Self-assembly of a highly stable, topologically interesting metallamacrocycle by bridging gold(I) ions with pyridyl-2,6-diphenyl 2- and diphosphanes

Article abstract of DOI:10.1002/anie.200600794

(Figure Presented) A Moebius arrangement of the bonds directly attached to a metallamacrocycle was observed for the Au^I complex [Au ₃(CNC)(μ-Ph₂PCH₂PPh₂) ₂]⁺, which was self-assembled by treating the lithium salt of pyridyl-2,6-diphenyl^2- (CNC) with [Au₂Cl ₂(μ-Ph₂PCH₂PPh₂)]. The trinuclear Au^I complex has intramolecular Au...Au and C-C...π interactions, exhibits a remarkable stability in solution, and is cytotoxic toward cancer cell lines.

Full text of DOI:10.1002/anie.200600794

Angewandte
Chemie
CNC Ligands
DOI: 10.1002/anie.200600794
Self-Assembly of a Highly Stable, Topologically
Interesting Metallamacrocycle by Bridging
Gold(I) Ions with Pyridyl-2,6-diphenyl2À and
Diphosphanes**
Steven C. F. Kui, Jie-Sheng Huang, Raymond Wai-
Yin Sun, Nianyong Zhu, and Chi-Ming Che*
Metallamacrocycles constructed through self-assembly play
an important role in the development of molecular architec-
ture and topology.[1] There have been numerous reports on
fascinating molecular assemblies that consist of metallamac-
rocycles, from catenanes,[1a] pseudorotaxanes,[1a,c] and helica-
tes[1a,b,d] to molecular polygons/polyhedrons.[1d] The Möbius
strip is another intriguing topology that has attracted consid-
erable attention from chemists[2] but remains rarely seen in
synthetic molecular assemblies. Previous reports are almost
all confined to Möbius arrangements of electronic orbitals or
spins, including many theoretical studies on Möbius aroma-
ticity or delocalization,[2] together with the syntheses of a
Möbius aromatic hydrocarbon[3] and a magnetic Möbius
strip.[4] The synthesis of a molecular Möbius strip, an organic
molecule consisting of three crown ether rings, was first
realized in 1982.[5] Recently, a Möbius strip of NbSe3 single
crystals was reported.[6] Herein, we report the formation of a
molecular assembly that contains a highly robust metal-
lamacrocycle, with the bonds directly attached to the metal-
lamacrocycle adopting a Möbius arrangement.
We have been exploring the chemistry of gold complexes
with a pyridyl-2,6-diphenyl2À (CNC) ligand. Our previous
work led to the isolation of several AuIII–CNC complexes[7]
that contain the tridentate CNC ligand (see the inset of
Scheme 1). In the course of developing the chemistry of AuI–
CNC complexes, we conceived that [Li2(CNC)(tmeda)2] (1;
tmeda = N,N,N’,N’-tetramethylethylenediamine)[8] would be
a useful alkylating agent. Treatment of 1 with [Au(PCy3)Cl]
(Cy = cyclohexyl) in dry toluene gave [Au2(CNC)(PCy3)2] (2;
reaction 1, Scheme 1) in 80% yield. Complex 2 is thermally
stable and undergoes decomposition to give metallic gold at
> 3258C. The 31P NMR spectrum of 2 in CD2Cl2 shows one
Scheme 1. Syntheses of 2–4 from 1 (note the omission of the tmeda
ligands in 1 for clarity). The inset depicts the coordination mode of
the CNC ligand in previously reported gold complexes.
sharp singlet at d = 57.35 ppm. The X-ray crystal structure of
2[9] (see the Supporting Information) features a CNC ligand
that bridges two AuI ions, an unreported coordination mode
of the CNC dianion in its coordination chemistry.[10]
In view of the propensity of the CNC ligand to bridge AuI
ions, we envisioned that this ligand could have a unique
application in constructing AuI metallamacrocycles. Previ-
ously, a wide variety of AuI metallamacrocycles had been
prepared by employing isocyanide-, acetylide-, pyridine-,
carboxylate-, and phosphane-based bridging ligands,[11] nota-
ble examples of which are the singly and doubly braided
[2]catenanes reported by Puddephatt and co-workers.[11b,c]
Our strategy for constructing the metallamacrocycles
presented herein is through self-assembly from 1 and AuI–
diphosphane complexes (reactions 2and 3, Scheme 1). Reac-
tion of 1 with [Au2Cl2(m-dppm)] (dppm = bis(diphenylphos-
phanyl)methane) in dry toluene for 24 h gave a yellow
suspension. Removal of the solvent followed by extraction
with dry CHCl3 and slow evaporation of the CHCl3 extract
afforded [Au3(CNC)(m-dppm)2]Cl (3-Cl) as yellow crystals in
86% yield. Under similar conditions, the reaction of 1 with
[*] Dr. S. C. F. Kui, Dr. J.-S. Huang, Dr. R. W.-Y. Sun, Dr. N. Zhu,
Prof. Dr. C.-M. Che
ꢀ
[Au2Cl2(m-Ph2PC CPPh2)] resulted in the formation of [Au4-
ꢀ
(CNC)2(m-Ph2PC CPPh2)2] (4), which was isolated as yellow
Department of Chemistry and Open Laboratory of Chemical Biology
Institute of Molecular Technology for Drug Discovery and Synthesis
The University of Hong Kong
Pokfulam Road, Hong Kong (P.R. China)
Fax: (+852)2857-1586
crystals in 75% yield by diffusion of Et2O into a solution of
CHCl3. Treatment of 3-Cl with excess LiClO4 and LiPF6
produced [Au3(CNC)(m-dppm)2]ClO4 (3-ClO4) and [Au3-
(CNC)(m-dppm)2]PF6 (3-PF6), respectively, in about 95%
yield. In the solid state, complexes 3-Cl, 3-ClO4, and 3-PF6
exhibited a high thermal stability similar to that of 2; complex
4 is less stable and decomposed at 1508C and subsequently
gave metallic gold at 2508C.
E-mail: cmche@hku.hk
[**] This study was supported by The University of Hong Kong
(University Development Fund), the Hong Kong Research Grants
Council, and the University Grants Committee of the Hong Kong
SAR of China (Area of Excellence Scheme, AoE/P-10/01).
X-ray crystal-structure determinations of 3-Cl·8.5CHCl3,
3-PF6·CH2Cl2·5CHCl3, and 4·3CHCl3 revealed a 16-mem-
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
[9]
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bered C8NP4Au3 metallamacrocycle in 3 and a 26-membered
C16N2P4Au4 metallamacrocycle in 4 (see Figure 1 and the
Supporting Information). The Au atoms in 3 and 4 form a
{Au3} triangle and a {Au4} parallelogram, respectively, with
Figure 2. Arrangement of the bonds directly attached to the 16-
membered metallamacrocycle C8NP4Au3 of 3 along a Möbius strip. A
Möbius strip is a unique single-sided surface, as evident by following
the track of the arrows.
ring of the CNC ligand; closest H···C distances: 2.826 Š for 3-
Cl·8.5CHCl3 and 2.848 Š for 3-PF6·CH2Cl2·5CHCl3). For
each of the dimers in 3-Cl·8.5CHCl3, there are also four
À
À
intermolecular C H···p interactions that arise from the C H
bonds of four CHCl3 molecules (two inside and two outside
the dimers) and the nearest CNC phenyl rings (closest H···C
distances: 2.540 and 2.739 Š for the interactions outside and
inside the dimers, respectively).
Figure 1. Perspective structures of 3-Cl and 4 determined by X-ray
crystallography along with the metallamacrocycles in the two com-
plexes. For 4, there is a crystallographic center of symmetry located in
the center of the molecule.
The structure of 3 remains intact in solution, as revealed
by mass-spectrometric and NMR spectroscopic analysis; for
example, complex 3-Cl exhibits a prominent cluster peak at
m/z 1589 in the FAB mass spectrum, which is assignable to
[Au3(CNC)(m-dppm)2]+. The 31P NMR spectra of 3-Cl, 3-
ClO4, and 3-PF6 each show two multiplets (AA’BB’ system)
with d ꢁ 30 (P1 and P4) and 37 ppm (P2 and P3; assignment
based on the 31P, 1H HOESY NMR spectra shown in the
Supporting Information), which is consistent with the C2-
symmetic structure of the molecule of 3. In the 1H NMR
spectra of 3-Cl, 3-ClO4, and 3-PF6, the Ha signal (d ꢁ 1.2ppm)
is substantially upfield from that of Hb (d ꢁ 4.0 ppm; see the
Supporting Information for an example), a phenomenon
attributable to the shielding of Ha by the phenyl ring of the
CNC ligand. The NOESY NMR spectrum of 3-Cl shows a
cross peak between Ha and H3 (see the Supporting Informa-
intramolecular Au···Au contacts of 3.015(29)–3.040(29) Š for
3 (Au1···Au2, Au2···Au3) and 3.178(10) Š for 4 (Au1···Au2,
Au1’···Au2’), which fall within the range of 2.9–3.2 Š expected
for the occurrence of weak AuI···AuI interactions.[12] The Au
C bond lengths of 2.034(14)–2.070(16) Š in 3 and 2.077(39)–
2.091(14) Š in 4 are comparable to those in 2 (2.053(9)–
2.059(13) Š).
À
Interestingly, the bonds directly attached to the 16-
membered metallamacrocycle C8NP4Au3 in
3 adopt a
Möbius arrangement. The Möbius strip that passes through
À
À
the C8NP4Au3 ring and the P C and C C bonds directly
attached to the ring is depicted in Figure 2. As a Möbius strip
is chiral, the crystal structure of 3 contains pairs of P and
M enantiomers (see the Supporting Information), thus ren-
dering 3 to be racemic.
À
tion). These data are in agreement with the intramolecular C
H···p interactions in the crystal structures of 3-Cl and 3-PF6.
In contrast, the 26-membered metallamacrocycle
C16N2P4Au4 in 4, which consists of a pair of P- and M-
[Au2(CNC)P2] moieties,[13] exhibits a fluxional behavior in
solution. This is evident from the variable-temperature
1H NMR (60 to À538C)[14] and 31P NMR spectra of 4 in
CDCl3 (see the Supporting Information for further details).
We propose that 4 is partially changed to its conformer 5 upon
dissolution in CDCl3, and there is an equilibrium between 4
and 5 in solution (Figure 3).[15] Indeed, the EXSY spectrum of
Further examination of the structures of 3-Cl·8.5CHCl3
and 3-PF6·CH2Cl2·5CHCl3 revealed the existence of intra-
À
molecular C H···p interactions, as indicated by the close
contacts (2.787–3.113 Š) between one of the methylene
hydrogen atoms in each dppm ligand (see the Supporting
Information) and the carbon atoms of the nearest phenyl
rings of the CNC ligand. In both crystal structures, 3 exists as
dimers, each of which consists of a pair of P and M enan-
À
tiomers linked by two intermolecular C H···p interactions (a
3
3
4
4
5
5
À
À À À
4 at À538C shows cross signals of H H ’, H H ’, H H ’,
C H bond of a dppm phenyl group with the nearest phenyl
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Angewandte
Chemie
variant CNE1, with a resist-
ance factor of 1.2(IC
(CNE1)/IC50(SUNE1)
-
50
ratio) less than one third of
that observed for cisplatin
(3.9). The IC50 value of 3-Cl
for normal human cells
CCD-19Lu was determined
to be 19.1 mM, thus indicat-
ing that this AuI compound
is 2.3–2.9-fold less toxic to
normal cells than to the
forging cancer cells.
In summary, we have
observed a new coordina-
tion mode of the pyridyl-
2,6-diphenyl2À ligand and
isolated two AuI compounds
that contain unprecedented
types of gold metallamacro-
cycles. Both types of metal-
lamacrocycle have intramo-
À
Figure 3. Proposed conformational changes of 4 in solution viewed from the top (upper) and side (lower) of
the molecules. The structure of 5 was built using Chem3D 5.0 on the basis of the crystal structure of 4.
lecular AuI···AuI and
C
6
6
8
8
À
À
À
H
H ’, H H ’, and Ph Ph’ pairs (see Figure 3 and the
H···p interactions; the metallamacrocycle with stronger
I
I
À
Supporting Information), together with the cross signals that
possibly arise from the exchanges between 4 and 5, in
accordance with the conformational changes shown in
Figure 3. Notably, the H3, H4, and H3’ signals of 4 (d = 5.7–
6.3 ppm) are considerably upfield from the corresponding
signals of 3 (d ꢁ 6.9–7.1 ppm), which could result from
Au ···Au and C H···p interactions is highly robust in solution
and shows interesting topological and cytotoxic properties,
whereas the other exhibits a unique fluxional behavior in
solution. The present work demonstrates that polydentate
cyclometalating ligands, such as pyridyl-2,6-diaryl2À, together
with AuI could be useful for constructing new classes of
molecules with unprecedented topology and properties.
À
intramolecular C H···p interactions (see the Supporting
À
Information). Such C H···p interactions do not exist in 5,
Received: March 1, 2006
Published online: June 22, 2006
consistent with the downfield shift of these signals, partic-
ularly for H3, upon increasing temperature (which increases
the 5/4 molar ratio).
Keywords: aurophilicity · gold · metallacycles · Möbius strip ·
Complexes 3-Cl, 3-ClO4, and 3-PF6 are remarkably stable
both in organic solvents (such as CH2Cl2, CHCl3, dimethyl-
formamide (DMF), and dimethylsulfoxide (DMSO)) and
under physiologically relevant conditions (see the Supporting
Information). The high stability of 3-Cl in solution relative to
most self-assembled polynuclear AuI compounds, including 4
(which decomposed within several days in a solution of CHCl3
at room temperature), prompted us to examine its cytotoxic
properties; gold compounds not only have long been used as
antiarthritic drugs but also are promising antitumor agents,[16]
and stability is an important issue in the design of new AuI
therapeutic agents. The cytotoxicities of 3-Cl toward cancer
cell lines (including cervical epithelioid carcinoma (HeLa)
and nasopharyngeal carcinoma (SUNE1 and its cisplatin-
resistant variant CNE1)) and normal lung fibroblast cells
(CCD-19Lu) were determined by the 3-(4,5-dimethylthiazol-
2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. From
the cytotoxicity profiles (see the Supporting Information), the
corresponding IC50 values (dose required for the inhibition of
50% cellular growth) of the cancer cell lines were determined
to be 6.53–8.20 mM, which are comparable to those of the
clinically used cisplatin (IC50 = 14.8 (HeLa), 2.3 (SUNE1),
and 8.9 mM (CNE1)). Importantly, 3-Cl was found to be
almost equally cytotoxic to SUNE1 and its cisplatin-resistant
.
structure elucidation
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Communications
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[13] Although it is possible to generate the P,P or M,M analogues of
4, no such structures were observed. Modeling studies revealed
that the P,P or M,M structure renders all the phenyl groups of
the two diphosphane ligands in an unfavorable eclipsed arrange-
ment, in contrast with the favorable staggered arrangement of
the phenyl groups of each diphosphane ligand in 4 (see the
Supporting Information). The molecules of 4 in the crystal
À
structure are linked by intermolecular C H···p interactions (a
À
C H bond of a dppm phenyl group with the nearest dppm
phenyl ring; closest H···C distances: 2.841 Š) to give 2D sheets.
[14] Further decrease in temperature resulted in freezing of the
CDCl3 solvent, which, together with the poor solubility of 4 in
other solvents, hampered NMR measurements at lower than
À538C.
[15] No molecules of 5 were observed in the crystal structure of 4.
The molecular symmetry of 4 (Ci) and 5 (C2h) would result in the
appearance of two singlets and one singlet, respectively, in their
31P NMR spectra. The observation of only one singlet at 08C or
above (see the Supporting Information) could arise from the
rapid conformational changes depicted in Figure 3. Lowering the
temperature to À408C causes the signals of
4 (d = 17.8,
14.7 ppm) and 5 (d = 17.0 ppm) to be resolved. The change
from 4 to 5 can be effected by breaking the AuI···AuI interactions
(note the longer AuI···AuI contact of 3.178(10) Š in 4 than that of
3.015(29)–3.040(29) Š in 3), accompanied by intramolecular
ꢀ
rotations to render the phenyl groups of each Ph2PC CPPh2
ligand in an eclipsed arrangement. Therefore, 5 should be
energetically less favored than 4, consistent with the increase in
the amount of 4 but decrease in the amount of 5 upon lowering
the temperature (see the Supporting Information).
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