λογος Beitr ̈ age zur organischen Synthese Hrsg.: Stefan Br ̈ ase Daniel M. Knoll Heterobimetallic [2.2]Paracyclophane Complexes and Their Application in Photoredox Catalysis Heterobimetallic [2.2]Paracyclophane Complexes and Their Application in Photoredox Catalysis Zur Erlangung des akademischen Grades eines /einer DOKTORS /DOKTORIN DER NATURWISSENSCHAFTEN (Dr. rer. nat.) von der KIT - Fakultät für Chemie und Biowissensc haften des Karlsruher Instituts für Technologie (KIT) genehmigte DISSERTATION von M. Sc. Daniel Maximilian Knoll aus Kassel Dekan: Prof. Dr. Manfred Wilhelm R e f e r e n t : Prof. Dr. Stefan Bräse Kor r eferent: Prof. Dr. Peter Roesky Tag der mün dlichen Prüfung : 13. 12 .20 19 Band 85 Beitr ̈ age zur organischen Synthese Hrsg.: Stefan Br ̈ ase Prof. Dr. Stefan Br ̈ ase Institut f ̈ ur Organische Chemie Karlsruher Institut f ̈ ur Technologie (KIT) Fritz-Haber-Weg 6 D-76131 Karlsruhe Bibliographic information published by the Deutsche Nationalbibliothek The Deutsche Nationalbibliothek lists this publication in the Deutsche Nationalbi- bliografie; detailed bibliographic data are available in the Internet at http://dnb.d- nb.de c © Copyright Logos Verlag Berlin GmbH 2020 Alle Rechte vorbehalten. ISBN 978-3-8325-5071-4 ISSN 1862-5681 Logos Verlag Berlin GmbH Comeniushof, Gubener Str. 47, 10243 Berlin Tel.: +49 030 42 85 10 90 Fax: +49 030 42 85 10 92 INTERNET: http://www.logos-verlag.de Für Mama, Papa und Melanie. “Errare humanum est, sed perseverare diabolicum.” – Seneca vii H ONESTY D ECLARATION This work was carried out from 2016 December 1 st through 2019 November 6 th at the Institute of Organic Chemistry, Faculty of Chemistry and Biosciences at the Karlsruhe Institute of Technology (KIT) under the supervision of Prof. Dr. Stefan Bräse. Die vorliegende Arbeit wurde im Zeitraum vom 1. Dezember 2016 bis 6. November 201 9 am Institut für Organische Chemie (IOC) der Fakultät für Chemie und Biowissenschaften am Karlsruher Institut für Technologie (KIT) unter der Leitung von Prof. Dr. Stefan Bräse angefertigt. Hiermit versichere ich, Daniel Maximilian Knoll, die vo rlie gende Arbeit selbstständig verfasst und keine anderen als die angegebenen Hilfsmittel verwendet sowie Zitate kenntlich gemacht zu haben. Die Dissertation wurde vo n der Fakult ät für Chemie und Biowiss enschaften des Karlsruher Instituts für Technologie angenommen und bisher an keiner anderen Hochschule oder Universität eingereicht. Die „Regeln zur Sicherung gute r wissenschaftlicher Praxis am Karlsruher Institut für Technologie (KIT)“ wurden beachtet. Hereby I, Daniel Maximilian Knoll, declare that I completed the work independently, without any improper help and that all material published by others is cite d pr operly. This thesis has not been submitted to any other university before. viii G ERMAN T ITLE OF THIS T HESIS Heterobimetallische Komplexe des [2.2]Paracyclophans und deren Anwendung in der Photoredoxkatalyse ix A BSTRACT The most important goal of current chemistry research is to provide green and sustainable routes to compounds of interest. One way of addressing this is the use of abundant and inexpensive sour ces of energy to drive reactions, with the prime example being visible light in photoredox cataly sis One recent promising approach is the use of heterobimetallic catalysts where two metals work in a cooperative fashion to achieve the desired transformatio n. However, very little is known about the exact mechanism of cooperativity. This is due to a lac k of heterobimetallic compounds that can be fine - tuned to obtain very specific answers regarding for example spatial design of the catalyst in question. In th is work, [2.2]paracyclophane (PCP) is presented as a new platform on which to build distance - vari able heterobimetallic complexes. PCP has been described as a “super - atom” molecule for its unique ability to hold up to 16 substituents in a precise spatial re lationship to each other. By using PCP as a platform, it is shown that a range of defined heterob imetallic complexes can be designed and prepared ( Figu re 1 1 ) The methods necessary for the synthetic transformations are developed and investigated for their broader synthetic applicability. Figu re 1 1 Distance modulation of two cata lytic metal centers. To demonstrate the potential of these complexes as catalysts, Au/Ru heterobimetallic complex es are evaluated regarding their performance in a dual p hotoredox catalytic arylative Meyer - Schuster rearrangement reaction. This reaction prov ides a very convenient and sustainable access α - arylated enones, an important building blocks for pharmaceutical relevant compounds. x K URZFASSUNG Eines der wichtigsten Z iele der modernen Chemie ist die Entdeckung grüner und nachhaltiger Syntheserouten. Eine Möglichkeit dieses Ziel zu erreichen besteht in der Verwendung günstiger und gut verfügbarer Energiequellen, um eine Reaktion voranzutreiben. Hierbei stellt sichtbares Licht ein Paradebeispiel dar. In den letzten Jahren haben sich dafü r heterobimetallische Katalysatoren, in denen die beiden enthaltenen Metallatome kooperativ miteinander arbeiten , als besonders geeignet erwiesen. Jedoch ist bis jetzt sehr wenig über den exakten Mechanismus der Koopera tivi tät bekannt. Dies liegt nicht zul etzt an der geringen Verfügbarkeit und Einstellbarkeit der bekannten Heterobimetallkomplexe, was zur Beantwortung spezifischer Fragestellungen hinsichtlich der räumlichen Anordnung der Met allatome notwendig wäre. In dieser Arbeit wird das [2.2]Paracyclopha n (PCP) als neuartige Plattform vorgestellt, auf der distanzvariable Heter o bimetallkomplexe aufgebaut werden können. PCP wurde als Superatom bezeichnet, da es die einzigartige Eigenschaft besitzt bis zu 16 Substituenten in einer präzisen räumlichen Struktu r zueinander zu fixieren. Mithilfe des PCP wird gezeigt, dass eine Reihe von definierten Heterobimetallkomplexen entworfen und synthetisiert werden kann. Die dazu notwendigen Methoden für die synthetischen Transformationen werden entwickelt und auf ihre ge nerelle synthetische Anwendbarkeit hin untersucht. Um das Potential der hergestellten K omplexe als Katalysatoren zu demonstrieren, werden die Au/Ru Heterobimetallkomplex e hinsichtlich ihre r Leistungsfähigkeit in einer dual photoredoxkatalysierten arylieren den Meyer - Schuster - Umlagerungsreaktion getestet. Diese Reaktion bietet einen einfachen und nachhaltigen Zugang zu α - arylierten Enonen, die ein wichtiger Baustein für die Synthese von pharm azeutisch relevanten Verbindungen sind. xi CONTENTS 1 INTRODUCTION ................................ ................................ ................................ ................... 1 1.1 [2.2]P ARACYCLOPHANE ................................ ................................ ................................ ............... 1 1.1.1 Introduction ................................ ................................ ................................ ................................ ......... 1 1.1.2 Applications of PCP ................................ ................................ ................................ ........................... 4 1.1.3 Pyridyl PCP ................................ ................................ ................................ ................................ ........... 8 1.2 P HOTOREDOX C ATALYSIS ................................ ................................ ................................ ........... 11 1.2.1 In troduction ................................ ................................ ................................ ................................ ...... 11 1.2.2 Mechanisms of Photoredox Catalysis ................................ ................................ ..................... 12 1.2.3 Dual Photoredox Catalysis ................................ ................................ ................................ .......... 15 2 AIM OF THIS WORK ................................ ................................ ................................ ......... 19 3 MAIN PART ................................ ................................ ................................ ......................... 21 3.1 S TRATEGY ................................ ................................ ................................ ................................ .... 21 3.1.1 Roadmap towards Heterobimetallic Complexes ................................ ............................... 21 3.2 D IFFERENTIATION AND S YNTHES IS OF H ETERODISUBSTITUTED PCP S ............................... 26 3.2.2 Conclusions ................................ ................................ ................................ ................................ ........ 31 3.3 PCP T RIFLUOROBORATES IN S UZUKI C ROSS - C OUPLING ................................ ........................ 32 3.3.1 Cross - Coupling of PCP ................................ ................................ ................................ ................... 32 3.3.2 Synthesis of PCP Trifluoroborates ................................ ................................ ........................... 41 3.3.3 Suzuki Cross - Coupli ng of PCP Trifluoroborates ................................ ................................ 43 3.3.4 Conclusions ................................ ................................ ................................ ................................ ........ 51 3.4 PCP - P ORPHYRIN C ONJUGATES ................................ ................................ ................................ 52 3.4.1 Introduction to Porphyrins ................................ ................................ ................................ ......... 52 3.4.2 Synthetic Access to Porphyrins on PCP ................................ ................................ .................. 53 xii 3.4.3 Heterobimetallic Complexes ................................ ................................ ................................ ...... 55 3.4.4 Conclusions ................................ ................................ ................................ ................................ ........ 63 3.5 C YCLOMETALLATED 2 - O XAZOLINYL PCP COMPLEXES ................................ ........................... 65 3.5.1 I ntroduction ................................ ................................ ................................ ................................ ...... 65 3.5.2 Oxazoline Synthesis from PCP Aldehyde ................................ ................................ ............... 66 3.5.3 Heterobimetallic Complexes of Gold and Ruthenium ................................ ...................... 68 3.5.4 Heterobimetallic Complexes of Gold and Palladium ................................ ....................... 72 3.5.5 Conclusions ................................ ................................ ................................ ................................ ........ 74 3.6 P HOT OREDOX C ATALYSIS WITH PCP A U /R U C OMPLEXES ................................ .................... 75 3.6.1 Introduction ................................ ................................ ................................ ................................ ...... 75 3.6.2 Synthetic Access to the pseudo - para Au/Ru Heterobimetallic Co mplex ................. 77 3.6.3 Synthetic Access to other Isomers ................................ ................................ ............................ 98 3.6.4 Application in Photoredox Catalysis ................................ ................................ .................... 103 3.6.5 Conclusions ................................ ................................ ................................ ................................ ..... 111 4 CONCLUSION A ND OUTLOOK ................................ ................................ ..................... 113 4.1 C ONCLUSION PCP T RIFLUOROBORATES IN S UZUKI C ROSS - C OUPLI NG .............................. 113 4.2 O UTLOOK PCP T RIFLUOROBORATES IN S UZUKI C ROSS - C OUPLING ................................ .... 113 4.3 C ONCLUSION PCP - P ORPHYRIN C ONJUGATES ................................ ................................ ........ 114 4.4 O UTLOOK PCP - P ORPHYRIN C ONJUGATES ................................ ................................ ............. 114 4.5 C ONCLUSION P HOTOREDOX C ATALYSIS WITH PCP A U /R U C OMPLEXES .......................... 116 4.6 O UTLOOK P HOTOREDOX C ATALYSIS WITH PCP A U /R U C OMPLEXES ................................ 117 5 EXPERIMENTAL METHO DS ................................ ................................ ......................... 118 5.1 G ENERAL I NFORMATION ................................ ................................ ................................ .......... 118 5.1.1 Cyclophane Nomenclature ................................ ................................ ................................ ....... 118 5.1.2 Depiction of Enantiomers/Diastereomers ................................ ................................ ........ 119 xiii 5.1.3 Devices and Analytical Instruments ................................ ................................ .................... 119 5.1.4 Solvents and Reagents ................................ ................................ ................................ ............... 121 5.2 S YNTHETIC M ETHODS AND C HARACTERIZATION D ATA ................................ ....................... 122 5.2.1 Synthetic Methods and Characterization Data for Chapter 3.2 .............................. 123 5.2.2 Synthetic Methods and Characterization Data for Chapter 3. 3 .............................. 131 5.2.3 Synthetic Methods and Characterization Data for Chapter 3.4 .............................. 154 5.2.4 Synthetic Methods and Characterization Data for Chap ter 3.5 .............................. 159 5.2.5 Synthetic Methods and Characterization Data for Chapter 3.6 .............................. 164 6 REFERENCES ................................ ................................ ................................ .................... 178 7 APPENDICES ................................ ................................ ................................ .................... 186 APPENDIX 1 X - RAY DAT A ................................ ................................ ............................... 187 APPENDIX 2 PHOTOREAC TOR ................................ ................................ ...................... 202 APPENDIX 3 LIST OF A BBREVIATIONS AND ACR ONYMS ................................ ..... 203 APPENDIX 4 CURRICULU M VITAE ................................ ................................ ................ 208 APPENDIX 5 LIST OF P UBLICATI ONS ................................ ................................ .......... 209 APPENDIX 6 ACKNOWLED GEMENTS ................................ ................................ .......... 211 1 1 I NTRODUCTION 1.1 [2.2]Paracyclophane 1.1.1 Introduction The backbone and molecule of interest in this work is [2.2]paracyclophane ( PCP , 1 ) , a molecule displaying an intriguing shape and properties . Its structure ( Figure 1 1 ) features two benzene rings (decks) that are cofacial - stacked and held in this arrangement by two ethyl br idges attached at the para positions of the benzene rings. Figure 1 1 Structure of PCP. Bond leng th s and distances are given in Å. These short bridges force the decks close r together than would be energetically favorable , thereby inducing a strain. T he distance between the benzene rings (3.09 Å) is short er than the van - der - Waals distance of the layers in graphene (3.40 Å) [1] Two phenomena arise from this strain: (i) a “bent and battered”, bo at - like form with the bridgehead carbons being shifted out - of - plane is adopted by the benzene rings, caused by repulsive forces between the m , [2] (ii) transannular through - space electronic 2 communication between the decks is enabled through the close proximity and th us overlap of the π - systems of the benzene rings. [3] The former phenomenon (i) leads to a less - than - aromatic character of the benzene rings. This can be s een spectroscopically, e.g. in the 1 H NMR spectrum of PCP, where the ar omatic proton peaks are shifted around 1 to 1.5 ppm upfield It also affects synthetic transformations , exhibiting chemical behavior that sometimes differ s significantly from the p - xyle ne ( the “monomer” of PCP) chemistry. The latter phenomenon (ii) has implications for the functionalization of the molecule. For example lithiation of one deck increases the electron density not only on one but also on the other deck, a lithiation of the no t - yet - lithiated deck becomes energeti cally less favorable [4] Furthermore, the electronic communication between the decks was reported t o be applied in molecular junctions [5] and molecular wires. [6,7] Both the unusu al shape and electronic situation of the benze ne rings are accompanied by the sterical encumbrance that is brought about by the para - disubstitution and additional shrouding of one face of each benzene ring by the other deck. Combined, these circumstances l ead to chemical beh a vior that is markedly diff erent from isolated p - xylene or even benzene, including sluggish or unexpected reactivity. One example, the cross - coupling chemistry of PCP , is discussed in detail in section 3.3 1.1.1.1 Discovery and Nomenclature The f irst discovery of PCP was reported in 1949 by Brown and Farthing, when they were analyzing the polymerization products of p - xylene. [8] Since then PCP has come a long way from a “lab curiosity” to a large array of applications in asymmetric catalysis, material sciences, supramolecular chemistry and medicine [1] The nomenclature o f these molecules following IUPAC rules can be quite laborious, thus a new nomenclature system was invoked. According to Vögtle et al. , the term “phane” describes a structure that contains at least one aromatic or ph enyl ring bridged by an a lk ane. If the a romatic ring is indeed a benzene derivative, the class if cyclophanes is described. The number of atoms in the bridging chains is given by an integer for each bridge separated by a period in square brackets in front of the name. Finally, in case of 3 cycloph anes the relative orientation of the bridgeheads on the benzene is given by the common prefixes ortho, meta, and para [9] 1.1.1.2 Chirality Another remarkable feature of PCP arises from the impeded rotation of the rings along their bridge - to - bridge axis. Introduction of a substitue nt other than hy drogen at any of the carbon centers renders these molecules chiral. If the bridges are substituted, common central chirality is observed, but when the substituent is located on one of the decks, the molecule becomes planar ch iral ( Figure 1 2 ). Interestingly, most compounds featuring planar chirality bear the PCP scaffold in their structure. [10] 1 2 3 Figure 1 2 Planar chirality of PCP. Re markably, PCPs configurational stability tolerates temperatures of up to 200 °C before racemization is observed. The racemization occurs through homolytic bond cleavage between the bridge carbon a toms, thus freeing PCP of its hindered rotation about the de cks and yielding a statistical distribution of both recombination products ( Scheme 1 1 ) T his phenomenon was exploited in a polymerization technique known as the Gorham process (see section 1.1.2.1 .). [11] + 3 2 3 Scheme 1 1 Racemization of PCP above 200 °C. If two substituents are located on the decks, a total of 7 regioisomers are observed ( Figure 1 3 ). The prefix “ps eudo” is used when the substituents are on differing decks. For 4 regioisomers with higher symmetry , the substituents must differ from each other (=heterodisubstitution) to enabl e planar chirality. Figure 1 3 Regioisomers of deck disubstituted PCP. Compounds marked with an asterisk are only chiral if heterodisubstituted. 1.1.2 Applications of PCP 1.1.2.1 The Gorham Process Already in 1947, Szwarc noted a brown residue forming in the cooler z ones of his pyrolysis apparatus that he used to investigate hydrocarbons and their pyrolytic behavior . He disassembled the apparatus to find that the formed residue could be peeled off mu ch like the “skin of a snake” and realized that a new polymer had bee n formed. He accidentally made the first vapor - deposited polymer. The process itself was significantly improved by Gorham at Union Carbide, finding optimized conditions at 550 °C and vacu um below 1 Torr. [12] In the Gorham process, both ethylene bridges are cleaved to produc e an intermediate para - xylylene that polymerizes on cool surfaces to generate parylene ( Scheme 1 2 ) . The starting material for all parylenes is PCP with various substituents that end up in the finalized polymer, thus giving the pol ymer tailor - made properties. Not surprisingly, this versatile process found numerous applications such as implantable electr onics [13] , biological, [14] microfluidical [15] and optical materials. [16] Through the vapor - deposition process, nearly surfaces of every shape and property can be coated evenly with a pinhole -