Impact of Stereo- And Regiochemistry on Energetic Materials

Article abstract of DOI:10.1021/jacs.9b06961

The synthesis, physical properties, and calculated performances of six stereo- and regioisomeric cyclobutane nitric ester materials are described. While the calculated performances of these isomers, as expected, were similar, their physical properties were found to be extremely different. By alteration of the stereo- and regiochemistry, complete tunability in the form of low- or high-melting solids, stand-alone melt-castable explosives, melt-castable explosive eutectic compounds, and liquid propellant materials was obtained. This demonstrates that theoretical calculations should not be the main factor in driving the design of new materials and that stereo- and regiochemistry matter in the design of compounds of potential relevance to energetic formulators.

Full text of DOI:10.1021/jacs.9b06961

Subscriber access provided by UNIV OF SOUTHERN INDIANA
Communication
Impact of Stereo- and Regiochemistry on Energetic Materials
Lisa M. Barton, Jacob T. Edwards, Eric C. Johnson, Eric J Bukowski, Rosario C.
Sausa, Edward F. C. Byrd, Joshua A. Orlicki, Jesse J Sabatini, and Phil S. Baran
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b06961 • Publication Date (Web): 30 Jul 2019
Downloaded from pubs.acs.org on July 30, 2019
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 6
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
Impact of Stereo- and Regiochemistry on Energetic Materials
Lisa M. Barton†, Jacob T. Edwards†, Eric C. Johnson‡, Eric J. Bukowski‡, Rosario C. Sausa§, Edward F.
C. Byrd§, Joshua A. Orlicki҂, Jesse J. Sabatini,*‡ and Phil S. Baran*†
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
†Department of Chemistry, Scripps Research, 10550 North Torrey Pines Road, La Jolla, California 92037
‡ CCDC US Army Research Laboratory, Energetics Synthesis & Formulation Branch, Aberdeen Proving Ground, MD 21005
§ CCDC US Army Research Laboratory, Detonation Sciences & Modeling Branch, Aberdeen Proving Ground, MD 21005
҂CCDC US Army Research Laboratory, Polymers Branch, Aberdeen Proving Ground, MD 21005
Supporting Information Placeholder
a Challenges in Energetics
Borderline Primary
Explosive
Secondary Explosive
O2NO
Me
ABSTRACT: The synthesis, physical properties and calculated
performances of six stereo- and regioisomeric cyclobutane
nitric ester materials is described. While the calculated
performances of these isomers, as expected, were similar, their
physical properties were found to be extremely different. By
altering the stereo- and regiochemistry, complete tunability in
the form of low-or high-melting solids, standalone melt-
castable explosives, melt-castable explosive eutectic
compounds, and liquid propellant materials were obtained. This
demonstrates that theoretical calculations should not be the
main factor in driving the design of new materials, and that
stereo- and regiochemistry matter when designing compounds
of potential relevance to energetic formulators.
ONO2
Ideal
Energetic
O2N
NO2
PETN
i.e.
IS
FS
ESD
i.e.
Tm
i.e. Tm, ρ,
Pcj, Vdet
TNT
O2NO
,
ONO2
IS, FS,
Extremely ESD
Sensitive
NO2
•Highly Sensitive
•High Energy
•Not Melt
Good
Physical
Properties
•State of the Art
Melt Castable
•Insensitive
Castable
O2NO
ONO2
Me
TMETN
•Liquid
•Highly Sensitive
Propellant
Plasticizer
Current Design:
Based largly on
computational
properties
Dogma in
Energetics:
Stereochemistry
Does Not Matter
ONO2
b Functional impact of stereochemistry and regiochemistry
H
N
H
N
Regioisomers
[Drugs]
Stereoisomers
[Fragrance]
Me
N
N
Me
NHSO2Ph
CO2H
In pursuit of designing high-performing energetic
materials,1 the main criteria today is based on theoretically
predicted performance properties.2 While a given material’s
synthetic accessibility and oxygen balance are factors in the
design of new energetics, historically these molecules have
been prepared based largely on computer calculated properties
(density, heat of formation (DH), detonation pressure (Pcj),
detonation velocity (Vdet), and specific impulse (Isp)). Hence,
many nitrated derivatives based on various nitrogen- and
oxygen-rich heterocyclic systems have been synthesized to-
date.3-10 Unfortunately, while many of these legacy materials
are high-performing based on computational calculations, they
are plagued by issues such as very high sensitivity, thermal
instability, moisture sensitivity, and in the case of nitrogen-rich
energetic salts, an incompatibility with many common
ingredients in an explosive or propellant formulation mixture.
For this reason, classic energetics such as the highly sensitive
primary explosive pentaerythritol tetranitrate (PETN), the
current state-of-the-art melt-castable explosive trinitrotoluene
(TNT), and the sensitive liquid plasticizer trimethylolethane
trinitrate (TMETN) still find common use today (Figure 1a).
Herein a long-overlooked strategy for the design of useful
energetic materials is presented in an effort to develop highly
energetic melt-castable and propellant plasticizing materials.
H
N
[IC50 αVβ3] 1.3 nM
Solubility: <0.1 mg/mL
O
Me
cis-rose oxide
very strong, sharp,
floral green
O
αVβ3 antagonists
Stereo- and Regiochemical
Configuration Essential
Me
vs.
N
N
Me
N
H
N
H
NHSO2Ph
H
N
O
Me
CO2H
[IC50 αVβ3] 0.48 nM
Solubility: 3.5 mg/mL
trans-rose oxide
weak, fruity,
herbal (minty)
O
c Cyclobutane-based energetics as a probe
O2NO
O2NO
O2NO
O2NO
ONO2
O2NO
ONO2
This
Work
ONO2
ONO2
O2NO
ONO2
1
[4 Possible Meso
Diastereomers]
ONO2
isomers have similar Study of relative energetic properties of
theoretical properties
stereo- and regioisomers
Figure 1. (a) Challenges and variables in the design of modern
energetics; (b) Impacts of stereo- and regiochemistry in medicine
and fragrances; (c) Platform to interrogate stereo- and
regiochemistry in energetics.
In designing energetic materials, exploration of a class of
materials based on systematic stereo- and regiochemical
1
ACS Paragon Plus Environment

Journal of the American Chemical Society
permutations is without precedent. This has largely stemmed
Page 2 of 6
Azetidine and cyclobutane moieties tolerate various
nitration conditions. Due to their ring strain, which further
increases performance by raising the heat of formation of the
system, nitro group-bearing materials containing these cores
have been designed in the past. Two of the most energetic
materials containing these strained rings are 1,1,3,3-tetranitro
cyclobutane (TNCB)14 and the melt-castable explosive
trinitroazetidine (TNAZ).15 TNCB was calculated to possess an
explosive power in excess of HMX, but unfortunately
decomposes at 165 ºC, and is hence of little practical value. Like
TNCB, TNAZ was also calculated to possess an explosive
performance in excess of HMX, possessing a melting point of
101-103 ºC and a decomposition temperature of 216 ºC, which
classifies it as a potential melt-castable explosive material.
Despite successful efforts to scale TNAZ,16 its vapor pressure
in the molten state was found to be significantly higher than that
of the benchmark melt-castable explosive TNT. This presented
a significant safety and processing hazard, all but ending
TNAZ’s potential applications as a melt-castable explosive
1
2
3
4
5
6
7
8
from the perception that stereo- or regioisomers are not
advantageous to pursue since the predicted performance
properties between the isomers will be minimal. Yet the critical
role of stereo- and regiochemistry is documented in nearly all
other areas of the chemical enterprise.11 For example, as shown
in Figure 1b, regioisomers can exhibit drastically different
physical properties and when recognition events take place with
chiral receptors, the stereochemistry of a small-molecule binder
matters.12-13
9
Herein, the long-held assumption that stereo- and
regiochemistry are of little influence in the energetics field is
challenged with a systematic analysis of a set of cyclobutane-
based nitric esters, differing only in stereo- and regiochemistry
(Figure 1c). Despite having similar theoretical performance
properties, this set of isomeric strained molecules exhibits
remarkable differences in physical properties, tunable by virtue
of simple stereo- and regiochemical changes.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
a
All possible meso Isomers of 1,2,3,4-cyclobutyl-based nitrate ester template 1
MeO2C
CO2Me
O
O2NO
O2NO
ONO2
ONO2
a. hv
b. Red-Al c. 100% HNO3
OMe
OEt
MeO
85%
[80 gram
scale]
82% (2 steps)
[gram scale]
MeO2C
CO2Me
O
O
2
8
[cis-trans-cis]
>1 kg prepared
CO2Et
MeO2C
CO2Me
O
b. Red-Al
d. t-BuOK
O2NO
ONO2
ONO2
+
c. 100% HNO3
EtO
85%
[>100 gram
scale]
MeO2C
CO2Me
O2NO
80% (2 steps)
[gram scale]
10
O
CO2Et
3
9
[all-trans]
>1 kg prepared
e. PPh3
77%
O2NO
O2NO
ONO2
ONO2
f. H2
Pd/C
EtO2C
CO2Et
EtO2C
EtO2C
CO2Et
[gram scale]
b. Red-Al c. 100% HNO3
92%
[gram scale]
91% (2 steps)
[gram scale]
4 (liquid)
[cis-cis-trans]
EtO2C
CO2Et
CO2Et
11
12
AcO
O
g. Acetophenone, hv
h. NaBH4
AcO
AcO
O2NO
ONO2
ONO2
O
O
32% (2 steps)
b. Red-Al c. 100% HNO3
+
O
O2NO
f. H2, Pd/C
85% (2 steps)
[gram scale]
5
88%
[gram scale]
O
13
[all-cis]
AcO
b
Selected constitutional Isomers
O2NO
O2NO
ONO2
(+)Pt/(–)Fe
j.
MeO2C
CO2Me
b. Red-Al
c. 100% HNO3
MeO2C
MeO2C
CO2Me
CO2Me
i. NaH
Br
Dimethyl Malonate
ONO2
NaI, MeOH
92%
[gram scale]
58%
[gram scale]
81% (2 steps)
[gram scale]
Br
6
14
15
[1,1,2,2]
MeO2C
CO2Me
Ph
Ph
b. Red-Al
c. 100% HNO3
k. KI, NaH
Diethyl Malonate
O
O
l. 1 M HCl
MeOH
O
O
O2NO
O2NO
ONO2
ONO2
EtO2C
EtO2C
OH
OH
7
57%
[gram scale]
73%
[gram scale]
79% (2 steps)
[gram scale]
OTs
18
[1,1,3,3]
17
OTs
16
EtO2C CO2Et
Scheme 1. Conditions: (a) hv, H2O, rt. (b) 60% Red-Al (5 equiv.), Toluene, 0 to 80 ºC, 16 h. (c) 100% HNO3, 0 ºC to rt (d) t-BuOK (0.3
equiv.), MeOH, 80 ºC, 24 h. (e) 10 (1 equiv.), Diethyl acetylenedicarboxylate (1 equiv.), PPh3 (1 equiv.), DCM, -15 ºC to rt, 48 h. (f) Pd/C
(5 mol%), H2, EtOAc, rt, overnight. (g) Maleic anhydride (1 equiv.), 2-butyne-1,4-diol diacetate (1.2 equiv.), acetophenone (0.2 equiv.), hv,
MeCN, rt, 9 days. (h) NaBH4 (1.03 equiv.), THF, -65 ºC to rt. (i) Dibromoethane (1 equiv.), Dimethyl malonate (5 equiv.), NaH (4 equiv.),
DMF, 80 ºC, 24 h. (j) NaI (0.67 equiv.), MeOH, Pt anode, Fe cathode, 100 mA, 6 F/mol. (k) Diethyl malonate (2.04 equiv.), NaH (2 equiv.),
KI (0.1 equiv.), DMF, 70 to 140 ºC, overnight. (l) 1 M HCl/MeOH (1:6), overnight.
2
ACS Paragon Plus Environment

Page 3 of 6
Journal of the American Chemical Society
material. It was noticed in searching the literature that tetra-
maleic anhydride were found to undergo [2+2] cycloaddition.
Direct reduction of the crude anhydride to the corresponding
cyclobutene-lactone to aid in isolation and hydrogenation gave
the all-cis product 13 as the sole diastereomer (convex approach
of H2). Lactone 13 was then directly subjected to reduction and
nitration to give the final meso stereoisomer 5.
1
2
3
4
5
6
7
8
(nitroxymethyl) cyclobutane, nor any of its isomers, had been
made and thus the physical and energetic properties stemming
from their stereo- and regiochemistries had not been studied. As
a result, the tetrasubstituted cyclobutane nitric ester scaffold 1
was chosen based on its nitrated structure and its ring strain,
coupled with its ability to introduce stereo- and regiochemistry
into the structure.
Two constitutional isomers of 1 were also targeted as a
control to gauge the influence of regiochemistry on the physical
and energetic properties within the same cyclobutane series
(Scheme 1B). To that end, dimethyl malonate was alkylated
with dibromoethane to give 14, in which the major byproduct
arose from the intermediate mono-addition adduct
intramolecularly cyclizing to give 1,1-diester cyclopropane. At
this point, all initial attempts to cyclize 14 under reported
bromination/thermal cyclization conditions24 proved entirely
irreproducible in our hands. Therefore, we instead turned to
electrochemical methods. Gratifyingly, we found that a slight
modification to the procedure reported by Elinson et al.25
cleanly gave the desired 15 in excellent yield under anodic
conditions (see SI). Two additional steps then gave access to the
1,1,2,2-tetrasubstituted nitric ester 6. Finally, the 1,1,3,3
constitutional isomer 7 could be accessed via the known
compound 1626 after alkylation, acetonide deprotection,
reduction of the diester, and nitration.
Scheme 1A outlines the scalable synthesis of all four
possible meso stereochemical isomers of compound 1 (2-5), as
well as two constitutional isomers (6-7). To begin, both
compounds 2 and 3 can be accessed by the photochemical
dimerization of dimethyl fumarate.17 This yields the head-to-
head dimer 8, in which the ester substituents around the central
cyclobutane ring have a cis-trans-cis relationship to one
another. Direct reduction of 8 gave the tetraol, which was
immediately subjected to nitration to provide 2. Conversely, 8
could be epimerized under basic conditions18 to afford its all-
trans stereoisomer 9. A similar sequence of reduction and
nitration furnished the all-trans nitric ester 3.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
To obtain the cis-cis-trans meso stereoisomer, 1019 was
employed in a 1,4-addition/intramolecular Wittig cyclization20
cascade to afford 11 as the sole diastereomer. Hydrogenation of
the cyclobutene set the remaining two stereocenters, which after
reduction and nitration yielded 4.
With cyclobutane isomers 2-7 in hand, each isomer’s
physical properties and sensitivities to impact, friction and
electrostatic discharge was determined. These values, along
with the theoretical energetic properties27, are given in Table 1.
As expected, based off the experimentally derived densities, the
calculated detonation velocities, detonation pressures, heats of
formation and specific impulses of isomers 2-7 were in close
agreement with one another. It is for this reason that the pursuit
of stereo- and regioisomeric structures in designing energetic
materials has historically been dismissed. An examination of
the physical properties, however, tells a much different story.
Synthesis of the all-cis stereoisomer 5 proved to be more
challenging as the route needed to be both highly scalable and
stereoselective for our purposes. Previous reports for the
synthesis of the all-cis stereoisomer of 1 commenced from
acenaphthylene21 (6% overall yield), cyclooctatetraene22 (5%
overall yield), or 2(5H)-furanone23 (3% overall yield, solid-state
dimerization at -78 ºC). It was reasoned that intercepting a
cyclic intermediate of different oxidation state may eliminate
some of the pitfalls that plagued previous syntheses. After much
experimentation, acetate-protected 2-butyne-1,4-diol and
Table 1. Physical properties, sensitivities and theoretical performance of isomers 2-7, TNT and TMETN.
[Blue] = Desirable Melt Castable Properties [Purple] = Desirable Propellant Properties [Red] = Undesirable Properties
Data category
Tm [ºC][a]
TNT
80.4
295.0
-74
TMETN
-3
2
3
4
5
6
7
106.0
198.5
-44.9
-9.0
47.5
<-40
186.8
-44.9
-9.0
100.8
194.3
-44.9
-9.0
85.9
146.9
196.2
-44.9
-9.0
Tdec [ºC][b]
ΩCO2 [%][c]
ΩCO [%][d]
ρ [gcm-3][e]
Pcj [GPa][f]
Vdet [ms-1][g]
Isp [s][h]
182.0
-34.5
-3.1
199.7
-44.9
-9.0
192.8
-44.9
-9.0
-24.7
1.65
19.3
6950
-
1.47
23.7
7050
247.0
-425.0
0.2028
-
1.64
1.605
22.9
1.543
24.5
1.66
1.683
24.6
1.651
24.4
24.5
24.5
7438
240.5
-510.1
6.2
7544
238.7
-535.9
6.2
7577
240.4
-512.0
9.0
7504
242.5
-480.8
6.2
7604
243.6
-465.5
4.7
7472
240.6
-509.2
6.2
ΔfH° [kJ mol–1][i]
IS[j] [J]
-59.3
15
FS[k] [N]
240
240
240
>360
0.125
240
>360
>0.25
>360
>0.25
ESD[l] [J]
0.25
-
0.125
0.125
0.125
[a] Tm = onset temperature of melting; [b] Tdec = onset temperature of decomposition; [c] ΩCO2 = CO2 oxygen balance; [d] ΩCO = CO oxygen balance; [e]
ρ = derived density from X-ray data; [f] Pcj = detonation pressure; [g] Vdet = detonation velocity; [h] Isp = specific impulse; [i] ΔfH° = molar enthalpy of
formation; [j] IS = impact sensitivity; [k] FS = friction sensitivity; [l] ESD = electrostatic discharge sensitivity
3
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 6
While melt-castable explosive candidates typically need to
explosives, melt-castable explosive eutectic compounds, high-
melting solid materials, and extreme low-melting liquid
materials. Such tunability has the potential to cater to both the
explosives and propellants community.
1
2
3
4
5
6
7
8
exhibit a minimum temperature difference of 75 ºC between
melting and decomposition temperatures and melt between 80-
125 ºC, the all-trans cyclobutane isomer 3 is a low-melting
energetic solid. Thus, its 47.5 ºC melting point is too low to be
considered a met-castable explosive. On the other hand, the all-
cis and cis-trans-cis cyclobutane isomers 5 and 2 both possess
melting and decomposition temperatures that allow them to find
potential use in melt-castable explosive eutectic formulations.
While 5 and 2 possess melting points slightly above 100 ºC,
these materials can be formulated with other high-energy
energetic compounds to form a melting point between 80-95 ºC.
This melting point range is ideal for melt-castable explosive
operations because it allows for steam heating to be employed
at ambient pressure during a casting operation, reducing
operating costs. In examining the cyclobutane regioisomers, 7
possesses too high of a melting point to be of practical value in
the melt-castable explosive arena. However, 6 exhibits a
melting point that fits well in the standalone melt-castable
range. Like TNT, 6 does not need to be mixed with anything to
further depress the melting point for casting operations to occur.
It is worth noting that melt-castable candidates 2, 5 and 6
possess detonation pressures that are ca. 25% more powerful
than TNT, exceeding the explosive power of the state-of-the-art
melt-castable ingredient by a wide margin. Furthermore, 2, 5
and 6 possess equivalent or lower friction sensitivities than
TNT. Although these three tetranitric ester materials have
higher impact sensitivities than TNT, 6 is still less sensitive to
impact than the commonly manufactured PETN (3 J), while 2
and 5 possess identical impact sensitivities to the ubiquitous
explosive RDX (6.2 J). The 0.125 J electrostatic discharge
sensitivity of 2, 5 and 6 is also equal to that of RDX. Thus,
possessing sensitivities that are equal to or lower than
commonly handled explosive materials demonstrates that these
melt-castable tetranitric ester candidates are safe to handle.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS
Publications website.
9
Detailed experimental procedures and analytical data (PDF)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
AUTHOR INFORMATION
Corresponding Authors
*jesse.j.sabatini.civ@mai.mil
*pbaran@scripps.edu
ORCID
Phil S. Baran: 0000-0001-9193-9053
Jesse J. Sabatini: 0000-0001-7903-8973
NOTES
The authors declare no competing financial interest.
ACKNOWLEDGMENT
Financial support for this work was provided by the Defense
Advanced Research Projects Agency (DARPA, Agreement No.
HR0011-18-9-0021). We are thankful to Dr. Anne Fischer for
insightful discussions, the NSF GRFP (predoctoral fellowship to
L.M.B.), the Department of Defense (NDSEG fellowship to
J.T.E.), and Bristol-Myers Squibb (Graduate Fellowship to J.T.E.).
We are grateful to Dr. Dee-Hua Huang and Dr. Laura Pasternack
(Scripps Research) for assistance with NMR spectroscopy.
REFERENCES
Surprisingly, cis-cis-trans isomer 4 is distinct from the other
cyclobutane tetranitric ester isomers in that it is a liquid, and
can thus be classified as a potential energetic plasticizer
ingredient for potential use in propellant formulations. As
presented in Table 1, 4 was found to possess a significantly
lower sensitivity to impact, yet possesses a higher density than
the propellant plasticizer TMETN.28 Although TMETN
possesses a slightly higher specific impulse compared to 4, it
has a relatively high freezing point of -3 ºC. Strikingly 4, which
differs from 2 (m.p. 106 ºC) by a single stereocenter, did not
freeze even at -40 ºC. The low freezing point of 4 offers
significant potential benefits with regard to propellant
formulation capabilities, such as forming high-energy freezing
point eutectic materials that are not currently possible with
TMETN. It thus appears that by taking advantage of the stereo-
and regiochemistry of a given CHNO molecule, it is possible to
develop an entirely tunable energetic system that can potentially
serve energetics formulators in both the explosives and
propellants field.
(1) a) Klapötke, T. M. Chemistry of High-Energy Materials, 3rd ed.;
De Gruyter: Berlin, 2015; (b) Agrawal, J.P.; Hodgson, R. D.
Organic Chemistry of Explosives; Wiley: Hoboken, NJ, 2007; c)
Dobratz, B. M. Properties of Chemical Explosives and Explosive
Simulants; UCRL-52997; Lawrence Livermore National
Labratory: CA, 1972.
(2) (a) Politzer, P.; Murray, J. S.; Seminario, J. M.; Lanes, P.; Grice,
M. E.; Concha, M. C. Computational characterization of energetic
materials. J. Mol. Struct. 2001, 573, 1-10 (b) Rice, B. M.; Hare, J.
J.; Byrd. E. F. C. Accurate Predictions of Crystal Densities Using
Quantum Mechanical Molecular Volumes. J. Phys. Chem. 2007,
111, 10874-10879 (c) Keshavarz, M. H. Prediction of heats of
sublimation of nitroaromatic compounds via their molecular
structure. J. Hazard. Mater. 2008, 151, 499-506.
(3) Huang, H.; Zhou, Z.; Liang, L.; Song, J.; Wang, K.; Cao, D.; Sun,
W.; Bian, C.; Xue, M. Nitrogen-Rich Energetic Monoanionic
Salts of 3,4-Bis(1H-5-tetrazolyl)furoxan. Chem. Asian J. 2012, 7,
707-714.
(4) Wei, H.; Zhang, J.; He, C.; Shreeve, J. M. Energetic Salts Based
on Furazan-Functionalized Tetrazoles: Routes to Boost Energy.
Chem. Eur. J. 2015, 21, 8607-8612.
(5) Gao, H.; Wang, R.; Twamley, B.; Hiskey, M. A.; Shreeve, J. M.
3-Amino-6-nitroamino-tetrazine (ANAT)-based energetic salts.
Chem. Commun. 2006, 38, 4007-4009.
In summary, it has been demonstrated that stereo- and
regiochemistry should play a significant role in the design of
new energetic materials and should not be dismissed on
theoretical grounds. Depending on the stereochemistry and
regiochemistry employed, tunable molecules were designed
that gave rise to low-melting solids, standalone melt-castable
(6) Klenov, M. S.; Guskov, A. A.; Anikin, O. V.; Churakov, A. M.;
Strelenko, Y. A.; Fedyanin, I. V.; Lyssenko, K. A.; Tartakovsky,
V. A. Angew. Chem. Int. Ed. 2016, 55, 11472-11475.
4
ACS Paragon Plus Environment

Page 5 of 6
Journal of the American Chemical Society
(7) Zhang, C.; Sun, C.; Hu, B.; Yu, C.; Lu, M. Synthesis and
(20) Yavari, I.; Nourmohammadian, F. Stereoselective Synthesis of
-
characterization of the pentazole anion cyclo-N5 in
Tetraalkyl Cyclobutene-1,2,3,4-tetracarboxylates. Synthesis of
Tetraalkyl (Z,Z)-Buta-1,3-diene-1,2,3,4-tetracarboxylates. J.
Chem. Research 1999, 512-513.
1
2
3
4
(N5)6(H3O)3(NH4)4Cl. Science 2017, 355, 374-376.
(8) Lin, Q. –H.; Li, Y. –C.; Liu, W.; Wang, Y.; Pang, S. –P. Nitrogen-
rich salts based on 5-hydrazino-1H-tetrazole: A new family of
high-density energetic materials. J. Mater. Chem. A. 2013, 1,
6776-6785.
(21) Griffin,
G.
W.;
Veber,
D.
F.
cis,cis,cis-1,2,3,4-
Tetracarbomethoxycyclobutane; structure of b-heptacyclene. J.
Am. Chem. Soc. 1960, 82, 6417.
5
6
7
8
(9) Xu, Z.; Cheng, G.; Zhu, S.; Lin, Q.; Yang, H. Nitrogen-rich salts
based on the combination of 1,2,4-triazole and 1,2,3-triazole
rings: A facile strategy for fine tuning energetic properties. J.
Mater. Chem. A. 2018, 6, 2239-2248.
(10) Thottempudi, V.; Zhang, J.; He, C.; Shreeve, J. M. Azo
substituted 1,2,4-oxadiazoles as insensitive energetic materials.
RSC Adv. 2014, 4, 50361-50364.
(22) Schroder, G.; Martin, W. Structure of the Cyclooctatetraene
Dimer of Melting Point 53 ºC. Angew. Chem. Int. Ed. 1966, 5,
130.
(23) Ohga, K.; Matsuo, T. A Study on the Photochemistry of a,b-
Unsaturated g-Lactones. I. The Structures of the Photodimers of
4-Hydroxycrotonic Acid g-Lactone. Bull. Chem. Soc. Jpn. 1970,
43, 3505-3510.
(24) (a) Kostyanovsky, R. G.; Krutius, O. N.; El’natanov, Y. I.
Reactions of alkylenebisbromomalonates with Nucleophiles.
Russ. Chem. Bull. 1994, 43, 2065-2069 (b) Gol’mov, V. P.;
Malevannaya, Z. P. A New Preparative Method for Cis-
cyclobutane-1,2-dicarboxylic Acid. Zhurnal Obshchei Khimii,
1961, 31, 665-669 (c) Vogel, I. Syntheses of Cyclic Compounds.
Part I. Ethyl bg-Dimethylbutane-aadd-tetracarboxylate and
Some Cyclobutane Compounds Derived Therefrom. J. Chem.
Soc. 1927, 1985-1994.
(25) Elinson, M. I.; Fedukovich, S. K.; Ugrak, B. I.; Nikishin, G. I.
Electrochemical Oxidation of Tetramethyl Esters of a,a,w,w-
Alcanetetracarboxylic Acids. Russ. Chem. Bull. 1992, 41, 1827-
1833.
(26) Pecquet, P.; Huet, F.; Legraverend, M.; Bisagni, E. Synthesis of
New Carbocyclic Analogues of Oxetanocin A and Oxetanocin G.
Heterocycles 1992, 34, 739-745.
(27) (a) Byrd, E. F. C.; Rice, B. M. Improved Heats of Formation of
Energetic Materials Using Quantum Mechanical Calculations. J.
Phys. Chem. A. 2006, 110, 1005-1013; (b) Byrd, E. F. C.; Rice,
B. M. A Comparison of Methods to Predict Solid Phase Heats of
Formation of Molecular Energetic Salts. J. Phys. Chem. A. 2009,
113, 345-352; (c) Rice, B. M.; Hare, J. J.; Byrd, E. F. C. Accurate
Predictions of Crystal Densities Using Quantum Mechanical
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(11) Eliel, E. L.; Wilen, S. H. Stereochemistry of Organic Compounds,
1st ed.; Wiley-Interscience: New York, 1994.
(12) Ishikawa, M.; Hiraiwa, Y.; Kubota, D.; Tsushima, M.; Watanabe,
T.; Murakami, S.; Ouchi, S.; Ajito, K. Tricyclic pharmacophore-
based molecules as novel integrin aVb3 antagonists. Part III:
Synthesis of potent antagonists with aVb3/aIIbb3 dual activity and
improved water solubility. Bioorg. Med. Chem. 2006, 14, 2131-
2150.
(13) Yamamoto,T.; Matsuda, H.; Utsumi, Y. Hagiwara, T. Kanisawa,
T. Synthesis and odor of optically active rose oxide. Tetrahedron
Lett. 2002, 43, 9077-9080.
(14) Archibald, T. G.; Garver, L. C.; Baum, K; Cohen, M. C. Synthesis
of polynitrocyclobutane derivatives. J. Org. Chem. 1989, 54,
2869-2873.
(15) Archibald, T. G.; Gilardi, R.; Baum, K.; George, C. Synthesis and
x-ray crystal structure of 1,3,3-trinitroazetidine. J. Org. Chem.
1990, 55, 2920-2924.
(16) Coburn, M. D.; Hiskey, M. A.; Archibald, T. G. Scale-up and
waste-minimization of the Los Alamos process for 1,1,3-
trinitroazetidine (TNAZ). Waste Management, 1998, 17, 143-
146.
(17) Lai,
M.
C.;
Chang,
C.
W.;
Ong,
C.
W.
Cyclobutanetetracarboxylate Compound and Preparation Method
Thereof. US Patent US20060089505A1, 2006.
(18) Suzuki, H.; Tamura, T. Cage-Shaped Cyclobutanoic
Dianhydrides and Process for Production Thereof. European
Patent EP1813592A1, 2005.
(19) Barr, K. J.; Scott, M. E.; Thompson, C. F.; Anthony, N.;
Cammarano, C. M.; Bakshi, R. K.; Mohanty, S. K.; Korapala, C.
S.; Latthe, P. R.; Kambam, V. N.; Sarkar, S. K.; Thatai, J. T.
Pyrrolidine derived beta 3 adrenegic receptor agonists. US Patent
US9486448B2, 2016.
Molecular Volumes. J. Phys. Chem. A. 2007, 111, 10874−10879;
(d) Rice, B. M.; Byrd, E. F. C. Evaluation of electrostatic
descriptors for predicting crystalline density.J. Comput. Chem.
2013, 34, 2146−2151. (e) Bastea, S.; Fried, L. E.; Glaesman, K.
R.; Howard, W. M.; Kuo, I. F. W.; Souers, P. C.; Vitello, P.
A.Cheetah 7.0 Thermochemical Code; Energetic Materials
Center, Lawrence Livermore National Laboratory: Livermore,
CA, 2012.
(28) Meyer, R.; Köhler, J.; Homburg, A. Explosives, 6th Edition, 2007,
227.
5
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 6 of 6
Table of Contents
1
Energetics: Stereo- and
Regiochemistry Matter!
Experimental
Computational
2
3
4
5
6
7
• Isomers are equal
• Same explosive properties
• No way to determine
physical properties
• Isomers are all different
• Melting Points from
<-40 to 146.9 ºC
O2NO
O2NO
O2NO
O2NO
ONO2
ONO2
ONO2
ONO2
Access to:
Dogma:
• Liquid Propellants
• Standalone Melt-castables
• Melt-castables Eutectics
• No Impact of Stereo- and
Regiochemistry
O2NO
O2NO
ONO2 O2NO
ONO2 O2NO
ONO2 O2NO
ONO2 O2NO
ONO2 O2NO
ONO2 O2NO
ONO2
O2NO
O2NO
ONO2
ONO2
O2NO
O2NO
ONO2
ONO2
ONO2
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
6
ACS Paragon Plus Environment