Biindole-bridged porphyrin dimer as allosteric molecular tweezers

Article abstract of DOI:10.1002/chem.200901988

A multiple-guest-binding molecular tweezers that exhibits notably strong positive allosteric guest binding phenomena has been reported. Tweezers-type zinc porphyrin dimer and biindole-conjugated monomeric porphyrin were synthesized and characterized H NMR

Full text of DOI:10.1002/chem.200901988

DOI: 10.1002/chem.200901988
Biindole-Bridged Porphyrin Dimer as Allosteric Molecular Tweezers
Chi-Hwa Lee, Hongsik Yoon, and Woo-Dong Jang*[a]
Molecular tweezers are a class of synthetic receptors with
open cavities, capable of binding guests using non-covalent
interactions, such as hydrogen bonding, metal coordination,
p–p interactions, and van der Waals forces.[1] The design of
synthetic receptors is an important issue in supramolecular
chemistry. Typically, the design of the anion-binding recep-
tor is attracting increased attention because many anions
play critical roles in chemical and biological processes.[2] Hy-
drogen bonding and electrostatic interactions allow the
binding and transport of anions in biological systems, such
as sulfate- and phosphate-binding proteins.[3] Recently, sev-
eral indole-based anion receptors have been reported, in
which the -NH protons in the indole moieties bind strongly
to several anions through hydrogen bonds.[4] On the other
hand, it is well known that zinc porphyrin works as a Lewis
acid by accepting axial ligands with lone pairs of electrons.
For example, 1,4-diazabicycloACTHNUGRTNEUNG[2.2.2]octane (DABCO) has a
strong binding affinity to some tweezers-type zinc porphyrin
dimers.[5] By combining zinc porphyrins and biindole, we de-
signed a new type of molecular tweezers for the simultane-
ous binding of DABCO as well as anionic guests. In this
work, we report a multiple-guest-binding molecular tweezers
that exhibits notably strong positive allosteric guest binding
phenomena.
Tweezers-type zinc porphyrin dimer (1) and biindole-con-
jugated monomeric porphyrin (2) were synthesized accord-
1
ing to Scheme 1 and characterized by H NMR (Figure 1),
13C NMR, and MALDI-TOF-MS analyses. Briefly, an ethyn-
yl group-bearing porphyrin (3) was synthesized from methyl
4-formyl benzoate, 4-(trimethylsilylethynyl)-benzaldehyde,
and dipyrromethane by Lewis acid-catalyzed condensation
with successive oxidation and coordination of zinc. After the
deprotection of trimethylsilyl group, 4 thus obtained was
conjugated with biindole moiety by Sonogashiraꢀs coupling
reaction to obtain 1 and 2.
At first, we expected that 1 can simultanuously accommo-
date anionic guest as well as DABCO. To test guest bind-
ings, we selected ClÀ as an anionic guest within various
anionic species because ClÀ has shown remarkably high
binding affinity to indole-based macrocyclic hosts or foldam-
ers.[4] 1H NMR study showed that adding either ClÀ or
DABCO caused spectral changes (Figure 1). Upon addition
of three equivalents of DABCO, resulting from the phenyl
and pyrrole b-protons of the porphyrin unit were mostly
shifted upfield, whereas the signal of NH protons in the
indole moiety exhibited a slight downfield shift (Figure 1a).
Chemical shift changes of protons in the indole moiety were
[a] C.-H. Lee, H. Yoon, Prof. W.-D. Jang
Department of Chemistry, College of Science
Yonsei University
262 Seongsanno, Seodaemun-gu, Seoul 120-749 (Korea)
Fax : (+82)2-364-7050
E-mail: wdjang@yonsei.ac.kr
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200901988.
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Chem. Eur. J. 2009, 15, 9972 – 9976

COMMUNICATION
Figure 2. Energy-minimized molecular models of host and host–guest
complexes.
the signal of the meso proton in porphyrin was largely shift-
ed upfield (d=0.21 ppm), whereas signals assigned to the
phenyl groups were mostly downfield shifted by the addition
of ClÀ. The energy-minimized structure of the 1ꢀClÀ com-
plex showed the possible formation of a side-on adduct of
ClÀ to the biindole moiety (Figure 2). According to the for-
mation of 1ꢀClÀ, the two porphyrin units become very
close, as a result of the p–p interactions. As a result, one of
the meso protons of the first porphyrin is located close to
the centre of the second porphyrin. This could be responsi-
ble for the signal of the meso proton in the porphyrin unit
being shifted upfield. As a control experiment, ClÀ was
added to 2. Although the signals of NH protons in biindole
moiety were greatly shifted downfield, in contrast to 1ꢀClÀ,
the signals of meso and pyrrole b protons were shifted
slightly upfield by the formation of 2ꢀClÀ complex
(Figure 3). In the case of 1, electronic environment of por-
Scheme 1. Reagents and conditions: i) BF3·Et2O, MeOH/CH2Cl2, 258C,
12 h; ii) p-chloranil, 258C, 4 h; iii) Zn(OAc)2, 258C, 12 h; iv) tetrabutyl-
AHCTUNGTRENNUNG
ammonium fluoride, CH2Cl2, 258C, 30 min; v) CuI, [Pd
THF, 258C, 12 h.
ACHTNUGNERTN(UGN PPh3)2Cl2], Et3N,
Figure 1. Partial 1H NMR spectra of a) 1ꢀDABCO, b) 1, c) 1ꢀClÀ, and
d) 1ꢀDABCO·ClÀ in [D8]THF at 258C.
relatively smaller than those in the porphyrin unit, indicat-
ing that the binding of DABCO mainly influence on the
electronic density of porphyrin rings. The energy-minimized
molecular modeling study (using a CAChe 7.5 MM3 force
field) of the 1ꢀDABCO complex indicated a perfectly sym-
metric, parallel conformation of the two porphyrin units
(Figure 2). Alternatively, strong chemical shift changes of
protons in the indole moiety as well as those in porphyrins
were observed when ClÀ was added (Figure 1c), indicating
that the binding of ClÀ influence on the electronic environ-
ment of either biindole moiety or porphyrin rings. The
signal of the NH proton was shifted a great deal, from d=
10.94 to 13.52 ppm, indicating that ClÀ strongly bound to
these NH protons through hydrogen bonding. Interestingly,
1
Figure 3. Partial H NMR spectra of a) 2 and b) 2ꢀClÀ in CDCl3 at 258C.
phyrin units was greatly changed by inclusion of ClÀ because
the two porphyrin units can interact each other. However,
the influence of ClÀ inclusion on porphyrin in 2 is very small
because 2 has only one porphyrin unit. When DABCO was
added to the 1ꢀClÀ complex, the proton signals of porphy-
rin units became close to the chemical shifts of the
1ꢀDABCO complex. However, the signal of NH proton has
shown more strong shift downfield, indicating that 1 can si-
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W.-D. Jang et al.
multaneously accommodate DABCO as well as ClÀ to form
a ternary complex (1ꢀDABCO·ClÀ).
Upon addition of DABCO, both Soret and Q band ab-
sorptions were drastically changed with clear isosbestic
points at l=357, 548, and 584 nm (Figure 4b). The Jobꢀs
plot demonstrated that DABCO and 1 had a 1:1 stoichiome-
try when forming a host–guest complex, where the Kassoc was
determined to be 2.02ꢂ106 mÀ1.
To determine the binding affinity of ClÀ to 1, a spectro-
scopic titration was carried out in THF at 258C. The absorp-
tion spectrum of 1 was changed by the addition of ClÀ, with
clear isosbestic points at l=304, 370, and 554 nm (Fig-
ure 4a). The continuous variation method (Jobꢀs plot)[6] to-
To confirm the influence of DABCO on ClÀ binding, ClÀ
was titrated into 1 in the presence of one equivalent of
DABCO. In the presence of DABCO, the binding affinity of
ClÀ to 1 was drastically increased (Kassoc =7.10ꢂ105 mÀ1),[7]
indicating that DABCO has a strong positive allosteric
effect[8] on the binding of ClÀ (Figure 5a). The binding of
Figure 5. Spectroscopic titration curves for a) ClÀ
(
with ClÀ; without
*
*
À
*
*
Cl ) and b) DABCO ( with DABCO; without DABCO)to 1.
DABCO to 1 may create an excellent cavity for the binding
of ClÀ to 1. The binding affinity of DABCO to 1 was also
greatly increased by the presence of one equivalent of ClÀ,
where Kassoc was determined to be 2.48ꢂ107 mÀ1 (Fig-
ure 5b).[7] The molecular modeling study of biindole moiety
indicated that the most stable conformation is the trans con-
formation,[4b,9] which can be changed to the cis conformation
by the addition of ClÀ. Therefore, the increased binding af-
finity of DABCO to 1 was attributed from the conforma-
tional change of 1 by inclusion of ClÀ.
Allosteric guest binding is one of the fundamental regula-
tion mechanisms in biological events, such as molecular rec-
ognition and catalytic activity.[10,11] Many proteins having
multiple-guest binding sites show allosteric guest binding
phenomena, in which the occurrence of guest binding can
influence other binding sites through conformational
changes to regulate additional guest-binding affinity.
Though various types of molecular tweezers have been re-
ported,[1] very few examples have controlled their guest
Figure 4. Spectroscopic titration of
1 with guests in THF at 258C.
a) [ClÀ]/[1]=0–9.3, [1]=1.9ꢂ10À5 m, b) [DABCO]/[1]=0-4.2, [1]=2.4ꢂ
10À6 m. Inset: Soret band of 1 with ClÀ and DABCO, respectively.
gether with the spectroscopic titration demonstrated that 1
and ClÀ form a 1:1 host–guest complex. The association con-
stant (Kassoc) for ClÀ to 1 was determined to be 4.93ꢂ104 mÀ1
by nonlinear curve-fitting analysis of the UV-vis titration
curve. As a reference, compound 5 (Scheme 1), biindole
moiety without porphyrin conjugation, was titrated with ClÀ,
where the Kassoc was determined to be 2.28ꢂ103 mÀ1. Interest-
ingly, 1 has about 20 times higher binding affinity for ClÀ
compare to 5, indicating that 1ꢀClÀ complex is possibly sta-
bilized by p–p interaction between two porphyrin units with
1.8 kcalmolÀ1 of free energy gain compare to 5ꢀClÀ com-
plex.
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Molecular Tweezers: Heterotopic Allosterism
COMMUNICATION
binding affinity by external stimuli.[1b,12] Therefore, the allos-
terism of molecular tweezers is particularly interesting, from
the viewpoint of binding affinity control by external stimuli.
In conclusion, the present study demonstrated that the
biindole-bridged zinc porphyrin dimer 1 binds an anionic
guest as well as DABCO in a strong positive allosteric
manner. By the introduction of porphyrin units to anion-ac-
ceptable biindole moiety, the binding affinity of ClÀ was sig-
nificantly enhanced, owing to the p–p interaction of porphy-
rin units. Furthermore, the binding affinity of ClÀ to 1 can
be controlled by the addition of DABCO. Following the ini-
tial guest accommodation, the trans conformation of the
biindole moiety may be changed to the cis conformation,
thereby significantly increasing the guest binding affinity.
On the other hand, the stimuli-responsive conformational
change of photofunctional porphyrin derivatives are particu-
larly interesting for the design of molecular level photo-
switching device, thereby the investigation of photophysical
properties are currently in progress in our research group.
Synthesis of 1 and 2: Biindole moiety (5; 0.1 g, 0.17 mmol), CuI (0.64 mg,
3.34 mmol), [PdACHTNUTRGNEUNG(PPh3)2Cl2] (2.3 mg, 3.34 mmol), and 4 (0.3 g, 0.50 mmol)
were placed in a Schlenk flask. The flask was degassed under high
vacuum and back-filled with nitrogen, and then degassed THF (30 mL)
and Et3N (3 mL) were added. The solution was stirred for 12 h at 258C,
and then reaction mixture was evaporated. The residue was purified by
column chromatography with 1% MeOH/CH2Cl2 to gave 1 (60 mg,
1
23%) and 2 (100 mg, 55%) as red solid. 1: H NMR (400 MHz, [D8]THF,
258C) d=10.94 (s, 2H, NH), 9.76 (s, 4H, meso-H), 9.10–9.05 (m, 12H),
8.94 (d, J=4.4 Hz, 4H), 8.48 (d, J=8 Hz, 4H), 8.35–8.32 (m, 8H), 8.15
(d, J=7.6 Hz, 4H), 7.76 (d, J=1.6 Hz, 2H), 7.67 (d, J=1.6 Hz, 2H), 7.10
(d, J=1.6 Hz, 2H), 4.12 (s, 6H), 1.52 ppm (s, 18H); 13C NMR (100 MHz,
[D6]DMSO, 258C), d=166.63, 148.82, 148.69, 148.66, 148.58, 147.55,
142.93, 142.69, 135.38, 134.78, 134.74, 132.17, 132.12, 131.96, 131.22,
131.21, 130.01, 128.85, 128.65, 128.16, 127.52, 123.76, 122.01, 118.25,
117.53, 105.96, 104.99, 101.04, 92.82, 88.08, 52.49, 34.42, 31.75 ppm;
MALDI-TOF-MS: m/z: calcd for C96H68N10O4Zn2: 1552.4 [M+]; found:
1555.52. 2: 1H NMR (400 MHz, CDCl3, 258C) d=10.17 (s, 2H, meso-H),
9.39 (d, J=4.4 Hz, 2 H), 9.33 (d, J=4.8 Hz, 2H), 9.16 (d, J=4.4 Hz, 2H),
9.03 (d, J=4.8 Hz, 2H), 8.80 (s, 1H, NH), 8.48 (d, J=8 Hz, 2H), 8.49–
8.47 (m, 3H), 8.31 (d, J=8 Hz, 2H), 8.10 (d, J=8 Hz, 2H), 7.73 (s, 1H),
7.71 (d, J=2 Hz, 1H), 7.65 (d, J=1.6 Hz, 1H), 7.60 (s, 1H), 6.98 (d, J=
2 Hz, 1H), 6.87 (d, J=2 Hz, 1H), 4.12 (s, 3H), 1.52 (s, 9H), 1.40 ppm (s,
9H); 13C NMR (100 MHz, CDCl3, 258C) d=167.69, 149.98, 149.70,
149.63, 147.63, 146.01, 144.12, 143.87, 143.02, 137.15, 135.97, 134.97,
134.89, 132.53, 132.30, 132.26, 132.22, 131.18, 130.93, 130.25, 129.98,
129.52, 128.82, 128.76, 128.08, 125.05, 122.68, 119.56, 118.87, 118.56,
118.12, 117.03, 106.65, 105.60, 101.15, 100.71, 93.40, 75.98, 52.63, 34.96,
34.84, 32.08, 31.99 ppm; MALDI-TOF-MS: m/z: calcd for C60H47N6O2Zn:
1076.35 [M+]; found: 1076.02.
Experimental Section
Measurements: Electronic absorption spectra were recorded by using a
JASCO model V-660 spectrometer. 1H and 13C NMR spectra were re-
corded at 258C in CDCl3, [D6]DMSO, or [D8]THF by using a Bruker
DPX 400 spectrometer. MALDI-TOF-MS was performed by using an
Applied Biosystems 4700 proteomics analyzer, with a-cyano-4-hydroxy-
cinnamic acid as a matrix.
Acknowledgements
Synthesis of 3: To
a mixture solution of methyl 4-formyl-benzoate
(1.62 g, 9.89 mmol) and 4-((trimethylsilyl)-ethynyl)benzaldehyde (2.00 g,
9.89 mmol) and dipyrromethane (2.89 g, 19.77 mmol) in CH2Cl2 (830 mL)
and MeOH (170 mL), BF3·Et2O (2 mL, 15.92 mmol) was added and
stirred for 12 h at 258C. And then, p-chloranil (9.72 g, 39.54 mmol) was
added, and the mixture was stirred for 4 h. The reaction mixture was con-
centrated to a volume of 200 mL, and then chromatography by silica gel
was done in 2% MeOH/CH2Cl2. Without further purification, the prod-
This work was supported by the Korea Science and Engineering Founda-
tion through the Center for Bioactive Molecular Hybrids (CBMH).
C.W.L. and H.Y. acknowledge a fellowship from the BK21 program from
the Ministry of Education, Science, and Technology, Korea.
Keywords: allosterism · biindole · molecular recognition ·
molecular tweezers · porphyrinoids
uct was dissolved in 10% MeOH/CH2Cl2 containing ZnACHTUNTRGENUG(N OAc)2 (6.51 g,
29.67 mmol) and then stirred for 12 h at 258C. The reaction mixture was
purified by column chromatography with 1% MeOH/CH2Cl2, where the
second fraction was collected and evaporated to dryness. The residue was
recrystallized from CH2Cl2/hexane to give 3 as a reddish purple powder
(0.9 g, 13%). 1H NMR (400 MHz, [D8]THF, 258C) d=10.31 (s, 2H,
meso-H), 9.43 (d, J=4.4 Hz, 4H), 9.03 (d, J=4.8 Hz, 2H), 9.01 (d, J=
4.4 Hz, 2H), 8.46 (d, J=8 Hz, 2H), 8.36 (d, J=8 Hz, 2H), 8.23 (d, J=
8 Hz, 2H), 7.89 (d, J=7.6 Hz, 2H), 4.26 (s, 3H), 0.36 ppm (s, 9H);
13C NMR (100 MHz, [D8]THF, 258C) d=167.41, 150.64, 150.60, 150.38,
149.18, 144.81, 135.67, 135.56, 132.61, 132.54, 132.47, 132.32, 130.79,
130.29, 128.36, 123.28, 119.60, 119.03, 106.80, 106.40, 95.22, 86.80, 52.37,
0.16 ppm; MALDI-TOF-MS: m/z: calcd for C39H30N4O2SiZn: 678.14 [M+];
found: 678.35.
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Received: August 3, 2009
Published online: August 31, 2009
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Chem. Eur. J. 2009, 15, 9972 – 9976