A golden opportunity: Benzofuranone modifications of aurones and their influence on optical properties, toxicity, and potential as dyes

Article abstract of DOI:10.3762/bjoc.15.171

Aurones are a small subclass of the flavonoid family known primarily for their unusual structure and the golden yellow color they impart to the flowers of snapdragons and cosmos. Most studies of aurones focus on their range of biological activities, but relatively little has been reported with respect to their optical properties, unlike their aza and thio analogs. What little is known has focused entirely on the influence of the benzylidene portion. In this study, the influence of substitution in the benzofuranone ring on the UV-vis spectrum is explored, as well as an initial screening of their toxicity and a qualitative preliminary study of their potential to act as fabric dyes.

Full text of DOI:10.3762/bjoc.15.171

A golden opportunity: benzofuranone modifications of
aurones and their influence on optical properties,
toxicity, and potential as dyes
Joza Schmitt and Scott T. Handy*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2019, 15, 1781–1785.
Department of Chemistry, Middle Tennessee State University,
Murfreesboro, TN 37132, USA
doi:10.3762/bjoc.15.171
Received: 25 April 2019
Accepted: 12 July 2019
Published: 25 July 2019
Email:
Scott T. Handy* - scott.handy@mtsu.edu
*
Corresponding author
This article is part of the thematic issue "Dyes in modern organic
chemistry".
Keywords:
aurone; dyeing; dyes; substitution effect; toxicity; UV–vis spectrum
Guest Editor: H. Ihmels
©
2019 Schmitt and Handy; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
Aurones are a small subclass of the flavonoid family known primarily for their unusual structure and the golden yellow color they
impart to the flowers of snapdragons and cosmos. Most studies of aurones focus on their range of biological activities, but relative-
ly little has been reported with respect to their optical properties, unlike their aza and thio analogs. What little is known has focused
entirely on the influence of the benzylidene portion. In this study, the influence of substitution in the benzofuranone ring on the
UV–vis spectrum is explored, as well as an initial screening of their toxicity and a qualitative preliminary study of their potential to
act as fabric dyes.
Introduction
Aurones are a fascinating minor sub-family of the flavonoid yet the application of aurones as dyes or pigments has not been
natural products [1,2]. While they feature the same C15 compo- reported or studied [3].
sition as other flavonoids, the skeleton is quite different,
featuring a benzofuranone connected to an aromatic ring via an Even the optical properties of aurones have had very minimal
exocyclic alkene. This unusual skeleton has attracted a modest study. The reports that have appeared have all focused on fluo-
amount of synthetic attention and fairly recently significant bio- rescent properties and have also been largely limited in scope to
logical focus. At the same time, aurones were first noted (and the influence of the benzylidene portion. Most noteworthy is the
indeed their name is derived from) for their golden yellow report by Bane and co-workers examining the UV–vis and fluo-
color. The colors of flavonoids in general have been appreci- rescent properties of a series of amino-substituted aurones [4].
ated and used for virtually the entirety of recorded history and Subsequently, Liu and co-workers explored the same series of
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aurones using computational methods to develop and validate sonable yields and excellent purity [8]. For hydroxy-substituted
the method for the rational design of new aurone fluorophores compounds, a more traditional base-mediated reaction was em-
[
5].
ployed [9]. Product purification was not as easy in these cases
and the product yield was sacrificed for the sake of high purity,
Two more recent studies have explored the influence of the so yields should not be considered optimized.
benzofuranone portion of the aurone system. Salas examined a
larger set of compounds featuring methoxy substitution at 4 or
5
-position on the benzofuranone and methoxy moiety and one
methoxy/bromo-substituted benzylidene group, but none in
which the benzofuranone was unsubstituted (see Figure 1 for
numbering) [6]. This meant that no comparison regarding the
influence of substitution could realistically be made. They did
observe that a methoxy group at the 5-position resulted in a
shift to longer wavelength by roughly 20 nm compared to a me-
thoxy substituent at the 4-position and a strong dependence
upon solvent polarity. While this shift was quite reasonably at-
tributed to the inductive effect of the oxygen, no other substitu-
tion was studied. Muñoz-Becerra and co-workers have also re-
ported a computational study of amino aurone derivatives with
variations in the benzofuranone portion of the molecule, though
all substitution was strictly at the 4-position of the benzofura-
none [7].
Figure 1: Aurone ring system and numbering.
Figure 2: Aurone syntheses.
As an extension of our on-going studies of the aurone ring
system, we chose to study the potential for aurones to be used
as dyes as well as a more extensive study of the impact of sub- Spectral and toxicity studies
stitution in the benzofuranone portion of the molecule on its With the desired compounds in hand, their UV–visible spectra
optical properties.
were recorded at concentrations between 29 and 44 μM in
acetonitrile (Figure 3 and Table 1). While not all substituents
were prepared at every position, some interesting trends were
observed. Substitution at the 4-position whether halogen or
Results and Discussion
Synthesis
We have previously reported the synthesis of a significant num- hydroxy afforded essentially identical lambda maxima
ber of new aurones by way of the common Knoevenagel con- (390 nm), slighly red-shifted compared to the unsubstituted
densation approach, mostly varying in the benzylidene portion. compound 1. On the other hand, hydroxy groups at the 6-posi-
To explore benzofuranone variations using this method, differ- tion result in a significant blue shift of this lambda max by
ent benzofuranone starting materials are required. Although not roughly 40 nm to around 338 nm, presumably due to their do-
likely to be the most colorful, we elected for simplicity’s sake nating effect and conjugation with the carbonyl oxygen.
to use p-tolualdehyde as the benzylidene precursor for all of the Halogen substituents at the 6-position generally had little effect,
new aurones. The synthesis itself was performed via one of two with the exception of the most electron-withdrawing fluorine,
methods (Figure 2). For all compounds without a free hydroxy which resulted in a slight blue-shift of roughly 10 nm. Unex-
group, the neutral alumina method of Varma combined with an pectedly, any halogen at the 5-position had an effect nearly
aldehyde scavenging step was employed to afford pure prod- identical to that of halogen at the 4-position, resulting in a slight
ucts without the need for any chromatography in generally rea- red-shift compared to the unsubstituted compound. On the other
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Figure 3: UV–vis spectral comparisons in acetonitrile.
hand, substitution at the 7-position had virtually no effect, observed. First, all hydroxylated aurones are comparatively
which is to be expected due to the lack of direct conjugation more toxic, displaying >50% inhibition at 200 μM. Methyl
with the carbonyl as well as the only modest electronic effects groups are similarly mostly more toxic. For the halogens, how-
of alkyl, chlorine, and bromine. In general, the substituent ever, location is fairly important, with the 6 or 7 position being
effects are all fairly modest and result in fairly moderate much less toxic (similar to tartrazine) and dramatically better
changes in the extinction coefficient (although hydroxy substi- than the unsubstituted base compound 1, with the unexpected
tution does definitely increase this value by roughly 50%).
exception of 7-bromo compound 10. Whether this trend is
general or not for aurone compounds is an interesting question
While these results on the impact of the benzofuranone portion for future study.
of aurones on their optical properties are interesting, if one were
to think about using them as dyes, toxicity is also an important Preliminary dyeing efforts
consideration. Generally, aurones are considered to be relative- As the initial inspiration for this work was the potential of
ly non-toxic, although data reported in the literature shows con- aurones as textile dyes, two of the more interesting compounds,
siderable variability even in this respect. An initial screening of aurones 15 and 10 were used in a very preliminary attempt at
toxicity was conducted at a fairly high concentration (200 μM) fabric dyeing. Three processes were compared: pre-, simulta-
on the present series of compounds using a standard HEP G2 neous, and post-mordanting. As can be seen in Figure 4, dyeing
inhibition assay (Table 1). Compared to a currently used yellow did occur in all cases. With aurone 10, simultaneous mordanting
dye (tartrazine), the aurones are similar to more toxic. Within qualitatively appeared to be better, while with aurone 15 pre-
the aurone series, though, an interesting pair of trends can be mordanting was superior. Aurone 15 afforded more vibrant
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Beilstein J. Org. Chem. 2019, 15, 1781–1785.
Table 1: Toxicity and UV spectral data for aurones.
Compound
Substituent
λmax (nm)a
ε (L mol−1 cm−1)
Hep G2 % inhibitionb
1
2
3
4
5
6
7
8
9
H
5-F
6-F
4-Cl
5-Cl
6-Cl
7-Cl
5-Br
6-Br
382
394
370
390
394
378
386
394
378
390
390
382
386
338
390
338
336
N/A
20208
17188
24252
17129
16551
23187
17247
15112
22435
22250
15470
19522
18380
33050
22664
30445
86.27 ± 1.09
87.01 ± 0.56
3.52 ± 3.39
15.13 ± 5.75
72.68 ± 2.77
25.07 ± 18.77
3.64 ± 3.64
59.35 ± 1.25
75.22 ± 3.84
5.85 ± 11.12
80.88 ± 1.38
24.95 ± 2.23
87.54 ± 1.61
66.79 ± 3.04
54.04 ± 4.65
67.76 ± 6.06
1
1
1
1
1
1
1
1
0
1
2
3
4
5
6
7
7-Br
5-Me
5- and 6-Me
7-Me
6-OH
4-OH
6-OH, 4-Me
6-OH, 7-Me
N/A
will not dissolve completely
N/A
78.58 ± 7.11
6.81
tartrazine
aUV–vis spectra determined in CH3CN. bToxicity values determined at 200 μM concentration of compound.
Figure 4: Fabric dying and photobleaching. The top two sets show dyed fabric strips with premordant, simultaneous, and post-mordant dying (top to
bottom) using aurone 10 after dyeing (left) and after one week of sun exposure (right). The bottom two are similarly dyed fabric strips with premordant,
simultaneous, and post-mordant dying (top to bottom) using aurone 15 after dyeing (left) and after one week of sun exposure (right). The fabric order
on the strip is acetate, rayon, sef, arnel, cotton, creslan, dacron 54, dacron 64, nylon 6.6, orlon 75, silk, polypropylene, viscose rayon, and wool from
left to right.
colors in general and also adhered to a wider range of fabrics. feature is quite remarkable and has the potential to make aurone
While several were natural fibers (silk and wool in particular), dyes useful in dyeing polypropylene, a substrate that is general-
synthetics including polypropylene were also substrates. This ly only dyed with any efficiency using an extrusion method. Of
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Beilstein J. Org. Chem. 2019, 15, 1781–1785.
equal interest was that a highly qualitative photobleaching study ORCID® iDs
indicated a significant degree of stability of these aurone-based
dyes, with simultaneous or pre-mordanting offering better
stability. Clearly further studies of the generality of this obser-
Joza Schmitt - https://orcid.org/0000-0001-9244-4909
Scott T. Handy - https://orcid.org/0000-0003-4199-7292
vation as well as its longer term retention and photostability are References
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Conclusion
In conclusion, the benzofuranone portion of the aurone skeleton
does have a definite impact on both the UV–vis spectral and
cytotoxicity properties of aurones. Interestingly, the position of
the substituent was often more important than the exact substit-
uent (at least for the examples studied), with halogen or
hydroxy at the 4-position are red-shifted by roughly 10 nm
compared to the unsubstituted compound and any halogen or
methyl at the 5-position likewise displays a similar shift. Only
hydroxylation at the 6-position displays a significant blue shift
by roughly 40 nm. With respect to toxicity, halogens were the
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8
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often times no worse than the unsubstituted benzofuranone
system. Finally, preliminary dyeing studies showed the ex-
pected absorption on natural fibers, but also an unexpected
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Experimental
Full details of the synthesis and photochemical studies can be
found in Supporting Information File 1 as well as copies of the
spectra for all new compounds. Raw data for the toxicity and
absorption studies can be found in Supporting Information
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http://creativecommons.org/licenses/by/4.0). Please note
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Supporting Information
Supporting Information File 1
The definitive version of this article is the electronic one
which can be found at:
doi:10.3762/bjoc.15.171
Experimental methods and spectra for all new compounds.
[
https://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-15-171-S1.pdf]
Supporting Information File 2
Absorption data and individual plots for all compounds.
[
https://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-15-171-S2.xlsx]
Acknowledgements
The support of Middle Tennessee State University and the
Department of Chemistry are gratefully acknowledged.
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