Copper(II) complexes of N-methylated derivatives of ortho- and meta-xylyl-bridged bis(1,4,7-triazacyclononane) ligands: Synthesis, X-ray structure and reactivity as artificial nucleases

Article abstract of DOI:10.1002/ejic.200800533

Two new binucleating ligands, 1,3-bis[(4,7-dimethyl-1,4,7-triazacyclononan- 1-yl)methyl]benzene (L^memx) and 1,2-bis-[(4,7-dimethyl-1,4,7- triazacyclononan-1-yl)methyl]benzene (L^meox), have been prepared from 1,4,7-triazatricyclo-[5.2

Full text of DOI:10.1002/ejic.200800533

FULL PAPER
DOI: 10.1002/ejic.200800533
Copper(II) Complexes of N-Methylated Derivatives of ortho- and meta-Xylyl-
Bridged Bis(1,4,7-triazacyclononane) Ligands: Synthesis, X-ray Structure and
Reactivity as Artificial Nucleases
Matthew J. Belousoff,[a] Bim Graham,*[a][‡] and Leone Spiccia*[a]
Dedicated in honour of Professor Jan Reedijk on the occasion of his retirement
Keywords: Copper(II) coordination chemistry / Dinuclear complexes / Macrocyclic ligands / Crystallography / Phosphate
ester hydrolysis
Two new binucleating ligands, 1,3-bis[(4,7-dimethyl-1,4,7-
triazacyclononan-1-yl)methyl]benzene (Lmemx) and 1,2-bis-
[(4,7-dimethyl-1,4,7-triazacyclononan-1-yl)methyl]benzene
(Lmeox), have been prepared from 1,4,7-triazatricyclo-
[5.2.1.04,10]decane and applied in the synthesis of the corre-
sponding copper(II) complexes, [Cu2(µ-AcO)2(Lmemx)](ClO4)2·
H2O (Cm) and [Cu2(η2-AcO)2(Lmeox)](ClO4)2 (Co). The X-ray
crystal structures confirmed the dinuclear nature of the com-
plexes, with pairs of copper(II) centres residing in distorted
square-pyramidal coordination environments. The nitrogen
donors on the ligands occupy three facially disposed coordi-
nation sites about each copper(II) centre, with two acetate
ligands completing the copper(II) coordination spheres. For
Cm, both acetate groups bridge the two metal centres, whilst
in Co each acetate chelates to a single metal centre. To assess
their utility as simple nuclease mimics, the metal complexes
were tested for their phosphate ester cleavage ability using
the model phosphodiester, bis(4-nitrophenyl)phosphate
(BNPP). It was found that Co exhibited the fastest rate of
BNPP hydrolysis (kobsd. = 2.4ϫ10–5 s–1), this rate being five
times faster than that of the CuII complex of the non-methyl-
ated analogue.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
studies. Tacn-derived complexes have been prepared that ef-
ficiently cleave model phosphate esters, RNA, DNA and
peptides.[3,5–10] One notable finding has been that N-alky-
lation of the tacn ring produces copper(II) complexes that
exhibit faster rates of phosphate ester cleavage. This has
been attributed in part to a reduced tendency for these com-
plexes to form hydrolytically inactive, hydroxo-bridged di-
meric species in solution.[11]
Many hydrolase enzymes contain more than one metal
centre at their active site,[12–16] which has led to efforts to
prepare dinuclear (and higher nuclearity) model complexes
that are able to mimic the synergistic action of the multiple
metal centres in these natural systems. Towards this end,
multi-macrocyclic ligand assemblies have been used to syn-
thesise polynuclear complexes that exhibit enhanced rates
of phosphate ester hydrolysis relative to mononuclear tacn
complexes. For example, Morrow and co-workers have re-
ported increases in hydrolytic activity for ZnII complexes of
bis(tacn) ligands compared to mononuclear ZnII-tacn com-
plexes.[17–19] Our own studies have shown that the dinuclear
copper(II) complexes of xylyl-bridged bis(tacn) ligands are
active as phosphate ester cleavage agents.[20] However,
these systems were not as active as anticipated, possibly due
to their conversion into hydrolytically inactive species in
solution.[5,7]
Introduction
A significant area of research in coordination chemistry
has been the design and synthesis of metal complexes as
low-molecular-weight mimics of the active sites of nuclease
and phosphatase metallo-enzymes. These studies have
sought to improve our knowledge of how these enzymes
function as well as lend understanding to basic metal ion
reactivity. The development of complexes as “artificial nu-
cleases” has also been spurred on by the possibility of pro-
ducing novel therapeutics that not only bind to targeted
DNA/RNA sequences, but also cleave the phosphate ester
bonds present within the sugar-phosphate backbones, ren-
dering them inactive.[1–4] Complexes of ligands derived from
the small, facially coordinating macrocycle, 1,4,7-triaza-
cyclononane (tacn), have featured prominently in these
[a] School of Chemistry, Monash University,
Victoria, 3800, Australia
Fax: +61-3-9905-4597
E-mail: leone.spiccia@sci.monash.edu.au
[‡] Current address: Medicinal Chemistry and Drug Action, Mon-
ash Institute of Pharmaceutical Sciences, Monash University
(Parkville campus),
Victoria, 3052, Australia
Fax: +61-3-9903-9582
E-mail: bim.graham@vcp.monash.edu.au
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M. J. Belousoff, B. Graham, L. Spiccia
FULL PAPER
We now report on our efforts to enhance the activities of groups, and a series of signals between ca. 3.2 and 3.8 ppm
these types of complexes through N-alkylation of the sup- for the methylene groups of the tacn rings. The xylyl meth-
porting xylyl-bridged bis(tacn) ligand structures. It was en- ylenes produced singlets at δ = 4.20 and 4.28 ppm for Lmemx
visaged that this simple modification would sterically hin- and Lmeox, respectively.
der the formation of hydroxo-bridged dinuclear complexes
The copper(II) complexes, [Cu2(µ-AcO)2(Lmemx)](ClO4)2·
and/or mononuclear sandwich-type structures, thus leading H2O (Cm) and [Cu2(η2-AcO)2(Lmeox)](ClO4)2 (Co), were
to higher effective concentrations of hydrolytically active formed by reacting the ligands Lmeox and Lmemx (as HCl
species in solution. Methylated derivatives of two bis(tacn) salts) with one equiv. of cupric perchlorate and one equiv.
ligands, 1,3- and 1,2-bis[(1,4,7-triazacyclononan-1-yl)- of cupric acetate at pH 7.0. Satisfactory C H N microanaly-
methyl]benzene (Lmx and Lox),[21] have been synthesised ses were obtained for both complexes, and IR spectroscopy
(Lmemx and Lmeox) and used in the preparation of two new confirmed the presence of the acetate groups. The υasym car-
CuII complexes, [Cu2(µ-AcO)2(Lmemx)](ClO4)2·H2O (Cm) boxylate stretches were observed at 1572 and 1560 cm–1 for
and [Cu2(η2-AcO)2(Lmeox)](ClO4)2 (Co). The ability of the Cm and Co, respectively.[25,26] In each case, the υsym stretch
complexes to cleave phosphate ester bonds was probed was difficult to assign due to the presence of υC=C stretches
using the well-studied model phosphodiester, bis(4-ni- in the 1400–1600 cm–1 region. The UV/Vis spectra showed
trophenyl)phosphate (BNPP),[7,17,18,22–24] and the results a weak dǞd transition at 668 nm, consistent with square-
compared to those obtained for previously reported com- pyramidal or distorted octahedral CuII coordination geom-
plexes.
etry,[27] and a strong band at 274 nm due to ligand πǞπ*
transitions.
Results and Discussion
Crystallography
Synthesis
The methylated ligands (Lmemx and Lmeox) were prepared
by modifications to the route first described by Farrugia et
al.[21] to prepare the two parent bis(macrocycles), Lmx and
Lox, as their hydrobromide salts. Two equivalents of 1,4,7-
triazatricyclo[5.2.04.10]decane were treated with one equiva-
lent of 1,3-bis(bromomethyl)benzene or 1,2-bis(bromo-
methyl)benzene to yield bis(amidimium) salt intermediates
(see Scheme 1). Hydrolysis and N-methylation of these salts
was carried out by heating them in a 1:1 mixture of formic
acid and aqueous formaldehyde. The fully N-methylated li-
gands were then isolated as their hexahydrochloride salts.
The X-ray crystal structure of Cm confirmed the forma-
tion of a dinuclear copper(II) complex with the formula,
[Cu2(µ-AcO)2(Lmemx)](ClO4)2·H2O. A representation of the
cationic unit is shown in Figure 1, with selected bonds
lengths and angles given in Table 1. Three of the five coor-
dination sites about each copper(II) centre are occupied by
the nitrogen atoms of a facially coordinating tacn macro-
cycle, and the other two by the oxygen atoms of two acetate
groups that bridge between the two centres. Both copper
centres exist in square-pyramidal coordination spheres, with
the Cu(1)–N(3) and Cu(2)–N(6) distances being Ͼ 0.1 Å
longer than the Cu–N distances in the basal plane. The
square-pyramidal geometry is distorted (with an Addi-
son[28] parameter of τ = 0.16; note that τ = 0 for ideal
square-pyramidal geometry and τ = 1 for trigonal-bipyram-
idal geometry), due mainly to the constraints imposed by
the tridentate coordination of the strained tacn macro-
cycles, forcing the N–Cu–N angles all below the ideal 90o.
For each copper centre, the two Cu–O distances to the
bridging acetates differ by 0.051(4) Å and 0.029(4) Å
for Cu(1)–O(1A)/Cu(1)–O(3A) and Cu(2)–O(2A)/Cu(2)–
O(4A), respectively.
Unlike many other copper(II) tacn-based complexes,
there is no weakly interacting solvent or counterion mole-
cule in proximity to the sixth, “vacant” coordination site.
Instead, a xylyl hydrogen, H(24), is in close proximity, but
not within bonding distance to the copper centres
[Cu···H(24) = 2.397(1) and 2.651 Å for Cu(1) and Cu(2),
Scheme 1. Synthesis of the ligands.
Spectroscopic analysis of the ligands confirmed their for- respectively; see Figure 1].
mation. Both the Lmemx and Lmeox salts showed m/z peaks
The bridging acetate groups in Cm result in a Cu···Cu
in their electrospray mass spectra at 209.2 and 417.3, corre- separation of 3.874(3) Å, compared to distances of ca.
sponding to [M + 2H]2+ and [M + H]+, respectively. The 2.9 Å found for structures featuring dihydroxo-bridged cop-
1H NMR spectra revealed the signals expected for the or- per(II) centres.[21,29] A least-squares plane analysis shows
tho- and meta-substituted aromatic rings, as well as a singlet that the angle between the planes of the acetate groups and
around 3.0 ppm in each case for the four equivalent methyl the basal coordination plane of Cu(1) are 61.29(2)o and
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CuII Complexes with New Binucleating Ligands
brane-bound form of this enzyme found in the bacteria
Methylococcus capsulatus (Bath), which has not been char-
acterized by X-ray crystallography, but which is believed to
use a mixed-metal (copper/iron) active site to carry out elec-
tron-transfer reactions, and the complex Cm could be a rel-
evant structural mimic for this enzyme.
Figure 1. Thermal ellipsoid plot of the complex cation in Cm [ther-
mal ellipsoids drawn at 50%; selected hydrogen atoms omitted for
clarity; dotted line indicates a close, non-bonding interaction with
H(24)].
Table 1. Selected bond lengths and angles for Cm.
Distance [Å]
Cu(1)···Cu(2) 3.874(3)
Cu(1)–O(3A) 1.935(3)
Cu(1)–O(1A) 1.986(3)
Angle [°]
O(3A)–Cu(1)–O(1A)
O(1A)–Cu(1)–N(1)
O(3A)–Cu(1)–N(2)
N(1)–Cu(1)–N(2)
O(3A)–Cu(1)–N(3)
N(1)–Cu(1)–N(3)
N(2)–Cu(1)–N(3)
O(3A)–Cu(1)–O(1A)
O(1A)–Cu(1)–N(1)
O(3A)–Cu(1)–N(2)
N(1)–Cu(1)–N(2)
O(3A)–Cu(1)–N(3)
N(1)–Cu(1)–N(3)
N(2)–Cu(1)–N(3)
92.15(1)
90.27(1)
92.02(1)
85.44(1)
95.95(1)
84.66(1)
84.85(2)
92.15(1)
90.27(1)
92.02(1)
85.44(1)
95.95(1)
84.66(1)
84.85(2)
Cu(1)–N(1)
Cu(1)–N(2)
Cu(1)–N(3)
2.041(3)
2.082(3)
2.204(3)
Figure 2. Bridging motifs found in CuII acetate dimers.
Cu(2)–O(2A) 1.955(3)
Cu(2)–O(4A) 1.984(3)
The X-ray crystal structure of Co, [Cu2(η2-AcO)2(Lmeox)]-
(ClO4)2, revealed the presence of a dinuclear copper(II)
complex cation (see Figure 3; selected bond lengths and
angles given in Table 2), in which the two tacn macrocycles
of the ligand lie on opposite sides of the plane of the central
aromatic ring. Thus, the complex adopts an anti configura-
tion, placing the two copper centres 6.578(4) Å away from
each other, nearly twice the Cu···Cu distance observed in
Cm. The complex is pseudo-C2 symmetric about an axis bi-
secting the o-xylyl bridge, and its general structural form
resembles that of a copper(II) complex of the non-alkylated
parent ligand, Lox, reported by Graham et al.[43] In Co,
however, bidentate acetate ligands replace the monodentate
bromide ligands in [Cu2(Lox)Br4]. In contrast to Cm, the
two acetate ligands in Co chelate to either Cu(1) or Cu(2),
forming constricted, three-membered chelate rings, with O–
Cu–O angles of 65.23(2) and 65.57(2)o for Cu(1) and Cu(2),
respectively. The chelating acetates do not bind symmetri-
cally to Cu(2), viz., a difference in the two Cu–O bond
lengths of 0.071(4) Å for Cu(2)–O(11)/O(12), cf., 0.005(4) Å
Cu(2)–N(4)
Cu(2)–N(5)
Cu(2)–N(6)
2.065(3)
2.074(3)
2.213(3)
78.14(2)o, and 75.67(3)o and 61.29(2)o for the basal plane
of Cu(2). Thus, the Cu2(µ2-ac)2 motif possesses pseudo-C2
symmetry. This motif is rare amongst the various binding
motifs that have been reported in the literature for cop-
per(II)-acetato complexes (see Figure 2). Tokii et al.[30] re-
ported the same binding mode in a copper(II) complexes
with 1,10-phenanthroline ligands. Their reported Cu···Cu
separation of 3.063(3) Å is much shorter than that found in
Cm due to the π–π interaction between the chelating phen
ligands on the two copper centres forming the dinuclear
complex. This causes the acetate bridge to bend, bringing
the two copper centres in closer proximity. The most com-
mon bridging motif observed in copper(II)-acetato com-
plexes is the Cu2(µ2-ac)4 unit, where four acetate ligands
bridge between two copper(II) centres, usually resulting in
C4 symmetry about the copper centres and closer Cu···Cu
distances of around 2.5 Å.[31] Structurally similar molecules
to Cm but which have a Cu2(µ2-ac)(µ-O) binding motif show
Cu···Cu distances around 3.3–3.6 Å.[32–36] These com-
pounds show promise as catalysts for catechol oxi-
dation,[32,36] and also as model systems for the tyrosinase
active site.[34] The Cm complex has some structural similari-
ties to the active site of the hydrolase enzyme, methane
mono-oxygenase,[37–42] which features a dicarboxalato-
bridged diiron core, but with an additional water-derived
Figure 3. Thermal ellipsoid plot of the complex cation in Co (ther-
ligand bridging the two iron(III) centres.[40] There is a mem- mal ellipsoids drawn at 50%; hydrogen atoms omitted for clarity).
Eur. J. Inorg. Chem. 2008, 4133–4139
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M. J. Belousoff, B. Graham, L. Spiccia
FULL PAPER
for Cu(1)–O(9)/O(10). This asymmetry in acetate binding (4-nitrophenolate) + –O3POPhNO2 (4-nitrophenylphos-
to Cu(2) may be due to the slightly weaker interaction of phate) + complex]. For this investigation, we used a large
the Cu(2) with the perchlorate anion (vide infra). As for excess of complex relative to BNPP (to ensure first-order
Cm, the Cu–Neq distances are significantly shorter kinetics) and studied the cleavage at a temperature of 50 °C
(by Ͼ 0.2 Å) than the Cu–Nax distances.
and near physiological pH (7.4). In the case of Co, the ab-
As a consequence of the arrangement of the nitrogen and sorbance-vs.-time data was fitted to an exponential function
oxygen donors, the geometry of the metal centre is once that yielded the rate constant directly. For the reaction of
again distorted from ideal square pyramidal, with the the Cm complex with BNPP, the data was fitted using the
angles in the basal plane of the pyramid all greatly deviating initial rates method reported by Burstyn et al.[6] The ob-
from the ideal 90o (see Table 2). This is evident from the tained rate constants for Co and Cm, as well as a series of
value of the geometric parameter, τ = 0.20.[28]
related complexes, are listed in Table 3.
The copper(II) centres in Co participate in very weak in-
teractions with the perchlorate anions (Figure 4), two of
which weakly bridge between two adjacent complex cation
units [Cu–O (perchlorate): 2.951(4) Å and 2.822(3) Å] form-
ing a head-to-head arrangement.
Table 3. Rates of reaction of copper complexes with BNPP.[a]
Compound
k
obsd. ϫ105 s–1 Ref.
[7]
Base-catalysed hydrolysis of BNPP at 100 °C 0.04
[7]
CuII-tacn[b]
0.025
4.3
3.7
0.52
0.086
2.43
0.11
[7]
CuII-iPr3tacn
[7]
CuII-Me3tacn
[20][b]
[20][b]
[Cu2Lox(H2O)4]4+
[Cu2Lmx(H2O)4]4+
[Cu2(η-AcO)2(Lmeox)](ClO4)2 (Co)
[Cu2(µ-AcO)2(Lmemx)](ClO4)2·H2O (Cm)
this work
this work
[a] Conditions used: [BNPP] = 0.015 m, [complex] = 1.0 m, I =
0.15  (NaClO4), T = 50 °C, pH 7.4 (buffered with MOPS). [b]
Conditions used: [BNPP] = 0.15 m, [complex] = 1.7 m, pH 7.4
(HEPES), I = 0.15  (NaClO4), and T = 50 °C. Abbreviations:
iPr3tacn = 1,4,7-tris(isopropyl)-1,4,7-triazacyclononane; Me3tacn =
1,4,7-trimethyl-1,4,7-triazacyclononane; Lox = 1,2-bis[(1,4,7-triaza-
cyclonon-1-yl)methyl]benzene; Lmx = 1,3-bis[(1,4,7-triazacyclonon-
1-yl)methyl]benzene.
Figure 4. Stick representation showing bridging of two complex
cations in Co by two weakly binding perchlorate anions (hydrogen
atoms and other counterions omitted for clarity).
Table 2. Selected bond lengths and angles for Co.
Previously published data (Table 3) indicated that the
two copper(II) centres in the Lox complex exhibit some de-
gree of cooperativity in carrying out the hydrolysis of
BNPP, whilst those in the Lmx complex act essentially inde-
pendently, because the rate constants for the dinuclear com-
plexes of Lox and Lmx are ca. 21- and threefold higher,
respectively, than that of the CuII-tacn complex. Secondly,
alkylation of the tacn ring nitrogen atoms generally leads
to rate enhancements. This is most pronounced for the mo-
nonuclear complexes, with the CuII complexes of Me3tacn
and iPr3tacn exhibiting rate constants 150- and 170-times
higher, respectively, than the CuII-tacn complex. Compari-
son of the rate constants for Co (the complex of the methyl-
ated Lox ligand) and the dinuclear copper(II) complex of
Lox indicate that simple N-methylation of the supporting
ligand structure results in a fivefold increase in rate con-
stant, while for the m-xylyl-bridged ligand, Lmx, N-methyl-
ation results in only a very slight increase in rate.
Distance [Å]
Cu(1)–Cu(2) 6.578(4)
Angle [°]
N(3)–Cu(1)–N(2)
N(3)–Cu(1)–N(1)
N(2)–Cu(1)–N(1)
O(9)–Cu(1)–O(10)
N(3)–Cu(1)–O(9)
N(2)–Cu(1)–O(9)
N(3)–Cu(1)–O(10)
N(2)–Cu(1)–O(10)
O(9)–Cu(1)–N(1)
O(10)–Cu(1)–N(1)
N(5)–Cu(2)–N(4)
N(6)–Cu(2)–N(4)
N(5)–Cu(2)–N(6)
O(12)–Cu(2)–O(11)
N(5)–Cu(2)–O(11)
N(6)–Cu(2)–O(11)
O(12)–Cu(2)–N(4)
O(11)–Cu(2)–N(4)
O(12)–Cu(2)–N(5)
O(12)–Cu(2)–N(6)
86.6(2)
Cu(1)–N(1) 2.259(5)
Cu(1)–N(3) 2.001(5)
Cu(1)–N(2) 2.012(5)
Cu(1)–O(9) 2.013(4)
Cu(1)–O(10) 2.018(4)
Cu(2)–N(4) 2.240(5)
Cu(2)–N(5) 1.994(5)
Cu(2)–N(6) 2.019(5)
Cu(2)–O(12) 1.986(4)
Cu(2)–O(11) 2.057(4)
84.76(2)
84.71(2)
65.57(2)
169.24(2)
101.43(2)
105.88(2)
166.57(2)
102.95(2)
101.08(2)
84.65(2)
85.36(2)
87.9(2)
65.23(2)
108.2(2)
158.2(2)
106.24(2)
110.07(2)
168.6(2)
96.3(2)
One reason that has been suggested for the higher rate
constants for the CuII complexes of Me3tacn and iPr3tacn
relative to the CuII-tacn complex is that the alkyl groups
hinder dimerisation of mononuclear cation units into a hy-
drolytically inactive, dihydroxo-bridged dinuclear complex,
Phosphate Ester Hydrolysis
The ability of the two complexes to hydrolyse phosphate or conversion into sandwich complexes of the form
esters was explored by examining their ability to accelerate [L2Cu]2+, which no longer have sites available for the at-
the cleavage of the model phosphodiester, BNPP, which, tachment of the substrate or the aqua ligands required to
upon hydrolysis, liberates a 4-nitrophenolate (NP) anion, a generate the coordinated nucleophile to attack the sub-
chromophore that adsorbs strongly at 400 nm [i.e. strate. These factors are also probably responsible for the
NO2PhOP(O)2OPhNO2 (BNPP) + complex Ǟ NO2PhO– enhanced rate constants of the dinuclear complexes of
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CuII Complexes with New Binucleating Ligands
Lmeox and Lmemx relative to those of Lox and Lmx, respec- corresponding dinuclear copper(II) complexes, [Cu2(η-
tively. However, in the case of the dinuclear complexes, the AcO)2(Lmeox)](ClO4) and [Cu2(µ-AcO)2(Lmemx)](ClO4)2·
effects of methylation on rate constant are not as impressive H2O. In these complexes, the acetato ligands were found to
as for the simple monuclear complexes, as can be seen in adopt chelating and bridging coordination modes, respec-
Table 3.
tively, owing to the structural constraints of the ortho- and
For the m-xylyl-bridged ligands, Lmx and Lmemx, it would meta-substituted xylyl backbone. Methylation of all four ni-
appear that the ligand geometry is particularly suited to trogen atoms of the o-xylyl-bridged bis(tacn) ligand results
intramolecular dihydroxo-bridge formation between cop- in a fivefold increase in the BNPP hydrolysis rate by the
per(II) centres. Indeed, the intramolecular dihydroxo- corresponding dinuclear copper(II) complex relative to that
bridged dinuclear copper(II) complex of Lmx has been iso- of the complex of the non-methylated ligand. In contrast,
lated by Farrugia et al.,[21] and we have structurally charac- N-methylation of the m-xylyl-bridged bis(tacn) ligand has
terised several copper(II) complexes of ligands featuring little impact on BNPP hydrolysis rates.
pairs of dihydroxo-bridged CuII-tacn units attached to the
meta positions of an aromatic ring.[44] Thus, at pH 7.4, sig-
nificant proportions of the dinuclear CuII complexes of Lmx
Experimental Section
and Lmemx could be present as intramolecular hydroxo-
General: All reagents and solvents used were of reagent or analyti-
cal grade and were used as received from commercial suppliers.
bridged dimers, substantially lowering the effective concen-
tration of hydrolytically active species in solution. The simi-
Distilled H2O was used throughout. Acetonitrile was pre-dried with
larity in the rate constant for hydrolysis of BNPP by the
4 Å sieves and used without further purification. 1,4,7-Triazatricy-
complexes of Lmx and Lmemx to that for the tacn complex
clo[5.2.1.04.10]decane was synthesized according to published meth-
ods.[46]
appears to bear this point out.
The data for the copper(II) complexes of the o-xylyl-
bridged ligands, Lox and Lmeox, indicate that N-methylation
translates into a much more significant (5-fold) increase in
rate constant than for the m-xylyl-bridged systems, suggest-
ing that alkylation of the secondary amines serves to more
effectively hinder the formation of hydrolytically inactive
species in solution in this case. This may be related to the
fact that the o-xylyl bridge is already less accommodating
of intramolecular dihydroxo-bridge formation between the
two copper(II) centres than the m-xylyl bridge (Zompa and
co-workers[45] have reported the logβ for formation of the
intramolecular hydroxo-briged dinuclear copper complex of
Lmx to be higher than that of Lox). Nonetheless, the fact
that the rate constant for Co is not significantly higher than
that of the CuII-Me3tacn complex suggests that N-methyl-
ation is unable to completely suppress intramolecular hy-
droxo-bridge formation between the proximal CuII centers
in the o-xylyl-bridged complex.
Instrumentation and Methods: All NMR spectra were recorded
using Bruker spectrometers. 1H and 13C spectra were performed in
D2O at 25 °C using a 400 MHz instrument. UV/Vis spectra were
recorded using Varian Cary 300 or Cary 5G spectrophotometers.
IR spectra were recorded using Perkin–Elmer FTIR 1600 series
spectrometer at 4.0-cm–1 resolution, using KBr discs. Cation-ex-
change column chromatography was performed using Sephadex
SP-C25 columns (Na+ form) with a 30-mm diameter. All mass
spectrometry was performed using a Micromass Platform II, with
an ESI source. The capillary voltage was at 3.5 eV and the cone
voltage at 35 V.
1,3-Bis[(4,7-dimethyl-1,4,7-triazacyclononan-1-yl)methyl]benzene
Hexahydrochloride (Lmemx·6HCl): An acetonitrile solution (5 mL)
of 1,3-bis(bromomethyl)benzene (0.284 g, 1.08 mmol) was added to
a stirred solution of 1,4,7-triazatricyclo[5.2.1.04,10]decane (0.300 g,
2.16 mmol) in acetonitrile (5 mL) was added dropwise . Once ad-
dition was complete, the reaction was stirred at room temperature
for 15 h. The resulting white precipitate was filtered, washed with
acetonitrile (2 x 3 mL) and diethyl ether (3ϫ10 mL), and then dis-
solved in a 1:1 v/v solution of formic acid and aqueous formalde-
hyde (40%) (20 mL). The flask was fitted with a reflux condenser
and the resulting solution was heated at 70 °C for 20 h. The mixture
was then cooled to room temperature and the solvent removed un-
der vacuum. The resulting oil was taken up in 2  HCl (20 mL)
and the solvent again removed under vacuum. Trituration of the
oily residue with acetone (10 mL) yielded a white solid correspond-
ing to the acid salt of Lmemx. This was filtered and washed with
acetone (10 mL) and diethyl ether (10 mL). Yield 0.51 g, 74%. ESI-
MS: m/z = 209.1889 [M + 2H]2+, 417.3695 [M + H]+. 1H NMR
(400 MHz, D2O): δ = 7.701–7.628 (m, 4 H, aromatic CH), 4.201
(s, 4 H, benzyl CH2), 3.714 (br., 10 H, tacn ring CH2), 3.414–3.219
(m, 14 H, tacn ring CH2), 3.041 (s, 12 H, N-CH3 ppm) ppm. 13C
NMR (300 MHz, D2O): δ = 132.967, 131.516, 130.276, 56.612,
53.262, 51.782, 48.291, 44.989, 30.758 ppm.
It should also be noted that our earlier work,[43] and a
subsequent study by Zompa and co-workers,[45] have shown
that Lox is capable of forming a stable mononuclear “sand-
wich complex” with Cu2+ ions. Upon dissolution of the di-
nuclear complex of Lox in aqueous solution, some complex
rearrangement may be occurring, leading to formation of
less active or inactive complexes, i.e. [LoxCu]2+
,
[LoxCu2(OH2)]2+ and Cu2+. The introduction of methyl
groups onto the four nitrogen atoms of Lox would be ex-
pected to sterically hinder, but not necessarily prevent, the
formation of such complexes. The moderate rate enhance-
ment observed in moving from the copper(II) complex of
Lox to that of the fully methylated analogue, Lmeox, may be
originating from subtle changes in species distribution.
1,2-Bis[(4,7-dimethyl-1,4,7-triazacyclononan-1-yl)methyl]benzene
Hexahydrochloride (Lmeox·6HCl): The product was obtained as a
white solid according to the procedure described above for
Lmemx·6HCl, starting from 1,4,7-triazatricyclo[5.2.1.04,10]decane
Conclusion
Two new methylated, xylyl-bridged bis(tacn) ligands
Lmeox and Lmemx have been prepared, together with their (0.312 g, 2.25 mmol) and 1,2-bis(bromomethyl)benzene (0.295 g,
Eur. J. Inorg. Chem. 2008, 4133–4139
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjic.org
4137

M. J. Belousoff, B. Graham, L. Spiccia
FULL PAPER
1.12 mmol). Yield 0.49 g, 69%. ESI-MS: m/z = 209.1895 [M +
bis(4-nitrophenyl)phosphate, BNPP, by the CuII complexes was
1
2H]2+, 417.3698 [M + H]+. H NMR (400 MHz, D2O): δ = 7.7757 measured at pH 7.4 (MOPS buffer) and T = 50 °C by following
(AB quartet, J1 = 3.56, J2 = 4.96 Hz, 2 H, aromatic CH), 7.6142
the formation of p-nitrophenolate ion (λmax = 400 nm, εmax =
(AB quartet, J1 = 3.56, J2 = 4.96 Hz, 2 H, aromatic CH), 4.283 (s, 18700 –1 cm–1) in solution containing 15 µ BNPP, 1 m CuII
4 H, benzyl CH2), 3.8021 (br., 8 H, tacn ring CH2), 3.4144 (br., 6 complex and I = 0.15  (NaClO4), with a Varian Cary 300 spectro-
H, tacn ring CH2), 3.2467 (br., 10 H, tacn ring CH2), 2.9855 (s, 12
photometer. Absorbance measurements were commenced after
H, N-CH3) ppm. 13C NMR (400 MHz, D2O): δ = 131.90, 129.53, 2 min and were continued for 8000 min with a reading taken every
62.32, 55.13, 53.24, 51.46, 48.62, 44.49, 30.34 ppm.
5 min. As the complex was in large excess compared to BNPP, the
appearance of NP (and cleavage of BNPP) was modelled as a first-
order process, Abs = A + Bekobsd.t, for Co, and using the initial rates
method for Cm, as per previous studies.[6,7]
[Cu2(µ-AcO)2(Lmemx)](ClO4)2·H2O (Cm): Aqueous solutions of Cu-
(ClO4)2·6H2O (100 m, 1 mL) and Cu(ac)2·H2O (100 m, 1 mL)
were added to an aqueous solution of Lmemx·6HCl (96 m, 2 mL).
The pH of the resulting solution was adjusted to pH 7.0 with so-
dium hydroxide, upon which the colour became a deep royal blue.
The solution was carefully taken to dryness under vacuum and the
resulting solid residue dissolved in acetonitrile and filtered. Diethyl
ether was diffused into the filtrate, upon which green crystals
formed. Yield 68 mg, 40%. UV/Vis (H2O): λmax (εmax, –1 cm–1) =
Crystallography: Intensity data for a green crystal of Cm and a dark
blue crystal of Co were measured at 123 K with a Nonius Kappa
CCD fitted with graphite-monochromated Mo-Kα radiation
(0.71073 Å). The data were collected to a maximum 2θ value of
55o and processed using the Nonius software. Crystal parameters
and details of the data collection are summarised in Table 4. Both
structures were solved by direct methods and expanded using stan-
dard Fourier routines in the SHELX-97 software package.[47,48] All
hydrogen atoms were placed in idealised positions, and all non-
hydrogen atoms were refined anisotropically.
272 (7100), 668 nm (56). IR: ν = 2924 (s), 2869 (s), 1572 (s), 1492
˜
(w), 1466 (s), 1432 (s), 1420 (s), 1347 (w), 1324 (w), 1292 (w), 1253
(w), 1224 (w), 1090 (br), 1012 (m), 984 (m), 890 (w), 821 (m), 787
(w), 753 (w), 714 (w), 668 (w), 624 (s) cm–1. C28H58Cl2Cu2N6O16
(930.8): calcd. C 36.8, H 6.2, N 9.2; found C 36.0, H 5.9, ⁿ 9.2.
[Cu2(η-AcO)2(Lmeox)](ClO4)2 (Co): Aqueous solutions of Cu(ClO4)2·
6H2O (100 m, 0.26 mL) and Cu(ac)2·H2O (100 m, 0.26 mL)
were added to an aqueous solution of Lmeox·6HCl (120 m,
0.5 mL). The pH of the resulting solution was adjusted to pH 7.0
with sodium hydroxide, upon which the colour became a deep royal
blue. Work-up as described for the synthesis of Cm gave blue crys-
tals of Co. Yield 36 mg, 69%. UV/Vis (H2O): λmax (εmax, –1 cm–1)
CCDC-610106 (for Cm) and -610107 (for Co) contain the supple-
mentary crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/datarequest/cif.
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= 274 (7400), 668 nm (68). IR: ν = 3443 (br), 2927 (m), 2875 (m),
˜
2832 (w), 1560 (m), 1508 (s), 1498 (s), 1460 (s), 1472 (s), 1411 (s),
1331 (m), 1299 (m), 1201 (w), 1095 (br. s), 995 (m), 974 (w), 946
(m), 902 (w), 836 (w), 818 (w), 792 (m), 747 (m), 736 (w), 696 (m),
658 (w), 624 (s) cm–1. C28H50Cl2Cu2N6O12 (860.7): calcd. C 39.1,
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Table 4. Crystal collection parameters for Cm·H2O and Co.
Crystal
Cm
Co
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Empirical formula
C28H52Cl2Cu2N6O13 C28H50Cl2Cu2N6O12
M [gmol–1
]
878.75
860.72
Crystal system
Space group
a [Å]
b [Å]
c [Å]
monoclinic
P21/n
orthorhombic
Pbca
15.029(3)
11.507(2)
21.503(4)
96.00(3)
3698.4(13)
4
15.041(3)
19.082(4)
25.166(5)
β [°]
Volume [Å3]
Z
7223(2)
8
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µ (Mo-Kα) [mm–1
]
1.364
1.393
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Dc [gcm–3
]
1.578
1.583
Data measured
90662
66176
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)
8495 (0.0820)
6361
8260 (0.1803)
3578
2832.
Observed data [I Ͼ2σI]
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[b]
Final R1[a], wR2 (obsd. data) 0.0539[a], 0.1326[b]
0.0697[a], 0.1363[b]
0.2005, 0.1880
–0.903, 0.700
Final R1, wR2 (all data)
0.0868, 0.1729
–1.238, 0.861
ρmin, ρmax [eÅ3]
[a] R = Σ(|Fo| – |Fc|)/Σ|Fo|. [b] RЈ = [Σw(|Fo| – |Fc|)2/ΣFo
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Received: May 27, 2008
Published Online: August 12, 2008
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Eur. J. Inorg. Chem. 2008, 4133–4139
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjic.org
4139