Triplet ground state (S = 1) pegylated bis(aminoxyl) diradical: Synthesis and the effect of water on magnetic properties

Article abstract of DOI:10.1039/b508094k

The synthesis and magnetic characterization of pegylated bis(aminoxyl) diradical with an S = 1 ground state are presented, revealing water-induced changes in the molecular conformation and magnetic properties. The Royal Society of Chemistry 2005.

Full text of DOI:10.1039/b508094k

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Triplet ground state (S 5 1) pegylated bis(aminoxyl) diradical:
synthesis and the effect of water on magnetic properties{
Gae¨lle Spagnol, Kouichi Shiraishi, Suchada Rajca and Andrzej Rajca*
Received (in Cambridge, UK) 9th June 2005, Accepted 26th August 2005
First published as an Advance Article on the web 16th September 2005
DOI: 10.1039/b508094k
monoradical 2, and their magnetic characterization in various
The synthesis and magnetic characterization of pegylated
bis(aminoxyl) diradical with an S 5 1 ground state are
presented, revealing water-induced changes in the molecular
conformation and magnetic properties.
media, including water.
Triplet ground state (S 5 1) organic diradicals with strong
ferromagnetic coupling are widely used as building blocks for
organic and organometallic magnets.1–3 Only a few diradicals are
both stable at ambient conditions and possess ferromagnetic
coupling of such strength that the singlet–triplet energy gap (2J) is
far greater than the thermal energy at room temperature.1,3
Nonadditive properties of such strongly-coupled S 5 1 diradicals,
which are enhanced compared to those of two independent (or
weakly coupled) S 5 K radicals, have not been significantly
explored beyond organic magnetism. In particular, understanding
of the effect of water on structure and magnetic properties of S 5 1
diradicals (and high-spin polyradicals) is important for their
applications in biological media.4
The synthesis of diradical 1 is outlined in Scheme 1.{ The Li–Br
exchange on bromobenzene 3,14 followed by the addition of
pegylated ketone 4, provides alcohol 5. After etherification of 5,
the ether 6 is treated with TBAF, to give dihydroxylamine 7.
Oxidation of 7 with Ag2O yields diradical 1. An analogous
synthetic route, starting from 815 (Scheme 1), provides mono-
radical 2 in overall yield of 33% for four steps.{ This synthetic
approach should be readily applicable to the preparation of
pegylated radicals.
In biological and polymer sciences, organic radicals, especially
aminoxyls, are intensively studied as spin labels, contrast agents for
magnetic resonance imaging (MRI), antioxidants, and mediators
for controlled radical polymerization.5–9 Numerous synthetic
approaches to water soluble aminoxyls have been reported,9 to
facilitate biological applications and polymerization in water.
Recently, water soluble bis(aminoxyl)s and oligo(aminoxyl)s were
investigated in biological sensing and magnetic imaging;6–8,10
however, only weakly-coupled bis(aminoxyl)s and oligo-
(aminoxyl)s, which may be viewed as ensembles of independent
S 5 K radicals at room temperature (above y1 K), were
prepared and studied.
The EPR spectra of 1 mM 1 in toluene, ethanol, water–ethanol
(1 : 2), and water–glycerol (2 : 1) at 140 or 135 K show the
expected dipolar patterns for S 5 1 states, including a moderately
intense half-field signal. The spectra in toluene, obtained after
slow cooling from room temperature to 140 K, are assigned to
a single S 5 1 diradical, with zero-field splitting (zfs) parameters,
One of the specific areas, in which water-soluble and strongly-
coupled S 5 1 diradicals would be of great interest, includes
contrast agents for MRI, currently dominated by the complexes of
S 5 7/2 GdIII and other paramagnetic metal ions.11 In conjunction
with the favorable in vivo properties of aminoxyls and
theoretically predicted proportionality of relaxivity to S(S + 1),12,13
bis(aminoxyl)s and oligo(aminoxyl)s with S . K at room
temperature provide novel insight into the design and under-
standing of contrast agents for MRI.6,7
In this paper, we describe the synthesis of polyethylene glycol
(PEG) functionalized (pegylated) S 5 1 diradical 1 and S 5 K
Department of Chemistry, University of Nebraska, Lincoln, Nebraska
68588-0304, USA. E-mail: arajca1@unl.edu; Fax: +1 402 472 9402;
Tel: +1 402 472 9196
{ Electronic supplementary information (ESI) available: Experimental
section, including 1H NMR spectra (synthetic intermediates and the
aminoxyls) and selected EPR spectra of the aminoxyls. See http://
dx.doi.org/10.1039/b508094k
Scheme 1 Reagents and conditions: (a) n-BuLi (1.2 equiv.), THF, 278 uC
to room temperature (65%); (b) NaH (5 equiv.), MeI (5 equiv.), THF, 0 uC
to 45 uC (90%); (c) TBAF (4.6 equiv.), THF, room temperature (95%); (d)
Ag2O (10 equiv.), CHCl3, room temperature (44%).
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|D/hc| 5 1.24 6 1022 cm21 and |E/hc| 5 1.13 6 1023 cm21
(Fig. 1). For rapidly cooled water-containing solutions of 1 (water–
ethanol and water–glycerol), the EPR spectra may be assigned to
two S 5 1 diradicals, presumably conformers. The spectral
simulations of the Dms 5 1 regions show that the major
and the minor S 5 1 diradicals have relatively smaller (y1.2 6
1022 cm21) and larger (y1.7 6 1022 cm21) values of |D/hc|,
respectively. For 1 in water–ethanol (1 : 2), the relative content of
the |D/hc| # 1.7 6 1022 cm21 diradical is about 10% vs. 30% in
water–glycerol (2 : 1). These results suggest that 1 in water at room
temperature may exist as two conformers (diastereomers) with
different dihedral angles between the nitroxide moieties and 1,3-
phenylene.16 Such conformers would possess, in principle, different
singlet–triplet energy gaps (2J).
The S 5 1 ground state and the value of 2J were determined by
SQUID magnetometry. Plots of xT vs. T (x, molar magnetic
Fig. 2 Plots of xT vs. T for diradical 1. For the plot at magnetic field
H 5 500 Oe, the temperature range is T 5 1.8–60 K; for all other plots,
T 5 1.8–290 K. The solid line shows an example of numerical fit to the
experimental data at H 5 30000 Oe, using eqn (1S) (ESI).{
susceptibility) for neat diradical
1 show a maximum of
xTmax 5 0.91 emu K mol21 near 100 K, with significant drop-
offs at both higher and lower temperatures (Fig. 2). An excellent
numerical fit to these data is obtained with three variable
parameters (eqn (1S), ESI{): singlet–triplet energy gap (2J/k 5
650 K or 2J 5 1.3 kcal mol21), mean-field parameter for
intermolecular interactions (h 5 22.2 K), and mass factor
(w 5 0.93).17 These results indicate that diradical 1 possesses the
S 5 1 ground state. However, the singlet–triplet energy gap of 1
exceeds RT at room temperature by a factor of 2–3 only, leading
to significant population of the singlet excited state at room
temperature. The value of 2J/k may be affected by out-of-plane
twisting of the aminoxyl moeties, caused by the sterically large
PEG-based substituent.16
For 17–25 mM 1 in D2O, qualitatively similar xT vs. T plots are
obtained. Notably, intermolecular antiferromagnetic interactions
remain significant (h # 22 K), suggesting aggregation of 1 in
water. Partial population of the singlet excited state at room
temperature is also consistent with the values of magnetic
1
susceptibility obtained from H NMR using the Evans method:
xT 5 0.81 ¡ 0.03 emu K mol21 for 15–21 mM 1 in H2O–D2O
(y1 : 1) at 295–298 K is obtained.18 Notably, a 1H NMR
resonance for the tert-butyl groups of the aminoxyl moieties
appears at 26.9 ppm in D2O vs. at 22.3 ppm in CDCl3. The
upfield 1H chemical shift in D2O suggests increased localization of
spin density at the aminoxyl moieties, as observed in sterically
hindered bis(aminoxyls), in which aminoxyl moieties are twisted
out of the plane of the 1,3-phenylene.19 This out-of-plane twisting
is also consistent with the EPR spectra of 1 in water-containing
matrices showing the presence of a conformer with relatively large
value of |D/hc| # 1.7 6 1022 cm21 20
.
We postulate that strong solvation of the PEG moiety of 1 in
the presence of water increases its effective volume, to increase the
twisting of the aminoxyls out of the plane of the 1,3-phenylene.
This in turn, weakens the exchange coupling between the
aminoxyls, thus decreasing the singlet–triplet energy gap for 1 in
water.
Longitudinal relaxation times (T1) of protons in water were
measured at 200 MHz, as a function of the concentration of 1
and 2 at 298 K. Relaxivities are obtained from the slopes of
1/T1 vs. concentration plots (Fig. 3). Relaxivities of 0.20 and
0.14 s21 mM21 are obtained for 1 and 2, respectively.21 Therefore,
the experimental relaxivity per aminoxyl moiety is significantly
lower in diradical 1 vs. monoradical 2. This is in contrast to the
higher relaxivity per aminoxyl in an S 5 1 diradical predicted from
the relative values of S(S + 1) 5 0.75, 1.5, and 2.0 for an S 5 K
monoradical, a weakly coupled diradical, and an S 5 1 diradical,
respectively. This is consistent with the weakened exchange
coupling for 1 in water but it implies that other factors decrease
Fig. 1 X-Band EPR spectra for diradical 1 in toluene (plots A for
DmS 5 1 and B for DmS 5 2) and EtOH–water (2 : 1, plots C for DmS 5 1
and D for DmS 5 2) at 135–140 K. In plots A and C, the simulations
correspond to one S 5 1 diradical and a mixture of two S 5 1 diradicals,
respectively. The center lines, most likely corresponding to S 5 K
monoradical impurities, are not simulated. Parameters for the simulations
are shown in Fig. 11S–13S (ESI).{
5048 | Chem. Commun., 2005, 5047–5049
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Fig. 3 Plots of 1/T1 (for protons of water) vs. mM concentration of
diradical 1 and monoradical 2 in H2O or phosphate buffer (50 mM,
pH 7.2).
8 A. T. Yordanov, K. Yamada, M. C. Krishna, J. B. Mitchell, E. Woller,
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the relaxivity in 1 as well. Aggregation of 1 would affect both
rotational correlation time and access of water (the exchange rate
of water). Furthermore, the electronic T1 of 1 may be lowered, due
to modulation of zfs and/or 2J.13
In summary, a versatile synthetic route to pegylated aminoxyls
is developed, making available water-soluble high-spin diradicals
for biologically related studies. Furthermore, discovery of the
water-induced changes in molecular conformation and magnetic
properties in the present work suggests that structures with
constrained, planarized conformations may be required to obtain
high-spin diradicals with 2J .. RT in water at room temperature.
The synthesis of such diradicals and their assembly into well-
defined, water accessible, high-symmetry structures with negligible
zfs is in progress in this laboratory.
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17 (a) The actual singlet–triplet energy gap may be somewhat smaller than
the fitted value of 2J/k 5 650 K, because of the possible slight over-
correction for diamagnetism using point-by-point correction and full
values of Pascal constants for 1 (ESI{); (b) The mass parameter w
accounts mainly for incomplete mass transfer of 1 to the SQUID sample
tube.
18 The values of xT measured by the Evans method are relatively less
accurate, e.g., due to strong interaction of water with the diradical or
incomplete mass transfer of 1.
This research was supported by the National Science
Foundation (grant No. CHE-0414936), including the purchase
of the Electron Paramagnetic Resonance (EPR) spectrometer
(grant No. DMR-0216788). We thank Sara Basiaga and Dr.
Joseph Dumais for their help with the NMR spectroscopy. We
thank Sumit Mukherjee and Kausik Das for their help with the
synthesis.
19 A. Rajca, K. Lu, S. Rajca and C. R. Ross, Chem. Commun., 1999,
1249–1250. The aminoxyl moieties in the 4,6-bis(trifluoromethyl)-N-
N9-di-tert-butyl-1,3-phenylenebis(aminoxyl) diradical are expected to be
more sterically hindered (significantly twisted out-of-plane) than in 1;
consequently, thermal population of the singlet excited state already
above 40 K was detectable by EPR spectroscopy, the value of
Notes and references
{ For details of synthesis and characterization of compounds 1, 2 and their
synthetic intermediates (e.g., 4–6 for 1), see ESI.
1
|D/hc| 5 1.5 6 1022 cm21 was relatively large, and the H resonance
corresponding to the tert-butyl groups of the aminoxyl moieties at
216 ppm was relatively upfield shifted.
20 A. Rajca, S. Utamapanya and J. Xu, J. Am. Chem. Soc., 1991, 113,
9235–9241.
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21 (a) Relaxivity of 3-carboxyl-2,2,5,5-tetramethylpyrrolidine-1-oxyl under
identical conditions is 0.15 s21 mM21; (b) Relaxivities of piperidine and
pyrrolidine S 5 K aminoxyls: P. Vallet, Y. Van Haverbeke,
P. A. Bonnet, G. Subra, J.-P. Chapat and R. N. Muller, Magn.
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