The structural aspects of the transformation of 3-nitroisoxazoline-2-oxide to 1-aza-2,8-dioxabicyclo[3.3.0]octane derivatives: Experimental and MEDT theoretical study

Article abstract of DOI:10.1016/j.molstruc.2019.04.061

Reaction of 3-nitroisoxazoline-2-oxide with monosubstituted ethenes, first time documented fifty years ago, have been reviewed. Structures of phenyl and cyano derivatives of 1-aza-2,8-dioxabicyclo[3.3.0]octane produced in [3 + 2]cycloaddition (32CA)betwee

Full text of DOI:10.1016/j.molstruc.2019.04.061

Accepted Manuscript
The structural aspects of the transformation of 3-nitroisoxazoline-2-oxide to 1-aza-2,8-
dioxabicyclo[3.3.0]octane derivatives: Experimental and MEDT theoretical study
Przemysław Woliński, Agnieszka Kącka-Zych, Błażej Dziuk, Krzysztof Ejsmont,
Agnieszka Łapczuk-Krygier, Ewa Dresler
PII:
S0022-2860(19)30462-4
DOI:
https://doi.org/10.1016/j.molstruc.2019.04.061
MOLSTR 26433
Reference:
To appear in: Journal of Molecular Structure
Received Date: 11 March 2019
Revised Date: 12 April 2019
Accepted Date: 15 April 2019
Please cite this article as: Przemysł. Woliński, A. Kącka-Zych, Błż. Dziuk, K. Ejsmont, A. Łapczuk-
Krygier, E. Dresler, The structural aspects of the transformation of 3-nitroisoxazoline-2-oxide to 1-
aza-2,8-dioxabicyclo[3.3.0]octane derivatives: Experimental and MEDT theoretical study, Journal of
Molecular Structure (2019), doi: https://doi.org/10.1016/j.molstruc.2019.04.061.
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ACCEPTED MANUSCRIPT
The structural aspects of the transformation of 3-nitroisoxazoline-2-oxide
to 1-aza-2,8-dioxabicyclo[3.3.0]octane derivatives: experimental and MEDT
theoretical study
Przemysław Woliński(1), Agnieszka Kącka-Zych*(1), Błażej Dziuk(2),
Krzysztof Ejsmont(2), Agnieszka Łapczuk-Krygier(1), Ewa Dresler(3)
1Department of Organic Chemistry, Cracow University of Technology, Warszawska 24, 31-155, Cracow, Poland
*Corresponding author: akacka@chemia.pk.edu.pl
2Faculty of Chemistry, University of Opole, Oleska 48, 45-052 Opole, Poland
3Institute of Heavy Organic Synthesis „Blachownia", Energetyków Str. 9, 47-225 Kędzierzyn-Koźle, Poland
ABSTRACT
Reaction of 3-nitroisoxazoline-2-oxide with monosubstituted ethenes, first time
documented fifty years ago, have been reviewed. Structures of phenyl and cyano derivatives
of 1-aza-2,8-dioxabicyclo[3.3.0]octane produced in [3+2] cycloaddition (32CA) between
styrene and acrylonitrile with 3-nitroisoxazoline-2-oxide were determined through single
crystal XRD analysis. The molecular mechanism of the title 32CA has been also analyzed
within the Molecular Electron Density Theory (MEDT) based on the M06-2X(PCM)/6-
311+G(d,p) calculations.
KEYWORDS: 3-nitroisoxazoline-2-oxide; (3+2) cycloaddition; Molecular Electron Density
Theory; Electron Localization Function; XRD analysis
GRAPHICAL ABSTRACT

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1. INTRODUCTION
Nitronates formally are esters of nitronic acids -aci form of aliphatic nitro compounds.
Thanks to their unique build they possess 1,3-dipolar character allowing them to participate in
32CA. Actually the relatively large library of both acyclic and cyclic nitronates is available.
Isoxazoline-2-oxides are example of cyclic nitronates which should be classified as zw-type
three atom components (TACs) [1] and are useful in synthesis of 1-aza-2,8-
dioxabicyclo[3.3.0]octanes through 32CA to substituted ethenes. Particularly, reaction of 3-
nitroisoxazoline-2-oxide (1) with styrene (2a) has been first carried out half century ago [2].
This reaction theoretically leads to four regio- and stereoisomeric 3(4)-exo(endo)-R-5-nitro-1-
aza-2,8-dioxabicyclo[3.3.0]octanes (3a,b - 6a,b) (Figure 1).
Figure 1. Possible products of 32CA 3-nitroisoxazoline N-oxide with monosubstituted
ethenes.
Tartakovskii et al. [2] investigated title reactions and they isolated the reaction product
from the postreaction mixture, but not diagnosed its individuality. Next, they proposed
structure based purely on elemental analysis and intuition because of apparatus restrictions.
Therefore, the question on the real structure of adduct derived in reaction between 3-
nitroisoxazoline-2-oxide (1) with monosubstituted, simple ethene derivatives is still actual and
require a deeper study. Based on the issues described above, we analyzed in the detail
reactions of 3-nitroisoxazoline-2-oxide (1) with styrene (2a) and acrylonitrile (2b) as model
ethane derivatives. This is a continuation of our comprehensive, theoretical [3-6] and
experimental [5-8] study about regio-, stereochemical aspects and molecular mechanism of
32CA involving nitro substituted components.
2. RESULTS AND DISCUSSION
Synthesis and spectral characteristics

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We started our work from synthesis of 1,3-dipolar component of studied reaction. To
synthesize 3-nitroisoxazoline-2-oxide (1) 1-bromo-3,3-dinitropropane is needed (Figure 2). It
can be prepared only through use of organomercuric compounds. Apart from their high
toxicity, low stability causes the need to perform every step of the synthesis immediately. In
the first step a flow of ethene is passed through an ethanolic solution of
bis(trinitromethyl)mercury until no more of bis(3,3,3-trinitropropyl)mercury precipitate is
formed [9]. Filtered off and dried product is then dissolved in methanol and reacted with
hydroxylamine to remove two isolated nitro groups. Precipitated potassium salt of bis(3,3-
dinitropropyl)mercury is filtered off, vacuum dried and added to 2N solution of hydrochloric
acid [10]. Produced bis(3,3-dinitropropyl)mercury is then brominated with bromine in
tetrachloromethane in presence of catalytic amount of benzoyl peroxide. After filtering off
precipitated mercuric bromide the 1-bromo-3,3-dinitropropane is then separated from
postreaction mixture through vacuum fractional distillation [11]. In the last step the 1-bromo-
3,3-dinitropropane is treated with aqueous solution of potassium acetate. In such environment
it undergoes intramolecular O-alkylation to form 3-nitroisoxazoline-2-oxide [12].
Figure 2. Synthesis of 3-nitroisoxazoline-2-oxide (1).
Based on the pure and individual 3-nitroisoxazoline-2-oxide (1) we started our tests
with choosing of reactions conditions involving ethene derivatives 2a and 2b. It was found,
that under the convenient conditions, the synthesis proceeds in anhydrous ethanol at room
temperature and full conversion of 1 is achieved after 5 to 7 days. Crude products, purified by
fractional crystallization from anhydrous ethanol, and its individuality has been confirmed by
TLC and HPLC tests. In both cases, single adduct was isolated from the reaction mixture.

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For resolving of the structure of obtained adducts, we performed comprehensive study,
started from data of CHN elemental analysis. It was found, that was convergent expected for
cycloadducts shown on Figure 1.
The IR spectra of the reaction products show the absorption bands, which confirm the
presence of nitro group. The NO2 stretch and bend frequencies are located at 1553 cm-1 and
1351 cm-1 and 1553, 1354 respectively for 3a and 3b. Besides the above-mentioned NO2
vibrations, there are also the most prominent O-N-O peaks within the
isoxazolidinoisoxazolidine ring at 1033 cm-1 and CH-stretch in the phenyl ring at 3029 and
2987 cm-1 and CH-bent 702 and 763 cm-1. However, there are only very weak band 2245 cm-1
confirming the presence of nitrile group of 3b. From the literature data it is known that this
band can be very weak or quite invisible in a situation where the carbon at which the CN
group is located is connected to an exocyclic oxygen atom [13]. This may suggest that the
nitrile group is located on the C3-position of the heterocyclic system. This implies that the
analyzed product could be adduct 3 or 4. However the IR spectrum does not allow to resolve
this problem unambiguously. Therefore, further analysis of the isolated compound was
necessary. Further information about the structure of the isolated compounds was obtained
1
from the H NMR spectra. In particular, the isoxazolidinoisoxazolidine system in 3a has
two five-membered rings — each with distinctive proton environments and two isolated spin
systems ABX (including H4, H4’,H3 protons) and ABXY (including H6, H6’, H7 and H7’).
So, two geminal proton (H4 and H4’) signals are in a stronger field (δ = 3.42 – 2.26
ppm), whereas the proton H3 is in a relatively weaker field (δ = 5.39 ppm) due to near
present oxygen atom and phenyl ring. Vicynal coupling constant are equal to 10.9 Hz and 5.4
Hz for relation H3–H4 and respectively H3–H4’. This confirms cis relative configuration of
H3 and H4 protons, and trans relations of H3–H4’. Next, two geminal proton H7 and H7’
signals are in a stronger field (δ = 4.43 ppm and δ = 4.30 ppm, respectively). The respective
values of coupling constants are equal: JH7-H7’= 14.5Hz, JH6-H7= 7.3Hz and JH6’-H7= 5.4 Hz. On
the other hand, the signals of protons H6 and H6’ are in weaker field (2.90 and 2.71). The
respective value of coupling constants are equal: JH6-H6’= 13.3Hz, JH6’-H7=5.4 Hz. The
multiplets corresponding to the five aryl protons are shifted in the evidently weakest field and
13
appear at δ = 7.47 – 7.34 ppm. In C-NMR spectrum, signals of -CH2- carbon atoms were
found at 67.9 (C7), 46.4 (C4), 39.3 (C6) ppm. The position of the signals corresponding to the
carbon atom C5 with nitro group is shifted into a regionof much higher frequencies (114.8
ppm). In similar way, the NMR spectrums 3b can be interpreted. Unfortunately, IR as well as

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NMR spectrums not provide evidently supports for identification of regio- and
stereochemistry of obtained adducts. For this purpose, we applied data obtained using RTG
technique.
It was found, that the molecular structures of 3a and 3b, with the atomic numbering
scheme presented in Figure 3, show selected geometric data given in Table 1. In the crystal
structure of 3a there are two independent molecules in the asymmetric unit (Figure 3a). The
N1 atom in the studied compounds lies about 0.6 Å out of the plane defined by the three
neighboring atoms (O2, O8 and C5). Additionally, the sum of the valence angles around the
N1 atom of 312.6 (1)º and 312.9 (1)º in 3a, 313.14 (1)º in 3b demonstrates clear sp3
hybridization (328º for sp3 and 360º for sp2). The other geometric parameters of 3a and 3b
(Tables S1 and S2 in Supplementary information) are normal and compare well with those
found in other crystal structures [14-17].
(a)
(b)
Figure 3. The molecular structures of 3a (a) and 3b (b) in the asymmetric part of unit cell.
Displacement ellipsoids are drawn at the 50% probability level.
Table 1. Selected geometrical parameters (Å, º) in the studied compounds.
3a
Parameters
N1-O8
3b
A
B
1.480 (2)
1.404 (2)
1.479 (2)
1.411 (2)
1.397 (2)
1.494 (2)
N1-O2

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O8-C7
O2-C3
N1-C5
1.421 (2)
1.469 (2)
1.528 (3)
1.423 (3)
1.469 (2)
1.510 (3)
1.458 (2)
1.420 (2)
1.518 (2)
O8-N1-C5
O2-N1-C5
O8-N1-O2
102.38 (15) 103.67 (16)
105.49 (16) 105.03 (15)
104.72 (14) 104.27 (15)
105.86 (13)
102.97 (13)
104.31 (12)
148.28 (13)
-82.74 (15)
-41.15 (18)
38.32 (17)
94.77 (18)
-127.71 (16)
33.52 (18)
-44.92 (17)
C3-O2-N1-O8
C7-O8-N1-O2
N1-O8-C7-C6
O8-C7-C6-C5
C7-C6-C5-C4
C6-C5-C4-C3
C5-C4-C3-O2
N1-O2-C3-C4
81.86 (18)
-85.14 (17)
-151.02 (16) 145.91 (16)
49.4 (2)
-37.0 (2)
128.7 (2)
-95.5 (2)
-36.7 (2)
39.9 (2)
-45.8 (2)
36.4 (2)
-131.8 (2)
91.0 (2)
39.9 (2)
-40.7 (2)
MEDT study of the 32CA 3-nitroisoxazoline-2-oxide (1) with model ethane derivatives
(2a,b)
Analysis of the stationary points involved in the 32CA 3-nitroisoxazoline-2-oxide (1)
with model ethane derivatives (2a,b) in ethanol indicates that this reaction takes place via a
one-step mechanism. These reactions begins with the formation of the molecular complex MC
(MC-1 and MC-2). Formation of these complexes are endergonic for reaction with styrene
(2a) and acrylonitrile (2b) by 6.1 kcal/mol (MC-1) and 6.5 kcal/mol (MC-2), respectively.
Further conversion of the reactions lead to the transition state structures (TS-1 and TS-2,
Figure 4). As the data of M06-2X(PCM)/6-311+G(d,p) calculations show, this change
demands a Gibbs free energy of 26.7 kcal/mol for reaction with participation of 2a and 27.5
kcal/mol for reaction with 2b. Afterwards, the TSs are converted to products 3a and 3b
(Table 2).
Table 2. Thermodynamic parameters for the 32CA 3-nitroisoxazoline-2-oxide (1) with model
ethane derivatives (2a,b) in ethanol (T=298 K; ∆H, ∆G in kcal·mol-1, ∆S in cal·mol-1·K-1).
Functional
Transition
∆H
∆G
∆S
-6.7
3.6 -34.5
1+2a→MC-1
1+2a→TS-1
1+2a→3a
11.6 25.6 -47.0
-23.5 -10.2 -44.3
B3LYP-D3
M06-2X
-2.1
6.3 -28.1
1+2b→MC-2
1+2b→TS-2
1+2b→3b
14.4 27.7 -44.6
-16.2 -2.5 -46.0
-4.9
6.1 -37.0
1+2a→MC-1

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12.0 26.7 -49.3
-37.3 -22.3 -50.4
-2.9 6.5 -31.4
14.0 27.5 -45.3
-29.8 -15.5 -48.0
1+2a→TS-1
1+2a→3a
1+2b→MC-2
1+2b→TS-2
1+2b→3b
-8.5
2.0 -42.9
1+2a→MC-1
1+2a→TS-1
1+2a→3a
12.5 25.3 -42.9
-35.3 -21.8 -45.2
M11
-3.1
6.4 -31.6
1+2b→MC-2
1+2b→TS-2
1+2b→3b
14.2 27.3 -43.8
-28.3 -14.1 -47.6
TS-1
TS-2
Figure 4. M06-2X(PCM)/6-311+G(d,p) Geometry of transition states (TS-1 and TS-2) of the
32CA 3-nitroisoxazoline-2-oxide (1) with model ethane derivatives (2a,b).
It should also be mentioned that DFT study using different B3LYP and M11
functionals with 6-311+G(d,p), 6-31G(d) and 6-31++G(d) basic sets gives a similar
representation of these reactions. In the case of calculations based on M11(PCM)/6-
311+G(d,p) theory levels, we observed a decrease in the Gibbs free energy and
B3LYP(PCM)/6-311+G(d,p) calculations for reactions with 2a suggests a decrease the Gibbs
free energy (Table 2). The thermodynamic parameters for the 32CA 3-nitroisoxazoline-2-
oxide (1) with model ethane derivatives (2a,b) for B3LYP, M06-2X and M11 functionals
with 6-311+G(d,p), 6-31G(d) and 6-31++G(d) basic sets are given in Tables S3 and S4 of the
Supplementary Materials.
Recently, Domingo proposed new reactivity theory – MEDT [1]. This theory, in which
stablishes that changes in electron–density, and not molecular orbital interactions, are
responsible for reactivity in organic chemistry, uses quantum chemical tools such as the
conceptual Density Functional Theory (DFT) reactivity indicator. Within MEDT, quantum
chemical tools based on the analysis of the electron density, such as the Electron Localization

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Function (ELF) [18], Bonding Evolution Theory (BET) [19] and Catastrophe Theory (CT)
[20-22] are used to study the molecular electron-density along the reaction path, in order to
study organic reaction. CT in combination with ELF gradient field constitutes a way to
rationalize the reorganization of electron pairing and a powerful tool for the unambiguous
determination of the molecular mechanisms of a given chemical reaction [20].
This theory is the basic tool for explaining the molecular mechanism of many types of
reactions [23-27]. To present changes in the course of the reactions of 3-nitroisoxazoline-2-
oxide (1) with styrene (2a) and acrylonitrile (2b), a MEDT study were carried out.
In order to characterize the molecular mechanism of the reaction of 3-nitroisoxazoline-
2-oxide (1) with styrene (2a), a BET study along the reaction was carried out. The complete
BET study is provided in the Supplementary Materials (Table S5). The sequential bonding
changes received from the MEDT analysis of the reaction of 3-nitroisoxazoline-2-oxide (1)
with styrene (2a) is shown in Table 3. From the BET analysis of this reaction some appealing
conclusions can be drawn: (i) molecular mechanism of the reaction of the 3-nitroisoxazoline-
2-oxide (1) to styrene (2a) can be topologically characterized by eight different phases, which
have been grouped into three different A-C Groups (Table 3, Figure 5); (ii) Group A,
containing Phases I-IV, in which the C3-C4 double bond breaks and we are also noticed
disappearance of pseudoradical center of V’(C5) and formation a new pseudoradical center
near the atom N1 – V(N1); (iii) Group B, containing Phases V and VI, in which we observed
the formation of pseudoradical center V(C4) which is next converted into the new bond
between atoms C4 and C5. At the beginning of the only phase of Group B, the TS-1 is found;
(iv) The last Group C, containing Phases VII and VIII, in which the bond O2-C3 is formed.
(v) It is worth nothing that the formation of bond between atoms C4 and C5 takes place
homolitically, while the O2-C3 bond is formed heterolytically.
Table 3. Sequential bonding changes along the reaction of the 3-nitroisoxazoline-2-oxide (1)
with styrene (2a), showing the equivalence between the topological characterization of the
different phases and the chemical processes occurring along them. Distances are given in
angstroms, Å, GEDT values in average number of electrons, [e] and relative energies are
given in kcal·mol-1.

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d1(O2-C3)
d2(C4-C5)
Topological
characterization
Chemical
process
Group
Phases
GEDT
∆E
Disappearance of the
V’(C3,C4) disynaptic basin
and V’(C5) monosynaptic
basin and formation of
V(N1) monosynaptic basin
Formation of the V(C4,C5)
Rupture of
the C3-C4
double bond
6.47 ≥ d1> 4.38
6.51 ≥ d2> 3.94
A
I-IV
0.07
11.1
disynaptic basin and V(C4) Formation of
4.38 ≥ d1> 3.90
3.94 ≥ d2> 3.16
B
C
V-VI
0.03
0.02
2.1
monosynaptic basin and
disappearance of V(C5)
monosynaptic basin
the C4-C5
bond
Formation of V(C3)
monosynaptic basin and
V(O2,C3) disynaptic basin
Formation of
the O2-C3
bond
3.90 ≥ d1> 2.72
3.16 ≥ d2> 2.88
VII-VIII
-22.9
In the case of reaction of the 3-nitroisoxazoline-2-oxide (1) with acrylonitrile (2b),
according to the BET analysis, we can distinguish nine topological changes along the reaction
path (Table 4, Figure 5). The complete BET study is provided in the Supplementary
Materials (Table S6). From this analysis, some appealing conclusion can be obtained: (i) the
reaction of the 3-nitroisoxazoline-2-oxide (1) with acrylonitrile (2b) can be characterized by
nine different phases which, in turn can be reorganized in three Groups A-C associated to
significant chemical changes (Table 4, Figure 5); (ii) in Group A, which containing Phases I-
IV, we observed the rupture of the double bond between atoms C3 and C4; (iii) in the next
Group B, which containing Phases V and VI, we observed the formation of C4-C5 bond.

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Formation of this bond takes place at C4-C5 lengths of 3.74 Å. At the beginning of this
Group, we observed the presence of TS-2 of this reaction; (iv) Group C containing Phases
VII-IX. This group is associated with the formation of O2-C3 bond. This O2-C3 bond, in the
case of reaction of the 3-nitroisoxazoline-2-oxide (1) with acrylonitrile (2b), take place
homolitically.
Table 4. Sequential bonding changes along the reaction of the 3-nitroisoxazoline-2-oxide (1)
with acrylonitrile (2b), showing the equivalence between the topological characterization of
the different phases and the chemical processes occurring along them. Distances are given in
angstroms, Å, GEDT values in average number of electrons, [e] and relative energies are
given in kcal·mol-1.
d1(O2-C3)
d2(C4-C5)
Topological
characterization
Chemical
process
Group
Phases
GEDT
∆E
Disappearance of the
V’(C3,C4) disynaptic basin
and V’(C5) monosynaptic
basin and formation of
V(N1) monosynaptic basin
Formation of the V(C4,C5)
Rupture of
the C3-C4
double bond
6.04 ≥ d1> 4.31
6.44 ≥ d2> 3.80
A
I-IV
0.10
12.2
disynaptic basin and V(C4) Formation of
4.31 ≥ d1> 3.98
3.80 ≥ d2> 3.28
B
V-VI
0.09
9.8
monosynaptic basin and
disappearance of V(C5)
monosynaptic basin
the C4-C5
bond

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Formation of V(C3) and
Formation of
the O2-C3
bond
3.98 ≥ d1> 2.70
3.28 ≥ d2>2.88
V’’(O2) monosynaptic
basins and V(O2,C3)
disynaptic basin
C
VII-IX
0.02
-15.6

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Figure 5. M06-2X(PCM)/6-31G(d) IRC profile including the ELF attractor positions for the
most relevant points of the reaction of the 3-nitroisoxazoline-2-oxide (1) with styrene (2a)
(top) and acrylonitrile (2b) (bottom).
3. EXPERIMENTAL
General
Materials used in our work were purchased from Sigma-Aldrich, POCh, and
Chempure and were used as received except for styrene and acrylonitrile which were distilled
prior use. Reactions advancement were monitored using Fluka’s silicagel (60F254) on Al foil
TLC plates with benzene and THF (8:2 v/v) as elution solution. We also used Knauer HPLC
with LiChrospher RP-18 250 x 4 mm column with precolumn from the same manufacturer.
HPLC eluent was acetonitrile and water (60:40 v/v). Melting points were measured using
Boetius PH MK-05 apparatus and are uncorrected. Elemental analysis was performed with
Perkin Elmer PE 2400 analyzer. Infrared spectra were recorded on Thermo Fisher Scientific
Nicolet iS 10 FT-IR using KBr pellets. 1H NMR spectra were measured on Bruker AMX500
spectrometer using TMS as internal standard.
X-ray crystallography
The single crystals of the compounds 3a and 3b were mounted on a CCD Xcalibur
diffractometer (graphite monochromatic, MoKα radiation, λ= 0.71073 Å) at 100.0(1) K. The
reciprocal space was explored by ω scans with detector positions at 60 mm distance from the
crystal. The diffraction data processing of studied compounds (Lorentz and polarization
corrections were applied) was performed using the CrysAlis CCD [28]. Both crystal structures
were solved by direct methods using SHELXS14program [29,30]. All non-hydrogen atoms
were located from difference Fourier synthesis and refined by least squares method in the full-
matrix anisotropic approximation using SHELXL14 software [29,30]. In both structures the H
atoms were located from difference Fourier synthesis and were refined using a riding model.
The structure drawings were prepared using SHELXTL program [29,30]. The
crystallographic data for the studied compounds and details of X-ray experiment are collected
in the Table 5. Crystallographic data for the both structures have been deposited with the
Cambridge Crystallographic Data Centre as supplementary publication nos. CCDC: 1898859
for 3a and 1898860 for 3b. These data can be obtained free of charge via
http://www.ccdc.cam.ac.uk/conts/retrieving.html, or from the Cambridge Crystallographic

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Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: 144 1223 336 033;
email:deposit@ccdc.cam.ac.uk.
Table 5. The crystal data, experimental details and refinement parameters for 3a and 3b.
Crystal data
3a
C11H12N2O4
236.23
3b
C6H7N3O4
Chemical formula
Mr
185.15
Crystal system, space
group
Triclinic, P-1
Monoclinic, P21/c
8.0478 (3), 11.3416 6.1090 (3), 11.7490
a, b, c (Å)
(4), 13.0227 (6)
(5), 10.8456 (5)
68.287 (4), 82.932
(3), 79.360 (3)
α, β, γ (°)
90, 105.082 (5), 90
V (Å3)
µ (mm−1)
1083.37 (8)
0.11
751.63 (6)
0.14
Crystal size (mm)
0.15 × 0.10 × 0.05
0.20 × 0.15 × 0.10
Data collection
No. of measured,
independent and
observed [I> 2σ(I)]
reflections
7431, 4172, 2254
4950, 1479, 1107
Rint
0.045
0.617
0.040
0.616
(sin θ/λ)max (Å−1)
Refinement
R[F2> 2σ(F2)], wR(F2),
S
0.049, 0.082, 0.86
0.043, 0.085, 1.04
No. of reflections
No. of parameters
ꢀρmax, ꢀρmin (e Å−3)
4172
1479
307
118
0.23 -0.24
0.24 -0.21
Synthesis of 3-nitroisoxazoline-2-oxide (1)
To a beaker containing solution of 4.7 g potassium acetate in 50 mL of distilled water,
10.2 g (0.048 mol) of 1,1-dinitro-3-bromopropane was added during 5 hours of stirring. The
reaction mixture was left to the next day. Precipitated crystals were filtered off, washed with
distilled water, dried, and crystallized twice from ethanol. Synthesized 3-nitroisoxazoline-2-
oxide weighted 5.2 g, which corresponds to 82% yield.
Physical data for 1: m.p. 96.1 °C (96.5°C [12]), found: 27.35% C, 2.87% H, 20.93% N, calc.
1
for C3H4N2O4 27.28% C, 3.05% H, 21.21% N; H NMR (500 MHz, CDCl3) δ 4.72 (t, 2H5),

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3.82 (t, 2H4); 13C NMR (125 MHz, CDCl3) 126 (C3), 64 (C5), 28 (C4); IR spectrum (KBr) (ν,
cm-1) 1619 (C=N), 1500, 1296 (NO2).
32CA of 3-nitroisoxazoline-2-oxide (1) with styrene (2a)
In a Erlenmeyer flask 0.66 g (0.005 mol) of 1 and 2.60 g (0.025 mol) of 2a in 10 mL
of anhydrous ethanol was combined. The reaction mixture was stirred in dark to full
conversion of 1 (monitored with HPLC and TLC) for 7 days. The unreacted alkene and
solvent was removed on rotary evaporator. The crude product was refined with fractional
crystallization from anhydrous ethanol to give 3-exo-phenyl-5-nitro-1-aza-2,8-
dioxabicyclo[3.3.0]octane pure enough for XRD analysis. Yield of the main product was 1.02
g which corresponds to 86% of theoretical yield.
Physical data for 3a: m.p. 81-83 °C, found: 55.90% C, 4.98% H, 11.75% N, calc. for
1
C11H12N2O4 55.93% C, 5.12% H, 11.86% N, H NMR (500 MHz, CDCl3) δ 7.47 – 7.34 (m,
5HPh), 5.69 (dd, J = 10.9, 5.4 Hz, 1H3), 4.43 (dd, J = 14.5, 7.3 Hz, 1H7), 4.30 (m,1H7), 3.42
13
– 3.26 (m, 2H4), 2.90 (dd, J = 13.3, 5.4 Hz, 1H6), 2.71 (m, 1H6); C NMR (125 MHz,
CDCl3) 114.8 (C5), 85.4 (C3), 67.9 (C7), 46.4 (C4), 39.3 (C6); IR spectrum (KBr) (ν, cm-1)
702, 763, 2987, 3029 (Ph),1553, 1351 (-NO2), 1033 (O-N-O).
32CA of 3-nitroisoxazoline-2-oxide (1) with acrylonitrile (2b)
In a Erlenmeyer flask 0.66 g (0.005 mol) of 1 and 1.33 g (0.025 mol) of 2b in 10 mL
of anhydrous ethanol was combined. The reaction mixture was stirred in dark to full
conversion of 1 (monitored with HPLC and TLC) for 5 days. The unreacted alkene and
solvent was removed on rotary evaporator. The crude product was purified with fractional
crystallization from anhydrous ethanol to give 3-exo-cyano-5-nitro-1-aza-2,8-
dioxabicyclo[3.3.0]octane pure enough for XRD analysis. Yield of the main product was 1.02
g which corresponds to 86% of theoretical yield.
Physical data for 3b: m.p. 98-100 °C, found: 38.97% C, 3.62% H, 22.52% N, calc. for
C6H7N3O4 38.92% C, 3.81% H, 22.70% N; 1H NMR (500 MHz, acetone) δ 5.65 (dd, J = 8.4,
3.4 Hz, 1H3), 4.76 – 4.48 (m, 2H7), 3.79 (ddd, J = 14.8, 3.4, 0.8 Hz, 1H4), 3.48 (dd, J = 14.8,
13
8.4 Hz, 1H4), 3.31 (m, 1H6), 2.90 (ddd, J = 13.5, 6.3, 2.9 Hz, 1H6); C NMR (125 MHz,
CDCl3) 116.8 (CN), 114.7 (C5), 72.4 (C3), 64.9 (C7), 41.7 (C4), 38.0 (C6); IR spectrum
(KBr) (ν, cm-1) 2245 (-CN),1553, 1354 (-NO2), 1001 (O-N-O).

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DFT calculations
Calculations were performed using the Prometheus computer cluster in the
CYFRONET regional computer centre in Cracow. All calculations were carried out with the
GAUSSIAN 16 package [31]. DFT calculations were performed using the B3LYP-D3 [32-
35], M06-2X [36] and M11 [37] functional together with the 6-311+G(d,p), 6-31G(d) and 6-
311+G(d) basis sets. The stationary points were characterized by frequency calculations in
order to verify the number of imaginary frequencies (zero for local minima and one for TSs).
The IRC [38] paths, computed using the second order González-Schlegel integration method
[39,40], were traced in order to obtain the energy profiles connecting TS to the two associated
minima of the proposed mechanism. Solvent effect of ethanol in the optimizations were taken
into account using the polarizable continuum model (PCM) as developed by Tomasi’s group
[41-43] in the framework of the self-consistent reaction field (SCRF) [44,45]. Values of free
energies in all calculations were calculated with the standard statistical thermodynamics at
25ºC and 1 atm [34].
Charge global electron density transfer (GEDT) [46] was calculated according to the
formula:
GEDT=-ΣqA
where qA is the net charge and the sum is taken over all the atoms of the substructure.
The topological analyses of the Electron Localization Function (ELF) were performed
with the TopMod [47] program using the corresponding M06-2X(PCM)/6-311+G(d,p)
monodeterminantal wavefuctions. ELF calculations were computed over a grid spacing of 0.1
a.u. for each structure and ELF localization domains were obtained for an ELF value of 0.75.
For the Bonding Evolution Theory (BET) [19] studies, the corresponding reaction paths were
followed by performing the topological analysis of the ELF for at least 195 nuclear
configurations along the IRC paths.
4. CONCLUSIONS
The structural aspects of the 1-aza-2,8-dioxabicyclo[3.3.0]octane derivatives synthesis
on the basis of the 3-nitroisoxazoline-2-oxide has been examined using experimental and
computational techniques. The constitution of isolated products has been confirmed without
any doubts using spectral methods and single crystal XRD analysis. The molecular
mechanism of the 32CA reactions leading to 1-aza-2,8-dioxabicyclo[3.3.0]octane derivatives

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has been studied within the MEDT using DFT method at the M06-2X(PCM)/6-311+G(d,p)
calculations. These reactions take place through a one-step mechanism. The reaction of the 3-
nitroisoxazoline-2-oxide (1) with styrene (2a), according to the BET analysis, can be
characterized by eight different phases, while in the reaction of the 3-nitroisoxazoline-2-oxide
(1) with acrylonitrile (2b) we can distinguish nine different phases. Worth noting is the fact
that the bond between atoms C4 and C5, in the case of reaction 1+2a, is formed homolitically,
while the bond O2-C3 take place heterolytically. In the case of reaction 1+2b, both C4-C5
and O2-C3 bonds are formed homolitically.
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The structural aspects of the 1-aza-2,8-dioxabicyclo[3.3.0]octane derivatives synthesis on the
basis of the 3-nitroisoxazoline-2-oxide has been examined using experimental and
computational techniques.
The constitution of isolated products has been confirmed without any doubts using spectral
methods and single crystal XRD analysis.
The reaction of the 3-nitroisoxazoline-2-oxide (1) with styrene (2a), according to the BET
analysis, can be characterized by eight different phases, while in the reaction of the 3-
nitroisoxazoline-2-oxide (1) with acrylonitrile (2b) we can distinguish nine different phases.