Self-assembled helices from 2,2′-Biimidazoles

Article abstract of DOI:10.1002/1521-3765(20010202)7:3<721::AID-CHEM721>3.0.CO;2-1

2,2′-Biimidazoles were synthesized by palladium(0)-catalyzed coupling of 2-iodoimidazoles bearing an alkyl and an ester group at the 4- and 5-positions, respectively. The products were found to be fluorescent and moderately soluble in organic solvents. Th

Full text of DOI:10.1002/1521-3765(20010202)7:3<721::AID-CHEM721>3.0.CO;2-1

FULL PAPER
Self-Assembled Helices from 2,2'-Biimidazoles
William E. Allen,[b] Christopher J. Fowler,[a] Vincent M. Lynch,[a] and
Jonathan L. Sessler*[a]
Abstract: 2,2'-Biimidazoles were syn-
thesized by palladium(0)-catalyzed cou-
pling of 2-iodoimidazoles bearing an
alkyl and an ester group at the 4- and
5-positions, respectively. The products
were found to be fluorescent and mod-
erately soluble in organic solvents.
Three biimidazoles were subjected to
single crystal X-ray diffraction analysis.
In all three instances, adjacent mole-
cules were found to be bound together
in the solid state by pairs of N-H ´´´ N
hydrogen bonds, forming twisted rib-
bon-like columns which resemble dou-
ble helices. The amount of helical twist
observed between neighboring biimida-
zole subunits in these helices varies with
the identity of the alkyl and ester
groups; in two cases it is approximately
608, whereas in the third it is about 908.
Mass spectra of six different biimida-
zoles display ions with masses corre-
sponding to dimers; this indicates that
these compounds retain some affinity
for each other in the gas phase. The
three most soluble biimidazoles also
show mass spectrometric peaks ascrib-
able to trimers and tetramers. The
solution-phase aggregation tendencies
of these latter three compounds were
studied by vapor pressure osmometry. In
each case, the apparent molecular
weight in 1,2-dichloroethane solution is
higher than would be expected for free
monomers.
Keywords: biimidazoles
´
helical
structures ´ hydrogen bonds ´ self-
assembly ´ supramolecular chemis-
try
structure of the final assembled product is to exploit hydrogen
bonding. H-bonds are directional, and they commonly form
Introduction
[3]
ˆ
Biological self-assembly displays a remarkable level of fidel-
ity. All of the information needed to form a particular
reproducible structure in vivo, such as a viral capsid, super-
structure DNA and RNA, or a specific a-helical polypeptide,
is encoded within the sequence and/or structure of the
constituent subunits. Construction of synthetic materials by
self-assembly[1] rather than by stepwise covalent synthesis is
economically desirable, but is hampered by an incomplete
understanding of how changes at the single-molecule level
influence the properties of the resulting self-assembled
material(s).[2] One way to exert some control over the
only when groups such as NH, OH, and C O are present.
Thus, the use of building blocks with carefully positioned
complementary hydrogen-bonding functionality can increase
the odds of producing ensembles where the individual
subunits are arranged in an expected way. This strategy has
been used to produce a variety of architectures, including
pseudospheres,[4] artificial protein b-sheets,[5] duplexes with
unnatural backbones,[6] molecular ªzippersº,[7] catenanes,[8]
dendrimers,[9] and grids.[10]
A structure which has been particularly inspiring to
synthetic chemists is the helix, as it occurs throughout Nature.
To date, a number of different approaches to the production
of artificial helical structures have been pursued. Molecules
like helicenes, Lehnꢀs polyheterocyclic strands,[11] and
Mooreꢀs m-phenylacetylene oligomers[12] define an ªall-cova-
lentº paradigm, in which the subunits are compelled to adopt
helical shapes in order to reduce steric crowding imposed by
their covalent frameworks. Interactions between transition
metal ions and oligopyridine ligands have also been used to
prepare single-, double-, and multiple-helical arrays. This
ªmetal-templateº approach, developed by the research
groups of Lehn,[13] Constable,[14] Newkome,[15] Sauvage,[16]
and many others,[17] takes advantage of the propensity of
metal ions such as CuI to assume predictable coordination
geometries. The molecular information required for helix
[a] Prof. Dr. J. L. Sessler, Dr. C. J. Fowler, Dr. V. M. Lynch
Department of Chemistry and Biochemistry
Institute for Cellular and Molecular Biology
The University of Texas at Austin, Austin, TX 78712-1167 (USA)
Fax : (‡1)512-471-7550
E-mail: sessler@mail.utexas.edu
[b] Prof. W. E. Allen
Department of Chemistry, East Carolina University
Greenville, NC 27858-4353 (USA)
Supporting information for this article is available on the WWW under
http://www.wiley-vch.de/home/chemistry/ or from the author. Details
for the syntheses of 14, 15, and 16; complete X-ray experimental,
figures showing atomic numbering schemes, tables of bond lengths and
angles, and tables of positional and thermal parameters for 12, 11, and 9.
Chem. Eur. J. 2001, 7, No. 3
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J. L. Sessler et al.
FULL PAPER
formation is thus encoded in the various metal ± ligand dative
bonds. This same sort of ªinformationº has also been used to
generate helical motifs by attaching polypeptide chains to
metal ± ligand complexes.[1a, c]
of a facile derivatization strategy that will not block either the
NH hydrogen bond donor or N lone pair acceptor sites. Such a
strategy does not currently exist.
Previously, it was found that the NH groups of 1 could be
protected using [2-(trimethylsilyl)ethoxy]methyl[20] (SEM)
groups. This affords an organic-soluble material which can
be further functionalized by halogenation[21] or lithiation.[22]
Unfortunately, the introduction of SEM, or other NH
protecting groups, eliminates the potential for hydorgen
bonding. A more attractive approach to attaining organic-
soluble 2,2'-biimidazoles involves placing solubilizing sub-
stituents at the 4-, 4'-, 5-, and 5'-positions. Such biimidazoles
have been produced by classical ring-closing reactions involv-
ing diamides.[23, 24] They can also be obtained by subjecting
unsubstituted 1 to harsh reaction conditions.[25, 26] In either
case, it is important to appreciate that such biimidazoles are
known only where the four substituents are identical (e.g.,
tetramethyl,[23] tetraphenyl,[24] tetrabromo,[25] and tetrani-
tro[26]). These derivatives are also relatively insoluble in
organic media.
While metal-coordinated systems have been studied in
great detail by numerous researchers, the appealing alterna-
tive of using hydrogen bonding or base-pair-like interactions
to stabilize synthetic helical arrays has also received atten-
tion.[18] In early seminal work, Hamilton et al. generated a
self-assembling double helical structure by exploiting amide ±
carboxylic acid pairing.[18a] Lehnꢀs group examined the
behavior of mixtures of tartaric acid-based derivatives, one
containing donor± acceptor± donor atoms and the other an
acceptor± donor± acceptor array.[18b] These molecules inter-
acted via complementary uracil/2,6-diamidopyridine base
pairs to form helical structures. Other hydrogen bonding
and base-pairing interactions have been used to form related
architectures in more recent years.[18c±k] For instance, inter-
actions between tartaric acid derivatives and bipyridyls have
been shown by Singh et al. to form supramolecular assemblies
under conditions of thermal induction in the solid state.[18c]
Reinhoudt and co-workers used enantiomerically pure cal-
ix[4]arene dimelamines and 5,5-diethylbarbituric acid to form
chiral hydrogen-bonded structures that display helical one-
handedness.[18d] Hydrogen bonding between hydroxyl groups
has been exploited to create enantiospecific formations of
helical tubands[18e] and a four leaf clover motif.[18f] Hydroxyl ±
pyridine interactions were used separately by Mazik et al. to
generate a multi-component array with an inner channel of
diameter 14 Š.[18g] Hydrogen bonding and p-stacking inter-
actions have been used in tandem to stabilize both single- and
triple-helical structures.[18h,i]
Synthesis: Our approach to generating solubilized 2,2'-biimi-
dazoles with free hydrogen-bonding groups was predicated on
the use of a transition metal mediated homocoupling strategy
(Scheme 1). Specifically, starting with imidazoles 2, 3, and 4,
halogenation at the unblocked 2-position provided the
precursors needed for coupling (i.e., 5 ± 7).
O
O
H
N
H
N
R1O
R2
R1O
R2
NIS, THF
reflux
I
N
N
While elegant, each of these approaches is characterized by
its own set of strengths and weaknesses, which means that the
search for new molecules capable of undergoing hydrogen
bond mediated self-assembly remains cogent. In this paper we
demonstrate that derivatized 2,2'-biimidazoles can serve as
precursors to solid-state hydrogen-bonded helices. 2,2'-Biimi-
dazole 1 was chosen as the functional nucleus of our supra-
molecular monomers, because it is capable of simultaneously
serving as both a hydrogen-
2: R1 = Et, R2 = nPr
3: R1 = Et, R2 = n-hexyl
4: R1 = Bn, R2 = Me
5 (84%)
6 (86%)
7 (60%)
O
O
H
N
H
[Pd(PPh3)4],
Et3N, PhCH3
R1O
R2
OR1
N
N
N
R2
110 °C,
sealed tube
8 (28%)
9 (44%)
10 (39%)
N
N
bond donor and acceptor, and
it is known to spontaneously
form polymeric chains in the
solid state.[19] While such chains
of 1 are flat, sterically encum-
N
H
N
H
Scheme 1. Palladium(0)-catalyzed synthesis of substituted biimidazoles.
1
The starting materials 2 ± 4 were readily obtained. Ethyl
4-propyl-5-imidazolecarboxylate (2), a known compound,[27]
was prepared by chlorinating ethyl butyrylacetate with
SO2Cl2, and cyclizing the resulting product in formamide/
water at reflux as previously described.[28] Following a similar
chlorination/cyclization procedure, hexyl-substituted imida-
zole 3 was synthesized from ethyl 3-oxononanoate.[29] Imida-
zole 4 was prepared by base-catalyzed transesterification of
commercially available ethyl 4-methyl-5-imidazolecarboxy-
late in benzyl alcohol.
bered biimidazoles (9, 11, and 12, see Scheme 1), the synthesis
of which is reported here, are found to self-assemble into
spiral columns in the crystal. These columns bear a striking,
albeit ªreversedº, resemblance to helical duplex DNA.
Results and Discussion
In order to serve as building blocks for self-assembled
structures, 2,2'-biimidazoles need to be rendered soluble in
organic solvents since this choice of media will enhance their
propensity to form intermolecular N-H ´´´ N bonds. This
requirement for solubility compels, in turn, the development
Attempts to iodinate compound 2 in the 2-position using
molecular iodine[30] (1 equiv I2, CHCl3/aq NaOH) failed to
provide any halogenated product; in contrast, treatment with
N-iodosuccinimide (NIS) in tetrahydrofuran (THF) while
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Chem. Eur. J. 2001, 7, No. 3

2,2'-Biimidazole Helices
721±729
heating at reflux afforded the desired iodide 5 in 84% yield.
Other halogenated derivatives of imidazole 2 could be
prepared using Br2/NaOAc/HOAc, or by protecting the NH
groups of 2 with the SEM group prior to iodination.[31]
However, isolation of the products required column chroma-
tography. So, the requisite coupling precursors (i.e., 5, 6, and
7) were most conveniently prepared by iodination of 2 ± 4 with
NIS.
Unlike the coupling of 4-iodoimidazoles,[30] which fails if the
imidazole-NH groups are not protected, 2-iodoimidazoles
5 ± 7 were successfully coupled using catalytic amounts of
tetrakis(triphenylphosphine)palladium(0). Sealed-tube reac-
tion of iodide 5 with [Pd(PPh3)4] (4 mol%) and triethylamine
(2 equiv) under argon while heating in toluene at 1108C for
48 h produced the symmetrical biimidazole 8 in 28% yield,
after collecting the precipitated product by filtration and
purifying it by recrystallization from methanol. Applying the
same reaction conditions, biimidazoles 9 and 10 were synthe-
sized in yields of 44% and 39%, respectively. Heterocoupling
of iodides 6 and 7 gave a mixture of products from which the
unsymmetrical biimidazole 11 could be isolated in 15% yield
after column chromatography on silica gel using hexanes/
EtOAc/CH2Cl2 (6:4:1 v/v/v) as eluents (Scheme 2). Increasing
O
O
H
N
H
N
EtO
nPr
OEt
nPr
N
N
8
CH3OH,
NaOH,
reflux
LiAlH4,
THF,
reflux
O
O
H
H
N
H
N
H
N
Me
Me
N
MeO
nPr
OMe
nPr
N
N
N
N
nPr
nPr
13 (92%)
12 (63%)
Scheme 3. Transesterification and reduction of biimidazole 8.
Spectroscopy: The electronic absorption spectra of diesters
8 ± 12, recorded in dichloromethane, are all characterized by
an absorbance maximum near 295 nm. The fluorescence
maximum for these (aerated) samples occurs around 350 nm.
The fluorescence emission appears intensely violet-blue to the
naked eye. Only 13, which lacks carboxylate groups, shows
somewhat different spectroscopic behavior. It is characterized
by an absorbance band at 298 nm and an emission band at
373 nm.
Solid-state helices: The modest organic solubility of the first
biimidazole we prepared, 8, provided a first hint that this class
of tetrasubstituted biimidazoles might self-assemble into
hydrogen-bonded networks in the solid state, as desired.
While repeated attempts to obtain crystals of 8 suitable for
X-ray diffraction analysis failed, high-quality single crystals of
the homologous biimidazole 12 could be obtained by allowing
a methanol solution to undergo slow evaporation. A repre-
sentative view of molecule 12, doubly hydrogen-bonded with
the two nearest neighbors, is shown in Figure 1. The two
propyl substituents are found at opposite corners of the
biimidazole, in an anti relationship to one another. The
imidazole NH atoms were located and refined, and found to
reside on the nitrogen atoms next to the alkyl groups.
Intramolecular N-H ´´´ Oester hydrogen bonding is not ob-
O
O
H
N
H
N
EtO
hexyl
BnO
Me
+
I
I
N
N
6
7
O
O
[Pd(PPh3)4],
Et3N, PhCH3
H
N
H
N
EtO
hexyl
OBn
110 °C,
sealed tube
N
N
Me
11 (15%)
Scheme 2. Palladium(0)-catalyzed synthesis of asymmetric biimidazole 11.
the temperature of the coupling reactions to 120 ± 1308C, or
using DMF as the reaction solvent,[30] did not improve the
yields. No coupling was observed in the absence of triethyl-
amine. Other possible transition metal-assisted routes to
biimidazoles were explored, and were found to be inferior to
the present procedure. For instance, attempted Ullmann
coupling of 5 (5 equiv Cu0), toluene or DMF, 1108C) did not
produce biimidazole product 8[32] and gave dehalogenated
material instead. Using nickel(0) as the coupling promoter[33]
(0.5 equiv Ni(COD)2, toluene, rt, irradiation with 500 W
lamp) provided the desired product 8, but only in low yield
(12% after column chromatography on silica gel using EtOAc
as the eluent).
Two additional biimidazoles were synthesized from 8.
Transesterification using methanol and sodium hydroxide
gave the dimethyl diester 12 in 63% yield, while the tetraalkyl
derivative 13 was prepared in 92% yield by exhaustive
reduction of the ester groups of 8 with lithium aluminum
hydride in THF (Scheme 3).
Table 1. Crystal data for (C16H22N4O4)3 ´ (CH3OH)0.5 (12), C24H30N4O4
(11), and (C24H38N4O4)4 ´ (CH3OH)0.5 (9).
12
11
9
formula
Mw
C
48.5H68N12O12.5
C24H30N4O4
438.52
triclinic
P
colorless
16.0220(5)
21.838(1)
22.585(1)
68.716(2)
71.315(3)
80.287(3)
6962.8(5)
12
C96.5H154N16O16.5
1802.36
monoclinic
P21/n
colorless
24.218(3)
17.867(2)
24.921(3)
90.0
96.79(1)
90.0
10708(2)
4
1019.15
monoclinic
C2/c
colorless
21.589(2)
28.437(3)
19.203(2)
90.0
112.57(1)
90.0
10886(2)
8
crystal system
space group
color
a [Š]
b [Š]
c [Š]
a [8]
b [8]
g [8]
V [Š3]
Z
T [K]
R
RW
193(2)
0.0739
0.1315
1.521
203(2)
0.0962
0.120
1.228
188(2)
0.124
0.217
1.134
GOF
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J. L. Sessler et al.
FULL PAPER
Figure 1. Molecular structure of biimidazole 12 showing hydrogen bonding
to the nearest two neighboring molecules. Thermal ellipsoids are scaled to
the 50% probability level. Hydrogen atoms on the imidazole nitrogens are
drawn arbitrarily small. Oxygen and nitrogen atoms are labeled, and are
colored red and blue, respectively.
served in the crystal, even though such hydrogen bonding
would produce five-membered rings. The central C C bond
lengths (C2 C6) found for the three crystallographically
independent molecules of 12 are 1.448(5) Š, 1.445(5) Š, and
1.439(5) Š. These values are similar to those observed in 1
(1.423(8) Š) and in 4,4',5,5'-tetranitro-2,2'-biimidazole (as
dihydrate, 1.441(1) Š; as diammonium salt, 1.451(1) Š).[26]
Unlike these latter structures, however, in which the imida-
zole rings are coplanar, the rings in each of the three unique
molecules of 12 are rotated by 9.4(0.4)8, 24.5(0.1)8, and
18.3(0.2)8 about their respective central C C bonds.
The hydrogen bonding between molecules of 12 gives rise
to infinitely long columns which propagate parallel to the b
axis of the crystal. Measured center-to-center, the separation
between columns is 10.8 Š and 9.6 Š in the a and c directions,
respectively. A portion of one of the columns is shown in
Figure 2a. The intermolecular N ´´´ N distances between
adjacent biimidazoles in a column range from 2.878(4) Š to
3.085(5) Š, indicative of strong N-H ´´´ N hydrogen bonding.
The two separate hydrogen-bonding paths, shown as dashed
lines in Figure 2a, twist about a mutual axis in a double helical
fashion. The amount of twist on moving from one biimidazole
to the next, given by the dihedral angle between the C2 C6
bonds of adjacent molecules, averages 608. The pitch per one
complete turn of the helix is 29.4 Š, corresponding to a rise of
4.9 Š per biimidazole. While Figure 2a shows only a right-
handed helix, the bulk crystals of 12 are not chiralÐany right-
handed twist in one column is offset by an equivalent left-
handed twist in an adjacent column.
Figure 2. Right-handed helices formed from 12 a), 9 b), and 11 c). Each
ribbon contains 12 biimidazole subunits that are divided at the 2,2' bond by
red and blue coloring in order to clarify the helical progression of the
column. Hydrogen bonds are shown as dashed lines. Columns a) and
c) complete two full rotations while b) completes three.
between neighboring biimidazoles within a column range
from 2.885(4) Š to 3.048(5) Š, and like 12, the dihedral angle
between the central C C bonds of adjacent molecules
averages 608. The pitch of the helix for 11 (29.2 Š) is nearly
identical to that of 12. From the perspective of any single
helix, there will be six neighboring helices; because of
symmetry considerations, there are three unique column-to-
column contacts. Measured center-to-center, these distances
are 11.6 Š, 11.8 Š, and 11.8 Š. Helices formed from 11 display
an additional level of organization which is not possible for 12.
Using a ªtwisted ladderº analogy, one of the ªuprightsº of the
ladder consists only of hexyl group/ethyl ester-substituted
imidazoles, while the other ªuprightº consists of only methyl
group/benzyl ester-type imidazoles.
X-ray diffraction analysis of the dihexyl-substituted biimi-
dazole 9 was also carried out. It revealed the expected anti
configuration of alkyl groups. In this case, however, the two
imidazole rings of 9 display a pronounced tilt relative to one
another which averages 42.48. As in 12 and 11, molecules of 9
self-associate in the solid state to produce double-helical
columns which run along the crystallographic b axis, although
the center-to-center distances between the columns are
The ªmixedº biimidazole 11, with four different groups at
the 4-, 4'-, 5-, and 5'-positions, was also subjected to X-ray
diffraction analysis. The resulting structure revealed six
unique (albeit very similar) molecules (of 11) in the crystal.
All six display an anti relationship between the methyl and
hexyl groups, and the amount of tilt between the imidazole
rings of each biimidazole was found to be 18.68, 16.78, 17.18,
16.98, 21.78, and 23.68, respectively. Biimidazole 11 (Figure 2c)
self-assembles into twisted columns with structural properties
resembling those of 12. The hydrogen-bonding distances
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Chem. Eur. J. 2001, 7, No. 3

2,2'-Biimidazole Helices
721±729
Table 2. Dimensional analysis of the helical ribbon formed from biimida-
zole 12 and B-DNA, as represented in Figure 3.
slightly larger for 9 (12.1 Š and 12.4 Š in the a and c
directions, respectively). Figure 2b shows part of one of the
columns. The quality of the data did not allow the NH protons
to be located, but the short intermolecular N ´´´ N distances
(averaging 2.8 Š) are consistent with hydrogen bonding
occurring between adjacent members of a helix. In contrast
to 12 and 11, helices formed from 9 display a 908 twist from
molecule to molecule, and a pitch per full turn of only 18 Š.
Biimidazole 9 thus displays the greatest degree of intra-
molecular imidazole ± imidazole rotation and the most pro-
nounced helical twist between molecules.
Double helix
12
B-DNA
10
ªbase pairsº per 3608 turn
pitch
vertical rise per ªbase pairº
helix diameter
6
29.4 Š
4.9 Š
34
3.4 Š
20
Š
10
Š
Š
hydrogen-bond distance
2.9 Š
2.9 Š
While double helical in aspect, the supramolecular struc-
tures formed from 9, 11, and 12 are not strictly DNA-like.
Rather, they can be viewed as being as ªreversedº or
ªinverted.º The backbone of DNA is constructed from
covalent bonds, while its two individual strands are bound
together through hydrogen bonding between base pairs. In the
case of the present helices, each biimidazole subunit can be
considered as representing a covalently linked ªbase pairº
(i.e., a pair of 2,2'-linked imidazoles). By contrast, the
ªbackboneº of the helices are formed by hydrogen-bonding
interactions, as opposed to phosphodiester linkages.
Figure 3, drawn to scale for one full rotation in each helix,
provides a graphical comparison between 12 and B-form
DNA. Among other things, Figure 3 helps highlight how the
various dimensional features of these two helical structures
are different; these comparisons are summarized in Table 2.
Along the helix axes, DNA is clearly more compressed. In the
case of 12, only six biimidazoles are required to complete one
3608 rotation of the helix, while a full turn of B-DNA contains
ten base pairs. However, the vertical pitch (i.e., the distance
covered in one full rotation) is similar in both structures,
measuring 29.4 Š for biimidazole 12 versus 34 Š for B-form
DNA. The greater rise per ªbase pairº in the case of 12 results
from the fact that in order to remain hydrogen bonded,
adjacent biimidazoles must approach each other in an
approximately edge-on manner, and cannot closely stack
face-to-face as do the base pairs of DNA. While hydrogen
bonding serves a different supramolecular function in the
natural and synthetic structures, the average hydrogen-bond
distances for both types of helices were found to be virtually
identical, namely 2.9 Š. This latter congruence serves to
underscore how a given type of intermolecular interaction,
hydrogen bonding in this case, can be expressed in terms of a
wide range of supramolecular structures.
Figure 3. Schematic representations of biimidazole 12 and B-DNA, drawn
to scale. See Table 2 for dimensional analysis.
dimer, is observed for all six samples tested in both ionization
modes. The monomeric form of the biimidazoles is dominant
in CI mode; this gives rise to the base peak in each spectrum,
but peaks corresponding to trimers and even tetramers are
nevertheless observed for the three most soluble biimidazoles
9 ± 11. When FAB ionization is used, the extent of observed
oligomerization is generally lower, except in the case of 9.
Under these analysis conditions, the peak corresponding to a
dimer of 9 (m/z ˆ 893) is approximately fourteen times more
intense than that for the monomer (Figure 4). In additional
Self-association in the gas and
liquid phases: In order to de-
termine whether self-associated
biimidazole oligomers persist in
the gas phase, saturated di-
chloromethane solutions of 8 ±
13 were analyzed using mass
spectrometry (MS) in chemical
ionization (CI) and fast-atom
bombardment (FAB) modes.
As shown in Table 3, an ion
‡
with m/z ˆ [2M] , presumably
arising from
a non-covalent
Figure 4. Mass spectrum of a dichloromethane solution of 9, analyzed in FAB ionization mode.
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J. L. Sessler et al.
FULL PAPER
MS experiments, not shown in Table 3, methanol solutions of
9 and 10 were analyzed in CI mode. This was done in order to
assess the influence of solvent on the gas-phase aggregation
properties of these representative species. For 9, the relative
intensity of the dimer ion fell from 39 in dichloromethane to 7
in methanol. For methanol solutions of 10, no higher-order
peaks were observed at all. Such findings are consistent with
the premise that intermolecular hydrogen-bonding interac-
tions are responsible for ensemble formation in the fluid
phase as in the solid state.
structure can effect the way in
which, or even whether, a helix
is formed. In the solid state, for
example, simple 2,2'-biimida-
zole 1 forms one-dimensional
chains in which all of the imi-
dazole rings are coplanar.[19] By
contrast, in helices formed from
9, 11, and 12, steric congestion
necessitates that the individual
imidazoles of each molecule
deviate from coplanarity in or-
der for short intermolecular
hydrogen bonds to be main-
tained. Furthermore, the side
chains of 9, 11, and 12 not only
induce helicity in the columns;
these substituents are them-
selves found to pack in a helical
fashion. These ancillary helical
features are most noticeable in
the case of mixed biimidazole
11. Here, as illustrated in Fig-
ure 5, the benzyl ester and hex-
Table 3. Mass spectrometric data for 2,2'-biimidazoles.[a]
observed peaks [m/z (%)]
biimidazole
tetramer
ionization mode monomer dimer
trimer
8
9
CI
CI
CI
CI
CI
CI
363 (100)
447 (100)
431 (100)
439 (100)
335 (100)
247 (100)
725 (1)
894 (39)
861 (8)
878 (21)
669 (28)
493 (12)
725 (1)
1340 (11) 1786 (1)
Figure 5. Space-filled repre-
sentation of the solid-state
structure of biimidazole 11
(Figure 2c), showing how the
benzyl ester (red) and hexyl
(blue) side chains wrap around
the biimidazole core in a helical
fashion.
10
11
12
13
8
1291 (4)
1721 (1)
1316 (12) 1755 (1)
1003 (2)
732 (2)
FAB 363 (62)
FAB 447 (7)
9
893 (100) 1340 (16) 1786 (3)
10
11
12
13
FAB 431 (85)
FAB 439 (100)
FAB 335 (100)
FAB 247 (100)
861 (6)
877 (18)
669 (2)
493 (2)
1291 (1)
1316 (2)
yl chains are seen to wrap individually in a right-handed
fashion around the helical core. Presumably, the incorpora-
tion of other groups on the single-biimidazole periphery may
allow for the generation of helices with as yet unobserved
geometries.
[a] Chemical ionization (CI) and fast-atom bombardment (FAB) measure-
ments run dichloromethane solutions at the UT-Austin, Department of
Chemistry and Biochemistry MS Facility.
In accord with the MS results, vapor pressure osmometry
(VPO) measurements provided evidence consistent with the
contention that biimidazoles 9 ± 11 self-associate in solution
(Table 4). The average molecular weights observed for
solutions of 9 and 10 in 1,2-dichloroethane are approximately
Experimental Section
Ethyl 4-propyl-5-imidazolecarboxylate[28] and ethyl 3-oxononanoate[29]
were prepared according to the published procedures. Tetrahydrofuran
and toluene were dried by distillation from Na/benzophenone and Na,
respectively. All other solvents and reagents were obtained from commer-
cial sources and used as received. Proton and 13C NMR spectra were
recorded on a General Electric QE-300 instrument; chemical shifts are
reported in ppm relative to internal TMS (for samples in CDCl3) or relative
to protons/carbon atoms in the deuterated solvent used. Electronic
absorption spectra were acquired on a Beckman DU 640B spectropho-
tometer. Fluorescence measurements were performed by exciting 5 Â
10 5 m dichloromethane solutions at 295 nm, using a Perkin ± Elmer LS-5
spectrophotometer. Low- and high-resolution mass spectra were obtained
upon dichloromethane solutions at the UT-Austin Department of Chem-
istry and Biochemistry MS Facility. Vapor pressure osmometry (VPO) was
performed by Galbraith Laboratories, Inc., Knoxville, TN. VPO measure-
ments were made at 278C upon samples which were 2.5 ± 7.0 Â 10 2 m in 1,2-
dichloroethane, using benzil as the instrument standard. Elemental
Analyses were performed by Atlantic Microlab, Inc., Norcross, GA.
those expected for self-assembled trimers (9: Mfound/Mcalcd
ˆ
2.8; 10: Mfound/Mcalcd ˆ 3.3). By contrast, the average molecular
weight recorded for solutions of the unsymmetrical biimida-
zole 11 is that expected for a dimer (Mfound/Mcalcd ˆ 1.9).
Biimidazole 8 proved too insoluble in dichloroethane to allow
for reliable VPO analysis.
Table 4. Solution-phase molecular weights for 2,2'-biimidazoles in 1,2-
dichloroethane as measured by vapor pressure osmometry (VPO).
1
1
biimidazole
Calcd monomer MW [gmol
]
Exptl MW [gmol ]
9
10
11
446
430
438
1241
1399
827
Ethyl 4-hexyl-5-imidazolecarboxylate (3): Ethyl 3-oxononanoate (40.1 g,
0.200 mol) was dissolved in chloroform (40 mL) in a 250 mL three-necked
flask. A thermometer was immersed in the stirring solution, and dropwise
addition of sulfuryl chloride (27.0 g, 0.200 mol) was begun. The rate of
addition was controlled such that the temperature of the reaction did not
rise above 358C. During the course of this addition, the mixture became
cloudy, and gas evolution was observed. Once the addition was completed,
the mixture was stirred for an additional 30 min. At this juncture, a
condenser was fitted to the flask and the contents heated to reflux. After
2 h, the resulting colorless mixture was allowed to cool, washed sequen-
tially with water and saturated aqueous potassium bicarbonate, and dried
over Na2SO4. Filtration and evaporation of the solvent left a colorless,
mobile liquid, which was purified by short-path vacuum distillation. The
product so obtained, ethyl 2-chloro-3-oxononanoate (40.3 g, 86%), was
In conclusion, compounds 9, 11, and 12 define a new class of
supramolecular monomers which self-associate through mul-
tiple hydrogen bonds to produce helices, and thus mimic some
characteristics of naturally-occurring macromolecules.[34]
They help to illustrate the range of architectures that may
be obtained through the judicious use of multifunctional
monomers, in this case ones capable of serving concurrently as
both hydrogen-bond donors and acceptors. They also high-
light in a dramatic way how simple changes in subunit
726
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0947-6539/01/0703-0726 $ 17.50+.50/0
Chem. Eur. J. 2001, 7, No. 3

2,2'-Biimidazole Helices
721±729
used directly without further purification. Specifically, ethyl 2-chloro-3-
oxononanoate (32.2 g, 0.137 mol), formamide (61.7 g, 1.37 mol), and water
(4.93 g, 0.274 mol) were combined in a 250 mL round-bottomed flask
containing a stir bar. The mixture was heated at reflux for 3 h, during which
time it became dark red. Upon standing at room temperature overnight, a
dark red oil separated out, floated to the top of the mixture, and solidified.
This solid was collected by vacuum filtration, washed with water, and
allowed to dry in the vacuum-induced stream of air for 15 min. A clean
filter flask was exchanged for the first one, and dichloromethane was
poured onto the filter cake. Most of the material dissolved. The filtrate was
dried over Na2SO4, filtered, and taken to dryness on a rotary evaporator.
This yielded a red-brown oil which partially crystallized upon standing. This
crude product was purified by dissolving it in the minimum amount of
2-propanol, and chilling the flask in a freezer overnight to yield light tan
crystals (5.20 g, 17%). An additional amount of product 3 (3.99 g, 13%)
was obtained by evaporating the mother liquor and subjecting the
viscous oil to flash column chromatography over silica gel using
EtOAc as the eluent. M.p. 139 ± 1408C; tR (EtOAc): 0.38; 1H NMR
(CDCl3): d ˆ 0.86 (t, 3H, CH2CH2CH2CH2CH2CH3), 1.1 ± 1.4 (m, 6H,
CH2CH2CH2CH2CH2CH3), 1.36 (t, 3H, OCH2CH3), 1.67 (m, 2H,
CH2CH2CH2CH2CH2CH3), 2.96 (t, 2H, CH2CH2CH2CH2CH2CH3), 4.36
(q, 2H, OCH2CH3), 7.72 (s, 1H, imid. C2H); 13C NMR (CDCl3): d ˆ 18.0,
18.3, 26.0, 29.5, 32.0, 32.4, 34.4, 61.5, 83.9, 125.3, 142.8, 156.1; LRMS (CI ‡ ):
34.4, 61.5, 83.9, 125.3, 142.8, 156.1; LRMS (FAB ‡ ): m/z (%): 351 (100)
‡
[M‡H] ; HRMS (FAB ‡ ): calcd for C12H20N2O2I 351.0570; found
351.0568; elemental analysis calcd (%) for C12H19N2O2I: C 41.16, H 5.47,
N 8.00; found: C 41.29, H 5.49, N 7.87.
Benzyl 2-iodo-4-methyl-5-imidazolecarboxylate (7): Following the method
described for 5 above, 4 (2.95 g, 19.1 mmol) in dry THF (40 mL) was
iodinated with NIS. Recrystallization from EtOAc afforded the desired
iodide derivative 7 (3.94 g, 60%) in the form of small off-white needles. An
analytical sample was prepared by dissolving the product in the minimum
amount of boiling EtOAc, allowing the solution to cool to rt, and chilling
the tightly-capped flask in a freezer overnight. M.p. 209 ± 2108C (dec);
1H NMR (CD3OD): d ˆ 2.44 (s, 3H, CH3), 5.29 (s, 2H, OCH2Ph), 7.25 ± 7.45
(m, 5H, ArH); 13C NMR ([D6]DMSO): d ˆ 10.9, 65.0, 86.2, 127.9, 128.0,
128.4, 130.5, 136.4, 139.6, 161.8; LRMS (CI ‡ ): m/z (%): 343 (100)
‡
[M‡H] ; HRMS (CI ‡ ): calcd for C12H12N2O2I 342.9944; found 342.9934;
elemental anaylsis calcd (%) for C12H11N2O2: C 42.13, H 3.42, N 8.19;
found: C 42.27, H 3.34, N 8.01.
Diethyl 4,4'-dipropyl-2,2'-biimidazole-5,5'-dicarboxylate (8): A thick-wal-
led pressure tube containing a stir bar was charged with iodide 5 (6.16 g,
20.0 mmol), [Pd(PPh3)4] (0.92 g, 0.80 mmol), triethylamine[35] (4.05 g,
40.0 mmol), and dry toluene (30 mL). With stirring, a stream of argon
was bubbled into the resulting gold-colored suspension for 10 min. The
tube was sealed and heated to 1108C for 48 h in the dark. During this time
the reaction mixture became first homogeneous and dark brown. Then the
crude product precipitated. The mixture was allowed to cool to ambient
temperature and the crude product was collected by filtration. It was then
washed with several 2 mL portions of ice-cold acetone until the washings
were colorless. Recrystallization from methanol afforded 8 (1.01 g, 28%) in
the form of fluffy white needles. M.p. 277 ± 2798C (dec); 1H NMR (CDCl3):
d ˆ 0.85 (t, 6H, CH2CH2CH3), 1.19 (t, 6H, OCH2CH3), 1.62 (m, 4H,
CH2CH2CH3), 2.93 (t, 4H, CH2CH2CH3), 4.25 (q, 4H, OCH2CH3);
13C NMR ([D6]DMSO): d ˆ 13.3, 14.2, 22.4, 26.5, 59.1, 127.8, 137.3, 141.3,
162.8; UV/Vis (CH2Cl2): lmax (e m 1 cm 1) ˆ 294 (24000), 305 (22400), 318
(sh, 12300) nm; fluorescence emission (CH2Cl2): lmax ˆ 352 nm; LRMS
‡
m/z (%): 225 (100) [M‡H] ; HRMS (CI ‡ ): calcd for C12H21N2O2
225.1603; found 225.1611; elemental analysis calcd (%) for C12H20N2O2:
C 64.26, H 8.99, N 12.49; found: C 64.17, H 8.93, N 12.42.
Benzyl 4-methyl-5-imidazolecarboxylate (4): A 500 mL round-bottomed
flask containing a stir bar was charged with ethyl 4-methyl-5-imidazole-
carboxylate (15.4 g, 0.10 mol), a single pellet of solid NaOH (ꢀ0.2 g), and
benzyl alcohol (205 mL). A short-path distillation apparatus was fitted to
the flask, and the contents were then heated to 1108C. After 24 h, the
temperature of the reaction mixture was raised to 1408C, and the system
was placed under vacuum (4 mm Hg). After approximately 125 mL benzyl
alcohol had been distilled off, the crude product started to precipitate in the
reaction flask. The vacuum was removed, and the flask was allowed to cool
undisturbed to rt. The crude product was collected by filtration and washed
with small portions of ice-cold absolute ethanol until the washings were
colorless. Recrystallization from absolute ethanol afforded 4 as off-white
plates (15.2 g, 70%). M.p. 202 ± 2038C; 1H NMR (CD3OD): d ˆ 2.46 (s, 3H,
CH3), 5.30 (s, 2H, OCH2Ph), 7.25 ± 7.45 (m, 5H, ArH), 7.59, (s, 1H, imid.
C2H); 13C NMR ([D6]DMSO): d ˆ 11.0, 64.8, 127.9, 128.4, 134.7, 136.6,
‡
‡
(CI ‡ ): m/z (%): 363 (100) [M‡H] , 725 (1) [2M‡H] ; LRMS (FAB ‡ ):
‡
‡
m/z (%): 363 (62) [M‡H] , 725 (1) [2M‡H] ; HRMS (CI ‡ ): calcd for
C18H27N4O4 363.2032; found 363.2031; elemental analysis calcd (%) for
C18H26N4O4: C 59.65, H 7.23, N 15.46; found: C 59.55, H 7.18, N 15.36.
Diethyl 4,4'-dihexyl-2,2'-biimidazole-5,5'-dicarboxylate (9): A thick-walled
pressure tube containing a stir bar was charged with the iodide derivative 6
(1.75 g, 5.00 mmol), [Pd(PPh3)4] (0.23 g, 0.20 mmol), triethylamine (1.01 g,
10.0 mmol), and dry toluene (10 mL). With stirring, a stream of argon was
bubbled into the gold-colored suspension for 10 min. The tube was sealed
and heated to 1108C for 48 h in the dark. A portion of the crude product
precipitated upon cooling; it was collected by filtration, washed with small
portions of ice-cold dichloromethane, and saved. The filtrate from this
procedure was evaporated to a brown residue, and purified by flash column
chromatography on silica gel using CH2Cl2/EtOAc (4:1 v/v) as the eluent.
The fractions glowing blue under UV light were evaporated and combined
with the crude product saved previously. Recrystallization from methanol
afforded biimidazole 9 (0.49 g, 44%) as a white solid. M.p. 180 ± 1928C; tR
(CH2Cl2/EtOAc, 4:1): 0.35; 1H NMR (CDCl3): d ˆ 0.78 (t, 6H,
CH2CH2CH2CH2CH2CH3), 0.9 ± 1.3 (brm, 18H, CH2CH2CH2CH2CH2CH3
and OCH2CH3), 1.51 (brm, 4H, CH2CH2CH2CH2CH2CH3), 2.89 (t, 4H,
CH2CH2CH2CH2CH2CH3), 4.16 (q, 4H, OCH2CH3); 13C NMR (CD3OD):
d ˆ 14.3, 14.7, 23.6, 26.9, 30.0, 30.3, 32.7, 61.5, 129.3, 132.8, 138.8, 164.1; UV/
Vis (CH2Cl2): lmax (e m 1 cm 1) ˆ 294 (24000), 306 (22100), 319 (sh,
11900) nm; fluorescence emission (CH2Cl2): lmax ˆ 352 nm; LRMS (CI ‡ ):
‡
163.0; LRMS (CI ‡ ): m/z (%): 217 (100) [M‡H] ; HRMS (CI ‡ ): calcd
for C12H13N2O2 217.0977; found 217.0970; elemental analysis calcd (%) for
C12H12N2O2: C 66.65, H 5.59, N 12.95; found: C 66.73, H 5.62, N 12.89.
Ethyl 2-iodo-4-propyl-5-imidazolecarboxylate (5): An oven-dried 250 mL
round-bottomed flask containing a stir bar was charged with dry THF
(100 mL) and ethyl 4-propyl-5-imidazolecarboxylate (2, 9.11 g, 50.0 mmol).
After stirring was commenced, the resulting suspension was treated with N-
iodosuccinimide (95%, 11.8 g, 50.0 mmol) all at once. The flask was then
wrapped in foil to exclude light, and the contents heated to reflux under Ar.
After 24 h, the reaction was allowed to cool to room temperature, and
saturated aqueous Na2S2O3 was added dropwise until the iodine color was
discharged. The mixture was diluted with equal volumes of EtOAc and
water, and the layers were separated. The organic phase was washed with
brine, dried over MgSO4, filtered, and evaporated to dryness to yield a
yellow solid. Recrystallization from EtOAc afforded the desired product 5
(12.9 g, 84%) as white needles. M.p. 194 ± 1958C; 1H NMR (CDCl3): d ˆ
0.91 (t, 3H, CH2CH2CH3), 1.20 (t, 3H, OCH2CH3), 1.68 (m, 2H,
CH2CH2CH3), 2.98 (t, 2H, CH2CH2CH3), 4.26 (q, 2H, OCH2CH3);
13C NMR (CDCl3): d ˆ 13.8, 14.2, 22.6, 28.1, 60.4, 84.3, 128.9, 147.0, 161.7;
‡
‡
‡
m/z (%): 447 (100) [M‡H] , 894 (39) [2M‡H] , 1340 (11) [3M‡H] , 1786
‡
‡
(1) [4M‡H] ; LRMS (FAB ‡ ): m/z (%): 447 (7) [M‡H] , 893 (100)
‡
‡
‡
‡
LRMS (CI ‡ ): m/z (%): 309 (100) [M‡H] ; HRMS (CI ‡ ): calcd for
[2M‡H] , 1340 (16) [3M‡H] , 1786 (3) [4M‡H] ; HRMS (CI ‡ ): calcd
for C24H38N4O4 446.2893; found 446.2887; elemental analysis calcd (%) for
C24H38N4O4 Â 0.5(CH3OH): C 63.61, H 8.72, N 12.11; found: C 63.65, H
8.57, N 12.24.
C9H14N2O2I 309.0100; found 309.0093; elemental analysis calcd (%) for
C9H13N2O2I: C 35.08, H 4.25, N 9.09; found: C 35.19, H 4.28, N 9.08.
Ethyl 4-hexyl-2-iodo-5-imidazolecarboxylate (6): Following the method
described for 5 above, 3 (0.97 g, 4.3 mmol) in dry THF (20 mL) was
iodinated with NIS. Recrystallization from EtOAc afforded the desired
iodide 6 (1.30 g, 86%) as white needles. M.p. 116 ± 1178C; 1H NMR
(CDCl3): d ˆ 0.83 (t, 3H, CH2CH2CH2CH2CH2CH3), 1.2 ± 1.5 (m, 6H,
CH2CH2CH2CH2CH2CH3), 1.27 (t, 3H, OCH2CH3), 1.65 (m, 2H,
CH2CH2CH2CH2CH2CH3), 2.97 (t, 2H, CH2CH2CH2CH2CH2CH3), 4.30
(q, 2H, OCH2CH3); 13C NMR (CDCl3): d ˆ 18.0, 18.3, 26.0, 29.5, 32.0, 32.4,
Dibenzyl 4,4'-dimethyl-2,2'-biimidazole-5,5'-dicarboxylate (10): A thick-
walled pressure tube containing a stir bar was charged with iodide 7 (0.90 g,
2.6 mmol), [Pd(PPh3)4] (0.12 g, 0.10 mmol), triethylamine (0.53 g,
5.2 mmol), and 20 mL of dry toluene. With stirring, a stream of argon
was bubbled into the resulting gold-colored suspension for 10 min. The
tube was sealed and heated to 1108C for 48 h in the dark. Upon cooling to
rt, the brown suspension was filtered through a sintered glass funnel. The
Chem. Eur. J. 2001, 7, No. 3
ꢁ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001
0947-6539/01/0703-0727 $ 17.50+.50/0
727

J. L. Sessler et al.
FULL PAPER
filter cake was washed with toluene (50 mL), and the filtrate was
evaporated to dryness to yield a viscous, dark brown oil. This oil was
purified by flash column chromatography on silica gel using CH2Cl2/EtOAc
(2:1 v/v) as the eluent to afford 10 (0.22 g, 39%) as a light yellow solid. tR
(CH2Cl2/EtOAc 2:1): 0.38; 1H NMR (CDCl3): d ˆ 2.25 (s, 6H, CH3), 5.16 (s,
4H, OCH2Ph), 7.10 ± 7.25 (m, 10H, ArH); 13C NMR (CDCl3): d ˆ 11.5, 66.1,
128.2, 128.3, 128.5, 135.4, 137.2, 138.7, 162.7; UV/Vis (CH2Cl2): lmax (e
diluted with EtOAc (300 mL). This organic solution was washed sequen-
tially with 1m aq NaOH (100 mL) and brine, then dried over MgSO4.
Filtration and rotary evaporation of the filtrate provided the crude product
as an off-white solid. This material was dissolved in the minimum amount
of boiling EtOAc and the solution filtered while hot. After cooling to rt, the
flask was chilled in a freezer overnight to give 13 (0.99 g, 92%) as off-white
crystals. M.p. 206 ± 2088C (dec); tR (CH2Cl2/CH3OH 6:1): 0.73; 1H NMR
(CDCl3): d ˆ 0.84 (t, 6H, CH2CH2CH3), 1.53 (m, 4H, CH2CH2CH3), 2.12 (s,
6H, CH3), 2.46 (t, 4H, CH2CH2CH3); 13C NMR (CD3OD): d ˆ 10.7, 13.9,
24.0, 28.2, 129.3, 133.2, 137.7; UV/Vis (CH2Cl2): lmax (e m 1 cm 1) ˆ 298
(18000), 305 (18700), 319 (sh, 11400) nm; fluorescence emission (CH2Cl2):
m
1 cm 1) ˆ 293 (23000), 306 (21800), 320 (sh, 11700) nm; fluorescence
emission (CH2Cl2): lmax ˆ 354 nm; LRMS (CI ‡ ): m/z (%): 431 (100)
‡
‡
‡
‡
[M‡H] , 861 (8) [2M‡H] , 1291 (4) [3M‡H] , 1721 (1) [4M‡H] ;
‡
‡
LRMS (FAB ‡ ): m/z (%): 431 (85) [M‡H] , 861 (6) [2M‡H] , 1291 (1)
‡
‡
[4M‡H] ; HRMS (CI ‡ ): calcd for C24H23N4O4 431.1719; found 431.1706;
lmax ˆ 373 nm; LRMS (CI ‡ ): m/z (%): 247 (100) [M‡H] , 493 (12)
‡
‡
‡
elemental analysis calcd (%) for C24H22N4O4 Â 0.5H2O: C 65.59, H 5.28, N
[2M‡H] , 732 (2) [3M‡H] ; LRMS (FAB ‡ ): m/z (%): 247 [M‡H] , 493
‡
12.75; found: C 65.47, H 5.22, N 12.60.
(2) [2M‡H] ; HRMS (CI ‡ ): calcd for C14H23N4 247.1923; found 247.1919;
1
elemental analysis calcd (%) for C14H22N4 Â ꢂ6EtOAc: C 67.49, H 9.01, N
Benzyl ethyl 4-methyl-4'-hexyl-2,2'-biimidazole-5,5'-dicarboxylate (11): A
thick-walled pressure tube containing a stir bar was charged with iodide
derivatives 6 (1.60 g, 4.56 mmol) and 7 (1.56 g, 4.56 mmol), [Pd(PPh3)4]
(0.42 g, 0.36 mmol), triethylamine (2.02 g, 20.0 mmol), and dry toluene
(30 mL). With stirring, a stream of argon was bubbled into the resulting
gold-colored suspension for 10 min. The tube was sealed and heated to
1108C for 48 h in the dark. Upon cooling to rt, the brown suspension was
filtered through a sintered glass funnel, and the filter cake was washed with
toluene (50 mL). TLC analysis on silica plates of the filtrate using hexanes/
EtOAc/CH2Cl2 (6:4:1 v/v/v) revealed the presence of three biimidazoles, 9
(fast spot), 10 (slow spot), and the desired 11 (middle spot). The filtrate was
evaporated to dryness to yield a dark brown solid. This crude produce was
subjected to flash column chromatography on silica gel using the eluent
system described above. Recrystallization from methanol afforded 11
(0.29 g, 15%) as a cream-colored solid. M.p. 191 ± 1958C; tR (hexanes/
EtOAc/CH2Cl2 6:4:1): 0.20; 1H NMR (CD3OD): d ˆ 0.88 (t, 3H,
CH2CH2CH2CH2CH2CH3), 1.2 ± 1.4 (brm, 6H, CH2CH2CH2CH2CH2CH3),
1.36 (t, 2H, OCH2CH3), 1.66 (brm, 2H, CH2CH2CH2CH2CH2CH3), 2.53 (s,
3H, CH3), 2.95 (t, 2H, CH2CH2CH2CH2CH2CH3), 4.32 (q, 2H, OCH2CH3),
5.32 (s, 2H, OCH2Ph), 7.3 ± 7.5 (m, 5H, ArH); 13C NMR ([D6]DMSO): d ˆ
11.0, 13.8, 14.2, 22.0, 24.8, 28.3, 29.1, 30.9, 59.3, 65.1, 117.8, 127.9, 128.0,
128.3, 128.5, 136.6, 137.2, 137.4, 137.5, 137.7, 137.8, 141.7, 141.9, 162.9, 163.0;
UV/Vis (CH2Cl2): lmax (e m 1 cm 1) ˆ 294 (24100), 306 (22200), 320 (sh,
11700) nm; fluorescence emission (CH2Cl2): lmax ˆ 354 nm; LRMS (CI ‡ ):
21.46; found: C 67.35, H 8.90, N 21.48.
X-ray experimental for 12: Crystals grew as thin colorless needles by slow
evaporation from a methanol solution. The data crystal was cut from a
larger crystal and had approximate dimensions 0.19 Â 0.22 Â 0.56 mm. The
data were collected using the w scan technique at 4 ± 88 per min, with a scan
range of 1.08 in w to a 2qmax ˆ 508 at 193 K on a Siemens P4 diffractometer,
equipped with a Nicolet LT-2 low-temperature device and using a graphite
monochromator with MoKa radiation (l ˆ 0.71073 Š). Details of crystal
data, data collection, and structure refinement are listed in Table 1. The
data were corrected for Lorentz polarization effects but not for absorption.
The structure was solved by direct methods and refined by full-matrix least-
squares on F2 with anisotropic displacement parameters for the non-H
atoms. The hydrogen atoms on carbon were calculated in ideal positions
with isotropic displacement parameters set to 1.2 Ueq of the attached atom
(1.5 Ueq for methyl hydrogen atoms). On molecule B, one propyl side chain
was disordered about two orientations. The site occupancy was refined
while refining a common isotropic displacement parameter for the atoms
involved, C23B and C24B, and C23C and C24C. The site occupancy factor
for C23B and C24B refined to 66(2)%. Thereafter, the displacement
parameters were refined without constraint. The hydrogen atoms on the
imidazole nitrogens were observed in a F map and refined with isotropic
displacement parameters. One partial occupancy methanol molecule was
located in the asymmetric unit. It was assigned a site occupancy factor of 1ꢂ2
after refining with unusually high Uiso values when the site occupancy factor
was set to 1. Complete details are given in the Supporting Information.
‡
‡
‡
m/z (%): 439 (100) [M‡H] , 878 (21) [2M‡H] , 1316 (12) [3M‡H] , 1755
‡
‡
(1) [4M‡H] ; LRMS (FAB ‡ ): m/z (%): 439 (100) [M‡H] , 877 (18)
‡
‡
[2M‡H] , 1316 (2) [3M‡H] ; HRMS (CI ‡ ): calcd for C24H31N4O4
439.2345; found 439.2326; elemental analysis calcd (%) for C24H30N4O4:
C 65.74, H 6.90, N 12.78; found: C 65.48, H 6.88, N 12.64.
X-ray experimental for 11: Crystals grew as colorless prisms by slow
evaporation from methanol. The data crystal was cut from a larger crystal
and had approximate dimensions 0.20 Â 0.30 Â 0.35 mm. The data were
collected on a Nonius Kappa CCD diffractometer using a graphite
monochromator with MoKa radiation (l ˆ 0.71073 Š). A total of 199
frames of data were collected using w scans with a scan range of 1.98 and a
counting time of 119s per frame. The data were collected at 708C using a
Oxford Cryostream low temperature device. Details of crystal data, data
collection, and structure refinement are listed in Table 1. The structure was
solved by direct methods and was refined in blocks by full-matrix least-
squares on F2 with anisotropic displacement parameters for the non-H
atoms. The anisotropic displacement parameters were restrained during
refinement to be approximately isotropic. The hydrogen atoms on carbon
were calculated in ideal positions with isotropic displacement parameters
set to 1.2 Ueq of the attached atom (1.5 Ueq for methyl hydrogen atoms). The
hydrogen atoms on the imidazole nitrogen atoms were located from a DF
map but were not subsequently refined. The positions were idealized with
Uiso set to 1.2 Ueq of the bound nitrogen atom. There are six crystallo-
graphically independent molecules in the asymmetric unit. Due to the large
number of atoms to be refined, the hexyl groups were restrained to have
similar bond lengths and angles during refinement. Complete details are
given in the Supporting Information.
Dimethyl 4,4'-dipropyl-2,2'-biimidazole-5,5'-dicarboxylate (12): Biimida-
zole 8 (100 mg, 0.276 mmol) and sodium hydroxide (221 mg, 5.52 mmol)
were combined in dry methanol (25 mL). The resulting mixture was heated
to reflux under argon for 24 h. After cooling, the solvent was removed by
using rotary evaporation, the residue was treated with dichloromethane
(50 mL) and 1m aq HCl (50 mL), and the layers were separated. The
aqueous layer was extracted with additional dichloromethane, and the
combined organic phases were dried over Na2SO4. Filtration and evapo-
ration of the filtrate gave a white solid, which was recrystallized from
methanol to afford 12 (58 mg, 63%). M.p. 249 ± 2518C (dec); tR (CH2Cl2/
EtOAc 1:1): 0.35; 1H NMR (CD3OD): d ˆ 0.96 (t, 6H, CH2CH2CH3), 1.70
(m, 4H, CH2CH2CH3), 2.95 (t, 4H, CH2CH2CH3), 3.86 (s, 6H, OCH3);
13C NMR ([D6]DMSO): d ˆ 13.3, 22.3, 26.4, 50.5, 127.6, 137.3, 141.5, 163.3;
UV/Vis (CH2Cl2): lmax (e m 1 cm 1) ˆ 293 (25000), 306 (22000), 320 (sh,
11000) nm; fluorescence emission (CH2Cl2): lmax ˆ 348 nm; LRMS (CI ‡ ):
‡
‡
‡
m/z (%): 335 (100) [M‡H] , 669 (28) [2M‡H] , 1003 (2) [3M‡H] ;
‡
‡
LRMS (FAB ‡ ): m/z (%): 335 (100) [M‡H] , 669 (2) [2M‡H] ; HRMS
(CI ‡ ): calcd for C16H23N4O4 335.1719; found 335.1719; elemental analysis
calcd (%) for C16H22N4O4: C 57.47, H 6.63, N 16.76; found: C 57.32, H 6.77,
N 16.61.
X-ray experimental for 9: Crystals grew as thin colorless needles by slow
cooling of a methanol solution. The data crystal was cut from a larger
crystal and had approximate dimensions 0.14 Â 0.26 Â 0.76 mm. The data
were collected using the w scan technique at 4 ± 108 per min, with a scan
range of 1.08 in w to a 2qmax ˆ 458 at 188 K on a Siemens P4 diffractometer,
equipped with a Nicolet LT-2 low-temperature device and using a graphite
monochromator with MoKa radiation (l ˆ 0.71073 Š). Details of crystal
data, data collection, and structure refinement are listed in Table 1. The
data were corrected for Lorentz polarization effects but not for absorption.
4,4'-Dimethyl-5,5'-dipropyl-2,2'-biimidazole (13): A stirred suspension of
diester 8 (1.59 g, 4.39 mmol) in dry THF (40 mL) was cooled to 08C under
argon. Lithium aluminum hydride (95%, 0.70 g, 18 mmol) was added in
small portions over 3 min, during which time the mixture warmed and
evolved H2. The gray suspension was heated to reflux for 24 h. After
cooling to rt, the mixture was carefully quenched by the dropwise addition
of ice water until no more effervescence was observed. It was then filtered.
The filter cake was washed with THF (300 mL), and the pink filtrate was
728
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0947-6539/01/0703-0728 $ 17.50+.50/0
Chem. Eur. J. 2001, 7, No. 3

2,2'-Biimidazole Helices
721±729
The structure was solved by direct methods and refined by full-matrix least-
squares on F2 with anisotropic displacement parameters for most of the
non-H atoms. There are four molecules of the biimidazole and one-half
molecule of methanol per asymmetric unit. The hydrogen atoms on carbon
were calculated in ideal positions (C H 0.96 Š) with isotropic displace-
ment parameters set to 1.2 Ueq of the attached atom (1.5 Ueq for methyl
hydrogen atoms). Several atoms of the hexyl groups and imidazole rings did
not refine well (see the Supporting Information). The hydrogen atoms on
the imidazole nitrogen atoms could not be found in a difference electron
density map after all other atoms were accounted for, and were therefore
not included in the final model. The site occupancy factors for the atoms of
the methanol molecules were estimated to be 0.5 due to the amount of
electron density in the region. Complete details are given in the Supporting
Information.
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Crystallographic data (excluding structure factors) for the structures
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Acknowledgement
W.E.A. was supported, in part, by an American Cancer Society Postdoc-
toral Fellowship. This work was further supported by grants from the
National Science Foundation (CHE9725399) and the R.A. Welch Founda-
tion (F-1018) to J.L.S.
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experiments
using
N,N-diisopropylethylamine
(40.0 mmol) instead of triethylamine in the coupling reaction in-
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Received: September 4, 2000 [F2710]
Chem. Eur. J. 2001, 7, No. 3
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