The synthesis and physical properties of novel polyaromatic profluorescent isoindoline nitroxide probes

Article abstract of DOI:10.1002/ejoc.200800597

New profluorescent mono- and di-isoindoline nitroxides (5, 11, 16 and 19) containing 9,10-diphenylanthracene and 9,10-bis(phenylethynyl)anthracene structural cores were synthesised by palladium-catalysed Suzuki and Sonogashira couplings. These nitroxide-f

Full text of DOI:10.1002/ejoc.200800597

FULL PAPER
DOI: 10.1002/ejoc.200800597
The Synthesis and Physical Properties of Novel Polyaromatic Profluorescent
Isoindoline Nitroxide Probes
Kathryn E. Fairfull-Smith[a] and Steven E. Bottle*[a]
Keywords: Nitroxides / Fluorescence / Radicals / Profluorescent probes
New profluorescent mono- and di-isoindoline nitroxides (5,
11, 16 and 19) containing 9,10-diphenylanthracene and 9,10-
bis(phenylethynyl)anthracene structural cores were synthe-
sised by palladium-catalysed Suzuki and Sonogashira coup-
lings. These nitroxide-fluorophore probes possess strongly
suppressed fluorescence, even in the presence of only one
nitroxide radical. Upon reduction, or reaction with other radi-
cals, normal fluorescence emission is returned. The signifi-
cant difference in fluorescence output between the nitroxides
and their corresponding diamagnetic analogues makes these
probes ideal tools for imaging polymer degradation using
fluorescence microscopy.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
cal trapping or redox activity, a diamagnetic species is
formed and normal fluorescence emission is restored. Thus,
nitroxide-fluorophore species have been utilized as very sen-
sitive probes for the detection of free-radical species.
Most of the nitroxide-fluorophore adducts synthesized
to date possess potentially labile linkages such as
esters,[5–7,11,14–18] amides[19–21] or sulfonamides.[22–25] Cleav-
age of the nitroxide moiety from the fluorophore restores
fluorescence independently from the radical reactions of the
nitroxide. Our group has focused on the synthesis of pro-
fluorescent nitroxides based on low reactivity, carbon atom-
only, extended aromatic frameworks. We have reported the
formation of an isoindoline nitroxide bearing a stilbene
fluorophore[26] and have also prepared an azaphenalene-
based profluorescent nitroxide.[27] Both of these fluoro-
phore-nitroxide adducts exhibit increased fluorescence fol-
lowing free-radical trapping to form an alkoxyamine.
Furthermore, we have reported the use of the novel profluo-
rescent nitroxide 1,1,3,3-tetramethyldibenzo[e,g]isoindolin-
2-yloxyl (TMDBIO) as a probe for monitoring the thermo-
oxidative degradation of polypropylene.[28–30] This probe,
which contains a phenanthrene fluorophore covalently
fused to a five-membered nitroxide-containing ring, allows
the detection by spectrofluorimetry of free radicals formed
during the “induction period” of polypropylene degrada-
tion.
Introduction
Nitroxides (aminoxyls) are stable free-radical species
which are finding increased use in a wide range of applica-
tions. Isoindoline nitroxides possess some advantages over
the more common nitroxide-containing piperidine or pyr-
rolidine units. The fused aromatic moiety imparts rigidity
on the ring system, making it less susceptible to ring-open-
ing reactions and providing greater chemical and thermal
stability in polymers.[1,2] Electron paramagnetic resonance
(EPR) linewidths for isoindoline nitroxides are also often
narrower,[3] leading to increased accuracy in EPR oximetry.
In addition, substitution onto the aromatic ring of the iso-
indoline system facilitates the synthesis of more complex
structures for a variety of applications with little impact on
the reactivity or stability of the nitroxide moiety.[4]
One common use for nitroxides is as sensitive probes for
the study of processes involving reactive free radical species.
Profluorescent nitroxides, which consist of a fluorophore
joined to a nitroxide moiety by a short covalent link, are
efficient quenchers of excited electronic states. As many
intermolecular quenching mechanisms rely on chance colli-
sions between an excited molecule and the nitroxide radical,
the linking together of these moieties increases the rate of
interaction which subsequently enhances the efficacy of
fluorescence quenching. Work by Blough[5–10] and Scai-
ano[11–13] has shown that fluorescence is significantly re-
duced in the presence of a nitroxide radical. Following radi-
In order to further expand the potential of the profluo-
rescent nitroxide technique to image polymer degradation
using fluorescence microscopy, we desired access to ni-
troxide-fluorophore probes possessing very high (masked)
quantum yields for maximum sensitivity for radical detec-
tion as well as excitation and emission profiles at longer
wavelengths outside the absorption bands of typical organic
chromophores.[31] Herein, we describe the synthesis and
[a] ARC Centre of Excellence for Free Radical Chemistry and Bio-
technology, Queensland University of Technology,
GPO Box 2434, Brisbane, QLD, 4001, Australia
Fax: +61-7-31381804
E-mail: s.bottle@qut.edu.au
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Eur. J. Org. Chem. 2008, 5391–5400
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5391

K. E. Fairfull-Smith, S. E. Bottle
FULL PAPER
physical properties of new profluorescent mono- and di-iso- tected product. In an attempt to improve the yield, the Su-
indoline nitroxides bearing the highly fluorescent cores of zuki–Miyaura cross-coupling reaction[36–38] was explored as
9,10-diphenylanthracene and 9,10-bis(phenylethynyl)an- an alternative synthetic route for the synthesis of BTMIOA
thracene. In addition, we examine the influence of either 5.
one or two nitroxide radicals on fluorescence suppression.
Both Hideg,[39–41] and Mayor[42] have shown that Suzuki
couplings can be performed in the presence of a nitroxide
moiety. Previous work in our group has shown Heck alken-
ylations[26] and Sonogashira couplings[43] are possible using
the brominated nitroxide 1 but this electron-rich aryl ring
exhibits lower reactivity in these palladium-catalysed reac-
tions. Hence, the more reactive iodo-nitroxide, 5-iodo-
1,1,3,3-tetramethylisoindolin-2-yloxyl (8), was chosen as the
coupling partner. The coupling of anthracene-9,10-dibo-
ronic acid with 8 under standard Suzuki conditions
[Pd(PPh3)4, Na2CO3, THF/H2O] gave BTMIOA 5 in 29%
yield after heating at 80 °C for 72 h. Under the same condi-
tions, the methoxyamine analogue, 9,10-bis(2-methoxy-
1,1,3,3-tetramethylisoindolin-5-yl)anthracene (6) was ob-
tained in somewhat increased yield (43%), following the re-
action of anthracene-9,10-diboronic acid with the iodo-
methoxyamine, 5-iodo-2-methoxy-1,1,3,3-tetramethylisoin-
doline (9). This methoxyamine was prepared using Fenton
chemistry by the reaction of 5-iodo-1,1,3,3-tetramethyliso-
indolin-2-yloxyl (8) with methyl radicals generated from di-
methyl sulfoxide, ferrous ions and hydrogen peroxide. In an
effort to improve these yields, 9,10-bis(4,4,5,5-tetramethyl-
1,3,2-dioxaborolan-2-yl)anthracene (7) was employed as a
coupling partner in the Suzuki reaction as pinacolate bo-
ronic ester derivatives are purported to promote multiple
couplings with aryl iodides.[44] Coupling of 7 with iodo ni-
troxide 8 under aprotic conditions utilising Pd(PPh3)4 and
silver carbonate in THF, furnished the desired product 5 in
an improved (47%) yield. However, the coupling of 7 with
8 under standard Suzuki conditions [Pd(PPh3)4, Na2CO3,
THF/H2O] gave BTMIOA 5 in a better yield of 57%
(Scheme 2). The yield of the methoxyamine analogue 6
could also be increased to 74% when 9,10-bis(4,4,5,5-
tetramethyl-1,3,2-dioxaborolan-2-yl)anthracene (7) was
treated with the iodomethoxyamine 9 under standard
Suzuki conditions [Pd(PPh3)4, Na2CO3, THF/H2O]
(Scheme 2).
Results and Discussion
Synthesis
It was initally envisaged that the diphenylanthracene-
based di-nitroxide target molecule, 9,10-bis(1,1,3,3-tetra-
methylisoindolin-2-yloxyl-5-yl)anthracene (BTMIOA) (5),
could be prepared by reaction of anthraquinone with a li-
thiated, protected nitroxide, followed by in situ reduction of
the resulting diol.[32] Thus, 5-bromo-1,1,3,3-tetramethyliso-
indolin-2-yloxyl (1) was protected by reduction with phenyl-
hydrazine in the presence of benzyl chloride and potassium
tert-butoxide to give the corresponding benzyloxyamine 2
in reasonable yield (60%) (Scheme 1). Lithiation of 2, reac-
tion with anthraquinone and reduction by tin(II) chloride
gave the desired 9,10-bis(2-benzyloxy-1,1,3,3-tetrameth-
ylisoindolin-2-yloxyl-5-yl)anthracene (4) in modest yield
(36%). The methoxyamine analogue 6 could also be pre-
pared using this methodology in 38% yield from 5-bromo-
2-methoxy-1,1,3,3-tetramethylisoindoline (3) and anthra-
quinone. Subsequent debenzylation of 4 proved problematic
on a preparative scale, due to a lack of solubility. A satu-
rated solution of 4 in acetic acid (≈ 0.14 m) underwent
catalytic hydrogenation to furnish BTMIOA 5 in moderate
yield (52%). Other methods for the preparative deben-
zylation of 4, such as oxidative cleavage with DDQ,[33] ex-
posure to boron tribromide[34] or acidic cleavage with meth-
anesulfonic acid,[35] did not provide the required depro-
In addition to preparing a diphenylanthracene-based di-
nitroxide, we sought to synthesise the mono-nitroxide ana-
logue, 10-phenyl-9-(1,1,3,3-tetramethylisoindolin-2-yloxyl-
5-yl)anthracene (11), in order to explore the impact of the
number of nitroxides on fluorescence suppression. Reaction
of
4,4,5,5-tetramethyl-2-(10-phenylanthracen-9-yl)dioxa-
borolane (10) with iodo nitroxide 8 under standard Suzuki
conditions [Pd(PPh3)4, Na2CO3, THF/H2O] gave the mono-
nitroxide 11 in good yield (79%) (Scheme 3). Similarly, the
methoxyamine derivative 12 was prepared by Suzuki coup-
ling of 10 with iodo-methoxyamine 9 in high yield (88%)
(Scheme 3).
The synthesis of the nitroxide probes containing 9,10-
bis(phenylethynyl)anthracene cores was achieved using the
Sonogashira cross-coupling reaction.[45–48] Sonogashira re-
actions in the presence of nitroxides have been detailed in
the literature by Hideg,[39] Schiemann[49] and Mayor.[50]
Scheme 1. Reagents and conditions: for 2: (a) BnCl, PhNHNH2,
tBuOK, THF, 60%; for 3: (b) H2O2, FeSO4.7H2O, DMSO, 20 min,
67%; (c) (i) nBuLi, THF, –78 °C, (ii) anthraquinone, THF, –78 °C
to room temp. (iii) SnCl2, AcOH/H2O, 50 °C, 16 h, for 4: 36%, for
6: 38%; (d) (i) Pd/C, AcOH, H2 (50 psi), 5 h, (ii) PbO2, 30 min,
52%.
5392
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 5391–5400

Novel Polyaromatic Profluorescent Isoindoline Nitroxide Probes
2-yloxyl-5-ethynyl)anthracene (16), in an isolated yield of
15% after heating at 80 °C for 1 h (all alkyne nitroxide 14
consumed according to TLC). Repeating the reaction in
solvents in which 9,10-diiodoanthracene (13) is more solu-
ble, such as THF (16% isolated yield) and toluene (21%
isolated yield), did not substantially improve the production
of 16. The low yield of the reaction reflects the competing
homocoupling of the acetylene nitroxide 14. However, the
yield could be improved to 57% when a larger excess of
acetylene nitroxide 14 (5 equiv.) was employed. For com-
parison, we attempted to prepare 16 using standard Sono-
gashira conditions [CuI, PdCl2(PPh3)2, Et3N]. Coupling of
9,10-diiodoanthracene (13) and the acetylene nitroxide 14
(3 equiv.) gave the desired bis-coupled product 16 in 41%
yield after refluxing for 16 h. Under identical conditions, 16
was obtained in a good yield (67%) when a larger excess
(5 equiv.) of 14 was used (Scheme 4). Thus, standard Sono-
gashira coupling can be achieved when the isoindoline ni-
troxide bears the alkyne moiety (and not the aryl halide
moiety). The methoxyamine analogue, 9,10-bis(2-methoxy-
1,1,3,3-tetramethylisoindolin-5-ethynyl)anthracene (17), was
obtained in modest yield (37%), following reaction of
acetylene methoxyamine 15 (3 equiv.) with 9,10-di-
iodoanthracene (13) under copper-free Sonogashira condi-
tions [DABCO, Pd(OAc)2, MeCN]. Alternatively, the de-
sired methoxyamine 17 could be synthesised via a standard
Sonogashira coupling reaction [CuI, PdCl2(PPh3)2, Et3N]
using 5 equiv. of 15 in excellent yield (98%) (Scheme 4).
Scheme 2. Reagents and conditions: (a) Fe2SO4.7H2O, H2O2,
DMSO, 15 min, 76%; (b) Pd(PPh3)4, Na2CO3, THF/H2O, 80 °C
(for 5: 57%, for 6: 74%).
Scheme 3. Reagents and conditions: (a) Pd(PPh3)4, Na2CO3, THF/
H2O, 80 °C, 3 d, (for 11: 79%, for 12: 88%).
More recently, we have reported the copper-free Sonoga-
shira coupling of isoindoline nitroxides to generate profluo-
rescent acetylene-linked probes.[43] Interestingly, in our
hands, standard Sonogashira conditions [CuI, PdCl2-
(PPh3)2, Et3N] gave none of the desired acetylene-linked
products when the bromo nitroxide 1 was treated with (tri-
methylsilyl)acetylene or phenylacetylene. As the presence of
Scheme 4. Reagents and conditions: (a) CuI, PdCl2(PPh3)2, Et3N,
85 °C, 16 h, (for 16: 67%, for 17: 98%).
To aid our fluorescence suppression investigations, we
CuI is known to hinder the Sonogashira cross coupling of also wished to synthesise the mono-nitroxide analogue, 10-
less active aryl halides[51] (by promoting the homocoupling (phenylethynyl)-9-(1,1,3,3-tetramethylisoindolin-2-yloxyl-5-
of the acetylene compounds), we initially chose to employ ethynyl)-anthracene (19). Pd/Cu-catalysed cross-coupling of
the more successful copper-free methodology originally re- phenylacetylene (0.33 equiv.) and 9,10-diiodoanthracene
ported by Li,[51] for the synthesis of probes possessing 9,10- (13), following the procedure of Mårtensson,[52] furnished
bis(phenylethynyl)anthracene cores. Reaction of 9,10-di- 10-iodo-9-phenylethynyl-anthracene (18) in 27% yield
iodoanthracene (13) with 3 equiv. of the acetylene nitroxide (Scheme 5). Subequent coupling of 18 and acetylene ni-
14 in the presence of DABCO and Pd(OAc)2 gave the troxide 14 using standard Sonogashira conditions [CuI,
desired compound, 9,10-bis(1,1,3,3-tetramethylisoindolin- PdCl2(PPh3)2, Et3N] produced the required mono-nitroxide
Eur. J. Org. Chem. 2008, 5391–5400
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5393

K. E. Fairfull-Smith, S. E. Bottle
FULL PAPER
19 in good yield (63%) (Scheme 5). The copper-free Sono- Table 1. Extinction coefficients and quantum yields for synthesised
mono- and di-nitroxide probes and their methoxyamine adducts.
gashira methodology [DABCO, Pd(OAc)2, MeCN] gave the
desired product 19 in 46% yield. The methoxyamine deriva-
tive, 9-(2-methoxy-1,1,3,3-tetramethylisoindolin-5-ethynyl)-
10-(phenylethynyl)anthracene (20), was prepared in good
yield (78%) via the Cu/Pd-catalysed coupling of 10-iodo-9-
(phenylethynyl)anthracene (18) and the alkyne 15
(Scheme 5).
Compound
Extinction coefficient
Quantum yield
[–1 cm–1]
[ΦF]
5
6
14 500[a]
13 740[a]
17 060[a]
17 380[a]
29 030[b]
31 320[b]
29 640[b]
27 450[b]
0.0029[c]
0.89[c]
11
12
16
17
19
20
0.023[c]
0.85[c]
0.022[d]
0.93[d]
0.04[d]
0.95[d]
[a] Measured in cyclohexane at 375 nm. [b] Measured in cyclohex-
ane at 430 nm. [c] Measured in cyclohexane using 9,10-diphenylan-
thracene as standard (375 nm excitation). [d] Measured in cyclohex-
ane using 9,10-bis(phenylethynyl)anthracene as standard (430 nm
excitation).
Scheme 5. Reagents and conditions: (a) phenylacetylene, Pd(PPh3)4,
CuI, Et3N, 85 °C, 16 h, 27%; (b) 5-ethynyl-1,1,3,3-tetramethylisoin-
dolin-2-yloxyl 14 or 5-ethynyl-2-methoxy-1,1,3,3-tetramethylisoin-
doline 15, CuI, PdCl2(PPh3)2, Et3N, 85 °C, 16 h (for 19: 63%, for
20: 78%).
Physical Properties
Figure 1. Fluorescence spectra of 9,10-diphenylanthracene-based
probes 5 (···), 6 (–), 11 (···) and 12 (–), 2.5 µ in cyclohexane, fol-
lowing excitation at 375 nm.
With the new profluorescent nitroxide probes (5, 11, 16
and 19) and their corresponding methoxyamine adducts (6,
12, 17 and 20) in hand, we examined their physical proper-
ties. The 9,10-diphenylanthracene-based compounds 5, 6,
11 and 12 displayed absorbance spectra and extinction coef- stantial quenching of fluorescence (Figure 2). Quantum
ficients characteristic of their parent compound, 9,10-di- yield measurements of 0.022 and 0.93 for compounds 16
phenylanthracene (Table 1). A comparison of the fluores- and 17, respectively, provided further evidence for this ef-
cence of the di-nitroxide 5 and its methoxyamine analogue fect. The mono-nitroxide derivative 19 was also capable of
6 revealed a substantial fluorescence suppression arising strongly suppressing fluorescence (Figure 2) with quantum
from the presence of the two nitroxides (Figure 1). This ef- yields of 0.04 and 0.95 obtained for compounds 19 and 20
fect was confirmed by the measured quantum yields (ΦF) respectively (Table 1).
of 0.0029 and 0.89 for compounds 5 and 6 respectively
The fluorescence profile from our preliminary work on
(Table 1). Interestingly, the mono-nitroxide analogue 11 the use of BTMIOA 5 as a probe for mapping the early
also demonstrated strongly suppressed fluorescence due to stages of polypropylene degradation suggested that the
quenching by the single nitroxide group (Figure 1). This ob- trapping of alkyl radicals occurs in two stages involving se-
servation was evident from the quantum yields (ΦF) of quential trapping of the two nitroxides.[31] To further ex-
0.023 and 0.85 obtained for compounds 11 and 12 respec- plore the significant fluorescence quenching observed in the
tively.
presence of only one nitroxide radical and to examine radi-
The compounds possessing 9,10-bis(phenylethynyl)an- cal trapping in solution, di-nitroxide 5 was titrated with
thracene cores (16, 17, 19 and 20) exhibited absorbance methyl radicals [generated using Fenton chemistry from the
spectra and extinction coefficients reflecting the parent reaction of hydrogen peroxide with iron(II) sulfate hepta-
structure, 9,10-bis(phenylethynyl)anthracene (Table 1). Ex- hydrate and DMSO]. Hydrogen peroxide was added por-
amination of the fluorescence of di-nitroxide 16 and its cor- tionwise (0.88 equiv. at a time) to a DMSO solution con-
responding methoxyamine adduct 17 again showed a sub- taining 5 and iron(II) sulfate heptahydrate. Aliquots of the
5394
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 5391–5400

Novel Polyaromatic Profluorescent Isoindoline Nitroxide Probes
Figure 2. Fluorescence spectra of 9,10-bis(phenylethynyl)anthra-
cene-based probes 16 (···), 17 (–), 19 (···) and 20 (–), 2.5 µ in cyclo-
hexane, following excitation at 430 nm.
reaction mixture were removed every 10 min and another
portion of hydrogen peroxide (0.88 equiv.) added. The ali-
quots were analysed by spectrofluorimetry (Figure 3) and
analytical HPLC (see Figures 4 and 5). The HPLC traces
and plot of integrated peak areas show the consumption of
di-nitroxide 5 and formation of mono-methyl trapped spe-
cies 21 (Figure 6) and di-methyl trapped product 6. Initially,
21 is formed in higher proportions than 6, due to the ran-
dom nature of the radical trapping. This observation is re-
flected in the fluorescence trace which shows a small lag at
the beginning (as the mono-trapped species 21 displays low
fluorescence – as shown for compound 11) before the fluo-
rescence increases steadily with the conversion of 21 to the
highly fluorescent compound 6. Thus, in contrast to a poly-
mer system in which radical trapping appeared to occur se-
quentially, in solution the radical trapping of di-nitroxide 5
occurs randomly as the nitroxide probe is not constrained
within a polymer matrix.
Figure 4. Analytical HPLC traces following the titration of 5 with
methyl radicals (formed by the addition of H2O2 into a DMSO
solution containing FeSO4·7H2O); (a) 0 equiv. H2O2, (b) 0.88 equiv.
H2O2, (c) 1.76 equiv. H2O2, (d) 2.64 equiv. H2O2, (e) 3.52 equiv.
H2O2, (f) 4.4 equiv. H2O2, (g) 5.28 equiv. H2O2, (h) 6.16 equiv.
H2O2, (i) 7.04 equiv. H2O2, (j) 7.92 equiv. H2O2.
Figure 5. The change in concentration of 5 (–––), 21 (– – –) and 6
(· · ·) with increasing addition of H2O2, as 5 is titrated with methyl
radicals.
Figure 3. Fluorescence emission in THF from the titration of
BTMIOA 5 with methyl radicals (375 nm excitation).
Figure 6. Monomethyl-trapped compound 21.
Eur. J. Org. Chem. 2008, 5391–5400
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5395

K. E. Fairfull-Smith, S. E. Bottle
FULL PAPER
points were measured with a Gallenkamp variable-temperature ap-
paratus by the capillary method and are uncorrected. Analytical
HPLC was carried out with an Agilent Technologies HP 1100
Series HPLC system using an Agilent Prep-C18 scalar column
(4.6ϫ150 mm, 10 µm) with a flow rate of 1 mL/min. Spectrofluori-
metry was undertaken with a Varian Cary Eclipse fluorescence
spectrophotometer. UV/Vis spectroscopy was performed with a
Varian Cary 50 spectrophotometer.
Conclusions
Novel profluoroescent mono- and di-isoindoline ni-
troxides possessing highly (masked) quantum yields were
synthesised using palladium-catalysed couplings. 9,10-Di-
phenylanthracene based probes (5 and 11) and their respec-
tive methoxyamine adducts (6 and 12) were synthesised via
Suzuki coupling reactions. The best yields (57–88%) were
obtained when iodo-nitroxide 8 or iodo methoxyamine 9
and the corresponding anthracene pinacol boronate were
utilised. Probes possessing 9,10-bis(phenylethynyl)anthra-
cene cores (16 and 19) and their methoxyamine derivatives
(17 and 20) were obtained through the Sonogashira coup-
ling of acetylene nitroxide 14 or acetylene methoxyamine
15 and the corresponding iodinated anthracene. Couplings
employing standard Sonogashira conditions [CuI,
PdCl2(PPh3)2, Et3N] gave the highest yields (63–98%). Ex-
amination of the fluorescent properties of the prepared
compounds revealed a substantial suppression of fluores-
cence for the nitroxide containing probes, even in the pres-
ence of only one nitroxide radical. Upon radical trapping to
form methoxyamines, the fluorescence of the high emission
fluorophores was restored. Titration of the di-nitroxide 5
with methyl radicals revealed that in solution, radical trap-
ping occurs randomly. The use of these novel nitroxide
probes as tools for imaging polymer degradation in poly-
propylene and other polymer systems is currently under in-
vestigation.
2-Benzyloxy-5-bromo-1,1,3,3-tetramethylisoindoline (2): 5-Bromo-
1,1,3,3-tetramethylisoindolin-2-yloxyl (1, 0.60 g, 2.30 mmol) was
dissolved in dry THF (20 mL) under argon. Following the addition
of benzyl chloride (1.74 g, 1.58 mL, 13.80 mmol), phenylhydrazine
(0.25 g, 0.22 mL, 2.30 mmol) was added slowly. After stirring for
5 min at room temperature, potassium tert-butoxide (0.52 g,
4.60 mmol) was added. The solution was left to stir for 2 h and
then diluted with diethyl ether (40 mL). The reaction mixture was
washed with water (2ϫ50 mL) and brine (2ϫ50 mL). The organic
phase was dried (anhydrous NaSO4) and concentrated at reduced
pressure. The obtained residue was submitted to silica column
chromatography (eluent 30% DCM, 70% hexane) to yield 2 as a
colourless oil (500 mg, 60%). IR (ATR): ν = 2973 and 2928 (alkyl
˜
CH3), 1479 and 1453 (aryl C–C), 1025 (O–CH2), 694 cm–1. (C-Br).
1H NMR (400 MHz, CDCl3): δ = 1.45 (br. s, 12 H, 4ϫCH3), 4.96
(s, 2 H, CH2), 6.99 (d, J = 8.05 Hz, 1 H, 7-H), 7.25 (d, J = 1.84 Hz,
1 H, 4-H), 7.31–7.46 (m, 6 H, 6-H and Ar-H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 25.1 (br., CH3), 29.8 (br., CH3), 67.36 (C),
67.44 (C), 79.5 (CH2), 120.8 (C), 123.3 (CH), 124.8 (CH), 127.8
(CH), 128.3 (CH), 128.4 (CH), 130.3 (CH), 138.0 (C), 144.0 (C),
147.3 (C) ppm. MS (EI): m/z (%) = 359/361 (5) [M+], 344/346 (10),
329/331 (25), 314/316 (≈ 1). HRMS: calcd. for C19H2281BrNO [M+]
361.0864; found 361.0854. HRMS: calcd. for C19H2279BrNO [M+]
359.0885; found 359.0880. C19H22BrNO (359.09/361.09): calcd. C
63.34, H 6.15, N 3.89; found C 63.29, H 6.09, N 3.85.
Experimental Section
General Methods: All air-sensitive reactions were carried out under
ultra-high purity argon. Tetrahydrofuran (THF) was freshly dis-
tilled from sodium benzophenone ketal, and acetonitrile distilled
from calcium hydride. Toluene was dried by storage over sodium
wire and triethylamine by storage over potassium hydroxide. Tetra-
kis(triphenylphosphane)palladium(0) was prepared freshly using
literature methods.[53] Anthracene-9,10-diboronic acid,[54] 9,10-
bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)anthracene[55] (7),
5-iodo-1,1,3,3-tetramethylisoindolin-2-yloxyl[31] (8), 5-iodo-2-
methoxy-1,1,3,3-tetramethylisoindoline[31] (9), 5-ethynyl-1,1,3,3-
tetramethylisoindolin-2-yloxyl[43] (14) and 5-ethynyl-2-methoxy-
9,10-Bis(2-benzyloxy-1,1,3,3-tetramethylisoindolin-2-yloxyl-5-yl)an-
thracene (4): n-Butyllithium (1.60  in hexanes, 1.25 mL,
2.00 mmol) was added to a solution of 2-benzyloxy-5-bromo-
1,1,3,3-tetramethylisoindoline (2) (0.60 g, 1.67 mmol) in dry THF
(8 mL) at –78 °C under argon. The solution was stirred for 10 min
and then transferred via syringe to a stirring suspension of anthra-
quinone (0.14 g, 0.71 mmol) in dry THF (18 mL) at –78 °C under
argon. The cold bath was removed and the solution stirred for 2 h.
The reaction mixture was treated with water/acetic acid (1:1,
18 mL) and tin(II) chloride dihydrate (5.58 g, 24.80 mmol) and
heated at 50 °C for 16 h. The resultant yellow solution was concen-
1,1,3,3-tetramethylisoindoline[43] (15), 4,4,5,5-tetramethyl-2-(10- trated in vacuo, then a mixture of chloroform and water (1:1,
phenylanthracen-9-yl)-dioxaborolane[55] (10), 9,10-diiodoanthra-
cene[56] (13) and 9-phenylethynyl-10-iodoanthracene[52] (18) were
synthesised using established literature procedures. All other rea-
gents were purchased from commercial suppliers and used without
60 mL) was added. The chloroform layer was removed and the
aqueous phase washed with chloroform (3ϫ30 mL). The com-
bined organic phases were washed with water (3ϫ30 mL), dried
(anhydrous NaSO4) and concentrated in vacuo. The resulting resi-
due was purified by silica column chromatography (eluent 30%
DCM, 70% hexane) to give 4 as a chalky white solid (190 mg,
1
further purification. H and 13C NMR spectra were recorded with
a Bruker Avance 400 spectrometer and referenced to the relevant
solvent peak. Low and high resolution mass spectra were recorded
at the Australian National University (ANU) using either a Micro-
mass autospec double focusing magnetic sector mass spectrometer
(EI+ spectra) or a Bruker Apex 3 fourier transform ion cyclotron
resonance mass spectrometer with a 4.7-T magnet (ESI+ spectra).
Formulations were calculated in the elemental analysis programs of
Mass Lynx 4.0 or Micromass Opus 3.6. Fourier transform infrared
(FTIR) spectra were recorded with a Nicolet 870 Nexus Fourier
Transform Infrared Spectrometer equipped with a DTGS TEC de-
tector and an ATR objective. Elemental analyses were carried out
by the University of Queensland Microanalytical Service. Melting
36%). M.p. 274–276 °C. IR (ATR): ν = 2970 and 2924 (alkyl CH ),
˜
3
1495 and 1453 (aryl C–C), 1025 (O–CH2) cm–1. 1H NMR
(400 MHz. CDCl3): δ = 1.53 (br. s, 12 H, 4ϫCH3), 1.63 (br. s, 12
H, 4ϫCH3), 5.07 (s, 4 H, 2ϫCH2), 7.21 (d, J = 10.0 Hz, 2 H, 7-
H), 7.33–7.52 (m, 18 H, Ar-H), 7.62 (dd, J = 6.9, 3.0 Hz, 4 H, Ar-
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 25.6 (br., CH3), 29.9
(br., CH3), 67.49 (C), 67.51 (C), 79.7 (CH2), 121.4 (CH), 124.5
(CH), 125.0 (CH), 127.0 (CH), 127.7 (CH), 128.3 (CH), 128.5
(CH), 130.0 (CH), 130.2 (C), 137.4 (C), 137.9 (C), 138.4 (C), 144.3
(C), 145.4 (C) ppm. MS (ES): m/z (%) = 737 (2) [MH+]. HRMS:
calcd. for C52H53N2O2 [MH+] 737.4107; found 737.4078.
5396
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 5391–5400

Novel Polyaromatic Profluorescent Isoindoline Nitroxide Probes
9,10-Bis(1,1,3,3-tetramethylisoindolin-2-yloxyl-5-yl)anthracene (5) (br., CH3), 30.0 (br., CH3), 65.6 (CH3), 67.2 (C), 121.4 (CH), 124.4
from Anthraquinone: 9,10-Bis(2-benzyloxy-1,1,3,3-tetramethylisoin-
dolin-2-yloxyl-5-yl)anthracene (4) (0.01 g, 0.014 mmol) was dis-
solved in glacial acetic acid (10 mL) and palladium on carbon (10
wt.-% loading, 0.01 g) added. The solution was placed in a Parr
hydrogenator under hydrogen (50 psi) with shaking for 5 h. The
resulting suspension was filtered through Celite and the Celite
washed thoroughly with acetic acid. The combined filtrates were
concentrated in vacuo and the residue taken up in chloroform
(10 mL) and washed with sodium hydrogen carbonate (saturated
aqueous solution, 3ϫ10 mL). The organic layer was dried (anhy-
drous Na2SO4) and concentrated at reduced pressure. Purification
of the resulting residue by silica gel chromatography (eluent 100%
chloroform) gave 5 as a cream coloured powder (4 mg, 52%). M.p.
(CH), 124.9 (CH), 127.0 (CH), 130.0 (CH), 130.2 (C), 137.3 (C),
137.9 (C), 144.3, (C), 145.4 (C) ppm. MS (EI): m/z (%) = 584 (35)
[M+]. HRMS: calcd. for C40H44N2O2 [M+] 584.3403; found
584.3405.
9,10-Bis(1,1,3,3-tetramethylisoindolin-2-yloxyl-5-yl)anthracene (5)
via Suzuki Coupling: A solution of dry THF (4 mL) containing
9,10-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)anthracene (7)
(0.16 g, 0.38 mmol), 5-iodo-1,1,3,3-tetramethylisoindolin-2-yloxyl
(8) (0.29 g, 0.94 mmol), anhydrous sodium carbonate (0.08 g,
0.75 mmol) and water (2 mL) was degassed by subjecting to three
freeze-pump-thaw cycles using a JAVAC brand electrically driven
oil-pump. Tetrakis(triphenylphosphane)palladium(0) (35.0 mg,
0.03 mmol) was added and the reaction mixture was heated at
80 °C under argon for 2 d. Water (20 mL) was added and the mix-
ture extracted with chloroform (3ϫ30 mL). The organic layers
were washed with brine (2ϫ20 mL), dried (anhydrous Na2SO4)
and concentrated in vacuo. The resulting residue was purified by
silica column chromatography (eluent 100% chloroform) to afford
5 as a cream-coloured solid (120 mg, 57%). The spectroscopic and
physical data acquired was consistent with that obtained for a pre-
viously synthesised sample of 5.
312–315 °C (dec.). IR (ATR): ν = 2970 and 2924 (alkyl CH), 1494
˜
and 1451 (aryl C–C), 1437 (N–O) cm–1.[57] MS (EI): m/z (%) = 554
(10) [M+]. HRMS: calcd. for C38H38N2O2 [M+] 554.2933; found
554.2936. C38H38N2O2·H2O (572.30): calcd. C 79.69, H 7.04, N
4.89; found C 79.84, H 6.99, N 4.83.
5-Bromo-2-methoxy-1,1,3,3-tetramethylisoindoline (3): Hydrogen
peroxide solution (30%, 0.17 mL) was added dropwise to a solution
of 5-bromo-1,1,3,3-tetramethylisoindolin-2-yloxyl (1) (0.20 g,
0.74 mmol) and iron(II) sulfate heptahydrate (0.42 g, 1.50 mmol) in
DMSO (5 mL). The resulting solution was stirred at room tempera-
ture for 20 min and then poured into aqueous sodium hydroxide
(1 , 200 mL). The mixture was extracted with diethyl ether
(3ϫ150 mL) and the combined organic layers dried (anhydrous
Na2SO4) and concentrated in vacuo. Purification by silica column
chromatography (eluent 10% ethyl acetate, 90% hexane) gave 3 as
9,10-Bis(2-methoxy-1,1,3,3-tetramethylisoindolin-5-yl)anthracene
(6) via Suzuki Coupling: A solution of dry THF (3 mL) containing
9,10-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)anthracene (7)
(0.10 g, 0.23 mmol), 5-iodo-2-methoxy-1,1,3,3-tetramethylisoindo-
line (9) (0.19 g, 0.58 mmol), anhydrous sodium carbonate (49.0 mg,
0.45 mmol) and water (1.25 mL) was degassed using three freeze-
pump-thaw cycles. Tetrakis(triphenylphosphane)palladium(0)
(21.0 mg, 0.018 mmol) was added and the reaction mixture was
heated at 80 °C under argon for 3 d. The solution was cooled, water
(20 mL) added and extracted with chloroform (3ϫ30 mL). The or-
ganic layers were washed with brine (2ϫ20 mL), dried (anhydrous
Na2SO4) and concentrated in vacuo. The resulting residue was
purified by silica column chromatography (eluent 30% DCM, 70%
hexane) to give 6 as a white solid (100 mg, 74%). The spectroscopic
and physical data acquired was consistent with that obtained for a
previously synthesised sample of 6.
a pale yellow oil (140 mg, 67%). IR (ATR): ν = 2974 and 2932
˜
(alkyl CH3), 1479 and 1462 (aryl C–C), 1050 (O–CH2), 640 (C–Br)
cm–1. 1H NMR (400 MHz, CDCl3): δ = 1.42 (br. s, 12 H, 4ϫCH3),
3.78 (s, 3 H, CH3), 6.98 (d, J = 8.05 Hz, 1 H, 7-H), 7.23 (d, J =
1.84 Hz, 1 H, 4-H), 7.35 (dd, J = 8.05, 1.87 Hz, 1 H, 6-H) ppm.
13C NMR (100 MHz, CDCl3): δ = 24.9 (br., CH3), 29.7 (br., CH3),
65.5 (CH3), 67.0 (C), 67.1 (C), 120.7 (C), 123.3 (CH), 124.8 (CH),
130.3 (CH), 144.2 (C), 147.4 (C) ppm. MS (EI): m/z (%) = 283/285
(7) [M+], 268/270 (100), 253/255 (5), 238/240 (7). HRMS: calcd. for
C13H1879BrNO [M+] 283.0572; found 283.0567. HRMS: calcd. for
C13H1881BrNO [M+] 285.0551; found 285.0544.
10-Phenyl-9-(1,1,3,3-tetramethylisoindolin-2-yloxyl-5-yl)anthracene
(11): A solution containing 5-iodo-1,1,3,3-tetramethylisoindolin-2-
yloxyl (8) (0.24 g, 0.76 mmol), 4,4,5,5-tetramethyl-2-(10-phenylan-
thracen-9-yl)dioxaborolane (10) (0.24 g, 0.63 mmol) and sodium
carbonate (0.08 g, 0.76 mmol) in dry THF (10 mL) and water
(5 mL) was prepared under argon. The solution was degassed using
three freeze-pump-thaw cycles. Tetrakis(triphenylphosphane)palla-
dium(0) (44 mg, 0.038 mmol) was added and the mixture heated at
80 °C for 3 d. Upon cooling, water (50 mL) was added and the
solution was extracted with diethyl ether (4ϫ50 mL). The com-
bined ether layers were washed with brine (2ϫ100 mL), dried (an-
hydrous Na2SO4) and concentrated at reduced pressure. Purifica-
tion by silica column chromatography (SiO2, eluent DCM) and
subsequent recrystallisation from DCM/hexane gave the desired
compound 11 as yellow needles (220 mg, 79%). M.p. 250–252 °C.
9,10-Bis(2-methoxy-1,1,3,3-tetramethylisoindolin-5-yl)anthracene (6)
from Anthraquinone: n-Butyllithium (1.60  in hexanes, 0.67 mL,
1.07 mmol) was added to a solution of 5-bromo-2-methoxy-1,1,3,3-
tetramethylisoindoline (3) (0.20 g, 0.71 mmol) in dry THF (2 mL)
at –78 °C under an atmosphere of argon. The solution was stirred
for 10 min and then transferred via syringe to a stirring suspension
of anthraquinone (0.037 g, 0.18 mmol) in dry THF (5 mL) at
–78 °C under argon. The cold bath was removed and the reaction
mixture was treated with water/acetic acid (1:1, 7 mL) and tin(II)
chloride dihydrate (1.42 g, 6.30 mmol) and heated at 50 °C for 5 h.
The yellow solution was concentrated in vacuo and then a mixture
of chloroform and water (1:1, 20 mL) was added. The chloroform
layer was removed and the aqueous phase washed with chloroform
(3ϫ10 mL). The combined chloroform phases were washed with
water (3ϫ20 mL), dried (anhydrous Na2SO4) and concentrated in
vacuo. The resulting residue was purified by silica column
chromatography (eluent 30% DCM, 70% hexane) to give 6 as a
IR (ATR): ν = 2975 and 2925 (alkyl CH), 1495 and 1452 (aryl C–
˜
C), 1439 (N–O) cm–1. [57] MS (EI): m/z (%) = 442 (5) [M+]. HRMS:
calcd. for C32H28NO [M+] 442.2171; found 442.2172. C32H28NO
(442.22): calcd. C 86.84, H 6.38, N 3.16; found C 86.68, H 6.30, N
3.16.
white solid (190 mg, 36%). M.p. Ͼ300 °C (dec). IR (ATR): ν =
˜
2971 and 2930 (alkyl CH), 1461 and 1438 (aryl C–C), 1052 (C–O)
cm–1. 1H NMR (400 MHz, CDCl3): δ = 1.51 (br. s, 12 H, 4ϫCH3),
1.61 (br. s, 12 H, 4ϫCH3), 3.89 (s, 6 H, 2ϫCH3), 7.21 (d, J =
10.1 Hz, 2 H, 7-H), 7.32–7.38 (m, 8 H, Ar-H), 7.72 (dd, J = 6.8,
9-(2-Methoxy-1,1,3,3-tetramethylisoindolin-5-yl)-10-phenylanthra-
cene (12): A solution containing 5-iodo-2-methoxy-1,1,3,3-tetra-
methylisoindoline (9) (0.16 g, 0.47 mmol), 4,4,5,5-tetramethyl-2-
3.2 Hz, 4 H, Ar-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 25.0 (10-phenylanthracen-9-yl)-dioxaborolane (10) (0.15 g, 0.39 mmol)
Eur. J. Org. Chem. 2008, 5391–5400
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5397

K. E. Fairfull-Smith, S. E. Bottle
FULL PAPER
and sodium carbonate (0.10 g, 0.94 mmol) in dry THF (6 mL) and
water (3 mL) was prepared under argon. The solution was de-
gassed, tetrakis(triphenylphosphane)palladium(0) (28.0 mg,
0.024 mmol) added and the mixture heated at 80 °C for 3 d. Upon
cooling, water (30 mL) was added and the mixture was extracted
with diethyl ether (4 ϫ30 mL). The combined ether layers were
washed with brine (2ϫ50 mL), dried (anhydrous Na2SO4) and con-
centrated at reduced pressure. Purification by silica column
chromatography (eluent 30% DCM, 70% hexane, sample loaded
in DCM) gave the desired compound 12 as a cream-coloured solid
(ES): m/z (%) = 633 (60) [MH+]. HRMS: calcd. for C44H45N2O2
[MH+] 633.3481; found 633.3490.
10-(Phenylethynyl)-9-(1,1,3,3-tetramethylisoindolin-2-yloxyl-5-eth-
ynyl)anthracene (19): A solution of 10-iodo-9-(phenylethynyl)an-
thracene (18) (30 mg, 0.074 mmol), bis(triphenylphosphane)palla-
dium(II) dichloride (3.2 mg, 6.2 mol-%), copper iodide (0.86 mg,
6.1 mol-%) in triethylamine (5 mL) was degassed using three freeze-
pump-thaw cycles. 5-Ethynyl-1,1,3,3-tetramethylisoindolin-2-yloxyl
(14) (41 mg, 0.19 mmol) was then added and the mixture heated at
85 °C for 16 h. The solvent was removed in vacuo and the resulting
residue dissolved in DCM (50 mL), washed with water (2ϫ50 mL)
and brine (2ϫ50 mL), dried (anhydrous Na2SO4) and concentrated
at reduced pressure. Purification by silica column chromatography
(eluent 20% EtOAc, 80% hexane, sample dry-loaded from DCM)
and subsequent recrystallisation from DCM/hexane gave 10-(phen-
ylethynyl)-9-(1,1,3,3-tetramethylisoindolin-2-yloxyl-5-ethynyl)an-
thracene (19) as orange needles (23 mg, 63%). M.p. 190–193 °C.
(158 mg, 88%). M.p. 222–224 °C. IR (ATR): ν = 2975 and 2932
˜
(alkyl CH), 1494 and 1456 (aryl C–C), 1439 (N–O), 1048 (C–O)
1
cm–1. H NMR (400 MHz, CDCl3): δ = 1.52 (br. s, 6 H, 2ϫCH3),
1.62 (br. s, 6 H, 2ϫCH3), 3.88 (s, 3 H, CH3), 7.22 (s, 1 H, 7-H),
7.31–7.38 (m, 6 H, Ar-H), 7.46–7.52 (m, 2 H, Ar-H), 7.54–7.65 (m,
3 H, Ar-H), 7.68–7.75 (m, 4 H, Ar-H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 25.2 (br., CH3), 29.9 (br., CH3), 65.5 (CH3), 67.18 (C),
67.22 (C), 121.4 (CH), 124.4 (CH), 125.0 (CH), 126.9 (CH), 127.0
(CH), 127.4 (CH), 128.4 (CH), 129.9 (C), 130.0 (C), 130.2 (CH),
131.3 (CH), 137.0 (C), 137.4 (C), 137.8 (C), 139.1 (C), 144.3 (C),
145.4 (C) ppm. MS (EI): m/z (%) = 457 (85) [M+]. HRMS: calcd.
for C33H31NO [M+] 457.2406; found 457.2407.
IR (ATR): ν = 2920 and 2851 (alkyl CH), 2190 (CϵC), 1490 and
˜
1459 (aryl C–C), 1435 (N–O) cm–1.[57] MS (EI): m/z (%) = 490 (20)
[M+]. HRMS: calcd. for C36H28NO [M+] 490.2171; found
490.2170. C36H28NO (490.22): calcd. C 88.13, H 5.75, N 2.85;
found C 88.11, H 5.39, N 2.85.
9,10-Bis(1,1,3,3-tetramethylisoindolin-2-yloxyl-5-ethynyl)anthracene
(16): A solution of 9,10-diiodoanthracene (13) (37.5 mg,
0.088 mmol), bis(triphenylphosphane)palladium(II) dichloride
(5 mg, 8.1 mol-%), copper iodide (1.3 mg, 7.8 mol-%) in triethyl-
amine (5 mL) was degassed using three freeze-pump-thaw cycles.
5-Ethynyl-1,1,3,3-tetramethylisoindolin-2-yloxyl (14) (0.09 g,
0.43 mmol) was then added and the mixture heated at 85 °C for
16 h. The solvent was removed in vacuo and the resulting residue
dissolved in DCM (50 mL). washed with water (2ϫ50 mL) and
brine (2ϫ50 mL), dried (anhydrous Na2SO4) and concentrated at
reduced pressure. Purification by silica column chromatography
(eluent 20% EtOAc, 80% hexane, sample dry-loaded from DCM)
afforded 9,10-bis(1,1,3,3-tetramethylisoindolin-2-yloxyl-5-ethynyl)-
anthracene (16) as a yellow solid (35 mg, 67%). M.p. 250 °C (dec).
9-(2-Methoxy-1,1,3,3-tetramethylisoindolin-5-ethynyl)-10-(phenyl-
ethynyl)anthracene (20): A solution of 10-iodo-9-(phenylethynyl)an-
thracene (18) (53 mg, 0.13 mmol), bis(triphenylphosphane)palladi-
um(II) dichloride (5.5 mg, 6.0 mol-%), copper iodide (1.5 mg,
6.0 mol-%) in triethylamine (9 mL) was degassed using three freeze-
pump-thaw cycles. 5-Ethynyl-2-methoxy-1,1,3,3-tetramethylisoin-
doline (15) (75 mg, 0.33 mmol) was then added and the mixture
heated at 85 °C for 16 h. The solvent was removed in vacuo and
the resulting residue dissolved in DCM (50 mL). washed with water
(2ϫ50 mL) and brine (2ϫ50 mL), dried (anhydrous Na2SO4) and
concentrated at reduced pressure. Purification by silica column
chromatography (eluent 100% hexaneǞ10% ethyl acetate, 90%
hexane; sample dry-loaded from DCM) gave 9-(2-methoxy-1,1,3,3-
tetramethylisoindolin-5-ethynyl)-10-(phenylethynyl)anthracene (20)
IR (ATR): ν = 2971 and 2926 (alkyl CH), 2195 (CϵC), 1489 and
˜
as a yellow solid (52 mg, 78%). M.p. 170–173 °C. IR (ATR): ν =
˜
1452 (aryl C–C), 1436 (N–O) cm–1.[57] MS (ES): m/z (%) = 603
(40) [MH+]. HRMS: calcd. for C33H32NO [MH+] 603.3016; found
603.2991.
2956 and 2925 (alkyl CH), 2196 (CϵC), 1489 and 1455 (aryl C–
1
C), 1052 (C–O) cm–1. H NMR (400 MHz, CDCl3): δ = 1.47–1.57
(br. s, 12 H, 4ϫCH3), 3.83 (s, 3 H, CH3), 7.20 (d, J = 7.8 Hz, 1 H,
7-H), 7.41–7.52 (m, 4 H, Ar-H), 7.64–7.69 (m, 5 H, Ar-H), 7.80
(dd, J = 8.0, 1.7 Hz, 2 H, Ar-H), 8.71 (ddd, J = 6.3, 3.6, 0.65 Hz,
4 H, Ar-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 25.0 (br.,
CH3), 29.5 (br., CH3), 65.5 (CH3), 67.1 (C), 67.2 (C), 85.8 (Cϵ),
86.5 (Cϵ), 102.3 (Cϵ), 102.7 (Cϵ), 118.3 (C), 118.6 (C), 121.8
(CH), 122.1 (C), 123.4 (C), 124.8 (CH), 126.77 (CH), 126.81 (CH),
127.2 (CH), 127.3 (CH), 128.6 (CH), 128.7 (CH), 131.0 (CH), 131.7
(CH), 132.07 (C), 132.09 (C), 145.8 (C), 146.2 (C) ppm. MS (ES):
m/z (%) = 506 (10) [MH+]. HRMS: calcd. for C37H32NO [MH+]
506.2478; found 506.2484.
9,10-Bis(2-methoxy-1,1,3,3-tetramethylisoindolin-5-ethynyl)anthra-
cene (17): A solution of 9,10-diiodoanthracene (13) (38.5 mg,
0.09 mmol), bis(triphenylphosphane)palladium(II) dichloride
(5.1 mg, 8.1 mol-%), copper iodide (1.4 mg, 8.1 mol-%) in triethyl-
amine (5.1 mL) was degassed using three freeze-pump-thaw cycles.
5-Ethynyl-2-methoxy-1,1,3,3-tetramethylisoindoline (15) (0.1 g,
0.44 mmol) (0.09 g, 0.43 mmol) was then added and the mixture
heated at 85 °C for 16 h. The solvent was removed in vacuo and
the resulting residue dissolved in DCM (70 mL). washed with water
(2ϫ70 mL) and brine (2ϫ70 mL), dried (anhydrous Na2SO4) and
concentrated at reduced pressure. Purification by silica column
chromatography (eluent 5 % EtOAc, 95 % hexane, sample dry-
loaded from DCM) gave 9,10-bis(2-methoxy-1,1,3,3-tetrameth-
ylisoindolin-5-ethynyl)anthracene (17) as a yellow solid (55 mg,
Quantum Yield and Extinction Coefficient Calculations: Quantum-
yield efficiencies of fluorescence for compounds 5, 6, 11, 12, 16,
17, 19 and 20 were obtained from measurements at five different
concentrations in cyclohexane using the following equation:
98%). M.p. 248–252 °C. IR (ATR): ν = 2958 and 2925 (alkyl CH),
˜
ΦF sample = ΦF standard ϫ(Absstandard/Abssample)ϫ
(Σ[Fsample]/Σ[Fstandard])
2199 (CϵC), 1488 and 1455 (aryl C–C), 1042 (C–O) cm–1
.
1H
NMR (400 MHz, CDCl3): δ = 1.57 (s, 24 H, 8ϫCH3), 3.83 (s, 6
H, 2ϫCH3), 7.2 (d, J = 7.8 Hz, 2 H, 7-H), 7.5 (d, J = 0.94 Hz, 2 where Abs and F denote the absorbance and fluorescence intensity,
H, 4-H), 7.62–7.78 (m, 6 H, Ar-H), 8.7 (dd, J = 6.6, 3.3 Hz, 4 H, respectively, and Σ[F] denotes the peak area of the fluorescence
Ar-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 25.0 (br., CH3),
29.8 (br., CH3), 65.5 (CH3), 67.13 (C), 67.22 (C), 85.8 (Cϵ), 102.7
spectra, calculated by summation of the fluorescence intensity.
9,10-Diphenylanthracene (ΦF = 0.9) and 9,10-bis(phenylethynyl)
(Cϵ), 118.5 (C), 121.8 (CH), 122.1 (C), 124.8 (CH), 126.8 (CH), anthracene (ΦF = 1.0) were used as standards. Extinction coeffi-
127.3 (CH), 131.0 (CH), 132.1 (C), 145.8 (C), 146.2 (C) ppm. MS cients were calculated from the obtained absorbance spectra.
5398
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 5391–5400

Novel Polyaromatic Profluorescent Isoindoline Nitroxide Probes
[7] J. L. Gerlock, P. J. Zacmanidis, D. R. Bauer, D. J. Simpson,
N. V. Blough, I. T. Salmeen, Free Radical Res. Commun. 1990,
10, 119–121.
[8] D. J. Kieber, N. V. Blough, Anal. Chem. 1990, 62, 2275–2283.
[9] D. J. Kieber, N. V. Blough, Free Radical Res. Commun. 1990,
10, 109–117.
Titration of 9,10-Bis(1,1,3,3-tetramethylisoindolin-2-yloxyl-5-yl)an-
thracene (5) with Methyl Radicals: Iron(II) sulfate heptahydrate
(15 mg, 4.17 mol) was added to a stirring solution of 9,10-
bis(1,1,3,3-tetramethylisoindolin-2-yloxyl-5-yl)anthracene (5)
(1.39 mg, 2.51 mmol) in DMSO (10 mL). A solution of hydrogen
peroxide (30%, 2.5 µL, 0.88 equiv.) in DMSO (97.5 µL) was added
and after stirring at room temperature for 10 min, an aliquot
(0.1 mL) was removed from the reaction and diluted with THF
(0.4 mL). The addition of hydrogen peroxide and removal of ali-
quots after 10 min was repeated 8 times. The aliquots were analysed
by analytical HPLC (mobile phase 72.5% THF in H2O, detection
at 254 nm) and their fluorescence measured. Authentic samples of
5, 6 and 21 were prepared and gave retention times consistent with
those observed in the titration.
[10] S. E. Herbelin, N. V. Blough, J. Phys. Chem. B 1998, 102, 8170–
8176.
[11] C. Coenjarts, O. Garcia, L. Llauger, J. Palfreyman, A. L. Vi-
nette, J. C. Scaiano, J. Am. Chem. Soc. 2003, 125, 620–621.
[12] M. G. Ivan, J. C. Scaiano, Photochem. Photobiol. 2003, 78,
416–419.
[13] A. Aspee, O. Garcia, L. Maretti, R. Sastre, J. C. Scaiano, Mac-
romolecules 2003, 36, 3550–3556.
[14] X.-F. Yang, X.-Q. Guo, Analyst 2001, 126, 1800–1804.
[15] X.-F. Yang, X.-Q. Guo, Anal. Chim. Acta 2001, 434, 169–177.
[16] G. Moad, D. A. Shipp, T. A. Smith, D. H. Solomons, J. Phys.
Chem. A 1999, 103, 6580–6586.
[17] O. G. Ballasteros, L. Maretti, R. Sastre, J. C. Scaiano, Macro-
molecules 2001, 34, 6184–8187.
[18] Y.-M. Dang, X.-Q. Guo, Appl. Spectrosc. 2006, 60, 203–207.
[19] C. Toniolo, M. Crisma, F. Formaggio, Biopolymers 1998, 47,
153–158.
[20] B. Pispisa, A. Palleschi, L. Stella, M. Venanzi, C. Toniolo, J.
Phys. Chem. B 1998, 102, 7890–7898.
[21] B. Pispisa, C. Mazzuca, A. Palleschi, L. Stella, M. Venanzi, M.
Wakselman, J.-P. Mazaleyrat, M. Rainaldi, F. Formaggio, C.
Toniolo, Chem. Eur. J. 2003, 9, 4084–4093.
9-(2-Methoxy-1,1,3,3-tetramethylisoindolin-5-yl)-10-(1,1,3,3-tetra-
methylisoindolin-2-yloxyl-5-yl)anthracene (21): A solution contain-
ing 9,10-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)anthracene
(7) (0.2 g, 0.48 mmol), 5-iodo-1,1,3,3-tetramethylisoindolin-2-
yloxyl (8) (0.18 g, 0.57 mmol), 5-iodo-2-methoxy-1,1,3,3-tetrameth-
ylisoindoline (9) (0.19 g, 0.57 mmol) and anhydrous sodium car-
bonate (0.1 g, 0.96 mmol) in dry THF (5 mL) and water (2 mL)
was degassed by subjecting to three freeze-pump-thaw cycles. Tetra-
kis(triphenylphosphane)palladium(0) (44.0 mg, 0.038 mmol) was
added and the reaction mixture was heated at 80 °C under argon
for 3 d. The resulting solution was cooled, water (50 mL) added
and the mixture extracted with chloroform (3ϫ50 mL). The or-
ganic layers were washed with brine (2ϫ50 mL), dried (anhydrous
Na2SO4) and concentrated in vacuo. The obtained residue was
purified by silica column chromatography (eluent 70% DCM, 30%
hexaneǞ100% DCM) to afford 21 as a cream-coloured solid
[22] E. Hideg, T. Kalai, K. Hideg, I. Vass, Biochemistry 1998, 37,
11405–11411.
[23] T. Kalai, E. Hideg, I. Vass, K. Hideg, Free Radical Biol. Med.
1998, 24, 649–652.
[24] E. Lozinsky, V. V. Martin, T. A. Berezina, A. I. Shames, A. L.
Weis, G. I. Likhtenshtein, J. Biochem. Biophys. Methods 1999,
38, 29–42.
1
(112 mg, 41%). M.p. 299–301 °C. H NMR (400 MHz, CDCl3): δ
= 1.51–1.58 (br. s, 12 H, 4ϫCH3), 3.89 (s, 3 H, CH3), 7.20–7.25
(m, 1 H, Ar-H), 7.33–7.45 (m, 6 H, Ar-H), 7.71–7.79 (m, 2 H,
Ar-H), protons near radical not observed. 13C NMR (100 MHz,
CDCl3): no signals observed. MS (ES): m/z (%) = 570 (20) [MH+].
HRMS: calcd. for C39H42N2O2 [MH+] 570.3246; found 570.3237.
[25] P. Bilski, K. Hideg, T. Kalai, M. A. Bilska, C. F. Chignell, Free
Radical Biol. Med. 2003, 34, 489–495.
[26] D. J. Keddie, T. E. Johnson, D. P. Arnold, S. E. Bottle, Org. Bi-
omol. Chem. 2005, 3, 2593–2598.
[27] J. P. Blinco, J. C. McMurtrie, S. E. Bottle, Eur. J. Org. Chem.
2007, 48, 4638–4641.
[28] A. S. Micallef, J. P. Blinco, G. A. George, D. A. Reid, E. Riz-
zardo, S. H. Thang, S. E. Bottle, Polym. Degrad. Stab. 2005,
89, 427–435.
Supporting Information (see also the footnote on the first page of
1
this article): H and 13C NMR spectra for compounds 3, 4, 6, 12,
17 and 20.
[29] J. P. Blinco, G. A. George, S. E. Bottle, Polym. Prepr. 2007, 48,
629–630.
[30] A. Micallef, S. Bottle, J. Blinco, G. George in ACS Symposium
Series, vol. 978, Polymer Durability and Radation Effects (Eds.:
M. C. Celina, R. A. Assink), American Chemical Society, 2008,
59–69.
[31] K. E. Fairfull-Smith, J. P. Blinco, D. J. Keddie, G. A. George,
S. E. Bottle, Macromolecules 2008, 41, 1577–1580.
[32] M. A. Wolak, B.-B. Jang, L. C. Palilis, Z. H. Kafafi, J. Phys.
Chem. B 2004, 108, 5492–5499.
Acknowledgments
We gratefully acknowledge financial support for this work from the
Australian Research Council Centre of Excellence for Free Radical
Chemistry and Biotechnology (CEO 0561607) and Queensland
University of Technology.
[33] N. Ikemoto, S. L. Schreiber, J. Am. Chem. Soc. 1992, 114,
2524–2536.
[34]
[35]
D. J. Hart, W.-P. Hong, L.-Y. Hsu, J. Org. Chem. 1987, 52,
4665–4673.
D. S. Matteson, H.-W. Man, O. C. Ho, J. Am. Chem. Soc. 1996,
118, 4560–4566.
N. Miyaura, A. Suzuki, Chem. Rev. 1995, 95, 2457–2483.
A. Suzuki in Handbook of Organopalladium Chemistry for Or-
ganic Synthesis (Ed.: E. Negishi), Wiley-Interscience, New
York, 2002.
Cross-Coupling Reactions: A Practical Guide (Ed.: N. Miyaura)
Springer, New York, 2002.
[1] G. Moad, E. Rizzardo, D. H. Solomon, Macromolecules 1982,
15, 909–914.
[2] P. G. Griffiths, E. Rizzardo, D. H. Solomon, Tetrahedron Lett.
1982, 23, 1309–1312.
[3] J. Shen, S. Bottle, N. Khan, O. Grinberg, D. Reid, A. Micallef,
H. Swartz, Appl. Magn. Reson. 2002, 22, 357–368.
[4] A. S. Micallef, R. C. Bott, S. E. Bottle, G. Smith, J. M. White,
K. Matsuda, H. Iwamura, J. Chem. Soc. Perkin Trans. 2 1999,
2, 65–71.
[36]
[37]
[38]
[39]
[40]
T. Kalai, M. Balog, J. Jeko, W. L. Hubbell, K. Hideg, Synthesis
2002, 16, 2365–2372.
T. Kalai, J. Jeko, Z. Berente, K. Hideg, Synthesis 2006, 3, 439–
446.
[5] N. V. Blough, D. J. Simpson, J. Am. Chem. Soc. 1988, 110,
1915–1917.
[6] S. A. Green, D. J. Simpson, G. Zhou, P. S. Ho, N. V. Blough,
J. Am. Chem. Soc. 1990, 112, 7337–7346.
Eur. J. Org. Chem. 2008, 5391–5400
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5399

K. E. Fairfull-Smith, S. E. Bottle
FULL PAPER
[41] B. Bognar, E. Osz, K. Hideg, T. Kalai, J. Heterocycl. Chem.
2006, 43, 81–86.
[42] C. Stroh, M. Mayor, C. von Haenisch, Eur. J. Org. Chem. 2005,
17, 3697–3703.
[50] C. Stroh, M. Mayor, C. von Haenisch, Tetrahedron Lett. 2004,
45, 9623–9626.
[51] J.-H. Li, Y. Liang, Y.-X. Xie, J. Org. Chem. 2005, 70, 4393–
4396.
[43] D. J. Keddie, K. E. Fairfull-Smith, S. E. Bottle, Org. Biomol.
Chem. DOI: 10.1039/b806963h.
[52] J. Kajanus, S. B. van Berlekom, B. Albinsson, J. Mårtensson,
Synthesis 1999, 1155–1162.
[44] M. S. Sherburn, D. J. Sinclair, J. Org. Chem. 2005, 70, 3730–
[53] D. R. Coulson, Inorg. Synth. 1971, 13, 121–124.
[54] Y. Kim, D. Shin, S. Kim, C. Ko, H. Yu, Y. Chae, S. Kwon,
Adv. Mater. 2001, 13, 1690–1693.
3733.
[45] H. A. Dieck, F. R. Heck, J. Organomet. Chem. 1975, 93, 259–
263.
[55] C. Yang, J. Jacob, K. Müllen, Macromolecules 2006, 39, 5696–
[46] L. J. Cassar, J. Organomet. Chem. 1975, 93, 253–257.
[47] K. Sonogashira, Y. Tohda, N. Hagihara, Tetrahedron Lett.
1975, 16, 4467–4470.
5704.
[56] B. F. Duerr, Y. S. Ching, A. W. Czarnik, J. Org. Chem. 1988,
53, 2120–2122.
[48] K. Sonogashira in Handbook of Organopalladium Chemistry for [57] The diagnostic IR band for a nitroxide is 1431 cm–1, see L.
Organic Synthesis (Ed.: E. Negishi), Wiley-Interscience, New
York, 2002.
[49] O. Schiemann, N. Piton, J. Plackmeyer, B. E. Bode, T. F.
Prisner, J. W. Engels, Nat. Protoc. 2007, 2, 904–923.
Rintoul, A. S. Micallef, D. A. Reid, S. E. Bottle, Spectrochim.
Acta, Part A 2006, 63, 398–402.
Received: June 20, 2008
Published Online: July 29, 2008
5400
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 5391–5400