The strength of parallel-displaced arene-arene interactions in chloroform

Article abstract of DOI:10.1021/jo050049t

(Chemical Equation Presented) Triptycene-derived compounds have been prepared to serve as conformational equilibrium reporters for direct measurements of arene-arene interactions in the parallel-displaced orientation. A series of such compounds bearing ar

Full text of DOI:10.1021/jo050049t

The Strength of Parallel-Displaced Arene-Arene Interactions in
Chloroform
Benjamin W. Gung,*,† Xiaowen Xue,† and Hans J. Reich‡
Department of Chemistry & Biochemistry, Miami University, Oxford, Ohio 45056, and Department of
Chemistry, University of Wisconsin, Madison, Wisconsin 53706
gungbw@muohio.edu
Received January 10, 2005
Triptycene-derived compounds have been prepared to serve as conformational equilibrium reporters
for direct measurements of arene-arene interactions in the parallel-displaced orientation. A series
of such compounds bearing arenes with different substituents were synthesized, and the ratios of
the syn and anti conformers were determined by variable-temperature NMR spectroscopy. The
syn conformer allows attached arenes to interact with each other while the anti conformer does
not. The free energies derived from the syn/anti ratios in chloroform range from slightly positive
(0.2 kcal/mol) to considerably negative (-0.98 kcal mol) values. The interactions between the arenes
bearing electron-donating groups (EDG) are either negligible or slightly repulsive, while the
interactions between arenes bearing electron-withdrawing groups (EWG) are attractive. Intermedi-
ate free energy values are obtained for those compounds bearing arenes with one EDG and one
EWG.
Introduction
organic chemists, the aromatic ring has long been sug-
gested to play a significant role in enhancing stereose-
lectivity. In the pioneering work on asymmetric induc-
tion, Corey showed the importance of the phenyl ring in
his 8-phenylmenthol chiral auxiliary.7 Subsequently,
aromatic rings have been suggested to selectively shield
diastereofaces in many reactions.8,9 Evans was able to
provide compelling evidence that π facial differentiation,
although controlled largely by steric effects, is enhanced
by π-π interactions.8
Nonbonded interactions between aromatic molecules
contribute significantly to the stability of biological
systems.1 Aromatic stacking interactions are abundant
between aromatic amino acid side chains in proteins and
have been observed in the complexes of medicinal drugs
and the targeted enzymes.2 Both the edge-to-face and the
parallel-displaced orientations were found.1,3 The biologi-
cal significance and the progress in the study of arene-
arene interactions have been reviewed.4-6 For synthetic
† Miami University.
Results and Discussion
‡ University of Wisconsin. E-mail: (H.J.R.) reich@chem.wisc.edu.
(1) Burley, S. K.; Petsko, G. A. Science 1985, 229, 23-28.
(2) Kryger, G.; Silman, I.; Sussman, J. L. J. Physiol.-Paris 1998,
92, 191-194.
Despite the important role played by aromatic stacking
interactions, the magnitude of individual arene-arene
interactions has been addressed mainly by computational
(3) McGaughey, G. B.; Gagne, M.; Rappe, A. K. J. Biol. Chem. 1998,
273, 15458-15463.
(4) Hunter, C. A.; Lawson, K. R.; Perkins, J.; Urch, C. J. J. Chem.
Soc., Perkin Trans. 2 2001, 651-669.
(7) Corey, E. J.; Ensley, H. E. J. Am. Chem. Soc. 1975, 97, 6908-9.
(8) Evans, D. A.; Chapman, K. T.; Bisaha, J. J. Am. Chem. Soc. 1988,
110, 1238-1256.
(5) Waters, M. L. Curr. Opin. Chem. Biol. 2002, 6, 736-741.
(6) Meyer, E. A.; Castellano, R. K.; Diederich, F. Angew. Chem., Int.
Ed. 2003, 42, 1210-1250.
(9) Jones, G. B. Tetrahedron 2001, 57, 7999-8016.
10.1021/jo050049t CCC: $30.25 © 2005 American Chemical Society
Published on Web 04/02/2005
J. Org. Chem. 2005, 70, 3641-3644
3641

Gung et al.
FIGURE 1. Sketches illustrating the syn and anti conforma-
tional isomers derived from 1,9-diaryl-substituted triptycene
derivative 1 (the sketch is a modified version of the drawing
by Oki).10
FIGURE 3. Experimental (left column) and simulated (right
column) 1H NMR spectra for the benzylic CH2 protons of com-
pound 9f at different temperatures. Simulation was done using
WINDNMR14 to give rate constants kab at the corresponding
temperature. From the rate constants kab, ∆Hq and ∆Sq were
extracted by plotting ln(k/T) vs (1/T). For compound 9f, ∆Hq
) 13.3 ( 0.5 kcal mol-1 and ∆Sq ) -1.1 ( 0.5 cal mol-1 K-1
.
interactions should lead to a higher than 2:1 syn/anti
ratio while the repulsive interactions lead to a smaller
than 2:1 syn/anti ratio. Thus, the syn/anti ratio deter-
mined at low temperature provides a measure of the
interactions between the two attached aryl groups,
Figure 2. This model system probes the interaction of two
attached arenes in the parallel displaced, rather than the
edge-to-face orientation according to molecular modeling
studies using MacroModel.12 The global minimum for
compound 1 with X ) Y ) H is shown in Figure 2. The
alternative T-shape orientation is prohibited by the
triptycene skeleton. Due to the constraint from the tether,
the two interacting arenes are not perfectly parallel as
indicated in Figure 2b. However, the minimum confor-
mation is similar to the benzene dimer configuration
predicted by computational studies with an interplanar
distance of 3.3-3.6 Å and a displacement of 1.6-1.8 Å.
A group of such conformational equilibrium reporters
have been prepared (7a-10d, Scheme 1). Four series of
the substituted 1,9-diaryltriptycene were studied in
which the X-substituents are H, Me, F, and CF3 for
compound series 7, 8, 9, and 10, respectively. By using
variable-temperature NMR, we have determined the syn/
anti isomeric ratios at -40 °C (Table 1) in CDCl3
solutions. The rate constants kab (see Figure 1) have been
determined by using line shape analysis at each temper-
ature.13,14 The simulation involves two independent rate
constants (Figure 1), the conversion of the syn isomers
to the anti, kab, and the interconversion between the two
enantiomeric syn conformers (kaa′). Excellent simulations
FIGURE 2. Computer-generated minimum conformation for
compound 1 (X ) Y ) H) using MacroModel:12 (a) space-filling
model and (b) cylindrical bonds model with the triptycene
skeleton omitted for clarity.
studies.6 To our knowledge, there are no specific experi-
mental methods to directly determine the magnitude of
parallel displaced arene-arene interactions thus far. We
have found, through molecular modeling and experimen-
tal studies, that modified triptycene-derived compounds
can be used to directly measure the strength of arene-
arene interactions in the parallel-displaced configuration
in organic solvents. Oki and co-workers pioneered the use
of the triptycene molecular system in the study of weak
molecular interactions.10,11 No work related to π-stacking,
however, has been reported using this system. The
conformational equilibrium between the symmetrical anti
form and the chiral syn forms in the triptycene molecular
system (1, Figure 1) can be measured by low-temperature
NMR spectroscopy by taking advantage of the slow
rotation of the C9-benzyl carbon-carbon bond in com-
pound 1.
At around -30 °C, the rotation around the C(9)-benzyl
carbon bond becomes sufficiently slow that the signals
for the syn and anti conformations decoalesce, with the
former becoming an AB quartet and the latter a singlet,
Figure 3. Therefore the benzyl CH2 group serves as a
conformational equilibrium reporter for the triptycene
molecular models. In a pure statistical state, a syn/anti
ratio of 2:1 should be observed when there is no interac-
tions between the arenes at C(1) and C(9). The attractive
(12) Mohamadi, F.; Richards, N. G. J.; Guida, W. C.; Liskamp, R.;
Lipton, M.; Caufield, C.; Chang, G.; Hendrickson, T.; Still, W. C. J.
Comput. Chem. 1990, 11, 440-467.
(13) Sandstro¨m, J. Dynamic NMR Spectroscopy; Academic Press:
London, U.K., 1982.
(10) Oki, M. Acc. Chem. Res. 1990, 23, 351-356.
(11) Oki, M.; Nishino, M.; Kaieda, K.; Nakashima, T.; Toyota, S.
Bull. Chem. Soc. Jpn. 2001, 74, 357-361.
(14) Reich, H. J. In WinDNMR: Dynamic NMR Spectra for Win-
dows; J. Chem. Educ. Software, 1996-2003; p 3D2. For an updated
version see: http://www.chem.wisc.edu/areas/reich/plt/winplt.htm.
3642 J. Org. Chem., Vol. 70, No. 9, 2005

The Strength of Arene-Arene Interactions
SCHEME 1
TABLE 1. Substituent Effect on the Ratios of Syn/Anti
Isomers and the Free Energies for Arene-Arene
calculated using the Eyring equation based on the
rotational rate constants.
a
Interactions in CDCl3
The anti conformation is less congested sterically.
Therefore the preference for the syn conformation must
arise from attractive interactions between the two at-
tached groups. The anti conformer does not allow inter-
actions between the two attached groups. In this study,
the population of the syn isomer is dependent on both
the X- and the Y-substituents and decreases in the
following order in terms of the Y-substituent, NO2 > CN
> Br > F > H > MeO > Me, and in the following order
based on the X-substituent: CF3 > F > H > Me.
Negligible temperature dependence of the syn/anti
ratios was observed for the majority of the compounds
in Table 1 and an increase in the population of the syn
conformation at lower temperatures was only observed
for the compounds with large syn/anti ratios (e.g., 10a).
By using the equation: ∆G ) ∆H - T∆S ) -RT ln Keq
) -RT ln(1/2syn/anti), free energies (∆G, T ) 233 °K) are
obtained for compounds 7a-11, Table 1. In general, the
interactions between the two arenes are attractive when
both X and Y are electron-withdrawing groups (EWG)
and repulsive when both X and Y are electron-donating
groups (EDG). The magnitude of the arene-arene interac-
tions observed in this study is smaller than the reported
computational values for benzene dimers in the gas phase
(∼-2 kcal/mol).15,16 However, they are in line with the
limited a few experimental observations.17-19 The differ-
ence between the current study and a previous study
using a “torsional balance” is the arene orientation and
the substituent effects. In the previous studies with an
edge-to-face model,20 no difference in the strength of
ratio
∆G° (-40 °C)antifsyn
entry compd
X
Y
(syn/anti)
(kcal/mol)
1
2
7a
7b
7c
7d
7e
7f
7g
8a
8b
8c
H
NO2
CN
F
Br
H
Me
MeO
NO2
CN
F
Br
H
Me
MeO
NO2
CN
F
Br
H
9.1
6.4
2.9
3.3
1.9
1.5
1.7
6.7
4.4
2.5
3.0
1.6
1.3
1.4
11.9
8.4
3.3
3.8
2.5
2.1
2.3
16.9
7.4
3.1
3.7
3.3
-0.69 ( 0.05
-0.55
-0.17
-0.24
0.02
0.14
0.07
-0.55
-0.36
-0.10
-0.19
0.10
0.20
0.17
-0.84
-0.67
-0.24
-0.29
-0.10
-0.02
-0.07
-0.98
-0.60
-0.22
-0.29
-0.24
H
3
H
4
H
5
H
6
H
7
H
8
Me
Me
Me
Me
Me
Me
Me
F
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
8d
8e
8f
8g
9a
9b
9c
9d
9e
9f
9g
10a
10b
10c
10d
11
F
F
F
F
F
Me
MeO
F
CF3 NO2
CF3
F
CF3 Me
CF3 MeO
H
n/a
(15) Sinnokrot, M. O.; Valeev, E. F.; Sherrill, C. D. J. Am. Chem.
Soc. 2002, 124, 10887-10893.
a The errors are estimated at (0.05 kcal/mol.
(16) Tsuzuki, S.; Honda, K.; Uchimaru, T.; Mikami, M.; Tanabe, K.
J. Am. Chem. Soc. 2002, 124, 104-112.
(17) Paliwal, S.; Geib, S.; Wilcox, C. S. J. Am. Chem. Soc. 1994, 116,
4497-4498.
can be achieved with kaa′ set to zero (see Figure 3), so we
conclude that this process is negligibly slow in this
system. This is reasonable, since this process requires
the two large groups to pass each other. The barrier
separating the anti and the syn conformers has been
(18) Jennings, W. B.; Farrell, B. M.; Malone, J. F. Acc. Chem. Res.
2001, 34, 885-894.
(19) McKay, S. L.; Haptonstall, B.; Gellman, S. H. J. Am. Chem.
Soc. 2001, 123, 1244-1245.
(20) Kim, E.; Paliwal, S.; Wilcox, C. S. J. Am. Chem. Soc. 1998, 120,
11192-11193.
J. Org. Chem, Vol. 70, No. 9, 2005 3643

Gung et al.
Conclusions
This study has shown that the current system works
well in directly determining individual attractive interac-
tions between arenes in the offset-stacked orientation.
The current results can be used in conjunction with
computational studies to evaluate the magnitude of
arene-arene interactions in solution. With a better
knowledge of the magnitude of arene-arene interactions,
it is possible to achieve a better understanding of the
contributions from arene-arene interactions in molecular
recognition involving biological macromolecular systems.
The current results are consistent with several recent
studies that polar/π forces are responsible for aromatic
stacking interactions. However the current study does
not rule out the possibility of charge-transfer interactions
if the aromatic systems are strongly different in electron
density. Extension of this system to the study of π-π
interactions with strongly electron-deficient and -rich
arenes is currently under way in our laboratories.
FIGURE 4. Plot of free energy of attraction (-∆G°) vs σpara
for compounds 9a-g. Experiments were conducted in CDCl3.
aromatic interactions was observed as a function of arene
substitution. The current study documents a greater
attractive force in the parallel-displaced orientation and
a significant difference in strength of interactions as a
function of substitution (see Figure 4).
Polar/π (dipole-dipole, dipole-multipole, and van der
Waals) forces, not charge-transfer (CT), have been sug-
gested to be responsible for aromatic stacking
interactions.8,21-23 The current study supports these
conclusions. No forced contact exists in either the syn or
the anti isomers in the current study. Therefore, the
preference for the syn conformation is entirely due to
attractive interactions. The arenes that show the stron-
gest attractive interactions are X ) CF3 and Y ) NO2
(∆G ) -0.98 ( 0.05 kcal/mol, entry 22, Table 1).
Compounds 7a-g with X ) H (entries 1-7, Table 1)
should be a reasonable model for the amino acid side
chain of phenylalanine (Phe). Our results show attractive
interaction between the two arenes if the other arene is
substituted with an EWG and repulsive interaction with
EDG (entries 1-7, Table 1). This indicates that in the
parallel displaced orientation a favorable arene-arene
interaction should occur with the side chain of Phe if the
other arene is electron poor, such as a protonated arene.
The control compound 11 shows a small preference for
the syn conformation indicating there is a small attractive
interaction between the acetyl group and the benzene
ring (∆G ) -0.24 ( 0.05 kcal/mol, entry 26, Table 1).
This weak interaction is most likely due to a lone pair-
π* attraction between the phenolic oxygen and the benzyl
aromatic ring. For compounds 7-10, this lone pair-π*
interaction is prohibited by the parallel arrangement of
the two attached arenes. Another possibility involves a
CH-π interaction, which has not been ruled out. More
studies are being conducted to identify the origin of this
weak attraction.
Experimental Section
A. Preparation of the Triptycene Derivatives. The
triptycene derivatives were prepared as shown in Scheme 1
following previously published procedures for similar
compounds.24-28 For general preparations and NMR spectro-
scopic data, see the Supporting Information.
B. Variable-Temperature NMR Procedures. The 1H
NMR spectra were recorded on a 300-MHz instrument with a
variable-temperature probe. A 0.05 M solution of the sample
in deuterated chloroform was placed in a high quality NMR
tube. All samples were degassed by passing nitrogen through
the sample for ∼1 min. The NMR tube was then capped and
sealed with Parafilm. The temperature of the NMR probe was
calibrated using a 13C internal thermometer.29 The process
involves recording the 13C NMR spectrum of tris(trimethylsi-
lyl)methane ((TMS)3CH) immediately before or after a 1H NMR
spectrum was recorded.29 Actual sample temperature was
determined from the calibration equation for CDCl3: T (°C) )
84.711 (∆δ) - 36.5, in which ∆δ is the 13C chemical shift
difference in ppm between the methyl and the methine carbons
of (TMS)3CH.29
Acknowledgment is made to the donors of the
Petroleum Research Fund (PRF #36841-AC4) adminis-
tered by the American Chemical Society.
Supporting Information Available: Experimental pro-
cedures for the preparation of compounds 5a-10d and 11. This
material is available free of charge via the Internet at
http://pubs.acs.org.
JO050049T
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3644 J. Org. Chem., Vol. 70, No. 9, 2005