parameters to be taken in account during design processes. Nanoparticles can be made of very different materials: metal (quantum dots, upconverter, gold nanoparticles), lipids (liposomes, micelles), etc…. Not all of them are suitable for in vivo applications due to their intrinsic toxicity, as in the case of quantum dots that have an amazing photophysical properties enhancing effects [178–180] but are unfortunately made of toxic metals.
1.4.5.1
Photosensitiser-Delivering Nanosystems
Another purpose of nanosystems can be the optimized delivery of the photosensitiser. Emulsions such as the widely used Cremophor EL®, nanogels [181] and pre-mixing
34
F. Dumoulin
with lipids [182], despite their promising effect, are out of the scope of this chapter and won’t be mentioned. Liposomes are an important representant of this use [183, 184]. The encapsulated drug (the photosensitiser in the case of photodynamic therapy) has a better uptake due to optimized endocytose, enhanced by the fusion of the liposome bilayer with the cell membrane, and eventual optimized localization in the organelles [185]. Depending on their composition, liposomes are degraded by photodynamic effect itself [186]. Dendrimer structures such as glycodendrimeric phenylporphyrins associated with liposomes are a type of nanostructures that proved very efficient to enhance the cell uptake of the photosensitiser. They combine the liposome carrying effect with the carbohydrates conjugation [187]. Micelles are more fragile system, used as well for photosensitiser carrying. Depending on their composition, their pH-related stability takes advantage of the tumoral acidic pH for a targeted delivery of the photosensitiser [188]. Protein-based nanoparticles Albumine nanoparticles with hematoporphyrin and gamma-emitting nuclides (99mTc) is a bimodal nanoparticle, used for concomitant scintigraphic imaging and photodynamic therapy [158]. Human Serum Albumin nanoparticles have been used to encapsulate an approved photosensitiser: pheophorbide. The nanoparticles have been designed to take advantage of the Enhanced Permeability and Retention effect of the tumour vasculature, retaining high molecular weight molecules (more than 40 kDa) in a much greater extend than normal cells [189–191]. HSA was a chosen macromolecule for this photosensitiser loading as it has no anti-genic effect and is biodegradable. The delivery of the pheophorbide proved to be as expected very efficient, and the overall phototoxicity after optimum irradiation condition determination was superior to those of free pheophorbide, thanks to the sole apoptosis occurring without necrosis induced by the irradiation [192–194]. The use of other plasma proteins for photosensitisers vectorization such as lipoproteins proved as well efficient to enhanced liposomes (used here this study as a membrane-model) – internalization [195].
1.4.5.2
Photosensitising Nanosystems
Nanoparticles are routinely a way to prepare multimodal objects and can be used as targeting photosensitising objects [92]. A nanoparticle with photodynamic purposes must exhibit the properties previously listed (see part 3. required properties of the photosensitisers). These properties are likely to be affected by the nanoparticle, being either enhanced, lowered or unchanged. A molecular design implies the covalent linkage of several moieties, each having some properties gathered on the molecular construct. In the case of nanoparticles, each of these moieties will be grafted or integrated separately, covalently or not.
1
Design and Conception of Photosensitisers
35
A targeting photosensitising nanoparticle bears some photosensitisers and the targeting units that are now brought together via the nanoparticles. Same things for the solubilizing functions, knowing that emulsion are widely utilized. The design of the nanoparticle 128 by the authors is a good example of the conception of a photosensitising nanoobject, with the following criteria [196]. Choice of the nanoparticles: mesoporous silica nanoparticles have easily tunable size and surface properties. Double decoration pattern: the nanoparticle is covalently linked to a water-soluble photosensitiser. The suitable trisulfonated monoaminoporphyrin was designed to be covalently grafted. Introduction of mannose units likely to target the breast cancer cells is the last feature of this nanoobject.
OH HO HO
OH
O −
O
SO3
NH H N
O O
S MSN
HN
N
−
(CH2)3 HNOCHN
SO3 NH
128
N
−
SO3
Three-component gold nanoparticles were designed [197]: the core gold nanoparticle is covalently bound to highly hodrophobic phthalocyanine, and the addition of a phase transfer agent (tetraoctylammonium bromide) for solubility purposes. This nanoconstruct exhibit most of the PDT desired properties: very good singlet oxygen generation, probably thanks to a heavy atom effect from the PTC-bromide atom, appropriate absorption wavelength (695 nm) due to the non-peripheral substitution pattern of the phthalocyanine, and suitable solubility. Nanoparticles made of organic polymers emerged in the last decade, and have been utilized for brain cancer surgery [198]. One of the advantage is their better clearance by the mononuclear phagocyte system, [199] overcoming one of the biggest problem related to biomedical nanoparticles use. The photophysical properties of dyes loaded encapsulated in these particles has been proved to be unaffected [200]. One should expect therefore bright scope for these polymeric nanopayloads. Upconverter nanoparticles have been described in a previous part of the chapter as they represent a new mode of excitation, nevertheless one should remember that it is among the more promising development of the nanotechnologies for biological and medical photodynamic applications.
36
1.5
F. Dumoulin
Conclusion
This chapter, with a selection of chosen examples, aimed at explaining how photosensitisers are designed. As for all the biological applications, implied criteria are numerous, and it is interesting to highlight the choices made depending on the purpose of the work.
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199. Gao D, Xu H, Philbert MA, Kopelman R (2008) Bioeliminable nanohydrogels for drug delivery. Nano Lett 8:3320–3324 200. Tang W, Xu H, Park EJ, Philbert MA, Kopelman R (2008) Encapsulation of methylene blue in polyacrylamide nanoparticles platforms protects its photodynamic effectiveness. Biochem Biophys Res Commun 369:579–583
Chapter 2
Recent Developments of Synthetic Techniques for Porphyrins, Phthalocyanines and Related Systems Ayşe Gül Gürek and Catherine Hirel
Abstract This chapter surveys two methods recently developed for the synthesis of porphyrins, phthalocyanines and related compounds: (i) microwave-assisted synthesis and (ii) the use of ionic liquids instead of conventional solvents. These two techniques, that can even be combined, offer several advantages such an increase in the yields and shorter reaction times when compared to the classical reaction conditions. Microwave-assisted reactions can be divided in two main categories, depending on the reaction medium (solid phase or solvent). As it will be discussed in Sect. 2.2 of this chapter, microwave irradiation affords higher yields and leads to noticeably cleaner reaction product. In addition to the green chemistry conditions, the use of an ionic liquid as the reaction solvent enhances the yields and eases the purification process in the synthesis of phthalocyanines and porphyrins, as will be discussed in Sect. 2.3.
2.1
Introduction
Generally, synthesis of phthalocyanines and porphyrins need long reaction times in high temperature boiling solvents that gives low to moderate yield reactions due to the formation of by-products and degradation of the reactants. To by-pass these problems, the development of convenient high-yield techniques is a prerequisite. Two techniques in the synthesis of porphyrins, phthalocyanines and related compounds have attracted a considerable amount of attention in recent years: the use of microwave irradiation instead of conventional thermal heating and utilization of ionic liquids instead of ordinary solvents. Before detailing the A.G. Gürek (*) • C. Hirel Chemistry Department, Gebze Institute of Technology, PO Box 141, 41400 Gebze, Kocaeli, Turkey e-mail:
[email protected];
[email protected] T. Nyokong and V. Ahsen (eds.), Photosensitizers in Medicine, Environment, and Security, DOI 10.1007/978-90-481-3872-2_2, © Springer Science+Business Media B.V. 2012
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Table 2.1 Experimental Conditions for the most common methods in meso-substituted porphyrin synthesis R -6 H+/ 6e− -4H2O
O + 4
4 R
NH
N H
H
N R
R HN
N
R
Solvent
Rothemund Pyridine
Adler (i) Propionic acid (ii) Acetic acid
Lindsey Dichloromethane Chloroform
Temperature
220°C
(i) 141°C (ii) 120°C
25°C
Catalyst
–
Same as solvent
TFA BF3.OEt2 BF3.OEt2/ethanol
Oxidant
–
O2
DDQ or p-Chloranil
Reactant concentration
3.6 M
0.3–1.0 M
0.001–0.1 M
Time of reaction
48 h
0.5–1.0 h
1h
Procedure
One step
One step
Two step
Purification
Crystal separation
Filtration
Chromatography
Yield
0.4) and have a long lifetime (> 1 ms); – the photosensitizer should have an high photo and thermodynamic stability. A good photosensitizer should be a single substance with constant composition and a high degree of chemical purity and sufficiently stable under physiological conditions; – the photosensitizer should have no toxicity in the dark; – the proposed drug must be soluble in the physiological solution. Many of these required properties can be easily solved by using the large experience of chemists on modern synthetic strategies (e.g. combinatorial). For example, the last
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requirement can be achieved by adding appropriate electrophylic substituents around the main ligand. Among all these factors determining the activity of a new PDT drug, the first two are the most important, while if we would like to promote Type II reactions the energy gap between the ground electronic state and the first excited one with different spin multiplicity (e.g. singlet-triplet) must have a value higher than that necessary to activate the first oxygen excited singlet. Since the most used drugs in PDT are porphyrin-like complexes, in this work we will examine a series of porphyrin-like systems with different numbers of p electrons, namely porphyrin (P), porphyrazin (Pz), chlorin (C), bacteriochlorin (BC), texaphyrin (Tex), phthalocyanine (Pc), naphthalocyanine (Nc) and anthracocyanine (Ac) and some of their complexes with transition metal cations. In order to design a new metal-porphyrin like PS we will investigate the properties of the ligands and the changes induced by the metalation process. Figure 3.1 shows
therapeutic window
850 800
λ max (nm)
750 700 650 600 550 500
1,4
Active in PDT (Type II reaction)
eV
1,2 1,0 0,8 0,6 0,4 BC
C
P
Pz
Tex
Pc
Nc
Ac
Molecule Fig. 3.1 Plot of the Qx band and DES−T values for the considered porphyrin-like systems
3 The Contribution of Theoretical Chemistry to the Drug Design…
127 H H H H
N
N
N
N
N
H H
H H
P
N H
H
H N
N
N H
H
N
H H
BC
H
N
H H
N
C
N
H
N
N
N
N
N
H N
N
N
H H N
+
N
OMe
N
OMe
N
Tex
Pz N N
N N
H
N N
N N
H N
N H
N
N
N
H N
N N
Pc
Nc
N N
N H
N
N
H N
N N
Ac Scheme 3.2 Structures of the examined porphyrin-like systems
the variation of the Q band absorption wavelength as a function of ligand species (Scheme 3.2). Considering that the optimal absorption wavelength for a PS active in PDT is in the range between 600 and 900 nm, the systems with absorption wavelength that can better penetrate into the tissue are BC, Tex, Pc, Nc and Ac. Thus, in principle,
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these five compounds can be considered as better candidates than C, P and Pz. As mentioned above, in order to induce the Type II reactions, the first excited triplet state should transfer its energy to the oxygen molecules and populate the reactive O2 singlet state. This means that the energy of the triplet state of the PS must have an energy higher than that of singlet oxygen (0.98 eV). In Fig. 3.1 the singlet-triplet energy gap (DES-T) is plotted against the considered porphyrin-like systems. As it is clear from this figure, Pc, Nc and Ac have DES-T lower than 0.98 eV. Using the data obtained for these two properties we can indicate only the BC and Tex compounds as reliable photosensitizers able to induce Type II reactions in PDT. What does happen if these ligands are metalated by transition metal ions? The presence of the metal can increase the stability of the system as well as induce an “heavy metal” effect and, consequently, increase the performance of the porphyrinlike systems as PS in PDT. In order to verify the effect of the metal atom on the properties of the bare porphyrin-like ligands, we have computed the maximum absorption Q band and the energy gap between the ground and first excited states, with different spin multiplicities, of the complexes formed by BC and the first-row transition metals. The results are collected in Fig. 3.2. From this figure it is clear that Q absorption band is not sensibly affected by the presence of the metal. In contrast, the energy gap, that in the free ligand is larger than 0.98 eV, is strongly reduced in the Iron complex. Also Nickel induces a reduction of the band gap of about 0.2 eV that remain essentially unaffected in the Co, Cu and Zn complexes. Finally it is worth to note the strong increase (about 0.4 eV) of the energy gap induced by the metalation of BC with the Mn ion. Analyzing the behaviour of these two reported properties it is evident that the “a priori” knowledge of the maximum absorption band and of the energy gap between states at different spin multiplicities (e.g. singlet-triplet) is very important before to start with the synthesis and experimental characterization of a new photosensitizer. In other words, the computed properties can address the design of new active drugs avoiding the experimental work expenses on the basis of the similarity of the new proposed molecules with others for which their biological activity is known, but which often do not give the expected results. Computational chemistry can give other important contributions not only in the interpretation of experimental data (e.g. the UV-Vis spectral assignments), but also in predicting electronic properties that often are difficult to measure (e.g. HOMO-LUMO gap) or that cannot be obtained experimentally (e. g. molecular orbital picture and composition, atomic charges). Furthermore, it provides powerful tools for rationalizing the experimental data and predict the behaviour of many important properties. Considering the porphyrin-like systems previously examined, their spectra can be roughly rationalized in terms of the four orbital Gouterman’s model (see Fig. 3.3), where the principal excitations involve the two highest occupied molecular orbitals (HOMO and next-HOMO) and the two lowest unoccupied molecular orbitals (LUMO and next-LUMO) [35]. The substitution or the modification of the porphyrin ring can affect these levels in different ways. In fact, the hydrogenation of outer
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850
therapeutic window
λ max (nm)
800
750
700
650
600 1,4
Active in PDT (Type II reaction)
1,2
eV
1,0 0,8 0,6 0,4 0,2
Mn-Bc
Fe-BC
Co-BC
Ni-BC
Cu-BC
Zn-BC
Molecule Fig. 3.2 Plot of the Qx band and DES−T values for first-row transition metal complexes of bacteriochlorin
carbon double bonds, resulting in BC and C (see Fig. 3.3), decreases the number of p electrons involved in the aromatic system (22 for P, 20 for BC, and 18 for C) inducing changes in the UV spectra. Qx bands are, indeed, red-shifted as one goes from P (532 nm) to BC (544 nm) and C (590 nm). Along this series, the Qx band is mainly composed of the HOMO- > LUMO transition and in a smaller amount of the next-HOMO - > next-LUMO. The Qy counterpart equally corresponds to next-HOMO - > LUMO
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L+1 L
E (eV)
−3 −4
H
−5
H-1
−6 −7 −8
BC
C
P
Pz
Tex
Pc
Nc
Ac
Fig. 3.3 Gouterman frontier molecular orbital energies for porphyrin-like free bases
and HOMO - > next-LUMO excitations (these orbitals are depicted in Fig. 3.4 and their energies are plotted in Fig. 3.3). An exception is represented by P, whose frontier orbitals are quasi-degenerate and the transition assignment can change from one calculation to another one. In fact, there is an inversion in Q band assignments between in vacuo and in aqueous solution assignment. Looking at the Fig. 3.3 we can observe that the reduction of pyrrole rings in BC and C results in an energy increases of the HOMO and next-LUMO orbitals, while next-HOMO and LUMO energies are quite constant for the three considered systems. The relaxation of degeneracy of HOMO and next-LUMO makes the HOMO/LUMO difference smaller, whereas the next-HOMO/next-LUMO gap is strengthened. Wavelengths of the Qx bands are, therefore, enhanced, and the corresponding oscillator strengths are also affected. In contrast, the symmetry variation in FBC and FBBC induces a partial cancellation of transition moments, and the oscillator strength is consequently raised [f(BC) = 0.098; f(C) = 0.243]. The same trend is observed for Qy bands but they are slightly blue-shifted from P (498 nm) to BC (491 nm) and C (483 nm). In the porphyrazine (Pz), the introduction of aza groups in the meso position significantly stabilizes, with respect to porphyrin (P), next-HOMO level, but also the other three Gouterman orbitals are slightly effected. The drastic modification of the porphyrin ring in the case of Tex corresponds to a strong stabilization of all the considered frontier orbitals. The Qx band is mainly composed by the HOMO-LUMO (71%) transition and the energy gap between these two levels becomes smaller. As a consequence, the excitation energy decreases and the transition is red shifted (634 nm) with respect to the P systems (526 nm). Analyzing the last three systems, starting from Pc, we underline that the annulations of further benzene rings at the Pc moiety increases the number of
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Fig. 3.4 Isodensity frontier molecular orbital plots (HOMO and LUMO) for Texaphyrin free base (Tex) and its manganese (II) complex
p electrons and the HOMO-LUMO gap decreases (2.35, 1.97 and 1.72 ev for Pc, Nc and Ac, respectively) and, consequently, the Q band sensibly shifts to longer wavelength (see Fig. 3.1). Also in these compounds, the main electronic transition is associated with the HOMO-LUMO levels (about 90%) and our computed gap indicate a decrease of the value in going from Pc to Nc (see Fig. 3.3). Due to its importance in the possible application of these compounds in the PDT it is worth to note that the value of the calculated oscillator strength for the Q band increases with the enlargement of the p system. The decrease in the HOMO-LUMO gap is almost determined by the destabilization of the HOMO as one goes from Pc (5.42 eV), to Nc (4.97 eV) and Ac (4.71 eV). The next-HOMO orbital follows the same behaviour, while the LUMO energy does not change considerably. The next-LUMO level is stabilized in going from Pc, to Nc and Ac. The Qy peak is mainly originated by a HOMO → next-LUMO transition (also in this case of about 90%) and to a smaller
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extend by the next-HOMO → LUMO one. For metal complexes, the contribution of d-metal orbital to HOMO and LUMO (and consequently upon electronic transitions) is pictorially shown in the case of Mn(II)-Tex complex (right part of Fig. 3.4). Finally, we underline that the calculated the transition energies well agree with the experimental data being the average error about 0.2 eV. So, the TDDFT simulation of the UV-Vis spectra of systems for which the experimental counterpart is not available or difficult to detect, can be considered reliable.
3.5
Conclusions
In this contribution we showed how the density functional theory, in its time-dependent formulation, is able to reproduce and rationalize spectroscopic parameters relevant for the photochemical processes. The agreement with the experimental results is quite good for both the electronic transitions and singlet-triplet energy gaps. On the basis of these results, we believe that this tool is useful in the design of new sensitizers active in the photodynamic therapy. Acknowledgements Financial support from the Università della Calabria and MIUR (PRIN 2008F5A3AF_005) is gratefully acknowledged.
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30. Petit L, Quartarolo A, Adamo C, Russo N (2006) Spectroscopic properties of porphyrin-like photosensitizers: insights from theory. J Phys Chem B 110:2398–2404 31. Lanzo I, Russo N, Sicilia E (2008) First-principle time-dependent study of magnesiumcontaining porphyrin-like compounds potentially useful for their application in photodynamic therapy. J Phys Chem B 112:4123–4130 32. Quartarolo AD, Sicilia E, Russo N (2009) On the potential use of squaraine derivatives as photosensitizers in photodynamic therapy: a TDDFT and RICC2 survey. J Chem Theory Comput 5:1849–1857 33. Perpète EA, Jacquemin D (2009) J Mol Struct THEOCHEM 914:100–105 34. Herzberg G (1950) Spectra of diatomic molecules. Van Nostrand Reinhold, New York 35. Gouterman M, Wagnière G, Snyder L (1963) Spectra of porphyrins: part II. Four orbital model. J Mol Spectrosc 11:108–127
Chapter 4
Photochemical and Photophysical Characterization Mahmut Durmuş
Abstract This chapter highlights the photophysical and photochemical parameters of photosensitizers, with a focus on the different measuring and calculation methods. Singlet oxygen generation, photodegradation quantum yield, fluorescence quantum yield and lifetime and triple state quantum yield and lifetime of the photosensitizers are detailed and data regarding these parameters for photosensitizing phthalocyanines are summarized. The effects of number and position of substituents, nature of central metal and solvents on these parameters of phthalocyanine photosensitizers are also given in Table 4.1.
4.1
Introduction
Photodynamic therapy (PDT) is an emerging cancer treatment that takes advantage of the interaction between light and a photosensitizing agent to produce reactive oxygen in cells [1]. A major objective for cancer treatment is the selective destruction of malignant cells without damage to normal tissues and functions. The mode of operation in PDT is based on specific wavelength of light excitation of a tumour-localized photosensitizer. After excitation, energy is transferred from the photosensitizer (in its triplet excited state) to ground state oxygen (3O2), forming singlet oxygen (1O2) that can destroy tumor cells. This process is the dominating initial elementary step of PDT, and it is followed by oxidation of cellular targets by 1 O2; the so-called Type II mechanism (Fig. 4.1) [2].
M. Durmuş (*) Chemistry Department, Gebze Institute of Technology, PO Box 141, 41400 Gebze, Kocaeli, Turkey e-mail:
[email protected] T. Nyokong and V. Ahsen (eds.), Photosensitizers in Medicine, Environment, and Security, DOI 10.1007/978-90-481-3872-2_4, © Springer Science+Business Media B.V. 2012
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Fig. 4.1 The pathway of the photodynamic therapy for the cancer cells
The increasing popularity of this treatment method is largely due to its selectivity to destruction of tumor cells: only tissues that are simultaneously exposed to the photosensitizer and light, in the presence of oxygen, are subjected to the cytotoxic reactions during PDT. Thus, under ideal circumstances only diseased tissues are eradicated, leaving the surrounding healthy cells undamaged. Since the first demonstration of the photodynamic action in the early 1900s [3], great effort has been devoted towards the development of PDT agents, which have specific light absorption and tissue distribution properties. Many potential new PDT drugs have been investigated including porphyrins, chlorins, and phthalocyanines. The drug properties deemed favorable for PDT include synthetic purity, effectiveness at far-red and near infrared wavelength absorption, where tissues are more transparent, fast clearance from the body after PDT activity. Several of the new drugs have progressed to clinical trials. The first photosensitizer used was a hematoporphyrin derivative (HPD) known as Photofrin@ after purification [4]. The U.S. Food and Drug Administration (FDA) approval was obtained in Canada (1993), Japan (1994), USA (1995) and France (April 1996), promoted the synthesis and development of second generation photosensitizers [5]. Among the more promising secondgeneration photosensitizers that are currently being evaluated for PDT applications are the phthalocyanines (Pcs). Pc derivatives have favorable photophysical and photochemical properties, which include strong absorbance at long wavelengths and chemical tunability through substituent addition on the periphery of the macrocycle or on the axial position for certain central metals [6–8]. Photophysic is the study of interaction of light with molecules which results in net physical change. Photochemical reactions take place as a result of some chemical changes as a response to light absorption. Figure 4.2 shows a Jablonski diagram representing the photophysical processes following light illumination. Investigation of the photophysical and photochemical properties of the photosensitizers are very useful in applications involving PDT.
4
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Fig. 4.2 Jablonski diagram
4.2
Singlet Oxygen Quantum Yields (FD)
Molecular oxygen is one of the most important substances on the earth. Oxygen comprises 21% of the atmosphere, 89% of seawater by weight, and at least 47% of the Earth’s crust. Almost all living organisms utilize oxygen for energy generation and respiration. Molecular oxygen has two unpaired electrons in its lowest energy state. The existence of unpaired valence electrons in a stable molecule is very rare in nature and confers high chemical reactivity (Fig. 4.3). The production of singlet oxygen can be accomplished through the use of photosensitizers (PS). The absorption of light by these compounds leads to an excited singlet state (1PS*) of the sensitizer. Through a process of intersystem crossing, the excited singlet state can spin-flip into a lower energy triplet state (3PS*) that reacts in an energy transfer reaction with the ground triplet state of oxygen. The sensitizer returns to its singlet ground state while, bringing oxygen molecule to the excited singlet state. Energy transfer between the triplet state of photosensitizers and ground state molecular oxygen leads to its conversion into singlet oxygen (1O2) [9]. This transfer must be as efficient as possible to generate large amounts of singlet oxygen. This is quantified by the singlet oxygen quantum yield (FD), a parameter giving an indication of the potential of molecules to be used as photosensitizers in applications where singlet oxygen is required (such as Type II mechanism) [10]. The singlet oxygen quantum yield (FD) corresponds to the number of 1O2 molecules generated by one
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Fig. 4.3 Molecular orbital diagrams for the three electronic configurations of molecular oxygen
Fig. 4.4 Photochemical processes (Type I and Type II) mechanism of PDT
photon absorbed by a photosensitizer [11]. It is therefore a key parameter defining a photosensitizer. Two different types of mechanisms (Type I and Type II) are suggested during photosensitization (photocatalysis) process. In Type II mechanism (Fig. 4.4), the photosensitizer is first excited to the triplet state, then transfers its energy to ground state oxygen, O2(3Sg). The latter is converted in its excited state, O2(1Dg), which is the active cytotoxic species resulting cell death [12–20]. Singlet oxygen is generated thanks to the interaction of oxygen in its triplet basic state (3O2) with a photosensitizer
4
Photochemical and Photophysical Characterization
139
in its triplet excited state (3PS*). The PS in its excited triplet state is quenched by ground state oxygen, hence singlet oxygen quantum yields are expected to be comparable to PS’ triplet state quantum yields [14]. In Type I (Fig. 4.4), the interaction of the PS in its excited triplet state with either ground state molecular oxygen or substrate molecules, results in the generation of superoxide and hydroperoxyl radicals, which are the active cytotoxic species (Fig. 4.4) [12, 15]. Many factors associated with the sensitizers are responsible for the magnitude of the determined quantum yield of singlet oxygen, including: triplet excited state energy, ability of substituents and solvents to quench the singlet oxygen, the triplet excited state lifetime and the efficiency of the energy transfer between the triplet excited state of the sensitizer and the ground state of oxygen [21].
4.2.1
Detection and Measurement of Singlet Oxygen
Detection and measurement of singlet oxygen depend on the generating system. Optical spectroscopy is a method routinely used in laboratories as well as for the detection of 1O2 in planetary atmospheres. Condensed phases require different techniques and the development of new procedures is continuously ongoing [11]. The generation of singlet oxygen by PS can be quantified by mainly three methods. In the first one, called the direct method, is the measurement of the luminescence of singlet oxygen. In the second method, called the indirect method, the quenching of the absorption of a singlet oxygen by a quencher (usually 1,3-diphenylisobenzofuran (DPBF) in organic solvents or antracene-9,10-bis-methylmalonate (ADMA) in aqueous solution) is measured. The level of quenching is directly related to the quantity of singlet oxygen. The third method is based on electroparamagnetic measurements. 4.2.1.1
Singlet Oxygen Luminescence Method
Singlet oxygen luminescence method is based on the luminescence emitted in the radiative decay of 1O2 at 1270 nm which is a spin forbidden process (Fig. 4.5). The intensity of the emitted luminescence is quite weak and requires extremely sensitive detectors to be observed and quantified. Laser light sources have been employed for photosensitized systems. In the flash photolysis technique, the 1O2 generating system is irradiated with a strong light flash which induces a luminescence pulse (Fig. 4.6). The dynamic course of 1O2 concentration [1O2] can be clearly recorded using Eq. 4.1 as described theoretically in the literature [13]. tD éë 1 O2 ùû = A tT - t D
é êexp ë
æ -t ö çè t ÷ø - exp T
æ -t ö ù çè t ÷ø ú D û
(4.1)
where the tD is the lifetime of 1O2, tT is the lifetime of photosensitizer at its triplet state, t is time in seconds and A is a coefficient involved in sensitizer concentration
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Fig. 4.5 Jablonski diagram showing the 1270 nm luminescence of singlet oxygen
Fig. 4.6 A schematic representation of the singlet oxygen detector system using the singlet oxygen luminescence at 1270 nm
4
Photochemical and Photophysical Characterization
141
Fig. 4.7 Schematic illustration of the set-up of an indirect detection of singlet oxygen
and singlet oxygen quantum yield. The singlet oxygen quantum yield may then be determined by the relative method using a standard (for example unsubstituted zinc phthalocyanine), Eq. 4.2: F D = F Std D
A A Std
(4.2)
std where F Std are the D is the singlet oxygen quantum yield for the standard, A and A coefficients of the sample and standard, respectively. The equipment uses a laser excitation source is shown in Fig. 4.6.
4.2.1.2
Chemical Method
Here the singlet oxygen quantum yield is determined by the measurement of the quenching of the absorption of a molecule sensitive to the presence of singlet oxygen. This is the most commonly used as it does not requires specific equipment, see the experimental set-up in Fig. 4.7 [22, 23]. The disappearance of the quencher absorption (417 nm for DPBF in DMSO or 380 nm for ADMA in aqueous media) is followed by UV-vis spectrophotometry (Fig. 4.8). Equation 4.3 is used to determine FD by the relative method, using standards. F D = F Std D
R . I Std abs R Std . Iabs
(4.3)
where F Std is the singlet oxygen quantum yield for the standard, R and RStd are the D quencher’s photobleaching rates in the presence of the respective photosensitizers Std and standards, respectively. Iabs and I abs are the rates of light absorption by the photosensitizers and standards, respectively. Solutions of photosensitizer containing
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M. Durmuş
a
1
Absorbance
0.8
0.6
0.4
0.2
0 300
400
500
600
700
800
700
800
Wavelength (nm)
b
1.2
Absorbance
1 0.8 0.6 0.4 0.2 0 300
400
500
600
Wavelength (nm)
Fig. 4.8 Change in absorption spectra of (a) DPBF for unsubstituted ZnPc in DMSO and (b) ADMA for ZnPcSmix in aqueous medium as singlet oxygen is produced by the photosensitizers
singlet oxygen quencher are prepared in the dark and irradiated with light using the setup shown in Fig. 4.7. DPBF or ADMA disappearances can be readily monitored by following the decrease in their absorption peaks at 417 and 380 nm, respectively (Fig. 4.8a for DPBF and Fig. 4.8b for ADMA). 4.2.1.3
Electron Paramagnetic Resonance Method
In recent times, electron paramagnetic resonance (EPR) is used for the detection of singlet oxygen. This method is not optical, but based on a highly sensitive detection of the energy transfer between the intrinsic magnetism of unpaired electrons and an external magnetic field, following this Eq. 4.4: DE = 2 μe B
(4.4)
4
Photochemical and Photophysical Characterization
143
me is magnetic moment of the electron (the Bohr magneton) and B is strength of the effective magnetic field. This is actually an indirect method: 1O2 itself is non-magnetic and cannot be detected directly by EPR. What is detected is the formation of a product oxidized by 1O2? As a condition, this oxidized product must have a long-lived free radical or a spin label that is identified by EPR. 2,2,6,6-Tetramethyl-4-piperidone (TEMP) is a routinely used spin label probe, due to its conversion into the free radical 2,2,6, 6-tetramethyl-4-piperidone-N-oxyl (TEMPO) when reacting with 1O2 (Scheme 4.1). The EPR spectrum of TEMPO in ethanol is characteristic, consisting of three equal intensity lines due to the nitroxide radical (I = 1 for the 14N7 atom).
O
O
+
1O 2
H+
N H
N O
.
Scheme 4.1 The generation of TEMPO detectable by EPR, resulting of the oxidation of 2,2,6, 6-tetramethyl-4-piperidone (TEMP) by 1O2
Other active oxygen species can be detected and identified with this spin label method, as in the case of superoxide forms which forms an unstable complex free radical (hydroxyl radical e.g.) with 5,5-dimethyl-1-pyrroline-1-oxide (DMPO). The corresponding EPR has four characteristic lines [11, 24–27].
4.3
Photodegradation Quantum Yields (Fd)
Degradation of the molecules under light irradiation can be used to study their stability and this is especially important for those molecules intended for use in photocatalysis such as photodynamic therapy applications. Photodegradation is the oxidative degradation of a photosensitizer under light illumination and this can be determined by the photodegradation quantum yield (Fd). Photodegradation of a molecule depends of course on the structure of the molecule but as well on its concentration, nature of the solvent and light intensity. Photodegradation is attributed to the in situ generation of singlet oxygen, an oxidative species which can oxidize the PS itself. A photosensitive photosensitizer illuminated by appropriate light generates singlet oxygen and is partially degradated via photooxydation reactions. Generally, phthalimide residue was found to be the photooxidation product following degradation of phthalocyanines (Scheme 4.2) [28]. This photodegradation results in a lowered intensity of the Q- and B-bands, without distortion of their neither shape nor formation of new bands (that would
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M. Durmuş
Scheme 4.2 Photodegradation of phthalocyanine by singlet oxygen (Modified from Ref. [28] © Elsevier)
0.6
Absorbance
0.5
0 sec 60 sec 120 sec 180 sec 240 sec 300 sec
0.4 0.3 0.2 0.1 0 300
400
500
600
700
800
Wavelength (nm)
Fig. 4.9 Photodegradation of the photosensitizers under light irradiation
evidence a phototransformation of the Pc concomitantly to the photodegradation) (Fig. 4.9). Generally, photodegradation quantum yield (Fd) determinations can be measured using the experimental set-up demonstrated in Fig. 4.7 [23, 29–31]. Photodegradation quantum yields may thus be determined using Eq. 4.5, Fd =
(Co - Ct ). V . N A Iabs . S . t
(4.5)
where C0 and Ct in mol dm−3 are the photosensitizers concentrations before and after light irradiation respectively, V is the reaction volume, NA is the Avogadro’s constant, S is the irradiated cell area and t is the irradiation time. Iabs is the overlap integral of the radiation source light intensity and the absorption of the samples and determined by Eq. 4.6. I abs =
a SI NA
(4.6)
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Photochemical and Photophysical Characterization
145
Fluorescence Quantum Yields (FF) and Lifetimes (tF)
4.4
Fluorescence is the emission of light by a molecule that has absorbed light. In most cases, emitted light has a longer wavelength than the absorbed light (Fig. 4.10). Fluorescence occurs when an orbital electron of a photosensitizer relaxes to its ground state by emitting a photon of light after being excited to a higher quantum state (see Fig. 4.2). The fluorescence quantum yield (FF) gives the efficiency of the fluorescence process. It is defined as the ratio of the number of photons emitted to the number of photons absorbed. Fluorescence quantum yields are affected by several parameters: presence and nature of the aggregation, nature of solvent, pH, photoinduced electron transfer or electronic energy transfer. Fluorescence quantum yields are generally determined by a comparative method, using a known standard having a structure related to the analyzed photosensitizer, for example unsubstituted ZnPc in the case of photosensitive phthalocyanines. Equation 4.7 may be employed [19, 20, 32, 33], using a standard. F F = F F (Std)
F . A Std .n 2 2 FStd . A . n Std
(4.7)
where F and FStd are the areas under the fluorescence emission curves of the fluorophore and the standard, respectively. A and AStd are the respective absorbances of the fluorophore and standard at the excitation wavelengths, respectively. n and n Std are the refractive indices of solvents used for the fluorophore and standard, respectively. Fluorescence lifetime (tF) refers to the average time a molecule stays in its excited state before fluorescing, and its value is directly related to that of fluorescence quantum yield (FF); i.e. the longer the lifetime, the higher the quantum yield of fluorescence. Any factor that shortens the fluorescence lifetime of a fluorophore indirectly reduces the value of FF. Such factors include internal conversion and 1000
1.6
800
600 0.8 400
200
0 550
Absorption Emission
Excitation
Absorbance
Intensity a.u.
1.2
0.4
0 650
750
Wavelength (nm)
Fig. 4.10 An example of absorption, fluorescence emission and excitation spectra of phthalocyanine photosensitizers
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M. Durmuş
intersystem crossing. As a result, the nature and the environment of a fluorophore determine its fluorescence lifetime. Lifetimes of fluorescence (tF) may be calculated using the Strickler-Berg equation (Eq. 4.8) [34]. F (λ ) ò λ 2 .d (λ ) ε (λ ) 1 -9 2 = 2.88 ´ 10 .n ò λ .d (λ ) τ0 F λ λ .d λ ( ) ( ) ò
(4.8)
where t0 is the natural radiative lifetime, n is the refractive index of the solvent, F is fluorescence emission, l is wavelength, e is the extinction coefficient. The time correlated single photon counting (TCSPC) equipment is often used for time domain measurements.
4.5
Triplet State Quantum Yields (FT) and Lifetimes (tT)
The ability of a photosensitizer to generate the toxic singlet oxygen species is determined by its triplet properties. For PDT, the triplet excited state of the photosensitizer is responsible for the generation of the reactive singlet oxygen species since the excited molecules transfer their energy to ground state oxygen to produce singlet oxygen which is essential for Type II mechanism of PDT. However, the efficiency of the other processes that deactivate this state including its non-radiative decay and phosphorescence must be minimal or controlled to give good PDT results. The triplet state efficiency is expressed as triplet quantum yield (FT), which has been defined as the number of molecules that undergo intersystem crossing and laser flash photolysis is used to determine the change in absorbance in the triplet state, which is directly related to the triplet quantum yield. The equipment employed for laser flash photolysis is shown in Fig. 4.11. Laser flash photolysis gives information about the triplet-triplet absorption and lifetime of the excited species. The triplet quantum yield (FT) is based on absorption of light by the triplet state generated during laser flash photolysis studies. For phthalocyanine photosensitizers the triplet absorption is at approximately 500 nm, far from the ground singlet state absorption (Fig. 4.12). This provides measurements of the triplet absorption easily since there is no overlap. The change in absorbance (DA) in the triplet state is directly related to the quantum yield of the triplet state, FT. The triplet quantum yields (FT) may be determined using standard with known FT by the triplet absorption method by Eq. 4.9 [35, 36] or singlet depletion method by Eq. 4.10 [16, 36–39]. F Sample = F Std T T
DASample . ε Std T T Sample DAStd T .ε T
(4.9)
F Sample = F Std T T
DASample . ε SStd S Sample DAStd S .ε S
(4.10)
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Photochemical and Photophysical Characterization
147
Fig. 4.11 The laser flash photolysis system for photophysical determinations
0 400
500
600
700
800
Wavelength (nm) -0.5
0.08
-1
ΔA
ΔA
0.06 0.04 0.02
-1.5
0 400
450
500
550
600
Wavelength (nm) -2
Fig. 4.12 Typical transient differential spectrum of phthalocyanine photosensitizer
Std where DA T and D A T are the changes in the triplet state absorbance of the photosensitizer and standard (such as unsubstituted ZnPc for phthalocyanines), respectively. DAs and D AStd S are the changes in the singlet state absorption of the photosensitizers and the standard, respectively. F STtd is the triplet state quantum yield for the standard. e T and ε TStd are the triplet state extinction coefficients for the photosensitizer and the standard, respectively. eS and ε SStd are the singlet state extinction coefficients for the photosensitizer and the standard, respectively.
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M. Durmuş 0.05
Delta A
0.04
0.03
0.02
0.01
0.00 0.000
0.001
0.002
0.003
0.004
Time (s)
Fig. 4.13 A typical triplet decay curve of phthalocyanine photosensitizer
The triplet state extinction coefficients (eT and ε Std ) are determined from the molar T extinction coefficients of photosensitizers’ respective singlet states (eS and ε Std S ), the changes in absorbances of the ground singlet states (DAs and D A Std ) and changes in S the triplet state absorptions (DAT and D A Std ), according to Eqs. 4.11 and 4.12 : T eT = e S
ε TStd = ε SStd
D AT D AS DATStd DASStd
(4.11)
(4.12)
The lifetimes of the transients may be determined from a software program such as OriginPro 7.5, used in fitting the triplet decay curve (Fig. 4.13).
4.6
Photophysical and Photochemical Data of Phthalocyanine Photosensitizers
Table 4.1 lists the photochemical and photophysical properties of phthalocyanines. The effects of the nature of substituents, substitution degree, position of the substituents, central metal atoms and nature of solvents on the photophysical and photochemical properties of phthalocyanine photosensitizers are discussed below.
4
Photochemical and Photophysical Characterization
4.6.1
149
Singlet Oxygen Quantum Yields (FD )
Energy transfer from triplet state of photosensitizers to ground state molecular oxygen leads to the production of singlet oxygen. Therefore singlet oxygen generation depends on the triplet state quantum yield and lifetime of a photosensitizer. Thus, the trend in variation of FD values within an array of photosensitizers should be parallel to the variations in their FT values. FD values of the phthalocyanine photosensitizers are lower in aqueous solutions than in organic solvents due to the aggregation behavior of phthalocyanine photosensitizers in aqueous solutions. The low singlet oxygen generation in water compared to other solvents such as deuterated water and DMSO is explained by the fact that singlet oxygen absorbs at 1270 nm, and water, which absorbs around this wavelength has a great effect on singlet oxygen lifetime, while DMSO which exhibits little absorption in this region has longer singlet oxygen lifetimes than water, resulting in large singlet oxygen generation in DMSO [16]. The values of FD are expected to increase on addition of detergents (e.g. Triton X-100) in aqueous solutions [175]. The same trend can be applied for the FT values of phthalocyanine photosensitizers. The singlet oxygen quantum yield (FD) values of the metal-free and metallo phthalocyanine photosensitizers in different solvents are given in Table 4.1. Mg, Ti, Zn, Cd, Hg, Al, Ga, In, Si, Ge and Sn are commonly used as central metals for FD measurements of phthalocyanine photosensitizers. Complexation of phthalocyanine compounds with transition metals gives photosensitizers with short triplet lifetimes [2]. Generally, closed shell or diamagnetic metal ions are selected as central metals because their phthalocyanine complexes give both high triplet yields and long lifetimes consequently they produce high singlet oxygen. The FD values of MPc complexes increase according to the atomic size of the metal ion due to heavy atom effect such as the FD values are 0.67 for ZnPc, 0.78 for CdPc and 0.82 for HgPc [107]. In general, MgPc complexes gave low FD values, most likely due to the large fluorescence expected for small central metals [42]. The number of sulfo groups is an influence on the generation of singlet oxygen. For a series of ZnPc(SO3)n(mix) (n = an average number of SO3 groups) complexes (Table 4.1), FD values are almost the same in DMSO, but an increase for FD values is observed with the increasing of value of n in PBS due to lowering aggregation. [42] The FD value is low for the more aggregated ZnPc(SO3)2.1(mix) (FD £ 0.01), but high for the mainly monomeric ZnPc(SO3)3.7(mix) (FD = 0.49) in PBS (Table 4.1) [42]. The FD values for tetrasulfonated MPc complexes increase as follows: ZnPc(SO3)4 (FD = 0.52) > ClGa(III) Pc(SO3)4 (FD = 0.41) > ClAl(III)Pc(SO3)4 (FD = 0.20) > H2Pc(SO3)4 (FD = 0.16) in DMF [30, 92]. MPc(COOH)8 (M = Zn, Al and Si) complexes have low FD values in aqueous solution. The FD values increase with the size of the central metal as follows: Zn (FD = 0.32) > Si (FD = 0.22) > Al (FD = 0.12) in aqueous solution [73, 74]. When considering the number of carboxyl groups on the phthalocyanine framework, the FD values obtained for ZnPc(COOH)8 (FD = 0.48) and ZnPc(COOH)4 (FD = 0.51) are similar in DMF (Table 4.1) [36, 62]. In general, the quaternization of the N atoms on the substituted groups cause a decrease of the FD values of phthalocyanine photosensitizers (Table 4.1).
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Table 4.1 Photophysical and photochemical parameters of phthalocyanine compounds R3
R2 R1
R4
R4 R3 R2 R1 X2
N
N
N
M
N
N
N
N
Compound
Metal
R1=R4=R2=R3=H R1=R2=R4=H, R3=SO3H
2H
R1=R2=R4=H, R3=CH2C(CH3)3 R1=R2=R4=H R3=O(CH2)2O(CH2)2OCH3 R1=R4=H R2=R3= O R1=R4=H R2=R3= O
O
R1=R4=H; R2=R3=SC5H11 R1=R4=H; R2=R3=SC8H17 R1=R4=H; R2=R3=SC12H25 R1=R2=R4=H H13C6O
R3=
OC6H13
O O H13C6O
R1=R2=R4=H
R3=
OC6H13
O
O O
R1=R2=R4=H OH
R3=
O
R2 R3 R4 R1
R3
H2Pc(SO3)2mix
R1
N
R4 R2
X1
4
Photochemical and Photophysical Characterization
Solvent
FF
tF (ns)
CHCl3 H2O DMF PBS+TX DMSO CHCl3 Toluene
0.55 0.62 0.60
6.5
0.24
7.3
1-ClNP
0.21
1-ClNP
FT
tT (ms)
151
Fd (×10−5) FD
Reference
170
0.09 0.16 0.02 0.11
504
0.19
[40] [30, 41] [30] [42] [42] [40] [43]
0.40
55
0.05
[44]
0.25
0.47
50
0.01
[44]
1-ClNP 1-ClNP 1-ClNP DMSO
0.10 0.13 0.15 0.12
0.39 0.40 0.38
62 51 44
0.04 0.04 0.04
[44] [44] [44] [45]
DMSO
0.18
DMSO
0.10
0.22 0.24
[45]
0.54
310
[46]
(continued)
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M. Durmuş
Table 4.1 (continued) Compound R1=R2=R3=H
Metal
O O
O O
R4=
O O
R1=R2=R3=H
O O O
R4=
O O
O
R1=R4=H; R2=R3=O(CH2)3CH3 R2=R3=H; R1=R4=O(CH2)3CH3 R2=R3=H, R1=R4=C8H17 R2=R3=H, R1=R4=C10H21 R2=R3=H, R1=R4=C12H25 R2=R3=H, R1=R4=C14H29 COOH
R1=R2=R3=R4= O COOH
R1=R4=H R2=R3=
O S NH O
R1=R4=H H3C R2=R3=
H3C OR
RO
N
N
RO N
N
N
OR
N
N OR
HN
NH RO
N
RO
N
NH N
HN N
OR
N
H3C R= RO
OR
RO
OR
H3C
4
Photochemical and Photophysical Characterization
tF (ns)
Fd (×10−5) FD
Solvent
FF
DMF
0.03 (CHCl3)
0.12
[47]
DMF
0.05 (CHCl3)
0.14
[47]
Toluene THF CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2
0.96 0.19 0.10 0.07 0.06 0.05
FT
tT (ms)
153
[40] [40] [48] [48] [48] [48]
5.0 4.8 5.0 5.1
DMF
Reference
0.27
[49]
THF
0.33
1.23
[50]
DMSO
0.03
0.07
[50]
Toluene
0.33
6.2
0.10
[51]
Toluene
0.04
0.8
Ga (OH )PcS > ZnPcS > Al (OH )PcS > Methylene Blue
In turn, the order of the stability of photosensitizers was following: Si (OH )2 PcS > Al (OH )PcS > ZnPcS > Rose Bengale > Methylene Blue The degradation of MPcS was evaluated by the decrease of the Q band at 680 nm in the UV-vis spectrum. Si(OH)2PcS-Amberlite IRA 400 catalyst showed particularly high activity and stability. This catalyst was re-used in five successive oxidations of phenol without notable loss of activity [47]. The influence of the phthalocyanine structure was studied in the photooxidation of 4-CP, 2,4-dichlorophenol, 2,4,5-trichlorophenol and PCP under visible light [51]. Octacarboxyphthalocyanine Zn and Al complexes (ZnPc(COOH)8, AlPc(COOH)8) as well as ZnPcS, AlPcS, ZnPcSn, AlPcSn, GePcSn, SiPcSn and SnPcSn were supported onto Amberlite IRA 900 with loading of 5 mmol/g. Amberlite IRA 900 ion exchange resin is a strongly basic, macro-reticular resin of moderately high porosity with benzyltrialkylammonium groups. These MPc photosensitizers were chosen because of their different photochemical and photophysical characteristics which might influence on the photoactivity towards the degradation of pollutants. The efficiency of singlet oxygen generation by photosensitizers in aqueous solution follows the trend: SiPcSn > ZnPc(COOH)8 > GePcSn = SnPcSn > ZnPcSn > ZnPcS > AlPcSn > AlPc(COOH)8 > AlPcS
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With all supported photosensitizers, photodegradation was more difficult for more chlorinated phenols (4-CP > DCP > TCP > PCP) and resulted mainly in the formation of chlorinated benzoquinones. The photocatalytic properties of the supported MPc were compared in oxidation of PCP at pH 10 using 1:99 catalyst/substrate ratio [51]. The order of photoactivity was following (conversion of PCP after 5 min, %): ZnPc(COOH)8 > SiPcSn > SnPcSn > ZnPcSn > GePcSn > ZnPcS > AlPcSn > AlPc(COOH)8 > AlPcS 29.8 26.0 24.4 21.1 16.5 12.8 10.7 10.7 6.2
The supported catalysts showed a superior catalytic activity compared to homogeneous counterparts and could be re-used [51]. Another approach for TCP degradation was realized using PdIIPcS as sensitizer, supported onto bentonite treated with surfactants which is widely used as a sorbent for uptake of organic pollutants from water [52]. PdPcS possesses a high quantum yield of 1O2 generation and a high photostability. This complex is aggregated in aqueous solution as evidenced by the 612 nm band in the UV-vis spectrum. The change of the maximum to 646 nm upon absorption at organoclay indicated PdPcS was supported mainly in monomer form. At pH 12, 0.3 mM TCP solution was completely degraded in the presence of 1 g/L PdPcS-organoclay material within 25 min reaching almost complete dechlorination after 300 min irradiation with l > 450 nm. This photocatalyst exhibited a good stability and recyclability. Bentonite can also be modified with AlPcS, but AlPcS-organoclay material was less active than Pd catalyst in the TCP photodegradation under the same conditions. This was in agreement with the 1 O2 quantum yield determined for PdPcS and AlPcS in homogeneous conditions.
9.4.6
Porphyrins as Photosensitizers
Iron porphyrins also exhibit photocatalytic activity in the oxidation of pollutants [53]. Iron tetrasulfophenylporphyrin (FeTPPS) supported onto Amberlite IRA 900 activated H2O2 in water under irradiation with l > 450 nm. The irradiation accelerated the degradation of Sulforhodamine B (SRB) and 2,4-dichlorophenol (DCP) with mineralization of 56% and 68% at a catalyst/substrate ratio 1:33 and 1:535, respectively. The release of inorganic SO4− from SRB and Cl− from DCP was 65% (160 min irradiation) and 70% (380 min irradiation), respectively. Several intermediate products (2-hydroxybenzoic acid, 4-(ethylamino)benzoic acid and 1,3-isobenzofurandione) were identified. However, cationic compounds like RhB and Malachite Green were not degraded, probably because of difficult approach to the catalyst embedded into cationic resin. The first order constants of photodegradation of 3 compounds by FeTPPS/AmberliteIRA900 – H2O2 system were determined: Sulforhodamine B
k1 = 1.3 × 10 −2 min −1
Orange II Salicylic acid
k1 = 1.2 × 10 −2 min −1 k1 = 6.2 × 10 −3 min −1
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The supported FeTPPS catalyst was stable enough to allow re-uses in five photocatalytic experiments without significant loss of activity. EPR spin trap experiments with DMPO showed the involvement of OH· radicals. Similarly to phthalocyanine analogue, hydroperoxo HOOFeIIITPPS complex was proposed to undergo a homolytic cleavage of O–O bond to form OH· responsible for degradation of pollutants. Impregnation of metal-free or copper tetra(4-tert-butylphenyl)porphyrin onto TiO2 surface improved the photocatalytic activity of the bare TiO2 in the degradation of 4-nitrophenol [54].
9.5
Combined TiO2 – MPc Systems
Owing to a wide 3.2 eV band gap of TiO2 only UV light accounting only for 4–5% of solar light can be used. In addition, the quantum yields for organic oxidation are low, e.g. 0.14 (l = 365 nm) for phenol oxidation using Degussa P25 TiO2 in water at pH 3 [55]. In order to use visible light TiO2 can be modified by supporting photosensitizers. The idea of modification of semiconductor surface by metal complexes as electron relays was introduced by Grätzel and co-workers [56]. Cobaltocenium dicarboxylate supported on colloidal TiO2 efficiently reduced methylviologen (MV2+) to the radical cation MV+· during laser flash photolysis. The attachment of sensitizer molecules in order to extend the photocatalytic activity of the catalyst into the visible part of the spectrum was demonstrated for the first time in 1980s [57, 58]. At the same time, thin films of MPc (M=Mg, Zn, Co, AlCl, Fe, TiO) were deposited onto semiconductor electrodes by Bard et al. [59]. This topic has mainly been devoted to the development of dyes-sensitized solar cells [60] and will not be covered in this chapter. Applications of phthalocyanine and porphyrins for molecular photovoltaics are discussed in details in recent review [61]. Stability of these composite catalysts is an important issue. Organic ligand of the adsorbed complex can be oxidized by generated active species. In this context, MPcs seem to be suitable photosensitizers. A high chemical and thermal stability of phthalocyanines coupled with their strong absorption in the visible region (Q band between 600 and 700 nm) make them interesting candidates for doping semiconductors [61]. In addition, the quantum yield of the redox process can be increased when a sensitizer absorbed onto semiconductor surface is excited by visible light followed by inter-phase transfer of electron from the sensitizer to semiconductor. In other words, a charge recombination can be diminished in this case. Moreover, by appropriate design of the dye it is possible to slow down interfacial electron transfer recombination dynamics and to favour the formation of O2−·. Indeed, a modification of the structure of porphyrin sensitizer grafted onto TiO2 surface showed a significant change in the rate of charge recombination between injected electrons in the TiO2 and the oxidized porphyrin [62]. The slower recombination rate was observed for the porphyrin with bulkier substituents most probably due to a larger physical separation of the porphyrin cation-radical from the semiconductor surface. The control of the electron transfer step allows improving the efficiency of such combined MPcTiO2 systems.
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This approach can be used for development of hybrid MPc-TiO2 materials for photodegradation of pollutants. After absorption of visible light MPc photosensitizer injects electrons in the conduction band of TiO2: hV MPc ⎯⎯ → MPc*
(
MPc* + TiO2 → MPc • + + TiO2 e − CB
)
Generation of oxygen active species and oxidation of the substrate by MPc+. initiate the degradation process: MPc* + O 2 → MPc +1 O 2
(
)
TiO2 e − CB + O2 → TiO2 + O•2− MPc • + + S → MPc + S• + The benefit of TiO2 support with respect to Al2O3 was shown in the photosensitized by supported H2Pc oxidation of phenol and benzoquinone [63]. H2Pc was supported onto TiO2 (Riedel de Haen, 100% anatase, 4 m2/g) and Al2O3 (Merck, 60 m2/g) with loadings of 24 mmol/g. Under irradiation by a halogen lamp (l > 450 nm, 38 mW/cm2) phenol was converted to maleic and fumaric acid accompanying by CO2 formation with 0.95 and 1.5 mol CO2/mole of phenol for H2PcAl2O3 and H2Pc-TiO2, respectively. Total O2 consumption was also higher for H2Pc-TiO2: 6.9 vs 4.2 mol/mol of phenol. The higher photocatalytic activity of H2Pc-TiO2 can be explained by an electron transfer from excited H2Pc to the conduction band of TiO2 and generation of superoxide radicals leading to the increase of the quantum yield and a higher mineralization of phenol. Cooperative action of TiO2 and supported phthalocyanine or porphyrin sensitizers (CuPc, H2Pc, CuP, H2P) was observed in photodegradation of 4-nitrophenol (125 W medium pressure Hg lamp, 300 K) [64]. Significantly, CuP-TiO2 and H2P-TiO2, stable after irradiation during 5–7 h in the absence of the substrate, exhibited a higher photoactivity than TiO2 itself. Three series of experiments were performed: (i) without filter, (ii) with 370 nm interference filter and (iii) with 420 nm cutoff filter. Initial reaction rates of 4-nitrophenol oxidation mediated by combined catalysts normalized on the rate in the presence of TiO2 follow the trend: (i) no filter : CuP − TiO 2 > CuPc − TiO 2 > H 2 P − TiO 2 > H 2 Pc − TiO 2 > TiO 2 1.57 1.32 1.2 1.07 1 (ii) 370 nm interference filter : CuP − TiO2 > CuPc − TiO2 > TiO2 > H 2 P − TiO2 > H 2 Pc − TiO2 1.63 1.54 1 0.83 0.54
In the case (ii) the initial rates values were lower by 3–4 times compared to rates obtained under conditions (i). Almost no photoactivity was observed for all materials when 420 nm cutoff filter was used showing the essential role of TiO2 photoexcitation.
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Superior photooxidation activity of CuP-TiO2 and CuPc-TiO2 compared with that of TiO2 suggests a cooperative mechanism involving both TiO2 and dye sensitizer (PS). Palmisano and co-workers proposed detailed set of reactions operating in this system (Adapted from ref. [64] with permission from Elsevier, Copyright 2003): Reaction involving TiO2:
(
hv
)
< 394 nm TiO2 @ PS ⎯⎯⎯⎯ → TiO2 e − CB + h + VB @ PS
Reactions involving e−CB: 3
O2 + e − CB → O•2−
1
O2 + e − CB → O•2−
H 2 O 2 + e − CB → OH • + OH − TiO2@PSCu II + e − CB → TiO2@PSCu I Reactions involving holes: OH − + h + VB → OH • H 2 O + h + VB → OH • + H + H 2 O 2 + h + VB → HO•2 + H + HO•2 + h + VB → O2 + H + TiO2@PS + h + VB → TiO2@PS+ Reactions involving sensitizer: 1
3
hv isc PS ⎯⎯ → PS* ⎯⎯ → PS* 3
3
PS* + 3O2 → PS + 1O2
PS* + 3O2 → PS+ + O•2−
TiO2@PS* → TiO2@PS+ + e − CB TiO2@PS+ + OH − → TiO2@PS + OH • TiO2@PS+ + 4NP → TiO2@PS + oxidationproducts
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Reactions involving radical species in aqueous phase: O•2 − + H 2 O → HO2• + OH − O•2− + H + → HO•2 2OH • → H 2 O 2 2HO•2 → H 2 O2 + O2 H 2 O 2 + O•2− → OH • + OH − + O 2 2HO•2 + O•2− → OH • + OH − + 2O2 Reactions involving metal of sensitizer: TiO2@PSCu I + 3 O2 → TiO2@PSCu II + O•2− TiO2@PSCu I +1 O2 → TiO2@PSCu II + O•2− TiO2@PSCu I + H 2 O2 → TiO2@PSCu II + OH • + OH − Oxidation reactions in aqueous phase: 1
O2 + 4NP → oxidationproducts
OH • + 4NP → oxidationproducts HO•2 + 4NP → oxidationproducts CuPc(COOH)4 – TiO2 showed a photocatalytic activity in degradation of Methyl Orange under irradiation with l > 550 nm [65]. The participation of CuPc(COOH)4 cation-radical was demonstrated in control experiments. AlPc(COOH)4 impregnated on several TiO2 samples was shown to be a good sensitizer for degradation of 4-CP in water under irradiation with l > 450 nm [55]. Among several parameters, such as AlPc(COOH)4 loading, the substrate concentration, pH and the amount of O2, the latter determined the efficiency of degradation. The optimum loading was about 1 wt.% providing a necessary balance between amounts of absorbed photons and absorbed O2 to achieve an optimal efficiency of oxidation. TiO2 functioned as electron mediator and AlPc(COOH)4 as sensitizer. The involvement of [AlPc(COOH)4]+, O2−· and OH− radicals was shown using EPR and trapping experiments. This catalyst was also used for oxidative degradation of phenol, 2,4-DCP, TCP, catechol, hydroquinone, salicylic acid and 4-sulfosalicylic acid. The stability of AlPc(COOH)4 –TiO2 was assessed in the oxidation of 4-CP. The rate of 4-CP degradation gradually decreased in successive runs because of slow decomposition of [AlPc(COOH)4]+. photogenerated on the TiO2 surface [55].
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The photocatalytic activity of TiO2 impregnated with lanthanide double Decker phthalocyanines LnPc2–TiO2 (Ln=Ce, Pr, Nd, Sm, Ho, Gd) was studied in degradation of 4-NP under irradiation with 125 W medium pressure Hg lamp (15.5 mW/ cm2) [66]. It is generally accepted that dimerization of regular phthalocyanine sensitizers leads to the loss of the photocatalytic activity because of the radiationless energy dissipation. However, all LnPc2–TiO2 materials showed a good photoactivity. Ho, Sm and Nd based catalysts were even slightly more active compared to anatase TiO2. A plausible explanation of this activity is that the presence of two macrocycles connected via lanthanide ion probably provides a better delocalization of the positive charge developed during photocatalytic process.
9.6
Conclusion
This chapter overviews principal photochemical methods used for degradation of pollutants. Although several photochemical approaches can be successfully used, the field is largely dominated by investigations dealing with applications of TiO2based photocatalysts. The state of the art and perspectives of the development of TiO2 materials for remediation have been covered in numerous recent comprehensive reviews [1, 2, 12]. For this reason, this area was only briefly discussed in this chapter. A major challenge that remains is an increase of photocatalytic efficiency of TiO2-based catalysts in terms of more effective use of visible light. To achieve this goal, several doping strategies have been developed and application of phthalocyanine sensitizers is one of them. Vast experimental results obtained in chemical and light-driven pollutant degradations with phthalocyanine complexes have never comparatively been reviewed. Moreover, researchers working with phthalocyanines in different fields of environmental applications are not obligatory aware of the related works in other areas. Mechanistic considerations have been discussed in as much detail as seems necessary to illustrate the essential features of different processes and to provide some background for the choice of optimal system for novel developments. However, the lack of sufficient quantitative data in original publications often makes difficult the direct comparison of the efficiency of different systems. While photosystems involving phthalocyanine sensitizers operate mainly via Type II pathway and generation of 1O2, photo-assisted processes in the presence of H2O2 include the formation of very active OH· radicals. In turn, a high activity of chemical systems consisting of iron phthalocyanines and H2O2 is associated with iron-centered active species, like oxo and peroxo complexes. Consequently, the search for better photosensitizers should not be restricted to diamagnetic MPc. The results obtained in FePc mediated photo-assisted oxidative degradation illustrate a usefulness of combined approaches. Recent discovery of remarkable catalytic properties of N-bridged diiron phthalocyanines capable of oxidizing methane, benzene, alkylaromatic compounds at very mild conditions [67–70] make these emerging catalysts very interesting to apply also in environmental remediation.
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Mechanistic studies are the subject of great interest which have played an important role in advancing fundamental knowledge in this field. The efforts in this direction should result in improving of existing photocatalysts and in development of new catalytic systems which might be a basis for future industrial applications.
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43. Lukyanets EA, Nemykin VN (2010) The key role of peripheral substituents in the chemistry of phthalocyanines and their analogs. J Porphyrins Phthalocyanines 14:1–40 44. Gürol I, Durmus M, Ahsen V (2010) Photophysical and photochemical properties of fluorinated and nonfluorinated n-propanol-substituted zinc phthalocyanines. Eur J Inorg Chem 1220–1230 45. Ozoemena K, Kuznetsova N, Nyokong T (2001) Photosensitized transformation of 4-chlorophenol in the presence of aggregated and non-aggregated metallophthalocyanines. J Photochem Photobiol A 139:217–224 46. Marais E, Klei R, Antunes E, Nyokong T (2007) Photocatalysis of 4-nitrophenol using zinc phthalocyanine complexes. J Mol Catal A 261:36–42 47. Wöhrle D, Suvorova O, Gerdes R et al (2004) Efficient oxidations and photooxidations with molecular oxygen using metal phthalocyanines as catalysts and photocatalysts. J Porphyrins Phthalocyanines 8:1020–1041 48. Gerdes R, Wöhrle D, Spiller W et al (1997) Photo-oxidation of phenol and monochlorophenols in oxygen-saturated aqueous solutions by different photosensitizers. J Photochem Photobiol A 111:65–74 49. Nensala N, Nyokong T (1997) Photosensitization reactions of neodymium, dysprosium and lutetium diphthalocyanine. Polyhedron 16:2971–2976 50. Nensala N, Nyokong T (2000) Photocatalytic properties of neodymium diphthalocyanine towards the transformation of 4-chlorophenol. J Mol Catal A 164:69–76 51. Agboola B, Ozoemena KI, Nyokong T (2006) Comparative efficiency of immobilized nontransition metal phthalocyanine photosensitizers for the visible light transformation of chlorophenols. J Mol Catal A 248:84–92 52. Xiong Z et al (2005) Enhanced photodegradation of 2,4,6-trichlorophenol over palladium phthalocyaninesulfonate modified organobentonite. Langmuir 21:10602–10607 53. Huang Y, Li J, Ma W et al (2004) Efficient H2O2 oxidation of organic pollutants catalyzed by supported iron sulfophenylporphyrin under visible light irradiation. J Phys Chem B 108:7263–7270 54. Mele G, Del Sole R, Vasapollo G et al (2005) TRMC, XPS, and EPR characterizations of polycrystalline TiO2 porphyrin impregnated powders and their catalytic activity for 4-nitrophenol photodegradation in aqueous suspension. J Phys Chem B 109:12347–12352 55. Sun Q, Xu Y (2009) Sensitization of TiO2 with Aluminium Phthalocyanine: factors influencing the efficiency for chlorophenol degradation in water under visible light. J Phys Chem C 113:12387–12394 56. Kölle U, Moser J, Grätzel M (1985) Dynamics of interfacial charge-transfer reactions in semiconductor dispersions. Reduction of cobaltoceniumdicarboxylate in colloidal titania. Inorg Chem 24:2253–2258 57. Anderson S, Constable EC, Dare-Edwards MP et al (1979) Chemical modification of a titanium (IV) oxide electrode to give stable dye sensitisation without a supersensitiser. Nature Lond 280:571–573 58. Ghosh PK, Spiro TG (1980) Photoelectrochemistry of tris(bipyridyl)ruthenium(II) covalently attached to n-type tin(IV) oxide. J Am Chem Soc 102:5543–5549 59. Giraudeau A, Fan FF, Bard A (1980) Semiconductor electrodes. 30. Spectral sensitization of the semiconductors titanium oxide (n-TiO2) and tungsten oxide (n-WO3) with metal phthalocyanines. J Am Chem Soc 102:5137–5142 60. Special issue on dye sensitized solar cells (2004) Coord Chem Rev 248(issues 13–14) 61. Martinez-Diaz MV, de la Torre G, Torres T (2010) Lighting porphyrins and phthalocyanines for molecular photovoltaics. Chem Commun 46:7090–7108 62. Clifford JN, Yahioglu G, Milgrom LR et al (2002) Molecular control of recombination dynamics in dye sensitised nanocrystalline TiO2 films. Chem Commun 1260–1261 63. Iliev V (2002) Phthalocyanine-modified titania – catalyst for photooxidation of phenols by irradiation with visible light. J Photochem Photobiol A 151:195–199
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64. Mele G, Del Sole R, Vasapollo G et al (2003) Photocatalytic degradation of 4-nitrophenol in aqueous suspension by using polycrystalline TiO2 impregnated with functionalized Cu(II)porphyrin or Cu(II)-phthalocyanine. J Catal 217:334–342 65. Chen F, Deng Z, Li X et al (2005) Visible light detoxification by 2,9,16,23-tetracarboxyl phthalocyanine copper modified amorphous titania. Chem Phys Lett 415:85–88 66. Mele G, Garcia-Lopez E, Palmisano L et al (2007) Photocatalytic degradation od 4-nitrophenol in aqueous suspension by using polycrystalline TiO2 impregnated with lanthanide doubleDecker phthalocyanine complexes. J Phys Chem C 111:6581–6588 67. Sorokin AB, Kudrik EV, Bouchu D (2008) Bio-inspired oxidation of methane in water catalyzed by N-bridged diiron phthalocyanine complex. Chem Commun 2562–2564 68. Sorokin AB, Kudrik EV (2008) N-Bridged diiron phthalocyanine catalyzes oxidation of benzene by H2O2 via benzene oxide with NIH Shift evidenced using benzene-1,3,5-d3 as a probe. Chem Eur J 14:7123–7126 69. Isci U, Afanasiev P, Millet JM et al (2009) Preparation and characterization of m-nitrido diiron phthalocyanines with electron-withdrawing substituents: application for catalytic aromatic oxidation. Dalton Trans 7410–7420 70. Afanasiev P, Bouchu D, Kudrik EV et al (2009) Stable N-bridged diiron (IV) phthalocyanine cation-radical complexes: synthesis and properties. Dalton Trans 9828–9836
Chapter 10
Photosensitisation and Photocatalysis for Synthetic Purposes Lucia Tonucci, Alessandro Cortese, Mario Bressan, Primiano D’Ambrosio, and Nicola d’Alessandro
Abstract The synthetic potential of photocatalytic and photosensitised routes is far from fully realised, even if the new concepts of green chemistry now have a central role. Photocatalysis, such as by means of semiconductors, represents a good tool to obtain industrially attractive chemicals, including conversion of alcohols to aldehydes, oxygenation of hydrocarbons, and reduction of nitrocompounds to amines. The more selective photosensitised reactions, which include photooxidation by singlet oxygen, are useful for obtaining oxygenated derivatives starting from unsaturated hydrocarbons; the reaction products are hydroperoxides, alcohols and carbonyl derivatives, with the main reactions being cycloadditions (4+2 and 2+2) and ene reactions (Schenck reaction). There are also the novel families of sensitisers, like fullerenes and metal macrocycles, which can provide promising alternatives to traditional organic photosensitisers.
10.1
Introduction
The pharmaceutical and food industries and many other industrial processes require various amounts of organic materials. If a derivative is not “natural” the only way to obtain it might be through chemical transformation of a natural raw material. Another problem is sustainability: renewable derivatives must be taken into consideration as a priority, compared to feedstock that comes from fossil fuels. Of course, the world of organic synthesis is huge, so our aim in the present chapter is to explore that part of it that refers to transformations that occur only in the presence of light. In other words, we will exclude all thermal reactions.
L. Tonucci • A. Cortese • M. Bressan • P. D’Ambrosio • N. d’Alessandro (*) Department of Science, University “G.D’Annunzio” of Chieti and Pescara, Viale Pindaro, 42, Pescara, Italy e-mail:
[email protected];
[email protected];
[email protected];
[email protected];
[email protected] T. Nyokong and V. Ahsen (eds.), Photosensitizers in Medicine, Environment, and Security, DOI 10.1007/978-90-481-3872-2_10, © Springer Science+Business Media B.V. 2012
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hν
R
R
*
*
Abs
Abs
energy transfer
Chemical reaction
Abs
R
*+R Abs
electron or atom transfer
Chemical reaction
Abs Fig. 10.1 Photochemical transformation scheme in which the reagent (R) is not involved in any interaction with the light
We start by introducing the field of photochemistry, which studies the interactions of light with matter that induce chemical transformations. As illustrated in Fig. 10.1, chemical reactions occur due to the energy that photons (hn) provide to a light absorber (Abs), which than makes this energy available for reactions. However, photochemistry embraces all photochemical transformations, where reagents can also absorb light. Our aim is to cover only the field of phototransformations where the reagents are transparent. Remaining within this last limitation, we can introduce two kinds of photochemical reactions that use substances that can absorb light, but that remain unchanged at the end of the reaction. After the photon absorption step, the excited substrate can evolve either by transferring this energy to other species or by reacting with a reagent in its ground state (Fig. 10.1, R), through electron or atom transfer. In both cases, a chemical reaction can occur. The great advantage of such transformations is the potential for high specificity and efficiency, and also the “mode” that is used to obtain the energy input that is sometimes necessary to allow a reaction to occur. This “mode” is particularly intriguing, since it is certainly much more “green” than the classical operations used in thermal chemistry, i.e. those where the heat is supplied by combustion or electricity, by the use of organic solvents, or of toxic metals, and so on. This use of light energy as a green energy source is not new, as even in the early 1900s, Giacomo Ciamician deplored the use of aggressive reagents and high temperatures in organic syntheses, and he believed in the possibility of carrying out photochemical reactions without depletion of the fossil resources [1, 2].
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Fig. 10.2 Photosynthesis, with the production of carbohydrates and oxygen from water and carbon dioxide
Today, the use of energy from light is specifically emphasized for industrial processes because “green chemistry” has become an indispensable concept for chemists and engineers in their thinking, designing and development of any synthetic reaction. The term “green chemistry” was coined by Paul Anastas in the early 1990s, when he was working for the U.S. Environmental Protection Agency. It was defined as “the design of new products and processes that reduce or eliminate the use and generation of hazardous substances” [3]. To meet the principles of green chemistry, the use of renewable feedstocks is fundamental, along with the use of clean solvents (water, supercritical carbon dioxide, ionic liquids, etc.), selective catalysts, non-toxic oxidants (hydrogen peroxide, molecular oxygen), and mild conditions of pressure and temperature. Over the last 20 years, many studies have been published in many and various fields that have followed the concepts expressed by some 12 green chemistry principles. For examples, oxidative catalytic reactions can be carried out in water rather than in organic solvents [4], or by using molecular oxygen as an oxidant, which is always of great interest as the only by-product here is water [5]. The main photochemical process that leads to organic derivatives is photosynthesis (Fig. 10.2). Above all, this is the most important natural event, and this is devoted
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Fig. 10.3 The principal applications of TiO2 as photocatalyst during the last 40 years
to the obtaining of organics starting from the very simple molecules of carbon dioxide and water. The role of photosynthesis is to store the energy of the sun through its transformation into a chemical form, i.e. carbohydrates. A consequence of this is that the water molecule is split, with production of molecular oxygen, while the other reagent, CO2, is fixed into the sugar. This natural event of photosynthesis has inspired a lot of research in the search for synthetic pathways that can be used to furnish a similar crucial result. At the end of the 1960s, Fujishima discovered an interesting phenomenon: when titanium dioxide electrode in an aqueous solution was exposed to a strong light, it produced a gas that bubbled off the surface of the electrode that disappeared when the light was switched off. That gas was shown to be oxygen, and hydrogen was also generated at the counter electrode, which was made of platinum. Thus, the result was a very interesting water-splitting reaction that produced hydrogen and oxygen, which can than be used as fuel. 2H 2 O + 4hv → O 2 + 2H 2
(10.1)
This phenomena is now known as the “Honda-Fujishima effect” [6]. Indeed, Fujishima discovered a system that mimics photosynthesis by using a very simple derivative, TiO2, which thus replaces the chlorophyll [7]. The main difference is obviously that TiO2 only absorbs in the UV region, and not in the Vis one, even if it has a higher stability than chlorophyll. From about 1975–1980, other studies used TiO2 as a redox system, as a photocatalyst in both oxidation (many examples) and reduction (a few examples) modes, thus opening the door for a new field called photocatalysis. The main applications developed over the last 30 years have been, above all, in environmental chemistry, such as for water and air purification, with phenomena that have been classified as advanced oxidation processes (AOP) [8]. More recently, the new concept of autopurification has been introduced into bio-architecture: again, with TiO2, but now in a nanosize form, which can be added to building materials with the goal of the photocatalysis of the degradation of environmental pollutants, such as organic derivatives, nitrogen oxides, to name but a few (Fig. 10.3) [9].
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Fig. 10.4 The most common polymorphic forms of TiO2: rutile (a), anatase (b) and brookite (c) (Source: http://ruby.colorado.edu/~smyth/Home.html)
A large part of the research that has been carried out in the past regarding photocatalysis has favoured the water-splitting reaction and the environmental applications towards the degradation of pollutants. In this last case, the goal is completely reversed, since the selectivity of these processes is not important, and, on the contrary, unselective reactions are required. On the other hand, when the photocatalysis acts as a tool in synthetic chemistry, the selectivity should be as high as possible, to provide reasonable yields of target products. The question now is: how can a photocatalytic system be designed to achieve this goal? The answer is not simple, nor immediate. Although the type of reactor is an important issue for the efficiency and selectivity of any photocatalytic reaction [10], we prefer here to leave aside this aspect, and instead to focus our attention on solvents and catalysts. The solvent certainly has an important role in the evaluation of the whole process, with the first limitation being the concentration of the solute: dilute solutions are used because light must penetrate into the reaction medium to a significant depth to provide efficient absorption from the catalyst. Furthermore, the solvent must be reasonably inactive and transparent to the wavelength range requested. Acetonitrile has been widely used because of both its low absorption in the UV-Vis range and its rare participation in a variety of potential chemical transformations [11]. However, acetonitrile is not a suitable choice if we are to consider our environment [12], and instead, where possible, water is indeed the best candidate to replace it. The advantage of the use of water is its total absence of toxicity and its particularly economic convenience. The most diffuse photocatalyst, remains TiO2, which exists in three polymorphic forms: rutile, anatase and brookite (Fig. 10.4). Historically, anatase and rutile were preferentially used, with anatase showing a higher photocatalytic activity [13]. However, the most used catalyst in environmental applications has been the P-25 TiO2 produced by Degussa (now part of Evonik Industries), in a mixture of anatase/rutile at about a 3:1 ratio. Interestingly, Ohno et al. [14] found that the photocatalytic oxidation of naphthalene is inefficient when
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rutile or anatase are used alone, whereas even a simple mixture of them definitely enhances the reaction. Their conclusion was that the particles of the two polymorphic forms must be in contact, thus leading to a synergistic effect [14]. A comparative study related to the selectivity of obtaining p-methoxybenzaldehyde starting from p-methoxybenzyl alcohol was reported by Augugliaro et al. [15], where three samples of home-made titania (rutile, anatase and brookite) were irradiated in water suspension. Rutile gave the best result in terms of selectivity. Particle size and crystallinity also have important roles: it has been reported that the selectivity in cyclohexane photooxidation is strictly dependent upon the particle size, as the yield of cyclohexanol increases with an increase in the diameter of the particles, whereas the productivity and the cyclohexanone yields both decrease [16]. Alternatively the performance of the photocatalyst can be modified by some metal deposition, which appears to lead to changes in the semiconductor surface properties. The added metal can enhance either the yield of particular products or the rate of the photocatalytic reaction [17]. This effect was first observed in the water-splitting photoreaction, where a photocatalyst of platinum deposited on TiO2, enhanced the production of hydrogen and oxygen [18]. Generally, noble metals deposited on TiO2 enhance the performance of the catalyst, and above all when a gas (namely hydrogen) is a reaction product. However, the metal does not always act in favour of the desired product: for example, gold deposited on anatase negatively affects the activity of the catalyst in the selective photooxidation of cyclohexane, which probably occurs because there is significant modification of the surface OH-population of the catalyst induced by the added metal [19]. Another example, which was reported by Ohthani and his group, deals with the effect of noble-metal-modified titania on the photocatalytic transformation of lysine to pipecolinic acid, where a small effect of the noble metal load on the catalytic activity of TiO2 was seen [20]. Modification of the catalyst surface can also be achieved by non-metal derivatives. In this case, it was recently reported that fluorination of the titania surface can enhance the selectivity for obtaining 1,3-dihydroxyacetone and glyceraldehyde in the photooxidation of glycerol [21]. In conclusion, although several studies have been carried out with the aim of optimization of selectivity, the choice of the catalytic system must still be considered case by case. As showed in Fig. 10.1, there is an alternative pathway by which the light absorber can transfer the energy to the reagent. Among photosensitized processes, the activation of oxygen is by far the most common for synthetic purposes, and this is the reason that from here on we focus our attention on this field. A number of reviews have been published on the chemistry of singlet oxygen [22–26]. However, we retain that a brief overview is necessary to introduce its synthetic potentiality. The existence of singlet oxygen was proposed in 1931 by Kautsky, on the basis of a study previously carried out by Mulliken, in 1928 [27, 28], when molecular orbital theory was applied to the oxygen molecule [29]. The first experimental evidence of the existence of singlet oxygen was published by Foote in 1964, where a solution of sodium hypochlorite and hydrogen peroxide was able to oxygenate olefins [30, 31]. In 1968, luminescence of singlet oxygen was reported
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for the first time, at 1,268 nm in benzene vapour, and it was demonstrated that the emission was due to the energy transfer from the excited state of benzene to oxygen [32]. It then took 8 years to directly measure luminescence in an air-saturated solution [33]. Meanwhile the word luminescence was replaced by phosphorescence, since singlet oxygen gives a forbidden intersystem transition to the final stable triplet state. For the synthetic use of singlet oxygen, as well as the early works by Schenck (see, for example, reference [34]), who investigated the formation of hydroperoxides from olefins for the first time, by the end of 1970s, diffuse applications in organic synthesis had been developed by several authors. We can cite the efforts of Gollnick, who irradiated a methanolic solution of Rose Bengal containing 2,3-dimethyl-2-butene [35], and the pioneering examples of synthetic singlet oxygen chemistry by the Italian group of Forzatti, where they oxidised alkenes to allyl hydroperoxides by methylene blue, in homogeneous solution or using the sensitiser supported on silica [36]. The diastereoselective oxyfunctionalisation of organic derivatives by the ene reaction is also worth noting. While its regioselectivity had been extensively studied previously, only after the 1990s was attention focused on stereocontrol [37]. This breakthrough substantially enhanced the utility of singlet oxygen in diastereoselective synthesis. At present, singlet oxygen is particularly evoked in important photoreactions that deal with the study of its biological effects. Triplet molecular oxygen is relatively stable and diffuses rapidly through most biological media, including cell membranes, which normally act as barriers for many substrates. On the contrary, singlet oxygen reacts quickly with a lot of biological substances, such as fatty acids and proteins, which restricts its ability to diffuse around the media. Thus, the degenerative action of singlet oxygen occurs only at short distances from the photosensitiser that generated it. This phenomena represents the conceptual basis of photodynamic therapies against cancers: molecules selectively attached in a region close to a tumor site can photosensitise the formation of singlet oxygen, which quickly reacts with its closest “neighbours” (for reviews, see references [38–41]). A photosensitiser is a light-absorbing substance that initiates a photochemical or photophysical reaction in another substance (molecule), and is not itself consumed in the reaction. As illustrated in Fig. 10.5, the photosensitiser (S0) must have a high absorption coefficient in the correct spectral region. Through photon absorption, S0 can be excited to S1* in its singlet state. After an intersystem crossing to the triplet state (T1*), the excited sensitiser can excite by a physical step, such as the energy transfer, whereby this second molecule can than react with an organic substrate (Fig. 10.5) [42]. In summarising there above concepts, we can conclude that our aim is to explore the literature to extrapolate all of the applications that are devoted to synthetic purposes that have made use of photocatalysis (atom or electron transfer) and photosensitisation (energy transfer).
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Energy S1* Intersystem Crossing
T1*
1O
2
Fluorescence Phosphorescence
S0 Ground state (Abs)
Photosensitiser
3O
2
Oxygen
Fig. 10.5 Singlet oxygen formation by a photosensitised process
10.2
Photocatalysis
As defined by Albini and co-workers, a photocatalyst is an active compound in its excited state that increases the reactivity of a substrate through a chemical step (i.e. electron or atom transfer) [42]. Here we have concerned ourselves, above all, with reactions that deal with synthetic purposes, leaving out all of the applications in environmental depollution, water-splitting, hydrogen formation and reduction of gases like CO2. Recently, many interesting reviews have been published about the concept of photocatalysis (see, for example, references [42–44]). The main photocatalysts we are dealing with here are semiconductors, polyoxometallated metal complexes (POM), and some other organic compounds. The chemical reactions mainly occurring by photocatalysis are: – – – –
Oxidation; Reduction; Alkylation; Other reactions, like activation of C–H and C–N bond, etc.
10.2.1
Oxidation Reactions
10.2.1.1
Alcohols
Alcohol oxidation still represents a big challenge for organic synthesis, as the more classical stoichiometric methods use unfriendly environmental reagents (e.g. high valent metals) and conditions that are no longer in agreement with the modern principles of green chemistry [3]. Metal catalysts have contributed to a reduce in the
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Photosensitisation and Photocatalysis for Synthetic Purposes H3C
OH
H3C
477
O
hν TiO2 acetonitrile
94%
Fig. 10.6 Oxidation of a 1-phenethyl alcohol to acetophenone by anatase TiO2
use of toxic reagents [45–47]; however, there remains the need to develop new methodologies that can contribute to reductions in the use of both materials and energy, as well illustrated by the new concept of the E-factor introduced by Sheldon [48]. Photocatalysis (with UV or visible light) can provide efficient methodologies to oxidise an alcohol functional group to a carbonyl/carboxyl group under green conditions. Many studies have been published in recent years that have dealt with the photocatalysis of benzyl or cyclic alcohols, to obtain their carbonyl derivatives. The oxidation of benzyl alcohols in dry acetonitrile in the presence of TiO2 (anatase) and neat oxygen (P = 1 atm) and irradiated with medium pressure Hg lamps was reported by Mohamed [49]. Figure 10.6 illustrates the oxidation of a secondary aromatic alcohol to acetophenone (with 94% yield). The by-product is benzoic acid, although it does not appear in concentrations higher than 2%. The TiO2 behaves as a classical semiconductor, for the ejecting of an electron (eCB−): *
hv + TiO2 ⎯⎯ → TiO2 → e −CB + hVB
(10.2)
Initially, the oxygen is reduced by the electron to a superoxide radical anion (O2·−), while the alcohol substrate, which is adsorbed on the titanium dioxide, entraps the positive hole and is transformed into a radical cation, which is easily oxidisable by O2·−. The benzyl alcohol oxidation reaction has been examined also in other studies. p-Methoxybenzyl and benzyl alcohols were oxidised by bubbling oxygen through a water solution irradiated by 366 nm light at 300 K in the presence of TiO2 from both home-made and purchased origins (Degussa and Merck) [50]. All semiconductors are active, but with some differences: the commercial oxides speed up the reactions, although the acid and hydroxylated derivatives were also formed; in the presence of the home-made TiO2, only benzaldehyde (28% selectivity) or methoxybenzaldehyde (41% selectivity) and CO2 were produced. By adding small amounts of simple alcohols to the reaction mixture, like methanol, ethanol or isopropanol, the reaction rate was slowed down, while the aldehyde selectivity increased. The authors explained this behaviour as competition between the simple alcohol and the benzyl alcohol in the mineralisation pathway.
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R
R
R'
H R Nb5+ O
Nb5+
O
Nb5+
H
OH
O
H
O
R'
+
hν
Nb5+ O
Nb4+
O
+
H
Nb5+
O
OH
1/2 O2 R
Nb4+
Nb4+
Nb4+
O
R'
O Nb4+
R
H2O
O
R' O
Fig. 10.7 The proposed mechanism for the activity of Nb2O5 as a photocatalyst
An interesting green oxidation of primary or secondary benzyl and aliphatic alcohols was reported by Shishido [51]. The neat substrates are irradiated by UV light (500 W, Hg ultra pressure lamps) at 323 K in an oxygen atmosphere (P = 1 atm) in the presence of Nb2O5 as photocatalyst (which can be recovered at the end of the reaction and reused, without loss of photocatalytic activity). The conversions were very high, although long times of irradiation were necessary (up to 10 days). The products were aldehydes/ketones, carboxylic acids and CO2. Some alcohols were also oxidised in the absence of oxides, but the yields and selectivities were different. Although Nb2O5 does not absorb in the visible region, the reactions can also occur at wavelengths around 400 nm, with good reactivity up to 480 nm. The reaction mechanism with Nb2O5 appears to be slightly different from that commonly reported for other semiconductors. Indeed, although a typical oxide like TiO2 can be active for the oxidation of alcohols, it shows a lower selectivity than Nb2O5. Furthermore, the reaction also occurs in the presence of visible light, which is a region where TiO2 (and also Nb2O5) does not absorb. Starting from the experimental data, this study concluded that the alcohol is adsorbed onto the surface oxide; this alcoholate of Nb5+ absorbs a visible photon, which allows the electron transfer process that reduces Nb5+ to Nb4+. The radical-alcoholate intermediate evolves to a carbonyl derivative, which is desorbed from the surface. Molecular oxygen provides the re-oxidising of Nb4+ to Nb5+ (Fig. 10.7). The alternative mechanism involving the superoxide radical anion appears not to be operative. The primary and secondary benzyl alcohols are effectively oxidised in the presence of some polyoxometalates (POMs). In particular, when the reaction was conducted on 4-methyl benzyl alcohol, in acetonitrile, with an oxygen atmosphere, at 293 K, irradiation of the solution with near UV and in the presence of H3PW12O40 encapsulated on silica, lead to the formation of the 4-methyl benzaldehyde at a 92% yield [52]. When encapsulated, this POM catalyst is more active than in a homogeneous
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Photosensitisation and Photocatalysis for Synthetic Purposes
POM
479
OH
OH
hν POM *
+
POMred + Ar
Ar
R
R
+ O2 O
POM
+ Ar
R
Fig. 10.8 The proposed mechanism for the activity of H3PW12O40 as a photocatalyst
phase, and the significantly higher activity of H3PW12O40/SiO2, as compared with that of pure H3PW12O40, has been attributed to the much greater specific surface area of the composite derivative [53]. Benzyl and alkyl alcohols have been selectively oxidised to carbonyl compounds in 2–3 h without overoxidation products, while low oxidation yields have been obtained in the case of aliphatic and aromatic non-benzyl alcohols. In the proposed mechanism (Fig. 10.8), the excited POM extracts one (or two) electron(s) from the alcohol substrate. The POM catalyst is reoxidised by oxygen and can be reused without any loss of activity. Oxidation of benzyl alcohol to benzaldehyde was reported by Rüther [54]. In spite of the use of acetonitrile as solvent, the methodology can still be considered green since the oxidation was performed by exposure to solar light and under aerobic conditions at room temperature, using the quaternary ammonium salt of S2M18O624− as photocatalyst (known as the Wells-Dawson anion; M = Mo and W). With 88% aldehyde selectivity obtained after 25 days of irradiation, there was 12% benzoic acid as a by-product. To prepare p-anisaldehyde, which is an important derivative in the synthetic chemical industry and is also used as a scent, it is possible to irradiate the p-methoxybenzyl alcohol in the presence of brookite TiO2 (prepared in the laboratory). Photocatalytic oxidation at room temperature leads to the aldehyde in a water mixture exposed to sunlight. The reported yield was 42% (at 65% conversion). After long times of irradiation, CO2 and traces of acids and open-chain derivatives were also detected [55]. Under similar conditions, but with neat benzyl alcohol, Ohkubo and co-workers [56] obtained benzaldehyde with the 9-phenyl-10-methylacridinium cation as photocatalyst. The reaction was conducted with visible light, and the only by-product detected was hydrogen peroxide. A summary of the photocatalysed oxidation of benzyl alcohols is reported in Table 10.1.
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Table 10.1 The photocatalytic oxidations of benzyl alcohols Product (yield, Substrate selectivity) Photocatalyst Solvent; reaction conditions 9-Phenyl-10No solvent; air (1 atm), 15 h, methylacridium r.t. ion O
OH
H
Reference [56]
(n.d.) O
OH
H
H3PW12O40/SiO2
CH3CN; O2 (1 atm), 1 h, r.t.
[52]
S2W18O624−
CH3CN; air (1 atm), 600 h, solar light
[54]
TiO2 (anatase)
CH3CN (dry); O2 (1 atm), 6 h, [49] r.t.
Nb2O5
No solvent; O2 (1 atm), 240 h, [51] 323 K
TiO2 (brookite, home made)
H2O; O2 (1 atm), 8 h, 300 K
TiO2 (home made)
H2O; methanol (small [50] amount), O2 (1 atm), 17 h, 300 K
(92%, n.d.) O
OH
H
(26%, 88%) H3C
OH
H3C
O
H3C
OH
H3C
O
(94%, 99%)
(95%, 96%) OH
O H
OCH3
OCH3
OH
(42%, 65%)
O H
OCH3
OCH3
[55]
(40%, 62%)
Cyclohexanol dehydrogenation to cyclohexanone can be obtained by irradiating either in the B or the Q band of the rhodium (III) Cl(tetraphenylporphyrinate) complex [57]. Geraniol, and in general primary and allyl alcohols (citronellol, trans-2-penten-1-ol, 1-pentanol) can be selectively photooxidised in the presence of P25-TiO2, at l >320 nm, in acetonitrile at 293 K and 1 atm oxygen [58]. In 1–2 h, citral was obtained with 60% selectivity, at 75% conversion of alcohol. Over-oxidation products and CO2 were not observed. Alkoxy radicals were revealed by electron spin resonance during the reaction, while OH· radicals were formed only by a marginal pathway, and consequently in very tiny amounts. The substrate was adsorbed on titania, and after the oxidation step, aldehyde was quantitatively released into solution.
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OH O
HO
OH
O
O
O
glyceraldehyde OH
HO
OH
dihydroxyacetone
OH
tartronic acid OH
HO
OH
O O
O
OH
O
hydroxyethanoic acid OH
OH
O
HO
OH
mesoxalic acid
formic acid OH
OH
HO
OH
O
HO
OH
O
glyceric acid
O
O
HO O
oxalic acid
hydroxypyruvic acid
Fig. 10.9 The most common products coming from selective oxidation of glycerol
The alcohol conversion was enhanced with the addition of increasing amounts of water, although the selectivity was reduced because CO2 began to be produced. The presence of water diminishes the amount of adsorbed geraniol, and at the same time, it increases the formation of OH·: the result is a loss of selectivity. This behaviour is analogous to the case of allyl alcohols (i.e. pentenyl alcohol), although in the last case, also in the dry mixture reaction, small amounts of CO2 are formed and OH· is seen. Irradiation (l 350 nm) of cyclohexene and cyclooctene at room temperature and 1 atm oxygen pressure, using iron(III) mesotetrakis(2,6-dichlorophenyl)porphyrin in the presence of a surfactant in aqueous media [63]. Surprisingly, from cyclooctene, the main reaction product was the epoxide, with a selectivity >90%, while from cyclohexene, the main reaction product was the a,b-unsaturated ketone. The regiochemistry of the photocatalysed oxidation of unsaturated hydrocarbons was recently investigated [64]. The visible-light photooxidation of cyclohexene
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483 H
O
h , O2
O
h , O2 O
h , O2
Fig. 10.10 Aromatic hydrocarbons photooxidised by diiron(III) bisporphyrin, with 100% selectivity
(room temperature, 1 atm O2) using commercial 5,10,15,20-tetrakis(pentafluorophe nyl)porphyrin-iron(III) chloride in dichloromethane and in the presence of several solid bases, led to the epoxide. The presence of the solid base was extremely important, as without this, the reaction went through porphyrin-photosensitised oxidation of the alkene (by singlet oxygen), which gave the expected allyl alcohol as the reaction product. Mg-Al hydrotalcite showed the best selectivity versus the epoxide. Porphyrins supported on cyclodextrines or Nafion in 2-propanol can photocatalyse the oxidation of cyclohexene to cyclohexenol and cyclohexenone. Of note, there is a difference in the turnover number (TON) and porpyhrin stability when the complex was used in a homogeneous or heterogeneous phase: cyclodextrine- and Nafion-supported catalysis showed an increased TON with a noticeably better chemical stability of the photocatalyst [65, 66]. Also, P25-TiO2 by Degussa has been used [67] to photocatalyse the oxidation of hydrocarbons, like ethylbenzene, toluene, cyclohexane and methylcyclohexane, to, respectively, acetophenone (selectivity, 100%), benzaldehyde (selectivity, 90%), a cyclohexanol/cyclohexanone mixture, and in the case of methyl cyclohexane, a mixture of several oxygenated products. The reactions were performed with a water suspension of TiO2 irradiated for 2 h. H2O2 (30%) was also added in the case of cyclohexane. The advantage of this reaction is that neither CO2 nor open-chain products were detected. Simple alkenes can be photooxidised efficiently in presence of semiconductors (e.g. TiO2, MoO3, WO3, CdS, CuMoO4). Propylene in a water mixture and in the presence of titania and oxygen was irradiated by a 500 W Hg lamp. Acetaldehyde was obtained here with a 78% yield, while small amounts of epoxide, alcohol and
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III
Fe
N
N
C6F5
N
hνvis O
O
C6F5
C6F5 III N
N
Fe N
C6F5
N C6F5
C6F5
N
II
Fe
N
O
N
C6F5
N
C6F5
C6F5 O N IV N
1/2 O2
N
C6F5
N
II
N
N
O
C6F5
N
C6F5
C6F5
Fe
Fe
N
C6F5
RH
C6F5
N
II
N
Fe N
N
C6F5
ROH
C6F5
Fig. 10.11 Photocatalytic cycle for the oxidation of hydrocarbons in presence of diiron(III)-moxo-bisporphyrin
higher molecular weight aldehydes were also formed [68]. The photooxidation of cyclohexane was investigated by Boarini under similar experimental conditions [69]. They studied the distribution of the products relative to the solvent used. By increasing the content of CH2Cl2 in the solvent mixture formed by cyclohexane itself and methylene chloride, the rate of formation of mono-oxygenated products was enhanced, and the production of CO2 was decreased. At the same time, the alcohol:ketone ratio was increased.
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SO3H
N
N SO3H
Fe(III)
HO3S
N
N
SO3H
Fig. 10.12 Iron (III) meso-tetrakis(sulphonatophenyl)porphyrin
Titania doped with 0.5% Fe3+ in an oxygen atmosphere can photocatalyse the near UV (365 nm) oxidation of toluene to benzaldehyde. Benzyl alcohol and carboxylic acid were detected only after long irradiation times [70]. The yield and selectivity of this doped TiO2 were higher than when the oxide was used alone. However, the doped catalyst tended to lose the iron, and hence the catalyst cannot be re-used [71]. An iron sulphonated porphyrin (Fig. 10.12) that is covalently bound to TiO2 can photocatalyse (365 nm, in pure oxygen) the oxidation of cyclohexane and cyclohexene within 3–4 h. Comparing the behaviour of the heterogeneous composite catalyst with both TiO2 and porphyrin used alone, in the first case, there was a greater selectivity for the formation of cyclohexanol, and generally versus the monooxygenate derivatives of cyclohexene (e.g. alcohol, ketone, epoxide). In addition, the turnover number was increased from 120 to 12,000 [72], while the formation of CO2 was negligible. Cyclohexane and cyclohexene can be oxidised, respectively, to cyclohexanol/ cyclohexanone and cyclohexenyl hydroperoxide/cyclohexenone under the following reaction conditions: l = 254 nm, 280 nm or 300 nm, 1 atm O2, 293 K, in the presence of the POM W10O324− supported on silica [73]. The cyclohexane oxidation
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OH
OH OH
+ OH
.
+
+
OH
Fig. 10.13 Oxidation of benzene by a hydroxyl radical
occurred in the absence of solvent or in dichloromethane. The ketone:alcohol ratio was 2.3:1, and the yield of CO2 was Au>Hg>Pd (Fig. 12.25); these highly transparent systems present an excellent compromise nonlinear absorption/transparency with low optical limiting thresholds up to 0.07 J cm−2 with 92% of linear transmittance [70, 71]. Phthalocyanines [72–79] and naphthalocyanines [80, 81] derivatives have been widely studied for RSA based OPL effects; porphyrins represents also an interesting class of molecules for nonlinear absorption [82–85]. Typical the ratio k between excited state absorption cross-section and ground state absorption cross-section is 25–30. Different strategies can be considered in the view of improved OPL efficiency in these molecules. In this context, significant improvements in the nonlinear response have been obtained in phthalocyanines and naphthalocyanines organo-metallic complexes, using the heavy-atom effect to increase the triplet state effect by intersystem crossing, with an attenuation of ns pulsed laser of a factor of 540 at 532 [86, 87].
12.3.3.1
Effect of the Substituent
The role of electron withdrawing substituent such as Fluor is studied using the openaperture Z-scan technique, which measures the transmittance of the sample translated through the focal point of a focused beam. When the sample reach the focal point, the beam intensity is increased leading to an enhancement of the nonlinear absorption and therefore to the decrease of the transmittance due to RSA in the present case.
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1.0
0.8
0.8
Transmittance
Transmittance
1.0
0.6 0.4 0.2 0.0
Pt-P cis-Pt-P
0.6 0.4
Hg-D Hg-T Hg-P
0.2
0.01 0.1 Input fluence/Jcm-2
1
0.01 0.1 Input fluence/Jcm-2
Transmittance
1.0 0.8 0.6 0.4
Pt-D Pt-T Pt-P
0.2
0.01 0.1 Input fluence/Jcm-2 PEt3 Ph Pt PEt3 C H 8 17
C8H17
PBu3
PEt3
Pt
Pt Ph
PBu3 C H 8 13 Pt-T
PBu3 Pt
C8H13
n
1 PEt3
PEt3 Pt Ph
Ph Pt PEt3
PEt3
C8H17
C8H17
PEt3
Pt-D
MeHg
HgMe
PBu3 C H C8H17 8 17 Ph2P PPh2 Pt-P Pt
C8H17 C8H17 Hg-D Hg
C8H17 C H 8 17 cis-Pt-P
a C8H17
a
C8H17
Hg-P Hg
MeHg C8H17
C8H17
Hg-T
HgMe C8H17
C8H17
Fig. 12.25 Top: optical limiting curves (nonlinear transmittance with linear transmittance of 92%) of selected metal polyynes structures (Bottom)
Figure 12.26 displays the increase of the nonlinear transmission in perfluorinated compound 24 with respect to that observed in differently substituted systems 25–26. This trend is ascribed to the enhancement of the transition dipole moment associated with transition involved in OPL in the case of molecule 24 [88]. As in the case of phthalocyanines, an enhancement of the nonlinear absorption can be obtained by a fine modification on the para-position of the meso-phenyl rings in [TPP(4-CCTMS)_H2] and in its complexes with respect to standard analogues and the benchmark C60 (Fig. 12.27) [89]. This is ascribed to the strong influence of
12
Chromophores for Optical Power Limiting F
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F F
F
R
F
R
F N
N F
N N
MX N
F
F
N
N
N
N
N N
MX N
F
N N
N
N F
F F F
R
R
F
25: MX = TiO; R = C(CH3)3 26: MX = TiO; R = CF3
F
24: MX = TiO 24
T / T0
1,0
1,8
24 25 26
0,6
−200
−100
0
100
z / 10-4 m
Fig. 12.26 Z-scan profiles of molecules 24–25 at 532 nm
substituent groups on the excited state absorption without any change in ground state absorption, and is illustrated by a larger change in transmission with increasing energy than in C60 or than in reference porphyrines. A similar effect has been observed in lanthanide porphyrins substituted by electron-rich moieties. [90]
12.3.3.2
Oligomerization
The oligomerization of phthalocyanines or porphyrins has been shown to lead to a significantly reduced saturation intensity of RSA with respect to the parent monomer [91–93]. The ratio between the excited state cross-section and that of the ground state is 50% weaker for the m-oxo bridged dimer of Fig. 12.28 with respect to that of the monomer; furthermore the monomer presents a higher nonlinear absorption coefficient at small laser intensities than that measured in the case of the dimer, while an inverse effect is observed at higher intensities [72]. Furthermore, Fig. 12.28
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R
R= N R
Si
N R
M N
N
R
M = 2H
TPP(4-CCTMS)_H2
M = ZH
TPP(4-CCTMS)_Zn
M = Ni
TPP(4-CCTMS)_Ni
M = GaCl
TPP(4-CCTMS)_GaCl
M = InCl
TPP(4-CCTMS)_InCl
M = SnCI2 TPP(4-CCTMS)_SnCI2
Transmittance
100
TPP_Zn_DCM TPP_Zn_DCM TPP(4-CCTMS)_Zn_DCM
10 10
100 1000 Input Peak Fluence (mJ/cm2)
10000
Transmittance
100
TPP(4-CCTMS)_Zn TPP(4-CCTMS)_N TPP(4-CCTMS)_GaCI TPP(4-CCTMS)_InCI TPP(4-CCTMS)_SnCI2 C60_Toluene TPP(4-CCTMS)_H2 Pc(I-Bu)InCI_DCM
10 10
100 1000 Input Peak Fluence (mJ/cm2)
10000
Fig. 12.27 Nonlinear optical transmission at 532 nm of standard and modified porphyrins
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Fig. 12.28 Normalized transmission with the incident pulse energy density for the monomer (circles) and the dimer (squares)
shows clearly that the m-oxo bridged dimer saturates at an energy density nearly 3.2 times weaker than that of the monomer. This type of behavior opens the way to the design of a two-layered performant device, with a first monomer layer followed by a dimer layer; this could lead to a decrease in transmission of nearly 80%. Fused porphyrin dimers revealed RSA in the NIR, which decays in a few hundred nanoseconds (Fig. 12.29a), while the comparison of the triplet excited state and ground state absorption spectra confirms this trend in the range 600–930 nm (Fig. 12.29b). In particular, this ESA is comparable to that of the ground state with peaks at 460, 625 and 870 nm with a ratio k = s ex / s gr = 6.9 [94].
12.3.3.3
Interactions with Carbone-Based Molecules
Graphene is a structure with remarkable electronic properties. The combination with porphyrins should give rise to materials with interesting properties. The hybrid material in Fig. 12.30 is based on a strong interaction between the excited state of the porphyrin, which presents a strong donor character, and the acceptor graphene
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N
Ar
N
N
N Zn
N
N Ar
785 nm probe
3
670 nm probe
0.9
2 630 nm probe 1
0.8
b
40
60 t/ns
80
100
2.0
σ0x
σ0
0.0
0 20
3.0
1.0
pump 532 nm 0
X = Br
4.0 σ/10-16 cm2
911 nm probe
1.0
X N
Ar
pulse intensity (arb units)
a normalised transmittance
N
Zn
X
400
120
600
800 λ / nm
1000
1200
Fig. 12.29 Nonlinear absorption of fused prorphyrins. (a) RSA at different wavelengths with a pump at 532 nm; (b) comparison of ground state (S0–S1) and excited state (T1–Tn) absorption spectra
1.2 NH N
HN N N HH N N
N HN NH N
N HN
C O
Tin=75%
HN O C Donor-Acceptor
HO O N C H O
OH O
ET O C
C O
NH
NH
PET N NH HN N
N NH HN N
fluorescence
Normalized transmittance
excitation
1.0
0.8
0.6
0.4 −20
TPP-NHCO-SPFGraphene TPP-NH2 graphene oxide the controlled sample C60
−10
0 z/mm
10
20
Fig. 12.30 Open-aperture Z-scan data (right) of graphene hybrid material (left) compared to those of C60, porphyrine and graphene oxide
moiety [95]. This is reflected by a fluorescence quenching due to several competitive processes such as photoinduced electron transfer (PET), energy transfer, as in the case of carbon nanotubes. The strong enhancement obtained in OPL efficiency of the hybrid system with respect to response of the parent moieties (graphene and porphyrin) is assumed to arise from the existence of these photo-induced processes (Fig. 12.30); it is worth noting that it leads to a more OPL efficient system than C60, the benchmark material in this field. This trend seems to be general to this type of graphene based material [96].
Chromophores for Optical Power Limiting
Output Fluence (J/cm2)
40 30 20
1 C60 SWNTs SWNT+TPP TPP Sn(OH)2DPP I II III
b
a
75%
10 0 0
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Transmittance
12
20 40 60 80 Input Fluence (J/cm2)
100
0.1
0.01
C60 SWNTs SWNT+TPP TPP Sn(OH)2DPP I II III
0.1 1 10 Input Fluence (J/cm2)
100
hv O NH N N HN
n
C
O N H
NHN NHN
n
C
O
NN Sn O N N
n
e− SWNT-TPP (I)
SWNT-NH-TPP (II)
SWNT-SnDPP (III)
Fig. 12.31 Top: optical limiting curves ((a) output fluence, (b) nonlinear transmittance) of C60, SWNT, parent 5,10,15,20-tetraphenylporphyrin TPP and trans-dihydroxo [5,15-bis-(3,5-dioctyloxyphyenyl)porphyrin]Tin(IV) (Sn(OH)2 DPP), SWNT+TPP, and porphyrin functionalised SWNT’s I, II, III (displayed in bottom)
Similarly, functionalized SWNT with RSA porphyrins have been shown to present a significant enhancement of OPL efficiency, with higher performances than those of the reference C60 and of the parent carbon nanotubes or porphyrin due to the combination of nonlinear scattering and RSA mechanisms, and to energy or PET between both moieties (Fig. 12.31) [97]. A similar trend is observed in the case of multiwall nanotubes covalently functionalized with conjugated metal free phthalocyanines [98].
12.3.3.4
Solid-State Results
The introduction of RSA systems in polymer host matrices is a good strategy to improve OPL efficiency with respect to the response observed in solution of the parent system [78, 99]. We will report the case of a supramolecular Zn-phthalocyanine in thin film (Fig. 12.32) [100]. Normalized transmission curves are compared in solution and in PPMA polymer (Fig. 12.32a): the drop observed around the focal point is higher in solid state (curve b) than in solution (curve a), suggesting a higher nonlinear absorption in PMMA. These curves allowed to determine relevant parameters characterizing OPL effect, such as the ratio k between the excited and ground state absorption cross-sections, the energy density output at saturation Fsat , and the nonlinear absorption coefficient b . The efficiency of the OPL process is related to high values of k and b and to a weak value of Fsat ; k and b are larger in solid state than in solution:
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Fig. 12.32 Comparison of nonlinear properties of the system in chloroform (a) or in polymer (b). (a) Open aperture Z-scan transmission; (b) OPL study
k = 18.6 and 16.2 respectively, while b presents a four order of magnitude higher value in solid than in solution (5.2 × 10−4 and 1.4 × 10−8 cm·W−1 respectively). Fsat is significantly weaker in PPMA than in chloroform (3.3 against 10.1 J·cm−1 respectively). All these results allow concluding to a better OPL efficiency in solid state, in good agreement with OPL curves displayed in Fig. 12.32b. The highest value of k in solid state could be related to weak intermolecular interactions in the polymer.
12.4
Conclusion
OPL has been widely used for ocular and sensors protection against lasers aggressions. Among different processes inducing OPL, multiphotonic absorption and reverse saturable absorption were shown to present interesting advantages with respect to other phenomena. Very low activation thresholds (as low as a few mJ·cm−2 in the ns regime) and strong laser attenuation can be obtained from the subpicosecond to the microsecond pulse regime by RSA, but only on a relatively narrow spectral band. Moreover, RSA behavior is initiated by one-photon absorption of the ground state, which means that RSA materials exhibit strong coloration. However, broadband OPL efficiency and acceptable color neutrality can be achieved by mixing several molecules, but only with a reduction of linear transmittance [101]. Such complexes have been successfully mixed in solid hosts (such as polymers and sol-gels) to obtain a neutral colorimetric aspect of the OPL [102]. On the contrary, the facts that 2PA is an instantaneous phenomena allows the use of transparent molecules and does not lead to saturation effect are of great interest for OPL applications.
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Different engineering approaches were considered, involving purely organic or metallic containing molecules. Generally for 2PA these consist in linear, 2D, dendritic or macrocyclic charge transfer systems; the charge transfer strength depends on the spectral range required for applications. A lot of molecules have been designed for the visible, NIR and IR such as telecommunications wavelengths. In addition to the optimization of 2PA efficiency in the targeted spectral range, it has been widely shown that OPL can be further enhanced by inducing ESA process, following 2PA in the same wavelength range. Heavy-metal atom that provides spin-orbit coupling enhances intersystem crossing (ISC) from an excited singlet state to a triplet state, leading to an enhancement of the OPL effect. This is described by a (2+1) PA phenomenon. For RSA, ISC molecules with efficient ESA with high ratio between excited and ground states absorption cross-sections, such as phthalocyanines or porphyrines derivatives, were shown to present improved OPL properties. The combination with other nonlinear effects, such as nonlinear scattering, or photo-induced electron transfer by interaction with carbon-based systems was shown to enhance OPL. Solid OPL materials allow post-processing and polishing. It is generally found that properties observed for the chromophore in the solid matrix are comparable to those in solution. Optical quality glasses with strong nonlinear absorption were obtained.
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Index
A Acellular flaccid artery, 328 N-Acetil-L-cysteine, 356 N-Acetylated L-phenyl alanine, 411 Acridine orange, 121, 332, 336, 449, 450 Actinic keratosis, 333–334, 395, 406, 409, 415 ADMA. See Antracene-9,10-bismethylmalonate Age-related macular degeneration (AMD), 2, 326 5-ALA. See 5-Aminolevulinic acid Alacare®, 395, 415 ALAS II encoding gene, 396 AMD. See Age-related macular degeneration 5-Aminolevulinic acid (5-ALA) amine, 20, 80, 270, 295, 411, 492, 495, 567 g-carbonyl, 411, 446 conjugates, 412, 419 dehydratase, 396 dimerisation, 414 discharge, 412 esters, 18, 402, 408–410, 412, 413, 418 free, 409, 411, 412, 418 hexyl ester, 395, 409, 411, 413 loading, 413 methyl ester, 395, 407, 409, 411, 415, 417 oligopeptide, 411 penetration, 404, 406, 408, 416 peptides, 410–411 synthetase, 494 undecanoyl, 413 Angiographic, 327 Annexin V-FITC apoptosis, 335, 337 Antracene-9,10-bis-methylmalonate (ADMA), 139, 141, 142, 271, 272
Antrin, 325 Apical, 402 Apoptosis, 34, 123, 124, 303, 322, 323, 326, 328, 329, 332, 334–337, 339, 410 Apoptotyoc, 335 Apurinic, 323 Apyrimidinic, 323 Athophysiologic alterations, 331 Athymic nude mice, 332 Attenuated total reflectance–Fourier transfer infrared (ATR–FT-IR), 363 Aurebacterium, 339 Axcan Pharma, 325 Azo-dye, 362
B Bacterial, 17, 29, 297, 298, 300, 305, 416 Bacterial siderophore, 416 Bacteriochlorins, 3, 7, 278, 316 BaFBr:Eu2+, 383 BaFBr:Mn2+, 383 Basolateral, 402 B.cereus, 339 Benzopyrridinon, 416 Benzyl-n-hexadecyldimethyl ammonium chloride ( BHDC), 195 Bioconjugation, 355–357, 363–364, 369, 371 Biodetection, 353 Biodistribution, 321, 339 Biofunctionalized, 355 Bioimaging, 353 Biolitec AG, 325 Biopassivation, 364
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656 Biosynthesis, 4, 328, 395, 396, 398, 400, 401, 415, 419, 508 2, 2’–Bipyridine, 285, 290, 364, 563, 568, Bovine serum albumin (BSA), 319, 326 Butyric acid, 410
C Cadmium selenide (CdSe), 352, 354–356, 358, 361–366, 368, 369, 372–375, 377, 378, 380, 381, 385, 489, 490, 620, 623 CaF2:Eu2+, 383 CaF2:Mn2+, 383 Camptothecin, 338 Cancers cervical, 418 interstitial, 418 CaPO4:Mn2+, 383 Carbodiimide, 357 Carcinoma basal cell, 406, 407, 413, 416 bladder, 399, 409, 411 mammary, 399, 418 squamous cell carcinoma, 332, 333, 406, 417 Carboanhydrases, 403 CaspACE, 335 Caspase, 330, 336 Cauterization, 333 Ce3+, 383 Ceramids, 404 Cerebral microvasculature, 330, 331 Cerebrospinal fluid, 402 Cetyltrimethylammonium chloride (CTAC), 155, 175 Characterization, 128, 135–257, 545–547 Chinese hamster, 333 Chloraluminium phtalocyanine, 336 Chlorin e6 (Chle6), 3, 25, 27, 30, 278, 279, 296, 325, 359 Cholesterol, 404, 405, 413, 508 Choriocapillaris, 326 Choroidal neovascularization (CNV), 326 Choroid plexus, 402 Chromophores, 11, 12, 321, 619–649 Citrate phosphate buffer, 414 Clinical trials, 9, 136, 302, 325, 326 Clonogenicity, 338 CLSM. See Confocal laser scanning microscopy CNV. See Choroidal neovascularization Colorimetric, 335 Combination therapy, 351–385
Index Confocal laser scanning microscopy (CLSM), 329 Coordination, 290, 299, 305, 356–358, 361–363, 366, 375, 403, 414, 444, 448, 452, 568, 572 COPO. See Coproporphyrinogen III oxidase Coproporphyrin III oxidase, 396–398 Coproporphyrinogen III, 396, 397 Coproporphyrinogen III oxidase (COPO), 396, 397 Corneocytes, 404, 405 Cremophore EL (CEL), 159, 175, 177, 209, 211, 213, 235, 237, 246, 248, 250, 252, 254 Cryosurgery, 415 Cryotherapy, 333 CTAC. See Cetyltrimethylammonium chloride Cysteamine, 356, 367, 379 Cysteamin-hydrochloride, 359 L-Cysteine, 356, 363, 383 Cysview®, 395, 410 Cytochrome c, 330, 336, 394 Cytoplasm, 322, 335, 336, 340, 395, 396 Cytosol, 330, 336, 396, 402, 409, 412 Cytotoxic, 32, 122, 123, 136, 138, 139, 298, 315, 316, 330, 331, 333, 334, 336, 337, 395, 416
D Dark states, 354 Decay time, 376–379, 383, 384 Deferoxamine (DFO), 416 Dermatological patch, 415 Design, 1–36, 121–132, 291, 305, 459, 471, 473, 508, 530, 537, 538, 544, 547, 550, 552, 572, 577, 584, 598, 599, 625, 627, 629, 633, 636, 645, 649 DFO. See Deferoxamine Diazaperylene, 362, 374, 375 Dihydroethidium, 382 Dimethyl isosorbide, 414 5,5-Dimethyl-1-pyrroline-1-oxide (DMPO), 143, 459 Dimethyl sulfoxide (DMSO), 101, 320, 406 Dimyristol phosphatidyl choline, 93, 413 glycerol, 10, 28, 292, 413, 417, 474, 481, 482 Dioleyl trimethyl ammonium propane, 413 Dipeptide, 410 1,3-Diphenylisobenzofuran (DPBF), 139, 271, 453 Dipole-dipole interaction, 369
Index Disulphonate, 327 DMPO. See 5,5-Dimethyl-1-pyrroline-1-oxide DMSO. See Dimethyl sulfoxide DNA cleavage, 335, 338 damages, 29, 323 double helix, 324, 337 internucleozomal cleavage, 335 open circular, 338 polymerase, 323 relaxed, 338 superhelical, 324 topoisomerases, 337 unwinding, 337 viscosity, 323, 324 winding, 337 DUSA Pharmaceuticals, 325 Dyes sensitized solar cells, 459, 532–598 Dysprosium, 339, 456
E Eagle’s minimal essential medium (MEM), 331 E.Coli, 299–301, 339, 419 EDTA. See Ethylenediaminetetra-acetate Effala®, 395, 415 Electro-curettage, 406 Electro-migration, 407, 408 Electron microscopy, 327, 332, 535 Electron paramagnetic resonance (EPR), 142–143 Electron transfer, 322, 326, 374, 375, 381, 439, 453, 456, 459, 460, 470, 475, 478, 487, 494, 529, 571, 577, 578, 592, 595, 649 Electro-osmosis, 407, 408 Electrophoresis, 337 Endogenous, 297, 328, 391–419 Endoplasmatic reticulum (ER), 336, 339 Endothelial, 24, 303, 323, 326, 327, 403 Endothelialisation, 328 Endothelium, 328, 330, 331, 402, 403 Energy transfer, 59, 123, 137, 139, 142, 145, 149, 268, 269, 322, 339, 353, 359, 364, 365, 369–374, 376–378, 381, 383–385, 453, 470, 475, 539, 576, 584, 599, 646 Enhanced permeability and retention (EPR), 34, 403, 412, 418, 450, 459, 462 Epithelia delineate, 404 Epithelial, 326, 332, 399, 401, 402, 404, 409
657 EPR. See Electron paramagnetic resonance; Enhanced permeability and retention ER. See Endoplasmatic reticulum Erbium:yttrium-aluminum-garnet (Er:YAG) laser, 406 Erythema, 330, 331, 334 Erythroblasts, 400 Erythropoietic porphyria, 392, 397 Ethidium bromide, 332 Ethylenediaminetetra-acetate (EDTA), 300, 416, 447 Ethyl etiopurpurin, 325, 328 N-Ethyl-N(3-dimethylaminopropyl), 357 Etoposide inhibitor, 338 Eucerin®, 408 Eudragit®, 415 Eukaryotes, 395 Exogenous, 393, 398, 399, 401, 402, 415, 418 Exponential, 33, 272, 319, 367, 368, 376, 377, 399 Extinction coefficient, 146, 352, 355, 364, 370, 550, 557, 560–569, 572, 580, 589, 592, 595, 596, 622
F Fatty acids, 405, 475 FC. See Ferrochelatase Fenestrated, 402, 403, 418 Ferritin, 400, 401 Ferrochelatase (FC), 396, 398, 399 Fetal calf serum, 331 Fibroblasts, 333, 399, 417 Fitzpatrick, 333 Flow cytometry, 337 Fluorescein angiography, 327 Fluorescence lifetime, 145 quantum yield, 145–146, 248–253 Fluorescent microscopy, 332, 337 Fluorophor, 476 Folate, 21, 384 Food and Drug Administration (FDA), 136, 326, 418 Formaldehyde, 410 Förster, 369, 370, 372, 374 Foscan®, 325, 332, 334 Fospeg, 334 Fossil, 391, 469, 470, 515 Franck-Condon factors, 322 Functionalization, 14, 52, 62, 64, 80, 91, 355, 627, 636, 640
658 G GABA-ergic receptors, 397 Galenic, 405, 412–418 g-amino butyric acid (GABA), 396, 401, 402 Gamma rays, 382 Gastro intestinal tract, 402, 414, 417 Genotoxicity, 332 Genotoxic potential, 330 GIy. See Glycine Gliolan®, 395, 409 Glutamic acid, 395 Glutathione, 356 Glycerol mono oleate, 417 Glycine (GIy), 356, 395, 396, 402 Glycolic acid, 416–418 N-Glycosidic, 323 Golgi, 336 Gross edema, 330, 331 erythema, 330, 331, 334
H Haemorrhage, 327, 328, 330 Hematoporphyrin (HPD), 4, 5, 34, 136, 316, 393, 394 Hexvix®, 395, 409, 410 2-[1-Hexyloxyethyl]-2-devinyl pyropheophorbide-a (HPPH), 287, 325 Histopathologic, 327, 328, 335 HPD. See Hematoporphyrin HPPH. See 2-[1-Hexyloxyethyl]-2-devinyl pyropheophorbide-a Human breast adenocarcinoma, 334, 336 bronchial epithelial cells, 409 epidermal keratinocyte, 332 glioblastoma, 334, 336 lung carcinoma, 409, 411 squamous head, 400 transferrin receptor, 400 Human serum albumin, 34, 319 Hydrodynamic, 319 Hydrogels, 413 Hydrophilic, 17, 21, 26, 29, 275, 279, 283–287, 289, 301–304, 316, 320, 322, 332, 334, 405, 412, 413, 417, 418 N-Hydroxy succinimide, 25, 357 Hypericin, 4, 8, 275, 320, 334 Hyperkeratotic, 405, 406 Hypsochromic, 318 Hypsochromic shift, 318 Hystocytic lymphoma, 334
Index I Immune, 302, 323, 335, 415 Immunoassay, 364 Immunogenic, 323, 355 Inflammatory, 328, 401, 502 Intercalation, 323, 324, 571 Internucleosomal, 329 Intersystem crossing (ISC), 2, 6, 7, 123, 137, 146, 250, 251, 253, 276, 295, 319, 453, 475, 476, 624, 640, 641, 649 Intracellular, 16, 17, 20, 26, 301, 316, 326, 329, 334, 336, 398, 409, 411, 413, 415, 416 Intradermal, 407 Intramuscular, 407 Intraoperative adjunct, 328 Intravenous, 320, 327, 332, 409, 418 Iontophoresis, 407–408 ISC. See Intersystem crossing Ischemia, 331 Isopropano, 414, 477, 489
J Jablonski, 122, 136, 137, 140, 354 Jurkat cells, 337
K Kerastick®, 395, 409, 415, 417 Keratinocyte, 332, 334, 411, 415 Keratolytic, 407 Keratosis, 333–334, 395, 406, 408, 409, 415 Ketones, 324, 478, 511 Kinetics, 376–378, 401, 404, 412, 439, 456, 482, 578, 592, 594
L LaF3:Ce3+, 383 LaF3:Tb3+, 384 Laser therapy, 333 Lecithin Organogel, 408 Levodopa, 398 Levulan®, 122, 325, 395, 409, 415, 417 Lifetimes, 6, 145–149, 248–257, 275, 279, 318–320, 322, 339, 371, 453, 454, 499, 537, 550, 566, 584, 585, 593, 594, 639 Light microscopy, 327, 332 Light Science Corporation, 325 Lipophilic layer, 405 stratum, 405 LuF3, 383
Index Luminescence, 16, 139–141, 300, 301, 353, 356, 357, 359, 361, 362, 365–384, 453, 474, 475, 508 Luminescence anisotropy decay, 378 Luminescent, 352, 354, 359, 364, 365, 373, 379, 381 Lung, 333, 400, 409, 411 Lutetium(III), 325, 456 Lu-Tex, 325 Lymph, 330, 405 Lymphoblastic, 334 Lymphoblast leukemia, 335 Lysosomes, 301, 322, 336, 339
M Macrophage, 303, 323, 327, 330, 331, 401 Macular degeneration, 2, 122, 325, 326 Malignant, 135, 304, 328–334, 336, 337, 340, 382, 394, 395, 409 Maltose, 373, 377 MB. See Methylene blue Melanoma, 332–334, 336, 400, 402, 406 MEM. See Eagle’s minimal essential medium Membrane blebbing, 336 Mercaptoacetic acid, 355 Mercaptoethanol, 365 3-Mercapto-1,2-propanediol, 356 Mercaptopropionic, 363 N-(2-Mercaptopropionyl)-glycine, 356 Merocyanine 540, 378 Meso(4-N-methylpyridyl)porphyrin, 365 Meso-tetrahydroxyphenylchlorin (mTHPC), 316, 334 Meso-tetraphenylporphyrin, 293, 365 Meso-tetra(4-sulfonatophenyl)porphine, 361 Meso-tetra(4-carboxyphenyl)porphyrin (MTCP), 365 Mesothelioma, 399 Metal free meso-tetra(ptrimethylaminophenyl)porphine, 359 Metastatic, 334, 335 Meta-tetrahydroxyphenylchlorin, 325 Methyl aminolevulinate (MLA), 325 Methylene blue (MB), 4, 29, 275, 276, 293, 298, 302, 318, 438, 454, 455, 457, 475, 497, 502, 503, 510 Methylvinylether/maleic anhydride, 414 Metvix®, 325, 395, 409, 410, 415 Meyer-Betz’, 393 Miravant, 325 Mitochondria benzodiazepine, 396, 397 cardiolipin, 336
659 Mono-L-aspartyl chlorin e6, 325 Monosaccharides, 412 Mosaic warts, 417 Motexafin lutetium, 325 Murine, 338, 407, 411, 416, 417 keratinocyte cell, 411 Mycosis, 418 Myelocytomatosis virus, 334 Myeloid, 323 Myrmecia wats, 417
N Nanocrystals, 352, 359, 639–641 gold, 418 Nanoparticles, 16, 33–35, 199, 275, 287, 319, 364, 382, 383, 403, 418, 419, 486, 489, 490, 530, 561, 590 Necrosis, 34, 123, 124, 303, 322, 325, 328–331, 337, 339 Neoplasmic tissues, 339 Neoplasms, 334, 340, 403, 418 Neoplastic, 322, 332, 393, 394, 397–405, 415, 417, 418 Neovascularisation, 326 Neurocognitive, 328 Neurological, 328, 409 Neuropathies, 397 Nociceptive nerve, 407 Non-neoplastic, 418 Non-radiatively, 354 Novartis Pharmaceuticals, 325 Nuclear Antigen, 335 Nucleosides, 412, 502
O Occlusion, 327, 328, 331, 333, 415 Octacarboxyphthalocyanine (OCPc), 294, 365, 457 Octakis(3-aminopropyloxy) phthalocyaninato, 336 Ocular, 326, 417, 648 Oesophageal mucosa, 414 Oesophagus, 414 Oleic acid, 417 Oligopeptide, 410, 411 Optical limiting, 620, 621, 629, 636, 638, 639, 641, 642, 647 Oral leukoplakia, 418 Organelles, 34, 317, 332, 333, 336, 339, 356 Oxygen ground state, 135, 138, 139, 146, 268, 354, 453
660 P PAN. See (2-Pyridylazo)-2-naphthol Paramagnetic, 318, 319 Parkinson’s disease, 398 Passivation, 364, 377, 378 PBG. See Porphobilinogen PBGD. See Porphobilinogen deaminase Peptides, 24, 29, 290, 353, 359, 377, 378, 385, 402, 410–411, 494 Pericytes, 327 Peroxides, 273, 324 Phagocytosis, 330, 331 Pharmacodynamics, 395, 412 Pharmacokinetic, 328, 334, 394, 413 Pharmacyclics Inc, 325 o-Phenanthroline, 362, 366 Phenyl–alanine, 411 Phosphatidyl glycerol, 413 Phospholipid micellas, 355 Photocatalysis, 143, 435–438, 469–515 Photochemistry, 274, 470 Photochlor, 325 PhotoCure, 325, 395 Photodegradation, 143–144, 246–248, 296, 297, 305, 324, 437, 438, 440, 451–456, 458, 460, 496 Photodisruption, 321 Photodynamic damage, 295, 323 therapy, 2, 5, 33, 34, 121–132, 135, 136, 143, 267, 269, 287, 296, 302–305, 315–340, 352, 382–384, 394, 587 Photoexcitation, 275, 354, 365, 375, 379, 385, 460 Photofrin®, 4, 122, 136, 277, 296, 317, 320, 325, 328, 329, 334, 394 Photography, 327, 529 Photophysics, 293, 370 Photosensitiser, 1–36, 475, 476, 497–499, 502, 503, 509, 510, 513–515 Phototype, 333 Photoxicity, 319 Photrex, 325 Phthalocyanine aluminum, 22, 25, 281, 290, 291, 293, 294, 299, 331, 332 indium, 246, 284 silicon, 7, 11, 283, 287, 319, 339, 365, 374 zinc, 141, 287, 290, 293, 299, 320, 329, 333, 510, 577, 578 Placebo, 407, 415 Plantar warts, 407, 417 Plumboporphyria, 397
Index Pluronic®, 408 Pollutants, 2, 267, 433–464, 472, 473 Poloxamer, 414 Poly (lactic co-glycolid acid), 418 Poly acrylate methacrylate, 415 Poly caprolactone, 418 Poly lactic acid, 418 Polysilanes, 355 Porfimer, 122, 325, 394 Porphobilinogen (PBG), 396, 397 Porphobilinogen deaminase (PBGD), 396, 397, 399, 403, 404 Porphyrias, 392, 395, 397, 398 Porphyrin, 23, 27, 31, 32, 48, 53, 63, 64, 67, 69–76, 80–83, 90, 94–101, 122, 126–130, 277, 287, 289, 290, 293, 295, 296, 305, 316–318, 321, 324, 326, 333, 339, 360, 362, 363, 365, 366, 369, 371, 375, 383, 384, 393, 396–399, 411, 416, 441, 459, 460, 482, 483, 498, 504, 510, 575–583, 638, 639, 645–647 Pre-uroporphyrinogen, 397 Proapoptotic factor, 336 Prodrugs, 398 Proliferation, 330–332, 335–337, 399, 415 Promega, 335 Propidium iodide (PI), 337 Propylene glycol, 83, 105, 414, 417, 495 Prostanoid, 323 Prostate, 25, 418 Protoporphyrin IX oxidase, 397 Protoporphyrinogen IX oxidase, 396, 397 Psoriasis, 406 Pyknotic nuclear chromatine, 336 (2-Pyridylazo)-2-naphthol (PAN), 362
Q Q bands, 317, 324, 359, 360 Quantum dots (QDs), 33, 352–356, 364, 382, 384, 533, 620, 641 Quantum size confinement, 35 Quantum yield, 3, 6, 123, 125, 137, 139, 141, 143–147, 149, 244, 247, 249, 254, 255, 270, 272, 273, 275–281, 284–287, 290, 292–296, 298, 299, 304, 318–320, 322, 325, 326, 339, 352, 354, 355, 364, 370–374, 376–380, 383–385, 437, 449, 453–456, 458–460, 585 Quencher, 139, 141, 142, 367, 368, 370, 375, 453, 454, 493
Index R Radioresistant, 315 Radiotherapy, 382, 383 Raman, 363 RB. See Rose Bengal Reactive oxygen species (ROS), 2, 16, 123, 297, 315–317, 323, 337, 382 Rose Bengal (RB), 275, 276, 286, 287, 298, 359, 455, 457, 475, 497, 499, 501, 502, 510, 514 Rosewell Park Cancer Institute, 325 Rostaporfin, 325 Rotational correlation time, 378
S Sarcoma, 334 SCC. See Squamous cell carcinoma Schmidt-Ruppin, 334 Schrodinger equation, 353 Scintillator, 383, 384 SDS. See Sodium dodecylsulfate Sebaceous glands, 405, 413 Semiconductor, 340, 352, 353, 382–385, 435–438, 459, 474, 476–478, 483, 486, 489, 491, 494–496, 528 531, 533–542, 547, 554, 557, 558, 564, 577, 578, 584, 586, 598, 599, 623 Singlet oxygen quantum yield, 137–143, 149–246, 268, 270, 272, 273, 275–277, 281, 284, 285, 289, 290, 292–295, 298, 304, 320, 321, 355, 453, 499 Sodium dodecylsulfate (SDS), 183 Solar energy, 304, 515, 527–599 Soret band, 277, 324, 383, 576, 579, 580, 599 Squamous cell carcinoma (SCC), 332, 333, 406, 417 Stern–Volmer, 368, 369 Stokes-Einstein-Debye model basale, 404 corneum, 404, 405, 407, 415–417 granulosum, 404 lucidum, 404 spinosum, 404 stratum, 404, 405, 407, 415–417 Stratum corneum, 404, 405, 407, 415–417 Streptomyces avidinii, 364 Subcutaneously, 333, 407, 416 Subcutis, 405 Subfoveal choroidal neovascularization, 326 Synergistic effect, 415, 416, 474 Synthesis, 1, 47, 128, 136, 284, 328, 352, 395, 469, 547, 636
661 T Talaporfin, 325 TAPc. See Tetraaminophthalocyanine Taporfin sodium, 325 Temoporfin, 325 TEMP. See 2,6,6-Tetramethyl-4-piperidone TEMPO. See 2,2,6,6-Tetramethyl-4piperidone-N-oxyl Tetraalkylhydroxy substituted zinc phthalocyanines, 333 Tetraaminophthalocyanine (TAPc), 91, 357, 358 Tetracarboxyphthalocyanine, 365 Tetrahexylhydroxy, 333 Tetrakis(2,9,16,23-tert-butyl) bisphthalocyanines, 339 Tetrakis(4-sulphonatophenyl) porphyrine, 336 2,6,6-Tetramethyl-4-piperidone (TEMP), 143 2,2,6,6-Tetramethyl-4-piperidone-N-oxyl (TEMPO), 143, 270 Tetramethyl-tetra-2,3-pyridinoporphyrazine, 361 Tetra(4-pyridyl)porphyrin, 363 Tetrapropylhydroxy, 333 Tetrapyridinetetrahydropophine, 363 Tetrapyrrol, 3, 5, 13, 20, 28, 351–385, 391, 395–397, 419 Tetrasulphophthalocyanine aluminum, 499, 510, 511 indium, 253 zinc, 365, 499, 511 Texaphyrin, 3, 122, 126, 131, 325 TGA. See Thioglycolic acid Theoretical chemistry, 2, 121–132 Thioglycolic acid (TGA), 357–359, 361, 363, 365, 367, 368, 372 373, 378, 380, 381 Thiopropionic acid (TPA), 357 Thrombosis, 325, 327, 328, 330, 331 Thymidine, 335 Time-resolved anisotropy, 378 Tin etiopurpurin, 328 TOPO. See Trioctylphosphine oxide TopoGEN, 337 Topo II, 337, 338 Topoisomerase II, 337 Toxicity, 33, 122, 125, 316, 325, 326, 329, 330, 354, 356, 418, 437, 473, 585, 588 TPA. See Thiopropionic acid Transferrin (Tf), 400 Transmembranous, 322 Transplantable Rous sarcoma, 334 Trapping, 271, 273, 376, 462 Tretrakis(o–aminophenyl)porphyrin, 383 Tributylphosphine, 365, 374 Tributylphosphine oxide, 365, 374 Triglycerides, 414
662 Trioctylphosphine oxide (TOPO), 337, 338, 355, 361–363, 365, 366, 368, 373, 374, 378 Tripeptides, 402 Triplet lifetime, 244, 254–256, 286, 320, 321 quantum yield, 146, 244, 254, 255, 281, 320 Tumour ablation, 323 antigens, 323 Tunneling, 374, 375 Two-photon excitation, 15–16, 269, 381, 382, 385, 640 Type III reaction, 322
U Unguentum, 413, 417 Uropophorphyrinogen III synthetase, 396 Uroporphyrin I, 396, 397 Uroporphyrinogen I, 397 Uroporphyrinogen III decarboxylase, 396, 397 synthase, 396, 397 US Food and Drug Administration, 136, 326, 418
V Vascular occlusion, 328, 331 stasis, 323, 333 stroma, 303, 323, 332
Index Vasoconstriction, 330, 331 Vasodilatation, 330, 331 Verteporfin therapy, 326 Viability, 332, 335, 337, 339, 441 Visco-elastic, 414 Viscosimetric, 324 Visudyne®, 5, 325, 326 Vitamin B12, 326 Vitamins, 20, 402, 412 Vulval intraepithelial neoplasia, 414
W Walker, 335 Witepsol H 15, 414
X X-chromosome, 396 X-linked sideroblastic anaemia, 396 X-ray-induced photodynamic therapy, 382–384 X-ray radiation, 382, 383, 385, 393
Z Zinc sulphide, 14, 19, 200, 352, 356, 358, 359, 361–363, 366, 368, 369, 372–375, 377, 378, 380, 382, 436, 491, 494, 620 Zwitterionic amino, 409
