Open-chain dications and betaines with imidazolium molecular motifs: Synthesis and structural aspects

Article abstract of DOI:10.1002/1099-0690(200204)2002:7<1221::AID-EJOC1221>3.0.CO;2-Q

The synthesis of trinuclear open-chain prototypes gave variable yields: > 53% for dications 1·2X and 2·2X and > 80% for proton-ionizable dications 3·2X-5·2X incorporating 1H-1,2,4-triazole moieties. Deprotonation of the latter compounds resulted in the formation of the betaine counterparts 13·X-15·X. The courses of the dequaternization reactions of compounds 4·2X and 5·2X were also studied. The structural properties of dicationic protophanes 1·2X and 2·2X, containing bis(imidazolium) motifs, were examined by ¹H and ¹³C NMR spectroscopy, electrospray mass spectrometry and by single-crystal X-ray diffraction analysis of the dication 1b·2PF₆. Weak noncovalent interactions between the dications and the hexafluorophosphate ions bias the protophane conformation both in solution and in the solid state. X-ray diffraction reveals that the PF₆^- counterions are located in a channel formed by the dications (1b²⁺). Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002.

Full text of DOI:10.1002/1099-0690(200204)2002:7<1221::AID-EJOC1221>3.0.CO;2-Q

FULL PAPER
Open-Chain Dications and Betaines with Imidazolium Molecular Motifs:
Synthesis and Structural Aspects[‡]
[a]
[a]
[a]
[b]
´
Ermitas Alcalde,* Neus Mesquida, Montserrat Alemany, Carmen Alvarez-Rua,
[b]
[a]
[a]
´
´
´
¨
Santiago Garcıa-Granda, Pedro Pacheco, and Lluısa Perez-Garcıa
Keywords: Betaines / Cations / Dequaternization / Nitrogen heterocycles / Protophanes
The synthesis of trinuclear open-chain prototypes gave vari- 13C NMR spectroscopy, electrospray mass spectrometry and
able yields: Ͼ 53% for dications 1·2X and 2·2X and Ͼ 80%
for proton-ionizable dications 3·2X−5·2X incorporating 1H-
1,2,4-triazole moieties. Deprotonation of the latter com-
by single-crystal X-ray diffraction analysis of the dication
1b·2PF6. Weak noncovalent interactions between the dicat-
ions and the hexafluorophosphate ions bias the protophane
pounds resulted in the formation of the betaine counterparts conformation both in solution and in the solid state. X-ray
−
13·X−15·X. The courses of the dequaternization reactions of
diffraction reveals that the PF6 counterions are located in a
compounds 4·2X and 5·2X were also studied. The structural channel formed by the dications (1b2+).
properties of dicationic protophanes 1·2X and 2·2X, con-
taining bis(imidazolium) motifs, were examined by 1H and
(
Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany,
2002)
Introduction
methylbenzene or by proton-ionizable 3,5-bis(dimethyl-
1,2,4-triazole) subunits (Figure 1). It is noticeable that di-
cationic protophanes 1·2X and 2·2X contain the trinuclear
component of [14]imidazoliophanes,[7] while dications
3·2X؊5·2X are related to [14]azolophanes with proton-ion-
izable 1,2,4-triazole subunits[1a] (Figure 1). Thus, the trinu-
clear protoheterophanes with two imidazole rings are ad-
vanced intermediates in the ‘‘3ϩ1’’ convergent, stepwise
synthesis of dicationic [14]metaheterophanes,[1,7] and the
‘‘3ϩ1’’ approach is template-controlled by chloride anions
(e.g., TBA·Cl),[8] especially for [14]imidazoliophanes.
The design of substrates for the ultimate preparation of
supramolecular species is an area of considerable interest
in organic chemistry. Acyclic polydentate building blocks
containing heteroaromatic units are of interest for the con-
struction of a broad array of molecules ranging from crown
ethers and macrocycles[2,3] to a variety of supramolecular
entities[4] and self-assembled helices,[5a] together with
metallo-supramolecular systems.[2,5b] In this context, the
syntheses and properties of a number of different 1,2,4-tria-
zole-containing macrocycles have been reported.[1,3a,3b] At
the same time, the chemistry of isolable N-heterocyclic
carbenes derived from azolium quaternary salts precursors
has been developed in recent years.[6]
The potential of the molecular and supramolecular beha-
viour of these compounds[9] prompted us to explore their
synthesis as well as to look for further insight into their
structural properties, both in solution and the solid state.
Understanding of the noncovalent interactions governing
the conformational pattern of the protophanes, as well as
their crystal packing, is a crucial issue regarding knowledge
of the bis(imidazolium)-based protoheterophanes. These in-
teractions are responsible for the location of the coun-
terions relative to the dication and are manifested not only
in the solid state but also in solution, as discussed in this
paper. Therefore, the implications of their presence go bey-
ond the chemical structure itself, and result in consequences
in chemical behaviour. On these premises, we report here
the synthesis of open-chain prototypes containing two im-
idazolium rings as common structural motifs: the dicationic
protophanes 1·2X؊5·2X and the betaine counterparts of
the proton-ionizable dications 3·2X؊5·2X. We also describe
results from the structural study of dicationic protophanes
In the context of our research concerning the design of
molecular scaffolds for supramolecular entities, we have be-
come engaged in the study of an ensemble of trinuclear di-
cationic protoheterophanes 1·2X, 2·2X, and 3·2X؊5·2X,
formed by two imidazolium rings linked either by 1,3-di-
[‡]
Heterocyclic Betaines, 47. Ϫ Part 46: Ref.[1a]
[a]
´
`
`
Laboratori de Quımica Organica, Facultat de Farmacia,
Universitat de Barcelona,
Avda. Joan XXIII s/n, 08028 Barcelona, Spain
Fax: (internat.) ϩ 34-93/402-1896
E-mail: betaines@farmacia.far.ub.es
[b]
´
´
´
Departamento de Quımica Fısica y Analıtica, Facultat de
´
Quımica, Universidad de Oviedo,
33006 Oviedo, Spain
Supporting information for this article is available on the
WWW under http://www.eurjoc.com or from the author.
Eur. J. Org. Chem. 2002, 1221Ϫ1231
WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002 1434Ϫ193X/02/0407Ϫ1221 $ 17.50ϩ.50/0
1221

E. Alcalde et al.
FULL PAPER
Figure 1 From protoheterophanes to dicationic protoheterophanes and their incorporation into [14]metaheterophanes
1·2X and 2·2X gained by NMR spectroscopy, mass spectro-
metry and X-ray diffraction analysis.
Results and Discussion
Dicationic Protophanes 1·2X and 2·2X[1b]
Synthesis
The quaternization reaction providing dications 1·2X and
2·2X under neutral conditions gave yields that depended on
the N-substituted imidazole used. Protophanes 1a·2Cl and
1b·2Br were obtained in Ͼ 75% yield on treatment of 1,3-
bis(chloromethyl)benzene (6) or 1,3-bis(bromomethyl)-5-
tert-butylbenzene (7) with N-methylimidazole (8), whereas
quaternization of N-adamantylimidazoles 9a and 9c pro-
ceeded in lower yields (Ͼ 53%) (Scheme 1). For proto-
phanes 2a·2Cl, 2b·2Br, and 2c·2Cl, different reaction condi-
tions in neutral media were investigated, and the best results
are described. The counterions of these dicationic proto-
phanes were changed by use of an ion-exchange resin (OHϪ
form) and the eluates were immediately treated with HX/
H2O in a pH range between 3 and 4 Ϫ see, for example,
1a·2PF6 or 2b·2PF6 in Scheme 1 (see Exp. Sect.). The struc-
tural properties of the new protophanes were examined by
1H NMR and 13C NMR spectroscopy and electrospray
mass spectrometry, and the structure of dication 1b·2PF6
was confirmed by a single-crystal X-ray analysis.
Scheme 1. Synthesis of dicationic protophanes 1·2X and 2·2X
conformational mobility; this flexibility was also observed
in the [14]metaheterophane frameworks.[1a,10] The proton
chemical shifts shown in Table 1 showed that the δH values
NMR Spectroscopy
The 1H NMR spectra of dications 1a·2X, 1b·2X, and of the acidic C(2Ј)-H, flanked by the two heteroatoms, and
2a؊c·2X (X ϭ ClϪ, BrϪ, PF6Ϫ) in [D6]DMSO showed 2-H from the aromatic ring were the most affected, and a
sharp singlets for the methylene protons, which indicates deshielding effect due to structural factors and the anion
1222
Eur. J. Org. Chem. 2002, 1221Ϫ1231

Open-Chain Dications and Betaines with Imidazolium Molecular Motifs
FULL PAPER
1
Table 1. Selected H NMR spectroscopic data of dicationic protoheterophanes 1a,b·2X and 2aϪc·2X
Compd.[a]
2Ј-H
4Ј-H
5Ј-H
ϪCH2Ϫ
2-H
4,6-H
1a·2Cl
9.64
9.39
9.21
9.57
9.30
9.15
10.10
9.57
10.02
9.94
7.76
7.75
7.72
7.74
7.74
7.71
8.13
8.07
7.96
Ϫ
7.92
7.84
7.74
7.90
7.83
7.75
8.04
7.87
7.96
Ϫ
5.48
5.47
5.41
5.42
5.41
5.37
5.51
5.39
5.41
5.30
7.68
7.60
7.48
7.43
7.31
7.20
7.95
7.28
7.94
6.82
7.44
7.44
7.40
7.54
7.52
7.49
7.53
7.50
7.56
6.79
1a·2Br
1a·2PF6
1b·2Cl
1b·2Br[b]
[c]
1b·2PF6
2a·2Cl[c]
2b·2Br[c]
2b·2PF6
2c·2Cl[c]
[a]
[b]
In [D6]DMSO (300 MHz) at a concentration range between 30 and 80 m.
Assignment by NOE. [c] 1H NMR spectra recorded
at 200 MHz.
Table 2. Concentration dependence of 1H NMR chemical shifts of dication 1b·2X [X ϭ Cl؊, Br؊, PF6Ϫ] in CD3CN, [D6]DMSO and
CD3OD (300 MHz) at 298 K
Compd. Conc. [m]
CD3CN
2-HЈ[a] 5Ј-H
Conc. [m]
[D6]DMSO
5Ј-H
Conc. [m]
CD3OD
5Ј-H
2-H
2Ј-H
2-H
7.31
2Ј-H
2-H
7.36
1b·2Cl
∆δХ[b]
∆δ[b]
2.8
6.3
9.74
9.79
7.57
7.58
7.66
7.67
Ϫ0.01
7.69
Ϫ0.03
7.72
Ϫ0.06
7.50
7.60
Ϫ0.10
7.64
Ϫ0.14
7.14
7.14
0
6.3
9.36
9.38
7.81
7.82
Ϫ0.02 Ϫ0.01
9.59 7.91
Ϫ0.23 Ϫ0.10
7.76
7.78
Ϫ0.06 Ϫ0.02
9.29 7.81
6.3
9.05
7.64
Ϫ0.05 Ϫ0.01
9.84 7.61
Ϫ0.10 Ϫ0.04
9.96 7.72
Ϫ0.22 Ϫ0.15
12.6
78.0
12.6
75.8
7.33
Ϫ0.02
7.44
Ϫ0.13
7.23
7.27
Ϫ0.04
7.30
Ϫ0.07
7.20
7.20
0
13.0
78.0
9.07
Ϫ0.02
9.12
7.64
0
7.66
7.38
Ϫ0.02
7.40
Ϫ0.04
7.38
7.42
Ϫ0.04
7.42
Ϫ0.04
7.27
7.25
ϩ0.02
7.25
∆δ[b]
Ϫ0.07 Ϫ0.02
1b·2Br
2.9
14.7
9.24
9.45
7.52
7.55
2.9
14.7
9.19
9.25
2.9
14.7
9.05
9.09
Ϫ0.04
9.11
7.64
7.64
0
∆δ[b]
Ϫ0.21 Ϫ0.05
9.54 7.62
35.4
35.4
35.4
7.66
∆δ[b]
Ϫ0.30 Ϫ0.10
Ϫ0.10 Ϫ0.05
9.15[d] 7.74
9.15[d] 7.74
Ϫ0.06 Ϫ0.02
[c]
[c]
1b·2PF6 2.3
7.46
2.3
11.6
2.3
11.6
7.57
7.57
0
7.57
0
11.6
8.45[d] 7.47
8.84
Ϫ
8.81
ϩ0.03
∆δ[b]
Ϫ
Ϫ0.01
0
0
7.74
0
27.9
8.43
7.47
7.14
0
27.9
9.14
ϩ0.01
7.20
0
27.9
∆δ[b]
ϩ0.02 Ϫ0.01
ϩ0.02
[a]
[b]
[c]
[d]
H numbering scheme see Table 1. ∆δ ϭ δ[min] Ϫ δ[x]
.
No signal observed due to H/D exchange. Broad signal.
effect was observed. Comparison of the δ(2Ј-H) and δ(2-H) HMQC (Supporting Information available; see also foot-
values of the N-adamantyl dication 2b·2PF6 showed that note on the first page of this article).
they were more deshielded than those of the N-methyl di-
1
cation 1b·2PF6 (Table 1). For the protophane pair 1b·2Cl Qualitative H NMR Observations
and 1b·2PF6, the deshielding effect was examined at nonag-
gregating concentrations (see below, Table 2). The 13C
Dicationic protophane 1b·2X (X ϭ ClϪ, BrϪ, PF6Ϫ) was
1
NMR chemical shifts for dications 1a·2X, 1b·2X, and further examined by H NMR in various solvents. The so-
2a؊c·2X were consistent with data from correlative sys- lution aggregation behaviour depended on the nature of the
tems,[1a,10] and individual assignments were made by counterion and the solvent polarity. In CD3CN and
Eur. J. Org. Chem. 2002, 1221Ϫ1231
1223

E. Alcalde et al.
FULL PAPER
[D6]DMSO, the proton chemical shifts for 1b·2Cl and 1b·Br reactions and the ring components in these macrocyclic sys-
depended on concentration, while they were unchanged for tems modulated their ionization behaviour. Direct elec-
1b·PF6.[11] In a more polar solvent such as [D4]methanol, trospray mass spectrometric evidence was obtained for
hydrogen bond and electrostatic interactions were weakened singly charged imidazolylidene ions [M Ϫ H]ϩ, which were
by solvation and no aggregation was detected for dications generated by simple systems with two imidazolium rings,
1b·2X (Table 2 and Supporting Information).
such as [14]imidazoliophanes (M·2X). Electrosprayed mac-
The anion effect and solvent polarity[9,12] had a strong rocyclic dications thus produced loss of the counterions and
influence on the chemical shift changes observed for 1b·2X, fission of the labile imidazolium CϪH bond, the three com-
especially for δ(2Ј-H), δ(5Ј-H), and δ(2-H), as a con- mon ions being [M]2ϩ and [M ϩ X]ϩ, together with the
sequence of hydrogen bonding with the counterions; this carbene species [M Ϫ H]ϩ. This representative peak ap-
result is similar to those found with [14]imidazoliophanes peared in the ESI mass spectra of the regiospecific deuter-
(M·2X, see below). At nonaggregating concentrations,[11] ated counterparts as the singly charged ion [M Ϫ D]ϩ,
the greatest deshielding effect corresponded to the acidic which validates the positive ion ESI-MS study.[13a]
2Ј-H protons of the imidazolium rings in dication 1b·2Cl.
Comparison of the δ(2Ј-H) values in compound pair 1b·2Cl
and 1b·2PF6 showed that the deshielding was up to
1.29 ppm in CD3CN, and ca. 0.21 ppm in [D6]DMSO and
[D4]methanol. According to the 1H NMR spectroscopic
data summarized in Table 2, the open-chain trinuclear di-
cation (1b2؉) showed weak noncovalent interactions with
the hexafluorophosphate counterions in solution, which
were also confirmed in the solid state by the X-ray diffrac-
tion analysis of the model protophane 1b·2PF6 (see below).
The positive ion ESI-MS of dications 1a·2X, 1b·2X,
2a·2X, and 2b·2X was performed as described elsewhere:[13a]
Samples were dissolved in a 1:1 mixture of H2O/CH3CN at
100 pmol·µLϪ1 and the cone voltage was varied between 50
and 120 V. The positive ESI response of the open-chain
imidazolium dications 1·2X and 2·2X resulted in the forma-
tion of the three characteristic ions [M]2ϩ, [M ϩ X]ϩ, and
[M Ϫ H]ϩ mentioned above. Several peaks arising from mo-
lecular fragmentation were also produced, especially in the
N-adamantyl series (Table 3). At 80 and 120 V, the singly
charged imidazolylidene species [M Ϫ H]ϩ was more
abundant in the N-methyl series; this result is similar to
those found with [14]imidazoliophanes (M·2X).[13a] As for
the N-adamantyl series, the base peak corresponded to the
doubly charged ions [M]2ϩ at low cone voltage while mo-
lecular fragmentation produced the singly charged fragment
ions at m/z ϭ 135.5 [Ad]ϩ and at m/z ϭ 429.7 [M Ϫ Ad]ϩ
as the most abundant species, at both 80 and 120V.
Electrospray Mass Spectrometry Analysis
Electrospray ionization has been used to examine an en-
semble of dicationic [14]imidazoliophanes (M·2X)[13a] and
multicharged [1n]azolophanes with proton-ionizable 1H-
1,2,4-triazole or/and 1,2,4-triazolate subunits[13] {dicationic
[14]azolophanes (MH2·2X), for example,[13b] see Figure 1}.
Several informative peaks were the result of proton-transfer
Table 3. Summary of data obtained from positive ion ESI-MS of 1a,b·2X and 2aϪc·2X
Vc Compd.
Ions, m/z ratio, relative abundance (%)[a]
Compd.
(mol. mass)[a] [M]2ϩ [M Ϫ H]ϩ [M ϩ X]ϩ [Ad]ϩ [M Ϫ Ad]ϩ
Ions, m/z ratio, relative abundance (%)[a]
[V] (mol. mass)[a]
[M]2ϩ
[M Ϫ H]ϩ
[M ϩ X]ϩ
1a·2Cl[b] (339.3) 134.2
267.4
5
50
18
267.4
1
303.8
1
15
20
348.3
10
20
Ϫ
359.9
5
20
15
404.4
5
50
10
2a·2Cl (579.7) 254.5 507.9
544.3
12
44
135.2 373.7
50
80
120
100
100
1
4
100
100
6
72
14
100
2
5
11
[c]
[c]
4
1a·2Br[d] (428.2) 134.2
2b·2Br (724.7) 282.5 563.9
644.8
14
36
20
848.6
3
135.2 429.7
[c]
50
80
120
100
10
Ϫ
100
3
32
100
4
28
25
[c]
90
Ϫ
100
[c]
5
1b·2Cl[e] (395.4) 162.2
323.5
2c·2Cl (884.1) 406.6 812.1
135.2 677.9
[c]
[c]
50
80
120
100
20
90
100
2
90
100
5
100
30
100
20
3
2
5
40
5
[c]
1b·2Br[f] (484.3) 162.2
323.5
[c]
50
80
120
100
[c]
35
20
[c]
1b·2PF6 (614.4) 162.2
323.5
469.4
10
100
10
[c]
50
80
120
100
20
10
20
100
[a] Molecular mass and ion m/z values apply to the lowest-mass component of any isotope distribution and are based on a scale in which
[b]
[c]
[d]
12C ϭ 12.000. Fragment ion at m/z ϭ 185.1 and at 120 V (100%). No signal observed. Fragment ion at m/z ϭ 92.8 and at 80 V
[e]
[f]
(100%). Fragment ion at m/z ϭ 175.8 and at 120 V (100%). Fragment ion at m/z ϭ 243.5 and at 80 V (100%) and fragment ion at
m/z ϭ 161.0 and at 120 V (100%).
1224
Eur. J. Org. Chem. 2002, 1221Ϫ1231

Open-Chain Dications and Betaines with Imidazolium Molecular Motifs
FULL PAPER
X-ray Analysis
terplanar separations between these imidazolium rings and
˚
˚
The molecular structure of 1b·2PF6 is depicted in Fig- the sandwiched one are of the order of 4.8 A and 8.9 A,
Ϫ
ure 2.[14] Both the tert-butyl group and the PF6 ions dis- respectively. The region between dications is occupied by
Ϫ
play thermal disorder, as reported for the hexafluorophos- PF6 counterions, also aligned along the b axis, filling the
phate counterions.[15] Although the crystal structure seems cavities between dications, and forming channels that ex-
to be mainly dominated by Coulombic forces, a series of tend through the crystal. The results obtained from the
noncovalent CϪH···F interactions is also observed and re- solid structure of 1b·2PF6 reflect the lack of hydrogen
Ϫ
veals association of the PF6 anions and the dication 1b bonding as well as π-π stacking.
through a combination of electrostatic and minimal hydro-
gen bonding. In particular, the shortest distances observed
˚
are: [H3···F4] ϭ 2.33 A and [C3ϪH3···F4] ϭ 151°;
˚
[H1A···F2] ϭ 2.47 A and [C1ϪH1A···F2] ϭ 147°, and
˚
[H5B···F5] ϭ 2.55 A and [C5ϪH5B···F5] ϭ 168°. For other
CϪH···F contacts, the distances are rather long to be con-
sidered hydrogen bonds.[16] The weak character of these in-
teractions is consistent with the poor complexing ability of
Ϫ
anions such as PF6
.
The dications 1b are ordered in continuous stacks along
Ϫ
the b crystallographic axis, with the PF6 counterions ar-
ranged in a channel (Figure 3). Indeed, each molecule is
stacked almost directly above its neighbour in adjacent unit
cells along the crystallographic b axis, with the imidazolium
˚
rings 13.4 A apart. The benzene ring is aligned nearly per-
pendicular to the plane of the axis, whereas the imidazolium
rings stack almost parallel to this plane, and therefore per-
pendicularly to the benzene ring [N(4)ϪC(5)ϪC(6)ϪC(10)
torsion angle: 75.1°]. Furthermore, the solid-state structure
shows nonequidistant intercalation of one imidazolium ring
of one molecule between two imidazolium rings of two dif-
Figure 3. Packing of dicationic protophane 1b·2PF6 viewed along
ferent molecules of the neighbouring parallel stack. The in- the crystallographic b axis
Figure 2. Molecular structure of 1b·2PF6
Eur. J. Org. Chem. 2002, 1221Ϫ1231
1225

E. Alcalde et al.
FULL PAPER
Dicationic Protophanes with a Proton-Ionizable
1,2,4-triazolate units provided relevant information on
these dicationic or betaine trinucleating systems, and was
well in accordance with the nature of the π-rich and π-defi-
cient heteroaromatic fragments. The chemical shift values
were similar to those seen in the building blocks[17] and in
[1n]azolophanes.[1a,18]
1,2,4-Triazole Ring, 3·2X؊5·2X[1c]
Synthesis
Quaternization of N-alkylimidazoles 8, 11, and 12 with
3,5-bis(chloromethyl)-1,2,4-triazole (10)[3c] under neutral
conditions gave the corresponding dicationic protophanes
3·2Cl؊5·2Cl (Ͼ 80%). However, purification of these di-
quaternary heteroaromatic salts was difficult, due to the
similar solubilities of the ionic species present in the reac-
tion mixtures, especially for protophanes 4·2Cl and 5·2Cl.
The pure dicationic protophanes were treated with an ion-
exchange resin (OHϪ form) and transformed into the be-
taine intermediates 13·OH؊15·OH, which are unstable, al-
though it was possible to record their 1H NMR spectra
(Scheme 2). The intermediate 13·OH was then acidified by
carefully controlled addition of HCl/H2O and the stable be-
taine 13·Cl was isolated.
1
Selected H NMR spectroscopic data in [D6]DMSO are
given in Table 4, and the 13C NMR parameters are listed
in the Supporting Information. Comparison of the proton
chemical shifts of betaine 13·Cl with those of the corres-
ponding dication 3·2Cl precursor shows that the δH values
of both the methylene spacers and 2-HЈ protons of the im-
idazolium rings are shifted upfield by Ϫ0.20 ppm. In the
compound pair 13·OH and 3·2Cl, the shielding effect was
up to Ϫ0.40 ppm (see ∆δ in Table 4).
Table 4. Selected 1H NMR spectroscopic data of dicationic pro-
toheterophanes 3؊5·2Cl and the betaines 13؊15·OH and 13·Cl
Compound[a]
2Ј-H
4Ј-H
5Ј-H
ϪCH2Ϫ
13·Cl
3·2Cl
9.29
9.49
Ϫ0.20
9.12
Ϫ0.37
9.38
9.61
Ϫ0.23
9.24
9.42
Ϫ0.18
7.71
7.80
Ϫ0.09
7.63
Ϫ0.17
7.70
7.85
Ϫ0.15
7.71
7.83
Ϫ0.12
7.76
7.87
Ϫ0.11
7.68
Ϫ0.19
7.77
7.88
Ϫ0.11
7.75
7.91
Ϫ0.16
5.46
5.66
Ϫ0.20
5.26
Ϫ0.40
5.29
5.60
Ϫ0.31
5.31
5.64
Ϫ0.33
[b]
∆δ
13·OH[c][d]
[e]
∆δ
14·OH
4·2Cl
[e]
∆δ
15·OH
5·2Cl
[e]
∆δ
[a] In [D6]DMSO (300 MHz). [b] ∆δ: Difference in the chemical shift
[c]
of betaine 13·Cl and its corresponding dication 3·2Cl. Unstable
[d]
compound in [D6]DMSO. Value obtained from different experi-
ments, the spectra being recorded at a constant concentration of
[e]
10 mg/3 mL in [D6]DMSO.
Difference in the chemical shift of
betaines 13؊15·OH and their corresponding dications 3؊5·2Cl.
Scheme 2. Synthesis of proton-ionizable dicationic protophanes
3·2XϪ5·2X and their corresponding betaines 13·X-15·X
Dequaternization Reactions
Dequaternization of several examples of N-azolylazolium
salts has been reported. Examples include compounds 16·X,
and debenzylation of the N-benzimidazolylimidazolium salt
16d·Cl produced 17 in good yield (73%) (Scheme 3); this
Spectroscopic Study
The dicationic protophanes 3·2Cl؊5·2Cl, the betaine was the first example of an imidazolium salt in which de-
13·Cl and the betaine intermediates 13·OH؊15·OH were quaternization proceeded through hydrogenolysis.[19] In this
1
characterized by their spectroscopic data (IR, H and 13C context, the model quaternary imidazolium salt 18·Br was
NMR). It was not possible, however, to obtain single crys- next examined. Thermal dequaternization produced N-
1
tals of these protophanes for X-ray analysis. Both the H benzylimidazole 11 (60%) and N-benzhydrylimidazole 12
and the 13C NMR of the protophanes with 1,2,4-triazole or (30%) along with alteration products (10%) (Table S1 and
1226
Eur. J. Org. Chem. 2002, 1221Ϫ1231

Open-Chain Dications and Betaines with Imidazolium Molecular Motifs
FULL PAPER
Scheme 3. Dequaternization reactions of azolium salts 16·X, 18·Br and dicationic protoheterophanes 4·2X, 5·2X
Exp. Sect. in the Supporting Information; see also footnote but the uncharged protophane 20 was not formed either by
on the first page of this article). In contrast, hydrogenolysis thermolysis or hydrogenolysis (Scheme 3). Several attempts
of 18·Br resulted in the formation of N-benzylimidazolium at this dequaternization were made; selected assays are
salt 19·Br in 94% yield. Moreover, catalytic hydrogenation listed in Tables S1 and S2 (see Supporting Information).
of N-benzhydrylimidazole 12 gave no reaction (Scheme 3,
and Table S2 and Exp. Sect. in the Supporting Information; benzhydryl-3,5-bis(1-imidazolylmethyl)-1,2,4-triazole (21a)
see also footnote on the first page of this article). with trifluoroacetic acid gave the N-unprotected dication
Alternatively, removal of the N-benzhydryl group of 1-
With these results in mind, dequaternization reactions of 22a·2CF3CO2, the ditrifluoroacetate dication counterpart
the dicationic protophanes 4·2X and 5·2X were examined, of the uncharged protophane 20, whereas catalytic hydro-
Scheme 4. Synthesis and dequaternization of N-benzhydrylprotophanes 21
Eur. J. Org. Chem. 2002, 1221Ϫ1231
1227

E. Alcalde et al.
FULL PAPER
mass Instruments). EIMS: HewlettϪPackard HP-5988A. The pH
was monitored with a CRISON micro-pH 2001 apparatus. Pyro-
lysis was performed with a Büchi GKR-50 Kugelrohr apparatus.
TLC: Merck precoated 60 F254 silica gel plates; detection by UV
light, and spots developed with a 10% aqueous solution of potas-
sium iodide or 3% aqueous solution of hexachloroplatinic acid.
Chromatography: SDS silicium oxide 60 ACC (30Ϫ75 µm). Ion-
exchange resin[1a] (I-E.R.): A column (0.5 inch diameter) was
packed with ion exchanger III resin or Amberlite IRA 401 (OHϪ
form) to a height of 5 inches. When a rotary evaporator was used,
genation gave no reaction (Scheme 4 and Supporting In-
formation). However, 3,5-bis(1-imidazolylmethyl)-1H-1,2,4-
triazole (20) has been prepared by an alternative route start-
ing from N-cyanomethylimidazole, which proceeded in two
steps (70%).[1a]
Preparation of the multitopic building blocks[1a] 21a and
21b started with 4-amino-3,5-bis(hydroxymethyl)triazole
(23)[3c] and followed a four-step sequence as shown in
Scheme 4. 1-Benzhydryl-3,5-bis(hydroxymethyl)-1,2,4-tria-
zole (25) was prepared by a procedure similar to those de- the bath temperature was 25 °C. In general, the compounds were
scribed by Scriven et al.:[20] The quaternization of 4-amino-
dried overnight at 25 °C in a vacuum oven. Microanalyses were
performed with a Carlo Erba 1106 Analyzer.
3,5-bis(hydroxymethyl)triazole (23)[3c] with benzhydryl
bromide gave the N-benzhydryl-protected cation 24·Br,
which was then transformed into compound 25. Sub-
sequent halogenation gave the 1-benzhydryl-3,5-bis(chloro-
Materials: Benzhydryl bromide, 1-bromoadamantane, 4,5-di-
methylimidazole hydrochloride, 4,5-diphenyl-1H-imidazole, 1H-im-
idazole, 1,3-bis(chloromethyl)benzene (6), 1-methyl-1H-imidazole
methyl)triazole (26), which reacted with the appropriate im- (8), and 1-benzyl-1H-imidazole (11) were purchased from commer-
cial sources. 1,3-Bis(bromomethyl)-5-tert-butylbenzene (7),[21] 1-(1-
idazoles to produce the multitopic molecules 21a and 21b.
adamantyl)-1H-imidazole (9a),[22] 3,5-bis(chloromethyl)-1H-1,2,4-
Finally, N-alkylation of bis(hydroxymethyl)-1,2,4-triazole
triazole (10),[3c] 1-benzhydryl-1H-imidazole (12),[23] 4-amino-3,5-bi-
27[3c] with benzhydryl bromide failed (see Exp. Sect.).
s(hydroxymethyl)-1H-1,2,4-triazole (23)[3c] and 3,5-bis(hydroxyme-
thyl)-1H-1,2,4-triazole (27)[3c] were prepared as described in the lit-
erature.
Conclusion
3,3Ј-Dimethyl-1,1Ј-[1,3-phenylenebis(methylene)]bis(imidazolium)
Dichloride (1a·2Cl): See Table 5. A mixture of 1,3-bis(chloro-
methyl)benzene (6, 1.75 g, 10 mmol) and 1-methylimidazole (8;
The syntheses of dicationic open-chain prototypes
1·2X؊5·2X, multitopic scaffolds based on two imidazolium
2.2 mL, 27.5 mmol) was heated to 135 °C under nitrogen for
units as their common structural motifs, are reported. The
10 min. The reaction mixture was allowed to cool to room temper-
proton-ionizable dications 3·2X؊5·2X were transformed
into the unstable betaines 13·OH-15·OH and also into the
ature and the solid obtained was triturated with dry hot acetone (3
ϫ 5 mL). The resulting solid was filtered to give 1a·2Cl.
stable betaine 13·Cl. Dequaternization reactions of dicat-
Counterion Exchange. ؊ Dications 1a·2Br and 1a·2PF6: See Table 5.
ions 4·2X and 5·2X by thermolysis and hydrogenolysis were
A solution of dicationic protophane 1a·2Cl (0.23 g, 0.68 mmol or
studied. The structural properties of dications 1·2X and
0.13 g, 0.4 mmol) in 96% ethanol (50 mL) was passed through a
1
2·2X were examined in detail by H NMR and positive ion
column packed with a strongly basic anion-exchange resin (Ion ex-
ESI-MS, and by the single-crystal X-ray diffraction analysis
of dication 1b·2PF6. Both in solution and in the solid state,
the bis(hexafluorophosphate) dications showed weak non-
covalent intermolecular interactions and, moreover, the
crystal packing of 1b·2PF6 indicated that the hexafluoro-
phosphate counterions are located between the dications
changer III, Merck, hydroxide form). The neutral eluates were
acidified to pH ϭ 3 either with 47% HBr solution or with a hexa-
Table 5. Physical data of dicationic protoheterophanes 1a,b·2X,
2aϪc·2X, and 3·2XϪ5·2X and betaines 13·OHϪ15·OH and 13·Cl
(1b2؉) in a channel. Further studies are now investigating Compd.
Reaction time [h]
Yield (%)[a]
M.p. [°C]
the use of dicatonic and betaine building blocks for the con-
struction of supramolecular scaffolds from dicationic and
dipolar to multipolar systems.
1a·2Cl
0.16
Ϫ
Ϫ
Ϫ
17
Ϫ
96
3.5
Ϫ
168
0.11
10.5
49
0.75
Ϫ
Ϫ
91
99
99
99
75
69
59
53
66
61
80
83
89
88
73
67
72
86
170Ϫ172
[b]
1a·2Br
1a·2PF6
1b·2Cl
1b·2Br
1b·2PF6
2a·2Cl
2b·2Br
2b·2PF6
2c·2Cl
3·2Cl
118Ϫ120
[b]
200Ϫ2
160Ϫ162[c]
115Ϫ116
Ͼ300[c]
Experimental Section
General Remarks: Melting points: CTPϪMP 300 hot-plate appar-
atus with ASTM 2C thermometer. IR (KBr disks or thin film):
211Ϫ212
272[c]
[d]
PerkinϪElmer 1430 and Nicolet 205 FT spectrophotometers.
1H NMR: Varian Gemini 200, Varian Gemini 300 and Varian 4·2Cl
159Ϫ161
Unity 300 spectrometers (200 MHz and 300 MHz). 13C NMR:
Varian Gemini 200 spectrometer (50.3 MHz). NOE 1H{1H}:
Varian Unity 300 spectrometer (75.4 MHz). HMQC and HMBC:
Varian Gemini 300 and VXR-500 spectrometers (300 MHz and
500 MHz). NMR spectra were determined in [D6]dimethyl sulfox-
ide, [D3]acetonitrile, and [D4]methanol, and chemical shifts were
referenced and expressed in parts per million (δ) relative to the
central peak of [D6]dimethyl sulfoxide or [D3]acetonitrile or
[D4]methanol. ESI-MS:[13] VG-Quattro mass spectrometer (Micro-
5·2Cl
5·2Br
13·OH
14·OH
15·OH
13·Cl
150Ϫ153
[d]
[d]
[d]
Ϫ
Ϫ
145Ϫ146
[d]
[a]
[b]
[c]
Yields were not optimized.
Foamy compound.
Recrystal-
lization solvent: 1b·2PF6 (ethanol), 2b·2Br (acetonitrile), 2c·2Cl
(acetone). Hygroscopic compound.
[d]
1228
Eur. J. Org. Chem. 2002, 1221Ϫ1231

Open-Chain Dications and Betaines with Imidazolium Molecular Motifs
FULL PAPER
fluorophosphoric acid solution, and the resulting solution was con- amantane (2.2 g, 10 mmol) was heated to 200 °C for 4 d. The reac-
centrated to dryness to afford the bromide 1a·2Br or the hexa- tion mixture was allowed to cool to room temperature, and chro-
fluorophosphate 1a·2PF6, respectively.
matographed on silica gel (SiO2; CH2Cl2/EtOH, 98:2, v/v). The
fractions containing the product were chromatographed on silica
gel (SiO2; hexane/EtOAc, 50:50, v/v) to give 9c.
3,3Ј-Dimethyl-1,1Ј-[5-tert-butyl-1,3-phenylenebis(methylene)]-
bis(imidazolium) Dibromide (1b·2Br): See Table 5. Ϫ Experiment 1:
A mixture of 1,3-bis(bromomethyl)-5-tert-butylbenzene (7;[21] 1.6 g,
5 mmol) and 1-methylimidazole (8; 1.1 mL, 13.8 mmol) was heated
to 135 °C under nitrogen for 10 min. The reaction mixture was
allowed to cool to room temperature and the slurry was triturated
with ethyl acetate (20 mL). The resulting solid was filtered to give
1a·2Br (22% yield). Experiment 2: A solution of 7[21] (1.6 g,
5 mmol) and 8 (1.1 mL, 13.8 mmol) in dry acetonitrile (15 mL) was
heated to reflux temperature under nitrogen for 5 h. The reaction
solvents were evaporated to dryness and the foamy solid was tritur-
ated with ethyl acetate (20 mL). The resulting solid was filtered to
give 1a·2Br (42% yield). Experiment 3: A solution of 7[21] (1.6 g,
5 mmol) and 8 (1.1 mL, 13.8 mmol) in dry dioxane (20 mL) was
heated to reflux temperature under nitrogen for 17 h. The reaction
solvents were evaporated to dryness and the foamy solid was tritur-
ated with ethyl acetate (20 mL). The resulting solid was filtered to
give 1a·2Br (75% yield).
3,3Ј-Diadamantyl-4,4Ј,5,5Ј-tetraphenyl-1,1Ј-[1,3-phenylenebis-
(methylene)]bis(imidazolium) Dichloride (2c·2Cl): See Table 5. A so-
lution of 1,3-bis(chloromethyl)benzene (6; 0.18 g, 1 mmol) in dry
dioxane (4 mL) was added under nitrogen to a solution of 1-adam-
antyl-4,5-diphenylimidazole (9c; 0.74 g, 2.1 mmol) in dry dioxane
(10 mL), and the mixture was heated to reflux temperature for 7 d.
The reaction mixture was allowed to cool to room temperature and
filtered, and the obtained solid was triturated with dry ethyl ether
(3 ϫ 2 mL) and dried to give 2c·2Cl.
3,3Ј-Dimethyl-1,1Ј-[3,5-(1H-1,2,4-triazolylene)bis(methylene)]-
bis(imidazolium) Dichloride (3·2Cl): See Table 5. Method A: A solu-
tion of 3,5-bis(chloromethyl)-1H-1,2,4-triazole (10;[3c] 1.6 g,
9.6 mmol) and 1-methylimidazole (8; 3.8 g, 24.0 mmol) was heated
to 135 °C under nitrogen for 7 min. The reaction mixture was co-
oled and triturated with dry acetone. The resulting solid was fil-
tered and dried to afford 3·2Cl. An analytical sample was obtained
by recrystallization with 2-propanol.
Counterion Exchange with Dication 1b·2Br. ؊ Dication 1b·2Cl: See
Table 5. A solution of dicationic protophane 1b·2Br (0.25 g,
0.52 mmol) in 96% ethanol (50 mL) was passed through a column
packed with a strongly basic anion-exchange resin (Ion exchanger
III, Merck, hydroxide form). The neutral eluates were acidified to
pH ϭ 3 with a concentrated hydrochloric acid solution, and the
resulting solution was concentrated to dryness to afford the brom-
ide 1b·2Cl. Ϫ Dication 1b·2PF6: See Table 5. A solution of ammo-
nium hexafluorophosphate (0.5 g) in water (5 mL) was added to a
solution of dicationic protophane 1b·2Br (0.14 g, 0.3 mmol) in
water (5 mL), and the mixture was stirred overnight. The resulting
solid was filtered and triturated in water (2 ϫ 5 mL) and diethyl
ether (3 ϫ 5 mL). The solid was filtered to afford the hexafluoro-
phosphate 1b·2PF6.
Dicationic Protophane 4·2Cl: See Table 5. Method B: A mixture of
3,5-bis(chloromethyl)-1H-1,2,4-triazole (10;[3c] 1.0 g, 6.0 mmol) and
1-benzyl-1H-imidazole (11; 3.8 g, 24.0 mmol) was heated to 140 °C
in a sealed tube for 10.5 h. The reaction mixture was cooled and
triturated with dry acetone (4 ϫ 100 mL). The resulting solid was
filtered, dissolved in water (100 mL) and washed in dichlorome-
thane (6 ϫ 100 mL). The aqueous layer was concentrated to dry-
ness to give 4·2Cl.
Dicationic Protophane 5·2Cl: See Table 5. Method C: N-Benzhydryl-
imidazole (12;[23] 1.4 g, 6.0 mmol) was added to a solution of 3,5-
bis(chloromethyl)-1,2,4-triazole (10;[3c] 0.5 g, 3.0 mmol) in dry ace-
tonitrile (25 mL), and the mixture was heated to 105 °C in a sealed
tube for 49 h. The reaction solvents were evaporated to dryness,
and the residue was dissolved in water (60 mL) and washed with
dichloromethane (8 ϫ 20 mL). The aqueous layer was concentrated
to dryness to give 5·2Cl.
3,3Ј-Diadamantyl-1,1Ј-[1,3-phenylenebis(methylene)]bis(imida-
zolium) Dichloride (2a·2Cl): See Table 5. A solution of 1,3-bis(chlo-
romethyl)benzene (6; 0.44 g, 2.5 mmol) in dry acetonitrile (10 mL)
was added under nitrogen to a solution of 1-adamantylimidazole
(9a;[22] 1 g, 5 mmol) in dry acetonitrile (20 mL), and the mixture
was heated to reflux temperature for 4 d. The reaction mixture was
allowed to cool to room temperature and filtered, and the obtained
solid was dried to give 2a·2Cl.
Dicationic Protophanes 4·2Br and 5·2Br: See Table 5. Method D:
An anion-exchange resin (Amberlist A-26, bromide form, 0.8 mmol
of bromide anion) was added to a solution of protophanes 4·2Cl
or 5·2Cl (0.1 mmol) in 96% ethanol (10 mL), and the suspension
was stirred at room temperature for 45 min. The suspension was
then filtered, the resin was washed with ethanol (2 ϫ 5 mL), and
the solution was concentrated to dryness to afford 4·2Br and 5·2Br,
respectively. Alternatively, a solution of protophane 5·2Cl (50 mg,
0.08 mmol) in 96% ethanol (20 mL) was passed through a column
packed with a strongly basic anion-exchange resin (Amberlite IRA-
401, hydroxide form). The neutral eluates were acidified with 47%
HBr solution, and the solution was concentrated to dryness to af-
ford the bromide 5·2Br.
3,3Ј-Diadamantyl-1,1Ј-[5-tert-butyl-1,3-phenylenebis(methylene)]-
bis(imidazolium) Dichloride (2b·2Br): See Table 5. A solution of 1,3-
bis(bromomethyl)-5-tert-butylbenzene (7;[21] 0.64 g, 2 mmol) and 1-
adamantylimidazole (9a;[22] 0.83 g, 4.1 mmol) was heated to reflux
temperature under argon for 3.5 h. The reaction mixture was al-
lowed to cool to room temperature and filtered, and the solid was
triturated with dry acetonitrile (20 mL). The resulting solid was
filtered to afford 2b·2Br.
Counterion Exchange. ؊ Dication 2b·2PF6: See Table 5. A solution
of dicationic protophane 2b·2Br (0.1 g, 0.14 mmol) in 96% ethanol
(50 mL) was passed through a column packed with a strongly basic
anion-exchange resin (Ion exchanger III, Merck, hydroxide form).
The neutral eluates were acidified to pH ϭ 3 with concentrated
hexafluorophosphoric acid solution, and the resulting solution was
concentrated to dryness to afford the hexafluorophosphate
2b·2PF6.
Betaines 13·OH؊15·OH: See Table 5. Method E: A solution of a
dicationic protophane 3·2Cl؊5·2Cl (0.1 g) in 96% ethanol (30 mL)
was passed through a column packed with a strongly basic anion-
exchange resin (Amberlite IRA 401, hydroxide form). The neutral
eluates were concentrated to dryness at room temperature to afford
the corresponding hydroxides 13·OH؊15·OH.
3,5-Bis(3-methyl-1-imidazoliomethyl)-1H-1,2,4-triazolate
(13·Cl): See Table 5. Method F: A solution of the dicationic proto-
1-(1-Adamantyl)-4,5-diphenyl-1H-imidazole (9c): See Table 5. A phane 3·2Cl (0.06 g, 0.2 mmol) in 96% ethanol (20 mL) was passed
mixture of 4,5-diphenylimidazole (4.4 g, 20 mmol) and 1-bromoad-
through a column packed with a strongly basic anion-exchange
1229
Eur. J. Org. Chem. 2002, 1221Ϫ1231

E. Alcalde et al.
FULL PAPER
resin (Amberlite IRA 401, hydroxide form). Hydrochloric acid so-
lution (0.12 , 1.5 mL, 0.2 mmol) was carefully added to the neut-
ral eluates. The solution was concentrated to dryness to give an
bromide (0.9 g, 3.5 mmol) in dry dimethylformamide (40 mL) was
stirred in a sealed tube at 90 °C for 48 h. The reaction mixture was
cooled, the solvent was evaporated to dryness, and the remaining
oil, which was washed in dry acetonitrile (2 ϫ 5 mL) and dried to oil was triturated with diethyl ether (3 ϫ 100 mL) and dichlorome-
afford 13·Cl.
thane (3 ϫ 10 mL). The resulting solid was suspended in water
(100 mL) and 35% HCl aqueous solution (3.7 mL, 35 mmol), and
a solution of sodium nitrite (0.5 g, 6.9 mmol) in water (40 mL) was
then added at a temperature between 0 and 10 °C. The solution
was neutralized to pH ϭ 7 with solid sodium carbonate, and the
solid was filtered to give 25.
1-Benzhydryl-3-benzylimidazolium Bromide (18·Br): See Table 5.
Benzhydryl bromide (1.55 g, 6.3 mmol) was added to a solution of
1-benzylimidazole (11; 1 g, 6.3 mmol) in dry acetonitrile (25 mL),
and the mixture was heated to reflux temperature for 12.5 h.
Benzhydryl bromide (0.4 g, 1.6 mmol) was then added and the mix-
ture was further refluxed for 73 h. The reaction mixture was washed
in diethyl ether (5 ϫ 100 mL), and the residue was dried to give
18·Br.
Attempted Formation of 25 from Hydroxy Derivative 27: 3,5-Bis(hy-
droxymethyl)-1H-1,2,4-triazole (27;[3c] 0.5 g, 4.0 mmol) was added
to a solution of 85% potassium hydroxide (0.26 g, 4.0 mmol) in dry
methanol (50 mL), and the mixture was stirred under nitrogen at
room temperature for 1 h. Benzhydryl bromide (1.08 g, 4.4 mmol)
was then added and the mixture was heated at 60 °C for 27 h. The
reaction solvents were evaporated to dryness and the residue was
dissolved in dry dimethylformamide. The solution was heated at
110 °C for 19 h and 125 °C for 22 h. The reaction progress was
monitored by TLC, which indicated the recovery of the starting
material 27.
Protophanes 21a and 21b: See Table 5. A suspension of 1H-imid-
azole (686 mg, 10.1 mmol) or 4,5-dimethylimidazole hydrochloride
(1.33 g, 10.1 mmol) and finely powdered 85% potassium hydroxide
(668 mg, 10.1 mmol and 1.34 g, 20.2 mmol, respectively) in dry di-
methylformamide (200 mL) was vigorously stirred under nitrogen
at room temperature for 1.5 h. A solution of 1-benzhydryl-3,5-
bis(chloromethyl)-1H-1,2,4-triazole (26; 1.67 g, 5.0 mmol) in dry
dimethylformamide (40 mL) was then added dropwise, and the
mixture was stirred at 80 °C for 47 h. The reaction mixture was
cooled, and the solvent was removed to dryness. The resulting oil
was extracted with dichloromethane (3 ϫ 50 mL) and brine. The
organic layers were collected, dried (Na2SO4) and filtered, and the
solvents were evaporated. The oily residue was purified by flash
chromatography (SiO2) with chloroform or chloroform/methanol
mixtures of increasing polarity. Compound 21a was further puri-
fied by trituration with hexane (2 ϫ 10 mL) to afford 21a as a
solid. For compound 21b, the fractions containing the product were
collected, the solvent was removed, and the residue was dissolved in
dichloromethane and water, neutralized to pH ϭ 7 with a saturated
aqueous solution of sodium carbonate and extracted with dichloro-
methane (3 ϫ 30 mL). The organic layers were dried (Na2SO4) and
filtered, and the solvents were evaporated to afford 21b.
1-Benzhydryl-3,5-bis(chloromethyl)-1H-1,2,4-triazole (26):
See
Table 5. Derivative 25 (0.7 g, 2.4 mmol) was added portionwise to
thionyl chloride (2.4 mL, 3.7 mmol) externally cooled with an ice
bath. The suspension was refluxed to 5 h. The mixture was cooled
and the excess of thionyl chloride was removed in a rotary evapor-
ator, and the residue was dissolved in dichloromethane (10 mL),
basified to pH ϭ 8 with a 2  sodium carbonate aqueous solution
and extracted with dichloromethane (3 ϫ 50 mL). The organic ex-
tracts were dried (Na2SO4) and filtered, and the solvents were evap-
orated to afford 26.
General X-ray Crystallographic Procedures. ؊ Dication 1b·2PF6:
Single crystals of 1b·2PF6, suitable for X-ray crystallography, were
grown by recrystallization of the salt from ethanol. The unit cell
parameters were obtained from the least-squares fit of 25
reflections (with θ between 10° and 13°). Data were collected at
293 K with the ω-2θ scan technique and a variable scan rate, with a
maximum scan time of 60 s per reflection. The final drift correction
factors were between 0.97 and 1.00. Profile analysis[24,25] was per-
formed on all reflections. Lorentz and polarization corrections
Preparation of Dicationic Protophane 22a·CF3CO2: See Table 5. A
stirred solution of protophane 21a (5.1 g, 12.9 mmol) and phenol
(5.1 g, 54.2 mmol) in trifluoroacetic acid (10 mL) was refluxed for
1 h. The reaction mixture was cooled, the solvent was removed to
dryness, and the resulting oil was triturated with dry diethyl ether
(4 ϫ 20 mL) and filtered to give the corresponding trifluoroacet-
ate 22a·2CF3CO2.
2
were applied and the data were reduced to Fo values. Semiempir-
ical absorption correction was applied using ψ-scans,[26] resulting
in maximum and minimum correction factors of 1.00 and 0.57,
respectively. The structure was solved by Patterson methods and
phase extension with DIRDIF-96.[27] Isotropic full-matrix, least-
squares refinement on F2 was carried out with SHELXL-97.[28]
Crystallographic symmetry was carefully checked and found to be
C2/c. The carbon atoms of the tert-butyl group were refined with
an occupancy factor of 0.5 in order to make them compatible with
the twofold axis that runs through C9. Hydrogen atoms were loc-
ated by Fourier difference synthesis, except those of the CH2 and
CH3 groups, which were placed geometrically. In this case, the co-
4-Amino-1-benzhydryl-3,5-bis(hydroxymethyl)-1,2,4-tri-
azolium Bromide (24·Br): See Table 5. A suspension of 4-amino-
3,5-bis(hydroxymethyl)-1,2,4-triazole (23;[3c] 0.5 g, 3.5 mmol) and
benzhydryl bromide (0.9 g, 3.5 mmol) in dry dimethylformamide
(40 mL) was stirred in a sealed tube at 90 °C for 48 h. The reaction
mixture was cooled, the solvent was evaporated to dryness, and
the resulting oil was triturated with diethyl ether (3 ϫ 100 mL),
dichloromethane (3 ϫ 20 mL) and methanol (3 ϫ 20 mL) to yield
the bromide 24·Br.
1-Benzhydryl-3,5-bis(hydroxymethyl)-1H-1,2,4-triazole ordinates were refined riding on their parent atom. During the final
(25): See Table 5. Method 1: A solution of sodium nitrite (9.4 mg, stages of the refinement, the positional parameters and the aniso-
13.7 mmol) in water (50 mL) was added dropwise to a suspension tropic thermal parameters of the non-H atoms were refined. The
of the bromide 24·Br (2.7 g, 6.8 mmol) in water (200 mL) and 35%
carbon atoms of the tert-butyl group were refined isotropically. All
HCl aqueous solution (7.2 mL, 68.4 mmol) at a temperature be-
hydrogen atoms not placed geometrically were refined isotropically
tween 0 and 10 °C. The suspension was stirred at room temperature using a common thermal parameter. Hydrogen atoms in CH2 and
for 22 h. The resulting solution was neutralized to pH ϭ 7 with
solid sodium carbonate and the solid formed was filtered and iden-
tified as 25. Method 2: A suspension of 4-amino-3,5-bis(hydroxy-
methyl)-1,2,4-triazole (23;[3c] 0.5 g, 3.5 mmol) and benzhydryl
CH3 groups were refined with a thermal parameter dependent on
the correspondent carbon atom. The function minimized was
[Σw(F2o Ϫ Fc2)2/Σw(F2o)2]1/2, w ϭ 1/[σ2(F2o) ϩ (0.1490·P)2 ϩ 2.0543·P],
where P ϭ [max(F2o,0) ϩ 2·Fc2]/3 with σ2(F2o) from counting statist-
1230
Eur. J. Org. Chem. 2002, 1221Ϫ1231

Open-Chain Dications and Betaines with Imidazolium Molecular Motifs
FULL PAPER
1997. [12b] C. Reichardt, Solvents and Solvents Effects in Organic
Chemistry, VCH Verlagsgesellschaft, Weinheim, 1988.
ics. The maximum shift to e.s.d. ratio in the last full-matrix, least-
squares cycle was less than 0.001. The final difference Fourier map
[13] [13a]
E. Alcalde, N. Mesquida, M. Vilaseca, Rapid Commun.
Ϫ3
˚
showed no peak higher than 0.552 e·A nor any deeper than
Mass Spectrom. 2000, 14, 1443Ϫ1447. [13b] E. Alcalde, N. Mes-
Ϫ0.455 e·AϪ3. Atomic scattering factors were taken from Interna-
˚
´
quida, I. Fernandez, E. Giralt, Rapid Commun. Mass Spec-
tional Tables for X-ray Crystallography.[29] Geometrical calcula-
tions were made with PARST.[30] The crystallographic plots were
made with EUCLID[31] and ORTEP-3.[32] All calculations were
made at the University of Oviedo on the Scientific Computer
Center and X-ray group VAX/AXP computers.
trom. 2000, 14, 1014Ϫ1016.
[14]
CCDC-159427 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
at www.ccdc.cam.ac.uk/conts/retrieving.html or from the Cam-
bridge Crystallographic Data Centre, 12, Union Road, Cam-
bridge CB2 1EZ, UK [Fax: (internat.) ϩ 44-1223/336-033; E-
mail: deposit@ccdc.cam.ac.uk].
[15]
P. R. Ashton, C. G. Claessens, W. Hayes, S. Menzer, J. F. Stod-
dart, A. J. P. White, D. J. Williams, Angew. Chem. Int. Ed. Engl.
1995, 34, 1862Ϫ1865, and references therein.
Acknowledgments
We are very grateful to Dr. Marta Vilaseca, Servei de EM de la
[16] [16a]
J. Fuller, R. T. Carlin, H. C. De Long, D. Haworth, J.
´
Divisio III Ϫ Universitat de Barcelona for running de ESI mass
Chem. Soc., Chem. Commun. 1994, 299Ϫ300. [16b] P. R. Ashton,
M. C. T. Fyfe, S. K. Hickingbottom, J. F. Stoddart, A. J. P.
White, D. J. Williams, J. Chem. Soc., Perkin Trans. 2 1998,
2117Ϫ2128.
´
´
spectra. We thank the Direccion General de Investigacion (MCYT
Ϫ Spain) for financial support, through grants PB 98-1164 and
BQU 2000-0219. Additional support came from the Comissionat
per a Universitats i Recerca de la Generalitat de Catalunya through
grant 1999SGR-77.
[17]
[18]
[19]
´
´
´
E. Alcalde, L. Perez-Garcıa, C. Miravitlles, J. Rius, E. Valentı,
J. Org. Chem. 1992, 57, 4829Ϫ4834.
`
´
E. Alcalde, C. Ayala, I. Dinares, N. Mesquida, F. Sanchez-Fer-
rando, J. Org. Chem. 2001, 66, 2281Ϫ2290.
[1] [1a]
´
´
`
E. Alcalde, N. Mesquida, L. Perez-Garcıa, S. Ramos, M.
E. Alcalde, I. Dinares, J. Org. Chem. 1991, 56, 4233Ϫ4238 and
Alemany, M. L. Rodriguez, Chem. Eur. J. 2002, 8, 474Ϫ484,
references cited therein.
[1b]
[20] [20a]
and references therein.
Abstracted from the PhD Thesis of
A new regiospecific synthesis of 1-alkyl-1,2,4-triazoles has
`
Neus Mesquida, Facultat de Farmacia, Universitat de Barce-
been reported[20b] and the main methods currently available for
lona, 1999. [1c] Abstracted from the PhD Thesis of Montserrat
the preparation of 1-substituted 1,2,4-triazoles reviewed.[20c,20b]
`
Alemany, Facultat de Farmacia, Universitat de Barcelona,
B. A. Astleford, G. L. Goe, J. G. Keay, E. F. V. Scriven, J. Org.
[20c]
1994.
Chem. 1989, 54, 731Ϫ732.
M. Balasubramanian, J. G.
[2]
Comprehensive Supramolecular Chemistry (Eds.: J. L. Atwood,
J. E. D. Davies, D. D. Macnicol, F. Vögtle), Pergamon, Ox-
ford, 1996.
Keay, E. F. V. Scriven, Heterocycles 1994, 37, 1951Ϫ1975.
S. S. Moore, T. L. Tarnowski, M. Newcomb, D. J. Cram, J.
Am. Chem. Soc. 1977, 99, 6398Ϫ6405.
[21]
[22]
[23]
[24]
[25]
[26]
[27]
[3] [3a]
´
´
G. De la Torre, C. G. Claessens, T. Torres, Eur. J. Org.
M. E. Gonzalez, B. Alarcon, P. Cabildo, R. M. Claramunt, D.
Sanz, J. Elguero, Eur. J. Med. Chem. 1985, 20, 359Ϫ362.
R. M. Claramunt, J. Elguero, R. Garceran, Heterocycles 1985,
23, 2895Ϫ2906.
[3b]
Chem. 2000, 2821Ϫ2830.
Chem. Res. 1997, 30, 338Ϫ345.
J. S. Bradshaw, R. M. Izatt, Acc.
[3c]
J. S. Bradshaw, R. B. Ni-
elsen, P.-K. Tse, G. Arena, B. E. Wilson, J. D. Dalley, J. D.
Lamb, J. J. Christensen, R. M. Izatt, J. Heterocycl. Chem. 1986,
23, 361Ϫ368.
D. F. Grant, E. J. Gabe, J. Appl. Crystallogr. 1978, 11,
114Ϫ120.
M. S. Lehman, F. K. Larsen, Acta Crystallogr., Sect. A 1974,
30, 580Ϫ584.
[4]
V. Balzani, A. Credi, F. M. Raymo, J. F. Stoddart, Angew.
Chem. Int. Ed. 2000, 39, 3348Ϫ3391.
[5] [5a]
W. E. Allen, C. J. Fowler, V. M. Lynch, J. L. Sessler, Chem.
A. C. T. North, D. C. Phillips, F. S. Mathews, Acta Crystallogr.,
Sect. A 1968, 24, 351Ϫ359.
[5b]
Eur. J. 2001, 7, 721Ϫ729 and references cited.
stable, D. Smith, Chem. Br. 1995, 33Ϫ37.
E. C. Con-
P. T. Beurskens, G. Beurskens, W. P. Bosman, R. de Gelder, S.
[6]
[7]
´
V. P. Böhm, W. A. Herrmann, Angew. Chem. Int. Ed. 2000,
39, 4036Ϫ4038.
Garcıa-Granda, R. O. Gould, R. Israe¨l, J. M. M. Smits, The
DIRDIF-96 program system, Crystallography Laboratory, Uni-
versity of Nijmegen, The Netherlands, 1996.
G. M. Sheldrick, SHELXL-97, A computer program for refine-
ment of crystal structures, University of Göttingen, Germany,
1997.
International Table for X-ray Crystallography, Kynoch Press,
Birmingham; present distributor: Kluwer Academic Publishers,
Dordrecht, 1974, vol. 4.
M. Nardelli, Comput. Chem. 1983, 7, 95Ϫ98.
A. L. Spek, The EUCLID package, in: Computational Crystal-
lography (Ed.: D. Sayre), Oxford Clarendon Press, Oxford,
1982, p. 528.
L. J. Farrugia, J. Appl. Crystallogr. 1997, 30, 565.
Received October 8, 2001
´
´
´
E. Alcalde, C. Alvarez-Rua, S. Garcıa-Granda, E. Garcıa-Rod-
[28]
[29]
´
´
´
rıguez, N. Mesquida, L. Perez-Garcıa, Chem. Commun. 1999,
295Ϫ296.
[8]
´
´
E. Alcalde, S. Ramos, L. Perez-Garcıa, Org. Lett. 1999, 1,
1035Ϫ1038.
[9] [9a]
P. D. Beer, P. A. Gale, Angew. Chem. Int. Ed. 2001, 40,
486Ϫ516. [9b] P. A. Gale, Coord. Chem. Rev. 2001, 213, 79Ϫ128.
[10]
[11]
[30]
[31]
´
´
E. Alcalde, N. Mesquida, M. Gisbert, L. Perez-Garcıa, Eur. J.
Org. Chem. 2001, 000Ϫ000, and references therein.
Protophanes 1b·2Cl and 1b·2Br in CD3CN do not aggregate
up to 12 m while in [D6]DMSO, 1b·2Cl does not aggregate
up to 75 m and 1b·2Br up to 35 m.
Supramolecular Chemistry of Anions (Eds.: A. Bianchi, K.
Bowman-Jones, E. Garcıa-Espana), Wiley-VCH, New York,
[32]
[12] [12a]
´
˜
[O01485]
Eur. J. Org. Chem. 2002, 1221Ϫ1231
1231