The effects of substituents on the geometry of π-π Interactions

Article abstract of DOI:10.1002/chem.201202253

We have designed and utilized a simple molecular recognition system to study the substituent effects in aromatic interactions. Recently, we showed that 3- and 3,5-disubstituted benzoyl leucine diethyl amides with aromatic rings of varying electronic chara

Full text of DOI:10.1002/chem.201202253

FULL PAPER
DOI: 10.1002/chem.201202253
The Effects of Substituents on the Geometry of p–p Interactions
Seth E. Snyder, Bin-Syuan Huang, Yu W. Chu, Huei-Shian Lin, and James R. Carey*[a]
Dedicated to William H. Pirkle on the occasion of his 78th birthday
Abstract: We have designed and utiliz-
ed simple molecular recognition
sized and crystallized a series of 4-sub-
stituted benzoyl leucine diethyl amides.
Surprisingly, only two of the 4-substi-
tuted compounds formed homochiral
dimers. A comparison among the 4-
substituted compounds that crystallized
as homochiral dimers and their 3-sub-
stituted counterparts revealed that
there are differences in regard to the
geometry of the aromatic rings with re-
spect to each other, which depend on
the electronic nature and location of
the substituent. The crystal structures
of the homochiral dimers that showed
evidence of direct, local interactions
between the substituents on the aro-
matic rings also displayed nonequiva-
lent dihedral angles in the individual
monomers. The crystallographic data
suggests that such “flexing” may be the
result of the individual molecules ori-
enting themselves to maximize the
local dipole interactions on the respec-
tive aromatic rings. The results present-
ed here can potentially have broad ap-
plicability towards the development of
molecular recognition systems that in-
volve aromatic interactions.
a
system to study the substituent effects
in aromatic interactions. Recently, we
showed that 3- and 3,5-disubstituted
benzoyl leucine diethyl amides with ar-
omatic rings of varying electronic char-
acter organized into homochiral dimers
in the solid state through a parallel dis-
placed p–p interaction and two hydro-
gen bonds, but no such homochiral di-
merization was observed for the unsub-
stituted case. This phenomenon sup-
ports the hypothesis that substituents
stabilize p–p interactions regardless of
their electronic character. To further
investigate the origin of substituent ef-
fects for p–p interactions, we synthe-
Keywords: homochirality · molecu-
lar recognition · pi–pi interactions ·
stacking interactions · substituent
effects
Introduction
interactions between the substituent and the other ring, not
p-polarization effects.[3e] Recently, Wheeler expanded upon
this model, hypothesizing that substituent effects may be ex-
plained in terms of direct, local interactions, such as the in-
teraction between local dipoles.[3a] Rashkin and Waters had
earlier provided experimental support that direct, local in-
teractions between substituents on interacting benzene rings
in a parallel displaced arrangement may contribute to stabi-
lizing p–p interactions.[4] Arnstein and Sherrill also hypothe-
sized that local interactions may contribute to stabilizing
parallel displaced p–p interactions, but emphasized that sub-
stituent effects should be viewed as a balancing of at least
four fundamental components including electrostatics, ex-
change repulsion, dispersion, and induction.[3f] Ringer and
Sherrill argued that the model proposed by Wheeler and
Houk significantly de-emphasized the role played by disper-
sion interactions.[3d] Furthermore, Sherrill et al. suggested
that both electron-withdrawing and electron-donating
groups are able to stabilize the electrostatic component of
p–p interactions through increased charge penetration ef-
fects.[5] Nonetheless, deciphering the role of the various in-
termolecular forces that control aromatic interactions, and
substituent effects, remains highly controversial. Hence,
there is a strong need for experimental models that can vali-
date these recent computational studies.
Aromatic interactions (e.g., p–p interactions) are amongst
the most well studied and least understood of all interac-
tions in the field of molecular recognition.[1] Simple electro-
static models have traditionally been employed to explain
the nature of these interactions.[2] However, over the past
decade, results derived from advanced computational calcu-
lations, have challenged the simple electrostatic models and
shed new light on the effects of substituents on p–p interac-
tions.[3]
There have been several new theories that have attempt-
ed to rationalize these computational results. Wheeler and
Houk hypothesized that although dispersive interactions sta-
bilize the interaction of substituted benzene rings in a sand-
wich configuration relative to the unsubstituted case, sub-
stituent effects can be explained primarily in terms of direct
[a] Dr. S. E. Snyder, B.-S. Huang, Y. W. Chu, H.-S. Lin,
Prof. Dr. J. R. Carey
Department of Applied Chemistry
National University of Kaohsiung
700, Kaohsiung University Road
Nanzih District, 811 Kaohsiung (Taiwan)
Fax : (+886)7-591-9348
E-mail: jcarey@nuk.edu.tw
We propose that chiral recognition systems that use small
molecules will provide exceptional models to investigate the
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201202253.
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nature of p–p interactions, particularly the influence of sub-
stituents on p–p interactions. Small-molecule chiral recogni-
tion systems have been studied in detail for more than two
decades and have served as the basis for the design of a
multitude of chiral chromatographic stationary phases,
chiral solvating agents, and catalysts.[6] A number of crystal
structures has been solved involving a 1:1 complex between
the chiral selector and a molecule that interacts with the se-
lector.[7] Invariably, these solid-state data have been consis-
tent with results derived from chromatographic and NMR
spectroscopic studies.[6c,d,8] Moreover, these crystal structures
have been used in the design of new generations of chiral
selectors and catalysts. Small-molecule chiral recognition
systems are simplistic, and require minimal interactions.
Thus, they provide an ideal opportunity to study molecular
interactions, in particular complex aromatic interactions,
which is the goal of the present manuscript. Additionally, as
discussed in detail below, we postulate that significant differ-
ences in the orientation of interacting aromatic rings in-
duced by substituents can best be ascertained through crys-
tallographic studies. Such orientation effects will be of fun-
damental importance to computational modelers that are
trying to elucidate the nature of aromatic interactions.
amides was prepared and crystallized. We hypothesize that
simple crystallographic systems such as those described
herein provide a means of uncovering the extent to which
small changes in the substitution pattern of interacting aro-
matic rings can influence the nature of the p–p interaction.
Results and Discussion
Structures of various racemic 2- and 4-substituted benzoyl
leucine diethyl amides crystallized in this study are depicted
in Figure 1. All of the compounds investigated in this study
Recently, we demonstrated that all racemic 3-substituted
and 3,5-disubstituted benzoyl leucine diethyl amides, regard-
less of the electronic nature of the substituent, undergo ho-
mochiral self-recognition in the solid state, whereas the un-
substituted compound does not.[9] The homochiral recogni-
tion system is minimalist in nature in that it requires only
three interactions, including a p–p interaction and two hy-
drogen-bonding interactions.[10] Furthermore, unlike some of
the early innovative models that involved interacting rings
that were spatially fixed with respect to each other,[2a–i,11] we
showed that the aromatic rings in the substituted dimers
have significant translational freedom, and thus can interact
in various orientations. We hypothesized that compounds
with aromatic rings involved in an energetically favorable
p–p interaction are capable of forming homochiral dimers
in the solid state. We further pointed out that the results
provided experimental support to the hypothesis that all
substituents, regardless of their electronic character, stabilize
p–p interactions.[5,9] The crystallographic data also revealed
that the orientation of the interacting aromatic rings is pro-
foundly influenced by the nature of the substituent on the
respective rings. For instance, the degree of horizontal dis-
placement (i.e., offset) and vertical displacement between
the interacting rings varies dramatically, in a substituent-de-
pendent manner. In particular cases, we observed evidence
of interactions between local dipoles on the rings, which
appear to influence the orientation. These results suggested
that a range of different stabilizing geometries is possible
for the parallel displaced p–p interactions and that the opti-
mal geometry appears to be dependent on the nature of the
substituents on the respective aromatic rings.
Figure 1. Structures of the racemic substituted benzoyl leucine diethyl
amides crystallized in this study.
were crystallized from hexane/dichloromethane. Additional-
ly, we crystallized several compounds in additional solvents
such as toluene, benzene, and acetone mixtures resulting in
largely similar structures in identical space groups.
A diverse set of geometric parameters has been used to
describe the spatial orientation between a pair of aromatic
compounds.[1e,3f,12a–g] For a rigorous geometric description of
the spatial orientation of a pair of interacting aromatic com-
pounds, see Moore et al.[12f] Common and simplistic parame-
ters used to define the offset face-to-face interaction include
the distance between the ring-to-ring centroids (d), the dis-
tance of the horizontal (I) and vertical (R) displacements of
the two interacting rings, the displacement angle (q), and
the tilt angle (a). These parameters are depicted in Fig-
ure 2.[9,12e] If the aromatic rings are stacked (i.e., sandwich
configuration) the displacement angle q is equal to 908, and
the horizontal displacement I is equal to 0 ꢁ. Tilt angles less
than 208 are considered as stacked or displaced-stacked
pairs.[12a] If the rings are parallel, the tilt angle a is equal to
08. If the rings are perpendicular, the tilt angle a is equal to
908 and the rings assume a T-shaped configuration, as op-
posed to a sandwich configuration or an offset stacked con-
figuration. Data displayed in Tables 1 and 2 are within typi-
cal values for horizontal (I) and vertical (R) displacements
To enhance our understanding of the influence of sub-
stituents on the orientation of the interacting aromatic rings,
a series of 2- and 4-substituted benzoyl leucine diethyl
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Geometry of p–p Interactions
FULL PAPER
Table 1. X-ray crystallographic analysis of 2- and 4-substituted benzoyl leucine diethyl amides.
Compound
Homochiral
dimer
q
[a] [8]
d[a] [ꢁ]
R[a] [ꢁ]
I[a] [ꢁ]
a[a] [8]
Space group[d]
Hydrogen bonds
lengths[ꢁ]
[b]
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1 f
1g
1h
1i
4-NO2
yes
yes
no
no
no
no
no
no
no
no
no
107.37
130.06
NA[e]
NA
NA
NA
NA
NA
NA
NA
3.78
4.51
9.89
9.65
7.31
7.40
7.38
10.25
8.35
9.21
8.99
3.61
3.45
NA
NA
NA
NA
NA
NA
NA
NA
NA
1.13
2.90
NA
NA
NA
NA
NA
NA
NA
NA
NA
14.29
8.60
0
0
65.38
54.74
56.58
0
0
0
0
C2/c
P21
2.05, 1.89
1.97, 2.03
2.19, 2.19
2.07, 2.07
2.06, 2.06
2.12, 2.12
2.15, 2.15
2.26, 2.26
1.97, 1.97
2.03, 2.03
2.05, 2.05
4-F[c]
4-Me
4-CN
P21/c
P21/n
Pbca
Pbca
Pbca
P21/n
P21/n
P21/c
P21/c
4-OMe
4-Cl
4-Br
4-H
2-NO2
2-Me
2-F
9
10
11
1j
1k
NA
[a] See the legend of Figure 2 for an definitions of q, d, R, I, and a. [b] Compound 1a crystallizes as a racemate containing homochiral dimers. [c] Com-
pound 1b crystallizes as a single enantiomer, that is a conglomerate. [d] We crystallized several compounds in additional solvents such as toluene, ben-
zene, and acetone mixtures resulting in largely similar structures in identical space groups. [e] NA=not available.
Figure 3. Crystal structures of a) 4-NO2 1a and b) 4-F 1b, which crystal-
lized as homochiral dimers with two hydrogen bonds (shown as cyan
lines) and a parallel displaced p–p interaction.
counterparts. Moreover, the aromatic rings of these com-
pounds are not involved in a p–p interaction. Notably, the
compounds 4-Me 1c and 4-CN 1d form heterochiral dimers
in the solid state with their aromatic rings directed away
from each other, similar to the unsubstituted benzoyl leu-
cine diethyl amide 1h.[9] A comparison between the crystal
structures of the 3-Me and 4-Me 1c benzoyl leucine diethyl
amides is shown in Figure 4. The 4-OMe 1e, 4-Cl 1 f, and 4-
Br 1g compounds form non-stacked, one dimensional
Figure 2. Geometric parameters used to define the orientation of two in-
teracting aromatic rings. a) The distance R of the ring centroid to the
plane defined by the opposite ring, and the ring-centroid-to-ring-centroid
distance (d). b) The horizontal displacement I between two ring cent-
roids. c) The tilt angle a. d) The displacement angle q is defined by the
smaller of the two angles defined by the ring-to-ring centroids to the
plane of the benzoyl rings.
of two interacting rings in the solid state. Typical values re-
ported in the literature range from 1–3 ꢁ for I and approxi-
mately 3.5 ꢁ for R.[12d] In addition, data shown in Tables 1
and 2 are in the range of d values reported in the literature,
which are as low as approximately 3 or as high as about
7 ꢁ.[12a,e,f,h]
heteroACHTNUTRGNEcUNG hiral chains through a single hydrogen bond from
the leucine amide of one monomer to the benzoyl oxygen
atom of the other monomer. A comparison between the
crystal structures of the 3-OMe and the 4-OMe 1e benzoyl
leucine diethyl amide is shown in Figure 5.
Seven different 4-substituted benzoyl leucine diethyl
amides were crystallized and analyzed. Crystallographic
data are provided in Table 1. As indicated in Table 1, the 4-
NO2 1a (Table 1, entry 1) and the 4-F compound 1b
(Table 1, entry 2) form homochiral dimers in the solid state
(shown in Figure 3). These two dimers are characterized by
two crossed hydrogen-bonding interactions and an offset
stacked p–p interaction, similar to the crystal structures of
their 3-substituted counterparts.
However, the other 4-substituted benzoyl leucine diethyl
amides (4-Me 1c, 4-CN 1d, 4-OMe 1e, 4-Cl 1 f, and 4-Br 1g
(Table 1, entries 3–7)) do not self-assemble into homochiral
dimers in the solid state, in contrast to their 3-substituted
The results presented above suggest that there may be dif-
ferences in the stability of the p–p interaction between the
3- and the 4-substituted benzoyl leucine diethyl amides. Be-
cause all of the 3-substituted compounds readily form homo-
chiral dimers in the solid state by using a geometrically con-
trolling p–p interaction as an element of molecular recogni-
tion, whereas the majority of the 4-substituted compounds
failed to self-assemble as such, the p–p interactions in the 3-
substituted compounds may be energetically more favorable
than the p–p interactions in the corresponding 4-substituted
compounds. Additionally, because the electron densities on
the rings of the 3-Me-, 3-OMe-, and 3-Br-substitued benzoyl
leucine diethyl amides are similar to that of their 4-substitut-
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Table 2. X-ray crystallographic analysis of 4-NO2 1a, 3-NO2, 4-F 1b, and 3-F dimers.
Compound
Homochiral
dimer
q[a] [8]
d[a] [ꢁ]
R[a] [ꢁ]
I[a] [ꢁ]
a[a] [8]
Space group
Hydrogen bond
lengths [ꢁ]
1
2
3
4
4-NO2
3-NO2
yes
yes
yes
yes
107.37
115.17
130.06
129.28
3.78
3.96
4.51
4.42
3.61
3.58
3.45
3.42
1.13
1.68
2.90
2.80
14.29
6.30
8.60
5.27
C2/c
P21/n
P21
2.05, 1.89
2.14, 2.20
1.97, 2.03
2.00, 2.00
[b]
4-F
3-F[b]
C2/n
[a] See the legend of Figure 2 for an definitions of q, d, R, I, and a. [b] For syntheses and crystal structures, see reference [9].
orientation between the aromatic rings of the 3-NO2 and the
4-NO2 1a benzoyl leucine diethyl amide dimers. A closer
look at the crystal structures of the aromatic portions of the
3-NO2 and the 4-NO2 1a dimer reveals that direct, local in-
teractions may explain the discrepancy between the orienta-
tions of the rings in the two dimers. The aromatic portions
of the 3-NO2 and the 4-NO2 1a dimer are shown in Fig-
Figure 4. Crystal structures of a) 3-Me and b) 4-Me 1c benzoyl leucine di-
ethyl amides. The 3-Me compound self-assembled into homochiral
dimers in the solid state, whereas the 4-Me compound 1c failed to do so.
AHCTUNGTREGuNNUN res 6a and b, respectively. Several different vantage points
Figure 5. Crystal structures of a) 3-OMe and b) 4-OMe 1e benzoyl leu-
cine diethyl amides. The 3-OMe compound self-assembled into homochi-
ral dimers in the solid state, whereas the 4-OMe compound 1e failed to
do so.
ed counterparts, factors other than the electron density
appear to be contributing to the enhanced p–p interactions
of the 3-substituted compounds. To elucidate the difference
between the 3- and 4-substituted benzoyl leucine diethyl
amides, we compared the crystallographic data of the two 4-
substituted benzoyl leucine diethyl amides that did self-as-
semble into homochiral crystals (compounds 1a and 1b)
with their 3-substituted counterparts. The relevant crystallo-
graphic data for the 4-NO2 1a, 3-NO2, 4-F 1b, and 3-F
dimers are summarized in Table 2. The crystal structure of
the 3-NO2 and the 4-NO2 1a dimers show significant differ-
ences, particularly with respect to the interacting aromatic
rings. For instance, compared with the 3-NO2 dimer, the hor-
izontal displacement I observed between the aromatic rings
in the 4-NO2 1a dimer is significantly smaller. In fact, the 4-
NO2 1a dimer shows the most overlap between the aromatic
rings of any of the compounds crystallized in this and our
previous work.[9] Moreover, unlike the 3-NO2 and 3,5-NO2
dimers, where the rings are essentially planar, the aromatic
rings of the 4-NO2 1a dimer are substantially out of plane
(a=14.298). Considering only the electronics of the aromat-
ic rings, one would not predict significant differences in the
Figure 6. The partial structures of a) 3-NO2,[9] b) 4-NO2 1a, and c) 4-F 1b
benzoyl leucine diethyl amides. The potential local dipole interactions
are displayed through dotted lines between two interacting aromatic
rings.
for each dimer are shown. For the 3-NO2 dimer, a nitro
group oxygen atom is neighboring and approximately paral-
lel to an aromatic hydrogen atom on the opposing aromatic
ring (Figure 6a). Consistent with observations of Rashkin
and Waters[4] and as discussed in our previous study,[9] this
orientation may suggest a stabilizing interaction between
the edge hydrogen atom of one ring and a nitro group
oxygen atom of the other ring.
Indeed, two different rotamers for each of the 3-NO2
monomers are possible, which would result in three different
orientations in which the two nitro groups can arrange
themselves with respect to each other. However, only the
rotamer, which results in the above-mentioned stabilizing in-
teractions, is present in the crystal structure. In the 4-NO2
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Geometry of p–p Interactions
FULL PAPER
1a dimer, the oxygen atoms of the nitro groups are approxi-
mately parallel and nearby to two ring hydrogen atoms on
the opposing ring (Figure 6b). Hence, there are at least four
direct, local stabilizing interactions when the rings are ori-
ented as shown in Figure 6b. This added stabilization may
explain why the 4-NO2 1a dimer self-assembles, whereas the
majority of the other 4-substituted compounds, including the
similarly electron-deficient 4-CN 1d, fail to do so. In con-
trast to the significant discrepancies observed between the
3-NO2 and the 4-NO2 1a benzoyl leucine diethyl amide
dimers, the crystal structures of the 3-F and the 4-F 1b ben-
zoyl leucine diethyl amides are highly similar. For instance,
as shown in Table 2, the aromatic rings of 3-F and 4-F 1b
have similar I, R, and q values. Additionally, the 4-F 1b
dimer shows evidence of a direct local interaction between
Scheme 1. 2-substituted benzoyl leucine diethyl amides form heterochiral
dimers with two hydrogen bonds (shown as cyan lines) in the solid state.
configurational summary of the 2- and 4-substituted com-
pounds). In the 2-substituted compounds prepared in this
study, the aromatic ring is significantly out-of-plane with the
adjacent carbonyl group, presumably to minimize steric in-
teractions. Hence, a p–p interaction is likely precluded.
As discussed above, we suggest that local interactions
may have a profound influence on the orientation of inter-
acting aromatic rings involved in a p–p interaction. If local
interactions between dipoles are influencing the stacking be-
tween the rings, the molecules may assume conformations to
optimize these interactions. Although it is often assumed
that small molecules will interact with each other only in
their lowest energy conformations, there is a possibility that
the presence of one molecule can influence the conforma-
tional state of the interacting molecule, and vice versa. For
instance, Lipkowitz performed molecular modeling studies
on 3,5-dinitrobenzoyl amino acid as chiral stationary phases
(CSPs) reacting with various analytes.[13] Lipkowitz pointed
out that just as in the pharmaceutical sciences where it is
recognized that the bio-active conformation of a drug mole-
cule need not be in the global minimum, the most effective
binding shape of the CSP and the analyte need not be the
lowest energy structures either. Moreover, Zehnacker and
Suhm reviewed studies on chiral recognition between neu-
tral molecules in the gas phase.[14] The authors noted that
the observed gas-phase complexes of the interacting mole-
cules are not always made from the most stable conformers
of each individual molecule and that the structures of the
molecules adapt to each other in a concerted way to opti-
mize the interaction energy.
À
À
the C F dipole on one ring and the C H dipole on the
other ring (Figure 6c).
However, there is a confounding difference between crys-
tal structure of the 3-F and the 4-F 1b benzoyl leucine dieth-
yl amides. The 3-F dimer crystallizes as a racemate in which
homochiral dimers are found in the unit cell. In contrast, 4-
F 1b crystallizes as a conglomerate in a chiral space group.
It should be noted that of all the 3-, 4-, and 3,5-disubstituted
benzoyl leucine diethyl amides investigated in this and our
prior study,[9] only compound 4-F 1b crystallizes as a con-
glomerate rather than as a racemic compound. Figure 7 de-
picts the crystal packing showing the unit cell content of the
4-F 1b conglomerate. The origin of this effect is currently
being investigated.
In Table 3, three sets of dihedral angles are shown for the
4-NO2 1a and the 4-F 1b homochiral dimers. Additionally,
the 3- and 3,5-disubstituted homochiral dimers of the previ-
ous study[9] and the dihedral angles of each of the molecules
forming the dimer are tabulated. As the (R,R)- and (S,S)-
dimers have identical dihedral angles, only values for the
(R,R)-dimers are tabulated. It is first noted that when com-
paring the dihedral angles of the various homochiral dimers,
there are some interesting differences. For instance, the di-
hedral angle O1-C3-C2-C1, which indicates the deviation
from planarity of the aromatic ring with respect to the
amide portion, shows a slight to moderate deviation from
planarity ranging from À5.8–À19.98, which is dependent
upon the substitution on the aromatic ring. Similar discrep-
ancies are observed in the N1-C3-C2-C1 and O4-C10-C9-N2
dihedral angles. As discussed above, molecular mechanics
Figure 7. Unit cell of (R)-4-F 1b benzoyl leucine diethyl amide.
In addition to the 4-substituted benzoyl leucine diethyl
amides described above, we also prepared a series of 2-sub-
stituted benzoyl leucine diethyl amides (see Table 1). None
of the 2-substituted compounds form homochiral dimers in
the solid state. Instead, the compounds form heterochiral
dimers without a p–p interaction, similar to the unsubstitut-
ed compound 1h (see graphical abstract and Scheme 1 for a
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J. R. Carey et al.
Table 3. Dihedral angles of the individual molecules comprising the homochiral dimers crystallized in the present study. The bold, red, and green colors
represent compounds with nonequivalent dihedral angles in the individual molecules of the dimer.
Compounds
Molecule 1
Molecule 2
O1-C3-C2-C1
N1-C3-C2-C1
O2-C5-C4-N1
O3-C8-C7-C6
N2-C8-C7-C6
O4-C10-C9-N2
1
2
3
4
5
6
7
8
4-NO2
4-F
3NO2
À18.4
À16.7
À10.6
À17.7
À12.0
À19.9
À18.8
À5.8
162.9
164.2
170.5
163.1
168.5
160.4
162.1
174.0
169.9
167.4
164.6
30.4
33.4
32.5
35.8
31.7
35.7
38.6
34.1
33.0
34.3
37.5
À14.9
À24.7
À13.4
À17.7
À12.0
À19.9
À18.8
À8.8
164.0
155.4
167.3
163.1
168.5
160.4
162.1
170.0
172.4
167.4
164.6
41.2
37.6
34.4
35.8
31.7
35.8
38.6
35.2
31.4
34.3
37.5
[a]
3-Me[a]
3-OMe[a]
3-Br[a]
3-F[a]
[a]
3,5-NO2
9
10
11
3,5-OMe[a]
3,5-Me[a]
3,5-F[a]
À11.3
À13.6
À16.0
À9.0
À13.6
À16.0
[a] These compounds were synthesized in our previous study.[9]
studies suggested that substituted benzoyl leucine com-
pounds are considerably conformationally flexible, which is
consistent with results observed here. However, why is the
substituent on the aromatic ring influencing conformational
preferences?
spect to each other (shown in Figure 8), which is larger than
the tilt angle (a) observed for the interacting aromatic rings
of other homochiral dimers. We suggest that the deviation
from planarity observed in the rings of the 4-NO2 1a dimer
(and perhaps the other homochiral dimers), is the result of
We postulate that the respective molecules comprising
each dimer are aligning themselves to maximize the favor-
ACHTUNGTRENNUNGable local interactions and/or minimize the repulsive local
interactions. Particularly telling is the fact that in several
cases, the individual molecules comprising the dimer show
nonequivalent dihedral angles and we refer to this phenom-
enon as “flexing”. Cases where there is flexing of the indi-
vidual molecules of the dimer are marked in bold in Table 3.
It is noteworthy that the five cases that show the most pro-
nounced flexing of the respective molecules in the dimer are
4-NO2 1a, 4-F 1b, 3-NO2, 3,5-NO2, 3,5-OMe dimers. In each
of these cases, the crystal structures show evidence of direct
À
local interactions between the negative end of the N O or
À
À
C F dipole on one ring, and the positive end of the C H
dipole on the other (see Figure 6).
It would appear then, that the rings are orientating them-
selves to maximize these interactions. This may be most
readily seen in the 4-NO2 1a dimer (Figure 6b), where the
rings appear to be orientating themselves to align four di-
poles simultaneously. The same degree of overlap would not
exist if the molecules comprising the dimer exhibited identi-
cal torsion angles. It is also noteworthy, that in the 4-NO2 1a
dimer, the aromatic rings are 14.298 out-of-plane with re-
Figure 8. Partial structure of the 4-NO2 1a benzoyl leucine diethyl amide:
a) top view, capped sticks; b) top view, space-filling model; c) side view,
space-filling model, a of 1a is 14.298.
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Geometry of p–p Interactions
FULL PAPER
maximizing the degree of overlap between the local dipoles
of the interacting rings.
account at least four components including electrostatic
forces, exchange repulsion, dispersion, and induction.[3f] The
contribution from each of these components in controlling
the nature of aromatic interactions remains an important
question.
The results presented herein may support the direct, local
model proposed by Wheeler and Houk.[3a–e] Nevertheless,
whether these direct, local interactions are controlling the
energetic of aromatic interactions remains an open question.
Although several of the homochiral dimers appear to exhibit
direct interactions between local dipoles on the aromatic
rings, the existence of these interactions is not obvious in all
homochiral dimers. For example, an interaction between the
Conclusion
In conclusion, we have shown that the position of a substitu-
ent on an aromatic moiety can have a profound effect on p–
p interactions. In our prior study, a series of 3- and 3,5-di-
À
À
C F and C H dipole of the interacting rings was observed
for the 4-F 1b dimer but not for the corresponding 3-F
dimer. Additionally, with respect to the 4-F 1b dimer, al-
though their appears to be a local dipole interaction be-
AHCTUNGTREGsNNNU ubstitued benzoyl leucine diethyl amides of varying elec-
tronic character was crystallized and characterized in the
solid state. All of the 3- and 3,5-disubstituted dimers self-as-
sembled into homochiral dimers in the solid state, with a
parallel displaced p–p interaction stabilizing each dimer.
However, no homochiral dimerization was observed in the
unsubstituted case. In the present study involving 4-substi-
tuted benzoyl leucine diethyl amides, only two of the com-
pounds, 4-NO2 1a and 4-F 1b, formed homochiral dimers
with stabilizing parallel displaced p–p interactions. The crys-
tallographic data suggest that local interactions between di-
poles may stabilize the interaction in the 4-NO2 1a and the
4-F 1b dimers and provide a driving force for homochiral di-
merization. However, the origin of the enhanced stabiliza-
À
À
tween the C F bond on one ring and the C H dipole on the
other, the centroid distance is one of the largest (4.51 ꢁ) ob-
served for all compounds that were crystallized in this and
the previous study.[9] If local interactions were the dominat-
ing factor, one might surmise that the interacting rings
would have a higher degree of overlap. Furthermore, in
compounds that do not possess strong dipole moments such
as the 3-Me dimer, the crystal structures do not clearly dis-
play direct, local interactions. Consequently, there may be
other factors influencing substituent effects in aromatic in-
teractions. Arnstein and Sherrill suggested that analyzing
substituent effects of aromatic interactions must take into
Table 4. Crystal structure analysis for compounds 1a–1 f.
1a
1b
1c
1d
1e
1 f
empirical formula
Mw
C17H25N3O4
335.40
C17H25FN2O2
308.39
C18H28N2O2
304.42
C18H25N3O2
315.41
C18H28N2O3
320.42
C17H25ClN2O2
324.84
T [K]
110(2)
110(2)
110(2)
110(2)
110(2)
110(2)
l [ꢁ]
0.71073
1.54178
0.71073
0.71073
0.71073
0.71073
crystal system
space group
a [ꢁ]
b [ꢁ]
c [ꢁ]
monoclinic
C2/c
19.2534(7)
19.3811(8)
21.0097(7)
90
monoclinic
P21
10.2718(2)
17.6424(4)
10.8798(2)
90
monoclinic
P21/n
10.0166(3)
9.8877(3)
17.5286(5)
90
monoclinic
P21/n
9.4313(3)
10.4584(4)
18.3036(7)
90
orthorhombic
Pbca
10.1124(2)
16.0981(4)
21.7719(6)
90
orthorhombic
Pbca
10.1373(3)
15.6596(4)
22.0323(6)
90
a [8]
b [8]
102.664(4)
90
7649.1(5)
16
1.165
0.084
116.793(3)
90
1759.96(6)
4
1.164
0.681
92.004(3)
90
1734.99(9)
4
1.165
0.076
98.284(4)
90
1786.56(11)
4
1.173
0.078
90
90
90
90
g [8]
V [ꢁ3]
Z
3544.26(15)
8
1.201
0.082
1392
0.60ꢂ0.46ꢂ0.42
3.03–29.12
À12ꢀhꢀ10
À20ꢀkꢀ21
À29ꢀlꢀ24
11571
3497.54(17)
8
1.234
0.227
1392
0.52ꢂ0.46ꢂ0.43
2.76–29.30
À12ꢀhꢀ13
À17ꢀkꢀ19
À29ꢀlꢀ21
10351
1calcd [MgmÀ3
]
m [mmÀ1
(000)
]
F
A
2880
664
664
680
crystal size [mm3]
q [8]
0.40ꢂ0.30ꢂ0.25
1.51–25.95
À15ꢀhꢀ23
À23ꢀkꢀ23
À25ꢀlꢀ25
16053
0.72ꢂ0.52ꢂ0.35
4.55–71.66
À12ꢀhꢀ12
À18ꢀkꢀ21
À13ꢀlꢀ13
14482
0.48ꢂ0.32ꢂ0.20
2.90–29.17
À13ꢀhꢀ13
À12ꢀkꢀ13
À15ꢀlꢀ23
8329
0.68ꢂ0.54ꢂ0.50
2.93–29.26
À12ꢀhꢀ12
À14ꢀkꢀ13
À24ꢀlꢀ25
15466
index ranges
reflns collected
independent reflns
7320
6090
4028
4241
4166
4093
R
(int)
0.0334
0.0316
0.0211
0.0266
0.0292
0.0222
completeness [%] to q [8]
max/min transmission
data/restraints/parameters
GooF on F2
98.0/25.95
1.00000/0.76940
7320/0/441
0.985
99.0/71.66
1.00000/0.80448
6090/1/399
1.181
99.9/26.00
1.00000/0.99723
4028/0/215
1.092
99.8/26.00
1.00000/0.97033
4241/0/212
1.039
99.9/26.00
1.00000/0.98634
4166/0/212
0.964
99.9/26.00
1.00000/0.99126
4093/0/203
0.997
R1, wR2 [I>2s(I)]
R1, wR2 (all data)
0.0635, 0.2015
0.0997, 0.2284
0.389/À0.244
0.0585, 0.1592
0.0620, 0.1625
0.721/À0.598
0.0390, 0.0749
0.0599, 0.0772
0.251/À0.236
0.0393, 0.0988
0.0582, 0.1032
0.306/À0.203
0.0399, 0.0994
0.0598, 0.1038
0.363/À0.214
0.0363, 0.0900
0.0564, 0.0938
0.305/À0.290
diff. peak/hole [eꢁÀ-3
]
Chem. Eur. J. 2012, 00, 0 – 0
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www.chemeurj.org
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J. R. Carey et al.
Table 5. Crystal structure analysis for compounds 1g–1k.
1g
1h
1i
1j
1k
empirical formula
Mw
C17H25BrN2O2
369.30
C17H26N2O2
290.40
C17H25N3O4
335.40
C18H28N2O2
304.42
C17H25FN2O2
308.39
T [K]
297(2)
297(2)
110(2)
297(2)
110(2)
l [ꢁ]
0.71073
1.54178
0.71073
1.54178
0.71073
crystal system
space group
a [ꢁ]
b [ꢁ]
c [ꢁ]
orthorhombic
Pbca
10.2088(5)
15.9887(11)
22.2875(11)
90
monoclinic
P21/c
10.3265(5)
9.9356(5)
19.3787(8)
90
monoclinic
P21/n
10.3883(3)
14.8162(4)
11.6216(3)
90
monoclinic
P21/c
8.7443(2)
17.3141(4)
12.3464(3)
90
monoclinic
P21/c
8.7136(3)
16.9065(5)
12.2036(4)
90
a [8]
b [8]
90
90
118.669
90
1744.50(14)
4
1.106
92.258(3)
90
1756.98(7)
4
1.151
0.590
109.958(3)
90
1756.98(7)
4
1.151
0.590
108.497(4)
90
1704.92(10)
4
1.201
0.086
g [8]
V [ꢁ3]
Z
3637.9(4)
8
1.349
2.268
1536
0.54ꢂ0.28ꢂ0.17
2.99–29.09
À8ꢀhꢀ13
À7ꢀkꢀ20
À22ꢀlꢀ29
10880
1calcd [MgmÀ3
]
m [mmÀ1
(000)
]
0.573
632
F
A
664
664
664
crystal size [mm3]
q [8]
0.78ꢂ0.55ꢂ0.48
5.15–71.79
À12ꢀhꢀ11
À10ꢀkꢀ11
À23ꢀlꢀ23
13273
0.76ꢂ0.62ꢂ0.42
4.59–72.19
À9ꢀhꢀ10
À11ꢀkꢀ21
À14ꢀlꢀ15
6834
0.76ꢂ0.62ꢂ0.42
4.59–72.19
À9ꢀhꢀ10
À11ꢀkꢀ21
À14ꢀlꢀ15
6834
0.72ꢂ0.62ꢂ0.45
2.98–29.32
À11ꢀhꢀ11
À20ꢀkꢀ23
À14ꢀlꢀ15
8241
index ranges
reflns collected
independent reflns
4295
3350
3376
3376
3954
R
(int)
0.0329
0.0189
0.0173
0.0173
0.0253
completeness [%] to q [8]
max/min transmission
data/restraints/parameters
GooF on F2
99.9/26.00
1.00000/0.94998
4295/0/187
1.097
98.8/71.00
1.00000/0.86644
3350/1/194
1.463
99.2/26.00
1.00000/0.85058
3376/0/222
1.029
99.270.00
1.00000/0.85058
3376/0/222
1.029
99.8/26.00
1.00000/0.98531
3954/0/222
0.966
R1, wR2 [I>2s(I)]
R1, wR2 (all data)
0.0440, 0.0863
0.1281, 0.0916
0.647/À0.607
0.0999, 0.3522
0.1225, 0.3757
0.695/À0.635
0.0530, 0.1488
0.0579, 0.1534
0.490/À0.412
0.0530, 0.1488
0.0579, 0.1534
0.490/À0.412
0.0590, 0.1667
0.0954, 0.1791
0.959/À0.469
diff. peak/hole [eꢁÀ-3
]
undisturbed at RT for several days. Tables 4 and 5 contain selected crys-
tallographic data for compounds 1a–1k. A semiempirical absorption cor-
rection was applied to all compounds with the exception of 1g. The data
for all compounds were refined by full-matrix least-squares methods on
F2. CCDC 887495 (1a), 887496 (1b), 887497 (1c), 887498 (1d), 887499
(1e), 887500 (1 f), 887501 (1g), 887505 (1h), 887502 (1i), 887503 (1j),
and 887504 (1k) contain the supplementary crystallographic data for this
paper. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
tion of the 3- and 3,5-disubstituted benzoyl leucine diethyl
amides is not clear and will require further investigation.
Experimental Section
General procedure for the synthesis of substituted benzoyl leucine acids:
The substituted benzoyl acid chloride was added to d,l-leucine that was
suspended in tetrahydrofuran. (Æ)-Propylene oxide was added under Ar
(or N2) at RT. The reaction mixtures were stirred no more than 24 h. Un-
reacted d,l-leucine was removed by filtration and the solutions were con-
centrated in vacuum. The crude products were purified by recrystalliza-
tion from acetonitrile or by flash chromatography.
Acknowledgements
This work was supported by the National University of Kaohsiung and
by the National Science Council (NSC) of Taiwan under contract number
NSC 98-2113M-390-006-MY2 and NSC 100-2113M-390-001-MY2. The
authors thank Prof. Yao-Yuan Chuang and Po-Chih Chen for fruitful dis-
cussions, Shang-Jhih Jiang for providing compound 1d, Yu-Tzu Chen for
providing compounds 1c, 1 f, and 1j, and Bo Y. Wang for the back cover
art. We also thank Dao-Wen Luo of the National Chung Hsing Universi-
ty for the collection of the single-crystal X-ray diffraction data.
General procedure for the synthesis of substituted benzoyl leucine
amides: Substituted benzoyl leucine diethyl amide derivatives were pre-
pared as follows: N,N’-Diisopropylcarbodiimide (DIC) was added drop-
wise to a stirred suspension of the substituted benzoyl leucine in CH2Cl2
for 10–15 min under Ar at 08C. Next, diethylamine was added dropwise
to the solution and the mixture was stirred overnight. The resulting solid
was removed by filtration and the filtrate was quenched with 5% aque-
ous KHSO4, 5% aqueous NaHCO3, and saturated aqueous NaCl solu-
tion. The organic layer was dried over MgSO4 and concentrated in
vacuum. The crude product was purified by flash chromatography and
the pure solid was recrystallized from hexane/dichloromethane. The
products were characterized by using 1H NMR, 13C NMR, IR, and UV
spectroscopy, HRMS, HPLC, and X-ray crystallography. See the Support-
ing Information for detailed methods and characterizations of new com-
pounds. To produce single crystals suitable for X-ray structure determina-
tion, the respective diethyl amide (40–45 mg) was added to CH2Cl2
(1 mL), followed by n-hexane (4 mL) and the solution was allowed to sit
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Geometry of p–p Interactions
FULL PAPER
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Received: June 25, 2012
Published online: && &&, 0000
Chem. Eur. J. 2012, 00, 0 – 0
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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J. R. Carey et al.
p–p Interactions
S. E. Snyder, B.-S. Huang, Y. W. Chu,
H.-S. Lin, J. R. Carey* . . . . . . &&&& — &&&&
The Effects of Substituents on the
Geometry of p–p Interactions
To dimerize or not to dimerize? The
position of a substituent on an aro-
matic moiety can have a profound
effect on p–p interactions. In the pres-
ent study, involving 4-substituted ben-
zoyl leucine diethyl amides, only cer-
tain compounds formed homochiral
dimers with a stabilizing parallel dis-
placed p–p interaction (see figure).
The crystallographic data suggest that
local interactions between dipoles may
provide a driving force for self-assem-
bly and for homochiral dimerization.
A series of benzoyl leucine amides…
…of varying electronic character were prepared. All
of the 3- and 3,5-disubstituted compounds assem-
bled into homochiral dimers in the solid state.
However, no homochiral dimerization was observed
in the unsubstituted case and in several 4-substi-
tuted cases (shown in yellow). The crystallographic
data suggests that local interactions between the
dipoles may stabilize the interaction in several of
the dimers (shown in red) and provides a driving
force for homochiral dimerization. For more details
see the Full Paper by J. R. Carey et al. on page &
& ff.
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10
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www.chemeurj.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!