Orientation and alkylation effects on cation-π interactions in aqueous solution

Article abstract of DOI:10.1021/ja0498538

We have investigated the orientation dependence of the cation-π interaction between a phenyl ring and a pyridinium ring in the context of a flexible model system in water. Of the four possible positions of the pyridinium nitrogen, ipso, ortho, meta, and para, we found a variation in the interaction energy of about 0.75 kcal mol^-1, with the stacking of the ipso-pyridinium ring providing the strongest interaction. The observed stability is attributed to the maximization of the electrostatic interaction, minimization of rotamers, and possible differences in hydration phenomena arising from alkylation.

Full text of DOI:10.1021/ja0498538

Published on Web 09/25/2004
Orientation and Alkylation Effects on Cation-π Interactions in
Aqueous Solution
Mark J. Rashkin, Robert M. Hughes, Nathaniel T. Calloway, and Marcey L. Waters*
Contribution from the Department of Chemistry, CB 3290, UniVersity of North Carolina,
Chapel Hill, North Carolina 27599
Received January 9, 2004; E-mail: mlwaters@email.unc.edu
Abstract: We have investigated the orientation dependence of the cation-π interaction between a phenyl
ring and a pyridinium ring in the context of a flexible model system in water. Of the four possible positions
of the pyridinium nitrogen, ipso, ortho, meta, and para, we found a variation in the interaction energy of
about 0.75 kcal mol-1, with the stacking of the ipso-pyridinium ring providing the strongest interaction. The
observed stability is attributed to the maximization of the electrostatic interaction, minimization of rotamers,
and possible differences in hydration phenomena arising from alkylation.
Introduction
Cation-π interactions1 have generated significant interest due
to their roles in protein structure,2 biomolecular recognition,3
and enzymatic catalysis.4 The cation-π interaction between a
positively charged π-system and an aromatic ring, such as the
interaction of arginine (Arg) with tryptophan (Trp), has been
proposed to be particularly stabilizing due to the additional van
der Waals and π-π stacking components of the interaction.2
Other cation-π interactions involving positively charged π-sys-
tems may also be important in biomolecular recognition, such
as the interaction of the pyridinium ring of NAD+ with Trp in
the binding site of a protein3d and the stacking of positively
charged alkylated DNA bases in excision-repair enzymes3c,4b
and mRNA cap binding proteins.3c
Figure 1. (a) Ab initio calculated structures of 1a-d in explicit water
(see Experimental Section). Green ) carbon, blue ) nitrogen, red ) oxygen,
white ) hydrogen. (b) ChemDraw representation of compounds 1a-d.
Gellman and co-workers have shown that there is an
orientation dependence on stacking interactions of neutral
heteroaromatic rings,5 which has relevance to base stacking.
However, to our knowledge, the impact of orientation of the
positive charge relative to the aromatic ring in a cation-π
interaction has not been investigated experimentally. In the
system described here, we investigated the cation-π interaction
between a phenyl ring and a pyridinium ring in compounds
1a-d in water and found that the orientation of the rings has a
significant impact on the magnitude of the interaction and that
alkylation of the pyridine ring can enhance the effect.
Results and Discussion
Design and Synthesis. The model system is based on our
previously reported system designed to examine offset stacked
aromatic interactions.6 As indicated by high level ab initio
calculations in explicit water7 (Figure 1), the system design
allows for the pyridinium ring to stack against the top phenyl
ring of the biaryl unit of compounds 1a-d in an offset stacked
conformation, placing the ortho-hydrogen of the pyridinium ring
(6) Rashkin, M. J.; Waters, M. L. J. Am. Chem. Soc. 2002, 124, 1860-1861.
(7) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M.
A.; Cheeseman, J. R.; Montgomery, J. A., Jr.; Vreven, T.; Kudin, K. N.;
Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.;
Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.;
Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa,
J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.;
Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Adamo, C.; Jaramillo,
J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.;
Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G. A.;
Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels,
A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.;
Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.;
Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz,
P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.;
Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.; Johnson,
B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A. Gaussian 98, A11;
Gaussian, Inc.: Pittsburgh, PA, 2003.
(1) (a) Ma, J. C.; Dougherty, D. A. Chem. Rev. 1997, 97, 1303-1324. (b)
Castellano, R. K.; Diederich, F.; Meyer, E. A. Angew. Chem., Int. Ed. 2003,
42, 1210-1250.
(2) Gallivan, J. P.; Dougherty, D. A. Proc. Natl. Acad. Sci. U.S.A. 1999, 96,
9459-9464.
(3) (a) Zacharias, N.; Dougherty, D. A. Trends Pharmacol. Sci. 2002, 23, 281-
287. (b) Mun˜oz-Caro, C.; Nino, A. Biophys. Chem. 2002, 96, 1-14. (c)
Quiocho, F. A.; Hu, G.; Gershon, P. D. Curr. Opin. Struct. Biol. 2000, 10,
78-86. (d) Yamamoto-Katayama, S.; Ariyoshi, M.; Ishihara, K.; Hirano,
T.; Jingami, H.; Morikawa, K. J. Mol. Biol. 2002, 316, 711-723.
(4) (a) Lee, S.; Lin, X.; McMurray, J.; Sun, G. Biochemistry 2002, 41, 12107-
12114. (b) Eichman, B. F.; O’Rourke, E. J.; Radicella, J. P.; Ellenberger,
T. Embo. J. 2003, 22, 4898-4909.
(5) McKay, S. L.; Haptonstall, B.; Gellman, S. H. J. Am. Chem. Soc. 2001,
123, 1244-1245.
9
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J. AM. CHEM. SOC. 2004, 126, 13320-13325
10.1021/ja0498538 CCC: $27.50 © 2004 American Chemical Society

Effects on Cation-
π
Interactions in Aqueous Solution
A R T I C L E S
Scheme 1. Synthesis of Model Systems for Investigation of the Orientation Dependence of the Cation-π Interaction
over the center of the phenyl ring. Hence, by varying the position
of the nitrogen in the pyridinium ring, the overlap with the
π-cloud of the anisole ring is systematically varied.
Table 1. Upfield Shifting of the Pyridinium Ring Protons in
Compounds 1a-d and N-Me-1b-d Relative to Control
Compounds 9a-d and N-Me-9b-d
∆δ (ppm)
Compounds 1a-d were synthesized as shown in Scheme 1.
The synthesis of 1a began with a Suzuki coupling of 2-bro-
mobenzaldehyde and the boronic acid 2 to give compound 3 in
85% yield. This was followed by reduction of compound 3 with
LiAlH4 and subsequent bromination with PBr3 to give com-
pound 4 in a 75% overall yield for the two steps. The final
product 1a was obtained in quantitative yield as a white solid
from reaction of 4 with pyridine.
proton
1a
1b
N-Me-1b
1c
N-Me-1c
1d
N-Me-1d
Ho1
Ho2
Hm1
Hm2
Hp
0.65
0.65
0.29
0.29
0.17
0.80
0.56
0.76
0.44
0.47
0.47
0.23
0.23
0.37
0.37
0.15
0.15
0.37
0.40
0.25
0.23
0.51
0.21
0.27
0.16
0.37
0.27
0.18
0.20
0.17
0.20
N-Me
0.09
A representative synthetic route of 1b began with the coupling
of 2-pyridinylmagnesium chloride8 and 2-bromobenzaldehyde
to give 6a in 52% yield. Compound 6a was acylated with acetic
anhydride followed by deoxygenation with samarium(II) iodide9
to produce 8a. Finally, Suzuki coupling of 8a with 2 afforded
the product 1b.
Conformational Analysis. We performed ab initio calcula-
tions in explicit water which indicate that compounds 1a-d
populate a stacked geometry in which the methoxy group is
distal to the pyridinium ring. Several other geometries are also
accessible in this system (Figure 2). For example, the offset
stacked geometry can occur either distal or proximal to the
methoxy group or the pyridinium ring can swing away from
the anisole ring, resulting in a splayed conformation. In some
cases, NH‚‚‚O, NH‚‚‚π, and CH‚‚‚O and CH‚‚‚π interactions
may also be possible.10
NOE studies were performed to investigate the favored
conformation of compounds 1a-d. NOEs between the methoxy
group and the pyridinium ring are expected for the proximal
stacked geometry as well as the NH‚‚‚O and CH‚‚‚O interac-
Figure 2. Possible conformations of compounds 1a-d.
tions. The fact that such NOEs are not observed suggests that
that these geometries are not significantly populated in water.
The lack of such NOEs is consistent with a distal stacked or
splayed geometry.
Comparison of aromatic upfield shifts from 1a-d to the
corresponding unstacked control compounds 9a-d (Figure 3)
provides additional evidence for the offset stacked orientation
of the pyridinium ring (Table 1). In each compound, all protons
on the pyridinium ring are shifted upfield, supporting a stacked
geometry as the favored conformation. In each case the ortho-
hydrogens demonstrate the greatest upfield shifting, indicating
(8) Trecourt, F.; Breton, G.; Bonnet, V.; Mongin, F.; Marsais, F.; Queguiner,
G. Tetrahedron Lett. 1999, 40, 4339-4342.
(9) Kato, Y.; Mase, T. Tetrahedron Lett. 1999, 40, 8823-8826.
(10) Similar CH‚‚‚O interactions between pyridinium CH groups and ether
oxygens have been shown to be important to self-assembly in some organic
solvents. (a) Houk, K. N.; Menzer, S.; Newton, S. P.; Raymo, F. M.;
Stoddart, J. F.; Williams, D. J. J. Am. Chem. Soc. 1999, 121, 63, 1479-
1487. (b) Raymo, F. M.; Houk, K. N.; Stoddart, J. F. J. Org. Chem. 1998,
63, 6523-6528.
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A R T I C L E S
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Table 2. Barriers to Rotation of 1a-d in D2O (pH 1, D2SO4) at
352 Ka
∆
G‡
∆∆G‡
1
1
cmpd
position
(kcal mol-
)
(kcal mol-
)
1a
1b
1c
1d
ipso
18.48
18.08
17.85
17.73
-0.75
-0.35
-0.12
ortho
meta
para
a Propagation of errors gives an uncertainty of (0.05 kcal mol-1
.
Scheme 3. Stacked Rotamers of 1c in the Syn and Anti
Conformations
Figure 3. Control compounds 9a-d.
Scheme 2. Stacked Conformation and Transition State of
Compounds 1a-d
The cation-π interaction is believed to arise largely from an
electrostatic interaction between a positive charge and the
quadrupole moment of an aromatic ring.1 Correspondingly, we
expected 1b to possess the strongest interaction and 1d to
possess the weakest interaction of the four compounds due to
their differences in ability to access an optimal orientation
between the positive charge and the center of the aryl ring.
Inspection of the rotational barriers in Table 2 indicates that
there is a significant variation in the rotational barriers of 1a-
d, amounting to 0.75 kcal mol-1. Compound 1a has the strongest
interaction followed by 1b then 1c and 1d. Inspection of the
relative positions of the pyridinium nitrogen in Figure 1 provides
insight into the order of stabilities of 1b-d. Compound 1b
places the N-H directly over the phenyl ring, whereas the
overlap of the N-H with the π-cloud is concomitantly less for
that they are in closest proximity to the face of the ring. For
example, the ortho-protons, Ho, of compound 1a are shifted
upfield 0.65 ppm, while Hm and Hp are only shifted 0.29 and
0.17 ppm, respectively. Moreover, alkylation of the nitrogen
results in only minor changes in the upfield shifting, indicating
that NH‚‚‚O and NH‚‚‚π interactions are not predominant, since
methylation would disrupt these interactions. Upfield shifting
of the N-methyl groups is also consistent with a stacked
geometry for each compound (Table 1). The preference for the
stacked geometry over other possible geometries is likely a result
of both a hydrophobic component to the aromatic interaction
and solvation of the ether oxygen and pyridinium NH by water.
Nonetheless, it is clear that the position of the nitrogen in the
ring influences the population of the stacked geometry, as the
pyridinium ring in 1d is not as shifted upfield as it is in 1a.
Determination of Interaction Energies. The 2′-methoxy
group was incorporated to desymmetrize the biaryl unit and
restrict rotation about the biaryl bond, resulting in diastereotopic
methylene hydrogens. The relative strengths of the cation-π
interactions were determined by measuring the rate of rotation
about the biaryl bond through dynamic NMR by fitting the line-
broadened spectrum of the diastereotopic methylene protons,
Ha and Hb, in D2O, pH 1, as a function of temperature.11 The
fitting was accomplished using the program gNMR.12 The
accuracy of the analysis is dependent on a known baseline line
width, which was provided by the unbroadened resonance of
the methoxy group in this system. The strength of the interaction
between the pyridinium and phenyl rings in this system is
proportional to the difference in the ground state and transition
state energies. Modeling of the transition state has indicated
that the biaryl rings are coplanar and the pyridinium group is
splayed, such that there is no interaction between the pyridinium
ring and the phenyl ring in the transition state (Scheme 2).
Therefore, any effect of the interaction between the pyridinium
ring and phenyl ring on the rotational barrier in compounds
1a-d may be attributed to differences in the ground-state
energies.
1c and 1d, resulting in an energetic variation of 0.35 kcal mol-1
.
However, it is not immediately obvious why the barrier of 1a
is significantly higher than that of 1b.
There may be several factors that contribute to the larger
interaction energy for compound 1a. The electron-withdrawing
cation in the ipso position polarizes the adjacent C-H bonds
resulting in very electron poor ortho-hydrogens. Of the four
compounds, 1a is unique in the fact that both ortho-hydrogens
are adjacent to the cation allowing both to receive maximum
inductive effects. In contrast, both the ortho- and meta-
pyridinium compounds, 1b and 1c, have two inequivalent
stacked rotamers (Scheme 3). The rotational barrier is dependent
on the relative populations of the syn and anti conformations.
Comparison of upfield aromatic shifting provides a method for
examining the stacked rotamer population. We compared 1b
and 1c to their corresponding unstacked control compounds 9b
and 9c (Table 1). As is evident by the difference in the upfield
shifting of the nondegenerate ortho and meta protons, the syn
population for 1b and 1c is 62% and 59%, respectively. Hence,
the inequivalency of the two stacked rotamers results in a larger
entropic cost for forming the preferred stacking interaction in
1b and 1c relative to 1a.
The nature of the pyridinium nitrogen may also play a role
in the difference in rotational barrier: the protonated nitrogen
in 1b-d may be involved in hydrogen bonding to the solvent
which is not possible for the quaternary nitrogen in compound
1a.13 The hydrogen bonded water molecules may create a sphere
of hydration that must be desolvated in order to access a cation-π
(11) Sandtro¨m, J. Dynamic NMR Spectroscopy; Academic Press: London, New
York, 1982.
(12) gNMR, V. 3.6; Cherwell Scientific Publishing.
(13) Meyer, S.; Louis, R.; Metz, B.; Agnus, Y.; Varnek, A.; Gross, M. New J.
Chem. 2000, 24, 371-376.
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Effects on Cation-
π
Interactions in Aqueous Solution
A R T I C L E S
Synthesis. A. 2-Methoxyphenylboronic Acid, 2. A round-bottom
flask charged with argon, anhydrous ether, and 2-bromoanisole (2.125
g, 11.36 mmol, 1.416 mL) was cooled to -78 °C. n-BuLi (12.5 mmol,
5.1 mL, 2.5 M in hexanes) was added dropwise, and the solution was
stirred for 1 h. The flask was then removed from the dry ice/acetone
bath, and trimethylborate (12.5 mmol, 1.29 g, 1.31 mL) was added
and allowed to warm to room temperature and stirred overnight. The
reaction was quenched with 20 mL of 2 N HCl and stirred for 30 min
followed by extraction into ether. The organic mixture was extracted
with 20 mL of 1 N NaOH in two portions. The aqueous layer was
washed with ether then neutralized with 1 N HCl resulting in a cloudy
solution. The suspension was then extracted into ether. The resulting
organic layer was then washed with water and brine followed by drying
over magnesium sulfate and concentrated in vacuo, resulting in 1.37 g
interaction. Methylation of 1b-d would allow the investigation
of such a possibility. However, increased steric hindrance of
an ortho-methylation makes comparison of the rotational barriers
impossible. In addition, determination of the rotational barrier
of N-methylated derivatives of 1c and 1d was not possible due
to interference of the water peak in the NMR spectra at the
reported temperatures. Nonetheless, we were able to compare
the upfield shifting of 1b-d to their N-methyl derivatives to
determine the influence of methylation on the stacking interac-
tion. In each case, the methylated compounds have similar, but
not identical, upfield shifting of the pyridinium protons.
Comparison of the syn/anti ratios for unmethylated and methy-
lated compounds provides insight into the impact of methylation
on the stacking interaction. For example, the syn/anti ratio for
1b is 62:38 as determined from the meta-proton chemical shifts,
whereas for N-Me-1b the ratio is 44:56. Hence, methylation
actually favors the anti orientation, presumably for steric reasons,
since the syn conformation would place the methyl group
directly over the anisole ring. Comparison of 1c to N-Me-1c
provides insight into the contribution of alkylation in the
stacking interaction in 1a, since both 1a and 1c place a C-H
group neighboring the nitrogen over the center of the anisole
ring. The population of the syn conformation is 63% for N-Me-
1c, as compared to 59% for 1c, which amounts to approximately
0.1 kcal mol-1 favoring the syn conformation when the nitrogen
is methylated. Hence, the fact that 1a is alkylated contributes
to its enhanced stacking affinity but is not the sole source of
the increased interaction energy.
1
of a white powder (86% yield). H NMR (300 MHz, CDCl3) δ 8.88
(d, 1H, J1 ) 7 Hz), 7.48 (t, 1H, J ) 8 Hz), 7.08 (t, 1H, J ) 6 Hz), 6.96
(d, 1H, J ) 8 Hz), 5.83 (s, 2H), 3.98 (s, 3 Hz).
2-(2-Methoxyphenylbenzealdhyde), 3. A round-bottom flask was
charged with argon, benzene, 2-bromobenzaldehyde (760 mg, 4.11
mmol), and compound 2 (750 mg, 4.93 mmol) at room temperature.
To the flask, Pd(PPh3)4 (94 mg, 0.08 mmol) and 2 mL of 2 M K2CO3
were added along with a reflux condenser. The reaction was allowed
to react overnight under reflux. Upon cooling, 5 mL of 30% H2O2 was
added and stirred for 30 min. The reaction mixture was extracted into
ether and washed with 20 mL of water followed by 20 mL of brine.
The organic layer was dried over magnesium sulfate and concentrated
in vacuo. The resulting oil was purified by column chromatography
(5:1 hexanes/ethyl acetate) to give a white solid (837 mg, 96% yield).
1H NMR (400 MHz, CDCl3) δ 9.93 (s, 1H), 8.14 (dd, 1H, J1 ) 8 Hz,
J2 ) 1 Hz), 7.79 (dT, 1H, J1 ) 8 Hz, J2 ) 1 Hz), 7.62 (t, 1H, J ) 7
Hz), 7.56 (m, 1H), 7.50 (d, 1H, J ) 8 Hz), 7.43 (dd, 1H, J1 ) 7 Hz,
J2 ) 1 Hz), 7.23 (dt, 1H, J1 ) 7 Hz, J2 ) 1 Hz), 7.12 (d, 1H, J ) 8
Hz), 3.88 (s, 3H). LR-MS (ESI): calculated ) 212.2; actual ) 212.0.
2′-Bromomethyl-2-methoxy-biphenyl, 4. A round-bottom flask was
charged with argon, THF (25 mL), and 3 (0.55 mmol). LiAlH4 was
subsequently added in small portions, and the reaction mixture was
allowed to stir for 1 h. The reaction was quenched with 1 N HCl (10
mL) and diluted with ethyl ether. The reaction was washed with 10
mL portions of sodium sulfate, water, and brine, respectively. Finally,
the organic layer was dried over magnesium sulfate and concentrated
in vacuo. The resulting product was then taken up in 10 mL of
chloroform under an atmosphere of argon. Phosphorus tribromide (54.7
mg, 0.20 mmol, 19 µL) was added as a 1 mL chloroform solution and
stirred for 2 h. The reaction was quenched with 10 mL of water followed
by a wash of 10 mL of sodium bicarbonate, water, and brine,
respectively. The organic layer was dried over magnesium sulfate and
concentrated in vacuo. The product was carried on to the formation of
compound 1a without purification.
Conclusions
We have found a significant orientation dependence of on
the cation-π interaction between a pyridinium ring and phenyl
ring. In this model system we have found that minimizing the
number of different rotamers and maximizing the polarization
of C-H bonds directly involved in the interaction with the
π-system provide the strongest interaction. Alkylation of the
nitrogen also enhances the interaction energy, depending on the
geometry of interaction. These results demonstrate the sensitivity
of cation-π interactions to orientation and alkylation. Moreover,
these studies demonstrate the ability to utilize cation-π interac-
tions to correctly orient guest molecules in molecular recognition
systems. We expect these findings to increase the utility of
cation-π interactions as tools for molecular recognition.
Experimental Section
General. All reageants and solvents were purchased from com-
mercial sources and used without additional purification unless
otherwise noted. Tetrahydrofuran and diethyl ether were dried via a
column of neutral alumina under nitrogen prior to use.15
1-(2′-Methoxy-biphenyl-2-ylmethyl)-pyridinium Bromide, 1a. In
a small vial pyridine (1 mL) was added to compound 4 (100 mg, 0.4
mmol) and was allowed to sit until a white precipitate formed. The
solution was diluted with ethyl ether and filtered to recover a white
solid. The solid was purified by washing with ethyl ether and dried
under reduced pressure to recover the desired product quantitatively.
1H NMR (500 MHz, D2O pH 1) δ 8.25 (t, 1H, J ) 7 Hz), 8.09 (d, 1H,
J ) 8 Hz), 7.63 (t, 1H, J ) 7 Hz), 7.57 (m, 1H), 7.44 (m, 2H), 7.30
(t, 1H, J ) 8 Hz), 7.10 (m, 1H), 6.86 (m, 2H), 6.79 (d, 1H, J ) 7 Hz),
4.88 (q, 2H, J ) 15 Hz), 3.34 (s, 3H); 13C NMR (75 MHz, D2O pH 1)
δ 155, 145, 144, 138, 131, 131, 130, 130, 130, 128, 127, 127, 121,
111, 63, 55. LR-MS (FAB): calculated ) 276.4; actual ) 276.2.
(2-Bromophenyl)-pyridin-2-yl-methanol, 6b. A dry round-bottom
flask charged with argon and a stirbar was filled with isopropylmag-
nesium chloride (2 M in THF, 5.2 mL, 10.4 mmol) followed by the
dropwise addition of 2-bromopyridine (1 mL, 10.4 mmol) while stirring
at room temperature. After 1 h 2-bromobenzaldehyde (1.34 mL, 11.5
mmol) was added and stirred for another 2 h while monitored by TLC.
Molecular Modeling. Explicit water calculations were performed
using Gaussian 98 (A 11).7 For each molecule, all possible rotamers
were constructed in Sybyl and placed in a droplet of 50 water molecules
using the XFIT algorithm.15 Structures were subsequently minimized
for 5000 iterations using the Powell method with the Tripos force field
and Gastieger-Huckel charges. Minimized, solvated structures were
subsequently optimized using the ONIOM method as implemented in
Gaussian 98 (A 11). In the ONIOM calculation, the molecule of interest
was treated at the HF/6-31g** level, and solvent molecules were treated
with the UFF force field.
(14) Pangborn, A. B.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.; Timmers,
F. J. Organometallics 1996, 15, 1518-1520.
(15) SYBYL 6.9, Tripos Inc. 1699 South Hanley Road, St. Louis, Missouri
63144, USA.
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A R T I C L E S
Rashkin et al.
The reaction was quenched with 10 mL of 1 N HCl. The aqueous layer
is washed with ether and then neutralized with 1 N NaOH resulting in
a cloudy solution. The suspension was then extracted into ether. The
resulting organic layer was then washed with water and brine followed
by drying over magnesium sulfate and concentrated in vacuo, recovering
1.45 g of an off-white colored powder (52% yield). 1H NMR (400 MHz,
CDCl3) δ 8.56 (d, 1H, J ) 5 Hz), 7.61 (t, 1H, J ) 7 Hz), 7.56 (d, 1H,
J1 ) 7 Hz), 7.33 (d, 1H, J ) 8 Hz), 7.23 (m, 2H), 7.11 (t, 1H, J ) 8
Hz), 6.73 (d, 1H, J ) 2 Hz), 5.48 (d, 1H, J ) 2 Hz). LR-MS (ESI):
calculated ) 264.1; actual ) 264.0.
(2-Bromophenyl)-pyridin-3-yl-methanol, 6c. See synthesis of 6b.
69% yield.1H NMR (300 MHz, CDCl3) δ 8.66 (s, 1H), 8.50 (d, 1H, J
) 5 Hz), 7.70 (dt, 1H, J1 ) 7 Hz, J2 ) 2 Hz), 7.61 (dd, 1H, J1 ) 7 Hz,
J2 ) 2 Hz), 7.56 (d, 1H, J ) 7 Hz), 7.38 (t, 1H, J ) 2 Hz), 7.26 (m,
1H), 7.19 (t, 1H, J1 ) 7 Hz, J2 ) 2 Hz), 6.35 (s, 1H). LR-MS (ESI):
calculated ) 264.1; actual ) 264.0.
(2-Bromophenyl)-pyridin-4-yl-methanol, 6d. In a separatory fun-
nel, 4-bromopyridine hydrochloride (2.5 g, 12.8 mmol) was deproto-
nated with 20 mL of 2 M K2CO3 and extracted into 20 mL of
dichloromethane. The organic layer was dried over MgSO4 and
evaporated. The resulting oil was taken up into 20 mL of THF in a
round-bottom flask and placed under an atmosphere of nitrogen. While
stirred at room temperature, isopropylmagnesium chloride (2 M in THF,
6.4 mL, 12.8 mmol) was added dropwise and stirred for 1 h. After 1
h, 2-bromobenzaldehyde (1.58 mL, 12.8 mmol) was added and stirred
for another 2 h while monitored by TLC. The reaction was quenched
with 10 mL of 1 N HCl. The aqueous layer is washed with ether and
then neutralized with 1 N NaOH resulting in a cloudy solution. The
suspension was then extracted into ether. The resulting organic layer
was then washed with water and brine followed by drying over
magnesium sulfate and concentrated in vacuo, recovering 1.05 g of an
off-white colored powder (31% yield). 1H NMR (300 MHz, CDCl3) δ
8.54 (d, 2H, J ) 6 Hz), 7.57 (d, 1H, J1 ) 8 Hz, J2 ) 2 Hz), 7.46 (d,
1H, J1 ) 7 Hz, J2 ) 2 Hz), 7.35 (m 3H), 7.18 (t, 1H, J1 ) 7 Hz, J2 )
2 Hz), 6.24 (s, 1H).
ether followed by washes with water and brine. The organic layer was
dried over magnesium sulfate and concentrated in vacuo. The resulting
oil was purified by column chromatography (10:1 hexanes/ethyl acetate)
to give 56 mg of product (46% yield). 1H NMR (400 MHz, CDCl3) δ
8.57 (d, 1H J ) 4 Hz), 7.58 (m, 2H) 7.27 (m, 2H), 7.12 (m, 3H), 4.32
(s, 2H). LR-MS (ESI): calculated ) 248.1; actual ) 248.0.
2-Bromobenzyl-3-pyridine, 8c. See synthesis of 8b. 66% yield. 1H
NMR (300 MHz, CDCl3) δ 8.50 (m, 2H), 7.59 (d, 1H, J ) 7 Hz), 7.40
(d, 1H, J ) 8 Hz), 7.18 (m, 4H), 4.12 (s, 2H).
2-Bromobenzyl-4-pyridine, 8d. See synthesis of 8b. 1H NMR (300
MHz, CDCl3) δ 8.64 (d, 2H, J ) 6 Hz), 7.73 (d, 1H, J ) 8 Hz), 7.74
(m, 1H), 7.26 (m, 4H), 4.25 (s, 2H).
2-(2′-Methoxy-biphenyl-2-ylmethyl)-Pyridine, 1b. A round-bottom
flask was filled with argon, 20 mL of benzene, compound 8b (102
mg, 0.41 mmol), and compound 2 (66 mg, 0.49 mmol) at room
temperature. To the flask Pd(PPh3)4 (23 mg, 0.02 mmol) and 2 mL of
2 M K2CO3 were added. The reaction was allowed to react overnight
under reflux. Upon cooling, 5 mL of 30% H2O2 was added and stirred
for 30 min. The reaction mixture was extracted into ether and washed
with 20 mL of water followed by 20 mL of brine. The organic layer
was dried over magnesium sulfate and concentrated in vacuo. The
resulting oil was purified by column chromatography (10:1 hexanes/
1
ethyl acetate) to give a yellow oil. H NMR (500 MHz, D2O pH 1) δ
8.1 (d, 1H, J ) 5 Hz), 8.047 (t, 1H), 7.536 (t, 1H), 7.405 (s, 1H),
7.329 (s, 1H), 7.18 (m, 2H), 7.073 (d, 1H, J ) 4.5 Hz), 6.751 (m, 3H),
4.155 (dd, 2H), 3.361 (s, 3H); 13C NMR (100 MHz, D2O pH 1) δ 155,
155, 146, 140, 138, 134, 131, 131, 130, 130, 128, 128, 128, 127, 124,
121, 111, 55, 38. LR-MS (ESI): calculated ) 275.3; actual ) 275.1.
3-(2′-Methoxy-biphenyl-2-ylmethyl)-pyridine, 1c. See synthesis of
1b. 1H NMR (500 MHz, D2O pH 1) δ 8.31 (d, 1H, J ) 6 Hz), 7.72 (d,
1H, J ) 8 Hz), 7.68 (s, 1H), 7.55 (q, 1H, J ) 6 Hz), 7.33 (d, 1H, J )
7 Hz), 7.21 (m, 2H), 7.11 (t, 1H, J ) 7 Hz), 6.81 (d, 2H, J ) 7 Hz),
6.75 (m, 2H), 6.61 (dd, 1H, J1 ) 8 Hz, J2 ) 2 Hz), 3.84 (q, 2H, J )
15 Hz), 3.32 (s, 3H); 13C NMR (75 MHz, D2O pH 1) δ 155, 155, 146,
140, 138, 138, 136, 131, 130, 130, 129, 128, 128, 127, 126, 124, 121,
54, 36. LR-MS (ESI): calculated ) 275.3; actual ) 275.1.
4-(2′-Methoxy-biphenyl-2-ylmethyl)-pyridine, 1d. See synthesis
of 1b (22% yield). 1H NMR (500 MHz, D2O pH 1) δ 8.27 (d, 2H J )
6 Hz), 7.42 (d, 1H, J ) 7 Hz), 7.32 (m, 6H), 7.09 (d, 1H, J ) 7 Hz),
6.86 (d, 1H, J ) 8 Hz), 6.82 (m, 2H), 4.08 (q, 2H, J ) 15 Hz), 3.45
(s, 3H). 13C NMR (75 MHz, D2O pH 1) δ 163, 155, 139, 138, 136,
130, 129, 129, 128, 127, 121, 111, 55, 40. LR-MS (ESI): calculated
) 275.3; actual ) 275.1.
2-Bromobenzyl-N-pyridine Bromide, 9a. A round-bottom flask was
filled with argon, 20 mL of THF, 2-bromobenzaldehyde (8.56 mmol),
and sodium cyanoborohydride (0.538 g, 8.6 mmol). The reaction was
allowed to stir for 1 h, then quenched with 1 N HCl (10 mL), and
diluted with diethyl ether. The ether layer was washed with water and
brine, dried over magnesium sulfate, and concentrated in vacuo. The
resulting white solid was taken up into 20 mL of chloroform under an
argon atmosphere. Phosphorus tribromide was added (271 uL; 2.85
mmol), and the reaction was allowed to stir for 1.5 h. The reaction
was quenched with 10 mL of water, followed by washes of sodium
bicarbonate, water, and brine. The organic layer was dried with
magnesium sulfate and concentrated in vacuo to give a yellow oil.
Pyridine (2 mL) was added, and the solution was allowed to stand until
a white precipitate formed. The precipitated product was filtered and
washed several times with diethyl ether (1.27 g, 60% overall yield).
1H NMR (500 MHz, D2O) δ 8.736 (d, 2H, J ) 6 Hz), 8.423 (t, 1H, J
) 7.5 Hz), 7.919 (t, 2H, J1 ) 7 Hz, J2 ) 8 Hz), 7.54 (d, 1H, J ) 8
Hz), 7.452 (d, 1H, J ) 7.5 Hz), 7.357 (t, 1H, J ) 7.5 Hz), 7.252 (t,
1H, J1 ) 8 Hz, J2 ) 7.5 Hz), 5.763 (s, 2H).
Acetic Acid (2-Bromo-phenyl)-pyridin-2-yl-methyl Ester, 7b. A
round-bottom flask charged with anhydrous methylene chloride,
compound 6a (394 mg, 1.49 mmol), acetic anhydride (167 µL, 181
mg, 1.78 mmol), pyridine (143 µL, 140 mg, 1.78 mmol), and DMAP
(36 mg, 0.298 mmol) and stirred overnight at room temperature. The
reaction mixture was quenched with water and adjusted to neutral pH.
The water was extracted with methylene chloride, and the organic layer
was dried over magnesium sulfate and concentrated in vacuo. The
product was purified by column chromatography with 1:1 hexanes/
ethyl acetate as the mobile phase resulting in 122 mg of a yellow oil
1
(52% yield). H NMR (300 MHz, CDCl3) δ 8.63 (d, 1H, J ) 5 Hz),
7.69 (t, 1H, J1 ) 8 Hz, J2 ) 2 Hz), 7.57 (d, 1H, J1 ) 2 Hz, J2 ) 2 Hz),
7.49 (d, 1H, J1 ) 8 Hz, J2 ) 2 Hz), 7.43 (d, 1H, J ) 3 Hz), 7.33 (t,
1H, J ) 7 Hz), 7.21 (m, 3H), 2.20 (s, 3H). LR-MS (CI): calculated )
305.0; actual ) 306.0.
Acetic Acid (2-Bromo-phenyl)-pyridin-3-yl-methyl Ester, 7c. See
1
synthesis of 7b. (84% yield). H NMR (300 MHz, CDCl3) δ 8.66 (s,
1H), 8.70 (d, 1H, J ) 5 Hz), 7.70 (dt, 1H, J1 ) 8 Hz, J2 ) 2 Hz), 7.57
(d, 1H, J ) 8 Hz), 7.52 (d, 1H, J ) 8 Hz), 7.43 (t, 1H, J ) 7 Hz), 7.29
(m, 1H), 7.20 (m, 2H), 2.17 (s, 3H). LR-MS (ESI): calculated ) 305.0;
actual ) 305.0.
Acetic Acid (2-Bromo-phenyl)-pyridin-4-yl-methyl Ester, 7d. See
1
synthesis of 7b. 84% yield. H NMR (300 MHz, CDCl3) δ 8.73 (d,
2H, J ) 6 Hz), 7.74 (d, 1H, J1 ) 8 Hz, J2 ) 1 Hz), 7.50 (m, 2H), 7.42
(d, 1H, J ) 6 Hz), 7.35 (m, 1H), 7.31 (s, 2H), 5.44 (s, 3H).
2-Bromobenzyl-2-pyridine, 8b. In a round-bottom flask charged
with Ar and a stirbar was filled 4a (167 mg, 0.55 mmol) and t-BuOH
(61 mg, 0.8 mmol, 78 µL) in 5 mL of THF. This was followed by the
addition of SmI2 (1.6 mmol, 16.4 mL, 0.1 M in THF) dropwise over
approximately 10 min. The mixture was stirred for 2 h while monitored
by TLC. The reaction was quenched with water and extracted with
Synthesis of Control Compounds 9b-9d. Purified compounds 8b-
8d were placed in scintillation vials with 5 mL of H2O and titrated to
pH 1 with 50% HBF4 . The aqueous solutions were subsequently frozen
and lyophilized in preparation for NMR analysis in D2O.
9
13324 J. AM. CHEM. SOC. VOL. 126, NO. 41, 2004

Effects on Cation-
π
Interactions in Aqueous Solution
A R T I C L E S
2-Bromobenzyl-2-pyridine, 9b. 1H NMR (500 MHz, D2O) δ 8.501
(d, 1H, J ) 6 Hz), 8.295 (t, 1H, J ) 8 Hz), 7.762 (t, 1H, J ) 7 Hz),
7.551 (d, 2H, J ) 8 Hz), 7.330 (m, 2H), 7.187 (t, 1H, J1 ) 7 Hz, J2 )
7.75 Hz), 4.433 (s, 2H).
Synthesis of N-Methyl-2-bromobenzyl-4-pyridinium Iodide
(N-Me-9d): See synthesis of N-Me-1c. H NMR (500 MHz, D2O) δ
8.412 (d, 2H, J ) 6.5 Hz), 7.601 (d, 2H, J ) 6 Hz), 7.488 (d, 1H, J )
8 Hz), 7.273 (m, 2H), 7.110 (t, 1H, J1 ) 8 Hz, J2 ) 7 Hz), 4.231 (s,
2H), 4.124 (s, 3H).
1
1
2-Bromobenzyl-3-pyridine, 9c. H NMR (400 MHz, D2O) δ 8.31
(d, 1H, J ) 6 Hz), 8.287 (s, 1H), 8.109 (d, 1H, J ) 8 Hz), 7.640 (t,
1H, J1 ) 7.2, J2 ) 6.4), 7.355 (d, 1H, J ) 8 Hz), 7.125 (m, 2H), 6.953
(t, 1H, J ) 7.6 Hz), 4.056 (s, 2H).
NMR Data Acquisition. A spectrum of each sample was taken at
10 °C temperature intervals from 298 K to coalescence on a Bruker
300AMX NMR. Temperature calibration was done through the use of
the known temperature dependence of ethylene glycol chemical shifts;
as a result, the spectrometer was calibrated to an accuracy of (0.2 K.
The sample was allowed to equilibrate at a given temperature for at
least 5 min before data acquisition. Temperature stability was assured
by NMR temperature calibration before and after each experiment
acquisition. Near the reported temperature, spectra were obtained at
decreased temperature intervals once equilibration had been achieved.
Water suppression NMR techniques were employed, when possible,
to maximize the signal-to-noise of the spectrum. Although there were
changes in chemical shift of the methylene hydrogens with changes in
temperature, these shifts were linear and were accounted for in the fitting
of the data.
2-Bromobenzyl-4-pyridine, 9d. 1H NMR (500 MHz, D2O) δ 8.446
(d, 2H, J ) 7 Hz), 7.671 (d, 2H, J ) 6.5 Hz), 7.530 (d, 1H, J ) 8 Hz),
7.281 (m, 2H), 7.135 (t, 1H, J1 ) 8 Hz, J2 ) 7 Hz), 4.300 (s, 2H).
Synthesis of N-Methyl-2-(2′-methoxy-biphenyl-2-ylmethyl)-py-
ridinium Methyl Sulfate (N-Me-1b). In a 1 dram vial compound 1b
(40 mg, 0.14 mmol) was combined with dimethyl sulfate (25 mg, 0.2
mmol) in benzene and reacted for 2 h. The reaction was quenched with
ether, and the precipitate was collected through filtration and washed
1
with ether to recover a white solid. H NMR (300 MHz, D2O) δ 8.37
(d, 1H, J ) 6 Hz), 8.03 (t, 1H, J ) 8 Hz), 7.58 (t, 1H, J ) 7 Hz), 7.35
(m, 3H), 7.26 (m, 2H), 7.16 (m, 1H), 6.86 (m, 3H), 4.23 (q, 2H, J )
15 Hz), 3.77 (s, 3H), 3.60 (s, 3H), 3.46 (s, 3H).
Synthesis of N-Methyl-3-(2′-methoxy-biphenyl-2-ylmethyl)-py-
ridinium Iodide (N-Me-1c): In a 1 dram vial compound 1c (25 mg,
0.1 mmol) was combined with 100 µL of iodomethane and reacted for
2 h. The reaction was quenched with ether, and the precipitate was
collected through filtration and washed with ether to recover a yellowish
NMR Data Analysis. Each spectrum was analyzed using the
program gNMR from Cherwell Scientific Publishing. The spectrum
was converted from a WIN-NMR file by gNMR. The methoxy protons
were simulated to determine the baseline line width. The line width
was then used to iterate on the diastereotopic methylene hydrogens
allowing us to determine the rate constant for rotation about the biaryl
bond. Each sample was acquired and analyzed at least twice to ensure
accuracy, with a standard deviation of 0.01 kcal mol-1 in all cases.
The reported ∆G‡ was determined from extrapolation of the data
collected near coalescence to 352 K. The error in the rate constant was
determined to be less than 5%, which corresponds to a total error of
(0.04 kcal mol-1 through propagation of errors in both k and T.
1
solid. H NMR (400 MHz, D2O) δ 8.33 (d, 1H, J ) 6 Hz), 7.78 (d,
1H, J ) 8 Hz), 7.69 (s, 1H), 7.60 (t, 1H, J ) 7 Hz), 7.47 (dd, 1H, J1
) 7 Hz, J2 ) 2 Hz), 7.35 (m, 3H), 7.11 (d, 1H, J1 ) 7 Hz, J2 ) 2 Hz),
6.88 (m, 3H), 3.97 (q, 2H, J ) 15 Hz), 3.99 (s, 3H), 3.44 (s, 3H).
Synthesis of N-Methyl-4-(2′-methoxy-biphenyl-2-ylmethyl)-py-
ridinium Iodide (N-Me-1d): See synthesis of N-Me-1c. 1H NMR (400
MHz, D2O) δ 8.76 (s, 2H), 7.40 (m, 1H), 7.36 (m, 2H), 7.29 (m, 1H),
7.22 (s, 2H), 7.13 (dd, 1H, J1 ) 7 Hz, J2 ) 2 Hz), 6.90 (d, 1H, J ) 9
Hz), 6.84 (m, 2H), 4.09 (s, 3H), 4.05 (q, 2H, J ) 15 Hz).
Synthesis of N-Methyl-2-bromobenzyl-2-pyridinium Iodide (N-
Me-9b): See synthesis of N-Me-1c. 1H NMR (500 MHz, D2O) δ 8.577
(d, 1H, J ) 6 Hz), 8.298 (t, 1H, J1 ) 8 Hz, J2 ) 6 Hz), 7.763 (d, 1H,
J ) 8.5 Hz), 7.735 (t, 1H, J1 ) 9.5 Hz, J2 ) 7), 7.572 (d, 1H, J ) 8
Hz), 7.265 (t, 1H, J1 ) 7.5 Hz, J2 ) 6.5 Hz), 7.142 (t, 1H, J1 ) 7.5
Hz, J2 ) 6.5 Hz), 7.07 (d, 1H, J ) 6.5 Hz), 5.291 (s, 2H), 4.12 (s,
3H).
Acknowledgment. This work was supported by an NSF
Career Award (CHE-0094068). N.T.C. thanks the Francis C.
and William P. Smallwood Foundation and the UNC Office of
Undergraduate Research for support.
Supporting Information Available: NMR spectra of com-
pounds 1a-d, 9a-d, N-Me-1b-d, and N-Me-9b-d. This
material is available free of charge via the Internet at
http://pubs.ac.org.
Synthesis of N-Methyl-2-bromobenzyl-3-pyridinium Iodide
1
(N-Me-9c): See synthesis of N-Me-1c. H NMR (400 MHz, D2O) δ
8.50 (d, 1H, J ) 6 Hz), 8.45 (s, 1H), 8.22 (d, J ) 8 Hz), 7.80 (t, 1H,
J ) 8 Hz), 7.40 (m, 2H), 7.18 (t, 1H, J1 ) 7 Hz, J2 ) 2 Hz), 4.25 (s,
2H), 4.19 (s, 3H).
JA0498538
9
J. AM. CHEM. SOC. VOL. 126, NO. 41, 2004 13325