Cofacial Organic Click Cage to Intercalate Polycyclic Aromatic Hydrocarbons

Article abstract of DOI:10.1021/acs.orglett.6b01554

The synthesis of a 3-fold symmetric cofacial organic cage (COC) through Cu(I)-catalyzed azide-alkyne cycloaddition is reported. The COC can function as an efficient receptor for carcinogenic polycyclic aromatic hydrocarbons to intercalate them in its intrinsic cavity through donor-acceptor and π? π stacking interactions. The association constants (K_a) are in the range of 3.7 × 10⁴ to 1.3 × 10⁶ M^-1. X-ray diffraction analysis authenticated that the polycyclic aromatic hydrocarbons (PAHs) are intercalated in the interior of the COC.

Full text of DOI:10.1021/acs.orglett.6b01554

Letter
pubs.acs.org/OrgLett
Cofacial Organic Click Cage to Intercalate Polycyclic Aromatic
Hydrocarbons
Jayanta Samanta†,‡ and Ramalingam Natarajan*,†,‡
†Organic and Medicinal Chemistry Division, CSIR-Indian Institute of Chemical Biology, 4, Raja S. C. Mullick Road, Kolkata 700032,
India
‡Academy of Scientific and Innovative Research (AcSIR), 4, Raja S. C. Mullick Road, Kolkata 700032, India
S
* Supporting Information
ABSTRACT: The synthesis of a 3-fold symmetric cofacial organic cage (COC) through
Cu(I)-catalyzed azide−alkyne cycloaddition is reported. The COC can function as an
efficient receptor for carcinogenic polycyclic aromatic hydrocarbons to intercalate them
in its intrinsic cavity through donor−acceptor and π···π stacking interactions. The
association constants (Ka) are in the range of 3.7 × 104 to 1.3 × 106 M−1. X-ray
diffraction analysis authenticated that the polycyclic aromatic hydrocarbons (PAHs) are
intercalated in the interior of the COC.
esign and synthesis of organic cage-like molecules with vast
interior space, capable of intercalating large organic guest
chemistry,9 might be a possible tool to obtain COCs, with
convergent recognition surface, when carefully chosen building
blocks are used. Although CuAAC reaction was often used to
synthesize large macrocycles,10 only limited organic cages, of any
topology, are known.11 In fact, there exists only two COCs
obtained through CuAAC reaction: one having limited guest
entry portal, thus reported to bind small azide anions only,11d and
the other having solubility issues for any host−guest complex-
ation.11a
Herein, we report the synthesis of a shape persistent COC,
obtained thorough CuAAC reaction in high yield, along with its
demonstrated ability to intercalate PAHs with great affinity,
confirmed by NMR, fluorescence, and single-crystal X-ray
diffraction (SCXRD) analyses.
D
molecules, has been a longstanding research activity1 and gained
significant attention in recent years.2 Among those various cages
with different topologies, cofacial organic cage (COC), with
convergent recognition surfaces on top and bottom panels and
three or more bridges linking them together, is a challenging
target for synthetic supramolecular chemist.3
The major utility of the COCs includes being an efficient host
to intercalate guest molecules such as polycyclic aromatic
hydrocarbons (PAHs) among others.3 Crucially, PAHs,
composed of two or more fused benzene rings, are prevalent
and persistent in the environment due to anthropogenic activities
and are carcinogenic.4 Synthetic hosts, such as cages and
cyclophanes with convergent recognition surfaces, capable of
binding PAHs are in great demand. However, there exists only a
few such receptors based on specific donor−acceptor
interactions,5 including Stoddart’s hexacationic ExCage3a and
BlueCage.3b The COCs might further be useful as transport
vehicles in biomedical applications and in enzyme-mimetic
catalysis.
Nevertheless, the few COCs, demonstrated with inclusion of
PAHs, were obtained in challenging synthetic conditions with
limited yield,3a,b in comparison with similar cofacial metal−
organic cages.6 High yielding reversible bond forming reactions,7
especially imine condensation,8 are often used to form the
COCs; however, no such cages capable of intercalating PAHs are
known so far. Thus, there remains a strong and urgent need for
ready access to COCs with convergent recognition surface
capable of intercalating PAHs and other large organic molecules
by any synthetic means.3a
Our strategy of accessing a COC relies on careful choice of
building blocks. We chose to utilize the C3-symmetric 2,4,6-
triaryl-1,3,5-triazine moieties with necessary azide and alkyne
functional groups on the aryl rings, separately.
Accordingly, we synthesized the necessary building blocks 1a
and 1b readily (Scheme 1).12 We subsequently performed the
CuAAC reaction by adding equimolar mixture of 1a and 1b in
THF/toluene (1:3, 0.4 mM, 20 mL), into a toluene (300 mL)
solution of CuI and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)
at 75 °C over 18 h, and further stirring the reaction mixture at the
110 °C over additional 24 h (Scheme 1). Subsequent purification
of the crude product by column chromatography resulted in the
desired COC 1, in 58% yield. The yield is remarkable considering
that the irreversible nature of the reaction and no other major
1
products were isolated during purification. H NMR and mass
We hypothesized that Cu(I)-catalyzed azide−alkyne cyclo-
addition (CuAAC) reaction, a better known example for the click
Received: May 30, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01554
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Letter
size and shape favors fast exchange between in-and-out of the
COC 1 in NMR time scale. However, anthracene (3),
phenanthrene (4), and triphenylene (6) showed mild upfield
shifts (Δδ = 0.1 ppm, Figures S6, S8, and S12) of their proton
resonances.
Scheme 1. Synthesis of the COC 1
We reasoned that complexation might be favorable in more
polar solvent for the nonpolar guests and nonpolar host.14
1
Subsequent H NMR analysis of the host−guest complexes of
2−6 with 1 in THF-d8/CDCl3 (2:1) revealed significant upfield
shift (Δδ = up to 0.5 ppm) for the guest resonances (Figures 3a,
spectral (see Supporting Information) analysis confirmed
formation of 1.
Crystals of 1, SCXRD, were readily grown by slow evaporation
from either CHCl3 or C2H4Cl2 and the analysis confirmed the
expected molecular structure with the desired COC topology
(Figure 1).
Figure 1. X-ray determined molecular structure of 1. (a) Thermal
ellipsoid plot in 50% probability level and (b) space filling
representation. The solvent molecules are not shown for clarity.
Figure 3. 1H NMR spectra of 5 ⊂ 1 (a) and 9 ⊂ 1 (b).
S5, S7, S9, S11, and S13). The aromatic protons, adjacent to the
1,3,5-triazine moieties, of 1 also underwent significant upfield
shift (Δδ = up to 0.2 ppm), thereby suggesting efficient
intercalation of the PAHs 2−6 inside 1 in favorable solvent.
Other larger PAHs, namely, benz(a)anthracene (7), benzo(a)-
phenanthrene (8), benzo(a)pyrene (9), perylene (10), and
benzo(ghi)perylene (11) exhibited significant upfield shift (Δδ =
up to 0.7 ppm) for their proton resonances upon complexation
with 1 (1:1 ratio) in CDCl3 itself and more pronounced shifts in
THF-d8/CDCl3 (2:1) (Figures 3b and S14−S23). Due to signal
overlap of the host and the guest resonance, NMR titration to
obtain the association constant appeared impossible. Subsequent
1H NMR analyses of still larger PAH coronene (12) and 1 in
CDCl3, as well as in THF-d8/CDCl3 (2:1), in 1:1 or 1:2 ratio,
even after heating the mixture at 60 °C for 3 days, did not show
any shift for the guest resonance (Figures S24 and S25); thereby
suggesting that 1 might not intercalate 12. Thus, it is quite
remarkable to note that the COC 1 can selectively intercalate 11
(C22H12) against 12 (C24H12).
The crystal structures reveal that in 1 the atom-to-atom (i)
interplanar distances between the two triazine moieties are 6.5−
6.7 Å and (ii) interbridge distances between any two triazole
moieties are ca. 13 Å. Expectedly, 1 crystallized with the solvent
molecules (CHCl3 or C2H4Cl2) included in the cavity and in the
crystal lattice.
In order to study the ability of 1 to complex the PAH guests
(Figure 2) in solution phase, we performed the initial host−guest
1
binding studies by H NMR analysis. We prepared equimolar
solutions of the host−guest complexes in CDCl3 and then
examined for any upfield shift for the guest resonances due to
magnetic shielding offered by 1 upon intercalation. Among the
PAHs of 2−6, naphthalene (2) and pyrene (5), curiously, did not
show any upfield shift (Figures S4 and S10); presumably their
UV−vis spectral analysis of 1:1 mixture of the COC 1 with
PAHs 2−11 and 12 as well showed enhanced molar absorption
coefficient, suggesting donor−acceptor interaction, but without
any new red-shifted charge-transfer band (Figures S26−S28).
We expected that the electron rich PAH guests (2−11), upon
being intercalated with the COC 1, might transfer the excited
energy to the low lying LUMO of the 1,3,5-triazine linked
aromatic panels of 1 and thus become nonemissive.6b
Accordingly, we performed the fluorescence titration experi-
ments, in CHCl3, by adding increasing amounts of 1 in excess (up
to 4−9 equiv) into the PAHs (2−11) solution placed in the cell;
thus, the guest molecules should be completely intercalated in 1
at the completion. As anticipated, we observed that fluorescence
Figure 2. PAH guest molecules examined for intercalation.
B
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intensities of the PAHs (2−11) were quenched upon the
addition of 1. The observed reduction in emission maxima was
plotted against the change in host concentration, and the
association constants (Ka) were calculated for a 1:1 binding
model by using nonlinear least-squares curve fitting (Figures
S29−S38).15 The association constants (Ka), listed in Table 1,
PAHs, buried inside the COC 1, appear to be highly solvated in
the crystalline state. The solvent molecules are in close contacts
with the intercalated PAHs (dC−Cl···C = 3.0 to 4.2 Å) and
propagate to form solvent-clustered canals.
The crystal structure of 2 ⊂ 1 provided an explanation for
higher affinity observed in the fluorescence titrations. Contrary
to other 1:1 PAHs ⊂ 1 complexes (3−11), the PAH 2
crystallized with 1 along with three molecules of it, one bound
inside the cage and other two are outside, but all in close contact,
and with a solvent molecule. The bound guest 2 inside the cage 1
is located in two orientations (85:15) with an interplanar angle of
26.3°, to form more favorable edge-to-face aromatic interaction
with the host (Figure 4b). This augments the reason for stronger
affinity of 1 toward 2 as observed in fluorescence experiments.
Closer inspection of the 11 ⊂ 1 complex confirms that the size
of 11 appears to be the maximum that can fit in 1 (Figures 4k,l
and S75). The whole of guest 11 and one of the triazole linkers of
the cage, closer to the bay area of the guest, were found to be in
two different orientations, i.e., disordered over two positions, in
order to reach the best fit. It suggests that a larger PAH in which
the bay area of 11 was closed with further annulation, i.e., the
Table 1. Thermodynamic Parameters for Binding of PAHs
a
with 1
PAH ⊂ 1
Ka (M−1
)
−∇G° (kJ/mol)
2 ⊂ 1
3 ⊂ 1
4 ⊂ 1
5 ⊂ 1
6 ⊂ 1
7 ⊂ 1
8 ⊂ 1
9 ⊂ 1
10 ⊂ 1
11 ⊂ 1
12 + 1
(1.2 0.26) × 106
(3.7 0.42) × 104
(1.56 0.07) × 105
(5.1 0.19) × 105
(6.27 0.37) × 104
(8.6 0.27) × 104
(1.39 0.18) × 105
(1.47 0.04) × 105
(4.3 0.18) × 104
(7.2 0.21) × 104
(6.75 0.5) × 104
34.63 0.54
26.04 0.28
29.62 0.11
32.55 0.09
27.36 0.15
28.15 0.08
29.81 0.17
29.48 0.07
26.42 0.1
27.65 0.13
27.53 0.2
1
PAH 12, cannot fit inside the cage, as suggested by H NMR
a
Measured at 25 °C in CHCl3.
results. Despite our repeated efforts, all our attempts to obtain
the crystals of 12 intercalated with 1 did not result in any desired
result. This further supports that the size of 11 appears to be the
largest PAH that can be intercalated in 1.
In summary, we have synthesized an organic cage 1, with two
cofacial aromatic platforms bridged through three triazole units,
using the exemplary click chemistry of CuAAC reaction, which is
otherwise unexplored to synthesize organic cages capable of
complexing large organic guests. We have demonstrated that the
COC 1, with a convergent aromatic recognition surface, can
intercalate PAHs efficiently, for which available designer
supramolecular receptors with specific recognition surfaces are
only a few and are highly sought after due to their carcinogenic
nature.
are in the range of 104 to 106 (M−1) for all PAHs. The measured
affinities clearly demonstrated the ability of COC 1 with
convergent recognition surface exerting aromatic π···π stacking
and donor−acceptor interactions with the nonpolar PAHs to
form favorable inclusion complexes even in nonpolar solvent.
Comparatively, other macrocycles and cyclophanes showed
similar affinities in polar solvents only.13,16 A similar fluorescence
titration of 1 against 12 also showed a remarkable quenching, and
the data can be fit into 1:1 binding model (Figure S39, Table 1).
1
However, based on the H NMR data, we suggest that the
observed quenching should primarily be due to external binding,
instead of intercalation.
SCXRD experiments of the host−guest complexes unequiv-
ocally confirmed that the PAHs (2−11) are intercalated inside
the COC 1 through aromatic face-to-face π···π stacking
interaction (Figure 4). Further, in several instances, one of the
three 1,2,3-triazole bridges of 1 appears to be rotatable to allow
the guest molecules readily into the interior of 1. The intercalated
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b01554.
■
S
Synthesis, details of NMR, UV−vis and fluorescence based
binding studies, and details of X-ray diffraction studies
(PDF)
X-ray data of (CHCl3)n ⊂ 1 (CIF)
X-ray data of (C2H4Cl4)n ⊂ 1 (CIF)
X-ray data of 2 ⊂ 1 (CIF)
X-ray data of 3 ⊂ 1 (CIF)
X-ray data of 4 ⊂ 1 (CIF)
X-ray data of 5 ⊂ 1 (CIF)
X-ray data of 6 ⊂ 1 (CIF)
X-ray data of 7 ⊂ 1 (CIF)
X-ray data of 8 ⊂ 1 (CIF)
X-ray data of 9 ⊂ 1 (CIF)
X-ray data of 10 ⊂ 1 (CIF)
X-ray data of 11 ⊂ 1 (CIF)
AUTHOR INFORMATION
Corresponding Author
■
Figure 4. X-ray determined intercalation complexes of 1 with PAHs.
The solvent molecules are not shown for clarity.
*E-mail: rnatraj@iicb.res.in.
C
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2009, 1945−1948. (d) Zhang, J.; Li, Y.; Yang, W.; Lai, S.-W.; Zhou, C.;
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
(13) Smithrud, D. B.; Diederich, F. J. Am. Chem. Soc. 1990, 112, 339−
343.
■
J.S. thanks UGC, India, for a Senior Research Fellowship. R.N.
thanks CSIR-IICB (BSC-0115) and SERB-India (SR/S2/RJN-
62-2012 and SB/S1/IC-26/2013) for financial support. We
thank Dr. Surajit Ghosh (CSIR-IICB) for generous access to his
group’s spectrophotometers.
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