Synthesis and multistate characterization of bis-flavylium dications-symmetric resorcinol- and phloroglucinol-type derivatives as stochastic systems

Article abstract of DOI:10.1039/c6ra12017b

Two symmetric bis-flavylium dications were readily synthesized and further evaluated for their multistate profile. Both systems were shown to be fully stochastic and behave like a single compound suggesting that the two flavylium moieties do not communica

Full text of DOI:10.1039/c6ra12017b

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Synthesis and Multistate Characterization of bis-Flavylium
Dications – Symmetric Resorcinol- and Phloroglucinol-Type
Derivatives as Stochastic Systems
Rceived 00th January 20xx,
Accepted 00th January 20xx
N. Basílio,a T. Garnier,b J. Avó,a M. Danel, b S. Chassaingb† and F. Pinaa†
DOI: 10.1039/x0xx00000x
Two symmetric bis-flavylium dications were readily synthesized and further evaluated for their multistate profile. Both
systems were shown fully stochastic and behave like a single compound suggesting that the two flavylium moieties do not
communicate via the bridge linking them. Global pKa values of ca. 4 regarding the acid-base reaction between flavylium
cation and quinoidal base were calculated by stopped flow. It was further demonstrated that the equilibrium between
AH+-AH+ and indistinguishable flavylium-quinoidal base isomers AH+-A (A-AH+) can be calculated by subtracting 0.3 pH
units to the observed acid-base constant. On the other hand, the equilibrium between both flavylium-quinoidal base
isomers and the bis-quinoidal base A-A is obtained by adding 0.3 pH units. Moreover, both systems do not have cis-trans
isomerization barrier and the rate constants of interconversion between flavylium cation and quinoidal base as a function
of pH are fitted with a mono-exponential and follow a bell-shaped curve. The systems proved also to be photochromic and
from the fitting of the bell-shaped curve, flash photolysis measurements and quantum yields, it is possible to calculate all
rate and equilibrium constants and construct a global energy-level diagrams. It was also proved that the rate constant to
form both isomers AH+-Ct from the bis-flavylium upon a pH jump from 1 to less acidic solutions is twice of the observed
value and the formation of the bis-trans-chalcone from the both isomers AH+-Ct is equal to the observed rate constant. An
energy-level diagram of all the multistate species was constructed from the equilibrium constants.
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pigment of European grapevine species (ie, Vitis vinifera), this
natural anthocyanin is known to be pushed into a well-established
multiequilibra network involving five distinct structural forms: the
red-colored flavylium cation (AH+) and its colored quinoidal
conjugate base (A), the colorless hemiketal species (B) as well as its
colorless (or pale-yellow) ring-opened counterparts (Cc and Ct)
(Scheme 1).6
Introduction
Flavylium (2-phenyl-1-benzopyrylium) derivatives constitute an
important family of natural pigments, which comprise i)
anthocyanins, the molecules responsible for most of the red and
blue colors of flowers and fruits,1,2 and ii) 3-deoxyanthocyanidins,
the colorants appearing in ferns and mosses as well as hybrids of
sorghum and purple corn3. Besides the above mentioned natural
pigments, a myriad of non-natural flavylium derivatives have been
synthesized, some of them exhibiting relevant photochromic
properties with practical applications as models for optical
memories, molecular logic gates and even to mimic elementary
properties of neurons.4
In order to characterize such a flavylium multistate system,7,8 it is
necessary to perform direct pH jumps defined as the addition of
base to equilibrated solutions of the flavylium cation (generally for
pH<1), thus triggering the sequence of reactions shown in Scheme
1. Also it is required to carry out reverse pH jumps, obtained by
addition of acid to equilibrated solutions at higher pH values.
Thus, after a direct pH jump, the flavylium cation (AH+) yields the
quinoidal base (A) upon proton transfer in competition with
hydration in position 2 to give the hemiketal (B) (Figure 1, Equ.(a) vs
Equ.(b)). The proton transfer is by far the faster reaction of the
From a structural viewpoint, flavylium compounds are generally
defined by the respective flavylium cation, which is nevertheless
only one of the species of a reversible sequence of chemical
reactions that are interconnected by external stimuli, such as pH,
light and removing or adding electrons (redox).4b,5 As illustrative
example, if one considers oenin which is the major flavylium-based
multistate and by consequence
A is formed before B. One
important breakthrough in this system was reported in the late
seventies by Brouillard and Dubois, who showed that A does not
hydrate in acidic medium.9 Consequently, the evolution of the
system takes place through the hemiketal while the quinoidal base
is a kinetic product that is in fast equilibrium and disappears
simultaneously with AH+. On the other hand, hemiketal B could
further open ring C and form cis-chalcone (Cc) (Figure 1, Equ.(c)),
itself in slow isomerization equilibrium with the trans-chalcone (Ct)
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(Figure 1, Equ.(d)). At higher pH values, ionized species are formed Regarding the kinetic processes after a direct pH jump, the
by deprotonation of the remaining hydroxyl groups (not shown in respective mathematical expressions are different according to the
Scheme 1). Altogether, the system can be simplified considering a existence or the lack of the cis-trans isomerization barrier. In the
single acid base equilibrium involving the species AH+ (acid) and CB first case, as in anthocyanins, three distinct steps are observed
(basic) where CB=A+B+Cc+Ct (Figure 1, Equ.(e)).
(Figure 2, Math.(a-c)). The first corresponds to the proton transfer,
the second to the hydration, considering that tautomerization is
faster (which is the general case except for very acidic pH values in
reverse pH jumps experiments), and the third is the isomerization
reaction.
OMe
OH
B
2
HO
-H
O
oenin (AH+)
red-colored
OMe
A
C
OGlc
Regarding the reverse pH jumps carried out from equilibrated or
pseudo-equilibrated solutions, equations (d) and (e) presented in
Figure 2 account for the respective kinetics. The first one is
observed when the final pH of the reverse pH jump is less acidic,
while the second corresponds to the case of regime change: the
hydration becomes faster than tautomerization at very high proton
concentrations, and the last reaction is the controlling step of the
kinetic process. In the absence of the cis-trans isomerization barrier
only one kinetic process (besides proton transfer) is observed as
reported in equation (f) (Figure 2). Representation of this rate
constant (ie, kobs) as a function of pH is a bell shaped curve, where
the left branch is controlled by the isomerization reaction while the
right branch by the hydration.10
OH
+H2O
-H
pKh
pKa
-H2O
-H
+H
OH
OMe
MeO
OMe
O
HO
O
HO
O
OMe
hemiketal (B)
colorless
OH
OGlc
OGlc
OH
OH
quinoidal
bases (A)
bluish red-colored
OMe
OMe
OH
OH
O
O
HO
OH
OMe
OMe
CO
OGlc
OGlc
Cc form
OH
OH
Hydration and proton transfer constants of oenin
pKa = 4.3
chalcones (Cc-Ct )
pKh = 2.8
colorless
to pale yellow
Determined in 0.1M citrate/phosphate buffer with
an ionic set at 1M by NaCl at T = 25°C
OMe
OH
HO
OH
OGlc
OMe
OH
O
Ct form
Scheme 1. Flavylium multistate systems – the case of oenin as illustrative
example.
ka
H3O+ proton transfer
AH+
Equ.(a)
+
+
A
B
+
+
H2O
k-a
kh
Ka
H3O+
hydration
AH+
B
Equ.(b)
Equ.(c)
Equ.(d)
Equ.(e)
2H2O
Figure 2. Flavylium multistate systems – mathematical expressions of the
key kinetic constants.
k-h
Kh
kt
To go further, shifting from flavylium monocations to more
sophisticated dicationic flavylium-based skeletons appears
attractive, because enabling the network of chemical reactions to
be influenced/extended by the presence of the second cationic
moiety. Although the synthesis of such sophisticated flavylium-
based systems, as flavylium-benzopyrylium11 skeleton A and bis-
flavylium skeletons B-E12, has been reported in the literature (Figure
3), their multistate characterization remains surprisingly very few
documented. To our knowledge, the bis-flavylium C where two
flavylium units are linked via a redox-responsive methyl viologen
bridge constitutes the only system whose multistate behavior has
been evaluated to date.12b Remarkably, the performed studies have
revealed that the system is not fully stochastic, especially regarding
the isomerization event (Figure 1, Equ.(d)).
Cc
Ct
ring-opening
k-t
ki
Kt
isomerization
Cc
k-i
ka
H3O+ acid-base global
equilibrium
AH+
+
CB
+
H2O
k-a
K'a
kn
k-n
and K'a = Ka + Kh + KhKt +KhKtKi
(n = a,h,t,i)
with Kn
=
Figure 1. Flavylium multistate systems – summary of the implicated
chemical equilibria and the corresponding kinetic/thermodynamic
constants.
2 | J. Name., 2012, 00, 1-3
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In this context and due to our interest in flavylium resorcinol or phloroglucinol, furnishing the desired bis-
chemistry4b,11,12a,13 as well as their potent applications4b-c,8,14, we flavylium
and in almost quantitative yields. The easy-to-
report herein on the synthesis and the full multistate perform ‘click’ feature of the bis-condensation deserves here
characterization of two symmetric bis-flavylium dications, the to be reminded, notably because the dications are isolated
resorcinol- and phloroglucinol-type salts 1 and 2 respectively in pure forms due to very simple work-up (ie.
1
2
1/2
a
a
(Figure 4).
filtration/washing sequence). Also worth noting is that both
dications were obtained with an excellent efficiency over the
four steps, ie. 75% and 74% overall yields for
1 and 2
respectively.
Figure 3. Selected examples of flavylium-based dications A-D and
tetracation E (aSee ref. 11; bSee ref. 12a; cSee ref. 12b; dSee ref. 12c; eSee ref.
12d).
Figure 4. Symmetric bis-flavylium dications 1 and 2 studied in the present
work.
Scheme 2. Synthesis of bis-flavylium dications
conditions: a) 1,3-dibromopropane (1.0
hydroxybenzaldehyde (2.4 equiv.), K2CO3 (3.0 equiv.), DMF, 100 °C, 12
h; b) (1.0 equiv.), HCCMgBr (2.6 equiv.), THF, 0°C to rt, 3 h; c) (1.0
equiv.), IBX (4.0 equiv.), EtOAc, 80 °C, 12 h; d) (1.0 equiv.), resorcinol
1
/
2
. Reagents and
equiv.), 4-
Results and discussion
3
4
Synthesis
5
(R=H) or phloroglucinol (R=OH) (2.0 equiv.), aqueous HPF6 (xs), AcOH,
rt, 48 h.
The synthesis of bis-flavylium 1 and 2 was achieved in line with
a procedure recently reported by us (Scheme 2).12a The
procedure consists of a four-step sequence taking advantage
of the acid-mediated condensation between bis-
Characterization of multistate systems
With these two symmetric bis-flavylium 1/2 in hand, we next
arylethynylketone
5
and resorcinol/phloroglucinol as last and
was first
investigated their multistate behavior, taking into account as
starting hypothesis that two equal flavylium multistates are
present in the molecules.
key step. The required condensation partner
5
prepared in three steps starting from commercially available
and cheap materials, namely 4-hydroxybenzaldehyde and 1,3-
dibromopropane. After coupling two equivalents of 4-
hydroxybenzaldehyde with one equivalent of the
dibrominated alkylating agent, the resulting bis-benzaldehyde
Physicochemistry
The pH dependent spectral variations of compounds
1 and 2
monitored by stopped flow 10 ms after a direct pH jump are
shown in Figure 5A and Figure 5B respectively. Inspection of
these figures indicates that these spectral changes are
compatible with a single acid-base equilibrium involving the
cationic flavylium forms and its quinoidal bases. The isosbestic
points show that flavylium forms disappear by increasing pH to
give exclusively the quinoidal bases (in this time scale). In the
3
was then efficiently converted to
addition-oxidation sequence, involving bis-propargynol
derivative as intermediate and employing ethynyl
magnesium bromide as nucleophilic reagent and 2-
iodoxybenzoic acid (IBX) as oxidant. With in hand, the key
5 via a nucleophilic
4
5
condensation step proved highly efficient with either
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1
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AH+---A
A---AH+
AH+---A
AH+---AH+
AH+---AH+
A---A
A---A
A---AH+
cases of both compounds 1/2, fitting was achieved by a single
acid-base equilibrium with pKa(
1)=3.9 and pKa(2)=4.0.
pK =3.9
0.6
a
0.6
A
B
A
B
469 nm
A
0.3
502 nm
0.4
0
0
0
1
2
3
4
5
6
7
1
2
3
4
5
6
7
1
2
3
4
5
6
7
A
pH
1
1
pH
pH
AH+---AH+
AH+---AH+
Ct---Ct
AH+---Ct
Ct---AH+
0.2
Ct---Ct
AH+---Ct
Ct---AH+
0
250
350
450
550
Wavelength (nm)
1.2
pK' =0.7
1
a
C
D
376 nm
467 nm
A
C
D
0
0.8
0
0
1
2
3
4
5
6
-1
0
1
2
3
4
pH
pH
0
0
1
2
3
4
5
pH
A
Figure 6. Mole fraction distribution of the diprotonated-monoprotonated
and neutral species of the equilibrium i) between flavylium cation and
quinoidal base in the case of 1 (A) and in the case of 2 (B), and ii) at the
thermodynamic equilibrium in the case of 1 (C) and in the case of 2 (D).
0.4
0
Remarkably, both bis-flavylium systems also behave as a single acid-
base at the thermodynamic equilibrium, thus involving flavylium
cation and trans-chalcone (Figure 1, Equ.(e)). Figures 5C-D indeed
250
350
450
550
Wavelength (nm)
Figure 5. UV/Vis spectral variations occurring upon a direct pH jump
from stock solutions of compounds 1/2
at pH1 (2.5x10-5 M/9.3x10-6 show the pH-dependent absorption of solutions of 1/2 after
M) to higher pH values. Spectra recorded immediately after the pH
jump in the case of 1 (A) and in the case of 2 (B). Spectra recorded at
the thermodynamic equilibrium in the case of 1 (C) and in the case of
equilibration for ca. 24h, revealing an extremely small pK’a value for
1 (ie. 0.7 and 3.3 for 1 and 2 respectively). These values compare
with pK’a=1.5 for the model compound 4’-methoxy-7-
hydroxyflavylium in the same conditions (ie. 50% water/ethanol,
v/v, room temperature, see Figure S1 in SI). Considering again the
systems as stochastic, the corresponding global equilibrium can be
accounted for by equation Equ.(g) depicted in Figure 7. The same
reasoning as above then leads to pK’a1(1)=0.4 and pK’a2(1)=1.0
(compares with pK’a1(1)=3.0 and pK’a2(1)=3.6 for 2), further
confirming the unusual higher acidity of the bis-flavylium 1.
2
(D). Insets: fittings (–) of the absorbance values (ꢀ/ꢁ) at the specified
wavelengths.
The global acid-base equilibrium can be accounted for by
equation Equ.(f) and the network of chemical reactions
depicted in Scheme 3.8,15 The pKa1 is defined as the acid-base
equilibrium between the diprotonated form (A2H22+) and the
sum of the monoprotonated species
(
A2H+), while pKa2
between the monoprotonated species (A2H+) and the neutral
form (A2). As mentioned above, both systems behave as a
single acid-base equilibrium corresponding i) in the case of
to the stochastic constant pKam )=3.9 and by consequence
pKa1( )= 3.6 and pKa2( )=4.2, and ii) in the case of , to
pKam )=4.0, pKa1( )= 3.7 and pKa2( )=4.3. Accordingly, these
1,
(
1
1
1
2
(
2
2
2
Figure 7. Deprotonation sequence of the bis-flavylium at the
thermodynamic equilibrium.
data then allowed us to determine the mole fraction
distribution of the respective species as shown in Figures 6A-B.
Having proved that the systems 1/2 are both stochastic, the
following discussion considers that similarly to the acid-base
reaction all micro-rate and equilibrium constants are the same and
the systems can be treated as a single one multistate flavylium.
From the spectra of Figures 5A-B to the spectra at the equilibrium
(Figures 5C-D), the systems evolve according to a single mono-
exponential decay as clearly shown in the insets of Figures 8A-B.
First, regarding the bis-flavylium 1, representation of a series of
direct pH jumps as a function of pH was fitted with Equ.(f) (Figure 2)
for the parameters pKa(1)=3.9, KhKtki=1.15x10-6 M-1s-1, k-i=10-5 s-1
and Ktki/k-h=1.9x10-4 M-1s-1 (Figure 8C). At extremely low pH values,
a term equal to kH [H+] should be added, kH =7.6x10-4 M-1s-1
3a
Ka1
Ka2
AH+
AH+
AH+
A
Equ.(f)
A
A
(where AH+
A
accounts for both isomers)
3b
A2H+
A1
Ka21
Ka11
A2H+
A1H+
A2
A1
A2
Scheme 3. Deprotonation sequences of the bis-flavylium.13
A1H+
Ka21
Ka22
cat
cat
should be added to account for a catalytic step recently observed as
a general behavior of flavylium networks most probably due to the
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catalytic effect by proton on the chalcones isomerization. Of note constant of the observed global process and disappears with the
the so-obtained representation of the kobs rate constant as a same rate constant of the global process.
function of pH is a typical bell-shaped curve, where the left branch
is controlled by the isomerization reaction while the right branch by Photochemistry
the hydration.
In the case of flavylium multistates lacking the cis-trans
isomerization barrier the number of relations between rate and
equilibrium constants of the system is not enough to carry out their
full characterization. However, in some cases it is possible to use
other stimuli rather than pH jumps to shift the multistate from the
equilibrium and follow the relaxation processes and in this way get
more information regarding the multistate. This is the case of the
trans-cis photo-induced Ct=Cc isomerization.
B
A
As shown in Figures 9A-B, the present bis-flavylium compounds 1/2
both exhibit photochromism because upon irradiation, the
absorption band of the flavylium cation increases at the expenses of
its trans-chalcone form. Furthermore, representation of the
quantum yields as a function of pH are presented in Figures 9C-D.
0.002
C
D
0.8
0.5
A
B
0.4
0.6
0.001
A
0.3
A
ꢀ
hν
0.4
0.2
0.1
0
ꢀ
h
ν
0.2
0
0
1
2
3
4
5
6
7
8
pH
0
250
350
450
550
300
400
500
600
700
Wavelength (nm)
Wavelength (nm)
0.16
E
C
D
0.08
0
1
2
3
4
5
6
7
8
Figure 8. (A) Spectral variations of 1 after a direct pH jump from pH 1 to pH
5 – Inset: fitting of the absorbance at 493 nm gives kobs=3.5x10-4 s-1 at pH 3.9.
(B) Spectral variations of 2 after a direct pH jump from pH 1 to pH 6.3 –
Inset: fitting of the absorbance at 493 nm gives kobs=7.0x10-5 s-1 at pH 4. (C)
Regarding 1, representation of a series of direct pH jumps (ꢀ) and reverse
pH jumps (ꢁ) from pH 7. (D) Same as C but in the case of 2. (E) Decay of the
flavylium cation 1 and trans-chalcone formation after a direct pH jump as in
the inset of (A) (red lines) - kinetics of the bis-flavylium disappearance to
give the intermediate with a unique flavylium and the final bis-trans-
chalcone.
pH
Figure 9. (A) Spectral variations upon irradiation of 1 at pH=3.8, irr =376 nm.
(B) Spectral variations upon irradiation of 2 at pH=4.2, irr=370 nm. (C)
Quantum yields of the photochemical reaction involving 1 as a function of
pH - Fitting was achieved with Math.(k) and (l) (Figure 11). (D) Same as C but
in the case of 2.
For clarity reasons, the following discussion will focus more
particularly on bis-flavylium 1. The flash photolysis of 1 was carried
at different pH values, and is shown for equilibrated solutions at pH
2 (Figure 10A). After the flash, there is a bleaching at 376 nm, a
wavelength where trans-chalcone Ct shows its absorption
maximum. The bleaching occurs because the species formed is cis-
chalcone Cc that has a low molar absorption coefficient at this
wavelength. The absorption at 376 nm is partially recovered in ca.
0.2 s at this pH value, indicating that part of cis-chalcone Cc gives
back trans-chalcone Ct. At the same time and with identical lifetime,
the flavylium cation is formed and as a result, the fraction of non-
recovered trans-chalcone Ct corresponds to the fraction of so-
In a similar way, fitting of the experimental data in Figure 8B with
Equ.(g) (Figure 2) was achieved for the parameters pKa(2)=4.0,
KhKtki=1.3x10-8 M-1s-1, k-i=2.2x10-5 s-1, Ktki/k-h=8.5x10-7 M-1s-1 and kH
=1.5x10-3 M-1s-1 (Figure 8D).
cat
As shown in Appendix 2 given in SI and taking into account that the
systems are stochastic, the rate constants for the formation of the
species AH+-AH+, AH+-Ct (Ct-AH+) and Ct-Ct can be calculated.
Interestingly enough, it can be proved that the intermediate species
bearing one flavylium cation and a trans-chalcone at each terminal
is formed with a rate constant two times higher than the rate
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formed flavylium cation. Representation of the rate constants of On the other hand, when the rate determining step is the
the flash photolysis experiments is shown in Figure 10A and, as tautomerization reaction as observed in Figure 10, the pH
observed for other flavylium multistates, the rates of the flash dependence of the quantum yield then follows Math.(l) (Figure 11).
photolysis follow two regimes. At higher pH values, since the A global fitting was finally carried out using Equ.(e) and Math.(f-l),
hydration is much slower than tautomerization, the equilibrium the resulting values of the parameters being summarized in Table 1.
between hemiketal and cis-chalcone is attained and Math.(g)
(Figure 11) could be used. At lower pH values occurs the change of
Table 1. Fitting parameters used to fit kinetic data
regime and hydration is much faster than tautomerization. Thus, all
the hemiketal that is formed upon ring closure gives immediately
KhKtki
Ktki/k-h
k-h
/
ki Kt /
(1+Kt)
(s-1)
ki +k-t
(M-1s-1)
(M-1s-1)
(1+Kt)
(s-1)
flavylium cation and Math.(h) (Figure 11) should be used for fitting.
(M-1s-1)
0.05
1
1
2
1.5x10-6
1.3 x10-8
1.9x10-4
8.5x10-7
1.4x103
6.0x104
0.26
0.03
0.36
0.7
With kH = 5 M-1s-1 and kOH = 2x109 M-1s-1 for 1 and kH = 200 M-1s-1
and kOH = 5x109 M-1s-1 for 2.
0
0.6
0
Full characterization
-0.08
0.2
0
0.4
Time (s)
0.8
1
2
3
4
5
6
7
8
From the parameters reported in Table 1, it is possible to calculate
all the rate and equilibrium constants of the system 1 and thus fully
characterize its multistate behavior. The data of the rate and
equilibrium and kinetic constants of 1 are presented respectively in
Table 2 and Table 3. In parallel, the full multistate characterization
of bis-flavylium 2 was performed using the same overall reasoning
and the calculated values are also given in Table 2 and Table 3.
pH
Figure 10. (A) Traces of the flash photolysis of 1 at pH 2. (B) Rate constants
of the flash photolysis as a function of pH - Fitting was achieved with
Math.(g) and Math.(h) (Figure 11).
Table 2. Equilibrium constants of bis-flavylium 1 and 2.
pKa / pK’a
3.9 / 0.9[a]
4.0 / 3.3
Kh (M-1)
1.2x10-6
3.5x10-7
Kt
2.7
Ki
1
2
3.55x104
2.70x104
0.05
[a] The large error between this theoretical value and the experimental (ie.
0.7) is most probably due to the uncertainty in measuring the pH values at
these extremely acidic solutions.
Table 3. Rate constants of bis-flavylium 1 and 2.
kh (s-1)
6.05x10-3
1.5x10-2
k-h (M-1s-1)
kt / k-t (s-1)
0.04 / 0.015
0.005 / 0.1
ki / k-i (s-1)
0.355 / 10-5
0.6 /2.2x10-5
Figure 11. Flavylium multistate systems – mathematical expressions of the
kinetic constants and quantum yields related to the photoinduced
isomerization process.
1
2
5.1x103
4.3x104
The pH-dependent quantum yields reported in Figure 9C provide
also significant kinetic information that can be used to calculate the
rate and equilibrium constants of the system. When the hydration
is the rate-determining step, the equilibrium between B and Cc is
established and the forward and backward reactions are
respectively given by Math.(i) (Figure 11) and Equ.(e) (Figure 1),
assuming that the tautomerization equilibrium is achieved.16
Further neglecting the contribution of k-i as well as
kh[H+]/([H+]+Ka),17 the pH-dependence of the quantum yield is thus
given by Math.(k) (Figure 11).
Finally, the data reported in Table 1 and Table 2 allow the
construction of an energy-level diagram which is very useful to
account for the details of the multistate, in particular to illustrate
the photochemistry (Scheme 4). In the particular case of 1, the
quantum yield at pH 3.9 is higher than at pH 5 because the forward
reaction from Cc to AH+/A is more efficient in the former. The
thermal back reaction to restore the equilibrium is much slower in
both cases. The species B and Cc are not easily accessible from the
thermodynamic point of view. Moreover, at pH 5, the thermal back
6 | J. Name., 2012, 00, 1-3
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reactions are slower than at pH 3.9. This is due to the fact that at
pH 5 there is more A in comparison with AH+. As mentioned in the
introduction, A is thus a kinetic product that retards the system to
get the equilibrium. A similar situation is observed in the case of 2
(see Figure S3 in SI).
Experimental section
Synthesis
General - All starting materials were commercial and were
used as received. Anhydrous solvents were freshly distilled
before use or were obtained from the M. Braun Solvent
Purification System (MB-SPS-800). The reactions were
monitored by thin-layer chromatography carried out on silica
plates (silica gel 60 F254, Merck) using UV-light for visualization.
Column chromatographies were performed on silica gel 60
(0.040-0.063 mm, Merck) using mixtures of ethyl acetate and
cyclohexane as eluents. – Evaporation of solvents were
conducted under reduced pressure at temperatures less than
30°C unless otherwise noted. – Melting points (mp) were
measured with a Stuart SMP30 apparatus in open capillary
tubes and are uncorrected. – IR spectra were recorded with a
Perkin-Elmer FTIR 1600 spectrometer (KBr disc) and values are
reported in cm-1. – 1H and 13C NMR spectra were recorded on i)
a Bruker Avance 300 spectrometer at 300 and 75 MHz,
respectively, and on ii) a Bruker Avance 500 spectrometer at
A
B
500 and 125 MHz, respectively. Chemical shifts
constants J are given in ppm and Hz, respectively. Chemical
shifts are reported relative to residual solvent as an internal
standard (acetonitrile-d3: 1.94 ppm for 1H and 1.32/118.3 ppm
δ and coupling
δ
for 13C; DMSO-d6: 2.50 ppm for H and 39.5 ppm for 13C). H
multiplicities are designated by the following abbreviations: s =
singlet, d = doublet, t = triplet, m = multiplet, quint. =
quintuplet, b = broad. Carbon multiplicities were determined
by DEPT135. – UV-Visible spectra were measured with a 8452A
Hewlett-Packard spectrophotometer in the solvents indicated.
Maximum absorption wavelengths λmax and molar extinction
1
1
Scheme 4. Energy-level diagram of bis-flavylium 1. Ilustration of the
pathways upon irradiation of the trans-chalcone (A) at pH 5, where the rate-
determining step is the hydration. (B) The same at pH 3.9 where the
hydration is faster.
coefficients
ε –
are given in nm and mol−1dm3cm−1.
Electrospray (ESI) and Desorption Chemical Ionization (DCI)
low/high-resolution mass spectra were obtained from the
'Service Commun de Spectroscopie de Masse' of the
Plateforme Technique, Institut de Chimie de Toulouse.
Conclusions
Symmetric bis-flavylium systems pose some interesting
theoretical questions regarding the influence of the bridge on
the chemical behavior of each terminal flavylium multistate.
The present system proved to be stochastic in the sense that
there is no measurable interaction between both flavylium
multistates. The kinetics and thermodynamics of the bis-
flavylium is identical to a single flavylium multistate lacking of
a cis-trans isomerization barrier. However, using the statistics,
it is possible to calculate the distribution of the species at the
molecular level. The pKa1 for removing one proton from the
bis-flavylium is 0.3 units lower than the observed pKa
(macroscopic) while the pKa2 for removing the second proton
is 0.3 units greater. The same is calculated for the equilibrium
involving flavylium cation and trans-chalcone (macroscopic
pK’a). Information of the kinetics at the molecular level can
also be achieved mathematically. While the kinetic process
after a direct pH jump is a single exponential (kobs), the rate at
the molecular level to give one trans-chalcone is twice kobs and
the rate to give the second trans-chalcone from the remaining
Procedure for the synthesis of 4,4’-(propane-1,3-
diylbis(oxy))dibenzaldehyde 3: To
a
solution of 1,3-
dibromopropane (2.02 g, 10.0 mmol, 1.0 equiv.) in DMF (30
mL) were added 4-hydroxybenzaldehyde (2.93 g, 24.0 mmol,
2.4 equiv.) and K2CO3 (4.15 g, 30.0 mmol, 3.0 equiv.). The
mixture was heated at 100°C and stirred overnight (i.e., 12h).
After cooling the reaction mixture to room temperature, H2O
(30 mL) was added to the mixture in order to precipitate the
reaction product. The mixture was filtered and the crude
product was purified by column chromatography
(cyclohexane/EtOAc – 9:1 to 7:3) to give
3 in pure form as a
white solid (2.55 g, 90%). Rf = 0.4 (cyclohexane/EtOAc, 7 : 3,
1
v/v); mp: 131-132 °C; IR (KBr): νmax 1690 cm-1; H NMR (300
MHz, DMSO-d6): δ = 9.87 (s, 2H), 7.88-7.85 (m, 4H), 7.17-7.14
(m, 4H), 4.27 (t, J = 6.6 Hz, 4H), 2.25 (quint., J = 6.3 Hz, 2H)
ppm; 13C NMR (75 MHz, DMSO-d6):
δ = 191.3, 163.4, 131.8,
129.7, 114.9, 64.7, 28.3 ppm; MS (DCI+) m/z (%): 285 (25) [M-
+
H+], 302 (100) [M-NH4 ].
Procedure for the synthesis of 1,1’-(4,4’-(propane-1,3-
flavylium cation is the same as kobs
.
diylbis(oxy))bis(4,1-phenylene))diprop-2-yn-1-ol 4: To
a
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173.4, 168.8, 167.4, 159.9, 155.0, 133.8, 133.4, 122.4, 122.3, 120.3,
117.5, 114.1, 103.9, 66.6, 29.4 ppm; UV/Vis (CH3CN/10% 1N HCl):
λmax (ε) = 466 (39000), 262 nm (16000 mol−1dm3cm−1); MS (ESI+) m/z
(%): 259 (100) [M2+].
solution of
3 (1.02 g, 3.6 mmol, 1.0 equiv.) in THF (10 mL) was
added a solution of commercial ethynylmagnesium bromide
(0.5 M in THF, 19 mL, 9.4 mmol, 2.6 equiv.) at 0 °C. After
addition of the Grignard reagent, the mixture was let warm
and stirred at rt until the complete consumption of
3 (TLC). A
saturated solution of NH4Cl was then added to the reaction
mixture and the THF was evaporated under vacuum. The
aqueous phase was extracted three times with EtOAc and the
organic layers were washed with H2O and brine and then dried
over Na2SO4. After evaporation of the solvent, the resulting
crude product was purified by column chromatography
bis(1'-((5,7-dihydroxy)benzopyrilium)phenoxy)
propane
dihexafluorophosphate 2: Yellow solid (400 mg, 95%). IR (KBr):
1
νmax 3410, 1640, 855 cm-1; H NMR (500 MHz, 1% TFA-d1 in
CD3CN): δ = 9.04 (d, J = 8.8 Hz, 2H), 8.32-8.27 (m, 4H), 7.94 (d, J
= 8.8 Hz, 2H), 7.21-7.18 (m, 4H), 6.96 (d, J = 2.2 Hz, 2H), 6.72
(d, J = 2.2 Hz, 2H), 4.38 (t, J = 6.2 Hz, 4H), 2.35 (quint., J = 6.2
Hz, 2H); 13C NMR (125 MHz, 1% TFA-d1 in CD3CN):
(cyclohexane/EtOAc – 4:1) to give
4 as a pale yellow solid (1.08
δ = 160.1,
g, 89%). Rf = 0.2 (cyclohexane/EtOAc, 7 : 3, v/v); mp: 109-110
1
159.6, 150.4, 133.2, 122.6, 117.7, 114.2, 111.5, 104.0, 96.9,
66.7, 29.9 ppm; UV/Vis (CH3CN/10% 1N HCl): λmax (ε) = 476
(21000), 416 (sh), 326 (6000), 278 nm (15000 mol−1dm3cm−1);
MS (ESI+) m/z (%): 275 (100) [M2+].
°C; IR (KBr): νmax 3330, 3300, 2110 cm-1; H NMR (300 MHz,
DMSO-d6): δ = 7.37-7.34 (m, 4H), 6.95-6.92 (m, 4H), 5.90 (d, J =
6.0 Hz, 2H), 5.27 (dd, J = 6.0, 2.4 Hz, 2H), 4.12 (t, J = 6.0 Hz,
4H), 2.16 (quint., J = 6.3 Hz, 2H) ppm; 13C NMR (75 MHz,
DMSO-d6):
62.0, 28.6 ppm; MS (DCI+) m/z (%): 319 (100) [M-OH+], 336 (15)
δ = 158.0, 134.1, 127.8, 114.1, 85.8, 75.6, 64.3,
Characterization of full multistates sytems
General - Stock solutions of
1 and 2 were prepared in
+
[M+], 354 (30) [M-NH4 ].
H2O:EtOH 1:1 (v:v) with HCl 0.1 M. The pH jumps were carried
out by addition of base (direct) or acid (reverse) to
Procedure for the synthesis of 1,1’-(4,4’-(propane-1,3-
diylbis(oxy))bis(4,1-phenylene))diprop-2-yn-1-one 5: To a solution
of 4 (2.5 mmol, 1.0 equiv.) in EtOAc (15 mL) was added freshly
prepared IBX18 (2.8 g, 10 mmol, 4.0 equiv.) in one portion. The
mixture was heated at 80 °C and stirred overnight (i.e., 12h). After
cooling the reaction mixture to room temperature, the mixture was
filtered and EtOAc was evaporated under vacuum. The resulting
crude product was purified by column chromatography
(cyclohexane/EtOAc, 4:1 to 1:1) to give 5 as a yellow solid (815 mg,
equilibrated solutions of
1 or 2. The pH of the solutions was
adjusted by addition of HCl, NaOH, or Theorell and
Stenhagen’s universal buffer and pH was measured in a
Radiometer Copenhagen PHM240 pH/ion meter. The final
percentage of EtOH was always 50% (v:v).
Measurements - UV-Vis absorption spectra were recorded in a
Varian Cary 100 Bio or Varian Cary 5000 spectrophotometers.
The stopped-flow experiments were conducted in an Applied
98%). Rf = 0.3 (cyclohexane/EtOAc, 7 : 3, v/v); mp: 145-146 °C; Photophysics SX20 stopped-flow spectrometer provided with a
IR (KBr): νmax 3230, 2090, 1635 cm-1; H NMR (300 MHz, DMSO-
1
PDA.1/UV photodiode array detector.
d6): δ = 8.05-8.02 (m, 4H), 7.16-7.13 (m, 4H), 5.00 (s, 2H), 4.28 (t, J =
Data analysis and fitting – All pKa values were determined
6.3 Hz, 4H), 2.25 (quint., J = 6.3 Hz, 2H) ppm; 13C NMR (75 MHz, from the absorbance versus pH experimental data. The
observed rate constants were obtained fitting the absorbance
DMSO-d6): δ = 175.3, 163.7, 131.7, 129.0, 114.8, 84.5, 80.3, 64.8,
+
28.2 ppm; MS (DCI+) m/z (%): 333 (20) [M-H+], 350 (100) [M-NH4 ].
versus time data to the integrated first order rate equation.
The thermodynamic and kinetic results were globally fitted to
General procedure for the synthesis of bis-flavylium compounds the reported equations using the Solver tool in an Excel
spreadsheet.
1/2: To a solution of resorcinol or phloroglucinol (1.0 mmol, 2.0
equiv.) and bis(arylethynylketone) 5 (0.5 mmol, 1.0 equiv.) in AcOH
(2 mL) was added aqueous HPF6 (0.5 mL, 60% in water). The
solution, becoming immediately dark red, was stirred at rt for 48
hours. The resulting mixture was then plunged into Et2O (20 mL)
where the bis-flavylium dihexafluorophosphate precipitated. The
solid was recovered by filtration, washed with Et2O and finally dried
under vacuum to give the expected dicationic species 1 and 2, from
resorcinol and phloroglucinol respectively.
Acknowledgements
This work was supported by the Associated Laboratory for
Sustainable Chemistry-Clean Processes and Technologies-
LAQV which is financed by national funds from FCT/MEC
(UID/QUI/50006/2013) and co-financed by the ERDF under the
PT2020 Partnership Agreement (POCI-01-0145-FEDER-007265).
NB gratefully acknowledges the post-doctorate grant from the
FCT/MEC (SFRH/BPD/84805/2012). SC, MD and TG gratefully
acknowledge the CNRS and University Paul Sabatier for
financial support. TG thanks the Agence Nationale de la
bis(1'-((7-hydroxy)benzopyrilium)phenoxy)propane
dihexafluorophosphate 1: Yellow solid (386 mg, 96%). IR (KBr):
νmax 3380, 1635, 855 cm-1; 1H NMR (500 MHz, 1% TFA-d1 in
Recherche (ANR-13-BS07-0017-02 ChOZe) for
a Post-Doc
CD3CN):
δ = 9.01 (d, J = 8.5 Hz, 2H), 8.42-8.41 (m, 4H), 8.19 (d, J =
fellowship. SC also wishes to thank Raymond BROUILLARD for
his mentorship in flavylium chemistry.
8.8 Hz, 2H), 8.12 (d, J = 8.8 Hz, 2H), 7.52 (d, J = 1.9 Hz, 2H), 7.44 (dd,
J = 8.8, 2.2 Hz, 2H), 7.29-7.27 (m, 4H), 4.43 (t, J = 6.2 Hz, 4H), 2.38
(quint., J = 6.1 Hz, 2H); 13C NMR (125 MHz, 1% TFA-d1 in CD3CN):
δ =
8 | J. Name., 2012, 00, 1-3
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G. A. Reynolds, J. A. van Allan, J. Heterocycl. Chem. 1969, 6,
623.
Notes and references
13 For synthetic aspects related to flavylium-based pigments,
see: (a) S. Chassaing, G. Isorez-Mahler, M. Kueny-Stotz, R.
Brouillard, Tetrahedron 2015, 71, 3066; (b) S. Chassaing, G.
1
For representative reviews or chapter books dealing with
anthocyanins, see: (a) F. Pina, V. Petrov, C. A. T. Laia, Dyes
Pigm. 2012, 92, 877; (b) K. Yoshida, K.-i. Oyama, T. Kondo in
Recent Advances in Polyphenol Research, Vol. 3 (Eds.: V.
Cheynier, P. Sarni-Manchado, S. Quideau), Wiley-Blackwell,
Chichester, 2012 pp. 99; (c) R. Brouillard, S. Chassaing, G.
Isorez, M. Kueny-Stotz, P. Figueiredo in Recent Advances in
Polyphenol Research, Vol. 2 (Eds.: C. Santos-Buelga, M. T.
Escribano-Bailon, V. Lattanzio), Wiley-Blackwell, Chichester,
2010, pp. 1; (d) K. Yoshida, M. Mori, T. Kondo, Nat. Prod.
Rep. 2009, 26, 884; (e) R. Brouillard, S. Chassaing, A.
Fougerousse, Phytochemistry 2003, 64, 1179.
Isorez, M. Kueny-Stotz, R. Brouillard, Tetrahedron Lett. 2008
,
49, 6999; (c) M. Kueny-Stotz, G. Isorez, S. Chassaing, R.
Brouillard, Synlett 2007, 1067.
14 For representative applications of flavylium-based pigments,
see: (a) F. Pina, J. Agric. Food Chem. 2014, 62, 6885; (b) G.
Calogero, A. Sinopoli, I. Citra, G. Di Marco, V. Petrov, A. M.
Diniz, A. J. Parola, F. Pina, Photochem. Photobiol. Sci. 2013
,
12, 883; (c) R. Jiang, A. Miyamoto, A. Martz, A. Specht, H.
Ishibashi, M. Kueny-Stotz, S. Chassaing, R. Brouillard, L. P. De
Carvalho, M. Goeldner, J. Nakebura, M. Nielsen, T. Grutter,
Brit. J. Pharmacol. 2011, 162, 1326; (d) R. Gomes, A. M. Diniz,
A. Jesus, A. J. Parola, F. Pina, Dyes Pigments 2009, 81, 69; (e)
M. Kueny-Stotz, S. Chassaing, R. Brouillard, M. Nielsen, M.
Goeldner, Bioorg. Med. Chem. Lett. 2008, 18, 4864.
15 For the mathematical treatment of Scheme 3b, see Appendix
1 given in Supporting Information.
16 At these pH values, the tautomerization is known to be much
faster than hydration.
17 k-i is relatively small at these pH values.
18 IBX was freshly prepared according to the procedure
reported in: M. Frigerio, M. Santagostino, S. Sputore, J. Org.
Chem. 1999, 64, 4537.
2
3
For an overview, see the following specific issue devoted to
anthocyanins: J. Agric. Food Chem. (Eds.: C. Santos-Buelga, N.
Mateus, V. De Freitas), 2014, vol. 62, issue 29.
For
representative
articles
dealing
with
3-
deoxyanthocyanins, see: (a) J. R. N. Taylor, P. S. Belton, T.
Beta, K. G. Duodu, J. Cereal Sci. 2014, 59, 257; (b) C. Petti, R.
Kushwaha, M. Tateno, A. E. Harman-Ware, M. Crocker, J.
Awika, S. DeBolt, J. Agric. Food Chem. 2014, 62, 1227; (c) L.
Wang, L. Dykes, J. M. Awika, Food Chem. 2014, 160, 246; (d)
B. Geera, L. O. Ojwang, J. M. Awika, J. Food Sci. 2012, 92,
877; (e) J. M. Awika, L. W. Rooney, R. D. Waniska, J. Agric.
Food Chem. 2004, 52, 4388; (f) J. M. Baranac, D. S. Amic, J.
Agric. Food Chem. 1990, 38, 2111; (g) J. G. Sweeny, G. A.
Iacobucci, J. Agric. Food Chem. 1983, 31, 531; (h) P. Coggon,
G. A. Moss, H. N. Graham, G. W. Sanderson, J. Agric. Food
Chem. 1973, 21, 727.
4
(a) A. Sousa, V. Petrov, P. Araujo, N. Mateus, F. Pina, V. De
Freitas, J. Phys. Chem. B 2013, 117, 1901; (b) F. Pina, M. J.
Melo, C. A. Laia, A. J. Parola, J. C. Lima, Chem. Soc. Rev. 2012
,
41, 869; (c) F. Pina, V. Petrov, C. A. T. Laia, Dyes Pigments
2012, 92, 877; (d) R. Gomes, A. M. Diniz, A. Jesus, A. J. Parola,
F. Pina, Dyes Pigments 2009, 81, 69; (e) F. Pina, M. J. Melo,
M. Maestri, P. Passaniti, V. Balzani, J. Am. Chem. Soc. 2000
,
122, 4496; (f) P. Figueiredo, J. C. Lima, H. Santos, M. C.
Wigand, R. Brouillard, A. L. Maçanita, F. Pina, J. Am. Chem.
Soc. 1994, 116, 1249.
5
6
F. Pina, J. Oliveira, V. De Freitas, Tetrahedron 2015, 71, 3107.
(a) M. Duenas, E. Salas, V. Cheynier, O. Dangles, H. Fulcrand,
J. Agric. Food Chem. 2006, 54, 189; (b) R. Brouillard, S.
Chassaing, A. Fougerousse, Phytochemistry 2003, 64, 1179.
The general behavior of flavylium compounds is recalled
here to guarantee clarity for non-experts in flavylium
chemistry.
For representative examples dealing with multistate
behavior and extensive characterization of monomeric
flavylium models, see: (a) F. Pina, R. Gomes, N. Basilio, A. T.
Cesar, J. Photochem. Photobiol. A 2013, 269, 1; (b) F. Pina, J.
C. Lima, A. J. Parola, C. A. M. Afonso, Angew. Chem. Int. Ed.
2004, 43, 1525; (c) F. Pina, M. J. Melo, A. J. Parola, M.
Maestri, V. Balzani, Chem. Eur. J. 1998, 4, 2001; (d) F. Pina,
M. J. Melo, H. Santos, J. C. Lima, I. Abreu, R. Ballardini, M.
Maestri, New J. Chem. 1998, 22, 1093.
7
8
9
(a) R. Brouillard, B. Delaporte, J. E. Dubois, J. Am. Chem. Soc.
1978, 100, 6202; (b) R. Brouillard, J. E. Dubois, J. Am. Chem.
Soc. 1977, 99, 1359.
10 For a representative example of bell-shaped curve, see
Figure 8A.
11 S. Chassaing, M. Kueny-Stotz, G. Isorez, R. Brouillard, Eur. J.
Org. Chem. 2007, 2438.
12 (a) M. Kueny-Stotz, R. Brouillard, S. Chassaing, Synlett 2012
,
2053; (b) A. M. Diniz, C. Pinheiro, V. Petrov, A. J. Parola, F.
Pina, Chem. Eur. J. 2011, 17, 6359; (c) A. R. Katritzky, P.
Czerney, J. R. Level, W. Du, Eur. J. Org. Chem. 1998, 2623; (d)
This journal is © The Royal Society of Chemistry 20xx
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Two as one! The network of chemical reactions involving two easy-to-prepare bis-flavylium
dications was explored from kinetic and thermodynamic viewpoints. By meansDoOfI: 1s0t.1o0p39p/Ce6dRA12017B
flow and flash photolysis techniques, the so-investigated systems overall proved stochastic,
thus revealing that no measurable interaction is taking place between the two multistate
flavylium moieties.
O
O
interaction? NO
HO
HO
O
?
R
stochastic
bis-flavylium dications
O
R=H, OH
R