Conformational regulation of multivalent terpyridine ligands for self-assembly of heteroleptic metallo-supramolecules

Article abstract of DOI:10.1021/jacs.0c06618

A two-ligand system composed of the predesigned multivalent and complementary terpyridine-based ligands was exploited to construct heteroleptic metallo-supramolecules and to investigate the self-assembly mechanism. Molecular stellation of the trimeric hex

Full text of DOI:10.1021/jacs.0c06618

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Article
Conformational Regulation of Multivalent Terpyridine Ligands
for Self-Assembly of Heteroleptic Metallo-Supramolecules
Shi-Cheng Wang, Kai-Yu Cheng, Jun-Hao Fu, Yuan-Chung Cheng, and Yi-Tsu Chan
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 03 Sep 2020
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Conformational Regulation of Multivalent Terpyridine Ligands for
Self-Assembly of Heteroleptic Metallo-Supramolecules
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Shi-Cheng Wang, Kai-Yu Cheng, Jun-Hao Fu, Yuan-Chung Cheng, and Yi-Tsu Chan*
Department of Chemistry, National Taiwan University, Taipei 10617, Taiwan
ABSTRACT: A two-ligand system composed of the predesigned multivalent and complementary terpyridine-based ligands was
exploited to construct heteroleptic metallo-supramolecules and to investigate the self-assembly mechanism. Molecular stellation
of the trimeric hexagon [Cd6L2 ] gave rise to the exclusive self-assembly of star hexagon [Cd18L16L3 ] through complementary ligand
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pairing between the ditopic and octatopic tectons. To understand how the intermolecular heteroleptic complexation influenced
the self-assembly pathway, the star hexagon was truncated into two triangular fragments, [Cd12L13L4 ] and [Cd12L13L5 ]. In the self-
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assembly of [Cd12L13L4 ], the conformational movements of hexatopic ligand L4 could be regulated by L1 to promote the subsequent
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coordination event, which was the key step to the successful multicomponent self-assembly. In contrast, the formation of
[Cd12L13L5 ] was hampered by the geometrically mismatched intermediates.
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dimethoxyphenyl)tpy and unsubstituted tpy ligands can af-
INTRODUCTION
ford a sole heteroleptic complex upon addition of CdII ions un-
Cooperative self-assembly prevails ubiquitously in construc-
der ambient conditions.12c The complementary ligand pair of-
tion and modulation of functional biomacromolecules in na-
fers facile access to preparation of discrete metallomacrocy-
ture.1 The cooperativity typically involves conformational reg-
cles as well as metallocages via multicomponent self-assem-
ulation of receptors2 or configurational pre-organization of
bly.12e,17
two or more building blocks3 to either increase or decrease
To elucidate the importance of conformational regulation of
multivalent ligands by intermolecular heteroleptic complexa-
tion, which resembles cooperative self-assembly in nature,
herein we design and synthesize a suite of multivalent ligands
L2−L5 and investigate the interplay in assembling with the
binding affinity in subsequent binding events. The bio-in-
spired molecular design with cooperativity has been demon-
strated in creation of artificial systems for applications in mo-
lecular recognition,4 catalysis,5 ion sensing,6 etc. Besides, such
a strategy could be applied to synthesis of sophisticated supra-
molecules in a well-controlled manner.7 However, it still re-
mains a challenge to rationally design molecular building
blocks for manipulation of inter- and intramolecular coopera-
tive interactions.
complementary ligand L1. The star hexagon [Cd18L16L3 ] con-
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sisting of the hexagonal core [Cd6L2 ] is constructed in excel-
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lent yield via one-pot heteroleptic complexation. The self-as-
sembly behavior of triangular fragments [Cd12L13L4 ] and
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[Cd12L13L5 ] derived from [Cd18L16L3 ] is examined by titration
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Well-defined metal-ligand coordination geometry provides
directional bonding to assemble molecular subcomponents in
a preprogrammed way, which is a promising approach for con-
struction of metallo-supramolecules.8 Aiming to further en-
hance geometrical diversity and complexity of assemblies,
comprehension of self-assembly mechanisms9 and develop-
ment of high-fidelity molecular recognition tools are essential
for preventing the formation of undesired products in a mul-
ticomponent system. Hence, several self-selective coordina-
tion strategies have been developed for mono-,10 bi-,11 and tri-
dentate12 ligands to fulfill the requirements. Among them, a
variety of multivalent 2,2':6',2''-terpyridine (tpy)-based ligands
can be obtained by palladium-catalyzed cross coupling reac-
tions,13 and serve as subcomponents for self-assembly of giant
metallo-supramolecules.14 In the supramolecular chemistry of
metal-tpy complexes, a stepwise approach is commonly used
to prepare predesigned metalloligands in order to eliminate
mismatched assemblies during self-assembly.8e,15 Nevertheless,
towards elevating the degree of molecular self-sorting,16 we
have demonstrated that an equimolar mixture of 6,6''-di(2,6-
experiments. The result indicates that the selective intermo-
lecular complexation between L1 and L4 leads to an appropri-
ate conformation of tetratopic intermediate [Cd2L1L4], which
allows for the formation of the desired product.
RESULTS AND DISCUSSION
6,6''-Substituted bis-tpy ligand L1 was prepared following the
reported protocol.12e Multivalent ligands L2, L3, L4, and L5
(Scheme 1) were synthesized through a series of Pd-catalyzed
Sonogashira and Suzuki-Miyaura coupling reactions
(Schemes S1-S4), and the structural characterization was care-
fully done by NMR spectroscopy (Figures S1-S25) and high-
resolution MALDI-TOF mass spectrometry (Figures S30-S33).
The self-assembly experiment started with the tetratopic lig-
and L2, which was reacted with 2 equiv of Cd(NO3)2 in
CHCl3/MeOH (1/1, v/v) at 25 °C for 30 min. The reaction mix-
ture was counterion-exchanged with excess NH4PF4, and then
stirred at 25 °C for additional 30 min (Figure 1a). After com-
1
plexation, the H NMR spectrum of the resultant complex
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Scheme 1. Chemical Structures and Cartoon Representations of Ligands L1, L2, L3, L4, and L5
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remained sharp and well split. In the aromatic region, in con-
trast to the downfield shifts of most of the signals, two dou-
blets from 6.6''-tpy protons exhibited significant upfield shifts,
indicating the formation of the octahedral coordination ge-
ometry of <tpy-CdII-tpy> connectivity.18 Two sets of tpy signals
with an integration ratio of 1:1 could be identified by using
COSY and ROESY NMR techniques (Figures S37 and S38). Par-
ticularly, in the ROESY spectrum, the singlet from Hi showed
the correlation signal to the purple-labelled phenylene pro-
tons Hb so that two types of the bistpy complexes in the as-
sembly could be unambiguously assigned. The methoxy
groups (Hj) and tert-butyl groups (Hk) still revealed sharp sin-
glets after complexation (Figure S35), supporting the for-
mation of a highly symmetric structure. In addition, the two
113Cd NMR singlets at δ 268.80 and 267.77 ppm clearly indi-
cated that the self-assembly has two kinds of CdII centers (Fig-
ure S55). All the related peaks in the DOSY spectrum pos-
sessing the same diffusion coefficient (D = 3.29 × 10-10 m2 s−1)
proved the formation of a single self-assembled structure in
solution (Figure S51).
High-resolution electrospray ionization mass spectrometry
(HR-ESI-MS) was used to verify the chemical composition of
the complex. The ESI spectrum showed one series of peaks in
Figure 1. (a) Self-assembly of trimeric hexagon [Cd6L2 ] and
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1H NMR spectra of L2 and [Cd6L2 ]. (b) ESI-MS spectrum of
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[Cd6L2 ] and isotope pattern of [M − 5PF6]5+.
agreement with the ions of trimeric hexagon [Cd6L2 ] at
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charge states from 5+ to 10+ (Figure 1b). In addition, elec-
2a) displayed two kinds of chemical environments for ligand
L1. Particularly, the peaks for the 3′,5′-tpy protons and the 2,6-
dimethoxyphenyl substituents (He and Hf) were split into two
signals with an integration ratio of 1:1, suggesting the for-
mation of two distinct heteroleptic complexes. The proper as-
signments for six sets of tpy protons, including two homolep-
tic and two heteroleptic complexes, were verified by COSY
and ROESY experiments (Figures S39−S42). It is noteworthy
that two triplets from the blue and green 5,5''-tpy protons of
L3 were assigned according to the ROESY spatial correlation
with methoxy groups Hg of L1, and the two heteroleptic con-
nections were distinguished by the correlation with t-butyl
groups Hh of L3 (Figure S42). Relative to the uncomplexed L3,
the blue and green 3′,5′-tpy protons exhibited significant up-
field shifts due to the shielding effect deduced from the 2,6-
dimethoxyphenyl substituents;12c on the other hand, the or-
ange and purple 3′,5′-tpy protons showed downfield shifts be-
cause of coordination to the electron-deficient CdII ions (Fig-
ure 2a). Consistently, the 113Cd NMR analysis (Figures 2a and
S56) revealed two signals at δ 271.83 and 271.21 ppm and two
peaks at δ 242.66 and 242.06 ppm with a 1:2 integration ratio,
corresponding to the homoleptic and heteroleptic connec-
tions, respectively. The DOSY NMR spectrum indicated the
existence of a sole species with D = 1.36 × 10-10 m2 s−1 in CD3CN
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trospray ionization coupled with traveling wave ion-mobility
mass spectrometry (ESI-TWIM-MS) was utilized to obtain ad-
ditional structural information.19 The ESI-TWIM-MS plot of
[Cd6L2 ] demonstrated a narrow drift time distribution for
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each charge state, indicating the absence of isomeric struc-
tures (Figure S61).20 The consistent correlation between the
experimental and theoretical collision cross-sections (CCSs)
supported the presence of the proposed structure (Figure S63
and Table S2).
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In geometrical stellation,21 a star hexagon can be produced by
extending the edges of a hexagon until they intersect to form
the new closed boundaries. Based on the successful self-as-
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sembly of [Cd6L2 ], we anticipated that a more complicated
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star-shaped metallo-supramolecule would be achieved
through the complementary ligand pairing12c,12e between lig-
ands L1 and L3. As compared with L2, octatopic ligand L3 has
four additional coordination units to pair with L1 to form the
external triangles. The complexation reaction of L1, L3, and
CdII ions in a precise molar ratio of 2:1:6 was conducted to ex-
amine the multicomponent self-assembly process. As ex-
pected, the 1H NMR spectrum of the resultant complex (Figure
(Figure S52). Eventually, the formulation of [Cd18L16L3 ] was
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confirmed by eleven ESI-MS peaks derived from 11+ to 21+ ions
(Figure 2b). In the ESI-TWIM-MS plot (Figure 2c), a single
stair pattern with narrow drift time distributions implied that
a discrete and rigid molecular star was assembled. The exper-
imental average CCS also agreed well with the theoretical av-
erage CCSs generated from 300 simulated conformations (Fig-
ure S64 and Table S3).
To shed light on the self-assembly mechanism of [Cd18L16L3 ],
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the star-shaped complex was chopped into two triangular
fragments (Scheme 2) and their self-assembly processes were
examined. Ligands L4 and L5 were synthesized by attaching
two 4-terpyridylphenyl units at para and ortho positions with
respect to the purple-labelled 4-terpyridylphenyl substituents,
respectively (Scheme 1). For construction of [Cd12L13L4 ], the
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hexatopic ligand L4 was assembled with L1 in the presence of
CdII ions. It was found that the desired triangle was produced
in excellent yield under mild conditions.
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The H NMR characterization (Figure 3a) of [Cd12L13L4 ] ex-
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hibited three significant upfield shifts for the 2,6-dimethoxy-
phenyl protons (He and Hf) of L1 and the blue-labelled 3',5'-tpy
portons of L4 as compared to the uncoordinated L1 and L4,
which were similar to the observation in [Cd18L16L3 ] that indi-
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cated the formation of the heteoleptic connectivity. The ex-
clusive formation of the target complex was confirmed by five
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distinct H NMR singlets at δ 9.04 (purple 3',5'-tpy Hs of L4),
9.02 (3',5'-tpy Hs of L1), 8.93 (orange 3',5'-tpy Hs of L4), 8.47
(blue 3',5'-tpy Hs of L4), and 4.32 (OCH3 of L4) ppm as well as
three 113Cd NMR peaks at δ 270.91, 269.98, and 241.35 ppm de-
rived from two homoleptic and one heteroleptic CdII nuclei
(Figures 3a and S57). The complete assignments were estab-
lished by COSY and ROESY NMR (Figures S43-S46). The
DOSY NMR spectrum (Figure S53) showed that all the rele-
vant signals have the same diffusion coefficient (D = 2.89 × 10-
10 m2 s−1). The assembled composition of [Cd12L13L4 ] was une-
Figure 2. (a) Self-assembly of star hexagon [Cd18L16L3 ] and 1H
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NMR spectra of L3, [Cd18L16L3 ], and L1. The inset is the 113Cd
quivocally determined by the intense ESI-MS peaks generated
from the 8+ to 16+ ions (Figure 3b), and its experimental aver-
age CCS of 1965.6 ± 7.6 obtained from the TWIM-MS analysis
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NMR spectrum of [Cd18L16L3 ]. (b) ESI-MS spectrum and (c)
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ESI-TWIM-MS plot of [Cd18L16L3 ].
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(Figure S62) was consistent with the modeled ones (Figure S65
and Table S4).
experiment was designed for the mechanistic study. Instead of
using 4 equiv of CdII ions, 2 equiv were applied to trapping the
intermediate species. An equimolar mixture of L1 and L4 was
reacted with 2 equiv of Cd(NO3)2. The ESI-MS spectrum
showed two peaks generated form the 3+ and 4+ ions of
[Cd2L1L4] (Figure S59a), implying that two heteroleptic con-
nections between L1 and L4 were formed. Due to the geomet-
rical complementarity, the blue-labelled tpy moieties of L4
were supposedly pinched by L1 to afford the tetratopic species
[Cd2L1L4] (Scheme 3a) where the internal rotation of the outer
coordination sites of L4 relative to the central scaffold was
hampered by the dinuclear ring. The restricted conformation
would facilitate the following cooperative coordination to
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Scheme 2. Self-Assembly of Triangular Fragments
[Cd12L13L4 ] and [Cd12L13L5 ]
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form complex [Cd12L13L4 ] because the entropy loss from the
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frozen rotation has been satisfied by the intermolecular het-
eroleptic complexation. The UV-vis titration was conducted to
further corroborate the proposed two-step mechanism. In-
deed, an isosbestic point at 326 nm was observed with increas-
ing amount of CdII up to 2 equiv, indicating the equilibrium
between the uncomplexed ligand mixture and intermediate
[Cd2L1L4] (Figure S60a). The isosbestic point was slightly
shifted to 321 nm by further addition of CdII to the stoichio-
metric point, suggesting that a new equilibrium between in-
termediate [Cd2L1L4] and triangle [Cd12L13L4 ] was established
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(Figure S60b).
To reflect how the restricted conformation of [Cd2L1L4] influ-
ences the stability of the trimeric hexagonal core held by six
homoleptic CdII connections, complexes [Cd6L2 ] and
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[Cd12L13L4 ] in CD3CN (1.2 × 10-4 M) were titrated with Cd(OTf)2,
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respectively (Figures S68-S70). The H NMR analyses indi-
cated that [Cd6L2 ] was completely dissociated into [Cd4L2]
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when 12 equiv of Cd(OTf)2 with respect to each homoleptic
CdII center were added. By contrast, 32 equiv of Cd(OTf)2 were
The complexation reaction of L1 (1 equiv), L5 (1 equiv), and
CdII ions (4 equiv) was conducted at 60 °C to construct
needed to fully break up [Cd12L13L4 ] into [Cd6L1L4]. Since
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[Cd12L13L4 ] and [Cd6L2 ] have the same core structure, the en-
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[Cd12L13L5 ] (Scheme 2). However, the resultant complex ex-
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hanced stability of [Cd12L13L4 ] could be attributed to its L1-
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regulated conformation. The self-assembly of [Cd12L13L4 ]
hibited relatively poor solubility in common organic solvents,
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such as MeOH, MeCN, and MeNO2. The H NMR spectrum
might be involved in chelate and/or interannular cooperativ-
ity,22 but a more detailed investigation of each isolated bind-
ing event is required to quantitatively identify the real occur-
rence.
(Figure S47) showed broad signals, which could not be
properly identified and displayed multiple diffusion distribu-
tions (D = 4.47~4.90 × 10-10 m2 s−1) in the DOSY experiment
(Figure S54). The corresponding hydrodynamic radii were
much smaller than those of [Cd6L2 ], [Cd12L13L4 ], and
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[Cd18L16L3 ] (Table S1). The ESI-MS spectrum (Figure S58) re-
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vealed that at least two species [Cd12L13L5 ] and [Cd10L14L5 ]
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were formed in the self-assembly process.
Given the aforementioned observations, the self-assembly of
triangular fragments were significantly influenced by the po-
sition of the extra tpy units. To exclude the possibility of form-
ing prevailing conformations, the theoretical AM1 semi-em-
pirical method was applied to evaluate the rotational barriers
around the pivotal arene and the triple bond (black benzene
rings labelled with e and g in Scheme 1) for ligands L4 and L5,
respectively (Figures S66 and S67). The theoretical calcula-
tions showed that in both cases the rotational barriers around
the triple bond are low (< 2.2 kcal/mol) and the side groups
should be freely rotatable at the room temperature. Our pre-
vious study indicated that the substituted tpy ligand has a
higher binding affinity to CdII ions.12c Hence, in the presence
of an insufficient amount of CdII ions, the formation of hetero-
leptic connections should dominate over that of homoleptic
ones. Based on this assumption, the stoichiometry-controlled
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Figure 3. (a) H NMR spectra of L4, [Cd12L13L4 ], and L1. The
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inset is the 113Cd NMR spectrum of [Cd12L13L4 ]. (c) ESI-MS
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spectrum of [Cd12L13L4 ] and isotope pattern of [M − 10PF6]10+
.
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To gain insights into the kinetic aspect, the ligand exchange
Scheme 3. (a) Proposed Self-Assembly Pathway for
[Cd12L13L4 ] and (b) Possible Structure of [Cd2L1L5]
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reaction between
a mononuclear heteroleptic complex
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([CdLALB](PF6)2) and a free 6,6''-di(2,6-dimethoxyphenyl)tpy
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ligand (LA) was investigated by H exchange spectroscopy
(EXSY) NMR experiments (Figure S71). The exchange rate (kex)
was estimated to be 1.6 × 10-2 s-1 at 25 °C in CD3CN/CDCl3 (1/1,
v/v), which is similar to that (1.9 × 10-2 s-1) between [Pd(py)4]2+
(py = pyridine) and free pyridine in CD3CN.23 Even though the
exchange rate for monotopic ligands is fast, the misassembled
yet stable intermediates deduced from multivalent ligand L5
and ditopic ligand L1 still interrupted the self-assembly of
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[Cd12L13L5 ].
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CONCLUSIONS
In summary, a family of multivalent tpy-based ligands L2-L5
were successfully synthesized through Pd-catalyzed cross cou-
plings and utilized to study the complementary interplay with
L1. The self-assembly of trimeric hexagon [Cd6L2 ] was
3
achieved under mild conditions and served as a basis for the
following molecular stellation. The star hexagon [Cd18L16L3 ]
3
On the other hand, when a 1:1 mixture of L1 and L5 was treated
with 2 equiv of Cd(NO3)2, the ESI-MS study showed the for-
mation of [Cd2L1L5] (Figure S59b). However, in comparison
with [Cd2L1L4], no matter where the heteroleptic complexa-
tion occurred, the intermediate [Cd2L1L5] would hinder the
was constructed via multicomponent self-assembly and its
structure was established by NMR, ESI-MS, and ESI-TWIM-
MS. To understand the assembly mechanism, the self-assem-
bly behavior of two triangular fragments derived from
[Cd18L16L3 ] was investigated by trapping possible intermedi-
3
self-assembly of target triangle [Cd12L13L5 ] upon treatment
3
ates and titration experiments. The mechanistic study mani-
fested that the intermolecular heteroleptic complexation of L4
or L5 with L1 plays a pivotal role in construction of the corre-
sponding triangles. The conformational regulation of L4 by L1
could facilitate the formation of the desired triangle
with additional CdII ions. The possible structure of [Cd2L1L5]
was illustrated in Scheme 3b, where the orange and purple tpy
units of L5 were complexed with L1 to generate a distorted di-
nuclear macrocycle. Accordingly, the model compound L6 was
synthesized to verify whether the heteroleptic complexation
with L1 could take place to produce the geometrically mis-
matched macrocycle (Figure 4 and Scheme S5). Notably, the
complexation reaction of L1 and L6 with CdII at 25 °C afforded
[Cd12L13L4 ] whose assembly process exhibited cooperative co-
3
ordination. On the other hand, the geometrically mismatched
intermediates impeded the self-assembly pathway leading to
[Cd12L13L5 ]. We anticipate that this study would lay the foun-
3
a mixture of [Cd2L1L6] (minor) and [Cd4L12L6 ] (major) (Figure
2
dation for rationally manipulating metal-mediated coopera-
tive interactions.
S48). After 1 h of heating at 80 °C, the mixture was completely
converted into [Cd2L1L6] whose structure was established by
NMR and ESI-MS (Figures 4 and S48-S50).
ASSOCIATED CONTENT
Supporting Information.
The Supporting Information is available free of charge on the
ACS Publications website at DOI:
Experimental details and characterization data (PDF)
Videos S1-S3: Energy-minimized models of [Cd6L2 ],
3
[Cd18L16L3 ], and [Cd12L13L4 ] (MOV)
3
3
AUTHOR INFORMATION
Corresponding Author
*ytchan@ntu.edu.tw
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This research was supported by the Ministry of Science and
Technology of Taiwan (MOST106-2628-M-002-007-MY3). We
gratefully thank Ms. S.-L. Huang at MOST (National Taiwan
University) for the assistance in NMR experiments.
Figure 4. Self-assembly and 1H NMR spectrum of the distorted
dinuclear macrocycle, [Cd2L1L6].
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