Organic Nanocrystals with Bright Red Persistent Room-Temperature Phosphorescence for Biological Applications

Article abstract of DOI:10.1002/anie.201705945

Persistent room-temperature phosphorescence (RTP) in pure organic materials has attracted great attention because of their unique optical properties. The design of organic materials with bright red persistent RTP remains challenging. Herein, we report a n

Full text of DOI:10.1002/anie.201705945

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Accepted Article
Title: Organic Nanocrystals with Bright Red Persistent Room-
Temperature Phosphorescence for Biological Applications
Authors: Seyed Mohammad Ali Fateminia, Zhu Mao, Zhiyong Yang,
Shidang Xu, Zhenguo Chi, and Bin Liu
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201705945
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10.1002/anie.201705945
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COMMUNICATION
Organic Nanocrystals with Bright Red Persistent Room-
Temperature Phosphorescence for Biological Applications
S. M. Ali FateminiaϮ [a], Zhu MaoϮ [b], Shidang Xu [a], Zhiyong Yang* [b], Zhenguo Chi* [b], Bin Liu* [a]
our ability to quench the non-radiative processes of organic
compounds remains limited.[20] So far, several strategies have
been applied to minimize the intermolecular and intramolecular
motions to activate the phosphorescence emission, which
include host–guest doping systems with supra-molecular gel
Abstract: Persistent room-temperature phosphorescence (RTP) in
pure organic materials has attracted great attention due to their
unique optical properties. The design of organic materials with bright
and red persistent RTP remains challenging. Herein, we report a
new design strategy for realizing high brightness and long lifetime of
red-emissive RTP molecules, which is based on introducing an
alkoxy spacer between the hybrid units in the molecule. The spacer
offers easy Br-H bond formation during crystallization, which also
facilitates intermolecular electron coupling to favor persistent RTP.
As majority of the RTP compounds have to be confined in a rigid
environment in order to quench non-radiative relaxation pathways for
bright phosphorescence emission, nanocrystallization is used to not
only rigidify the molecules, but also offer the desirable size and
water-dispersity for biomedical applications.
entrapping,[21] metal-organic framework coordination[22] and rigid
24]
solid protection,[4] polymer assistance,[23,
and crystal
formation.[16] Except for the crystallization approach, additional
molecules or matrices are always involved in the rigidification
methods, which add complexity to their applications with
compromised performance due to the diluted RTP molecule
concentration. This is particularly
a concern in biological
applications as the biocompatibility and negligible interference
between the matrix and the biosystem must be ensured which
adds further limitations to the design. Therefore, crystal
formation is a rather ideal strategy to bring RTP materials into
biological applications. Since the first report on crystallization
induced phosphorescence emission from pure organic
compounds (i.e. benzophenone and its derivatives) at room
temperature,[16] the number of organic compounds showing CIP
Pure organic materials with persistent room-temperature
phosphorescence (RTP) are an advantageous alternative to
their organometallic counterparts. This is mainly because they
are considerably cheaper, environmentally safer and biologically
more compatible, allowing a wide range of optical, electronic and
biological applications, such as electroluminescence, data
storage, molecular sensing and time-resolved bioimaging.[1-3] As
opposed to loosely-bonded electrons in organometallic materials,
the highly bonded nature of electrons in pure organic materials
restricts their ability to decay through radiative relaxation
pathways from triplet states. Therefore, triplet states in organic
materials are prone to non-radiative relaxations through thermal
and collisional processes.[4] In addition, the triplet states are
easily quenched by atmospheric oxygen molecules via triplet-
triplet energy transfer. As such, intense phosphorescent
materials are largely known to exist in inert gas and at very low
temperatures, which in turn limits their practical applications.[5]
Recently, researchers discovered several examples of pure
organic materials that exhibited persistent phosphorescence in
air and at room temperature.[6-13] These discoveries sparked
several attempts to find a general strategy to design more of
such materials for various applications. It was found that, to yield
efficient RTP, several key factors have to be considered. The
first is to promote intersystem crossing (ISC), and the second is
to suppress the non-radiative relaxation pathways such as
intermolecular motions.[14, 15] To promote ISC and to favor pure
organic RTP, heavy halogen atoms, as well as organic groups
with lone electron pairs, such as aromatic carbonyls, have been
successfully introduced to organic compounds.[16-19] However,
(crystallization-induced
phosphorescence)
has
gradually
expanded in the past few years.[4] However, all these crystals
are too large in size for biological applications, and the majority
of the RTP compounds with high brightness are more or less
limited to short wavelength emissions, which hampers their
bioimaging applications.[25-27]
It is well-known that long-lasting luminescence and good
biocompatibility are highly desirable for in-vitro and in-vivo
imaging without the interference of autofluorescence. Despite
the fact that RTP materials have proven to have such qualities,
there are very few successful attempts to bring them into
biological systems.[28] This is because compounds with long-
wavelength emission are generally needed to overcome the bio-
substrate auto-fluorescence. In addition, a strategy should be
available to control the crystal size to nanometer range so that
they become compatible with biological systems. Moreover, the
obtained nanocrystals should remain emissive as the oxygen
molecules dissolved in the aqueous media can effectively
quench their phosphorescence. This further requires the
quantum yield of the RTP molecules to be high enough so that
they can remain emissive when they are well-dispersed in
aqueous media.[29]
One of the first attempts to produce red-emissive RTP
materials was done by Bolton et al, based on planar
naphthalene derivatives. To promote ISC, aromatic carbonyl and
heavy halogen atoms were incorporated in the structure. The
lifetime and efficiency of the red-emissive crystals are 0.6 ms
and 1%, respectively. Due to self-quenching of the molecule,
crystallization has to be done in a host-guest system, reducing
the quantity of the molecule in crystals to be only 1%.[4] To
address the limitations of self-quenching and the need of using a
host-guest system, An et al designed a non-planar structure
comprised of a phenylphosphine and two carbazolyl groups.
Two factors were considered in their design in order to yield
higher brightness and longer lifetime. Firstly, O, N and P atoms
were used to favor ISC transition, thanks to the lone-pair
electrons. Moreover, substituents were included in the chemical
structure to enhance the formation of H-aggregates, which
stabilized the triplet excited state, and therefore increased the
lifetime. The resulting pure phosphorescent crystals showed red
emission with a long lifetime of more than 1 s. However, the
quantum yield of the crystals was only around 2%.[6] Later, Yang
et al further increased the quantum yield of red organic RTP
compounds to 5% by combining the heavy halogen atom effect
[a]
[b]
S. M. A. Fateminia, S. Xu, Dr. B. Liu
Department of Chemical and Biomolecular Engineering
National University of Singapore
4 Engineering Drive 4, Singapore, 117585 (Singapore)
E-mail: cheliub@nus.edu.sg
Z. Mao, Dr. Z. Yang, Dr. Z. Chi
PCFM Lab, GDHPPC Lab, Guangdong Engineering Technology
Research Center for High-performance Organic and Polymer
Photoelectric, Functional Films, State Key Laboratory of OEMT
School of Chemistry
Sun Yat-sen University, Guangzhou 510275 (China)
E-mail: yangzhy29@mail.sysu.edu.cn; chizhg@mail.sysu.edu.cn
S. M. A. Fateminia and Z. Mao contributed equally to this work.
[†]
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201705945
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COMMUNICATION
and intermolecular electronic coupling (IEC). They showed that it
was possible to combine the advantages of n and π units
through electronic coupling of two adjacent molecules, which in
turn produced hybrid ISC transitions and resulted in bright long-
lived RTP.[11]
In this contribution, we report a new design strategy to
modulate the IEC and the heavy atom effects independently by
simply introducing a soft proper alkoxy spacer group between
the hybrid units for long-lived and highly emissive red RTP. The
nanocrystals of the compound were further produced to
demonstrate their potentials in biological applications. The
adjacent carbazolyl plane and points nearly parallel to it (dashed
purple line, Figure S6), which in turn weakens the effect of
heavy halogen atom on carbazolyl unit. In contrast, the CBr
bond in C-C4-Br crystal directs almost vertically to the adjacent
carbazolyl plane (dashed purple line, Figure 1a). Moreover, the
bromine atom is located in close proximity of the C=C bond in
the carbazolyl group (dashed orange line with the length of
3.429 Å, Figure 1a). To explore the effect of such stronger bond
formation on the emission properties of C-C4-Br, the
luminescence spectra of the crystals were measured under
steady-state and delayed mode (30 ms delay) (Figure 1b). The
molecular design starts from a reported persistent RTP molecule, results reveal that at room temperature, the only emissive
C-Br, which is one of the brightest red phosphorescent
compounds reported so far.[11] C-Br has
persistent
phosphorescence emission at 549 nm with a lifetime of 280 ms,
pathway in C-C4-Br crystals is phosphorescence. The new
design results in more than 200% enhancement in the
phosphorescence quantum efficiency of C-C4-Br (11%) as
compared to C-Br (5%). Considering the long phosphorescent
lifetime of 0.14 s is observed for C-C4-Br, it represents one of
the most efficient red-emissive persistent RTP materials
reported so far.
a
[10, 11]
benefiting from the strong IEC effect.
To further improve
the brightness of red RTP, a stronger heavy halogen atom effect
is desired, which can be achieved through the formation of a
stronger bond between the bromine atom of one molecule and
the carbazolyl plane of the neighboring molecule in the
crystalline form. A soft butoxy spacer is thus introduced into C-
Br thereby spatially separating the carbazole and the 4-
bromobenzophenone groups to offer the new molecule (C-C4-
Br) with a higher level of conformational flexibility (Scheme 1).
Such a change is expected to facilitate the bond formation
between the head of one molecule and the tail of the other in the
[11]
crystalline form, leading to a more efficient IEC
intermolecular heavy halogen
and
effect.[30]
Scheme 1. The molecular design strategy for a red RTP compound with high
efficiency and long lifetime.
The synthetic route to C-C4-Br is shown in Figure S1. C-
C4-Br was obtained in 90% yield after four steps of reactions
from 4-bromo-4’-hydroxybenzophenone and 9-(4-bromobutyl)-
1
9H-carbazole. H, 13C NMR and high resolution mass (HRMS)
characterization reveal that the final product and the
intermediates are of right structures with high purity (Figures S2-
S4). The absorption and photoluminescence (PL) spectra of C-
C4-Br in tetrahydrofuran (THF) solution are shown in Figure S5.
It has an absorption maximum at 350 nm; however, no
detectable emission is observed due to the dominance of non-
radiative relaxation pathways of C-C4-Br in solution. On the
other hand, the PL spectrum of C-C4-Br in crystalline powders
has two clear peaks at 570 and 620 nm. The position of
emission peaks is similar to C-Br; however, C-C4-Br crystals are
clearly brighter. To further explore the effect of crystallization on
molecular configuration, single crystal structure analysis is
performed. The results of crystal structure analysis in Figures 1a
and S6 reveal that both crystals of C-Br and C-C4-Br exhibit
strong IEC effect represented by the dashed green lines. In C-Br,
this effect exists between the carbonyl group of one molecule
and the carbazolyl group of the adjacent molecule; while in C-
C4-Br, it happens between the two different carbazolyl groups of
two neighboring molecules. The similar packing is also found in
carbazole crystals with a distance of 3.716 Å between molecules
(Figure S6a). The shorter distances between the carbazole rings
for the coupled C-C4-Br molecules (3.421 and 3.538 Å, green
dashed lines in Figure 1a) indicate stronger intermolecular
interactions in C-C4-Br crystals. Despite the similarity in the IEC
effect, the heavy halogen atom effect is different in the two
crystals. The CBr bond in the C-Br crystal is far from the
Figure 1. (a) Positioning of C-C4-Br molecules in the single crystal structure
(b) The steady state and persistent (delay 30 ms) luminescence spectra of C-
C4-Br crystal at room temperature; The PL spectra of (c) C-C4-Br and (d) C-Br
in different states at 77K: diluted solution in 2-methyl-tetrahydrofuran (red
curve) and crystal powder (blue curve). Fl.
= fluorescence, Ph. =
phosphorescence, S1 = the lowest singlet excited state, T1 = the lowest triplet
excited state of mono-molecule in crystal powder. T’1 = the lowest triplet
excited state of the IEC hybrid units for the persistent RTP in crystal; (e) the
PL spectra of C-C4-Br large crystals in different environments.
As shown in Figures 1c and 1d, despite enhancement of
the long-lived phosphorescent peaks, new phosphorescent
peaks are presented in their PL spectra of both crystal samples
of C-Br and C-C4-Br at low temperature (77K), due to the
suppression of competitive non-radiative thermal decay process.
To understand the origin of phosphorescence emissions from C-
C4-Br crystals at 77 K, the RTP photos and the
phosphorescence (delay) spectra of carbazole, 4-bromo-4’-
methoxyl-benzophone (BMB) and C-C4-Br samples are shown
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10.1002/anie.201705945
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in Figures S8 and S9, respectively. It was found that carbazole,
BMB and C-C4-Br exhibit RTP only in crystals, and no RTP is
observed in either solution state or when the molecules are
doped in Zeonex films, revealing that the intramolecular
interaction itself does not lead to RTP. Detailed analysis also
reveals that the RTP in C-C4-Br crystals is dominated by the
carbazole emission at room temperature, as they share the
similar emission spectra while the characteristic peak at 510 nm
for BMB crystals is not visible in the RTP spectrum of C-C4-Br.
When the C-C4-Br crystals are cooled to 77 K, the
phosphorescent emission is still dominated by the carbazole
molecules, but the emission peaks from 420-500 nm seem to
resemble that of molecular emission (particularly BMB emission
as carbazole does not give noticeable phosphorescence as
molecular species).
Figures S10 and S11 are frontier orbitals associated with
ISC. Different from the isolated C-C4-Br molecules, where the
HOMO and LUMO are clearly localized on the carbazole and
BMB, respectively, the HOMO and HOMO-2 orbitals are
dispersed on both carbazole groups of the two coupled C-C4-Br
molecules in crystals, which indicate intermolecular components
in the relative intersystem crossing channels. Furthermore, the
most major possible ISC channel for coupled C-C4-Br molecules
more amorphous particles are converted to nanocrystals;
however, it does not change significantly after 120 s, indicating
that all the amorphous nanoparticles are converted to
nanocrystals. Therefore, 120
s is taken as the optimum
treatment time for nanocrystallization. The peaks in the PL
spectrum of nanocrystals in suspension are almost the same as
solid powder of bulk crystals (Figure 2d), showing that neither
nanocrystallization nor dispersion in aqueous medium could
completely quench the phosphorescence emission of C-C4-Br.
Morphology studies reveal that the nanoaggregates before
treatment have the same shape and diffraction pattern as
amorphous nanoaggregates formed at fw = 90% with an average
size of 80 nm (Figure S14). However, after 120 s treatment, the
particles form rod-like structures with a slight increase in size to
180 nm (Figure 2c). The crystallinity of single nanocrystal is
confirmed by (SAED) pattern (inset of Figure 2b). The formation
of nanocrystals in solid state is further evidenced with their XRD
spectrum after treatment (Figure 2e). A similar trend is also
observed in C-Br nanocrystallization process (Figure S15),
however, the C-Br nanocrystals are only emissive in solid state,
and no emission is detected in aqueous medium. The difference
between C-C4-Br and C-Br as nanocrystals is due to the higher
quantum yield of C-C4-Br, which makes it glow even after being
(Figure S12, from HOMO to LUMO) is an intermolecular process, partially quenched by water and oxygen molecules. Quantitative
which transfers from carbazole of one C-C4-Br to BMB of an
adjacent molecule. These results reveal that IEC effect plays an
important role in yielding high RTP in C-C4-Br crystals.
measurements performed on nanocrystals of C-C4-Br reveal a
larger degree of phosphorescence quenching in the presence of
O2 as compared to bulk crystals. This can be attributed to the
higher surface to volume ratio in nanocrystals, and therefore a
larger fraction of atoms are available to be exposed directly to
the environment to partially quench the luminescence (Figures
S13b and 13c), yet the C-C4-Br nanocrystals remain quite
emissive. As emission in aqueous media is crucial for bringing
the phosphorescence properties into biological applications; the
rest of the study is mainly focused on C-C4-Br.
For biological applications, the exposure of RTP materials
to O2 is inevitable. As O2 is a strong quencher of the excited
triplet state, the compound needs to be bright enough to remain
emissive even after being partly quenched by O2 present in the
aqueous medium. Therefore, the influence of oxygen on the
persistent RTP of the C-C4-Br crystals was further explored. As
shown in Figure 1e, the bulk crystal powders show some
sensitivity to oxygen. Both the emission intensity and lifetime
reduce slightly after the environment is changed from helium to
air (Figures 1e and S13a). The decrease is even more obvious
when the crystals were exposed to oxygen. This is a clear
indication that the O2 molecules can quench the triplet excitons.
To make the crystals suitable for biological applications,
their sizes have to be adjusted to sub-micro range. In this case,
a nanocrystallization strategy is applied to obtain very small size
crystals.[29] The nanocrystallization method is based on
ultrasonication of the amorphous nanoaggregates of the
compound in a solvent/anti-solvent medium (e.g. THF/water) in
which crystallization can happen. As higher fraction of the
antisolvent can be effective in decreasing the crystal size, a
morphological study in mixtures of different THF/water ratios
was conducted first in order to obtain the proper volume fraction
of water (fw) for nanocrystallization. Starting with fw = 80%, the
initially formed particles are amorphous nanoaggregates (Figure
S10b). After storage for a day, micrometer-long ribbon-like C-
C4-Br crystals emerge (Figure S10d). A higher fw of 85% still
results in the formation of ribbon-like crystals after 3 days
storage (Figure S10c), which appear to be smaller than those
formed at fw = 80%. This is due to the decreased crystal growth
rate resulted from the higher antisolvent fraction. However,
raising fw to 90% does not cause any further size reduction, but
rather amorphous nanoaggregates remain intact (Figure 2a)
due to domination of anti-solvent to solvent properties.[29]
Therefore, fw
=
85% is chosen as the medium in
nanocrystallization with the assistance of ultrasound waves.
Starting from the amorphous nanoaggregates in the medium,
the PL spectrum of the suspension is recorded regularly to
monitor the crystallization process (Figure 2b). It is found that
Figure 2. SEM images of (a) amorphous nanoaggregates formed in fw = 90%
and (b) at different treatment time in suspension (c) nanocrystals with their
respective SAED pattern as inset; PL spectra of C-C4-Br nanoparticles (d) in
solid-state; (e) XRD spectrum of C-C4-Br nanocrystals, crystal powders and
the two phosphorescence peaks appear after 30
s of
ultrasonication. The PL intensity grows by time, showing that
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10.1002/anie.201705945
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COMMUNICATION
simulation form the single crystal data; (f) the luminescence of nanocrystals
and amorphous nanoaggregates of C-C4-Br (the orange body) and fluorescein
(the leaves) under different illumination conditions.
bright phosphorescence emission. This study opens new
opportunities to further explore the application of purely organic
persistent RTP compounds in biological world.
Figure 2f demonstrates the persistent phosphorescence
emission of the C-C4-Br at room temperature. In the first row,
one starts with an orange fruit made of C-C4-Br nanocrystals
and leaves made of fluorescein. In the second row, half of the
orange on the left is substituted with amorphous
nanoaggregates of C-C4-Br. There is not any obvious difference
between the two orange fruits under visible light, however, under
365 nm UV irradiation, the difference becomes evident.
Nanocrystalline parts of the orange as well as the fluorescein
leaves are emissive while the amorphous part of the fruit does
not show any emission, which is in accordance with PL
measurements described earlier. After turning the UV light off,
the fluorescent leaves turn off immediately, leaving the
phosphorescence emission from the orange fruit to emit which is
clearly visible by naked-eye.
Acknowledgements
The authors are grateful to the Singapore National Research
Foundation (R279-000-444-281 and R279-000-483-281), the
National University of Singapore (R279-000-482-133), Institute of
Materials Research and Engineering of Singapore (IMRE/13-
8P1104), NSFC (21672267, 51473185, 51603232 and 61605253),
863 Program (SS2015AA031701), Science and Technology
Planning Project of Guangdong (2015B090913003) and the
Fundamental Research Funds for the Central Universities.
Keywords: organic materials • persistent room temperature
phosphorescence • nanocrystals • bioimaging
The
C-C4-Br
nanocrystals
and
amorphous
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cancer cells to demonstrate their potential biological applications.
Although time-gated microscopy is the best option to
differentiate auto-fluorescence from the phosphorescence
emission, the lifetime of C-C4-Br is several orders of magnitude
longer than the detection limit of time-gated microscopes.
Therefore, we collected the cells labelled with C-C4-Br
nanocrystals and show that the RTP can be effectively used to
differentiate the cells from the fluorescein fluorescence
interference (Figure 3). In addition, a confocal laser scanning
microscopy (CLSM) was used to perform the imaging process.
Figures 3a-3d show images of cells incubated with both
amorphous nanoaggregates and nanocrystals. No emission
signal is observed from cells incubated with amorphous
nanoaggregates; however, a bright phosphorescence emission
in the red channel is collected for the well-internalized
nanocrystals. Moreover, the nanocrystals also show excellent
biocompatibility based on MTT assays shown in Figure S16,
demonstrating their good potentials in cellular imaging.
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In conclusion, a pure organic persistent RTP compound
with bright red phosphorescence was designed and synthesized.
The high brightness was mainly due to the IEC and
intermolecular heavy atom effect as a result of the introduction
of a free chain linker in the molecular design, which significantly
enhances the intermolecular interaction between the head of
one molecule and the tail of the adjacent one. To successfully
bring the molecule into aqueous media, nanocrystals with an
average size of 180 nm were prepared, which showed bright
phosphorescence in aqueous media with excellent
biocompatibility. The nanocrystals were directly applied for
imaging of breast cancer cells, showing effective uptake and
This article is protected by copyright. All rights reserved.

10.1002/anie.201705945
Angewandte Chemie International Edition
COMMUNICATION
COMMUNICATION
A bright pure organic compound with
red persistent room temperature
phosphorescence is synthesized. Its
nanocrystals show excellent
S. M. Ali Fateminia, Zhu Mao, Shidang
Xu, Zhiyong Yang, , Zhenguo Chi, Bin
Liu
Page No. – Page No.
biocompatibility, water dispersity and
retaining bright phosphorescence in
aqueous media, which show great
potentials in bioimaging.
Organic Nanocrystals with Bright
Red Persistent Room-Temperature
Phosphorescence for Biological
Applications
This article is protected by copyright. All rights reserved.