Safer and Convenient Synthesis of 3,4-Dicyanofuroxan

Article abstract of DOI:10.1021/acs.oprd.9b00186

A safer, convenient, cost-effective, and scalable synthesis for 3,4-dicyanofuroxan (C₄N₄O₂) is described. Dropwise treatment of a well-stirred suspension of cyanoacetic acid in dichloromethane with concentrated mixed acid (HNO₃/H₂SO₄) affords dicyanofuroxan in 72% yield and in 84% purity after liquid chromatography analysis. Single crystal X-ray diffraction studies further confirm the product and yield its molecular conformation and crystal packing. During the dropwise addition of mixed acid, self-heating occurs, and this event is necessary for the reaction to adequately proceed. However, such self-heating is limited to the refluxing temperature of dichloromethane. This new method supersedes the previous methods used to synthesize dicyanofuroxan, which were low-yielding and of significantly lower purity, irreproducible, relied on expensive reagents, and suffered from dangerous exothermic profiles.

Full text of DOI:10.1021/acs.oprd.9b00186

Communication
Cite This: Org. Process Res. Dev. XXXX, XXX, XXX−XXX
pubs.acs.org/OPRD
Safer and Convenient Synthesis of 3,4-Dicyanofuroxan
†
†
‡
,†
Eric C. Johnson, Eric J. Bukowski, Rosario C. Sausa, and Jesse J. Sabatini*
†
‡
Energetic Technology Branch and Energetic Materials Science Branch, CCDC US Army Research Laboratory, Aberdeen Proving
Ground, Maryland 21005, United States
*
S Supporting Information
RESULTS AND DISCUSSION
■
ABSTRACT: A safer, convenient, cost-effective, and
The most widely accepted synthesis of dicyanofuroxan,
scalable synthesis for 3,4-dicyanofuroxan (C N O ) is
6
4
4
2
reported by Parker et al., is summarized in Scheme 1. The
described. Dropwise treatment of a well-stirred suspension
of cyanoacetic acid in dichloromethane with concentrated
mixed acid (HNO /H SO ) affords dicyanofuroxan in
Scheme 1. Synthesis of DCFO by Parker et al.
3
2
4
7
2% yield and in 84% purity after liquid chromatography
analysis. Single crystal X-ray diffraction studies further
confirm the product and yield its molecular conformation
and crystal packing. During the dropwise addition of
mixed acid, self-heating occurs, and this event is necessary
for the reaction to adequately proceed. However, such
self-heating is limited to the refluxing temperature of
dichloromethane. This new method supersedes the
previous methods used to synthesize dicyanofuroxan,
which were low-yielding and of significantly lower purity,
irreproducible, relied on expensive reagents, and suffered
from dangerous exothermic profiles.
synthesis features a reaction of cyanoacetic acid with 100%
HNO in the presence of catalytic oleum performed in a
3
solvent medium of trifluoracetic acid. This reaction occurs via
the dimerization of the dinitroacetonitrile intermediate.
According to Parker et al., oleum is critical to the success of
this reaction, as the absence of this sulfuric acid-containing
catalyst does not yield any product. The reaction is heated to
40 °C, and the nitric acid is added dropwise to the mixture.
When the reaction is completed, it is poured onto crushed ice
and is extracted with dichloromethane. These extracts are then
washed with water until a pH of 6−7 is reached. Evaporation
of the solvent affords DCFO in a low purity of just 59% (See
Supporting Information). Parker et al. report that a clean
product can be obtained upon recrystallization from carbon
tetrachloride. Use of this solvent today, however, is
discouraged for environmental and human health reasons.
When performing the procedure described by Parker et al.,
significant care must be taken during the dropwise addition of
KEYWORDS: synthesis, energetic materials, explosives,
propellants, process chemistry
INTRODUCTION
■
3
,4-Dicyanofuroxan (DCFO) is a common intermediate in the
synthesis of a host of energetic materials. It has been used to
make energetic heterocyclic compounds in which the cyano
1
moieties are derivatized to the 1H-tetrazole, 1-hydroxyte-
2
3
trazole, and 1,2,4-oxadiazole moieties. DCFO is a known
4
hypergolic material, and while first prepared by Weiland in
925, the most reliable synthesis was reported by Parker et al.
in 1962. Despite other reports in the literature by
Grundmann, Nickel, and Bansal in 1975 and Mel’nikova et
HNO
3
, as this reaction is prone to violent exotherms under
5
these conditions. On larger scales, we have observed that even
1
6
multihour dropwise addition of HNO still results in a steep
3
7
temperature increase, in which the solution refluxes violently
(75−80 °C), producing a significant volume of NOx gases in
the process. For these reasons, the Parker et al. synthesis of
DCFO is typically done only on the small-scale. Our
laboratories have limited the synthesis of DCFO by the Parker
method to 5 g, and large-scale reactions using this process are
certainly not advised.
8
al. in 2001 concerning the synthesis of DCFO, the
aforementioned route by Parker has remained the current
method of choice. The Grundmann, Nickel, and Bansal route
to DCFO involves a lengthy four-step synthetic process from
glyoxal, with yields being ∼30%, while the route reported by
Mel’nikova et al. is also a low-yielding four-step sequence,
which was irreproducible in our hands. Unfortunately, the
reliable synthesis method of Parker et al. is expensive, suffers
from low yields, and contains a significant exothermic profile.
Because DCFO is a popular intermediate in the synthesis of
energetic materials, a reproducible, cost-effective, safer, and
higher-yielding method pertaining to the synthesis of this
material is of high interest. In this paper, we report such a
procedure and confirm the product by single crystal X-ray
diffraction.
Thirteen years after Parker et al. reported the synthesis of
DCFO, Grundmann, Nickel, and Bansal disclosed the
synthesis of this material from glyoxal, which involved the
treatment of dicyanoglyoxime (4) with nitrous oxide to induce
7
ring closure to form DCFO (1) (Scheme 2). Although this
9
synthetic sequence has been found to be reproducible, it
suffers from a lengthy synthesis compared to the Parker et al.
Received: May 6, 2019
This article not subject to U.S. Copyright.
Published XXXX by the American Chemical
Society
A
DOI: 10.1021/acs.oprd.9b00186
Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
Communication
Scheme 2. Grundmann, Nickel, and Bansal Synthesis of
DCFO
Scheme 4. Optimized Synthesis of DCFO
Our process in synthesizing DCFO is given in Scheme 4.
Upon suspending cyanoacetic acid in dichloromethane with
vigorous stirring, we opted to not chill the reaction but instead
immersed the reaction vessel in a water bath at 27 °C. Mixed
acid was then added over a 3 h period, during which time the
reaction slowly self-heated and a gentle reflux with minimal
NOx gases was observed. During the addition process, the
water bath reached a maximum of 32 °C. When addition of the
mixed acid was completed, the reaction mixture was stirred for
an additional hour, during which time the temperature of the
water bath cooled to 25 °C. This gentle self-heating event
appears to be critical for the reaction to proceed and to obtain
good yields. The reaction mixture was then poured onto
crushed ice, warmed to ambient temperature, and extracted
with dichloromethane. The combined organic extracts were
then washed with water until a pH of 6−7 was achieved.
Removal of the solvent afforded DCFO as a white/pale yellow
solid.
synthesis as well as relatively low yields in the final two
reactions of the synthetic sequence. As a result, the
Grundmann, Nickel, and Bansal synthesis results in just a
3
0% yield of product.
In 2001, Mel’nikova et al. reported a synthesis of DCFO via
the diazotization of nitrosoaminofurazan (7) through the
supposed elimination of a cationic species produced during the
8
course of the reaction (Scheme 3). Unfortunately, attempts to
synthesize DCFO in our laboratories using this method failed
to yield any product. In addition, this pathway has limited
scalability due to the low overall yield (ca. 16%), the lengthy
synthesis to obtain this intermediate, and the potential issues
associated with large-scale diazotizations of energetic furazan
intermediates.
Because of the synthetic utility of DCFO to the energetic
materials community, we sought to develop a safer, scalable,
and higher-yielding process for making this material. We
reasoned that a variation of the Parker et al. synthesis would be
ideal, as DCFO could be obtained in a single step from
cyanoacetic acid. We reasoned that employing dichloro-
methane in place of trifluoroacetic acid as the solvent in this
reaction was advantageous for various reasons. The refluxing
temperature of dichloromethane (39.6 °C) is much lower than
trifluoroacetic acid (72.4 °C), and it was believed that the
lower refluxing temperature would improve the safety margin,
minimize byproducts, and thus improve scalability, yields, and
purity. Dichloromethane was much cheaper than trifluoro-
acetic acid and was already shown to be an optimal extraction
solvent of DCFO when the reaction reached the workup stage
With DCFO in hand, we then assessed its purity by liquid
chromatography analysis. According to our analysis, DCFO
synthesized by the Parker et al. method was obtained in a
purity of just 59%, whereas DCFO synthesized by the method
outlined in Scheme 4 was obtained in a much improved purity
of 84% (see Supporting Information). The safer process in
Scheme 4 has been scaled-up numerous times in our
laboratories to afford DCFO in about 60 g quantities with a
high degree of reproducibility. Although the identities of the
impurities present in DCFO are not clear at this time, they
have been determined not to negatively influence further
reactions in our laboratories. Although attempts at recrystall-
izing DCFO in 84% purity from solvents other than carbon
tetrachloride failed to yield a more pure product, we have
successfully converted the crude DCFO to its bis-amidoxime
derivative by employing 50% aqueous hydroxylamine, and this
bis-amidoxime is isolated in very high purity (see Supporting
2
,10
Information) and a reasonable yield of 68%.
(
Scheme 4). Knowing that the Parker et al. synthesis of DCFO
Further confirming the validity of our synthesis, we
determined a crystal structure for DCFO by single crystal X-
ray diffractometry. The details of the data acquisition and
structure solution and refinement are provided in the
required the use of oleum, we decided to employ a premixed
acid (1:2 mixture of 100% HNO /98% H SO ) to the
suspension of cyanoacetic acid in dichloromethane, thus
eliminating the need for oleum in the reaction. We report
only the optimized mixed acid ratio required, as altering this
ratio significantly leads to an extensive loss of product.
3
2
4
1
1−14
Supporting Information.
DCFO crystallizes in the
orthorhombic Pna2 space group with eighth molecules in its
1
unit cell. Its asymmetric unit comprises two independent
Scheme 3. Synthesis of DCFO by Mel’nikova et al.
B
DOI: 10.1021/acs.oprd.9b00186
Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
Communication
Figure 1. Molecular conformation and atom-numbering schemes of compounds 1, comprising two distinct molecules (1 and 1A) in its asymmetric
unit. All of the atoms are shown as 50% probability displacement ellipsoids.
molecules (1 and 1A, see Figure 1). Each molecule adopts a
near planar conformation [C1/C2/C3/C4/N1/N1/N3/N4/
O1/O2; r.m.s. deviation = 0.019 Å (1) and 0.025 Å (1A)],
with the largest deviation resulting from the C1/C1A atoms
safety standpoint, the Chinese patent claims that addition of
mixed acid to the stirring suspension of cyanoacetic acid in
dichloromethane must be done cold (i.e., 0−5 °C) to obtain a
reasonable amount of product. When we attempted to
reproduce this portion of the procedure, it was found that
no reaction occurred at cold temperatures. Upon warming the
reaction mixture, however, the reaction spontaneously self-
heated, which produced a spirited refluxing event, along with a
significant formation of NOx gases. Clearly, following the
experimental procedural guidelines of the aforementioned
patent is not recommended for anyone who is cognizant of
their own safety.
[distances of C1/C1A atoms to their respective plane =
−
0.030 (2) and −0.044 (2) Å]. Their bond lengths and angles
3,15−21
are in the usual ranges of typical furoxan derivatives,
and
they are in excellent agreement with those reported by
2
2
Pasinszki et al. The molecular planes subtend a dihedral
angle of 65.43 (4)° and exhibit a plane centroid-to-plane
centroid distance of 5.358 (1) Å. A superimposition of the two
structures yields a r.m.s. deviation of 0.030 Å.
Intermolecular interactions play a key role in the crystal
packing of molecules. Figure 2A shows the interactions for 1,
whose contact distances range between 2.96 (4) and 3.195 (3)
Å. The shortest contact length results from the N1A ring atom
interacting with the N3A atom of adjacent molecules [N1A···
CONCLUSIONS
■
In summary, we have developed a scalable and reproducible
method for the synthesis of DCFO in 72% yield and 84%
purity and have found that it can be used in further reactions
without further purification. Our process relies on the dropwise
addition of mixed acid to a suspension of cyanoacetic acid in
dichloromethane. We have found that a controlled self-heating
event, in which the reaction mixture refluxes gently as opposed
to violently, is critical for obtaining high yields in this reaction.
Our process removes the need to use expensive trifluoroacetic
acid, oleum, and does not employ toxic carbon tetrachloride as
a recrystallization solvent. This new route confirmed in part by
X-ray crystallography represents a more scalable, reliable, and
reproducible synthesis as compared to those reported
previously.
i
N3A = 2.961 (4) Å; symmetry code (i) 2 − x, 1 − y, −1/2 +
z], whereas the longest contact length involves the C3 and
N2A atoms of the asymmetric unit molecules 1 and 1A,
respectively, [C3···N4A = 3.185 (3) Å] (see Figure 1). Figure
2
B reveals the molecular stacking for 1 along the b-axis
direction. On the basis of the molecular mass and lattice
constants of a = 10.18098 (5) Å, b = 10.8181 (4) Å, c =
1
1
1
0.1946 (4) Å, and α = β = γ = 90°, we obtain a density of
3
.610 g/cm at −23 °C. A similar analysis yields a value of
3
.594 g/cm at 22 °C, in excellent agreement with the reported
3
22
value of 1.584 g/cm obtained at the same temperature.
It should be worth noting that we felt the need to publish
our optimized procedure described in Scheme 4 because of the
inability to reproduce experimental procedures in the Chinese
patent literature. For example, this patent claims that altering
the mixed acid ratio still results in DCFO being obtained in
significant yields and purities. We found this not to be the case,
as the mixed acid ratio provided in Scheme 4 is critical for
good yields to be obtained. Furthermore, the Chinese patent
EXPERIMENTAL SECTION
■
Chemicals and solvents were used as received from Sigma-
2
3
1
3
Aldrich. C NMR spectra were recorded using a Bruker 101
MHz instrument. The chemical shifts quoted in parts per
million in the text refer to typical standard tetramethylsilane in
CDCl as the solvent. Infrared spectra were measured with a
3
Bruker Alpha-P FTIR instrument. Melting and decomposition
temperatures were measured at a heating rate of 5 °C/min
using a TA Instruments Q10 DSC instrument. Liquid
chromatography analysis of DCFO samples were obtained
using an Agilent 1200 series instrument. Single crystal X-ray
diffraction studies were performed with a SuperNova Dualflex
claims that replacing 100% HNO with 90% or even 70%
3
HNO in the mixed acid system still gives high yields and
3
purities of DCFO. However, we observed that replacing 100%
HNO3 with 70−90% HNO3 yields significantly lower
quantities of DCFO. Perhaps most importantly from the
C
DOI: 10.1021/acs.oprd.9b00186
Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
Communication
immersed in a 27 °C water bath, which was not heated
externally throughout the course of the reaction. In a separate
6
3
1
00 mL beaker, 98% concentrated H SO (368 g, 200 mL,
2 4
.75 mol, 3.18 equiv) was stirred and cooled to 0 °C. Then
00% HNO (151 g, 100 mL, 2.40 mol, 2.03 equiv) was added
3
at such a rate that the temperature of the mixture did not rise
above 25 °C. The mixed acid solution was stirred for 10 min
and was then poured into the addition funnel. The mixed acid
solution was added to the reaction mixture over a 3 h period.
During this addition period, the cyanoacetic acid was drawn
into solution, and self-heating occurred that resulted in the
reaction mixture achieving a gentle reflux, while the temper-
ature of the water bath reached a peak temperature of 32 °C.
Because the reaction mixture became biphasic as the mixed
acid was added, vigorous stirring was continued throughout the
course of the reaction to ensure optimal yields were obtained.
After addition of the mixed acid was complete, the reaction
mixture was stirred for 1 h.
The reaction mixture was then poured onto 1 kg of crushed
ice with vigorous stirring, and this mixture was stirred until the
ice melted and the solution had achieved ambient temperature.
The solution was then transferred to a 3 L separatory funnel,
and the CH Cl layer was drained. The solution in the
2
2
separatory funnel was then extracted three more times with
00 mL portions of CH Cl . At this stage, the aqueous layer
5
2
2
was discarded, and the combined organic extracts were
returned to the separatory funnel. The combined organic
extracts were washed five times with 500 mL portions of
distilled water until a pH of 6−7 was reached, during which
time the CH Cl phase had become colorless. The organic
2
2
phase was dried over MgSO , filtered, and concentrated in
4
vacuo (water bath temperature = 30 °C) to afford a yellow
liquid, which crystallized when residual CH Cl was removed
2
2
by means of a vacuum pump. The resulting light yellow/white
crystalline solid was identified as DCFO (57.6 g, 72%, 84%
purity); Tmelt = 30.4−37.7 °C; T (onset) = 228.1 °C; Tpeak
=
dec
−
1
2
65.1 °C; IR (neat) cm 2255.13 (w), 1628.36 (s), 1460.73
13
(
s), 1306.96 (m), 1099.99 (m), 1038.43 (s); C NMR (101
MHz, CDCl ) δ 131.73, 104.97, 102.76, 95.50.
3
ASSOCIATED CONTENT
Figure 2. (A) Atom−atom intermolecular contacts and (B) crystal
packing for 1 viewed along the b-axis direction. Dashed lines represent
intermolecular interactions.
■
*
S
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.oprd.9b00186.
1
3
1
C and H spectra for compound 2 (PDF)
diffractometer containing an EosS2 charge-couple device
detector and a molybdenum Mo-Kα (λ = 0.71073 Å) radiation
source. The crystal was kept at −23.0 (1) °C during data
collection. CCDC number 1912929 (for 1) contains the
supplementary crystallographic data for this paper. These data
can be obtained free of charge from the Cambridge
Crystallographic Data Centre.
Caution! Although we did not experience any problems in
performing the reaction described in this paper, proper laboratory
precautions should be taken. Laboratories and personnel should be
properly grounded, and safety equipment such as heavy Kevlar/
steel gloves, reinforced Kevlar coat, ballistic face shield, ear plugs,
and blast shields are necessary.
13C spectrum, DSC trace, IR spectrum, and X-ray
crystallographic data for compound 1 (PDF)
Liquid chromatography analysis of compound 1 (CIF)
AUTHOR INFORMATION
■
*
Corresponding Author
E-mail: jesse.j.sabatini.civ@mail.mil.
ORCID
Rosario C. Sausa: 0000-0003-3183-0106
Jesse J. Sabatini: 0000-0001-7903-8973
Author Contributions
E.C.J., E.J.B., and J.J.S. performed the synthesis reactions.
E.C.J. and E.J.B. conducted the analytical analysis. R.C.S.
performed the X-ray experiments and analysis. J.J.S. wrote the
bulk of the paper.
3
,4-Dicyanofuroxan (1). In a 2 L three-neck round-
bottom flask equipped with a stirbar, cyanoacetic acid (100 g,
.18 mol, 1.00 equiv) was suspended in 400 mL of CH Cl
1
2
2
with vigorous stirring. The flask was then fitted with a reflux
condenser and a 500 mL liquid addition funnel, and was
D
DOI: 10.1021/acs.oprd.9b00186
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Communication
Notes
(15) Cady, H. H.; Larson, A. C.; Cromer, D. T. The crystal structure
of benzotrifuroxan (hexanitrosobenzene). Acta Crystallogr. 1966, 20,
The authors declare no competing financial interest.
3
(
36−341.
16) Prout, C. K.; Hodder, O. J. R.; Viterbo, D. The crystal and
ACKNOWLEDGMENTS
■
molecular structure of 4,6-dinitrobenzfuroxan. Acta Crystallogr., Sect.
B: Struct. Crystallogr. Cryst. Chem. 1972, B28, 1523−1526.
(17) Cameron, A. F.; Freer, A. A. Crystal and molecular structure of
Funding from the US Army and the Office of Naval Research is
greatly acknowledged. The authors thank Dr. Joshua A. Orlicki
for carbon NMR assistance of DCFO.
3-methyl-4-nitrofuroxan, C
H N O . Acta Crystallogr., Sect. B: Struct.
3 3 4
3
Crystallogr. Cryst. Chem. 1974, B30, 354−357.
(
18) Stepanov, A. I.; Dashko, D. V.; Astrat’ev, A. A. 3,4-bis(4′-
ABBREVIATIONS
■
nitrofurazan-3′-yl)furoxan: A Melt Cast Powerful Explosive and a
Valuable Building Block in 1,2,5-Oxadiazole Chemistry. Cent. Eur. J.
Energy Mater. 2012, 9 (4), 329−342.
DCFO = dicyanofuroxan; HNO = nitric acid; H SO =
sulfuric acid; TFA = trifluoroacetic acid; CH Cl = dichloro-
3
2
4
2
2
methane
(19) He, C.; Gao, H.; Imler, G. H.; Parrish, D. A.; Shreeve, J. M.
Energetic salts of 4-nitramino-3-(5-dinitromethyl-1,2,4-oxadiazolyl)-
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E
DOI: 10.1021/acs.oprd.9b00186
Org. Process Res. Dev. XXXX, XXX, XXX−XXX