Synthesis, Secondary Structure, and Anion Binding of Acyclic Carbohydrate-Derived Oligo(amide-triazole)s

Article abstract of DOI:10.1002/ejoc.201801320

A family of linear, carbohydrate-derived oligo(amide-triazole)s has been designed and synthesized. These molecules possess a regular distribution of triazole rings (from one to four) linking the carbohydrate units to give dimer to pentamer derivatives. Their binding to halide anions was qualitatively analyzed by means of NMR spectroscopy and mass spectrometry. All the compounds were able to bind chloride anions, with a stoichiometry that depended on the chain length. The dimer and trimer gave 2:1 host/chloride ratio, while the tetramer and pentamer gave 1:1 complexes. The secondary structure of the oligo(amide-triazole)s was studied using NMR spectroscopy and circular dichroism. These studies showed that the larger host molecules (tetramer and pentamer) adopted a stabilized U-turn and were able to bind just one chloride anion. Only the pentamer displayed a helical conformation, which was slightly distorted in the presence of chloride salts. Interestingly, chloride binding involves not only the triazole-CH but also H atoms from the carbohydrate moieties. These compounds could be applied for chloride sensing by ESI-MS.

Full text of DOI:10.1002/ejoc.201801320

A Journal of
Accepted Article
Title: Synthesis, Secondary Structure and Anion Binding of Acyclic
Carbohydrate-derived Oligo(amide-triazole)s
Authors: Daniela M. Fidalgo, Maria Eugenia Monge, Oscar Varela, and
Adriana Kolender
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to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201801320
Link to VoR: http://dx.doi.org/10.1002/ejoc.201801320
Supported by

10.1002/ejoc.201801320
European Journal of Organic Chemistry
FULL PAPER
Synthesis, Secondary Structure and Anion Binding of Acyclic
Carbohydrate-derived Oligo(amide-triazole)s
Daniela M. Fidalgo,[a,b] María Eugenia Monge,[c] Oscar Varela,*[a,b] and Adriana A. Kolender*[a,b]
Abstract: A family of linear, carbohydrate-derived oligo(amide-
triazole)s has been designed and synthesized. These molecules
possess a regular distribution of triazole rings (from one to four)
linking the carbohydrate units to give dimer to pentamer derivatives.
Their binding to halide anions was qualitatively analyzed by means
of NMR spectroscopy and mass spectrometry. All the compounds
nitrogen donors, carbanionic and mesoionic carbene donors.[11]
The groups of Flood,[12,13] Craig,[14] Hecht,[15] Beer,[16] Schubert,[17]
and Kubik[18-21] have significantly contributed to the study of
1,2,3-triazoles as anion receptors. Oligo and polytriazoles can
adopt a U-turn conformation either mediated by metal cations or
anions, or by dipole-dipole interactions. If the two ends of a U-
turn structure are very bulky or the number of triazole rings
increases, the chain ends would not align on the same plane,
were able to bind chloride anions, with
a stoichiometry that
depended on the chain length. The dimer and trimer gave 2:1
host:chloride ratio, while the tetramer and pentamer gave 1:1
complexes. The secondary structure of the oligo(amide-triazole)s
was studied using NMR spectroscopy and circular dichroism. These
studies showed that the larger host molecules (tetramer and
pentamer) adopted a stabilized U-turn and were able to bind just one
chloride anion. Only the pentamer displayed a helical conformation,
which was slightly distorted in the presence of chloride salts.
Interestingly, chloride binding involves not only the triazole-CH but
also H atoms from the carbohydrate moieties. These compounds
could be applied for chloride sensing by ESI-MS.
but would form
a
helical structure.[22] Rotational flexible
oligotriazole molecules can adopt a reinforced chiral helical
conformation upon binding to chloride anion; in this conformation
they were able to induce high levels of chirality via a close chiral
anion-pair complex.[23] Anion receptor chemistry deals with the
design of molecules that are able to recognize, respond to, or
sense species carrying
a
negative charge. This area of
wide number or
supramolecular chemistry comprises
a
applications, including organocatalysis, separation of anion
mixtures in industrial or radioactive waste, and development of
anion sensors capable of detecting trace levels of anionic
species.[24] Recently it has been reported the application of click
prodiginines, soluble in DMSO, as anionophores able to promote
transmembrane anion permeation in cells.[25]
Introduction
In a previous work[26] we have reported the microwave-assisted
The copper(I) assisted azide-alkyne cycloaddition (CuAAC),
developed by Sharpless and Meldal,[1,2] is a prototype of a click
reaction.[3] This reaction leads to the formation of 1,4-
disubstituted 1,2,3-triazole rings; while in the ruthenium(II)-
catalyzed version of the cycloaddition, 1,5-disubstituted are
formed instead.[4] In the absence of a metal catalyst, a mixture of
both disubstituted triazole rings are usually obtained.[5]
Disubstituted 1,2,3-triazole rings have been considered as non-
classical mimetics of peptide linkages in terms of geometry and
electronic properties, being the 1,4- or 1,5-disubstituted isomers
respective surrogates of trans and cis peptide bonds.[6-8] Besides,
the hydrogen bonding donor capability of the amide N-H could
be replaced by the triazole C-H bond.[9,10] The 1H-1,2,3-triazoles
and their derivatives are attractive molecules due to their unique
combination of accessibility and diversity of supramolecular
interactions. The ring contains a highly polarized C-H linkage
that allows anion complexation by hydrogen bonding, as well as
metal N- or C-coordination with anionic, neutral, or cationic
CuAAC
polymerization
of
bio-based
α-azide-ω-alkyne
monomers 2, that afforded stereoregular poly(amide-triazole)s 3
with high regioselectivity (Scheme 1). The monomers were
prepared starting from
D
-glucono-1,5-lactone (1), an inexpensive
-glucose, as
and commercially available derivative of
D
a
renewable resource. The poly(amide-triazole)s were highly
insoluble in water and in most organic solvents, except for TFA-
DMSO. Moreover, they were stable to acid (0.5 m
M TFA, 40 °C,
7 days) or alkaline (0.5 mM NaOH, 40 °C, 7 days) conditions.
These results suggested that the polymer chains were closely
packed to form a complex network stabilized by hydrogen
bonding and dipolar interactions. Due to their high nitrogen
content, the polymers were assayed as metal-trapping agents.
The preliminary studies showed an acceptable retention of
metals, as CuII and CrVI.
[a]
Lic D. M. Fidalgo, Dr O. Varela, Dr A. A. Kolender
Universidad de Buenos Aires. Facultad Ciencias Exactas y
Naturales,
Departamento de Química Orgánica. Ciudad Universitaria, Pab. 2,
C1428EHA, Buenos Aires, Argentina
E-mail: adrianak@qo.fcen.uba.ar; varela@qo.fcen.uba.ar
https://www.qo.fcen.uba.ar/personal/profesores/
Lic D. M. Fidalgo, Dr O. Varela, Dr A. A. Kolender
Consejo Nacional de Investigaciones Científicas y Técnicas
(CONICET)-UBA Centro de Investigación en Hidratos de Carbono
(CIHIDECAR).
[b]
[c]
Dr M. E. Monge
CONICET, Centro de Investigaciones en Bionanociencias (CIBION).
Godoy Cruz 2390, C1425FQD, Buenos Aires, Argentina
Scheme 1. Poly(amide-triazole)s obtained from D-glucono-1,5-lactone
Supporting information for this article is available on the WWW
under http://dx.doi.org/.
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European Journal of Organic Chemistry
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The poly(amide-triazole)s 3a-3c possessed stereocenters that
could induce defined preferred conformations, and the rigid
bicyclic system of condensed 1,3-dioxane rings could lead to
additional conformational constraints. The triazole rings in the
polymer chain should be able to induce a local U-turn with the
rigid carbohydrate moieties, in combination with the flexibility
with tosyl chloride gave compound 10a as main product,
together with a minor amount of chlorinated compound 10b.
These compounds were isolated by column chromatography
and both of them yielded azide 11, upon reaction with NaN3. The
overall yield of 11 from ω-hydroxyacid 8 was 55%, and 40% from
D
-glucono-1,5-lactone.
provided by the methylene spacers of the repeating units. In fact, Microwave-assisted CuAAC was conducted between azide 11
some observed NOE contacts corresponding to triazole-CH with
amide-NH, H-4 and H-5 (from the carbohydrate residue)
suggested that some regions of the polymer could adopt a
helical conformation. With the aim of exploring conformational
preferences derived from the combination of stereochemical
features, amide and triazole interactions, with increasing
polymerization degree, herein we report the synthesis of a series
and alkyne 12, to give the dimer 4 as the first amide-triazole
derivative of the series (Scheme 2). Further substitution by azide
(DMF, 60 °C, 18 h) gave the expected 13a (56% yield) together
with compound 13b (22% yield). This by-product was produced
by abstraction of the Hα to carbonyl group and elimination of the
β-substituent. However, shorter reaction time and higher
temperature under microwave (Mw) irradiation improved the
yield of the desired product 13a (81%, after purification). The
CuAAC reaction of ω-azide-α-ester 13a with alkyne 12 yielded
trimer 5, with two 1,4-disubstituted-triazole rings. The
subsequent substitution of tosyl group by azide to give
compound 14, was also carried out with conventional heating or
under Mw irradiation. In the case of conventional heating, the
desired azide 14 was obtained (80% yield) after 24 h, with minor
amounts of unsaturated by-product. Although Mw irradiation
gave a lower yield (70%), it was preferred since complete
conversion was achieved in only 1 h, without formation of the
unsaturated derivative. The solubility of the oligo(amide-
triazole)s decreased with the chain length and precluded
purification by column chromatography or recrystallization.
However, compound 14 was obtained in an acceptable degree
of purity and was subjected to CuAAC reaction with alkyne 12,
to give tetramer 6. The low solubility of the oligomers of
increasing chain length also forced us to increase the solvent
polarity for the CuAAC reaction. For dimer 4, the cycloaddition
was carried out in acetonitrile; while for trimer 5 and tetramer 6,
of oligo(amide-triazole)s 4-7, derived from D-glucono-1,5-lactone
and propargylamine (Scheme 2). Since the adopted
conformations of 4-7 would influence their interactions with
charged species, we have evaluated these oligo(amide-
triazole)s as anion receptors, using methodologies based on
NMR spectroscopy and mass spectrometry (MS). MS has
predominately been used as a qualitative tool in the analysis of
complexes, with limitations in obtaining quantitative results.
Mathieson et al.[27] proposed the application of electrospray
ionization (ESI) MS for both the qualitative and quantitative
measurement of ion binding, with validation by solution 1H NMR.
In the present study we have applied both NMR and MS to
determine the binding stoichiometries of oligo(amide-triazole)s
4-7. To the best of our knowledge, this is the first report on anion
binding in acyclic carbohydrate-derived triazole compounds.
DMF and DMSO were respectively used. Compound
6
precipitated from the reaction mixture and subsequent
substitution of the tosyl group by azide could only be partially
achieved (DMSO, 120 °C), to yield a complex mixture of
products of difficult separation. Therefore, an alternative
synthetic approach was designed to obtain pentamer 7 via the
dimer 16 (Scheme 4). Since either free carboxylic acids or azide
derivatives proved to be less soluble than tosylated methyl
esters, the synthesis of 16 started from methyl ester 4.
Treatment of 4 with LiOH in methanol gave the carboxylic acid
15, which was converted into the N-propargylamide 16. CuAAC
reaction between alkyne 16 and azide 14, in DMF, led to the
pentamer 7.
Scheme 2. Oligo(amide-triazole)s synthesized by CuAAC reaction
Results and Discussion
Synthesis
D
-Glucono-1,5-lactone was used as the common starting
material for the synthesis of methyl ester 9[28] and amide 12,[26]
via the protected gluconic acid 8 (Scheme 3). Treatment of 9
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Scheme 3. Synthesis of oligo(amide-triazole)s 4-6.
Scheme 4. Synthesis of pentamer 7.
The structure of the oligomers was confirmed by NMR
spectroscopy. All the NMR spectra were recorded in [D6]DMSO,
since it was the only solvent able to dissolve all the compounds.
linked to the triazole ring were shifted to lower fields, in
comparison with those of the methylenes vicinal to the azide or
alkyne functions. The methylene protons H-6a, H-6b (linked to
the triazole nitrogen) were the most deshielded and appeared as
two well separated signals. For dimer 4, H-4 and H-4’ gave
resonances at higher field, in the same the region of the
methoxyl group.
1
Thus, the H NMR spectrum of dimer 4 (Figure 1) exhibited
diagnostic amide and triazole resonances at 8.17 and 7.81 ppm,
respectively, being the latter overlapped with one of the doublets
of the tosyl group. The resonances of both methylene groups
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The general pattern of the spectra remained almost unchanged
with the increasing number of repeating units from oligomers 4
to 7, and they were also similar to that of the poly(amide-
triazole) 3a. The main differences consisted in the increasing
complexity of the NH and triazole-CH signals, as well as in the
expected increment in the relative integration of the peaks (the
integral of the aromatic tosyl signal at 7.50 ppm was assigned as
2H for all the spectra). The integrals of H-3, H-5 and H-6a
signals of the terminal (tosyl containing) unit remained practically
unchanged from 4 to 7. These facts validated the estimation of
average-number molecular weights of the poly(amide-triazole)s
according to the integrals of the signals.[26]
The 13C NMR spectra of dimer 4 (see Supporting Information)
exhibited the carbon signals of amide (167.0 ppm), ester (167.8
ppm), and triazole (123.4 ppm and 145.1 ppm, for C-7 and C-8
respectively). Moreover, the general pattern of the 13C NMR
spectra of the oligomers were in agreement with those of the
poly(amide-triazole) 3a.[26]
to the pattern observed in the CDCl3 spectra. Upon addition of
TBA chloride, triazole-CH underwent a slight downfield shifting
in comparison to pure [D6]DMSO, while amide-NH was shifted
upfield. This behavior for the amide-NH resonance could be
explained if this proton is involved in an intramolecular NH…O
bond with an oxygen from the sugar residue, and such a bond is
disrupted by halide or DMSO.[30]
Qualitative studies by NMR spectroscopy were also performed
for compounds 6 and 7 with halides. Since these oligo(amide-
triazole)s were soluble in the milimolar range only in DMSO, the
NMR experiments were carried out in [D6]DMSO, which also
dissolved appropriately the tetramethylammonium (TMA) halide
salts. The 1H NMR spectra for 6 and 7 were noticeably changed
upon addition of halides, both in the shape and chemical shifts
of the amide-NH, triazole-CH (H-7), and H-4, 4’ signals (Figure
2). However, the ∆
δ values were small due to the mentioned H-
bonding acceptor capacity of DMSO. Thus, the observed ∆
δ
were averaged values of the chemical shifts of a given proton
that interacted either with halide or DMSO.
Ion binding studies
The spectra of tetramer 6 and pentamer 7 recorded in presence
of Cl‒, Br‒, or I‒, indicated that the more electronegative chloride
induced the most intense displacement of the triazole protons.
These signals were partially overlapped with one doublet of the
tosyl group, which remained unchanged in the presence of
halide salts. The addition of chloride slightly affected the NH
signals, and an unexpected change in chemical shift was
registered for the H-4 nuclei that are closer to triazole rings.
The anion binding of oligo(amide-triazole)s to halides was also
investigated using ESI MS. Direct infusion electrospray
ionization single quadrupole MS (DI-ESI-SQ-MS) experiments
were conducted in acetonitrile-water-isopropanol mixtures with
analyte levels in the micromolar range, in the presence of
potassium halide salts, as TMA salts are inconvenient for this
technique.
The nitrogen-rich 1,2,3-triazole ring possesses a highly polarized
C-H linkage which is able to interact with anions by hydrogen
bonding.[11] Therefore, we have explored the potential capacity
of carbohydrate-derived oligo(amide-triazole)s 4-7 as receptors
for halide anions (Cl-, Br-, and I-).
Qualitative ion binding studies have been conducted using NMR
spectroscopy. In solution, anion binding can be associated to a
competition between two solvation spheres for the anion: one
provided by the solvent and the other one controlled by a folded
cavity lined with triazole-CH and amide-NH protons. The anion
sizes are primary determinants of the binding strength by the
flexible oligomers. The affinity of the receptors for a given anion
is typically well correlated with the downfield shifts of the
triazole-CH protons upon binding.[29] On the other hand, a polar
and hydrogen bonding acceptor solvent like DMSO could
interact with triazole-CH, amide-NH and other potential donors in
the host molecule.
In the first instance, DI-ESI-SQ-MS experiments were conducted
in the positive ion mode. Compound 5 was selected as a proxy
of the oligo(amide-triazole)s series to explore the binding
capability of the compounds towards cations in the presence of
a complexing agent. The mass spectrum of compound 5
exhibited the base peak at m/z 973 ([M+Na]+). Additional peaks
at m/z 991 ([M+K]+), 958 ([M+K-MeOH]+), 499 ([M+2Na]2+), and
491 ([M+HCHO+2H]2+) were detected (see Supporting
Information). When KCl was added to trimer 5, the intensity of
[M+K]+ ion was highly increased, though the [M+Na]+ ion was
still the base peak. The intensities of both [M+Na]+ and [M+K]+
peaks were reduced in one order of magnitude upon addition of
15-crown-5 and the most intense signals were [M+Na]+ and
[M+2Na]2+. Thus, trimer 5 formed adduct ions with Na+ and K+
rather than H+ despite the electrolytically-induced decrease in
solution pH generated in the ESI source.[31] Therefore, crown
ether was added to oligomer solutions for anion binding assays,
to minimize oligo(amide-triazole) interactions with Na+ or K+, and
to enhance anion binding.
To assess the influence of the solvent effect on the NMR
experiments we employed dimer 4, as this was the only member
of the series that was soluble in CDCl3. Thus, the 1H NMR
spectra of 4 were recorded in CDCl3 or [D6]DMSO, in the
absence or presence of halide anions (See Supporting
Information). Upon addition of tetrabutylammonium (TBA) halide
salts, the whole pattern of the spectrum recorded in CDCl3 was
modified, suggesting an overall conformational change of the
receptor. The displacement of the signals was stronger when
increasing the electronegativity of the halogen. In general, all
signals were shifted upfield, except for triazole-CH that moved
downfield. The most pronounced downfield shifting was
observed for chloride, and this displacement was taken as an
initial proof of anion binding.
When the solvent employed was [D6]DMSO, all the resonances
in the 7.0-8.5 ppm range were shifted downfield. As expected,
the amide-NH signal underwent the strongest shifting, and
moved to a lower field relative to that of triazole-CH, in contrast
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Figure 1. 1H NMR spectra (500 MHz, [D6]DMSO) of oligo(amide-triazole)s 4-7, and poli(amide-triazole) 3a.
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Figure 2. Partial 1H NMR (500 MHz, [D6]DMSO) spectra of compounds 6 and 7 in the absence or presence of TMA halide salts (60 equiv.): (a) 6 (3 m
M); (b) 6 in
the presence of TMA Cl; (c) 6 in the presence of TMA Br; (d) 6 in the presence of TMA I; (e) 7 (3 m
TMA Br; (h) 7 in the presence of TMA I.
M); (f) 7 in the presence of TMA Cl; (g) 7 in the presence of
Qualitative anion binding was then studied by DI-ESI-SQ-MS in
the negative ion mode for oligo(amide-triazole)s 6 and 7, pure or
combined with KCl, KBr, or both of them, always in the presence
of 15-crown-5, in the molar ratios described in Figure 3. In spite
of their similar structure, compounds 6 and 7 showed relevant
differences in their ESI MS. The main signals observed in the
mass spectrum of pure compound 6 were due to [M-H]‒,
[M+H2O-H]‒, [M+HCO2]‒, and [M+H2O+HCO2]‒; however, no
peaks for due to [M+Cl]‒ or [M+Br]‒ were observed, suggesting
that potential nonspecific binding with halide traces remained
under the limit of detection. Nonspecific binding happens when
chemical species trapped in the same nanodroplet start to
interact as the solvent evaporates.[32,33] When chloride or
bromide salts were added, the main ionic species detected
1502)
,
[M-H]‒ (m/z 1517), [M+OH]‒ (m/z 1532), and
[M+H2O+HCO2]‒ (m/z 1579) ions. Addition of KCl rendered a
more intense [M+Cl]‒ peak, although the spectrum fingerprint
was retained. Upon addition of KBr, a peak for the [M+Br]‒ ion
was observed, but with an intensity 50% lower than that of the
[M+Cl]‒ ion.
On the other hand, it is relevant to mention some common
features for both oligomers 6 and 7. Their mass spectra did not
exhibit the [2M+Cl]‒ or [2M+Br]‒ ions, indicating the absence of
2:1 host:chloride stoichiometry, even under favorable conditions
for its formation. Remarkably, when both halides were present in
equal concentration, the [M+Cl]‒ ion highly prevailed, suggesting
higher selectivity for Cl‒ complexation over Br‒. However,
tetramer 6 showed higher selectivity and lower nonspecific
binding than pentamer 7 under similar conditions.
‒
corresponded to [M+Cl] and [M+Br]‒ (m/z 1269 and 1314,
respectively). Less intense signals, attributed to the loss of
formaldehyde from methylidene groups ([M-HCHO+Cl]‒ and [M-
HCHO+Br]‒), were also observed.
In the spectrum of pure compound 7, the [M+Cl]‒ (m/z 1552)
was the base peak, probably due to nonspecific binding to
chloride traces and possible contribution of an ESI
mechanism[33] different from the typical ion evaporation model
(IEM).[34] This distinctive behavior for 7 may be attributed to the
particular helical conformation adopted for this compound in
solution (see Conformational analysis). Additional ionic species
observed in the spectrum corresponded to [M-HCHO+OH]‒ (m/z
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Figure 3. DI-ESI-SQ-MS (negative ion mode) of (a) oligo(amide-triazole) 6 : 15-crown-5 (1:1, 10 µ
crown-5 (1:1:1, 10 µ 6); (d) 6 : KCl: KBr : 15-crown-5 (1:10:10:10, 1 µ 6); (e) 7 : 15-crown-5 (1:1; 5 µ
15-crown-5 (1:1:1; 5 µ 7); (h) 7 : KCl : KBr : 15-crown-5 (1:10:10:10; 1 µ 7)
M
6); (b) 6 : KCl : 15-crown-5 (1:1:1, 10 µ
M
6); (c) 6 : KBr : 15-
7); (g) 7 : KBr :
M
M
M
7); (f) 7 : KCl : 15-crown-5 (1:1:1; 5 µM
M
M
Since qualitative analysis indicated high affinity of compounds 6
and 7 to chloride, binding stoichiometries for all the oligo(amide-
triazole)s 4-7 were determined by the Job´s Method of
Continuous Variation for the host (H) and guest (G)
compounds.[35] For this purpose we have employed NMR
spectroscopy and DI-ESI-SQ-MS. A significant advantage of MS
in this approach is that each ionic species generated in the ESI
source, analyzed, and detected by the spectrometer provides
one specific signal that can be easily identified. In contrast, NMR
spectroscopy in the fast exchange time-scale gives a change in
chemical shift that is proportional to the ratio of complexed host
at equilibrium over the total host concentration, providing
valuable information about the nuclei involved in the interaction.
Oligo(amide-triazole)s
samples
were
prepared
with
concentration ranges adequate for NMR and MS, according to
their sensitivity. Oligo(amide-triazole) compounds acted as host
(H) and the chloride anion as guest (G). Experimental data
obtained from each technique were fitted using a Gaussian
function (See Supporting information) and the maximum values
were used to obtain the stoichiometry of the H-G complexes.
For Job plots using NMR spectroscopy, the changes in chemical
shifts of the triazole protons (H-7) were measured. The triazole-
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CH signals were assigned with the assistance of 2D-NMR
techniques. For those compounds that had more than one
triazole ring (5-7), individual Job plots were calculated for each
proton, and the results were coincident in all cases. The
resulting stoichiometries of the oligo(amide-triazole)s-chloride
complexes were 2:1 for compounds 4 and 5, while for tetramer 6
and pentamer 7 the stoichiometry was 1:1.
Conformational analysis
Optical rotations can provide an insight into the conformation,
mostly for large molecules.[38] Therefore, the optical rotations of
the oligo(amide-triazole)s 4-7 have been measured (Table 1)
and their values increased with the increasing number of
repeating units in the series. Compound 7, with the longest
chain, showed an outstanding large value ([α]D
25 = +624.2). For
The MS peaks of thermodynamically preferred species could be
accompanied by those from artefacts and from nonspecific
complexes. Therefore, we have chosen the Job plots procedure
to confirm the stoichiometries of the complexes, rather than the
less accurate direct observation of peaks. The DI-ESI-SQ-MS
experiments were recorded using oligo(amide-triazole) solutions
mixed with equimolar solutions of KCl, also containing crown-
ether. The concentration of crown-ether was maintained
constant for all the experiments, and the molar fractions of host
and guest were varied. In the case of oligomers 4 and 5, the
[M+Cl]‒ and [2M+Cl]‒ ions were observed and Job plots were
calculated for each species, giving a maximum at 0.62 for
compounds 4-6, higher optical activity values were observed
upon TMA chloride addition, relative to the values obtained in
the absence of the anion. In contrast, a decrease on the optical
activity was observed when TMA chloride was added to a
solution of pentamer 7. These results were consistent with an
ordered conformation achieved by pentamer 7, but which could
not be attained by the minor members of the series. This
conformation would be distorted but still prevailed after chloride
-62
addition. Similar large optical rotations ([α]D
= +490) were
observed for poly(triphenylmethyl-methacrylates) and were
attributed to the helicity of the rigid isotactic sequence of
repeating units.[39] Helicenes are examples of small organic
molecules with exceptionally high optical activity due to helical
conformation.[40]
compound
4 and 0.67 for compound 5 (See Supporting
information). Thus, the stoichiometry of these oligo(amide-
triazole)s-chloride complexes was 2:1, in agreement with NMR
results. For tetramer 6 and pentamer 7, the maximum was
respectively observed at 0.56 and 0.54 molar fraction, in
agreement with a 1:1 stoichiometry for the oligo(amide-triazole)-
chloride complex. As mentioned above, the main adduct ions in
the mass spectra of compounds 6 and 7 were the [M+Cl]‒,
without any evidence of the presence of higher complexes.
These results show that dimer 4 and trimer 5, which contain
respectively one or two triazole rings, give rise to the 2:1
complexes. Both triazole residues in trimer 5 seem to bind to
chloride, since their resonances were shifted in the presence of
the anion. However, only one triazole per molecule would bind to
chloride, as the rigid nature of the carbohydrate backbone
makes the distance unsuitable for the interaction with the other
triazole ring of the same molecule. In contrast, higher oligomers
6 and 7 should be flexible enough to bind to two triazole
residues in the same molecule. All the triazole rings in
Table 1. Optical rotations of monomer 2a, poly(amide-triazole) 3a, and
oligo(amide-triazole)s 4-7, in the presence or absence of TMA chloride.
25
Compound
2a[a]
[α]D
+89.6
+162.2
+ 110.6
+49.8
+50.6
+67.2
+82.0
+72.3
+80.0
+624.2
+495.6
3a[a]
3a: Cl‒ (1 : 1)[b]
4[a]
4 : Cl‒ (2 : 1)[a]
5[a]
5 : Cl‒ (2 : 1)[a]
6[a]
6 : Cl‒ (1 : 1)[a]
7[b]
compounds
6
and
7
exhibited similar chemical shift
displacements, suggesting that all of them are committed with
chloride binding. This may be achieved by simultaneous
interaction between chloride and two triazoles, or either through
sequential interaction with different pairs of rings, in the fast
NMR time-scale.
7 : Cl‒ (1 : 1)[b]
Recent reports have posed objections to the applicability of Job
plots.[36,37] However, the procedure may be applied taking into
account some recommendations regarding the structure and
properties of the receptors, the use of independent procedures
of analysis, and the testing of residuals distribution for the
performance of the model. In the present work, we have paid
careful attention to all those recommendations. Thus, the Job
plots were calculated using two independent techniques at
different concentration ranges, which led to the same
stoichiometry for the oligo(amide-triazole)-chloride complexes.
[a] c = 0.2-0.5, DMSO. [b] c = 0.02-0.06, DMSO.
The circular dichroism (CD) is also useful for assessing
conformations. Therefore, the CD spectra of compounds 4-7
were recorded and only compound 7 exhibited CD activity (a
maximum at 205 nm and a shoulder at 223 nm; Figure 4). The
oligo(amide-triazole) family have the same chromophores,
amide and triazole groups with n→π* and π→π* transitions, as
well as the same chiral backbones, and they only differ in the
number of repeating units. Thus, the CD signal observed for
pentamer 7 could be attributed to an ordered conformation that
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10.1002/ejoc.201801320
European Journal of Organic Chemistry
FULL PAPER
was not achieved in the shorter oligomers. Furthermore, the
a small distortion of the helical conformation in the interaction
with chloride. Moreover, as the chemical shift of amide-NH
remained practically unchanged upon addition of chloride, the
NH-Cl‒ interaction should be negligible. Probably this NH is
involved in the formation of hydrogen bonding with O-2’ or O-3’,
to give 5 or 6-membered rings,[43] respectively. It has been
previously found that triazole-CH have stronger interactions than
amide-NH with halide anions in amidetriazoles.[44]
observed maxima are consistent with those of a protein α-helix
formed from D-amino acid residues, even though in our case the
solvent composition prevented the observation of a negative
peak below 195 nm. An octameric molecule, constituted by
carbohydrate-derived amino acid monomers, with a helical
secondary structure, showed a similar CD spectrum.[41] The
temperature-dependent CD experiment for compound 7 was
measured in the range 0-80 °C. The CD remained almost
unchanged up to 60 °C, while at 80 °C the signal intensity at 205
nm was reduced to 28% of the value reached at 0 °C. The CD
signal was not recovered upon immediate cooling of the solution.
In the presence of chloride salt, the general pattern of the
spectra was kept, but it was less intense. The CD signal was
more affected with the raise of temperature in the whole range,
and at 80 °C the intensity of the band at 205 nm was reduced to
13% of the initial value. Thus, pentamer 7 would attain a helical
conformation which is stable until 60 °C. The helix would
undergo distortion in the presence of chloride and became less
stable with the temperature increase.
Additionally, the folding of oligo(amide-triazole)s 4-7 was studied
using 2D NOESY experiments. The NOESY spectrum of
compound 4 showed just one contact between amide-NH and
triazole-CH (H-7). Trimer 5 and tetramer 6 exhibited some
additional NOE interactions for triazole-CH (signals of H-7, H-7’
or H-7’’ are indistinguishable in the NOESY spectra and are
labelled as H-7) and NH protons. However, the spectrum of
pentamer 7 exhibited new cross-peaks involving methylidene
protons with H-7 and amide-NH. Also an enhanced intensity was
observed for the cross-peak of H-7 with H-4,H-4’ (See
Supporting information). These NOE interactions were relevant
to explain the conformational preference of the pentamer. The
H-4,H-4’ nuclei interact with the triazole H-7 included in the
same repeating unit, since no cross-peak was observed for H-4’’
(Figure 5). Moreover, the contact between triazole-CH and
amide-NH is indicative of the proximity of these protons in space.
These facts are consistent with a U-conformation centred on the
triazole ring, which is also in agreement with the helical
conformation of the pentamer. A representation of such a
conformation of a model compound analogue of 7, having the
tosyl group replaced by OMe, is shown in Figure 5(b). This
conformation is the result of a preliminary molecular modelling
using the semiempirical method AM1, and including distance
constraints consistent with observed NOE contacts. The NOESY
spectrum of polymer 3a exhibited the same cross-peaks as 7,
with two additional ones (triazole-CH, methylene (H-9) and
amide-NH, H-4). These results suggested the presence of
ordered (helical) regions inserted in the random coil
conformation of the polymer chain.[42] Accordingly, the optical
rotation value of the polymer 3a is smaller than that of 7, but
larger in comparison to those of monomer 2a and oligomers 4-6.
In the presence of chloride, the NOESY spectrum of pentamer 7
showed an increased intensity of the contact between triazole-
CH and H-4,H-4’; while the cross-peaks between methylidene
with H-7 and with amide-NH were not detected. Furthermore,
amide-NH, triazole-CH and H-4’ still remained close in space
(NOE contacts observed). These results were in agreement with
Figure 4. Temperature dependence of CD spectra of compound 7 (10 µ
M in
2:2:1 CH3CN-H2O-iPrOH) (a) in the absence or (b) in the presence of KCl (40
equiv.). (c) Temperature variation of CD, measured at 205 nm, in absence or
presence of chloride salt.
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10.1002/ejoc.201801320
European Journal of Organic Chemistry
FULL PAPER
Figure 5. Relevant detected NOE interactions [a] H-7, NH; [b] H-7, H-4 and H-7, H-4’; [c] NH,O-2 hydrogen bond; [d] H-7, H-5 and H-7, H-5’: (a) for a linear
representation of pentamer 7; (b) for a schematic helical conformation of a model structure of pentamer 7 (the terminal tosyl group was replaced by OMe)
consistent with
a helical conformation for the pentameric
oligo(amide-triazole) 7. This ordered conformation was distorted
by the presence of chloride, even though remained stable in
solution below 60 °C. The active site in the pentamer backbone
that interact with chloride involved the triazole-CH, amide-NH,
and H-4’ from the carbohydrate residue.
Conclusions
In summary, we report here the synthesis of a family of linear
sugar-derived oligo(amide-triazole)s with chains of an increasing
number of carbohydrate and triazole units, from one (dimer) to
four (pentamer). These molecules have been designed to act as
anion receptors. The binding affinities of the oligomers with
halide anions have been studied using NMR spectroscopy and
ESI MS. The affinity order was Cl‒ > Br‒ > I‒ for tetramer 6 and
pentamer 7. The binding stoichiometries have been estimated:
dimer 4 and trimer 5 formed 2:1 complexes while tetramer 6 and
These oligo(amide-triazole)s could be applied for chloride
sensing by ESI MS. The tetramer 6 should be particularly useful
for this purpose, as is more selective to chloride than pentamer
7, and displays lower nonspecific binding.
pentamer 7 gave a 1:1 stoichiometry. Anion selectivity is not an Experimental Section
intrinsic property of 1,2,3-triazole or amide functional groups, but
rather a confluence of conformational and solvation effects.[29]
General Experimental Methods. Analytical thin-layer chromatography
(TLC) was performed on Silica Gel 60 F254 aluminum-supported plates
Optical rotation values, NOE contacts and CD experiments were
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10.1002/ejoc.201801320
European Journal of Organic Chemistry
FULL PAPER
(layer thickness 0.2 mm). Visualization of the spots was effected by
exposure to UV light, by charring with a solution of 5% (v/v) sulfuric acid
in EtOH, containing 0.5% p-anisaldehyde or with a cerium molibdate
solution. Column chromatography was performed with Silica Gel 60
(230–400 mesh). Microwave reactions were carried out in an Anton Paar
Monowave 300 reactor in closed vials; the temperature was monitored by
an external infrared sensor. Optical rotations were measured at 25 ºC
and are expressed as cm3 g-1 dm-1. Nuclear magnetic resonance (NMR)
spectra were recorded with a Bruker Avance II 500 instrument (1H: 500
MHz; 13C: 125.7 MHz). Spectra were referenced to the residual solvent
signals.[45] The assignments were assisted by 2D COSY, HMBC, NOESY
and HSQC techniques. High resolution mass spectrometry (HRMS) was
carried out using electrospray ionization (ESI) either with a Bruker
microTOF Q II or with a Waters Xevo G2S QTOF instrument. The QTOF
mass spectrometer was operated in negative ion mode with a probe
capillary voltage of 2.3 kV, and in the positive ion mode with a capillary
voltage of 2.5 kV. The sampling cone voltage was set to 30.0 V. The
source and desolvation gas temperatures were set to 120 and 300 °C,
respectively. The nitrogen gas desolvation flow rate was 600 L h-1, and
the cone desolvation flow rate was 10 L h-1. The mass spectrometer was
calibrated across the range of m/z 50-1200 using a 0.5 mM sodium
formate solution prepared in 2-propanol/water (90:10 v/v). Data were drift
corrected during acquisition using a leucine encephalin (m/z 554.2615 for
ESI‒ and 556.2771 for ESI+) reference spray infused at 2 μL min-1, every
15 seconds. Data were acquired in the range of m/z 50-1200, and the
scan time was set to 0.5 s. Circular dichroism experiments were
performed with a spectrometer equipped with a temperature controller in
quartz cells of 10 mm path length.
1 H; H-6b), 3.85 (s, 3H; COCH3,), 3.9 (t, 3J (H-3,H-4) = 3J (H-4,H-5) = 1.5
Hz, 1 H; H-4), 4.13 (t, 3J (H-2,H-3) = 3J (H-3,H-4) = 1.8 Hz, 1 H; H-3),
4.15 (m, 3J (H-4,H-5) = 2.0 Hz, 3J (H-5,H-6b) = 5.9 Hz, 3J (H-5,H-6a) = 8.2
Hz, 1 H; H-5), 4.35 (d, 3J (H-2,H-3) = 2.0 Hz, 1 H; H-2), 4.81 (d, 3J (H,H) =
6.1 Hz, 1 H; OCH2O), 4.95 (d, 3J (H,H) = 6.1 Hz, 1 H; OCH2O), 5.03 (d, 3J
(H,H) = 6.1 Hz, 1 H; OCH2O), 5.30 (d, 3J (H,H) = 6.1 Hz, 1 H; OCH2O);
13C NMR (125.7 MHz, CDCl3, 25 °C, TMS): δ = 40.7 (C-6), 52.9 (OCH3),
67.1 (C-3), 71.0 (C-4), 75.7 (C-5), 76.8 (C-2), 88.6, 92.6 (OCH2O) 167.9
(C=O). HRMS (ESI/Q-TOF) m/z: [M
275.0293; found: 275.0292. [M + K]+, calcd for C9H13ClO6K: 291.0032;
+
H]+ calcd for C9H13ClO6Na
found: 291.0026.
Methyl 6-azido-6-deoxy-2,4:3,5-di-O-methylidene-D-gluconate (11).
a) From 10a. Sodium azide (0.44 g, 6.76 mmol) was added to a solution
of 10a (1.35 g, 3.48 mmol) in DMF (8 mL). The mixture was stirred at
80 °C for 2 h, and then concentrated at reduced pressure. Excess of
NaN3 was filtered through Celite. Compound 11 was isolated as a white
crystalline solid (0,77 g, 86%) by column chromatography (20:80
hexane-EtOAc). m.p. 122 °C (recryst from EtOAc-hexane); [α]D
25 = +23,0
(c = 0.5 in CH2Cl2); 1H NMR (500 MHz, CDCl3, 25 °C, TMS): δ = 3.54 (dd,
3J (H-5,H-6a) = 6.5 Hz, 3J (H-6a,H-6b) = 13.0 Hz, 1 H; H-6a), 3.67 (dd, 3J
(H-5,H-6b) = 6.5 Hz, 3J (H-6a,H-6b) = 13.0 Hz, 1 H; H-6b), 3.73 (t, 3J (H-
3,H-4) = 3J (H-4,H-5) = 1.5 Hz, 1 H; H-4), 3.83 (s, 3H, COCH3,), 4.07 (m,
3J (H-4,H-5) = 1.5 Hz, 3J (H-5,H-6b) = 3J (H-5,H-6a) = 6.5 Hz, 1 H; H-5),
4.12 (t, 3J (H-2,H-3) = 3J (H-3,H-4) = 1.7 Hz, 1 H; H-3), 4.33 (d, 3J (H-2,H-
3) = 2.0 Hz, 1 H; H-2); 4.78 (d, 3J (H,H) = 6.6 Hz, 1 H; OCH2O), 5.00 (d,
3J (H,H) = 5.8 Hz, 1 H; OCH2O); 5.05 (d, 3J (H,H) = 5,8 Hz, 1 H; OCH2O),
5.27 (d, 3J (H,H) = 6.6 Hz, 1 H; OCH2O); 13C NMR (125.7 MHz, CDCl3,
25 °C, TMS): δ = 49.7 (C-6), 52.7 (OCH3), 66.9 (C-3), 71.6 (C-4), 74.7
(C-5), 76.5 (C-2), 88.6, 92.3 (OCH2O), 167.7 (C=O). HRMS (ESI/Q-TOF)
m/z: [M + Na]+ calcd for C9H13N3O6Na 282.0702; found: 282.0727.
2,4:3,5-Di-O-methylidene-D-gluconic acid and its methyl ester (9) were
-glucono-1,5-lactone (1) as already described.[28]
obtained from
D
Tetramethylammonium (TMA) chloride was recrystallized from 2-
propanol and dried at 110 °C under vacuum; TMA bromide and iodide, as
well as potassium chloride and bromide, were dried before use as
described above.
b) From 10b. To a solution of compound 10b (0.45 g, 1.78 mmol) in
DMF (4 mL) was added NaN3 (0.22 g, 3.38 mmol). The mixture was
stirred at 80 °C for 2 days, filtered through Celite and the resulting
solution was concentrated. Compound 11 (0.30 g, 82%) was isolated by
column chromatography (20:80 hexane-EtOAc), and showed identical
physical and spectroscopic properties as the compound described above.
Synthesis
Compound 4. To a solution of compounds 11 (0.263 g, 1 mmol) and
12[26] (0.417 g, 1 mmol) in CH3CN (5.5 mL), CuOAc (0.006 g, 0.05 mmol)
was added. The mixture was subjected to Mw irradiation at 70 °C for 1 h,
under Ar atmosphere. Compound 4 precipitated from the reaction mixture
and was recovered by centrifugation. The solid was subsequently
washed with 0.16 M EDTA, H2O and acetone. The product was isolated
Methyl 2,4:3,5-di-O-methylidene-6-O-tosyl-D-gluconate (10a). To a
solution of 9[28] (0.8 g; 3.41 mmol) in pyridine (6 mL) was added tosyl
chloride (1.1 g; 5.76 mmol). The mixture was stirred for 20 h at room
temperature, until complete consumption of 9. After concentration at
reduced pressure, compound 10a (0,99 g, 75%) was isolated first as a
white crystalline solid by column chromatography (40:60 hexane-EtOAc).
25
as a white solid (0.77 g, 86%). m.p. 209 °C (recryst from DMSO-
= +49.0 (c = 0.5 in CH2Cl2); 1H NMR (500 MHz,
m.p. 103 °C (recryst from EtOAc-hexane); [α D
]
= +18.3 (c = 0.6 in
25
CH2Cl2); 1H NMR (500 MHz, CDCl3, 25 °C, TMS): δ = 2.46 (s, 3 H;
CH3Ph), 3.76 (s, 1 H; H-4), 3.81 (s, 3 H; CH3O), 4.05 (s, 1 H; H-3), 4.07-
4.12 (m, 1 H; H-5), 4.22-4.28 (m, 2 H; H-6), 4.30 (d, 3J (H-2,H-3) = 1.8 Hz,
1 H; H-2), 4.76 (d, 3J (H,H) = 6.5 Hz, 1 H; OCH2O), 4.86 (d, 3J (H,H) = 6.1
Hz, 1 H; OCH2O), 4.94 (d, 3J (H,H) = 6.1 Hz, 1 H; OCH2O), 5.24 (d, 3J
(H,H) = 6.5 Hz, 1 H; OCH2O), 7.38 (d, 3J (H,H) = 8.2 Hz, 2 H; H-aromatic),
7.80 (d, 3J (H,H) = 8.2 Hz, 2 H; H-aromatic).13C NMR (125.7 MHz, CDCl3,
25 °C, TMS): δ = 52.8 (OCH3), 67.0 (C-6), 67.5 (C-3), 70.5 (C-4), 73.2
(C-5), 76.6 (C-2), 89.0, 92.4 (OCH2O), 128.1, 130.2, 132.3, 145.7 (C-
aromatic), 167.9 (C=O). HRMS (ESI/Q-TOF) m/z: [M + H]+ calcd for
C16H21O9S 389.0913; found: 389.0901.
acetone); [α]D
[D6]DMSO, 25 °C, TMS): δ = 2.43 (s, 3 H; CH3Ph), 3,69 (s, 3 H; CH3O),
3.70 (s, 1 H; H-4’), 3.80 (s, 1 H; H-4), 3.97 (m, 3J (H-5’,H-6’a) = 4.8 Hz, 3J
(H-5’,H-6’b) = 8.5 Hz, 1 H; H-5’), 4.05 (s, 1H, H-3’), 4.19 (m, 3J (H-5,H-6a)
= 4.7 Hz, 1 H; H-5), 4.19 (d, 3J (H-2’,H-3’) = 1.7 Hz, 1 H; H-2’), 4.27 (dd,
3J (H-5’,H-6’a) = 4.8 Hz, 3J (H-6’a,H-6’b) = 11.4 Hz, 1 H; H-6’a), 4.30-4.31
(m, 2H; H-9a, H-3), 4.36 (m, 3J (H-9b,NH) = 6.0 Hz, 3J (H-6’a,H-6’b) =
15.2 Hz, 1 H; H-9b), 4.54 (m, 3J (H-5,H-6’b) = 8.7 Hz, 3J (H-6’a,H-6’b) =
11.4 Hz, 1 H; H-6’b), 4.61 (m, 3J (H-2,H-3) = 1.7 Hz, 3J (H-5,H-6a) = 4.7
Hz, 3J (H-6a,H-6b) = 14.4 Hz, 2 H; H-2, H-6a), 4.72-4.77 (m, 5 H;
OCH2O), 5.07-5.11 (m, 4 H; H-6b, OCH2O), 7.50 (d, 3J (H,H) = 8.1 Hz, 2
H; H-aromatic), 7.81 (s, 1 H; H-7), 7.83 (d, 3J (H,H) = 8.1 Hz, 2 H; H-
aromatic), 8.17 (t, 3J (H-9a,NH) = 3J (H-9b,NH) = 6.0 Hz, 1 H; NH); 13C
NMR (125.7 MHz, [D6]DMSO, 25 °C, TMS): δ = 21.1 (CH3-Ph), 34.1 (C-
9), 46.1 (C-6), 51.2 (OCH3), 66.2 (C-6’), 67.5 (C-3), 67.5 (C-3’), 69.1 (C-
4’), 69.3 (C-4), 73.2 (C-5’), 74.4 (C-5), 75.5 (C-2), 76.7 (C-2´), 123.4 (C-
7), 127.8, 130.2, 132.1, 145.2 (C-aromatic), 145.1 (C-8), 167.0 (HNCO),
Next fractions from the column (50:50 hexane-EtOAc) afforded methyl 6-
chloro-6-deoxy-2,4:3,5-di-O-methylidene-
D-gluconate (10b), as a white
crystalline solid (0.08 g, 10%). m.p. 139-140 °C (recryst from EtOAc-
25
hexane); [α]D
= +37,9 (c = 0.2 in CH2Cl2). 1H NMR (500 MHz, CDCl3,
25 °C, TMS): δ = 3.75 (dd, 3J (H-5,H-6a) = 5.9 Hz, 3J (H-6a,H-b) = 11.6
Hz, 1 H; H-6a), 3.79 (dd, 3J (H-5,H-6b) = 8.2 Hz, 3J (H-6a,H-6b) = 11.6 Hz,
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10.1002/ejoc.201801320
European Journal of Organic Chemistry
FULL PAPER
167.8 (CH3OCO). HRMS (ESI/Q-TOF) m/z: [M
+
Na]+ calcd for
was recovered by centrifugation. The solid was sequentially washed with
C
27H34N4O14SNa 693.1664; found: 693.1684.
0.16 M EDTA, H2O and acetone to give 5 (0.458 g, 94%) as a white solid.
25
m.p. 259 ºC (recryst from DMSO-acetone); [α D
]
= +67.2 (c = 0.4 in
DMSO); 1H NMR (500 MHz, [D6]DMSO, 25 °C, TMS): δ = 2.43 (s, 3 H;
CH3Ph), 3.69 (s, 3 H; CH3O), 3.70 (s, 1 H; H-4’’), 3.80 (s, 2 H; H-4, H-4’),
3.96 (m, 3J (H-5’’,H-6’’a) = 4.9 Hz, 3J (H-5’’,H-6’’b) = 8.6 Hz, 1 H; H-5’’),
4.05 (s, 1 H; H-3’’), 4.18-4.21 (m, 3J (H-5,H-6a) = 4.6 Hz, 3J (H-5,H-6b) =
Compound 13a. To a solution of compound 4 (0.300 g, 0.45 mmol) in
anhydrous DMF (0.76 ml), NaN3 (0.03 g, 0.46 mmol) was added. The
mixture was stirred under N2 at 60 °C overnight. After concentration,
compound 13a (0.136 g, 56%) was obtained as a white crystalline solid
10.0 Hz, 3 H; H-5, H-5’, H-2’), 4.25-4.42 (m, 3J (H-5’’,H-6’’a) = 4.8 Hz, 3
J
by column chromatography (80:20 EtOAc-MeOH). m.p. 209-210 °C
25
(decomp) (recryst from H20); [α D
]
= +56.4 (c = 0.5 in DMSO); 1H NMR
(H-6’’a,H-6’’b) = 11.3 Hz, 8 H; H-2’, H-3, H-3’, H-6’’a, H-9, H-9’), 4.54 (m,
1H, 3J (H-5’’,H-6’’b) = 8.8 Hz, 3J (H-6’a,H-6’b) = 11.3 Hz, 1 H; H-6’’b),
4.60-4.64 (m, 3J (H-5,H-6a) = 3J (H-5’,H-6’a) = 4.6 Hz, 3J (H-6a,H-6b) =
3J (H-6’a,H-6’b) = 14.4 Hz, 3 H; H-2, H-6a, H-6’a), 4.72-4.82 (m, 7 H;
OCH2O), 5.07-5.11 (m, 7 H; H-6b, H-6’b, OCH2O), 7.49 (d, 3J (H,H) = 8.1
Hz, 2 H; H-aromatic), 7.81 (s, 1 H; H-7’), 7.83 (s, 1 H; H-7), 7.83 (d, 3J
(H,H) = 8.1 Hz, 2 H; H-aromatic), 8.17 (t, 3J (H-9’a,NH’) = 3J (H-9’b,NH’) =
6.0 Hz, 1 H; NH’), 8.19 (t, 3J (H-9a,NH) = 3J (H-9b,NH) = 6.0 Hz, 1 H;
NH); 13C NMR (125.7 MHz, [D6]DMSO, 25 °C, TMS): δ = 21.1 (CH3-Ph),
34.1 (C-9, C-9’), 46.1 (C-6, C-6’), 51.9 (OCH3), 66.2 (C-6’’), 67.2, 67.4
(C-3, C-3’), 67.5 (C-3’’), 69.1 (C-4’’), 69.3; 69.8 (C-4, C-4’), 73.1 (C-5’’),
74.4 (C-5, C-5’), 75.5 (C-2), 76.7 (C-2’’), 76.8 (C-2’), 86.7 87.2; 91.7
(OCH2O), 123.3 (C-7, C-7’), 127.8; 130.2; 132.1 (C-aromatic); 144.19 (C-
8, C-8’), 145.2 (C-aromatic), 167.0, 167.1 (CONH); 167.8 (CO2CH3).
HRMS (ESI/Q-TOF) m/z: [M + H]+ calcd for C38H49N8O19S 953.2829;
found: 953.2848; [M + Na]+ calcd for C38H48N8O19SNa 975.2649; found:
975.2669.
(500 MHz, [D6]DMSO, 25 °C, TMS): δ = 3.41 (dd, 3J (H-5’,H-6’a) = 4.8 Hz,
3J (H-6’a,H-6’b) = 13.2 Hz, 1H; H-6’a), 3.69 (s, 4 H; H-4’, CH3O), 3.80 (s,
1 H; H-4), 3.95 (dd, 1H, 3J (H-5’,H-6’a) = 4.8 Hz, 3J (H-5’,H-6’b) = 9.7 Hz,
1 H; H-5’), 4.09 (dd, 1H, 3J (H-5’,H-6’a) = 9.7 Hz, 3J (H-6’a,H-6’b) = 13.2
Hz, 1 H; H-6’b), 4.14 (s, 1H; H-3’), 4.19 (dd, 3J (H-5,H-6a) = 4.7 Hz, 3J (H-
5,H-6b) = 10.4 Hz, 1 H; H-5), 4.28-4.32 (m, 3J (H-2’,H-3’) = 1.2 Hz, 3J (H-
7a,NH) = 5.9 Hz , 3 H; H-2’, H-3, H-9a), 4.38 (dd, 1H, 3J (H-9b,NH) = 6.0
Hz, 3J (H-9a,H-9b) = 15.1 Hz, 1 H; H-9b), 4.60-4.64 (m, 3J (H-5,H-6a) =
4.6 Hz, 3J (H-6a,H-6b) = 10.4 Hz, 2 H; H-2, H-6a), 4.77 (d, 3J (H,H) = 6.5
Hz, 1 H; OCH2O), 4.80 (d, 3J (H,H) = 6.5 Hz, 1 H; OCH2O), 4.84 (d, 3J
(H,H) = 6.5 Hz, 1 H; OCH2O), 4.80 (d, 1H, 3J (H,H) = 6.5 Hz, 1 H;
OCH2O); 5.00 (d, 3J (H,H) = 6.5 Hz, 1 H; OCH2O); 5.05-5.11 (m, 4 H; H-
6b, OCH2O), 7.82 (s, 1 H; H-7), 8.19 (t, 3J (H-9a,NH) = 3J (H-9b,NH) =
6.0 Hz, 1 H; NH); 13C NMR (125.7 MHz, [D6]DMSO, 25 °C, TMS): δ =
34.1 (C-9), 46.1 (C-6), 46.6 (C-6’), 51.9 (OCH3), 67.4 (C-3’), 67.5 (C-3),
69.3 (C-4), 70.1 (C-4’), 74.4 (C-5), 74.6 (C-5’), 75.5 (C-2), 76.8 (C-2´),
86.2, 86.4, 91.3 (OCH2O), 123.3 (C-7), 145.0 (C-8), 167.1 (HNCO), 167.8
(CH3OCO). HRMS (ESI/Q-TOF) m/z: [M + Na]+ calcd for C20H27N7O11Na
564.1649; found: 564.1661. The byproduct 13b was isolated as a white
Compound 14. To a solution of compound 5 (0.30 g, 0.32 mmol) in
anhydrous DMSO (4.3 mL) was added NaN3 (0.04 g, 0.64 mmol). The
reaction mixture was stirred under Ar atmosphere at 100 °C for 24 h.
Compound 14 precipitated from the reaction mixture upon addition of
acetone and it was recovered by centrifugation. The solid was
sequentially washed with acetone-H2O (90:10) and acetone. Compound
solid, from further fractions of the column (90:10 EtOAc-MeOH).
25
Compound 13b (0.05 g, 22%); m.p. 189-190 °C (recryst from H20). [α D
]
= +12.2 (c = 0.5 in DMSO). 1H NMR (500 MHz, [D6]DMSO, 25 °C, TMS):
δ = 3.42 (dd, 3J (H-5’,H-6’a) = 5.0 Hz, 3J (H-6’a,H-6’b) = 13.3 Hz, 1 H; H-
6’a), 3.69 (s, 1 H; H-4’), 3.73 (s, 3 H; CH3O), 3.81 (m, 3J (H-5,H-6b) = 3.0
Hz, 3J (H-4,H-5) = 7.3 Hz, 3J (H-5,H-6a) = 3J (H-5,OH) = 6.4 Hz, 1 H; H-5),
3.95 (m, 3J (H-5’,H-6’b) = 5.0 Hz, 3J (H-5’,H-6’b) = 9.9 Hz, 1 H; H-5’), 4.09
(dd, 1H, 3J (H-5’,H-6’a) = 9.9 Hz, 3J (H-6’a,H-6’b) = 13.2 Hz, 1 H; H-6’b),
4.15 (s, 1 H; H-3’), 4.27 (dd, 3J (H-3,H-4) = 2.2 Hz, 3J (H-4,H-5) = 7.3 Hz,
1 H; H-4), 4.30 (d, 1H, 3J (H-2’,H-3’) = 1.7 Hz, 1 H; H-2’), 4.32-4.37 (m, 3
H; H-6a, H-9), 4.51 (dd, 3J (H-5,H-6b) = 3.0 Hz, 3J (H-6a,H-6b) = 14.1 Hz,
1 H; H-6b), 4.81 (d, 3J (H,H) = = 6.4 Hz, 1 H; OCH2O), 4.83 (d, 3J (H,H) =
6.5 Hz, 1 H; OCH2O), 5.00 (d, 3J (H-,H-) = 6.5 Hz, 1 H; OCH2O), 5.06 (d,
3J (H,H) = 5.8 Hz, 1 H; OCH2O), 5.11 (d, 3J (H,H) = 6.4 Hz, 1 H; OCH2O),
5.27 (d, 3J (H,H) = 5.8 Hz, 1 H; OCH2O), 5.79 (s, 3J (H-5,OH) = 6.4, 1 H;
OH), 6.26 (d, 3J (H-3,H-4) = 2.2 Hz, 1 H; H-3), 7.76 (2, 1 H; H-7), 8.17 (t,
3J (H-9a,NH) = 3J (H-9b,NH) = 6.1 Hz, 1 H; NH); 13C NMR (125.7 MHz,
[D6]DMSO, 25 °C, TMS): δ = 34.2 (C-9), 46.6 (C-6’), 52.1, 51.2 (C-6,
OCH3), 67.4 (C-3’), 70.1 (C-4’), 70.9 (C-5), 73.5 (C-4), 74.6 (C-5’), 76.8
(C-2´), 86.4, 89.6, 91.3 (OCH2O), 112.8 (C-3), 123.8 (C-7), 143.4 (C-2),
144.8 (C-8), 161.3 (CH3OCO), 167.2 (HNCO). HRMS (ESI/Q-TOF) m/z:
[M + Na]+ calcd for C19H25N7O10Na: 534.1534; found: 534.1555.
14 (0.21 g, 80%). m.p. 229 ºC (recryst from DMSO-acetone); [α]D
25 +67.0
(c = 0.6; DMSO); 1H NMR (500 MHz, [D6]DMSO, 25 °C, TMS): δ = 3.42
(dd, 3J (H-5’’,H-6’’a) = 4.9 Hz, 3J (H-6’’a,H-6’’b) = 13.3 Hz, 1 H; H-6’’a),
3.69 (s, 1 H; CH3O), 3.71 (s, 1 H; H-4’’), 3.80 (s, 2 H; H-4, H-4’), 3.95 (dd,
3J (H-5’’,H-6’’a) = 4.9 Hz, 3J (H-5’’,H-6’’b) = 9.8 Hz, 1 H; H-5’’), 4.09 (dd,
3J (H-5’’,H-6’’a) = 9.8 Hz, 3J (H-6’’a,H-6’’b) = 13.3 Hz, 1 H; H-6’’b), 4.15 (s,
1 H; H-3’’), 4.19 (m, 2 H; H-5, H-5’), 4.29 (d, 3J (H-2’’,H-3’’) = 1.68 Hz, 1
H; H-2’’), 4.30 (s, 2 H; H-3, H-3’), 4.32 (d, 3J (H-2’,H-3’) = 1.43 Hz, 1 H; H-
2’), 4.28-4.40 (m, 4 H; H-9, H-9’), 4.62-4.64 (m, 3 H; H-2, H-6a, H-6’a),
4.76-4.85 (m, 6 H; OCH2O), 5.00 (d, 3J (H,H) = 6.6 Hz, 1 H; OCH2O),
5.06-5.12 (m, 7 H; H-6b, H-6’b, OCH2O), 7.82, 7.83 (2s, 2 H; H-7, H-7’),
8.19 (m, 2 H; NH, NH’); 13C NMR (125.7 MHz, [D6]DMSO, 25 °C, TMS): δ
= 34.1 (C-9, C-9’), 46.1 (C-6, C-6’), 46.6 (C-6’’), 51.9 (OCH3), 67.2, 67.3
(C-3, C-3’), 67.4 (C-3’’), 69.3, 69.8 (C-4, C-4’), 70.1 (C-4’’), 74.4, 74.5 (C-
5, C-5’), 74.6 (C-5’’), 75.5 (C-2), 76.8 (C-2, C-2’), 86.2, 86.4, 91.3,
(OCH2O), 123.3 (C-7, C-7’), 145.0 (C-8, C-8’), 167.1 (CONH, CONH’),
167.8 (CO2CH3). HRMS (ESI/Q-TOF) m/z [M
+
Na]+ calcd for
C31H41N11O16Na 846.2630; found: 846.2652.
Microwave-assisted synthesis of 13a. To a solution of compound 4
(0.300 g, 0.45 mmol) in anhydrous DMF (0.76 ml), NaN3 (0.03 g, 0.46
mmol) was added. The mixture was stirred under N2 and subjected to Mw
irradiation at 80 °C for 5 h, until complete consumption of the starting 4.
After concentration, the residue was subjected to column
chromatography (80:20 EtOAc-MeOH) to give compound 13a (0.19 g,
81%) as a white crystalline solid, which showed identical physical and
spectroscopic properties as the compound described above.
Microwave-assisted synthesis of 14. To a solution of compound 5
(0.11 g, 0.11 mmol) in dry DMSO (1.5 mL) was added NaN3 (0.02 g, 0.25
mmol). The mixture was heated under Mw irradiation at 100 °C for 1 h
(Ar atmosphere). Compound 5 (0.07 g, 70%) was isolated by the same
procedure described for 13a.
Compound 6. To a solution of compounds 12 (0.15 g, 0.19 mmol) and
14 (0.08 g, 0.19 mmol) in anhydrous DMSO (5 mL) CuOAc (0.001 g, 0.01
mmol) was added. The mixture was heated under Mw irradiation at
Compound 5. To a solution of compounds 12 (0.21 g, 0.51 mmol) and
13a (0.28 g, 0.51 mmol) in DMF (5 mL) was added CuOAc (0.003 g,
0.024 mmol). The mixture was heated under Mw irradiation at 100 °C for
30 min (Ar atmosphere). Compound 5 precipitated from the mixture and it
100°C for 30 min (Ar atmosphere). Upon cooling, compound 6
precipitated off and it was recovered by centrifugation. The solid was
sequentially washed with 0.16 M EDTA, H2O and acetone to give
compound 6 (0.17 g, 78%) as a white solid. m.p. 250 ºC (decomp)
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801320
European Journal of Organic Chemistry
FULL PAPER
(recryst from DMSO-acetone); [α]D
25 = +72.3 (c = 0.3 in DMSO); 1H NMR
74.4 (C-5), 76.7 (C-2, C-2’), 81.1 (C-2’’), 86.2, 86.8, 91.2, 91.4 (OCH2O),
123.3 (C-7), 127.8, 130.2, 132,1 (C-aromatic), 144.9 (C-8); 145.2 (C-
aromatic); 166.9, 167.0 (CONH, CONH’). HRMS (ESI/Q-TOF) m/z: [M +
H]+ calcd for C29H36N5O13S 694.2025; found: 694.2043.
(500 MHz, [D6]DMSO, 25 °C, TMS): δ = 2.08 (s, 3 H; CH3Ph), 3.69 (s, 3
H; CH3O), 3.70 (s, 1 H; H-4’’), 3.79 (s, 3 H; H-4, H-4’), 3.96 (m, 3J (H-
5’’,H-6’’a) = 4.8 Hz, 3J (H-5’’,H-6’’b) = 8.5 Hz, 1 H; H-5’’), 4.05 (s, 1 H; H-
3’’), 4.18-4.22 (m, 4 H; H-5, H-5’, H-2’), 4.30 (s, 3 H; H-3, H-3’), 4.32 (s, 2
H; H-2’), 4.25-4.42 (m, 7 H; H-6’’a, H-9, H-9’); 4,54 (m, 3J (H-5’’,H-6’’b) =
8,5 Hz, 3J (H-6’’a,H-6’’b) = 11,4 Hz, 1 H; H-6’’b); 4,60-4,64 (m, 4 H; H-2,
H-6a, H-6’a); 4.72-4.82 (m, 9 H; OCH2O), 5.05-5.12 (m, 11 H; H-6b, H-
6’b, OCH2O), 7.50 (d, 3J (H,H) = 8.1 Hz, 2 H; H-aromatic), 7.81-7.84 (m,
5 H; H-7, H-7’, H-7’’,H-aromatic), 8.16 (t, 3J (H-9’’a,NH’’) = 3J (H-
9’’b,NH’’) = 6.0 Hz, 1 H; NH’’), 8.19 (t, 3J (H-9a,NH) = 3J (H-9b,NH) = 6.0
Hz, 2 H; NH, NH’); 13C NMR (125.7 MHz, [D6]DMSO, 25 °C, TMS): δ =
21.1 (CH3-Ph), 34.2 (C-9, C-9’, C-9’’), 46.1 (C-6, C-6’), 51.9 (OCH3), 66.2
(C-6’’), 67.2 (C-3’), 67.4 (C-3), 67.5 (C-3’’), 69.1 (C-4’’), 69.3 (C-4), 69.8
(C-4’), 73.1 (C-5’’), 74.4 (C-5, C-5’), 75.5 (C-2), 76.7 (C-2’’), 76.8 (C-2’),
86.2, 86.8, 91.3, 91.4 (OCH2O), 123.4 (C-7, C-7’, C-7’’), 127.8, 130.2,
132.1 (C-aromatic), 145.0 (C-8, C-8’, C-8’’), 145.2 (C-aromatic), 167.0,
167.1 (CONH, CONH’), 167.8 (CO2CH3). HRMS (ESI/Q-TOF) m/z: [M +
H]+ calcd for C49H63N12O24 1235.3750; found: 1235.3722.
Compound 7. To a solution of compounds 14 (0.080 g, 0.09 mmol) and
16 (0.060 g, 0.09 mmol) in dry DMSO (1.1 mL), CuOAc (0.006 g, 0.005
mmol) was added. The mixture was subjected to Mw irradiation at 100 °C
for 30 min (Ar atmosphere). Compound 7 precipitated from the mixture
upon addition of acetone and it was collected by centrifugation. The solid
was sequentially washed with 0.16M EDTA, H2O and acetone, to give
compound 7 (0.12 g, 84%) as a white solid. m.p. 253 ºC (decomp)
+624.2 (c 0,06; DMSO); 1H NMR
25
(recryst from DMSO-acetone); [α]D
(500 MHz, [D6]DMSO, 25 °C, TMS): δ = 2.42 (s, 3 H; CH3Ph), 3.69 (s, 4
H; H-4’’, CH3O), 3.79 (s, 4 H; H-4, H-4’), 3.96 (m, 1 H; H-5’’), 4.04 (s, 1 H;
H-3’’), 4.20 (m, 5 H; H-5, H-5’, H-2’’), 4.29 (s, 4 H; H-3, H-3’), 4.31 (s, 3
H; H-2’), 4.25-4.41 (m, 9 H; H-6’’a, H-9, H-9’), 4.53 (m, 1 H; H-6’’b); 4,60-
4,62 (m, 5 H; H-2, H-6a, H-6’a), 4.73-4.82 (m, 11 H; OCH2O), 5.04-5.11
(m, 13 H; H-6b, H-6’b, OCH2O), 7.50 (d, 3J (H,H) = 8.3 Hz, 2 H; H-
aromatic), 7.81-7.83 (m, 6 H; H-7, H-7’, H-aromatic), 8.16-8.20 (m, 4 H;
NH, NH’); 13C NMR (125.7 MHz, [D6]DMSO, 25 °C, TMS): δ = 21.2 (CH3-
Ph), 34.2 (C-9, C-9’), 46.1 (C-6, C-6’), 51.9 (OCH3), 66.2 (C-6’’), 67.2 (C-
3’), 67.4 (C-3, C-3’’), 69.2 (C-4’’), 69.4 (C-4), 69.8 (C-4’), 73.2 (C-5’’),
74.4, 74.5 (C-5, C-5’), 75.6 (C-2), 76.7 (C-2’’), 76.8 (C-2’), 86.3, 86.8,
91.3, 91.4 (OCH2O), 123.4 (C-7, C-7’), 127.8, 130.3, 132.1 (C-aromatic),
145.0 (C-8, C-8’), 145.2 (C-aromatic), 167.1 (HNCO, HNCO’), 167.9
Compound 15. To a solution of compound 4 (0.37 g, 0.56 mol) in
MeOH-H20 2:1 (12 mL), 5% LiOH in MeOH-H20 2:1 was added dropwise
until reaching pH 8. The solution was stirred at room temperature for 5 h,
keeping pH 8. Finally, the solution was acidified to pH 5, upon addition of
Dowex 50WX4 (H+). The mixture was filtered and concentrated to give
compound 15 (0.31 g, 85%) as a white solid. m.p. 210 °C (decomp)
25
(recryst from H2O-acetone); [α]D
= +52.3 (c = 0.6 in DMSO); 1H NMR
(CH3OCO). HRMS (ESI/Q-TOF) m/z: [M
+
Na]+ calcd for
(500 MHz, [D6]DMSO, 25 °C, TMS): δ = 2.43 (s, 3 H; CH3Ph), 3.70 (s, 1
H; H-4’), 3.77 (s, 1 H; H-4), 3.96 (m, 3J (H-5’,H-6’a) = 4.8 Hz, 3J (H-5’,H-
6’b) = 8.6 Hz, 1 H; H-5’), 4.05 (s, 1 H; H-3’), 4.17-4.20 (m, 3J (H-2’,H-3’) =
1.7 Hz, 3J (H-5,H-6a) = 4.6 Hz, 3J (H-5,H-6b) = 10.6 Hz, 2 H; H-2’, H-5),
4.25-4.28 (m, 3J (H-5’,H-6’a) = 5.9 Hz, 3J (H-9a,NH) = 5.9 Hz, 3 H; H-3, H-
6’a, H-9a), 4.61 (m, 3J (H-9b,NH) = 5,9 Hz, 3J (H-9a,H-9b) = 14.6 Hz, 1 H;
H-9b), 4.44 (d, 3J (H-2,H-3) = 1.8 Hz, 1 H; H-2), 4.54 (m, 3J (H-5’,H-6’b)=
8.6 Hz, 3J (H-6’a,H-6’b) = 11.3 Hz, 1 H; H-6’b), 4.61 (m, 3J (H-5,H-6a) =
4.6 Hz, 3J (H-6a,H-6b) = 14.5 Hz, 1 H; H-6a), 4.71-4.77 (m, 5 H; OCH2O),
5.04-5.12 (m, 4 H; H-6b, OCH2O), 7.50 (d, 3J (H,H) = 8.1 Hz, 2 H; H-
aromatic), 7.81 (s, 1 H; H-7), 7.83 (d, 3J (H,H) = 8.1 Hz, 2 H; H-aromatic),
8.16 (t, 1 H; NH); 13C NMR (125.7 MHz, [D6]DMSO, 25 °C, TMS): δ =
21.1 (CH3-Ph), 34.1 (C-9), 46.1 (C-6), 66.2 (C-6’), 67.5 (C-3’), 67.6 (C-3),
69.1 (C-4’), 69.5 (C-4), 73.1 (C-5’), 74.4 (C-5), 75.4 (C-2), 76.7 (C-2’),
86.2, 86.8, 91.3 (OCH2O), 123,3 (C-7), 127.8, 130.2, 132.1 (C-aromatic),
145.0 (C-8), 145.2 (C-aromatic), 167.0 (CONH), 168.7 (CO2H). HRMS
(ESI/Q-TOF) m/z: [M + H]+ calcd for C26H33N4O14S 657.1708; found:
657.1681.
C60H76N16O29SNa: 1539.4577; found: 1539.4574.
ESI MS measurements.
Experiments were conducted using a Waters SQD2 single quadrupole
mass spectrometer with an electrospray ionization (ESI) source. The
instrument was operated in positive ion mode with a probe capillary
voltage of 3.5 kV and in negative ion mode with a capillary voltage of 3.0
kV. The sampling cone voltage was set to 45.0 V. The source and
desolvation gas temperatures were set to 150 and 350 °C, respectively.
The nitrogen gas desolvation flow rate was 550 L h−1, the cone gas flow
rate was 10 L h−1. The mass spectrometer was calibrated across the
range of m/z 20−2023 with a sodium and cesium iodide solution. Data
were acquired in scan mode with a scan duration of 0.2 sec and unit
resolution. Samples were introduced into the ESI source using direct
infusion at a flow rate of 10 µL min-1, and each run was acquired for 2
min. Technical duplicates were acquired in all cases. Data acquisition
and processing were carried out using MassLynx, version 4.1 software.
Compound 16. To a solution of compound 15 (0.25 g, 0.39 mmol),
DIPEA (0.54 mL, 1.10 mmol) and TBTU (0.12 g, 0.39 mmol) in
anhydrous DMF (3.2 mL), propargylamine (30 μL, 0.47 mmol) was added.
Job plot. Solutions of compounds 4-6 (10 µ
M in 1:1 acetonitrile-water) or
compound 7 (5 µM in 3:3:4 acetonitrile-water-iPrOH) were prepared. To
these solutions, 15-crown-5 was added in the amount required to reach
the same concentration as the oligo(amide-triazole). Convenient volumes
The solution was stirred at room temperature for 24
h and then
concentrated. The solid obtained was washed with MeOH and H2O, to
of host stock solution of oligo(amide-triazole)s 4-6 were mixed with 10 µ
M
give 16 as a white solid (0.21 g, 80%). m.p. 245 °C (recryst from DMSO-
25
acetone); [α]D
KCl solution in 1:1 acetonitrile-water (5 µM KCl in 3:3:4 acetonitrile-water-
= +68.8 (c = 0.5 in CH2Cl2); 1H NMR (500 MHz,
iPrOH for 7), containing also 15-crown-5. The final volume for each
individual experiment was 2 mL. Thus, crown ether and total (host +
guest) concentrations were kept constant during the experiments.
[D6]DMSO, 25 °C, TMS): δ = 2.43 (s, 3 H; CH3Ph), 3.04 (s, 1 H; H-3’’),
3.70 (s, 1 H; H-4’), 3.75-3.80 (m, 2 H; H-1’’a, H-4), 3.95 (m, 2 H; H-1’’b,
H-5’), 4.05 (s, 1 H; H-3’), 4.16-4.19 (m, 2 H; H-2’, H-5), 4.24-4.28 (m, 5 H;
H-2, H-3, H-6’a, H-9), 4.54 (m, 3J (H-5,H-6’b) = 8.9 Hz, 3J (H-6’a,H-6’b) =
11.3 Hz, 1 H; H-6’b), 4.62 (m, 3J (H-5,H-6a) = 4.3 Hz, 3J (H-6a,H-6b) =
14.0 Hz, 1 H; H-6a), 4,71-4,77 (m, 3 H; OCH2O); 4.81 (d, 1 H; OCH2O);
5.04-5.12 (m, 5 H; H-6b, OCH2O), 7.50 (d, 3J (H,H) = 8.1 Hz, 2 H; H-
aromatic), 7.80 (s, 1 H; H-7), 7.83 (d, 3J (H,H) = 8.1 Hz, 2 H; H-aromatic),
8.13-8.16 (m, 2 H; NH, NH’’); 13C NMR (125.7 MHz, [D6]DMSO, 25 °C,
TMS): δ = 21.1 (CH3-Ph), 27.7 (C-1’’), 34.1 (C-9), 46.1 (C-6), 66.1 (C-6’),
67.1 (C-3), 67.5 (C-3’), 69.1 (C-4’), 69.7 (C-4), 72.5 (C-3’’), 73.1 (C-5’),
NMR measurements. Job plot. Convenient volumes of solutions of
oligo(amide-triazole)s 4-7 (5 m
TMA chloride solutions, in order to have a total 600 µL volume with
constant 5 m (host + guest) concentration, while the molar fraction was
M in [D6]DMSO) were mixed with 5 mM
M
varied. The change in the chemical shift of triazole protons was
measured, relative to that of the pure compound.
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10.1002/ejoc.201801320
European Journal of Organic Chemistry
FULL PAPER
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Financial support by the National Research Council of Argentina
(CONICET, Project PIP 11220150100443CO, Project PUE
2292016010006800), the University of Buenos Aires (Project
20020130100571BA), and the National Agency of Scientific and
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