opus4.kobv.de€¦ · Teile dieser Arbeit sind bereits veröffentlicht: • A. Fingerhut, Y. Wu, A. Kahnt, J. Bachmann, S. B. Tsogoeva, Synthesis and Electrochemical and Photophysical

Development of new biomimetic non-heme iron

epoxidation catalysts and new pyridine-derived light

absorbing systems

Entwicklung von neuen biomimetischen nicht-häm

Eisenkatalysatoren und neuen Pyridin-abgeleiteten

lichtabsorbierenden Systemen

Der Naturwissenschaftlichen Fakultät

der Friedrich-Alexander-Universität Erlangen-Nürnberg

zur

Erlangung des Doktorgrades Dr. rer. nat.

vorgelegt von

Anja Fingerhut, M.Sc.

aus Nürnberg

Als Dissertation genehmigt von der Naturwissenschaftlichen Fakultät der Friedrich-Alexander-

Universität Erlangen-Nürnberg

Tag der mündlichen Prüfung: 13. Juni 2017

Vorsitzender des Promotionsorgans: Prof. Dr. Georg Kreimer

Gutachter/in: Prof. Dr. Svetlana Tsogoeva

Prof. Dr. Andriy Mokhir

Die vorliegende Arbeit wurde am Institut für Organische Chemie des Departments Chemie

und Pharmazie der Friedrich-Alexander-Universität Erlangen-Nürnberg unter Leitung von

Prof. Dr. Svetlana B. Tsogoeva in der Zeit von Juli 2012 bis März 2017 erstellt.

Teile dieser Arbeit sind bereits veröffentlicht:

• A. Fingerhut, Y. Wu, A. Kahnt, J. Bachmann, S. B. Tsogoeva, Synthesis and Electrochemical

and Photophysical Characterization of New 4,4’-π-Conjugated 2,2’-Bipyridines that are End-

Capped with CyanoacrylicAcid/Ester Groups, Chem. - Asian J. 2016, 11, 1232-1239.

• A. Fingerhut, O. V. Serdyuk, S. B. Tsogoeva, Non-heme iron catalysts for epoxidation and

aziridination reactions of challenging terminal alkenes: Towards sustainability, Green Chem.

2015, 17, 2042-2058.

Veröffentlichungen unabhängig von dieser Arbeit:

• A. Fingerhut, D. Grau, S. B. Tsogoeva, "Peptides as asymmetric organocatalysts", Book

Chapter in "Sustainable Catalysis", M. North (Ed.), RSC 2015, Vol. 2, Chapter 13, 309-353. in

press.

• F. E. Held, A. Fingerhut, S. B. Tsogoeva, Insights into the spontaneous emergence of

enantioselectivity in an asymmetric Mannich reaction carried out without external catalyst,

Tetrahedron: Asymmetry 2012, 23, 1663-1669.

Für meine Eltern und Freunde

Mal trumpft man auf, mal hält man stille,

mal muß man kalt sein wie ein Lurch,

des Menschen Leben gleicht der Brille:

man macht viel durch.

(Heinz Erhardt)

Table of Contents

I

Table of Contents

Table of Contents _________________________________________________________________________________ I

List of Abbreviations ___________________________________________________________________________ IV

1 Non-heme Iron Catalyzed Epoxidation of Olefins ____________________________________ 1

1.1 Meaning of Iron ______________________________________________________________________ 1

1.2 Highlights in Enantioselective Epoxidation without Iron _____________________ 2

1.3 Highlights in Non-heme Iron Catalyzed Epoxidation of Olefins ______________ 4

1.4 Motivation and Aim ________________________________________________________________ 10

1.5 Results and Discussion ____________________________________________________________ 12

1.5.1 Epoxidation with imine-based ligands _____________________________________________ 12

1.5.2 Epoxidation with imidazole-based ligands ________________________________________ 17

1.5.2.1 Preliminary screening of simple imidazoles 17

1.5.2.2 Screening of reaction conditions using an achiral ligand 18

1.5.2.3 Synthesis and screening of chiral imidazole-based peptide-like ligands 20

1.5.2.4 Insight into catalyst formation via UV/Vis spectroscopy 26

1.5.2.5 Screening of reaction conditions using a chiral ligand 27

1.5.2.6 Substrate screening 29

1.5.3 One-pot procedure towards β-amino alcohol _____________________________________ 32

1.5.4 SiO2 catalyzed rearrangement of epoxide __________________________________________ 34

1.5.5 Non-heme iron catalyzed aziridination ____________________________________________ 37

1.6 Conclusion ___________________________________________________________________________ 41

1.7 Experimental Section ______________________________________________________________ 42

1.7.1 Methods, materials and instruments _______________________________________________ 42

1.7.2 Syntheses and spectroscopic data __________________________________________________ 43

1.7.2.1 Ligand synthesis 43

1.7.2.2 Synthesis of olefins and racemic epoxide references 54

1.7.2.3 Non-heme iron catalyzed epoxidation of olefins 58

1.7.2.4 One-pot procedure towards β-amino alcohol 60

1.7.2.5 SiO2 catalyzed rearrangement of epoxides 61

1.7.2.6 Non-heme iron catalyzed aziridination 62

2 Synthesis of Pyridine-derived Ligands for Light Absorbing Metal Complexes _ 63

2.1 The Sun – An Attractive Source of Energy ______________________________________ 63

2.2 Pyridine-Based Compounds in Photoscience __________________________________ 66

Table of Contents

II

2.3 Motivation and Aim ________________________________________________________________ 75

2.4 Results and Discussion ____________________________________________________________ 76

2.4.1 Synthesis of new 2,2’-bipyridine ligands via conventional approach ____________76

2.4.1.1 Synthesis of a 2,2’-bipyridine building block 76

2.4.1.2 Synthesis of new 2,2’-bipyridine ligands end-capped with acceptor units 77

2.4.1.3 Photophysical and electrochemical investigations 82

2.4.1.4 Synthetic approaches towards new ruthenium complexes 85

2.4.1.5 Synthesis of new 2,2’-bipyridine ligands containing thiophene 92

2.4.2 Synthesis of pyridine-based ligands in an organocatalytic one-pot procedure 101

2.5 Conclusion _________________________________________________________________________ 105

2.6 Experimental Section ____________________________________________________________ 107

2.6.1 Methods, materials and instruments _____________________________________________ 107

2.6.2 Syntheses and spectroscopic data_________________________________________________ 108

2.6.2.1 Synthesis of a 2,2’-bipyridine building block 108

2.6.2.2 Synthesis of new 2,2’-bipyridine ligands end-capped with acceptor units 109

2.6.2.3 Synthetic approaches towards new ruthenium complexes 112

2.6.2.4 Synthesis of new 2,2’-bipyridine ligands containing thiophene 113

2.6.2.5 Synthesis of pyridine-based ligands in an organocatalytic one-pot procedure 115

3 Investigations of 1,4-Dihydropyridine-based Systems in Photocatalysis______ 117

3.1 NAD(P)H and NAD(P)H Models _________________________________________________ 117

3.2 1,4-Dihydropyridines in Transfer Hydrogenation Reactions ______________ 118

3.2.1 Photocatalytic regeneration of NAD(P)H _________________________________________ 118

3.2.2 1,4-Dihydropyridine as reductive equivalent ____________________________________ 119

3.2.3 1,4-Dihydropyridine with regeneration system _________________________________ 120

3.3 Motivation and Aim _______________________________________________________________ 123

3.4 Results and Discussion ___________________________________________________________ 125

3.4.1 Photocatalytic regeneration of Hantzsch ester___________________________________ 125

3.4.2 Photocatalytic transfer hydrogenation via 1,4-dihydropyridine regeneration 128

3.5 Conclusion _________________________________________________________________________ 136

3.6 Experimental Section ____________________________________________________________ 137

3.6.1 Methods, materials and instruments _____________________________________________ 137

3.6.2 Syntheses and spectroscopic data_________________________________________________ 138

4 Summary of the Thesis _________________________________________________________________ 141

4 Zusammenfassung der Dissertation _________________________________________________ 144

Table of Contents

III

References_____________________________________________________________________________________ 148

Appendix ______________________________________________________________________________________ 159

Danksagung ________________________________________________________________________________ 159

Lebenslauf __________________________________________________________________________________ 161

List of Abbreviations

IV


ADH alcohol dehydrogenase

br s broad singulet

°C degree Celsius

calcd calculated

conc. concentration

conv. conversion

CT charge-transfer

d days

d doublet

DBU 1,8-diazabicyclo[5.4.0]undec-7-ene

dd doublet of doublet

DCM dichloromethane

dt doublet of triplet

DTBS ditriflate di-tert-butylsilyl bis(trifluoromethanesulfonate)

dtd doublet of triplet of doublet

DIPEA diisopropylethylamine

DMF dimethylformamide

dmgH2 dimethylglyoxime

DMSO dimethyl sulfoxide

DS-PEC dye sensitized photoelectrochemical cell

DSSC dye sensitized solar cell

dq doublet of quartet

EA ethyl acetate

ee enantiomeric excess

ESI-MS electro spray ionisation - mass spectrometry

ETA ethanolamine

equiv. equivalents

FDH formate dehydrogenase

g gram

GDH glutamate dehydrogenase

GP general procedure

h hours

HOMO highest occupied molecular orbital


V

HPLC high performance liquid chromatography

H2Pydic pyridine-2,6-dicarboxylic acid

HWE Horner-Wadsworth-Emmons

Hz hertz

ICT intramolecular charge-transfer

ILCT intraligand charge-transfer

J scalar coupling constant

LED light-emitting diode

LUMO lowest unoccupied molecular orbital

m multiplet

M molarity

mCPBA meta-chloroperoxybenzoic acid

mg milligram

MHz megahertz

min minutes

ml milliliter

MLCT metal-to-ligand charge-transfer

mmol millimole

mol mole

M.p. melting point

MS mass spectrometry

m/z mass to charge ratio

n-BuLi n-butyllithium

n.d. not determined

NHE normal hydrogen electrode

NLO non-linear optics

NMR nuclear magnetic resonance

o.n. overnight

PE petrol ether

PMP p-methoxyphenyl protecting group

ppm parts per million

q quartet

quin quintet

rac racemic

r.t. room temperature

s singlet

https://en.wikipedia.org/wiki/Normal_hydrogen_electrode


VI

SDSSC solid-state dye sensitized solar cells

t triplet

TBAH tetrabutylammonium hydroxide

td triplet of doublet

temp. temperature

TEOA triethanolamine

TLC thin layer chromatography

TMS trimethylsilyl

TMSOTf trimethylsilyl trifluoromethanesulfonate

tR retention time

UV/Vis ultraviolet/visible

VT variable temperature

µl microliter

µmol micromole

δ chemical shift in ppm

Chapter 1 Non-heme Iron Catalyzed Epoxidation of Olefins

1

1 Non-heme Iron Catalyzed Epoxidation of Olefins

1.1 Meaning of Iron

In the last decades great efforts have been made to bring the chemistry of synthesis to a high

level in sustainability, efficiency and selectivity. Catalysts are used in about 80% of all synthesis

of chemicals and pharmaceutical compounds in industry. This development depicts an

economically and environmentally friendly development towards “Green Chemistry”

principles.1,2 Many of these catalysts are organometallic compounds and contain palladium,

rhodium, iridium and ruthenium. But even though they are well established for a broad range of

reactions these metals are toxic and rare, what leads to higher costs in catalyst preparation for

large scale applications.3 To overcome these disadvantages, catalysts which contain iron, copper,

zinc and manganese attracted attention because these first row transition metals are relatively

nontoxic and low priced due to their ubiquity in nature. With its 4.7 wt% iron is the second most

abundant metal in the earth crust and with it the most beneficial one for applications in “Green

Chemistry”.4 It is easily accessible for laboratories due to the fact that many iron salts and

complexes are either commercially available5 or the syntheses are described in literature.6 Iron

appears in many biological systems such as metalloproteins, which are natural and highly

efficient catalysts. Based on these examples, new synthetic iron complexes can be modeled.

These newly designed ‘bioinspired’ or ‘biomimetic’ complexes are able to imitate the mechanism

in the active site of the metalloprotein as for instance the activation of oxygen in metabolistic

iron systems.7 Iron provides a strong Lewis acidity and a facile change of the oxidation state,

which enables the application of its complexes to a broad range of enantioselective and non-

enantioselective catalytic reactions: additions, substitutions, cycloadditions, hydrogenation,

reductions, oxidations, coupling reactions, isomerizations, rearrangements and

polymerizations.8,2,3,9,10 The surrounding ligands of the artificial active sites influence the

reactivity and selectivity of the catalyst. This enables the rational design of the iron complex

based on the relationship between structure and action. Thus, steric and electronic tuning of

chiral ligands might result in efficient low cost catalysts for enantioselective synthesis.11,12

However, further modifications of existing iron-based systems in regard to easy handling, higher

stability, activity and selectivity are still required in order to bring the catalysts closer to future

large scale applications in industry. Nevertheless, iron-based homogeneous catalysis was found

to be a promising alternative to noble metal catalysis. Examples recently published in literature

provide further insight into the great potential and the ability to keep up with other highly

efficient but less economically and ecologically benign catalytic systems.


2

1.2 Highlights in Enantioselective Epoxidation without Iron

Epoxides represent an important class of compounds. The strained three-membered rings are

useful building blocks in the synthesis of fine chemicals and pharmaceuticals due to the variety

of different ring opening reactions they can undergo, as depicted in Figure 1.

Figure 1 Epoxide Transformations via ring opening reactions.

Some synthetic modifications in the preparation of bioactive compounds and chiral drugs are

ring-opening,13 ring-expansion,14 and intermolecular rearrangement reactions.15 A broad range

of nucleophiles enable the stereo- and regioselective ring opening which results in versatile

1,2-difunctional products (see Figure 1). Besides, chiral epoxides are common subunits in

indispensable biologically active synthetic and naturally occurring molecules like antitumor

agents,16 antibiotics,17 and enzyme inhibitors.15,18-25

The most venerable approach towards highly requested epoxides is the oxidation of olefins via

enantioselective or non-enantioselective oxygen transfer. In the last decades, several efficient

asymmetric catalytic methods have been developed for the epoxidation of olefins.

In 1980, an approach which gained great recognition within the chemical community was

published by Sharpless. The enantioselective method oxidizes allylic alcohols by using titanium-

tartrate complexes as catalyst and tert-butyl hydroperoxide as the oxidant.11,12,26 Epoxides were

formed with good yields ranging from 70% to 85% with high enantioselectivities >90%. The high

enantioselectivities were generated via oxygen transfer directed by either the D-(-)-diethyl

tartrate ligand or the L-(-)-enantiomer, independently of the allylic alcohol substitution pattern.

The Sharpless epoxidation was honored with a Nobel prize in 2001 for William S. Knowles, Ryoji

Noyori and K. Barry Sharpless.

A widespread approach towards enantioselective epoxidation is the use of salen complexes as

catalysts with metal centers like manganese, chromium, titanium, cobalt, ruthenium, copper or

palladium. A main breakthrough was reported in 1990 almost at the same time by Katsuki and

Jacobsen both using chiral manganese-salen complexes for enantioselective epoxidation of

unfunctionalized alkenes (see Scheme 1).27-29


3

Scheme 1 Asymmetric Mn(III)-salen catalyzed epoxidation developed by Jacobsen28 and Katsuki.29

Catalyst 1 developed by Jacobsen reached in combination with iodosomesitylene as oxidizing

agent yields up to 73% (for cis-β-methylstyrene) and enantioselectivities up to 93% (for

1,4-dioxaspiro[4.5]dec-6-ene), while showing superior catalytic activity for cis-olefins. The lowest

ee-value was 20% (93% yield) and was obtained by using trans-β-methylstyrene as substrate.28

In contrast, Katsukis’s catalyst 2 reached yields up to 93% and ee-values up to 50% under

different reaction conditions as for instance the application of iodosobenzene as oxidizing

agent.29 The highest ee-value of 50% was obtained in case of trans-β-methylstyrene as substrate,

however, the yield was quite low with 12%. In 1991, Jacobsen presented a further modified

catalyst based on complex 1 by introducing additional tert-butyl groups and applying chiral

1,2-diaminocyclohexane as starting material.30 This catalyst, meanwhile known as “Jacobsens’s

catalyst”, reached yields ranging from 63% to 96% and ee-values between 89% to 98%.

A successful enantioselective organocatalytic method was developed by Shi in the period

between 1996 to 2002.31-39 Excellent enantioselectivities were obtained for trans-di- and tri-

substituted olefins, conjugated cis-disubstituted olefins and styrenes by using fructose derived

chiral ketone derivatives as catalyst and oxone as the oxidant.

In the last few years further advances towards efficient bioinspired iron catalyzed epoxidation

have been made using either porphyrin system or non-heme iron complexes. The main driving

force for the development of iron-based catalysts is the before mentioned advantage over

catalytic processes using more expensive and toxic metals. While previously studied heme iron

systems were not found to be highly enantioselective, non-heme iron complexes enable a

promising excess towards new enantioselective epoxidation catalysts in a sustainable and

economically more attractive way.40,41


4

1.3 Highlights in Non-heme Iron Catalyzed Epoxidation of Olefins

As non-heme iron catalysis provide an economical and environmentally friendly solution for

enantioselective and non-enantioselective epoxidation of olefins, literature provides a range of

constructive examples. These highlighted systems which are presented in this chapter are of

particular interest for the development of a new generally applicable non-heme iron catalytic

system for all classes of olefins including the challenging ones like terminal, electron deficient

and highly substituted olefins. These examples are also of particular interest with regard to future

large scale industrial applications.10,42-44,9

In 1999, Jacobsen and co-workers presented one of the early cutting-edge approaches in

enantioselective non-heme iron catalyzed epoxidation (see Scheme 2).45 The biomimetic

catalytic oxidation of trans-β-methylstyrene with H2O2 as the oxidizing agent is carried out by

using a polymer-supported non-heme iron complex generated from a peptide-like ligand

anchored on polystyrene and an iron salt. They identified the most promising ligand from a

library with different combinations of chiral peptide-like ligands and a variety of metal ion

sources. The most promising combination, ligand 3 and iron(II) chloride, led to 78% conversion

and 20% enantiomeric excess of the corresponding epoxide (see Scheme 2). The peptide-like

ligand bearing a N2O binding motif and the iron center probably form a biomimetic N2OFeCl2

complex even though the coordination structure of the catalyst was not provided by the authors.

Scheme 2 Enantioselective non-heme iron catalyzed epoxidation by Jacobsen and co-workers.45

Almost a decade later in 2007, the group of Beller published an in situ generated catalyst for

epoxidation with H2O2 (see Scheme 3).46 The catalyst was generated from a chiral

1,2-diphenylethylenediamine derivative 4 as ligand and pyridine-2,6-dicarboxylic acid (H2Pydic)

as co-ligand which coordinates to the iron center. The catalytic system was applicable to a broad

range of substrates containing aromatic non-terminal olefins yielding the corresponding

epoxides with up to 94% and enantioselectivities up to 97%. The results concerning yield and

enantioselectivity were found to be dependend on substrate symmetry and bulkiness. Further

modification of the ligand made the catalytic system applicable for enantioselective epoxidation

of terminal aromatic olefins, although their corresponding epoxides were obtained with only

8-26% ee.47


5

Scheme 3 Enantioselective non-heme iron catalyzed epoxidation by Beller and co-workers.46

Besides, Beller and co-workers published further in situ generated non-heme iron catalytic

systems for non-enantioselective epoxidation reaction. In 2007, they introduced the first non-

heme iron catalytic system which allows both, epoxidation of aliphatic and aromatic olefins

catalyzed by an in situ formed complex from pyrrolidine, H2Pydic as co-ligand and

FeCl3 x 6 H2O.48,49 The system yielded sterically challenging substrates like 2-vinylnaphthalene

with 40% and α-methylstyrene with 64%.

They further reported non-heme iron catalysts, which contained biomimicking ligands such as

benzylamine derivatives in combination with H2Pydic50 or imidazole derivatives such as

1-(2,6-diisopropylphenyl)imidazole (5, see Scheme 4).51-53 The catalytic system applying ligand 5

and H2O2 as the oxidant afforded racemic non-terminal and terminal epoxides in good yields, no

matter if they were aromatic or aliphatic. Aromatic terminal olefins reached yields of up to 88%

and terminal aliphatic olefins 53%. Via mechanistic investigations they demonstrated that in the

presence of water an equilibrium between the in situ formed mononuclear iron(III) species and

an oxo diiron(III) complex is adjusted.

Scheme 4 Non-heme iron catalyzed epoxidation by Beller and co-workers.51

A simple and easily manageable catalytic system for non-enantioselective non-heme iron

epoxidation was published in 2011 by Beller and Costas (see Scheme 5).54 By applying imidazole

and bioinspired β-keto ester as co-substrate in presence of FeCl3 x 6 H2O, a biomimetic iron

epoxidation catalyst is formed in situ using air as the oxidant. The O2 activation was reported to


6

be similar to the activation process in co-substrate-dependent non-heme oxygenases. The

authors propose [FeIII(β-keto ester-H)2-(imidazole)]+ (6, Scheme 5) as the catalytic active species

and superoxide as oxidizing species. For non-terminal aromatic olefins yields up to 96% were

obtained favoring trans-olefins, while yields of aromatic terminal olefins were ranging between

30% and 50%. Oxidation of aliphatic olefins achieved the corresponding epoxide in 24% to 44%

yield.

Scheme 5 Non-heme iron catalyzed epoxidation by Beller and co-workers.54

In 2008, Kwong and co-workers presented a chiral diiron-sexipyridine complex 7 for

enantioselective epoxidation of olefins with H2O2 (see Scheme 6).55 After only 3 minutes of

reaction time styrene derived epoxides were achieved in yields ranging from 50% to 100%

revealing enantiomeric excesses between 15% and 43%. Worth mentioning is the fact that

aliphatic cyclooctadiene was oxidized with 95% yield forming the monoepoxide, while 1-heptene

remained unreacted in the system. Furthermore, the authors indicated the electrophilic nature

of the active oxidant via intermolecular competition experiments.

Scheme 6 Enantioselective non-heme iron catalyzed epoxidation by Kwong and co-workers.55

A further promising epoxidation system was published in 2011 by Yamamoto and co-workers for

epoxidation of β,β-substituted enones applying in situ formed iron catalysts from Fe(OTf)2 and

ligands which provide an axially chiral biaryl moiety linked to phenanthroline.56 The reaction

system required peracetic acid as oxidizing agent.

A different enantioselective approach was published by the Tsogoeva group in 2012 (see

Scheme 7).57 The authors applied a primary amine derived non-symmetrical Schiff base ligand 8


7

which forms an in situ complex in combination with FeCl3·6 H2O. The catalytic epoxidation was

carried out with H2O2 as oxidizing agent for a wide range of different olefins. While trans-stilbene

and related derivatives reached yields up to 84% with up to 30% ee, styrene only led to 44% yield

of the corresponding epoxide with an enantiomeric excess of 21%.

Scheme 7 Enantioselective non-heme iron catalyzed epoxidation by Tsogoeva and co-workers.57

A successful family of non-heme iron catalysts is represented by octahedral complexes

coordinating a bis-amino-bis-pyridine ligand. The groups of Que,58,59 Costas,60,61 Sun,62,63

Bryliakov and Talsi64 obtained very promising results concerning yields and enantioselectivity. In

2011 and 2012, Sun and co-workers presented bioinspired iron(II) complexes with ligands based

on a chiral ethylenediamine backbone for enantioselective epoxidation of α,β-unsaturated

ketones or multisubstituted enones using H2O2 as the oxidant and acetic acid as additive.63,62 They

obtained the corresponding epoxides in high yields and enantioselectivities up to 98%. However,

the enantioselective epoxidation of terminal olefins, e.g. styrene, was not possible.

One of these promising approaches towards bioinspired enantioselective non-heme iron

catalyzed epoxidation with H2O2 was published by Costas in 2013.60

Scheme 8 Enantioselective non-heme iron catalyzed epoxidation by Costas and co-workers.60


8

Several complexes coordinating aminopyridine ligands with a bipyrrolidine backbone were

tested. They investigated the effect of electron-donating and electron-withdrawing groups at the

pyridine on yield and enantioselectivity of the epoxidation reaction. The best catalyst was found

to be substituted with a dimethylamine group at the coordinating pyridine (9, see Scheme 8).

The catalyst was active for a broad substrate spectrum in epoxidation reaction (selected

examples of target epoxides are depicted in Scheme 8). Catalytic amounts of carboxylic acids

((S)-ibuprofen or 2-ethylhexanoic acid (2-eha)) were applied as additive, which assisted in O-O

cleavage favoring the formation of the electrophilic oxygen delivering iron species.

In 2015, Costas and co-workers published a further study of these bioinspired non-heme iron

catalysts, but this time utilizing N-protected amino acids as co-ligands for the asymmetric

epoxidation of α-alkyl-substituted styrenes.61 The numerous screened amino acids synergistically

cooperated with the iron center and favor the activation of H2O2 for an efficient enantioselective

oxygen transfer. Using 9 in combination with N-Npha-ILeu-OH, a screening with bulky α-alkyl-

substituted styrene derivatives was carried out with yields up to 94% and enantioselectivities up

to 97% (see Scheme 9). Besides, cis-β-methyl-styrene was oxidized with 81% yield and 87% ee.

Scheme 9 Enantioselective non-heme iron catalyzed epoxidation of α-alkyl-substituted styrenes by

Costas and co-workers.61

In 2014, Kühn and co-workers published for the first time an iron(II) N-heterocyclic carbene

complex applicable for non-enantioselective epoxidation reactions of olefins by using H2O2 as the

oxidant.65 The yields of aromatic and aliphatic, terminal and non-terminal epoxides ranged

between 11% and 92% with moderate to high selectivities by applying a catalyst loading of

2 mol%. In order to enhance stability and activity, further modifications of the catalyst were

performed. In 2015, they published an iron(III) tetracarbene complex (depicted in Scheme 10)

which lowered the oxidant decomposition by radical pathways. Applying the new complex for

the same aromatic and aliphatic olefins as tested before a lowering of catalyst loading to

0.375 mol% was enabled and yields ranging from 46% to quantitative yield were obtained.


9

Scheme 10 Iron(III) carbene complex catalyzed epoxidation by Kühn and co-workers.66

Owing to the auspicious results in literature and the economical and ecological advantages of

iron, the non-heme iron catalysis is a promising epoxidation method for future large scale

application in industry especially in combination with H2O2 as desirable oxidant. However, as

literature demonstrated terminal olefins were found to be a challenging substrate for

enantioselective non-heme iron catalytic systems.67 But among all classes of olefins the terminal

ones are important substrates due to the appearance of the corresponding chiral epoxides in

biologically active natural products and popular building blocks in the synthesis of e.g. β-blockers,

HIV protease inhibitors, polyol and polyene antibiotics (see Scheme 11).13,20-24

Scheme 11 Terminal epoxides in bioactive natural products and building blocks in drug synthesis.20-24


10

1.4 Motivation and Aim

Scientific literature of the last decades provides a multitude of different methods towards

epoxides, due to the high demand of these strained three-membered rings as biologically active

compounds or building blocks in drug synthesis. Among all these methods, non-heme iron

catalysis represents a promising opportunity to develop an environmentally and economically

friendly approach to generate versatile epoxides by oxidation of olefins. However, routes by

which chiral terminal epoxides were obtained using non-heme iron complexes are rare and if

available with yields and enanatioselectivites to be in need of improvement. Terminal epoxides

represent an important class of epoxides but are obviously one of the most challenging

substrates in oxidation processes as well. Therefore, the development of new enantioselective

non-heme iron catalytic systems for the epoxidation of terminal alkenes poses an attractive task.

Besides, the ability to combine the non-heme iron catalytic system with an oxidizing agent such

as H2O2, which is inexpensive and environmentally friendly, is highly required.

Thus, the main objective of this chapter was the development and investigation of new non-

heme iron catalysts for enantioselective epoxidation of terminal olefins using H2O2 as terminal

oxidant. 2-Vinylnaphthalene (11) was chosen as model substrate since it was found to be

challenging and meaningful at the same time owing to its bulkiness and its use as precursor in

drug synthesis.68,69 Among all non-heme iron complexes applying H2O2 as oxidant, only Beller’s

catalyst in situ formed from pyrrolidine, H2Pydic and FeCl3 x 6 H2O was tested for this substrate

yielding racemic 2-vinylnaphthalene oxide (12) with 40%.49

The applied non-heme iron catalyst should be easily accessible as well as easily manageable.

Therefore a simple catalytic system should be chosen which operates dependably under non-

inert conditions. Furthermore, the active complex should be generated in situ prior to substrate

and oxidant addition, as depicted in Scheme 12.

Scheme 12 Aim: enantioselective non-heme iron catalyzed epoxidation with in situ catalyst formation.


11

This procedure avoids a previous complex synthesis and is therefore time and cost saving. The

complex should be constituted from FeCl3 x 6 H2O as iron source and a simple and stable chiral

ligand providing coordination sites (see Scheme 12). Thus, inspired by nature and based on

preliminary studies in the groups of Tsogoeva,57 Beller51,54 and Jacobsen,45 ligands which are

imine-based or imidazole-based should fulfill these requirements. They should be investigated

for the chosen model reaction of 2-vinylnaphthalene (11, Scheme 12). Besides, this chapter

should give further insight into catalyst characterization, possible catalyst application in

aziridination and further transformations of the epoxide via ring opening or rearrangement.


12

1.5 Results and Discussion

1.5.1 Epoxidation with imine-based ligands

In 2012, the Tsogoeva group published several new imine-based ligands which were tested for

epoxidation reaction and sulfoxidation forming in situ non-heme iron and vanadium complexes

prior to substrate addition.57 Among all tested ligands, ligand 8 showed the best result in non-

heme iron catalyzed epoxidation reaction for a variety of different non-terminal olefins with

good yields (already mentioned in Scheme 7). However, styrene as terminal olefin showed the

least promising yield of 44%. With regard to this published results and further studies in the

Tsogoeva group, the imine-based ligand 8 represented the starting point of this work.70,71 Ligand

8, which is easily accessible by condensation of 3,5-di-tert-butylsalicylaldehyde and

(1R,2R)-(+)-1,2-diphenylethylenediamine was tested for the epoxidation of the model substrate,

2-vinylnaphthalene (11), representing a challenging terminal olefin (see Scheme 13). The actual

catalytically active iron species is generated in situ and enables the oxygen transfer from H2O2 to

the substrate, releasing the target epoxide. The in situ catalyst formation is known as a time-

saving, economically and ecologically friendly method avoiding preliminary catalyst synthesis.57,72

Scheme 13 Screening of imine-based ligands: Conversion determined from raw material via 1H-NMR;

ee-values determined via chiral HPLC measurement.

The general reaction procedure which was used employed dichloromethane as solvent, as well

as 20 mol% ligand, 10 mol% FeCl3 x 6 H2O, 5 mol% H2Pydic as additive and the addition of

1.5 equivalents of aqueous H2O2 (30 wt%). These published reaction conditions57 were applied in

a modified version by adding the oxidant via syringe pump over a 1 h period and not in one


13

portion as previously described. The corresponding epoxide was obtained by low conversion but

with 38% ee as depicted in Scheme 13. Without syringe pump the corresponding epoxide was

obtained with a lower ee-value of 32%.70 Despite low NMR resolution due to paramagnetic

FeIII-residues the integration of substrate and product signals for determination of conversion

was possible with a minor error margin. In the synthesis of 8 the symmetrically substituted

bisadduct 13 is obtained as side product via double condensation (depicted in Scheme 13). It was

already found to be inactive for epoxidation of trans-stilbene.71 By testing this bisadduct ligand

13 for the model reaction only traces of racemic product were observed (see Scheme 13). This

observation supports the conclusion that the additional hydroxy group depicts an additional

binding site for coordination to the iron and with it the activation of the H2O2 is blocked at the

metal center. An asymmetrically substituted bisimine 14 without an additional coordinating site

was tested as well (see Scheme 13). Ligand 14 was obtained from condensation of ligand 8 with

2-naphthaldehyde. Applying ligand 14 in the model reaction resulted in a slightly improved

conversion compared to the result with ligand 8. However, the enantioselectivity was lower with

33% ee. To get an overview over further potentially active ligands for the model reaction system

towards terminal epoxides, a set of different imine-based ligands was tested. All tested ligands

15-21, depicted in Scheme 14, were kindly provided by Dr. Kerstin Stingl.73 However, neither

imine-based ligands containing a binaphtyl unit nor imine-based ligands with a peptide unit as

well as ligands which combine both binaphtyl and peptide unit were found to be active. In no

case did the application lead to more than tarces of the epoxide (see Scheme 14). These product

traces were only analyzed by HPLC in the case of ligand 18. The generated epoxide 12 was

determined as racemic mixture and was possibly the result of a running background reaction.

Hence, it was proposed that either again all coordination sites were blocked by the ligands 15-

21 and therefore no oxidant activation at the iron core was possible or the substrate could not

be kept in close proximity to the metal ion. A further possibility could be that the provided

cavities of the ligand to incorporate the metal ion did not fit.


14

Scheme 14 Screening of imine-based ligands containing binaphthyl and/or peptide unit: Conversion

determined from raw material via 1H-NMR; ee-values determined via chiral HPLC

measurement.

Inspired by Kwong’s chiral diiron-sexipyridine complex 7 (see Scheme 6),55 a combination of the

most promising ligand 8 regarding enantioselectiviety and a bipyridine unit seemed to be

promising. Synthesis towards the bipyridine linked dimer 25 started from 2,6-dibromopyridine

(22) over a two-step synthesis yielding [2,2'-bipyridine]-6,6'-dicarbaldehyde (24, see Scheme 15).

Afterwards, a double condensation reaction was carried out from [2,2'-bipyridine]-

6,6'-dicarbaldehyde (24) and ligand 8 (1:2 molar ratio). Although the target compound 25 could

be identified by 1H-NMR spectroscopy and a HR-MS (ESI) measurement from the raw material,

the new ligand could not yet be obtained in pure form. The purification of ligand 25 bearing four

imines using the standard SiO2 column chromatography method did not result in better product

purity.


15

Scheme 15 Route of synthesis towards ligand 25.74,75

Although the unreacted [2,2'-bipyridine]-6,6'-dicarbaldehyde (24) was removed during the

purification process the back reaction of the condensation reaction took place at the imine

functionalities in particular at the imine derived from ligand 8. For that reason

3,5-di-tert-butylsalicylaldehyde was detected in the 1H-NMR spectra of product containing

fractions. Due to this back reaction several other side products were identified via NMR

spectroscopy and MS spectrometry. Even though the proposed ligand 25 was found to be

unstable towards standard purification procedures due to the four imine units an isolated

fraction containing ligand 25 besides other side products was used for the model reaction (see

Scheme 16). If ligand 25 was highly active for the model reaction of terminal olefins, the

enantiomeric excess of the target epoxide 12 would be at least higher than reached with

monomer 8. The reaction time was prolonged to 3.5 h for both ligands, in order to facilitate the

comparison by possibly increased conversions.


16

Scheme 16 Comparison of imine-based ligand and its bipyridine linked dimer 25: Conversion determined

from raw material via 1H-NMR; ee-values determined via chiral HPLC measurement

(* = containing degradation products from purification process).

The conversions estimated from 1H-NMR of the catalysis raw material obtained for ligand 8 and

25 were in same range (see Scheme 16). Furthermore, the enantiomeric excess of product 12

obtained with ligand 25 (30%) was slightly lower than the enantiomeric excess achieved with

ligand 8 (33%). Therefore, a repetition of the synthesis of 25 and optimization of the purification

method to gain the pure ligand was obsolete. Applying ligand 8 further reaction conditions were

screened. Lowering the amount of ligand to a 1:1 ratio (8 : FeCl3 x H2O) and doubling the catalyst

loading to 40 mol% (2:1 ratio) led to a decrease in enantioselectivity while the conversion was

kept in the same range as reported before.

In general, chiral imine-based ligands for non-heme iron catalalyzed epoxidation are an easily

accessible possibility to generate enantiomerically enriched epoxides. However, this chapter

showed that they were less efficient ligands for the chosen model reaction system of terminal

olefins. Even though the condensation towards imine-based ligands is a simple reaction, these

compounds suffer from an undesirable back reaction during purification and possibly during

catalysis reaction especially in presence of H2O from the aqueous H2O2 solution. All recorded

1H-NMR spectra of the catalysis raw material showed aldehyde signals after the oxidation

process. The reduction of the imine functionality was also not found to be a solution for this

problem. Previous work in the Tsogoeva group showed lower enantioselectivities for terminal

epoxides by using the reduced analog of ligand 8.70 For further investigations, more stable ligands

were required which are just as easily prepared as the imine-based ligands.


17

1.5.2 Epoxidation with imidazole-based ligands

Several examples from literature suggested that imidazole was found to be a promising ligand in

non-heme iron catalyzed epoxidation as depicted in Scheme 2, Scheme 4 and Scheme 5.45,51-54

These approaches all used nature as a guideline. Imidazole mimics the function of the axial

histidine imidazole in metalloenzymes such as cytochrome P-450, peroxidase, and catalase.76 To

date, among all these bioinspired or biomimetic examples no chiral imidazole-based ligand has

been developed for an efficient highly enantioselective epoxidation of terminal olefins via non-

heme iron catalysis.

1.5.2.1 Preliminary screening of simple imidazoles

In order to get an idea about catalytically valuable imidazole structures and substitution patterns,

some simple and commercially available achiral imidazoles were screened as iron ligand in non-

enantioselective epoxidation of 2-vinylnaphthalene (11, see Scheme 17).

Scheme 17 Screening of imdazole-based ligands: yields determined via 1H-NMR with pyrazine as internal

standard.

Due to the change from imine-based ligands to imidazole-based ligands and with it a change in

solubility and stability of the catalytic system, the reaction conditions of the model reaction as

described in chapter 1.5.1 were slightly modified according to literature known procedures.51

Since 2-methyl-2-butyl alcohol was found to be an appropriate solvent in many different

enantioselective homogeneous metal catalyzed reactions and its lower toxicity compared to

dichloromethane, it was the solvent of choice for further investigations.51-54 77-79 The amount of


18

H2O2 was raised to 3.5 equivalents. The oxidant was diluted with 2-methyl-2-butyl alcohol and

added to the mixture during the whole reaction time of 1 h via syringe pump. The catalyst itself

is again formed in situ from 5 mol% FeCl3 x 6 H2O and 10 mol% of a coordinating imidazole-based

compound (see Scheme 17). Isolation of the terminal epoxides with standard column

chromatography methods was found to be problematic and had to be avoided. SiO2 is able to

catalyze the rearrangement of the epoxide towards the corresponding aldehyde (see chapter

1.5.4). For that reason and because of previously mentioned paramagnetic effect in identifying

the conversion via NMR, a method to determine yield with an internal standard had to be

developed. The polar reaction solvent was evaporated to enable a short SiO2-plug with

dichloromethane in order to get rid of iron(III)-residues while avoiding epoxide rearrangement

in prolonged contact with the SiO2. Dichloromethane was evaporated and a defined amount of

pyrazole as internal standard was added to the redesolved mixture in chloroform-d6. After

subsequent 1H-NMR measurement, the yield was determined by calculation taking the integral

areas of internal standard and target epoxide into account.

Applying the modified catalysis and analysis procedure to the model reaction using the simple,

unsubstituted imidazole (26) as ligand the target epoxide 12 was achieved in 40% yield (see

Scheme 17). In contrast, applying N-methylimidazole (27) and 1-(trimethylsilyl)imidazole (28)

afforded the epoxide 12 only with 11% and 29%, respectively. In case of the 2,4-substituted

imidazole derivative 29, only product traces could be observed. This led to the assumption that

in case of 29 an important position of the heterocyclic ring either for H2O2 activation or

coordination is blocked or at least sterically hindered. Examples from literature proposed that

the proton at the C2 position of the imidazole is necessary for activation of the H2O2 at the iron

center forming the ferric hydroperoxo species FeOOH.80,51 The result obtained with imidazole 29

is in line with this assumption. Although the N-substituted imidazoles 27 and 28 showed

moderate catalytic activity in the model reaction, N-butylimidazole (30) providing the same

substitution pattern reached 50% yield. This fact excludes a correlation between the general

N-substitution and an inferior activity of the in situ formed catalyst. Furthermore,

N-benzylimidazole (31) led with 30% yield to a comparable result as 28. The best result was

obtained with N-phenylimidazole (32) with 53% yield which surpassed Beller’s

pyrrolidine/H2Pydic system for 2-vinylnaphthalene (11) as substrate.49

1.5.2.2 Screening of reaction conditions using an achiral ligand

For further insight into the model reaction system some reaction conditions were screened for

the most promising imidazole 32. Lowering or raising of either the reaction temperature or the

substrate concentration led without exception to reduced product formation (see Table 1,


19

Entry 2-6). Longer reaction times had no impact on product formation and the target epoxide

was obtained in yields up to 52% (see Table 1, Entry 7 and 8). It can at least be said that no

degradation of the epoxide took place in the reaction mixture over the time.

Table 1 Screening of reaction conditions using ligand 32.

Entry Substrate Conc.

[mM]

Temp. Time

[h]

Additive or Reaction

Modification

Yield

[%]a)

1 50 r.t. 1 - 53

2 25 r.t. 1 - 42

3 100 r.t. 1 - 25

4 50 0 °C 1 - 13

5 50 15 °C 1 - 22

6 50 50 °C 1 - 27

7 50 r.t. 3b) - 52

8 50 r.t. 16 - 50

9 50 r.t. 1 5 mol% H2Pydic 19

10 50 r.t. 1 5 mol% acetic acid 44

11 50 r.t. 1 5 mol%

(S)-(+)-mandelic acid

26 (rac)

12c) 50 r.t. 1 - 55

13 50 r.t. 1 under nitrogen

atmosphere

<5

14 50 r.t. 1 in situ catalyst

generation for 1 hd)

54

15 50 r.t. 1 under light irradiation 52

a) Yields determined via 1H-NMR with pyrazine as internal standard; b) H2O2 addition over whole reaction time;

c) 20 mol% ligand and 10 mol% iron salt; d) 1 h stirring of catalyst components prior to substrate and oxidant addition.

Furthermore, carboxylic acid additives were screened e.g. H2Pydic and acetic acid, which both

already demonstrated a synergistic effect in non-heme iron catalytic systems (see Scheme 3,

Scheme 6, Scheme 7 and in chapter 1.5.1).46,57,55 In general carboxylic acids are known for their


20

positive effect as co-catalyst in organo- and metal-catalyzed reactions.81 In non-heme iron

catalysis the carboxylic acid acts as coordinating ligand and facilitates the O-O cleavage and thus

promotes the formation of the active iron oxo species.82,60 This approach is inspired by similar

processes operating in cytochrome P-450. Beside H2Pydic and acetic acid, (S)-(+)-mandelic acid

was tested as well. It represents a simple but chiral carboxylic acid which is able to coordinate to

the iron center with the ability to induce chirality at the formed epoxide. Using 5 mol% H2Pydic

the yield of 12 was lowered to 19% (see Table 1, Entry 9). The same effect was observed for

(S)-(+)-mandelic acid and the product was found to be racemic (see Table 1, Entry 11). Acidic acid

had no significant impact on the model reaction except a slight decrease of yield (see Table 1,

Entry 10). Even double catalyst loading did not raise the yield over 55% (see Table 1, Entry 12).

Interestingly, when the reaction was carried out under N2 atmosphere, only product traces were

formed (see Table 1, Entry 13). This indicates that the surrounding air participates somehow in

the formation of a catalytic active species. The formation of a self-assembled µ-oxo-iron(III)

dimer as catalytically active species might be an explanation as already described by Jacobsen82

and Stack.83 But in situ catalyst generation prior to the substrate and oxidant addition to ensure

self-assembly of the possibly instable complex had no positive impact on yield (see Table 1,

Entry 14). To exclude potential light induced decomposition of the H2O2 or the formation of a

light sensitive complex, the effect of irradiation during the reaction process was investigated by

applying a cold-light source (white high-power-LED, 400-700 nm; see Table 1, Entry 15).

However, the yield of the target epoxide was in the same range as reported without additional

irradiation.

1.5.2.3 Synthesis and screening of chiral imidazole-based peptide-like ligands

Based on this preliminary screening of simple imidazoles, the most promising one

N-phenylimidazole (32, Scheme 17) was used as achiral blueprint for the design of further chiral

ligands and their application in enantioselective epoxidation of 2-vinylnaphthalene (11). Inspired

by nature ligand 32 was combined with a small chiral peptide-like moiety 35, which contributes

to the incorporation of an iron ion, imitating a catalytically active enzyme pocket. This artificial

enzyme cavity should direct the substrate to the activated oxygen, forming exclusively one

enantiomer. The synthesis of 36 is carried out as depicted in Scheme 18. Starting compound 32

was formylated according to literature procedure with n-BuLi and DMF achieving compound 33

with 96% yield.84 An EDC-coupling reaction with an in situ deprotection step using Boc-protected

L-tert-leucine and (R)-3,3-dimethyl-2-butylamine afforded 35 with 92% yield. The condensation

reaction of 33 with 35 and subsequent reduction of the raw material with NaBH4 yielded the

target compound 36 with 15% yield.


21

Scheme 18 Route of synthesis towards imidazole-based peptide-like ligand 36.84

All imidazole-based peptide-like ligands 37-42 tested for further non-heme iron catalytic

experiments (see Scheme 20) were prepared following a similar procedure as described for

ligand 36, depicted in Scheme 19. The required imidazole carboxaldehydes were either

commercially available or synthesized according to literature procedure.85

Scheme 19 Synthesis of imidazole-based peptide-like ligands 37-42.


22

The newly designed ligand 36 contains two tert-butyl groups which are known to have a positive

effect on enantioselectivity compared to other residues due to their bulkiness. Thus, unfavorable

steric interactions can be avoided as described for the salen-type ligand in Jacobsen’s catalyst

(see Scheme 1).28 After the reductive amination, depicted in Scheme 18, the peptide-like moiety

is linked to the C2 position of the N-phenylimidazole via a CH2 group. Hence, a chemically stable

ligand was tailored providing a [NN]-binding motif for the coordination to a metal center

comparable to the one in salalen ligands.86,87

Applying ligand 36 to the model reaction system already used for the screening of imidazole

derivatives the target epoxide 12 was obtained in 27% yield and 34% ee (see Scheme 20). Even

the yield is inferior to the one obtained with ligand 32 (53% yield), ligand 36 surpassed the imine-

based ligand 8 reaching only about 17% conversion and comparable enantioselectivity (see

Scheme 13). In order to get an insight into the function of the C2 position of the imidazole moeity

a ligand without C2-substitution has to be tested. This imidazole substitution might have been

the reason for the low catalyst activity regarding malfunctional H2O2 activation applying ligand

29 in the preliminary screening (chapter 1.5.2.1, see Scheme 17).51 Thus, ligand 37 was tested

providing the same [NN]-coordination motif but without C2-substitution due to the

1,4-substitution pattern. However, no significant improvement in yield (32%) and in addition a

decrease in enantiomeric excess (3%) was observed with ligand 37 (see Scheme 20).

Furthermore, the influence of the N-imidazole residue was investigated by testing N-methylated

ligand 38 providing a 1,2-substituted imidazole. Although the preliminary screening of the

methylated imidazole 27 let assume a decrease in yield compared to the N-phenylated ligand 32

(Scheme 17), with ligand 38 the yield increased to 44% and the enantiomeric excess was 26%

(see Scheme 20). The enantiomeric excess could be further improved to 36% by lowering the

reaction temperature to 0 °C. However, at the same time the yield dropped to 23%. Ligand 39

with an 1,4-substituted imidazole moiety led to a racemic epoxide with only 24% yield and

showed the same effect as the phenylated 1,4-substituted imidazole ligand 37. At that point

ligand 40 was tested providing a 1,5-substituted imidazole and thus not bearing a [NN]-binding

site. The product was obtained in 10% yield as racemate (see Scheme 20). This result

demonstrated the importance of the [NN]-coordination motif present in ligand 38 and 39, since

with these ligands it was possible to reach higher yields of the target product 12. Applying

N-unsubstituted ligands 41 and 42, the same tendencies were observed as previously described

for the N-phenylated (36 and 37) and N-methylated ones (38 and 39). With ligand 41 epoxide 12

was obtained in 35% yield and with 34% ee (see Scheme 20). The enantioselectivity was slightly

improved to 36% by carrying out the reaction at 0 °C, but the yield decreased to 23%. Ligand 42

was found to be less efficient than 41 with a decrease in yield and enantioselectivity (29% yield,


23

16% ee; depicted in Scheme 20). The screening revealed 38 as the most promising ligand offering

a compromise between good yield and good enantioselectivity.

Scheme 20 Screening of chiral peptide-like imdazole-based ligands: yields determined via 1H-NMR with

pyrazine as internal standard; ee-values determined via chiral HPLC measurement

(* = smaller scheduled quantity of 332 µmol substrate was used).

In order to reveal the important functional groups of ligand 38 for the in situ formed catalyst,

modified ligands 46, 47, 49 and 50 were tested as structural analogues of the parent compound

for the model reaction of 2-vinylnaphthalene (11, Scheme 21). Within the scope of this work,

ligand 43, 46 and 47 were synthesized (see Scheme 21). Ligands 44 and 48 were kindly provided

by Dr. Jorge Vargas-Caporali (dashed frames, Scheme 21). A methylation reaction of the

secondary amine of 38 was carried out with formic aldehyde and sodium triacetoxyborohydride

obtaining ligand 43 with 31% yield, as depicted in Scheme 21. Ligand 44 was obtained by


24

reduction of ligand 38 with AlCl3-LiAlH4. Starting from L-proline, a Boc-protection in 66% yield

(forming 45) and a following EDC coupling reaction with subsequent deprotection was carried

out either with (R)-3,3-dimethyl-2-butylamine or the previously synthesized amine 35 (see

Scheme 21). After reductive amination with 1-methyl-2-imidazolecarboxaldehyde, ligand 46 was

obtained in 27% yield and ligand 47 with 65% yield (see Scheme 21). Ligand 48 was synthesized

starting from already available building blocks 34 and 35 using previously described reaction

procedures (EDC-coupling and reductive amination; see Scheme 21).

Scheme 21 Routes of synthesis towards structural analogues of 38.

The screening of these ligands should confirm the proposed [NN]-coordination motif as binding

moiety to the iron center and give further insight if and how catalytically active iron species are

formed. When ligand 43 was applied to the catalytic model oxidation of 2-vinylnaphthalene (11)

the target epoxide 12 was obtained in 12% yield and was racemic (see Scheme 21). Thus, the

secondary nitrogen in 38 played a key role in the enantioselective epoxidation probably due to


25

the salalen-like binding event which was suppressed in case of ligand 43. Furthermore, when

ligand 44 was applied, not providing the amide derived carbonyl function of ligand 38, only

product traces were observed with negligible enantiomeric excess (see Scheme 21). This led to

the assumption that either the carbonyl oxygen of 38 coordinates to the iron center or an amide-

nitrogen is required for the formation of an active iron complex and no secondary amine at this

position. Moreover, the role of the peptide-like backbone was investigated, if either a more rigid

or a more flexible one is required. For this purpose, the more rigid amino acid L-proline was

incorporated obtaining ligand 46 instead of the more flexible L-tert-leucine. Applying ligand 46

to the model reaction, only traces of 2-vinylnaphthalene oxide (12) were observed with small

enantiomeric excess (see Scheme 22). This corroborates the assumption that neither the tertiary

nitrogen of the proline unit (comparable with ligand 43) nor the less flexible backbone enabled

the formation of a catalytically active complex and thus H2O2 activation and oxygen transfer was

prevented. In addition, comparing ligand 46 with 38, it is conceivable that the missing positive

effect of the L-tert-leucine-derived tert-butyl group led to the inferior result.

Scheme 22 Screening of ligands 43, 44, 46, 47 and 48 as structural analogues of 38: yields determined via

1H-NMR with pyrazine as internal standard; ee-values determined via chiral HPLC

measurement.

A combination of an L-proline and an L-tert-leucine moiety within one peptide-like ligand built

up 47. Testing 47 for the model reaction, the target epoxide was obtained in only 9% yield and

11% enantiomeric excess. In parallel, a second L-tert-leucine unit was incorporated and with it


26

an extended version of 38 was formed with ligand 48 in order to investigate the positive influence

of the L-tert-leucine moiety. The enantioselective epoxidation applying ligand 48 led to 40% yield

which is in the range as reached with 38. However, the enantiomeric excess was lowered from

26% to 18%. Keeping the comparison of 46 and 38 in mind, the comparison of 47 and 48 showed

that the proline unit inhibits somehow the formation of a catalytically active iron species.

1.5.2.4 Insight into catalyst formation via UV/Vis spectroscopy

Even though the ligand screening revealed some insights into important functionalities and

properties of the imidazole-based peptide-like ligand, UV/Vis spectroscopy measurements were

carried out to gain evidence for the in situ complex formation process (see Figure 2). The

circumstance that 2-methyl-2-butyl alcohol is a strong absorbing solvent could be neglected due

to the fact that all measured samples were dissolved in 2-methyl-2-butyl alcohol and the

measurements were analyzed above 225 nm.88 The absorption spectra of ligand 35 (0.5 mM;

violet) and FeCl3 x 6 H2O (0.25 mM; blue) were individually measured in 2-methyl-2-butyl alcohol,

as depicted in Figure 2. The comparison of these two absorption spectra with the one of the

mixture in a 2:1 molar ratio (ligand to iron source) showed a distinct shift of the characteristic

FeCl3 x 6 H2O absorption maxima (red; Figure 2). The change of high-energy transitions (250-

400 nm) indicated that the iron interacted with ligand 38, forming a complex with 0.25 mM.89-91

An additional structural change of the previously generated iron complex took place as soon as

H2O2 was added (17.5 mM; H2O2-to-complex ratio as in the actual model reaction) suggested by

a further UV/Vis spectrum (green; Figure 2). This is attributed to the formation of an oxygen-

transferring iron species.47

Figure 2 Investigation of complexation using UV/Vis spectroscopy.

-1

-0,5

0

0,5

1

1,5

2

2,5

3

220 270 320 370 420 470 520

Ab

sorb

ance

λ [nm]

FeIII complex with ligand 38 (c = 0.25 mM)

FeCl3 x 6 H2O Abs

FeCl3 x 6 H2O + Ligand Abs

FeCl3 x 6 H2O + Ligand + H2O2 Abs

Ligand Abs


27

1.5.2.5 Screening of reaction conditions using a chiral ligand

Further investigation of the catalytic system using ligand 38 dealt with the possibility that

coordination positions of the iron center are blocked by an unnecessary excess of the ligand with

the use of a 2:1 molar ratio of ligand to iron source. This is likely because ligand 38 provides more

than two possible coordination sites compared to one for ligand 32. This option could suppress

H2O2 activation and consequently reduce the amount of formed epoxide. This possibility was

excluded when the amount of ligand 38 was reduced to a 1:1 molar ratio (Table 2, Entry 2). The

yield decreased while the enantiomeric excess stayed constant. This result points out that a 2:1

molar ratio of ligand to iron source is required for efficient catalysis in further experiments. Even

though the double amount of ligand has no influence on enantioselectivity, it was found to lead

to a better yield (Table 2, Entry 1). The in situ complexation of a mixed catalyst derived from

ligands 32 and 38 (each added with 5 mol%) led to 30% yield with 18% ee (Table 2, Entry 3).

Table 2 Screening of reaction conditions using ligand 38.

Entry Ligand Additive or Reaction

Modification

Yield

[%]a)

ee

[%]b)

1 10 mol% 38 - 44 26

2 5 mol% 38 - 31 26

3 5 mol% 38 / 5 mol% 32 - 30 18

4 10 mol% 38 in situ catalyst generation for 1 h

under air streamc)

42 24

5 10 mol% 38 5 mol% (S)-(+)-mandelic acid 32 26

a) Yields determined via 1H-NMR with pyrazine as internal standard; b) ee-values determined via chiral HPLC

measurement; c) 1 h stirring of catalyst components prior to substrate and oxidant addition.

Comparing this result in particular with Table 2, Entry 2 and Table 1, Entry 1 it can be proposed

that the combination of both ligands did not show any synergistic effect. It rather negatively

affected their independent catalytic activity. 1 h in situ catalyst generation prior to substrate and


28

oxidant addition for self-assembly of the complex which is favored under air atmosphere had no

positive impact on the model reaction using ligand 32 (see Table 1, Entry 14). Nevertheless, the

effect of a direct air stream into the catalyst mixture during 1 h in situ complex generation prior

to substrate and oxidant addition was investigated in case of the model reaction using ligand 38

(Table 2, Entry 4). However, once again no change in yield and enantioselectivity could be

detected. Furthermore, the influence of (S)-(+)-mandelic acid as additive on the reaction applying

ligand 38 was investigated. By adding 5 mol% (S)-(+)-mandelic acid, no change in

enantioselectivity and a decrease in yield from 44% to 32% was observed (Table 2, Entry 5). The

same happened to the model reaction system applying achiral ligand 32 as discussed before. The

yield decreased when 5 mol% (S)-(+)-mandelic acid were added and 2-vinyllnaphtyl oxide (12)

was formed as a racemate (Table 1, Entry 11). Hence, an effect of (S)-(+)-mandelic acid on the

enantioselectivity can be excluded under these reaction conditions.

The reaction procedure used for non-heme iron catalyzed epoxidation using imine-based ligands,

discussed in 1.5.1, was found to be improved by adding H2Pydic as additive.57 In order to

investigate the potential influence of (S)-(+)-mandelic acid, this reaction procedure seemed to be

suitable. At that point the reaction conditions were changed again. Thus, the amount of H2O2

(1.5 equiv.) and the temperature (0 °C) were reduced. However, 2-methyl-2-butyl alcohol was

kept as solvent and not changed back to dichloromethane owing to the property of ligand 38.

Table 3 Screening of chiral peptide-like imdazole-based ligand 38 using (S)-(+)-mandelic acid as

additive.

Entry Ligand 38

[mol%]

FeCl3 x H2O

[mol%]

(S)-(+)-Mandelic Acid

[mol%]

Yield

[%]a)

ee

[%]b)

1 10 5 5 27 42

2 5 5 15 20 37

3 20 10 10 43 38


measurement.


29

Applying these reaction conditions, the addition of 5 mol% (S)-(+)-mandelic acid as additive led

to a slight increase in enantiomeric excess to 42% (Table 3, Entry 1). To further investigate the

effect of the chiral additive and its contribution to the in situ formed complex, the amount of

(S)-(+)-mandelic acid was raised to 15 mol% and the amount of ligand 38 reduced to 5 mol% to

exclude a full occupation of all coordination positions. However, the effect on the results of the

modified reaction system was small and the values of yield and enantiomeric excess (see Table

3, Entry 2) were slightly inferior as already described for the reaction system without additive

using 10 mol% ligand 38 and 3.5 equiv. H2O2 at 0 °C (see Scheme 20). Carrying out the reaction

with twice the amount of all catalyst generating compounds, 43% yield and 38% enantiomeric

excess were obtained (Table 3, Entry 3). This was so far the best result concerning a combination

of good yield and good enantioselectivity. However, taking the reaction mass efficiency92 into

account, 20 mol% ligand 38, 10 mol% of the iron source and 10 mol% (S)-(+)-mandelic acid is an

amount of substances which is disproportionate to the result. Thus, with regard to sustainability,

the model reaction system as described before was found to be the most suitable for further

investigations concerning substrate preferences: 10 mol% ligand 38, 5 mol% FeCl3 x 6 H2O,

3.5 equiv. H2O2 (Scheme 20, ligand 38).

1.5.2.6 Substrate screening

A screening of several classes of olefins, such as non-terminal, electron rich and electron deficient

ones with different steric and electronic properties, should elucidate the characteristics of the

catalyst by drawing conclusions from substrate preference. All tested substrates were found to

be oxidized with lower yield than the model substrate, 2-vinylnaphthalene (12) as depicted in

Table 4. A reason for this could be on the one hand the good accessibility of the terminal electron

rich double bond of 11 to the iron center due to less electronic repulsion. On the other hand,

good stabilization of the spatial demanding naphthyl moiety could be an explanation as well. In

comparison with the model epoxide 12, styrene oxide was obtained in a lower yield (30%),

providing a smaller π-system and with it a less electron rich terminal bond (Table 4, Entry 2). The

same effect was even more pronounced with styrene derivatives bearing electron-withdrawing

groups such as 4-nitrostyrene and 1,2-dichloro-4-vinylbenzene, which resulted in even lower

yields (14% and 28%, Table 4, Entry 3 and Entry 4).

With one exception all styrene derivatives which were monosubstituted in α and unsubstituted

in β-position showed with 25% to 29% ee enantioselectivities in the same range as obtained for

2-vinylnaphthalene oxide (12, 26% ee). 4-methoxystyrene bearing an electron-donating group

was oxidized with only 5% yield and 14% enantiomeric excess (Table 4, Entry 5). This result was


30

surprising due to the expected tendency, that electron rich terminal olefins were favored by the

catalyst. This behavior excludes the simple explanation that the oxidizing iron species formed

during the catalytic process provides an electrophilic nature. The more sterically demanding

double bond of α-methyl styrene led to 22% yield and a lower enantiomeric excess of 16%

(Table 4, Entry 6).

Table 4 Screening of substrates.

Entry Substrate Yield

[%]a)

ee

[%]b)

1

44 26 (R)

2

30 27 (S)

3

14 29 (R)

4

25 25 (R)c)

5

5c) 14c)

6

22 16 (S)

7

32 50

8

<5 n.d.

9

27 16 (R)

10

<5 27 (2R,3S)

11d)

7 51 (2R,3S)


measurement; c) Value determined from corresponding β-aminoalcohol after aminolysis with isopropylamine; d) In

situ catalyst generation with 38 (5 mol%), FeCl3 x 6 H2O (5 mol%), (S)-(+)-mandelic acid (15 mol%), 1.6 ml 2-Me-2-BuOH,

followed by the addition of alkene (166 µmol) and 2 equiv. H2O2 via syringe pump at r.t. (3 h reaction time).


31

Surprisingly, when β-methylstyrene was employed as substrate, the yield of the corresponding

epoxide was with 32% in the range of the unsubstituted styrene but the enantiomeric excess of

50% was relatively high compared to all other tested olefins (Table 4, Entry 7). With this result

the here presented enantioselective epoxidation system excels Jacobsen’s polymer supported

peptide-based system concerning enantioselectivity (see Scheme 2).45 Taking the moderate yield

of 32% obtained for β-methylstyrene oxide into account no conclusion could yet be drawn about

the electronic nature of the oxidizing iron species. Though the methyl group at the β-position

could explain the enhanced enantiomeric excess. It might direct the substrate in a more defined

way to the H2O2 activating iron center within the chiral catalyst surrounding. A tested terminal

olefin in which the double bond is disconnected from the π-system of the phenyl ring only gave

traces of product (Table 4, Entry 8). This indicates that the catalyst is less active for electron

deficient aliphatic double bonds even if they are terminal. It can be proposed that a phenyl

moiety in direct neighborhood is highly required to enable the catalyzed epoxidation process. In

case of trans-stilbene, which represents nonterminal symmetrically substituted aromatic olefins,

the yield was 27% with 16% enantiomeric excess (Table 4, Entry 9). The lower enantiomeric

excess in comparison to styrene could be explained by the difficult access of the catalyst to the

double bond and with it the suppressed chiral information during the oxygen transferring

process. In case of trans-chalcone as representative for electron deficient but non-terminal

olefins, only product traces were observed again but with an ee-value of 27% (Table 4, Entry 10).

However, by using (S)-(+)-mandelic acid under reaction conditions described in Table 3, Entry 2

at room temperature the enantioselectivity was raised to 51% (Table 4, Entry 11). Even though

the yield was still quite low, the result was interesting due to the great influence of

(S)-(+)-mandelic acid on enantioselectivity specifically for this substrate. It was proposed that not

only the formation of the iron oxo species is favored by the carboxylic acid as described in

literature.82,60 Maybe an additional interaction between the chiral acid as additive and the

carbonyl function of chalcone enhanced the enantiodiscriminating effect.

In summary, this chapter revealed the development of a new biomimetic enantioselective non-

heme iron catalyzed epoxidation system. A screening of different imidazole-based peptide-like

ligands for the in situ generated chiral iron(III) catalysts took the imidazole substitution pattern,

coordinating motif and further important functionalities into account. The most promising

imidazole-based peptide-like ligand 35 for the oxidation of 2-vinylnaphthalene (11) was found to

favor the transformation of terminal electron rich styrene-based olefins. Although the substrate

screening revealed 2-vinylnaphthalene (11) as the most appropriate substrate concerning yield,

the two non-terminal substrates chalcone and β-methyl styrene showed the most promising

results concerning enantioselectivity.


32

1.5.3 One-pot procedure towards β-amino alcohol

Owing to the growing demand in sustainable processes in chemical industry, the principle of one-

pot synthesis gained recognition in the last decade. However, this procedure is not only a

desirable approach from the ecological point of view. One-pot synthesis also means a more

economical handling of chemicals. One or more intermediary purification steps are avoided

which in turn reduces waste, time and manual operations to a minimum.93-96,13

Aminolysis is an important modification which epoxides can undergo, forming a valuable class of

compounds: 2-aminoalcohols. Biologically active chiral compounds like β-adrenergic blockers,

which contain a 2-aminoalcohol moiety, were already synthesized in an organocatalytic one-pot

process. The enantioselective epoxidation step is combined with a subsequent aminolysis

reaction preserving chirality and forming (R)-pronethalol and (R)-dichloroisoproterenol.13,97 The

combination of the developed non-heme iron catalyzed systems using imidazole-based peptide-

like ligands (presented in 1.5.2) followed by an aminolysis reaction in a one-pot process is

discussed in this chapter.

The compatibility with an aminolysis reaction was tested for the two previously described

epoxidation methods using 2-vinylnaphthalene (11) as substrate and 38 as ligand. Method A was

carried out at room temperature with a ligand-to-metal-ratio of 2:1 as described in Table 4,

Entry 1. Method B was carried out at 0 °C with 15 mol% (S)-(+)-mandelic acid as additive as

described before in Table 3, Entry 2. Method B was tested to investigate a possible negative

effect of (S)-(+)-mandelic acid on the aminolysis reaction. Table 3, Entry 2 was chosen due to the

high amount of additive which was used even though the yield and enantioselectivity were

inferior compared to the other entries using (S)-(+)-mandelic acid.

The first approach in the course of this work was a simple addition of 18 equivalents of isopropyl

amine to the reaction mixture after method A was carried out. Prior quenching of the oxidant

with saturated aqueous Na2SO3 solution was not performed (Table 5, Entry 1). Subsequently, the

reaction mixture was heated to 50 °C for 18 h. The target compound, named (R)-pronethalol,

was obtained in 37% yield and 23% ee after purification via SiO2 column chromatography. The

2-aminoalcohols were found to be stable towards standard purification methods and it was not

necessary to use an internal standard for the determination of yield. The results concerning yield

and enantioselectivity were in the same range as described for the epoxide step before

(44% yield, 26% ee; Table 4, Entry 1). The minor decrease in yield can be explained by the

isolation process of the 2-aminoalcohol. Thus, the developed epoxidation reaction systems using

method A needed no further adaption like solvent change or quenching of reagents to make the

aminolysis feasible. Applying the same approach for method B, similar compatibility of the

developed non-heme iron epoxidation system with a subsequent aminolysis was observed as


33

described for method A (Table 5, Entry 2). The obtained yield (15%) was slightly lower than

described for the separate epoxidation step using (S)-(+)-mandelic acid as additive (20% yield,

37% ee; Table 3, Entry 2). The enantiomeric excess was found to be preserved. Hence, no

negative effect of (S)-(+)-mandelic acid on the aminolysis reaction was observed.

Table 5 One-pot procedure towards 2-aminoalcohols.

Entry Substrate Methoda) Yield

[%]b)

ee

[%]c)

1

A 37 23 (R)

2

B 15 36 (R)

3

A 24 25 (R)

4d)

A 5 14

a) Method A: Epoxidation procedure as described in Table 2, Entry 1 with ligand 38 (10 mol%), FeCl3 x H2O (5 mol%);

Method B: Epoxidation procedure as described in Table 3, Entry 2 with ligand 38 (5 mol%), FeCl3 x H2O (5 mol%),

(S)-(+)-mandelic acid (15 mol%); b) Yield is isolated yield via preparative SiO2 column chromatography; c) ee-values

determined via chiral HPLC measurement; d) Same approach was already listed in Table 4, Entry 5.

Beside 2-vinylnaphthalene, the process was successfully carried out for 1,2-dichloro-

4-vinylbenzene forming (R)-dichloroisoproterenol (Table 5, Entry 3) and for 1-methoxy-

4-vinylbenzene (Table 5, Entry 4) as substrates. In the case of 1,2-dichloro-4-vinylbenzene, no

distinct loss of yield was monitored either. The determination of yield and enantiomeric excess

of the 1-methoxy-4-vinylbenzene oxide was only found to be feasible after the one-pot

procedure from the corresponding 2-aminoalcohol (Table 4, Entry 5). Thus, no comparable

values for the separate epoxidation reaction were available.

This chapter demonstrated successfully the first attempts towards a new environmentally and

ecologically friendly method in synthesizing 2-aminoalcohols like the β-adrenergic blockers

(R)-pronethalol and (R)-dichloroisoproterenol. The aminolysis conditions were found to match

perfectly with the reaction conditions of the previously developed non-heme iron catalyzed

epoxidation. No further adaption of reaction conditions was needed.


34

1.5.4 SiO2 catalyzed rearrangement of epoxide

Isolation of the terminal epoxides using SiO2 for column chromatography was found to catalyze

the rearrangement of the epoxide towards the corresponding acetaldehyde derivatives (as

described in 1.5.2). SiO2 (Macherey-Nagel Silica gel 60 M) acted as a Lewis acid during the

purification process and hence favored the rearrangement.98,99 This phenomenon was not

observed for isolation of non-terminal olefins. The so called Meinwald rearrangement is known

to be catalyzed by Lewis acids forming carbonyl compounds, as depicted in Scheme 23.100

Scheme 23 Schematic illustration of Lewis acid (LA) catalyzed Meinwald rearrangement.100

The migratory aptitude of the epoxide substituents and the employed solvent were identified as

critical in determining the product distribution of the reaction (A and B in Scheme 23).101 Lewis

acids such as boron trifluoride diethyletherate, lithium salts, magnesium bromide or

methylaluminium bis(4-bromo-2,6-di-tert-butylphenoxide) (MABR) were found to be active in

stoichiometric quantities.102-104 Besides, catalytic amounts of palladium salts, indium trichloride,

iridium trichloride, bismuth salts, gallium salts and copper tetrafluoroborate were used for the

activation of the epoxide favoring the rearrangement process.105-111 Since the growing interest in

heterogeneous catalysis, some mesoporous materials like aluminosilicate have been identified

as catalysts for Meinwald rearrangement which can be easily filtered off.112-115

Even though acetaldehyde derivatives are versatile compounds, some of their synthesis and

purification procedures are extensive and thus suffer from low yields.116,117 It is an attractive task

to get an approach to this class of compounds via simple and efficient transformation combined

with easy purification. Examples from literature already demonstrated the Meinwald

rearrangement as a good starting point and source of aldehydes, which are not easy to purify or

handle, in one-pot or domino reactions.116,118,119

With regard to the investigated model reaction of chapter 1.5.1 and 1.5.2 using

2-vinylnaphthalen oxide (12) as target epoxide, the first investigations concerning Meinwald

rearrangement were carried out with this substrate. The substrate 12 was obtained by oxidation

of 2-vinylnaphthalen (11) using meta-chloroperoxybenzoic acid (mCPBA) as the oxidant. The

purification only included aqueous work up, recrystallization and placing under vacuum to

remove the volatile olefin residue, in order to avoid column chromatography. However, small


35

amounts of impurities remained and therefore the amount of applied substrate for catalysis was

determined via 1H-NMR using pyrazine as internal standard.

Since the rearrangement of 2-vinylnaphthalen oxide (12) towards 2-(naphthalen-

2-yl)acetaldehyde (49) was observed during column chromatography with hexane and ethyl

acetate as eluent, the first approach to investigate this phenomenon was carried out in ethyl

acetate with 5.40 g/mmol SiO2 per amount of substrate (Table 6, Entry 1). The reaction mixture

was an organic gel-like suspension and the SiO2 could be easily filtered off. However, no

conversion of the epoxide was observed after 18 h at room temperature. The solvent was

changed to dichloromethane, which was used before to dissolve the reaction mixture and enable

SiO2 column chromatography for purification. Finally, the corresponding aldehyde 49 was formed

and after 18 h the reaction mixture was filtered and 1H-NMR showed an epoxide-aldehyde ratio

of 30 to 70 (Table 6, Entry 2). When the amount of SiO2 was reduced in order to a have a less gel-

like mixture, the aldehyde was fully consumed after 18 h reaction, even the yield of 49

determined via pyrazine was only 29% (Table 6, Entry 3). An explanation for the low yield of the

product at full conversion and in absence of side products could be chemical or physical

absorption of the epoxide. In order to reduce the reaction time the temperature was raised to

the boiling point of dichloromethane (40 °C).

Table 6 Screening of reaction conditions for Si-based catalyzed Meinwald rearrangement of

2-vinylnaphthalen oxide (12).

Entry Catalyst Amount of

Catalyst

Solvent Temp. Time

[h]

Yield [%]a)

(Epoxide :

Aldehyde)

1 SiO2 5.40 g/mmol EtOAc r.t. 18 -

2 SiO2 5.40 g/mmol DCM r.t. 18 n.d. (30:70)

3 SiO2 3.33 g/mmol DCM r.t. 18 29 (0:100)

4 SiO2 3.33 g/mmol DCM reflux 2.5 32 (0:100)

5 SiO2 65 g/mmol DCM reflux 21 <5

6 TMSOTf 5 mol% DCM r.t. 6 decomp.

7 DTBS ditriflate 5 mol% DCM r.t. 2.5 decomp.

a) Yields determined via 1H-NMR with pyrazine as internal standard.

The reaction under reflux was monitored by TLC and resulted in 32% yield at full conversion of

the substrate after 2.5 h (Table 6, Entry 4). When the amount of SiO2 was reduced to 65 g/mmol


36

after 2.5 h, no conversion was observed on the TLC plate and the reaction was stirred further

(Table 6, Entry 5). After 21 h only traces of product could be observed. In addition, the effect of

other Si-based Lewis acids was investigated. The addition of catalytic amounts of trimethylsilyl

trifluoromethanesulfonate (TMSOTf, Table 6, Entry 6) and di-tert-butylsilyl

bis(trifluoromethanesulfonate) (DTBS ditriflate, Table 6, Entry 7) led to decomposition of the

substrate and the corresponding aldehyde 49 was not detected in the raw mixture. Therefore,

the weak Lewis acidity of SiO2 was found to be beneficial for this substrate.98,99

A further screening for Meinwald rearrangement conditions was carried out for commercially

available styrene oxide. Thus, critical purification of the epoxide substrate was avoided. Due to

the volatility of styrene oxide (50) and 2-phenylacetaldehyde (51), chloroform-d1 was used as

solvent. This solvent enabled subsequent NMR measurement after filtration without evaporation

of the reaction solvent. When the reaction was carried out applying 3.33 g/mmol SiO2 at room

temperature, only traces of product 51 were observed after 18 h (Table 7, Entry 1). When the

reaction temperature was raised to reflux conditions of chloroform-d1 (60 °C), the epoxide-

aldehyde ratio was found to be 74:26 after 5 h (Table 7, Entry 2). Thus, temperature favored the

conversion towards the aldehyde but not as strongly as observed for 2-vinylnaphthalen oxide

(12). With lower substrate concentration but longer reaction time, the yield improved to 36%

with an epoxide-aldehyde ratio of 26:74 (Table 7, Entry 3).

Table 7 Screening of reaction conditions for Si-based catalyzed Meinwald rearrangement of styrene

oxide (51).

Entry Amount of

SiO2

[g/mmol]

Solvent Substrate

Conc. [M]

Temp. Time

[h]

Yield [%]a)

(Epoxide :

Aldehyde)

1 3.33 CDCl3 0.15 r.t. 18 <5

2 3.33 CDCl3 0.15 reflux 5 17 (74:26)

3 3.33 CDCl3 0.03 reflux 18 36 (26:74)

4 1.67 CDCl3 0.03 reflux 18 30 (54:46)

5 3.33 CDCl3 + H2O (5:2) 0.03 reflux 18 -

6 3.33 2-Me-2-BuOH 0.03 reflux 18 9

a) Yields determined via 1H-NMR with pyrazine as internal standard.

Under the same reaction conditions but with half of the SiO2 loading (1.67 g/mmol), the catalysis

gave the product with 30% yield and with a ratio of 54 to 46 (epoxide:aldehyde), as depicted in


37

Table 7, Entry 4. With lower amount of SiO2 (Table 7, Entry 4) yield and epoxide-aldehyde ratio

correlated more, in comparison to Table 7, Entry 3. This fact supports the hypothesis of chemical

or physical absorption of substrate on the SiO2, which is possibly taking place during the catalysis.

To minimize this absorption process by favoring the cleavage process of the substrate or product

from SiO2, water was added to the reaction mixture (Table 7, Entry 5). However, no reaction took

place at all. Even though no solution for the absorption process was found, Entry 5 gave at least

a hint about the required anhydrous reaction conditions. With regard to further one-pot

transformations with non-heme iron catalyzed epoxidation, the catalyzed Meinwald

rearrangement was carried out in 2-methyl-2-butyl alcohol instead of chloroform-d1 (Table 7,

Entry 6). But even under reflux after 18 h reaction time, only 9% yield of the corresponding

aldehyde were achieved. The reliability of this value is not fully guaranteed, due to the proximity

of the boiling points of 2-methyl-2-butyl alcohol and 2-phenylacetaldehyde (51), even though the

solvent should be evaporated earlier. In order to investigate the potential access to chiral

aldehydes, the SiO2 catalyzed Meinwald rearrangement was applied to α-methylstyrene oxide

(52). Indeed, after 6 h under reflux in dichloromethane the epoxide 52 was fully consumed and

the aldehyde 53 was formed (Scheme 24). With regard to future HPLC measurements the

unpurified aldehyde was reduced to the corresponding alcohol 54 using NaBH4. The reduction

was found to be feasible by raw product 1H-NMR.

Scheme 24 Meinwald rearrangement of α-methylstyrene oxide (52) and subsequent reduction.

However, the purification and HPLC characterization of 54 was not part of this work and

therefore was not performed.

In summary, a simple transformation of terminal epoxides towards the corresponding aldehydes

via Meinwald rearrangement was shown to be feasible with SiO2, which was conventionally used

for column chromatography.

1.5.5 Non-heme iron catalyzed aziridination

Aziridines are the nitrogen equivalents of epoxides and are highly useful intermediates and

building blocks of fine chemicals as well as pharmaceuticals.15 As shown in chapter 1.3, several

promising approaches in non-heme iron catalysis towards epoxides were developed. However,


38

in case of non-heme iron catalyzed aziridination only a few examples are known and among them

even less deal with an enantioselective approach.67

In order to investigate the applicability of the non-enantioselective, non-heme iron epoxidation

catalyst used in chapter 1.5.2 (Table 1, Entry 1) for aziridination reaction, a new model reaction

was chosen. Following a procedure known from literature by Cramer and Jenkins in a modified

way, 1-azido-4-methylbenzene (55) was chosen as nitrogen source and 1-decene (56) as terminal

olefin.120,121 The original procedure of Jenkins and Cramer, published in 2011, used an iron(II)

complex containing a macrocyclic tetracarbene ligand (58, in Scheme 25).120

Scheme 25 Non-heme iron catalyzed aziridination with macrocyclic tetracarbene complexes 58 and 59 by

Jenkins and Cramer.120,121

They obtained the aziridine 57 in 70% yield by applying a catalyst loading of 0.1 mol%. In 2016,

Cramer published a second-generation iron aziridination catalyst that is supported by a borate

containing macrocyclic tetracarbene (59, in Scheme 25).121 Here, a yield of 95% was reached

using 1 mol% of 59 as catalyst. Due to the high excess of 1-decene (56), the use of an additional

solvent became obsolete, as shown in Scheme 25. However, when non-heme iron epoxidation

catalyst with ligand 32 was applied, the catalyst components could not be fully dissolved in 53

and thus 2-methyl-2-butyl alcohol was added and the reaction was carried out in a 1:1 mixture

of 2-methyl-2-butyl alcohol and 1-decene (56, Table 8, Entry 1). After the reaction mixture was

stirred for 1 day at room temperature, no conversion could be detected. Hence, the reaction

temperature was raised to 90 °C for 3 days. After purifying the mixture via column

chromatography with deactivated SiO2, the product was isolated in 22% yield. In order to

investigate a possible background reaction, 1-azido-4-methylbenzene (55) was heated in

1-decene (56) for 18 h at 90 °C (Table 8, Entry 2). Indeed, without any additional iron catalyst the

target aziridine 57 was isolated in 59% yield. Thus, in case of the applied in situ formed catalyst

using ligand 33, the complex was not only catalytically ineffective but the background reaction


39

was suppressed. Therefore, the challenge for this aziridination model reaction was to excel the

background reaction and reach full conversion in a shorter reaction time. To achieve this goal,

four different imidazole-based carbene complexes were tested as catalysts based on the

promising result of Jenkins and Cramer (58, 59 in Scheme 25). The complexes 60 to 63 depicted

in Figure 3 were kindly provided by the working group of Prof. Dr. K. Meyer from the Institute for

Inorganic Chemistry at the Friedrich-Alexander University Erlangen-Nürnberg.

Figure 3 Imidazole-based carbene iron complexes 60-63 provided by working group of Prof. Dr. K.

Meyer.

Applying carbene complex 60, which can appear in two forms in dependence from the solvent,

the aziridine was obtained in 44% yield after purification (Table 8, Entry 3). For complex 61

(Table 8, Entry 4) and 62 (Table 8, Entry 5) the achieved yield was only slightly increased to 50%

and 46%, respectively, but neither exceled the reaction without catalyst. The carbene complex

63 was found to be the best performing catalyst among all tested complexes, reaching 58% yield.

Yet 63 was just as efficient as the background reaction and led to the same amount of product

(Table 8, Entry 6). This indicates the complex did not influence the whole reaction process at all.

Hence, none of the tested complexes 60 to 63 depicted in Figure 3 were able to favor the

aziridinination reaction and did not perform better as the background reaction.

With regard to enantioselective transformations of the in situ generated catalysis systems or

potential carbene complexes for aziridination, the background reaction has to be suppressed

otherwise the enantioselectivity will be low. A possible way to circumvent the background

reaction could be the lowering of temperature from 90 °C to room temperature. This proposal is

confirmed by Entry 1 of Table 8. No product formation could be observed on the TLC within one


40

day until the temperature was raised to 90 °C. However, no further investigations concerning

non-heme catalyzed aziridination reaction were carried out.

Table 8 Catalyst screening for non-heme iron catalyzed aziridination.

Entry Catalyst Time Temp. Yield

[%]a)

1 (af16-66)b) FeCl3 x 6 H2O, Ligand 32 4 d r.t. (1 d) 90 °C (3 d) 22

2 (af16-50) without catalyst 18 h 90 °C 59

3 (Af16-67) [(BIMPNMes,Ad,Me)FeII(Cl)] 60 18 h 90 °C 44

4 (Af16-70) [(HBIMENMes)FeII](PF6) 61 18 h 90 °C 50

5 (af16-73) [(MIMPNMes,Ad,Me)FeII] 62 18 h 90 °C 46

6 (Af16-54) [(TIMENMes)FeII](BF4)2 63 18 h 90 °C 58

a) Yield is isolated yield via deactivated SiO2 column chromatography; b) 1:1 mixture of 2-methyl-2-butyl alcohol and

1-decene (56).


41

1.6 Conclusion

Two classes of easy accessible chiral ligands were investigated, in order to develop an efficient

non-heme iron catalysis system for enantioselective epoxidation of terminal olefins: imine-based

ligands and imidazole-based peptide-like ligands. As model reaction for the in situ generated

catalysts the epoxidation of 2-vinylnaphthalene (11) was chosen. Applying imine-based ligands

forming an iron complex in combination with FeCl3 x 6 H2O, conversions of up to 33% and

ee-values of up to 38% were obtained. However, imine-based ligands suffer from undesirable

degradation during the catalysis process. Thus, the more stable imidazole-based peptide-like

ligands are beneficial. A set of ligands was synthesized and tested, taking the imidazole

substitution pattern, coordinating motif and further important functionalities into account.

Among all synthesized ligands, compound 38 was identified as the most promising, providing a

[NN]-binding motif, beneficial tert-butyl groups and an amide function contributing to the iron

coordination (see Scheme 26). 2-Vinylnaphthalene oxide (12) was obtained in 44% yield and thus

exceeded the so far existing non-heme iron catalyzed systems. With an enantiomeric excess of

26% the first enantioselective non-heme iron catalyst for epoxidation of 2-vinylnaphthalene (11)

was developed. Although, the in situ generated catalyst was not active in aziridination reaction,

the new catalytic epoxidation system was found to be compatible with a following aminolysis

reaction in a one-pot process. This one-pot reaction is a promising route towards

pharmaceutically relevant 2-aminoalcohols (see Scheme 26). Besides, a SiO2 catalyzed Meinwald

rearrangement of the obtained epoxides was observed and depicts a promising method for easy

access to valuable acetaldehyde derivatives (see Scheme 26).

Scheme 26 Enantioselective non-heme iron catalyzed epoxidation with ligand 38; Combination with

aminolysis in a one-pot process and SiO2 catalyzed Meinwald rearrangement of corresponding

epoxide.


42

1.7 Experimental Section

1.7.1 Methods, materials and instruments

Chemicals:

All chemicals used for synthesis were purchased from commercial sources and were used

without further purification. Nitrogen served as protective gas. All solvents were purified by

distillation or were purchased in HPLC-grade-quality. All products were dried in high vacuum

(10-3 mbar).

The following instruments were used for the analytical and preparative work:

Thin layer chromatography (TLC):

Thin layer chromatography (TLC) was performed on silica gel TLC cards (Alugramm® SIL G/UV254,

layer thickness 0.20 mm, Macherey-Nagel) with fluorescence indicator (wavelength: 254 nm).

Preparative (flash) column chromatography:

Preparative (flash) column chromatography was performed on Macherey-Nagel Silica gel 60 M

(0.04–0.063 mm) as stationary phase.

Mass spectrometry (ESI-MS):

Mass spectral analysis was conducted on BRUKER DALTONICS micrOTOF II using electrospray

ionization.

Mass spectrometry (MALDI-MS):

Mass spectra were recorded on a Shimadzu Biotech Axima Confidence spectrometer with matrix

assisted laser desorption/ionization.

NMR spectroscopy:

1H-NMR (13C-NMR) spectra were recorded at room temperature on a Bruker Avance 300 or JEOL

JNM GX 400 spectrometer operating at 300 MHz or 400 MHz. All chemical shifts are given in the

ppm scale and refer to the non-deuterized proportion of the solvent. NMR raw data was

processed with the program MestReC 4.7.0.0. To characterize the multiplicities of the signals,

the following abbreviations are used: s (singlet), d (doublet), t (triplet), q (quartet), quin (quintet),

m (multiplet), dd (doublet of doublet), br s (broad singlet), br d (broad doublet), br t (broad

triplet).


43

Infrared spectrometry (IR):

All spectra were recorded on a Varian IR-660 apparatus in ATR mode and in substance.

Absorption maxima were noted in wave numbers [cm-1].

High performance liquid chromatography (HPLC):

HPLC spectra were recorded at room temperature on an Agilent Technologies 1200 Series HPLC

system. As a stationary phase, the following columns were utilized: IA (Daicel Chiralpak), IB

(Daicel Chiralpak), IC (Daicel Chiralpak), AS (Daicel Chiralpak), OD (Macherey-Nagel).

Polarimeter:

Optical rotations were determined on a PerkinElmer polarimeter, model 341, λ = 546 nm.

Cold-light lamp:

Light irradiation experiments with a cold-light source were carried out with a LED-high

performance cold-light source from Zett Optics (model: ZLED CLS 6000). The light flux is

600 lumen, which correlates approximately with a 150 Watt halogen lamp. The spectral

distribution of the white high-power-LED goes from approximately 400 nm to 700 nm.

1.7.2 Syntheses and spectroscopic data

1.7.2.1 Ligand synthesis

Synthesis of imine-based ligands

Ligand (8)

A mixture of 3,5-di-tert-butylsalicylaldehyde (478 mg, 2.04 mmol) and 4.5 g

4 Å-molecular sieve is stirred for 3 h in 15 ml DCM at room temperature under

inert conditions. Afterwards, (1R,2R)-(+)-1,2-diphenylethylenediamine

(433 mg, 2.04 mmol) is added and the reaction mixture is stirred for 3 h. The

molecular sieve is filtered off, the solution is concentrated (at 30 °C bath

temperature) and purified by flash column chromatography applying a steady

N2-pressure (SiO2, PE/EtOAc 7:3) to afford the target compound as a yellowish

solid (463 mg, 1.08 mmol; 53%). The impurity with bis-imine is 5%. The obtained spectroscopic

data are in accordance with literature.122

1H-NMR (300 MHz, CDCl3, r.t.): δ [ppm] = 13.59 (s, 1H), 8.45 (s, 1H), 7.38 (d, J = 2.5 Hz, 1H), 7.21-

7.09 (m, 10H), 7.07 (d, J = 2.4 Hz, 1H), 4.40 (d, J = 7.9 Hz, 1H), 4.29 (d, J = 7.8 Hz, 1H), 1.62 (br s,

2H), 1.46 (s, 9H), 1.27 (s, 9H).


44

Ligand (14)70

A mixture of ligand 8 (283 mg, 660 µmol) and 5 g 4 Å-molecular sieve

is stirred in 12 ml DCM at room temperature under inert conditions.

Then, 2-naphthaldehyde (105 mg, 670 µmol) and trimethylamine

(133 mg, 182 µl, 1.31 mmol) are added and the reaction mixture is

stirred for 3 h. The molecular sieve is filtered off, the solution is

concentrated (at 30 °C bath temperature) and purified by column

chromatography (SiO2, PE/EtOAc gradient from 19:1 to 7:3) to afford

the target compound as a yellowish solid (144 mg, 254 µmol; 38%). The obtained spectroscopic

data are in accordance with literature.

1H-NMR (300 MHz, CDCl3, r.t.): δ [ppm] = 13.80 (s, 1H), 8.48 (s, 1H), 8.31 (s, 1H), 8.03 (dd, J1 =

8.6 Hz, J2 = 1.6 Hz, 1H), 7.91 (d, J = 1.5 Hz, 1H), 7.83-7.73 (m, 3H), 7.51-7.41 (m, 2H), 7.39-7.11

(m, 11H), 6.87 (d, J = 2.4 Hz, 1H), 4.86-4.69 (m, 2H), 1.44 (s, 9H), 1.13 (s, 8H).

6,6'-dibromo-2,2'-bipyridine (23)74

2,6-Dibromopyridine (22, 5.00 g, 21.1 mmol) is dissolved in 30 ml Et2O and

cooled to -60 °C under inert atmosphere. Then n-BuLi (2.11 g, 13.2 ml,

21.1 mmol, 2.5 M solution in hexane) is added dropwise. After the reaction

mixture is stirred for 2 h at -40 °C, a solution of phosphorous oxychloride

(490 µl, 5.30 mmol) in 20 ml Et2O is added. The reaction mixture is stirred for

additional 2 h and then warmed to room temperature. Afterwards, 30 ml of water are added to

the reaction mixture. The Et2O layer is separated and washed with water and dried over Na2SO4.

After removing the solvent, the crude product is separated by column chromatography (SiO2,

hexane/EtOAc 8:1). After recrystallization from benzene, the target compound is obtained as a

white solid (1.03 g, 3.28 mmol; 31%). The obtained spectroscopic data are in accordance with

literature.

1H-NMR (300 MHz, CDCl3, r.t.): δ [ppm] = 8.36 (dd, J1 = 7.7 Hz, J2 = 0.9 Hz, 2H), 7.65 (t, J = 7.8 Hz,

2H), 7.49 (dd, J1 = 7.9 Hz, J2 = 0.9 Hz, 2H).

13C-NMR (75 MHz, CD2Cl2, r.t.): δ [ppm] = 155.6, 141.6, 139.3, 128.6, 120.1.

[2,2'-bipyridine]-6,6'-dicarbaldehyde (24)75

6,6'-Dibromo-2,2'-bipyridine (23, 516 mg, 1.64 mmol) is dissolved in 25 ml dry

THF under inert conditions and slowly added to a solution of n-BuLi (317 mg,

1.98 ml, 3.17 mmol, 2.5 M solution in hexane) in 30 ml THF at -78 °C, avoiding

formation of precipitate and temperature increase above -70 °C. The dark red

solution is stirred below -75 °C for 1 h before DMF (362 mg, 384 µl, 4.95 mmol)


45

is added in 5 ml THF. The reaction mixture is stirred for an additional 1.5 h and allowed to warm

to -30 °C whereupon 10 ml of 4 M HCl are added. The reaction mixture is allowed to reach room

temperature. After adding petrol ether, the aqueous layer is separated from the organic phase.

The aqueous layer is basified to pH 9 with sat. aqueous NaHCO3 solution and extracted with warm

CHCl3. The combined organic layers are washed with brine, dried over MgSO4 and concentrated

in vacuo. Trituration with MeOH of the solidified residue affords the target compound as a white

solid (171 mg, 804 µmol; 49%).

1H-NMR (300 MHz, CDCl3, r.t.): δ [ppm] = 10.17 (d, J = 0.8 Hz, 2H), 8.81 (dd, J1 = 7.0 Hz, J2 = 2.1 Hz,

2H), 8.20-7.94 (m, 4H).

Synthesis of L-Proline- or L-tert-Leucine-based amines

Boc-L-tert-Leucine (34)70

L-tert-Leucine (2.00 g, 15.3 mmol) is dissolved in 14 ml of MeOH and 16 ml

of 1 M aqueous NaOH. Afterwards the reaction mixture is cooled to 0 °C.

Then Boc2O (3.66 g, 16.8 mmol) is added and the reaction mixture is stirred

overnight at room temperature. Methanol is removed under reduced

pressure. The pH of the resulting solution is adjusted to 2 by adding 1 M HCl. The solution is

extracted with EtOAc. The combined organic extracts are washed with brine once, dried over

anhydrous Na2SO4 and evaporated to dryness in vacuo. The title compound is obtained as a white

solid (3.10 g, 13.4 mmol; 88% yield). The obtained spectroscopic data are in accordance with

literature.

1H-NMR (300 MHz, DMSO-d6, r.t.): δ [ppm] = 6.81 (br d, J = 9.0 Hz, 1H), 3.74 (d, J = 9.0 Hz, 1H),

1.37 (s, 9H), 0.92 (s, 9H).

Boc-L-Proline (45)

Boc2O (1.14 g, 5.21 mmol) is added at 0 °C to a solution of L-proline (500 mg,

4.34 mmol) in 5 ml of 1 M aqueous NaOH and 5 ml of MeOH. Afterwards, the

reaction mixture is warmed to room temperature and stirred overnight.

Then MeOH is removed, the solution is acidified to pH = 2 with an aqueous

solution of 1 M HCl and extracted with EtOAc. The organic layers are combined and washed with

brine. Evaporation of the solvent affords the title compound as a white solid (621 mg, 2.88 mmol;

66%). The obtained spectroscopic data from the recorded 1H-NMR of the raw material are in

accordance with literature.123

1H-NMR (300 MHz, CDCl3, r.t.): δ [ppm] = 4.34-4.24 (m, 1H), 3.52-3.28 (m, 2H), 2.34-2.25 (m, 1H),

2.02-1.86 (m, 3H), 1.47-1.41 (m, 9H).


46

(S)-2-Amino-N-((R)-3,3-dimethylbutan-2-yl)-3,3-dimethylbutanamide (35)

Boc-L-tert-Leucine (34, 1.99 g, 9.30 mmol) and (R)-3,3-dimethyl-2-butylamine

(1.23 ml, 9.30 mmol) are dissolved in 30 ml of DCM. Added to the solution are:

EDC·HCl (1.96 g, 10.2 mmol), HOBt (1.57 g, 10.2 mmol) and DIPEA (3.84 g,

5.20 ml, 29.7 mmol). After stirring the resulting mixture at room temperature

overnight 10 ml of 10% citric acid is then added to quench the reaction. The

organic layer is separated and washed with saturated aqueous NaHCO3 and brine, dried over

anhydrous sodium sulphate, filtered and concentrated under reduced pressure to afford a white

solid. The residue is dissolved in 10 ml of dioxane and cooled to 0 °C. 1 ml of 12 M HCl is added

dropwise. The mixture is stirred at room temperature for 1 h and the solution is concentrated

under reduced pressure. The residue is taken up in 5 ml of water and 2 M NaOH solution is added

until no further formation of precipitate is observed. The resulting mixture is extracted with

DCM. The separated organic phase is washed with brine and then dried over anhydrous Na2SO4.

Purification via column chromatography (SiO2, DCM/MeOH 49:1) affords the title compound as

a white solid (1.83 g, 8.50 mmol; 92%).

1H-NMR (300 MHz, CDCl3, r.t.): δ [ppm] = 6.63 (d, J = 8.4 Hz, 1H), 3.81 (dq, J1 = 6.8 Hz, J2 = 9.7 Hz,

1H) 3.07 (s, 1H), 1.03 (d, J = 6.8 Hz, 3H), 0.99 (s, 9H), 0.88 (s, 9H).

13C-NMR (75 MHz, CDCl3, r.t.): δ [ppm] = 172.7, 64.8, 52.4, 34.1, 34.0, 26.9, 26.3, 16.1.

HR-MS (ESI) m/z: [M+H]+ calcd for C12H27N2O: 215.21179; found: 215.21241.

(S)-N-((R)-3,3-dimethylbutan-2-yl)pyrrolidine-2-carboxamide

Boc-L-Proline (45, 620 mg, 2.88 mmol) and (R)-3,3-dimethyl-2-butylamine

(382 µl, 2.88 mmol) are dissolved in 12 ml DCM. EDC (608 mg, 3.17 mmol), HOBt

(428 mg, 3.17 mmol) and DIPEA (931 mg, 1.25 ml, 7.20 mmol) are added to the

reaction mixture. The mixture is allowed to stir for 19 h at room temperature.

Afterwards, 4 ml of 10% citric acid are added to the mixture. The organic layer is seperated and

washed with a saturated solution of NaHCO3 and brine. It is dried over anhydrous Na2SO4 and

concentrated under reduced pressure to afford a yellow oil. This oil is cooled to 0 °C and

HCl/dioxane (2.1 ml of a 4 M solution) is added over the course of one hour. The mixture is

allowed to warm to room temperature within one hour and the solution is concentrated in vacuo.

The unpurified product is dissolved in water and the solution is made basic (pH = 12) by adding

3 N NaOH. The resulting solution is extracted with DCM. The separated organic phase is washed

with brine and dried over anhydrous Na2SO4. After removing the solvent in vacuo, the raw

material is obtained as a white solid and used without further purification or characterization.


47

(S)-N-((S)-1-(((R)-3,3-dimethylbutan-2-yl)amino)-3,3-dimethyl-1-oxobutan-2-yl)pyrrolidine-

2-carboxamide

(S)-2-amino-N-((R)-3,3-dimethylbutan-2-yl)-3,3-dimethylbutanamide (35,

511 mg, 2.40 mmol) and Boc-L-proline (46, 506 mg, 2.40 mmol) are

dissolved in 15 ml of DCM. EDC·HCl (575 mg, 3.00 mmol), HOBt (388 mg,

3.00 mmol) and DIPEA (1.16 g, 1.60 ml, 9.00 mmol) are added to the

solution. The reaction mixture is stirred overnight at room temperature.

5 ml of 10 % citric acid are added to quench the reaction. The organic layer is seperated and

washed with 10 ml of saturated aqueous NaHCO3 solution and 5 ml brine and concentrated under

reduced pressure to afford a white solid. The residue is dissolved in 3 ml of dioxane, cooled to

0 °C, and 1 ml of 12 M HCl is added dropwise. The mixture is allowed to warm to room

temperature within 1 h. The solution is concentrated under reduced pressure. The residue is

taken up in 4 ml of water and 2 M NaOH solution is added until no further precipitation is

observed. The mixture is extracted with DCM. The separated organic phase is washed with brine

and then dried over anhydrous Na2SO4. The solvent is evaporated to dryness and the raw product

is dried in vacuo providing the title compound as a white powder. The raw material is used

without further purification or characterization.

Synthesis of imidazole-based aldehydes

1-phenyl-1H-imidazole-2-carbaldehyde (33)84

Under inert conditions a solution of 1-phenylimidazole (100 mg, 87.7 µl,

690 µmol) in 1 ml dry THF is cooled to -50 °C. During cooling, a solution of

n-BuLi (44.2 mg, 276 µl, 690 µmol, 2.5 M solution in hexane) in 1 ml dry THF is

added dropwise to the reaction mixture within 30 min. After stirring for 1 h

at -50 °C DMF (75.6 mg, 79.6 µl, 1.04 mmol) is added and the reaction mixture

is warmed to room temperature within 2 h and further stirred overnight. After adding 1 ml

4 N HCl, 4 ml 2 N HCl and solid K2CO3, the product is extracted with DCM. The combined organic

layers are dried over Na2SO4. After removing the solvent, the product is obtained as a yellow oil

(114 mg, 661 µmol; 96%). The obtained spectroscopic data are in accordance with literature.

1H-NMR (300 MHz, CDCl3, r.t.): δ [ppm] = 9.80 (d, J = 0.8 Hz, 1H), 7.57-7.22 (m, 7H).


48

1-phenyl-1H-imidazole-4-carbaldehyde

CuI (93.0 mg, 488 µmol), 1,10-phenanthroline (88.0 mg, 488 µmol), tripotassium

phosphate (1.56 g, mmol, 7.35 mmol) and 4-imidazolecarboxaldehyde (330 mg,

3.43 mmol) are placed under inert conditions in a flask with 5 ml dry DMF. After

stirring at room temperature for 10 min, bromobenzene (386 mg, 258 µl,

2.46 mmol) is added. The reaction mixture is heated to 120 °C for 65 h. After

cooling to room temperature, the solution is diluted with 20 ml EtOAc and filtered through silica

gel. The organic phase is washed with brine and then dried over MgSO4. After concentration

in vacuo the raw product is recrystallized from DCM and pentane, which affords the pure product

as a white solid (112 mg, 650 µmol; 26%). The obtained spectroscopic data are in accordance

with literature.124

1H-NMR (300 MHz, CDCl3, r.t.): δ [ppm] = 9.94 (s, 1H), 7.92 (dd, J1 = 14.0 Hz, J2 = 1.3 Hz, 2H), 7.69-

7.29 (m, 5H).

Synthesis of 3-methyl-4-formylimidazol and 1-methyl-4-formylimidazol85

NaH (60% oil dispersion, freshly washed with n-hexane under inert

atmosphere, 166 mg, 4.16 mmol) is dissolved in 5.6 ml DMF and cooled to

0 °C. Subsequently 4-formylimidazole (400 mg, 4.16 mmol) and MeI (664 mg,

4.68 mmol) are added and the reaction mixture is stirred for 4 h at room

temperature. After evaporation of the solvent, the yellowish solid is dissolved in DCM and

washed with water. The aqueous layer is extracted with DCM, the combined organic layers are

dried over Na2SO4 and the solvent is removed in vacuo. During purification by column

chromatography (SiO2, DCM/MeOH 49:1) product 3-methyl-4-formylimidazol is eluted first

(white solid, 37.9 mg, 340 µmol; 8%) followed by product 1-methyl-4-formylimidazol is obtained

as a yellowish oil (41.7 mg, 380 µmol, 9%). The obtained spectroscopic data are in accordance

with literature.

3-methyl-4-formylimidazol:

1H-NMR (300 MHz, CDCl3, r.t.): δ [ppm] = 9.74 (d, J = 1.0 Hz, 1H), 7.76 (s, 1H), 7.59 (s, 1H), 3.92

(d, J = 0.6 Hz, 3H).

1-methyl-4-formylimidazol:

1H-NMR (300 MHz, CDCl3, r.t.): δ [ppm] = 9.82 (s, 1H), 7.56 (d, J = 1.3 Hz, 1H), 7.49 (s, 1H), 3.74

(s, 3H).


49

Synthesis of imidazole-based peptide-like ligands

General procedure: Reductive amination (GP1)

The L-Proline or L-tert-Leucine-based amine is dissolved as 2 M DCM solution, followed by the

addition of the imidazole-based aldehyde (1-1.3 equiv.) and MgSO4 (0.2 g/ml). The mixture is

allowed to stir overnight at room temperature. Afterwards solids are removed by filtration and

the resulting solution is concentrated in vacuo. The residue is dissolved as 2 M MeOH solution

and cooled to 0 °C. NaBH4 (3 equiv.) and a catalytic amount of conc. HCl is added to the reaction

mixture. The mixture is allowed to stir for 30 min at 0 °C and 1 h at room temperature. Then, an

equal volume of saturated NaHCO3 solution is added to quench the reaction. After extraction

with DCM, the separated organic phase is washed with brine, dried over anhydrous Na2SO4 and

concentrated in vacuo to afford the raw product. Purification of the resulting raw material is

carried out SiO2 via column chromatography using DCM and MeOH and/or recrystallization from

DCM and pentane.

Ligand (36)

The synthesis is carried out according to GP1. The target compound is

obtained from (S)-2-Amino-N-((R)-3,3-dimethylbutan-2-yl)-3,3-dimethyl-

butanamide (35, 47.6 mg, 222 µmol) and 1-phenyl-1H-imidazole-

2-carbaldehyde (33, 49.7 mg, 289 µmol) after purification via column

chromatography (SiO2, DCM/MeOH 49:1) as a white solid (12.1 mg,

33.0 µmol; 15%).

1H-NMR (300 MHz, CD2Cl2, r.t.): δ [ppm] = 7.51-7.36 (m, 5H), 7.08 (d, J = 1.3 Hz, 1H), 7.05 (d, J =

1.3 Hz, 1 H), 6.50 (br d, J = 9.1 Hz, 1H), 3.80-3.74 (m, 1H), 3.72 (d, J = 14.0 Hz, 1H), 3.53 (d, J =

13.9 Hz, 1H), 2.72 (s, 1H), 0.95 (s, 9H), 0.86 (s, 9H), 0.83 (d, J = 6.8 Hz, 3H).

13C-NMR (100 MHz, CD2Cl2, r.t.): δ [ppm] = 171.7, 146.4, 137.8, 129.9, 128.7, 128.2, 125.9, 121.4,

72.5, 52.8, 44.7, 34.2, 34.0, 27.4, 26.5, 16.2.

HR-MS (ESI) m/z: [M+H]+ calcd for C22H35N4O: 371.28054; found: 371.28081; m/z: [M+Na]+ calcd

for C22H34N4NaO: 393.26248; found: 393.26263.

[α]D20 = -64° (c = 0.15, DCM).

IR (ATR, solid): ṽ [cm-1] = 3447, 3193, 3067, 2954, 2905, 2871, 1306, 1644, 1555, 1500, 1470,

1306, 1255, 1141, 1126, 1115, 1082, 962, 915, 818, 764, 734, 693, 569, 540.


50

Ligand (34)


obtained from (S)-2-Amino-N-((R)-3,3-dimethylbutan-2-yl)-

3,3-dimethylbutanamide (32, 108 mg, 504 µmol) and 1-phenyl-

1H-imidazole-4-carbaldehyde (30, 112 mg, 650 µmol) after

purification via column chromatography (SiO2, DCM/MeOH 49:1) as a

white solid (150 mg, 405 µmol; 80%).

1H-NMR (300 MHz, CDCl3, r.t.): δ [ppm] = 7.77 (d, J = 1.4 Hz, 1H), 7.47-7.32 (m, 5H), 7.11 (s, 1H),

7.02 (d, J = 9.8 Hz, 1H), 3.85 (dq, J1 = 6.8 Hz, J2 = 9.8 Hz, 1H), 3.73 (d, J = 14.2 Hz, 1H), 3.51 (d, J =

13.9 Hz, 1 H), 2.82 (s, 1H), 2.08 (s, 1H), 1.05 (d, J = 6.8 Hz, 3H), 0.98 (s, 9H), 0.89 (s, 9H).

13C-NMR (100 MHz, CDCl3, r.t.): δ [ppm] = 172.4, 141.9, 137.6, 135.7, 130.3, 127.8, 121.6, 115.9,

72.3, 52.9, 46.2, 34.4, 34.0, 27.8, 26.8, 16.6.


[α]D20 = -42° (c = 0.15, DCM).

IR (ATR, solid): ṽ [cm-1] = 3326, 3054, 2958, 2870, 1648, 1600, 1505, 1475, 1365, 1306, 1251,

1130, 1067, 993, 967, 818, 757, 690, 522.

Ligand (42)



butanamide (35, 93.4 mg, 436 µmol) and 4-imidazolecarboxaldehyde

(54.5 mg, 567 µmol) without any further purification as a white solid

(99.8 mg, 339 µmol; 78%).

1H-NMR (400 MHz, CDCl3, r.t.): δ [ppm] = 7.55 (s, 1H), 6.98 (br d, J = 9.0 Hz, 1H), 6.76 (s, 1H), 3.82

(dq, J1 = 6.8 Hz, J2 = 13.5 Hz, 1H), 3.75 (d, J = 14.0 Hz, 1H), 3.42 (d, J = 14.1 Hz, 1H), 2.71 (s, 1H),

1.04 (d, J = 6.8 Hz, 3H), 0.91 (s, 9H), 0.88 (s, 9H).

13C-NMR (100 MHz, CDCl3, r.t.): δ [ppm] = 172.6, 136.1, 135.3, 116.4, 70.9, 52.8, 44.3, 34.0, 33.5,

27.3, 26.3, 16.2.

MS (MALDI-TOF): m/z = 295 [M+H]+, 317 [M+Na]+.


[α]D21 = -21° (c = 0.15, DCM).

IR (ATR, solid): ṽ [cm-1] = 3314, 3170, 3114, 2958, 2869, 1642, 1516, 1463, 1396, 1365, 1233,

1210, 1130, 987, 933, 818, 731, 661, 623, 495.


51

Ligand (39)



butanamide (35, 86.3 mg, 403 µmol) and 1-methyl-4-formylimidazol

(44.4 mg, 403 µmol) after purification via column chromatography (SiO2,

DCM/MeOH 49:1) as a white solid (67.7 mg, 219 µmol; 54%).

1H-NMR (300 MHz, CDCl3, r.t.): δ [ppm] = 7.30 (s, 1H), 7.00 (br d, J = 9.6 Hz, 1H), 6.67 (s, 1H), 3.79

(dq, J1 = 6.8 Hz, J2 = 9.8 Hz, 1H), 3.60 (d, J = 13.8 Hz, 1H), 3.58 (s, 3H), 3.36 (d, J = 14.1 Hz, 1H),

2.73 (s, 1H), 2.34 (s, 1H), 1.00 (d, J = 6.8 Hz, 3H), 0.91 (s, 9H), 0.84 (s, 9H).


33.2, 27.4, 26.4, 16.1.


[α]D21 = -17° (c = 0.15, DCM).

IR (ATR, solid): ṽ [cm-1] = 3327, 2956, 2870, 1618, 1508, 1462, 1365, 1307, 1232, 1160, 1131, 991,

816, 738, 618, 482.

Ligand (38)



butanamide (35, 973 mg, 4.54 mmol) and 1-methyl-

2-imidazolcarbaldehyde (500 mg, 4.54 mmol) after purification via

column chromatography (SiO2, DCM/MeOH 49:1) and recrystallization

(DCM/pentane) as a white solid (461 mg, 1.50 mmol; 33%). The obtained spectroscopic data are

in accordance with literature.125

1H-NMR (300 MHz, CDCl3, r.t.): δ [ppm] = 6.90 (d, J = 1.2 Hz, 1H), 6.78 (d, J = 1.2 Hz, 1H), 6.49

(br d, J = 9.6 Hz, 1H), 3.88 (dq, J1 = 9.8 Hz, J2 = 6.8 Hz, 1H), 3.77 (d, J = 13.9 Hz, 1H), 3.59 (s, 3H),

3.58 (d, J = 13.9 Hz, 1H), 2.65 (s, 1H), 2.14 (s, 1H), 1.03 (d, J = 6.8 Hz, 3H), 0.93 (s, 9H), 0.89 (s, 9H).


32.6, 27.1, 26.4, 16.4.

Ligand (40)



butanamide (35, 73.8 mg, 340 µmol) and 3-methyl-4-formylimidazol

(37.9 mg, 340 µmol) after purification via column chromatography (SiO2,


52

DCM/MeOH gradient from 49:1 to 9:1) and recrystallization (DCM/pentane) as a white solid

(29.5 mg, 96.0 µmol; 28%).

1H-NMR (300 MHz, CDCl3, r.t.): δ [ppm] = 7.40 (s, 1H), 6.87 (s, 1H), 6.11 (d, J = 10.9 Hz, 1H), 3.91

(dq, J1 = 9.7 Hz, J2 = 6.8 Hz 1H), 3.70 (d, J = 14.0 Hz, 1H), 3.65 (s, 3H), 3.51 (d, J = 14.0 Hz, 1H), 2.58

(s, 1H), 2.12 (s, 1H), 1.03 (d, J = 6.8 Hz, 3H), 0.91 (s, 9H), 0.90 (s, 9H).


31.5, 27.0, 26.3, 16.3.

HR-MS (ESI) m/z: [M+H]+ calcd for C17H33N4O: 309.26489; found: 309.26588; m/z: [M+Na]+ calcd

for C17H32N4NaO: 331.24683; found:331.24775.

[α]D20 = -55° (c = 0.15, DCM).

IR (ATR, solid): ṽ [cm-1] = 3221, 3188, 3035, 2955, 2869, 2831, 1655, 1550, 1511, 1472, 1455,

1361, 1239, 1187, 1131, 1104, 929, 831, 806, 714, 659, 484, 442.

Ligand (41)

The synthesis is carried out according to GP1. However, instead of DCM

in the first step, MeOH is used for both steps. The target compound is


butan-amide (35, 108 mg, 504 µmol) and 2-imidazolecarboxaldehyde

(48.0 mg, 504 µmol). Purification of the resulting material by

recrystallization (DCM/pentane) affords the desired compound as a white solid (65.0 mg,

221 µmol; 44%).

1H-NMR (300 MHz, CDCl3, r.t.): δ [ppm] = 6.91 (s, 2H), 6.70 (d, J = 9.3 Hz, 1H), 3.88 (d, J = 14.8 Hz,

1H), 3.84-3.76 (m, 1H), 3.56 (d, J = 14.8 Hz, 1H), 2.66 (s, 1H), 0.99 (d, J = 6.8 Hz, 3H), 0.93 (s, 9H),

0.85 (s, 9H).


16.2.


[α]D22 = -79° (c = 0.15, DCM).

IR (ATR, solid): ṽ [cm-1] =3352, 3163, 3053, 2955, 2870, 1637, 1526, 1464, 1365, 1248, 1228, 1108,

988, 800, 739, 679, 627, 479.


53

Ligand (47)

The synthesis is carried out according to GP1. The target compound

is obtained from (S)-N-((S)-1-(((R)-3,3-dimethylbutan-2-yl)amino)-

3,3-dimethyl-1-oxobutan-2-yl)pyrrolidine-2-carboxamide (329 mg,

1.06 mmol) and 1-methyl-2-imidazolecarboxaldehyde (139 mg,

1.26 mmol) after purification via column chromatography (SiO2,

DCM/MeOH gradient from DCM pure to 19:1) as a white solid (281 mg, 693 µmol; 65% yield).

1H-NMR (300 MHz, CDCl3, r.t.): δ [ppm] = 7.90 (d, J = 10.2 Hz, 1H), 6.86 (d, J = 1.3 Hz, 1H), 6.78 (d,

J = 1.3 Hz, 1H), 6.57 (s, 1H), 4.37 (dd, J1 = 10.2 Hz, J2 = 2.2 Hz, 1H), 3.96-3.54 (m, 6H), 3.19 (dd, J1 =

9.9 Hz, J2 = 4.5 Hz, 1H), 2.82 (ddd, J1 = 9.4 Hz, J2 = 6.6 Hz, J3 = 2.5 Hz, 1H), 2.56 (td, J1 = 9.9 Hz, J2 =

6.4 Hz, 1H), 2.21 (dtd, J1 = 13.0 Hz, J2 = 9.9 Hz, J3 = 7.9 Hz, 1H), 1.95-1.57 (m, 3H), 1.01 (d, J =

6.9 Hz, 3H), 0.95 (s, 9H), 0.78 (s, 9H).


51.1, 34.8, 34.4, 33.2, 30.9, 26.6, 26.1, 24.1, 15.9.

MS (MALDI-TOF): m/z = 406 [M+H]+, 428 [M+Na]+.

HR-MS (ESI) m/z: [M+H]+ calcd for C22H40N5O2: 406.31765; found: 406.31766.

[α]D32 = -45° (c = 0.15, DCM).

IR (ATR, solid): ṽ [cm-1] = 3467, 3303, 3242, 2959, 2879, 1648, 1508, 1476, 1366, 1250, 1185,

1134, 986, 932, 735, 664, 499, 415.

Ligand (46)


obtained from unpurified raw material of (S)-N-((R)-3,3-dimethylbutan-

2-yl)pyrrolidine-2-carboxamide (617 mg, 2.88 mmol) and 1-methyl-

2-imidazolecarboxaldehyde (317 mg, 2.88 mmol) after recrystallization

(DCM/pentane) as a white solid (229 mg, 790 µmol; 27%).

1H-NMR (300 MHz, CDCl3, r.t.): δ [ppm] = 7.30 (d, J = 9.8 Hz, 1H), 6.92 (d, J = 1.2 Hz, 1H), 6.79 (d,

J = 1.2 Hz, 1H), 3.93-3.69 (m, 3H), 3.63 (s, 3H), 3.23 (dd, J1 = 4.3 Hz, J2 = 10.1 Hz, 1H), 3.02 (dd,

J1 = 4.4 Hz, J2 = 11.2 Hz, 1H), 2.64-2.55 (m, 1H), 2.22-1.67 (m, 4H), 0.93 (d, J = 6.8 Hz, 3H), 0.85 (s,

9H).


32.8, 31.0, 26.1, 24.3, 16.2.

MS (MALDI-TOF): m/z = 293 [M+H]+, 315 [M+Na]+, 607 [2M+Na]+.


[α]D23 = -49° (c = 0.15, DCM).


54

IR (ATR, solid): ṽ [cm-1] = 3354, 3100, 2965, 2870, 2803, 1662, 1511, 1455, 1367, 1285, 1133,

1035, 976, 934, 766, 653, 469.

Ligand (43)

Formic aldehyde (37 wt% in H2O, 53.0 µl, 650 µmol, 1.3 equiv.) is added

to ligand 38 (154 mg, 500 µmol) in 3 ml DCM. After addition of catalytic

drops of glacial acetic acid the reaction mixture is stirred overnight at

room temperature. Then sodium triacetoxyborohydride (159 mg,

750 µmol) is added to the reaction mixture, which is stirred again

overnight. Afterwards, the reaction is quenched with 10 ml saturated NH3Cl solution, and stirred

for 1.5 h. The organic layer is separated and washed with water, dried over Na2SO4 and

concentrated. The target compound is obtained as a white solid (50.0 mg, 155 µmol; 31%).

1H-NMR (300 MHz, CDCl3, r.t.): δ [ppm] = 6.89 (s, 1H), 6.82 (s, 1H), 6.75 (d, J = 8.3 Hz, 1H), 3.89

(dq, J1 = 6.8 Hz, J2 = 9.5 Hz, 1H), 3.78-3.65 (m, 5H), 2.52 (s, 1H), 2.48 (s, 3H), 1.04 (d, J = 6.8 Hz,

3H), 0.96 (s, 9H), 0.80 (s, 9H).


33.5, 32.7, 27.3, 26.7, 16.4.

MS (MALDI-TOF): m/z = 323 [M+H]+.


[α]D20 = -168° (c = 0.15, DCM).

IR (ATR, solid): ṽ [cm-1] = 3433, 3286, 2954, 2867, 2805, 1649, 1532, 1502, 1451, 1364, 1262,

1178, 1128, 1113, 1013, 965, 811, 743, 708, 667, 626, 472.

1.7.2.2 Synthesis of olefins and racemic epoxide references

2-vinylnaphthalene (11)

To a stirred suspension of 2-naphthaldehyde (909 mg, 5.82 mmol) and

methyltriphenylphosphonium bromide (2.49 g, 6.97 mmol) in 35 ml THF NaH

(629 mg, 26.2 mmol) is added under inert conditions at 0 °C. Then, the mixture

is stirred at room temperature overnight, washed with brine, dried over Na2SO4

and concentrated in vacuo. After purification by column chromatography (SiO2, Hexane/EtOAc

9:1) the product is obtained as a white solid (601 mg, 3.90 mmol; 67%). The obtained

spectroscopic data are in accordance with literature.126

1H-NMR (300 MHz, CDCl3, r.t.): δ [ppm] = 7.88-7.74 (m, 4H), 7.68 (dt, J1 = 8.5 Hz, J2 = 1.8 Hz, 1H),

7.53-7.45 (m, 2H), 6.93 (ddd, J1 = 17.6 Hz, J2 = 10.9 Hz, J3 = 1.6 Hz, 1H), 5.92 (dd, J1 = 17.4 Hz, J2 =

1.5 Hz, 1H), 5.38 (dd, J1 = 10.8 Hz, J2 = 1.6 Hz, 1H).


55

1-Nitro-4-vinylbenzene127

Methyltriphenylphosphonium bromide (2.14 g, 6.00 mmol) and DBU (990 mg,

972 µl, 6.50 mmol) are added to 4-nitrobenzaldehyde (755 mg, 5.00 mmol) in

25 ml THF under inert conditions at 0 °C and stirred for 2 h. Then, the reaction

mixture is warmed to room temperature and stirred overnight. Afterwards, THF is evaporated

and the residue is taken up in DCM. The organic phase is washed with brine, dried over MgSO4

and concentrated in vacuo. The purification is carried out via column chromatography (SiO2,

hexane/ EtOAc 12:1) and the product is obtained as a yellowish oil which solidifies in the cold

(251 mg, 1.68 mmol; 34%). The obtained spectroscopic data are in accordance with literature.

1H-NMR (300 MHz, CDCl3, r.t.): δ [ppm] = 8.17 (d, J = 8.8 Hz, 2H), 7.52 (d, J = 8.6 Hz, 2H), 6.76 (dd,

J1 = 17.6 Hz, J2 = 10.9 Hz, 1H), 5.91 (dd, J1 = 17.6 Hz, J2 = 0.5 Hz, 1H), 5.48 (dd, J1 = 10.9 Hz, J2 =

0.5 Hz, 1H).

1,2-Dichloro-4-vinylbenzene

Methyltriphenylphosphonium bromide (2.14 g, 6.00 mmol) and DBU (990 mg,

972 µl, 6.50 mmol) are added to 3,4-dichlorobenzaldehyde (875 mg, 5.00 mmol)

in 25 ml THF under inert conditions at room temperature. The reaction mixture

is stirred overnight. Afterwards, the organic phase is washed with brine, dried

over MgSO4 and concentrated in vacuo. The purification is carried out via column

chromatography (SiO2, Hexane/ EtOAc 19:1) and the product is obtained as a colorless oil

(556 mg, 3.21 mmol; 64%). The obtained spectroscopic data are in accordance with literature.128


J1 = 8.3 Hz, J2 = 2.0 Hz, 1H), 6.60 (dd, J1 = 17.6 Hz, J2 = 10.9 Hz, 1H), 5.73 (d, J = 17.5 Hz, 1H), 5.31

(d, J = 10.9 Hz, 1H).

General procedure: Epoxidation of olefins with mCPBA (GP2)

A mixture of olefin (490 µmol-7.69 mmol) and NaHCO3 (0.9-1.2 equiv.) is stirred in DCM at room

temperature. After adding mCPBA (77% purity, 0.9-1.2 equiv.), the reaction mixture is stirred

overnight. The next day, the reaction is washed with 5% Na2S2O5 aqueous solution and saturated

NaHCO3 solution. The organic layer is dried over MgSO4. Then, the solvent is removed under

reduced pressure and the target compound is obtained.


56

2-(Naphthalen-2-yl)oxirane (12)

The synthesis is carried out according to GP2. The target compound is obtained

from 2-vinylnaphthalene (11, 100 mg, 648 µmol) and mCPBA (77% purity,

129 mg, 576 µmol) after purification via column chromatography (SiO2,

hexane/EtOAc 19:1) as a white solid (29.0 mg, 170 µmol; 26%). The obtained


1H-NMR (300 MHz, CDCl3, r.t.): δ [ppm] = 7.90-7.74 (m, 4H), 7.55-7.41 (m, 2H), 7.32 (dd, J1 =

8.5 Hz, J2 = 1.8 Hz, 1H), 4.02 (dd, J1 = 4.1 Hz, J2 = 2.6 Hz, 1H), 3.21 (dd, J1 = 5.4 Hz, J2 = 4.1 Hz, 1H),

2.90 (dd, J1 = 5.4 Hz, J2 = 2.5 Hz, 1H).

Chiral HPLC (Chiralpak AS): n-Hexane/i-PrOH 99:1, 0.5 ml/min flow rate, λ = 254 nm: tR =

18.2 min (R), 19.8 min (S).

Chiral HPLC (Chiralpak IC): n-Hexane/i-PrOH 99:1, 0.9 ml/min flow rate, λ = 254 nm: tR = 11.7 min

(R), 12.9 min (S).

2-(3,4-dichlorophenyl)oxirane


from 1,2-dichloro-4-vinylbenzene (84.8 mg, 490 µmol) and mCPBA (77% purity,

129 mg, 576 µmol) after purification via column chromatography (SiO2,

Hexane/EtOAc 19:1) as a colorless oil (61.0 mg, 323 µmol). The obtained



J1 = 8.2 Hz, J2 = 2.1 Hz, 1H), 3.79 (dd, J1 = 4.1 Hz, J2 = 2.5 Hz, 1H), 3.12 (dd, J1 = 5.4 Hz, J2 = 4.0 Hz,

1H), 2.71 (dd, J1 = 5.4 Hz, J2 = 2.5 Hz, 1H).

2-Methyl-2-phenyloxirane (52)


from α-methyl styrene (909 mg, 1.00 ml, 7.69 mmol) and mCPBA (77% purity,

1.80 g, 7.69 mmol) after purification via distillation (3.5 x 10-1 mbar, 60 °C) as a

colorless oil with 89% purity. Purification for HPLC analysis is carried out via

preparative TLC (Hexane/DCM 4:1). The obtained spectroscopic data are in accordance with

literature.112

1H-NMR (300 MHz, CDCl3, r.t.): δ [ppm] = 7.46-7.23 (m, 5H), 2.95 (d, J = 5.4 Hz, 1H), 2.78 (dt, J1 =

5.4 Hz, J2 = 0.8 Hz, 1H), 1.70 (d, J = 0.8 Hz, 3H).

Chiral HPLC (OD): n-Hexane/i-PrOH 99:1, 1.0 ml/min flow rate, λ = 254 nm: tR = 5.4 min (R),

6.1 min (S).


57

2-Methyl-3-phenyloxirane


from trans-β-methylstyrene (67.0 mg, 73.7 µl, 567 µmol) and mCPBA (77% purity,

152 mg, 678 µmol) after full consumption of reactant and purification via

preparative TLC (Hexane/EtOAc 19:1). The obtained spectroscopic data from the

raw product are in accordance with literature.129

1H-NMR (300 MHz, CDCl3, r.t.): δ [ppm] = 7.43-7.07 (m, 5H), 3.58 (d, J = 2.1 Hz, 1H), 3.04 (qd, J1 =

5.1 Hz, J2 = 2.1 Hz, 1H), 1.45 (d, J = 5.1 Hz, 3H).

Chiral HPLC (Chiralpak AS): n-Hexane/i-PrOH 99:1, 0.5 ml/min flow rate, λ = 210 nm: tR = 10.5 min,

13.9 min (no assignment of (R)- and (S)-enantiomer).

2-Benzyloxirane


from allylbenzene (591 mg, 662 µl, 5.00 mmol) and mCPBA (77% purity, 1.73 g,

10.0 mmol) after full consumption of reactant and after purification via column

chromatography (SiO2, hexane/ethyl acetate gradient from 9:1 to 4:1) as a colorless oil (436 mg,

3.25; 65%). The obtained spectroscopic data are in accordance with literature.130

1H-NMR (300 MHz, CDCl3, r.t.): δ [ppm] = 7.38-7.20 (m, 5H), 3.21-3.08 (m, 1H), 2.97-2.76 (m, 3H),

2.54 (dd, J1 = 5.0, J2 = 2.7 Hz, 1H).

Phenyl(3-phenyloxiran-2-yl)methanone131

Chalcone (300 mg, 1.44 mmol) is dissolved in 5 ml dichloroethane.

Afterwards, DBU (152 mg, 149 µl, 144 µmol) and t-BuOOH (260 mg, 576 µl,

2.88 mmol) are added at 0 °C. The reaction mixture is stirred for 25 h at

room temperature, then diluted with 10 ml chloroform and 5 ml water,

followed by addition of solid Na2S2O5. The mixture is further stirred for 15 min. After separation

of the organic layer, drying and filtration the solvent is evaporated. The purification is carried out

via column chromatography (SiO2, Hexane/EtOAc gradient from 49:1 to 9:1) and the product is

obtained as a white solid (237 mg, 1.06 mmol; 73%).


8.3 Hz, J2 = 6.8 Hz, 2H), 7.43-7.30 (m, 5H), 4.29 (d, J = 1.9 Hz, 1H), 4.06 (d, J = 1.9 Hz, 1H).

13C-NMR (75 MHz, CDCl3, r.t.): δ [ppm] =193.0, 135.4, 135.3, 133.9, 129.0, 128.8, 128.7, 128.3,

125.7, 60.9, 59.3.

Chiral HPLC (OD): n-Hexane/i-PrOH 90:10, 1.0 ml/min flow rate, λ = 245 nm: tR = 9.5 min (2S, 3R),

10.5 min (2R, 3S).132


58

1.7.2.3 Non-heme iron catalyzed epoxidation of olefins

General procedure: Catalysis with imine-based ligand (GP3)

A mixture of FeCl3 x 6 H2O (5 mol%), imine-based ligand (20 mol%) and H2Pydic (10 mol%) in

1.6 ml DCM is stirred under air at room temperature for 1 h. Afterwards 2-vinylnaphtalene (11,

25.6 mg, 166 µmol) is added and the reaction mixture is cooled to 0 °C. H2O2 (30% wt% in H2O,

24 µl, 249 µmol) is added via a syringe pump over a 1 h period. Then, the reaction mixture is

stirred for additional 2 h at 0 °C. The reaction is quenched with 30 µl of a saturated aqueous

Na2SO3 solution. Afterwards, the organic phase is washed with water and evaporated to dryness

under reduced pressure. The conversion is determined via 1H-NMR of the raw material. The

purification for HPLC sample preparation is carried out via preparative TLC (Hexane/EtOAc).

General procedure: Catalysis with imidazole-based ligands without additive (GP4)

To a solution of FeCl3 x 6 H2O (6.80 mg, 25.0 µmol, 5 mol%) in 9 ml 2-Me-2-BuOH an imidazole-

based ligand (50.0 µmol, 10 mol%) is added at room temperature under air. After adding the

olefin (500 µmol), H2O2 (30% wt% in H2O, 170 µl, 1.50 mmol) mixed with 830 µl 2-Me-2-BuOH is

added via a syringe pump over a 1 h period. The reaction is quenched with 50 µl of a saturated

aqueous Na2SO3 solution. After extraction with DCM the organic phases are combined and

evaporated to dryness. The crude mixture is filtered through a SiO2-plug (1 cm, eluted with DCM).

In order to determine yield via 1H-NMR, pyrazine is added in a defined amount as internal

standard. The purification for HPLC sample preparation is carried out via preparative TLC

(Hexane/EtOAc).

General procedure: Catalysis with imidazole-based ligands (S)-(+)-mandelic acid (GP5)

A mixture of FeCl3 x 6 H2O (5-10 mol%), ligand 38 (5-20 mol%) and (S)-(+)-mandelic acid

(5-15 mol%) in 1.6 ml 2-Me-2-BuOH is stirred under air at room temperature for 1 h. Afterwards,

2-vinylnaphtalene (11, 25.6 mg, 166 µmol) is added and the reaction mixture is cooled to 0 °C.

H2O2 (30% wt% in H2O, 24 µl, 249 µmol) is added via a syringe pump over a 1 h period. Then, the

reaction mixture is stirred for additional 2 h at 0 °C. The reaction is quenched with 30 µl of a

saturated aqueous Na2SO3 solution. After extraction with DCM, the organic phases are combined

and evaporated to dryness under reduced pressure. The crude mixture is filtered through a SiO2-

plug (1 cm, eluted with DCM). In order to determine yield via 1H-NMR, pyrazine is added in a

defined amount as internal standard. The purification for HPLC sample preparation is carried out

via preparative TLC (Hexane/EtOAc).


59

Epoxides with available racemic references

2-(4-Nitrophenyl)oxirane

The synthesis is carried out according to GP4. The obtained spectroscopic data

from the recorded 1H-NMR of the raw material are in accordance with

literature.133 Purification is carried out via preparative TLC (Hexane/EtOAc

12:1).


2.5 Hz, J2 = 4.0 Hz, 1H), 3.19 (dd, J1 = 4.1 Hz, J2 = 5.5 Hz, 1H), 2.74 (dd, J1 = 2.5 Hz, J2 = 5.5 Hz, 1H).

Chiral HPLC (Chiralpak IC): n-Hexane/i-PrOH 95:5, 1.0 ml/min flow rate, λ = 254 nm: tR = 13.9 min

(R), 14.8 min (S).

2-Phenyloxirane (50)



commercially available 2-phenyloxirane and literature.134 Purification is carried

out via preparative TLC (Hexane/EtOAc 19:1).

1H-NMR (400 MHz, CDCl3, r.t.): δ [ppm] = 7.40-7.24 (m, 5H), 3.85 (dd, J1 = 4.1 Hz, J2 = 2.6 Hz, 1H),

3.13 (dd, J1 = 5.5 Hz, J2 = 4.1 Hz, 1H), 2.79 (dd, J1 = 5.5 Hz, J2 = 2.6 Hz, 1H).

Chiral HPLC (OD): n-Hexane/i-PrOH 99:1, 1.0 ml/min flow rate, λ = 210 nm: tR = 6.8 min (R),

7.2 min (S).

2,3-Diphenyloxirane



commercially available 2,3-diphenyloxirane and literature.57 Purification is

carried out via preparative TLC (Hexane/EtOAc 97:3).

1H-NMR (400 MHz, CDCl3, r.t.): δ [ppm] = 7.30-7.39 (m, 10H), 3.86 (s, 2H).

Chiral HPLC (Chiralpak IB): n-Hexane/i-PrOH 92:8, 1.0 ml/min flow rate, λ = 254 nm: tR = 4.9 min

(R), 6.3 min (S).


60

1.7.2.4 One-pot procedure towards β-amino alcohol

General procedure: GP4 or GP5 in combination with aminolysis (GP6)

The non-heme iron catalyzed epoxidation is carried out as described in GP4 or GP5. Instead of

adding saturated aqueous Na2SO3 solution, isopropylamine (18 equiv.) is added and the reaction

mixture is stirred for 18 h at 50 °C. Then, the solvent is evaporated and the raw material is purified

via SiO2 column chromatography.

(R)-Pronethalol


obtained as a yellowish solid after purification via column

chromatography (SiO2, EtOAc/MeOH/NH3(aq) 50:4:1). The obtained


1H-NMR (400 MHz, CDCl3, r.t.): δ [ppm] = 7.87-7.76 (m, 4H), 7.45 (ddd, J1 = 9.4 Hz, J2 = 5.2 Hz, J3 =

1.9 Hz, 3H), 5.43 (s, 1H), 4.88 (dd, J1 = 8.9 Hz, J2 = 3.5 Hz, 1H), 3.02 (ddd, J1 = 12.1 Hz, J2 = 3.7 Hz,

J3 = 1.7 Hz, 1H), 2.88 (pd, J1 = 6.3 Hz, J2 = 1.6 Hz, 1H), 2.76 (dd, J1 = 12.1 Hz, J2 = 8.9 Hz, 1H), 1.10

(ddd, J1 = 6.3 Hz, J2 = 3.5 Hz, J3 = 1.3 Hz, 6H).

Chiral HPLC (Chiralpak IC): n-Hexane/i-PrOH/ETA 94.9:5:0.1, 1.0 ml/min flow rate, λ = 280 nm:

tR = 8.3 min (R), 10.9 min (S).

(R)-Dichloroisoproterenol


obtained as a white solid after purification via column chromatography

(SiO2, EtOAc/MeOH/NH3(aq) 50:4:1). The obtained spectroscopic data are



J1 = 8.3 Hz, J2 = 2.0 Hz, 1H), 4.60 (ddd, J1 = 9.1 Hz, J2 = 3.8 Hz, J3 = 1.4 Hz, 1H), 3.11-2.96 (m, 2H),

2.96-2.69 (m, 2H), 2.56 (dd, J1 = 12.1 Hz, J2 = 9.1 Hz, 1H), 1.20-0.91 (m, 6H).

Chiral HPLC (Chiralpak IC): n-Hexane/i-PrOH/ETA 94.9:5:0.1, 0.5 ml/min flow rate, λ = 280 nm:

tR = 10.0 min (R), 10.9 min (S).

(R)-2-(Isopropylamino)-1-(4-methoxyphenyl)ethan-1-ol


obtained as a white solid after purification via column chromatography

(SiO2, EtOAc/MeOH/NH3(aq) 50:4:1). The obtained spectroscopic data are



61


J1 = 9.3 Hz, J2 = 3.4 Hz, 1H), 3.78 (s, 3H), 3.03-2.81 (m, 2H), 2.70 (dd, J1 = 12.1 Hz, J2 = 9.3 Hz, 1H),

1.12 (dd, J1 =6.3 Hz, J2 = 1.4 Hz, 6H).


22.3.


1.7.2.5 SiO2 catalyzed rearrangement of epoxides

General procedure: Epoxide rearrangement (GP7)

1.67-5.40 g/mmol SiO2 is added to a solution of epoxide (150 µmol, 0.03-0.15 M) in CDCl3 the

mixture is stirred for a certain time under reflux or at room temperature. After filtration and

addition of pyrazine in a defined amount as internal standard, the yield is determined via 1H-NMR

measurement.

2-Phenylacetaldehyde (51)

The synthesis is carried out according to GP7 using commercially available

2-phenyloxirane (50) as starting compound. The obtained spectroscopic data

from the recorded 1H-NMR of the raw material are in accordance with a

commercially available reference and literature.136

1H-NMR (400 MHz, CDCl3, r.t.): δ [ppm] = 9.73 (t, J = 2.4 Hz, 1H), 7.41-7.26 (m, 5H), 3.67 (d, J =

2.5 Hz, 2H).

2-(Naphthalen-2-yl)acetaldehyde (49)

The synthesis is carried out according to GP7 using 12 as starting compound.

The purification of the reaction mixture is carried out via column

chromatography (SiO2, Hexane/EtOAc 19:1). The obtained spectroscopic data

are in accordance with literature.136,137

1H-NMR (400 MHz, CDCl3, r.t.): δ [ppm] = 9.81 (t, J = 2.4 Hz, 1H), 7.89-7.75 (m, 3H), 7.68 (d, J =

1.7 Hz, 1H), 7.53-7.41 (m, 2H), 7.31 (dd, J1 = 8.4 Hz, J2 = 1.8 Hz, 1H), 3.84 (d, J = 1.6 Hz, 2H).

2-Phenylpropanal (53)

The synthesis is carried out according to GP7 using 52 as starting compound. The

purification of the reaction mixture is carried out via column chromatography

(SiO2, hexane/DCM 4:1). The obtained spectroscopic data are in accordance with

literature.136


62

1H-NMR (300 MHz, CDCl3, r.t.): δ [ppm] = 9.67 (d, J = 1.4 Hz, 1H), 7.70-6.92 (m, 5H), 3.62 (q, J =

7.0 Hz, 1H), 1.43 (d, J = 7.1 Hz, 3H).

1.7.2.6 Non-heme iron catalyzed aziridination

1-Azido-4-methylbenzene (55)138

After suspending p-toluidine (500 mg, 4.67 mmol) in 3 ml 17% HCl at room

temperature, the mixture is cooled to 0 °C. Then, NaNO2 (315 mg, 4.57 mmol) in

1.5 ml water is cooled to 0 °C and added slowly to the reaction mixture.

Afterwards, the mixture is stirred for 30 min at 0 °C. A solution of NaN3 (305 mg,

4.69 mmol) in 3 ml water is added dropwise to the mixture, which is stirred for

additional 2 h at room temperature. Afterwards, the reaction mixture is extracted with DCM. The

combined organic phases are dried over Na2SO4. After evaporation under reduced pressure, the

product is obtained as a brownish oil (324 mg, 2.43 mmol; 52%). The obtained spectroscopic data

are in accordance with literature.

1H-NMR (400 MHz, CDCl3, r.t.): δ [ppm] = 7.14 (d, J = 7.8 Hz, 2H), 6.91 (d, J = 8.4 Hz, 2H), 2.31 (s,

3H).

General procedure: Iron catalyzed aziridination (GP8)

2-Octyl-1-(p-tolyl)aziridine (57)

p-Tolyl azide (55, 100 mg, 750 µmol) is added to 1-decene (53, 5.27 g, 7.11 ml,

37.6 mmol) under inert atmosphere. After adding the iron catalyst (5 mol%), the

reaction mixture is heated to 90 °C and then stirred for 18 h. The mixture is

removed from the heat and the remaining 1-decene (53) is evaporated from the

raw material, which is afterwards purified via column chromatography (SiO2,

deactivated with Et3N, Hexane/EtOAc 49:1). The obtained spectroscopic data are in accordance

with literature.120,121

1H-NMR (400 MHz, CDCl3, r.t.): δ [ppm] = 7.00 (d, J = 8.2 Hz, 2H), 6.86 (d, J = 8.3 Hz, 2H), 2.25 (s,

3H), 2.10-1.90 (m, 3H), 1.68-1.06 (m, 14H), 1.05-0.69 (m, 3H).


29.5, 29.3, 27.7, 22.6, 20.6, 14.1.

Chapter 2 Synthesis of Pyridine-derived Ligands for Light Absorbing Metal Complexes

63

2 Synthesis of Pyridine-derived Ligands for Light Absorbing

Metal Complexes

2.1 The Sun – An Attractive Source of Energy

Nowadays, the generation of energy is highly dependent on fossil fuels. However, the limitation

of fossil fuels results in increasing prices. Even though prices recently decreased due to the access

to new resources using the fracking method, the amount of CO2 which is created by burning

conventional fuels is undesirably high. The output of such a magnitude is known to promote

global warming. Thus, the discovery of renewable energy becomes the major scientific challenge

of the 21st century.139 The sun is found to be an attractive source for clean and renewable energy.

Among new technologies that can replace fossil fuels the conversion of solar energy into storable

forms is likely to play a key role. Any future energy demand would be satisfied since the amount

of solar energy that reaches the earth per hour is higher than the amount of energy that is

needed per year.140 To achieve this goal, light needs to be harvested and efficiently converted

into electric power or transformed into “solar fuel” like hydrogen. Hence, the technologies of the

future are photovoltaics such as dye sensitized solar cells (DSSC, Figure 4) and their combination

with electrolysis of water in a photoelectrochemical cell known as dye sensitized

photoelectrochemical cell (DS-PEC, Figure 5), both of them utilizing sensitizer-based

photocatalytic processes.141-145

Figure 4 Energy diagram of the photocatalytic process in DSSC.146,144

In 1991, O’Regan and Grätzel published a significantly improved version of DSSC (see Figure 4).147

Here, a monolayer of dye attached to a mesoporous semiconductor (mostly TiO2) performs light


64

absorbance and charge separation occurs at the semiconductor/dye interface. The fabrication of

a DSSC is easy, the costs are low, it is lightweight and provides flexibility in design.143 Compared

to devices with inorganic semiconductor oxides the dye sensitized ones have energy levels which

are easier to fine tune. The lowest unoccupied molecular orbital (LUMO) and the highest

occupied molecular orbital (HOMO) of organo-metal complexes and organic dyes in DSSC can

undergo specific modifications of their molecular structures and therefore their spectral

response.148 As depicted schematically in Figure 4, a typical n-type DSSC contains three major

components. The working electrode consists of mesoporous TiO2 providing attached dye

molecules. Besides the platinum counter electrode, there is an electrolyte (I3-/I-) as redox

mediator. Owing to sunlight absorption, a sensitizer electron is excited from the HOMO to the

LUMO (resulting in D*), which is then injected into the conduction band of TiO2. Subsequently

the oxidized dye molecule is regenerated by the reduced component of the electrolyte (I-). The

injected electron in the conduction band migrates to the back contact of the TiO2 film and thus

to the counter electrode, where the oxidized component of the electrolyte is reduced.144 A

possible p-type DSSC operates in inversed fashion by hole injection from the photoexcited dye

(D*) into the valence band of a p-type semiconductor such as NiO.149

In 2009, the concept of DSSC was successfully extended to DS-PECs, which are mainly based on

n-type DSSC, however, with two operating catalytic reactions.150,151 The redox mediating

electrolyte used in DSSC is replaced by a water oxidation catalyst, which is coupled to the dye

molecule in order to regenerate the oxidized dye to the ground state after the photoexcitation

process (depicted in Figure 5).

Figure 5 Energy diagram of the photocatalytic water splitting process in DS-PEC.146


65

The water molecules which are present in the cell are oxidized to oxygen releasing protons at the

photoanode. The injected electron derived from photoexcited dye migrates through TiO2 and the

external circuit to the platinum counter electrode. Here, proton reduction occurs and hydrogen

is generated. Thus, the overall cleavage of water is fulfilled.


66

2.2 Pyridine-Based Compounds in Photoscience

Light-harvesting materials which are needed for energy conversion in DSSC or DS-PEC, as shown

in chapter 2.1, comprise a photosensitizer dye and an electron-accepting moiety (e.g. metal

oxide). These components provide strong absorption cross-sections in a wide range of the visible

spectrum. Besides, a high LUMO energy-level of the photosensitizer dye is necessary to enable

electron injection in the metal oxide semiconductor conduction band. For the synthesis of

strongly emissive materials, heterocycles containing nitrogen (e.g. pyridines) are widely used as

building blocks.152,153 The good accessibility to new pyridine-based π-extended materials is

enabled by the facile derivatization of pyridine rings by introducing functionalities such as

anchoring groups, which causes fine tuning of optical properties.153-155 These modifications can

be attributed to the change in LUMO and HOMO states.

Besides DSSC or DS-PEC, bipyridine-based π-extended compounds can be applied as organic

emissive materials in non-linear optics (NLO). They demonstrated electromagnetic radiation due

to intramolecular charge-transfer (ICT) and emit from the corresponding photoexcited state.

Here, symmetrical 2,2’-bipyridines which are 4,4’-π-conjugated and end-capped with a donor

functionality are common structures. Le Bozec and co-workers published a variety of

2,2’-bipyridine chromophores with potential application in NLO.156-159 By simple modifications of

the π-linker or the donor moiety, did they demonstrate how the electronic absorption property

could be tuned. Some 4,4’-π-cojugated 2,2’-bipyridines chromophores (64-66), which were

designed by the group of Le Bozec, are depicted in Figure 6.

Figure 6 4,4’-π-Cojugated 2,2’-bipyridines by Le Bozec and co-workers for NLO.156-158

Le Bozec and co-workers observed that the bathochromic shift is consistent with relative values

of the donor strengths.156 Besides, the redshift caused by intraligand charge-transfer (ILCT) was


67

found to be dependent on the linker unit (e.g. phenylazo, thienylvinyl, phenylimino (64, see

Figure 6), styryl or vinyl). The strongest redshift was observed in the case of a phenylazo linker.

Furthermore, the coordination of 4,4’-bis(dibutylaminostyryl)-[2,2’]-bipyridine (66, n = 1) to zinc,

mercury, palladium and rhenium gave rise to fluorophores, spanning a wide range of

wavelengths in the visible spectrum. Even though the introduction of a hydroxy function (65, see

Figure 6) did not significantly affect the optical properties and thermal stability of the ligand. This

new family of ligands bearing a hydroxy function was the starting point for further

transformations towards polymers or multipodal ligands (unsymmetrical ligands).158 Moreover,

Bozec and his group worked on 2,2’-bipyridines extended with 4,4’-oligophenylenevinylenes via

Horner-Wadsworth-Emmons (HWE) reaction (66, n = 2 or 3, Figure 6) as analogues of the parent

compound 4,4’-bis(dibutylaminostyryl)-[2,2]-bipyridines (66, n = 1).157 The parent compound and

its analogues 64-66 all provided high thermal stability. While the absorption bands did not show

any significant redshift, the emissive bands did with increasing length of the conjugated system.

Besides, the conjugated lengths showed strong influence on the fluorescence quantum yield.

In 2012, Das and co-workers published a series of 4,4’-π-conjugated-2,2’-bipyridines providing a

D-π-A-A-π-D architecture with heterodonor functionalities (R2 in 67, R3 in 68, Figure 7).153 The

synthesis of these dyads was carried out either via Knoevenagel-type reaction in the case of

compound class 67 or via HWE reaction in case of compound class 68 (see Figure 7). In the route

of synthesis towards compound class 68 a prior Knoevenagel-type reaction is required in order

to obtain the aldehyde precursor. The intramolecular charge separation in 67 and 68 between

the donor end-capping functionality and the pyridine acceptor heterocycle was demonstrated by

photophysical studies including absorption and emission behavior.

Figure 7 2,2’-Bipyridines D-π-A-A-π-D Dyads by Das and co-workers.153

Owing to the solvent-sensitive photoluminescent behavior these fluorophores were found to be

more polar in the emitting state than in the ground electronic state. Further tendencies

concerning structure−function relationship were revealed in this study. The coexistence of both


68

the methoxy and the amino donor function in the same phenyl ring modulates the emitting state.

This was proven by the fact that a bathochromic shifted fluorescence was observed comparing

chromophores with the dyads having either methoxy or amino donor groups.

Bipyridine, terpyridine or phenanthroline-based π-extended compounds are widely used as

ligands in metal complexes.160 These inorganic compounds find application in

electrochemistry,161 especially in light-emitting diods162 or as dyes for DSSC.154,155,143,163 Besides,

the complexes were also applied in NLO.164-167 As mentioned before, Le Bozec published several

4,4’-π-cojugated [2,2’]-bipyridines (see Figure 6) with the ability to coordinate to metal ions for

potential application in NLO.168,169,156 Among a variety of different complexes formed with

ligand 66 (n = 1, Figure 6), which all showed photoluminescence, a µ-oxo-rhenium(VII) complex

dimer 69 (see Figure 8) provided a significant redshift of the absorption maximum compared to

the ligand itself, even more shifted than observed for a rhenium(I) complex. In general, they

clearly depicted that the redshift could be tuned by the Lewis acidity or oxidation state of the

metal ion or the geometry of the complex.

Figure 8 µ-Oxo-Re(VII) complex dimer by Le Bozec.156

Many examples from literature showed how π-extended ligands exert a fine tuning effect on

photophysical and electrochemical properties of the complex by influencing the metal-to-ligand

charge-transfer (MLCT) process.106,170,171 This fine tuning effect can be performed either by a

ligand with an electron-withdrawing nature providing a low lying π* molecular orbital or by a

strong donor ligand which destabilizes the metal t2g orbital.170,171

With regard to the improved version of DSSC by O’Regan and Grätzel in 1991 (see 2.1) the

development of new photosensitizing ruthenium(II) complexes gained attention. In 1992, Grätzel

and Kalyanasundaram published highly luminescent Ru(II) complexes with

4,4‘-di-(p-carboxyphenyl)-2,2’-bipyridine ligands (one complex 72 exemplarily depicted in

Figure 9).172 The introduction of an additional phenyl moiety in 72 compared to 71 caused a

redshift of the lowest energy charge-transfer (CT) band along the series from 70 to 72 (see

Figure 9).173,174 This result was in line with the increased electron-withdrawing nature of the


69

ligand in 72. Furthermore, more intense absorption was observed but the properties of the

excited state (luminescence and transient absorption) remained the same. However, the acid-

base properties in ground state and excited state were different. Inefficient sensitization of 72

was obtained on TiO2 electrodes, which might be caused by the largely localized charges on the

diamine framework without extending through the phenyl spacer to the carboxyl unit.

Figure 9 Homoleptic Ru(II) complexes with different bipyridine ligands.172-174

A major breakthrough in the development of efficient ruthenium(II)-based complexes for DSSC

was achieved in 1993 by Grätzel and co-workers.175 The authors synthesized different

heteroleptic complexes with two 2,2’-bipyridyl-4,4’-dicarboxylate ligands and two coordinating

ions (Cl-, Br-, I-, CN-, SCN-). Their absorption, luminescence and redox behavior studies revealed

cis-di(thiocyanato)bis(2,2’-bipyridyl-4,4’-dicarboxylate)ruthenium(II) (73, commonly known as

N3) as the most promising redox sensitizer (see Figure 10). It was found to harvest a large fraction

of visible light in combination with a relatively long excited-state lifetime.

Figure 10 N3 dye (73) for DSSC published by Grätzel and co-workers.175

The carboxylate functions of the bipyridine ligands assured efficient adsorption on the TiO2

surface, providing electronic coupling between charge-transfer excited state and the


70

semiconductor conduction band. Thus, ultrafast electron injection took place with nearly 100%

quantum yield. For the first time, a device based on a simple molecular light absorber was

fabricated, which was able to compete with the efficiency of conventional photovoltaic cells.

In contrast to the previously named bipyridine ligands, a terpyridine-based π-conjugated ligand

was published in 2012 by Adeloye and co-workers.171 By incorporating this ligand into a

homoleptic ruthenium(II) complex 74 (see Figure 11) the authors revealed improved

photophysical and redox properties in comparison with a simple homoleptic ruthenium(II)

terpyridine complex ([Ru(tpy)2]2+). This might be attributed to the presence of electron-

withdrawing carboxylic acids, which lowered the π* orbital of the ligand leading to a smaller

energy gap with the dπ-metal center orbital. Furthermore, the two trans-methyl groups, which

act as electron-donating substituents, stabilized the hole at the metal center and with it led to

increased quantum yield and lifetime. Owing to these properties, complex 74 was considered to

be suitable for application in DSSC, therapeutic applications and/or energy transfer functions.

Figure 11 Homoleptic Ru(II) complex by Adeloye and co-workers.171

A donor-acceptor ruthenium(II) polypyridyl complex 76 was published for application as

sensitizer in p-type NiO-based DSSC by Hammarström and co-workers in 2012 (see Figure 12).176

Figure 12 Ru(II) polypyridyl complexes for p-type DSSC by Hammarström and co-workers.176


71

The authors investigated competing kinetic processes in complexes 75 and 76 and showed that

the use of an electron-accepting phenanthroline-based ligand in a ruthenium(II) photosensitizer

increased the efficiency of the cell. Explanations for this are the increased recombination time

and the fact that the regeneration of the reduced sensitizer occurred faster for the appended

complex 76 than for 75. In case of 76, the electronic separation of the electron from the NiO

surface was improved. The energetic matching with the redox couple [Co(dtb)3]3+/2+ was

beneficial, as well.

A further possibility to adapt the spectral and redox properties of the complex to its

requirements is the extension of the coordinating pyridine-based ligand with a large π-extended

system. The so called antenna functions were found to suppress charge recombination by spatial

separation.177 4,4’-Functionalized π-conjugated-2,2’-bipyridines even exhibit two parallel

conjugated π-extended antennas. These antenna dyes found application in solid-state dye

sensitized solar cells (SDSSC), which should overcome inefficient sealing and leakage problems

of the cell in comparison with conventionally used liquid-state DSSC.178 In SDSSC the ruthenium

complexes appear in combination with an amorphous organic hole-transporter with suitable

redox potential.179

This approach was presented for instance in 2009 by Thelakkat and co-workers following the

donor-antenna dye concept.180 They synthesized a series of different bipyridyl donor-antenna

ligands in multistep procedures including Vilsmeier-Haack formylation and Wittig reaction as the

common key steps (ligands of 77 and 78 exemplarily presented in Figure 13). From these new

ligands, five different heteroleptic ruthenium(II) complexes were obtained via common

complexation one-pot procedure.181,182 Next to the attached antenna ligand, a bipyridyl

carboxylic acid anchor ligand and two SCN- ions were bound to the metal center. Absorption

measurements of the complexes containing π-extended antennas showed very high extinction

coefficients over a broad range of the spectra. The electron injection from the dyes into the TiO2

conduction band was found to be feasible for all ruthenium complexes as proven by

electrochemical measurements, as well as the regeneration of the oxidized dyes by amorphous

organic hole-transporter.


72

Figure 13 Heteroleptic Ru(II) complexes with donor-antenna ligands by Thelakkat and co-workers.180

Also in 2009, Wu, Zakeeruddin and Grätzel published a new stable heteroleptic ruthenium(II)

complex 79 carrying a π-conjugated-2,2’-bipyridin-based antenna ligand for thin-film DSSC, as

depicted in Figure 14.183 The ligand consisted of an electron-rich 3,4-ethylendioxythiophene

(EDOT) moiety and alkyl-substituted carbazole acting as hole-transporting unit, which enhanced

spectral response. Its synthesis was carried out via Ullmann N-arylation for connecting the EDOT

with the carbazole, followed by Stille coupling to link the antennas to the 2,2’-bipyridine moiety.

The absorption spectrum of 79 displayed three absorption bands centered at 295 nm, 397 nm

and 547 nm. The lower energy MLCT band at 547 nm depicted a high molar absorption

coefficient, which was caused by the electron-donating ability of dioxyethylene of EDOT and the

π-extension with thiophene. Owing to this, the complex enabled increasing photocurrent density

with thinner TiO2 films.

Figure 14 Heteroleptic Ru(II) complex with antenna ligand by Wu, Zakeeruddin and Grätzel and co-

workers.183

A further application of pyridine-based compounds in photoscience was demonstrated in 2008

by Schmuttenmaer, Crabtree, Brudvig and Batista.184 They published a terpyridine ligand 80

functionalized with an acetylacetonate anchoring moiety for efficient binding to TiO2

nanoparticles, relevant for engineering photocatalytic and photovoltaic devices (see Figure 15).

The acetylacetonate moiety of ligand 80 was obtained via CuI mediated coupling from


73

pentanedione and iodobenzoic acid, which is then converted to the acylchloride. In presence of

DIPEA, this acylchloride underwent amide formation with the terpyridine-based amine obtaining

ligand 80. Complexation of ligand 80 with manganese(II) enabled visible-light sensitization of TiO2

nanoparticles due to interfacial electron transfer, as evidenced by UV-Vis spectroscopy of

colloidal thin films and aqueous suspensions. Ligand 80 induces favorable directionality of the

electron transfer owing to the positioning of the electronic levels in electron donor and acceptor

moiety of the chromophore ligand, as depicted in Figure 15. Thus, the manganese surface

complex provided a highly efficient charge separation process triggered by photoexcitation,

which is followed by ultrafast electron injection into the conduction band of TiO2.

Figure 15 Mn(II) complexation and TiO2 binding of ligand 80 by Schmuttenmaer, Crabtree, Brudvig,

Batista and co-workers.184

Pointing out the importance of bipyridine ligands in further advances of photocatalytic water

splitting, Buda and co-workers recently published a computational study about a proposed

supramolecular complex carrying ligand 81 which consisted of a fully organic dye covalently

bound to ruthenium(II) center via a bipyridine coordination site as water oxidation catalyst (see

Figure 16).185

Figure 16 Schematic representation of the proposed photoanode with ligand 81 by Buda and co-

workers.185


74

The authors performed semiempirical quantum-classical simulations and ab initio Molecular

Dynamics simulations. With this methods they were able to show that the photoexcited system

induced heterogeneous electron injection which is the driving force for activation of the

ruthenium catalyst. The electron transfer between catalyst and oxidized antenna was

concomitant with the diffusion of one proton from the metal-coordinated water. Thus, the first

proton-coupled electron transfer (PCET) step for catalytic water oxidation was executed. PCET is

a key part of the efficient energy conversion in photosystem II (PSII) and analogous artificial

photocatalytic system. This process depicted the driving force for activation of the ruthenium

catalyst.

As demonstrated in this chapter, during the last decades, scientists found in pyridine-based

compounds a versatile class of substances with great potential in photoscience. Areas of

application range from DSSCs to DS-PECs as well as NLOs using the pure organic pyridine-based

compounds or using them as ligands coordinating to metal centers. Among all these compounds,

bipyridines were strongly represented with variations in conjugation lengths or electronic

properties tuned via end-capping units having either an electron-withdrawing or an electron-

donating nature. Small structural modifications (so called fine tuning) led to changes in spectral

response and redox properties with regard to the area of application.


75


Pyridine-based π-extended compounds are versatile compounds in DSSC,176,180,183 DS-PEC184 or

NLO.156-159 Especially 2,2’-bipyridines are an important class of compounds, which represent a

basic framework in new organic or inorganic light emitting materials. Focusing on the

π-conjugated-2,2’-bipyridines, the field of research is dominated by antennas end-capped with a

donor functionality, as described by Thelakkat and co-workers (in Figure 13) and by Wu,

Zakeeruddin and Grätzel (in Figure 14).180,183 Examples for synthesis and investigation of

2,2’-bipyridine π-extended systems end-capped with an electron-accepting group (also

applicable as anchor moiety on metaloxide surface) remain rare. π-Conjugated-2,2’-bipyridine

antennas end-capped with a cyanoacrylic acid or a cyanoacrylic acidester moiety with the ability

to act as anchoring group on TiO2 surface were not reported yet. Thus, the main objective of this

chapter is the development of a conventional synthetic route towards these underrepresented

compounds and their electrochemical and photophysical characterization with regard to

potential application as ligands in DSSC, DS-PEC (see Scheme 27). The design of these new target

compounds end-capped with cyanoacrylic acid or a cyanoacrylic acidester was inspired by

organic dyes providing a triphenylamine moiety as donor moiety instead of the here envisaged

bipyridine unit.186,187,139 Next to the development of new synthetic routes, the first attempts

towards complexation of ligands for potential application in photocatalytic processes should be

investigated as well (see Scheme 27). Promising examples from literature encouraged the

approach towards new thiophene containing ligands, either as conjugated linker unit (see

Figure 14) or end-capping functionality (see Figure 13) with donor properties.180,183,188 Thus,

further insights into modifications of the 2,2’-bipyridine compounds should be given in this

chapter with the incorporation of a bithiophene linker or a thiophene-derived end-capping

moiety (see Scheme 27). Furthermore, this chapter shall give an insight into the first advances of

developing a one-pot process towards new pyridine-based ligands in contrast to conventional

synthetic approaches.

Scheme 27 Aim: conventional synthesis of new 2,2’-bipyridines as ligands in metal complexes.


76


2.4.1 Synthesis of new 2,2’-bipyridine ligands via conventional approach

2.4.1.1 Synthesis of a 2,2’-bipyridine building block

As starting point for the synthesis of new π-conjugated-2,2’-bipyridines 4,4‘-bis(diethyl-

phosphonatomethyl)-2,2‘-bipyridine (85) was synthesized according to a literature known

procedure developed and modified by Fraser, Nazeeruddin and Castellano.189-191 This building

block 85 represents a versatile compound, which can undergo Wittig-type reaction, so called

Horner-Wadsworth-Emmons (HWE) reaction with a broad range of aldehydes forming a trans-

oriented double bond, beneficial for easy extension of a π-conjugated system. The synthesis of

compound 85 was carried out in a three-step synthesis starting with the commercially available

4,4’-dimethyl 2,2’-bipyridine (82), as depicted in Scheme 28.

Scheme 28 Three-step synthesis of building block 85.189-191

The first step of the synthesis was the silylation of 4-4'-dimethyl-2,2'-bipyridine (82) forming

4,4'-bis(trimethylsilyl)-2-2'-bipyridine (83, Scheme 28). The methyl groups of compound 82 were

deprotonated by lithium diisopropylamide (LDA) and converted with chlorotrimethylsilane

(TMS-Cl) forming product 83. In order to prevent further silylation, the subsequent addition of

ethanol was required for reaction quenching. Compound 83 was obtained in 92% yield after

aqueous workup.189

In the second reaction step the TMS groups were successively removed with CsF as anhydrous

fluoride source forming carbanions (see Scheme 28). Hexachloroethane reacted with the

generated carbanions via an electrophilic attack and the desired chloro compound 84 was finally

obtained in 86% yield after purification by column chromatography on deactivated SiO2.


77

According to literature conditions, the addition of 4 equivalents of the electrophile increased the

reaction rate.190

In the final step, compound 84 was converted to 4,4'-bis(diethylphosphonatomethyl)-

2,2'-bipyridine (85) via Michaelis-Arbuzov reaction (see Scheme 28). This reaction took place by

a SN2 mechanism, wherein a quaternary phosphorus was formed after the attack of

triethylphosphite. After rearrangement the pentavalent phosphorus compound 85 was

generated. Subsequent purification by column chromatography on deactivated SiO2 led to the

desired product 85 in 86% yield.

2.4.1.2 Synthesis of new 2,2’-bipyridine ligands end-capped with acceptor units

The increase of the π-conjugated system of the two antennas between the 2,2'-bipyridine and

the end-capping units with additional double bonds and a 2,5-dimethoxyphenyl linker moiety is

beneficial for a broader absorption in the visible-light region of the electromagnetic spectrum.180

As mentioned before in chapter 2.4.1.1, the application of a HWE reaction was the reaction of

choice in order to extend the system of building block 85. To avoid formation of side products

during the attachement of the 2,5-dimethoxyphenyl linker, a monoprotection of the

dibenzaldehyde 86 was required (see Scheme 29). The reaction was carried out according to

similar procedures from literature.192 The monoacetal 87 was obtained under stoichiometric

control by using ethylene glycol in small excess and a catalytic amount of p-toluenesulfonic acid.

After purification with column chromatography using deactivated SiO2, the new compound 87

was obtained in 50% yield.

Scheme 29 Monoprotection of dibenzaldehyde with ethylene glycol forming linker unit 87.

The following HWE reaction was carried out between the monoprotected dibenzaldehyde 87 and

the pentavalent phosphorus compound 85 in a 2:1 molar ratio forming a trans-oriented double

bond as depicted in Scheme 30. The reaction proceeded in dry THF using potassium tert-butoxide

as base. Thus, the extension of the π-conjugated two-armed bipyridine was achieved and

compound 88 was obtained after 39 h of reflux and aqueous workup in 97% yield. The formation

of an exclusively trans-oriented olefin was proven by the coupling constant detected via 1H-NMR,

which was found to be around 16 Hz.193


78

After the HWE coupling reaction, acidic hydrolysis of the acetals regained the aldehyde moieties

of the two-armed antenna 2,2’-bipyridine 88 (see Scheme 30). The deprotection was carried out

in chloroform by adding dropwise aqueous HCl.

Scheme 30 Synthesis of compound 89 via HWE reaction and acetal hydrolysis.

However, after 10 h reaction time the acetals were not completely converted as monitored via

TLC and 1H-NMR spectroscopy of the basified raw material. Thus, the deprotection step had to

be repeated for an additional 10 h. After basic aqueous workup the target compound was

obtained in almost quantitative yield without further purification. Even for further reproduction

experiments of compound 89, prolonging the reaction time or increasing the amount of HCl did

not show deprotection in either one of the experiments.

Compound 89 was used as key building block for the synthesis of new ligands. The now available

free aldehyde functions of the two-armed 2,2’-bipyridine derivative 89 enabled the simple

attachment of end-capping moieties via Knoevenagel condensation reaction. In order to obtain

compound 90, bipyridine 89 was treated with an excess of cyanoacetic acid (40 equiv.) in

presence of piperidine as base in refluxing acetonitrile for 24 h (see Scheme 31). The target

compound 90 was obtained as orange solid which was sparingly soluble in every solvent well-

established and available in the laboratory. The reason for the insolubility could be traced back

to the attached cyanoacrylic acid moiety. This phenomenon of difficult solubility was reported

before in literature for organic compounds after attachment of this end-capping moiety.186,187,194


79

However, this disadvantage enabled simple purification by trituration with THF and acetone.

Product 90 was obtained in 63% yield.

Scheme 31 Synthesis of ligand end-capped with cyanoacrylic acid via Knoevenagel reaction.

Owing to its insolubility, it was difficult to characterize the product and to ensure its purity via

NMR spectroscopy, which required an appropriate concentration of the product in DMSO-d6.

Several approaches were carried out to improve solubility including heating of the sample or

variable temperature NMR (VT-NMR) at higher temperature, but at some point the resolution of

the spectra suffered and no characteristic coupling properties could be determined. The best

result was obtained by adding several drops of hot DMF to the product prior to the sample

preparation in DMSO-d6. Hence, the recorded 1H-NMR spectrum showed splitting of signals

providing characteristic coupling constants of the trans-double bonds and the two pyridines,

even though the signal-to-noise ratio was quite low and solvent impurities appeared

predominantly in the high field region (see Figure 17).

Figure 17 1H-NMR (400 MHz) of compound 90 in DMSO-d6 (* = DMF, ** = impurities, + = H2O, ++ = DMSO).

*

+

*

++

**

** **

**

1 3 10 7 5 2 4 6

8/9


80

However, a 13C-NMR could not be recorded due to an excessively long measurement time. The

identification of the target compound via mass spectrometry was slightly easier, because of the

lower sample concentration which is required for the detection. In order to ionize and detect

hardly soluble compounds, MALDI is the method of choice. Thus, compound 90 was detected via

MALDI-TOF measurement. Even detection and identification by ESI-MS for high resolution mass

analysis was possible but with rather low intensity.

Concerning further spectroscopic, photophysical or electrochemical characterizations

insolubility can be a big disadvantage, if the concentration must be in a higher order of magnitude

as required for NMR spectroscopy for instance. Thus, slight modifications of the end-capping

moiety in the 2,2’ bipyridine dyad 90 might be beneficial without significantly changing electronic

properties and with it photophysical behavior.

In order to realize this goal, the key building block 89 reacted with a high excess of cyanoacetic

acid butyl ester via Knoevenagel condensation, as depicted in Scheme 32. The reaction mixture

was stirred for 24 h under reflux in acetonitrile in presence of piperidine. The raw material was

obtained after filtration and extraction with dichloromethane. The purification via

recrystallization using dichloromethane and diethyl ether achieved the target ligand 91 as bright

orange colored solid in 46% yield.

Scheme 32 Synthesis of ligand end-capped with cyanoacrylic acid ester via Knoevenagel reaction.

The good solubility of the target compound 91 in solvents such as dichloromethane enabled

characterization with NMR spectroscopy (1H- and 13C-NMR) and ESI-MS measurmentes for high

resolution mass spectrometry of compound 91 without difficulties. As depicted in Figure 18,

1H-NMR spectroscopy allowed easy monitoring of the extension of the π-conjugated two-armed

2,2’-bipyridine via HWE, acidic hydrolysis and Knoevenagel condensation. Thus, an efficient and

simple route of synthesis towards the two new ligands 90 and 91 end-capped with electron-

accepting moieties was developed.


81

Figure 18 Stacked 1H-NMR (300 MHz) spectra of compound 85, 88, 89 and 91 in CDCl3 (* = DCM).

A further approach towards avoiding insolubility as depicted by ligand 90 might be the

replacement of the cyanoacrylic acid end-capping moiety by a methylene malononitrile unit. For

this purpose, malononitrile (40 equiv.) was used as CH-acidic compound performing a

Knoevenagel reaction with the key building block 89 which should furnish compound 92 (see

Scheme 33). However, a broad range of products was detected via TLC, probably due to the

various options of different condensation reactions between the nitrile moieties of product and

malononitrile itself, which is present in great excess.

Scheme 33 Attempted synthesis of ligand end-capped with methylene malononitrile via Knoevenagel

reaction.

The compound 92 could not be identified in the 1H-NMR spectrum of the brownish mushy raw

material. Thus, further purification approaches were found to be unnecessary.

*


82

2.4.1.3 Photophysical and electrochemical investigations

Further investigations of the synthesized 2,2’-bipyridines 90 and 91 concerning adsorption

behavior, photophysical and electrochemical properties were required for future applications in

DSSC or DS-PEC, as metal coordinating ligand or organic dye itself. The cooperation with the

working group of Prof. Dr. J. Bachmann from the Institute of Inorganic Chemistry and the working

group of Dr. A. Kahnt from the Institute of Physical Chemistry, both at the Friedrich-Alexander

University Erlangen-Nürnberg, enabled insights into the photophysical and electrochemical

properties, discussed in this chapter.195

The question, if the ligands are able to bind to the surface of TiO2 colloids through an ester linkage

was answered by the group of Bachmann by applying spectroscopic ellipsometry technique on

Si/SiO2/TiO2 wafers. Crystalline colloids coated with a thin layer of amorphous TiO2 provide a high

number of reactive sites which can undergo a linkage with the ligands.196,197 As the ellipsometry

spectrum showed (see Figure 19a), both compounds 90 (blue) and 91 (green) adsorbed onto

amorphous TiO2. For each compound three curves were shown: before soaking (light colored),

after soaking (normal colored), after additional overnight rinse in pure solvent (dark colored).

The shift of the curves from their inititial states ensured the adsorption even after the overnight

rinse. However, in contrast of the behavior on amorphous TiO2, when crystalline TiO2 was used,

providing less reactive sites, the curves of 90 and 91 showed a different result (see Figure 19b).

Here, in the case of compound 90 (blue), no stable chemisorbed layer was observed, probably

owing to hydrogen bonding interactions between the pyridines and the carboxylic acids, which

then might be blocked for linking. This was not observed for ligand 91 (green).

Figure 19 Adsorption behavior of ligand 90 (blue) and 91 (green) on TiO2: a) with amorphous TiO2 or b)

crystalline TiO2.195

Moreover, voltammetric measurements were carried out in the group of Bachmann which

allowed conclusion if the electron, which is photoexcited into the LUMO of the ligand has enough

energy to be injected into the TiO2 conduction band. As depicted in Figure 20, the differential

pulse voltammetry curves showed reduction potentials of -0.22 V for 90 and -0.06 V for 91 (vs.

λ / nm

400 500 600 700 800

900

900

b) a)


83

NHE; see arrows), which were close to the energy level of the TiO2 valence band (-0.31 vs NHE).

Thus, a sufficient LUMO energy for efficient electron transfer is guaranteed.

Figure 20 Differntial pulse voltammetry of ligand 90 (blue) and 91 (green) in DCM/DMSO (1:1 v/v).195

To get closer insight into the photophysical behavior, UV/Vis measurements of compound 90 and

91 were carried out in the group of Kahnt, provididing absorption spectra, as depicted in

Figure 21. The ground state absorption of both compounds was found to be almost identical with

maxima at 346 nm and 430 nm (90) and 350 nm and 436 nm (91).

Figure 21 Absorption spectra in THF: a) of ligand 90 b) of ligand 91.195

Strong fluorescence was found to appear between 450 nm and 750 nm upon photoexcitation at

420 nm of both compounds (see Figure 22). Compound 90 showed the maximum at 496 nm and

compound 91 at 513 nm. The fluorescent quantum yields were calculated with 0.085 (90) and

0.075 (91) with tetraphenylporphyrin (0.11) and zinc tetraphenylporphyrin (0.03) as references.

Figure 22 Fluorescence spectra of a) ligand 90 and b) ligand 91 in THF (photoexcited at 420 nm).195


84

Fluorescence-lifetimes at 500 nm were obtained upon photoexcitation at 403 nm with 1.3 ns (90)

and 1.1 ns (91) from the corresponding fluorescence-time profiles, depicted in Figure 23. The

instrument response function is shown in black (see Figure 23).

Figure 23 Fluorescence-time profiles at 500 nm of a) ligand 90 and b) ligand 91 in THF (photoexcited at

403 nm).195

Transient absorption measurements were carried out in order to get insight into the formation

and fate of excited states using femtosecond laser photolysis. Photoexcitation at 387 nm with

femtosecond laser pulses elucidated two dominating maxima in the transient absorption spectra

of both compounds at 580 nm and 810 nm referring to S1 SN transitions (see Figure 24).

Figure 24 Femtosecond transient absorption spectra in argon saturated THF: after 1 ps (black), 10 ps

(red), 100 ps (green), 1000 ps (blue) and 5500 ps (cyan) of a) ligand 90 and b) ligand 91

(photoexcitation at 387 nm).195


85

Figure 25 Corresponding absorption time profiles at 580 (black) and 810 nm (red) of a) ligand 90 and

b) ligand 91.195

The decay of the transient absorption to the ground state was recorded with a lifetime of 1.2 ns

(90) and 1.0 ns (91), see Figure 25. This result is consistent with the observed fluorescence-

lifetimes (see Figure 23).

These photophysical characterization revealed the two bipyridine compounds 90 and 91 as

potential photosensitizer dyes for photocatalytic applications. The LUMO energies match relative

to TiO2 conduction band in combination with a sufficient long-lived singlet first excited state of

more than 1 ns. This would enable efficient electron transfer. Apart from the slightly different

adsorption behavior of ligand 90 and 91, photophysical and electrochemical properties were

found to be identical despite one having an acid functionality and one having an ester

functionality attached, as proposed in chapter 2.4.1.2.

2.4.1.4 Synthetic approaches towards new ruthenium complexes

The efficiency values of DSSC with inorganic dyes range already between 11 and 12% but offer

further room for improvement.143 An access to new sensitizers is the incorporation of organic

dyes with extended π-system as ligand in ruthenium complexes as previously described in

chapter 2.2. 180,183,172 The complexation of the π-extended ligand enables a fine tuning effect on

the obtained complex and thus modulation of photophysical and electrochemical properties of

the complex.

Thus, first complexation experiments of the new 2,2’-bipyridine-derived organic antennas 90 and

91 should offer first insights into the development of new inorganic dyes for photocatalytic

purposes. The π-conjugated 2,2’-bipyridines end-capped either with cyanoacrylic acid (90) or

cyanoacrylic acidbutylester (91) might be the starting point for future experiments: A screening

of different modes of anchoring of the corresponding metal-based photosensitizers 93, 94 or 95

onto the TiO2 surface and subsequent investigation of photocatalytic performance (see

Scheme 34) might give a hint about beneficial ligand structures and anchoring modes.


86

Scheme 34 Different anchoring possibilities onto TiO2 surface (labeled red).

In order to investigate the feasibility of complexation chemistry under the present laboratory

conditions, a reproduction experiment was carried out first. With regard to the preparation of

complexes which provide a general structure including thiocyanate and 2,2'-bipyridine-

4,4'-dicarboxylic acid (96) as ligands, the synthesis of N3 (73) was chosen (already mentioned in

chapter 2.2, Figure 10).

For this purpose and for the preparation of new complexes (e.g. complex 93 or 94, Scheme 34)

2,2'-bipyridine-4,4'-dicarboxylic acid (96) was synthesized according to literature procedure, as

depicted in Scheme 35.198

Scheme 35 Synthesis of 2,2'-bipyridine-4,4'-dicarboxylic acid (96).198

2,2'-bipyridine-4,4'-dicarboxylic acid (96) was obtained in 66% yield by oxidation of

4,4’-dimethyl-2,2’-bipyridine (82) using potassium dichromate. Owing to insolubility, no

characterization of compound 96 was possible via NMR spectroscopy or mass spectrometry.

The test reaction to prepare N3 (73) was carried out according to general literature procedure

for heteroleptic thiocyanate complexes for the coordination of a π-extended 2,2’-bipyridine and

compound 96 as ligands, even though in the case of complex 73 ligand 96 has to be incorporated


87

twice (see Scheme 36). The use of [Ru(II)(p-cymene)Cl2]2 as starting material provides the

opportunity to obtain the desired heteroleptic octahedral Ru(II)bis(bipyridyl)(NCS)2 structure via

an efficient one-pot synthesis by subsequent addition of the respective ligands. This reaction

procedure was chosen as prove of concept for the synthesis of the planned complexes as

depicted in Scheme 34.181,182 The general procedure started with the addition of a π-conjugated

2,2’-bipyridine ligand dissolved in dry DMF to a solution [Ru(II)(p-cymene)Cl2]2 in dry DMF under

inert conditions. Afterwards, the mixture was stirred for four hours at 80 °C in the dark. After

addition of ligand 96 the temperature was raised to 160 °C for four hours. Then, ammonium

thiocyanate was added and the mixture was stirred at 130 °C for additional four to five hours.

The solvent was evaporated and the excess of ammonium thiocyanate was washed off with

water. The exclusion of light and the sequential temperature changes should prevent

photoinduced or thermal cis-trans isomerization, even though generally the trans-complex

(Ru(II)bis(bipyridyl)(X)2) might suffer from instability due to the unfavorable interaction of the

hydrogens on the opposing bipyridine ligands.199,200 Besides, photoinduced ligand substitution

with DMF should be suppressed when the reaction is carried out in the dark.201

Due to the small reaction quantity in the synthesis of N3 (73), no purification via Sephadex LH-20

and thus no determination of yield was carried out (see Scheme 36). After recrystallization of the

raw material the 1H-NMR measurement of the violet residue dissolved in DMSO-d6 recorded the

proton signals of the target compound N3 (73), which were in accordance to literature (see

Scheme 36).202

Scheme 36 Synthesis and 1H-NMR signals of N3 (73) dye (* = DMF).202

No side products were detected and the cis-isomerism of the two 2,2'-bipyridine-

4,4'-dicarboxylic acid ligands (96) was ensured by the splitting pattern in the 1H-NMR spectrum

*


88

(see Scheme 36). Besides, complex 73 was detected and identified via MALDI-TOF measurement.

Thus, the reaction procedure under present laboratory conditions was found to be feasible.

The same literature procedure181 was applied to make heteroleptic complex 93 synthetically

accessible, providing the ligands 90 and 96 in cis position (see Scheme 37). The recorded 1H-NMR

spectrum of the violet raw material in DMSO-d6 showed signals in the downfield region which

should refer to aromatic protons of the ligands and or ruthenium complexes. However, the low

resolution owing to low solubility of the sample did not allow further indications via NMR

spectroscopy about the obtained raw material. ESI-MS measurements of the raw material using

methanol/dichloromethane (v/v 1:1) as solvent were carried out. Signals with the highest

intensity could be clearly assigned to the N3 (73) complex, providing the characteristic isotopic

pattern of a ruthenium complex, although the before mentioned obtained noisy 1H-NMR signals

of the raw material NMR spectrum could not ensure the formation of the cis-isomer of complex

73. No unreacted ligand 90 remained in the raw material and could be detected by ESI-MS, which

indicated complexation of the ligand in some way. Although some heavy species were detected

with higher intensity and characteristic isotopic pattern of a ruthenium complex at m/z =

868.0588 and m/z = 1067.1236, no assignment of this ruthenium species to the target complex

93 or other side products was possible.

Scheme 37 Attempted synthesis of heteroleptic complex 93.

The complexation procedure as described for ligand 90 was carried out for ligand 91 as well (see

Scheme 38). As already described for the experiment towards complex 93 (see Scheme 37),

owing to low resolution and low solubility of the raw material no conclusions about the obtained


89

structures could be drawn via NMR spectroscopy. ESI-MS measurements of the raw material

using methanol/dichloromethane (v/v 1:1) as solvent detected heavy ruthenium complex species

with m/z = 991.1571, m/z = 1064.2064, m/z = 1091.2107, m/z = 1164.2598 and

m/z = 1191.2648, all showing characteristic isotopic pattern. Purification with Sephadex LH-20

and tetrabutylammonium hydroxide (TBAH) did not lead to improvement of purity of the raw

material and with it to simplified characterization and elucidation of the obtained structures in

the reaction mixture.

Scheme 38 Attempted synthesis of heteroleptic complex 94.

In order to simplify the detection of the target complexes via mass spectrometry, the last

reaction step, adding ammonium thiocyanate, was left out and chloro complexes instead of

thiocyanate containing complexes should be obtained. It might be the case for some metal

complexes that ionization by loss of a coordinating chloride is favored compared to a

coordinating thiocyanate.203 Thus, the reaction attempt depicted in Scheme 38 was repeated

without adding ammonium thiocyanate (see Scheme 39).

Scheme 39 Attempted synthesis of heteroleptic chloro complex 97.


90

Indeed, the investigation of the raw material (see Scheme 39) via MALDI-TOF measurement

could ensure the formation of the target complex 97 ionized by the loss of chloride and ionized

by an additional sodium ion, as depicted in Figure 26. Besides, complex 98 was detected as chloro

complex analogue to N3 (73) from the mixture.

Figure 26 MALDI-MS measurement of raw material with characteristic isotopic pattern of Ru complex.

However, the recorded 1H-NMR in methanol-d4 of the raw material showed no signals relating

to complex 97. It is likely that no detection was possible due to insolubility in methanol. Only

complex 98 and probably its trans-isomer were detected in small amounts. Thus, filtration with

methanol was carried out. But further characterization of the obtained residue did not lead to

further clarification of the reaction outcome (yield, cis/trans isomerism via NMR, solubility),

which might be caused by degradation of the target complex 97.

A synthetic approach towards complex 95 (see Scheme 34) was carried out but the addition of

ammonium thiocyanate was again avoided in order to get a better insight into the reaction

outcome by MALDI-TOF measurement (see Scheme 40). However, a MALDI-TOF measurement

of the raw material detected only the ionized uncoordinated ligand 90 and signals of the ionized

complex 100 with major intensity. No signals with characteristic isotopic pattern of complex 99

were observed. Some heavy species with m/z = 1036 and m/z = 1021 were detected, providing a

characteristic ruthenium complex isotopic pattern but could not be assigned to a specific

complex structure. Besides, the raw product 1H-NMR, which was recorded in methanol-d4,

detected the cis-complex 100 according to literature NMR data (characteristic signal of complex

100 labeled red, Scheme 40).204 Owing to signal distribution of further signals in the aromatic

region of the recorded 1H-NMR (see Scheme 40) it is proposed that two additional ruthenium

complexes, one providing trans-isomerism (characteristic signal of complex 102 labeled green,

Scheme 40) and one providing cis-isomerism (characteristic signal of complex 101 labeled red,

Scheme 40), were contained in the raw mixture. Here, either two chloride ligands or two identical

solvent molecules might coordinate (X in complexes 100, 101, 102 in Scheme 40).

[M(97)-Cl]+

[M(98)-Cl]+


91

Scheme 40 Attempted synthesis of heteroleptic chloro complex 99 with cutout from recorded 1H-NMR of

the raw material (* = DMF).

Owing to low resolution of the recorded 1H-NMR spectrum and thus low signal to noise ratio, no

further assignment of the signals was possible. It is also conceivable that characteristic trans- or

cis-complex signals (see Scheme 40) could be caused by a complex coordinating only one

4,4'-dimethyl-2,2'-bipyridine (82) to the ruthenium center, with two solvent molecules instead

of the second 4,4'-dimethyl-2,2'-bipyridine (82) (structures are not depicted in Scheme 40). By

changing the order of addition in the reaction procedure and starting with 4,4'-dimethyl-

2,2'-bipyridine (82) and [Ru(II)(p-cymene)Cl2]2 at 80 °C followed by the addition of ligand 90, the

trans-complex corresponding signals (labeled green in Scheme 40) appeared almost exclusively

in the recorded raw material 1H-NMR spectrum. Neither in the 1H-NMR nor in the MALDI-TOF

spectrum a formation of complex 99 was observed.

Some further approaches such as modification of temperature and order of addition of ligands

were carried out. However, no target complex providing the desired heteroleptic octahedral

structure Ru(II)bis(bipyridyl)(NCS)2 or Ru(II)bis(bipyridyl)(Cl)2 was observed except in the case of

the attempted synthesis towards complex 97. Coordination of ligands 90 and 91 to a ruthenium

center was found to be challenging. An explanation for this might be the electron-withdrawing

1 1 (100) 1 (101) 2

3

*


92

end-capping moiety, which required a different synthetic approach for complexation than the

commonly used one-pot procedure starting from [Ru(II)(p-cymene)Cl2]2.181 Here, the applied

π-extended ligands provided electron-donating end-capping moieties.180,183 The 2,2'-bipyridines

moieties in case of ligand 90 and 91 might be hindered for coordination due to a lack of electron

density. Thus, a synthetic approach to bring the ligands to the ruthenium center could be the

procedure as described for complex 76, a dye for p-type DSSC (see Figure 12). Here, the

phenanthroline ligand coordinates to previously synthesized complex 98 via microwave assisted

reaction in water and acetic acid. A further explanation for the hindered coordination of the new

2,2’-bipyridines might be the nitrile moieties in both ligands, competing for coordination to the

metal center.205 However, further experiments to get detailed insight into the challenging

complexation of ligand 90 and 91 were not carried out within the framework of this work.

2.4.1.5 Synthesis of new 2,2’-bipyridine ligands containing thiophene

Literature provides a variety of thiophene containing ligands incorporated in promising

complexes for application in photochemistry. The ligands contain the thiophenes either as

conjugated linker unit or end-capping functionality with donor properties (see Figure 13 or

Figure 14).180,183,188 They were found to a have advantageous tuning effects in terms of increasing

the molar extinction coefficient and enhancing the light harvesting capacity as well as the

spectral response.188 Thus, further insights into new synthetic attempts towards thiophene

containing 2,2’-bipyridine compounds should be discussed here.

The first synthetic approach should deal with the incorporation of a thiophene unit instead of a

carboxylic acid or acid ester into the end-capping moiety of the ligand next to the nitrile (see

target ligand 103 in Scheme 41). The nitrile itself might enable TiO2 binding, necessary for further

photocatalytic applications.205

Scheme 41 Attempted synthesis of ligand 103 end-capped with methylene thiopheneacetonitrile via

Knoevenagel reaction.


93

The planned formation of the methylene thiopheneacetonitrile end-capping moiety was carried

out via Knoevenagel reaction starting from the key building block 89 and an excess of thiophene-

2-acetonitrile (see Scheme 41). However, after refluxing the reaction mixture in acetonitrile for

24 h, a brownish not bright colored sticky mixture with insoluble particles was obtained.

Although, the title compound could be identified from the raw material via MALDI-TOF with

m/z = 747 as [M(103)+H]+, the title compound could neither be identified in the recorded

1H-NMR spectra in methanol-d4, DMSO-d6 and chloroform-d1 of the raw material nor after a

filtration process, which indicates insolubility of compound 103. Thus, further purification

approaches to isolate compound 103 were found to be unnecessary. Modifications of reaction

conditions in order to yield ligand 103 were not envisaged owing to the presumed insolubility.

A further synthetic approach towards a ligand end-capped with a thiophene moiety was carried

out but this time containing an additional methyl group instead of a nitrile functionality. Thus,

the electronic property of the end-capping moiety changed from an electron-accepting to an

electron-donating property. This might lead to improved handling for future complexation

approaches in contrast to the challenges described for ligands 90 and 91 in chapter 2.4.1.4. To

perform the attachment of this end-capping moiety a further HWE reaction was performed with

the key building block 89. Hence, the synthesis of precursor 106 was required prior to the HWE

reaction. Compound 106 was obtained from 2’-acetylthiophene via sodium borohydride

reduction to gain 1-(thiophen-1-yl)ethanol (105), as depicted in Scheme 42.206

Scheme 42 Snythesis of ethyl phosphate precursor 106 via reduction206 and Michaelis-Arbuzov

reaction.207

The reduction was followed by a Michaelis-Arbuzov reaction furnishing diethyl-1-(thiophen-

2-yl)ethylphosphate (106, Scheme 42).207 Subsequently, the obtained precursor 106 was applied

in a HWE reaction with key building block 89 (see Scheme 43). The reaction was carried out in

THF under reflux for 24 h. Hence, the formation of a trans-oriented double bond and with it the

extension of the conjugated system in target compound 107 was enabled. The recorded raw

material 1H-NMR spectrum showed full consumption of compound 89. Next to the assigned

signals of product 107 some signals of potential side products were detected as well. In order to

purify the raw material, several recrystallization attempts were carried out since column

chromatography was not found to be suitable for separation from side products.


94

Scheme 43 Synthesis of ligand 107 end-capped with propenyl thiophene via HWE reaction.

After recrystallization from diethyl ether and dichloromethane, the recorded 1H-NMR spectra

showed a reduced proportion of side products, inter alia of compound 106. Nevertheless, despite

remaining impurities, the target compound 107 was detected via ESI-MS for high resolution mass

analysis. Further recrystallization with hot methanol removed the remaining reactant 106. An

1H-NMR spectrum recorded in dichloromethane-d2 revealed the 32 expected proton signals of

compound 107 (no signal overlap in the aromatic region as it was the case for chloroform-d3 as

solvent). But still interfering signals could be identified from the recorded 1H-NMR spectrum. A

recorded 2D NMR (COSY) did not show any valuable indications to elucidate the structure of the

compound causing the interfering signals. It is worth noting the fact, that even though a clear

solution of the NMR sample could be obtained with a low maximum concentration (only ~5 mg/

2 ml) by repeated ultrasonication, gentle heating and subsequent cooling, after several minutes

some turbidity reappeared. Thus, the NMR measurements were carried out with slightly cloudy

solutions. Several recrystallization attempts were applied to purify target ligand 107 using

dichloromethane and hexane or dichloromethane and diisopropyl ether. However, the best

result was obtained by recrystallizing from hot methanol and in a second pass from

dichloromethane and hexane (HPLC grade), as shown by a 1H-NMR spectrum depicted in

Figure 27.

Decomposition of the target compound 107 in solution could be an explanation for the appearing

interfering 1H-NMR signals despite all purification attempts. The stability in solution was studied

via 1H-NMR spectroscopy. A sample was dissolved in chloroform-d3 and a 1H-NMR spectrum was

recorded. Subsequently, the sample was stored in solution for one week in the dark, to exclude

the effect of light. The 1H-NMR spectrum which was recorded after that time did not reveal any

significant change, which demonstrated the stability of compound 107 in solution. Having a

closer look at the interfering 1H-NMR signals (labeled with red frame, Figure 27), they were found

to be closely related to the signals of the target compound 107 in a particular way. The coupling

constants were similar and the integrals of the interfering signals after different recrystallization

attempts differ in equal proportion to each other and to the signals of target compound 107.


95

Figure 27 1H-NMR (400 MHz) of compound 107 in CDCl3 (* = DCM, + = H2O).

Thus, it was proposed that the interfering signals detected via 1H-NMR (labeled with red frame

Figure 27), which were observed even after repeated crystallization attempts, might come from

intermolecular interaction (π-π stacking or self-aggregation)208,209 or photocatalyzed E/Z

isomerization in solution.210-213

NMR spectroscopy is an excellent tool that gives information about the molecular arrangement,

the size and the stability of the supramolecular aggregates in solution.208 The weak and reversible

non-covalent intermolecular interactions of monomers are sensitive to concentration changes,

which causes shifted signals detected in an 1H-NMR spectrum. Thus, the easiest approach to

investigate possible intermolecular interaction was comparing the recorded 1H-NMR spectra

before (spectrum Figure 28a, maximum concentration at 5 g/ 2 ml before precipitation) and after

dilution (spectrum Figure 28b, concentration at 5 g/ 4 ml). Owing to low sample concentration,

a high number of scans is required for the NMR measurement. The lower concentration of the

second 1H-NMR measurement led to lower resolution of the spectrum, as expected. Spectrum

Figure 28b after dilution still showed the two interfering signals at 6.6 and 6.7 ppm as observed

in the spectrum Figure 28a. However, a pyridine assigned signal was slightly shifted downfield,

appearing before dilution as doublet of doublet at 7.48 ppm and after dilution at 7.60 ppm as

broad singlet (labeled green in Figure 28). The proton signal of the pyridine linked double bond

of compound 107 was slightly shifted as well, while preserving the coupling constant of the

doublet characteristic for trans-orientation (J = 16.4 Hz; labeled grey in Figure 28). A shift of

*

+

1 3

11

7

4

2

6

14

10

5

13 12

8/9


96

0.3 ppm in downfield direction and signal broadening was observed for a further pyridine proton

of compound 107 (labeled blue in Figure 28) while the one without labeling did barely show any

shift. The small interfering signals (labeled with red frame in the upper cutout 7.4 to 8.8 ppm in

Figure 27) were not observed in the aromatic region between 7.4 and 9.0 ppm. This might have

happened due to low resolution of the spectrum or signal overlap.

Figure 28 1H-NMRs (400 MHz) of compound 107 a) before and b) after dilution in CDCl3.

However, signal overlap was proposed to be the best explanation owing to the remaining signals

which stayed unaffected at 6.6 and 6.7 ppm. A correlation between the interfering signals and

concentration dependend intermolecular interactions is not fully proven. Nevertheless,

concentration dependend intermolecular interactions might occur for compound 107 (labeled

blue, grey and green in Figure 28) but was not further examined within the framework of this

work.

To investigate potential photocatalyzed E/Z isomerization as origin of the appearing interfering

signals (labeled with red frame Figure 27), a further experiment monitored by 1H-NMR

measurements was carried out. First of all, a 1H-NMR spectrum of product 107 was recorded

right after sample preparation. Afterwards, the sample tube was placed at the window under

daylight illumination for three days. Then, the sample tube was taken for a second 1H-NMR

measurement and a further proton spectrum was recorded for comparison (spectra Figure 29a

and Figure 29b). Indeed, the integral ratio of interfering signals to products signals increased,

while the ratio among each other was kept in the same range (spectra Figure 29a and Figure 29b:


97

pyridine signals at 8.66 ppm in both spectra were normalized as 2 including interfering signals).

The coupling constant of the pyridine linked trans-double bond was kept constant (labeled grey,

Figure 29). Thus, E/Z isomerization of this double bond could be excluded. It is proposed that if

the interfering signals arise in connection with E/Z isomerism, the isomerization might take place

at the thiophene linked double bond.

Figure 29 1H-NMRs (400 MHz) of compound 107 a) before and b) after illumination with daylight.

In case of a trans-oriented double bond the proton (labeled blue in 107, Figure 29) was assigned

to the signal at 7.08 ppm in the 1H-NMR spectrum (labeled blue, in Figure 29a). The interfering

signal at 6.57 ppm was assigned to the characteristic proton signal of the thiophene linked cis-

double bond (labeled blue, in Figure 29b) that showed a trans-cis-difference of 0.5 ppm. After

irradiation, the signal underwent doubling of the integral. Further statements were not enabled

by analysis of the spectra owing to signal overlapping (also caused by chloroform-d3).

Inconsistently, irradiation with a cold-light lamp (white high-power-LED, 400-700 nm, 6 h),

revealed changes of the 1H-NMR proton signals but led to a different spectrum, as depicted in

Figure 29 after daylight irradiation. Although the E/Z isomerism was still not fully proven the

irradiation experiment with daylight could at least prove a causal link between light and the

interfering signals. This assumption was reinforced by the fact that instability in solution could

be excluded, as proven by the one-week storage in solution and in the dark without degradation.

To get further insight into the origin of the interfering signals, a possible attempt was the full

conversion of the thiophene linked double bond into cis-orientation to exclusively obtain the


98

(Z,E,E,Z)-isomer of ligand 107. For this purpose, irradiation with high energy UV-light was carried

out. However, the irradiation with UV-light for 6 h (300-415 nm; 250 Watt) only led to full

degradation of compound 107. To investigate the proposed photocatalyzed E/Z isomerization of

compound 107 in detail additional experiments, which were not part of this work, are required

to support this hypothesis.

A further promising approach to tune the properties of 2,2’-bipyridine-derived ligands, was the

introduction of a different π-extended linker. An alternative key building block containing a

bithiophene π-bridge should be developed in contrast to the previously applied building block

89, containing a dimethoxyphenyl moeity. Thus, a bithiophene linker precursor 110 was

synthesized via a two step reaction, including a reductive coupling step with NiCl2/Zn214 and an

aldehyde protection step (see Scheme 44). In order to avoid side product formation when the

linker 110 is attached to the 2,2’-bipyridine building block 85 (see Scheme 45), the

monoprotection of the diealdehyde was required as already described for dibenzaldehyde 86

(see Scheme 29). The protection was carried out according to the synthesis of compound 87 and

similar procedures from literature.192

Scheme 44 Two-step synthesis of bithiophene linker 110.214

However, the monoprotected bithiophene aldehyde 110 was not obtained in pure form,

although purification via column chromatography was done twice using deactivated SiO2. Several

recrystallizations were carried out as well but the recorded proton spectra of compound 110 still

showed impurities of the double protected and the fully unprotected bithiophene. The fractions

provided different ratios of impurities. This might indicate deprotection during the purification

processes. The purest fraction contained 8% bis-protected 2,2'-bithiophene and 7% of the

unprotected 2,2'-bithiophene.

Scheme 45 Synthesis attempt towards compound 111.


99

As prove of concept, this fraction of compound 110, containing small amounts of impurities, was

applied in a HWE reaction with 2,2’-bipyridine building block 85, forming compound 111 (see

Scheme 45). Besides already existing and new side products, compound 111 was identified from

the raw material via MALDI-TOF (m/z = 681 [M+H]+) and 1H-NMR measurement. A 2,2’-bipyridine

compound which underwent only one HWE reaction instead of two was detected as side product

via MALDI-TOF measurement. Recrystallization from dichloromethane and pentane could

improve the purity of the target compound 111, as shown by a 1H-NMR spectrum (see

Figure 30).

Figure 30 1H-NMR (300 MHz) of compound 111 containing impurities (* = DCM, += H2O).

The formation of the new trans-oriented double bonds in compound 111 (labeled red, Figure 30)

was clearly proven by the two doublets showing a coupling constant of 16.0 Hz (labeled red in

the spectrum, Figure 30). Partial deprotection of the aldehydes in compound 111 was suggested

owing to the signals appearing at 9.84 and 9.86 ppm (labeled with grey frame, Figure 30). These

signals and other related interfering signals could not be clearly assigned to the signals of the

impurity in the applied fraction of bithiophene linker 110 or the linker 110 itself. Thus, they might

have originated from a monoprotected or a fully deprotected version of compound 111. This was

further investigated by subsequent deprotection of the slightly contaminated compound 111 by

adding diluted HCl (see Scheme 46). However, the expected simplification of the recorded raw

material 1H-NMR spectrum in comparison to the spectrum recorded before (see Figure 30) was

not observed. The desired product 112 was not obtained in the raw material as the 1H-NMR

spectrum and the MALDI-TOF measurement confirm. The 1H-NMR spectrum revealed a new

*

+

6-9

4

10

11/12

5 3 1 2


100

signal at 9:90 ppm which might correspond to a newly formed aldehyde but neither characteristic

double bond signals nor signals which could be assigned to the bithiophene bridge were

observed. This indicated degradation of compound 111, which is caused by the applied acidic

deprotection conditions, as described in Scheme 46.

Scheme 46 Attempted deprotection step towards compound 112.

Owing to the observed sensitivity of 111 under acidic deprotection conditions and further related

disadvantages for future applications, a different synthetic approach towards 112 was not

developed.


101

2.4.2 Synthesis of pyridine-based ligands in an organocatalytic one-pot procedure

Besides pyridine moieties, quinolines are an important heterocyclic unit in several organic and

inorganic sensitizers, applied for DSSCs (113 exemplarily depicted in Figure 31).215-217 Hence, the

development of practical synthetic routes towards these heterocyclic compounds is of significant

importance. Novel one-pot approaches can be an environmentally friendly and economical

option in the synthesis of a new sensitizer.93-96,13

Figure 31 Near-IR sensitizer for DSSC developed by Funaki, Sugihara and co-workers.217

In 2007, Córdova and co-workers published an enantioselective amine catalyzed Michael

addition aldol condensation domino reaction between 2-aminobenzaldehyde (114) and a variety

of α,β-unsaturated aldehydes. The valuable 1,2-dihydroquinolines were obtained in high yields

with very good chemo- and enantioselectivities. A screening of different solvents (acetonitrile,

dimethylformamide), additives (benzoic acid, 2-nitrobenzoic acid), various chiral prolinol-based

catalysts, different reaction times and temperatures revealed dimethylformamide, -25 °C, the

use of 20 mol% benzoic acid and 20 mol% of the TMS protected diphenylprolinol catalyst as best

performing reaction conditions. The reaction was found to be feasible for enal substituents such

as aryl, alkyl and ester groups.218

In 2008, Yao and co-workers published a similar pyrrolidine catalyzed Michael addition aldol

condensation domino reaction towards dihydroquinoline, using 2-aminobenzaldehyde (114) and

(2E)-4-(acetyloxy)-2-butenal (115) in combination with a subsequent oxidation with MnO2 in a

one-pot process, obtaining quinoline 116, as depicted in Scheme 47.219

Scheme 47 One-pot process towards quinoline 116 developed by Yao and co-workers.219

Although literature provides promising one-pot procedures towards dihydroquinolines or rather

quinolines, neither of these procedures was tested for the synthesis of pyridinyl dihydroquinoline


102

carbaldehydes as target compounds (118, see Scheme 48). After subsequent oxidation of

dihydroquinolines towards quiolines, these compounds 119 might be valuable structures in

organic or inorganic sensitizers (as ligands). They could be easily accessible in a one-pot process

and might undergo further modifications for tuning of sensitizer properties (120; see

Scheme 48).

Scheme 48 Aim: One-pot process towards pyridinyl quinoline-based sensitizer.

To investigate the feasibility of this proposed one-pot procedure, the synthesis of the reactants

2-aminobenzaldehyde (114) and (E)-3-(pyridin-2-yl)acrylaldehyde (117) was required and carried

out according to known literature procedures as depicted in Scheme 49.220,221

Scheme 49 Synthesis of 2-aminobenzaldehyde (114) and (E)-3-(pyridin-2-yl)acrylaldehyde (117).220,221

To ensure the feasibility of the one-pot process under the present laboratory conditions, at first

a reproduction experiment was carried out by using achiral pyrrolidine as catalyst instead of

enantiopure TMS protected diphenylprolinol, which was applied in literature. Reaction

conditions without additive were chosen, using 20 mol% pyrrolidine in acetonitrile as depicted

in Scheme 50.218


103

Scheme 50 Reproduction experiment: One-pot process towards dihydroquinoline 125.218

After 7 h at room temperature and purification of the raw material, product 125 was obtained in

71% yield from 2-aminobenzaldehyde (114) and (E)-cinnamic aldehyde (124; see Scheme 50).

Literature provided a reaction outcome of 78% yield (79% ee) of dihydroquinoline 125, using the

chiral catalyst.218 Thus, the reproducibility of the applied one-pot procedure was deemed to exist

under the present laboratory conditions.

The reaction conditions applied before to the reproduction experiment were used for the first

attempt towards dihydroquinoline 118 via a one-pot process, starting from compound 114 and

compound 117 (see Table 9, Entry 1). No conversion towards the desired target compound 118

or any other intermediary product was observed and no other reaction took place as proven by

TLC and the recorded 1H-NMR spectrum. This result indicates that the reaction feasibility might

be strongly affected by the pyridine moiety, which might be attributed to its basicity.

Table 9 Screening of reaction conditions for the one-pot process towards dihydroquinoline 118.

Entry Pyrrolidine

[mol%]

Solvent Benzoic Acid

[mol%]

Temp. Time Yield

[%]

1 20 MeCN - r.t. 24 h -

2 20 DMF 20 r.t. 8 d -

3 20 DMF 100 r.t. 3 d -

4 20 DMF 20 60 °C 80 °C 3 d -

5 10 DCM 10 r.t. 3 d -

Owing to that assumption and the previously described screening of reaction conditions, the

solvent was changed to DMF and benzoic acid was used as additive (see Table 9, Entry 2).

However, after this reaction attempt neither TLC nor 1H-NMR measurements of the reaction

mixture could detect a new compound which might correspond to compound 115. Increasing

the amount of additive from 20 mol% to 100 mol% benzoic acid did not affect the reaction at all

(see Table 9, Entry 3). Heating for three days did not result in the formation of product 115 either


104

(see Table 9, Entry 4). Even though some additional signals were detected in the 1H-NMR

spectrum of the raw material, TLC and MALDI-TOF analysis did not give indication of product

formation. By applying the reaction conditions as previously described in Scheme 47,219 using

dichloromethane as solvent, the reactants remained again unchanged in the raw mixture after

three days of stirring at room temperature (see Table 9, Entry 5).

Even though several synthetic attempts were carried out, neither the formation of the desired

target compound 115 was observed nor could the reason of the hindered reaction process be

clarified.


105

2.5 Conclusion

In the framework of this work, a conventional route of synthesis towards three new

4,4’-π-conjugated 2,2’-bipyridine-based compounds, bearing a dimethoxyphenyl linker, was

developed (see Scheme 51).

Scheme 51 Developed π-conjugated 2,2’-bipyridines 90, 91 and 107.

Two electron-accepting end-capping moieties were successfully attached to a π-extended

2,2’-bipyridine system, obtaining new sensitizer 90 and 91 for photochemical application. The

possible implementation of compounds 90 and 91 for photochemical purposes was found to be

feasible due to adsorption behavior studies on TiO2, photophysical and electrochemical

characterization of the dyes. These investigations revealed that compounds 90 and 91 enable

efficient electron transfer of the photoexcited state to the TiO2 conduction band. Coordination

of 90 and 91 as ligands to a ruthenium center was found to be challenging. An explanation for

this might be the electron-withdrawing end-capping moiety which required a different synthetic

approach for complexation than the commonly used one-pot procedure starting from

Ru(II)bis(bipyridyl)(NCS)2 complexes.181 Just in one case of a synthesis attempt towards a ligand

91 bound ruthenium complex did the coordination take place since the target complex was

identified via MALDI-TOF measurement. However, no further isolation and characterization was

possible.

In contrast to the dyes 90 and 91 end-capped with an electron-acceptor moiety a third sensitizer

107 end-capped with propenyl thiophene was made accessible (see Scheme 51). However,

purification was found to be challenging, which might be caused by light induced E/Z isomerism

as an 1H-NMR-based experiment indicated. An attempted synthesis towards further sensitizers

containing a bithiophene linker instead of the dimethoxyphenyl linker was found to be

unfeasible, owing to degradation problems during extension of the π-system.

Moreover, a known one-pot procedure218,219 starting from 2-aminobenzaldehyde and a variety

of α,β-unsaturated aldehydes towards quinolines was planned to be extended to an easy and


106

sustainable synthesis strategy towards pyridinyl quinoline carbaldehydes as versatile sensitizer

building block. A variety of different reaction conditions were screened for 2-aminobenzaldehyde

and pyridinyl acrylaldehyde as starting compounds but all of them were considered to be

incompatible with the change of the α,β-unsaturated substrate and no pyridinyl quinoline could

be obtained.


107



Chemicals:




(10-3 mbar).










ionization.

Mass spectrometry (MALDI-MS):

Mass spectra were recorded on a Shimadzu Biotech Axima Confidence spectrometer with matrix

assisted laser desorption/ionization.

Melting point:

The melting point was determined with an Electrothermal Appendix B IA 9100 instrument.

NMR spectroscopy:






108


m (multiplet), dd (doublet of doublet), br s (broad singlet), br t (broad triplet).

Cold-light lamp:





UV-lamp:

Light irradiation experiments in the UV-region were carried out with a UV-hand lamp with

250 Watt from Hartmann (model UV-H 255). The spectral distribution of the lamp goes from

300 nm to 415 nm.


2.6.2.1 Synthesis of a 2,2’-bipyridine building block

4,4‘-Bis(trimethylsilyl)-2,2‘-bipyridine (83)191

DIPA (4.82 g, 6.68 ml, 47.5 mmol) is dissolved in 65 ml dry THF under inert

conditions and cooled to -78 °C. Then n-BuLi (2.64 g, 16.5 ml, 41.2 mmol, 2.5 M

solution in hexane) is added. After addition of 4-4‘-dimethyl-2,2’-bipyridine (82,

3.51 g, 18.9 mmol) in 115 ml dry THF within a period of 30 minutes the reaction

mixture turns dark red. After 1 h stirring, chlorotrimethylsilane (5.41 g, 6.33 ml,

47.5 mmol) is added followed by the rapid addition of 13 ml dry ethanol. The obtained yellow

solution is poured into 360 ml of a saturated aqueous NaHCO3 solution, which is extracted with

DCM. The organic phases are combined and then washed with brine and dried over Na2SO4. The

solvent is removed under reduced pressure. The target compound is obtained as yellowish solid

(5.73 g, 17.4 mmol; 92%). The obtained spectroscopic data are in accordance with literature.


J1 = 5.1 Hz, J2 = 1.8 Hz, 2H), 2.17 (s, 4H), 0.01 (s, 18H).

13C-NMR (300 MHz, CDCl3, r.t.): δ [ppm] = 155.8, 151.2, 148.5, 123.4, 120.7, 27.5, -1.9.


109

4,4’-Bis(chloromethyl)-2,2’bipyridine (84)191

Compound 83 (5.54 g, 16.7 mmol), hexachloroethane (16.5 g, 69.8 mmol) and CsF

(10.9 g, 69.8 mmol) are dissolved in 45 ml of anhydrous acetonitrile under inert

atmosphere. The reaction mixture is heated to 65 °C for 4 h. After cooling to room

temperature, the reaction mixture is extracted with EtOAc. The combined organic

layers are dried over Na2SO4. After removal of the solvent, the obtained crude

product is purified via column chromatography (SiO2, deactivated with Et3N, hexane/EtOAc

gradient from hexane pure to 2:1). The main product is obtained as white solid (3.25 g,

12.9 mmol; 77%). The obtained spectroscopic data are in accordance with literature.

1H-NMR (400 MHz, CDCl3, r.t.): δ [ppm] = 8.67 (dd, J1 = 5.0 Hz, J2 = 0.6 Hz, 2H), 8.42 (dd, J1 = 1.7 Hz,

J2 = 0.6 Hz, 2H), 7.37 (dd, J1 = 5.0 Hz, J2 = 1.8 Hz, 2H), 4.62 (s, 4H).

4,4‘-Bis(diethylphosphonatomethyl)-2,2‘-bipyridine (85)191

Compound 84 (3.25 g, 12.8 mmol) is dissolved in triethylphosphite (26.9 g,

28 ml, 162 mmol) under inert atmosphere, heated to 140 °C and stirred for 24 h.

After cooling to room temperature, the reaction mixture is purified via column

chromatography (SiO2, deactivated with Et3N, EtOAc/MeOH 4:1). After removal

of the solvent, the main product is obtained as an off-white solid (5.12 g,


1H-NMR (300 MHz, CDCl3, r.t.): δ [ppm] = 8.57 (d, J = 5.0 Hz; 2H), 8.30 (s, 2H), 7.30-7.27 (m, 2H),

4.04 (dq, J1 = 8.2 Hz, J2 = 7.1 Hz, 8H), 3.21 (d, J = 22.4 Hz, 4H), 1.24 (t, J = 7.1 Hz, 12H).

2.6.2.2 Synthesis of new 2,2’-bipyridine ligands end-capped with acceptor units

4-(1,3-Dioxalan-2-yl)-2,5-dimethyloxybenzaldehyde (87)

2,5-Bis-methyloxy-1,4-dibenzaldehyd (86, 500 mg, 2.58 mmol), ethylene

glycol (208 mg, 187 µL, 3.35 mmol) and p-toluenesulfonic acid (9.80 mg,

2 mol%) are dissolved in 10 ml dry toluene and stirred for 21 h under reflux.

After cooling to room temperature, the solution is washed with distilled water,

dried over MgSO4 and the solvent is removed under reduced pressure.

Subsequently the crude product is purified via column chromatography (SiO2, petroleum

ether/EtOAc 4:1). The target compound is obtained as a white solid (307 mg, 1.29 mmol; 50%).

1H-NMR (300 MHz, CDCl3, r.t.): δ [ppm] = 10.41 (s, 1H), 7.30 (s, 1H), 7.20 (s, 1H), 6.06 (s, 1H),

4.15-4.00 (m, 4H), 3.88 (s, 3H), 3.83 (s, 3H).


110


65.4, 56.2, 56.2.


4,4'-Bis((E)-4-(1,3-dioxolan-2-yl)-2,5-dimethoxystyryl)-2,2'-bipyridine (88)

A suspension of potassium tert-butoxide (65.0 mg, 579 mmol) in 6 ml

dry THF is added dropwise under inert atmosphere to a solution of

compound 85 (89.0 mg, 195 µmol) and 4-(1,3-dioxolan-2-yl)-

2,5-dimethoxybenzaldehyde (87, 102 mg, 428 µmol) in 2 ml dry THF.

The yellow brownish reaction mixture is then heated to reflux for 39 h.

After completion of the reaction, which is monitored via TLC, 30 ml

water (HPLC grade) are added. THF is evaporated from the reaction

mixture and the residue is taken up with DCM. The organic phase is

separated from the aqueous phase. The combined organic phases are dried over MgSO4. After

removal of the solvent the product is dried in vacuum. The title compound is obtained as

yellowish solid (119 mg, 190 µmol; 97%).

1H-NMR (300 MHz, CDCl3, r.t.): δ [ppm] = 8.65 (d, J = 5.1 Hz, 2H), 8.53 (s, 2H), 7.77 (d, J = 16.5 Hz,

2H), 7.45 (dd, J1 = 5.2 Hz, J2 = 1.6 Hz, 2H), 7.17 (d, J = 16.2 Hz, 2H), 7.14 (s, 2H), 7.13 (s, 2H), 6.12

(s, 2H), 4.18-4.02 (m, 8H), 3.90 (s, 6H), 3.89 (s, 6H).


126.6, 120.8, 118.8, 110.0, 109.7, 99.0, 65.3, 56.3, 56.1.


4,4'-((1E,1'E)-[2,2'-Bipyridine]-4,4'-diylbis(ethene-2,1-diyl))bis(2,5-di-methoxybenzaldehyde) (89)

6 ml 2 M HCl is gradually added to a solution of compound 88 (119 mg,

190 µmol) in 18 ml chloroform. The red reaction mixture is stirred for

15 h. Then, the organic layer is separated, washed with saturated

aqueous NaHCO3 solution and brine and finally dried over MgSO4. The

solvent is evaporated. In order to complete the deprotection step, the

crude product is again treated gradually with 6 ml 2 M HCl in 18 ml

chloroform. Then the organic layer is separated again, washed with

saturated aqueous NaHCO3 solution and brine and dried over MgSO4.

The solvent is evaporated and the title compound is obtained as yellow solid (100 mg, 186 µmol;

98%).


111


(d, J = 16.5 Hz, 2H), 7.49 (dd, J1 = 5.2 Hz, J2 = 1.5 Hz, 2H), 7.36 (s, 2H), 7.30 (d, J = 16.5 Hz, 2H),

7.21 (s, 2H), 3.97 (s, 6H), 3.91 (s, 6H).


124.9, 121.1, 119.1, 117.8, 110.4, 109.4, 56.2, 56.1.


(2E,2'E)-3,3'-(((1E,1'E)-[2,2'-Bipyridine]-4,4'-diylbis(ethene-2,1-diyl))bis(2,5-dimethoxy-4,1-phe-

nylene))bis(2-cyanoacrylic acid) (90)

Cyanoacetic acid (970 mg, 11.4 mmol) and piperidine (971 mg,

1.13 ml, 11.4 mmol) are added to a suspension of compound 89

(153 mg, 285 µmol) in 12 ml dry acetonitrile. The yellow

suspension is stirred for 24 h at 90 °C. After the addition of DCM

and 2 M H3PO4, the mixture turns orange and is filtered. The

residue is washed with THF and acetone and dried in vacuum. The

title compound is obtained as orange hardly soluble solid (87.2 mg,

130 µmol; 46%). NMR-Characterization partially enabled by

addition of small amounts of hot DMF.

M.p.: 280 °C (decomposition).

1H-NMR (400 MHz, DMSO-d6, r.t.): δ [ppm] = 8.72 (d, J = 4.8 Hz, 2H), 8.60 (s, 2H), 8.24 (s, 2H),

7.84 (s, 2H), 7.78 (d, J = 16.3 Hz, 2H), 7.70 (dd, J1 = 4.9 Hz, J2 = 1.5 Hz, 2H), 7.66 (d, J = 16.3 Hz,

2H), 7.54 (s, 2H), 3.95 (s, 6H), 3.90 (s, 6H).

13C-NMR could not be recorded due to an excessively long measurement.



IR (ATR, solid): ṽ [cm-1] = 3599, 2948, 2836, 2363, 2215, 2115, 1921, 1711, 1588, 1498, 1464,

1415, 1352, 1251, 1215, 1031, 960, 864, 810, 731, 660, 567, 484, 430.


112

Dibutyl 3,3'-(((1E,1'E)-[2,2'-bipyridine]-4,4'-diylbis(ethene-2,1-diyl))bis(2,5-dimethoxy-4,1-pheny-

lene))(2E,2'E)-bis(2-cyanoacrylate) (91)

Butyl cyanoacetate (2.05 g, 1.24 ml, 14.5 mmol) and piperidine

(1.23 g, 1.43 ml, 14.5 mmol) are added to a suspension of

compound 89 (117 mg, 218 µmol) in 9 ml dry acetonitrile. The

yellow suspension is stirred for 24 h at 90 °C. After cooling to room

temperature the mixture is filtered and the residue is taken up

with DCM. After evaporation of the solvent the product is dried in

vacuum. The title compound is obtained after recrystallization

from DCM and Et2O as orange solid (107 mg, 137 µmol; 63%).

M.p.: 255 °C.


(s, 2H), 7.77 (d, J = 16.5 Hz, 2H), 7.48 (d, J = 5.1 Hz, 2H), 7.31 (d, J = 16.4 Hz, 2H), 7.15 (s, 2H), 4.31

(t, J = 6.6 Hz, 4H), 3.95 (s, 6H), 3.94 (s, 6H), 1.73 (m, 4H), 1.46 (dq, J1 = 14.4 Hz, J2 = 7.3 Hz, 4H),

0.97 (t, J = 7.4 Hz, 6H).


132.0, 129.9, 127.4, 120.9, 116.4, 110.8, 109.3, 109.2, 101.3, 66.3, 56.2, 56.2, 30.5, 19.1, 13.5.



IR (ATR, solid): ṽ [cm-1] = 3604, 3057, 2963, 2362, 2213, 2017, 1913, 1804, 1717, 1635, 1576,

1497, 1457, 1404, 1357, 1296, 1209, 1150, 1084, 1024, 951, 906, 849, 737, 677, 641, 602, 550.

2.6.2.3 Synthetic approaches towards new ruthenium complexes

[2,2'-Bipyridine]-4,4'-dicarboxylic acid (96)198

4,4’-Dimethyl-2,2’-bipyridine (82, 2.00 g, 10.9 mmol) is added to 50 ml stirred

H2SO4. Then potassium dichromate (10.0 g, 34.0 mmol) is added slowly in small

portions. Occasional cooling with a water bath is required to keep the

temperature of the reaction mixture between 70 °C and 80 °C during the addition

of dichromate. Afterwards, the reaction mixture is continually stirred until the

temperature falls to room temperature. The deep green mixture is poured into 400 ml of ice

water and filtered. The yellowish solid is further refluxed in 60 ml of 50% HNO3 for 4 h. The

solution is poured into ice water and diluted with water. The precipitate is filtered, washed with

water and acetone and dried in vacuum. The target product is obtained as white powder (1.76 g,

7.20 mmol; 66%). Due to insolubility no characterization is possible.


113

2.6.2.4 Synthesis of new 2,2’-bipyridine ligands containing thiophene

1-(Thiophen-1-yl)ethanol (105)206

NaBH4 (450 mg, 12.0 mmol) is added to a solution of 2’-acetylthiophene (104,

1.00 g, 7.90 mmol) in 8 ml EtOH at room temperature. After 1 h, the reaction

mixture is diluted with 25 ml water and extracted with 40 ml EtOAc. The aqueous

layer is washed with EtOAc. The combined organic phases are washed with brine,

dried over anhydrous Na2SO4 and concentrated in vacuo. The product is obtained as colorless oil

(720 mg, 5.60 mmol; 70%). The obtained spectroscopic data are in accordance with literature.

1H-NMR (300 MHz, CDCl3, r.t.): δ [ppm] = 7.22 (dd, J1 = 1.5 Hz, J2 = 5.0 Hz, 1H), 6.95 (m, 2H), 5.11

(q, J = 6.4 Hz, 1H), 1.59 (d, J = 6.4 Hz, 3H).

Diethyl-1-(thiophen-2-yl)ethylphosphate (106)207

ZnBr2 (1.35 g, 6.00 mmol) is added to a mixture of 1-(thiophen-1-yl)ethanol (105,

700 mg, 5.46 mmol) and triethylphosphite (4.73 ml, 4.54 g, 27.3 mmol), which is

then stirred for 4 h at room temperature. The consumption of the starting

material is monitored by TLC. The reaction mass is poured over crushed ice

containing concentrated HCl. The aqueous phase is extracted with chloroform and dried over

Na2SO4. The solvent is removed in vacuo and the product is purified via column chromatography

(SiO2, hexane/EtOAc 1:1). The product is obtained as colorless oil (776 mg, 3.13 mmol; 57%).

Since the product shows light sensitivity it is stored in the dark. The obtained spectroscopic data

are in accordance with literature.

1H-NMR (CDCl3, 300 MHz, r.t.): δ [ppm] = 7.16 (m, 1H), 6.99 (m, 1H), 6.93 (m, 1H), 4.03 (m, 4H),

3.46 (dq , J1 = 7.4 Hz, J2 = 22.2 Hz, 1H), 1.59 (dd, J1 = 7.4 Hz, J2 = 17.8 Hz, 3H), 1.34 (t, J = 7.1 Hz,

6H).

HR-MS (ESI) m/z: [M+H]+ calcd for C10H18O3PS: 249.07088; found: 249.07074; m/z: [M+Na]+ calcd

for C10H17NaO3PS: 271.05282; found: 271.05257.


114

4,4'-bis((E)-2,5-dimethoxy-4-((E)-2-(thiophen-2-yl)prop-1-en-1-yl)styryl)-2,2'-bipyridine (107)

A suspension of potassium tert-butoxide (208 mg, 1.85 mmol) in

19 ml anhydrous THF is added dropwise to a solution of

compound 89 (334 mg, 624 µmol) and diethyl-1-(thiophen-

2-yl)ethylphosphate (106, 309 mg, 1.25 mmol) in 12 ml anhydrous

THF under inert conditions. The brown reaction mixture is heated

under reflux for 40 h. The reaction is quenched by adding 120 ml

water (HPLC grade) and extracted with DCM. The combined

organic phases are dried over MgSO4. The title compound is

obtained after recrystallization from hot MeOH and DCM/hexane as orange solid (267 mg,

368 µmol; 59%). The degree of contamination with the assumed (Z,E,E,Z)-isomer of 107 is 20%.

M.p.: 145 °C; 150 °C (decomposition).

1H-NMR (400 MHz, CDCl3, r.t.): δ [ppm] = 8.67 (d, J = 5.1 Hz, 2H), 8.57 (s, 2H), 7.81 (d, J = 16.4 Hz,

2H), 7.48 (dd, J1 = 5.2 Hz, J2 = 1.8 Hz, 2H), 7.23-7.16 (m, 4H), 7.15 (dd, J1 = 3.5 Hz, J2 = 1.2 Hz, 2H),

7.12 (s, 2H), 7.08 (s, 2H), 7.01 (dd, J1 = 5.1 Hz, J2 = 3.6 Hz, 2H), 6.89 (s, 2H), 3.88 (d, J = 3.7 Hz,

12H), 2.29 (d, J = 1.4 Hz, 6H).


126.3, 125.2, 124.5, 124.2, 123.4, 121.4, 120.8, 119.0, 113.9, 109.7, 109.1, 56.3, 56.1, 17.8.


HR-MS (ESI) m/z: [M+H]+ calcd for C44H41N2O4S2: 725.25023; found: 725.24776.

IR (ATR, solid): ṽ [cm-1] = 3223, 3077, 2920, 2852, 1717, 1585, 1493, 1458, 1405, 1258, 1203,

1091, 1032, 956, 800, 691, 601, 471.

[2,2'-Bithiophene]-5,5'-dicarbaldehyde (109)214

5-Bromothiophene-2-carbaldehyde (108, 2.21 g, 1.25 ml, 11.6 mmol) is slowly

added to a mixture containing NiCl2 (154 mg, 1.18 mmol), triphenylphosphine

(3.03 g, 11.6 mmol), zinc dust (2.70 g, 41.3 mmol) and 80 ml DMF under inert

conditions. The resulting brown suspension is refluxed for 15 h and then

cooled to room temperature followed by filtration. The filtrate is diluted with

chloroform and washed with water and saturated aqueous NaHCO3 solution followed by drying

over MgSO4. The target compound is obtained after purification via column chromatography

(SiO2, DCM) (534 mg, 2.40 mmol; 41%). The obtained spectroscopic data are in accordance with

literature.222

1H-NMR (400 MHz, CDCl3, r.t.): δ [ppm] = 9.90 (s, 2H), 7.70 (d, J = 3.9 Hz, 2H), 7.40 (d, J = 3.9 Hz,

2H).


115

5'-(1,3-Dioxolan-2-yl)-[2,2'-bithiophene]-5-carbaldehyde (110)

[2,2'-bithiophene]-5,5'-dicarbaldehyde (109, 534 mg, 2.40 mmol), ethylene

glycol (196 mg, 176 µL, 3.15 mmol) and p-toluenesulfonic acid (10.1 mg,

2 mol%) are dissolved in 40 ml dry toluene and stirred for 21 h under reflux.

After cooling to room temperature, the solution is washed with distilled

water, dried over MgSO4 and the solvent is removed under reduced

pressure. Subsequently the crude product is purified via column chromatography (SiO2,

deactivated with Et3N, hexane/DCM/EtOAc 5:1:1). The target compound is obtained as a yellow

solid (325 mg, 1.22 mmol; 51%). The impurity with bis-protected 2,2'-bithiophene is 8% and

unprotected 2,2'-bithiophene is 7%. The obtained spectroscopic data are in accordance with

literature.223

1H-NMR (300 MHz, CDCl3, r.t.): δ [ppm] = 9.84 (s, 1H), 7.64 (d, J = 4.0 Hz, 1H), 7.22 (dd, J1 = 3.8 Hz,

J2 = 1.4 Hz, 2H), 7.09 (d, J = 3.8 Hz, 1H), 6.07 (s, 1H), 4.31-3.90 (m, 4H).

2.6.2.5 Synthesis of pyridine-based ligands in an organocatalytic one-pot procedure

2-Aminobenzaldehyde (114)220

MnO2 (11.1 g, 128 mmol) is added to a solution of 2-aminobenzyl alcohol (121,

3.00 g, 24.4 mmol) in 90 ml DCM. The mixture is stirred at room temperature for

48 h. After filtration of the raw material the solvent is evaporated and the target

compound is obtained (2.52 g, 20.8 mmol; 85%). The obtained spectroscopic data are in

accordance with literature.

1H-NMR (300 MHz, CDCl3, r.t.): δ [ppm] = 9.84 (s, 1H), 7.45 (dd, J1 = 7.8 Hz, J2 = 1.7 Hz, 1H), 7.37-

7.13 (m, 1H), 6.72 (ddd, J1 = 7.9 Hz, J2 = 7.1 Hz, J3 = 1.1 Hz, 1H), 6.62 (d, J = 8.3 Hz, 1H), 6.10 (s,

2H).

(E)-3-(pyridin-2-yl)acrylaldehyde (117)221

(Formylmethylene)triphenylphosphorane (123, 6.00 g, 19.7 mmol) is added to a

solution of formylpyridine (122, 2.11 g, 19.7 mmol) in 200 ml toluene. The

reaction mixture is stirred for 48 h at room temperature. Afterwards the solvent

is evaporated and the crude material is purified via column chromatography (SiO2, hexane/EtOAc

gradient from 2:1 to 1:2). The target compound is obtained as brownish solid (780 mg,



116

1H-NMR (300 MHz, CDCl3, r.t.): δ [ppm] = 9.70 (d, J = 7.8 Hz, 1H), 8.60 (ddd, J1 = 4.8 Hz, J2 = 1.9 Hz,

J3 = 1.0 Hz, 1H), 7.68 (td, J1 = 7.7 Hz, J2 = 1.8 Hz, 1H), 7.49-7.35 (m, 2H), 7.28-7.16 (m, 1H), 7.00

(dd, J1 = 15.8 Hz, J2 = 7.8 Hz, 1H).

2-Phenyl-1,2-dihydroquinoline-3-carbaldehyde (125)218

Under inert conditions, (E)-cinnamic aldehyde (124, 33.0 mg, 31.5 µl,

250 µmol) and 2-aminobenzaldehyde (114, 36.3 mg, 300 µmol) are added to

a stirred solution of pyrrolidine (4.10 µl, 50.0 µmol) in 500 µl acetonitril at

room temperature. The reaction mixture is stirred for 7 h. Purification of the

reaction mixture via column chromatography (SiO2, hexane/EtOAc 10:1)

furnishes the target compound (41.8 mg, 178 µmol; 71%). The obtained spectroscopic data are

in accordance with literature.

1H-NMR (300 MHz, CDCl3, r.t.): δ [ppm] = 9.47 (s, 1H), 7.36 (dq, J1 = 8.1 Hz, J2 = 2.1 Hz, 2H),

7.29-7.18 (m, 4H), 7.18-7.05 (m, 2H), 6.64 (td, J1 = 7.4 Hz, J2 = 1.0 Hz, 1H), 6.51-6.39 (m, 1H), 5.66

(d, J = 1.8 Hz, 1H), 4.59 (br s, 1H).

Chapter 3 Investigations of 1,4-Dihydropyridine-based Systems in Photocatalysis

117

3 Investigations of 1,4-Dihydropyridine-based Systems in

Photocatalysis

3.1 NAD(P)H and NAD(P)H Models

Nicotinamide adenine dinucleotide (NADH, 126) and nicotinamide adenine dinucleotide

phosphate (NADPH, 128) are omnipresent in many biological system by mediating a variety of

enzymatic redox processes as cofactor (see Figure 32).224 Their reactivity in hydrogenation

processes is based on the dihydropyridine core (depicted with bold bonds in Figure 32) which

can undergo hydride detachment at the C4 position resulting in aromatization of the heterocycle

whereby the oxidized NAD(P)+ (127 and 129) is formed.

Figure 32 Nicotinamide-based cofactors NAD(P)H (126 and 128) and NAD(P)H models (130-132).

Several synthetic nicotinamides-based models were designed since the second half of the 20th

century, mainly for mechanistic studies of the redox process in living organisms.225,226 There are

experimental data which support both hypotheses: oxidation takes place as a single-step hydride

transfer or as a sequential electron-proton-electron transfer.227 With growing demand of utilizing

the cofactor couple in organic synthesis, models such as 1-benzyl-1,4-dihydronicotinamide

(BNAH, 130) and the Hantzsch ester (131) became a good alternative to their costly parent

compounds and thus common NAD(P)H (126 and 128) mimics (see Figure 32). These

1,4-dihydropyridines are known to reduce aldehydes, ketones and activated olefins and were

used in various asymmetric organocatalytic protocols.228 Even chiral representatives of

nicotinamides (132,229 exemplarily depicted in Figure 32) were designed and found to reduce in

enantioselective fashion in the presence of magnesium perchlorate.


118

3.2 1,4-Dihydropyridines in Transfer Hydrogenation Reactions

3.2.1 Photocatalytic regeneration of NAD(P)H

Although several efficient NAD(P)H mimics have been developed (see Figure 32), the use of

NAD(P)H (126 and 128) is still necessary in biocatalysis owing to the cofactor depended enzymes

which were applied. Since regeneration of the nicotinamide-based cofactors is a critical issue in

biocatalysis in order to decrease costs, several advances towards regeneration of NAD(P)H (126

and 128) were achieved. However, conventional regeneration methods including the use of a

second enzyme or chemical electrodes suffer from drawbacks such as catalyst instability, low

specific activity and limited applications.230 Although photochemical regeneration is at its

infancy, this approach might overcome the problems by utilizing clean and abundant solar

energy.

In 2009, Park and co-workers demonstrated superior catalytic NADH (126) regeneration

performance with several visible light harvesting xanthene dyes such as phloxine B, erythrosine

B, eosin Y (133, Scheme 52) and rose bengal in presence of a rhodium-based catalyst 134 as

mediator and triethanolamine (TEOA) as an electron donor.231,232

Scheme 52 Photochemical regeneration of NADH using a Rh catalyst 134 and visible-light energy.231

The authors observed a donor-acceptor relationship under visible light irradiation between the

organometallic catalyst 134 and the xanthene photosensitizer, in which the halogen substitution

of the dye was found to play a modulating key role. The reduced NADH (126) is released by

accepting the hydride from the metal complex which was previously generated there from

photo-excited electrons of the dye and a proton from the aqueous phase. The dye is regenerated

by the electron donor (TEOA). In 2012, the authors presented a successful combination of the

NADH (126) regenerataion system (using proflavine instead of eosin Y as sensitizer) with

glutamate dehydrogenase (GDH) enzyme for L-glutamate synthesis.232

In 2012, Kim and co-workers further developed the photocatalytic regeneration of NADH (126)

by applying the cheap and readily available complex CoIII(dmgH)2pyCl (135) as mediator instead


119

of a more expensive rhodium-based catalyst (see Scheme 53). They studied the influence of

pyridine substituents in the cobalt complex on the conversion and revealed the complex

containing the unsubstituted pyridine 135 as the best performing catalyst. Besides, the authors

were able to demonstrate the reduction of CO2 by formate dehydrogenase (FDH) by applying the

CoIII(dmgH)2pyCl/eosin Y/TEOA system for NADH (126) regeneration.

Scheme 53 Photochemical regeneration of NADH (126) using the CoIII(dmgH)2pyCl catalyst (135) and

visible-light energy.233

The NADH production rate was found to be depended on the cobalt catalyst 135, NAD+ (127) and

TEOA. This indicated that the electron transfer from the photoexcited eosin Y (133) to the cobalt

center of compound 135 generating the hydride is the crucial step in NADH (126) generation.

3.2.2 1,4-Dihydropyridine as reductive equivalent

Besides several non-enantioselective applications, 1,4-dihydropyridines, especially the Hantzsch

ester (131), have become a powerful tool in enantioselective hydrogenation of olefins, ketones

and imines in organic syntheses and organocatalysis or metal catalysis.234 Two examples from

literature are presented here to get an insight into the asymmetric hydrogenation approaches

using 1,4-dihydropyridines as reductive equivalents.

In 2006, MacMillan and co-workers published the first enantioselective organocatalytic reductive

amination (see Scheme 54).235 Following nature, the enzyme bearing chiral information and the

NAD(P)H cofactor (126 or 128) were replaced by a BINOL phosphate derivative 136 as small

organic catalyst and the Hantzsch ester (131) as a NAD(P)H mimic.


120

Scheme 54 Enantioselective organocatalytic reductive amination by MacMillan and co-workers.235

In the same year, Yang and List reported an enantioselective reduction of α-ketoesters by a chiral

copper(II) bisoxazoline complex mimicing alcohol dehydrogenase (ADH), as depicted in

Scheme 55.236

Scheme 55 Asymmetric transfer hydrogenation of a-ketoesters by a chiral copper(II) bisoxazoline

complex.236

The copper catalyst is formed in situ from copper(II) triflate and a chiral ligand 138. The Hantzsch

ester (131) is applied as biomimetic hydrogen donor in the transfer hydrogenation.

3.2.3 1,4-Dihydropyridine with regeneration system

NAD(P)H mimics, especially the Hantzsch ester (131), are expensive as stoichiometric reducing

agents.234 Thus, it would be desirable to carry out the reactions using a catalytic amount of

NAD(P)H mimic in combination with a regeneration system, as described for NAD(P)H (126 and

128) and its photocatalytic regeneration in chapter 3.2.1.

In 1985, a photocatalytic transfer hydrogenation for reduction of imines with in situ regeneration

of a N-methylated Hantzsch ester (139) was reported by Singh and co-workers (see

Scheme 56).237 The authors reported yields up to 80% of the corresponding amines for

experiments carried out under light irradiation with catalytic amounts of compound 139.


121

Scheme 56 Photocatalytic transfer hydrogenation by Hantzsch ester-based two-phase regeneration

system.237

The experiments were carried out in a two-phase reaction system of benzene and water (see

Scheme 56). Although the authors did not comment on the entire mechanism, it is an obvious

assumption that the pyridinium compound 140, which is formed after the hydride transfer, is

soluble in water. Thus, it is reduced in the aqueous phase by sodium dithionite generating the

hydride source 139 which dissociates back to the organic phase, where the hydride transfer takes

place under light irradiation with a 25 W medium-pressure mercury-vapor lamp. Light is known

to enhance rate acceleration of the dihydropyridine oxidation, possibly by the UV-region of

light.238,239 The authors suggest that under light irradiation the Hantzsch ester transfers electrons

to the imine in the ground state followed by proton transfer which was reported before in the

case of N-methylacridan.240 BNAH (130) was applied in the two-phase light irradiation

experiment in catalytic amounts as well but did not lead to product formation. Sodium

bicarbonate has to be present in the aqueous phase to prevent acidification. Besides, the authors

were able to demonstrate, that reduction of N-arylideneanilines takes place in glacial acetic acid

using 131 as reductive equivalent in the dark even though imines are known for not reducing

without light in a neutral medium.

In 2006, Liu, Wu and co-workers presented a hydrogenation procedure of α,β-epoxy ketones

under light irradiation with a 450 W high-pressure mercury-vapor lamp to form hydroxyl ketones

applying catalytic amounts of BNA+Br- (141-bromide, see Scheme 57, Conditions B).239 As

reported by Singh and co-workers (see Scheme 56), a two-phase system was used to gain the

consumed BNAH (130) by reduction with sodium dithionite in the aqueous phase. Rate

acceleration in presence of light was demonstrated by the comparison of the reaction times with

(2 h; Scheme 57, Conditions B) and without (26 h; Scheme 57, Conditions A) irradiation until full

conversion.


122

Scheme 57 Photocatalytic transfer hydrogenation by BNA+Br- (141-bromide) ester-based two-phase

regeneration system.239

In 2011, Zhou and co-workers presented a biomimetic asymmetric hydrogenation of

benzoxazinones with up to 98% yield and up to 99% ee in presence of a chiral phosphoric acid

142 and a catalytic amount of the Hantzsch ester (131). In situ recycling of 131 was enabled by

[Ru(p-cymene)I2]2 under hydrogen gas (see Scheme 58).241

Scheme 58 Asymmetric hydrogenation of benzoxazinones applying Hantzsch ester (131) regeneration

with [Ru(p-cymene)I2]2 under H2 gas.241

The authors proposed that after the phosphoric acid catalyzed transfer hydrogenation the

obtained pyridine 137 undergoes hydrogenation catalyzed by [Ru(p-cymene)I2]2 in order to close

the catalytic cycle.


123


1,4-Dihydropyridines, are valuable reduction equivalents in hydrogenation of olefins, ketones

and imines in enantioselective and non-enantioselective synthesis. Owing to the fact that

transfer hydrogenation is a frequently used reaction, 1,4-dihydropyridines, similarly to their

natural parent compound NAD(P)H (126 and 128), embody an important but expensive reagent

in organic synthesis. Thus the in situ regeneration of 1,4-dihydropyridines in hydrogenation

processes is highly desirable.

Photocatalysis provides an opportunity to apply clean and abundant solar energy. There are two

obvious starting points to apply photocatalysis in transfer hydrogenation. On the one hand the

consumption of 1,4-dihydropyridine might be reduced and on the other hand a more efficient

use of 1,4-dihydropyridine might be enabled under light irradiation.

Within the framework of this thesis, the first task was the investigation of a potential

photocatalytic regeneration system of the Hantzsch ester (131) starting from the corresponding

pyridine (137) inspired by the photocatalytic NADH (126) recycling, using eosin Y (133), an

electron donor and a transition metal catalyst (see Scheme 52 and Scheme 53).231,233 The future

perspective might be a combination of the developed photocatalytic hydride source

regeneration system (solid arrow) with an organocatalyzed transfer hydrogenation cycle for

enantioselective imine reduction (dashed arrows, see Scheme 59a).

Scheme 59 Aim: a) potential photocatalytic Hantzsch ester (131) regeneration system for application in

organocatalyzed imine reduction. b) investigation of N-methylated Hantzsch ester (139)

regeneration system with sodium dithionite for application in photoinduced hydride

reduction of imines.

A two-phase regeneration system of the N-methylated Hantzsch ester (139) with sodium

dithionite in combination with a photoinduced transfer hydrogenation of an imine was already

demonstrated in literature by Singh and co-workers in 1985 (see Scheme 56).237


124

A second task should be further investigation of this recycling system in combination with

photoinduced transfer hydrogenation with regard to expanding the substrate spectrum from

aldimines to ketimines for a future enantioselective hydride transfer in presence of a chiral

catalyst in the organic phase (see Scheme 59b).


125


3.4.1 Photocatalytic regeneration of Hantzsch ester

The development of a light driven photoredox catalysis system for in situ regeneration of a

hydride source would allow the decrease of 1,4-dihydropyridines in the transfer hydrogenation

reaction to a catalytic amount (see Scheme 59a). Such recycling systems are known for

NADH (126) and should be investigated for Hantzsch ester (131) regeneration.

As reported by Park231 and Kim,233 a xanthene-based sensitizer such as eosin Y (133) is required

for light absorption, followed by initial photoexcitation and oxidation. Eosin Y (133) is less

expensive and less toxic compared to transition metal complexes, easy to handle and excited by

visible light.242 As such it was applied for the following photocatalytic investigations. A sacrificial

electron donor amine, such as diisopropylethylamin (DIPEA)210 or triethanolamine (TEOA)231,233

has to be present in the mixture to regenerate the oxidized sensitizer and to enable the use of

catalytic amounts of eosin Y (133). For the generation and delivery of a hydride, a mediating

transition metal catalyst is required. Owing to its good synthetic accessibility and its promising

application in NADH (126) regeneration, CoIII(dmgH)2pyCl (135) was found to be appropriate for

Hantzsch ester (131) regeneration as well.243,233 Thus, CoIII(dmgH)2pyCl (135) was synthesized

according to literature procedure from CoCl2 x 6 H2O and dimethylglyoxime (dmgH2, 143). The

target complex 135 was obtained in 48% yield (see Scheme 60).243

Scheme 60 Synthesis of CoIII(dmgH)2pyCl complex (135).243

In a potential Hantzsch ester regeneration system a proton source is needed to form the

transferable hydride at the cobalt center in combination with the electron gained from the

photooxidation process. This can either stem from the aqueous solvent itself, for instance a

phosphate buffer as in the case of NADH (126) generation (see Scheme 52 and Scheme 53), or

alternatively, if an aprotic solvent is used, a further proton donating additive has to be added.

Such additives were reported before in literature as proton source in hydride transfer reactions,

for instance i-propyl alcohol, which was used for ketone reduction.244 Azeotropic mixtures of

formic acid and triethyl amine or sodium formate and water were found to be utilizable as proton

source in combination with transition metal complexes generating and transferring the

hydride.245,246 Generally, working under inert atmosphere is highly required to suppress possible


126

oxidative pathways by O2 from air which could quench sacrificial radical species as a radical

trapper. Moreover, air might favor the pyridine forming back reaction in presence of eosin Y

(133).247 The following experiments (see Table 10) to investigate possible Hantzsch ester (131)

regeneration used the corresponding pyridine 137 as starting material, which was priorly

obtained from oxidation of the Hantzsch ester (131) itself with NaClO2 (see Scheme 61).248

Scheme 61 Oxidation of Hantzsch ester (131).248

All experiments, depicted in Table 10, were carried out with 1 equivalent of eosin Y (133) to

ensure maximum light harvesting. To exclude the possibility that in case of Hantzsch ester (131)

regeneration a transfer hydrogenation reaction without participation of a transition metal

catalyst was enabled, two recycling experiments applying only eosin Y (133) as sensitizer, DIPEA

as electron donor and a proton source were carried out (see Table 10, Entry 1 and Entry 2). This

possibility was reported before by Tung and co-workers.249 They developed a simple

photocatalytic nitrobenzene reduction method employing eosin Y (133) as the photocatalyst and

TEOA as the reducing agent in an ethanol water mixture under green light irradiation. With

regard to further combination of the regeneration cycle with an organocatalyzed transfer

hydrogenation cycle (see Scheme 59a), benzene was applied as solvent (see Table 10, Entry 1).

In this case a proton source was required. Benzoic acid was chosen owing to good solubility in

benzene. In parallel, a similar experiment was carried out in phosphate buffer as described for

NADH (126) regeneration (see Table 10, Entry 2). However, in both cases after 70 h of light

irradiation with a 500 Watt halogen spotlight (using potassium dichromate solution as UV-filter)

no conversion towards the Hantzsch ester (131) could be observed as proven by TLC and 1H-NMR

measurements of the raw materials. In the case of phosphate buffer as solvent, previous

extraction with dichloromethane was required. The experiments were repeated but with

1.3 equivalents of CoIII(dmgH)2pyCl (135). However, no conversion towards the Hantzsch ester

(131) was observed using either benzene, phosphate buffer or DMF as solvent (see Table 10,

Entry 3, 4 and 5). The proton source was changed as well to formic acid in case of benzene and

DMF as solvent, to ensure solvation of all components, even though an emulsion was obtained.

Applying DMF as solvent, the most homogeneous mixture was obtained. Owing to successful

application of TEOA in NADH (126) regeneration in literature, the electron donor DIPEA was

replaced by TEOA. Entry 6 (see Table 10) represents the reaction conditions successfully applied

for NADH (126) regeneration. However, it was not found to be appropriate for Hantzsch ester


127

(131) regeneration. No conversion of compound 137 towards the Hantzsch ester (131) was

observed in case of DMF as solvent and a solvent mixture of DMF and phosphate buffer both in

combination with TEOA (see Table 10, Entry 7 and 8). Applying a reaction system with i-propyl

alcohol as proton source and TEOA as electron donor in DMF no photocatalytic reduction of

compound 137 was detected (see Table 10, Entry 9).

Table 10 Screening of reaction conditions for photocatalytic regeneration of 1,4-dihydropyridine 131

applying CoIII(dmgH)2pyCl (135) as catalyst.

Entry Solvent

Proton

Source

Electron

Donor

Time Conv.

1a)b) benzene 10 equiv. benzoic acid 10 equiv. DIPEA 70 h -

2a)b) phosphate buffer solvent 10 equiv. DIPEA 70 h -

3b) benzene 380 equiv. formic acid 35 equiv. DIPEA o.n. -

4c) phosphate buffer solvent 400 equiv. DIPEA 2.5 h -

5b) DMF 380 equiv. formic acid 35 equiv. DIPEA o.n. -

6b) phosphate buffer solvent 15 w/v% TEOA 3.75 h -

7d) DMF 380 equiv. formic acid 15 w/v% TEOA 3.5 h -

8e) DMF/phosphate

buffer

solvent 15 w/v% TEOA 2 h -

9b) DMF 260 equiv. i-propyl

alcohol

15 w/v% TEOA 3.75 h -

a) without 135; b) 10 mM substrate concentration; c) 0.5 mM substrate concentration; d) 5 mM substrate

concentration; e) 12.5 mM substrate concentration.

Even though no experiment could manage the photocatalytic formation of the Hantzsch ester

(131) the study revealed the different solubilities of all necessary components in one appropriate

solvent or a two-phase system as the biggest challenge to master with regard to a future

combination of the regeneration cycle with an organocatalytic hydride transfer cycle.


128

3.4.2 Photocatalytic transfer hydrogenation via 1,4-dihydropyridine regeneration

Besides photocatalytic regeneration of the Hantzsch ester (131, see chapter 3.4.1), examples

from literature presented further options to recycle the consumed 1,4-dihydropyridine after

transfer hydrogenation reaction (chapter 3.2.3). The simplest regeneration system was

presented by Singh in 1985 and Liu and Wu in 2006 (see Scheme 56 and Scheme 57).237,239 They

applied a two-phase reaction system with benzene or ethyl acetate and water, while the aqueous

phase contained sodium dithionite and sodium bicarbonate where the pyridine (140 or

141-bromide) was reduced and thus regenerated for transfer hydrogenation in the organic

phase.

The choice of an easy model reaction system was the starting point for investigations of the

photocatalytic transfer hydrogenation with recyclable catalytic amounts of a 1,4-dihydropyrdine.

Thus, the the easily accessible N-PMP protected imine 144 was chosen as model substrate for

transfer hydrogen experiments. The imine 144, already used by Singh and co-workers (see

Scheme 56),237 was obtained by condensation from p-anisidine and p-anisaldehyde. An

experiment using an equimolar amount of the unmodified Hantzsch ester (131) was carried out

to ensure the feasibility of the transfer hydrogenation in absence of an recycling system under

the present laboratory conditions (see Scheme 62). The laboratory conditions included the

surrounding daylight, which makes the reduction feasible in neutral medium.237 The reaction

towards the product amine 145 was performed with 75% conversion, which was determined by

1H-NMR using a reference 1H-NMR spectrum of product 145 (obtained from NaBH4 reduction).

The reaction mediated by the Hantzsch ester (131) is generally considered as direct hydride

transfer.250

Scheme 62 Testreaction: transfer hydrogenation with Hantzsch ester (131) as reductive equivalent.

As reported by Singh and co-workers an N-substituted Hantzsch ester 139 derivative is required

for the two-phase reaction system.237 In contrast to the Hantzsch ester (131) which undergoes

direct hydride transfer, the reaction which is mediated by Hantzsch ester derivative 139 possibly

appears as electron-transfer mechanism.240 For the implementation of a reproduction


129

experiment, the synthesis of N-methylated 1,4-dihydropyridine 139 was attempted according to

literature procedure (see Scheme 63a).251

Scheme 63 a) Attempted synthesis towards N-methylated 1,4-dihydropyridine 139.251 b) Synthesis

towards N-methylated pyridinium salt 140-triflate.

However, the target compound 139 was not obtained by using sodium hydride and methyl

p-toluenesulfonate. The reaction was found to be highly sensitive to moisture and air and thus

working under nitrogen atmosphere using the schlenk technique was insufficient and the

reaction procedure required glovebox conditions. To simplify the synthetic accessibility and

future handling of the modified Hantzsch ester (139), the synthesis of a N-methylated pyridinium

salt 140 might be a more promising approach. In case of a working recycling system either the

N-methylated 1,4-dihydropyridine 139 or the corresponding pyridinium salt 140 might be

applied. Thus, methylation of the pyridine 137 using trifluoromethane sulfonate was carried out

and the pyridinium salt 140-triflate was obtained in 50% yield (see Scheme 63b).

A catalytic amount (5 mol%) of the obtained 140-triflate was applied in the literature

reproduction transfer hydrogenation experiment (see Table 11, Entry 1). Degassed and

ultrasonicated solvents were used and the reaction mixture was irradiated for 8 hours with a

400 Watt high-pressure mercury-vapor lamp (spectral distribution: 184-578 nm) in a reactor with

external cooling under nitrogen atmosphere. A subsequent yellow coloring occurred in the

organic phase after the final addition of 140-triflate indicating successful reduction of the

pyridinium compound in the aqueous phase. However, no transfer hydrogenation took place

during the reaction time and no product amine 145 could be detected by TLC and 1H-NMR

measurement from the separated organic phase. The yellow organic phase was found to be

almost colorless after irradiation, which might be caused by degradation of the in situ formed

N-methylated Hantzsch ester (139). Indeed, the 1H-NMR measurement of the raw material did

not show any signals related to compound 139 or 140-triflate. Thus, the 400 Watt high-pressure

mercury-vapor lamp was replaced by a UV-lamp with reduced power (250 Watt) in order to

prevent degradation. No reactor system was available as in case of the UV-lamp, thus the


130

external cooling was limited. But with an additional reflux condenser the temperature of the

reaction mixture was kept at least below 60 °C. The reproduction experiment of the model

reaction was performed overnight with 5 mol% 140-triflate (see Table 11, Entry 2). TLC and raw

product 1H-NMR spectroscopy could detect traces of product and signals which might

correspond to a Hantzsch ester derived dihydropyridine 139 (~4 mol%).

Table 11 Photoinduced transfer hydrogenation with recycling system of N-methylated

1,4-dihydropyridine 139.

Entry Light Source

(Spectral Distribution)

Loading of Hydride

Source (140-triflate)

Time Conv.

1 400 Watt high-pressure mercury-

vapor lamp (184-578 nm)

5 mol% 8 h -

2a) 250 Watt UV-lamp (300-415 nm) 5 mol% o.n. tracesb)

3a) 250 Watt UV-lamp (300-415 nm) 1 equiv. 2 d 11%c)

a) Temperature around 60 °C; b) Detected from TLC and raw product 1H-NMR; c) Determined from raw product

1H-NMR.

To verify the formation of the product and the regenerated dihydropyridine 139, the model

reaction was repeated with 1 equivalent 140-triflate using the UV-lamp (see Table 11, Entry 3).

After 2 days of irradiation TLC indicated product formation and the separated organic phase was

roughly purified by chromatography with a short SiO2 column (eluent: hexane/ethyl acetate 9:1).

Thus, determination of 11% conversion towards amine 145 was enabled by the recorded 1H-NMR

spectrum. The 1H-NMR spectra of further isolated fractions were studied in order to elucidate

the exact structure of the 139 derived compounds, such as 139 itself, a 1,2-dihydropyridine

derivative or other possible dimers as reported in literature for reduction processes of 140-salts

without participation in a two-phase transfer hydrogenation reaction.252-254 An enhanced

dimerization of compound 139 under light irradiation would explain the low conversion of the

transfer hydrogenation owing to inactivation of the hydride source.


131

Figure 33 1H-NMR spectrum (300 MHz) probably corresponding to compound 139 (* = CDCl3).

The obtained 1H-NMR spectrum of the main side product fraction contains proton signals which

are mainly in accordance with the literature data of compound 139 but might suffer from signal

overlap (H3 and H5 of 139, labeled blue; Figure 33).251 Furthermore, the integrals of the signals

do not fully correspond solely to compound 139 as the only present Hantzsch ester derived

compound (H1, labeled green; Figure 33). Besides, the 1H-NMR spectrum shows impurities

originated from imine 144 and degradation products of this imine such as p-anisidine and

p-anisaldehyde (labeled with red frames in Figure 33).

For further clarification of the reduction process of 140-triflate in the aqueous phase, a reduction

experiment in absence of an organic phase for transfer hydrogenation was carried out according

to literature procedure (see Scheme 64).254 Sodium bicarbonate and sodium dithionite were

added to an aqueous solution of 140-triflate, which was stirred for 30 minutes at 60 °C.

Scheme 64 Proposed reaction outcome after reduction of N-methylated pyridinium salt 140-triflate.254

*

1 3/5

2

4


132

Afterwards, the mixture was extracted with deuterated dichloromethane and a 1H-NMR

spectrum was recorded quickly (see Figure 34a). The yellowish extract was found to change the

color over time obtaining a greenish solution, from which a 1H-NMR was recorded as well

(see Figure 34b). The literature 1H-NMR data which was available for 1,2-dihydropyridine (146)252

and the dimers 147 and 149253, which were obtained by different reduction methods but enabled

a comparison with the recorded spectrum (see Figure 34a). The 1H-NMR data of these references

were obtained at maximum 100 MHz what might explain slight shifting of the signals of the newly

recorded spectra, shown in Figure 34, which were recorded at 300 MHz. Dimer 148 (see Figure

33) was proposed before in literature as target compound after reduction of 140-salts but its

formation could not be verified until now and no spectroscopic data was available in literature.

The comparison of the available data indicates, that side product 146 (see Scheme 64) was not

formed, which was concluded from the missing vinylic proton signal at 7.48 ppm (see

Figure 34a).252 However, dimer 149 might be present in the reaction mixture (see Figure 34a) but

the signals might overlap with the signal assigned to compound 139 (see Figure 33).

Furthermore, the formation of dimer 147 might be excluded as well, even though compound 147

would explain the observed singlet signals between 2.55 ppm and 3.25 ppm (see Figure 34). But

the expected vinylic signal should appear at around 7.80 ppm.253

Figure 34 1H-NMR spectrum (300 MHz) of raw mixture from reduction of compound 140-triflate: a) right

after reduction process; b) after keeping NMR-sample in solution and color change (* = CDCl3,

+ = H2O).

4 2

1

3

*

2 1/3

+


133

Demethylation of compounds 139 or 140 during the reduction process can be excluded by

comparing the 1H-NMR date of the Hantzsch ester 131 with the one of the corresponding

pyridine 137. It is worth mentioning that the interfering signals, which appear in Figure 34a and

remained unassigned to a distinct structure (labeled with red frames), represent the main

product in Figure 34b after keeping the NMR-sample in solution (in presence of light). Even

though there is no literature data available for dimer 148, the obtained 1H-NMR spectrum

corresponds best to the structure of compound 148 with regard to integrals, shifts and signal

distribution. The appearance of a pyridine signal indicates a dimerization process towards

compound 148 or a 148-related structure (see Figure 34). The green labeled signals assigned to

the CH2-groups (and CH3-groups) of the ethyl ester functionalities in compound 148 should show

two different quartets (and triplets). However, a broadend signal appeared next to the quartet

and the triplet, respectively (labeled green, Figure 34b). This might indiciate the presenece of a

148-derived light induced radical or polymer species.

Even though the structures of the reductively generated 139-related species were not entirely

proven, the suspected dimerization prozess might be enabled by reaction of two formed

intermediates with each other, which is equivalent to quenching of an ongoing electron-transfer

mechanism in presence of light. In the targeted two-phase transfer hydrogenation system, this

would lead to termination of the recycling system of the Hantzsch ester derivative 139. However,

the fact that the approach applying 1 equivalent 140-triflate (see Table 11, Entry 3) enabled the

isolation of the reactive species 139 was attributed to the high amount of applied 140-triflate.

Singh and co-workers had already mentioned that their two-phse transfer hydrogenation system

(chapter 3.2.3, Scheme 56) was not feasible with BNAH (130).237 However, this statement

requires further investigation because BNAH (130) was in fact found to be active in epoxide

hydrogenation applying catalytic amounts of BNA+Br- (141-bromide) with a two-phase reaction

system from ethyl acetate and water (chapter 3.2.3, Scheme 57).239 Although BNAH (130) might

also undergo dimerization in presence of light, a one-electron transfer and reduction still might

occure.255 Thus, a catalytic amount of BNA+Br- (141-bromide) was applied in the transfer

hydrogenation forming amine 145 from imine 144 applying the reaction conditions reported by

Liu and Wu (solvent mixture: ethyl acetate/water 1:1, Table 12)239 and the ones reported by

Singh and co-workers as well (solvent mixture: benzene/water 1:1, Table 12).239 Firstly, 5 mol%

BNA+Br- (141-bromide) were used in the model reaction using ethyl acetate as organic phase for

transfer hydrogenation (Table 12, Entry 1). Owing to poor solubility of the imine 144 in ethyl

acetate a few drops of benzene were added. After two days of irradiation with a UV-lamp

(250 Watt) as used before (see Table 11) neither product 145 was observed nor recycled BNAH

(130) was present in the raw material of the organic phase as proven by 1H-NMR sepctroscopy.

Furthermore, a similar experiment was carried out with benzene as organic phase as well as a


134

higher amount of BNA+Br- (141-bromide) to get an easier insight into the reaction outcome by

investigating the raw material (Table 12, Entry 2). However, no amine 145 and no BNAH (130)

was detected. Some interfering signals might inidicate dimerization of BNAH (130), which was

not further investigated. The application of a cold-light lamp (600 lumen) instead of the UV-lamp

in a further experiment led to a decrease of the irradiation power and minimization of the UV-

light proportion. The previous experiments were repeated under these conditions; once with

ethyl acetate and once with benzene as organic phase (Table 12, Entry 3 and Entry 4).

Unfortunately, these experiments showed no product formation, although BNAH (130) was fully

recycled and detected with a loading of 5 mol%.

Table 12 Photoinduced transfer hydrogenation with recycling system of BNAH (130).

Entry Light Source Solvent

Mixture

Loading of BNA+Br-

(141-bromide)

[mol%]

Time

[h]

Recycled

BNAH (130)

[mol%]

Conv.

1 250 Watt

UV-lamp

EtOAc/H2Oa) 5 48 - -

2 250 Watt

UV-lamp

benzene/H2O 20 24 - -

3 cold-light lamp EtOAc/H2Oa) 5 27 5 -

4 cold-light lamp benzene/H2O 5 23 5 -

a) Addition of benzene owing to insolubility of 144 in pure EtOAc.

The experiments, reported in Table 12, prove that neither a UV-lamp nor a cold-light lamp were

beneficial for an efficient electron-transfer in the two-phase model reaction applying BNA+Br-

(141-bromide). This goes in line with the observations made by Singh and co-workers.237

However, it is noteworthy that a further experiment was carried out according to literature

procedure as described by Liu and Wu (see Scheme 57).239 This test reaction should prove the

reproducibility of the published hydrogenation results of α,β-epoxy ketones under present

laboratory conditions. In a test reaction trans-chalcone oxide was irradiated for 2 hours with the


135

UV-lamp (250 Watt) in presence of 10 mol% BNA+Br- (141-bromide) in a two-phase reaction

system (ethyl acetate/water 1:1). In fact, the conversion was determined with 55% towards the

corresponding hydroxyl ketone by 1H-NMR measurement of the raw material (literature: 100%

conversion with a 450 W high-pressure mercury-vapor lamp).

To fully prove the unsuitability of BNAH (130) for transfer hydrogenation of imine 144,

BNA+Br- (141-bromide) was separately reduced in 83% yield (see Scheme 65) and applied to the

model reaction in absence of an aqueous phase (see Scheme 66).

Scheme 65 Synthesis of BNAH (130) by reduction of BNA+Br- (141-bromide).

As expected no conversion towards amine 145 was observed and imine 144 and BNAH (130)

remained unreacted in the reaction mixture. Thus, BNAH (130) was found to be inefficient as

electron or hydride source in transfer hydrogenation of imines, even though the hydrogenation

of α,β-epoxy ketones was feasible forming hydroxyl ketones.

Scheme 66 Attempted transfer hydrogenation with BNAH (130).


136

3.5 Conclusion

There are two options to combine photocatalysis with the transfer hydrogenation of an imine

containing a 1,4-dihydropyridine recycling system, which were both investigated in this chapter.

The first option and thus the first task was the development of a light driven photoredox catalysis

system for in situ regeneration of the Hantzsch ester (131) from the corresponding pyridine (137),

which might allow future utilization of catalytic amounts of 1,4-dihydropyridines in transfer

hydrogenation reactions. For this purpose several reaction conditions were screened applying

eosin Y (133) as a sensitizer and CoIII(dmgH)2pyCl (135) as mediating transition metal catalyst in

combination with different proton sources, electron donors and reaction media (see

Scheme 67a). However, no experiment could manage the formation of the Hantzsch ester (131)

under light irradiation. The study revealed the different solubilization properties of all

compounds as the biggest challenge.

The second task investigated a two-phase reaction system of photoinduced transfer

hydrogenation of an imine 144 combined with a sodium dithionite containing recycling system

of the N-methylated Hantzsch ester (139). However, just in the case of an equimolar amount of

the synthesized N-methylated pyridinium salt 140-triflate the product amine 145 was observed

with more than traces (11% conversion; see Scheme 67b). Thus, it was not able to reproduce the

photoinduced transfer hydrogenation reported before by Singh and co-workers directly applying

N-methylated 1,4-dihydropyridine 139.237 Separate investigation of the recycling system

revealed a breakdown of the N-methylated Hantzsch ester (139) regeneration system in the

aqueous phase in the presence of light. Moreover, BNAH (130) was proven to be fully inefficient

in transfer hydrogenation of the imine 144 with recycling system as well as without.

Scheme 67 a) Investigation of photocatalytic recycling of compound 131; b) Recycling of N-methylated

Hantzsch ester (139) by sodium dithionite in combination with a photoinduced transfer

hydrogenation of imine 144.


137



Chemicals:




(10-3 mbar).










ionization.

NMR spectroscopy:






m (multiplet), dd (doublet of doublet), br s (broad singlet), br t (broad triplet).

Cold-light lamp:




138



UV-lamp:

Light irradiation experiments in the UV-region were carried out with a UV-hand lamp with

250 Watt from Hartmann (model UV-H 255). The spectral distribution of the lamp goes from

300 nm to 415 nm.

Halogen spotlight:

Light irradiation experiments with a halogen spotlight were carried out with a TPS pro 0002

500 Watt lamp. The spectral distribution of the lamp goes from approximately 350 nm to

750 nm.

High-pressure mercury-vapor lamp:

Light irradiation experiments with a 400 Watt high-pressure mercury-vapor lamp were carried

out in a protective reactor with external cooling. The spectral distribution of the lamp goes from

184 nm to 578 nm.


1-Benzyl-1,4-dihydropyridine-3-carboxamide (BNAH, 130)256

Under inert atmosphere, 1-benzyl-3-carbamoylpyridinium bromide (BNA+Br-,

141-bromide, 50.0, 171 µmol) and NaHCO3 (72.0 mg, 857 µmol) are dissolved in

1 ml distilled water. Na2S2O4 (149 mg, 857 µmol) is added and the reaction

mixture is stirred at room temperature for 4 h in the dark. The formed precipitate

is extracted with DCM and dried over MgSO4. The target compound is obtained

as yellow solid (36.3 mg, 169 µmol; 99%). The obtained spectroscopic data are in accordance

with literature.257

1H-NMR (CDCl3, 300 MHz, r.t.): δ [ppm] = 7.39-7.17 (m, 5H), 7.13 (d, J = 1.7 Hz, 1H), 5.71 (dd,

J1 = 8.0 Hz, J2 = 1.7 Hz, 1H), 5.32 (br s, 2H), 4.72 (dt, J1 = 8.1 Hz, J2 = 3.5 Hz, 1H), 4.26 (s, 2H), 3.15

(dd, J1 = 3.5 Hz, J2 = 1.7 Hz, 2H).

http://www.dict.cc/englisch-deutsch/halogen+spotlight.html


139

Chloro(pyridine)bis(dimethylglyoximato)cobalt(III) (CoIII(dmgH)2pyCl) (135)243

Pyridine (430 mg, 439 µl, 5.25 mmol) is added under inert atmosphere to

a hot solution (70 °C) of dimethylglyoxime (dmgH, 143, 1.38 g, 11.8 mmol),

CoCl2 x 6 H2O (1.25 g, 5.25 mmol) and NaOH (210 mg, 5.25 mmol) in 50 ml

of 95% ethanol. After cooling to room temperature a stream of air is blown

through the mixture for 30 min. The reaction mixture is then allowed to

stand for 1 h at room temperature, during which period the product is crystallized out of the

solution. The brown crystals are collected by filtration, washed successively with water, ethanol

and diethyl ether. The residue is dissolved in acetone. After evaporation of the solvent the target

compound is obtained as brown solid (1.01 g, 2.52 mmol; 48%). The obtained spectroscopic data

from the raw material are in accordance with literature.258

1H-NMR (300 MHz, DMSO-d6, r.t.): δ [ppm] = 8.02 (d, J = 5.0 Hz, 2H), 7.89 (t, J = 7.5 Hz, 1H), 7.46

(dd, J1 = 7.5 Hz, J2 = 6.5 Hz, 2H), 2.31 (s, 12H).

Diethyl 2,6-dimethylpyridine-3,5-dicarboxylate (137)248

NaClO2 (326 mg, 3.00 mmol) is added to a solution of diethyl 1,4-dihydro-

2,6-dimethyl-3,5-pyridinedicarboxylate (131, 507 mg, 2.00 mmol) in 10 ml

EtOH/H2O (1:1). After the addition of 400 µl HCl, the reaction mixture is

stirred for 1 h at room temperature. Then the mixture is concentrated under

reduced pressure and the residue is diluted with 10% NaHCO3 solution and extracted with EtOAc.

The organic layer is washed with brine and dried over anhydrous Na2SO4. For methylation

reaction, the raw product is used without further purification. For Hantzsch ester regeneration

experiments (chapter 3.4.1) the purification was carried out via column chromatography (SiO2,

hexane/EtOAc 9:1) and the product was obtained as a an off-white solid (347 mg, 1.38 mmol;

69%). The obtained spectroscopic data are in accordance with literature.259

1H-NMR (300 MHz, CDCl3, r.t.): δ [ppm] = 8.50 (s, 1H), 4.23 (q, J = 7.1 Hz, 4H), 2.67 (s, 6H), 1.26

(t, J = 7.2 Hz, 6H).

3,5-Bis(ethoxycarbonyl)-1,2,6-trimethylpyridin-1-ium trifluoromethanesulfonate (140-triflate)

A solution of diethyl 2,6-dimethylpyridine-3,5-dicarboxylate (137, 62.0 mg,

247 µmol) in 5 ml dry DCM is cooled to 0 °C under inert atmosphere. Methyl

trifluoromethanesulfonate (42.0 mg, 256 µmol) is added dropwise. The

reaction mixture is stirred overnight at 0 °C. Afterwards the reaction

mixture is stirred for 24 h at room temperature. Then water is added, the

aqueous phase is separated and evaporated to dryness. The target compound is obtained as

colorless oil (51.2 mg, 123 µmol; 50%).


140

1H-NMR (400 MHz, CD3CN, r.t.): δ [ppm] = 8.94 (s, 1H), 4.44 (q, J = 7.1 Hz, 4H), 4.10 (s, 3H), 2.98

(s, 6H), 1.39 (t, J = 7.1 Hz, 6H).

13C-NMR (100 MHz, CD3CN, r.t.): δ [ppm] = 164.3, 161.2, 145.8, 130.8, 64.4, 43.1, 20.4, 14.2.

19F-NMR (282 MHz, CD3CN, r.t.): δ [ppm] = -79.8.

HR-MS (ESI) m/z: [M-OTf]+ calcd for C14H20NO4: 266.13868; found: 266.13869.

IR (ATR, solid): ṽ [cm-1] = 3448, 2989, 2023, 1726, 1604, 1495, 1471, 1446, 1373, 1247, 1152,

1023, 861, 762, 691, 633, 573, 514.

(E)-N,1-bis(4-methoxyphenyl)methanimine (144)

p-Anisidine (100 mg, 800 µmol) is dissolved in 4 ml DCM. Afterwards

anhydrous MgSO4 (600 mg) and p-anisaldehyde (109 mg, 97 µl, 800 µmol)

are added. The reaction mixture is stirred overnight and then filtered to

remove MgSO4. After solvent evaporation the solid is washed with

acetonitrile to obtain the target compound as off-white solid (176 mg, 729 µmol; 91%). The

obtained spectroscopic data are in accordance with literature.260

1H-NMR (CDCl3, 300 MHz, r.t.): δ [ppm] = 8.36 (s, 1H), 7.79 (d, J = 8.8 Hz, 2H), 7.16 (d, J = 8.9 Hz,

2H), 6.90 (dd, J1 = 16.2, J2 = 8.8 Hz, 4H), 3.82 (s, 3H), 3.78 (s, 3H).

4-Methoxy-N-(4-methoxybenzyl)aniline (145)

NaBH4 (14.2 mg, 375 µmol) and a catalytic amount of conc. HCl are added

to a solution of (E)-N,1-bis(4-methoxyphenyl)methanimine (144, 52.0 mg,

216 µmol) in 5 ml EtOH. The reaction mixture is first stirred overnight at

room temperature and then refluxed for additional 6 h. After solvent

evaporation the reaction mixture is taken up in Et2O, the organic phase is washed with brine and

dried over MgSO4. Without further purification the target compound is obtained as yellowish

solid (45.5 mg, 187 µmol; 87%). The obtained spectroscopic data are in accordance with

literature.261

1H-NMR (CDCl3, 300 MHz, r.t.): δ [ppm] = 7.27 (td, J1 = 7.8 Hz, J2 = 6.9 Hz, J3 = 3.4 Hz, 2H), 6.94-

6.81 (m, 2H), 6.82-6.67 (m, 2H), 6.67-6.50 (m, 2H), 4.20 (s, 2H), 3.79 (s, 3H), 3.73 (s, 3H).

Summary of the Thesis

141

4 Summary of the Thesis

The thesis consists of three independent research topics:

Chapter 1: Non-heme Iron Catalyzed Epoxidation of Olefins

Chiral terminal epoxides are valuable subunits in bioactive compounds and versatile building

blocks in the synthesis of fine chemicals and pharmaceuticals.

Within the framework of this work a new biomimetic enantioselective non-heme iron catalyzed

epoxidation system for terminal olefins was developed and investigated. The epoxidation of

2-vinylnaphthalene was chosen as model reaction applying in situ generated complexes as

catalysts originated from a ligand and FeCl3 x 6 H2O. A screening of different imidazole-based

peptide-like ligands for the in situ generated chiral iron(III) catalysts took the imidazole

substitution pattern, coordinating motif and further important functionalities into account.

Among all synthesized ligands the L-tert-leucine-derived ligand providing a [NN]-binding motif, a

1,2-substituted imidazole and beneficial tert-butyl groups was identified as the most promising

one. The catalyst system was tested for different terminal and non-terminal substrates.

Scheme Enantioselective non-heme iron catalyzed epoxidation of terminal olefins; Combination of the

epoxidation method with an aminolysis in a one-pot process; SiO2 catalyzed Meinwald

rearrangement of the corresponding epoxides.

Moreover, the catalyst was applied in aziridination reaction wherein it was found to be inactive.

However, the new catalytic epoxidation system could be combined in a one-pot process with a

following aminolysis reaction towards pharmaceutically relevant 2-aminoalcohols. Besides, a

SiO2 catalyzed Meinwald rearrangement of the obtained terminal epoxides was observed and

suggested as promising method for an easy access to acetaldehyde derivatives.


142

Chapter 2: Synthesis of Pyridine-derived Ligands for Light Absorbing Metal Complexes

Since pyridine-based compounds were found to be versatile structures for sensitizer in DSSC, DS-

PEC or NLO, a variety of different 2,2’-bipyridines were designed during the last decades,

providing different linkers and different end-capping moieties.

In the scope of this chapter three new 4,4’-π-conjugated 2,2’-bipyridine-based compounds

containing a dimethoxyphenyl linker were synthesized by conventional approach starting from

4,4’-dimethyl 2,2’-bipyridine. These two ligands with electron-accepting end-capping moieties

contain either a cyanoacrylic acid or a cyanoacrylic acid ester unit. This ligands were investigated

in regard to their adsorption behavior on TiO2, photophysical and electrochemical properties.

Further coordination experiments forming ruthenium(II) complexes demonstrated this to be a

challenging task. The third ligand, which was end-capped with an electron-donating propenyl

thiophene unit, was made synthetically accessible, even though the ligand was not obtained in

fully pure form because it was suspected to undergo light induced E/Z isomerism in solution.

A new one-pot procedure towards pyridinyl quinoline-derived ligands was attempted to be

developed, but was found to be infeasible under the chosen conditions.

Scheme New synthesized 4,4’-π-conjugated 2,2’-bipyridines.


143

Chapter 3: Investigations of 1,4-Dihydropyridine-based Systems in Photocatalysis

Since 1,4-dihydropyridines such as the Hantzsch ester or BNAH were known to be efficient

NAD(P)H mimics, these compounds found a variety of applications as reductive equivalents in

enantioselective and non-enantioselective catalysis. Although 1,4-dihydropyridines are

important compounds, they are cost-intensive as well when they have to be used in equimolar

amounts. Thus, there is a high demand for the development of an efficient in situ recycling

system. With regard to a sustainable recycling system the utilization of solar power might be a

promising option.

Thus, the photocatalytic regeneration of the Hantzsch ester was investigated by screening of

different proton sources, electron donors and reaction media in combination with eosin Y as a

photosensitizer and CoIII(dmgH)2pyCl as mediating transition metal catalyst. However, within the

framework of this study no photocatalytic recycling of the Hantzsch ester was enabled. The

different solubilization properties of all compounds were identified as the biggest challenge to

overcome.

Moreover, a two-phase reaction system which combines photoinduced transfer hydrogenation

of an imine with recycling of catalytic amounts of a N-methylated Hantzsch ester by reduction

with sodium dithionite was investigated. However, just when an equimolar amount of the

synthesized N-methylated pyridinium salt was applied, conversion from the imine towards the

amine could be observed. While searching for an explanation for this behaviour, a breakdown of

the N-methylated Hantzsch ester recycling system was observed in the aqueous phase in the

presence of light.

Scheme Recycling of N-methylated Hantzsch ester by sodium dithionite in combination with a

photoinduced transfer hydrogenation of the imine.

Zusammenfassung der Dissertation

144

4 Zusammenfassung der Dissertation

Die Arbeit besteht aus drei unabhängigen Forschungsthemen:

Kapitel 1: Nicht-häm Eisen-katalysierte Epoxidierung von Olefinen

Chirale terminale Epoxide sind wertvolle Einheiten in bioaktiven Verbindungen und vielseitig

einsetzbare Bausteine in der Synthesis von Feinchemikalien und Arzneimitteln. Im Rahmen

dieser Arbeit wurde ein neues biomimetisches enantioselectives System zur katalytischen

Epoxidierung von terminalen Olefinen entwickelt und untersucht. Für die Anwendung von in situ

generierten Komplexen als Katalysator, ausgehen von einem Liganden und FeCl3 x 6 H2O, wurde

die Epoxidierung von 2-Vinylnaphthalin als Modellreaktion gewählt. Ein Screening von

verschiedenen in situ generierten chiralen Eisen(III)katalysatoren aus Imidazol-basierten Peptid-

ähnlichen Liganden berücksichtigte das Substitutionsmuster von Imidazol, das

Koordinationsmotiv und weitere wichtige funktionelle Gruppen der Liganden. Von allen

synthetisierten Liganden wurde der L-tert-Leucin-abgeleitete Ligand mit einem

[NN]-Bindungsmotif, einem 1,2-substituierten Imidazol und sterisch vorteilhaften

tert-Butylgruppen als der vielversprechendste ausgewählt. Der generierte Katalysator wurde für

verschiedene terminale und nicht-terminale Substrate getestet.

Schema Enantioselective Nicht-häm Eisen-katalysierte Epoxidierung von terminalen Olefinen;

Kombination der Epoxidierungsmethode mit einer Aminolyse in einem One-pot-Prozess; SiO2-

katalysierte Meinwald-Umlagerung der entsprechenden terminalen Epoxide.

Darüber hinaus wurde der Katalysator für einen Aziridinierungsprozess getestet, jedoch aber als

inaktiv befunden. Allerdings konnte die neue katalytische Epoxidierungsmethode in einem One-

pot-Prozess mit einer Aminolyse zur Darstellung von pharmazeutisch relevanten


145

2-Aminoalkoholen kombiniert werden. Ebenso konnte eine SiO2-katalysierte Meinwald-

Umlagerung der erhaltenen terminalen Epoxide beobachtet werden, was eine vielversprechende

Methode für die einfache Darstellung von Acetaldehydderivaten in Aussicht stellt.


146

Kapitel 2: Synthese von Pyridin-abgeleiteten Liganden für lichtabsorbierende Metallkomplexe

Seitdem Pyridin-basierte Verbindungen als vielseitig einsetzbare Strukturen in DSSC, DS-PEC oder

NLO befunden werden, wurden in den letzten Jahrzehnten eine Vielzahl von verschiedenen

2,2‘-Bipyridinen mit unterschiedlichen Linkern und Endcappingeinheiten designt.

Im Zuge dieser Arbeit wurden ausgehend von 4,4’-Dimethyl-2,2’-bipyridin drei neue

4,4’-π-konjugierte 2,2’-Bipyridine mit einem Dimethoxyphenyllinker durch konventionelle

Synthesemethoden hergestellt. Die zwei Liganden mit elektronenziehenden Encappingeinheiten

weisen einmal eine Cyanacrylsäure- und eine Cyanacrylsäureestereinheit auf. Diese Liganden

wurden bezüglich Ihres Adsorptionsverhaltens auf TiO2 und ihrer photophysikalischen und

elektrochemischen Eigenschaften getestet. Weitere Koordinationsexperimente zur Darstellung

von Ruthenium(II)komplexen erwiesen sich als schwierig. Der dritte Ligand, welcher mit einer

elektronenschiebenden Encappingeinheit versehen ist, konnte synthetisch zugänglich gemacht

werden, auch wenn die Verbindung nicht mit absoluter Reinheit erhalten werden konnte,

vermutlich verursacht durch lichtinduzierte E/Z-Isomerie in Lösung.

Zur Darstellung von Pyridin-haltigen Quinolin-abgeleiteten Liganden sollte ein neuer One-pot-

Prozess entwickelt werden, was jedoch unter den gewählten Bedingungen nicht ermöglicht

werden konnte.

Schema Neue synthetisierte 4,4’-π-konjugierte 2,2’-Bipyridine.


147

Kapitel 3: Untersuchung von 1,4-Dihydropyridin-basierten Systemen in der Photokatalyse

Seit 1,4-Dihydropyridine, wie der Hantzsch Ester oder BNAH, als wirksame NAD(P)H Mimetika

bekannt sind, wurde eine Vielzahl von Anwendungen in der enantioselectiven und nicht-

enantioselectiven Katalyse als reduktive Äquivalente gefunden. Obwohl 1,4-Dihydropyridine

wichtige Verbindungen sind, ist die Verwendung kostspielig durch ihren Einsatz in äquimolaren

Mengen. Daher bedarf es der Entwicklung eines effizienten in situ Recyclingsystems. Im Hinblick

auf ein nachhaltiges Recyclingsystem kann die Verwendung von Sonnenenergie eine

vielversprechende Option sein.

Somit wurde die photokatalytische Regeneration des Hantzsch Esters durch ein Screening

verschiedener Komponente untersucht. Hierbei wurden verschiedene Protonenquellen,

Elektronendonatoren und Reaktionsmedia in Kombination mit Eosin Y als Photosensibilisator

und CoIII(dmgH)2pyCl als vermittelnder Übergangsmetall-katalysator getestet. Jedoch konnte im

Rahmen dieser Arbeit keine photokatalytische Wiedergewinnung des Hantzsch Esters erreicht

werden. Es stellte sich heraus, dass die unterschiedlichen Löslichkeiten aller nötigen

Komponenten die größte Herausforderung ist, die es gilt zu meistern.

Darüber hinaus wurde ein Zweiphasensystem untersucht, welches die photoinduzierte

Transferhydrierung eines Imins mit einem Recyclingsystem kombiniert, das durch Reduktion mit

Natriumdithionit von katalytischen Mengen eines N-methylierten Hantzsch Esters arbeitet.

Allerdings nur im Fall von äquimolar eingesetzten Mengen des synthetisierten N-methylierten

Pyridiniumsalzes konnte ein Umsatz des Imins zum Amin beobachtet werden. Bei der Suche nach

einer Erklärung für dieses Verhalten, konnte ein Zusammenbruch des Recyclingsystems des

N-methylierten Hantzsch Esters in der wässrigen Phase in Anwesenheit von Licht beobachtet

werden.

Schema Recycling des N-methylierten Hantzsch Esters mit Natriumdithionit in Kombination mit

photoinduzierter Transferhydrierung eines Imins.

References

148

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Appendix

Danksagung

Nicht ganz ein Monat, aber die Arbeit ist fertig geschrieben…

An dieser Stelle möchte ich zuallererst meiner Doktormutter Frau Prof. Dr. Svetlana B. Tsogoeva

danken, dass sie mich auf dem Weg zu dieser Arbeit betreut und begleitet hat. Danke für die

vielen aufschlussreichen Gespräche und wissenschaftlichen Diskussionen.

Für die finanzielle Unterstützung während meiner Promotion möchte ich der Erika Giehrl-Stiftung

(Stipendium), dem Programm zur Förderung der Chancengleichheit für Frauen in Forschung und

Lehre (Stipendium) und der GSMS (Graduiertenschule; für Konferenzen und Winterschool)

danken.

Ein ganz besonderer Dank gilt auch meinen Kollegen und Freunden im Arbeitskreis, die mich

durch alle Höhen und Tiefen der letzten 5 Jahre begleitet haben: Felix (Danke für die levellos

lustige Laborehe, mein grandioser Gatte), Christina (zusammen jammert es sich doch immer

schöner, ganz besonders gut mit Klopapier in der Hose), Aysun (Thanks for serving me cigköfte

and coffee, my heart – Yes, my lady), Tony (Danke für die Erweiterung meines musikalischen und

cineastischen Horizonts), Domi G. (der vergessliche Pronotions-Harmonie-Domi <3), Volker (der

IT-Volki und mein Lieblingsmacho für die vielen chemischen Diskussionen), Anton (my beloved

sarcastic Apple-ton), Lena (meine geliebte Fußballgöttin mit 3 Haaren ), Flo (ich grüble heute

noch über den anspruchsvollen Bildungskalenderblättern), Carola (awesome cigarette roller),

Dr. Maksim (thanks for your kind crazyness), Beni (Weinassistent).

… und natürlich auch den Ehemaligen: Kerstin (Danke für den fränggischen Wind im AK),

Christoph (Danke für den schwäbischen Wind im AK und die coole Putzfrau), Shengwei, Jorge,

Mohammad, Olga und Lenny.

Allen meinen fast-Arbeitskollegen und Freunden aus Lehrstuhl I und II möchte ich ebenso

danken, dass sie mir mit zahlreichen Grill- und Bierabenden eine wunderbare Zeit am Institut und

in Erlangen beschert haben. Bine (die Klobabine, tatsächlich das Binigste und Beste hier im Haus),

Domi P. (wir zwei, der Bonsaiclub Erlangen), Kathrin (Bürsteinheiten!), Jasi (die Tante, der Jost,

meine Toolfreundin), Sabrina (Almächd, die Auslandssabrina mitm Energy), Consti (eigentlich ist

er auch ein echtes Mäusekind), Joe (ich, das Sekretariat und Veranstaltungsbüro vom dicken Kind

) und viele viele viele mehr.

Auch möchte ich mich bei allen Angestellten des Instituts für Ihre Hilfe und Unterstützung

bedanken. Mein Dank gilt Christian Placht und Harald Maid (NMR-Spektroskopie; Danke fürs

Appendix

160

Knobeln und Unterhalten beim Messen), Eva Zeisel (Elementaranalyse), Margarete Dzialach und

Wolfgang Donaubauer (Massenspektrometrie; Danke für die nahezu problemlose Erfüllung

diverser Sonderwünsche), Hannelore Oschmann, Robert Panzer und Detlef Schagen

(Chemikalienausgabe und Sondermüllentsorgung; Danke für die netten Unterhaltungen über

Gott und die Welt und das Chemikum), Stefan Fronius, Bahram Saberi und Dominik Roth

(Glasbläserei; Danke fürs Zusammenfügen von dem was ich zerstört habe), Horst Meyer

(mechanische Werkstatt; Danke für die Unterstützung mit HPLC-Schrauberwerkzeug und bei

meinem Fahrradschloss), Holger Wohlfahrt (elektrische Werkstatt), Dr. Frank Hampel (Danke, für

die regelmäßige Aufklärung über die Ungerechtigkeit der Welt und die Sinnlosigkeit des Daseins),

Dr. Alexander Scherer (Danke für das TIPS-Keton), Pamela Hampel, Christiane Brandl-Ritter, Ute

Grochulla (Verwaltung).

Meinen Praktikanten Thomas, Alexander, Miriam und Corinna möchte ich auch ausdrücklich

danken, dass sie überdurchschnittlich motivierte und unterhaltsame Studenten waren und mich

bei der Synthese unterstützt haben.

Besonderer Dank gilt auch nochmal allen meinen ‚Korrektören‘: Tony (sooooo ein gutes

Korrekturauge, trotz schlechter Augen ), Chau (geht runter wie Öl, wenn jemand sagt, dass es

sich schön liest), Katrin Knu (ich hoffe ich habe dir in den letzten Monaten einige schöne Stunden

beim Korrigieren im Zug und beim nächtlichen Tanzen beschert), Lena (mein Nummerngirl für

den krönenden Abschluss).

Nicht zu vergessen sind natürlich all die überaus wichtigen wo-anders-Chemiker und nicht-

Chemiker im Hintergrund, die die manchmal etwas gnatschige Anja unterstützt, motiviert und

aufgebaut haben: Danke an meine Eltern und Freunde!

Es sollen auch die Dinge nicht unerwähnt bleiben, die zur Motivation und als Überlebensmittel

in harten Zeiten gedient haben: Ich danke den unzähligen Albernheiten im Labor, der Musik und

dem Vorrat an Gummibärchen.

Huch… da ist jetzt aber tatsächlich wieder viel geredet worden.

Lange Rede, kurzer Sinn:

Danke, Thank you, Благодарю, Díky, Teşekkür ederim, Gracias, Grazie, Merci und Dannge!

Appendix

161

Lebenslauf

Persönliche Daten

Name

Geburtsdatum

Geburtsort

Anja Carola Fingerhut

04. Mai 1987

Nürnberg (Deutschland)

Ausbildung

07.2012 – heute Promotion in der Organischen Chemie, FAU Erlangen-Nürnberg

Institut für Organische Chemie

Arbeitskreis von Prof. Dr. S. B. Tsogoeva

Titel: Development of new biomimetic non-heme iron epoxidation

catalysts and new pyridine-derived light absorbing systems.

10.2010 – 03.2012 Masterstudium in Molecular Science, FAU Erlangen-Nürnberg

Studienschwerpunkte: Drug Discovery, Molekulare Biologie,

Instrumentelle, forensische und bioanalytische Chemie

Masterarbeit betreut von Prof. Dr. S. B. Tsogoeva

(Organische Chemie) im Bereich der Organoautokatalyse

Titel: Investigations on new enantioselective organoautocatalytic

Mannich reactions.

10.2007 – 09.2010 Bachelorstudium in Molecular Science, FAU Erlangen-Nürnberg

Bachelorarbeit betreut von Prof. Dr. H. Gröger

(Organische Chemie) im Bereich der Biokatalyse

Titel: Enoatreduktase-katalysierte Reduktion von

C=C-Doppelbindungen unter in situ-Cofaktorregenerierung.

10.2006 – 02.2007 Magisterstudium der Neueren Deutschen Literatur,

Kunstgeschichte und Psychologie, FAU Erlangen-Nürnberg

06.2006 Abitur, Gymnasium Eckental, Eckental-Eschenau

Documents

opus4.kobv.de€¦ · Teile dieser Arbeit sind bereits veröffentlicht: • A. Fingerhut, Y. Wu, A. Kahnt, J. Bachmann, S. B. Tsogoeva, Synthesis and Electrochemical and Photophysical