Synthesis of 1,5-diisopropyl substituted 6-oxoverdazyls

Article abstract of DOI:10.1039/b510075e

1,5-Diisopropyl-6-oxo-verdazyl free radicals were synthesized via the condensation of BOC protected isopropyl hydrazine with phosgene, deprotection with aqueous HCl, condensation with aldehydes to form tetrazanes and finally oxidation to give the free rad

Full text of DOI:10.1039/b510075e

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A R T I C L E
Synthesis of 1,5-diisopropyl substituted 6-oxoverdazyls†
Emily C. Pare´, David J. R. Brook,*‡ Aaron Brieger, Mick Badik and Marie Schinke
Department of Chemistry and Biochemistry, University of Detroit Mercy, Detroit, MI, 48221,
USA. E-mail: djbrook@scu.edu; Fax: +1 408 554 7811; Tel: +1 408 554 4796
Received 18th July 2005, Accepted 12th October 2005
First published as an Advance Article on the web 2nd November 2005
1,5-Diisopropyl-6-oxo-verdazyl free radicals were synthesized via the condensation of BOC protected isopropyl
hydrazine with phosgene, deprotection with aqueous HCl, condensation with aldehydes to form tetrazanes and
finally oxidation to give the free radicals. The introduction of isopropyl groups results in free radicals that show
greater solubility in a variety of solvents and are more stable than their methyl substituted counterparts. ESR shows
reduced hyperfine coupling to the isopropyl methine hydrogens consistent with this hydrogen being in the plane of the
verdazyl ring.
a conformation provides some steric protection for the free
radical, while still allowing the coordination of metal ions to
Introduction
Stable free radicals, in addition to their intrinsic interest, are
N2 and N4.
important in a variety of applications. Recent examples include
The synthesis of 1,5-dimethyl-6-oxoverdazyls typically pro-
spin labels to probe polymer structure,1 catalysts for ‘living’ free
ceeds through the reaction of methyl hydrazine with phosgene to
radical polymerizations2 and components of metallo-organic
form a bis-hydrazide, followed by condensation with an aldehyde
polymers with unusual magnetic properties.3–5 Despite their
to form a tetrazane and subsequent oxidation to give the
utility, there are a only a limited number of stable free radical
verdazyl (Scheme 1).7,13Introduction of alternate alkyl groups
families. Nitroxides and the closely related imino nitroxides and
is limited by the availability of the corresponding hydrazine
nitronyl nitroxides are probably the most extensively studied,
and the regiochemistry of the condensation with phosgene. We
however other systems such as semiquinones and verdazyls may
report a synthesis of 1,5-diisopropyl verdazyls utilizing the BOC
also have potential applications.6 In particular the 1,5-dimethyl-
protecting group to circumvent these problems.
6-oxoverdazyls (1) are relatively easily synthesized with a variety
of functional groups in the 3 position.7
Experimental
General
NMR spectra were recorded on a JEOL Eclipse+ 300 MHz
FTNMR spectrometer and referenced to the residual solvent
protons in the deuterated solvent. Coupling constants are
With the nitrogen atoms in the 2 and 4 positions available
reported in Hz. IR spectra were recorded as thin films on NaCl
to coordinate metal ions, these systems have potential for a
plates using a Perkin-Elmer Spectrum 2000 FTIR spectrometer.
wide variety of applications. Unfortunately, the stability of these
Mass spectra were recorded on an Agilent 1100 series ion trap
systems is variable depending on the nature of the substituent in
spectrometer with electrospray ionization using 0.1 M ammo-
the 3 position. While the radicals can frequently be characterized
nium acetate in ethanol as solvent or on a Hewlett-Packard
by ESR, this instability can hinder further study. This is
6890 GCMS with electron impact ionization. ESR spectra were
particularly frustrating with potential ligands such as the 3-
recorded on a Bruker ESP300e X band spectrometer or a Varian
E-12 X band spectrometer with an HP model 5245L frequency
(2ꢀ-pyridyl)- (1a) and 3-(2ꢀ-imidazolyl) (1c) substituted species.
Several coordination compounds of the former have been
counter. Samples for ESR were dissolved in toluene (∼5 ×
10−4 mol L−1) and degassed via three freeze(77 K)–pump(0.1
Torr)–thaw cycles before measurement. The field was calibrated
by placing a dilute sample of MnO in CaO next to the sample.
The resonant field positions of the Mn2+ lines were computed
by 4th order perturbation theory and the appropriate field
correction was applied to all spectra. ESR spectra were simulated
with the program WINSIM.14
reported,8–10 but the free radical itself must be stored in the long
term either as the charge transfer complex with hydroquinone,11
or under liquid nitrogen.12 We were interested in the introduction
of alternative alkyl groups in the 1 and 5 positions, in particular
to increase radical stability and solubility and also to control
coordination geometry. Specifically we chose to target the 1,5-
diisopropyl system. Calculations suggest that the preferred
conformation for these radicals places the two isopropyl methyl
groups above and below the plane of the verdazyl ring. Such
Di-tert-butyl-2,2ꢀ-carbonylbis-(2-isopropylhydrazine-
carboxylate) (5)
† Electronic supplementary information (ESI) available: Experimental
details of the synthesis and characterization of tetrazanes 7b–g and
verdazyls 8b–g. See DOI: 10.1039/b510075e
‡ Present Address: Department of Chemistry, Santa Clara University,
Santa Clara, CA 95050, USA
tert-Butyl 2-isopropylhydrazinecarboxylate (4)15 (20.6 g,
0.118 mol) was dissolved in dry toluene and 1 equivalent (11.9 g,
0.118 mol) dry triethylamine added. To this solution was added a
solution of 20% phosgene in toluene (31 mL, 0.06 mol) dropwise
Scheme 1
T h i s j o u r n a l i s
4 2 5 8
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 4 2 5 8 – 4 2 6 1
T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 5
©

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at a rate of less than one drop per second. During addition
a copious precipitate of triethylamine hydrochloride formed.
When addition was complete, the solution was stirred at room
temperature for 2 h, filtered and the filtrate evaporated to give
the crude product. This was purified by recrystallization from
heptane to give 9.75 g (0.026 mol, 44%) of the bis hydrazide
with mp 148–150 ◦C (decomp.) (found: C 54.30 H 9.07 N 14.84.
calcd for C17H34N4O5: C 54.52 H 9.15 N 14.96%); mmax(NaCl
General procedure for verdazyl free radicals:
1,5-diisopropyl-3-pyridin-2-yl-6-oxoverdazyl (8a)
In a typical procedure, 2,4-diisopropyl-6-(pyridin-2-yl)-1,2,4,5-
tetrazinan-3-one (164 mg) was refluxed with 1.5 mol eq.
benzoquinone in 5 mL toluene for 1 h. When TLC indicated
that the starting material had been consumed the resulting
solution was cooled, filtered and evaporated. Chromatography
of the residue on silica gel eluting with 9:1 CH2Cl2–EtOAc
gave the verdazyl as an orange crystalline solid (53 mg, 32%)
recrystallized from CH2Cl2–heptane with mp 122–123 ◦C; UV-
plate)/cm−1 3255 (N–H), 2978 (C–H), 1712 (C O), 1659 (C O);
dH (300 MHz, CDCl3, 55 ◦C) 1.12 (12H, d, J = 6.6, (CH3)2-CH),
1.47 (18H, s, (CH3)3C), 4.15 (2H, septet, J = 6.6, (CH3)2-CH),
6.48, (2H, br s, NH); dC (75 MHz, CDCl3, 55 ◦C) 19.4, 28.2, 52.3,
81.2, 155.9, 162.3 (motionally broadened); MS (electrospray)
375 (MH+, 46%), 319 (38, MH+ tBu), 263 (100, MH+ 2tBu).
=
=
vis (MeCN) 409, 450 nm(sh); mmax(NaCl plate)/cm−1 2973, 2920
+
=
(C–H), 1686 (C O); MS (electrospray) 261 (MH , 100%). Purity
was determined by HPLC on a 150 mm C18 reverse phase
column, eluting isocratically for 2 min with 30% acetonitrile–
70% 0.1 M aqueous ammonium acetate (pH 6.95) followed
by a gradient to 70% acetonitrile over 10 min and isocratic
elution thereafter. A UV-vis diode array was used for analyte
detection. The product eluted at 9.8 min and was determined to
be approximately 98% pure by integration.
2,4-Diisopropylcarbonohydrazide bis-hydrochloride (6)
Di-tert-butyl
2,2ꢀ-carbonylbis(2-isopropylhydrazinecarboxy-
late) (5) (0.655 g, 1.75 mmol) was dissolved in 10 mL ethanol
and 5 mL concentrated hydrochloric acid and warmed on a hot
plate for 0.5 h during which time a mild effervescence occurred.
The solution was allowed to cool overnight. Removal of the
solvent and excess acid under vacuum left the bis-hydrazide bis
hydrochloride as off-white crystals (0.426 g, 99%). The sample
for analysis was recrystal◦lized from n-butanol to give white
needles with mp 188–190 C (found: C 32.74 H 8.38 N 21.48.
calcd for C7H20N4O·2 HCl·0.5 H2O: C 32.82 H 8.26 N 21.87%);
mmax(NaCl plate)/cm−1 2974 (C–H), 2880, 2689 (broad, NH),
Results
The reported syntheses of 1,5-dimethyl and 1,5-dibenzyl ver-
dazyls rely on the more nucleophilic nature of the substituted
nitrogen in the alkyl hydrazine. Reaction with phosgene gives the
2,4-dialkyl substituted bis-hydrazide13 which is taken on to form
the verdazyl.7,16 This regiochemical selectivity is almost certainly
an electronic effect, which may be diminished by steric effects;
consequently we felt that an analogous reaction with isopropyl
hydrazine would give, at best, a mixture of regioisomers. Since
the tert-butyloxycarbonyl protected form of hydrazine, tert butyl
carbazate, is commercially available, we elected to use the BOC
group to enforce the required regiochemistry. The synthesis is
outlined in Scheme 2.
Reduction of acetone tert-butyloxycarbonylhydrazone with
sodium cyanoborohydride following the procedure of
Callabretta and co-workers15 gave a mixture of the BOC
protected isopropyl hydrazine (4) and its cyanoborane adduct.
Modification of the workup procedure using a 1M aqueous
potassium hydroxide instead of aqueous bicarbonate wash gave
4 directly as a white crystalline solid. The reaction of the
hydrazine with phosgene gave rather mixed and irreproducible
results until we used toluene as solvent and carefully dried the
triethylamine by distillation from calcium hydride. The resulting
hydrazide (5) shows a conformationally restricted structure in
NMR with the methyl groups of the isopropyl appearing as a
broad singlet. Raising the temperature sharpened the spectrum
considerably resolving the doublet resulting from coupling to
the methine hydrogen. In the carbon spectrum however, one of
=
1712 (C O); dH (300 MHz, D2O) 1.07 (d, J = 6.9) 4.02 (septet,
J = 6.9); dC (75 MHz, D2O) 18.1, 55.7, 161.1; MS (electrospray)
175 (MH+, 100%).
General procedure for tetrazanes: 2,4-diisopropyl-6-pyridin-2-yl-
1,2,4,5-tetrazinan-3-one (7a)
In a typical procedure, 2 mmol of 2,4-diisopropylcarbono-
hydrazide bis-hydrochloride and 2 mmol of 2-pyridylcar-
boxaldehyde were dissolved in the minimum amount of ethanol.
To this solution was added 4 mmol of sodium acetate in ethanol
and the solution allowed to stand at room temperature for 15 h.
After this period the mixture was filtered and evaporated and
the residue recrystallized from heptane to give the tetrazane
◦
(460 mg, 87%) with mp 160–162 C (found C 59.15 H 8.01 N
26.29. calcd for C13H21N5O C 59.29 H 8.04 N 26.59); mmax(NaCl
plate)/cm−1 3226 (NH), 3187 (C–H), 2966 (C–H), 2930 (C–H),
−1
=
1594 (C O) cm ; dH (300 MHz, CDCl3) 1.09 (6H, d, J = 6.6),
1.11 (6H, d, J = 6.6), 4.44 (1H, s) 4.70 (2H, septet, J = 6.6), 7.35
(1H, ddd, J = 6.6, 5.0, 1.0), 7.44 (1H, dt, J = 6.6, 1.0), 7.78 (1H,
td, J = 6.6, 2.0) 8.58 (1H, ddd, J = 5.0, 2.0, 1.0); dC (75 MHz,
CDCl3) 18.5, 19.5, 47.7, 72.3, 123.9, 124.3, 137.7, 149.3, 153.6,
154.4; MS (electrospray) 264 (MH+, 100%).
Scheme 2
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 4 2 5 8 – 4 2 6 1
4 2 5 9

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Table 2 Visible maxima and extinction coefficients for 8a–g in
acetonitrile
the carbonyl carbons is observed only as a broad hump even at
55 ◦C.
Deprotection of 5 was initially attempted with CF3COOH–
Et3SiH at room temperature, however significant trifluoroacety-
lation of the product was observed. Excess hydrochloric acid
in ethanol gave clean deprotection to give 2,4-diisopropyl-
carbonohydrazide bis-hydrochloride (6) as a white solid. Unlike
the protected species, this molecule shows no apparent confor-
mational restriction in solution at room temperature.
Condensation of the hydrazide with aldehydes in 95%
ethanol–sodium acetate gave the tetrazanes (7a–g) as colorless
crystalline solids. In these materials the two isopropyl methyl
groups are diastereotopic and give two distinct doublets in the
1H NMR and two signals in the 13C NMR.
A variety of conditions have been reported for the oxidation
of 3-oxotetrazanes to verdazyl radicals.7,8,11,16–23 Though we
have found aqueous/alcoholic oxidation conditions useful in
the past, the poor solubility of the diisopropyl tetrazanes in
aqueous systems makes this method impractical. Oxidation to
the verdazyl free radicals (8a–g) was accomplished with benzo-
quinone in toluene.11 Unlike the previously reported synthesis
using this method,24 hydroquinone adducts were not observed
and the hydroquinone precipitated from the reaction mixture
as it cooled. Filtration and evaporation gave verdazyls (8a–g)
which were purified by chromatography on silica gel followed
by recrystallization from dichloromethane–heptane or ethanol–
water. The free radicals can be identified by their distinct UV-
visible spectra with a sharp transition near 410 nm and broad
transition showing some vibronic structure between 450 and
500 nm. This gives them a pink to orange color depending
upon the substituent in the 3 position. In a previous study of
k/nm (e/L mol−1 cm−1
)
8a
8b
8c
8d
8e
8f
409 (1330), 450 (380)
410 (1300), 450 (390)
410 (1110), 450sh (290)
420 (1030), 495 (350), 555sh, (150)
420 (1230), 502sh (570), 520 (590), 550sh (310)
422 (1040), 500sh (350) 523 (450), 562 (340)
422 (1350), 504 (480)
8g
1,5-dimethyl substituted species these maxima were tentatively
identified as p–p* and n–p* transitions based on computational
results.8 Details of spectral maxima are reported in Table 1.
The ESR spectra of the isopropyl substituted verdazyls are
all very similar and can be simulated accounting for coupling
to four nitrogens and two hydrogens. Hyperfine parameters for
radicals 8a–g are shown in Table 2 along with data for related
verdazyl radicals 1–3. Experimental and simulated spectra for
8a are shown in Fig. 1.
Discussion
The above methodology results in the formation of isopropyl
substituted verdazyl radicals in a relatively straightforward
manner. To demonstrate the versatility of the pathway we have
synthesized verdazyls with 3-subtituents that have so far been
unreported or have significant problems. In particular the chelat-
ing 3-(2ꢀ-pyridyl)- (1 R3 = 2-pyridyl) and 3-(6ꢀ-methylpyrid-
2ꢀ-yl)- (1 R3 = 6-methyl-2-pyridyl) substituted free radicals
Fig. 1 Experimental (top) and simulated (bottom) ESR spectra of 8a.
Table 1 ESR hyperfine parameters for 8a–g and related radicals 1–3
aN2,4/mT
aN1,5/mT
aH/mT
Linewidth/mT
g
8a
0.650
0.659
0.656
0.661
0.657
0.648
0.658
0.649
0.663
0.645
0.529
0.518
0.520
0.525
0.518
0.551
0.519
0.513
0.508
0.450
0.150
0.121
0.122
0.115
0.130
0.157
0.123
0.546
0.300
—
0.070
0.070
0.050
0.075
0.070
0.073
0.068
—
2.0043
2.0044
2.0044
2.0047
2.0044
2.0044
2.0044
8b
8c
8d
8e
8f
8g
1 (R = Ph)7
2 (R = Ph)7
3 (R = Ph)17
—
—
4 2 6 0
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 4 2 5 8 – 4 2 6 1

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have been previously reported but are relatively unstable.8,12,25
Similarly our previous attempts to study the 3-(2ꢀ-imidazolyl)-
and the 3-(2ꢀ-quinolyl) systems have been hampered by poor
stability. For example a solution of 0.3 mM 1(R3 = 2-pyridyl)
at room temperature lost 20% of the absorbance at 410 nm
over a 4 day period. Over the same period the corresponding
diisopropyl substituted verdazyls 8a,d show very little (<1%)
signal decay. The other species show similar or greater stability.
Crystalline samples appear to be indefinitely stable in air in a
standard laboratory refrigerator greatly facilitating the synthesis
of coordination compounds.
The phenolic OH in the 2-hydroxy and 4-hydroxyphenyl
substituted verdazyls provides a potential site for further
derivatization or possibly metal coordination. Synthesis of the
4-hydroxyphenyl verdazyl system has been previously hampered
by the very low solubility of the corresponding dimethyl
tetrazane precursor. Similarly, attempts to synthesize the cor-
responding dimethyl tetrazane from salicylaldehyde resulted
only in complex, intractable mixtures. Use of the diisopropyl
bis(hydrazide) circumvents these problems and allows for the
clean synthesis of both tetrazanes and corresponding verdazyls.
We note that remarkably, semiquinone formation does not
appear to compete with the formation of the verdazyl.
All of the free radicals are soluble in non-polar solvents such as
toluene and heptane allowing the measurement of well resolved
ESR spectra. Hyperfine coupling to nitrogen is very similar to
that observed for other verdazyls, however the coupling to the
two isopropyl methine hydrogens is significantly lower than that
observed for the corresponding methyl hydrogens. This suggests
that in the major conformations of the molecule the methine C–
H lies in the plane of the verdazyl ring, minimizing coupling
between it and the p system. A similar phenomenon was
observed with 1,5-dibenzyl substituted verdazyl free radicals7
which, with two hydrogens on a methylene group next to
the verdazyl, show hyperfine coupling intermediate between
the methyl and isopropyl systems (Table 2). No evidence
was seen for the contribution of semiquinone type tautomers
in the hydroxyphenyl substituted species, though the greater
red shift in the electronic spectrum for the 2-hydroxy species
expanding the utility of verdazyl free radicals as spin probes
and ligands for metal ions. In addition it should be possible to
extend the methodology to groups other than isopropyl in the 1
and 5 positions. These possibilities are being further investigated
in our laboratory.
Acknowledgements
This work was supported by the Petroleum Research Fund
(Grant 39923-B1 to DJRB) and the National Science Foun-
dation for purchase of ES-MS instrumentation (Award CHE-
0116181). We would also like to thank Dr Shulamith Schlick
and Dr Andrew Ichimura for help with ESR measurements.
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(8f, kmax = 560 nm) vs the 4-hydroxy species (8e, kmax
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¨
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Conclusion
Substitution of methyl groups for isopropyl groups in 6-
oxoverdazyl radicals results in species with enhanced stability
and solubility. The synthetic protocol allows the synthesis of
verdazyl free radicals with new substituents in the 3 position,
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 4 2 5 8 – 4 2 6 1
4 2 6 1