Bidirectional Association of Branched Noncovalent Complexes of Tetrazoles and 1,3,5-Tris(4,5-dihydroimidazol-2-yl)benzene in Solution

Article abstract of DOI:10.1021/jo990830z

Noncovalent 3:1 complexes were obtained by combining acidic tetrazoles with the tribasic 1,3,5-tris(4,5-dihydroimidazol-2-yl)benzene (1). A branched structure and the use of solubilizing groups ensured that the resulting complexes dissolved in a range of nonpolar organic solvents. An X-ray crystal structure analysis of a model complex with tetrazole showed a completely planar, C₃-symmetrical, hydrogen-bonded molecule that salt-packed along the crystallographic c axis with an interplanar spacing of 3.31 A. Model binding studies between a tetrazolate and a protonated 1,3-bis(4,5-dihydroimidazol-2-yl)benzene allowed an association constant of 2470 ± 400 M^-1 to be measured in the competitive solvent mixture CDCl₃/CD₃OD (97:3). The ionic nature and the extended planarity of the tetrazole complexes' core favored the formation of supramolecular stacks not only in the solid, but also in (nonpolar) solution. Self-association was evidenced by NMR and CD spectroscopy as well as by vapor-pressure osmometry.

Full text of DOI:10.1021/jo990830z

J . Org. Chem. 1999, 64, 6425-6433
6425
Bid ir ection a l Associa tion of Br a n ch ed Non cova len t Com p lexes of
Tetr a zoles a n d 1,3,5-Tr is(4,5-d ih yd r oim id a zol-2-yl)ben zen e in
Solu tion
Arno Kraft,*,† Frank Osterod,† and Roland Fro¨hlich‡
Institut fu¨r Organische Chemie und Makromolekulare Chemie II, Heinrich-Heine-Universita¨t Du¨sseldorf,
Universita¨tsstrasse 1, D-40225 Du¨sseldorf, Germany, and Organisch-Chemisches Institut der Universita¨t,
Westfa¨lische Wilhelms-Universita¨t Mu¨nster, Corrensstrasse 40, D-48149 Mu¨nster, Germany
Received May 20, 1999
Noncovalent 3:1 complexes were obtained by combining acidic tetrazoles with the tribasic 1,3,5-
tris(4,5-dihydroimidazol-2-yl)benzene (1). A branched structure and the use of solubilizing groups
ensured that the resulting complexes dissolved in a range of nonpolar organic solvents. An X-ray
crystal structure analysis of a model complex with tetrazole showed a completely planar,
C3-symmetrical, hydrogen-bonded molecule that salt-packed along the crystallographic c axis with
an interplanar spacing of 3.31 Å. Model binding studies between a tetrazolate and a protonated
1,3-bis(4,5-dihydroimidazol-2-yl)benzene allowed an association constant of 2470 ( 400 M-1 to be
measured in the competitive solvent mixture CDCl3/CD3OD (97:3). The ionic nature and the extended
planarity of the tetrazole complexes’ core favored the formation of supramolecular stacks not only
in the solid, but also in (nonpolar) solution. Self-association was evidenced by NMR and CD
spectroscopy as well as by vapor-pressure osmometry.
In tr od u ction
a disk-shaped complex by strong hydrogen-bonding,
followed by stacking of the disks) for the supramolecular
organization of small building blocks in solution.
Self-assembly has become of great interest to chemists
stimulated by Nature’s ability to perfectly control the
formation of stable aggregates in solution.1 A number of
recent examples emphasize how even high-molar-mass
supramolecular molecules2 and polymers3 can be obtained
in solution through the noncovalent interactions between
small building blocks. A judicious combination of com-
pounds with suitable functional headgroups that are
capable of molecular recognition thus bypasses many
purification problems that are frequently encountered
during the chemical synthesis of large molecules. We
wondered whether it might be possible to combine two
different association processes (viz., the self-assembly of
Various acidic heterocycles have acted as substitutes
for carboxylic acids in drug design,4 but they have hardly
found use in supramolecular chemistry. In medicinal
chemistry, tetrazoles are the most frequently encountered
bioisosteres5 of carboxylic acids. The two functional
groups have comparable acidity and binding properties,6
with the tetrazole being more resistant against metabolic
degradation. In two recent reports we described the
formation of simple 3:1 complexes between carboxylic
acids and tris(imidazoline) base 1 in nonpolar solvents,
† University of Du¨sseldorf. Present address: Department of Chem-
istry, Heriot-Watt University, Edinburgh EH14 4AS, United Kingdom.
E-mail: a.kraft@hw.ac.uk.
‡ University of Mu¨nster.
(1) For reviews, see: (a) Lawrence, D. S.; J iang, T.; Levett, M. Chem.
Rev. 1995, 95, 2229-2260. (b) Philp, D.; Stoddart, J . F. Angew. Chem.,
Int. Ed. Engl. 1996, 35, 1154-1196.
(2) For recent examples, see: (a) Yang, J .; Marenday, J .-L.; Geib,
S. J .; Hamilton, A. D. Tetrahedron Lett. 1994, 35, 3665-3668. (b)
Whitesides, G. M.; Simanek, E. E.; Mathias, J . P.; Seto, C. T.; Chin,
D. N.; Mammen, M.; Gordon, D. M. Acc. Chem. Res. 1995, 28, 37-44.
(c) Marsh, A.; Silvestri, M.; Lehn, J .-M. Chem. Commun. 1996, 1527-
1528. (d) Zimmerman, S. C.; Zeng, F.; Reichert, D. E. C.; Kolotuchin,
S. V. Science 1996, 271, 1095-1098. (e) Huck, W. T. S.; Hulst, R.;
Timmerman, P.; van Veggel, F. C. J . M.; Reinhoudt, D. N. Angew.
Chem., Int. Ed. Engl. 1997, 36, 1006-1008. (f) Stupp, S. I.; LeBonheur,
V.; Walker, K.; Li, L. S.; Huggins, K. E.; Keser, M.; Amstutz, A. Science
1997, 276, 384-389. (g) Zimmerman, S. C.; Wang, Y.; Bharathi, P.;
Moore, J . S. J . Am. Chem. Soc. 1998, 120, 2172-2173. (h) Kenda, B.;
Diederich, F. Angew. Chem., Int. Ed. Engl. 1998, 37, 3152-3156. (i)
Park, H. S.; Lin, Q.; Hamilton, A. D. J . Am. Chem. Soc. 1999, 121,
8-13.
(3) (a) Sijbesma, R. P.; Beijer, F. H.; Brunsveld, L.; Folmer, B. J .
B.; Hirschberg, J . H. K. K.; Lange, R. F. M.; Lowe, J . K. L.; Meijer, E.
W. Science 1997, 278, 1601-1604. (b) Percec, V.; Ahn, C.-H.; Barboiu,
B. J . Am. Chem. Soc. 1997, 119, 12978-12979. (c) Zimmerman, N.;
Moore, J . S.; Zimmerman, S. C. Chem. Ind. (London) 1998, 604-610.
(d) Yamaguchi, N.; Nagvekar, D. S.; Gibson, H. W. Angew. Chem., Int.
Ed. Engl. 1998, 37, 2361-2364.
such as chloroform or benzene.7 We now found that
replacement of the carboxylic acid by a tetrazole gives
(4) Tetrazole drugs have found practical use as angiotension II
converting enzyme antagonists in the treatment of hypertension:
Wittenberger, S. J . Org. Prep. Proc. Int. 1994, 26, 499-531.
(5) For a definition of the term “bioisostere” see: Patrick, G. L. An
Introduction to Medicinal Chemistry; Oxford University Press: Oxford,
1995; p 328.
(6) 5-Aryltetrazoles have pKa values comparable to those of their
corresponding benzoic acids. The pKa of, for example, benzoic acid is
4.25 and that of 5-phenyltetrazole is 4.32: Abraham, M. H.; Duce, P.
P.; Prior, D. V.; Barratt, D. G.; Morris, J . J .; Taylor, P. J . J . Chem.
Soc., Perkin Trans. 2 1989, 1355-1375. For comparison, protonated
2-phenylimidazoline has a pKa of 9.88 similar to those of alkylamines:
Ferna´ndez, B.; Perillo, I.; Lamdan, S. Ibid. 1973, 1371-1374. The
differences in pKa values are large enough for proton transfer to be
expected in polar solvents. In fact, neutralization takes place in
aqueous solution on combining 1 and 3 equiv of a water-soluble
tetrazole.
10.1021/jo990830z CCC: $18.00 © 1999 American Chemical Society
Published on Web 07/30/1999

6426 J . Org. Chem., Vol. 64, No. 17, 1999
Kraft et al.
Sch em e 1
Sch em e 2
zonitriles (Scheme 1). Nitrile 7 was derived from an acid
chloride precursor that was first converted to an amide
and then dehydrated using a literature procedure.9
Oxadiazole-substituted benzonitriles 10a ,b were obtained
from two previously reported aryl iodide derivatives10
after replacing the iodide by CN using copper(I) cyanide11
in boiling N-methylpyrrolidone (NMP). Tetrazoles were
prepared from the corresponding nitriles by 1,3-cycload-
dition of NH4N312,13 or triethylammonium azide.14 Yields
were satisfactory in most cases; for derivatives with more
than one long alkoxy side chain reaction times had to be
prolonged since the addition of azide to electron-rich
nitriles proceeds more slowly.12
All tetrazole complexes were easily prepared by simply
dissolving a 3:1 mixture of a tetrazole and tris(imidazo-
line) 17,15 in warm ethanol or, alternatively, combinations
of a good solvent with a less volatile nonsolvent, such as
CHCl3/EtOH (12h ,i) or MeOH/MeCN (12a ), prior to
concentration of the solution. All complexes 12 crystal-
lized after a concentrated solution was cooled to room
temperature, and one recrystallization usually provided
analytically pure samples (Scheme 2).
Cr ysta l Str u ctu r e of a Mod el Com p lex. Needles
suitable for X-ray crystallography were obtained after
slow evaporation of a methanolic solution of complex 12a .
The X-ray crystal structure of this model complex shows
a planar, C3-symmetrical molecule (Figure 1a). Each
tetrazole forms three hydrogen bonds, two of which are
between nitrogen atoms N-12 and N-13 of the tetrazole
similar 3:1 salts, but that, in addition, tetrazole com-
plexes further organized to columnar supramolecular
assemblies in the crystal and in solution. A sufficient
degree of branching, increased molar masses (between
1300 and 2500 g mol-1), and a judicious choice of
solubilizing groups largely helped to inhibit crystalliza-
tion.8 Thus, solubility was warranted despite strong self-
association, and a stacking process could be studied in
solution over a wide concentration range without com-
plications by precipitating aggregates.
(9) Saednya, A. Synthesis 1985, 184-185.
(10) Kraft, A. Liebigs Ann./ Recueil 1997, 1463-1471.
(11) Newman, M. S.; Boden, H. J . Org. Chem. 1961, 26, 2525.
(12) For general overviews of tetrazole syntheses, see: (a) Butler,
R. N. In Comprehensive Heterocyclic Chemistry, A Review of the
Literature 1982-1995; Katritzky, A. R., Rees, C. W., Scriven, E. F. V.,
Storr, R. C., Eds.; Pergamon: Exeter, 1996; Vol. 4, pp 621-678. (b)
Meier, H. R.; Heimgartner, H. In Methoden der Organischen Chemie
(Houben-Weyl), Hetarene III/ Teil 4; Schaumann, E., Ed.; Georg Thieme
Verlag: Stuttgart, 1994; Vol. E8d/4, pp 664-795.
Resu lts
Syn th esis. Nitriles 2 and 4 were prepared by alkyla-
tion of commercially available mono- and dihydroxyben-
(7) (a) Kraft, A.; Fro¨hlich, R. Chem. Commun. 1998, 1085-1086.
(b) Kraft, A. J . Chem. Soc., Perkin Trans. 1 1999, 705-714. For a
related report on carboxylic acid complexes with a tris(tetrahydropy-
rimidine) base see: (c) Kraft, A.; Reichert, A. Tetrahedron 1999, 55,
3923-3930.
(13) For applications of tetrazoles as intermediates in the synthesis
of 1,3,4-oxadiazole-based electron-transporting materials, see: (a)
Bettenhausen, J .; Strohriegl, P. Macromol. Rapid Commun. 1996, 17,
623-631. (b) Bettenhausen, J .; Strohriegl, P. Adv. Mater. 1996, 8, 507-
510.
(14) Koguro, K.; Oga, T.; Mitsui, S.; Orita, R. Synthesis 1998, 910-
914.
(15) (a) Kra¨nzlein, G.; Bastian, H. (IG Farben). German Patent D.
R. P. 695473, 1937; Chem. Abstr. 1941, 35, 141b. (b) Kraft, A.; Osterod,
F. J . Chem. Soc., Perkin Trans. 1 1998, 1019-1025.
(8) Such
a
strategy has previously been used for ensuring the
solubility of shape-persistent dendrimers and other large disk-shaped
molecules: (a) Moore, J . S. Acc. Chem. Res. 1997, 30, 402-413. (b)
Palmans, A. R. A.; Vekemans, J . A. J . M.; Fischer, H.; Hikmet, R. A.;
Meijer, E. W. Chem. Eur. J . 1997, 3, 300-307.

Bidirectional Association of Noncovalent Complexes
J . Org. Chem., Vol. 64, No. 17, 1999 6427
below imidazolinium cations (Figure 1b,c). The sliding
distance between a 3:1 complex relative to its nearest
neighbor in an adjacent plane is 6.93 Å. Whether this is
general for tetrazole-1 complexes or due to solvent
inclusion and crystal packing effects has to be verified
by other crystal structures and is currently the subject
of further investigations.
P r op er ties of Tetr a zole Com p lexes. Most tetrazole
complexes 12 were easily obtained in analytical purity;
however, the included solvent (mostly water) was some-
times difficult to remove as the crystal structure of 12a
has already demonstrated. Whereas the solubility of tris-
(imidazoline) 1 is negligible and that of most tetrazoles
is low in nonpolar organic solvents, complexes with
sufficient solubilizing groups and/or a considerable degree
of branching dissolved easily in chloroform. A simple tert-
butyl group (12c) was clearly insufficient in providing
solubility in CHCl3. In contrast, the solubility of com-
plexes 12e-i in CHCl3 was quite high (>200 mg mL-1).
No molecular ions could be detected by mass spectrom-
etry using chemical ionization, fast atom bombardment,
or matrix-assisted laser desorption/ionization. An at-
tempt to determine the molar mass of complex 12g by
gel-permeation chromatography (GPC) in CH2Cl2 at 25
°C failed owing to extreme broadening; elution of both
components of the complex occurred long after the elution
peaks of low-molar-mass standards. This observation
strongly suggested that adhesion to the column material
took place17 since the tetrazole itself was easily analyzed
by GPC.
Support for the formation of 3:1 complexes in nonpolar
solution could, nevertheless, be obtained by J ob’s method
of continuous variation18 and by vapor-pressure osmom-
etry (VPO). When we determined the stoichiometry of the
complex formed by protonated tris(imidazoline) 13 and
the tetrabutylammonium salt 14, the maximum of the
J ob plot was observed at a mole fraction of 0.25 as
expected for a 3:1 complex (Figure 2).19 For additional
confirmation, the number-average molar mass Mn of
several complexes was measured in CHCl3 at 35 °C by
F igu r e 1. (a, top) Crystal structure of 12a . (b, middle)
Molecular arrangement in the unit cell, viewed along the
crystallographic c axis (hydrogen atoms not shown). (c, bottom)
Side view showing stacking interactions in the crystal struc-
ture of 12a (water molecules have been omitted for clarity).
(16) An alternative binding geometry for some or all of the tetrazole
ligands cannot be entirely excluded where the heterocycle’s second and
third nitrogen atoms hydrogen bond to the imidazoline-NH groups.
Although we failed to obtain crystals of a tetrazole complex other than
12a that were suitable for X-ray crystallography, such a binding
arrangement was found in the crystal structures of two related
complexes between a tetrazole and 1,3,5-tris(3,4,5,6-tetrahydropyri-
midin-2-yl)benzene (A. Kraft, R. Fro¨hlich, unpublished results).
(17) A similar observation has been made for polymeric amidine
bases which adhere to phosphated and passivated metal surfaces:
Wulff, G.; Scho¨nfeld, R. Adv. Mater. 1998, 10, 957-959.
(18) (a) J ob, P. Ann. Chim. 1928, 9, 113-203. (b) Blanda, M. T.;
Horner, J . H.; Newcomb, M. J . Org. Chem. 1989, 54, 4626-4636.
(19) The insolubility of tetrakis[3,5-bis(trifluoromethyl)phenyl]bo-
rate 13 in neat chloroform made addition of acetonitrile necessary.
Since self-association of tetrazole complexes was not suppressed under
these conditions, J ob’s analysis had to be conducted at low concentra-
tion (10-3 M). Even with acetonitrile as cosolvent, the HA chemical
shift of a 3:1 complex did not significantly differ from that in neat
chloroform, suggesting that complexation remained largely unaffected.
and the NH groups of the binding imidazolines;16 the
inclusion of four water molecules per molecule of complex
in crystals of 12a accounts for a third hydrogen bond
between the tetrazole’s N-14 and one of the H2O mol-
ecules. Contacts close to the sum of the van der Waals
radii (2.7 Å) are observed between HA, benzene ring‚‚‚
N-12tetrazole and HA‚‚‚N-13tetrazole (2.60 and 2.62 Å).
The planar complex stacks along the crystallographic
c axis with an interplanar distance of 3.31 Å, whereby
the negatively charged tetrazolates salt-pack above and

6428 J . Org. Chem., Vol. 64, No. 17, 1999
Kraft et al.
electric dipole field induced by the tetrazolate-imidazo-
linium ion pairs that both result from complexation.21
A
broad NH singlet at δ ≈ 12-13 in CDCl3 is characteristic
for hydrogen bonding. This signal is, however, too broad
to be followed during NMR titration or dilution experi-
ments, especially at lower concentrations.
Deter m in a tion of Com p lexa tion Con sta n ts. The
1H NMR chemical shifts of tetrazole complexes 12d ,g,h
in CDCl3 remained unchanged upon dilution to 10-5 M,
indicating that dissociation did not occur to any notice-
able extent even at this low concentration. Few cases
allow all three association constants for a 3:1 complex to
be derived from a single measurement, for example, when
the association process is highly cooperative. We there-
fore decided on binding studies between a tetrazolate and
bis(imidazoline)s 15 and 16, since these model com-
pounds only give rise to 1:1 and 2:1 complexes.
F igu r e 2. J ob plot for the protonated tris(imidazoline) 13
binding tetrazolate 14. The mole fraction x of 13 is defined as
[13]/([13] + [14]). The total concentration was maintained at
10-3 M in CDCl3/CD3CN (6:1),19 and the change in the HA
chemical shift ∆δ ) δobsd - δ0 was determined for various
compositions (δ0 is the chemical shift of the HA singlet in 13).
It was found that the HA signals of bis(imidazoline)s
were also sensitive to the extent of complexation. When
protonated bis(imidazoline) 15 was titrated with increas-
ing amounts of tetrazolate 14 in CDCl3/CD3CN (6:1), the
HA signal shifted downfield continuously until 1 equiv
of tetrazolate had been added. Excess 14 caused an
upfield shift of the HA signal. The resulting deviation of
the NMR titration curve from a hyperbolic shape pointed
to the formation of 2:1 complexes. Although the data can
be analyzed in principle, we decided to avoid the com-
plication of 2:1 complex formation by adding a more polar
cosolvent (methanol) in a sufficient amount that 1:1
binding was still taking place, whereas binding of a
second tetrazolate was suppressed. 1H NMR dilution
studies22 were therefore conducted with an equimolar
mixture of 14 and 15 in the more competitive solvent
mixture CDCl3/CD3OD (97:3). Figure 4 shows that bind-
ing could indeed be interpreted by a 1:1 host-guest
complex formation, allowing an association constant Ka
of 2470 ( 400 M-1 to be calculated. A similar NMR
dilution experiment, this time with the easily accessible
and defined 2:1 complex 16, gave a comparable binding
F igu r e 3. 1H NMR spectra (500 MHz, 25 °C) of (a) 13 in
CDCl3/CD3CN (6:1), (b) 12c in CDCl3/CD3CN (6:1), and (c) 12c
in CD3OD.
VPO. At concentrations in the range of 8-67 mM, we
found Mn values of 1650 g mol-1 for 12g and 2350 g mol-1
for 12i (both against polystyrene 2000 as standard) that
correlated well with the respective calculated molar
masses of 1622 and 2259 g mol-1
.
1H NMR Sp ectr a . The HA and NH resonances of
tetrakis[3,5-bis(trifluoromethyl)phenyl]borate salt 13 in
a CDCl3/CD3CN (6:1) solvent mixture19 were observed at
δ ) 8.48 and δ ) 9.1, respectively (Figure 3a). All
1
tetrazole complexes showed comparable H NMR chemi-
cal shifts at δ ≈ 8.6 for the HA signal in typical polar
solvents, such as DMSO-d6, CD3OD (Figure 3c), or D2O.20
In contrast, complexes that dissolved in nonpolar solvents
(in which dissociation became negligible) gave rise to an
HA signal at much lower field (δ ≈ 9.9 in CDCl3) as
illustrated by Figure 3b. Such a large downfield shift of
∆δ ≈ 1.4 for the aromatic HA signal cannot be explained
by simple solvent effects alone. It is attributed to close
tetrazole-N‚‚‚HA contacts and to the presence of an
isotherm and association constant (2100 ( 500 M-1
)
although the observed binding curve started to deviate,
not surprisingly, from a theoretical 1:1 isotherm once the
concentration exceeded 10-2 M.
(21) Gu¨nther, H. NMR-Spektroskopie, 3rd ed.; Thieme: Stuttgart,
1992; pp 92-94.
(22) (a) Wilcox, C. S. In Frontiers in Supramolecular Chemistry and
Photochemistry; Schneider, H.-J ., Du¨rr, H., Eds.; VCH: Weinheim,
1991; pp 123-143. (b) Macomber, R. S. J . Chem. Educ. 1992, 69, 375-
378.
(20) The chemical shift of tetrazole complexes in polar solvents was
almost identical to the chemical shift of salts of protonated 1 containing
noncoordinating anions, such as 1‚3HCl (δH ≈ 8.6 in CD3OD and D2O)
or 13 (δH ) 8.57 in CD3OD), and suggests that tetrazole complexes
dissociate completely in these solvents.

Bidirectional Association of Noncovalent Complexes
J . Org. Chem., Vol. 64, No. 17, 1999 6429
tions were indicative of an additional association process.
Upfield shifts in conjunction with line-broadening are
diagnostic of self-association resulting from the stacking
of aromatic π-systems.23
The formation of species with increased molar mass
was supported by VPO data. The number-average molar
mass of 12h was larger than calculated for a monomeric
complex (1922 g mol-1), and Mn could be estimated to
exceed 6000 g mol-1 (corresponding to an association
degree of g3.3) at concentrations g0.02 M in CHCl3 at
35 °C.
Assuming the isodesmic model of indefinite self-as-
sociation,23 an association constant Kstacking of 250 ( 20
M-1 in neat CDCl3 at 25 °C was calculated from the
concentration dependence of the chemical shift of the HA
signal.24 All NMR signals remained distinct, in ac-
cordance with a limited but ordered stacking process.
Stack formation and dissociation occurred fast on the
NMR time scale since only a single set of signals was
detected.25
F igu r e 4. Changes of the chemical shift of the HA signal upon
dilution of a solution containing equimolar amounts of 14 and
15 in CDCl3/CD3OD (97:3) at 25 °C. The curve represents the
calculated isotherm for 1:1 binding.
Self-association of complex 12g was much less pro-
nounced. Whereas Kstacking was almost negligible in CDCl3
(8 ( 1 M-1 at 25 °C), solvophobic interactions between
molecules in the less polar solvent C6D6 raised Kstacking
to 1860 ( 420 M-1. Solutions of the complex in cyclohex-
1
ane-d12 displayed extremely broad H NMR signals that
made it impossible to derive an association constant by
NMR measurements (Figure 6). In this context, it is
interesting to note that, when association was further
increased by lowering the temperature, 1 wt % solutions
of 12g in hexane formed thermally reversible gels at
about -20 °C.
The extensive self-association of tetrazole complexes
with long alkoxy side chains in hydrocarbon solvents
suggested the possibility that the structure of a self-
associating chiral complex (12e,f) may be further char-
acterized by circular dichroism (CD). Despite the pres-
ence of six stereogenic centers in the (S)-configurated
citronellyloxy substituents, chiral complex 12e showed
no CD effect in chloroform. In contrast, a positive Cotton
effect was observed for an equally concentrated solution
in cyclohexane (Figure 7). The enantiomeric complex 12f
showed an identical effect with opposite sign. E. W.
Meijer and co-workers recently observed helical columnar
aggregates of chiral C3-symmetrical molecules in hydro-
carbons.26 They found pronounced CD effects even for
mixtures containing a small amount of chiral (“ser-
geants”) and an excess of achiral (“soldiers”) compound
which can be interpreted by the “sergeant-and-soldiers”
principle.27 No CD effect could be detected even after
F igu r e 5. 1H NMR spectra (500 MHz, CDCl3, 25 °C) of 12h
at various concentrations: (a) 10-4 M, (b) 10-3 M, (c) 10-2 M,
and (d) 10-1 M.
(24) The mean number of monomers per stack (i.e., the association
degree) as calculated from Kstacking was furthermore consistent with
the increase in molar mass measured by VPO.
Sta ck in g. Despite the fact that complexation was
(25) Although the dynamics of association were too fast to be
resolved on the NMR time scale, another dynamic process could be
identified if the 1H NMR spectra of a self-associating complex were
run at the same concentration and temperature but at different NMR
frequencies. Changes in line shape of the signals of the outermost
substituents (viz., the OCH2 triplet of 12g or the AA′XX′ signals of
the para-disubstituted phenylenes of 12h ) became then apparent at
higher concentration (that is, when stack formation started to play a
role), and were attributed to hindered rotation around the aryl-
tetrazole C-C single bond. For a previous discussion of the rotational
barrier around the C(aryl)-C(tetrazolate) bond, see: Alkorta, I.; Rozas,
I.; Elguero, J . J . Chem. Soc., Perkin Trans. 2 1998, 2671-2675.
(26) Palmans, A. R. A.; Vekemans, J . A. J . M.; Havinga, E. E.;
Meijer, E. W. Angew. Chem., Int. Ed. Engl. 1997, 36, 2648-2651.
(27) Green, M. M.; Reidy, M. P. J . Am. Chem. Soc. 1989, 111, 6452-
6454.
1
strong in chloroform, the H NMR spectra of all chloro-
form-soluble tetrazole complexes, especially those of 12h ,
changed considerably with increasing concentration in
CDCl3 (Figure 5). In a concentration range from 10-4 to
10-1 M, aromatic signals as well as the imidazoline-CH2
singlet broadened and shifted upfield (∆δ between 0.24
and 0.95), the more so, the nearer the respective proton
was to the core of the complex. Since complexation was
complete at concentrations above 10-5 M, these observa-
(23) For a general review, see: Martin, R. B. Chem. Rev. 1996, 96,
3043-3064.

6430 J . Org. Chem., Vol. 64, No. 17, 1999
Kraft et al.
Discu ssion
Like carboxylic acids, tetrazoles with their comparable
acidity are equally capable of forming 3:1 complexes with
tris(imidazoline) 1. The crystal structure of tetrazole
complex 12a revealed a completely planar and C3-
symmetrical arrangement that was in stark contrast to
the structure of a recently published complex between 1
and trifluoroacetic acid in which each carboxylate bound
differently and twisted out of the plane containing the
central benzene ring.7 Unlike a carboxylate, the smaller
tetrazolate fits quite easily into the gap between two
meta-positioned imidazolines. The influence on the as-
sociation constant Ka was, however, marginal. In the
competitive solvent mixture CDCl3/CD3OD (97:3), 5-(p-
tert-butylphenyl)tetrazolate (Ka ) 2470 ( 400 M-1, ∆G°
) 19.4 kJ mol-1) was found to bind only slightly better
to our model bis(imidazoline) 15 than benzoate7 (Ka )
990 ( 230 M-1, ∆G° ) 17.1 kJ mol-1).
The major consequence of the planarity of the complex
is a tendency of the molecules to stack not only in the
crystal (Figure 1), but also in solution. As we report in
this paper, various tetrazole complexes (12d -h ) self-
associate in chloroform and other nonpolar solvents,
always provided that solubilizing groups and a certain
degree of branching counteract the formation of insoluble
aggregates.
F igu r e 6. 1H NMR spectra (500 MHz, 25 °C, 1 mg/mL) of
Recently, J . S. Moore and co-workers found that shape-
persistent dendrimers29 and macrocycles8a have a similar
inclination toward π-stacking. At about the same time,
E. W. Meijer and co-workers reported strong self-associa-
tion for large disk-shaped molecules.8b,30 Both groups
suggested that a planarized core strongly promotes
stacking in solution. We are now able to show that such
a disk-shaped structure can be assembled through a
simple association process prior to stack formation.
Self-association of complexes 12d -h in various sol-
vents was evident from NMR, VPO, and CD measure-
ments. Since aryl-substituted tetrazoles31 and 1,3,4-
oxadiazoles32 are flat π-systems, we attribute the consider-
able 1H NMR upfield shifts and the more than 3-fold
increase in number-average molar mass Mn for 12h to
the stacking of the complex’s extended planar core.
Increased line widths of NMR signals were in accord with
the expected slowing of the rates of motion and a
shortening of the T2 relaxation times once the molecules
12g (a) in CDCl3, (b) in C6D6, and (c) in cyclohexane-d12
.
F igu r e 7. CD spectra of a 0.85 mM solution of 12e in
chloroform and 12e, its enantiomer 12f, and 18 in cyclohexane
at 25 °C. All CD spectra are the average of four measurements
(path length 0.1 mm).
(28) After being heated from room temperature to above the melting
point, complex 12g exhibited a very fine texture. Slow (between 0.2
and 0.5 °C/min) cooling from the isotropic liquid phase resulted in the
growth of homeotropic digitized stars. Such a dendritic growth was
followed by the development of birefringent pseudofocal conic or fanlike
textures. Although this is characteristic for the formation of a columnar
liquid-crystalline mesophase, the required low cooling rates caused
rapid decomposition and discoloration that led to the disappearance
of the developing texture owing to a continuous drop in the clearing
temperature (Kraft, A.; Osterod, F.; Peters, L.; Reichert, A. Polym.
Mater. Sci. Eng. 1999, 80, 18-19). Investigations toward the improve-
ment of thermal stability and X-ray diffraction studies of potentially
liquid-crystalline carboxylic acid and tetrazole complexes with 1 are
underway.
addition of a substantial amount (30%) of chiral 12e to
achiral 12g. This obviously resulted from extensive
scrambling of chiral ligands and a loss of chiral informa-
tion that is not possible in Meijer’s example but can occur
in hydrogen-bonded assemblies.
Th er m a l P r op er ties. According to differential scan-
ning calorimetry (DSC) measurements and polarization
optical microscope studies, various aryl-substituted tet-
razole complexes underwent a melting transition to a
liquid-crystalline mesophase. Depending on substitution,
melting temperatures ranged between 140 °C (12d ,g) and
230 °C (12h ). Chiral complexes 12e,f were found to be
waxy at room temperature and became birefringent once
sheared. Unfortunately, all tetrazole complexes were
thermally unstable and started to rapidly decompose at
their isotropization temperatures, especially when samples
were heated above 200 °C for longer than a few minutes.
This thermal instability hampered our attempts to obtain
recognizable textures by annealing.28
(29) Pesak, D. J .; Moore, J . S. Angew. Chem., Int. Ed. Engl. 1997,
36, 1636-1639.
(30) Similarly, a polystyrene-oligothiophene-polystyrene triblock
copolymer also shows aggregation in solution owing to an extended
planar π-system: Hempenius, M. A.; Langeveld-Voss, B. M. W.; van
Haare, J . A. E. H.; J anssen, R. A. J .; Sheiko, S. S.; Spatz, J . P.; Mo¨ller,
M.; Meijer, E. W. J . Am. Chem. Soc. 1998, 120, 2798-2804.
(31) This is illustrated by a crystal structure of 5-(4-hydroxyphenyl)-
tetrazole: Gallardo, H.; Begnini, I. M.; Vencato, I. Acta Crystallogr.
1997, C53, 143-144.
(32) C.f. Tokuhisa, H.; Era, M.; Tsutsui, T. Adv. Mater. 1998, 10,
404-407.

Bidirectional Association of Noncovalent Complexes
J . Org. Chem., Vol. 64, No. 17, 1999 6431
Sch em e 3
associate. Solubility of 12h was still high in CHCl3, up
to 300 mg/mL, despite a high Kstacking value of 250 ( 20
M-1. The lower tendency of complex 12g toward self-
association may be readily explained by a reduced surface
area of the aromatic π-system since 12g has twelve
(hetero)aromatic rings less than 12h . In the case of
complex 12i, the additional bulky tert-butyl groups
impeded self-association almost completely.
The attractive forces that can give rise to stack
formation are salt-packing effects and π-π interactions
between the (hetero)aromatic rings. The former are
clearly observed in the packing of 12a in the crystal
lattice. Considering that a first-generation dendrimer of
similar structure and size was found to have a relatively
low Kstacking value of 2 M-1 in chloroform if π-π interac-
tions alone were responsible for the stacking process,10
electrostatic interactions may therefore present the
dominating contribution toward the self-association of
1
12h . The upfield shifts that are observed in the H NMR
spectra may then be attributed to the increasing com-
pensation of positive charges by stacking with negative
charges at higher concentrations. Such an additional
dipolar field could still be supported by π-π overlap
between aromatic and heteroaromatic rings.33
they decomposed rapidly on melting to an isotropic liquid.
Differential scanning calorimetry measurements and
polarization optical microscope studies indicated that
several complexes, especially those with long alkoxy side
chains (12d -g), possessed a liquid-crystalline (possibly
columnar) mesophase that will be the subject of further
investigations in due course.34
Much higher concentrations were necessary before
alkoxyphenyl-substituted complexes 12d -g showed no-
ticeable signs of self-association in CHCl3. On the other
hand, these complexes dissolved easily in nonpolar
solvents. Extensive self-association was evident from very
1
broad H NMR signals in cyclohexane (Figure 6). In this
solvent, chiral complex 12e with its six stereogenic
centers displayed a small, but significant, circular dichro-
ism. The same effect, but with opposite sign, was found
for the enantiomeric complex 12f. The absence of a Cotton
effect for a solution of 12e in CHCl3 at the same
concentration correlated, in fact, with our NMR investi-
gations according to which no significant self-association
took place at the concentration used for measuring the
Con clu sion
In summary, this study demonstrates how binding
interactions between tetrazoles and tris(imidazoline) 1
result in complexes 12 and how self-assembly was
followed by self-association. The tetrazole-1 complexes
were found to stack both in the crystal and in solution.
Ordered macromolecules are thus accessible through a
combination of two association processes that occur
within and orthogonal to the plane of the complex’s core
without interference between both noncovalent interac-
tions (hydrogen bonding and salt-packing). We trust that
these findings open up an avenue toward other ordered
columnar structures (e.g., supramolecular liquid crys-
tals). It should further allow us to even mimic the self-
assembly principle used by Nature for numereous non-
covalently linked superstructures, such as the tobacco
mosaic virus in which the self-assembly of a small protein
generates the protein coat for the virus’s RNA.35
1
CD spectrum. For comparison, the H NMR signals of a
chiral carboxylic acid complex 18 (Scheme 3) were still
resolved in cyclohexane, and it was not possible to detect
a CD effect under the same conditions used for tetrazoles
12e,f (Figure 7). Obviously, the nonplanar conformation
of carboxylic acid complexes seriously restricted the
extent of self-association.
As with most tetrazoles and especially their anions,12
the tetrazole complexes had limited thermal stability and
(33) It should be taken into account that π-π interactions between
electron-deficient aromatic systems (such as with the 1,3,4-oxadiazole-
containing ligand 11a ) are very favorable and may equally promote
stacking interactions: (a) Hunter, C. A.; Sanders, J . K. M. J . Am.
Chem. Soc. 1990, 112, 5525-5534. (b) Zhang, J .; Moore, J . S. Ibid.
1992, 114, 9701-9702. (c) Cozzi, F.; Cinquini, M.; Annuziata, R.; Siegel,
J . S. Ibid. 1993, 115, 5330-5331. (d) Hunter, C. A. Angew. Chem.,
Int. Ed. Engl. 1993, 32, 1584-1586. (e) Shetty, A. S.; Zhang, J .; Moore,
J . S. J . Am. Chem. Soc. 1996, 118, 1019-1027. (f) Tobe, Y.; Utsumi,
N.; Kawabata, K.; Naemura, K. Tetrahedron Lett. 1996, 37, 9325-
9328.
(34) Stacking interactions are also well-known for columnar liquid-
crystalline mesophases of suitably substituted condensed aromatic
compounds. For recent examples, see: (a) Reference 8b. (b) van de
Craats, A. M.; Warmann, J . M.; Mu¨llen, K.; Geerts, Y.; Brand, J . D.
Adv. Mater. 1998, 10, 36-38. Columnar liquid-crystalline mesophases
were already reported for a number of self-assembled compounds: (c)
Mariani, P.; Mazabard, C.; Garbesi, A.; Spada, G. P. J . Am. Chem.
Soc. 1989, 111, 6369-6373. (d) Kleppinger, R.; Lillya, C. P.; Yang, C.
J . Am. Chem. Soc. 1997, 119, 4097-4102. (e) Beginn, U.; Zipp, G.;
Mo¨ller, M.; J ohansson, G.; Percec, V. Macromol. Chem. Phys. 1997,
198, 2839-2852. (f) Sua´rez, M.; Lehn, J .-M.; Zimmerman, S. C.;
Skoulios, A.; Heinrich, B. J . Am. Chem. Soc. 1998, 120, 9526-9532
and references therein.
Exp er im en ta l Section
Gen er a l Meth od s. All solvents were distilled prior to use.
DSC: heating rate 10 °C/min. Cr ) crystalline phase, M )
liquid-crystalline mesophase, and I ) isotropic liquid. VPO
measurements were performed in CHCl3 at 35 °C against
benzil or polystyrene standards (Fluka, Switzerland) as refer-
ence. The number-average molar mass Mn was determined for
solutions in a concentration range between about 8 and 60 mg
of complex/g of CHCl3.
5-(4-Dod ecyloxyp h en yl)tetr a zole (3). 4-Dodecyloxyben-
zonitrile36 (10.0 g, 34.8 mmol), NaN3 (2.49 g, 38.3 mmol), NH4-
Cl (2.12 g, 39.7 mmol), and dimethylformamide (200 mL) were
stirred at 110 °C for 20 h. The suspension was then poured
into water (350 mL)/concentrated HCl (5 mL). The crude
(35) Klug, A. Angew. Chem., Int. Ed. Engl. 1983, 22, 565-582.
(36) Schubert, H.; Zaschke, H. J . Prakt. Chem. 1970, 312, 494-506.

6432 J . Org. Chem., Vol. 64, No. 17, 1999
Kraft et al.
product was collected by suction filtration and recrystallized
from aqueous acetone. Yield: 5.68 g (49%). Colorless solid. Mp
152-155 °C. 1H NMR (500 MHz, CDCl3/DMSO-d6, 1:1): δ 0.87
(t, J ) 6.9 Hz, 3 H), 1.20-1.38 (m, 16 H), 1.45 (tt, J ) 7.7, 6.5
Hz, 2 H), 1.78 (tt, J ) 8.2, 7.0 Hz, 2 H), 4.03 (t, J ) 6.5 Hz, 2
H), 7.05 and 7.98 (AA′XX′, 4 H). 13C NMR (125 MHz, CDCl3/
DMSO-d6, 1:1): δ 14.0, 22.3, 25.6, 28.8, 28.90, 28.95, 29.16,
29.19, 29.22, 31.5, 67.8, 115.0, 116.3, 128.5, 161.0. MS (CI,
NH3): m/z 365 (M + NH3 + NH4+, 19%), 348 (M + NH4+, 100),
331 (M + H+, 76). Anal. Calcd for C19H30N4O: C, 69.05; H,
9.15; N, 16.95. Found: C, 69.11; H, 9.07; N, 16.89. Rf (CH2-
Cl2/MeOH, 9:1) 0.27.
mL, 22 mmol) in CH2Cl2 (20 mL) was added dropwise to an
ice-cold solution of 3,4,5-tris(hexyloxy)benzamide (8.44 g, 20.0
mmol) and triethylamine (5.5 mL, 40 mmol) in CH2Cl2 (20 mL).
The light yellow mixture was stirred for 30 min, then diluted
with CH2Cl2 (20 mL), washed with 0.5 M aqueous NaOH (20
mL), 0.1 M aqueous HCl (2 × 25 mL), and water (3 × 20 mL),
and dried over Na2SO4. The solvent was removed in a vacuum,
and the crude product was purified by distillation (Kugelrohr,
1
230 °C/0.02 mbar) to furnish 5.60 g (69%) of a yellow oil. H
NMR (300 MHz, CDCl3): δ 0.87-0.95 (m, 9 H), 1.27-1.54 (m,
18 H), 1.68-1.86 (m, 6 H), 3.96 (t, J ) 6.4 Hz, 4 H), 4.06 (t, J
) 6.6 Hz, 2 H), 6.82 (s, 2 H). 13C NMR (75 MHz, CDCl3): δ
13.99, 14.05, 105.5 (CH, CH3), 22.57, 22.65, 25.65, 25.69, 29.2,
30.2, 31.5, 31.7, 69.2, 73.9 (CH2), 118.5, 140.2, 153.7, 156.6
(ipso-C, CdN). IR (KBr, cm-1): δ 2226. MS (CI, NH3): m/z
421 (M + NH4+, 100%). Anal. Calcd for C25H41NO3: C, 74.40;
H, 10.24; N, 3.47. Found: C, 74.01; H, 10.57; N, 3.97. Rf (CH2-
Cl2/MeOH, 9:1) 0.95.
5-[3,4,5-Tr is(h exyloxy)p h en yl]tetr a zole (8). A solution
of 7 (3.61 g, 8.95 mmol), NaN3 (1.16 g, 17.9 mmol), and NH4Cl
(1.05 g, 19.7 mmol) in NMP (20 mL) was stirred at 110 °C for
8 h. The yellow-brown solution was added dropwise to water
(150 mL)/concentrated HCl (2 mL) under vigorous stirring. The
resulting yellow precipitate was collected by suction filtration,
dried, and purified by column chromatography (CH2Cl2/MeOH,
10:1) to give 1.38 g (35%) of a colorless solid. Mp 92 °C. 1H
NMR (300 MHz, CDCl3): δ 0.80-0.95 (m, 9 H), 1.20-1.50 (m,
18 H), 1.65-1.82 (m, 6 H), 3.92 (t, J ) 6.3 Hz, 2 H), 4.04 (t, J
) 6.6 Hz, 4 H), 7.31 (s, 2 H). 13C NMR (75 MHz, CDCl3): δ
13.99, 14.05, 105.5 (CH, CH3), 22.57, 22.65, 25.65, 25.69, 29.2,
30.2, 31.5, 31.7, 69.2, 73.9 (CH2), 118.5, 140.2, 153.7, 156.6
(ipso-C, CdN). MS (CI, NH3): m/z 464 (M + NH4+, 100%), 447
(M + H+, 37). Anal. Calcd for C25H42N4O3: C, 67.23; H, 9.48;
N, 12.54. Found: C, 67.38; H, 9.63; N, 12.80. Rf (CH2Cl2/MeOH,
9:1) 0.33.
3,4-Bis[3,7-(S)-dim eth yl-6-octen yloxy]ben zon itr ile (4a).
(S)-Citronellyl bromide (4.38 g, 20.0 mmol), 3,4-dihydroxyben-
zonitrile (1.35 g, 10.0 mmol), K2CO3 (2.76 g, 20.0 mmol), and
a pinch of KI in dry acetone (80 mL) were heated to reflux for
40 h. After filtration of the still hot suspension, the solution
was concentrated, combined with CH2Cl2 (100 mL), filtered,
and concentrated. The crude product was purified by distilla-
tion (Kugelrohr, 230 °C/0.02 mbar) and column chromatogra-
phy (hexane/ethyl acetate, 20:1). Yield: 1.88 g (46%). Colorless
oil. [R]25 -5° (c 3.5 × 10-3 M, CHCl3). 1H NMR (500 MHz,
D
CDCl3): δ 0.97 (br d, 6 H), 1.20-1.28 (m, 2 H), 1.37-1.44 (m,
2 H), 1.60 (br s, 6 H), 1.68 (br s, 6 H), 1.61-1.74 (m, 4 H),
1.85-2.07 (m, 6 H), 4.00-4.10 (m, 4 H), 5.07-5.13 (m, 2 H),
6.87 (d, J ) 8.8 Hz, 1 H), 7.07 (d, J ) 1.9 Hz), 7.22 (dd, J )
8.8, 1.9 Hz, 1 H). 13C NMR (125 MHz, CDCl3): δ 17.7, 19.6,
25.7, 29.7, 112.7, 116.0, 124.57, 124.62, 126.3 (CH, CH3), 25.5,
35.8, 35.9, 37.14, 37.16, 67.5, 67.8 (CH2), 103.6, 119.4, 131.3,
131.4, 149.1, 153.1 (ipso-C, CN). MS (CI, NH3): m/z 429 (M +
NH4+, 100%). IR (KBr, cm-1): v 2224. Anal. Calcd for C27H41
-
NO2: C, 78.78; H, 10.04; N, 3.40. Found: C, 78.60; H, 10.35;
N, 3.44. Rf (CH2Cl2/MeOH, 9:1) 0.92.
5-[3,4-Bis(3,7-(S)-d im eth yl-6-octen yloxy)p h en yl]tetr a -
zole (5a ). A mixture of 4a (1.25 g, 3.03 mmol), NaN3 (260 mg,
4.00 mmol), and triethylammonium chloride (551 mg, 4.00
mmol) in toluene (10 mL) was stirred at 100 °C for 40 h. The
suspension was then added to water (130 mL)/concentrated
HCl (20 mL). The toluene layer was separated, and the
aqueous phase was further extracted with toluene. The
combined organic extracts were concentrated, and the crude
product was further purified by column chromatography (first
CH2Cl2 and then CH2Cl2/MeOH, 9:1). Yield: 1.01 g (74%).
Gen er a l P r oced u r e for th e P r ep a r a tion of th e Com -
p lexes. Imidazoline base 115b and tetrazole (3 equiv) were
dissolved in hot ethanol (ca. 40 mL/mmol), to which, if
necessary (as in the case of 12h ,i), a certain amount of CHCl3
(5-10 mL) was added as cosolvent. After filtration of the hot
solution and concentration, the crude product was crystallized
from the solvent (mixture) indicated for each complex and
thoroughly dried at 50-100 °C/10-5 mbar.
Colorless solid. Mp 90-93 °C. [R]25 -8° (c 2.2 × 10-3 M,
Com plex 12a. Yield: 73% (MeCN/MeOH). Colorless needles.
Mp 257-259 °C dec. 1H NMR (500 MHz, DMSO-d6): δ 3.82
(s, 12 H), 8.54 (s, 3 H), 8.87 (s, 3 H). Anal. Calcd for
D
1
CHCl3). H NMR (500 MHz, CDCl3): δ 0.93 (d, J ) 6.3 Hz, 3
H), 0.95 (d, J ) 6.3 Hz, 3 H), 1.16-1.26 (m, 2 H), 1.33-1.42
(m, 2 H), 1.58 (s, 3 H), 1.59 (s, 3 H), 1.66 (s, 3 H), 1.67 (s, 3 H),
1.58-1.72 (m, 4 H), 1.82-2.07 (m, 6 H), 4.01-4.10 (m, 4 H),
5.06-5.12 (m, 2 H), 6.93 (d, J ) 8.2 Hz, 1 H), 7.56-7.82 (m, 2
H). 13C NMR (125 MHz, CDCl3): δ 17.6, 19.49, 19.56, 25.69,
29.7, 112.0, 113.2, 120.7, 124.62, 124.70 (CH, CH3), 25.49,
35.95, 36.02, 37.2, 67.6, 67.8 (CH2), 115.8, 131.17, 131.28,
C
18H24N18‚2H2O: C, 40.91; H, 5.34; N, 47.70. Found: C, 40.89;
H, 5.33; N, 47.97.
Com p lex 12d . Yield: 55% (EtOH). Light yellow solid.
DSC: Cr1 88 (∆H 79 J g-1) Cr2 139 (∆H 6 J g-1) M 193 (∆H 29
1
J g-1) Idec. H NMR (500 MHz, CDCl3, 10-3 M): δ 0.88 (m, 9
H), 1.28-1.45 (m, 48 H), 1.46 (br s, 6 H), 1.79 (br qui, 6 H),
3.99 (br t, J ) 5.6 Hz, 6 H), 4.29 (br s, 12 H), 6.97 and 7.97
(AA′XX′, 12 H), 9.84 (br s, 3 H). 13C NMR (125 MHz, CDCl3/
CD3OD, 5:2): δ 14.2, 115.2, 128.6, 133.0 (CH, CH3), 23.0, 26.3,
29.5, 29.66, 29.73, 29.90, 29.91, 29.93, 29.95, 29.97, 46.6, 68.5
(CH2), 121.0, 126.7, 160.7, 161.2, 164.2 (ipso-C, CdN). Anal.
Calcd for C72H108N18O3‚2H2O: C, 66.02; H, 8.62; N, 19.25.
Found: C, 65.70; H, 8.70; N, 19.20.
149.6, 151.9, 156.6 (ipso-C, CdN). MS (CI, NH3): m/z 472 (M
+
+
C
NH4
,
100%), 455 (M
+
H+, 40). Anal. Calcd for
27H42N4O2: C, 71.33; H, 9.31; N, 12.32. Found: C, 70.21; H,
9.46; N, 13.96. Rf (CH2Cl2/MeOH, 9:1) 0.48.
5-[3,4-Bis(3,7-(R)-d im eth yl-6-octen yloxy)p h en yl]tetr a -
zole (5b). Analogous preparation as for 5a . [R]25 +3° (c 3.5
D
× 10-3 M, CHCl3).
3,4,5-Tr is(h exyloxy)ben zon itr ile (7). A stream of gaseous
NH3 was bubbled through a solution of 68b (14.3 g, 32.4 mmol)
in dry toluene (200 mL) over 3 h. The mixture was then
concentrated in a vacuum, and the brown residue was recrys-
tallized from acetone (500 mL)/water (100 mL) to yield 8.97 g
(66%) of 3,4,5-tris(hexyloxy)benzamide as a colorless solid. Mp
Com p lex 12e. Yield: 50% (EtOH/MeCN). Waxy yellow
solid. Clearing point: 150-162 °C dec. [R]25D -6° (c 7.7 × 10-4
1
M, CHCl3). [R]25 17° (c 7.7 × 10-4 M, cyclohexane). H NMR
D
(500 MHz, CDCl3): δ 0.97 (d, J ) 5.7 Hz, 9 H), 0.98 (d, J )
5.7 Hz, 9 H), 1.18-1.29 (m, 6 H), 1.36-1.46 (m, 6 H), 1.60 (s,
9 H), 1.61 (s, 9 H), 1.67 (s, 9 H), 1.68 (s, 9 H), 1.61-1.75 (m,
12 H), 1.87-2.10 (m, 18 H), 4.05-4.15 (m, 12 H), 4.29 (s, 12
H), 5.11 (m, 6 H), 6.95 (d, J ) 8.2 Hz, 3 H), 7.58 (dd, J ) 8.2,
1.9 Hz, 3 H), 7.65 (d, J ) 1.9 Hz, 3 H), 9.87 (s, 3 H). UV
(cyclohexane): λmax 254 nm (ꢀ 55 200 M-1 cm-1). Anal. Calcd
for C96H144N18O6‚H2O: C, 69.28; H 8.84; N, 15.15. Found: C,
68.84; H, 8.93; N, 15.45.
1
90 °C. H NMR (300 MHz, DMSO-d6): δ 0.82-0.93 (m, 9 H),
1.22-1.50 (m, 18 H), 1.68-1.77 (m, 6 H), 3.86 (t, J ) 6.3 Hz,
2 H), 3.95 (t, J ) 6.6 Hz, 4 H), 7.18 (s, 2 H), 7.30 (s, 1 H), 7.93
(s, 1 H). 13C NMR (75 MHz, DMSO-d6): δ 13.81, 13.83, 105.8
(CH, CH3), 22.09, 22.12, 25.20, 25.24, 28.8, 29.7, 31.0, 31.1,
68.3, 72.3 (CH2), 139.6, 152.1, 167.3 (ipso-C, CdO). IR (KBr,
cm-1): ν 3361, 3189, 1649. MS (CI, NH3): m/z 439 (M + NH4
,
Com p lex 12f. Yield: 33% (MeCN/MeOH). Waxy yellow
+
100%), 422 (M + H+, 98). Anal. Calcd for C25H43NO3: C, 71.22;
H, 10.28; N, 3.32. Found: C, 71.28; H, 10.01; N, 3.53. Rf (CH2-
Cl2/MeOH, 9:1) 0.67. A solution of trichloroacetyl chloride (2.5
solid. [R]25 +6° (c 6.8 × 10-4 M, CHCl3).
D
Com p lex 12g. Yield: 82% (EtOH). Light yellow crystals.
DSC: Cr 73 (∆H 28 J g-1) M1 126 (∆H 1 J g-1) M2 146 (∆H 3

Bidirectional Association of Noncovalent Complexes
J . Org. Chem., Vol. 64, No. 17, 1999 6433
1
J g-1) Idec. H NMR (500 MHz, CDCl3, 10-3 M): δ 0.88-0.93
and dried. Chromatography (CH2Cl2/ether, 7:1) furnished 0.86
(m, 27 H), 1.31-1.36 (m, 36 H), 1.44-1.53 (m, 18 H), 1.74-
1.85 (m, 18 H), 4.00 (t, J ) 6.3 Hz, 6 H), 4.06 (t, J ) 6.3 Hz,
12 H), 4.31 (s, 12 H), 7.30 (s, 6 H), 9.84 (s, 3 H). 13C NMR (75
MHz, CDCl3): δ 14.05, 14.11, 105.4, 133.7 (CH, CH3), 22.6,
22.7, 25.8, 39.4, 30.3, 31.6, 31.8, 45.8, 69.2, 73.5 (CH2), 125.0,
125.3, 138.7, 153.4, 162.9, 163.2 (ipso-C, CdN). VPO (CHCl3,
35 °C): Mn 1650 g mol-1 (against benzil as standard), 1800 g
mol-1 (against polystyrene 2000 as standard). Anal. Calcd for
g (80%) of a colorless oil. [R]25 +6° (c 2.2 × 10-3 M, CHCl3).
D
1H NMR (500 MHz, CDCl3): δ 0.94 (d, J ) 6.3 Hz, 3 H), 0.96
(d, J ) 7.0 Hz, 6 H), 1.15-1.29 (m, 3 H), 1.31-1.47 (m, 3 H),
1.59 (s, 3 H), 1.60 (s, 6 H), 1.67 (s, 3 H), 1.68 (s, 6 H), 1.51-
1.79 (m, 6 H), 1.80-2.09 (m, 9 H), 4.00-4.15 (m, 6 H), 5.05-
5.15 (m, 3 H), 7.33 (s, 2 H). 13C NMR (125 Hz, CDCl3): δ 17.63,
17.66, 19.4, 15.5, 25.7, 29.4, 29.6, 108.5, 124.7, 124.9 (CH, CH3,
1 signal missing), 25.5, 36.2, 37.2, 37.2, 37.3, 67.5, 71.7 (CH2,
1 signal missing), 123.7, 131.1, 131.3, 143.1, 152.9, 171.6 (ipso-
C, CdO). MS (CI, NH3): m/z 602 (M + NH4+, 100%), 585 (M
+ H+, 10). Anal. Calcd for C37H60O5‚2H2O: C, 71.57; H, 10.39.
Found: C, 71.13; H, 10.63. Rf (CH2Cl2/MeOH, 9:1) 0.60.
C
90H144N18O9: C, 66.64; H, 8.95; N, 15.54. Found: C, 66.46;
H, 9.05; N, 15.31. Rf (CH2Cl2/MeOH, 9:1) 0.40 (smearing).
Com p lex 12h . Yield: 69% (EtOH/CHCl3). Colorless solid.
DSC: Cr1 194 (∆H 5 J g-1) Cr2 232 (∆H 4 J g-1) M 250 (∆H 5
1
J g-1) Idec. H NMR (500 MHz, CDCl3, 10-4 M): δ 1.39 (s, 54
Com p lex 18. Yield: 37% (MeCN/MeOH). Waxy white solid.
[R]25 +6° (c 9.7 × 10-4 M, CHCl3).1H NMR (500 MHz,
H), 4.57 (s, 12 H), 7.59 and 8.14 (AA′XX′, 24 H), 8.89 (s, 3 H),
D
1
9.09 (s, 6 H), 9.95 (br s, 3 H), 12.95 (br s, 6 H). H NMR (500
CDCl3): δ 0.94 (d, J ) 6.3 Hz, 9 H), 0.95 (d, J ) 7.0 Hz, 18 H),
1.12-1.28 (m, 9 H), 1.34-1.44 (m, 9 H), 1.59 (s, 27 H), 1.67 (s,
27 H), 1.50-1.77 (m, 18 H), 1.78-2.08 (m, 27 H), 3.98-4.10
(m, 18 H), 4.13 (s, 12 H), 5.10 (br s, 9 H), 7.33 (s, 6 H), 10.17
(s, 3 H).
MHz, DMSO-d6): δ 1.36 (s, 54 H), 3.96 (br s, 12 H), 7.70 and
8.15 (AA′XX′, 24 H), 8.58 (s, 3 H), 8.73 (t after resolution
enhancement, J ) 1.5 Hz, 3 H), 8.93 (d after resolution
enhancement, J ) 1.5 Hz, 6 H). 13C NMR (125 MHz, CDCl3,
10-2 M): δ 31.1, 126.0, 126.9, 124.1, 126.7, 133.5 (CH, CH3),
45.9 (CH2), 35.1, 120.5, 125.1, 125.2, 132.1, 155.6, 160.6, 162.4,
163.1, 165.0 (ipso-C, CdN). VPO (CHCl3, 35 °C): Mn 6050 g
mol-1 (against benzil as standard), 6300 g mol-1 (against
polystyrene 2000 as standard), 6640 g mol-1 (against polysty-
rene 5000 as standard). Anal. Calcd for C108H108N30O6‚2H2O:
C, 66.24; H, 5.76; N, 21.46. Found: C, 66.04; H, 5.74; N, 21.21.
Com p lex 12i. Yield: 90% (EtOH/CHCl3). Colorless solid.
Sin gle-Cr ysta l X-r a y Diffr a ction An a lysis of 12a . Crys-
tal structure data for 12a (single crystals were obtained after
slow evaporation from MeOH through a closed vial): formula
C
18H32N18O4, M ) 564.62, crystal dimensions 0.50 × 0.15 ×
0.10 mm, a ) b ) 14.680(2) Å, c ) 6.623(1) Å, γ ) 120°, V )
1236.1(4) Å3, Fcalcd ) 1.517 g cm-3, F(000) ) 596 e, m ) 9.66
cm-1, empirical absorption correction via æ scan data (0.957
e C e 0.999), Z ) 2, hexagonal, space group P63/m (no. 176),
l ) 1.54178 Å, T ) 223 K, ω/2θ scans, 2816 reflections collected
((h, (k, +l), [(sin θ)/λ] ) 0.62 Å-1, 925 independent and 485
observed reflections [I g 2 σ(I)], 82 refined parameters, R )
0.067, wR2 ) 0.218, maximum residual electron density 0.24
(-0.35) e Å-3, hydrogens (excluding those of the crystal water
molecules) calculated and refined as riding atoms. The data
set was collected with an Enraf Nonius CAD4 diffractometer.
Programs used: data reduction MolEN, structure solution
SHELXS-86, structure refinement SHELXL-93, graphics
SCHAKAL-92 and DIAMOND.
Dec >300 °C. H NMR (500 MHz, CDCl3, 10-2 M): δ 1.42 (s,
1
108 H), 4.59 (s, 12 H), 7.66 (t, J ) 1.5 Hz, 6 H), 8.03 (d, 12 H),
8.90 (t, J ) 1.5 Hz, 3 H), 9.11 (d, 6 H), 9.91 (s, 3 H). VPO
(CHCl3, 35 °C): Mn 2350 g mol-1 (against benzil as standard),
2570 g mol-1 (against polystyrene 2000 as standard). Anal.
Calcd for C132H156N30O6‚2H2O: C, 69.09; H, 7.03; N, 18.31.
Found: C, 68.92; H, 7.23; N, 18.47.
Com p lex 16. From 1,3-bis(4,5-dihydro-1H-imidazol-2-yl)-
benzene7b and 5-(tert-butylphenyl)tetrazole (2 equiv).13b
Yield: 59% (MeCN/MeOH). Colorless crystals. DSC: Cr 156
(∆H 109 J g-1) M 198 (∆H 51 J g-1) I. 1H NMR (500 MHz,
CDCl3/CD3OD, 13:1): δ 1.34 (s, 18), 4.16 (s, 8 H), 7.46 (t, J )
7.9 Hz, 1 H), 7.47 and 7.92 (AA′XX′, 8 H), 8.00 (dd, J ) 7.9,
1.6 Hz, 2 H), 8.66 (br s, 1 H). Anal. Calcd for C34H42N12‚H2O:
C, 64.13; H, 6.96; N, 26.39. Found: C, 63.97; H, 7.01; N, 26.24.
3,4,5-Tr is[3,7-(R)-d im eth yl-6-octen yloxy]ben zoic Acid
(17). Methyl gallate (1.31 g, 7.1 mmol), (R)-citronellyl bromide
(5.00 g, 22.8 mmol), K2CO3 (3.15 g, 22.8 mmol), and a pinch of
KI were stirred in dry acetone (50 mL) at reflux for 60 h. After
filtration of the still hot suspension, the solution was concen-
trated. The crude product was purified by column chromatog-
raphy (hexane/ethyl acetate, 9:1). Yield: 2.39 g (56%). A
solution of the ester (1.10 g, 1.8 mmol) in ethanol (100 mL)
was combined with a solution of KOH (0.40 g, 7.1 mmol) in
water (40 mL) and heated to reflux for 3 h. The solution was
acidified with HCl, concentrated, and extracted with CHCl3
(100 mL). The organic extracts were concentrated in a vacuum
Ack n ow led gm en t. We thank the Deutsche Fors-
chungsgemeinschaft, the Fonds der Chemischen Indus-
trie, and Professor G. Wulff for generous support as well
as Ms. H. Fu¨rtges and Ms. S. J ohann for assistance in
the preparation of starting materials.
Su p p or tin g In for m a tion Ava ila ble: Details of the X-ray
crystal structure determination of 12a , preparation of 10a -
b, 11a -b, and 14, NMR dilution experiment for 16 in CDCl3/
CD3OD (97:3) at 25 °C, 1H NMR spectra and VPO data for
12h , 1H NMR spectra and DSC data of 12g, and 1H NMR
spectra of 18. This material is available free of charge via the
Internet at http://pubs.acs.org.
J O990830Z