Controlled keto-enol tautomerism of coumarin containing β-ketodithioester by its encapsulation in cucurbit[7]uril

Article abstract of DOI:10.1039/c7nj03265j

Conventional spectroscopy techniques (UV-Vis, fluorescence and NMR), mass spectrometry and molecular modeling studies are used to assess the inclusion of cucurbit[7]uril (CB7) with coumarin 7-N,N-diethylamino-2H-chromen-2-one derivatives bearing ethyl acetoacetate (CAM1) and methyl β-ketodithioester (CAM2) moieties. For the first time, it has been demonstrated that the macrocycle CB7 is able to stabilize the keto tautomeric form of both coumarin derivatives. More interestingly, it was also seen that for CAM2, the macrocycle CB7 shifts the keto-enol equilibrium from its enol form to the keto tautomer after its inclusion, establishing important differences with inclusion in β-CD, while for CAM1, the macrocycle CB7 maintains the original keto form.

Full text of DOI:10.1039/c7nj03265j

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ISSN 1144-0546
PAPER
Jason B. Benedict et al.
The role of atropisomers on the photo-reactivity and fatigue of
diarylethene-based metal–organic frameworks
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Controlled keto-enol tautomerism of coumarin containing β-
ketodithioester by its encapsulation in cucurbit[7]uril.
M. E. Aliaga,*[a] L. García-Río,[b] A. Numi,[a] A. Rodríguez,[a] Sandra Arancibia-Opazo,[a] A. Fierro,[a]
and A. Cañete.*[a]
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
Abstract: Conventional spectroscopy techniques (UV-Vis, fluorescence and NMR), mass
spectrometry and molecular modeling studies were used to assess the inclusion of cucurbit[7]uril
(CB7) with coumarin 7-N,N-diethylamino-2H-chromen-2-one derivatives bearing ethyl
acetoacetate (CAM1) and methyl β-ketodithioester (CAM2) moieties. For the first time, it has
been demonstrated that the macrocycle CB7 is able to stabilize the keto tautomeric form of both
coumarin derivatives. More interestingly, it was also seen that for CAM2, the macrocycle CB7
shifts the keto-enol equilibrium from its enol form to the keto tautomer after its inclusion,
establishing important differences with the inclusion in β-CD, while for CAM1, the macrocycle CB7
maintains the original keto form.
www.rsc.org/
Other authors have studied the inclusion of a monocarbonyl
compound, like the cardiotonic drug milrinone (MIR), and
Introduction
Keto-enol equilibrium plays an important role in many fields
of biochemistry and chemistry.1 This phenomenon has
attracted significant attention because the quantitative shift
of such equilibria toward one or another tautomeric form
can be assessed by modulating environmental properties.1e-
the host cucurbit[7]uril (CB7). They found that the keto form
of MIR, which is the dominant species in water, is converted
into other cationic forms in the presence of CB7.4 More
recently, a study conducted by Saleh et al. (2016)5 reported
that when other monocarbonyl species like oxyluciferin dye
were assessed, the macrocycle CB7 was able to shift the
equilibrium toward the keto form. Nevertheless, for
dicarbonyl compounds in the presence of the CB7 host, there
has been no reporting on the stability of some specific
tautomeric forms. It is important to note that this issue is of
significant relevance considering the difference of reactivity
of dicarbonyl compounds in comparison with monocarbonyl
compounds. Here, our interest is on coumarin derivatives
containing systems with dicarbonyl moieties bound at
position 3 of the coumarin scaffold. We have recently
demonstrated that the host β-CD forms an inclusion complex
with the enol tautomer of a dicarbonyl compound like ethyl
acetoacetate bearing 7-hydroxy coumarin.6 On the other
hand, our exploratory study found that neither the above
mentioned 7-hydroxy coumarin nor benzoylacetone are able
to form inclusion complexes with CB7. Taking this into
account, here we report new supramolecular systems
containing the coumarin (7-N,N-diethylamino-2H-chromen-
2-one) derivatives bearing ethyl acetoacetate (CAM1) and
methyl β-ketodithioester (CAM2) moieties as guests, and
CB7 as a host; see structures in the Scheme 1. It was
expected that the 7-N,N-diethylamino group bearing
coumarin derivatives would interact mainly with CB7, based
g,2
Researches have evidenced the use of supramolecular
host-guest systems for the selective interaction of the
corresponding keto or enol forms, and this has acquired
greater relevance.1f,3-6 Among the diverse macrocyclic hosts
proposed for this purpose, cyclodextrins3,6,7 have been the
most studied; and recently, some research involving
cucurbiturils4,5 has been reported. Regarding the guests
tested, the keto-enol tautomerism of monocarbonyl4,5 and β-
dicarbonyl compounds3,6 has been addressed in the
literature. Iglesias et al.3 demonstrated that the presence of
either β-cyclodextrin (β-CD) or sodium dodecyl sulfate
micelles shifts the benzoylacetone keto-enol equilibrium to
the enol tautomer, due to the preferential binding of such
tautomeric forms. In addition, the same authors
demonstrated that β-CD increases the percentage of the
enol of the substrates 2-acetyl-1-tetralone and 2-acetyl-
cyclohexanone via the formation of inclusion complexes
between the enol tautomer of the substrates and β-CD.7
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on analogy with similar compounds that contains Second, in order to know which tautomeric form is
diethylamino group.8-10
predominant, the effect of the media polarity on the UV-Vis
spectra of both dyes was evaluated.
As shown in Figures S11A and S11B, in all tested solvents,
both coumarin derivatives exhibited
a characteristic
absorption band in the region of 350-500 nm. At this point, it
is important to mention that another one of our recent
studies6 pointed to ethyl acetoacetate bearing 7-hydroxy
coumarin, which exhibited two UV-Vis absorption bands in
aqueous solutions, assigned to the presence of two
tautomeric forms, i.e. keto (KH) and enol (EH) tautomers.
Interestingly, and as previously mentioned, the substitution
of 7-hydroxy by a 7-N,N-diethylamino group as is described
here, results in a single band, not only in an aqueous
solution, but also in most of the tested solvents (Figure S11).
This result could be attributed to the predominance of the
tautomeric form (KH) which is helped by the greater electron
releasing effect of diethylamino1g (σp = -0.72) vs hydroxyl
group (σp = -0.37) existent in coumarin.
Scheme 1. Structures of compounds used in this study: coumarin guests
(CAM1 and CAM2) and the host molecule (CB7).
Thus, considering all the aforementioned studies, we
hypothesize that the dicarbonyl free chain bearing coumarin
would continue to interact with the portals of CB7. This could
lead to the establishment of differences in the modulation of
the keto-enol equilibrium of these derivatives in the
presence of CB7. Moreover, our purpose was to assess a
sulfur-containing analogue of methyl acetoacetate
compound for the first time.
With the aim of deepening such spectrophotometric
characterization, mainly in terms of the predominance of a
specific tautomeric form by CAM1 and CAM2, experiments
1
using H NMR were done. Figure S1A shows the spectrum
when CAM1 alone was assessed in DMSO-d6 as a solvent. In
this spectrum, the 1H NMR signals that might play an
important role in the tautomeric equilibrium of CAM1 are
those assigned to –CH2– at 3.94 ppm, for its KH form, and
that of –C=CH-C at 6.38 ppm, associated with its EH form.
Furthermore, considering the integration of both signals, it
was estimated that the percentages are ∼90% (KH form) and
∼10% (EH), in DMSO-d6, while in the presence of acetonitrile
(Figure S1B) and mixtures of it solvent with water, we only
observe the contribution of the KH form. In view of this, we
suggested that the absorption band described in Figure
S11A, centered at 453 nm, is mainly attributable to the KH
form being the predominant tautomer for CAM1. Moreover,
it is noteworthy that according to the signals obtained in the
1H NMR spectrum of CAM1, in the presence of CB7, (Figures
S12 and S13), this guest forms an inclusion complex with
CB7, keeping its keto tautomeric form (100%). In addition, it
is relevant to mention that the main shifts were observed in
the protons in the diethylamino group, similar behavior was
observed when the intermediate 2 (Scheme 2) was also
assessed in the presence of CB7 (Figure S14). Details of the
characterization of these inclusion complexes are presented
in the Supporting Information, Figures S12-S18.
Results and discussion
First, CAM1 and CAM2 dyes were synthesized using 4-
(diethylamino)salicylaldehyde (1) as starting material, by the
conventional methodology to obtain coumarin.11 In
particular, the aldehyde was condensed either by
a
Knoevenagel reaction with diethyl 3-oxopentanedioate to
obtain CAM1, or with ethyl 3-oxobutanoate to obtain
coumarin intermediate 2.6 The latter was reacted with
dimethyl carbonotrithioate in basic media to obtain CAM2,
see Scheme 2.
1
On the other hand, in the case of CAM2, the H NMR signals
(DMSO-d6; Figure S4A) attributed to –CH2– of its KH form do
not appear, while a signal at 7.67 ppm, associated with the
proton present in –C(OH)=CH-C(S)-SMe of EH form does
appear. Therefore, these results indicate that the EH
tautomeric form is the main one for CAM2. Considering this
relevant NMR information, it is proposed that the absorption
band shown in the UV-vis spectra of CAM2 (Figure S11B)
practically corresponds to the EH form. The latter would be a
Scheme 2. Synthetic route to obtain CAM1 and CAM2 guests.
CAM1 and the new coumarin CAM2 were synthesized
in yields of 70% and 15%, respectively. The structures of the
dyes were confirmed by 1H NMR and 13C NMR
spectroscopies, as well as by high-resolution mass spectra
(HRMS-ESI); see Supporting Information (Figures S1-S10).
consequence of
a
strong intramolecular interaction,
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In relation to the determination of the stoichiometry of both
inclusion complexes, and based on Job plot (Figure S17) and
ESI-mass spectrometry analysis (Figure S15), it was
established that 1:1 host/guest complexes are formed. Once
the stoichiometry was established, we determined the
association constants, K1. These constants, between dyes
(CAM1 and CAM2) and CB7, were obtained by fluorescence
titration experiments. As an example, in the case of CAM2,
its concentration remained constant and the concentration
of CB7 increased between 0 and 150 ꢀM.
hydrogen-bond type, induced by the sulfur atom present in
the β-ketodithioester moiety of the dye.12
Nevertheless, in the case of a solution containing CAM2 and
CB7, Figure 1 illustrates important changes in the 1H NMR
spectrum of CAM2 alone (A) in comparison with that
obtained after the addition of CB7 (B). In fact, surprisingly, it
was observed that in the latter spectrum, Figure 1(B), a new
signal appears at 8.35 ppm, which is associated with the Hb
aromatic proton of its KH form. This is a consequence of the
stabilization of this tautomeric form when the macrocycle
CB7 is present.
Inset to Figure 2 shows the variation of the fluorescence
intensity of CAM2 with the concentration of CB7. Fitting this
data to a 1:1 binding model9, an apparent equilibrium
constant KCAM2CB7 value of (1.3±0.4) ×105 M−1 was determined
(in aqueous solution). In the case of CAM1, a binding
1
constant value of (3.9±0.2)×103 M− was calculated (Figure
S20).
Figure 1. Partial comparison of 1H NMR spectra (400 MHz) for: (A) CAM2
alone, (B) CAM2 plus CB7 (3 eq.) and (C) CAM2 plus β-CD (3 eq.) in
CD3CN/D2O.
Furthermore, it is known that the EH form for dicarbonyl
acetoacetate6
and
Figure 2. Fluorescence spectra of the coumarin-derivative CAM2 (10 μM)
with increasing concentrations of CB7 (0-150 μM). Inset shows the
Fluorescence titration of 10 μM CAM2 with CB7 in aqueous solution. The
effective binding constant was determined as KCAM2CB7 = (1.3 ± 0.4) × 105 M–1
fluorescence titration curves for the respective dye with CB7 (in aqueous
solutions). Excitation and emission slits of 5 (nm) were used.
compounds,
such
as
ethyl
benzoylacetylacetone3, are the predominant forms, either in
low-polarity aprotic solvents or β-CD. Thus, arise the
relevance to asses what happens with CAM2 when β-CD is
employed instead of CB7. With regard to this, Figures 1C and
S19 show that the signals associated to the EH tautomeric
form of CAM2 are maintained in the presence of β-CD.
Therefore, the most interesting fact that has been evidenced
is that CB7 shifts the tautomeric equilibrium of the CAM2
dye alone, from its EH (predominant tautomer) to the KH
form, stabilizing it, whereas β-CD maintains the EH form of
CAM2.
Given that for the CAM2 dye it is possible to control its
tautomerism by CB7, studies of its interactions using
docking13 and molecular dynamic simulations were also
done.14 As mentioned above, experimental data indicates
that CAM2 dye in the presence of CB7 is mainly in its KH
form. Thus, in order to evaluate the binding energy of this
complex, molecular docking methodology was used to
generate it, taking into account its KH tautomeric form.
In addition, the changes in the characteristic absorption
bands (Figure S11) and the emission spectra of CAM2 and
CAM1 when CB7 is present (Figure 2 and S20, respectively)
confirms the formation of an inclusion complex between
them. Indeed, we also observed that the slightly fluorescent
coumarin dyes CAM1 (quatum yield Φf of 0.011) and CAM2 (
Φf ≈ 0.0014) were converted into species with higher
quantum yields (Φf ≈ 0.035 and 0.0055, respectively) in
aqueous solutions containing CB7. This is in accordance with
other studies reported for different coumarin-CB7
complexes.8-10
The results show that the CAM2-CB7 complex has a binding
energy
of
-2.1
kcal/mol,
which
is approximately 1 kcal/mol more stable than that of the
CAM1-CB7 complex. This result is in accordance with the
larger apparent binding constant value experimentally
determined for CAM2-CB7 (KCAM2CB7 = 1.3× 105 M–1) in
comparison with the CAM1-CB7 complex (KCAM1CB7 = 3.9 × 103
M–1).
Alternatively, the pair (CAM2-CB7) was solvated and
submitted to a molecular dynamic simulation for 10 ns.
Figure 3A shows the molecular dynamic simulation of the
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inclusion complex CAM2-CB7, in the absence and presence An additional study involving the pair (CAM1-CB7) was
of water, at times 0 and 10 ns. It was observed that in the conducted for comparison purposes. As shown in Figure 4A,
beginning, the thioester group of CAM2 was located inside the molecular dynamic simulation of the inclusion complex
the CB7 macrocycle, and it remain there during whole CAM1-CB7, in the absence and presence of water, can be
simulation. On the other hand, the lateral chain was observed at times 0 and 10 ns. Figure 4B displays the change
extended during the simulation (5.1 Å), as shown in Figure of the initial position (obtained from docking) in the host-
3B. Nevertheless, the thioester group interacted with water guest complex of CAM1-CB7 at top left and bottom left.
molecules generating hydrogen bonds during the whole According to these results, it can be observed that the
simulation (Figure 3C). It is important to mention that similar ketoester chain of the guest CAM1 moves around 9 Å from
results were obtained when times higher than 10 ns (until 55 the border of CB7 (Figure 4B).
ns) of molecular dynamics simulations were performed (not
shown).
Figure 4. A) Molecular dynamic simulation of inclusion complex of CAM1-
CB7 at 0 and 10 ns. The upper and bottom pictures show the system without
Figure 3. A) Molecular dynamic simulation of inclusion complex of CAM2-
solvent and the system solvated, respectively). B) Changes in the position of
solvent and the solvated system, respectively. B) Changes in the position of CAM1 during the simulation. A close view shows the conformation of the
CB7 at 0 and 10 ns. The upper and bottom pictures show the system without
CAM2 during the simulation. A close view shows the conformation of the
lateral chain of CAM2. C) Hydrogen bonds between the host-guest complex
and water during the simulation. The light and dark cyan colors represent
the carbon atoms for CAM2, while the white color represents the carbon
atoms of CB7.
lateral chain of CAM1. C) Hydrogen bonds between the host-guest complex
and water during the simulation. The green and cyan colors represent the
carbon atoms for CAM1, while the white color represents the carbon atoms
of CB7.
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Furthermore, the reorganization of CAM1 causes the
aromatic center to change by 90º and at the same time the
N,N-diethylamino group shifts the original position in 2.5 Å,
interacting more and better with water molecules, which is
reflected in a hydrogen bond network (Figure 4C).
Despite the fact that it has been demonstrated that water
molecules can be encapsulated inside of CB715 in both host-
guest complexes, the CB7 host underwent a deformation in
order to accommodate the guest (Figure 5A), generating
favorable interactions in the absence of water molecules.
Furthermore, a study of the long-range interactions of host-
guest complexes was carried out using Particle Mesh Ewald
(PME).16 An upper view of the CB7 macrocycle in its
complexes with CAM1 (Figure 5B) and CAM2 (Figure 5C)
shows that a less negative potential is generated with CAM2
when compared with CAM1, which is reasonable in view of
the solvation of the former.
Figure 6. Docking studies of the inclusion complexes of CAM2-CB7 (A) and
CAM2-β-CD (B).
Conclusions
In summary, CB7 is able to form 1:1 host-guest complexes
with the KH tautomeric form of coumarin 7-N,N-
diethylamino-2H-chromen-2-one derivatives bearing ethyl
acetoacetate and methyl β-ketodithioester moieties.
Interestingly, for the guest (CAM2), the macrocycle CB7
shifts the keto-enol equilibrium from its enol form to the
keto tautomer after its inclusion. It establishes important
differences of the inclusion of this kind of guest with CB7 and
β-CD. It also enables the proposal that the architecture of
the dye can be structurally modified by an external stimulus,
like the incorporation of the macrocycle CB7. It is proposed
that the aforementioned evidence could have a significant
impact on the modulation of the reactivity of dicarbonyl
compounds using a supramolecular strategy.
Figure 5. (A) Schematic representation of the change of the diameter of CB7
during the simulation. The long-range electrostatic interactions of host-
guest complexes were treated using the Particle Mesh Ewald (PME) method
for (B) CAM1-CB7 complex and (C) CAM2-CB7 complex. Charge distribution
on the complexes is represented with blue, white and red color for positive,
neutral and negative charge, respectively.
Experimental
Materials and equipment
In order to explain the stabilization of different tautomeric
forms between CAM2 and the macrocycles CB7 or β-CD,
docking studies were carried out. For this dye different
binding modes were observed in β-CD and CB7, where the
main modification is related to the solvent exposition of the
diethylamino group. In fact, as shown in Figure 6, in the
presence of β-CD, CAM2 exposes its diethylamino group to
the solvent and the enol binding to the thioester group
remains inside the cavity. However, when CAM2 forms a
complex with CB7, the thioester group remains outside the
cavity and interacts with solvent water molecules favoring
the KH tautomeric form, and CAM2-CB7 is the most stable
complex (Table S1). The stabilization of the KH form by CB7
could be attributed to the electrostatic interaction of the
protons present in the –C(O)-CH2-C(S)-SMe moiety of the KH
form of CAM2 with ureido oxygens on the CB7 portals, which
would promote the extinction of the EH form.
All solvents and reagents were purchased from Sigma-Aldrich
and used as received. Unless indicated otherwise, all
solutions employed in this study were prepared in aqueous
solution (pH=5.5). The compounds ethyl 3-(7-(diethylamino)-
2-oxo-2H-chromen-3-yl)-3-oxopropanoate
methyl 3-(7-(diethylamino)-2-oxo-2H-chromen-3-yl)-3-
oxopropanedithioate (CAM2) were synthesized according
to the procedures described in the Supporting Information.
Absorption and steady-state fluorescence spectra were
obtained using a HP-8453 diode array spectrophotometer
and Cary Eclipse fluorescence spectrophotometer,
respectively.
High-resolution mass spectrometry (HRMS-ESI) studies.
High-resolution mass spectra (HRMS-ESI) were obtained
from Thermo Fisher Scientific Exactive Plus mass
spectrometer. The analysis for the reaction products was
performed with the following relevant parameters: heater
temperature, 50 °C; sheath gas flow, 5; sweep gas flow rate,
0 and spray voltage, 3.0 kV at negative mode. The accurate
(CAM1)
and
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mass measurements were performed at a resolution of random individuals with a population size of 100 individuals
140.000.
was employed, a maximum number of 2.5 x 106 energy
evaluations, a maximum number of 27,000 generations, a
Electrospray ionization mass spectrometry (ESI-MS/MS).
The detection of the inclusion complex CAM1-CB7 was mutation rate of 0.02 and a cross-over rate of 0.80. The
undertaken on an AB SCIEX Triple Quad™ 4500 LC/MS/MS docked compound complexes were built using the lowest
Mass Spectrometer equipped with a Turbo Ion Spray (AB docked-energy binding positions.
Sciex) ion source. Specific compound-dependent MS Molecular dynamic simulations
parameters for each dye were determined by direct infusion Each host-guest complex was solvated with a TIP3 water
into the MS of individual standards dissolved in 10% (vol/vol) model and submitted to molecular dynamics (MD)
acetonitrile (concentration of 25 μM) at a flow rate of 7 simulations for 10 ns using a NPT ensemble. NAMD 2.6 was
μL/min. The 4500 QTRAP system was operated in positive ion used to perform MD calculations.18,19 Periodic boundary
mode using the multiple reaction monitoring (MRM) scan conditions were applied to the system in the three
type. A declustering potential (DP) of +180, entrance coordinate directions.
A pressure of 1 atm and a
potential (EP) of +10, and collision cell exit potential (CXP) of temperature of 310 K were maintained.
+25 were used. The ion spray voltage was set at +3500 V,
Keywords: keto-enol equilibrium • β-ketodithioester •
cucurbit[7]uril • coumarin • dicarbonyl compounds.
source temperature was set at 300 °C, collision gas (CAD)
was set to high, and source gas GS1 and GS2 were set to 10
and 20, respectively. All data were acquired using Analyst
1.6.2 (AB Sciex).
Acknowledgements
Nuclear magnetic resonance (NMR) studies.
1H NMR spectra were obtained at 25 °C on Bruker Avance
400 MHz spectrometer using TMS as an internal standard.
The NMR spectra were processed with MestreNova software
v9.0.
This work was supported by FONDECYT grant #1170753,
FONDEQUIP EQM-130032, Institutional Fellowship for Academics
(VRI-PUC) and
Pontificia
Universidad
Católica
de
Chile Projects 3913-189-81 and Puente Nº P1708/2017.
Determination of the quantum yield of emission.
Fluorescence quantum yields of dyes were measured using a
solution of quinine sulfate in 0.5 mol/L H2SO4 as standard (Φs
= 0.546). All values were corrected taking into account the
solvent refraction index. Quantum yields were calculated
using Eq. 1, where the subscripts x and s denote sample and
standard, respectively, Ф is the quantum yield, η is the
refractive index, and Grad is the gradient from the plot of
integrated fluorescence intensity vs. absorbance.
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5
6
M. E. Aliaga, A. Fierro, I. Uribe, L. García-Río, A. Cañete,
Chem. Phys. Chem. 2016, 17, 3300-3308.
Molecular Docking
In order to obtain information regarding the principal host-
guest interactions, the molecular docking of CAM1 and
CAM2 in CB7 was carried out using AutoDock 4.0 suite.18 In
general, the grid maps were calculated using the autogrid4
option and were located on the center of β-CD. The volumes
for the grid maps were 40 x 40 x 40 points (a grid-point
spacing of 0.375 Å). The autotors option was used to define
the rotating bonds in the ligand. In the Lamarckian genetic
algorithm (LGA) dockings, an initial population of 1500
7
8
E. Iglesias, J. Incl. Phen. Mac. Chem. 2005, 52, 55-62.
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66; (e) R. N. Dsouza, U. Pischel, W. M. Nau, Chem. Rev. 2011,
111, 7941-7980 and references therein.
6 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/C7NJ03265J
Journal Name
M. E. Aliaga, L. García-Rio, M. Pessêgo, R. Montecinos, D.
Fuentealba, I. Uribe, M. Martín-Pastor, O. García-Beltrán,
ARTICLE
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E. Villa, C. Chipot, R. D. Skeel, L. Kalé, K. Schulten, J. Comput.
Chem. 2005, 26, 1781-1802.
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New Journal of Chemistry
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CB7
β-CD
CAM2
CB7 shifts the tautomeric equilibrium of the CAM2, from its enol- to the keto-form, whereas -CD maintains
the enol form.