Synthesis and spectroscopic properties of fused-ring-expanded aza-boradiazaindacenes

Article abstract of DOI:10.1002/asia.201000641

A series of fused-ring-expanded aza-boradiazaindacene (aza-BODIPY) dyes have been synthesized by reacting arylmagnesium bromides with phthalonitriles or naphthalenedicarbonitriles. An analysis of the structure-property relationships has been carried out based on X-ray crystallography, optical spectroscopy, and theoretical calculations. Benzo and 1,2-naphtho-fused 3,5-diaryl aza-BODIPY dyes display markedly red shifted absorption and emission bands in the near-IR region (>700a nm) due to changes in the energies of the frontier MOs relative to those of 1,3,5,7-tetraaryl aza-BODIPYs. Only one 1,2-naphtho-fused aza-BODIPY of the three possible isomers is formed due to steric effects, and 2,3-naphtho-fused compounds could not be characterized because the final BF ₂ complexes are unstable in solution. The incorporation of a i￡N(CH₃)₂ group at the para-positions of a benzo-fused 3,5-diaryl aza-BODIPY quenches the fluorescence in polar solvents and results in a ratiometric pH response, which could be used in future practical applications as an NIR "turn-on" fluorescence sensor.

Full text of DOI:10.1002/asia.201000641

FULL PAPERS
DOI: 10.1002/asia.201000641
Synthesis and Spectroscopic Properties of Fused-Ring-Expanded
Aza-Boradiazaindacenes
Hua Lu,[a, b] Soji Shimizu,[b] John Mack,[b] Zhen Shen,*[a] and Nagao Kobayashi*[b]
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Abstract: A series of fused-ring-ex-
panded aza-boradiazaindacene (aza-
BODIPY) dyes have been synthesized
by reacting arylmagnesium bromides
with phthalonitriles or naphthalenedi-
carbonitriles. An analysis of the struc-
ture–property relationships has been
carried out based on X-ray crystallog-
raphy, optical spectroscopy, and theo-
retical calculations. Benzo and 1,2-
naphtho-fused 3,5-diaryl aza-BODIPY
dyes display markedly red shifted ab-
sorption and emission bands in the
near-IR region (>700 nm) due to
changes in the energies of the frontier
MOs relative to those of 1,3,5,7-tetraar-
yl aza-BODIPYs. Only one 1,2-naph-
tho-fused aza-BODIPY of the three
possible isomers is formed due to steric
effects, and 2,3-naphtho-fused com-
pounds could not be characterized be-
cause the final BF2 complexes are un-
stable in solution. The incorporation of
ꢀ
a
of
NACHTNGUTRENNU(G CH3)2 group at the para-positions
a
benzo-fused 3,5-diaryl aza-
BODIPY quenches the fluorescence in
polar solvents and results in a ratiomet-
ric pH response, which could be used
in future practical applications as an
NIR “turn-on” fluorescence sensor.
Keywords: BODIPYs
·
density
functional theory · dyes/pigments ·
fluorescence · IR spectroscopy
Introduction
result in nonradiative deactivation pathways.[1g,3] There has
been increasing interest in the use of boradiazaindacene
(BODIPY) dyes for these applications,[4] since they often
have superior spectral characteristics to those of fluoresceins
and rhodamines. BODIPYs have already started to be used
in some contexts.[5]
Over the past decade there has been considerable interest in
the synthesis of organic chromophores with strong absorp-
tion and fluorescence bands in the near-IR (NIR) region
due to advances in optical imaging, microarrays, and electro-
phoresis and the need to develop labels and optical sensors
for biological and medical applications.[1] A key advantage
of NIR dyes is that the scattering of light, autofluorescence,
and absorption by tissues and cells is minimized.[1f,2] Tradi-
tionally, cyanine dyes, such as Cy3 or Cy5, have been used
for these applications, but poor photostability and low fluo-
rescence quantum yields are often encountered, because ro-
tation and photoisomerization of the flexible structure can
The BODIPY p-system typically absorbs and emits in the
480–540 nm region.[6] Marked red shifts of the absorption
and emission maxima have been achieved through aryl or
styryl substitution at the 1-, 3-, 5-, and/or 7-positions,[7] aro-
matic ring fusion,[7h,8] by incorporating an oxygen atom into
the p-system to coordinate the boron,[9] or by replacing the
meso-carbon atom with an aza-nitrogen atom to form an
aza-BODIPY.[10] Over the past decade, aza-BODIPY dyes
have been studied extensively by the OꢁShea research
group.[11,14–15] A key advantage of aza-BODIPY dyes is that
a marked red shift of the absorption and emission bands rel-
ative to conventional BODIPY dyes can be achieved with-
out modifying the key properties of BODIPY dyes, such as
their high molar absorption coefficients, narrow and struc-
tured absorption and emission bands, small Stokes shifts,
high fluorescence quantum yields, and photostability. Two
methods have typically been used to prepare aza-BODIPY
dyes with 1,3,5,7-tetraaryl substituents,[4b,12] the reaction of a
pyrrole with a nitrosopyrrole, which is prepared either in a
separate step or in situ, and the formation of aza-dipyrrome-
thene skeletons from chalcones and nitromethane, or cya-
nide, followed by a condensation reaction with ammonium
acetate. Carreira and co-workers recently reported a further
bathochromic shift of the lowest-energy absorption band
maximum of conventional 1,3,5,7-tetraaryl aza-BODIPY
dyes from 688 to 740 nm by restricting the conformational
flexibility of the 3- and 5-diaryl moieties by incorporating
additional carbocyclic or heterocyclic rings.[10c,12a] However,
the synthesis of these compounds requires six steps.
[a] Dr. H. Lu, Prof. Z. Shen
State Key Laboratory of Coordination Chemistry
Nanjing National Laboratory of Microstructures
School of Chemistry and Chemical Engineering
Nanjing University, Nanjing 210093 (China)
Fax : (+86)25-8331-4502
The use of NIR fluorescent aza-BODIPY dyes in practical
applications is only likely to become feasible when a facile
and commercially viable synthetic method has been devel-
oped. Our recently reported novel synthetic method for ob-
taining benzo-fused aza-BODIPY, 2, in moderate yield
through a two-step reaction of phthalonitrile and an aryl-
magnesium bromide may provide the solution,[13] since
phthalonitrile is commercially available and arylmagnesium
E-mail: zshen@nju.edu.cn
[b] Dr. H. Lu, Dr. S. Shimizu, Dr. J. Mack, Prof. N. Kobayashi
Department of Chemistry, Graduate School of Science
Tohoku University, Sendai 980–8578 (Japan)
Fax : : (+81)22-795-7719
E-mail: nagaok@m.tohoku.ac.jp
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201000641.
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Z. Shen and N. Kobayashi et al.
FULL PAPERS
bromides are easily prepared.
A marked red shift of the ab-
sorption and emission bands
was observed relative to the
spectra of conventional 1,3,5,7-
tetraaryl
aza-BODIPY
dyes.[13,14] The introduction of
additional substituent groups
on the precursors is straightfor-
ward, so the spectral properties
of the aza-BODIPY product
can be readily fine-tuned. This
can be problematic with other
aza-BODIPY synthetic meth-
ods. Phthalonitriles are used in-
dustrially during the synthesis
of phthalocyanines, so the syn-
thesis and properties of substi-
tuted phthalonitriles have al-
ready been studied in depth.[15]
In this paper, we explore the
synthesis of a wider range of
3,5-diaryl aza-BODIPY dyes
based on the reaction of aryl-
Scheme 1. Synthesis and chemical structures of the aromatic-ring-fused aza-BODIPY and aza-dipyrromethene
dyes. a) dry benzene, RT, 1 h; b) BF3·OEt2, triethylamine, benzene, reflux.
magnesium
phthalonitriles and naphthale-
nedicarbonitriles (Scheme 1).
bromides
with
Optical spectroscopy and time-dependent DFT (TD-DFT)
calculations are used to investigate the impact of fused-ring-
expansion and the introduction of aryl groups with strongly
electron-donating dimethylamino substituents at the para-
positions on the electronic structure and fluorescence prop-
erties of the aza-BODIPY chromophore.
only one of the three possible 1,2-naphtho-fused aza-
BODIPY isomers, 5a, was formed in 28% yield (Scheme 1).
1
The structure of 5a was determined based on the H NMR
spectrum (Figure 1). The assignment of the proton signal is
based on the integrated intensities and coupling patterns ob-
served in the H–H COSY NMR spectrum (see the Support-
ing Information). A doublet signal at very low field (ca. d=
9.54 ppm) was assigned to the protons on the naphthalene
moiety, which lie closest to the meso-nitrogen atom. A simi-
Results and Discussion
1
lar signal was recently reported in the H NMR spectrum of
Synthesis
[1,2-q]porphyrazine.[16] Unfortunately,
tribenzoACTHNUGTRENNUG[b,g,l]naphthoAHCTUNGTRENNGUN
Fused-ring-expanded aza-BODIPYs were prepared by using
a method that we have reported previously.[13] Compounds
2–4 (Scheme 1) were formed in approximately 24–28%
yields by reacting a phthalonitrile (0.1 mol) with an arylmag-
nesium bromide (0.25 mol) followed by treatment with
BF3·OEt2. When 1,2-naphthalenedicarbonitrile was used,
2,3-naphtho-fused aza-BODIPYs could not be isolated due
to instability in solution, but precursors 6 and 7 have been
characterized based on MALDI-TOF MS and the presence
of characteristic aza-dipyrromethene bands in the UV/Vis
absorption spectra (see the Supporting Information, Fig-
ure S3).
The use of substituted phthalonitriles provides scope for
introducing additional substituent groups, which can be used
to further fine-tune the electronic and optical properties of
the aza-BODIPY dye. Tetrafluorophthalonitrile and 4,4’-
N,N’-dimethylaminophenyl magnesium bromide were select-
ed as precursors, since aza-BODIPYs containing both elec-
tron–donor and acceptor moieties are likely to exhibit novel
electron-transfer properties. When the synthesis was carried
out, however, the molecular weight of the aza-BODIPY
target compound ([M]+ =675 amu) could not be detected
by MALDI-TOF-MS. The main peak was observed instead
at m/z: 441, despite the fact that multiple signals observed
Abstract in Chinese:
1
in the H NMR spectrum at d=8.12 and 6.77 ppm (m, 4H),
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Fused-Ring-Expanded Aza-Boradiazaindacenes
with the Grignard reagent to form an aza-dipyrromethene.
BF3·OEt2 can be used to convert the aza-dipyrromethene
into the aza-BODIPY dye.
X-ray Crystal Structures of 4 and 8
The X-ray crystal structure of 4 is shown in Figure 2. The
ꢀ
boron atom is coordinated by two nitrogen atoms (B N
bond lengths of 1.564 and 1.573 ꢂ) and two fluorine atoms
ꢀ
(B F bond lengths of 1.375 and 1.379 ꢂ) in a tetrahedral ge-
ometry. The structure is similar to those observed previously
in BODIPY structures.[13,14,18] The N4 C20 and N5 C28
bonds (average value: 1.368 ꢂ) are shortened due to conju-
gation with the lone-pair electrons of the nitrogen atoms in
the dimethylamino groups. The indacene moiety has a
highly planar structure. The average root-mean-square (rms)
deviation of the indacene plane atoms is 0.0452 ꢂ. The dihe-
dral angles between the indacene plane and the phenyl rings
at the 3- and 5-positions are 49.5 and 43.48, respectively
(Figure 2). The conjugation properties and the planarity of
the p-system play a key role in determining the spectroscop-
ic properties of BODIPYs. The structure of 8 is also planar
with an rms value of 0.0307 ꢂ. The dihedral angle between
the phenyl ring C9–C14 and the plane of the p-system is
ꢀ
ꢀ
Figure 1. 1H NMR spectrum of 5a in CDCl3.
along with singlet peaks at d=3.12 and 3.09 ppm (s, 6H),
are consistent with the presence of two dimethylaminophen-
yl substituents. X-ray crystallographic analysis revealed that
8 had been obtained (Figure 2).
ꢀ
ꢀ
32.58. The N1 C1 and N3 C8 bond lengths (1.314 and
1.291 ꢂ, respectively) are consistent with double-bond char-
acter, in contrast, for instance, with the significantly longer
ꢀ
ꢀ
bond lengths (1.405 ꢂ) of N1 C8 and N3 C17 (Figure 2).
Head-to-tail p–p stacking interactions are observed in the
molecular packing diagrams with interplanar separations of
approximately 3.2 ꢂ for 4 and 3.37 ꢂ for 8 (Figure 3).
Optimized Geometries of 5a–c
Although three isomers, 5a–c, can potentially be formed
when 1,2-naphthalenedicarbonitrile is used as the precursor
(Scheme 1), only isomer 5a was isolated and characterized.
Steric effects are the most likely explanation for this.
B3LYP geometry optimizations were carried out to explore
this question. Somewhat surprisingly, the indacene plane of
5a is predicted to be near planar (Figure 4), despite the fact
that the outer benzene rings of the 2,3-naphthalene moieties
are aligned towards each other. The absence of a meso-sub-
stituent in the aza-BODIPY structure reduces the scope for
steric crowding. In the structures of 5b and 5c, interatomic
distances of approximately 2.63 ꢂ are predicted between hy-
drogen atoms of the peripheral 1,2-naphtho-fused ring moi-
eties and carbon atoms of the phenyl substituents (Figure 4).
This is considerably shorter than the sum of the van der
Waals radii for the carbon and hydrogen atoms of benzene,
2.77 ꢂ.[19] It seems probable, therefore, that there is a much
higher energy barrier to the formation of 5b and 5c.
Figure 2. Front (top) and side (bottom) ORTEP views of the molecular
structure of 4 and 8 with the thermal ellipsoids set at 50% probability.
The reaction mechanism in Scheme 2 is based on two re-
actions of phthalonitrile and phenylmagnesium bromide that
were previously proposed by other authors.[17] In the 1920s,
Weiss and Schlesinger[17a] reported that an unsubstituted ver-
sion of 8 is obtained in very low yield. Bredereck and Voll-
mann[17b] later claimed that this was incorrect and that aza-
dipyrromethene is instead formed in moderate yield. The X-
ray structures of 4 and 8 (Figure 2) provide definitive evi-
dence that both reactions are, in fact, possible. After an ini-
tial nucleophilic attack by the Grignard reagent at the
carbon atom of the nitrile moiety, magnesium [(2-
cyanoaryl)ACHTUNGTRENNUNG(aryl)methylene]amide bromide (11) is formed,
which subsequently undergoes ring cyclization to form mag-
nesium (3-aryl-1H-isoindol-1-ylidene)amide bromide (10).
The magnesium salt of 10 reacts with either the aryl magne-
sium compound to form 8 or with the phthalonitrile to form
magnesium (Z)-[3-(3-aryl-1H-isoindol-1-ylideneamino)-1H-
isoindol-1-ylidene]amide bromide (9), which then reacts
Absorption and Fluorescence Spectroscopy
The main absorption band of 2 in dichloromethane lies at
712 nm and the corresponding fluorescence band lies at
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Z. Shen and N. Kobayashi et al.
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Scheme 2. Reaction mechanisms for the formation of aza-BODIPY and 8.
736 nm. Fused-ring-expansion with benzene rings results in
a 62 nm red shift of the absorption band relative to that of
1,3,5,7-tetraaryl aza-BODIPYs (lmax ꢁ650 nm).[14] Smaller
extinction coefficients are observed in the spectrum of 3
when electron-withdrawing fluorine substituents are added
at the para-positions, but the other spectroscopic properties,
such as the absorption and fluorescence band maxima and
the quantum yield remain almost unchanged. When two di-
methylamino substituents are present at the para-positions
of the phenyl rings in 4, the absorption peak at 794 nm be-
comes significantly broader than those observed in the spec-
trum of 2. A significant red shift of 82 nm is observed for
the band center of the lowest-energy absorption band in di-
chloromethane. Slight red shifts of 25 and 17 nm are ob-
served in the absorption and emission bands of the 1,2-
naphtho-fused compound, 5a, along with small changes in
the full width at half maximum (fwhm), Stokes shift, and
fluorescence quantum yield values.
phores.[20] In contrast, the fwhm of 4 changes markedly due
to the relatively large ground-state dipole moment of
6.39 D. The integrated intensity of the lowest-energy absorp-
tion band remains constant regardless of any change in the
solvent polarity (Figure 5).
The fluorescence spectra typically exhibit mirror symme-
try with the absorption bands. The lack of a clear trend in
the emission band centers of 2, 3, and 5a is consistent with
emission from the relaxed Franck–Condon excited state.[8c]
The absorbance band centers and Stokes shifts of 2 and 3
are relatively insensitive to solvent effects with only a minor
blue shift observed at high solvent polarity in acetonitrile
relative to nonpolar hexane solutions. However, the fluores-
cence quantum yield and Stokes shift of 4 exhibit a marked
solvent dependence. The fluorescence quantum yield of 4 is
0.10 in hexane, but only 0.01 in dichloromethane and aceto-
nitrile. Quenching of fluorescence intensity in polar solvents
is often attributed to an intramolecular charge-transfer pro-
cess[18,21,22] and may be related to efficient nonradiative re-
laxation caused by conical intersections formed between the
potential-energy surfaces of close-lying excited states of the
same multiplicity.[23]
Three solvents with markedly differing polarities were se-
lected to carry out an in depth investigation of the photo-
physical properties of 2–5a. For 2, 3, and 5a, the fwhm of
the lowest-energy absorption bands increases slightly as a
function of solvent polarity (Table 1), probably due to the
high rigidity and weak dipolar nature of the chromo-
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Fused-Ring-Expanded Aza-Boradiazaindacenes
Figure 5. Absorption and fluorescence spectra of 2–5a in dichlorome-
thane (c), hexane (c), and acetonitrile (c).
Molecular Orbits and Transition
TD-DFT calculations were carried out to derive an en-
hanced understanding of the observed spectroscopic proper-
ties of 2–5a (see the Supporting Information). Figure 6 con-
tains a partial MO energy diagram for the frontier p-MOs
at the B3LYP/6-31G(d) level of theory. The lowest-energy
excitation of 4 is predicted to lie at 655 nm (f=0.79) and to
arise primarily from the HOMO!LUMO one-electron
transition (Table 2). The HOMO and LUMO of 4 are both
destabilized relative to those of 2 due to the strong electron-
donating properties of the dimethylamino substituents.
There is a marked red shift of the absorption and emission
bands of 4, as the destabilization of the HOMO is greater
Figure 3. Molecular packing in the crystal structures of 4 and 8 viewed
along the a-axis.
Figure 4. B3LYP-optimized geometries of the three 1,2-naphtho-fused isomers 5a, 5b, and 5c calculated with the 6-31G(d) basis set.
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Z. Shen and N. Kobayashi et al.
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Table 1. Spectroscopic data of 2–5a in hexane, dichloromethane, and acetonitrile at 298 K.
MOs. The broader and weaker
absorption band of 5a in the
500—550 nm range can be as-
Dye
Solvent
labs [nm]
fwhm [nm]
e [mꢀ1 cmꢀ1
]
lem [nm]
Stokes shift [nm]
Ff
2
hexane
CH2Cl2
MeCN
hexane
CH2Cl2
MeCN
hexane
CH2Cl2
MeCN
hexane
CH2Cl2
MeCN
705
712
704
707
713
702
765
794
789
728
737
729
43
47
48
41
46
48
63
82
90
37
43
58
n.d.[a]
95000
51000
n.d.[a]
63000
44000
n.d.[a]
174000
91000
n.d.[a]
71000
35800
725
736
725
726
724
726
796
830
833
739
753
745
20
24
21
19
11
24
31
36
45
11
16
16
0.24
0.14 signed to the second and third
0.20
0.17
0.16
0.19
0.10
0.01
0.01
0.30
0.14
0.20
lowest-energy transitions, which
are predicted to lie at 505 and
502 nm (f=0.02, 0.16), and to
3
arise
primarily
from
the
4
HOMO–1!LUMO
and
HOMO–2!LUMO transitions,
respectively (Table 2 and the
Supporting Information).
5a
Additional theoretical calcu-
lations were carried out for 3,5-
diaryl-aza-BODIPY (12) and
[a] Not determined due to low solubility.
than that of the LUMO. The wavelengths and intensities of
the second to fourth lowest-energy transitions in the calcu-
lated spectrum closely match the experimental data in the
430—580 nm region (Table 2 and the Supporting Informa-
tion, Figure S2). The lowest energy band of the 1,2-naphtho-
fused compound, 5a, shifts to longer wavelength by approxi-
mately 25 nm (Figure 5). The HOMO and LUMO of 5a are
almost fully localized on the aza-BODIPY core and have
nodal patterns, which are very similar to those of the fron-
tier MOs of 2 (Figure 6). The HOMO–LUMO energy gap is
almost unchanged and the red shifts of the absorption and
emission bands closely match the trends predicted in the
theoretical calculations. The lowest-energy transition of 3 is
predicted to lie at 595 nm (f=0.75) well to the blue of the
corresponding band of 4 due to the effect of the electron-
withdrawing substituents on the energies of the frontier
the corresponding 2,3-naphtho-fused aza-BODIPY com-
pound (13) so that the effect of fused-ring expansion could
be explored (Table 3). A consistent red shift of the S0!S1
band is observed as each additional pair of benzene rings is
added to the p-system. Since the core of the aza-BODIPY
structure forms part of the p-system of tetraazaporphyrins
Figure 6. Energy-level diagram for the frontier p-MOs of dyes 2–5a. Nodal patterns of each MO are shown at an isosurface value of 0.02.
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Fused-Ring-Expanded Aza-Boradiazaindacenes
Table 2. Calculated electronic excitations energies, oscillator strengths,
and the related wave functions.
Dye Energy [eV] l [nm] f[a]
Wave function[b]
!
2
3
4
2.10
2.08
1.89
2.61
2.79
3.18
590
595
655
476
444
390
0.75 62%jL H>
!
0.75 62%jL H>
!
!
0.79 64%jL H>, 1%jL H-2>
!
!
0.22 88%jL H-1>, 5%jL+1 H>
!
0.02 88%jL H-2>
!
!
0.25 82%jL+1 H>, 1%jL H-1>,
!
2%jL H-4>
!
!
5a
1.98
2.46
2.47
627
505
502
0.60 64%jL H>, 5%jL H-2>
!
0.02 92%jL H-1>
!
!
0.16 88%jL H-2>, 1%jL H>
[a] Oscillator strength. [b] The wave functions based on the eigenvectors
predicted by TD-DFT.
(also known as porphyrazines), a comparison can also be
made with the Q bands of the corresponding porphyrazine
(Pz), phthalocyanine (Pc), and 1,2- and 2,3-naphthalocya-
nine (1,2-Nc and 2,3-Nc) compounds (Table 3).[16b] A similar
consistent red shift of the S0!S1 band is observed. Although
greater variation is observed in the calculated oscillator
strengths of the fused-ring-expanded porphyrazines, due to
the orbital angular momentum properties of the cyclic heter-
oaromatic tetrapyrrole structure,[24] it seems reasonable to
conclude that trends observed in the wavelengths of fused-
ring-expanded porphyrazines can be used as a guide to de-
termine the optical properties of the corresponding aza-
BODIPY. Since a very wide range of fused-ring-expanded
porphyrazines have been characterized,[25] this should great-
ly facilitate the selection of phthalonitriles required to syn-
thesize aza-BODIPYs with properties suitable for use in
specific practical applications.
Detailed insights have also been derived on the electronic
structures and optical spectroscopy of 2,3-naphtho-fused di-
pyrromethene intermediates 6 and 7. Comparison with ex-
perimental data is problematic in the context of 7, since it is
very unstable and decomposes almost immediately in solu-
tion.
Figure 7. Energy-level diagram for the frontier p-MOs of dyes 1, 6, and 7
(top) and the corresponding BODIPY complexes (bottom). Nodal pat-
terns of each MO are shown at an isosurface value of 0.02.
The HOMOs of 6 and 7 are delocalized over the entire in-
dacene plane, unlike that of 5a (Figure 6 and 7). The ener-
gies of the HOMO and LUMO of 6 are destabilized relative
to the frontier MOs of 1. The same trend is also observed in
calculations carried out for 2 and the corresponding aza-
BODIPY compounds (BF2-6 and BF2-7). It seems safe to
conclude that BF2-6 and BF2-7 are easily oxidized by oxygen
in solution and this accounts for why they are too unstable
to be isolated and characterized. A large red shift from 650
to 754 nm is observed for the lowest-energy absorption band
of BF2-6 relative to 2 (see the Supporting Information, Fig-
ure S4), since the destabilization of the HOMO is greater
than that of the LUMO, thus resulting in narrowing of the
HOMO–LUMO band gap (DE=2.13 for 1, 1.82 eV for 6).
The lowest-energy band is consistently predicted to arise
from the HOMO!LUMO transition (Table 2 and the Sup-
porting Information, Table S4). A further red shift from 754
to 806 nm is observed in the
spectrum of 7 relative to that of
Table 3. Calculated wavelengths (lcalcd), intensities, and the observed wavelengths (lobs) of the S0!S1 transi-
6 due to the presence of the di-
methylamino substituents (see
the Supporting Information,
Figure S3). A further slight nar-
rowing of the HOMO–LUMO
band gap (DE=1.78 eV for 7)
is predicted in the TD-DFT cal-
tions of fused-ring-expanded aza-BODIPYs and porphyrazines.
Fused ring
BODIPY
lcalcd [nm]
f[a]
lobs [nm]
ZnPz[b]
lcalcd [nm]
f[a]
lobs [nm]
–
12
2
5a
13
517
590
627
706
0.69
0.75
0.6
n.a.[c]
712
737
Pz
Pc
1,2-Nc
2,3-Nc
500
593
n.a.
695
0.14
0.40
n.a.
0.59
586
672
n.a.
756
benzo
1,2-naphtho
2,3-naphtho
0.74
n.a.
[a] Oscillator strength. [b] Fused-ring-expanded zinc porphyrazine compounds. [c] n.a.=not available.
Chem. Asian J. 2011, 6, 1026 – 1037
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1033

Z. Shen and N. Kobayashi et al.
FULL PAPERS
culation (Figure 7). The same trends in the HOMO energies,
HOMO–LUMO band gaps, and the wavelengths of the
lowest-energy bands are also predicted for 2, BF2-6, and
BF2-7 (Figure 7 and Table 2 and the Supporting Information,
Figure S5 and Table S4).
energy absorption bands observed for aza-BODIPYs rela-
tive to those of the corresponding BODIPY dyes. When the
p-conjugation system is extended to form the 1,2-naphtho-
fused aza-BODIPY 5a, only minor changes are observed in
the first oxidation and reduction steps as would be anticipat-
ed based on the small changes observed in the HOMO and
LUMO energies (Figure 6 and 8). A significant decrease in
the first oxidation potential would be expected if a 2,3-naph-
tho-fused aza-BODIPY could be successfully synthesized,
due to the marked destabilization predicted for the HOMO
(Figure 7).
Electrochemistry
The electrochemical properties of the aza-BODIPYs were
studied by cyclic voltammetry in dichloromethane with 0.1m
tetra-n-butylammonium perchlorate (TBAP) as a supporting
electrolyte. The effects of the replacement of the meso-
carbon atom with a nitrogen atom and fused-ring expansion
of the p-conjugation system can be assessed by comparing
the redox potentials for 3, 5a, and the corresponding con-
ventional alkyl-substituted BODIPY compound (Figure 8).
In our previous studies of BODIPYs, an extension of the p-
pH-Dependent Absorption and Fluorescence Spectroscopy
of 4
OꢁShea et al. recently reported a dimethylamino-substituted
1,3,5,7-tetraaryl aza-BODIPY with pH-dependent colori-
metric and fluorescent “turn-on” responses.[11b] Two proto-
nation steps were observed during titration with trifluoro-
acetic acid (TFA). The pH dependence of the absorption
and fluorescence bands of the corresponding benzo-fused
3,5-diaryl aza-BODIPY was analyzed based on the sequen-
tial addition of TFA to a dichloromethane solution of 4.
Upon addition of TFA, a stepwise blue shift of the 794 nm
band is observed along with a slight decrease of the extinc-
tion coefficient (Figure 9). Further addition of TFA results
Figure 8. The CV scans of 3 and 5a.
conjugation system of the indacene chromophore through
fusion with benzene rings at b-pyrrole positions caused a sig-
nificant destabilization of the HOMO energy level, while
the LUMO energy level is only slightly destabilized. For ex-
ample, the reduction and oxidation potentials of the conven-
tional alkyl-substituted BODIPY were observed at ꢀ1560
and 760 mV (vs. ferrocenium/ferrocene (Fc+/Fc)), respec-
tively, while those of the benzo-fused BODIPY lie at ꢀ1530
and 330 mV (vs. Fc+/Fc), respectively.[8c]
The cyclic voltammogram of aza-BODIPY 3 contains an
irreversible one-electron reduction step at ꢀ610 mV and a
reversible oxidation step at 460 mV (vs. Fc+/Fc). The first
reduction potential is substantially lower than that of alkyl-
substituted BODIPYs, as the incorporation of the electro-
negative nitrogen atom at the meso-carbon position causes a
marked stabilization of the LUMO. In DFT calculations, a
large MO coefficient is predicted at the meso-carbon posi-
tion in the LUMO, while, in contrast, this atom lies on a
nodal plane of the HOMO (Figure 6). The stabilization of
the LUMO leads to narrowing of the HOMO–LUMO band
gap and hence results in the marked red shift of the lowest-
Figure 9. Absorption and fluorescence (lex =650 nm) spectra of 4 in di-
chloromethane titrated with TFA.
1034
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Chem. Asian J. 2011, 6, 1026 – 1037

Fused-Ring-Expanded Aza-Boradiazaindacenes
in a decrease in the intensity of the 771 nm band of 4-H+
and a new blue shifted absorption band at 724 nm. The pres-
ence of an isosbestic point at 740 nm is consistent with the
quantitative formation of a diprotonated 4-2H+ species. The
emission band of 4 gradually increases in intensity and is
shifted to the blue after the addition of TFA because the
electron-donating properties of dimethylamino substituents
are eliminated upon protonation. Emission intensity increas-
es because the absorption intensity increases at the excita-
tion wavelength due to the spectral changes, which occur
when less electron density is accepted by the aza-BODIPY
chromophore. As the concentration of TFA is increased, the
formation of the 4-2H+ species results in an additional
markedly blue shifted band at 745 nm, which gradually in-
creases in intensity to 15 times that of the lowest-energy ab-
sorption band of 4 (Figure 8). The absorption and fluores-
cence spectra of 4-2H+ are similar to those of 2, which con-
tains unfunctionalized phenyl rings. The TFA titration spec-
tra reveal that 4 can be used as a ratiometric “turn-on” fluo-
rescence sensor for changes in pH and that NIR dyes with
ratiometric “turn-on” response can be designed rationally
by introducing electron-donating substituents at the para-
position of the phenyl rings of fused-ring-expanded aza-
BODIPYs.
of the arylmagnesium precursor, there is an intensification
and red shift of the lowest energy aza-BODIPY absorption
band from 712 to 794 nm in dichloromethane and a quench-
ing of the fluorescence in polar solvents. These processes
can be utilized to provide a ratiometric “turn-on” probe for
changes in pH, based on the effect of protonation at the di-
methylamino groups. Attempts to design and synthesize aza-
BODIPYs suitable for use in aqueous media are currently
underway.
Experimental Section
General: All reagents were obtained from commercial suppliers and used
without further purification unless otherwise indicated. All air and mois-
ture-sensitive reactions were carried out under a nitrogen atmosphere.
Triethylamine was obtained by simple distillation. The 1H NMR spectro-
scopic measurements were made by using a Bruker 500 MHz spectrome-
ter and a JEOL GSX-400 spectrometer with CDCl3 as the solvent. Mass
spectra were recorded on Perspective Biosystem MALDI-TOF MassVoy-
ager DCE-S12 and Micromass LCT ESI-TOF MS spectrometers. HRMS
were recorded on a Bruker Daltonics Apex-III spectrometer. Fluores-
cence spectral measurements were carried out by using a Hitachi F-4500
spectrofluorometer. Electronic absorption spectra were recorded with Hi-
tachi U-3410 and JASCO V-570 spectrophotometers. Quantum yields
were determined relative to magnesium phthalocyanine (FF =0.84, upon
excitation at 630 nm).[26] Selected redox properties were studied by cyclic
voltammetry in TBAP (0.1m) in acetonitrile on a Perkin–Elmer electro-
chemical analysis system model 283 with a platinum disk as the working
electrode, Ag/AgCl as the quasi-reference electrode, and a platinum wire
as the counter-electrode. Redox potentials were referenced internally
against Fc+/Fc. All measurements were performed under an inert atmos-
phere with a scan rate of 100 mVsꢀ1 at room temperature.
Conclusions
The synthesis, characterization, and theoretical analysis of a
series of fused-ring-expanded aza-BODIPY NIR dyes have
been described. The use of phthalonitriles and arylmagnesi-
um bromides as precursors is clearly very promising and
could eventually provide a facile method for bulk synthesis,
which will facilitate the use of aza-BODIPYs in practical ap-
plications, but challenges remain. 2,3-Naphtho-fused aza-
BODIPY was found to be unstable in solution, while aza-
BODIPY was only obtained as a trace level product when
fluoro- and dimethylamino substituents were introduced on
the phthalonitrile and arylmagnesium bromide precursors,
due to the formation of an isoindoline compound, 8. Further
studies are underway to investigate in depth which types of
substituted phthalonitriles and naphthalenedicarbonitriles
can be used to form aza-BODIPYs as the major product.
Benzo- and 1,2-naphtho-fused aza-BODIPYs and 2,3-naph-
tho-fused compounds exhibit modified spectroscopic proper-
ties due to changes to the energies of the frontier MOs, but
the high molar absorptivity of the lowest energy S0!S1
band and the key fluorescence properties of BODIPY are
retained. The red shift observed in the wavelength of the
S0!S1 absorption band parallels that observed for the Q
band of the corresponding phthalocyanine and naphthalo-
cyanine complexes.[16b] This suggests that it may be possible
to make use of trends observed in the properties of NIR ab-
sorbing phthalocyanines as a guide to enable the rational
design of aza-BODIPY structures with properties suitable
for specific practical applications. When an electron-donat-
ing dimethylamino group is introduced at the para-position
Synthesis: The general procedure for the preparation of dyes 2–5a is to
first vigorously stir phthalonitrile (100 mmol) in a dry benzene solution
(40 mL). A diethyl ether or tetrahydrofuran solution (THF; 40 mL) of
the relevant Grignard reagent (0.25 mol) is then added at room tempera-
ture and the resulting mixture is stirred for a further 1 h. The flask is
then cooled to 0–58C and the excess of the Grignard reagent is decom-
posed carefully with 20% ammonium chloride. The solvent is removed
by using a rotary evaporator and the residue distilled with water steam,
filtered, dried, and subsequently treated with BF3·OEt2 in the presence of
triethylamine in refluxing benzene. Column chromatography was used to
purify 2–5a, followed by recrystallization from CH2Cl2/hexane. The melt-
ing point of each compound exceeds 2008C.
Compound 3: Compound 3 was prepared from phthalonitrile and 4-fluo-
rophenylmagnesium bromide in 24% yield under similar reaction condi-
tions and was treated with BF3·OEt2 in the presence of triethylamine in
1
refluxing benzene. UV/Vis (CH2Cl2): lmax (e)=713 nm (63000); H NMR
(400 MHz, CDCl3, 297 K): d=8.12 (d, J=8 Hz, 2H), 7.89 (m, 4H), 7.61
(d, J=8.4 Hz, 2H), 7.53 (m, 4H), 7.49 (dd, J1 =8.8, J2 =5.2 Hz, 2H),
7.29 ppm (m 2H); MALDL-MS m/z: 481.297; HRMS-ESI: m/z: calcd for
C28H16BF4N3Na+: 504.1266 [M+Na]+; found: 504.1264.
Compound 4: Compound 4 was prepared in 25% yield from phthaloni-
trile and 4,4’-N,N’-dimethyl-aminophenylmagnesium bromide in a similar
manner. UV/Vis (CH2Cl2): lmax (e)=794 nm (174000); MALDL-MS m/z:
531.272; HRMS-ESI: m/z: calcd for C32H28BF2N5Na+: 554.2298
[M+Na]+; found: 554.2301.
Compound 5a: Compound 5a was prepared in 28% yield from 1,2-naph-
thalenedicarbonitrile in a similar manner. UV/Vis (CH2Cl2): lmax (e)=
737 nm (71000); 1H NMR (500 MHz, CDCl3, 297 K): d=9.54 (d, J=
8.4 Hz, 2H), 7.91 (m, 6H), 7.80 (m, 2H), 7.64 (m, 4H), 7.54 ppm (m
8H); MALDI-TOF-MS m/z: 545.367; HRMS-ESI: m/z: calcd for
C36H22BF2N3Na+: 568.1767 [M+Na]+; found: 568.1769.
Compounds 6 and 7: Compounds 6 and 7 were prepared from 2,3-naph-
thalenedicarbonitrile with phenylmagnesium bromide and 4,4’-N,N’-di-
Chem. Asian J. 2011, 6, 1026 – 1037
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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1035

Z. Shen and N. Kobayashi et al.
FULL PAPERS
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m/z: 496.43 for 6, 583.396 for 7.
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purified by water steam distillation and column chromatography.
1H NMR (400 MHz, CDCl3, 297 K): d=8.12 (m, 4H), 6.77 (m, 4H), 3.12
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X-ray structure determination: Data collection for 4 and 8 was carried
out at ꢀ1008C on a Rigaku Saturn CCD spectrometer with graphite-
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CCDC-774743 and -774744 contain the supplementary crystallographic
data for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_
request/cif.
Computational details: The G03W software package[29] was used to carry
out gas-phase DFT geometry optimizations. The hybrid B3LYP function-
al was selected and 6-31G(d) basis sets were used. The same approach
was used to obtain excitation energies and oscillator strengths from TD-
DFT calculations.
Acknowledgements
Financial support was provided by the National Natural Science Founda-
tion of China (nos. 20971066 and 21021062), the Chinese Ministry of Ed-
ucationꢁs Program for New Century Excellent Talents in Universities
(no.NCET-08–0272), the Major State Basic Research Development Pro-
gram of China (grant nos. 2011CB808704 and 2007CB925103), and a
Grant-in-Aid for Scientific Research on Innovative Areas (no. 20108007,
“pi-Space”) from the Japanese Ministry of Education, Culture, Sports,
Science, and Technology (MEXT).
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Received: September 4, 2010
Published online: March 4, 2011
Chem. Asian J. 2011, 6, 1026 – 1037
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
1037