Bis-Metal Complexes of Doubly N-Confused Dioxohexaphyrins as Potential Near-Infrared-II Photoacoustic Dyes

Article abstract of DOI:10.1021/jacs.9b13475

We investigated the detailed photophysical properties of a series of bis-metal (Zn and Cu) dioxohexaphyrin complexes as potential second near-infrared (NIR-II)-light responsive dyes. A cisoid-configured 28π-electron-conjugated dioxohexaphyrin analogue (c-3a) containing two peculiar confused pyrrole moieties in the framework is identified as a reduced isomer derivative of a transoid 26π-dioxohexaphyrin (t-2a). The symmetry-altered structure of c-3a affords a heteroleptic inner environment within the NNNN/NNOO donor core, which imparts its highly flexible electronic features and nonplanar geometry. The macrocycle c-3a can be transformed into the corresponding 26π-electron congener (c-2a) having a coplanar rectangular structure by unique solvent-mediated redox reactivity. Furthermore, upon metal complexation, saddle-distorted bis-metal complexes (c-M2-2a) were formed as the 26π-conjugated structural isomer of the trans-dioxohexaphyrin species (i.e., t-M2-2a). These isoelectronic dioxohexaphyrins demonstrate precise geometry-dependent photophysical properties. Broad tailing NIR-II absorption, weak emissive character, and rapid-decay of the S1 state are observed for c-Zn2-2a. In contrast, the coplanar t-M2-2a exhibits efficient photoacoustic response upon laser excitation with NIR-II light (λ > 1000 nm). To the best of our knowledge, this is the first example of an expanded porphyrin-based photoacoustic contrast agent responsive to NIR-II light.

Full text of DOI:10.1021/jacs.9b13475

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Article
Bis-Metal Complexes of Doubly N-Confused Dioxohexaphyrins
as Potential Near Infrared-II Photoacoustic Dyes
Keito Shimomura, Hiroto Kai, Yuma Nakamura, Yongseok Hong, Shigeki Mori, Koji Miki, Kouichi
Ohe, Yusuke Notsuka, Yoshihisa Yamaoka, Masatoshi Ishida, Dongho Kim, and Hiroyuki Furuta
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 09 Feb 2020
Downloaded from pubs.acs.org on February 9, 2020
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Bis-Metal Complexes of Doubly N-Confused Dioxohexaphyrins as
Potential Near Infrared-II Photoacoustic Dyes
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⊥
⊥
Keito Shimomura, Hiroto Kai, Yuma Nakamura, Yongseok Hong, Shigeki Mori, Koji Miki, Kouichi Ohe, Yusuke
†
‡
†
Notsuka,ǁ Yoshihisa Yamaoka,ǁ Masatoshi Ishida,*, Dongho Kim,*, and Hiroyuki Furuta*,
†Department of Chemistry and Biochemistry, Graduate School of Engineering, and Center for Molecular Systems, Kyushu University, Fukuoka
819-0395, Japan
‡Department of Chemistry, Yonsei University, Seoul 03722, Korea
§Advanced Research Support Center, Ehime University, Matsuyama 790-8577, Japan
⊥
Department of Energy and Hydrocarbon Chemistry, Graduate School of Engineering, Kyoto University, Kyoto 615-8510, Japan
ǁDepartment of Advanced Technology Fusion, Graduate School of Science and Engineering, Saga University, Saga 840-8502, Japan
ABSTRACT: We investigated the detailed photophysical properties of a series of bis-metal (Zn and Cu) dioxohexaphyrin complexes as po-
tential second near-infrared (NIR-II)-light responsive dyes. A cisoid-configured 28p-electron-conjugated dioxohexaphyrin analog (c-3a)
containing two peculiar “confused pyrrole” moieties in the framework is identified as a reduced isomer derivative of a transoid 26p-
dioxohexaphyrin (t-2a). The symmetry-altered structure of c-3a affords a heteroleptic inner environment within the NNNN/NNOO donor
core, which imparts its highly flexible electronic features and nonplanar geometry. The macrocycle c-3a can be transformed into the corre-
sponding 26p-electron congener (c-2a) having a coplanar rectangular structure by unique solvent-mediated redox reactivity. Furthermore,
upon metal complexation, saddle-distorted bis-metal complexes (c-M2-2a) were formed as the 26p-conjugated structural isomer of the trans-
dioxohexaphyrin species (i.e., t-M2-2a). These isoelectronic dioxohexaphyrins demonstrate precise geometry-dependent photophysical
properties. Broad tailing NIR-II absorption, weak emissive character, and rapid-decay of the S1 state are observed for c-Zn2-2a. In contrast, the
coplanar t-M2-2a exhibits efficient photoacoustic response upon laser excitation with NIR-II light (l >1000 nm). To the best of our
knowledge, this is the first example of an expanded porphyrin-based photoacoustic contrast agent responsive to NIR-II light.
upon, broadband ultrasonic emission is generated in the biological
■
INTRODUCTION
tissue by thermal expansion, which can be detected by an acoustic
transducer. Absorption in the NIR-II window provides clear ad-
vantages over that in the conventional NIR-I window (700–1000 nm)
for deeper tissue imaging as it provides higher maximum permissible
exposures (MPEs)20 (e.g., lex at 800 nm is ~300 mW/cm2 and at 1064
nm is ~1000 mW/cm2 per laser pulse) and reduced light scattering21,22
in the tissues. The PA properties of small molecular NIR dyes, such as
indocyanine green (ICG),23 aza-BODIPYs,24,25 bis(benzothiadiazole)-
derivatives (e.g., NIRb-14),26,27 benzi-phthalocyanine,28 and hybrid
cyclopyrrole analog (C-P1P4F1)29,30 have been extensively examined.
Distorted phosphorus-phthalocyanine (P-Pc) showing strong absorp-
tion around 1000 nm has been proven to be an efficient PA agent for
deep in-vitro imaging to depths of several centimeters upon excitation
using a Nd:YAG laser (1064 nm).31,32 Such research is of fundamental
interest as a means to explore the structure-property relationships of
NIR-II absorbers as potential PA contrast agents, which are currently
in high demand for biomedical applications.
Expanded porphyrins consisting of more than five pyrrole rings have
recently emerged as an important class of near-infrared (NIR) dye
chromophores owing to their large and flexible p-conjugated scaffolds.
Accordingly, they offer new possibilities in the development of optical
materials for use in fields ranging from light-harvesting to sensing and
therapeutic applications.1–5 Their distinct photophysical properties
are exclusively conformation-dependent based on Hückel and Möbi-
us topological aromaticity.6 Furthermore, their unique ability to coor-
dinate various metal ions leads to well-defined p-conjugated struc-
tures in solution, aiding the design of novel NIR dyes for biological
applications.7
Meso-aryl-substituted hexaphyrin (4) has been extensively studied
owing to their conformation-dependent optical features, including
cation-responsive NIR emission,8,9 NIR-light excited photother-
mal/photodynamic properties,10,11 and NIR-light chiral recognition
ability (Figure 1).12–16
Absorption in the far NIR region beyond 1000 nm (termed as the
second near-infrared region, or NIR-II) is an attractive property for
photoacoustic imaging (PAI) technologies.17–19 In PAI, incident light
photons are absorbed by a dye agent and converted into heat. There-
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In this study, we investigated the photophysical properties of diox-
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ohexaphyrins, including the first structurally characterized cisoid-
analog (c-3), along with the symmetrical transoid-congener (t-2;
Scheme 1). The resulting cisoid 28p-electron derivative is converted
to the corresponding Hückel 26p-conjugated form through aerobic
oxidation in basic solvents such as dimethylformamide (DMF) as well
as upon bis-metalation. In fact, the resulting 26p-conjugated cisoid
dioxohexaphyrins (c-2 and c-M2-2) are considered to be isomeric
species of transoid-derivatives with different core geometries. The
alteration of molecular symmetry in the cis- and trans-homologs plays
a vital role in their photophysical and PA properties. To the best of
our knowledge, the PA properties of hexaphyrin-related macrocycles
have not been previously reported. In this study, the bis-metal com-
plexes of dioxohexaphyrins exhibit superior PA spectral features re-
sponsive to NIR-II light.
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Figure 1. (a) Excitation (absorption) energy-structure relationship
for several representative NIR-PA dyes and some expanded porphy-
rins. (b) Redox-interconvertible hexaphyrins containing doubly N-
confused congeners with different molecular symmetries can serve as
functional and tunable NIR-II PA dyes.
To create well-defined NIR-II dyes, chemical modification of the
hexapyrrolic core by a N-confusion approach as a means to tailor the
inner coordination sphere is a viable approach.33,34 The implementa-
tion of confused pyrrole rings (highlighted in sky-blue in Figure 1)
connected at the a- and b’-positions between the meso-carbon atoms
of the parent hexaphyrin skeleton allows a predominantly planar rec-
tangular conformation because of the hydrogen-bond network be-
tween the inward-facing nitrogen atoms and carbonyl groups of the
pyrrole rings.35,36 Thus, the doubly N-confused dioxohexaphyrin t-2 is
rigidified upon accommodation of a metal atom at either symmetric
NNNO sphere with the highly planar 26p-circuit (t-M2-2; Figure 1b).
Analogously to planar p-systems, the rearrangement of confused
pyrroles as a pair to a cisoid configuration upon metal coordination at
the NNNN–NNOO core (c-M2-2; Figure 1b) would provide a new
prototype three-dimensional saddle-distorted hexaphyrin isomer.37,38
However, such complexes have yet to be observed. Nevertheless,
knowledge of this phenomenon can provide insight into the effect of
saddle distortion on fundamental photophysical properties. Accord-
ingly, works related to saddle-distorted tetrapyrrolic systems have
revealed their intriguing properties, such as the relatively high Lewis
acidity of the central metal ion, relatively low redox potential, rapid
decay of excited states, and weaker aromaticity.39 However, the effect
Scheme 1. Synthetic Route to Dioxohexaphyrins t-2, c-2, and c-3,
and their Bis-Metal Complexes t-M2-2 and c-M2-2
■ RESULTS AND DISCUSSION
Synthesis and Characterization of Nonaromatic Dioxohex-
aphyrin c-3. Previously, we reported that the conventional acid-
catalyzed [3+3]-condensation of a N-confused tripyrrane (1) and
pentafluorobenzaldehyde in CH2Cl2, followed by 2,3-dichloro-5,6-
dicyano-1,4-benzoquinone (DDQ) oxidation yields transoid 26p-
conjugated doubly N-confused dioxohexaphyrin t-2a as the major
product along with the 28p-conjugated dioxo-congener having
of such distortion on the nonradiative decay of laterally p-extended
porphyrins (i.e., hexaphyrins) is still not fully understood.
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nonaromatic character as a minor product (Scheme 1).37,38 Currently,
we have not yet fully characterized the structure and properties of the
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latter species. The synthesis of dioxohexaphyrin c-3a using the modi-
fied protocol was revisited in this study. Short-term exposure (ca. 2 h)
to the oxidant DDQ and careful purification led to the isolation of c-
3a as a major product (Scheme 1). Due to the highly polar nature of
the product, a careful column purification procedure was needed.
This involved i) passing through a short alumina column pad to elim-
inate the tarry polymers, and ii) purification by silica gel column
chromatography to collect the brown-colored fraction containing the
hexaphyrin derivatives (ca. 10% yield).
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Figure 3. H NMR spectra of (a) c-3a in CDCl3 and (b) c-2a ob-
tained upon standing in DMF-d7 solution under air for 4 days. Insets
are the partial spectra in CDCl3 at 248 K and the magnified region
(7.5–8.5 ppm) in DMF-d7, respectively.
Effect of Solvent on the Redox-Induced Transformation into
Aromatic Congeners. Typically, 28p-conjugated hexaphyrin deriva-
tives exhibit highly flexible features dependent on their distinct con-
formations (e.g., rectangular or Möbius twist species).41,42 This sol-
vent-dependent conformational change gives rise to topological
switching in the aromaticity. The color of the solution of c-3a varies
depending on the choice of solvent. For example, with polar solvents
(e.g., DMF), bright green solutions are obtained, and a characteristic
Soret band at 636 nm and Q-like bands around 900 nm emerge in the
Figure 2. (a) UV-Vis-NIR absorption spectrum of c-3a in CH2Cl2
and (b) its absorption spectrum changes upon standing in DMF un-
der aerobic conditions. The final spectrum (obtained after 48 h) is
shown in red.
Analysis of the product c-3a using NMR, UV-Vis-NIR spectrosco-
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absorption spectrum (black line shown in Figure 2b). The H NMR
py, and high-resolution mass spectrometry indicates a 28p nonaro-
matic electronic structure with cisoid-geometry (see Supporting In-
formation). In the mass spectrum of c-3a, the M+ peak observed at
m/z = 1494.0908 (1494.0856 calcd for C66H16N6O2F30) is two mass
units larger than the parent peak of t-2a. The UV-Vis-NIR absorption
spectrum of c-3a in CH2Cl2 presents a broad and poorly defined fea-
spectrum of c-3a recorded in DMF-d7 shows an inequivalent signal
pattern in the entire spectral region (-1–10 ppm) (Figure S7a). With
the aid of 2D-NMR spectroscopy, absence of two NH signals implies
that the species may be deprotonated because of the distinct basicity
of the DMF solvent.43 Deprotonation of c-3a by titration with n-
tetrabutylammonium fluoride in CH2Cl2 resulted in a similar spectral
change (Figure S9).44–46 Although our efforts failed to identify the
accurate conformation, presumably due to the dynamic conforma-
tional behavior in solution and the facile redox reactivity (vide infra),
the spectroscopic features indicate the formation of a dianionic Mö-
bius-twist aromatic species, presumably (c-3a2-; eq 1).47 This behav-
ior is analogous to that of regular 28p hexaphyrins, which show sol-
vent-dependent topological switching (Figure 2b).48 Furthermore, a
similar spectrum is seen using CD3OD, suggesting the predominance
of the twisted conformer with distinct aromaticity (Figure S10). In
this spectrum, all the NH protons are replaced with deuterons, result-
ing in the appearance of ten peripheral CH signals. In THF-d8 solu-
tion, the conformational interconversion is dynamic and fast as in-
ture (Figure 2a). The 1H NMR spectrum reveals five sets of b-pyrrolic
protons in the typical sp2-alkenic region (5–7 ppm), which suggests
the absence of diatropic ring current (Figure 3a). Under low-
temperature NMR measurement, three sets of inner NH signals ap-
pear in the lower-field region (10–14 ppm), which suggests that there
are no keto-enol tautomeric forms for c-3a. Several possible conform-
ers, such as a rectangular, figure-of-eight, triangle, and dumbbell shape,
can be assumed for c-3a (Figure S6 in the Supporting Information).
With the aid of theoretical calculation, the distorted rectangular ge-
ometry can be one of the considerable structures in terms of the
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thermodynamic stabilization energy.40 Critically, the F NMR spec-
trum exhibits specific 3(2+1):1:2 integral patterns for the meso-aryl
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ring para-position F atoms, providing a ready indication of the low-
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ferred from the temperature-variable absorption and H NMR spec-
tral changes (Figure S11). An averaged H NMR spectral feature of a
mixture of isomers, nonaromatic and postulated aromatic, was ob-
served.
ered molecular symmetry of the hexaphyrin core (Figure S1b in the
Supporting Information). This is in sharp contrast to the spectrum of
the transoid t-2a, which presents a symmetrical 2:2:2 ratio pattern for
the para-fluorine resonances, which is normal for a rectangular struc-
ture (Figure S1c). Thus, we assumed that c-3a adopts a lower-
symmetry structure where the inner carbonyl groups are facing in the
same direction as the macrocycle.
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ic structures. The harmonic oscillator model of aromaticity (HOMA)
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value for c-2b was estimated to be 0.792, indicating aromatic charac-
ter.52 On this basis, a distinct 26p conjugated circuit can be considered
for c-2a, which is attributed to aerobic oxidation of the dianionic c-3a
to the coplanar 26p aromatic species c-2a.
The intrinsic chemical instability of c-2a was observed by removal
of the DMF solvent and re-dissolving in CH2Cl2, which gave the orig-
inal brownish-color solution. Upon passing through a short SiO2
column, the initial 28p species c-3a was recovered. Furthermore, the
corresponding 26p aromatic congener c-2a was not obtained by
chemical oxidation with DDQ or MnO2 in less polar solvents such as
CH2Cl2 andtoluene.
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Analysis of excited-state dynamics by femtosecond time-resolved
transient absorption (fs-TA) spectroscopy is a powerful tool for gain-
ing insight into the extent of aromaticity in a material.53–55 The fs-TA
spectrum for the Hückel-aromatic c-2a prepared in situ in DMF solu-
tion shows stronger ground-state bleaching (GSB) bands compared
to the excited-state absorption (ESA) (Figure 5b). The decay time
constant for c-2a (310 ps) is much longer than that observed in the
typical 26p Hückel-aromatic hexaphyrin 4 (98 ps) and the transoid-
isomer t-2a (62 ps).56,57 This is in sharp contrast to the spectra ob-
tained from toluene, which exhibit stronger ESA bands with short-
lived S1-state lifetimes for c-3a (ts = 35 ps) (Figure 5a). The emer-
gence of emission characteristics for c-2 in DMF (lem = 1060 nm, lex
= 635 nm) is also consistent with typical spectroscopic signature of
aromatic hexaphyrins (Figure S16). The long decay component in the
TA spectra of c-2a can be explained by intersystem crossing to the
triplet state. In fact, the TA spectral data for dianionic c-3a (proposed
to be a Möbius twist) tentatively formed in DMF show similar fea-
tures, such as strong GSB bands and the longer singlet lifetime of 200
ps (Figure S16a). This aromatic diagnostic feature is likely identical to
those of c-2a generated in DMF.
Figure 4. X-ray crystal structures of (a) c-2b and (c) c-Cu2-2a as
viewed from the top and side (50% thermal ellipsoids probabilities).
The hydrogen atoms, co-crystallized solvent molecules, and meso-
pentafluorophenyl/TIPS-ethynyl groups are omitted for clarity. Out-
of-plane displacements (in units of Å) of the core atoms of (b) c-2b
and (d) c-Cu2-2a from the mean plane of 36 atoms.
Unprecedentedly, the dianionic form of the 28p dioxohexaphyrin
(c-3a2-) in DMF solution transforms into the corresponding aromatic
species (i.e., c-2a) under ambient conditions (Scheme 1). The ab-
The aromatic features of c-2a were further investigated using densi-
ty functional theory (DFT) calculations at the B3LYP/6-31G(d,p)
level of theory. The molecular structure of c-2a resembles a regular
26p hexaphyrin congener with rectangular geometry. In fact, the re-
sulting coplanar geometry of c-2a is thermodynamically unfavorable
sorption spectrum of the c-3a2- product was measured for a solution
sample after standing for 24 h and compared with the aromaticity-
associated spectral signature (red line shown in Figure 2b). The
1
change in the H NMR spectrum of c-3a2- indicates the distinct con-
compared with that of the transoid-structural isomer t-2a (DEcis-trans
=
+26.32 kcal mol–1) or another ciosoid-isomers (e.g., DE ~ +16.8kcal
mol-1) (Figure S17a). However, the solvation (most likely hydrogen-
bonding interactions between the peripheral NHs and DMF mole-
cules) may affect stabilizing the rectangular conformer (Figure
S17b).41 The frontier molecular orbitals (MOs) of c-2a, however,
show degenerate HOMO-1/HOMO and LUMO/LUMO+1 states,
following standard Gouterman’s four-orbital model, like t-2a (Figure
6).48 The configurational interactions between the frontier MOs result
in the characteristic absorption transitions of aromatic porphyrinoids
(Figure S18 and Table S2). The negative nucleus-independent chem-
ical shift (NICS(0)) value determined at the global center of the mac-
rocycle (-12.1 ppm) and clockwise ring current densities in the ani-
sotropy of the induced current density (ACID) plot both indicate
distinct 26p aromaticity (Figure S19a).58,59 The ACID plot of c-2a
reveals a clockwise ring current flow in the macrocyclic ring under an
external magnetic field. In the case of the transoid-isomer t-2a, the
core structure of the optimized structure is greatly flattened due to the
intrinsic inner hydrogen-bonding network, which gives rise to the
higher negative NICS(0) value of -13.8 ppm as well as remarkably
strong ring current revealed by the ACID plot (Figure S19b).
formational change, as inferred from the signal distribution; six char-
acteristic C-H signals in the high-field region (2–4 ppm), four
deshielded peripheral C-H resonances (7–9 ppm), and four NH sig-
nals in the 11–14 ppm (Figure 3b). The difference between the chem-
ical shifts of the most shielded and deshielded hydrogen atoms (DdCH-
NH) is estimated to be -14.88 ppm, which is attributed to the presence
of a strong diamagnetic ring current in the product. Along with the
inequivalent resonance pattern of the 19F NMR spectrum, a rectangu-
lar core structure was predicted, as shown in Scheme 1 (Figure S12).
Evidence of the rectangular structure was provided by X-ray crystallo-
graphic analysis of the meso-ethynyl-substituted derivative (c-2b)
(Figure 4a and Table S1).49 The corresponding confused rings (B/E
rings depicted in Figure 4a) are located diagonally on the opposite
corners of the rectangular-shaped hexaphyrin core with outward di-
recting amide groups.50 The central pyrrole rings (A/D rings) are
tilted by ca. 30° from the mean plane of the core, like that observed for
rectangular 26p hexaphyrins (Figure 4b).51 The co-crystalized DMF
molecules interact with the outward-pointing NH moiety. The Ca–
N–Ca bond angle of the regular C/F rings is calculated to be 100.58°.
The relatively small angle indicates a preference for imino-type pyrrol-
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metal complexes (i.e., c-Zn2-2a and c-Cu2-2a) in approximately quan-
1
titative yields. Interestingly, the metalation was completed in a short
time (ca. 30 min) under the above conditions, which was considerably
faster than that observed with t-2a (ca. 24 h), presumably due to the
pre-organized distorted geometry of c-3a allowing facile metal access
to the Lewis basic inner nitrogen and oxygen sites.36 The solid-state
geometry of bis-copper complex c-Cu2-2a was unambiguously de-
termined by X-ray crystallographic analysis (Figure 4c and Table S1).
Two copper atoms are located within the porphyrin-like square planar
NNNN site as well as the compressed tetrahedral NNOO one. There
are no counter anions in the crystal lattice. Unlike the highly planar t-
Cu2-2a, the complex c-Cu2-2a has a severely saddle-distorted core
geometry with a large mean deviation value of 0.80 Å (Figure 4d).
The HOMA value was calculated to be 0.761, reflecting weaker p-
overlapping interactions. Presence of seven-membered rings at the
heteroleptic NNOO copper coordination site gives rise to a distorted
saddle-shape geometry, as inferred from the smaller average angles for
N–Cu–O(N) at the NNOO site (148.0°) than that of N–Cu–N at the
NNNN site (158.0°). The above distorted structure of c-Cu2-2a is in
sharp contrast to that of transoid t-Cu2-2a, which has a mean devia-
tion value of 0.01 Å (Figure S14).35 This distinct saddle-distorted core
gives rise to intrinsic photophysical properties (vide infra).
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Figure 5. Femtosecond transient absorption spectra of (a) c-3a in
toluene and (b) c-2a in DMF upon standing the solution in air. Insets
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show the decay-time profiles with least-square fitting curves.
Figure 7. (a) UV-Vis-NIR absorption spectra of c-Zn2-2a (red line)
and c-Cu2-2a (black line) in CH2Cl2. (b) Fluorescence spectrum of c-
Zn2-2a in CH2Cl2 upon excitation at 610 nm. (c) Partial H NMR
spectrum of c-Zn2-2a in CD2Cl2 at 298 K.
1
In the same way, the distinct bis-zinc(II) complex c-Zn2-2a shows
26p aromatic character, as supported by the optical and NMR spec-
troscopic analyses. The 1H NMR spectrum of c-Zn2-2a shows five sets
of b-proton signals in the typical aromatic region (d = 8.88–7.72
ppm) at room temperature (Figures 7c and S20). When the complex
was treated with an excess amount of pyridine, remarkably high-field
shifted signals of the pyridines (o-, m-, p-CHs) bound at the Lewis
acidic zinc centers of the complex (i.e., c-Zn2-2a(Py)2) were observed
at d = 4.56, 5.79, and 6.63 ppm, respectively (Figure S19a). Upon
lowering the temperature to -60 °C, anisotropic spectral separation of
the proton signals at 3.47 (o-CH), 4.43 (o-CH), 5.16 (m-CH), 5.75
(m-CH), 6.08 (p-CH), and 6.64 (p-CH) ppm was observed (Figure
S20b). This is due to the unsymmetrical binding of the pyridines at
the NNNN- and NNOO-supported zinc centers in c-Zn2-2a. As re-
Figure 6. MO energy diagrams of (a) c-2a and (b) t-2a as derived by
B3LYP/6-31G(d,p)-level DFT calculations.
1
vealed by the H NMR spectrum of t-Zn2-2a, the weaker diatropic
ring current effect might be attributed to distortion of the 26p-
electron circuit.9 The characteristic Soret-like band at l = 623 nm and
resolved Q-like bands in the NIR region as well as an actual fluores-
cent emission at lem = 1010 nm indicate the aromatic signatures of the
resulting dioxohexaphyrin (Figure 7a,b). The relative emission inten-
sity is ca. five-fold smaller than that of t-Zn2-2a, which is well-
p
Transformation into 26 Aromatic Bis-Metal complexes. Bis-
metal complexation of c-3a accompanied by two-electron oxidation
yields 26p aromatic dioxohexaphyrin species (Scheme 1). Treatment
with either zinc(II) or copper(II) acetate salts in a CH2Cl2/MeOH
mixed solution at room temperature resulted in the formation of bis-
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agreement with a short-lived S1 excited-state lifetime for c-Zn2-2a
(detailed experimental procedures are given in the Supporting Infor-
mation).
Upon nanosecond pulsed laser irradiation of a DMF solution of c-
1
2
3
4
5
6
7
8
with a decay constant of tS = 220 ps in toluene compared with that of
t-Zn2-2a (tS = 267 ps) (Figure S16b).56 Instead, the relatively long
decay component arising from population of the triplet-state manifold
is likely increased.
Zn2-2a, actual acoustic waves from the dye were detected using a
piezoelectric transducer (Figure 9c). The resulting PA spectra of c-
Zn2-2a reveal the relatively intense PA signals in the NIR energy re-
gion (beyond 800 nm). Interestingly, the overall PA spectral features
reflect the absorption spectrum. This result indicates that the intrinsic
absorption profile (i.e., absorption coefficient, e) of the dioxohex-
aphyrin-based dye governs the PA response. Excellent correlation
linearity is observed for the concentration of the sample solution vs.
PA intensity (Figure S23). The PA spectrum for the non-fluorescent
bis-copper complex c-Cu2-2a, the maximum intensity was found to be
almost identical to that of emissive c-Zn2-2a (Figure 9d). The meas-
urements were conducted at the same concentration (1 mM) and
laser power fluence, and the absorption coefficient value and quantum
yield of nonradiative decay (Fnr; ca. 1) for both samples are quasi-
similar. Therefore, Grüneisen coefficient (Γ) value may govern the PA
response for c-M2-2a.61
In the MO diagram of the distorted c-Zn2-2a, unsymmetrical den-
sity distributions are shown along with the highly degenerate
HOMO/HOMO-1 and LUMO/LUMO+1 pair. Thus, the resulting
HOMO-LUMO energy gap becomes larger than that of t-Zn2-2a
(Figure 8).60 The time-dependent (TD) DFT calculations indicate a
distinctly lower oscillator strength (f) for the lowest energy transition,
which is in accordance with the absorption spectra (Figure S21 and
Table S3). The distortion of the core geometry does indeed cause the
weak 26p-aromatic nature as indicated by the relatively small negative
NICS(0) value of -6.24 ppm for the global center of the macrocycle
in c-Zn2-2a compared with that in t-Zn2-2a (-15.28 ppm).59 Fur-
thermore, the less effective connectivity of the current densities in the
ACID plot support this conclusion (Figure S22).58 However, even
with this distortion, it is anticipated that the strain energy of the sad-
dle-distorted c-Zn2-2a is quite small (+0.96 kcal mol–1) relative to that
of t-Zn2-2a. This is consistent with the fact that the skeletal flexibility
of large oligopyrrolic macrocyclic systems can be exploited to tune
aromaticity that is dependent on conformation.5
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Figure 8. MO energy diagrams of (a) c-Zn2-2a and (b) t-Zn2-2a
obtained by B3LYP/6-31G(d,p) level DFT calculations.
NIR PA Response. As observed, the cisoid-derivative c-Zn2-2a is
less emissive with a shorter excited-state lifetime than that of transoid
t-Zn2-2a (vide supra). We therefore evaluated the nonradiative decay
of the dioxohexaphyrins using a nanosecond pulse PA measurement
system.61,62 Due to the intrinsically low excited-state energy of the
dioxohexaphyrin, the driving force for the energy transfer from the
putative triplet excited state of the dioxohexaphyrin to the dioxygen
should be negligible (Figure 9a). Therefore, absence of reactive oxy-
Figure 9. (a) Schematic of the photoexcitation decay process of the
metallohexaphyrins; ABS, absorption; FL, fluorescence; ND, nonradiative
decay. (b) Time courses of absorption changes at certain energies for t-
Zn2-2a (black), t-Cu2-2a (red), IR-26 (blue), and IR-1040 (purple) upon
laser irradiation at 1064 nm. NIR PA spectra of (c) c-Zn2-2a, (d) c-Cu2-
2a, (e) t-Zn2-2a, and (f) t-Cu2-2a in DMF (top) along with the steady-
state absorption spectra (bottom). (g) PA images (probed at 1030 and
1064 nm) of t-Cu2-2a and t-Zn2-2a in a glass-capillary (dimensions = 20
mm × 1 mm) in comparison with a blank solvent (DMF). Concentration
of sample solution is 1 mM.
1
gen species (e.g., O2) may be attributed to the extraordinarily high
photostability of dioxohexaphyrins.10 For the actual production of PA
(light-in/acoustic-out) signals, photostable bis-metal complexes (e.g.,
c-M2-2a and t-M2-2a) with NIR absorptions and low fluorescence
quantum yields (ΦFL < 0.001) should be suitable as PA contrast dyes
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Clearly, the PA properties of transoid bis-metal complexes are re-
■
ASSOCIATED CONTENT
1
markable, with higher responses in the NIR-II region (Figures 9e,f
and S23). The relative intensity factors of the PA signal (from the
DMF solution excited at 760 nm) for the transoid t-Zn2-2a and t-Cu2-
2a are estimated to be 1.2- and 1.4-fold higher, respectively, compared
with those of freebase t-2a (Figure S24). This implies that the metal-
coordination of t-2a enhances the PA signal intensity. The PA re-
sponse for t-M2-2a is further higher than those of commercially avail-
able indocyanine green (ICG; 2.5~2.9-fold) and regular hexaphyrin 4
(1.3–1.5-fold), respectively (Figure S24). Different with the cisoid-
derivative system, the Γ factor may be apparently higher for non-
emissive t-Cu2-2a than emissive t-Zn2-2a with a large absorption
coefficient, which affords a relatively large PA signal. 56 Due to the
inherent molecular orbital interaction, the transoid t-Cu2-2a showed
broader PA spectral feature, which could be advantageous to effective
photo-excitation of the dye (Figure S25). The result indicates the
electronic tunability of the PA properties for transoid-
dioxohexaphyrin dyes through metal complexation.
Supporting Information
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9
The Supporting Information is available free of charge on the ACS
Publications website at DOI: 10.1021/jacs.xxxxxxx.
Full experimental methods including detailed synthetic procedures,
synthesis and characterization data, NMR, FAB MS, spectroscopic
data, X-ray crystallographic details, and DFT calculations (PDF)
Crystallographic data for c-Cu2-2a (CIF)
Crystallographic data for c-2b (CIF)
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■
AUTHOR INFORMATION
Corresponding Author
*ishida.masatoshi.686@m.kyushu-u.ac.jp
*dongho@yonsei.ac.kr
*hfuruta@cstf.kyushu-u.ac.jp
ORCID
Importantly, the extraordinarily high photostability of the diox-
ohexaphyrin dyes compared to those of commercially available NIR-
II dyes, i.e., IR-26 and IR-1040, should be advantageous for deep PA
imaging applications in terms of MPE (Figures 9b and S26). Fur-
thermore, the PA images obtained by employing t-Cu2-2a and t-Zn2-
2a as NIR-II PA dyes reveal the wavelength-dependent signal re-
sponse in the NIR-II region, whereas no signals are generated by the
blank solution (Figure 9g). Although further studies on the structure-
PA property relationships are needed, these dioxohexaphyrin-based
dyes can be a new entry to the NIR-II PA imaging agents.
Shigeki Mori: 0000-0001-6731-2357
Koji Miki: 0000-0002-4670-2302
Kouichi Ohe: 0000-0001-8893-8893
Masatoshi Ishida: 0000-0002-1117-2188
Dongho Kim: 0000-0001-8668-2644
Hiroyuki Furuta: 0000-0002-3881-8807
Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS
■
CONCLUSIONS
The present work at Kyushu University was supported by JSPS
KAKENHI Grant Numbers (JP19H04586 and JP19K05439). Fund-
ing from the Tokuyama Research Foundation is gratefully acknowl-
edged. The work at Yonsei University was supported by the Strategic
Research (NRF2016R1E1A1A01943379) through the National
Research Foundation of Korea (NRF) funded by the Ministry of
Science.
In summary, we have presented a novel core-modification for con-
trolling the molecular geometries of dioxohexaphyrin scaffolds. This
strategy allowed us to distinguish strongly aromatic transoid- and
nonaromatic cisoid-dioxohexaphyrin homologs, t-2 and c-3, respec-
tively. The latter 28p-conjugated species demonstrated unique redox
reactivity, interconverting to the 26p Hückel-aromatic congeners c-2
and c-M2-2 upon solvent-assisted oxidation and bis-metalation-
induced oxidation, respectively. The new cisoid-homologs possessing
two carbonyl groups within the same cavity (c-M2-2) have a saddle-
■
distorted p-conjugated circuit with moderate aromaticity. The core
distortion of bis-metal complexes was reflected in the alteration of
their photophysical properties, that is, broader NIR absorption, weak-
er emission, shorter excited-state lifetimes, and lower photoacoustic
response. In contrast, the transoid-dioxohexaphyrin t-2a possessing
two symmetrical “NNNO” coordination spheres afforded the corre-
sponding bis-metal complexes t-M2-2a with extraordinary photosta-
bility and intense NIR-II absorption/emission/PA signals owing to
their distinctly aromatic electronic structures.
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Keito Shimomura, Hiroto Kai, Yuma Nakamura, Yongseok Hong, Shigeki Mori, Koji Miki, Kouichi Ohe, Yusuke
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Notsuka,ǁ Yoshihisa Yamaoka,ǁ Masatoshi Ishida,*, Dongho Kim,*, and Hiroyuki Furuta*,
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