Heterophane prototypes containing azolium and/or azole anion-binding motifs

Article abstract of DOI:10.1039/c3ob41214h

Revisiting a '3 + 1' convergent stepwise strategy permitted the synthesis of [1₄]imidazoliophane 2·2Br in excellent yield for a macrocyclization. The new [1₄]triazoliophane 3 and bis(1,2,3-triazolium) counterpart 4·2Cl were less synt

Full text of DOI:10.1039/c3ob41214h

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[14]Heterophane prototypes containing azolium
and/or azole anion-binding motifs†
Cite this: Org. Biomol. Chem., 2013, 11,
6385
Neus Mesquida,* Immaculada Dinarès, Anna Ibáñez and Ermitas Alcalde*
Revisiting a ‘3 + 1’ convergent stepwise strategy permitted the synthesis of [14]imidazoliophane 2·2Br in
excellent yield for a macrocyclization. The new [14]triazoliophane 3 and bis(1,2,3-triazolium) counterpart
4·2Cl were less synthetically accessible and the hybrid derivative 5·Cl proved troublesome to prepare. Tri-
azolophane 3 was devoid of anion-binding affinities, while charged [14]heterophane prototypes showed
a particular preference for acetate. When association constants were compared, dicationic systems 2·2PF6
and 4·2PF6 showed greater values than monocationic macrocycle 5·PF6, and the highest affinities corre-
sponded to the bis(imidazolium) receptor 2·2PF6.
Received 12th June 2013,
Accepted 30th July 2013
DOI: 10.1039/c3ob41214h
www.rsc.org/obc
excellent binding affinities, discussing the contribution of
different types of noncovalent interactions involved in anion
Introduction
The number of fundamental roles played by anions in biologi- recognition. Thus, the uncharged pyrrolyl-based triazolophane
cal and chemical processes have resulted in a demand for contains C–H and N–H hydrogen bond donor groups,28
anionic synthetic receptors, of great interest in the fields of whereas the triazolium phane counterpart has a set of hydro-
anion transport, extraction and sensing.1–6 The functions of gen bonds from the pyrrole N–H, benzene C–H and quaternary
molecular and supramolecular charged systems can be modu- 1,2,3-triazolium (C–H)+ structural motifs.29
lated by tuning different counteranion effects in solution, and
Cyclophanes, heterophanes and calixarenes constitute a
representative developments in tailored mechanostereochemi- source of novel host systems with a potentially broad array of
cal systems have been discussed.7 Quaternary azolium salts molecules and shapes. During the 1990s, the heteroaromatic
and azoles have gained a place among the anion-binding func- ring components present in heterocalixarenes and hetero-
tional groups and have emerged as attractive starting points phanes were normally uncharged heteroaromatic moieties
for the design of a variety of host systems, from synthetic such as calixpyrroles, e.g. calix[14]pyrroles, which are easy to
anion receptors and sensors to transporters.8–20 In recent synthesize and have recognized anion-binding properties.30
years, there have been particular advances in the chemistry of Particularly significant was that the few charged moieties were
imidazolium-based systems,9–12,21–23 and at the same time the usually pyridinium nuclei.8,9 In this context, we should
1,2,3-triazole family has emerged as a source of appropriate mention the [14]meta-heterophane 1·2A built up from 1H-1,2,4-
structural motifs for anion binding.8,13–16 ‘Click triazoles’ triazolyl-3(5)methylimidazolium salt units where the 1H-1,2,4-
feature widely in the recent chemical literature, and their triazole and the imidazolium rings are linked in a 1,3-alternat-
application to abiotic anion receptors16 and in supramolecular ing fashion.31,32 A logical extension of this work was then
systems17 has been reviewed. Moreover, 1,2,3-triazole and centred in the dicationic [14]meta-imidazoliophane prototypes,
1,2,3-triazolium-based sensors for the binding of cations, e.g. 2·2A, with two aromatic rings and maintaining the
anions, small molecules and biomolecules have also been the imidazolium nuclei as anion recognition motifs functioning
subject of numerous studies.18–20,24–27 Recently, Sessler and mainly through a combination of electrostatics and hydrogen
co-workers have investigated two hybrid heterophanes act- bonding interactions.9,33–35 Continuing our research on
ing as receptors for pyrophosphate anions, which exhibited heterophane prototypes for processes controlled by hydrogen
bonding networks, we focused our attention on the following
models: the bis(1,2,3-triazolo)phane 3, the bis(1,2,3-triazo-
lium) counterpart 4·2A and the hybrid [14]heterophane 5·A,
Laboratori de Química Orgànica, Facultat de Farmàcia, Universitat de Barcelona,
Avda. Joan XXIII s/n, 08028 Barcelona, Spain. E-mail: neusmesquida@ub.edu,
ealcalde@ub.edu
†Electronic supplementary information (ESI) available: Synthesis of 6, 9 and 10,
the latter combining imidazolium and 1,2,3,-triazole motifs
in
a 1,3-alternating manner. These prototypes contain
uncharged heteroaromatic π-excedent rings, i.e. azoles, and/or
highly π-deficient heteroaromatic quaternary azolium rings
(Fig. 1).
assays related to the synthesis of 5·Cl, NMR and ESI(+)-HRMS spectra of macro-
cycles 3, 4·2Cl and 5·Cl, and details of NMR titrations. See DOI: 10.1039/
c3ob41214h
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Scheme 1 ‘3 + 1’ Convergent synthesis of [14]imidazoliophanes 1·2A and
2·2A. Equivalent amounts of the reagents in dry acetonitrile, reflux temperature,
at a concentration of: (i) 2.3 mM, 48 h; (ii) 8.0 mM, 96 h; (iii) 5.0 mM, 48 h.
Fig. 1 [14]meta-Heterophane prototypes 1·2A–5·A.
Results and discussion
Receptor synthesis
The synthesis of [14]heterophanes 1·2A–5·A required a variety
of synthetic approaches, as shown in Schemes 1–3.
By following a ‘3 + 1’ convergent stepwise synthesis pre-
viously described by our group,31–35 bis(imidazolium) cyclo-
phanes 1·2A and 2·2A were obtained in 51% and 57% yield,
respectively, which is a remarkably good result for a macro-
cyclization reaction. A modification of the described experi-
mental conditions towards the cyclophane framework,
decreasing both the concentration of the starting materials
and the reaction time, resulted in 2·2Br in excellent 81% yield
(Scheme 1).
In order to synthesize the [14]triazolophane 3, we proposed
a double azide–alkyne cycloaddition, but when a click proto-
col, previously used for an efficient synthesis of rigid triazolo-
phanes,24 was applied to dialkyne 6 and diazide 7, the targeted
macrocycle 3 was obtained in very low yield (10%), since it was
extremely difficult to purify. After a trial of different reaction
Scheme 2 Azide–alkyne cycloadditions – click chemistry – to prepare [14]tri-
azolophane 3: (i) dropwise addition of reagents over 10 h to CuI, DBU, PhMe at
25 °C, 18 h at 25 °C and 4 h at 70 °C; (ii) dropwise addition of reagents over
10 h to CuSO4·5H2O, sodium ascorbate, t-BuOH–H2O (1 : 1) at 25 °C, 18 h at
25 °C. Quaternisation of [14]triazolophane 3: (iii) Me3O·BF4 in CH2Cl2 at 25 °C,
40 h; (iv) anion-exchange resin (Cl− form).
conditions, the best yield of pure 3 was only 19% (Scheme 2). (benzyltriazolylmethyl)amine and [Cu(CH3CN)4]PF6 as the CuI
Shortly after the synthesis of 3 was completed, a double azide– complex.27 This protocol will be borne in mind in our ongoing
alkyne cycloaddition was reported in good yields using tris- research.
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Scheme 3 Synthesis of hybrid [14]heterophane 5·Cl applying a three-step synthetic protocol from advanced azide and alkyne components 9 and 10: (i) Cu2O,
H2O–AcOEt (4 : 1), rt, 16 h; (ii) SOCl2, CH2Cl2, rt, 2 h; (iii) dropwise addition of 1H-imidazole–KOH to trinucleating protophane 12 in CH3CN over 4 h, followed by
48 h reflux; (iv) dropwise addition of trinucleating protophane 12 to 1H-imidazole–KOH in CH3CN over 20 min, followed by 48 h reflux.
Firstly, dialkyne 6 and diazide 7 needed to be synthesized 2·2Br,31–35 and the pentanucleating bis(imidazole) protophane
from dibromide 8. Thus, while diazide 7 was obtained by reac- 13 was obtained instead in 75% yield (Scheme 3). It should be
tion with NaN3 in DMF, dialkyne 6 was prepared in good yield pointed out that an attempt to shorten the sequential protocol
(84%) by insertion of two acetylenic groups in 8 using ethynyl- leading to cyclophane 5·Cl by following a different synthetic
trimethylsilane in the presence of ethylmagnesium bromide route also proved ineffective (see Scheme S2 in ESI†).
and copper(I) bromide as the catalyst, followed by cleavage of
The advanced intermediates 9 and 10 had been previously
silyl groups using TBA·F in acetic acid (see Scheme S1 in ESI†). synthesized from the benzylic alcohol 14. Protection of 14 with
Quaternising the 1,2,3-triazole rings of macrocycle 3 with the (tert-butyl)dimethylsilyl group followed by nucleophilic
Me3O·BF4 gave the dicationic counterpart 4·2BF4, which was substitution of the resulting silylated 15 with NaN3 in DMF
then passed through an anion-exchange resin (Cl− form) to afforded azide 9 in 67% overall yield. On the other hand,
give pure [14]triazoliophane 4·2Cl in 33% overall yield alkyne 10 was synthesized using silylated 16 (prepared in turn
(Scheme 2).
from alcohol 14 and hexamethyldisilazane in MeNO2), and
In the synthesis of the hybrid [14]heterophane 5·Cl, applying the same experimental protocol as in dialkyne 6, with
although different multi-step synthetic routes could be a yield of 55% (see Scheme S3 in ESI†).
applied, a reasonable pathway appeared to involve a three-step
Finally, in order to examine the anion-binding behaviour of
protocol starting with an azide–alkyne cycloaddition reaction these cyclophanes, compounds 1·2Cl, 2·2Br, 4·2Cl and 5·Cl
between the advanced azide 9 and alkyne 10, using Cu2O–H2O were transformed to the corresponding hexafluorophosphates
as a catalytic system. The resulting trinuclear open-chain com- 2·2PF6, 4·2PF6 and 5·PF6, chloride 2·2Cl, acetates 1·2AcO and
pound 11 was then converted to bis(chloromethyl)trinuclear 2·2AcO, and dihydrogenphosphate 2·2H2PO4 with excellent
protophane 12 by treatment with SOCl2. The dropwise addition yields, following our anion-exchange resin (A− form) method36
of 1H-imidazole-KOH over the trinucleating key-precursor 12 (Scheme 4).
produced the targeted hybrid heterophane 5·Cl in 45% yield
along with bis(imidazole) pentanuclear protophane 13 (16%).
Spectroscopy and spectrometry
Notably, the ‘3 + 1’ convergent synthesis of 5·Cl failed when
following our standard protocol previously successfully applied
to bis(imidazolium) cyclophane prototypes, e.g. 1·2Cl and
The new heterophanes 3–5·A were characterized on the basis
of their spectroscopic and spectrometric data. The 1H NMR
spectra in DMSO-d6 of 3–5·A showed a sharp singlet due to the
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Scheme 4 Counteranion exchange of [14]imidazoliophanes 1·2Cl, 2·2Br, 4·2Cl and 5·Cl.
methylene hydrogen atoms, indicating a high degree of confor- studies with 5·PF6 in DMSO-d6 were not pursued either, after a
mational flexibility, comparable to that in dications 1·2A and similar observation of a low chemical shift variation between
2·2A31–35 (see the Experimental section and Table S1 in ESI†). the macrocycle and 5·Cl.
Cyclophanes 3 and 4·2Cl were assigned by 1D-NOESY experi-
ments, and 5·Cl by a ROESY experiment (see ESI†). The key dicationic heterophane 2·2A was soluble in CD3CN but not in
NMR responses are shown in Fig. 2. CDCl3 and vice versa for the more lipophilic uncharged triazolo-
The solubility of 2·2A–5·A proved to be variable since the
Furthermore, in order to confirm the chemical formula of phane 3, while charged 4·2A and 5·A were soluble in both.
[14]cyclophane 5·Cl (M·Cl, C29H36N5Cl) and discard the pres- DMSO-d6 was the only solvent usable for all the heterophanes.
ence of the related [18]cyclophane (M·2Cl, C58H72N10Cl2), we
Owing to the solvent effects,37,38 dications 2·2A exhibited
examined its ESI(+)-HRMS spectrum, which showed that the greater deshielding of the acidic protons in a less polar
experimental and calculated isotopic patterns of the ion [M]+ solvent. Thus, a comparison of chemical shifts of hexafluoro-
were in agreement (Fig. 3).
phosphate and the other azolium salts showed appreciable
An initial analysis of potential anion-binding behaviour of variations, the largest difference in CD3CN being 3.08 ppm,
the flexible [14]heterophanes 1·2A–5·A was performed by com- corresponding to the imidazolium protons H(a) in 2·2AcO and
paring their 1H NMR spectral data at a non-aggregating con- 2·2PF6, which in DMSO-d6 was only 1.09 ppm. On the other
centration of 0.003 M in different solvents. Compounds 2·2A, hand, the largest difference in DMSO-d6 corresponded to the
4·2A and 5·A showed that the most affected proton chemical 2·2H2PO4 and 2·2PF6 pair (1.57 ppm).
shifts corresponded to the imidazolium H(a) and H(b)/(d) in
the phenylene ring as well as H(c) of 1,2,3-triazole/1,2,3-triazo-
lium, indicating their participation as hydrogen bonding
Anion binding studies
motifs in the anion binding (see Table 1, and Tables S1 and S2 The anion-binding behaviour of receptors 2·2PF6, 3, 4·2PF6
in ESI†).
and 5·PF6 was examined with chloride, acetate, cyanide and
1
Unfortunately, compounds 1·2A showed a very low solubility dihydrogenphosphate anions by H NMR titrations in CD3CN,
in CDCl3 and CD3CN, and although it was possible to prepare DMSO-d6 or CDCl3 using tetrabutylammonium salts as the
0.003 M solutions in DMSO-d6, further studies with this anion source (see Fig. S1–S28 in ESI†). Unfortunately, titration
solvent were discarded due to the barely downfield shift dis- experiments in aqueous media could not be carried out due to
played by the imidazolium H(a) when chloride or acetate was the low solubility of receptor models 2·2PF6–5·PF6 in D2O at
compared with hexafluorophosphate salts. Chloride-binding 0.003 M.
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Fig. 2 (a) Key 1H-NMR responses for 3 in CDCl3 and DMSO-d6 and 4·2Cl in DMSO-d6 (1D-NOESY experiments). (b) Partial 1H-NMR ROESY spectrum (CDCl3,
500 MHz) of 5·Cl.
Regarding the uncharged [14]triazolophane 3, no changes perturbation in the presence of TBA·A, it becomes apparent
were observed in the 1H NMR spectra after the addition of that the cooperation of the imidazolium motif is required for
even a large excess of TBA·Cl or TBA·AcO when using either the anion recognition in these [14]heterophane prototypes.
CDCl3 or DMSO-d6.
The Job’s plot analysis of bis(azolium) cyclophanes 2·2PF6
In contrast, titrations of the charged macrocycles 2·2PF6, and 4·2PF6 as well as the hybrid derivative 5·PF6, when titra-
4·2PF6 and 5·PF6 with acetate showed that the bis(imidazo- tions were carried out in CD3CN, revealed a 1 : 1 receptor to
lium) receptor 2·2PF6 underwent a dramatic deshielding of its anion binding stoichiometry and the association constants of
C(2)–H heteroaromatic proton with Δδ H(a) ≈ 3 ppm, whereas each type of shifted protons – H(a), H(b), H(c) and/or H(d) –
in the bis(triazolium) receptor 4·2PF6 the effect was less were determined by fitting the respective titration data using
intense in the C(5)–H heteroaromatic proton (Δδ H(c) ≈ the WinEQNMR2 program.39
2 ppm), confirming that imidazolium units have a better
In order to compare the studied receptors, the average
affinity profile for anions than triazolium. In parallel, in the Ka values (summarized in Table 2, and Tables S3 and S4
monocationic system 5·PF6 a similar downfield shift in the in ESI†) were calculated from the individual Ka values consider-
imidazolium unit was observed upon addition of 5 equivalents ing that all shifted protons were involved in the anion
of a titrant, while the triazole hydrogen reached Δδ H(c) ≈ interaction.
1 ppm (see Fig. 4a). If this result is compared with those
Results showed that the Ka values of bis(imidazolium) cyclo-
obtained with uncharged triazolophane 3, where neither the phane 2·2PF6 are at least 2-fold higher than the values corres-
phenylene H(b) nor triazole H(c) hydrogen atoms showed any ponding to the bis(triazolium) dication 4·2PF6, supporting that
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Fig. 3 [14]Cyclophane 5·Cl: calculated and experimental isotopic patterns of the ion [M]+.
Table 1 Selected 1H NMR (300 MHz) chemical shift values of compounds 1·2A–5·A in DMSO-d6, CD3CN or CDCl3 at 0.003 M
DMSO-d6
H(a)
CD3CN
H(a)
CDCl3
H(a)
Compd
Anion
Cl−
H(b)
H(c)
H(d)
H(b)
H(c)
H(d)
H(b)
H(c)
H(d)
1·2Aa,b
9.03
9.00
8.89
9.48
9.28
10.37
10.85
—
—
—
9.35
9.32
—
—
—
—
—
—
—
—
—
—
7.76
8.71
8.60
7.84
7.83
—
—
—
—
—
—
—
6.23
6.70
6.66
6.33
6.33
−
PF6
AcO−
2·2Ab
Cl−
6.81
6.62
7.31
7.88
6.26
7.14
7.08
6.35
6.31
11.00
8.35
11.43
8.46
6.51
8.15
—
—
—
—
—
—
−c
PF6
AcO−
−a
H2PO4
3a,c
4·2A
—
—
—
11.67
8.81
6.41
7.84
7.03
7.47
6.49
6.98
6.45
7.26
6.99
7.39
6.56
Cl−
—
—
9.27
8.37
7.73
6.71
6.78
6.33
9.23
7.80
7.84
7.41
7.16
6.45
6.71
6.36
10.01
7.90
8.62
7.72
−c
PF6
5·A
Cl−
−c
PF6
a Not soluble in CD3CN at 0.003 M. b Not soluble in CDCl3 at 0.003 M. c Not soluble in D2O at 0.003 M.
the presence of imidazolium motifs increases the anion recog- by one order of magnitude than the hybrid system 5·PF6,
nition ability in CD3CN in comparison with triazolium units. demonstrating that dicationic systems interact more strongly
Additionally, bis(azolium) heterophanes exhibited a higher Ka with the anion.
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Fig. 4 1H NMR titration of compounds 2·2PF6, 4·2PF6 and 5·PF6 with tetrabutylammonium acetate following the imidazolium H(a) [2·2PF6 and 5·PF6], triazolium
H(c) [4·2PF6] and triazole H(c) [5·PF6] protons in (a) CD3CN and (b) DMSO-d6.
Table 2 Association constants Ka (M−1) measured for receptors 2·2PF6, 4·2PF6
and 5·PF6 with a range of anions added as tetrabutylammonium salts at 298 Ka
in DMSO-d6 although with lower Ka values (see Table 2). Bis-
(imidazolium) receptor 2·2PF6 again gave higher Ka than the
bis(triazolium) model 4·2PF6, showing a Δδ H(a) 2-fold higher
than Δδ H(c) with the acetate anion (see Fig. 4b), thus confirm-
Receptor
Anion
2·2PF6
4·2PF6
5·PF6
ing its greater anion-binding properties as a hydrogen bond
donor motif.
Cl−b
4946
9074
1944
4799
185
AcO−b
CN−b
H2PO4
Cl−c
495
Finally, attempts to obtain adequate single crystals of the
various [14]heterophane prototypes for X-ray diffraction ana-
lysis, after trying different crystallization experimental con-
ditions, have been unsuccessful up to now. Similarly, blending
the uncharged triazolophane 3 with TBA·Cl failed to provide
single crystals of the [3 + TBA·Cl] complex. Efforts are currently
being directed towards obtaining some theoretical and physico-
chemical evidence that will allow us to compare the anion-
binding properties of these receptor models.
Recapping the results, after the qualitative anion-binding
study, compound 1·2A was discarded since no significant vari-
ation of the chemical shift was observed, while [14]hetero-
phane prototypes 2·2PF6–5·PF6 were selected for the evaluation
of their anion-binding behaviour with selected anions: Cl−,
AcO−, CN− and H2PO4−. The flexible triazolophane 3 showed
no response even when a large amount of a titrant agent was
added in either CDCl3 or DMSO-d6, whereas bis(azolium)cyclo-
phanes 2·2PF6 and 4·2PF6, together with the hybrid counter-
part 5·PF6, showed an affinity to oxoanions, especially acetate,
in CD3CN or DMSO-d6, with the highest Ka exhibited by the bis-
(imidazolium) system 2·2PF6, followed by bis(triazolium)
model 4·2PF6, and then, with a considerable difference, by
monocationic macrocycle 5·PF6 (Fig. 5).
1200
668
90d
4007f
−b
e
e
g
90
62
—
AcO−c
CN−c
H2PO4
460
86
227
75
h
g
—
667i
248
215
−c
a Average of the association constants determined for each shifted
hydrogen atom. Average errors ≤10% except where noted. b Titration
conducted in CD3CN. c Titration conducted in DMSO-d6. d Average
error 14%. e Precipitation occurred during titration. f Average error
11%. g Titration not carried out. h If after addition of a large excess of
the anion Δδ ≤ 0.1 ppm, the data were not processed. i Average error
12%.
Reaffirming the experimental results exposed above, the
highest affinity of these heterophane systems was observed for
acetate, followed by chloride, while it was significantly lower
for cyanide. Thus, the calculated Ka of the complex formed
between imidazolium 2·2PF6 and acetate was close to 104 M−1
,
whereas for triazolium 4·2PF6 it was about 5000 M−1, and for
hybrid 5·PF6 about 500 M−1. Notably, the titration of hetero-
phane 5·PF6 with TBA·H2PO4 gave Ka ∼ 4000 M−1, suggesting
that the values for the dicationic heterophanes 2·2PF6 and
4·2PF6 would be even higher, but unfortunately, precipitation
occurred during the titration experiments, probably due to a
strong interaction between the receptor and the H2PO4− anion,
although this cannot be quantified.
Conclusions
When titration experiments were repeated in a competitive
solvating solvent such as DMSO-d6, the internal hydrogen A ‘3 + 1’ convergent stepwise strategy was successfully applied
atoms of bis(imidazolium)phane 2·2PF6, H(a) and H(b) exhi- to synthesize [14]imidazoliophane 2·2Br in excellent yield for a
bited more significant downfield shifts than those of the bis(tri- macrocyclization. In clear contrast, the new [14]triazolophane 3
azolium) counterpart 4·2PF6, H(b) and H(c). As in CD3CN, the was far less synthetically accessible, and the quaternisation to
studied [14]heterophanes exhibited a preference for oxoanions give the charged bis(1,2,3-triazolium) counterpart 4·2Cl
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Fig. 5 Acetate affinity of the [14]heterophane prototypes 2·2PF6–5·PF6.
proceeded in only modest yield. Particularly complex was the Inova 500 (500 MHz) spectrometers at 298 K. Chemical shifts
multistep route leading to prototype 5·Cl, which alternatively were referenced and expressed in ppm (δ) relative to TMS for
combines imidazolium and 1,2,3-triazole motifs, since the chloroform-d. 13C NMR: Varian Gemini 300 (75.4 MHz),
coexistence of two different heteroaromatic rings requires an Mercury 400 (100.6 MHz) and Varian Inova 500 (125.6 MHz)
elaborate synthetic process. When we studied anion binding spectrometers at 298 K. Chemical shifts were referenced and
by 1H-NMR, changes in chemical shift values after the expressed in ppm (δ) relative to the central peak of chloroform-d
addition of a titrant agent were only observed in the charged (77.0 ppm). ESI(+)-MS: mass spectra were obtained using an
2·2PF6, 4·2PF6 and 5·PF6. In contrast, the hydrogen bond LC/MSD-TOF (2006) mass spectrometer from Agilent Techno-
donor properties of the triazole rings in the uncharged macro- logies; the sample was introduced into the source with an
cycle 3 were negligible. Interestingly, in 5·PF6, the cooperation HPLC system (Agilent 1100). TLC: Merck precoated silica gel
between an imidazolium and a triazole unit resulted in accep- 60 F254 plates or aluminium oxide 60 F254 plates using UV
table anion recognition. The affinity profile of these [14]azolio- light (254 nm) as a visualizing agent and/or an H2PtCl2 3%
phanes showed a preference for acetate, and the C(2)–H aq.–KI 10% aq. (1 : 1) or KMnO4 ethanolic solution. Column
hydrogen atom in imidazolium moieties exhibited greater chromatography was performed on silica gel 60 ACC 35–70 μm
deshielding than C(5)–H in triazolium units, suggesting stron- Chromagel (SDS) or Aluminium Oxide 90 standardized activity
ger anion binding by hydrogen bonds, which was reflected by II–III (Merck).
bis(imidazolium) receptor 2·2PF6 exhibiting the highest Ka
[14]meta-Heterophanes 1·2Cl and 1·2PF6,31,32 1,1′-[(5-tert-
values. Thus, the association constant for acetate in CD3CN butylbenzene-1,3-diyl)dimethanediyl]bis(1H-imidazole),33,34
was close to 104 M−1 for bis(imidazolium) receptor 2·2PF6 and and 3-(bromomethyl)-5-tert-butylphenyl)methanol 1440 were
about 5000 M−1 for the bis(triazolium) system 4·2PF6, which prepared as previously described.
was reduced to one-tenth the level for monocationic macro-
[14]meta-Heterophane 1·2AcO. The counteranion exchange
cycle 5·PF6. These [14]heterophane models allowed a direct to synthesize 1·2AcO from 1·2Cl was carried out by following
assessment of the concerted action of the different hydrogen our anion exchange resin (A− form) method.36
bond donor motifs present in the designed prototypes.
Mp 220–1 °C. IR (ATR): ν(CO2−)1568 cm−1 1H NMR
.
Despite their limitations, both azolium and azole structural (300 MHz, DMSO-d6): δ 0.85 (t, 12H), 1.29 (m, 16H), 1.89 (s,
motifs appeared to be attractive starting points for the design 6H, AcO−), 2.61 (t, 8H), 5.42 (s, 8H), 8.89 (s, 2H) ppm.
of novel anion recognition systems.
[14]Imidazoliophane 2·2Br. To a stirred solution of 1,1′-
[(5-tert-butylbenzene-1,3-diyl)dimethanediyl]bis(1H-imidazole)
(0.25 g, 0.85 mmol) in dry CH3CN (130 mL) was added drop-
wise a solution of 1,3-bis(bromomethyl)-5-tert-butylbenzene
(0.272 g, 0.85 mmol) in dry CH3CN (45 mL) under an argon
atmosphere. The reaction solution was refluxed for 48 h and
Experimental section
General methods and materials
Commercially available reagents were used without further evaporated to dryness. The resulting residue was crushed with
purification. All solvents are of reagent grade and MeOH was dry acetone (25 mL) and filtered to give macrocycle 2·2Br
distilled prior to use. Melting point: Gallenkamp Melting (0.421 g, 81%) as a white solid. The spectral data of 2·2Br were
Point Apparatus MPD350.BM2.5 with a digital thermometer identical to those previously described.33,34
and are uncorrected. IR (attenuated total reflection or thin
[14]Imidazoliophanes 2·2PF6, 2·2Cl, 2·2AcO and 2·2H2PO4.
film): Thermo Nicolet Avatar 320 FTIR. 1H NMR: Varian The counteranion exchanges to synthesize 2·2PF6, 2·2Cl,
Gemini 300 (300 MHz), Mercury 400 (400 MHz) and Varian 2·2H2PO4 and 2·2AcO were carried out by following our
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anion exchange resin (A− form) method.36 The spectral data of evacuated and backfilled with argon 3 times. After stirring for
2·2PF6 and 2·2Cl were identical to those previously 40 h, MeOH (1.0 mL) was added and the resulting mixture was
described.33,34
evaporated to dryness. A methanolic solution of the obtained
residue was passed through a column packed with an anion
2·2H2PO4: Mp 273–5 °C. IR (ATR): ν(PvO)1158 cm−1
.
1H NMR (400 MHz, DMSO-d6): δ 1.27 (s, 18H), 5.39 (s, 8H), exchange resin (Cl− form),41 and then washed with MeOH
7.56 (s, 4H), 7.64 (s, 4H), 7.88 (s, 2H), 10.87 (s, 2H) ppm.
(50 mL), MeOH–CH3CN (50 mL, 1 : 1) and CH3CN (50 mL). The
eluates were evaporated to dryness and the residue was puri-
2·2AcO: Mp 229–31 °C. IR (ATR): ν(CO2−)1561 cm−1
.
1H NMR (400 MHz, CD3CN): δ 1.29 (s, 18H), 1.82 (s, 6H, AcO−), fied by alumina column chromatography (CH2Cl2–MeOH, mix-
5.29 (s, 8H), 7.35 (s, 4H), 7.58 (s, 4H), 8.15 (s, 2H), 11.43 (s, 2H) tures of increasing polarity as the eluent) to afford 4·2Cl
ppm. 1H NMR (400 MHz, DMSO-d6): δ 1.29 (s, 18H), 1.61 (s, (20 mg, 33%) as a yellow solid.
6H, AcO−), 5.39 (s, 8H), 7.31 (s, 2H), 7.59 (s, 4H), 7.75 (s, 4H),
10.37 (s, 2H) ppm.
Mp 190–2 °C. 1H NMR (400 MHz, CDCl3, 51.43 mM): δ 1.24
(s, 9H), 1.27 (s, 9H), 4.30 (s, 6H), 4.35 (s, 4H), 5.79 (s, 4H), 7.15
(s, 1H), 7.30 (s, 2H), 7.42 (s, 2H), 7.93 (s, 1H), 9.67 (s, 2H) ppm.
13C NMR (CDCl3, 100.6 MHz, 51.43 mM): δ 29.6 (CH2), 31.2
(CH3), 31.4 (CH3), 34.9, 35.1, 38.6 (CH3), 57.1 (CH2), 125.9
(CH), 126.3 (CH2), 127.4 (CH), 130.0 (CH), 134.1, 135.1, 144.7,
153.4, 153.8 ppm. ESI(+)-HRMS calc. for C30H40N6 [M]2+:
242.1652, C30H40ClN6 [M + Cl]+: 519.2997; found: 242.1649,
519.2988.
[14]Triazolophane 3
Experiment 1. To a degassed solution of 1,8-diaza[5.4.0]bi-
cycloundec-7-ene (2.45 mL, 164 mmol) in toluene (200 mL)
heated to 70 °C, CuI (48 mg, 0.25 mmol) was added under an
argon atmosphere. A solution of the 1-tert-butyl-3,5-di(prop-
2-yn-1-yl)benzene 6 (172 mg, 0.82 mmol) and 1,3-bis(azido-
methyl)-5-(tert-butyl)benzene 7 (200 mg, 0.82 mmol) in dry
toluene (40 mL) was slowly added over 10 h and the solution
was then stirred for 18 h at room temperature and 4 h at 70 °C.
The reaction mixture was cooled to room temperature and fil-
tered through a short column of alumina (EtOAc/NH3–MeOH,
4 : 1), and the filtrate was evaporated to dryness. The residue
was purified by silica gel column chromatography (CH2Cl2–
MeOH, mixtures of increasing polarity as the eluent) to afford
cyclophane 3 (39 mg, 10%) as a white solid.
[14]Triazoliophane 4·2PF6. The counteranion exchange of
4·2PF6 was carried out by following our anion exchange resin
(A− form) method.36
Mp 123–5 °C. IR (ATR): ν(PF6) 826 cm−1
.
1H NMR
(300 MHz, CDCl3, 3.14 mM): δ 1.35 (s, 9H), 1.36 (s, 9H), 4.03
(s, 4H), 4.24 (s, 6H), 5.57 (s, 4H), 6.99 (s, 1H), 7.03 (s, 1H), 7.28
(s, 2H), 7.48 (s, 1H), 7.90 (s, 2H) ppm.
Hybrid [14]heterophane 5·Cl
Experiment 2. To a degassed solution of tert-BuOH–H2O
(230 mL, 1 : 1) was added CuSO4·5H2O (102 mg, 0.41 mmol)
and sodium ascorbate (162.4 mg, 0.82 mmol), and the result-
ing mixture was stirred at room temperature while flushing
argon for 30 min. A solution of 1,3-bis(azidomethyl)-5-(tert-
butyl)benzene 7 (200 mg, 0.82 mmol) and 1-tert-butyl-3,5-di-
(prop-2-yn-1-yl)benzene 6 (216 mg, 1.02 mmol) in tert-BuOH–
H2O (45 mL, 1 : 1) was then added dropwise for 10 h under an
argon atmosphere at room temperature. The resulting solution
was stirred overnight at the same temperature and was evapo-
rated to dryness. The crude reaction was filtered through a
short column of alumina (EtOAc/NH3–MeOH, 4 : 1) and the fil-
trates were evaporated to dryness. The resulting residue was
Experiment 1. To a stirred solution of 1H-imidazole (33 mg,
0.48 mmol) in dry CH3CN (45 mL) was added powdered KOH
(41 mg, 0.62 mmol) in one portion at room temperature under
an argon atmosphere. After 2 h, the resulting mixture was
added dropwise over a period of 4 h to a solution of dichloride
9 (200 mg, 0.44 mmol) in dry CH3CN (45 mL) and refluxed for
48 h. The reaction mixture was evaporated to dryness and the
resulting residue was purified by silica gel column chromato-
graphy (CH2Cl2–MeOH, mixtures of increasing polarity as the
eluent) to afford pentanucleating protophane 10 (20 mg, 16%)
as a pale yellow oil and the macrocycle 5·Cl (96 mg, 45%) as a
white solid.
Experiment 2. A suspension of 1H-imidazole (33 mg,
purified by crushing with CH3CN (20 mL) and by silica gel 0.48 mmol) and powdered KOH (27 mg, 0.48 mmol) in dry
column chromatography (CH2Cl2–MeOH, mixtures of increas- CH3CN (57 mL) was stirred at room temperature for 2 h under
ing polarity as the eluent) to afford cyclophane 3 (72 mg, 19%) an argon atmosphere. A solution of dichloride 9 (200 mg,
as a white solid.
0.44 mmol) in dry CH3CN (30 mL) was added dropwise over a
Mp > 300 °C. 1H NMR (400 MHz, CDCl3): δ 1.32 (s, 9H), period of 20 minutes and refluxed for 48 h. The reaction
1.34 (s, 9H), 4.03 (s, 4H), 5.46 (s, 4H), 6.40 (s, 1H), 6.45 (s, 1H) mixture was cooled to room temperature, filtered and the
6.98 (s, 2H), 7.17 (s, 2H), 7.35 (s, 2H) ppm. 13C NMR (CDCl3, solvent evaporated to dryness. The resulting residue was puri-
100.6 MHz): δ 31.4 (CH3), 31.5 (CH3), 32.3 (CH2), 34.8, 35.0, fied by silica gel column chromatography (CH2Cl2–MeOH, mix-
53.9 (CH2), 121.5 (CH), 122.7 (CH), 124.2 (CH), 124.9 (CH), tures of increasing polarity as the eluent) to afford
125.5 (CH), 136.2, 139.4, 151.8, 153.2 ppm. ESI(+)-HRMS calc. pentanucleating protophane 10 (94 mg, 75%).
Protophane 10. 1H NMR (400 MHz, CDCl3): δ 1.23 (s, 18 H),
4.02 (s, 2H), 5.04 (s, 2H), 5.07 (s, 2H), 5.42 (s, 2H), 6.80 (s, 1H),
6.82 (s, 1H), 6.87 (s, 2H), 7.01 (s, 1H), 7.04–7.07 (m, 2H), 7.1 (s,
1H), 7.11 (s, 1H), 7.19 (s, 1H), 7.21 (s, 1H), 7.51 (d, J = 4.4 Hz,
2H) ppm. 13C NMR (CDCl3, 100.6 MHz): δ 31.1 (CH3), 31.2
(CH3), 32.2 (CH2), 34.6, 34.7, 50.6 (CH2), 50.9 (CH2), 53.9
for C28H35N6 [M + H]+: 455.2918; found: 455.2919.
[14]Triazoliophane 4·2Cl. A solution of triazolophane 3
(50 mg, 0.11 mmol) in dry CH2Cl2 (15 mL) was evacuated and
backfilled with argon 3 times. Trimethyloxonium tetrafluoro-
borate (45 mg, 0.30 mmol) was then added in one portion
at room temperature and the reaction mixture was again
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(CH2), 119.2 (CH), 121.3 (CH), 122.5 (CH), 123.8 (CH), 124.5
IR (thin film): 3293 (uC–H), 2096 (–CuCH) cm−1. H NMR
(CH), 124.7 (CH), 124.8 (CH), 125.7 (CH), 129.5 (CH), 129.8 (CD3Cl, 300 MHz): 1.32 (s, 9H), 2.19 (t, J = 2.5 Hz, 2H), 3.60
(CH), 135.4, 136.1, 136.9, 137.3 (CH), 139.5, 147.5, 152.4, (dd, J = 0.6, 2.7 Hz, 4H), 7.17–7.18 (m, 1H), 7.24–7.25 (m, 2H)
153.2 ppm. ESI(+)-HRMS calcd for C32H41N7 [M + 2H]2+ ppm. 13C RMN (CD3Cl, 300 MHz): 24.9 (CH2), 31.3 (CH3), 70.9
261.6706, C32H40N7 [M + H]+ 522.3340; found 261.6714, (CH), 82.1, 123.4 (CH), 124.6 (CH), 136.0, 151.8 ppm.
522.3346.
1,3-Bis(azidomethyl)-5-(tert-butyl)benzene 7. Diazide 7 was
Macrocycle 5·Cl. Mp 202–4 °C. 1H NMR (500 MHz, CDCl3,
6 mM): δ 1.30 (s, 9H), 1.32 (s, 9H), 4.16 (s, 2H), 5.40 (s, 2H), 5.47
(s, 2H), 5.57 (s, 2H), 7.03 (d, J = 5 Hz, 2H), 7.15 (s, 1H), 7.25 (s,
1H), 7.30 (s, 1H), 7.43 (s, 1H), 7.44 (s, 1H), 7.64 (s, 1H), 8.88 (s,
1H), 11.59 (s, 1H) ppm. 13C NMR (CDCl3, 100.6 MHz, 43 mM):
δ 31.2 (CH3), 31.3 (CH3), 31.8 (CH2), 34.7, 34.8, 53.5 (CH2), 53.7
(CH2), 53.8.0 (CH2), 122.2 (CH), 123.1 (CH), 123.4 (CH), 123.7
(CH), 124.3 (CH), 125.3 (CH), 126.2 (CH), 126.9 (CH), 133.6,
134.6, 137.2, 137.9 (CH), 141.9, 147.0, 152.4, 153.0 ppm.
ESI(+)-HRMS calcd for C29H36N5 [M]+ 454.2971; found 454.2995.
Hybrid [14]heterophane 5·PF6. The counteranion exchange
of 5·PF6 was carried out by following the anion exchange resin
(A− form) method.36
prepared according a protocol described in the literature.42
1
IR (thin film): 3293(uC–H), 2096 (–CuCH) cm−1. H NMR
(CD3Cl, 300 MHz): 1.32 (s, 9H), 2.19 (t, J = 2.5 Hz, 2H), 4.20
(dd, J = 0.6, 5.4 Hz, 4H), 7.17–7.18 (m, 1H), 7.24–7.25 (m, 2H)
ppm. 13C NMR (CD3Cl, 300 MHz): 24.9 (CH2), 31.3 (CH3), 70.9
(CH), 82.1, 123.4 (CH), 124.6 (CH), 136.0, 151.8 ppm.
1,3-Bis(bromomethyl)-5-(tert-butyl)benzene 8. To [5-(tert-
butyl)-1,3-phenylene]dimethanol40 (1.73 g, 8.92 mmol) cooled
to 0 °C, HBr (48% v/v, 15.2 mL, 0.14 mol) was added dropwise,
and the reaction remained at reflux for 16 h. The reaction
mixture was diluted with water (100 mL) and extracted with
CH2Cl2 (3 × 150 mL). The organic layers were dried over anhy-
drous Na2SO4, filtered and evaporated to dryness to give the
dibromide 8 (2.79 g, 98%) as a white solid. The spectral data of
8 were identical to those previously described.38
Mp 287–9 °C. IR (ATR): ν(PF6) 841 cm−1
.
1H NMR
(300 MHz, CDCl3, 3 mM): δ 1.33 (s, 9H), 1.35 (s, 9H), 4.09
(s, 2H), 5.26 (s, 2H), 5.29 (s, 2H), 5.53 (s, 2H), 6.49 (s, 1H), 6.56
(s, 1H), 7.07 (t, 2H), 7.18 (s, 1H), 7.33 (s, 1H), 7.39 (s, 1H), 7.44
(s, 1H), 7.72 (s, 1H), 8.81 (s, 1H) ppm. 1H NMR (300 MHz,
CD3CN, 3 mM): δ 1.35 (s, 9H), 1.36 (s, 9H), 4.05 (s, 2H), 5.23 (s,
4H), 5.55 (s, 2H), 6.33 (s, 1H), 6.36 (s, 1H), 7.34 (t, 2H), 7.37
(s, 1H), 7.41 (s, 1H), 7.45 (s, 1H), 7.50 (s, 1H), 7.55 (s, 1H), 8.37
[3-(Azidomethyl)-5-(tert-butyl)benzyloxi](tert-butyl)dimethyl-
silane 9. Azide 9 was prepared according a protocol described
in the literature.42
1
IR (thin film): 2196 (–N3) cm−1. H NMR (CD3Cl, 400 MHz):
0.11 (s, 6H), 0.96 (s, 9H), 1.33 (s, 9H), 4.33 (s, 2H), 4.76 (s, 2H),
7.09 (s, 1H), 7.19 (s, 1H), 7.35 (s, 1H) ppm. 13C NMR (CD3Cl,
400 MHz): −5.2 (CH3), 18.4, 25.9 (CH3), 31.3 (CH3), 34.7, 55.2
(CH2), 64.9 (CH2), 123.0 (CH), 123.1 (CH), 123.8 (CH), 134.9,
141.8, 151.8 ppm. CI-MS: m/z 351 [M + NH4]+.
1
(s, 1H) ppm. H NMR (300 MHz, DMSO-d6, 3 mM): δ 1.31 (s,
9H), 1.32 (s, 9H), 4.01 (s, 2H), 5.37 (s, 2H), 5.38 (s, 2H), 5.60 (s,
2H), 6.31 (s, 1H), 6.33 (s, 1H), 7.39 (t, 2H), 7.52 (s, 2H), 7.72
(s, 1H), 7.74 (s, 1H), 7.83 (s, 1H), 9.32 (s, 1H) ppm.
[3-(tert-Butyl)-5-(prop-2-yn-1-yl)phenyl]methanol 10. To
a
1-tert-Butyl-3,5-di(prop-2-yn-1-yl)benzene 6. To a solution of
commercial ethynyltrimethylsilane (9.1 mL, 64.5 mmol) in
THF (26 mL) cooled to 0 °C, i-PrMgCl (2 M in THF, 32.2 mL,
64.5 mmol) was added dropwise. After 30 min at 0 °C and
30 min at room temperature, CuBr was added in one portion
(1.39 g, 9.7 mmol). The resulting mixture was stirred for
30 min at room temperature before adding dibromide 8
(2.58 g, 8.06 mmol), and was then refluxed for 5 h. The
reaction mixture was poured into a saturated NH4Cl aqueous
solution (500 mL) and extracted with hexane (3 × 500 mL). The
combined organic layers were washed with H2O (500 mL),
dried over anhydrous Na2SO4, filtered and concentrated under
reduced pressure. The crude material obtained as a red oil
(2.82 g) was used directly in the next step without further puri-
fication. To a solution of the previous residue in anhydrous
THF (20 mL) at 0 °C, acetic acid (2.3 mL, 39.8 mmol) and
TBAF·3H2O (14.0 g, 39.8 mmol) were added. The resulting
mixture was stirred at room temperature for 18 h, and was con-
centrated to dryness. EtOAc (150 mL) was added and the
mixture was washed with H2O (125 mL) and brine (125 mL).
The organic layer was dried over anhydrous Na2SO4, filtered
and concentrated under reduced pressure. The residue was
purified by column chromatography on silica gel (hexane–
EtOAc, mixtures of increasing polarity as the eluent) affording
dialkyne 6 (1.42 g, 84%) as a yellow oil.
mixture of alcohol 14 (1.5 g, 5.7 mmol) in CH3NO2 (6.0 mL),
hexamethyldisilazane (1.2 mL, 5.72 mmol) was added drop-
wise. The resulting mixture was stirred at room temperature
for 30 min and concentrated under reduced pressure. The sily-
lated compound 16 (1.74 g) obtained as a yellow oil was used
directly in the next step without further purification. To a solu-
tion of ethynyltrimethylsilane (3 mL, 21.12 mmol) in THF
(17 mL) cooled to 0 °C, i-PrMgCl (2 M in THF, 10.6 mL,
21.12 mmol) was added dropwise. After 30 min at 0 °C and
30 min at room temperature, CuBr (0.454 g, 3.17 mmol) was
added in one portion. The resulting mixture was stirred for
30 min at room temperature before adding benzylbromide 16
(1.74 g, 5.28 mmol). The mixture was then refluxed for 5 h,
poured into a saturated NH4Cl aqueous solution (340 mL) and
the aqueous layer was extracted with hexane (2 × 340 mL). The
combined organic layers were washed with water (340 mL),
dried over anhydrous Na2SO4, filtered and concentrated under
reduced pressure. The crude material obtained as a yellow
brown oil (1.8 g) was used directly in the next step without
further purification. To a solution of the previous residue in
anhydrous THF (13 mL) stirred at 0 °C, acetic acid (0.75 mL,
13.1 mmol) and TBAF·3H2O (9.21 g, 26.2 mmol) were added
and stirred at room temperature for 18 h. The reaction mixture
was concentrated to dryness, EtOAc (100 mL) was added, and
the mixture was washed with water (80 mL) and brine (80 mL).
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The organic layer was dried over anhydrous Na2SO4, filtered
{[3-(Bromomethyl)-5-(tert-butyl)benzyl]oxy}(tert-butyl)-
and concentrated under reduced pressure. The residue was dimethylsilane 15. To a solution of commercial tert-butyl-
purified by column chromatography on silica gel (hexane– dimethylsilyl chloride (2.91 mL, 16.8 mmol) and N,N-diisopropyl-
EtOAc, mixtures of increasing polarity) affording alkyne 10 ethylamine (2.7 mL, 15.55 mmol) in CH2Cl2 (20 mL) stirred at
(640 mg, 55%) as a yellow oil.
0 °C for 1 h, a solution of alcohol 14 (1.6 g, 6.22 mmol) in
IR (thin film): 3300–3400 (–OH, uC–H), 2096 (–CuCH) CH2Cl2 (24mL) was added. The resulting mixture was stirred
cm−1. 1H NMR (CD3Cl, 300 MHz): 1.32 (s, 9H), 2.18–2.20 (t, J = overnight at room temperature and was acidified with 1 N HCl
5.3 Hz, 1H), 3.60 (dd, J = 0.6, 10 Hz, 2H), 4.68 (s, 2H), (20 mL) at 0 °C. The organic layer was separated and washed
7.19–7.20 (m, 1H), 7.28 (dd, J = 1.5, 18 Hz, 2H) ppm. 13C NMR with 5% NaHCO3 aqueous solution (40 mL), water (50 mL) and
(CD3Cl, 300 MHz): 25.1 (CH2), 31.5 (CH3), 34.9, 65.7 (CH2), brine (50 mL), and dried over anhydrous Na2SO4, filtered and
70.7 (CH), 82.3, 122.7 (CH), 123.9 (CH), 124.5 (CH), 136.2, concentrated under reduced pressure. The residue obtained
141.0, 152.1 ppm. CI-MS: m/z 220 [M + NH4]+.
was purified by column chromatography on neutral silica gel
(3-(tert-Butyl)-5-{[1-(3-(tert-butyl)-5-{[(tert-butyldimethylsilyl)- (hexane–EtOAc, mixtures of increasing polarity) affording the
oxy]methyl}benzyl)-1H-1,2,3-triazol-4-yl]methyl}phenyl)methanol silylated compound 15 (1.6 g, 68%) as a pale yellow oil.
11. To a solution of azide 9 (1.3 g, 3.9 mmol) in EtOAc–H2O
1H NMR (CD3Cl, 400 MHz): 0.11 (s, 6H), 0.96 (s, 9H), 1.33
(4.5 mL, 1 : 9) was added a solution of alkyne 10 (946 mg, (s, 9H), 4.51–4.60 (m, 2H), 4.74–4.75 (m, 2H), 7.17 (s, 1H),
4.68 mmol) in EtOAc (0.5 mL) and Cu2O (55.85 mg, 7.2–7.28 (m, 1H), 7.3–7.34 (m, 1H) ppm. 13C NMR (CD3Cl,
0.39 mmol). After stirring the reaction mixture at room temp- 400 MHz): −5.2 (CH3), 18.4, 25.9 (CH3), 31.3 (CH3), 34.3 (CH2),
erature for 20 h, CH2Cl2 (60 mL) and saturated NH4Cl aqueous 34.7, 64.8 (CH2), 123.3 (CH), 123.9 (CH), 124.6 (CH), 137.2,
solution (35 mL) were added, and the mixture was stirred for 141.7, 151.7 ppm. CI-MS: m/z 389 [M + NH4]+.
30 min. The phases were separated and the aqueous layer was
Determination of binding constants by 1H NMR titrations.
1
extracted with CH2Cl2 (3 × 30 mL). The combined organic All the H NMR experiments were performed using a 300 MHz
extracts were dried over anhydrous Na2SO4, filtered and evapo- spectrometer at 298 K. All anions were added as TBA salts.
rated to dryness. The resulting residue was purified by silica gel A solution (ca. 3 mM) of hosts (2.15 μmol) in CD3CN (0.7 mL)
column chromatography (hexane–EtOAc, mixtures of increas- or DMSO-d6 (0.7 mL) was used and aliquots of 5 μL of the
ing polarity as the eluent) to afford alcohol 11 (1.56 g, 75%) as anion solution (85.84 mmol L−1) were then added until satur-
a yellow oil.
IR (thin film): ν(OH) 3359 cm−1
ation was observed. Spectra were recorded after each addition,
.
1H NMR (400 MHz, and the sample was shaken thoroughly before measure-
CDCl3): δ 0.07 (s, 6H), 0.92 (s, 9H), 1.27 (s, 9H), 1.28 (s, 9H), ment. The resulting titration data were analyzed using the
4.06 (s, 2H), 4.63 (s, 2H), 4.69 (s, 2H), 5.45 (s, 2H), 6.96 (s, 1H), WinEQNMR2 software39 to calculate the binding constants.
7.04 (s, 1H), 7.12 (s, 2H), 7.19 (s, 1H), 7.24 (s, 1H), 7.34 (s, 1H)
ppm. 13C NMR (CDCl3, 100.6 MHz): δ −5.1 (CH3), 18.5, 26.0
(CH3), 31.4 (CH3), 31.5 (CH3), 32.6 (CH2), 34.8, 34.9, 54.4
(CH2), 64.9 (CH2), 65.7 (CH2), 121.5 (CH), 122.4 (CH), 122.8
Acknowledgements
(CH), 123.5 (CH), 123.7 (CH), 124.7 (CH), 125.3 (CH), 134.5, The authors thank the University of Barcelona for support,
139.2, 141.0, 142.2, 152.0, 152.3 ppm. ESI(+)-MS: m/z 536.4 SCT-UB for the use of their instruments and the AGAUR (Gen-
[M + H]+, 1071.7 [2M + H]+.
eralitat de Catalunya), Grup de Recerca Consolidat 2009SGR562.
1,4-Bis[3-(chloromethyl)-5-(tert-butyl)benzyl]-1H-1,2,3-triazole Thanks are also due to Dr Sara López for contributing to the
12. To a stirred solution of alcohol 11 (800 mg, 1.495 mmol) chemical synthesis. We also thank Lucy Brzoska for helpful
in CH2Cl2 (10 mL) was added dropwise a solution of SOCl2 discussions on semantics and style.
(3.26 mL, 44.85 mmol) in CH2Cl2 (10 mL) at room tempera-
ture. After stirring for 3 h, the resulting mixture was evaporated
to dryness. The residue obtained was suspended with satu-
rated Na2CO3 aqueous solution (150 mL) and extracted with
References
EtOAc (5 × 250 mL). The combined organic extracts were dried
over anhydrous Na2SO4, filtered and evaporated to dryness to
afford dichloride 12 (684 mg, 99%) as a pale yellow solid.
Mp 92–4 °C. 1H NMR (400 MHz, CDCl3): δ 1.28 (s, 18H),
4.07 (s, 2H), 4.53 (s, 2H), 4.54 (s, 2H), 5.47 (s, 2H), 7.07 (d, J =
1.2 Hz, 2H), 7.16 (s, 1H), 7.21 (t, J = 1.8 Hz, 1H), 7.22 (t, J = 1.6
Hz, 1H), 7.25 (t, J = 1.8 Hz, 1H), 7.36 (t, J = 1.6 Hz, 1H) ppm.
13C NMR (100.6 MHz, CDCl3): δ 31.3 (CH3), 31.4 (CH3), 32.5
(CH2), 34.8, 34.9, 46.2 (CH2), 46.7 (CH2), 54.2 (CH2), 121.6
(CH), 124.0 (CH), 125.2 (CH), 125.3 (CH), 126.1 (CH), 135.2,
137.5, 138.2, 139.4, 152.3, 153.0 ppm. ESI(+)-MS: m/z [M + H]+
458.2, [2M + H]+ 917.4.
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