One-step synthesis of novel flavylium salts containing alkyl side chains in their 3-, 4′-, 5- or 6-positions and their photophysical properties in micellar media

Article abstract of DOI:10.1002/ejoc.200400318

A one-step preparation of several flavylium salts containing alkyl side chains in their 3-, 4′-, 5- or 6-positions is described. Flavylium salts with alkyl side chains in positions 3 or 4′ were isolated from reactions between 2,4-dihydroxybenzaldehyde and

Full text of DOI:10.1002/ejoc.200400318

FULL PAPER
One-Step Synthesis of Novel Flavylium Salts Containing Alkyl Side Chains
in Their 3-, 4Ј-, 5- or 6-Positions and Their Photophysical Properties in
Micellar Media
[
a]
[a]
[a]
[a]
Ana C. Fernandes,* Carlos C. Rom a˜ o, Carla P. Rosa, Vera P. Vieira,
[a]
[b]
[a]
Ant o´ nio Lopes, Palmira F. Silva, and Ant o´ nio L. Ma c¸ anita
Keywords: Alkyl side chain / Hydrophobic flavylium salts / Micelles / Photochromism / Ultrafast proton transfer
A one-step preparation of several flavylium salts containing
alkyl side chains in their 3-, 4Ј-, 5- or 6-positions is described. anionic (SDS), cationic (CTAB) or neutral (C12
in water, but readily incorporate into aqueous dispersions of
10) surfactants
E
Flavylium salts with alkyl side chains in positions 3 or 4Ј were
isolated from reactions between 2,4-dihydroxybenzaldehyde
and decanophenone, dodecanophenone and 4Ј-hexyl- or 4Ј-
dodecylacetophenone. Flavylium salts with alkyl side chains
in positions 5 or 6 were prepared through reactions between
benzoylacetone and 4-hexyl-, 4-dodecyl- or 5-pentylresor-
cinol. The new compounds are insoluble or sparingly soluble
above their critical micellar concentrations. They also pre-
sent interesting spectroscopic properties − namely, ultra-fast
proton transfer in the excited state − and the 4Ј derivatives
also exhibit photochromic behaviour, which might have sev-
eral applications in the field of self-assembled systems.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2004)
Introduction
cyanins in the excited state. Firstly, flavylium cations un-
dergo proton transfer to water in 5Ϫ20 ps (depending on
Anthocyanins are natural pigments of the flavonoid fam- the specific anthocyanin); that is, they are ‘‘super-photoac-
[
13]
ily (polyphenols), largely responsible for red and purple col- ids’’ with excited state pK ഠ Ϫ1.
Secondly, flavylium
cations are also powerful oxidants (excited state reduction
a
[
1]
ours in the plant world, in particular in flowers and fruits.
In naturally occurring anthocyanins, the flavylium chromo- potential ca. 2.5 V vs. H /H electrode).
ϩ
[14]
Consequently,
phore is substituted in various ways with OH, OMe and β- electron transfer to anthocyanins competes with ultra-fast
2
glycosyloxy groups (Figure 1).
proton transfer, even when the electron donor possesses a
relatively high ionization potential (8Ϫ9 eV), as in the case
[
15]
of benzoic and cinnamic acid derivatives.
From the biochemical point of view, anthocyanins also
[
16]
[17]
exhibit anti-inflammatory,
tective
vasoprotective,
neuropro-
activities in animal
models, and have been shown to exert anti-proliferative ef-
[
18]
[19Ϫ20]
and anti-hyperglycemic
[
21Ϫ23]
fects in cell cultures.
In addition, they also seem to
Figure 1. The flavylium cation form of common natural antho-
1
2
3
cyanins R ϭ H, β-glycosyl; R , R , R ϭ H, OH, OMe, O-β-glyco- play a role in preventing human pathologies related to oxi-
syl
[24Ϫ28]
dative stress.
Nevertheless, it is not yet established
Anthocyanins are used as food colorants,[2,3] laser dyes,[4]
which form or forms of the anthocyanin is or are involved.
Finally, the photooxidative properties of the flavylium
[5,6]
sensitizers for electrophotographic recordings
or photo-
[
13]
[
7]
form pose some puzzling questions as to the in vivo role
of anthocyanins, which in plant vacuoles are associated
voltaic TiO cells and as models for optical memory
2
[
8Ϫ12]
systems.
Recent studies have revealed two unusual
[
29]
with natural electron donors (IP ഠ 7.5 eV) such as quer-
citrin.
properties of the coloured flavylium cation forms of antho-
[
[
a]
b]
Attachment of a long aliphatic (lipophilic) chain may
confer interesting attributes on a (hydrophilic) flavylium
cation, such as surfactant behaviour, water insolubility and
solubility in low-polarity solvents. Specifically, it might be
expected that such functionalized flavylium salts in aqueous
dispersions of micro-heterogeneous media (i.e., micelles,
microemulsions and vesicles) should exclusively incorporate
Instituto de Tecnologia Qu ´ı mica e Biol o´ gica da Universidade
Nova de Lisboa,
Quinta do Marqu eˆ s, EAN, Apt 127, 2781-901 Oeiras, Portugal
Fax: (internat.) ϩ 351-214411277
E-mail:anacris@itqb.unl.pt
Instituto Superior T e´ cnico da Universidade T e´ cnica de Lisboa,
Av. Rovisco Pais, 1049-001, Lisboa, Portugal
Fax: (internat.) ϩ 351-218419606
E-mail: macanita@ist.utl.pt
Eur. J. Org. Chem. 2004, 4877Ϫ4883
DOI: 10.1002/ejoc.200400318
© 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4877

A. C. Fernandes et al.
FULL PAPER
into the interfaces of these microaggregates. This antici-
pated property opens routes to two planned studies in 1 and 2 was confirmed by analysis of their H and
The presence of the alkyl side chains in the flavylium salts
1
13
C
1
which anthocyanins seem to be appropriate, provided that NMR spectra. In the H NMR spectrum of 1, for example,
they remain in the interface: anthocyanin/antioxidant elec- the resonances corresponding to the protons of the alkyl
tron transfer in confined media, mimicking plant vacuoles, side chain were observed as two triplets at δ ϭ 0.43 (8ЈЈ-H)
and proton transfer for probing proton/water structure and and 2.59 ppm (1ЈЈ-H), one multiplet at δ ϭ 0.81Ϫ0.92 ppm
mobility at charged interfaces. Such studies cannot be car- (3ЈЈ-H-7ЈЈ-H) and one broad singlet at δ ϭ 1.31 ppm (2ЈЈ-
ried out with the non-functionalized flavylium salts, be- H) (see Exp. Sect.). In the 13C NMR spectra the signals
cause they are soluble in water and do not preferentially corresponding to the carbon atoms of the alkyl chain were
bind to neutral or positively charged micelles.[
30,31]
observed between δ ϭ 14.4 and 32.9 ppm (Figure 2).
Several pyrylium salts with long alkyl chains were pre-
pared by S. Balaban.[32Ϫ36] Introduction of an alkyl side
chain at the 4-positions of flavylium (benzopyrylium) cat-
ions Ϫ involving the addition of sodium benzotriazolate to
the flavylium salts, deprotonation by butyllithium at low
temperature, treatment with an alkyl halide and final loss
[
37,38]
of benzotriazole anion Ϫ has been studied previously.
Here we report an easy one-step procedure for the syn-
thesis of several flavylium salts containing alkyl side chains
in their 3-, 4Ј-, 5- or 6-positions. These positions cover all
possible orientations of the alkyl group around the mol-
ecule, which also enables different orientations of the
hydroxy group (which can be titrated) towards water when
the compounds are included in the microaggregates. We
also address some relevant photophysical properties of the
synthesized compounds.
Figure 2. Labelled carbon atoms of the flavylium salts
The 4Ј-hexyl- and 4Ј-dodecylacetophenone 3 and 4 (for
use in the synthesis of the flavylium salts 5 and 6) were
prepared by FriedelϪCrafts acylation of phenylhexane or
phenyldodecane with acetyl chloride in the presence of alu-
minium chloride (Scheme 2). The singlets at δ ϭ 2.55 ppm
1
(
CH ) in the H NMR spectra of the compounds 3 and 4,
3
and vibrations corresponding to the CϭO group in the in-
frared spectra, at 1682 cm for 3 and 1679 cm for 4,
Results and Discussion
Ϫ1
Ϫ1
confirmed the insertion of the acetyl group.
Synthesis
Introduction of alkyl side chains with eight and ten car-
bon atoms in the 3-positions of the flavylium salts 1 and 2
was possible by means of a reaction between 2,4-dihydroxy-
benzaldehyde and decanophenone or dodecanophenone
(Scheme 1). Compounds 1 and 2 were isolated in 36% and
43% yields, respectively.
Scheme 2. Synthesis of flavylium salts containing an alkyl side
chain in position 4Ј
The reaction between the 4Ј-hexyl- and 4Ј-dodecylaceto-
phenone and 2,4-dihydroxybenzaldehyde allowed the prep-
aration of the flavylium salts 5 and 6 in 48% and 73% yields,
1
13
respectively (Scheme 2). Analysis of the H and C NMR
spectra confirmed the presence of the alkyl chains in the
structures of the flavylium salts 5 and 6 (see Exp. Sect.).
Scheme 1. Synthesis of flavylium salts containing an alkyl side
chain in position 3
4878
© 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 4877Ϫ4883

One-Step Synthesis of Novel Flavylium Salts
FULL PAPER
Flavylium salts 7؊9 with alkyl side chains in their 5- and of flavylium salts (Scheme 4): hydration (K ), tautomeri-
h
6
-positions were isolated from reactions between ben- sation (K ) and isomerisation (K ).
t
i
zoylacetone and 4- or 5-alkylresorcinol derivatives
The effect of the micelle charge on the acid-base equilib-
(
Scheme 3). The flavylium salt 7, containing an alkyl side rium of 8 can be appreciated in Figure 3, c [pK (CTAB) ϭ
a
chain with five carbon atoms, was prepared in 67% yield 2.05 and pK (SDS) ϭ 7.05]. The five orders of magnitude
a
from 5-pentylresorcinol, while the flavylium salts 8 and 9, change in the acidity constant K is much larger than the
a
containing alkyl side chains with six and twelve carbon variation in the effective proton concentration at the micelle
[
40]
atoms, respectively, were obtained from 4-hexyl- or 4-do- surface between CTAB and SDS.
Instead, it reflects the
decylresorcinol in 71% and 99% yields, respectively.
strong effect of the micelle charge on the deprotonation rate
constants, the flavylium cation being stabilised by the nega-
tively charged SDS micelle and destabilised by the positively
[
31]
charged CTAB micelle.
The proton-transfer rate con-
stants of these compounds can be evaluated from light-
Scheme 3. Synthesis of flavylium salts containing an alkyl side
chain in positions 5 and 6
Relevant Physical and Spectroscopic Properties
All the flavylium salts (1, 2, 5Ϫ9) are insoluble or spar-
ingly soluble in water, but dissolve in water/non-aqueous
mixtures when the non-aqueous solvent (e.g., methanol,
polyethylene glycol, acetonitrile) is above 20Ϫ30% (v/v).
For compounds with alkyl side chains containing more
than 10 carbon atoms (6 and 9), the fraction of non-aque-
ous solvent had to be raised above 40% in order to make
them soluble in these mixtures. Additionally, there is some
evidence for self-aggregation (micelle formation) of these
compounds in the above mixtures. Specifically, there is a
decrease in the surface tension with increasing concen-
tration of the flavylium salt, which is now under detailed
study. Along with that, and regardless of the pH, all of the
newly synthesized compounds readily incorporate into
aqueous dispersions of anionic (SDS), cationic (CTAB) or
neutral (Triton X-100, C E ) surfactants above their criti-
1
2 10
cal micelle concentrations.
Absorption spectra of 8 in aqueous solutions of SDS and
CTAB micelles (Figure 3, a and b) show the flavylium cat-
؉
ion AH absorption at low pH values (λmax ഠ 430 nm),
while this is progressively replaced by the spectrum of the
deprotonated base form A (λmax ഠ 480 nm) at higher pH
values. The isosbestic point indicates that only these two
forms are present. Predominance of the base form at less Figure 3. Absorption spectra of 8 in aqueous solutions of: (a) SDS
2
0 mm micelles, and (b) CTAB 20 mm micelles, at the labelled pH
acidic pH values is typical of 4-methyl-substituted flavylium
values, and (c) HenderssonϪHasselbach plots for the titration of 8
[
39]
salts.
This is an advantage for study of the acid-base
in the same micelle solutions of SDS (filled symbols) and CTAB
equilibrium with little interference from the other equilibria (open symbols)
Eur. J. Org. Chem. 2004, 4877Ϫ4883
www.eurjoc.org
© 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4879

A. C. Fernandes et al.
FULL PAPER
Scheme 4
jump experiments,[41] and so compound 8 (and probably 7
and 9) can be regarded as useful probes of interfacial effects
on the kinetics and energetics of proton transfer.
In Figure 4, fluorescence spectra of 8 in SDS (see a in
Figure 4) and CTAB (see b in Figure 4) micelles show, in
addition to the emission of the flavylium cation (λmax
80 nm), the emission of the base form (λmax ഠ 580 nm).
The emission spectrum of 8 in CTAC, at pH ϭ 0.01, shows
strong emission of the base form, even though this form 480 nm and 580 nm, respectively
does not exist in the ground state at that pH (see b and c
ഠ
Figure 4. Normalised fluorescence spectra of 8 (λexcitation
30 nm) in aqueous solution of: (a) SDS 20 mm micelles, and (b)
CTAB 20 mm micelles at the labelled pH values; emissions of the
flavylium cation and of the base form are observed at λmax
ϭ
4
4
ഠ
in Figure 3). This observation demonstrates the occurrence
of ultra-fast excited-state proton transfer (ESPT) from the
flavylium cation to water, as observed with all studied syn-
thetic and natural anthocyanins.[
13,39,42]
In water, excited
state deprotonation of 4-methyl-substituted flavylium salts
is actually controlled by the Debye relaxation time of water
[
12]
(
ca. 6Ϫ7 ps). Compound 8 can thus be used to examine
the effect of interfaces (micelle, membrane, etc.) on water
mobility (water structure) in the interface vicinity, by meas-
urement of the excited state deprotonation rate constant in
such media. Such studies are not possible with water-sol-
uble non-functionalised flavylium salts, due to the low ef-
[31]
ficiency of incorporation into the interface.
A second interesting example of the spectroscopic
properties of the synthesized compounds is illustrated with
Figure 5. Absorption spectra of 5 in aqueous solution of C12
E
10
2
0 mm at pH values: (1) 0.06; (2) 0.43; (3) 1.13; (4) 2.18; (5) 2.92
5
. The predominant form of this compound (as well as 6)
[43]
at less acidic pH values is the C -chalcone form (λmax
ഠ
Z
3
80 nm), rather than the base (spectrum in SDS, at pH ϭ state C /C isomerisation,[43] thus converting the solution
Z E
7
.74, in Figure 5). The apparent pKapp is heavily dependent colour from pale yellow to deep orange (i.e., 5 is photo-
[
44]
on the surfactant, as found with 8 (5.1, and 0.5 in SDS and chromic). Tuning of this photochromic effect in microag-
C E micelles). The predomination of the C form, at less gregates is now possible with the aid of the functionalised
1
2
10
Z
acidic pH values, is typical of 4Ј-substituted flavylium compounds 5 and 6.
[
44]
salts. Excitation of the C , in the near UV, displaces the
The 3-substituted flavylium salts (compounds 1 and 2)
Z
equilibrium towards the flavylium cation, through excited mimic the behaviour of natural anthocyanins in the sense
4880
© 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 4877Ϫ4883

One-Step Synthesis of Novel Flavylium Salts
FULL PAPER
that the hemiacetal (λmax ഠ 280 nm) and the C forms are (16 mmol) and phenylhexane or phenyldodecane (16 mmol). After
E
having been heated at 50 °C for 1 h, the reaction mixture was co-
oled to room temperature and poured into ice and water (10 mL).
The reaction mixture was extracted with dichloromethane (3 ϫ
the most stable at less acidic pH values (Figure 6). Alky-
lation at the 3-position decreases the apparent pKapp (ap-
proximately equal to the hydration pK in the case of 1) to
h
100 mL), dilute sodium hydroxide solution (2 ϫ 50 mL) and water
ca. 4.8 in SDS micelles and 0.05 in C E micelles. This
1
2 10
(
2 ϫ 50 mL), and was finally dried with sodium sulfate. After evap-
property is convenient for study of co-pigmentation effects
oration of the solvent, the product was purified by silica gel column
chromatography with EtOAc/hexane (1:6) as eluent.
[
45]
(
fer
colour stabilisation)
and excited state electron trans-
[14]
of hydrophobic co-pigments such as flavones, which
1
4
Ј-Hexylacetophenone (3): Yellow oil. Yield 41% (1.34 g). H NMR
solubilize in micelles.
(
6
2
300 MHz, CDCl
3
, 25 °C): δ ϭ 0.86 (br. s, 3 H, 6ЈЈ-H), 1.28 (br. s,
H, 3ЈЈ-H to 5ЈЈ-H), 1.60 (br. s, 2 H, 2ЈЈ-H), 2.55 (s, 3 H, CH ),
.63 (t, J ϭ 9.0, 6.0 Hz, 2 H, 1ЈЈ-H), 7.24 (d, J ϭ 9.0 Hz, 2 H, 3Ј-
3
H, 5Ј-H), 7.86 (d, J ϭ 9.0 Hz, 2 H, 2Ј-H, 6Ј-H) ppm. IR (neat):
Ϫ1
ν˜ ϭ 1682 (CϭO) cm . C14
H20O (204.3): calcd. C 82.30, H 9.87;
found C 82.62, H 9.93.
4
3
6
1
2
9
Ј-Dodecylacetophenone (4): White solid. Yield 54% (2.49 g). M.p.
1
9Ϫ40 °C. H NMR (300 MHz, CDCl
.0 Hz, 3 H, 12ЈЈ-H), 1.18Ϫ1.27 (m, 18 H, 3ЈЈ-H to 11ЈЈ-H),
.58Ϫ1.62 (m, 2 H, 2ЈЈ-H), 2.55 (s, 3 H, CH ), 2.63 (t, J ϭ 9.0 Hz,
H, 1ЈЈ-H), 7.24 (d, J ϭ 9.0 Hz, 2 H, 3Ј-H, 5Ј-H), 7.85 (d, J ϭ
3
, 25 °C): δ ϭ 0.85 (t, J ϭ
3
Ϫ1
.0 Hz, 2 H, 2Ј-H, 6Ј-H) ppm. IR (neat): ν˜ ϭ 1679 (CϭO) cm
.
20
C H32O (288.5): calcd. C 83.27, H 11.18; found C 83.52, H 11.37.
General Procedure for the Preparation of 3- and 4Ј-Alkylflavylium
Salts 1, 2, 5 and 6: Equimolar amounts of decanophenone, dodeca-
nophenone, 4Ј-hexylacetophenone or 4Ј-dodecylacetophenone
(
2.4 mmol) and 2,4-dihydroxybenzaldehyde (2.4 mmol) were dis-
Figure 6. Absorption spectra of 1 in aqueous solution of C12
E
10
solved in acetic acid (20 mL). Gaseous hydrogen chloride was
gently bubbled into the mixture (4 h). After stirring at room tem-
perature for about 12 h, the reaction mixture was left at 0 °C for
another 12 h. The precipitate was filtered off and washed with di-
ethyl ether.
2
0
0 mm at pH values: (1) Ϫ0.61; (2) Ϫ0.31; (3) 0.06; (4) 0.18; (5)
.44; (6) 0.58; (7) 0.96; (8) 1.22
Conclusion
7-Hydroxy-3-octylflavylium Chloride (1): Red solid. Yield 36%
(
3
0.32 g). M.p. 159Ϫ161 °C. UV/Vis (MeOH/HCl): λmax ϭ 260, 300,
57, 425 nm. H NMR (300 MHz, [D ]methanol ϩ DCl, 25 °C):
4
Flavylium salts with alkyl side chains in their 3-, 4Ј-, 5-
or 6-positions can be prepared in moderate to excellent
yields by an easy one-step method. These compounds have
several potential applications in the area of self-assembled
1
δ ϭ 0.43 (t, 3 H, J ϭ 6.6, 6.9 Hz, 8ЈЈ-H), 0.81Ϫ0.92 (m, 10 H, 3ЈЈ-
H to 7ЈЈ-H), 1.31 (br. s, 2 H, 2ЈЈ-H), 2.59 (t, J ϭ 7.2, 8.1 Hz, 2 H,
1
ЈЈ- H), 7.05 (s, 1 H, 8-H), 7.11 (d, J ϭ 9.0 Hz, 1 H, 6-H),
and interface systems, due to the remarkable chemical ver- 7.26Ϫ7.35 (m, 3 H, 3Ј-H, 4Ј-H, 5Ј-H), 7.54 (d, J ϭ 7.2 Hz, 2 H,
satility of flavylium salts, both in the ground and in the 2Ј-H, 6Ј-H), 7.87 (d, J ϭ 9.0 Hz, 1 H, 5-H), 8.98 (s, 1 H, 4-H) ppm.
1
3
excited states (multiequilibria, photochromism and ultra-
fast proton and electron transfer in the excited state).
4
C NMR (300 MHz, [D ]methanol ϩ DCl, 25 °C): δ ϭ 14.4, 23.6,
3
1
0.1, 31.2, 31.9, 32.9, 103.0, 122.3, 124.5, 130.4, 131.2, 131.3, 131.8,
34.3, 134.5, 158.6, 161.8, 171.9, 173.1 ppm. ESI-MS: m/z ϭ 335
for C23
27 2 2
H O . C23H27ClO (370.9): calcd. C 74.48, H 7.34; found
C 74.65, H 7.28.
Experimental Section
3-Decyl-7-hydroxyflavylium Chloride (2): Dark green solid. Yield
General Remarks: Melting points were determined with a Büchi
43% (0.41 g). M.p. 145Ϫ147 °C. UV/Vis (MeOH/HCl): λ ϭ 263,
max
1
13
1
530 apparatus and are uncorrected. H and C NMR spectra were
300, 360, 428 nm. H NMR (300 MHz, [D ]methanol ϩ DCl, 25
4
recorded with a Bruker AMX 300 spectrometer. IR spectra were
recorded with a Unicam Mattson model 7000 FTIR spectrometer,
UV/Vis absorption spectra with a Olis Cary-15 spectrophotometer
conversion, and fluorescence spectra with a SPEX Fluorolog 212
in L conformation. The pH was measured at 20 °C with a Crison
micropH 2002, with the exception of very acidic solutions (pH Ͻ
°C): δ ϭ 0.22 (t, J ϭ 5.7, 6.9 Hz, 3 H, 10ЈЈ-H), 0.59 (br. s, 14 H,
3ЈЈ-H to 9ЈЈ-H), 1.10 (br. s, 2 H, 2ЈЈ-H), 2.38 (t, J ϭ 7.2 Hz, 2 H,
1ЈЈ-H), 6.84 (s, 1 H, 8-H), 6.90 (d, J ϭ 9.0 Hz,1 H, 6-H), 7.07Ϫ7.13
(m, 3 H, 3Ј-H, 4Ј-H, 5Ј-H), 7.33 (d, J ϭ 7.2 Hz, 2 H, 2Ј-H, 6Ј-H),
1
3
7.66 (d, J ϭ 9.0 Hz, 1 H, 5-H), 8.77 (s, 1 H, 4-H). C NMR
(300 MHz, [D ]methanol ϩ DCl, 25 °C): δ ϭ 14.4, 23.6, 30.1, 30.3,
4
4
2), for which values of proton concentration (HClO ) were used. 30.5, 30.6, 31.2, 31.8, 33.0, 102.9, 122.3, 124.5, 130.4, 131.2, 131.3,
Microanalyses were performed at the Elemental Analysis Service
of ITQB and the mass spectra were recorded at the Mass Spec-
trometry Service of ITQB.
131.9, 134.3, 134.5, 158.5, 161.8, 171.9, 173.1 ppm. ESI-MS: m/z ϭ
363 for C H O . C H ClO (399.0): calcd. C 75.26, H 7.83;
2
5
31
2
25 31
2
found C 75.47 H 7.95.
General Procedure for the Preparation of 4Ј-Hexyl- and 4Ј-Dodecyl-
4Ј-Hexyl-7-hydroxyflavylium Chloride (5): Yellow-green solid. Yield
acetophenones (3 and 4): Acetyl chloride (2.3 mL, 32 mmol) was 48% (0.39 g). M.p. 155Ϫ157 °C. UV/Vis (MeOH/HCl): λmax ϭ 268,
1
added dropwise over 5 min to a mixture of aluminium chloride
305, 363, 445 nm. H NMR (300 MHz, [D
4
]methanol ϩ DCl, 25
Eur. J. Org. Chem. 2004, 4877Ϫ4883
www.eurjoc.org
© 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 4881

A. C. Fernandes et al.
FULL PAPER
°
C): δ ϭ 0.26 (t, J ϭ 6.6 Hz, 3 H, 6ЈЈ-H), 0.71 (br. s, 6 H, 3ЈЈ-H,
ЈЈ-H, 5ЈЈ-H), 1.07 (t, J ϭ 6.6, 6.9 Hz, 2 H, 2ЈЈ-H), 2.16 (t, J ϭ
.6 Hz, 2 H, 1ЈЈ-H), 6.86 (d, J ϭ 9.0 Hz, 1 H, 6-H), 6.94Ϫ6.97 (m,
H, 3Ј-H, 5Ј-H, 8-H), 7.62 (d, J ϭ 9.0 Hz, 1 H, 5-H), 7.77Ϫ7.86 76.47, H 8.63.
31.4, 33.0, 102.9, 116.0, 120.8, 128.5, 129.9, 130.3, 131.1, 136.5,
138.8, 159.0, 169.5, 169.9, 170.4 ppm. ESI-MS: m/z ϭ 405 for
C H O . C28H37ClO (441.1): calcd. C 76.25, H 8.46; found C
28 37 2 2
4
6
3
(
m, 3 H, 3-H, 2Ј-H, 6Ј-H), 8.64 (d, J ϭ 8.4 Hz, 1 H, 4-H) ppm.
1
3
C NMR (300 MHz, [D ]methanol ϩ DCl, 25 °C): δ ϭ 14.6, 23.8,
4
3
1
0.2, 32.2, 33.0, 37.4, 104.0, 114.3, 121.5, 123.8, 128.3, 130.9, 131.7,
34.7, 154.7, 156.4, 161.4, 171.7, 173.7 ppm. ESI-MS: m/z ϭ 307
Acknowledgments
This work was supported by the Funda c¸ a˜ o para a Ci eˆ ncia e Tecnol-
ogia (FCT), Portugal (Project POCTI/QUI/38884/2001). C. R.
thanks the FCT for a research grant (032/BIC/2002). Maria da
Concei c¸ a˜ o Almeida and Ana Coelho are acknowledged for provid-
ing elemental analysis and mass spectrometry data, respectively, at
their services in ITQB.
for C21
C73.77, H 6.81.
23 2 2
H O . C21H23ClO (342.9): calcd. C 73.57, H 6.76; found
4Ј-Dodecyl-7-hydroxyflavylium Chloride (6): Brown solid. Yield
7
3% (0.74 g). UV/Vis (MeOH/HCl): λmax ϭ 268, 305, 363, 445 nm.
1
H NMR (300 MHz, [D ]methanol ϩ DCl, 25 °C): δ ϭ 0.33 (t,
4
J ϭ 5.4, 6.3 Hz, 3 H, 12ЈЈ-H), 0.72Ϫ0.80 (m, 17 H, 3ЈЈ-H-11ЈЈ-H),
.16 (br. s, 2 H, 2ЈЈ-H), 2.25 (t, J ϭ 7.2, 7.8 Hz, 2 H, 1ЈЈ-H), 6.94
d, J ϭ 9.0 Hz, 1 H, 6-H), 7.02Ϫ7.05 (m, 3 H, 3Ј-H, 5Ј-H, 8-H),
.70 (d, J ϭ 9.0 Hz, 1 H, 5-H), 7.86Ϫ7.95 (m, 3 H, 3-H, 2Ј-H, 6Ј-
1
(
7
[
1]
T. Goto, T. Kondo, Angew. Chem. Int. Ed. Engl. 1991, 30,
7Ϫ33.
G. A. Iacobucci, J. G. Sweeny, Tetrahedron 1983, 39,
3005Ϫ3038.
N. Chigurapati, L. Saiki, C. Gayser, A. K. Dash, Int. J. Pharm.
2002, 241, 293Ϫ299.
P. Czerney, G. Graness, E. Birckner, F. Vollmer, W. Rettig, J.
Photochem. Photobiol. A 1995, 89, 31Ϫ36.
S. Maruyama, T. Kubota, K. Kojima, H. Tamura, M. Harada,
Ger. Offen. 2,230,303; Chem. Abstr. 1973, 79, 414.
T. Kubota, K. Kojima, M. Ohta, Ger. Offen. 2,249,448; Chem.
Abstr. 1974, 80, 406.
N. J. Cherepy, G. P. Smestad, M. Grätzel, J. Z. Zhang, J. Phys.
Chem. 1997, 101, 9342Ϫ9351.
F. Pina, M. J. Melo, M. Maestri, P. Passaniti, N. Comaioni, V.
Balzani, Eur. J. Org. Chem. 1999, 3199Ϫ3207.
F. Pina, M. Maestri, V. Balzani, Chem. Commun. 1999,
107Ϫ114.
F. Pina, A. Roque, M. J. Melo, M. Maestri, L. Belladelli, V.
Balzani, Chem. Eur. J. 1998, 4, 1184Ϫ1191.
1
13
H), 8.72 (d, J ϭ 8.7 Hz, 1 H, 4-H) ppm. C NMR (300 MHz,
]methanol ϩ DCl, 25 °C): δ ϭ 14.7, 21.3, 23.9, 30.5, 30.9, 32.3,
[2]
[D
4
[
[
[
[
[
[
[
3]
4]
5]
6]
7]
8]
9]
3
1
3.3, 37.5, 104.1, 114.4, 121.6, 123.8, 128.3, 131.0, 131.8, 134.8,
54.8, 156.5, 161.5, 171.7, 173.8 ppm. ESI-MS: m/z ϭ 391 for
27 35 2 2
C H O . C27H35ClO (427.0): calcd. C 75.94, H 8.26; found C
75.99, H 8.55.
General Procedure for the Preparation of 5- and 6-Alkylflavylium
Salts 7؊9: These compounds were obtained from reactions be-
tween benzoylacetone and 5-pentyl-, 4Ј-hexyl- or 4Ј-dodecylresorci-
nol according to the general procedure for the preparation of 3-
and 4Ј-alkylflavylium salts.
7-Hydroxy-4-methyl-5-pentylflavylium Chloride (7): Orange solid.
Yield 67% (0.54 g). M.p. 98Ϫ100 °C. UV/Vis (MeOH/HCl): λmax
ϭ
1
3
°
03, 380, 438 nm. H NMR (300 MHz, [D
C): δ ϭ 0.45 (t, J ϭ 6.9 Hz, 3 H, 5ЈЈ-H), 0.91Ϫ0.93 (m, 4 H, 3ЈЈ-
H, 4ЈЈ-H), 1.30 (t, J ϭ 7.2 Hz, 2 H, 2ЈЈ-H), 2.41 (t, J ϭ 7.2, 8.1 Hz,
H, 1ЈЈ-H), 2.61 (s, 3 H, CH ), 6.69 (s, 1 H, 6-H), 7.14 (s, 1 H, 8-
H), 7.25Ϫ7.38 (m, 3 H, 3Ј-H, 4Ј-H, 5Ј-H), 7.98Ϫ8.03 (m, 3 H, 2Ј-
4
]methanol ϩ DCl, 25
[10]
[11]
F. Pina, M. J. Melo, M. Maestri, R. Ballardini, V. Balzani, J.
Am. Chem. Soc. 1997, 119, 5556Ϫ5561.
2
3
[
[
12]
13]
A. Roque, C. Lodeiro, F. Pina, M. Maestri, R. Ballardini, V.
Balzani, Eur. J. Org. Chem. 2002, 2699Ϫ2709.
P. Moreira, L. Giestas, C. Yihwa, C. Vautier-Giongo, F. Quina,
A. L. Ma c¸ anita, J. C. Lima, J. Phys. Chem. A 2003, 107,
H, 6Ј-H, 3-H) ppm. 1 C NMR (300 MHz, [D
3
]methanol ϩ DCl,
5 °C): δ ϭ 14.3, 23.4, 31.2, 32.5, 37.7, 109.9, 115.7, 117.7, 129.8,
30.6, 131.2, 137.3, 157.7, 160.4, 160.7, 171.5, 175.6 ppm. ESI-MS:
23ClO (342.9): calcd. C 73.57, H
4
2
1
4203Ϫ4210.
m/z ϭ 307 for C21
H
23
O
2
. C21
H
2
[
[
14]
15]
A. L. Ma c¸ anita, Proc. of 1st Iberian Conference on Photochem.,
Santiago de Compostela, Spain, 2003, p. 7.
6.76; found C 73.80, H 6.85.
6-Hexyl-7-hydroxy-4-methylflavylium Chloride (8): Yellow solid,
S. G. Lias, J. E. Bartmess, J. F. Liebman, J. L. Holmes, R. D.
Levin, W. G. Mallardin, S. G. Lias, R. D. Levin, S. A. Kafafi,
‘‘Ion Energetics Data’’ in NIST Chemistry WebBook, NIST
Standard Reference Database Number 69 (Eds.: P.J. Linstrom,
W.G. Mallard), National Institute of Standards and Technol-
ogy, Gaithersburg MD, 20899, July 2001 (http://webbook.-
nist.gov).
H. Wang, M. G. Nair, G. M. Strasburg, Y. Wang, A. M. Bo-
oren, J. I. Gray, D. L. Dewitt, J. Nat. Prod. 1999, 62, 294Ϫ296.
A. Ghiselli, M. Nardini, A. Baldi, C. Scaccini, J. Agric. Food
Chem. 1998, 46, 361Ϫ367.
yield 71% (0.60 g). M.p. 192Ϫ194 °C. UV/Vis (MeOH/HCl):
1
λ
max ϭ 265, 300, 425 nm. H NMR (300 MHz, [D
4
]methanol ϩ
DCl, 25 °C): δ ϭ 0.10 (t, J ϭ 6.9 Hz, 3 H, 6ЈЈ-H), 0.53Ϫ0.63 (m,
8
8
6
H, 3ЈЈ-H-5ЈЈ-H), 0.86Ϫ0.96 (m, 2 H, 2ЈЈ-H), 2.07 (t, J ϭ 7.5,
.1 Hz, 2 H, 1ЈЈ-H), 2.28 (s, 3 H, CH ), 6.79 (s, 1 H, 8-H),
.90Ϫ7.03 (m, 3 H, 3Ј-H, 4Ј-H, 5Ј-H), 7.42 (s, 1 H, 5-H), 7.63Ϫ7.68
]methanol
ϩ DCl, 25 °C): δ ϭ 14.1, 23.3, 30.0, 30.1, 31.1, 32.5, 102.6, 115.7,
3
[16]
(
m, 3 H, 3-H, 2Ј-H, 6Ј-H) ppm. 13C NMR (300 MHz, [D
4
[
[
17]
18]
1
1
20.6, 128.2, 129.6, 130.1, 130.8, 136.2, 138.5, 158.8, 169.2, 169.7,
70.1 ppm. ESI-MS: m/z ϭ 321 for C22 25ClO (356.9):
J. A. Josephi, B. Shukitt-Hale, N. A. Denisova, D. Bielinski,
A. Martin, J. J. McEwen, P. C. Bickford, J. Neurosci. 1999,
H
25
O
2
. C22
H
2
calcd. C 74.04, H 7.06; found C 74.13, H 7.24.
1
9, 8114Ϫ8121.
[
[
19]
20]
6-Dodecyl-7-hydroxy-4-methylflavylium Chloride (9): Yellow solid.
T. Matsiu, S. Ebuchi, M. Kobayashi, K. Fukui, K. Sugita, N.
Terahara, K. Matsumoto, J. Agric. Food Chem. 2002, 50,
7244Ϫ7248.
Yield 99% (1.03 g). M.p. 165Ϫ167 °C. UV/Vis (MeOH/HCl):
1
λ
max ϭ 265, 300, 425 nm. H NMR (300 MHz, [D
DCl, 25 °C): δ ϭ 0.29 (t, J ϭ 6.0, 7.5 Hz, 3 H, 12ЈЈ-H), 0.69Ϫ0.81
m, 18 H, 3ЈЈ-H-11ЈЈ-H), 1.14 (br. s, 2 H, 2ЈЈ-H), 2.29 (t, J ϭ 7.8,
4
]methanol ϩ
T. Tsuda, F. Horio, K. Uchida, H. Aoki, T. Osawa, J. Nutr.
2
003, 133, 2125Ϫ2130.
(
[21]
S. Y. Kang, N. P. Seeram, M. G. Nair, L. D. Bourquin, Cancer
Lett. 2003, 194, 13Ϫ19.
7
.5 Hz, 2 H, 1ЈЈ-H), 2.49 (s, 3 H, CH
.12Ϫ7.23 (m, 3 H, 3Ј-H, 4Ј-H, 5Ј-H), 7.64 (s, 1 H, 5-H), 7.85Ϫ7.90
]methanol
ϩ DCl, 25 °C): δ ϭ 14.4, 21.0, 23.7, 30.3, 30.4, 30.5, 30.6, 30.7,
3
), 6.99 (s, 1 H, 8-H),
7
[22]
[23]
D. X. Hou, Curr. Mol. Med. 2003, 3, 149Ϫ159.
I. Konczak-Islam, M. Yoshimoto, D. X. Hou, N. Terahara, O.
Yamakawa, J. Agric. Food Chem. 2003, 51, 5916Ϫ5922.
(
m, 3 H, 2Ј-H, 6Ј-H, 3-H) ppm. 13C NMR (300 MHz, [D
4
4882
© 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 4877Ϫ4883

One-Step Synthesis of Novel Flavylium Salts
FULL PAPER
M. Bogatian, G. Mihai, M. Plaveti, F. Chiraleu, M. Maganu,
V. Badescu, T. Balaban, Rev. Roum. Chim. 1998, 43, 315Ϫ320.
M. Bogatian, V. C ˆı mpeanu, S. Serban, G. Mihai, T. Balaban,
Rev. Roum. Chim. 2001, 46, 115Ϫ120.
A. R. Katritzky, P. Czerney, J. R. Level, W. Du, Eur. J. Org.
Chem. 1998, 2623Ϫ2629.
A. R. Katritzky, P. Czerney, J. R. Levell, J. Org. Chem. 1997,
[
[
24]
25]
[35]
[36]
H. Matsumoto, Y. Nakamura, M. Hirayama, Y. Yoshiki, K.
Okubo, J. Agric. Food Chem. 2002, 50, 5034Ϫ5037.
S. Miranda-Rottmann, A. A. Aspillaga, D. D. Perez, L. Vas-
quez, A. L. Martinez, F. Leighton, J. Agric. Food Chem. 2002,
[
[
[
[
[
[
37]
38]
39]
40]
41]
42]
50, 7542Ϫ7547.
[
[
[
[
[
26]
27]
28]
29]
30]
M. P. Kahkonen, M. Heinonen, J. Agric. Food Chem. 2003,
51, 628Ϫ633.
M. P. Kahkonen, J. Heinamaki, V. Ollilainen, M. Heinonen, J.
Agric. Food Chem. 2003, 83, 1403Ϫ1411.
J. M. Kong, L. S. Chia, N. K. Goh, T. F. Chia, R. Brouillard,
Phytochemistry 2003, 64, 923Ϫ933.
J. S. Wright, E. R. Johnson, D. J. Carpenter, J. Am. Chem. Soc.
62, 8198Ϫ8200.
J. C. Lima, I. Abreu, M. H. Santos, R. Brouillard, A. L. Ma-
c¸ anita, Chem. Phys. Lett. 1998, 298, 189Ϫ195.
C. Drummond, F. Grieser, Photochem. Photobiol. 1987, 45,
19Ϫ34.
A. L. Ma c¸ anita, P. Moreira, J. C. Lima, F. H. Quina, C. Yihwa,
C. Vautier-Giongo, J. Phys. Chem. A 2002, 106, 1248Ϫ1255.
L. Giestas, C. Yihwa, J. C. Lima, C. Vautier-Giongo, A. Lopes,
F. H. Quina, A. L. Ma c¸ anita, J. Phys. Chem. A 2003, 107,
3263Ϫ3267.
F. Pina, L. Benedito, M. J. Melo, A. J. Parola, J. C. Lima, A.
L. Ma c¸ anita, An. Quim. 1997, 93, 111Ϫ118.
P. Figueiredo, J. C. Lima, M. H. Santos, M. C. Wigand, R.
Brouillard, A. L. Ma c¸ anita, F. Pina, J. Am. Chem. Soc. 1994,
116, 1249Ϫ1254.
2
001, 123, 1173Ϫ1183.
J. C. Lima, C. Vautier-Giongo, A. Lopes, E. C. Melo, F. H.
Quina, A. L. Ma c¸ anita, J. Phys. Chem. A 2002, 106,
5
851Ϫ5859.
[
31]
C. Vautier-Giongo, C. Yihwa, P. F. Moreira Jr., J. C. Lima,
[43]
A. A. Freitas, F. H. Quina, A. L. Ma c¸ anita, Langmuir 2002,
1
8, 10109Ϫ10115.
[
[
[
32]
33]
34]
[44]
T. Balaban, M. Bogatian, M. Plaveti, V. Badescu, G. Mihai,
Rev. Roum. Chim. 1991, 36, 229Ϫ234.
M. Bogatian, C. Deleanu, G. Mihai, T. Balaban, Z. Natur-
forsch., Teil B 1992, 47, 1011Ϫ1015.
M. Bogatian, G. Mihai, M. Plaveti, F. Chiraleu, C. Deleanu, V.
Badescu, T. Balaban, Rev. Roum. Chim. 1996, 41, 979Ϫ987.
[45]
G. Mazza, R. Brouillard, Food Chem. 1987, 25, 207.
Received May 6, 2004
Eur. J. Org. Chem. 2004, 4877Ϫ4883
www.eurjoc.org
© 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4883