Improved synthesis of functionalized mesogenic 2,6-bisbenzimidazolylpyridine ligands

Article abstract of DOI:10.1016/j.tet.2008.05.075

A versatile one-pot synthetic platform for the preparation of a range of functionalized 2,6-bisbenzimidazolylpyridine (Bip) derivatives is presented. This protocol significantly reduces the cost and time of previous synthetic routes, while facilitating sc

Full text of DOI:10.1016/j.tet.2008.05.075

Tetrahedron 64 (2008) 8488–8495
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Improved synthesis of functionalized mesogenic
2,6-bisbenzimidazolylpyridine ligands
Blayne M. McKenzie a, Adriane K. Miller a, Rudy J. Wojtecki a, J. Casey Johnson a, Kelly A. Burke a,
,
,
*
Karis A. Tzeng b, Patrick T. Mather a y, Stuart J. Rowan a
a Department of Macromolecular Science and Engineering, Case Western Reserve University, 2100 Adelbert Road, Cleveland, OH 44106, USA
b Hathaway Brown School, 19600 North Park Blvd., Shaker Heights, OH 44122, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A versatile one-pot synthetic platform for the preparation of a range of functionalized 2,6-bisbenzimid-
azolylpyridine (Bip) derivatives is presented. This protocol significantly reduces the cost and time of pre-
vious synthetic routes, while facilitating scale up to multi-gram quantities in good yields (63–90%). The
previous synthetic methodology was improved through judicious choice of the reducing agent and solvent
in the reduction/ring-closing step. Via this platform, we also successfully accessed a mesogenic Bip ligand
and herein report initial liquid crystalline properties of this derivative.
Received 7 March 2008
Received in revised form 13 May 2008
Accepted 16 May 2008
Available online 21 May 2008
Keywords:
Supramolecular chemistry
Terdentate
Ó 2008 Elsevier Ltd. All rights reserved.
Metal–ligand coordination
Liquid crystal
1. Introduction
ligands in areas such as urea recognition,11 DNA binding,12
nanoparticle preparation,13 and catalysis.14 We have been in-
Over the years, the development of aromatic aza-heterocycles as
ligands has provided a valuable resource for researchers working in
the field of metal–ligand coordination.1 Aromatic terdentate
ligands are one important class of such aza-ligands, of which ter-
pyridine (Terpy, Fig. 1a) is the most widely utilized and studied.2 An
alternative terdentate aza-ligand, which has garnered much less
attention, is the 2,6-bisbenzimidazolylpyridine (Bip, Fig. 1b) core.
Nonetheless, this molecular framework has been shown by
a number of groups to be versatile and useful in a variety of areas.
For example, Piguet and co-workers have used Bip derivatives
extensively in several studies of liquid crystalline complexes con-
taining lanthanides,3,4 to access triple helicates,5 and to study the
communication between lanthanides and transition metals.6
Benicewicz and co-workers7 have prepared a polymeric analog of
Bip and studied its potential as a material for fuel cell membranes,
while Haga and co-workers have studied Bip derivatives in multi-
layered structures8 and prepared ruthenium complexes with Bip
derivatives with the goal of developing pH-sensitive molecular
switches.9 A number of other groups have studied the physical
properties of Bip derivative complexes10 and investigated these
vestigating Bip derivatives for use in a number of related areas,
including chemical sensors15 and in a variety of metallo-supra-
molecular polymers,16 ranging from thermoplastic elastomers17
and gels18 to processable poly(p-xylylene)19 and poly(p-phenylene
ethynylene).20
The most common route10c,21 to simple Bip derivatives is the
reaction of o-diaminobenzene derivatives with 2,6-pyridine di-
carboxylic acid using 85% phosphoric acid at temperatures ex-
ceeding 200 ꢀC, in which the key step is the formation of the
benzimidazole rings. However, the harsh conditions of this reaction
limit its utility to access a wide variety of highly substituted Bip
materials in good yield.
With the goal of expanding the repertoire of Bip ligands that can
be incorporated into macromolecular assemblies, an efficient and
* Corresponding author. Tel.: þ1 216 368 4242; fax: þ1 216 368 4202.
E-mail address: stuart.rowan@case.edu (S.J. Rowan).
Present address: Biomaterials Institute and Biomedical and Chemical Engi-
Figure 1. Metal-binding conformation of the terdentate ligands (a) terpyridine (Terpy)
and (b) 2,6-bisbenzimidazolylpyridine (Bip) with labeled functional sites: R, R0, X, and
Y. The gray spheres represent metal ions.
y
neering Department, Syracuse University, Syracuse, NY 13244, USA.
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.05.075

B.M. McKenzie et al. / Tetrahedron 64 (2008) 8488–8495
8489
Scheme 1. Synthesis of 2,6-bis(10-ethyl-50-methoxybenzimidazol-20-yl)pyridine (Bip1). (A) NH2Et, high pressure flask, 105 ꢀC, 24 h, 92%; (B) SOCl2, DMF, 75 ꢀC, 2 h, quantitative; (C)
CHCl3, NEt3, reflux, 8 h, 60% (Ref. 22); (D) activated iron, EtOH, H2O, HCl, reflux, 12 h, 75% (Ref. 22); (E) (i) NMP, 50 ꢀC, 8 h; (ii) activated iron, NMP, HCl, 90 ꢀC, 12 h, EDTA in H2O, 90%;
(F) (i) DMF, rt, 18 h; (ii) Na2S2O4, DMF, EtOH, H2O, 85 ꢀC, 18 h, 70%.
robust synthetic approach to highly functionalized Bip derivatives
is necessary. Herein we report a versatile synthetic platform, which
allows facile access to such compounds in high yields and multi-
gram quantities. We go on to describe how such ligands can be
readily functionalized to access monomers suitable for polymeri-
zation and that these simple derivatives possess mesogenic
properties.
yield after purification by column chromatography. Thus, the
overall yield of Bip1 from 2 and 4 was 45%. We have also followed
this synthetic protocol and have accessed Bip1 in similar overall
yields (45%, Table 1) in a process that required 3–4 days to complete
from 2 and 4.
With the goal of being able to quickly obtain multi-gram
quantities of Bip derivatives we sought ways to streamline this
protocol and improve its yield while maintaining the ability to
access a range of functionalized Bip ligands.
2. Results and discussion
2.1. Previous Bip derivative syntheses
2.2. Modification of the Bip protocol: one-pot synthesis with
NMP as the solvent
Piguet and co-workers22 published an elegant solution to the
synthesis of functionalized Bip derivatives from an N-alkyl-o-
nitroaniline derivative and 2,6-pyridine dicarboxylic acid chloride.
An example of this is shown in Scheme 1. Targeting Bip1, ethyl-
amine was reacted with the commercially available 4-chloro-3-
nitroanisole (1) yielding the desired N-ethyl-2-nitroaniline (2).
2,6-Pyridine dicarboxylic acid (3) was then activated with thionyl
chloride to produce 2,6-pyridine dicarboxylic acid chloride (4),
which was subsequently reacted with 2 in the presence of triethyl
amine in chloroform to yield 5 in 60% yield after purification via
column chromatography. The desired Bip derivative could then be
accessed under relatively milder conditions compared to the pre-
viously described method by reduction of the nitro group and
subsequent ring-closing with activated iron and hydrochloric acid
in aqueous ethanol at 80 ꢀC. Excess iron was removed using a sat-
urated aqueous ethylenediaminetetraacetic acid (EDTA) solution
and the crude reaction mixture was neutralized using aqueous
ammonium hydroxide. The derivative Bip1 was isolated in 75%
Work by Korshak and co-workers23 showed that poly-
benzimidazoles can be accessed by reacting aromatic ditopic o-
nitroamines and aryl diacid chlorides. The major difference in this
approach as compared to the Piguet method described above was
the use of N-methyl-2-pyrrolidinone (NMP) as the solvent in a one-
pot reaction. NMP was chosen to increase solubility of the polymer
and thus enhance the propensity for complete reduction and ring-
closing. Thus, our first modification to the procedure utilized by
Piguet and co-workers was to directly synthesize Bip1 from 2 and 4
in one-pot using NMP as a common solvent for both reactions
(Scheme 1, Ei and Eii). Upon addition of saturated aqueous EDTA and
sodium bicarbonate to the reaction mixture, Bip1 precipitated in
90% yield (pure by 1H NMR), removing the need for chromatogra-
phy. Thus, not only does this procedure double the yield of the
reaction, it also reduces the preparation time for Bip1, from the
starting materials 2 and 4, from ca. four days to one day.
To further examine the versatility of this synthetic protocol, we
targeted a range of substituted Bip derivatives (Table 1). With
a view to accessing soluble macromolecular architectures we
wanted to pursue Bip ligands, which showed enhanced solubility.
We, therefore, decided to synthesize Bip ligands, which have sol-
ubilizing groups (n-hexyl) at the 10-positions (R0 sites, Fig. 1b). To
achieve this, hexylamine was reacted with 1 at 85 ꢀC producing the
oily product 6 (Scheme 2a), which was then reacted with 4 under
the same modified conditions using NMP as the reaction medium.
On account of the ‘desired’ increased solubility of Bip2, it did not
precipitate and required column chromatography, which might
help to explain the slightly lower yield (63%) compared to Bip1. We
were also interested in Bip ligands with extended ‘arms’, so we
investigated the synthesis of ligands, which have an aryl sub-
stituent in the 50-positions (X sites, Fig. 1b). Addition of either
ethylamine or hexylamine to 2,4-dibromonitrobenzene (7) yielded
N-ethyl-4-bromo-2-nitroaniline (8) and N-hexyl-4-bromo-2-
nitroaniline (9), respectively. Suzuki coupling24 of 8 or 9 with 4-
methoxyphenyl boronic acid in the presence of a palladium(0)
catalyst yielded the extended o-nitro-4-(40-methoxy)phenylani-
lines 10 and 11 (Scheme 2b), respectively. Gratifyingly, subsequent
reaction of 10 or 11 with 4, using our modified conditions allowed
access to Bip3 and Bip4, respectively, in good yield. Like Bip1, the
Table 1
Bip derivatives, preparation methodology, and isolated yield
Bip derivative substitution
pattern (Fig. 1b)
Methoda
Isolated yieldb (%)
R
R0
X
Y
d
Bip1
H
Et
OMe
H
Two stepc
Fe
Na2S2O4
Fe
Na2S2O4
Fe
Na2S2O4
Fe
Na2S2O4
Fe
Fe
Na2S2O4
Na2S2O4
45 (lit.: 4522
)
90
70
63
65
83
72
72
69
84
72
70
81
Bip2
Bip3
Bip4
H
H
H
n-Hex
Et
OMe
H
H
H
PhOMe
PhOMe
n-Hex
Bip5
Bip6
H
OBn
Et
Et
H
OMe
Me
H
Bip7
OMe
Et
OBn
H
a
Unless otherwise stated, these reactions were performed using either activated
iron/HCl (‘Fe’) or sodium dithionite in aqueous ethanol (‘Na2S2O4’).
b
Starting from the appropriate o-nitroaniline and dicarboxylic acid chloride.
Two-step synthesis following the protocol published by Piguet and co-workers.
Combined yield from the two-step reaction.
c
d

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B.M. McKenzie et al. / Tetrahedron 64 (2008) 8488–8495
Scheme 2. (a) (A) NH2(n-hex), 85 ꢀC, 24 h, 90%. (b) (A) NH2Et, high pressure flask, 105 ꢀC, 24 h, 93% or NH2(n-hex), 85 ꢀC, 24 h, 94%; (B) 4-methoxphenyl boronic acid, K2CO3, THF,
H2O, Pd(PPh3)4, 75 ꢀC, 18 h, 96–98%. (c) (A) NH2Et, high pressure flask, 105 ꢀC, 24 h, 95%. (d) (A) (i) MeOH, H2SO4, 80 ꢀC, 4 h; (ii) BnBr, K2CO3, acetonitrile, 70 ꢀC, 22 h; (iii) precipitate
from hot EtOH with KOH; (iv) precipitate from H2O with HCl, quantitative; (B) SOCl2, DMF, 75 ꢀC, 2 h, quantitative.
R0¼ethyl derivative, Bip3, precipitated from the saturated aqueous
EDTA/base solution and was shown to be pure by 1H NMR (83%
yield). However, the n-hexyl derivative, Bip4 required column
chromatography to yield, in 72%, the pure product. Using this
methodology, we also synthesized Bip5, which has methyl sub-
stituents at the 60-positions (Y sites, Fig. 1b). As before, the sub-
stitution on the benzimidazole moiety was determined by the
nature of the o-nitroaniline (Scheme 2c, 13) starting material.
In a number of our previous studies,15–20 we have utilized
a functional group on the 4-position to access Bip end-capped
macromonomers. Therefore, we went on to study the potential of
this synthetic methodology to access highly functionalized Bip
derivatives where one of the substituents was in the 4-position.
Thus, we started by protecting chelidamic acid (14) with a benzoxy
moiety to yield 15 (Scheme 2d).25 Following activation with thionyl
chloride, 16 can be reacted with an appropriate N-alkyl-o-nitro-
aniline derivative, e.g., 2, using our modified protocol to access
Bip6. As before for the R0¼ethyl derivative no column was required
to purify Bip6 (it precipitated from the saturated aqueous EDTA/
base solution). However, removal of the FeII did appear more dif-
ficult than for previous ligands, possibly on account of the electron
donating properties of the alkoxy group on the 4 position (Fig. 1b)
enhancing metal binding. Thus, extensive washing with multiple
batches of aqueous EDTA was required to extract the FeII from Bip6.
Using this modified NMP/one-pot strategy, six derivatives
(Bip1–Bip6) were successfully synthesized in good to excellent
overall yields ranging from 63–90% (Table 1).
major disadvantages. First, the oxidized FeII binds strongly within
the Bip cavity and needs to be removed by thorough washing with
aqueous EDTA. An additional issue that becomes a significant
problem for large-scale synthesis is the cost of the activated iron;
currently approximately $40 for 5 g, which produces ca. 3 g of Bip
derivative.
Work by Fokas and co-workers26 showed that benzimidazoles
can be accessed in one step by reacting o-nitroanilines and aryl
aldehydes in the presence of the reducing agent sodium dithionite
(Na2S2O4) in a dimethyl sulfoxide/ethanol/water mixture at 70–
80 ꢀC. Inspired by this, we hypothesized that Na2S2O4 could replace
activated iron in the reduction/ring-closing step in our one-pot Bip
synthesis. If successful, this procedure would eliminate the need for
activated iron and therefore washing the product with EDTA. Fur-
thermore, with an eye toward scaling up, Na2S2O4 is approximately
20 times less expensive than activated iron.
Gratifyingly, following in situ formationof 5, simpleaddition of an
aqueous ethanolic solution of Na2S2O4 results in the formation of
Bip1from2and4 (Scheme1, Fi andFii). Additionofsaturatedaqueous
sodium bicarbonate solution to the reaction mixture resulted in the
precipitation of crude Bip1. Extraction of this solid with dichloro-
methane (DCM) yielded the desired product in 70% yield, which was
confirmed by 1H NMR. While this purification methodology was ef-
ficient for Bip1, as before, the n-hexyl derivatives (Bip2 and Bip4) did
not precipitate from the basic aqueous solution. Therefore, to facili-
tate a more efficient workup of these ligands, we replaced NMP with
a lower boiling aprotic solvent, N,N-dimethylformamide (DMF).
Usingthis DMF-basedprotocol wewereabletoaccessBip1–Bip4and
Bip6 (Table 1) in yields similar to the one-pot activated iron/HCl
method (65–81%). An additional derivative with benzoxy sub-
stituents in the 50-positions (X sites, Fig. 1b) and a methoxy sub-
stituent in the 4-position (Scheme 3) was also prepared via these
reaction conditions, yielding Bip7 in 81% yield (Table 1).
2.3. Use of sodium dithionite and aqueous ethanol as the
reducing agent in the one-pot synthesis of Bip derivatives
While the above new one-pot procedure works effectively, the
use of activated iron in the reduction/ring-closing step has two
Scheme 3. (A) BnBr, K2CO3, acetonitrile, 70 ꢀC, 22 h, quantitative; (B) NH2Et, high pressure flask, 105 ꢀC, 24 h, 95%; (C) (i) MeOH, H2SO4, 80 ꢀC, 4 h; (ii) CH3I, K2CO3, acetonitrile,
70 ꢀC, 22 h; (iii) precipitate from hot EtOH with KOH, 90%; (D) SOCl2, DMF, 75 ꢀC, 2 h, quantitative; (E) (i) DMF, rt, 18 h; (ii) Na2S2O4, DMF, EtOH, H2O, 85 ꢀC, 18 h, 81%.

B.M. McKenzie et al. / Tetrahedron 64 (2008) 8488–8495
8491
2.4. Synthesis and liquid crystalline properties of Bip8
To demonstrate the facile conversion of these Bip derivatives
into monomers suitable for polymerization, we converted Bip1 into
the alkene-functionalized Bip8 (Scheme 4) via a two-step process
adapted from the literature.22,27 The methoxy groups were depro-
tected with boron tribromide (BBr3) in DCM and the resulting
phenolic groups were reacted with 5-bromopentene to access Bip8
in good yield (75% from Bip1). Interestingly, these simple ligands
display thermotropic liquid crystalline properties upon cooling (I
97.7 N w2 ꢀC g). The differential scanning calorimetry (DSC) cooling
(top) trace in Figure 2 reveals, upon cooling from 200 ꢀC, a small
exotherm at 97.7 ꢀC. Polarized light optical microscopy (POM) im-
ages taken during a similar thermal program show a transition
from an isotropic state to a birefringent Schlieren texture indicative
of nematic liquid crystalline order (Fig. 2). The temperature of this
phase transition (w100 ꢀC) corresponds to the exotherm in the DSC
cooling trace. Further cooling reveals a Tg of approximately 2 ꢀC in
the DSC, while POM reveals that the liquid crystallinity remains
Figure 3. Bip8 binding with
a
lanthanide nitrate and POM images showing the
resulting transition from
a liquid crystalline to an isotropic state (POM: Bip8/
Eu(NO3)3¼1:1).
intact throughout the cooling. This transition appears to be mono-
tropic, as, upon heating, no liquid crystalline transitions are
apparent via DSC or POM. Upon heating, the monomer does exhibit
a Tg (w9 ꢀC) before it recrystallizes at 42.5 ꢀC and subsequently
melts at 106.5 ꢀC.
Piguet and co-workers have designed a variety of mesogenic Bip
derivatives and have observed liquid crystalline behavior of such
ligands in 1:1 lanthanide complexes.3,4 We hypothesized that with
our ‘simple’ mesogens the addition of metals would disrupt liquid
crystallinity, in part, on account of the smaller aspect ratio and
generally less stable mesogenic phases relative to many of the
Piguet systems. As a simple demonstration of the chemo-re-
sponsive nature of Bip8, we examined the POM of the free ligand
and its 1:1 complex with Eu(NO3)3. Figure 3 shows that the
Bip8$Eu(NO3)3 complex shows no birefringence, indicative of
a ‘switching off’ of the ligand’s liquid crystalline behavior upon
complexation with Eu(NO3)3 at room temperature. Since the
binding of such metal ions to Bip is reversible, this could provide
a facile route to interesting chemo-responsive liquid crystalline
materials.
Scheme 4. Synthesis of Bip8. (A) BBr3, rt, 4 h, quantitative; (B) Br(CH2)3CH]CH2,
K2CO3, 4:1 THF/methanol, 75 ꢀC, 12 h, 75%.
3. Conclusion
Using a one-pot procedure, we successfully synthesized highly
functionalized Bip derivatives (Bip1–Bip7) with increased yields
(63–90% vs 45% for the two-step protocol) and subsequently re-
duced preparation time from approximately four days to one day. In
addition, the R0¼ethyl derivatives were determined pure by 1H
NMR and did not require column chromatography. Substituting
Na2S2O4 for activated iron in the reduction/ring-closing step sig-
nificantly reduced the cost of the synthesis and eliminated the need
to decomplex FeII from the Bip cavity, further simplifying workup.
Overall, the modifications to this protocol proved to be versatile for
a range of substituents on the Bip core and allowed access to these
ligands on a multi-gram scale. We are currently investigating in-
corporating these derivatives into a range of macromolecular
architectures.
Figure 2. DSC thermogram and POM images of Bip8 showing the transition from an
isotropic to a liquid crystalline state upon cooling. DSC thermal program: equilibrate at
ꢁ90 ꢀC, heat to 200 ꢀC at 10 ꢀC/min, hold 1 min, cool to ꢁ90 ꢀC at 10 ꢀC/min, hold 1 min,
heat to 200 ꢀC at 10 ꢀC/min, hold 1 min, cool to ꢁ90 ꢀC at 10 ꢀC/min. POM thermal
program: heat to 200 ꢀC at 10 ꢀC/min, hold 10 min, cool to ꢁ10 ꢀC at 10 ꢀC/min, hold
1 min, heat to 25 ꢀC at 10 ꢀC/min, heat to 200 ꢀC at 10 ꢀC/min, hold 1 min, cool to ꢁ10 ꢀ
C
at 10 ꢀC/min. Trace and images are from second cools.

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B.M. McKenzie et al. / Tetrahedron 64 (2008) 8488–8495
4. Experimental
temperatures using Spot software (Diagnostic Instruments, Inc.).
Spatial dimensions were calibrated using a stage micrometer with
10
m line spacing. Either a 50ꢂ/0.5 NA or a 20ꢂ/0.4 NA achromat
4.1. General
m
long working-distance objective lens (Olympus LMPlanFI) was
employed. The Instec hotstage was equipped with a liquid nitrogen
LN2-P cooling accessory for accurate temperature control during
heating and cooling runs. The ligand POM sample was dissolved in
chloroform to give a 0.5 wt % solution. For the metal-binding ex-
periment, the ligand and one molar equivalent of Eu(NO3)3 were
weighed into a vial, dissolved in acetonitrile, and dried in vacuo. This
complex was then dissolved in acetonitrile to give a 0.5 wt % solu-
tion. Microscopy slides were prepared by dropping these solutions
onto clean microscope slides, which were covered to slow evapo-
ration until this was complete. To clear thermal history, the samples
were heated to 200 ꢀC, held at 200 ꢀC for 1 min, cooled to ꢁ10 ꢀC at
10 ꢀC/min, held at ꢁ10 ꢀC for 1 min, and finally heated to 25 ꢀC at
10 ꢀC/min. The samples were then heated to 200 ꢀC at 10 ꢀC/min,
held at 200 ꢀC for 1 min, and cooled to ꢁ10 ꢀC at 10 ꢀC/min. Optical
micrographs were collected during these second heating and cool-
ing steps.
4-Hydroxypyridine-2,6-dicarboxylic acid (chelidamic acid) was
purchased from TCI America and tetrakis(triphenylphosphine)
palladium(0) catalyst was purchased from Strem, Inc. All solvents,
ammonium chloride, potassium carbonate, potassium hydroxide,
sodium dicarbonate, and sodium hydroxide were purchased from
Fisher Scientific. Ethylenediaminetetraacetic acid was purchased
from Acros. All other chemicals including activated iron were
purchased from Aldrich. Solvents were dried accordingly via
distillation.
4.1.1. Infrared spectra
IR spectra were recorded as potassium bromide disks on a ABB
Bomem MB104 FT-IR spectrometer.
4.1.2. NMR spectra
NMR spectra were recorded on either a Varian Inova 600 MHz
NMR spectrometer (13C NMR¼150.8 MHz) or a Varian Mercury
300 MHz NMR spectrometer (13C NMR¼75.5 MHz) using the deu-
terated solvents chloroform-d, deuterium oxide, or dimethyl sulf-
oxide-d6, purchased from Norell, Inc., USA.
4.2. Synthesis
N-Ethyl-4-methoxy-2-nitroaniline (2)22 was synthesized
according to the literature procedures.
4.1.3. Mass spectra
Mass spectra were recorded on a Bruker AutoFlex III MALDI-TOF
MS instrument using the matrix 2-(4-hydroxyphenylazo)benzoic
acid (HABA) and potassium iodide (KI), if necessary.
High resolution mass spectra were carried out on a Kratos
MS25RFA GC/mass spectrometer using the fast atom bombardment
(FAB) capability.
4.2.1. General N-ethyl-2-nitroaniline synthesis
Using a heavy wall glass pressure vessel, the halogenated ni-
trobenzene compound (10 g) was dissolved in 60–80 mL ethyl-
amine (70 wt %) in water solution. The reaction vessel was sealed,
placed in an oil bath heated to 105 ꢀC, and stirred for at least 24 h.
The reaction was allowed to cool, poured into dichloromethane
(DCM, 50 mL), and washed with half saturated ammonium chloride
(3ꢂ, 100 mL). The organic solvent was removed in vacuo.
4.1.4. High pressure liquid chromatography
All high pressure liquid chromatography (HPLC) experiments
were run on a Varian ProStar with reverse-phase C18 silica analyt-
ical column using the following procedures: flow rate¼1 mL/min,
solvent A¼H2O (0.10% trifluoroacetic acid, TFA), solvent
B¼acetonitrile (MeCN, 0.08% TFA). Solvent program: 98%, A 2% B.
Ramp to 2% A, 98% B, over 20 min, hold for 10 min. Elution time was
reported at 365 nm wavelength, unless otherwise noted.
4.2.1.1. 4-Bromo-N-ethyl-2-nitroaniline (8).28 Purified via column
chromatography on silica (chloroform, CHCl3). Red/orange solid,
yield: 93%, mp: 86–89 ꢀC, TLC: 50:50 hexanes/CDCl3 Rf¼0.50. 1H
NMR (600 MHz, CDCl3)
d
(ppm): 8.31 (d, 1H, J¼2.4 Hz, ArH), 7.95 (br
s, 1H, ArH), 7.48 (m, 1H, ArH), 6.75 (d, 1H, J¼9.6 Hz, ArH), 3.33 (m,
2H, CH2CH3), 1.36 (t, 3H, J¼6.0 Hz, CH2CH3). 13C NMR (150.8 MHz,
CDCl3)
d (ppm): 144.3, 138.8, 128.8, 115.4, 106.1, 37.8, 14.2. IR (KBr):
4.1.5. Differential scanning calorimetry
3376, 3319, 2981, 2909, 2863, 1614, 1562, 1505, 1474, 1426, 1348,
1264, 1233, 1158, 1137, 1073, 1031 cmꢁ1. HPLC: 20.5 min. HRMS
(FAB, Mþ) calcd for C8H9N2O2Br 243.9847, found 243.9841.
Differential scanning calorimetry (DSC) experiments were per-
formed on a TA Instruments Q100 DSC equipped with a refrigerated
cooling system (RCS). The DSC cell resistance and capacitance were
calibrated using the Tzero calibration procedure (TA Instruments-
Waters LLC), and the cell constant and temperature were calibrated
using an indium standard. All samples were run under flowing
nitrogen atmosphere and were heated and cooled at rate of
10 ꢀC/min through the temperature range of ꢁ90 to 200 ꢀC. This
temperature range proved sufficient to analyze the glass, melting,
and isotropization (clearing) transitions in this study. The glass
transition temperatures were determined by taking the midpoints
of the stepwise change in the heat flow signal from the second
heating and second cooling traces. Recrystallization, melting, and
clearing temperatures of these monomers were determined from
either the peak maximum (for exotherm) or minimum (for endo-
therm) on the second heating or cooling traces.
4.2.1.2. N-Ethyl-5-methyl-2-nitroaniline (13). Purified via column
chromatography on silica (hexanes/DCM¼100:0–0:100). Orange
solid, yield: 95%, mp: 53–56 ꢀC, TLC: 50:50 hexanes/CDCl3 Rf¼0.37.
1H NMR (300 MHz, CDCl3)
d
(ppm): 8.00 (d, 1H, J¼1.5 Hz, ArH), 7.97
(br s,1H, NH), 6.57 (s,1H, ArH), 6.39 (dd,1H, J¼0.9,1.5 Hz, ArH), 3.29
(m, 2H, CH2), 2.31 (s, 3H, ArCH3), 1.33 (t, 3H, J¼3.6 Hz, CH2CH3). 13
C
NMR (75.5 MHz, CDCl3)
d (ppm): 147.9, 145.6, 129.8, 126.8, 117.0,
113.5, 37.9, 22.5, 14.7. IR (KBr): 3373, 3352, 2966, 2921, 2875, 1629,
1580, 1497, 1475, 1342, 1318, 1263, 1182, 1150, 1076, 1013 cmꢁ1
.
HPLC: 18.9 min. HRMS (FAB, MHþ) calcd for C9H13N2O2 181.0977,
found 181.0985.
4.2.1.3. 4-Benzoxy-N-ethyl-2-nitroaniline
(19). 4-Chloro-3-nitro-
phenol (1.00 g, 5.76 mmol), distilled acetonitrile (30 mL), K2CO3
(4.00 g), and benzyl bromide (1.032 g, 6.036 mmol) were reacted at
75 ꢀC for 24 h under an Ar atmosphere. Solvent was removed in
vacuo leaving yellow orange crystals. The crude product was
dissolved in chloroform and washed with water. The solvent was
removed in vacuo yielding yellow orange crystals that melted at
36–38 ꢀC, which were used without further purification. TLC: 50:50
4.1.6. Polarized light optical microscopy
Polarized light optical microscopy (POM) studies were per-
formed using an Olympus BX51 microscope equipped with 90ꢀ
crossed polarizers, a HCS402 hot stage from Instec Inc., and a digital
camera (14.2 Color Mosaic Model from Diagnostic Instruments,
Inc.). Images were acquired from the camera at selected

B.M. McKenzie et al. / Tetrahedron 64 (2008) 8488–8495
8493
DCM/hexanes Rf¼0.33. This product was used following the pro-
cedures for N-ethyl-2-nitroaniline synthesis, above. The product
was purified via column chromatography on silica (hexanes/
DCM¼100:0–0:100), which also separated out the byproducts from
reactions with benzyl bromide. Bright red crystals, overall yield:
95%, mp: 83–86 ꢀC, TLC: 50:50 DCM/hexanes Rf¼0.21. 1H NMR
131.4, 128.1, 127.2, 123.8, 114.3, 55.3, 37.8, 14.4. IR (KBr): 3455, 3367,
2975, 2938, 2887, 2857, 1628, 1607, 1559, 1505, 1474, 1424, 1351,
1248, 1173, 1052, 1028 cmꢁ1. HPLC: 21.3 min (
l
¼310 nm). HRMS
(FAB, Mþ) calcd for C15H16N2O3 272.1168, found 272.1161.
4.2.3.2. N-Hexyl-2-nitro-4-(40-methoxy)phenylaniline (11). Purified
via column chromatography on silica (CHCl3/hexanes¼70:30–
100:0). Yield: 96%, mp: 79–81 ꢀC, TLC: 50:50 hexanes/CDCl3
(600 MHz, CDCl3) d (ppm): 7.98 (s, 2H, PyrH), 7.39 (m, 4H, ArH), 7.05
(dd, 2H, J¼9.3, 3.0 Hz, ArH), 4.85 (q, 2H, J¼7.2 Hz, CH2CH3), 3.90 (s,
3H, OCH3), 1.37 (t, 3H, J¼7.2 Hz, CH3). 13C NMR (150.8 MHz, CDCl3)
Rf¼0.26. 1H NMR (600 MHz, CDCl3)
d (ppm): 8.36 (s, 1H, ArH), 8.07
d
(ppm): 156.0, 150.7, 150.3, 142.8, 130.1, 114.2, 110.8, 101.1, 55.8,
(br s, 1H, ArH), 7.66 (dd, 1H, ArH), 7.47 (d, 2H, J¼8.4 Hz, ArH), 6.95
(d, 2H, J¼8.4 Hz, ArH), 6.90 (d, 1H, J¼9.0 Hz, ArH), 3.83 (s, 3H,
OCH3), 3.32 (q, 2H, J¼6.6 Hz, NCH2),1.73 (p, 2H, J¼7.2 Hz, NCH2CH2),
1.45 (m, 2H, NCH2CH2CH2), 1.34 (m, 4H, CH2CH2CH3), 0.90 (m, 3H,
39.9, 15.5. IR (KBr): 3379, 3358, 3044, 2963, 2927, 2848, 1635, 1574,
1529, 1511, 1384, 1345, 1278, 1218, 1155, 1055, 1010 cmꢁ1. HPLC:
21.4 min. MALDI-MS (m/z, matrix: none): [MþK]þ 312.
CH2CH3). 13C NMR (150.8 MHz, CDCl3)
d (ppm): 144.5, 138.8, 128.8,
4.2.2. General N-hexyl-2-nitroaniline synthesis
115.5, 106.1, 43.1, 31.4, 28.8, 26.6, 22.5, 14.0. IR (KBr): 3352, 2954,
2933, 2854, 1631, 1607, 1562, 1505, 1360, 1245, 1185, 1158, 1049,
The appropriate halogenated nitrobenzene (43 mmol) was
added to a round bottom flask followed by 70 mL of hexyl amine.
The flask was stirred at 75 ꢀC for 12 h. The reaction volume was
diluted with DCM and extracted with half saturated ammonium
chloride (3ꢂ100 mL) and water (1ꢂ200 mL). The organic phase was
dried over Na2SO4 and the solvent was removed in vacuo.
1025 cmꢁ1. HPLC: 24.3 min (
l
¼310 nm). HRMS (FAB, Mþ) calcd for
C19H24N2O3 328.1787, found 328.1787.
4.2.4. Addition of alkoxy substituent to 4-hydroxypyridine-2,6-
dicarboxylic acid
4.2.2.1. N-Hexyl-4-methoxy-2-nitroaniline (6). Purified via column
chromatography on silica (hexanes/DCM¼100:0–0:100). Red oil,
yield: 90%, TLC: 50:50 hexanes/CDCl3 Rf¼0.21. 1H NMR (600 MHz,
4.2.4.1. 4-Benzoxypyridine-2,6-dicarboxylic acid (15). 4-Benzoxy-
pyridine-2,6-dicarboxylic dipotassium salt was prepared according
to the literature procedure25 and dissolved in 20 mL deionized
water. Hydrochloric acid was added dropwise until the solution
reached a pH of 1 and a white precipitate formed. Yield: quanti-
CDCl3)
d
(ppm): 8.02 (br s, 1H, NH), 7.58 (d, 1H, J¼3.0 Hz, ArH), 7.13
(dd, 1H, J¼3.0, 9.6 Hz, ArH), 6.81 (d, 1H, J¼9.6 Hz, ArH), 3.78 (s, 3H,
OCH3), 3.27 (q, 2H, J¼5.4 Hz, NCH2),1.70 (p, 2H, J¼7.2 Hz, NCH2CH2),
1.42 (p, 2H, J¼7.2 Hz, NCH2CH2CH2), 1.32 (m, 4H, CH2CH2CH3), 0.89
1
tative, mp: 120–122 ꢀC. H NMR (600 MHz, DMSO-d6, 40 ꢀC)
d
(ppm): 7.95 (s, 2H, PyrH), 7.45 (d, J¼7.64 Hz, ArH), 7.39 (t,
(t, 3H, J¼7.2 Hz, CH2CH3). 13C NMR (150.8 MHz, CDCl3)
d
(ppm):
J¼7.36 Hz, ArH), 7.34 (d, J¼7.36 Hz, 5H, PhH), 5.33 (s, 2H, OCH2). 13
C
149.1, 141.5, 130.2, 127.3, 115.1, 106.6, 55.7, 43.2, 31.4, 29.0, 26.7, 22.5,
14.0. IR (KBr): 3376, 2957, 2933, 2857, 1574, 1523, 1493, 1443, 1348,
NMR (150.8 MHz, DMSO-d6, 40 ꢀC)
d (ppm): 167.1, 166.0, 150.5,
136.3, 129.3, 129.0, 128.6, 114.6, 70.8.
1273, 1231, 1149, 1061, 1043 cmꢁ1. HPLC: 22.3 min (
l¼280 nm).
HRMS (FAB, Mþ) calcd for C13H20N2O3 252.1474, found 252.1466.
4.2.4.2. 4-Methoxypyridine-2,6-dicarboxylic
dipotassium
salt
(20). Chelidamic acid (14, 2.00 g, 10.9 mmol), degassed methanol
(100 ml), and concentrated sulfuric acid (H2SO4, 20 drops) were
combined and refluxed at 80 ꢀC for 4 h. After cooling, the mixture
was neutralized with a saturated solution of sodium bicarbonate
(NaHCO3) in water. The solvent was removed in vacuo, producing
a yellow to white solid. Distilled acetonitrile (120 mL), K2CO3 (16 g),
and iodomethane (2.28 g, 16.1 mmol) were added to the flask and
refluxed at 70 ꢀC for 22 h. Solvent was removed in vacuo. The
resulting product was extracted with DCM (3ꢂ75 mL) from water.
The organic layer was dried in vacuo. In a large beaker, ethanol
(100 mL) and potassium hydroxide (KOH, 4.00 g) were stirred and
heated until the KOH was fully dissolved. The product was dis-
solved in additional hot ethanol (150 mL). The hot ethanol/product
mixture was slowly added to the hot ethanol/KOH mixture and
a white precipitate immediately formed. The mixture stirred for
45 min. The white precipitate was filtered off and washed with
50 mL of hot ethanol to remove excess KOH. Yield: 2.68 g (90%),
4.2.2.2. 4-Bromo-N-hexyl-2-nitroaniline (9). Purified via column
chromatography on silica (CHCl3). Red crystals, yield: 94%, mp:
25 ꢀC, TLC: 50:50 hexanes/CDCl3 Rf¼0.52. 1H NMR (600 MHz,
CDCl3)
d
(ppm): 8.28 (d, 1H, J¼2.4 Hz, ArH), 8.02 (br s, 1H, NH), 7.46
(dd, 1H, J¼2.4, 9.0 Hz, ArH), 6.74 (d, 1H, J¼9.0 Hz, ArH), 3.26 (m, 2H,
NCH2), 1.70 (tt, 2H, J¼7.2 Hz, NCH2CH2), 1.42 (m, 2H, NCH2CH2CH2),
1.32 (m, 4H, CH2CH2CH3), 0.89 (m, 3H, CH2CH3); 13C NMR
(150.8 MHz, CDCl3)
d (ppm): 144.5, 138.8, 128.8, 115.5, 106.1, 43.1,
31.4, 28.8, 26.6, 22.5, 14.0. IR (KBr): 3449, 3386, 2957, 2927, 2857,
1623, 1565, 1505, 1478, 1402, 1351, 1260, 1236, 1155, 1067 cmꢁ1
.
HRMS (FAB, Mþ) calcd for C12H17N2O2Br 300.0473, found 300.0476.
4.2.3. General Suzuki coupling reaction
The appropriate 4-bromo-2-nitrobenzeneamine (12.24 mmol),
4-methoxphenyl boronic acid (1.86 g, 12.2 mmol), and K2CO3
(3.21 g) were added to a round bottom flask. THF (86 mL) and water
(34 mL) were combined and added to the flask, which was sub-
sequently flushed with Ar. Tetrakis(triphenylphosphine)palla-
dium(0) catalyst (0.78 g, 0.67 mmol) was then added. The round
bottom was again flushed with Ar and heated to 75 ꢀC for 18 h,
stirring rapidly. The organic layer was removed in vacuo and the
resulting dispersion extracted with chloroform (3ꢂ100 mL).
mp: decomposes above 330 ꢀC. 1H NMR (600 MHz, D2O)
7.31 (s, 2H, PyrH), 4.63 (s, 3H, OCH3). 13C NMR (150.8 MHz, D2O/
DMSO-d6) (ppm): 173.0, 167.5, 154.9, 111.1, 55.8. IR (KBr): 2948,
d (ppm):
d
1628, 1589, 1435, 1396, 1354, 1299, 1263, 1115, 1046, 995, 943, 886,
811, 792 cmꢁ1. HPLC: 14.5 min (
for C8H5NO5K3 311.9079, found 311.9078.
l
¼280 nm). HRMS (FAB, MKþ) calcd
4.2.3.1. N-Ethyl-2-nitro-4-(40-methoxy)phenylaniline (10). Purified
via column chromatography on silica (CHCl3/hexanes¼70:30–
100:0). Red/orange solid, yield: 98%, mp: 104–107 ꢀC, TLC: 50:50
4.2.5. General synthesis of 2,6-pyridine dicarboxylic acid chloride
(4, 16, 21)
In a dry 250 mL round bottom flask, 6.0 mmol dry 2,6-pyridine
carboxylic acid, 20 mL thionyl chloride, and 0.5 mL anhydrous N,N-
dimethylformamide (DMF) were stirred for 2 h in an oil bath heated
to 75 ꢀC under an Ar atmosphere. The excess thionyl chloride was
removed in vacuo. These products were used without further
purification assuming quantitative yields.
hexanes/CDCl3 Rf¼0.21. 1H NMR (600 MHz, CDCl3)
d (ppm): 8.37 (d,
J¼2.4 Hz, 1H, ArH), 8.00 (br s, 1H, NH), 7.67 (m, 1H, ArH), 7.48 (d,
J¼9.0 Hz, 2H, ArH), 6.96 (d, 2H, J¼9.0 Hz, ArH), 6.91 (d,1H, J¼9.0 Hz,
ArH), 3.84 (s, 3H, OCH3), 3.39 (m, 2H, NCH2), 1.39 (t, 3H, J¼7.2 Hz,
CH2CH3). 13C NMR (150.8 MHz, CDCl3)
d (ppm): 158.9, 144.3, 134.8,

8494
B.M. McKenzie et al. / Tetrahedron 64 (2008) 8488–8495
4.2.6. General synthesis of 2,6-bisbenzimidazolylpyridine
derivatives using activated iron in mineral oil
ArH), 7.53 (br d, 2H, J¼8.4 Hz, ArH), 7.03 (d, 4H, J¼8.4 Hz, ArH), 4.83
(q, 4H, J¼7.2 Hz, NCH2), 3.88 (s, 6H, OCH3), 1.41 (t, 6H, J¼7.2 Hz,
Procedure A. This procedure was modified from the literature.23
The appropriate N-alkyl-o-nitroaniline derivative (12.0 mmol) dis-
solved in N-methyl pyrrolidinone (NMP, 12 mL) was added into the
reaction vessel with the appropriate diacid chloride and stirred
under an Ar atmosphere at 50 ꢀC. After 8 h, activated iron in min-
eral oil (5 g), NMP (38 mL), and hydrochloric acid (10 mL) were
slowly added to the reaction flask. The reaction was stirred for 12 h
in a 90 ꢀC oil bath under an Ar atmosphere. The contents of the
reaction were poured into saturated aqueous EDTA solution
(500 mL) and neutralized with sodium bicarbonate.
CH2CH3). 13C NMR (75.5 MHz, CDCl3)
d (ppm): 158.9, 150.4, 149.9,
143.5, 138.1, 136.2, 135.4,134.3, 128.4, 125.7, 123.2, 118.1, 114.3, 110.3,
55.4, 39.9, 15.5. IR (KBr): 2972, 2902, 1607, 1568, 1517, 1474, 1426,
1337, 1278, 1241, 1176, 1154, 1100, 1031, 991, 904, 810, 735 cmꢁ1
.
HPLC: 21.3 min. HRMS (FAB, MHþ) calcd for C37H34N5O2 580.2712,
found 580.2712.
4.2.7.4. 2,6-Bis(10-n-hexyl-50-(400-methoxy)phenylbenzimidazol-20-
yl)pyridine (Bip4). Procedure A. Purified via column chromatogra-
phy on silica (CHCl3/MeOH¼97:3). Off-white solid, yield: 72%.
Procedure B. Purified via column chromatography on silica (CHCl3/
MeOH¼97:3). Yield: 69%, mp: 200 ꢀC. TLC: 97:3 DCM/MeOH
4.2.7. General synthesis of 2,6-bisbenzimidazolylpyridine
derivatives using sodium dithionite
Rf¼0.49. 1H NMR (600 MHz, CDCl3)
d
(ppm): 8.34 (d, 2H, J¼7.8 Hz,
Procedure B. The appropriate N-alkyl-o-nitroaniline derivative
(12.0 mmol) dissolved in anhydrous DMF (5 mL) was added to the
reaction vessel with the appropriate diacid chloride and stirred
under an Ar atmosphere at room temperature for 18 h. Pure
Na2S2O4 (85%) added in a 4 molar excess, additional DMF (20 mL),
and EtOH (20 mL) were added to the solution and the temperature
was increased to 85 ꢀC. Deionized water (20 mL) was added and the
reaction was heated to reflux for 18 h under an Ar atmosphere. The
reaction was allowed to cool to room temperature and 4 M NaOH
was added to the solution. Solvents were removed in vacuo. The
crude product was dissolved in DCM (50 mL) and was washed with
water (3ꢂ100 mL). DCM was removed in vacuo.
PyrH), 8.08 (t, 1H, J¼8.4, 7.8 Hz, PyrH), 8.03 (s, 2H, ArH), 7.63 (d, 4H,
J¼9 Hz, ArH), 7.58 (dd, 2H, J¼8.4 Hz, ArH), 7.50 (d, 2H, J¼8.4 Hz,
ArH), 7.03 (d, 4H, J¼8.4 Hz, ArH), 4.73 (t, 4H, J¼7.2, 7.8 Hz, NCH2),
3.88 (s, 6H, OCH3), 1.76 (tt, 4H, J¼7.2 Hz, NCH2CH2), 1.08 (m, 12H,
CH2CH2CH2CH3), 0.66 (m, 6H, CH2CH3). 13C NMR (150.8 MHz, CDCl3)
d
(ppm): 158.6, 150.4, 149.7, 143.0, 138.0, 135.9, 135.2, 134.0, 128.1,
125.2, 122.9, 117.8, 114.0, 110.2, 55.1, 44.8, 30.9, 29.8, 26.1, 22.1, 13.5.
IR (KBr): 2972, 2957, 2924, 2987, 2860, 1650, 1607, 1562, 1465, 1435,
1260, 1179, 1091, 1031, 1016, 910, 841, 816, 798 cmꢁ1. HPLC:
23.3 min. HRMS (FAB, MHþ) calcd for C45H50N5O2 692.3964, found
692.3960.
4.2.7.5. 2,6-Bis(10-ethyl-60-methylbenzimidazol-20-yl)pyridine
(Bip5). Procedure A. Purified via column chromatography on silica
(DCM/MeOH¼100:0, 98:2,.90:10). Off-white solid, yield: 84%, mp:
175–178 ꢀC, TLC: 98:2 DCM/MeOH Rf¼0.18. 1H NMR (300 MHz,
4.2.7.1. 2,6-Bis(10-ethyl-50-methoxybenzimidazol-20-yl)pyridine
(Bip1). Procedure A. Precipitated from neutralized aqueous EDTA
solution described above. White solid, yield: 90%. Procedure B.
Recrystallized from DCM/methanol (MeOH). Yield: 70%, mp: 202–
204 ꢀC, TLC: 98:2 DCM/MeOH Rf¼0.21. 1H NMR (300 MHz, CDCl3)
CDCl3)
d
(ppm): 8.30 (d, 2H, J¼7.5 Hz, PyrH), 8.01 (t, 1H, J¼7.5 Hz,
PyrH), 7.74 (d, 2H, J¼6.0 Hz, ArH), 7.25 (s, 2H, ArH), 7.17 (dd, 2H,
J¼0.15, 6.0 Hz, ArH), 4.76 (q, 4H, J¼6.0 Hz, NCH2), 2.55 (s, 6H,
ArCH3), 1.35 (t, 6H, J¼6.0 Hz, CH2CH3). 13C NMR (75.5 MHz, CDCl3)
d
(ppm): 8.32 (d, 2H, J¼9.0 Hz, PyrH), 8.02 (t, 1H, J¼8.2 Hz, PyrH),
7.35 (d, 2H, J¼11.6 Hz, ArH), 7.34 (d, 2H, J¼3.1 Hz, ArH), 7.02 (dd, 2H,
J¼8.7, 3.2 Hz, ArH), 4.78 (q, 4H, J¼8 Hz, CH2), 3.90 (s, 6H, OCH3), 1.36
d
(ppm): 150.1, 149.5, 141.1, 137.9, 136.2, 133.6, 125.3, 124.4, 119.8,
(t, 6H, J¼8.0 Hz, CH2CH3). 13C NMR (75.5 MHz, CDCl3)
d
(ppm):
110.0, 39.7, 22.0, 15.4. IR (KBr): 2972, 2921, 2048, 1596, 1590, 1565,
156.6, 150.0, 149.9, 143.6, 138.0, 130.6, 125.3, 114.0, 110.7, 101.8, 55.8,
39.8, 15.5. IR (KBr): 3044, 2975, 2938, 2893, 2836, 1619, 1586, 1497,
1436, 1406, 1336, 1327, 1287, 1179, 1061, 814, 750 cmꢁ1. HPLC:
18.7 min
396.2188, found 396.2205.
(
l
¼310 nm). HRMS (FAB, MHþ) calcd for C25H26N5
1490, 1432, 1345, 1279, 1200, 1155, 1115, 1034, 947, 886, 800 cmꢁ1
.
HPLC: 18.5 min. HRMS (FAB, MHþ) calcd for C25H26N5O2 428.2086,
found 428.2089.
4.2.7.6. 4-Benzoxy-2,6-bis(10-ethyl-50-methoxybenzimidazol-20-yl)-
pyridine (Bip6). Procedure A. Precipitated from neutralized aqueous
EDTA solution described above. Washed with EDTA (3ꢂ100 mL).
Off-white solid, yield: 72%. Procedure B. Washed with MeOH. Yield:
70%, mp: 206–208 ꢀC, TLC: 97:3 DCM/MeOH Rf¼0.30. 1H NMR
4.2.7.2. 2,6-Bis(10-hexyl-50-methoxybenzimidazol-20-yl)pyridine
(Bip2). Procedure A. Purified via column chromatography on silica
(DCM/MeOH¼100:0, 98:2,.90:10). Yellow oil, yield: 63%. Pro-
cedure B. Purified with column chromatography on silica (DCM/
MeOH¼100:0, 98:2,.90:10). Yield: 65%, TLC: 98:2 DCM/MeOH
(600 MHz, CDCl3)
d
(ppm): 7.94 (s, 2H, PyrH), 7.45 (d, 2H, J¼6.4 Hz,
ArH), 7.40 (t, 2H, J¼6.4 Hz, ArH), 7.33 (m, 5H, ArH), 7.05 (dd, 2H,
J¼0.2, 8.3 Hz, ArH), 5.27 (s, 2H, OCH2), 4.70 (q, 4H, J¼6.3 Hz, NCH2),
3.89 (s, 6H, OCH3), 1.37 (t, 3H, J¼6.2 Hz, CH3). 13C NMR (150.8 MHz,
Rf¼0.35. 1H NMR (600 MHz, CDCl3)
d
(ppm): 8.27 (d, 2H, J¼7.8 Hz,
PyrH), 8.03 (t, 1H, J¼7.8 Hz, PyrH), 7.33 (d, 2H, J¼9.0 Hz, ArH), 7.32
(s, 2H, ArH), 7.01 (dd, 2H, J¼2.4, 8.9 Hz, ArH), 4.68 (t, 4H, J¼7.2 Hz,
NCH2), 3.90 (s, 6H, OCH3), 1.71 (p, 4H J¼7.2 Hz, NCH2CH2), 1.05 (m,
12H, CH2CH2CH2CH3), 0.65 (t, 6H, J¼7.2 Hz, CH2CH3). 13C NMR
CDCl3)
d (ppm): 166.3, 156.8, 151.8, 150.2, 143.7, 135.7, 130.9, 129.0,
128.6, 127.7, 114.2, 112.3, 110.9, 102.0, 70.5, 56.1, 40.1, 15.8. IR (KBr):
3081, 2954, 2933, 2858, 2842, 1620, 1586, 1568, 1490, 1430, 1276,
1197, 1152, 1107, 1028, 1010, 829, 789 cmꢁ1. HPLC: 19.4 min. HRMS
(FAB, MHþ) calcd for C32H32N5O3 534.2505, found 534.2510.
(150.8 MHz, CDCl3)
d (ppm): 156.7, 150.0, 149.9, 144.1, 138.2, 130.9,
125.3, 114.1, 110.9, 101.7, 55.8, 44.9, 31.1, 30.0, 26.2, 22.2, 13.6. IR
(KBr): 2951, 2922, 2909, 2854, 1689, 1657, 1580, 1498, 1435, 1278,
1200, 1158, 1106, 1031, 953, 826, 804 cmꢁ1. HPLC: 21.1 min. HRMS
(FAB, MHþ) calcd for C33H42N5O2 540.3338, found 540.3355.
4.2.7.7. 2,6-Bis(50-benzoxy-10-ethylbenzimidazol-20-yl)-4-methoxy-
pyridine (Bip7). Procedure B. Washed with MeOH. Off-white solid,
yield: 81%, mp: 160–162 ꢀC, TLC: 97:3 DCM/MeOH Rf¼0.27. 1H NMR
4.2.7.3. 2,6-Bis(10-ethyl-50-(400-methoxy)phenylbenzimidazol-20-yl)-
pyridine (Bip3). Procedure A. Precipitated from neutralized aqueous
EDTA solution described above. Off-white solid, yield: 83%. Pro-
cedure B. Recrystallized from DCM/MeOH. Yield: 72%, mp: 222–
227 ꢀC. TLC: 97:3 DCM/MeOH Rf¼0.35. 1H NMR (600 MHz, CDCl3)
(600 MHz, CDCl3) d (ppm): 7.84 (s, 2H, PyrH), 7.34–7.50 (m, 14H,
PhH), 7.09 (dd, 2H, ArH), 5.17 (s, 4H, OCH2), 4.76 (q, 4H, NCH2), 4.03
(s, 3H, OCH3), 1.35 (t, 3H, CH3). 13C NMR (150.8 MHz, CDCl3)
d
(ppm): 155.9, 151.8, 150.3, 142.8, 137.5, 131.9, 131.1, 128.1, 127.7,
114.9, 111.7, 110.8, 103.8, 71.0, 56.0, 40.1, 15.7. IR (KBr): 3075, 2972,
2927, 2897, 2866, 1623, 1590, 1571, 1490, 1472, 1423, 1378, 1345,
d
(ppm): 8.38 (d, 2H, J¼7.2 Hz, PyrH), 8.08 (t, 1H, J¼7.8 Hz, PyrH),
8.04 (s, 2H, ArH), 7.63 (d, 4H, J¼9.0 Hz, ArH), 7.59 (d, 2H, J¼8.4 Hz,
1309, 1279, 1173, 1115, 1040, 1013, 971, 919, 829, 796, 735 cmꢁ1
.

B.M. McKenzie et al. / Tetrahedron 64 (2008) 8488–8495
8495
HPLC: 20.8 min. HRMS (FAB, MHþ) calcd for C38H36N5O3 610.2818,
found 610.2828.
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4.2.8. Alkylation of Bip1 ligand
4.2.8.1. 2,6-Bis(10-ethyl-50-(n-penten-400-yl-1-oxy)benzimidazol-20-
yl)pyridine (Bip8). Bip1 was converted from the methoxy de-
rivative into the analogous phenolic derivative via the literature
procedures.20 In a dry 50 mL round bottom flask with a water
condenser attached, dry phenolic derivative (0.30 g, 0.75 mmol), 5-
bromopentene (0.47 g, 3.0 mmol), K2CO3 (0.55 g), and 4:1 tetra-
hydrofuran/MeOH mixture (10 mL) were stirred for 12 h in an oil
bath heated to 75 ꢀC under an Ar gas. All solvents were removed in
vacuo until completely dry. The dried compound was dissolved in
DCM (100 mL) and washed with water three times. The organic
layers were combined and solvent was removed in vacuo. Purified
via column chromatography on silica (CHCl3/MeOH¼100:0,
98:2,.90:10). White solid, yield: 75%, mp: 106.5 ꢀC from DSC, TLC:
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98:2 DCM/MeOH Rf¼0.24. 1H NMR (600 MHz, CDCl3)
d (ppm): 8.30
(d, 2H, J¼7.8 Hz, PyrH), 8.02 (t, 1H, J¼8.1 Hz, PyrH), 7.34 (d, 2H,
J¼8.4 Hz, ArH), 7.31 (2H, J¼1.2 Hz, ArH), 5.87 (m, 2H, H2C]CH), 5.04
(dd, 4H, J¼10.2, 40.2 Hz, H2C]CH), 4.77 (q, 4H, J¼7.2 Hz, NCH2),
4.06 (t, 4H, J¼6.6 Hz, OCH2), 2.28 (q, 4H, J¼6.6 Hz, OCH2CH2CH2),
1.94 (p, 4H, J¼7.2 Hz, OCH2CH2), 1.35 (t, 6H, J¼7.2 Hz, CH3). 13C NMR
11. Chetia, B.; Iyer, P. K. Tetrahedron Lett. 2006, 47, 8115–8117.
12. Vaidyanathan, V. G.; Nair, B. U. Eur. J. Inorg. Chem. 2003, 3633–3638.
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13094.
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7799–7808.
(150.8 MHz, CDCl3)
d (ppm): 156.1, 150.1, 150.0, 143.7, 138.1, 138.0,
130.8, 125.5, 115.4, 114.7, 110.8, 102.9, 68.1, 40.1, 30.5, 28.7, 15.9. IR
(KBr): 3068, 2972, 2938, 2899, 2863, 1622, 1577, 1423, 1272, 1192,
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2007, 13, 7828–7836.
1176, 1106, 1064, 965, 907, 810 cmꢁ1. HPLC: 21.0 min (
l
¼310 nm).
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Encyclopedia of Supramolecular Chemistry; Atwood, J. L., Steed, J. W., Eds.; Taylor
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HRMS (FAB, MHþ) calcd for C33H38N5O2 536.3025, found 536.3034.
Acknowledgements
This material is based upon work supported by the National Sci-
ence Foundation under Grant Nos. CAREER CHE- 0133164, CHE-
0704026, CAREER CTS-0093880, a National Science Foundation
Graduate Research Fellowship awarded to K.A.B. (DGE-0234629), and
the Case Western Reserve University President’s Research Initiative.
TheauthorsaregratefultoDr. J.BenjaminBeckforhelpfuldiscussions.
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