Synthesis and switching properties of new derivatives of azoresveratrol

Article abstract of DOI:10.1016/j.dyepig.2019.107666

The synthesis and response upon light irradiation of azoresveratrol and six derivatives are reported. While UV irradiation of para-hydroxy trans compounds leads to thermally unstable cis isomers, the para-methoxy and the para-phosphoric ester substituents

Full text of DOI:10.1016/j.dyepig.2019.107666

Dyes and Pigments 171 (2019) 107666
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Dyes and Pigments
journal homepage: www.elsevier.com/locate/dyepig
Synthesis and switching properties of new derivatives of azoresveratrol
a
b
b
c
b
Jérôme Berthet , Laurence Agouridas , Siyao Chen , Hassan Allouchi , Patricia Melnyk ,
d
a,∗
Benoît Champagne , Stéphanie Delbaere
a
Univ. Lille, CNRS, UMR 8516, LASIR – Laboratoire de Spectrochimie Infra-rouge et Raman, F-59000, Lille, France
Univ. Lille, Inserm, CHU Lille, UMR-S 1172 – JPArc – Centre de Recherche Jean-Pierre Aubert Neurosciences et Cancer, F-59000, Lille, France
Univ. de Tours, EA 7502 SIMBA – Laboratoire de Chimie Physique, Faculté de Pharmacie, 31, Avenue Monge, F-37200, Tours, France
Laboratory of Theoretical Chemistry, Theoretical and Structural Physical Chemistry Unit, Namur Institute of Structured Matter, University of Namur, Rue de Bruxelles,
1, B-5000, Namur, Belgium
b
c
d
6
A R T I C L E I N F O
A B S T R A C T
Keywords:
Azobenzene
Photoswitching
Thermal relaxation
UV irradiation
NMR
The synthesis and response upon light irradiation of azoresveratrol and six derivatives are reported. While UV
irradiation of para-hydroxy trans compounds leads to thermally unstable cis isomers, the para-methoxy and the
para-phosphoric ester substituents result in reaching a high conversion and increasing the thermal stability. In
addition, the phosphoric ester azo derivative presents similar properties in organic and aqueous solutions,
opening the way towards biological applications.
DFT calculations
1. Introduction
trihydroxy-trans-stilbene, Scheme 1) has been reported to play a major
role in the formation or disaggregation of fibrils or amyloid, proteic
Photoswitchable molecules have been extensively investigated over
species implied in many neurodegenerative diseases. Despite its poor
bioavailability, it exhibits multiple positive biological activities, mainly
anti-oxidizing, anti-inflammatory and neuroprotective capacities
[16,17]. Resveratrol can be photochemically isomerized between the
trans and cis isomers, but the cyclization/oxidation of it into the phe-
nanthrenic derivative by-product [18] impedes its biological photo-
application. We therefore aimed at boosting resveratrol promising
properties in the field of photopharmacology applied to neurodegen-
erative diseases using photoswitchable azoresveratrol derivatives by
exploring the effect of electron-donating group in azobenzenes sub-
stituted in the para position with hydroxy, alkoxy and phosphoric ester
groups. Here, we report on the synthesis of very simple molecular
structures and on their photoresponse upon light irradiation and on
their thermal relaxation investigated by UV/visible and NMR spectro-
scopies.
the past few years due to their potential in technological advanced
applications ranging from molecular electronics [1] to biology [2].
These applications rely on the reversible interconversion, being induced
by light at least in one direction, between two (meta)stable states which
have different properties. In the area of electronic devices such as
switches, transistors and logic gates, diarylethenes represent one of the
most widely synthesized and studied (P-type) molecular switches
nowadays. They are based on cyclization/opening reactions induced by
UV/visible illumination. In the field of photopharmacology, photo-
switches are of particular interest, especially the reversible trans-cis
photoisomerization of azobenzenes. Indeed, light induces changes in
the molecular length and polarity of the azobenzenes, which have
multiple positive biological advantages [3,4]. At equilibrium in the
dark, azobenzenes exist in the more stable trans conformation. Irra-
diation with UV light produces a large fraction of the cis isomer, which
can revert back to the trans state thermally (T-type) or upon irradiation
with visible light [5]. The thermal cis-to-trans isomerization of azo-
benzenes has attracted much attention, being the subject of many
theoretical and experimental investigations [6–9], with a relaxation
rate highly depending on the number, the nature and the position of
substituents in the phenyl groups decorating the azo bond [10–14].
Similarly to various polyphenols, resveratrol [15] (3,5,4′-
2. Results and discussion
2.1. Synthesis
Azoresveratrol 1 and its derivative 2 were prepared as described in
the literature [19–21]. Methylation of 2 in the presence of methyl io-
dide [22] afforded the fully protected azoresveratrol derivative 4
∗
Corresponding author.
E-mail address: stephanie.delbaere@univ-lille.fr (S. Delbaere).
https://doi.org/10.1016/j.dyepig.2019.107666
Received 28 May 2019; Received in revised form 21 June 2019; Accepted 24 June 2019
Available online 25 June 2019
0143-7208/ © 2019 Elsevier Ltd. All rights reserved.

J. Berthet, et al.
Dyes and Pigments 171 (2019) 107666
their trans azo configuration and 7 was proved to be the tautomeric
quinone-phenylhydrazone derivative with more particularly the sig-
nature of the -C=O resonance at 187.2 ppm in 13C NMR spectrum
(
Figures S2-S5). In fact, in all solvents used, chloroform, methanol and
acetonitrile, 7 presents always the same spectrum, indicating that the
tautomeric equilibrium expected for arylazo-phenol compounds [24] is
completely shifted towards the hydrazone form, whereas totally shifted
towards the azo form for 1-5. As for 6, it exists as a tautomeric equi-
librium mixture in acetonitrile and methanol (95:5 and 88:12 azo:hy-
drazone, respectively), but is 100% in the hydrazone form in chloro-
form (Figures S7-S9).
2.3. Switching properties investigated by UV/visible and NMR spectroscopy
All the compounds (resveratrol and the seven azo derivatives in
acetonitrile) were submitted to irradiation to induce the photo-
isomerization trans→cis, then the thermal evolution of the samples was
recorded. UV/visible and NMR spectroscopy were used to run the
transformations. Irradiation with 313 nm light at 22 °C of resveratrol
led to the formation of the cis isomer, followed by cyclization/oxidation
into the phenanthrenic derivative by-product (Figures S10-13), as al-
ready reported in the literature [18]. Irradiation with 365 nm light at
Scheme 1. Chemical structures of resveratrol and 1–7 and synthetic routes.
22 °C was then applied to the azo derivatives 1–5. Only changes in the
spectra of 4 and 5 could be observed, with the hypsochromic shift and
decrease of the main UV/visible band (λmax = 304 and 289 nm for 4
(Figure S24) and 5 (Figure S29), respectively) whereas the intensity of
the lower band at 436 and 432 nm for 4 and 5, respectively was in-
creased. By NMR spectroscopy, new resonances were detected while the
signals of the initial trans isomer decreased in intensity (Figures S25 and
S31). No spectral variation was evidenced at 22 °C for 1–3, because of a
very short life time of photoproducts. Then, experiments on these three
hydroxy derivatives were repeated at −45 °C. Irradiation with 365 nm
light at low temperature converted the initial trans state of 1–3 into a
new photoproduct as evidenced with the appearance of a set of new
whereas the phosphoric ester derivative 5 was obtained from reaction
of 2 with phosphoryl chloride in the presence of triethylamine [23].
Ortho-substituted azoresveratrol compounds 3, 6 and 7 were prepared
according to a similar procedure [21] via diazotization of aniline de-
rivatives using sodium nitrite followed by in situ addition of phenol
derivatives (Scheme 1).
2.2. Spectroscopic characterization of 1–7
The spectral properties of the seven synthesized azo derivatives
1
signals in H spectra (Fig. 3, S18, S22).
were investigated by UV/visible spectroscopy, correlated with their
structures by NMR spectroscopy. Compounds 1–5 exhibited a strong
band peaking between 300 and 400 nm, with a maximum ranging from
The photoproducts generated at 22 °C from 4 and 5 and at −45 °C
from 1–3 were unambiguously identified as their cis isomers. The cis
1
1
configuration of the -N=N- double bond was nicely evidenced by H- H
NMR dipolar correlations (Figure S28) between protons located in each
benzene ring and by a shielding of all signals. This is in total agreement
with a structure where both phenyl groups are in close spatial inter-
actions, leading to lower values of the chemical shifts by the shielding
effect of the aromatic rings. Finally, for the two derivatives 6 and 7, no
change was detected upon irradiation using whatever the solvent
(acetonitrile, chloroform, methanol), the temperature (22 °C, −45 °C,
−80 °C) and the wavelength of the irradiation light (365, 436 nm).
When the photostationary state (PSS, Table 1) was reached, the
3
48 to 354 nm (allowed π-π* transition of the trans isomer) associated
with molar absorption coefficient between 2.1 and
.7 × 10 L mol cm , and a weaker broad band around 460 nm
a
ε
4
−1
−1
2
(
forbidden n-π* transition) (Fig. 1). The replacement of the ethylenic
bond in resveratrol with an azo junction bathochromically shifted the
absorption band associated with a small increase of the ε values. By
contrast,
compound
6
absorbed
shoulder
at
377 nm
450 nm
4
4
−1
−1
−1
(
(
ε = 1.9 × 10 L mol cm
ε = 0.8 × 10 L mol cm ) while 7 displayed a broad and higher
)
with
a
at
−1
4
−1
−1
absorption band at 425 nm (ε = 4.5 × 10 L mol cm ).
1
thermal evolution of samples was followed by recording H NMR
NMR spectroscopy (Fig. 2) clearly indicated that 1–5 were under
spectra at regular time intervals. By measuring the peak-intensities of
signals for the trans and cis isomers, the time-evolution of concentra-
tions at −45 °C for 1, 2 and 3 (Figures S16, S19, S23) and at 22 °C for 4
and 5 (Figures S26 and S32) was plotted. With the exception of the
compound 5, the thermal decay of all cis isomers was mono-exponential
Δ
(k , Table 1). In contrast, the thermal relaxation of the cis isomer of 5
followed a bi-exponential decay. Solvent effects can be suggested to
explain such a behavior. As the derivative 5 is soluble in water, ex-
periments of photoisomerization and thermal relaxation were repeated
in D
. Irradiation with 365 nm light led to the formation of 70% of the cis
isomer of 5 in D O at PSS (Fig. 4), which followed again a bi-ex-
ponential evolution in the dark, although accelerated (Figure S34). An
additional assay was then performed in D O where pH was adjusted at 8
by adding NaOD. About 94% of the cis isomer was produced at PSS
Figure S35). In contrast, its thermal stability at 22 °C was so high that
2
O (at 2.5 mM, T = 22 °C), where pH was determined to be equal to
2
2
2
(
Fig. 1. UV/visible absorption spectra of resveratrol and azo derivatives 1–7 in
acetonitrile.
no significant evolution could be observed.
To induce the back cis→trans isomerization of the derivative 5 in
2

J. Berthet, et al.
Dyes and Pigments 171 (2019) 107666
Fig. 2. 1H NMR spectra of the a) azo derivative 2 and b) quinone-phenylhydrazone derivative 7 in CD
CN.
3
Fig. 3. 1H NMR spectra of 1 in acetonitrile-d
at −45 °C a) before and b) after irradiation with 365 nm light (PSS).
3
3

J. Berthet, et al.
Dyes and Pigments 171 (2019) 107666
Table 1
Ratio at photostationary state between the cis and trans isomers, PSS (cis:trans), rate constants of relaxation, k
Δ
with experimental temperature (T); time to convert
50% of the cis isomer into the trans isomer, t1/2, for the derivatives 1–5 with experimental conditions (Solvent).
Solvent
PSS (cis:trans)
k
Δ
(T)
t
1/2
−
3
3
s−1 (−45 °C)
s−1 (−45 °C)
CD
3
CN
24:76
4.1 × 10
3.0 × 10
2.8 min (−45 °C)
3.9 min (−45 °C)
1
−
CD
3
CN
25:75
64:36
2
3
4
−
4
6
s−1 (−45 °C)
CD
3
CN
1.4 × 10
5.5 × 10
82 min (−45 °C)
−
s−1 (22 °C) k = 3.5 × 10−5 s−1 and k’ = 1.8 × 10−4 s−1 (22 °C)
CD
CD
3
CN
83:17
87:13
34.9 h (22 °C)
1.8 h (22 °C)
3
CN + PPA
−
5
5
−1
−1
−4 −1
CD
3
CN
90:10
70:30
94:06
89:11
88:12
82:18
k = 1.8 × 10
k = 4.0 × 10
s
s
and k’ = 1.2 × 10
and k’ = 3.4 × 10
s
(22 °C)
(22 °C)
4 h (22 °C)
1.7 h (22 °C)
–
2.3 d (30 °C)
15 h (40 °C)
8.2 h (45 °C)
−
−4 −1
D
2
D
2
D
2
D
2
D
2
O (pH = 2)
O (pH = 8)
O (pH = 8)
O (pH = 8)
O (pH = 8)
s
5
No significant evolution (22 °C)
−6
−5
−5
−1
−1
−1
3.4 × 10
1.3 × 10
2.4 × 10
s
s
s
(30 °C)
(40 °C)
(45 °C)
#
−1
D
2
O, light and temperature effects were studied. Upon visible light ir-
ΔH = 100.6 kJ mol
were deduced (Figure S40), in agreement with
radiation (436 nm), the reversion from cis to trans was not fully ac-
complished, but an equilibrium of cis-trans (25%–75% at pH = 2
the energy barrier for the azobenzene thermal isomerization [10,25].
Finally, as it clearly appeared that the thermal behavior of 5 in cis
configuration is correlated to solvent acidity, the thermal response of
the cis isomer of 4, having the structure the closest one to 5, was in-
vestigated after irradiation with 365 nm light, in the presence of phe-
(
Figure S33c) and 39 %–61% at pH = 8 (Figure S35c)) was reached due
to both isomers absorbing 436 nm light. A very good reproducibility
was observed when the derivative 5 in D O at pH = 8 was submitted to
2
successive cycles of irradiation with 365 nm then 436 nm light, showing
then excellent cycling performance (Figure S36). When the relaxation
3 2
nylphosphonic acid (PPA) to mimic the effect of PO H substituent.
While in the absence of acid, the decay of the 4 cis isomer was mono-
exponential, in the presence of acid, it became bi-exponential and was
accelerated (Figure S27).
temperature of the sample in D
2
O at pH = 8 was raised at 30, 40 and
45 °C, the thermal isomerization from cis to trans became efficient and
followed a mono-exponential decay, with half-life times from 2.3 days
to 8 h in the range of the investigated temperatures (Figures S37-S39).
3
. Discussion
From the Eyring plots ln (k
Δ
/T) vs. 1/T, the standard entropy and en-
#
−1 −1
thalpy of activation,
ΔS = −17.9 J mol
K
and
From the set of experiments and data reported in Table 1, it is clear
Fig. 4. 1H NMR spectra of 5 in D
2
O (pH = 2) at 22 °C a) before and b) after irradiation with 365 nm light (PSS).
4

J. Berthet, et al.
Dyes and Pigments 171 (2019) 107666
that the photoisomerization from trans to cis of the azoresveratrol de-
rivatives 1–5 investigated is realized upon adequate light irradiation
and the ratio between trans and cis isomers depends on temperature,
solvent and substituents [5,6,10–14]. Substituents on the phenyl rings
appear to strongly affect the thermal cis-to-trans relaxation rate. 1 and 2
present the lowest conversion ratio into the cis isomers (24 and 25%,
respectively) associated with the lowest thermal stability (4.1 and
N8C9 bond length and then the N7N8 one. This protonation is asso-
ciated with a variation of the N8C9 bond length by about 0.06–0.08 Å,
and with a decrease of the C-OMe bond length by about 0.03 Å and a
concomitant increase of the O-Me bond length by about 0.01 Å. The
N7N8 bond length is longer in the trans and cis quinone-phenyl hy-
drazone 2, then the bond order is much smaller, associated also with a
substantial reduction of the bond length alternation (BLA). For the
methoxy derivative 4, the same trends are observed although less
pronounced, in agreement with the large difference observed experi-
mentally about the thermal relaxation of the cis isomer. Upon proto-
nation, 50% of the excess positive charge goes to the NN bridge and
−3
−1
3.0 × 10
s
, respectively), and these results were obtained at low
temperature to slow the relaxation. Both have a hydroxy group in para
position of one phenyl group. Experiments being conducted in polar
acetonitrile containing non-negligible amount of water, one can expect
intermolecular hydrogen bonds between the nitrogen atom and the
solvent proton, as well as between the para-OH group and the water
oxygen atom [26,27], which then favor a hydrazone-like electronic
distribution with a single N–N bond. The free rotation around the N–N
bond facilitates the recovery of the more stable trans isomer. Although
the mechanism of isomerization has been debated (i.e. rotation, in-
version, concerted inversion) [9,28–30], an increase in dipole character
+
50% to the methoxy-phenyl ring π-conjugated to the N=NH group.
The para-methoxy substituent on the phenyl group in 4 works as a
strong electron donor towards the protonated nitrogen atom (N7),
leading to the hydrazone-type resonance structure in which the positive
charge is delocalized on both nitrogen (N7) and oxygen atom in the
methoxy group, then accelerating the rate of relaxation as observed
experimentally when compared with the thermal evolution of 4 without
PPA addition. This conclusion can also be applied to the derivative 5,
with the phosphoric ester substituent playing itself the role of acid
catalyst. We can then suggest that the thermal cis-to-trans isomerization
of the para-hydroxy (1–3) and of the para-methoxy 4-protonated and
para-phosphoric ester 5-protonated derivatives proceeds through a
mechanism involving rotation of the N-N bond. At neutral pH for the cis
isomers 4 and 5, it is more difficult to conclude definitively but it seems
reasonable to propose that the relaxation involves also the rotation of
the N-N bond.
(
or resonance) lowers the activation barrier for thermal relaxation,
accelerating the reversion from the cis to trans isomers. However, in the
case of 3, having also a hydroxy group in its para-phenyl position, the
trans-cis photoconversion and the thermal stability of the cis isomer at
−1
−
45 °C are higher (64% and 1.4 x 10-4 s ) than results obtained with
1
and 2. Previous studies showed that azobenzenes carrying two or
more ortho-substituents exhibit higher thermal stability compared to
the unsubstituted azobenzene [10–12,31–33]. This “ortho-effect” is
likely due to steric hindrance between the ortho-methyl groups and the
lone pair electrons of nitrogen atoms, causing retardation in the cis-to-
trans conversion [31]. In contrast, ortho-methoxy groups (6–7) have a
completely opposite effect as no trace of the cis isomer could be de-
tected, even at low temperature. In that case, the quinone-phenylhy-
drazone derivative was detected in solution, alone or in tautomeric
equilibrium with the azo from, probably stabilized by some in-
tramolecular interactions between NH and the oxygen atom of the
methoxy group. Now, considering the azo derivatives 4 and 5 that are
substituted by para-methoxy and para-phosphoric ester, respectively,
their behavior can be compared with that of the derivative 2, having
the hydroxy group in its para-phenyl position. A huge increase in the
conversion ratio and thermal stability was observed as already reported
with similar structures (para-hydroxy-azobenzene and para-alkoxy (O-
4. Conclusion
In conclusion, azoresveratrol and six of its derivatives were in-
vestigated to evidence their photochemical response as well as their
behavior during thermal relaxation. When the phenyl group was para-
substituted with OH, the cis photoproduct was only detectable at low
temperature showing a very fast relaxation (1 and 2) towards its trans
isomer. Indeed, the -N=N- π-bond is disrupted, due to the azo-hy-
drazone tautomeric equilibrium, followed by the rotation around the
remaining σ-bond. The substitution of the phenyl groups with methyls
in ortho position (3) resulted in slowing down the relaxation (factor
20 at −45 °C). Inversely, the substitution with methoxy groups (6 and
7) shifted the equilibrium toward the hydrazone-type form and no cis
isomer could be observed.
When OH was replaced with methoxy (4) or phosphoric ester (5)
group, the cis isomer could be accumulated at ambient temperature
since it was much more thermally stable. The thermal relaxation from
the cis toward the trans isomers was accelerated by the acidic conditions
associated with a bi-exponential decay. However, the corresponding
rate constants at ambient temperature remained largely lower than
those determined for hydroxy derivatives at low temperature.
Among all compounds studied, the phosphoric ester derivative 5 is
the most promising one for biological applications. Indeed, it is water-
soluble and could be photoconverted with 365 nm light producing a
huge amount of the cis isomer (94%), which is among the highest
conversion reported today. It has a very good thermal stability and can
be switched back photochemically with 436 nm light, although not
completely. Its cycling performance is excellent as a very good re-
producibility was observed upon successive cycles of 365/436 nm light
irradiation. These promising properties pave the way to the future de-
sign of azoderivatives showing a full conversion in both directions upon
distinct wavelengths of irradiation.
6
C H11) azobenzene) [34]. The authors justified the enhancement in the
thermal stability of the cis isomer with alkoxy substituent by the fact
that the thermal reversion cis-to-trans proceeded through an inversion
mechanism while for hydroxy-azobenzene, it involved a rotation route.
Also, we observed an increase of the thermal rates of relaxation cis-to-
trans of 4 and 5 at low pH. Such an effect where protonation at the azo
moiety reduces the activation barrier and then accelerates the relaxa-
tion, has already been reported [35–42]. The most plausible explana-
tion is to suggest an acid-base equilibrium between the non-protonated
and protonated cis and trans isomers of 4 + PPA and 5 (Scheme 2) [43].
At low pH, two rate constants of relaxation were measured, the faster
one being associated to the cis-to-trans isomerization of the protonated
species because they are believed to be able to easily isomerize via the
rotation about the -N=N- bond due to a decrease in the double bond
character.
The geometries of 2 (azo and hydrazone derivatives in trans and cis
configurations) and 4 (azo and protonated azo derivatives in trans and
cis configurations) in their electronic ground state were optimized by
DFT calculations at the ωB97X-D/6-311G* level (solvent = acetoni-
trile) [44] allowing to determine geometric parameters and Mulliken
charges (Tables S2 and S3). Representative bond lengths and Mulliken
charges are gathered in Table 2. For 2 in the trans and cis configura-
tions, the azo-to-hydrazone transformation mostly affects the N8C9
bond length and then the N7N8 one. This transformation is associated
with a variation of the N8C9 bond length by about 0.11–0.12 Å for both
tautomers. The protonation of the derivative 4 also mostly affects the
5. Experimental section
5.1. General methods
Chemicals and solvents were obtained from commercial sources,
5

J. Berthet, et al.
Dyes and Pigments 171 (2019) 107666
Scheme 2. Thermal relaxation pathways of the azo derivative 5.
and used without further purification unless otherwise noted. Reactions
were monitored by TLC performed on Macherey-Nagel Alugram Sil
4
and C Interchim UPTISPHERE.
®
Analytical HPLC was performed on a Shimadzu LC-2010AHT system
equipped with a UV detector set at 254 nm and 215 nm. Compounds
were dissolved in 50 μL buffer B and 950 μL buffer A, and injected into
60/UV254 sheets (thickness 0.2 mm).
Purification of products was carried out by either column chroma-
tography or thick layer chromatography. Column chromatography was
carried out on using Macherey-Nagel silica gel (230–400 mesh). The
purity of final compounds was verified by two types of high pressure
liquid chromatography (HPLC) columns: C18 Interchim UPTISPHERE
the system. The following eluent systems were used: buffer A (H
2
O/
O/TFA, 80:20:0.1). HPLC re-
) were obtained at a flow rate of 0.2 mL/min for
35 min using the following conditions: a gradient run from 100% of
TFA, 100:0.1) and buffer B (CH
3 2
CN/H
tention times (HPLC t
R
Table 2
Bond lengths (Å), Bond length alternationa and Mulliken charge (a.u.) distributionb on the representative fragments of the azo derivatives 2 (azo and hydrazone
tautomers) and 4 (non-protonated and protonated) in their trans and cis configurations as determined at the IEFPCM/ωB97X-D/6-311G* level (in acetonitrile).
2
-trans
2-cis
2-trans-Hydrazone
2-cis-hydrazone
4-trans
4-cis
4-trans H+
4-cis H+
d(C3N7)
d(N7N8)
d(N8C9)
d(C12-O17)
d(O17-X)
BLA
1.425
1.244
1.414
1.350
0.961
0.176
0.13
1.438
1.239
1.433
1.353
0.961
0.197
0.02
1.403
1.303
1.308
1.227
-
1.431
1.310
1.310
1.228
-
1.424
1.244
1.413
1.347
1.419
0.175
0.13
1.438
1.239
1.433
1.350
1.418
0.197
0.02
1.417
1.256
1.357
1.320
1.430
0.131
0.38
1.444
1.260
1.354
1.318
1.431
0.139
0.07
0.045
0.40
0.061
0.17
q(C3)
q(N7)
q(N2)
q(C9)
−0.23
−0.21
0.10
.017
−0.18
0.01
−0.15
−0.18
0.17
−0.10
−0.17
0.11
−0.23
−0.21
0.10
−0.17
−0.18
0.01
−0.01
−0.12
0.16
0.06
−0.10
0.11
a
BLA = ½ (d(C3N7) – 2 x d(N7N8) + d(N8-C9)).
H charges were summed to their attached C/O/N atom.
b
6

J. Berthet, et al.
Dyes and Pigments 171 (2019) 107666
273.12337; Found 273.12375. HPLC: C18
= 34.3 min, purity 97%. C column: t = 27.2 min, purity
4 R
97%. FTIR: ν (cm ): 3077, 2993, 2958, 2834, 1602, 1582, 1501,
1455, 1437, 1305, 1251, 1149, 1030, 827.
buffer A over 1 min, then to 100% of buffer B over the next 30 min.
The melting point analyses were performed on a Stuart melting
point SMP10 and are uncorrected.
Infrared spectra were performed on Bruker FT-IR spectrometer
model α.
Mass spectra were recorded on a Varian triple quadrupole 1200W
mass spectrometer equipped with a non-polar C18 TSK-gel Super ODS
+H]+ Calcd for C15
column: t
H
17
N
2
O
3
R
−1
(E)-4-((3,5-dimethoxyphenyl)diazenyl)phenyl dihydrogen phosphate 5
[23]. To a solution of 2 (400 mg, 1.55 mmol) in CH
a CaCl guard tube was added POCl (0.577 mL, 6.2 mmol) in CH
(1.15 mL) dropwise. The reaction mixture was stirred for 5 min at 10 °C.
Et N (0.431 mL, 3.1 mmol) in CH Cl (1.15 mL) was added dropwise to
2
Cl
2
(5.77 mL) using
2
3
2
Cl
2
(
(
4.6 × 50 mm) column, using electrospray ionization and a UV detector
diode array). HRMS-ESI spectra were recorded on a Thermo Scientific
3
2
2
Exactive spectrometer.
Preparative HPLC were performed using a Shimadzu semi-pre-
parative HPLC system using an Apollo column C18 250 mm × 22 mm
the mixture. The solution was stirred for 1h at 10 °C. Water (10 mL) was
then added and the mixture was stirred for 30 min at 22 °C. The pH of
the reaction mixture was adjusted to c.a. 1 using HCl (1 M). The product
from Grace. Gradients used CH
3
CN/0.1% trifluoroacetic acid and
was extracted twice with CH
2 2
Cl . Combined organic layers were dried
water/0.1% trifluoroacetic acid at a flow rate of 6 mL/min.
over MgSO , filtered and evaporated under reduced pressure. The crude
4
NMR spectra were recorded on Bruker Neo-500 or Avance-300
product was purified by semi-preparative HPLC to afford compound 5
(180 mg, 34%) as a brown-red powder. Mp: > 150 °C. H NMR
1
13
1
13
1
spectrometers ( H, 500 MHz, C, 125 MHz, or H, 300 MHz, C,
5 MHz) equipped with TXI or QNP probe, using standard sequences.
Data sets were processed using Bruker Topspin 4.0.2 software. Samples
were dissolved in acetonitrile-d or chloroform-d or methanol-d or
water-d in NMR glass tubes (5 mm). Chemical shifts are expressed in
7
(CD
3
OD, 300 MHz) δ(ppm): 7.93 (d, J = 8.7 Hz, 2xH-3), 7.38 (dd,
4
J = 8.9 Hz, JP-H = 1.0 Hz, 2xH-4), 7.10 (d, J = 2.3 Hz, 2xH-1), 6.63 (t,
13
3
1
4
J = 2.3 Hz, 1xH-2), 3.86 (s, 2xCH
δ(ppm): 161.3 (2xCq), 154.3 (Cq), 153.8 (d, JP-C = 6.6 Hz, Cq), 149.1
(Cq), 123.9 (2xCH), 120.5 (d, 3
P-C = 5.0 Hz, 2xCH), 103.1 (1xCH),
100.4 (2xCH), 54.6 (2xCH ). HRMS (ESI ) [M-H] Calcd for
P 337.05840; Found 337.05588. HPLC: C18 column:
= 25.5 min, purity 98%. HPLC: C column: t = 13.8 min, purity
3
).
3
C NMR (CD OD, 75 MHz)
2
2
ppm relative to residual proton signal in deuterated solvents. Chemical
shifts are reported as position (δ in ppm), multiplicity, coupling con-
stant (J in Hz), integral. The attributions of protons and carbons were
achieved by analysis of 2D experiments (COSY, NOESY, HSQC and
HMBC).
J
−
-
3
14 14 2 6
C H N O
t
R
4
R
−1
98%. FTIR: ν (cm ): 3098, 2944, 2834, 1591, 1498, 1427, 1289,
1208, 1160, 966, 927, 835.
Photoirradiation was carried out directly into the NMR tube in a
home-built apparatus. The emission spectrum of a 1000 Watt Xe-Hg
high-pressure short-arc lamp (Newport), filtered by a band-pass glass
filter (Lot QuantumDesign 011FG09 : 259 < λ < 388 nm with
General procedure for the preparation of azo-compounds 3, 6 and 7.
[21] To an ice-cold solution of aniline derivative (1 eq) in aqueous 1 M
HCl (3 eq) and THF (2.5 mL/mmol) at 0 °C was added NaNO (1.2 eq)
2
dissolved in water (2.5 mL/mmol) at 0 °C. The mixture was stirred for
30 min at 0 °C. An ice-cold solution of phenol derivative (1.2 eq.) in
aqueous 1 M NaOH (3 eq) was added dropwise to the reaction mixture
at 0–5 °C. The mixture was stirred for 1h at 0 °C. THF was evaporated.
The residue was taken in EtOAc and water, extracted twice with EtOAc.
λ
max = 330 nm and T = 79%) or a heating absorbing glass filter (Lot
QuantumDesign KG1: 300 < λ < 800 nm) and interferential filter
(
λ = 313 nm and T = 17%, λ = 365 nm and T = 30%, λ = 436 nm and
T = 50%) was focused on the end of a silica light-pipe (length 6 cm,
diameter 8 mm), leading the light to the spinning sample tube, inserted
in a quartz dewar. The temperature of the sample was controlled with a
Combined organic layers were washed with aqueous sat. NH
over MgSO , filtered and evaporated under reduced pressure. The re-
sidue was purified by flash chromatography.
(E)-3-methyl-4-(o-tolyldiazenyl)phenol 3. According to the general
procedure, compound was purified by flash chromatography
(Cyclohexane/EtOAc, 0–30%) and obtained as a brown solid (118 mg,
90%). Mp: 122 °C. 1H NMR (CD
4
Cl, dried
variable temperature unit (B-VT1000-Bruker, over
a
range of
4
1
23–423 K). After irradiation, the NMR sample tube was rapidly
transferred to the NMR probe where experiments were acquired.
To follow the time-evolution of concentrations, the NMR irradiated
3
1
sample was kept in the spectrometer at controlled temperature and H
NMR spectra were recorded at regular time intervals for a long period.
In each recorded spectrum, well-resolved signals characteristic of each
compound were integrated and the sum was normalized to the value of
3
OD, 300 MHz) δ(ppm): 7.63 (d,
J = 8.8 Hz, 1xH-3), 7.56 (dd, J = 7.4 and 1.2 Hz, 1xH-4), 7.27 (m, H-5,
H-6, H-7), 6.78 (d, J = 2.8 Hz, 1xH-1), 6.69 (dd, J = 8.8 and 2.7 Hz,
−1
13
1
00% or to the initial value of concentration in mol L (mass balance
respected).
UV/visible spectra were recorded on Cary50 spectrometer.
3 3
1xH-2), 2.69 (s, 2xCH ). C NMR (CD OD, 75 MHz) δ(ppm): 160.3
(Cq), 151.1 (Cq), 144.6 (Cq), 140.6 (Cq), 136.9 (Cq), 130.8 (CH), 129.5
(CH), 126.0 (CH), 117.0 (CH), 116.5 (CH), 115.2 (CH), 113.3 (CH),
−
-
Photoirradiation was carried out directly in the cuvette with a 200 Watt
high-pressure Xe-Hg lamp equipped with the same filters as defined
previously (λ = 313, 365 or 436 nm).
16.5 (CH
225.10224; Found 225.10019. HPLC: C18 column: t
purity > 99%. HPLC: C column: t = 25.3 min, purity 98%. FTIR: ν
cm ): 3276, 3019, 2923, 1591, 1479, 1455, 1237, 1152, 1033, 860,
827, 761.
3
), 16.3 (CH
3
). HRMS (ESI ) [M-H] Calcd for C14
15 2 3
H N O
R
= 32.8 min,
4
R
−1
(
5
.2. Synthesis
(E)-3-methoxy-4-((2-methoxyphenyl)diazenyl)phenol 6. According to
(
E)-1-(3,5-dimethoxyphenyl)-2-(4-methoxyphenyl)diazene 4 [22]. To
a solution of 2 (125 mg, 0.484 mmol) in acetone (4.8 mL) was added
CO (200 mg, 1.45 mmol) and MeI (60.3 μL, 0.968 mmol). The mix-
ture was stirred at room temperature overnight and monitored by TLC
Cyclohexane/EtOAc). The mixture was evaporated, dissolved in
CH Cl , washed twice with water, dried over MgSO , filtered and
the general procedure, compound 6 was purified by flash chromato-
graphy (CH
2 2
Cl /MeOH, 0–2%) and obtained as a brown solid (168 mg,
1
K
2
3
40%). Mp: > 170 °C. H NMR (CD OD, 300 MHz) δ(ppm): (major form,
3
azo derivative) 7.61 (d, J = 8.9 Hz, 1xH-5), 7.52 (dd, J = 7.9 Hz and
1.2 Hz, 1xH-12), 7.40 (t, J = 7.2 Hz, 1xH-10), 7.17 (d, J = 8.3 Hz, 1xH-
9), 6.99 (t, J = 7.6 Hz, 1xH-11), 6.59 (d, J = 2.1 Hz, 1xH-2), 6.43 (dd,
(
2
2
4
13
evaporated under vacuum. The residue was purified by flash chroma-
tography (Cyclohexane/EtOAc, 0–30%) to afford compound 4 as a
brown solid (118 mg, 90%). Mp: 115 °C. H NMR (CD
δ(ppm): 7.89 (d, J = 9.0 Hz, 2xH-3), 7.08 (d, J = 9.0 Hz, 2xH-4), 7.06
d, J = 2.2 Hz, 2xH-1), 6.60 (t, J = 2.3 Hz, 1xH-2), 3.89 (s, 1xCH
.85 (s, 2xCH
J = 8.8 and 2.2 Hz, 1xH-6), 3.99 (s, 1xCH
(CD OD, 75 MHz) δ(ppm): 162.6 (Cq), 159.1 (Cq), 156.3 (Cq), 142.8
(Cq), 136.2 (Cq), 131.0 (CH), 120.4 (CH), 118.1 (CH), 116.8 (CH),
3 3
), 3.96 (s, 1xCH ); C NMR
3
1
3
OD, 300 MHz)
1
112.6 (CH), 107.7 (CH), 99.4 (CH), 55.4 (CH
3 3
), 55.2 (CH ). H NMR
(
3
(
(
3
),
(CD OD, 500 MHz) δ(ppm): (minor form, hydrazone derivative) 7.71
3
13
3
). C NMR (CDCl
3
, 75 MHz) δ(ppm): 162.5 (Cq), 161.3
(dd, J = 8.0 and 1.4 Hz, 1xH-12), 7.37 (d, J = 9.9 Hz, 1xH-5), 7.17 (m,
1xH-10), 7.11 (dd, J = 8.1 and 1.0 Hz, 1xH-9), 7.06 (t, J = 7.6 Hz, 1xH-
11), 6.35 (dd, J = 9.8 and 1.8 Hz, 1xH-6), 6.06 (d, J = 1.8 Hz, 1xH-2),
2xCq), 154.5 (Cq), 146.6 (Cq), 124.4 (2xCH), 114.0 (2xCH), 102.5
1xCH), 100.2 (2xCH), 54.7 (1xCH ), 54.6 (2xCH ). HRMS (ESI ) [M
3 3
+
7

J. Berthet, et al.
Dyes and Pigments 171 (2019) 107666
+
+
4
.09 (s, 1xCH
259.10772; Found 259.10840. HPLC:
= 26.9 min, purity > 99%. HPLC: column:
purity > 99%. FTIR: ν (cm ): 3442, 2999, 2935, 2831, 1605, 1579,
475, 1429, 1308, 1244, 1117, 1026, 832, 756.
,5-dimethoxy-4-(2-(2-methoxyphenyl)hydrazone)cyclohexa-2,5-die-
none 7. According to the general procedure, compound 7 was purified
by flash chromatography (CH Cl /MeOH, 0–5%) and obtained as a red-
brown solid (407 mg, 87%). Mp: > 220 °C. H NMR (CD
3
), 4.02 (s, 1xCH
3
). HRMS (ESI ) [M+H] Calcd for
18 column:
= 16.3 min,
Acknowledgements
C
14
H
13
N
2
O
3
C
t
R
C
4
t
R
The calculations were performed on the computing facilities of the
Consortium des Équipements de Calcul Intensif (CÉCI, http://www.
ceci-hpc.be), and particularly those of the Technological Platform on
High-Performance Computing located at UNamur (http://www.ptci.
unamur.be), for which the authors gratefully acknowledge the financial
support of the FNRS-FRFC, of the Walloon Region, and of the University
of Namur.
−
1
1
3
2
2
1
3
OD, 300 MHz)
δ(ppm): 7.68 (dd, J = 7.9 and 1.5 Hz, 1x-12), 7.09 (m, H-10, H-9, H-
1
1), 5.81 (d, J = 1.8 Hz, 1xH-2), 5.77 (d, J = 1.9 Hz, 1xH-6), 4.04 (s,
Appendix A. Supplementary data
1
3
CH
1
1
3
), 4.00 (s, CH
3
), 3.89 (s, CH
3
). C NMR (CD
3
OD, 75 MHz) δ(ppm):
87.2 (Cq), 163.6 (Cq), 160.7 (Cq), 148.0 (Cq), 131.2 (Cq), 125.0 (CH),
21.9 (CH), 121.2 (CH), 113.9 (CH), 110.8 (CH), 100.6 (CH), 99.8
Supplementary data to this article can be found online at https://
doi.org/10.1016/j.dyepig.2019.107666.
+
+
(
CH), 55.9 (CH
3
), 55.4 (CH
289.11828; Found 289.11874. HPLC: C18
column: t = 18.1 min, purity
9%. FTIR: ν (cm ): 3289, 3053, 2954, 1626, 1596, 1523, 1407,
3 3
), 55.3 (CH ). HRMS (ESI ) [M+H]
Calcd for C15
column: t
9
1
H
17
N
2
O
4
References
R
= 27.9 min, purity 96%. C
4
R
−
1
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