Tuning the Activation Wavelength of Photochromic Oxazines

Article abstract of DOI:10.1002/cphc.201600141

The activation wavelength of a photochromic oxazine can be shifted bathochromically with the introduction of a methoxy substituent on the chromophore responsible for initiating the photochemical transformation. This structural modification permits switchi

Full text of DOI:10.1002/cphc.201600141

DOI: 10.1002/cphc.201600141
Articles
Tuning the Activation Wavelength of Photochromic
Oxazines
[a]
[a, b]
[a]
[c]
Subramani Swaminathan, Jaume Garcia-Amorós,
Ek Raj Thapaliya, Santi Nonell,
[a]
[a]
Burjor Captain, and FranÅisco M. Raymo*
The activation wavelength of a photochromic oxazine can be
shifted bathochromically with the introduction of a methoxy
substituent on the chromophore responsible for initiating the
photochemical transformation. This structural modification per-
mits switching under mild illumination conditions, enhances
the photoisomerization quantum yield and ensures outstand-
ing fatigue resistance. Thus, these results can guide the design
of new members of this family of photoresponsive molecular
switches with improved photochemical and photophysical
properties.
1. Introduction
[
1–5]
Photochromic compounds
interconvert reversibly between
a given property of interest simply by turning an illuminating
source on and off repeatedly. For example, commercial oph-
thalmic lenses rely on the thermal reversion of photochromic
components to lower their transmittance in response to sun-
light reversibly. The timescales required to reset the original
state of most thermally-reversible photochromic compounds,
however, are relatively long and can even extend to several
hours in some instances. Furthermore, they often have modest
fatigue resistances and can only tolerate a limited number of
switching cycles. These stringent limitations are encouraging
research efforts aimed at the identification of alternative struc-
tural designs to accelerate thermal reversion and minimize
photoinduced degradation. Indeed, a few families of photo-
chromic compounds capable of reverting spontaneously on
states with distinct absorption properties in the visible region
of the electromagnetic spectrum, under the influence of opti-
cal stimulations. As a result, pronounced changes in color ac-
company their photoinduced transformations. Additionally, the
very same structural modifications responsible for altering
their ability to absorb visible radiations can also cause signifi-
cant changes in dipole moment, fluorescence, geometry and
redox potentials. In turn, the photoregulation of such molecu-
lar properties translates into the opportunity to control reversi-
bly electrical (conductivity), optical (absorption coefficient and
refractive index) and mechanical (shape) properties at the mac-
roscopic level with light. Indeed, photocontrollable molecular
and supramolecular assemblies as well as photoresponsive
liquid and solid materials can be designed around the unique
sub-second timescales and tolerate thousands of switching
[6]
[7–10]
behavior of this particular class of molecular switches.
cycles have already been developed.
In fact, their out-
Some photochromic compounds switch from their initial to
final states under illumination, but then revert spontaneously
standing performance enabled the implementation of photon-
ic applications (dynamic holography and superresolution imag-
ing) that cannot be replicated with their conventional counter-
parts.
[1–5]
to the original forms once irradiation is terminated.
There-
fore, such molecular switches permit the modulation of
Our laboratory developed photochromic compounds with
fast switching speeds and excellent fatigue resistances based
on the photoinduced opening and thermal closing of oxazine
[
a] Dr. S. Swaminathan, Dr. J. Garcia-Amorós, E. R. Thapaliya, Prof. B. Captain,
Prof. F. M. Raymo
Laboratory for Molecular Photonics, Department of Chemistry
University of Miami
[
11]
rings.
These molecules fuse 2H,3H-indole and 2H,4H-ben-
zo[1,3]oxazine heterocycles within their covalent skeleton (e.g.,
[
12,13]
1
301 Memorial Drive, Florida, 33146-0431 (USA)
1a in Figure 1).
Upon illumination with a pulsed Nd:YAG
E-mail: fraymo@miami.edu
laser, operating at 355 nm, the [CÀO] bond at the junction of
the two heterocycles cleaves to open the oxazine ring and pro-
duce a zwitterionic isomer (e.g., 1b in Figure 1) in its ground
state within the duration of the laser pulse (6 ns). The photo-
chemical product incorporates a phenolate chromophore that
absorbs in the visible region of the electromagnetic spectrum.
As a result, the appearance of an intense visible absorption ac-
companies this photoinduced reaction. The photogenerated
isomer then reverts to the original species with first-order ki-
netics, after the spontaneous closing of the oxazine hetero-
cycle.
[
b] Dr. J. Garcia-Amorós
Grup de Materials Orgànics
2
Institut de Nanoci›ncia i Nanotecnologia (IN UB)
Departament de Química Orgànica, Universitat de Barcelona
Martí i FranquØs 1, E-08028, Barcelona (Spain)
[
c] Prof. S. Nonell
Grup O’Enginyeria Molecular
Institut Químic de Sarrià, Universitat Ramón Llull
Via Augusta 390, E-08017, Barcelona (Spain)
Supporting Information for this article can be found under: http://
dx.doi.org/10.1002/cphc.201600141.
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Articles
Figure 1. Photoinduced and reversible interconversion of the ring-closed (a) and -open (b) isomers of 1 and 2 together with their reversible transformation
into the corresponding protonated forms (c) under the influence of acid and base.
The introduction of substituents on the phenylene ring of
the 2H,3H-indole heterocycle of 1a or the condensation of for-
mylated chromophores to the methyl group on its chiral
center can be exploited to tune the absorption properties of
the corresponding zwitterionic isomers with minimal influence
This substituent encourages intersystem crossing to enable the
opening of the oxazine ring along the potential energy surface
of the corresponding triplet state. In principle, additional sub-
stituents could be introduced in any one of the three positions
available on the phenoxy ring to control its absorption proper-
ties. In fact, literature data on 2-nitrobenzyl derivatives demon-
strate that substitution with a pair of alkoxy groups is a viable
strategy to shift bathochromically the absorption of these par-
ticular photocleavable protecting groups and even allow their
[14–16]
on the photoinduced and thermal switching steps.
In fact,
the latter strategy provides the opportunity to activate the
fluorescence of the condensed chromophore with the photoin-
duced opening of the oxazine ring and led to the develop-
ment of photoactivatable fluorophores for superresolution
[
20]
activation with visible light. These considerations suggested
the incorporation of a methoxy group in position 2 of the
phenoxy chromophore, in the shape of 2a, and the investiga-
tion of the influence of this substituent on the behavior of the
resulting oxazine. This article reports the synthesis and struc-
tural characterization of this novel member of our family of
molecular switches together with a detailed analysis of its elec-
trochemical, photochemical and photophysical properties.
[
17]
imaging. By contrast, all the structural modifications of the
-nitrophenoxy fragment, attempted in our laboratory so far,
resulted in the suppression of the photochemical response
4
[
17c,18]
with one exception.
Yet, this particular component is the
chromophoric subunit that must be excited to initiate the pho-
tochromic transformation. Its main absorption band has a maxi-
mum at ca. 310 nm with a molar absorption coefficient (e) of
À1
À1
[11a]
ca. 10 mm cm and extends only up to 380 nm.
As a con-
sequence, either large concentrations of these compounds are
required to ensure sufficient absorbance at the Nd:YAG laser 2. Results and Discussion
line (355 nm) that is normally employed to switch them or
2.1. Synthesis and Structural Characterization
high illumination intensities must be employed to allow the
detection of the corresponding zwitterionic isomers with ac-
ceptable signal-to-noise ratios. Therefore, viable strategies to
tune the absorption of the chromophore responsible for acti-
vating the photochromic transformation without detrimental
effects on quantum yield and fatigue resistance are very much
needed. Furthermore, the ability to extend such absorption
into the visible region would even allow to avoid ultraviolet ra-
diations altogether and would be particularly useful for biolog-
ical applications.
Compound 2a was synthesized in three steps from 3-me-
thoxy-5-nitrosalicylaldehyde (Figure 2). Specifically, reduction of
the aldehyde group to generate 3, bromination of the primary
alcohol to produce 4 and condensation to 2,3,3-trimethyl-3H-
indole afford the target oxazine 2a in an overall yield of 22%.
The structural identities of the intermediates and final com-
pound were confirmed by electrospray ionization mass spec-
1
13
trometry (ESIMS) as well as by H and C nuclear magnetic res-
onance (NMR) spectroscopies.
[
19]
[17c,18]
Computational
and spectroscopic
studies indicate
Single crystals of 2a, suitable for X-ray diffraction analysis,
could be obtained after the diffusion of hexane/iso-propylether
vapors into an acetonitrile solution of the compound. The re-
that the nitro group in position 4 of the phenoxy chromo-
phore is essential to induce the photochromic transformation.
Figure 2. Synthesis of 2a.
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1
2
.2. H NMR Spectroscopy
The chiral center at the junction of the two heterocycles in 2a
imposes two distinct environments on the pair of methyl
groups in position 3 of the indole fragment and on the two
methylene protons of the oxazine ring. Consistently, the
1
H NMR spectrum (a in Figure 4) of 2a reveals two singlets for
*
&
the methyl protons (Me and Me ) at 1.13 and 1.50 ppm and
*
&
an AB system for the methylene protons (H and H ) centered
at 4.66 ppm, when recorded in [D ]acetonitrile at 248 K. Upon
3
warming the solution up, the two singlets broaden and even-
tually coalesce in a single peak (b–f in Figure 4). Similarly, the
two doublets within the AB system broaden and coalesce into
a single peak. The temperature dependence of these resonan-
ces is a result of the interconversion between the two enantio-
Figure 3. ORTEP representation (50% thermal ellipsoids) of the crystal struc-
ture of 2a.
1
mers of 2a on the H NMR time scale. This degenerate site-ex-
sulting structure (Figure 3) confirms the formation of an oxa-
zine ring with an approximately-orthogonal arrangement be-
tween the two fused heterocycles. The crystallographic analysis
also confirms the presence of a methoxy substituent on the 4-
nitrophenoxy chromophore with the methyl group pointing
away from the oxazine heterocycle to minimize steric con-
strain.
change process demands the thermal cleavage of the [CÀO]
bond at the junction of the two heterocycles with the forma-
tion of the ring-open intermediate 2b. The kinetic parameters
(Table 1) for the ring-opening process can be estimated from
the analysis of the temperature dependence of the line widths
*
&
associated with the singlets for Me and Me in the slow-ex-
[
21]
change regime. Comparison of the resulting values to those
1
Figure 4. Partial H NMR spectra (500 MHz, CD
3
CN, 5 mm) of 2a at 248 (a), 268 (b), 278 (c), 298 (d), 308 (e), and 333 K (f).
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Table 1. Kinetic parameters associated with the thermal ring opening of
Table 2. Photochemical and photophysical parameters of 1a, 1b, 2a and
2b.
[a]
[a]
1
a and 2a.
¼
6
¼
6
¼6
K
Op
À1
DG Op
DH Op
DS Op
l
a
ꢀ
l
b
t
À1
À1
À1
À1
[s
]
[kcalmol
]
[kcalmol
]
[kcalK mol
]
[nm]
[nm]
[ns]
1
2
a
a
199Æ7
768Æ5
14.31Æ0.02
13.63Æ0.03
13.5Æ0.2
15.1Æ0.3
-0.003Æ0.001
0.005Æ0.001
1
2
318
346
0.03
0.3
440
480
22
151
¼6
¼6
[
a] The rate constant (kOp), free energy (DG Op), enthalpy (DH Op), and en-
a b
[a] The wavelengths (l and l ) of maximum absorbance for the ring-
¼6
tropy (DS Op) of activation at 298 K were determined by variable-temper-
ature H NMR spectroscopy in CD
are literature values (ref. [11a]).
closed and -open isomers, quantum yield (ꢀ) for the photoisomerization
and lifetime (t) of the ring-open isomer at 298 K were determined by
steady-state and time-resolved absorption spectroscopies in MeCN. The
data reported for 1 are literature values (ref. [11a]).
1
3
CN (ref.[21]). The data reported for 1a
[
11a]
measured previously for 1a,
under otherwise identical ex-
spectrum of 1a (b in Figure 5), recorded under otherwise iden-
tical conditions, shows that the presence of the methoxy sub-
stituent in 2a imposes a bathochromic shift of 28 nm, in
agreement with the logic behind the design of this particular
compound. Additionally, the spectrum of 2a does not reveal
any detectable absorbance in the wavelength range where the
2-methoxy-4-nitrophenolate chromophore of 2b is expected
to absorb. In fact, the tetrabutylammonium salt of 6, which in-
corporates essentially the same chromophore of 2b, absorbs
at 450 nm with a e of 18.4 mm cm (c in Figure 5). These ob-
servations indicate that the stationary concentration of the
ring-open isomer is below the detection limit, under these ex-
perimental conditions.
perimental conditions, indicates that the methoxy group of 2a
has a pronounced influence on the thermal opening of the ox-
azine ring. Specifically, the presence of this particular substitu-
ent leads to a fourfold increase in the rate constant (kOp in
Table 1) for the site-exchange process. This change corre-
¼6
sponds to a decrease in free-energy barrier (DG
in Table 1)
Op
À1
of ca. 0.7 kcalmol and appears to be mostly a consequence
¼6
of entropic gain (DS
in Table 1). In fact, methoxy substitu-
Op
¼6
À1
À1
tion is actually enhancing the enthalpy (DH
in Table 1) of
Op
À1
activation by about 1.6 kcalmol . However, such an increase is
¼6
À1
offset by a change in TDS
of about 2.4 kcalmol . Presuma-
Op
bly, the elongation of the cleaving [CÀO] bond relieves steric
constrain around the methoxy substituent in the correspond-
ing transition state to facilitate conformational changes in this
group and cause a significant gain in entropy.
The oxazine ring of 2a opens to form 2c upon acidification
(Figure 1). This structural transformation converts the 2-me-
thoxy-4-nitrophenoxy chromophore into the corresponding
phenol. As a consequence, the absorption maximum shifts
from 346 to 328 nm (d in Figure 5) and the resulting band re-
sembles that observed for 5 (e in Figure 5). Additionally, a new
2
.3. Steady-State Absorption Spectroscopy
[
14c]
band for the indolium cation of 2c appears at 288 nm.
After
The absorption spectrum of 2a (a in Figure 5), recorded in ace-
tonitrile at 298 K, shows a band with a maximum at 346 nm (l
treatment with base, 2c switches back to 2a and the original
spectrum is restored (f in Figure 5).
a
À1
À1
in Table 2) and an e of 9.96 mm cm . This particular absorp-
tion tails into the visible region and is associated with the 2-
methoxy-4-nitrophenoxy chromophore. Comparison to the
2.4. Time-Resolved Absorption Spectroscopy
Illumination of an aerated acetonitrile solution of 2a, main-
tained at 298 K, with a Nd:YAG laser, operating at a wavelength
of 355 nm and an energy of only 0.8 mJ, excites the 2-me-
thoxy-4-nitrophenoxy chromophore. The subsequent cleavage
of the [CÀO] bond at the junction of the two heterocycles re-
sults in the formation of 2b within the duration of the laser
pulse (6 ns) and a quantum yield (ꢀ in Table 2) of 0.3. Consis-
tently, the absorption spectrum (a in Figure 6), recorded after
laser excitation, shows a band centered at ca. 480 nm (l in
b
Table 2) for a ground-state absorption of the anionic chromo-
phore of 2b. Indeed, this transient band resembles the steady-
state absorption of the tetrabutylammonium salt of 6 (b in
Figure 6) and decays on a nanosecond timescale with the
spontaneous reisomerization of 2b back to 2a. Monoexponen-
tial fitting of the absorbance evolution (c in Figure 6) reveals
the lifetime (t in Table 2) of 2b to be 151 ns, under these ex-
perimental conditions. The very same transient absorption
with identical decay is also detected without molecular
oxygen, in agreement with its assignment to a ground-state
Figure 5. Absorption spectra (0.1 mm, MeCN, 298 K) of 2a before (a) and
after the addition of CF
3 2 2 3
CO H (d, 20 equiv.) and then K CO (f, 100 equiv.),
1
a (b), the tetrabutylammonium salt of 6 (c) and 5 (e).
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Figure 6. Absorption spectra of solutions (0.1 mm, MeCN, 298 K) of either 2a (a), recorded 6 ns after pulsed illumination at 355 nm (0.8 mJ, 6 ns), or the tetra-
butylammonium salt of 6 (b), absorbance evolution (c) at 480 nm, after the pulsed illumination of the former solution with the corresponding monoexponen-
tial fitting, and temperature dependence of kCl for 2b (d) and 1b (e).
absorption rather than an electronic transition in the triplet
manifold. Furthermore, this photochromic compound can be
switched for thousands of cycles without any sign of degrada-
tion. In fact, the transient absorbance (Figure S1 of the Sup-
porting Information, SI), detected for 2b after pulsed illumina-
tion, remains virtually unchanged even after up to 5000 excita-
tion cycles in aerated solution.
2.5. Cyclic Voltammetry
The cyclic voltammogram of 2a (a in Figure 7) shows waves at
+0.88 and À1.44 V for the irreversible oxidation of the indole
heterocycle and quasi-reversible reduction of the nitro group,
The behavior of 2a upon excitation parallels that reported
[
11a]
for 1a.
Comparison of the corresponding photochemical
and photophysical parameters, however, indicates that the me-
thoxy substituent facilitates the photoisomerization, delays the
thermal reisomerization and shits bathochromically the absorp-
tion of the ring-open isomer. Specifically, ꢀ and t increase by
approximately one order of magnitude with substitution and
lb shifts by 40 nm (Table 2).
¼6
¼6
The enthalpy and entropy (DH and DS in Table 3) of ac-
Cl
Cl
tivation for the thermal ring closing of 1b and 2b can be esti-
mated from the temperature dependence (d and e in Figure 6)
of the corresponding rate constants (k in Table 3) determined
Cl
from the absorbance decays. Comparison of the resulting
¼
6
¼6
values indicates that DH
and TDS
increase by about 2.0
Cl
Cl
À1
and 0.9 kcalmol
respectively with methoxy substitution.
These effects translate into an enhancement in free energy
¼6
À1
(
DG in Table 3) of activation of about 1.1 kcalmol and ap-
Cl
proximately a sixfold decrease in kCl.
Table 3. Kinetic parameters associated with the thermal ring closing of
[a]
1
b and 2b.
¼
6
¼
6
¼6
k
Cl
À1
DG Cl
DH Cl
DS Cl
À1
À1
À1
À1
[s
]
[kcalmol
]
[kcalmol
]
[kcalK mol ]
7
6
1
2
b
b
4”10
7”10
7.09Æ0.05
8.23Æ0.06
0.23Æ0.05
2.27Æ0.06
À0.023Æ0.001
À0.020Æ0.001
¼6
¼6
[
a] The rate constant (kCl), free energy (DG Cl), enthalpy (DH Cl), and en-
¼
6
tropy (DS ) of activation at 298 K were determined by time-resolved ab-
sorption spectroscopy in MeCN. The data reported for 1b are literature
values (ref. [11a]).
Figure 7. Cyclic voltammograms [1 mm, MeCN, Bu
4
NPF
in MeCN), 100 mVs ] of 2a (a and b) and 1a (c and d)
before (a and c) and after (b and d) the addition of CF CO H (20 equiv.).
6
(0.1m), V vs. Ag/
+
À1
Ag (1 mm AgNO
3
3
2
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respectively. Upon acidification, 2a switches to 2c with the
concomitant conversion of the indole heterocycle into an indo-
lium cation and the disappearance of the former peak from
the corresponding voltammogram (b in Figure 7). Additionally,
this structural transformation converts the 2-methoxy-4-nitro-
phenoxy fragment into the corresponding phenol and causes
the appearance of two waves at À0.99 and À1.49 V for consec-
utive and irreversible reductions of the nitro group. In fact, this
voltammetric response is typical of nitrophenyl derivatives
100 Bio spectrometer, using quartz cells with a path length of
0
.5 cm. Time-resolved absorption spectra were recorded upon exci-
tation with a Q-switched Nd-YAG laser (355 nm, 6 ns pulse width,
.8 mJ per pulse). The concomitant absorbance changes were
0
monitored orthogonally with a white-light analyzing beam pro-
duced by a PTI Xe lamp (75 W) in combination with a dual-grating
PTI 101 monochromator coupled to a Hamamatsu R928 photomul-
tiplier for detection. All experiments were performed using quartz
cells with a path length of 1.0 cm. The quantum yield for the pho-
tochromic transformation of 2a into 2b was determined with
[22]
[14a]
a benzophenone standard, following a literature protocol.
Vol-
under acidic conditions.
tammograms were recorded with a CH Instruments 610A electro-
The electrochemical behavior of 2a parallels that observed
for 1a under otherwise identical conditions. Specifically, the
cyclic voltammogram (c in Figure 6) of the latter compound
also shows waves at +0.85 and À1.53 V for the irreversible oxi-
dation of the indole heterocycle and quasi-reversible reduction
of the nitro group, respectively. Upon acidification, the waves
for the consecutive and irreversible reductions of the nitro
group can be detected at À0.85 and À1.48 V (d in Figure 6).
Thus, methoxy substitution causes only modest negative shifts
in the potentials for the reduction of the nitro group before
and after acidification.
chemical analyzer in MeCN solutions of Bu NPF (0.1m) at a scan
4
6
À1
rate of 100 mVs under Ar, using a three-electrode cell. The refer-
+
ence was a Ag/Ag electrode (1 mm AgNO in MeCN). The counter
3
and working were a platinum wire and a glassy-carbon electrode,
respectively.
Synthesis of Compound 2a
A solution of 4 (350 mg, 1 mmol) and 2,3,3-trimethyl-3H-indole
(
2
215 mL, 1 mmol) in MeCN (13 mL) was heated under reflux for
4 hours. After cooling down to ambient temperature, the solvent
was distilled off under reduced pressure. The residue was suspend-
ed in H O (50 mL) and extracted with CH Cl (3”50 mL). The com-
2
2
2
3. Conclusions
bined organic layers were dried over Na SO and the solvent was
2 4
distilled off under reduced pressure. The residue was purified by
The activation wavelength of a photochromic oxazine can be
shifted bathochromically with the introduction of a methoxy
substituent in position 2 of its 4-nitrophenoxy chromophore.
This structural modification positions the absorption maximum
at 346 nm and allows the effective switching of the resulting
compound with a Nd:YAG laser operating at a wavelength of
column chromatography [SiO : hexane/EtAC (92:8, v/v)] to give 2a
2
+
(
200 mg, 45%). ESIMS: m/z=341.1497 [M+H] (m/z calcd for
1
C H N O =341.1496); H NMR (CDCl ): d=1.24 (3H, s), 1.54 (3H,
19
21
2
4
3
s), 1.60 (3H, s), 3.77 (3H, s), 4.58 (2H, s), 6.56 (1H, d, 7.52 Hz) 6.83
(1H, d, 7.04 Hz), 7.09–7.13 (2H, m), 7.49 (1H, s), 7.73 ppm (1H, s);
13
C NMR [(CD ) CO]: d=16.3, 18.6, 25.8, 39.8, 48.4, 55.9, 103.4,
3 2
1
1
05.2, 109.1, 115.9, 119.6, 120.7, 122.5, 127.8, 138.6, 140.1, 147.6,
49.1, 149.4 ppm.
3
55 nm with an energy of only 0.8 mJ. Additionally, the pres-
ence of a methoxy substituent enhances the quantum yield for
photoisomerization by one order of magnitude and has no
detrimental effects on the fatigue resistance. Specifically, this
photochromic compound can be operated for up 5000 excita-
tion cycles with no sign of degradation, even in the presence
of molecular oxygen. Furthermore, the absorption band of the
chromophore responsible for activating the photochromic
transformation extends into the visible region and, as a result,
should permit photoinduced switching with laser lines
Synthesis of Compound 3
A solution of 2-hydroxy-3-methoxy-5-nitrobenzaldehyde (400 mg,
2
mmol) and NaBH (77 mg, 2 mmol) in EtOH (10 mL) was stirred
4
for 4 hours at ambient temperature. The solvent was distilled off
under reduced pressure and the residue was suspended in H O
2
(
20 mL), diluted with aqueous HCl (1m, 5 mL) and extracted with
EtOAc (3”50 mL). The combined organic layers were dried over
Na SO and the solvent was distilled off under reduced pressure to
(
405 nm) routinely employed for biological applications. Thus,
2
4
these results demonstrate that methoxy substitution is a viable
strategy to tune the activation wavelength of this family of
photochromic oxazines and even improve their photochemical
performance.
give 3 (320 mg, 79%). ESIMS: m/z=222.0388 [M+Na]+ (m/z calcd
1
for C
H NNaO =222.0373); H NMR (CDCl ): d=2.13 (1H, s), 4.02
9 5 3
8
(
3H, s), 4.84 (2H, s), 6.62 (1H, s), 7.76 (1H, s), 7.99 ppm (1H, s);
1
3
C NMR [(CD ) CO]: d=55.9, 58.2, 104.9, 115.6, 128.9, 140.2, 146.6,
3
2
1
49.3 ppm.
Experimental Procedures
Synthesis of Compound 4
Materials and Methods
A solution of 3 (400 mg, 2 mmol) and PBr3 (142 mL, 2 mmol) in
Chemicals were purchased from commercial sources and used as
received, with the exception of MeCN, which was distilled over
CHCl3 (10 mL) was stirred for 12 hours at ambient temperature.
The mixture was diluted with H O (20 mL) and extracted with
2
CaH . Compound 1a was prepared according to a literature proce-
CHCl3 (3”50 mL). The combined organic layers were dried over
Na SO and the solvent was distilled off under reduced pressure to
2
[11a,12]
dure.
Reactions were monitored by thin-layer chromatogra-
2
4
À
phy, using aluminum sheets coated with silica (60, F254). ESIMS
were recorded with a Bruker micrOTO-Q II spectrometer. NMR
spectra were recorded with a Bruker Avance 400 spectrometer.
Steady-state absorption spectra were recorded with a Varian Cary
give 4 (350 mg, 63%). ESIMS: m/z=259.9562 [MÀH] (m/z calcd
1
for C H BrNO =259.9553); H NMR (CDCl ): d=4.03 (3H, s), 4.58
8
8
4
3
13
(2H, s), 7.77 (1H, s), 7.99 ppm (1H, s); C NMR (CDCl3): d=26.3,
57.2, 105.5, 113.1, 119.9, 122.0, 141.0, 146.6, 149.9 ppm.
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Articles
Crystallographic Analysis
J. Abe, Chem. Commun. 2015, 51, 1375–1378; n) H. Yamashita, T. Ikeza-
wa, Y. Kobayashi, J. Abe, J. Am. Chem. Soc. 2015, 137, 4952–4955.
Yellow single crystals were obtained after diffusion of hexane/iPr O
[9] a) A. A. Beharry, O. Sadovski, G. A. Woolley, J. Am. Chem. Soc. 2011, 133,
19684–19687; b) M. Blanco-Lomas, S. Samanta, P. J. Campos, G. A.
Woolley, D. Sampedro, J. Am. Chem. Soc. 2012, 134, 6960–6963; c) S. Sa-
manta, A. Babalhavaeji, M. X. Dong, G. A. Woolley, Angew. Chem. Int. Ed.
2
(
1:1, v/v) into a MeCN solution of 2a maintained at À108C. The
data crystal was mounted onto the end of a thin glass fiber using
Paratone-N for data collection at 100 K under a flow of N . X-ray in-
2
2013, 52, 14127–14130; Angew. Chem. 2013, 125, 14377–14380; d) S.
tensity data were measured with a Bruker SMART APEX2 CCD-
[23]
Samanta, A. A. Beharry, O. Sadovski, T. M. McCormick, A. Babalhavaeji, V.
Tropepe, G. A. Woolley, J. Am. Chem. Soc. 2013, 135, 9777–9784; e) S.
Samanta, T. M. McCormick, S. K. Schmidt, D. S. Seferos, G. A. Woolley,
Chem. Commun. 2013, 49, 10314–10316; f) A. Rullo, A. Reiner, A. Reiter,
D. Trauner, E. Y. Isacoff, G. A. Woolley, Chem. Commun. 2014, 50, 14613–
14615; g) M. Dong, A. Babalhavaeji, M. J. Hansen, L. Kalman, G. A. Wool-
ley, Chem. Commun. 2015, 51, 12981–12984; h) M. X. Dong, A. Babalha-
vaeji, S. Samanta, A. A. Beharry, G. A. Woolley, Acc. Chem. Res. 2015, 48,
based diffractometer, using Mo Ka radiation (l=0.71073 Š). The
raw data frames were integrated with the SAINT+ program by
using a narrow-frame integration algorithm. Corrections for Lorentz
and polarization effects were also applied with SAINT+. An empiri-
cal absorption correction based on the multiple measurement of
equivalent reflections was applied using the program SADABS. The
structure was solved by a combination of direct methods and dif-
ference Fourier syntheses and refined by full-matrix least-squares
2662–2670.
2
[24]
[10] a) J. Garcia-Amorós, M. C. R. Castro, P. Coelho, M. M. M. Raposo, D. Velas-
co, Chem. Commun. 2013, 49, 11427–11429; b) J. Garcia-Amorós, A. Bu-
cinskas, M. Reig, S. Nonell, D. Velasco, J. Mater. Chem. C 2014, 2, 474–
on F with the SHELXTL software package. Compound 2a crys-
tallized in the monoclinic crystal system and the systematic absen-
ces in the data were consistent with the unique space group P2 /n.
1
480; c) J. Garcia-Amorós, A. Cuadrado, M. Reig, V. De Waele, O. Poizat,
All non-hydrogen atoms were refined with anisotropic displace-
ment parameters. Hydrogen atoms were placed in geometrically-
idealized positions and included as standard riding atoms during
the least-squares refinements. Crystal data, data collection parame-
ters and results of the analysis are listed in Table S1.
D. Velasco, Chem. Eur. J. 2015, 21, 14292–14296.
11] a) M. Tomasulo, S. Sortino, A. J. P. White, F. M. Raymo, J. Org. Chem.
2005, 70, 8180–8189; b) M. Tomasulo, S. Sortino, F. M. Raymo, Org. Lett.
2005, 7, 1109–1112.
[12] For an early synthesis of 1a, see: a) A. A. Shachkus, J. Degutis, A. Jezer-
skaite, in Chemistry of Heterocyclic Compounds, Vol. 35 (Eds.: J. Kovac, P.
Zalupsky), Elsevier, Amsterdam, 1987, pp. 518–520; b) A. A. Shachkus, J.
Degutis, A. G. Urbonavichyus, Khim. Geterotsikl. Soedin. 1989, 5, 672–
[
Keywords: heterocycles · isomerization · molecular switches ·
oxazines · photochromism
676; Chem. Heterocycl. Compd. 1989, 562–565.
[
13] For related spectroscopic studies on 1a, see: a) M. Barkauskas, V. Marty-
naitis, A. Sackus, R. Rotomskis, V. Sirutkaitis, M. Vengris, Lithuanian J.
Phys. 2008, 48, 231–242; b) V. Voiciuk, K. Redeckas, V. Martynaitis, R.
Steponaviciute, A. Sackus, M. Vengris, Phys. Chem. Chem. Phys. 2015, 17,
17828–17837.
[
[
[
[
[
[
[
1] Photochromism: Memories and Switches (Ed.: M. Irie), Chem. Rev. 2000,
00, 1683–1890.
2] Synthetic and Natural Photoswitches (Eds.: D. Bassani, J. Hofkens, J. L.
Pozzo), Photochem. Photobiol. Sci. 2010, 9, 117–264.
1
[14] a) M. Tomasulo, S. Sortino, F. M. Raymo, Adv. Mater. 2008, 20, 832–835;
b) M. Tomasulo, S. Sortino, F. M. Raymo, J. Org. Chem. 2008, 73, 118–
126; c) E. Deniz, M. Tomasulo, S. Sortino, F. M. Raymo, J. Phys. Chem. C
2009, 113, 8491–8497; d) E. Deniz, J. Cusido, S. Swaminathan, M. Battal,
S. Impellizzeri, S. Sortino, F. M. Raymo, J. Photochem. Photobiol. A 2012,
229, 20–28.
[15] For related derivatives of 1a, see: a) K. Redeckas, V. Voiciuk, R. Stepona-
viciute, V. Martynaitis, A. Sackus, M. Vengris, J. Phys. Chem. A 2014, 118,
5642–5651; b) K. Redeckas, V. Voiciuk, R. Steponaviciute, V. Martynaitis,
A. Sackus, M. Vengris, J. Photochem. Photobiol. A 2014, 285, 7–15; c) V.
Voiciuk, K. Redeckas, V. Martynaitis, R. Steponaviciute, A. Sackus, M. Ven-
gris, J. Photochem. Photobiol. A 2014, 278, 60–68; d) G. Ragait e˙ , V. Mar-
tynaitis, V. Kri sˇ cˇ i u¯ nien e˙ , N. Kleizien e˙ , K. Redeckas, V. Voiciuk, M. Vengris,
3] Photochromism (Eds.: G. Favaro, M. Irie), J. Photochem. Photobiol. C
2011, 12, 71–236.
4] Special Issue Photochromic Control of Molecular and Macroscopic Proper-
ties (Eds.: F. M. Raymo, D. Gust), Isr. J. Chem. 2013, 53, 229–311.
5] New Frontiers in Photochromism (Eds.: M. Irie, M. Yokoyama, Y. Seki),
Springer, New York, 2013.
6] Molecular Switches (Eds.: B. L. Feringa, W. L. Brown), Wiley-VCH, Wein-
heim, 2011.
7] a) J. J. Rack, N. V. Mockus, Inorg. Chem. 2003, 42, 5792–5794; b) A. A.
Rachford, J. L. Petersen, J. J. Rack, Inorg. Chem. 2005, 44, 8065–8075;
c) N. V. Mockus, D. Rabinovich, J. L. Petersen, J. J. Rack, Angew. Chem.
Int. Ed. 2008, 47, 1458–1461; Angew. Chem. 2008, 120, 1480–1483;
d) B. A. McClure, N. V. Mockus, D. P. Butcher, D. A. Lutterman, C. Turro,
J. L. Petersen, J. J. Rack, Inorg. Chem. 2009, 48, 8084–8091; e) B. A.
McClure, J. J. Rack, Angew. Chem. Int. Ed. 2009, 48, 8556–8558; Angew.
Chem. 2009, 121, 8708–8710; f) B. A. McClure, E. R. Abrams, J. J. Rack, J.
Am. Chem. Soc. 2010, 132, 5428–5436; g) B. A. McClure, J. J. Rack, Inorg.
Chem. 2011, 50, 7586–7590; h) K. Garg, J. T. Engle, C. J. Ziegler, J. J.
Rack, Chem. Eur. J. 2013, 19, 11686–11695; i) A. W. King, Y. H. Jin, J. T.
Engle, C. J. Ziegler, J. J. Rack, Inorg. Chem. 2013, 52, 2086–2093; j) A. W.
King, L. Wang, J. J. Rack, Acc. Chem. Res. 2015, 48, 1115–1122.
8] a) K. Fujita, S. Hatano, D. Kato, J. Abe, Org. Lett. 2008, 10, 3105–3108;
b) Y. Kishimoto, J. Abe, J. Am. Chem. Soc. 2009, 131, 4227–4229; c) Y.
Harada, S. Hatano, A. Kimoto, J. Abe, J. Phys. Chem. Lett. 2010, 1, 1112–
ˇ ˇ
A. Sackus, Dyes Pigm. 2015, 113, 546–553.
[16] For related derivatives of 1a, see: a) Y. Prostota, P. J. Coelho, J. Pina, J. S.
de Melo, Photochem. Photobiol. Sci. 2011, 10, 1346–1354; b) Y. Prostota,
J. Berthet, S. Delbaere, P. J. Coelho, Dyes Pigm. 2013, 96, 569–573.
[17] a) E. Deniz, S. Sortino, F. M. Raymo, J. Phys. Chem. Lett. 2010, 1, 3506–
3509; b) E. Deniz, M. Tomasulo, J. Cusido, I. Yildiz, M. Petriella, M. L.
Bossi, S. Sortino, F. M. Raymo, J. Phys. Chem. C 2012, 116, 6058–6068;
c) M. Petriella, E. Deniz, S. Swaminathan, M. J. Roberti, F. M. Raymo, M. L.
Bossi, Photochem. Photobiol. 2013, 89, 1391–1398; d) J. Garcia-Amorós,
S. Swaminathan, S. Sortino, F. M. Raymo, Chem. Eur. J. 2014, 20, 10276–
10284.
[
[18] a) M. Šxman Petersen, E. Deniz, M. Brøndsted Nielsen, S. Sortino, F. M.
Raymo, Eur. J. Org. Chem. 2009, 4333–4339; b) E. Deniz, M. Battal, J.
Cusido, S. Sortino, F. M. Raymo, Phys. Chem. Chem. Phys. 2012, 14,
10300–10307.
1115; d) S. Hatano, K. Fujita, N. Tamaoki, T. Kaneko, T. Nakashima, M.
Naito, T. Kawai, J. Abe, J. Phys. Chem. Lett. 2011, 2, 2680–2682; e) N.
Ishii, T. Kato, J. Abe, Sci. Rep. 2012, 2, 819; f) N. Ishii, J. Abe, Appl. Phys.
Lett. 2013, 102, 163301; g) K. Mutoh, M. Sliwa, J. Abe, J. Phys. Chem. C
[19] F. M. Raymo, J. Phys. Chem. A 2012, 116, 11888–11895.
ˇ
[20] P. Klµn, T. Solomek, C. G. Bochet, A. Blanc, R. Givens, M. Rubina, V. Popik,
2013, 117, 4808–4814; h) T. Iwasaki, T. Kato, Y. Kobayashi, J. Abe, Chem.
A. Kostikov, J. Wirz, Chem. Rev. 2013, 113, 119–191.
Commun. 2014, 50, 7481–7484; i) K. Shima, K. Mutoh, Y. Kobayashi, J.
Abe, J. Am. Chem. Soc. 2014, 136, 3796–3799; j) H. Yamashita, J. Abe,
Chem. Commun. 2014, 50, 8468–8471; k) K. Arai, Y. Kobayashi, J. Abe,
Chem. Commun. 2015, 51, 3057–3060; l) K. Mutoh, Y. Nakagawa, A. Sa-
kamoto, Y. Kobayashi, J. Abe, J. Am. Chem. Soc. 2015, 137, 5674–5677;
m) T. Yamaguchi, M. F. Hilbers, P. P. Reinders, Y. Kobayashi, A. M. Brouwer,
[21] Below the coalescence temperature, two well-separated singlets can be
*
&
1
observed for the methyl protons Me and Me in the H NMR spectra
(a–c in Figure 4). Under these conditions, the line width (Dn) of either
one of the two singlets is related to the rate constant (k) of the degen-
erate site-exchange process according to Equation (1), where Dn is the
0
line width at the stopped-exchange limit (J. H. Nelson, Nuclear Magnetic
ChemPhysChem 2016, 17, 1852 – 1859
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Articles
Resonance Spectroscopy, Prentice Hall, Upper Saddle River, NJ, 2003.).
Following this protocol, kOp can be determined at any temperature (T)
[23] Apex2 Version 2.2-0 and SAINT+ Version 7.46A; Bruker Analytical X-ray
System, Inc., Madison, Wisconsin, USA, 2007.
[24] a) G. M. Sheldrick, SHELXTL Version 6.1, Bruker Analytical X-ray Systems,
Inc., Madison, Wisconsin, USA, 2000; b) G. M. Sheldrick, Acta Crystallogr.
Sect. A 2008, 64, 112–122.
À1
À1
within the slow-exchange regime. A plot of ln(kOp
T
) against T can
then be fitted to Equation (2), where R is the gas constant, to extract
°
°
the enthalpy (DH Op) and entropy (DS Op) of activation. Finally, the free
°
energy (DG Op) of activation can be calculated at any T using Equa-
tion (3).
k
Op =p(DnÀDn
0
) (1)
À1
°
°
À1
ln(kOp
T
)=ÀDH Op(RT)À1+DS Op
R +23.76 (2)
°
°
°
DG Op =DH OpÀTDS Op (3).
Manuscript received: February 8, 2016
Accepted Article published: March 22, 2016
Final Article published: March 31, 2016
[
22] D. S. Silvester, A. J. Wain, L. Aldous, C. Hardacre, R. G. Compton, J. Elec-
troanal. Chem. 2006, 596, 131–140.
ChemPhysChem 2016, 17, 1852 – 1859
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