Azolium-linked cyclophanes: A comprehensive examination of conformations by 1H NMR spectroscopy and structural studies

Article abstract of DOI:10.1021/jo049097o

The synthesis and characterization of a series of azolium-linked cyclophanes are reported. The cyclophanes consist of two azolium groups (17 examples) or three imidazolium groups (1 example) linked to two benzenoid units (benzene, naphthalene, p-xylene, m

Full text of DOI:10.1021/jo049097o

Azoliu m -Lin k ed Cyclop h a n es: A Com p r eh en sive Exa m in a tion of
1
Con for m a tion s by H NMR Sp ectr oscop y a n d Str u ctu r a l Stu d ies†
Murray V. Baker,* Mark J . Bosnich, David H. Brown, Lindsay T. Byrne, Valerie J . Hesler,
Brian W. Skelton, Allan H. White, and Charlotte C. Williams
Chemistry M313, The University of Western Australia, Crawley, WA 6009, Australia
mvb@chem.uwa.edu.au
Received May 28, 2004
The synthesis and characterization of a series of azolium-linked cyclophanes are reported. The
cyclophanes consist of two azolium groups (17 examples) or three imidazolium groups (1 example)
linked to two benzenoid units (benzene, naphthalene, p-xylene, mesitylene, 1,2,3,4- and 1,2,4,5-
tetramethylbenzene, 2,6-pyridine, and p-tert-butylphenol) via methylene groups. Cyclophanes
containing ortho-, meta-, and para-substitution patterns in the benzenoid units were examined.
The conformations of the cyclophanes were examined in solution by variable-temperature NMR
studies and in the solid state by crystallographic studies. The p-cyclophanes and mesitylene-based
1
m- and o/m-cyclophanes are rigid on the NMR time scale, as indicated by sharp H NMR spectra
at all accessible temperatures. The non-mesitylene-based m-cyclophanes and the o-cyclophanes
are fluxional on the NMR time scale at high temperatures, but in most cases, specific conformations
can be “frozen out” at low temperatures. Many structures deduced from solution studies were
consistent with those in the solid state.
In tr od u ction
Cyclophanes have been of interest for many years.1-3
The literature includes an eclectic array of cyclophanes,
with examples containing various aromatic groups (e.g.,
benzene, pyridine, naphthalene, thiophene, pyrrole, imi-
dazole, and so forth) linked by a variety of structural
elements (e.g., aliphatic chains, chains containing het-
eroatoms, and aromatic and heteroaromatic groups). In
this paper, we confine ourselves to the class of azolium-
linked cyclophanes, structures in which two aromatic
units (benzene-, pyridine-, and naphthalene-based units
in our study) are linked by two or more azolium units
(Figure 1). In recent years, much interest has focused on
cationic azolium-linked cyclophane systems.4-21 This class
includes cyclophanes with two5,12 or three linking units:
F IGURE 1. Azolium-linked cyclophanes.
4,22 cyclophanes where the linking units are placed ortho,
meta, or para on the aromatic units;4,5,17 imidazolium,
benzimidazolium, and benzotriazolium linking units;12,18,19
† From the Ph.D. thesis of C. C. Williams.
(1) Vo¨gtle, F. Cyclophane Chemistry; Wiley: Chichester, U.K., 1993.
(2) Keehn, P. M.; Rosenfeld, S. M. Cyclophanes; Academic Press:
New York, 1983; Vol. 1.
(3) Keehn, P. M.; Rosenfeld, S. M. Cyclophanes; Academic Press:
New York, 1983; Vol. 2.
(12) Bitter, I.; To¨ro¨k, Z.; Csokai, V.; Gru¨n, A.; Bala´zs, B.; To´th, G.;
Keseru´, G. M.; Kova´ri, Z.; Czugler, M. Eur. J . Org. Chem. 2001, 2861-
2868.
(13) Cabildo, P.; Claramunt, R.; Sanz, D.; Elguero, J .; Enjalbal, C.;
Aubagnac, J .-L. Rapid Commun. Mass Spectrom. 1996, 10, 1071-1075.
(14) Cabildo, P.; Sanz, D.; Claramunt, R. M.; Bourne, S. A.; Alkorta,
I.; Elguero, J . Tetrahedron 1999, 55, 2327-2340.
(15) Magill, A. M.; McGuinness, D. S.; Cavell, K. J .; Britovsek, G.
J . P.; Gibson, V. C.; White, A. J . P.; Williams, D. J .; White, A. H.;
Skelton, B. W. J . Organomet. Chem. 2001, 617-618, 546-560.
(16) Yuan, Y.; Gao, G.; J iang, Z.-L.; You, J .-S.; Zhou, Z.-Y.; Yuan,
D.-Q.; Xie, R.-G. Tetrahedron 2002, 58, 8993-8999.
(17) Zhou, C.-H.; Xie, R.-G.; Zhao, H.-M. Org. Prep. Proced. Int. 1996,
28, 345-369.
(18) Rajakumar, P.; Murali, V. Tetrahedron 2000, 56, 7995-7999.
(19) Rajakumar, P.; Dhanasekaran, M. Tetrahedron 2002, 58, 1355-
1359.
(20) Ramos, S.; Alcalde, E.; Doddi, G.; Mencarelli, P.; Pe´rez-Garc´ıa,
L. J . Org. Chem. 2002, 67, 8463-8468.
(21) Shi, Z.; Thummel, R. P. J . Org. Chem. 1995, 60, 5935-5945.
(22) Yuan, Y.; Zhou, H.; J iang, Z.; Yan, J .; Xie, R. Acta Crystallogr.
2000, C56, e34-e35.
(4) Baker, M. V.; Bosnich, M. J .; Williams, C. C.; Skelton, B. W.;
White, A. H. Aust. J . Chem. 1999, 52, 823-825.
(5) Baker, M. V.; Skelton, B. W.; White, A. H.; Williams, C. C. J .
Chem. Soc., Dalton Trans. 2001, 111-120.
(6) Baker, M. V.; Skelton, B. W.; White, A. H.; Williams, C. C.
Organometallics 2002, 21, 2674-2678.
(7) Barnard, P. J .; Baker, M. V.; Berners-Price, S. J .; Skelton, B.
W.; White, A. H. Dalton Trans. 2004, 1038-1047.
(8) Simons, R. S.; Garrison, J . C.; Kofron, W. G.; Tessier, C. A.;
Youngs, W. J . Tetrahedron Lett. 2002, 43, 3423-3425.
(9) Garrison, J . C.; Simons, R. S.; Talley, J . M.; Wesdemiotis, C.;
Tessier, C. A.; Youngs, W. J . Organometallics 2001, 20, 1276-1278.
(10) Alcalde, E.; Ramos, S.; Pe´rez-Garc´ıa, L. Org. Lett. 1999, 1,
1035-1038.
(11) Alcalde, E.; Alvarez-Ru´a, C.; Garc´ıa-Rodriguez, S.; Mesquida,
N.; Pe´rez-Garc´ıa, L. J . Chem. Soc., Chem. Commun. 1999, 295-296.
10.1021/jo049097o CCC: $27.50 © 2004 American Chemical Society
Published on Web 10/02/2004
7640
J . Org. Chem. 2004, 69, 7640-7652

Azolium-Linked Cyclophanes
and aromatic units based on benzene, pyridine, and
naphthalene (Figure 1).5,9,12,16,19 A number of different
aspects of these azolium-linked cyclophanes have been
studied, including synthesis,4,12,17-20 conformational be-
havior,12,14 anion binding properties,11,16 and mass spec-
tral properties.13 Imidazolium and benzimidazolium units
of the cyclophanes are precursors to (benz)imidazolylidenes
(N-heterocyclic carbenes), which are of much current
interest in metal coordination chemistry (e.g., 1 and
2).5-7,9,15,23
Many of the previous studies of azolium-linked cyclo-
phanes have focused on synthesis or specific properties
of a small number of cyclophanes. An exception is the
recent work of Bitter et al., which included the synthesis
of a broad selection of azolium-linked cyclophanes and
the use of NMR spectroscopy, X-ray crystallography, and
computational methods for the analysis of conforma-
tions.12 Our interests in azolium-linked cyclophanes are
also multidimensional. In this paper, we report a broad
examination of a well-defined series of azolium-linked
cyclophanes. Our study includes a 1,3,5-cyclophane and
ortho-, meta-, para-, and mixed ortho/meta-substituted
azolium-linked cyclophanes containing a variety of azo-
lium units and aromatic units (Figure 2). We have used
X-ray techniques and NMR methods, especially variable-
temperature NMR, to gain insights into the conforma-
tional behavior of the cyclophanes in the solid state and
in solution.
Resu lts a n d Discu ssion
Syn th esis a n d Gen er a l P r op er ties. The azolium-
linked cyclophanes (Figure 2), as bromide salts, were
easily synthesized by the reaction of a poly(azol-1-
ylmethyl)arene and an appropriate poly(bromomethyl)-
arene in a suitable solvent (usually acetone) at reflux or
at room temperature (Scheme 1). The cyclophanes either
precipitated from the reaction solution or were readily
recovered by the removal of solvent. This method pro-
duced the azolium-linked cyclophanes in good to high
yields (60-90%) and is similar to methods reported
recently for various cyclophanes, including some listed
in Figure 2.4-6,9-12,14,15,17-19,21 p-Cyclophane 5‚2Br is pro-
duced as a mixture of two isomers, pseudo-geminal-5a
and pseudo-ortho-5b, and from this mixture, pseudo-
geminal isomer 5a can be selectively crystallized.4 In-
terestingly, m-cyclophane 10‚2Br, which incorporates
both pyridine and mesitylene units, could only be pre-
pared if the precursors were 2,6-bis(bromomethyl)pyri-
dine and 2,4-bis(imidazol-1-ylmethyl)mesitylene. How-
ever, o/m-cyclophane 18‚2Br was easily prepared via both
possible pathways, for example, from 1,2-bis(bromo-
FIGURE 2. Azolium-linked cyclophanes in this study, grouped
according to substitution pattern.
(23) Garrison, J . C.; Simons, R. S.; Kofron, W. G.; Tessier, C. A.;
Youngs, W. J . J . Chem. Soc., Chem. Commun. 2001, 1780-1781.
J . Org. Chem, Vol. 69, No. 22, 2004 7641

Baker et al.
SCHEME 1
terns for the o-C6H4 units in the case of 13, Figure 3).
The benzenoid moieties in each conformation were either
mutually syn or anti, and the basis for the assignment
in each case is discussed in detail below.
1,3,5-Cyclop h a n e a n d th e p-Cyclop h a n es. 1,3,5-
Cyclophane (3) and p-cyclophanes 4-6 showed beauti-
fully simple NMR spectra (Table 1) containing only sharp
lines, with no evidence of any significant conformational
exchange process.4 The NMR spectra for 3-6 do not
change significantly with temperature. In each case, the
signal due to the imidazolium H2 protons is considerably
upfield compared to the H2 signals for acyclic imidazo-
lium salts (3, δ 5.79; 4, δ 7.93; 5, δ 6.32; and 6, δ 5.86; cf.
1,3-dibenzylimidazolium chloride,24 δ 10.04, d6-DMSO; δ
9.49, D2O). This result is consistent with the H2 protons
in the cyclophanes being magnetically shielded by the
benzene rings.4 For the series of p-cyclophanes 4-6, as
the number of methyl groups on the cyclophane increases,
the signal due to the azolium H2 protons shifts upfield,
possibly reflecting slight changes in the orientation of the
imidazolium rings. As the number of methyl groups on
the aromatic core increases, pivoting of the imidazolium
rings about their N-N axes should be restricted by steric
interactions with the methyl groups, in turn, forcing the
imidazolium groups to orient such that their H2 protons
would be directed more toward the center of the region
of magnetic shielding from the benzene rings. Alterna-
tively, it may be that increased electron density in the
benzene rings due to the electron donating effect of the
additional methyl groups may increase the shielding
effects.
SCHEME 2
methyl)benzene and 1,3-bis(imidazol-1-ylmethyl)benzene
or from 1,2-bis(imidazol-1-ylmethyl)benzene and 1,3-bis-
(bromomethyl)benzene.
In general, the cationic cyclophanes, as their bromide
salts, were insoluble in acetone, sparingly soluble in
DMSO and methanol, and freely soluble in water. Most
of the cyclophanes were purified by recrystallization from
methanol that had not been rigorously dried and were
crystallized with occluded water, which was evident from
1
the microanalytical data and H NMR spectra. Crystals
grown more slowly, for single-crystal X-ray studies, often
contained methanol or water molecules in the crystal
lattice (see Structural Studies). Benzotriazolium/pyridine
m-cyclophane 11‚2Br and octamethyl o-cyclophane 14‚
2Br proved to be quite soluble and were readily recrys-
tallized from acetone, dichloromethane, or methanol.
1H NMR Stu d ies: Con for m a tion s of Cyclop h a n es
in Solu tion . Various azolium-linked cyclophanes and
related bridged azolium species in solution have been
observed previously to exhibit interesting dynamic be-
havior.12,14,16,21 Such behavior has been interpreted in
terms of interconversion between syn and anti conforma-
tions (Scheme 2, showing the syn and anti conformations
of a bridged azolium species reported by Shi and Thum-
mel).21
1
o-Cyclop h a n es. At room temperature, the H NMR
spectra of o-cyclophanes 13-17 were very broad and
proved difficult to interpret. At higher temperatures, the
spectra sharpened and each system showed a single
signal for the benzylic protons. These results suggest that
the o-cyclophanes exist in various conformations that
interconvert on the NMR time scale at elevated temper-
atures. The benzylic signals still remained somewhat
broad, however, even at 66 °C, suggesting that the
interconversion of the different conformations was slow
on the NMR time scale. Low-temperature 1H NMR
studies were undertaken for three imidazolium-linked
o-cyclophanes (13, 14, and 16). These studies showed two
conformations of the cyclophanes (syn and anti) to be
“frozen out” at -73 °C.
For the azolium-linked cyclophanes studied in this
work, the number and multiplicity of signals in the H
1
Low -Tem p er a tu r e 1H NMR Stu d ies of o-Cyclo-
NMR spectra showed that these structures can also exist
in a variety of conformations. Some cyclophanes consisted
of a single conformation that was rigid on the NMR time
scale; others consisted of at least two distinct conforma-
tions interconverting rapidly on the NMR time scale, and
some showed conformational lability on a time scale that
was amenable to variable-temperature NMR studies. The
1H NMR data for the cyclophanes are summarized in
Tables 1 and 2, with Table 1 containing data for the rigid
cyclophanes and for the nonrigid cyclophanes at the
“slow-exchange” limit and Table 2 containing data for the
nonrigid cyclophanes at the “fast-exchange” limit. In the
NMR studies discussed below, the cyclophanes were
characterized as their bromide salts. In all of the identi-
fied conformations of the cyclophanes, the azolium units
were mutually syn. This assignment is based on the
1
p h a n e 13. At -73 °C, H NMR signals due to distinct
syn and anti conformations are present, with the anti
conformations being dominant (anti:syn 3.5:1, Figure 3a;
the anti conformation is also found in the solid state; see
Structural Studies and Figure 7a). Two benzylic signals
(δ 5.30, 6.33), one imidazolium H4/H5 signal (δ 6.93), and
an imidazolium H2 signal (δ 9.67) were assigned to a syn
conformation. Four benzylic signals (δ 5.20, 5.43, 5.90,
5.93), two imidazolium H4/H5 signals (δ 6.98, 7.64), and
an imidazolium H2 signal (δ 8.63) were assigned to an
anti conformation. The signals due to the arene protons
of both conformations overlapped in the region δ 7.7-
7.9. For the syn conformation, the downfield position of
the imidazolium H2 signal and the upfield position of the
1
symmetry of the H NMR signals due to the protons of
the arene groups (e.g., AA′XX′ rather than ABCD pat-
(24) Claramunt, R. M.; Elguero, J .; Meco, T. J . Heterocycl. Chem.
1983, 20, 1245-1249.
7642 J . Org. Chem., Vol. 69, No. 22, 2004

Azolium-Linked Cyclophanes
TABLE 1. 1H NMR Da ta for Rigid Cyclop h a n e Br om id e Sa lts a n d for F lu xion a l Cyclop h a n e Dibr om id e Sa lts a t th e
“Slow -Exch a n ge” Lim it
cyclophane
H2
H4/H5
benzylic CH2
5.61 (s)
arene
other
3a
5.79 (br t, 1.8 Hz)
7.93 (s)
6.32 (br t, 1.7 Hz)
7.97 (d, 1.8 Hz)
7.96 (s)
7.62 (d, 1.7 Hz)
2.21 (6 × CH3)
4b
5.32 (s)
7.35 (s)
7.12 (s)
5a a
4.95 (d, 14.1 Hz),
5.32 (d, 14.1 Hz)
5.47 (s)
1.90 (4 × CH3)
6c
8c
5.86 (s)
7.23 (s)
8.04 (s)
8.02 (s)
2.01 (8 × CH3)
1.53 (2 × CH3),
2.35 (4 × CH3)
1.49 (1 × CH3),
2.36 (2 × CH3)
5.31 (d, 15.3 Hz),
5.49 (d, 15.3 Hz)
5.14 (d, 14.7 Hz),
5.29 (d, 14.7 Hz),
5.31 (d, 15.1 Hz),
5.42 (d, 15.1 Hz)
syn A 5.13 (d, 14 Hz),
5.75 (d, 14 Hz);
syn B 5.19 (d, 14 Hz),
5.53 (d, 14 Hz)
7.10 (s)
10a
12d
13d
8.14 (br s, Wh/2 4 Hz) 7.46 (d, 2.1 Hz),
7.19 (s), 7.49 (d, 7.8 Hz),
7.80 (t, 7.8 Hz)
7.47 (d, 2.1 Hz)
syn A 9.19 (s);e
syn B 8.20 (s)e
syn A 7.73 (s);
syn B 7.85 (s)
syn A 7.66 (s);
syn B 7.73 (s)
syn A 1.28 (s, Bu),
t
9.9 (OH);e syn B 1.36
(s, Bu), 9.6 (OH)e
t
anti 8.63
anti 6.98, 7.64 (2 × s); anti 5.20, 5.43, 5.90,
7.68-7.90 (m)
(br s, Wh/2 18 Hz);
syn 9.67
syn 6.93 (s)
5.93 (4 × d, 14.4 Hz);
syn 5.30, 6.33
(br s, Wh/2 17 Hz)
8.48 (br s, Wh/2 7 Hz) 6.84, 7.54
(2 × d, 14.4 Hz)
14d
16d
5.45-5.80f (several d)
2.37 (2 × CH3),
2.41 (2 × CH3),
2.43 (4 × CH3)
anti 8.97
(br s, Wh/2 30 Hz);
syn 9.65
anti 7.04, 7.64 (2 × s); anti 5.30, 5.61, 5.76,
7.70-7.79, 8.05-8.13,
8.18-8.24 (3 × m);
8.34, 8.44 (2 × s)
syn 6.91 (s)
6.00 (4 × d, 14.8 Hz);
syn 5.47, 6.42
(br s, Wh/2 23 Hz)
9.11 (s)
(2 × d, 14.8 Hz)
18d
7.61, 8.00 (2 × br m)
5.41-5.57 (3 × d),
6.25 (d, 14.2 Hz)
4.51 (s), 7.33-7.38
(br d, ∼7 Hz),
7.39-7.45 (br t, ∼7 Hz),
7.73-7.79 (m),
7.90-7.96 (m)
7.27 (s), 7.57-7.63,
7.94-8.00 (2 × m)
19c
8.50 (br s, Wh/2 8 Hz) 7.75, 7.93 (2 × s)
5.20 (d, 14.5 Hz),
5.41 (d, 15.4 Hz),
5.49 (d, 15.4 Hz),
5.67 (d, 14.5 Hz)
1.14 (1 × CH3),
2.49 (2 × CH3)
a
Solution in D2O recorded at 500 MHz at ambient temperature. b Solutions in d6-DMSO recorded at 300 MHz at ambient temperature.
c Solution in d6-DMSO recorded at 500 MHz at ambient temperature. Solutions in CD3OD at -70 ( 3 °C at 500 MHz. e H/D exchanges
d
occur rapidly in CD3OD; data obtained using solutions in CH3OH at -70 ( 3 °C at 500 MHz. f Peaks obscured by the large solvent (OH)
signal.
1
imidazolium H4/H5 signal indicate that the conformation
is one in which the imidazolium H2 protons are directed
away from the o-xylyl units (i.e., the H2 protons do not
point into the cavity formed by the magnetically aniso-
tropic benzene rings and, therefore, are not shielded by
them). As the temperature is increased to -53 °C (Figure
3b), signals due to the anti conformation begin to broaden
and have almost merged into the spectrum baseline at
-33 °C (Figure 3c). The fact that the signals due to the
anti conformation begin to broaden, while the signals due
to the syn conformation remain sharp, can be explained
in terms of an interconversion of two equivalent anti
conformations by rotation of the imidazolium units about
their N-N axes (Scheme 3). This process would exchange
the imidazolium H4 and H5 environments and exchange
the environments of the two types of exo-benzylic protons
and the two types of endo-benzylic protons. At temper-
atures above -33 °C, the signals due to the syn confor-
mation also begin to broaden, and as the temperature is
increased further, they appear to coalesce with signals
from the anti conformation (Figure 3, parts d-f). These
changes can be interpreted in terms of the flipping of the
o-xylyl units, which would interconvert syn and anti
conformations. At 57 °C (Figure 3g), rapid exchange
between the syn and anti conformations causes all of the
benzylic protons to become equivalent and all the imi-
dazolium H4/H5 protons to also become equivalent.
The H NMR signals due to the imidazolium H4 and
H5 protons of the anti conformation coalesce at -13 ( 5
°C. Assuming that the separation of the signals at this
temperature in the absence of exchange is 334 Hz (the
value seen at -73 °C), we estimate the rate constant for
the anti/anti exchange process at -13 °C to be ∼740 s-1
and the free energy of activation for this process to be
∼49 kJ mol-1 (12 kcal mol-1). Similarly, the signals due
to the imidazolium H4/H5 protons of the anti and syn
conformations coalesce at 27 ( 2 °C. Assuming the
separation of these signals in the absence of exchange to
be 200 Hz (the value estimated from spectrum recorded
at -13 °C), we estimate the rate constant for the anti f
syn conversion at 27 °C to be ∼120 s-1 and the free energy
of activation for this process to be ∼61 kJ mol-1 (15 kcal
mol-1). (Full details of these calculations are provided in
the Supporting Information.)
1
Low -Tem p er a tu r e H NMR Stu d ies of Octa m eth -
yl o-Cyclop h a n e 14 a n d Na p h th a len e-Ba sed o-Cy-
clop h a n e 16. In solutions at -70 °C, 14 existed prima-
rily in the anti conformation and was rigid on the NMR
time scale. (The conformation identified in the solid state
by X-ray studies was also anti; see Structural Studies.)
1
Key features of the H NMR spectrum (freshly prepared
solution) that lead to this conclusion included sharp
doublets at δ 6.84 and 7.54 (3J H,H ) 1.9 Hz), which are
attributed to the imidazolium H4/H5 protons, and a
J . Org. Chem, Vol. 69, No. 22, 2004 7643

Baker et al.
other
TABLE 2. 1H NMR Da ta for F lu xion a l Cyclop h a n e Dibr om id e Sa lts a t th e “F a st-Exch a n ge” Lim it a
cyclophane
H2
H4/H5
benzylic CH2
5.44 (s)
arene
7
9.42 (s)
7.82 (s)
7.10 (s); 7.42-7.51,
7.57-7.63 (2 × m)
7.59 (d, 7.7 Hz),
7.98 (t, 7.7 Hz)
7.60-7.89 (m),
7.77 (d, 7.8 Hz),
8.13 (t, 7.8 Hz)
7.61 (s)
9
9.20 (br m)
8.65 (br s)
7.67 (br m)
5.62 (s)
6.32 (s)
11b
12c
13d
7.70 (d, 1.6 Hz)
5.43 (s)
1.28 (tBu),
9.56 (br s, OH)
8.60 (br s, Wh/2 90 Hz) 7.12 (br s, Wh/2 20 Hz) 5.60 (br s, Wh/2 40 Hz) 7.64-7.72,
7.80-7.88 (2 × m)
14d
15d
8.52 (br s, Wh/2 10 Hz) 7.10 (br s, Wh/2 6 Hz)
8.76 (br s, Wh/2 12 Hz)
5.60 (br s, Wh/2 5 Hz)
2.33, 2.37 (2 × s)
5.77 (br s, Wh/2 15 Hz) 7.12 (br s, Wh/2 16 Hz),
7.34 (br s, Wh/2 35 Hz);
7.74-7.82,
7.95-8.04 (2 × m)
16d
17e
8.83 (br s, Wh/2 45 Hz) 7.24 (br s, Wh/2 9 Hz)
9.04 (br s, Wh/2 17 Hz)
5.78 (br s, Wh/2 15 Hz) 7.69-7.77, 8.03-8.11
(2 × m); 8.42 (s)
5.97 (br s, Wh/2 40 Hz) 7.11 (br s, Wh/2 19 Hz),
7.18-7.71 (very br s);
7.73-7.82,
8.11-8.20 (2 × m);
8.59 (br s, Wh/2 5 Hz)
18
20
9.00 (s)
8.79 (s)
7.73 (d, 1.9 Hz),
7.93 (d, 1.9 Hz)
5.49, 5.77 (2 × s)
4.92 (s); 7.36-7.48,
7.66-7.69,
7.86-7.89 (3 × m)
7.44 (d, 7.7 Hz); 7.64-7.69,
7.85-7.89 (2 × m);
7.90 (t, 7.7 Hz)
7.55, 7.80 (2 × br m)
5.60 (s), 5.82
(br s, Wh/2 17 Hz)
a
b
Solutions in d6-DMSO at 500 MHz at ambient temperature, unless otherwise indicated. Solution in CD3OD at 500 MHz at ambient
temperature. c Solution in d6-DMSO at 500 MHz at 50 °C. Solutions in d6-DMSO at 300 MHz at 66 °C. e Solutions in d6-DMSO at 300
d
MHz at 77 °C.
singlet at δ 8.48, which is attributed to the imidazolium
H2 protons. The fact that the imidazolium H4/H5 protons
had different chemical shifts, combined with the H2
protons having a chemical shift indicative of shielding
by one aromatic ring (cf. δ 8.63 for the H2 protons in anti-
13), points to an anti conformation. The various methyl
groups appeared in the region δ 2.37-2.43, but unfortu-
nately, the expected set of four doublets for the benzylic
protons was obscured by the large methanol/water (OH)
signal. In spectra of solutions containing 14 recorded at
-73 °C, a small signal at δ 9.61 was tentatively assigned
to the imidazolium H2 protons of syn-14. The signal was
small, however, corresponding to only about 3% of the
total amount of cyclophane present, and other signals due
to this conformation (if present) were obscured by signals
due to the anti conformation and the solvent. The small
proportion of the syn conformation in this sample may
be a consequence of the added bulk of the tetramethyl
functionalized aromatic rings and consequent steric
interactions between these rings and the imidazolium
units that disfavor the syn conformation in this system.
and 19) and those that do not (7, 9, 11, 12, 18, and 20).
Cyclophanes incorporating a mesitylene unit are rigid on
the NMR time scale at all accessible temperatures, as
1
indicated by sharp H NMR spectra in which the signals
for the benzylic protons appear as characteristic sharp
doublets; an analogous result was recently reported for
21‚2PF6.16 In the 1H NMR spectrum of a solution of 8
(see Figure S2 in the Supporting Information), there are
only two doublets for the benzylic protons, which suggests
that the cyclophane is locked in a syn conformation
(Figure 4). The H2 signal for 8 (δ 7.23, d6-DMSO) is
upfield relative to those of simple imidazolium ions. This
upfield chemical shift is consistent with 8 being in a
conformation where the H2 protons are shielded by the
magnetically anisotropic mesitylene rings (Figure 4). For
10 (see Figure S3 in the Supporting Information), there
are four doublets for the benzylic protons, two for the
benzylic protons adjacent to the pyridine group, and two
for the benzylic protons adjacent to the mesitylene group
1
(assignments confirmed by H-13C HSQC and 1H-13C
HMBC 2D NMR experiments). The similarities of the
chemical shifts for the mesitylene/benzylic protons in 8
and 10 suggest that the conformation of the mesitylene
unit with respect to the imidazolium units in 10 is the
same as that in 8. Furthermore, the chemical shift of the
imidazolium H2 protons for 10 (δ 8.14, D2O) is signifi-
cantly more downfield than that for 8 (δ 7.23, d6-DMSO),
which suggests that in 10 these protons are subjected to
shielding by only one aromatic ring. These observations
suggest that, in solution, cyclophane 10 is in the anti
conformation (Figure 4). We note, however, that in the
1H NMR spectrum of 10, H4 and H5 have very similar
chemical shifts. This result at first seems counter to the
1
Naphthalene-based o-cyclophane 16 was shown by H
NMR spectroscopy to exist as a mixture of frozen out syn
and anti conformations in a CD3OD solution at -73 °C
(see also Figure S1 in the Supporting Information). For
o-cyclophanes 13, 16, and 14, the anti:syn ratios at -73
°C were 3.5:1, 4.3:1, and >30:1, respectively. In this
series, the anti:syn ratio increases with the steric bulk
of the aromatic group (benzene vs naphthalene vs tet-
ramethylbenzene).
m -Cyclop h a n es a n d o/m -Cyclop h a n es. The m- and
o/m-cyclophanes studied can be broadly categorized into
two groups: those that contain a mesitylene unit (8, 10,
7644 J . Org. Chem., Vol. 69, No. 22, 2004

Azolium-Linked Cyclophanes
1
F IGURE 3. Variable-temperature H NMR spectra (500.1 MHz, CD3OD) of o-cyclophane 13. Key (see Scheme 3): a ) benzylic
protons for anti-13, b ) imidazolium protons for anti-13, c ) benzylic protons for syn-13, d ) imidazolium protons for syn-13, and
x ) solvent (OH) peak.
SCHEME 3
F IGURE 4. Conformations of rigid m- and o/m-cyclophanes.
1H NMR chemical shifts used to assign the conformations are
indicated on each conformation.
also adopts the anti conformation (Figure 4). The chemi-
cal shifts of the H4 (δ 7.75, d6-DMSO) and H5 (δ 7.93,
d6-DMSO) imidazolium protons (assignments based on
1H-13C HSQC and 1H-13C HMBC 2D NMR experiments)
provide further evidence for an anti conformation. The
upfield shift of H4 compared to that of H5 is consistent
with the H4 protons receiving more shielding than the
H5 protons by the o-xylyl group. The solution conforma-
tions deduced by NMR (syn for 8 and anti for 10 and 19)
suggestion of an anti conformation since, in an anti
conformation, different shielding effects would be ex-
pected for H4 and H5; it may be that the cyclophane
adopts a “flattened” anti conformation, in which the
pyridine ring lies closer to the plane defined by the four
1
N atoms. The H NMR spectrum for 19 (see also Figure
S4 in the Supporting Information) is similar to that of
10 (four sets of sharp doublets and a signal for H2
downfield to that of 8), suggesting that, in solution, it
J . Org. Chem, Vol. 69, No. 22, 2004 7645

Baker et al.
F IGURE 5. Variable-temperature 1H NMR spectra (500.1 MHz, CD3OD) of o/m-cyclophane 18. Key: a ) imidazolium H4 protons,
b ) imidazolium H5 protons, c ) o-benzylic protons, d ) m-benzylic protons, e ) m-xylyl H2 protons, and x ) solvent (OH) peak.
SCHEME 4
are similar to the solid-state conformations identified in
X-ray studies (see Structural Studies and Figures 7f, 7c,
and 7b, respectively).
The m- and o/m-cyclophanes that do not contain a
mesitylene group (7, 9, 11, 12, 18, and 20) are all nonrigid
on the NMR time scale. The signals for the benzylic
protons in the 1H NMR spectra of 7, 9, 11, and 20 appear
as singlets at room temperature and also at temperatures
as low as 220 K, indicating that these cyclophanes are
not conformationally rigid. The conformational lability
of 9 has been recently identified by Bitter and co-
workers.12 The chemical shifts of the signals correspond-
ing to the imidazolium H2 protons in 7 (δ 9.42, d6-DMSO)
and 9 (δ 9.20, d6-DMSO) are much more downfield than
those for the rigid cyclophanes 8 and 10. This result
suggests that, in the dominant conformations of these
cyclophanes, the imidazolium H2 protons are not mag-
netically shielded by the benzene rings; the cyclophanes
may, for example, adopt syn conformations in which the
imidazolium H2 protons are exo with respect to the
cyclophane skeleton (cf. the conformation shown below
for syn-18, Scheme 4), or the benzene rings may simply
lie closer to the “plane” of the cyclophane (cf. the meta-
substituted benzene ring in the flattened structure in
Scheme 4). For 7, 9, 11, and 20, exchange processes are
rapid on the NMR time scale, even at -53 °C; the 1H
NMR spectra for these cyclophanes at -53 °C are similar
to those at room temperature. For o/m-cyclophane 18 and
phenol m-cyclophane 12, however, the exchange pro-
cesses are sufficiently slow at low temperatures that
particular conformations can be frozen out.
1
Low -Tem p er a tu r e H NMR Stu d ies of o/m -Cyclo-
1
p h a n e 18. A H NMR study of 18 (Figure 5) indicates
that at -73 °C this cyclophane exists in a single confor-
mation, tentatively assigned as a flattened conformation
(Scheme 4). This assignment is based on the observations
that (i) the signal due to the H2 proton of the m-xylyl
group (the proton between the benzylic substituents on
the m-xylyl unit) appears at unusually high field (δ 4.51),
consistent with the m-xylyl unit being oriented so that
this proton is in a region of shielding between the
imidazolium groups, and (ii) the downfield chemical shift
7646 J . Org. Chem., Vol. 69, No. 22, 2004

Azolium-Linked Cyclophanes
1
F IGURE 6. H/D exchange in imidazolium-linked cyclophanes. The H/D exchange was monitored by H NMR spectroscopy. Spectra
were recorded using ∼0.04 M solutions of cyclophane bromide salts in D2O at 300 MHz and ambient temperature. Conditions
required for complete exchange of the protons: HA ) D2O, room temperature, <10 min; HB ) D2O, 100 °C, 1 h; HC ) D2O, 2 equiv
of NaOH, room temperature, <10 min; HD ) D2O, 2 equiv of NaOH, 100 °C, 1 h; and HE ) D2O, 2 equiv of NaOH, 100 °C, >24
h. Exchange was not detectable for protons attached to benzene or pyridine rings or methylene protons in 3, 6, and 8.
of the signal due to the imidazolium H2 protons (δ 9.11)
is indicative of these protons not experiencing shielding
by the benzene rings. The imidazolium H4/H5 protons
resonate at δ 7.61 and 8.00, consistent with the existence
of a conformation where the upfield signal corresponds
to protons shielded by the o-xylyl ring. At low tempera-
tures, the benzylic protons appear as two pairs of
doublets, and these pairs coalesce to two singlets at
higher temperatures, indicative of a process that inter-
converts two equivalent (mirror image) conformations.
Interestingly, however, these coalescences in the NMR
spectra are accompanied by marked shifts in the signals
due to the m-xylyl H2 proton (downfield) and the imida-
zolium H5 protons (upfield). It may be that as the
temperature is increased, the conformation becomes more
syn-like (Scheme 4) so that the imidazolium H5 protons
experience increased shielding due to the proximity of
S5 in the Supporting Information): (i) the number and
multiplicity of H NMR signals observed for each con-
1
formation are consistent with the imidazolium groups
mutually syn and the phenol groups being mutually syn
in each case; (ii) for each conformation, the benzylic
protons (exo and endo) appear as a pair of doublets; and
(iii) the signals due to the imidazolium H2 protons appear
at δ 9.19 (major conformation, ∼67%) and 8.20 (minor
conformation, ∼33%). The upfield position of the latter
is consistent with the H2 protons of the minor conforma-
tion being shielded by the magnetically anisotropic
benzene rings. The dominant conformation (syn A, Scheme
5) is the same as that characterized in the solid state
(see Figure 7g).
1
As the temperature is increased, the H NMR signals
for the two conformations coalesce so that, in the 1H NMR
spectrum at room temperature, all signals are singlets.
This result indicates the existence of exchange processes
that interconvert the two equivalent forms of syn A and
interconvert the two equivalent forms of syn B and also
interconvert syn A with syn B. The anti conformations
were not detected at any temperature but are presumably
transient intermediates in the exchange pathways. The
NMR behavior exhibited by 12 is reminiscent of that of
calix[4]arenes in that, at low temperatures, the 1,3
alternate conformation is frozen out for calix[4]arene, but
1
the m-xylyl group (thus the H5 H NMR signal moves
upfield) and the H2 protons of the m-xylyl group move
out of the region of shielding between the imidazolium
1
groups (thus the H NMR signal moves downfield).
Low -Tem p er a tu r e 1H NMR Stu d ies of P h en ol
m -Cyclop h a n e 12. At -73 °C in methanol solutions,
phenol m-cyclophane 12 exists in two frozen out syn
conformations, assigned as syn A and syn B (Scheme 5)
on the basis of the following observations (see also Figure
J . Org. Chem, Vol. 69, No. 22, 2004 7647

Baker et al.
F IGURE 7. Different cyclophane types that were structurally characterized and their observed conformations. (a) Bis(o-phenylene)
cation 13. This anti conformation was also observed in both of the two independent cations of the bis(o-tetramethylphenylene)
array (14), (b) o-phenylene(sym-trimethyl-m-phenylene) cation 19, (c) m-phenylene(sym-trimethyl-m-phenylene) cation 10, and
(d) bis(sym-m-pyridyl) cation 11. (e) The syn-type conformation was found in the o-phenylene(sym-m-pyridyl) cation 20, (f) bis-
(sym-m-mesityl) cation 8, and (g) bis(1-hydroxyl-4-tert-butyl-2,6-m-phenylene) cation 12. All structures are at ∼153 K and shown
with 50% probability amplitude displacement ellipsoids (except for a, at 300 K and 20% probability ellipsoids).
7648 J . Org. Chem., Vol. 69, No. 22, 2004

Azolium-Linked Cyclophanes
SCHEME 5
SCHEME 6. P ossible H/D Exch a n ge Mech a n ism
for th e Meth yl Gr ou p s of 3
the calixarene structure becomes labile at higher tem-
peratures.25
also quite facile,6 a result that is presumably a conse-
quence of the enhancement of acidity of these pro-
tons by the pyridine group.30 Exchange of methylene
protons in 7 (isostructural to 9) and 4 occurred more
slowly than for 9. In 3, 6, and 8, no exchange of
methylene protons was detected, perhaps, because
the exchange reactions are slowed by the steric hin-
drance associated with the methyl groups in these
cyclophanes. The exchange of methyl protons in 3 is
surprising since the methyl groups are several bonds
removed from the imidazolium units. Base-catalyzed
exchange of the methyl protons might occur via an
o-xylenyl intermediate (Scheme 6). If this mechanism
were to operate in the case of 5, H/D exchange of
the methyl protons could be accompanied by equilibra-
tion of pseudo-ortho-5b and pseudo-geminal-5a isomers.
This possibility could not be tested, however, because
when H/D exchange experiments were conducted
starting with pure pseudo-geminal-5a , no exchange of
methyl protons was observed. As an additional test, H/D
exchange studies were performed on the non-cyclophane
salt 22‚3Br under the same conditions as detailed in
Figure 6. H/D exchange occurred readily at the imida-
zolium H2 and H4/H5 positions in 22‚3Br, without
complication, under conditions similar to those for the
exchange of the corresponding protons in the cyclo-
phane salt 3‚3Br. However, in contrast to the situation
for 3‚3Br, exchange of the benzylic methyl protons in
22‚3Br was slow (25% exchange after 24 h at 100 °C
in the presence of 2 equiv of NaOH for 22, compared
to 90% exchange within 1 h under similar conditions
for 3). In further contrast to the situation for 3, H/D
exchange of the benzylic methyl protons in 22 was
accompanied by partial (but not complete) decomposi-
tion of the cation, as indicated by the appearance of
extra signals in the benzylic, N-methyl, and benzylic/
Of the cyclophanes that have meta-type aromatic
groups (derived from benzene, mesitylene, or pyridine),
only those that contain at least one mesitylene unit never
show conformational mobility on the NMR time scale.
This result presumably arises because interconversion
of conformations in a mesitylene-based system would
require the passage of a methyl group through the
cyclophane macrocycle between the imidazolium rings,
with greater steric hindrance than that of the analogous
processes in non-mesitylene-based cyclophanes. Interest-
1
ingly, the H NMR signal for the C2 methyl group in all
of the mesitylene-based cyclophanes lies significantly
upfield of the signals due to the other mesitylene methyl
groups, a result that may reflect the C2 methyl group
being in an environment shielded by the ring currents
of the imidazolium units.
H/D Exch a n ge Rea ction s in D2O. Studies of the
1,3,5-cyclophane salt (3‚3Br) in D2O solutions revealed
some interesting H/D exchange reactions (Figure 6). The
1H NMR spectra of freshly prepared D2O solutions
containing 3‚3Br show singlets due to the four different
types of protons: the imidazolium H2 protons, the
imidazolium H4/H5 protons, the methylene protons, and
the methyl protons. When a sample was allowed to stand
for a few days at room temperature or 1 h in a steam
bath, the 1H NMR signal due to the imidazolium H2
protons at δ 5.64 disappeared due to the H/D exchange.
2
The presence of H bonded to the imidazolium C2 was
confirmed by 13C NMR; in the 13C NMR spectrum, the
signal due to C2 was split into a 1:1:1 triplet (1J C,D ) 29
Hz). Addition of a small amount of NaOH to the sample
resulted in the rapid H/D exchange of the imidazolium
H4/H5 protons (δ 7.83), and when the sample was heated
in a steam bath for a few days, the protons of the methyl
groups were also exchanged. Similar H/D exchange
reactions were observed for other azolium-linked cyclo-
phanes, as exemplified in Figure 6.
1
methyl regions of the H NMR spectrum (see the Sup-
Some trends in the ease of H/D exchange are apparent.
In all cases, the imidazolium H2 protons exchange most
readily, followed by the less-acidic imidazolium H4/H5
protons. The ability of imidazoles and imidazolium ions
to undergo the H/D exchange of H2 and H4/H5 is well-
known.26-29 Exchange of the methylene protons in 9 is
porting Information). These decomposition products did
not include N-methylimidazole, a product which would
be expected if H/D exchange of the benzylic/methyl
protons in 22 proceeds via an o-xylylene intermediate
analogous to that shown in Scheme 6. Although the
absence of N-methylimidazole among the decomposition
products counts against the possibility of an o-xylylene
intermediate for 22, the significant differences between
the course of H/D exchanges for 22 and 3 make us
reluctant to exclude the possibility of such an intermedi-
(25) Comprehensive Supramolecular Chemistry: Molecular Recogni-
tion, Receptors for Molecular Guests; Atwood, J . L., Davies, J . E. D.,
MacNicol, D. D., Vo¨gtle, F., Eds.; Pergamon Press: New York, 1996;
Vol. 2, Chapter 4.
(26) Wong, J . L.; Keck, J . H., J r. J . Org. Chem. 1974, 39, 2398-
2403.
(27) Takeuchi, Y.; Yeh, H. J . C.; Kirk, K. L.; Cohen, L. A. J . Org.
Chem. 1978, 43, 3565-3570.
(28) Hardacre, C.; Holbrey, J . D.; McMath, S. E. J . J . Chem. Soc.,
Chem. Commun. 2001, 367-368.
(29) Denk, M. K.; Rodezno, J . M. J . Organomet. Chem. 2001, 617-
618, 737-740.
(30) Abu-Shanab, F. A.; Wakefield, B. J .; Elnagdi, M. H. Adv.
Heterocycl. Chem. 1997, 68, 181-221.
J . Org. Chem, Vol. 69, No. 22, 2004 7649

Baker et al.
TABLE 3. Cyclop h a n e Descr ip tor sa (see text)
θ2/4
φ1
φ3
ø1/2
ø1/4
ø3/2
ø3/4
C(22)‚‚‚(C42) H(22)‚‚‚H(42) N(23)‚‚‚N(41) N(21)‚‚‚N(43)
o-Cyclophane Systems
13‚2Br 14.9(1) 136.3(1)
14‚2Br 15.1(2) 132.4(1)
(1)
12.2(1) 87.2(1) 83.3(1) 89.8(1) 88.3(1)
3.5(1) 80.7(1) 87.1(3) 89.5(1) 87.2(1)
3.047(3)
3.033(4)
2.84(4)
2.83b
3.210(3)
3.232(4)
3.227(3)
3.177(4)
(2)
21.7(2) 132.4(1)
3.8(1) 80.7(1) 83.0(1) 85.7(1) 86.4(1)
3.002(5)
3.120(3)
2.68b
3.276(4)
3.132(3)
3.248(4)
3.132(3)
23
7.84(6) 119.51(8) 119.51(8) 80.2(1) 86.8(1) 86.8(1) 80.2(1)
o/m-Cyclophane Systemsd
5.07(9) 60.29(9) 76.8(1) 75.2(1) 78.5(1) 89.4(1) 3.922(3)
3.119(3)c
20‚2Br 28.0(1)
3.97(3)
2.95(2)
4.427(3)
5.073(2)
3.363(3)
4.194(3)
19‚2Br 63.54(7) 157.01(6) 16.23(6) 70.36(6) 63.01(6) 70.15(6) 68.39(6)
3.888(2)
m-Cyclophane Systems
11‚2Br 18.0(1)
17.1(3)
68.2(2)
86.9(2) 85.9(3) 85.9(3) 81.2(2) 81.2(2)
92.9(3) 83.0(2) 83.0(2) 82.2(2) 82.2(2)
8.94(7) 136.83(7) 86.83(7) 84.85(7) 71.36(8) 72.08(8)
16.7(5) 16.4(5) 80.5(5) 80.5(5) 80.5(5) 80.5(5)
4.944(9)e
(n/a)
4.696(8)
4.636(9)
(1)
(2)
15.7(1)
4.848(8)
4.660(3)
4.542(2)
4.990(3)
4.607(8)
5.351(2)
5.402(2)
5.518(3)
4.627(8)
5.378(2)
5.402(2)
5.989(3)
10‚2Br 53.88(9)
8‚2Br 70.6(6)
3.86(3)
3.5b
4.38(5)
12‚2Br 40.1(1) 146.58(8) 140.01(8) 81.7(1) 88.58(8) 81.4(1) 82.7(1)
a
b
In degrees and Å. Estimated value. c The equivalent O‚‚‚O distance; details for this compound from a local 150 K redetermination
deposited with this paper (see also ref 21). Ring 1, ortho; ring 3, meta. e The equivalent N‚‚‚N distance.
d
ate in the very facile H/D exchange of benzylic/methyl
may be parametrized in diverse ways. Taking the highest
positions in 3.
symmetry array of 8‚2Br as a convenient datum, prime
descriptors are (a) the interplanar dihedral angle between
the two imidazole C3N2 rings, θ [the imidazolium C(n2)H
groups pointing “inward”, as here, representing a positive
angle; see Table 3], and (b) the interplanar dihedral
angles, φ, between the pair of six-membered aromatic
rings and a median plane through the C(n2) atoms and
the midpoints of the two C(n4)-C(n5) bonds; a further
distortion may be indicated by the difference in “equiva-
lent” angles between the phenylene and imidazole planes,
ø. We now discuss the individual members and types in
more detail.
Str u ctu r a l Stu d ies. Gen er a l. A number of cyclo-
phane salts have been characterized (mostly solvated,
with the solvent being modeled as water and/or metha-
nol) by single-crystal X-ray structure determinations; for
example, the complexes take the form (cyclophane)Br2‚
n(solvent). In most cases, one formula unit, devoid of
crystallographic symmetry, comprises the asymmetric
unit of the structure, but in 14‚2Br, there are two such
independent formula units; in 8‚2Br, it is a quarter of
the formula unit, with the cation here reaching its
highest potential symmetry (2 mm), and in 11‚2Br, it is
half, with the cation having m symmetry. In general, the
crystal packing is far from haphazard, a prime determi-
nant being the considerable planar components of the
cations which pack against adjacent cations, frequently
related by inversion or other symmetry operations. The
bromide anions and solvent molecules appear to be
secondary in their influence in this respect, filling
interstices and hydrogen bonding with each other, al-
though where the cation form is favorable, inclusion may
occur (e.g., 8‚2Br, Figure 7f). The cation conformations
In d ivid u a l Exa m p les. One extreme cation form in
the present arrays may be taken as that presented when
the linking six-membered rings are both bound ortho.
Here, these are represented by the unsubstituted o-
cyclophane cation 13 (Figure 7a) and the heavily substi-
tuted octamethyl o-cyclophane cation 14. In both cases,
the disposition of ring 3, with respect to the median plane
of the cation, is much flatter than the disposition of ring
1, with the latter being limited in this respect by the
emergence of contacts between H(25,44) (imidazolium
H4/H5 protons) and the phenylene units. The nature of
the array, with one φ being acute and the other obtuse
(i.e., an anti conformation), may be characteristic of
species with a pair of o-phenylene bridges because of
either mechanical or statistical necessity. In the previ-
ously studied diazolone (23),21 however, both phenylene
groups have an obtuse φ (i.e., a syn conformation, with
the phenylene groups lying away from the diazolone
oxygen atoms). The packing of 13‚2Br is of a common
type found herein, where in projection down the short
7650 J . Org. Chem., Vol. 69, No. 22, 2004

Azolium-Linked Cyclophanes
cell axis, the macrocycle plane lies quasi-normal to the
axis, with aromatic planes confronting inversion-related
counterparts and with anions and solvent disposed
between the planes. The packing found in 14‚2Br is of a
different type; the cations are arranged in sheets per-
pendicular to a, with the anions and solvents in inter-
in the crystal packing (the cations forming a loose web)
with the anion/solvent component, considerably disor-
dered, occupying tunnels within. In 10‚2Br, with one of
the pyridine nitrogens supplanted by a methyl substitu-
ent and reversion to a bis(imidazolium) system, the
resulting conformation is consistent with previous ex-
pectations, the pyridyl being bent back with obtuse φ,
while the mesitylene unit, as elsewhere, has φ acute; the
angle θ between the imidazolium planes is large. The
crystal packing, again, is dominated by an array of
macrocycle planes normal to the short axis of the cell,
including solvent hydrogen bonded to Br(1) [Br(1)‚‚‚
H,O(0) ) 2.42(3) and 3.278(2) Å], with the other anions
[Br(2)] between them. Finally, in 8‚2Br, a system with
two intrusive methyl substituents, these lie out of the
macrocycle cavity, which now includes a water molecule
[O(01)‚‚‚H(22) ) 2.4 Å (estimated)], with the inclination
of the imidazolium rings being extremal. The cations are
disposed about the cell diagonals with other solvent
molecules and anions between them. A final variant on
the latter is found in 12‚2Br, where, with methyl sub-
stituents replaced by hydroxyl, the pitch of the bridges
is reversed; phenolic oxygen‚‚‚H(22,42) (imidazolium H2
protons) contacts range between 2.61(5) and 3.10(3) Å.
“Hermaphroditic self-inclusion” is found in the packing,
the cup of the molecule including a tert-butyl group from
an adjacent molecule. Anion/solvent strings fill the
remaining voids [Br(1)‚‚‚H,O(01) ) 2.30(7), 3.217(3) Å;
H,O(02) ) 2.56(5), 3.312(3) Å; H,O(03) ) 2.37(5), 3.271(3)
Å]. Br(2)‚‚‚H,O(32) ) 2.36(4), 3.150(2) Å is an anion‚‚‚
phenolic group contact, the other phenolic interaction
being to one of the water molecules [O(02)‚‚‚H,O(12) )
1.92(4), 2.667(3) Å].
1
leaving sheets, here, about x ) 0, /2.
When the bridges between the imidazole rings are
expanded, the next form is the o-phenylene/m-phenylene
(ortho/meta) type. The simplest example of this type is
the pyridine-derived 20‚2Br, in which the position be-
tween the azolylmethyl substituents (the pyridyl nitro-
gen) is devoid of any substituent. In 20‚2Br, we now find
that both phenylene rings lie over C(n2) (n ) 2 and 4)
with the imidazolium C(n2)H atoms pointing into the
cavity between the arene rings. The arene rings have
quite different pitches to the median plane of the cation,
with that of the o-phenylene ring being closely parallel,
as in the above bis(o-phenylene) examples, and that of
the m-pyridyl being steeply pitched (Figure 7e). The cell
packing here is similar to that of 13‚2Br, the macrocycles
lying side by side, inclusive of inverses, and aromatic
planes confronting, with anion and solvent molecules
between them. A variation on this form is the cation of
19‚2Br, where the pyridine is replaced by a mesitylene
unit so that a bulky methyl substituent (methyl 321) now
supplants the pyridine nitrogen (Figure 7b). The dihedral
angle between the pair of imidazolium rings is now
greatly enlarged, possibly to accommodate the steric
requirements of methyl 321, which can only lie here
[rather than over H(22,42)], and it may be in response
to this change in dihedral angle that φ1 for the o-
phenylene moiety is now obtuse once more. The crystal
packing for 19‚2Br appears to be primarily dictated by
bromide-water hydrogen bonding: Br(1)‚‚‚H(016),O(01)
) 2.61(2), 3.496(2) Å; Br(2)‚‚‚H(02a),O(02) (1 - x, 2 - y,
1 - z) ) 2.49(3), 3.314(2) Å; and H(02)‚‚‚H(01a),O(01) (1
Con clu sion
We have reported the synthesis of a variety of azolium-
linked cyclophanes and used NMR and X-ray diffraction
methods to characterize their conformational behavior.
Most of the cyclophanes are conformationally labile in
solution at room temperature, but at lower temperatures,
the exchange processes could be slowed sufficiently to
enable particular conformations to be characterized for
many of the cyclophanes. In these studies, the effects of
1
magnetically anisotropic aromatic rings on the H NMR
chemical shifts of various protons in the cyclophane
structures were useful indicators of the conformation of
the cyclophane skeleton. In all o- and m-cyclophanes
characterized, the azolium groups were mutually syn,
whereas the benzenoid rings were mutually syn in some
cases and mutually trans in others; in some cases (e.g.,
the o-cyclophane 13) both conformations coexist. Analysis
of variable-temperature 1H NMR spectra recorded for
solutions of o-cyclophane 13 enabled the estimation of
rate constants for two different processes involved in the
interconversion of the different conformations, namely,
(a) rotation of the imidazolium rings and (b) ring flip of
the benzenoid rings. Invariably, the dominant conforma-
tion detected in solution by NMR studies was also the
conformation shown by X-ray studies to exist in the solid
state. The cyclophanes also exhibited interesting H/D
exchange phenomena in D2O solutions, most notably a
surprisingly facile exchange of benzylic/methyl protons
in the case of 1,3,5-cyclophane cation 3.
1
1
- x, y - /2, /2 - z) ) 2.08(3), 2.811(2) Å.
In 11‚2Br, we now find a bis(m-phenylene)-bridged-
type system, albeit, with both arenes being 2,6-pyridyl
units. Despite the underlying symmetry of the array,
expressed in the asymmetric unit being made up two
half-formula units, each cation being bisected by a
vertical mirror plane, the result is quite unsymmetrical.
The two molecules of the asymmetric unit are of the same
basic type, but there are profound degrees of differences
among the various parameters. The central five-mem-
bered rings are now triazoles (rather than imidazoles)
with a consequent lack of central hydrogen atoms and,
peripherally, a different profile as a consequence of the
fused aromatic rings, with projecting hydrogen atoms at
their 4 and 7 positions, which may inhibit folding back
of the six-membered bridging rings, inhibiting acute φ.
The increased content of the azolium planes is reflected
J . Org. Chem, Vol. 69, No. 22, 2004 7651

Baker et al.
(164 mg, 71%). (See the Supporting Information for full
characterization.)
Many of the azolium-linked cyclophanes examined in
this work, in particular the o-cyclophanes, are precursors
of structurally interesting transition-metal complexes of
N-heterocyclic carbenes in which the carbene units are
part of a cyclophane skeleton. The conformations of the
cyclophane skeletons in the carbene complexes5,7 fre-
quently resemble those seen for the parent azolium-
linked cyclophanes in this work. Studies of the synthesis,
structure, and reactivity of azolium-linked cyclophanes
and cyclophane-carbene complexes are ongoing in our
laboratory, and we will report further results in due
course.
Ack n ow led gm en t. We thank the Australian Re-
search Council for a Discovery Grant (to M.V.B. and
A.H.W.) and an Australian Postgraduate Award (to
C.C.W.), and The University of Western Australia for a
University Postgraduate Award (to V.J .H.). We also
thank Dr. Anthony Reeder for mass spectroscopy stud-
ies, and Professors Dieter Wege (University of Western
Australia) and Max Crossley (University of Sydney) for
valuable discussions concerning H/D exchange reac-
tions.
Exp er im en ta l Section
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
tails for the synthesis of bis(bromomethyl)arenes, bis(azol-1-
ylmethyl)arenes, and azolium-linked cyclophanes, and spec-
troscopic characterization, structure determinations (see also
CCDC:239647-239655), determination of rate constants for
exchange processes involving 13, and selected 1H NMR spectra.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Cyclophane salts were synthesized by reaction of poly(azol-
1-ylmethyl)arenes and poly(bromomethyl)arenes in acetone or
acetonitrile. A typical example is given below.
19‚2Br. R,R′-Dibromo-o-xylene (113 mg, 0.428 mmol) in
acetone (100 mL) was added to a stirred solution of 2,4-bis-
(imidazol-1-ylmethyl)mesitylene (120 mg, 0.428 mmol) in
acetone (100 mL). The mixture was stirred for 3 days, and the
precipitate was collected and recrystallized from methanol. The
cyclophane salt (19‚2Br) was obtained as a colorless powder
J O049097O
7652 J . Org. Chem., Vol. 69, No. 22, 2004