Glucose-Targeted Metallodrugs for Cancer Therapy

Glucose Functionalisation of
Manganese (I) CORMs and
novel Di-Iron (II)
Metallodrugs
Conor Fennell 4BS9
15365371
Supervisor: Dr. Luca Ronconi

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Abstract
The increased demand for glucose exhibited by cancer cells in comparison to healthy cells
described by the ‘Warburg Effect’ has inspired the development of rationally designed
glycoconjugate drugs in order to target cancer cells specifically. The field of medicinal
inorganic chemistry has yielded several cytotoxic metal compounds that are particularly
effective at inducing cell death in cancer cells since the development of cisplatin in the 1970s.
Combining these two factors has led to the development of metal-drug glycoconjugates that
exhibit specific targeting of and resulting cellular internalisation with cancer cells. This aims
to increase the overall effectiveness of the chemotherapy whilst simultaneously reducing the
drugs toxicity in the body. In this project, two metal complexes that exhibit cytotoxicity were
identified as suitable candidates for glycoconjugation utilising a dithiocarbamato-
isonipecotamide ligand (Fig.A.) that was previously conjugated with a sugar by the Ronconi
research group. Figure A below provides an analogy of the desired result of this research
project: A ‘Trojan horse’ glycomimetic compound that allows the cellular ‘bomb’ to induce
cell death once internalised by the cancer cell. The first compound for which this synthesis was
attempted with was a MnI
Br(CO)5 CORM (4r). This CORM-glycoconjugate (6) was
successfully synthesised and characterised. The second metal complex with which this
synthesis was attempted was a novel di-ironII
complex [FeII
2(µ-CNMeXyl)(µ-
CO)(CO)2(Cp)2](CF3SO3) developed by Fabio Marchetti et al.1
A model metal-
dithiocarbamto-isonipecotamide compound to which future glycoconjugates of this metal can
be compared to was successfully synthesised and characterised (7). The development of this
compound furthers the possibility of future procedures being identified to synthesis a di-iron
glycoconjugate of this type.
Figure A. Metallodrug (bomb)-dithiocarbamato-isonipecotamide-glycoconjugate (Trojan horse) analogy

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Acknowledgements
I would like to thank my parents, Marie and Wayne, for their unwavering support throughout
my entire degree. Their guidance and support through every stage of my education is
immeasurable in value and for them I am truly grateful.
I would like to thank my supervisor, Dr. Luca Ronconi for his expertise and assistance
throughout this project. I would like to acknowledge the extra time he spent in helping me
complete this project in the limited time that was allocated.
I would also like to thank the two Greeks, Giannias Titilas and Eirini Fotopolou for their
guidance and help in completing this project. I would like to thank them for the all the
knowledge they have shared with me, including the eloquent Greek phrases.
I would like to thank Ellen Keyes and Roberta Bottiglieri for putting up with my despairing
attitude throughout final year, and succumbing to none of it. It was a truly enjoyable
experience to share a lab with them.
I must also thank the NUIG Dept. of Chemistry for providing me the environment and all the
necessary facilities to carry out this project.
Thank you to Lucy for being a bottomless pit of positivity and for keeping my head screwed
on at all times.
Finally, I would like to thank Naoise O’Beirne, his wonderful Bodum French Press coffee
and Roger the ‘Jacked’-Russell terrier for providing a necessary escape from campus every
lunchtime in our final year.

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Symbols and Abbreviations
(I) + 1 oxidation state
(II) + 2 oxidation state
α Alpha
ATP Adenosine triphosphate
β Beta
BC Before Christ
cm-1
wavenumber (IR)
CO Carbon Monoxide
CORM CO – releasing molecule
° C Degrees Celcius
E. coli Escherichia coli
GLUT Glucose Transporter
ppm parts per million (NMR)
σ Sigma
π Pi
δ Chemical shift (ppm) (NMR)
δ bending vibration (IR)
ν stretching vibration (IR)
νa Asymmetric stretch
νs Symmetric stretch
r.t. Room temperature
d doublet (NMR)
dd doublet of doublet (NMR)
m multiplet (NMR)
td triplet of doublet (NMR)
tt triplet of triplet (NMR)
qd quartet of doublet (NMR)
s singlet (NMR)
TLC Thin Layer Chromatography
dtc dithiocarbamato
Inp Isonipecotamide

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Glu Glucose
DCM Dichloromethane
THF Tetrahydrofuran
DMF Dimethylformamide
H2O water
P2O5 Phosphorous Pentoxide
DIPEA N,N – Diisopropylethylamine
ax Axial
eq Equatorial
TSTU N,N,N′,N′-Tetramethyl-O-(N-succinimidyl)uroniumtetrafluorborat

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Table of Contents
Abstract..................................................................................................................................................1
Acknowledgements ...............................................................................................................................2
Symbols and Abbreviations .................................................................................................................3
1. Introduction.......................................................................................................................................7
1.1. Background ................................................................................................................................7
1.1.1. Anti-cancer metallodrugs...................................................................................................7
1.1.2. Development of metal-based glycoconjugates for the target of anti-cancer
chemotherapy................................................................................................................................9
1.1.3. Utilisation of dithiocarbamato scaffolds .........................................................................10
1.2. Building the Bomb – Choosing the Cytotoxic Metal Centre................................................11
1.2.1. Manganese(I)-based CO-Releasing Molecules ...............................................................11
1.2.2. Identification of a novel di-iron(II) metallocene with cytotoxic activity......................11
2. Training ...........................................................................................................................................12
2.1. Spectroscopy and characterisation of synthetic products ....................................................12
2.1.1. Infrared spectroscopy.......................................................................................................12
2.1.2. Nuclear Magnetic Resonance Spectroscopy of Metal Complexes ................................14
2.2. Monitoring reaction progression............................................................................................15
2.2.1. Thin-layer Chromatography (TLC)................................................................................15
3. Objectives and aim of project ........................................................................................................17
4. Results and Discussion....................................................................................................................19
4.1. Route A .....................................................................................................................................20
4.2. Route B......................................................................................................................................24
4.3. Route C .....................................................................................................................................30
5. Conclusions......................................................................................................................................34
6. Experimental ...................................................................................................................................35
6.1. Materials...................................................................................................................................35
6.2. Instrumentation........................................................................................................................35
6.2.1. Perkin-Elmer Frontier 400 FT-IR Spectrophotometer.....................................................35

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6.2.2. JEOL 400 MHz NMR ECX-400 Spectrometer ..................................................................35
6.3. Synthesis and Characterisation ..................................................................................................36
6.3.1. Route A ..............................................................................................................................36
6.3.2. Route B...............................................................................................................................38
6.3.3. Route C ..............................................................................................................................43
7. References........................................................................................................................................45
8. Appendix..........................................................................................................................................47
9. Affidavit ...........................................................................................................................................49
10. Project Risk Assessment...............................................................................................................50

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1. Introduction
1.1. Background
Metal ions an integral role in human physiology. For instance, the transport of oxygen
throughout the body for cellular respiration relies on the presence of iron(II) in haemoglobin;2
copper ions in cytochrome-c oxidase aid electron transfer required in mitochondrial
respiration,3
and molybdenum(II) present in sulfite oxidase aids the detoxification of harmful
sulfites in the body.4
Additionally, metal-containing formulations have been exploited by humans for millennia to
treat a number of diseases. As far back as 2500 BC the Chinese have utilised gold salts to
treat a variety of ailments, particularly skin ulcers and smallpox,5
whereas the ancient
Egyptians recognised the wound healing properties of zinc.6
At the turn of the 20th
century, the development of metal-based drugs, like the arsenic(III)
derivative Salvarsan developed by Paul Ehrlich to treat syphilis7
and the anti-tuberculosis
drug potassium dicyanoaurate discovered by Robert Koch8
, inspired research into the use of
metals in medicine throughout the 20th
century and up to the current day.
Figure 1.1: The two arsenical molecules of which Salvarsan is comprised. [generated with ChemDraw]
1.1.1. Anti-cancer metallodrugs
In spite of this however, the monumental discovery of the first anticancer metal drug, like
many other significant scientific discoveries in human history, occurred serendipitously. In
1965, Barnett Rosenberg of Michigan State University was studying the effect of electric
field lines on E. coli bacteria when he noticed that the bacteria surrounding the platinum
electrodes became filamentous, indicating that proteins within the cells had been denatured in
some way and that the cells had died.9
Unknown to Rosenberg initially, he had synthesised
cis-diamminedichloridoplatinum(II), the platinum(II) complex that came to be known as

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cisplatin. Cisplatin formed as an electrolysis by-product of the platinum electrodes and the
ammonium chloride solution containing the bacterial cells.
Cisplatin was first tested in 1968 on tumour-transplanted mice. The mice were injected with a
dose of cisplatin and showed a major regression of the tumour size. In a short time span, in
relation to modern drug testing, the first human patients were treated with cisplatin in 1971.9
Cisplatin proved effective in treating testicular and ovarian cancers, notably increasing the
testicular cancer 10-year survival rate to where it currently stands at over 95%.10
However,
cisplatin displays acute kidney toxicity and tumour resistance to its effects, after prolonged
treatment with the drug.11
Further development of platinum drugs followed to overcome these issues with cisplatin,
leading to the development of drugs such as carboplatin and oxaliplatin.12
(Fig1.2)
Figure 1.2. Platinum(II) anti-cancer compounds. [generated with ChemDraw]
Inspired by the ability of platinum derivatives to induce cell death, the potential targeting
capability of metal complexes, the need to identify less toxic alternatives to platinum, and
motivated by the continually increasing rates of cancer diagnosis across the globe, triggered
research to evaluate the anti-cancer capabilities of other metal ions including gold(I/III),
ruthenium(II/III) and gallium(III) to mention a few.11
Thus began the renaissance of
medicinal inorganic chemistry, with the generation of thousands of metal-based anti-cancer
agents over the past 50 years.
In modern times, metal-based chemotherapeutics have been showing potential for the
treatment of cancer, owing to an exciting new age in drug discovery and development based
on target specific rationale in order to improve the effectiveness and decrease the toxic side-
effects of the drugs.

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1.1.2. Development of metal-based glycoconjugates for the target of anti-cancer
chemotherapy
Significant progress in the field of oncology throughout the 20th
and early 21st
centuries
identified the major characteristics of cancerous cells by uncovering the unique signalling and
metabolic pathways possessed by these cells compared to healthy ones. Targeting these
unique “hallmarks of cancer” founds the basis of chemotherapeutic development.13
A general characteristic of tumour cells is the rapid proliferation in the body. As a result,
tumour cells require rapid replication of the biomolecules in the cell in order to undergo
mitosis into two viable daughter cells to sustain higher levels of proliferation. Human cells
contain many nucleotides, lipids and amino acids, each of which require carbon and nitrogen
atoms in order to be produced. Therefore, a higher demand for the two main molecules that
undergo catabolism, glucose and glutamine, arises in tumour cells. Additionally, the higher
replication demands of the tumour cell will result in the prioritising of glucose metabolism
for biomolecule replication as opposed to ATP production. In this case, the tumour cell
favours aerobic glycolytic metabolism over oxidative phosphorylation.14
This phenomenon
known as “the Warburg effect” was identified by Otto Warburg in 1924.15
Aerobic
glycolytic metabolism involving the production of lactate from glucose produces only 2
molecules of ATP per glucose molecule whereas oxidative phosphorylation produces 36
molecules of ATP per molecule of glucose.16
The irrefutable need for the biological
‘currency’ that is ATP by every cell results in the over-expression of glucose transport
proteins know as GLUTs on the cell membrane of rapidly-proliferating tumour cells in order
to compensate for the increased demand for glucose uptake. The large volume of GLUTs
present in the cell membrane of tumour cells in particular, give reason for them to be prime
targets for rationally designed chemotherapeutic drugs.17
Based on this rationale, glycomimetic compounds are desirable in anti-cancer drug design.
Conjugation of glycomimetic compounds to a cytotoxic metal-centre aims to improve the
selectivity towards cancer cells via GLUT-mediated cellular internalisation and thus improve
the effectiveness of the metal drug in the human body.15

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Figure 1.3: GLUT mediated glycolytic pathway [L. Ronconi,et al. Metallodrugs, , DOI:10.1515]
1.1.3. Utilisation of dithiocarbamato scaffolds
As outlined above, nephrotoxicity and physiological instability are the fundamental barriers
that need to be overcome to progress the field of metal drug design. The strong affinity
towards sulfur groups and subsequent binding to sulfur containing biomolecules shown by
many transition metals, hinders the desired outcome of the drugs in the body. According to
‘Hard-Soft Lewis Acid-Base Theory’ (HSAB Theory), the ‘soft’ sulfur atoms form strong
bonds with ‘soft’ and ‘borderline’ transition metal centres including platinum(II),
manganese(I) and iron(II).18
Overcoming this affinity towards sulfur-binding was therefore
targeted by research groups with hopes of decreasing the toxicity and inefficiency of
metallodrugs.19
Dithiocarbamates were identified as intrinsic chemoprotectant ligands. The sulfur atoms of
the bidentate-binding dithiocarbamates form stable bonds with the metal centre and prevent
ligand substitution with other monodentate-binding sulfur containing molecules within the
human body due to the stability conferred by the “chelate effect”20
. Simply put, there is a
greater energy cost in the breaking of two coordinate sulfur bonds than a monodentate sulfur
bond. Additionally, the change in entropy of a bidentate ligand upon coordination is
significantly lower than the change of entropy of a monodentate ligand upon coordination.
The chemoprotectant dithiocarbamato ligand that is desired for this project is based on carbon
disulfide bound to isonipecotamide. The isonipecotamide allows covalent bond formation at

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the amide nitrogen with our desired sugar, thus making dithiocarbamates of this type the ideal
candidates to fulfil the role of the scaffold that is required to conjugate the metal drug with
the sugar. The amide functional group also improves the overall solubility of the
glycoconjugates in water.
Figure 1.4: Dithiocarbamato-isonipecotamide ligand. [generated with ChemDraw]
1.2. Building the Bomb – Choosing the Cytotoxic Metal Centre
1.2.1. Manganese(I)-based CO-Releasing Molecules
The toxicity of Carbon Monoxide (CO) in the human body is common knowledge and is well
documented throughout literature. CO has a higher affinity towards haemoglobin than O2,
meaning that when inhaled and present in the bloodstream it will bind to haemoglobin and
prevent O2 from doing so, thus preventing essential oxygen transport. Recent studies
however, have discovered therapeutic properties of CO in controlled doses. CO gas exhibits
effective anti-inflammatory properties, and has proven to be an effective antimicrobial agent.
Useful as these properties may be, CO gas remains difficult to manipulate in order to gauge
the correct dosage and to target the afflicted areas, balancing its toxicity against its curative
abilities. The development of CO-Releasing Molecules (CORMs) has greatly overcome these
issues. CORMs can be utilised to target the desired areas and release controlled amounts of
CO, thus maximising the effectiveness and desired outcome of the curative CO molecules.
CORMs containing transition metal centres have particular desirability due to the synergistic
nature of Metal-CO bonding. The CO (σ-π*) back-bonding that occurs improves both
reactivity and stability, allowing for desirable CO release kinetics and activation of release 21,
22
.
1.2.2. Identification of a novel di-iron(II) metallocene with cytotoxic activity
A metallocene is a class of organometallic compound defined as a metal centre that is bound
to two cyclopentadienyl (Cp) groups via π-electron donation. The first of these type of
molecules to be synthesised was ferrocene in 1951. Since this time, many derivatives of this
molecule and their properties have been well documented. The anti-cancer properties of iron
(II) metallocenes, particularly those with coordinated CO groups, are well established.23

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2. Training
2.1. Spectroscopy and characterisation of synthetic products
2.1.1. Infrared spectroscopy
Infrared (IR) spectroscopy is a useful tool for characterising reagents and products in
synthetic chemistry. The method is based on the observance of unique molecular bond
vibrations of a compound as a means to identify its structure.
Chemical bonds vibrate at specific frequencies (relating to energy) that correspond to well-
defined vibrational energy levels. Electromagnetic light radiation with wavelengths in the
region of 300µm – 700nm form the infrared region in the electromagnetic spectrum. Infrared
radiation is equal in energy to the vibrational energy levels of molecules. The intensity of
absorbance of particular IR frequencies by a compound provides information on the types of
chemical bonds that are present in the compound.
In accordance with Hooke’s law of harmonic oscillators, it is observed that the value k, the
force constant that describes the strength of the chemical bond, is lower in value when it is
applied to larger masses. Therefore, larger atoms such as transition metals require radiation
from lower frequencies of IR light to vibrate chemical bonds between them and other
atoms.24
For this reason, IR radiation in the ‘far’ region of the IR spectrum (𝜈̅ = 600 cm-1
–
33cm-1
) proves very useful in the characterisation of metal compounds. The interpretation of
Far-IR spectroscopic data was an integral aspect of this project.
ν̅ =
1
2𝜋𝑐
√
𝑘
𝜇
Figure 2.1: Hooke’s law in which k = force constant and µ = the reduced mass
Mid-IR spectroscopy is particularly effective in characterisation of chemical bonds between
smaller organic molecules that make up the fundamental functional groups in organic
chemistry. The presence of amides, hydroxyls and other organic functional groups in the
compounds synthesised in this project required the use of Mid-IR spectra for characterisation.
Upon irradiation of the molecules with IR radiation, the chemical bond can vibrate in two
different ways. The bonds can stretch or they can bend. There exists four types of bending
vibrations. The symbols and sub-classes of these two vibrational modes are detailed in Fig2.2

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Figure 2.2: IR spectroscopy vibrational modes and their corresponding symbol 25
IR spectroscopy is an effective tool to discriminate between cis- and trans- isomers of metal
complexes. The spectra of complexes with the same molecular formula can differ depending
on the isomer present; whether the ligands are symmetrically orientated or not. Identification
of the number of ν(CO) signals present and the wavenumber they appeared at in the IR
spectra of the synthetic products obtained in this project was used to discern whether the
desired product was obtained.
A CsI beam splitter is favoured over a potassium bromide (KBr) beam splitter in this project
as CsI has a greater working range and allows spectroscopic data to be collected in the Far-IR
region 26
.
Training: Perkin Elmer – Frontier 400 FT-IR spectrophotometer.
1. ~ 5 mg of analyte was triturated with ~ 10 mg of CsI using a pestle and mortar until a
homogenous powder was obtained.
2. The analyte powder was loaded into press apparatus between two smooth disks.
3. The press apparatus was placed under maintained compression for two 30 min intervals
using the compressor.
4. The freshly prepared disk was carefully loaded into the sample holder.
5. The Frontier FT-IR was calibrated to measure MID-IR (16 scans between 4000 cm-1
– 400
cm-1
at a resolution of 4 cm-1
) and was calibrated to measure FAR-IR (32 scans between 600
cm-1
– 200 cm-1
at a resolution of 2 cm-1
).
6. Background scans were performed before each measurement. The sample holder was
loaded into the spectrometer and IR spectra were obtained. Measurements were made at room
temperature.
7. IR spectra were processed using OMNIC 5.1 (Nicolet Instrument Corporation).

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2.1.2. Nuclear Magnetic Resonance Spectroscopy of Metal Complexes
Nuclear magnetic resonance (NMR) spectroscopy is to a synthetic chemist as a paintbrush is
to an artist or cement is to a builder. It is the greatest tool in enabling their work. NMR
spectroscopy is the most effective method used to elucidate the structure of unknown
products and is the best form of proof that a desired product has been successfully
synthesised.
In essence, NMR spectroscopy measures the interaction of magnetically active nuclei with a
large external magnetic field. The degree of interaction with this magnetic field (chemical
shift) is indicative of the environment in which the nucleus in question exists.
A magnetic pulse of a specific radiofrequency (Hz) excites magnetic nuclei from an α-spin
state (+1/2) to a β-spin state (-1/2). Upon relaxation of the excited nucleus to the α-spin state,
a magnetic pulse of a certain frequency is released. The frequency emitted corresponds to the
difference in energy of the two spin states. This frequency is known as the Larmor Frequency
and the ratio between it and the excitation pulse frequency is used to obtain the chemical shift
(δ) of the nucleus in question.
The chemical shift of each signal provides information on the environment of the nucleus in
question i.e. of what functional group is the signal characteristic. These signals can undergo
splitting arising from interactions (coupling) with proximate magnetic nuclei. This is called
the multiplicity of the signal. Furthermore, the integration of a signal provides information on
the amount of equivalent nuclei that are involved in the emission of this signal. NMR spectra
generally contain well-defined signals and a combination of these parameters are used to
elucidate structures of compounds with a high level of certainty.
Unfortunately, this is not always the case. Often an undesired occurrence called ‘linewidth
broadening’ arises in the NMR spectra of compounds containing quadrupolar nuclei.
Quadrupolar nuclei are those that possess asymmetrical electric fields such that their nuclear
magnetic spin number I >
1
2
. These nuclei possess several excited energy states of similar
energy. The excited nuclei can exist in many of these similar high-energy states for very short
time periods. Overall, this results in rapid relaxation to the ground state, which broadens the
signal corresponding to this nucleus or to nuclei that are coupled to this quadrupolar nucleus
27
. Mn(I) is a quadrupolar nucleus (I >
1
2
) and as a result, the NMR spectra collected for the

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manganese containing complexes in this project suffered from high levels of linewidth
broadening. An example is provided in Fig2.3.
Figure 2.3: 1
H NMR of Compound (6)
Training: JEOL 400 MHz NMR ECX-400 Spectrometer.
1. A vial containing 0.75 ml of the desired deuterated solvent was opened and ~ 10 mg of
analyte sample was added.
2. The solution was homogenised using a Pasteur pipette to empty and refill the vial.
3. The solution was transferred to an NMR tube and was subsequently submitted to the NUIG
NMR Centre.
4. NMR spectra were processed using MestReNova version 11.1 (Mestrelab Research S.L.)
2.2. Monitoring reaction progression
2.2.1. Thin-layer Chromatography (TLC)
The first attempt of the synthesis of (4) following Route A(i) was deemed unsuccessful after
examination of spectroscopic data. It was suggested that the synthesis had failed because the
reaction had not been allowed sufficient time to proceed due to the high concentrations of
residual reagents. The reaction was reattempted on 15/1/2019 and was allowed a longer
reaction time of 2 days under stirring as opposed to 12 hours allowed in the first attempt.
To ensure the reaction proceeded to completion in the second attempt, TLC was used in order
to monitor the reaction progression.

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TLC separates mixtures into their individual components based on their polarity. TLC
involves the use of a stationary phase and a mobile phase. The polar interactions between the
individual components and the mobile phase determines the rate at which the components
travel up the plate 28
. A drop of each reagent, the reaction mixture and a combination are all
placed at the same height on the TLC plate. Comparison of each of the spots with another is
used to determine if the reaction has proceeded to completion, i.e. the reagent spots are no
longer present in the reaction mixture. The plates were stained with potassium permanganate
to enhance the visualisation of the spots under UV irradiation.
Figure 2.3: TLC silica plates prepared during experimental procedure Route A(i) in order of production.
As observed (fig 2.3), the Mn-reagent and the Zn-reagent spots diminished over time.
However, the reaction was not a success and the spots of both reagents can be observed in the
reaction mixture section of the final plate.
TLC was performed with Merck 60F254 silica gel coated aluminium sheets as the stationary
phase. Ethyl acetate (CH3COOC2H5) was selected as the mobile phase.

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3. Objectives and aim of project
Utilisation of glycomimetic ligands to gain access within the cancerous cell membrane via
GLUT-mediated cellular internalization wherein a cytotoxic metal complex can induce its
effect; forms the rationale to which this research project is based upon. Moreover, the
likening of the cytotoxic metal-drugs to Greek soldiers hiding within the glycoconjugate
ligand Trojan horse that is used to get inside cell membrane Walls of Troy forms a splendid
analogy.
Figure 1.3: Motif of Trojan horse and smart bomb analogy. [Generated with ChemDraw]
In synthesising potential anticancer agents, we begin with the cytotoxic metal complex,
identifying a cellular bomb, and then using a dithiocarbamate-isonipecotamide scaffold,
stabilise the metal complex in physiological conditions and provide a binding site to allow the
formation of a glycoconjugate.
The aim of this final year thesis project is to fully synthesise and characterise compounds (4),
(6) and (7).
A Manganese (I) CORM of the type [Mn(I)-(dtc-Inp)-(CO)4] was selected for development in
this research project. A glycoconjugate of this CORM can potentially display selectivity
towards tumour cells via GLUT mediated cellular internalization and can release CO
molecules under the oxidative stress experienced in cancerous cells, thus inducing cell death.

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[Mn(I)(dtc-Inp)(CO)4] (4) [Mn(I)(dtc-Inp-(1-OMe-glucosamine))(CO)4] (6)
Compound (4) was synthesised to serve as a model with which (6) would be compared
against. Compound (6) was already available. However, a greater quantity of this compound
was desired for further testing by collaborators. This project aimed to synthesise and purify
more of this compound following the same procedures designed by Pettenuzzo in his PhD
thesis.
A novel di-iron(II) metallocene (2r) was identified as a desirable metal centre to attempt
glycoconjugation with the dithiocarbamate chosen for this project (Fig 1.4) to produce
compound (7). This di-iron(II) compound was first synthesised by Fabio Marchetti et al. and
was shown to exhibit cytotoxic properties, the mode of action remains unclear.1
[Fe2(µ-CNMeXyl)(µ-CO)(CO)2(Cp)2](CF3SO3) (2r)
[Fe2{(µ-CNMe(Xyl))(µ-CO)(CO)(Cp)2}(dtc-Inp-NH2] (7)

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Compound (7) will serve as a model compound for future glycoconjugate compounds
developed of the type: [Fe2{(µ-CNMe(Xyl))(µ-CO)(CO)(Cp)2}(dtc-Inp-Glu)]. This
compound has not previously been synthesised, however similar compounds have. The
synthetic procedure used to synthesize this compound were based on methods developed by
Fabio Marchetti et al 1
.
Both (6) and (7) have been synthesised and characterised in this project.
4. Results and Discussion
The synthetic routes performed to obtain the targeted products (4), (6) and (7) are described
in this section.
Route A was the approach taken to synthesise (4). This route was initially carried out via
attempted transmetallation of [Zn(dtc-Inp-NH2)2] (1) with [Mn(I)Br(CO)5] (4r). This method
(Route A(i)) proved to be unsuccessful after examination of NMR and IR spectroscopy of the
obtained product. However, Route A(ii) proved successful in synthesising (4) by reacting (4r)
with the already available sodium salt [Na(dtc-Inp-NH2)] (1a) that occurs in the first step in
the synthesis of (1).
Route B was the procedure carried out to synthesise (6). The first step required the synthesis
of (5). (5) was used to transmetallate the dithiocarbamato scaffold and the bound amino sugar
to the metal centre (4r). Two reagents were used in the first step of this synthesis (5a) and
(5b). [Zn(dtc-Inp-OSuccinimide)2] (5a) was synthesised by reacting Na2[Zn(dtc-Inp-O)-
2]·2H2O (5r) and TSTU in DMF. [1-OMe-2-deoxy-2-amino-(α,β)-D-glucopyranoside] (5b)
was previously purified and characterised by another member of the research group. This
synthetic procedure successfully yielded (5). The second step of Route B describes the
synthetic procedure that was successfully carried out to synthesise the target compound (6).
Route C was the synthetic procedure undertaken to synthesise (7) successfully. This
procedure first required the activation of [FeII
2(µ-CNMeXyl)(µ-CO)(CO)2(Cp)2](CF3SO3)
(2r) to [FeII
2(µ-CNMeXyl)(µ-CO)(CO)(NCMe)(Cp)2](CF3SO3) (2) by treatment with
anhydrous trimethylamine ((CH3)3NO) in acetonitrile (CH3CN), obtaining the compound (2).
Finally the resulting compound (2) was treated with (1a) obtaining the target compound (7).

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4.1. Route A
Scheme 1. Synthetic route to [Mn(I)(dtc-Inp)(CO)4] (4)
Scheme 1 above demonstrates the two methods attempted to synthesise (4). Each precursor
and product was analysed using FT-IR. This was also the case with 1
H-NMR, with each
precursor and product being analysed aside from (4r) which contains no protons. Route A(i)
outlined above was not successful. This procedure was attempted on two separate occasions.
No consistent explanation as to why this synthesis proved unsuccessful after two attempts has
been postulated.
Route A(ii) involved the mixing of (1a) with (4r) in methanol for 3 hours under reflux at a
maintained temperature of 40°C to obtain the product (4). The quadrupolar nucleus of
manganese(I) made characterisation with 1
H-NMR difficult to achieve. Signals were assigned
(Fig 4.1.), yet FT-IR was relied on more in this case to confirm to success of the synthesis.

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Figure 4.1. 1
H-NMR spectrum of (4) in DMSO-d6.
The stacked 1
H-NMR spectra below in (Fig 4.2.) showed the presence of characteristic
signals of the (dtc-Inp-NH2) in the product synthesised and the reagent (1a). The signals δ
7.36 (s, 1H, NH cis), δ 6.88 (s, 1H, NH trans) had very slightly shifted downfield compared
to the reagent (1a) that produced signals at δ 7.22 (s, 1H, NH cis), δ 6.69 (s, 1H, NH trans).
The signal at δ 1.46 (br. m, 2H, C3ˈ,5ˈ
Hax) produced by (4) was in agreement with the signal at
δ 1.40 (qd, 2H, C3’,5’
Hax) in the 1
H-NMR spectrum of (1a). Although these signals were an
indication of the presence of the (dtc-Inp-NH2) ligand in the reaction product, it could not be
confirmed that this ligand was bound to the MnI
metal centre from the NMR data alone. FT-
IR data was used to confirm that the ligand was bound to the metal centre and that the desired
product (4) was present in the ochre-yellow coloured powder obtained from the reaction
scheme.

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Figure 4.2. 1
H-NMR stacking of compound (4) and (1a) in DMSO-d6.
FT-IR data in the mid-IR range of the product (4) and the reagents (4r) and (1a) is presented
in Figure 4.3. Presence of the (dtc-Inp-NH2) ligand is observed by the characteristic (ν, N-
CSS) stretching mode at 1502.17 cm-1
in the case of (4) and at 1472 cm-1
for (1a). An amide
carbonyl stretch is detected in the mid-IR spectrum of (4) at 1667.52 cm-1
, with a similar peak
at 1643 cm-1
present in the mid-IR spectrum of (1a). Further evidence of the dithiocarbamato
ligand in the product compound (4) is given by the characteristic (νa, SCS) at 1013.26 cm-1
with a similar peak appearing at 1004 cm-1
in the spectrum of (1a). Four stretching
frequencies of C=O are expected in the mid-IR range of the desired product as it would
indicate that the MnI
centre has had a CO group substituted by the chelation of the two sulfur
atoms. Unfortunately, the overlap of the C=O stretching frequencies in the mid-IR spectrum
of (4) 2085.13/1986.19/1909.24 cm-1
(ν, C=O) made it difficult to decipher the amount of
different C=O bonds present and as such, the synthesis could not be deemed successful from
this information. However, examination of the Mn-CO bending frequencies yielded
promising results. In the mid-IR spectrum of (4r) a broad and intense peak at 616.05 cm-1
suggests the overlap of several δ Mn-CO absorptions. In the mid-IR spectrum of (4) however,
two sharp intense δ Mn-CO peaks at 662.79 cm-1
and 626.78 cm-1
suggest that there is one
less Mn-CO bond present in the product compound (4) as the broad overlapping peak is no
longer visible.
NH cis & trans
NH cis & trans
ans
NH cis & trans

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Figure 4.3. Mid-IR stacking (4000 cm-1
– 400 cm-1
) of (4), (4r), and (1a) (CsI disk).
Figure 4.4. presents the stacked far-IR spectra of (4), (4r) and (1a). The new band observed
at 369.57 cm-1
(νa, S-Mn-S) confirms that the dithiocarbamato ligand has coordinated with
the MnI
metal centre and (4) has been successfully obtained. Further evidence is provided by
the disappearance of the Mn-Br stretch at 219.77 cm-1
of the reagent in the spectrum of (4).
Figure 4.4. Far-IR stacking (600 cm-1
– 200 cm-1
) of (4), (4r), and (1a) (CsI disk).
(ν, N-CSS)
(ν, N-CSS)
(δ, Mn-CO)
(δ, Mn-CO)
(νa, SCS)
)
(νa, SCS)
(νa, S-Mn-S)
)
(ν, Mn-Br)
[MnI
(dtc-Inp-NH2)(CO)4] (4)
[MnI
Br(CO)5] (4r)
[Na(dtc-Inp-NH2)] (1a)
[MnI
(dtc-Inp-NH2)(CO)4] (4)
[MnI
Br(CO)5] (4r)

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4.2. Route B
Scheme 2. Synthetic route to [MnI
(dtc-Inp-(1-OMe-glucosamine))(CO)4] (6)
Each precursor and reagent displayed in Scheme 2 above was characterised by FT-IR, 1
H-
NMR and 13
C-NMR spectroscopy where possible. (5) was synthesised by mixing suspensions
of (5a) and (5b) in DMF with DIPEA. A yield of 36.3% of compound (5) was obtained and
after characterisation with 1
H-NMR and FT-IR spectroscopic data was deemed adequate for
transmetallation with (4r) to obtain the CORM-glycoconjugate (6). Zinc dithiocarbamate
compounds are effective in performing transmetallation reactions with transition metals.29
The 1
H-NMR spectrum of (5) (Fig4.5.) showed a doublet at δ 7.78 ppm. This signal

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corresponds to (R-NH-R) proton, which suggests that the amino sugar had formed, with the
doublet multiplicity being attributed to scalar coupling with the proton bound to the carbon
atom in the 2’-position of the sugar. There is no signal further downfield than δ 4.56 ppm in
the 1
H-NMR spectrum of the sugar (5b) (Fig4.6.).
Figure 4.5: 1
H-NMR spectrum of (5) in DMSO-d6
(d, 2H, R-NH-R)

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Figure 4.6: 1
H-NMR spectrum of (5b) in DMSO-d6
The FT-IR spectrum in the mid-IR range of (5) (Fig4.7.) lends further proof of the amide
which is not existent on either of the starting reagents (5b) and (5a). The bending of the
amide (δip, CNH) at 1557.18 cm-1
confirms the successful synthesis of (5).
Figure 4.7. Mid-IR spectrum (4000 cm-1
– 400 cm-1
) of (5) (CsI disk).

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A solution of (5) in DMF was added dropwise to a solution of [MnI
Br(CO)5] in 1:1
DMF/Acetone under stirring and protected from UV radiation in a flask covered in foil. The
reaction mixture was stirred at r.t. in the dark for 4.5 hrs to yield compound (6). The
percentage yield was 130% suggesting that unfiltered ZnBr2 salt remained in the ochre-
yellow powder obtained. Characterisation of this compound was performed solely using FT-
IR spectroscopic data due to the difficulty that arose in attaining decipherable NMR spectra
with the quadrupolar nucleus of MnI
.30
The synthesis and characterisation of the model
compound (4) was of great assistance in the characterisation of compound (6). As with
compound (4), the presence of the (νa, S-Mn-S) absorbance at 379.58 cm-1
and (νs. SCS) at
520.43 cm-1
in the far-IR spectrum confirmed that the transmetallation reaction was
successful and that the chelating dithiocarbamto ligand had coordinated to the MnI
metal
centre. These values obtained from the far-IR spectrum for compound (6) provided in Figure
4.8 below, were in agreement with the literature.22
Figure 4.8. Far-IR spectrum (600 cm-1
– 200 cm-1
Further proof that the desired compound (6) had been synthesised was given by the mid-IR
spectrum obtained (Fig.4.9.). In this case, there were sharp peaks at 2084.46 cm-1
, 2030.24
cm-1
, 2010.00 cm-1
and 1930.59 cm-1
which each represented a different C=O stretch. This is
indicative of the desired product, which is expected to possess four coordinated C=O groups,
each within a different chemical environment.

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Figure 4.9. Mid-IR spectrum (4000 cm-1
– 600 cm-1
Comparing the differences between the mid-IR spectra of model compound (4) and (6) can
demonstrate the presence of the gylcoconjugate in (6) (Fig4.10.). The (δip, CNH) at 1607.19
cm-1
in the mid-IR spectrum of (4) is replaced by (δip, CNH) at 1511.81 cm-1
. The decrease in
energy required to enact this particular bending vibration in (6) suggests that in the place of
the small hydrogen atom bound to the nitrogen in (4) is now a larger molecule, such as a
sugar. As discussed in section 2.1.1. larger molecules require lower amounts of energy to
vibrate.24

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Figure 4.10. Stacked mid-IR spectra of (6), (4) and (5).
The aim of this project was to synthesise compound (6) and based on the evidence provided
from the FT-IR spectra presented in this section, it has been confirmed that this compound
has been synthesised.

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4.3. Route C
Scheme3. Synthetic route to [FeII
2{(µ-CNMe(Xyl))(µ-CO)(CO)(Cp)2}(dtc-Inp-NH2] (7)
Each precursor and reagent displayed in Scheme 3 above was characterised by FT-IR and
NMR spectroscopy. The first step of this reaction scheme involved the activation of
compound (2r) to the active compound (2). This step involved the substitution of a terminal
CO group with an acetonitrile (NCMe) group. This substitution increases the reactivity of the
di-ironII
complex as the more labile NCMe group allows for nucleophilic attack of one of the
ironII
atoms to occur more readily.31
(2r) was synthesised by dissolving (2) and trimethyl
amine in acetonitrile under stirring and inert N2 atmosphere for 1 hr. The first attempt of this
synthesis was deemed a failure upon examination of the 1
H-NMR spectrum obtained which
was indecipherable (Fig4.11.). It was eventually established that the poor quality of the
spectrum obtained was due to the reaction of the synthesised product with the NMR solvent
DMSO-d6, and not the failure of the synthesis itself. The synthesis was reattempted and the
1
H-NMR spectroscopy of (5) was performed using CDCl3 as the NMR solvent.

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Figure 4.11. Indecipherable 1
Substitution of the CO with NCMe will result in the two ironII
atoms becoming non-
equivalent. The presence of two isomeric forms of (2) can serve as evidence of the success of
this substitution. From examination of the 1
H-NMR spectrum of (2r), distinct singlets are
observed for cyclopentadienyl signals. In the 1
H-NMR spectrum of (2), there are several
overlapping signals observed for the cyclopentadienyl groups due to the presence of two
unequivalent FeII
atoms and two isomeric forms of (2). The signals of lower intensity
represent the minor isomer. These observations are displayed in Figure 4.12.
Figure 4.11. 1
H-NMR stacking of (2) and (2r).
multiple signals of Cp observed
singlet signals of Cp

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The second step in Scheme3 above details the synthesis of the desired final compound (7).
Compound (7) was synthesised by treatment of a solution of (2) in THF with a suspension of
(1a) in THF. 1
H-NMR spectroscopy in CDCl3 was used to characterise this compound
(Fig4.12.). Signals at δ 5.19 ppm (d, 2H, C2’,6’
Heq), δ 3.29 ppm (m, 2H, C2’,6’
Hax), δ 2.46 ppm
(m, 1H, C4’
H), δ 1.97 ppm (m, 2H, C3’,5’
Heq) and δ 1.85 ppm (m, 2H, C3’,5’
Hax) confirmed the
presence of the dithiocarbamto-isonipecotamide ligand in the product of the synthesis.
Additionally, the signals at δ 5.55 ppm (s, 1H, HNH, (cis)) and δ 5.44 ppm (s, 1H, HNH,
(trans)) provided further evidence of the presence of the isonipecotamide group in the
obtained synthetic product (7). However, examination of FT-IR spectroscopic data was relied
on to provide evidence of the coordination of sulfur to the nucleophilic attack susceptible
ironII
atom.
Figure 4.12. 1
H-NMR spectrum of (7) IN CDCl3. Signals circled in green are indicative of isonipecotamide.
Similar to the other synthetic products discussed previously, the identification of a metal-
sulfur stretching absorbance in the far-IR spectrum was integral to proving the success of the
synthesis proposed in Scheme3. The stacked far-IR spectra of compound (7), (2) and (1a)
presented below (Fig4.13) shows the appearance of an absorbance at 434.25 cm-1
in the
spectrum of (7). This is not present in the other two spectra (2) and (1a). This peak is

of 52
assigned to the stretching vibration of Fe-S. This peak, is weak in intensity owing to the
structure of the synthesised molecule (7) in which this bond is not greatly polarised.
Figure 4.13. Stacked far-IR spectra (600-200 cm-1
) of (7), (2) and (1a).
The mid-IR spectrum of (7) (Fig4.14.) displays the the characteristic (νa, CSS) stretching
mode at 920.44 cm-1
which lends further proof of the presence of the (dtc-Inp-NH2) ligand.
Figure 4.14. Mid-IR spectrum (4000-600 cm-1
) of synthetic product (7).
434.25 cm-1
(ν, Fe-S) (7)
(2)
(1a)

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5. Conclusions
Synthesis of the desired MnI
-glycoconjugate CORM compound (6) had been achieved in this
project, following methods developed by Andrea Pettenuzzo in his PhD thesis.22
This
successful synthesis provides evidence of the effectiveness of dithiocarbamates as scaffolds
in the development of metal-glycoconjugates. Future development of similar MnI
-
glycoconjugate CORMs with variety in the sugar utilised can be achieved from replication
these methods. Potentially, an ideal MnI
-glycoconjugate CORM with suitable bioactivity,
selectivity for tumour cells and suitable solubility can be developed.
Although there was insufficient time available to synthesize a novel di-iron glycoconjugate in
this project period, the novel di-iron dithiocatbamato-isonipecotamide complex that was
synthesised successfully, compound (7), can serve as an appropriate model compound to
compare future glucoconjugates developed of the type [Fe2(dtc-Inp-Glu)] against. The range
of metals from which metal glycoconjugate anticancer agents can be engineered with, has
potentially increased with the successful synthesis of (7). The successful coordination of the
dithiocarbamato-isonipecotamide ligand to the di-ironII
complex provides evidence of the
versatility and usefulness of this ligand as an effective scaffold for the synthesis of metal-
glycoconjugate anti-cancer agents.

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6. Experimental
6.1. Materials
Isonipecotamide, CS2,[Zn(OAc)2],(α,β)-D-glucosamine hydrochloride, N-acetyl-(α,β)-D-
glucosamine, DIPEA, MeOH, NaOH, P2O5, CsI, trimethylamine ((CH3)3NO), acetonitrile
(CH3CN), HCl (37%), HNO3(65%), DMF, acetone, diethyl ether, hexane, silica gel,
potassium permanganate, DCM, [MnI
Br(CO)5], [FeII
2(µ-CNMeXyl)(µ-CO)(CO)2(Cp)2](CF-
3SO3), THF, DMSO-d6, CDCl3-d3, MeOD-d4.
6.2. Instrumentation
6.2.1. Perkin-Elmer Frontier 400 FT-IR Spectrophotometer
FT-IR spectra were recorded in solid CsI disks at room temperature in the range 4000-400 cm-
1
(32 scans, resolution 4 cm-1
) for Mid-IR spectra and in the range 600-200 cm-1
(32 scans,
resolution 2 cm-1
) for Far-IR spectra. Data was processed using OMNIC version 5.1 (Nicolet
Instrument Corporation).
6.2.2. JEOL 400 MHz NMR ECX-400 Spectrometer
NMR spectra were acquired using the appropriate deuterated solvent at room temperature. This
spectrometer was equipped with z-field gradients. Data was processed using MestReNova
version 11.1 (Mestrelab Research S.L.) The typical acquisition parameters for 1D 1
H-NMR
spectra (1
H: 399.78 MHz) were as follows: 16 transients, spectral width 6.0 kHz, 16k data
points, relaxation delay 1.0 s. Spectra were processed using exponential weighting with a
resolution of 0.5 Hz and a line-broadening threshold of 0.1 Hz. Typical acquisition parameters
for 1D 13
C NMR spectra (13
C: 100.53 MHz): 512 transients, spectral width 25.1 kHz, 32k data
points, relaxation delay 2.0 s. The pulse sequence was optimized for proton-decoupling at
1
J(13
C,1
H) = 145 Hz. Spectra were processed using exponential weighting with a resolution of
2.0 Hz and a line-broadening threshold of 2.5 Hz.
1
H and 13
C chemical shifts were referenced to TMS at 0.00 ppm via internal referencing to the
residual peak of the deuterated solvent employed.

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6.3. Synthesis and Characterisation
6.3.1. Route A
[ZnII(dtc-Inp-NH2)2] (1)
(155 mg, 3.88 mmol) NaOH was dissolved in 5 ml MeOH and was added dropwise to a
solution of (500 mg, 3.9 mmol) isonipecotamide in 5 ml MeOH under stirring. This solution
was cooled to 0°C in an ice-bath. (235 µL, 3.9 mmol) Carbon Disulfide (CS2) was added
dropwise to the cooled solution (pH = 10). Solution turned yellow colour. After 3hrs stirring,
pH dropped to ~ 7.5 and an additional (235 µL, 3.9 mmol) CS2 was added dropwise. Solution
was placed in fridge overnight for 17 hrs at 4°C. This solution was added dropwise to (430
mg, 1.95 mmol) of ZnII
(OAc).H2O in 1 ml distilled water under stirring. A white coloured
precipitate formed. The precipitate was centrifuged at 3100 rpm and washed with H2O (3 x
15 ml). The precipitate was dried under vacuum over P2O5 to yield a white solid. Compound
(B) was obtained (746 mg, 87.01% yield). MW: 439.978 g mol-1
.
1H-NMR (400 MHz, DMSO-d6, 298K, δ, ppm): 7.37 (s, 2H, NH cis), 6.88 (s, 2H, NH trans),
4.84 (d, 4H, C2ˈ,6ˈ
Heq), 3.27 (m, 4H, C2ˈ,6ˈ
Hax), 2.41 (tt, 2H, C4ˈ
H), 1.83 (m, 4H, C3ˈ,5ˈ
Heq),
1.55 (m, 4H, C3ˈ,5ˈ
Hax). 13C-NMR (100 MHz, DMSO-d6, 298 K, δ, ppm): 202.3 (NCSS),
175.62 (C=O), 50.73 (C2ˈ,6ˈ
H2), 40.14 (C4ˈH)(overlap with solvent signal), 28.36 (C3ˈ,5ˈ
H2).
FT-IR (CsI disk, 𝜈̅max, cm-1
): 3437.99/3329.71/3208.09 (br, νa/s, NH2), 1668.52 (vs, C=O
(amide I)), 1493.01 (s, ν, N-CSS), 1007.39 (νa, SCS), 531.77 (νs, SCS), 391.78 (νa, ZnS4).
Spectroscopic data is in agreement with literature values.22

of 52
Figure6.1: 1
[Mn(I)(dtc-Inp)(CO)4] (4)
A solution of (77.9 mg, 0.301 mmol) Na(dtc-Inp-NH2).CH3OH (1a) in 2 mL MeOH was
added dropwise to solution (82.4 mg, 0.300 mmol) [MnI
Br(CO)5] (4r) in 10 mL MeOH under
stirring in a round-bottomed flask covered in foil to protect (4r) from UV radiation. The
mixture was allowed to stir at 40°C under reflux in inert N2 atmosphere for 3 hrs. A yellow
coloured solution was afforded in the flask after this stirring period. The solution was
evaporated to dryness. A red oily substance remained after evaporation. 20 mL of diethyl
ether was added and the substance was triturated until the ether had evaporated in air,
yielding a yellow coloured solid. The solid was dissolved in acetone and was subsequently
filtered to remove insoluble NaBr salts. The filtered solution was evaporated to dryness.
Another trituration with 20 mL of diethyl ether was performed. The ether was evaporated
under a gentle stream of N2 gas. The remaining solid was placed under vacuum and over P2O5
to dry. A fine ochre-yellow coloured powder was obtained. This powder was compound (4)
(69.87 mg, 62.9% yield). MW: 369 g mol-1
.
1H-NMR (400 MHz, DMSO-d6, 298K, δ, ppm): 7.36 (s, 1H, NH cis), 6.88 (s, 1H, NH trans),

of 52
4.61 (br. d, 2H, C2ˈ,6ˈ
Heq), 3.32 (br. d, 2H, C2ˈ,6ˈ
Hax), 1.85 (br. m, 2H, C3ˈ,5ˈ
Heq), 1.46 (br. m,
2H, C3ˈ,5ˈ
Hax). C4ˈ
H not detected (overlap with solvent signal at ca. 2.50 ppm.). 13C-NMR not
obtained due to difficulty in obtaining decipherable spectrum from coupling of carbon-13
nuclei with quadrupolar MnI
nuclei. FT-IR (CsI disk, 𝜈̅max, cm-1
): 3346.97/2931.35 (br. νa/s,
NH2), 2085.13 (ν, C≡O) 1986.19/1909.24 (br. vs, ν, C≡O overlap), 1667.52 (vs, C=O (amide
I)), 1607.19 (δip, CNH (amide II)), 1502.17 (ν, N-CSS), 1013.26 (νa, SCS), 662.79/626.78 (δ,
Mn–CO), 520.11 (ω, νs, SCS), 369.4 (ω, νa, SMnS). Spectroscopic data is in agreement with
literature values.22
6.3.2. Route B
Na2[Zn(dtc-Inp-O)2]·2H2O (5r)
NaOH (.0619 g, 15.48 mmol) dissolved in 15 mL water was added under stirring to a solution
of isonipecotic acid (1 g, 7.74 mmol) in 30 mL methanol. The mixture was stirred for 5 mins
to allow for all reagents to be fully solubilised. The mixture was treated dropwise with CS2
(0.56 mL, 9.29 mmol), and was stirred for 2 hrs in an ice bath. After this period, the mixture
was stirred at r.t. overnight. A solution of [Zn(OAc)2]∙2H2O (0.849 g, 3.87 mmol) in water
was added dropwise to the reaction mixture under stirring over a 3 hr period. A white solid
precipitated in the mixture. The mixture was stored in a fridge at 4 °C overnight. The
precipitate was filtered then washed with methanol (25 mL) and diethyl ether (25 mL). The
white solid was dried under vacuum and over P2O5 to yield compound (5r) as a white solid
(64.9% yield). MW: 228 g mol-1
). 1H-NMR (400 MHz, DMSO-d6, 298K, δ, ppm): 4.64 (s,
2H, C2’,6’
Heq), 3.43 (m, 2H, C2’,6’
Hax (overlap with H2O)), 2.42 (m, 1H, C4
’H), 1.84 (d, 2H,
C3’,5’
Heq), 1.60 (t, 2H, C3’,5’
Hax). FT-IR (CsI disk, 𝜈̅max, cm-1
): 2949.39 and 2856.74 (νa,s
(CH2) + (CH)), 1443.65 (ν, N-CSS), 1005.00 (νa, CSS), 527.42 (νs CSS) + (δ SCS), 395.66
(νa S-Zn-S), 344.49 (δ SCN), 258.97 (δa S-Zn-S).

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[ZnII(dtc-Inp-OSuccinimide)2] (5a)
(500 mg, 9 mmol) of (5r) was solvated in Dry DMF (10 ml) under stirring and inert N2
atmosphere for 20 minutes. 32 µl of DIPEA was added dropwise and the reaction mixture was
allowed to stir for 15 minutes. 600 mg of TSTU was added to the reaction mixture. A 1:1
mixture of ethanol/water was added to the reaction mixture, which led to the formation of a
white precipitate. The precipitate was isolated by filtration and was dried over P2O5 under
vacuum. (31.5% yield). Mw: 668.1 g mol-1
. 1
H-NMR (400 MHz, DMSO-d6, 298K, δ, ppm): 4.74
(m, 4H, C2,’6’
Heq), 3.55 (m, 4H, C2’,6’
Hax), 3.22 (m, 2H, C4
’H), 2.82 (s, 4H, CH2), 2.10 (d, 4H, C3’,5’
Heq),
1.71 (m, 4H, C3’,5’
Hax). 13
C-NMR (100 MHz, DMSO-d6, 298 K, δ, ppm): 203.73 (NCSS), 170.64 (C=O
(succ)), 169.80 (C=O (ester)), 51.03 (C2’,6’
), 36.77 (C4
’), 31.23 (C3’,5’
), 25.93 (CH2 (succ)). FT-IR (CsI
disk, 𝜈̅max, cm-1
): 1816.62 (νip, C=O (succinimidyl)), 1784.29 (δ, νoop, C=O succ), 1719.18 (νs, ν, C=O,
ester), 1496.96 (ν, N-CSS), 1266.35 (ν, C-OSu), 988.62 (νs, νa SCS) 566.28 (νs SCS), 371 (νa, ZnS4).
[ZnII(dtc-Inp-(1-OMe-glucosamine))2] (5)
A mixture of 1-OMe-2-deoxy-2-amino-(α,β)-D-glucopyranoside (5a) (165 mg, 0.86 mmol)
and N,N-diisopropylethylamine (DIPEA, 47.5 µL, 0.272 mmol) was suspended in 2 mL of
dry DMF under stirring and inert N2 atmosphere. A suspension of [Zn(dtc-Inp-
OSuccinimide)2] (5b) in 2 mL dry DMF was added dropwise to the mixture under stirring.
The reaction mixture was stirred under inert N2 atmosphere at r.t. for 17 hrs. 30 mL of MeOH
was added and a white precipitate formed. The solid was centrifuged at 3100 rpm and washed
with MeOH (3 x 15 mL). NMR characterisation of this solid revealed that it was not the

of 52
desired product. Solids had precipitated overnight in the mother solution that was removed
during centrifugation and placed in a fridge at 4°C. This precipitate was centrifuged and
washed with MeOH (2 x 10 mL). The precipitate was dried under vacuum and over P2O5 to
yield a white solid (5) (81 mg, 36.3% yield). MW: 820.24 g mol-1
.
1H-NMR (400 MHz, DMSO-d6, 298K, δ, ppm): (the following signals refer to the α-anomer
conformation of the sugar. The signals for the β-anomer were not detectable.) 7.78 (d, 2H,
NH), 4.97 (d, 2H, C4’
OH), 4.81 (m, 4H, C2ˈ, 6ˈ
H eq), 4.69 (d, 2H, C3’
OH), 4.54-4.50 (m, 4H,
C1’
H + C6’
OH), 3.67-3.63 (m, 4H, C2’
H + C6’
H), 3.49-3.47 (m, 4H, C3’
H + C6’
H’), 3.43 (m,
6H, C5’
H + C2ˈ,6ˈ
Hax), 3.29 (s, 6H, OCH3), 3.15-3.10 (m, 2H, C4’
H), 2.54 (m, 2H, C4ˈ
H), 1.82-
1.76 (m, 4H, C3ˈ,5ˈ
Heq), 1.62-1.57 (m, 4H, C3ˈ,5ˈ
Hax). 13C-NMR (100 MHz, DMSO-d6, 298 K,
δ, ppm): A 13
C-NMR spectrum of experimental quality could not be obtained, as the signals
were too weak to be identified. Multiple attempts to obtain an intelligible spectrum proved
unsuccessful. An example of the 13
C-NMR spectrum is provided below in Fig5.1. FT-IR
(CsI disk, 𝜈̅max, cm-1
): 3299.83 (br. ν, NH), 2932.43 (ν, OH), 1645.13 (ν, C=O (amide I)),
1557.18 (δip, CNH (amide II)), 1492.8 (ν, N-CSS), 1061.97/1040.68 (vs, ν, C-OH + C1’
-O-
CH3 overlap), 950.51 (νa, SCS), 577.11 (νs, SCS), 382.81 (νa, ZnS4). Spectroscopic data
provided is in agreement with literature values.22
Fig6.3: 1
H-NMR spectrum of (5) in DMSO-d6.

of 52
Fig6.3: 13
C-NMR spectrum of (5). the signals are too weak and are not observed.
[MnI(dtc-Inp-(1-OMe-glucosamine))(CO)4] (6)
A solution of (22 mg, 0.027 mmol) [ZnII
(dtc-Inp-(1-OMe-glucosamine))2] (5) in 3 mL dry
DMF was added dropwise to a solution of (14.9 mg, 0.054 mmol) [MnI
Br(CO)5] (4r) in 1:2
dry DMF/acetone under stirring and protected from UV radiation in a flask covered with foil.
The reaction mixture was stirred at r.t. in the dark for 4.5 hrs. A yellow coloured solution was
obtained in the flask after this period. The acetone was removed under the rotary evaporator.
The solution was treated with 60 mL 1:1 ether/hexane, which afforded the precipitation of a
yellow solid. The mixture was stored at - 20°C for the weekend (~66 hrs). The solid that had
settled after this period was centrifuged and the supernatant was removed. The solid was
washed with diethyl ether (2 x 15 mL) and DCM (2 x 15 mL). Upon addition of DCM the
solid turned a red colour. The solid was placed under vacuum and over P2O5 to dry. A fine
ochre-yellow powder (6) was obtained (19.2 mg, 130% yield – misrepresented due to
remaining ZnBr2 salt). MW: 545.52 g mol-1
.
1H-NMR (400 MHz, DMSO-d6, 298K, δ, ppm): Spectrum obtained was unintelligible due to

of 52
linewidth broadening resulting from coupling of 1
H nuclei with quadrupolar MnI
nucleus.
The 1
H-NMR spectrum obtained is displayed in Fig5.2 below. 13C-NMR (100 MHz, DMSO-
d6, 298 K, δ, ppm): Spectrum obtained was unintelligible due to coupling of 13
C nuclei with
quadrupolar MnI
nucleus. FT-IR (CsI disk, 𝜈̅max, cm-1
): 3412.93 (br. ν, NH), 2931.29 (ν,
OH), 2084.46/2030.24/2010.00/1930.59 (vs, ν, C≡O), 1645.55 (vs, ν, C=O (amide I)),
1511.81 (δip, CNH (amide II), 1446.71 (ν, N-CSS), 1056.45 (br. ν, C-OH), 948.51 (νa, SCS),
662.49/627.06 (m. δ, Mn–CO), 520.43 (νs, SCS), 379.58 (νa, SMnS). Spectroscopic data
provided is in agreement with literature values.22
Fig5.2: 1
H-NMR spectrum of (6) obtained in DMSO-d6. Accurate assignment of signals not achievable due to
linewidth broadening caused by coupling of protons with quadrupolar MnI
nucleus.

of 52
6.3.3. Route C
[FeII
2(µ-CNMeXyl)(µ-CO)(CO)(NCMe)(Cp)2](CF3SO3) (2)
Major Isomer Minor Isomer
(107.6 mg, 0.172 mmol) [FeII
2(µ-CNMeXyl)(µ-CO)(CO)2(Cp)2](CF3SO3) (2r) was dissolved
in 10 mL acetonitrile (MeCN) under stirring at r.t. under inert N2 atmosphere. (19.6 mg,
0.261 mmol) anhydrous trimethylamine (Me3NO) was triturated into a fine powder and was
added to the solution of (2r) in MeCN. Mixture was stirred under inert N2 atmosphere for 1
hr. An outlet for CO gas evolved during the reaction was affixed to the reaction flask.
Filtration was performed to remove undesired solids that had formed. Filtered solution was
evaporated to dryness under rotary evaporator and the remaining black-brown coloured
residue was placed under vacuum and over P2O5 to dry. Dark-brown coloured crystalline
powder (2) was yielded (64.4 mg, 59.9% yield). MW: 634.23 g mol-1
.
1H-NMR (500 MHz, CDCl3, 298K, δ, ppm): (‘*’ denotes signal from minor isomer) 7.35–
7.14 (m, 3H, C3’,4’,5’,
-H (Xyl)), 5.13 (s, 5H, Cp*), 5.01 (s, 5H, Cp) 4.87 (s, 3H, N(CH3)), 4.44,
(s, 5H, Cp), 4.33 (s, 5H, Cp*), 2.69 (s, 6H, C2’
-CH3 (Xyl)), 2.45 (s, 6H, C6’
-CH3 (Xyl)*), 2.15
(s, 6H, C6’
-CH3 (Xyl)), 2.02 (s, 3H, NCMe), 1.96 (s, 3H, NCMe*). 13C-NMR (125.7 MHz,
CDCl3, 298 K, δ, ppm): 264.4 (µ-CO), 211.5 (CO), 148.4 (C1’
(Xyl)),133.0 (C2’
H (Xyl)),
132.7 (C6’
H (Xyl)), 131.5 (CNMe), 130.4 (C5’
H (Xyl)), 129.2 (C3’
H (Xyl)), 129.1 (C4’
H
(Xyl)), 89.1 (Cp*), 88.0 (Cp), 87.8 (Cp), 86.9 (Cp*). FT-IR (CsI disk, 𝜈̅max, cm-1
): 3109.31
(ν, CH (Cp)), 2990.53 (ν, CH (Xyl)), 2116.18 (ν, CN), 1967.06 (ν, CO terminal), 1800.06 (ν,
µ-CO), 1519.73 (ν, CN), 444.49 (ν, Fe-Cp), 412.71 (ν, Fe-NCMe), 392.19 (ν, Fe-CO
terminal), 350.62 (ν, Fe-µ-CO), [1257.06/1222.59/1148.33/1028.70 (νa, νs, intense bands due
to counter-ion CF3SO4). Spectroscopic data provided is in agreement with literature values.31

of 52
[FeII
2(µ-CNMeXyl)(µ-CO)(CO)(dtc-Inp-NH2)(Cp)2] (7)
(61.1 mg, 0.096 mmol) [FeII
2(µ-CNMeXyl)(µ-CO)(CO)(NCMe)(Cp)2](CF3SO3) (2) was
dissolved in 15 mL THF and was treated with a suspension of (29.1 mg, 0.113 mmol) (1a) in
5 mL THF under stirring at 69°C in inert N2 atmosphere under reflux for 45 mins. Black-
brown coloured precipitate had formed after this reaction period. The mixture was stored at -
20°C for the weekend (~ 66 hrs). The mixture was centrifuged and the supernatant was
removed and evaporated under rotary evaporator. A black-brown coloured residue was
obtained and was dried under vacuum over P2O5. The black-brown coloured precipitate was
centrifuged and washed with water (3 x 15 mL) and acetone (3 x 15 mL). The precipitate was
dried under vacuum over P2O5. NMR and IR spectroscopy revealed that the obtained
precipitate was not the desired product. The residue obtained from the supernatant was
triturated with 4 mL of distilled H2O (insoluble). The residue was centrifuged and washed
with H2O (2 x 10 mL) and was then dried under vacuum over P2O5. A red-brown coloured
powder was obtained. (96.8 mg, 155.6% yield) (the presence of CF3SO3 salt accounts for
inordinate yield). MW: 647 g mol-1
.
1H-NMR (400 MHz, CDCl3, 298K, δ, ppm): 6.81-6.77 (m, 3H, C3’,4’,5’
H (Xyl)), 5.55 (s, 1H,
HNH, (cis)), 5.44 (s, 1H, HNH, (trans)), 5.19 (d, 2H, C2’,6’
Heq), 5.07 (s, 5H, Cp), 4.61 (s, 3H,
NCH3), 4.39 (s, 5H, Cp), 3.29 (m, 2H, C2’,6’
Hax), 2.66 (s, 3H, H3C-Xyl), 2.46 (m, 1H, C4’
H),
2.12 (s, 3H, H3C-Xyl), 1.97 (m, 2H, C3’,5’
Heq), 1.85 (m, 2H, C3’,5’
Hax). FT-IR (CsI disk, 𝜈̅max,
cm-1
): 3437.32-3204.42 (br. νa, νs, NH2), 3110.66 (ν, CH (Cp)), 2948.70/2927.76/2859.84 (ν,
CH, νa, νs, CH2, CH3), 2118.01 (ν, CN), 1966.96 (ν, CO terminal), 1795.12 (ν, µ-CO),
1674.03 (ν, C=O (amide I)), 1614.06 (δ, NH2 (amide II)), 1502.02 (ν, N-CSS), 1444.79 (ν, C-
NH2 (amide III)), 1262.01/1222.06/1159.90/1031.16 (various reagent counter-ion stretches
(CF3SO4)), 920.44 (νa, CSS), 450.36 (ν, Fe-Cp), 434.25 (ν, Fe-S), 395.74 (ν, Fe-CO
terminal), 347.80 (ν, Fe-µ-CO). Spectroscopic data provided is in agreement with literature
values.22, 32

of 52
7. References
1 V. G. Albano, L. Busetto, F. Marchetti, M. Monari, S. Zacchini and V. Zanotti, Zeitschrift fur
Naturforsch. - Sect. B J. Chem. Sci., , DOI:10.1515/znb-2007-0317.
2 R. Casiday and R. Frey, Hemoglobin and the Heme Group: Metal Complexes in the Blood for
Oxygen Transport,
http://www.chemistry.wustl.edu/~edudev/LabTutorials/Hemoglobin/MetalComplexinBlood.ht
ml, (accessed 21 January 2019).
3 D. Goodsell, Cytochrome c Oxidase, http://pdb101.rcsb.org/motm/5, (accessed 11 January
2019).
4 R. Hille, Molybdenum enzymes, .
5 Z. Huaizhi and N. Yuantao, China’s Ancient Gold Drugs, .
6 L. N. Magner, A history of medicine, Taylor & Francis, 2005.
7 R. by P. J. Sadler, Platin. Met. Rev., , DOI:10.1595/147106708X259497.
8 S. P. Fricker, Dalt. Trans., 2007, 0, 4903.
9 L. Kelland, Nat. Rev. Cancer, 2007.
10 L. B. Travis, C. Beard, J. M. Allan, A. A. Dahl, D. R. Feldman, J. Oldenburg, G. Daugaard, J.
L. Kelly, M. E. Dolan, R. Hannigan, L. S. Constine, K. C. Oeffinger, P. Okunieff, G.
Armstrong, D. Wiljer, R. C. Miller, J. A. Gietema, F. E. van Leeuwen, J. P. Williams, C. R.
Nichols, L. H. Einhorn and S. D. Fossa, JNCI J. Natl. Cancer Inst., 2010, 102, 1114–1130.
11 U. Ndagi, N. Mhlongo and M. E. Soliman, Drug Des. Devel. Ther., 2017, 11, 599–616.
12 A. Basu, Sci. Revs. Chem. Commun, 2015, 5, 77–87.
13 D. Hanahan and R. A. Weinberg, Cell, 2000, 100, 57–70.
14 M. G. Vander, L. C. Cantley, C. B. Thompson, C. B. Thompson, M. G. Vander Heiden and L.
C. Cantley, 2015, 324, 1029–1033.
15 A. Pettenuzzo, R. Pigot and L. Ronconi, Metallodrugs, 2016, 1, 36–61.
16 J. ZHENG, Oncol. Lett., 2012, 4, 1151–1157.
17 A. Pettenuzzo, R. Pigot and L. Ronconi, Metallodrugs, , DOI:10.1515/medr-2015-0002.
18 R. G. Pearson and D. H. Busch, Hard and Soft Acids and Bases, 1963.

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19 C. Iccf, Advances in Anticancer Agents in Medicinal Chemistry Volume 2 Edited By : Michelle
Prudhomme, vol. 2.
20 The Chelate Effect - Chemistry LibreTexts,
https://chem.libretexts.org/Courses/Johns_Hopkins_University/030.356_Advanced_Inorganic_
Laboratory/Lab_A%3A_Octahedral_Complexes_and_the_Spectrochemical_Series/The_Chela
te_Effect, (accessed 28 February 2019).
21 A. Ismailova, D. Kuter, D. S. Bohle and I. S. Butler, Bioinorg. Chem. Appl., 2018.
22 A. Pettenuzzo and M. Chem, .
23 G. Gasser, I. Ott and N. Metzler-Nolte, J. Med. Chem., 2011, 54, 3–25.
24 J. T. Burke, J. Chem. Educ., 1997, 74, 1213.
25 Basic types of vibrations and their description with Greek symbols. | Download Table,
https://www.researchgate.net/figure/Basic-types-of-vibrations-and-their-description-with-
Greek-symbols_tbl1_224873040, (accessed 3 March 2019).
26 S. Systems LLC, Infrared Beamsplitters, .
27 I. P. Gerothanassis and C. G. Kalodimos, J. Chem. Educ., 1996, 73, 801.
28 thin layer chromatography,
https://www.chemguide.co.uk/analysis/chromatography/thinlayer.html, (accessed 4 March
2019).
29 M. S. Vickers, J. Cookson, P. D. Beer, P. T. Bishop and B. Thiebaut, J. Mater. Chem., 2006,
16, 209–215.
30 P. S. Ireland, C. A. Deckert and T. L. Brown, J. Magn. Reson., 1976, 23, 485–491.
31 V. G. Albano, L. Busetto, M. Monari and V. Zanotti, J. Organomet. Chem., ,
DOI:10.1016/S0022-328X(00)00337-5.
32 V. G. Albano, L. Busetto, F. Marchetti, M. Monari, S. Zacchini and V. Zanotti, Zeitschrift fur
Naturforsch. - Sect. B J. Chem. Sci., 2007, 62, 427–438.

of 52
8. Appendix
Compound and characterisations obtained from Roberta Bottiglieri.
FT-IR: (CsI disk, ṽmax, cm-1
): 3390.17 (br, ν, O-H (methanol)), 3361.25 (br, νa, NH2),
3198.04 (br, νs, NH2), 1643.32 (vs, C=O (amide I)), 1625.49 (s, δip, CNH2 (amide II)),
1471.63 (s, ν, N-CSS), 1203.27 (s, ν, C-O (methanol)), 1004.24 (s, νa, SCS), 545.10 (νs,
SCS). 1H-NMR: (500 MHz, DMSO-d6, 298 K, δ , ppm): 7.22 (s, 1H, NH (cis)), 6.69 (s, 1H,
NH (trans)), 5.78 (d, 2H, C2ˈ,6ˈ
Heq), 4.09 (q, 1H, OH (methanol)), 3.17 (d, 3H, CH3
(methanol)), 2.83 (td, 2H, C2ˈ,6ˈ
Hax), 2.29 (tt, 1H, C4ˈ
H), 1.61 (dd, 2H, C3ˈ,5ˈ
Heq), 1.39 (qd, 2H,
C3ˈ,5ˈ
Hax). 13C{1H} NMR: (100 MHz, DMSO-d6, 298 K, δ, ppm): 213.5 (NCSS), 176.5
(C=O), 48.6 (C2ˈ,6ˈ
H2), 48.6 (CH3 (methanol)), 42.0 (C4ˈ
H), 28.5 (C3ˈ,5ˈ
H2).
[1-OMe-2-deoxy-2-amino-(α,β)-D-glucopyranoside] (5b)
Compound and characterisations obtained from Andrea Pettenuzzo
1H-NMR: (400 MHz, DMSO-d6, 298 K, δ, ppm): 4.55 (d, 1H, C1’
H α), 4.07 (br, 3.6H, C3’
OH
α+β + C4’
OH α+β + C6’
OH α+β), 3.98 (d, 0.2H, C1’
H β), 3.68-3.64 (m, 0.2H, C6’
H β), 3.62 (dd,
1H, C6
’H α), 3.45 (dd, 1.2H, C6’
H α + C6’
H β (overlap)), 3.38 (s, 0.6H, OCH3 β), 3.31 (ddd,
1H, C5’
H α), 3.26 (s, 3H, OCH3 α), 3.22 (dd, 1H, C3’
H α, C3’
H β), 3.07-3.00 (m, 1.6H, C3’
H β +
C4’
H α+β + C5’
H β), 2.45 (dd, 1H, C2’
H α), 2.40-2.36 (m, 0.2H, C2’
H β), 1.79 (s, 3.2 H,
CH3COO-). 13C{1H} NMR: (100 MHz, DMSO-D6, 298 K, δ, ppm): 174.4 (CH3COO-
),

of 52
104.47 (C1’
β), 99.59 (C1’
α), 77.18 (C3
’ β), 76.13 (C5’
β), 74.40 (C3
’ α), 73.15 (C5
’ α), 70.36
(C4
’ α), 70.13 (C4
’ β), 61.12 (C6
’ β), 60.96 (C6
’ α), 57.25 (C2
’ β), 56.11 (OCH3 β), 56.01 (C2
’ α),
54.38 (OCH3 α), 23.1 (CH3COO-
).
[Fe2(µ-CNMeXyl)(µ-CO)(CO)2(Cp)2](CF3SO3) (2r)
1H-NMR (400 MHz, DMSO-d6, 298K, δ, ppm): 7.43 (m, 3H, C3’,4’,5’,
H (Xyl)), 5.68 (s, 5H,
Cp), 5.00 (s, 5H, Cp) 4.43 (s, 3H, NCH3), 2.63 (s, 3H, C2’
-CH3 (Xyl)), 2.09 (s, 3H, C6’
-CH3
(Xyl)). 13C-NMR (125.7 MHz, CDCl3, 298 K, δ, ppm): 264.4 (µ-CO), 211.5 (CO), 173.8
(CO), 148.4 (C1’
(Xyl)),147.7 (C2’
H (Xyl)), 133.2 (C6’
H (Xyl)), 131.7 (C5’
H (Xyl)), 129.9
(C3’
H (Xyl)), 129.1 (C4’
H (Xyl)), 91.0 (Cp), 89.9 (Cp).
Fig8.1: 1
H-NMR spectrum of (2r) in DMSO-d6

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9. Affidavit
Student Declaration on Plagiarism, Collusion or Copying
I declare that this material, which I now submit for assessment, is my own work and that any assistance
I received in its preparation is fully acknowledged and disclosed in the document. To the best of my
knowledge and belief, all sources have been properly acknowledged, and the assessment task contains
no plagiarism.
I understand that plagiarism, collusion, and/or copying are grave and serious offences and am aware
that penalties could include a zero mark for this assessment, suspension or expulsion from NUI Galway.
I have read the NUI Galway code of practice regarding plagiarism at www.nuigalway.ie/plagiarism.
I acknowledge that this assessment submission may be transferred and stored in a database for the
purposes of data-matching to help detect plagiarism. I declare that this document was prepared by me
for the purpose of partial fulfilment of requirements for the programme for which I am registered with
the AUA. I also declare that this assignment, or any part of it, has not been previously submitted by me
or any other person for assessment on this or any other course of study or another college.
Student Name
___________________________
Student Signature Date

of 52
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