Highly efficient non-covalent energy transfer in all-organic macrocycles

Article abstract of DOI:10.1039/c3cc45128c

The use of aromatic organic macrocycles as supramolecular hosts for non-covalent energy transfer is reported herein. These macrocycles lead to stronger binding and more efficient energy transfer compared to commercially available γ-cyclodextrin. This energy transfer was particularly efficient for the highly toxic benzo[a]pyrene with a fluorescent BODIPY acceptor, with up to a 5-fold increase in the fluorophore emission observed.

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Highly efficient nonꢀcovalent energy transfer in allꢀorganic macrocycles
Bhasker Radaram,a Joshua Potvina and Mindy Levine*a
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
promote intraꢀcavity energy transfer.
5
The use of aromatic organic macrocycles as supramolecular
hosts for nonꢀcovalent energy transfer is reported herein.
These macrocycles lead to stronger binding and more
efficient energy transfer compared to commercially available
γꢀcyclodextrin. This energy transfer was particularly efficient
10 for the highly toxic benzo[a]pyrene with a fluorescent
BODIPY acceptor, with up to a 5ꢀfold increase in the
fluorophore emission observed.
The complexation of small molecules in organic macrocycles is a
highly active area of research, with applications including
15 supramolecular catalysis,1 smallꢀmolecule detection,2 and
macrocycleꢀpromoted energy transfer.3 We have previously
shown that γꢀcyclodextrin, a wellꢀknown supramolecular host,4
promotes efficient energy transfer from several polycyclic
aromatic hydrocarbons (PAHs) and polychlorinated biphenyls
20 (PCBs) to fluorophore acceptors.5 This energy transfer occurs
with up to 35% efficiency, and has significant potential
applications in developing arrayꢀbased detection schemes.6
The use of aromatic macrocycles as supramolecular hosts can
lead to even stronger binding of aromatic guests and higher
25 energy transfer efficiencies, as these macrocycles can bind
aromatic guests via πꢀπ stacking7 in addition to hydrophobic
binding.8 Four examples of such macrocycles were synthesized
(Figure 1) (synthetic details provided in the ESI). Briefly, a
double Williamson etherification reaction9 followed by a double
30 Suzuki reaction10 rapidly assembled the linear precursors. The
50
Figure 1: Structures of supramolecular hosts, with electronꢀrich segments
highlighted in red, and electronꢀdeficient segments in blue. Height and
width dimensions are shown on macrocycle 1, and the key protons
involved in NMR studies are indicated by letters “c” and “d”
key macrocyclization reactions were accomplished via a double
11
55 Table 1 Cavity dimensions of compounds 1ꢀ4 in the energyꢀminimized
conformations
etherification reaction (for compound 1)
Mitsunobu reaction (for compounds 2ꢀ4). 12
or via a double
Compound
Height
9.1 Å
5.0 Å
5.7 Å
9.7 Å
Width
11.2 Å
12.6 Å
13.0 Å
8.0 Å
These macrocycles include three structures that are electronicallyꢀ
35 dissymmetric (1ꢀ3), with clearly defined electronꢀrich and
electronꢀdeficient components to the macrocycle, and one that is
electronically symmetric (4). The electronically dissymmetric
structures are designed to bind an electronꢀrich analyte near the
electronꢀdeficient component of the macrocycle, and an electronꢀ
40 deficient fluorophore near the electronꢀrich segment of the
macrocycle, to form a stack of four aromatic components with
alternating electronic character that will undergo efficient energy
transfer. Whether such dissymmetry improves the binding and
energy transfer efficiencies was tested by comparison to control
45 macrocycle 4, which lacks such dissymmetry.
1
2
3
4
Once synthesized, macrocycles 1ꢀ4 were used for two key
applications: (a) as supramolecular hosts to bind aromatic PAHs;
and (b) as hosts for nonꢀcovalent energy transfer from PAHs to
60 fluorophore 7 (Figure 2).14
The binding of aromatic PAHs in macrocycles 1ꢀ4 was measured
by adding concentrated solutions of the macrocycle and PAH in
THF to an aqueous solution of phosphate buffered saline. The
fluorescence emission spectrum of the PAH was measured in the
65 presence of increasing amounts of the macrocycle. This
experimental design resulted in a mostly aqueous solution, which
maximized hydrophobic binding of the PAHs.
Semiꢀempirical PM3ꢀlevel calculations of the macrocycles
indicate that all of them have internal dimensions analogous to
that of γꢀcyclodextrin (Table 1),13 and sufficiently large to
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H3C
45 macrocycle interior. Because macrocycle 2 binds benzo[a]pyrene
with high affinities, the likelihood of its success as a host for
supramolecular energy transfer was increased.
a
H
CH3
H
N
HS
H3C
10
F
B
N
F
Table 2 1H NMR chemical shifts for 2:6 complex
CH3
6
7
H
b
5
NMR proton
Peak A
Initial (ppm)
9.005
Final (ppm) Change in ppm
9.021
8.482
5.465
4.549
+0.016
+0.021
ꢀ0.077
ꢀ0.022
Figure 2: PAH energy donors (5 and 6) and fluorophore acceptor (7) used
Peak B
Peak C
Peak D
8.471
5.542
4.571
in macrocycleꢀpromoted energy transfer
Among all macrocycles tested, macrocycle 2 was the most
efficient supramolecular host for binding benzo[a]pyrene 6, with
other PAHꢀmacrocycle combinations leading to negligible
binding. This binding was quantified by measuring changes in the
emission spectra of benzo[a]pyrene: the addition of 0.061 mM of
macrocycle 2 to 0.029 mM solution of benzo[a]pyrene 6 resulted
5
10 in a 4ꢀfold increase in the benzo[a]pyrene emission (Figure 3a).
The sharp increase in the excimer band around 500 nm with
increasing amounts of the macrocycle strongly suggests a 1:2
host: guest complex, even in the presence of a ca. 2ꢀfold excess of
the supramolecular host. Fitting this data to a BenesiꢀHildebrand
15 equation for a 1:2 complex revealed an apparent binding constant
of 5 x 109 Mꢀ2,15 which is among the highest binding constants
observed for this highly toxic analyte.16 By comparison, the
addition of macrocycle 2 to a solution of anthracene resulted in
no significant changes in the anthracene emission beyond spectral
20 broadening (Figure 3b).
50 Figure 4: 1H NMR chemical shifts for 2: 6 complex. (a) Protons A; (b)
Protons B; (c) Protons C; (d) Protons D. The designation of protons AꢀD
are shown in Figures 1 and 2.
The efficiency of such energy transfer was quantified in two
ways:
55 (a) by measuring the decrease in the donor emission from adding
an energy acceptor, according to Equation 1:
Donor decrease = FDA/FD
(1)
where FDA and FD are the integrated emission of the donor in the
presence and absence of acceptors;19
60 and (b) by measuring the increase in the acceptor emission from
adding the energy donor, according to Equation 2:
Fluorophore increase = IDA/IA
(2)
Figure 3: Analyte emission spectra in the presence of increasing amounts
of macrocycle 2 for (a) benzo[a]pyrene and (b) anthracene. Black line: [2]
= 0 mM; red line: [2] = 0.020 mM; blue line: [2] = 0.061 mM.
where IDA is the integrated emission of the fluorophore from
analyte excitation, and IA is the integrated emission of the
65 fluorophore (from excitation at the same wavelength) in the
absence of the analyte.
The results of macrocycleꢀpromoted energy transfer are
summarized in Table 3. These experiments were conducted under
mostly aqueous conditions to maximize the favourable
70 hydrophobic binding and πꢀπ stacking between the aromatic PAH
donor, aromatic fluorophore acceptor, and aromatic macrocycle.
25 This binding was further confirmed by 1H NMR titration
studies.17 The titration of benzo[a]pyrene into a solution of
macrocycle 2 in CDCl3 resulted in
a shift of both the
benzo[a]pyrene peaks and the macrocycle peaks (Table 2; Figure
4). The fact that macrocycle protons C and D shift noticeably
30 indicates that benzo[a]pyrene associates with both sides of the
macrocycle, although more with the electronꢀdeficient side (as
indicated by a larger shift in the C protons). The simultaneous
shifts in the host and guest peaks suggest a close association
between the host and the guest, and are consistent with the
Table 3 Results of macrocycleꢀpromoted energy transfer between
compound 6 and compound 7
Host
Fluorophore Increase
Donor Decrease
1
35 fluorescence data. H NMR data also supports the formation of a
Macrocycle 1
Macrocycle 2
Macrocycle 3
Macrocycle 4
3.3
5.3
2.4
3.6
0.90
0.57
0.80
0.72
1:2 complex, as the NMR shifts of peaks A and B shifted
substantially on going from 0 equivalents to 2 equivalents of
benzo[a]pyrene, and only minimally between 2 equivalents and 4
equivalents of benzo[a]pyrene.
40 In addition to their ability to bind PAHs, macrocycles 1ꢀ4 were
also investigated for their ability to promote energy transfer from
analytes 5 and 6 to highly fluorescent BODIPY 7.18 The success
of this proximityꢀinduced energy transfer depends significantly
on whether the PAH donors and fluorophore acceptors bind in the
a 360 nm excitation in all cases; fluorophore increase calculated
75 according to Equation 2 and donor decrease calculated according to
Equation 1. Control experiments in the absence of a macrocycle showed
no significant energy transfer.
The results clearly indicate that macrocycle 2 was the most
efficient host for nonꢀcovalent energy transfer, as measured both
2
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DOI: 10.1039/C3CC45128C
by the increase in fluorophore emission more than 5ꢀfold and by
increased steric bulk.
the decrease in donor emission to 57% of its initial value (Figure 45 In summary, reported herein is the use of aromatic organic
5a and 5b). The minimal amount of excimer emission observed in
these spectra strongly suggests that fluorophore 7 displaces one
molecule of benzo[a]pyrene from the macrocycle’s interior.
Interestingly, macrocycle 4 was substantially less efficient than
macrocycles as supramolecular hosts for PAH binding and nonꢀ
covalent energy transfer. One of the new macrocycles, compound
2, is substantially more efficient than known macromolecules at
binding benzo[a]pyrene and promoting energy transfer from this
5
macrocycle 2 at promoting supramolecular energy transfer 50 toxin to a fluorophore. More generally, the ability to modify the
between benzo[a]pyrene 6 and BODIPY 7 (Figure 5c and 5d).
The only difference between the two hosts is the replacement of
10 the perfluorophenyl ring in macrocycle 2 with a phenyl ring in
macrocycle 4, which effectively removes the electronic
supramolecular host for this energy transfer via synthetic organic
chemistry provides optimal flexibility in tuning and optimizing
such nonꢀcovalent energy transfer. The scope of macrocycleꢀ
promoted energy transfer and its use in arrayꢀbased detection
dissymmetry from the structure. This direct comparison indicates 55 scheme is currently under investigation, and results will be
that electronic dissymmetry provides
a
direct benefit for
reported in due course.
supramolecular energy transfer efficiencies.
15 Macrocycle 2 was also substantially more efficient at promoting
such energy transfer compared to γꢀcyclodextrin.5 Using γꢀ
cyclodextrin as a supramolecular host resulted predominantly in
the formation of a benzo[a]pyrene excimer, with only weak
energy transfer observed. This excimer effectively obscured the
20 fluorophore emission peak, rendering such a system ineffectual
for benzo[a]pyreneꢀbased energy transfer and detection. In
contrast, using macrocycle 2 resulted in a strong BODIPY peak
and minimal benzo[a]pyrene excimer emission under identical
experimental conditions. The ability to use benzo[a]pyrene in
25 such energy transfer schemes (and detection schemes based on
such energy transfer) is particularly relevant, due to the high
toxicity and known carcinogenicity of benzo[a]pyrene.20 Control
experiments with macrocycle 2 and BODIPY 7 indicated that no
energy transfer occurred from the very weakly fluorescent
30 macrocycle to the BODIPY fluorophore.
Notes and references
a Department of Chemistry, University of Rhode Island, 51 Lower College
Road, Kingston, RI 02881, USA. Fax 401-874-5072; Tel: 401-874-4243;
60 E-mail: mlevine@chm.uri.edu
† This research was funded in part by a grant from the Gulf of Mexico
Research Initiative (GOMRI).
† Electronic Supplementary Information (ESI) available: Syntheses of
macrocycles 1ꢀ4, fluorophore 7, 1H NMR titration details, fluorescence
65 experimental details, copies of spectra for all new compounds. See
DOI: 10.1039/b000000x/
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