Electronically tuned 1,3,5-triarylpyrazolines as Cu(I)-selective fluorescent probes

Article abstract of DOI:10.1039/b918311f

We have prepared and characterized a Cu(I)-responsive fluorescent probe, constructed using a large tetradentate, 16-membered thiazacrown ligand ([16]aneNS₃) and 1,3,5-triaryl-substituted pyrazoline fluorophores. The fluorescence contrast ratio

Full text of DOI:10.1039/b918311f

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Organic &
Biomolecular
Chemistry
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Volume 8 | Number 2 | 21 January 2010 | Pages 285–480
ISSN 1477-0520
FULL PAPER
Manjusha Verma et al.
Electronically tuned
1,3,5-triarylpyrazolines as Cu(I)-
PERSPECTIVE
Tracey M. Gloster and Gideon J. Davies
Glycosidase inhibition: assessing
selective fluorescent probes
mimicry of the transition state
1477-0520(2010)8:2;1-I

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Electronically tuned 1,3,5-triarylpyrazolines as Cu(I)-selective
fluorescent probes†
Manjusha Verma, Aneese F. Chaudhry, M. Thomas Morgan and Christoph J. Fahrni*
Received 4th September 2009, Accepted 23rd October 2009
First published as an Advance Article on the web 2nd December 2009
DOI: 10.1039/b918311f
We have prepared and characterized a Cu(I)-responsive fluorescent probe, constructed using a large
tetradentate, 16-membered thiazacrown ligand ([16]aneNS3) and 1,3,5-triaryl-substituted pyrazoline
fluorophores. The fluorescence contrast ratio upon analyte binding, which is mainly governed by
changes of the photoinduced electron transfer (PET) driving force between the ligand and fluorophore,
was systematically optimized by increasing the electron withdrawing character of the 1-aryl-ring,
yielding a maximum 50-fold fluorescence enhancement upon saturation with Cu(I) in methanol and a
greater than 300-fold enhancement upon protonation with trifluoroacetic acid. The observed
fluorescence increase was selective towards Cu(I) over a broad range of mono- and divalent transition
metal cations. Previously established Hammett LFERs proved to be a valuable tool to predict two of
the PET key parameters, the acceptor potential (E(A/A-) and the excited state energy DE00, and thus to
identify a set of pyrazolines that would best match the thermodynamic requirements imposed by the
donor potential E(D+/D) of the thiazacrown receptor. The described approach should be applicable for
rationally designing high-contrast pyrazoline-based PET probes selective towards other metal cations.
The fluorescence contrast between bound and unbound probe
Introduction
directly depends on the change in PET driving force (-DGet), the
major parameter for optimizing the contrast ratio and switching
properties.12 According to the Rehm-Weller formalism, the driving
force for PET depends on the ground state donor and acceptor
potentials, E(D+/D) and E(A/A-), respectively, and the excited
state energy DE00, which corresponds to the transition energy
between the vibrationally relaxed ground and excited states
(eqn 1).13
Synthetic fluorescent probes are powerful analytical tools to detect
metal cations with high selectivity and exquisite sensitivity down
to the single molecule level.1 Over the past decade, a broad
range of fluorescent probes have been developed that exhibit high
selectivity towards many of the nonredox-active metal cations,
such as Ca(II),2,3 Mg(II),3,4 Zn(II),5 or Cd(II).6 In comparison, the
fluorescence detection of redox-labile cations such as Cu(II/I)7,8
or Fe(III/II)9,10 remains challenging due to interference of metal-
mediated quenching pathways, for example through electron trans-
fer reactions, increased triplet conversion rates, or energy transfer
processes involving energetically low-lying metal-centered states.
These undesired quenching pathways can be reduced or even
eliminated by using a rigid probe architecture that electronically
decouples the metal binding site from the fluorophore.11 Despite
this spatial separation, metal binding to the receptor moiety can
be effectively communicated through a photoinduced electron
transfer (PET) switching mechanism. In this type of fluorescence
switch, emission is quenched in absence of the analyte through
PET from the metal receptor, which is acting as an electron
donor, to the excited fluorophore, acting as the acceptor. Metal
binding reduces the donating ability of the receptor, which in turn
renders PET less favorable, resulting in reduced quenching and
thus enhanced emission. For maximum sensitivity, the unbound
probe should exhibit little or no background fluorescence and
undergo a bright emission enhancement upon analyte binding.
(1)
The parameter wp captures the Coulombic stabilization energy
of the radical ion pair intermediate formed upon electron transfer.
Based on eqn (1), it can be readily seen that the increase in donor
potential E(D+/D) upon metal binding results in a decrease of the
PET driving force, -DGet, and thus a reduced ET quenching rate.
By properly adjusting the remaining parameters, E(A/A-) and
DE00, the PET switching properties can in principle be optimized
for any metal receptor; however, it is typically difficult to predict
how structural changes of the fluorophore, such as attaching
electron donating or withdrawing groups, will affect the two
parameters.
To address this difficulty, we recently devised a systematic
approach for optimizing the fluorescence contrast ratio through
electronic tuning of the PET driving force.14 Our strategy takes
advantage of the rather unique electronic structure of 1,3,5-
triarylpyrazoline fluorophores, which allow for adjustment of
DE00 without significantly altering E(A/A-).15,16 As illustrated
with Chart 1 (left), this fluorophore platform is composed of
a conjugated p-system with two aryl-substituents in the 1- and
3-positions, which are connected through the central pyrazo-
line core. The third aryl ring, which is attached in the 5-
position, is electronically decoupled from the p-system through an
School of Chemistry and Biochemistry, Petit Institute for Bioengineering and
Bioscience, Georgia Institute of Technology, 901 Atlantic Drive, Atlanta,
Georgia, 30332, U.S.A. E-mail: fahrni@chemistry.gatech.edu
† Electronic supplementary information (ESI) available: NMR spectra of
compounds 1–6. See DOI: 10.1039/b918311f
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of organic molecules.20 Given the lack of experimental Hammett
constants for polysubstituted aromatics, we derived computational
c
substituent constants (s ) as recently described by Galabov et al.,21
and established LFERs for predicting the PET thermodynamics
of polyfluoro-substituted pyrazoline fluorophores.16 Based on a
training set of a total of 20 pyrazolines of type I (R3 = H) with
varying numbers of fluoro-substitutents attached to the 1- and
3-aryl rings, we established a set of LFERs (eqn (2a) and (2b))
that related the experimental E(A/A-) and DE00 values with the
c
corresponding pair of computational Hammett constants s1 and
c
s2, which reflect the electron withdrawing abilities of the 3- and
Chart 1
1-aryl rings, respectively.16
sp3-hybridized carbon atom and can be functionalized as a metal
receptor to construct a PET fluorescent probe.8,9,17 Most impor-
tantly, the HOMO and LUMO densities occupy two distinctly
different regions of the p-system, where the HOMO is primarily
localized on the 1-aryl and the LUMO on the 3-aryl ring. Due to
this spatial separation, electron withdrawing substituents attached
to the 1-aryl ring lead to an increase in DE00 but affect E(A/A-)
only to a minor degree, whereas electron withdrawing substituents
on the 3-aryl ring increase E(A/A-) without major changes to
DE00.14–16 Hence, by choosing the appropriate substituents on the
3-aryl ring, such that E(A/A-) matches the donor potential of
the metal receptor, DE00 can be increased stepwise by increasing
the electron withdrawing ability of the 1-aryl ring, for example
through attaching an increasing number of fluoro-substituents
until the optimal contrast ratio is achieved. Based on this approach
we were able to systematically optimize the fluorescence contrast
of a simple pH-responsive probe of type I functionalized with a
dimethylamino group (R3 = NMe2), which upon protonation gave
a fluorescence enhancement of greater than 400-fold.14
This initial success prompted us to apply the above strategy
towards optimizing the contrast ratio of a Cu(I)-responsive PET
probe, a significantly more challenging problem compared to
the initial pH-responsive probe. Because Cu(I) is a soft Lewis
acid, we anticipated that the change in donor potential would
be much smaller compared to the pH probe, which yielded an
electrochemically inactive anilinium cation upon protonation. For
this reason, fine tuning of the PET driving force appears to be
particularly important for optimizing the contrast ratio of a Cu(I)-
responsive probe. To selectively bind Cu(I) over other mono- and
divalent metal cations, we chose a 16-membered trithiazacyclohex-
adecane ([16]aneNS3) macrocycle as the receptor moiety (Chart 1,
right). According to statistical multivariate examination of a large
number of half-wave potentials of Cu2+/Cu+ couples complexed
to N, S, and O-donor ligands, large thioether macrocycles greatly
favor Cu(I) over Cu(II) coordination.18 In addition, we took
advantage of recently established linear free energy relationships
(LFERs)16 to predict the PET thermodynamics for a set of fluoro-
substituted pyrazolines that would best match the donor-potential
of the Cu(I)-receptor moiety.
(2a)
(2b)
Furthermore, the sum of the above linear equations yielded a
single LFER (eqn (2c)) for the combined parameters (E(A/A-) +
DE00) with a correlation coefficient of r = 0.986 (training set mean
unsigned error MUE = 0.028 eV).
(2c)
Because the donor potential E(D+/D) is set by the type of metal
receptor employed, the combined E(A/A-) and DE00 parameters
directly define the tunable range of the PET driving force according
c
c
to eqn (1). Assuming that the Hammett constants s1 and s2 of
each ring are varied between 0 and 1.19, corresponding to an
unsubstituted and perfluorinated aryl ring, respectively, DGet can
be adjusted over a range of 0.96 V according to eqn (2c). Since
the 1-aryl ring is introduced during the last step of the pyrazoline
synthesis (vide infra), adjustment of the PET driving force is best
accomplished by varying R2 (s2) while leaving R1 (s1) constant.
Although in this case the tunable range is reduced to approximately
0.53 eV, such a window is still sufficiently large for optimizing
the contrast ratio. As pointed out above, the 3-aryl group locks
the acceptor potential within a narrow range, and therefore, its
substitution pattern must be carefully chosen to match the donor
potential of the metal receptor. With an estimated donor potential
of 0.45 V (vs. Fc+/0) for the macrocyclic dialkylaniline receptor,
a minimum PET driving force of -DGet = 0 would require a
c
c
c
3-aryl ring Hammett constant of s1 = 0.58 according to the
LFER of eqn (2)c. A comparison with the previously derived
computational Hammett constants16 for poly-fluoro-substituted
c
aryl-rings suggests that a 2,5-difluoro substituted ring (s1 = 0.58)
would match best this value. Since it is not necessary to start
the probe optimization at a zero driving force (which would
not produce significant PET quenching), we decided to utilize
a slightly more electron withdrawing 3,5-difluoro substituted ring
c
(s1 = 0.65), thus yielding an estimated tunable potential window
of -DGet between 0.03 and 0.56 eV.
Synthesis
Results and discussion
Based on the above considerations, we synthesized a series of
pyrazolines derivatives 1a–f, in which the [16]aneNS3 macrocycle
was combined with a 3,5-difluorophenyl substituent in the 3-
position and a 1-aryl ring bearing increasing numbers of fluoro
substituents (Scheme 1). The key step in accessing the racemic
pyrazolines 1a–f was the aldol condensation of benzaldehyde
Predicting the PET thermodynamics based on Hammett LFERs
Hammett substituent constants19 (s) have been widely used
to correlate the electron withdrawing and donating abilities of
substituents with the chemical reactivity and molecular properties
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Scheme 1 Synthesis of pyrazoline derivatives 1a–f (a substituent key is provided in Table 1).
derivative 5 with 3,5-difluoroacetophenone followed by cyclization
with the respective aryl hydrazines to give the desired pyrazolines.
Aldehyde 5 was accessed directly through Vilsmeier formylation
of ligand 4, which was obtained by macrocyclization of N,N-
bis(3-iodopropyl)aniline22 3 with bis(3-mercaptopropyl)sulfide23
2. Although the use of Cs2CO3 has been reported to be most
effective for macrocyclizations to produce thiocrown ethers,24 we
observed comparable yields using the inexpensive base 1,1,3,3-
tetramethylguanidine in refluxing acetonitrile, which provides the
benefits of a less time consuming work-up when the reaction is
conducted on a multigram scale. Although we prepared the entire
set of derivatives prior to their photophysical characterization,
the 1-aryl ring critical for tuning the contrast ratio is introduced
in the very last step of the synthetic protocol, thus facilitating the
stepwise optimization of the photophysical properties.
Fig. 1 Normalized absorption (dotted traces) and emission spectra (solid
traces) of compounds 1a–f. The arrows indicate the direction of the band
shift with increasing number of fluoro substituents. The shaded area
indicates the tunable range of the excited-state energy DE00.
position is expected to act as a sigma acceptor, the overall
electron withdrawing ability of the aryl ring is attenuated through
substantial p-donation, an effect we previously observed in a
structurally related series of fluoro-substituted pyrazolines.16
In agreement with a stepwise increase of the PET driving force
(vide infra), the quantum yields in neutral methanol gradually
decreased as the number of fluoro-substituents increased from
1a through 1d (Table 1). For derivatives 1e and 1f the emission
intensities and the associated signal : noise ratios were too
low for accurate quantum yield determinations. Under acidic
conditions, all compounds responded with a strong fluorescence
enhancement, an observation that is consistent with protonation
of the aniline donor, which in turn renders PET less favorable.
The absorption and emission energies remained unchanged re-
gardless of the proton concentration, indicating that none of the
fluorophore heteroatoms are directly involved in a protonation
equilibrium.
Photophysical characterization
The LFERs described by eqn (2a–c) were derived from pho-
tophysical data acquired in acetonitrile; however, this solvent
exhibits a significant affinity towards Cu(I) and can act as
an effective competing ligand against the macrocycle. For this
reason, we carried out the following photophysical studies in
methanol as a substitute. The dielectric constants of the two
solvents are almost identical, and thus the half-wave potentials
and excited state energies of the derivatives are expected to remain
similar within the accuracy of the LFER. A compilation of the
acquired photophysical data is given in Table 1. As expected,
the absorption and emission maxima shifted to higher energies
with increasing number of fluoro-substituents on the 1-aryl-ring,
and consequently, the zero-zero transition energies DE00 were
also increased stepwise (Fig. 1). The observed trend is consistent
with a gradually decreasing charge delocalization from the 1-N-
pyrazoline nitrogen to the 3-aryl ring for both the excited and
ground state of the pyrazoline p-system.14,16 Interestingly, the
perfluoro-substituted derivative 1f exhibits only a small increase
in DE00 compared with compound 1e containing only four fluoro-
substituents. While the additional fluoro-substituent in the para
The fluorescence enhancement factor f e, defined as the ratio of
the quantum yield under acidic and neutral conditions, gradually
increased up to 335 and closely followed the expected trend
delineated in the earlier model study.14 Although it was not possible
to obtain accurate enhancement factors for the strongly quenched
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Table 1 Photophysical data of pyrazoline derivatives 1a–f in methanol at 298 K
b
c
UF
f e
Compd
R
abs lmax/nm em lmax/nm
Stokes shift/cm-1 DE00/cm-1a
neutrald
acidice
Cu(I)f
acidic
Cu(I)
1a
1b
1c
1d
1e
1f
H
3-F
2,5-F2
2,3,5-F3
2,3,5,6-F4
2,3,4,5,6-F5
371
366
355
350
330
323
476
461
451
436
420
423
5950
5630
6000
5640
6440
7320
23 980
24 510
25 170
25 750
27 060
27 300
0.058
0.029
0.0084
0.0014
n.d.g
0.23
0.36
0.40
0.47
0.21
0.044
0.20
0.19
0.12
0.07
0.024
0.0063
4
3
7
14
50
—
—
12
48
335
—
—
n.d.g
a Zero-zero transition energy; estimated based on DE00 = (Eabs (max)+Eem(max))/2. b Fluorescence quantum yield; quinine sulfate as reference.
c Fluorescence enhancement factor f e = UF/Uneutral
.
d Neat methanol. e 180 mM trifluoroacetic acid in methanol. f 10 mM [Cu(I)(CH3CN)4]PF6 in
methanol (0.1% acetonitrile). g Signal : noise ratio insufficient for accurate determination.
derivatives 1e and 1f, inspection of the quantum yields under acidic
conditions revealed substantially lower recovery yields, and thus
presumably a reduced enhancement factor as expected based on
the previously devised model.14 For comparison, an analogous
derivative of 1e carrying the same fluoro substitution pattern but
lacking the dialkylamino moiety showed a quantum yield of 69%,16
thus indicating that the weak fluorescence emission of 1e is due
to PET quenching rather than an indirect effect of the increased
number of fluoro substituents.
throughout the titration, suggesting no significant interactions
between Cu(I) and the nitrogen atoms on the pyrazoline ring.
In addition, we tested the fluorescence response of 1d towards
a range of mono- and divalent metal cations. As illustrated by
the bar graph in Fig. 3, fluorophore 1d responded with good
selectivity towards Cu(I); only coordination of Fe(II) and Cu(II)
led to a small emission increase. Competition experiments with
equimolar amounts of Cu(I) and each of the respective metal
cations showed in each case full recovery of the fluorescence
emission, suggesting that the large thiazacrown preferentially
binds to Cu(I) and effectively discriminates over all other metal
cations tested.
Fluorescence response and selectivity towards metal cations
Upon addition of excess [Cu(I)(CH3CN)4]PF6, all probes exhibited
a substantial increase in fluorescence; however, the enhancement
factors were consistently lower compared to acidic conditions
(Table 1). The degree of fluorescence enhancement again paralleled
the number of fluoro-substituents, reaching a maximum f e of 50 for
the trifluoro-substituted derivative 1d. The presence of additional
fluoro-substituents (compounds 1e and 1f) resulted again in poor
recovery of the fluorescence emission upon Cu(I) binding.
A titration of 1d with [Cu(I)(CH3CN)4]PF6 in methanol revealed
a linear increase of the fluorescence intensity with increasing
Cu(I) concentration (Fig. 2). Consistent with a 1 : 1 binding
stoichiometry, the saturation occurred at an equimolar ratio of
Cu(I) and 1d. As already observed for the protonation induced
emission increase, the emission wavelength remained unchanged
Fig. 3 Fluorescence response of pyrazoline 1d as a function of added
metal cations in methanol (298 K, excitation at 345 nm, emission 436 nm).
White bars: equimolar concentration of 1d and the indicated metal cation.
Grey bars: Competition with equimolar amount of [Cu(I)(CH3CN)4]PF6
and the respective metal cation.
Photoinduced electron transfer thermodynamics
To determine the driving force of PET quenching in the absence
of analyte according to eqn (1), we measured the ground state
donor and acceptor potentials of each derivative 1a–f under
neutral conditions (Table 2). Because the reduction potentials
of the studied pyrazolines resided outside the potential window
accessible in methanol, we used acetonitrile as the solvent. The
estimated DGet values closely mirror the above trend of the
quantum yields under neutral conditions (Table 1). The smallest
PET driving force yielded the highest quantum yield and vice
versa. Consistent with previous results,14 the PET driving force
steadily increased with increasing number of fluoro-substituents
Fig.
2
Fluorescence titration of pyrazoline 1d (6.5 mM) with
[Cu(I)(CH3CN)4]PF6 in MeOH (298 K, excitation at 345 nm). Inset:
Molar-ratio plot for the fluorescence intensity change at 436 nm.
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the combined experimental parameters (E(A/A-)+DE00), thus
demonstrating that the LFER not only captured the overall trend
of the PET driving force changes but predicted individual data with
sufficient accuracy to aid in choosing a fluoro-substituent pattern
that matched the thermodynamic requirements of the thiazacrown
aniline electron donor.
Table 2 Donor and acceptor reduction half-wave potentials and electron
transfer parameters for pyrazoline derivatives 1a–f
compd E1/2(D+/D)/Va
E1/2(A/A-)/V
DE00/eVb -DGet/eVc
1a
1b
1c
1d
1e
1f
0.46
0.46
0.48
0.48
0.49
0.49
-2.53
-2.50
-2.46
-2.42
-2.39
-2.35
2.97
3.04
3.12
3.19
3.35
3.38
0.03
0.13
0.23
0.34
0.52
0.59
Conclusions
a Half-wave potential in acetonitrile/0.1 M Bu4NPF6 vs. Fc+/0 at 298 K,
glassy carbon working electrode, Ag/AgNO3 reference electrode, 100 mV
s-1 scan rate. b Zero-zero transition energy in methanol; estimated based
on DE00 = (Eabs (max)+Eem(max))/2. c Electron transfer free energy change
calculated on the basis of the Rehm-Weller eqn (1). The ion-pair
stabilization energy was estimated to be wp = -0.045 eV.14
With their rigid molecular architecture and rationally tunable
photophysical properties, 1,3,5-triaryl pyrazolines are well suited
to meet the challenges associated with the design of PET
probes geared towards the detection of metal cations such as
Cu(I) that typically induce fluorescence quenching or yield only
small emission enhancements. By stepwise increasing the electron
withdrawing character of the 1-aryl ring, we were able to gradually
adjust the PET quenching efficiency for the unbound probe while
at the same time optimizing the fluorescence enhancement up to
50-fold upon Cu(I) binding. The previously established Hammett
LFERs proved to be a valuable tool to predict the PET parame-
ters(E(A/A-) and DE00, and thus to identify a set of pyrazolines
that would best match the thermodynamic requirements imposed
by the donor potential E(D+/D) of the thiazacrown receptor.
Despite the fact that the previous LFERs were calibrated in
acetonitrile, the predicted PET parameters E(A/A-) and DE00
agreed well with the experimental data in methanol. While it
would be difficult to predict which of the pyrazoline derivatives
might offer the best fluorescence enhancement for a given receptor,
the LFER approach is well suited to narrow down the choices
to a small set of derivatives. It is noteworthy that the 335-
fold fluorescence enhancement in acidic methanol greatly exceeds
the maximum contrast achieved for Cu(I)-binding for the same
derivative 1d. At present, we can only speculate about the reasons
responsible for this large difference. Being a monovalent soft Lewis
acid, Cu(I) would be expected to induce a smaller change in donor
potential compared to protonation. Furthermore, the unbalanced
coordination environment of the NS3 donor set might weaken
the interaction between the aniline nitrogen and Cu(I). Finally,
Cu(I) might potentially engage in competitive quenching pathways
and thus limit the maximum achievable quantum yield. We are
currently addressing these questions with detailed time-resolved
spectroscopic studies.
Table 3 Predicted photoinduced electron transfer parameters of com-
pounds 1a–f
c
a
compd
s2
E(A/A-)/Vb
DE00/eVc
DE00+E(A/A-)/eV
1a
0.03
0.34
0.59
0.86
1.07
1.19
-2.54
-2.50
-2.48
-2.45
-2.42
-2.41
0.024d
3.03
3.13
3.22
3.31
3.38
3.42
0.072d
0.49
0.63
0.74
0.86
0.96
1.01
0.056d
1b
1c
1d
1e
1f
MUEd
a Computational Hammett constant for the 1-aryl ring according to
c
reference 16 (the 3-aryl ring is identical in all compounds with s2
=
0.65). b Acceptor potential calculated from LFER of eqn (2a). c Zero-zero
transition energy calculated from LFER of eqn (2b). d Mean unsigned
error.
attached to the 1-aryl ring. A closer inspection of the potential
values revealed that the uniform increase in -DGet was primarily
due to changes in the excited state energy. Consistent with an
electron transfer reaction originating from the aniline moiety for
all of the derivatives, the measured donor potentials showed a
narrow distribution with an average E(D+/D) of 0.48 0.01 V. The
acceptor potentials also remained narrowly focused with an
average E(A/A-) of -2.44 0.06 V.
To gauge the reliability of the Hammett LFER approach
for predicting the PET parameters, we used the corresponding
c
c
computational Hammett constants s1 and s2 of each derivative
to calculate E(A/A-) and DE00 according to eqn (2a) and (2b)
(Table 3). A comparison of the predicted acceptor potentials
E(A/A-) with the experimental values listed in Table 2 showed very
good agreement with a mean unsigned error of MUE 0.024 V. The
average error for the zero-zero transition energies DE00 is somewhat
higher with MUE = 0.072 eV, and a closer inspection revealed
that the energies were uniformly overestimated. The combined
parameters estimated according to eqn (2c) yielded a slightly lower
MUE of 0.056 eV.
Experimental
Absorption and fluorescence spectroscopy
◦
UV-vis absorption spectra were acquired at 25 C with a Varian
Cary Bio50 spectrometer with constant-temperature accessory.
Emission spectra were recorded with a PTI fluorimeter. The
fluorescence spectra were corrected for the spectral response of the
detection system and for the spectral irradiance of the excitation
source (via a calibrated photodiode). For all measurements the
path length was 1 cm with a cell volume of 3.0 mL. Sample
solutions were filtered through 0.45 mm Teflon membrane filters to
remove interfering dust particles. Quantum yields were determined
using quinine sulfate dihydrate in 1.0 M H2SO4 as a fluorescence
standard (Uf = 0.54 0.05).25
Altogether, the accuracy for prediction of the PET parameters
E(A/A-) and DE00 for compounds 1a–f compares well with the
reliability trends observed in the previous test set of compounds,16
which also showed a good agreement for E(A/A-) (MUE = 0.026)
and a consistent overestimation for DE00 (MUE = 0.061). Further-
more, compound 1a which was initially chosen as the starting point
for the contrast optimization procedure agreed within 0.05 eV with
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Molar ratio titration with Cu(I). A solution of 1d (6.5 mM)
in methanol was titrated with 0.1 molar equivalent aliquots of
[Cu(I)(CH3CN)4]PF6 (0.51 mM stock solution in 10% MeCN–
MeOH (v/v)). After addition of each aliquot, the solution was
allowed to equilibrate and an emission spectrum was acquired
(excitation at 345 nm).
13C NMR (CDCl3, 100 MHz) d 23.2, 30.0, 33.0. MS (70eV) 182
([M+], 100), 107 (65), 74 (67), 41 (65). EI HRMS m/z calcd for
[M+] C6H14S3 182.0258, found 182.0265.
N,N-Bis(3-iodopropyl)aniline (3)22. A mixture of N,N-bis(3-
hydroxy-propyl)aniline27 (8.10 g, 38.7 mmol) and Et3N (22 mL,
4 equiv.) in CH2Cl2 (140 mL) was cooled in an ice bath under
a stream of nitrogen, and methanesulfonyl chloride (9.0 mL, 3
equiv.) was added dropwise with rapid stirring over a period of
5 min. The reaction mixture was stirred for 1 h and quenched by
adding crushed ice. A solution of NaH2PO4 (6.7 g in 40 mL H2O)
was added. The organic layer was separated, dried with Na2SO4,
and concentrated under reduced pressure. The residue was taken
up in acetone (50 mL) and a solution of NaI (17.5 g, 3 equiv.) in
acetone (50 mL) was added. The mixture was stirred overnight,
diluted with water (200 mL) and extracted with tert-butyl methyl
ether. The extract was washed twice with water and brine, dried
with Na2SO4, and concentrated under reduced pressure to give the
product as a yellow–brown oil. Yield 15.4 g (93%). Rf 0.44 (15 :
1 hexanes: EtOAc). IR (film) nmax/cm-1 2926, 1598, 1504, 1228,
Metal ion selectivity studies. A solution of 1d (6.5 mM) in
methanol was equilibrated with an equimolar amount of the
respective metal cation and the emission spectrum acquired (exci-
tation at 345 nm). An equimolar amount of [Cu(I)(CH3CN)4]PF6
(5.10 mM stock solution in MeCN) was subsequently added and
the emission spectra acquired (excitation at 345 nm). Stock solu-
.
tions of the following metal salts in water were used: NaClO4 H2O,
.
.
.
.
Mg(NO3)2 6H2O, Ca(BF4)2 2H2O, MnSO4 2H2O, Fe(BF4)2 6H2O,
.
Ni(NO3)2 6H2O, Cu(TfO)2, Zn(OTf)2, CdCl2, and HgCl2.
Cyclic voltammetry
The donor and acceptor potentials of the pyrazoline fluorophores
were determined through cyclic voltammetry in acetonitrile con-
taining 0.1 M Bu4NPF6 as an electrolyte with a CH-instruments
potentiostat (model 600A). The samples were measured under an
inert gas at a concentration of 3 mM in a single compartment cell
with a glassy carbon working electrode, a Pt counter electrode, and
a Ag/AgNO3 (10 mM in 0.1 M Bu4NPF6/CH3CN) nonaqueous
reference electrode. All potentials were referenced to the ferroce-
nium/ferrocene couple (Fc+/0) as an internal or external standard.
1
1199. H NMR (CDCl3, 400 MHz) d 2.08 (p, J = 6.8 Hz, 4H),
3.20 (t, J = 6.6 Hz, 4H), 3.42 (t, J = 7.0 Hz, 4H), 6.69–6.74 (m,
3H), 7.19–7.25 (m, 2H). 13C NMR (CDCl3, 100 MHz) d 3.7, 30.7,
51.6, 112.7, 116.7, 129.3, 147.4. MS (70eV) 429 ([M+], 26), 274
(100), 146 (28). EI HRMS m/z calcd for [M+] 428.9450, found
428.9470.
13-Phenyl-1,5,9-trithia-13-azacyclohexadecane (4). Iodide 3
(8.99 g, 21.0 mmol), thiol 2 (3.82 g, 21.0 mmol), and 1,1,3,3-
tetramethylguanidine (5.3 mL, 2.0 equiv.) were each dissolved
in CH3CN, placed in 10 mL all-plastic syringes, and diluted
to 10 mL. The resulting solutions were simultaneously and
continuously added via syringe pump over a period of 60 h to
a refluxing solution of 1,1,3,3-tetramethylguanidine (0.66 mL,
0.25 equiv.) in acetonitrile (750 mL) under nitrogen. The reaction
mixture was cooled and concentrated under reduced pressure. The
residue was stirred with toluene (150 mL) for 1 h. The precipitated
salt was filtered out, and the filtrate was chromatographed on
silica gel (hexanes-tert-butyl methyl ether) to give the product as
a colorless, viscous oil. Yield 2.40 g (32%). Rf 0.35 (8 : 1 hexanes-
MTBE), 0.34 (10 : 1 Hexanes: EtOAc). IR (film) nmax/cm-1 2916,
2851, 1598, 1504, 1365, 1261. 1H NMR (CDCl3, 400 MHz) d 1.92
(p, J = 7.0 Hz, 4H), 1.95 (p, J = 7.1 Hz, 4H), 2.62 (t, J = 6.9 Hz,
4H), 2.68 (t, J = 6.9 Hz, 4H), 2.69 (t, J = 7.0 Hz, 4H), 3.46 (t,
J = 7.2 Hz, 4H), 6.66–6.71 (m, 3H), 7.19–7.25 (m, 2H). 13C NMR
(CDCl3, 100 MHz) d 27.5, 29.6, 29.8, 30.8, 31.0, 50.4, 112.5, 116.2,
129.2, 148.1. MS (70eV) 355 ([M+], 100), 221 (18), 193 (17), 180
(27), 146 (46), 120 (29), 106 (26), 77 (11). EI HRMS m/z calcd for
[M+] C18H29NS3 355.1462, found 355.1458.
Synthesis
Materials and reagents. 3,5-difluoroacetophenone, 3-fluoro-
phenylhydrazine hydrochloride (Aldrich), 2,5-difluorophenyl-
hydrazine,
phenylhydrazine (Oakwood, West Columbia, SC); 2,3,5-trifluoro-
phenylhydrazine was synthesized from 1,2,3,5-tetrafluorobenzene
(Aldrich) following a published procedure.26 NMR: d in ppm vs.
SiMe4 (0 ppm, 1H, 400 MHz). MS: selected peaks, m/z. Flash
chromatography (FC): Merck silica gel (70-230 mesh). TLC:
0.25 mm, Merck silica gel 60 F254, visualizing at 254 nm or with
5% phosphomolybdic acid in EtOH.
2,3,5,6-tetrafluorophenylhydrazine,
pentafluoro-
Bis(3-mercaptopropyl)sulfide (2)23. A mixture of 3-chloro-1-
propanol (25 mL, 300 mmol) and Na2S·9H2O (35 g, 146 mmol)
in 120 mL of aq. NaOH (0.5%) was heated at reflux for 12 h
under nitrogen. The reaction mixture was cooled to 0 ◦C, and
aq. 37% HCl (100 mL) was added, followed by thiourea (34 g,
447 mmol). The mixture was refluxed under nitrogen for 2 days,
cooled to 0 ◦C, and NaOH pellets (93 g, 2.3 mol) were added with
rapid stirring. The mixture was refluxed under nitrogen for 4 h and
placed in a 2 L Erlenmeyer flask. After addition of crushed ice, the
solution was acidified with 37% aq. HCl (100 mL). The product
was extracted with tert-butyl methyl ether (3 x 120 mL). The extract
was dried with Na2SO4 and concentrated under reduced pressure
4-(1,5,9-Trithia-13-azacyclohexadecan-13-yl)benzaldehyde (5).
Dimethylformamide (8.5 mL, 110 mmol) was cooled in an ice
bath, and POCl3 (5.0 mL, 55 mmol) was added over a period
of 30 min. The resulting mixture was added to a solution of 4
(2.40 g, 6.75 mmol) in DMF (8 mL). After stirring for 45 min at
75 ◦C, the mixture was cooled to room temperature, poured into
water (200 mL), and made basic with NaOH. CH2Cl2 (50 mL) was
added, and the mixture was stirred for 1 h. The organic layer was
separated, and the aqueous layer was extracted with CH2Cl2 (2 x
50 mL). The combined organic extracts were concentrated under
1
to yield the product as a colorless oil (21.3 g, 80%). H NMR
indicated the presence of a trace of 1,3-propanedithiol, and this
was completely removed by heating the product to 150 ◦C for
45 min under a stream of nitrogen (purified yield 18.0 g, 68%).
Rf 0.41 (15 : 1 hexanes: EtOAc). IR (film) nmax/cm-1 2929, 2845,
2549, 1435, 1344, 1295, 1251. 1H NMR (CDCl3, 400 MHz) d 1.37
(t, J = 8.1 Hz, 2H), 1.88 (p, J = 7.0 Hz, 4H), 2.59–2.68 (m, 8H).
368 | Org. Biomol. Chem., 2010, 8, 363–370
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reduced pressure, and the residue was taken up in benzene (25 mL)
and washed with water. The solution was dried with Na2SO4 and
concentrated under reduced pressure to give the product as a
yellow–brown oil. Yield: 2.56 g (99%). Rf 0.44 (2 : 1 hexanes:
EtOAc). IR (film) nmax/cm-1 2935, 2848, 1667, 1597, 1524, 1406,
1364, 1198, 1168, 818. 1H NMR (CDCl3, 400 MHz) d 1.93 (p, J =
6.9 Hz, 4H), 1.99 (p, J = 7.0 Hz, 4H), 2.64 (t, J = 6.6 Hz, 4H), 2.70
(t, J = 6.9 Hz, 4H), 2.72 (t, J = 7.0 Hz, 4H), 3.61 (t, J = 7.5 Hz,
4H), 6.68 (d, J = 9.0 Hz, 2H), 7.72 (d, J = 9.0 Hz, 2H), 9.73 (s,
1H). 13C NMR (CDCl3, 100 MHz) d 26.9, 29.1, 29.4, 30.5, 30.9,
49.9, 110.8, 124.9, 132.0, 152.3, 189.8. MS (70eV) 383 ([M+], 100),
249 (15), 208 (26), 174 (44), 134 (25), 87 (13), 41 (14). EI HRMS
m/z calcd for [M+] C10H29NOS3 383.1411, found 383.1392.
17.0, 12.4 Hz, 1H), 5.23 (dd, J = 12.3, 6.9 Hz, 1H), 6.58 (d, J =
14.7 Hz, 2H), 6.71 (tt, J = 8.8, 2.4 Hz, 1H)), 6.78 (tt, J = 7.2,
1.2 Hz, 1H), 7.08 (d, J = 6.6 Hz, 4H), 7.17 (t, J = 8.7 Hz, 4H).
19F NMR (CDCl3, 376 MHz) d 110.4 (t, J = 7.7 Hz, 2F). MS (70
eV) 611 ([M+], 100), 477 (19), 376 (12), 257 (15). EI HRMS m/z
calcd for [M+] C33H39F2N3S3 611.2274, found 611.2229.
( )-13-(4-(3-(3,5-Difluorophenyl)-1-(3-fluorophenyl)-4,5-di-
hydro-1H -pyrazol-5-yl)phenyl)-1,5,9-trithia-13-azacyclohexa-
decane (1b). Yield: 89%. IR (film) nmax/cm-1 2927, 1611, 1563,
1520, 1393, 1261, 1180, 1117, 986, 851. 1H NMR (CDCl3,
400 MHz) d 1.86–1.95 (m, 8H), 2.56 (t, J = 6.8 Hz, 4H), 2.67
(t, J = 6.9 Hz, 4H), 2.68 (t, J = 7 Hz, 4H), 3.07 (dd, J = 17.3,
6.6 Hz, 1H), 3.44 (t, J = 7.2 Hz, 4H), 3.73 (dd, J = 17.1, 12.3 Hz,
1H), 5.22 (dd, J = 12.3, 6.6 Hz, 1H), 6.48 (tdd, J = 8.4, 2.5, 0.8 Hz,
1H), 6.61 (d, J = 8.9 Hz, 2H), 6.76 (tt, J = 8.8, 2.3 Hz, 1H), 6.79
(ddd, J = 8.4, 2.2, 0.8 Hz, 1H), 6.86 (dt, J = 11.8, 2.3 Hz, 1H),
7.08 (d, J = 8.9 Hz, 2H), 7.10–7.13 (m, 1H), 7.17–7.23 (m, 2H).
19F NMR (CDCl3, 376 MHz) d -110.1 (t, J = 7.8 Hz, 2F), -113.0
(ddd, J = 12.1, 8.4, 6.6 Hz, 1F). MS (70 eV) 629 ([M+], 100), 495
(24), 418 (22), 392 (22), 275 (15). EI HRMS m/z calcd for [M+]
C33H38F3N3S3 629.2180, found 629.2146.
(E)-3-(4-(1,5,9-trithia-13-azacyclohexadecan-13-yl)phenyl)-1-
(3,5-difluorophenyl)prop-2-en-1-one (6). Aldehyde 5 (385 mg,
1.0 mmol) and 3,5-difluoroacetophenone (172 mg, 1.1 mmol) were
dissolved in 4 mL of ethanol–benzene (1 : 1) at 40 ◦C. Pyrrolidine
(0.2 mL, 2 equiv) was then added,◦the reaction flask was sealed,
and the mixture was stirred at 40 C for 24 h. The mixture was
diluted with 25 mL of ethanol and concentrated to a volume
of 10 mL. An additional 15 mL of ethanol was added, and the
mixture was stirred at 0 ◦C for 4 h. The orange crystalline product
was filtered off and dried under vacuum. Yield: 384 mg (73%). IR
(KBr) nmax/cm-1 2920, 1569, 1521, 1359, 1297, 1158, 984, 809. 1H
NMR (CDCl3, 400 MHz) d 1.93 (p, J = 6.9 Hz, 4H), 1.98 (p, J =
7.0 Hz, 4H), 2.64 (t, J = 6.6 Hz, 4H), 2.70 (t, J = 7.0 Hz, 4H),
2.72 (t, J = 7.1 Hz, 4H), 3.58 (t, J = 7.4 Hz, 4H), 6.66 (d, J =
8.9 Hz, 2H), 6.99 (tt, J = 8.5, 2.4 Hz, 1H), 7.50 (ddd, J = 7.9, 2.4,
1.2 Hz, 2H), 7.53 (d, J = 8.9 Hz, 2H), 7.80 (d, J = 15.4 Hz, 1H).
13C NMR (CDCl3, 100 MHz) d 27.2, 29.4, 29.6, 30.8, 31.1, 50.1,
107.3 (t, JCF = 25.5 Hz), 111.1 (dd, JCF = 18.7, 7.1 Hz), 111.7,
115.3, 122.0, 131.0, 142.2 (t, JCF = 7.4 Hz), 147.1, 150.3, 162.9
(dd, JCF = 250.2, 12.0 Hz), 187.5 (t, JCF = 1.9 Hz, broad). 19F
NMR (CDCl3, 376 MHz) d 109.2 (t, J = 7.4 Hz, 2F). MS (70 eV)
521 ([M+], 100), 387 (23), 312 (30), 286 (35), 141 (21). EI HRMS
m/z calcd for [M+] C27H33NOS3 521.1692, found 521.1726.
( )-13-(4-(3-(3,5-Difluorophenyl)-1-(2,5-difluorophenyl)-4,5-di-
hydro-1H -pyrazol-5-yl)phenyl)-1,5,9-trithia-13-azacyclohexa-
decane (1c). Yield: 63%. IR (film) nmax/cm-1 2919, 2851, 1619,
1
1505, 1441, 1377, 1198, 1118, 989. H NMR (CDCl3, 400 MHz)
d 1.92–1.82 (m, 8H), 2.55 (t, J = 6.8 Hz, 4H), 2.65 (dt, J = 6.9,
1.8 Hz, 8H), 3.19 (dd, J = 16.9, 3.8 Hz, 1H), 3.37 (t, J = 7.1 Hz,
4H), 3.68 (dd, J = 16.8, 11.7 Hz, 1H), 5.62 (td, J = 11.6, 3.7 Hz,
1H), 6.48–6.42 (m, 3H), 6.84–6.75 (m, 2H), 6.95 (d, J = 8.7 Hz,
2H), 7.24–7.22 (m, 2H), 7.33 (ddd, J = 9.9, 6.5, 3.1 Hz, 1H). 19
F
NMR (CDCl3, 376 MHz) d 109.9 (t, J = 8.0 Hz, 2F), -118.6 (m,
1F), -130.9 (m, 1F). MS (70 eV) 647 ([M+], 100), 513 (28), 412 (20),
293 (12). EI HRMS m/z calcd for [M+] C33H37F4N3S3 647.2086,
found 647.2079.
( )-13-(4-(3-(3,5-Difluorophenyl)-1-(2,3,5-trifluorophenyl)-4,5-
dihydro-1H-pyrazol-5-yl)phenyl)-1,5,9-trithia-13-azacyclohexa-
decane (1d). Yield: 59%. IR (film) nmax/cm-1 2920, 2850, 1615,
1516, 1453, 1191, 1142, 990, 854. 1H NMR (CDCl3, 400 MHz) d
1.90–182 (m, 8H), 2.56 (t, J = 6.8 Hz, 4H), 2.66–2.62 (m, 8H),
3.19 (dd, J = 17.0, 3.7 Hz, 1H), 3.39 (t, J = 7.1 Hz, 4H), 3.69 (dd,
J = 16.9, 11.6 Hz, 1H), 5.62 (td, J = 11.6, 3.7 Hz, 1H), 6.37–6.30
(m, 1H), 6.49 (d, J = 14.8 Hz, 2H), 6.79 (tt, J = 8.7, 2.3 Hz, 1H),
6.95 (d, J = 11.5 Hz, 2H), 7.14–7.08 (m, 1H), 7.23–7.18 (m, 2H).
19F NMR (CDCl3, 376 MHz) d -109.8 (t, J = 7.6 Hz, 2F), -116.0
(dddd, J = 11.7, 10.9, 8.2, 3.0 Hz, 1F), -135.2 (ddt, J = 20.0, 10.3,
3.0 Hz, 1F), -156.6 (dddd, J = 20.0, 11.7, 9.8, 5.2 Hz, 1F). MS (70
eV) 665 ([M+], 100), 531 (30), 430 (22), 311 (14). EI HRMS m/z
calcd for [M+] C33H36F5N3S3 665.1992, found 665.1978.
Synthesis of racemic 1,3,5-triarylpyrazolines from 5 and polyflu-
orophenylhydrazines (General method). A mixture of the corre-
sponding chalcone (0.09 mmol) and fluoro-substituted phenyl-
hydrazine (1.3 molar eq.), hydrochloric acid (1.3 molar eq.) and
K2CO3 (0.25 molar eq.) in anhydrous ethanol (1 mL) was heated
at 90 ◦C for 12 h (Note: if phenylhydrazine was used as HCl salt,
no additional HCl was added). Upon completion of the reaction
(TLC), the mixture was cooled to room temperature and diluted
with water (10 mL). The precipitated product was filtered off, and
washed consecutively with aq. HCl (1 M) and NaOH (5%). In
cases where no precipitate was formed, the reaction mixture was
extracted twice with EtOAc. The combined organic phases were
washed with aq. HCl (1 M) and NaOH (5%), dried (Na2SO4),
and concentrated under reduced pressure. The crude product was
purified by flash chromatography.
( )-13-(4-(3-(3,5-Difluorophenyl)-1-(2,3,5,6-tetrafluorophenyl)-
4,5-dihydro-1H -pyrazol-5-yl)phenyl)-1,5,9-trithia-13-azacyclo-
hexadecane (1e). Yield: 66%. IR (film) nmax/cm-1 2922, 2852,
1615, 1505, 1372, 1262, 1146, 1119, 990. 1H NMR (CDCl3,
400 MHz) d 1.91–1.83 (m, 8H), 2.56 (t, J = 6.7 Hz, 4H), 2.67–2.63
(m, 8H), 3.19 (dd, J = 17.0, 7.2 Hz, 1H), 3.39 (t, J = 7.1 Hz, 4H),
3.62 (dd, J = 16.9, 11.8 Hz, 1H), 5.46 (dd, J = 11.9, 7.4 Hz, 2H),
6.50 (d, J = 8.7 Hz, 2H), 6.73–6.64 (m, 1H), 6.77 (tt, J = 10.9,
2.2 Hz, 1H), 7.06 (d, J = 8.6 Hz, 2H), 7.19–7.17 (m, 2H). 19F NMR
( )-13-(4-(3-(3,5-Difluorophenyl)-1-phenyl-4,5-dihydro-1H -
pyrazol-5-yl)phenyl)-1,5,9-trithia-13-azacyclohexadecane
(1a).
Yield: 83%. IR (film) nmax/cm-1 2917, 2849, 1615, 1595, 1516,
1393, 1199, 1118, 981. 1H-NMR (CDCl3, 400 MHz) d 1.93–1.86
(m, 8H)), 2.57 (t, J = 6.8 Hz, 4H), 2.69–2.65 (m, 8H)), 3.03 (dd,
J = 17.0, 7.0 Hz, 1H), 3.40 (t, J = 7.2 Hz, 4H), 3.69 (dd, J =
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(CDCl3, 376 MHz) d -109.9 (t, J = 7.7 Hz, 2F), -140.6 (ddd, J =
21.2, 10.8, 8.8 Hz, 2F), -149.0 (ddd, J = 21.2, 8.8, 8.4 Hz, 2F).
MS (70 eV) 683 ([M+], 100), 549 (29), 448 (26). EI HRMS m/z
calcd for [M+] C33H35F6N3S3 683.1897, found 683.1843.
and Y. Yamamoto, J. Am. Chem. Soc., 2008, 130, 12564; L. Xue, Q. Liu
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Tolmachev, J. Daub and K. Rurack, J. Am. Chem. Soc., 2005, 127,
13522.
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and C. Huang, Tetrahedron Lett., 2007, 48, 3709; H. J. Jung, N. Singh
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Chem. Soc., 2000, 122, 968; K. Rurack and U. Resch-Genger, Chem.
Soc. Rev., 2002, 31, 116.
( )-13-(4-(3-(3,5-Difluorophenyl)-1-(perfluorophenyl)-4,5-di-
hydro-1H -pyrazol-5-yl)phenyl)-1,5,9-trithia-13-azacyclohexa-
decane (1f). Yield: 90%. IR (film) nmax/cm-1 2919, 2852, 1615,
1516, 1372, 1262, 1187, 1119, 1064, 989. 1H NMR (CDCl3,
400 MHz) d 1.86–1.94 (m, 8H), 2.58 (t, J = 6.8 Hz, 4H), 2.65–2.69
(m, 8H), 3.21 (dd, J = 16.9, 8.2 Hz, 1H), 3.42 (t, J = 7.1 Hz, 4H),
3.62 (dd, J = 16.8, 3.6 Hz, 1H), 5.34 (dd, J = 11.5, 8.8 Hz, 1H),
6.52 (d, J = 8.8 Hz, 2H), 6.79 (tt, J = 8.7, 2.3 Hz, 1H), 7.09 (d,
J = 8.7 Hz, 2H), 7.16–7.23 (m, 2H). 19F NMR (CDCl3, 376 MHz)
d -109.9 (t, J = 8.0 Hz, 2F), -148.2 (dd, J = 22.0, 4.9 Hz, 2F),
-161.2 (t, J = 22.0 Hz, 1F), -163.7 (td, J = 22.0, 4.9 Hz, 2F). MS
(70 eV) 701 ([M+], 100), 567 (25), 466 (24). EI HRMS m/z calcd
for [M+] C33H34F7N3S3 701.1803, found 701.1789.
12 M. Kollmannsberger, K. Rurack, U. Resch-Genger, W. Rettig and J.
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Tetrahedron, 2004, 60, 11067.
Acknowledgements
Financial support from the National Institutes of Health
(R01GM067169) is gratefully acknowledged.
13 D. Rehm and A. Weller, Isr. J. Chem., 1970, 8, 259.
14 J. Cody, S. Mandal, L. Yang and C. J. Fahrni, J. Am. Chem. Soc., 2008,
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