Challenges in chelating positron emitting copper isotopes: Tailored synthesis of unsymmetric chelators to form ultra stable complexes

Article abstract of DOI:10.1039/c0dt01395a

The synthesis of chelators that form high stability complexes with copper(ii) isotopes and do not suffer from transchelation in vivo has been a goal for many chemists. Such chelators will facilitate the exploitation of the ⁶⁴Cu isotope (t_1/2 = 12.7 h, β⁺ (19%); β^- (39%); EC (41%)) for positron emission tomography imaging studies, which has a longer half life relative to the more commonly used ¹⁸F (t_1/2 = 109.8 min) and ¹¹C (t_1/2 = 20.4 min) isotopes. One option is the CBTE2A chelator, which has been championed by Weisman, Wong and Anderson, and, more recently, alternate bifunctional chelator (BFC) versions have been synthesised. Improved synthetic methods are required for unsymmetric derivatisation of these chelators to allow more selective biomolecule attachment. This work investigates synthetic routes to form new unsymmetric chelating ligands via stepwise reaction of the bisaminal precursor, determines their X-ray structures and demonstrates cold copper(ii) isotope complex formation.

Full text of DOI:10.1039/c0dt01395a

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PAPER
Challenges in chelating positron emitting copper isotopes: tailored synthesis of
unsymmetric chelators to form ultra stable complexes†
Jon D. Silversides, Rachel Smith and Stephen J. Archibald*
Received 15th October 2010, Accepted 9th March 2011
DOI: 10.1039/c0dt01395a
The synthesis of chelators that form high stability complexes with copper(II) isotopes and do not suffer
from transchelation in vivo has been a goal for many chemists. Such chelators will facilitate the
+
exploitation of the 64Cu isotope (t1/2 = 12.7 h, b (19%); b- (39%); EC (41%)) for positron emission
tomography imaging studies, which has a longer half life relative to the more commonly used 18F (t1/2
109.8 min) and 11C (t1/2 = 20.4 min) isotopes. One option is the CBTE2A chelator, which has been
championed by Weisman, Wong and Anderson, and, more recently, alternate bifunctional chelator
(BFC) versions have been synthesised. Improved synthetic methods are required for unsymmetric
=
derivatisation of these chelators to allow more selective biomolecule attachment. This work investigates
synthetic routes to form new unsymmetric chelating ligands via stepwise reaction of the bisaminal
precursor, determines their X-ray structures and demonstrates cold copper(II) isotope complex
formation.
publication of a conjugation reaction attaching a peptide to one
Introduction
of the carboxylate arms via an amide linker, A.10 This was followed
in 2004 by our publication of the first BFC of CBTE2A with both
carboxylic acid functionalities intact and the reactive site for a bio-
targeting moiety on the carbon backbone, B.11,12 In 2008, Brechbiel
and co-workers followed this up with a branched arm derivative,
C, which also retains both carboxylic acid functional groups and
has a single site for conjugation with an improved overall yield
in synthesis of the chelator.13 Further BFCs based on the cross-
bridged (CB) cyclam framework (D and E) were published in
2010,14,15 with Lewis and co-workers producing the first ‘click’
chemistry derivative. There is a patent granted on the use of
CB azamacrocyclic chelators in copper radiopharmaceuticals to
Procter & Gamble (filed in 2001) and certain CBTE2A BFCs with
branched arms were patented by GE (filed in 2004).16,17
There is clearly a desire to produce new molecular constructs
incorporating this chelator. However there is an inherent issue
with the synthesis of many of these compounds (A and C–E) that
should be tackled: they all require unsymmetric functionalisation
of the central macrocycle unit. This is problematic as it leads to low
yields or product mixtures unless a highly selective reaction can
be found. The cyclam unit with non-adjacent nitrogens linked by
an ethyl bridge is not particularly easy to produce on a large scale
and following this with a single step which has a yield of between
11 and 39% is undesirable.13,18 Sun and co-workers did achieve a
reaction in an impressive 55% but this still required separation
from a mixture of products.14
There have been important developments in the use of chelating
ligands to form complexes with positron emitting copper iso-
topes over the last ten years.1,2 Two of the key advances have
been to further develop the potential of hypoxia imaging using
thiosemicarbazone ligands and to produce chelators for high
stability complex formation that allow more efficient delivery of
the longer lived 64Cu (t1/2 = 12.7 h) isotope to targeted tissue
sites by attachment to peptides or antibodies.3–8 An advantage
of the 64Cu isotope is its low average positron energy which means
that the gamma emitting annihilation reaction will occur closer
to the compound location. Other metal ion positron emitters are
also being investigated for a range of potential clinical diagnostic
applications, including the generator-produced isotopes 62Cu and
68Ga.
The chelator that appears to have one of the most favourable
stability/transchelation profiles, and also balances the charge
of the copper(II) centre with carboxylate pendant arms, is the
CBTE2A chelator first brought to prominence by Weisman, Wong
and co-workers.9 To achieve delivery at specific cellular or tissue
targets a bifunctional version of this chelator is required and there
has been a surge of interest in these compounds since the first
Department of Chemistry, The University of Hull, Cottingham Road,
Hull, UK, HU6 7RX. E-mail: s.j.archibald@hull.ac.uk; Fax: +44(0)1482
466410; Tel: +44(0)1482 465488
In this work we aim to find a different approach to the synthesis
of non-symmetrically functionalised cross-bridged macrocycle
precursors to offer synthons for the production of series of
bifunctional chelators, see Fig. 1. This will improve access to some
† Electronic supplementary information (ESI) available: CIF files, tables
of bond lengths and angles, Hirshfeld surface plots and H-bonding
parameters are included for all X-ray structures. CCDC reference numbers
803779–803782. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c0dt01395a
This journal is
The Royal Society of Chemistry 2011
Dalton Trans., 2011, 40, 6289–6297 | 6289
©

developed methods that can be applied to the stepwise reaction
of tetracyclic bisaminals with alkyl halides.19–23 It also builds on
the synthetic work of Kolinski, Weisman and Lukes.24–27 Our aim
is to use this approach to incorporate handles for bioconjugation
reactions onto the cross-bridged (CB) cyclam chelator, such as
primary amine groups, which can be reacted efficiently with
proteins and peptides via a number of well characterised pathways.
Synthesis
The synthetic route leading to unsymmetric substitution is shown
in Scheme 1. The bisaminal intermediate produced via the
condensation of glyoxal with cyclam,27 1, allows quaternisation
of one tertiary amine using alkyl halides.24 Benzyl-DTAP, 2, has
been reported several times before. A second tertiary amine may
be stereoselectively quaternised using a further alkyl halide to
yield unsymmetrical bis-ammonium salts, 4 and 5. The asymmet-
rically substituted bisaminal, benzyl-methyl-DTAP, 4, has been
published by Kotek et al., and we report the crystal structure
below.25 In this study, we also used a cyano-substituted benzyl
group as a pendant arm, 3. The addition of the second pendant
arm occurred in over 85% isolated yield in both cases, with a
two-week reaction time, which is comparable to the addition of a
second benzyl group.
Fig. 1 Unsymmetrically substituted cross-bridged (CB) cyclam chelators
synthesised in this work.
of the known chelators and allow design and synthesis of a novel
series of BFCs.
Results and discussion
Reductive ring cleavage using borohydride in ethanol, in an
analogous procedure to that of Weisman et al.,28 affords the
cross-bridged cyclams, 6 and 7, in an overall yield of over 70%
from 1 in each case. 7 is the first example of a cross-bridged
cyclam with a N-substituted cyano group. The cyano group can
be reduced to an alkyl amine in order to facilitate conjugation
Asymmetric derivatives
Our approach is to use the reactivity of the bisaminal bridged
precursor to control the functionalisation pattern with a series
of higher yielding reactions. The initial steps follows the work
of Handel, Tripier and their respective co-workers, who have
Scheme 1 Synthetic routes to produce unsymmetric cross-bridged cyclam chelators.
6290 | Dalton Trans., 2011, 40, 6289–6297 This journal is The Royal Society of Chemistry 2011
©

Table 1 Crystal data for the single-crystal X-ray structures of 4, 6, [Cu6(OH2)](ClO4)2 and 11
4·2H2O
[H26](ClO4)2·0.5MeOH
[Cu6(OH2)](ClO4)2
[H11]Br·0.5C7H8O
Formula
Mr
Crystal system
C20H36N4O2I2
618.33
Orthorhombic
C20.5H38N4O8.5Cl2
547.45
Monoclinic
C20H36N4O9Cl2Cu
610.97
Orthorhombic
C21.5H40.5N4O2.5Br
474.99
Triclinic
¯
Space group
Pca21
P21/c
Pca21
P1
˚
a/A
16.4087(6)
10.9231(7)
13.3642(8)
90
17.4472(18)
11.3606(12)
15.194(2)
90
15.571(2)
9.7171(9)
16.678(2)
90
9.426(3)
11.423(4)
12.534(5)
63.15(2)
87.27(3)
81.51(3)
1190.6(7)
2
˚
b/A
˚
c/A
a/◦
b/◦
g /◦
90
90
2395.3(2)
4
1.715
2.648
150
2.71–34.83
278802
10134
0.0644
98.6% (34.83)
1.0161
0.0496, 0.1273
0.0630, 0.1373
0.0120(6)
2.049/-1.681
101.430(10)
90
2951.9(6)
4
1.232
0.267
150
2.38–34.84
62025
12678
0.1142
99.9% (25.00)
0.990
0.1161, 0.3265
0.2549, 0.3692
0.011(2)
1.612/-0.536
90
90
2523.5(5)
4
1.608
1.135
150
2.44–34.83
57231
10817
0.1636
99.7% (25.00)
0.716
0.0453, 0.0873
0.1941, 0.1152
—
3
˚
V/A
Z
Dc/Mg m-3
1.325
1.752
150
2.76–30.00
26864
6939
0.1153
99.8% (25.00)
0.928
0.1073, 0.2958
0.2412, 0.3685
—
m(Mo-Ka)/mm-1
T/K
q range/◦
Measured reflections
Unique reflections
Rint
Completeness (q/◦)
Goodness-of-fit on F2
R1, wR2 (I > 2s(I))
R1, wR2 (all data)
Extinction coefficient
-3
˚
Drmax/min/e A
0.728/-2462
1.484/-1.312
to biological targeting molecules, and provide a rapid route to
cross-bridged cyclam conjugates, as we have previously shown
with a C-substituted cross-bridged cyclam system.11 Reduction
was achieved using lithium aluminium hydride in a 77% yield. We
have previously demonstrated that the reduction of a nitrophenyl
group to an aminophenyl is possible without cleavage of the
benzyl linkage by using a poisoned Pd on C catalyst with H2 to
give a functional group for conjugation.29 The benzylamine group
has the advantage of higher reactivity, in comparison to aniline
derivatives, with some classical bioconjugation functional groups
including isothiocyanates.30
These methods offer high yielding preparations to form cross-
bridged cyclam derivatives with single conjugation handles from a
common precursor. Cold copper(II) complex formation with 6, 7
and 8 was attempted using stoichiometric amounts of hydrated
metal salts in methanol at reflux. Complexation with other
transition metal ions would be expected to require anhydrous
conditions, due to the lack of coordinating pendant arms, which
can assist in the transfer of the metal ion into the cavity. The
copper(II) ion was incorporated into the cavity of the macrocycle
and analysis of the complexes carried out by UV/vis, mass
spectrometry and, in the case of [Cu6(OH2)]2+, single-crystal X-ray
crystallography.
X-Ray structures of unsymmetrical derivatives
Although the synthesis of 4 has been previously reported,25 the
crystal structure of this compound has not been determined.
X-Ray quality crystals of bisammonium salt 4 were obtained
by evaporation from water. The rigidity of the bisaminal sys-
tems result in little distortion of the bond lengths and angles
when compared to symmetrically substituted bis-benzyl and bis-
methyl analogues, see Tables 1 and S1 (ESI†), and Fig. 2. The
X-ray structure shows the dihydrate of the salt is present in the
solid state, with hydrogen bonding occuring between the water
of crystallisation and the iodide anions. 4·2H2O displays a 3-D
hydrogen bonded framework, similar to that of the bis-benzylated
bisaminal reported by Kotek et al.25 In this case, the bisaminal
Fig. 2 ORTEP representations of the cations of 4 (left), 6 (middle) and [Cu6(OH2)]2+ (right). Counter-anions and hydrogen atoms have been omitted for
clarity, excepting water or N–H hydrogens. Selected bond lengths for [Cu6(OH2)]2+ (A): Cu(1)–O(1) 2.025(3), Cu(1)–N(1) 2.159(4), Cu(1)–N(2) 2.111(3),
˚
Cu(1)–N(3) 2.041(3), Cu(1)–N(4) 2.085(4); Selected bond angles (◦): O(1)–Cu(1)–N(3) 166.04(14), O(1)–Cu(1)–N(1) 103.57(13), N(1)–Cu(1)–N(4)
92.56(15), N(1)–Cu(1)–N(3) 87.90(13), N(2)–Cu(1)–N(4) 177.34(14).
This journal is
The Royal Society of Chemistry 2011
Dalton Trans., 2011, 40, 6289–6297 | 6291
©

azamacrocycle is not involved in the H-bonding network which is
formed between the water molecules and iodide counter anions,
see Fig. S1 and Table S6 (ESI†).
Incorporating carboxylate pendant arms for copper(II)
coordination
The incorporation of carboxylate pendant arms is important for
both overall stability of the copper(II) complex and rapid kinetics
of complex formation. The branched carboxylate arm used in
compounds C and D offers an alternate method for bioconjugation
via orthogonal deprotection steps. At the same time as Sun and
Brechbiel were investigating these derivatives, we had also been
studying the potential for branched carboxylate arm incorporation
with a cross-bridged cyclam, see ESI† for further information.40
Colourless crystals of 6 were produced as a minor by-product
during the complexation reaction with copper(II) perchlorate. The
structure shows the diprotonated ligand, with the protons located
on the nitrogen atoms orienting the pendant arms, see Tables 1
and S2 (ESI†), and Fig. 2. This parallels the bis-methyl cross-
bridged cyclam ligand previously reported by Weisman et al.8 and
exhibits intramolecular hydrogen bonding between the nitrogen
atoms forming the cavity. Nitrogens N1 and N3 are protonated,
with H-bonds forming to adjacent N atoms across the propyl
bridge (N4 and N2, respectively), see Fig. 2 and S2, and Table
S7 (ESI†). Two perchlorate counter-ions and a partial occupancy
methanol solvent molecule are present in the asymmetric unit and
do not show any H-bonding interactions.
There are eighteen structurally characterised copper(II) com-
plexes of cross-bridged (CB) cyclams in the crystallographic
database, using eight different CB cyclam derivatives.18,28,31–38
X-Ray quality crystals of the copper(II) complex, [Cu6(OH2)]2+,
were grown by evaporation of a methanolic solution. The con-
formation of the tetraazamacrocycle is fixed by the ethylene
bridge, and little distortion between the ligand and complex is
observed, see Table 1 and Fig. 2. As expected for a bis-substituted
cross-bridged cyclam, the tetradentate ligand adopts a cis-folded
conformation, and the pendant arms do not eclipse each other
when viewed along the N(2)–Cu–N(4) axis. The copper(II) ion
is held at 2.7◦ outside of the cavity with respect to this axis, and
displays a five-coordinate geometry with an aquo ligand occupying
the fifth coordination site. The aquo ligand hydrogen bonds to
both perchlorate counterions in the asymmetric unit but does not
appear to form an extended H-bonding network, see Fig. S3 and
Table S9 (ESI†).
The geometry of the copper ion can be described as square
pyramidal with a distortion towards trigonality of 18.8%, as
defined by the t parameter of Addison and co-workers.39 This
is similar to the geometry previously observed in a bis-benzylated
CB cyclam copper(II) complex with a chloride ligand.28 However,
it is markedly lower than the 32.2% distortion observed in the
dimethylated CB cyclam copper(II) complex previously reported
by Hubin et al.33 As may be expected due to lower steric restraints,
the O–Cu–N angle is more acute towards the methyl arm than the
benzyl arm. The Cu–N–C angles along the pendant arms are also
more acute than in corresponding symmetrical complexes with a
chloride counterion occupying the fifth coordination site, due to
the increased steric requirements of the chloride in comparison to
the aquo ligand.
Mono-functionalisation with a carboxymethyl arm
The main issue in forming unsymmetric compounds such as 11,
which is a known compound, is the fact that cross-bridged cyclam
with two equivalent secondary amines must be mono-alkylated.
This monoalkylation strategy has been used to form chelators of
the type A, C and E. In most of these cases, for this reaction step,
the reported yield was below 40% and separation from a mixture
of compounds was required. A key improvement to this process
would be a higher yielding synthesis that only results in a single
macrocyclic product, reducing the waste resulting from the use of
an excess of a highly valuable precursor, which takes many weeks
to synthesise.
Our chosen route was to form the asymmetric cross-bridged
cyclam derivative with one methylcarboxyester arm and one
benzyl arm, which could then be selectively deprotected to give
a secondary amine site for subsequent reaction, see Scheme 2.
For example, an improved synthesis of C type chelators would be
possible as the published procedure to produce the non-symmetric
macrocycle with the branched ester arm goes via a step with 16%
yield that requires chromatographic separation.13 The route to
form the mono-arm CB derivative starts with the reaction of
tert-butyl-carboxymethyl bromide with the quaternized benzyl
aminal to form 9 in 82% yield followed by reduction with sodium
borohydride using the characterised routes and the cleavage
of the benzyl group in a Pd on C catalysed hydrogenolysis
reaction.
In general, the solvent of choice for such hydrogenolysis
reactions is acetic acid, as reported by Weisman et al. However, this
is unacceptable for the debenzylation of 10, due to the presence
of tert-butyl groups. These may be cleaved by acid catalysed
hydrolysis, so methanol was used as a solvent, which results in
the production of benzyl alcohol as a side product rather than
toluene. This reaction produces mono-substituted cross-bridged
cyclam, 11. As already discussed, functionalisation of this deriva-
tive can then be achieved by well documented synthetic routes
Scheme 2 High yielding and selective synthetic route to form a mono-substituted derivative with a masked carboxymethyl pendant arm.
6292 | Dalton Trans., 2011, 40, 6289–6297 This journal is The Royal Society of Chemistry 2011
©

using the secondary amine reactive site. Hence, more sterically
demanding pendant arms may be utilised with the cross-bridged
system.
X-Ray crystal structure of carboxymethyl ester chelator
A crystalline sample of 11 was formed from the mother-liquor
over two weeks. The crystal structure shows that the removal of
the benzyl group has been effected without hydrolysis of the tert-
butyl ester pendant arm, see Table 1 and Fig. 3. The ligand is
protonated at the N3 secondary amine position and charge is
balanced by a bromide counter ion. One of the hydrogens on N3
participates in trans-cavity hydrogen bonding with appropriate
interaction distances to both N1 and N2, see Table S9 (ESI†). The
other hydrogen atom located on N3 is involved in a hydrogen-
bonding interaction with the bromide counter ion as the acceptor.
Also present in the unit cell is a benzyl alcohol molecule produced
during the debenzylation step. This spans the asymmetric unit
boundary, and the molecule has been independently refined,
with a best fit occupancy of 0.5. The alcohol H atom was
placed in a H-bonding position with the bromide counter
anion.
Complexes of both ligands were formed with copper(II) per-
chlorate. It is worth considering the coordination number that is
adopted by the copper(II) ion. It is shown by the Cu2+-CBTE2A
complex that it is possible for two acetate pendant arms to occupy
the two available cis equatorial coordination sites.37 Due to the
size and the weakly coordinating nature of the perchlorate anion,
the coordination of a perchlorate ion to the sixth coordination
site of [Cu12]+ and [Cu13]+ is not expected. This is supported by
the mass spectrometry data for both [Cu12]ClO4 and [Cu13]ClO4
which show the positive mass ion with no other coordinated or
associated anion.
Ligand 10 was also reacted with copper(II) chloride to form
[Cu12]Cl. The UV/vis spectrum shows similar maximum absorp-
tions and extinction coefficients for the transitions, suggesting a
similar coordination environment exists in both complexes. This
is supported by the results of mass spectrometry experiments
on [Cu12]Cl, which show no evidence of a bound chloride
counter-ion. It is suggested that in all three of the unsymmetric
carboxymethyl functionalised cross-bridged ligand complexes, the
chelator may act as the only donor to a five coordinate metal ion
in solution.
Conclusions
Synthetic routes have been investigated to produce cross-bridged
cyclam chelators in improved yields opening up the possibility
for new efficient routes to bifunctional chelators that can be
labelled with copper radioisotopes. Initial compounds have been
synthesised incorporating a benzylamine functional group (8) for
conjugation or further modification. The inclusion of carboxylate
functionality in the chelators was achieved with an efficient
protection/deprotection strategy which demonstrated that the
tert-butyl ester was sufficiently robust to undergo the reduction
and debenzylation steps without significant cleavage (11). Ester
cleavage was observed on cold copper(II) ion chelation to give
bound chelator 13. These synthetic procedures will also be
important to the development of other bioactive bridged cyclam
compounds including protein binding complexes.44–46
Fig. 3 ORTEP representation of the protonated 11 cation. Hydrogen
atoms (apart from the amino protons), counter-ions and water molecules
have been omitted for clarity.
Cold copper complex formation of monocarboxymethyl chelators
Hydrolysis of the ester groups attached to carboxymethyl pendant
arms can occur during copper(II) complexation to provide a
coordinating acetate arm which enhances the metal binding and
also offers a rapid route to the desired complex without the need for
a deprotection step. This was observed during complex formation
for the asymmetrical cross-bridged ligands, 10 and 11 carried out
in methanol, forming bound chelators 12 and 13. The complexes
were analysed by UV/vis spectroscopy and electrospray ionisation
mass spectrometry. High-resolution mass spectrometry confirmed
the production of the deprotected species. Coordination via the
carboxyl oxygen is normally expected for such carboxymethyl
cross-bridged cyclam complexes, although coordination via the
carbonyl oxygen has been observed in both our work and in the
literature.41–43
We are continuing this work to investigate further targeted
synthesis of these chelators, bioconjugation reactions and radi-
olabelling.
Experimental
NMR spectra were obtained using a JEOL400 spectrometer.
UV/visible spectra were obtained using an Agilent 800 diode
spectrometer. Electrospray mass spectra were obtained using a
Finnigan LCQ spectrometer. Accurate mass measurements were
carried out by the EPSRC’s National Mass Spectrometry Service at
Swansea. All materials were purchased from Aldrich Chemical Co.
or Lancaster Synthesis Ltd, and used as supplied. Cyclam,47 1,19 224
This journal is
The Royal Society of Chemistry 2011
Dalton Trans., 2011, 40, 6289–6297 | 6293
©

and 424 were synthesised in accordance with literature procedures.
We have recently communicated the preparation of 6.35 11 has
previously been synthesised via a lower yielding route.13
3a-(4-Cyanobenzyl)-8a-methyldecahydro-3a,5a,8a,10a-tetraa-
zapyrenium diiodide (5). 3a-(4-Cyanobenzyl)decahydro-
3a,5a,8a,10a-tetraazapyrenium bromide (3) (2.00 g, 4.8
mmol), was suspended in dry MeCN (100 ml) under nitrogen.
Iodomethane (25 ml, 415.0 mmol) was added dropwise. The
white suspension was left to stir for 10 days. A second portion
of iodomethane (13 ml, 208.0 mmol) was added after 5 days.
Excess iodomethane was removed by flowing nitrogen through
the suspension for 30 min. The solid was collected by filtration,
washed with diethyl ether (2 ¥ 50 ml) and dried in vacuo to yield a
white powder (2.90 g, 100%).
Diffraction data sets were collected on a Stoe IPDS-II im-
˚
age plate diffractometer, using Mo-Ka (0.71073 A) radiation.
The temperature of each crystal was kept at 150(1) K during
data collection and controlled using the Oxford Cryosystems
Cryostream Cooler.48 Data collection was attempted on a number
of crystals in each sample to gain the best quality data but in
some cases the small size or poor quality gave weak diffraction.
Data sets were all collected to q = 35◦ with the data for 11
truncated to q = 30◦. For weakly diffracting crystals, refinement
was attempted with both full and truncated data sets. A numerical
absorption correction was applied to 4 based on crystal shape.
All structures were solved by direct methods (SHELXS49) and
refined against F2 (SHELXL50). Hydrogen atoms located on
carbon atoms were placed geometrically and refined against a
riding model with Uiso = 1.2Ueq of the carrier atom or Uiso = 1.5Ueq
for methyl groups. In structures 6 and 11 the amino protons were
located on Fourier difference maps, and constrained to acceptable
1H NMR (400 MHz, DMSO): d 8.02 (d, 2H, J = 8.1 Hz, H-Ar),
7.82 (d, 2H, J = 8.1 Hz, H-Ar), 5.16 (m, 2H, CH2Ar), 4.96 (m, 2H,
Haminal), 4.28 (m, 2H, N-a-CH2), 3.81 (m, 1H, N-a-CH2), 3.62 (td,
1H, J = 13.1 Hz, 3.4 Hz, N-a-CH2), 3.53 (td, 1H, J = 13.1 Hz, 3.4
Hz, N-a-CH2), 3.43–3.40 (m, 2H, N-a-CH2), 3.28–3.24 (m, 2H,
N-a-CH2), 3.17 (d, 2H, N-a-CH2), 3.03 (m, 2H, N-a-CH2), 2.87
(m, 2H, N-a-CH2), 2.63 (td, 1H, J = 12.2 Hz, 2.8 Hz, N-a-CH2),
2.48 (m, 1H, N-b-CH2), 2.28–2.25 (m, 1H, N-b-CH2), 2.15 (s, 3H,
CH3), 1.85 (d, 1H, J = 14.4 Hz, N-b-CH2), 1.74 (d, 1H, J = 14.4
1
N–H distances (0.91 A). The WinGX package was used for
Hz, N-b-CH2). 13C{ H} NMR (100 MHz, DMSO): d 134.38 (CH-
˚
refinement and production of data tables, and ORTEP-3 used
for structure visualisation.51 Hydrogen bonding was determined
using SHELXL and by generation of Hirshfeld surface plots
based on dnorm using CrystalExplorer (see ESI†).52 Disordered
or partial occupancy solvent was located on the difference map
and modelled in accordance with spectroscopic data and/or
recrystallisation solvent; a 0.5 occupancy methanol was located in
the structure of 6 and a disordered benzyl alcohol in the stucture
of 12 and appropriate restraints (DFIX) applied. All ORTEP
representations show ellipsoids at the 50% probability level.
CAUTION: Perchlorate salts are potentially explosive when
dry. Although no problems were encountered in these
preparations, care should be exercised when using these
compounds.
Ar), 132.90 (CH-Ar), 131.12 (C-Ar), 118.09 (CN), 113.41 (C-Ar),
75.16 (Caminal), 75.10 (Caminal), 63.91 (CH2Ar), 59.82, 59.54, 50.33,
50.17, 48.71, 47.38, 47.02, 45.90, 45.72, 18.25 (N-b-CH2), 18.00
(N-b-CH2). MS: (ESI) m/z 176 (100 [M – 2I-]2+). HRMS: calc. for
C21H31N5: 176.6280, found 176.6284.
4-Benzyl-11-methyl-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane
(6). To a stirred solution of 4 (2.50 g, 4.29 mmol) in ethanol
(125 mL) was added in small portions sodium borohydride (4.0 g,
106 mmol), and the mixture was stirred at r.t. for 16 days. Water
(20 mL) was added, and solvents were removed under reduced
pressure. The white residue was taken up into water (40 mL),
made basic (pH 14, KOH), and extracted with dichloromethane (4
¥ 50 mL). The combined organic extracts were dried over MgSO4
and solvents were removed to yield a colourless oil (1.26 g, 89%).
1H NMR (400 MHz, CDCl3): d 7.29 (m, 5H, CHaromatic), 3.99 (m,
1H, N-a-CH2), 3.79 (m, 2H, H2Cbenzylic), 3.13 (m, 3H, N-a-CH2),
2.88 (m, 1H, N-a-CH2), 2.68 (m, 2H, N-a-CH2), 2.41 (m, 8H,
N-a-CH2), 2.27 (m, 3H, N-a-CH2), 2.19 (s, 3H, CH3), 1.49 (m, 4H
Syntheses
3a - (4 - cyanobenzyl)decahydro - 3a,5a,8a,10a - tetraazapyrenium
bromide (3). 1 (3.50 g, 15.7 mmol) was dissolved in dry MeCN
(150 ml), 4-(bromomethyl)benzonitrile (7.72 g, 39.4 mmol) was
added and the solution was stirred under argon for 3 days. The
resulting precipitate was filtered off and washed with diethyl ether
(2 ¥ 25 ml) to yield a white solid (5.00 g, 76%).
1
N-b-CH2). 13C{ H} NMR (100 MHz, CDCl3), d 140.93 (Caromatic),
128.81 (CHaromatic), 127.91 (CHaromatic), 126.41 (CHaromatic), 59.93 (N-
a-CH2), 59.39 (N-a-CH2), 57.77 (N-a-CH2), 56.66 (N-a-CH2),
56.55 (N-a-CH2), 56.15 (N-a-CH2), 55.98 (N-a-CH2), 54.94 (N-
a-CH2), 54.01 (N-a-CH2), 52.08 (N-a-CH2), 51.90 (N-a-CH2),
42.83 (N-a-CH3), 27.82 (N-b-CH2), 26.91 (N-b-CH2). MS (ES)
m/z 331 [M + H]+. HRMS: calc. for C20H35N4: 331.2856, found
331.2860.
1H NMR (400 MHz, D2O): d 7.92 (d, 2H, J = 8.4 Hz, H-Ar),
7.72 (d, 2H, J = 8.4 Hz, H-Ar), 5.22 (d, 1H, J = 13.4 Hz, CH2Ar),
4.35 (d, 1H, J = 1.9 Hz, Haminal), 4.24 (td, 1H, J = 13.4 Hz, 3.8
Hz, CH2Ar), 3.72 (s, 1H, Haminal), 3.62-3.47 (m, 2H, N-a-CH2),
3.36–3.33 (m, 1H, N-a-CH2), 3.26 (td, 1H, J = 13.4 Hz, 2.7 Hz,
N-a-CH2), 3.15–3.04 (br m, 8H, N-a-CH2), 2.63 (td, 1H, J = 13.1
Hz, 3.1 Hz, N-a-CH2), 2.53–2.47 (m, 2H, N-b-CH2), 2.36–2.17
(m, 3H, N-a-CH2), 1.79 (d, 1H, J = 14.7 Hz, N-b-CH2), 1.46 (d,
1-(4-Cyanobenzyl)-8-methyl-1,4,8,11-tetraazabicyclo[6.6.2]-
hexadecane
(7). 3a-(4-Cyanobenzyl)-8a-methyldecahydro-
3a,5a,8a,10a-tetraazapyrenium diiodide (5) (2.50 g, 4.2 mmol)
was dissolved in ethanol (120 ml) and sodium borohydride (6.29
g, 166.0 mmol) was added in small portions over a period of 1 h.
The clear solution was stirred for 14 days. Water (80 ml) was
added to quench the reaction and solvents were removed in vacuo.
The residue was taken up in water (100 ml) and made strongly
basic (pH 14, KOH). The basic solution was extracted with
dichloromethane (4 ¥ 100 ml), the combined organic extracts were
1
1H, J = 14.7 Hz, N-b-CH2). 13C{ H} NMR (100 MHz, D2O):
d 134.18 (CH-Ar), 133.41 (CH-Ar), 131.27 (C-Ar), 118.88 (CN),
113.95 (C-Ar), 82.78 (Caminal), 69.75 (Caminal), 61.76 (CH2Ar), 60.44
(N-a-CH2), 54.15 (N-a-CH2), 53.52 (N-a-CH2), 52.12 (N-a-CH2),
51.54 (N-a-CH2), 48.84 (N-a-CH2), 46.76 (N-a-CH2), 42.15 (N-a-
CH2), 18.60 (N-b-CH2), 18.20 (N-b-CH2). MS: (ESI) m/z 338 (100
[M – Br-]+). HRMS: calc. for C20H28N5: 338.2340, found 338.2339.
6294 | Dalton Trans., 2011, 40, 6289–6297
This journal is
The Royal Society of Chemistry 2011
©

dried (Na2SO4) and evaporated in vacuo to yield a yellow–cream
oil (1.31 g, 88%).
[18.4, 18.2] (CH2-b-N). MS, m/z: 427 [M - H]+, 100%; 337 [M -
CH2C6H5]+, 64%; 281 [M(337) - C(CH3)3]+, 24%. HRMS: calc.
for C25H39N4O2: 427.3073, found 427.3071.
1H NMR (400 MHz, CDCl3): d 7.52 (d, 2H, J = 8.1 Hz, H-Ar),
7.38 (d, 2H, J = 8.1 Hz, H-Ar), 4.02 (m, 1H, N-a-CH2), 3.75–3.60
(m, 2H, CH2Ar), 3.17 (d, 1H, J = 14.4 Hz, N-a-CH2), 3.00 (d,
1H, J = 8.1 Hz, N-a-CH2), 2.76 (m, 1H, N-a-CH2), 2.68–2.55 (m,
3H, CH3), 2.43–2.12 (br m, 16H, N-a-CH2), 1.44–1.32 (m, 4H,
4-Benzyl-11-tert-butylcarboxymethyl-1,4,8,11-tetraazabicyclo-
[6.6.2]hexadecane (10). To a stirred solution of 11 (400 mg, 0.68
mmol) in ethanol (40 mL) was added in small portions sodium
borohydride (100 mg, 2.7 mmol), and the mixture was stirred
at r.t. for 8 days. Water (10 mL) was added, and solvents were
removed under reduced pressure. The white residue was taken up
into water (40 mL), made basic (pH 14, KOH), and extracted with
dichloromethane (4 ¥ 50 mL). The combined organic extracts were
dried over MgSO4 and solvents were removed to give a yellow oil.
Yield: 85%. 1H NMR (400 MHz, CDCl3): d 7.39–7.29 (m, 5H, H-
Ar), 4.68 (s, 2H, CH2Ar), 3.31 (s, 2H, CH2CO2R), 3.21–3.06 (m,
3H, CH2N), 2.99–2.82 (m, 7H, CH2N), 2.70–2.52 (m, 9H, CH2N),
2.43–2.36 (m, 2H, CH2N), 2.23–2.17 (m, 2H, CH2N), 1.73–1.62
(m, 2H, CH2-b-N), 1.46 (s, 9H, CH3), 1.43–1.19 (m, 2H, CH2-
1
N-b-CH2). 13C{ H} NMR (100 MHz, CDCl3): d 146.96 (C-Ar),
131.88 (CH-Ar), 129.35 (CH-Ar), 119.08 (CN), 110.28 (C-Ar),
59.92 (CH2Ar), 59.41 (N-a-CH2), 57.84 (N-a-CH2), 56.92 (N-
a-CH2), 56.71 (N-a-CH2), 56.14 (N-a-CH2), 55.89 (N-a-CH2),
54.98 (N-a-CH2), 54.07 (N-a-CH2), 52.14 (N-a-CH2), 51.89 (N-
a-CH2), 42.73 (CH3), 27.91 (N-b-CH2), 26.87 (N-b-CH2). MS:
(ESI) m/z 356 (100 [M]+). HRMS: calc. for C21H34N5: 356.2809,
found 356.2811.
1-(4-Aminomethylbenzyl)-8-methyl-1,4,8,11-tetraazabicyclo[6.
6.2]hexadecane (8). Lithium aluminium hydride (0.19 g, 5.0
mmol) was suspended in dry THF (20 ml). To this, 1-(4-
cyanobenzyl)-8-methyl-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane
(7) (1.45 g, 4.1 mmol) in dry THF (20 ml) was added dropwise
under ice-cooling. After complete addition the mixture was stirred
for 30 min then heated to reflux for 3 h. The reaction was cooled
in an ice-bath, water (0.21 ml) was added dropwise followed by
15% sodium hydroxide (0.21 ml) followed by a second portion
of water (0.62 ml). The resulting white precipitate was filtered
off and washed with THF (2 ¥ 10 ml) then water (2 ¥ 5 ml). The
aqueous layer was made strongly basic (pH > 12, KOH) and
extracted with THF (5 ¥ 25 ml). The organic phases were dried
(Na2SO4), filtered and concentrated in vacuo to yield a yellow oil
(1.13 g, 77%).
1
b-N). 13C{ H} NMR (100 MHz, CDCl3): d 170.6 (CO2R), 72.1
(C(CH3)3), 64.9 (CH2Ar), 60.0 (CH2CO2R), [57.2, 56.8, 56.7, 55.9,
55.8, 54.7, 51.0, 48.2] (CH2N), 28.3 (CH3), [28.0, 23.4] (CH2-b-N).
MS, m/z: 431 [M+H]+. HRMS: calcd. for C25H43O2N4: 431.3383,
found 431.3381.
4 - tert - Butylcarboxymethyl - 1,4,8,11 - tetrabicyclo[6.6.2]hexa-
decane (11). A solution of 12 (0.25 g, 0.58 mmol) in methanol
(10 mL) was added to a suspension of 10% palladium on carbon
(50 mg) in methanol (10 mL). The suspension was then shaken in
a Parr hydrogenation apparatus overnight under pressure of H2
(50 psi). Hydrogen was released and the suspension was filtered
through a pad of Hyflo filter-aid and washed with methanol (3
¥ 5 mL). Solvent was removed from the combined filtrate and
washings, and the residue was taken up into 30% sodium hydroxide
solution. The product was extracted with dichloromethane (5 ¥
20 mL), the combined organic extracts were dried, and solvent
was removed to yield a brown oil. Yield: 70% (corrected for
the presence of a small amount of benzyl alcohol based on
the integration of the NMR spectrum). 1H NMR (400 MHz,
CD3OD): d 3.31–3.11 (m, 4H, CH2CO2R, CH2N), 2.97–2.50 (m,
16H, CH2N), 2.44–2.37 (m, 2H, CH2N), 1.74–1.50 (m, 2H, CH2-
1H NMR (400 MHz, CDCl3): d 7.30 (d, 2H, J = 7.8 Hz, H-
Ar), 7.23 (d, 2H, J = 7.8 Hz, H-Ar), 3.98 (m, 1H), 3.83 (m, 4H),
3.77–3.73 (m, 2H), 3.20–3.01 (m, 4H), 2.87 (m, 1H), 2.73–2.61 (m,
3H, CH3), 2.52–2.23 (br m, 14H, N-a-CH2), 1.85 (m, 2H, N-b-
CH2), 1.61–1.46 (m, 1H, N-b-CH2), 1.41–1.34 (m, 1H, N-b-CH2).
1
13C{ H} NMR (100 MHz, CDCl3): d 141.11 (C-Ar), 139.51 (C-
Ar), 129.05 (CH-Ar), 126.70 (CH-Ar), 67.90, 59.63, 59.08, 57.88,
56.48, 56.22, 55.89, 54.79, 53.89, 52.28, 52.07, 42.93, 30.27 (CH3),
26.79, (N-b-CH2), 25.55 (N-b-CH2). MS: (ESI) m/z 360 (100 [M
+ H]+). HRMS: calc. for C21H38N5: 360.3124, found 360.3122.
1
b-N), 1.48 (s, 9H, CH3), 1.43–1.02 (m, 2H, CH2-b-N). 13C{ H}
NMR (100 MHz, CD3OD): d 174.0 (CO2R), 82.9 (C(CH3)3),
66.0 (CH2CO2R), [59.9, 57.9, 57.5, 57.3, 57.1, 55.6, 53.5, 52.2,
51.3] (CH2N), 32.0 (CH2-b-N), 29.3 (CH3), 27.7 (CH2-b-N). m/z:
341 [M + H]+. HRMS: calc. for C18H37O2N4: 341.2915, found
341.2915.
3a-Benzyl-8a-tert-butylcarboxymethyldecahydro-3a,5a,8a,10a-
tetraazapyrenium dibromide (9). To a stirred solution of 2 (356
mg, 853 mmol) in dry acetonitrile (30 mL) was added benzyl
bromide (6.0 mL, 50.5 mmol), and the solution was stirred for 16
days. Solvent was removed and the orange oily residue was washed
with diethyl ether (4 ¥ 50 mL), and the resulting solids collected
by filtration to yield a white solid (410 mg, 82%). 1H NMR (400
MHz, D2O): d 7.62–7.54 (m, 5H, H(Ar)), 5.44 (br s, 1H, CH), 5.31
and 4.53 (AB, 2H, J 13.0 Hz, CH2Ar), 4.88 (br s, 1H, CH), 4.72–
4.61 (m, 2H, CH2N), 4.42–4.31 (m, 2H, CH2N), 4.05 and 3.81
(AB, 2H, CH2CO2R), 3.95–3.88 (m, 1H, CH2N), 3.64–3.58 (m,
1H, CH2N), 3.48–3.34 (m, 3H, CH2N), 3.26–3.12 (m, 5H, CH2N),
2.73 (td, 1H, J 12.0, 3.0 Hz, CH2N), 2.52–2.41 (m, 1H, CH2N),
2.00–1.72 (m, 2H, CH2-b-N), 1.54 (s, 9H, CH3), 1.53–1.46 (m, 2H,
[Cu6](ClO4)2. To a stirred solution of 6 (50 mg, 150 mmol)
in methanol (10 mL) was added dropwise a solution of a
stoichiometric amount of Cu(ClO4)2·6H2O in methanol (2 mL).
The solution was heated to reflux for 2 h and, after cooling, filtered
through a pad of Hyflo filter-aid before the solvents were removed.
After cooling, the solution was decanted from the colourless
crystals, and purified by size exclusion chromatography (Sephadex
LH-20, MeOH). Solvent was removed from the eluent to give a
blue solid (57 mg, 59%). UV/vis (MeCN): lmax = 623 nm, e =
180 M-1 cm-1. HRMS: calc. for C20H34N4Cu: 393.2074, found
393.2083.
1
CH2-b-N). 13C{ H} NMR (100 MHz, CDCl3): d 163.1 (CO2R),
133.4 (C(Ar)CH2), [131.6, 129.7, 125.0] (C(Ar)), 87.9 (C(CH3),
[77.1, 76.4] (NCN), 67.1 (CH2Ar), 66.2 (CH2CO2R), [62.4, 60.6,
58.3, 53.4, 51.3, 51.2, 49.1, 46.9, 46.4, 46.0] (CH2N), 27.3 (CH3),
[Cu8](OAc)2. 8 (150 mg, 0.42 mmol) was dissolved in degassed
anhydrous methanol (15 ml), an anhydrous methanolic (5 ml)
This journal is
The Royal Society of Chemistry 2011
Dalton Trans., 2011, 40, 6289–6297 | 6295
©

solution of copper(II) acetate monohydrate (93 mg, 0.46 mmol)
was added dropwise and the mixture was refluxed under nitrogen
for 24 h. The resulting solution was concentrated in vacuo to ~5
ml and purified via size exclusion chromatography to yield a blue
solid (123 mg, 54%). UV/vis (H2O): lmax = 657 nm, e = 66 M-1
cm-1. MS: (ESI) m/z 480 (100 [M - CH3CO2 - H]+). HRMS: calc.
for C23H39N5CuO2: 480.2400, found 480.2403.
6 P. D. Bonnitcha, A. L. Vavere, J. S. Lewis and J. R. Dilworth, J. Med.
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[Cu12]Cl. To a solution of 12 (42.6 mg, 98.9 mmol) in methanol
(6 mL) was added dropwise a solution of copper(II) chloride
dihydrate (16.9 mg, 99.1 mmol) in methanol (2 mL). The solution
turned sapphire blue upon initial addition of copper(II) salt. The
solution was heated to reflux for 2 h. Solvent was removed, and the
residue was purified by size exclusion chromatography (methanol)
to yield a green solid (38.3 mg, 74%). UV/vis (MeCN): lmax = 601
nm, e = 220 M-1 cm-1. ES-MS, m/z: 436 [M - Cl - H]+.
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13 C. A. Boswell, C. A. S. Regino, K. E. Baidoo, K. J. Wong, A. Bumb,
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[Cu12](ClO4). To a solution of 12 (40.9 mg, 95.0 mmol) in
methanol (6 mL) was added dropwise a solution of copper(II)
perchlorate hexahydrate (35.2 mg, 95.0 mmol) in methanol (2
mL). The solution turned sapphire blue upon initial addition
of copper(II) salt. The solution was heated to reflux for 2 h.
Solvent was removed, and the residue was purified by size exclusion
chromatography (methanol) to yield a blue solid (47.6 mg, 72%).
UV/vis (MeCN): lmax = 611 nm, e = 251 M-1 cm-1. MS, m/z:
436 [M - ClO4 - H]+. HRMS: calc. for C21H33O2N4Cu: 436.1894,
found 436.1895.
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18 J. E. Sprague, Y. Peng, A. L. Fiamengo, K. S. Woodin, E. A. Southwick,
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methanol (10 mL) was added dropwise a solution of copper(II)
perchlorate hexahydrate (58.0 mg, 157 mmol) in methanol (5 mL).
The solution turned purple upon initial addition of copper(II)
salt. The solution was heated to reflux for 2 h, during which time
the solution turned blue. The solution was filtered through Hyflo
filter-aid and solvent was removed to yield a blue solid (88.2 mg,
92%). After removal of solvent, the solid was washed with diethyl
ether. UV/vis (MeCN): lmax = 596 nm, e = 110 M-1 cm-1. HRMS:
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We would like to acknowledge the University of Hull for an 80th
Anniversary studentship awarded to R. S., and the EPSRC for
funds to purchase the diffractometer on which the X-ray data were
collected. S. J. A. thanks the Yorkshire Forward for the award
of a Yorkshire Enterprise Fellowship in translational molecular
imaging technologies. We would also like to acknowledge the use
of the EPSRC’s National Mass Spectrometry Service Centre at
Swansea, and the Chemical Database Service at Daresbury.
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