Transfer Hydrogenation: Employing a Simple, in Situ Prepared Catalytic System

Home , Transfer hydrogenation

Transfer Hydrogenation: Employing a Simple, in situ Prepared Catalytic System

Thesis by

Eleanor Pei Ling Ang

In Partial Fulfillment of the Requirements

For the Degree of

Master of Science

King Abdullah University of Science and Technology

Thuwal, Kingdom of Saudi Arabia

Eleanor Ang Pei Ling

EXAMINATION COMMITTEE PAGE

The thesis of Eleanor Pei Ling Ang is approved by the examination committee.

Committee Chairperson:

Prof. Kuo-Wei Huang

Committee Members:

Prof. Jörg Eppinger

Prof. Zhiping Lai

ABSTRACT

Transfer hydrogenation has been recognized to be an important synthetic method in both academic and industrial research to obtain valuable products including alcohols.

Transition metal catalysts based on precious metals, such as Ru, Rh and Ir, are typically employed for this process. In recent years, iron-based catalysts have attracted considerable attention as a greener and more sustainable alternative since iron is earth abundant, inexpensive and non-toxic. In this work, a combination of iron disulfide with chelating bipyridine ligand was found to be effective for the transfer hydrogenation of a variety of ketones to the corresponding alcohols in the presence of a simple base. It provided a convenient and economical way to conduct transfer hydrogenation. A plausible role of sulfide next to the metal center in facilitating the catalytic reaction is demonstrated.

ACKNOWLEDGEMENTS

I would like to express my gratitude to my supervisor, Professor Kuo-Wei Huang, for his guidance, support, valuable insights and advice throughout the course of this research.

I would also like to acknowledge Prof. Jörg Eppinger and Prof. Zhiping Lai for their kind agreement to be part of my examination committee.

My appreciation also goes to all members in Pofesso Huag’s goup and KAUST

Catalysis Center (KCC) who have helped me in one way or another and for making my time at King Abdullah University of Science and Technology a great experience.

Finally, my heartfelt gratitude is extended to my husband for his patience, care and encouragement.

TABLE OF CONTENTS

Page

EXAMINATION COMMITTEE PAGE ...... 2

ABSTRACT ...... 3

ACKNOWLEDGEMENTS ...... 4

TABLE OF CONTENTS ...... 5

LIST OF ABBREVIATIONS ...... 7

LIST OF ILLUSTRATIONS ...... 8

LIST OF TABLES ...... 10

Chapter 1: Reduction of C=O ……………………………………….………………………..…………... 11

1.1 General Background on Transfer Hydrogenation .………………………………… 13

1.2 Developments in Transfer Hydrogenation ……..………..………….….…..………. 14

1.3 Ru-, Rh- and Ir- Catalyzed Transfer Hydrogenation …..………….………...….. 18

1.4 Iron-Catalyzed Transfer Hydrogenation ……..………..………….…..………….….. 24

Chapter 2: Iron-Based Catalytic System in Transfer Hydrogenation …….…..…….……. 31

2.1 Introduction .………………………………………..……………………………….….………….. 31

2.2 Results and Discussion …………………………………………………………………………… 33

2.2.1 Optimization of reaction conditions .…………….……………………….………….. 34 6

2.2.2 Control reactions ……….…….………..……………………………………………………... 37

2.2.3 Plausible role of sulfides ……….……………..…….………….………………….……... 38

2.3 Conclusion ………………………….………..……………………………………………………... 39

2.4 Experimental Section …………………..…………………………………………………….... 40

Chapter 3: Molybdenum-Based Catalytic System in Transfer Hydrogenation .……… 41

3.1 Introduction .………………………………………..………………………………….……….….. 41

3.2 Results and Discussion …………………………………………………………….….……….. 42

3.3 Using a Different Hydrogen Donor …….………………………………………….…….. 45

3.4 Scope of the Catalytic Transfer Hydrogenation ……………………….…….……… 45

3.5 Experimental Section …………………..…………………………………………………….... 47

Chapter 4: Mechanistic insights .…………………………………………………………………….…… 49

4.1 Introduction .………………………………………..……………………………….….………….. 49

4.2 Results and Discussion …………………………………………………………………………… 49

4.2.1 ReactIR .…………….…………………………………………….…………………….………….. 50

4.2.2 APCI-MS ……….…….………..…………………………………………………………………... 53

4.2.3 Proposed Mechanism ……….…….………..….…………………………………………... 58

4.3 Conclusion ………………………….………..……………………………………………………... 64

4.4 Experimental Section …………………..…………………………………………………….... 65

REFERENCES ...... 66

APPENDIX ...... 72 7

LIST OF ABBREVIATIONS

APCI Atmospheric Pressure Chemical Ionization ATR Attenuated Total Reflection DPEN 1,2-diphenyl-1,2-ethylenediamine FeS iron sulfide FeS2 iron disulfide GC Gas Chromatography h hour IR Infrared KOH potassium hydroxide m/z mass/charge Mes mesityl group MPV Meerwein-Ponndorf-Verley MS Mass Spectrometry MoS2 molybdenum disulfide NHC N-heterocyclic carbene NMR Nuclear Magnetic Resonance R organic substituent

LIST OF ILLUSTRATIONS

Scheme 1. A typical metal hydride reduction ...... 11

Scheme 2. A typical catalytic hydrogenation ...... 12

Scheme 3. Catalytic transfer hydrogenation using isopropanol as hydrogen source ..... 13

Scheme 4. Hydrogen transfer in Meerwein-Ponndorf-Verley reduction ...... 15

Figure 1. Catalytic cycle of ruthenium dihyride mediated transfer hydrogenation ...... 16

Figure 2. Tasfe hdogeatio ediated Sho’s atalst ………………………………..... 19

Figure 3. Selected examples of ruthenium-ased tasfe hdogeatio atalsts …... 21 Figure 4. Selected examples of rhodium-based transfer hydrogenation catalysts ...... 22

Figure 5. Selected examples of iridium-based transfer hydrogenation catalysts ...... 24

Figure 6. Ketone hydrogenation catalysts of Casey and Guan and Shvo with hydridic M-H and protonic O-H groups. ……………………………………………………………………………………...... 26

Figure 7. Repesetatie eaples of Gao’s goup PNNP ligads ad thei io complexes ...... 27

Scheme 5. Partial PNNP ligand reduction in the iron comple ……………………………...... 28

Figure 8. Aieiiediphosphie io oplees ……………………………………………...... 29

Figure 9. Iron-NHC complexes for transfer hydrogenation …………….………………….…...... Figure 10. Proposed mechanism for transfer hydrogenation of ketones catalyzed by Ru12 ………………………………………..………………………………………………………………………………... 32

Scheme 6. Formation of dearomatized iron complex in the pesee of a ase …...... 33 Scheme 7. Iron-catalyzed transfer hydrogen of cyclohexanone ...... 34

Figure 11. Kinetics of the transfer hydrogenation of cyclohexanone using the combination of iron disulfide with 6-amino-,’-bipyridie …………….………………….……... Scheme 8. Transfer hydrogenation of cyclohexanone using the combination of iron disulfide ith ,’-bipyridine ...... 38 Scheme 9. Transfer hydrogenation of cyclohexanone using the combination of molybdenum disulfide with 6-amino-,’-bipyridine ...... 42 9

Figure 12. Kinetics of the transfer hydrogenation of cyclohexanone using the combination of molybdenum disulfide with 6-amino-,’-bipidie .…………..…………... 43 Scheme 10. Transfer hydrogenation of cyclohexanone using the metal chloride salt ... 44

Figure 13. (a-d) Reaction spectra recorded at different time intervals for the: a) & b) iron-catalyzed transfer hydrogenation of cyclohexanone using 6-amino-,′-bipyridine ad ,′-bipyridine, respectively as the ligand, c) & d) reaction involving iron disulfide with 6-amino-,′-bipyridine and just 6-amino-,′-bipyridine, respectively without the substrate cyclohexanone. (e) Reference spectra for the solvent isopropanol and the ligand 6-amino-,′-ipidie dissoled i isopopaol. …………………………………………... Figure 14. APCI-MS analysis after the transfer hydrogenation using an in situ combination of 6-amino-,’-bipyridine with iron disulfide ………………………….…….……... 53 Figure 15. Possible iron species formed from aminobipyridine binding to the iron sulfide …………………………………………………………………………………………………………………………………… 54

Figure 16. Possile io die speies ……………………………………………………………………….. 54 Figure 17. Isotopic distribution centered around m/z = 259 in a) experimental and 2+ simulated mass spectra of b) the doubly charged dimeric species [M2+Fe2S2] and c) its corresponding monomeric species [M+FeS]+ ………………..…………………………….…………….. 56 Figure 18. Possible corresponding monomeric iron species from homolytic cleavage of the S-S bond during the ionization process ………………….……..……………………….…………….. 57

Figure 19. APCI-MS analysis after the reaction between iron disulfide with 6-amino-,′- bipyridine in the presence of the base, without the sustate ….……………………………….. 58 Figure 20. Proposed mechanism for catalytic transfer hydrogenation of ketone via the direct hydrogen transfer route .………………………………..…………………………………..…………... 60 Figure 21. Proposed mechanism for catalytic transfer hydrogenation of ketone via the hydridic route .……………………………………………………………………….……………………..…………... 62 Figure 22. A plausible mechanism for transfer hydrogenation of ketone mediated by the two iron centers connected by a disulfide idge .……………………………….………..…………... 63

LIST OF TABLES

Table 1. Optimization of reaction conditions for the transfer hydrogenation of cyclohexanone ...... 36

Table 2. Control experiments for the transfer hydrogenation of cyclohexanone …...... 38 Table 3. Control reactions for the transfer hydrogenation of cyclohexanone ...... 47

Table 4. Substrate scope for transfer hydrogenation of ketones using the iron- and molybdenum-ased atalti sstes …………………………….…………………………………...... 50

Chapter 1

Reduction of Carbonyl (C=O) Groups

The reduction of unsaturated compounds is one of the most fundamental transformations in organic synthesis, which is important at both laboratory and industrial levels.1,2 A wide span of reduction protocols have been developed for unsaturated compounds, however, this thesis will focus on the reduction of carbonyl compounds. The reduction of carbonyl compounds to alcohols is important for the production of many fine and bulk chemicals. Metal hydride reduction, direct hydrogenation and transfer hydrogenation are the three general methods that are employed to carry out this transformation.2

Traditionally, this transformation was performed using stoichiometric amounts of hydride reagents3 such as lithium aluminium hydride or sodium borohyride (Scheme 1).

Scheme 1. A typical metal hydride reduction

The hydride reagents are highly reactive and can be difficult to handle. Moreover, the metal hydride reduction generates stoichiometric waste as by-product, which must be 12 disposed of properly, making this method not environmentally and economical sustainable.

Clearly, the atom economy and sustainability of this reaction could be significantly improved by catalytic hydrogenation4 using molecular hydrogen (Scheme 2).

Scheme 2. A typical catalytic hydrogenation

Transfer hydrogenation5 has emerged as an alternative method to classic catalytic hydrogenation for the preparation of alcohols from ketones and to a lesser extent, aldehydes. Transfer hydrogenation has certain advantages over the alternative methodologies. As compared to the use of stoichiometric hydride reagents, the positive aspects are the use of cheaper and less hazardous reagents and minimization of stoichiometric waste can be achieved. Compared with the direct use of hydrogen gas, which involves risks and constraints associated with this reagent as well as the need for pressure vessels, the advantages are its operational simplicity, safety5,6,7 and that the hydrogen equivalent can be weighed. Hence, in recent decades, transfer hydrogenation has become the center of research in hydrogenation science.8

1.1 General Background on Transfer Hydrogenation

Transfer hydrogenation is defined as the reduction of multiple bonds with the aid of a hydrogen donor i the pesee of a atalst.7 The characteristic feature of a hydrogen donor is its two hydrogen that, in the presence of a suitable promoter, can be mobilized such that one of the hydrogen is transferred to the carbonyl oxygen as a proton and the other to the carbon as a hydride (Scheme 3).

Scheme 3. Catalytic transfer hydrogenation using isopropanol as hydrogen source

Theoretically, a hydrogen source can be any chemical compound whose hydrogen can be mobilized in such a way. For practical application, the two compounds that are commonly utilized as hydrogen donors for transfer hydrogenation are isopropanol and formic acid.9

With the use of isopropanol, a base like an alkali metal hydroxide or alkoxide is usually required as a promoter5,10 to extract the hydrogen from the donor. When isopropanol is used the hydrogen donor, upon transferring its two hydrogen, it becomes a hydrogen acceptor and competes with the substrate until equilibrium is reached.10 The reaction is reversible and under thermodynamic control. In order to shift the equilibrium towards the product side, a large excess of the hydrogen donor is needed. Hence, in this case, 14 isopropanol is commonly used as the solvent too. Isopropanol is easy to handle, environmentally benign, cheap, dissolves many substrates and is transformed into acetone after the transfer hydrogenation reaction, which can be readily removed.11

When formic acid is used as the hydrogen donor10,12, it is dehydrogenated to carbon dioxide, which makes the reaction irreversible and under kinetic control. In addition, a weak base such as triethylamine is sufficient to extract the hydrogen and the transfer hydrogenation reaction can be carried out under aqueous conditions. However, formic acid is not compatible for use with several catalysts due to the inherent acidity of formic acid. It may lead to decomposition of the catalyst upon dissolution or loss of catalytic activity as the acid inhibits the activation step of the starting complex promoted by the base.5,13

1.2 Developments in Transfer Hydrogenation

In the 1920s, Meerwein, Ponndorf and Verley reported that aluminium alkoxides were able to reduce ketones to the corresponding alcohols with isopropanol.14 The reduction occurs via a direct hydrogen transfer route, which proceeds through the formation of a cyclic six-membered transition state whereby the ketone and isopropanol are simultaneously coordinated to the metal center (Scheme 4).

Scheme 4. Hydrogen transfer in Meerwein-Ponndorf-Verley reduction14

Transfer hydrogenation became apparent to chemists as a useful process for the reduction of carbonyl compounds when this was established as a synthetic protocol. It is known as the Meerwein-Ponndorf-Verley (MPV) reduction. However, the drawbacks of the MPV reduction are the large amounts of the aluminum reagent required and undesired side products.15

The next milestone was the discovery that transition metal complexes could catalyze the transfer hydrogenation of ketones. Henbest, Mitchell and co-workers first reported the iridium-catalyzed reduction of cyclohexanones to alcohols in the presence of isopropanol in the 1960s.16 The seminal contribution by Sasson and Blum in the 1970s led to the development of transition metal-catalyzed transfer hydrogenation.17 They demonstrated that dichlorotris(triphenylphosphine)ruthenium(II) complex

[RuCl2(PPh3)3] was active for the transfer hydrogenation of α,β-unsaturated ketones.

This work was later improved by Chodhu ad Bäkall in the 1990s, when they found acceleration in the rate of the ruthenium-catalyzed transfer hydrogenation of aliphatic and aromatic ketones in the presence of a base as a co-catalyst.18 The effect of the base is ascribed to generating the highly active ruthenium dihyride species [RuH2(PPh3)3]. The 16

reaction of [RuCl2(PPh3)3] and the isopropanol hydrogen source in the presence of a base forms the metal isopropoxide via displacement of the chloride and subsequent β- elimination gives the ruthenium dihydride species, which is catalytically active for the transfer hydrogenation (Figure 1).19

Figure 1. Catalytic cycle of ruthenium dihyride mediated transfer hydrogenation19

For transition metal catalysts, the transfer hydrogenation generally occurs via the hydridic route, which involves a metal hydride intermediate. Depending on the number of hydrogen, one or two, that the intermediate species contains, the reaction pathway is via the mono- or dihydridic route.20 In the latter, the C-H and O-H hydrogen from the hydrogen donor lose their identity after being transferred to the metal to give the dihydride. In the former, only the C-H hydrogen of the donor is transferred to the metal 17 as a hydride while the O-H hydrogen of the donor stays a proton during the process and their identities are kept.

When the substrate is coordinated directly to the metal, the catalytic reaction proceeds through an inner sphere mechanism via alkoxide formation.21,22 Alternatively, it can take place through the outer sphere mechanism in which the hydrogen transfer occurs without coordination of the substrate to the metal. The ligand and metal interact and work together in activating the substrate through non-covalent interactions such as hydrogen bonding and dipolar interactions. Such cooperative effect is known as metal- ligand ifutioal atalsis.23-26

In the early 1980s, the first reports on ruthenium-catalyzed asymmetric transfer hydrogenation emerged.27 Enantiopure alcohols, which can be obtained from the asymmetric transfer hydrogenation of carbonyl compounds, are important intermediates in pharmaceuticals and agrochemicals. The seminal work by Noyori and co-workers using [RuClη6-arene)(TsDPEN)] in 1995, provided one of the most significant breakthroughs in this field.28 The presence of the N-H functionality was found to enhance the activity. The Ru-H/NH2 moiety played an essential role in the catalytic transfer hydrogenation process through a concerted delivery of a proton from N-H in the ligand and hydride from Ru-H via an outer sphere mechanism was proposed. This

oopeatie effet as oied Nooi as etal-ligad ifutioal atalsis.

Since then, research efforts have been focused on the development of transition metal catalysts containing chiral ligands for asymmetric transfer hydrogenation. 18

In the last two decades, the transfer hydrogenation as a synthetic tool for the reduction of ketones has steadily gained importance and it can now be considered a method of choice to accomplish this transformation.

1.3 Ru-, Rh- and Ir- Catalyzed Transfer Hydrogenation

Ruthenium-based catalysts are by far the most widely used to mediate transfer hydrogenation. In 1986, Sho’s goup29 reported the synthesis of the ruthenium complex 1, which was originally found to be very efficient in direct hydrogenation of ketones, was later applied in transfer hydrogenation reaction.30 The dinuclear complex 1 dissociates upon heating into the active reducing form 1’ and the coordinatively unsaturated and therefore, highly reactive species 1”. The complex 1’ operates through an outer sphere mechanism involving a simultaneous transfer of hydride from the ruthenium center and proton from the hydroxyl group on cyclopentadienyl ligand to the carbonyl group of the ketone substrate. 1” upon dehydrogenation of the hydrogen donor isopropanol, the active transfer hydrogenation catalyst is regenerated. This so-

alled Sho’s atalst as the fist epoted eaple of etal-ligand bifunctional

atalst. 19

Figure 2. Tasfe hdogeatio ediated Sho’s atalst30

A variety of half-sandwich ruthenium complexes containing cyclopentadienyl, arene or indenyl have been extensively investigated in transfer hydrogenation.8 The ruthenium phenylindenyl complex 2 was also studied in transfer hydrogenation and its catalytic activity was found to surpass that of the Sho’s catalyst in the reduction of benzophenone with an isopropanol/potassium hexamethyldisilazide system.31 Using 2, almost complete conversion was reached, whereas with 1, only 30 % conversion was achieved in the same time. A simple ruthenium bipyridine complex 2 was also highly active in the reduction of a variety of aromatic ketones (TOF 150,000 h-1 for 20 acetophenone) using potassium tert-butoxide as base in isopropanol.32 Interestingly, the ruthenium complex 3 bearing triazole-based scorpionate ligand was reported to be an effetie atalst fo the edutio of aetopheoe ad ’-nitroacetophenone under base-free conditions and it was proposed that decoordination of one triazole ring in the ligand facilitates the transfer hydrogenation by acting as a pendant base.33

Ruthenium complexes 4a and b with tridentate dipyrazolylpyridine NNN ligands were found to catalyze the transfer hydrogenation of of aryl ketones efficiently in the presence of potassium hydroxide at room temperature.34 An increase in catalytic activity was observed when n-butyl group was introduced in the 5-positions of the pyrazole rings. A ruthenium complex with similar NNN backbone was also reported and using the complex 5 bearing a 2-(benzoimidazol-2-yl)-6-(pyrazol-1-yl)pyridine ligand, transfer hydrogenation of ketones and aldehydes efficiently could be carried out at room temperature with 0.2 mol% catalyst loading.35 An NNC ligand constitutes another type of ruthenium complex 6, which was reported to be exhibit high catalytic activity in the transfer hydrogenation of a variety of ketones.36 In most cases, the ketone substrates reached more than 98 % conversion within one minute (TOF values up to 178,200 h-1) using 0.1 mol% of the ruthenium complex in isopropanol at reflux in the presence of a base. 21

Figure 3. Selected ruthenium-based transfer hydrogenation catalysts

Besides ruthenium, complexes based on rhodium and iridium are also typically employed in catalytic transfer hydrogenation. These metal complexes containing N, P,

O, S, C element-based ligands with various forms such as half-sandwich and multidentate metal complexes and also, metal-N-hetereocyclic carbenes are perhaps the most classic and popular catalysts for transfer hydrogenation.8

In rhodium-catalyzed transfer hydrogenation, the half-sandwich rhodium complexes are the most extensively used. The η5‐Cp*-rhodium complexes 8a and b bearing a bis(phosphine)amine PNP ligand catalyzed the transfer hydrogenation of substituted acetophenones in isopropanol at reflux with 94-99% conversions.37 The complexes 9a 22 and b were the first Rh species explored for transfer hydrogenation using glycerol as the solvent and hydrogen donor, which is cheap, non-toxic and biodegradable.38 They were found to be effective for catalytic transfer hydrogenation of ketones and aldehydes.

Complex 9a with the (Se, Se) ligand performed slightly better than complex 9b with the

(S, S) ligand.

A new tethered half-sandwich rhodium complex 10 containing TsDPEN was reported39, which showed excellent catalytic performance in terms of reactivity and selectivity for the asymmetric transfer hydrogenation of various ketones using formic acid/triethylamine mixture as the hydrogen donor. The corresponding alcohols were obtained under mild conditions with 68-99% yield and 70-99% ee.

Figure 4. Selected rhodium-based transfer hydrogenation catalysts

In the case of iridium, the iridium trihydride complex IrH3[(iPr2PC2H4)2NH] was reported to a highly effective catalyst for the transfer hydrogenation of ketones.40 Using only

0.001 mol% of this complex, acetophenone was converted to give the corresponding 23 alcohol in high yield. It was believed that its reactivity was attributed to the availability of the hydrogen on the nitrogen for concerted hydrogen transfer from both the N-H and

Ir-H to the ketone substrate. In iridium-catalyzed transfer hydrogenation, the iridium-

NHC complexes are one of the most outstanding examples.41 The family of N- heterocyclic carbene (NHC) ligands has gained popularity in coordination chemistry and organometallic catalysis, mainly due to their strong coordination ability as σ-donors, high stability and tunable steric and electronic properties. Nola’s group pioneered the use of transition-metal complexes bearing NHC ligands in transfer hydrogenation. The group applied a series of iridium complexes [Ir(cod)(py)(NHC)]PF6 and notably, the complex 8 with cyclohexyl substituent provided the best catalytic performance.42 It catalyzed the transfer hydrogenation of ketones, including pinacolone with low catalyst loading and short reaction time using isopropanol as the hydrogen donor in the presence of potassium hydroxide base. Catee’s goup epoted a e ai-stable and moisture sensitive iridium complex 9 containing a chelating bis(NHC) ligand which could carry out the transfer hydrogenation of ketones efficiently.43 For example, benzophenone was converted quantitatively to benzhydrol in just 4 minutes. This complex was also found to catalyze the transfer hydrogenation of aldehydes to primary alcohols.44 Several other iridium-NHC complexes41 have been successfully applied as catalysts for the transfer hydrogenation of ketones, including the interesting complex 10

epoted Roo’s goup45, whereby a cyclopentadienyl ring is tethered to the NHC.

This complex was used at low catalyst loading for the transfer hydrogenation of ketones, down to 0.01 mol% for cyclohexanone. 24

Figure 5. Selected iridium-based transfer hydrogenation catalysts

1.4 Iron-catalyzed Transfer Hydrogenation

As shown above, the use of transition metal catalysts based on second or third row transition metals, in particular Ru, Rh and Ir, has proven to be a powerful tool to perform transfer hydrogenation.8,46-48

However, the scarcity of these precious metals along with their high cost and significant toxicity makes it desirable to look for more economical and environmentally friendly alternatives. Therefore, development of new catalysts based on first row transition metals, which are abundant, cheap and less toxic, has attracted significant attention in recent years.49

In particular, iron offers significant advantages over precious metals. Iron is the second

ost audat etal i the eath’s crust and various iron sources are easily available and cheap. Moreover, iron compounds are relatively non-toxic. Iron is a biologically essential element50 present in a number of metalloproteins that play a role in a range of 25 physiological functions. For these reasons, the iron-catalyzed transfer hydrogenation has increasingly gained research interest.51-53

As early as 1985, Vancheesan’s goup used iron carbonyls as catalysts for the transfer hydrogenation of ketones to alcohols in a liquid-liquid biphasic system with the aid of

54 phase transfer agent. Among the three iron carbonyls used, Fe3(CO)12 worked the best.

Moderate yields of the corresponding alcohols were obtained. An induction period was

- observed and they proposed that iron carbonyl hydride [HFe3(CO)11] was the active species, which is formed from reaction of Fe3(CO)12 with the hydroxide ions of the base, liberating CO2 in the process.

Bianchini and co-workers reported that the cis-hydride dihydrogen iron complex

[FeH(H2){P(CH2CH2PPh2)3}]BPh4] could selectively reduce benzylideneacetone by hydrogen transfer from a secondary alcohol to give the allyl alcohol in 95% yield.55 The loss of dihydrogen from the starting complex creates a vacant coordination site for the incoming ketone. However, when other α,β-unsaturated ketones were tested, poor catalytic performance was observed.

More recently, Beller and co-workers used in situ prepared iron porphyrin catalysts, mimicking biologically occurring iron complexes for the transfer hydrogenation of

56 ketones. The combination of Fe3(CO)12 with porphyrin compounds such as tetraphenylporphyrin and tetrapyridyl porphyrin was utilized. The reaction was carried out at 100 °C and only worked best when a large amount of sodium isopropoxide base was applied. 26

Up to this point, the results obtained were encouraging but not yet competitive in terms of conversions and stereoselectivity of well-established Ru-, Rh- or Ir-based catalysts.

In 2007, Casey and Guan reported ketone hydrogenation using a well-defined iron complex57, which is structurally related to the well-known Shvo’s ruthenium catalyst30

(Figure 6).

Figure 6. Ketone hydrogenation catalysts of Casey and Guan57 (left) and Shvo30 (right) with hydridic M-H and protonic O-H groups.

The Shvo-type iron complex was found to be able to catalyze the transfer hydrogenation of acetophenone using isopropanol as the hydrogen donor.

Gao’s goup epoted that the first example of the iron-catalyzed asymmetric transfer hydrogenation of ketones in 2004, using a catalyst system generated in situ from mixing the iron carbonyl hydride complex [NHEt3][Fe3H(CO)11] with the tetradentate diaminodiphosphine PNNP ligands (Figure 7).58,59

Figure 7. PNNP ligands used Gao’s goup i the in situ formation of iron catalysts35

Well-defined and more active iron-based transfer hydrogenation catalysts were later

epoted Mois’ goup. In 2008-9, Mois’ goup deeloped a series of iron complexes containing the diimine version of the PNNP ligand.60-61 The iron complexes showed great catalytic performance when applied in the transfer hydrogenation of ketones in the presence of a base. In addition, the group published a study which revealed that activation of the complex trans-[Fe(CO)(Br)(Ph2PCH2CH=N−S,S)-

C(Ph)H−CPhH−N=CHCH2PPh2)][BPh4] in basic isopropanol led to reduction of one of the imine groups in the PNNP moiety due to addition of hydride from the isopropoxide

(Scheme 5). The resulting complex 10 with the half reduced, deprotonated ligand exhibited excellent catalytically activity for the transfer hydrogenation of acetophenone.62 28

Scheme 5. Partial PNNP ligand reduction in the iron complex63

Based on this finding, the synthesis of iron complexes 12a to c (Figure 8) bearing partially saturated PNNP ligand with both amine and imine functionalities was conducted. Using these complexes, the transfer hydrogenation could be performed under mild reaction conditions.63,64 The complex 12b gave the highest TOF of 152 s-1 in the reduction of acetophenone, while the complex 12c displayed the best enantioselectivity (90 % ee). A particularly interesting substrate is 3,5- bis(trifluoromethyl)acetophenone, which was reduced with TOF of 200 s-1 and 90% ee using the complex 12c to produce the corresponding (R)-alcohol, which is an intermediate for the synthesis of a neurokinin-1 receptor antagonist, Aprepitant that is useful for the treatment of chemotherapy-induced emesis65. These two iron complexes are among the most active catalysts known for the transfer hydrogenation of ketones and imines, comparable with successful precious-metal based catalysts. 29

Figure 8. Amine(imine)diphosphine iron complexes63,64

A completely new design of iron complexes based on N-heterocyclic carbene (NHC) ligands have been published in recent years. The iron-NHC complexes 13-17 (as shown in Figure 9) were found to be good catalysts for the transfer hydrogenation of ketones.66-68

Figure 9. Iron-NHC complexes for transfer hydrogenation66-68

In summary, global efforts in sustainability along with increasing prices and concerns over long-term supplies of precious metals have spurred interest in the area of iron catalysis. Iron-catalyzed transfer hydrogenation has led to promising results. In the near future, we can expect to see significant increase in the use of iron-based catalysts and real applications in industries. However, at the moment, a large number of the reported protocols use exotic iron complexes and expensive ligands. This overshadows the main objective of using iron-based catalysts. Therefore, the development of a truly sustainable protocol for transfer hydrogenation remains a challenge.

Chapter 2

Iron-Based Catalytic System in Transfer Hydrogenation

2.1 Introduction

Although transfer hydrogenation has been well-developed over several decades, there are still areas for improvement. In transition metal-catalyzed transfer hydrogenation, as we have seen, typically precious metals are employed, expensive metal precursors, ligands or multi-step synthesis are also involved.

Previously, in our group, a dearomatized PN3P ruthenium pincer complex was shown to have good catalytic reactivity for the transfer hydrogenation of ketones in the presence of a base.26 Notably, dearomatization of the pyridine ring in the ruthenium pincer complex was found to be important for the catalytic transfer hydrogenation to take place and dearomatization-rearomatization served as the driving force for the reaction

(Figure 10).

Figure 10. Proposed mechanism for transfer hydrogenation of ketones catalyzed by

Ru1227

Inspired by this dearomatization-rearomatization concept, we would like to see if we can apply this concept to carry out the transfer hydrogenation using a simple and cheap catalytic system. Catalytic systems generated in situ offer certain advantages over the isolated complexes since tedious synthesis and work up are not required. In this regard, catalytic system consisting of cheap, commercially available metal salt and ligand is undoubtedly attractive. Surprisingly, this has not been well utilized.

Herein, we focus on applying a simple, iron-based catalytic system consisting of cheap, commercially available iron salt and 6-amino-,’-bipyridine in the transfer hydrogenation reaction. Iron is a cheap alternative to precious metals but certain iron salts like the more commonly used Fe(BF4)2 is more expensive, hence we screen other iron salts in this work. The aminobipyridine with a N-H arm was used as the ligand to assist the dearomatization process (Scheme 6).

Scheme 6. Formation of dearomatized iron complex in the presence of a base

2.2 Results and Discussion

The catalytic activity of the iron-based catalytic system comprising 6-amino-,’- bipyridine with iron sulfides was first investigated using cyclohexanone as the substrate

(scheme 7). For the transfer hydrogenation reaction (as shown in scheme 3), in a typical experiment, cyclohexanone (1 mmol) was used as the starting material and isopropanol functions as both hydrogen donor and solvent. The reaction was carried out for 20 hours and the conversion of cyclohexanone was determined by Gas Chromatography-

Mass Spectrometry (GC-MS) analysis. 34

A base is usually needed when isopropanol is used as the hydrogen donor in order to activate the starting complex for catalysis, regardless of the nature of the catalyst.9,69,70

Scheme 7. Iron-catalyzed transfer hydrogen of cyclohexanone

2.2.1 Optimization of reaction conditions

The reaction conditions were optimized using iron disulfide or sulfide (1 mol% with respect to the substrate) as the metal precursor and 6-amino-,’-bipyridine (1 mol% with respect to the substrate) as the ligand by varying parameters such as the amount of potassium hydroxide (KOH) as the base (2, 5 and 10 mol% with respect to the substrate), temperature (40 °C, 60 °C and 80 °C). In addition, we also tested it with the iron chloride salt and the results are summarized in Table 1.

Table 1. Optimization of reaction conditions for the transfer hydrogenation of cyclohexanone

Entrya Fe salt Base (mol%) Temperature (°C) Conversionb (%)

1 FeS2 2 80 22

2 FeS 2 80 36

3 FeS2 5 80 33

4 FeS 5 80 49

5 FeS2 10 80 >99

6 FeS 10 80 74

7 FeS2 10 40 2

8 FeS2 10 60 29

9 FeCl2 10 80 40

a Reaction conditions: ketone (1 mmol), Fe salt (1 mol%), 6-amino-,’-bipyridine (1 mol%), 2-

propanol (2 mL), under argon. bDetermined by GC-MS analysis.

Therefore, the optimal reaction condition was to use iron disulfide as the metal precursor in the presence of 10 mol% of base (KOH) at 80 °C.

Notably, when iron dichloride was used as the metal salt, the conversion dropped significantly. This suggests a plausible role of sulfides in facilitating the transfer hydrogenation reaction. 36

Under the optimized reaction conditions, samples were taken periodically from the reaction mixture and analyzed by GC-MS to monitor the progress of the catalytic reaction over time. The results are plotted as shown in Figure 11.

100 90 80 70 60 50 40

Conversion (%) Conversion 30 20 10 0 0 2 4 6 8 10 12 14 16 18 20 Time (h)

Figure 11. Kinetics of the transfer hydrogenation of cyclohexanone using the combination of iron disulfide with 6-amino-,’-bipyridine

Since complete conversion was achieved after 20 hours, this is set as the optimized reaction time.

2.2.2 Control Reactions

Control experiment with the iron disulfide (1 mol%) alone under similar reaction conditions was conducted. In addition, the transfer hydrogenation was carried out with just the aminobipyridine ligand (1 mol%). In order to exclude known base-catalyzed71,72 transfer hydrogenation of ketones, a control experiment with only the base KOH was also performed. The results are summarized in Table 2.

Table 2. Control experiments for the transfer hydrogenation of cyclohexanone

Entrya Metal precursor Ligand Yieldb (%)

1 FeS2 - 38

2 -  30

3 - - 26

4 FeS2  92

aReaction conditions: ketone (1 mmol), KOH (10 mol%), 2-propanol (2 mL), 80 °C, under

argon, for 20 h. bDetermined by GC-MS analysis.

Based on the above results, it is evidently clear that presence of the ligand is critical in achieving the needed catalytic activity. The percentage yield obtained was high when iron disulfide was combined with the ligand. This may be explained by the chelating bipyridine ligand binding to the iron disulfide, thereby stabilizing and increasing the solubility of the iron disulfide during the transfer hydrogenation, aiding this process. 38

Indeed, our strategy indeed worked. A simple, iron-based catalytic system generated in situ from the combination of iron disulfide and 6-amino-,’-bipyridine, in the presence of a simple base, was found to be effective for the transfer hydrogenation of cyclohexanone with isopropanol as the hydrogen donor.

2.2.3 Plausible role of sulfides

In order to determine if dearomatization-rearomatization was the driving force for the transfer hydrogenation as we proposed, the ligand was replaced. Instead of 6-amino-

,’-bipyridine, ,’-bipyridine was used (Scheme 8).

Scheme 8. Transfer hydrogenation of cyclohexanone using the combination of iron disulfide with ,’-bipyridine

When ,’-bipyridine was used as the ligand, which has no amino group to assist dearomatization of the pyridine ring, almost complete conversion of cyclohexanone to cyclohexanol was obtained too. This result suggests that using iron disulfide as the metal precursor for the transfer hydrogenation, dearomatization-rearomatization is not 39 needed for the reaction to occur or the condition does not allow dearomatization- rearomatization to take place.

A bipyridine ligand could simply aid the transfer hydrogenation by binding to the iron disulfide and increase the solubility of the iron disulfide through complexation. More importantly, the sulfides play a plausible role in facilitating the transfer hydrogenation reaction, as mentioned earlier in Section 2.2.1. In addition, in Section 2.2.2, we see that both the iron disulfide and bipyridine ligand are essential to achieve a good catalytic reactivity. Based on these results, the importance of both the metal disulfide and a chelating bipyridine ligand to drive the catalytic transfer hydrogenation is highlighted.

2.3 Conclusion

In conclusion, an in situ prepared catalytic system using the combination of iron disulfide and a chelating bipyridine ligand was found to be effective for the transfer hydrogenation of cyclohexanone in the presence of a simple base. For such a catalytic system, dearomatization-rearomatization is not needed for the transfer hydrogenation to occur. However, this suggests that the dearomatization-rearomatization is more pronounced in the pincer system. Nevertheless, it provided a convenient and economical way to conduct transfer hydrogenation. The presence of both the iron disulfide and bipyridine ligand was essential to achieve a good catalytic reactivity. The chelating bipyridine ligand could aid in the transfer hydrogenation process by binding to 40 the iron disulfide, thereby stabilizing and increasing the solubility of the iron disulfide in the reaction mixture. In addition, the sulfides next to the metal center play a plausible role in facilitating the catalytic reaction.

2.4 Experimental Section

FeS2 (99.8% trace metals basis) and FeCl2 (98%) were purchased from Sigma-Aldrich. FeS

(99% Fe on metal basis) was from Strem Chemicals. KOH (99.99%) was bought from Alfa

Aesar. Isopropanol (99.8 %) was purchased VWR Chemicals. The ligands were commercially available. All chemicals were used without further purification.

GC-MS data were acquired using an Agilent 7890A GC system connected to an Agilent

5975C mass spectrometer with a triple-axis detector, using an Agilent HP-5MS capillary column (30 m x 250 µm x 0.25 µm).

A typical procedure for the catalytic transfer hydrogenation: FeS2 (0.01 mmol, 1 mol%),

6-amino-,’-bipyridine (0.01 mmol, 1 mol%), potassium hydroxide (0.1 mmol, 10 mol%), ketone (1 mmol) and isopropanol (2 mL) were added into a Schlenk flask under argon atmosphere. The reaction mixture was stirred and heated for specified time at 80

°C (oil bath temperature). After this period, a sample was taken, diluted with dichloromethane, passed through a short plug of silica and subjected to GC-MS analysis to determine the conversion and yield of the reaction. 41

Chapter 3

Molybdenum-Based Catalytic System in Transfer Hydrogenation

3.1 Introduction

With the success of the iron-based catalytic system, we would like to see if we can apply the same protocol to other metal disulfide.

While most of the inexpensive, abundant transition metals are from the first row of the periodic table, molybdenum, which is from the second row, is an exception as it is much less expensive than precious metals.49 In transfer hydrogenation of ketones, the number of examples reported using molybdenum catalysts for the transfer hydrogenation reaction so far is limited.73,74 Herein, it provided an opportunity to develop a new catalyst system based on molybdenum.

In this work, we examined the reactivity of a simple, molybdenum-based catalytic system consisting of commercially available molybdenum disulfide and 6-amino-,’- bipyridine in the transfer hydrogenation reaction.

3.2 Results and Discussion

The catalytic activity of the molybdenum-based catalytic system consisting of molybdenum disulfide and 6-amino-,’-bipyridine was first investigated using cyclohexanone as the substrate for the transfer hydrogenation reaction (as shown in scheme 9).

Scheme 9. Transfer hydrogenation of cyclohexanone using the combination of molybdenum disulfide with 6-amino-,’-bipyridine

Indeed, we were delighted to see that the molybdenum-based catalytic system worked as well. To compare the catalytic activity of the molybdenum-based catalytic system with that of the iron, samples were taken periodically from the reaction mixture and analyzed by GC-MS. The results are plotted as shown in Figure 12.

100 90 80 70 60 50 40

Conversion (%) Conversion 30 20 10 0 0 2 4 6 8 10 12 14 16 18 20 Time (h)

Figure 12. Kinetics of the transfer hydrogenation of cyclohexanone using the combination of molybdenum disulfide with 6-amino-,’-bipyridine

Using the molybdenum-based catalytic system, the transfer hydrogenation of cyclohexanone proceeded faster as compared to that of the iron.

A control experiment with molybdenum disulfide (1 mol%) alone under similar reaction conditions was conducted and the result is shown in Table 3.

Table 3. Control reactions for the transfer hydrogenation of cyclohexanone

Entrya Metal precursor Ligand Yieldb (%)

1 MoS2 - 39

2 -  30

3 - - 26

4 MoS2  93

aReaction conditions: ketone (1 mmol), KOH (10 mol%), 2-propanol (2 mL), 80 °C, under

argon, for 20 h. bDetermined by GC-MS analysis.

From the table above, we note that the presence of the ligand is important to achieve a good catalytic reactivity for the transfer hydrogenation of cyclohexanone, like in the case of iron. This can also be explained by the chelating bipyridine ligand aiding the transfer hydrogenation process through binding to the molybdenum disulfide, thereby stabilizing and increasing its solubility in the reaction mixture.

To further investigate, molybdenum disulfide was replaced with the chloride salt, molybdenum pentachloride and the transfer hydrogenation was carried out under the same reaction conditions (Scheme 10).

Scheme 10. Transfer hydrogenation of cyclohexanone using the metal chloride salt 45

When molybdenum pentachloride was used as the metal salt instead, the conversion dropped significantly to 37%. Hence, we suspect that the sulfides next to the metal play a plausible role in facilitating the transfer hydrogenation reaction.

3.3 Using a Different Hydrogen Donor

For further investigation, formic acid/triethylamine was used in place of isopropanol as the hydrogen donor. The transfer hydrogenation was performed with varying ratios of triethylamine: formic acid (1:1, 5:2) in different solvents (toluene and acetonitrile).

However, no conversion of cyclohexanone to cyclohexanol was observed. The loss of catalytic activity may be due to the acid inhibiting the activation step promoted by the base.12 The presence of the base KOH could indeed be essential for the in situ formation of the active catalyst and for promoting the catalytic transfer hydrogenation reaction.

3.4 Scope of the Catalytic Transfer Hydrogenation

Next, aliphatic and aromatic ketones were used as substrates to investigate the scope of both the iron- and molybdenum-based catalytic systems in the transfer hydrogenation reaction and the results are summarized in Table 4.

Table 4. Substrate scope for transfer hydrogenation of ketones using the iron- and molybdenum-based catalytic systems

Entrya Substrate Product Conversionc (%) Yieldc (%)

1 >99 92

2b >99 93

3 >99 95

4b >99 95

5 88 86

6b 89 87

7 98 94

8b 98 94

9 97 87

10b 98 88

11 80 75

12b 80 76

a Reaction conditions: ketone (1 mmol), FeS2 (1 mol%), 6-amino-,’-bipyridine (1 mol%), KOH (10

b c mol%), 2-propanol (2 mL), 80 °C, under argon, for 20 h. MoS2 was used. Determined by GC-MS

analysis. 47

Both the iron- and molybdenum-based catalytic systems were found to be effective for the transfer hydrogenation of aliphatic and aromatic ketones. Among the substituted aromatic ketones, those having electron-withdrawing F, Br substituents (entries 7 to 10) gave high product yields while that having electron-donating methyl substituent (entries

11 and 12) produced lower yield. This can be explained by the presence of an electron- withdrawing substituent which decreases the electron density on the carbonyl group of the ketone, making it more susceptible to undergo reduction.

3.5 Experimental Section

FeS2 (99.8 % trace metals basis) and MoS2 (99 %) were purchased from Sigma-Aldrich.

KOH (99.99 %) was bought from Alfa Aesar. Isopropanol (99.8 %) was purchased VWR

Chemicals. The ligand is commercially available. All chemicals were used without further purification.

GC-MS data were acquired using an Agilent 7890A GC system connected to an Agilent

5975C mass spectrometer with a triple-axis detector, using an Agilent DB-WAX capillary column (60 m x 250 µm x 0.25 µm).

A typical procedure for the catalytic transfer hydrogenation: MoS2 (0.01 mmol, 1 mol%),

Chapter 4

Mechanistic insights

4.1 Introduction

As reviewed in Chapter 1, transfer hydrogenation may proceed by two different reaction pathways, namely, the direct hydrogen transfer and the hydridic route. In Chapter 2, we noted that in the transfer hydrogenation, the presence of both the iron disulfide and bipyridine ligand was essential to achieve a good catalytic reactivity. The chelating bipyridine ligand could aid in the transfer hydrogenation process by binding to the iron disulfide, thereby stabilizing and increasing the solubility of the iron disulfide in the reaction mixture. The sulfides next to the metal center play a plausible role in facilitating the catalytic reaction. In Chapter 3, we see that a simple, cheap iron-based catalytic system was effective for the transfer hydrogenation of a variety of ketones using isopropanol as the hydrogen donor in the presence of a base.

4.2 Results and Discussion

In order to determine the structure of the iron complex formed, equimolar amounts of iron disulfide and 6-amino-,’-bipyridine were reacted together in different solvents

(tetrahydrofuran, acetonitrile and methanol) without and in the presence of KOH and 50 also, without and with heating. However, preliminary attempts to isolate the iron complex were not successful, perhaps due to the limited solubility of iron disulfide or that the iron complex formed may not be stable enough to isolate.

In light of the success of the in situ prepared iron-based catalytic system, we would like to probe how the metal and ligand work together to catalyze the transfer hydrogenation, the possible intermediate involved and study the plausible role of the sulfides. Since iron is paramagnetic, instead of Nuclear Magnetic Resonance (NMR), the transfer hydrogenation of cyclohexanone with isopropanol as the hydrogen donor using the iron-based catalytic system (refer to Scheme 7 and 8) was studied in situ by

Attenuated Total Reflection-Infrared (ATR-IR) spectroscopy using a ReactIR spectrometer.

4.2.1 ReactIR

The combination of iron disulfide with 6-amino-,’-bipyridine was used first to study the catalytic transfer hydrogenation in situ using a ReactIR probe.

Legend ______At the start 5h 10 h 15 h 20 h ______Ref: Isopropanol Ref: 6-amino-2,2′-bipyridine dissolved in isopropanol

Based on the ReactIR spectrum obtained (Figure 13 a), it can be seen that as the reaction progresses, the peak at 1708 cm-1, which belongs to the C=O stretch of the substrate cyclohexanone gradually disappears and a peak at 1715 cm-1 belonging to the

C=O stretch of acetone appears. The peak remained nearly unchanged after 18 hours.

This showed that transfer hydrogenation had taken place. Simultaneously, a peak around 1560 cm-1 appeared and increased quickly at the beginning. We hypothesize that this is associated with the C=N stretch of the bipyridine ring in 6-amino-,’-bipyridine when it is attached to iron. The catalytically active species may be forming as the reaction proceeds. When the transfer hydrogenation reaction was performed the same way with ,’-bipyridine instead, a similar trend was observed in the ReactIR spectrum

(Figure 13 b).

To test our hypothesis, iron disulfide and the aminobipyridine were reacted together under the same reaction condition, without just the substrate cyclohexanone. From the

ReactIR spectrum obtained (Figure 13 c), we see the peak around 1560 cm-1 at the beginning and this peak decreased quickly with time. This observation can be explained by the iron bipyridine complex first forming but since there is no substrate to react with, it becomes the inactive species and the peak disappears. In addition, when the aminobipyridine was reacted with the base KOH in isopropanol, in the absence of iron disulfide, the peak around 1560 cm-1 was not observed in the ReactIR spectrum 53 obtained (Figure 13 d). It was only seen when both iron disulfide and the biyridine ligand were present in the reaction mixture. Based on the results, the absorption peak around

1560cm-1 most likely belongs to C=N stretch of the bipyridine ring when it is coordinated to iron, generating the iron bipyridine complex in situ for the transfer hydrogenation.

However, the results were not conclusive. In order to gain further insights into the iron- catalyzed transfer hydrogenation, after the catalytic reaction, a sample was taken from the reaction mixture and analyzed by Atmospheric Pressure Chemical Ionization-Mass

Spectrometry (APCI-MS).

4.2.2 APCI-MS

APCI-MS analysis was used as a tool to explore the possible structure of the intermediate formed from mixing the metal disulfide with the bipyridine ligand.

[M+H]+ = M

Figure 14. APCI-MS analysis after the transfer hydrogenation using an in situ combination of 6-amino-,’-bipyridine with iron disulfide 54

At first, we postulate that the possible iron species formed could be [M+FeS+H]+, whereby the aminobipyridine binds to the iron sulfide (as shown in Figure 15).

Figure 15. Possible iron species formed from aminobipyridine binding to the iron sulfide

However, for this singly charged species, the m/z value is 260, which does not match the observed value exactly (Figure 14). Hence, instead of the monomer species, we look at the possibility of an iron dimer species that is doubly charged.

Figure 16. Possible iron dimer species

2+ The doubly charged dimer [M2+Fe2S2] (as shown in Figure 16) has the m/z value of 259, which corresponds to that observed in the mass spectrum.

In order to confirm, we look at the isotopic distribution and compared it with that of the simulated spectrum. When comparing the observed isotopic pattern of the dimeric

2+ species [M2+Fe2S2] with its simulated isotopic distribution, we noticed that there are variations and the peaks cannot be fully explained (Figure 17). The isotopic distribution seems to more likely belong to its corresponding monomeric species [M+FeS]+ (as shown in Figure 18), which may be obtained by homolytic cleavage of the S-S bond during the ionization process. The observed isotopic pattern is in good agreement with the simulated isotopic distributions but the dimeric species is also present, as indicated by the secondary peak next to that at m/z value of 259.2 and the region around m/z value of 258 not being flat in the experimentally determined mass spectrum.

256 257 258 259 260 261 262 263 264

256 258 260 262 264

Figure 17. Isotopic distribution centered around m/z = 259 in a) experimental and

2+ simulated mass spectra of b) the doubly charged dimeric species [M2+Fe2S2] and c) its corresponding monomeric species [M+FeS]+

Figure 18. Possible corresponding monomeric iron species from homolytic cleavage of the S-S bond during the ionization process

Based on the APCI-MS analysis, the dimer species with the ligand coordinated to the iron sulfide is likely to be present in the reaction mixture. This species may not be the catalytically active species but it provided an idea of what is generated from mixing the metal disulfide with the bipyridine ligand.

In addition, a sample was also taken from the reaction mixture obtained after the reaction between iron disulfide with 6-amino-,′-bipyridine in the presence of the base

KOH, without the substrate cyclohexanone and analyzed by APCI-MS.

= M

Figure 19. APCI-MS analysis after the reaction between iron disulfide with 6-amino-,′- bipyridine in the presence of the base, without the substrate

When the reaction was conducted in the absence of the substrate, the iron species with the ligand coordinated was not present. The iron bipyridine complex was only formed in the previous case when the substrate cyclohexanone was present. This suggests the in situ formation of the active catalyst during the transfer hydrogenation reaction, which further validates our earlier hypothesis.

4.2.3 Proposed Mechanism

Based on the possible intermediate (Figure 16) formed by mixing the metal disulfide with the bipyridine ligand as mentioned in the above section and the plausible role that the sulfides next to the metal center play in facilitating the catalytic transfer hydrogenation reaction as highlighted in Chapter 2, accordingly, we propose plausible 59 mechanisms with reference to the known direct hydrogen transfer and hydridic route,5,21-26 as reviewed in Chapter 1.

First, we propose that the catalytic reaction may occur via the direct hydrogen transfer route (Figure 20), whereby a six-membered ring transition state is involved in the cycle such as the one originally proposed for the MPV reduction14.

Initial proton transfer from the hydrogen donor isopropanol and coordination of the isopropoxide ion to the metal center forms the iron alkoxide 1. Next, the ketone substrate is coordinated to the iron center, which makes the carbonyl group more electrophilic and susceptible to attack by the hydride. The iron center provides an organized cyclic transition state for a concerted hydride transfer from the alkoxide to the carbonyl carbon of the substrate. At this point, the new carbonyl (acetone) dissociates and finally, isopropanol in the solution displaces the alcohol product, regenerating the catalyst 1. 60

Figure 20. Proposed mechanism for catalytic transfer hydrogenation of ketone via the direct hydrogen transfer route

Alternatively, the catalytic reaction may occur via the hydridic route (Figure 21), whereby a metal hydride intermediate is formed.

The first step is the same as that in the previous mechanism, which involves initial proton transfer from the hydrogen donor isopropanol and coordination of the isopropoxide ion to the metal center to give the iron alkoxide 1. Suseuet β-hydride elimination generates an active metal hydride species 2, releasing acetone. It is followed by the simultaneous transfer of hydride from Fe-H and proton from the S-SH arm to the ketone substrate via an outer sphere mechanism, like i the ase of Sho’s30 and

28 Nooi’s catalyst involving the OH and NH2 moiety in the ligands, respectively. Upon dehydrogenation of the hydrogen donor isopropanol, the active catalytic species 2 is regenerated and the catalytic cycle is completed.

Figure 21. Proposed mechanism for catalytic transfer hydrogenation of ketone via the hydridic route

However, these two mechanisms do not account for the difference in reactivity when iron sulfide or iron disulfide was used as the metal precursor for the in situ prepared iron-based catalytic system. Based on the results obtained in Chapter 2, the iron disulfide system was shown to perform better than that of the iron sulfide. Presumably, the difference in reactivity could arise from the disulfide bridging two iron, thereby allowing interaction between the two iron centers. Accordingly, a plausible mechanism is shown in Figure 22. 63

Figure 22. A plausible mechanism for transfer hydrogenation of ketone mediated by the two iron centers connected by a disulfide bridge

Initial deprotonation of the hydrogen donor isopropanol in the presence of a base forms the isoproxide ion, which coordinates to one of the two iron centers to give the iron 64 alkoxide 3. The other cationic iron center has an empty site for an incoming ketone substrate to bind. This is followed by a concerted hydride transfer from the alkoxide to the carbonyl carbon of the substrate to give the dinuclear iron species 4. At this point, the new carbonyl (acetone) dissociates and finally, isopropanol in the solution displaces the alcohol product. The catalytic cycle is completed with regeneration of the catalytic complex 3.

4.3 Conclusion

In summary, an in situ prepared catalytic system using the combination of iron disulfide and chelating bipyridine ligand was found to be effective for the transfer hydrogenation of ketones in the presence of a simple base. For such a catalytic system, dearomatization-rearomatization is not needed for the transfer hydrogenation to occur. These observations may suggest that the dearomatization-rearomatization is more pronounced in the pincer system. It provides a convenient and economical way to conduct transfer hydrogenation. The difference in catalytic reactivity between using the iron sulfide and iron disulfide as the metal precursor could be explained by the possible formation of a dimeric iron species in the case of iron disulfide, while the iron sulfide only exists as a monomeric species. In the dimeric species, the two iron centers may interact with each and facilitate the catalytic transfer hydrogenation process.

4.4 Experimental Section

FeS2 (99.8% trace metals basis) was purchased from Sigma-Aldrich. KOH (99.99%) was bought from Alfa Aesar. Other chemicals and solvents of high purity (ACS grade or higher) were purchased from Sigma-Aldrich and VWR Chemicals. The ligands were commercially available. All chemicals and solvents were used without further purification.

In situ ATR-IR analyses were conducted with a Mettler Toledo ReactIR 45m spectrometer equipped with a DiComp (diamond-composite) ATR probe. The probe tip was inserted into the reaction mixture and the ReactIR analysis system was programed to collect a spectrum every 15 minutes for 1 day.

APCI mass spectra were recorded using an Advion Expression Compact Mass

Spectrometer (CMS), equipped with a standard APCI source. Samples were introduced by automated extraction from a TLC plate using the Advion Plate Express.

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APPENDIX

Abundance

TIC: eapl-cycloh-fes2-.D\data.ms 3.4e+07 3.2e+07 3e+07 2.8e+07 2.6e+07 2.4e+07

2.2e+07

2e+07

1.8e+07 1.6e+07 1.4e+07 1.2e+07 1e+07

8000000 6000000 4000000 2000000 0 6.00 7.00 8.00 9.00 10.00 11.00 12.00 13.00 14.00 Time-->

Abundance

TIC: eapl-cycloh-mos2-.D\data.ms 3.4e+07 3.2e+07 3e+07

2.8e+07

2.6e+07

2.4e+07 2.2e+07 2e+07 1.8e+07 1.6e+07

1.4e+07 1.2e+07 1e+07 8000000 6000000

4000000 2000000 0 6.00 7.00 8.00 9.00 10.00 11.00 12.00 13.00 14.00 Time-->

Abundance

Scan 298 (6.919 min): eapl-cyclohexan-1--.D\data.ms 57.1 82.1 8000000

67.1 7000000

6000000

5000000

44.1 4000000

3000000

2000000 29.1

1000000 100.1

15.1 110.9 121.0 133.1 147.0 0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 m/z--> Figure 1. GC-MS analysis of the Fe- (top) and Mo-catalyzed (bottom) transfer hydrogenation of cyclohexanone 73

Abundance TIC: eapl1011-cyclopentan2.D\data.ms 2.5e+07 2.4e+07 2.3e+07 2.2e+07 2.1e+07

2e+07

1.9e+07

1.8e+07 1.7e+07 1.6e+07 1.5e+07 1.4e+07

1.3e+07 1.2e+07 1.1e+07 1e+07 9000000

8000000

7000000

6000000 5000000 4000000 3000000 2000000 1000000 6.00 7.00 8.00 9.00 10.00 11.00 12.00 13.00 14.00 Time--> Abundance

TIC: eapl1011-cyclopentan.D\data.ms 2.6e+07

2.5e+07

2.4e+07 2.3e+07 2.2e+07 2.1e+07 2e+07

1.9e+07 1.8e+07 1.7e+07 1.6e+07 1.5e+07

1.4e+07 1.3e+07 1.2e+07 1.1e+07 1e+07

9000000 8000000 7000000 6000000 5000000

4000000 3000000 2000000

1000000

0 6.00 7.00 8.00 9.00 10.00 11.00 12.00 13.00 14.00 Time-->

Abundance

Scan 180 (6.194 min): eapl1011-cyclop.D\data.ms 44.1 57.1 8000000

7000000

6000000

5000000

68.1 4000000 86.1 29.1

3000000

2000000

1000000

15.1 103.1 117.1 133.0 147.1 0 0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 m/z--> Figure 2. GC-MS analysis of the Fe- (top) and Mo-catalyzed (bottom) transfer hydrogenation of cyclopentanone

Abundance

TIC: eapl-aceto-a.D\data.ms 3.2e+07 3e+07

2.8e+07 2.6e+07 2.4e+07 2.2e+07 2e+07

1.8e+07 1.6e+07 1.4e+07 1.2e+07 1e+07

8000000 6000000 4000000

2000000

0 6.00 7.00 8.00 9.00 10.00 11.00 12.00 13.00 14.00 Time--> Abundance TIC: eapl1011-acetophen2-.D\data.ms 3e+07 2.8e+07

2.6e+07 2.4e+07 2.2e+07

2e+07 1.8e+07 1.6e+07

1.4e+07

1.2e+07

1e+07

8000000

6000000

4000000

2000000 0 6.00 7.00 8.00 9.00 10.00 11.00 12.00 13.00 14.00 Time-->

Abundance

Scan 714 (9.477 min): eapl1011--acetop.D\data.ms 78.1 107.1 122.1 8000000 51.1

7500000

7000000

6500000

6000000

5500000

5000000

4500000

4000000

3500000

3000000

2500000

2000000

1500000

1000000 27.1

500000 93.1 13.1 139.0 155.1 177.2 191.1 0 0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180 190 m/z--> Figure 3. GC-MS analysis of the Fe- (top) and Mo-catalyzed (bottom) transfer hydrogenation of acetophenone 75

Abundance

TIC: eapl15-11-fluoroacet.D\data.ms 3.2e+07 3e+07

2.8e+07

2.6e+07

2.4e+07 2.2e+07 2e+07 1.8e+07 1.6e+07

1.4e+07 1.2e+07 1e+07 8000000 6000000

4000000 2000000

6.00 7.00 8.00 9.00 10.00 11.00 12.00 13.00 14.00 Time-->

Abundance

TIC: eapl15-11-fluoroac-mos2.D\data.ms 3.2e+07 3e+07 2.8e+07 2.6e+07

2.4e+07

2.2e+07

2e+07 1.8e+07 1.6e+07 1.4e+07 1.2e+07

1e+07 8000000 6000000 4000000 2000000

0 6.00 7.00 8.00 9.00 10.00 11.00 12.00 13.00 14.00 Time--> Abundance

Scan 752 (9.711 min): eapl1511-fluoroa.D\data.ms 97.1 125.1 8000000

7500000

7000000 140.1

6500000 77.1 6000000

5500000

5000000

4500000

4000000

3500000 43.1 3000000

2500000

2000000

1500000

1000000 62.8

500000 29.1 15.1 111.1 163.1 177.1 192.1 0 0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180 190 m/z--> Figure 4. GC-MS analysis of the Fe- (top) and Mo-catalyzed (bottom) transfer hydrogenation of ’-fluoroacetophenone

Abundance TIC: eapl1611-bromoaceto.D\data.ms 2.8e+07 2.6e+07 2.4e+07 2.2e+07 2e+07 1.8e+07

1.6e+07 1.4e+07 1.2e+07

1e+07 8000000 6000000

4000000 2000000 6.00 7.00 8.00 9.00 10.00 11.00 12.00 13.00 14.00 Time-->

Abundance

TIC: eapl1611-bromoace.D\data.ms 2.8e+07 2.6e+07 2.4e+07

2.2e+07 2e+07 1.8e+07 1.6e+07 1.4e+07

1.2e+07 1e+07 8000000

6000000 4000000 2000000

6.00 7.00 8.00 9.00 10.00 11.00 12.00 13.00 14.00 Time--> Abundance

Scan 1253 (12.791 min): eapl1611-bromoa--.D\data.ms 77.1 187.0 8000000 157.0

7000000

6000000 121.1 43.1 5000000

4000000

3000000

2000000

103.1 1000000

15.1 139.0 207.1 239.1 261.1 0 0 20 40 60 80 100 120 140 160 180 200 220 240 m/z--> Figure 5. GC-MS analysis of the Fe- (top) and Mo-catalyzed (bottom) transfer hdogeatio of ’-bromoacetophenone 77

1 1-(4-Bromophenyl)ethanol. H NMR (CDCl3, 400 MHz): δ. d, , A, δ. d, , A, 13 1 δ. s, , CHCH3OH), δ. , , CHCH3OH), δ. d, , CHCH3OH). C{ H} NMR

(CDCl3, MHz: δ. C, δ. (CH), δ. CH, δ. C), δ.

(CHCH3OH, δ. CHCH3OH).

* H H H e a H H d *

* *

Figure 6. 1H NMR spectrum of 1-(4-bromophenyl)ethanol (top) and 13C NMR spectrum of 1-(4-bromophenyl)ethanol (bottom) in CDCl3 78

Abundance TIC: eapl1311-methylac.D\data.ms 7e+07 6.5e+07 6e+07

5.5e+07 5e+07 4.5e+07 4e+07 3.5e+07 3e+07 2.5e+07 2e+07 1.5e+07 1e+07 5000000 0 6.00 7.00 8.00 9.00 10.00 11.00 12.00 13.00 14.00 Time-->

Abundance

TIC: eapl1411-aceto-2.D\data.ms 7e+07 6.5e+07 6e+07 5.5e+07

5e+07

4.5e+07 4e+07 3.5e+07

3e+07 2.5e+07 2e+07

1.5e+07 1e+07 5000000

0 6.00 7.00 8.00 9.00 10.00 11.00 12.00 13.00 14.00 Time--> Abundance

Scan 796 (9.981 min): eapl1311-methyla.D\data.ms 43.1 77.1 93.1 121.1 136.1 8000000

7500000

7000000

6500000

6000000

5500000

5000000

4500000

4000000

3500000 63.1 3000000

2500000

2000000

1500000

1000000 27.1

500000 107.1 13.1 153.1 177.2 191.0 0 0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180 190 m/z--> Figure 7. GC-MS analysis of the Fe- (top) and Mo-catalyzed (bottom) transfer hydrogenation of ’-methylacetophenone