Crystal structures of the "two" 4-aminofurazan-3-carboxylic acids

Article abstract of DOI:10.1002/jhet.821

The crystal structures of the two compounds reported to be 4-aminofurazan-3-carboxylic acid have been determined. The compound reported by Sheremetev et al. (J Heterocycl Chem 2005, 42, 519) is the actual 4-aminofurazan-3-carboxylic acid. The compound reported by Meyer (Org Prep Proced Int 2004, 36, 361) is the interesting complex formed from a molecule of the acid and a molecule of the potassium salt of the acid..

Full text of DOI:10.1002/jhet.821

January 2012
Crystal Structures of the ‘‘Two’’ 4-Aminofurazan-3-carboxylic
Acids
227
Rodney L. Willer,a* Robson F. Storey,a Mark Frisch,b
and Jeffery R. Deschampsb
aSchool of Polymers and High Performance Materials, The University of Southern Mississippi,
Hattiesburg, Mississippi 39406
bCode 6930, Naval Research Laboratory, Washington, District of Columbia 20375
Additional Supporting Information may be found in the online version of this article.
*E-mail: rodney.willer@usm.edu
Received November 18, 2010
DOI 10.1002/jhet.821
Published online 25 October 2011 in Wiley Online Library (wileyonlinelibrary.com).
The crystal structures of the two compounds reported to be 4-aminofurazan-3-carboxylic acid have
been determined. The compound reported by Sheremetev et al. (J Heterocycl Chem 2005, 42, 519) is
the actual 4-aminofurazan-3-carboxylic acid. The compound reported by Meyer (Org Prep Proced Int
2004, 36, 361) is the interesting complex formed from a molecule of the acid and a molecule of the po-
tassium salt of the acid.
J. Heterocyclic Chem., 49, 227 (2012).
INTRODUCTION
pound we had isolated was indeed 1. We made several
additional batches of the material over a period of about
a year and always obtained the same product until, on
the fifth batch, we isolated a compound, 2, with a differ-
ent crystal habit (plate for 2 vs. prisim for 1). In addi-
tion, the 13C-NMR chemical shifts for 2 (161.3, 156.9,
and 143.1 ppm) were nearly identical to those reported
by Meyer.
Except for the differences in 13C-NMR shifts, the rest
of the spectral properties were quite similar. Significant
differences were found in the elemental analyses and
thermal properties of the two compounds. The com-
pound with the shifts reported by Sheremetev et al. gave
an almost perfect C, H, N analysis for C3H3N3O3 (cal-
culated: C, 27.92; H, 2.34; N, 32.55; found C, 27.80; H,
2.42; N, 32.63), whereas the compound with Meyer’s
shifts gave results that differed significantly (found C,
24.15; H, 1.62; N, 28.25). Obvious differences were
observed in the DSC thermograms of the two com-
pounds, as shown in Figures 2 and 3.
In connection with several projects, we had need for
a sizable quantity of 4-aminofurazan-3-carboxylic acid,
1. There are two recent publications describing synthe-
ses of this compound, one by Meyer [1] and one by
Sheremetev et al. [2] The two syntheses are quite simi-
lar, involving the same starting compound, similar
reagents, and intermediate, as outlined in Figure 1. The
final neutralization step is conducted at ambient temper-
ature in the Sheremetev procedure [2] and at 0ꢀC in the
Meyer procedure [1]. This turns out to be a critical dif-
ference between the two procedures.
When we made our first batch using Meyer’s proce-
dure, we obtained a product that seemed to match his
reported properties except that the 13C-NMR chemical
shifts were different. Meyer reported shifts of 161.3,
157.1, and 143.3 ppm, whereas the compound we iso-
lated had shifts of 160.7, 156.8, and 140.4 ppm. All
NMR spectra were recorded in DMSO-d6, except as
noted, as were the spectra in refs. 1 and 2. This con-
cerned us until we noted that the 13C-NMR shifts
reported by Sheremetev et al. [2] (160.5, 156.8, and
140.4 ppm) were nearly identical to ours. The fact that
Sheremetev et al. had transformed their product into
other compounds and had obtained X-ray crystal struc-
tures on them, gave us great confidence that the com-
At this point, we turned to X-ray crystallography to
establish the exact structure of the two compounds. A
preliminary analysis of Meyer’s compound showed the
presence of a heavy atom. There were two possibilities,
chlorine and potassium. We then reconsidered the
results of the elemental analysis and found that the
C
V
2011 HeteroCorporation

228
R. L. Willer, R. F. Storey, M. Frisch, and J. R. Deschamps
Vol 49
Figure 1. Generalized synthesis of 1.
analytical results fit quite well for a molecular formula
of C6H5N6O6K (calculated: C, 24.33; H, 1.70; N, 28.37:
found: C, 24.15; H, 1.62; N, 28.25). An analysis of the
compound for potassium gave results consistent with
that molecular formula (calculated: K, 13.20: found:
13.2%). With this information in hand, the structure eas-
ily refined to the interesting complex formed between
the acid and the potassium salt of the acid (Fig. 4). Sim-
ilar structures have been observed previously [3,4].
Chemical confirmation of this structure comes from
the fact that recrystallization of 2 from acidic water pro-
duces 1 and the fact that the treatment of 1 with 0.5
equiv of potassium hydroxide followed by recrystalliza-
tion of the mixture produces 2 (Fig. 5). We also meas-
ured the 13C-NMR chemical shifts for the sodium salt of
1 in a mixture of H2O/D2O and obtained shifts of 163.8,
156.12, and 144.1 ppm. Thus, Meyer’s compound has
chemical shifts that are a rough average of 1 and its so-
dium salt.
uniqueness of the four molecules can be seen in the
hydrogen bonding (Supporting Information Table S6). In
three of the molecules, N1 forms one normal H-bond
and one bifurcated H-bond, whereas in the fourth mole-
cule N1 forms only a bifurcated H-bond. O6 forms a bi-
furcated H-bond in one molecule while in the remaining
molecules O6 forms a single H-bond with a donor-H-
acceptor angle of 152ꢀ 6 9ꢀ. The disparity of the sizes
and shapes of the displacement ellipsoids indicates pos-
sible twinning in the crystal which we were not able to
resolve in the diffraction experiment. Data collection
was attempted on multiple crystals of this compound
and all were similarly flawed with some showing signs
of severe twinning as evidenced by streaking in the dif-
fraction pattern and broad spots.
It is somewhat puzzling that 2 would form in such
acidic conditions. The best explanation would be that if
the acidification process is done slowly and at a low
enough temperature, 2 starts to crystallize out and once
it has crystallized it is stable under the conditions. It
should be noted that 2 is also completely stable to
recrystallization from neutral water. It is very easy to
avoid the isolation of 2 by simply heating the reaction
after the acidification step to dissolve the product, insur-
ing that the pH is still less than 1, then cooling the mix-
ture to crystallize the product.
For completeness, we determined the X-ray crystal
structure for 1 (Fig. 6). The crystal data for the two
compounds are summarized in Table 1.
There are several points that should be noted in the
results of the X-ray diffraction of 1 (Fig. 6). At first
glance, there would appear to be a center of symmetry
among the four molecules in the asymmetric unit. Care-
ful examination of the positions of the protons on O6,
O6A, O6B, and O6C reveals that this is not a center of
symmetry. Testing with PLATON [5] indicates that
there is no missed symmetry. Further evidence on the
EXPERIMENTAL
4-Aminofurazan-3-carboxylic acid, 1. A 1000-mL three-
neck round-bottomed flask is equipped with a mechanical
Figure 2. DSC thermogram of 4-aminofurazan-3-carboxylic acid, 1.
Figure 3. DSC thermogram of Meyer’s compound, 2.
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Crystal Structures of the ‘‘Two’’ 4-Aminofurazan-3-carboxylic Acids
229
Figure 4. X-ray crystal structure of Meyer’s compound, 2. Displacement ellipsoids are at the 50% level.
stirrer, 125-mL pressure equalizing dropping funnel, and a
thermometer. Methyl cyanoacetate [59.4 g (53.4 mL, 0.60
mol)], sodium nitrite (50.0 g, 0.724 mol), and water (240 mL)
are added to the flask, and the contents stirred and chilled to
0ꢀC using a salt/ice bath. Acetic acid (46 mL, 0.80 mol) is
added dropwise over 15 min. The cooling bath is removed and
the mixture stirred for 4 h. The reaction is recooled to 0ꢀC
using a salt/ice bath, and the pH is adjusted to 1 using conc.
HCl (ꢁ60 mL). The solution is transferred to a 1000-mL sepa-
ratory funnel and extracted with ethyl acetate (3ꢂ 150 mL).
The combined ethyl acetate extracts are washed with 100 mL
of brine, dried over MgSO4, and then concentrated in vacuo to
yield the product. The yield is 76.8 g (0.60 mol).
A 1000-mL three-neck round-bottomed flask was equipped
with a mechanical stirrer and thermometer. Water (150 mL) is
added. This solution is stirred and potassium hydroxide (33.6
g, 0.60 mol) is added. The solution is cooled with an ice bath
and 50% hydroxylamine (39.6 g, 0.60 mol) is added. Methyl
2-cyano-2-(hydroxyimino)acetate (76.8 g, 0.60 mol) is dis-
solved in 150 mL water and added in small portions to the
stirred mixture. The cooling bath is removed. After the mixture
is stirred for 1.5 h, additional KOH (67.2 g, 1.2 mol) is added
portion-wise to the orange-red mixture. The mixture is heated
to 100ꢀC for 2 h using an oil bath. The mixture is cooled to
10ꢀC using an ice bath and then acidified to pH < 1 using
conc. hydrochloric acid (ꢁ125 mL). The solution is heated
until all the product is in solution, and the pH is rechecked to
make sure it is still below 1. Additional concentrated hydro-
chloric acid is added if necessary. The solution is chilled to
0ꢀC using a salt-ice bath. After about 1 h, the product is col-
lected and dried. The yield is 49.2 g (0.38 mol, 64%). The
melting (decomposition) point by DSC (3ꢀ/min) is 220ꢀC (ref.
2; 213–214ꢀC).
Synthesis of 2 from 1. Authentic 4-aminofurazan-3-carbox-
ylic acid, 1, (1.29 g, 10 mmol), 5 mL of H2O, and 85% KOH
(0.33 g, 5 mmol) are combined in a 20-mL scintillation flask
equipped with a magnetic stirring bar. The contents are stirred
at 100ꢀC until the acid dissolves. The mixture is then cooled
to 0ꢀC and the product collected and dried. The yield of 2 is
1.40 g (4.7 mmol, 94%). The compound is identical in all
respects to the product isolated from the Meyer’s procedure.
X-Ray Crystal Structure of Compounds 1 and 2. Single-
crystal X-ray diffraction data on 1 and 2 were collected at
100ꢀK and 173ꢀK, respectively, using MoKa radiation (k ¼
˚
0.71073 A) and a Bruker APEX 2 CCD area detector. The
samples were prepared for data collection by coating with high
viscosity microscope oil (Paratone-N, Hampton Research). The
oil-coated crystal was mounted on a MicroMesh mount (MiTe-
Gen) and transferred immediately to the diffractometer. Cor-
rections were applied for Lorentz, polarization, and absorption
effects. The structure was solved by direct methods and refined
by full-matrix least squares on F2 values using the programs
found in the SHELXTL suite (Bruker, SHELXTL v6.10, 2000,
Bruker AXS, Madison, WI). Parameters refined included
atomic coordinates and anisotropic thermal parameters for all
non-hydrogen atoms. Hydrogen atoms were included using a
riding model [coordinate shifts of N applied to H atoms] with
˚
NAH distance set at 0.86 A.
The 0.301 ꢂ 0.224 ꢂ 0.136 mm3 crystal of 1 was triclinic in
˚
space group P ꢃ1 with unit cell dimensions a ¼ 9.755(8) A, b
ꢀ
˚
˚
¼ 9.775(8) A, c ¼ 11.463(14) A, a ¼ 108.362(12) , b ¼
105.613(12)ꢀ, and c ¼ 108.118(8)ꢀ. Data were 92.0% complete
to 24.41ꢀy. The asymmetric unit contains four molecules. Full
information on data collection, refinement, and results of the X-
ray studies are given in Supporting Information Tables S1–S6.
The 0.64 ꢂ 0.20 ꢂ 0.04 mm3 crystal of 2 was monoclinic
in space group P2/c with unit cell dimensions a ¼ 10.060(4)
ꢀ
˚
˚
˚
Figure 5. Interconversion of compounds 1 and 2.
A, b ¼ 4.5742(18) A, c ¼ 12.170(5) A, and b ¼ 107.298(6) .
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

230
R. L. Willer, R. F. Storey, M. Frisch, and J. R. Deschamps
Vol 49
Figure 6. X-ray crystal structure of 4-aminofurazan-3-carboxylic acid, 1. Displacement ellipsoids are at the 50% level.
Table 1
Crystal data and structure refinement for compounds 1 and 2.
1
2
Empirical formula
C3H3N3O3
129.08
100(2) K
C3H2.50K0.50N3O3
148.13
173(2) K
Formula weight
Temperature
Wavelength
Crystal system
Space group
Unit cell dimensions (A and
˚
˚
0.71073 A
Triclinic
0.71073 A
Monoclinic
P2/c
P ꢃ1
ꢀ
˚
)
a ¼ 9.755(8)
b ¼ 9.775(8)
c ¼ 11.463(14)
a ¼ 108.362(12)
b ¼ 105.613(12)
c ¼ 108.118(8)
a ¼ 10.060(4)
b ¼ 4.5742(18)
c ¼ 12.170(5)
a ¼ 90
b ¼ 107.30(1)
c ¼ 90
3
˚
3
˚
Volume
Z
Density (calculated)
Absorption coefficient
F(000)
900.6(15) A
534.7(4) A
8
4
1.859 Mg/m3
0.169 mmꢃ1
504
1.840 Mg/m3
0.537 mmꢃ1
300
Crystal size
y range for data collection
Index ranges
0.301 ꢂ 0.224 ꢂ 0.136 mm3
2.05 to 24.41ꢀ
ꢃ10 ꢄ h ꢄ 11
ꢃ10 ꢄ k ꢄ 11
ꢃ11 ꢄ l ꢄ 13
5919
0.64 ꢂ 0.20 ꢂ 0.04 mm3
2.12 to 28.76ꢀ
ꢃ13 ꢄ h ꢄ 13
ꢃ5 ꢄ k ꢄ 6
ꢃ16 ꢄ l ꢄ 16
5340
Reflections collected
Independent reflections
Completeness to y ¼ 25.00ꢀ
Absorption correction
Max. and min. transmission
Refinement method
2738 [R(int) ¼ 0.0415]
1385 [R(int) ¼ 0.0664]
92.0%
99.9%
Semi-empirical from equivalents
0.984 and 0.909
Full-matrix least-squares on F2
0.9773 and 0.9508
Data/restraints/parameters
Goodness-of-fit on F2
Final R indices [I > 2r(I)]
R indices (all data)
2738/252/293
0.946
1385/3/97
1.040
R1 ¼ 0.0467, wR2 ¼ 0.0989
R1 ¼ 0.0825, wR2 ¼ 0.1144
0.015(5)
R1 ¼ 0.0549, wR2 ¼ 0.0911
R1 ¼ 0.0777, wR2 ¼ 0.0963
Extinction coefficient
Largest diff. peak and hole
ꢃ3
ꢃ3
˚
˚
0.696 and ꢃ0.233 e A
0.383 and ꢃ0.428 e A
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January 2012
Crystal Structures of the ‘‘Two’’ 4-Aminofurazan-3-carboxylic Acids
231
Data were 99.9% complete to 25.00ꢀ y. The asymmetric unit
contains two molecules sharing a single proton between their
carboxyl groups plus one potassium ion. Full information on
data collection, refinement, and results of the X-ray studies are
given in Supporting Information Tables S7–S12.
REFERENCES AND NOTES
[1] Meyer, K. G. Org Prep Proced Int 2004, 36, 361.
[2] Sheremetev, A. B.; Aleksandrova, N. S.; Dmitriev, D. E.;
Averkiev B. B.; Antipin, M. Y. J Heterocycl Chem 2005, 42, 519.
´ ´
[3] Barczynski, P.; Kowalczyk, I.; Grundwald-Wyspianska, M.;
Szafran, M. J Mol Struct 1999, 484, 117.
Acknowledgments. This work was funded by grants
N00014081006 (USM) and N00014-10-AF-0-0002 (NRL) from
the Office of Naval Research (Dr. Clifford Bedford). The assis-
tance of Mr. Matthew Jackson with the DSC experiments is grate-
fully acknowledged.
[4] Banerjee, A. K.; Layton, A. J.; Nyholm, R. S.; Truter, M.
R. J Chem Soc A 1969, 2536.
[5] (a) Spek, A. L. PLATON, A Multipurpose Crystallographic
Tool, Utrecht University: Utrecht, The Netherlands, 2010; (b) Spek,
A. L. Acta Crystallogr Sect D 2009, D65, 148.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet