Synthesis and characterisation of bis-cyclen based dinuclear lanthanide complexes

Article abstract of DOI:10.1039/b514106k

The design and synthesis of several bis-macrocyclic cyclen (1,4,7,10-tetraazacyclododecane) ligands and their corresponding lanthanum or europium complexes is described; these dinuclear lanthanide systems were made by connecting two macrocyclic cyclen moi

Full text of DOI:10.1039/b514106k

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Synthesis and characterisation of bis-cyclen based dinuclear lanthanide
complexes
Thorfinnur Gunnlaugsson* and Andrew J. Harte
Received 4th October 2005, Accepted 9th February 2006
First published as an Advance Article on the web 14th March 2006
DOI: 10.1039/b514106k
The design and synthesis of several bis-macrocyclic cyclen (1,4,7,10-tetraazacyclododecane) ligands
and their corresponding lanthanum or europium complexes is described; these dinuclear lanthanide
systems were made by connecting two macrocyclic cyclen moieties through a rigid, covalent,
p-xylylenediamide bridge or a flexible aliphatic hexane bridge. These ligands were subsequently
functionalised with six acetamide pendant arms (CONR1R2: R1 = R2 = H or CH3, or R1 = H, R2 =
CH3). The corresponding lanthanide bis-complexes were then formed by reaction with La(III) and
Eu(III) triflates, yielding overall cationic (+VI charged) complexes.
ligand in order to allow comparison with mononuclear lanthanide
Introduction
systems previously reported by us4 and by Morrow et al.20 To the
Currently, there is significant interest in the development of
best our knowledge, 1–3 and 16 are the first examples of such
synthetic enzyme mimics, based on functionalised macrocyclic
dinuclear cyclen lanthanide complexes.
ligands, which can catalyse or accelerate the hydrolysis or cleavage
of phosphate esters.1,2,3 Such macrocycle design gives rise to a
reorganised platform where cofactors commonly employed by
natural substrates can be included with the aim of achieving fast
and affective hydrolysis. We have, over the past few years, synthe-
sised many such mimics based on the use of divalent transition
and trivalent lanthanide ion coordination complexes.4 For the
latter, we have focused our efforts on the use of the macrocycle
1,4,7,10-tetraazacyclododecane, or cyclen, as such a structural
platform for the synthesis of mononuclear lanthanide complexes.
In these, the four ring nitrogen moieties of cyclen have been func-
tionalised using acetamides, small peptides, simple amines and
heterocyclic units as cofactors. These structures have given rise to
kinetically and thermodynamic stable complexes with lanthanide
ions such as Eu(III) and La(III). These aforementioned synthetic
modifications have also given rise to significant enhancements in
Results and discussion
Design and synthesis
the rate of hydrolysis of the RNA model compound HPNP (2-
hydroxypropyl-p-nitrophenylphosphate), commonly used for such
studies, and in the cleavage of mRNA strands.
Our design consisted of a simple spacer (aliphatic or aromatic)
separating the cyclen lanthanide complexes. Each cyclen structure
has eight coordinating sites, with four of these coordination
sites provided by the nitrogens of the ring and the remaining
four provided by amide functionalities, three of which consist of
simple acetamide pendant arms, while the fourth amide is part
of the spacer structure itself. As the lanthanide ions have high
coordination requirements, the remaining coordination sites are
expected to be occupied by solvent molecules such as water, one
for Eu(III) and two for La(III).†
Many enzymes that promote phosphodiester hydrolysis utilise
more than one metal centre.1,2,5,6,7 Because of this, ribonuclease
mimics have recently been reported where two or more transition
metal ions have been employed within a single molecule.2,8,9–19,20–24
However, the development of such lanthanide-based macrocycles
is less common. Herein, we present the design and synthesis of
several bis-macrocyclic, dinuclear lanthanide systems 1–3 and 16,
and their Eu(III) and La(III) complexes with the aim of achieving
cooperative effects between two metal centres, and hence faster
hydrolysis of phsophodiesters. Our strategy was to connect the
two macrocyclic complexes together with a covalent spacer that
would be either rigid (as in the case of 1–3) or flexible, e.g. 16.
The cyclen macrocycle was chosen as the basic template for the
Our first target in the current study was the incorporation of a
xylylene bridge into the cyclen structure, yielding the ligands 1, 2
and 3, Scheme 1. The synthesis of 1,4-bis-(2-chloro-acetylamino)-
xylylene, 7 was attempted in several organic solvents, by acylation
† Even though this design was aimed towards achieving enhanced activity
in phosphodiester hydrolysis, it is also applicable for use in other fields
such as the development of novel contrast agents for magnetic resonance
imaging. We are currently investigating this.
School of Chemistry, Centre for Synthesis and Chemical Biology, Trinity
College Dublin, Dublin 2, Ireland. E-mail: gunnlaut@tcd.ie; Fax: +353 1
671 2826; Tel: +353 1 608 3459
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Scheme 1 Attempted synthesis of 1–3 using the alkylation of 7 by the
heptadentate cyclen ligands such as 6 in DMF.
of p-xylylenediamine using chloroacetyl chloride in the presence
of a base, such as triethylamine. Unfortunately, these conditions
only gave the desired product in low yield and often highly impure.
Consequently, we attempted the synthesis of 7 using modified
Schotten–Baumann conditions, by carrying out the reaction in
water in the presence of NaOH, rather than in the usual two
solvent phase mixture. This modified procedure involved reacting
the diamine, along with four equivalents of NaOH in H2O with
four equivalents of chloroacetyl chloride. The resulting solution
was left to stir overnight and the desired product 7, precipitated out
of solution and was isolated by filtration in 75% yield with no need
for further purification. This method was further investigated in
our laboratory and extended to the formation of a range of other
aliphatic and aromatic based a-chloroamides and shown to be
highly successful.
We have recently developed a method for the formation of
heptadentate triamide ligands of cyclen in one-step synthesis from
the corresponding a-chloroamides and cyclen.25a Consequently,
the synthesis of 1–3 was attempted by reacting the corresponding
ligands 4–6, with 7. The synthesis of 3 was first attempted
by reacting 6 with 7 in DMF and in the presence Cs2CO3 at
80 ◦C, Scheme 1. Unfortunately, the desired product was only
obtained in low yield of 16% after a tedious workup. Due to
the insolubility of 7 in many organic solvents such as CH3CN,
THF and CH3Cl (only partially soluble) this alkylation was
not particularly successful and as a result this approach was
abandoned. Instead, we attempted the synthesis of 1–3 using an
alternative method developed by Parker et al., which involved
the use of a molybdenum carbonyl protected cyclen complex,
formed by reacting cyclen with molybdenum hexacarbonyl under
inert atmosphere in dry dibutyl ether.25b The product, 1,4,7-
molybdenum tris carbonyl-(1,4,7,10-tetraazacyclododecane) 8,
which allows for the selective functionalisation of one of the
amino moieties of the ring, was isolated by filtration in 88% yield.
This was reacted with half an equivalent of 7, in the presence
of one equivalent of both Cs2CO3 and KI in DMF, Scheme 2.
The resulting solution was then heated at 85 ◦C for 40 h. After
filtration, the DMF was removed under reduced pressure and
the resulting residue was left stirring overnight in an aqueous
solution of HCl (15% v/v), in order to deprotect the cyclen
moieties. Following this, the solution was washed with CH2Cl2
and the pH of the aqueous fraction was adjusted to ca. 13 using
KOH (pellets). This solution was then extracted with CH2Cl2 and
the resulting organic solution was dried over K2CO3 before the
solvent was removed under reduced pressure. The desired product
Scheme 2 Synthesis of the bis-cyclen macrocycle 10 from molybdenum
tris carbonyl-(1,4,7,10-tetraaza-cyclododecane) (8).
10 was isolated as yellow oil in 41% yield. The inherent symmetry
of 10 was evident in the1H NMR where the aromatic protons
resonated as a singlet at 7.25 ppm (overlapping with the CDCl3
signal). The four benzylic protons appeared at 4.38 ppm, while the
acetamide protons resonanced at 3.19 ppm. The cyclen protons
appeared as two singlets at 2.61 and 2.50 ppm, respectively. The
13C NMR spectra of 10 showed the presence of one carbonyl group
at 171.1 ppm, while the aromatic signals were observed at 137.2
and 127.7 ppm, respectively. The mass spectrum presented signals
at m/z 561.4, 583.4, 599.4 and 281.2 corresponding to the [M +
H], [M + Na], [M + K] and [M + 2H]/2 species, respectively.
The intermediate 10 allows for the incorporation of six further
amide or carboxylate pendant arms, and as such is an ideal scaffold
for the further development of new lanthanide ion complexes. We
are currently in the process of constructing a large library of such
molecules using amino acids, dipeptides, amines and heterocyclic
moieties which can be incorporated into 10, via the corresponding
a-chloroamide.
The hexane spacer analogue 11, was also synthesised under
similar conditions by stirring 8 with half an equivalent of 12 in
DMF at 85 ◦C for 40 h, in the presence of two equivalents of
Cs2CO3 and KI, Scheme 3. However, unlike 10, 11 was isolated
as its hydrochloride salt in 37% yield after precipitation from a
Scheme 3 Synthesis of the bis cyclen macrocycle unit 11, from the
aliphatic diamide spacer 12.
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EtOH–conc. HCl 5 : 1 solution. As in the case of 10, the 1H NMR
of 11 in D2O was relatively simple due to the high degree of symme-
try in the molecule. The two acetamide protons were observed at
3.31 ppm, while the cyclen protons resonated as two broad signals
at 3.06 and 2.88 ppm, respectively. The three sets of methylene
protons from the alkyl spacer were observed at 2.88 ppm (over-
lapping with 8 cyclen protons), 1.39 and 1.20 ppm, respectively.
The mass spectrum contained two signals at m/z 541.6 and 271.4
corresponding to the [M + H] and [M + 2H/2] species. Elemental
analysis confirmed the presence of the six HCl molecules.
Having obtained 10 and 11, the remaining amino moieties of
the cyclen rings were functionalised with pendant amide arms,
which would fulfil the high coordination requirements of the
lanthanide ions. Initially, simple acetamide arms (Scheme 4) were
investigated in order to probe the validity of the bis lanthanide
systems as cleaving agents for phosphodiester hydrolysis as they
would allow comparison with analogous mononuclear lanthanide
systems previously reported by Morrow et al. The three pendant
arms employed in this case were, 2-chloroacetamide, 13, 2-chloro-
N-methylacetamide 14 and 2-chloro-N,N-dimethylacetamide, 15.
As previously mentioned, the bis-cyclen ligand 10, was only
sparingly soluble in solvents such as MeCN, CH2Cl2 and CHCl3
and using these solvents, the alkylation did not proceed, even under
reflux. Consequently, the reactions were conducted in refluxing
EtOH solution in the presence of KI and the relevant base. The
primary amide 1, was isolated in 57% yield, after precipitation
from CH2Cl2, followed by recrystallisation from boiling EtOH. In
a similar way, 2 was isolated in 30% yield, whereas, 3 was found
to be soluble in CH2Cl2 and so was isolated in 38% yield after
washing with H2O and 0.1 M HCl solutions.
respectively, while the aromatic carbon signals were observed at
136.6 and 127.1 ppm, respectively. Eight methylene signals were
also observed between at 58.1 and 42.2 ppm. High-resolution
mass spectrometry and elemental analysis both confirmed that
the desired product had been formed. Characterisation of 2 and 3
yielded similar results (see the Experimental section).
In a similar manner the hexane linker analogue of 1 was
synthesised by refluxing 11 in EtOH, with seven equivalents of
bromoacetamide in the presence of fourteen equivalents of Et3N. A
large excess of Et3N was needed, as 11 had been synthesised
as the hexa-HCl salt. The desired product 16, Scheme 5, was
isolated in 83% yield, after precipitation from CH2Cl2, followed
by further precipitation from i-propanol–EtOH 3 : 1 mixture. As
anticipated, the 1H NMR (400 MHz, D2O) revealed the high
degree of symmetry inherent in the molecule, as four of the
methylene resonances of the alkyl chain appeared at 1.38 and
1.19 ppm, respectively. Moreover, the 13C NMR revealed the three
carbonyl peaks at 174.2, 173.5 and 169.7 ppm as well as eight
methylene resonances between 56.1 and 25.3 ppm, respectively.
Scheme 5 Synthesis of the bis acetamide cyclen ligand 16 and the resulting
La(III) complex 16La2.
The La(III) and the Eu(III) complexes of 1–3 (Scheme 4) and
the La(III) complex of 16 (Scheme 5) were prepared by refluxing
each ligand with two molar equivalents of the relevant lanthanide
triflate salt in dry MeOH for 16 h. The resulting solution was
filtered and reduced in volume to ca. 5 mL, and added dropwise to
a swirling solution of ether. This produced white precipitates that
were collected by filtration and washed with ether. The resulting
complexes were subsequently further purified by precipitation
from CH2Cl2, giving the desired complexes 1La2, 1Eu2, 2La2, 2Eu2,
3Eu2, and 16La2 in 50–90% yields.
Analysis of the resulting Eu(III) complexes using 1H NMR
(400 MHZ) confirmed that the desired bis complexes were formed
successfully. For instance, the 1H NMR spectrum of 1Eu2, shown
in Fig. 1, showed resonances appearing at 26.16, −2.66, −5.25,
−9.09, −11.28, and −13.56 ppm. These are indicative of the pres-
ence of the Eu(III) ion, that acts as a paramagnetic shift reagent,
which in the cyclen complexes results in shifted axial and equato-
rial protons of the cyclen and acetamide CH2s, implying a square
antiprismatic geometry for each of the lanthanide centres.26,27 The
electrospray mass spectrum (ESMS) also showed that complexa-
tion had occurred, as seen by the characteristic europium isotope
distribution pattern for [1Eu2 + 4Trif]/2 in Fig. 2, which shows
the calculated and the observed isotopic distribution patterns.
Scheme 4 Synthesis of the three ligands 1–3 and their corresponding
La(III) and Eu(III) complexes.
1
The H NMR in D2O (400 MHz) of 1, revealed the expected
high degree of symmetry, where four aromatic protons resonated at
7.16 ppm while the benzyl protons were observed at 4.26 ppm. The
13C NMR was more confirmative, revealing the presence of three
signals at 173.8, 173.4 and 170.2 ppm for the amide carbonyls,
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Table 1 Results from the excited state lifetime measurements and the
a
determination of the hydration state (q) of 1Eu2, 2Eu2, and 3Eu2
Complex
sH O/ms
kH O/ms−1
sD O/ms
kD O/ms−1
q ( 0.5)
2
2
2
2
1Eu2
2Eu2
3Eu2
0.507
0.553
0.553
1.971
1.808
1.808
2.265
2.451
1.851
0.440
0.408
0.541
0.9
1.0
1.1
a All measured at neutral pH or pD at room temperature.
lifetimes (s) for these complexes were measured in D2O and H2O,
respectively, after direct excitation of the Eu(III) ion at 395 nm.
The lifetimes obtained from these two solvents were then used to
determine the hydration state of the complexes, or the q value,
using eqn (1):
Fig. 1 The 1H NMR (400 MHz, D2O) of 1Eu2 showing the shifted axial
and equatorial protons of the ring and the a-protons.
qEu(III) = 1.2 [(1/sH2O − 1/sD2O) − 0.25–0.075x]
(1)
which was developed by Horrock et al.28 and later modified by
Parker et al.29 to allow for the quenching of N–H oscillators. The
results of these measurements and the resulting q-values are shown
in Table 1. As expected, each of the Eu(III) complexes were found
to have one metal bound water molecule per Eu(III) ion, giving
an overall nine coordinate environment at each metal ion centre
within the complexes.
Conclusion
In this article we have presented the synthesis of several bis
cyclen ligands that were bridged by either flexible hexyl diamide
or rigid p-xylyl diamide spacers 1, 2, 3 and 16. The lanthanide
complexes of these ligands, 1La2, 1Eu2, 2La2, 2Eu2, 3Eu2, and
16La2, were characterised using conventional methods. We are
currently carrying our a comprehensive study of the ability of
these complexes to cleave HPNP and RNA molecules.‡
Fig. 2 Top: the calculated isotopic distribution pattern for [1Eu2
+
4Trif]/2. Bottom: the obtained ESMS (+ mode) isotopic distribution
pattern for the same.
The europium complexes 2Eu2 and 3Eu2 gave similar results to
that observed for 1Eu2, e.g. their 1H NMR spectra (in D2O) showed
the expected shifted resonances for the a-methylene protons and
the axial and the equatorial protons of the cyclen macrocycle
between +30 and −16 ppm. Moreover, as in the case of 1Eu2,
the correct europium isotope distribution pattern was observed
Experimental
Starting materials were obtained from Sigma Aldrich, Strem
Chemicals and Fluka. Solvents used were HPLC grade unless
otherwise stated. H NMR spectra were recorded at 400 MHz
1
using a Bruker Spectrospin DPX-400, with chemical shifts ex-
pressed in parts per million (ppm or d) downfield from the
standard. 13C NMR were recorded at 100 MHz using a Bruker
Spectrospin DPX-400 instrument. Infrared spectra were recorded
on a Mattson Genesis II FTIR spectrophotometer equipped
with a Gateway 2000 4DX2-66 workstation. Mass spectroscopy
was carried out using HPLC grade solvents. Mass spectra were
determined by detection using Electrospray on a Micromass
LCT spectrometer, using a Water’s 9360 to pump solvent. The
system was controlled by MassLynx 3.5 on a Compaq Deskpro
1
in the ESMS for both of these complexes. The H NMR and
the ESMS of the corresponding La(III) complexes also revealed
that the desired products were obtained. IR spectroscopy also
confirmed the formation of the desired lanthanide complexes as
the carbonyl vibration bands were shifted to lower frequency upon
complexation of the metal ions, e.g. for 1, 2, 3 and 16 the carbonyl
stretch occurred at 1678, 1657, 1647 and 1670 cm−1, respectively,
whereas for the corresponding Eu(III) complexes 1Eu2, 2Eu2, and
3Eu2, these were shifted to 1665, 1638 and 1621 cm−1, respectively.
For the La(III) complexes, this shift was even more pronounced
being 1634, 1638 and 1635 cm−1 for 1La2, 2La2 and 16La2,
respectively.
‡ Preliminary evaluation of the ability of these compounds to cleave HPNP
has been undertaken. All complexes promote the hydrolysis of HPNP, e.g.
for 1La2, the rate enhancement (krel) was ca. 733 fold. In comparison 16La2,
was significantly faster with ca. 2058 fold enhancement at pH 7.4, over the
unanalysed reaction. This is a four fold enhancement over the mononuclear
analogue, indicating a cooperative rate enhancement. Moreover, as a
function of pH the rate profile for 16La2 gave rise to a bell-shaped pH-
dependent curve which peaked at physiological pH. We are currently
evaluating these phenomena in greater detail; results will be published
in due course.
Determination of the hydration state of the Eu(III) complexes
As previously discussed, the above bis-cyclen Eu(III) complexes
1Eu2, 2Eu2, and 3Eu2, were expected to have one free coordination
site, and this vacant site was expected to be occupied by a metal
-bound water molecule. In order to confirm this, the excited state
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workstation. Uv-Vis spectroscopy analysis was carried out on
a Varian Cary 100 UV-Vis spectrophotometer. Luminescence
measurements were carried out on Varian Carey Eclipse spectro-
photometer.
solution was filtered and washed with CH2Cl2 (3 × 20 mL). The
aqueous layer was then basified to pH >13 with KOH pellets and
was subsequently filtered and extracted with CH2Cl2 (5 × 20 mL).
The organic extracts were combined and dried over K2CO3. The
solvent was removed under reduced pressure to yield 10 as a
yellow oil (0.35 g), in 41% yield. Calculated for C28H53N10O2:
[M + H] m/z = 561.4353. Found: m/z = 561.4340 (−2.4 ppm).
dH (400 MHz, CDCl3) 8.45 (s, 2H, NH), 7.25 (s, 4H, Ar–H),
4.39 (d, J = 6.0 Hz, 4H, CH2NH), 3.18 (s, 4H, CH2CO), 2.61
(s, 24H, cyclen CH2), 2.50 (s, 8H, cyclen CH2).dC (100 MHz,
CDCl3) 171.1, 137.2, 127.7, 58.6, 52.8, 46.6, 46.2, 45.1, 42.4. Mass
spectrum (MeOH, ES+) m/z. Expected: 560.4. Found: 561.4
[M + H], 583.4 (M + Na), 599.4 (M + K), 281.2 [M + H]/2. IR
tmax (cm−1) 3194, 2724, 2362, 1640, 1543, 1269, 1170, 1076, 1020,
972, 941, 722.
1,4-Bis-(2-chloroacetylamino)xylyene (7)
p-Xylylenediamine (0.50 g, 3.67 mmol), was placed in a 100 mL
RBF with NaOH (0.59 g, 14.70 mmol), and dissolved in H20
(10 mL). The solution was placed in an acetone–ice bath and al-
lowed to cool. Chloroacetyl chloride (1.66 g, 14.70 mmol) was then
added dropwise over 1 h. The solution was left to stir overnight and
the resulting precipitate was then filtered and washed with water
and ether. The product was isolated as white solid, 0.79 g, 75%
yield. Mp 206–207 ◦C. Calculated for C12H14N2O2Cl2: C, 49.85;
H, 4.88; N, 9.69. Found: C, 49.64; H, 4.75; N, 9.55. Calculated
for C12H14N2O2Cl2Na [M + Na] m/z = 311.0330. Found m/z =
311.0339 (+ 2.8 ppm). dH (400 MHz, DMSO) 8.72 (b.s, 2H, N–H),
7.22 (s, 4H, Ar–H), 4.26 (d, 4H, J = 6.0 Hz, CH2NH), 4.11 (s, 4H,
CH2Cl). dC (100 MHz, DMSO) 165.9, 137.5, 127.3, 42.6, 42.2.
Mass spectrum: (MeOH, ES+): m/z. Expected: 288.0. Found:
311.0 [M + Na], 326.9 [M + K]. IR tmax (cm−1) 3280, 3072,
2952, 1656, 1549, 1415, 1267, 1235, 1066, 1001, 831, 769, 680,
547, 416.
2-{4,10-Bis-carbamoylmethyl-7-[(4-{[2-(4,7,10-tris-
carbamoylmethyl-1,4,7,10-tetraazacyclododec-1-yl)-
acetylamino]methyl}benzylcarbamoyl)methyl]-1,4,7,10-
tetraazacyclododec-1-yl}acetamide (1)
The bis-cyclen ligand 10 (0.11 g, 0.19 mmol), bromo acetamide
(0.19 g, 1.36 mmol) and Et3N (0.19 g, 1.95 mmol) were placed
in a 50 mL RBF. EtOH (20 mL) was added and the solution
was refluxed at 85 ◦C for 40 h. After cooling, the solution
was filtered and then reduced in volume (5 mL) before it was
added dropwise to a solution of CH2Cl2 (150 mL). The resulting
precipitate was filtered, dissolved in hot EtOH (5 mL) and
left to stand. The resulting precipitate was filtered, yielding a
pale yellow solid (0.10 g), in 57% yield. Mp decomposes above
163 ◦C. Calculated for C40H70N16O8·(CH2Cl2)2·(H2O)2·MeOH: C,
45.26; H, 7.24; N, 19.64. Found: C, 45.19; H, 6.89; N, 19.51.
Calculated for C40H72N16O8: [M + 2H] m/z = 904.5719. Found:
m/z = 904.5726 (+ 0.8 ppm). dH (400 MHz, D2O) 7.16 (s, 4H,
Ar–H), 4.26 (s, 4H, CH2NH), 3.46 (bs, 4H, CH2CO), 3.27 (s, 4H,
2-Chloro-N-[3-(2-chloroacetylamino)propyl]acetamide (12)
Compound 12 was synthesised using 1,3 diamino propane (0.44 g,
6.00 mmol), was placed in a 100 mL RBF with NaOH (0.72 g,
18 mmol) and dissolved in H2O (25 mL). The solution was placed
in an ice bath at 0 ◦C and allowed to cool. Chloroacetyl chloride
(1.65 g, 15.00 mmol) was then added dropwise over 1 h and
the solution left to stir overnight. The solution was then filtered
and the precipitate was washed with ether. The solution was
then extracted with CH2Cl2 (4 × 20 mL) and the solvent was
subsequently evaporated and the residue suspended in ether and
filtered. The product was isolated as a white solid, 0.28 g, 20%
yield. Mp 128–129 ◦C. Calculated for C7H12N2O2Cl2Na [M +
Na] m/z = 249.0174. Found m/z = 249.0168 (−2.2 ppm). dH
(400 MHz, CDCl3) 7.17 (s, 2H, NH), 4.09 (s, 4H, CH2Cl), 3.38
(dt, 4H, J = 6 Hz, J = 6 Hz, CH2NH), 1.73 (quintet, 2H, J =
6 Hz, CH2). dC (100 MHz, CDCl3) 166.3, 42.2, 35.9, 28.9. Mass
spectrum: (MeOH, ES+): m/z. Expected: 226.0. Found: 249.0
[M + Na]. IR tmax (cm−1) 3283, 3078, 3005, 2970, 2953, 2879,
2361, 1675, 1638, 1554, 1464, 1448, 1401, 1316, 1292, 1269, 1249,
1194, 1128, 923, 759, 626, 574, 469, 414.
=
=
=
CH2C O), 3.19 (s, 6H, CH2C O), 3.12 (s, 2H, CH2C O), 2.75
(bs, 32H, cyclen CH2). dC (100 MHz, D2O) 173.8, 173.4, 170.2,
136.6, 127.1, 58.1, 56.9, 56.7, 56.1, 55.5, 55.3, 50.2, 42.2. Mass
spectrum: (MeOH, ES+) m/z. Expected: 902.6. Found: 902.7
(M+), 924.7 (M + Na), 451.9 (M + 2H)/2, 301.7 (M + 3H)/3. IR
tmax (cm−1) 3336, 2949, 2831, 2074, 1959, 1678, 1551, 1420, 1288,
1117, 971, 902, 806, 647, 469.
2-{4,7-Bis-methylcarbamoylmethyl-10-[(4-{[2-(4,7,10-tris-
methylcarbamoylmethyl-1,4,7,10-tetraazacyclododec-1-yl)-
acetylamino]methyl}benzylcarbamoyl)methyl]-1,4,7,10-
tetraazacyclododec-1-yl}acetamide (2)
2-(1,4,7,10-Tetraazacyclododec-1-yl)-N-{4-[(2-1,4,7,10-tetra-
azacyclododec-1-yl-acetylamino)methyl]benzyl}acetamide (10)
The bis-cyclen ligand 10 (0.28 g, 0.50 mmol), K2CO3 (0.25 g,
1.85 mmol) and 2-chloro-N-methylacetamide (0.35 g, 2.25 mmol)
were placed in a 100 mL RBF. EtOH (30 mL) was added and
the solution was refluxed at 85 ◦C for 40 h. After cooling, the
solution was filtered to remove the cream precipitate and the
EtOH was removed under reduced pressure. The residue was
suspended in CH2Cl2 (30 mL) and filtered. The resulting solid
was dissolved in EtOH (5 mL) and added to CH2Cl2–Et2O 25 : 7.
The resulting precipitate was filtered and then dissolved in a small
volume of EtOH (<10 mL) and left to sit overnight. The resulting
precipitate was filtered and was then dissolved in DMF and
1,4,7,-Molybdenum tris carbonyl-(1,4,7,10-tetraazacyclodo-
decane) 825b (1.08 g, 3.07 mmol), 1,4-bis-(2-chloroacetylamino)-
xylyene (7) (0.44 g, 1.5 mmol), Cs2CO3 (1.00 g, 3.07 mmol) and
KI (0.49 g, 3.07 mmol) were placed in a 100 mL RBF. To this was
added DMF (50 mL) under vacuum and the solution was freeze–
pump–thawed three times. The resulting solution was left to stir
for 40 h at 85 ◦C, under argon. After cooling to room temperature,
the resulting cream precipitate was filtered off and the DMF
removed under reduced pressure. The residue was dissolved in
HCl (15% v/v; 25 mL) and left stirring overnight. This aqueous
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filtered, before being precipitated from Et2O to yield a yellow solid
(0.15 g), in 30% yield. Mp decomposes above 139 ◦C. Calculated
for C46H82N16O8·CH2Cl2·H2O·EtOH: C, 51.79; H, 8.16; N, 19.72.
Found: C, 51.72; H, 7.48; N, 19.67. Calculated for C46H84N16O8
[M + 2H] m/z = 988.6658. Found m/z = 988.6623. (−3.6 ppm).
dH (400 MHz, D2O) 7.12 (s, 4H, Ar–H), 4.22 (s, 4H, CH2NH),
3.21 (s, 4H, CH2CO), 2.86 (bs, 12H, CH2CO), 2.57 (s, 8H, cyclen
CH2), 2.52 (s, 18H, CH3), 2.43 (s, 24H, cyclen CH2). dC (100 MHz,
D2O) 173.6, 172.9, 136.7, 127.1, 62.8, 57.4, 51.3, 41.9, 25.0. Mass
spectrum: (MeOH, ES+): m/z. Expected: 986.6. Found: 987.9
[M + H], 1024.9 [M + K], 531.9 [M+ 2 K]/2, 512.9 [M + K]/2,
494.0 [M + 2H]/2. IR tmax (cm−1) 3453, 3276, 3080, 2943, 2820,
2067, 1657, 1549, 1449, 1412, 1371, 1308, 1245, 1152, 1116, 972,
870, 707, 587.
for C43H70N16O17F9S3139La2 [M + 3 triflate]/3 m/z = 1627.2250.
Found m/z = 1627.2285 (+ 2.1 ppm). dH (400 MHz, D2O)
7.26, 4.36, 3.54, 3.52, 3.37, 3.22. Mass spectrum: (MeOH, ES+):
m/z. Expected: 542.4. Found: 542.4 [M + 3Trif]/3, 885.11 [M +
4Trif]/2. IR tmax (cm−1) 3401, 2872, 1669, 1634, 1466, 1253, 1169,
1084, 1029, 913, 639, 575, 518.
1Eu2. The complex 1Eu2 was prepared using 1 (0.13 g,
0.15 mmol) and Eu(CF3SO3)3 (0.20 g, 0.33 mmol) yielding a pale
yellow solid upon drying (0.25 g), in 80% yield. Mp decomposes
above 215 ◦C. Calculated for C40H70N16O8·Eu2·(CF3SO3)6(H2O)2:
C, 25.85; H, 3.49; N, 10.48. Found: C, 26.31; H, 3.48; N, 10.03.
Calculated for C42H70N16O14F6S2151Eu153Eu [M + 2triflate] m/z =
1504.3014. Found m/z = 1504.3027 (+0.9 ppm). dH (400 MHz,
D2O) 27.10, 26.28, 7.33, 7.16, 5.87, 4.20, 3.61, 3.22, 2.87, 1.93, 1.75,
1.55, 1.14, 1.04, −2.65, −5.25, −8.22, −9.09, −11.28, −13.55.
Mass spectrum: (MeOH, ES+): m/z. Expected: 1208.4. Found:
901.1 [M + 4Trif]/2, 376.5 [M + 2Trif]/4. IR tmax (cm−1) 3374,
1665, 1459, 1252, 1150, 1082, 1029, 989, 638.
2-{4,10-Bis-dimethylcarbamoylmethyl-7-[(4-{[2-(4,7,10-tris-
dimethylcarbamoylmethyl-1,4,7,10-tetraazacyclododec-1-
yl)acetylamino]methyl}benzylcarbamoyl)methyl]-1,4,7,10-
tetraazacyclododec-1-yl}-N,N-dimethylacetamide (3)
2La2. The complex 2La2 was synthesised using 2 (35.20 mg,
35.66 lmol) and La(CF3SO3)3 (42.00 mg, 71.67 lmol). The
resulting yellow–brown precipitate was dried in a dessicator
(53 mg), in 69% yield. Mp decomposes above 215 ◦C. Calculated
for C46H82La2N16O8·(CF3SO3)6·(H2O)4·(CH2Cl2)5: C, 25.77; H,
3.79; N, 8.44. Found: C, 26.17; H, 3.39; N, 8.35. dH (400 MHz,
D2O) 7.26, 4.37, 3.23, 2.74. Mass spectrum: (MeOH, ES+): m/z.
Expected: 1264.4 Found: 930.5 [M+ 4Trif]/2, 570.4 [M+ 3Trif]/3,
390.9 [M+ 2Trif]/4. IR tmax (cm−1) 3518, 3326, 3131, 2955, 1638,
1417, 1255, 1168, 1086, 1029, 761, 639, 575, 517.
The bis-cyclen ligand 10 (0.15 g, 0.26 mmol), Cs2CO3 (0.30 g,
0.92 mmol), 2-chloro-N,N-dimethylacetamide (0.21 g, 1.70 mmol)
and KI (0.13 g, 0.92 mmol) were placed in a 100 mL RBF
and dissolved in EtOH (20 mL). The solution was refluxed at
85 ◦C for 4 d. The solution was filtered to remove the cream
precipitate and the solvent removed under reduced pressure. The
residue was dissolved in CH2Cl2 (30 mL) and filtered. The CH2Cl2
was extracted with 0.1 M HCl (4 × 20 mL), which was then
washed with CH2Cl2 (4 × 15 mL). The pH was adjusted to 7
using K2CO3 (10%) and the solution extracted with CH2Cl2 (4 ×
15 mL). The solvent was then removed to give a clear oil which
solidified after drying under vacuum over P2O5 (0.11 g), in 38%
yield. Mp decomposes above 124 ◦C. Calculated for C52H96N16O8
[M + 2H] m/z = 1072.7597. Found m/z = 1072.7567 (−2.8 ppm).
dH (400 MHz, CDCl3) 7.17 (s, 4H, Ar–H), 4.31 (s, 4H, CH2NH),
3.49 (s, 4H, CH2CO), 3.09 (bm, 12H, CH2CO), 2.89 (bm, 68H,
cyclen and CH3). dC (100 MHz, CDCl3) 170.8, 170.4, 169.4, 139.8,
126.7, 63.6, 59.8, 55.6, 50.3, 48.3, 42.1, 36.5, 35.7, 35.3, 34.9. Mass
spectrum: (MeOH, ES+) m/z. Expected: 1070.7. Found: 1071.9
[M + H], 535.9 [M + 2H]/2, 357.9 [M + 3H]/3. IR tmax (cm−1)
3448, 3279, 3055, 2933, 2817, 1647, 1542, 1508, 1450, 1403, 1348,
1301, 1262, 1102, 1062, 1006, 950, 900, 822.
2Eu2. The complex 2Eu2 was prepared by using 2 (36.40 mg,
36.88 lmol) and Eu(CF3SO3)3 (46.40 mg, 77.45 lmol). This
yielded a pale yellow solid (66.00 mg), in 81% yield. Mp
decomposes above 215 ◦C. Calculated for C45H79N16O8Eu2·
(CF3SO3)6·(H2O)2·(CH2Cl2)5: C, 25.87; H, 3.66; N, 8.47. Found:
C, 25.75; H, 3.29; N, 8.31. dH (400 MHz, D2O) 26.81, 8.41, 5.62,
3.51, 2.60, 2.04, 1.03, 0.78, −2.47, −6.26, −8.14, −11.88, −13.76.
Mass spectrum: (MeOH, ES+): m/z. Expected: 1292.5. Found:
944.3 [M+ 4Trif]/2, 580.0 [M+ 3Trif]/3. IR tmax (cm−1) 3504,
3324, 3134, 2951, 1638, 1419, 1256, 1168, 1083, 1029, 978, 639,
575, 517.
3Eu2. The complex 3Eu2 was synthesised using 3 (58.00 mg,
54 lmol) and Eu(CF3SO3)3 (90.00 mg, 120 lmol, 2.2 equivalents).
The product was successfully isolated as a yellow solid (58.00
mg), in 47% yield. Mp decomposes above 235 ◦C. Calculated for
C52H94N16O8Eu2·(CF3SO3)6·(H2O)2·(CH2Cl2)6: C, 27.30; H, 3.94;
N, 7.96. Found: C, 27.02; H, 3.61; N, 8.33. dH (400 MHz, D2O)
31.63, 9.90, 3.21, 2.81, 2.56, 1.51, 1.14, 1.00, 0.76, 0.24, −1.04,
−5.89, −7.44, −7.94, −12.30, −13.22, −16.19. Mass spectrum:
(MeOH, ES+) m/z. Expected: 1376.6. Found: 985.1 [M + 4trif]/2,
607.1 [M + 3trif]/3, 557.1 [M + 2trif]/3, 343.1. IR tmax (cm−1) 3465,
2872, 2350, 1621, 1463, 1253, 1163, 1081, 1029, 957, 911, 824, 758,
638, 574, 427.
General procedure for synthesis of lanthanide complexes
Lanthanide complexes were prepared by refluxing each ligand with
the relevant lanthanide triflate (2.1 equivalents) in MeOH (15 mL)
for 16 h. The resulting solution was filtered and reduced in volume
to ca. 5 mL. This solution was added dropwise to swirling Et2O
(100 mL) and the resulting precipitate was collected by filtration.
The complexes were further purified by precipitation from CH2Cl2
(75 mL) and isolated by filtration. The complexes were dried under
vacuum over P2O5.
1La2. The complex 1La2 was synthesised using 1 (41.0 mg,
45.40 lmol) and La(CF3SO3)3 (53.2 mg, 90.80 lmol) giving an
oil which became a yellow solid upon drying in a dessicator (83
mg), in 88% yield. Mp decomposes above 227 ◦C. Calculated
for C40H70N16O8·La2·(CF3SO3)6·(H2O)4·(MeOH)4: C, 26.39; H,
4.16; N, 9.85. Found: C, 26.26; H, 3.76; N, 9.51. Calculated
2-(1,4,7,10-Tetraazacyclododec-1-yl)-N-[6-(2-1,4,7,10-
tetraazacyclododec-1-yl-acetylamino)hexyl]acetamide (11)
1,6-Bis-(2-chloroacetylamino)hexane (12) (0.40 g, 1.49 mmol),
molybdenum cyclen (8) (1.05 g, 2.97 mmol), Cs2CO3 (1.45 g,
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4.46 mmol) and KI (0.20 g, 0.12 mmol) were placed in a 100 mL
RBF. DMF (35 mL) was added under vacuum and the suspension
was freeze–pump–thawed three times. The reaction was left to
stir for 120 h at 85 ◦C under argon. After cooling, the solution
was filtered and the DMF was removed under reduced pressure.
The residue was suspended in HCl (15%; 25 mL) and left stirring
overnight. The solution was filtered and then washed with CH2Cl2
(3 × 20 mL). The aqueous solution was basified with KOH
and extracted with CH2Cl2 (4 × 20 mL). The CH2Cl2 was dried
over K2CO3, filtered and the solvent removed. The residue was
dissolved in EtOH (15 mL) and conc. HCl (3 mL) was added and
the solution. The resulting precipitate was filtered and washed with
EtOH to yield a brown solid (0.42 g), in 37% yield. Mp decomposes
above 178 ◦C. Calculated for C26H62N10O2Cl6·MeOH: C, 40.97; H,
8.40; N, 17.69. Found: C, 41.14; H, 7.97; N, 17.77. dH (400 MHz,
D2O) 3.31 (s, 4H, CH2CO), 3.06, (s, 24H, cyclen CH2), 2.88 (bs,
12H, cyclen CH2 & CH2NCO), 1.39 (bs, 4H CH2), 1.20 (s, 4H,
CH2). dC (100 MHz, D2O) 172.4, 54.9, 49.2, 43.9, 42.2, 41.8, 39.1,
27.6, 25.3. Mass spectrum: (MeOH, ES+) m/z. Expected: 540.5.
Found: 541.6 [M + H], 271.4 [M + 2H/2]. IR tmax (cm−1) 3427,
2935, 2648, 1647, 1554, 1444, 1375, 1271, 1175, 1075, 1009, 947,
728, 574, 489.
Acknowledgements
We thank Trinity College Dublin, Enterprise Ireland and the
Center for Synthesis and Chemical Biology, for financial support
and Dr John E. O’Brien for assisting with NMR.
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a yellow solid (13.70 mg), in 87% yield.
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