Synthesis of polynitroxides based on nucleophilic aromatic substitution

Article abstract of DOI:10.1021/ol101529u

The scope and limitations of the synthesis of polynitroxides by nucleophilic substitution of electron-deficient fluorinated aromatic compounds are described. The method provides a facile route to the formation of polynitroxides exhibiting strong electron exchange between nitroxide groups.

Full text of DOI:10.1021/ol101529u

ORGANIC
LETTERS
2010
Vol. 12, No. 16
3696-3699
Synthesis of Polynitroxides Based on
Nucleophilic Aromatic Substitution
Olaf Zeika, Yongjun Li, Steffen Jockusch, Gerard Parkin, Aaron Sattler,
Wesley Sattler, and Nicholas J. Turro*
Department of Chemistry, Columbia UniVersity, New York, New York 10027
njt3@columbia.edu
Received July 3, 2010
ABSTRACT
The scope and limitations of the synthesis of polynitroxides by nucleophilic substitution of electron-deficient fluorinated aromatic compounds are
described. The method provides a facile route to the formation of polynitroxides exhibiting strong electron exchange between nitroxide groups.
Nitroxides are stable, persistent free radicals that are
important materials in many fields of science and technology
as a result of their electron spin and/or redox properties. For
example, nitroxides have been employed as organic ferro-
magnets, as contrast agents in nuclear magnetic imaging, as
labels in electron magnetic resonance imaging, and as
radiation protectors during whole brain radiotherapy.1 We
have been interested in the ESR properties of polynitroxides
for some time.2 The ESR properties of polynitroxides differ
fromthoseofmononitroxidesifsufficientelectronspin-electron
spin exchange occurs between two or more of the nitroxide
moieties. In particular, nitroxides have shown potential use
as paramagnetic relaxation agents.3 The strength of para-
magnetic relaxation is proportional to the concentration of
magnetic species. In addition, for polynitroxides, the para-
magnetic enhancement will depend not only on the concen-
tration of individual molecules but also on the number of
nitroxides that are involved in spin-spin interactions. For
example, a bis-nitroxide might behave as two independent
spin 1/2 species (two doublets) in the same molecule or as
a coupled spin 1 species (a triplet). Which situation applies
depends on the distance between the unpaired electrons.
Recently, polynitroxides have been employed as electron
spin agents for dynamic nuclear polarization (DNP)
experiments in which the sensitivity of NMR signals has
been shown to be enhanced by orders of magnitude.4 It
occurred to us that there was a need for a convenient,
general and efficient synthesis of polynitroxides of broad
scope that would allow examination of their structure-
relaxation agent or structure-DNP agent properties. We
report a strategy, along with its scope and limitations, for
(1) (a) Kovarski, A. L.; Sorokina, O. N. J. Magn. Magn. Mater. 2007,
311, 155. (b) Crayston, J. A.; Devine, J. N.; Walton, J. C. Tetrahedron
2000, 56, 7829. (c) Hyodo, F.; Soule, B. P.; Matsumoto, K.; Matsumoto,
S.; Cook, J. A.; Hyodo, E.; Sowers, A. L.; Krishna, M. C.; Mitchell, J. B.
J. Pharm. Pharmacol. 2008, 60, 1049. (d) Fuchs, J.; Groth, N.; Herrling,
T. Biol. Magn. Reson. 2003, 18, 483. (e) Metz, J. M.; Smith, D.; Mick, R.;
Lustig, R.; Mitchell, J.; Cherakuri, M.; Glatstein, E.; Hahn, S. M. Clin.
Cancer Res. 2004, 10, 6411.
(3) (a) Berner, B.; Kivelson, D. J. Phys. Chem. 1979, 83, 1401. (b)
Carvalho, R. A.; Peters, J. A.; Geraldes, C. F. G. C. Inorg. Chim. Acta
1997, 262, 167. (c) Gillespie, J. R.; Shortle, D. J. Mol. Biol. 1997, 268,
158. (d) Sartori, E.; Ruzzi, M.; Turro, N. J.; Komatsu, K.; Murata, Y.;
Lawler, R. G.; Buchanenko, A. L. J. Am. Chem. Soc. 2008, 130, 2221.
(4) (a) Matsuki, Y.; Maly, T.; Ouari, O.; Karoui, H.; LeMoigne, F.;
Rizzato, E.; Lyubenova, S.; Herzfeld, J.; Prisner, T.; Tordo, P.; Griffin,
R. G. Angew. Chem., Int. Ed. 2009, 48, 4996. (b) Song, C.; Hu, K.-N.; Joo,
C.-G.; Swager, T. M.; Griffin, R. G. J. Am. Chem. Soc. 2006, 128, 11385.
(2) (a) Turro, N. J.; Khudyakov, I. V.; Bossmann, S. H.; Dwyer, D. W.
J. Phys. Chem. 1993, 97, 1138. (b) Turro, N. J.; Khudyakov, I. V.; Dwyer,
D. W. J. Phys. Chem. 1993, 97, 10530. (c) Maliakal, A. J.; Turro, N. J.;
Bosman, A. W.; Cornel, J.; Meijer, E. W. J. Phys. Chem. A 2003, 107,
8467.
10.1021/ol101529u  2010 American Chemical Society
Published on Web 07/28/2010

the synthesis of polynitroxides based on nucleophilic
aromatic substitution reactions of fluorinated aromatic
substrates 1-8 shown in Figure 1.
Y groups associated with the aromatic ring in the
generalized substrate of eq 1. Thus, we anticipated that
nucleophilic aromatic substitution by T- could replace up
to five fluorine atoms with nitroxide groups along with
mono-, bis-, tris-, and tetra-nitroxides not only as inter-
mediates but also as plausibly synthesizable targets under
the proper reaction conditions.
Scheme 1. Preparation of Nitroxides from Fluorinated Core 1
Figure 1. Fluorinated core structures.
Nucleophilic Substitution of Fluorinated Aromatic
Compounds. Fluorinated aromatics possessing strong electron-
withdrawing substituents are very reactive toward substitution
of the fluorine atom by nucleophiles.5 Thus, as shown in eq 1,
a strategy for the synthesis of polynitroxides involves the use
of electron-deficient fluorinated aromatics, such as those in
Figure 1, through the substitution of fluorine by the alkoxide
anion (T-) of the mononitroxide, 4-hydroxy-2,2,6,6-tetrame-
thylpiperidine oxide (TEMPOL). The hydroxyl group of
TEMPOL is readily converted into the corresponding 4-alkoxide
anion (T-) under basic conditions. In eq 1, the activation for
the substitution of fluorine can be provided by an electron-
deficient aromatic benzene nucleus (e.g., X ) C-CN or C-NO2)
or an electron-deficient heteroatom nucleus (e.g., X ) N). The
Yn groups in eq 1 can be either potentially substitutable F atoms
or further electron-withdrawing groups (e.g., X ) C-CN or
C-NO2). Other possibilities are shown in Figure 1, which shows
the electron-deficient aromatic “cores” selected for this inves-
tigation. A set of variations of the core structures 1-3 were
selected to test the scope of the polynitroxide syntheses. In
structures 4 and 5 two fluorine atoms are replaced by hydrogen
atoms. In structures 6-8 a second electron-withdrawing group
(CN) is added to the core.
Preparation of Nitroxides from Aromatic Fluorinated
Cores. Scheme 1 summarizes the results of nitroxide
syntheses with the core aromatic 1 possessing a cyano
electron-withdrawing group (Figure 1) as a starting material.
Under appropriately controlled reaction conditions, it was
possible to synthesize the mononitroxide 1T1, the bis-nitroxide
1T2, the tris-nitroxide 1T3, and the tetra-nitroxide 1T4 in
moderate to high yields. However, the corresponding penta-
nitroxide 1T5 could only be synthesized in low yield using
1T3 as a starting material.
The results of other attempts to completely substitute
fluorine atoms by nitroxide groups are shown in eqs 2-7.
From core aromatic 2 possessing a nitro electron-withdrawing
group, the tetra-nitroxide 2T4 was synthesized in acceptable
yield (50%, eq 2).
This strategy is potentially of wide scope and flexibility
because of the structural variations provided by the X and
Evidently steric and possibly electronic effects consider-
ably hinder the substitution of the fifth F atom at the mild
(5) Chambers, R. D.; Hassan, M. A.; Hoskin, P. R.; Kenwright, A.;
Richmond, P.; Sandford, G. J. Fluorine Chem. 2001, 111, 135.
Org. Lett., Vol. 12, No. 16, 2010
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temperatures selected as model conditions for the nitroxide
synthesis. In particular, steric hindrance for substituting the
fifth F atom of 1 and 2 is confirmed in the case of 5, in
which all three F atoms were substituted to produce the tris-
nitroxide 5T3 in very good yield (81%, eq 3).
Characterization of the Nitroxides. The structures of the
nitroxides reported were established by a combination of mass
spectrometry, 19F NMR spectroscopy, and EPR spectroscopy.
In the case of 1T1, 1T2, 1T3, and 8T4, the structures were also
determined by single crystal X-ray diffraction, as illustrated for
The scope of the polynitroxide synthesis is demonstrated with
the perfluorinated pyridine 3 as a starting material. The tris-
nitroxide 3T3 was formed in moderate yield (50%, eq 4). In the
case of 8, a pyridine that possesses a second electron withdraw-
ing group (CN) in the 4 position, the tetra-nitroxide 8T4 was
produced in good yield (68%, eq 5).
Figure 2. Molecular structure of 8T4 as determined by single crystal
X-ray diffraction.
Finally, in the case of the tetrafluorinated structures 6 (eq 6)
and 7 (eq 7) possessing two electron-withdrawing groups, the tris-
nitroxide 6T3 and tetra-nitroxide 7T4 were produced, respectively.
The selectivity in the nucleophilic substitution allows for
targeted spin labeling of a specific position on the aromatic
core with an 15N isotope of T. For example, the partly
substituted compound 1T3 was synthesized at mild temper-
atures (Scheme 1) followed by substitution of one of the
remaining F-atoms with an isotope labeled 15N-T- at elevated
temperatures, which yields a tetra-nitroxide with three 14N
nitroxides and one 15N nitroxide (15N-1T4, eq 8).
As an extension of the syntheses the method was employed
to use 2,4,5-tri(pentafluorophenyl)-triazine 9 as a core, which
possesses 15 potentially displaceable F atoms. If nine F atoms
were substituted, then a nona-nitroxide, 9T9, would be
produced (eq 9). The formation of 9T9 was confirmed by
mass spectrometry.
Figure 3. EPR spectra of 1T1-1T5 in deoxygenated CHCl3 at room
temperature.
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Org. Lett., Vol. 12, No. 16, 2010

8
T4 in Figure 2. Of note, all of the hydrogen atoms were located,
Figure 3 as examples. A detailed and quantitative analysis
of the EPR spectra of the nitroxides reported here will be
the subject of another manuscript.
In summary, we report a direct synthetic procedure
employing nucleophilic aromatic substitution for the prepara-
tion of polynitroxides starting with the fluorinated cores 1-9.
The scope and limitations of the synthetic strategy is
elucidated. In general, the yields of polynitroxides are good,
except for replacing a final sterically hindered fluorine
substituent.
and there was no residual electron denisty comparable to that
of a hydrogen atom in the vicinity of the oxygen atoms, which
thereby provides evidence for the nitroxide formulation. Further
evidence for the nitroxide nature of the compound is provided
by the fact that there are no short intermolecular oxygen contacts
that would have otherwise been expected if there were hydroxy
groups present.
A point of considerable interest in the EPR of polyni-
troxides is the extent of electron spin-spin interactions.
If the nitroxide groups of a polynitroxide are significantly
coupled by electron exchange, the number of lines in the
EPR spectrum is expected to be 2N + 1, where N is the
number of electron exchange coupled nitroxides in
the molecule.6 All of the EPR spectra obtained for the
polynitroxides described above were consistent with the
2N + 1 rule. The EPR spectra of 1T1-1T5 are shown in
Acknowledgment. The authors thank the National Science
Foundation for its generous support of this research through
grants NSF-CHE-07-17518 and NSF-CHE-07-49674.
Supporting Information Available: Synthetic procedures
and analysis, and CIF files for X-ray diffraction studies. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(6) (a) Corvaja, C.; DeMarchi, M.; Toffoletti, A. Appl. Magn. Reson.
1997, 12, 1. (b) Bosman, A. W.; Janssen, R. A. J.; Meijer, E. W.
Maromolecules 1997, 30, 3606.
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