Organometallic chemistry volume38

Specialist Periodical Reports

Edited by Ian J S Fairlamb and Jason M Lynam

Organometallic Chemistry
Volume 38


Organometallic Chemistry
Volume 38



A Specialist Periodical Report

Organometallic Chemistry
Volume 38
A Review of the Recent Literature

Editors
I. Fairlamb and J. Lynam, University of York, UK
Authors
Rory L. Arrowsmith, University of Bath, UK
M.P. Cifuentes, Australian National University, Canberra, Australia
Sarah B.J. Dane, University of Cambridge, UK
Philip J. Harford, University of Cambridge, UK
L.J. Higham, Newcastle University, UK
M.G. Humphrey, Australian National University, Canberra, Australia
Anant R. Kapdi, Institute of Chemical Technology, Mumbai, India
Timothy C. King, University of Cambridge, UK
Sofia I. Pascu, University of Bath, UK

Hubert Smugowski, University of Bath, UK
A.E.H. Wheatley, University of Cambridge, UK
D.S. Wright, University of Cambridge, UK


If you buy this title on standing order, you will be given FREE access
to the chapters online. Please contact with proof of
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Thank you.

ISBN 978-1-84973-376-2
ISSN 0301-0074
DOI 10.1039/9781849734868
A catalogue record for this book is available from the British Library
r The Royal Society of Chemistry 2012
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Preface
Ian J. S. Fairlamb and Jason M. Lynam
DOI: 10.1039/9781849734868-FP005

The format for this Volume follows on from recent publication in this series
with two types of contributions: Critical reviews and comprehensive reviews.
The critical reviews in this Volume discuss both fundamental aspects of
organometallic chemistry and also its interface with other fields of study.
Rory Arrowsmith, Sofia Pascu and Hubert Smugowski discuss how
metal complexes may be applied to biomedical chemistry with a view to
developing novel imaging agents. Building on a report in Volume 37, Lee
Higham describes investigations into how the air-stability of primary
phosphine ligands may be predicted using a combination of experimental
and theoretical studies. Anant Kapdi has reviewed the application of metal
catalyst systems in C–H bond and C–X activation processes, particularly
aligned with organic chemistry.
Comprehensive reviews of the organometallic chemistry in this Volume
detail the literature published in 2010 on the chemistry of metal clusters
written by Mark Humphrey and Marie Cifuentes, the chemistry of the alkali
and coinage metals by Philip Harford and Andrew Wheatley as well as
recent developments in Group 2 (Be-Ba) and Group 12 (Zn-Hg) compounds
by Sarah Dane, Timothy King and Dominic Wright.
This Volume therefore covers many synthetic and applied aspects of
modern organometallic chemistry from various areas of the periodic table.

Department of Chemistry, University of York, York YO51 5DD, UK
E-mail: ;

Organomet. Chem., 2012, 38, v–v | v

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CONTENTS
Cover
Ball and stick representation of
Grubbs generation II catalyst.

Preface
Ian J. S. Fairlamb and Jason M. Lynam

v

New developments in the biomedical chemistry of metal complexes:
from small molecules to nanotheranostic design
Rory L. Arrowsmith, Sofia I. Pascu and Hubert Smugowski
Introduction
Summary
Acknowledgements
Authors
References

1

Air-stable chiral primary phosphines part (ii) predicting the
air-stability of phosphines
Beverly Stewart, Anthony Harriman and Lee J. Higham
Introduction
Conclusions
References

1
26
26
26
27

36

36
45
45

Organomet. Chem., 2012, 38, vii–viii | vii

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Organometallics aspects of C–H bond activation/functionalization
Anant R. Kapdi

1 Introduction
2 Historical background
3 Electrophilic aromatic substitution (SEAr mechanism)
4 Oxidative addition mechanism
5 Concerted metalation deprotonation (CMD)
(s-bond metathesis of C–H bond)
6 Summary
References

48
48
50
51
58
63
67
67

Organo-transition metal cluster complexes

75

Mark G. Humphrey and Marie P. Cifuentes
1 Introduction
2 Theory
3 Medium and high-nuclearity clusters
4 Group 7
5 Group 8
6 Group 9
7 Group 10

8 Group 11
9 Mixed-metal clusters
Abbreviations
References

75
75
76
77
77
82
82
83
83
88
89

Alkali/coinage metals – organolithium, organocuprate chemistry
Philip J. Harford and Andrew E. H. Wheatley
1 The alkali metals
2 Group 11 metals
Abbreviations
References

91
96
106
108

Group 2 (Be–Ba) and group 12 (Zn–Hg)

112

Sarah B. J. Dane, Timothy C. King and Dominic S. Wright
Scope and organisation of the review
References

112
123

viii | Organomet. Chem., 2012, 38, vii–viii

91


Abbreviations
Ac
acac
acacen
Ad
AIBN
ampy
Ar
Ar*
Ar 0 f
arphos
ATP
Azb
9-BBN
BHT

Biim
BINAP
bipy
Bis
bma
BNCT
Bp
bpcd
bpk
Bpz4
But2bpy
t-bupy
Bz
Bzac
cbd
1,5,9-cdt
chd
chpt
CIDNP
[Co]
(Co)
cod
coe
cot
CP/MAS
Cp
CpR

acetate
acetylacetonate

N,N 0 -ethylenebis(acetylacetone iminate)
adamantyl
azoisobutyronitrile
2-amino-6-methylpyridine
aryl
2,4,6-tri(tert-butyl)phenyl
3,5-bis(trifluoromethyl)phenyl
1-(diphenylphosphino)-2-(diphenylarsino)ethane
adenosine triphosphate
azobenzene
9-borabicyclo[3.3.1]nonane
2,6-dibutyl-4-methylphenyl
biimidazole
2,2 0 -bis(diphenylphosphino)-1,1 0 -binaphthyl
2,2 0 -bipyridyl
bis(trimethylsilyl)methyl
2,3-bis(diphenylphosphino)maleic anhydride
boron neutron capture therapy
biphenyl
4,5-bis(diphenylphosphino)cyclopent-4-ene-1,3-dione
benzophenone ketyl (diphenylketyl)
tetra(1-pyrazolyl)borate
4,4 0 -di-tert-butyl-2,2 0 -bipyridine
tert-butylpyridine
benzyl
benzoylacetonate
cyclobutadiene
cyclododeca-1,5,9-triene
cyclohexadiene
cycloheptatriene

chemically induced dynamic nuclear polarisation
cobalamin
cobaloxime [Co(dmg)2 derivative]
cycloocta-1,5-diene
cyclooctene
cyclooctatriene
cross polarisation/magnetic angle spinning
Z5-cyclopentadienyl
Z5-alkylcyclopentadienyl

Organomet. Chem., 2012, 38, ix–xiii | ix

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Cp*
Cp 0
Cp00
CV
CVD
Cy
Cyclam
Cym
Cyttp
dab
dabco
dba
dbpe

DBU
DCA
depe
depm
DFT
diars
diarsop
dien
diop
DIPAMP
diphos
dipp
dipyam
DMAD
DMAP
dmbpy
DME
DMF
dmg
dmgH
dmgH2
DMP
dmpe
dmpm
dmpz
DMSO
dpae
dpam
dppa
dppb

Z5-pentamethylcyclopentadienyl
trimethylsilylcyclopentadienyl
tetramethylethylcyclopentadienyl
cyclic voltammetry(ogram)
chemical vapour deposition
cyclohexyl
1,4,8,11-tetraazacyclotetradecane
p-cymene
PhP(CH2CH2CH2PCy2)2
1,4-diazabutadiene
1,4-diazabicyclo[2.2.2]octane
dibenzylideneacetone
1,2-bis(dibutylphosphino)ethane
1,8-diazabicyclo[5.4.0]undec-7-ene
9,10-dicyanoanthracene
1,2-bis(diethylphosphino)ethane
1,2-bis(diethylphosphino)methane
density functional theory
o-phenylenebis(dimethyl)arsine
{[(2,2-dimethyl-1,3-dioxolan-4,5-diyl)bis(methylene)]bis-[diphenylarsine]}
diethylenetriamine
{[(2,2-dimethyl-1,3-dioxolan-4,5-diyl)bis(methylene)]bis-1-[diphenylphosphine]}
1,2-bis(phenyl-o-anisoylphosphino)ethane
1,2-bis(diphenylphosphino)ethane
2,6-diisopropylphenyl
di-(2-pyridyl)amine
dimethyl acetylenedicarboxylate
2-dimethylaminopyridine
dimethylbipyridine

1,2-dimethoxyethane
N,N-dimethylformamide
dimethylglyoximate
monoanion of dimethylglyoxime
dimethylglyoxime
dimethylpiperazine
1,2-bis(dimethylphosphino)ethane
bis(dimethylphosphino)methane
1,3-dimethylpyrazolyl
dimethyl sulfoxide
1,2-bis(diphenylarsino)ethane
bis(diphenylarsino)methane
1,2-bis(diphenylphosphino)ethyne
1,4-bis(diphenylphosphino)butane

x | Organomet. Chem., 2012, 38, ix–xiii


dppbz
dppe
dppf
dppm
dppp
DSD
edt
EDTA
ee
EELS
EH MO
ELF

en
ES
EXAFS
F6acac
Fc
Fe*
Fp
Fp 0
FTIR
FVP
glyme
GVB
HBpz3
HBpz*3
H4cyclen
HEDTA
hfa
hfacac
hfb
HMPA
HNCC
HOMO
IGLO
im
Is*
ISEELS
KTp
LDA
LiDBB
LMCT

LNCC
MAO
Me2bpy

1,2-bis(diphenylphosphino)benzene
1,2-bis(diphenylphosphino)ethane
1,1 0 -bis(diphenylphosphino)ferrocene
bis(diphenylphosphino)methane
1,3-bis(diphenylphosphino)propane
diamond–square–diamond
ethane-1,2-dithiolate
ethylenediaminetetraacetate
enantiomeric excess
electron energy loss spectroscopy
extended Hu¨ckel molecular orbital
electron localisation function
ethylene-1,2-diamine
MS electrospray mass spectrometry
extended X-ray absorption fine structure
hexafluoroacetylacetonate
ferrocenyl
Fe(CO)2Cp*
Fe(CO)2Cp
Fe(CO)2Z5-(C5H4Me)
Fourier transform infrared
flash vacuum pyrolysis
ethyleneglycol dimethyl ether
generalised valence bond
tris(pyrazolyl)borate
tris(3,5-dimethylpyrazolyl)borate

tetraaza-1,4,7,10-cyclododecane
N-hydroxyethylethylenediaminetetraacetate
hexafluoroacetone
hexafluoroacetylacetonato
hexafluorobutyne
hexamethyl phosphoric triamide
high nuclearity carbonyl cluster
highest occupied molecular orbital
individual gauge for localised orbitals
imidazole
2,4,6-triisopropylphenyl
inner shell electron energy loss spectroscopy
potassium hydrotris(1-pyrazolyl)borate
lithium diisopropylamide
lithium di-tert-butylbiphenyl
ligand to metal charge transfer
low nuclearity carbonyl cluster
methyl alumoxane
4,4 0 -dimethyl-2,2 0 -bypyridyl
Organomet. Chem., 2012, 38, ix–xiii | xi


Me6[14]dieneN4

5,7,7,12,14,14-hexamethyl-1,4,8,11-tetraazacyclotetradeca-4,11-diene
Me6[14]N4
5,5,7,12,12,14-hexamethyl-1,4,8,11-tetraazacyclotetradecane
4,7-Me2phen
4,7-dimethyl-1,10-phenanthroline
3,4,7,8-Me4phen

3,4,7,8,-tetramethyl-1,10-phenanthroline
Mes
mesityl
Mes*
2,4,6-tributylphenyl
MeTHF
methyltetrahydrofuran
mcpba
metachloroperbenzoic acid
MLCT
metal–ligand charge transfer
MTO
methylrhenium trioxide
nap
1-naphthyl
nb
norbornene
nbd
norbornadiene
NBS
N-bromosuccinimide
NCS
N-chlorosuccinimide
NCT
neutron capture theory
Neo
neopentyl
Np
1-naphthyl
np3

N(CH2CH2PPh2)3
nta
nitrilotriacetate
OEP
octaethylporphyrin
OTf
trifluoromethanesulfonate (triflate)
OTs
p-toluenesulfonate (tosylate)
Pc
phthalocyanin
PES
photoelectron spectroscopy
PMDT
pentamethylenediethylenetetramine
pd
pentane-2,4-dionate
phen
1,10-phenanthroline
pic
pyridine-2-carboxylic acid
Pin
(þ)-pinanyl
Pmedta
pentamethyldiethylenetriamine
pp3
P(CH2CH2PPh2)3
[PPN] þ
[(Ph3P)2N] þ
py

pyridine
pydz
pyridazine
pz
pyrazolyl
R-PROPHOS
(R)-(þ)-1,2-bis(diphenylphosphino)propane
R,R-SKEWPHOS (2R,4R)-bis(diphenylphosphino)pentane
RDF
radial distribution function
ROMP
ring opening metathesis polymerisation
sal
salicylaldehyde
salen
N,N 0 -bis(salicylaldehydo)ethylenediamine
saloph
N,N-bisalicylidene-o-phenylenediamine
xii | Organomet. Chem., 2012, 38, ix–xiii


SCF
TCNE
TCNQ
terpy
tetraphos
TFA
tfbb
tfacac
THF

thsa
tht
TMBD
TMEDA
tmp
TMS
tol
TP
TP*
TPP
Trip
Triph
triphos
TRIR
Tsi
TTF
vi
WGSR
XPS
Xyl

self consistent field
tetracyanoethylene
7,7,8,8-tetracyanoquinodimethane
2,2 0 ,200 -terpyridyl
1,1,4,7,10,10-hexaphenyl-1,4,7,10-tetraphosphadecane
trifluoroacetic acid
tetrafluorobenzobarrelene
trifluoroacetylacetonato
tetrahydrofuran

thiosalicylate (2-thiobenzoate)
tetrahydrothiophen
NNN 0 N00 -tetramethyl-2-butene-1,4-diamine
(tmena) tetramethylethylenediamine
2,2,6-6-tetramethylpiperidino
tetramethylsilane
tolyl
hydrotris(1-pyrazolyl)borate
hydrotris(2,5-dimethylpyrazolyl)borate
meso-tetraphenylporphyrin
2,4,6-triisopropylphenyl
2,4,6-(triphenyl)phenyl
1,1,1-tris(diphenylphosphinomethyl)ethane
time resolved infrared (spectroscopy)
tris(trimethylsilyl)methyl (Me3Si)3C
tetrathiafulvalene
vinyl
water gas shift reaction
X-ray photoelectron spectroscopy
xylyl

Organomet. Chem., 2012, 38, ix–xiii | xiii



New developments in the biomedical
chemistry of metal complexes: from small
molecules to nanotheranostic design
Rory L. Arrowsmith, Sofia I. Pascu* and Hubert Smugowski
DOI: 10.1039/9781849734868-00001

Introduction
Molecular imaging is a key area for development worldwide. In 2007, this
was defined by the Society of Nuclear Medicine as a new interdisciplinary
research field, which is at the interface between clinical and preclinical
research. This is highlighted by the increasing demand for new imaging
probes for specific biological targets.1 By the end of 2010 more than 3.2
million positron emission tomography (PET) studies have been carried out
worldwide. It is widely recognised that optimal disease management is
achieved by monitoring patient status before, during and after therapy. PET
agents offer high resolution, non-invasive imaging with provision of
invaluable diagnosis of biological function at agent concentrations below
the pharmacological threshold. There is currently intense interest in the
development of new PET agents for imaging a wide range of disease states,
and of new drugs for targeted radiotherapy. Drugs containing a radionuclide are known as radiopharmaceuticals and can be used for diagnosis
and/or therapy. Radiopharmaceuticals chosen for the purpose of diagnosis
are usually positron emitters (PET) or gamma emitters (SPECT), whereas
therapeutic radiopharmaceuticals usually rely upon bÀ emission and the
Auger effect causing cell death. The choice of radioisotope is also made
according to an optimum half-life, which at the same time minimises
radiation doses whilst giving sufficient time for synthesis and accumulation.
The first pilot trial of PET imaging with 64Cu labeled trastuzumab
(Herceptint, a monoclonal antibody therapeutic) in metastatic breast
cancer has been completed in USA in 2010.2 The choice of radionuclide is
dependent on availability, half-life and pharmacokinetics. The isotope 18F
(t1/2 109.8 min) is most widely used for imaging applications, especially as
18
Fluorodeoxyglucose (18FDG) where there are no limitations owing to the
availability of a cyclotron typically needed for radionuclide generation.
18

FDG, the ‘‘gold standard’’ for PET imaging tumours/ischaemic
myocardium in clinical practice, lacks selectivity and is not universally
applicable for imaging all tumours: for example does not image hypoxic
tumors per se. Common cyclotron-produced positron emitters such as 11C
(t1/2 20.4 min) and 18F (t1/2 109.8 min) have relatively short lives in the
context of following relatively slow biological processes such as the accumulation of a labeled monoclonal antibody at a target site in vivo. The most
commonly used positron emitting isotopes are 18F, 11C, 13N, 15O, however
there is growing interest in use of metal radioisotopes such as 60Cu, 64Cu,
Chemistry Department, University of Bath, Claverton Down, Bath, UK, BA2 7AY.
E-mail:

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68

Ga and 89Zr.3,4 The relatively long half-life of 64Cu (t1/2 12.7h) as well as
the availability of 68Ga (t1/2 1.13 h) from commercial, portable, generators
makes these attractive radioisotopes for PET imaging as these may be used
at a site remote from a cyclotron. Imaging with readily available metallic
radioisotopes for Single Photon Emission Computed Tomography
(SPECT) such as 99mTc (t1/2 6 h) and 111In (t1/2 2.8 days) are by far the most
widely used in nuclear medicine on a global scale. The first tomographic
device, SPECT, was developed by Kuhl and Edwards in 1963. In this
technique detection of the gamma emissions from the radionuclide enable a
3D image to be produced.5

Compared with SPECT, PET imaging has the crucial advantage in terms
of sensitivity and resolution. Such metallic radionuclides ultimately undergo
uptake within cells and while the distribution of these complexes can be
determined in vivo at the 1–2 mm range of resolution, little is known of their
fate once they are in the intercellular environment. This often hampers the
rational design of new diagnostics and therapeutics and ultimately the
accurate diagnosis of cancer. There is growing interest in molecular imaging
as a non-invasive, highly sensitive methods capable of both early diagnosis
and enhancing the understanding of the molecular basis of the disease.6,7
Molecular imaging also combines understanding of molecular function
with in vivo imaging. As a result it can report upon disease mechanisms at a
cellular and sub-cellular level, as well as the effectiveness and selectivity
towards target cells of a specific therapy. Optical imaging, therefore, can be
used to follow the uptake of luminescent complexes in both cells and
multicellular organisms. In vitro studies not only function as a platform for
assessing the suitability of in vivo work and as a drug discovery tool, but also
reveal uptake of small molecules into components of the cell via colocalisation studies, which in turn gives an indication of the likely activity that
an investigated compound may show in vivo. This in turn enhances the
mechanistic understanding of pharmacological processes involved. Recent
publications of luminescent metal complexes for which their properties were
explored in biological systems, will be highlighted with a strong emphasis on
organometallic compounds. Furthermore, in vivo optical imaging can
enable detection of tumours on the basis of the selectivity of the imaging
probe, with high sensitivity yet without exposure to ionising radiation.
This review will discuss recent advancements of metal complexes for
imaging at a cellular level using optical imaging and at an organism level
with a focus on multimodality imaging probe design – including those
applicable for Single Photon Emission Computed Tomography (SPECT),
Positron Emission Tomography (PET), Magnetic Resonance Imaging
(MRI) and Near Infra-Red (NIR).

Radiopharmaceuticals and multimodality probe design considerations
Radiopharmaceuticals are designed to answer a specific medical need and
are based on the knowledge of molecular biology. The first generation of
radiopharmaceuticals involved radioactive isotopes aimed at mimicking
normal biological processes, such as 2-[18F]-fluoro-2-deoxy-D-glucose and
[99mTcO4]2À , which take advantage of higher glucose uptake by cancer cells
and mimic iodine uptake by the thyroid, respectively.8 There is a current
2 | Organomet. Chem., 2012, 38, 1–35


HO2C

N

N

N

N

CO2H

CO2H

HO2C

HO2C

N

N

N

N

CO2H

HO2C

N

N

CO2H

N
CO2H

HO2C

HO2C
DOTA

Fig. 1

TETA

NOTA

Frequently used chelators for radiopharmaceuticals.

trend towards ‘second generation’ radiopharmaceuticals that use a biologically active molecule (BAM), such as a peptide or antibody for specific
targeting. Much of the work utilises the labeling of standard chelating
agents such as 1,4,7,10-tetraazacyclododecane-N,N 0 ,N00 ,N 000 ,-tetraacetic
acid (DOTA), triethylenetetramine (TETA) or 1,4,8,11-tetraazacyclododecane-1,4,8,11-tetraacetic acid (TETA), (Fig. 1) conjugated to a
biomolecule (BAM) via a linker and a chelator.9
Developments such as the scintillation detector and improved detection
technology aided the advancement of PET and SPECT. Despite the
scintillation detector remaining virtually the same as the original designed
by Anger in 1958, the recent development of the dual-headed gamma
camera has had a significant positive effect on PET. Multiple detector
systems also achieved better sensitivity and efficiency to enable simultaneous scanning of multiple sections. Combining modalities such as SPECT/
CT, PET/X-ray, PET/MRI, or most frequently PET/CT, allows for better
image quality, shorter scanning time and reduced costs. This results in more
efficient use of radiopharmaceuticals and more facile recognition of
abnormalities. The synergistic combination of PET and MRI holds promise
for a successful next generation of dual-modality scanners in medical
imaging. These instruments will provide accurate diagnoses thanks to the
sensitive and quantifiable signal of PET and the high soft-tissue resolution
of MRI. Furthermore, patients will receive reduced radiation doses. However, these new tools require a new class of imaging probes. Therefore, there
has recently been increasing interest in the development of dual-modality
PET–MRI agents.9 A standard dual-modal PET-MRI imaging agent was
based on a PET isotope and gadolinium.10 The second generation of dual/
multimodal contrast agents are synthesised using MNPs, having a proven
record of biocompatibility and a track record of extensive use in the clinic as
MRI contrast agents.11,12
A combination with optical imaging enables both greater understanding
of the probe both in cells and in an organism as well as enabling the
identification of a tumour; the advantages of the high sensitivity of PET and

SPECT, which are not limited by tissue penetration as is optical imaging
and presents itself as a very interesting marriage of modalities with potential
to improve both scientific knowledge and patient diagnosis and therapy.
There are only very few examples in the literature described as dual/multimodality hybrid nanomaterial used for PET/MRI or PET/MRI/NIRF.
The development of PET radiopharmaceuticals labeled with generatorproduced PET radionuclides has facilitated greater use of this imaging
method in clinical nuclear medicine. For example, the 68Ge/68Ga parent and
Organomet. Chem., 2012, 38, 1–35 | 3


daughter radionuclides are ideal for this: the half life of 68Ga isotope (68
min) is long enough to achieve the synthesis of a wide variety of radiopharmaceuticals and allow for long data acquisitions, thus enhancing the
images quality (vide infra).
There is significant research effort carried out that focuses on finding new
theranostic targets, of which is beyond the scope of this review (see Ref. 13
for further information). It can be envisaged that diagnostic radiometals,
such as 64Cu, 67Ga, 68Ga, 99mTc for example may be used as future diagnostic agents which are simultaneously amenable for coupling with radiotherapeutic agents such as 177Lu, 90Y, 111In or 212Pb: this could even allow
for follow-up treatments provided the chemical properties of the complex
are not altered significantly by the change in metal. A diagnostic agent and a
therapeutic agent make a ‘theranostic pair’. However, intrinsically cytotoxic
agents could also be radiolabelled with another approach being to utilise
nanoparticles filled with a drug targeted with a BAM.
Nanomedicines design in imaging applications
Drug delivery methods involving nanomedicines to deliver14 chemotherapeutics selectively to tumours have been developed in recent years.
Succesful examples reported were based on designs that involved coupling
drugs to receptor-specific ligands and/or protection of the drug by wrapping in a polymer or lyposome with enhanced kinetic stability in vitro. The
precise way in which such nanomedicines act within cells remains
unknown.
Currently, it is believed that using fluorescence microscopy techniques to
image radiolabelled nanomedicines within cells (nanotheranostics) could
provide valuable information on the cell behaviour and generate the next

generation of contrast agents. Molecular imaging probes can act as diagnostic therapeutics, allowing prediction of response to treatment, dosimetry
to be calculated on an individual basis as well as opening the possibility of
simultaneous diagnosis and therapy – these theranostics remain a holy grail.
Nanoparticles, such as core-shell silica coated magnetic nanoparticles,
gold nanoparticles or quantum dots have become very attractive for biological and medical applications because of the progressions in methods for
their synthesis, coatings and analysis.15 There are various fields within the
biosciences where nanoparticles can be very useful, such as tissue engineering; drug, radionuclide and gene delivery; magnetic resonance imaging
contrast enhancement; hyperthermia; detoxification of biological fluids; cell
separation; tissue repair and magnetofection.16–18
In this review, several examples for the use of nanoparticles involving
transition metal or gallium or indium complexes for biomedical applications
will be discussed. The major disadvantage of most medical treatments is
that they are non-specific. The damaging side effects of therapeutic remedies
are caused by their administration: they are not targetted specifically, but
employ general distribution systems. This makes direct drug delivery the
most promising application of magnetic nanoparticles. Nanoparticles are
capable of carrying pharmaceuticals on their surface, and by applying an
external magnetic field, the drugs could be directed to the target organ for
accurate release.19 With only 1 in 10,000 immuno-targeted therapies
4 | Organomet. Chem., 2012, 38, 1–35


reaching their target, encapsulation within nanoparticles is an attractive
form of drug delivery for release into tumours.14
Magnetic nanoparticles (MNPs) are of particular interest due to their
potential firstly to enable imaging that unlike gadolinium chelates do not
rapidly accumulate in the liver, secondly to act as a drug targeting system
and thirdly that they can be covered with biocompatible coatings preventing
the body’s innate immune system from attacking the drug carriers. Additionally, with the use of an external magnetic field and gradient, it is possible
to confine the particles to a designated tissue area.20 Their use in MRI is still

under consideration, however, thanks to new methods of particle synthesis,
functionalisation, coatings and analysis, MNPs are even more attractive for
all kinds of medical applications in the future. For a recent review on
magnetic nanoparticles in theranostics see Ref. 21.
This review emphasises recent developments of luminescent metal complexes (including the gallium, indium and the transition elements) for
imaging in vitro and/or in vivo, whilst highlighting multimodal imaging,
theranostics (combined ‘all-in-one’ diagnostics and therapeutics) and
selected examples from coordination chemistry and nanotechnology covering molecular imaging probe design and testing.
Transition metal-based imaging and therapy probes
Iridium. Iridium(III) complexes are of great interest due to their high
phosphorescence, which is as a result of the rapid intersystem crossing from
a singlet state to a triplet state due to the 5d electronic configuration.
Thanks to the largely ligand-based phosphorescence origin of Ir(III) complexes, the emission wavelength is tuneable, leading to a large array of
applications in addition to those in bioimaging.22 Iridium complexes display
large Stokes shifts, long lifetimes and limited photobleaching when compared to organic fluorophores. Despite this until recently few iridium(III)
complexes were reported to enter cells.
Yu et al. developed two cationic iridium polypyridine complexes in 2008
for cytoplasmic imaging, with low cytotoxicity and with emission in green
and red respectively, both displaying internalisation in the cell.25 Subsequently iridium(III) polypyridine indole complexes showing high cytotoxicity and uptake in cells was demonstrated by Lo et al. in 2009.26 From 2010
onwards there have been an growing number of iridium(III) complexes
developed and entering cells, with increasingly interesting properties and
potential within this field. Li et al. developed cationic iridium(III) complexes
displaying low cytotoxicity as phosphorescent cytoplasm imaging agents,
possessing variable emission properties by way of varying the ligand
structure.27 It was possible to achieve colours from blue to red purely by
modifying the pyridine coordinate, with further modifications carried out to
attain a NIR probe. The large Stokes shifts, exclusive cytoplasmic uptake
and insignificant cytotoxicity bring excellent potential to enhance colocalisation studies; since the tunable properties ensure the choice of a probe with
non-overlapping emission. Furthermore, Williams et al. reported an iridium
complex, 1 distinguishable from standard organic dyes using a 10 ns delay in

laser pulse and acquisition (see Fig. 2).28 An iridium(III) complex developed
by Li et al., could luminesce upon entry to the nucleus by way of a
Organomet. Chem., 2012, 38, 1–35 | 5


(a)

(b)

(c)
N
N

N

Ir
N

N

1
Fig. 2 Fluorescence microscopy of complex (1), denoted Ir(ppy)2(pybz) in CHO cells published by Williams et al.28 The complex was co-localised with a nuclear stain (Hoechst). Images
were acquired without a delay between pulse and acquisition (left) and with a delay (right).

(a)

(b)

(c)

S

(d)

S

O

O
Ir

Ir

O

N

O

N

COOH

2

2

2

3

Fig. 3 Iridium complexes reported by Takeuchi et al. where increas ed fluorescence indicates
hypoxic tumours in nude mice, where for compound 2 (left) lex=445–490, lem=580 nm and
compound 3 (right) lex=575–605 nm, lem=645 nm.35

molecular transporter via a reaction-based mechanism.29 This allows
selective and rapid nuclear imaging of live cells with very low cytotoxicity at
the concentration required for imaging. Notably, zwitterionic iridium(III)
complexes have also been developed and displayed uptake in cells.30 Furthermore, photoswitchable iridium complexes were designed that can reversibly switch between an open and a closed from when irradiated with light.31
Iridium complexes have recently been investigated as luminescent sensors
able to monitor the variation of homocysteine and cysteine levels in cells (of
significance to the physiological balance in biology), in this case using a
cationic iridium(III) complex.32 Furthermore, zinc ion sensing in vitro was
possible via a family of cyclometallated iridium(III) polypyridine compounds including a di-2-picolylamine.33
Li et al. demonstrated the capacity of an iridium complex, unusual in that
it did not includ a pyridine structure, to able to monitor the levels of Hg(II),
which was found to be proportional to phosphorescence emission within
cells.34 Interestingly, iridium complexes for which luminescence was quenched by oxygen were designed for hypoxia imaging in vivo (see Fig. 3).35
Compound 3 could even be detected within the tumour 6 to 7 mm from the
skin surface.
The bioconjugation of iridium complexes remains currently under
intense exploration. For example, two new, cyclometalated iridium(III) and
rhodium(III) bis(pyridylbenzaldehyde) complexes were designed by Lo
et al. in 2010 both with and without biotin tags, with their uptake followed
in HeLa cells.36 Furthermore, cell-penetrating peptides conjugated to Ir(III)
6 | Organomet. Chem., 2012, 38, 1–35


(a)

(b)

(c)

(d)
MLAKGLPPKSVLVKGGH

N

HN

N

H
N
HRKKRRQRRR

Ir
N

N

HGRKKRRQRRR

N

N

NH

Ir

N

N
H

4

5

Fig. 4 [Ir-HTat], 4 (left) and [Ir-P450dHTat], 5 (right) incubated in HeLa cells and imaged by
confocal microscopy, where yellow indicates co-localisation of nucleoli & vesicular structures
(with Rhodamine B-Tat) and MitoTracker respectively.37 In each case, green corresponds to
the iridium complex.

phenylpyridine complexes showed cytoplasmic and vesicular uptake,
mitochondrial and nucleoli targeting was achieved using dual-functional
peptide [Ir-HTat], 4 and [Ir-P450dHTat], 5 and respectively (see Fig. 4).37
A peptide-labelled iridium complex was synthesised and successfully found
to visualise, using fluorescence lifetime imaging (FLIM), the expression of
a chemokine receptor, a G protein-coupled membrane receptor with a
function in metastatic spread of cancer.38
Two cyclometallated iridium(III) complexes were developed by Li et al.,
one showing increased luminescence in the solid state.39 This feature
was exploited by inserting the complex into polymer nanoparticles and
visualised in epidermal carcinoma (KB) cells. Furthermore, an exciting
development towards multimodal imaging and with theranostic potential
was carried out by Hsiao et al. using multi-purpose silica-coated iron oxide
nanoparticles functionalised with an iridium complex for MRI, in vitro

phosphorescence imaging and photodynamic therapy.40
Rhenium and Technetium. 99mTc is a metastable gamma-emitting isotope
which was first isolated in 1959 and played a crucial role in medical diagnosis as it paved the way to metal-based radiopharmaceuticals applications.
Initially used in 1961 for thyroid diagnosis 99mTc currently has wide
applications in imaging such as of the brain, heart, liver, kidney and bone
imaging and is the most commonly used radioisotope for SPECT. Despite
this, 99mTc hinders the binding of organ specific pharmaceuticals, due to its
non-physiological nature. Since there is no stable isotope of technetium, for
in vitro luminescence imaging it is possible to make use of isostructural
rhenium complexes as a comparable analogue.41
As highlighted above, iridium(III) and rhenium(I) polypyridine complexes are of particular relevance as sensors, due to good quantum yields
and especially so since the high environmental sensitivity of rhenium(I)
polypyridine complexes was reported.23,24 Rhenium(I) complexes have long
luminescent lifetimes and significant Stokes shifts, making them highly
suitable as in vitro probes. Coogan et al. have developed numerous
tricarbonyl polypyridyl rhenium(I) complexes for imaging cells.43–45
Notably reporting in 2011 a Re(I) complex that can act as a carrier of ions
such as silver and copper. The unfilled form of the complex does not enter
cells, however in the case of Ag þ filling it can enter the nucleoli.46 Interestingly, dinuclear tricarbonyl rhenium(I) complexes appended to peptide
Organomet. Chem., 2012, 38, 1–35 | 7


(a)

(b)

(c)

(d)
O

H
N

T
10

N
(OC)3Re

N

NH2

O

Cl
Cl

Re(CO)3
T = Thymine PNA monomer

6

Fig. 5 A bimetallic Re(I) compound 6 (d) in the nucleus (a) and in the cytoplasm (b), where
(c) is an overlay of (a) and (b).42

nucleic acid showed rapid cell uptake, low cytotoxicity and have the ability
to distinguish between the nucleus and cytoplasm via different excitation/
emission properties (see compound 6, Fig. 5).42 Tricarbonyl rhenium
complexes have also been developed by Lo et al. for metal ion sensing

in vitro and displayed increased luminescence emission and a larger lifetime
upon Zn(II) or Cd(II) binding.47
Rhenium(I) complexes suitable for bioconjugation and fluorescence
imaging are currently under development.48 Notably, a cytotoxic folic
acid-PEG derivatised Re(I) complex was followed in A2780/AD cells.49
Interestingly, rhenium(I) complexes with an appended a–D-glucose were
developed with the potential as glucose uptake monitors, showing
mitochondrial uptake and cytotoxicity that did not depend on cell type.50
Polypyriderhenium(I) bis-biotin complexes were observed in HeLa cells by
laser scanning confocal microscopy.51,52 Subsequently, rhenium complexes
with polylactide conjugates displayed cell uptake in A2780 cells.53
As mentioned above, isostructural Re/99mTc complexes can be developed
for in vitro and in vivo investigations respectively. For example, Pelecanou
et al. designed Re and 99mTc complexes incorporating the [M(CO)3(NNO)]
unit covalently attached to 2-(4 0 -aminophenyl)benzothiazole (an anticancer
agent) for theranostic applications.55 Recently they explored new Re and Tc
complexes of the same family with those highlighted above, by optical and
SPECT imaging respectively, demonstrating greater uptake in cell lines of
cancerous origin with respect to non-cancerous lines.56 The first instance of
substituting a well established chelator with a 1,2,3-triazole analogue for
complexation of Re/99mTc without modifying compound biological effect
was reported by Mindt et al. in 2008.57 The isostructural Re/99mTc folic acid
analogues were synthesised using a Cu(I) catalysed cycloaddition method,
known as a ‘‘click reaction’’ that allowed chelation and bioconjugation in
one step, which the authors named ‘‘click-to-chelate’’. Moreover, Mindt
et al. designed several new imaging probes for PET, SPECT, NIR or MRI
from a single folic acid based precursor, using 67Ga, 111In and 99mTc agents
8 | Organomet. Chem., 2012, 38, 1–35

for SPECT, Cy 5.5 for optical imaging and 18F for PET.58 The 111In-DTPA
folate complex has recently been reported as with the capacity to quantify
macrophage activation.59 The authors demonstrated that the later stages of
osteoarthritis can be correlated to reduced macrophage activation, allowing
monitoring of the disease progression, for which there are no clinical
measures at present. Furthermore the same group has used click reactions
to design tridentate di-1,2,3-triazole chelator imaging tracers and also
multifunctional 99mTc complexes, as a platform for a broad number of
potential purposes including multimodal imaging probe development.60,61
This efficient and facile synthesis combined with uptake in folic acid
receptor expressing KB cells and tumour targetting in mice confirms the
promise of this procedure.
Rhenium and technetium complexes have also been designed to enter the
nucleus and bind to DNA, an example of which was by Santos et al. who
synthesised tricarbonyl pyrazolyl-diamine rhenium(I) complexes that show
potential for the development of future targeted radiopharmaceuticals.62
Furthermore, tricarbonyl rhenium and technetium complexes with acridine
derivatives showed nuclear uptake via fluorescence and activity based
studies respectively.63 Recently, Alberto et al. developed rhenium and
technetium complexes comprising of a DNA interchelator for nuclear
targeting, a biologically active molecule (here a bombesin analogue, 7) and a
linker, cleavable upon cell entry displaying uptake in both the nucleus and
the cytoplasm (see Fig. 6).54,64
Multimodal imaging probe are also under development, such as
recently by Faulkner et al. for MRI and luminescence imaging by Gd3 þ
and a rhenium fluorophore.65 Furthermore, the first dinuclear rhenium/
technetium complex was designed in 2011 for dual modal fluorescence/
SPECT imaging and also has potential for therapy via 188Re.66
An interesting nanocomposite with potential application in multimodal
imaging was reported by Hafeli.67 Silica coated magnetite nanoparticles

were modified with an amino silane coupling agent (N-[3-(trimethyoxysilyl)
propyl]-ethylenediamine) and histidine. This enabled the radiolabelling
of magnetic nanoparticles with PET radiotracer 188Re with high yield.
The stability of the synthesised nanocomposite was also shown in in vitro
experiments. The authors suggested theranostic application of this
nanocomposite, that it could be used in magnetically targeted cancer

N

N

N

N

O

O

N (CO)
Re
CN

H
N
O
O

(a)

(b)

O
N
H

NH

H
N
O

NH
O
N
H

N
H
N
O

O
N
H

H
N
O

S

NH
O
N
H

NH
O

7
Fig. 6 A rhenium tricarbonyl complex conjugated to a bombesin analogue and an intercalator, compound 7, visualised in fixed PC-3 cells by fluorescence microscopy (left), where
green represents the complex and blue the DAPI nuclear stain.54

Organomet. Chem., 2012, 38, 1–35 | 9


radiotherapy and also as a dual-modal imaging agent.67 Radioactive magnetic nanoparticles, a potential tracer for diagnosis in nuclear medicine,
were described by Kim et al. Radiolabelling was conducted using
technetium pertechnetate (99mTcO4À ) and then alginic acid was adsorbed
on the particles.68
Ruthenium. The majority of fluorescent ruthenium complexes reported to
date do not contain a metal-carbon bond, however a small number of
luminescent ruthenium organometallic complexes with uptake in cells have
been reported. A di-carbonyl tris(2.2 0 -bipyridyl) ruthenium(II) chloride
complex was encapsulated within the hydrophobic supercages of a zeolite.
Fluorescence quenching by dissolved oxygen was monitored as a function of
concentration and was demonstrated in vitro in macrophage cells.69 Seven
organometallic porphyrin complexes (for example compound 8), five of which
ruthenium and one with analogous iridium and rhodium complexes, were

developed by Therrien et al. for photodynamic therapy.70 The ruthenium
complexes localised in granular structures within the cytoplasm (Fig. 7),
comparing well to the uptake demonstrated by the porphyrin ligand itself.
Furthermore, excellent phototoxicity was observed for all ruthenium complexes indicating real potential for the combination of both chemotherapeutic
and photodynamic activity against cancer. There have been some very interesting examples of ruthenium complexes from coordination chemistry, some of
which will be discussed here. There have recently been a small number of
ruthenium complexes designed for the purpose of nuclear uptake and DNA
binding, for example Palaniandavar et al. developed a [Ru(phen)2(dppz)]2+
complex, where dppz=2,5-bis(2-pyridyl)pyrazine, capable of defined and
intense staining of the nucleus, showing potential to challenge commercial dyes
such as Hoechst.71 A ruthenium beta-cyclodextran complex shown to translocate DNA and on the basis of its ability to aggregate DNA was designed for
use of inhibition of DNA enzymes (such as topoisomerase and Hind III).72
A new ruthenium(II) complex attached to a porphyrin was reported to
show potential since it can be imaged and activated therapeutically using
two-photon fluorescence.73 In 2010, Xu et al. designed a family of
b–carboline ruthenium(II) complexes that are intrinsically fluorescent, enter

Ru Cl
Cl N

Cl Ru
N Cl
N
NH

HN
N

Cl N
Ru Cl

(a)

(b)

N Cl
Cl Ru

8

Fig. 7 Fluorescence microscopy of an organometallic ruthenium porphyrin complex (right) in
Me300 cells, where blue, green and red correspond to a DAPI stained nucleus, lysotracker green
and the ruthenium complex.70

10 | Organomet. Chem., 2012, 38, 1–35