Influence of the cis/trans configuration on the supramolecular aggregation of aryltriazoles

Article abstract of DOI:10.3762/bjoc.15.282

The ability of trans- and cis-1,2-glucopyranosyl and cyclohexyl ditriazoles, synthesized by CuAAC "click" chemistry, to form gels was studied, their physical properties determined, and the self-aggregation behavior investigated by SEM, X-ray, and EDC stud

Full text of DOI:10.3762/bjoc.15.282

Influence of the cis/trans configuration on the supramolecular
aggregation of aryltriazoles
Sara Tejera, Giada Caniglia, Rosa L. Dorta, Andrea Favero, Javier González-Platas
and Jesús T. Vázquez*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2019, 15, 2881–2888.
Instituto Universitario de Bio–Orgánica “Antonio González”,
Departamento de Química Orgánica, Universidad de La Laguna,
doi:10.3762/bjoc.15.282
38206 La Laguna, Tenerife, Spain
Received: 29 July 2019
Accepted: 08 November 2019
Published: 28 November 2019
Email:
Jesús T. Vázquez* - jtruvaz@ull.edu.es
Associate Editor: H. Ritter
*
Corresponding author
©
2019 Tejera et al.; licensee Beilstein-Institut.
Keywords:
License and terms: see end of document.
circular dichroism; cis/trans configuration; gels; triazole; X-ray
diffraction
Abstract
The ability of trans- and cis-1,2-glucopyranosyl and cyclohexyl ditriazoles, synthesized by CuAAC "click" chemistry, to form gels
was studied, their physical properties determined, and the self-aggregation behavior investigated by SEM, X-ray, and EDC studies.
The results revealed that self-assembly was driven mainly by π–π stacking interactions, in addition to hydrogen bonding, with the
aromatic rings adopting a high degree of parallelism, as seen in crystal packings and ECD data. Furthermore, π–bromine interac-
tions between the bromine atom of the aryl substituents and the triazole units might also contribute to an overall stabilization of the
supramolecular aggregation of bis(4-bromophenyl)triazoles. The trans or cis spatial disposition of the triazole rings is highly im-
portant for gelation, with the cis configuration having higher propensity.
Introduction
Structures self-assembled by noncovalent interactions give rise During the synthesis and characterization process of glucosyl
to supramolecular architectures with specific physical and/or mono- and ditriazole derivatives, which we carried out in order
chemical properties. Gels are colloid systems in which the to analyze the use of aryltriazoles for the determination of
dispersed phase has combined with the dispersion medium to absolute configuration [15], we serendipitously discovered that
yield a semisolid material. Gels from low-molecular-weight these glucosyl ditriazoles led to gels. Therefore, we carried out
gelators have potential applications in high-tech materials [1-3] the corresponding supramolecular studies and report herein the
and biomedical sciences [3-6]. Triazole derivatives have shown ability of ditriazoles to form gels, their physical properties, as
excellent gelation properties [7-10], in addition to a broad range well as the dependence of these properties on the cis/trans rela-
of biological activities [11-14].
tive configuration.
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Beilstein J. Org. Chem. 2019, 15, 2881–2888.
Results and Discussion
in position 2. Compounds 9 and 10 were selected to monitor the
A large set of mono- and ditriazoles was synthesized using effects of the unprotected hydroxy groups, and the last pair,
cycloaddition reactions based on "click" chemistry [16-18] of 14/12, for being a non-glycosyl system, yet with the same
azides and alkynes catalyzed by Cu(I) salts, the CuAAC reac- cis/trans relationship as the former compounds. In addition, the
tion. Self-assembling properties were not observed for any of available compounds 8a, 8b, and 8e (cis) [15] were also tested
the prepared monotriazoles, namely the 4-substituted for gelation to support the results.
1
-glucopyranosyltriazoles 1a–g and 2a–g (Scheme 1) [15].
However, most ditriazoles 7a–g and 8a–g (Scheme 2) showed Compounds 7 and 8 (Scheme 2) were successfully prepared
supramolecular features, i.e., their DMSO solutions prepared from the corresponding alkynes and diazides 5 and 6, respec-
for NMR analyses spontaneously transformed into gels inside tively. In this context, it was required to isolate 5 and 6 before
the NMR tubes.
the coupling reaction could be performed.
Three cis-/trans-configured pairs of compounds were chosen Compounds 9 and 10 (Scheme 3) were obtained in good yields
for a gelation ability study. Thus, analogue pairs 8f/7f by treatment of 7f and 8f, respectively, with sodium methoxide
(
Scheme 2), 10/9 (Scheme 3), and 14/12 (Scheme 4) were in CH2Cl2/MeOH.
selected. The pair 8f/7f was chosen for having different
anomeric configurations in the glucosyl system, and therefore The trans- and cis-1,2-di(triazol-1-yl)cyclohexanes 12 [14] and
different cis/trans relationships with the equatorial substituent 14 (Scheme 4), respectively, were prepared from 1-bromo-4-
Scheme 1: Structures of 4-substituted 1-glucopyranosyltriazoles 1a–g
and 2a–g [15].
Scheme 3: Compounds 9 (trans) and 10 (cis) [15].
Scheme 2: Synthesis of 1,2-cis-/trans-bistriazoles 7a–7g and 8a–8g [15].
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Beilstein J. Org. Chem. 2019, 15, 2881–2888.
Scheme 4: Synthesis of (1R,2R)- and (1R,2S)-1,2-bis-(4-(4-bromophenyl)-1H-triazol-1-yl)cyclohexane (12 and 14).
ethynylbenzene and their corresponding diazides, 11 and 13,
through CuAAC reactions [16-18].
As can be seen in Figure 1 and Table 1, all these compounds
except 9 (having a trans configuration) formed gels in DMSO
or DMSO/H2O mixtures. While the ditriazole species with an
α-anomeric configuration, 8f (cis), was able to form gels at dif-
ferent concentrations and DMSO/H2O ratios, its β-anomer 7f
(
trans) only formed a gel when the sample was exposed to a
Figure 1: Tube inversion test: gels formed by compounds 7f, 8f, 10,
2, and 14.
temperature of 8 °C in a refrigerator. This temperature gave rise
to an opaque gel that melted above 18 °C (Table 2). The same
approach, along with reduction of the minimum gelation con-
1
centration to 1.1% w/w (in DMSO) was used to obtain a gel was critically dependent on the cis/trans configuration present
based on 8f. In addition, this compound proved to be an effec- in the molecule.
tive translucent/transparent low-molecular-weight gelator in
aqueous solutions of DMSO, forming gels in DMSO/H2O, 2:1, To confirm this result, the supramolecular properties of trans-
v/v at a minimum concentration of 0.8% w/w. The presence of and cis-1,2-bis(4-(4-bromophenyl)-1H-triazol-1-yl)cyclo-
water favored gel formation, decreased the gelation concentra- hexanes 12 and 14, having the same configuration as com-
tion, and the gel's appearance became translucent/transparent. In pounds 7f and 8f, respectively, were analyzed. Both com-
addition, these gels were stable for several months in sealed pounds formed gels, but the trans stereoisomer 12 did so only at
vials, although they could be disrupted by agitation or heating. a low temperature (8 °C) in DMSO (G = 1.1, w/w), similar to
However, the gel state could be restored through cooling.
the β-anomer 7f, which possessed the same trans configuration.
On the other hand, the cis stereoisomer 14 formed an opaque
The triol 9 (trans) did not lead to any gel, while its α-anomer 10 gel at room temperature in DMSO/H2O, 9:1, v/v (G = 0.8,
cis) produced translucent and transparent gels, respectively, in w/w), showing a higher potency for gelation, similar to 8f. As
:1 and 1:2 ratios of DMSO/H2O, v/v (Table 1 and Table 2). In such, this relationship mirrors the behavior observed for the
(
1
addition, compound 10 (cis) exhibited the lowest minimum 7f/8f pair. Table 2 also contains the different Tgs values ob-
gelation concentration, 0.5% w/w in DMSO/H2O (1:2, v/v). tained by the dropping ball method.
Compounds having an α-anomeric configuration (cis), indepen- Supportive of these conclusions is the facility of cis-configured
dent of the hydroxy groups, were either acetylated (8f) or not ditriazoles to form gels. Thus, compound 8a, with alkyl groups
(
10), forming gels much easier than their corresponding in position 4 on the triazolyl groups, and compound 8e, with
β-anomers (trans). This showed that their ability to form gels tolyl groups in that position, gelled easily (Table 1 and Table 2).
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Beilstein J. Org. Chem. 2019, 15, 2881–2888.
Table 1: Gelation test results for compounds 7f, 8a, 8b, 8e, 8f, 9, 10, 12, and 14 (in % w/w).
#
Config
DMSO
DMSO/H2O
DMSO/H2O
(3:1, v/v)
DMSO/H2O
(2:1, v/v)
DMSO/H2O
(1:1, v/v)
DMSO/H2O
(1:2, v/v)
(
9:1, v/v)
7
f
f
β (trans)
α (cis)
G 1.1a
G 5.0
G 1.1a
–
–
p
p
p
p
p
p
8
G 0.8
G 0.8
9
β (trans)
α (cis)
trans
cis
cis
cis
s
s
s
–
p
p
s
p
p
–
–
–
p
s
p
p
p
G 0.5
p
p
susp
p
10
12
14
8a
8b
8e
G 0.7
p
p
susp
susp
G 1.0
G 1.1a
s
–
–
–
G 0.8
p
–
–
–
G 1.0
weak G
G 1.0
cis
susp
aGelling at T = 8 °C (refrigerator); G = gel; p = precipitate; s = soluble; susp = suspension.
Table 2: Critical gelation concentration (CGC, in % w/w) and gel–sol transition temperature (Tgs, via dropping-ball method) for compounds 7f, 8a, 8b,
8e, 8f, 10, 12, and 14.
#
Config
Conditions
CGC
Tgs (°C)
Appearance
7
8
8
8
8
f
f
f
f
f
β (trans)
α (cis)
α (cis)
α (cis)
α (cis)
α (cis)
α (cis)
trans
cis
cis
cis
cis
cis
DMSOa
DMSO
DMSOa
1.1
5.0
1.1
0.8
0.8
0.7
0.5
1.1
0.8
1.0
–
20 ± 2
63 ± 1
20 ± 2
93 ± 3
95 ± 3
68 ± 1
94 ± 3
20 ± 2
50 ± 2b
87 ± 3
–c
opaque
translucent
opaque
translucent
transparent
translucent
transparent
opaque
DMSO/H2O (3:1, v/v)
DMSO/H2O (2:1, v/v)
DMSO/H2O (1:1, v/v)
DMSO/H2O (1:2, v/v)
DMSOa
DMSO/H2O (9:1, v/v)
DMSO/H2O (2:1, v/v)
DMSO/H2O (2:1, v/v)
DMSO/H2O (1:1, v/v)
DMSO/H2O (2:1, v/v)
10
10
12
14
8a
8b
8e
8e
opaque
opaque
–
1.0
1.0
96 ± 2
92 ± 2
opaque
translucent
aGelling at T = 8 °C (refrigerator). bTube inversion test. cSoft gel: dropping-ball method failed.
In addition, 4-methoxycarbonyl-substituted ditriazole 8b also structure having thin and short fibers. The xerogel of com-
formed a gel, which was, however, too soft for the dropping pound 12 showed long, thin, and relatively straight fibers, with
ball method to be performed correctly. Therein, the ball lack of torsion, as well as regularity of the network. Its cis
dropped down immediately, and changing the DMSO/water stereoisomer 14 showed a fibrous network, but of much shorter
ratio did not improve this result. In any case, the results ob- length. However, the gel of compound 10 showed a different
tained using 8a and 8e point at the fact that the presence of morphology, with short and planar films or scales. This could
either the phenyl groups or the bromine atoms are not strictly be due to the high proportion of water in the gel and/or the pres-
necessary for gelation, although both might contribute to an ence of the three free hydroxy groups in its structure, changing
overall stabilization of the supramolecular aggregation.
its intermolecular self-assembly behavior.
Optical micrographs of the xerogels formed from compounds Various efforts were made to crystallize the obtained com-
f, 8f, 10, 12, and 14 were obtained by SEM (Figure 2). pounds; however, only 12 led to single crystals suitable for
7
Analyses of these images revealed typically fibrous networks X-ray crystallography. Its analysis (Figure 3) not only con-
for all except 10. Compound 7f (trans) showed a dense, thin, firmed the structure, but in addition showed a well-organized
short, and interlaced/tangled fiber network. The corresponding crystal packing (Figure 4) where the alternate disposition of the
α-anomer 8f (cis) exhibited an irregular, porous, and dense molecules displayed a parallelism between the p-bromophenyl
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Beilstein J. Org. Chem. 2019, 15, 2881–2888.
Figure 3: ORTEP representation of the molecular structure of com-
pound 12 (trans configuration) obtained from X-ray diffraction data.
Figure 2: SEM images of the xerogels of compounds 7f (DMSO, top
left), 8f (DMSO/H2O, 3:1, v/v, top right), 10 (DMSO/H2O, 1:1, v/v, mid-
dle left), 10 (DMSO/H2O, 1:2, v/v, middle right), 12 (DMSO, bottom
left), and 14 (DMSO/H2O, 9:1, v/v, bottom right).
groups as well as between the triazole rings, and therefore the
presence of multiple intermolecular π–π stacking and
π–bromine [19] interactions. This compound precipitated in the
presence of any amount of water and gelled only in DMSO at a
low temperature.
Figure 4: Crystal packing of compound 12 (trans configuration) in
DMSO.
Electronic circular dichroism (ECD) is a powerful technique to
study supramolecular systems [20,21], since many interactions
Compound 10 produced pseudo-crystals in DMSO/H2O (1:1, responsible for the presence of CD Cotton effects occur through
v/v) and its X-ray analysis was not accurate enough to resolve space, such as the well-known ECD exciton chirality method
its structure. However, its crystal packing (Figure 5) deserves [22-24].
discussion. As with compound 12, this packing revealed a num-
ber of π–bromine interactions [19], together with a high degree ECD of compound 10 in a DMSO/H2O (1:2, v/v) solution and
of π–π stacking interactions between the aromatic rings, and in gel form were successfully measured (Figure 6). ECD of the
also that they occured between specific phenyltriazoles. Specifi- solution exhibited negative first/positive second exciton Cotton
cally, these interactions formed between the phenyltriazole effects at 262 (Δε = −8.6) and 242 nm (Δε = +3.3), respectively
moieties in position 1 of a monosaccharide (A) and the phenyl- (Figure 6, in black), identical to those obtained for this com-
triazole functions in position 1 of its vicinal monosaccharide (B, pound in CH3CN [15], although of lower intensity. On the other
Figure 5, red lines). Similarly, the phenyltriazole substituents in hand, the ECD spectrum of the gel instead exhibited a normal
position 2 of this monosaccharide (B) interacted with a corre- Cotton effect at 253 nm (Δε = −3.8), which, at the same time,
sponding phenyltriazole in position 2 of the vicinal monosac- was the wavelength of its absorption maximum (Figure 6, in
charide (C, Figure 5, green lines). In addition, it is worth men- blue). The striking absence of exciton Cotton effects is in com-
tioning the presence of a number of DMSO solvate molecules plete agreement with the high degree of parallelism between the
in the crystal packing next to the hydroxymethyl group in posi- chromophores, as observed in the crystal packing (Figure 5).
tion 6 in the gg rotamer, likely linked through hydrogen bonds. Two chromophores can only be coupled under an exciton inter-
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Beilstein J. Org. Chem. 2019, 15, 2881–2888.
Figure 6: CD spectra of compound 10 (cis) in DMSO/H2O (1:2, v/v) in
solution (in black) and as gel (in blue).
formed hydrogen bonds between the hydroxymethyl groups in
position 6 and DMSO molecules while in a gg rotamer confor-
mation. The different types of EDC spectra obtained for com-
pound 10 in solution (exciton) and in gel (non-exciton), using
DMSO/H2O, 1:2, v/v, is in total agreement with the supramo-
lecular structure of the crystal packing of this compound
(
Figure 5).
Figure 5: Crystal packing of 10 (cis configuration) in DMSO/H2O (1:1,
v/v). Colored lines: π–π stacking interactions between phenyltriazoles
in positions 1 (red lines) and 2 (green lines).
Experimental
General information
action if the angle between the 1La transitions is different from 1H NMR spectra were recorded at 500 and 600 MHz, and
0
° or 180°, since this interaction is governed by an equation 13C NMR spectra at 100, 125, and 150 MHz (VTU 300.0 K).
with a vectorial product. The lack of exciton pairwise interac- Chemical shifts are reported in ppm. The residual solvent peak
tions between the two chromophores in positions 1 and 2 of was used as an internal reference. HRMS was performed by
each molecule could be due to the intercalation of a third HRTOFMS in positive mode (ES+). For analytical and prepara-
chromophore between the two former in a parallel disposition to tive thin-layer chromatography, silica gel ready-foils and glass-
one of them (see Figure 5).
backed plates (1 mm) were used, respectively. These were visu-
alized using UV light at λ = 254 nm and/or developed by
spraying with AcOH/H2O/H2SO4 (20:4:1, v/v/v) and heating to
Conclusion
In summary, the capacity of di-1,4-disubstituted 1,2,3-triazoles 150 °C. Column chromatography was performed using silica
to form gels was studied taking the dependence on the trans/cis gel (0.015–0.04 mm) and n-hexane/EtOAc solvent systems. All
configuration of the molecules into account. The results clearly reagents were obtained from commercial sources and used
show that compounds having the cis configuration are more without further purification. Solvents were dried and distilled
prone to forming thermoreversible gels than those with the before use. ECD was recorded in the range of 200–400 nm at
trans configuration. In fact, compound 10, with an α-anomeric room temperature by using 10 mm quartz cells. SEM images
configuration (cis), showed the lowest gelation concentration at were taken by a TEM, JEOL JEM 1010 belonging to the Elec-
room temperature (G 0.5% w/w) in DMSO/H2O, 1:2, v/v.
tronic Microscopy Service (SEGAI) of the University of La
Laguna, Spain.
The crystal structures obtained for either the cis or trans config-
uration through X-ray diffraction studies can be considered Compounds 7f, 8f, 9, 10, 11, and 12 were prepared and charac-
good approximations to the supramolecular structure of aryltria- terized as described in reference [15].
zoles in gels. Thus, these compounds showed a high degree of
parallelism between the phenyltriazolyl rings, therefore Gelation test
revealing the presence of π–π stacking and π–bromine interac- Melting points were measured using the dropping ball method.
tions. In addition, compound 10 (cis), with free hydroxy groups, For that, a stainless steel ball of ca. 3 mm diameter (m =
2
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Beilstein J. Org. Chem. 2019, 15, 2881–2888.
1
1
30.2 mg) was placed on the gel in a tube with a diameter of (m, 8H), 7.18 (s, 2H), 5.18 (m, 2H), 2.57 (m, 2H), 2.34 (m, 2H),
cm. This was placed inside an oil bath together with a ther- 2.19 (m, 2H), 2.77 ppm (m, 2H); 13C NMR (150 MHz, CDCl3)
mometer, and the temperature of the gel melting was recorded. δ 146.2, 131.9, 128.9, 127.1, 122.2, 119.9, 60.8, 28.0, 22.3
ppm; HRESIMS (m/z): [M + Na]+ calcd for C22H2079Br2N6Na,
Synthesis and characterization
549.0014; found, 549.0023; [M + Na]+ calcd for
,2-Bis[4-(4-bromophenyl)-1H-1,2,3-triazol-1-yl]-1,2- C22H2079Br81BrN6Na, 550.9993; found, 551.0006; [M + Na]+
1
dideoxy-α-ᴅ-glucopyranoside (10): This compound was pre- calcd for C22H2081Br2N6Na, 552.9973; found, 552.9977; anal.
pared as described before [15]. UV (CH3CN) λmax (ε) 253 nm calcd for C22H20Br2N6, C, 50.02; H, 3.82; N, 15.91%; found,
(
48000); CD (CH3CN) λext (Δε) 242 (+8.9), 261 (−26.5), C, 49.67; H, 3.90; N, 16.22%.
2
2
99 nm (+1.1); CD (DMSO:H2O, 1:2, v/v) λext (Δε) 242 (+3.3),
62 (−8.6), 295 nm (+3.0); CD of gel (DMSO:H2O, 1:2, v/v)
Supporting Information
λext (Δε) 253 nm (−3.8).
Supporting Information File 1
An SEM image collection of the xerogels and X-ray data
for compound 12.
(
1R,2S)-1,2-Diazidocyclohexane (13): For the synthesis of this
compound, (1R,2S)-1,2-diaminocyclohexane and TfN3 were re-
quired. (a) The triflyl azide was prepared as follows: Sodium
azide (922 mg, 14.2 mmol), dissolved in pyridine (15 mL), was
cooled to 0 °C under vigorous stirring. Then, triflic anhydride
[
https://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-15-282-S1.pdf]
(
1.7 mL, 10.1 mmol) was added dropwise, and the reaction
mixture was left for 2 h at 0 °C under vigorous stirring. During Acknowledgements
that time, a small amount of precipitate appeared, which was re- This work was supported by the Spanish MINECO and cofi-
moved by filtration. The yellow solution was directly used in nanced by the European Regional Development Fund (ERDF)
the next step. (b) To a solution of (1R,2S)-1,2-diaminocyclo- CTQ2014-56362-C2-1-P. The authors thank Prof. David Díaz
hexane (0.42 mL, 3.5 mmol) in 5 mL of pyridine, CuSO4·5H2O (University of Regensburg) for his help and useful suggestions.
(
15 mg, 0.06 mmol) was added while stirring. The mixture was
cooled in an ice bath and the above-prepared solution of triflyl ORCID® iDs
azide added dropwise. The resulting green reaction mixture was
allowed to warm to room temperature and left for 20 h. The
reaction mixture was diluted with CH2Cl2 (100 mL) and
extracted using diluted HCl until the pH value was acidic
Giada Caniglia - https://orcid.org/0000-0002-8116-0131
Rosa L. Dorta - https://orcid.org/0000-0002-4565-0301
Andrea Favero - https://orcid.org/0000-0001-5119-2071
Javier González-Platas - https://orcid.org/0000-0003-3339-2998
Jesús T. Vázquez - https://orcid.org/0000-0002-3622-3148
(
(
4 × 20 mL). The organic phase was washed with NaHCO3
2 × 10 mL) and dried with sodium sulfate. Then, the organic
solvent was removed at reduced pressure, keeping the tempera- References
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