Self-assembled hexadecanitroxide

Article abstract of DOI:10.1021/ol901028h

A radical-armed guanosine derivative shows drastic magnetic changes by addition (removal) of alkali metal cations corresponding to the reversible assembly (disassembly). In the presence of templating metal ions, the assembly is formed by 8 molecules and 1

Full text of DOI:10.1021/ol901028h

ORGANIC
LETTERS
2009
Vol. 11, No. 14
3004-3007
Self-Assembled Hexadecanitroxide
Paolo Neviani, Elisabetta Mileo, Stefano Masiero, Silvia Pieraccini,
Marco Lucarini,* and Gian Piero Spada*
Alma Mater Studiorum - UniVersita` di Bologna, Dipartimento di Chimica Organica
“A. Mangini”, Via San Giacomo 11, 40126 Bologna, Italy
marco.lucarini@unibo.it; gianpiero.spada@unibo.it
Received May 11, 2009
ABSTRACT
A radical-armed guanosine derivative shows drastic magnetic changes by addition (removal) of alkali metal cations corresponding to the
reversible assembly (disassembly). In the presence of templating metal ions, the assembly is formed by 8 molecules and 16 open-shell
moieties confined in a sphere with a diameter of ca. 30 Å.
Among noncovalent interactions, multiple hydrogen bonds
have widely been adopted to control the formation of highly
ordered nanoarchitectures1 because of their directionality,
selectivity, and dynamic nature.2 One versatile multiple
hydrogen bonding unit is represented by guanosine. Depend-
ing on their substitution pattern, solvent, and cation avail-
ability, lipophilic guanosine derivatives spontaneously self-
associate to give either H-bonded ribbons or quartet-based
columnar structures3 that can be interconverted by the
appropriate external chemical stimulus.4,5 As it is possible
to functionalize the guanosines in the C8 position and/or at
the sugar hydroxy functions, they are ideal and promising
scaffolds to locate functional units in preprogrammed posi-
tions.4-6
(1) See, a few recent examples: (a) Schenning, A. P. H. J.; Meijer, E. W.
Chem. Commun. 2005, 3245–3258. (b) Jonkheijm, P.; Miura, A.; Zdanows-
ka, M.; Hoeben, F. J. M.; De Feyter, S.; Schenning, A. P. H. J.; De Schryver,
F. C.; Meijer, E. W. Angew. Chem., Int. Ed. 2004, 43, 74–78. (c) Wu¨rthner,
F.; Yao, S.; Heise, B.; Tschierske, C. Chem. Commun. 2001, 2260–2261.
(d) Yagai, S.; Mahesh, S.; Kikkawa, Y.; Unoike, K.; Karatsu, T.; Kitamura,
A.; Ajayaghosh, A. Angew. Chem., Int. Ed. 2008, 47, 4691–4694. (e) Yagai,
S.; Seki, T.; Karatsu, T.; Kitamura, A.; Wu¨rthner, F. Angew. Chem., Int.
Ed. 2008, 47, 3367–3371.
(4) Graziano, C.; Pieraccini, S.; Masiero, S.; Lucarini, M.; Spada, G. P.
Org. Lett. 2008, 10, 1739–1742
.
(5) (a) Spada, G. P.; Lena, S.; Masiero, S.; Pieraccini, S.; Surin, M.;
Samor`ı, P. AdV. Mater. 2008, 20, 2433–2438. (b) Betancourt, J. E.; Mart´ın-
Hidalgo, M.; Gubala, V.; Rivera, J. M. J. Am. Chem. Soc. 2009, 131, 3186–
3188
.
(6) A few selected recent papers: (a) Lena, S.; Masiero, S.; Pieraccini,
S.; Spada, G. P. Chem.sEur. J. 2009, Published online: May 6, 2009, DOI:
10.1002/chem.200802506. (b) Sreenivasachary, N.; Lehn, J. M. Proc. Natl.
Acad. Sci. U.S.A. 2005, 102, 5938–5943. (c) Kaucher, M. S.; Harrell, W. A.,
Jr.; Davis, J. T. J. Am. Chem. Soc. 2006, 128, 38–39. (d) Arnal-He´rault,
C.; Banu, A.; Barboiu, M.; Michau, M.; van der Lee, A. Angew. Chem.,
Int. Ed. 2007, 46, 4268–4272. (e) Zhong, C.; Wang, J.; Wu, N.; Wu, G.;
Zavalij, P. Y.; Shi, X. Chem. Commun. 2007, 3148–3150. (f) Arnal-He´rault,
C.; Pasc, A.; Michau, M.; Cot, D.; Petit, E.; Barboiu, M. Angew. Chem.,
Int. Ed. 2007, 46, 8409–8413. (g) Kumar, A. M. S.; Sivakova, S.; Marchant,
R. E.; Rowan, S. J. Small 2007, 3, 783–787. (h) Otero, R.; Scho¨ck, M.;
Molina, L. M.; Lægsgaard, E.; Stensgaard, I.; Hammer, B.; Besenbacher,
(2) Lehn, J.-M. Supramolecular Chemistry Concepts and PerspectiVes;
VCH: Weinheim, 1995.
(3) (a) Davis, J. T.; Spada, G. P. Chem. Soc. ReV. 2007, 36, 296–313.
(b) Liu, X.; Kwan, I. C. M.; Wang, S.; Wu, G. Org. Lett. 2006, 8, 3685–
3688. (c) Araki, K.; Yoshikawa, I. Top. Curr. Chem. 2005, 256, 133–165.
(d) Sessler, J. L.; Sathiosatham, M.; Doerr, K.; Lynch, V.; Abboud, K. A.
Angew. Chem., Int. Ed. 2000, 39, 1300–1303. (e) Sivakova, S.; Rowan,
S. J. Chem. Soc. ReV. 2005, 34, 9–21. (f) Lena, S.; Masiero, S.; Pieraccini,
S.; Spada, G. P. Mini-ReV. Org. Chem. 2008, 5, 262–273. (g) Garcia-Arriaga,
M.; Hobley, G; Rivera, J. M. J. Am. Chem. Soc. 2008, 130, 10492–10493.
F. Angew. Chem., Int. Ed. 2005, 44, 2270–2275
.
10.1021/ol901028h CCC: $40.75
Published on Web 06/19/2009
 2009 American Chemical Society

Recently we have shown that the scaffolding of the
persistent radical unit 4-carbonyl-2,2,6,6-tetramethylpiperi-
dine-1-oxyl (TEMPO), is achieved by taking advantage of
the self-assembly templated by potassium ions of the
guanosine derivative 1 into a H-bonded network.4 In the
presence of potassium ions, this compound can form in fact
a D4-symmetric octameric assembly [18K]+ containing eight
spin centers showing a weak electron spin-spin exchange
interaction. Reversible interconversion, fueled by cation
release and complexation, allows the switching between
discrete quartet-based assemblies and molecularly dissolved
1 (or its ribbon-like supramolecular oligomers), thus the
control of the intermolecular weak spin-spin interactions.
The system described in our previous communication4 was
the first example of a reversible introduction-suppression of
a weak spin-spin exchange in a self-recognizing and self-
assembling molecule controlled by the addition/removal of
a templating cation.7 Our next challenge was to increase the
spin exchange difference between the two states to obtain
drastic magnetic changes before and after addition of the
metal cation.
Figure 1. G-quartet motif and a schematic representation of D4
and C4-symmetric octamers. Red and blue color refers to the two
heterotopic faces of the G-quartet.
or tail-to-tail)6a,8 and this structural variation could originate
a different (higher) spin-spin interaction.
We will show that 2a, despite the presence of two bulky
substituents, forms indeed a K+-templated octameric as-
sembly giving rise to very strong spin-spin interactions
comparable to those observed in very concentrated mono-
radical solutions. This finding is consistent with the proposed
structure consisting of 16 radical units confined within the
complex.
Because steric hindrance potentially introduced by the
double substitution in O5′ and O3′ could destabilize su-
pramolecular assemblies, CD spectroscopy was initially
employed to prove the self-assembly of 2a to give quartet-
based structures in CH2Cl2 upon K-Pic extraction.
Circular dichroism is diagnostic of either the formation
of G-quartet based assemblies9 or the stacking polarity of
two contiguous G-quartets.10 In fact, the tetramers do not
stack in register, but are rotated with respect to each other
to give, in the 230-300 nm region, characteristic of the
π-π* transitions of guanine chromophore, a double signed
exciton-like CD signal. This couplet, whose sign allows the
assignment of the stacking helicity (handedness), exhibits
opposite signed bands at ca. 260 and 240 nm for the head to
tail (C4-symmetric) stacking while both bands are blue-shifted
by 20-30 nm in the D4-symmetric stacking.10
In this communication, we report on the self-assembly
properties of derivative 2a where two TEMPO units are
connected to the guanosine deoxynucleoside at the O5′ and
O3′ positions. This target molecule has been chosen for two
reasons: (i) in the metal templated assembled species of 2a
the number of paramagnetic units doubles, possibly leading
to significant enhancement of magnetic coupling; (ii) passing
from ribo-guanosine (such as 1) to 2′-deoxyguanosine
derivatives, the discrete K+-templated assembly was expected
to be C4-symmetric (the two faces of the G-quartets are
heterotopic and, in principle, the two quartets in the octamer
can be arranged in three different orientations, see Figure 1,
C4-symmetric head-to-tail, and D4-symmetric head-to-head
(7) Self-assembled spin cage containing four radical centers have also
been reported: Nakabayashi, K.; Ozaki, Y.; Kawano, M.; Fujita, M. Angew.
Chem., Int. Ed. 2008, 47, 2046–2048.
(8) C4-symmetic octamers are described, for example, in: (a) Marlow,
A. L.; Mezzina, E.; Spada, G. P.; Masiero, S.; Davis, J. T.; Gottarelli, G.
J. Org. Chem. 1999, 64, 5116–5123. D4-symmetric octamers are described,
for example, in: (b) Martic´, S.; Liu, X.; Wang, S.; Wu, G. Chem.sEur. J.
2008, 14, 1196–1204. (c) Kaucher, M. S.; Lam, Y.-F.; Pieraccini, S.;
Gottarelli, G.; Davis, J. T. Chem.sEur. J. 2005, 11, 164–173.
(9) Paramasivan, S.; Rujan, I.; Bolton, P. H. Methods 2007, 43, 324–
331. Gottarelli, G.; Spada, G. P.; Garbesi, A. In ComprehensiVe Supramo-
lecular Chemistry; Sauvage, J.-P.; HosseiniM. W., Eds.; Pergamon: Oxford,
1996; Vol. 9, pp 483-506.
(10) (a) Gray, D. M.; Wen, J.-D.; Gray, C. W.; Repges, R.; Repges, C.;
Raabe, G.; Fleishhauer, J. Chirality 2008, 20, 431–440. (b) Gottarelli, G.;
Masiero, S.; Spada, G. P. Enantiomer 1998, 3, 429–438. (c) Gottarelli, G.;
Lena, S.; Masiero, S.; Pieraccini, S.; Spada, G. P. Chirality 2008, 20, 471–
485.
Figure 2. CD spectra of 2a (5 mM) before (red line) and after
(black line) K-Pic extraction. CD spectra of 2a/K-Pic complex
sample after dilution to 0.5 mM (blue line) and after addition of 4
equiv [2.2.2] cryptand (green line).
Org. Lett., Vol. 11, No. 14, 2009
3005

Figure 2 shows CD spectra of solutions of 2a recorded
before (red trace) and after (black trace) solid-liquid
extraction of potassium picrate K-Pic (i.e., after stirring the
guanosine solution with solid K-Picssee Supporting Infor-
mation). While the solution of 2a shows a weak Cotton effect
corresponding to the guanine chromophore, in the presence
of K-Pic an intense negative CD coupling with the negative
and positive components at around 265 and 245 nm,
respectively, is observed: this feature is diagnostic of a C4-
symmetric assembly of (at least) two G-quartets chirally
rotated. Intensity and shape of the CD spectrum do not
change with concentration, in the range 8-0.5 mM (see
Figure 2, blue trace), suggesting that in these conditions the
self-assembled structure is maintained. The molar ratio
between 2a and K-Pic has been determined spectrophoto-
metrically to be >8:1 (see Supporting Information). These
findings suggest that the assembly is a C4-symmetric octamer
formed by two head-to-tail stacked G-quartets.
higher spin states arising from multiple interactions between
the 16 radical units.
At 77 K in CH2Cl2 glass, the spectrum of the octamer
(see Figure 3, trace c) showed only a featureless single peak
in the g ≈ 2 region and a weak |∆ms| ) 2 peak at 1660 G.
The observation of a |∆ms| ) 2 transition also support the
presence of intermolecular spin-spin interaction. However,
the signal of |∆ms| ) 2 transition is very weak, indicating
that these transition probabilities are extremely small as a
result of a small D-value of the high spin-spin states from
the octamer. Accordingly to previous investigation11,12 on
symmetric tetraradical, we attributed the lack of resolvable
zero field splitting to the time-averaged symmetry of the
complex (Vide infra).
Reversible interconversion between uncomplexed and
octameric forms was demonstrated by addition of four
equivalents of [2.2.2] cryptand to a solution containing the
assembly. Under these conditions the EPR and CD spectra
returned to the original signals (see Figure 2, green trace,
and Supporting Information).13
Because of the presence of two paramagnetic units, the
1H NMR spectra of 2a are characterized by a very low
spectral resolution and their analysis turned out far more
complicated than for derivative 1. Therefore we prepared
and characterized by CD and NMR compound 2b in which
the paramagnetic moiety is replaced by the closed-shell
structurally related 3,3,5,5-tetramethyl-4-oxocyclohexanecar-
boxylate fragment. Because of the much higher resolution
of NMR spectra, a full characterization of the assembly could
be obtained for this derivative.
Figure 3. ESR spectra of 2a (0.5 mM) before (a) and after (b)
K-Pic extraction. (c) ESR spectrum recorded at 77 K in CH2Cl2
glass in the presence of K+.
Figure 3 shows ESR spectra recorded on 2a in CH2Cl2
(before, trace a, and after, trace b, K-Pic extraction). In the
absence of metal cations, the spectrum is characterized by
three equally spaced lines with a broadening between them,
this being an indication that intramolecular spin exchange
is occurring. In sharp contrast, the ESR spectrum recorded
after solid-liquid extraction of potassium picrate shows
mainly one broad signal whose integrated intensity corre-
sponds to the initial amount of radicals. The broadening (peak
to peak line width ) 12 G) of the signal is independent of
concentration and temperature, and thus interassembly
interactions and motional broadening can be discounted. This
spectrum is reminiscent of those obtained from very con-
centrated nitroxide solutions (>0.05 M).11 Since the spectrum
was obtained at 0.5 mM concentration, the signal broadening
is ascribed to the proximity of spin centers of 2a within the
framework of the octamer. This signal may contain not only
a triplet transition but also other multiplet transitions from
Figure 4. Portion of the 600 MHz NOESY spectrum of the
octameric complex between 2b and K-Pic, recorded at rt in CD2Cl2
(mixing time 150 ms) showing the interquartet correlations.
The proton spectrum of a CD2Cl2 solution of 2b after
K-Pic extraction (see Supporting Information) is character-
ized by the doubling of almost all of the signals. Integration
(11) Wertz, J. E.; Bolton, J. R. Electron Spin Resonance; Chapman and
Hall: New York, 1986.
3006
Org. Lett., Vol. 11, No. 14, 2009

of the picrate signal at 8.75 ppm and H8 signals (8.03 and
7.48 ppm) supports a 8:1 stoichiometry for the complex. The
signal doubling is thus consistent with a C4-symmetric
octamer. This is confirmed by NOESY spectra (Figure 4 and
Supporting Information), which show the features of an
octamer composed of an all-anti quartet stacked on top of
an all-syn quartet in an head-to-tail relative orientation.7 In
particular, the characteristic interquartet correlations between
syn-H8 (7.48 ppm) and anti-H1′ (6.43 ppm) and between
anti-H8 (8.03 ppm) and syn-H5′/H5′′ (4.79 and 4.53 ppm)
can be observed.
Shape and intensity of CD spectra of 2b (before and after
K-Pic extraction) are quite similar to those of 2a (see
Supporting Information) suggesting a similar self-assembly
behavior.
Figure 5. Structure of the octamer that refer to the time interval of
dynamic simulation between 2000th to the 2250th ps.
distance between radical oxygen atoms of 7.5 Å, which is
expected given a strong spin-spin interaction between all
of them.
Based on CD and NMR data we can conclude that in the
presence of K+ both derivatives 2a and 2b self-associate into
two stacking G-quartets in a head-to-tail arrangement with
the metal ion sitting in the central cavity, to form a
C4-symmetric octamer.
Although self-assembly of a paramagnetic guanosine in
the presence of alkali metal ions has already been reported,
here we have shown the advantages of obtaining a supramo-
lecular hexadecanitroxide from 2a, a derivative with two
open-shell moieties; in particular, ESR line-broadening due
to dipolar and/or exchange effects is more remarkable
because of increasing pathways of the radical-radical
contact. The present work should be regarded as the first
example of a radical-armed self-assembling scaffold showing
drastic magnetic changes by addition-removal of diamagnetic
alkali metal cations.14
To obtain a more detailed picture of the geometry of the
octamer, stochastic dynamics (SD) simulations were per-
formed by using the AMBER* force field of Macromodel
7.0 program. Initially, a Monte Carlo conformational search
was carried out by rotating all rotable bonds and by
preserving all-anti quartet stacked on top of an all-syn quartet
in an head-to-tail relative orientation. The most stable
conformation found by this procedure was then used in the
dynamic simulation. The simulations were run at 300 K with
time steps of 1 fs and an equilibrium time of 500 ps before
dynamic run. The total simulation time was set to 5000 ps
in order to achieve full convergence. Molecular dynamics
calculations (see Figure 5 and Supporting Information)
confirm the C4-symmetric nature of the octamer and indicate
the presence of four triradical modules protuding from the
two tetramers and pointing outside the assembly (in green)
and a tetraradical module located on top of the all-anti quartet
(in red). In the triradical module the nitroxide are arranged
in isosceles triangles. In each triangle, the distance between
the oxygen atoms of the three nitroxides is in the range
9.5-10.5 and 6-7 Å, which is expected to lead to three
spin-spin interactions with high J values. The tetraradical
unit is, instead, arranged in a rombic fashion with an average
Acknowledgment. We thank MIUR, through their Na-
tional Research Programmes (PRIN), for financial support.
Supporting Information Available: Experimental details;
CD, NMR, ESR spectra; video file of MD. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL901028H
(12) (a) Rajca, A.; Mukherjee, S.; Pink, M.; Rajca, S. J. Am. Chem.
Soc. 2006, 128, 13497–13507. (b) Kirste, B.; Grimm, M.; Kurreck, H. J. Am.
Chem. Soc. 1989, 111, 108–114.
(13) The low-intensity negative couplet present also before K-Pic
addition in the CD spectrum is due to Na+ (or K+) contamination resulting
from the synthetic procedure.
(14) Metal-induced magnetic exchange coupling in paramagnetic aza-
crowns have also been reported. Igarashi, K.; Nogami, T.; Ishida, T. Chem.
Commun. 2007, 501–503.
Org. Lett., Vol. 11, No. 14, 2009
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