The δ2,2′-bi(2H-1,4-benzothiazine) structural motif of red hair pigments revisited: Photochromism and acidichromism in a unique four-state system

Article abstract of DOI:10.1002/ejoc.201200673

Complete spectral and computational characterization of δ^2,2′-bi(2H-1,4-benzothiazine) (BBTZ) demonstrated that the structures of the stable yellow form and the photogenerated red form were assigned incorrectly and should be revised to the cis (Z) and trans (E) isomers, respectively. A blue elusive dication generated upon further protonation of the violet cationic form was also identified by UV spectroscopy and DFT calculations. On the basis of these data, BBTZ can be appreciated as a robust four-state system for various applications. Copyright

Full text of DOI:10.1002/ejoc.201200673

Job/Unit: O20673
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Date: 25-07-12 10:28:00
Pages: 6
SHORT COMMUNICATION
DOI: 10.1002/ejoc.201200673
2,2Ј
The Δ -Bi(2H-1,4-benzothiazine) Structural Motif of Red Hair Pigments
Revisited: Photochromism and Acidichromism in a Unique Four-State System
[a]
[a]
[a]
[b]
Loredana Leone, Orlando Crescenzi, Alessandra Napolitano,* Vincenzo Barone, and
Marco d’Ischia[
a]
Dedicated to the memory of Ernesto Fattorusso
Keywords: Dyes/Pigments / Photochromism / Chromophores / Isomerization
Complete spectral and computational characterization of
dication generated upon further protonation of the violet cat-
ionic form was also identified by UV spectroscopy and DFT
calculations. On the basis of these data, BBTZ can be ap-
preciated as a robust four-state system for various applica-
tions.
2
,2Ј
Δ
-bi(2H-1,4-benzothiazine) (BBTZ) demonstrated that the
structures of the stable yellow form and the photogenerated
red form were assigned incorrectly and should be revised to
the cis (Z) and trans (E) isomers, respectively. A blue elusive
Introduction
yellow isomer (λmax = 453 nm) was reported to give an un-
stable red species with a maximum at 470 nm and a detect-
able shoulder around 530 nm, which was consistently as-
signed the structure of the cis or Z-isomer (Z-BBTZ). In
acidic media, a deep violet chromophore was described as
a result of a 100-nm bathochromic shift in the parent ab-
sorption maximum. Such a marked shift would be a conse-
quence of the peculiar disposition of the cross-conjugated
push–pull systems, which would be highly sensitive to pro-
tonation at the imine-type nitrogen atom(s) with conse-
quent enhancement of the “pull” component.
The broad diversity of natural π-conjugated organic
chromophores provides a unique source of inspiration for
the rational design and implementation of molecular anten-
nas, reporter groups, and smart systems for molecular re-
cognition, light harvesting, photoconversion, biosensing,
and other biomedical and technological applications. Sur-
prisingly little attention has been devoted so far to Δ2
-
,2Ј
bi(2H-1,4-benzothiazine) (BBTZ), a peculiar heterocyclic
system first described in the 1970s[ as the photoactive mo-
tif of red human hair pigments, pheomelanins, and tri-
1]
[
2]
chochromes, and characterized by an intriguing photo-
chromic and pH-dependent chromophore.[1a,3] Because of
the relevance of BBTZ derivatives to the high susceptibility
of red-haired individuals to sunburn, skin cancer, and mela-
[
4]
noma, the photochemical and photophysical properties of
this system have been the focus of intense interest; however,
the potential of BBTZ for biomedical or technological ap-
plications has not yet received due consideration, despite its
[5]
relatively facile synthetic access.
According to the original report,[ BBTZ exists under
ordinary conditions in a stable yellow form which was as-
signed the trans or E-configuration (E-BBTZ), without
however detailed spectral characterization or other experi-
3a]
Scheme 1. Early notions about BBTZ structure and chromophore.
Parallel to that study, an X-ray investigation of 3,3Ј-di-
mental piece of evidence (Scheme 1). Upon irradiation, the phenyl derivatives of BBTZ (3,3Ј-DPBBTZ) revealed that
the most stable forms in those cases possess a cis configura-
[
6]
[
a] Department of Chemical Sciences, University of Naples
tion. This unexpected observation was attributed to the
stacking interactions between the phenyl rings stabilizing
the cis configuration relative to the trans isomer. Since then,
however the structural and spectral characterization of the
various forms of the parent BBTZ was never addressed in
detail, due also to the failure to obtain useful crystals for
“
Federico II”,
via Cintia 4, 80126 Naples, Italy
E-mail: alesnapo@unina.it
[b] Scuola Normale Superiore,
Piazza dei Cavalieri 7, 56126 Pisa, Italy
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200673.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Job/Unit: O20673
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Pages: 6
L. Leone, O. Crescenzi, A. Napolitano, V. Barone, M. d’Ischia
SHORT COMMUNICATION
X-ray analysis. The issue of conflicting configurations of ported the cis configuration of the inter-ring double bond
the BBTZ system was only marginally addressed in subse- (the interproton distance measured in the DFT model is
quent papers dealing with trichochromes,[
therefore unsettled.
7,3c]
remaining 1.90 Å) and effectively ruled out the trans configuration
(4.67 Å).
Intrigued by the potential of melanin-based functional
materials for biomedical and technological applications, we
recently were prompted to revisit the structural properties
and chromophore of BBTZ by an integrated experimental
and computational approach. Main outcomes of this study,
reported herein, include the structural reassignment of
BBTZ and the discovery of an elusive diprotonated form
that escaped the attention of previous workers.
1
13
1
13
Table 1. H and C resonance assignment based on H– C hetero-
nuclear experiments for the yellow BBTZ. Numbering as shown in
Scheme 1.
Position
δ
H
[ppm]
HSQC, δ
ppm]
C
HMBC, δ
C
[ppm]
[
2
3
120.7
143.7
139.0
130.8
128.9
128.0
125.7
122.3
–
8.83
120.7, 139.0
–
122.3, 128.0
139.0, 125.7
4a
5
7.55
7.28
7.25
7.22
6
7
8
Results and Discussion
8a
–
Prior to spectral investigation, DFT calculations em-
ploying the PBE0 functional[ [TD-PBE0/6-311++G-
8]
(2d,2p)//PBE0/6-31+G(d,p)] were performed to characterize
the BBTZ chromophore and associated electronic transi-
tions. Quite surprisingly, the predicted absorption maxi-
mum of the cis forms virtually overlapped that of the stable
yellow species, whereas that of the trans isomer matched the
absorption spectrum of the unstable red species generated
by exposure to sunlight. This unexpected result hinted at
an incorrect assignment of the configurations of the two
species. Assignment of the proton and carbon resonances
followed from analysis of 2D NMR spectra (Table 1) for
the yellow species (Supporting Information, Table S1). Un-
fortunately, it was not possible to grow suitable crystals of
the yellow stable form of BBTZ to clarify its configuration
unambiguously. However, strong suggestive evidence in
support of the structural reassignment came from complete
Figure 1. X-half filtered NOESY-HSQC spectrum (CDCl
yellow form of BBTZ (selected region).
3
) of the
1
13
H NMR and C NMR characterization of the yellow and
red species, which gave results that matched fairly well with
the spectra of the cis and trans isomers, respectively, simu-
lated within the Gauge–Including Atomic Orbitals (GIAO)
The counterintuitive prevalence of the cis form can be
rationalized based on the tendency of the push–pull RS–
CH=CH=NRЈ system to adopt a trans arrangement (i.e.,
corresponding to the situation in Z-BBTZ). For the cis
benzothiazine isomer, the expected planar skeleton (C2v
symmetry) is found; by contrast, the trans isomer displays
[
9]
ansatz at the PBE0/6-311+G(d,p) level (Supporting Infor-
mation). Simple energetic consideration also lent support
to this assignment, inasmuch as most computational levels
explored (Supporting Information), including notably the
PBE0/6-31+G(d,p) level adopted for geometry optimiza-
tions, MP2 calculations with sufficiently large basis sets, as
a C equilibrium structure, in which deviations from planar-
i
ity are localized in the thiazine rings, and only marginally
affect the planarity of the S–C2(C3)=C2Ј(C3Ј)–SЈ system
[
10]
well as the high accuracy CBS-QB3 model chemistry,
(
Figure 2). The planar (C ) trans structure represents in
2h
predicted a higher stability for the cis form. More compel-
ling evidence supporting structural revision of the stable
yellow species to the cis isomer came from a gradient-se-
lected X-half filtered NOESY-HSQC experiment,[ which
allows NOE cross-peaks to be detected between chemically
equivalent protons, exploiting the statistical mixture of dif-
–1
fact a first-order saddle point, some 1.6 kcalmol in energy
above the C conformer. Unfavorable non-bonded interac-
i
tions between the H3 protons and the sulfur centers on the
opposite ring are relieved to some extent by distortion of
11]
the C2h structure (S–H3Ј distance = 2.50 Å) to the C con-
i
former (2.61 Å).
1
2
1
13
1
ferent C– H and C– H isotopomers in natural abun-
dance to break the equivalence of the protons. To minimize
the influence of any imperfect suppression of the diagonal
signals, the experiment is acquired without heteronuclear
decoupling during acquisition; therefore, the NOEs are ob-
1
3
served in correspondence of the C satellite peaks of the
proton signal. The spectrum thus obtained (Figure 1) dis-
Figure 2. Geometry optimized structures of E-BBTZ (left) and Z-
played a prominent H3–H3Ј NOE, which strongly sup- BBTZ (right) at the PBE0/6-31+G(d,p) level of theory.
2
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Photochromism and Acidichromism in a Unique Four-State System
Efficient control and regulation of chromophores is an
Both the absorption maximum and NMR spectroscopic
essential requisite for practical applications. Because a data of the first formed violet species in acids were in fairly
strong acid-induced shift was originally described as the good agreement with DFT predictions (Supporting Infor-
most spectacular property of BBTZ, the acidichromic be- mation) for an N-protonated derivative with a cis configura-
havior of this chromophore was re-examined. Figure 3 tion (Figure 4). Attempts to characterize the blue diproton-
1
shows the absorption profile of Z-BBTZ at neutral pH and ated product by H NMR spectroscopy were unsuccessful,
after acidification to pH Ͻ 4.
because the compound could be generated only in a
strongly acidic aqueous medium where the solubility was
poor. Apparently, addition of acids to DMSO or other or-
ganic solvents was insufficient to generate the diprotonated
species. Nonetheless, both chemical arguments and DFT
calculations concurred to support the structure of an N,NЈ-
diprotonated species in a cis configuration for the blue
chromophore (Figure 4).
Figure 4. Geometry optimized structures of mono- (left) and dipro-
tonated (right) derivatives of BBTZ at the PBE0/6-31+G(d,p) level
of theory.
Interestingly, DFT energy data for both the mono- and
di-N-protonated species predicted a greater stabilization of
the cis against the trans isomers compared to the neutral
forms (Supporting Information). On the basis of these data,
a novel picture of BBTZ as a four-state system with photo-
chromic and pH-dependent behavior (Figure 5) is proposed
(Scheme 2).
Figure 3. (a) Acid-dependent behavior of BBTZ chromophore:
neutral, yellow species (black), photoirradiated species (red); pH 4
(
violet), 2 m HCl (blue); (b) computed spectra for the neutral,
monocation and dication species of BBTZ. Full line, neutral forms:
cis, C2v minimum (black), trans C minimum (red) (relative energy
.6 kcalmol ). Dashed line, N-monoprotonated forms: cis Cs
minimum (black), trans C1 minimum (red) (relative energy
i
–1
1
–1
3
.3 kcalmol ). Dashed-dotted, N,NЈ-diprotonated forms: cis C2
Figure 5. BBTZ as a four-state chromic system. From left to right:
Z form; E form, protonated form, diprotonated form.
minimum (black), trans C2 minimum (red) (relative energy,
–1
4.8 kcalmol ).
As previously reported, a violet species with an intense
maximum at 556 nm developed, which reversibly shifted to
the original maximum upon neutralization. The reaction
proved to be completely reversible over at least five cycles
(not shown). Under more forcing acidic conditions, for ex-
ample, in 2 m HCl, a new species became detectable that
had apparently escaped the attention of previous workers.
This latter species, supposedly a diprotonated derivative, ex-
hibited an absorption maximum at 590 nm, and its forma-
tion was accompanied by a distinct color change of the
solution from violet to deep blue. Plots of absorbance at
556 and 453 nm vs. pH (Supporting Information) indicated
a pK value of ca. 2.5 for the protonated species, whereas it
a
was not possible to obtain reliable information on the acid-
ity constant of the diprotonated species.
Scheme 2. Schematic illustration of the revised four-state BBTZ
system. Regulatory effects of light and protons are highlighted.
Eur. J. Org. Chem. 0000, 0–0
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L. Leone, O. Crescenzi, A. Napolitano, V. Barone, M. d’Ischia
SHORT COMMUNICATION
The potential of BBTZ for photo- and pH-controlled re- (yellow species) = 0.44, R
f
(red species) = 0.66; diethyl ether/hexane,
:1]. At maximum degree of conversion the solution was taken to
9
versible writing processes was briefly assessed in a prelimi-
nary set of experiments. A silica gel plate was dipped into
a dichloromethane solution of BBTZ and then dried. The
yellow-orange plate thus obtained was exposed to HCl va-
pors through a handmade mask containing the letter F to
generate a well-defined image (Figure 6, right panel). This
image was instantaneously erased by exposure to vapors of
ammonia. Conversely, exposure of the yellow plate to HCl
vapors generated a blue background on which a yellow let-
ter E was clearly inscribed by the above mask-aided opera-
tion using ammonia vapors (Figure 6, left panel). The same
write–erase–rewrite operations could be repeated several
dryness and rapidly purified by column chromatography (diethyl
ether/hexane, 9:1). NMR spectroscopic data for BBTZ yellow and
red forms are reported in the Supporting Information. Back reac-
tion of the red form was complete at room temperature after at
least 18 h, and accelerated (2 h) by heating to 40 °C, in agreement
[3a]
with previous report.
NMR Experiments: The gradient-selected X-half filtered NOESY-
HSQC sequence described by Gschwind et al.[ was implemented
with a Bruker 600 DRX instrument equipped with a cryo probe
11]
13
and z axis gradients; X-half filter delays were optimized for a C–
1
H scalar coupling constant of 185 Hz, which is appropriate for the
C3– H3 pair. The sample contained about 5 mg of the yellow
. Spectra
1
3
1
times without apparent modification. The color on plate form of the parent bibenzothiazine in 0.5 mL of CDCl
3
was fairly resistant in the absence of acidic or alkaline va- were recorded at 298.0 K using data sets of 4096ϫ256 points with
a mixing time of 2.0 s, 32 scans for each increment, and a relaxation
pors and in the dark or under low light intensity conditions.
delay of 4 s, and were calibrated on the residual solvent peak. The
data matrix was zero-filled in both dimensions to give a matrix of
4Kϫ1K points; apodization with a squared cosine-bell in F
1
and
exponential multiplication in F was applied.
2
Computational Analysis: All calculations were performed with the
Gaussian package of programs.[ Geometry optimizations were
12]
[
8]
carried out at the DFT level, with a hybrid functional (PBE0)
and a reasonably large basis set [6-31+G(d,p)]. For each species,
different tautomers/conformers were explored. Computations were
performed either in vacuo, or by adoption of a polarizable contin-
uum medium (PCM)[ to account for the influence of the solution
13]
Figure 6. Writing Professor Fattorusso’s initials with BBTZ. Left
panel: HCl-exposed background, NH vapors through the mask,
right panel: neutral background, HCl vapors through the mask.
environment. In view of the faster convergence,
van der Waals cavity based on universal force field (UFF) radii
a scaled
3
[
14]
was used, and polarization charges were modeled by spherical
Gaussian functions.[ Vibrational-rotational contributions to the
free energy were also computed. Additional energy computations
were performed for the neutral form in vacuo at the MP2 level with
15]
Conclusions
]
different basis sets, and at the CBS-QB3 level . UV/Vis spectra of
An integrated NMR and DFT re-examination of the bi- the main species were computed in vacuo or in solution using the
[
16]
benzothiazine core of the photoactive red hair melanin pig- time-dependent density functional theory (TD-DFT) approach,
with the PBE0 functional and the 6-311++G(2d,2p) basis set. To
produce graphs, transitions below 5.6 eV were selected, and an ar-
bitrary Gaussian line width of 0.15 eV was imposed; the spectra
were finally converted to a wavelength scale. NMR shielding ten-
ments has led to reformulation of the stable yellow form of
this photochromic system as the cis (Z) rather than trans
(E) isomer, in contrast with the original assignment. The E
isomer could be readily generated by irradiating the Z iso-
mer with sunlight. Under strongly acidic conditions a novel
elusive BBTZ-derived species dark blue in color was also
disclosed, which was formulated as the Z-configured dicat-
ion. These results underscore the potential of BBTZ as a
peculiar, highly chromic, proton- and photon-responsive,
four-state system for diverse applications, for example, in
optical technological devices.
sors were computed within the Gauge-Including Atomic Orbitals
[9]
(
GIAO) ansatz at the PBE0/6-311+G(d,p) level. Computed iso-
tropic shieldings were converted into chemical shifts using as refer-
ence the values obtained at the same level for benzene.
Supporting Information (see footnote on the first page of this arti-
1
13
cle): Experimental/computed H NMR and C NMR spectra,
HMBC and HSQC spectra, computed UV/Vis spectra for BBTZ,
relative energies of conformers of E/Z BBTZ and related model
compounds.
Experimental Section
Acknowledgments
Synthesis of BBTZs: The Z-BBTZ was prepared following the re-
[
3a]
ported procedure
with modifications. The deep-violet reaction
CO and the yellow
This work was supported in part by grants from Italian Ministero
dellЈUniversità e della Ricerca (MIUR) (PRIN 2008 project).
mixture as obtained was treated with 1 m Na
2
3
precipitate was collected by centrifugation and purified by column
chromatography (diethyl ether/hexane, 9:1) in the dark. The eluates
taken to dryness under vacuum in an ice bath gave the product in
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[
3a]
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ane (3–5 mm) were exposed to sunlight in quartz vials and the con-
version of the yellow to red form was followed by TLC analysis [R
f
4
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Received: May 18, 2012
Published Online: ᭿
[
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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5

Job/Unit: O20673
/KAP1
Date: 25-07-12 10:28:00
Pages: 6
L. Leone, O. Crescenzi, A. Napolitano, V. Barone, M. d’Ischia
SHORT COMMUNICATION
Photochromism
The stable yellow form of Δ2,2Ј-bi(2H-1,4-
benzothiazine) (BBTZ) is shown to be the
Z rather than E isomer, as originally sug-
gested. The latter configuration pertains to
the red photoexcited form. A blue species
produced by diprotonation of BBTZ in 2 m
HCl is also disclosed. BBTZ is thus pro-
posed as a robust bioinspired four-state
chromic system.
L. Leone, O. Crescenzi, A. Napolitano,*
V. Barone, M. d’Ischia ...................... 1–6
The Δ2,2Ј-Bi(2H-1,4-benzothiazine) Struc-
tural Motif of Red Hair Pigments Re-
visited: Photochromism and Acidichro-
mism in a Unique Four-State System
Keywords: Dyes/Pigments
/ Photochro-
mism / Chromophores / Isomerization
6
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