Controlling hydrogen-bond preferences in bipyridines with competing binding sites

Article abstract of DOI:10.1016/j.molstruc.2009.11.033

The design and synthesis of a family of supramolecular reagents (SRs) based on ethynyl-spaced substituted bipyridines are described, and their potential use as molecular 'hubs' for the predictable construction of binary and ternary co-crystals is explored. Each SR was synthesized in good yields through consecutive Pd-catalyzed Sonogashira cross-coupling reactions. Crystal structures of three binary co-crystals are presented with each structure clearly illustrating how accurate supramolecular assembly control can be achieved by increasing/decreasing the strength of the participating hydrogen-bond interactions.

Full text of DOI:10.1016/j.molstruc.2009.11.033

Journal of Molecular Structure 972 (2010) 35–40
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstruc
Controlling hydrogen-bond preferences in bipyridines with competing binding sites
*
Christer B. Aakeröy , Nate Schultheiss, John Desper
Department of Chemistry, Kansas State University, 111 CBC 213, Manhattan, KS, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 9 October 2009
Received in revised form 12 November 2009
Accepted 13 November 2009
Available online 20 November 2009
The design and synthesis of a family of supramolecular reagents (SRs) based on ethynyl-spaced substi-
tuted bipyridines are described, and their potential use as molecular ‘hubs’ for the predictable construc-
tion of binary and ternary co-crystals is explored. Each SR was synthesized in good yields through
consecutive Pd-catalyzed Sonogashira cross-coupling reactions. Crystal structures of three binary co-crys-
tals are presented with each structure clearly illustrating how accurate supramolecular assembly control
can be achieved by increasing/decreasing the strength of the participating hydrogen-bond interactions.
Ó 2009 Elsevier B.V. All rights reserved.
Keywords:
Co-crystals
Hydrogen bonds
Crystal engineering
Molecular recognition
1. Introduction
more basic benzimidazole site preferentially forms hydrogen bonds
to a more acidic carboxylic acid while the pyridine site forms
Organizing and constructing multi-component supermolecules
from individual entities through reliable and versatile supramolec-
ular synthetic strategies is an ever-increasing challenge in crystal
engineering [1]. The hydrogen bond is the most widely used non-
covalent interaction for synthesizing organic-based assemblies
due to its strength and directionality, but also because it can be
fine-tuned geometrically and electronically [2]. These attributes
have been utilized recently in the design of co-crystals where mul-
tiple hydrogen bond donors and acceptors compete within a single
crystallization reaction [3].
Isonicotinamide is a well-known supramolecular reagent (SR)
capable of forming both binary and ternary co-crystals with ex-
pected connectivity and topology [4]. If isonicotinamide is
combined with a monocarboxylic acid in a 1:1 ratio, the outcome
is typically a binary co-crystal where the acid interacts through
an O–HÁ Á ÁN hydrogen-bond with the pyridine (the best hydro-
gen-bond acceptor), while an amide-amide homodimer creates a
four-component supermolecule. When two different aromatic
acids are combined with isonicotinamide in a 1:1:1 ratio, the pyr-
idine site forms a hydrogen bond with the stronger carboxylic acid,
while the amide functionality, second best acceptor, binds to the
weaker acid. There are some limitations associated with isonicoti-
namide as a supramolecular building block, however, since its two
binding sites reside on the same molecular backbone and they can,
therefore, not be electrostatically altered independently, Scheme 1.
Another ditopic SR based on a combination of pyridyl- and benz-
imidazole binding sites can also form ternary co-crystals where the
hydrogen bonds with the weaker of the two carboxylic acids [5].
However, in contrast to the situation in isonicotinamide, the two
hydrogen-bond acceptors are electrostatically independent (e.g.,
the addition of a substituent on one ring will not affect the inherent
properties of the binding site on the other aromatic ring) which en-
ables electrostatic fine-tuning of the individual hydrogen-bonding
sites thereby increasing the versatility of the SR, Scheme 1.
Although the pyridyl and benzimidazole moieties are uncou-
pled, the comparison incorporates different heterocycles of varied
basicity and shape, i.e., 5-membered ring vs. 6-membered ring. In
order to eliminate the possibility that ring-size and/or shape-
complementary affects competitive intermolecular binding, we
need to examine two similar N-heterocyclic moieties attached to
the same uncoupled backbone.
Consequently, three different ethynyl-spaced substituted bip-
yridines were synthesized and characterized where the electro-
static nature of each binding site could be altered through the
use of electron-donating (–OMe) or electron-withdrawing (–F)
substituents around each pyridyl-heterocycle, Scheme 2.
Herein, we present the synthesis of three ethynyl-spaced
bipyridines 1–3 and our initial efforts to construct binary co-crys-
tals with predictable connectivities and stoichiometries.
2. Experimental
2.1. Materials and methods
All chemicals were purchased from Aldrich and used without
further purification unless otherwise noted. Bis(triphenylphos-
* Corresponding author. Tel.: +1 785 532 6665; fax: +1 785 532 6666.
E-mail address: aakeroy@ksu.edu (C.B. Aakeröy).
0022-2860/$ - see front matter Ó 2009 Elsevier B.V. All rights reserved.
doi:10.1016/j.molstruc.2009.11.033

36
C.B. Aakeröy et al. / Journal of Molecular Structure 972 (2010) 35–40
magnesium sulfate. The solvent was removed on a rotary evapora-
tor and the residue chromatographed on silica with a hexanes/
ethyl acetate mixture (10:1) as the eluant. The product was iso-
lated as a light brown solid. The product 1 was recrystallized from
toluene producing amber block shaped crystals (480 mg, 84%).
M.p: 133–135 °C; 1H NMR (dH; 400 MHz, CDCl3): 8.41 (d,
J = 1.6 Hz, 1H), 8.38 (s, 1H), 8.30 (d, J = 2.4 Hz, 1H), 7.95–7.90 (m,
1H), 7.31 (t, J = 1.4 Hz, 1H), 6.97 (dd, J = 8.4 Hz, J = 2.4 Hz, 3H),
3.88 (s, 3H); IR (KBr pellet)
t 3045, 1576, 1488, 1415, 1253,
1226 cmÀ1
.
2.2.2. [1-(2-Fluoropyrid-5-yl)-2-(3-pyrid-5-yl)ethyne] (2)
2-Fluoro-5-bromopyridine (1.60 g, 9.09 mmol), 3-ethynylpyri-
dine (1.30 g, 12.6 mmol), copper iodide (45 mg, 0.237 mmol), tri-
phenylphosphine (225 mg, 0.859 mmol), bis(triphenylphosphine)
palladium(II) dichloride (130 mg, 0.185 mmol) were added to a
round bottom flask. Tetrahydrofuran (30 mL) and triethylamine
(30 mL) were added and dinitrogen bubbled through the resultant
mixture for 10 min. A condenser was attached and the mixture
heated at 70 °C under a dinitrogen atmosphere. The reaction was
monitored by TLC and allowed to cool to room temperature upon
completion (48 h). The solution was then diluted with 50 mL of
ethyl acetate, washed with water (3 Â 100 mL) then washed with
saturated aqueous sodium chloride (1 Â 100 mL). The organic layer
was separated and dried over magnesium sulfate. The solvent was
removed on a rotary evaporator and the residue chromatographed
on silica with a hexanes/ethyl acetate mixture (10:1) as the eluant.
The product 2 was isolated as a light orange solid (1.58 g, 88%).
M.p: 63–65 °C; 1H NMR (dH; 400 MHz, CDCl3): 8.78 (d, J = 2 Hz,
1H), 8.59 (dd, J = 4.6 Hz, J = 1.4 Hz, 1H), 8.42 (d, J = 1.6 Hz, 1H),
7.95–7.91 (m, 1H), 7.82 (dt, J = 7.6 Hz, 1.8 Hz, 1H), 7.32 (dd,
J = 7.8 Hz, J = 5 Hz, 1H), 6.97 (dd, J = 8.6 Hz, J = 3 Hz, 1H); IR (KBr
Scheme 1. Two ditopic SRs; isonicotinamide, has
pyridyl/benzimidazol-1-yl-based SRs display a decoupled framework.
a coupled backbone, while
pellet)
t .
3065, 2223, 1576, 1487, 1247 cmÀ1
2.2.3. [1-(3-Methoxypyrid-5-yl)-2-(3-pyrid-5-yl)ethyne] (3)
3-Bromopyridine (396 mg, 2.51 mmol), 3-methoxy5-ethynyl-
pyridine (400 mg, 3.01 mmol), copper iodide (16 mg, 0.084 mmol),
triphenylphosphine (60 mg, 0.226 mmol), bis(triphenylphos-
phine)palladium(II) dichloride (60 mg, 0.086 mmol) were added
to a round bottom flask. Tetrahydrofuran (20 mL) and triethyl-
amine (20 mL) were added and dinitrogen bubbled through the
resultant mixture for 10 min. A condenser was attached and the
mixture heated at 70 °C under a dinitrogen atmosphere. The reac-
tion was monitored by TLC and allowed to cool to room tempera-
ture upon completion (48 h). The solution was then diluted with
50 mL of ethyl acetate, washed with water (3 Â 100 mL) then
washed with saturated aqueous sodium chloride (1 Â 100 mL).
The organic layer was separated and dried over magnesium sulfate.
The solvent was removed on a rotary evaporator and the residue
chromatographed on silica with a hexanes/ethyl acetate mixture
(10:1) as the eluant. The product 3 was isolated as an off-white so-
lid (455 g, 87%). M.p: 100–102 °C; 1H NMR (dH; 400 MHz, CDCl3):
8.780(d, J = 1.2 Hz, 1H), 8.60 (dd, J = 4.8 Hz, J = 1.6 Hz, 1H), 8.40
(d, J = 1.2 Hz, 1H), 8.31 (d, J = 8.31 Hz, 1H), 7.84 (dt, J = 7.6 Hz,
Scheme 2. Three bifunctional SRs each possessing two different hydrogen-bonding
moieties.
phine)palladium(II) dichloride was purchased from Strem while
trimethylsilylacetylene was purchased from GFS chemicals. Melt-
ing points were determined on a Fisher–Johns melting point appa-
ratus and are uncorrected. Compounds were prepared for infared
spectroscopic (IR) analysis as a mixture in KBr. 1H NMR spectra
were recorded on a Varian Unity plus 400 MHz spectrometer in
CDCl3.
2.2. Synthesis
2.2.1. [1-(2-Fluoropyrid-5-yl)-2-(3-methoxypyrid-5-yl)ethyne] (1)
2-Fluoro-5-bromopyridine (441 mg, 2.5 mmol), 3-methoxy-5-
ethynylpyridine (400 mg, 3.01 mmol), copper iodide (16 mg,
0.084 mmol), triphenylphosphine (60 mg, 0.226 mmol), bis(tri-
phenylphosphine)palladium(II) dichloride (60 mg, 0.086 mmol)
were added to a round bottom flask. Tetrahydrofuran (20 mL)
and triethylamine (20 mL) were added and dinitrogen bubbled
through the resultant mixture for 10 min. A condenser was at-
tached and the mixture heated at 70 °C under a dinitrogen atmo-
sphere. The reaction was monitored by TLC and allowed to cool
to room temperature upon completion (48 h). The solution was
then diluted with 50 mL of ethyl acetate, washed with water
(3 Â 100 mL) then washed with saturated aqueous sodium chlo-
ride (1 Â 100 mL). The organic layer was separated and dried over
1.8 Hz, 1H), 7.34–7.32 (m, 1H), 3.90 (s, 3H); IR (KBr pellet)
t
3048, 2210, 1576, 1414, 1227, 700 cmÀ1
.
2.3. Supramolecular synthesis
2.3.1. [1-(2-Fluoropyrid-5-yl)-2-(3-methoxypyrid-5-yl)ethyne] Á [4-
nitrobenzoic acid] (4)
1-(2-Fluoropyrid-5-yl)-2-(3-methoxypyrid-5-yl)ethyne (10.0
mg, 0.044 mmol) and 4-nitrobenzoic acid (7.0 mg, 0.042 mmol)
were added to a test tube and dissolved in 10 mL of acetonitrile.
Upon slow evaporation of the solvent over 4 days, needle-shaped

C.B. Aakeröy et al. / Journal of Molecular Structure 972 (2010) 35–40
37
crystals formed. M.p: 150–152 °C; IR (KBr pellet)
1911, 1707, 1534, 1341, 1253, 718 cmÀ1
t
3098, 2419,
2.4. X-ray crystallography
All datasets were collected at low temperature using MoK
.
a
radiation, Table 1. Except for 6, which was collected on a SMART
APEX diffractometer, datasets were collected on Bruker SMART
100 equipment. Data were collected using SMART or APEXII soft-
ware [6]. Initial cell constants were found by small widely sepa-
rated ‘‘matrix” runs. An entire hemisphere of reciprocal space
was collected. Scan speed and scan width were chosen based on
scattering power and peak rocking curves.
Unit cell constants and orientation matrix were improved by
least-squares refinement of reflections thresholded from the entire
dataset. Integration was performed with SAINT [7], using this im-
proved unit cell as a starting point. Precise unit cell constants were
calculated in SAINT from the final merged dataset. Lorenz and
polarization corrections were applied. Absorption corrections were
not applied. The datasets for 4 and 5 were corrected for extinction;
parameters for both datasets refined to values that were signifi-
cantly different from zero.
2.3.2. [1-(2-Fluoropyrid-5-yl)-2-(3-pyrid-5-yl)ethyne] Á [4-nitroben-
zoic acid] (5)
1-(2-Fluoropyrid-5-yl)-2-(3-pyrid-5-yl)ethyne (9.0 mg, 0.045
mmol) and 4-nitrobenzoic acid (8.0 mg, 0.048 mmol) were added
to a test tube and dissolved in 2 mL of ethanol. Upon slow evapo-
ration of the solvent over 4 days, rod-shaped crystals formed. Dec.
165 °C; IR (KBr pellet)
t 3059, 2415, 1951, 1717, 1576, 1521, 1489,
1310, 717 cmÀ1
.
2.3.3. [1-(3-Methoxypyrid-5-yl)-2-(3-pyrid-5-yl)ethyne] Á [3,5-
dinitrobenzoic acid] (6)
1-(3-Methoxypyrid-5-yl)-2-(3-pyrid-5-yl)ethyne
(10.0 mg,
0.048 mmol) and 3,5-dinitrobenzoic acid (20.0 mg, 0.094 mmol)
were added to a test tube and dissolved in 5 mL of methanol. Upon
slow evaporation of the solvent over 2 days, yellow rod-shaped
crystals formed. M.p: 139–141 °C; IR (KBr pellet)
t 3098, 2419,
Data were reduced with SHELXTL [8]. The structures were
solved in all cases by direct methods without incident. Positions
of the carboxylic acid hydrogen atoms were allowed to refine; all
other hydrogen atoms were assigned to idealized positions and
were allowed to ride. Occupancy factors for partially occupied sites
were allowed to refine until the last stages of data processing at
which point they were assigned to fixed values.
1911, 1707, 1534, 1341, 1253, 718 cmÀ1
.
Table 1
Crystal data and structure refinement parameters for 1 and 4–6.
Compound
1
4
5
6
Emperical formula C13H9FN2O C13H9FN2O
C7H5NO3
C12H7FN2O
C7H5NO3
365.32
Triclinic
P-1, 2
C13H10N2O
2 (C7H4N2O6)
634.47
Triclinic
P-1, 2
Formula weight
Crystal system
Space group, Z
a (Å)
228.22
Monoclinic Triclinic
P2(1)/n, 4 P-1, 2
7.1841(16) 3.7993(5)
395.34
3. Results and discussion
3.7472(4)
10.2937(14)
b (Å)
c (Å)
13.160(3)
11.410(2)
90
98.923(16) 92.251(8)
90
1065.7(4)
203(2)
1.422
0.104
11.3845(13) 13.1520(13) 10.6249(14)
SRs 1–3 were prepared in good yields via multiple Pd-catalyzed
Sonogashira [9] cross-coupling reactions, Scheme 3. The starting
precursors, 3-methoxy-5-ethynylpyridine and 3-ethynylpyridine,
were prepared as previously reported [10].
Recrystallizations were carried out for SRs 1–3 in a variety of
solvents; however, crystals suitable for single-crystal X-ray diffrac-
tion were only obtained for 1. The crystal structure of 1-(2-fluoro-
20.213(2)
95.741(6)
16.3768(18) 13.8098(18)
a
(ꢀ)
87.566(7)
87.877(9)
88.320(5)
805.51(15)
173(2)
102.139(2)
110.992(3)
93.559(3)
1362.9(3)
100(2)
b (ꢀ)
c
(ꢀ)
92.370(8)
868.30(18)
173(2)
V (Å3)
T (°K)
Dc (g cm
–3
)
1.512
1.506
1.546
–1
l
(mm
)
0.118
0.116
0.126
pyrid-5-yl)-2-(3-methoxypyrid-5-yl)ethyne
1
contains one
Reflections
Collected
Independent
Observed
[I > 2
R[I > 2
molecule in the asymmetric unit with both heterocycles alligned
in a coplanar arrangement, Fig. 1. Relatively weak C–HÁ Á ÁN and
C–HÁ Á ÁO hydrogen bonds extend the molecules into a 1-dimen-
sional strand.
In an attempt to probe the importance of molecular electrostat-
ics to direct co-crystal formation we prepared three co-crystals
6894
2422
1569
10,984
3934
1861
5440
3431
1992
15,651
7774
6194
r
r
(I)]
(I)]
0.0645
0.1575
0.0661
0.1681
0.0519
0.1457
0.0675
0.1753
wR2
Scheme 3. Outlined synthetic route for SRs 1–3.

38
C.B. Aakeröy et al. / Journal of Molecular Structure 972 (2010) 35–40
a C(13)Á Á ÁO(32) distance of 3.141 Å. Secondary C–HÁ Á ÁN hydrogen
bonds, between the proton of the methoxy-substituted pyridine
ring and the nitrogen atom of the fluoro-substituted ring, generate
a 2:2 supermolecule, Fig. 5.
The formation of the 1:2 co-crystal of 6, Fig. 6, is driven by two
O–HÁ Á ÁN hydrogen bonds with O(31)Á Á ÁN(11) and O(41)Á Á ÁN(21)
distances of 2.567(2) and 2.579(2) Å, respectively. A complemen-
tary C–HÁ Á ÁO hydrogen bond is formed between the proton of an
aryl ring to the carbonyl of the acid moiety with a C(26)Á Á ÁO(42)
distance of 3.165 Å, respectively.
In crystal structures 4 and 5, 1:1 binary co-crystals are formed
through carboxylic acid/pyridine hydrogen bonds. Both SRs 1 and
2 contain a pyridine ring substituted in the ortho-position with a
fluorine substituent coupled to either a methoxy-substituted pyr-
idine or simple pyridine in which the carboxylic acid can bind. In
both cases the carboxylic acid forms a hydrogen bond to the pyr-
idyl ring consisting of greater basicity, i.e., methoxy-pyridine or
pyridine (Fig. 1). Attempts at generating a 1:2 SR/acid co-crystal
with either SR 4 or 5 and aromatic carboxylic acids, by increasing
4–6, by allowing 1 and 2 to react in a 1:1 stoichiometry and 3 to
react in a 1:2 stoichiometry with aromatic carboxylic acids.
The primary motif in the crystal structure of 3 contains one SR 1
and one 4-nitrobenzoic acid molecule connected through the acid
and methoxy-substituted pyridine moieties, Fig. 2. The primary
synthon is an O–HÁ Á ÁN hydrogen bond with O(31)Á Á ÁN(11) distance
of 2.633(3) Å. Complementary C–HÁ Á ÁO hydrogen bonds form be-
tween the proton of an aryl ring to the carbonyl of the acid moiety
with a C(13)Á Á ÁO(32) distance of 3.240 Å. Secondary C–HÁ Á ÁN
hydrogen bonds, between the proton of the methoxy-substituted
pyridine ring and the nitrogen atom of the fluoro-substituted ring,
generates a 2:2 supermolecule, Fig. 3.
In the crystal structure of 5, one SR 2 and one 4-nitrobenzoic
acid are brought together by an O–HÁ Á ÁN(py) hydrogen bond be-
tween the carboxylic acid and the non-fluorinated pyridine moiety,
O(31)Á Á ÁN(21) distance of 2.611(2) Å, Fig. 4.
Complementary C–HÁ Á ÁO hydrogen bonds are present between
the proton of an aryl ring to the carbonyl of the acid moiety with
Fig. 1. Labeled thermal-ellipsoids plot (50% probability level) of SR 1.
Fig. 2. Labeled thermal-ellipsoids plot (50% probability level) of the 1:1 binary co-crystal of 4.

C.B. Aakeröy et al. / Journal of Molecular Structure 972 (2010) 35–40
39
Fig. 3. Four component supermolecule formed through multiple O–HÁ Á ÁN, C–HÁ Á ÁO and C–HÁ Á ÁN hydrogen bonds in 4 [12].
Fig. 4. Labeled thermal-ellipsoids plot (50% probability level) of the 1:1 binary co-crystal of 5.
Fig. 5. Four component supermolecule of 5 formed through multiple O–HÁ Á ÁN, C–HÁ Á ÁO and C–HÁ Á ÁN hydrogen bonds.
the ratio of acid, were unsuccessful. However, we do not believe
that having the fluorine atom in the ortho-position hinders the
nitrogen atom from participating in hydrogen bonding with a
carboxylic acid, since it participates in forming C–HÁ Á ÁN hydrogen
bonds with a neighboring molecule. Furthermore, in the crystal
structure of 1-(6-chloropyridin-3-ylmethyl)-3-phenyl-1H-pyra-
zole-5-carboxylic acid [11] the carboxylic acid forms an
O–HÁ Á ÁN to the pyridyl site despite the presence of a chlorine
substituent ortho to the nitrogen atom.
bond acceptors in the formation of O–HÁ Á ÁN hydrogen bonds with
two carboxylic acid molecules. Attempts were made to generate a
1:1 binary co-crystal, by reacting both components, i.e., SR 3 and an
aromatic carboxylic acid in a 1:1 ratio; however, suitable crystal-
line materials were not obtained.
4. Conclusions
Although only three co-crystals are presented herein, we have
demonstrated that the electronic characteristic of an individual
hydrogen-bond acceptor can be modified through covalent
The crystal structure 6 comprises a 1:2 SR/acid binary co-crystal
in which both pyridine nitrogen atoms are acting as hydrogen-

40
C.B. Aakeröy et al. / Journal of Molecular Structure 972 (2010) 35–40
Fig. 6. Labeled thermal-ellipsoids plot (50% probability level) of the 1:2 binary co-crystal, 6.
‘switching’ (achieved by covalently affixed substituents), which, in
turn, drives the assembly of co-crystals. The primary hydrogen
bonds and preferred interactions involving the ditopic acceptor
molecules in these structures can be rationalized in the context
of an electrostatic view of hydrogen-bond interactions. In the
two cases, 4 and 5, where a 1:1 binary co-crystal was obtained,
the carboxylic acid did bind to the best hydrogen-bond acceptor
(the site accompanied by the methoxy group), which is consistent
with the hypothesis that the best donor will preferentially bind to
the best acceptor. In the third case, 6, both binding sites are in-
volved in an interaction with a carboxylic acid. This may not be
completely surprising since the potential differences between the
two sites in 1–3 are relatively small. Due to the synthetic ease of
cross-coupling functionalized pyridines, a variety of other suitable
electron rich/deficient bipyridines are possible, allowing for a
greater scope of functionalized SRs to be tested. The next logical
step is to co-crystallize two carboxylic acids of varied acidity with
SRs such as 1–3, in an attempt to form ternary co-crystals with pre-
dictable and desirable connectivities and stoichiometries.
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Acknowledgements
[12] Images created using Mercury 1.4.1.
We are grateful for financial support from the Johnson Center
for Basic Cancer Research and the NSF (CHE-0316479).