An isoquinoline as cation assisted ON-OFF-ON fluorescence switch with methionine and fluoride ion

Article abstract of DOI:10.1016/j.tetlet.2012.12.025

Basic Al₂O₃-Cu(OTf)₂ acts as an efficient heterogeneous catalyst for the one step synthesis of 1-amino-3-aryl isoquinoline (IQ) from tricyanomesitylene. This IQ shows fluorescence ON-OFF-ON molecular switch to fluoride ion, Br?nsted-Lowry bases (amines) in the presence of H⁺, and also selective to methionine with Hg²⁺ in an analogous manner.

Full text of DOI:10.1016/j.tetlet.2012.12.025

Tetrahedron Letters 54 (2013) 1067–1070
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
An isoquinoline as cation assisted ON–OFF–ON fluorescence switch with
methionine and fluoride ion
⇑
Tapas Kumar Achar , Ved Prakash , Himansu S. Biswal, Prasenjit Mal
School of Chemical Sciences, National Institute of Science Education and Research (NISER), Institute of Physics Campus, PO Sainik School, Bhubaneswar, Orissa 751 005, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Basic Al2O3–Cu(OTf)2 acts as an efficient heterogeneous catalyst for the one step synthesis of 1-amino-3-
aryl isoquinoline (IQ) from tricyanomesitylene. This IQ shows fluorescence ON–OFF–ON molecular
switch to fluoride ion, Brønsted–Lowry bases (amines) in the presence of H+, and also selective to methi-
onine with Hg2+ in an analogous manner.
Received 20 September 2012
Revised 7 December 2012
Accepted 8 December 2012
Available online 19 December 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Fluorescence
Fluoride sensor
Ethionine sensor
Molecular switch
Lab-on-a-molecule
Examples of isoquinoline based natural products1 as well as
their biological activities are considerably well known.2 Several
methodologies have been reported in the literature for the synthe-
sis of isoquinoline derivatives, whereas, very few have been known
for the synthesis of 1-amino-3-aryl-isoquinolines from the corre-
sponding o-tolunitriles.3 Generally, synthesis of isoquinoline4 from
o-tolunitriles has been documented in the literature by using a
strong base for example, alkyl lithium or amide bases in relatively
harsh condition.5,6 These methodologies are reported only for the
mono-cyano derivatives and no report has been found for the syn-
thesis of isoquinolines from the o-alkyl aromatic cyano derivatives
having either multiple cyano group or any sensitive functional
group like aldehydes. However, we have developed a methodology
that is, basic Al2O3–Cu(OTf)2 mediated synthesis of isoquinoline
derivatives (IQ, Fig. 1) under heterogeneous condition7,8 as a single
step reaction from tricyanomesitylene (1)9 in 45% yield.
for example, 1 using Lewis acid is hitherto unknown. This hetero-
geneous catalyst was efficient for the synthesis of isoquinolines
with multiple functional groups. However, our attempt to synthe-
size the IQ using the literature reported procedures like using LDA
or butyl lithium was unsuccessful and an inseparable mixture of
polymeric products were obtained (Supplementary data or SI,
Fig. S4). To understand the role of basic alumina, reactions were
carried out in the presence of neutral as well as acidic alumina–
Cu(OTf)2 combinations and interestingly reactions were found to
be sluggish. Probably, basic alumina helps to initiate the formation
of tautomer 2 in the presence of Lewis acid (Fig. 1b). Furthermore,
Cu(OTf)2 in the absence of alumina support in appropriate solvents,
Cu(OTf)2–silica gel combination, or other Lewis acids12 like
La(OTf)3, Yb(OTf)3, FeCl3 etc. also failed to give the desired prod-
uct13 in reasonable yields (ca. <10%).
The IQ was isolated as a fluorescent compound (Table 1) and
that prompted us to investigate its competency as sensory mate-
rial.14,15 The fluorescence detection at the emission maxima of
the cation loaded probe was utilized to explore either the ratio
or the change in intensities of these two species considering that
coordination of certain cations at the nitrogen donating centers
of the isoquinoline moiety may alter the fluorescence response.16
Strategically, one should be able to detect one’s cation in the pres-
ence of other competitors, selectively for example, certain metal
ions like zinc(II) and mercury(II) exhibit contrasting fluorescence
response to a particular system.17 Thus, the input regulated emis-
sion behavior of IQ could lead to the construction of electronic
function at the molecular level for example, ON–OFF switch.18
And addition of anion to the cation loaded system could again
Scheme 1 represents the proposed mechanism for the forma-
tion of IQ from 1. The mechanism can be rationalized as the initial
10
step is tautomerization of 1 into 2 in the presence of Cu(OTf)2
(Lewis acid, Scheme 1a).
In Scheme 1(b), it is shown that the reaction of tautomer 2 and
Lewis acid adduct of 1 led to the formation of intermediate 3 which
further rearranges to the IQ via 4 and 5. To the best of our knowl-
edge, like photo-induced tautomerization of o-alkyl aromatic car-
bonyl compounds,11 tautomerization of o-alkyl aromatic nitriles
⇑
Corresponding author.
E-mail address: pmal@niser.ac.in (P. Mal).
These authors contributed equally to this work.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.12.025

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T. K. Achar et al. / Tetrahedron Letters 54 (2013) 1067–1070
build up a new or extended molecular electronic function which
ultimately may lead to input controllable ON–OFF–ON molecular
switches19–21 from
functionality.22
a
simpler ON–OFF system via dual
The fluorescence quantum yield UFl of IQ was found to be 0.88
in chloroform (Table 1) and fluorescence lifetime sFl was 10.9 ns.
The IQ displays notable selectivity in terms of fluorescence output
(quenching) for H+ and Hg2+ compared to the other cations such as
Li+, Na+, K+, Ca2+, Mg2+, Ba2+, Ni2+, Co2+, Cu2+, Zn2+, Cd2+ etc. This
selective cation binding ability of IQ was further exploited toward
anion binding by the cation loaded ligand as a dual functional sys-
tem. The dual functionality technique is becoming a popular tech-
nique due to its convenience of handling and cost effectiveness. As
shown in Figure 2, when IQ was coupled with H+, it shows discrim-
ination for fluoride ion (e.g., fluorescence enhancement) compared
to other anions like chloride, bromide, iodide, perchlorate etc. In
the literature, contrasting to halogen bonding,23 fluoride ion detec-
tion24 has been reported by exploiting different interactions like
hydrogen bonding,24 boron-fluoride,25 silicon-fluoride,26 anion-
p27 etc. in either non-aqueous or aqueous media.28,29,13 Moreover,
detection of fluoride ion by a proton coupled system (Fig. 2) is rel-
atively little known.28 The detection limit of IQ is found to be quite
high that is, ꢀ10À5 M for H+ and ꢀ10À6 M for FÀ in DCM.
Figure 1. Synthesis of IQ from tricyanomesitylene 1.
CN
CN
H
C
H
C
CN
(a)
CuII
H2C
CN
CN
CN
NC
NC
HN
N
N
CuII
1
2
CuII = Lewis Acid
CN
CN
(b)
HN
CN
H
CN
CN
H2C
CuII
NC
N
CN
NH
CN
CN
NC
3
CN
CN
The successful execution of the detection of fluoride ion by the
proton coupled IQ, also motivated us to explore the potential of
binding of sulfur containing amino acids (cysteine or methionine)
by IQ + Hg2+ complex system. Due to poor solubility of cysteine
in organic solvents, our focus was mainly on methionine during
the present studies. Even though, in the literature, the detection
of cysteine by Hg2+ coupled ligands is well executed, report on
methionine sensor is either scanty or unexplored in an analogous
manner. Contrastingly, methionine attached to pyrene or naphtha-
H
CN
H
IQ
NC
HN
NH2
N
CN
5
4
NH
Scheme 1. (a) Lewis acid catalyzed tautomerization of 1–2; (b) mechanism of
formation of IQ from the reaction of 1 and 2.
lene based ligands were used to detect Hg2+
. Interestingly,
IQ + Hg2+ combination was found to be a successful attempt for
methionine sensor (Fig. 3). The fluorescence response of IQ in the
presence of different ions also led to a development of fluorescence
ON–OFF–ON switch. To the best of our knowledge, this is an
unprecedented example of methionine sensor using dual function-
ality technique.
In order to get further insight into the binding sequence as well
as the mechanism of binding of IQ with cation and followed by cat-
ion assisted anion,30 we were interested to determine the binding
constants of IQ in the presence of (H+) as well as (H+ + FÀ) using
UV/vis absorption and fluorescence titration. Firstly, we have
established 1:1 binding of IQ and H+ using Job’s plot (SI). The good
agreement of the binding constants obtained by both methods
Table 1
Fluorescence quantum yield (UFl), absorption and emission wavelengths of IQ
Entry Solvent
kmax (abs) eÂ103 (molÀ1 cmÀ1
)
kmax (em) Ufl
1
2
3
4
5
6
7
Chloroform
DCM
354
354
13.4
14.8
8.0
455
458
484
484
486
478
491
0.88
0.78
0.67
0.66
0.57
0.67
0.65
Isopropanol 357
Ethanol
358
356
357
362
12.1
12.7
12.5
10.2
Methanol
Acetonitrile
DMSO
Figure 2. (a) Emission spectra of IQ at 1.0 Â 10À5 M (excitation wavelength 350 nm) and in the presence of 2.0 equiv of H+ ion and followed by 2.0 equiv of FÀ ion
(dichloromethane was used as solvent). (b) Emission spectra of IQ at 1.0 Â 10À4 M and in the presence of 4 equiv of Hg2+ ion and followed by 14 equiv of methionine (right,
acetonitrile was used as solvent).

T. K. Achar et al. / Tetrahedron Letters 54 (2013) 1067–1070
1069
Figure 4. X-ray crystal structure of IQ+H++ClÀ complex, N–H. . .Cl bonds is shown in
yellow color; the numbers across the bond indicate bond distance in Å.
Figure 3. Proposed mechanism for cation (H+) assisted molecular ON–OFF–ON
switch with anion (FÀ) and the model structure of IQ + Hg2+ + Methionine complex
8 (inset).
led to quenching of fluorescence that is, OFF state. Consequently,
after addition of anion (FÀ) or amino acid (methionine) the
enhancement of fluorescence was observed that is, ON state.
Thus, IQ could build ON–OFF–ON molecular switches with fluoride
Table 2
Vertical excitation energy and oscillator strength of IQ, IQ + H+, and IQ + H+ + FÀ as
obtained from the TD-B3LYP/6-31G⁄ level of theory
ion as well as with methionine in the presence of H+ and Hg2+
,
Entry System
Vertical excitation
Oscillator
Transition
respectively. The proposed models of IQ + H+, IQ + H+ + FÀ, and
IQ + Hg2+ + methionine as shown in Figure 3, obtained from DFT
calculation.
energy kmax in (nm)
strength (f)
1
2
3
IQ
360.24
373.47
0.1452
0.0055
0.1556
p
p
p
–
–
–
p⁄
p⁄
p⁄
IQ + H+
IQ + H+ + FÀ 359.77
The experimentally observed ON–OFF–ON mechanism is also
strongly supported by the DFT and TD-DFT (time dependent den-
sity functional theory) calculation (see Table 2 and Figs. S24, S25
in SI).
(UV/vis and fluorescence) for [IQ + H+] as well as [(IQ + H+)+FÀ] in
DCM (UV/vis: logb1 = 4.62 0.01 and logb2 = 5.99 0.02; fluores-
cence: logb1 = 4.78 0.01 and logb2 = 6.17 0.01) allowed a rea-
sonably accurate determination of the speciation curves in
solution (Figs. S14, 15, in SI). Similarly, the binding constant data
for [IQ + Hg2+] as well as [(IQ + Hg2+) + methionine] in acetonitrile
were: using UV/vis: logb1 = 3.25 0.01 and logb2 = 2.17 0.08.
From the analysis of the speciation curves we were able to extract
the information of exact amount of [IQ + H+] at different concentra-
tions of acid in combination with the individual contributions from
IQ.
To support and rationalize our experimental findings, we have
taken the help of quantum chemical calculation. The ground state
geometry optimization followed by frequency calculation of IQ,
IQ + H+, IQ + H+ + FÀ, IQ + Hg2+, and IQ + Hg2+ + methionine were
performed using the density functional theory (DFT; B3LYP/6-
31G⁄). The details of the theoretical calculation have been provided
in supporting information. The DFT calculations suggest that the
ground state dipole moment of IQ is 6.52 Debye and its direction
is toward the isoquinoline moiety of IQ (Fig. S24, in SI). In addition,
the time dependent density function theory (TDDFT) studies show
The mechanism of cation assisted fluorescence response of
either FÀ or methionine by IQ was further confirmed by X-ray crys-
tal structure analysis. We were successful in co-crystallizing IQ and
HCl instead of HF by slow evaporation of IQ solution in dichloro-
methane–methanol (1:1) and HCl at room temperature (Fig. 4).
We assumed that both fluoride and chloride ion should behave
analogously because after addition of the anion to IQ + H+ there
was 36% enhancement of fluorescence intensity with chloride ion
compared to 95% with fluoride ion (Fig. S19, in SI). It is shown in
Figure 4, H+ gets associated to isoquinoline nitrogen atom (rather
than –NH2 group) which acts as chloride ion acceptor via two N–
H. . .Cl hydrogen bonds. Bond distances of aromatic N–H. . .Cl and
amine N–H. . .Cl are found to be 2.24 Å and 2.32 Å, respectively.
The torsion angle between the isoquinoline ring and the aromatic
group is 105°.
In addition to X-ray analyses (vide supra), NMR and IR titration
experiments were also helpful to shed some light upon the associ-
ation behavior of H+ or Hg2+ with IQ (Fig. 3). After protonation at
isoquinoline nitrogen atom, the methyl groups at À6 and À8 posi-
tions are expected to experience the deshielding effect due to res-
onance (Fig. S5, in SI). As can be seen from 1H NMR spectra (Fig. S6),
methyl protons of À6 and À8 protons have a downfield shift of 0.08
and 0.11 ppm, respectively. Analogous behavior was also observed
for the methyl groups of 3-aryl group of IQ. Similarly, when FÀ was
added to IQ + H+, significant up field shift of amine proton (9.27–
5.89 ppm, Fig. S7, in SI) indicates the participation of fluoride ion
with the amine proton of IQ. This apparently demonstrates the
structure of the complexes IQ + H+ and IQ + H+ + FÀ as proposed
in Figure 3. In parallel, we have also established the structure of
IQ + Hg2+ using IR spectra analyses, when 1H NMR study led to
that the orbitals involved are
p
and p⁄ and the isoquinoline and
phenyl moieties are very weakly coupled as they are almost per-
pendicular to each other. This observation is also further supported
by X-ray crystal structure analysis (vide infra).
Solvent polarity dependent kmax shift (red shifted absorption in
more polar solvent, Fig. S9, in SI) and the value of molar extinction
coefficient (absorption studies, Table 1) clearly prove that IQ is
fluorescent due to the
p electron delocalization across the isoquin-
oline moiety. As a result, during the addition of cation, firstly the
donor part of IQ has interacted with added cation (H+/Hg2+) and

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T. K. Achar et al. / Tetrahedron Letters 54 (2013) 1067–1070
inconclusive results. It is shown in Figure S8 (SI) that –NH2 peak
ꢁ3550 cmÀ1 remains unchanged during the addition of Hg2+, fol-
lowed by methionine. Therefore, it is convincing that the nature
of IQ and Hg2+ association is same as it is proposed in Figure 3. Fur-
thermore, we have also demonstrated the possible structure of
IQ + Hg2+ + methionine. Addition of non-sulfur containing amino
acids like alanine, isoleucine, tryptophan etc. did not change the
emission behavior of IQ + Hg2+. Significantly, the addition of ethane
thiol (50 equiv) or dimethyl sulfide (70 equiv) to the solution of
IQ + Hg2+ led to an enhancement of emission intensity of IQ up
to ꢁ65% and ꢁ63%, respectively (Figs. S21, S22, in SI). However,
14 equiv of methionine was needed for >90% of recovery of emis-
sion intensity (Fig. 2) and also ethyl 2-mercaptoacetate (70 equiv)
did not alter the emission nature of IQ + Hg2+ (Fig. S23, in SI). These
facts clearly point not only toward the proposed structure of
IQ + Hg2+ + methionine complex is 8 (Fig. 3) but also the selective-
ness of methionine for IQ + Hg2+ system.
X-ray crystal structure analysis. The crystallographic data for
IQ+H++ClÀ complex have also been deposited with the Cambridge
Crystallographic Data Centre as entry CCDC 888629. These data
can be obtained free of charge from. The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/ciffile)
associated with this article can be found, in the online version, at
http://dx.doi.org/10.1016/j.tetlet.2012.12.025.
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Supplementary data
Supplementary data (the file contains the details of synthesis
procedure, photo-physical studies, theoretical calculations and