Synthesis of Macrocyclic Receptors with Intrinsic Fluorescence Featuring Quinizarin Moieties

Article abstract of DOI:10.1021/acs.joc.5b00223

An unprecedented class of macrocycles with intrinsic fluorescence consisting of phenolic trimers and quinizarin is developed. Though they are lacking strong hydrogen bonds as observed in calixarenes, the two examples introduced here each adopt a vase-like

Full text of DOI:10.1021/acs.joc.5b00223

Article
pubs.acs.org/joc
Synthesis of Macrocyclic Receptors with Intrinsic Fluorescence
Featuring Quinizarin Moieties
M. Burger,† F. Katzsch,† E. Brendler,‡ and T. Gruber*,†
̈
†Institute of Organic Chemistry, Technische Universitat Bergakademie Freiberg, Leipziger Strasse 29, Freiberg/Sachsen, Germany
̈
‡Institute of Analytical Chemistry, Technische Universitat Bergakademie Freiberg, Leipziger Strasse 29, Freiberg/Sachsen, Germany
̈
S
* Supporting Information
ABSTRACT: An unprecedented class of macrocycles with intrinsic fluorescence consisting of phenolic trimers and quinizarin is
developed. Though they are lacking strong hydrogen bonds as observed in calixarenes, the two examples introduced here each
adopt a vase-like conformation with all four aromatic units pointing in one direction (syn orientation). This “cone” conformation
has been confirmed by NMR spectroscopy, molecular modeling, and X-ray crystallography. The laminar, electron-rich
fluorophore as part of the macrocycle allows additional contacts to enclosed guest molecules.
lower rim or in lateral positions,11 hence bearing the responsive
unit more or less in the periphery of the molecule. A rather less
INTRODUCTION
■
Because of their high sensitivity, selectivity, and response time,
developed approach is the replacement of the phenolic units of a
calixarene against fluorogenic moieties, which so far had only
been shown for a complete exchange in the case of the
calixnaphthalenes.12 To the best of our knowledge, the
replacement of only one of the phenolic units of a calixarene
has not been explored yet, though the combination of
conformational flexibility on the one hand and rigidity on the
other seems a rather auspicious concept (Scheme 1). By inserting
a condensed aromatic system, the resulting receptor is envisaged
to enable better C−H···π and cation···π interactions with a
methylammonium ion guest and at the same time allow an
efficient quantification of host/guest interactions.
fluorescence-based analytical techniques are extensively used in
different fields of science. Respective sensors have been
employed to detect a wide range of chemical and biochemical
species as for example cations, anions, neutral molecules,
biochemical analytes, and gases.1 Thereby, the quality of the
complexation equilibrium is indicated by a change in the
intensity of the emitted light.2 In many cases, the sensor-active
materials used consist of a macrocycle connected to a pendant
fluorophore. Much less studied are examples where the
fluorophore is part of the recognition unit. The relevant
literature very often includes condensed aromatic compounds
such as naphthalene,3 anthracene,4 pyrene,5 fluorene,6 or related
fluorophores.7
As a proof of concept to our approach, we advanced the
synthesis of two rather simple representatives (1 and 2),
featuring a tert-butyl group at the upper and methoxy units at the
lower rim. As a fluorophore, we chose quinizarin (1,4-
dihydroxyanthraquinone)13,14 delivering a receptor with a well-
balanced combination of soft π-electrons and hard H-bond
acceptors (CO, OR), which is joined with putative function-
alized phenolic trimers via ether bridges (Scheme 2).
During our research on artificial hosts for methylammonium
ions, we focused on cyclophanes as the macrocyclic recognition
unit. They are a well-known class of supramolecular receptors,
with the name being derived from their general constitution as
“cyclic phenyl alkanes”.8 Especially [1n]m-cyclophanes, so-called
calixarenes, have attracted considerable attention over the last
decades and are one of the best investigated cyclophane
subfamilies,9 as they have a rather stable cavity and advantageous
host/guest properties.10 Moreover, they are easily prepared and
allow a wide range of derivatization reactions, which make them
ideal candidates for the preparation of sensor-active compounds.
In most cases, fluorophores were introduced at the upper or
Received: January 30, 2015
Published: April 16, 2015
© 2015 American Chemical Society
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Scheme 1. Exchange of a Phenolic Unit of a Calix[4]arene against a Fluorophore Leads to a Receptor with Intrinsic Fluorescence
a
Scheme 2. (a) Synthesis of Monodemethylated Trimer 5. (b) Syntheses of Macrocycles 1 (58%) and 2 (18%)
a
Reaction conditions: (i) 1. NaH, THF/DMF, 2. MeI; (ii) (CH2O)n, ZnBr2, HBr/AcOH; (iii) K2CO3, acetone.
Scheme 3. (a) Selective Ether Scission Induced by C−H···Br Contacts of the Double Bisbromomethylated Intermediate in the
a
Synthesis of 5. (b) The Energy-Minimized Structure Delivers C−H···Br Distances of 2.92 and 2.96 Å, Respectively
a
Only one of the bromomethylated anisole units is shown in detail.
trimers (5 or 6, respectively). As the preparation of 615 has been
RESULTS AND DISCUSSION
■
achieved by a Blanc-analogue reaction on 316 as described for a
Syntheses of Fluorescophanes 1 and 2. The key step
during the synthesis of the two title compounds is the formation
related compound,17 we want to focus here on the synthesis of 5.
of ether bridges between quinizarin and bisbromomethylated
For similar partially methylated oligomers, two different
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procedures have been applied so far: partial methylation of
phenolic trimers with dimethyl sulfate18 on the one hand and
isoaromatization of cyclohexanone derivatives19 on the other.
We perceived another route via selective demethylation of a
permethylated trimer as starting material. For that purpose,
phenolic trimer 3 has been fully methylated in the first step to
yield trimethoxy derivative 4, which was subsequently treated
with paraformaldehyde, zinc bromide, and hydrogen bromide in
acetic acid (Scheme 2). In the first step of the reaction, two
CH2Br groups are introduced into the molecule, similar to a
Blanc reaction. For the originating compound, we assume an
interaction of the CH2Br bromine atoms with the methoxy
groups located at the same aromatic unit, withdrawing electron
density from the respective ether oxygen atom. Suggested by
molecular modeling, C−H···Br contacts are about 2.92 and 2.96
Å, respectively, which is shorter than the sum of the van der
Waals radii of hydrogen and bromine (3.05 Å). Hence, the
electrophilic attack of a proton, viz., the first reaction step of an
ether scission, will preferably occur at the central anisole moiety
(Scheme 3).
With all particular trimeric fragments in hand, the synthesis of
macrocycles 1 and 2 was implemented. Potassium carbonate has
been applied as a base to deprotonate the two phenolic hydroxyl
groups of quinizarin and facilitates a nucleophilic substitution
analogously to a Williamson ether synthesis. As trimer 5 contains
phenolic protons such as quinizarin, we examined the calculated
pKa values: 7.5 for quinizarin and 10.3 for a monophenolic
trimer20 similar to 5. Thus, quinizarin is expected to be
deprotonated over 100 times faster than trimer 5. To yield the
smallest possible cycle during reaction, we used a high dilution
apparatus21 applying the principle of Ziegler and Ruggli.22 With
this concept, title compounds 1 and 2 were synthesized in
moderate to good yields (58% and 18%, respectively). The
somewhat lower yields in the cyclization step of 2 may be
attributed to the phenolic hydrogen at the middle aromatic unit
of trimer 5: it is feasible to assume that it is also abstracted to a
certain extent during the reaction delivering side products.
Conformational Studies. The given similarity of the target
compounds with calixarenes suggests an analogue conforma-
tional behavior. As described for permethylated calix[4]arenes,23
we expected rather complicated 1H and 13C NMR spectra for 1
and 2. Surprisingly, both compounds delivered very clear NMR
data (Figures S4−S7, Supporting Information, SI). In the 13C
NMR spectra the signals for Ar−CH2−Ar were found at 31.5 (1)
and 30.3 ppm (2), suggesting a syn orientation for the three
aromatic units involved.24 Together with the 1H NMR data for
the aromatic protons, this points to a stable, highly symmetric
conformation (cone) at room temperature. In both macrocycles,
two constitutionally different methylene bridges can be
identified, Ar−CH2O−Ar and Ar−CH2−Ar, producing different
chemical shifts. The OCH2 group in 1 gives a broad singlet at
5.37 ppm; in 2 we found a broad doublet at 5.42 ppm. Whereas 2
delivers two broad singlets for the Ar−CH2−Ar protons at 3.43
and 4.30 ppm, the analogous signals in 1 are extremely
broadened due to coalescence, underlying the signals of the
OMe groups. These findings indicate unstable conformations at
room temperature that may be explained from conformational
conversions in 1 and 2. These do not affect the chemical and
magnetic environments of the aromatic nuclei, however, but do
significantly for the methylene bridges.
Figure 1. Details of the 1H NMR spectra of 1 (a) and 2 (b, c) at different
temperatures in CDCl3.
rather flexible, indicating a lower coalescence temperature than
observed for the tert-butylcalix[4]arene (52 °C25 in CDCl3). As
the temperature had been lowered, the broad singlets of Ar−
CH2O−Ar split into a pair of doublets with 2J coupling constants
The broad signals for the bridging methylene groups
stimulated 1D and 2D NMR studies at lower temperatures,
with typical spectra displayed in Figure 1. Both title molecules are
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Figure 2. Observed NOEs, indicated by dotted lines, for title compounds 1 (a) and 2 (b) in CDCl3 at 20 °C. No NOE contacts indicating conformations
other than a cone were observed for either cyclophane.
of 15 Hz for 1 and 2. Lacking of strong hydrogen acceptors, 1
shows a higher flexibility than 2 as also proven by the behavior of
the Ar−CH2−Ar units: even at −40 °C the conformational
conversion in compound 1 does not allow the complete
resolution of the couplings between the axial (endo) and
equatorial (exo) protons (2J = 15 Hz, each). Interestingly, in 2
the aromatic protons H3 (H19) and H5 (H17) of ring A (C),
H37 (H38) at quinizarin ring D, and the hydroxyl proton are
subjected to a considerable downfield shift during cooling. We
attribute this to a decreasing thermal dynamic mobility of the
pending hydroxyl and methoxy groups. It is feasible to assume
that at the same time hydrogen bonding of H37 (H38) and the
hydroxyl proton with the two oxygen atoms of the methoxy
groups is strengthened. Hence, the aromatic protons H3 (H19)
and H5 (H17) of ring A (C) are turning slightly away from the
shielding cyclophane cavity. For the aromatic region of cycle 1 we
only found insignificant shifts during cooling for H5 (H17), H10
(H12), and H37 (H38), though not for H3 (H19). Noteworthy,
all aromatic signals exhibit broadening as the temperature was
lowered, suggesting dynamic conformational exchange (Figure
S8, SI).
As the pending methoxy groups are not directly involved in the
coalescence, we anticipated sharp 1H NMR signals for OCH3 at
room temperature, which proved to be true for cycle 2. A
respective singlet at 3.91 ppm for the OCH3 groups indicates a
more or less rigid cavity, supposedly fixed by strong O−H···O
hydrogen bonds between the hydroxyl and the methoxy
moieties. In 1 only the central methoxy group delivered a
sharp singlet (3.67 ppm). However, the methyl groups of the two
outer anisole units in 1 gave a rather broad singlet at 3.72 ppm.
Obviously, the methoxy group at ring B is much more flexible at
room temperature than the ones at ring A and C. The OCH3
signal on the B ring was broadened and upfield-shifted (3.67 ppm
→3.18 ppm) with the temperature lowering; this is typical for
methoxy groups pointing into a cyclophane cavity.26 As the
conformation of the macrocyclic backbone is getting more stable
while cooling to −40 °C, the free rotation of methoxy group B is
obstructed and slowed down to the NMR time scale. Owing to
the obstructed rotation of the methoxy group(s), a rather low
resolution of the two doublets of Ar−CH2−Ar and the
broadened OCH3 singlet(s) even at −45 °C is observed.
In principle, the anthraquinone units in the target molecules
can adopt two positions: opposite the anisole moieties or away
from them. To solve this issue, we performed 2D NOESY spectra
of 1 and 2 at room temperature and −40 °C (for 2), elucidating
the proximity of the different aromatic units of the molecule
(Figure 2 and Figures S9 and S10, SI). For both macrocycles, we
found NOEs between the aromatic protons H5/H10 and H12/
H17 (1: 6.81/7.25 ppm; 2: 6.89/7.19 ppm) indicating that all
three aromatic moieties are in a syn conformation even at room
temperature. This is also confirmed by interactions between the
tert-butyl groups of rings A and C with the one of ring B (0.86/
1.38 ppm for 1 and 0.88/1.34 ppm for 2). The arrangement of
the anthraquinone unit has been determined from interactions of
quinizarin ring D (H37) with other regions of the molecule. For
1, we observed NOEs between H37 and OCH2 (6.78/5.37) as
well as H37 to the methoxy group of ring B (6.78/3.63), which is
only possible when all four aromatic units are in a syn
arrangement, i.e., the macrocycle is in a cone conformation.
The same conformation can be assumed in 2, as its OH group is
involved in dipolar interactions with H37/38 of ring D (6.62/
7.13 ppm). At −40 °C we were able to identify additional NOEs
between H5 (H17)/H10 (H12) and the axial proton of the
adjacent methylene bridges.
Molecular Modeling Studies. For supplementing the
spectroscopy studies on the conformational properties of both
macrocycles, we performed molecular modeling studies. With
exception of a strong hydrogen bond between the phenolic OH
and a neighboring methoxy moiety in 2, no strong hydrogen
bonds have been found. However, the quinizarin units in both
target molecules are engaged into inverse-bifurcated C−H···O
contacts (Figure 3), stabilizing the cone conformation of both
cycles (Figure S1, SI).
Single X-ray Studies. To verify the results from the
spectroscopic and the modeling studies, we investigated the
molecular structure of the title compounds by X-ray crystallog-
raphy. When crystallized from acetonitrile/chloroform and
acetonitrile, respectively, compounds 1 and 2 gave the inclusion
compounds 1a [1·acetonitrile·chloroform (2:2:1)] and 2a [2·
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Table 1. Selected conformational parameters of compounds
1a and 2a
a
interplanar angles (deg)
1a (1)
1a (2)
2a
mpla A/mpla C
41.9
79.2
73.1
41.8
72.8
37.7
11.0
45.0
35.9
68.5
78.1
36.5
74.0
32.1
11.0
40.1
33.4
76.4
79.5
51.4
72.4
52.3
8.6
b
mpla B/mpla Q
c
mpla M /mpla A
mpla M/mpla B
mpla M/mpla C
mpla M/mpla Q
mpla D/mpla F
ACN/mpla M
Figure 3. Common H-bonding motif in 1 and 2 found by molecular
modeling studies. 1: a = 2.721 Å, 2.692 Å; b = 2.729 Å, 2.752 Å; 2: a =
2.543 Å, 2.638 Å; b = 2.583 Å, 2.630 Å.
46.8
a
Aromatic rings: ring A: C1···C6; ring B: C8···C13; ring C: C15···
b
acetonitrile (3:1)] (Table S1, SI). Perspective views of the
asymmetric units and the crystal packings are displayed in
Figures 4−7. For the description of the molecular conformations
of the host compounds, we determined the inclination of the
aromatic rings with respect to the mean plane of the four
methylene groups of the molecules. Complementarily, the
dihedral angles between pairs of opposite arene rings have
been designated. These parameters together with structural
details on the quinizarin units are summarized in Table 1;
specifics on hydrogen bonds and other contacts are listed in
Table S2 (SI).
C20; ring D: C36···C49; ring F: C42···C47. Best plane through
atoms of the quinizarin unit: C36···C49. Best plane through the
c
carbon atoms of the methylene bridges C7, C14, C35, C50.
Crystallization of trimethoxy receptor 1 from acetonitrile/
chloroform (1:1) gives inclusion compound 1a in the monoclinic
space group C2/c. The asymmetric unit consists of two
crystallographically independent host molecules, two acetonitrile
(ACN) molecules, and one molecule of chloroform. The
CH3CN guests are incorporated within the host cavities, the
chloroform is situated clathrate-like in lattice voids. (In total, the
Figure 4. (a) Molecular structure of macrocycle 1 in the 2:2:1 inclusion with acetonitrile and chloroform (1a). Only host molecule 1 is displayed; all
guest molecules and hydrogen atoms have been omitted for clarity. The disorder of the two tert-butyl groups concerned is not displayed. (b) Asymmetric
unit of 1a shown with 50% displacement probability. Only hydrogen atoms involved in intra- and intermolecular contacts are presented.
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structure contains a solvent-accessible void of ca. 40 Å3). In both
independent hosts of 1a, viz., molecule 1 and molecule 1′, the
four aromatic units of the macrocycle point in the same direction
with corresponding interplanary angles A/C and B/quinizarin of
41.9° (35.9°) and 79.2° (68.5°), respectively (Figure 4a, Table
1). For the centroid-to-centroid distance between the facing
arenes, we found 6.83 Å (6.75 Å) and 7.00 Å (7.18 Å), which is
considerably larger than for pinched cone calixarenes.27 By way
of interest, the bulky quinizarin moiety points toward the cavity.
This conformation seems to be stabilized by intramolecular C−
H···O contacts [d(O···H) = 2.32−2.64 Å] between two aromatic
protons of the quinizarin (H37, H38; H87, H88) and the oxygen
atoms of two outer methoxy groups (O1, O3; O8, O10). In
Figure 4b the trapezoidal form of the cavity becomes obvious,
being a result of the ring extension by two oxygen atoms
compared to a calix[4]arene. The anthraquinone moieties are
both bended by 11°; a phenomenon which is also observed in the
structures of quinizarin28 (1.5°), dimethoxyquinizarin29 (22.0°),
and quinizarin diacetate30 (8.1°). As it is typical for tert-butyl
groups, one in each independent host molecule is disordered
(SOF = 94.4% and 5.6%).
The acetonitrile molecules within the cavities of molecules 1
and 1′ are tilted by 40.0° and 45.1°, respectively, against the mean
plane of the methylene bridges; they are more or less collinear
with the aromatic rings B and B′. The ACN methyl groups point
into the cavity; each of these endo CH3CN guests is fixed by one
C−H···π contact to the aromatic unit A (A′) [d(centroid···H) =
2.88 and 2.29 Å, respectively] and one C−H···O contact to the
methoxy oxygen of ring B (B′) [d(O···H) = 2.56 and 2.57 Å,
respectively]. In contrast, the slightly acidic H atom of the exo
guest chloroform is engaged in a three-centered hydrogen
bond.31 Additionally, we found a Cl···π contact32 to the ring B′ in
molecule 1′ [d(centroid···Cl) = 3.505(2) Å].
The two independent molecules 1 and 1′ are connected via
their anthraquinone units developing a handshake-like motif.
The distance of rings F and F′ is 3.411 Å, which suggests aromatic
face-to-face contacts. By way of interest, also the quinone moiety
is engaged into these interactions. In the overall packing, we
found slightly displaced stacks of quinizarin residues units in the
direction of the crystallographic c axis featuring π···π stacking
[d(D···D) = 3.454(2) Å] (Figure 5). Thereby, two dependent
molecules are additionally connected via C−H···O contacts
involving methylene and methoxy groups and quinizarin oxygen
atoms [d(centroid···H) = 2.53−2.46 Å].
When crystallized from acetonitrile, title compound 2 was
found to form a 1:3 inclusion compound (2a) in the monoclinic
space group P21/n (Figure 6). One of the guest molecules is
accommodated inside the cavity (endo) and the two others
outside the cavity (exo) of the host molecule. Similar to 1a, the
macrocyclic framework adopts a pinched cone conformation
with interplanary angles of 33.4° (A/C) and 76.4° (B/
quinizarin), respectively (Table 2). The cup-shape of the
molecule is stabilized by a strong O−H···O hydrogen bond,
which links the phenolic hydroxyl group to one of the
neighboring methoxy atoms. Like in 1a, the sterically demanding
anthraquinone moiety is turned toward the cavity (mpla M/mpla
Q = 52.3°), and again we found stabilizing C−H···O contacts
involving the two methoxy oxygens and quinizarine ring D
[d(O···H) = 2.49 and 2.75 Å, respectively] The enlarged cavity is
able to incorporate one acetonitrile molecule which is fixed by
three C−H···π-interactions33 to the aromatic rings A, B, and C.
Noteworthy, it is tilted by an angle of 48.7° against the mean
plane of the four carbon atoms of the methylene bridges and
Figure 5. Packing details in the inclusion compound 1a. The
characteristic stacking of the anthraquinone moieties is highlighted in
gray. Disordered tert-butyl groups, guest molecules, and hydrogen atoms
are omitted for clarity.
thereby parallel to the quinizarin unit. Very likely, the reasons for
this is a kind of π···π stacking, involving quinizarin ring D and the
CN triple bond in the acetonitrile [d = 3.384(2) Å]. Additionally,
the latter is engaged in an intramolecular C−H···π contact with a
tert-butyl H atom H30 (d = 2.83 Å).
In the packing of 2a, two hosts are paired via their quinizarin
units developing C−H···π contacts [d(H35A···centroid F) =
2.93 Å]. Interestingly, we also observed a close proximity
between bridge oxygen O4 and a neighboring quinone unit in
ring E [d = 3.215(2) Å] (Figure 7). These contacts resemble
charge-transfer-like complexes which are already known from
quinones and sulfur.34 Unlike molecule 1, we observe no
continuous aromatic stacking. In the overall packing, all three of
the included solvent molecules take part with the exo-oriented
acetonitrile molecules mediating the connection of the host
molecules.
Fluorescence Studies. To extensively characterize the new
receptors 1 and 2, we studied their luminescent behavior in
DMSO solution in comparison to that of quinizarin (1,4-
dihydroxyanthraquinone) and 1,4-dimethoxyanthraquinone.35
The absorption and fluorescence spectra are presented in Figure
8. Absolute excitation maxima, λ(ex)max, absolute emission
maxima, λ(em)max, and the associated Stokes shifts are
summarized in Table 2. The Lambert−Beer law is valid in the
entire concentration interval. The fluorescence spectra have been
collected at the respective absorption maxima.
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Figure 6. Molecular structure of 2a, showing 50% probability displacement representation.
develop a rather pronounced plateau; this may result from a
higher aggregation of the molecules.
Table 2. Fluorescence Data for 1, 2, Quinizarin, and 1,4-
Dimethoxyanthraquinone in DMSO (20 °C)
1,4-
CONCLUSION
compound
1
2
quinizarin
dimethoxyanthraquinone
■
λ(ex)max (nm)
423
539
116
438
548
110
481
560
79
426
540
114
Two unprecedented cyclophanes (1 and 2) with intrinsic
fluorescence have been synthesized from putative linear trimers
and quinizarin applying the principle of Ziegler and Ruggli.22 The
constitution of the molecules is related to that of methylated
calixarenes, though we observed a different conformational
behavior. In general, trimethoxy cycle 1 shows a flexibility higher
than that of the monophenolic cycle 2, which is stabilized by a
strong hydrogen bond. For each of the title compounds,
temperature-dependent 1H NMR spectroscopy revealed a typical
sharpening of the methylene resonances and a conformational
stabilization with decreasing temperatures. These findings justify
the assumption of “cone” conformations with all four aromatic
units pointing in one direction for both cycles. This hypothesis is
supported by respective shifts of the methylene carbons in the
13C NMR spectra and pertinent NOEs. The cup-shape of both
title molecules has also been confirmed by molecular modeling
and X-ray crystallography. It seems opportune to assume that C−
H···O contacts between the methoxy oxygen atoms and the
λ(em)max (nm)
Stokes shift (nm)
Quinizarin shows a broad absorption maximum at 481 nm,
which corresponds to the red color of its solution. Macrocycles 1
and 2 as well as 1,4-dimethoxyanthraquinone experience a
hypsochromic shift to 423, 438, and 426 nm, respectively, being
in coherence with their yellow solutions. The color change is
obviously a result of the altered electronic situation connected
with the etherification of the hydroxyl groups of the quinizarin.
The fluorescence maxima for 1 and 2 have been determined with
539 and 548 nm, which is slightly lower than for quinizarin (560
nm) and similar to 1,4-dimethoxyanthraquinone (540 nm). The
resulting Stokes shifts are considerable higher for the macro-
cycles and 1,4-dimethoxyanthraquinone than for quinizarin. By
way of interest, the excitation and emission spectra of quinizarin
Figure 7. (a) Dimer formation in the packing of 2 in its 1:3 acetonitrile inclusion compound (2a). Guest molecules and hydrogen atoms are left out for
clarity. (b) The two paired anthraquinone units in 2a resemble a charge-transfer complex.
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Figure 8. Excitation and fluorescence emission spectra of macrocycles 1 (a), 2 (b), quinizarin (c), and 1,4-dimethoxyanthraquinone (d) at different
concentrations in DMSO.
fluorescence measurements have been carried out using quartz cuvettes
quinizarin fulfill here the function of the strong O−H···O bonds
(10 × 10 mm) and diluting the respective stock solutions in DMSO (1: c
= 1.3 mmol/L; 2: c = 1.2 mmol/L; quinizarin: c = 1.2 mmol/L; 1,4-
dimethoxyanthraquinone: c = 1.2 mmol/L) to the concentrations
specified. NMR spectra were recorded at 500.1 (1H NMR) and 125.7
MHz (13C NMR), respectively, with sample temperatures regulated at
293 K, unless otherwise stated. Spectra have been assigned using COSY,
DEPT-135, HSQC, and HMBC. Chemical shifts δ are reported in parts
per million relative to the internal reference TMS. Multiplicity is
abbreviated as follows: s (singlet), d (doublet), t (triplet), and m
(multiplet). Analytical TLC was performed on precoated silica gel plates
(60 F254). The reagents and solvents were used as purchased from the
chemical suppliers, with the exception of those for cyclization reaction
(dried dynamically over molecular sieves, 3 Å). The trimers 316 and 615
as well as quinizarin36 were prepared according to literature procedures.
1,4-Dimethoxyanthraquinone is commercially available. For the energy
minimizations, we used the program MacroModel V.9.8 (OPLS_2001
force field, MCMM, 1000 steps).
5-tert-Butyl-1,3-bis(5-tert-butyl-2-methoxybenzyl)-2-me-
thoxybenzene (4).37 The phenolic trimer 3 (5.50 g, 11.6 mmol) was
dissolved in THF (130 mL) and DMF (10 mL). Subsequently, NaH
(60% in paraffin, 3.00 g, 127.6 mmol) and MeI (8.7 mL, 139.50 mmol)
were added carefully. Heating under reflux for 4 h produced a white
precipitate. Subsequently, the solvent was evaporated and the residue
taken up in chloroform and water. The organic phase was separated and
the solvent removed almost completely. The white precipitate of 4
formed after addition of MeOH was filtered, washed first with MeOH
and then with ether, and dried afterward. Yield: 5.85 g (97%). Mp 138−
found in calixarenes to stabilize the cone conformation. Morever,
fast exchange processes in the NMR spectra of 1 and 2 suggest
two rather similar cone forms for each cycle similar to pinched
cone calixarenes.
As demonstrated by excitation and fluorescence emission
spectra, the incorporation of an anthraquinone unit into a
cyclophane does not change its luminescent behavior. The
additional plane, electron-rich fluorophore in 1 and 2 allows
additional interactions toward potential guest molecules as
shown for acetonitrile complexes. We found a better fit between
host and guest with more stabilizing C−H···O and C−H···π
contacts in comparison to the somewhat smaller calix[4]arenes.
This is especially true for cycle 2, where all three hydrogen atoms
of the acetonitrile molecule are involved in the complexation. By
regarding acetonitrile as a simple model of methylamines, these
findings are encouraging the further development of this
promising new class of macrocycles. Our next step in this
respect will be the introduction of hydrophilic groups to the
molecules resulting in water-soluble receptors.
EXPERIMENTAL SECTION
Materials and Methods. Melting points have been determined on a
microscope heating stage and are uncorrected. IR spectra were
measured as KBr pellets and with the ATR method. The UV/vis and
■
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DOI: 10.1021/acs.joc.5b00223
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The Journal of Organic Chemistry
Article
139 °C (lit.:38 140−141 °C). 1H NMR (CDCl3): 1.17 (s, 9H, C(CH3));
1.22 (s, 18H, C(CH3)); 3.61 (s, 3H, ArOCH3); 3.81 (s, 6H, ArOCH3);
4.03 (s, 4H, ArCH2Ar); 6.80 (d, 2H, ArCH, 3JHH = 8.5 Hz); 6.98 (s, 2H,
9H, C(CH3)); 3.50 (s, 2H, ArCH2Ar);39 3.63 (s, 3H, ArOCH3); 3.72 (s,
6H, ArOCH3); 4.31 (s, 2H, ArCH2Ar);39 5.37 (s, 4H, ArCH2OAr); 6.78
(s, 2H, 37-, 38-ArCH); 6.81 (s, 2H, 5-, 17-ArCH); 7.11 (d, 2H, 3-, 19-
ArCH, 4JHH = 1.5 Hz); 7.25 (s, 2H, 10-, 12-ArCH); 7.69 (m, 2H, 44-, 45-
ArCH); 8.18 (m, 2H, 43-, 46-ArCH); 13C NMR (CDCl3): 31.0
(C(CH3)); 31.5 (CH2); 31.6 (C(CH3)); 33.9, 34.2 (C(CH3)); 60.3,
62.3 (ArOCH3); 64.4 (OCH2); 122.7 (40-, 49- ArC); 123.0 (37-, 38-
ArC); 124.0 (3-, 19-ArC); 126.3 (43-, 46-ArC); 126.8 (10-, 12-ArC);
127.0 (5-, 17-ArC); 128.3 (2-, 20-ArC); 132.9 (9-, 13-ArC); 133.0 (44-,
45-ArC); 134.3 (42-, 47-ArC); 134.5 (6-, 16-ArC); 145.8 (11-ArC);
146.7 (4-, 18-ArC); 151.9 (36-, 39-ArC); 153.8 (1-, 15-ArC); 155.0 (8-
ArC); 183.4 (CO). m/z (SI): Calcd: 780.40, found: 803.37 (M +
Na+). IR (cm−1): 3442, 2960, 2905, 2870, 2826, 1668, 1595, 1567, 1483,
1465, 1255, 1238, 1216, 1014, 727. Elemental analysis calculated for
C51H56O7·1/2CH3COOCH2CH3: C, 77.16%; H, 7.33%. Found: C,
77.01%; H, 7.36%.
ArCH); 7.06 (d, 2H, ArCH, 4JHH = 2.5 Hz); 7.18 (dd, 2H, ArCH, 3JHH
=
8.5 Hz, JHH = 2.5 Hz); 13C NMR (CDCl3): 30.0 (CH2), 31.4, 31.5
(C(CH3)); 34.0, 34.2 (C(CH3)); 55.4, 61.0 (ArOCH3); 109.7, 123.3,
126.1, 127.7, 129.1, 132.5, 142.8, 145.9, 154.9, 155.4 (ArC). m/z (SI):
Calcd: 516.36, found: 555.26 (M + K+) IR (cm−1): 2951, 2901, 2865,
2836, 1609, 1505, 1461, 1245, 1135, 1011, 816. Elemental analysis
calculated for C35H48O3: C, 81.35%; H, 9.36%. Found: C, 81.72%; H,
9.82%.
4
1,3-Bis{[3-(bromomethyl)-5-(tert-butyl)-2-methoxyphenyl]-
methyl}]-5-(tert-butyl)-2-hydroxybenzene (5). Methyl ether 4
(3.00 g, 5.8 mmol), paraformaldehyde (0.42 g, 14.0 mmol), and glacial
acetic acid (40 mL) were stirred for 1 h at 70 °C in a bomb tube. To the
white suspension were added zinc bromide (1.30 g, 5.8 mmol) and
hydrogen bromide (33% in glacial acetic acid, 5.8 mL), and stirring was
continued for 5 h at 70 °C. After cooling, the clear brown solution was
poured into water, whereupon a white cloudy suspension appeared.
After extraction with CH2Cl2, the organic phase was dried over MgSO4
and the solvent was evaporated under reduced pressure. The resulting
brown oil was column chromatographed on SiO2 (eluent: n-hexane/
ethyl acetate, 14:1) to yield 0.38 g (9%) of a beige solid. Mp 158−160
°C. TLC: Rf = 0.19 (SiO2; n-hexane/chloroform, 1:1). 1H NMR
(CDCl3): 1.20 (s, 27H, C(CH3)); 3.93 (s, 4H, ArCH2Ar); 3.95 (s, 6H,
ArOCH3); 4.58 (s, 4H, ArCH2OAr); 6.98 (s, 2H, ArCH); 7.15 (d, 2H,
ArCH, 4JHH = 2.5 Hz); 7.24 (d, 2H, ArCH, 4JHH = 2.5 Hz); 7.34 (s, 1H,
ArOH); 13C NMR (CDCl3): 28.8, 31.0 (CH2); 31.3, 31.5 (C(CH3));
34.0, 34.3 (C(CH3)); 62.2 (ArOCH3); 125.6, 126.5, 126.7, 128.9, 130.3,
133.3, 142.7, 147.8, 149.9, 153.2 (ArC). m/z (APCI): Calcd: 688.19,
found: 687.50 [M−]. IR (cm−1): 3374, 2956, 2901, 2866, 1600, 1481,
1434, 1218, 1203, 988, 880, 751. Elemental analysis calculated for
C36H48Br2O3·2H2O: C, 59.67%; H, 7.23%. Found: C, 59.17%; H, 7.06%.
Additionally to 5, we isolated 0.15 g (4% yield) of the fully methylated
trimer 6.
41,81-Dimethoxy-2,10-dioxa-61-hydroxy-44,64,84-tri-tert-
butyl-1(1,4)-anthraquinona-4,6,8(2,6)-tribenzenacyclodeca-
phane (2). Yield: 75 mg (18%). Mp 234−236 °C. TLC: Rf = 0.22 (SiO2;
n-hexane/ethyl acetate, 2:1). 1H NMR (CDCl3): 0.88 (s, 18H,
C(CH3)); 1.34 (s, 9H, C(CH3)); 3.44 (br s, 2H, ArCH2Ar); 3.91 (s,
6H, ArOCH3); 4.30 (br s, 2H, ArCH2Ar); 5.38 (br s, 2H, ArCH2OAr);
5.45 (br s, 2H, ArCH2OAr); 6.62 (s, 1H, ArOH); 6.89 (d, 2H, 5-, 17-
ArCH, 4JHH = 2.5 Hz); 7.13 (s, 2H, 37-, 38-ArCH); 7.19 (s, 2H, 10-, 12-
ArCH); 7.23 (d, 2H, 3-, 19-ArCH, 4JHH = 2.5 Hz); 7.68 (m, 2H, 44-, 45-
ArCH); 8.15 (m, 2H, 43-, 46-ArCH); 13C NMR (CDCl3): 30.3 (CH2);
30.9, 31.7 (C(CH3)); 33.9, 34.0 (C(CH3)); 63.3 (OCH2); 63.8
(ArOCH3); 121.7 (37-, 38-ArC); 122.7 (40-, 49-ArC); 125.0 (3-, 19-
ArC); 126.2 (44-, 45-ArC); 126.4 (10-, 12-ArC); 126.5 (9-, 13-ArC);
127.1 (5-, 17-ArC); 128.2 (2-, 20-ArC); 132.0 (6-, 16-ArC); 132.9 (43-,
46-ArC); 134.5 (42-, 47-ArC); 142.1 (11-ArC); 147.8 (21-, 29-ArC);
150.0 (8-ArC); 151.5 (36-, 39-ArC); 152.5 (1-, 15-ArC); 183.3 (CO).
m/z (SI): Calcd: 766.39, found: 789.40 (M + Na+). IR (cm−1): 2953,
1667, 1635, 1591, 1568, 1483, 1237, 1210, 981, 795, 726. Elemental
analysis calculated for C50H54O7·1/2 CH3COOCH2CH3: C, 77.01%; H,
7.21%. Found: C, 76.91%; H, 7.60%.
X-ray Structure Determination. Crystals of compounds 1a, 2a,
and 4 suitable for X-ray diffraction have been obtained by slow
evaporation of the respective solution (1 in acetonitrile/chloroform
(1:1), 2 in acetonitrile and 4 in ethyl acetate). The intensity data were
collected at 100 K on a Bruker Kappa diffractometer equipped with an
APEX II CCD area detector and graphite-monochromatized Mo Kα
radiation (λ = 0.71073 Å) employing φ and ω scan modes. The data
were corrected for Lorentz and polarization effects. Semiempirical
absorption correction was applied using the SADABS program.40 The
SAINT program40 was used for the integration of the diffraction profiles.
The crystal structures were solved by direct methods using SHELXS-
9741 and refined by full-matrix least-squares refinement against F2 using
SHELXL-97.41 All non-hydrogen atoms were refined anisotropically.
Hydrogen atoms were positioned geometrically and allowed to ride on
their parent atoms. Geometrical calculations were performed using
PLATON, and molecular graphics were generated using SHELXTL.41
The crystallographic data for the structures in this paper have been
deposited with the Cambridge Crystallographic Data Centre; CCDC
numbers: 1042786 (1), 1042787 (2), and 1042788 (4).
1,3-Bis{[3-(bromomethyl)-5-(tert-butyl)-2-methoxyphenyl]-
methyl}]-5-(tert-butyl)-2-methoxybenzene (6). Under an argon
atmosphere, methyl ether 4 (4.75 g, 9.2 mmol), dissolved in TFA (20
mL), was treated with bromomethyl methyl ether (1.0 mL, 1.53 g, 12.3
mmol). After 24 h, the brownish solution was quenched with water,
followed by extraction with CHCl3. The organic phase was dried over
MgSO4, and the solvent was evaporated under reduced pressure. The
resulting green oil was column chromatographed on SiO2 (eluent: n-
hexane/chloroform, 1:1→ 1:2) to yield 0.70 g (11%) of a colorless oil,
which crystallized later. Mp 120−122 °C. TLC: Rf = 0.25 (SiO2; n-
1
hexane/chloroform, 1:1). H NMR (CDCl3): 1.16 (s, 9H, C(CH3));
1.21 (s, 18H, C(CH3)); 3.59 (s, 3H, ArOCH3); 3.84 (s, 6H, ArOCH3);
4.08 (s, 4H, ArCH2Ar); 4.61 (s, 4H, ArCH2Br); 6.94 (s, 2H, ArCH);
7.02 (d, 2H, ArCH, 4JHH = 2.5 Hz); 7.25 (d, 2H, ArCH, 4JHH = 2.6 Hz);
13C NMR (CDCl3): 29.1, 29.9 (CH2); 31.3, 31.4 (C(CH3)); 34.2, 34.3
(C(CH3)); 60.8, 61.3 (ArOCH3); 126.2, 126.2, 128.9, 130.3, 132.5,
133.9, 146.5, 147.0, 154.5, 154.7 (ArC). m/z (SI): Calcd: 702.21, found:
725.30 [M + Na+], 741.3 [M + K+]. IR (cm−1): 3672, 2955, 2826, 1583,
1480, 1220, 1203, 1006, 882. Elemental analysis calculated for
C36H48Br2O3·H2O: C, 62.45%; H, 7.22%. Found: C, 62.13%; H, 7.41%.
General Synthetic Procedures for Macrocycles 1 and 2. Under
an argon atmosphere, the respective trimer 5 or 6 and quinizarin, each
dissolved in dry acetone (250 mL per 0.55 mmol of the trimer), are
slowly dropped into a refluxing suspension of K2CO3 (4 equiv) in dry
acetone (100 mL per 0.55 mmol trimer) using a high-dilution
apparatus.21 The color of the reaction mixture changes from dark blue
to dark green. After 48 h of refluxing, solid components are removed by
filtration. The solvent was evaporated, and the resulting reddish brown
oil was column chromatographed on SiO2 (eluent for 1: chloroform/
ethyl acetate, 24:1; eluent for 2: n-hexane/ethyl acetate, 2:1) to yield
macrocycles 1 and 2 as orange solids.
ASSOCIATED CONTENT
■
S
* Supporting Information
Energy-minimized structures of 1 and 2. H and 13C NMR
1
spectra of compounds 1, 2, 4, 5, and 6; NOESY spectra of 1 and
2. Selected details of the data collection; table of distances and
angles of inter- and intramolecular contacts in the structures of
1a, 2a, and 4; description of the X-ray structure of 4. X-ray
crystallographic data files (CIF) for 1, 2, and 4. The Supporting
Information is available free of charge on the ACS Publications
website at DOI: 10.1021/acs.joc.5b00223.
2,10-Dioxa-44,64,84-tri-tert-butyl-41,61,81-trimethoxy-1(1,4)-
anthraquinona-4,6,8(2,6)-tribenzenacyclodecaphane (1). Yield
435 mg (58%). Mp 280−282 °C. TLC: Rf = 0.44 (SiO2; chloroform/
ethyl acetate, 24:1).1H NMR (CDCl3): 0.86 (s, 18H, C(CH3)); 1.38 (s,
4890
DOI: 10.1021/acs.joc.5b00223
J. Org. Chem. 2015, 80, 4882−4892

The Journal of Organic Chemistry
Article
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AUTHOR INFORMATION
■
Corresponding Author
*Tel: +49 3731 392390. E-mail: Tobias.Gruber@chemie.tu-
freiberg.de.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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̈
■
(14) Bhattacharya, D.; Sathiyendiran, M.; Wu, J.-Y.; Chang, C.-H.;
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Financial support from ‘Fonds der Chemischen Industrie’ and
the Institute of Organic Chemistry, University of Freiberg, is
gratefully acknowledged. Furthermore, we thank M. Stapf for his
helpful advice.
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