Rapid synthesis of cross-bridged cyclam chelators for copper(II) complex formation

Article abstract of DOI:10.1016/j.crci.2013.02.013

Copper(II) complexes of 1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (cross-bridged cyclam) derived chelators show high kinetic stability relative to less rigid non-bridged azamacrocyclic chelators and have applications as radiopharmaceuticals in PET imaging. Rapid synthesis of two novel bis-benzyl cross-bridged cyclam derivatives was achieved in 24 h compared to the typical synthesis times, between 14 and 30 days. The X-ray crystal structures are reported for the copper(II) complexes with 1,3-dibromobenzyl and tolyl derivatives revealing different ligand coordination environments. Both structures show tetradentate coordination of the tetraazamacrocycle with axial elongation along the N-Cu-N axis for the 1,3-dibromobenzyl derivative (Cu-N distances: axial av. 2.48(8) ?, equatorial av. 2.081(7) ?).

Full text of DOI:10.1016/j.crci.2013.02.013

C. R. Chimie 16 (2013) 524–530
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´
Full paper/Memoire
Rapid synthesis of cross-bridged cyclam chelators for copper(II) complex
formation
*
Jon D. Silversides, Benjamin P. Burke, Stephen J. Archibald
Department of Chemistry, The University of Hull, Cottingham Road, Hull, HU6 7RX, United Kingdom
A R T I C L E I N F O
A B S T R A C T
Article history:
Copper(II) complexes of 1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (cross-bridged cyclam)
derived chelators show high kinetic stability relative to less rigid non-bridged azamacro-
cyclic chelators and have applications as radiopharmaceuticals in PET imaging. Rapid
synthesis of two novel bis-benzyl cross-bridged cyclam derivatives was achieved in 24 h
compared to the typical synthesis times, between 14 and 30 days. The X-ray crystal
structures are reported for the copper(II) complexes with 1,3-dibromobenzyl and
tolyl derivatives revealing different ligand coordination environments. Both structures
show tetradentate coordination of the tetraazamacrocycle with axial elongation along the
N–Cu–N axis for the 1,3-dibromobenzyl derivative (Cu–N distances: axial av. 2.48(8)
Received 18 October 2012
Accepted after revision 11 February 2013
Available online 30 March 2013
Keywords:
Macrocycle
Coordination chemistry
Cyclam
Copper
˚
˚
A, equatorial av. 2.081(7) A).
Radiopharmaceuticals
PET imaging
´
ß 2013 Academie des sciences. Published by Elsevier Masson SAS. All rights reserved.
1. Introduction
have been investigated for applications in positron
emission tomography (PET) imaging [8,11–16]. 67Cu is
1,4,8,11-Tetraazacyclotetradecane (cyclam) based
macrocycles form complexes of high thermodynamic
and kinetic stability with transition metals [1–4].
N-functionalised derivatives are selective metal ion
chelators and are commonly used as the chelating
component (known as a bi-functional chelator or BFC)
of targeted radiopharmaceuticals in nuclear medicine
[5–8]. A bi-functional chelator contains a reactive site for
attachment to a targeting group (such as an antibody or
peptide) and, ideally, will fully retain the radiolabel
under physiological conditions to allow localisation at
the target site without transchelation occurring [9,10].
We are particularly interested in copper radioisotopes
60Cu, 61Cu, 62Cu and 64Cu, which are positron emitters
with half-lives varying from 0.16 to 12.7 h that
a longer-lived b emitter (t1/2 = 61.9 h) that has been
used in targeted radiotherapy [17,18]. Cross-bridged
cyclam derivatives are promising candidates as copper
radioisotope chelators for tumour targeting applications,
due to the increased kinetic stability of the complexes
[19–21].
The synthesis of cross-bridged macrocycles is generally
a lengthy procedure, with a two-step (bis-substitution
followed by reduction) reaction time of up to 32 days
[22,23]. Initial mono-substitution of glyoxal cyclam with
an alkyl halide is generally quite fast, with standard
reaction times of 12–24 h [23–25]. However, one-pot bis-
substitutions are usually more time consuming as the
reactivity of the second exo-position after mono-alkylation
is greatly reduced and therefore, occurs at a much slower
rate [20,22,26–29].
In this work, two cross-bridged cyclam ligands were
synthesised with an overall bis-substitution reaction time
of less than 24 h, copper(II) complexes were produced and
characterised by X-ray crystallography.
* Corresponding author.
E-mail addresses: s.j.archibald@hull.ac.uk, stevearchibald@yahoo.co.uk
(S.J. Archibald).
1631-0748/$ – see front matter ß 2013 Acade´mie des sciences. Published by Elsevier Masson SAS. All rights reserved.
http://dx.doi.org/10.1016/j.crci.2013.02.013

J.D. Silversides et al. / C. R. Chimie 16 (2013) 524–530
525
Table 1
Bis-substitution reactions of bisaminal 3.
Reference
Substrate
Stoichiometry
(2:X)
T
Time
scale
Yield
[24]
MeI
1:10
1:4
60 8Ca
75 8C
r.t.
12 h
8 h
86%
[24]
BH3–THF
BzBr
86%
[20]
1:16
1:4
14 d
16 h
16 h
93%
This work
This work
MeBzBr
Br2BzBr
r.t.
93%
(38%)b
1:4
r.t.
r.t.: room temperature.
a
Sealed vessel.
b
Mixture of mono-substituted and bis-substituted products. Yield of
bis-substituted product by NMR.
The second exo-nitrogen position of 3 generally effects
its nucleophilic substitutions at a slower rate than the first,
and the appending of two benzyl arms can require reaction
times between 10 and 16 days [20,34,38]. However, using
4-methylbenzyl bromide and 3,5-dibromobenzyl bromide,
the bis-substituted bisaminal salts were produced within
16 h which is more in line with the results indicated in the
patents [36,37]. These bis-substitutions are unusual due to
the short time scale involved in the reactions, and the
relatively low excess of substrate employed compared to
other reported preparations.
2. Results and discussion
2.1. Ligand synthesis
In the case of the substitution of 4-methylbenzyl
bromide, 4 was exclusively produced within 16 h, whereas
the substitution of 3,5-dibromobenzyl bromide resulted in
a mixture of 5 and mono-substituted cyclam (Scheme 1).
The di-substitution makes it possible to convert these
species to cross-bridged macrocycles using a reductive
ring cleavage. Electronic effects may contribute to the
stabilisation of the intermediates formed in the substitu-
tion reactions. It is also possible to achieve rapid bis-
substitution with methyl iodide at elevated temperature
using a five-fold excess of alkylation agent (Table 1).
Benzyl pendent arms can be removed to produce the
parent macrocyclic backbone (1,4,8,11-tetraazabicy-
clo[6.6.2]hexadecane), for example L1 and L3, to which
the alternative pendent arm systems can be attached
[20,34]. This route is well established, and can be adopted
in any strategy requiring pendent armed cross-bridged
cyclams. The published yield from bisaminal 3 to macro-
cycle L1 is 65% [20]. Once reduced to the parent
macrocyclic backbone, L1, substitution reactions at the
secondary amines can be used to add pendant arms, such
as the acetate arms that further stabilise copper(II)
complex formation in L2. Acetate or amine pendant arms,
An investigation into the nucleophilic substitutions of
substituted benzyl bromides by glyoxal bridged cyclam 3
using the bisaminal methodology was carried out [30].
The mono-substitution of benzyl bromide by the tetra-
cyclic bisaminal generally proceeds in good yields
with short reaction times of between 2 h and 3 days
[23,25,31–33]. Not only does the mono-substitution of
benzyl bromides by
3 occur rapidly, but also the
precipitation of the quaternary ammonium salt signals
the completion of the first substitution. The formation of
one-step bis-subsitituted glyoxal cyclams generally
involves the use of a large excess of the benzyl bromide
and/or long reaction times, [20,23–25,34,35] with con-
ditions and yields summarised in Table 1. However, not
all bis-substituted compounds synthesised could suc-
cessfully be reduced to form cross-bridged cyclam
derivatives, this reduction was unsuccessful for the
borane compound [24]. There are two patents published
that report significantly shorter reaction times are
possible indicating that further studies should be carried
out which stimulated the interest in reducing reaction
times [36,37].
Scheme 1. Synthesis of bis-substituted derivatives of glyoxal cyclam, reduction to form the cross-bridged macrocycle and copper(II) complex formation.

526
J.D. Silversides et al. / C. R. Chimie 16 (2013) 524–530
or click chemistry can be used for conjugation reactions,
forming convalent links to targeting groups, such as
peptides for binding to biological targets [20,34,39]. The
yield may be improved upon for some pendent armed
systems by appending the desired arms directly to the
bisaminal to reduce the number of synthetic steps [32].
The bis-substitution by 3 to produce 4 and 5 was
followed by a reductive ring cleavage step carried out using
a procedure with a shorter timescale and higher tempera-
ture than is normally adopted for cross-bridged cyclam
systems [31,33,40–42]: a 30-min stir at room temperature
after the addition of sodium borohydride followed by a 2-
hour reflux. This is in contrast to the room temperature 10–
16-day stir more generally used for reduction to the cross
bridge cyclam macrocycle [20,32,34,43]. Interestingly, this
increased temperature and shortened time frame seemed
not to have a detrimental effect on the production of the
cross-bridged variants, 1 and 2. The synthesis of 1 returned
an excellent yield (87%) from 3, while the production of 2
occurred alongside the side-bridged (piperazino cyclam)
chelator due to the mixture of mono- and bis- substituted
ammonium salts. This mixture was not separated and was
used in the complex formation preparation.
2.2. Copper(II) complexation
Copper(II) complexes of cross-bridged cyclam form
more kinetically stable complexes than many other
macrocycles due to the structural rigidity [44]. However,
longer timescale and higher temperature complexation
conditions are generally required in comparison to non-
bridged or less basic cyclams. The cross-bridged ligands are
remarkably basic, binding a proton within the cavity of the
ligand, forming hydrogen bonds between macrocyclic
amines. Protons effectively compete with metal ions for
occupation of the cavity [19].
This work uses the complexation conditions of Weisman
et al. [20]. The ligand and one equivalent of copper(II) salt
were dissolved in methanol, and heated under reflux for
2 hours, during which colour changes in the solution were
often observed upon the addition of copper salt. The colour
changes were significantly less rapid than the addition of
copper(II) salt to side-bridged cyclam ligands [31]. This is
due to the slower complex formation of copper(II) ions with
cross-bridgedligandscomparedtothelessrigid macrocyclic
ligands. This can be a disadvantage in radiolabelling
procedures where rapid complexation is preferred and
temperature-sensitive biomolecules are often used.
The combination of the shorter reaction times for both
steps means that 1 and 2 could be synthesised with an
overall reaction time of less than 24 h, compared with
times of up to 32 days in previous studies. However, the
elevated temperature for the reduction may not be
compatible with ester containing pendant arms and so,
further studies may be required to determine the
appropriate conditions when more sensitive functional
groups are present.
2.3. X-ray crystal structures of [Cu1NO3]+ and [Cu2Cl2]
Crystals of sufficient quality for single crystal X-ray
diffraction were grown by vapour diffusion of diethyl ether
into methanolic solutions of the complex, and appeared
after approximately 7 days. These crystal structures are
shown in Figs. 1 and 2.
Fig. 1. An ORTEP plot (50% probability ellipsoids) of the single crystal X-ray structure of [Cu1NO3]NO3ÁCH3OH.

J.D. Silversides et al. / C. R. Chimie 16 (2013) 524–530
527
Fig. 2. An ORTEP plot (50% probability ellipsoids) of the single crystal X-ray structure of [Cu2Cl2]. The elongated N(2)–Cu(1)–N(4) axis is shown with dashed
bonds.
The folded cis-V configuration is evident, [45] with the
copper(II) ion sitting within the macrocyclic cavity. There
is no interaction between the pendent arms of the
macrocycle and the copper(II) ion. This may be due to
the increased steric bulk of the aryl group of the pendent
arms. The pendent arms of the two structures are directed
away from the macrocycle, and are oriented at different
angles to each other with respect to the axial Cu–N plane.
The difference in orientation could be attributed to the
bound counterions, the geometry they impart on the metal
ion, and the steric repulsion along macrocyclic axes. There
are also variations between the two structures in the
symmetry of the crystal packing of the macrocycles within
the crystal lattice (Supplementary data).
As there is no interaction between the copper(II) ion
and the pendent arms, it is possible for counterions to
occupy both vacant cis coordination sites. This is observed
for [Cu2Cl2], in which the two chloride ligands bind to the
copper(II) ion to complete the octahedral coordination
sphere. In [Cu1NO3]NO3ÁCH3OH, the nitrate counterion
completes a five coordinate geometry and the sixth
coordination site is blocked by the position of O(3) of
the nitrate. The nitrate anion is monodentate, with
distortion from the intermediate position between the
two equatorial nitrogen donors by 8.28. The position of the
nitrate donor results in a near linear N(1)–Cu(1)–O(1)
angle at 168.55(11)8, while the corresponding N(3)–Cu(1)–
O(3) angle is 153.18. The Cu–O distances are significantly
˚
different, with the Cu–O(3) distance being 0.75 A longer
than the Cu–O(1) bond length, hence, not forming a
bonding interaction. [46]
The constraint of the ethylene bridge restricts the
angle between the equatorial nitrogen atoms and the
copper(II) ion to 86.86(11)8. The Cu–N distances are
comparable to those previously observed for similar
constrained complexes. [35,47] There is a significant
difference between the Cu–N(1) and Cu–N(3) bond
distances involving the bridgehead nitrogens, which
have previously been observed to be of comparable
magnitude. [20,48,49] The longest of these two bonds is
that of the N(3)–Cu interaction which occupies the apical
position in the square based pyramidal geometry and
demonstrates that there is sufficient flexibility in the
macrocyclic chelator to accommodate the bond elonga-
tion preferred for copper(II).
[Cu2Cl2] is an octahedral complex, and it is expected
that a Jahn–Teller type distortion will be observed along
one of the ligand axes. In contrast to [Cu1NO3]NO3ÁCH3OH,
Fig. 3. [Cu1NO3]NO3ÁCH3OH and [Cu2Cl2] viewed along the N–Cu–N axis (ORTEP plots at 50% probability with the H-atoms removed for clarity).

528
J.D. Silversides et al. / C. R. Chimie 16 (2013) 524–530
Table 2
Table 3
o
˚
Crystal data for the single crystal X-ray structures of [Cu2Cl2] and
[Cu1NO3]NO3ÁCH3OH.
Selected bond lengths (A) and angles ( ) for the single crystal X-ray
structures of [Cu1NO3]+ and [Cu2Cl2].
[Cu2Cl2]
[Cu1NO3]NO3ÁCH3OH
Bond lengths/angles
[Cu1NO3]+
Bond lengths/angles
[Cu2Cl2]
Formula
C26N4H34Cl2Br4Cu C29N6H43O7Cu
Mr
856.65
651.23
Cu(1)-N(1)
Cu(1)–N(2)
Cu(1)–N(3)
Cu(1)–N(4)
Cu(1)–O(1)
Cu(1)–Cl(1)
Cu(1)–Cl(2)
2.038(3)
2.096(3)
2.154(3)
2.131(3)
1.989(3)
–
2.071(7)
2.455(8)
2.091(7)
2.495(8)
–
Crystal system
Space group
Monoclinic
P21/c
Triclinic
¯
P1
˚
a/A
14.207(2)
13.9892(14)
16.133(3)
90
8.7231(15)
14.248(3)
14.316(2)
117.139(12)
100.121(13)
95.291(14)
1528.3(5)
2
˚
b/A
˚
c/A
2.322(2)
2.302(2)
a o
b o
g o
/
–
/
113.877(12)
90
N(1)–C(11)
1.503(4)
1.473(5)
1.534(5)
85.19(12)
86.86(11)
93.21(12)
93.18(11)
177.83(12)
85.27(11)
168.55(11)
–
1.488(11)
1.493(11)
1.505(11)
79.3(3)
83.2(3)
95.9(3)
92.0(3)
171.0(2)
79.8(3)
–
/
N(3)–C(12)
3
˚
Volume/A
2932.1(7)
4
C(11)–C(12)
Z
N(1)–Cu(1)–N(2)
N(1)–Cu(1)–N(3)
N(1)–Cu(1)–N(4)
N(2)–Cu(1)–N(3)
N(2)–Cu(1)–N(4)
N(3)–Cu(1)–N(4)
N(1)–Cu(1)–O(1)
N(1)–Cu(1)–Cl(1)
N(1)–Cu(1)–Cl(2)
N(2)–Cu(1)–O(1)
N(2)–Cu(1)–Cl(1)
N(2)–Cu(1)–Cl(2)
N(3)–Cu(1)–O(1)
N(3)–Cu(1)–Cl(1)
N(3)–Cu(1)–Cl(2)
N(4)–Cu(1)–O(1)
N(4)–Cu(1)–Cl(1)
Density (calc.)/Mg/m3
1.941
1.415
m
MoK (mmÀ1
)
6.42
0.770
a
T/K
range/o
150
150
u
2.76–30.35
35705
2.42–29.77
36891
Measured reflections
Unique reflections [Rint
]
8517 [0.1191]
99.7%
8901 [0.1169]
100.0%
Completeness (uo
)
92.47(18)
168.5(2)
–
Goodness-of-fit on F2
R1, wR2 (I > 2 (I))
0.854
0.802
–
s
0.0594, 0.1062
0.1778, 0.1405
0.00128(14)
0.0510, 0.1075
0.1491, 0.1406
0.0250(15)
88.40(11)
–
R1, wR2 (all data)
Extinction coefficient
Largest diff. peak
98.41(17)
89.94(18)
–
–
0.970 and À0.999 0.725 and À1.232
102.99(11)
–
À3
˚
and hole/e A
167.8(2)
93.3(2)
–
–
93.42(11)
–
89.43(17)
the bridgehead nitrogen donor atoms form bonds of
expected length, [44,48] as do the chloride counter anions
[20]. The nitrogen donors, associated with the pendent
arms, are the ligands that are extended along the z axis. The
3. Conclusion
˚
mean distorted Cu–N bond length of 2.475 A shows
˚
elongation in the order of 0.4 A from the other nitrogen
donors in this example.
A rapid synthesis of two novel cross-bridged cyclam
chelators (1 and 2) has been demonstrated with 1 isolated
as a pure compound and 2 separated by complex formation
and recrystallisation. A dramatic decrease in two-step
reaction times is observed compared to the standard
synthetic conditions to produce benzyl cross-bridged
cyclams. Copper(II) complexes of these ligands were
synthesised and characterised by X-ray crystallography
showing an interesting variation in the coordination
environment and the potential for distortion in the Cu–
N bonds of the macrocyclic chelator. These structures show
that despite the additional rigidity imposed by the
ethylene bridge between non-adjacent nitrogens of the
cyclam ring, there is still sufficient flexibility to elongate
along the N–Cu–N axis. This distortion may be linked to the
presence of two chloride ligands offering sufficient
energetic benefit to offset the penalty of a less favourable
conformation of the macrocyclic chelator. The rapid
synthesis developed in this work could have a significant
impact on the production of cross-bridged cyclam
chelators for their use in radiopharmaceutical applications,
such as PET imaging.
The angle at which the pendent arms are located with
respect to the N(2)–Cu(1)–N(4) plane varies between the
two structures. This is attributed to the location of the
counterion(s) within the cavity. The bound nitrate
counterion of [Cu1NO3]NO3ÁCH3OH is situated approxi-
mately above the centre of the cavity. As a result, the
pendent arms are bent away from each other, as viewed
along the N–Cu–N axis (Fig. 3). This minimises the steric
repulsion between the aryl pendent arms and the nitrate
counterion. The mean angle of bend of the pendent arms is
29.68 from the axial N–Cu–N plane bisecting the equatorial
nitrogen atoms (Table 2)
As the two chloride ions are occupying the cis-
equatorial sites in [Cu2Cl2], the position of the pendent
arms with the least steric hindrance involves bisecting the
angle between the equatorial ligands, as viewed down the
N–Cu–N axis (Fig. 3). This results in the aryl groups being
practically co-planar.
There remains a slight twist of the pendent arms away
from the axial N–Cu–N plane, with a mean twist angle of
12.48. The twist of the ethylene bridge causes the equatorial
twistingofthechloride counterionsinopposite directionsto
reduce steric repulsion, (Supplementary data, Fig. S1). The
mean angle of twist of the four donors from the mean plane
is 10.58. As a result, in order to bisect the Cl–Cu–Cl angle, the
pendent arms must twist away from the axial N–Cu–N
plane, giving the orientation observed (Table 3).
4. Experimental
All the reagents and solvents were purchased from
Sigma-Aldrich Limited, Lancaster Chemicals Limited (Alfa-
Aesar) or Fisher Chemicals Limited, and were used as
supplied unless otherwise stated. All 1H-NMR and proton

J.D. Silversides et al. / C. R. Chimie 16 (2013) 524–530
529
decoupled 13C-NMR spectra were collected on a JEOL JNM-
LA400 spectrometer, at 400 and 100 MHz respectively, and
referenced against residual solvent signals. Mass spec-
trometry was carried out by electrospray ionisation (ESI)
with the data collected on a Finnigan LCQ spectrometer or
by the EPSRC National Mass Spectrometry Service at the
University of Swansea on a Waters ZQ4000 spectrometer.
UV/visible spectra were obtained using an HP-Agilent 8453
diode array spectrometer.
Mixture of 4-(3,5-dibromobenzyl)-1,4,8,11-tetraaza-
bicyclo[10.2.2.]hexadecane and 4,11-bis(4,6-dibromo-
benzyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane 2
To a stirred solution of 3 (89.7 mg, 403 mmol) in
acetonitrile (20 mL) was added 3,5-dibromobenzyl bromide
(379 mg, 1.15 mmol) and the solution was stirred at room
temperature for 16 h. Solvent was removed and the residue
was washed with diethyl ether (4 Â 30 mL) to yield a white
solid (136 mg) (5), which was not isolated. To a stirred
solution of this white solid (126 mg) in ethanol (30 mL) was
added slowly sodium borohydride (136 mg, 3.59 mmol),
and themixturewas stirredfor 30 min atroomtemperature,
then heated under reflux for 2 h. After cooling to room
temperature, water (10 mL) was added to decompose the
excess NaBH4, and the solvents were removed. Water
(30 mL) was added to the residue, the solution was made
basic (KOH, pH 14), and extracted with dichloromethane
(4 Â 30 mL). Combined organic extracts were dried, and
solvent was removed to yield a colourless oil (86.4 mg of the
product mixture, 38% bis-substituted based on NMR). 1H-
The diffraction data set was collected on a Stoe IPDS-II
imaging plate diffractometer using Mo K
a radiation
˚
(k = 0.71073 A). The crystal was kept at 150 K during data
collection using the Oxford Cryosystems Cryostream
Cooler. The structures were solved using direct methods
(SHELXS) and refined against F2 (SHELXL) [36]. H atoms
were placed in idealised positions or located on the
difference map, and refined using a riding model with C–
˚
˚
H = 0.97A, N–H = 0.91A and Uiso(H) = 1.2 times Ueq of the
carrier atom. All non-H atoms were refined anisotropically.
The WinGX package was used for refinement and
production of data tables, and ORTEP-3 was used for
structure visualisation [50,51].
NMR (CDCl3):
d 7.58–7.56 (m), 7.51 (m), 7.41 (d, J 2.0 Hz),
7.38 (d, J 2.0 Hz), 3.54 (s), 3.29–3.12 (m), 2.91–2.88 (m),
2.74–2.68 (m), 2.60–2.47 (m), 2.43–2.37 (m), 2.28–2.25 (m),
1.88–1.86 (m), 1.71–1.67 (m), 1.59–1.20 (m). 13C-NMR
4.1. Synthetic procedures
(CDCl3):
d 143.6, 142.5, 132.7, 131.2, 130.5, 130.4, 122.8,
Glyoxal cyclam (3) (cis-perhydrotetraazapyrene) was
synthesised in accordance with literature procedures [26].
3a,8a-bis(4-methylbenzyl)-decahydro-3a,5a,8a,11a-
tetraazapyrenium dibromide 4
122.5, 59.1, 58.6, 56.3, 56.2, 55.7, 55.5, 55.5, 53.9, 53.0, 50.7,
50.2, 49.3, 49.3, 48.4, 48.1, 48.1, 25.0, 23.5, 22.0.
[Cu1(NO3)]NO3
To a stirred solution of 1 (49.7 mg, 114
methanol (10 mL) was added dropwise a solution of
copper(II) nitrate trihydrate (36.1 mg, 149 mol) in
mmol) in
To a stirred solution of 3 (128 mg, 575 mmol) in
acetonitrile (20 mL) was added 4-methylbenzyl bromide
(333 mg, 1.80 mmol) and the solution was stirred at room
temperature for 16 h. The solvent was removed and the
residue was washed with diethyl ether (4 Â 30 mL) to yield
m
methanol (5 mL). The blue solution was heated under
reflux for 2 h. The solvent was removed, and the residue
was purified by size exclusion chromatography (methanol)
to yield a blue solid (62.9 mg, 89%). MS, m/z: 497 [M]+.
HRMS: calcd for C28H42N4Cu1: 497.2700; found 497.2703.
The single crystal X-ray structure of [Cu1NO3]NO3 was
obtained. The crystals were grown by vapour diffusion of
diethyl ether at room temperature into solutions of
[Cu1(NO3)]NO3 (3 mg) in methanol (0.5 mL) over a period
of ca. one week.
a white solid (316 mg, 93%). 1H-NMR (DMSO-d6):
d 7.54
and 7.36 (AB, 8H, J 8.0 Hz, H(Ar)), 5.31 (s, 2H, CH), 5.17 and
4.89 (AB, 4H, J 13.0 Hz, CH2–Ar), 4.27 (td, 2H, J 13.0, 5.0 Hz,
CH2–N), 3.64 (td, 2H, J 13.0, 3.5 Hz, CH2–N), 3.48–3.24 (m,
10H, CH2–N), 2.98 (d, 4H, J 13.0 Hz, CH2–N), 2.85–2.80 (m,
2H, CH2–b–N), 2.37 (s, 6H, CH3), 1.80 (br d, 2H, J 15.0 Hz,
CH2– –N).
b
4,11-bis(4-methylbenzyl)-1,4,8,11-tetraazabicy-
clo[6.6.2]hexadecane 1
[Cu2Cl2]
To a stirred solution of a mixture containing ca. 40% 2
(39.9 mg) in methanol (10 mL) was added dropwise a
solution of copper(II) chloride dihydrate (14.4 mg,
To a stirred solution of 4 (201 mg, 339 mmol) in ethanol
(30 mL) was added slowly sodium borohydride (460 mg,
12.2 mmol), and the mixture was stirred for 30 min at room
temperature, then heated under reflux for 2 h. After cooling
to room temperature, water (10 mL) was added to decom-
pose excess NaBH4, and the solvents were removed. Water
(30 mL) was added to the residue, the solution was made
basic (KOH, pH 14), and extracted with dichloromethane
(4 Â 30 mL). The combined organic extracts were dried, and
the solvent was removed to yield a white solid (139 mg,
84.5 mmol) in methanol (5 mL). The blue solution was
heated under reflux for 2 h. The solvent was removed, and
the residue was purified by size exclusion chromatography
(methanol) to yield a green solid (42.2 mg). MS, m/z: 572
[M–CH2C6H3Br2+Cl]+. The single crystal X-ray structure of
[Cu2Cl2] was obtained. Crystal growth experiments yielded
a smallamountofpure[Cu2Cl2]andthecrystalsweregrown
by vapour diffusion of diethyl ether at room temperature
into a solution of a mixture containing [Cu2Cl2] (5 mg) in
methanol (0.5 mL) over a period of ca. one week.
94%). 1H-NMR (CDCl3):
d 7.19–7.04 (m, 8H, H(Ar)), 3.93–
3.87 (m, 1H, CH2–N), 3.71–3.61 (m, 5H, CH2–Ar x 4H, CH2–N
x 1H), 3.23–3.04 (m, 5H, CH2–N), 2.93–2.71 (m, 7H, CH2–N),
2.45–2.26 (m, 6H, CH2–N), 2.30 (s, 6H, CH3), 1.68–1.22 (m,
Acknowledgements
4H,CH2–
(C(Ar)–CH3), [129.7, 129.1] (C(Ar)), 57.7 (CH2–Ar), [57.5,
b d137.4(C(Ar)–CH2),132.5
–N).13C-NMR(CDCl3):
We acknowledge the EPSRC for funds, which enabled
the purchase of the Stoe IPDS-II diffractometer. We thank
the University of Hull for the provision of a scholarship for
54.2, 53.3, 51.9, 50.3] (CH2–N), 24.1 (CH3), 21.0 (CH2–b–N).
MS, m/z: 435 [M+H]+.

530
J.D. Silversides et al. / C. R. Chimie 16 (2013) 524–530
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CCDC-905919 and 905920 contains the supplementary
crystallographic dataforthispaper. These data can beobtained
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