Synthesis, NMR analysis and X-ray crystal structure of 6,12-bis(4- fluorophenyl)-3,9-dioxatetraasterane

Article abstract of DOI:10.1016/j.molstruc.2011.09.056

Tetraethyl 2,4,8,10-tetramethyl-6,12-bis(4-fluorophenyl)-3,9- dioxapentacyclo[6.4.0.0^2,7.0^4,11.0^5,10] dodecane-1,5,7,11-tetracarboxylate (1, simplified as 6,12-bis(4-fluorophenyl)-3, 9-dioxatetraasterane) was synthesized b

Full text of DOI:10.1016/j.molstruc.2011.09.056

Journal of Molecular Structure 1006 (2011) 489–493
Contents lists available at SciVerse ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstruc
Synthesis, NMR analysis and X-ray crystal structure
of 6,12-bis(4-fluorophenyl)-3,9-dioxatetraasterane
⇑
Xiu-Qing Song, Hui-Qin Wang, Hong Yan , Cheng-Liang Ni, Ru-Gang Zhong
College of Life Science & Bioengineering, Beijing University of Technology, Beijing, China
a r t i c l e i n f o
a b s t r a c t
Tetraethyl 2,4,8,10-tetramethyl-6,12-bis(4-fluorophenyl)-3,9-dioxapentacyclo[6.4.0.02,7.04,11.05,10]dode-
cane-1,5,7,11-tetracarboxylate (1, simplified as 6,12-bis(4-fluorophenyl)-3,9-dioxatetraasterane) was
synthesized by [2 + 2] photocyclization of diethyl 2,6-dimethyl-4-(4-fluorophenyl)-4H-pyran-3,5-dicar-
boxylate (2) in solution. The NMR analysis of 1 is discussed in detail by the splittings and assignments
of signals according to the three-dimensional structure. Single-crystal X-ray diffraction shows that 1 is
situated on an inversion center. The molecular symmetry is close to C2h except for the terminal ethyl
groups.
Article history:
Received 4 March 2011
Received in revised form 29 September 2011
Accepted 29 September 2011
Available online 25 October 2011
Keywords:
3,9-Dioxatetraasterane
4H-pyran
Ó 2011 Elsevier B.V. All rights reserved.
Synthesis
X-ray crystal structure
NMR analysis
1. Introduction
Bruker AV 400 spectrometer at ambient temperature (25 °C). Infra-
red spectra were recorded on a Bruker VERTEX70 instrument as
The synthesis and characterization of polycyclic hydrocarbons
are of fundamental interest because their unique chemical and
physical properties can have pharmacological applications [1–4],
such as in the treatment of Parkinson’s disease, Alzheimer’s disease,
influenza and AIDS [5–8]. Typical polycyclic hydrocarbons include
cubane, prismane and tetraasterane, etc. The skeleton of tetraaste-
rane consists of two parallel cyclobutanes fused with four cyclohex-
anes. Its 3,9-diaza and 3,9-dioxa derivatives with C2 symmetry are
exceedingly rare among organic compounds and possess inhibitory
activity against HIV-1 protease [9,10]. In order to discuss the spatial
structure effects on the NMR spectrum, 6,12-bis(4-fluorophenyl)-
3,9-dioxatetraasterane (1, tetraethyl 2,4,8,10-tetramethyl-6,12-
bis(4-fluorophenyl)-3,9-dioxapentacyclo[6.4.0.02,7.04,11.05,10]dode-
cane-1,5,7,11-tetracarboxylate) was singled out and prepared by
the [2 + 2] photocyclization of diethyl 2,6-dimethyl-4-(4-fluoro-
phenyl)-4H-pyran-3,5-dicarboxylate (2) in solution instead of in
the solid state [11] (Scheme 1).
potassium bromide pellets. Mass spectra were recorded on a Bru-
ker Esquire 6000 mass spectrometer. Elemental analyses, as indi-
cated by the symbols of the elements, were within 0.3% of the
theoretical values and were performed using a Leco CHNS-932
apparatus.
The chemical agents used in this study were all commercially
available. Diethyl 2,6-dimethyl-4-(4-fluorophenyl)-4H-pyran-3,5-
dicarboxylate (2) was prepared by a previously described method
[12]. 1H NMR (400 MHz; CDCl3): d 1.20 (t, 6H, –CH3), 2.35 (s, 6H,
–CH3), 4.04–4.14 (m, 4H, –CH2), 4.73 (s, 1H, –CH), 6.89–6.93 (m,
2H, Ar–H), 7.17–7.21 (m, 2H, Ar–H). 13C NMR (100 MHz; CDCl3):
d
14.10, 18.68, 37.81, 60.35, 108.10, 114.59/114.80, 129.96/
130.04, 141.28/141.32, 158.16, 160.3/162.7, 166.6.
2.2. Synthesis of 3,9-dioxatetraasterane (1)
Diethyl 2,6-dimethyl-4-(4-fluorophenyl)-4H-pyran-3,5-dicar-
boxylate (2, 2.5 g) was dissolved in 250 mL of methanol. The solu-
tion was stirred in a photochemistry glass fitted with a condenser
and nitrogen inlet tube, and was placed 1 cm from a quartz water-
cooled jacket of a 400 W mercury vapor lamp. While compound 1
crystallized during irradiation, remnant 1 precipitated from the
solution after condensation and was recrystallized from methanol
and dichloromethane with a 26.8% yield. Compound 1 formed col-
orless block-shape crystals which melted with decomposition at
273.4–275.2 °C. 1H NMR (400 MHz; CDCl3): d 1.14 (t, 12H, –CH3),
1.67 (s, 12H, –CH3), 3.83–4.00 (m, 8H, –CH2), 4.25 (s, 2H, –CH),
2. Experimental
2.1. Physical measurements
Melting points were determined using an X-5 apparatus (open
capillaries, uncorrected values). NMR spectra were acquired on a
⇑
Corresponding author. Tel.: +86 1067396642; fax: +86 1067392001.
E-mail address: hongyan@bjut.edu.cn (H. Yan).
0022-2860/$ - see front matter Ó 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.molstruc.2011.09.056

490
X.-Q. Song et al. / Journal of Molecular Structure 1006 (2011) 489–493
F
COOEt
EtOOC
O
F
hv
F
O
EtOOC
COOEt
CH3OH
COOEt
EtOOC
O
2
1
Scheme 1. Synthesis of 1 by irradiation.
6.91 (m, 4H, Ar–H), 7.51 (m, 4H, Ar–H) ppm. 13C NMR (100 MHz,
CDCl3): d 14.01, 23.39, 45.29, 56.83, 60.51, 77.28, 114.68/114.89,
132.92, 132.89/132.97, 160.71/163.16, 169.24. IR (ATR, KBr): 836,
1023, 1260, 1372, 1478, 1504, 1602, 1715, 2989 cmꢀ1. MS (m/z):
719.2 (M++Na), 735.1 (M++K). Anal. calc. for C38H42F2O10: C,
65.51; H, 6.08; F, 5.45. Found: C, 65.65; H, 6.07; F, 5.46.
(4-fluorophenyl)-4H-pyran-3,5-dicarboxylate (2) with a yield of
26.8% after 40 h irradiation by a 400 W mercury lamp in methanol.
In the reaction, 1 was separated directly from methanol and recrys-
tallized in a solution of dichloromethane and methanol. Compared
with the solid method [11], this reaction was advantageously easy
to handle and magnify in a solvent. The topochemistry in solution
revealed that the [2 + 2] photocyclization was restrained by the po-
tential reaction of double bonds of neighboring molecules, hydro-
gen bonds and steric hindrances [14]. The photocyclization of
4H-pyran 2 followed the topochemistry in solution, resulting in
the formation of cage 1 by double bond closure.
2.3. X-ray crystallography
The X-ray data was measured with graphite-monochromatized
Mo K
a radiation (k = 0.71073 Å) on a Rigaku RAXIS RAPID IP dif-
The
6,12-bis(4-fluorophenyl)-3,9-dioxatetraasterane
(1)
fractometer at ambient temperature. The structure was solved by
direct methods (SHELXS-97) [13]. Structure refinement employed
full-matrix least-squares on F2 using SHELXL-97; all of the non-
hydrogen atoms were refined with anisotropic displacement
parameters. All of the hydrogen atoms were fixed in positions of
ideal geometry and refined isotropically based on the correspond-
ing C-atoms [U(H) = 1.2Ueq(C) or 1.5Ueq(Cmethyl)]. Structure refine-
ment parameters for 1 are given in Table 1 and crystallographic
data were deposited with the Cambridge Crystallographic Data
Centre under deposition number CCDC 711765.
showed an inversion symmetry center and two-fold symmetry, to
a certain extent, for the combination of two 4H-pyrans in head-
to-tail style. The molecule is situated on an inversion center in
the crystal. The molecular symmetry in the crystal is close to C2h ex-
cept for the terminal ethyl groups. It contains four tetrahydropy-
rans and two cyclobutanes (Fig. 1). The tetrahydropyran rings are
in boat conformation individually encircled and interlinked by the
cyclobutanes and perpendicular to the cyclobutane planes. The
deviations of bottoms and prows of the boat were within 0.2° and
0.3°, indicating that the cage core is mostly compact and ordered.
The cyclobutane moiety of 1 adopt a flat square conformation
with the endocyclic torsion angles (C1–C2–C3–C4) of ꢀ2.39(14)°.
The four valence angles are all about 90° with deviations within
0.6°. The four C–C bonds have similar bond lengths of C1–C2
(1.575(3) Å), C2–C3 (1.571(3) Å) and C1–C4 (1.570(3) Å); the bond
length of C3–C4 (1.584(3) Å) is slightly longer than that of others,
perhaps due to the departure of the phenyl ring at C5 from an axial
orientation (deflection 5.3°). This ring makes a short C–Hꢁ ꢁ ꢁF con-
tact (C(6)–H(6)ꢁ ꢁ ꢁF(1), Table 2).
3. Results and discussion
6,12-Bis(4-fluorophenyl)-3,9-dioxatetraasterane (1) was pre-
pared by the [2 + 2] photocyclization of diethyl 2,6-dimethyl-4-
Table 1
Crystal data and structure refinement for 1.
Empirical formula
Formula weight
C38H42F2O10
696.72
Temperature
293(2) K
The tetrahydropyran rings of 1 had a characteristic boat confor-
mation like a flattened envelope in the range of 109.73(16)–
114.89(16)°. The two neighbor tetrahydropyran rings had different
degrees of puckering, one slightly flattened and the other obviously
puckered. The dihedral angle of the two apex planes in one
(O1–C1–C2–C5–C40–C30 ring) was 85.1° and that of the other
(O1–C1–C4–C50–C20–C30 ring) was 94.9°.
Compared with the similar crystal structure [11], 1 is stabilized
not only by weak intra- and intermolecular C–Hꢁ ꢁ ꢁO hydrogen
bonds but by weak intermolecular C–Hꢁ ꢁ ꢁF hydrogen bonds (Table
2). All of the tetrahydropyran rings show a bigger prow (the C2–
C5–C40 angle 109.7(16)°, the bond lengths 1.539(3) Å (C2–C5)
and 1.544(3) Å (C5–C40)) and a smaller stern (the C1–O1–C30 angle
118.2(14)° with bond lengths of 1.427(2) Å (O1–C1) and 1.434(2) Å
(O1–C30)). In addition, the eclipsed orientation strain was relieved
by bridge bonds at all corners (O1 and C5 atoms) connecting the
two cyclobutanes. Most of the substituents of the cage were equa-
torial and fixed by geometry; only the prow of the tetrahydropyran
rings experienced more crowding for the bulky groups (phenyl and
ester groups). The ester groups extended freely and deviated to
some extent from ideal geometry due to intermolecular hydrogen
Wavelength
0.71073 Å
Crystal system, space group
Unit cell dimensions
Monoclinic, P21/n
a = 10.713(2) Å
b = 11.957(2) Å
c = 13.945(3) Å
a
= 90°
b = 98.82(3)°
c
= 90°
Volume
1765.1(6) Å3
Z
2
Calculated density
Absorption coefficient
F(000)
Crystal size
h Range for data collection
Index ranges
Reflections collected/unique
Refinement method
Data/restraints/parameters
Goodness-of-fit on F2
Final R indices [I > 2
R indices (all data)
1.311 Mg mꢀ3
0.101 mmꢀ1
736
0.45 ꢂ 0.25 ꢂ 0.20 mm3
2.57–25.02°
ꢀ12 ꢃ h ꢃ 12, ꢀ14 ꢃ k ꢃ 14, ꢀ16 ꢃ l ꢃ 16
10,232/3095 [Rint = 0.0360]
Full-matrix least-squares on F2
3095/0/227
1.000
r(I)]
R
R
1 = 0.0455, wR2 = 0.1163
1 = 0.0716, wR2 = 0.1243
Extinction coefficient
Largest diff. peak and hole
0.038(3)
0.313 and ꢀ0.254 e Åꢀ3

X.-Q. Song et al. / Journal of Molecular Structure 1006 (2011) 489–493
491
Fig. 1. ORTEP diagram of cage 1 (thermal ellipsoids at 50% probability).
Table 2
bonds. The orientation of the methyl groups did not deviate from
the optimal positions. Because of the Csp3 nature of the substituent
at C5, the phenyl ring orientation was anchored by H5 ester groups
and the intermolecular contacts of F1ꢁ ꢁ ꢁH–C6 and O1ꢁ ꢁ ꢁH–C18.
The hydrogen bonds in 1 were formed by the two ester groups
of tetrahydropyran (Table 2). The hydrogen bond of O3ꢁ ꢁ ꢁH–C8
linked two screw-axis-related molecules. Although the two ester
groups are chemically equivalent, their different intermolecular
Geometry of the short intermolecular C–Hꢁ ꢁ ꢁX contacts (Å and °).
D–Hꢁ ꢁ ꢁA
d(D–H)
d(Hꢁ ꢁ ꢁA)
2.484
2.628
2.706
d(Dꢁ ꢁ ꢁA)
3.428
3.427
3.570
(D–Hꢁ ꢁ ꢁA)
164.4
140.9
155.0
C(8)–H(8)ꢁ ꢁ ꢁO(3)
C(6)–H(6)ꢁ ꢁ ꢁF(1)
C(18)–H(18)ꢁ ꢁ ꢁO(1)
0.971
0.960
0.930
Symmetry transformations used to generate equivalent atoms: #1 ꢀx, 1 ꢀ y, 1 ꢀ z;
#2 ꢀx, ꢀy, 1 ꢀ z.
Fig. 2. The partial 1H NMR spectrum of 1.

492
X.-Q. Song et al. / Journal of Molecular Structure 1006 (2011) 489–493
and C10). A one-proton singlet at d 4.27 ppm is assigned to the
C5 proton corresponding to the proton singlet at d 4.73 ppm in
1H NMR spectrum of 2. The coupling splits of carbon and hydrogen
atoms in the aryl groups were due to the fluorine atom and as-
signed in the range of 114.68–163.16 ppm and 6.90–7.53 ppm,
respectively.
An unexpected splitting proton resonance in the 1H NMR spec-
trum of 1 was methylene of the ester groups (Fig. 2). The peak did
not show a normal quadruplet by coupling from hydrogen atoms of
the neighbor methyl in the ester groups, but displayed a several
well-regulated multiplets (chemical shift 3.83–4.00 ppm). The
hydrogen atom pairs of the methylene groups were likely located
in an inequivalent magnetic field due to the spatial structure of
the molecule. One of the ester groups (C7–O2–C8–C9) was chosen
as an example to explain the symmetry properties of 1 in further
detail. The splitting mode of the methylene group was a quadru-
plet of quadruplets with an integral ratio of 1:3:3:1 for the four
peaks in a quadruplet, and clearly indicated that H8a and H8b
are not equivalent. Therefore, they should couple to each other
and the vicinal neighbors H9. In the 1H–1H COSY spectrum
(Fig. 3), the methylene (C8) showed two symmetrical pairs, which
were split due to the three hydrogen atoms of the methyl, the vic-
inal coupling constant was 7.2 Hz. In the 1H–13C COSY spectrum
(Fig. 4), the 60.51 ppm signal correlated with the proton signals as-
signed as H8a/H8b in the 1H NMR spectrum, the geminal coupling
constant was 10.8 Hz.
Fig. 3. The partial 1H–1H COSY spectrum of 1.
It is interesting that the geminal pair of hydrogen atoms of
methylene (CH2) shows abnormal splitting. The molecular struc-
ture of 1 has a mirror plane passing through two oxygen atoms
and two fluorine atoms and a symmetry center located on the cen-
ter of cage (Fig. 1). This makes the four ethyl groups chemically
equivalent. The whole molecule was symmetrical, however, along
the pseudo-axially oriented C5-aryl substituents, the planes of
the aryl groups and H5 almost bisected the cage. One of hydrogen
atom of methylene is nearby phenyl ring the other is nearby H3, so
two hydrogen atoms of methylene are in different chemical envi-
ronments. The normal splitting of chemically equivalent methy-
lene resonances is just affected by the hydrogen atoms of the
neighboring methyl group. In this case, methylene splits quartet
peak (dd, 2J = 10.8 Hz) by the geminal coupling each other, and
each peak splits quartet (q, 3J = 7.2 Hz) by methyl group (C9). The
methylene resonance appears at 3.92 ppm with sixteen splits.
The hydrogen atoms (H9) of the methyl (C9) located at the end po-
sition of the ester group can rotate fast, thus eliminating the mag-
netic inequivalence. The corresponding signals appeared at
1.2 ppm with triplet splitting (q, 3J = 7.2 Hz).
4. Conclusions
Fig. 4. The partial 1H–13C COSY spectrum of 1.
The novel 6,12-bis(4-fluorophenyl)-3,9-dioxatetraasterane
(1, tetraethyl 2,4,8,10-tetramethyl-6,12-bis(4-fluorophenyl)-3,9-
dioxapentacyclo[6.4.0.02,7.04,11.05,10]dodecane-1,5,7,11-tetracar-
boxylate3,9-dioxatetraasterane) was synthesized by photocyclization
of diethyl 2,6-dimethyl-4-(4-fluorophenyl)-4H-pyran-3,5-dicar-
environment changed their conformations. Another ester group far
away from the appropriate hydrogen bond donor was blocked pos-
sibly by the torsion angle of this ester group (C11–O4–C12–C13,
117.3(3)°). The O1ꢁ ꢁ ꢁH–C18 and F1ꢁ ꢁ ꢁH–C6 hydrogen bond of the
cage stabilized the whole system, thus restricting the location of
every molecule.
boxylate (2) in solution.
A single-crystal X-ray diffraction
study for 1 shows that all of the bond angles within the tetrahydro-
pyran rings are in the range of 109.73(16)–114.89(16)° and that
these rings are appreciably more planar than the normal boat
conformation. The C–C–C bond linking the bridging carbon atoms
were similarly distorted from tetrahedral geometry. The 1H NMR
spectrum for 1 shows unusual splitting in the ester portions of
the molecule, which is attributed to magnetic inequivalence of
methylene H atoms due to the position of the nearby phenyl
ring.
The 13C NMR spectrum of 1 showed two signals at d 56.83 ppm
(assigned to the equivalent C1 and C2 atoms in the bridges) and at
d 77.28 ppm (assigned to the equivalent C3 and C4 atoms in the
bridges). In 1H NMR spectrum of 1, a six-proton singlet at d
1.67 ppm was assigned to the protons of the methyl groups (C6

X.-Q. Song et al. / Journal of Molecular Structure 1006 (2011) 489–493
493
Supplementary material
References
[1] W.J. Geldenhuys, S.F. Malan, J.R. Bloomquist, A.P. Marchand, C.J.V. Schyf, Med.
Res. Rev. 25 (2005) 21.
Crystallographic data for structural analysis reported in this
paper were deposited with the Cambridge Crystallographic Data
Centre under deposition number CCDC 711765. These data can
be obtained free of charge at www.ccdc.cam.ac.uk/conts/
retrieving.html.
[2] H. Yan, G.J. Xing, L.L. Zhou, J.Y. Huang, Chin. J. Org. Chem. 20 (2000) 649.
[3] A.J.H. Klunder, B. Zwanenburg, Chem. Rev. 89 (1989) 1035.
[4] P.E. Eaton, Angew. Chem., Int. Ed. Engl. 31 (1992) 1421.
[5] W.J. Geldenhuys, S.F. Malan, T. Murugesan, C.J.V. Schyf, J.R. Bloomquist, Bioorg.
Med. Chem. 12 (2004) 1799.
[6] A. Mdzinarishvili, W.J. Geldenhuys, T.J. Abbruscato, U. Bickel, J. Klein, C.J.V.
Schyf, Neurosci. Lett. 383 (2005) 49.
[7] Y.L. Janin, Bioorg. Med. Chem. 15 (2007) 2479.
Acknowledgements
[8] L.T. Eremenko, L.B. Romanova, M.E. Ivanova, V.S. Malygina, L.S. Barinova, G.V.
Lagodzinskaya, V.P. Lodygina, I.L. Eremenko, G.G. Aleksandrov, Russ. Chem.
Bull., Int. Ed. 56 (2007) 1408.
[9] A. Hilgeroth, A. Billich, H. Lilie, Eur. J. Med. Chem. 36 (2001) 367.
[10] H. Yan, C.L. Ni, H.Q. Wang, CN Patents, CN 101041662, 2007.
[11] H. Yan, H.Q. Wang, C.L. Ni, X.Q. Song, Acta Cryst. E 62 (2006) o1951.
[12] C.L. Ni, X.H. Song, H. Yan, X.Q. Song, R.G. Zhong, Ultrason. Sonochem. 17 (2)
(2009) 367.
This work was financially supported by National Natural Sci-
ences Foundation (No. 20872009) and Key Projects in the National
Science & Technology Pillar Program during the Eleventh Five-Year
Plan Period (No. 2008ZX10001-015).
Appendix A. Supplementary material
[13] G.M. Sheldrick, SHELXLS-97: Program for the Solution of Crystal Structure,
University of Göttingen, 1997.
[14] X.H. Zhu, C.L. Ni, H. Yan, R.G. Zhong, J. Photopolym. Sci. Technol. 22 (2009) 379.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.molstruc.2011.09.056.