Novel (E)-1-(pyrrole-2-yl)-3-(aryl)-2-(propen-1-one) derivatives as efficient singlet oxygen quenchers: Kinetics and quantum chemical calculations

Article abstract of DOI:10.1039/c5ra13203g

Chalcones constitute an important group of natural and synthetic products that have been screened due to their wide range of pharmacological applications. Herein, we studied the antioxidant activity of five newly synthetized (E)-1-(pyrrole-2-yl)-3-(aryl)-2-(propen-1-one) (PAPs) derivatives against singlet oxygen (¹O₂). The differences among the compounds are related to aryl substitution in the p-position where: 3a = C₆H₅, 3b = 4-H₃COC₆H₄, 3c = 4-FC₆H₄, 3d = 4-ClC₆H₄, 3e = 4-BrC₆H₄. The PAPs were synthesized using a Claisen-Schmidt condensation reaction between 2-acetylpyrrole and aromatic aldehydes under ultrasonic irradiation (yields between 79-86%) and were characterized by IR, mass spectrometry, NMR and quantum chemical calculations. The total singlet oxygen quenching rate constants (k_Q) of the PAPs were measured spectrophotometrically in ethanol at 25°C and determined by using the Stern-Volmer model. As the character of the EWGs is increased from 3a to 3e, the k_Q diminishes smoothly. The best quencher is found to be the 3a compound (where the aryl group is unsubstituted) with a k_Q = 5.71 (±0.21) × 10⁷ M^-1 s^-1, which is similar to those for other antioxidants e.g. flavonoids. These results suggest these compounds are efficient quenchers of singlet oxygen and their potential applicability in biological systems.

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Novel (E)-1-(pyrrole-2-yl)-3-(aryl)-2-(propen-1-one) derivatives as
efficient singlet oxygen quenchers: Kinetics and quantum
chemical calculations
Received 00th July 2015,
Accepted 00th XXX 2015
Carlos E. Diaz-Uribe,*a William Vallejo,a Wilmar Castellar,a Jorge Trilleras,b Stephanie Ortiz,b Angela
Rodriguez-Serrano,c Ximena Zarated and Jairo Quirogae
DOI: 10.1039/x0xx00000x
www.rsc.org/
Chalcones constitute an important group of natural and synthetic products that have been screened due to their wide
range of pharmacological applications. Herein, we studied the antioxidant activity of five newly synthetized (E)-1-(pyrrole-
2-yl)-3-(aryl)-2-(propen-1-one) (PAPs) derivatives against singlet oxygen (1O2). The differences among the compounds are
related to the aryl substitution in the p-position where: 3a = C6H5, 3b = 4-H3COC6H4, 3c = 4-FC6H4, 3d = 4-ClC6H4,
3e = 4-BrC6H4. The PAPs were synthesized by Claisen–Schmidt condensation reaction between 2-acetylpyrrole and
aromatic aldehydes under ultrasonic irradiation (yields between 79–86%) and were characterized by IR, mass
spectrometry, NMR and quantum chemical calculations. The total singlet oxygen quenching rate constants (kQ) by the PAPs
were measured spectrophotometrically in ethanol at 25 °C and determined by using the Stern-Volmer model. As the
character of the EWGs is increased from 3a to 3e, the kQ diminishes smoothly. The best quencher is found to be the 3a
compound (where the aryl group is unsubstituted) with a kQ = 5.71 (±0.21) x107 M-1 s-1, which is similar to those for other
antioxidants e.g. flavonoids. These results suggest these compounds as efficient quenchers of singlet oxygen and their
potential aplicability in biological systems.
β
-carotene (in vivo).10
1. Introduction
Antioxidant properties of flavonoids have been extensively
studied in vitro due to their nutritional and medical
relevance.11 These compounds may function as quenchers of
singlet oxygen (Eq. 1), leading to mechanisms that can be
merely collisional (physical quenching, kq), with regeneration
of ground state triplet oxygen, or the interaction can result in a
chemical reaction (reactive quenching, kr), where the
compounds are oxidized. When more than one process
contributes to the total rate (kQ), they need to be considered
together (kQ = kq + kr)
The lowest excited electronic state of molecular oxygen,
commonly known as singlet oxygen (1O2(a1
∆g)), is a reactive
oxygen species of special interest in chemical and medicinal
research over the years. Its unique reactivity in a number of
photochemical processes in a variety of systems1-3 including
e. g. lipids, sterols, proteins, DNA, and RNA4-5 results in the
degradation of biological systems and cell death. These events
have been associated to different pathologies such as
pigmentation, cataract, skin aging, and cancer.6-8 Several
antioxidants are known to quench singlet oxygen, both by
physical and chemical mechanisms, the protective effects of
the natural antioxidant constituents of fruit and vegetables
have been attributed to the carotenoids, vitamins C, E and the
flavonoids.9 Nevertheless, a recent study demonstrates that
intracellular singlet oxygen is not efficiently deactivated by
1O2 + Flavonoid kQ→Physical Quenching (kq )+ Chemical Reaction (kr )
(1)
The singlet oxygen quenching rates kQ by flavonoids have
been reported.12-13 The physical quenching mechanism of
certain electron-rich systems is known to be charge transfer.
The formation of an exciplex takes place with subsequent
decay to ground-state compounds and is related to the
oxidation potential. Molecules with low oxidation potentials
a.Grupo de Investigación en Fotoquímica y Fotobiología. Universidad del Atlántico.
(Eox
≤
1.9 V vs SCE) are efficient quenchers of 1O2. In
Kilómetro
carlosdiaz@mail.uniatlantico.edu.co
7
Vía Puerto Colombia, Barranquilla, Colombia. e-mail:
flavonoids the efficiency of the physical quenching (kq) is
mainly controlled by the presence of a catechol moiety on ring
B, whereas the structure of ring C (particularly the presence of
a hydroxyl group activating the 2,3-double bond) is the main
factor determining the efficiency of the chemical reactivity (kr)
of flavonoids with 1O2. The total reactivity scale (kQ) is
dominated by kq, which is in general higher than kr.14
b.Grupo de Investigación en Compuestos Heterocíclicos. Universidad del Atlántico.
Kilómetro 7 Vía Puerto Colombia, Barranquilla, Colombia.
c. Grupo de Fotodinámica Molecular, Universidad de los Andes, Carrera 1 No. 18A -
10, Bogotá, Colombia. e-mail: as.rodriguez@uniandes.edu.co
d.Instituto de Ciencias Químicas Aplicadas, Facultad de Ingeniería, Universidad
Autónoma de Chile, Av. Pedro de Valdivia 641, Santiago, Chile.
e. Grupo de Investigación de Compuestos Heterocíclicos, Universidad del Valle, A. A.
25360, Cali, Colombia.
†Electronic Supplementary Informaꢀon (ESI) available: Cartesian coordinates (and
geometries) of the ground and first triplet states computed by quantum chemical
calculations as well as the IR and NMR experimental spectra are presented. See
DOI: 10.1039/x0xx00000x
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Quencher
1O2
Na2MoO4
H2O2
Chemical quenching (kr) + Physical quenching (kq)
+
kQ
(2)
(3)
kd
(1)
kOx
Rubrene
(4)
3O2
Oxidized - Rubrene
Scheme 1 Singlet oxygen oxidation of rubrene induced by NaMoO4 and hydrogen peroxide under dark condition.
1H NMR (400 MHz) and 13C NMR (100 MHz) spectra were
recorded at room temperature on a Bruker Ultra Shield 400
using CDCl3 as solvent. The EIMS were run on a Shimadzu GC–
MS 2010 spectrometer, which was operating at 70 eV. The IR
spectra were recorded as KBr pellets on a Shimadzu FTIR-8400
instrument. The ultrasonic irradiation was performed by using
a Branson ultrasonic cleaner bath, model 1510, 115v, 1.9 L
with mechanical timer (60 min with continuous hold) and
heater switch, 47 kHz. The aromatic aldehydes and solvents
used, such as, ethanol, dichloromethane and ethyl acetate
were obtained from Merck Chemical Company. 2-
Acetylpyrrole was obtained from Aldrich.
Nowadays, there is a great interest in the pharmacological
potential of chalcones as they are precursors of flavones,
isoflavones, aurones and anthocyanins which are regarded as
cyclic chalcones, and their closely related physiological and
medical relevancies.15-16 This family of molecules constitutes
an important group of natural and synthetic products that
have been screened for their wide range of pharmacological
activities as antibacterial, anti-tumor, anti-inflammatory,
antifungal and antioxidant agents.17-18
Chalcones are 1,3-diphenyl-2-propene-1-ones, where two
aromatic rings are linked by a three carbon
α,β-unsaturated
carbonyl system. These structures can be easily synthesized by
the Claisen–Schmidt condensation, as used in this work, which
involves cross aldol condensation of appropriate aldehydes
and ketones by base catalysed or acid catalysed reactions
followed by dehydration. Because of their pharmaceutical
importance, in the present investigation we have studied the
antioxidant activity of the newly synthetized (E)-1-(1H-pyrrol-
2-yl)-3-arylprop-2-en-1-one derivatives 3(a–e) (PAPs) against
singlet oxygen. The compounds were characterized by FT-IR,
1H-NMR, 13C-NMR and MS. The overall quenching rate
constants were determined by using a Stern–Volmer plot
derived from the steady-state kinetics. Theoretical calculations
were performed in order to get further insights on the
molecular structure, electronic and reactivity properties of
these new systems.
2.2 General procedure for the synthesis of PAPs.
A mixture of 2-acetylpyrrole (5 mmol), appropriate aromatic
aldehyde (5 mmol), NaOH (2 mmol) and ethanol (2 mL), was
sonicated for 5–20 minutes in the water bath of an ultrasonic
cleaner bath. The progress of the reaction was monitored by
TLC using dichlorometane:ethyl acetate (9:1 v/v) as eluent. The
reaction mixture was cooled in ice-water bath. The formed
precipitate was filtered, washed with cool water and purified
by recrystallization from ethanol to give the PAP derivatives
3(a-f) in high yields of 79–86%.
(E)-3-phenyl-1-(1H-pyrrol-2-yl)prop-2-en-1-one (3a). IR (v
cm−1, KBr): 3237 (N-H); 1650 (C=O). NMR 1H (CDCl3, δ ppm):
9.98 (s, 1H, NH); 7.83 (d, J = 15.6 Hz, 1H, Hβ); 7.63 (m, J = 7.52
Hz, 2H, Ho); 7.40 (m, J = 7.27 Hz, 3H, Hm, Hp); 7.36 (d, J =
15.81 Hz, 1H, Hα); 7.12 (s, 1H, H5, Hetaryl); 7.09 (s, 1H, H3,
Hetaryl); 6.36 (s broad, 1H, H4, Hetaryl). NMR 13C (CDCl3, δ
ppm): 178.6 (C=O); 142.0 (Cβ); 134.7; 132.8; 129.8 (Cα); 128.6;
128.0; 125.1; 121.7; 116.1; 110.6. MS (ESI, positive scan) m/z =
197.3 (M+).
H
H
O
Ar
NH
O
N
2aꢀe
Ar
NaOH/Ethanol
CH3
(E)-3-(4-methoxyphenyl)-1-(1H-pyrrol-2-yl)prop-2-en-1-one
3b). IR (v cm−1, KBr): 3259 (N-H); 1646 (C=O). NMR 1H (CDCl3, δ
1
3aꢀe
O
(
Fig. 1 Synthesis scheme of (E)ꢀ1ꢀ(1Hꢀpyrrolꢀ2ꢀyl)ꢀ3ꢀarylpropꢀ2ꢀenꢀ1ꢀ
one derivatives (PAPs). The Ar corresponds to 3a = C6H5,
3b = 4ꢀH3COC6H4, 3c = 4ꢀFC6H4, 3d = 4ꢀClC6H4, 3e = 4ꢀBrC6H4.
ppm): 9.85 (s, 1H, NH); 7.79 (d, J = 15.6 Hz, 1H, Hβ); 7.59 (d, J =
8.89 Hz, 2H, Hm); 7.24 (d, J = 15.6 Hz, 1H, Hα); 7.09 (s, 1H, H5,
Hetaryl); 7.05 (s, 1H, H3, Hetaryl); 6.93 (d, J = 8.78 Hz, 2H, Ho);
6.34 (s broad, 1H, H4, Hetaryl); 3.84 (s, 3H, OCH3). NMR 13C
(CDCl3, δ ppm): 178.7 (C=O); 161.1; 141.7 (Cβ); 132.9; 129.7;
127.5; 124.7 (Cα); 119.3; 115.6; 114.0; 110.5; 55.1. MS (ESI,
positive scan) m/z = 227.9 (M+); 160.96 (M+- C4H4N).
2 Materials and Methods
2.1 Reagents and equipment
All reagents used in this work were analytical grade, the UV-Vis
(E)-3-(4-fluorophenyl)-1-(1H-pyrrol-2-yl)prop-2-en-1-one
(
3c). IR (v cm−1, KBr): 3266 (N-H); 1448 (C=O). NMR 1H (CDCl3, δ
spectra were taken in
a
Hewlett-Packard 8453
spectrophotometer. FT-IR spectra (KBr) were recorded in a ppm): 9.62 (s, 1H, NH); 8.26 (d, J = 8.78 Hz, 2H, Hm); 7.82 (d, J
Bruker Tensor 27 spectrometer. Melting points were = 15.8 Hz, 1H, Hβ); 7.76 (d, J = 8.78 Hz, 2H, Ho); 7.43 (d, J =
determined using a Thermo Scientific Fluke 51 II, model IA 15.8 Hz, 1H, Hα); 7.15 (s, 1H, H5, Hetaryl); 7.10 (s, 1H, H3,
9100 melting point apparatus and are reported uncorrected. Hetaryl); 6.38 (s broad, 1H, H4, Hetaryl). NMR 13C (CDCl3, δ
2 | RSC Adv., 2015, 00, 1-3
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ppm): 188.6 (C=O); 139.2 (Cβ); 128.8; 126.1; 125.8 (Cα); 124.2; Geometry optimization of the electronic ground states of PAPs
117.0; 111.4 MS (ESI, positive scan) m/z = 215.1 (M+).
were performed using the B3LYP20-21 functional and the TZVP22
basis set as implemented in the Turbomole 6.3 program
package.23 The minima of the first triplet states (T1) of PAPs
were determined by unrestricted density functional theory
(UDFT) due to triplet instabilities when using a TD-DFT
gradient.24 DFT-D3 corrections to the dispersion energy were
accounted in all geometry optimizations.25 The conductor-like
screening model (COSMO, ε = 24.852) has been used for the
simulation of a bulk ethanolic environment (electrostatic
solvent effects).26-28 Harmonic vibrational frequencies were
computed numerically employing the SNF program.29
(E)-3-(4-chlorophenyl)-1-(1H-pyrrol-2-yl)prop-2-en-1-one
3d). IR (v cm−1, KBr): 3273 (N-H); 1645 (C=O). NMR 1H (CDCl3, δ
(
ppm): 11.97 (s, 1H, NH); 7.86 (d, J = 8.54 Hz, 2H, Hm); 7.70 (d, J
= 15.8 Hz, 1H, Hβ); 7.62 (d, J = 15.5 Hz, 1H, Hα); 7.49 (d, J =
8.28 Hz, 2H, Ho); 7.37 (s, 1H, H5, Hetaryl); 7.16 (s, 1H, H3,
Hetaryl); 6.27 (s broad, 1H, H4, Hetaryl). NMR 13C (CDCl3, δ
ppm): 178.5 (C=O); 140.8 (Cβ); 136.0; 133.5; 133.1; 129.4;
129.1 (Cα); 125.6; 116.5; 111.1. MS (ESI, positive scan) m/z =
231.7 (M+); 233.04 (M+ + 2)
(E)-3-(4-bromophenyl)-1-(1H-pyrrol-2-yl)prop-2-en-1-one
3e). IR (v cm−1, KBr): 3270 (N-H); 1644 (C=O). NMR 1H (CDCl3, δ
The adiabatic excitation energies of the T1 states of PAPs
were obtained from single-point energy calculations using the
density functional theory / multi-reference configuration
interaction (DFT/MRCI) method.30 The main idea is to account
for static electron correlation via MRCI while the dynamic
electron correlation is treated by DFT. The configuration state
functions (CSFs) of the MRCI expansion uses Kohn–Sham (KS)
orbitals computed employing the BHLYP functional. This hybrid
approximation is known to yield reliable excitation energies at
a reasonable cost for medium to large size of organic
chromophores and within errors around of 0.2 eV.31-32 Here,
we follow the same DFT/MRCI procedures for calculating the
electronic state properties (for a C1 point group and 10 roots
(
ppm): 10.02 (s, 1H, NH); 7.79 (d, J = 15.6 Hz, 1H, Hβ); 7.58 (d, J
= 8.53 Hz, 2H, Hm); 7.53 (d, J = 8.28 Hz, 2H, Ho); 7.37 (d, J =
15.6 Hz, 1H, Hα); 7.17 (s, 1H, H5, Hetaryl); 7.12 (s, 1H, H3,
Hetaryl); 6.39 (s broad, 1H, H4, Hetaryl). NMR 13C (CDCl3, δ
ppm): 178.5 (C=O); 140.8 (Cβ); 133.9; 133.0; 132.1; 129.6;
125.7 (Cα); 124.4; 122.5; 116.6; 111.1. MS (ESI, positive scan)
m/z = 275.0 (M+); 277.1 (M+ +2).
2.3 Determination of overall singlet oxygen quenching rate
1
The overall rates constants kQ (=kq + kr) for the reaction of O2
with PAPs were determined in ethanol solution at 25 °C
through competition reaction method using rubrene as
standard compound and analyzing the first-order rate constant
(S) of the decay curve of rubrene. Singlet oxygen was induced
from dark chemical reaction of Na2MoO4 and H2O2. The overall
rate constant was determined using a Stern–Volmer plot
derived from steady state kinetics (see Scheme 1). The
reciprocal lifetimes were represented as a function of the PAPs
concentration and the bimolecular rate constants were
determined from the slope of the linear plots. The
experimental errors were estimated to be <5% in the rate
constants (kQ) determination. All measurements were
performed at 25 ± 0.5 oC.
for
A
representation) as in previous work.33 The MRCI
expansions were built up from the one-particle basis of the
optimized Kohn–Sham orbitals with the COSMO method.
3 Results and Discussion
3.1 Synthesis and characterization of the PAPs
Conventionally, enonic derivatives are obtained via Claisen-
Schmidt condensation reaction.34 Variations in such
methodology were performed, where ultrasound radiation
was used during the reaction to obtain the PAPs in short time
and with good yields. Since the aim was to study the
antioxidant properties of the compounds, we did not evaluate
the effects of other reaction parameters (temperature,
catalyst and solvent). In general, for reactions of this type, the
reaction rate increases with temperature.35 The (E)-1-(1H-
pyrrol-2-yl)-3-arylprop-2-en-1-one (PAPs) derivatives were
prepared with excellent yields starting with 2-acetylpyrrole
and aromatic aldehydes in the presence of NaOH (solid) in
ethanol under ultrasonic irradiation at room temperature
during 5–20 minutes. The yield percentage (see Table 1) of the
reaction was estimated by stoichiometric analysis of the
starting materials and the final weight of product obtained
after purified by recrystallization with ethanol and complete
drying (compared to the stoichiometric expected quantity).
The structures of all the synthesized compounds were
confirmed by IR, 1H-NMR, 13C-NMR and MS. The corresponding
spectra for each of the compounds are provided as supporting
information (SI).
Rubrene oxidation with a chemical source of singlet oxygen
in microemulsion was performed to check singlet oxygen
quenching activity.19 The microemulsion was prepared at room
temperature (298 K) by adding an aqueous solution of 0.2 M
Na2MoO4.2H2O (290.4 mg in 6 mL of water) dropwise to a
magnetically stirred slurry of SDS (4.7 g), 1-butanol (9.4 g), and
methylene chloride (60 mL). After a few minutes, the turbid
suspension was converted into a mobile and transparent
liquid. Then, 2.0 x 10-4 mol of rubrene was introduced into a
small Erlenmeyer flask plus 15 mL of microemulsion. The
medium was magnetically stirred for 10 minutes and stored in
darkness to prevent the autosensitized photooxidation of
rubrene. After that, 50 μmol of H2O2 were added to the red
solution and the reaction medium was stirred with
a
microscale magnetic bar at room temperature. The samples
solutions also contained PAPs (as quenchers, 0 - 3.0x10-3 M).
The oxidation of rubrene was monitored by visible
spectroscopy at 522 nm.
2.4 Quantum chemical calculations
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The preparation of chalcones under basic conditions and reaction may occur mainly via a physical or a chemical
using sonochemical method provides several advantages such pathway is a balance between spin-orbit and electronic
as operational simplicity, reduction of the processing time, coupling, and entropic (diffusion) factors.
higher yield, safety, environment friendly protocol and to
Many studies show that the substituent in the aromatic
enhance the efficiency of the catalyst.36 This is due to the rapid
micromixing and the resulting faster reaction (also possibly
due to the formation of local hot spots) to form the
chalcone.37-39
ring influence the overall rate constants values.14,42-43 For
example, kQ increased as the number of -OH groups
substituted to the aromatic skeleton (that is, the total
electron-donating capacity) increases. Along, the heavy-atom
contribution on rate constant kQ has been studied, several
halogenated anilines with similar oxidation potentials were
used as quenchers.44 Aniline without halogenated substituent
has the higher kQ value than the compounds with chlorine and
bromine in acetonitrile, possibly due to halogens (-F, -Cl
and -Br) are electron withdrawing groups (EWGs) and
inefficient for electron delocalization, hence with a lower
capacity to stabilize resonance structures.
Table 1. Reaction time (tr), melting point (Tf) and % yield for compounds
3(a–e)
Comp. 3
3a
Ar
tr (min.)
Tf(°C)
140
137
170
165
185
Yield (%)
C6H5
10
5
86
86
80
79
83
3b
4-H3COC6H4
4-FC6H4
4-ClC6H4
4-BrC6H4
3c
20
20
20
3d
3e
3a
R² = 0.9952
2.8
3b
3.2 Overall rate constants (kQ) for the quenching of 1O2
R² = 0.9903
3c
Singlet oxygen decay occurs mainly via 4 routes (reactions 1 to
4, scheme 1): non-radiative decay (1), chemical quenching (2),
physical quenching (3) and reaction with rubrene (4). The total
quenching rate constants for the reaction of singlet oxygen
with PAPs in ethanol were determined from the measured
first-order decay of singlet oxygen in the absence and
presence of PAPs according to Eq. 2 derived from the steady-
2.3
3d
R² = 0.9840
3e
R² = 0.9801
1.8
R² = 0.9861
1.3
state treatment of scheme
1 (both with same initial
0.8
concentration of rubrene). The PAPs inhibited the oxidation of
rubrene and its effect was concentration dependent.
0.0
0.5
1.0
1.5
2.0
2.5
3.0
[PAP]/mM


Fig. 2 Plot of S0/SS vs concentrations (mM) of PAPs.
k + k
(
)
S0
SS
q
r
(2)
=1+ 
 PAPs
[
]
kd




Many heterocyclic compounds also act as quenchers of
singlet oxygen.45-47 The interest in obtaining this type of
heterocyclic chalcone derivatives is due to their versatility as
starting materials in the synthesis of a series of heterocyclic
compounds.48 However, α,β-unsaturated systems in
combination with substituted aromatic rings with electron
releasing groups (ERGs) and heterocyclic rings such as pyrrole
(6 πe- in a 5-membered ring) can influence the antioxidant
properties of the molecule. The rate constants (kQ) for some
flavonoids are similar to PAPs: chrysin (2.01 x 107 M-1s-1),
Where S0 and SS are slopes of the first-order plots of
disappearance of singlet oxygen (acceptor), rubrene, in the
absence and presence of PAPs, respectively. And, kd is the rate
of deactivation of singlet oxygen in ethanol. A plot of S0/SS vs
concentration of PAPs is shown in Fig. 2. The overall rate
constants (kQ) were calculated using the value of kd in ethanol
(kd = 8.3x104 s-1), reported by Merkel and Kearns.40 The kQ
values obtained for PAPs are listed in Table 2. Based on this
kinetics for the oxygen quenching, the trend of the measure
values upon aryl substitution show that the fastest process
proceeds for the 3a compound (p-unsubstituted) with a rate
constant of kQ = 5.71 x 107 M-1 s-1. These rate constants
diminishes smoothly upon p-substitution of the aryl group by -
OCH3, -F, -Cl and -Br (3b-e PAPs) maintaining the same order
of magnitude. This result indicates that the PAPs can act as
scavengers of singlet oxygen. It has been postulated in the
literature that the bimolecular reactions of singlet oxygen (also
quenching processes) may occur via a reversible and rapid
formation of a charge transfer encounter complex (exciplex)
that could evolve through chemical reaction pathways or
singlet-singlet energy transfer.14,41 The latter mechanism
generates the triplet state of the quencher (via ISC) and the
ground state of molecular oxygen. The fate in which the
Table 2. Overall rate constants (kQ) for the quenching of 1O2 by PAPs.
DFT/MRCI adiabatic excitation energies (∆Ead) of the first triplet states (T1) in
ethanolic environment (COSMO, ε = 24.852)
Comp. 3
3a
Ar =
C6H5
kQ (M-1s-1)
∆Ead [eV]*
2.20(2.34)
2.05(2.23)
2.24(2.39)
2.19(2.33)
2.16(2.31)
5.71 (±0.21) x107
4.85 (±0.10) x 107
3.87 (±0.22) x 107
2.42 (±0.24) x 107
1.94 (±0.18) x 107
3b
4-H3COC6H4
4-FC6H4
4-ClC6H4
4-BrC6H4
3c
3d
3e
*The values in parenthesis correspond to the more unstable anti conformation.
See details in the text, section 3.3.
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Fig. 3 Ground state minima of PAPs optimized at the B3LYPꢀD3/TZVP + COSMO(ε = 24.852) level of theory. Bond lengths are
presented in pm. Relative energies ( E in kJ/mol) and Gibbs energies ( G in kJ/mol) of the local minima relative to the lowest energy
conformer are computed using the DFT/MRCI method.
∆
∆
(where the p-substitution at the aryl group corresponds to a
methoxy group) the variations can range up to 3.7°. All the
calculated distances show only small variations when changing
the EWG at the p-position by -OCH3, -F, -Cl and -Br groups. As
expected, the substitution effects are visible taking into
account the differences of the calculated C-X bond lengths.
apigenin
(2.84 x 107 M-1s-1),
catechins
(1.09 x 107
-
1.47 x 108 M-1s-1).43 These PAPs have similar singlet oxygen
quenching activity to synthetic antioxidants like tert-butyl-
(3.37 x 107 M-1s-1)
hydroxyanisol
and
tert-di-Butyl-
hydroxytoluene (4.26 x 106 M-1s-1).49 However, the quenching
rate of PAPs is one to three orders of magnitude smaller than
that of
β
-carotene (1.58 x 1010 M-1 s-1) and
α
-tocopherol
Two different molecular configurations are possible,
(2.06 x 108 M-1 s-1), which are well known as representatives depending on the position of the pyrrole group relative to the
singlet oxygen quenchers.50-51
carbonyl oxygen (syn or anti). The syn configurations are found
to be more stable than the anti conformers due to the
presence of a intramolecular hydrogen bond between the
carbonyl oxygen and the pyrrole proton (-C=O…H-N-), see
Fig. 3. The length of these hydrogen bonds is calculated to be
of about 254 pm which is unaffected by EWGs p-aryl
Most reactions of 1O2 with biological targets (lipids, sterols,
proteins (amino acids), DNA, and RNA occur via chemical
rather than physical routes inducing cell death and
mutations.4-5 For instance, the quenching rates are
9.0 x 103 M-1s-1 for stearic acid, 1.7 x 104 M-1s-1 for oleic acid,
4.2 x 104 M-1s-1 for linoleic acid, 5.7 x 104 M-1s-1for cholesterol,
and 5.1 x 105 M-1s-1 for DNA.14 The kQ values observed in this
work are 2 to 4 orders of magnitude larger than those fatty
acids and DNA. This result suggests that these compounds may
contribute to the protections of the lipid peroxidation and the
substitution. The DFT/MRCI energy difference (∆E) between
these configurations is in between 14.2 and 30.1 kJ/mol,
suggesting a major population of the syn conformers at
ambient temperature.
The T1 (πHπL*) state. A DFT/MRCI calculation of the vertical
degradation of DNA in photosynthetic systems, by quenching electronic spectra of the PAPs revealed that all the T1 states
1O2.
are generated by a HOMO - LUMO transition, see Fig. 4.
UDFT/COSMO geometry optimizations of these states revealed
true minima on the corresponding potential energy surfaces.
3.3 Computational studies
Herein, the results obtained by quantum chemical calculations The involved MOs are seen to be delocalized over the whole
are presented. First, the ground state geometrical properties molecular structure for each of the PAPs. The HOMO and
and stability of two different conformers of PAPs are LUMO orbitals of all the compounds are very similar, a single
discussed. In order to open the discussion about the physical difference in the shape of the HOMO orbital of the 3b
and chemical quenching of singlet oxygen by PAPs, the compound (Ar = 4-H3COC6H4) can be seen where there is no
electronic properties computed at the adiabatic T1 state density node at the carbonyl oxygen of the chalcone (both syn
minima and the local reactivity indexes computed at the and anti configurations). This would make a difference in the
ground state geometry are also analyzed. The cartesian energetic stability of the T1 state.
The respective DFT/MRCI adiabatic energies (∆
Ead) of the
coordinates of all the computed minima and the frontier
molecular orbitals (MOs) computed at the T1 states are
provided in the SI.
T1(πHπL*) states of 3a-e are listed in Table 2. The method
places the energy of all the T1 states above 2 eV and, as
expected, again the syn configuration of the PAPs show a
higher stability compared to the anti conformers (energies
shown in parenthesis in Table 2). Within the syn series, the
most stable T1 state corresponds to the 3b-syn compound
(2.05 eV) while the 3c-syn presents the highest energy
Ground state (S0) properties. The optimized ground state
minima of PAPs at the B3LYP-D3/TZVP + COSMO(ε = 24.852)
level are presented in Fig. 3. The geometries are found to be
almost planar respect to the pyrrole, propenone and aryl
groups; since the deviations from the planarity through these
groups do not exceed 1.6° degrees. For the 3d compound
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(2.24 eV). The adiabatic energy of the T1 state of the PAPs
tends to decrease by heavy atom effect when going from
Ar = 4-FC6H4 to 4-BrC6H4.
∂E
∂N




(3)
ꢀ
=
= −χ
r

v(r )
2



1 ∂ E
1 ∂
ꢀ



(4)
η
=
=


2 ∂N2
r
2 ∂N
r

v(r )

v(r )
In numerical applications, these reactivity indexes are
calculated following approximations using the Koopmans'
theory and finite differences leading to Eqs. 5 and 6. Here, I
and A correspond to the ionization energy and electron affinity
while E(
πH) and E(πH) correspond to the orbital energies of the
HOMO and LUMO, respectively.
1
1
(5)
(6)
ꢀ ≈ − (I + A) ≈ (E(πL ) + E(πH ))
Fig. 4 BHLYP Frontier MOs of some selected PAPs calculated at the
optimized B3LYPꢀD3/TZVP + COSMO (ε = 24.852) ground state
minima.
2
2
1
1
η ≈ (I − A) ≈ (E(πL ) − E(πH ))
2
2
An energy transfer process between singlet oxygen and a
quencher depends on many aspects as vibronic interactions,
short (e.g. overlap of the electron clouds) and long range (e.g.
The ω index as defined in Eq. 7 measures the propensity of
molecule to receive electronic charge from a donor.
a
Therefore, ω is thought as a sort of “electrophilicity power".
ꢀ2
antenna-type
dipole-dipole
interactions)
interactions.
(3)
Nevertheless, as a general rule, there should be a very low-
energy barrier for promoting a fast energy transfer. In this
framework, we analyze the energy differences between singlet
oxygen and the adiabatic T1 state of PAPs.
ω
=
2η
Table 3. Estimated energies for the HOMO and LUMO orbitals (E(πH) and
E(πH)), chemical potential (µ), chemical hardness (η), and electrophilicity (ω)
calculated for the optimized B3LYPꢀD3/TZVP + COSMO (ε = 24.852)
ground state minima of the PAPs
The observed decrease on the experimental rate constants
of quenching singlet oxygen from the 3a to 3d compounds
does not correlate well with the respective trend of the
adiabatic energies for the T1 states. Moreover, being the
reported energy for singlet oxygen of 0.98 eV,52 energy
transfer from singlet oxygen to the ground state of 3a-e to
produce their T1 states (>2 eV) constitutes a endoergic process.
These two facts announce that the physical quenching of
singlet oxygen from PAPs is not a feasible pathway. Therefore,
it is possible to suggest that the mechanism corresponds to
chemical quenching.
Comp. 3
3a-syn
3b-syn
3c-syn
3d-syn
3e-syn
E(πH)/eV
-6.38
E(πL)/eV
-2.46
ꢀ/eV
-4.42
-4.64
-4.41
-4.46
-4.47
η/eV
1.96
1.83
1.96
1.93
1.92
ω/eV
4.99
5.89
4.97
5.16
5.19
-6.47
-2.81
-6.37
-2.46
-6.39
-2.53
-6.39
-2.55
For this analysis, we restricted the discussion to the
lowest-energy syn conformers in the ground state. As can be
seen from the data collected in Table 2, µ adopts low and
similar values from compound 3a-syn to 3e-syn in
between -4.62 to -4.41 eV. That means, these PAPs tend to
react as source of electrons which enhance their antioxidant
Chemical reactivity indexes. In order to rationalize the
interaction of the PAPs with singlet oxygen through a chemical
quenching pathway, a set of local reactivity descriptors were
computed. In the framework of the conceptual Density
Functional Theory,53 here we have analyzed the estimated
activity. While the values of µ and
η diminishes as kQ for
chemical potential
(
µ
), chemical hardness
(η), and
electrophilicity (ω).54-57These set of values are reported in
Table 3. Moreover, the HOMO and LUMO orbitals essential for
these computations are presented in Fig. 4. Accordingly we
have tried to correlate the measured kQ values with these
global properties.
compounds 3c-syn to 3e-syn, ω does inversely correlate. This
means that the increase of the power of the EWDs by -F, -Cl
and -Br in the 3c-syn to 3e-syn is reasonable with respect to
the impact of the global reactivity/polarization indexes
indicating the presence of a charge transfer interaction with
singlet oxygen in which the PAPs are the electron donors.
These results confirm the nature of the quenchers. However,
these trends are not well satisfied in the same manner for
compounds 3a-syn and 3b-syn with respect the observed
variations the chemical reactivity indexes for compounds
3c-syn to 3e-syn, when addressing to the tendency of decay on
kQ. The compound 3a-syn shows almost equal values than for
The µ in Eq. 3 represents the infinitesimal change of energy
when electronic charge is added to a molecular system at a
r
constant external potential of the nuclei (
), fact closely
v(r )
related with its electronegativity (χ
derivative of the chemical potential, one arrives at
). Using a second order
(Eq. 4)
η
and measures how the electronegativity of a system decreases
when an infinitesimal amount of electronic charge is added
into it.
3c-syn of the µ,
magnitudes are the smallest of the series for µ and η, and the
highest for the index. As all the kQ determined
η and ω indexes. While, for 3b-syn these
ω
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experimentally are of the same order of magnitude
107 M-1s-1), in consequence, it is possible to conclude that
4. Conclusions
(
∼
In this work, we synthesized five new derivatives from (E)-1-
(1H-pyrrol-2-yl)-3-arylprop-2-en-1-one (PAPs); compounds
3(a-e). The structural differences within the series is the p-
substitution of the aryl group, where Ar = -C6H5, 4-H3COC6H4,
4-FC6H4, 4-ClC6H4, 4-BrC6H4 respectively from 3a to 3e. The
because of this fact, the reactivity indexes display a similar
description for the systems.
In order to clarify the dependency of the reactivity with
singlet oxygen on the electron density among the PAPs, we
had also analyzed the charge transfer properties and the
condensed fukui functions. In Fig. 5, we included the
wavefunctions for electrophilic (f-) and nucleophilic (f+) attacks.
Considering that singlet oxygen may attack sites with high
electron density, the double bond of PAPs would be the
preferable reaction pathway for the chemical quenching.
These results are consistent with the known reactivity of
singlet oxygen with unsaturated fatty acids (and flavonoids)
1
synthesis of the compounds was confirmed by FT-IR. H-NMR,
13C-NMR, MS. Moreover, the electronic and geometrical
properties of these new chalcones were characterized by
quantum chemical calculations.
Through Stern–Volmer plots and steady-state kinetical
analysis, the antioxidant capacity of the PAPs against singlet
oxygen has been evaluated. The large values of the rate
constants demonstrated that these novel compounds could
inhibit the rubrene oxidation by efficiently quenching of singlet
oxygen. The best quencher is the compound 3a (where the aryl
group is unsubstituted) with a total singlet oxygen quenching
rate constant (kQ) value of 5.71 (±0.21) x107 M-1 s-1 in ethanolic
solution. Through the heavy atom effects evaluated from
compounds 3a to 3e, a smooth decay on kQ values has been
observed although preserving the order of magnitude. This
kinetic study, therefore, suggests the applicability and
evaluation of these compounds as singlet oxygen quenchers in
biological systems promoting protection from oxidative
damage.
where the reaction could involve the formation of
a
hydroperoxide intermediate through an ene-like attack or via a
[2+2] concerted-cycloaddition to form an endoperoxide. Other
centers where singlet oxygen may attack can be seen in Fig. 5,
where is visible that the presence of the voluminous -OCH3
group and the heavy atoms smoothly changes the local
electronic properties of the PAPs, and therefore their
particular way to react. Therefore, the reactivity will depend
on the interactions occurring in the encounter complex formed
of PAPs with singlet oxygen where the fukui wavefunctions
also show a strong amplitude at the pyrrole group.
Acknowledgements
The authors thank to COLCIENCIAS for financial support
through contract No 0622-2013 of "Proyectos de semilleros de
investigación" (Conv. 617/2013) and FONDECYT (11140563).
A.R.-S. thanks Prof. Jörg Tatchen for helpful discussions. X.Z.
thanks Fondo de Apoyo a Asistencia a Eventos Científicos
Nacionales o Internacionales, Dirección de Investigación y
Postgrado, Universidad Autónoma de Chile.
Fig. 5 Condensed fukui functions for nucleophilic (f+) and electrophilic
(f ꢀ) attacks for compounds 3a-c.
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bimolecular situation. A more deep understanding of the
reaction would include by a detailed exploration of the
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intermediates to yield the reaction products by different
pathways. We are looking forward to open this discussion soon
in a study under development.
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