1,3,4-Oxadiazoles for crystal engineering. convenient synthesis and self-assembly: Nonchiral chains versus chiral helices

Article abstract of DOI:10.1021/cg400649h

A series of new 1,3,4-oxadiazoles containing carboxylic and halogen groups and a double bond have been synthesized in good yields and a multigram scale. This was achieved at room temperature from readily available 1,2-diacylhydrazines using a cheap conden

Full text of DOI:10.1021/cg400649h

Article
pubs.acs.org/crystal
1,3,4-Oxadiazoles for Crystal Engineering. Convenient Synthesis and
Self-Assembly: Nonchiral Chains versus Chiral Helices
Oleksii V. Gutov*
Institute of Organic Chemistry, NAS Ukraine, Murmanska st. 5, Kyiv 02094, Ukraine
S
* Supporting Information
ABSTRACT: A series of new 1,3,4-oxadiazoles containing carboxylic and
halogen groups and a double bond have been synthesized in good yields and a
multigram scale. This was achieved at room temperature from readily available
1,2-diacylhydrazines using a cheap condensation reagent (the solution of P2O5 in
H2SO4). Single-crystal X-ray diffraction analysis has shown that all studied 1,3,4-
oxadiazole-containing acids are self-assembled by intermolecular H-bonds into
supramolecular zigzag chains or helices, depending on the tecton molecular
structure and the type of H-bonding. Factors affecting helix formation have been
found, and a Cambridge Structural Database (CSD) survey has been performed
to support these findings. Moreover, it has been demonstrated that the tuning of
the crystal structure leading to spontaneous symmetry breaking for supramolecular helices based on nonchiral molecules is
possible even by as little change in molecular structure as a shift from an isopropyl substituent to a cyclopropyl. Subsequently, the
studied 1,3,4-oxadiazole-containing acids and related compounds are found to be easily accessible building blocks for crystal
engineering of new chiral materials with tunable supramolecular arrangement.
bond acceptors separated by two to three single bonds,
allowing a variety of different conformations. The present work
describes the illuminating results of the self-assembly studies of
1,3,4-oxadiazole-containing carboxylic acids in the crystal state,
which reveal the dependence of helical supramolecular
structure on the tectone molecular composition. The current
paper also demonstrates the efficient and convenient room
temperature synthesis of the series of new 1,3,4-oxadiazoles
using as original dehydration reagent a solution of P2O5 in
sulfuric acid. Different substituents were introduced to the
1,3,4-oxadiazoles to study their effect on crystal packing of
labile polydentate organic ligands.
INTRODUCTION
■
1,3,4-Oxadiazoles exhibit an exceptionally wide range of
biological activities including anticancer, anti-inflammatory,
antidiabetic, fungicidal, herbicidal, pesticidal, analgesic, anti-
convulsant, anti-HIV, antibacterial, antihypertensive, antiobesity
and plant growth regulator activities.1 Furthermore, azole-
containg carboxylic acids possess high potential as polydentate
ligands for the synthesis of metal−organic frameworks for
storage, separation, catalysis, or other applications. Therefore,
efficient synthetic methods are necessary to afford new 1,3,4-
oxadiazoles, and evaluate their properties (which can be
estimated by crystal structure and self-assembly investigations).
Moreover, 1,3,4-oxadiazole-based mimics have been selected as
useful peptidomimetics for different purposes, including helical
secondary structure emulation.2 Design of helical structures is
of particular interest3 due to their chiral nature.
Substantial progress has been made recently in crystal
structure prediction;4 however, the design of organic crystals
with desired space group symmetry and controlled arrangement
of supramolecular motifs still remains a great challenge. The
elucidation of the self-assembly principles of organic molecules
is of paramount importance to resolve countless biological
phenomena, design and create new functional materials, etc.
Complete understanding of these processes (especially those
leading to spontaneous symmetry breaking5) still has not been
achieved. Therefore the current study strives to investigate this
problem.
EXPERIMENTAL SECTION
■
NMR spectra were recorded on Bruker Avance and Varian VXR-300
spectrometers. Chemical shifts are reported in ppm units relative to
the residual solvent signals. 1,2-Diacylhydrazines were synthesized
using literature procedures.7,8 Single crystals suitable for X-ray
diffraction measurements were obtained by the recrystallization of
1,3,4-oxadiazoles from ethanol.
General Cyclization Method. The corresponding 1,2-diacylhy-
drazine (X mol as indicated) was added under mechanical stirring
during 1−2 h at room temperature to a solution of 270X g of P2O5 in
270X mL of H2SO4. After 12 h of stirring, the resulting mixture was
poured into an aqueous solution of sodium hydrogen carbonate. The
mixture was extracted with dichloromethane. The solvent was
removed in vacuo, and the residue was purified by recrystallization
from an appropriate solvent or by vacuum distillation.
Our research is focused on the self-organization of labile
polydentate organic ligands.6 3-(1,3,4-Oxadiazol-2-yl)propionic
and acryl acids were selected as very appropriate candidates for
these studies since they possess a H-bond donor and several H-
Received: April 28, 2013
Revised: July 18, 2013
© XXXX American Chemical Society
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1a. X = 0.029 mol (5 g). Yield 0.9 g (20%, low due to the high water
best of our knowledge this simple but useful reagent was not
mentioned previously in the literature.
1
solubility). Mp 80 °C. H NMR (300 MHz, DMSO-d6): δ 12.37 (s,
1H), 2.99 (s, 2H), 2.70 (s, 2H), 2.50 (s, 3H). 13C NMR (75.4 MHz,
DMSO-d6): δ 172.8, 165.7, 163.5, 29.8, 20.3, 10.4. Anal. Calcd for
C6H8N2O3: C, 46.15; H, 5.16; N, 17.94. Found: C, 46.18; H, 5.19; N,
17.91.
a
Scheme 1
1
1b. X = 0.5 mol (101 g). Yield 67 g (73%). Mp 76 °C. H NMR
(400 MHz, DMSO-d6 + CCl4): δ 12.31 (s, 1H), 3.16 (m, 1H), 3.01 (t,
2H), 2.71 (t, 2H), 1.28 (d, 6H, J = 6.9 Hz). 13C NMR (75.4 MHz,
DMSO-d6): δ 172.8, 170.3, 165.6, 29.8, 25.6, 20.4, 19.7. Anal. Calcd
for C8H12N2O3: C, 52.17; H, 6.57; N, 15.21. Found: C, 52.12; H, 6.60;
N, 15.24.
a
R = Me (1a), i-Pr (1b), c-Pr (1c), or phenyl (1d).
1
1c. X = 0.14 mol (28 g). Yield 17.3 g (68%). Mp 86−88 °C. H
Synthetic details are provided in the Experimental Section.
Generally, readily available 1,2-diacylhydrazines7,8 have been
converted to the corresponding desired 1,3,4-oxadiazoles by
stirring at room temperature in a solution of P2O5 in H2SO4.
Fortunately this method also successfully affords a variety of
other new 1,3,4-oxadiazoles, such as 3−5 (bearing carboxyl and
haloalkyl groups and a double bond, see structures below),
confirming its wide applicability. Most of the 1,3,4-oxadiazoles
have been obtained with high yields (up to 91%) on a
multigram scale (up to 90 g). Together with the low price of all
the required reagents, it makes this new pathway to the 1,3,4-
oxadiazole system attractive for industrial applications.
NMR (400 MHz, DMSO-d6): δ 13.32 (s, 1H), 2.98 (t, 2H), 2.69 (t,
2H), 2.18 (m, 1H), 1.11 (d, 2H), 0.96 (s, 2H). 13C NMR (75.4 MHz,
DMSO-d6): δ 172.8, 167.8, 165.0, 29.8, 20.3, 7.7, 5.7. Anal. Calcd for
C8H10N2O3: C, 52.74; H, 5.53; N, 15.38. Found: C, 52.69; H, 5.56; N,
15.42.
1
1d. X = 0.59 mol (140 g). Yield 90 g (70%). Mp 138−140 °C. H
NMR (400 MHz, DMSO-d6): δ 12.44 (s, 1H), 7.97 (d, 2H, J = 6.8
Hz), 7.60 (m, 3H), 3.14 (t, 2H), 2.81 (t, 2H). 13C NMR (75.4 MHz,
DMSO-d6): δ 173.2, 166.3, 164.2, 131.9, 129.5, 126.6, 123.8, 30.2,
20.9.
3. X = 0.335 mol (66.9 g). Yield 51.2 g (84%). Mp 85−90 °C.1H
NMR (400 MHz, CDCl3): δ 10.19 (s, 1H), 6.78 (d, 1H, J = 13 Hz),
6.49 (d, 1H, J = 13 Hz), 3.24 (m, 1H), 1.40 (d, 6H, J = 6.8 Hz). 13C
NMR (75.4 MHz, DMSO-d6): δ 170.9, 166.7, 161.3, 131.3, 117.5,
25.8, 19.8. Anal. Calcd for C8H10N2O3: C, 52.74; H, 5.53; N, 15.38.
Found: C, 52.70; H, 5.57; N, 15.41.
1
4. X = 0.462 mol (92.4 g). Yield 77.3 g (82%). Mp 160 °C. H
NMR (400 MHz, DMSO-d6): δ 13.38 (s, 1H), 7.92 (m, 1H), 7.76 (m,
3H), 2.55 (s, 3H). 13C NMR (125.7 MHz, DMSO): δ 168.1, 164.5,
164.2, 133.0, 132.2, 132.1, 130.8, 130.2, 123.9, 10.9. Anal. Calcd for
C10H8N2O3: C, 58.82; H, 3.95; N, 13.72. Found: C, 58.78; H, 4.00; N,
13.76.
Supramolecular Structures. Molecular and crystal
structures of 1,3,4-oxadiazole-containing acids 1a,b,c,d and 3
have been determined by the X-ray diffraction method (for
details, see Supporting Information). It has been found that in
all the studied crystals, molecules form endless supramolecular
chains or nets defined by intermolecular H-bonds. In the case
of compound 1a, solvent water molecules are incorporated into
this supramolecular architecture, preventing the formation of
the COO−H···N bonding motif common to all of the
remaining compounds in this series. In the following, we
focus only on nonsolvated structures.
In the crystals of nonhydrated compounds 1b,c,d and 3,
molecules are self-assembled (by two types of COO−H···N
hydrogen bonds with similar geometrical parameters, summar-
ized in the Supporting Information) into two different
associations depending on which of the two oxadiazole nitrogen
atoms participates (Figure 1).
Molecules of the compounds 1d and 3 form zigzag chains
connected by the α-type hydrogen bonds (Figure 2); however,
if the bonding mode is shifted from α to β (compounds 1b and
1c), the supramolecular arrangement of the H-bonded
associates is changed from zigzag chains to 3D helices with a
screw axis along the chains (Figure 3).
This shift in the bonding mode has led us to the assumption
that the particular supramolecular architecture assumed by the
1,3,4-oxadiazole-containing carboxylic acids depends upon
which H-bonding mode is followed. In order to check the
generality of this assumption, a CSD survey has been
performed. Since only one crystal structure of an 1,3,4-
oxadiazole-containing carboxylic acid has been reported so far
(which in fact shows the same binding mode as our helical
oxadiazoles and finally adopts helical arrangement as well,
Supporting Information, Figure S1f), we have done an
5. X = 0.228 mol (40.5 g). Yield 33.3 g (91%). Colorless liquid, bp
1
100 °C/2 mmHg. H NMR (400 MHz, DMSO-d6): δ 3.74 (t, 2H),
2.95 (t, 2H), 2.46 (s, 3H), 2.15 (m, 2H). 13C NMR (125.7 MHz,
CDCl3): δ 165.6, 163.6, 43.5, 28.8, 22.4, 10.7. Anal. Calcd for
C6H9ClN2O: C, 44.87; H, 5.65; N, 17.44. Found: C, 44.83; H, 5.68; N,
17.48.
RESULTS AND DISCUSSION
■
Synthesis of 1,3,4-Oxadiazoles. The most commonly
encountered pathway to the 1,3,4-oxadiazole system is the
cyclization of readily available 1,2-diacylhydrazines.9 However,
in our case (general formula 1), this process is complicated
because of the presence of a carboxyl group, which is often
affected by the dehydration reagents. We screened different
synthetic conditions for the cyclization of 1,2-diacylhydrazines.
It has been found that the most widely used reagents for such
cyclization, thionyl chloride and phosphorus oxychloride,
instead of desired 3-(5-alkyl-1,3,4-oxadiazol-2-yl)propionic
acids produce mainly N-(2,5-dioxo-pyrrolidin-1-yl)-alkanoyla-
mide 2, where the carboxyl group is involved in cyclization
(Scheme S1, Supporting Information). The protection−
deprotection of the carboxyl group also does not seem to be
useful due to the possible hydrolysis of the 1,3,4-oxadiazole ring
in acidic and basic media. Polyphosphoric and sulfuric acids
(which have been successfully applied for the facile formation
of 3-(5-phenyl-1,3,4-oxadiazol-2-yl)propionic acids7) do not
work in the case of dialkyl-1,3,4-oxadiazoles. The usage of
oleum as a dehydration reagent also leads to the product 2.
Finally we have found that only the mixture P2O5−H2SO4 as a
dehydration reagent provides the desired, previously unknown
5-alkyl-1,3,4-oxadiazole propionic acids 1 (Scheme 1). To the
B
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atoms in the molecule between the H-bond donor and
acceptor.
a
Scheme 2. Queries Used for the CSD Search
a
X = N, O; Y = C, N, O; Z = any non-metal.
Figure 1. α (left) and β (right) H-bonding modes in oxadiazole-
containing acids leading to different supramolecular arrangement. X =
(CH2)2 for 1b,c,d and (CH)2 for 3.
The search using the query “A” provided us with 275
structures of organic molecules, among which only 25 possess
the same bonding mode (β) as our helical oxadiazoles. Most of
these 25 structures adopt a helical arrangement of H-bonded
chains as well (Supporting Information Table S2, Figure S1),
demonstrating a general tendency in β H-bonded tectones to
form helical supramolecular structures. Additionally two more
helical supramolecular associations have been found in the
structures based not on the β bonding mode but on a similar
arrangement formed by the same number of atoms in the
monomer between the H-bond donor and acceptor as in 1b
and 1c (Supporting Information, Figure S2). There are several
exceptions (where β bonding mode does not lead to a screw
axis, Supporting Information, Figure S3), in which additional
strong intermolecular interactions (such as ionic and multiple
H-bonding, π-stacking) appear to determine the crystal
arrangement.
Further generalization of this study is possible only after
much wider analysis of the CSD. For example, the query “B”
search covers all organic structures containing H-donor and
acceptor distant by the same number of atoms as in 1b and 1c
but without the restriction for five-membered heterocyclic
carboxylic acids. Such a search in the current version of CSD
provided 72423 structures, and the study of all of them is
beyond the scope of the current paper.
Figure 2. Crystal packing of 1d (top) and 3 (bottom).
We have found also several helical supramolecular associa-
tions formed by α H-bonds as a result of the query “A” search.
This indicates that helicates are probably common for long
labile chains generally, which is supported by many well-known
examples in Nature. So there should be an additional reason
why the H-bonded associations of compounds 1d and 3, as
previously mentioned, do not necessarily lead to a helical
supramolecular structure. Similarly to the exceptions presented
in Table S2 and Figure S3 (Supporting Information), the
reason is an additional intermolecular interaction; here that is
the π-stacking effect, which plays a substantial role in the crystal
packing of the compounds 1d and 3 due to the extended π-
orbital surface with the presence of a phenyl ring or a double
bond. In compound 1d, neighboring H-bonded chains are
stabilized by the π-stacking of the phenyl and oxadiazole rings
(Supporting Information, Figure S4) with shortest C−C
distances of about 3.3 Å. In compound 3, molecules in the
neighboring H-bonded chains are linked by the π-stacking of
the double bond with the oxadiazole moiety (Supporting
Information, Figure S5, the shortest contact, C−C 3.32 Å).
Figure 3. Right- and left-handed symmetrical helices in 1b (left) and
two different but one-handed helices in 1c (right). Helical pitch is
10.98 Å in 1b and 11.85 Å in 1c.
extended CSD-search. For that we used the query “A” (Scheme
2) covering all common five-membered heterocyclic carboxylic
acids bearing H-bond donors (N,O) with the same number of
C
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In contrast, there is no obvious π-stacking in the crystals of
compounds 1b and 1c, and finally the molecules are organized
into supramolecular helices by β-H-bonding.
that covers all common five-membered heterocyclic acids with
the same number of atoms in the molecule between the H-
bond donor and acceptor as in 1b and 1c. Moreover, it has
been shown that the tuning of crystal structure, which leads to
spontaneous symmetry breaking for supramolecular helices
based on nonchiral molecules, is possible even by as little
change in molecular structure as a shift from an isopropyl
substituent to a cyclopropyl. Subsequently, studied 1,3,4-
oxadiazole-containing acids and related compounds are found
to be easily accessible building blocks for crystal engineering of
new chiral materials with tunable supramolecular arrangement
that depends on a type of substituents.
Extremely interesting is the fact that the small difference
between isopropyl and cyclopropyl groups of 1b and 1c leads
to a substantial difference in supramolecular structure. The
space group is changed with the spontaneous chiral resolution
of enantiomeric forms of 1c helices (Figure 3). The crystal of
isopropyl-substituted 1b belongs to the nonchiral space group
Pbca and consists of antiparallel enantiomeric helices. (Racemic
mixtures commonly crystallize in nonchiral space groups.) In
contrast, the crystal of cyclopropyl-substituted compound 1c is
chiral (space group P21); it consists of parallel homochiral
supramolecular helices. In this case, asymmetry is apparently
compensated by the existence of the molecule in two
conformations differentiated by the cyclopropyl group
orientation (Figure 4). This packing motif probably cannot
be achieved by molecules like 1b bearing the bulkier isopropyl
group.
ASSOCIATED CONTENT
■
S
* Supporting Information
Compound 2 synthesis scheme, geometry parameters of
hydrogen bonds in the compounds 1b,c,d and 3, the results
of the CSD survey, crystal packing of 1d and 3, crystallographic
parametrs and thermal ellipsoid plots for the studied 1,3,4-
oxadiazoles, and copies of the 1H NMR and 13C NMR spectra.
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: AVGutov@gmail.com.
Present Address
†Center for Nanofabrication and Molecular Self-Assembly,
Northwestern University, 2145 Sheridan Road, Evanston, IL
60208-3113, USA.
Figure 4. Two different one-handed helices in the 1c crystal. The
cyclopropyl group is oriented toward the oxadiazole oxygen atom
(upper strand) or the nitrogen atom (lower strand). Hydrogen atoms
have been omitted for clarity.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The author is grateful to Prof. A. N. Chernega, Dr. E. B.
Rusanov, and Yu. G. Vlasenko for support and fruitful
discussions and to Dr. V. V. Pirozhenko for assistance with
the NMR spectra. The work has been done in the Institute of
Organic Chemistry, National Academy of Sciences of Ukraine,
under its support.
The difference in crystal packing of two very similar
compounds (1b and 1c) demonstrates that the chiral resolution
leading to enantiomerically pure crystals of achiral compounds
can be selected by Nature as just one of the possible tools for
the energy minimization. These tools are the subject of our
further studies, involving a wide range of related substrates,
with the aim to discover the principles underlying homochiral
self-assembly of nonchiral molecules and finally rational design
of new chiral materials.
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The current paper demonstrates the efficient and convenient
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