Identification of 7,4′-dihydroxy-5-methoxyflavylium in "dragon's blood": To be or not to be an anthocyanin

Article abstract of DOI:10.1002/chem.200600837

The compound 7,4′-dihydroxy-5-methoxyflavylium (dracoflavylium) was identified as the major red colorant in samples of the resin "dragon's blood", extracted from the tree Dracaena draco. The complex network of reversible chemical reactions that dracoflavy

Full text of DOI:10.1002/chem.200600837

FULL PAPER
DOI: 10.1002/chem.200600837
Identification of 7,4’-Dihydroxy-5-methoxyflavylium in “Dragonꢀs Blood”: To
Be or Not To Be an Anthocyanin
Maria J. Melo,*[a, b] Micaela Sousa,[a, b] A. Jorge Parola,[a] J. SØrgio Seixas de Melo,[c]
Fernando Catarino,[d] Joaquim MarÅalo,[e] and Fernando Pina*[a]
Abstract: The compound 7,4’-dihy-
droxy-5-methoxyflavylium (dracoflavy-
lium) was identified as the major red
colorant in samples of the resin “drag-
onꢀs blood”, extracted from the tree
Dracaena draco. The complex network
of reversible chemical reactions that
dracoflavylium undergoes in aqueous
solution is fully described; for the first
time, all the equilibrium constants that
enable a complete characterisation of
the system have been obtained (K’a =
1.6”10ꢀ4, Ka1 =1.0”10ꢀ4, Ka2 =3.2”
10ꢀ8, KCt1 =1.0”10ꢀ7, KCt2 =1.3”10ꢀ10).
It is concluded that the red colour is
due to a stable quinoid base, A, which
is the major species at pH 4–7. It is fur-
ther shown that this compound does
not fit the commonly accepted defini-
tions of anthocyanidin nor 3-deoxyan-
thocyanidin. Similarly to synthetic fla-
vylium salts, the natural compound
7,4’-dihydroxy-5-methoxyflavylium
gives rise to several species (multistate
system) reversibly interconverted by
external stimuli, such as pH.
Keywords: dyes/pigments · flavyli-
um salts
· kinetics · multistate
systems · natural products
Introduction
on the causes of colour in flowers and fruits[2c] tends to be
forgotten, and is seldom cited as such. Moreover, the con-
cept that the red colour of the resin named “dragonꢀs
blood” is given by natural flavylium compounds has been
Red colorants from “dragonꢀs blood”: Synthetic flavylium
salts,[1] anthocyanins[2] and natural flavylium compounds,[3]
discovered in this order, all have the 2-phenyl-1-benzopyry-
lium chromophore in common. It is worth noting that the
crucial and fundamental paper by Willstätter and Mallinson
[4]
overlooked during the past fewdecades.
Dragonꢀs blood is a natural resin, presenting a rich, deep-
red colour, obtained from various trees, namely, Dracaena
draco and Dracaena cinnabaris belonging to the Dracaena-
ceae family. It is known that it appears in injured areas of
the tree,[5] and it has been used for centuries for medical
and artistic purposes.[6]
[a] Dr. M. J. Melo, M. Sousa, Dr. A. J. Parola, Prof. Dr. F. Pina
REQUIMTE-CQFB, Chemistry Department
Faculty of Sciences and Technology of the NewUniversity Lisbon
Campus da Caparica (Portugal)
The suggestion that dracorubin (Table 1), one of the red
compounds isolated from a commercial, powdered dragonꢀs
blood resin,[7] was a 2-phenyl-1-benzopyran derivative was
made by Brockmann and Haase in 1936.[7a] Later, in 1943,
Brockmann and Junge published the first structure of anoth-
er of the red colorants, which was named dracorhodin
(Table 1);[8] in their paper they concluded that dracorhodin
was a natural 2-phenyl-1-benzopyrylium (a flavylium salt)
that should belong to the anthocyanin family.[8] A more
straightforward synthesis, and consequent confirmation of
this molecule, was published by Robertson and Whalley in
1950.[9a] However, the structure of dracorubin had to wait
until 1950 to be fully unveiled by Robertson and Whal-
ley;[9b,c] and only in 1976 was it synthesised.[9d] In the mean-
time, two other red colorants from dragonꢀs blood were
characterised (lacking the methyl group in the 6-position)
Fax : (+351)21-294-8550
E-mail: mjm@dq.fct.unl.pt
fjp@dq.fct.unl.pt
[b] Dr. M. J. Melo, M. Sousa
Department of Conservation and Restoration
NewUniversity Lisbon (Portugal)
[c] Dr. J. S. S. de Melo
Chemistry Department
Coimbra University (Portugal)
[d] Prof. Dr. F. Catarino
Botanical Garden
University of Lisbon (Portugal)
[e] Dr. J. MarÅalo
Chemistry Department
Instituto Tecnológico Nuclear (Portugal)
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author.
Chem. Eur. J. 2007, 13, 1417 – 1422
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1417

ed to anthocyanins,[12] the natural colorants responsible for
the exuberance of reds, blues and purples in nature. It is
worth noting that the distribution of the species reported in
Scheme 1 is dramatically dependent on the substitution pat-
tern of the 2-phenyl-1-benzopyran. Anthocyanins are char-
acterised by a hydroxyl group
Table 1. Chemical structures responsible for the red colour in dragonꢀs
blood resins.
Structure[a]
Year[b]
dracorhodin
1943, [8]1950[9a]
in positions 4’ and 7, and a
sugar group in position
3
(mono
and
A
nordracorhodin
1971[4b]
(Scheme 2). On the other hand,
in anthocyanidins the hydroxyl
groups take the positions of the
glycosides, leading to unstable
structures in solution. On the
contrary, the so-called deoxyan-
thocyanidins correspond to “an-
Scheme 2. In the basic chemi-
cal structure of anthocyanins, a
hydroxyl group in positions 4’
and 7 is present, and a sugar
(Gl) in position 3 (monoglyco-
sides) or positions 3 and 5 (di-
dracorubin
1936, 1937,[7] 1950,[9b] 1976[9d]
thocyanidins”[13] lacking the hy- glycosides).
droxyl group in position 3 (but
dracoflavylium
2006
bearing an hydroxyl in position
5), and are quite stable in solution.
In the 1970s, it was firmly established by Dubois and
Brouillard (anthocyanins)[14] and McClelland (synthetic fla-
vylium salts)[15] that both families of compounds undergo
multiple structural transformations in aqueous solution, fol-
lowing the same basic mechanisms (Scheme 1).[16] The flavy-
lium cation (AH+) is the dominant species in very acidic
solutions, but with increasing pH a series of more or less re-
versible chemical reactions take place: 1) deprotonation
leading to the quinoid base (A), 2) hydration of the flavyli-
um cation giving rise to the colourless hemiacetal (B),
3) tautomerisation reaction, responsible for ring opening, to
[a] The structures correspond to the quinoid bases (A). [b] Years in
which the structures were discovered and published.
and named nordracorhodin (Table 1) and nordracorubin.[4b]
Again, these compounds were obtained from a commercial
batch of a resin imported from Singapore; most probably,
these resins were from the palm tree Daemonorops draco.
The most interesting aspect of Table 1 is that all of the struc-
tures are simply the quinoid base (A) of the respective fla-
vylium cation (AH+), as can be
confirmed in Scheme 1. In
other words, at sufficiently
acidic pH values, in all of them,
the quinone is protonated and a
hydroxyl group is formed, lead-
ing to the respective flavylium
cation.
In the following years, many
other compounds from dragonꢀs
blood resins—with precise geo-
graphic origins and plant spe-
cies—were characterised,[10,11]
but none could be responsible
for the dragonꢀs blood red
colour, unlike those previously
reported in Table 1,[11] owing to
a lack of conjugation between
the three rings, a requirement
for obtaining this colour.
Equilibria in solution: As
stated above, dracorhodin was
regarded as a natural flavylium
salt.[8] Flavylium salts are relat- Scheme 1. Network of chemical reactions for dracoflavylium.
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Dragonꢀs Blood
FULL PAPER
give the pale-yellow Z-chalcone
form (Cc), and finally, 4) cis–
trans isomerisation to form the
pale-yellow E-chalcone (Ct).
Furthermore, at higher pH, and
depending on the number of
hydroxyl groups, further depro-
Scheme 3. Synthetic approach for 7,4’-dihydroxy-5-methoxyflavylium/dracoflavylium.
tonated species are found, such
as Ctnꢀ and Anꢀ. The relevant
contribution for colour is given
(pKa1 =4.0); further increase of the pH leads to an absorp-
tion band characteristic of the pink ionised base Aꢀ (pKa2 =
7.5).[16a] The spectra obtained at thermal equilibrium for
pH<6 is shown in Figure 1 (bottom). The flavylium cation
is again the dominant species at more acidic pH values, but
for higher pH values an equilibrium is established between
the base A (63%) and the trans-chalcone Ct (37%).
by AH+ and the quinoid bases.
In this work, we report on the discovery of a natural fla-
vylium in dragonꢀs blood resin from Dracaena draco, the
compound 7,4’-dihydroxy-5-methoxyflavylium,[17] from here
onwards called dracoflavylium (as it is the first natural flavy-
lium discovered in a Dracaena draco tree). This compound
does not fit the commonly accepted definition of an antho-
cyanidin,[13] or 3-deoxyanthocyanidin as some authors re-
cently have proposed for analogous structures from Arrabi-
daea chica,[18] as a methoxy group was found in position 5.
The dracoflavylium structure, and principally its chemical
behaviour, is closer to the so-called synthetic flavylium
salts,[15,17] as will be described throughout this work.
7,4’-Dihydroxy-5-methoxyflavylium (3) was also synthes-
ised according to Scheme 3. Formylation of 4-methoxyresor-
cinol (1) led to salicylaldehyde 2, which reacts with 4’-hy-
droxyacetophenone under acidic conditions to give flavyli-
um salt 3.
Results and Discussion
In order to understand the chemistry of 7,4’-dihydroxy-5-
methoxyflavylium and its pH colour dependence, a complete
characterisation of all equilibrium and transient species was
carried out in acidic and basic media.
Acidic media: Similarly to the other flavylium compounds,
7,4’-dihydroxy-5-methoxyflavylium is involved in a complex
network of chemical reactions (Scheme 1) in which the dif-
ferent forms can be reversibly interconverted by changing
the pH: the yellowflavylium cation ( AH+), the quinoid
bases (red A and pink Aꢀ) reached by deprotonation of
AH+, hemiketal species B obtained by hydration at the 2-
position of AH+, cis-chalcone Cc formed from hemiketal B
and trans-chalcone Ct and ionised trans-chalcones (Ctꢀ,
Ct2ꢀ), obtained from Cc by means of a cis–trans isomerisa-
tion reaction. The ionised Cc forms that are also formed as
transient species were omitted for simplification.
The spectral variations of 7,4’-dihydroxy-5-methoxyflavyli-
um occurring after approximately one minute upon displac-
ing the system from equilibrium by means of a pH jump
from the stock solutions at pH 1 to higher pH values are re-
ported in Figure 1 (top). At very acidic pH the absorption
band of the yellowflavylium cation, AH+, is dominant; by
increasing the pH a newband centred at l=493 nm is ob-
tained owing to the formation of the red quinoid base A
Figure 1. Top: Spectral variations occurring immediately (ca. 1 min) upon
a pH jump from equilibrated solutions of the dracoflavylium (4”10ꢀ6 m)
at pH 1.0 to higher pH values; Bottom: the same after thermal equilibra-
tion. Inset: calculated pKa1 and pKa2.
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M. J. Melo, F. Pina et al.
One interesting feature of the chemistry of most 2-
phenyl-1-benzopyrylium derivatives, including anthocyanins,
that contributes to the different species distribution ob-
served immediately after and at equilibrium (Figures 1 and
2) is the fact that hemiketal B is exclusively formed through
the hydration of AH+, and not from the hydration of A.[13]
In kinetic terms, the rate of formation of B is given by
Equation (1), that is, it is proportional to the concentration
of flavylium cation.
d½BŠ
¼ kh½AHþŠꢀkꢀh½BŠ½HþŠ
ð1Þ
dt
This behaviour has implications for the kinetics of the disap-
pearance of A. When a pH jump from equilibrated solutions
at very acidic pH values, for example pH 1, is carried out to
sufficiently high pH values, base A is immediately formed
because proton transfer is a very fast reaction, much faster
than the hydration to give B. Taking into account that AH+
and A are in fast equilibrium, A only disappears because
AH+ leads to B, which in turn will evolve to Ct, through Cc.
At near-neutral pH values the concentration of AH+ is very
low, and by consequence A becomes a kinetic product,
which evolves slowly to equilibrium (kobs =1.7”10ꢀ4 sꢀ1 at
pH 6.0).
Figure 2. Spectral variations of the trans-chalcone species, taken immedi-
ately upon a pH jump from the equilibrated solutions at pH 12.0 to lower
pH values. Inset: determination of the respective pKa values at l=480
and 320 nm.
Table 2. Equilibrium constants for 7,4’-dihydroxy-5-methoxyflavylium at
258C (estimated error: 10%).
K’a
Ka1
Ka2
KCt1
KCt2
1.6”10ꢀ4
1.0”10ꢀ4
3.2”10ꢀ8
1.0”10ꢀ7
1.3”10ꢀ10
Basic media: In moderately basic media, base Aꢀ is immedi-
ately formed by deprotonation of the hydroxyl groups, and
disappears through the nucleophilic attack by OHꢀ, leading
to
a
final product Ct
2ꢀ(Ctꢀ), with rate constant 55”
A
[OHꢀ] sꢀ1. At pH 8–9 the concentration of hydroxyl is very
low, and by consequence Aꢀ is also a kinetic product, which
takes several days to reach equilibrium. The percentage of
Aꢀ at equilibrium, pH 8.8, is 31%, in good agreement with
the value calculated by using Equation (12) in the Support-
ing Information. On the contrary, at pH>12 the reaction is
fast, leading to a final product that was confirmed by
1H NMR spectroscopy as Ct2ꢀ.
The pKa of the trans-chalcones was measured by carrying
out a titration starting from Ct2ꢀ back to acidic medium, and
the spectra monitored after one minute; the values pKCt2
=
Figure 3. Variation of mole fraction distribution with pH for 7,4’-dihy-
droxy-5-methoxyflavylium, at 258C [obtained by using Eqs. (9)–(14) in
the Supporting Information and the equilibrium constants reported in
Table 2].
9.3 (Ct2ꢀ/Ctꢀ) and pKCt1 =7.0 (Ctꢀ/Ct) were obtained
(Figure 2). When a pH jump from equilibrated solutions at
pH 12 to 1 was carried out (Figure 2) the flavylium cation
formed with a rate constant of 2.1”10ꢀ3 sꢀ1, which indicates
the existence of a moderate barrier for the cis–trans isomeri-
sation as reported for the parent compound 7,4-dihydroxy-
flavylium.[16c–e] A cycle starting from pH 1 (AH+) to 12 (Ct2)
and back to pH 1 allows recovery of all the initial flavylium
cations, showing the excellent reversibility of the system.
As shown in the Supporting Information, the set of equi-
librium constants calculated through this work, and reported
in Table 2, permits the calculation of the mole fraction dis-
tribution of all species of the network at the equilibrium, as
shown in the conclusive Figure 3.
and for moderately basic solutions there is also a contribu-
tion from the pink colour of the ionised base, Aꢀ.
Conclusion
Dragonsꢀs blood is yellowin strongly acidic solutions, be-
cause the different species present, shown in Table 1, are fla-
vylium cations (AH+) at these pH values. At moderately
acidic pH values, the red quinoid base A is formed, which
gives the resin its characteristic colour. To the best of our
knowledge, this is the first known natural flavylium com-
Inspection of Figure 3 clearly shows that at moderately
acidic pH values such as those measured for the resin, the
concentration of the red base at equilibrium is very high,
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Dragonꢀs Blood
FULL PAPER
ment with published data for this compound);[24] 1H NMR (D2O/NaOD,
pD>12, 308C, equilibrated, Ct2ꢀ form): d=3.59 (s, 3H; OCH3), 5.33 (s,
1H; H6 or H8), 6.37 (d, J=9.0 Hz, 2H; H3’+H5’), 7.51 (d, J=15.9 Hz,
1H; H3), 7.58–7.63 (m, 3H; H6 or H8, H2’+H6’), 8.09 ppm (d, J=
15.9 Hz, 1H; H4); HRMS: m/z: calcd for C16H11O4ꢀ: 267.06628; found:
267.06634 [MꢀH]ꢀ; calcd for C15H9O4ꢀ: 253.05063; found: 253.04991
[MꢀCH3]ꢀ; elemental analysis calcd (%) for C16H14O8S·3.5H2O (Mr =
429.40 gmolꢀ1): C 44.76, H 4.93, S 7.47; found: C 44.91, H 4.02, S 7.35.
pound for which the base is the major species at biological
pH (63%). One other interesting aspect is the unusual sta-
bility of the pink ionised base: at pHꢁ8–9, the final equilib-
rium contains 30% ionised base. For the most common an-
thocyanins and 3-deoxyanthocyanidins[15,19] in moderately
acidic to neutral pH, colourless B is the major species, to-
gether with Ct. The existence of a hydroxyl group at the 5-
position and not in the 3-position leads to thermodynamical-
ly more-stable red quinoid bases; but not to the pair red
(AH+)/blue (A), only to yellow( AH+)/red (A). Blue col-
ours are formed, in anthocyanins, through beautiful and
complex supramolecular structures, as brilliantly shown by
GoTo, Kondo and collaborators.[20]
Finally we would like to propose the name dracoflavylium
for the 7,4’-dihydroxy-5-methoxyflavylium salt, in spite of
the fact that all the compounds in Table 1 should be consid-
ered bases of a flavylium compound. We would like to em-
phasise that the red colour in dragonꢀs blood, extracted
from Draceana draco, is caused by this family of molecules.
Table 3. 1H and 13C NMR data[a] for 7,4’-dihydroxy-5-methoxyflavylium
hydrogen sulfonate.
Position
1H NMR
COSY
13C NMR
HMBC[b]
d [ppm] (J [Hz])
d [ppm]
2
3
4
5
6
7
8
173.1
111.1
149.1
161.0
100.9
160.3
96.7
8.09 (d, 9.2)
9.08 (d, 9.2)
4
3
C2, C10
C2, C9, C5
6.78 (s)
7.03 (s)
8
6
C5, C10, C8
C7, C10, C6
9
10
1’
2’,6
3’,5’
4’
172.4
113.8
121.0
133.4
118.5
167.6
57.8
8.32 (d, 9.3)
7.07 (d, 9.3)
3’, 5’
2’, 6’
C2, C4’, (C2’, C6’)
AHCTREUNG
ExperimentalSection
5-OCH3
4.09 (s)
General: All reagents and solvents used were of analytical grade. Sol-
vents used for spectroscopic studies were of spectroscopic or equivalent
grade, and the water used was of Millipore grade. NMR spectra were re-
corded on a Bruker AMX400 spectrometer operating at 400 MHz (1H)
or 100 MHz (13C). High-resolution mass spectra (HRMS) were obtained
by means of laser desorption/ionisation (LDI) with a Finnigan FT/MS
2001-DT Fourier transform ion cyclotron resonance mass spectrometer
(FTICR/MS), equipped with a 3 tesla superconducting magnet and cou-
pled to a Spectra-Physics Quanta-Ray GCR-11 Nd:YAG laser operating
at the fundamental wavelength (l=1064 nm). Elemental analyses were
obtained on a Thermofinnigan Flash EA 1112 Series instrument.
[a] See the Experimental Section for details. [b] Correlation from H to
the indicated carbon atoms.
Acknowledgements
This work was supported by the Portuguese Science Foundation and
FEDER through the Associate Laboratory for Green Chemistry and the
projects POCI/QUI/55672/2004 (The Molecules of Colour in Art: a Pho-
tochemical Study) and POCTI/EAT/33782/2000 (An Interdisciplinary
Approach to the Study of Colour in Portuguese Manuscript Illumina-
tions).
Isolation and identification of 7,4’-dihydroxy-5-methoxyflavylium: The
resin was extracted from Dracaena draco centenary trees existing in the
region of Lisbon (Autumn 2005) as well as from trees in the Funchal Nat-
ural Park (Island of Madeira, Summer 2005). The red colorants[21] were
extracted by using methanol (acidified, [H+]ꢁ10ꢀ2 m), and separated by
using HPLC with a DAD detector (Thermofinnigan, Surveyor PDA 5), a
RP-18 column and a water (pH 1.5)/methanol gradient.[22]
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[2] a) R. Willsttäter, A. E. Everest, Justus Liebigs Ann. Chem. 1913,
401, 189–232; b) R. Willsttäter, H. Mallinson, Justus Liebigs Ann.
Chem. 1915, 408, 15–41; c) R. Willsttäter, H. Mallinson, Justus Lie-
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1937, 70, 1733–1738; c) The authors stated that the most common
origin for the commercial (Merck) resin was the palm tree Calamus
draco (Daemonorops draco).
The identification of the isolated compound was made on the basis of
HRMS and 1H NMR spectroscopy, although complete structure confir-
mation required the synthesis of 7,4’-dihydroxy-5-methoxyflavylium. The
isolated compound had the same retention time (tR =20.50 min), UV/Vis
spectra by HPLC-DAD (lmax =477 nm) and the same molecular mass
peaks (HRMS: m/z: calcd for C16H11O4ꢀ: 267.06628; found: 267.06646
[MꢀH]ꢀ; calcd for C15H9O4ꢀ: 253.05063; found: 253.05025 [MꢀCH3]ꢀ) as
1
the synthesised flavylium. The H NMR spectra of the isolated and of the
synthesised compounds in acidic CD3OD are identical, except for some
peak overlap owing to the presence of minor impurities in the isolated
sample.
Synthesis of 7,4’-dihydroxy-5-methoxyflavylium hydrogen sulfate: The
title compound was prepared from condensation of 4’-hydroxyacetophe-
none (0.575 g, 4.2 mmol) and 2,4-dihydroxy-6-methoxybenzaldehyde[23]
(0.710 g, 4.2 mmol). The reagents were dissolved in acetic acid (20 cm3),
and concentrated sulphuric acid (5 cm3) was added; the temperature was
kept below50 8C (ꢁ10 min). The red solution was stirred overnight. Ad-
dition of diethyl ether led to the precipitation of a deep-red solid that
was filtered, washed with cold water and with diethyl ether, and dried
under vacuum to give the product (0.707 g, 46% not optimised). The
product can be recrystallised from acetic acid. 1H NMR (400 MHz,
CD3OD/CF3CO2D, 30 8C, AH+ form): see Table 3 (values are in agree-
[8] H. Brockmann, H. Junge, Ber. Dtsch. Chem. Ges. B 1943, 76, 751–
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Received: June 14, 2006
Published online: November 20, 2006
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