Synthesis and characterization of a paramagnetic receptor based on cyclobis(paraquat-p-phenylene) tetracation

Article abstract of DOI:10.1016/j.tetlet.2008.05.088

Synthesis of a new class of π-electron-deficient tetracationic cyclophane ring, cyclobis(paraquat-p-phenylene), carrying one or two paramagnetic side-arms based on 2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO) moiety has been achieved in five steps startin

Full text of DOI:10.1016/j.tetlet.2008.05.088

Tetrahedron Letters 49 (2008) 4784–4787
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis and characterization of a paramagnetic receptor based
on cyclobis(paraquat-p-phenylene) tetracation
*
Andrea Margotti, Costanza Casati, Marco Lucarini, Elisabetta Mezzina
Department of Organic Chemistry ‘A. Mangini’, University of Bologna, Via San Giacomo 11, I-40126 Bologna, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Synthesis of a new class of p-electron-deficient tetracationic cyclophane ring, cyclobis(paraquat-p-phen-
Received 21 April 2008
Revised 14 May 2008
Accepted 19 May 2008
Available online 23 May 2008
ylene), carrying one or two paramagnetic side-arms based on 2,2,6,6-tetramethylpiperidine-N-oxyl
(TEMPO) moiety has been achieved in five steps starting from 2,5-dimethyl benzoic acid. The possibility
of exploiting the proposed cyclophanes as hosts in rotaxane-like structures was tested preparing the
monoradical receptor by the clipping procedure in the presence of 1,5-dimethoxynaphthalene (DMN).
The addition of template allows the isolation of the monoradical complex with DMN.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Nitroxide
Cyclophanes
Host–guest chemistry
Free radicals
Many areas of chemistry take advantage of the information
obtained by the combination of molecules of open-shell configura-
tion and chemical stability, owing to the properties displayed by
long lifetime radicals to be isolated as pure compounds and
observed by conventional spectroscopic methods. Stable radicals1
have been used to obtain structural, dynamic and reactivity
information using electron paramagnetic resonance (EPR) spec-
troscopy, and for this reason have been introduced in techniques
such as spin labelling,2 spin trapping3 and EPR imaging,4 as well
as in the development of new materials displaying magnetic and
conductivity properties,5 or in metal-radical hybrid solid investiga-
tion towards molecule-based magnets.6
cyclobis(paraquat-p-phenylene) (CBPQT)4+, carrying one or two
paramagnetic side-arms (1aÅ and 1bÅÅ, respectively) based on
2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO) moiety as depicted
in Figure 1.12 The electron-deficient macrocycle was chosen
because of its use as ‘molecular shuttle’ in most of the molecular
devices proposed by Stoddart and co-workers.13 The reported
radical-armed (CBPQT)4+ macrocycle represents a promising host
for the preparation of paramagnetic supramolecular architectures,
in which spin-spin interactions can be reversibly switched on–off
by the movement of the paramagnetic shuttle.
In order to obtain the new macrocycles the bis-pyridinium pre-
cursors salts, either in the unsubstituted (6a) or in the one-armed
(6b) form, were linked with a benzylic dibromide 5 containing the
nitroxide functionality.
Scheme 1 outlines the synthesis of 5. Ester 2, obtained by the
acid-catalyzed treatment of 2,5-dimethylbenzoic acid with etha-
nol,14 was subjected to an NBS radical bromination with AIBN as
the initiator to afford the benzylic dibromide 3. Reduction of 3
using diisobutylaluminium hydride (DIBAL-H) as the reducing
agent, gave the corresponding alcohol 4 in good yields. Subsequent
esterification of 4 with 4-carboxy-TEMPO (4-COOH-TEMPO) affor-
ded the dibromide radical 5.
Amongst the open-shell species, nitroxides R2NOÅ represent the
most well-known class of stable radicals.7 The versatility of these
radicals is further due to the opportunity of behaving like a ‘nor-
mal’ diamagnetic compound, with the possibility of performing di-
verse organic reactions on molecules carrying a nitroxide group
without affecting the radical site itself.
Supramolecular chemistry8 and host–guest chemistry9 may
benefit by this possibility, since introduction of a paramagnetic
centre into a molecule acting as a component of the ‘supermole-
cule’ is potentially attractive to modulate the behaviour of
molecular devices. Recent literature examples of macrocycles
carrying paramagnetic centres are represented by paramagnetic
calix[4]arenes10 or cyclodextrin-labelled nitroxides.11
The modified dipyridinium salt 6b was prepared by stirring 5
with 2 equiv of 4,40-bipyridine in DMF at room temperature
according to the reaction conditions reported in the Scheme 1.
Chromatography by silica gel column (MeOH/NH4Cl/MeNO2) affor-
ded 6b as a reddish solid in good yield.
Here, we report the synthetic procedure for the preparation of a
new class of
p-electron-deficient tetracationic cyclophane ring,
Formation of the cyclophanes shown in Figure 1 was achieved
using the clipping methodology consisting in mixing 5 and salt
6a or 6b in refluxing acetonitrile for 24–48 h (Scheme 2).
* Corresponding author. Tel.: +39 05 209 5692; fax: +39 05 209 5688.
E-mail address: elisabetta.mezzina@unibo.it (E. Mezzina).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.05.088

A. Margotti et al. / Tetrahedron Letters 49 (2008) 4784–4787
4785
H'α
N
H'β Hβ
Hα
N
Hα
N
Hβ
a
N
N
a
ON
Ho
O
Hp
4 PF6
4 PF6
Hm
NO
NO
N
N
N
a'
a'
b'
H'β
H'α
O
H'α
Hβ'
Hα'
H'β
1b
1a
NO
O
= CH2OC(O)TEMPO
NO
=
O
Figure 1. Structures of the paramagnetic macrocycles 1aÅ and 1bÅÅ.
Scheme 1.
N
N
N
N
N
N
1) MeCN
Δ, 24-48 h
R
4 PF6
2 PF6
+
5
2) NH4PF6/H2O
13-15%
R'
R'
N
N
6a-6b
1a - 1b
a, R' = H
b, R' = R = CH2OC(O)TEMPO
Scheme 2.
Compounds 1aÅ and 1bÅÅ were recovered by precipitation from the
reaction mixture, and isolated without chromatography after
exchanging the Clꢀ counterions of the cyclophane with saturated
aqueous NH4PF6, as an orange-brown solid.15
(trace a) is reported. Because of the paramagnetic units the NMR
spectrum shows a very low spectral resolution. In particular, the
spectrum is characterized by the lack of the radical heterocyclic
signals, and by very broad signals due to the CBPQT protons. In
order to render the paramagnetic host suitable for a complete
characterization by NMR, it was necessary to quantitatively
convert it to the analogous N-hydroxy amine derivatives (1a-OH)
Structural assignment of the new CBPQT-based macrocycles 1aÅ
and 1bÅÅ was justified on the basis of ESI-MS and 1D, 2D NMR anal-
yses. In Figure 2, the 1H NMR spectrum (600 MHz, CD3CN) of 1aÅ

4786
A. Margotti et al. / Tetrahedron Letters 49 (2008) 4784–4787
the latter is an effective guest for electron-deficient CBPQT4+-based
cyclophanes.18 Actually, addition of the template favours the
clippage at room temperature between the bis-pyridinium salt
6a and the radical dibromide 5 in DMF, and affords a powder after
5 days.13 Separation of the TLC purple spots of the crude on a silica
gel column (MeOH/NH4Cl (2M)/CH3NO2 4:4:2) and product isola-
tion after treatment with saturated aqueous NH4PF6 give
[1aÅꢁDMN] (7Å) complex as a purple solid in 33% yield.19 The sche-
matic representation18 of 7Å is reported in Figure 4.
C6H4
b b'
OMe
Hp
Hm
Ho
Hβ
a
Hα
CH2O
H2 '
a'
b)
a)
H3 '
H4 '
Proof of the formation of the host-guest complexation has been
attained by UV–vis and NMR measurements. The absorption spec-
trum of 7Å (Fig. 5) recorded in water at 298 K shows a broad band in
C6H4
a a' b b'
Hp
Hm
Ho
Hβ
Hα
the visible region (kmax = 530 nm,
e
= 275 Mꢀ1 cmꢀ1) resulting from
-electron-defi-
CH 2
O
charge transfer interaction between DMN and the
p
cient bipyridinium units of the cyclophane 1aÅ and DMN.
Two main features may be outlined looking at the 1H NMR spec-
trum of the radical complex (Fig. 2, trace b). (i) The viologen host
9
8
7
6
5
4
δ / ppm
signals (H and Hb) are significantly shifted towards lower
frequencies (Dd = 0.2, 0.45 ppm). The most pronounced shifts are
a
Figure 2. 1H NMR spectra (600 MHz, CD3CN, 298 K) of the monoradical host 1aÅ (a)
and its complex with 1,5-dimethoxynaphthalene 7Å (b). The signals were assigned
on the basis of 2D ROESY experiments using the labels reported in Figure 1. The
dashed lines indicate the most pronounced signal shifts of the complex relatively to
the free host.
recorded for Hb, which owing to their central location in the
macrocycle are most affected from the inclusion of the guest. Also
the guest undergoes proton displacements after involvement in the
complex, substantial upfield shifts being measured for all the aro-
matic protons. (ii) All the radical host signals in the complexed
form (trace b) show much better resolution than those of the free
by adding directly inside the NMR sample stoichiometric amounts
of phenylhydrazine.16
macrocycle (trace a), the signals of H and Hb being splitted in four
a
The spectrum of 1a-OH (see Supplementary data) shows well-
and two sets of resonances, respectively. Because line broadening
of nuclear magnetic resonances in spin-labelled molecules is
distance dependent,20 the last observation must be related to the
position assumed by the radical arm in the free macrocycle and
resolved signals for the viologen protons (H and Hb); the presence
a
of the radical arm in the structure is evident by the peak shift of Ha0
close to the substituent (assigned by 2D ROESY experiments), and
by the splittings of the methylene signals (a and a0) of the 1,4-para-
phenylene unit, as a consequence of the arm-modified symmetry
of CBPQT4+. Detection of new sharp signals relative to the piperi-
dine moiety emerging after radical reduction allows the complete
1H picture of the macrocycle.
In Figure 3 is instead reported the spectrum of the diradical
CBPQT 1bÅÅ. It should be noted that it exhibits separate signals of
H
and H0 per viologen unit, and a couple of methylene proton res-
a
a
onances (a and a0), due to the presence of a radical substituent in
each phenyl ring of the tetracationic cyclophane. In the spectrum
of the paramagnetic host appears also one set of peaks belonging
to the nitroxyl heterocyclic ring, despite the existence of a para-
magnetic centre.17
The possibility of using the proposed receptors as a component
in rotaxane-like structure was verified by repeating the clipping
procedure for preparation of the macrocycles in the presence of
1,5-dimethoxynaphthalene (DMN), as it is well established that
Figure 4. Schematic complex structure.
0.4
0.3
Me
A
0.2
0.1
0.0
a
Heq
H'β
Hβ
H'α
CH2O
a'
Hα
HmHp
Ho
Hax
4-H
8
6
4
2
400
500
600
700
δ ppm
Wavelength (nm)
Figure 3. 1H NMR spectra (600 MHz, CD3CN, 298 K) of 1bÅÅ. The signals were assi-
gned on the basis of 2D ROESY experiments by using the labels reported in the
molecular structure of Scheme 1.
Figure 5. Spectrum UV–vis of the complex [7aÅ]ꢂ4Br in H2O (0.8 mM). In the same
spectral region 1aÅ does not show any significant absorption.

A. Margotti et al. / Tetrahedron Letters 49 (2008) 4784–4787
4787
Lahti, P. M., Ed.; Marcel Dekker: New York, 1999; (c) Rawson, J. M.; Alberala, A.;
Whalley, A. J. Mater. Chem. 2006, 16, 2560–2575.
in the complex. In the former case, the broadening of the lines
indicates that the nitroxide could be located in a position close
to the macrocyclic receptor21 similar to that found by Cooke et
al. in their armed CBPQT4+ derivative containing a pyrrole moi-
ety.22 Reasonably, complexation displaces the radical substituent
from its original position to a new position in which the free radical
part is farther from the macrocycle, thus resulting in an improve-
ment of spectral resolution.
6. (a) Caneschi, A.; Gatteschi, D.; Sessoli, R. Acc. Chem. Res. 1989, 22, 392–398;
(b) Manriquez, J. M.; Yee, G. T.; McLean, R. S.; Epstein, A. J.; Miller, J. S.
Science 1991, 252, 1415–1417; (c) Inoue, K.; Hayamizu, T.; Iwamura, H.;
Hashizume, D.; Ohashi, Y. J. Am. Chem. Soc. 1996, 118, 1803–1804; (d) Ise, T.;
Ishida, T.; Hashizume, D.; Iwasaki, F.; Nogami, T. Inorg. Chem. 2003, 42, 6106–
6113.
7. (a) Forrester, A. R.; Hay, J. M.; Thomson, R. H. Organic Chemistry of Stable Free
Radicals; Academic Press: London, 1968; (b) Rozanstev, E. G. Free Nitroxyl
Radicals; Plenum: New York, 1970; (c) Rozantsev, E. G.; Sholle, V. D. Synthesis
1971, 401; (d) Rozantsev, E. G.; Sholle, V. D. Synthesis 1971, 190; (e) Keana, J. F.
W. Chem. Rev. 1978, 78, 37–64.
8. Lehn, J.-M. Supramolecular Chemistry; Wiley-VCH: Weinheim, 1995.
9. (a) Cram, D. J. Angew. Chem., Int. Ed. Engl. 1988, 27, 1009–1020; (b) Cram, D. J.
Science 1983, 219, 1177–1183.
10. Rajca, A.; Mukherjee, S.; Pink, M.; Rajca, S. J. Am. Chem. Soc. 2006, 128, 13497–
13507.
11. (a) Ionita, G.; Chechik, V. Org. Biomol. Chem. 2005, 3, 3096–3098; (b) Bardelang,
D.; Rockenbauer, A.; Jicsinszky, L.; Finet, J.-P.; Karoui, H.; Lambert, S.; Marque,
S. R. A.; Tordo, P. J. Org. Chem. 2006, 71, 7657–7667; (c) Franchi, P.; Fanì, M.;
Mezzina, E.; Lucarini, M. Org. Lett. 2008, 10, 1901–1904.
12. The synthesis of mono- and bis-nitroxides derived from [2,2]-paracyclophane
has been already reported: Forrester, A. R.; Ramasseul, R. J. Chem. Soc. (B) 1971,
1638–1644.
Further support for the hypothesis that the heterocycle position
changes upon complexation comes from the observation of down-
field shifts for the piperidine protons when passing from the re-
duced free macrocycle 1a-OH to the corresponding diamagnetic
complex 7-OH (the NMR signals due to the heterocylic protons
are too broad to be detected in the spectrum of 1Å and 7Å).
EPR spectra of CH3CN solutions containing 1Å or 7Å were also re-
corded. The spectra show typical nitroxide EPR signals with the
high field line slightly broadened due to restricted tumbling. Quite
unexpected, the two radicals show very similar 14N hyperfine split-
tings, aN (15.82 G for 1Å and 15.75 G for 7Å), indicating that the com-
plexation does not significantly affect the spin distribution on the
nitroxide moiety.
13. Balzani, V.; Credi, A.; Raymo, F. M.; Stoddart, J. F. Angew. Chem., Int. Ed. 2000, 39,
3349–3391.
14. Benniston, A. C.; Harriman, A. Synlett 1993, 223–226.
Attempts to isolate the complex between the diradical CBPQT4+
(1bÅÅ) with DMN were unsuccessful, thus indicating that formation
of host–guest complex with DMN is considerably less favourable in
this case, presumably owing to the steric hindrance of the two
arms opposing to the insertion of the guest.
15. Compound 1aÅ:
A solution of 6a (0.240 g, 0.34 mmol) and 5 (0.164 g,
0.34 mmol) in dry acetonitrile (50 ml) was heated under reflux for 24 h.
More dibromide 5 (0.071 g, 0.14 mmol) was added and the reaction mixture
was refluxed for an additional 24 h. After the solution was cooled down to
room temperature, the precipitate was filtered off and washed with
acetonitrile (10 ml) and Et2O (10 ml). The solid was dissolved in water and
treated with
a saturated aqueous solution of NH4PF6 until no further
In conclusion, we have described the preparation of two new
receptors based on CBPQT tetracation bringing one or two substit-
uents on the paraphenylene units, whereby the arms contain per-
sistent paramagnetic centres. In particular, the monoradical
receptor 1aÅ is able to complex eletron-rich molecules. The com-
plex with DMN, isolated by flash chromatography, provides evi-
dence that replacement of the radical arm with DMN in the
complex imparts a drastic change upon the spectral proton signals
of the cavity, that appear well resolved and separated, contrary to
what happens in the free receptor which displays broad signals.
Therefore, the radical arm becomes a probe to detect inclusion
complex formation. We believe that the reported radical-armed
macrocycles may represent promising hosts for the preparation
of more complexed paramagnetic supramolecular architectures,
that is, rotaxanes or catenanes, which can be employed as mole-
cular magnetic devices.
precipitation was observed. The precipitate was filtered off and washed with
water, MeOH, Et2O and dried, affording
a reddish powder (0.058 g,
0.044 mmol) in 13% yield. 1H NMR (600 MHz, CD3CN, 298 K): d = 8.80–9.20
(m, 8H, H , H0 , H ), 8.30–8.50 (m, 8H, Hb, H , H Þ, 7.40–7.80 (m, 7H, HAr
,
0
0
0
a
a
b
C6H4), 5.75–6.10 (m, 8H, a, a0, b, b0), 5.20–5.35b(br s, 2H, CH2O); positive ESI-
MS: m/z 1167.7 [MꢀPF6]+, 511.2 [Mꢀ2PF6]2+. Compound 1bÅÅ: A solution of 6b
(0.140 g, 0.15 mmol) and 5 (0.071 g, 0.15 mmol) in dry acetonitrile (23 ml) was
heated under reflux for 24 h. After the solution was cooled down to room
temperature, the precipitate was filtered off and washed with acetonitrile
(10 ml) and Et2O (10 ml). The solid was dissolved in water and treated with a
saturated aqueous solution of NH4PF6 until no further precipitation was
observed. The precipitate was filtered off and washed with water, MeOH, Et2O
and dried, affording a brown powder (0.036 g, 0.023 mmol) in 15% yield. 1H
NMR (600 MHz, CD3CN, 298 K): d = 8.98 (br s, 4H, H ), 8.90 (br s, 4H, H0 ), 8.43
a
a
a
(br s, 8H, Hb, H0bÞ, 7.20–7.80 (m, 6H, HAr), 5.75–6.10 (m, 8H, a, a0), 5.10–5.40 (br
s, 4H, CH2O), 2.92–3.20 (m, 1H, 4-H), 2.02–2.12 (m, 2H, Heq), 1.64–1.76 (m, 2H,
Hax), 1.44 (s, 12H, Me).
16. Mezzina, E.; Fanì, M.; Ferroni, F.; Franchi, P.; Menna, M.; Lucarini, M. J. Org.
Chem. 2006, 71, 3773–3777.
17. From the spectral data it is not possible to gain information on the possible
isomers, which can be formed in the biradical respect to the relative
orientation of the radical arms both in the paraphenylene portions (pseudo-
meta, o pseudo-para) and in the macrocycle (sin or anti). For a discussion on the
possible isomers in disubstituted paracyclophanes see Ref. 12.
Acknowledgements
18. (a) Odell, B.; Reddington, M. V.; Slawin, A. M. Z.; Spencer, N.; Stoddart, J. F.;
Williams, D. J. Angew. Chem., Int. Ed. Engl. 1988, 27, 1547–1550; (b) Ashton, P.
R.; Odell, B.; Reddington, M. V.; Slawin, A. M. Z.; Stoddart, J. F.; Williams, D. J.
Angew. Chem., Int. Ed. Engl. 1988, 27, 1550–1553.
Financial support from MUR (Contract 2006033539) and from
the University of Bologna is gratefully acknowledged. We also like
to thank Fiammetta Ferroni for technical assistance, Dr. Andrea
Zattoni and Dr. Paolo Nanni for helpful discussion.
19. Compound 7aÅ:
A solution containing 2a (0.1 g, 0.14 mmol), 5 (0.066 g,
0.14 mmol), DMN (0.079 g, 0.42 mmol) and NaI (0.007 g) in dry DMF (10 ml)
was stirred at room temperature for 5 days under nitrogen. The solvent was
removed under vacuum and the residue was chromatographed over a silica gel
column (length 6 cm, i.d. 1.5 cm) using a mixture of MeOH/NH4Cl (2 M)/
CH3NO2 (4:4:2) as eluent. The fractions containing the complex, indicated by
purple spots of TLC analysis (Rf 0.40), were combined together and
concentrated in vacuo. The residue was dissolved in water and a saturated
aqueous solution of NH4PF6 was added to afford 7aÅ. The precipitate was
washed with water and dried, furnishing the complex as a purple solid in 33%
Supplementary data
Supplementary data (spectroscopic characterization of all new
compounds) associated with this article can be found, in the online
version, at doi:10.1016/j.tetlet.2008.05.088.
yield. 1H NMR (600 MHz, CD3CN, 298 K): d = 8.88 (d, J = 4.8 Hz, 2H, H0 ), 8.86 (d,
a
0
J = 4.8 Hz, 2H, H0 ), 8.83 (s, 2H, H ), 8.75 (s, 2H, H ), 7.99 (s, 6H, Hb, H ), 7.93 (s,
0
References and notes
a
a
a
b
0
2H, Hb ), 7.78 (br s, 1H, Ho) 7.67 (s, 4H, C6H4), 7.48 (br s, 2H, Hm, Hp), 6.86 (m,
2H, H-30), 6.67 (d, J = 7.2 Hz, 2H, H-20), 5.88–5.98 (m, 2H, a0), 5.80 (s, 2H, a), 5.77
(s, 2H, b) 5.76 (s, 2H, b), 5.50–5.65 (m, 2H, H-40), 5.37 (br s, 2H, CH2O), 3.98 (s,
6H, OMe).
1. For a recent review see: Hicks, R. G. Org. Biomol. Chem. 2007, 5, 1321–1338.
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20. Ref. 2, pp 339–372.
21. The formation of a self-complexing system having the radical inside the cavity
cannot be proved by NMR because of the lack of the nitroxide heterocyclic
signals in the spectrum.
22. Cooke, G.; Woisel, P.; Bria, M.; Delattre, F.; Garety, J. F.; Hewage, S. G.; Rabani,
G.; Rosair, G. M. Org. Lett. 2006, 8, 1423–1426.