Penfactual

NCBINCBI Logo
Skip to main content

Skip to navigation
Resources
How To
About NCBI Accesskeys
PMC
US National Library of Medicine
National Institutes of Health
Search database
PMC
Search term
Search
Advanced Journal listHelp
COVID-19 is an emerging, rapidly evolving situation.
Get the latest public health information from CDC: https://www.coronavirus.gov
Get the latest research information from NIH: https://www.nih.gov/coronavirus
Find NCBI SARS-CoV-2 literature, sequence, and clinical content:

https://www.ncbi.nlm.nih.gov/sars-cov-2/
Journal ListACS Cent Sciv.6(1); 2020 Jan 22PMC6978839

Logo of acscentsci
ACS Cent Sci. 2020 Jan 22; 6(1): 54–75.
Published online 2019 Dec 27. doi: 10.1021/acscentsci.9b01096
PMCID: PMC6978839
PMID: 31989026
Molecular and Crystal Features of Thermostable Energetic Materials: Guidelines for Architecture
of “Bridged” Compounds
Hui Li,†‡ Lei Zhang,corresponding author*§ ∥ Natan Petrutik,‡ Kangcai Wang, ⊥ Qing Ma,‡ ⊥
Daniel Shem-Tov,‡ Fengqi Zhao,† and Michael Gozincorresponding author*‡
Author information Article notes Copyright and License information Disclaimer
This article has been cited by other articles in PMC.
Associated Data
Supplementary Materials
Go to:
Abstract
An external file that holds a picture, illustration, etc.
Object name is oc9b01096_0025.jpg
Extensive density functional theory (DFT) calculation and data analysis on molecular and crystal
level features of 60 reported energetic materials (EMs) allowed us to define key descriptors that
are characteristics of these compounds’ thermostability. We see these descriptors as reminiscent
of “Lipinski’s rule of 5”, which revolutionized the design of new orally active pharmaceutical
molecules. The proposed descriptors for thermostable EMs are of a type of molecular design,
location and type of the weakest bond in the energetic molecule, as well as specific ranges of
oxygen balance, crystal packing coefficient, Hirshfeld surface hydrogen bonding, and crystal
lattice energy. On this basis, we designed three new thermostable EMs containing bridged,
3,5-dinitropyrazole moieties, HL3, HL7, and HL9, which were synthesized, characterized, and
evaluated in small-scale field detonation experiments. The best overall performing compound
HL7 exhibited an onset decomposition temperature of 341 °C and has a density of 1.865 g cm–3,
and the calculated velocity of detonation and maximum detonation pressure were 8517 m s–1 and
30.6 GPa, respectively. Considering HL7’s impressive safety parameters [impact sensitivity (IS) =
22 J; friction sensitivity (FS) = 352; and electrostatic discharge sensitivity (ESD) = 1.05 J] and the
results of small-scale field detonation experiments, the proposed guidelines should further
promote the rational design of novel thermostable EMs, suitable for deep well drilling, space
exploration, and other high-value defense and civil applications.
Go to:
Short abstract
A comprehensive computational analysis of energetic materials allowed the drawing of
thermostability guidelines, inspiring the design of new thermostable explosives, which were
synthesized and evaluated.
Go to:
Introduction
As our civilization progresses and expands, the need for natural resources and minerals, as well
as deeply buried fossil fuel, gases, and oil, is followed by an ever-growing consumption and
demand.1 For efficient extraction of raw petroleum, perforating guns, based on shaped explosive
charges, are commonly used to start the oil flow. These shaped explosives ensure efficient
penetration into the well-surrounding soil, allowing easier and faster access to the soil-imbedded
deposits.2 Deep charges, based on highly thermostable energetic materials, are being vastly used
on the verge of their thermostable threshold at a depth of 6 km where the temperature reaches
230 °C.3
The expected depletion of easily accessible natural minerals, fossil fuel, gases, and oil reservoirs
around the world is driving the oil and gas industry to explore and reach deposits as deep as 10
km. This encourages the pursuit for novel highly thermostable energetic materials capable of
operating in the deep well environment. When currently used explosives in perforation guns are
subjected to conditions beyond their temperature–time stability limits, they start to gradually
decompose, resulting in a significantly deteriorated performance or even detonation failure.
On the other end of the spectrum, thermostable energetic materials are essential to satisfy the
safety requirements of in-space operating systems.4 For example, the Apollo spacecraft was
installed with more than 210 pyrotechnic devices serving a variety of applications, including
launch escape tower separation, booster stage separation, as well as lunar module separation and
landing gear deployment.5 These mission-critical tasks’ success completely relies on the
performance of highly thermostable energetic materials (EMs), such as
1,2-bis(2,4,6-trinitrophenyl)ethene (HNS; C8, FigureFigure1313), exhibiting a decomposition
temperature (Td) of 318 °C.6

Figure 13
Family A of single-ring EMs.9,23,28,34,35
With this ever-growing demand for new and improved EMs, the discovery of new materials
mainly relies on an experimental smart-screening approach. Nevertheless, the technological
progress of current computational power can be harnessed to assist the development of EMs
with desired properties. There are several important molecular design strategies to obtain
explosives with improved thermostability. Beyond preparation of explosive salts, a popular
approach is the introduction of amino groups to aromatic carbocyclic and heterocyclic rings in
structures of neutral explosive molecules.7 Another important methodology for enhancing heat
resistance relies on the connection of two or more energetic rings together, directly or through
various “bridges”. The later design methodology was extensively explored by Shreeve in
condensing N,N′-alkylene-bridged symmetric and asymmetric bis-azoles,8,9 Klapotke in
utilizing a bis(1,3,4-oxadiazole)-bridging moiety between two trinitro-benzene rings,10,11
Pagoria,12 and other investigators.
With the rapid improvement in methods for molecular and crystal modeling, the direct
simulation of crystal properties, rather than properties of isolated molecules, becomes more
feasible.13 Utilizing supercomputers, empirical guidelines and rules, derived from energetic
crystals, can become powerful tools for the molecular and crystal design of the future EMs.
Principles for crystal engineering of insensitive EMs were described by Chaoyang Zhang, who
studied the crystal packing–impact sensitivity relationships, working toward efficient strategies
for designing high-performance insensitive EMs.14 A set of guiding principles for architecting
new explosophores with desired properties were reported by Qinghua Zhang in his research
focused on accelerating the discovery of insensitive EMs by the use of a “materials genome”
approach.15 Attempts of a comprehensive end-to-end design of novel bridged explosives were
also reported by Kuklja and co-workers.12 In a series of publications, they presented a
methodical design, synthesis, and characterization of 1,2,4-oxadiazole-bridged explosives,
showing advantages of calculation-based systematic properties–structure analysis. Furthermore,
extensive studies addressing the influence of molecular design and structure on the thermal
stability of high-energy compounds were performed by Manelis and co-workers.16
In our perspective, the aforementioned molecular-level approaches in the field of EMs are
significant steps forward, reminiscent of the impact created by the ground-breaking Lipinski’s
“Rule of Five”.17 The latter set of critical guidelines for the desired molecular structural features
revolutionized pharmaceutical research, becoming a key guiding molecular-design methodology
for the development of novel pharmacophores and orally active therapeutic agents.18 Since
heat-resistant explosives are typically solid crystalline organic materials, their mechanical
sensitivity, thermostability, and detonation properties greatly depend on the interactions
between individual molecules in crystals, as well as the crystals’ size and shape.
Here, we report the design, synthesis, and performance evaluation of three new thermostable
explosives—1,2-bis(3,5-dinitropyrazol)ethane (HL3), 5,5 ′-
bis(3,5-dinitropyrazol)-2,2′-bi(1,3,4-oxadiazole) (HL7), and 4,4 ′-(3,5-dinitropyrazolyl)methane
(HL9), in which two bis(3,5-dinitro-1H-pyrazole) moieties were connected to each other via their
C-4 carbon by ethylene, bis(1,3,4-oxadiazole), and methylene bridges, respectively. The
molecular designs of these new compounds were based on a comprehensive analysis of X-ray
crystallography data and thermal properties of 60 previously reported EMs
(FiguresFigures1313–17). For more methodological processing of the structural data, all EMs in
this study were divided into five representative families: (Family A) single-ring explosives;
(Family B) “bridgeless” explosives, in which two energetic rings are connected directly to each
other; (Family C) explosives, in which two energetic rings are connected via a “simple bridge”;
(Family D) explosives, in which two energetic rings are connected via a “complex bridge”; and
(Family E) “fused-rings” explosives, in which two energetic rings are connected via more than a
single “bridge”.

Figure 17
Family E of “fused-rings” EMs in which two energetic rings are connected via more than a
“simple bridge”.45−47
By analyzing the crystallographic data of 60 reported EMs and conducting high-throughput

density functional theory (DFT) calculations on supercomputers, we searched for the most
influential molecular and crystal level parameters that would show a certain level of correlation
with these EMs’ thermostability. In the present work, the thermostability of explosive crystals
was defined by DSC-measured onset temperature, at which structural changes and
decomposition are initiated in these crystals. At the molecular level, we examined correlations of
the type of the “bridge” (if present) in the molecule, the reactivity of this “bridge” and other
bonds in the molecule, as well as molecular oxygen balance (OB) with respect of the
thermostability of the corresponding EM. At the crystal level, valuable correlations were found
between EMs’ thermostability and intermolecular parameters including the crystal’s packing
coefficient (PC), hydrogen bonding amount in a crystal, and crystal’s lattice energy (LE).
By deducing common parameters and features (explosives thermostability general

trends—ETGTs) found in the molecular and crystal structures of the reported EMs, we
implemented these guidelines into the design of three new thermostable EMs (HL3, HL7, and
HL9). Computational detonation performance, as well as small-scale field detonation
experiments, showed the validity of our ETGT approach for the design of a new generation of top
performing thermostable EMs for deep drilling and space applications. In the future, this
approach may significantly contribute to the design of novel EMs, utilizing machine learning
methodologies.19
Go to:
Results and Discussion
Synthesis
Based on our guidelines for the architecture of “bridged” thermostable explosives, we developed
synthetic methodologies for the preparation of three new compounds. The first compound,
1,2-bis(3,5-dinitro-pyrazol)ethane (HL3; FigureFigure11), was prepared in three steps, starting
with synthesis of 1-(ethoxymethyl)-4-methyl-3,5-dinitropyrazole (HL1) in 94% yield. We
considered straightforward synthetic approaches for the preparation of
1,2-bis(3,5-dinitropyrazol)ethane (HL3), via a nitration of 1,2-bis(1H-pyrazolate)ethane.20
However, since no synthetic methodology was reported for the latter compound, we eventually
decided to utilize a similar oxidative coupling strategy typically used for preparation of
1,2-bis(2,4,6-trinitrophenyl)-ethane21 (a precursor of 1,2-bis(2,4,6-trinitrophenyl)ethane; HNS)
from 2-methyl-1,3,5-trinitrobenzene (TNT). This oxidative coupling reaction allows formation of
a carbon–carbon bond between two nitro-activated methyl groups of TNT and, in our case, of
compound HL1, using KOtBu base in THF, which is followed by addition of bromine, to produce
key intermediate 1,2-bis(1-(ethoxymethyl)-3,5-dinitro-pyrazol)ethane (HL2) in 94% yield. The
protection step was found to be necessary, as all attempts to make a direct transformation from
compound 4-MDNP22,23 to the target compound HL3were unsuccessful under a broad range of
reaction conditions and temperature regimes. The final conversion of compound HL2 to the
target compound HL3was performed in 88% yield, by utilizing trifluoroacetic acid solution in
CH2Cl2as a deprotecting agent, leading to an overall yield of 77% for HL3, while starting from
4-MDNP.

Figure 1
Synthesis of compound HL3.
The second energetic compound, 5,5 ′-bis(3,5-dinitro-1H-pyrazol-4-yl)-2,2 ′-bi(1,3,4-oxadiazole)

(HL7; FigureFigure22), was prepared in four steps, starting with a synthesis of
3,5-dinitro-1H-pyrazole-4-carboxylic acid (HL4) in 67% yield, via selective methyl group
oxidation of 4-MDNP with Na2Cr2O7·2H2O, under acidic conditions.24

Figure 2
The oxidation reaction was followed by two-step transformation of HL4 acid into the
corresponding 3,5-dinitropyrazole-4-carbohydrazide (HL5) in 74% yield: first, by reacting the
acid HL4 with thionyl chloride; next, with 1H-benzo[d][1,2,3]triazole; and then, by treating in
situ formed (1H-benzo[d][1,2,3]triazol-1-yl)(3,5-dinitro-1H-pyrazol-4-yl)methanone with
NH2NH2·H2O. Subsequently, carbo-hydrazide HL5 was converted into the key intermediate
N′1,N′2-bis(3,5-dinitro-1H-pyrazole-4-carbonyl)oxalohydrazide (HL6) in 75% yield, by reacting
compound HL5 with oxalyl chloride. Attempts to react freshly prepared
3,5-dinitro-1H-pyrazole-4-carbonyl chloride with oxalyl dihydrazide, utilizing a similar
methodology described for the preparation of 5,5 ′-
bis(2,4,6-trinitrophenyl)-2,2′-bi(1,3,4-oxadiazole) (TKX55),11 did not result in our case in the
formation of the key intermediate HL6, and the starting oxalyl dihydrazide was recovered from
our reaction mixtures. The final simultaneous bis-cyclization of two adjacent 1,3,4-oxadiazole
rings was achieved by treating compound HL6 with H2SO4 oleum, which led to formation of the
target 5,5′-bis(3,5-dinitro-pyrazol)-2,2′-bi(1,3,4-oxadiazole) (HL7) in 83% yield.
The synthesis of the third new energetic compound in this study, 4,4 ′-
(3,5-dinitropyrazolyl)methane (HL9; FigureFigure33), was achieved in two steps, starting with
thermal isomerization of hydrobromide salt of 1,1′-dipyrazolylmethane (DPM) into 4,4 ′-
dipyrazolylmethane (HL8) key precursor, in 56% yield. Our initial strategy to prepare compound
HL8 included one-pot reaction of pyrazole with CH2Br2, which included a tedious
sublimation-based purification step.25 However, due to expected scalability issues of such a
protocol, we eventually preferred technically simpler isomerization of the isolated DPM route.
The key precursor HL8 was then fully nitrated to form the target explosive 4,4 ′-
(3,5-dinitropyrazolyl)methane (HL9) in 51% yield, using a fuming HNO3 in H2SO4 oleum
nitration mixture at 100 °C.

Figure 3
All new energetic compounds HL3, HL7, and HL9, as well as their precursors and intermediates,
were comprehensively characterized by 1H and 13C NMR, mass spectrometry, infrared
spectroscopy, and elemental analysis (Figures S4–S18, Supporting Information). 13C NMR spectra
of HL7 showed a peak at 93.7 ppm that was assigned to the C-4 ipso-carbons of
3,5-dinitropyrazolyl rings of this compound. In comparison, we found that C-4 carbons of
3,5-dinitropyrazolyl rings in HL3 and HL9 have chemical shifts of 113.9 and 110.2 ppm,
respectively. These observations were explained on the basis of the electron density calculations,
which showed that the valence charge density at the 3,5-dinitropyrazolyl rings in HL7 is
somewhat higher than in HL3 and HL9 (FigureFigure44). Quantitatively, the Mulliken charges
surrounding the C-4 carbons in 3,5-dinitropyrazolyl rings were calculated to be 3.85, 3.95, and
3.89 e for HL3, HL7, and HL9, respectively, matching our 13C NMR results, as higher electron
density around a certain carbon atom should result in the upfield chemical shift for this atom.

Figure 4
Analysis of the valence charge density distribution in compounds HL3 (A), HL7 (B), and HL9
(C). The electron density maps are shown in the plane of one of the 3,5-dinitropyrazolyl rings of
these compounds.
X-ray Crystallography
We further analyzed the structure of compounds HL3, HL7, and HL9 by X-ray crystallography. In
addition, for comparison and comprehensive analysis purposes, a crystal structure of 4-MDNP
was obtained. Although the synthesis of the latter compound was previously described by
Shevelev,22,23 its crystallographic structure was not reported. 4-MDNP crystals suitable for X-ray
diffraction studies were obtained by crystallization from ethanol. 4-MDNP crystallizes in the
monoclinic space group P21/C, with four molecules in each unit cell (Z = 4) and a density of 1.674
g cm–3 (CCDC 1910475; FigureFigure55). All the non-hydrogen atoms of the 4-MDNP molecule
are located in the same plane (FigureFigure55a,b), while each 4-MDNP molecule interacts with
two adjacent molecules through N–H···N and N–H···O hydrogen bonds (HBs), forming flat
nanobands with a width of 1.1 nm (FigureFigure55c). These nanobands are interacting with each
other via van der Waals interactions, creating a wavelike layered three-dimensional structure
(FigureFigure55d). The distance between two nearby methyl groups belonging to two different
nanobands in the same layer is 3.879 Å and significantly longer than the length of the alkane
single C–C bond.26

Open in a separate window
Figure 5
Crystal structure and structure analysis of 4-MDNP. (a) Top view of the 4-MDNP molecule. (b)
Side view of the 4-MDNP molecule. (c) Hydrogen bonding interaction within a single “layer” of
4-MDNP molecules in a crystal structure of this compound. (d) Side view of wavelike stacking
between two “layers” of 4-MDNP molecules in a crystal structure of this compound.
Intermolecular interactions analysis for crystals of 4-MDNP. (e) Hirshfeld surface. (f ) Fingerprint
plot. (g) Individual atomic contact percentage contribution to the Hirshfeld surface.
The intermolecular N–H···N and N–H···O HBs were also clearly illustrated from the red spots on
the Hirshfeld surface as shown in FigureFigure55e and from the spikes on the bottom left in the
2D-fingerprint as shown in FigureFigure55f. In FigureFigure66 5g, the individual interatomic
contacts percentage contribution confirms the conclusion, in which HBs possess 41.9% of the
total weak interactions of the 4-MDNP crystal. The hydrogen bonding attraction makes the
molecules associated with a lattice energy of 25.22 kcal mol–1 and a packing coefficient of 71.92%.

Figure 6
Crystal structure of HL3. (a) Top view of the HL3 molecule. (b) Side view of the HL3 molecule.
(c) Hydrogen bonding interaction within a single “layer” of HL3 molecules in a crystal structure
of this compound. (d) Side view of wavelike stacking between two “layers” of HL3 molecules in a
crystal structure of this compound. Intermolecular interactions analysis for crystals of HL3. (e)
Hirshfeld surface. (f ) Fingerprint plot. (g) Individual atomic contact percentage contribution to
the Hirshfeld surface.
HL3 crystals suitable for X-ray diffraction studies were obtained by crystallization from ethanol.
HL3 crystallizes in the monoclinic space group P21/C, with two molecules in each lattice cell (Z =
2) and a density of 1.809 g cm–3 (CCDC 1910476; FigureFigure66). Only a half molecule of HL3 is
contained in the asymmetric unit, demonstrating relatively high structural symmetry of HL3.
The molecular structure of HL3 could be seen as two 4-MDNP moieties connected by a single
sp2–sp2 C–C bond, forming a “step”-connected two parallel planes structure
(FigureFigure66a,b). The length of this C–C bond is 1.532 Å, which is much shorter than the
in-plane band-to-band closest methyl–methyl groups distance in the crystal structure of
4-MDNP (3.879 Å). Similar to 4-MDNP, in the crystal structure of HL3, each molecule interacts
with four adjacent molecules through N–H···N and N–H···O HBs, forming two-dimensional
layers as shown in FigureFigure66c. These two-dimensional layers are also interacting with each
other via van der Waals interactions, creating a wavelike layered three-dimensional structure
(FigureFigure66d). Due to the much shorter distance between two methylene groups in HL3
versus the methyl–methyl distance in 4-MDNP, the packing of the HL3 crystal is tighter, leading
to a higher crystal density obtained for HL3.
The intermolecular N–H···N and N–H···O HBs were also confirmed in Hirshfeld surface analysis
as shown in FigureFigure66e and 2D-fingerprint as shown in FigureFigure66f. The thicker spikes
and shorter di + de values in FigureFigure66f suggest that the HBs in HL3 are greater in number
and stronger as compared to those in the 4-MDNP crystal. As shown in FigureFigure66g, the HBs
take 46.6% of the total weak interactions in HL3, which is 4.7% higher comparing to 4-MDNP.
This leads HL3 to have a higher lattice energy (46.68 kcal mol–1) and an improved packing
coefficient (76.25%).
All attempts to obtain solvent-free crystals of HL7 were unsuccessful under a broad range of
solvent conditions including of ethanol, acetone, ethyl acetate, and even fuming nitric acid. HL7
crystals crystallized from the mentioned solvent were all found to be the HL7 hydrate or HNO3
solvated HL7. HL7 dihydrate crystallizes in the monoclinic space group Cc, with four molecules
in each lattice cell (Z = 4) and density of 1.854 g cm–3 (CCDC 1910477; FigureFigure77). There is a
single molecule of HL7 and two molecules of water located in an asymmetric unit. In the
molecular structure of HL7, two 1,3,4-oxadiazole rings of the bridge are positioned in the same
plane, while the 3,5-dinitropyrazolyl rings are connected with the 1,3,4-oxadiazole rings through
C–C bonds with dihedral angles of 61.7° and 78.3°, respectively. Each HL7 molecule interacts with
four adjacent water molecules through N–H···O and O–H···O HBs, forming water-bridged
interactions between HL7 molecules and creating a layered structure.

Figure 7
Crystal structure of HL7. (a) Top view of an HL7 molecule. (b) Side view of an HL7 molecule. (c)
Hydrogen bonding interaction within a single “layer” of HL7 molecules in a crystal structure of
this compound. Intermolecular interactions analysis for crystals of HL7. (d) Hirshfeld surface.
(e) Fingerprint plot. (f ) Individual atomic contact percentage contribution to the Hirshfeld
surface.
The asymmetry of the spikes in FigureFigure77f is caused by the unequal electronic structure
when looking outward and inward of the Hirshfeld surface as shown in FigureFigure77d. Due to
the presence of water molecules, the lattice energy significantly increase to 85.90 kcal mol–1
while the packing coefficient decreases to 74.87%.
HL9 crystallizes in the monoclinic space group P21/C, with four molecules in each lattice cell (Z
= 4) and density of 1.820 g cm–3 (CCDC 1910478; FigureFigure88). There is a single molecule of
HL9 located in an asymmetric unit. In the molecular structure of HL9, the 3,5-dinitropyrazolyl
rings are positioned in two different planes, with a dihedral angle of 85.4°. Each HL9 molecule
interacts with four nearby-located HL9 molecules through HBs of N–H···O (2.214 Å) and
N–H···O (2.034 Å), forming nanobands, which in turn are creating a layered structure.
Compared to HL7, both the amount and strength of the hydrogen bonding interactions of HL9
are slightly improved, as shown in FigureFigure88e,f. However, due to the lower symmetry of the
crystal (SGN 9) as compared to that of HL7 (SGN 14), HL9 has a similar crystal packing
coefficient of 73.43%.

Figure 8
Crystal structure of HL9. (a) Top view of an HL9 molecule. (b) Side view of an HL9 molecule. (c)
Hydrogen bonding interaction within a single “layer” of HL9 molecules in a crystal structure of
this compound. Intermolecular interaction analysis for HL9. (d) Hirshfeld surface. (e)
Fingerprint plot. (f ) Individual atomic contact percentage contribution to the Hirshfeld surface.
Physicochemical and Energetic Properties

The thermal behavior of compounds HL3, HL7, and HL9 was studied by differential scanning
calorimetry (DSC) and thermogravimetric analysis (TGA) at a heating rate of 5 °C min–1. Each of
these compounds showed a single intense exothermic decomposition peak without melting
(Figures S17 and S18; Supporting Information). Decomposition of the energetic compound from
its solid state, rather than the liquid phase, is highly desirable for a compound which could be
considered as a potential heat-resistant explosive since the rate of degradation is significantly
enhanced when the substance is placed as a molten phase.27 The onset decomposition
temperatures for HL3, HL7, and HL9 were determined to be 351, 341, and 262 °C, respectively,
while the peak decomposition temperatures were observed at 359, 343, and 269 °C, respectively.
Thus, the thermal performance of HL3 and HL7 was found to be significantly better than that of
commonly used thermostable explosive HNS (Td 318 °C; Table 1), and comparable or even better
than LLM-105 (Td 345 °C),28 suggesting the potential usability of HL3 and HL7 compound as
new heat-resistant EMs.
Table 1
Properties of Compounds HL3, HL7, HL9, and Reference Explosives
compound Tda ρb (g cm–3) ΔHfc (kJ mol–1) VODd (m s–1)
Pe (GPa) ISf (J) FSg (N) ESDh (J)
HL3 351 1.805 184.3 8,234 28.6 10 352 1.12
HL7 341 1.865 446.5 8,517 30.6 22 352 1.05
HL9 262 1.810 224.2 8,357 29.7 14 352 0.98
HNS 318 1.740 78.2 7,612 24.3 5 240 0.8
LLM-105 345 1.910 –12.0 8,560 33.4 28 >360 1.02
aOnset decomposition temperature by DSC (heating rate of 5 °C min–1).
bDensity measured by helium gas pycnometer (at 25 °C).
cCalculated standard molar enthalpy of formation.
dCalculated velocity of detonation.
eCalculated detonation pressure.
fImpact sensitivity evaluated by a drop hammer (2.5 kg) BAM technique.
gFriction sensitivity evaluated by a BAM technique.
hElectrostatic discharge sensitivity.
The densities of EMs HL3, HL7, and HL9 were measured by gas pycnometer at ambient
temperature and found to be 1.805, 1.865, and 1.810 g cm–3, respectively, higher than the
reference thermostable HNS explosive (1.740 g cm–3).29 Furthermore, evaluations of the
sensitivity by standard BAM methods to impact, friction, and electrostatic discharge for the
newly synthesized thermostable EMs show significantly higher stability than HNS in all safety
parameters, while HL7 shows comparable safety to LLM-105 (Table 1).15
The enthalpies of formation (ΔHf) of HL3, HL7, and HL9 were calculated by the isodesmic
reactions approach,30 using Gaussian 09 software,31 and found to be 184.3, 446.5, and 224.2 kJ
mol–1, respectively. The relatively higher calculated ΔHf of compound HL7 could be explained
by the presence of two adjacent 1,3,4-oxadiazole rings constructing its bridged structure.
Applying the measured ambient temperature density and the calculated solid-state ΔHf values
into EXPLO5 (v6.02) software32 allowed us to predict the velocity of detonation (VOD) and
detonation pressure (Pd) for HL3, HL7, and HL9 (Table 1). The calculated VODs for HL3, HL7,
and HL9 were 8234, 8517, and 8357 m s–1, respectively. The maximum detonation pressures for
HL3, HL7, and HL9 were 28.6, 30.6, and 29.7 GPa, respectively.
Energetic Evaluation and Detonation Experiments

In order to evaluate the energetic properties of materials HL3 and HL7 versus reference
materials, small-scale reactivity tests (SSRTs) were performed. SSRTs measures the performance
of EMs, allowing preliminary evaluation without requiring scaled up synthesis for full-scale
detonation tests. In our experiments, 9.0 g of a powdered EM was pressed with a pressure of 0.5
ton, using a hydraulic press, at room temperature, into a stainless steel (316) cylinder with an
outer diameter of 28 mm, 4 mm wall thickness, and 2 mm thickness at the bottom
(FigureFigure99a). A pressed charge was placed on an aluminum (3003) witness plate, to
measure the brisance of the evaluated EM via the volume of the postdetonation dent mark. The
pressed charge was initiated with a standard detonator, consisting of 850 mg of RDX and 150 mg
of PbN3 (FigureFigure99c,d). The detonation of the pressed charge was carried out in open air, 1
m above the ground. The charge generated a shock wave, followed by a pressure blast that was
recorded by three pressure sensors (ENDEVCO), each positioned 1.0 m away from the charge
(FigureFigure99e). Voltage signals from the sensors, obtained via a standard signal amplifier,
were recorded on an analog oscilloscope and translated into real-time pressure values. All the
detonation experiments were filmed with a high-speed camera (Phantom v610), operated at
10 000 frames s–1 (selected frames are presented in FigureFigure99f–i). Reference detonations
with nonenergetic (9.0 g of water) and representative energetic charges (9.0 g of HNS) were also
conducted. Subsequently, the dent marks on the witness plates (FigureFigure1010a–d) were
mapped with the assistance of a three-dimensional laser scanner (Nikon MMDx 50) attached to
a robotic measuring arm (MCAx 20) to produce maximum precision point cloud files (STL) that
were converted to solid objects (FigureFigure1010e–h). The diameters, depths, and volumes of
these objects were calculated by dedicated software (SolidWorks; FigureFigure1010i–l).

Figure 9
(a) View of an exemplary pressed EM charge witness plate. (b) Witness plate. (c) Assembly of a
system prior to detonation. (d) Schematic presentation of the charge detonation setup. (e)
Schematic presentation of the field measurement setup including high-speed video camera and
pressure sensors. (f–i) Frames from high-speed video clip of the detonation experiment of HL7
(f, frame before detonation; g, first frame of detonator initiation; h, frame of the main charge
initiation; i, frame of the maximum fire ball).

Figure 10
(a–d) Postdetonation dent marks on witness plates with the remaining bottom of the
stainless-steel cylinder. (e–h) Three-dimensional mapping of dent marks for water, HNS, HL3,
and HL7, respectively. (i–l) Side view of three-dimensional SolidWorks objects of the dent marks
and their diameters and depth; corresponding SolidWorks calculated volumes are shown in
Table 2.
Obtained pressure changes were found to match the expected behavior of an unconfined high
explosive, characterized by a rapid pressure increase at the shock front, followed by a
quasiexponential decay back to an ambient pressure (FigureFigure1111). A negative phase follows,
in which the pressure is less than ambient, characterized by oscillations between negative and
positive overpressure fading away after about 2 ms.
Figure 11
(a) Measured detonation pressures for inert (water) and energetic reference (HNS) charges. (b)
Compared measured detonation pressures for HL3, HL7, and HNS charges.
The recorded detonation pressure for water, as a nonenergetic reference, was measured with a
maximal overpressure of 9.80 KPa, which is attributed to the booster, leaving a very shallow dent
with a volume of only 0.20 cm3 (FiguresFigures1010i and and11a;11a; Table 2), and the cylindrical
body remaining fractured but intact. For HNS, HL3, and HL7 only the bottoms of the metal
cylinders were recovered, while the body of the cylinders was fully fragmented, as evident from
the high-speed video recordings. Results for the reference HNS explosive have shown a maximal
measured detonation overpressure of 29.84 KPa (FigureFigure1111; Table 2), with a clear dent on
the witness plate with a volume of 2.21 cm3, a depth of 4.47 mm, and a diameter of 37.08 mm
(FigureFigure1010b,f,j; Table 2). Evaluation of newly synthesized thermostable EMs HL3 and HL7
showed a higher maximal recorded detonation overpressure of 32.64 and 32.08 KPa, respectively
(FigureFigure1111b; Table 2). While the measured dent volume for HL7 was 2.17 cm3, with a depth
of 4.25 mm and a diameter of 37.61 mm (FigureFigure1010d,h,l; Table 2) implying a great brisance
capability correlating with its detonation overpressure, the dent volume of HL3 was found to be
lower, of 1.31 cm3, with a depth of 2.59 mm and a diameter of 34.25 mm (FigureFigure1010c,g,k;
Table 2). Although HL3 had greater detonation overpressure than both HL7 and HNS, the
emanating low volume and low diameter of the dent on the witness plate can be attributed to
lower brisance as a result of lower achieved density under equal mechanical compression (0.5
ton) applied during the preparation of all charges.33
Table 2
Results of Detonation Experiments for Compounds HL3, HL7, Inert, and Energetic References
material exp. maximal overpressure [kPa] dent diameter [mm] dent depth
[mm] dent volume [cm3]
1 water 9.80 31.32 0.45 0.20
2 HNS 29.94 37.08 4.47 2.21
3 HL7 32.08 37.61 4.25 2.17
4 HL3 32.64 34.25 2.59 1.31
Our field experiments showed that HL7 EM exhibited brisance and detonation overpressure
comparable to HNS, while being more insensitive and thermostable, strongly supporting the
validity of the bridged molecular design approach for new heat-resistant explosives. We believe
that properly pressed HL3 EM could exhibit comparable performance while having superior
thermostability.
Ab Initio Molecular Dynamics Calculations

In order to study the initial kinetics of the chemical bonds under heating stimulus, we performed
ab initio molecular dynamics simulations with the HASEM package for the optimized structures
of HL3, HL7, HL9, and HNS crystals. We employed the canonical (NVT) ensemble to simulate
the heating of the systems from 0 to 1000 K for 10 000 steps, with the time step set as 0.2 fs. For
each iteration of the atomic positions, the density matrix tolerance was set to be 5.0 × 10–6 e, and
the atomic force tolerance was 0.04 eV Å–1. The potential energy, pressure, and temperature of
the four systems converged from ∼300 steps. From then on, the temperature of each system was
constrained at around 1000 K. We assumed that the chemical bond broke when it was stretched
beyond the cutoff percentage relative to the equilibrium state. The breaking of the chemical
bonds for each molecule was counted within the simulation duration, as shown in
FigureFigure1212. The breaking of chemical bonds occurred competitively between the first and
second weakest bonds, which are shown in detail in Tables S2 and S3 of the Supporting
Information. The total count of bond breaking indicated that the order of the thermostability of
the four compounds was HL3 > HL7 > HNS > HL9, which was satisfactorily consistent with the
experiments as determined by DSC and TGA techniques. Note that the chemical kinetics shown
in FigureFigure1212 would vary with the temperature and heating rate.

Figure 12
Count of bond breaking for C-NO2 and bridge bonds as well as their sum (per molecule) for the
HL3, HL7, HL9, and HNS compounds.
Molecular and Crystal Structure Assessment and Categorization of the Reported and Newly
Synthesized EMs
For the better understanding of how molecular and crystal structures could be correlated with
EMs’ thermostability, a collection of 60 reported explosives was divided into five different
families. Each family contains molecules with specific structural features, in which the type of
the “bridge” (if present) served as the primary selection criterion (FiguresFigures1313–17). Based
on this criterion, the categorization and comprehensive properties studies of these EMs allowed
us to propose reasonable designs for new bridged thermostable explosives:HL3, HL7, and
HL9..1717

Figure 14
Family B of “bridgeless” EMs in which two energetic rings are connected directly one to
another.9,36

Figure 16
Family D of “bridged” EMs in which two energetic rings are connected via a “complex
bridge”.11,39−45
Go to:
DFT Calculations
General Methodology
Density functional theory (DFT) calculations were performed to determine and compare the
physicochemical properties of 60 previously reported and 3 newly synthesized EMs
(FiguresFigures1111–15) on a molecular level (Gaussian 09 and HASEM software) and on a
crystalline material level (HASEM software). The reliability of the HASEM software in describing
EMs’ crystal structures, energetics, mechanical parameters, thermodynamic properties,
detonation performance, and sensitivity under external stimulus has been extensively verified by
the comparison with experiments and CCSD(T) results.48 In addition, the HASEM software was
constructed based on the J parallel Adaptive Structured Mesh applications Infrastructure
(JASMIN), thereby allowing the high-efficient parallel computing of large-scale systems on
modern supercomputers.49 The investigated properties included covalent bonding
characteristics, such as type, distribution, length, strength, and decomposition location;
molecular characteristics, such as bridging configuration (type of bridging) and bridge reactivity,
oxygen balance, molecular size, and heat of formation; crystal structure characteristics, such as
crystal volume, lattice lengths, lattice angles, crystal density, packing coefficient, crystal space
group, and number of molecules located in each unit cell; as well as characteristics of crystal
lattice energy (LE; lattice energy) and material energetic performance, such as detonation
velocity, detonation pressure, heat of explosion, and explosion temperature. LE is defined as the
energy difference between the total energy of constituent molecules in each free state and the
total energy of the crystal.

Figure 15
Family C of “bridged” EMs in which two energetic rings are connected via a “simple
bridge”.8,11,37,38
To study crystal packing arrangements in all EMs mentioned in this work, we calculated the
intermolecular interactions (CrystalExplorer software),50 which included the enclosed volume,
surface area, globularity, and asphericity of the Hirshfeld surface of each molecule. The Hirshfeld
surface area is an alternate measure of the molecular size, resembling the molecular weight. The
contribution to the Hirshfeld surface from each individual atomic contact was also quantified
and analyzed.
Taking the lattice parameters and atomic coordinates from single-crystal X-ray diffraction
analysis as input, the geometries of the 63 EMs were optimized on the basis of the conjugate
gradient method.51 The calculated structures were considered by us as fully optimized, when the
residual forces were less than 0.03 eV Å–1, and the stress components were less than 0.1 GPa for
each structure. All parameters of the fully optimized calculated structures showed a very high
level agreement with the experimental parameters of the same compounds obtained by X-ray
crystallography (FigureFigure1818). For lattice lengths, lattice angles, and cell volumes, the linear
correlation coefficients between the calculated and experimental values were 0.999, 0.992, and
0.999, respectively, with the standard errors of 0.17 Å, 0.69°, and 22.73 Å3, respectively. These
minute discrepancies between the calculated and the experimental values show the reliability
and robustness of the calculation methods that were used in this work.

Figure 18
Results of the reliability validation of our calculation method. Comparison between calculated
and experimental values of (A) lattice lengths, (B) lattice angles, and (C) cell volumes for crystals
of 60 previously reported with 3 newly synthesized EMs.
Molecular Level Correlations

Our first evaluated correlation was the type of the bridge, connecting two energetic rings, versus
the examined EM’s thermostability. The full temperature range correlation graph for all 63 EMs
included in this study is shown in Figure S31 (SI), while FigureFigure1919a presents a focused
temperature range version of the Figure 31S (SI) full temperature range graph. In
FigureFigure1919a only the EMs with thermostability above 250 °C (defined by us as
thermostable) are included. Analyzing the distribution of the various thermostable compounds
among all EMs included in this study, we found that only 44% among single ring EMs (Family A)
could be described as thermostable, while the remaining 66% of these materials would have
thermostability below 250 °C (FigureFigure1919b). In contrast, all bridged EMs (Families B–E)
showed typically better statistics (above 46%) in being thermostable than single-ring
compounds, with Family D (EMs in which two energetic rings are connected via a “complex
bridge”) and Family E (“fused-rings” EMs) show the highest probabilities of 82% and 67%,
respectively, of the compounds in these families being stable above 250 °C. These findings clearly
show that the inclusion of bridges into molecular structures of EMs, and in particular “complex”
bridges and “fused” rings, should lead to improved thermostability of the resulted molecules
versus nonbridged single-ring versions of related EMs. The “bridge” approach should provide a
promising and effective methodology for the molecular design of the heat-resistant explosives.
One of the possible underlying physical mechanisms of the bridge-related thermostability
phenomena could be a significantly improved heat conductivity and distribution within a
bridged or a “fused” molecular structure of thermostable EM. Therefore, one of our new
molecules, HL7 (a member of Family D), was designed to incorporate the bis(1,3,4-oxadiazole)
complex bridge, as its structural features to attain an improved thermostability.

Figure 19
(a) Focused temperature range (>250 °C) correlations between a bridge type in EM, with this
compound thermostability (full temperature range correlations are shown in Figure S31;
Supporting Information). (b) Distribution of the thermostable EMs among all bridged EMs
mentioned in this study, with respect to their bridge type. (c) Focused temperature range (>250
°C) correlations between the bridge bond reactivity and the thermostability of bridged EMs (full
temperature range correlations are shown in Figure S32; Supporting Information). (d)
Distributions of the thermostable EMs with respect to their bridge bond reactivity among all
bridged EMs.
Searching for additional parameters that could be responsible for thermostability on a molecular
level, we calculated the stability of all bonds present in molecular structures of all EMs in our
study. The results of these calculations, including compounds’ crystal structures of which
contained solvents, and calculated solvent-free crystal structures of the same compounds, are
shown in Tables S6 and S7 (SI). These calculations allowed us to pinpoint the most plausible
locations of the first and the second chemical bonds that would undergo seizure upon molecule
decomposition. One of the parameters that may significantly influence the thermostability of a
molecule could be whether these chemical bonds are broken at the bridges or at the energetic
ring terminals.
Therefore, we introduced two criteria to examine a hypothesis of the bridge bonds

seizure-related thermostability. These criteria, defined as “Does the first bond break at the
bridge” and “Does the second bond break at the bridge”, were plotted versus corresponding EM
thermostability in a three-dimensional arrangement (Figure S32; Supporting Information), and
its focused version is shown in FigureFigure1919c. We found that, based on these criteria, the
thermostability trend was clear, especially in cases of EMs with both the first and the second
chemical bond seizures at the bridge (“Yes/Yes” columns, FigureFigure1919c,d) which were found
to be predominantly thermostable (73% out of all compounds in this group). Two of our new
compounds, HL3 and HL7, belong to this specific category, in which EMs from Family D
(“complex” bridge) and Family E (“fused” rings) are mainly prevalent. In our perspective, the
underlying physical mechanism of the bridge bond seizure-related thermostability provides an
alternate route, a type of a sacrificial buffer zone, to otherwise initial disintegration of the
energetic ring terminals, upon exposure of the bridged energetic molecule to the thermal
stimulus. Thus, in our opinion, one of the proposed guidelines for the design of new
thermostable EMs should be introduction of a sacrificial “complex” bridge moiety or “fused”
rings arrangement, into a molecular structure of the target explosive.
Following more general observations of the location of the weakest bonds during thermal
decomposition, we closely checked the chemistry and the strength of these bonds. For these
purposes, the lengths and strengths of all covalent bonds in all 63 examined EMs were calculated
(1842 bonds in total; Tables S2 and S3; Supporting Information). The types and statistical
distribution of the first and second weakest bonds are shown in FigureFigure2020a and Figure
S32 and Table S7 (SI). We found that the C–NO2 bond was by far the most prevalent type of the
first weakest bond, with length in the range 1.38–1.56 Å and the bond strength ranging from 71.63
to 128.23 kcal mol–1. The bridge bonds, such as C–C, C–O, and C–N, with the lengths in the range
1.37–1.56 Å and the strengths ranging from 50.69 to 129.07 kcal mol–1, are very likely to be the
first or the second weakest bonds in the examined bridged EMs. In addition, C–O, C–N, N–N,
and N–O bonds in heterocycle moieties of the relevant EMs (1.37–1.42 Å; 62.97–116.97 kcal mol–1)
can also function as the weakest bonds. As shown in FigureFigure2020a, EMs with C–C bridge
bonds, C–NO2, or heterocyclic bonds, as their weakest bonds, have more than 50% probability to
be thermostable.
Figure 20
(a) Distribution of the 1st and the 2nd weakest bonds among various types of covalent bonds in
all 63 EMs mentioned in this study. (b) Focused temperature range (>250 °C) correlations
between the strength of the 1st weakest bond and the thermostability in all 63 EMs (full
temperature range correlations are shown in Figure S32; Supporting Information). (c)
Distributions of all 63 EMs with respect to the strength of their 1st weakest bond.
Also, a general correlation was found between the value of the weakest bond strength and the
thermostability in all relevant EMs (Figure S32; Supporting Information), and more focused
correlations are shown in FigureFigure2020b, presenting data for EMs with thermostability
above 250 °C. For example, compounds D5 (TKX55) and HL7 were calculated to have the same
weakest bond type (C–O bonds in their 1,3,4-oxadiazole rings) that has very close bond strengths
of 98.72 and 96.84 kcal mol–1, respectively, making these explosives exhibit a similar
thermostability of 335.011 and 340.8 °C, respectively (a pink cluster, FigureFigure2020b).
Explosives C2 (bis[2,4,6-trinitro-phenyl]amine),38E2
(2,3,5,6-tetranitro-4H,9H-dipyrazolo[1,5-a:5′,1 ′-d][1,3,5]triazine),46 and HL9 were calculated to
have C–NO2 and bridged bonds to be the first and second weakest bonds, with the
corresponding bond strength distributed in the narrow range 95.91–100.12 kcal mol–1, showing a
close thermostability of these explosives of 254.0, 261.2, and 261.9 °C, respectively (a purple
cluster, FigureFigure2020b). On a molecular level, there is a certain degree of structural
resemblance between C2 and E2 EMs, which have 1,3,5-trinitrobenzene and
3,4-dinitro-1H-pyrazole energetic rings, respectively, connected by a bridging NH group, and
HL9 that has two 3,5-dinitro-1H-pyrazole energetic rings, connected by a bridging CH2 group.
FigureFigure2020c presents a percentage distribution of thermostable EMs among all examined

explosives, with respect to these explosives’ first weakest bond strength. We found a clear
relationship between the weakest bond strength and the thermostability of the examined EMs.
This relationship indicated that the increase in the strength of the weakest covalent bond in the
molecule would lead to an overall stronger molecular structure, less prone to decomposition and
therefore more stable to external stimuli, including heat. However, this obvious conclusion
regarding the bond strength was never previously quantified for EMs. Following this analysis, we
think that the design of molecular structures in which the weakest bond strength would be
above 95 kcal mol–1 could be an effective methodology to achieve EMs with improved
thermostability.
EMs typically contain both oxidizing and reducible functional groups or components in their
structure or composition. The oxygen balance (OB) is a calculated parameter that is used to
describe to which degree a certain EM or its formulation could be oxidized, with OB equal to 0%
considered as the exact amount of oxygen atoms present in EM for the complete oxidation of all
oxidizable atoms to carbon dioxide and water leading to the best performance,52 but with a price
of a high sensitivity. The results of OB calculations exhibited a remarkable correlation with EMs’
sensitivity to mechanical impact and the detonation performance, making OB values among
critical parameters in design of new explosives.15 Thus, we plotted correlation between OBs of all
EMs in this study with respect to their thermostability (FigureFigure2121a and Figure S34;
Supporting Information). We draw a similarity cluster for compound HL3 (a purple oval,
FigureFigure2121a) that included single ring EMs A4 (TATB), A13 (DADNPO),35 and A15 (ANPZ),
as well as bridged EMs D8(42) and D10 (PYX),44 which are among the best performing
heat-resistant explosives, with thermostability in the range 350.7–366.4 °C and OB values in the
range from −62.3 to −48.0%. In the second cluster for compound HL7 (a pink oval,
FigureFigure2121a) we included, closely positioned in terms of its parameters, a single ring
explosive A14 (LLM-105).28 Thermostability of both A14 and HL7 compounds was in the range
345.3–340.8 °C, with close OB values of −37.0% and −39.1%, respectively, strongly indicating that
the “bridged” approach could be a viable alternative to the molecular design of thermostable
EMs based on closely positioned alternating nitro and amino groups on the same aromatic ring.
In the third cluster (a colorless oval, FigureFigure2121a), we included structurally related (bridged
dinitropyrazolyl rings) compounds E2 and HL9 that exhibit very close thermostability of 261.2
and 261.9 °C, respectively, and have similar OB values of −35.2% and −39.0%, respectively. We
found that for thermostable EMs (with thermostability above 250 °C) the typical OB values were
in the range from −80% to −30% (the “island of thermostability”), with prevalence of the
thermostability going down, as OB values get closer to −30% (FigureFigure2121b).

Figure 21
(a) Focused temperature range (>250 °C) correlations between the oxygen balance values and
thermostability of all 66 EMs (full temperature range correlations are shown in Figure S34;
Supporting Information). (b) Distributions of the thermostable EMs, with respect to their OB
values, among all EMs mentioned in this study.
Although we could not find an obvious correlation between molecular weight of all examined
EMs and their thermostability (Figure S35; Supporting Information), bridged explosives with
molecular weight above 550 Da were clearly thermostable, supporting our previous statement
regarding the capability of a molecule to dissipate heat by an appropriate molecular structure.
Crystal Level Correlations

In addition to molecular structures of various solid EMs, since these materials are used in bulk,
their crystal structures and in-crystal molecular interactions play a great role in EMs’ detonation
performance, mechanical and thermal stability, and processability. Following our studies related
to different aspects of molecular level correlations, we expanded our investigation toward
in-crystal arrangements and interactions of these energetic molecules. The first examined
parameter was a crystal packing coefficient (PC), which quantifies the fraction of the volume in a
crystal that is occupied by hard sphere atoms. The PC parameter was reported to be in a good
correlation with a range of physicochemical properties of EMs.53 The results of correlation
between EMs’ crystal PC and their thermostability showed that many heat-resistant explosives
occupy a relatively narrow packing range between 73% and 77% (focused correlations for EMs
with thermostability above 250 °C are shown FigureFigure2222a; full range correlations for all
EMs in this study are shown in Figure S36; Supporting Information). Compound HL3 has a
similar PC value (76.3%) to heat-resistant explosives A14 (LLM105) and E1,45 where HL7 has a
very close PC value (74.9%) to analogous D5 (TKX55; a pink cluster, FigureFigure2222a).
Interestingly, compound HL9 was found to have a close PC value (73.4%) to explosive C2 (a
purple cluster, FigureFigure2222a), showing further correlation between these two bridged EMs
to the above-mentioned molecular stability studies presented in FigureFigure2222b. From
FigureFigure2222b that took into account all EMs in this study, we can learn that, for EMs with a
higher probability to be thermostable, the preferable crystal PC values should be above 73%, with
all our newly synthesized bridged compounds HL3, HL7, and HL9 fitting perfectly into the
optimum range of PC values.

Figure 22
(a) Focused temperature range (>250 °C) correlations between the EM crystal packing coefficient
values and the thermostability of these explosives (full range temperature correlations are shown
in Figure S36; Supporting Information). (b) Distributions of the thermostable EMs, with respect
to their PC values, among all EMs mentioned in this study.
We further looked into correlations between the number of molecules found in each unit cell of
all EMs mentioned in this study and these EMs’ thermostability (Figure S37; Supporting
Information). We found that the prevalent number of molecules in the primitive cells of
thermostable EMs was 2, 4, and 8 (Figure S37c; Supporting Information). A correlation between
the space group number (SGN) of crystal structures of the examined EMs and their
thermostability showed that most of these compounds have P21/c (SGN 14), P21/n (SGN 14), and
P212121 (SGN 19) symmetries. As a general observation, the thermostable EMs have low crystal
symmetry, with a space group number below 19 (Figure S38c; Supporting Information). Notably,
two of our newly synthesized HL3 and HL9 compounds were found to match both the prevalent
number of molecules in the primitive cell and the space group number criteria, having 2 and 4
molecules in their crystal cell and the SNG of 14, similar to heat-resistant explosives A15 (ANPZ),
D6, A14 (LLM105), and several others.
As in the above-mentioned case of no obvious correlation between the molecular weight of

examined EMs and their thermostability (Figure S35; Supporting Information), we could not
observe a clear trend in attempts to find a correlation between the Hirshfeld surface area of each
molecule in a crystal and the examined EMs’ thermostability (Figure S39; Supporting
Information). Thermostable bridged explosives from the Family D, with the Hirshfeld surface
area above 400 Å2, were found in this range, further supporting the hypothesis that molecular
size is related to the capability of a molecule to dissipate the heat.
Hydrogen bonding is known to be an important factor governing EM’s reactivity to external

stimuli. Therefore, we evaluated a correlation between the hydrogen bonding population (HBP,
measured in %) and hydrogen bonding area (HBA, measured in Å2) on a Hirshfeld surface54 of
all 63 EMs mentioned versus these compounds’ thermostability (Figure S40, Supporting
Information). By analyzing the distribution of the thermostable EMs among all evaluated EMs,
with respect to their HBPs, we determined that their preferred HBP values should be in a range
between 20% and 70%. This is consistent with a previous theoretical work that intermolecular
HBs between hydroxylammonium cations and anions are primarily responsible for the increase
in the PC of energetic ionic salts.55 The highest probability of an EM to be thermostable was
found in explosives having HBP in the relatively narrow range 50–70%. The latter group of
explosives includes single-ring compounds, such as A4 (TATB), A15 (ANPZ), A13 (DADNPO), and
A14 (LLM105), as well as some bridged EMs, such as D5 (TKX55), E9,47D7,41 and D9.43
Our further analysis of correlation between EMs’ HBAs and their thermostability showed that
heat-resistant explosives prevalently have HBA values in a range between 90 and 180 Å2
(FigureFigure2323). Grouping compounds with similar HBA and thermostability properties
together, we could draw three different clusters for each of HL3, HL7, and HL9 explosives. The
pink cluster that includes HL3, A13 (DADNPO), D6, and D10 (PYX), the HBA values are 136.51,
133.06, 136.69, and 134.63 Å2, respectively, where the corresponding thermostability of these
explosives was 351.0, 354.0,35 362.0,40 and 360.0 °C,44 respectively (FigureFigure2323a). We can
also point out a similarity between compound HL7 (with calculated solvent-free crystal
structure) and explosives E1 and A14 (LLM105; the purple cluster), as well as similarity of HL9 to
E2 (the colorless cluster).

Figure 23
(a) Focused temperature range (>250 °C) correlation between hydrogen bonding area on a
Hirshfeld surface and the thermostability of evaluated EMs (full range correlations are shown in
Figure S41; Supporting Information). (b) Distribution of the thermostable EMs, with respect to
their hydrogen bonding area on a Hirshfeld surface of each molecule, among all 63 EMs
mentioned in this study.
An additional crystal parameter affecting EM’s solid-state properties is the lattice energy (LE),
which is a quantification parameter of crystal packing forces, as well as a crystal’s intermolecular
association strength. We studied a correlation between the LE (measured in kcal mol–1) in all
mentioned EMs in this study, versus these compounds’ thermostability (FiguresFigures2424A
and Figure S41, Supporting Information). By analyzing the distribution of the thermostable EMs
among all evaluated EMs, with respect to their LEs, we determined that their preferred LE values
should be above 25 kcal mol–1.

Figure 24
(a) Focused temperature range (>250 °C) correlation between the lattice energy and the
thermostability of all evaluated EMs (full range correlations are shown in Figure S41; Supporting
Information). (b) Distribution of the thermostable EMs, with respect to their lattice energy for
each molecule, among all 63 EMs mentioned in this study.
Among explosives having close LEs and thermostability values, we found compounds such as
single-ring A13 (DADNPO) and A14 (LLM105); A15 (ANPZ) and “complex-bridge” D10 (PYX); as
well as fused-rings E4 and bridgeless polynitropyrazole isomers B2 and B4. Our newly
synthesized explosive HL3 has an outstanding thermostability of 351.0 °C because of its very high
LE of 46.68 kcal mol–1. While our newly synthesized solvent-free explosives HL7 and HL9 are
both falling in the narrow range 35–40 kcal mol–1, the significant difference in their
thermostability could be explained by different molecular structures of their bridges,
overpowering the influence of their crystal structures.
Go to:
Conclusions
A general objective of this research was to explore and map features and advantages of “bridged”
molecular structures on the thermostability of a broad range of energetic materials (EMs) and
then to implement deduced guidelines for the design of new thermostable explosives.
On the molecular level, our first design guideline for the improvement of the thermostable
properties of EMs is the introduction of a sacrificial “complex” bridge moiety or “fused” rings
arrangement into the structure of the new explosive. We found a clear correlation between the
value of the weakest bond strength and the thermostability of the EMs. This correlation was
never reported previously. The bridged EMs having C–C bridge bonds, C–NO2, or heterocyclic
bonds, as their weakest bonds, show more than 50% probability to be thermostable, while the
design of molecules with the weakest bond strength above 95 kcal mol–1 could be an effective
methodology to achieve improved thermostability. With respect to the oxygen balance
parameter, we found that the optimum OB values for thermostable EMs should be in the range
from −80% to −30% (the “island of thermostability”).
In terms of the crystal structure-related parameters, we found a good correlation between the
thermostability and the crystal packing coefficient, which for thermostable explosives should be
the narrow range 73–77%. In the case of the thermostability correlation with Hirshfeld surfaces’
hydrogen bonding population (HBP) and hydrogen bonding area (HBA) parameters, relatively
narrow ranges with distributions of 50–70% and 90–180 Å2, respectively, were observed. An
additional examined crystal level parameter was the crystal’s lattice energy (LE), which was
found to be above 25 kcal mol–1 in the evaluated thermostable EMs.
On the basis of our comprehensive study of various molecular level and crystal level parameter
correlations with the thermostability of 60 reported EMs, three new insensitive, thermostable,
and high-performing energetic materials, having bridged molecular structures, HL3, HL7, and
HL9, were designed, synthesized, characterized, and evaluated in small-scale field detonation
experiments. We found that best overall performing compound HL7 exhibited a remarkable
onset decomposition temperature of 341 °C and has a density of 1.865 g cm–3. It has a calculated
velocity of detonation and maximum detonation pressure of 8517 m s–1 and 30.6 GPa,
respectively.
Considering HL7’s impressive safety parameters (IS = 22 J, FS = 352, and ESD = 1.05 J) and results
of fast camera-monitored small-scale field detonation experiments, we believe that our proposed
molecular and crystal guidelines and criteria for the design of thermostable explosives could be a
valuable and indispensable asset in the architecture of future thermostable energetic materials,
pushing the relevance of our conclusions to the higher technology readiness level.
Go to:
Acknowledgments
The authors are thankful for the support provided by the Tel-Aviv University and the National
Natural Science Foundation of China [No. 21603172 and 11604017].
Go to:
Supporting Information Available
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acscentsci.9b01096.
Materials, synthesis, and analytical data including NMR, MS, DSC, FTIR, elemental analysis,
X-ray crystallography, as well as details of detonation and computational studies, supplementary
figures, and tables (PDF)
Video S1: detonation experiment of HL7 (ZIP)
Go to:
Notes
Note that the DFT calculation and data analysis of molecular and crystal features of the series of
explosives allowed the definition of key descriptors of thermostability.
Go to:
Supplementary Material
oc9b01096_si_001.pdf(6.8M, pdf )
oc9b01096_si_002.zip(11M, zip)
Go to:
References
Larcher D.; Tarascon J. M. Towards Greener and more Sustainable Batteries For Electrical Energy
Storage. Nat. Chem. 2015, 7, 19.10.1038/nchem.2085. [PubMed] [CrossRef ] [Google Scholar]
a. Galante E.; Haddad A.; Marques N. Application of Explosives in the Oil Industry. Int. J. Oil Gas
Coal Technol. 2013, 1, 16.10.11648/j.ogce.20130102.11. [CrossRef ] [Google Scholar]
b. Barker J. M. In Thermally Stable Explosive System for Ultra-High-Temperature Perforating,
Society of Petroleum Engineers, SPE 166179, the SPE Annual Technical Conference and
Exhibition, New Orleans, Louisiana, USA, 2013; 166179.10.2118/166179-MS [CrossRef ]
c. Abdel-Aal H. K.; Aggour M. A.; Fahim M. A.. Petroleum and Gas Field Processing; CRC Press:
New York, 2015; pp 41–51. [Google Scholar]
Majorowicz J.; Nieuwenhuis G.; Unsworth M.; Phillips J.; Verveda R. In High Temperatures
Predicted in the Granitic Basement of Northwest Alberta – An Assessment of the EGS Energy
Potential, Proceedings of 39th Workshop on Geothermal Reservoir Engineering, Stanford, USA,
February, 2014.
a. Kilmer E. E. Heat-Resistant Explosives for Space Applications. J. Spacecr. Rockets 1968, 5,
1216.10.2514/3.29452. [CrossRef ] [Google Scholar]
b. Tang Y.; He C.; Imler G. H.; Parrish D. A.; Shreeve J. M. Aminonitro Groups Surrounding a
Fused Pyrazolotriazine Ring: A Superior Thermally Stable and Insensitive Energetic Material.
ACS Appl. Energy Mater. 2019, 2, 2263.10.1021/acsaem.9b00049. [CrossRef ] [Google Scholar]
a. Brauer K. In Present and Future Applications of Pyrotechnic Devices and Pyrotechnic Systems
for Spacecraft”, 19th Congress of the International Astronautical Federation, New York, USA,
October, 1970.
b. Hwang D. H.; Han J. H.; Lee J.; Lee Y.; Kim D. A Mathematical Model for the Separation
Behavior of a Split Type Low-Shock Separation bolt. Acta Astronaut. 2019, 164,
393.10.1016/j.actaastro.2019.07.035. [CrossRef ] [Google Scholar]
a. Shipp K. G. Reactions of α-Substituted Polynitrotoluenes. I. Synthesis of 2,2’,4,4’,6,6’-
Hexanitrostilbene. J. Org. Chem. 1964, 29 (9), 2620.10.1021/jo01032a034. [CrossRef ] [Google
Scholar]
b. Rieckmann T.; Völker S.; Lichtblau L.; Schirra R. Investigation on the Thermal Stability of
Hexanitrostilbene by Thermal Analysis and Multivariate RSegression. Chem. Eng. Sci. 2001, 56
(4), 1327–1335. 10.1016/S0009-2509(00)00355-9. [CrossRef ] [Google Scholar]
c. Gilbert E. The Preparation of Hexanitrostilbene from Hexanitrobibenzyl. Propellants, Explos.,
Pyrotech. 1980, 5, 168.10.1002/prep.19800050606. [CrossRef ] [Google Scholar]
a. Agrawal J. P. Past, Present & Future of Thermally Stable Explosives. Cent. Eur. J. Energy 2012, 9
(3), 273–290. [Google Scholar]
b. Agrawal J. P.High energy materials: propellants, explosives and pyrotechnics; Wiley-VCH
Verlag GmbH: Germany, 2010; pp 1–464. [Google Scholar]
Yin P.; Zhang J.; Parrish D. A.; Shreeve J. M. Energetic N,N’-Ethylene-Bridged Bis(nitropyrazoles):
Diversified Functionalities and Properties. Chem. - Eur. J. 2014, 20,
16529.10.1002/chem.201404991. [PubMed] [CrossRef ] [Google Scholar]
Kumar D.; Tang Y.; He C.; Imler G. H.; Parrish D. A.; Shreeve J. M. Multipurpose Energetic
Materials by Shuffling Nitro Groups on a 3,3 ′-Bipyrazole Moiety. Chem. - Eur. J. 2018, 24,
Klapötke T. M.; Witkowski T. G.; Wilk Z.; Hadzik J. Experimental Study on the Heat Resistant
Explosive 5,5′-Bis(2,4,6-trinitrophenyl)-2,2’-bi(1,3,4-oxadiazole) (TKX-55): the Jet Penetration
Capability and Underwater Explosion Performance. Cent. Eur. J. Energ. Mater. 2016, 13,
821.10.22211/cejem/65824. [CrossRef ] [Google Scholar]
Klapötke T. M.; Witkowski T. G. 5,5′-Bis(2,4,6-trinitrophenyl)-2,2 ′-bi(1,3,4-oxadiazole) (TKX-55):
Thermally Stable Explosive with Outstanding Properties. ChemPlusChem 2016, 81,
357.10.1002/cplu.201600078. [CrossRef ] [Google Scholar]
a. Tsyshevsky R.; Pagoria P.; Zhang M.; Racoveanu A.; Parrish D. A.; Smirnov A. S.; Kuklja M. M.
Comprehensive End-to-End Design of Novel High Energy Density Materials: I. Synthesis and
Characterization of Oxadiazole Based Heterocycles. J. Phys. Chem. C 2017, 121,
23865.10.1021/acs.jpcc.7b07585. [CrossRef ] [Google Scholar]
b. Tsyshevsky R.; Pagoria P.; Smirnov A. S.; Kuklja M. M. Comprehensive End-to-End Design of
Novel High Energy Density Materials: II. Computational Modeling and Predictions. J. Phys.
Chem. C 2017, 121, 23865.10.1021/acs.jpcc.7b07585. [CrossRef ] [Google Scholar]
c. Tsyshevsky R.; Smirnov A. S.; Kuklja M. M. Comprehensive End-To-End Design of Novel High
Energy Density Materials: III. Fused Heterocyclic Energetic Compounds. J. Phys. Chem. C 2019,
123, 8688.10.1021/acs.jpcc.9b00863. [CrossRef ] [Google Scholar]
a. Kroonblawd M. P.; Sewell T. D.; Maillet J. B. Characteristics of Energy Exchange Between Inter-
and Intramolecular Degrees of Dreedom in Crystalline 1,3,5-Triamino-2,4,6-Trinitrobenzene
(TATB) with Implications for Coarse-Grained Simulations of Shock Waves in Polyatomic
Molecular Crystals. J. Chem. Phys. 2016, 144 (6), 06450110.1063/1.4941332. [PubMed] [CrossRef ]
[Google Scholar]
b. Moustafa S. G.; Schultz A. J.; Ko e D. A. Very Fast Averaging of Thermal Properties of Crystals
by Molecular Simulation. Phys. Rev. E 2015, 92, 04330310.1103/PhysRevE.92.043303. [PubMed]
[CrossRef ] [Google Scholar]
c. Pulido A.; Chen L.; Kaczorowski T.; Holden D.; Little M. A.; Chong S. Y.; Slater B. J.; McMahon
D. P.; Bonillo B.; Stackhouse C. J.; Stephenson A.; Kane C. M.; Clowes R.; Hasell T.; Cooper A. I.;
Day G. M. Functional Materials Discovery Using Energy-Structure-Function Maps. Nature 2017,
543, 657.10.1038/nature21419. [PMC free article] [PubMed] [CrossRef ] [Google Scholar]
d. Musil F.; De S.; Yang J.; Campbell J. E.; Day G. M.; Ceriotti M. Machine learning for the
structure–energy–property landscapes of molecular crystals. Chem. Sci. 2018, 9,
1289.10.1039/C7SC04665K. [PMC free article] [PubMed] [CrossRef ] [Google Scholar]
a. Ma Y.; Zhang A.; Zhang C.; Jiang D.; Zhu Y.; Zhang C. Crystal Packing of Low-Sensitivity and
High-Energy Explosives. Cryst. Growth Des. 2014, 14, 4703.10.1021/cg501048v. [CrossRef ] [Google
Scholar]
b. Zhang C.; Wang X.; Huang H. π-Stacked Interactions in Explosive Crystals: Buffers against
External Mechanical Stimuli. J. Am. Chem. Soc. 2008, 130, 8359.10.1021/ja800712e. [PubMed]
c. Tian B.; Xiong Y.; Chen L.; Zhang C. Relationship between the crystal packing and impact
sensitivity of energetic materials. CrystEngComm 2018, 20, 837.10.1039/C7CE01914A. [CrossRef ]
[Google Scholar]
Wang Y.; Liu Y.; Song S.; Yang Z.; Qi X.; Wang K.; Liu Y.; Zhang Q.; Tian Y. Accelerating the
Discovery of Insensitive High-Energy-Density Materials by a Materials Genome Approach. Nat.
Commun. 2018, 9, 2444.10.1038/s41467-018-04897-z. [PMC free article] [PubMed] [CrossRef ]
[Google Scholar]
a. Manelis G. B.; Nazin G. M.; Rubtsov Yu I.; Strunin V. A.. Thermal Decomposition and
Combustion of Explosives and Propellants; Taylor & Francis: New York, 2003. [Google Scholar]
b. Manelis G. B.; Nazin G. M.; Prokudin V. G. Models for unimolecular reactions in the solid
phase and stability prediction of energetic compounds in the condensed state. Russ. Chem. Bull.
2011, 60 (7), 1440–1447. 10.1007/s11172-011-0215-7. [CrossRef ] [Google Scholar]
c. Nazin G. M.; Prokudin V. G.; Manelis G. B. Thermal stability of high-energy compounds. Russ.
Chem. Bull. 2000, 49 (2), 234–237. 10.1007/BF02494664. [CrossRef ] [Google Scholar]
d. Korsunskii B. L.; Manelis G. B.; Nazin G. M.; Stolyarov P. N. Methodological problems in
determination of the thermal stability of explosives. Russian Chemical Journal 1997, 41 (4), 49–
53. [Google Scholar]
a. Chagas C. M.; Moss S.; Alisaraie L. Drug Metabolites and their Effects on the Development of
Adverse Eeactions: Revisiting Lipinski’s Rule of Five. Int. J. Pharm. 2018, 549,
133.10.1016/j.ijpharm.2018.07.046. [PubMed] [CrossRef ] [Google Scholar]
b. Lipinski C. A. Rule of Five in 2015 and Beyond: Target and Ligand Structural Limitations,
Ligand Chemistry Structure and Drug Discovery Project Decisions. Adv. Drug Delivery Rev. 2016,
101, 34.10.1016/j.addr.2016.04.029. [PubMed] [CrossRef ] [Google Scholar]
c. Zhang M. Q.; Wilkinson B. Drug Discovery Beyond the ‘Rule-of-Five. Curr. Opin. Biotechnol.
2007, 18, 478.10.1016/j.copbio.2007.10.005. [PubMed] [CrossRef ] [Google Scholar]
Shultz M. D. Two Decades under the Influence of the Rule of Five and the Changing Properties of
Approved Oral Drugs. J. Med. Chem. 2019, 62, 1701.10.1021/acs.jmedchem.8b00686. [PubMed]
Elton D. C.; Boukouvalas Z.; Butrico M. S.; Fuge M. D.; Chung P. W. Applying machine learning
techniques to predict the properties of energetic materials. Sci. Rep. 2018, 8,
9059.10.1038/s41598-018-27344-x. [PMC free article] [PubMed] [CrossRef ] [Google Scholar]
a. Li D.; Ma P.; Niu J.; Wang J. Recent Advances in Transition-Metal-Containing Keggin-type
Polyoxometalate-based Coordination Polymers. Coord. Chem. Rev. 2019, 392,
49.10.1016/j.ccr.2019.04.008. [CrossRef ] [Google Scholar]
b. Tian A.; Ni H.; Ji X.; Tian Y.; Liu G.; Ying J. Influence of Pendant
2-[1,2,4]triazol-4-yl-ethylamine and Symmetrical Bis(pyrazol) Ligands on Dimensional Extension
of POM-Based Compounds. RSC Adv. 2017, 7, 30573.10.1039/C7RA03884D. [CrossRef ] [Google
Scholar]
c. Tian A.; Yang Y.; Ying J.; Li N.; Lin X. L.; Zhang J. W.; Wang X. L. The Key Role of – CH3 Steric
Hindrance in Bis(pyrazolyl) Ligand on Polyoxometalate-based Compounds. Dalton Trans. 2014,
43, 8405.10.1039/c4dt00107a. [PubMed] [CrossRef ] [Google Scholar]
a. Bellamy A. J. Synthesis of Hexanitrostilbene (HNS) using a Kenics Static Mixer. Org. Process
Res. Dev. 2010, 14, 632.10.1021/op1000644. [CrossRef ] [Google Scholar]
b. Lu T.; Yao K.; Mao Y.; Xu J.; Wang P.; Lu M. A Novel and Efficient Synthesis of
Hexanitrostilbene by N-Hydroxyphthalimide/FeCl2-Catalyzed Aerobic Dehydrogenation of
Hexanitrobibenzyl. J. Energ. Mater. 2013, 31, 217.10.1080/07370652.2012.710870. [CrossRef ]
[Google Scholar]
c. Wang P.; Lu T. T.; Lu M. A Green and Effective Approach of Two-Step 2,2 ′,4,4 ′,6,6 ′-
Hexanitrostilbene Preparation and Its Industrial Scale Study. Org. Process Res. Dev. 2016, 20,
668.10.1021/acs.oprd.5b00422. [CrossRef ] [Google Scholar]
Zaitsev A. A.; Kortusov I.; Dalinger I.; Kachala V.; Popova G.; Shevelev S. Nitropyrazoles 16. The
use of methoxymethyl group as a protecting group for the synthesis of
4-methyl-3-nitro-5-R-pyrazoles. Russ. Chem. Bull. 2009, 58, 2118.10.1007/s11172-009-0289-7.
Zaitsev A. A.; Vatsadze I.; Dalinger I.; Kachala V.; Nelyubina Y. V.; Shevelev S. Nitropyrazoles 15.
Synthesis and some transformations of 1-(2,4-dinitrophenyl)-4-methyl-3,5-dinitropyrazole. Russ.
Chem. Bull. 2009, 58, 2109.10.1007/s11172-009-0288-8. [CrossRef ] [Google Scholar]
Zaitsev A. A.; Cherkasova T. I.; Dalinger I. L.; Kachala V. V.; Strelenko Y. A.; Fedyanin I. V.; Solkan
V. N.; Shkineva T. K.; Popova G. P.; Shevelev S. A. Nitropyrazoles. Russ. Chem. Bull. 2007, 56,
2074.10.1007/s11172-007-0323-6. [CrossRef ] [Google Scholar]
a. Trofimenko S. Geminal Poly(1-pyrazolyl)alkanes and their Coordination Chemistry. J. Am.
Chem. Soc. 1970, 92, 5118.10.1021/ja00720a021. [CrossRef ] [Google Scholar]
b. Wheate N. J.; Broomhead J. A.; Collins G.; Day A. I. Thermal Rearrangement of N-Substituted
Pyrazoles to 4,4’-Dipyrazolylmethane and 1,1,2-(4,4’,4”-Tripyrazolyl)ethane. Aust. J. Chem. 2001,
54, 141.10.1071/CH00151. [CrossRef ] [Google Scholar]
Allen F. H.; Kennard O.; Watson D. G.; Brammer L.; Orpen A. G.; Taylor R. Tables of Bond
Lengths Determined by X-ray and Neutron Diffraction. Part 1. Bond Lengths in Organic
Compounds. J. Chem. Soc., Perkin Trans. 2 1987, S1.10.1039/p298700000s1. [CrossRef ] [Google
Scholar]
Urbański T.; Vasudeva S. K. Heat Resistant Explosives. J. Sci. Ind. Res. 1978, 37 (5), 250. [Google
Scholar]
Wang H. B.; Wang Y. H.; Li Y. X.; Liu Y. C.; Tan Y. X. Scale-up Synthesis and Characterization of
2,6-diamino-3,5-dinitropyrazine-1-oxide. Def. Technol. 2014, 10, 343.10.1016/j.dt.2014.07.008.
Singh B.; Malhotra R. Hexanitrostilbene and its Properties. Def. Sci. J. 1983, 33,
165.10.14429/dsj.33.6170. [CrossRef ] [Google Scholar]
a. Dorofeeva O. V.; Osina E. L. Performance of DFT, MP2, and Composite ab initio Methods for
the Prediction of Enthalpies of Formations of CHON Compounds Using Isodesmic Reactions.
Comput. Theor. Chem. 2017, 1106, 28.10.1016/j.comptc.2017.03.006. [CrossRef ] [Google Scholar]
b. Xu Z.; Cheng G.; Yang H.; Ju X.; Yin P.; Zhang J.; Shreeve J. M. A Facile and Versatile Synthesis
of Energetic Furazan-Functionalized 5-Nitroimino-1,2,4-Triazoles. Angew. Chem., Int. Ed. 2017,
56, 5877.10.1002/anie.201701659. [PubMed] [CrossRef ] [Google Scholar]
Frisch M. J.; Trucks G. W.; Schlegel H. B.; Scuseria G. E.; Robb M. A.; Cheeseman J. R.; Scalmani
G.; Barone V.; Mennucci B.; Petersson G. A.; Nakatsuji H.; Caricato M.; Li X.; Hratchian H. P.;
Izmaylov A. F.; Bloino J.; Zheng G.; Sonnenberg J. L.; Hada M.; Ehara M.; Toyota K.; Fukuda R.;
Hasegawa J.; Ishida M.; Nakajima T.; Honda Y.; Kitao O.; Nakai H.; Vreven T.; Montgomery J. A.
Jr.; Peralta J. E.; Ogliaro F.; Bearpark M.; Heyd J. J.; Brothers E.; Kudin K. N.; Staroverov V. N.;
Kobayashi R.; Normand J.; Raghavachari K.; Rendell A.; Burant J. C.; Iyengar S. S.; Tomasi J.;
Cossi M.; Rega N.; Millam J. M.; Klene M.; Knox J. E.; Cross J. B.; Bakken V.; Adamo C.; Jaramillo
J.; Gomperts R.; Stratmann R. E.; Yazyev O.; Austin A. J.; Cammi R.; Pomelli C.; Ochterski J. W.;
Martin R. L.; Morokuma K.; Zakrzewski V. G.; Voth G. A.; Salvador P.; Dannenberg J. J.; Dapprich
S.; Daniels A. D.; Farkas O.; Foresman J. B.; Ortiz J. V.; Cioslowski J.; Fox D. J.. Gaussian 09;
Gaussian, Inc.: Wallingford, CT, 2013.
Suceska M.EXPLO 5; Brodarski Institute: Zagreb, Croatia, 2013.
a. Pimbley G. H.; Bowman A. L.; Fox W. P.; Kershner J. D.; Mader C. L.; Urizar M. J.. Investigating
Explosive and Material Properties by Use of the Plate Dent Test; Los Alamos Scientific
Laboratory: Los Alamos, New Mexico, 1980. [Google Scholar]
b. Frem D. Predicting the Plate Dent Test Output in Order to Assess the Performance of
Condensed High Explosives. J. Energ. Mater. 2017, 35, 20.10.1080/07370652.2016.1143059.
a. Fedyanin I. V.; Lyssenko K. A. New Hydrogen-bond-aided Supramolecular Synthon: A Case
Study of 2,4,6-trinitroaniline. CrystEngComm 2013, 15, 10086.10.1039/c3ce41227j. [CrossRef ]
[Google Scholar]
b. Thallapally P. K.; Jetti R. K. R.; Katz A. K.; Carrell H. L.; Singh K.; Lahiri K.; Kotha S.; Boese R.;
Desiraju G. R. Polymorphism of 1,3,5-Trinitrobenzene Induced by a Trisindane Additive. Angew.
Chem., Int. Ed. 2004, 43, 1149.10.1002/anie.200352253. [PubMed] [CrossRef ] [Google Scholar]
c. Kohno Y.; Hiyoshi R. I.; Yamaguchi Y.; Matsumoto S.; Koseki A.; Takahashi O.; Yamasaki K.;
Ueda K. Molecular Dynamics Studies of the Structural Change in
1,3-Diamino-2,4,6-trinitrobenzene (DATB) in the Crystalline State under High Pressure. J. Phys.
Chem. A 2009, 113, 2551.10.1021/jp809240x. [PubMed] [CrossRef ] [Google Scholar]
d. Nair U. R.; Gore G. M.; Sivabalan R.; Pawar S. J.; Asthana S. N.; Venugopalan S. Preparation
and Thermal Studies on Tetranitrodibenzo Tetraazapentalene (TACOT): A Thermally Stable
High Explosive. J. Hazard. Mater. 2007, 143, 500.10.1016/j.jhazmat.2006.09.065. [PubMed]
e. Chaykovsky M.; Adolph H. G. Synthesis and Properties of Some Trisubstituted
Trinitrobenzenes. TATB Analogs. J. Energ. Mater. 1990, 8, 392.10.1080/07370659008225431.
f. Klapötke T. M.; Mieskes F.; Stierstorfer J.; Weyrauther M. Studies on Energetic Salts Based on
(2,4,6-Trinitrophenyl)guanidine. Propellants, Explos., Pyrotech. 2016, 41,
217.10.1002/prep.201500338. [CrossRef ] [Google Scholar]
g. Li B. T.; Dong H.; Zhang S.; Chin J. Y. J. Energy Mater. 2003, 11, 85. [Google Scholar]
h. Licht H. H.; Ritter H. 2,4,6-Trinitropyridine and Related Compounds, Synthesis and
Characterization. Propellants, Explos., Pyrotech. 1988, 13, 25.10.1002/prep.19880130107.
i. Averkiev B. B.; Antipin M. Y.; Yudin I. L.; Sheremetev A. B. X-ray Structural Study of Three
Derivatives of Dinitropyrazine. J. Mol. Struct. 2002, 606, 139.10.1016/S0022-2860(01)00862-6.
j. Zaitsev A. A.; Kortusov I. O.; Dalinger I. L.; Kachala V. V.; Popova G. P.; Shevelev S. A.
Nitropyrazoles 16. The use of Methoxymethyl Group as a Protecting Group for the Synthesis of
4-methyl-3-nitro-5-R-pyrazoles. Russ. Chem. Bull. 2009, 58, 2118.10.1007/s11172-009-0289-7.
Zhi-wei H.; Shi-long Y.; Zu-liang L. Chin. J. Explos. Propell. 2013, 36, 51. [Google Scholar]
a. Roháč M.; Zeman S.; Růžička A. Crystallography of 2,2′,4,4 ′,6,6 ′-Hexanitro-1,1 ′-biphenyl and Its
Relation to Initiation Reactivity. Chem. Mater. 2008, 20, 3105.10.1021/cm702829k. [CrossRef ]
[Google Scholar]
b. Tang Y.; He C.; Imler G. H.; Parrish D. A.; Shreeve J. M. A C–C Bonded 5,6-fused Bicyclic
Rnergetic Molecule: Exploring an Advanced Energetic Compound with Improved Performance.
Chem. Commun. 2018, 54, 10566.10.1039/C8CC05987J. [PubMed] [CrossRef ] [Google Scholar]
c. Domasevitch K. V.; Gospodinov I.; Krautscheid H.; Klapötke T. M.; Stierstorfer J. Facile and
Selective Polynitrations at the 4-pyrazolyl Dual Backbone: Straightforward Access to a Series of
High-Density Energetic Materials. New J. Chem. 2019, 43, 1305.10.1039/C8NJ05266B. [CrossRef ]
[Google Scholar]
d. Tang Y.; Kumar D.; Shreeve J. M. Balancing Excellent Performance and High Thermal Stability
in a Dinitropyrazole Fused 1,2,3,4-Tetrazine. J. Am. Chem. Soc. 2017, 139,
13684.10.1021/jacs.7b08789. [PubMed] [CrossRef ] [Google Scholar]
e. Liu L.; Zhang Y.; Zhang S.; Fei T. Heterocyclic Energetic Salts of 4,4 ′,5,5 ′-
Tetranitro-2,2′-Biimidazole. J. Energ. Mater. 2015, 33, 202.10.1080/07370652.2014.970246.
f. Yin P.; Shreeve J. M. From N-Nitro to N-Nitroamino: Preparation of High-Performance
Energetic Materials by Introducing Nitrogen-Containing Ions. Angew. Chem., Int. Ed. 2015, 54,
14513.10.1002/anie.201507456. [PubMed] [CrossRef ] [Google Scholar]
g. Chavez D. E.; Bottaro J. C.; Petrie M.; Parrish D. A. Synthesis and Thermal Behavior of a Fused,
Tricyclic 1,2,3,4-Tetrazine Ring System. Angew. Chem., Int. Ed. 2015, 54,
12973.10.1002/anie.201506744. [PubMed] [CrossRef ] [Google Scholar]
h. Fischer N.; Fischer D.; Klapötke T. M.; Piercey D. G.; Stierstorfer J. Pushing the limits of
energetic materials – the synthesis and characterization of dihydroxylammonium 5,5 ′-
bistetrazole-1,1′-diolate. J. Mater. Chem. 2012, 22, 20418.10.1039/c2jm33646d. [CrossRef ] [Google
Scholar]
a. Terrier F.; Xie H. Q.; Farrell P. G. The Effect of Nitro-Substitution Upon Diphenylmethane
Reactivity. J. Org. Chem. 1990, 55, 2610.10.1021/jo00296a014. [CrossRef ] [Google Scholar]
b. Bölter M. F.; Klapötke T. M.; Kustermann T.; Lenz T.; Stierstorfer J. Improving the Energetic
Properties of Dinitropyrazoles by Utilization of Current Concepts. Eur. J. Inorg. Chem. 2018,
2018, 4125.10.1002/ejic.201800781. [CrossRef ] [Google Scholar]
c. Huang J. L.; Cheng B. B.; Ma Q. Chin. J. Energy Mater. 2011, 240. [Google Scholar]
Zhang J.; Wang J.; Xu H. F. Chin. J. Energy Mater. 2013, 21, 7. [Google Scholar]
d. Yang C. H.; Lu Y. M.; Yan M. Q.; Li J.; Wu J.; Li Q. Y.; Yang J.; Shen L.; Yang G. W.; Zou J. H.
Nitrogen–rich 1, 2-bis(tetrazol-5-yl)ethane and its Carboxylate Derivative for Potential Energetic
Materials. ChemistrySelect 2016, 1, 2757.10.1002/slct.201600494. [CrossRef ] [Google Scholar]
e. Fischer D.; Gottfried J. L.; Klapötke T. M.; Karaghiosoff K.; Stierstorfer J.; Witkowski T. G.
Synthesis and Investigation of Advanced Energetic Materials Based on Bispyrazolylmethanes.
Angew. Chem., Int. Ed. 2016, 55, 16132.10.1002/anie.201609267. [PubMed] [CrossRef ] [Google
Scholar]
Huang H.; Zhou Z.; Song J.; Liang L.; Wang K.; Cao D.; Sun W.; Dong X.; Xue M. Energetic Salts
Based on Dipicrylamine and Its Amino Derivative. Chem. - Eur. J. 2011, 17,
a. Zeng Z.; Guo Y.; Twamley B.; Shreeve J. M. Energetic Polyazole Polynitrobenzenes and Their
Coordination Complexes. Chem. Commun. 2009, 6014.10.1039/b915090k. [PubMed] [CrossRef ]
[Google Scholar]
b. Zhang Y.; Zhou C.; Wang B.; Zhou Y.; Xu K.; Jia S.; Zhao F. Synthesis and Characteristics of
Bis(nitrofurazano)furazan (BNFF), an Insensitive Material with High Energy-Density.
Propellants, Explos., Pyrotech. 2014, 39, 809.10.1002/prep.201400057. [CrossRef ] [Google
Scholar]
c. Li H. Q.; An C. W.; Du M. Y. Chin. J. Explos. Propell. 2016, 39, 58. [Google Scholar]
d. Zhang X.; Xiong H.; Yang H.; Cheng G.
14,16,34,36,54,56,74,76-Octanitro-2,4,6,8-tetraoxa-1,3,5,7(1,3)-tetrabenzenacyclooctaphane and
its Derivatives: Thermally Stable Explosives with Outstanding Properties. New J. Chem. 2017, 41,
5764.10.1039/C7NJ01057E. [CrossRef ] [Google Scholar]
Liu N.; Shu Y.-j.; Li H.; Zhai L.-j.; Li Y.-n.; Wang B.-z. Synthesis, characterization and properties
of heat-resistant explosive materials: polynitroaromatic substituted
difurazano[3,4-b:3′,4′-e]pyrazines. RSC Adv. 2015, 5, 43780.10.1039/C5RA07105D. [CrossRef ]
[Google Scholar]
Aizikovich A.; Shlomovich A.; Cohen A.; Gozin M. The Nitration Pattern of Energetic
3,6-diamino-1,2,4,5-tetrazine Derivatives Containing Azole Functional Groups. Dalton Trans.
2015, 44, 13939.10.1039/C5DT01641J. [PubMed] [CrossRef ] [Google Scholar]
Zeman S.; Roháč M.; Friedl Z.; Růžička A.; Lyčka A. Crystallography and Structure–Property
Relationships of 2,2″,4,4′,4″,6,6′,6″-Octanitro-1,1′: 3 ′,1″-Terphenyl (ONT). Propellants, Explos.,
Pyrotech. 2010, 35, 130.10.1002/prep.200900054. [CrossRef ] [Google Scholar]
Wei J.; Li F.; Xu J.; Peng X. Synthesis and Thermal Stability of New Polynitrostilbenes. Aust. J.
Chem. 2015, 68, 919.10.1071/CH14400. [CrossRef ] [Google Scholar]
Klapötke T. M.; Stierstorfer J.; Weyrauther M.; Witkowski T. G. Synthesis and Investigation of
2,6-Bis(picrylamino)-3,5-dinitro-pyridine (PYX) and Its Salts. Chem. - Eur. J. 2016, 22,
Altmann K. L.; Chafin A. P.; Merwin L. H.; Wilson W. S.; Gilardi R. Chemistry of
Tetraazapentalenes. J. Org. Chem. 1998, 63, 3352.10.1021/jo972252x. [CrossRef ] [Google Scholar]
Yin P.; Zhang J.; Imler G. H.; Parrish D. A.; Shreeve J. M. Polynitro-Functionalized
Dipyrazolo-1,3,5-triazinanes: Energetic Polycyclization toward High Density and Excellent
Molecular Stability. Angew. Chem. 2017, 129, 8960.10.1002/ange.201704687. [PubMed] [CrossRef ]
[Google Scholar]
Tang Y.; He C.; Imler G. H.; Parrish D. A.; Shreeve J. M. Ring Closure of Polynitroazoles via an
N,N′-alkylene Bridge: Towards High Thermally Stable Energetic Compounds. J. Mater. Chem. A
2018, 6, 8382.10.1039/C8TA02704H. [CrossRef ] [Google Scholar]
a. Zhang L.; Jiang S.-L.; Yu Y.; Long Y.; Zhao H.-Y.; Peng L.-J.; Chen J. Phase Transition in
Octahydro-1,3,5,7-tetranitro-1,3,5,7-tetrazocine (HMX) under Static Compression: An
Application of the First-Principles Method Specialized for CHNO Solid Explosives. J. Phys.
Chem. B 2016, 120, 11510.10.1021/acs.jpcb.6b08092. [PubMed] [CrossRef ] [Google Scholar]
b. Zhang L.; Wu J.-Z.; Jiang S.-L.; Yu Y.; Chen J. From Intermolecular Interactions to Structures
and Properties of a Novel Cocrystal Explosive: A First-Principles Study. Phys. Chem. Chem. Phys.
2016, 18, 26960.10.1039/C6CP03526D. [PubMed] [CrossRef ] [Google Scholar]
c. Zhang L.; Yao C.; Yu Y.; Jiang S.-L.; Sun C. Q.; Chen J. Stabilization of the Dual-Aromatic
cyclo-N5- Anion by Acidic Entrapment. J. Phys. Chem. Lett. 2019, 10,
2378.10.1021/acs.jpclett.9b01047. [PubMed] [CrossRef ] [Google Scholar]
d. Zhang L.; Jiang S.-L.; Yu Y. Revealing Solid Properties of High-energy-density Molecular
Cocrystals from the Cooperation of Hydrogen Bonding and Molecular Polarizability. Sci. Rep.
2019, 9, 1257.10.1038/s41598-018-37500-y. [PMC free article] [PubMed] [CrossRef ] [Google
Scholar]
e. Zhang C.; Sun C.; Hu B.; Yu C.; Lu M. Synthesis and Characterization of the Pentazolate Snion
Cyclo-N5–in(N5)6(H3O)3(NH4)4Cl. Science 2017, 355, 374.10.1126/science.aah3840. [PubMed]
f. Zhang L.; Yao C.; Yu Y.; Wang X.; Sun C. Q.; Chen J. ChemPhysChem 2019, 20,
2525.10.1002/cphc.201900674. [PubMed] [CrossRef ] [Google Scholar]
g. Zhang L.; Yu Y.; Xiang M. A Study of the Shock Sensitivity of Energetic Single Crystals by
Large-Scale Ab Initio Molecular Dynamics Simulations. Nanomaterials 2019, 9,
1251.10.3390/nano9091251. [PMC free article] [PubMed] [CrossRef ] [Google Scholar]
h. Zong H.-H.; Zhang L.; Zhang W.-B.; Jiang S.-L.; Yu Y.; Chen J. Structural, Mechanical
Properties, and Vibrational Spectra of LLM-105 Under High Pressures from a First-Principles
Study. J. Mol. Model. 2017, 23, 275.10.1007/s00894-017-3446-1. [PubMed] [CrossRef ] [Google
Scholar]
Mo Z.; Zhang A.; Cao X.; Liu Q.; Xu X.; An H.; Pei W.; Zhu S. JASMIN: A Parallel Software
Infrastructure for Scientific Computing. Front. Comput. Sci. China 2010, 4,
480.10.1007/s11704-010-0120-5. [CrossRef ] [Google Scholar]
Wolff S. K.; Grimwood D. J.; McKinnon J. J.; Turner M. J.; Jayatilaka D.; Spackman M. A..
CrystalExplorer 3.1; University of Western Australia, 2012.
Hestenes M. R.; Stiefel E. L. Methods of Conjugate Gradients for Solving Linear Systems. Journal
of Research of the National Bureau of Standards 1952, 49, 409.10.6028/jres.049.044. [CrossRef ]
[Google Scholar]
a. He P.; Zhang J.-G.; Wang K.; Yin X.; Zhang T.-L. Combination Multinitrogen with Good
Oxygen Balance: Molecule and Synthesis Design of Polynitro-Substituted
Tetrazolotriazine-Based Energetic Compounds. J. Org. Chem. 2015, 80,
5643.10.1021/acs.joc.5b00545. [PubMed] [CrossRef ] [Google Scholar]
b. Lin H.; Yang D.-D.; Lou N.; Zhu S.-G.; Li H.-Z. Computational Design of High Energy Density
Materials with Zero Oxygen Balance: A Combination of Furazan and Piperazine Rings. Comput.
Theor. Chem. 2018, 1139, 44.10.1016/j.comptc.2018.07.005. [CrossRef ] [Google Scholar]
a. Zhang J.; Mitchell L. A.; Parrish D. A.; Shreeve J. M. Enforced Layer-by-Layer Stacking of
Energetic Salts towards High-Performance Insensitive Energetic Materials. J. Am. Chem. Soc.
2015, 137, 10532.10.1021/jacs.5b07852. [PubMed] [CrossRef ] [Google Scholar]
b. Zhang W.; Zhang J.; Deng M.; Qi X.; Nie F.; Zhang Q. A Promising High-Energy-Density
Material. Nat. Commun. 2017, 8, 181.10.1038/s41467-017-00286-0. [PMC free article] [PubMed]
a. McKinnon J. J.; Jayatilaka D.; Spackman M. A. Towards Quantitative Analysis of Intermolecular
Interactions with Hirshfeld Surfaces. Chem. Commun. 2007, 3814.10.1039/b704980c. [PubMed]
b. McKinnon J. J.; Mitchell A. S.; Spackman M. A. Hirshfeld Surfaces: A New Tool for Visualising
and Exploring Molecular Crystals. Chem. - Eur. J. 1998, 4,
2136.10.1002/(SICI)1521-3765(19981102)4:11<2136::AID-CHEM2136>3.0.CO;2-G. [CrossRef ] [Google
Scholar]
Meng L.; Lu Z.; Ma Y.; Xue X.; Nie F.; Zhang C. Enhanced Intermolecular Hydrogen Bonds
Facilitating the Highly Dense Packing of Energetic Hydroxylammonium Salts. Cryst. Growth
Des. 2016, 16, 7231.10.1021/acs.cgd.6b01409. [CrossRef ] [Google Scholar]
Articles from ACS Central Science are provided here courtesy of American Chemical Society
Formats:
Article | PubReader | ePub (beta) | PDF (4.9M) | Citation
Share
Share on Facebook FacebookShare on Twitter TwitterShare on Google Plus Google+
Save items
View more options
Similar articles in PubMed
Energetic multifunctionalized nitraminopyrazoles and their ionic derivatives: ternary
hydrogen-bond induced high energy density materials.
[J Am Chem Soc. 2015]
A Family of Energetic Materials Based on 1,2,4-Oxadiazole and 1,2,5-Oxadiazole Backbones With
Low Insensitivity and Good Detonation Performance.
[Front Chem. 2019]
Energetic N,N'-ethylene-bridged bis(nitropyrazoles): diversified functionalities and properties.
[Chemistry. 2014]
Energetic Butterfly: Heat-Resistant Diaminodinitro trans-Bimane.
[Molecules. 2019]
Diagnostic techniques in deflagration and detonation studies.
[Chem Cent J. 2015]
See reviews...
See all...
Cited by other articles in PMC
Recent Advances in Synthesis and Properties of Nitrated-Pyrazoles Based Energetic Compounds
[Molecules. 2020]
Novel All-Nitrogen Molecular Crystals of Aromatic N10
[Advanced Science. 2020]
Strategies for Achieving Balance between Detonation Performance and Crystal Stability of
High-Energy-Density Materials
[iScience. 2020]
See all...
Links
PubMed
Taxonomy
Recent Activity
ClearTurn Off
Direct Quantification of Damaged Nucleotides in Oligonucleotides Using an Aeroly...
Direct Quantification of Damaged Nucleotides in Oligonucleotides Using an Aerolysin Single
Molecule Interface
ACS Central Science. 2020 Jan 22; 6(1)76
Molecular and Crystal Features of Thermostable Energetic Materials: Guidelines f...
GTP Cyclohydrolase 1/Tetrahydrobiopterin Counteract Ferroptosis through Lipid Re...
GTP Cyclohydrolase 1/Tetrahydrobiopterin Counteract Ferroptosis through Lipid Remodeling
An Activity-Based Methionine Bioconjugation Approach To Developing Proximity-Act...
An Activity-Based Methionine Bioconjugation Approach To Developing Proximity-Activated
Imaging Reporters
Programmable Bivalent Peptide–DNA Locks for pH-Based Control of Antibody Activit...
Programmable Bivalent Peptide–DNA Locks for pH-Based Control of Antibody Activity
See more...
Support CenterSupport Center
External link. Please review our privacy policy.
NLMNIHDHHSUSA.gov
National Center for Biotechnology Information, U.S. National Library of Medicine
8600 Rockville Pike, Bethesda MD, 20894 USA
Policies and Guidelines | Contact
NCBINCBI Logo
Skip to main content
Skip to navigation
Resources
How To
About NCBI Accesskeys
PMC
US National Library of Medicine
National Institutes of Health
Search database
PMC
Search term
Search
Advanced Journal listHelp
COVID-19 is an emerging, rapidly evolving situation.
Get the latest public health information from CDC: https://www.coronavirus.gov
Get the latest research information from NIH: https://www.nih.gov/coronavirus
Find NCBI SARS-CoV-2 literature, sequence, and clinical content:

https://www.ncbi.nlm.nih.gov/sars-cov-2/
Journal ListACS Cent Sciv.6(1); 2020 Jan 22PMC6978832

Logo of acscentsci
ACS Cent Sci. 2020 Jan 22; 6(1): 76–82.
Published online 2020 Jan 9. doi: 10.1021/acscentsci.9b01129
PMCID: PMC6978832
PMID: 31989027
Molecule Interface
Jiajun Wang,†‡# Meng-Yin Li,†# Jie Yang,‡# Ya-Qian Wang,‡ Xue-Yuan Wu,†‡ Jin Huang,§
Yi-Lun Ying,† and Yi-Tao Longcorresponding author*†
Author information Article notes Copyright and License information Disclaimer
Associated Data
Supplementary Materials
Go to:
Abstract
DNA lesions such as metholcytosine(mC), 8-OXO-guanine (OG), inosine (I), etc. could cause
genetic diseases. Identification of the varieties of lesion bases are usually beyond the capability of
conventional DNA sequencing which is mainly designed to discriminate four bases only.
Therefore, lesion detection remains a challenge due to massive varieties and less distinguishable
readouts for structural variations at the molecular level. Moreover, standard amplification and
labeling hardly work in DNA lesion detection. Herein, we designed a single molecule interface
from the mutant aerolysin (K238Q), whose sensing region shows high compatibility to capture
and then directly convert a minor lesion into distinguishable electrochemical readouts.
Compared with previous single molecule sensing interfaces, the temporal resolution of the
K238Q aerolysin nanopore is enhanced by two orders, which has the best sensing performance in
all reported aerolysin nanopores. In this work, the novel K238Q could discriminate directly at
least three types of lesions (mC, OG, I) without labeling and quantify modification sites under
the mixed heterocomposition conditions of the oligonucleotide. Such a nanopore
electrochemistry approach could be further applied to diagnose genetic diseases at high
sensitivity.
Go to:
Short abstract
Herein, we designed a single molecule interface from the mutant aerolysin (K238Q), whose
sensing region shows high compatibility to capture and then directly convert a minor DnA lesion
into distinguishable electrochemical readouts.
Epigenetic modified DNA nucleotide causes protein dysfunction inducing tumors or even cancer
diseases. Commonly, mass spectrometry or fluorometry are the approaches to identify the
modified nucleotide bases. In a typical HPLC/mass spectrometry analysis,1 lesion segments
could be discriminated at high resolution; however it requires tedious HPLC purification of the
specific lesion part. Other reagents or labeling processes based on fluorometry provide feasibility
as well as accuracy, but lack generalization to each lesion variant. In addition, the lesion types,
with the most common instance being methylated cytosine (mC), occurred at a frequency of one
per 1 million repeats, which indicates ultrahigh sensitivity is required.2 Because of the massive
types of lesions and the low occurrence, the sequencing and identification of the lesion unit even
in a heterogeneous condition are too challenging for conventional approaches.
A generalized, label-free single molecule technique is required to address these limitations, and
the nanopore electrochemistry approach is presented here. The nanopore can be the most
prominent tool for DNA sequencing and lesion nucleotide detecting. In a proof-of-concept
experiment,103 a single-stranded DNA molecule is driven through α-hemolysin under an electric
field. Transient ionic fluctuation is obtained to directly measure the polynucleotide length. More
recently, the nanopore catalyzed by phi29 DNA polymerase is engineered allowing real-time
detection of numerous nucleotide additions.3 The nanopore is also engineered by site-directed
mutagenesis to slow down the DNA translocation owing to stronger noncovalent interaction
allowing base identification.4 Nonetheless, none of these techniques achieved lesion detection
in a mixed condition, owing to the few contributions from the single lesion occurrence in terms
of mass, charge, or structure.
Currently, more powerful nanopores are presented, for instance, MspA,5 ClyA,6 CsgG,7
aerolysin,8 YaxAB complex,9 FraC,10 OmpG,11 Lysenin,12 CymA,13 FhuA,14 etc. Alternatively,
careful design of nucleotide chains forms a hairpin structure or primer that could hook the
segment inside the nanopore lumen. This approach allows the oxidative derivatives and even
mispairing domain to fall into the sensitive region to be detected.15,16 Among the
above-mentioned nanopores, aerolysin from Aeromonas hydrophila as one of the smallest pore
owes ∼1.1 nm pore diameter.17 Prominently, wild-type (WT) aerolysin could identify a single base
difference8 and single methylated cytosine18 at the end of a homonucleotide mixture solution.
Nevertheless, the detection of multiple lesion types in a heteronucleotide mixture is still
challenging.
It has been reported that both interaction and steric effects between the analyte and sensing
interface in the nanopore determine the sensitivity.19 The space confined by the nanopore
should enhance the weak interaction including the H-bond, van der Waal force, and electrostatic
force so as to improve the single molecule probing capability.20 By testing with a model
nucleotide segment (dA4), the residence time with prominent mutants such as K238E and
K238G is 20 and 50 times longer than the WT, generating higher sensitivity. However, according
to the statistical analysis of residence time and I/I0 for lesion nucleotides, the overlapped scatter
distribution suggested the inefficient separation ability with these mutants (separation ability,
denoted as S, correlates with the half-peak width following the previous protocol28). Therefore,
we challenged the aerolysin nanopore to discriminate mixtures of more types of lesion units at
different positions of a heteronucleotide. So far, a series of aerolysin nanopores, e.g., K238E,21
K238F,22 K238G,22 R282G,23 Q212R,23 N226Q,23 K238C,24 K238Y,24 K238C,25 and other
aerolysin nanopores26,27 are designed, which attempted to discriminate a single nucleotide in a
heteronucleotide, at a single molecule level. Nonetheless, no such mutant provides sufficient
sensing ability to discriminate multiple lesions in a heteronucleotide. Herein, we present the
best mutant aerolysin, K238Q, to quantify lesion nucleotides, which shows the strongest sensing
capability among all the reported biological nanopores in nucleotide detection. To consider the
weak interaction between each base and “key” amino acid (i.e., K238), glutamine (Q) was then
chosen due to its strong interaction with nucleotide bases.29 Under constant voltage (+100 mV),
the K238Q constantly opens at 52 ± 2 pA (for experimental and characterization detail, please
refer to Supporting Information, Figures S1–S2; I–V relation refers to Figure S3). When applying
the model nucleotide segment, dA4, K238Q reads the residue current and residence time as 34.5
± 0.5 pA (I/I0 = 0.58) and 122 ± 19 ms respectively at 120 mV, which induces a half-peak width 0.5
pA. Comparing WT and all the mutants, the time domain resolution reported so far has reached
the best for aerolysin, leading to an enhanced temporal resolution for single nucleotide
discrimination by two orders. In this content, we demonstrate that the K238Q nanopore could
discriminate three types (mC, OG, I) and quantify modifications under a mixed
heterocomposition condition.

Figure 1
Aerolysin nanopore measuring modified oligonucleotide. The aerolysin is composed of seven
monomers, and the K238Q contains seven mutant sites (7K238Q). The modified nucleotides
8-oxo-guanine (blue), inosine (black), and 5-methylcytosine (red) at different positions on the
model nucleotide segments are shown as a scheme. (A) A typical K238Q aerolysin inserted into
an artificial lipid bilayer with substrates added from the cis side. The implementation of (B)
additional zoomed-in diagram (red box in (A)) showing the position of the 238 site inside the
aerolysin lumen and the sensing mechanism to dA4. The electrochemical signals from dA4 with
WT (left) and K238Q (right) aerolysin are given. (C) The scatter plot shows the event distribution
of dX4 (X = A, C, T) with WT (left) and K238Q (right). Residence time (τ) is prolonged two
orders of magnitude, inducing a better separation (S) capability. The scatter plot shows the event
distribution of dX4 (X = A, C, T), which all can be discriminated by K238Q.
Go to:
Results
Assessment of the New K238Q Aerolysin Nanopore
We examined the sensing ability of K238Q with our model segment, dA4. The residence time of
the interaction is taken as an indicator which demonstrated two orders of magnitude increase
than the WT, reached 122 ± 19 ms at 120 mV bias voltage. The prolonged residence time reflects
that the dA4 and nanopore interaction is enhanced attributes to the glutamine (Q) replacement.
The residue current (Ires) of the interaction is also regarded. In the case of dA4 probed by
K238Q, the Ires is ca. 34.5 ± 0.5 pA (corresponds to Ires/I0 = 0.58) which is only slightly higher
than WT (Ires/I0 = 0.51). Through the test with the model segment, the strong interaction
between Glutamine (Q) and the nucleotide base reflects in the much longer residence time. The
performance of K238Q discriminating dA4 with small half-peak width (1.0 pA) suggesting good
nucleotide identifying ability with great potential.
Then, other homo-oligonucleotide, deoxycytosine dC4, and deoxythymine dT4 were added
successively to the dA4 measurement. Each substrate appeared as a distinguishable signature
signal, which suggests the single K238Q aerolysin nanopore is capable of identifying the dX4 (X
= A, C, T) from the mixed solution. The histogram of the residue currently show a clear Gaussian
distribution of the mixture of the dX4. Moreover, considering the peak distribution of Ires, the
adenine contributes the smallest value (34.5 ± 0.5 pA), then cytosine (40.1 ± 1.0 pA) and thymine
(42.5 ± 1.0 pA). The larger residue current corresponds to a larger steric exclusion. Comparing the
molecular weight of the four nucleoside bases (G < A < T < C), the steric effect of single nanopore
analysis however is in a different order (A < G < T < C). The result suggests the noncovalent
interaction is more pronounced than the steric effect interaction. From a structure inspection,
the replacement of the positively charged arginine (K) with uncharged glutamine (Q) makes the
lumen more negatively charged due to the unpairing with the neighboring E258 causing a
decreased energy barrier for the cations. Moreover, the glutamine interact strongly with
nucleotide base attributes to hydrogen bond as well as the van der Waals force.29 Typically,
glutamine (Q) interacts strongest with adenine, which in turn explains the best identification to
our model segment, dA4. Moreover, dA4, dC4, and dT4 have a separation (S) of SdA-dT = 3.67
pA and SdT-dC = 1.23 pA. The strongest noncovalent interaction between Q and dA provides the
best separation ability of K238Q in discriminating the homonucleotide segments.

Figure 2
Distribution of current and duration from the K238Q interaction with X4 (X = A, C, T). The color
bar illustrates the accumulation of each DNA segment. From the top figure, A4 was first
introduced, and then C4 and T4 were added successively with different peaks that correlate to
each segment. A histogram of the current distribution of the mixture was plotted in the bottom
figure to demonstrate the current distribution and separation ability of K238Q. The data were
acquired in 1.0 M KCl, 10 mM Tris, and 1.0 mM EDTA at pH 8.0 and +120 mV in the presence of
2.0 μM dX4.
Single Base Detection

WT aerolysin could discriminate homonucleotide segments, 5 ′-XA3 (X = A, G, T, C), in a mixture
solution,30 while the discrimination of heteronucleotides remains poor due to insufficient
current resolution. The K238Q aerolysin nanopore is evaluated to probe a single nucleotide base
in a heteronucleotide sequence. We then designed the heteronucleotide as 5 ′-XGTA (X = A, C, T,
G). The heteronucleotide segments were mixed sequentially and examined by K238Q, and the
results are given in FigureFigure33. The two current indicators, residue current and residence
time of the blockages, are examined. Regarding to residue current, the blockages show a clear
Ires, which is centered at 44.40 ± 0.22 pA, 46.16 ± 0.24 pA, and 46.78 ± 0.40 pA for AGTA, TGTA,
and CGTA respectively. The averaged residence time for AGTA has the largest duration, which is
49.42 ms, and TGTA and CGTA have a duration of 22.63 and 11.08 ms, respectively. The current
separation of the analytes is SAGTA-TGTA = 1.76 pA and STGTA-CGTA = 0.62 pA.

Figure 3
Distribution of current and duration from K238Q interaction with XGTA (X = A, C, T). The color
bar illustrates the accumulation of each DNA segment. From the top figure, AGTA was first
introduced, and then TGTA and CGTA were added successively with different peaks that
correlate to each segment. A histogram of the current distribution of the mixture was plotted at
the bottom figure to demonstrate the current distribution and separation ability of K238Q. The
data were acquired in 1.0 M KCl, 10 mM Tris, and 1.0 mM EDTA at pH 8.0 and +140 mV in the
presence of 2.0 μM XGTA.
To this end, we have shown that the K238Q could discriminate a single base difference in a
heteronucleotide mixture without labeling or an amplification process.
Single Base Modification Detection

The WT aerolysin has shown its capability to discriminate the single methylation group at the 5 ′
end of homonucleotide segments (i.e., CAAA versus mCAAA).18 Later, a mutant analogue
K238G31 enables the discrimination of methylation that occurred in the second position from
the 5′ end of a randomly designed heteronucleotide segment (i.e., ACGA vs AmCGA). However,
other types of epigenetic modifications could not be properly discriminated due to poor
sensitivity. We herein evaluate the amperometric resolution of K238Q in sensing the three types
of DNA lesions (i.e., oG, I, mC) occurring in a heteronucleotide segment.
The nucleotide, 5′-ACGA, as the model segment, is directly read by the K238Q. As examples of
epigenetic modification, the guanine (G) was modified into I or oG, respectively. Moreover,
methylation was introduced into the cytosine (C). The modified model nucleotides are denoted
as 5′-ACIA, 5′-ACoGA, and 5′-AmCGA. As expected, the K238Q could discriminate each type of
lesion from each other as demonstrated in FigureFigure33a. Following the mass increase order of
5′-ACIA, 5′-ACGA, 5′-AmCGA, 5′-ACoGA, the histogram of the residue current was centered at
59.32 ± 0.44 pA, 58.61 ± 0.42 pA, 57.28 ± 0.35 pA, and 60.30 ± 0.49 pA respectively. The residence
times are averaged at 11.37, 15.14, 30.13, and 12.07 ms. Neither the current nor the residence time
matches the order of mass magnitude; moreover, the modification on the single nucleotide base
makes ca. 20 Da difference in molecule weight, which is less than 2% of the model nucleotide. It
is assumed that the separation of different types of epigenetic modification is achieved
predominantly from the noncovalent interaction between nucleotide base and the sensing
region rather than simply the steric effect which is negligible. Regarding the separation
capability of K238Q in lesion detection, SAmCGA-ACGA = 1.33 pA, SACGA-ACIA = 0.71 pA, and
SACIA-ACoGA = 0.98 pA, which are much better than the K238G (data not shown). However, the
TGTA and GGTA could not be discriminated by this nanopore even under strong osmotic
pressure (Figure S4), which needs further improvements. In order to prove that the superior
separation capability comes from the noncovalent interaction, the methylcytosine (mC) at
different positions on a nucleotide segments is designed and examined by the K238Q.
Following the previous model segment, 5′-ACGA, another CG pair is introduced making a longer
model nucleotide 5′-ACGCGA. The cytosine at both second and fourth positions are methylated.
Since the weight of the methylation group is negligible and the nucleotide translocates linearly
across the sensing region, the longer model nucleotide is modified into 5 ′-AmCGCGA and 5 ′-
AmCGmCGA. The mixture is probed by K238Q, and the residue current as well as residence time
are adopted to analyze the blockages. The results are given inFigureFigure55 showing the
powerful capability of K238Q in discriminating methylcytosine at different positions of a
nucleotide segment. Such outcome could not be achieved by the other aerolysin nanopores
especially under label-free, heterocomposition, and mixed condition.

Figure 5
Distribution of current and duration from K238Q interaction with ACGCGA and the modified
DNA segments. The color bar illustrates the accumulation of each DNA segment. From the top
figure, AmCGmCGA was first introduced, and then AmCGCGA and ACGCGA were added
successively with different peaks raised correlate to each segment. A histogram of the current
distribution of the mixture was plotted in the bottom panel to demonstrate the current
distribution and separation ability of K238Q. The data were acquired in 1.0 M KCl, 10 mM Tris,
and 1.0 mM EDTA at pH 8.0 and +140 mV in the presence of 2.0 μM ACGCGA and the modified
segments.

Figure 4
Distribution of current and duration from K238Q interaction with ACGA and the modified
segments. The color bar illustrates the accumulation of each DNA segment. From the top figure,
AmCGA was first introduced, and then ACGA, ACIA, and ACoGA were added successively with
different peaks that correlate to each segment. A histogram of the current distribution of the
mixture was plotted in the panel to demonstrate the current distribution and separation ability
of K238Q. The data were acquired in 1.0 M KCl, 10 mM Tris, and 1.0 mM EDTA at pH 8.0 and
+180 mV in the presence of 2.0 μM ACGA and the modified segments.
It is noteworthy that the previous 5′-ACGA model showed the mass contribution is negligible,
and the trend matches well with the noncovalent interaction from different position. More
specifically, the outcome demonstrated that the current distribution of detected ACGCGA,
AmCGCGA, and AmCGmCGA are centered at 36.36 ± 0.58 pA, 35.36 ± 0.52 pA, and 33.42 ± 0.49
pA respectively. The residence times are averaged 39.7, 26.1, and 21.8 ms, respectively. Regarding
the separation ability of K238Q to the modified base at different positions,
SAmCGmCGA-AmCGCGA = 1.36 pA and SAmCGCGA-ACGCGA = 0.61 pA. On the basis of the
previous oligonucleotide interaction with K238Q, the presence of adenine interacts strongly with
Q, which provides the longest residence time, while cytosine interacts the weakest with Q and
provides a relatively short residence time. Moreover, the nucleotide containing adenine gives the
largest separation than the other segments. According to this correlation, we could assume that
the glutamine (Q) interacts more strongly with methylcytosine (mC) than cytosine (dC). Even
the mC position and quantification with glutamine (Q) could be measured or probed in the
aerolysin nanopore lumen with the specified design.
Go to:
Conclusion
The K238Q aerolysin nanopore achieved discrimination of different types of epigenetic modified
nucleotide at different positions with no labeling and amplification. The point mutation K238Q
prolongs the nucleotide residence inside the nanopore lumen, thus enhancing the noncovalent
interaction to be distinguishable.
We first probed homonucleotide, and taking the example of dA4, the residence time is
prolonged two orders of magnitude than WT. More importantly, neither of the two important
parameters, residue current and residence time, showed a correlation with the mass
contribution, or steric effect. To prove this, we designed a heteronucleotide with a single base
and even side chain difference. The K238Q well separated the mixture of these samples, again,
not following the steric trend. To this point, the epigenetic modifications contribute less than 2%
of the weight, and consequently, we assume the mass contribution is not dominant in our
nanopore analysis and could be neglected. Then, a longer model nucleotide with methylated
cytosine at different positions is introduced for the purpose of single nucleotide base precise
probing. Both the current and residence time decrease with the increase in the number of
methylation sites at different positions. We finally could conclude that the noncovalent
interaction is sensed and utilized for the separation of different types of epigenetic modifications
at different positions.
Taking advantage of the superior sensing ability for the epigenetic modification by K238Q, the
application could be applied to real-time monitoring the enzyme cleavage process,8 even
achieving quantification of different types of damaged nucleotide bases. The analysis of a longer
nucleotide chain could be obtained by optimizing the measuring condition (e.g., LiCl, MgCl2).32
Better current separation (S) could be achieved by applying an asymmetric salt concentration
gradient. By controlling the amino acid composition at the sensing region, nucleotide bases and
modified bases interaction with amino acid could be predicted, and even the interaction
between amino acid groups from a peptide could be mapped, due to its confined space.33−36
Moreover, the parallelization and miniaturization of the nanopore based single molecule
label-free detection method could be applied to real sample diagnoses, with the most prominent
example being the recognition of a conformation change of a homonucleotide with its
application.37,38
Go to:
Materials and Methods
All model nucleotides and modified nucleotides were synthesized and purified by Sangon
Biotech Co., Ltd. (Shanghai, China). Chemical compounds such as KCl (≥99%) and decane
(anhydrous, ≥99%) were purchased from Sigma-Aldrich Co., Ltd. (St. Louis, MO, USA).
Phosphor lipid (1,2-diphytanoyl-snglycero-3-phosphocholine) (powder, ≥99%) was obtained
from Avanti Polar Lipids, Inc. (Alabaster, AL, USA). The other chemical compounds were
obtained from Aladine (Shanghai, China). Proaerolysin was obtained from Escherichia coli
according our previous reports.21,22 For experimental and characterization detail, please refer to
Supporting Information. The membrane formation and single nanopore experiments were
performed identical to the standard protocol.39 Single channel current was obtained from a
patch clamp amplifier (Axon 200B) and digitized by an A/D converter (DigiData 1440A),
Molecular Devices, Sunnyvale, CA, USA. All the data points were sampled at 100 kHz and filtered
at 5 kHz. The data analysis procedure follows the previous work.30
Go to:
Supporting Information Available
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acscentsci.9b01129.
Detailed K238Q purification process and single-channel electrochemical methodologies. Figure
S1 shows the sequencing spectra of the K238Q plasmid. Figure S2 shows the SDS page
characterization of K238Q and WT aerolysin. Figure S3 gives the I–V behavior of K238Q and WT
aerolysin. Figure S4 shows discrimination of XGTA by K238Q under asymmetry conditions (PDF)
Go to:
Author Contributions
# J.W., M.-Y. L., and J. Y. contributed equally. Y-L.Y. and Y-T.L. initiated the project. J.W., M-Y.L.,
and J.Y. performed the experiments and data analysis. Y-Q.W., X-Y.W., and J. H. mutated the
protein. J. W., M-Y. L., J. Y., Y-L. Y., and Y-T. L. were involved in the manuscript writing. The
manuscript was written through contributions of all authors.
Go to:
Notes
This research was supported by National Natural Science Foundation of China (21834001 and
61871183, 61901171). Y.-L.Y. is sponsored by National Ten Thousand Talent Program for Young
Top-Notch Talent. J.W. is sponsored by the Shanghai Sailing Program (19YF1410500) and China
Postdoctoral Science Foundation (2019M651412, 2019T120309).
Go to:
Notes
The authors declare no competing financial interest.
Go to:
Supplementary Material
oc9b01129_si_001.pdf(2.4M, pdf )
Go to:
References
Cadet J.; Poulsen H. Measurement of oxidatively generated base damage in cellular DNA and
urine. Free Radical Biol. Med. 2010, 48 (11), 1457.10.1016/j.freeradbiomed.2010.03.004. [PubMed]
Wu H.; Zhang Y. Reversing DNA methylation: mechanisms, genomics, and biological functions.
Cell 2014, 156 (1–2), 45.10.1016/j.cell.2013.12.019. [PMC free article] [PubMed] [CrossRef ] [Google
Scholar]
Kasianowicz J. J.; Brandin E.; Branton D.; Deamer D. W. Proc. Natl. Acad. Sci. U. S. A. 1996, 93,
13770–13773. 10.1073/pnas.93.24.13770. [PMC free article] [PubMed] [CrossRef ] [Google Scholar]
Lieberman K. R.; Cherf G. M.; Doody M. J.; Olasagasti F.; Kolodji Y.; Akeson M. Processive
replication of single DNA molecules in a nanopore catalyzed by phi29 DNA polymerase. J. Am.
Chem. Soc. 2010, 132 (50), 17961.10.1021/ja1087612. [PMC free article] [PubMed] [CrossRef ]
[Google Scholar]
Rincon-Restrepo M.; Mikhailova E.; Bayley H.; Maglia G. Controlled translocation of individual
DNA molecules through protein nanopores with engineered molecular brakes. Nano Lett. 2011, 11
(2), 746.10.1021/nl1038874. [PMC free article] [PubMed] [CrossRef ] [Google Scholar]
Butler T. Z.; Pavlenok M.; Derrington I. M.; Niederweis M.; Gundlach J. H. Single-molecule DNA
detection with an engineered MspA protein nanopore. Proc. Natl. Acad. Sci. U. S. A. 2008, 105
(52), 20647.10.1073/pnas.0807514106. [PMC free article] [PubMed] [CrossRef ] [Google Scholar]
Soskine M.; Biesemans A.; Moeyaert B.; Cheley S.; Bayley H.; Maglia G. An engineered ClyA
nanopore detects folded target proteins by selective external association and pore entry. Nano
Lett. 2012, 12 (9), 4895.10.1021/nl3024438. [PMC free article] [PubMed] [CrossRef ] [Google
Scholar]
Goyal P.; Krasteva P. V.; Van Gerven N.; Gubellini F.; Van den Broeck I.; Troupiotis-Tsailaki A.;
Jonckheere W.; Pehau-Arnaudet G.; Pinkner J. S.; Chapman M. R.; Hultgren S. J.; Howorka S.;
Fronzes R.; Remaut H. Structural and mechanistic insights into the bacterial amyloid secretion
channel CsgG. Nature 2014, 516 (7530), 250.10.1038/nature13768. [PMC free article] [PubMed]
Cao C.; Ying Y.-L.; Hu Z.-L.; Liao D.-F.; Tian H.; Long Y.-T. Discrimination of oligonucleotides of
different lengths with a wild-type aerolysin nanopore. Nat. Nanotechnol. 2016, 11 (8),
713.10.1038/nnano.2016.66. [PubMed] [CrossRef ] [Google Scholar]
Bräuning B.; Bertosin E.; Praetorius F.; Ihling C.; Schatt A.; Adler A.; Richter K.; Sinz A.; Dietz H.;
Groll M. Structure and mechanism of the two-component α-helical pore-forming toxin YaxAB.
Nat. Commun. 2018, 9 (1), 1806.10.1038/s41467-018-04139-2. [PMC free article] [PubMed]
Huang G.; Voet A.; Maglia G. FraC nanopores with adjustable diameter identify the mass of
opposite-charge peptides with 44 Da resolution. Nat. Commun. 2019, 10 (1),
835.10.1038/s41467-019-08761-6. [PMC free article] [PubMed] [CrossRef ] [Google Scholar]
Wang J.; Bafna J.; Bhamidimarri S.-P.; Winterhalter M. Small molecule permeation across
membrane channels: Chemical modification to quantify transport across OmpF. Angew. Chem.,
Int. Ed. 2019, 58, 4737.10.1002/anie.201814489. [PubMed] [CrossRef ] [Google Scholar]
Podobnik M.; Savory P.; Rojko N.; Kisovec M.; Wood N.; Hambley R.; Pugh J.; Wallace E. J.;
McNeill L.; Bruce M.; Liko I.; Allison T. M.; Mehmood S.; Yilmaz N.; Kobayashi T.; Gilbert R. J. C.;
Robinson C. V.; Jayasinghe L.; Anderluh G. Crystal structure of an invertebrate cytolysin pore
reveals unique properties and mechanism of assembly. Nat. Commun. 2016, 7,
11598.10.1038/ncomms11598. [PMC free article] [PubMed] [CrossRef ] [Google Scholar]
van den Berg B.; Bhamidimarri S. P.; Prajapati J. D.; Kleinekathöfer U.; Winterhalter M.
Outer-membrane translocation of bulky small molecules by passive diffusion. Proc. Natl. Acad.
Sci. U. S. A. 2015, 112 (23), E2991.10.1073/pnas.1424835112. [PMC free article] [PubMed] [CrossRef ]
[Google Scholar]
Locher K. P.; Rees B.; Koebnik R.; Mitschler A.; Moulinier L.; Rosenbusch J. P.; Moras D.
Transmembrane signaling across the ligand-gated FhuA receptor: crystal structures of free and
ferrichrome-bound states reveal allosteric changes. Cell 1998, 95 (6),
771.10.1016/S0092-8674(00)81700-6. [PubMed] [CrossRef ] [Google Scholar]
Schibel A. E. P.; An N.; Jin Q.; Fleming A. M.; Burrows C. J.; White H. S. Nanopore detection of
8-Oxo-7,8-dihydro-2 ′-deoxyguanosine in immobilized single-stranded DNA via adduct
formation to the DNA damage site. J. Am. Chem. Soc. 2010, 132 (51), 17992.10.1021/ja109501x.
[PMC free article] [PubMed] [CrossRef ] [Google Scholar]
Jin Q.; Fleming A. M.; Johnson R. P.; Ding Y.; Burrows C. J.; White H. S. Base-excision repair
activity of uracil-DNA glycosylase monitored using the latch zone of alpha-Hemolysin. J. Am.
Chem. Soc. 2013, 135 (51), 19347.10.1021/ja410615d. [PMC free article] [PubMed] [CrossRef ]
[Google Scholar]
Iacovache I.; De Carlo S.; Cirauqui N.; Dal Peraro M.; van der Goot F. G.; Zuber B. Cryo-EM
structure of aerolysin variants reveals a novel protein fold and the pore-formation process. Nat.
Commun. 2016, 7, 12062.10.1038/ncomms12062. [PMC free article] [PubMed] [CrossRef ] [Google
Scholar]
Yu J.; Cao C.; Long Y. T. Selective and sensitive detection of methylcytosine by Aerolysin
nanopore under serum condition. Anal. Chem. 2017, 89 (21), 11685.10.1021/acs.analchem.7b03133.
[PubMed] [CrossRef ] [Google Scholar]
Cao C.; Li M.-Y.; Cirauqui N.; Wang Y.-Q.; Dal Peraro M.; Tian H.; Long Y.-T. Mapping the
sensing spots of aerolysin for single oligonucleotides analysis. Nat. Commun. 2018, 9 (1),
2823.10.1038/s41467-018-05108-5. [PMC free article] [PubMed] [CrossRef ] [Google Scholar]
Ying Y.-L.; Long Y.-T. Nanopore-based single-biomolecule interfaces: From information to
knowledge. J. Am. Chem. Soc. 2019, 141 (40), 15720.10.1021/jacs.8b11970. [PubMed] [CrossRef ]
[Google Scholar]
Wang Y..-Q.; Cao C.; Ying Y.-L.; Li S.; Wang M.; Huang J.; Long Y.-T. Rationally designed sensing
selectivity and sensitivity of an aerolysin nanopore via site-directed mutagenesis. ACS Sens. 2018,
3 (4), 779.10.1021/acssensors.8b00021. [PubMed] [CrossRef ] [Google Scholar]
Wang Y.-Q.; Li M.-Y.; Qiu H.; Cao C.; Wang M.-B.; Wu X.-Y.; Huang J.; Ying Y.-L.; Long Y.-T.
Identification of essential sensitive regions of the aerolysin nanopore for single oligonucleotide
analysis. Anal. Chem. 2018, 90 (13), 7790.10.1021/acs.analchem.8b01473. [PubMed] [CrossRef ]
[Google Scholar]
Wu X.-Y.; Wang M.-B.; Wang Y.-Q.; Li M.-Y.; Ying Y.-L.; Huang J.; Long Y.-T. Precise construction
and tuning of an aerolysin single-biomolecule interface for single molecule sensing. Chin. Chem.
Soc. 2019, 1 (3), 304. [Google Scholar]
Li M.-Y.; Wang Y.-Q.; Lu Y.; Ying Y.-L.; Long Y. Single molecule study of hydrogen bond
interactions between single oligonucleotide and aerolysin sensing interface. Front. Chem. 2019,
7, 528.10.3389/fchem.2019.00528. [PMC free article] [PubMed] [CrossRef ] [Google Scholar]
Lu Y.; Wu X.-Y.; Ying Y.-L.; Long Y.-T. Simultaneous single-molecule discrimination of cysteine
and homocysteine with a protein nanopore. Chem. Commun. 2019, 55 (63),
9311.10.1039/C9CC04077C. [PubMed] [CrossRef ] [Google Scholar]
Wang J.; Li M.-Y.; Yang J.; Wu X.-Y.; Huang J.; Ying Y.-L.; Long Y.-T. Label-free detection of solo
oligonucleotide lesion based on site-direct mutagenized aerolysin nanopore. Biophys. J. 2019, 116
(3), 148a.10.1016/j.bpj.2018.11.822. [CrossRef ] [Google Scholar]
Li M.-Y.; Wang Y.-Q.; Ying Y.-L.; Long Y.-T. Revealing the transient conformations of a single
flavin adenine dinucleotide using an aerolysin nanopore. Chem. Sci. 2019, 10,
10400.10.1039/C9SC03163D. [CrossRef ] [Google Scholar]
Hu Z. L.; Li Z. Y.; Ying Y. L.; Zhang J.; Cao C.; Long Y. T.; Tian H. Real-time and accurate
identification of single oligonucleotide photoisomers via an aerolysin nanopore. Anal. Chem.
2018, 90 (7), 4268.10.1021/acs.analchem.8b00096. [PubMed] [CrossRef ] [Google Scholar]
Luscombe N. M.; Laskowski R. A.; Thornton J. M. Amino acid–base interactions: a
three-dimensional analysis of protein–DNA interactions at an atomic level. Nucleic Acids Res.
2001, 29 (13), 2860.10.1093/nar/29.13.2860. [PMC free article] [PubMed] [CrossRef ] [Google
Scholar]
Cao C.; Yu J.; Li M.-Y.; Wang Y.-Q.; Tian H.; Long Y.-T. Direct readout of single nucleobase
variations in an oligonucleotide. Small 2017, 13 (44), 1702011.10.1002/smll.201702011. [PubMed]
Wang Y. Q.; Li M. Y.; Qiu H.; Cao C.; Wang M. B.; Wu X. Y.; Huang J.; Ying Y. L.; Long Y. T.
Identification of essential sensitive regions of the aerolysin nanopore for single oligonucleotide
analysis. Anal. Chem. 2018, 90 (13), 7790.10.1021/acs.analchem.8b01473. [PubMed] [CrossRef ]
[Google Scholar]
Hu Z.-L.; Li M.-Y.; Liu S.-C.; Ying Y.-L.; Long Y.-T. A lithium-ion-active aerolysin nanopore for
effectively trapping long single-stranded DNA. Chem. Sci. 2019, 10 (2), 354.10.1039/C8SC03927E.
[PMC free article] [PubMed] [CrossRef ] [Google Scholar]
Ying Y.-L.; Zhang J.; Gao R.; Long Y.-T. Nanopore-based sequencing and detection of nucleic
acids. Angew. Chem., Int. Ed. 2013, 52 (50), 13154.10.1002/anie.201303529. [PubMed] [CrossRef ]
[Google Scholar]
Ying Y.-L.; Cao C.; Hu Y.-X.; Long Y.-T. A single biomolecule interface for advancing the
sensitivity, selectivity and accuracy of sensors. Nat. Sci. Rev. 2018, 5 (4), 450.10.1093/nsr/nwy029.
Wang J.; Yang J.; Ying Y.-L.; Long Y.-T. Nanopore-based confined spaces for single-molecular
analysis. Chem. - Asian J. 2019, 14 (3), 389.10.1002/asia.201801648. [PubMed] [CrossRef ] [Google
Scholar]
Gu Z.; Ying Y.-L.; Long Y.-T. Nanopore sensing system for high-throughput single molecular
analysis. Sci. China: Chem. 2018, 61 (12), 1483.10.1007/s11426-018-9312-3. [CrossRef ] [Google
Scholar]
Guo J.; Chen Y.; Jiang Y.; Ju H. Polyadenine-modulated dna conformation monitored by
surface-enhanced raman scattering (SERS) on multibranched gold nanoparticles and its sensing
application. Chem. - Eur. J. 2017, 23 (39), 9332.10.1002/chem.201700883. [PubMed] [CrossRef ]
[Google Scholar]
Abbassi-Daloii T.; Yousefi S.; de Klerk E.; Grossouw L.; Riaz M.; t Hoen P. A. C.; Raz V. An alanine
expanded PABPN1 causes increased utilization of intronic polyadenylation sites. NPJ. Aging and
Mechanisms of Disease 2017, 3, 6.10.1038/s41514-017-0007-x. [PMC free article] [PubMed]
Cao C.; Liao D.-F.; Yu J.; Tian H.; Long Y.-T. Construction of an aerolysin nanopore in a lipid
bilayer for single-oligonucleotide analysis. Nat. Protoc. 2017, 12 (9), 1901.10.1038/nprot.2017.077.
[PubMed] [CrossRef ] [Google Scholar]
Articles from ACS Central Science are provided here courtesy of American Chemical Society
Formats:
Article | PubReader | ePub (beta) | PDF (3.5M) | Citation
Share
Share on Facebook FacebookShare on Twitter TwitterShare on Google Plus Google+
Save items
View more options
Similar articles in PubMed
Identification of Essential Sensitive Regions of the Aerolysin Nanopore for Single
Oligonucleotide Analysis.
[Anal Chem. 2018]
A General Strategy of Aerolysin Nanopore Detection for Oligonucleotides with the Secondary
Structure.
[Small. 2018]
Biological Nanopores: Confined Spaces for Electrochemical Single-Molecule Analysis.
[Acc Chem Res. 2018]
Aerolysin, a Powerful Protein Sensor for Fundamental Studies and Development of Upcoming
Applications.
[ACS Sens. 2019]
The aerolysin nanopore: from peptidomic to genomic applications.
[Nanoscale. 2018]
See reviews...
See all...
Links
PubMed
Taxonomy
Recent Activity
ClearTurn Off
Direct Quantification of Damaged Nucleotides in Oligonucleotides Using an Aeroly...
Molecule Interface
Molecular and Crystal Features of Thermostable Energetic Materials: Guidelines f...
GTP Cyclohydrolase 1/Tetrahydrobiopterin Counteract Ferroptosis through Lipid Re...
GTP Cyclohydrolase 1/Tetrahydrobiopterin Counteract Ferroptosis through Lipid Remodeling
An Activity-Based Methionine Bioconjugation Approach To Developing Proximity-Act...
An Activity-Based Methionine Bioconjugation Approach To Developing Proximity-Activated
Imaging Reporters
Programmable Bivalent Peptide–DNA Locks for pH-Based Control of Antibody Activit...
Programmable Bivalent Peptide–DNA Locks for pH-Based Control of Antibody Activity
See more...
Support CenterSupport Center
External link. Please review our privacy policy.
NLMNIHDHHSUSA.gov
National Center for Biotechnology Information, U.S. National Library of Medicine
8600 Rockville Pike, Bethesda MD, 20894 USA
Policies and Guidelines | Contact

Penfactual

Загружено:

Сведения о документе

Оригинальное название

Авторское право

Доступные форматы

Поделиться этим документом

Поделиться или встроить документ

Параметры публикации

Этот документ был вам полезен?

Это неприемлемый материал?

Авторское право:

Доступные форматы

Penfactual

Загружено:

Авторское право:

Доступные форматы

NCBINCBI Logo

Skip to main content

Get the latest public health information from CDC: https://www.coronavirus.gov

Get the latest research information from NIH: https://www.nih.gov/coronavirus

Find NCBI SARS-CoV-2 literature, sequence, and clinical content:

Journal ListACS Cent Sciv.6(1); 2020 Jan 22PMC6978839

An external ﬁle that holds a picture, illustration, etc.

An external ﬁle that holds a picture, illustration, etc.

By analyzing the crystallographic data of 60 reported EMs and conducting high-throughput

By deducing common parameters and features (explosives thermostability general

An external ﬁle that holds a picture, illustration, etc.

The second energetic compound, 5,5 ′-bis(3,5-dinitro-1H-pyrazol-4-yl)-2,2 ′-bi(1,3,4-oxadiazole)

An external ﬁle that holds a picture, illustration, etc.

An external ﬁle that holds a picture, illustration, etc.

An external ﬁle that holds a picture, illustration, etc.

An external ﬁle that holds a picture, illustration, etc.

An external ﬁle that holds a picture, illustration, etc.

An external ﬁle that holds a picture, illustration, etc.

An external ﬁle that holds a picture, illustration, etc.

Physicochemical and Energetic Properties

Energetic Evaluation and Detonation Experiments

An external ﬁle that holds a picture, illustration, etc.

An external ﬁle that holds a picture, illustration, etc.

Ab Initio Molecular Dynamics Calculations

An external ﬁle that holds a picture, illustration, etc.

An external ﬁle that holds a picture, illustration, etc.

An external ﬁle that holds a picture, illustration, etc.

An external ﬁle that holds a picture, illustration, etc.

An external ﬁle that holds a picture, illustration, etc.

Molecular Level Correlations

An external ﬁle that holds a picture, illustration, etc.

Therefore, we introduced two criteria to examine a hypothesis of the bridge bonds

FigureFigure2020c presents a percentage distribution of thermostable EMs among all examined

An external ﬁle that holds a picture, illustration, etc.

Crystal Level Correlations

An external ﬁle that holds a picture, illustration, etc.

As in the above-mentioned case of no obvious correlation between the molecular weight of

Hydrogen bonding is known to be an important factor governing EM’s reactivity to external

An external ﬁle that holds a picture, illustration, etc.

An external ﬁle that holds a picture, illustration, etc.

Video S1: detonation experiment of HL7 (ZIP)

Get the latest public health information from CDC: https://www.coronavirus.gov

Get the latest research information from NIH: https://www.nih.gov/coronavirus

Find NCBI SARS-CoV-2 literature, sequence, and clinical content:

Journal ListACS Cent Sciv.6(1); 2020 Jan 22PMC6978832

An external ﬁle that holds a picture, illustration, etc.

An external ﬁle that holds a picture, illustration, etc.

Single Base Detection

An external ﬁle that holds a picture, illustration, etc.

Single Base Modiﬁcation Detection

An external ﬁle that holds a picture, illustration, etc.

An external ﬁle that holds a picture, illustration, etc.

Вам также может понравиться