Hydroxypyridinechromene and pyridinechalcone: Two coupled photochrom systems

Article abstract of DOI:10.1002/chem.200901884

Substitution of the phenyl group in 2-hydroxychalcones by a 4-pyridine unit dramatically changes the network of chemical reactions of this compound: trans-chalcone-type(Ct), d.v-chalcone-type (C_c), and a hemiketal (hydroxy-4-pyridinechromene) (B) and their protonated forms are formed, but the presence of a flavylium-type cation could not be detected even at very acidic pH values. Moreover, whereas in 2-phenyl-2-benzopyryli urn compounds B and Cc are generally elusive species whose kinetic processes in aqueous solutions occur on the sub-second time-scale, in the present compound these species equilibrate on a timescale four orders of magnitude lower. Complete characterization of the equilibrium and kinetics of the reaction network could thus be achieved by ¹H NMR spectros- copy and UV/Vis spectrophotometry. The network of chemical reactions exhibits cis-tmns photoisomerization, as well as photochromism between the hemiketal and the chalcone-type spe-cies. The irradiation of Ct in MeOH/ H₂O (1:1) at 365 nm produces B almost quantitatively through two consecutive photochemical reactions: Ct→C _c pho-toisomerization followed by Cc→ B photo ring closure with a global quan-tum yield of 0.02. On the other hand, irradiation of B at 254 nm leads to a photostationary state composed by 80% Ct and 20% B, with a quantum yield of 0.21.

Full text of DOI:10.1002/chem.200901884

FULL PAPER
DOI: 10.1002/chem.200901884
Hydroxypyridinechromene and Pyri
ACHTUNGTRENdNUNG inechalcone:
Two Coupled Photochromic Systems
Yoann Leydet, A. Jorge Parola,* and Fernando Pina*[a]
Abstract: Substitution of the phenyl
utions occur on the sub-second time-
scale, in the present compound these
species equilibrate on a timescale four
orders of magnitude lower. Complete
characterization of the equilibrium and
kinetics of the reaction network could
thus be achieved by H NMR spectros-
copy and UV/Vis spectrophotometry.
The network of chemical reactions ex-
hibits cis–trans photoisomerization, as
group in 2-hydroxychalcones by a 4-
pyridine unit dramatically changes the
network of chemical reactions of this
compound: trans-chalcone-type (Ct),
cis-chalcone-type (Cc), and a hemiketal
(hydroxy-4-pyridinechromene) (B) and
their protonated forms are formed, but
the presence of a flavylium-type cation
could not be detected even at very
acidic pH values. Moreover, whereas in
2-phenyl-2-benzopyrylium compounds
B and Cc are generally elusive species
whose kinetic processes in aqueous sol-
well as photochromism between the
hemiketal and the chalcone-type spe-
cies. The irradiation of Ct in MeOH/
H2O (1:1) at 365 nm produces B almost
quantitatively through two consecutive
photochemical reactions: Ct!Cc pho-
toisomerization followed by Cc!B
photo ring closure with a global quan-
tum yield of 0.02. On the other hand,
irradiation of B at 254 nm leads to a
photostationary state composed by
80% Ct and 20% B, with a quantum
yield of 0.21.
1
Keywords: chromenes · isomeriza-
tion · multistate systems · photo-
chromism · tautomerism
Introduction
such as benzo- and naphthopyrans bearing alkyl, oxoalkyl,
or aromatic substituents, spiropyrans, and spirooxazines, is
able to perform coloration/decoloration cycles with an effi-
ciency close to unity and with a strong resistance to photo-
degradation.[2] Kinetics of coloration and/or decoloration
can be also tuned through choice of substituents, which
allows one to envisage the use of chromenes for many appli-
cations such as the development of optical variable trans-
mission materials and optical switches and memories.[4]
It is worth noting that chromenes appear in the network
of chemical reactions taking place in 2-phenyl-1-benzopyry-
lium derivatives (flavylium salts) that possess the same basic
structure of anthocyanins, the ubiquitous colorants responsi-
ble for most of the red and blue colors of flowers and
fruits.[5] In particular, hydroxyphenylchromenes appear as
transient hemiketal species during the thermal conversion
(pH jump) between flavylium cations and trans-chalcones as
well as during the appearance of the flavylium cation/qui-
Chromenes constitute one of the major classes of naturally
occurring compounds and prove to be particularly attractive
in medical sciences[1] as well as in chemistry due to their par-
ticular photochromism based on electrocyclic ring-opening
[2]
ꢀ
at the pyran C O bond. The photochromism of chromenes
was extensively studied and the mechanism established by
Becker and co-workers.[3] These authors showed that these
molecules, upon UV irradiation, yield open metastable pho-
toproduct(s) with the structure of o-quinone allides, which
are generally colored due to increased electronic delocaliza-
tion. The photoproducts can recover thermally and/or pho-
tochemically to the starting material. This family of photo-
chromic compounds, which covers a variety of structures
[a] Dr. Y. Leydet, Dr. A. J. Parola, Prof. F. Pina
Departamento de Quꢀmica, REQUIMTE
Faculdade de CiÞncias e Tecnologia
Universidade Nova de Lisboa (Portugal)
Fax : (+35)121-294-8550
noidal
base
upon
irradiation
of
trans-chalcone
(Scheme 1).[6,7]
The network of chemical reactions occurring in flavylium
compounds is shown in Scheme 1. The equilibrium species
at sufficiently acidic pH values is the flavylium cation AH+.
When the pH is raised, the flavylium cation undergoes hy-
dration to give the hemiketal B (chromene). The cis-chal-
E-mail: fjp@dq.fct.unl.pt
ajp@dq.fct.unl.pt
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200901884.
Chem. Eur. J. 2010, 16, 545 – 555
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
545

the last author, only scarce experimental evidence was given
to prove the existence of B (or Cc) as photoproducts. On
the other hand, irradiation of Cc or B could give back the
Ct species. In aqueous media, the B and Cc species are gen-
erally in fast equilibrium, and it is not possible to exclude
excitation of Cc while irradiating B due to the superposition
of their absorption spectra. In other words, no strong evi-
dence for the selective irradiation of the hemiketal B was
reported in those works.
Taking into account the reaction network in Scheme 1,
the introduction of positively charged groups in the 2-hy-
droxychalcone skeleton may avoid formation of the flavyli-
um cation at acidic pH, thereby promoting the stability of
the hemiketal/chromene species over a large pH range. Sub-
stitution of the phenyl attached to the carbonyl group of the
chalcone by a pyridine could in principle lead to this desid-
eratum.
In this paper, we report on the synthesis, thermodynamics,
kinetics, and photochemistry of a new pyridinechalcone
compound in which the phenyl group has been substituted
by a 4-pyridine moiety. The reaction network of this com-
pound includes Ct-, Cc-, and B-type compounds (and their
protonated forms) and excludes formation of the flavylium-
type cation, even at very acidic pH values.
Scheme 1. Hydroxyphenylchromene (hemiketal, B) as part of the net-
work of chemical reactions involving 2-phenyl-1-benzopyrylium
ACHTUNGTRENNUNGcompounds.
cone (Cc) is formed from B by a tautomeric ring-opening
process and the trans-chalcone (Ct) by isomerization of the
former. The system can proceed forward and backward by
the action of the pH and light.[8]
The reactions occurring in Scheme 1 can be accounted for
by means of the following set of equations [Eqs. (1), (2), and
(3)]:
Results and Discussion
AHþþ2 H2O Ð BþH3Oþ Kh
B Ð Cc Kt
ð1Þ
ð2Þ
ð3Þ
Thermodynamic equilibrium: Compound 1 was synthesized
by condensation of salicylaldehyde with 4-acetylpyridine
under basic conditions (ethanol/KOH). The absorption spec-
tra of a freshly prepared solution of 1 in MeOH/H2O (1:1)
upon pH jumps that cover the full pH range are represented
in Figure 1. Figure 1A and B depict the spectra immediately
after each pH jump, and Figure 1C and D are at the equilib-
rium.
The absorption spectra reported in Figure 1A and B show
the existence of two different sets of isosbestic points, which
can be attributed to the several acidic and basic species of 1,
hereafter designated as trans-chalcones Ct+, Ct, and Ctꢀ, as
Cc Ð Ct Ki
Equations (1) to (3) can be substituted by a single acid–base
equilibrium,[8] as shown by Equation (4):
AHþþ2 H2O Ð CBþH3Oþ Ka0
ð4Þ
in which [CB]=[B]+[Cc]+[Ct] and K0a =Kh+KhKt+KhKtKi.
According to the nature of the substituents in the flavyli-
um backbone, the mole fraction distribution of the conjugat-
ed base CB can be constituted by 1) almost 100% of Ct
when hydroxy[8] or amino[9] substituents are present in posi-
tions 7 and/or 4’; 2) a majority of B in 3-substituted flavyli-
um compounds,[10] as in anthocyanins (ca. 68% in malvidin
diglucoside),[11] or 3) exclusively A in the case of 4-methyl-
flavylium compounds bearing hydroxyl substituents.[12]
In previous papers, the photochemistry of the trans–cis
isomerization of 2-hydroxychalcones was extensively studied
by our group[8,9,13] and other authors.[14–16] Irradiation of the
trans-chalcone in pure aqueous solutions or in water/organic
solvent mixtures leads to Cc and/or B that rapidly form a
flavylium cation or quinoidal base depending on pH. In or-
ganic solvents, irradiation of the trans-chalcone (Ct) leads to
Cc and/or B, as suggested by the groups of Czerney,[15] Mat-
sushima,[14g] and Hiratsuka,[17] even if, with the exception of
shown in Scheme 2. The first set regards the protonation of
þ
the pyridine (Figure 1A, pKCa t =3.2) and the second one the
deprotonation of the phenol (Figure 1B, pKCa t =8.9). The
first pKa value is comparable to 3.6 for 4-acetylpyridine,[18]
and the second one is in accordance with the usually ob-
served pKa values in similar 2-hydroxychalcones, in which
the pyridine is substituted for phenyl.[9b,19] Whereas the ab-
sorption spectra in the neutral and basic regions do not
evolve significantly with time, as evidenced by comparing
Figure 1B and D, in acidic media the solutions present com-
pletely different spectra over time, as shown in Figure 1A
and C. This means that although Ct and Ctꢀ are the clearly
predominant equilibrium species in the neutral and basic re-
gions, in the acidic region Ct+ evolves to other species.
The spectral variations in the acidic region are not com-
patible with flavylium-type cation formation since the char-
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Chem. Eur. J. 2010, 16, 545 – 555

Hydroxypyridinechromene and Pyridinechalcone
FULL PAPER
values of the systems by 2–3 pH
units.[20,21] The kinetics of the
disappearance of protonated
trans-chalcone Ct+ in an acidic
medium is very slow and ap-
proximately 48 h are needed to
reach a complete equilibration
at room temperature ((295ꢁ
1) K), which is in agreement
with the existence of a cis–trans
isomerization barrier.[22]
To fully characterize the spe-
cies involved in the network,
1H NMR spectroscopic studies
were performed at different pD
values. Figure 2 shows the
NMR spectra as a function of
pD for freshly prepared solu-
tions and for the same solutions
upon thermal equilibration in
the dark (full assignment of
peaks is presented in Table S1
in the Supporting Information).
The 1H NMR spectrum of
freshly prepared (CD3OD/D2O
1:1) neutral solution of com-
pound 1 is shown in Figure 2c.
The trans-chalcone Ct was un-
equivocally identified by the
Figure 1. Absorption spectra of freshly prepared 1 in methanol/water (1:1) as a function of pH, immediately
after pH jumps to the A) acidic and B) basic regions, and after thermal equilibration in the dark (2 d, (295ꢁ
1) K), C and D, acid and basic regions, respectively.
Scheme 2. Acid–base species of compound 1 and their respective pKa
values.
acteristic absorption band of AH+, always redshifted rela-
tively to Ct, is not observed in the visible region of the spec-
tra. According to 1H NMR spectroscopy (see below), the
mole fraction distribution at the equilibrium at pH 0.3 is a
mixture of Ct+ (37%) and approximately equal amounts of
protonated cis-chalcone (Cc+) and hemiketal (B+), approxi-
mately 31.5% of each one.
Figure 2. 1H NMR spectra (400 MHz, 300 K) of 1 in D2O/CD3OD 1:1 at
different pD values, immediately after dissolution (traces, a, c, and e) and
+
upon thermal equilibration in the dark (traces b and d); Ct+
(
*
); B
+
&
*
(
); Cc ( ).
The lack of flavylium cation can be explained by the pro-
tonation of the pyridine at pH values where formation of
the flavylium cation would be expected.[6–8] The positive
charge in the pyridinium moiety prevents the formation of a
2+ charged species due to the intramolecular electrostatic
repulsion. This result is in agreement with the behavior of 2-
phenyl-1-benzopyrylium systems in cetyltrimethylammoni-
um bromide (CTAB) micelles, in which the positively
charged surface of the micelle renders the formation of the
flavylium cation more difficult, thereby lowering the pKa0
coupling constant between protons H3 and H4 (3J
ACTHNUTRGNEU(GN H3,H4)=
16.0 Hz). Upon thermal equilibration (ca. 2 days at (295ꢁ
1) K), the spectrum in Figure 2d shows that two new species
were formed in very low extension, most probably Cc and
B. Dissolution of compound 1 under basic conditions
(CD3OD/D2O 1:1, NaOD; pD=12.0) leads to a high-field
shift of the spectrum relative to the neutral solution (Fig-
ure 2e) with a concomitant change in color from light yellow
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547

Y. Leydet, A. J. Parola, and F. Pina
to orange. These changes indicate the formation of Ctꢀ, con-
The NMR spectroscopic data in Figure 3 presents three
plateaus between pD=3.5 and pD=6 that allow one to cal-
culate Ki =8.0 and Kt =1.0. Similarly, for pD<1, three other
plateaus arise and yield Ki+ =1.2 and Kt+ =1.0. In combin-
ing these data with the two pKa values of Ct obtained by
UV/Vis spectrophotometry (Figure 1A and B), the following
reaction network and respective equilibrium constants for
the acid-neutral region can be drawn (Scheme 3).
firmed also by the persistent large value of the coupling con-
3
stant of the protons on the C=C double bond, J
N
15.9 Hz. The spectra of the Ctꢀ species evolves only slightly
with time and apparently originates two new species in low
extension (<5%; not shown).
When the neutral light yellow solution of freshly prepared
Ct is subjected to a pD jump to pD=0.3, the yellow colora-
1
tion increases. The H NMR spectrum registered immediate-
ly after addition of a drop of concentrated DCl (Figure 2a)
shows the existence of a sole species with peaks shifted to
low field, which is compatible with the formation of proton-
ated trans-chalcone Ct+, as confirmed by the coupling con-
stant around the C=C double bond (3J
ACTHNUTRGNE(NUG H3,H4)=15.8 Hz;
Table S1 in the Supporting Information). The large changes
in the chemical shifts of the pyridine protons (Table S1) rel-
ative to the others are one piece of evidence for the proto-
nation of the pyridine nitrogen. Contrary to what was ob-
served under neutral and basic conditions, in acidic media
the spectrum of Ct+ largely evolves in time with the appear-
ance of two new species in almost equal amounts (Fig-
ure 2b) with a concomitant change in color to light yellow.
These results are consistent with the formation of Cc+, fol-
lowed by a tautomerization (ring opening) that leads to the
protonated hemiketal (hydroxy-4-pyridinechromene) B+, as
confirmed by 1H and 13C NMR spectroscopy (see below).
No AH+ could be detected under acidic conditions, even at
pH<ꢀ1 (concd H2SO4).
Scheme 3. Thermodynamic equilibria present in methanolic aqueous sol-
utions (1:1) of compound 1. The pKa values for Ct were obtained from
þ
þ
þ
þ
Figure 1A and B; pKCa c was obtained through KCa c =KaCt Ki+/Ki; pKBa
þ
þ
was obtained through KBa =KaCc Kt+/Kt; the other equilibrium constants
were obtained from the NMR spectroscopic data in Figure 3.
On the basis of Scheme 3, the total concentration of com-
pound 1 is given by Equation (5):
The spectra of thermally equilibrated solutions in the
dark registered in the acidic region show three sets of peaks
corresponding to B/B+, Cc/Cc+, and Ct/Ct+ (the acid–base
pairs are in fast equilibrium on the NMR spectroscopic
timescale), as can be seen in the traces of Figure 2b and d.
Experiments run at several intermediate pH values (Fig-
ure S1 in the Supporting Information) corroborate these
data and allow one to obtain the distribution of the three
acid–base conjugate pairs present in equilibrated solutions
in the acidic pH region (Figure 3).
C0 ¼ ½Ctþꢂþ½Ccþꢂþ½Bþꢂþ½Ctꢂþ½Ccꢂþ½Bꢂþ½Ctꢀꢂþ½Ccꢀꢂ
ð5Þ
By using Equation (5), individual expressions for the mole
fraction of each species can be obtained as a function of
þ
proton concentration and the equilibrium constants KaCt
,
þ
þ
KCa c , KBa , KCa t, KaCc, Ki+, and Kt+ [Eqs. (S1)–(S9) in the Sup-
porting Information].
The absorption spectra in Figure 1C and D present clear
isosbestic points, which suggest that the overall system after
equilibration behaves with pH as a diprotic species. In sum-
ming up the mole fractions of the corresponding protonated
species, the expressions obtained are indeed compatible
with this interpretation [Eqs. (6), (7), and (8)]:
2
½Ctþꢂ þ ½Ccþꢂ þ ½Bþꢂ
½Hþꢂ
ð6Þ
ð7Þ
ð8Þ
¼
2
½Hþꢂ þKobs1½Hþꢂ þ Kobs1Kobs2
C0
2
½Ctꢂ þ ½Ccꢂ þ ½Bꢂ
Kobs1½Hþꢂ
¼
2
½Hþꢂ þKobs1½Hþꢂ þ Kobs1Kobs2
C0
½Ctꢀꢂ þ ½Ccꢀꢂ
Kobs1Kobs2
¼
2
½Hþꢂ þKobs1½Hþꢂ þ Kobs1Kobs2
C0
Figure 3. Distribution of the species constituting the reaction network of
compound 1 in the acidic region according to 1H NMR spectroscopic
data in Figure 2 (see also Figure S1 in the Supporting Information): nor-
+
+
with the following expressions for the observed acidity con-
stants [Eqs. (9) and (10)]:
*
malized areas of the peaks corresponding to Ct /Ct H3’5’ ( ); B /B H3
+
&
*
(
); Cc /Cc H3 ( ).
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Hydroxypyridinechromene and Pyridinechalcone
FULL PAPER
þ
þ
KBa þ KaCcþKtþ þ KaCt KtþKiþ
spectively). The spectrum of B was obtained upon irradia-
tion of Ct at 365 nm until the stationary state was reached
(it contains 100% B; see below), whereas that of Cc was ob-
tained from the same solution after thermal equilibration
ð9Þ
Kobs1
¼
¼
1 þ Ktþ þ KtþKiþ
KCa cKCa cþKtþ þ KaCtKCa t KtþKiþ
þ
ð10Þ
Kobs2
1
1 þ Ktþ þ KtþKiþ
and determining the composition by H NMR spectroscopy
(80% Ct+10% B+10% Cc). The two species are character-
ized by opposite maximum wavelength shifts relative to the
Ct band maximum. Whereas B shows a strong blueshift
(lmax =296 nm), the spectrum of Cc presents comparatively
a slight redshift (lmax =380 nm).
Theoretical calculations using ZINDO-S/CI (99 single ex-
cited configurations) on AM1-RHF-optimized geometries
confirmed the relative energies of the lowest-energy elec-
tronic transitions experimentally observed (Table S2 in the
Supporting Information). In the case of the B species, the
conjugation between the pyridine and the phenol ring is in-
terrupted after formation of the hemiketal middle ring, thus
explaining the observed blue shift. In the Cc species, three
minimum energy conformers could be found, two of them
with coplanarity of the conjugated system and a zwitterionic
and nonplanar conformer. In one of the planar conformers
(Figure 5,left), an intramolecular hydrogen bond between
With the exception of the acidity constants related to Cc+,
B+, and Cc, the thermodynamic constants intervening in
Equations (9) and (10) are known either from UV/Vis
þ
1
(KCa t ) or H NMR spectroscopy (Ki+, Ki, Kt+, Kt) experi-
þ
þ
ments. The acidity constants KCa c and KaB can be calculated
þ
þ
þ
þ
from KCa c =KCa t Ki+/Ki and KaB =KaCc Kt+/Kt, respectively,
and were included in Scheme 3. Assuming that KCa c is similar
to KCa t, as often observed in 2-hydroxychalcones,[21] and sub-
stituting all constants in Equations (9) and (10), pKobs1 =3.5
and pKobs2 =9.0 are obtained, which is in good agreement
with the values obtained experimentally in Figure 1C and D,
respectively.
It is worth noting that the composition at equilibrium
under acidic conditions in the reaction network of com-
pound 1 can be tuned by changing the solvent. Whereas in a
solvent mixture MeOH/H2O 1:1 the distribution of species
is the one represented in Figure 3, in pure acidic water only
Ct+ and B+ (45:55) can be detected as shown by H NMR
1
spectroscopy (Figure S2 in the Supporting Information).
The absorption spectra of all the species present in metha-
nolic aqueous solutions of compound 1 could be deduced by
combining UV/Vis and 1H NMR spectroscopic data
(Figure 4). The spectrum of Ct is dominated by a typical
chalcone transition in the near-UV region (lmax =362 nm).
Both the protonation of the pyridine and the deprotonation
of the phenol group lead to a redshift of lmax in agreement
with an increase of the charge delocalization in the struc-
tures of Ct+ and Ctꢀ (lmax =383 nm and lmax =455 nm, re-
Figure 5. Minimum-energy conformers of Cc (left) and Cc+ (right) opti-
mized using the AM1-RHF semiempirical method implemented in the
Hyperchem 7.5 package.[30]
the proton of the phenol and the oxygen of the carbonyl
group is formed, and the predicted lmax according to the mo-
lecular orbital calculations is redshifted relative to Ct
(Table S2). The other planar conformer (not shown), in
which the phenol ring is rotated 1808 relative to that in
Figure 5 (left), and the zwitterionic form (not shown) are
predicted to have nearly the same lmax as Ct. On this basis,
the fact that the Cc lmax is redshifted relative to that of Ct
(Figure 4) suggests that Cc may have a significant amount of
the hydrogen-bonded conformer in solution.
In MeOH/H2O 1:1 solvent mixtures, B+ and Cc+ could
not be isolated from each other due to the fast tautomeriza-
tion process under acidic conditions. However, a spectrum
of B+ was obtained in pure aqueous solution at pH 1.0
Figure 4. Absorption spectra of the several species originating from com-
pound 1 in H2O/CH3OH 1:1: pHꢃ1 for B+ (H2O), Cc+, and Ct+; pHꢃ6
for B, Cc, Ct; pHꢃ12 for Ctꢀ. The spectra were obtained in the follow-
ing way: Ct, Ctꢀ, Ct+ came from Figure 2A and B; B was obtained from
an irradiated solution of Ct; B+ was obtained upon thermal equilibration
of Ct in water at pH 1.0 (45% Ct++55% B+); Cc+ was obtained from
equilibrated solution at pHꢃ1 (37% Ct++31.5% B++31.5% Cc+), as-
suming that the spectrum of B+ does not change significantly on going
from H2O to H2O/CH3OH 1:1; Cc was obtained from irradiated solutions
of Ct upon thermal recovery (80% Ct+10% B+10% Cc).
1
where no Cc+ is observed, as confirmed by H NMR spec-
troscopy (Figure S2 in the Supporting Information). Assum-
ing that the spectrum of B+ does not change significantly on
going from acidic water to acidic methanolic aqueous solu-
tions (in which B+ exists in equilibrium with Cc+; Fig-
ure 2b), the spectrum of Cc+ could be deduced. Contrary to
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549

Y. Leydet, A. J. Parola, and F. Pina
the Ct+/Ct pair in which Ct+ is redshifted relative to Ct, the
lmax of Cc+ (305 nm) is strongly blueshifted relative to Cc.
Indeed, theoretical calculations showed that the protonation
of the pyridine disrupts the intramolecular hydrogen bond
in a conformation that is no longer planar (Figure 5,right).
This interruption in the conjugation between the pyridine
and the phenol rings is compatible with the observed blue-
shift (Table S2). The spectrum of B+ showed no significant
shift after the protonation of pyridine in B, which is in
agreement with the exclusion of the pyridine ring from con-
jugation as already observed with B.
On the basis of the kinetics in Scheme 4, Equations (11),
(12), and (13) were used in the fitting:
d½Bꢂ
ð11Þ
ð12Þ
ð13Þ
¼ ꢀkt½Bꢂ þ kꢀt½Ccꢂ
dt
d½Ccꢂ
¼ ꢀðkꢀt þ kiÞ½Ccꢂ þ kt½Bꢂ þ kꢀi½Ctꢂ
¼ ꢀkꢀi½Ctꢂ þ kt½Ctꢂ
dt
d½Ctꢂ
dt
Kinetic studies: Thermally equilibrated solutions of Ct at
neutral pH in MeOH/H2O 1:1 contain only a small propor-
tion of Cc and B (see Figure 2d), thus rendering a kinetic
study of the reaction difficult. However, irradiated solutions
of Ct in the same conditions lead to approximately 100% B
(see below), thereby allowing the thermal recovery kinetics
study of the irradiated solutions.
The kinetics in Figure 6 (right) are nicely fitted with the
equations derived from Scheme 4, thus showing the exis-
tence of an intermediate assigned to Cc (see the NMR spec-
troscopic data below). Also the plateaus observed upon
equilibration yield constants (Kt =1.1, Ki =8.6, 308 K) that
are in relatively good agreement with the ones obtained
from thermal evolution starting from Ct (Kt =1.0, Ki =8.0,
300 K). The mechanism of formation of Ct from B in
Scheme 4 is in accordance with the one usually observed for
several related 2-hydroxychalcones.[8] However, in 2-hydrox-
ychalcones, the Cc is often an elusive compound; it exists in
fast equilibrium with the hemiketal B, with rate constants on
the sub-second timescale. Figure 6 (right) clearly shows that
in compound 1, B and Cc equilibrate on a much longer
timescale, approximately four orders of magnitude slower.
To explain this difference in the tautomerization rates be-
tween Cc and B derived from 2-phenyl- and from 2-(4’-pyri-
dine)-1-benzopyrylium, the formal charges were calculated
(AM1-RHF level, Figure S4 and Table S4 in the Supporting
Information). The Cc derived from 1 shows a charge density
at the phenolic oxygen considerably lower than the charge
at the same atom in the parent compound (ꢀ0.250 vs.
ꢀ0.364). This lower charge reflects the lower nucleophilicity
of the oxygen. At the same time, the Cc derived from com-
pound 1 shows a slightly lower positive charge (lower elec-
trophilicity) at the carbonyl carbon where the nucleophilic
ring-closure reaction occurs (+0.319 vs. +0.342). Thus, a
slower ring closure is expected for the Cc derived from com-
pound 1, as experimentally observed.
In the case of B derived from compound 1, in which the s
bond is already formed and has to be broken to lead to Cc,
the charge densities (at the same oxygen and carbon atoms)
reflect the ionic contribution for the bond energy or the re-
combination efficiency after bond breaking (aborting Cc for-
mation). In this case, the charge densities at O9 and C2 are
larger in the case of B derived from compound 1, which is
expected to lower the efficiency of Cc formation as experi-
mentally observed.
It is known that the hemiketal/cis-chalcone tautomeriza-
tion equilibrium in flavylium derivatives is catalyzed by
acids.[7,13] The addition of a drop of concentrated acid to an
irradiated solution of Ct containing approximately 100% B
shows the immediate formation of protonated Cc+ and B+
species, thereby underlining a huge difference between the
kinetic rate constants for tautomerization under acidic and
To distinguish between B and Cc, the thermal evolution
1
after irradiation was followed by H NMR spectroscopy at
four different temperatures. As an example, the results for
T=308 K are presented in Figure 6 (see Figure S3 in the
Figure 6. Left) Kinetics of the thermal recovery at 308 K of irradiated sol-
utions of compound 1 at neutral pD in CD3OD/D2O 1:1, followed by
1
*
^
600 MHz H NMR spectroscopy: Ct H4 ( ); B H3 (&); Cc H3 ( ).
Right) The data was fitted by loading Equations (11), (12), and (13) into
Berkeley Madonna Software,[23] imposing the constraints Kt =kt/kꢀt and
Ki =ki/kꢀi, and using the values from the plateaus to calculate Kt and Ki.
Supporting Information for complete data). The 1H NMR
spectroscopic peaks in Figure 6 (left) were integrated and
normalized to deduce the mole fraction for each species
(Figure 6,right). Individual kinetic rate constants could then
be obtained by fitting the mole fractions with the Berkeley
Madonna Software[23] and considering Cc as an intermediate
species between B and Ct (Scheme 4).
Scheme 4. Kinetic scheme for the thermal recovery of irradiated solutions
of 1 in neutral media.
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Chem. Eur. J. 2010, 16, 545 – 555

Hydroxypyridinechromene and Pyridinechalcone
FULL PAPER
neutral conditions (Figure S5 in the Supporting Informa-
tion).
ACHTUNGTRENNUNG
¼
cesses are characterized by low activation entropies (DS ).
The kinetic constants obtained for the direct and reverse
tautomerization and cis–trans isomerization reactions at dif-
ferent temperatures were plotted using the Eyring equation
(Figure 7) to deduce the respective thermodynamic activa-
In spite of the fact that B has a closed structure and Cc an
open one, the most stable conformation of Cc is not expect-
ed to differ much from the structure of B; Cc is almost pre-
organized for ring closure. A search for lowest energy con-
formers (see above) yields a structure for Cc showing an in-
tramolecular hydrogen bond between the carbonyl group
and the phenolic hydrogen, a structure even more similar to
that of B, thereby corroborating the similarity of the experi-
¼
¼
¼
tion parameters (DH , DS , and DG ; Table 1).
¼
mentally observed values for DS for B!Cc and Cc!B.
Regarding the isomerization reaction, strongly negative
activation entropies are observed for both processes, thereby
indicating a transition state with a more constrained struc-
ture than those of Cc and Ct. More striking is the fact that
¼
negative activation enthalpies (DH ) are also observed for
both processes. Negative temperature effects on reaction
rates have been rationalized by the postulate of an inter-
mediate in a pre-equilibrium situation or in elementary re-
actions when very negative activation entropies are ob-
served.[24] In the present case, both situations can be
evoked: in the former hypothesis, a tautomer formed from
Cc or Ct could be involved as an intermediate, and similar
2-hydroxychalcones are known to have tautomers;[25] the
latter hypothesis applies directly in the face of the strongly
negative activation entropies observed.
The overall thermodynamic and kinetic data obtained for
compound 1 are summarized in Scheme 5.
*
*
Figure 7. Eyring plots for the direct (kt, , c) and reverse (kꢀt
,
, b)
&
tautomerization (top) and for cis–trans (ki, , c) and trans–cis (kꢀi, &,
b) isomerization reactions of 1 (bottom).
Scheme 5. Thermodynamic diagram and kinetic constants for the reaction
network of compound 1 in acidic and neutral conditions.
Table 1. Thermodynamic activation parameters for the direct and reverse
tautomerization and isomerization reactions of 1.
B!Cc
109.9
35.2
99.3
Cc!B
108.0
30.7
98.8
Cc!Ct
ꢀ131.8
ꢀ695.6
76.9
Ct!Cc
ꢀ148.8
ꢀ768.7
81.8
Photochemistry: Irradiation of compound 1 (MeOH/H2O
1:1, pH 6.0) was carried out at 365 nm, near the lmax of Ct
(Figure 8A). The spectral variations are compatible with the
disappearance of Ct and concomitant formation of B or Cc,
or both, with a quantum yield (F) of 0.02. Irradiation at
254 nm of the previous photostationary state (obtained upon
irradiation at 365 nm) leads to the recovery of Ct up to
around 80% with a quantum yield of F=0.21 (Figure 8B).
Under acidic conditions (MeOH/H2O 1:1, pH 1.0), in which
equilibrated solutions of compound 1 contain approximately
one third of each protonated species (Ct+, Cc+, and B+), ir-
radiation at 254 nm gives rise to spectral modifications
showing that Ct+ is formed from B+ and/or Cc+ (Fig-
ure 8C).
¼
DH [kJmolꢀ1
]
¼
DS [JKꢀ1 molꢀ1
]
¼
DG [kJmolꢀ1] (300 K)
¼
The similarity of the free energies of activation, DG , for
the ring-opening (B!Cc) and for the ring-closure (Cc!B)
processes reflect the same order of magnitude of the kt and
kꢀt rate constants, respectively 8.6ꢂ10ꢀ5 and 7.5ꢂ10ꢀ5 sꢀ1
¼
(308 K). On the other hand, the lower value of DG for the
cis–trans relative to the trans–cis isomerization reflects the
relation ki =3.9ꢂ10ꢀ2 sꢀ1 >kꢀi =4.5ꢂ10ꢀ3 sꢀ1 (308 K). The
¼
equilibrium constants at 300 K calculated from DGꢄt =DG
¼
¼
¼
A
N
A
A
On the other hand, in pure aqueous solution at pH 1.0,
where only Ct+ (45%) and B+ (55%) are present, the for-
Chem. Eur. J. 2010, 16, 545 – 555
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
551

Y. Leydet, A. J. Parola, and F. Pina
reaching the photostationary
state are presented in Figure 10
(for full 13C assignments, see
Tables S5 and S6 in the Sup-
porting Information). Two sets
of resonances are present and
are attributed to the photoprod-
uct and to some (thermal) re-
covery of Ct during the time of
the experiment. Strong differ-
ences between the two products
can be observed. In particular,
the large difference in chemical
shifts in carbon atoms C2 (d=
192.8 ppm in Ct vs. 95.7 ppm in
the photoproduct) and C4 (d=
141.1 vs. 125.3 ppm) are not
compatible with the presence of
a carbonyl group in the photo-
product, thus proving that it
must be assigned to the hemi-
ketal
B and that no Cc is
formed. Exclusive formation of
a hemiketal upon irradiation of
some trans-2-hydroxychalcones
was claimed by Hiratsuka et al.
on the basis of UV/Vis absorp-
tion and 1H NMR spectra, but
no conclusive 13C NMR spectro-
scopic data was presented.[17]
The lack of Cc upon irradiation
Figure 8. Continuous irradiation of compound 1 (1.0ꢂ10ꢀ4 m in MeOH/H2O 1:1). A) Irradiation of a fresh solu-
tion at pH 6.0 (100% Ct), lirr =365 nm. B) Irradiation of the solution obtained in A at lirr =254 nm. C) Irradia-
tion of an equilibrated solution at pH 1.0 (37% Ct+, 31.5% Cc+, 31.5% B+), lirr =254 nm. D) Irradiation of
an equilibrated aqueous solution of 1 at pH 1.0 (45% Ct+, 55% B+), lirr =254 nm in water.
mation of Ct+ upon irradiation of B+ at 254 nm gives a
direct evidence of the photochromism of the protonated
chromene (Figure 8D). The presence of an isosbestic point
(l=260 nm) shows that Cc+ does not appear during irradia-
tion. In the basic region, no significant spectral variations
were observed upon one hour of irradiation at 365 nm,
thereby showing that the Ctꢀ species is photochemically in-
active.
To characterize the species that are formed upon irradia-
tion of neutral solutions of 1 (CD3OD/D2O 1:1) at 365 nm,
1H NMR spectra were run before, during, and after reaching
the photostationary state (traces a, b, and c in Figure 9, re-
Figure 9. 1H NMR spectra (400 MHz, a–c; 600 MHz, d; 300 K) of 1 in
D2O/CD3OD 1:1 at a) neutral solution, pDꢃ6.0, before irradiation
(100% Ct); b) in the course of irradiating at 365 nm; c) after reaching
the photostationary state upon irradiation at 365 nm (ꢃ100% B);
d) after thermal equilibration of the irradiated solution in (c).
spectively). The trans-chalcone Ct was converted in one
unique product characterized by a lower coupling constant
between protons H3 and H4 (3J
ACTHNUTRGNE(UNG H3,H4)=9.8 vs. 16.0 Hz for
Ct). No other species were observed during the irradiation,
1
or at the photostationary state. The rather close H chemical
shifts of Cc and B (e.g., d=5.83 vs. 5.88 ppm for H3;
Table S1 in the Supporting Information) do not allow one to
conclude which of them is the observed photochemical
product. However, the 13C chemical shift of the carbonyl
found in Cc and that of the carbon in the hemiketal group
of B are expected to be quite different.[26] Heteronuclear
multiple-bond correlation (HMBC) spectra registered after
of Ct can only be explained if an efficient photochemical
step converts Cc into B (photo ring closure), since the ther-
mal conversion of Cc into B is very slow when the phenyl
ring is substituted by pyridine, as seen above.
The thermal recovery of the irradiated solution (ca. 100%
1
B; Figure 9c) was followed by H NMR spectroscopy with
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Chem. Eur. J. 2010, 16, 545 – 555

Hydroxypyridinechromene and Pyridinechalcone
FULL PAPER
photometry. In the first case, by the reason reported above
(fast enolization), and in the second one by an efficient Cc
to Ct photoisomerization. A similar behavior was reported
for 4’-methoxyflavylium for which FCt–Cc =0.04 and FCc–Ct
=
0.5.[27b]
In acidic media (MeOH/H2O 1:1), the irradiation of an
equilibrated mixture of compound 1 (lirr =254 nm, pH 1.0,
37% Ct+, 31.5% Cc+, 31.5% B+) produces a photostation-
ary state in which Ct+ is the predominant species, a result
qualitatively similar to the one obtained at neutral pH
values (Figure 8C). In water, at pH 1.0, a similar situation
was observed (Figure 8D).
Conclusion
The insertion of a pyridine group in the 2-hydroxychalcone
structure considerably modifies the chemical reaction net-
work, excluding the formation of the flavylium ion and
showing B+ and Cc+ as the stable species in very acid
media. All the species of the network have been character-
Figure 10. HMBC spectra (600 MHz, 300 K) of 1 in D2O/CD3OD 1:1, pD
ꢃ6 before (red) and after irradiation at 365 nm (blue). In the black box
are the correlations between C2 and H3’+H5’, H2’+H6’, H4, and H3 in
B; in the red box are the correlations between C2 and H4, H2’+H6’, and
H3 in Ct.
1
ized by H NMR spectroscopy (most by 13C NMR spectros-
copy as well) and steady-state absorption. In particular, the
hemiketal B (a hydroxy-4-pyridinechromene) and the cis-
chalcone Cc were clearly characterized by 13C NMR spec-
troscopy. The ring opening/closure is unusually slow when
compared with the same process in 2-hydroxychalcone de-
rivatives, which was explained in terms of different electron-
ic charge densities. In an acid medium, the ring-opening/clo-
sure tautomerization process is much faster and similar to
the one observed for 2-hydroxychalcones derivatives due to
acid catalysis.
The irradiation of Ct produces B through two consecutive
photochemical reactions: Ct!Cc photoisomerization fol-
lowed by Cc!B photo ring closure with a global quantum
yield of 0.02. On the other hand, irradiation of B leads to a
photostationary state composed of 80% Ct and 20% B,
with a quantum yield of 0.21.
formation of B and Cc in equilibrium with Ct, as reported
above in Figures 6 and 9d.
The photochemical product of the irradiation of Ct at
365 nm, approximately 100% B (MeOH/H2O 1:1), was irra-
diated at 254 nm, a wavelength at which this last species ab-
sorbs. The photostationary state thus obtained (Figure 8B) is
composed of approximately 80% Ct and 20% B. This result
is compatible with a photo ring opening of B to give the cis-
enol that could give Ct, since enolization is known to be
very fast in the presence of protic solvents, followed by cis–
trans photoisomerization to form Ct.[17] Alternatively, the
cis-enol could tautomerize to Cc and this one photoisomer-
ize to Ct, as observed in some cis-2-hydroxychalcones
(Scheme 6).[27]
In both photochemical reactions of Figure 8A and B, the
Cc was not detected by H NMR spectroscopy or spectro-
Experimental Section
1
Synthesis: All reagents and solvents
used were of analytical grade. The
NMR spectra at 298.0 K were ob-
tained using a Bruker AMX400 oper-
ating at 400.13 (1H) and 100 MHz
(13C) or on a Bruker Avance 600 oper-
ating at 600.13 Hz (1H) and 150.91 Hz
(13C). Mass spectra experiments were
run using an Applied Biosystems Voy-
ager PRO (MALDI-TOF MS). Ele-
mental analyses was performed using
a
Thermofinnigan Flash EA 1112
Series instrument.
Synthesis of compound 1: A degassed
solution of potassium hydroxide (1.0 g,
17.8 mmol) dissolved in
a minimum
Scheme 6. General scheme for a dual photochromic system involving chromene(hemiketal), cis-chalcone, and
trans-chalcone.
amount of water was added under an
argon atmosphere at room tempera-
Chem. Eur. J. 2010, 16, 545 – 555
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www.chemeurj.org
553

Y. Leydet, A. J. Parola, and F. Pina
ture to a stirred, degassed solution of 4-acetylpyridine (1.21 g, 10 mmol)
and salicylaldehyde (1.22 g, 10 mmol) in ethanol. The solution turned red
instantaneously, thereby indicating the deprotonation of the phenol
group. The reaction mixture was stirred at room temperature overnight.
After this period, the solution was neutralized and concentrated under
reduced pressure. The resulting solid was filtered and purified by column
chromatography on silica gel using a mixture of dichloromethane/ethyl
acetate (80:20, v/v). The solvent was evaporated to yield a yellow solid
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1
(510 mg, 23%). H NMR (400 MHz, CD3OD/D2O 1:1, 258C): d=8.79 (d,
J(H2’–H6’,H3’–H5’)=5.4 Hz, 2H; H3’–H5’), 8.09 (d, J
1H; H4), 7.92 (d, J(H2’–H6’,H3’–H5’)=5.4 Hz, 2H; H2’–H6’), 7.66 (d, J-
(H3,H4)=16.0 Hz, 1H; H3), 7.71 (d, J(H5,H6)=7.5 Hz, 1H; H5), 7.37
(t, J(H7,H8)=8.1 Hz, J(H6,H7)=7.1 Hz, 1H; H7), 6.99 (t, J(H5,H6)=
7.5 Hz, J(H6,H7)=7.1 Hz, 1H; H6), 6.96 ppm (d, J(H7,H8)=8.1 Hz, 1H;
ACHTUNGTREN(NGNU H3,H4)=16.0 Hz,
A
ACHTUNGTRENNUNG
A
R
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
H8); 13C NMR (100 MHz, CD3OD/D2O 1:1, 258C): d=192.8 (C9), 157.2
(C2), 150.2 (C3–C5’), 145.4 (C1’), 144.1 (C4), 133.2 (C7), 129.5 (C5),
122.2 (C2’–C6’), 121.2 (C3), 121.1 (C10), 120.5 (C6), 116.3 ppm (C8); MS
(MALDI-TOF): m/z: 225.1 [M+]; elemental analysis calcd (%) for
C14H11NO2: C 74.65, N 6.22, H 4.92; found: C 74.57, N 6.35, H 5.08.
Measurements: Solutions were prepared using Millipore water and spec-
troscopic methanol (when needed). The solution pH was adjusted by ad-
dition of HCl, NaOH, or the universal buffer of Theorell and Stenha-
gen,[28] and was measured using a Radiometer Copenhagen PHM240 pH/
ion meter. UV/Vis absorption spectra were recorded using a Varian-Cary
100 Bio spectrophotometer or on a Shimadzu VC2501-PC. For NMR
spectroscopy experiments, compound 1 was dissolved in a solution of
D2O and CD3OD. When required, the pH was adjusted by addition of
small aliquots of DCl (ca. 0.5m) or NaOD (0.1m). Photoexcitation in con-
tinuous irradiation experiments were carried out using a xenon/medium-
pressure mercury arc lamp, and the excitation bands (254 and 365 nm)
were isolated with interference filters (Oriel). The incident light intensity
was measured by ferrioxalate actinometry.[29]
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Acknowledgements
We acknowledge LabRMN at FCT-UNL and Rede Nacional de RMN
(supported with funds from FCT-MCTES) for access to the facilities. The
Portuguese FCT-MCTES is also acknowledged for financial support
through project PTDC/QUI/67786/2006 and a post-doc grant SFRH/
BPD/44230/2008 (Y.L.). J. C. Lima, C. Laia, and V. Petrov are kindly ac-
knowledged for fruitful discussions.
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