Pyridine-containing m-phenylene ethynylene oligomers having tunable basicities

Article abstract of DOI:10.1021/ol0363016

Incorporation of a pyridine monomer into the backbone of a m-phenylene ethynylene oligomer allows functionalization of the interior binding cavity of the folded oligomer. The basicity of the inwardly directed pyridine moiety was modulated by changing the

Full text of DOI:10.1021/ol0363016

ORGANIC
LETTERS
2004
Vol. 6, No. 5
659-662
Pyridine-Containing m-Phenylene
Ethynylene Oligomers Having Tunable
Basicities
Jennifer M. Heemstra and Jeffrey S. Moore*
Departments of Chemistry and Materials Science & Engineering,
600 South Mathews AVenue, The UniVersity of Illinois at Urbana-Champaign,
Urbana, Illinois 61801
moore@scs.uiuc.edu
Received November 25, 2003
ABSTRACT
Incorporation of a pyridine monomer into the backbone of a m-phenylene ethynylene oligomer allows functionalization of the interior binding
cavity of the folded oligomer. The basicity of the inwardly directed pyridine moiety was modulated by changing the substituents on the
pyridine ring and through oligomer folding, granting access to a pK range of 5−14 in acetonitrile.
a
Nature’s alphabet of amino acids contains only five residues
having acidic or basic side chains. Yet, using only these five
residues, enzymes are able to meet all of their needs for acids
and bases to direct substrate binding and reaction catalysis.1
This remarkable versatility arises in part from the ability of
enzymes to modulate the pKa values of these amino acid
side chains.2 The literature is rich with examples of su-
pramolecular assemblies that selectively bind guest molecules
and promote chemical transformations.3,4 Moreover, Rebek
and co-workers have used acid-base interactions to direct
substrate binding in cavitand molecular containers.5 However,
we are unaware of any reports of cavitand molecules that
incorporate acidic or basic functional groups having tunable
pKa values. Here we describe the synthesis and pKa deter-
mination of a series of m-phenylene ethynylene (PE) oligo-
mers that fold into cavitand-like structures and incorporate
pyridine moieties with tunable basicities.
Phenylene ethynylene oligomers 1 previously studied by
our group and others6 have been found to adopt a compact
helical conformation in polar solvents such as acetonitrile.7
From this, we predicted that functionalization of the binding
cavity could be accomplished through incorporation of a
basic moiety into the PE backbone. Substituted pyridines are
(1) Bugg, T. An Introduction to Enzyme and Coenzyme Chemistry;
Blackwell Science, Inc.: Cambridge, MA, 1997.
(2) Joshi, M. D.; Sidhu, G.; Nielsen, J. E.; Brayer, G. D.; Withers, S.
G.; McIntosh, L. P. Biochemistry 2001, 40, 10115-10139.
(3) For reviews, see: (a) Murakami, Y.; Kikuchi, J.; Hisaeda, Y.;
Hayashinda, O. Chem. ReV. 1996, 96, 721-758. (b) Sanders, J. K. M. Chem.
Eur. J. 1998, 4, 1378-1383. (c) Luning, U. J Mater. Chem. 1997, 7, 175-
182. (d) Motherwell, W. B.; Bingham, M. J.; Six, Y. Tetrahedron 2001,
57, 4663-4686.
(4) (a) Chen, J.; Rebek, J., Jr. Org. Lett. 2002, 4, 327-329. (b) Purse,
B. W.; Ballester, P.; Rebek, J., Jr. J. Am. Chem. Soc. 2003, 125, 14682-
14683.
(6) (a) Inouye, M.; Chiba, J.; Nakazumi, H. J. Org. Chem. 1999, 64,
8170-8176. (b) Blatchly, R. A.; Tew, G. N. J. Org. Chem. 2003, 68, 8780-
8785.
(5) Wash, P. L.; Renslo, A. R.; Rebek, J., Jr. Angew. Chem., Int. Ed.
2000, 39, 3821-3823.
(7) Prince, R. B.; Saven, J. G.; Wolynes, P. G.; Moore, J. S. J. Am.
Chem. Soc. 1999, 121, 3114-3121.
10.1021/ol0363016 CCC: $27.50 © 2004 American Chemical Society
Published on Web 02/11/2004

suitable for this purpose as their incorporation into the PE
backbone can be achieved without significantly disrupting
the folded conformation of the oligomer, and the basicity of
the nitrogen lone pair can be modulated by changing the
substituents on the pyridine ring.8 We also wanted to explore
the effect of oligomer folding on the basicity of the pyridine
moiety, as the helical cavity of a folded oligomer may
provide a hydrophobic, solvent-sheltered local environment,
and π-stacking interactions could potentially help to stabilize
the pyridinium species.9 To investigate the extent to which
pyridine basicity can be modulated through changes in ring
electronics and local environment, two sets of oligomers were
synthesized having various substituents on the pyridine ring.
Of these oligomers, trimers 2 are too short to form a helix,
but tridecamers 3 have sufficient length to adopt a helical
conformation with the pyridine monomer sandwiched be-
tween the two terminal phenyl rings.10
Scheme 1. Synthesis of Pyridine Monomersa
a Reagents and conditions: (a) H2SO4, HNO3, 120 °C. (b)
triisopropylsilyl acetylene, Pd2(dba)3, CuI, PPh3, Et3N, 40 °C. (c)
K2CO3, MeOH, 65 °C. (d) Fe, AcOH, 70 °C. (e) CH2O, NaBH3CN,
AcOH, 35 °C. (f) trimethylsilyl acetylene, Pd2(dba)3, CuI, PPh3,
Et3N, 60 °C. (g) trimethylsilyl acetylene, Pd2(dba)3, CuI, PPh3, Et3N,
80 °C.
The first step in generating oligomers 2 and 3 was the
synthesis of substituted pyridine monomers 6, 8, 9, and 10
as outlined in Scheme 1. Starting from 2,6-dichloropyridine
N-oxide,11 treatment with nitric acid gave 2,6-dichloro-4-
nitropyridine (4),12 which was converted to 4-nitropyridine
monomer 5 by Pd-catalyzed cross-coupling with triisopro-
pylsilyl acetylene. Reaction of 5 with potassium carbonate
in methanol gave 4-methoxypyridine monomer 6.13 In a
parallel synthesis, reduction of remaining 5 with elemental
iron and acetic acid gave 7,14 which was subsequently
converted to 4-N,N-(dimethylamino)pyridine monomer 8 via
reductive amination15 (Scheme 1a). Isonicotinic acid methyl
ester monomer 9 and unsubstituted pyridine monomer 10
were obtained through Pd-catalyzed cross-coupling of methyl
2,6-dichloroisonicotinate (Scheme 1b) and 2,6-dichloro-
pyridine (Scheme 1c), respectively, with trimethylsilyl
acetylene.
To complete the synthesis of oligomers 2 and 3, the
appropriate pyridine monomer was first subjected to TBAF
for removal of the silyl protecting groups. Then, Pd-catalyzed
cross-coupling with 2 equiv of iodide-terminated PE mono-
mer (11) or hexamer (12)7 gave the desired oligomer
(Scheme 2). Results for the synthesis of the pyridine-
containing oligomers are summarized in Table 1.
(8) Jaffe, H. H.; Doak, G. O. J. Am. Chem. Soc. 1955, 77, 4441-4444.
(9) Kearney, P. C.; Mizoue, L. S.; Kumpf, R. A.; Forman, J. E.; McCurdy,
A.; Dougherty, D. A. J. Am. Chem. Soc. 1993, 115, 9907-9919.
(10) Based on a helical model having six PE monomers per turn unit, as
described in: Matsuda, K.; Stone, M. T.; Moore, J. S. J. Am. Chem. Soc.
2002, 124, 11836-11837.
To explore the effect of oligomer folding on pyridine
basicity, it was necessary to carry out pKa measurements for
oligomers 2 and 3 under solvent conditions that promote helix
formation. UV spectroscopy can be used to evaluate the
ability of a solvent to promote helix formation in PE
(11) Kaneko, C.; Uchiyama, K.; Sato, M.; Katagiri, N. Chem. Pharm.
Bull. 1986, 34, 3658-3671.
(12) Landor, S. R.; Fomum, Z. T.; Asobo, P. F.; Landor, P. D.; Johnson,
A. J. Chem. Soc., Perkin Trans. 1 1989, 251-254.
(13) Xie, C.; Runnegar, M. T. C.; Snider, B. B. J. Am. Chem. Soc. 2000,
122, 5017-5024.
(14) Pattarawarapan, M.; Chen, J.; Steffensen, M.; Burgess, K. J. Comb.
Chem. 2001, 3, 102-116.
(15) Gribble, G. W.; Nutaitis, C. F. Synthesis 1987, 709-711.
Org. Lett., Vol. 6, No. 5, 2004
660

Scheme 2. Synthesis of Pyridine-Containing Oligomers
Figure 1. UV spectra of 3c (blue) and 3c‚H+ (red) in acetonitrile.
The ratio of absorbance bands at 303 and 289 nm changes only
minimally upon protonation and indicates a folded conformation
for both species. Absorbance at 350-425 nm increases upon
protonation, signifying formation of the pyridinium species.
oligomers.16 The ratio of absorbance bands at 303 and 289
nm for an oligomer in a given solvent is indicative of the
predominant conformation of the PE backbone, with low
values of A303/289 corresponding to a high degree of folding.
lead to errors resulting from unwanted intermolecular
interactions such as homoconjugation between a compound
and its ionized species.
Koppel and co-workers have recently developed a method
for measuring pKa values in acetonitrile that minimizes these
sources of error.18 This method uses UV-vis spectroscopy
to measure ∆pKa values for sets of compounds having similar
aciditities. After measurements have been made for multiple
sets of compounds, an acidity scale is constructed on the
basis of these relative pKa differences. To assign absolute
pKa values to the acidity scale, a compound for which the
pKa value has been determined reliably is chosen to serve
as a reference. By obtaining only the pKa value of the
reference compound using direct titration methods, errors
resulting from inaccuracies in measuring the acidity of
acetonitrile media are greatly reduced. Also, the use of UV
spectroscopy allows ∆pKa measurements to be carried out
at low concentrations, decreasing the possibility of errors
arising from unwanted intermolecular interactions. Given that
pyridine chromophores are known to undergo a bathochromic
shift in UV absorbance upon protonation,19 this method
appeared to be suitable for measuring the pKa values of
oligomers 2 and 3.
In the UV spectra of oligomers 3, the region below 350
nm is dominated by the PE chromophore, so upon protona-
tion of the pyridine moiety, the most easily detectable change
occurs at 350-425 nm (Figure 1). As a result, acquiring
∆pKa measurements between oligomers 3 and other com-
pounds requires that those compounds likewise have an
absorbance band in the region of 350-425 nm that is
responsive to changes in protonation state. To address this
need, a series of azobenzene indicators was developed, and
these indicators were used in conjunction with the methods
developed by Koppel and co-workers to obtain pKa values
for oligomers 2 and 3 (Table 2).20
Table 1. Yields for Oligomers 2a-e and 3a-e
oligomer
R1
yield (%)
2a w 5 + 11
2b w 9 + 11
2c w 10 + 11
2d w 6 + 11
2e w 8 + 11
3a w 5 + 12
3b w 9 + 12
3c w 10 + 12
3d w 6 + 12
3e w 8 + 12
NO2
CO2Me
H
OMe
NMe2
NO2
CO2Me
H
41
84
66
48
66
47
51
84
51
48
OMe
NMe2
The UV spectra of 3 in both unprotonated and protonated
forms indicated that the oligomers adopt a helical conforma-
tion in acetonitrile (Figure 1), and thus acetonitrile was
chosen as the solvent for all pKa measurements. Measurement
of pKa values in acetonitrile is well documented, with values
reported for over 300 compounds.17 However, the reliability
of much of these data is questionable, as values reported by
different authors often deviate by more than one pKa unit.18
These deviations may arise from difficulties in measuring
the acidity of acetonitrile media, accounting for the unreli-
ability of pKa values determined via direct titration methods.
Also, the high concentrations required for some methods can
(16) Hill, D. J.; Moore, J. S. Proc. Natl. Acad. Sci. U.S.A. 2002, 99,
5053-5057.
(17) Izutsu, K. Acid-Base Dissociation Constants in Dipolar Aprotic
SolVents; IUPAC Chemical Data Series No. 35; Blackwell Scientific:
Oxford, 1990.
(18) Leito, I.; Kaljurand, I.; Koppel, I. A.; Yagupolskii, L. M.; Vlasov,
V. M. J. Org. Chem. 1998, 63, 7868-7874.
(19) Swain, M. L.; Woodward, C. F.; Brice, B. A. J. Am. Chem. Soc.
1949, 71, 1341-1345.
Org. Lett., Vol. 6, No. 5, 2004
661

Changing the substituent on the pyridine ring has little
impact on the overall hydrophobicity of the binding cavity,
and thus it is unlikely that the local environment of the helical
cavity is sufficiently solvent-sheltered to be responsible for
the observed shifts in pKa upon folding. Rather, these changes
in pKa more likely result from pyridinium-π interactions
involving the terminal phenyl rings of the oligomers. The
electron density of a phenyl ring has been shown to dictate
both the sign and intensity of pyridinium-π interactions, with
electron-rich phenyl rings stabilizing the pyridinium species
and electron-poor phenyl rings having a destabilizing effect.21
We hypothesize that the electronics of the pyridine ring has
an analogous effect, with electron-donating substituents on
the pyridine ring giving rise to stabilizing pyridinium-π
interactions and electron-withdrawing substituents on the
pyridine ring giving rise to destabilizing pyridinium-π
interactions. This hypothesis is further supported by the
absence of a significant effect of folding on the basicity of
oligomers having intermediate pKa values, as the sign of the
pyridinium-π interaction would be expected to change from
negative to positive in this range.
Table 2. pKa Values of Pyridine-Containing Oligomers
In conclusion, the binding cavity of a PE oligomer can be
functionalized by incorporation of a basic pyridine moiety.
The pKa values of the oligomers reveal that the basicity of
the pyridine nitrogen is easily modulated by changing the
substituents on the pyridine ring, allowing access to a broad
pKa range in acetonitrile. Additionally, changes in the local
environment of the pyridine ring upon oligomer folding can
be used to further modulate the pKa values of some PE
oligomers.
Incorporation of a pyridine functionality having tunable
basicity into PE oligomers demonstrates our ability to
program information onto the surface of the oligomer binding
cavity. This information may be used to direct substrate
binding and reaction catalysis, allowing PE oligomers to act
as artificial enzymes. Future studies will explore the use of
pyridine-contianing oligomers to promote alkylation and acyl
transfer reactions.
a pKa values are measured in acetonitrile and represent the dissociation
constant of the protonated pyridinium ion. All measurements are accurate
to (0.1 pKa units
The measured oligomer pKa values reveal that modulating
the basicity of the pyridine moiety is, not surprisingly, easily
accomplished by changing substituents on the ring, allowing
access to a pKa range of 5-14 in acetonitrile. Folding was
also found to have a minor impact on the pKa values of the
oligomers, and unexpectedly, this effect was found to be
stabilizing for some oligomers but destabilizing for others.
Upon comparing the pKa values of tridecamers 3 with the
corresponding trimers (2), it appears that for oligomers
having electron-rich pyridine rings, folding stabilizes the
pyridinium species, as 3e is 0.3 pKa units higher that 2e,
equivalent to a free energy difference (∆∆Gprotonation) of 0.4
kcal‚mol-1. However, for oligomers having electron-poor
pyridine rings, folding destabilizes the protonated species,
as evidenced by a pKa difference of -0.4 between 2a and
3a, equivalent to a ∆∆Gprotonation of -0.5 kcal‚mol-1.
Acknowledgment. This research was funded by the
National Science Foundation (CHE 00-91931) and the
Department of Energy, Division of Materials Sciences
(DEFG02-91ER45439). J.M.H. thanks the University of
Illinois for a doctoral fellowship.
Supporting Information Available: Detailed descrip-
tions of all experimental procedures and accompanying
analytical data. This material is available free of charge via
the Internet at http://pubs.acs.org.
OL0363016
(20) Details to be published separately: Heemstra, J. M.; Moore, J. S.
Tetrahedron 2003, submitted for publication.
(21) Hunter, C. A.; Low, C. M. R.; Rotger, C.; Vinter, J. G.; Zonta, C.
Proc. Natl. Acad. Sci. U.S.A. 2002, 99, 4873-4876.
662
Org. Lett., Vol. 6, No. 5, 2004