Azacalixquinarenes: From Canonical to (Poly-)Zwitterionic Macrocycles

Article abstract of DOI:10.1021/acs.joc.8b02847

Azacalixquinarenes, a new family of macrocycles composed of diaminobenzoquinone diimine units linked by dinitrobenzene rings, are synthesized by selective oxidation of the parent azacalixarenes. Crystallographic analyses of two compounds demonstrated the presence of canonical (uncharged) and zwitterionic quinones within a single structure. The electron-withdrawing nature of the dinitrobenzene moieties can trigger the intramolecular H-transfer that generates zwitterionic ground-state quinones. The nature of the N-substituents and the polarity of the solvent have a crucial impact on the equilibrium between the canonical and zwitterionic forms that present distinct optical and electrochemical properties. Thus, within [4]- and [6]-membered macrocycles, poly-zwitterionic structures can be reached, as demonstrated experimentally and theoretically using first-principle approaches.

Full text of DOI:10.1021/acs.joc.8b02847

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Article
Azacalixquinarenes: from Canonical to (Poly-)Zwitterionic Macrocycles
Simon Pascal, Lucien Lavaud, Cloé Azarias, Alexandre Varlot,
Gabriel Canard, Michel Giorgi, Denis Jacquemin, and Olivier Siri
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02847 • Publication Date (Web): 04 Jan 2019
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Azacalixquinarenes: from Canonical to (Poly-)Zwitterionic Macrocy-
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Simon Pascal,*,† Lucien Lavaud,† Cloé Azarias,‡ Alexandre Varlot,‡ Gabriel Canard,† Michel
Giorgi,§ Denis Jacquemin,*,‡ and Olivier Siri*,†
† Aix Marseille Université, CNRS UMR 7325, CINAM, Campus de Luminy, cas 913, 13288 Marseille cedex 09, France
‡ Laboratoire CEISAM, CNRS UMR 6230, Université de Nantes, 2, rue de la Houssinière, 44322 Nantes, France
§ Fédération des Sciences Chimiques de Marseille-Spectropole, FR 1739 Aix-Marseille Université, 13397 Marseille,
France
ABSTRACT: Azacalixquinarenes, a new family of macrocycles
constituted of diaminobenzoquinone diimine units linked by
dinitrobenzene rings are synthesized by selected oxidation of
the parent azacalixarenes. Crystallographic analyses of two
compounds demonstrated the presence of (uncharged) canoni-
cal and zwitterionic quinones within a single structure. The
electron-withdrawing nature of the dinitrobenzene moieties can
trigger the intramolecular H-transfer that generates zwitterion-
ic-ground state quinones. The nature of the N-substituents and
the polarity of the solvent have a crucial impact on the equilib-
rium between the canonical and zwitterionic forms that present
distinct optical and electrochemical properties. Thus, within [4]- and [6]-membered macrocycles, poly-zwitterionic struc-
tures can be reached, as demonstrated experimentally and theoretically using first-principle approaches.
ACP can be viewed as a masked conjugated azaca-
lixquinone. Its aromatic core involving 18 π-electrons
INTRODUCTION
Heteroatom-bridged calixarenes are an evolved class of
calixarene macrocycles1, 2 in which the introduction of a
bridging heteroatom in lieu of a methylene link provides
additional features such as: (i) the tuning of the cavity
size and of the conformation (e.g. 1,3-alternate structure);
(ii) new redox properties; and (iii) conjugation between
the units of the macrocyclic oligomer.3, 4 Beyond the wide
range of heteroatom-containing calixarenes developed
during the past decades, azacalixarenes (ACA) demon-
strated an undeniable versatility regarding structure-
properties shaping.5 Since seminal works in the late nine-
ties on polyazacalixarenes,6-10 this family has been grow-
ing to incorporate trypticene moieties,11, 12 pyridine units,13,
14 and covalently-bonded metallic centers conferring unu-
sual reactivity.15-20 Noteworthy, ACA macrocycles were
valorized for carbon dioxide uptake,21, 22 fullerene or ani-
ons complexation23-25 and demonstrated to be relevant as
hole- and spin-containing architectures.26, 27 In 2013, the
azacalixphyrin (ACP, Figure 1) was reported as the only
known “azacalixarene-like” derivative introducing four
oxidized tetraaminobenzene units that promote a stable
bis-zwitterionic ground electronic state.28-33 Consequently
confers to the ACP a strong absorption ca. 900 nm that
can be tuned by substitution of the peripheral imine func-
tions (Figure 1, R = H, aryl, alkyl).30, 34
Figure 1. Previously reported azacalixphyrin macrocycle
(top) and illustration of the canonical-zwitterionic equilibri-
um in 2,5-diaminobenzoquinone diimines (bottom).
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Chart 1. Scope of the study (only the canonical form With the aim to combine several of these systems in a
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is represented).
single molecule and study the impact on the canoni-
cal/zwitterionic equilibrium, we naturally focused our
attention on the elaboration of macrocyclic architectures
of types 2 or 3 presenting an alternation of quinones and
aromatic rings substituted with EWG. We report herein
their synthesis from ACA precursors and demonstrate
that these macrocycles (2a-c and 3a), named azaca-
lixquinarenes (ACQ), can be seen as “hemi-
azacalixphyrins”, i.e. an intermediary class of ACA-ACP
derivatives featuring an alternation of dinitro-substituted
aromatic rings and diaminobenzoquinone diimine rings.
As for model compounds 1a-d, the quinoidal fragments
within ACQs can be either stabilized under canonical
(uncharged) or zwitterionic forms depending on given
parameters (N-substituents, solvent), allowing to reach
unprecedented poly-zwitterionic systems.
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RESULTS AND DISCUSSION
Synthesis. The access to the target ACQs 2a-c was envis-
aged by chemical oxidation of the azacalix[4]arene pre-
cursors (Scheme 1). Therefore, the preparation of ACA 7a-
c was carried out following a well-established strategy
starting from precursors 4a-c, incorporating octylamine
or selected aniline moieties, which were reduced under
acidic conditions in presence of Sn(II) salts or Fe powder,
then substituted by 1,5-difluoro-2,4-dinitrobenzene
(DFDNB) to afford the adducts 6a-c.30, 34
Interestingly, we recently reported that the constituting
unit of ACP, the monocyclic 2,5-diamino benzoquinone
diimine, can be also stabilized under a zwitterionic
ground state if it is functionalized with strongly electron-
withdrawing aromatic substituents (EWG, Figure 1).35 In
the case of quinone 1a featuring 5-fluoro-2,4-
dinitrophenyl moieties (Chart 1), the zwitterionic form
was found to dominate in both solution and solid states.
Scheme 1. Synthesis of compounds 1a-d, 2a-c and 3a (quinones only represented under their canonical forms).
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These intermediates were converted to the corresponding
azacalix[4]arene 7a-c using one equivalent of tetraamino-
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benzenes 4a-c in refluxing acetonitrile. For compound 6d,
previously unknown, the reaction was carried out at room
temperature and a low concentration of 5d (10-2 M) was
necessary to reach a moderate yield (43%, Table S1). Such
poor efficiency is presumably imputable to a lack of regi-
oselectivity during the nucleophilic aromatic substitution
of the electron-rich adduct 5d on DFDNB. Unfortunately,
for the same reason, it was impossible to reach the corre-
sponding azacalix[4]arene 6d using classical conditions.
The synthesis of azacalix[6]arenes 8a was more straight-
forward and allowed the isolation of the macrocycle in
only one step from octylamine-decorated tetraaminoben-
zene 5a, with however a poor 5% yield.24 Note that the
formation of higher order macrocycles was not observed.
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As expected, series of azacalix[4]arenes 7a-c and azaca-
lix[6]arene 8a could be oxidized to the corresponding
azacalixquinarenes 2a-c and 3a using 2 and 3 equivalents
of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ),
respectively. The reaction proceeded rapidly, nevertheless
purification was more tedious for aryl-substituted qui-
nones 2b-c which revealed a poor solubility in organic
solvents. In contrast, macrocycles 2a and 3a, featuring
octyl chains, show a surprisingly good solubility in di-
chloromethane and were obtained in 82% and 90% yields,
respectively. Eventually, care was taken to verify that the
ACQ 2a could be converted to the corresponding ACP by
reducing the nitro functions in presence of Pd/C and
excess hydrazine in refluxing tetrahydrofuran for 2 days.
Following a classical workup and overnight aerial oxida-
tion, the expected bis-zwitterionic ACP-C8 (Figure 1, ACP
with R = C8H17) was isolated in a 97% yield (see Experi-
mental Section for details).
Figure 2. Single crystal structures of canonical 1b with se-
lected bond lengths (Å). Anisotropic displacement ellipsoids
plot at the 50 percent probability level.
Single crystals of 2a were obtained from a dichloro-
methane-acetonitrile solution and the structure is pre-
sented in Figure 3. Considering the striking effect of the
environment on the ground state structure of the ACQs
(vide infra), it is worth to underline that crystals of 2a
obtained from acetone or dimethylformamide solutions
gave rise to the exact same structure and packing. An
unusual solid-state structure is evidenced for this ACQ
corresponding to the mixed form zc-2a (Scheme 2), which
presents two aromatic dinitrobenzene moieties binding
two oxidized rings, one of them being a zwitterion struc-
ture, the other being a canonical structure. The former
ring is characterized by two 6π-electrons subunits, one
cationic and the other anionic, linked by single bonds
(1.50 Å). Within each cyanine systems, the bond length
alternation nearly vanishes (BLA ca. 0.01 Å) due to the
strong delocalization of the charges along the trimethine
motifs. Surprisingly, for both oxidized rings, the two 6π-
electrons subsystems are not belonging to the same plane,
with an angle of 6° for the zwitterionic system and 4° for
the canonical one. One can notice that the presence of
these two quinone rings within ACQ 3a also induces a
strong distortion of the 1,3-alternate configuration, com-
pared to parent analogous ACA structures.36 The only
acidic hydrogen atom borne by the macrocyclic core is
involved in a 1.98 Å hydrogen bond with one of the pe-
ripheral nitro function. The distance between the two
oxidized ring centroids is 6.86 Å, this value being close to
the one found in unsubstituted ACP (6.65 Å) and stand-
ing out from classical 1,3-alternate ACA 7a, which pre-
sents a distance of 4.74 Å between the two octyl- substi-
tuted aromatic rings.24 The angle formed between the two
3
With the perspective to study them as model compounds,
the quinone 1a-d were prepared from the aromatic de-
rivatives 6a-d, following their treatment with a stoichio-
metric amount of DDQ in degassed chloroform.35 The
compounds were conveniently purified either by precipi-
tation or by flash column chromatography and finally
isolated with good yields (67-80%).
Structural analysis. X-ray quality crystals could be ob-
tained for quinone 1b by slow evaporation of an acetoni-
trile solution. All H-atoms were found experimentally for
1b, as well as the H-atoms for the central cycles and
amines in 2a and 3a, except the one for amine N6 in 3a
(see Figure 4) that was introduced at geometrical posi-
tion. Unlike the previously reported crystal structure of
1a, featuring a zwitterionic ground state,35 the molecule 1b
presents an alternation of single and double bonds in
both subunits of the quinoidal ring (BLA ca. 0.10 Å; Figure
2). Thus, the presence of slightly electron-donating aro-
matic substituents in 1b promotes an unequivocal canoni-
cal ground state. This unexpected result, which helps to
rationalize the optical properties of ACQ 2b (see below),
is consistent with theoretical predictions and experi-
mental evidences that aryl-substituted ACPs tend to sta-
bilize canonical tautomers due to the extent of delocaliza-
tion brought by the aryl substituents.31, 34
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Figure 3. Single crystal structure of 2a. Selected bond lengths (Å) and the electronic structure of each rings are indicated: zwit-
terionic (z), canonical (c) and aromatic (Ar). N-octyl chains are omitted for clarity. Anisotropic displacement ellipsoids plot at
the 50 percent probability level.
Scheme 2. Possible H-transfers and tautomeric structures of series 1a-d, azacalix[4]quinarenes 2a-c and azaca-
lix[6]quinarene 3a. c and z stand for canonical and zwitterionic, respectively. Note that only one structure for
compounds containing at least one c unit is shown here but other (generally less stable) tautomers can be
drawn, see Schemes S1, S2, and S3 in the ESI.
planes of the quinone rings is ca. 110°, which is compara-
ble to the data measured for unsubstituted ACP (see Ta-
ble S3).
centroids is equal to 2.443 Å and 2.497 Å for the canonical
and the aromatic rings respectively. In both independent
molecules the macrocycle presents three aromatic dini-
trobenzene moieties, two canonical quinones and one
zwitterionic ring, thus corresponding to the structure
zcc-3a in Scheme 2. It is worthy to note that both acidic
hydrogen atoms (NH) borne by the central core are sym-
metrically distributed and involved in H-bonds with the
closest nitro functions. The 1,2,4,5-alternate structure
(u,d,d,u,d,d) is very similar to the parent 8a, with howev-
er a distortion brought by the zwitterionic ring. Note that
one dinitro aromatic ring is folded inside the cavity and
occupies the available space.
Finally, ACQ 3a was crystallized from evaporation of a
solution in acetone and stands as one of the rare example
of six-membered azacalix-derivatives (Figure 4).13, 14, 21, 23, 24,
37, 38
The structure reveals that 3a crystallizes with two
independent molecules in the asymmetric unit that stack
together through two π-π ring interactions between, on
one hand, two of their canonical c cycles and, on the
other hand, two of their aromatic cycles. Indeed the dis-
tance between the centroids is equal to 4.359(4) Å be-
tween the canonical cycles and 4.270(4) Å between the
aromatic ones, while the dihedral angles are equal to
7.5(3)° and 1.6(3)° respectively. The slippage between the
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substituted diamino benzoquinone diimines.39, 40 In con-
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trast, the absorption of p-dimethylaminoaniline-
substituted 1d shows a panchromatic absorption spanning
from 400 to 800 nm. Two main transitions can be identi-
fied at 654 and 570 nm, and are counter-intuitively theo-
retically attributed to the forms c-1d and z-1d, respective-
ly (vide infra). In any case, this result underlines that, for
aniline substituted quinones 1b-d, very electron-rich
auxochromes are needed to trigger the proton transfer
and subsequently observe the presence of the zwitterion.
The solvatochromism of this series has been recorded in
different solvents ranging from toluene to DMSO and
shows a very low impact on the absorption of canonical
compounds 1b-c, while a moderate hyperchromic effect is
observed for 1a and 1d in solvent of high polarity due to
the generation of the zwitterionic forms (Figure S30).
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Figure 5. Electronic absorption spectra of the quinones in
acetone.
The absorption solvatochromism of the macrocycle 2a is
particularly interesting since a strong evolution of the
lower energy transition is monitored depending on the
solvent (Figure 6). Going from toluene to dichloro-
methane solution, the molar extinction coefficient in-
creases from ca. 720 to 4200 M-1.cm-1. In acetone, a transi-
tion centered at 660 nm starts to emerge and ultimately
becomes the most intense band in DMSO (ε = 6800 M-
1.cm-1). With the help of theory (Figure S46 and Table S16
in the ESI), the hyperchromic shift in the less polar sol-
vents compared to z-1a is attributed to the stronger ab-
sorbance of zc-2a in solution (tripling of the oscillator
strength compared to 1a), while the growing blue-shifted
transition corresponds to the bis-zwitterionic zz-2a. In a
different way, the ACQ 2b presents characteristic “canon-
ical-type” absorption spectra with negligible differences in
the range of solvents screened. In contrast, the macrocy-
cle 2c shows the apparition of a band at 700 nm in the
most polar solvents such as DMF and DMSO (ε = 4200 M-
1.cm-1). Such behavior is tentatively assigned to the for-
mation of mixed species zc-2c following intramolecular
proton transfer in the corresponding bis-canonical mac-
rocycle. Finally, the [6]-membered macrocycle 3a exhibits
a very similar progression of absorption that of 2a. The
broad transition at ca. 650-700 nm observed in toluene
and dioxane potentially implies the presence of at least
Figure 4. Single crystal structures of 3a. The electronic struc-
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ture of each rings are indicated: zwitterionic (z), canonical
(c) and aromatic (Ar). N-octyl chains are omitted for clarity.
Anisotropic displacement ellipsoids plot at the 50 percent
probability level.
Photophysical properties. The electronic absorption
spectra of the quinones recorded in acetone solution (ca.
2.10-5 M) are compiled in Figure 5. As a model compound,
alkyl-substituted compound 1a exhibits a characteristic
broad absorption band centered at ca. 700 nm, which is
the fingerprint of the zwitterionic form z-1a. This transi-
tion is attributed to an intramolecular charge transfer
(ICT) from the anionic trimethine to the cationic one
(cyanine-to-cyanine ICT), its intensity depending on the
proportion of ground-state zwitterion in solution.35 This
analysis is corroborated by theoretical calculations (see
Figure S34 and Table S9 in the ESI). Quinones 1b and 1c,
which
possess
trimethoxyaniline
and
m-
trifluoromethylaniline moieties do not present such tran-
sition, which hints at a prominent canonical ground-state
for these compounds, the strong UV band and its tail in
the visible region being classical features of tetra-
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Figure 6. UV-Vis-NIR absorption solvatochromism of 2c, 2a and 3a in toluene (―), 1,4-dioxane (―), ethyl acetate (―), di-
chloromethane (―), acetone (―), N,N-dimethylformamide (―) and dimethylsulfoxide (―).
one zwitterionic quinone among the three oxidized rings
of 3a (see tautomer zcc-3a in Figure 4 and Scheme 2). The
growing transition noticed in DMSO is most probably due
to the evolution towards species zzc-3a and/or zzz-3a
(see calculations below).
icant variation of more than 150 mV. This canoni-
cal/zwitterionic equilibrium is probably responsible for
the decrease of the electrochemical gaps ( 200 mV) of 1a,
2a and 3a when changing DCM by DMF (Figure 7), while
those of 1b and 2b are only slightly affected ( 50 mV).
Cyclic voltammetry. The redox properties of compounds
1a-d, 2a-c and 3a were analyzed by recording their cyclic
voltammograms (CV) in DCM and in DMF solutions
(containing 0.1 M of [(nBu4N)PF6] and using ferrocene as
an internal standard (Figures S28 and S29). The corre-
sponding oxidation and reduction half-wave potential E1/2
values are given versus the oxidation potential of ferro-
cene and are listed in Table S4. In DCM, each CV features
up to three irreversible reduction waves and up to two
oxidation ones. In DMF, no oxidation potential values of
compounds 1c and 2c are reported since these processes
are occurring out of the solvent electro-chemical window.
For the 1a-d series, the first reduction processes centered
on the most electron-accepting di-nitro-fluorobenzene
moieties have E1/2 values that are not strongly affected by
the nature of the N-substituents nor by the solvent polari-
ty. For example, in both solvents, the replacement of the
electron-withdrawing m-trifluoromethylphenyl groups of
1c by electron-donating p-dimethylaminophenyl ones in
1d induces a cathodic shift of the first reduction wave by
less than 50 mV. In contrast, in the four membered mac-
rocycle 2a-c series, where the fluorine atoms have been
replaced by tetraaminobenzoquinone moieties, such vari-
ation of the N-substitution has a noticeable effect on the
first reduction E1/2 values. For example, the first reduction
waves located at –1.06 V (DCM) and –1.00 V (DMF) for 2a
(Figure 7) are found at –0.78 V (DCM) and at –0.84 V
(DMF) when studying 2c. The first oxidation potential
values are significantly affected by the nature of the N-
substituents and/or by the solvent polarity. For example,
in DCM, when going from 1b and 2b to 1c and 2c, the
increasing electron-accepting strength of the N-
substituents produces an anodic shift of the first oxida-
tion wave by more than 250 mV. The variation of the first
oxidation E1/2 value with the solvent polarity can also be
used as an additional proof of the occurrence of a canoni-
cal/zwitterionic balance. Indeed, if the solvent polarity
has a limited impact on the location of the oxidation of
the canonical 1b and 2b compounds, it induces, for the
oxidation E1/2 values of compounds 1a, 2a and 3a, a signif-
Figure 7. Cyclic voltammograms of compound 2a in DCM
(black) and DMF (red) solutions.
Theoretical calculations. In order to obtain further
insights into the underlying electronic structures and
evaluate the relative stabilities of the various tautomers,
DFT and TD-DFT calculations have been performed on all
the systems studied herein. Let us first compare the crys-
tallographic structures with the one modelled in gas
phase for 1b, 2a, and 3a. For the two former compounds,
we have performed a full tautomeric search, i.e., model-
ling not only structures presenting rings of z and/or c
forms (displayed in Scheme 2), but also accounting for
other possible types of rings (see Schemes S1 and S2 in the
ESI). For 1b, among the four tautomers considered, theory
predicts that the canonical c form is the most stable by
more than 2 kcal.mol-1 compared to the other forms,
which is in perfect agreement with the X-ray structure.
One notices that the a and x tautomers (see the ESI for
representation) are much less stable (>10 kcal.mol-1, Table
S5) than the z and c structures, which is also consistent
with our previous work on a similar compound.35 The BLA
determined for c-1b is ca. 0.07 Å, only slightly smaller
than in the XRD (vide supra). For 2a, among the thirteen
different tautomers considered, it turns out that the mac-
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rocycles presenting a least one ring of type a or x are very polarity as expected (Table S16). For both zc and zz, the
unlikely with relative free energies exceeding 15 kcal.mol-1
(Table S6) which is perfectly consistent with the results
obtained for 1b. While only the zc-2a structure has been
evidenced experimentally, theory predicts that the cc
structure is slightly more stable than zc. However, the
computed difference (1 kcal.mol-1) is within DFT error bar
and could be overcome by crystal packing effects, not
accounted for in the calculations. In zc-2a, the DFT de-
termined CC bond lengths in the zwitterionic cycle are
1.386 and 1.389 Å (external side), and 1.388 and 1.405 Å
(internal side), in very good match with the experimental
values (Figure 3). For 3a, according to the previous obser-
vations, only the possible tautomers that combine z
and/or c type of rings have been taken into account
(Scheme S3 and Table S7). Due to its strongly distorted
structure, for a given tautomer, several non-equivalent
conformers can be drawn and a full conformational
search has therefore been performed. It turns out that, in
gas phase, only the zcc form in the exact same confor-
mation as the crystallographic structure was found to be
stable, the other structures being less stable by at least 3
kcal.mol-1.
absorption spectra computed in the two solvents are ex-
tremely similar (see Figure S51), with the first dipole-
allowed absorption of zz appearing at smaller wavelength
than the one of zc (565 and 621 nm, respectively, see Ta-
ble S17), for the same reason as in 1d (i.e., the first transi-
tion in zz is forbidden). Therefore, the experimentally
observed solvatochromism, that is, the increase of the
intensity of the blueshifted zwitterionic band when going
from DCM to DMSO (see Figure 8), is due to the changes
in the relative population of the tautomers rather than a
direct solvent effect on their individual spectra. In the zc-
2a structure, the band at 621 nm is clearly centered on the
z cycle (Figure S48). For 2b, theory predicts that the cc
tautomer is the most stable and that the zz structure is
unlikely (relative free energy of 3.8 kcal.mol-1, Table S19)
whereas the zc tautomer is only 1.1 kcal.mol-1 above cc.
Given the computed spectra (Figure S52), one can there-
fore probably attribute the small extension of the foot of
the band toward the red in 2b to the formation of a small
amount of zc. For 2c, theory predicts that only the cc
exists in solution, the free energies of the other zc and zz
forms being relatively high, e.g., 3.8 kcal.mol-1 for zc (Ta-
ble S21). This is the only theoretical result not consistent
with experiment that returns the presence of zwitterionic
forms in the most polar solvents (vide infra).
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Let us now turn towards an analysis of the results ob-
tained in solution. We have chosen DMSO as reference
solvent except when noted. For 1a, only the z form, pre-
senting a band at 602 nm according to TD-DFT (Table
S9), is likely to exist in DMSO, the c tautomer being 5
kcal.mol-1 less stable. As stated above, this 602 nm transi-
tion involves a significant CT between the two cyanine
subunits (Figure S35), consistent with our previous
work.35 In contrast, for 1b and 1c, theory finds that the
canonical form is preferred by at least 4 kcal.mol-1 (Tables
S10 and S12). The c-1b and c-1c compounds present their
lowest absorption at 527 and 495 nm, respectively (Fig-
ures S36 and S39). There is therefore a clear agreement
with the experimental spectra observed for these three
species: only the c structures are present and their spectra
are blueshifted compared to z-1a. Eventually for 1d, DFT
returns almost isoenergetic z and c tautomers, which are
therefore likely to coexist in solution (Table S14). This can
explain the broad long-wavelength band obtained in the
experimental spectra. Unexpectedly, the absorption band
at the longest wavelength is attributed to the c-1d (651
nm, f=0.49) whereas the first significant absorption of z-
1d appears are higher energies (540 nm, f=0.85, see Table
S15 and Figure S43). This is because the S1 state of z-1d,
computed at 667 nm is totally dark. As can be seen in
Figures S41 and S42, all the lowest dipole-allowed transi-
tions present a significant CT character, the p-amino-
phenyl moieties acting as donor groups and the central
core acting as acceptor.
Figure 8. Theoretical absorption spectra of different tauto-
meric forms of azacalixquinarenes 2a and 3a computed in
DMSO. The theoretical spectra are obtained using a broad-
ening Gaussian with a FWHM of 2500 cm-1 to convolute the
stick spectrum.
As previously shown and consistently with the experi-
ments, theory predicts that the most stable form of 3a in
gas phase corresponds to the zcc tautomer. Interestingly,
going to DCM and DMSO leads to markedly different
results (Table S23). Indeed, unsurprisingly, the more polar
is the solvent, the more the "z-heavy" structures are stabi-
lized. Indeed, in DCM (DMSO), theory predicts that the
zzc (zzz) form is the most stable one. The theoretical
spectra of these three species are given in Figures 8 and
S59 and one notices that the long-wavelength absorption
For 2a, the free energies and UV-Vis spectra have been
calculated in both DCM and DMSO. The results are dis-
played in the ESI. The computed free energies indicate
that the cc forms are not likely to be present in solution
(> 5 kcal.mol-1), whereas the difference between the zc
and zz forms increases when going from DCM to DMSO
hinting that the ratio of the latter increases with solvent
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Figure 9. Representation of the TD-DFT electron density difference for the three lowest excited-states of 3a in three of its tau-
tomeric forms. The blue and red regions respectively indicate decrease and increase of density upon photon absorption (contour
threshold: 0.0008 au).
band presents a nearly equal position in zcc, zzc and zzz,
EXPERIMENTAL SECTION
DETAILS
&
THEORETICAL
whereas its intensity is roughly proportional to the ratio
of zwitterionic rings. The lowest electronic transitions for
these three species have been characterized (Figure 9).
The long-wavelength bright states (> 550 nm) are local-
ized on the zwitterionic part(s) for the three tautomers of
3a, whereas the canonical moieties are related to absorp-
tion at higher energies (ca. 470 nm).
Reagents. All reagents were purchased from Alfa-Aesar
or Sigma-Aldrich and used as received. When heating was
required, oil bathes were used. Column chromatography
were performed using Silica 60M (0.04-0.063 mm) pur-
chased from Macherey-Nagel. Compounds 1a,35 6a and
7a,30 6b-c and 7b-c,34 8a24 were prepared following previ-
ously reported protocols.
CONCLUSION
A new class of macrocycle, the azacalixquinarene family
has been synthesized by partial oxidation of azaca-
lixarenes. Single crystal structures highlighted that the
cavity volume in four-membered macrocycles was higher
than in the parent ACA due to the distortion brought by
the imine functions. Importantly, [4]- and [6]-membered
ACQs 2a and 3a presented one of their quinone cycle
under zwitterionic electronic structure at the solid state.
The nature of the N-substituents influences the ground
state of the quinone units, alkyl chains and strong elec-
tron-donating aryl moieties allowed to promote a zwitter-
ionic character. The evolution of the absorption profiles
observed in solution was rationalized by TD-
DFT,highlighting the preponderance of zwitterionic units
in polar environment. This fine, easily tunable balance
between the presence of canonical and zwitterionic moie-
ties within a same macrocyclic architecture paves the way
to several sensing applications.
Analytical methods and apparatus. NMR spectra were
recorded on a JEOL ECS400 NMR spectrometer at room
temperature, otherwise noted. NMR chemical shifts are
given in ppm (δ) relative to Me4Si with solvent resonances
1
used as internal standards (CDCl3: 7.26 ppm for H and
13
1
77.2 for C{1H}; Acetone-d6: 2.05 ppm for H and 29.8 for
13C{1H}; DMSO-d6: 2.50 ppm for H and 39.5 for 13C{1H}).
1
UV-Vis-NIR absorption spectra were recorded on a
VARIAN CARY 50 SCAN spectrophotometer at room
temperature. NMR peak assignments were confirmed
using a DEPT-135 method. Optical properties were rec-
orded in spectrophotochemical grade solvents. HRMS
(ESI) and MS (ESI) analyses were performed on a QStar
Elite (Applied Biosystems SCIEX) or a SYNAPT G2 HDMS
(Waters) spectrometers by the “Spectropole” of the Aix-
Marseille University. These two instruments were
equipped with an ESI or MALDI source spectrometer, and
a TOF mass analyzer.
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Single Crystal X-ray Diffraction. Suitable crystals for computational details are available in Section VII of the
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compounds 1b, 2a and 3a were obtained from slow evapo-
ration from acetonitrile, dichloromethane/acetonitrile
and acetone respectively. They were mounted on a Rigaku
Oxford Diffraction SuperNova diffractometer and meas-
ured at 203 K, 250 K and 150 K respectively, at the Cu
radiation (=1.54184 Å). Data collection, reduction and
multiscan ABSPACK correction were performed with
CrysAlisPro (Rigaku Oxford Diffraction). Using Olex241
the structures were solved with the ShelXT42 structure
solution program using Intrinsic Phasing and refined with
ShelXL42 using least-square minimization. Crystals of 1b
were found to be twins and all H-atoms were determined
experimentally. Structures of 2a and 3a revealed severe
disordered for the octylamine moieties and hard con-
straints were applied during the refinement process. For
both compounds the H-atoms for the central cycles and
the amines were found experimentally except for atom
N6 in 3a. The remaining H-atoms were introduced at
geometrical positions and all H-atoms were refined with
riding coordinates to their parent atoms and with their
Uiso parameters constraint to 1.2Ueq(parent atoms) for
the CH, CH2, and NH and 1.5Ueq(parent atoms) for the
CH3. Compound 3a crystallized with 2 independent mole-
cules in the asymmetric unit.
SI.
Synthesis
of
N1,N1'-(4,6-dinitro-1,3-
phenylene)bis(N4,N4-dimethylbenzene-1,4-diamine)
(4d). 1,5-difluoro-2,4-dinitrobenzene (2 g, 9.80 mmol, 1
equiv.), N,N-dimethyl-p-phenylenediamine (2.936 g, 21.56
mmol, 2.5 equiv.) and N,N-diisopropylethylamine (5.12
mL, 29.40 mmol, 3 equiv.) were heated at 145 °C for 2
hours. The reaction mixture was cooled to room tempera-
ture and the precipitate was filtered, washed several times
with ethanol, Et2O and dried under vacuum to afford the
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product as a dark brown solid (3.94 g, 92%). H NMR
(CDCl3, 400 MHz): δ = 9.55 (br s, 2H, NH), 9.31 (s, 1H,
CH), 6.99 (d, J = 8.9 Hz, 4H, CH), 6.63 (d, J = 8.9 Hz, 4H,
CH), 6.30 (s, 1H, CH), 2.94 (s, 12H, N(CH3)2). 13C{1H} NMR
(CD2Cl2, 100 MHz): δ = 149.6 (C), 148.2 (C), 129.6 (CH),
126.6 (CH), 126.3 (C), 125.3 (C), 109.5 (CH), 95.1 (CH), 40.7
(CH3). HRMS (ESI+) calculated for [M+H]+: 437.1932
+
(C22H25N6O4 ), found: 437.1932.
Synthesis
of
N1,N5-bis(4-
(dimethylamino)phenyl)benzene-1,2,4,5-tetraamine
tetrahydrochloride (5d). In a pressure bomb, com-
pound 4d (1 g, 2.29 mmol, 1 equiv.) and SnCl2•2H2O (4.136
g, 18.33 mmol, 8 equiv.) were dissolved in 10 mL of con-
centrated HCl (12 N) and 10 mL of chloroform. The bomb
was closed with a Teflon seal and the mixture was stirred
at 60 °C for 15 h. The resulting precipitate was filtered,
washed several times with concentrated HCl (3 x 20 mL),
DCM, Et2O and finally dried under vacuum to afford the
product as a withe powder (739 mg, 72%). The compound
was stored at -4 °C to prevent its oxidation to the corre-
Electrochemistry. Cyclic voltammetry (CV) data were
recorded using a BAS 100 (Bioanalytical Systems) potenti-
ostat and the BAS100W software (v2.3). All the experi-
ments were conducted under an argon atmosphere in a
standard one-compartment using a three electrodes set-
up: a Pt working electrode (Ø = 1.6 mm), a Pt counter
electrode and an Ag/AgCl reference electrode (filled with
a 3 M NaCl solution). Tetra-n-butylammonium hex-
afluorophosphate ([TBA][PF6]) was used as supporting
electrolyte (10-1 M), with a concentration of the electro-
active compound ca. 10-3 M. The reference electrode was
1
sponding quinone. H NMR (DMSO-d6, 400 MHz): δ =
8.65 (br s, 2H, NH), 7.66 (d, J = 9.0 Hz, 4H, CH), 7.41 (s,
1H, CH), 7.09 (s, 1H, CH), 7.06 (d, J = 9.0 Hz, 4H, CH),
3.08 (s, 12H, N(CH3)2). No 13C{1H} NMR spectrum could be
recorded owing to the poor stability in solution. HRMS
(MALDI) calculated for [M+H]+: 376.2370 (C22H28N6),
found: 376.2360.
calibrated using ferrocene (E°(Fc/Fc+)
= 0.46V/SCE
(DCM), 0.46V/SCE (DMF)).43 The scan rate was 100 mV/S.
The solution was degassed using argon before recording
each reductive scan, and the working electrode (Pt) was
polished before each scan recording.
Synthesis of N1,N5-bis(4-(dimethylamino)phenyl)-
N2,N4-bis(5-fluoro-2,4-dinitrophenyl)benzene-1,2,4,5-
tetraamine (6d). Compound 5d (500 mg, 1.11 mmol, 1
equiv.) and 1,5-difluoro-2,4-dinitrobenzene (227 g, 1.11
mmol, 1 equiv.) were dissolved in 110 mL of acetonitrile.
The solution was cooled to 0 °C and degassed under Ar-
gon bubbling for 30 minutes. N,N-diisopropylethylamine
(1.55 mL, 8.90 mmol, 8 equiv.) was added dropwise to the
solution. The reaction mixture was stirred for 2 h at 0 °C,
then warmed to 25 °C and stirred for 15 h. The crude solu-
tion was filtered to remove insoluble materials and the
filtrate was evaporated under reduced pressure. The resi-
due was subjected to column chromatography over silica
gel using dichloromethane/ethyl acetate (9:1) as eluent to
afford the product as a brown solid (125 mg, 30%). Rf: 0.47
(SiO2, dichloromethane/ethyl acetate, 9:1). 1H NMR
DFT and TD-DFT Calculations. All calculations have
been made with Gaussian-16,44 replacing the alkyl chains
C8H17 by methyl groups in all the calculations for the sake
of computational time. We have used the PBE045 global
hybrid functional for all our calculations. For compounds
1a-d and 2a, we have optimized the ground-state geome-
try with the 6-311++G(2d,2p) basis set, whereas larger
compounds 2b-c and 3a have been optimized using the
more compact 6-31G(d) atomic basis set. We verified the
absence of imaginary frequencies by computing analyti-
cally the Hessian at the same level of theory. The excited-
state calculations were performed with TD-DFT deter-
mined with the CAM-B3LYP46 exchange-correlation func-
tional in combination with the 6-311++G(2d,2p) atomic
basis set. This functional has been preferred to PBE0 as
several charge transfer states are considered in this study.
The solvent effects were modeled through the well-
known Polarizable Continuum Model (PCM).47 Extra
(CDCl3, 400 MHz): δ = 9.37 (br s, 2H, NH), 9.11 (d, JH-F
=
7.6 Hz, 2H, CH), 6.96 (s, 1H, CH), 6.92 (d, J = 8.8 Hz, 4H,
CH), 6.66 (d, JH-F = 13.1 Hz, 2H, CH), 6.63 – 6.60 (m, 5H,
CH), 5.56 (s, 2H, NH2), 2.90 (s, 12H, N(CH3)2). 13C{1H}
NMR (CDCl3, 400 MHz, 100 MHz): δ = 159.8 (d, JC-F = 271
Hz, C), 149.4 (d, JC-F = 13 Hz, C), 148.3 (C), 144.3 (C), 128.9
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(C), 128.3 (CH), 127.9 (C), 127.6 (CH), 127.3 (C), 124.8 (CH),
solid (76 mg, 76%). 1H NMR (DMSO-d6, 400 MHz, 353 K):
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4
5
6
7
8
113.3 (CH), 112.6 (C), 103.7 (d, JC-F = 27 Hz, CH), 99.9 (CH),
40.8 (CH3). HRMS (ESI+) calculated for [M+H]+: 745.2289
(C34H31N10O8F2+), found: 745.2288.
δ = 9.60 (br s, 2H, NH), 8.89 (d, JH-F = 7.9 Hz, 2H, CH),
7.18 – 6.88 (m, 6H, CH), 6.78 (d, JH-F = 14.3 Hz, 2H, CH),
6.75 – 6.60 (m, 4H, CH), 2.85 (s, 12H, N(CH3)2). Com-
pound was too insoluble to record a 13C{1H} NMR spec-
trum. HRMS (ESI+) calculated for [M+H]+: 743.2132
(C34H29N10O8F2+), found: 743.2130.
Synthesis of (3E,6E)-N1-(5-fluoro-2,4-dinitrophenyl)-3-
((5-fluoro-2,4-dinitrophenyl)imino)-N4-(3,4,5-
trimethoxyphenyl)-6-((3,4,5-
trimethoxyphenyl)imino)cyclohexa-1,4-diene-1,4-
diamine (1b). To a solution of compound 6b (100 mg,
0.119 mmol, 1 equiv.) in 3 mL of degassed chloroform was
added 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (27 mg,
0.119 mmol, 1 equiv.) and the mixture was stirred at 25 °C
for 30 minutes. After concentration under reduced pres-
sure, the crude residue was purified by column chroma-
tography over silica gel using dichloromethane/ethyl
acetate (9:1) as eluent. The obtained compound was final-
ly passed through a basic activated alumina pad (Brock-
mann I) via DCM to afford the product as a dark solid (72
mg, 72%). Rf: 0.70 (SiO2, dichloromethane/ ethyl acetate,
Synthesis of ACQ 2a. To a solution of ACA 7a (50 mg,
0.047 mmol, 1 equiv.) in 2 mL of degassed chloroform was
added 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (22 mg,
0.095 mmol, 2 equiv.) and the mixture was stirred at 25 °C
for 1 h. After concentration under reduced pressure, the
crude residue was purified by column chromatography
over silica gel using dichloromethane as eluent to afford
the product as a brown-green solid (41 mg, 82%). Rf: 0.80
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(SiO2, dichloromethane). H NMR (CDCl3, 400 MHz): δ =
8.91 (s, 2H, CH), 8.45 (br s, 4H, NH), 6.92 (s, 2H, CH), 6.14
(s, 2H, CH), 5.46 (s, 2H, CH), 3.38 (t, J = 6.8 Hz, 8H, N-
CH2), 1.76 (quint, J = 7.2 Hz, 8H, CH2), 1.56 – 1.25 (m, 40H,
1
13
9:1). H NMR (DMSO-d6, 400 MHz): δ = 9.71 (br s, 2H,
CH2), 0.88 (t, J = 7.0 Hz, 12H, CH3). C{1H} NMR (CDCl3,
NH), 8.91 (d, JH-F = 7.5 Hz, 2H, CH), 7.80 (d, JH-F = 12.7 Hz,
2H, CH), 6.65 (s, 1H, CH), 6.43 (s, 4H, CH), 6.34 (s, 1H,
CH), 3.69 (s, 12H, OCH3), 3.62 (s, 6H, OCH3). 13C{1H} NMR
(DMSO-d6, 100 MHz): δ = 157.8 (d, JC-F = 270 Hz, C), 153.1
(C), 148.1 (C), 147.6 (C), 146.4 (C), 140.0 (C), 134.8 (C), 134.1
(C), 130.8 (C), 125.5 (CH), 110.4 (d, JC-F = 27 Hz, CH), 102.3
(CH), 99.0 (CH), 91.8 (CH), 60.0 (OCH3), 55.8 (OCH3).
HRMS (ESI+) calculated for [M+H]+: 837.1922
(C36H31F2N8O14+), found: 837.1920.
100 MHz): δ = 152.5 (C), 148.8 (C), 147.9 (C), 134.3 (C), 126.1
(CH), 110.2 (CH), 89.8 (CH), 85.3 (CH), 45.5 (N-CH2), 31.8
(CH2), 29.3 (CH2), 29.2 (CH2), 29.0 (CH2), 27.2 (CH2), 22.6
(CH2), 14.1 (CH3). HRMS (ESI+) calculated for [M+H]+:
+
1049.6295 (C56H81N12O8 ), found: 1049.6295.
Synthesis of ACQ 2b. To a solution of ACA 7b (50 mg,
0.039 mmol, 1 equiv.) in 2 mL of degassed chloroform was
added 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (18 mg,
0.039 mmol, 2 equiv.) and the mixture was stirred at 25 °C
for 30 minutes. After concentration under reduced pres-
sure, the particularly insoluble residue was purified by
flash column chromatography over silica gel using di-
chloromethane/acetone (9:1) as eluent to afford the prod-
uct as a green solid (26 mg, 52%). Rf: 0.40 (SiO2, di-
Synthesis of (3E,6E)-N1-(5-fluoro-2,4-dinitrophenyl)-3-
((5-fluoro-2,4-dinitrophenyl)imino)-N4-(3-
(trifluoromethyl)phenyl)-6-((3-
(trifluoromethyl)phenyl)imino)cyclohexa-1,4-diene-
1,4-diamine (1c). To a solution of compound 1c (100 mg,
0.126 mmol, 1 equiv.) in 2 mL of degassed tetrahydrofuran
was added dropwise 2,3-dichloro-5,6-dicyano-1,4-
benzoquinone (28.7 mg, 0.126 mmol, 1 equiv.) in 2 mL of
degassed tetrahydrofuran and the mixture was stirred at
room temperature for 4 h. After concentration under
reduced pressure, the crude residue was washed with
ethanol and diethyl ether to afford the product as a
1
chloromethane/acetone, 9:1). H NMR (DMSO-d6, 400
MHz): δ = 9.54 (br s, 4H, NH), 8.95 (br s, 2H, CH), 7.55
(br s, 2H, CH), 7.11 (br s, 2H, CH), 6.40 (br s, 8H, CH),
6.34 (br s, 2H, CH), 3.67 (br s, 24H, OCH3), 3.67 (br s, 12H,
OCH3). Compound was too insoluble to record a 13C{1H}
NMR spectrum. HRMS (ESI+) calculated for [M+2H]2+:
633.1940 (C60H58N12O202+), found: 633.1940.
1
brown solid (80 mg, 80%). H NMR (DMSO-d6, 400
Synthesis of ACQ 2c. To a solution of compound 7c (80
mg, 0.068 mmol, 1 equiv.) in 2.5 mL of degassed tetrahy-
drofuran was added dropwise 2,3-dichloro-5,6-dicyano-
1,4-benzoquinone (30.72 mg, 0.136 mmol, 2 equiv.) in 2.5
mL of degassed tetrahydrofuran and the mixture was
stirred at 25 °C for 19 h. After concentration under re-
duced pressure, the crude residue was washed with etha-
nol and was purified by flash column chromatography
over neutral aluminium oxide using dichloro-
methane/acetone (95:5) as eluent to afford the product as
a brown solid (31 mg, 38%). Rf: 0.48 (SiO2, dichloro-
MHz): δ = 9.97 (br s, 2H, NH), 8.93 (d, JH-F = 7.2 Hz, 2H,
CH), 7.82 (d, JH-F = 12.6 Hz, 2H, CH), 7.65 – 7.35 (m, 8H,
CH), 6.72 (s, 1H, CH), 6.13 (s, 1H, CH). Compound was too
insoluble to record a 13C{1H} NMR spectrum. HRMS (ESI+)
+
calculated for [M+H]+: 793.1036 (C32H17 F8N8O8 ), found:
793.1041.
Synthesis
of
(E)-N1-((E)-5-((4-
(dimethylamino)phenyl)amino)-2-((5-fluoro-2,4-
dinitrophenyl)amino)-4-((5-fluoro-2,4-
dinitrophenyl)imino)cyclohexa-2,5-dien-1-ylidene)-
N4,N4-dimethylbenzene-1,4-diamine (1d). To a solution
of compound 6d (100 mg, 0.134 mmol, 1 equiv.) in 2 mL of
degassed tetrahydrofuran was added 2,3-dichloro-5,6-
dicyano-1,4-benzoquinone (31 mg, 0.134 mmol, 1 equiv.) in
2 mL of degassed tetrahydrofuran and the mixture was
stirred at 25 °C for 1 h. After concentration under reduced
pressure, the crude residue was washed with ethanol,
diethyl ether and pentane to afford the product as a green
1
methane/petroleum ether, 7:3). H NMR (DMSO-d6, 400
MHz): δ = 9.80 (br s, 4H, NH), 8.97 (s, 2H, CH), 7.62 –
7.38 (m, 18H, CH), 7.20 (s, 2H, CH), 6.12 (s, 2H, CH).
Compound was too insoluble to record a 13C{1H} NMR
spectrum. HRMS (ESI+) calculated for [M+H]+: 1177.2034
+
(C52H29F12N12O8 ), found: 1177.2046.
Synthesis of ACQ 3a. To a solution of ACA 8a (10 mg,
0.006 mmol, 1 equiv.) in 2 mL of degassed chloroform was
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The Journal of Organic Chemistry
Michel Giorgi: 0000-0002-4367-1985
Denis Jacquemin: 0000-0002-4217-0708
Olivier Siri: 0000-0001-9747-3813
added 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (4.3
1
2
3
4
5
6
7
8
mg, 0.018 mmol, 3 equiv.) and the mixture was stirred at
25 °C for 30 minutes. After concentration under reduced
pressure, the crude residue was purified by flash column
chromatography over silica gel using dichloromethane as
eluent to afford the product as a green solid (9 mg, 90%).
Note that column purification had to be performed quick-
ly since degradation of the compound was observed on
Notes
The authors declare no competing financial interest.
AKNOLEDGEMENTS
The authors thank the ANR for support in the framework of
the EMA grant. We thank Joachim Galiana (Marseille) for his
help in synthesizing macrocycle 3a. This research used re-
sources of (i) the GENCI-CINES/ IDRIS; (ii) Centre de Calcul
Intensif des Pays de Loire; (iii) a local Troy cluster and (iv)
HPC resources from ArronaxPlus (Grant No. ANR-11-EQPX-
0004 funded by the French National Agency for Research).
Spectropole of Aix-Marseille University is acknowledged for
mass spectrometry.
1
silica gel. Rf: 0.74 (SiO2, dichloromethane). H NMR (ace-
tone-d6, 400 MHz): δ = 8.69 (br s, 2H), 6.67 (br s, 2H),
5.78 (br s, 2H), 3.56 (m, 12H, NCH2), 1.81 (m, 12H, CH2),
1.50 (m, 12H, CH2), 1.29 (m, 48H, CH2), 0.89 (t, J = 6.9 Hz,
18H, CH3). Quinoid units meet relaxation issues that yield
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uncomplete or unresolved NMR signals. H NMR spec-
trum recorded in DMSO-d6 at 353 K reveals the missing
13
signals (see ESI) No C{1H} NMR spectrum could be rec-
orded due to poorly resolved signals and poor solubility.
HRMS (ESI+) calculated for [M+2H]2+: 787.4739
(C84H122N18O122+), found: 787.4737.
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Lucien Lavaud: 0000-0001-8445-2159
Gabriel Canard: 0000-0002-3572-9091
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