Preparation and pH-switching of fluorescent borylated arylisoquinolines for multilevel molecular logic

Article abstract of DOI:10.1021/jo401147t

The preparation of pH-switchable fluorescent borylated arylisoquinoline dyes via a flexible iridium-catalyzed route is reported. The obtained dyes feature aromatic amino substitution and lateral aliphatic amino groups as electron donors. The photophysical

Full text of DOI:10.1021/jo401147t

Article
pubs.acs.org/joc
Preparation and pH-Switching of Fluorescent Borylated
Arylisoquinolines for Multilevel Molecular Logic
Vania F. Pais,† Mauricio Lineros,† Rocío Lopez-Rodríguez,‡,∥ Hamdy S. El-Sheshtawy,§
̂
́
Rosario Fernandez,∥ Jose M. Lassaletta,‡ Abel Ros,*,‡ and Uwe Pischel*,†
́
́
†CIQSOCenter for Research in Sustainable Chemistry and Department of Chemical Engineering, Physical Chemistry, and Organic
Chemistry, University of Huelva, Campus de El Carmen s/n, 21071 Huelva, Spain
‡Institute for Chemical Research (CSIC-US), C/Amer
́
ico Vespucio 49, 41092 Seville, Spain
§Chemistry Department, Faculty of Science, South Valley University, 83523 Qena, Egypt
∥Department of Organic Chemistry, University of Seville, C/Prof. García Gonzal
ez 1, 41012 Seville, Spain
́
S
* Supporting Information
ABSTRACT: The preparation of pH-switchable fluorescent borylated aryliso-
quinoline dyes via a flexible iridium-catalyzed route is reported. The obtained dyes
feature aromatic amino substitution and lateral aliphatic amino groups as electron
donors. The photophysical properties of the internal charge transfer dyes were
studied, which was complemented by density functional theory calculations.
Appreciable fluorescence quantum yields (Φf up to ca. 0.4) and characteristic
spectral fingerprints in the green to red emission range were observed. The
fluorescence modulation upon multiple and orthogonal protonation with triflic
acid was studied and led to the interpretation of multilevel switching including
off−on−off, ternary, and quaternary responses.
switches.14−20 The integration of off−on−off PET switches
INTRODUCTION
■
with polymeric materials21−23 or in higher-order supra-
molecular structures such as micelles was demonstrated as
well.24−26 Some other designs included fluorescent or
luminescent assemblies based on transition metal ion
complexes with pH-switchable ligands where the modulation
of the emission output signal was achieved by controlling PET
and energy transfer (EnT).27−32 All-photonic off−on−off
switching, that is, switches that work exclusively with optical
inputs and outputs, has been observed for other photophysical
designs.33,34 The variation of π-conjugation in purely organic
systems was described as another viable mechanism to achieve
off−on−off or on−off−on fluorescence switching.35,36 Finally,
acidochromic switching inspired by classical pH azobenzene-
based indicators has been used for the implementation of an
off−on−off chromogenic response.37 While the previously
described switches use multilevel input signals, for example,
low, medium, and high proton concentrations, their output is
read through a binary low−high (0−1) convention. On the
other hand, fluorescent systems that allow for the reading of
three or even four stable output states leading to ternary or
quaternary switching are rather rare. Some of the few reported
strategies toward this ambitious and nontrivial objective
harnessed the switching of fluorophores by sequential
modulation of excited state processes such as internal charge
transfer (ICT), PET, and EnT. In this way low−medium−high18
The design of molecular and supramolecular switches that
change their fluorescence properties upon interaction with
chemical inputs is not only an academically rewarding exercise
but has also contributed decisively to the enormous success of
chemosensing in analytical chemistry applications in environ-
mental sciences, life sciences, and clinical diagnostics.1−5 The
measurement of pH by means of fluorescent probes is a simple
but instructive example for the conceptual approach to
fluorescence switching. In the majority of cases, the electronic
properties of electron donors and acceptors that are integrated
with the fluorophore architecture are modulated by proto-
nation. This may give rise to fluorescence enhancement or
quenching as well as to ratiometric responses. The change of
the optical reporter signal can be straightforwardly translated
into switching between off and on states, which are verbal
descriptions of binary 0 or 1, respectively. This conceptual
analogy has paved the way to interpret the functions of such
switches in terms of molecular information processing and
logic.6−12 While simple off−on (signal enhancement) or on−off
(quenching) fluorescence switching by pH modulation is
described abundantly in the literature, the design of more
complex signal responses in the form of off−on−off or on−off−
on patterns and interpretations beyond the binary 0 and 1
notation in the form of multivalued logic and memory remains
a challenging task.12,13 The combination of two antagonistic
proton receptors with a fluorophore and photoinduced electron
transfer (PET) as communication mechanism has given rise to
a general strategy for off−on−off and also on−off−on
Received: May 24, 2013
Published: July 30, 2013
© 2013 American Chemical Society
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Scheme 1. Structures of BAI Dyes 1−4 and Their Nonborylated Analogues M1−M4
as well as the inverse sequence38 were demonstrated. Other
approaches include the protonation and deprotonation of
fluorescent ligands that are integrated in metal ion coordination
complexes,39,40 the pH-control of polyamine−fluorophore
conjugates,41 and the exploitation of excited-state proton
transfer.41 An example for a Zn(II) input-driven ternary switch
showing a medium−off−on fluorescence output sequence based
on a squaraine dye was reported as well.42
methodology was applied analogously in the synthesis of the
nonborylated arylisoquinolines M2 and M3. The nucleophilic
substitution of 1-(8-methoxynaphthalen-1-yl)isoquinoline43
with the corresponding lithium amides afforded the products
M2 and M3 with a yield of 68% and 73%, respectively. This
methodology (method B, Scheme 2b) provides a useful
alternative to Buchwald’s methodology48 that is based on a
palladium-catalyzed one-pot borylation/Suzuki coupling start-
ing from the corresponding haloarenes (method A, Scheme
2b). In the concrete case of compound M2, the latter method
gave the product with only 17% yield.43 Compound M4 was
synthesized in a synthetic sequence (Scheme 2d) that started
with the preparation of A4 (86% yield) from 1-chloroan-
thracene and N-methylpiperazine using a palladium-catalyzed
Buchwald−Hartwig coupling. The subsequent regioselective
bromination at the 4-position of A4, followed by a palladium-
catalyzed one-pot borylation/Suzuki coupling48 of B4 with 1-
chloroisoquinoline, gave compound M4 in 31% yield.
In the present study the aim of our research was the modular
design of multilevel switches based on the class of fluorescent
borylated arylisoquinoline (BAI) dyes (see general structure in
Scheme 1), recently introduced by us. In a previous work43 we
have shown that the presence of the boronic ester substituent
modulates the electronic properties and consequently the
observation of ICT fluorescence in a rather advantageous
manner (good quantum yields and fine-tuned emission
covering a large part of the visible spectrum). The multi-
responsive features of BAI dyes were exploited through the
protonation of the isoquinoline moiety and the formation of an
ate complex between the trivalent boron center and fluoride
ions.44,45 Interestingly, in the context of switching, triarylboron
compounds were shown to yield three spectrally differentiated
fluorescent states through the application of protons and
fluoride ions inputs.46 However, as an important difference and
as explored in the examples discussed previously, we
concentrate herein on switches that generate bi- and multistable
fluorescence output responses as a function of a single input
signal (protons) that is applied at different concentration levels.
To this end we prepared a series of amino-substituted BAI
dyes (see Scheme 1) that behave as organic fluorescent
polybases. We were able to show that the control of the
electronic structure of the dyes can effectively lead to new
molecular entities behaving as off−on−off and on−off−on′
switches as well as ternary and quaternary switches with
potential for information processing.12
The introduction of the boronic ester substituent was carried
out following a methodology recently reported by some of us
that is based on the iridium(III)-catalyzed nitrogen-directed
ortho-borylation of arylisoquinolines.49,50 The herein-exploited
compounds 1−4 were obtained with this method in very good
to excellent yields. The reaction worked well at 55 °C, affording
the desired ortho-borylation products 2 and 4 in 61% and 80%
yield, respectively (Scheme 2e). The borylation of the
substrates M1 and M3 required elevated reaction temperatures
(80 °C) to afford the desired borylated products 1 and 3 in
89% and 58% yield, respectively. The need for higher
temperatures can be attributed to the low C−H bond acidity
of 1 and to the ability of the NMe2 group of 3 to compete with
the N(sp2) atom of the isoquinoline for the vacant coordination
site of the catalyst.51 The H NMR and 11B NMR analyses
1
revealed unambiguously that internal B−N interactions are
clearly dependent on the steric hindrance around the central
bond between the isoquinoline and the aryl moiety. On the one
hand, the hindered products 2−4 showed no B−N interaction
which can be identified by the 1H NMR signals of the
diastereotopic pinacol methyl groups, having two singlet
resonances at 0.74−0.94 ppm. On the other hand, for the
unhindered product 1, an internal B−N interaction was
inferred because the pinacol methyl groups were equivalent
and appeared as a single resonance at 1.41 ppm. These
assignments were further confirmed by the 11B NMR spectra of
the products: the hindered products 2−4 showed a signal in the
31−32 ppm range, while for compound 1 the B−N interaction
resulted in a strong shielding, and the signal appeared upfield
RESULTS AND DISCUSSION
■
Synthesis of the Borylated Arylisoquinolines 1−4 and
Their Nonborylated Model Chromophores. The non-
borylated compounds M1−M4, which served also as photo-
physical models (see following sections), were used as
precursors of the borylated title compounds. The synthesis of
the nonborylated arylisoquinolines as well as their borylated
derivatives is summarized in Scheme 2. Starting from the
previously reported compound A1, the nucleophilic substitu-
tion of the methoxy group with lithium 4-methylpiperazin-1-
ide47 afforded compound M1 in 76% yield. The same
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Scheme 2. Synthesis of BAI Dyes 1−4 and Their Nonborylated Analogues M1−M4
shifted at 13 ppm. These observations are in agreement with
reported data for both types of boron atoms, that is,
tricoordinated B (dyes 2−4) and tetra-coordinated B (dye 1).52
Molecular Design Principle for Multiple Fluorescence
Switching. BAI dyes show fluorescence emission which
originates from an ICT state. This has been recently
demonstrated by us for an extended series of BAI dyes by
time-dependent density functional theory (TD-DFT) calcu-
lations, the observation of characteristic solvatochromic effects,
and the conclusive correlation between redox and emission
properties.43 TD-DFT calculations revealed the same ICT
phenomena also for the herein-investigated dyes: in general
(with the exception of dye 4) the highest occupied molecular
orbital (HOMO) is mainly located on the borylated aminoaryl
electron donor moiety, while the lowest unoccupied molecular
orbital (LUMO) involves mainly the isoquinoline part
(electron acceptor) (see following sections).
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BAI dyes 1−4 contain various orthogonal protonation sites:
(a) a lateral tertiary amine is the most basic moiety (typical pKa
ca. 8−10 in water, for example, pKa ca. 8.4 for 1,4-
dimethylpiperazine)53 and (b) the less basic isoquinoline
moiety (pKa ca. 4.8 for parent isoquinoline in 1/1 methanol/
water).54 The nitrogen at the aryl ring could also be protonated
(in fact only observed for dye 3; see following), giving rise to a
third protonation site. However, the latter nitrogen is evidently
the least basic site because of the involvement of its lone pair in
the ICT process and the electrostatic repulsion caused by the
neighboring protonated lateral amino function.
NMR spectrum. However, by selecting the signal of the proton
ortho to the isoquinoline N as indicator, a very clear trend was
notable: until 1 equiv was added, this signal did not change,
while in the course of the addition of a second equivalent of
TfOH, a clear upfield shift and a merge with other aromatic
proton signals resulted. In conclusion, in agreement with the
pKa values of the basic sites in dye 2, the first equivalent of acid
led to the protonation at the lateral aliphatic amino N, while the
second acid equivalent protonated the isoquinoline N.
The polybasic behavior enabled the sequential pH control of
the electronic properties that guide ICT processes as well as
PET involving the lateral aliphatic amino group. This resulted
consequently in a modulation of the fluorescence response.
This photophysical scenario is schematically summarized in
Scheme 3 and will be discussed case-by-case for the investigated
dyes 1−4 (see following sections).
The orthogonal protonation behavior of the investigated BAI
dyes is illustrated by the representative example of dye 2. The
1H NMR spectra were observed as a function of the added
equivalents of triflic acid (TfOH; CF3SO3H) (see Figure 1).
Scheme 3. Mechanistic Proposal for Excited-State
Interactions in the BAI Dyes 1−4
DFT Calculations. To establish the ICT character of the
investigated dyes 1−4, DFT calculations were performed. The
ground state geometries (see Supporting Information) were
optimized by the application of the Kohn−Sham DFT with the
Becke 3 Lee−Yang−Parr (B3LYP) hybrid functional method
and the 6-31+G(d,p) basis set. The energy-minimized
structures of the BAI dyes 2−4 revealed a nearly perpendicular
positioning of the isoquinoline ring with respect to the aryl
residue (tilt angles: 86.7° for 2, 84.6° for 3, and 86.5° for 4).
The distance between the isoquinolyl N and the B atom was
measured as being between 3.52 and 3.55 Å for these three
dyes. This distance is slightly larger than the sum of the van der
Waals radii of B (1.92 Å) and N (1.55 Å),55 indicating the
absence of interaction between the Lewis acid and base centers.
This notion agrees with the observations made by 11B NMR
spectroscopy (see previous sections), which clearly supported
the absence of B−N coordinative bonding for the dyes 2−4.
However, in the case of dye 1, for which 11B NMR predicted a
tetra-coordinated B (see previous sections), the optimized
geometry showed a tilt angle of 59.0°, smaller than the ones
obtained for the compounds 2−4. This resulted in a
significantly reduced B−N distance of 3.21 Å, which is shorter
than the sum of the van der Waals radii and thereby supports
the notion of the formation of an intramolecular Lewis pair.
The frontier molecular orbitals were calculated by application
of the TD-DFT at the B3LYP/6-31+G(d,p) level of theory.
The corresponding contour plots of the HOMO and the
LUMO for each dye and the molecular orbital energies are
shown in Figure 2. For the BAI dyes 1−3 the HOMO was
located on the amino-substituted aryl electron donor moiety,
while the LUMO had its largest contribution from the
isoquinoline residue, functioning as electron acceptor in the
ICT process. The anthracene-substituted dye 4 was an
Figure 1. 1H NMR spectra of dye 2 in acetonitrile-d3 upon successive
addition of TfOH (0−2 equiv). The square marks the proton in the
ortho position relative to the isoquinoline N; the circle marks the N−
CH3 protons of the piperazinyl unit; see discussion in text.
Upon addition of 1 equiv of TfOH, it was clearly seen that the
N−CH3 methyl protons were downfield shifted (Δδ = +0.62
ppm), while the aromatic protons were much less or not at all
affected. This is indicative of the exclusive protonation of the
lateral aliphatic amino group in the first step. As expected, the
protons of the piperazinyl methylene neighboring the N−CH3
group (α-CH2) were also downfield shifted by ca. 0.6 ppm
(merging with the signal of the methylene protons closer to the
N at the aryl residue; β-CH2) on addition of the first equivalent
of TfOH. With increasing amounts of acid (>1.0 equiv) the β-
CH2 protons suffered downfield shifts as well, and signal
splitting for both the α- and β-CH2 groups was seen. The
addition of a second equivalent of TfOH led to pronounced
1
and rather complex changes in the aromatic region of the H
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Figure 2. HOMO−LUMO contour plots and orbital energies of dyes 1−4.
exception. Here the HOMO was located on the piperazinyl−
anthryl donor moiety, and the LUMO was on the borylated
anthryl electron acceptor residue, pointing to a more locally
excited state. However, the LUMO+1 (which lies close to the
LUMO) orbital (−1.54 eV) of dye 4 had its major contribution
from the isoquinoline moiety (see Supporting Information),
akin to the observations made for the LUMOs of the dyes 1−3.
For these reasons, the ICT character of dye 4 was similar to
that of the other dyes. This has been confirmed independently
by the observation of a solvatochromic effect.56
On the one hand, the absolute HOMO and LUMO gas-
phase energies for compounds 1−3 were situated at ca. −5.3 eV
and ca. −1.5 eV, respectively, leading to an energy gap of ca. 3.8
eV (see Figure 2). On the other hand, dye 4 showed a reduced
energy gap of ca. 3.3 eV (see Figure 2), which coincides with
the fact that this dye also showed the most red-shifted
fluorescence emission (see following sections).
Photophysical Properties. The UV−vis absorption and
fluorescence properties of the BAI dyes 1−4 in acetonitrile
solution are summarized in Table 1, and the corresponding
spectra are shown in Figure 3. Dyes 2 and 3 showed UV−vis
absorption bands at a maximum around 323 nm, typical for
substituted naphthalenes and isoquinolines. The anthracene-
derived dye 4 showed an absorption peak at 321 nm
(isoquinoline) and a red-shifted band with two maxima at
388 and 401 nm. The UV−vis absorption spectrum of dye 1
had, at first glance, a surprisingly broad absorption band at 420
nm. This can be ascribed to neither the phenyl moiety nor the
isoquinoline. However, one must bear in mind that the
intramolecular formation of a Lewis pair through the
unequivocally evidenced B−N interaction further increases
the electron density at the piperazinyl−phenyl moiety and also
turns the isoquinoline into a stronger electron acceptor. This
provides an explanation for the observation of this spectral
feature which we ascribe to a ground-state charge-transfer band.
The ICT character of the fluorescent state of the herein-
investigated dyes is well supported by the general observation
of broad and rather red-shifted emission bands (λf,max between
560 and 638 nm). For ICT a trend relationship between the
emission energy (as rated by the maximum of the fluorescence
band) and the electron donating character of the piperazinyl-
substituted aryl moieties is expected.43 It was gratifying to
Table 1. Photophysical Properties of the BAI Dyes 1−4 and
Their Protonated Forms in Acetonitrile
a
b
λabs, max, nm ε, M−1cm−1 λf, max, nm
Φf
τf, ns
1
420
12300
559
0.07 0.65 (82%), 6.64
(18%)
1H+
400
370
10200
5300
530
537
0.45 5.60
2+
1H2
0.01 1.15 (18%), 5.67
(82%)
2
323
9600
9800
9800
7500
8000
9100
6400
5400
5400
5900
599
0.37 5.44
0.50 7.09
2H+
311, 322
327, 340
323
576
2+
2H2
3
3H+
c
c
c
607
0.35 6.01
0.39 6.88
323
600
2+
3H2
3H3
4
340
c
c
c
3+
333, 340
388, 401
380, 399
447
0.03 1.24
0.23 4.87
0.20 4.05
0.01 11.00
526, 638
502, 622
502
4H+
2+
4H2
342, 388,
406
a
The molar absorption coefficient refers to the longest-wavelength
b
absorption maximum. The lifetime of the major component (≥95%)
is shown except for the cases where two exponentials contributed
significantly. Nonfluorescent species.
c
Figure 3. UV−vis absorption (solid lines) and fluorescence spectra
(dashed lines) of the investigated BAI dyes in acetonitrile: black, 1;
blue, 2; green, 3; red, 4.
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observe that dye 4 showed the most red-shifted emission in the
investigated series because the piperazinyl−anthryl unit is
assumed to be the easiest one to oxidize. The somewhat blue-
shifted emission maxima of the naphthalene-containing dyes 2
and 3 followed this rationalization. Dye 1, containing the most
difficult to oxidize aryl residue, showed expectedly the lowest
emission wavelength maximum. However, in comparison to
dyes 2−4, it was still higher than may be expected. This is
clearly related to the ground state B−N interaction in 1 (see
previous sections), which turns the aryl residue into a better
electron donor and the isoquinoline into a better electron
acceptor. Hence, the resulting excited ICT state is expected at
relatively low energy, corresponding to the red-shifted
emission.
Effects of Protonation. As outlined previously, the BAI
dyes 1−4 were designed to serve as proton-sensitive polybasic
fluorescent switches. Noteworthy, the UV−vis absorption
spectra corresponding to the acid titrations of the investigated
dyes showed clear isosbestic points for the orthogonal
protonation steps (see Figure 5a and 5b for the example of
dye 1 and the Supporting Information for the other dyes). This
hints of well-defined equilibria in the different phases of the
titration, thereby supporting the previously discussed sequential
protonation of the basic receptor sites. Interestingly, the long-
wavelength absorption band of dye 1 showed a slight blue shift
by ca. 20 nm upon the first protonation (see following
discussion) and then vanished in the second protonation step
of the isoquinoline in favor of a new band at ca. 370 nm. The
disappearance of the B−N interaction in the second
protonation, but not in the first one, was independently
confirmed by 11B NMR spectroscopy (see Supporting
Information). These results are once more in agreement with
the orthogonal protonation behavior for the herein-investigated
dyes.
The relatively low quantum yield of Φf = 0.07 of dye 1 is a
consequence of a relatively efficient PET from the lateral N of
the piperazinyl substituent (see discussion following). On the
other hand, dyes 2−4 showed yellow to orange emission colors
(see Figure 4) with quite significant quantum yields (Φf =
It was anticipated that the lateral aliphatic amino function
would be able to engage in electronic interactions with the
excited ICT state of the dye, possibly via PET (see Scheme 3).
This would lead to ICT fluorescence quenching that can be
inverted upon protonation as the result of the deactivation of
the electron-donating amine. This assumption is based on the
observations made for other ICT fluorophores with attached
amino functions at their “donor sites”.4,57 Despite this
potentially common mechanistic PET feature of the inves-
tigated dyes, quite variable photophysical effects were observed
for the first protonation step (see Table 1 and the emission
color changes depicted in Figure 4 for the different
monoprotonated forms). In general, the efficiency of PET
depends sensibly on the redox potentials of the involved
electron donor (the amine) and acceptor (the BAI dye) as well
as on the energy of the ICT state.58 Given the variation of some
of these parameters (especially the electron acceptor properties
and ICT energies) in the investigated series of compounds, the
differentiated response to protonation of the lateral electron-
donating amine can be reasonably rationalized. In detail, for dye
1 a significant increase of the fluorescence quantum yield by a
factor of ca. 6 was seen. This trend was also accompanied by
the observation of a longer lifetime (see Table 1) and a much
brighter emission perception (see Figure 4) as compared to the
nonprotonated dye. Obviously, the protonation leads to the
suppression of a quite efficient PET. The B−N interaction (see
previous discussion) increases the ground-state electron
acceptor character of the isoquinoline. Furthermore, the in
comparison to the other dyes somewhat higher ICT state
energy favors PET as well. As a side observation, the
fluorescence maximum of 1H+ was blue-shifted by ca. 30 nm,
which is in line with a slight destabilization of the ICT state
(see previous sections for a related effect in the UV−vis
absorption spectrum of dye 1). This may occur because of the
sharing of the proton between the both piperazinyl N atoms
and the consequent lowering of the electron donor strength of
the N that is connected to the aryl moiety.20 With respect to
this “blue shift effect” for the monoprotonated form, similar
observations were made for dyes 2 and 4 (Δλ = 16−24 nm).
The smallest blue shift (Δλ = 9 nm) was seen for dye 3, where
the two N atoms are not as preorganized as in the
conformationally more restricted piperazinyl. Returning to the
discussion of the emission intensity changes upon monoproto-
Figure 4. Color perception and brightness of the BAI dyes 1−4 in the
absence of acid and in the presence of one or two equivalents TfOH in
acetonitrile solutions.
0.23−0.37), pointing to less strong PET effects. In the case of
dye 4, which has a quite low-lying ICT state, the enhanced
nonradiative deactivation as consequence of the energy gap law
contributes to the somewhat lower quantum yield as compared
to dyes 2 and 3 (see Table 1). The fluorescence lifetimes for
dyes 2−4 varied between 4.87 and 6.01 ns. Compound 1
showed a much shorter lifetime of 0.65 ns (along with a minor
component of 6.64 ns). This confirms the trend of a lower
emission quantum yield of 1 as compared to the other dyes.
The nonborylated arylisoquinolines M1−M4 were included
as model compounds in this study. In comparison to their
borylated analogues the emission spectra of M1−M4 were
blue-shifted, and lower fluorescence quantum yields were
obtained (see Table S1 in Supporting Information). These
observations underline the crucial role of the boron-substitution
in the excited-state behavior of dyes 1−4. This is in agreement
with the general observations made for other BAI dyes.43
Interestingly, for dye M1 also the UV−vis absorption spectrum
changed dramatically. The missing possibility of intra-Lewis
pair formation led to a blue shift of more than 80 nm for the
longest-wavelength absorption band.
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Figure 5. UV−vis absorption and fluorescence titration of dye 1 (8.2 μM) with TfOH in acetonitrile; (a) UV−vis spectra (0−1.0 equiv of TfOH),
(b) UV−vis spectra (1.0−2.1 equiv of TfOH), (c) fluorescence spectra (0−1.0 equiv of TfOH); (d) fluorescence spectra (1.0−2.1 equiv of TfOH).
The sample was excited at 336 nm (isosbestic point maintained throughout the complete titration).
nation, the fluorescence switching effects of dyes 2−4 were
significantly different in comparison to compound 1. Dye 2
yielded a smaller quantum yield enhancement factor [Φf(2H+)/
Φf(2), ca. 1.4], but given the already significant fluorescence
quantum yield in the absence of protons, the emission
efficiency of 2H+ is quite appreciable (Φf = 0.50). Dye 3
increased its fluorescence quantum yield by an even smaller
factor [Φf(3H+)/Φf(3), ca. 1.1] and dye 4 did practically not
change its emission quantum yield; see Table 1. For dyes 2−4
the PET effects are obviously weaker than they are for dye 1.
This may be because of the missing B−N interaction and the
comparatively less strong electron-acceptor character of the
isoquinoline part. However, some modest PET from the lateral
amino N was observed for dyes 2 and 3. In the case of dye 4,
the ICT state is too low-lying to favor any PET. The less
dramatic changes of the quantum yields upon monoprotona-
tion of dyes 2−4 are easily detected with the naked eye (see
Figure 4).
The second protonation (addition of 2 equiv of TfOH),
which happens at the isoquinolyl moiety, consistently yielded a
practically quantitative quenching of the ICT fluorescence (see
Table 1 and Figure 4). This has been observed and discussed
recently by us for related BAI dyes.43 The main reason for this
effect is the increased acceptor strength of the protonated
isoquinoline that leads to a rather low-lying ICT state.
Presumably, this state, following the energy gap law, deactivates
preferentially via nonradiative pathways. Dye 3 is different from
the other dyes insofar as the third protonation step, this time at
the N that is connected to the naphthyl residue, was observed.
Such behavior is very unlikely for the monoprotonated
piperazinyl unit in dyes 1, 2, and 4, which would have to
accommodate two positive charges in very close proximity.
However, also for dye 3 a larger excess (20 equiv) was
necessary to see the formation of 3H33+. This species showed a
strongly blue-shifted emission at a maximum of 450 nm (see
Figure 6), indicative of an ICT that has been energetically
destabilized by the excessive weakening of the electron donor
strength of the protonated nitrogen.
Figure 6. Fluorescence spectra of dye 3 (black line) with the addition
of 1 equiv (3H+, red line), 2 equiv (3H22+, green line, nonfluorescent),
and 20 equiv of TfOH (3H33+, blue line).
Implementation of Multilevel Logic Switches. The
fluorescence modulation through proton-controlled PET and
ICT processes makes the investigated dyes interesting
candidates for the implementation of multivalued logic (see
Table 2). Most logic switches work on the basis of binary
principles, i.e., high (binary 1) and low (binary 0) signals.
However, a strong interest in the design of switches that can
differentiate between more than two levels for the input and
output signals has recently evolved.12 That is, for example, low
(0), medium (1), and high (2) in the case of ternary switching.
In this sense off−on−off switches differentiate three input signal
levels: at a low input the switch is off, at medium input signal
level an on state is observed, and at high input levels an off
output again results. The design challenge lies in the precise
control of orthogonal receptor sites which should trigger
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Table 2. Truth Table for the Multivalued Switching of the BAI Dyes 1−4
fluorescence output
a
b
b
cd
,
bd
,
H+ input
dye 1 (λobs = 530 nm)
dye 2 (λobs = 576 nm)
dye 3 (λobs = 526 nm)
dye 4 (λobs = 622 nm)
0
0
1
0
1
2
0
2
1
1
0
1
3
2
0
3
1
output:
binary
ternary
quaternary
binary
off−on−off
medium−on−off
on−off
a
b
d
The input levels 0, 1, and 2 indicate the number of equiv of TfOH; input level 3 (only applicable to dye 3) corresponds to 20 equiv of TfOH.
c
Fluorescence maximum of the monoprotonated form of the dye. Monitored at a wavelength where all forms (3, 3H+, 3H22+, and 3H33+) emit.
Monitoring the fluorescence output for 3 at 600 nm (3H+) or for dye 4 at 580 nm (away from the maximum of any implied form) yields the
reconfiguration of the switch toward an on−off (dye 3) or medium−on−off (dye 4) output signaling pattern.
Figure 7. Fluorescence titration curves of dyes 1 (a), 2 (b), 3 (c), 4 (d) upon addition of TfOH. For observation wavelengths see Table 2.
opposing fluorescence modulation events (i.e., enhancement
and quenching).
As discussed previously, dye 3 offers the possibility of three
protonation steps, and therefore four states can be observed: 3,
3H+, 3H22+, and 3H33+. These are differentiated by their
emission quantum yields and in the case of the triprotonated
form by a significantly different spectral position of the
fluorescence. The choice of the emission maximum of the
monoprotonated dye 3H+ at 600 nm as readout channel leads
basically to a simple binary on−off switching. However, when
selecting a strategic wavelength where all four forms of the dye
have an emission response (526 nm), a four-level response
(quaternary logic corresponding to 0, 1, 2, 3) was observed: 3
As results from the previously discussed protonation
behavior of compound 1, this dye fulfills these criteria, and
thus it behaves as an off−on−off switch (see Table 2). The
corresponding fluorescence titration monitored at the emission
maximum of 1H+ is shown in Figure 7a. Furthermore, the
proton inputs for each modulation (off−on and on−off) are
degenerate (1 equiv of TfOH for each step), and therefore the
switch is equally discussed as an XOR logic gate:59 the presence
of either (degenerate) proton input results in a high
fluorescence, while the absence or simultaneous presence of
both inputs yields a low fluorescence signal.
Dye 2, in its nonprotonated state, showed a considerable
fluorescence which was further increased upon the first
protonation of the lateral N of the piperazinyl substituent.
The second protonation, involving the isoquinolyl N, quenches
the fluorescence quantitatively. Monitoring the fluorescence
output at the maximum of the monoprotonated form 2H+ (see
Figure 7b) led to the observation of a tristable switch with a
medium (1)−on (2)−off (0) signal pattern. Here, both the
input and output signals are represented by three discrete levels
(see Table 2).
(level 2), 3H+ (level 3), 3H2 (level 0), and 3H3 (level 1)
(see Figure 7c and Table 2). Such switches with fourfold
stability are extremely rare.39 Taking into account the
pronounced spectral shift for the triprotonated dye 3, the
switching can be as well interpreted as on−off−on′ modulation,
where the two on situations correspond to different emission
wavelengths (e.g., 600 and 447 nm). The realization of such
functions has been described recently as nontrivial60,61 and the
herein described ICT dye 3 provides an interesting mechanistic
extension for such switch types.
2+
3+
Finally, when monitoring the intensity at the emission
maximum of the monoprotonated form of the anthracene-
derived BAI dye 4, a conventional on−off binary switch resulted
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quality. Trifluoromethane sulfonic acid (triflic acid; TfOH; CF3SO3H,
98%) and phosphazene base P2-Et (98%) were purchased from
commercial suppliers and used as received.
upon the addition of 2 equiv of protons (see Figure 7d and
Table 2). Notably, by choosing the emission output channel at
580 nm (away from the emission maximum of any involved
species), a medium−on−off pattern, as for dye 2, was again
observed. In summary, the investigated series of BAI dyes
enables the possibility to adapt the switching behavior from
binary via ternary to quaternary outputs by controlling the
electronic properties through orthogonal protonation events.
Notably, the initial level of fluorescence (and thereby the
switching pattern for the first protonation step: off-on or
medium-on) is a direct translation of the PET efficiency in the
unprotonated dye. In turn the PET process can be reasonably
controlled by fine-tuning electronic properties of the aryl
residue, providing an interesting tool for the molecular design
of multilevel switches.
All reactions were carried out by employing standard techniques in
oven-dried Schlenk tubes under argon atmosphere. Anhydrous
tetrahydrofuran (THF) was obtained using Grubbs-type solvent
drying columns. Anhydrous 1,4-dioxane was obtained by distillation
from sodium using benzophenone as indicator. Ethylacetate (EtOAc),
methanol (MeOH), n-hexane, and dichloromethane (CH2Cl2) were
purchased from commercial suppliers and used without further
purification. Reagents, metallic precursors, and ligands for the
syntheses were purchased from commercial suppliers and used as
received. The only exceptions were 1-methylpiperazine and N,N,N′-
trimethyl-1,3-propanediamine that were dried over CaH2 and distilled
before use. Potassium tert-butoxide was stored in a dry glovebox. The
reagents 1-methyl-4-(naphthalen-1-yl)piperazine,47 1-chloroanthra-
cene,62 and 1-(8-methoxynaphthalen-1-yl)isoquinoline43 were pre-
pared following described methodologies.
Spectroscopic Measurements and Fluorescence Titrations.
The dyes were tested for their nonprotonated state by adding 1 equiv
phosphazene base P2-Et, which in no case yielded significant changes
in the UV−vis or fluorescence spectra. The TfOH stock solutions were
calibrated by previous fluorescence titration (λobs = 416 nm) using
recrystallized commercial 9-(N-methylamino)methylanthracene as
indicator.20
All photophysical measurements were performed with air-
equilibrated acetonitrile solutions at room temperature, using quartz
cuvettes (1 cm optical path length). The UV−vis absorption spectra
were obtained with a standard spectrophotometer. The fluorescence
spectra were recorded with a fluorimeter equipped with a xenon flash
lamp as excitation source and corrected for the spectral sensitivity of
the photomultiplier detector. The fluorescence quantum yields were
determined with quinine sulfate (Φf = 0.55 in 0.05 M sulfuric acid) as
reference63 and corrected for refractive index differences of the used
solvents. The error margin of the quantum yields is estimated to be
10% (except for dye 4 where it is 20%).
The lifetime measurements were performed by means of time-
correlated single photon counting with picosecond pulsed UV-LEDs
(λ = 335 nm, pulse width fwhm 758 ps; λ = 338 nm, pulse width fwhm
625 ps; λ = 367 nm, pulse width fwhm 745 ps) or a picosecond pulsed
diode laser (λ = 442 nm, pulse width fwhm 78 ps) as excitation
sources. The error of the lifetimes is estimated to be 5%.
The fluorescence titrations were performed by adding aliquots of a
TfOH stock solution. The samples were excited at wavelengths where
the changes in the UV−vis spectra were minimal in the course of the
titration.
DFT Calculations. The calculations were made with the program
Gaussian 03.64 The ground-state geometries were optimized by
applying the Kohn−Sham DFT. The B3LYP method with the 6-
31+G(d,p) basis set was used for the full structural optimization and
frequency calculations. The latter were done in order to verify the
stationary points on the potential energy surface. For the calculations
of the HOMO and LUMO frontier orbital energies, the TD-DFT at
the B3LYP/6-31+G(d,p) level was applied.
Synthesis of Dyes and Their Precursors. 1-(4-
Methoxyphenyl)isoquinoline A1. A Schlenk tube was charged
with a solution of 1-chloroisoquinoline (327 mg, 2 mmol), 4-
methoxyphenylboronic acid (365 mg, 2.4 mmol), Na2CO3 (424 mg, 4
mmol), and Pd(PPh3)4 (69 mg, 3 mol %). After three cycles of
vacuum-argon flushing, toluene (2 mL), MeOH (0.4 mL), and H2O
(0.5 mL) were sequentially added. The reaction mixture was stirred at
110 °C overnight, then cooled to room temperature, quenched with
H2O (10 mL), and extracted with CH2Cl2 (3 × 20 mL). The organic
layer was dried over anhydrous MgSO4, filtered, concentrated, and the
residue was purified by flash chromatography on silica gel (EtOAc/n-
hexane 1:5) to give A1 (430 mg, 91%) as a colorless solid. The
spectroscopic data matched those reported in the literature.65
1-(4-(4-Methylpiperazin-1-yl)phenyl)isoquinoline M1. A sol-
ution of 1-methylpiperazine (144 μL, 1.3 mmol) in dry THF (1.0 mL)
was stirred at 0 °C under argon. A solution of 2.5 M n-butyllithium in
CONCLUSIONS
■
The absorption and fluorescence properties of arylisoquinolines
can be tuned by amino-substitution, the degree of π-
conjugation of the aryl residue, and the presence of a boronic
acid ester substituent. The prepared BAI dyes 1−4 constitute
examples of efficient fluorophores that are based on ICT
processes and that possess very characteristic emission
fingerprints in the green to red spectral region. Furthermore,
the presence of various basic groups enabled the observation of
multiple and orthogonal protonation phenomena. This
provided a convenient tool for achieving fluorescence enhance-
ment as well as quenching by pH-induced switching. As a
general observation, the protonation of the lateral amino N
yielded hypsochromically shifted emission signatures along with
increased quantum yields. The second protonation step of the
less basic isoquinoline triggered a practically quantitative
fluorescence quenching. In the case of dye 3, a third
protonation step was observed that manifested itself in a new
emission band in the blue spectral region. The mechanistic
explanation of the observed fluorescence modulation relies on
the involvement of PET and the destabilization or stabilization
of ICT states. For some of the protonated dyes, fluorescence
quantum yields of up to 0.5 were obtained, increasing further
the already quite appreciable quantum yields of the non-
protonated dyes (ca. 0.2−0.4). The reading of the fluorescence
response as output dependent on the proton input signals
yielded a set of functional molecules with the potential of
multilevel logic switching ranging from binary and ternary
responses to extremely rare quaternary behavior. The
implementation of such functions is of interest in the context
of molecular logic-based computation.12
EXPERIMENTAL SECTION
■
1
Materials and Methods. H NMR and 13C NMR spectra were
recorded at 400 or 500 MHz and 100 or 125 MHz, respectively, using
the solvent peak for CDCl3 as the internal reference (7.26 ppm and
77.0 ppm for 1H and 13C, respectively). 11B NMR spectra were
recorded with complete proton decoupling at 160 MHz using
BF3·Et2O (0.00 ppm for 11B NMR) as internal standard. Electro-
spray−ionization (EI) high-resolution mass spectra were recorded
with a QTRAP mass spectrometer (hybrid triple quadrupole/linear
ion trap mass spectrometer). Flash column chromatography was
performed on silica gel (35−70 μm or 70−200 μm). Analytical thin-
layer chromatography was done with aluminum backed plates (1.5 ×
5.0 cm) precoated (0.25 mm) with silica gel. The compounds were
visualized by exposure to UV light or by dipping the plates in a
solution of 5% (NH4)2Mo7O24 × 4H2O in 95% ethanol (w/v), and
then the plates were heated. Acetonitrile was of UV spectroscopic
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n-hexane (0.52 mL, 1.3 mmol) was added dropwise through a septum.
The reaction mixture was stirred at 0 °C for 30 min and then at room
temperature for 1 h. Then A1 (235 mg, 1.0 mmol) was added, and the
reaction mixture was refluxed overnight. After it was cooled, the
mixture was quenched with H2O (10 mL) and extracted with CH2Cl2
(3 × 10 mL). The combined organic phase was dried over anhydrous
Na2SO4, filtered, and concentrated to dryness. The crude product was
purified by flash chromatography on silica gel (CH2Cl2/MeOH 20:1)
to give M1 (230 mg, 76%) as a pale yellow solid. mp 165−167 °C. 1H
NMR (400 MHz, CDCl3): δ 8.58 (d, 1H, J = 5.7 Hz), 8.21 (d, 1H, J =
8.2 Hz), 7.87 (d, 1H, J = 8.2 Hz), 7.70−7.65 (m, 3H), 7.59 (d, 1H, J =
5.8 Hz), 7.53 (t, 1H, J = 8.0 Hz), 7.08 (d, 2H, J = 8.2 Hz), 3.35 (t, 4H,
J = 4.8 Hz), 2.65 (t, 4H, J = 4.8 Hz), 2.40 (s, 3H). 13C NMR (100
MHz, CDCl3): δ 160.5, 151.4, 142.2, 137.0, 131.0, 130.6, 129.8, 127.8,
126.9, 126.9, 126.7, 119.2, 115.4, 55.0, 48.6, 46.1. HRMS (EI) m/z:
M+ calcd for C20H21N3 303.1735; found, 303.1744.
N-[4-(Isoquinolin-1-yl)naphthalen-1-yl]-N,N,N′-trimethylpro-
pane-1,3-diamine M3. A solution of N,N,N′-trimethyl-1,3-propane-
diamine (191 μL, 1.3 mmol) in dry THF (1 mL) was stirred at 0 °C
under argon. A solution of 2.5 M n-butyllithium in n-hexane (0.52 mL,
1.3 mmol) was added dropwise through a septum. The reaction
mixture was stirred at 0 °C for 30 min and then at room temperature
for 1 h. Then 1-(8-methoxynaphthalen-1-yl)isoquinoline (285 mg, 1
mmol) was added, and the reaction mixture was refluxed overnight.
After cooling, the mixture was quenched with H2O (15 mL) and
extracted with CH2Cl2 (3 × 10 mL). The combined organic phase was
dried over Na2SO4, filtered, and concentrated to dryness. The reaction
crude was purified by flash chromatography on silica gel (CH2Cl2/
MeOH 10:1, 1% Et3N) to give M3 (270 mg, 73%) as a yellow-brown
viscous oil. 1H NMR (500 MHz, CDCl3): δ 8.68 (d, 1H, J = 5.7 Hz),
8.35 (d, 1H, J = 8.4 Hz), 7.92 (d, 1H, J = 8.3 Hz), 7.73 (d, 1H, J = 5.7
Hz), 7.69−7.67 (m, 2H), 7.51−7.46 (m, 2H), 7.41 (t, 1H, J = 8.0 Hz),
7.39 (d, 1H, J = 8.0 Hz), 7.30 (t, 1H, J = 7.5 Hz), 7.25 (d, 1H, J = 8.3
Hz), 3.25 (t, 2H, J = 7.0 Hz), 2.94 (s, 3H), 2.59−2.48 (m, 2H), 2.35
(s, 6H), 1.97−1.91 (m, 2H). 13C NMR (125 MHz, CDCl3): δ 160.8,
150.6, 142.4, 136.5, 133.6, 132.2, 130.1, 129.8, 128.4, 127.9, 127.7,
127.1, 126.8, 126.5, 126.1, 125.3, 124.1, 120.0, 115.2, 57.4, 54.4, 45.0,
43.2, 25.0. HRMS (EI) m/z: M+ calcd for C25H27N3 369.2205; found,
369.2208.
1-(Anthracen-1-yl)-4-methylpiperazine A4. A dried Schlenk
tube was charged with palladium(II) acetate (Pd(OAc)2; 3.8 mg, 0.017
mmol), SPhos (13.4 mg, 0.034 mmol), sodium tert-butoxide (226 mg,
2.35 mmol), and 1-chloroanthracene (357 mg, 1.68 mmol). After three
consecutive cycles of vacuum-argon flushing, dry toluene (1.7 mL) and
N-methylpiperazine (224 μL, 2.02 mmol) were added with the help of
a syringe. The reaction mixture was heated to 60 °C for 2 h, cooled to
room temperature, and diluted with H2O (10 mL) and EtOAc (5 mL).
The organic phase was separated, and the aqueous phase was extracted
with EtOAc (3 × 10 mL). The combined organic phase was dried over
anhydrous MgSO4, filtered, and concentrated to dryness. The crude
product was purified by flash chromatography on silica gel (CH2Cl2/
MeOH 10:1) to give A4 (400 mg, 86%) as a bright yellow viscous oil.
1H NMR (500 MHz, CDCl3): δ 8.76 (s, 1H), 8.41 (s, 1H), 8.05 (dd,
1-(4-Bromonaphthalen-1-yl)-4-methylpiperazine A2. Follow-
ing the procedure described in the literature,66 a solution of 1-methyl-
4-(naphthalen-1-yl)piperazine (2.26 g, 10 mmol) in acetonitrile (60
mL) was treated with N-bromosuccinimide (1.96 g, 11 mmol), and the
reaction mixture was stirred overnight at room temperature.
Subsequently the reaction mixture was concentrated to dryness, and
the resulting solid was extracted with an n-hexane/EtOAc 2:1 mixture
(3 × 50 mL). After evaporation of the solvent, the crude product was
purified by flash chromatography on silica gel (CH2Cl2/MeOH 20:1)
1
to give A2 (2.87 g, 94%) as a light brown solid: mp 92−94 °C. H
NMR (500 MHz, CDCl3): δ 8.22 (d, 2H, J = 8.3 Hz), 7.68 (d, 1H, J =
8.0 Hz), 7.58 (t, 1H, J = 7.6 Hz), 7.53 (t, 1H, J = 7.6 Hz), 6.96 (d, 1H,
J = 8.0 Hz), 3.13 (br s, 4H), 2.73 (br s, 4H), 2.43 (s, 3H). 13C NMR
(125 MHz, CDCl3): δ 149.6, 132.8, 130.2, 129.7, 127.7, 127.2, 126.1,
124.0, 117.2, 115.5, 55.5, 52.9, 46.1. HRMS (EI) m/z: M+ calcd for
C15H17BrN2 304.0575 (79Br), 306.0555 (81Br); found, 304.0578
(79Br), 306.0556 (81Br).
1-(4-(4-Methylpiperazin-1-yl)naphthalen-1-yl)isoquinoline
M2. Method A: Following a described procedure,48 a dried Schlenk
tube was charged with tris(dibenzylideneacetone)dipalladium(0)
(Pd2dba3; 12 mg, 0.012 mmol), 2-dicyclohexylphosphino-2′,6′-
dimethoxybiphenyl (SPhos; 39 mg, 0.096 mmol), bis(pinacolato)-
diboron (B2Pin2; 305 mg, 1.2 mmol), A2 (366 mg, 1.2 mmol), and
KOAc (200 mg, 2.04 mmol). After three cycles of vacuum-argon
flushing, 1,4-dioxane (4.0 mL) was added. The reaction mixture was
heated to 110 °C for 6 h. At this point 1-chloroisoquinoline (163 mg,
1.0 mmol) in 1,4-dioxane (1.0 mL) and a 5 M aqueous solution of
K3PO4 (1.0 mL) were added into the reaction flask. The mixture was
heated to 110 °C overnight, cooled to room temperature, and diluted
with H2O (10 mL) and EtOAc (20 mL). The organic phase was
separated, and the aqueous phase was extracted with EtOAc (3 × 20
mL). The combined organic phase was dried over anhydrous MgSO4,
filtered, and concentrated to dryness. Flash chromatography on silica
gel (CH2Cl2/MeOH 15:1→5:1) gave M2 (60 mg, 17%) as a light
yellow foam. Method B: A solution of 1-methylpiperazine (72 μL, 0.65
mmol) in dry THF (0.5 mL) was stirred at 0 °C. A solution of 2.5 M
n-butyllithium in n-hexane (0.260 mL, 0.65 mmol) was added
dropwise. The reaction mixture was stirred at 0 °C for 30 min and
then at room temperature for 1 h. Then 1-(8-methoxynaphthalen-1-
yl)isoquinoline (143 mg, 0.5 mmol) was added, and the reaction
mixture was refluxed overnight. After cooling, the mixture was
quenched with H2O (10 mL) and extracted with CH2Cl2 (3 × 10 mL).
The combined organic phase was dried over anhydrous Na2SO4,
filtered, and concentrated to dryness. The reaction crude was purified
by flash chromatography on silica gel (CH2Cl2/MeOH 20:1) to give
M2 as light yellow foam (120 mg, 68%). 1H NMR (400 MHz,
CDCl3): δ 8.72 (d, 1H, J = 5.7 Hz), 8.35 (d, 1H, J = 8.5 Hz), 7.95 (d,
1H, J = 8.3 Hz), 7.76 (d, 1H, J = 5.7 Hz), 7.72−7.68 (m, 2H), 7.55−
7.48 (m, 2H), 7.45−7.42 (m, 2H), 7.33 (t, 1H, J = 8.3 Hz), 7.29 (d,
1H, J = 7.2 Hz), 3.29 (br s, 4H), 2.82 (br s, 4H), 2.50 (s, 3H). 13C
NMR (100 MHz, CDCl3): δ 160.7, 150.2, 142.4, 136.5, 133.5, 132.3,
130.1, 128.9, 128.4, 127.9, 127.8, 127.0, 126.8, 126.5, 126.2, 125.3,
123.8, 120.0, 114.1, 55.6, 52.9, 46.2. HRMS (EI) m/z: M+ calcd for
C24H23N3 353.1892; found, 353.1894.
1H, J = 6.0, 2.0 Hz), 7.99 (dd, 1H, J = 6.0, 2.0 Hz), 7.71 (d, 1H, J = 8.5
Hz), 7.48−7.46 (m, 2H), 7.39 (t, 1H, J = 8.0 Hz), 7.05 (d, 1H, J = 7.5
Hz), 3.25 (br s, 4H), 2.81 (br s, 4H), 2.48 (s, 3H). 13C NMR (125
MHz, CDCl3): δ 149.5, 133.0, 131.5, 131.2, 128.7, 127.8, 127.6, 126.6,
125.4, 125.3, 125.1, 123.7, 122.4, 113.3, 55.7, 52.9, 46.2. HRMS (EI)
m/z: M+ calcd for C19H20N2 276.1626; found, 276.1627.
1-(4-Bromoanthracen-1-yl)-4-methylpiperazine B4. Follow-
ing a described procedure,66 a solution of A4 (270 mg, 0.98 mmol) in
acetonitrile (16 mL) was treated with N-bromosuccinimide (196 mg,
1.08 mmol), and the reaction mixture was stirred overnight at room
temperature. Then the reaction mixture was concentrated to dryness,
and the crude was purified by flash chromatography on silica gel
(CH2Cl2/MeOH 20:1) to give B4 (238 mg, 68%) as a yellow viscous
1
oil. H NMR (500 MHz, CDCl3): δ 8.78 (s, 1H), 8.77 (s, 1H), 8.07
(m, 2H), 7.68 (d, 1H, J = 7.8 Hz), 7.53−7.51 (m, 2H), 6.87 (d, 1H, J =
7.8 Hz), 3.20 (br s, 4H), 2.80 (br s, 4H), 2.47 (s, 3H). 13C NMR (125
MHz, CDCl3): δ 149.7, 132.1, 131.4, 130.9, 129.1, 128.4, 128.3, 126.8,
126.1, 126.0, 123.2, 117.2, 113.8, 55.5, 53.0, 46.2. HRMS (EI) m/z:
M+ calcd for C19H19BrN2 354.0732 (79Br), 356.0711 (81Br); found,
354.0733 (79Br), 356.0723 (81Br).
1-(4-(4-Methylpiperazin-1-yl)anthracen-1-yl)isoquinoline
M4. Following a described procedure,48 a dried Schlenk tube was
charged with Pd2dba3 (9.5 mg, 0.01 mmol), SPhos (31.5 mg, 0.08
mmol), B2Pin2 (251 mg, 0.99 mmol), B4 (350 mg, 0.99 mmol), and
KOAc (165 mg, 1.68 mmol). After three cycles of vacuum-argon
flushing, 1,4-dioxane (3.4 mL) was added with the help of a syringe.
Then the reaction mixture was heated overnight to 110 °C.
Subsequently 1-chloroisoquinoline (134 mg, 0.83 mmol) dissolved
in 1,4-dioxane (1.0 mL) and 5 M aqueous solution of K3PO4 (0.8 mL)
were added by a syringe into the reaction flask. The reaction mixture
was heated to 110 °C for 10 h, cooled to room temperature, and
diluted with H2O (10 mL) and EtOAc (20 mL). The organic phase
was separated and the aqueous phase was extracted with EtOAc (3 ×
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20 mL). The combined organic phase was dried over anhydrous
MgSO4, filtered, and concentrated to dryness. Flash chromatography
on silica gel (CH2Cl2/MeOH 20:1→10:1) gave M4 (105 mg, 31%) as
55.0, 45.5, 42.8, 25.9, 24.4, 24.1, (C−B not observed). 11B NMR (160
MHz, CDCl3): δ 32.2 (br s) ppm; HRMS (EI) m/z: M+ calcd for
C31H38BN3O2 495.3057; found, 495.3054.
1
1-[4-(4-Methylpiperazin-1-yl)-2-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)anthracen-1-yl]isoquinoline 4. Following the
previously described general procedure for Ir-catalyzed borylation,
starting from M4 (84 mg, 0.21 mmol) and carrying out the reaction at
55 °C, flash chromatography on silica gel (CH2Cl2/MeOH 10:1) gave
a yellow-orange foam. H NMR (500 MHz, CDCl3): δ 8.86 (s, 1H),
8.74 (d, 1H, J = 5.5 Hz), 8.04 (d, 1H, J = 8.0 Hz), 7.96 (s, 1H), 7.95
(d, 1H, J = 7.0 Hz), 7.79 (d, 1H, J = 5.5 Hz), 7.73−7.66 (m, 3H), 7.48
(d, 1H, J = 7.5 Hz), 7.43 (t, 1H, J = 8.0 Hz), 7.39 (t, 1H, J = 8.0 Hz),
7.34 (t, 1H, J = 7.5 Hz), 7.18 (d, 1H, J = 7.5 Hz), 3.36 (br s, 4H), 2.89
(br s, 4H), 2.53 (s, 3H). 13C NMR (125 MHz, CDCl3): δ 160.8, 150.2,
142.5, 136.6, 132.4, 132.0, 131.6, 131.1, 130.2, 128.6, 128.5, 128.3,
127.9, 127.6, 127.5, 127.1, 126.9, 125.5, 125.4, 122.7, 120.1, 112.8,
55.7, 52.9, 46.2. HRMS (EI) m/z: M+ calcd for C28H25N3 403.2048;
found, 403.2058.
General Procedure for the Ir-Catalyzed Borylation. Following
a recently described method,49 a dried Schlenk tube was charged with
the substrate (M1, M2, M3 or M4) and B2Pin2 (1 equiv). After three
cycles of vacuum-argon flushing, 1 mL of catalyst stock solution67 per
0.5 mmol of substrate and pinacolborane (HBPin; 5 mol %) were
added. The reaction mixture was stirred at 55−80 °C until reaching
quantitative consumption of the starting material (as indicated by TLC
monitoring). The mixture was cooled to room temperature,
concentrated to dryness, and the crude products were purified by
column chromatography (CH2Cl2/MeOH mixtures).
1-[4-(4-Methylpiperazin-1-yl)-2-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)phenyl]isoquinoline 1. Following the previ-
ously described general procedure for Ir-catalyzed borylation, starting
from M1 (76 mg, 0.25 mmol) and carrying out the reaction at 80 °C,
flash chromatography on silica gel (CH2Cl2/MeOH 10:1) gave 1 (95
mg, 89%) as an orange foam. 1H NMR (400 MHz, CDCl3): δ 8.82 (d,
1H, J = 8.2 Hz), 8.42 (d, 1H, J = 6.3 Hz), 8.12 (d, 1H, J = 8.6 Hz),
7.85 (d, 1H, J = 8.2 Hz), 7.77 (t, 1H, J = 8.0 Hz), 7.67 (t, 1H, J = 8.0
Hz), 7.51 (d, 1H, J = 6.3 Hz), 7.32 (d, 1H, J = 2.7 Hz), 6.83 (dd, 1H, J
= 8.6, 2.7 Hz), 3.43−3.40 (m, 4H), 2.60−2.57 (m, 4H), 2.36 (s, 3H),
1.41 (s, 12H, 4 × CH3). 13C NMR (100 MHz, CDCl3): δ 157.6, 153.0,
139.0, 134.5, 132.1, 129.7, 128.3, 127.5, 127.4, 125.1, 119.0, 117.3,
114.0, 80.1, 55.0, 47.8, 46.1, 27.3, (C−B not observed).11B NMR (160
MHz, CDCl3): δ 13.0 (br s) ppm; HRMS (EI) m/z: M+ calcd for
C26H32BN3O2 429.2588; found, 429.2575.
1
4 (89 mg, 80%) as an orange foam. H NMR (500 MHz, CDCl3): δ
8.82 (s, 1H), 8.69 (d, 1H, J = 5.7 Hz), 8.02 (d, 1H, J = 8.6 Hz), 7.91
(d, 1H, J = 8.2 Hz), 7.87 (s, 1H), 7.76 (d, 1H, J = 5.7 Hz), 7.66−7.61
(m, 2H), 7.51 (d, 1H, J = 8.5 Hz), 7.47 (s, 1H), 7.42 (t, 1H, J = 7.5
Hz), 7.33−7.29 (m, 2H), 3.39 (br s, 4H), 2.89 (br s, 4H), 2.53 (s, 3H),
0.94 (s, 6H), 0.75 (s, 6H). 13C NMR (125 MHz, CDCl3): δ 162.1,
148.6, 142.1, 140.5, 136.1, 132.2, 131.6, 131.4, 130.0, 129.6, 128.6,
128.5, 128.3, 127.7, 126.8, 126.6, 126.4, 125.7, 125.2, 122.2, 119.5,
117.1, 83.2, 55.7, 52.7, 46.2, 24.4, 24.1, (C−B not observed). 11B NMR
(160 MHz, CDCl3): δ 32.2 (br s) ppm; HRMS (EI) m/z: M+ calcd for
C34H36N3O2B 529.2901; found, 529.2915.
ASSOCIATED CONTENT
* Supporting Information
■
S
1H NMR spectrum of A1, 1H and 13C NMR spectra of A2, A4,
B4, M1−M4, and 1−4, UV−vis absorption and fluorescence
spectra of the compounds M1−M4, 11B NMR spectra of dye 1
upon protonation, UV−vis absorption and fluorescence spectra
of dyes 2−4 upon titration with TfOH, photophysical
properties of the compounds M1−M4, optimized ground-
state geometries and calculation details for dyes 1−4, LUMO+1
contour plot of dye 4, and solvatochromic shifts of the emission
of dye 4. This material is available free of charge via the Internet
at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: abel.ros@iiq.csic.es, uwe.pischel@diq.uhu.es.
■
1-[4-(4-Methylpiperazin-1-yl)-2-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)naphthalen-1-yl]isoquinoline 2. Following
the previously described general procedure for Ir-catalyzed borylation,
starting from M2 (71 mg, 0.2 mmol) and carrying out the reaction at
55 °C, flash chromatography on silica gel (CH2Cl2/MeOH 10:1) gave
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
1
2 (58 mg, 61%) as a yellow foam. H NMR (400 MHz, CDCl3): δ
This work was funded by the Spanish Ministry for Economy
and Competitiveness (Grants CTQ2011-28390 for U.P.,
CTQ2010-15297 and CTQ2010-14974 for A.R., Ph.D. fellow-
ship for R.L-R.), European FEDER funds, and the Junta de
8.64 (d, 1H, J = 5.6 Hz), 8.29 (d, 1H, J = 8.8 Hz), 7.87 (d, 1H, J = 8.0
Hz), 7.70 (d, 1H, J = 5.6 Hz), 7.61 (td, 1H, J = 7.4, 1.2 Hz), 7.54 (s,
1H), 7.49 (d, 1H, J = 8.4 Hz), 7.48 (td, 1H, J = 7.6, 1.6 Hz), 7.34−7.24
(m, 3H), 3.28 (br s, 4H), 2.78 (br s, 4H), 2.46 (s, 3H), 0.92 (s, 6H),
0.74 (s, 6H). 13C NMR (100 MHz, CDCl3): δ 162.1, 148.9, 142.0,
139.7, 136.0, 133.6, 130.2, 129.9, 129.6, 127.7, 127.4, 126.6, 126.4,
126.1, 125.9, 123.5, 119.3, 118.9, 83.1, 55.7, 52.8, 46.3, 24.4, 24.1, (C−
B not observed). 11B NMR (160 MHz, CDCl3): δ 31.1 (br s) ppm;
HRMS (EI) m/z: M+ calcd for C30H34BN3O2 479.2744; found,
479.2754.
N-[4-(Isoquinolin-1-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxa-
borolan-2-yl)naphthalen-1-yl]-N,N,N′-trimethylpropane-1,3-di-
amine 3. Following the previously described general procedure for Ir-
catalyzed borylation, starting from M3 (92 mg, 0.25 mmol) and
carrying out the reaction at 80 °C, flash chromatography on silica gel
(CH2Cl2/MeOH 10:1, 1% Et3N) gave 3 (71 mg, 58%) as an orange
viscous oil. Note: The product may be contaminated with Et3NHCl
that can be removed washing a CH2Cl2 solution of the product with a
saturated aqueous NaHCO3 solution. 1H NMR (400 MHz, CDCl3): δ
8.64 (d, 1H, J = 5.7 Hz), 8.34 (d, 1H, J = 8.5 Hz), 7.87 (d, 1H, J = 8.2
Hz), 7.70 (d, 1H, J = 5.7 Hz), 7.61 (t, 1H, J = 7.6 Hz), 7.56 (s, 1H),
7.48−7.45 (m, 2H), 7.32 (t, 1H, J = 7.6 Hz), 7.29−7.24 (m, 2H), 3.22
(t, 2H, J = 7.3 Hz), 2.96 (s, 3H), 2.41−2.37 (m, 2H), 2.25 (s, 6H),
1.92−1.87 (m, 2H), 0.92 (s, 6H), 0.74 (s, 6H). 13C NMR (100 MHz,
CDCl3): δ 162.2, 149.8, 141.9, 139.4, 136.0, 133.6, 131.1, 129.9, 129.6,
127.8, 127.3, 126.6, 126.3, 126.0, 125.8, 123.9, 120.0, 119.3, 83.1, 57.7,
́
Andalucia (Grants 2008/FQM-3685 for U.P., 2008/FQM-3833
and 2009/FQM-4537 for A.R., Ph.D. fellowship for V.F.P.).
A.R. acknowledges the European Union for a Marie Curie
Reintegration Grant (FP7-PEOPLE-2009-RG-256461) and the
́
Consejo Superior de Investigaciones Cientificas (CSIC,
Madrid) for a JAE-Doc Fellowship. H.S.E.-S. thanks the
Computational Laboratory for Analysis, Modeling, and Visual-
ization at the Jacobs University Bremen (Germany) for
computation time.
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tetrahydrofuran. Sonication for 1 h was used to facilitate dissolution.
The resulting red-brown solution was kept under argon.
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