Copper(ii) complexes ofN-propargyl cyclam ligands reveal a range of coordination modes and colours, and unexpected reactivity

Article abstract of DOI:10.1039/d0dt03736b

The coordination chemistry ofN-functionalised cyclam ligands has a rich history, yet cyclam derivatives with pendant alkynes are largely unexplored. This is despite the significant potential and burgeoning application ofN-propargyl cyclams and related com

Full text of DOI:10.1039/d0dt03736b

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Copper(II) complexes of N-propargyl cyclam
ligands reveal a range of coordination modes and
colours, and unexpected reactivity†
Cite this: Dalton Trans., 2021, 50,
3931
Andrew J. Counsell, a Mingfeng Yu, b Mengying Shi,a Angus T. Jones,a
James M. Batten, a Peter Turner,a Matthew H. Todd *c and
a
Peter J. Rutledge
*
The coordination chemistry of N-functionalised cyclam ligands has a rich history, yet cyclam derivatives
with pendant alkynes are largely unexplored. This is despite the significant potential and burgeoning
application of N-propargyl cyclams and related compounds in the creation of diversely functionalised
cyclam derivatives via copper-catalysed azide–alkyne ‘click’ reactions. Herein we describe single crystal
X-ray diffraction and spectroscopic investigations of the coordination chemistry of copper(II) complexes
of cyclam derivatives with between 1 and 4 pendant alkynes. The crystal structures of these copper com-
plexes unexpectedly reveal a range of coordination modes, and the surprising occurrence of five unique
complexes within a single recrystallisation of the tetra-N-propargyl cyclam ligand. One of these species
exhibits weak intramolecular copper-alkyne coordination, and another is formed by a surprising intra-
molecular copper-mediated hydroalkoxylation reaction with the solvent methanol, transforming one of
the pendant alkynes to an enol ether. Multiple functionalisation of the tetra-N-propargyl ligand is demon-
strated via a ‘tetra-click’ reaction with benzyl azide, and the copper-binding behaviour of the resulting
tetra-triazole ligand is characterised spectroscopically.
Received 30th October 2020,
Accepted 21st January 2021
DOI: 10.1039/d0dt03736b
rsc.li/dalton
chemosensing,5,6 biomimicry,7,8 molecular switches,9,10 supra-
molecular systems,11,12 catalysis,13–15 and medicine.16–19
Introduction
Cyclam 1 (Fig. 1) and N-functionalised cyclam derivatives have
a long and distinguished history as macrocyclic ligands that
give rise to metal complexes with diverse and interesting pro-
perties, with their coordination modes, reactivity, and bioactiv-
ity continuing to draw sustained research interest.1–4
Functionalisation of one or more of the secondary amines
in the azamacrocycle is easily achieved, affording diverse and
significant changes to the properties of the resulting ligand and
metal complexes. The variance of their properties depends pri-
marily upon the degree of amine substitution, the electronic
and steric properties of the N-substituents, the metal cation, the
nature of anionic species present during complexation, and
pH.3 The resultant versatility has enabled the application of
cyclam derivatives across a wide range of areas including
Pendant groups including amine, alcohol, thiol, ester, car-
boxylic acid, amide, carbamate, urea, sulfonamide, nitrile,
thioester, pyridyl, triazolyl and phosphonate functionality have
been incorporated in side-arms of varying length and
complexity,2,3 to modulate properties such as chelate effects, the
selectivity of metal ion-binding, side-chain reactivity, and
pendant lability. From the simple aminoethyl derivative 2 used
to study the pH-dependence of side-chain coordination to a che-
lated nickel ion,20 this field has expanded to include com-
pounds such as the dansylate 3 cast as the basis for a light-emit-
ting molecular machine,10 the likes of naphthalimide derivative
4 which incorporate fluorescent dyes for metal ion sensing,21–23
and molecules of general structure 5, which have demonstrated
potency against drug-resistant Mycobacterium tuberculosis
(Fig. 1).24,25 Relatively little attention has been paid to
cyclam derivatives bearing alkyne pendant groups and the
metal complexes they form. The recently reported surface modi-
fication of glassy carbon electrodes for CO2 reduction with a
series of [Ni(alkynyl-cyclam)]2+ complexes serves as an isolated
example.26
aSchool of Chemistry, The University of Sydney, Sydney, New South Wales 2006,
Australia. E-mail: peter.rutledge@sydney.edu.au; Tel: +61 2 9351 5020
bDrug Discovery and Development, Cancer Research Institute, Clinical and Health
Sciences, University of South Australia, Adelaide, South Australia 5001, Australia
cSchool of Pharmacy, University College London, 29-39 Brunswick Square, London
WC1N 1AX, UK. E-mail: matthew.todd@ucl.ac.uk; Tel: +44 207 753 5568
†Electronic supplementary information (ESI) available. CCDC 2012628–2012634
and 2019803. For ESI and crystallographic data in CIF or other electronic format
see DOI: 10.1039/d0dt03736b
We have ongoing interests in N-propargyl cyclams as precur-
sors for Cu(I)-catalysed azide–alkyne Huisgen ‘click’ reactions,
which enable the introduction of more complex pendant func-
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Fig. 2 Functionalised cyclam ligands 6–9 bearing pendant alkynes.
ESI†), which was alkylated, deprotected with basic work-
up,29,33 and then methylated with an Eschweiler–Clarke reac-
tion to form 7 in good overall yield (62%).
Initial attempts to synthesise 8 via alkylation of tri-Boc
cyclam with methyl bromoacetate failed at the deprotection
stage. Once the tri-Boc/ester intermediate 10 is unmasked and
exposed to the basic conditions used in the reaction with pro-
pargyl bromide, mono N-alkylated cyclam 11 is prone to an
intramolecular cyclisation reaction forming bicyclic lactam 12
(Scheme 2), as reported previously for the ethyl ester analogue
of 11 and related systems.34,35 Ligand 8 was instead obtained
directly from cyclam 1 via a one-pot synthesis with the slow,
sequential addition of propargyl bromide and methyl bromoa-
cetate in strict 3 : 1 stoichiometry under basic conditions
(Scheme 1) in a poor but tolerable yield (10%). The tetrapro-
pargyl ligand 9 was prepared in good yield (72%) using the
direct, one-step tetra-N-alkylation reaction we have recently
reported, with propargyl bromide and a base in a ‘miscible
biphasic’ system.36
Metal complexes were prepared by dissolving each of the
ligands 6–9 in ethanol with copper(II) perchlorate and heating
at reflux for one hour, then cooling on ice to precipitate the
complex. This procedure, adapted from one we have previously
reported for related systems,24,37 afforded the metal complexes
[Cu(6)](ClO4)2·CH3OH, [Cu(7)](ClO4)2·H2O, [Cu(8)](ClO4)2·H2O,
and [Cu(9)](ClO4)2 in high yields (77–81%).
Fig. 1 Cyclam 1 and derivatives 2–5 with pendant ligands that have a
broad range of applications.
tionality as in 4 and 5 above,27–29 a strategy that has also been
employed in a number of other metal chelating systems.30
Herein we report the structural characterisation of the
copper complexes of N-propargyl cyclams 6–9 bearing 1–4
pendant alkynes (Fig. 2). This group of ligands was chosen to
probe the effect that the degree of amine substitution, and the
electronic and steric properties of the N-substituents, have
upon the structures of the Cu(II) complexes. The complexes
exhibit an interesting variety of alkyne coordination modes
and stereochemistry across the series and individually.
Structures of the Cu(II) complexes of 6–9 are reported, includ-
ing a series of the Cu(9) complex obtained from a single recrys-
tallisation, and an unexpected enol ether complex derived
from the reaction of Cu(9) with methanol solvent.
Structural characterisation of mono-, di- and tri-propargyl
complexes
Single crystals of the Cu(II) perchlorate complexes of ligands 6,
8 and 9 were obtained either through the slow diffusion of an
aqueous Cu(ClO4)2 phase with a methanolic phase containing
the ligand, or via the slow evaporation of a methanolic solu-
Results and discussion
Synthesis of ligands and metal complexes
Preparation of the mono N-propargyl cyclam 6 proceeded in tion of the complex. Attempts to crystallise [Cu(7)](ClO4)2 from
good overall yield (68%) from cyclam 1 (Scheme 1 and methanol were unsuccessful, and this was instead accom-
Scheme S1, ESI†) using previously reported methods.26,31,32 plished via the slow evaporation of a solution of the complex
The bis-alkyne derivative 7 was obtained through conversion in acetonitrile. Structure determination and crystallographic
of cyclam 1 to a bis-aminal-bridged intermediate (Scheme S1, details are provided electronically as part of the ESI.†
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Scheme 1 Synthesis of ligands 6–9 and their copper complexes. Reagents and conditions: a. (i) (Boc)2O, Et3N, CH2Cl2, −15 °C to rt, 16 h, 77%; (ii)
BrCH2CuCH, Na2CO3, rt, 16 h, 95%; (iii) TFA/CH2Cl2 (1 : 5), rt, 72 h, 93%; (iv) Cu(ClO4)2·6H2O, EtOH, reflux, 1 h, 80%; b. (i) CH2O, H2O, rt, 16 h, 76%;
(ii) BrCH2CuCH, CH3CN, rt, 16 h, 90%; (iii) CH2O, HCO2H, H2O, reflux, 24 h, 90%; (iv) Cu(ClO4)2·6H2O, EtOH, reflux, 1 h, 81%; c. (i) BrCH2CuCH (3.0
eq.), BrCH2CO2CH3 (1.0 eq.), Na2CO3, CH3CN, reflux, 16 h, 10%; (ii) Cu(ClO4)2·6H2O, EtOH, reflux, 1 h, 77%; d. (i) BrCH2CuCH, H2O/CH3CN (1 : 1),
NaOH, rt, 16 h, 72%; (ii) Cu(ClO4)2·6H2O, EtOH, reflux, 1 h, 80%. See Scheme S1 and synthesis and characterisation section of the ESI† for further
details.
Scheme 2 Attempted synthesis of 8 via 10 was unsuccessful as the mono-N-alkyl cyclam 11 cyclises to the bicyclic lactam 12 in alkaline solution.
Reagents and conditions: (i) (Boc)2O, Et3N, CH2Cl2, −15 °C to rt, 16 h, 77%; (ii) BrCH2CO2CH3, Na2CO3, rt, 16 h, 95%; then deprotection with 2 M HCl
in 1,4-dioxane, rt, and attempted alkylation with BrCH2CuCH and Na2CO3, rt. Cyclised product 12 was not isolated, but has been reported pre-
viously to form under similar conditions, see text for further details.
Table 1 Selected bond distances (Å) within the metal coordination
sphere observed in structures of the N-propargyl cyclam complexes [Cu
(6)](ClO4)2, [Cu(7)](ClO4)2, and [Cu(8)](ClO4)2
[Cu(6)](ClO4)2
[Cu(7)](ClO4)2
[Cu(8)](ClO4)2
Cu–O1a
Cu–O5a
Cu–N1
Cu–N2
Cu–N3
Cu–N4
Cu–N1Sb
Cu–O1c
2.5170(18)
2.5403(18)
2.0802(19)
2.015(2)
2.0281(19)
2.008(2)
2.126(3)
2.074(3)
2.111(3)
2.081(3)
2.229(3)
2.1071(19)
2.0615(18)
2.0844(18)
2.0529(17)
2.2477(15)
a O of perchlorate. b N of solvent (acetonitrile). c Carbonyl O of pendant
ester.
Fig. 3 Olex2 depiction of trans-III-[Cu(6)](ClO4)2, with displacement
ellipsoids shown at the 50% level. A disordered methanol solvate mole-
cule is not shown.
2.008(2) to 2.0802(19) Å, similar to the theoretical expectation
of 2.07 Å.38 The relatively long metal to oxygen axial bond
lengths of 2.5170(18) and 2.5403(18) Å reflect the character of
perchlorate ion, and presumably Jahn–Teller distortion. The
Complex [Cu(6)](ClO4)2 adopts a slightly distorted octa- angles formed between the macrocycle nitrogen, metal, and
hedral geometry, with weak axial perchlorate coordination to perchlorato oxygen sites range from 85.37(7) to 94.37(7)° for
the metal centre (Fig. 3 and ESI Fig. SX1,† Table 1 and one perchlorate counterion and 84.77(8) to 95.08(7)° for the
Table SX1†). The Cu–N macrocyclic amine distances vary from second. The perchlorato oxygen to metal to trans perchlorato
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oxygen angle is 177.50(6)°. The metal ion is displaced 0.023(1) (1) Å from the line defined by one of the pairs of opposing
Å from the least squares plane defined by the equatorial nitro- nitrogen atoms (N1, N3), with both in this pair bearing an
gen atoms, 0.010(1) Å from the line defined by one of the pairs alkyne residue, and 0.458(1) Å from that of the second pair
of opposing nitrogens (N1, N3), and 0.058(1) Å from that of the (N2, N4). The [Cu(7)(CH3CN)]2+ complex dication adopts the
second pair (N2, N4).
trans-I configuration.44
Following chelation of a metal ion, a cyclam complex will
Like the [Cu(7)(CH3CN)]2+ complex dication, the single
adopt one of five configurations according to the spatial orien- crystal structure of [Cu(8)]2+ is essentially five coordinate
tations of the backbone amine substituents: RSRS, RRRS, (Fig. 5 and ESI Fig. SX3†), with a distorted square pyramidal
SSRR, RSSR and RRRR, respectively termed trans-I to trans-V coordination sphere and
a
trans-I configuration.44 Here
(where the arrangement of cyclam nitrogens is planar); or a though, axial ligation involves the carbonyl oxygen of the
corresponding cis form (where the cyclam is ‘folded’)—noting pendant methyl ester, with a bond length of 2.2477(15) Å
that some forms will be highly strained and/or impossible to (Table 1). There is a significant distortion of the coordination
adopt.39 The cyclam fragment [Cu(6)]2+ adopts the preferred geometry, with the macrocycle nitrogen to metal to axial
trans-III configuration, with adjacent N-alkyl substituents (R-N- oxygen angles ranging from 78.14(7) to 102.41°. This distortion
(CH2)3-N-R) displaced from the Cu–N plane. In spite of the ten- is further reflected in the τ value of 0.35. The metal to macro-
dency for similar complexes to exhibit metal-alkyne cycle nitrogen distances vary from 2.0529(17) to 2.1071(19) Å.
coordination,40–42 no such interaction is observed here There again appears to be a weak interaction, presumably pri-
between the N-propargyl group (C11–C13) and the metal marily electrostatic, between the metal cation and a perchlor-
centre.
ate counterion trans to the pendant carbonyl oxygen, separated
As is the case with [Cu(6)]2+, the single crystal structure of by 3.649(2) Å. The metal is displaced 0.222(1) Å from the least
the [Cu(7)(CH3CN)]2+ complex dication lacks coordination of squares plane defined by the equatorial nitrogen atoms,
the propargyl substituent to the metal centre (Fig. 4 and ESI −0.078(1) Å from the line defined by one of the pairs of oppos-
Fig. SX2†). The presence of acetonitrile, a softer and more ing nitrogen atoms (N1, N3), and 0.447(1) Å from that of the
effective Lewis base, evidently precludes axial perchlorate second pair (N2, N4). The negative offset indicates displace-
coordination; the macrocyclic complex is essentially five coor- ment towards the nitrogen equatorial plane.
dinate with an apical copper(II) to acetonitrile nitrogen bond
length of 2.229(3) Å (see also Table 1). There appears to be a
Tetra-propargyl ligand 9 forms several different Cu(II)
weak–presumably electrostatic–interaction between the metal
complexes
ion and the oxygen of a perchlorate anion trans to the aceto-
The crystallisation of [Cu(9)](ClO4)2 produced five visibly dis-
tinct crystals in the crystal growth flask (Fig. 6). The crystals
were obtained via slow liquid–liquid diffusion overnight at
nitrile, with the metal ion to oxygen site distance being 3.914
(4) Å. The metal coordination environment is distorted square-
pyramidal, with a trigonal index (τ) of 0.34 (where τ ranges
from 0 to 1, indicating the extent of transition from the ideal
square pyramidal to ideal trigonal bipyramidal geometries,
respectively).43 The metal is displaced 0.276(1) Å from the least
squares plane defined by the equatorial nitrogen atoms, 0.095
Fig. 4 Olex2 depiction of trans-I-[Cu(7)(CH3CN)](ClO4)+, with ellipsoids
shown at the 50% probability level. The second perchlorate counterion
is not shown.
Fig. 5 Olex2 depiction of trans-I-[Cu(8)](ClO4)+, with ellipsoids shown
at the 50% probability level. The second perchlorate counterion is not
shown.
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Fig. 6 Photographs of crystals isolated following the slow diffusion of aqueous Cu(ClO4)2 with a methanolic solution of 9: (9A) trans-I-[Cu(9)]
(ClO4)2; (9B) trans-III-[Cu(9)](ClO4)2; (9C) trans-I/III-([Cu(9)](ClO4)2)2·H2O; (9D) trans-I-[Cu(1,4,8-propargyl-11-(2-methoxypropene)cyclam)]
(ClO4)2·H2O and (9E) trans-I-[Cu(1,4,8-propargyl-11-(2-methoxypropene)cyclam)](ClO4)2·0.25CH3OH.
Table 2 Selected bond lengths (Å) and angles (°) within the metal
coordination sphere observed in structures of the complex
[Cu(9)](ClO4)2, 9A–9C
room temperature, of a 0.1 M aqueous solution of Cu(ClO4)2,
with a 0.1 M methanolic solution of 9. Distinguished here with
labels 9A to 9E, the structures obtained from each exhibit sig-
nificant variation in donor ligand configuration, conformation
and even the ligand species, which was surprising given each
complex assembly occurred from a single set of components
under identical conditions.
9C
9A
9Ba
trans-I
trans-III
trans-I 9C-1
trans-III 9C-2e
Cu–N1
Cu–N2
Cu–N3
2.0711(17)
2.0959(18)
2.0999(18)
2.1274(17)
2.359(9)d
2.1127(16)
2.0283(15)
2.059(2)
2.061(2)
2.063(2)
2.069(2)
2.890(2)
2.028(2)
2.125(2)
Crystal 9A was found to comprise a trans-I-[Cu(9)](ClO4)+
complex cation (Fig. 7 and ESI Fig. SX4, Table 2 and
Table SX2†). The structure geometry is five-coordinate square
pyramidal (τ = 0.03), with an axial perchlorate ligand and a co-
ordinated cyclam adopting the favourable trans-I configur-
ation. The metal is displaced 0.206(1) Å from the least squares
plane defined by the equatorial nitrogen atoms, 0.219(1) Å
from the line defined by one of the pairs of opposing nitrogen
atoms (N1, N3), and 0.192(1) Å from that of the second pair
(N2, N4).
The metal ion to cyclam nitrogen distances vary from
2.0711(17) to 2.1274(17) Å (Table 2). The coordinated perchlor-
ate anion is disordered over two orientations (Fig. SX4, ESI†),
with coordination bond lengths of 2.359(9) Å for the major
component and 2.301(17) Å for the minor component. The
complex cation is pseudo-oligomeric, with the copper of one
Cu–N4
Cu–Ob
Cu–Ob
2.301(17)d
Cu–alkynec
N1–Cu–N2
N1–Cu–N3
N1–Cu–N4
N2–Cu–N3
N2–Cu–N4
N3–Cu–N4
N1–Cu1–Ob
N2–Cu1–Ob
N3–Cu1–Ob
N4–Cu1–Ob
2.93
93.40(6)
3.04
2.93
93.87(9)
93.87(7)
167.92(7)
85.06(7)
84.87(7)
169.55(7)
94.00(7)
94.09(9)
169.76(8)
86.57(9)
86.41(9)
163.81(8)
95.81(9)
98.48(7)
81.49(7)
91.72(7)
82.41(7)
a Third and fourth nitrogen sites generated through inversion oper-
ation 1 − x, 1 − y, 1 − z. b Oxygen sites of perchlorate. c Metal to alkyne
centroid distance. d Disordered perchlorate. e Third and fourth nitro-
gen sites generated through inversion operation −x, 1 − y, −z.
complex cation weakly interacting with the coordinated per-
chlorate of a second (Fig. SX5, ESI†), with metal to neighbour-
ing perchlorate oxygen distances of approximately 3.51 Å for
the major perchlorate orientation and 3.68 Å for the minor
orientation.
Crystal 9B was found to comprise a pseudo-octahedral
trans-III-[Cu(9)]2+ complex dication in which axial ligation
involves weak alkyne π system coordination. Located on an
inversion centre, the complex dication has symmetrical bond
lengths of approximately 2.93 Å (Fig. 8, Table 2 and ESI
Fig. SX6, Table SX2†). Observation of the trans-III isomer of
tetra-N-substituted cyclam derivatives is relatively unusual,
with adoption of this spatial arrangement highly dependent
on solvent conditions and the counterion.3,18,45 Recent
examples of trans-III tetra-N-substituted cyclam complexes
with coordinated pendant arms include a bis-methylene-phos-
phonato nickel(II) complex reported by Blahut et al. (CCDC
1430239†),46 and the tetraacetamide-cobalt(II) complex
described by Bond et al. (CCDC 1949780†).47
Fig. 7 Olex2 depiction of complex cation 9A, trans-I-[Cu(9)](ClO4)+,
with displacement ellipsoids shown at 50% probability level. Disordered
sites are highlighted with ‘faded’ colours. The second perchlorate coun-
terion is not shown.
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Fig. 8 Olex2 depiction of complex dication 9B trans-III-[Cu(9)]2+ with
displacement ellipsoids shown at the 50% probability level. The two per-
chlorate counterions are not shown. The complex dication resides on an
inversion site and the superscript ‘i’ denotes −x, 1 − y, −z.
Crystal 9C was found to contain two distinct [Cu(9)](ClO4)2
complex molecules – for convenience labelled as 9C-1 and
9C-2 – and a water molecule. The 9C-1 complex molecule is
pseudo-octahedral in character, with weak axial perchlorate
coordination trans to weak π coordination from an N-propargyl
residue (Fig. 9 and ESI Fig. SX7a†). The cyclam fragment has a
trans-I disposition. The metal ion is displaced 0.066(1) Å from
the least squares plane defined by the equatorial nitrogen
atoms, −0.184(1) Å from the line defined by one of the pairs of
opposing nitrogen atoms (N1, N3), and 0.291(1) Å from that of
the second pair (N2, N4).
The metal to perchlorate oxygen atom distance is 2.890(2) Å
and the metal to π-bond distance is approximately 3.04 Å. The
metal to cyclam nitrogen distances range from 2.059(2) to
2.069(2) Å, with the shortest associated with the weakly co-
ordinated alkyne substituent.
Fig. 9 Olex2 depictions of (a) complex 9C-1 trans-I-[Cu(9)](ClO4)+ and
(b) complex dication 9C-2 trans-III-[Cu(9)]2+, with displacement ellip-
soids shown at the 50% probability level. The perchlorate counterions
are not shown.
The 9C-2 complex molecule is also pseudo-octahedral in
character, but with bis axial 1,8-N-propargyl π coordination
propargyl residues is unexpectedly replaced by an enol ether. It
would appear that hydroalkoxylation of the alkyne has
occurred to form an enol ether, 13, via reaction with the
methanol solvent. Recrystallisation of Cu(9) from other alco-
hols was investigated, but no corresponding hydroalkoxylation
reaction was observed in solvents other than methanol.
and trans-III macrocycle configuration (Fig.
9 and ESI
Fig. SX7b†). Residing on an inversion centre, the complex has
symmetrical and necessarily weak axial coordination bonds of
approximately 2.93 Å. Located on an inversion centre, the
unique metal to cyclam nitrogen distances are 2.028(2) and
2.125(2) Å (Table 2).
Both located on inversion sites, the structural features of
the pseudo octahedral trans-III 9C-2 dication are similar to
those of the pseudo octahedral trans-III 9B complex dication
(Table 2). Not surprisingly, the structural features of the
pseudo octahedral trans-I 9C-1 complex cation differ signifi-
cantly from those of the square pyramidal trans-I 9A perchlor-
ato complex cation.
High resolution mass spectrometry of material from the
same crystal batch supports the single crystal structure deter-
minations, returning molecular ion peaks at 223.60899,
224.11072,
224.60813,
and
225.10993
([M]2+
for
C23H36CuN4O2+ calculated as 223.60925, 224.11039, 224.60780,
225.10948) with the correct isotope patterns.
Differing in colour intensity, the asymmetric unit of 9D
contains a water molecule, while that of 9E instead contains a
methanol solvent molecule. While both have axial ether
coordination and a trans axial interaction with one of the two
perchlorate counterions, there is a significant difference in the
An unexpected enol ether
The fourth and fifth isolated crystal types, 9D and 9E (Fig. 10, nature of their respective perchlorate interactions. The axially
ESI Fig. SX8, SX9, and Table SX2†), were found to contain positioned perchlorate of 9D is ordered, while that of 9E is dis-
copper cyclam complex cations in which one of the pendant ordered. Further, the metal to perchlorate oxygen separation in
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Fig. 10 Olex2 depictions of the structures obtained from (a) crystal 9D and (b) crystal 9E of trans-I-[Cu(1-(2-methoxyallyl)-4,8,11-tri(prop-2-yn-1-
yl)-1,4,8,11-tetraazacyclotetradecane]2+, ([Cu(13)]2+). Displacement ellipsoids are shown at the 30% and 50% probability level respectively in (a) and
(b). The second perchlorate is not shown in both cases, and nor is a water molecule in crystal 9D and a methanol solvate in crystal 9E. Disorder is
highlighted with ‘faded’ colours. The formed enol ether 13 is depicted in (c).
Table 3 Selected bond lengths (Å) and angles (°) within the metal coordi-
nation sphere observed in structures of the complex [Cu(13)](ClO4)2,
9D and 9E
displaced 0.156(1) Å from the least squares plane defined by
the equatorial nitrogen atoms, −0.084(1) Å from the line
defined by one of the pairs of opposing nitrogen atoms (N1,
N3), and 0.395(1) Å from the second pair (N2, N4).
9D
9Ea
The cyclam nitrogen to copper to ether oxygen angles vary
in 9D from 74.34(11) to 101.07(11)°, and in 9E they range from
74.39(8) to 101.87(9)°. The metal to cyclam nitrogen distances
in 9D vary from 2.048(3) to 2.089(3) Å, and in 9E these dis-
tances span from 2.047(2) to 2.109(2) Å.
trans-I
trans-I
Cu–N1
Cu–N2
Cu–N3
Cu–N4
Cu–O (ether)
Cu–O (ClO4
N1–Cu–N2
N1–Cu–N3
N1–Cu–N4
N2–Cu–N3
N2–Cu–N4
N3–Cu–N4
N1–Cu1–O (ether)
N2–Cu1–O (ether)
N3–Cu1–O (ether)
2.078(3)
2.048(3)
2.089(3)
2.089(3)
2.574(2)
3.200(4)
95.16(13)
175.37(13)
85.52(13)
86.09(14)
161.59(12)
94.70(15)
74.34(11)
99.14(10)
101.07(11)
98.75(11)
85.92(12)
83.82(12)
98.65(12)
77.88(12)
2.084(2)
2.047(2)
2.109(2)
2.057(2)
2.607(2)
3.883(10)a
94.59(9)
175.42(9)
86.14(10)
85.51(9)
157.80(9)
95.51(10)
74.39(8)
101.87(9)
101.10(8)
99.69(8)
80.8(2)a
−
)
A mechanism for hydroalkoxylation
The intramolecular copper-mediated hydroalkoxylation event
observed and characterised by X-ray crystallography is an intri-
guing outcome. Although various examples of metal-catalysed
alkyne hydroalkoxylation reactions have been reported, rela-
tively few of these are intermolecular.48 The addition of alco-
hols to alkynes is typically achieved using a palladium cata-
lyst,49 however examples of copper-activated hydroalkoxylation
have been reported. Copper-catalysed intramolecular hydroalk-
oxylations have been used in the synthesis of benzofurans
other heteroaromatic systems.50,51 Bertz et al. reported a rare
example of intermolecular hydroalkoxylation, in which ethanol
was added to ethyl propiolate in the presence of copper(II)
sulfate to generate ethyl 3,3-diethoxypropionate.52 While Kang
and co-workers recently reported the related reaction of
N4–Cu1–O (ether)
−
N1–Cu1–O (ClO4−
N2–Cu1–O (ClO4−
N3–Cu1–O (ClO4−
N4–Cu1–O (ClO4
)
)
)
)
79.41(18)a
103.7(2)a
78.81(18)a
a Disordered perchlorate orientation with shortest metal to oxygen
distance.
9D is 3.200(4) Å, whereas the shortest metal to perchlorate exogenous primary amines (benzyl amine or n-propylamine)
oxygen distance in 9E is 3.883(10) Å (Table 3). While the latter with pendant alkyne arms on macrocyclic copper(II) and nickel
presumably reflects an electrostatic interaction, the shorter (II) complexes, thus achieving hydroamination of the alkyne
distance in 9D suggests some degree of covalent coordination. pendant.53 There are also parallels between the formation of
The copper to ether oxygen distance in 9D is 2.574(2) Å, [Cu(13)]2+ from [Cu(9)]2+ and the solvolysis of CuN bonds in
slightly shorter than in 9E at 2.607(2) Å. The two complex pendant N-alkylnitriles by macrocyclic copper(II) complexes
cations are distorted square pyramidal in character, though 9D reported by Barefield (hydrolysis of nitrile to amide),54 and
may be regarded as pseudo octahedral. The trigonal index (τ) Schröder (methanolysis of nitrile to imino-ether) and co-
of 9D is 0.23, while that of 9E is 0.29. The metal of 9D is dis- workers.55
placed 0.163(1) Å from the least squares plane defined by the
We postulate that the metal is required for the observed
equatorial nitrogen atoms, −0.084(1) Å from the line defined methanolysis of [Cu(9)]2+ to [Cu(13)]2+, as observed by
by one of the pairs of opposing nitrogen atoms (N1, N3), and Schröder and co-workers with their nitrile complexes,55 and
0.331(1) Å from the second pair (N2, N4). The metal of 9E is that solvolysis occurs after complexation. We have previously
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Scheme 3 Proposed mechanism for formation of enol ether complex [Cu(13)]2+ from the reaction of [Cu(9)]2+ with the solvent methanol. Top:
reaction via transient alkyne coordination to the metal, which enables attack by methanol on the π system; bottom: reaction to form a copper-alkox-
ide species via coordination of methanol to the metal, followed by nucleophilic attack of this on the uncoordinated alkyne (which approximates to
an allowed 5-exo-dig cyclisation).
reported a structure for ligand 9 from a crystal obtained by
evaporation of a methanolic solution of 9 in the presence of
KClO4, without any evidence of the methanolysis reaction. In
contrast, pure bulk Cu(9) undergoes this methanolysis reaction
when crystallised via slow evaporation from methanol
solution.
Table 4 Electronic absorption data for Cu(II) complexes of compounds
6–9 and 14 in CH3OH (unless otherwise indicated)
Complex
λmax/nm (ε/M−1 cm−1
)
[Cu(6)]2+
[Cu(7)]2+
[Cu(8)]2+
[Cu(9)]2+
[Cu(14)]2+
264 (6600), 536 (110)
303 (8240), 541 (180)
296 (7000), 606 (200)
307 (7700), 543 (220)
Late transition metal-catalysed alkyne hydroalkoxylation
reactions are usually envisaged to proceed via coordination of
the pendant π system to the metal, which activates the alkyne
316 (6500), 654 (290)a
a DMF used as solvent.
and enables nucleophilic attack by the alkoxy group.56,57
A
plausible mechanism for the formation of [Cu(13)]2+ from [Cu
(9)]2+ in this way is outlined in Scheme 3. However the struc-
tural data obtained for [Cu(9)]2+ reveal only weak coordination
between alkyne and the copper centre with ligand 9 in the
solid state (crystal 9B, Fig. 8), with the perchlorate counterion
competing for copper coordination with the alkyne (crystal 9A,
Fig. 7). This suggests either that transient alkyne coordination
to copper occurs to enable the attack by methanol (Scheme 3,
top path), or that the observed hydroalkoxylation follows an
alternative mechanism, perhaps via formation of a copper-alk-
oxide species through coordination of methanol to the copper,
and nucleophilic attack of this on the uncoordinated alkyne,
with perchlorate facilitating the required proton transfer
(Scheme 3, bottom path).
increases from the mono-N-functionalised [Cu(6)]2+, to the
complexes of the tetra-N-alkylated ligands 7–9. Little difference
in the d-d transition energy is observed between [Cu(7)]2+ and
[Cu(9)]2+, which suggests that any Cu(II)-propargyl interaction
which may occur is limited to two pendants. As expected, re-
placement of a propargyl group with a methyl ester in [Cu(8)]2+
results in a further red shift. The relative strength of the
coordination environments around the central Cu(II) ion
exhibited in the structural data (above) is consistent with the
d–d transition energies observed in the spectra, with the latter
increasing alongside the strength of pendant coordination.
Derivatisation of tetra-propargyl derivative 9
To demonstrate the utility of 9 as a precursor to more complex
tetra-functionalised cyclam derivatives, the ‘tetra-click’ tetra-
UV-visible spectroscopy
UV-visible spectra of Cu(II) perchlorate complexes of 6–9 in triazolyl cyclam species 14 was synthesised via a copper(I)-cata-
methanol were obtained; absorption maxima are presented in lysed azide–alkyne cycloaddition (CuAAC) of 9 with benzyl
Table 4. The electronic spectrum of each complex exhibits an azide (Scheme 4a). To minimise the sequestration of the
intense ligand-to-metal charge transfer (LCMT) band in the UV copper(I) catalyst by the macrocyclic starting material and
region (264–307 nm),58 alongside a comparatively weaker product, copper(I) iodide – relatively insoluble in most organic
absorption band in the visible region (536–606 nm) corres- solvents – was used as a heterogeneous catalyst. Monitoring
ponding to Cu(II) d–d transitions. λmax values for all transitions the reaction mixture via mass spectrometry indicated that
are typical of N-alkylated cyclam derivatives.37 A bathochromic sequestration of the catalyst did occur to some extent.
shift is observed as the number of functionalised amine However, the tetra-click product 14 could be isolated in moder-
3938 | Dalton Trans., 2021, 50, 3931–3942
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Scheme 4 Synthesis of ‘tetra-click’ tetra-triazolyl cyclam 14. Reagents and conditions: (i) benzyl azide 15, CuI, sodium ascorbate, DIPEA, THF, rt, 5
d, 30%; (ii) bromide 16, H2O/CH3CN (1 : 1), NaOH, rt, 16 h, 71%. See synthesis and characterisation section of the ESI† for further details.
ate yield (46% on 100 mg scale, 30% on 0.50 g scale) by collect-
ing the precipitate formed during the reaction and subjecting
this directly to flash column chromatography over silica.
Accordingly,
a convergent route to 14 was developed
(Scheme 4b), with a view that an increased yield could be
achieved if the CuAAC was conducted in the absence of the
cyclam. Bromide 16 was formed in two steps from benzyl
azide,59 and in the critical step, used to alkylate cyclam 1 in
good yield (71%).
The spectroscopic properties of 14 were investigated along-
side 9 for comparison. The stoichiometry of complexation of
both 9 and 14 with Cu(II) was investigated by UV-visible spec-
trophotometric titrations, and returned results that are consist-
ent with previous studies on similar cyclam ligands.21,28,37 The
UV-visible titration of 9 in methanol with Cu(ClO4)2 showed
the absorbances at 307 and 543 nm steadily increasing with
the addition of Cu(ClO4)2, to reach their maxima upon the
addition of one equivalent of Cu(II) (Fig. 11). No significant
increase in absorbance at either wavelengths was observed
with further addition of Cu(II). Similar observations were made
in the titration of 14 in DMF with Cu(ClO4)2 (Fig. 12). Job’s
Fig. 12 UV-visible spectrophotometric titrations of 14 (0.5 mM) with
Cu(ClO4)2 (50 mM) at intervals of 5 min in DMF at 25 °C, with inset enlar-
ging the region between 500–850 nm.
plot experiments confirmed each stoichiometric ratio to be
1 : 1 (Fig. S1, ESI†).
Conclusions
Four N-propargyl cyclam ligands have been synthesised and
their copper complexes investigated. To the best of our knowl-
edge, crystal B of [Cu(9)](ClO4)2 constitutes the first cyclam
derivative to exhibit intramolecular non-acetylide alkyne
coordination, although this coordination is weak. Several
ligand systems have been reported previously to exhibit mono-
meric η2-alkyne coordination,60,61 including the notable alkyne
‘cages’,62,63
and
organometallic
acetylide
cyclam
complexes.64,65 Xu and Chao prepared the Nd(III) complex of
tetra-N-propargyl cyclen, however none of the pendant alkynes
were coordinated to the metal in that complex.66 Similarly, a
variety of alkyne-containing cyclen-based lanthanoid com-
plexes investigated by Milne et al. did not exhibit alkyne
coordination to the metal.67 Ellis et al. successfully prepared a
series of alkyne-containing N-alkylated derivatives of the
9-membered N,N′,N″-1,4,7-triazacyclononane (TACN) ring
system but did not isolate any metal complexes,68 whereas
Fig. 11 UV-visible spectrophotometric titrations of 9 (0.1 mM) with Cu
(ClO4)2 (30 mM) at intervals of 5 min in CH3OH at 25 °C, with inset enlar-
ging the region between 450–700 nm.
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Baker et al. have reported a copper(I) complex of the smaller C13H26ClCuN4O4+ 400.09331, 401.09667, 402.09150, 403.09486,
TACN azamacrocycle with an intramolecularly-coordinated 404.08855, 405.09191 ([M
ClO4]+). Anal. calcd for
−
pendant alkyne.69 A search of the Cambridge Structural C13H26Cl2CuN4O8·CH3OH: C 31.56, N 10.51, H 5.68; found C
Database yields few examples of amine-bound metal ions with 31.74, N 10.77, H 5.48. Crystals suitable for single crystal X-ray
a coordinating alkyne connected through the chelator back- diffraction were readily grown by slow evaporation of a metha-
bone. Aurora et al. isolated a Cu(II) polyamido complex con- nolic solution of the complex.
taining a C-propargyl group which exhibited a weak apical
[Cu(7)](ClO4)2. Ligand 7 (20 mg, 0.072 mmol) and Cu
interaction between alkyne and metal with C–Cu distances of (ClO4)2·6H2O (27 mg, 0.072 mmol) were complexed according
2.805(4) and 2.737(4) Å.42 Seebald et al. recently reported the to the general complexation procedure to give [Cu(7)](ClO4)2 as
structure of a mono-N-propargyl cobalt(II) cyclam complex, a purple solid (33 mg, 81%). M.p. 131–134 °C (decomposed).
designed for use as an NMR probe,31 and there are a small UV-Vis (CH3OH) λmax/nm (ε/M−1 cm−1) 303 (8240); 541 (180).
number of other examples in the literature of more heavily IR νmax/cm−1 3504, 3243, 2936, 2269, 1653, 1477, 1370, 1340,
functionalised azamacrocycles bearing pendant N-propargyl 1072, 996, 956, 931, 861, 835, 797, 727, 673, 620, 537, 497, 469.
groups.53,70 Intramolecular η2-alkyne interactions were also HRMS (ESI+) m/z 466.14011, 467.14343, 468.13853, 469.14182,
recently observed in a series of coordinated lithium acetylide 470.13540, 471.13843 [M − ClO4]+; calcd for C18H32ClCuN4O4
+
complexes.71
466.14026, 467.14362, 468.13832, 469.14178, 470.13550,
In addition, we have isolated multiple crystals of [Cu(9)] 471.13886 [M − ClO4]+. Anal. calcd For C18H32Cl2CuN4O8·H2O:
(ClO4)2 from a single crystallisation, with each structure exhi- C 36.96, N 9.58, H 5.86; found C 37.12, N 9.51, H 5.51. Crystals
biting a unique coordination complex, configuration, or con- suitable for single crystal X-ray diffraction were readily grown
formation of the ligand 9. The formation of a collection of dis- by slow evaporation of
a solution of the complex in
tinct species from a single set of components suggests that the acetonitrile.
complexes are similar energetically.
[Cu(8)](ClO4)2. Ligand 8 (20 mg, 0.052 mmol) and Cu
Finally the ‘tetra-click’ reaction of 9 with benzyl azide to (ClO4)2·6H2O (19 mg, 0.052 mmol) were complexed according
form tetra-triazole 14 provides proof of concept for the to the general complexation procedure to give [Cu(8)](ClO4)2 as
straightforward derivatisation of the tetra-N-propargyl ligand a blue solid (26 mg, 77%). M.p. 118–121 °C (decomposed).
9, which will enable further developments in the design and UV-Vis (CH3OH) λmax/nm (ε/M−1 cm−1) 296 (7000); 606 (200).
synthesis of macrocyclic metal ion sensors, and target-acti- IR νmax/cm−1 3265, 2971, 2119, 1683, 1603, 1456, 1388, 1340,
vated metal complexes for biomedical applications.
1302, 1272, 1252, 1081, 991, 959, 930, 912, 808, 729, 672, 622.
HRMS (ESI+) m/z 548.14545, 549.14882, 550.14322, 551.14656,
522.14069, 553.14391 [M − ClO4]+; calcd for C22H34ClCuN4O6
+
548.14574, 549.14910, 550.14381, 551.14726, 552.14099,
553.14434 [M − ClO4]+. Anal. calcd for C22H34Cl2CuN4O10·H2O:
C 39.62, N 8.40, H 5.44. Found: C 39.99, N 8.28, H 5.24.
Experimental
Synthetic procedures
Synthetic procedures and characterisation data for ligands are Crystals suitable for single crystal X-ray diffraction were readily
detailed in the ESI.† grown by slow evaporation of a methanolic solution of the
Safety note: Perchlorate salts of metal complexes with complex.
organic ligands are potentially explosive. Only small amounts
[Cu(9)](ClO4)2. Ligand 9 (50 mg, 0.14 mmol) and Cu
of material should be prepared and these should be handled (ClO4)2·6H2O (52 mg, 0.14 mmol) were complexed according to
with caution.
the general complexation procedure to give [Cu(9)](ClO4)2 as a
General procedure for preparation of metal complexes. To a blue solid (69 mg, 80%). M.p. 118–120 °C (decomposed).
solution of N-functionalised cyclam (1.0 eq.) in EtOH (0.1 M) UV-Vis (CH3OH) λmax/nm (ε/M−1 cm−1) 307 (7700); 543 (220).
was added dropwise a solution Cu(ClO4)2·6H2O (0.8–1.0 eq.) in IR νmax/cm−1 3249, 2846, 1678. HRMS (ESI+) m/z 514.14048,
EtOH (0.1 M) at room temperature. The reaction mixture was 515.14370, 516.13816, 517.14129, 518.13563, 519.13916 [M −
+
heated at reflux for 1 h, cooled on an ice bath and the solvent ClO4]+; calcd for C22H32ClCuN4O4 514.14026, 515.14361,
was decanted. The remaining residue was washed with ice- 516.13845, 517.14181, 517.14181, 518.13550, 519.13886 [M −
cold EtOH (3 × 20 mL) and Et2O (3 × 20 mL), and dried in ClO4]+. Anal. calcd for C22H32Cl2CuN4O8: C 42.97, N 9.11, H
vacuo to give the desired metal complex.
5.25. Found: C 43.23, N 9.12, H 5.21. Spectrometric and
[Cu(6)](ClO4)2. Ligand (128 mg, 0.537 mmol) and elemental analyses were conducted on bulk material isolated
6
Cu(ClO4)2·6H2O (160 mg, 0.432 mmol) were complexed accord- from complexation in ethanol according to General Procedure
ing to the general complexation procedure (substituting MeOH for Preparation of Metal Complexes. The series of unique crys-
for EtOH) to give [Cu(6)](ClO4)2 as a purple-pink powder tals characterised by X-ray diffraction was obtained via slow
(173 mg, 80%). M.p. 264–265 °C. UV-Vis (CH3OH) λmax/nm (ε/ liquid–liquid diffusion (0.1 M aqueous solution of Cu(ClO4)2;
M−1 cm−1) 264 (6600); 536 (110). IR νmax/cm−1 3548, 3241, 0.1 M methanolic solution of 9) at room temperature over-
2929, 2888, 1632, 1429, 1367, 1297, 1236, 1057, 619. HRMS night. The described coloured crystal series was attained and
(ESI+) m/z 400.09330, 401.09699, 402.09102, 403.09476, identified by eye on all repeated attempts of the diffusion.
404.08847,
405.09208
([M
−
ClO4]+);
calcd
for Suitable single crystal specimens were selected from the crys-
3940 | Dalton Trans., 2021, 50, 3931–3942
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tallisation suspension and attached with Exxon Paratone N oil
to a short length of fibre supported on a thin piece of copper
wire inserted in a copper mounting pin.
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10 L. Fabbrizzi, F. Foti, M. Licchelli, P. M. Maccarini,
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Single crystal X-ray diffraction data were collected on an
Agilent SuperNova equipped with an Atlas CCD. The crystal
was harvested from amongst the diffusion supernatant, and
affixed to a thin mohair fibre attached to a goniometer head
with Exxon Paratone N. The crystal was quenched in a continu-
ous stream of dry N2 regulated by an Oxford Cryosystems
Cryostream at 150(2) K. Mirror monochromated Cu-Kα radi-
ation from a micro-source was used for data collection. Data
reduction and finalisation were conducted with CrysAlisPro.71
In general, structures were obtained using ShelXS and, in all
cases, extended and refined with ShelXL-2018/3.72
Computations and image generation were undertaken with the
assistance of the WinGX,73 ShelXle74 and Olex275 user inter-
faces. In general, all non-hydrogen atoms were modelled with
anisotropic displacement parameters, and a riding atom
model applied for hydrogen atoms.
12 G. Jens, W. Thomas and K. Burkhard, Curr. Org. Synth.,
2007, 4, 390–412.
CCDC reference numbers 2012628–2012634 and 2019803.†
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Conflicts of interest
There are no conflicts of interest to declare.
15 T. Hoppe, S. Schaub, J. Becker, C. Würtele and
S. Schindler, Angew. Chem., Int. Ed., 2013, 52, 870–873.
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Acknowledgements
We acknowledge and pay respect to the Gadigal people of the
Eora Nation, the traditional owners of the land on which we
research, teach and collaborate at the University of
Sydney. M. Yu was supported by a University of Sydney
International Scholarship (USydIS), and J. Batten by a Research
Training Program (RTP) Scholarship from the Australian
Government. We acknowledge the facilities and the scientific
and technical assistance of Sydney Analytical, a core research
facility at The University of Sydney, the Australian Research
Council for funding through Discovery Project grant
DP120104035, and Professor Cameron Kepert for crystallo-
graphic insights.
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