Improved Access to 1,8-Diformyl-carbazoles Leads to Metal-Free Carbazole-Based [2 + 2] Schiff Base Macrocycles with Strong Turn-On Fluorescence Sensing of Zinc(II) Ions

Article abstract of DOI:10.1021/acs.inorgchem.7b02763

Development of a new and high yielding synthetic route to 1,8-diformyl-carbazoles 3 (3a 3,6-di-tert-butyl substituted; 3b 3,6-unsubstituted) is reported. Use of a Heck coupling reaction, followed by ozonolysis, has greatly facilitated the preparation of these interesting head units in useful quantities. An initial foray into the new generations of Schiff base macrocycles that ready access to these head units (3) opens up, has led to the direct (i.e., metal-free) synthesis of two [2 + 2] macrocycles from 3a or 3b with 1,2-diaminoethane, H₂L^tBu (4a) and H₂L^H (4b), respectively, obtained as yellow powders in high yields (87-88%). The dizinc complex [Zn₂L^H(OAc)₂] (5b) was isolated as a bright yellow solid in 83% yield, by 1:2:2 reaction of H₂L^H with zinc(II) acetate and triethylamine. Aldehydes 3a and 3b, macrocycle H₂L^H, and complex [Zn₂L^H(OAc)₂] (5b) have been structurally characterized. The carbazole NH makes bifurcated hydrogen bonds with the pair of flanking 1,8-diformyl-moieties in 3, or 1,8-diimine-moieties in H₂L^H, leading to a flat, all-cis conformation. The stepped conformation of the metal-free macrocycle H₂L^H is retained in [Zn₂L^H(OAc)₂], despite deprotonation and binding of two zinc(II) centers within the two tridentate pockets. The N₃O₂ coordination of the zinc ions is completed by one μ_1,1- and one μ_1,3- bridging acetate anion. Excitation of nanomolar [Zn₂L^H(OAc)₂] in DMF at 335 nm results in clearly visible blue fluorescence (λ_max = 460 nm). Further studies on the H₂L^H macrocycle revealed turn-on fluorescence, with selectivity (over Ca²⁺, Mg²⁺ and a range of 3d dications) and nanomolar sensitivity for zinc(II) ions, highlighting one of the many potential applications for these new carbazole-based Schiff base macrocycles.

Full text of DOI:10.1021/acs.inorgchem.7b02763

Article
Cite This: Inorg. Chem. XXXX, XXX, XXX−XXX
pubs.acs.org/IC
Improved Access to 1,8-Diformyl-carbazoles Leads to Metal-Free
Carbazole-Based [2 + 2] Schiff Base Macrocycles with Strong Turn-On
Fluorescence Sensing of Zinc(II) Ions
Stuart J. Malthus, Scott A. Cameron, and Sally Brooker*
Department of Chemistry and the MacDiarmid Institute for Advanced Materials and Nanotechnology, University of Otago, P.O. Box
56, Dunedin 9054, New Zealand
*
S Supporting Information
ABSTRACT: Development of a new and high yielding
synthetic route to 1,8-diformyl-carbazoles 3 (3a 3,6-di-tert-
butyl substituted; 3b 3,6-unsubstituted) is reported. Use of a
Heck coupling reaction, followed by ozonolysis, has greatly
facilitated the preparation of these interesting head units in
useful quantities. An initial foray into the new generations of
Schiff base macrocycles that ready access to these head units
(
3) opens up, has led to the direct (i.e., metal-free) synthesis of two [2 + 2] macrocycles from 3a or 3b with 1,2-diaminoethane,
tBu
(4a) and H2LH (4b), respectively, obtained as yellow powders in high yields (87−88%). The dizinc complex
H2L
H
H
[
Zn L (OAc) ] (5b) was isolated as a bright yellow solid in 83% yield, by 1:2:2 reaction of H L with zinc(II) acetate and
2
2
2
H
H
triethylamine. Aldehydes 3a and 3b, macrocycle H L , and complex [Zn L (OAc) ] (5b) have been structurally characterized.
2
2
2
The carbazole NH makes bifurcated hydrogen bonds with the pair of flanking 1,8-diformyl-moieties in 3, or 1,8-diimine-moieties
H
H
in H L , leading to a flat, all-cis conformation. The stepped conformation of the metal-free macrocycle H L is retained in
[
2
2
H
Zn L (OAc) ], despite deprotonation and binding of two zinc(II) centers within the two tridentate pockets. The N O
2
2
3
2
coordination of the zinc ions is completed by one μ - and one μ - bridging acetate anion. Excitation of nanomolar
1
,1
1,3
H
H
[
Zn L (OAc) ] in DMF at 335 nm results in clearly visible blue fluorescence (λ = 460 nm). Further studies on the H2L
2
2
m
a
x
2+
2+
macrocycle revealed turn-on fluorescence, with selectivity (over Ca , Mg and a range of 3d dications) and nanomolar
sensitivity for zinc(II) ions, highlighting one of the many potential applications for these new carbazole-based Schiff base
macrocycles.
2
7
32
INTRODUCTION
diformyl-carbazole head units, until our report in 2017. Prior
to our paper, only a small set of complexes of acyclic 1,8-
■
Macrocycles are a very powerful class of ligand, not least due to
the control they exhibit over the coordination environment of
33−36
diimino-carbazole ligands had been reported.
diformyl-carbazoles (3), required for accessing these Schiff base
macrocyclic and acyclic ligands, were prepared using three very
different routes, reported by the groups of Gibson,
The key 1,8-
1
−8
the metal ion(s). Schiff base macrocycles are a popular class
of macrocycles, as they can be readily accessed by the metal
templated condensation of dialdehyde or diketone (head unit)
3
3,34
37
32,38
9
−11
Nakagawa, and Brown/Brooker
(Scheme 1). Deprotona-
and diamine (linker) components.
Head units featuring, for
tion of the resulting tridentate 1,8-diimino-carbazole ligands
facilitated complexation with manganese(II), iron(II or III),
cobalt(II), nickel(II), copper(II), or palladium(II).
example, pyridine, phenol, pyridazine, pyrrole, dipyrrole,
triazole, dihydroxybenzene, and diphenylamine moieties have
been utilized to form Schiff base macrocyclic complexes that
have a wide range of applications, for example, as hydrogen
However, the three routes reported to date to the key 1,8-
3
2−34,38
12−14
15
diformyl-carbazole head units 3 (Scheme 1)
are
and time-consuming, and so
had severely limited our access to systems derived from
evolution catalysts,
CO /epoxide copolymerization catalysts, spin crossover
11
carbon dioxide reduction catalysts,
32,38
33,34
16
nontrivial
or hazardous,
2
1
7,18
19,20
switches,
single molecule magnets,
antimicrobials,
24
32,33
21−23
them.
metalloenzyme models,
nuclear waste remediation, and
25,26
Herein, we describe a new and reliable route that facilitates
the larger scale preparation of 3, which in turn opens up the
exploration of ligands and complexes derived from it.
Specifically, we report here the preparation of the first
examples of [2 + 2] Schiff base macrocycles to be derived
from these carbazole head units. The metal-free condensation
DNA binding agents.
We have a long-standing interest in Schiff base macrocycles
27
utilizing diphenylamine-based systems, for example, to (a)
2
8
generate redox active complexes, (b) fine-tune the spin states
27
2
9
of nickel(II), and (c) generate hyperactive catalysts for the
16,30,31
ring-opening polymerization of lactide into polylactide.
In looking to develop the next generation of related Schiff base
macrocycles, we identified in a recent literature review that
there were no Schiff base macrocyclic systems based on 1,8-
Received: October 27, 2017
©
XXXX American Chemical Society
A
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Inorganic Chemistry
Article
Scheme 1. Literature Routes to 1,8-Diformyl-carbazoles 3a
Scheme 2. New Route to 1,8-Diformyl-carbazoles 3a (R =
32,37,38
33,34
33a
(R = tBu),
3b (R = H),
and 3c (R = Me)
tBu) and 3b (R = H) and the Subsequent Direct Synthesis of
tBu
Two Metal-Free [2 + 2] Schiff Base Macrocycles, H L and
H2L
2
H
1
,8-dibromo-carbazole 1a was converted into 1,8-dibromo-
carbazole 1b, in one step in good yield (70%) and short
a
The new route reported herein is shown in Scheme 2.
reaction time, using a reverse Friedel crafts reaction (the
protocol used is based on a related literature transformation ).
41
These two 1,8-dibromo-carbazoles 1 are then reacted with
of the 3a (3,6-di-tert-butyl substituted) or 3b (3,6-unsubsti-
styrene in a Heck coupling, under an atmosphere of N , using a
2
tuted) 1,8-diformyl-carbazoles with 1,2-diaminoethane gener-
palladium catalyst, to access the 1,8-distyryl-carbazoles 2.
Considerable optimization of this reaction led to identification
of the best conditions: a solvothermal reaction of a suspension
of the reagents in a small volume of THF and triethylamine,
sealed in a Teflon tube inside a steel pressure vessel and heated
to well beyond the boiling point of THF. This produced both
1,8-distyryl-carbazoles 2 in greater than 70% yield and was
scalable (>2 g per 50 mL pressure vessel).
tBu
H
ates two [2 + 2] macrocycles, H2L
and H L , respectively
2
(
Scheme 2), which show selective and strong turn-on
H
fluorescence in the presence of zinc(II) ions. Indeed, H2L
shows potential as a competitively selective, sensitive and strong
turn-on blue fluorescence sensor of zinc(II) ions, highlighting one
of the many new and exciting applications that we hope to
access through this new family of carbazole-based Schiff base
macrocycles.
Synthesis of these two distyryl compounds (2) places double
bonds in the positions required in order to access the required
dialdehydes by ozonolysis, a route that we and others had
successfully taken to access another interesting head unit, 3,6-
RESULTS AND DISCUSSION
■
Synthesis of 1,8-Diformyl-carbazoles (3). Previous work
with 1,8-diformyl-carbazole head units 3 has relied on the use
of two different, but nontrivial, time-consuming and scale
limiting synthetic routes to access them (Scheme 1); hence,
42,43
diformylpyridazine.
A DCM solution of the respective 1,8-
distyryl-carbazole, at −78 °C, was bubbled with O /O
3
2
(Caution!) for about 5 min (until blue-green color indicates
saturation by ozone), then purged with N2 before being
quenched with dimethyl sulfide. After warming the solution to
room temperature, the solvent was removed and column
chromatography used to purify the solid. The desired 1,8-
diformyl-carbazoles 3a and 3b were obtained as bright yellow
and orange-yellow solids, respectively, in good to high yields
32−34,38
very few such studies have been reported to date.
To
alleviate this problem, a new synthetic route starting from
known 1,8-dibromo-carbazoles 1 was devised, in which they are
converted into the desired 1,8-diformyl-carbazoles 3 by means
of a Heck coupling, followed by ozonolysis (Scheme 2). We
illustrate this approach here, with the preparation of two such
1
1,8-diformyl-carbazoles, 3,6-di-tert-butyl substituted 3a and 3,6-
70−90% (see the SI, Figures S1−S8 for H NMR spectra of all
unsubstituted 3b.
compounds reported in this paper).
The two 1,8-dibromo-carbazole starting materials employed
Crystal Structures of 1,8-Diformyl-carbazoles 3a and
3b. Single crystals of both dialdehydes were grown by slow
evaporation of chloroform solutions and were analyzed by X-
ray diffraction (Figure 1; also see the SI, Table S1 and Figures
S9−S12 for all crystallographic details). Both contain the whole
molecule in the asymmetric unit, with both of the aldehyde
39
here, 3,6-di-tert-butyl-1,8-dibromo-carbazole 1a and 1,8-
4
0
dibromo-carbazole 1b, are both literature compounds.
However, the reported synthesis of 1b involved multiple
steps from carbazole and had a low overall yield, so an
alternative route is employed here. Specifically, 3,6-di-tert-butyl-
B
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Article
half of the overall molecule. The structure shows the two rigid
head units of the macrocycle, with the planes of the two head
units running parallel. The pair of imine nitrogen atoms (N2
and N3A; N2A and N3) face in toward the proton (H1; H1A)
of the carbazole amine between them due to forming a
bifurcated hydrogen bond (Figure 2).
Synthesis of Dizinc(II) Complex 5b. The neutral dizinc
H
complex [Zn L (OAc) ] (5b) was prepared by reaction of the
2
2
H
metal-free macrocycle H2L with 2 equiv of zinc(II) acetate
Figure 1. Crystal structures of 3b (left) and 3a·CHCl (right; solvent
of crystallization not shown). Thermal ellipsoids drawn at 50%
probability.
3
and 2 equiv of triethylamine in refluxing CHCl :MeOH (1:1).
3
The product was isolated as an analytically pure bright yellow
solid by removing the solvents, washing the crude solid with
ice-cold methanol, and filtering.
As zinc(II) is diamagnetic, the 1H NMR spectrum of
oxygen atoms (O1/O2) facing inward and hydrogen bonding
to the amine proton (N1-H) of the carbazole head unit.
Synthesis of [2 + 2] Schiff Base Macrocycles. With
these key aldehydes, 3, now readily available in large quantities,
forming a wide range of metal-free Schiff base macrocycles (and
H
[
Zn L (OAc) ] was obtained, in CDCl as it is highly soluble
2
2
3
in this solvent (Figure S8). This confirms the loss of the NH
proton. It also reveals a slight upfield shift in the imine proton
H
signal in the zinc complex relative to that seen for H L , and
2
32,44
that the 8 alkyl linker CH hydrogen atoms appear as two 4H
2
noncyclic ligands) from them is being actively explored,
doublets in the complex, whereas they were a single singlet (all
and the first examples of [2 + 2] macrocycles are presented
herein.
H
equivalent) in H L . The latter observation, that the 8H singlet
2
resolves as two 4H peaks, is because there is now one signal for
The direct, i.e., metal-free, synthesis of macrocycles from a
dialdehyde head unit and diamine lateral component is usually
challenging, as a variety of different sized macrocycles as well as
oligomeric materials are possible. Added to this, Schiff base
macrocycles are not always stable metal-free. However, the
direct synthesis of both [1 + 1] and [2 + 2] Schiff base
macrocycles was successful for the analogous diphenylamine
each position in space of the two CH protons, either up or
2
down, relative to the 1,3 acetate bridge (see later, Figure 3).
2
8,30,45
head units,
as well as for [1 + 1] Schiff base carbazole
3
2
macrocycles, so it was attempted here also.
Condensation of a 1:1 ratio of the head unit, 3a or 3b, and
,2-ethylene diamine in a small volume of refluxing ethanol
1
proved successful, with the [2 + 2] macrocycles precipitating on
formation. The precipitate also included a small amount of
insoluble material, likely to be polymeric in nature, which could
be easily removed after dissolving the macrocycle in chloro-
form, then simply filtering to remove the byproduct. This
worked exceedingly well for both 3a and 3b, with the respective
H
Figure 3. Crystal structure of [Zn L (OAc) ], hydrogen atoms
2
2
removed for clarity; symmetry operation A is 1 − x, 1 − y, 1 − z.
Thermal ellipsoids drawn at 50% probability.
tBu
H
[
2 + 2] macrocycles, H2L and H L , obtained as analytically
2
pure pale yellow solids in yields of >80%.
H
The cryospray mass spectrum shows a major peak at 655.0750
Crystal Structure of H L . Single crystals of the macro-
2
H
+
H
m/z corresponding to [Zn L (Cl)] , confirming the presence
cyclic ligand H L were grown by diethyl ether vapor diffusion
2
2
of the dizinc [2 + 2] Schiff base macrocyclic core (adventitious
chloride obtained from surroundings). The complex was also
characterized by microanalysis, UV−vis spectroscopy (Figure
S13), and X-ray crystallography (see the Experimental Section
and the SI for characterization details).
into a 1:1 chloroform:ethanol solution of the compound and
analyzed by X-ray diffraction (Figure 2; also the SI, Table S1,
Figures S9 and S10). The asymmetric unit for this structure is
Crystal Structure of Dizinc(II) Complex 5b. Single
H
crystals of [Zn L (OAc) ] (5b) are grown by slow cooling of
2
2
the reaction solution (see the SI, Figure S9). This neutral
complex crystallized with half the molecule in the asymmetric
unit and the other half generated by inversion. Hence, both of
the bridging acetate anions are disordered by symmetry over
two sites (50:50): one forms a 1,3-bridge and the other a 1,1-
bridge (Figure 3; also the SI, Figure S11).
The structure confirms that loss of the carbazole amine
protons (N1-H) generates two tridentate pockets that bind the
two zinc(II) centers. Each zinc(II) center has an N O donor
3
2
set, but due to the acetate disorder, one of them is square
pyramidal (τ = 0.08) while the other is closer to trigonal
bipyramidal (τ = 0.59). Note τ = 0 for a square pyramid versus
1 for a trigonal bipyramid. The macrocycle conformation in
this complex is almost identical to that of the free macrocycle,
46
H
Figure 2. Crystal structure of H L ; symmetry operation A is 1 − x, 1
2
−
y, 1 − z. Thermal ellipsoids drawn at 50% probability.
C
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with only a slight variation in the alkyl chain conformations in
base). In general, the zinc-induced fluorescence of Schiff base
macrocycles is proposed to be due to the chelated-enhanced
fluorescence effect (CHEF), an effect that zinc is particularly
good at inducing (whereas heavy metal ions and paramagnetic
order to accommodate the pair of, μ - and μ -acetate bridged,
1
,1
1,3
zinc(II) centers (SI, Figures S11 and S12).
Fluorescence Testing. Zinc ions are essential to life and
play a wide range of roles throughout biology, so the
development of chemosensors capable of visualizing them by,
preferably “turn-on”, fluorescence has been the subject of
71−73
metal ions usually do not).
In the present case, it is likely
that the zinc(II) ions are binding to the lone pairs of electrons
of the imine nitrogen atoms which were previously blocking the
47−51
74
considerable activity.
Recent work into sensing zinc ions
photoinduced electron-transfer effect (PET), allowing fluo-
by chelation enhancement of fluorescence has utilized both
rescence to occur.
5
2−57
58−61
acyclic
and macrocyclic
ligands as probes. Macro-
This result, of four zinc ions interacting with each
macrocycle, was interesting as it had been expected that only
two zinc(II) ions would do so, by coordinating in the binding
pockets of the macrocycle in the manner seen for the isolated
dizinc complex (Figure 3). To probe this result further, a H
NMR titration study in d-DMF was undertaken, looking at
cyclic probes, such as well-known Robson and corrole
macrocycles, are favored due to stabilization of the resulting
complex by the macrocyclic effect. In the case of such chelating
agents, the incorporated fluorophore is often a large area of
aromatic conjugation, with a couple of examples of Schiff base
chemistry being employed to extend the conjugation through
the imine double bond as well as provide a donor atom for
1
H
H
solutions of (a) H L , (b) H L with 2 equiv of zinc(II)
2
2
H
acetate, (c) H L with 4 equiv of zinc(II) acetate, and (d) the
2
5
2,62−64
binding the zinc ion.
In the other class, the
isolated dizinc complex 5b (see Figures S17−S21). This study
was limited by the very poor solubility of the macrocycle in
DMF (the only solvent that both the macrocycle and metal
salts dissolved in), with long 1H NMR acquisition times
(hours) required. Nevertheless, the H NMR spectra of these
solutions are informative. In particular, for the solutions
fluoroionophores, one of the under-utilized fluorophores is
6
5,66
carbazole,
which has been widely utilized in other areas of
6
7−70
chemistry due to its excellent photophysical properties.
1
Hence, the observation of strong blue fluorescence by the
isolated dizinc carbazole complex 5b when irradiated with 335
nm light (Figure 4) prompted testing of the two macrocycles as
H
containing 2 or 4 equiv of Zn(OAc) with H L , (a) there is
2
2
almost no difference between the spectra, (b) while broad, an
NH proton signal is seen, and (c) a minor species of apparently
lower symmetry is also seen in both of those spectra (Figures
S19 and S20). Finally, the peaks of the major species in those
two solutions were almost identical to those observed for the
isolated dizinc complex 5b.
To further probe the role of the acetate anion in the
formation of the 4:1 Zn to H2LH species (maximum
fluorescence, Figures S15 and S16), the fluorescence titration
study was repeated with zinc(II) tetrafluoroborate (Figure S22).
This reveals interesting changes in behavior, with (a) the initial
0
.4 equiv of zinc(II) tetrafluoroborate gave a much larger
percentage of the maximum fluorescence intensity (at λmax
70 nm) compared to the zinc(II) acetate titration, and (b) the
=
4
H
H
maximum fluorescence intensity was achieved upon addition of
only 2 equiv of zinc(II) tetrafluoroborate (see Figures S16, S22,
and S23). These results are consistent with the acetate anion
Figure 4. UV−vis spectra of H L (dotted blue) and [Zn L (OAc) ]
2
2
2
(
dotted red) in DMF (left axis, dotted curves) and the fluorescence
spectra, 350−600 nm, of H L with 4 equiv of zinc(II) (blue) and
Zn L (OAc) ] (red), irradiated at 335 nm (right axis, solid curves).
H
2
H
H
[
playing a key role in the formation of the 4:1 species with H2L
2
2
in solution, probably by coordination to zinc(II), which
tetrafluoroborate is unlikely to do instead, hence leading to
the observed 2:1 species in that case.
The earlier fluorescent testing with zinc(II) acetate was
performed without added base. In contrast, 2 equiv of
potential turn-on fluorescence chemosensors for zinc(II) ions.
−9
−1
Initial tests of 1.1 × 10 mol L DMF solutions (DMF was
chosen as it was found to be the only solvent in which both the
macrocycle and metal salts were soluble) of each of the two
macrocycles with 4 equiv of zinc(II) acetate (no additional
base), exciting at 335 nm, resulted in strong turn-on blue
fluorescence, with a slight shift in λmax (510 nm) compared to
the dizinc complex (460 nm). Both visual and analytical
detection of zinc(II) ions is possible at nanomolar concentrations.
triethylamine was added to prepare the structurally charac-
H
terized dizinc complex [Zn
L (OAc)
], in which the carbazole
2
2
N-H groups have been deprotonated, facilitating binding of two
zinc(II) ions in the resulting pair of tridentate pockets of the
macrocycle (Figure 3; also the SI, Figure S11). For
completeness, 2 equiv of zinc(II) acetate was added to a
H
tBu
H L gave a more intense fluorescence (40.24 a.u.) than H L
2
2
H
(
6.44 a.u.; see Figure S14), so only the stronger sensor, the
2
DMF solution of [Zn L (OAc) ]: this does not alter the
2
2
H
H L macrocycle, was tested further.
fluorescent response (λmax 460 nm, Figure S24).
33
The fluorescence intensity at 510 nm was monitored as the
amount of zinc(II) acetate added to a DMF solution of H2LH
was increased from 0 to 10 equiv. From 0 to 4 equiv of zinc(II),
the fluorescence intensity increased linearly, after which the
addition of further equivalents of zinc(II) produced no
significant change (Figures S15 and S16). This is consistent
with the tetra-imine macrocycle interacting with one zinc(II)
ion per imine nitrogen atom, under these conditions (no added
As deprotonation of carbazole can be slow, the effect of
added base was probed in more detail, over time, as follows. To
a DMF solution that contained 2 equiv of zinc(II) acetate per
H
H2L was added 2 equiv of base (triethylamine), and the
fluorescence spectra were monitored over the subsequent 9 h
(Figures S25 and S26; after 9 h, the macrocycle started to break
down and therefore fluorescence was lost). The increase in
intensity of the peak at 460 nm over time after base addition
D
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reflects the macrocycle deprotonating and forming a dizinc
complex (Figure S27). Clearly, the macrocycle still functions as
an effective fluorescent zinc sensor under basic conditions, with
only a shift in λmax and change in maximum equivalents of zinc
to allow for if quantification is required.
H2L was then tested against a range of other first row
transition metal(II) ions, as well as the most common biological
dications, calcium and magnesium (Figures 5 and 6). The
through the design and application of a new synthetic route.
This breakthrough enables ready access to larger quantities of 3
which really opens up the development of exciting new
generations of carbazole-based Schiff base ligands and
complexes, which have potential applications in catalysis,
redox, photophysics, and sensing applications. Herein, this
potential is illustrated by the synthesis of two metal-free [2 + 2]
H
H
tBu
macrocycles, H L and H L , and a strongly blue fluorescent
2
2
H
dizinc macrocyclic complex, [Zn L (OAc) ] (λ = 460 nm).
Subsequent fluorescence studies showed that the H2L
2
2
max
H
macrocycle produces intense turn-on blue fluorescence in the
presence of zinc(II) ions at very low, nanomolar, concen-
trations. In competitive studies, H2LH also shows strong
selectivity for zinc(II) ions over other first row transition
metal(II) ions (Mn−Cu) as well as other biologically relevant
H
metal(II) ions (Ca and Mg). Testing the H L macrocycle with
2
added base showed retention of the blue fluorescence, but with
a decrease in the λmax toward that of the isolated dizinc
complex. These fluorescence results are very promising, but
clearly the solubility of the system needs to be improved
significantly, preferably to allow testing in water (rather than
being limited to DMF as at present). However, a wary eye will
also need to be kept open to the stability of the system in such
solvents. The increased solubility in water may be achievable by
appropriate choice of R substituents, such as polyethylene
glycol (PEG) “tails”, at the 3- and 6-positions of the carbazole
rings. In summary, this new synthetic route to 1,8-diformyl-
carbazoles (3) has unlocked the door to the synthesis of many
exciting new carbazole-based Schiff base macrocycles and
complexes.
Figure 5. A series of 2.0 × 10 mol L−1 DMF solutions of H L and
−
7
H
2
2+
M , above in natural light and below under 366 nm light.
EXPERIMENTAL SECTION
Chemicals were used as received, including PdCl (PPh ) and
dimethylsulfide (DMS), except for the following: 3,6-di-tert-butyl-
■
2
3 2
1
,8-dibromo-carbazole was prepared according to the literature
39
method, and NBS was recrystallized from water before use.
Triethylamine was dried over KOH pellets before use. Dry THF
and toluene were dried by a Pure Solv MD-6 solvent purification
system; all other solvents used were reagent grade and used without
further purification. Both Heck coupling reactions were performed
under an atmosphere of nitrogen. Ozone was produced by an
Envirozone Ozonator model VT-5.
Figure 6. Competitive binding studies of 6.8 × 10−9 mol L−1 H L in
H
2
DMF, with 4.6 equiv of both Zn(OAc) and M(OAc) (M = Ca, Mg,
2
2
Mn to Cu), λex = 335 nm, λem = 510 nm.
1
,8-Dibromo-9H-carbazole (1b). To a solution of 1,8-dibromo-
results show excellent fluorescent selectivity for zinc(II), with at
least 5 times greater emission signal for zinc(II) at λmax = 510
nm than for any of the other transition metal(II) ions. The next
strongest fluorescence signals came from the two biologically
relevant dications, calcium and magnesium, but these were still
weak relative to that of zinc.
3
,6-di-tert-butyl-9H-carbazole (1.1254 g, 2.574 mmol) in dry toluene
(50 mL) was added anhydrous AlCl (0.9928 g, 7.446 mmol) in small
portions. The flask was capped and the orange solution was stirred at
RT. After 1 h, the solution had changed to a dark green-brown color.
After stirring for 4 h, the reaction was quenched and washed with
water (2 × 50 mL) and the aqueous phase was further extracted into
DCM (3 × 50 mL). The organic fractions were dried over MgSO4,
filtered, and the solvent was removed under reduced pressure, yielding
a pale orange, oily solid. The crude material was dissolved in Et O (3
mL) and precipitated by refrigeration (4 °C), resulting in an off-white
solid (0.5824 g, 70%) that was filtered and dried under vacuum.
3
Competition studies, using 1:4:4 mixtures of macrocycle:zinc-
(
II) ion:other metal(II) ion, were employed to further test the
H
2
selectivity of H L for zinc(II) ions (Figure 6). The macrocycle
2
clearly strongly favors interacting with zinc(II) ions over the
other first row transition metal(II) ions: only cobalt(II) and
copper(II) ions compete to some extent with the zinc(II) ions,
as shown by a slightly lower fluorescence intensity than is
observed when only zinc(II) is present. The result of the
copper(II) experiment is particularly interesting as copper(II)
ions are expected to have a stronger binding affinity than
zinc(II) ions according to the Irving−Williams series.
−
ESI(−) MS (m/z) = 321.8895 [C H NBr ] . Anal. Calcd for
12
6
2
C H NBr : C, 44.35; H, 2.17; N, 4.31. Found: C, 44.62; H, 2.08; N,
1
2
7
2
1
4.11%. H NMR (400 MHz, CDCl ) δ (ppm) = 8.320 (NH, s, 1H),
3
7.963 (4CzH, d[J = 7.6], 2H), 7.601 (CzH, dd [J = 1.2,8.0], 2H),
7
=
1
(
(
.145 (CzH, t [J = 8.0], 2H). 13C NMR (100 MHz, CDCl ) δ (ppm)
3
137.84 (Cz), 128.85 (Cz), 124.94 (Cz), 121.33 (Cz), 119.95 (Cz),
04.56 (Cz). IR (KBr): (cm ) = 3454 (w), 1603 (w), 1559 (w), 1494
m), 1424 (s), 1298 (s), 1228 (m), 1183 (s), 1144 (w), 890 (w), 830
w), 757 (s), 724 (s), 678 (w), 568 (w).
1,8-Bis((E)-styryl)-3,6-di-tert-butyl-9H-carbazole (2a). 1,8-Di-
−1
CONCLUSION
Key 1,8-diformyl-carbazole compounds (3a and 3b) have been
synthesized in reliable, high yielding, and scalable reactions
■
bromo-3,6-di-tert-butyl-9H-carbazole (0.9997 g, 2.287 mmol), styrene
(609.1 mg, 5.849 mmol), PdCl (PPh ) (40.8 mg, 0.058 mmol),
2
3 2
E
DOI: 10.1021/acs.inorgchem.7b02763
Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry
Article
triethylamine (5 mL), and dry THF (5 mL) were added to a 25 mL
(m), 1467 (m), 1443 (w), 1395 (w), 1366 (w), 1316 (w), 1267 (w),
1237 (w), 1215 (m), 1204 (w), 1177 (w), 1138 (w), 1110 (w), 1099
(w), 1053 (m), 1023 (w), 946 (w), 914 (w), 879 (m), 816 (w), 781
(w), 754 (w), 728 (w), 710 (w), 669 (w), 639 (s), 623 (s), 567 (w).
1,8-Diformyl-9H-carbazole (3b). Behind a blast shield, a light
yellow solution of 1,8-bis((E)-styryl)-9H-carbazole (103.2 mg, 0.462
mmol) in DCM (35 mL) was cooled to −78 °C (dry ice/acetone) and
then subjected to O /O (Caution! Highly reactive, potentially
heavy-walled reaction chamber, degassed with N and tightly closed.
2
The mixture was heated to 115 °C for 24 h (Caution! Pressure). After
cooling, water (20 mL) was added and the reaction mixture was
extracted with DCM (3 × 20 mL). The solvent was removed under
reduced pressure. The resulting solid was taken up in DCM (ca. 2 mL)
and run through a pad of silica (20 mL) using DCM. The solvent was
removed under reduced pressure and the resulting crude product was
3
2
washed with cold cyclohexane, yielding a bright-yellow solid (0.785 g,
explosive ozonides being formed) gas until O3 saturation in the
DCM (<5 min). The resulting greenish solution was purged with
nitrogen, resulting in a yellow solution to which DMS (ca. 0.5 mL)
was added, resulting in a darker yellow solution. The solution was
allowed to return to RT and the solvent was removed under reduced
pressure, yielding a dark orange solid. The crude material was purified
by column chromatography through silica (30 mL) in DCM, yielding
+
7
1%). ESI(+) MS (m/z) = 506.2827 [C H NNa] . Anal. Calcd for
36
37
C H N·0.5H O: C, 87.76; H, 7.77; N, 2.84. Found: C, 87.40; H,
7
3
6
37
2
1
.52; N, 2.81%. H NMR (400 MHz, CDCl ) δ (ppm) = 8.296 (NH,
3
s, 1H), 8.043 (4CzH, d [J = 1.5], 2H), 7.659 (CzH, d [J = 1.5], 2H),
7
.637 (o-StyH, d [J = 7.6], 4H), 7.488 (Cz-CHCH, d [J = 16], 2H),
7
.424 (m-StyH, t [J = 7.6], 4H), 7.314 (p-StyH, t [J = 7.2], 2H), 7.284
13
(
Cz-CHCH, d [J = 16], 2H), 1.508 (tBu, s, 18H). C NMR (100
the desired product as a yellow-orange solid (R 0.21, 58.3 mg, 95%).
f
MHz, CDCl ) δ (ppm) = 143.25 (Cz), 137.67 (Cz-CHCH-C),
Anal. Calcd for C H NO : C, 75.33; H, 4.06; N, 6.27. Found: C,
3
14
9
2
1
1
1
36.41 (Cz), 128.95 (m-Sty), 130.08 (Cz-CHC), 127.91 (p-Sty),
75.06; H, 4.05; N, 6.00%. ESI(+) MS (m/z) = 246.0527 [C H -
14 9
+
1
26.68 (o-Sty), 125.41 (Cz-CHC), 124.50 (Cz), 121.79 (Cz),
NO Na] . H NMR (400 MHz, CDCl ) δ (ppm) = 11.724 (NH, s,
2
3
−1
20.59 (Cz), 116.32 (Cz), 34.95 (tBu), 32.21 (tBu). IR (KBr): (cm )
1H), 10.253 (CHO, s, 2H), 8.365 (Cz, dt [J = 8.0, 0.8], 2H), 7.918
1
3
=
3482 (w), 3028 (w), 2951 (s), 2928 (w), 2865 (m), 1599 (m), 1487
(Cz, dd [J = 7.2, 1.2], 2H), 7.451 (Cz, t [J = 7.6], 2H). C NMR (100
(
s), 1393 (w), 1361 (m), 1356 (w), 1280 (m), 1244 (m), 951 (s), 868
MHz, CDCl ) δ (ppm) = 192.82 (CHO), 138.48 (Cz), 132.10 (Cz),
3
(
m), 758 (m), 737 (s), 691 (s), 639 (w), 553 (w).
126.98 (Cz), 123.55 (Cz), 120.61 (Cz), 120.16 (Cz). IR (KBr):
−1
1
,8-Bis((E)-styryl)-9H-carbazole (2b). 1,8-Dibromo-9H-carba-
(cm ) = 3432 (m), 2811 (w), 2737 (w), 1675 (s), 1611 (w), 1591
(s), 1494 (m), 1440 (w), 1385 (m), 1326 (m), 1305 (w), 1222 (m),
1189 (m), 1114 (s), 1066 (w), 1028 (m), 810 (m), 782 (s), 775 (m),
715 (w), 633 (s).
zole (336.7 mg, 1.036 mmol), PdCl (PPh ) (15.3 mg, 0.019
mmol), styrene (328.0 mg, 3.149 mmol), triethylamine (5 mL), and
dry THF (5 mL) were added to a 25 mL heavy-walled reaction
2
3 2
tBu
chamber, degassed with N and tightly closed. The reaction chamber
H2L (4a). To a pale yellow refluxing solution of 1,8-diformyl-3,6-
2
was heated at 115 °C for 28 h (Caution! Pressure). After cooling,
water (30 mL) was added and the reaction mixture was extracted with
DCM (2 × 25 mL). The combined organic phase was dried over
magnesium sulfate and filtered. The solvent was removed under
reduced pressure and the resulting powder was loaded onto a column
loaded with silica (30 mL) in DCM which was eluted, which yielded a
di-tert-butyl-9H-carbazole 3a (40 mg, 0.119 mmol) in ethanol (10 mL)
was added ethylene diamine (7.2 mg, 0.120 mmol) as an ethanol
solution (1 mL). The resulting yellow solution was refluxed for 4 h,
initial precipitation appearing after 1 h. After cooling to room
temperature, the precipitate was isolated by filtration and washed with
ethanol (20 mL) to give the product as a pale yellow solid (38 mg,
+
bright-yellow solid (306.8 mg, 80%). ESI(−) MS (m/z) = 370.1604
88%). ESI (+) MS (m/z) = 741.4675 [C H N Na] . Anal. Calcd For
48
58
6
−
[
C H N] . Anal. Calcd for C H N: C, 90.53; H, 5.70; N, 3.77.
C H N ·0.5EtOH: C, 79.31; H, 8.29; N, 11.33. Found: C, 79.19; H,
28
20
28 21
48 58
6
1
1
Found: C, 90.40; H, 5.63; N, 3.89%. H NMR (400 MHz, CDCl ) δ
8.38; N, 11.31. H NMR (400 MHz, CDCl ) δ (ppm) = 12.079 (NH
3
3
(
(
7
7
2
ppm) = 8.459 (NH, s, 1H), 8.020 (CzH, d [J = 7.6], 2H), 7.637
CzH, dd [J = 7.6, 0.8], 2H), 7.630 (o-StyH, dd [J = 8.0, 1.4], 4H),
(5), s, 1H), 8.570 (CHN (3), s, 2H), 7.818 (CzH (1/2), s, 2H),
6.962 (CzH (1/2), s, 2H), 4.524 (CH (4), s, 4H), 1.285 (tBu (6), s,
2
3
−1
−1
.489 (Cz-CHCH, d [J = 16], 2H), 7.427 (m-StyH, t [J = 7.6], 4H),
18H). UV−vis, (DMF): λ
(ε/dm mol cm ) = 300(14830),
max/nm
.323 (p-StyH, tt [J = 7.2, 1.2], 2H), 7.296 (Cz-CHCH, d [J = 16],
332(17454), 368(11297).
H), 7.295 (CzH, t [J = 7.6], 2H). 13C NMR (100 MHz, CDCl ) δ
H L (4b). To a pale yellow refluxing solution of 1,8-diformyl-9H-
H
3
2
(
ppm) = 137.72 (Cz), 137.50 (Cz-CHCH-C), 130.69 (Cz-CH
carbazole 3b (50 mg, 0.224 mmol) in ethanol (20 mL) was added
ethylene diamine (13.4 mg, 0.230 mmol) as an ethanol solution (1
mL). The resulting yellow solution was refluxed for 4 h, initial
precipitation appearing after 1 h. After cooling to room temperature,
the precipitate was isolated by filtration and washed with ethanol (20
mL) to give the product as a pale yellow solid (48 mg, 87%). ESI (+)
CH), 128.98 (m-Sty), 128.08 (p-Sty), 126.75 (o-Sty), 124.41 (Cz),
1
6
(
1
7
24.39 (Cz-CHCH), 123.78 (2/7-Cz), 121.40 (1/8-Cz), 120.42 (3/
-Cz), 119.97 (4/5-Cz). IR (ATR diam.): (cm ) = 3464 (w), 3025
−1
w), 1594 (w), 1491 (m), 1448 (w), 1426 (m), 1420 (m), 1337 (m),
312 (m), 1221 (m), 1168 (w), 1061 (w), 957 (m), 950 (m), 771 (s),
53 (w), 733 (s), 689 (s), 585 (w), 564 (w), 549 (w), 476 (w).
+
+
MS (m/z) = 495.2304 [C H N ] , 517.2119 [C H N Na] . Anal.
32
27
6
32 26
6
1
,8-Diformyl-3,6-di-tert-butyl-9H-carbazole (3a). Behind a
Calcd For C H N ·0.2EtOH: C, 77.24; H, 5.44; N, 16.68. Found: C,
3
2
26
6
1
blast shield, a light yellow solution of 1,8-bis((E)-styryl)-3,6-di-tert-
butyl-9H-carbazole (307.2 mg, 0.635 mmol) in DCM (50 mL) was
cooled to −78 °C (dry ice/acetone) and then subjected to O /O
77.19; H, 5.45; N, 16.49. H NMR (400 MHz, CDCl ) δ (ppm) =
3
13.343 (NH (5), s, 1H), 8.678 (CHN (3), s, 2H), 8.189 (CzH (1/
2), d [J = 8.0], 2H), 7.570 (CzH (1/2), d [J = 7.2], 2H), 7.300 (CzH
(6), t [J = 7.2], 2H), 4.284 (CH (4), s, 4H). UV−vis, (DMF): λ
3
2
(
Caution! Highly reactive, potentially explosive ozonides being
2
max/nm
(ε/dm3 mol
−1
cm ) = 285(18313), 315(22854), 355(8768),
−1
formed) gas until O saturation in the DCM (<5 min). The resulting
3
greenish solution was purged with nitrogen, resulting in a yellow
solution to which DMS (0.5 mL) was added, resulting in a darker
yellow solution. The solution was allowed to return to RT and the
solvent was removed under reduced pressure, yielding a dark orange
solid. The crude material was purified by column chromatography
369(11071).
H
H
[Zn L (OAc) ]·CHCl (5b). To a refluxing solution of H L (110
2
2
3
2
mg, 0.222 mmol) in CHCl was added a methanol solution (60 mL) of
3
zinc(II) acetate dihydrate (110 mg, 0.501 mmol). To the resulting pale
yellow solution was added triethylamine (45 mg, 0.445 mmol), giving
a bright yellow solution that was refluxed for 16 h. After cooling, the
solvent was removed to give a bright yellow solid which was washed
with methanol (100 mL) to give the product as a bright yellow solid
(135 mg, 83%). Anal. Calcd For Zn L (OAc) ·0.4CHCl : C, 55.66; H,
3.90; N, 10.70. Found: C, 55.56; H, 4.04; N, 10.54. ESI (+) MS (m/z)
through silica (50 mL) in DCM, yielding a light-yellow solid (R 0.48,
f
1
4
3
1
2
46.5 mg, 69%). Anal. Calcd for C H NO : C, 78.77; H, 7.51; N,
22 25 2
.18. Found: C, 78.87; H, 7.70; N, 4.13%. ESI(+) MS (m/z) =
+
1
H
58.1746 [C H NO Na] . H NMR (400 MHz, CDCl ) δ (ppm) =
22
25
2
3
2
2
3
1.450 (NH, s, 1H), 10.235 (CHO, s, 2H), 8.405 (CzH, d [J = 2.0],
H), 7.940 (CzH, d [J = 2.0], 2H), 1.515 (tBu, s, 18H). 13C NMR
= 655.0750 [C H N Zn Cl] . H NMR (400 MHz, CDCl ) δ (ppm)
+
1
3
2
24
6
2
3
(
(
(
100 MHz, CDCl ) δ (ppm) = 193.09 (CHO), 143.30 (Cz), 137.12
= 8.563 (CHN, s, 2H), 8.328 (CzH, d [J = 6], 2H), 7.562 (CzH, d
3
Cz), 129.61 (Cz), 123.64 (Cz), 123.58 (Cz), 120.12 (Cz), 34.98
[J = 6], 2H), 7.251 (CzH, t [J = 6.4], 2H), 4.187 (CH , d [J = 8],
2
a
−1
3
tBu), 32.05 (tBu). IR (ATR diam.): (cm ) = 3429 (m), 2954 (m),
2H), 3.987 (CH , d [J = 8], 2H). UV−vis, (DMF): λmax/nm (ε/dm
2
b
−1 −1
2
899 (w), 2866 (w), 2792 (w), 1671 (m), 1617 (w), 1590 (m), 1481
mol cm ) = 309(20925), 335(22253), 368(19092), 412(19450).
F
DOI: 10.1021/acs.inorgchem.7b02763
Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry
Article
H
Single crystals of [Zn L (OAc) ] were grown by slow cooling of the
cycles “Old Complexes Offer New Attractions. Coord. Chem. Rev.
2015, 296, 125−152.
2
2
reaction solution to room temperature.
(
12) Brooker, S.; Kelly, R. J.; Plieger, P. G. A pyridazine Schiff-base
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.inorg-
chem.7b02763.
macrocycle hosts a dicobalt centre in five different redox states:
■
I
II
evidence for a mixed valent Co Co species. Chem. Commun. 1998,
079−1080.
13) Szymczak, N. K.; Berben, L. A.; Peters, J. C. Redox rich dicobalt
*
S
1
(
macrocycles as templates for multi-electron transformations. Chem.
Commun. 2009, 6729−6731.
Additional crystallographic data; NMR and fluorescence
spectra (PDF)
(14) McCrory, C. C. L.; Uyeda, C.; Peters, J. C. Electrocatalytic
Hydrogen Evolution in Acidic Water with Molecular Cobalt
Tetraazamacrocycles. J. Am. Chem. Soc. 2012, 134, 3164−3170.
Accession Codes
(15) Chapovetsky, A.; Do, T. H.; Haiges, R.; Takase, M. K.;
CCDC 1542955−1542958 contain the supplementary crystal-
lographic data for this paper. These data can be obtained free of
charge via www.ccdc.cam.ac.uk/data_request/cif, or by email-
ing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
Marinescu, S. C. Proton-Assisted Reduction of CO2 by Cobalt
Aminopyridine Macrocycles. J. Am. Chem. Soc. 2016, 138, 5765−5768.
(16) Thevenon, A.; Romain, C.; Bennington, M. S.; White, A. J. P.;
Davidson, H. J.; Brooker, S.; Williams, C. K. Di-zinc lactide
polymerization catalysts: Hyper-activity by control of ligand
conformation and metallic cooperativity. Angew. Chem., Int. Ed.
2
(
016, 55, 8680−8685 and inside front cover.
17) Brooker, S.; Plieger, P. G.; Moubaraki, B.; Murray, K. S. [Co
L(NCS) (SCN) ]:The first cobalt complex to exhibit both exchange
II
AUTHOR INFORMATION
Corresponding Author
E-mail: sbrooker@chemistry.otago.ac.nz.
■
2
2
2
coupling and spin crossover effects. Angew. Chem., Int. Ed. 1999, 38,
08−410 and front cover feature.
18) Brooker, S.; de Geest, D. J.; Kelly, R. J.; Plieger, P. G.;
*
4
(
ORCID
Sally Brooker: 0000-0002-5878-8238
Notes
The authors declare no competing financial interest.
Moubaraki, B.; Murray, K. S.; Jameson, G. B. Exchange coupled high-
spin, low-spin and spin-crossover dicobalt(II) complexes of a
pyridazine-containing Schiff-base macrocycle: control of cobalt(II)
spin state by choice of axial ligands. J. Chem. Soc., Dalton Trans. 2002,
2
(
080−2087.
ACKNOWLEDGMENTS
■
19) Yamashita, A.; Watanabe, A.; Akine, S.; Nabeshima, T.; Nakano,
We thank the University of Otago (including award of a Ph.D.
scholarship to S.A.C.), the Division of Sciences (for the award
of a Ph.D. scholarship to S.J.M.), and the MacDiarmid Institute
for Advanced Materials and Nanotechnology for supporting
this research. We are grateful to the referees for constructive
suggestions which we took on board when revising our
manuscript.
III
II3
M.; Yamamura, T.; Kajiwara, T. Wheel-shaped Er Zn Single-
Molecule Magnet: a macrocyclic approach to designing magnetic
anisotropy. Angew. Chem., Int. Ed. 2011, 50, 4016−4019.
̈
(20) Feltham, H. L. C.; Lan, Y.; Klower, F.; Ungur, L.; Chibotaru, L.
F.; Powell, A. K.; Brooker, S. A non-sandwiched macrocyclic mono-
lanthanide single molecule magnet: the key role of axiality. Chem. -
Eur. J. 2011, 17, 4362−4365 and back cover.
(
21) McKee, V. Macrocyclic Complexes as Models for Nonporphine
Metalloproteins. Adv. Inorg. Chem. 1993, 40, 323−399.
22) Brooker, S. Complexes of thiophenolate-containing Schiff-base
macrocycles and their amine analogues. Coord. Chem. Rev. 2001, 222,
3−56.
23) Givaja, G.; Volpe, M.; Edwards, M. A.; Blake, A. J.; Wilson, C.;
Schroder, M.; Love, J. B. Dioxygen Reduction at Dicobalt Complexes
of a Schiff Base Calixpyrrole Ligand. Angew. Chem., Int. Ed. 2007, 46,
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24) Arnold, P. L.; Jones, G. M.; Odoh, S. O.; Schreckenbach, G.;
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