Singlet oxygen-responsive photorelease of tyramine

Article abstract of DOI:10.1002/bkcs.12385

A system capable of photoreleasing tyramine has been developed. The photodonor system consists of an isoindole cage of tyramine and a biscyclometalated Ir(III) complex singlet oxygen (¹O₂) photosensitizer. Photoirradiation at a wavelength of 365 nm produces tyramine, as evidenced by mass spectrometry and ¹H NMR spectroscopy. The photorelease proceeds through two steps involving the formation of a Diels–Alder-type [2 + 4] cycloadduct of ¹O₂, followed by the slow and spontaneous decomposition of the adduct into tyramine and 2-benzoylbenzophenon.

Full text of DOI:10.1002/bkcs.12385

Received: 19 June 2021
DOI: 10.1002/bkcs.12385
Revised: 30 July 2021
Accepted: 6 August 2021
C O M M U N I C A T I O N
Singlet oxygen-responsive photorelease of tyramine
Dong Yeun Jeong1,2 | Seung Yeon Yi1 | Youngmin You1,2
1Division of Chemical Engineering and Materials
Science, Ewha Womans University, Seoul,
Republic of Korea
2Graduate Program in System Health Science
and Engineering, Ewha Womans University,
Seoul, Republic of Korea
Abstract
A system capable of photoreleasing tyramine has been developed. The
photodonor system consists of an isoindole cage of tyramine and a bis-
cyclometalated Ir(III) complex singlet oxygen (1O2) photosensitizer. Photo-
irradiation at a wavelength of 365 nm produces tyramine, as evidenced by
mass spectrometry and 1H NMR spectroscopy. The photorelease proceeds
through two steps involving the formation of a Diels–Alder-type [2 + 4] cyclo-
Correspondence
Youngmin You, Division of Chemical
Engineering and Materials Science, Ewha
Womans University, Seoul 03760,
Republic of Korea.
1
adduct of O2, followed by the slow and spontaneous decomposition of the
adduct into tyramine and 2-benzoylbenzophenon.
Email: odds2@ewha.ac.kr
K E Y W O R D S
Funding information
Midcareer Research Program, Grant/Award
Number: NRF-2019R1A2C2003969
iridium complex, photocage, photodelivery, singlet oxygen, tyramine
Tyramine, 2-(4-hydroxyphenyl)ethylamine, belongs to the
family of biogenic trace amines in the human body.
Although the trace level of tyramine remains lower than
those of classical biogenic amino neurotransmitters, such
as γ-aminobutyric acid, local concentrations at neural syn-
apses are considerably high.1 Growing evidence indicates
that tyramine is intimately involved in a variety of neuro-
physiological processes. For examples, Borowsky and co-
workers found that neurotransmission is mediated by
tyramine binding of G protein-coupled receptors.2 The
disruption in the homeostasis of tyramine elicits fatal neu-
rodegenerative conditions. Psychiatric disorders, such as
depression, hypertension, and schizophrenia, are linked
to the failure of optimal level of tyramine.3 The other
pathological conditions, including migraine and Parkin-
sonism, are also proposed to be related with the
dysregulation of tyramine.4,5 However, despite the patho-
physiological importance, the molecular mechanism
underlying the biological actions of tyramine has yet been
fully established. The immaturity is due to the underdevel-
opment of molecular tools of tyramine. In particular,
stimuli-responsive molecular donors of tyramine remain
sparse in the literature, although they are anticipated to
be employed for therapeutic purposes.
Thus, it is anticipated that photodonors of tyramine will
serve as powerful tools to study the biological actions of
tyramine. Despite the prospects, there is only one report of
a photodonor of tyramine. Etchenique and co-workers
found that a Ru(II) diimine complex could liberate a tyra-
mine monodentate ligand under photoillumination at a
wavelength of 450 nm.6
In this research, we developed a photodonor of tyra-
mine (DPSY4). DPSY4 was based on 1,3-diphenyl-2H-
isoindole (Scheme 1). Tyramine was incorporated into the
isoindole core through the nitrogen atom. DPSY4 is highly
reactive toward the Diels–Alder-type [2 + 4] cycloaddi-
tion reaction with singlet dioxygen (1O2, hereafter). The
1O2-adduct, an endoperoxide, is spontaneously cleaved
into tyramine and 2-benzoylbenzophenone (BBP, hereaf-
1
ter). We employed a O2 photosensitizer to trigger the
two-step release of tyramine. We previously validated the
1O2-mediated photouncaging of hydrogen sulfide7 and
β-phenethylamines.8 This strategy is valuable as the pho-
toexcitation wavelength can be conveniently controlled
by choosing a 1O2 photosensitizer.9 Herein, we report the
synthesis and reactivities of DPSY4. The photorelease
reaction was characterized with mass spectrometry and
1H NMR and UV–vis absorption spectroscopy.
One viable approach to attaining high-precision release
is to employ photons. The photoinduced release can be
executed noninvasively with very high spatiotemporal pre-
cisions. In addition, the progress of photoinduced release
can be controlled by a photon dose-dependent manner.
DPSY4 was prepared through consecutive reductive
amination reactions between BBP and tyramine in the
presence of NaBH4 in a 13% yield (Scheme 2). DPSY4
exhibited insufficient stabilities under light and an aer-
obic condition. This limited stability prohibited long-
Bull Korean Chem Soc. 2021;1–4.
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JEONG ET AL.
[Ir(ppy)2(phen)]PF6 led to the disappearance of the DPSY4
peak with the concomitant emergence of the peaks mar-
ked with * (retention time = 0.6–1.0 min) and ** (retention
time = 3.7 min). The former peak contained multiple bands;
mass spectra (positive mode, ESI) contained the m/z values
of 195.12, 210.23, and 407.11, which could be assigned as
[H(N-oxide of tyramine)(CH3CN)]+, [H(tyramine)(THF)]+, and
[KNa(tyramine)2(H2O)2Cl]+, respectively. The close matches
between the theoretical isotope distributions and the exper-
imental values support the assignments (Figure 1b and
Figure S2). The latter peak revealed the m/z value of
287.11. This mass value should be assigned as [H(BBP)]+,
as its theoretical isotope distribution coincides perfectly
with the experimental result (Figure 1c). These observa-
tions collectively indicate the photoinduced cleavage of
DPSY4 into tyramine and BBP and are consistent with
our proposed mechanism (Scheme 1). DPSY4 retained
sufficient stability unless photons and O2 were provided
(Figure S3). The result indicates that the tyramine release
proceeded by 1O2.
S C H E M E 1 Photorelease of tyramine mediated by photosensitized
1
The generation of tyramine was further validated by H
singlet oxygen (1O2)
NMR (300 MHz) spectroscopy. Figure 2 shows the evolution
1
of H NMR spectra of aerated CD2Cl2 containing 3.0 mM
DPSY4 and 100 μM [Ir(ppy)2(phen)]PF6 recorded during the
course of continuous photoirradiation (365 nm, 4 W). Two
triplet peaks in the ethylene unit of DPSY4 appeared at 4.56
(Ha) and 2.49 (Hb) ppm. Photoirradiation provoked the
appearance of a triplet peak at 2.41 ppm and a quartet peak
at 3.45 ppm. These peaks are assigned as α-(Hb’) and
β-protons (Ha’) with respect to the free amine of tyramine,
respectively. The broad multiplet peak due to
NH2
S C H E M E 2 Synthesis of DPSY4
emerged at 3.20 ppm. These spectral signatures are consis-
tent with the generation of tyramine, although DPSY4 was
not fully consumed under the photoirradiation condition.
As the final phase of our study, the kinetics of the pho-
toinduced uncaging reaction was monitored using UV–vis
absorption spectroscopy. Aerated CH3CN of 10 μM DPSY4
and 0.3 μM [Ir(ppy)2(phen)]PF6 was photoirradiated at a
wavelength of 365 nm (4 W), during which UV–vis absorp-
tion spectra were taken. The fresh DPSY4 exhibited a broad,
structured absorption band in the region of 290–430 nm
(Figure 3a). This vibronically resolved band is due to the
π–π* transition localized within the isoindole core. Photo-
irradiation led to a hypochromic shift (i.e., a decrease in the
absorbance) of this band, which indicates the disruption of
the isoindole unit. The shift accompanied a hyperchromic
shift (i.e., an increase in the absorbance) of a peak at a
wavelength of 251 nm. This 251 nm peak is reminiscent of
BBP (see the dotted gray curve in Figure 3a); therefore, the
chromic shifts are consistent with the mechanism that
involves the conversion of DPSY4 into BBP.
term storage and the large-scale synthesis. All the
spectroscopic studies were, thus, performed with
freshly prepared samples.
Tyramine release from DPSY4 was examined in aera-
ted CH3CN containing [Ir(ppy)2(phen)]PF6 (ppy = 2-
phenylpyridinato; phen = 1,10-phenanthroline), a 1O2
photosensitizer, under continuous photoirradiation at a
wavelength of 365 nm (4 W). [Ir(ppy)2(phen)]PF6 was cho-
sen as it produces the triplet-excited state with a unitary
quantum yield. The triplet state energy of [Ir(ppy)2(phen)]
1
PF6 is 2.13 eV which is greater than that (0.97 eV) of O2.10
This energetic disposition facilitates spontaneous triplet–
triplet energy transfer to the ground-state molecular oxygen
to form 1O2. Actually, the quantum yield for 1O2 photosensiti-
zation (ΦΔ) of [Ir(ppy)2(phen)]PF6 was determined to be as
high as 0.52.10
Figure 1 compares the liquid chromatograms of tyra-
mine, BBP, [Ir(ppy)2(phen)]+, DPSY4, and a mixture of
DPSY4 and [Ir(ppy)2(phen)]+. Peaks corresponding to the
authentic tyramine and BBP appeared at retention time at
0.6 and 3.7 min, respectively. DPSY4 and [Ir(ppy)2(phen)]+
eluted at retention time 10.1 and 1.6 min. Photoirradiation
(365 nm, 4 W) of the mixture of 1.0 mM DPSY4 and 100 μM
Note that the UV–vis spectral changes are devoid of iso-
sbestic points. The absence of an isosbestic point suggests
the presence of a chromic intermediate species, because
tyramine is spectroscopically silent in the observation region.
The chromic intermediate is likely an endoperoxide of
DPSY4. Although the endoperoxide species could not be

JEONG ET AL.
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F I G U R E 1 Photoinduced release of tyramine from DPSY4. (a) Liquid chromatograms of aerated CH3CN containing 1.0 mM DPSY4 and 100 μM [Ir
(ppy)2(phen)]PF6 recorded during continuous photoirradiation at a wavelength of 365 nm (4 W). The colored chromatograms correspond to the
authentic samples, including tyramine (red), [Ir(ppy)2(phen)]PF6 (green), BBP (blue), and DPSY4 (orange). (b,c) Mass spectra for the peaks marked with *
(elution time = 0.6 min) and ** (elution time = 3.7 min) which correspond to the photoreleased tyramine (b) and BBP (c), respectively. (b) Top,
theoretical values for [KNa(tyramine)2(H2O)2Cl]+ (m/z = 407.11); bottom, observed values. (c) Top, theoretical values for [H(BBP)]+ (m/z = 287.11);
bottom, observed values
In order to follow the stepwise uncaging mediated by
the endoperoxide, we recorded the temporal changes of
the 251 nm absorbance. This wavelength was chosen as
it exhibited a stepwise decay-and-rise profile (Figure 3b).
Nonlinear least-squares fit of the biphasic profile to an
exponential decay-and-rise model returned a decay time
constant (τ1) and a rise time constant (τ2) of 27 s and
1471 s, respectively. The shorter value of τ1 than τ2 indi-
cates the fast formation of the endoperoxide of DPSY1,
followed by the slow decomposition into BBP and tyra-
mine. The tyramine release slower than the endoperoxide
formation is undesirable because tyramine may be over-
oxidized by 1O2 during continuous photoirradiation in the
presence of [Ir(ppy)2(phen)]PF6. The photochemical quan-
tum yield for the tyramine release was determined based
on the ferrioxalate actinometry, to be 5.3% (365 nm, pho-
ton flux = 2.3 Â 10À8 einstein sÀ1). This value is smaller
than those (6% and 9%) reported for photodonors of
F I G U R E 2 1H NMR (300 MHz) spectra of aerated CD2Cl2 containing
3.0 mM DPSY4 and 100 μM [Ir(ppy)2(phen)]PF6 recorded during
continuous photoirradiation at a wavelength of 365 nm (4 W). The peak
marked with * is the residual solvent (EtOAc)
β-phenethylamines,8 which is likely due to the oxidative
1
degradation of the released tyramine by O2. One viable
approach to accelerating the tyramine release would
involve substituent control that weakens the O O bond
1
detected by our mass spectrometry and H NMR spectros-
copy due to its high instability, its intermediacy is essential
for the formation of BBP and tyramine.
of the endoperoxide. It would be instrumental to intro-
duce electron-withdrawing substituents at the peripheral
phenyl rings of DPSY4.

4
JEONG ET AL.
(a)
(b)
F I G U R E 3 (a) UV–vis absorption spectra of aerated CH3CN containing 10 μM DPSY4 and 0.3 μM [Ir(ppy)2(phen)]PF6 recorded during continuous
photoirradiation at a wavelength of 365 nm (4 W; 0–34 min). The inset photos show absorption and fluorescence emission of the mixture solution
before and after the 34 min photoirradiation. (b) Temporal changes of the absorption difference at a wavelength of 251 nm. The red curve is the fit to
an exponential decay-and-rise model. τ1 and τ2 are time constants of the fit, which correspond to the formation of the endoperoxide intermediate
(orange structure in the bottom scheme) and the dissociation of the endoperoxide into BBP and tyramine (blue structures in the bottom scheme). k1
and k2 are calculated through the relationships, k1 = 1/τ1 and k2 = 1/τ2
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1
nitrogen atom. A O2 photosensitizer was combined with
the isoindole derivative of tyramine. Photoinduced
release of tyramine occurred through a two-step reaction,
1
which involved the formation of a O2-endoperoxide of
the tyramine donor, followed by slow decomposition of
the endoperoxide into tyramine and BBP, as supported
by UV–vis absorption spectroscopy. Finally, the tyramine
production was validated unambiguously by mass spec-
1
trometry and H NMR spectroscopy. One disadvantage of
using the tyramine donor is the poor stability against air
and light. We anticipate that judicious substituent control
over the isoindole core will improve the stability of the
donor and the rate for tyramine production.
SUPPORTING INFORMATION
Additional supporting information may be found in the
online version of the article at the publisher’s website.
ACKNOWLEDGMENTS
This work was supported by the Midcareer Research Pro-
gram (NRF-2019R1A2C2003969).
How to cite this article: D. Y. Jeong, S. Y. Yi, Y. You,
Bull Korean Chem Soc 2021, 1. https://doi.org/10.
1002/bkcs.12385
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