Stacking interactions between nitrogen-containing six-membered heterocyclic aromatic rings and substituted benzene: Studies in solution and in the solid state

Article abstract of DOI:10.1021/jo702354x

(Figure Presented) The stacking interactions between an aromatic ring and a pyridine or a pyrimidine ring are studied by using a series of triptycene-derived scaffolds. The indicative ratios of the syn and anti conformers were determined by variable-temperature NMR spectroscopy. The syn conformer aligns the attached aromatic ring and the heterocycle in a parallel-displaced orientation while the anti conformer sets the two rings apart from each other. Comparing to the corresponding control compounds where a benzene ring is in the position of the heterocycle, higher attractive interactions are observed as indicated by the higher syn/anti ratios. In general, the attractive interactions are much less sensitive to the substituent effects than the corresponding nonheterocycles. The greatest attractive interactions were observed between a pyrimidine ring and a N,N- dimethylaminobenzene, consistent with a predominant donor-acceptor interaction. The interactions between a pyridine ring and a substituted benzene ring show that the pyridine is comparable to that of a NO₂- or a CN-substituted benzene ring except for the unpredictable substituent effects.

Full text of DOI:10.1021/jo702354x

Stacking Interactions between Nitrogen-Containing Six-Membered
Heterocyclic Aromatic Rings and Substituted Benzene: Studies in
Solution and in the Solid State
Benjamin W. Gung,*,† Francis Wekesa,† and Charles L. Barnes‡,§
Department of Chemistry & Biochemistry, Miami UniVersity, Oxford, Ohio 45056, and Elmer O.
Schlemper X-Ray Diffraction Center, UniVersity of Missouri-Columbia, Columbia, Missouri 65211
gungbw@muohio.edu; barnesch@missouri.edu
ReceiVed NoVember 6, 2007
The stacking interactions between an aromatic ring and a pyridine or a pyrimidine ring are studied by
using a series of triptycene-derived scaffolds. The indicative ratios of the syn and anti conformers were
determined by variable-temperature NMR spectroscopy. The syn conformer aligns the attached aromatic
ring and the heterocycle in a parallel-displaced orientation while the anti conformer sets the two rings
apart from each other. Comparing to the corresponding control compounds where a benzene ring is in
the position of the heterocycle, higher attractive interactions are observed as indicated by the higher
syn/anti ratios. In general, the attractive interactions are much less sensitive to the substituent effects
than the corresponding nonheterocycles. The greatest attractive interactions were observed between a
pyrimidine ring and a N,N-dimethylaminobenzene, consistent with a predominant donor-acceptor
interaction. The interactions between a pyridine ring and a substituted benzene ring show that the pyridine
is comparable to that of a NO2- or a CN-substituted benzene ring except for the unpredictable substituent
effects.
Introduction
medicinal drugs and the targeted enzymes.4 To understand
aromatic stacking interactions, extensive theoretical studies of
benzene dimers and substituted benzene dimers have been
reported.5-10 However, there have been few theoretical studies
on the stacking interactions between a heterocyclic aromatic
Noncovalent interactions between aromatic molecules play
a major role in the stability of biological systems.1,2 In addition
to the prominent role in DNA and RNA structures,3 aromatic
stacking interactions have been observed in the complexes of
† Miami University.
(4) Kryger, G.; Silman, I.; Sussman, J. L. Three-dimensional structure
of a complex of E2020 with acetylcholinesterase from Torpedo californica.
J. Physiol. (Paris) 1998, 92, 191-194.
(5) Jorgensen, W. L.; Severance, D. L. Aromatic Aromatic Interactionss
Free-Energy Profiles for the Benzene Dimer in Water, Chloroform, and
Liquid Benzene. J. Am. Chem. Soc. 1990, 112, 4768-4774.
(6) Jaffe, R. L.; Smith, G. D. A quantum chemistry study of benzene
dimer. J. Chem. Phys. 1996, 105, 2780-2788.
‡ University of Missouri-Columbia.
§ To whom questions regarding X-ray structure analysis should be addressed.
(1) Burley, S. K.; Petsko, G. A. Aromatic-Aromatic Interactionsa
Mechanism of Protein-Structure Stabilization. Science 1985, 229, 23-28.
(2) Meyer, E. A.; Castellano, R. K.; Diederich, F. Interactions with
aromatic rings in chemical and biological recognition. Angew. Chem., Int.
Ed. 2003, 42, 1210-1250.
(3) Guckian, K. M.; Schweitzer, B. A.; Ren, R. X. F.; Sheils, C. J.;
Tahmassebi, D. C.; Kool, E. T. Factors contributing to aromatic stacking
in water: Evaluation in the context of DNA. J. Am. Chem. Soc. 2000, 122,
2213-2222.
(7) Hobza, P.; Selzle, H. L.; Schlag, E. W. Potential energy surface for
the benzene dimer. Results of ab initio CCSD(T) calculations show two
nearly isoenergetic structures: T-shaped and parallel-displaced. J. Phys.
Chem. 1996, 100, 18790-18794.
10.1021/jo702354x CCC: $40.75 © 2008 American Chemical Society
Published on Web 02/12/2008
J. Org. Chem. 2008, 73, 1803-1808
1803

Gung et al.
anti ratio represents the degree of preference for the interactions
between the C1 and the C9 groups.
Our recent studies on aromatic interactions using the trip-
tycene-derived model system allowed quantitative studies of the
magnitude of noncovalent interactions. Our previous study
involved the normal arene-arene interactions, and we have now
expanded our study to the interactions between a six-membered
nitrogen-containing heterocycle and a benzene ring.
Molecular modeling with MacroModel with MMFFs force
field shows that the replacement of the C1-benzoate with a
pyridine or pyrimidine carboxylate does not change the stacking
conformation. The global minimum conformation is the syn
conformation with the pyrimidine ring and the benzyl group
assuming a parallel-displaced conformation. We are aware of
the limitations of the molecular mechanics model in the
calculations of the stacking interactions. Any serious inclusion
of London dispersion forces should consider using a high level
of theory in computations.17 The only purpose of the molecular
mechanics calculations is to examine the three-dimensional
structure of the model compounds. The results show that the
replacement of the C1 benzoate with a 6-membered heterocycle
does not change the parallel displaced conformation in the syn
isomer.
The synthesis of the desired heterocyclic (6a-7g) started with
9-substituted benzyltriptycene-1,4-diol, which have been re-
ported by us recently, Scheme 1.13,15,16 The hydroxyl group at
the C4 position is protected as a pivalate ester. The precursors
(5a-g) to model compounds (6a-7g) were then treated with
the corresponding aryl acyl chloride in the presence of a base
to yield the desired target products. Pyridine-4-acyl chloride is
commercially available. Pyrimidine-4-acyl chloride was prepared
from 4-methylpyrimidine via SeO2 oxidation followed by
treatment of oxalyl chloride.18 The resulting acyl chloride was
used in situ to prepare the target esters (6a-7g).
FIGURE 1. Equilibrium between syn and anti conformations in the
triptycene-derived scaffold. The C9-benzyl bond has hindered rotation.
At low temperature, the two conformations can be observed by 1H NMR
spectroscopy.
ring and a benzene ring.11,12 To our knowledge, no solution
experimental studies have been reported on the relative strength
of stacking interactions between a heterocycle and a benzene
ring. Recently we reported experimental studies of arene-arene
interactions in organic solvents using the triptycene-derived
scaffold.13,14 This report details our study of the interactions
between a pyrimidine or a pyridine ring and a substituted
benzene. We found that these 6-membered nitrogen-containing
heterocycles when arranged in a parallel-displaced configuration
with a benzene ring in general exhibit higher attractive interac-
tions than the corresponding normal arene-arene interactions.
Furthermore, we found that the attractive interactions are much
less sensitive to substituent effects than the corresponding
arene-arene interactions.
A variable-temperature NMR study was carried out in
chloroform with these model compounds. Two conformational
isomers, the syn and the anti, were observed at low temperatures
as usual. This is due to the slow rotation of the bridgehead CH2
group in these compounds on the NMR time scale, which allows
the integration of the peak area for each conformation and the
determination of the syn/anti isomer ratio for each compound
(Figure 2).
The primary solution NMR data are shown in Table 1. The
syn conformation is preferred for all heterocyclic model
compounds (6a-7f), in contrast to the control compounds (8a-
f). The observed syn/anti ratios range from below the statistical
value of 2 for control compounds (8a-d) to an almost exclusive
syn conformation at -50 °C for the pyrimidine-dimethylami-
nobenzyl pair (6a).
Results
The triptycene-derived model system allows the two aromatic
rings, one attached to the bridgehead (C9 in the triptycene name
system) and the other to C1, to assume a near, but not perfect,
parallel displaced conformation in the syn conformation, Figure
1. The stacking contact between the C9 arene and the C1
heterocycle is at near van der Waals’ distance in the syn
conformation, but not possible in the anti conformation.15,16
Since the triptycene scaffold provides an otherwise identical
environment for the syn and the anti conformation, the syn/
(8) Sinnokrot, M. O.; Valeev, E. F.; Sherrill, C. D. Estimates of the ab
initio limit for π-π interactions: The benzene dimer. J. Am. Chem. Soc.
2002, 124, 10887-10893.
(9) Tsuzuki, S.; Honda, K.; Uchimaru, T.; Mikami, M.; Tanabe, K. Origin
of attraction and directionality of the x/x interaction: Model chemistry
calculations of benzene dimer interaction. J. Am. Chem. Soc. 2002, 124,
104-112.
(10) Sinnokrot, M. O.; Sherrill, C. D. Substituent effects in π-π
interactions: Sandwich and T-shaped configurations. J. Am. Chem. Soc.
2004, 126, 7690-7697.
(11) Mignon, P.; Loverix, S.; De Proft, F.; Geerlings, P. Influence of
stacking on hydrogen bonding: Quantum chemical study on pyridine-
benzene model complexes. J. Phys. Chem. A 2004, 108, 6038-6044.
(12) Waller, M. P.; Robertazzi, A.; Platts, J. A.; Hibbs, D. E.; Williams,
P. A. Hybrid density functional theory for π-stacking interactions: Ap-
plication to benzenes, pyridines, and DNA bases. J. Comput. Chem. 2006,
27, 491-504.
(13) Gung, B. W.; Xue, X. W.; Reich, H. J. The strength of parallel-
displaced arene-arene interactions in chloroform. J. Org. Chem. 2005, 70,
3641-3644.
(14) Oki, M. 1,9-Disubstituted Triptycenessan Excellent Probe for Weak
Molecular-Interactions. Acc. Chem. Res. 1990, 23, 351-356.
A single crystal was obtained for one of the pyrimidine-
containing model compounds where X ) Br on the C9-benzyl
(15) Gung, B. W.; Patel, M.; Xue, X. W. A threshold for charge transfer
in aromatic interactions? A quantitative study of π-stacking interactions. J.
Org. Chem. 2005, 70, 10532-10537.
(16) Gung, B. W.; Xue, X. W.; Reich, H. J. Off-center oxygen-arene
interactions in solution: A quantitative study. J. Org. Chem. 2005, 70,
7232-7237.
(17) Grimme, S.; Antony, J.; Schwabe, T.; Muck-Lichtenfeld, C. Density
functional theory with dispersion corrections for supramolecular structures,
aggregates, and complexes of (bio)organic molecules. Org. Biomol. Chem.
2007, 5, 741-758.
(18) Tagawa, Y.; Yamashita, K.; Higuchi, Y.; Goto, Y. Improved
oxidation of active methyl group of N-heteroaromatic compounds by
selenium dioxide in the presence of tert-butyl hydroperoxide. Heterocycles
2003, 60, 953-957.
1804 J. Org. Chem., Vol. 73, No. 5, 2008

Stacking Interactions between Heterocyclic Aromatic Rings and Substituted-Benzene
SCHEME 1. Preparation of the Model Compounds
ring (6f, Figure 3). Surprisingly the anti conformation is shown,
in contrast to its solution structure based on 1H NMR data, which
shows overwhelming syn conformation (6f, Table 1).
In light of the apparent contradiction between the solution
data and the crystal structure of 6f, it is appropriate to report
here our variable-concentration study performed at -50 °C in
chloroform. The syn/anti ratios were examined by using low-
temperature 1H NMR on samples from a serial dilution
performed on a sample of 6f at an initial concentration of 0.2
M. A gradual increase of syn/anti ratio was observed as the
sample concentration became more dilute (see Table 2). This
observation indicates that intermolecular interactions are more
prominent at higher concentration, which is expected and should
reduce the preference for the syn conformation. This interpreta-
tion is further confirmed by careful examination of the X-ray
structure of 6f, which shows that two molecules of 6f in the
crystal cell align their pyrimidine ring with one of the benzene
rings of the triptycene scaffold from the other molecule. Detailed
discussion is presented in the following section.
Discussion
Gas-phase molecular mechanics calculations indicate that the
syn conformations are preferred for the heterocyclic compounds
examined in this study. Variable-temperature NMR data are
consistent with this prediction and the syn/anti ratios are
determined to be from 3.0 to ∼19.4 for the heterocycle-
containing compounds (Table 1). Yet the crystal structure of
6f indicates an anti conformation (Figure 4). A rational
explanation can be reached by a close examination of the crystal
structure. Figure 4 shows two adjacent molecules in the X-ray
structure of compound 6f in two perspectives, which indicates
that the two molecules are reciprocally parallel, stacked with
each other.
In other words, an offset stacking conformation positions C4
of the pyrimidine ring near the center of the benzene ring of
the triptycene skeleton. The distance from the plane of the
pyrimidine ring to the plane of the benzene ring is ∼3.5 Å.
This relative position of the two stacked aromatic rings should
be highly favorable with high electron density area of the
benzene ring near the low electron density area of the pyrimidine
ring. A secondary CH-O interaction from the most acidic
proton of the pyrimidine ring to the phenolic oxygen of the
adjacent molecule is also possible. However, stacking interaction
is the dominant force because the H-O distance is 2.98 Å,
which indicates a weak CH-O attraction. No apparent CH-π
interaction could be identified in the crystal structure.
FIGURE 2. A representative temperature-dependent NMR signals (300
MHz in CDCl3) from the bridgehead C(9)H2 protons. The spectra shown
are from compound 6e, where the AB quartet is due to the syn
conformation and the singlet at 4.6 ppm is due to the anti conformation.
J. Org. Chem, Vol. 73, No. 5, 2008 1805

Gung et al.
TABLE 1. Ratios of Syn/Anti Isomers at Different Temperatures
for Model Compounds 6a-8fa
syn/anti ratio in CDCl3 at
different temperatures
compd C1Aryl
6a pyrimidine NMe2 12.7
6b pyrimidine OMe
6c pyrimidine Me
6d pyrimidine H
X
-10 °C -20 °C -30 °C -40 °C -50 °C
13.3
6.4
9.3
8.3
7.9
11.4
3.4
4.9
5.6
5.5
4.8
7.8
6.0
1.2
1.7
1.9
1.9
2.1
3.0
15.5
7.8
11.1
9.8
8.3
13.7
3.4
5.3
5.4
5.7
5.3
8.4
6.1
1.2
1.7
1.8
1.9
2.3
3.2
17.9
7.8
19.4
8.9
6.2
8.2
7.9
7.6
9.6
3.1
4.7
5.3
5.0
4.5
7.6
5.6
1.3
1.6
2.1
1.8
2.0
2.9
11.5
10.9
10.1
16.3
3.7
5.6
5.8
6.1
5.5
8.5
6.3
1.1
1.8
1.8
2.0
2.4
3.3
14.0
12.4
11.4
18.9
4.1
5.7
6.0
6.8
5.7
9.3
6.4
1.1
1.6
1.8
2.0
2.5
3.3
6e
6f
pyrimidine F
pyrimidine Br
7a
pyridine
NMe2
7b pyridine
7c pyridine
7d pyridine
OMe
Me
H
7e
7f
7g
8a
pyridine
pyridine
pyridine
C6H5
F
Br
NO2
NMe2
OMe
Me
H
8b C6H5
8c C6H5
8d C6H5
FIGURE 4. X-ray structure of compound 6f displayed as a stick model
in two perspectives. The structure shows that the pyrimidine ring is
parallel stacked with a benzene ring from an adjacent molecule in the
crystal cell. The distance from the plane of the pyrimidine ring to the
plane of the benzene ring is ∼3.5 Å. The 4-bromobenzyl group is anti
to the pyrimidine ring.
8e
8f
C6H5
C6H5
F
Br
a The experiments were performed in CDCl3 unless stated otherwise.
All reported experimental data are averages of duplicate runs.
possible for the C1 pyrimidine group to align with a benzene
ring of the triptycene scaffold intramolecularly. Thus, we are
observing intramolecular interactions in solution due to entropic
effects while the crystal structure reflects intermolecular interac-
tions. This interpretation is supported by the variable-concentra-
tion data in Table 2. A gradual increase in syn/anti ratio was
observed when the sample concentration was incrementally
diluted. However, even at the highest concentration examined,
the syn conformation is still nearly 14 times that of the anti
isomer for compound 6f. Intermolecular interactions are largely
eliminated in solution due to entropic and solvent effects. The
following discussion will be centered on solution study.
Once we can concentrate on the intramolecular interactions
between the 6-member nitrogen-containing heterocycle and the
C9 benzyl group using the solution NMR data presented in Table
1, the substituent effects on the benzene ring can be examined.
For the pyrimidine derivatives (6a-f), the syn/anti ratio changes
significantly with temperature. This enables us to obtain both
∆H and ∆S by using the van’t Hoff eq 1.
FIGURE 3. X-ray structure of compound 6f shown in ellipsoid plot.
In contrast to the solution 1H NMR data, an anti conformation is
observed in the crystal structure.
lnKeq ) -∆H°/RT + ∆S°/R
(1)
TABLE 2. Ratios of Syn/Anti Isomers at Different Concentrations
for Model Compound 6f (in CDCl3)a
1
where Keq ) /2(syn/anti) and R is the gas constant.
Entropic effects in noncovalent interactions are considered
vitally important for studies in guest-host chemistry.19,20 This
study provides some entropic information for π-stacking
between a heterocycle and a benzene ring. Thermodynamic
parameters are collected in Table 3. Some caution should be
taken with these data since the enthalpy and entropy obtained
when using the van’t Hoff equation assume a constant enthalpy
value in the surveyed temperature range that may or may not
be true.
0.2 M 0.1 M 0.05 M 0.03 M 0.02 M 0.01 M
syn/anti ratio
13.6
13.9
14.1
14.9
15.9
18.4
a The experiment was performed at -50 °C.
The intermolecular stacking arrangement is more likely to
be free of strain than the intramolecular stacking arrangement.
In the absence of entropic factors, the intermolecular stacking
interaction becomes more favorable in the solid state environ-
ment. In addition, the benzene ring of the triptycene scaffold
should have a higher electron density than the bromo-substituted
benzene ring in 6f. From the syn/anti ratio data in Table 1, the
pyrimidine ring is electron-deficient enough to favor interactions
with electron-rich aromatic rings such as the Me2NC6H4 group
(6a, Table 1). Therefore, it is not surprising that the pyrimidine
ring aligns with an electron-rich benzene ring intermolecularly
in the solid state. However, due to structural restraint it is not
The thermodynamic data obtained are summarized in Table
3 along with those of six compounds from our previous study
(19) Searle, M. S.; Williams, D. H. The Cost of Conformational Orders
Entropy Changes in Molecular Associations. J. Am. Chem. Soc. 1992, 114,
10690-10697.
(20) Martinez, A. G.; Barcina, J. O.; Cerezo, A. D. Influence of highly
preorganised 7,7-diphenylnorbornane in the free energy of edge-to-face
aromatic interactions. Chem.-Eur. J. 2001, 7, 1171-1175.
1806 J. Org. Chem., Vol. 73, No. 5, 2008

Stacking Interactions between Heterocyclic Aromatic Rings and Substituted-Benzene
TABLE 3. Thermodynamic Parameters Obtained through
served for X ) Me or H and a very small attractive interaction
was observed for X ) F (compounds 8c-8e, Table 3). When
the benzene ring is substituted with an electron-withdrawing
group (such as a CN, compounds 9c-9e, Table 3), a small
favorable enthalpy and favorable entropic interactions were
observed. The CN-substituted benzene derivatives give an
overall attractive interaction comparable to that of the hetero-
cycles. Notwithstanding the different proportions of contribu-
tions from enthalpic and entropic components, the free energy
results appear to be consistent with the concept that a -Nd
group for -Cd substitution in a 6-membered aromatic ring
reduces the electron density from the π-system.24
From the data in Table 3, the pyrimidine ring interacts with
the substituted benzene ring mainly by an enthalpy-driven
process. The entropies for the stacking interactions are all
negative. On the contrary, it is interesting to note that the
stacking interactions between two benzene rings although small
are all favored by entropy effects (compounds 8c-9e, Table
3). The pyridine derivatives are somewhere in between, some
have a positive entropy and others a negative entropy term. Our
interpretation for these differences is solvent effects, i.e., the
stacked conformation between a pyrimidine ring and a benzene
ring, is entropically more disfavored than when the two rings
are separated. This is similar to many host-guest systems where
enthalpy-entropy compensation is often observed.2 On the other
hand, the stacked conformation between two benzene rings is
slightly more entropically favored than when the two rings are
separated. The difference lies in the interactions with the solvent
molecule CDCl3. The stacking interactions in normal benzene
rings appear to be slightly favored by a desolvation entropy.2
1
a
Variable-Temperature H NMR Studies in CDCl3
compd
C1Aryl
X
∆H° c
∆S° d
∆G° c
6a
6b
6c
6d
6e
6f
7a
7b
7c
7d
7e
7f
7g
8c
8d
8e
9cb
9db
9eb
pyrimidine NMe2 -1.34 ( 0.06 -1.5 ( 0.5 -0.91 ( 0.3
pyrimidine OMe -1.08
pyrimidine Me
-1.9
-2.9
-2.6
-2.1
-4.5
-2.0
-0.6
0.6
-1.4
-1.0
0.5
0.7
1.6
-0.52
-0.64
-0.62
-0.64
-0.7
-1.51
-1.38
-1.24
-2.0
pyrimidine
pyrimidine
H
F
pyrimidine Br
pyridine
pyridine
pyridine
pyridine
pyridine
pyridine
pyridine
C6H5
C6H5
C6H5
C6H4CN
C6H4CN
C6H4CN
NMe2 -0.75
OMe -0.60
Me
H
-0.16
-0.43
-0.53
-0.44
-0.40
-0.71
-0.57
-0.03
-0.03
-0.13
-0.46
-0.69
-0.82
-0.34
-0.84
-0.71
-0.58
-0.36
0.44
0.19
0.0
-0.03
-0.04
-0.1
F
Br
NO2
Me
H
0.7
0.4
1.4
2.2
F
Me
H
F
2.4
a∆G° values were calculated at T ) 298 K. The experimental errors are
calculated using linear regression analysis of the data points over the
experimental temperature range.21 b Reference 13. c Units: kcal mol-1
.
d Units: cal mol-1 K-1
.
to serve as control experiments. The experimental errors are
calculated by using linear regression analysis of the data points
over the experimental temperature range.21 In general, the
enthalpy values have much smaller errors than the entropy
values because the former was calculated from the slope and
the latter from the intercept.
All heterocyclic model compounds (6a-7f) studied show
attractive interactions between the C9-substituted aromatic ring
and the C1 heterocycle group. The strongest interaction is
observed between the pyrimidine group and the electron-rich
Me2NC6H4 group (6a, Table 2). Hammett plots did not give a
For aromatic rings without strong electron density-altering
substituents, previous studies have in general supported the
notion that simple electrostatic forces are dominant in arene-
arene stacking interactions.13,25,26 One of the supporting pieces
of evidence is that all arene-arene interactions display similar
substituent effects that gave good correlation in a Hammett plot.
The lack of a general trend in substituent effects in the
heterocycle series indicates that more complex forces are
involved in the heterocycle-benzene stacking interactions.
These forces likely include London dispersion and local dipole-
dipole and donor-acceptor interactions. The normally useful
simplification to treat an aromatic ring as a quadrupolar subject
does not work on these nitrogen-containing heterocycles.27,28
To identify these forces involved, more studies are planned.
One such plan involves the change of the substituent position
on the C9 benzene ring. This could detect the importance of
the directionality of the local dipoles introduced by the
heteroatom. High-level computational studies are also planned
and a partition of the calculated total interaction energy into
relevant components should help to reveal the interplay of
various physical forces in heterocycle-benzene interactions.
good correlation between the substituent constants (σpara or σmeta
)
and the free energies obtained.22 The Hammett σ parameters
are known to not necessarily correlate with the π-electron
density on the aromatic rings. This point has been discussed by
both Dougherty and Sherrill.10,23 While there is hardly any trend
in substituent effects, the electron-rich Me2NC6H4 group is most
attractive with the pyrimidine ring and least attractive with
the pyridine ring (6a and 7a, entries 1 and 7, Table 3). These
observations can be attributed to an attractive donor-acceptor
interaction in 6a and repulsive electrostatic interactions in
7a. In general, in order to have a donor-acceptor type of
interaction, the acceptor must meet a certain threshold in elec-
tron deficiency. Previously we have observed similar types of
donor-acceptor interactions in the corresponding C6F5CO2
derivative.15
The entries 17 to 19 in Table 3 are taken from our previous
study13 and along with compounds 8c-e they serve as control
compounds and provide some illuminating comparisons. When
an unsubstituted benzene ring is in the position of the hetero-
cycle, repulsive enthalpies and favorable entropies were ob-
(24) Albert, A. Heterocyclic Chemistry: an Introduction, 2nd ed.; The
Athlone Press: New York, 1968.
(25) Cozzi, F.; Cinquini, M.; Annuziata, R.; Siegel, J. S. Dominance of
Polar/π over Charge-Transfer Effects in Stacked Phenyl Interactions. J. Am.
Chem. Soc. 1993, 115, 5330-5331.
(26) Cozzi, F.; Cinquini, M.; Annunziata, R.; Dwyer, T.; Siegel, J. S.
“Polar/π Interactions between Stacked Aryls in 1,8-Diarylnaphthalenes. J.
Am. Chem. Soc. 1992, 114, 5729-5733.
(27) Luhmer, M.; Bartik, K.; Dejaegere, A.; Bovy, P.; Reisse, J. The
Importance Of Quadrupolar Interactions In Molecular Recognition Processes
Involving A Phenyl Group. Bull. Soc. Chim. Fr. 1994, 131, 603-606.
(28) Ma, J. C.; Dougherty, D. A. The cation-π interaction. Chem. ReV.
1997, 97, 1303-1324.
(21) Shoemaker, D. P.; Garland, C. W.; Nibler, J. W. Experiments in
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Gung et al.
mamide and the resulting solution was stirred at room temperature
under N2 overnight. Solvent was removed under reduced pressure
and the residue was redissolved in 5 mL of dichloromethane. This
solution was then added dropwise to a solution of 5a (1.43 mmol)
with a catalytic amount of N,N-dimethylaminopyridine in dichlo-
romethane (3 mL) and triethylamine (3 mL) at room temperature.
The mixture was stirred at room temperature for 10 min and then
refluxed (50 °C) for 2 h. The reaction was allowed to cool to room
temperature, quenched with 20 mL of water, and extracted with
dichloromethane (3 × 20 mL). The combined organic phase was
dried over anhydrous magnesium sulfate. Solvent was removed
under reduced pressure and the residue was purified by flash column
chromatography to afford 6a as a yellow solid: mp 190-191 °C;
1H NMR (300 MHz, CDCl3) δ 1.55 (9H, s), 3.70 (3H, s), 4.25
(2H, br), 5.49 (1H, s), 6.32-6.48 (2H, br), 6.61-7.10 (10H, m),
7.30-7.59 (3H, m), 8.85 (1H, br), 9.39 (1H, br); 13C NMR (75
MHz, CDCl3) δ, 27.4, 29.7, 33.6, 39.4, 40.7, 48.6, 112.2, 120.0,
121.3, 122.8, 123.1, 123.6, 124.9, 125.3, 125.4, 130.2, 136.2, 136.5,
143.3, 143.4, 148.6, 150.3, 150.6, 163.4, 176.4; HRMS calcd for
C39H35N3O4 + Na 632.2525, found 632.2530.
Summary
Parallel displaced stacking interactions between a six-
membered heterocycle (pyridine or pyrimidine) and a substituted
benzene ring were quantitatively studied in solution. Both
pyridine and pyrimidine were found to have a greater attractive
interaction with a substituted benzene ring than the correspond-
ing arene-arene interactions. An X-ray structure analysis of
compound 6f shows that two molecules are reciprocally parallel
stacked with each other with their pyrimidine ring and one of
the triptycene scaffold benzene rings. Although the anti
conformation is observed in the crystal structure, the syn
conformation was observed for 6f overwhelmingly in solution,
which is attributed to entropic effects. Namely, entropy disfavors
intermolecular interactions which lead to favorable intramo-
lecular stacking interactions. A Hammett plot did not give a
good correlation with the free energies obtained. This is viewed
as evidence for more complex physical forces involved in the
heterocycle-benzene interactions. These forces may include
London dispersion and local dipole-dipole and donor-acceptor
interactions. Further studies are planned to change the position
of the substituent on the C9 benzene ring in an attempt to
identify the predominant physical forces.
Acknowledgment. We are grateful for support from the
National Institutes of Health (GM069441). We thank Professor
Rainer Glaser for helpful discussion and for facilitating the X-ray
structure analysis.
Experimental Section
Supporting Information Available: Experimental procedures
including low-temperature NMR spectroscopy and X-ray structure
analysis including a CIF file. This material is available free of
charge via the Internet at http://pubs.acs.org.
Representative Procedure for the Preparation of the Model
Compounds: 9-(4-(Dimethylamino)benzyl)-1-pyrimidinoyloxy-
4-(pivaloyloxy)triptycene (6a). To a suspension of 4-pyrimidine
carboxylic acid (2.07 mmol) and oxalyl chloride (0.25 mL) in
dichloromethane (5 mL) was added one drop of N,N-dimethylfor-
JO702354X
1808 J. Org. Chem., Vol. 73, No. 5, 2008