Gung et al.
energy of 3.77 kcal/mol at the MP2/6-31G** level of
theory.8 Our study was carried out in chloroform solution.
The strongest binding energy was determined for 2e (X
) CF3) at 0.47 ( 0.05 kcal/mol. It is expected that the
attraction is much smaller since the aromatic ring in 2e
is not nearly as electron-deficient as hexafluorobenzene.
Furthermore, the solvent chloroform is expected to at-
tenuate the lp-arene interaction by competitively form-
ing weak CH-O hydrogen bonds to the oxygen in
discussion.27
It is reasonable to suggest that the secondary interactions
are from van der Waals forces between the COR group
and the C(9) aromatic ring, which increase when the
contacting area between the two components is increased.
Thus, the syn/anti ratio increases as a function of the
group on C(1) oxygen among 2a-5a according to the
following order: Me < CHO < COMe < COEt. When R
) i-Pr, the syn conformation is favored, but the prefer-
ence is smaller than when R ) Et. We attribute this to
the size of the isopropyl group, which causes some steric
repulsion in the syn conformation. Steric effects are
assumed to be absent for R ) CHO, COMe, and COEt
groups. The fact that a higher syn/anti ratio was observed
in the order of Me < CHO < COMe < COEt supports
the argument that van der Waals contact area deter-
mines the order of attractive interactions among the
electron-rich 2a-5a.
There is a repulsive interaction in the syn conformation
of 7 when R ) CF3 (entry 24, Table 1), and the anti
conformation is preferred. This result excludes the argu-
ment that the preference for the syn conformation is due
to arene-carbonyl dipole interactions. The CF3CO group
should have the largest dipole moment among the
compounds in Table 1. This repulsive interaction also
cannot be explained by steric effects. According to Mac-
roModel calculations, the syn conformer of 7 is more
stable than the anti conformer by ∼1 kcal/mol in contrast
to the experimental results. A CF3 group is definitely
smaller than an isopropyl group and probably smaller
than an ethyl group.28 Molecular mechanics is best to
detect steric repulsions, but not equipped to detect
various types of electronic repulsions. The observed
repulsive interactions in the syn conformation of 7 can
be rationalized by the fact that the CF3 group in the syn
conformation is positioned in the cone area of the C(9)
arene where substantial negative electrostatic potential
is centered. Repulsive interactions are expected between
the π-cloud and the fluorine atoms of the CF3 group.
Through this study we have demonstrated that one can
improve the performance of molecular mechanics by
taking into account the electron density locations on
aromatic rings.
There was no charge-transfer band in the UV spectrum
of compound 2e. Therefore, the origin of the attraction
appears to be electrostatic interactions. Previous studies
have shown that for arene-lp interactions to be attrac-
tive, the aromatic π-system must be electron-deficient.8,9
However, compounds 2a and 2b, which bear an electron-
donating group on the C(9) arene, prefer the syn confor-
mation although only to a small degree (entries 1 and 2,
Table 1). Considering the short distance between the
MeO oxygen and the C(9) aromatic ring, it is counterin-
tuitive that the interaction is not repulsive in the syn
conformation of 2a and 2b (syn/anti ratio: 2.3-2.4:1).
The answer may come from considering the structure of
benzene. Benzene has a large, permanent quadrupole
moment,24 such that there is substantial negative elec-
trostatic potential above and below the plane of the ring
and a belt of positive potential around the edge. There-
fore, an oxygen lone pair should be attracted to the
positive potential of the edge by electrostatic interactions.
Since the syn/anti ratios are only slightly higher than
the statistical 2:1 ratio for 2a and 2b, van der Waals
interactions between the MeO group and the aromatic
ring and CH-π interactions may play a more prominent
role in the preference for the syn conformation. However,
CH-π interactions cannot be the dominant force after
examining the entire data in Table 1. CH-π interactions
would prefer an electron-rich arene while the lp-π
interactions prefer an electron-deficient arene.
For compounds 3-7, the interactions are between an
ester group at C(1) and the arene at C(9). The carbonyl
group of the ester reduces the electron density on the
oxygen atom leading to a reduced lp-arene interaction.
Such is the case when the arene is substituted with the
electron-withdrawing group CF3. Compound 2e with a
C(1) methoxy group has a higher population of the syn
conformation (syn/anti ratio: 5.5:1) than compounds 4e,
5e, and 6e (syn/anti ratio: 3.4-4.4:1), all of which have
a C(1) ester group. This is consistent with MeO being a
better donor than an OCOR group and also consistent
with the electrostatic argument.
Summary
Quantitative experimental determination of lp-π in-
teractions with the oxygen atom approaching the edge
of an aromatic ring is reported. The dominant attractive
interactions in compounds 2-7 are electrostatic in nature
as shown by the substituent effect on both the C(9) arene
and the C(1) oxygen atom in 2-7. Compounds 2a-e with
a MeO group at C(1) are more responsive to the nature
of the substituent X on the C(9) arene than compounds
3-7 in terms of syn/anti ratios. The interactions between
an electron-rich arene (X ) Me or MeO) and MeO are
weakly attractive with the methoxy oxygen located near
the edge of the aromatic ring. For the C(1) ester series
of compounds (3-7), the R group is positioned in the cone
area of the C(9) arene in the syn conformation. As such,
A small reversal was observed when the C(9) arene has
an electron-donating group (2-6a, X ) Me): compounds
3a, 4a, 5a, and 6a with a C(1) acetate group have a
slightly higher syn conformation than 2a (syn/anti ra-
tio: 2.4-3.3:1 versus 2.3:1). This suggests that there is
a secondary interaction in addition to the electrostatic
force between the phenolic oxygen and the arene. When
the primary electrostatic interactions are diminished due
to increased arene electron density in the case of 2a-
6a, the secondary interactions become more important.
(27) Huang, Y.; Rawal, V. H. J. Am. Chem. Soc. 2002, 124, 9662-
9663.
(28) Timperley, C. M.; White, W. E. J. Fluorine Chem. 2003, 123,
65-70.
7236 J. Org. Chem., Vol. 70, No. 18, 2005