Synthesis and characterisation of lanthanide-hydroporphyrin dyads

Article abstract of DOI:10.1039/c4dt02448f

Fluorescence spectroscopy is in many ways the ideal tool for the interrogation of complex biological systems, as it is non-invasive, sensitive, and offers high spatiotemporal resolution. For biomedical imaging luminescent probes absorbing and emitting in the red-to-near infrared (NIR) region are best suited to maximise tissue penetration and minimise damage to cellular components. NIR-emitting lanthanides (Ln) sensitised with red-absorbing antennae are promising candidates for these applications, assuming the challenges of poor photophysical properties and tedious syntheses of the complexes are overcome. Chlorins are porphyrin-type tetrapyrroles with intense red absorption. Recently chlorins have been shown to sensitise Yb and Nd emission when incorporated into Ln-complexes. Here we expand on our previous work, and explore the effect of chlorin structure, metallation state, chlorin-Ln-complex linker length and mode of attachment on the properties of chlorin-Ln complexes. As chlorin absorption bands are ～20 nm fwhm and readily tunable, a deeper understanding of structure-property relationships would enable the use of chlorin-Ln complexes in multicolour imaging using antenna-specific excitation. A detailed description of antenna and complex syntheses and photophysical characterisation is given. A number of challenges were identified, which will have to be addressed in future studies to enable multicolour imaging using the NIR-emitting lanthanides.

Full text of DOI:10.1039/c4dt02448f

Volume 44 Number 6 14 February 2015 Pages 2501–2916
Dalton
Transactions
An international journal of inorganic chemistry
www.rsc.org/dalton
ISSN 1477-9226
PAPER
K. Eszter Borbas et al.
Synthesis and characterisation of lanthanide-hydroporphyrin dyads

Dalton
Transactions
PAPER
Synthesis and characterisation of lanthanide-
hydroporphyrin dyads†
Cite this: Dalton Trans., 2015, 44,
2541
Ruisheng Xiong, Julien Andres, Kira Scheffler and K. Eszter Borbas*
Fluorescence spectroscopy is in many ways the ideal tool for the interrogation of complex biological
systems, as it is non-invasive, sensitive, and offers high spatiotemporal resolution. For biomedical imaging
luminescent probes absorbing and emitting in the red-to-near infrared (NIR) region are best suited to
maximise tissue penetration and minimise damage to cellular components. NIR-emitting lanthanides (Ln)
sensitised with red-absorbing antennae are promising candidates for these applications, assuming the
challenges of poor photophysical properties and tedious syntheses of the complexes are overcome.
Chlorins are porphyrin-type tetrapyrroles with intense red absorption. Recently chlorins have been shown
to sensitise Yb and Nd emission when incorporated into Ln-complexes. Here we expand on our previous
work, and explore the effect of chlorin structure, metallation state, chlorin–Ln-complex linker length and
mode of attachment on the properties of chlorin–Ln complexes. As chlorin absorption bands are ∼20 nm
fwhm and readily tunable, a deeper understanding of structure–property relationships would enable the
use of chlorin–Ln complexes in multicolour imaging using antenna-specific excitation. A detailed
description of antenna and complex syntheses and photophysical characterisation is given. A number of
challenges were identified, which will have to be addressed in future studies to enable multicolour
imaging using the NIR-emitting lanthanides.
Received 12th August 2014,
Accepted 15th October 2014
DOI: 10.1039/c4dt02448f
www.rsc.org/dalton
molecule analytes,6 and in the ratiometric detection of
enzymes.7 An advantage of using Ln complexes stems from the
Introduction
The tagging of a large number of species in a straightforward chemical similarity of the metals,8 which provides access to
and readily decodable manner is a challenge in chemical compounds with different functions by a simple exchange of
biology as well as medical diagnostics.1 Luminescence is metal centre. This aspect has been beautifully demonstrated
an attractive readout signal for such applications due to its by accessing NIR-emitting MOF barcodes by variation of the
sensitivity and high resolution, and relatively low cost of the Ln-mixture composition,9 and by ICP-MS multiplex analysis of
instrumentation. Furthermore, luminescence imaging is non- lanthanide-labelled protease substrates10 and viral DNA.11 In
invasive, and is thus well-suited to real-time detection. Lantha- another example, a pair of complexes with an azaxanthone
nide (Ln) luminescence, consisting of sharp, long-lived emis- sensitiser afforded either a red-emitting fluorescent cellular
sion bands which cover the visible (Tm, Tb, Eu, Dy, Sm) to the stain (Ln = Eu), or a singlet oxygen-generating photosensitiser
near IR (NIR, Yb, Nd and Er) range is increasingly relied on in (Ln = Tb).12
this area.2 As Ln intrinsic extinction coefficients are only of a
The extension of multicolour imaging to the red and NIR is
few cm−1 M−1 their excited state is typically obtained via photo- motivated by the lower levels of background signals in this
sensitisation by organic chromophores. As foremost examples area, and, for biological applications, the deeper tissue pene-
of multicolour imaging, Tb and Eu complexes have been used tration of such light.13 Because of the inherent low quantum
in FRET-pairs with organic dyes and quantum dots to enable yield of NIR emitting lanthanide complexes, current chal-
multiplex detection of cancer biomarkers,3 as well as to study lenges include limited access to sensitive instrumentation for
biomolecule interactions.4,5 Cocktails of responsive Ln com- the detection of NIR-signals, and the dearth of readily manipu-
plexes have been used in the two-colour detection of small- lated, tunable, strongly absorbing organic fluorophores.
The enhanced sensitivity of the Ln-excited states to nearby
O–H, N–H and even C–H oscillators can amplify even minor
Department of Chemistry – BMC, Uppsala University, 75123 Uppsala, Sweden.
structural differences to a detrimental effect. This has been
E-mail: eszter.borbas@kemi.uu.se
addressed through ligand deuteration14–16 and fluorination,17
†Electronic supplementary information (ESI) available: Additional photophysical
as well the application of cage-type Ln-binding motifs18
instead of the synthetically more tractable macrocyclic units.
characterisation and copies of 1H and 13C NMR spectra. See DOI: 10.1039/
c4dt02448f
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Nevertheless, tetraazamacrocyclic ligands are most widespread
as they are cheap, readily available, and their selective
functionalisations are well documented.19,20 However, the
above-mentioned sensitivity of the Ln-excited states justifies
the systematic investigation of different ligand microenviron-
ments created by the macrocycle substituents. Such studies are
still relatively rare.
Beyond luminescence applications, LnIII-ions are used in
magnetic resonance imaging (Gd),21,22 X-ray crystallography
(Tb)23 and biomolecule NMR spectroscopy (Tm, Dy).24–27 Thus,
the combination of a Gd-complex with a red-absorbing/red-
emitting chromophore could provide dual MRI-luminescence
bimodal imaging agents in case antenna fluorescence is
utilised. One class of suitable red-absorbing chromophores is
tetrapyrroles, for example porphyrins and dihydroporphyrins
(chlorins).28,29 Importantly, porphyrins and chlorins have been
shown to sensitise NIR emitting Ln ions,28–31 and therefore
such complexes are potential red-absorbing NIR-emitters.
Tetrapyrroles are good singlet oxygen sensitisers for PDT,32,33
which suggests that access to theranostic agents for combined
MRI-photodynamic therapy should be an option. The excellent
Cu-binding of porphyrinic macrocycles has been exploited
previously to obtain (64Cu)PET–(Gd)MRI bimodal imaging
agents through the combination of 64Cu-porphyrins and 1–4
Gd-DOTA-units.34,35 Similar avenues are open for chlorin–Ln
dyads, hinting at the potential versatility of these systems.
We have recently reported the synthesis of two sets of Ln-
complexes with free base monoaryl, or free base or zinc diaryl
chlorin antennae.36 NIR-emission was observed from several of
these complexes upon 337 nm-excitation. Tamiaki and co-
workers have reported Yb-emission when sensitised by chloro-
phyll derivatives.37 Here we report the synthesis of an extended
set of chlorin-equipped Ln-complexes. We have systematically
varied the metallation state of the antenna, and the type,
length and flexibility of the linker connecting the Ln-binding
site to the chlorin. We have performed a detailed photo-
physical investigation of the antennae in the presence and
absence of the lanthanide acceptors, and the preliminary
study of the effect of the above factors on the Ln-emission.
Scheme 1 Synthesis of azide- and alkyne-functionalised chlorin
antennae.
judged by TLC analysis of the crude products, which were used
without further purification. The macrocyclisation affords the
zinc chelates of the chlorins. The zinc was retained in the case
of the azide, alkyne or TIPS-alkyne-functionalised chlorins.
These were destined for Cu-catalyzed azide-alkyne cyclo-
additions (CuAAC), and the central zinc was a protecting group
for the macrocycle. Such a use of zinc metallation is wide-
spread for CuAAC of porphyrins.41 Preliminary experiments
with the free base chlorins also showed that Cu-complexation
by the chlorin completely shut down the cycloaddition.
In our previous work tert-butyl-ester-functionalised chlorin
was a key building block,36 and we prepared Ln-complexes
incorporating this motif either as the free base (Yb and Nd) or
as the zinc chelate (Nd). Here we wished to gain access to a
palette of metallated chlorins in order to study the effect of
the central metal on Ln photophysics (Scheme 2). First
zinc chelate 6 was demetallated by treatment with p-TsOH.
Our initial plan was to introduce Cu2+, Pd2+ and Ni2+ at this
Results and discussion
Synthesis
The synthesis of the chlorin antennae with carboxylate,
azide and alkyne reactive groups was based on Lindsey’s
method.38,39 The key step is a one-pot 2 + 2 macrocyclisation
consisting of an acid-catalysed condensation of a tetrahydrodi-
pyrrin (Western half,40 4) and a 1-bromo-9-formyldipyrro-
methane (Eastern half), followed by an oxidative cyclisation
under basic conditions. The Eastern halves were synthesised
in two steps from aldehydes 1a–d via the corresponding dipyr-
omethanes in moderate to excellent yields (Scheme 1). For the
Vilsmeier formylation the use of oxalyl chloride usually gave
more consistent results than POCl3, with somewhat higher
yields. Bromination of 3a–d to afford 4a–d was quantitative as
stage. Treatment of 7 with Cu(OAc)2·H2O at room temperature,
42
or with Pd(acac)2
or Ni(OAc)2·4H2O under microwave
irradiation afforded the corresponding chlorins 8Cu, 8Pd or
8Ni in high yield. The relative apolarity of 8Cu, 8Pd and 8Ni
enabled the straightforward purification of these chelates.
These metallochlorins were expected to be stable to moderately
acidic conditions, as previously reported chlorin complexes of
these metals were demetallated only under harsh conditions
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Chart 1
connected chlorin carboxylic acids to amine-carrying cyclen
derivatives using HATU as the coupling agent with DIPEA in
DMF.36 These conditions were readily applicable to the new
substrates. After ∼48 h complete consumption of the chlorins
was seen by TLC-analysis of the reaction mixtures. The coup-
ling products were isolated in high yields (65–93%) by
aqueous-organic work-up, followed by column chromato-
graphy on silica gel. When the cyclen ligand with tert-butyl
ester groups was coupled to 9Ni the reaction was slower.
Addition of a second portion of reagents to the reaction
mixture resulted in complete consumption of starting chlorin,
and the product (13Ni-tBu) was isolated in 80% yield.
Ligand deprotections and lanthanide complexations were
followed by RP-HPLC. Hydrolysis of the methyl esters was sur-
prisingly difficult. Treatment of a solution of 13Pd, 13Ni or
13Cu in CH2Cl2–MeOH with a 4-fold excess of NaOH dissolved
in MeOH–H2O resulted in only partial hydrolysis even after
1 week of heating at 60 °C. By RP-HPLC-analysis a mixture was
observed, with two major components. We were not able to
Scheme 2 Synthesis of metallated chlorin carboxylic acids.
1
unambiguously assign the two peaks, however, H NMR analy-
sis of the crude reaction mixture suggested the presence of
unhydrolysed methyl esters. Addition of first LiOH (10 equiv.),
and then KOH (10 equiv.) resulted in the formation of a single
compound in all cases. The yield of the hydrolysis is poor after
chromatographic purification of the products (∼25%). We
attempted the thermolysis of 13Ni-tBu to the triacid by micro-
wave heating in pyridine at 225 °C. However, these conditions
resulted in unacceptably high levels of decomposition, and
were abandoned.
Complexations of the lanthanides with the ligands 14,
14Ni, and 14Pd were performed in MeOH at 70 °C in the pres-
ence of the appropriate chloride salts. Upon completion of the
reaction 15NiLn precipitated out. Surprisingly, unlike the
other Ln-complexes, 15PdLn was very apolar, and it could be
purified by extracting it into CH2Cl2. There was a marked
difference between the rate of Ln-complexation, with 15NiLn
forming within minutes, 15PdLn requiring several hours to
complete, and the free base 15Ln proceeding to only ∼50%
conversion in several days (Scheme 3).
(e.g. concentrated H2SO4/TFA or thiol/TFA).43,44 Surprisingly,
exposure to even as mild conditions as 10% TFA in CH2Cl2
resulted in significant (in the case of 8Pd almost quantitative)
loss of the metal within minutes, making the acidic cleavage
of the tert-butyl ester unfeasible. It was possible to thermally
cleave the ester (8Ni, 210 °C, 30 min, 83%), this method
resulted in retention of the metal and essentially no decompo-
sition of the macrocycle. Alternatively, unprotected 736 could
be metallated. The formation of 9Cu was very straightforward,
proceeding at room temperature with complete consumption
of starting material within 5 min. The Pd-chelate required
much harsher conditions, and typically the use of large excess
of Pd(acac)2 with extensive microwave heating was necessary. It
was crucial to drive the reaction to completion as the separ-
ation of free base and metallochlorins was not possible under
any of the conditions we tried. However, once all free base
chlorin was consumed the metal chelates 9Ni and 9Pd were
readily isolated in analytically pure form in 83–85% yield by
silica column chromatography (MeOH–CH2Cl2 = 1 : 10).
Chlorin-appended Ln-complexes were also prepared using
Cu-catalysed azide-alkyne cycloadditions between azide-
or alkyne-functionalised chlorins 5a–d and Ln-complexes
10Ln and 11Ln bearing complementary reactive groups
With the functionalised chlorins in hand we attempted the
synthesis of chlorin–lanthanide dyads by reaction with the
cyclen-based building blocks shown in Chart 1. Previously we
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Scheme 3 Formation of the metallochlorin-appended lanthanide
complexes.
Scheme 5 Cycloaddition between alkynyl chlorins and azido lantha-
nide complex.
CuAAC in a myriad different settings,45 its use for Ln-complex
functionalisation is not problem-free. Reactions reported to
date are often sluggish,46,47 low-yielding,6 or limited in scope
due to the harshness of reaction conditions.48 The complexity
of reactions mixtures combined with the low solubility of Ln
complexes makes purifications tedious. Nevertheless, where
appropriate conditions were identified, often products with
interesting properties – to which the trizole bridge was integral
– were obtained.49
CuAAC between 5a and 11Ln progressed smoothly in the
presence of CuOAc/NaAsc as CuI-source and TBTA50 as ligand.
The use of DMSO was important to get a homogeneous solu-
tion, which in turn appears to be crucial for an efficient reac-
tion of these substrates. We reacted 5b with 12Ln, and 5d with
12Ln under similar conditions to obtain ZnNTLn and
ZnTNLn, respectively. The reaction between 5c and 11Ln
returned only starting material both under these conditions,
Scheme 4 Cycloaddition between azidochlorin and alkynyl lanthanide
complexes.
(Schemes 4 and 5). This way we were hoping to vary the length
of the linker, its rigidity, as well as the reactivity profiles of
the coupling partners. Despite the successful application of
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and those reported previously for a range of Ln-complexes Finally, the ability of the chlorin chromophores to sensitise
(CuI, piperidine : CH3CN, microwave heating).48 Purification the NIR emitting lanthanide ions was also investigated.
of CuAAC-products was performed as follows. The reaction
The specific and interesting photophysical features of
mixture was concentrated under vacuum, and the residue was porphyrin derivatives are their very high extinction coeffi-
dissolved in MeOH. Et2O was added, yielding a dark green pre- cients, large Stokes shifts and their ability to sensitise oxygen
cipitate, which was collected by centrifugation. The precipi- to produce reactive singlet oxygen.32,51 The photophysical
tation procedure was repeated until a solid was obtained that properties of porphyrins can be rationalised by a four orbitals
was pure by RP-HPLC analysis. We were not able to obtain representation (Gouterman orbitals, two HOMOs and two
analytically pure ZnNTNd and ZnTNLa this way.
LUMOs).51,52 The most intense absorption peaks are located in
the blue and are known as the B-band or Soret band. Weaker
absorption bands (Q-bands) are found in the green to red
region, giving porphyrins and chlorins their characteristic red
and green colours, respectively.
Chemical characterization
All diamagnetic compounds were characterised using standard
1H and 13C NMR and FT-IR spectroscopy, and HR-ESI-MS. In
all cases the data were in accordance with the expected struc-
tures. Some of the (formyl)dipyrromethane derivatives, the
zinc chlorins 5c and 5d-TIPS were difficult to purify. For the
latter, cleavage of the TIPS group, or demetallation to the free
base chlorins afforded readily purifiable compounds. Attach-
ment of the chlorins to the protected cyclen derivatives
afforded compounds with complex NMR-spectra, as typical for
such species. The identity and the purity of these compounds
could be ascertained using a combination of 1D and 2D
1H NMR spectroscopies, HR-MS and RP-HPLC. The hydrolysis
of the methyl esters in 13Pd, 13Ni and 13Cu was sluggish even
under harsh conditions, and the products were isolated in
small quantities. The low solubility of the products (14Ni,
14Pd and 14Cu), and the paramagnetic nature of the latter pre-
Porphyrin-type structures have notoriously poor solubilities,
and tend to aggregate. The chlorin reference compounds 6–8
were soluble in MeOH, DMSO, THF and toluene. The free base
(7) crystallised overnight from MeOH at concentrations higher
than 0.1 mM. This crystallisation was not observed in solu-
tions of the metallated chlorins 6 and 8. In order to compare
the chlorin references with our previous results,36 when solubi-
lity permitted the measurements were carried out in methanol.
The measurements of 7 were also undertaken in DMSO, yield-
ing bathochromic shifts of the peaks and concentration depen-
dent modifications of the extinction coefficients (see ESI,†
Fig. S1 and S2). The linearity range of the Beer-Lambert law
was assessed for 6–8, and good linearity was found in all cases
up to 5 × 10−6 M. At higher concentrations, deviations become
more and more apparent, especially for the Zn chlorin 6
(see ESI†).
Absorption properties of 6–8 are presented in Table 1 and
Fig. 1. The decadic molar extinction coefficients for the Soret
band and Q-band were calculated by averaging the values
obtained from the MeOH solutions at concentrations of
0.1 μM, 0.5 μM, 1 μM and 5 μM (linearity range of the absor-
bance, see ESI,† Fig. S3). They show an increase of the absorp-
tion compared to the free base in the order 2H ≤ Ni < Pd < Zn
< Cu. Nevertheless, error calculations (taking into account the
error on the mass and volume used to prepare the solutions,
as well as the error on the absorbance measurements)
showed that some of these extinction coefficients could
be quite similar. The well-known hypsochromic shifts upon
complexation of porphyrin-type molecules with metallic
ions can be observed when comparing the chlorin free base
1
cluded the recording of good quality H and 13C NMR spectra.
We were able to prepare 14Cu independently from 13, which is
a fully characterised intermediate, by treatment of a solution
of 13 in CH2Cl2–MeOH with 1 equiv. Cu(OAc)2·H2O. Addition
of the metal salt to the ligand solution resulted in an immedi-
ate colour change from dark green to blue. UV-Vis absorption
spectroscopy revealed the instantaneous disappearance of the
Q-band characteristic of the free base chlorin (λmax = 632 nm),
and the appearance of the one typical of the Cu-species (λmax
=
596 nm). It seems that metallation of the chlorin proceeds
much faster than Cu-binding to the cyclen unit, and selectivity
is easily achieved. This material was used as an RP-HPLC refer-
ence compound during the hydrolysis of 13Pd, 13Ni and 13Cu.
This experiment also suggests that chlorin cupration is
a viable reaction for the late-stage radiolabelling of chlorin-
containing compounds.
The paramagnetic compounds, i.e. all Cu-chelates, as well
Gd-, Yb- and Nd-complexes were characterised by a combi-
nation of HR-ESI-MS or MALDI-MS, RP-HPLC and FT-IR.
These complexes and the others containing a chlorin unit
were also subjected to photophysical characterisation, which is
described below.
Table 1 Absorption properties of the chlorin reference compounds in
methanol. Minimal error due to weight, volume and measurement
inaccuracies given in brackets
B-band
εB/M−1
Q-band
λmax/nm
εQ/M−1
a
λmax/nm
cm−1
cm−1
IB/IQ
7(2H)
6(Zn)
8Cu
8Ni
8Pd
401
404
397
395
390
1.3(3) × 105
2.5(6) × 105
2.7(6) × 105
1.3(3) × 105
1.7(4) × 105
632
602
596
595
583
2.6(6) × 104
4(1) × 104
5(2) × 104
3.8(9) × 104
7(2) × 104
3.9
6.0
5.4
3.3
2.5
Photophysical characterisation
A photophysical characterisation of the chlorin antennae
without the appended lanthanide moiety (chlorin reference
compounds 6–8) was first undertaken. It was then extended to
chlorin–lanthanide dyads attached by a series of linkers. a Ratio calculated from the absorbances at a concentration of 1 μM.
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Fig. 3 Phosphorescence of 8Pd at 77 K in MeOH.
The fluorescence quantum yields of the chlorins were calcu-
lated relative to tetraphenylporphyrin (TPP, see a discussion
on the choice of standard in the ESI†). Free base chlorin 6
exhibited the highest quantum yield of the series with 23%,
with 8.4% obtained for Zn chlorin 7, and 0.05% for 8Pd. The
fluorescence emission of 8Ni was too weak for the quantum
yield to be measured accurately, and finally, 8Cu was comple-
tely non-emissive. These values are typical for free base and
metallated chlorins.53
The quenching of the emission by Cu was as expected. The
low fluorescence quantum yield of the Pd chlorin was also
anticipated because of the increased intersystem crossing rate
(and thus more pronounced phosphorescence) that should
occur with such a heavy ion. This last point seems to be con-
firmed by low temperature phosphorescence measurements.
At 77 K, chlorin phosphorescence from 8Pd was observed at
760 nm (Fig. 3), whereas the fluorescence was completely extin-
guished. All the other chlorins retained their fluorescence
emission at low temperature, but their phosphorescence
was too far in the NIR to be observed with our setup. The life-
time of the triplet state of the Pd chlorin obtained by mono-
exponential fit of the phosphorescent emission decay was
365 μs.
Fig. 1 Absorption spectra of the chlorin reference compounds 6–8 in
MeOH (1 μM, 1 cm pathlength).
reference compounds 7 with the Zn (6), Cu (8Cu), Ni (8Ni) and
Pd (8Pd) complexes. The Soret band is shifted from 408 nm for
the free base to 392 nm for the Pd complex, whereas the
Q-band is shifted from 634 nm to 583 nm. The Q-band is
therefore more affected by the presence of the metal than the
B-band.
In order to keep the absorbance as low as possible but still
obtain a decent signal, the emission photophysical properties
of the chlorin reference compounds were measured at a con-
centration of 1 μM. This concentration was also used to calcu-
late the IB/IQ ratio, the lower concentrations having a larger
relative error on the absorbances, which is illustrated by plot-
ting the IB/IQ ratio as a function of the concentration (see ESI,†
Fig. S4).
The emission and excitation spectra of compounds 6–8 are
shown in Fig. 2. The fluorescence bands are located between
589 nm (8Pd) and 635 nm (free base 7). The Ni chlorin had a
very low emission, and required that the monochromators
be set at high apertures, which yields significant broadening
of the emission bands. The excitation spectra overlap quite
well with the absorption spectra.
The photophysical properties of these chlorin compounds
are promising for singlet oxygen production and for the
sensitisation of NIR-emitting lanthanide ions. However, when
a Ln-do3a moiety is grafted on the chlorin chromophore, the
solubility changes drastically. The lanthanide complexes are
no longer soluble in methanol and are only poorly soluble
in water. Complexes with increased solubility would thus be
highly desirable.54
Saturated solutions were prepared by allowing solid
chlorin–Ln-complexes to stand in water overnight. 10% of THF
was then added, but no significant improvement of the solubi-
lity was observed. The solutions were then filtered and the fil-
trate was diluted in water to obtain comparable absorbances
for all complexes. Because of this solubility issue, no extinc-
tion coefficients could be estimated. The absorbances
were thus normalised to highlight the differences in their
absorption structures (Fig. 4).
The shape of the absorption spectra was quite different for
the same Zn chlorin core with different lanthanide ions in the
do3a moiety attached to the chlorin chromophore via the same
triazole linker (Fig. 4). While the spectra of the Gd and Nd
complexes were very similar, the B-band of the Yb complex was
very different. The maximum of the Soret band of the Gd and
Fig. 2 Emission (red) and excitation (blue) spectra of the emissive
chlorin reference compounds 6 (Zn), 7 (2H), 13Cu, 13Pd and 13Ni, 1 μM
in methanol at room temperature.
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tion complicates the comparison of the sample absorption
with the reference standard. These quantum yields are there-
fore to be taken with caution. We calculated Φf = 0.5% for
ZnNTGd and ZnNTYb, 0.23% for ZnNTNd and 0.08% for the
reversed clicked linker ZnTNYb. Despite all precautions, the
reversed linker seems once more to behave differently and
yields a lower fluorescence quantum yield. We could not find
evidence that this lower quantum yield is correlated with an
increased luminescence from the Yb ion since our setup was
not able to measure NIR emission.
Finally, we tried to investigate the NIR emissions from the
lanthanide ions of a Pd- or free base chlorin-appended Nd
do3a complex and Yb do3a complex. Unfortunately, the charac-
teristic NIR peaks of Yb (980 nm) and Nd (1064 nm) could not
be observed at the maximum aperture of the available setup,
even in deuterated solvents and in deoxygenated solutions,
which means that the NIR emission should be extremely weak.
In our previous work demonstrating the Yb and Nd sensitis-
ation by chlorin chromophores, the NIR emission was faint,
and required a laser excitation to be observed. Further studies
with an instrumentation optimised for NIR emissions would
be required to assess the potential of these dyads as NIR emit-
ters. In parallel, solid state measurements could provide valu-
able results. Lanthanide complexes are usually stronger
emitters in solid state than in solution.
Fig. 4 Normalised absorbances of chlorin-appended lanthanide com-
plexes in H2O, diluted saturated solutions.
Nd is a broad band around 349 nm whereas the Yb has a
normal peak around 409 nm. The broad band is also
present in the Yb complex, and has a slightly lower extinction
than the peak at 409 nm. The peak at 409 nm appears on the
spectra of the Gd and Nd complexes as a shoulder of the
349 nm broad band. Moreover, the Yb complex with the
reversed clicked linker is completely different, with absorption
features similar to those of the Zn chlorin reference
compound. The Q-band is at the same energy (609 nm) for all
these complexes.
Because of the poor solubility of the complexes, these
changes of the absorption spectra may be due to different
types of aggregates. The broadened, red-shifted bands com-
pared to the chlorin reference compound also support aggrega-
tion. If so, the reversed clicked linker could help limit
aggregation by recovering solubilised species that are closer to
the chlorin reference compound.
Conclusions
The de novo synthesis of a set of hydroporphyrins (chlorins)
with various reactive groups (COOH, azide, alkyne) were pre-
pared. Such bioconjugatable red-absorbing chromophores
could be useful for targeted photodynamic therapy or fluo-
rescence imaging. Attachment of the chlorins to lanthanide
complexes was achieved using either a three-step ligand coup-
ling-deprotection-Ln-complexation protocol, or CuAAC with
pre-formed lanthanide complexes. The photophysics of the
chlorin reference compounds were well characterised and were
promising. However, once appended to NIR-emitting lantha-
nides, no NIR sensitisation could be observed. The linker in
this type of chlorin–lanthanide dyads was found to be crucial
for the photophysical properties, and probably also plays a sig-
nificant role in outlining aggregation. The poor solubility of
these structures is indeed a major issue that should be con-
sidered when designing such molecular tools. Therefore, deri-
vatisations of the chlorin moiety with solubilising groups or
linkers54,55 using the same chemistry developed here could
transform these molecules into valuable probes. It is worth
noting that even in this limited set of compounds, very small
overlap between the Q-band absorption of the different com-
pounds, as well as between their emission bands is achievable
by simple metallation, suggesting that multicolour excitation
spectroscopy is a possibility with suitable instrumentation.
Finally, an investigation of the chlorin moieties for singlet
oxygen production provides an interesting avenue for PDT-
applications.
The fluorescence of Zn chlorin clicked lanthanide do3a
complexes is similar irrespective of the lanthanide ion or the
triazole linker geometry (Fig. 5). The fluorescence quantum
yields were estimated relative to TPP. Scattering due to aggrega-
Fig. 5 Emission (red) and excitation (blue) spectra of triazole-linked
complexes in water.
This journal is © The Royal Society of Chemistry 2015
Dalton Trans., 2015, 44, 2541–2553 | 2547

Paper
Dalton Transactions
the sample (s) and of the reference (ref). Excitation wave-
lengths where the absorptances of the samples and of
the reference were the same were chosen (i.e. where the
Experimental
General procedures
1H NMR (300 MHz, 400 MHz or 500 MHz) and 13C NMR absorptions are identical, so are the absorptances). The low
(75 MHz, 100 MHz or 125 MHz) spectra were recorded on a temperature measurements were done in quartz capillaries at
Varian 300, a Varian 400 or a Bruker 500 MHz instrument, 77 K by immersion in a quartz Dewar filled with liquid
respectively. Chemical shifts were referenced to residual nitrogen.
solvent peaks and are given as follows: chemical shift
(δ, ppm), multiplicity (s, singlet; br, broad singlet; d, doublet,
2
Is Aref ðnsÞ
Φs ¼
2 Φref
ð1Þ
Iref As
ðnref
Þ
t, triplet; q, quartet; m, multiplet), coupling constant (Hz),
integration. IR experiments were performed on a Perkin Elmer
spectrum-100 FT-IR spectrometer equipped with an ATR acces-
sory. HR-ESI-MS analyses were performed on a Bruker Micro-
TOF ESI mass spectrometer, or by the mass spectrometry
Synthesis
General procedure for dipyrromethane synthesis. Following
service of the Ecole Polytechnique Federale de Lausanne. Com- a previously reported procedure,59 the aldehyde (1 equiv.) was
pounds 1c,56 1d,57 6, 7 and 7-COOH,36 2-azido O-tosyletha- dissolved in pyrrole (20 equiv.), and InCl3 (0.1 equiv.) was
nol,58 and Western half40 were synthesised as reported in added to this solution. The reaction mixture was stirred
the literature. Complexes 11Ln,46 12Ln,48 and ligand 1036 were at room temperature under a nitrogen atmosphere for ∼3 h.
prepared analogously to known compounds. All other chemi- When TLC-analysis (petroleum ether–EtOAc–CH2Cl2 = 7 : 1 : 2)
cals were from commercial sources and used as received. indicated the disappearance of the aldehyde, powdered NaOH
Microwave heating was performed with a Biotage Initiator (0.5 equiv.) was added. Stirring was continued for an
instrument.
additional 15 min. The mixture was filtered, the filter cake was
washed with a small amount of CH2Cl2, and the filtrate was
concentrated under reduced pressure. The dark oily residue
Chromatography
Preparative chromatography was performed using silica was purified by column chromatography [silica, petroleum
(230–400 mesh). Thin layer chromatography was performed ether–EtOAc–CH2Cl2 (7 : 1 : 2)] to afford the dipyrromethanes.
on silica-coated aluminium plates. Samples were visualised by
2a. Brown oil (83%): tR 3.909 min; νmax 3372, 2931, 2871,
UV-light (254 and 356 nm), or by staining with KMnO4/K2CO3. 2103, 1608, 1557, 1508, 1459, 1300, 1237, 1174, 1090,
1
RP-HPLC was performed on an Agilent Technologies 1100 1026 cm−1; H NMR (300 MHz, CDCl3) 3.59 (t, J = 4.8 Hz, 2H),
system using a Chromolith® Performance RP-18 end-capped 4.15 (t, J = 4.8 Hz, 2H), 5.40 (s, 1H), 5.94 (d, J = 0.6 Hz, 2H),
100 mm*4.6 mm HPLC column with water (0.1% TFA): CH3CN 6.20–6.22 (m, 2H), 6.67–6.68 (m, 2H), 6.91, 7.16 (ABq, J =
(0.1% TFA) eluent system (0 min: 100% water; 8 min: 100% 8.6 Hz, 4H), 7.88 (br, 1H); 13C NMR (75 MHz, CDCl3) 43.2,
CH3CN; 10 min: 100% CH3CN). Detection wavelengths: 214, 50.2, 67.1, 107.2, 108.4, 114.7, 117.3, 129.6, 132.9, 135.1, 157.2;
254, 397, 596 nm.
HR-ESI-MS calcd 306.1360 obsd 306.1350 [(M − H)–, M =
C17H17N5O].
Photophysical measurements
2b. Off-white solid (62%): tR 3.743 min; νmax 3381, 3289,
All measurements were performed in spectroscopic grade 2923, 2120, 1606, 1507, 1215, 1176, 1113, 1089, 1025 cm−1
;
solvents. Quartz cells with 1 cm or 0.2 cm optical pathlengths 1H NMR (400 MHz, CDCl3) 2.51 (s, 1H), 4.68 (s, 2H), 5.44
were used for the room temperature measurements. The absor- (s, 1H), 5.91 (s, 2H), 6.16 (d, J = 2.4 Hz, 2H), 6.70 (s, 2H), 6.93
bances were measured by a Varian Cary 100 Bio UV-Visible (d, J = 8.2 Hz, 2H), 7.15 (d, J = 8.2 Hz, 2H), 7.91 (br, 2H);
spectrophotometer. The emission and excitation spectra, life- 13C NMR (100 MHz, CDCl3) 43.2, 55.9, 75.6, 78.6, 107.2, 108.4,
times and quantum yields were measured by a FluoroMax-4P 115.0, 117.2, 129.4, 132.7, 135.2, 156.5; HR-ESI-MS calcd
from Horiba. NIR measurements were attempted on a Fluoro- 275.1200 obsd 275.1190 [(M − H)−, M = C18H16N2O].
log-3 from Horiba equipped with a red sensitive PMT spanning
2c. Pale brown solid (70%): tR 3.734 min; νmax 3372, 3100,
the 400–1100 nm spectral range. All emissions were corrected 2409, 2115, 1678, 1502, 1283, 1114, 1089, 1027 cm−1; H NMR
by the wavelength sensitivity (correction function) of the (400 MHz, THF-d8) 5.37 (s, 1H), 5.64 (s, 1H), 5.94 (d, J = 4.0 Hz,
spectrometer. The quantum yields were measured at room 2H), 6.60 (d, J = 4.0 Hz, 2H), 6.96, 7.19 (ABq, J = 10.0 Hz, 4H),
temperature and relative to fluorescence grade tetraphenyl- 9.71 (br, 1H); 13C NMR (100 MHz, THF-d8) 43.6, 106.7, 107.0,
porphyrin (TPP). A 1 μM concentration solution of TPP in 116.7, 118.4, 129.8, 132.7, 137.9, 140.9; HR-APPI-MS calcd
toluene was used as a quantum yield standard, Φf = 11%. 263.1165 obsd 263.1170 [M+, M = C15H13N5].
1
The quantum yields were calculated according to eqn (1), with
2d. Yellow oil (99%): tR 6.223 min; νmax 3378, 2943, 2865,
Φs the quantum yield of the sample, Φref the quantum yield 2155, 1679, 1557, 1506, 1463, 1404, 1221, 1090, 1028 cm−1
;
of the reference, I the integrated corrected emission intensity 1H NMR (400 MHz, THF-d8) 1.15–1.21 (m, 21H), 5.38 (s, 1H),
of the sample (s) and of the reference (ref), A the absorptance 5.66 (s, 2H), 5.93–5.94 (m, 2H), 6.59 (s, 2H), 7.16, 7.35 (ABq, J =
(≠ absorbance) of the sample (s) and of the reference (ref) 8.0 Hz, 4H), 9.70 (br, 2H); 13C NMR (100 MHz, THF-d8) 11.3,
at the excitation wavelength and n the refractive indexes of 18.1, 44.1, 88.7, 106.7, 107.0, 107.7, 116.8, 121.1, 128.4, 131.4,
2548 | Dalton Trans., 2015, 44, 2541–2553
This journal is © The Royal Society of Chemistry 2015

Dalton Transactions
Paper
132.4, 144.5; HR-ESI-MS calcd 401.2418 obsd 401.2421 128.2, 130.0, 132.4, 132.5, 140.7, 142.2, 178.7; HR-ESI-MS calcd
[(M − H)−, M = C26H34N2Si].
431.2526 obsd 431.2513 [(M + H)+, M = C27H34N2OSi].
General synthesis of monoformyl-dipyrromethanes. A solu-
General procedure for chlorin formation. Based on the pro-
tion of the dipyrromethane in anhydrous CH2Cl2 [0.1 M after cedure developed for sparsely substituted chlorins.39 A solu-
addition of (COCl)2] was cooled in an ice-water bath under a tion of the formyldipyrromethane (0.1 M in THF) was cooled
nitrogen atmosphere. This solution was treated with the Vils- in an acetone-dry ice bath.
A single portion of NBS
meier reagent formed from (COCl)2 (1.2 equiv.) and DMF (1.05 equiv.) was added, and the reaction mixture was stirred
(0.5 mL) at 0 °C. The reaction was monitored by TLC analysis for 1 h. The cooling bath was removed, and the mixture was
[petroleum ether–EtOAc (3 : 1)], if required an additional diluted with sat. aq. NaHCO3 and EtOAc. The phases were sep-
portion (0.5 equiv.) of the Vilsmeier reagent was added after arated. The aqueous layer was extracted with EtOAc, and the
30 min. When TLC analysis indicated the consumption of combined organic layers were dried (Na2SO4). The organic
the starting material and the formation of a major, more layer was concentrated under reduced pressure without
polar compound, aqueous NaOH was added. The phases were heating. The dark brown, oily residue was used in the conden-
separated, and the aqueous layer was extracted with CH2Cl2. sation step without further purification. The Eastern half
The combined organic layer was washed with water and brine, and the Western half40 (1 equiv.) were dissolved in CH2Cl2
and was dried (Na2SO4). The solvent was evaporated and the (0.05 M), and the solution was placed under a N2 atmosphere.
oily residue was purified by column chromatography [silica, A solution of p-TsOH·H2O (5 equiv.) in MeOH (1 M) was added
petroleum ether–EtOAc (3 : 1→2 : 1)].
dropwise. Stirring was continued for 30 min. The reaction was
3a. Brown, slowly solidifying oil (55%): tR 3.741 min; νmax quenched by the addition of tetramethylpiperidine (TMPi,
3250, 2931, 2869, 2105, 1631, 1561, 1508, 1485, 1412, 1350, 10 equiv.), and the mixture was concentrated under reduced
1
1300, 1236, 1173, 1040 cm−1; H NMR (300 MHz, CDCl3) 3.58 pressure without heating. The dark yellow solid thus obtained
(t, J = 4.8 Hz, 2H), 4.11 (t, J = 4.8 Hz, 2H), 5.48 (s, 1H), was dissolved in CH3CN (0.005 M). TMPi (25 equiv.), Zn(OAc)2
5.92–5.95 (m, 1H), 6.08–6.11 (m, 1H), 6.13–6.16 (m, 1H), (15 equiv.), and finally AgOTf (3 equiv.) were added, and the
6.70–6.72 (m, 1H), 6.81–6.89 (m, 3H), 7.06–7.10 (m, 2H), 8.31 flask was placed into a bath pre-heated to 85 °C. The mixture
(br, 1H), 9.21 (d, J = 2.1 Hz, 1H), 9.76 (br, 1H); 13C NMR was heated open to the air for 18–24 h. When TLC analysis
(75 MHz, CDCl3) 43.3, 51.1, 67.0, 107.7, 108.5, 110.8, 114.8, (silica, CH2Cl2) indicated that chlorin formation was complete,
117.9, 122.6, 129.5, 130.8, 132.2, 133.4, 143.3, 157.5, 178.7; the mixture was concentrated, and briefly dried to remove
HR-ESI-MS calcd 334.1280 obsd 334.1309 [(M
M = C18H17N5O2].
−
H)−, high-polarity solvent residues. The crude product was loaded
onto a silica chromatography column, and the chlorin, a dark
3b. Brownish oil (42%): tR 3.583 min; νmax 3281, 2825, 2120, green apolar band, was isolated by elution with CH2Cl2–
1634, 1507, 1485, 1413, 1351, 1302, 1262, 1216, 1175, petroleum ether.
1
1025 cm−1; H NMR (300 MHz, CDCl3) 2.52 (t, J = 2.2 Hz, 1H),
5a. Green solid (37%): tR 5.572 min; νmax 2955, 2927, 2107,
1H NMR
4.67 (d, J = 2.2 Hz, 2H), 5.47 (s, 1H), 5.94 (s, 1H), 6.08–6.10 (m, 1610, 1575, 1523, 1508, 1236, 1175, 1005 cm−1
;
1H), 6.14–6.17 (m, 1H), 6.70–6.72 (m, 1H), 6.87–6.93 (m, 3H), (400 MHz, CDCl3/CD3OD) 2.00 (s, 6H), 3.42 (t, J = 4.8 Hz, 2H),
7.10 (d, J = 8.7 Hz, 2H), 8.17 (br, 1H), 9.25 (s, 1H), 9.48 (br, 4.04 (t, J = 4.8 Hz, 2H), 4.46 (s, 2H), 7.06 (d, J = 8.4 Hz, 2H),
1H); 13C NMR (75 MHz, CDCl3) 43.3, 55.8, 75.7, 78.5, 107.8, 7.95 (d, J = 8.4 Hz, 2H), 8.49 (d, J = 4.0 Hz, 1H), 8.54 (s, 1H),
108.6, 110.8, 115.0, 115.2, 117.9, 122.3, 129.4, 130.7, 132.2, 8.58–8.59 (m, 2H), 8.65 (d, J = 4.4 Hz, 1H), 8.73 (d, J = 4.4 Hz,
133.5, 143.0, 156.8, 178.7; HR-ESI-MS calcd 303.1139 obsd 1H), 8.83 (d, J = 4.0 Hz, 1H), 9.03 (d, J = 4.0 Hz, 1H), 9.56 (s,
303.1079 [(M − H)−, M = C19H16N2O2].
1H); 13C NMR (400 MHz, CDCl3/CD3OD) 34.8, 49.3, 54.2, 54.4,
3c. Brown solid (38%): tR 3.734 min; νmax 3244, 2921, 2854, 71.0, 97.3, 100.1, 112.7, 116.5, 126.5, 130.5, 131.1, 131.6, 132.5,
1
2122, 1640, 1504, 1484, 1412, 1348, 1286, 1178, 1044 cm−1; H 136.5, 138.7, 140.1, 149.95, 150.0, 150.2, 151.3, 156.9, 157.8,
NMR (300 MHz, CDCl3) 5.52 (m, 1H), 6.09–6.11 (m, 1H), 161.6, 162.8, 174.8. HR-ESI-MS calcd 564.1494 obsd 564.1485
6.14–6.16 (m, 1H), 6.71–6.73 (m, 1H), 6.89–6.96 (m, 3H), [(M + H)+, M = C30H25N7OZn].
7.12–7.16 (m, 2H), 8.33 (br, 1H), 9.24 (d, J = 1.2 Hz, 1H), 9.87
5b. Bluish-green solid (50%): tR 5.444 min; νmax 3293, 2957,
1H NMR
(br, 1H); 13C NMR (75 MHz, CDCl3) 43.5, 108.0, 108.6, 110.9, 1617, 1508, 1218, 1176, 1052, 1007, 992 cm−1
;
118.1, 119.3, 122.6, 129.7, 130.3, 132.4, 137.4, 139.2, 142.8, (400 MHz, CDCl3/CD3OD) 2.00 (s, 6H), 2.67 (s, 1H), 4.46 (s,
178.8; HR-ESI-MS calcd 314.1012 obsd 314.1013 [(M + Na)+, 2H), 4.88 (s, 2H), 7.27 (d, J = 8.8 Hz, 2H), 8.02 (d, J = 8.0 Hz,
M = C16H13N5O].
2H), 8.53–8.55 (m, 2H), 8.58–8.60 (m, 2H), 8.69 (d, J = 4.4 Hz,
3d. Brown oil (88%): tR 6.068 min; νmax 3253, 2942, 2864, 1H), 8.74 (d, J = 4.4 Hz, 1H), 8.84 (d, J = 4.4 Hz, 1H), 9.04 (d, J =
2154, 1630, 1560, 1487, 1463, 1413, 1350, 1220, 1177, 1042, 4.4 Hz, 1H), 9.56 (s, 1H); 13C NMR (100 MHz, CDCl3/CD3OD)
1018, 996 cm−1 1H NMR (300 MHz, CDCl3) 1.05–1.16 (m, 31.0, 45.4, 50.4, 75.8, 78.8, 93.4, 96.2, 108.7, 113.0, 122.5,
;
21H), 5.51 (s, 1H), 5.94–5.97 (m, 1H), 6.07–6.09 (m, 1H), 6.16 126.6, 127.2, 127.7, 128.6, 132.5, 132.7, 134.7, 136.4, 146.0,
(dd, J1 = 6.0 Hz, J2 = 2.4 Hz, 1H), 6.71–6.74 (m, 1H), 6.88–6.90 146.3, 152.9, 153.9, 157.0, 158.8, 170.8; HR-ESI-MS calcd
(m, 1H), 7.08–7.10 (m, 2H), 7.39–7.43 (m, 2H), 8.21 (br, 1H), 532.1236 obsd 532.1248 [M+, M = C31H24N4OZn].
9.24 (s, 1H), 9.58 (br, 1H); 13C NMR (75 MHz, CDCl3) 11.3,
5c. Green solid (23%): tR 5.742 min; νmax 3034, 2956, 2923,
18.7, 43.9, 91.2, 106.5, 108.1, 108.7, 110.9, 118.1, 122.4, 122.8, 2410, 2253, 2120, 2086, 1614, 1523, 1503, 1300, 1269, 1180,
This journal is © The Royal Society of Chemistry 2015
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Paper
Dalton Transactions
1143, 1049, 1005 cm−1
;
1H NMR (400 MHz, CDCl3) 2.02 (s, and the mixture was heated at 180 °C for 30 min with micro-
6H), 4.52 (s, 2H), 7.34 (d, J = 7.8 Hz, 2H), 8.06 (d, J = 7.8 Hz, wave irradiation. The mixture was concentrated, and the
2H), 8.47 (d, J = 3.9 Hz, 1H), 8.56 (s, 1H), 8.62–8.64 (m, 3H), residue purified by column chromatography [silica, pentane–
8.75 (d, J = 3.9 Hz, 1H9, 8.85 (d, J = 3.9 Hz, 1H), 9.06 (d, J = CH2Cl2 (1 : 2)]. A reddish green solid was obtained (68%):
3.9 Hz, 1H), 9.58 (s, 1H); 13C NMR (75 MHz, CDCl3) 43.3, 55.8, tR 6.616 min; νmax 2960, 2927, 1752, 1642, 1511, 1368,
75.7, 78.5, 107.8, 108.6, 110.8, 115.0, 115.2, 117.9, 122.3, 129.4, 1217 cm−1 1H NMR (400 MHz, CDCl3) 1.59 (s, 9H), 1.81 (s,
;
130.7, 132.2, 133.5, 143.0, 156.8, 178.7; HR-ESI-MS calcd 6H), 4.13 (br, 2H), 4.74 (s, 2H), 7.17 (d, J = 7.8 Hz, 2H), 7.82 (d,
519.1144 obsd 519.1164 [M+, M = C28H21N7Zn].
J = 7.8 Hz, 2H), 8.14 (s, 1H), 8.23 (s, 1H), 8.32–8.34 (m, 2H),
5d-TIPS. Green solid (12%): tR 7.679 min; νmax 2942, 2865, 8.47–8.48 (m, 2H), 8.60 (d, J = 4.3 Hz, 1H), 8.78 (d, J = 4.3 Hz,
2154, 1615, 1524, 1501, 1463, 1221, 1051, 1007, 992 cm−1
;
1H), 9.21 (s, 1H); 13C NMR (100 MHz, CDCl3) 28.2, 45.8, 50.2,
1H NMR (400 MHz, CDCl3/CD3OD) 1.17 (s, 21H), 1.96 (s, 6H), 66.0, 82.5, 93.5, 96.2, 113.2, 126.7, 127.4, 128.0, 128.5, 133.0,
4.47 (br, 2H), 7.74 (d, J = 7.4 Hz, 2H), 7.96 (d, J = 7.4 Hz, 2H), 133.1, 133.8, 134.0, 157.7, 168.1; HR-APPI-MS calcd 603.1901
8.40 (s, 1H), 8.50 (s, 1H), 8.55 (s, 2H), 8.68 (s, 1H), 8.77 (s, 1H), obsd 603.1910 [(M + H)+, M = C34H32N4O3Ni].
8.99 (s, 1H), 9.51 (s, 1H); 13C NMR (100 MHz, CDCl3/CD3OD)
8Cu. A solution of 7 (50 mg, 0.1 mmol) in CHCl3–MeOH
11.4, 18.7, 30.9, 45.3, 50.3, 91.1, 93.5, 96.2, 107.4, 108.7, 122.0, (9 : 1, 20 mL) was treated with Cu(OAc)2·H2O (10 equiv.).
122.2, 126.7, 127.7, 128.3, 130.1, 132.5, 133.6, 143.3, 146.0, The mixture was stirred at room temperature overnight. The
146.2, 146.6, 152.8, 153.8, 158.9, 170.8; HR-ESI-MS calcd sample was diluted with water and CH2Cl2, the phases were
659.2543 obsd 659.2594 [(M + H)+, M = C39H42N4SiZn].
separated, and the aqueous layer was extracted with CH2Cl2.
5d. A sample of 5d-TIPS (27 mg, 0.055 mmol) in CH2Cl2 The combined organic layer was washed with water, dried
(2 mL) was treated with AcOH (5 μL) and TBAF60 in THF (2 mL, (Na2SO4) and concentrated. The residue purified by column
1 M). After 1 h TLC-analysis indicated the complete consump- chromatography [silica, pentane–CH2Cl2 (1 : 2)] affording a
tion of the starting material. Water and EtOAc were added to dark blue-green solid (58%): tR 6.910 min; νmax 2957, 1750,
the reaction mixture, the phases were separated, and the 1639, 1602, 1539,1515, 1380, 1366, 1326, 1215, 1151, 1054,
organic phase was washed with water, and dried (Na2SO4). 1006 cm−1
Column chromatography [silica, CH2Cl2–petroleum ether [M+, M = C34H32CuN4O3].
(1 : 1)] afforded a dark green solid (55%): tR 5.626 min; νmax
9Pd. Following the procedure developed by Bruckner,42
3288, 2954, 2922, 2854, 1610, 1521, 1498, 1445, 1262,1215, microwave vial was charged with 7-COOH (19 mg, 0.038 mmol)
1050, 1003 cm−1 1H NMR (400 MHz, CDCl3/CD3OD) 1.99 (s, and Pd(acac)2 (236 mg, 0.775 mmol). Pyridine (4 mL) was
;
HR-ESI-MS calcd 607.1765 obsd 607.1768
a
;
6H), 2.86 (s, 1H), 4.46 (s, 2H), 7.32 (d, J = 7.6 Hz, 2H), 8.05 (d, added, the vial was capped, and the mixture was heated at
J = 8.0 Hz, 2H), 8.46 (d, J = 4.4 Hz, 1H), 8.54 (s, 1H), 8.59–8.61 180 °C for 30 min with microwave irradiation. The mixture was
(m, 3H), 8.72 (d, J = 4.0 Hz, 1H), 8.82 (d, J = 4.0 Hz, 1H), 9.02 concentrated, and the residue was purified by column chrom-
(d, J = 4.4 Hz, 1H), 9.55 (s, 1H); 13C NMR (100 MHz, CDCl3/ atography [silica, CH2Cl2–MeOH (20 : 1→10 : 1)]. A pink solid
CD3OD) 31.0, 45.4, 50.4, 93.6, 96.3, 108.7, 117.1, 121.7, 126.8, was obtained (70%): tR 5.596 min; νmax 2923, 2854, 1740, 1635,
127.3, 127.8, 128.3, 132.3, 132.6, 135.0, 139.1, 139.9, 145.8, 1604, 1510, 1427, 1362, 1328, 1228, 1214, 1177, 1059,
146.0, 146.3, 146.9, 152.9, 153.9, 159.0, 170.9. HR-ESI-MS calcd 1009 cm−1 1H NMR (400 MHz, CD3OD/CDCl3) 1.94 (s, 6H),
;
503.1136 obsd 503–1209 [(M + H)+, M = C30H22N4Zn].
8Pd. Following the procedure developed by Bruckner,42
4.48 (s, 2H), 4.86 (s, 2H), 7.23 (d, J = 8.2 Hz, 2H), 7.88 (d, J =
8.2 Hz, 2H), 8.45 (d, J = 4.3 Hz, 1H), 8.49 (s, 2H), 8.64–8.67 (m,
a
microwave vial was charged with 7 (47 mg, 0.086 mmol) and 3H), 8.76 (d, J = 4.3 Hz, 1H), 8.89 (d, J = 4.7 Hz, 1H), 9.60 (s,
Pd(acac)2 (131 mg, 0.43 mmol, 5 equiv.). Pyridine (6 mL) was 1H); 13C NMR (100 MHz, CD3OD/CDCl3) 30.2, 45.2, 49.7, 65.1,
added, the vial was capped, and the mixture was heated at 95.1, 97.5, 109.7, 112.9, 123.3, 126.2, 126.9, 127.1, 127.4, 131.7,
180 °C for 30 min with microwave irradiation. The mixture 134.3, 134.6, 137.3, 137.5, 138.3, 138.8, 142.0, 144.6, 145.5,
was concentrated, and the residue was purified by column 149.9, 157.7, 161.6, 171.4; HR-ESI-MS calcd 593.0822 obsd
chromatography [silica, pentane–CH2Cl2 (1 : 2)]. A pink solid 593.0979 [(M − H)−, M = C30H24N4O3Pd].
was obtained (63%): tR 6.669 min; νmax 2961, 2926, 1748, 1626,
9Ni. Procedure 1. A microwave vial was charged with 8Ni
1509, 1259, 1215, 1150, 1079, 1006 cm−1; H NMR (400 MHz, (20 mg, 0.040 mmol). Benzonitrile (2 mL) was added, the vial
CDCl3/CD3OD) 1.55 (s, 9H), 1.94 (s, 6H), 4.50 (s, 2H), 4.72 (s, was capped, and the mixture was heated at 210 °C for 30 min
2H), 7.16 (d, J = 8.4 Hz, 2H), 7.89 (d, J = 8.4 Hz, 2H), 8.47 (d, J = with microwave irradiation. The mixture was concentrated,
4.4 Hz, 1H), 8.50 (s, 1H), 8.62 (s, 1H), 8.64 (d, J = 4.4 Hz, 1H), and the residue purified by column chromatography [silica,
8.77 (d, J = 4.0 Hz, 1H), 8.88 (d, J = 4.4 Hz, 1H), 9.61 (s, 1H); CH2Cl2–MeOH (20 : 1→10 : 1)]. A dark green solid was obtained
13C NMR (100 MHz, CDCl3/CD3OD) 24.1, 26.7, 41.5, 62.0, 78.8, (83%).
1
105.9, 109.0, 122.3, 123.0, 123.3, 127.9, 128.0, 130.4, 130.7,
Procedure 2. A microwave vial was charged with 7-COOH
153.7, 164.5; HR-APPI-MS calcd 651.1595 obsd 651.1697 (30 mg, 0.061 mmol) and Ni(OAc)2·H2O (152 mg, 0.61 mmol,
[(M + H)+, M = C34H32N4O3Pd].
8Ni. microwave vial was charged with
10 equiv.). Pyridine (3 mL) was added, the vial was
(27 mg, capped, and the mixture was heated at 180 °C for 30 min with
A
7
0.049 mmol) and Ni(OAc)2·4H2O (122 mg, 0.49 mmol, microwave irradiation. The mixture was concentrated, and the
10 equiv.). Pyridine (3 mL) was added, the vial was capped, residue was purified by column chromatography [silica,
2550 | Dalton Trans., 2015, 44, 2541–2553
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Dalton Transactions
Paper
CH2Cl2–MeOH (20 : 1→10 : 1)]. A dark green solid was obtained for the 4.09–9.17 ppm region. 1.20–3.77 [m, contains 1.75 (s,
(81%): tR 5.557 min; νmax 2922, 1611, 1509, 1456, 1380, 1317, 6H)] 4.09 (s, 2H), 4.63 (s, 2H), 7.18 (d, J = 7.8 Hz, 2H),
1238, 1176, 1051, 1003, 988 cm−1
;
1H NMR (400 MHz, 7.40–7.41 (m, 0.51H), 7.46–4.74 (m, 1H), 7.74–7.78 (m, 2.5 H),
CD3OD/CDCl3) 1.74 (s, 6H), 3.96 (s, 2H), 4.75 (s, 2H), 7.19 (d, 7.93 (s, 1.25H, DMF), 8.12 (s, 1H), 8.20 (as, 3H), 8.29 (d, J =
J = 7.9 Hz, 2H), 7.74 (d, J = 7.9 Hz, 2H), 8.04 (s, 1H), 8.12 (s, 4.3 Hz, 1H), 8.36 (d, J = 4.7 Hz, 1H), 8.43 (d, J = 4.3 Hz, 1H),
1H), 8.17 (s, 1H), 8.23 (d, J = 4.0 Hz, 1H), 8.34 (d, J = 4.3 Hz, 8.54 (d, J = 4.3 Hz, 1H), 8.74 (d, J = 4.3 Hz, 1H), 9.17 (s, 1H).
1H), 8.44 (d, J = 3.9 Hz, 1H), 8.50 (d, J = 3.9 Hz, 1H), 8.73 (d, J =
General procedure for methyl ester deprotection. A sample
4.3 Hz, 1H), 9.14 (s, 1H); 13C NMR (100 MHz, CD3OD/CDCl3) of the protected ligand (0.028 mmol) was dissolved in THF
19.9, 27.7, 45.4, 49.7, 64.9, 93.2, 95.9, 108.2, 112.9, 124.3, (0.5 mL). 1 M LiOH (aq, 0.5 mL), 1 M NaOH (aq, 0.5 mL) and
126.5, 127.2, 127.9, 130.5, 132.8, 133.8, 157.7, 171.4, 174.0; 1 M KOH (aq, 0.5 mL) were added, and the reaction mixture
HR-ESI-MS calcd 545.1129 obsd 545.1169 [(M
M = C30H23N2NiO3].
−
H)−, was heated at 70 °C for 2–3 days. The reaction progress was
monitored by RP-HPLC. If deemed necessary, additional
9Cu. A solution of 7-COOH (5 mg, 0.010 mmol) in CH2Cl2– portions of LiOH or KOH were added. When RP-HPLC analysis
MeOH (3 : 1, 4 mL) was treated with Cu(OAc)2·H2O (10 equiv.). indicated the complete consumption of the starting material,
The mixture was stirred at room temperature for 5 min. the reaction mixture was concentrated, and the residue
The sample was concentrated, and the residue was purified was purified by column chromatography [silica, CH2Cl2–
by column chromatography [silica, CH2Cl2–MeOH (20 : 1)] MeOH (10 : 1→5 : 1)].
affording a green solid (85%): tR 5.787 min; νmax 2921, 2852,
1639, 1602, 1464, 1424, 1226, 1053, 1007, 994 cm−1
14Pd. Pink solid (26%): tR 5.577 min; νmax 3341, 2949, 2837,
1453, 1018, 844 cm−1; 1H NMR (400 MHz, THF-d8) 1.91 (s, 6H),
;
HR-ESI-MS calcd 550.1072 obsd 550.1090 [(M − H)−, M = 1.91–3.37 (∼23H), 4.53 (s, 2H), 4.77 (s, 2H), 7.17 (d, J = 8.0 Hz,
C30H24CuN4O3].
2H), 7.82 (d, J = 8.0 Hz, 2H), 8.40 (d, J = 3.7 Hz, 1H), 8.44 (d, J =
General procedure for amide bond formation. The chlorin 4.7 Hz, 1H), 8.49 (d, J = 4.3 Hz, 1H), 8.63 (d, J = 4.7 Hz, 1H),
carboxylic acid (1 equiv.) and the amine-functionalised cyclen 8.69–8.74 (m, 3H), 8.87 (d, J = 4.7 Hz, 1H), 9.63 (s, 1H);
(1.1 mmol) were dissolved in anhydrous DMF (0.024 M). The 13C NMR (100 MHz, CDCl3/THF-d8) 13.4, 19.9, 22.4, 27.7, 29.4,
solution was cooled in an ice-water bath, and DIPEA 29.7, 31.7, 45.4, 49.7, 64.9, 93.2, 95.9, 108.2, 112.9, 126.5,
(2.2 equiv.) and HATU (1.1 mmol) were added. The reaction 127.2, 127.7, 127.9, 132.5, 132.7, 133.8, 157.7, 174.0;
was allowed to warm to room temperature, and stirring was HR-MALDI-MS calcd 966.3141 obsd 966.2492 [(M + H)+, M =
continued for ∼24–48 h. When TLC analysis indicated the C46H53N9O8Pd].
complete consumption of the starting chlorin, the reaction
14Cu. Dark blue solid (23%): tR 5.792 min; νmax 3676, 2972,
mixture was diluted with EtOAc and dil. aq. NaHCO3. The 2902, 2342, 2326, 1641, 1394, 1229, 1063 cm−1; HR-MALDI-MS
phases were separated, and the aqueous layer was extracted calcd 922.3308 obsd 922.5175 (M+, M = C46H53CuN9O8).
with EtOAc. The combined organic phases were washed with
water twice, and dried (Na2SO4). The organic layer was concen- 2988, 2901, 2357, 2342, 2326, 1406, 1394, 1250, 1057 cm−1
trated, and the oily residue was purified by column chromato- 1H NMR (500 MHz, THF-d8) Due to solvent overlap with
graphy [silica, CH2Cl2–MeOH (20 : 1→10 : 1)]. cyclen-CH2, C(O)NHCH2 and CH2CO2H signals, integral values
13Pd. Pink solid (93%): tR 5.277 min; νmax 2958, 2842, 1732, are only reported for the 4.13–9.24 ppm region. 4.13 (br, 2H),
1510, 1441, 1311, 1221, 1173, 1113, 1009 cm−1 1H NMR 4.82 (br, 2H), 5.49–5.54 (m, 1H), 7.23 (br, 2.80H), 7.42 (br,
14Ni. Dark green solid (20%): tR 6.190 min; νmax 3678,
;
;
(400 MHz, CDCl3/CD3OD) Multiple conformers were seen, 0.5H), 7.78 (br, 2.44H), 8.24–8.29 (m, 4H), 8.43–8.58 (m, 3H),
peaks are reported for all of them. Due to solvent overlap and 8.79 (br, 1H), 9.24 (br, 1H); HR-ESI-MS calcd 918.3443 obsd
uncertainties in integration, integral values are only reported 918.3489 [(M + H)+, M = C46H53N9NiO8].
for the 4.49–9.59 ppm region. 1.17–3.80 (m), 1.93 (s), 4.49 (s,
General procedure for lanthanide complexation. A sample
1.74H), 4.61 (s, 1.16H), 7.22–7.23 (m, 1.74H), 7.51 (m, 0.35H), of the unprotected ligand (1 equiv.) and the appropriate
7.77–7.88 (m, 3.19H), 8.21–8.23 (m, 0.43H), 8.41–8.49 (m, lanthanide chloride (1.1 equiv.) were dissolved in MeOH
2.83H), 8.58 (m, 0.62H), 8.63 (s, 1.85H), 8.69 (s, 1H), 8.74 (s, (2 mL). The reaction mixture was heated at 70 °C, and moni-
1H), 8.87 (s, 1H), 9.59 (s, 1H); HR-ESI-MS calcd 1008.3611 tored by RP-HPLC. When necessary, an additional portion of
obsd 1008.3627 [(M + H)+, M = C49H59N9O8Pd].
LnCl3 was added (up to 10 equiv.). When RP-HPLC-analysis
13Cu. Bluish-green solid (92%): tR 5.414 min; νmax 3412, indicated the complete consumption of the free ligand, or the
2957, 2834, 1730, 1641, 1516, 1441, 1381, 1310, 1219, 1178, stopping of the reaction despite the addition of further por-
1112, 993 cm−1; HR-ESI-MS calcd 965.4193 obsd 965.3855 tions of lanthanide salt, the mixture was allowed to cool to
[(M + H)+, M = C49H59CuN9O8].
room temperature. The pure product precipitated out from the
13Ni. Dark green solid (65%): tR 5.906 min; νmax 2925, reaction mixture for 15NiLn. Complexes 15PdLn were purified
1735, 1649, 1439, 1381, 1211, 1170, 996; 1H NMR (400 MHz, by dissolution in methanol and diethyl ether, in which the
CDCl3) Multiple conformers were seen, peaks are reported for other components of the reaction mixture were not soluble.
all of them. Even after extensive purification and drying
Pd15Ln. Ln = Yb, dark pink solid (too small quantity to be
∼1 molecule of DMF was retained. Due to solvent overlap and accurate): tR 6.134 min; νmax 3338, 2947, 2836, 1450,
uncertainties in integration, integral values are only reported 1016 cm−1. Ln = Nd, dark pink solid (too small quantity to be
This journal is © The Royal Society of Chemistry 2015
Dalton Trans., 2015, 44, 2541–2553 | 2551

Paper
Dalton Transactions
accurate): tR 6.136 min; νmax 3339, 2947, 2836, 1449,
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1020 cm−1
; HR-ESI-MS calcd 1103.1846 obsd 1103.1979
(M − H)+ [(M + H)+, M = C46H49N9NdO8Pd].
Ni15Ln. Ln = Yb, dark green solid (quant.): tR 5.558 min;
νmax 3336, 2923, 2325, 1605, 1419, 1225, 1058, 998 cm−1. Ln =
Nd, dark green solid (quant.): tR 5.559 min; νmax 3331, 2923,
2325, 1602, 1509, 1420, 1225, 1058, 998 cm−1
.
General procedure for CuAAC. Procedure for 0.01 mmol of
chlorin substrate. The alkyne and the azide (1 equiv. chlorin,
1.5 equiv. Ln-complex) were dissolved in DMSO (0.2 mL). 10 X. Yan, L. Yang and Q. Wang, Angew. Chem., Int. Ed., 2011,
TBTA50 (0.1 equiv.), and CuOAc (0.1 equiv.) were added dis-
50, 5130.
solved in DMSO (0.2 mL), followed by NaAsc (0.5 equiv., in 11 Y. Luo, X. Yan, Y. Huang, R. Wen, Z. Li, L. Yang, C. J. Yang
15 μL H2O). The reaction mixture was stirred at room tempera- and Q. Wang, Anal. Chem., 2013, 85, 9428.
ture until TLC analysis indicated the complete consumption 12 G.-L. Law, R. Pal, L. O. Palsson, D. Parker and K.-L. Wong,
of the starting chlorin. The mixture was concentrated under Chem. Commun., 2009, 7321.
reduced pressure, and the product was precipitated from 13 S. Faulkner, S. J. A. Pope and B. P. Burton-Pye, Appl.
MeOH with Et2O (Ln-complexes). Spectrosc. Rev., 2005, 40, 1.
ZnTNYb. Dark green solid (quant.): tR 5.063 min; νmax 1612, 14 C. Bischof, J. Wahsner, J. Scholten, S. Trosien and M. Seitz,
1399, 1318, 1223, 1177, 1086, 1052, 988 cm−1; HR-ESI-MS
J. Am. Chem. Soc., 2010, 132, 14334.
calcd 1141.2457 obsd 1141.2467 [(M
C47H50N11O7YbZn].
+
Na)+,
M
=
15 C. Doffek, N. Alzakhem, C. Bischof, J. Wahsner, T. Gueden-
Silber, J. Luegger, C. Platas-Iglesias and M. Seitz, J. Am.
Chem. Soc., 2012, 134, 16413.
ZnNTLn. Ln = Gd, dark green solid (quant.): tR 5.123 min;
νmax 3364, 2161, 1603, 1380, 1316, 1231, 1176, 1083, 1051, 16 C. Doffek, N. Alzakhem, M. Molon and M. Seitz, Inorg.
989 cm−1; HR-MALDI-MS calcd 1102.2417 obsd 1102.2424
Chem., 2012, 51, 4539.
(M+, M = C47H50GdN11O7Zn). Ln = Yb, dark green solid 17 G. Mancino, A. J. Ferguson, A. Beeby, N. J. Long and
(quant.): tR 5.128 min; νmax 3388, 1177, 1383, 1316, 1226, 1177, T. S. Jones, J. Am. Chem. Soc., 2005, 127, 524.
1085, 1052 cm−1. Ln = Nd, dark green solid (quant): tR 18 N. Alzakhem, C. Bischof and M. Seitz, Inorg. Chem., 2012,
5.152 min; HR-MALDI-MS calcd 1086.2256 obsd 1086.2331
(M+, M = C47H50NdN11O7Zn).
51, 9343.
19 M. Suchý and R. H. E. Hudson, Eur. J. Org. Chem., 2008,
4847.
20 E. Pershagen and K. E. Borbas, Coord. Chem. Rev., 2014,
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6Yb. Dark green solid (quant.): tR 5.033 min; νmax 3361,
2959, 2923, 1607, 1399, 1316, 1222, 1087, 1005, 988 cm−1
ESI-MS calcd 1088.2 obsd 1089.6 [M−, M = C46H48N11O6YbZn].
;
21 P. Caravan, J. J. Ellison, T. J. McMurry and R. B. Lauffer,
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Acknowledgements
This work was funded by the Swedish Research Council
(project grant 2013-4655), Stiftelsen Olle Engkvist Byggmäs-
tare, an Erasmus fellowship (to K.S.), and the Department of
Chemistry – BMC. We thank Elias Pershagen for help with
recording the HR-MS data.
Notes and references
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