Iron-Catalyzed Reactions and X-Ray Absorption Spectroscopic Studies

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Arnar Guðmundsson Iron-Catalyzed Reactions and X-Ray Absorption Spectroscopic Studies of Palladium- and Iron-Catalyzed Reactions and X-Ray Absorption Spectroscopic of Palladium- Studies and Ruthenium-Catalyzed Reactions Ruthenium-Catalyzed Reactions

Arnar Guðmundsson

Arnar Guðmundsson was born in Reykjavík, Iceland. After finishing his bachelor studies in biochemistry at the University of Iceland, he moved to Sweden to pursue his masters and doctoral studies under the guidance of Prof. Jan-Erling Bäckvall.

ISBN 978-91-7911-264-6

Department of Organic Chemistry

Doctoral Thesis in Organic Chemistry at Stockholm University, Sweden 2020

Iron-Catalyzed Reactions and X-Ray Absorption Spectroscopic Studies of Palladium- and Ruthenium-Catalyzed Reactions Arnar Guðmundsson Academic dissertation for the Degree of Doctor of Philosophy in Organic Chemistry at Stockholm University to be publicly defended on Friday 22 January 2021 at 10.00 in Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B.

Abstract The focus of this thesis is twofold: The first is on the application of iron catalysis for organic transformations. The second is on the use of in situ X-ray absorption spectroscopy (XAS) to investigate the mechanisms of a heterogeneous palladium- catalyzed reaction and a homogeneous ruthenium-catalyzed reaction. In chapters two, three and four, the use of iron catalyst VI, or its analog X, is described for (I) the DKR of sec-alcohols to produce enantiomerically pure acetates; (II) the cycloisomerization of α-allenols and α-allenic sulfonamides, giving 2,3-dihydrofuran or 2,3-dihydropyrrole products, respectively, with excellent diastereoselectivity; and (III) the aerobic biomimetic oxidation of primary- and secondary alcohols to their respective aldehydes or ketones. In the fifth chapter, XAS is used to elucidate the mechanisms of a Pd(II)-AmP-MCF-catalyzed lactonization reaction of acetylenic acids. The catalyst was known to deactivate during the reaction and the XAS studies identified the cause of this deactivation. A reactivation strategy was subsequently developed based on these findings. In the sixth and final chapter, XAS is used to examine the activation mechanism of a ruthenium racemization catalyst and a ruthenium-acyl intermediate which had previously been speculated to be formed in the activation process was confirmed.

Keywords: Iron, XAS, Cycloisomerization, DKR, Oxidation.

Stockholm 2020 http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-184285

ISBN 978-91-7911-264-6 ISBN 978-91-7911-265-3

Department of Organic Chemistry

Stockholm University, 106 91 Stockholm

IRON-CATALYZED REACTIONS AND X-RAY ABSORPTION SPECTROSCOPIC STUDIES OF PALLADIUM- AND RUTHENIUM-CATALYZED REACTIONS

Arnar Guðmundsson

Iron-Catalyzed Reactions and X-Ray Absorption Spectroscopic Studies of Palladium- and Ruthenium- Catalyzed Reactions

Arnar Guðmundsson ©Arnar Guðmundsson, Stockholm University 2020

ISBN print 978-91-7911-264-6 ISBN PDF 978-91-7911-265-3

Cover Picture: "The Pond" by Guðmundsson Productions

Printed in Sweden by Universitetsservice US-AB, Stockholm 2020 "All is as thinking makes it so" - Marcus Aurelius

Abstract

The focus of this thesis is twofold: The first is on the application of iron catalysis for organic transformations. The second is on the use of in situ X-ray absorption spectroscopy (XAS) to investigate the mechanisms of a heterogeneous palladium-catalyzed reaction and a homogeneous ruthenium-catalyzed reaction. In chapters two, three and four, the use of iron catalyst VI, or its analog X, is described for (I) the DKR of sec-alcohols to produce enantiomerically pure acetates; (II) the cycloisomerization of -allenols and -allenic sulfonamides, giving 2,3-dihydrofuran or 2,3-dihydropyrrole products, respectively, with excellent diastereoselectivity; and (III) the aerobic biomimetic oxidation of primary- and secondary alcohols to their respective aldehydes or ketones. In the fifth chapter, XAS is used to elucidate the mechanisms of a Pd(II)-AmP-MCF-catalyzed lactonization reaction of acetylenic acids. The catalyst was known to deactivate during the reaction and the XAS studies identified the cause of this deactivation. A reactivation strategy was subsequently developed based on these findings. In the sixth and final chapter, XAS is used to examine the activation mechanism of a ruthenium racemization catalyst and a ruthenium-acyl intermediate which had previously been speculated to be formed in the activation process was confirmed.

i Populärvetenskaplig sammanfattning

Avhandlingen omfattar två projektdelar. I den första delen har järnkatalysatorer studerats för att åstadkomma organiska transformatioiner och i den andra delen har röntgenabsorptionsspektroskopi använts för att studera mekanismen av en heterogen palladium-katalyserad reaktion och en homogen rutenium-katalyserad reaktion. Användning av järnföreningar som katalysatorer i organisk syntes har tilldragit sig stort intresse under senare år då järn är mycket billigt och dessutom en miljövänlig metall. I kapitel 2 och 3 används en ny typ av järnkatalysator för dynamisk kinetisk resolvering (DKR) av alkoholer och cykloisomerisering av α-allenoler och α-alleniska sulfonamider. Med hjälp av dessa reaktioner kan man framställa en rad viktiga enantiomert rena alkoholer och heterocykliska föreningar med hög stereoselektivitet. I kapitel 4 har samma typ av järnkomplex använts i en ny biomimetisk oxidation av alkoholer där luft utnyttjas som oxidationsmedel. I kapitel 5 har röntgenabsorptionsspektroskopi använts för att studera mekanismen för en laktonisering som katalyseras av heterogent palladium. Genom denna studie ökade kunskapen om reaktionen och man kunde vidta åtgärder som ledde till en aktiv katalysator där deaktivering minimerades. I kapitel 6 användes röntgenabsorptionsspektroskopi för att undersöka aktiveringen av en ruteniumkatalysator som tidigare använts som racemiceringskatalysator i DKR. Ett intermediat som tidigare föreslagits kunde nu identifieras och med denna metod erhölls bindningsavstånd för intermediatet i lösning.

ii List of Publications

This thesis is based on the following papers, which will be referred to by the Roman numerals I-VI. Reprints were made with kind permission from the publishers. This thesis is in part based on an earlier half-time report as described in Appendix C along with contribution by the author to each publication.

I. Chemoenzymatic Dynamic Kinetic Resolution of Secondary Alcohols Using an Air- and Moisture-Stable Iron Racemization Catalyst Gustafson, K. P. J.; Guðmundsson, A.; Lewis, K.; Bäckvall, J.-E.* Chem. Eur. J. 2017, 23, 1048-1051.

II. Efficient Formation of 2,3-Dihydrofurans via Iron-Catalyzed Cycloisomerization of -Allenols Guðmundsson, A.; Gustafson, K. P. J.; Mai, B. K.; Yang, B.;* Himo, F.;* Bäckvall, J.-E.* ACS Catal. 2018, 8, 12-16.

III. Diastereoselective Synthesis of N-Protected 2,3- dihydropyrroles via Iron-Catalyzed Cycloisomerization of - Allenic Sulfonamides Guðmundsson, A.;† Gustafson, K. P. J.;† Mai, B.K.; Hobiger, V.; Himo, F.;* Bäckvall, J.-E.* ACS Catal. 2019, 9, 1733-1737.

IV. Iron(II)-Catalyzed Aerobic Biomimetic Oxidation of Alcohols Guðmundsson, A.; Schlipköter, K. E.; Bäckvall, J.-E.* Angew. Chem. Int. Ed. 2020, 59, 5403-5406.

V. In Situ XAS Investigation of the Deactivation and Reactivation Mechanisms of a Heterogeneous Palladium(II) Catalyst During the Cycloisomerization of Acetylenic Acids Yuan, N.; † Guðmundsson, A.; † Gustafson, K. P. J.; Oschmann, M.; Tai, C.-W.; Persson, I.; Zou, X.; Verho, O.;* Bajnóczi, É. G.;* Bäckvall, J.-E.* Accepted Manuscript

iii

VI. In Situ Structural Determination of a Homogeneous Ruthenium Racemization Catalyst and its Activated Intermediates Using X-Ray Absorption Spectroscopy Gustafson, K. P. J.;† Guðmundsson, A.;† Bajnóczi, É. G.;† Yuan, N.; Zou, X.;* Persson, I.;* Bäckvall, J.-E.* Chem. Eur. J. 2020, 26, 3411-3419.

† Authors contributed equally to the publication.

Publications not included in this thesis:

Highly Selective Palladium-Catalyzed Hydroborylative Carbocyclization of Bisallenes to Seven-Membered Rings Zhu, C.; Yang, B.; Mai, B. K.; Palazzotto, S.; Qiu, Y.; Guðmundsson, A.; Ricke, A.; Himo, F.;* J.-E. Bäckvall.* J. Am. Chem. Soc. 2018, 140, 14324-14333.

Efficient Aerobic Oxidation of Organic Molecules by Multistep Electron Transfer Liu, J.; Guðmundsson, A.; J.-E. Bäckvall.* Accepted Manuscript

On the Use of Iron in Organic Chemistry Guðmundsson, A.; J.-E. Bäckvall.* Molecules. 2020, 25, 1349-1368.

iv Contents

Abstract...... i

Populärvetenskaplig sammanfattning ...... ii

List of Publications ...... iii

Contents ...... v

Abbreviations ...... vii

1. Introduction ...... 1 1.1 Catalysis ...... 1 1.2 Chirality ...... 2 1.3 Kinetic resolution and dynamic kinetic resolution ...... 4 1.4 Transfer hydrogenation and racemization ...... 6 1.5 The Chemistry of Iron ...... 9 1.5.1 Knölkers Catalyst ...... 10 1.6 X-Ray absorption spectroscopy ...... 12 1.6.1 X-ray absorption edge near edge structure (XANES)...... 13 1.6.2 Extended X-ray absorption fine structure (EXAFS) ...... 13 1.6.3 Advantages and limitations of XAS...... 14 1.7 Objective of this thesis ...... 14

2. Chemoenzymatic Dynamic Kinetic Resolution of Secondary Alcohols Using an Air- and Moisture-Stable Iron Racemization Catalyst (Paper I) ...... 15 2.1 Introduction ...... 15 2.2 Optimization studies of the the racemization and DKR...... 16 2.3 Reaction scope of the DKR ...... 18 2.4 Conclusions ...... 19

3. Iron-Catalyzed Cycloisomerization of Functionalized -Allenes (Papers II and III) ...... 20 3.1 Introduction ...... 20

v 3.2 Reaction screening for the cyclization of -allenols ...... 21 3.2 Reaction scope of the cyclization of -allenols ...... 22 3.3 Reaction screening for the cyclization of -allenic sulfonamides .. 24 3.4 Reaction scope of the cyclization of -allenic sulfonamides ...... 25 3.5 Mechanistic study ...... 26 3.6 Conclusions ...... 29

4. Iron(II)-Catalyzed Biomimetic Aerobic Oxidation of Alcohols (Paper IV) .... 30 4.1 Introduction ...... 30 4.2 Screening of the reaction conditions ...... 31 4.3 Substrate scope ...... 34 4.4 Conclusions ...... 36

5. In Situ Investigations of the Deactivation Mechanism of a Heterogeneous Palladium(II) Catalyst During the Cycloisomerization of Acetylenic Acids (Paper V) ...... 37 5.1 Introduction ...... 37 5.2 XAS Results ...... 38 5.3 Recycling studies ...... 47 5.4 Conclusions ...... 50

6. In Situ Structural Determination of a Homogeneous Ruthenium Racemization Catalyst and its Activated Intermediates Using X-Ray Absorption Spectroscopy (Paper VI) ...... 51 6.1 Introduction ...... 51 6.2 NMR and in situ IR studies ...... 53 6.3 XANES ...... 54 6.4 EXAFS...... 58 6.5 Substrate addition ...... 62 6.6 Conclusions ...... 62

7. Summary ...... 63

Appendix A: Calculated free energy profile for the formation of allenol 6k (energies are given in kcal/mol) ...... 65

Appendix B: Calculated free energy profile for the formation of allenic sulfonamide 8j (energies are given in kcal/mol) ...... 66

Appendix C: Contribution list ...... 67

Appendix D: Reprint Permissions ...... 68

Acknowledgements...... 69

References ...... 71

vi Abbreviations

Abbreviations and acronyms are used in agreement with standards of the subject.1 Only nonstandard and unconventional ones that appear in the thesis are listed here.

AmP Aminopropyl BQ 1,4-Benzoquinone CALB Candida Antarctica lipase B Cat. Catalyst CPME Cyclopentyl methyl ether d.r. Diastereomeric ratio DCE Dichloroethane DFT Density functional theory DIPE Diisopropyl ether DKR Dynamic kinetic resolution ee Enantiomeric excess EXAFS Extended X-ray absorption fine structure KR Kinetic resolution MCF Mesocellular foam MTBE Methyl tert-butyl ether NMR Nuclear magnetic resonance NOE Nuclear Overhauser effect PS-C Lipase from Burkholderia cepacia immobilized on ceramic beads rac Racemic sec Secondary TMANO Trimethylamine N-oxide TON Turnover number XANES X-ray absorption near edge structure XAS X-ray absorption spectroscopy XRD X-ray diffraction

vii

viii 1. Introduction

1.1 Catalysis A catalyst is an additive, used in less than stoichiometric amounts, which increases the rate of a chemical reaction by providing an alternate transition state without being consumed in the process. This transition state has a lower activation energy than that of the uncatalyzed reaction, but does not affect the free energy of the reaction (Figure 1).2 Catalysis thus allows for certain reactions that have high kinetic barriers and would otherwise be difficult to accomplish, either due to excessive reaction times or harsh conditions, to be performed faster and/or under milder conditions. About 90% of commercial chemical compounds produced industrially use catalysis in at least one step of their synthesis, which is a testament to its usefulness.3

Figure 1. A comparison of the reaction process of a catalyzed reaction versus an uncatalyzed reaction.

Catalysis can be divided into two main groups: Homogeneous and heterogeneous. In homogeneous catalysis, the substrate and the catalyst are in the same phase, whereas in heterogeneous catalysis they are in different phases. The advantages of heterogeneous catalysts are that they generally

1 show higher stability and can be separated from a mixture and recycled much easier than homogeneous catalysts. 4 For these reasons, they are attractive candidates for industrial applications and are used in important large-scale processes such as the Ziegler-Natta polymerization 5 , 6 and Haber-Bosch ammonia synthesis.7 Homogeneous catalysts on the other hand are often more active and selective compared to their heterogeneous counterparts.8 They are also easier to analyze and characterize, which in turn simplifies the process of modifying and tuning them for a specific reaction. In the design of heterogeneous catalysts, the collaboration of multiple fields of chemistry, materials science and physics is required to properly characterize the catalyst structure.9,10 In the 1960’s organic chemistry was revolutionized by the application of transition metals, which allowed for unprecedented reactivity not achievable before through classical chemical means. These catalysts permit a high degree of electronic and steric tuning through the design of the ligand environment around the metal center, which can completely alter the catalytic activity of the metal.11

1.2 Chirality

The symmetry of molecules is very important in chemistry and one important geometric property that molecules have is chirality. Chirality is very prevalent in nature, has significant impact on the behavior of biologically active compounds and is essential for the existence of life on Earth.12 Chirality arises when the bond sequence in a molecule is the same, but two or more spatial arrangements are possible that are not superimposable on each other. If these non-superimposable compounds are mirror images, they are called enantiomers and if they are not, they are called diastereomers. Louis Pasteur first discovered the chiral property of molecules in 1848 when he separated the two enantiomers of sodium ammonium tartrate.13 The grouping at which an asymmetry arises in a molecule is called a stereogenic unit and for each one present, the molecule can exist in two different stereoisomeric forms, i.e. for n stereogenic units there are 2n stereoisomers of a compound, although for some molecules the stereoisomers can be fewer than 2n if they have a plane of symmetry. Either these stereogenic units can be atoms that have non-identical groups bonded to them and are then called chiral centers, or they can be an axis around which the attached groups cannot rotate. Enantiomers have identical physical properties like melting- and boiling points, but when interacting with other chiral elements, enzymes for example, they can behave very differently. An

2 example of this phenomenon is Asparagine. The naturally occurring L-Asparagine is tasteless or bitter, whereas the unnatural D-Asparagine tastes sweet (Figure 2).14 Diastereomers can have different properties in both chiral and achiral environments.

Figure 2. The two enantiomers of Asparagine.

Ethambutol, a major pharmaceutical on the market for the treatment of tuberculosis, is sold as a single enantiomer (Figure 3). This compound was originally sold as a racemic mixture but was found to cause blindness and to have other serious side effects. When the activity of the two enantiomers was investigated, it was discovered that the (S,S)-enantiomer was over 500 times more potent than the (R,R)-enantiomer. 15,16 Further, the (R,R)-enantiomer was found to have caused most of the side-effects and the use of the racemic mixture was subsequently discontinued in favor of the pure (S,S)-enantiomer. This and many other examples highlight the importance of enantiomerically pure compounds and because of this, the development of methods capable of preparing them is vital. The three main methods used today are: (I) The chiral pool approach, where naturally occurring chiral compounds like amino acids are used as starting materials; (II) asymmetric synthesis, in which an external chiral molecule is used to induce chirality; and (III) the resolution of a racemic mixture, where a chiral resolving agent, which reacts preferentially with one enantiomer, is used. The reverse process of producing a racemate from enantiomerically pure starting material is called racemization.

Figure 3. The two enantiomers of Ethambutol.

3 1.3 Kinetic resolution and dynamic kinetic resolution

Kinetic resolution (KR) is the separation of two enantiomers from a mixture. In a KR, a resolving agent, typically an enzyme or another chiral molecule, reacts significantly faster with one of the enantiomers which leads to an enantiomerically enriched product (Scheme 1).

Scheme 1. R-selective enzymatic kinetic resolution.

Unfortunately, enzymes are not perfectly selective and will catalyze the transformation of the slower reacting enantiomer as well, although at a much lower rate. Because of this, the reaction must be stopped before it reaches 50% conversion. If this is not done, the ee will be lower since the enzyme will inevitably react with the unfavored enantiomer if that is the only one it has access to. Alternatively, if enantiomerically enriched starting material is desired, the reaction can be run past 50% conversion. The enantiomeric ratio (E-value) is used to compare the selectivity of different resolving agents. This term is defined as the ratio of the reaction rates for the two enantiomers (E = kfast / kslow). The E-value is a constant for a particular reaction and is calculated using one of equations 1, 217 or 3.18 The E-value can thus be determined by knowing two of the three parameters; enantiomeric excess of the product (eep), enantiomeric excess of the substrate (ees) and the conversion of the substrate (c).

ln[1−c(1+푒푒 )] 퐸 = p Eq. (1) ln[1−c(1−푒푒p)]

ln[1−c(1−푒푒 )] 퐸 = s Eq. (2) ln[1−c(1+푒푒s)]

푙푛[푒푒 (1−푒푒 )/(푒푒 +푒푒 )] 퐸 = p s p s Eq. (3) 푙푛[푒푒p(1+푒푒s)/(푒푒p+푒푒s)]

As mentioned before, enzymes are often used as resolving agents in KR and the general reaction mechanism for a serine hydrolase-catalyzed transacylation is shown in Scheme 2. All serine hydrolases, which includes lipases, serine proteases and esterases, work through a similar mechanism.19 A three amino acid catalytic triad, consisting of histidine, serine and aspartic

4 acid/glutamic acid, plays a key role. The acid residue coordinates to histidine, which deprotonates serine. This serine residue then attacks the ester as it enters the oxyanion hole to form a tetrahedral intermediate (TI). The alcohol leaves and the acylated form of the enzyme is generated. A different alcohol then enters and attacks the ester to give TI′, which breaks apart to release the transesterified product and the free enzyme.

Scheme 2. General reaction mechanism of serine hydrolases.

Despite the usefulness of KR, the fact that only one enantiomer is reactive is a significant drawback and limits the theoretical maximum yield to 50%.20,21 One way to circumvent this limitation is through the introduction of a racemization catalyst which interconverts the two enantiomers in situ and thus keeps the substrate racemic throughout the entire resolution. This modification increases the maximum theoretical yield to 100% and the process is then called dynamic kinetic resolution (DKR) (Scheme 3).22,23,24 For a successful DKR, several criteria must be fulfilled: (I) The enzyme must be highly enantioselective (E ˃ 20 so that eep ˃ 90%). (II) The racemization catalyst must only racemize the substrate and not the product. (III) The rate of racemization needs to be faster than the reaction rate for the faster reacting enantiomer (krac ˃ kfast). As long as the enzyme is extremely

5 selective, this is less of an issue and it is often enough that krac ˃ kslow. (IV) The resolution and the racemization must be compatible with one another and work under the same reaction conditions. This is in many cases a major problem.25

Scheme 3. R-selective enzymatic dynamic kinetic resolution.

There are different racemization methods available depending on the compound that needs to be racemized. Some examples include acid/base racemization, 26 thermal racemization, enzyme-catalyzed racemization and racemization via redox reactions. 27 In this thesis the focus will be on racemization via transfer hydrogenation (a redox-type reaction) using a homogeneous iron catalyst.

1.4 Transfer hydrogenation and racemization

In a transfer hydrogenation reaction, a pair of hydrogen atoms are transferred from a hydrogen donor, other than molecular hydrogen, to a hydrogen acceptor, e.g. a ketone or an imine via a catalyst (Scheme 4).

Scheme 4. Metal-catalyzed transfer hydrogenation.

The development of intermolecular transfer hydrogenation began in the early 20th century, led by Meerwein, Ponndorf and Verley, where aluminium isopropoxide (Al(Oi-Pr)3) was used as a catalyst for the reduction of ketones to alcohols.28 The reverse reaction, i.e. the oxidation of alcohols to ketones, was later developed by Oppenauer using acetone as the hydrogen acceptor 29 (Scheme 5). Since using stoichiometric amounts of Al(Oi-Pr)3 is both wasteful and expensive, modern methods generally use isopropanol as the hydrogen donor, or acetone as the hydrogen acceptor, and a transition metal 30 catalyst in place of Al(Oi-Pr)3 (Scheme 5).

Scheme 5. Meerwein-Ponndorf-Verley reduction and Oppenauer oxidation.

The first example of a transition metal-catalyzed hydrogen transfer was reported by Henbest in the 1960’s using an iridium catalyst. 31 A ruthenium-catalyzed protocol was later reported by Sasson and Blum.32 The main drawbacks of these early attempts were low turnover frequency and harsh reaction conditions. A breakthrough occurred when it was discovered that the addition of base dramatically increases the rate of transfer hydrogenation. 33 Many milder systems have been reported since then, mainly based on ruthenium, iridium, rhodium, and, more recently, iron.34,35 Two main mechanistic pathways have been proposed for transfer hydrogenation: Main group metals are thought to react through direct hydrogen transfer, and transition metals through a hydridic route.34b, 36 Meerwein-Ponndorf-Verley (MPV) reduction is thought to occur through direct hydrogen transfer, which proceeds through the six-membered transition state depicted in Scheme 6. The substrates are held in close proximity by the catalyst and the hydride is delivered without the formation of a metal-hydride intermediate.30a, 37

Scheme 6. Direct hydrogen transfer mechanism of MPV reduction.

In the hydridic route, the hydride is transferred in a stepwise manner facilitated by a metal catalyst. The metal hydride is normally generated through β-hydride elimination of the alkoxide. This route can be further divided into the monohydridic and dihydridic routes. In these routes, the metal transfers either one or two hydrogen atoms, respectively.37, 38 The monohydridic mechanism can be further subdivided into two different pathways: Inner and outer sphere. In the inner sphere mechanism, formation of the metal hydride involves direct covalent binding of the alcohol to the metal center, leading to a metal alkoxide. The metal hydride is subsequently formed via β-hydride elimination. The outer sphere mechanism proceeds without any coordination of the alcohol to the metal center. In both cases the metal hydride migrates from the metal to the carbonyl carbon. The two mechanisms are depicted in Scheme 7.

Scheme 7. Inner and outer sphere monohydridic mechanisms.

Examples of metal complexes used for the racemization of sec-alcohols, some of which have been applied in DKR, are depicted in Figure 4. 39 Williams reported the first example of a racemization via transfer hydrogenation of sec-alcohols in a DKR study in 1996. This procedure gave the esterified product in 98% ee, although only in 60% yield. 40 Shortly thereafter the group of Bäckvall reported a DKR using ruthenium dimer complex I41 with excellent yields and ee.42 Since then catalysts based on many different metals have been developed.39

Figure 4. Examples of transition metal racemization catalysts for sec-alcohols.

The group of Baratta reported pincer ruthenium and osmium complexes II, which efficiently racemize both aromatic and aliphatic sec-alcohols. 43 Feringa, de Vries and coworkers reported the use of iridacycle III along with a doubly mutated haloalcohol dehydrogenase for the synthesis of enantiomerically pure epoxides from sec-alcohols. 44 This iridium system worked at ambient temperatures and interestingly showed higher racemization rates for chlorohydrins than sec-alcohols, and was thus complementary to previous ruthenium protocols. In an effort to move away from expensive and rare transition metals like ruthenium and iridium in chemoenzymatic DKR, other catalytic systems have been developed. An example of such a system is the AlMe3/binol/CALB system developed by the group of Berkessel, which racemizes both aliphatic and benzylic sec-alcohols at ambient temperatures. 45 A number of vanadium-based protocols have also been

8 developed over the past decade. The group of Akai demonstrated that oxyvanadium(V) complex IV could racemize allylic sec-alcohols through 1,3-transposition of the hydroxyl group. This complex was successfully incorporated into DKR protocols with several different lipases. 46 Heterogeneous variants were also prepared which were capable of racemizing benzylic, heteroaromatic and propargylic alcohols. In addition, they could be recycled with no loss in activity up to six times. Despite these advancements in the use of cheaper and more abundant alternatives, pentaphenylcyclopentadienyl ruthenium complex V, reported by Bäckvall, remains the most efficient and versatile transfer hydrogenation catalyst used for the racemization of sec-alcohols to date.47

1.5 The Chemistry of Iron

Iron is the most abundant element in the Earth by mass and the second most common metal in the crust.48 Around 2.4 billion years ago the Great Oxidation Event occurred on Earth, changing the atmosphere, and making it more oxidative. This resulted in ferric (+III) iron complexes becoming more stable over their ferrous (+II) counterparts.49 In its ferric oxidation state iron normally forms water-insoluble complexes like hematite (Fe2O3) or magnetite (Fe3O4), but despite the low solubility of ferric complexes at biological pH, iron is still the most common transition metal that Nature uses in living organisms and is vital for the chemical processes of life - oxygen binding, electron transport, DNA synthesis and cell proliferation, to name only a few. The prevalence of iron in organisms is due to its wide redox potential range, abundance and the ease with which its properties can be tuned by exploiting its many oxidation states, electron spin states, and redox potential.50 In addition to the low solubility of ferric iron complexes, another problem that organisms face in their use of iron is the redox cycling of ferric and ferrous forms and the tendency of these forms to react with O2 or H2O2 to form hydroxyl- and hydroperoxyl radicals. This cycling is exemplified in equations 4, 5 and 6, which show the iron-catalyzed disproportionation of H2O2. The radicals generated through this process readily attack macromolecules within a cell and to prevent these attacks, special precautions must be taken to sequester iron. Bacteria use low molecular weight siderophores that specifically chelate iron and mammals store and secrete iron from extracellular carrier proteins like ferritin.

9 퐼퐼 퐼퐼퐼 • − 퐹푒 + 퐻2푂2 → 퐹푒 + 퐻푂 + 퐻푂 Eq. (4)

퐼퐼퐼 퐼퐼 • + 퐹푒 + 퐻2푂2 → 퐹푒 + 퐻푂푂 + 퐻 Eq. (5)

• • 2퐻2푂2 → 퐻푂 + 퐻푂푂 + 퐻2푂 Eq. (6)

Over the past few decades, most catalytic protocols using transition metals have focused on noble transition metals like Pd, Ru, Ir and Pt, and these metals have been used to great effect in many reactions.51 Noble metals have some advantages over their base counterparts, perhaps the most prominent one being their preference for undergoing two-electron processes. Noble metals have their drawbacks however: They are expensive, have a non-renewable supply and are often dangerous for the environment. In academia these factors may not pose too much of a problem, but they are a significant issue for large-scale industrial production. Therefore, base metals like iron, copper and nickel have risen in prominence as alternatives to their noble metal counterparts. Iron in particular is attractive due to its abundance and because of the explosion in interest in iron catalysis that has occurred over the past decade, Beller in 200852 and Bolm in 200953 declared that the age of iron has begun. Organoiron chemistry began in 1891 with the discovery of iron pentacarbonyl by Mond 54 and Berthelot. 55 It was used sixty years later industrially in the Reppe process of hydroformylation of ethylene to form propionaldehyde and 1-propanol in basic solutions. 56 An important event was the discovery of ferrocene in 1951, 57 the structure of which was determined in 1952 58 , 59 and led to the Nobel prize being awarded to Wilkinson and Fischer in 1973. The discovery of the Haber–Bosch process was another milestone in iron chemistry.60 This process uses an inorganic iron catalyst for the production of ammonia and sparked an agricultural revolution. Although iron clearly has many advantages, there are significant drawbacks associated with using organoiron catalysts such as difficult synthetic pathways, lack of robustness, poor atom economy and low activity or enantioselectivity. Before organoiron catalysis reaches its full potential, these limitations will need to be overcome.61

1.5.1 Knölkers Catalyst

Iron catalysts have been applied in many different transformations including cross-coupling reactions and transfer hydrogenation reactions. 62 , 63 , 64 (Cyclopentadienone)iron tricarbonyl complexes, first synthesized by Reppe and Vetter in 1953,65 constitute a prominent class of catalysts for hydrogen transfer reactions. The iron hydride analogue of catalysts of this type is known by the trivial name “Knölkers complex” due

10 to the fact that complex VII was originally isolated by the group of Knölker in 199966, although it found its first application in the hydrogenation of aldehydes and ketones in the group of Casey (Scheme 8). 67a It was later discovered that VII could be generated in situ from the air- and moisture stable precursor VI. This generation can be accomplished in a variety of ways; through exposure to an oxidant, base or light irradiation, in the presence of a hydrogen source. This discovery made the complex much more practical to use.68

Scheme 8. Formation of Knölkers complex.

After this discovery, different groups reported on the use of this catalyst and its analogues in various reactions employing both achiral 69 , 70 ,71 and chiral variants.72 Selected examples of these reactions are shown in Figure 5.

Figure 5. Examples of reactions that can be performed with Knölkers catalyst (VII) or its analogues.

Casey and Guan reported on the use of VII in the hydrogenation of ketones in 2007 (Figure 5a) and Guan later reported the oxidation of alcohols using the same catalyst in 2010 (Figure 5b).67a,67c Subsequently

11 Beller reported in 2011 the asymmetric hydrogenation of imines using VII in tandem with chiral phosphoric acids (Figure 5c).72d Complex VI was used in the alkylation of amines with alcohols as reported by Feringa and Barta in 2014 (Figure 5d).68b In 2015 Beller and Darcel reported the -alkylation of ketones with alcohols using analogues of VI in a hydrogen borrowing strategy (Figure 5e).68c These examples show the versatility of VI and VII, as well as the wide breadth of fundamental transformations that can be accomplished using iron catalysis.

1.6 X-Ray absorption spectroscopy

Wilhelm Röntgen originally discovered the absorption of X-rays by matter in 1895 and that different types of matter showed differing degrees of transparency. This discovery had profound implications for medicine and has led to radiology being the most productive diagnostic method available.73 The development of X-ray absorption spectroscopy (XAS) began 10 years after Röntgens discovery, although rather slowly due to it being overshadowed by the success of X-ray diffraction (XRD), and its reliance on the availability of powerful X-ray sources such as synchrotrons. XAS is an analytical technique that elucidates molecular geometry and electronic structure through the measurement of the linear absorption coefficient. At certain energies there is a steep increase in the absorption where the incident X-ray is able to excite electrons from their ground state to vacant electron shells or all the way to the continuum, generating core holes and photoelectrons. The XAS data is obtained by tuning the photon energy of an XAS beamline to this energy range. XAS is element-specific and can be used to determine the local structure around absorbing atoms.74 Unlike XRD, which requires samples to be crystalline or a powder, XAS can be applied to systems in all forms of aggregation and requires only an elemental concentration in the millimolar range. An XAS spectrum can be divided into two regions: X-ray absorption near edge structure (XANES) and extended X-ray absorption fine structure (EXAFS) (Figure 6). The XAS spectra shown in the thesis have their absorption normalized. This normalization must be done due to fluctuation in the synchrotron beam.

Figure 6. A XANES Pd K-edge spectrum of a Pd(II) catalyst.

1.6.1 X-ray absorption edge near edge structure (XANES)

The energy range of XANES is defined as around 10 eV below the absorption edge up until 50-200 eV above the absorption edge.75 The main contributions to this part of the spectrum are from 1s → np transitions, where np is the lowest unoccupied p orbital. Excitations at this energy level cause multiple scattering events that are normally the main contributors, although single-scatterings can also be observed. This region provides information about the oxidation state and the coordination environment of the absorbing atom and can be used to determine geometric structure, charge on the absorbing atom and ligand arrangement in many cases. When the energy supplied by the beam is high enough to produce a photoelectron (through the excitation of an electron to the continuum), a sharp rise in absorption is observed. This absorption threshold is defined as the inflection point of this rising edge and is used as a metric of the charge on the metal center.

1.6.2 Extended X-ray absorption fine structure (EXAFS)

At energies higher than the LUMO level, the absorption of an X-ray provides enough energy for an absorbing atom to ionize.76 The photoelectron generated can be backscattered by nearby atoms and as the energy of the

13 X-ray increases, the wavelength of the photoelectron becomes shorter. The interference between the outgoing and backscattered photoelectrons gives rise to an interference pattern, which is in turn determined by the distances between the absorbing atom and the other atoms in its environment. The particularities of an EXAFS spectrum thus depend on the specific environment around the absorbing atom, are unique to each compound and can give detailed structural information.

1.6.3 Advantages and limitations of XAS

The main advantage of XAS is that it is element specific. One can study an element without interference from other elements present. In the case of a protein that has two different metals, for example Fe and Mo in nitrogenase, one of the metals can be selectively studied without interference from the other. In addition, XAS is not limited by the state of the sample and is only sensitive to the local environment around the absorbing atom. Consequently, samples can be run as solids or solutions. Lastly, it is not “silent”; the metal of interest will always be seen in an XAS spectrum in contrast to some other optical or spectroscopic techniques. There are a few disadvantages to XAS. First, it is difficult to distinguish between scattering atoms that have similar atomic numbers, e.g. C, N or O; S or Cl; Mn or Fe. This is because these atoms often form bonds of very similar lengths. Care must also be taken when deciding between backscattering atoms that have very different atomic numbers and are at different distances from the absorbing atom as the fits obtained can be equally good in both cases. Another issue is that although distances can normally be reliably obtained from EXAFS, the range of data, for practical reasons like the presence of the K-edge of another metal, can limit the resolution of distance determination. Lastly, the signal that is detected is an average of all the atoms of a chosen type. This can be an issue for example when you have nanoparticles where the surface and core atoms are in vastly different environments.

1.7 Objective of this thesis

The aim of this thesis has been twofold: (I) To develop novel iron-catalyzed transformations - DKR of sec-alcohols, cycloisomerization of functionalized allenes and biomimetic oxidation using iron catalyst VI or its analogue X. (II) To use XAS to investigate catalytic processes involving either heterogeneous Pd(II)-AmP-MCF or a homogeneous ruthenium catalyst.

14 2. Chemoenzymatic Dynamic Kinetic Resolution of Secondary Alcohols Using an Air- and Moisture-Stable Iron Racemization Catalyst (Paper I)

2.1 Introduction Attempts had previously been made in the Bäckvall group to develop an enzymatic iron-catalyzed DKR of sec-alcohols using iron pincer complex VIII for racemization (Scheme 9). This complex was the first iron catalyst reported for this purpose, but unfortunately, although effective as a racemization catalyst, this pincer complex could not be incorporated into a lipase-based DKR because of catalyst inhibition by the ester product. 35d

Scheme 9. Iron pincer complex VIII used in the racemization of sec-alcohols.

Iron catalyst VII (Scheme 8, vide supra) had been used in an earlier report for the hydrogenation of aldehydes bearing an ester substituent and was therefore a good racemization catalyst candidate for a chemoenzymatic DKR.67a The aim of this work was to develop the first iron-catalyzed racemization protocol using catalyst VI (Scheme 8), and to apply it in a chemoenzymatic DKR of sec-alcohols. A similar work to the one presented here was published by the group of Rueping on a DKR of sec-alcohols using iron catalyst VII.77 The group of Zhou also reported a related protocol using a similar iron catalyst in the DKR of sec-alcohols after the publication of this work.78

15 2.2 Optimization studies of the the racemization and DKR

The reaction optimization began by using 10 mol% of VI to racemize (S)-1a in toluene at 90 °C with TMANO as activator. The reaction worked under these conditions, but deactivation of the catalyst was observed which was most likely due to poisoning by trimethylamine, which is formed on activation of the catalyst. When the reaction was run in the absence of TMANO, no racemization was observed, which is unsurprising since the tricarbonyl complex needs to be activated to be an effective transfer hydrogenation catalyst. Etheric solvents were found in an earlier report by our group to reduce the extent of deactivation during racemization and anisole was chosen as the model solvent for the racemization (Table 1, entry 1).35d In an attempt to make the system more efficient, additives were screened. The addition of 0.5 equiv. of ketone 2 was found to dramatically increase the rate of racemization (entry 2). This can be explained by the fact that the slow step in the transfer hydrogenation catalyzed by the iron catalyst is known to be the reduction of the carbonyl. By increasing the concentration of 2, the overall reaction rate increases. The addition of an inorganic base dramatically increased the racemization rate (entries 3-4). To rule out that this effect of the bases was due to them sequestering water, an experiment was conducted using Na2SO4 with and without TEA, which showed that it was indeed the basicity that causes the increased reactivity (entry 5). The more basic conditions most likely cause the iron hydride complex to be more reactive. K2CO3 performed slightly better in the racemization than Na2CO3, but Na2CO3 was more compatible with the enzymes and performed better in the KR. Lowering the amount of 2 to 0.2 equiv. led to a lower, though still acceptable, racemization rate (entry 6) and the temperature could be lowered to 60 °C, making the procedure more tolerable for different enzymes (entry 7). The conditions in entry 7, using Na2CO3 instead of K2CO3 were chosen as the optimal conditions for the DKR.

16 Table 1. Screening of the racemization conditions for alcohol (S)-1a using catalyst VI.

Entrya T (°C) 2 (equiv.) Additive ee of 1ab 30 min 60 min 1 90 - - 76% 52%

2 90 0.5 - 43% 22%

3 90 0.5 Na2CO3 14% 4%

4 90 0.5 K2CO3 10% 2% 84% 5 90 0.5 Na SO 74% (32%)c 2 4 (62%)c

6 90 0.2 K2CO3 26% 4%

7 60 0.2 K2CO3 76% 58% a General reaction conditions: 1.0 mmol of (S)-1a, 0.1 mmol of VI, 0.1 mmol of TMANO, 1.0 mmol of additive and 1 mL anisole. b ee-values were determined by chiral GC. c 0.8 equiv. of TEA were added.

After optimizing the racemization conditions, the acyl donors to be used in the DKR were screened next. Aryl acetates performed best, with other activated esters like isopropenyl- or vinyl acetate forming acetone and acetaldehyde, which compete with the substrate and interfere with the reaction. Phenyl acetate was found to be the best acyl donor. DKR reactions are often sensitive to the concentration of the substrate and this was also the case here. A substrate concentration of 1.0 M resulted in minimal racemization in the presence of CALB and dilution to 0.25 M was found to be optimal.

17 2.3 Reaction scope of the DKR Once all reaction parameters had been optimized, the reaction scope for the sec-alcohols was investigated (Scheme 10). The ketone used in each reaction is the one which corresponds to each sec-alcohol used as substrate. The standard benzylic substrate 1a was esterified in 84% yield with 98% ee. Phenylethanol derivatives bearing electron-withdrawing substituents gave the corresponding esters 4b and 4c in 87% and 84% yield, respectively, with excellent ee. Electron-rich aryls also performed well, and 4d and 4e were isolated with excellent ee and in 89% and 85% yield, respectively. Unexpectedly, the electron-deficient alcohol 4f could only be isolated in 62% yield with an ee of 96%. Longer chain alcohols like 1-phenylpropanol were readily acetylated and acetate 4h was isolated in 75% yield with excellent ee. Burkholderia cepacia lipase (PS-C) could also be used as a resolving agent and yielded aliphatic acetate 4i in 78% yield and 95% ee.

Scheme 10. Reaction scope for the chemoenzymatic DKR of sec-alcohols. Reaction conditions: 1.0 mmol of 1, 0.2 mmol of ketone, 2 mmol of 3, 0.10 mmol of VI, 0.10 mmol of TMANO and 12 mg/mmol of CALB in 4 mL of anisole at 60 °C. The ee was determined by chiral column using GC or HPLC. a Lipase PS-C was used.

18 The reaction was also scaled up to 10 mmoles with 1g as substrate to demonstrate the practical utility and reliability of the protocol. The product, 4g, was subsequently isolated in 83% yield and 96% ee (Scheme 11).

Scheme 11. Scale-up of the DKR.

2.4 Conclusions A DKR of sec-alcohols using CALB as the resolving agent and iron tricarbonyl complex VI for racemization was developed. Numerous acetates, both benzylic and aliphatic, were synthesized using this method in good to excellent yields and excellent ee. The rate of racemization was found to be significantly improved by basic conditions. The reaction conditions were mild enough so that two different enzymes, CALB and PS-C, were compatible with the protocol and the practical utility of the method was demonstrated by the large scale synthesis of 4g, with minimal loss of yield or ee.

19 3. Iron-Catalyzed Cycloisomerization of Functionalized -Allenes (Papers II and III)

3.1 Introduction

In 2016, the Bäckvall group reported a one-pot KR-cyclization protocol of -allenols using CALB and Shvo’s catalyst (I), with the original goal of developing a DKR of -allenols. 79 The KR of the allenol was found to proceed easily, but on exposure to I, a cyclization to the 2,3-dihydrofuran was observed instead of the expected racemization (Scheme 12).

Scheme 12. (a) Previously reported ruthenium-catalyzed cycloisomerization reaction of -allenols and (b) this work.

The activated iron complex VI′ is an isoelectronic analogue to one of the monomers formed when I is thermally dissociated (I′′) (Scheme 13). Because of this fact and based on our experience with VI described in Chapter 2, we thought that VI could have similar reactivity to I in this reaction. The aim of this project was thus to apply VI to either develop a functional DKR if VI were to successfully racemize the substrate that I could not, or to explore an analogous transformation to the previously reported ruthenium-catalyzed one.

Scheme 13. Activation of Knölkers complex (VII) and Shvo’s catalyst (I).

After the completion of Paper II, a similar cyclization of β-allenols to 3,4-dihydro-2H-pyrans was reported by the group of Rueping.80 They also reported a cyclization of α-allenols and α-allenic carbamates to 2,3- dihydrofurans and pyrroles during the completion of Paper III.81

3.2 Reaction screening for the cyclization of -allenols Initial screenings for the -allenol cyclization began using the optimized conditions from the DKR study discussed in Chapter 2 (Table 1, entry 7, vide supra). Under these conditions, 6a was obtained in 70% yield as the sole product (Table 2, entry 1). After this encouraging result, catalyst loading and solvents were screened. The catalyst loading could be reduced to 5 mol%, without significant loss of yield (entry 2), although further reduction to 1 mol% led to a substantial loss of yield (entry 3). Non-polar solvents were found to be superior to polar ones, with DCM and toluene giving the best results (entries 4-7). More polar solvents gave low yields, most likely due to stronger coordination to the catalyst (entries 8-12). DCM was chosen over toluene as the ideal solvent mainly due to the relatively high volatility of 6a. Another Fe(II) catalyst, the simple iron salt Fe(OAc)2 was tested as well, but gave no product, indicating that the bifunctional cyclopentadienyl ligand of VI plays an important role. The reaction worked without K2CO3, but the reactions were more reproducible when it was used.

21 Table 2. Reaction screening for the cyclization of 5a using VI.

Catalyst loading NMR yield of 6a Entrya Solvent (mol%) (%)b 1 Anisole 10 70 2 Anisole 5 50 3 Anisole 2.5 14 4 DCM 5 90 5 Diethyl ether 5 82 6 Toluene 5 95 7 CPME 5 24 8 EtOAc 5 18 9 THF 5 11 10 MeCN 5 0 11 DMF 5 3 12 Water 5 0 a General reaction conditions: The reaction was conducted under Ar at r.t. with 0.5 mmol of b 5a, 0.025 mmol of VI, 0.025 mmol of TMANO, 0.5 mmol of K2CO3 and 0.5 mL of solvent. Yield after 2 hours determined by 1H NMR analysis using 1,3,5-trimethoxybenzene as internal standard.

3.2 Reaction scope of the cyclization of -allenols Once the optimal reaction conditions for the cyclization of -allenols had been determined, the substrate scope was investigated. The electronic properties of the aryl group had little effect on the reaction and 6a-6f were isolated in good to excellent yields (Scheme 14). Sterically hindered aryls with substituents in the meta or ortho positions readily cyclized (6g-6h), as did aliphatic alcohols, exemplified by 6i, which was isolated in 92% yield. -Allenols having a substituent in the 2-position were investigated as well. Two diastereomeric forms of the 2,3-dihydrofuran products formed through the cyclization of these substrates are possible, and given the mild conditions of the reaction, we hypothesized that the reaction might be diastereoselective. This was indeed the case and when 2-substitued substrates 5k-n were cyclized, the corresponding diastereomerically enriched products were formed with a d.r. of up to 98:2, in every case

22 favoring the trans diastereomer. Increasing the steric bulk of the R2 substituent led to a higher d.r. The corresponding ruthenium protocol using I was less selective as well as lower yielding compared to the results with iron catalyst VI and afforded only a moderate 4:1 selectivity in favor of the trans diastereomer in the case of 6k. In addition, the use of I gave the other structural isomer, the 2,5-dihydrofuran, in approximately 20% yield.

Scheme 14. Reaction scope for the cyclization of α-allenols. General reaction conditions: The reaction was conducted under Ar atmosphere at r.t. with 0.5 mmol of 5, 0.025 mmol of VI, 0.025 mmol of TMANO, 0.5 mmol of K2CO3 and 0.5 mL of DCM. All yields shown are isolated yields.

Substitution on the terminal side of the allene was also explored, but -allenol 5r gave only around 15% NMR yield of 2,3-dihydrofuran 6r under the optimized reaction conditions. However, when the reaction was performed in toluene at higher temperature, 6r was obtained in 96% yield (Scheme 15). An important observation to note is that at around 65% conversion the starting racemic diastereomer had been resolved with a d.r. of 8:1, showing that a kinetic resolution of these substrates might be possible using VI as a resolving agent.

Scheme 15. Cyclization of terminally substituted allenol 5r.

As mentioned previously, VII is a reported racemization catalyst. An important question to answer therefore was whether any racemization of the -allenol takes place. To this end (S)-5a was synthesized through KR with CALB and then exposed to the optimal cyclization reaction conditions to see if any loss of ee would occur. No racemization of (S)-5a was detected and enantiomerically enriched 2,3-dihydrofuran (S)-6a was isolated with no loss of ee.

Scheme 16. Synthesis of (S)-6a through KR and subsequent cyclization.

3.3 Reaction screening for the cyclization of -allenic sulfonamides

In an attempt to broaden the substrate scope, various N-functionalized allenes were tested in the cyclization. Cbz-, Teoc- and acyl- protected amines were stable, but did not give any product. The simple primary amine proved unstable and decomposed quickly. But the Ms-protected amine cyclized readily, although it required higher temperature and a change of solvent to toluene compared to the -allenols (Table 3, entry 2). The fact that only the Ms-protected allenic amine cyclized suggests that the acidity of the NH proton plays an important role in the mechanism. The solvent screening for the -allenic sulfonamides followed the same pattern as for the -allenols, with non-polar solvents performing the best (entries 3-5). Interestingly, a modest yield of 36% was observed in water using 10 mol% of VI.

24 Table 3. Reaction screening for the cyclization of 7a using VI.

Catalyst loading Entrya Solvent NMR yield of 8a (%)b (mol%) 1c DCM 10 0 2 Toluene 5 >95 3 CPME 5 69 4 DCE 5 51 5 Dioxane 5 35 6 MeCN 5 3 7 EtOAc 5 7 8d THF 5 9 9 Water 10 36 a General reaction conditions: The reaction was conducted under Ar at 70 C with 0.5 mmol of b 7a, 0.025 mmol of VI, 0.025 mmol of TMANO, 0.5 mmol of K2CO3 and 0.5 mL of solvent. Yield after 2 hours determined by 1H NMR analysis using 1,3,5-trimethoxybenzene as internal standard. c Reaction was run at room temperature. d Full conversion to product was observed after running the reaction overnight.

3.4 Reaction scope of the cyclization of -allenic sulfonamides Next, the substrate scope for the -allenic amides was investigated (Scheme 17). Similar trends were seen as for the -allenols. The electronic properties of the aryl group on the -allenic sulfonamides had little effect on the reaction and the corresponding N-mesylated 2,3-dihydropyrroles 8a-h were isolated in good to excellent yields. Aliphatic substrates could also be cyclized and the spirocylic pyrrole 8i was isolated in 96% yield. As with the -allenols, the prochiral variants of these substrates were also investigated and substrates with alkyl groups in the 2-position of the α-allenic sulfonamide gave rise to their corresponding diastereomeric 2,3-dihydropyrroles in good yield and were isolated as the trans diastereomers exclusively (8j-8l).

Scheme 17. Reaction scope for the cyclization of α-allenic sulfonamides. General reaction conditions: The reactions were conducted under Ar at 70 C with 0.5 mmol of 7, 0.025 mmol VI, 0.025 mmol of TMANO, 0.5 mmol of K2CO3 and 0.5 mL toluene for 16 h. a Yield was determined by NMR using 1,3,5-trimethoxybenzene as internal standard. Unless otherwise noted the yields given are isolated yields. b Isolated yield of the trans diastereomer. Stereochemistry was determined through NOE experiments.

3.5 Mechanistic study A reasonable way for the reaction to proceed would be through the intermediate formation of 2,5-dihydrofuran 9, which then isomerizes to 6a (Scheme 18). To determine whether this was the case, 9 was subjected to the optimized cyclization conditions for -allenols. 9 was found to be completely inert under these conditions and no formation of 6a was detected, ruling out that 9 is an intermediate in the reaction.

Scheme 18. Unsuccessful synthesis of 6a from 9.

26 To further elucidate the mechanism of the reaction, density functional theory (DFT) calculations were performed using 6a as a representative example (See Appendix A). On the basis of these calculations, the mechanism in Scheme 19 is proposed. The catalytic cycle begins with the coordination of 6a to VI′. The lowest binding mode is the coordination of the hydroxyl group to form Int-0, after the formation of which, the hydroxyl group is replaced by the terminal allene double bond to give Int-1, which is about 8.1 kcal/mol higher than Int-0. Once the terminal allene has been activated, cyclization occurs through an attack by the hydroxyl group, which is assisted by a second allenol molecule, via TS-1 (See Appendix A) to form Int-2. Once the vinylic iron Int-2 is formed, the bifunctional ligand facilitates the isomerization of Int-2 to Int-4 via iron carbene Int-3. Protodemetalation occurs next to give Int-5, and the catalytic cycle ends with dissociation of Int-5 to give the product and the regenerated VI′. TS-2 (between Int-2 and Int-3) is the rate-determining step (RDS) according to the calculations with an overall barrier of 20.9 kcal/mol, although the other steps (TS-1, TS-3 and TS-4) are all similar in energy, so the RDS cannot be confidently assigned solely on the basis of DFT calculations. The formation of the cis product goes through TS-2′ (See appendix A), where the protonation proceeds from the other face of the double bond. The energy of this transition state is about 1.8 kcal/mol higher than that of TS-2, and this energy difference corresponds to a d.r. of approximately 95:5, which fits well with the experimental results. Generation of the 2,5-dihydrofuran isomer, which proceeds through protodemetalation of Int-2, was also considered (See Appendix A). This protodemetalation is 5.7 kcal/mol higher in energy than the one in TS-2, which is consistent with the fact that the 2,5-dihydrofuran is not observed.

Scheme 19. Proposed catalytic cycle for the formation of 6.

The formation of 2,3-dihydropyrroles follows a similar trend as for 2,3-dihydrofurans (See Appendix B). One thing to note is that the calculations slightly underestimate the selectivity of the reaction. The calculated energy difference between TS-3 vs TS-3′ is 1.4 kcal/mol, which corresponds to a d.r. of 90:10, while the experimental result is that the trans product is exclusively formed. The binding is also slightly different. For allenols, the initial binding to the iron center is through the hydroxyl group which is then exchanged by the terminal allene double bond. Coordination of the nitrogen atom of the sulfonamide on the other hand, due to steric hindrance of the mesylate group, has an energy 1.9 kcal/mol higher compared to the alcohol and the direct coordination of the allene is therefore lower in energy. Another difference is in the cyclization step. For allenols, the nucleophilic attack of oxygen and the proton transfer occur in a concerted manner with the assistance of another allenol molecule, whereas for allenic sulfonamides these occur in a stepwise fashion.

28 The stabilization of TS-2 compared to TS-2′ in allenols (or TS-3 and TS-3′ for sulfonamides) and the resulting diastereomeric preference can be explained by the fact that in TS-2 there is a stabilizing interaction between the ortho hydrogen of the aryl group and the hydroxyl group of the catalyst. This is not possible in TS-2′ as the aryl group is oriented away from the ligand (Figure 7). This difference was calculated to be 1.8 kcal/mol and 1.5 kcal/mol for allenols and allenic sulfonamides, respectively, which fits well with the experimental stereochemical outcome.

Figure 7. Comparison of TS-2 and TS-2′ for 6k.

3.6 Conclusions

The diastereoselective iron-catalyzed synthesis of 2,3-dihydrofurans and 2,3-dihydropyrroles from functionalized allenes was developed. Benzylic and aliphatic allenes could be cyclized with this protocol in mostly excellent yields. When 1,2-substituted allenes were used, the cyclization proceeded diastereoselectively. The mechanism was investigated through DFT calculations, which showed that the bifunctionality of the cyclopentadienyl ligand played a key role. The diastereomeric preference was also rationalized through a stabilizing interaction between the ortho-hydrogen on the aryl ring of the substrate and the hydroxyl group on the bifunctional ligand, which is only possible in the transition state that leads to the trans product.

29 4. Iron(II)-Catalyzed Biomimetic Aerobic Oxidation of Alcohols (Paper IV)

4.1 Introduction One of the most important reactions in organic chemistry is the oxidation reaction and many industrially important chemical transformations involve oxidation steps. Since oxidation is a fundamental reaction class, many oxidation methods have been developed, but despite this, there is still a high demand for more selective, mild, efficient and scalable methods. 82 Particularly interesting are oxidative strategies used by living organisms.83 In these types of reactions, oxidants such as molecular oxygen (O2) and hydrogen peroxide (H2O2) are normally used and they are ideal for industrial processes due to their low cost and ecologically friendly nature. Directly oxidizing an organic substrate with H2O2 or O2, however, is challenging because of the large difference in oxidation potential between the oxidant and the substrate. The way that this problem is solved in Nature is through the application of an ensemble of enzymes and co-enzymes that act as catalysts and electron transfer mediators (ETMs), which lower the energy barrier for the electron transfer. These ETMs oxidize a substrate successively through a process called the electron transport chain (ETC), using O2 as the terminal oxidant. 84 This approach bypasses the high kinetic barrier associated with direct oxidation and replaces it with a series of smaller and more manageable steps. The biomimetic approach depicted in Scheme 20 has been successfully applied in our group in the past, most prominently using Ru-85 and Pd-catalysis86 amongst others.87 In one of these earlier studies, the use of Shvo′s catalyst (I) is detailed in the oxidation of sec-alcohols (Figure 4, vide supra).85a Since dimeric complex I dissociates into two monomers in solution at slightly elevated temperatures as explained in chapter 5 (papers II and III), we envisioned that VI, or one of its analogues, could facilitate a similar transformation. Fe(III) porphyrin complexes have been reported in somewhat similar biomimetic oxidation protocols,88 but no examples on the use of Fe(II) complexes exist.

Scheme 20. The biomimetic oxidation approach.

4.2 Screening of the reaction conditions The project began by determining which 1,4-benzoquinone (BQ) derivative was optimal under inert and stoichiometric conditions (Table 4). The only variant that was found to give more than one turnover was 2,6-dimethoxy-BQ (DMBQ) (entry 4).

Table 4. Optimization of the reaction with respect to the BQ-derivative.

GC yield 10 GC yield 30 GC yield 60 Entrya BQ-derivative min (%)b min (%)b min (%)b 1 BQ 5 5 5 2 Tetrafluoro BQ 3 4 4 2,6-dimethoxy-3- 3 4 5 5 methyl BQ 4 DMBQ 7 8 9 5 DDQ 4 4 5 6 Naphtoquinone 4 5 5 a General reaction conditions: The reaction was conducted under Ar atmosphere at 100 °C with 0.5 mmol of 10a, 0.6 mmol of BQ-derivative, 0.025 mmol of VI, 0.025 mmol of TMANO and 3 mL of toluene. b Yield was determined by GC analysis.

Since the oxidation of a more electron-rich alcohol requires a lower oxidation potential and is thus easier to achieve, the model substrate was switched to 1-(p-methoxyphenyl)ethanol (10b) and the catalyst loading was also increased to 10 mol%. After implementing these two changes, a

31 significantly higher yield was obtained (Table 5, entry 1). Since the aim of the project was to develop an aerobic oxidation reaction, we attempted to run the reaction in both air and pure O2 with cobalt complex IX (Scheme 20) as oxygen activator (entries 2-3). Switching from inert to aerobic conditions resulted in the expected oxidative deactivation of the catalyst, with the effect being more severe in pure O2. Next, several solvents were screened in the presence of air, with anisole giving the best result by far (entry 7). To demonstrate that VI was necessary for the reaction to proceed, a blank reaction without VI was performed, which as expected gave negligible yield of ketone product 11b (entry 8).

Table 5. Optimization of atmosphere and solvent.

GC yield GC yield GC yield Entrya Solvent Atmosphere 10 min 30 min 60 min (%)b (%)b (%)b 1c Toluene Ar 15 21 26 c 2 Toluene O2 7 7 8 3 Toluene Air 9 12 14 4 CPME Air 11 11 11 5d THF Air 8 8 8 6 2-Me THF Air 8 9 10 7 Anisole Air 40 44 47 8e Anisole Air 3 3 3 a General reaction conditions: The reaction was conducted at 100 °C with 0.5 mmol of 10b, 0.6 mmol DMBQ, 0.24 mmol of IX, 0.05 mmol of VI, 0.05 mmol of TMANO and 3 mL of solvent. b Yield was determined by GC analysis. c Without IX. d Run at 70 °C. e Blank reaction without VI.

32 The group of Funk reported dimethylphenyl-substituted (DMPh) catalyst derivative X to be more active in both the oxidation of alcohols and in the reduction of ketones and aldehydes. The reason for the increased activity was speculated to be due to its resistance to oxidative deactivation.89 We attempted to use X in our biomimetic oxidation next and this led to a significant improvement over to the use of VI (Table 6, entry 1).

Figure 8. DMPh catalyst X (DMPh = 3,5-dimethylphenyl).

The next step was to make the reaction catalytic with respect to IX, X and DMBQ. When the amounts of DMBQ and cobalt complex IX were reduced to those used in our previous ruthenium-catalyzed oxidation of alcohols,85a there was a significant drop in conversion (entry 2). Doubling the amounts of either X or DMBQ increased the conversion (entries 3-4), although when both were increased, only a marginal further increase in conversion was observed (entry 5). Changing the amount of IX did not affect the reaction rate (cf. entries 3 and 6). The conversion dropped significantly when the temperature was lowered to 80 °C (entry 7). Reducing the concentration of O2 from 21% to 2% did not affect the yield significantly (entry 8). To see if water affected the reaction, 2 equiv. of water were added which resulted in a slight loss in conversion (cf. entries 6 and 9). The inclusion of 4 Å molecular sieves did not lead to any observed improvement and in fact proved slightly detrimental (entry 10). By increasing the concentration twofold (from 0.17 M to 0.33 M), full conversion could be obtained after 1 hour (entry 11). The addition of 1 equiv. of K2CO3 did not affect the conversion but led to a more robust and easily reproducible procedure (entry 12).

33 Table 6. Optimization of the amounts of IX, X and DMBQ.

Amount of GC yield Amount of Amount of GC yield 60 Entrya DMBQ 10 min X (mol%) IX (mol%) min (%)b (mol%) (%)b 1 10 40 120 81 81 2 10 2 20 50 54 3 10 2 40 67 74 4 20 2 20 65 76 5 20 4 40 70 80 6 10 4 40 68 75 7c 10 4 40 18 41 8d 10 4 40 59 69 9e 10 4 40 58 64 10f 10 4 40 67 71 11g 10 4 40 81 >95 12 g, h 10 4 40 80 >95 a General reaction conditions: The reaction was conducted under air at 100 °C with 0.5 mmol b c d of 10b and 3 mL of anisole. Yield was determined by GC analysis. 80 °C. 2% O2 atmosphere. e Addition of 2 equiv. of water. f Addition of 4 Å molecular sieves. g Higher h concentration (0.33 M of 10b, 1.5 mL of anisole). Addition of 1 equiv. of K2CO3.

4.3 Substrate scope Once the reaction had been optimized, the next step was to investigate the substrate scope starting with substitutions on the aromatic ring. Benzylic sec-alcohols with neutral or electron-donating groups on the aromatic ring could be easily oxidized and gave the corresponding ketones in high yields (Scheme 21, 11a-11c). Electron-withdrawing groups on the other hand required higher catalyst loading and even then gave lower yields in the range of 60-80% (11d-11f). This impaired reactivity can be explained by the fact that electron-deficient benzylic alcohols are not as easily oxidized as their electron-rich counterparts. This lower reaction rate coupled with deactivation by O2, is what gives rise to the lowered yield. Surprisingly, the nitrile-substituted ketone 11f was isolated in 60% yield even though nitrile groups typically coordinate strongly to iron. Increasing the steric bulk, by using 10g led to some loss in yield and 11g was isolated in 70% yield. Alkyl-substituted alcohols could also be oxidized and 11i was obtained from

34 10i in 80% isolated yield. Oxidation of primary alcohols was investigated as well and these substrates were oxidized to their corresponding aldehydes 11k-11m, which were in most cases isolated in good to excellent yields. This stands in stark contrast to our previous work on the ruthenium-catalyzed biomimetic oxidation of alcohols, where aldehydes could not be obtained from primary alcohols due to disproportionation caused by Shvo’s catalyst.85a

Scheme 21. Substrate scope. General reaction conditions: The reaction was conducted under air at 100 °C with 0.5 mmol of 10, 0.05 mmol of X, 0.05 mmol of

TMANO, 0.2 mmol DMBQ, 0.02 mmol of IX, 0.5 mmol of K2CO3 and 1.5 mL of anisole. a Isolated yield. b NMR yield determined by using 1,3,5-trimethoxybenzene as internal standard. c 0.1 mmol (20 mol%) of X used.

35 4.4 Conclusions The first Fe(II)-catalyzed biomimetic aerobic oxidation of alcohols was developed, where electron transfer mediators were used to lower the energy barrier to ensure smooth electron transfer from substrate to O2. This electron transfer system is similar to the respiratory chain in living organisms and by using this biologically inspired method, various aldehydes and ketones could be efficiently prepared from their corresponding primary or secondary alcohols in good to excellent yields.

36 5. In Situ Investigations of the Deactivation Mechanism of a Heterogeneous Palladium(II) Catalyst During the Cycloisomerization of Acetylenic Acids (Paper V)

5.1 Introduction A common problem encountered in catalysis is deactivation of the catalytically active species, which can drastically reduce the TON or completely inhibit the reaction. Therefore, understanding the mechanisms of potential deactivation pathways is extremely important. Previously in the Bäckvall group, we have reported the synthesis of a heterogeneous Pd(II)-AmP-MCF catalyst, which has been applied in many different transformations,90,91 including the cycloisomerization of acetylenic acids.92 Although the Pd(II)-AmP-MCF was a highly efficient catalyst, it was found to lose its activity over subsequent catalytic cycles. Leaching was ruled out and therefore the most likely cause of the deactivation was the transformation of the active catalyst into a catalytically inactive species. Interestingly, treatment with BQ was found to restore the activity of the catalyst, suggesting that the cause of the deactivation was reductive in nature. To understand this phenomenon better, XAS studies were undertaken to monitor the change in the Pd species both during deactivation and reactivation. Two acetylenic acids, 5-hexynoic acid (12a) and phenylpent-4- ynoic acid (12b), were used in these cycloisomerizations. Both these reactions as well as reactivation by BQ were monitored in situ using XAS. The results obtained were invaluable for understanding the deactivation pathway as well as to design a strategy to bypass the deactivation. The Pd(II)-AmP-MCF catalyst has been studied previously by XAS and each Pd center was found to be bound to two aminopropyl groups of the catalyst support and two chlorides, which originate from the Pd source used 93 in the synthesis, Li2PdCl4. The in situ measurements were carried out using a custom-built reactor and the reaction conditions depicted in Scheme 22. All the data collected in this study was obtained at beamline P64 at the Petra III Extension, DESY, Hamburg, Germany. The data was collected with a

37 time resolution of ca. 6 min. The reactions were measured by in situ XAS and the recycled catalysts were measured using standard sample holders for powders. The XAS data was collected in transmission mode at the Pd K-edge with an energy range from 24.00 to 25.00 keV. A Pd foil was measured simultaneously and its first inflection point was used to calibrate the energy of the spectra.

Scheme 22. Pd(II)-AmP-MCF catalyzed cycloisomerization of acetylenic acids 12a and 12b to their corresponding lactones.

5.2 XAS Results The catalysts, which had been recycled after one reaction cycle with 12a (hereafter labelled recycled C1) and 12b (hereafter labelled recycled C2) were first measured ex situ. The XANES portions of the XAS spectra of C1 and C2 are shown in Figure 9, along with a Pd foil and unused Pd(II)-AmP- MCF as references for Pd(0) and Pd(II), respectively. The spectra shown in Figure 9 have clear differences. In C1, there is only a small change after the absorption edge compared with the unused Pd(II)-AmP-MCF, whereas for C2, the change is much more drastic and there is a strong resemblance to the Pd foil reference. From this it is clear that recycled catalysts C1 and C2 contain Pd species that are different both from each other and from those of the unused catalyst and that this difference is largely influenced by the choice of substrate. The absorption edges of recycled C1 and C2 are positioned in between the unused catalyst and the Pd foil which have oxidation states of +II and 0, respectively. This means that a partial reduction has taken place for both C1 and C2, with the effect being greater for C2.

Figure 9. Ex Situ Pd K-edge XANES spectra of unused Pd(II)-AmP-MCF, recycled C1 and C2 and a Pd foil reference.

To estimate the extent of reduction in the palladium species in C1 and C2, a linear combination fit (LCF) of the XANES spectra was performed (Figure 10). The XANES spectrum for C1 could not be fitted using only combinations of the Pd foil and Pd(II)-AmP-MCF. This indicates that there are other Pd species present, likely in the form of Pd(N/O)4 coordination. This conclusion is supported by principal component analysis (PCA), which showed that at least three species are required to describe C1. The conclusion of the LCF fit for C1 is that around 10% of the Pd atoms have been reduced to Pd(0). In contrast to C1, The XANES spectrum of C2 could be fitted well by 60% Pd foil and 40% Pd(II)-Amp-MCF, although the presence of a small amount of a third species cannot be ruled out. This confirms that a significant reduction has occurred in C2.

Figure 10. LCF of the Pd K-edge XANES spectra of (a) recycled C1 and (b) recycled C2. The XANES spectra of the Pd foil and unused Pd(II)-AMP-MCF were used as the references for Pd(0) and Pd(II), respectively.

39 The EXAFS spectra of recycled C1 and C2 were analyzed next. The Fourier transformed EXAFS spectra are depicted in Figure 11 and the refinement parameters are shown in Table 7. In the unused catalyst, there are two predominant peaks, which correspond to Pd–N and Pd–Cl (Figure 11a). For recycled C1, the Pd atoms were found to have about two N/O-ligands, with a mean distance of 2.03 Å. The bond distance of Pd-N/O and its Debye-Waller coefficients in both recycled C1 and the the unused catalyst are similar, which suggests that the aminopropyl ligand on Pd is unchanged on reaction of Pd(II)-AmP-MCF with 12a. On the other hand, the average number of Pd–Cl bonds decreases from 2.0 to 0.8 in the recycled C1 and this signal appears as a small shoulder in the main Pd-N peak at ca. 1.8 Å (without phase correction) in Figure 11b. The average Pd-Pd bond number is 0.5 and this signal, which represents single scattering, shows up at ca. 2.4 Å (without phase correction). The overall conclusion for C1 then is that the Pd centers primarily have amino ligands, and only a small fraction of them have formed metallic Pd aggregates. In addition, a significant amount of Cl− ligands have been removed from the Pd centers, with the average bond number being reduced from 2.0 to 0.8. In the case of recycled C2, the Pd-Pd signal at 2.74 Å is by far the most predominant signal and contribution from Pd-N/O was found to be minor (Figure 11c). This minor signal is most likely caused by oxidation of the surface of the Pd aggregates.

Figure 11. Fourier transformed k3-weighted EXAFS spectra of (a) unused Pd(II)- AmP-MCF and (b) recycled C1 and (c) recycled C2. The spectra are not phase corrected and the k ranges used to perform Fourier transform are 2–13, 2–10 and 2– 12 Å–1, respectively.

40 Table 7. Number of distances, N, mean distances, d (Å), and Debye-Waller 2 2 ퟐ coefficients, σ (Å ) and Many-body amplitude reduction factor, 푺ퟎ, are shown for the EXAFS studies of the catalyst under different conditions. The standard deviations in parentheses were obtained from k3-weighted least square refinement of the EXAFS function χ(k) and do not include systematic errors of the measurement. Underscored parameters were optimized from several trials and were fixed in the individual refinements.

2 2 ퟐ Samples Signal N d (Å) σ (Å ) 푺ퟎ Pd–N 2.0 2.023(2) 0.0035(3) 0.93(2) Pd(II)-AmP-MCF Pd–Cl 2.0 2.294(2) 0.0058(2)

Pd–N/O 2.0 2.034(4) 0.0032(7) 0.93(5) Recycled C1 Pd–Cl 0.8 2.337(5) 0.0035(9) Pd–Pd 0.5 2.72(1) 0.011(2)

Pd–N/O 0.5 2.07(3) 0.004(3) 0.92(4) Recycled C2 Pd–Pd 8.0 2.741(2) 0.0062(2)

Catalyst before addition Pd–N/O 1.0 2.05(1) 0.003(2) 0.92(8) of BQ (12b) Pd–Pd 7.0 2.734(3) 0.0042(6)

Catalyst after addition Pd–N/O 0.6 2.05(4) 0.002(6) 0.9(1) of BQ (reactivation, Pd–Cl 0.6 2.35(3) 0.004(4) 12b) Pd–Pd 7.0 2.726(5) 0.0064(8)

Catalyst after addition Pd–N/O 1.5 2.011(8) 0.002(2) 0.84(7) of BQ (prevention of Pd–Cl 1.5 2.303(6) 0.003(1) deactivation, 12b) Pd–Pd 1.5 2.731(6) 0.0075(7)

Transmission electron microscopy (TEM) was performed as well to further investigate the Pd aggregates (Figure 12a and b). In both recycled C1 and C2, Pd nanoparticles were found, although there was a considerable difference in the size of the particles, with C2 having much larger particles than C1. This difference in Pd particle size correlates with the bond lengths of the Pd–Pd determined by the EXAFS data (see Table 7). The average Pd-Pd bond distance would be expected to decrease with smaller particle size as there is a larger proportion of surface atoms in a smaller particle which have lower coordination numbers than the interior ones. 94 , 95 The EXAFS data in Figure 11b suggested however that these Pd aggregates were the minor Pd species in the recycled C1, meaning that there are Pd species in other forms than the nanoparticles visible in TEM for C1.

Figure 12. TEM images of the recycled C1 (a) and C2 (b), showing the Pd nanoparticles.

To further study the reaction, in situ XAS measurements were performed using unused Pd(II)-AmP-MCF along with substrates 12a and 12b individually. Before the in situ measurements were performed however, the effect of solvent on the catalyst had to be investigated. The XANES spectra of dry Pd(II)-AmP-MCF and Pd(II)-AmP-MCF suspended in toluene are compared in Figure 13. The spectra are identical, meaning that there is no change in the environment around Pd on solvation in toluene.

Figure 13. Pd K-edge XANES spectra of dry Pd(II)-AmP-MCF and Pd(II)-AmP-MCF suspended in toluene.

Once solvent interference was ruled out, the in situ measurements were initiated with both 12a and 12b and the XAS spectra were collected at 6 minute intervals (Figure 14 and Figure 15). In both cases, there is an

42 immediate change in the environment around Pd (Figure 14 and Figure 15, 6 min). The main difference between the two reactions is that in the case of 12a, there is no further change after this point and the spectrum matches well with the ex situ measurement of C1. The opposite was observed for 12b, where there was a continuous change over the course of the reaction. The features in the case of 12b are very similar to those of the ex situ spectrum of the recycled C2 after 31 min. Thus, the extent of Pd aggregate formation is much more pronounced when 12b is used and almost all of the Pd(II) is reduced to Pd(0), whereas for 12a there is no change after the initial 6 minute change.

Figure 14. Representative in situ Pd K-edge XANES spectra of Pd(II)-AmP-MCF during the cycloisomerization of 12a over time.

Figure 15. Representative in situ Pd K-edge XANES spectra of Pd(II)-AmP-MCF during the cycloisomerization of 12b over time

43 Next we focused on investigating the extensive reduction observed in the reaction with 12b, and on determining the identity of the reducing agent. A blank experiment was performed in which the unused Pd(II)-AmP-MCF was suspended in toluene together with 12b, but with neither triethylamine (TEA) nor BQ present. The mixture was heated to 50 °C before the data was collected. A slight edge shift towards lower energy being observed, but no significant reduction of the Pd occurred (Figure 16), suggesting that the substrate is not the cause.

Figure 16. Pd K-edge XANES spectra of the Pd(II)-AmP-MCF when mixing with toluene and 12b, and without TEA and BQ.

In the next experiment, TEA was slowly introduced to the reactor and the XANES spectra for this are shown in Figure 17. There is a clear gradual transformation into metallic Pd aggregates during the continuous introduction of TEA, which means that TEA clearly acts as a reductant.

Figure 17. Pd K-edge XANES spectra of Pd(II)-AmP-MCF when slowly introducing TEA into the reaction mixture.

44 Although the recycled catalyst C2 had been found to suffer from deactivation after one reaction cycle, it could be reactivated on exposure to BQ. To study this reactivation process, in situ XAS measurements were performed. The catalytic process using the recycled catalyst from reaction with 12b, before and after the addition of BQ was studied and the XANES and FT-EXAFS spectra are shown in Figure 18. On addition of BQ, the amplitude of the XANES spectra decreases, meaning that BQ most likely causes a decrease in the size of the Pd nanoparticles. The spectra also have features indicative of metallic Pd aggregates. The FT-EXAFS spectra before and after the addition of BQ are compared in Figure 18b-c. A small shoulder peak at ca. 1.9 Å (no phase correction) became more distinct after BQ was added. The EXAFS refinement shows that before the addition of BQ, only Pd–Pd and Pd–N/O signals are present in the first coordination shell of Pd (see Table 7). This observation indicates that the shoulder around 1.9 Å is due to Pd–Pd single scattering as shown in Figure 18b, although, Pd–Cl interactions would also be expected to have a similar distance (see Figure 11a). The appearance of the Pd–Pd single scattering satellite is due to the relatively short k range applied to perform the Fourier transform (2-10.5 Å−1), which had to be unified to facilitate the comparison of different spectra. The peak at ca. 1.9 Å is more pronounced in Figure 18c than in Figure 18b, which suggests an additional scattering signal other than the satellite peak from Pd–Pd single scattering. A single scattering signal corresponding to Pd–Cl was discovered through EXAFS refinement, and its average coordination number was determined to be ca. 0.6 (Table 7). A detailed discussion of the coinciding positions of the Pd–Cl distance and the Pd–Pd single scattering satellite peak can be found in a previous study. 96 Most importantly, this observation provides experimental evidence for the reactivation of C2 after catalyzing the cyclization of 12b. The function of BQ is to oxidize any Pd(0) species, which may have been formed during the reaction, back to Pd(II). The most likely scenario is that a portion of the surface atoms of the Pd aggregates become oxidized and bound to Cl− ligands again, which causes the restored catalytic activity.

Figure 18. Representative in situ Pd K-edge (a) XANES spectra of recycled catalyst from reaction with 12b, (b) Fourier transformed k3-weighted EXAFS spectra of the recycled catalyst from reaction with 12b before the addition of BQ and (c) after the

45 addition of BQ. The spectra in Figure 18b-c are not phase corrected and are Fourier transformed on the same k range, 2–10.5 Å–1.

From the understanding of the reaction gained through the XAS experiments, a strategy to prevent the transformation of Pd(II) complexes into Pd(0) aggregates was developed. Instead of adding BQ afterwards to reactivate the inactive metallic Pd aggregates, it was instead added in the beginning of the reaction and TEA was then introduced after the addition of BQ. The catalyst under these reaction conditions was measured by in situ XAS and the representative spectra are shown in Figure 19. When the catalyst was added to 12b, the edge shifted slightly towards a lower energy and the post-edge region of the spectrum changed slightly as well. Upon the addition of BQ, the edge position was essentially unchanged, while the region after the edge continued to change slightly and then ceased (Figure 19a). TEA was added next and the resulting XANES spectra are shown in Figure 19b. No changes occurred when TEA was added and no further formation of metallic Pd aggregates were detected. The Fourier transformed EXAFS spectrum of the catalyst after the addition of BQ is shown in Figure 19c and the refinement parameters are summarized in Table 7. The refinement confirmed that in addition to the Pd–N/O and Pd-Cl bonds, only a small component belonging to Pd–Pd bonds could be seen. It should be noted that these Pd aggregates are likely caused by 12b and not by TEA. These results show that the introduction of BQ in the beginning of the reaction can effectively prevent the reductive deactivation.

Figure 19. (a) Representative in situ Pd K-edge XANES spectra of Pd(II)-AmP-MCF after addition of substrate 12b and BQ and (b) Continued measurements of the XANES spectra from Figure 19a after the addition of TEA. (c) Fou- rier transformed k3-weighted EXAFS spectrum of Pd(II)-AmP-MCF after the addition of BQ. The spectrum in Figure 19c is not phase corrected and is Fourier transformed on the k range of 2–10 Å–1.

46 5.3 Recycling studies To further validate the XAS results, recycling studies of the reactions with 12a and 12b using Pd(II)-AmP-MCF were undertaken (Table 2). No significant loss of activity was observed when Pd(II)-Amp-MCF was used in the cyclization of 12a until after three cycles (Table 8, entries 1-5). This is in agreement with the XAS results discussed above which showed that C1 was only reduced to a small extent. However, on cyclization of 12b, the catalyst lost almost all of its activity after the first cycle (entries 6-7).

Table 8. Recycling of the catalyst with substrates 12a and 12b.

Entrya Substrate Cycle NMR Yield (%)b 1 12a 1 78 2 12a 2 74 3 12a 3 75 4 12a 4 26 5 12a 5 32 6 12b 1 42 7 12b 2 <5 a Reaction conditions: 0.4 mmol 12a or 12b, 0.08 mmol of TEA, 0.012 mmol of Pd(II)-AmP- MCF and 1 mL of toluene. b NMR yield was determined by using 1,3,5-trimethoxybenzene as internal standard.

In an attempt to compare the activities of recycled C1 and C2 after one reaction cycle with their respective substrates, they were used to cyclize a third substrate, 12c, in the absence of BQ and using the standard reaction conditions reported in our previous study.92 In this comparison, C2 had significantly lower activity than C1 (Table 9, entries 1-2). The recovered catalysts were then in each case stirred with 1 mol% of BQ before the start of the reaction, which fully restored their activity (entries 3-4). Additional experiments were also performed where 1 mol% of BQ was present from the beginning of the reaction (entries 5-6). In this case, no loss of activity was observed for either catalyst.

47 Table 9. Cycloisomerization of 12c using recycled C1 and C2.

Entrya Recycled cat. NMR Yield (%)b 1 C1 90 2 C2 77 3c C1 99 4c C2 95 5d C1 99 6d C2 99 a Reaction conditions: 0.4 mmol 12c, 0.08 mmol of TEA, 0.012 mmol Pd(II)-AmP-MCF and 1 mL toluene. b NMR yield was determined by using 1,3,5-trimethoxybenzene as internal standard. c 1 mol% of BQ used to reactivate the catalyst before the reaction.d 1 mol% of BQ added in the beginning of the reaction.

Since having 1 mol% of BQ from the beginning of the reaction was found to be best as shown in Table 9, the experiments in Table 9 were repeated using substrates 12a and 12b (Table 10). For 12a full conversion was observed for the first four cycles, and it was only in the fifth cycle that the activity slightly dropped and traces of 12a remained (entries 1-5). For 12b, the same positive effect was observed. Deactivation of the catalyst still occurred (entries 6-10), though to a significantly smaller extent than when BQ was omitted, where full deactivation was observed in the second cycle (Table 9, entries 6-7).

48 Table 10. Recycling of the catalyst with substrates S1 and S2.

Entry Substrate Cycle NMR Yield (%) 1 S1 1 >99 2 S1 2 >99 3 S1 3 >99 4 S1 4 >99 5 S1 5 95 6 S2 1 85 7 S2 2 82 8 S2 3 57 9 S2 4 41 10 S2 5 28 Reaction conditions: 0.4 mmol 12a or 12b, 0.08 mmol of TEA, 0.012 mmol of Pd(II)-AmP-MCF, 0.0004 mmol BQ and 1 mL of toluene. NMR yield was determined by using 1,3,5-trimethoxybenzene as internal standard.

There is a considerable difference between the sizes of the Pd aggregates in C1 and C2, and this difference is influenced by whether 12a or 12b is used as substrate as can be seen in the TEM images in Figure 12. The most likely reason for the difference observed is the differing coordination strength of the two alkyne functionalities in the substrates (which in one case is terminal and in the other internal). The phenyl-substituted alkyne in 12b is congested and therefore coordination to palladium is more difficult. On the other hand, the terminal alkyne moiety of substrate 12a is much less hindered and thus is able to form a stronger complex with palladium, which in turn protects the palladium from both reduction by TEA and aggregate formation.

49 5.4 Conclusions A mechanistic study on the cycloisomerization of acetylenic acids with a heterogeneous Pd(II) catalyst using XAS was carried out. With this technique, it proved possible to follow in situ changes in the oxidation states and coordination environments of the Pd species during the course of the reaction. These XAS studies also validated our hypothesis that the deactivation mechanism of the Pd(II)-AmP-MCF catalyst was due to the formation of catalytically-inactive Pd(0)-aggregates. Although TEA was found to be responsible for the reduction of the Pd(II)-centers, the rate and the extent of this reductive process were affected by the choice of acetylenic acid substrate. From the results obtained from these XAS studies, a method was developed for reactivating the catalyst. By adding 1 mol% of BQ at the beginning of the reaction, high catalytic activity could be maintained throughout subsequent catalytic cycles with complete suppression of the reductive deactivation. This study serves as a convincing example of how XAS can be used to study reactions with heterogeneous catalysts in real time, and how this technique can help with the development of more efficient catalytic protocols.

50 6. In Situ Structural Determination of a Homogeneous Ruthenium Racemization Catalyst and its Activated Intermediates Using X-Ray Absorption Spectroscopy (Paper VI)

6.1 Introduction To develop novel catalysts and catalytic processes, it is essential to have a thorough understanding of the activation mechanism. Typical problems encountered when investigating the activation mechanism of a transition metal complex are that the lifetime of the intermediates is short and that the probing methods used are indirect. In situ/operando XAS has predominantly been applied to heterogeneous catalysts (an example of which has been discussed in Chapter 5), and only a few examples of homogeneous metal catalysts have been reported.97 In the few reports that do exist, the focus is either on the X-ray absorption near edge structure (XANES) in an operando setup98 or on accumulated intermediates.99 Dicarbonyl (pentaphenylcyclopentadienyl) ruthenium chloride (XIa) is a transfer hydrogenation catalyst, which has been used for racemization in numerous DKRs of a variety of alcohols (Scheme 23). 100 Previous mechanistic studies proposed that the activation process for XIa proceeds through acyl intermediate XIIa,102e and in situ FT-IR spectroscopic measurements as well as low-temperature 13C-NMR supported this hypothesis.102f The first step of the proposed mechanism is the activation of XIa by t-BuOK to ruthenium-acyl complex XIIa, after the formation of which the t-BuO- displaces the chloride to form XIIIa, which is the active catalyst (Scheme 23).100a, 100f, 101 When alcohol substrate (S)-14 is added, it displaces the t-BuO- group on the Ru center through an alkoxide exchange, forming XIVa. For the oxidation of the alcohol ligand to occur, a vacant site must be generated on the Ru center and this was proposed to occur through CO dissociation on the basis of DFT calculations which was later confirmed by 13CO exchange studies.102g Once the CO has dissociated, β-hydride elimination takes place to form XV. Re-addition of the hydride can then happen from either face of the carbonyl, resulting in the formation of rac-XIV after which the product is released through alkoxide exchange,

51 finishing the catalytic cycle. The exact activation mechanism of catalyst XI and similar complexes has proven to be elusive and the subject of some debate.102

Scheme 23. Proposed mechanism for the racemization of sec-alcohols catalyzed by XI.

The purpose of this study was to perform in situ XAS measurements to investigate the local structure around the Ru center and confirm the formation of ruthenium-acyl complex XIIa. To this end, a temperature- and stirring-controlled in situ/operando reactor, which had previously been applied to investigate a heterogeneous catalyst in an operando study, was used.103,104

52 6.2 NMR and in situ IR studies Earlier mechanistic studies involving catalyst XIa as well as the in situ IR studies of acyl intermediate XIIa have only been performed in toluene.102f This is a problem for the in situ XAS measurements because the activation process in toluene is too fast for detecting a transient intermediate like XII. Complexes XIa-c have also been used in DKR studies in THF.105 Complex XIIa would be expected to be stabilized in this solvent due to its polar nature, leading to a slower activation process and a higher concentration of XIIa. Additionally, complexes XIa-c are more soluble in THF, which leads to a better signal in the XAS measurement. A high concentration of the catalyst is also required to get good signal-to-noise ratio when using the custom-made glass reactor in an in situ/operando XAS setup. To make sure that the change of solvent and concentration did not affect the activation process, in situ IR and 13C-NMR measurements were taken in THF and the same reactivity pattern was observed as for toluene (Figure 20a).102f The lifetime of intermediate XIIa (characteristic peak at 1933 cm−1) was found to be significantly increased in THF, with full conversion to XIIIa taking 2 hours to reach instead of 5 min in toluene. On addition of substrate (S)-14a, a slight blue-shift in the IR signal was observed as XIVa forms (Figure 20b).

Figure 20. a) In situ IR spectrum of the activation of XIa by t-BuOK in THF, focused on 2090–1912 cm−1 over time. b) In situ FT-IR graph of the activation of XIa after addition of substrate 1-phenylethanol ((S)-14a).

13 C-NMR experiments of the activation process of XIa in THF-d8 were also performed and the characteristic carbonyl peaks of XIIa were observed at 209.0 and 208.3 ppm. This observation rules out the possibility of the activation process proceeding through simple Cl- dissociation and the results gained from the 13C-NMR and the FT-IR studies of XIIa are not compatible with two equivalent CO ligands being present. Cl− dissociation could in

53 principle be detected through an XAS study of the Cl K-edge, 106 but unfortunately, this would require transmission experiments, which are run at concentrations that are incompatible with the reaction setup used here.107

6.3 XANES To further confirm that the environment around the Ru center in XIa is unperturbed on change of solvent, the XANES spectra of catalyst XIa in toluene and THF were compared and their features were found to be identical (Figure 21).

Figure 21. Parts of the XANES spectra of XIa in both toluene (dashed line) and THF (unbroken line).

The K-edge was observed at 22125 eV, meaning that the oxidation state of the Ru catalyst is +II. Neither during the activation nor catalysis does the edge energy change significantly, which suggests that the oxidation state of Ru remains unchanged during the process. 108 When t-BuOK is added, a slight edge shift of 0.6 eV towards lower energies occurs and subsequently disappears upon reaching the activated state, meaning that there is an instantaneous change to the environment around Ru, after which there is a gradual transformation towards something that resembles more the original catalyst (Figure 22).

Figure 22. Normalized XANES spectra of XIa dissolved in THF over the course of the activation process recorded after the addition of t-BuOK at 5 minute intervals (only selected spectra are shown for clarity).

This small edge shift on addition of t-BuOK is due to the transformation of one CO ligand into an acyl group, which decreases the amount of electron back-donation from the Ru and leads to a higher electron density around the Ru center. The XANES spectra of catalysts XIa, XIb and XIc are all very similar, which suggests that the substitution of the aryl ring on the ligand does not impact the local geometry around the Ru center (see Figure 23 for a comparison of XIa and XIb).

Figure 23. a) Normalized XANES spectra of XIa dissolved in THF during the course of activation recorded at 5 minute intervals after the addition of t-BuOK (the measurements were started within 1 min after the addition of t-BuOK) and after the addition of (S)-14a (added after 65 min) as substrate (dashed line). b) Normalized XANES spectra of XIb dissolved in THF, over the course of activation recorded every 5 minute intervals after the addition of t-BuOK (the measurements were started within 1 min after the addition of t-BuOK) and after the addition of (S)-14a (added after 50 min) as substrate (dashed line).

As mentioned before, an instantaneous change occurred in the XANES spectrum of XIa after the addition of t-BuOK. The larger peak around 22135 lowered slightly in intensity and shifted to a higher energy; however, the most prominent change is the almost instantaneous and complete disappearance of the peak around 22160 eV (Figure 23a, cf. spectra at 0 min and 5 min). This peak slowly reforms over the span of 45 min, but never regains its original intensity. The disappearance to this peak suggest that there is a radical change in the coordination environment of the Ru center (indicative of the transformation of XIa to XIIa) and the formation of a new peak at the same energy suggests that a complex with an environment that is more similar to the original catalyst is formed (cf. XIa and XIIIa). After 45 min, no further changes occur. After 65 min (S)-14a was added, which caused a minor shift in the peak at 22160 eV to higher energy (Figure 23a, dashed line), suggesting only a small change in the environment around the Ru center on addition of substrate which is consistent with the proposed transformation of XIIIa to XIVa. The exact same experiments were performed with the more electron-rich XIb (Figure 23b). The same trends were seen when using this catalyst, with the only notable difference being that the activation process is much faster, taking only about 25 min. When the electron-poor variant XIc was used, instantaneous change to XIIc was observed, but no further change occurred after that, with the spectra after 5 min and 24 h being virtually identical

56 (Figure 26b). Thus, XIc never achieves the fully activated form XIIIc. The conclusion that can be drawn after studying variants XIb and XIc is that the electronic nature of the Cp ligand plays a very important role in the activation process. The reaction rates for the activation processes of XIa and XIb were esti- mated using the intensity of the peak at 22160 eV in the XANES spectra (Figure 23a, vide supra). These values are only estimates however, since other geometrical changes can have an effect on the intensity, but since the activation mechanism is the same in both cases, a reasonable comparison can be made. Figure 24 shows the normalized intensity values of the XANES peak as a function of time. From this data, the half-lives of XIa and XIb were calculated to be 28 min and 6 min, respectively, meaning that the activation process of XIb is about 5 times faster than that of XIa.

Figure 24. Normalized intensity values measured at the characteristic peak at 22160 eV as a function of time during the course of activation of catalysts XIa and XIb.

57 6.4 EXAFS The coordination environment around Ru over the course of the activation was further investigated by analysing the EXAFS spectra. The Fourier transformed (FT) EXAFS spectrum of XIa dissolved in THF (Figure 25), shows no degree of difference compared to that of the solid structure, which shows that there is no change in the structure of the complex on solvation. The FT-spectrum of XIa in THF contains two main peaks and all the bond distances and Debye-Waller coefficients can be found in Table 11. The more prominent peak at around 1.8 Å (not phase corrected) corresponds to the bond distances of the 5 C atoms of the Cp ring, the 2 C atoms of the CO’s and the Cl coordinated to Ru. The refined bond distances for these are 1.906 Å, 2.240 Å and 2.436 Å, respectively. The second distinct peak around 2.5 Å (not phase corrected) corresponds to Ru∙∙∙O and Ru–C–O multiple scatterings (MS) of the linear CO ligands with the refined distances of the Ru∙∙∙O of the carbonyls being 3.045 Å. These MS events occur when the absorbing atom is in a linear or close to linear chain of atoms.109,110 The bond distances concluded from the EXAFS data fit well with the single crystal data of complex XIa reported in an earlier study.99 As mentioned above, the EXAFS spectra as a whole are shown in Figure 25a. The spectra were treated individually and only representative cases are shown in Figure 25b. As determined from the XANES discussion, after only 5 minutes the local structure around Ru undergoes a radical change (XIa 5 min in Figure 25a and b) and the overall intensity of the signal decreases. The intensity of the second main peak in particular drops dramatically. This peak corresponds to MS from CO ligands and the drastic drop in intensity suggests that the number of CO ligands had been reduced. There was a distinct separation between the two peaks before, which no longer exists in spectrum XIa 5 min, which suggests that a new signal has arisen around 2.7 Å. The best fit for these results has five Ru–C distances with an average distance of 2.269 Å, which corresponds to the Cp ring, one Ru–Cl bond with a distance at 2.346 Å, two Ru∙∙∙O distances of around 2.697 Å and two Ru–C bond distances of about 1.859 Å (Table 11). The interpretation of these results is that there is a hexa-coordination around the Ru centre which consists of one Cl, one CO, one acyl-ester and the Cp ligand (which has a hapticity of 5 and occupies three coordination sites on Ru), all of which fit well with the proposed intermediate XIIa. The Debye-Waller factors are not much larger than the ones for XIa, implying that there is one dominant species in the reaction system after 5 minutes and that there is only a very minor contribution from a second species. The Ru-Cl bond is significantly shortened when XIa and XIIb are compared (by 0.08 Å). The reason for this is that when a CO ligand is transformed into an acyl group, the back- donation to Ru is significantly reduced, which causes the Ru-Cl bond to shorten.

58 The main peak at around 1.8 Å shifts slightly to shorter distances over the course of the activation process and the peak around 2.5 Å, which corresponds to the CO distances, gradually rises in intensity as XIIIa is reached (XIa 55 min in Figure 25a and b). The best fit for these results for the active catalyst XIIIa corresponds to a coordination of a Cp ligand, two COs, and t-BuO- to Ru.

Figure 25. a) Fourier transformed EXAFS spectra of XIa dissolved in THF during the course of activation. b) Fourier transform of the EXAFS spectra of XIa dissolved in THF (XIa 0 min), and at 5, and 55 minutes after the addition of the t-BuOK (XIa 5 min, and XIa 55 min, respectively). c) Fourier transform of the EXAFS spectra of the activated catalyst XIa (XIa 55 min) and after the addition of 1-phenylethanol (XIa (S)-14). k-range 2 – 10 Å–1, no phase correction (ΔR ~ 0.5 Å).

The more electron rich catalyst XIb was also investigated and exhibited the same trends as XIa. Since the activation process for XIb is much faster than that of XIa, the first spectrum obtained is already a mixture of different species (Figure 26a, XIb 5 min). Because of this, a good fit can only be made by using several possible coordinating moieties, which include broken coordination numbers of the Cl ligand, the CO’s, the acyl-group and the t-BuO- group. The faster activation rate also means that the refined Debye-Waller factors are somewhat large, which is consistent with a fast reaction with multiple species. After reaching the activated complex XIIIb (Figure 26a, XIb 45 min), the process can be described with the same model as the one for catalyst XIa. The electron poor catalyst XIc is transformed immediately to XIIc (Figure 26b, XIc 5 min), but does not achieve the activated form XIIIc even after 24 hours.

Figure 26. a) Fourier transform of the EXAFS spectra of XIb dissolved in THF (XIb 0 min), and at 5 and 45 minutes after the addition of t-BuOK (XIb 5 min and XIb 45 min, respectively). The inset shows Fourier transform of the EXAFS spectra of the activated catalyst XIIIb (XIb 45 min) and after the addition of 1-phenylethanol (XIb (S)-14). The k-range is 2 – 10 Å–1, no phase correction (ΔR ~ 0.5 Å). b) Fourier transform of the EXAFS spectra of XIc dissolved in THF (XIc 0 min), at 5 minutes and 24 hours after the addition of t-BuOK (XIc 5 min and XIc 24 h, respectively), k-range 2 – 10 Å–1, no phase correction (ΔR ~ 0.5 Å).

60 Table 11. The k space fitted models for the Ru K-edge EXAFS measurement of catalyst XIa in THF at different stages during the reaction. Number of distances (N), mean distances (R/Å) and the Debye-Waller factor (σ2/Å2) are shown. Fitted parameters for the multiple scattering paths are omitted for the sake of clarity.

Structure Bond N R σ2

5 2.240(8) 0.0016(9) 2 1.906(5) 0.0018(6) XIa 2 3.045(6) 0.0062(5)

1 2.436(8) 0.0044(5)

5 2.269(11) 0.0089(9) a 2 1.859(12) 0.0125(18)

1 3.007(18) 0.0093(9) XIIa 2b 2.697(8) 0.00361(8)

1 2.346(6) 0.0062(9)

5 2.278(15) 0.0039(12) 2 1.894(5) 0.0057(7) XIIIa 2 3.025(12) 0.0086(4)

1 2.095(9) 0.0026(9) a It is not possible to distinguish between the two Ru-C bond distances. The value given is an average of the two. b It is not possible to distinguish between the two Ru-O distances. The value given is an average of the two.

61 6.5 Substrate addition

When substrate (S)-14a was added to the activated complexes XIIIa and XIIIb, the XANES spectra of XIVa and XIVb showed very similar features (Figure 23, vide supra, dashed lines), as did their respective Fourier transforms (Figure 25c and inset in Figure 26a). It became clear that an octahedral hexa-coordinated geometry is retained upon this alkoxide exchange. The best fit to the data involves coordination of the two CO ligands and the Cp ring, but the last coordination site cannot be assigned with certainty. Based on the XANES spectrum, it is most likely a loosely bound oxygen species, but the EXAFS contribution is on the level of noise. The fact that the alkoxide ligand of XIVa-c cannot be clearly identified implies that an equilibrium is established where the substrate molecules are rapidly exchanged.

6.6 Conclusions XAS was used to investigate the activation process of catalysts XIa-c and all the intermediate Ru species were identified. The structure of the key ruthenium-acyl intermediate XIIa, which had been proposed in earlier reports, was confirmed. It was found that the rate of activation depended strongly on the electronic nature of the Cp ligand, with the electron-rich variant XIb being activated fastest and the electron-poor variant XIc never reaching the activated state at all. When the substrate, (S)-14a, was added, a fast dynamic equilibrium was established between the two enantiomers of XIVa-b and ketone XV which resulted in poorly resolved spectra for these species and only average structures were obtained.

62 7. Summary

This thesis has explored many aspects of catalysis, mainly the application of organoiron catalysts in different organic transformations – DKR, cycloisomerization and biomimetic oxidation. It has also dealt with XAS studies of palladium- and ruthenium-catalyzed reactions. In the first project, an iron-catalyzed DKR of sec-alcohols was developed using catalyst VI. Different substituents with electron-poor or electron-rich properties as well as sterically hindered groups could be tolerated. Various enantiomerically pure acetates were isolated using this protocol and it was discovered that the addition of base was a key factor for promoting an efficient racemization. Both CALB and PS-C could be used as acylating agents and the procedure could be scaled up tenfold. The second and third projects describe the use of iron catalyst VI in the cycloisomerization of allenic alcohols and allenic sulfonamides giving 2,3- dihydrofurans and -dihydropyrroles, 2,3 respectively. Highly diastereoselective variants of these reactions were developed and the mechanisms were investigated through DFT calculations and deuterium labelling experiments. The reactions were postulated to proceed via a carbene intermediate and the bifunctionality of the catalyst was found to have a key role. The stereochemical outcome was rationalized through an attractive interaction between the hydroxyl group of the catalyst and the aryl substituent of the substrate. This interaction is only possible in the transition state that leads to the trans product. In the fourth project, iron catalyst X, a structural analog of VI, was used in the first reported Fe(II)-catalyzed biomimetic aerobic oxidation of alcohols. In this process, electron transfer mediators were used to lower the energy barrier to ensure smooth electron transfer from the substrate to O2, which is evocative of the respiratory chain in living organisms. By using this biologically inspired method, various aldehydes and ketones could be efficiently prepared from their corresponding primary or secondary alcohols in good to excellent yields. In the fifth project, a mechanistic XAS investigation was carried out on a heterogeneous palladium(II) catalyst used in the cycloisomerization of acetylenic acids. It was possible to follow changes to the oxidation states and coordination environments of palladium in situ over the course of the reaction. The earlier hypothesis that the deactivation was caused by Pd(0) aggregates was validated through these experiments and TEA was found to

63 be the cause of the deactivation through reduction of Pd(II), but the rate and extent of this reductive deactivation was found to be dependent on the acetylenic acid substrate. From the results obtained from these XAS studies, a reactivation strategy was developed in which a small amount of BQ was included from the start of the reaction to prevent this reductive aggregation. In the sixth project, XAS was used to obtain detailed structural information about a homogeneous ruthenium catalyst in an in situ operando system. The instantaneous formation of the proposed acyl intermediates XIIa-c, as well as the subsequent slow transformation into the activated alkoxide complexes XIIIa and XIIIb, were confirmed with these experiments. Rates of activation differed between the different catalyst variants and were found to dependent strongly on the electronic properties of the Cp ligand. For XIc, the activation process was seriously inhibited by the strongly electron-withdrawing character of the Cp ligand.

64 Appendix A: Calculated free energy profile for the formation of allenol 6k (energies are given in kcal/mol)

65 Appendix B: Calculated free energy profile for the formation of allenic sulfonamide 8j (energies are given in kcal/mol)

66 Appendix C: Contribution list

This thesis is in part built upon an earlier half-time report (defended in May 2019). Papers I-III were included in the half-time report. The author contributed to each paper as follows:

I. Performed half of the additive screening and substrate scope work with Karl Gustafson. Assisted with writing the paper.

II. Initiated the project. Performed half the experimental work with Karl Gustafson. Wrote most of the paper with Karl Gustafson.

III. Initiated the project. Performed half the experimental work with Karl Gustafson. Wrote most of the paper with Karl Gustafson.

IV. Initiated the project. Performed the majority of the experimental work with Kim Schlipköter. Wrote the manusript.

V. Performed half of the synthetic experimental work with Karl Gustafson. Wrote one of the beamline proposals with Ning Yuan. Did not do any calculations or fittings. Wrote part of the manuscript.

VI. Performed half of the synthetic experimental work with Karl Gustafson. Wrote one of the beamline proposals with Ning Yuan. Did not do any calculations or fittings. Wrote part of the manuscript.

67 Appendix D: Reprint Permissions

Reprint permissions were kindly granted for each publication by the following publishers:

V. Yuan, N.; † Guðmundsson, A.; † Gustafson, K. P. J.; Oschmann, M.; Tai, C.-W.; Persson, I.; Zou, X.; Verho, O.;* Bajnóczi, É. G.;* Bäckvall, J.-E.* Accepted Manuscript

68 Acknowledgements

My supervisor, Prof. Jan-Erling Bäckvall. Thank you for accepting me, first a masters student, and later as a Ph.D. student in your group. For the excellent teaching philosophy of allowing your students the academic freedom to pursue their own ideas, which is necessary to produce truly independent researchers.

Prof. Pher Andersson, for being my assistant supervisor, being interested in my work and taking the time to read through and correct this thesis.

Dr. Karl Gustafson, for all the heated arguments in the office, all the collaborations on our projects and for being a great person in general!

Dr. Ning Yuan, for the very enjoyable synchrotron time and for always being in a good mood, even despite the stress.

Dr. Daniels Posevins and Dr. Michael Oschmann for all the philosophical discussions and support, especially during the end of my Ph.D.

Dr. Bin Yang, a.k.a. Mike “the Bullet” Tomassi, for your supervision and support during my earlier masters studies, for encouraging me to pursue a Ph.D. and your collaboration on the allenol project.

Dr. Tamas Görbe for all the enjoyable conversations in the office and for teaching me all about lattes, scarves and the hipster life.

All of my co-workers and co-authors throughout my projects.

Past and present members of the JEB group that I’ve had the pleasure to meet and know: Karl Gustafson, Tamas Görbe, Bin Yang, Daniels Posevins, Michael Oschmann, Can Zhu, Jie Liu, Man-Bo Li, Weijun Kong, Srimanta Manna, Ramesh Veluru, Oscar Verho, Simon Hilker, Youai Qiu, Johanna Löfgren, Anuja Nagendiran, Tuo Jiang, Rickard Lihammar, Simon Kessler, Alexandre Bruneau, Teresa Bartholomeyzik, Kayla Lewis, Monica Schroll,

69 Ylva Wikmark, Debasis Banerjee, Javier Mazuela, Maria Humble, Patrick Federmann and all the others I’ve undoubtedly forgotten to mention.

All the past and present members of the office: Karl Gustafson, Tamás Görbe, Daniels Posevins, Michael Oschmann, Kim Schlipköter, Alexey Volkov, Fredrik Tinnis, Tove Slagbrand, Rabia Ayub, Srifa Pemikar, Viola Hobiger and Monireh Pourghasemi.

The students I had the pleasure to supervise: Alexander Ricke, Kim Elisabeth Schlipköter, Sara Palazzotto, Viola Hobiger and Florine Behra.

The administrative staff for keeping everything running so smoothly: Louise Lehto, Carin Larsson, Jenny Nilsson, Kristina Romare, Ola Andersson, Martin Roxengren, Gülsün Kücükgöl, Jonas Ståhle. Gabriella Ågren, Sigrid Mattsson, Petra Godin and Isabella Hagedorn.

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