Synthesis of organobromines as a tool for their characterisation and environmental occurrence assessment Andreas Rydén Department of Materials and Environmental Chemistry Stockholm University Stockholm 2013 i Doctoral Thesis 2013 Department of Materials and Environmental Chemistry Stockholm University SE-106 91 Stockholm Sweden Abstract Polybrominated diphenyl ethers (PBDEs) have been intensively used as flame retardants (FRs) and have become ubiquitous environmental pollutants. PBDEs form hydroxylated PBDEs (OH-PBDEs) as metabolites. Further, some OH-PBDEs and methoxy-PBDEs (MeO-PBDEs) are natural products. These are all compounds of environmental and health concern and it is therefore important to confirm their identity and to assess their environmental levels and toxicities. Hence, it is vital to obtain authentic reference standards of individual PBDEs and OH/MeO-PBDEs. The thesis main aim was to develop synthesis methods of congener specific PBDEs, OH- and MeO-PBDEs. The second aim was to identify and quantify PBDEs, OH- and MeO-PBDEs in environmental samples. The third was to propose an abbreviation system for FRs. O-Arylation of brominated phenols, using either symmetrical or unsymmetrical brominated diphenyliodonium salts, was selected for synthesis of PBDEs and OH- /MeO-PBDEs. A total of 16 MeO-PBDEs, 11 OH-PBDEs, 1 diMeO-PBDE and 1 EtO-MeO-PBDE were synthesised. Three novel unsymmetrical diaryliodonium triflates were synthesised and used in synthesis. Optimisations were made to construct a reliable general method for congener specific PBDE synthesis, which was used in the synthesis of 8 representative PBDE congeners. The products were generally characterised by electron ionisation mass spectrometry (EIMS) and nuclear magnetic resonance (NMR) spectroscopy. Identification of PBDEs and OH-PBDEs in various matrixes was based on gas chromatographic and mass spectrometric analyses. Fourteen OH-PBDE congeners were identified in a pooled human blood sample. One previously uncharacterised natural PBDE analogue was identified as 6-OH-6’-MeO-BDE-194, and quantified in Swedish blue mussels. PBDE congeners and other BFRs were identified and quantified in workers and dust from a smelter in Sweden. A structured and practical abbreviation system was developed for halogen- and phosphorus containing FRs. © Andreas Rydén, Stockholm 2013 ISBN 978-91-7447-800-6 Printed in Sweden by US-AB, Stockholm 2013-10-21 Distributor: Department of Materials and Environmental Chemistry, Stockholm University ii Tillägnad Frans iii Table of contents Abstract.................................................................................................ii Table of contents .................................................................................iv List of papers .......................................................................................vi Abbreviations......................................................................................vii 1 Introduction .......................................................................................1 1.1 Flame retardants .........................................................................3 1.2 Brominated flame retardants and analogues...............................4 2 PBDEs, their metabolites and natural analogues...............................8 2.1 Polybrominated diphenyl ethers .................................................8 2.1.1 Chemical structures and classes of PBDEs .........................8 2.1.2 Physicochemical characteristics and reactivity ...................9 2.1.3 Environmental occurrence and sources of exposure .........10 2.1.4 Biological fate and effects .................................................12 2.2 Hydroxylated and methoxylated PBDEs..................................13 2.2.1 Chemical structure and properties .....................................14 2.2.2 Environmental occurrence and biological effects..............15 2.3 Aim of thesis.............................................................................16 3. Synthesis of selected organobromines............................................18 3.1 Synthetic routes to PBDEs .......................................................18 3.1.1 Bromination of diphenyl ether...........................................18 3.1.2 Bromination of prefabricated PBDEs................................20 3.1.3 Nucleophilic aromatic substitution....................................20 3.1.4 Ullmann ether synthesis.....................................................21 3.1.5 PBDEs from arylboronic acids..........................................22 3.1.6 Synthesis via aminodiphenyl ethers ..................................22 3.1.7 Synthesis via diaryliodonium salts ....................................24 3.2 Synthesis of mono and di-functionalised PBDEs.....................35 3.2.1 Synthesis of MeO-PBDEs via S NAr..................................35 3.2.2 Synthesis of MeO-PBDEs via brominated diphenyliodonium salts...............................................................39 3.2.3 Synthesis of di-functionalised PBDEs...............................46 4 Identification and quantification of selected organobromines.........49 4.1 Identification of OH-PBDEs as metabolites in human blood samples ...........................................................................................49 4.2 Identification and quantification of a phenolic di-functionalised PBDE in blue mussels ....................................................................52 4.3 Identification of BFRs in E-waste dust.....................................54 4.4 BFRs in blood from personnel at a Swedish smelter facility ...55 iv 5 Definitions and novel abbreviations of flame retardants.................57 5.1 Overarching definitions for flame retardants............................57 5.2 Overarching abbreviations for flame retardants .......................58 6 Future perspectives..........................................................................60 7 Svensk sammanfattning...................................................................62 8 Acknowledgements .........................................................................64 9 Appendix A......................................................................................66 10 Reference list .................................................................................67 v List of papers This thesis is based around the following articles, referred to in the text by their roman numerals. Hitherto unpublished manuscripts are also included. Paper I Rydén, A., Nestor, G., Jakobsson, K., and Marsh, G., (2012), Synthesis and tentative identification of novel polybrominated diphenyl ether metabolites in human blood, Chemosphere , 88 , 1227-1234. Paper II Rydén, A., Marsh, G., (2013), Synthesis of polybrominated diphenyl ethers via unsymmetrical diaryliodonium triflates, (manuscript) Paper III Winnberg, U., Rydén, A., Löfstrand, K., Asplund, L., Bignert, A., Marsh, G., (2013), Novel octabrominated phenolic diphenyl ether identified in blue mussels from the Swedish west coast, (submitted manuscript) Paper IV Rydén, A., Strid, A., Athanassiadis, I., Bergman, Å., (2013), Occurrence and potential human exposure to brominated flame retardants at a Swedish smelter handling electronic scrap, (manuscript) Paper V Bergman, Å., Rydén, A., Law, R.J., de Boer, J., Covaci, A., Alaee, M., Birnbaum, L., Petreas, M., Rose, M., Sakai, S., Van den Eede, N., and van der Veen, I., (2012), A novel abbreviation standard for organobromine, organochlorine and organophosphorus flame retardants and some characteristics of the chemicals, Environ. Int ., 49 , 57-82. Papers and manuscripts not included in this thesis are listed below. Aydin, J., Rydén, A., Szabo, K.J., 2008. Chiral palladium-pincer complex catalyzed asymmetric condensation of sulfonimines and isocyanoacetate. Tetrahedron: Asymmetry 19 , 1867-1870. Von Stedingk, H., Xie, H., Hatschek, T., Foukakis, T., Rydén, A., Bergh, J., Rydberg, P., (2013), Validation of a novel analytical procedure for quantification of the level of phosphoramide mustard formed in individuals being treated with cyclophosphamide. (manuscript) The published papers are printed with the permission from the copyright holders. vi Abbreviations BAF bioaccumulation factor BB-209 decabromobiphenyl BDE brominated diphenyl ether BDMS bromodimethylsulfonium bromide BFRs brominated flame retardants BTBPE 1,2-bis(2,4,6-tribromophenoxy)ethane BTMA benzyltrimethylammonium tribromide b.w. body weight CDE chlorinated diphenyl ether CFRs chlorinated flame retardants DBDPE decabromodiphenyl ethane 4,4’-DDE 1,1-bis-(4-chlorophenyl)-2,2-dichloroethene DDT 2,2-bis(4-chlorophenyl)-1,1,1-trichloroethane DIPEA N,N -diisopropylethylamine DMAC N,N-dimethylacetamide DOM directed ortho metalation EAS electrophilic aromatic substitution ECHA European Chemicals Agency ECNI electron capture negative ionisation EFSA European Food Safety Authority EI electron ionisation formyl-PBDEs polybrominated phenoxybenzaldehydes FR flame retardant GC-EIMS gas chromatography electron ionisation mass spectrometry GCMS gas chromatography mass spectrometry HBB hexabromobenzene HBCDDs hexabromocyclododecanes IUPAC International Union of Pure and Applied Chemistry Log K OW octanol-water partition coefficient m-CPBA meta -chloroperoxybenzoic acid MeO-PBDEs methoxylated polybrominated diphenyl ethers NH 2-PBDEs amine functionalised polybrominated diphenyl ethers NMR nuclear magnetic resonance OECD Organisation for Economic Co-operation and Development