A simple chiral recognition system to investigate substituent effects on π-π Interactions

Article abstract of DOI:10.1021/ol3014057

We have used a simple molecular recognition system to study substituent effects in aromatic interactions. A series of substituted benzoylleucine diethyl amides with aromatic rings of varying electronic character were crystallized. All of the substituted d

Full text of DOI:10.1021/ol3014057

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
A Simple Chiral Recognition System to
Investigate Substituent Effects on πÀπ
Interactions
Seth E. Snyder, Bin-Syuan Huang, Yu-Tzu Chen, Huei-Shian Lin, and James R. Carey*
Department of Applied Chemistry, National University of Kaohsiung, 700,
Kaohsiung University Road, Nanzih District, 811 Kaohsiung, Taiwan
jcarey@nuk.edu.tw
Received May 21, 2012
ABSTRACT
We have used a simple molecular recognition system to study substituent effects in aromatic interactions. A series of substituted benzoylleucine
diethyl amides with aromatic rings of varying electronic character were crystallized. All of the substituted dimers organized into homochiral
dimers in the solid state but with pronounced differences in regard to the orientation of the aromatic rings with respect to each other. However, no
homochiral dimerization was observed in the unsubstituted case.
Deciphering the nature of aromatic interactions is a
longstanding goal in the field of molecular recognition.1
Despite myriad experimental and computational studies
directed at πÀπ interactions, the molecular bases of these
interactions remain controversial.2 Simple electrostatic
models such as the well-known HunterÀSanders and
polar/π models have been used to explain the mechanistic
rationale driving these interactions.3 However, more
recent high-level computational studies measuring the
effect of substituents on aromatic interactions have chal-
lenged the simple electrostatic models.2,4 Surprisingly, in
contrast to predictions from the HunterÀSanders and
polar/π models, these computational studies reveal en-
hanced interactions in the sandwich configuration of all
substituted dimers relative to the unsubstituted benzene.
Moreover, several studies predict that increasing the num-
ber of substituents on the aromatic moiety results in
increased stabilization.2,4i Similar results are observed
using computational models for parallel displaced πÀπ
interactions.4c,e A number of innovative new theories have
been postulated to rationalize these results, which have
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r
10.1021/ol3014057
XXXX American Chemical Society

emphasized the role of direct local interactions,4e disper-
sion effects, and charge penetration effects.5
DNB rings reinforced by two hydrogen bonds. Such
homochiral self-recognition is also observed in solution
and has been applied to the development of new chiral
selectors for chromatographic separations.7a,c,9
There have been various innovative experimental mod-
els to study the energetics of the πÀπ interaction, which
often rely on using conformationally restrained molecules
that force two aromatic rings on the molecule to interact in
a particular orientation, such as a sandwich configuration
or a parallel displaced configuration.3a,b,6 However, it is
not clearwhetherresultsfromthesesystemscan be general-
ized since the interacting rings may be oriented in a way
that is energetically unfavorable within the constraints of
the molecule projecting the rings but may be energetically
favorable if the rings are able to assume an optimized
orientation (e.g., horizontal displacement) with respect
to each other. With the foregoing in mind, we postulate
that simple small molecule chiral recognition systems
will provide excellent models to study the nature of πÀπ
interactions and the influence of substituents on these
interactions.
Indeed, πÀπ interactions have been an essential element
in the design of chiral selectors and chiral catalysts.7 The
πÀπ sandwich interaction between a highly electron-
deficient aromatic ring and a highly electron-rich ring
has been designed into many chiral recognition systems.7b
Moreover, the parallel displaced interaction between two
electron-deficient rings has been observed in the solid state
of several small molecule chiral recognition systems.8 For
instance, we reported the homochiral self-recognition be-
tween enantiomers of 3,5-dinitrobenzoyl (DNB) leucine
amide derivatives.8a The chiral recognition mechanism
involves a parallel displaced πÀπ interaction between the
To fully explore the influence of substituents on πÀπ
interactions, we have expanded our study of chiral self-
recognition to include a variety of 3-substituted and
3,5-disubstituted benzoylleucine diethyl amides of varying
electronic character. Structures of the compounds crystal-
lized in this study are depicted in Figure 1. Our goal was to
determine whether replacement of the DNB ring with
aromatic rings of varying electron character would result
in similar homochiral dimerization in the solid state and
to determine the influence of substituents on the geometry
of the πÀπ interaction. While the dual hydrogen-
bonding interactions present in the homochiral dimers
(see Figure S2ÀS7 Supporting Information and Abstract
Graphic) will likely provide some degree of steric constraint
which may prevent the rings from assuming their optimal
orientation with respect to each other, examination with
space-filling models suggests that there is a significant
amount of translational and rotational space that the rings
can occupy with respect to each other while still retaining
the dual hydrogen-bonding interactions. Furthermore,
molecular mechanics energy minimization studies revealed
that conformational minima are relatively broad for DNB
amino acid derivatives and rotational barriers of the ben-
zene ring to the benzoyl carbon are low.7b,c Hence, various
low energy conformations are expected to be present, each
of which could contribute to homochiral dimerization. As
the nature of the aromatic substituent is not likely to affect
the rotational barriers, the series of compounds investigated
herein is also expected to be conformationally flexible.
Results of X-ray crystallographic analysis of the 3-sub-
stituted and 3,5-disubstituted benzoylleucine diethyl
amides are shown in Table 1. All compounds were crystal-
lized from hexane/dichloromethane. As shown in entries
1À5 of Table 1, all of the 3-substituted compounds orga-
nize into homochiral dimers in the solid state. Crystal
structuresoffivedifferent 3-substitutedhomochiraldimers
are depictedinFiguresS2a,dÀg (Supporting Information).
Similar to our prior study with 3,5-DNB leucine diethyl
amide 1f, the crystallographic results indicate that three
intermolecular interactions are responsible for chiral self-
recognition, two crossed hydrogen-bonding interactions,
and a parallel displaced πÀπ interaction.8a,9 Notably, the
sandwich configuration was not observed in any of the
crystalline homochiral dimers. As in the prior study, chiral
selection occurs in the unit cell of all of the 3-substituted
dimers, as only homochiral (S,S) and (R,R) dimeric com-
plexes are found. Moreover, as shown in entries 6À9 of
Table 1 and in Figures S2b,hÀj (Supporting Information),
all 3,5-substituted compounds assemble into homochiral
dimers in the solid state, including the electron-rich
3,5-dimethyl-substituted compound (entry 8 in Table 1).
Figure 1. Structure of racemic substituted benzoylleucine
diethyl amides crystallized in this study.
(5) Hohenstein, E. G.; Duan, J.; Sherrill, C. D. J. Am. Chem. Soc.
2011, 133, 13244–13247.
(6) (a) Xia, J. L.; Liu, S. H.; Cozzi, F.; Mancinelli, M.; Mazzanti, A.
Chem.;Eur. J. 2012, 18, 3611–3620. (b) Gung, B. W.; Emenike, B. U.;
Alverz, C. N.; Rakovan, J.; Kirschbaum, K.; Jain, N. Tetrahedron Lett.
2010, 51, 1648–1650. (c) Gung, B. W.; Xue, X.; Reich, H. J. J. Org.
Chem. 2005, 70, 3641–3644.
(7) (a) Snyder, S. E.; Carey, J. R.; Pirkle, W. H. Tetrahedron 2005, 61,
7562–7567. (b) Pirkle, W. H.; Pochapsky, T. C. Chem. Rev. 1989, 89,
347–362. (c) Pirkle, W. H.; Pochapsky, T. C. J. Am. Chem. Soc. 1987,
109, 5975–5982.
(8) (a) Snyder, S. E.; Volkers, P. I.; Engebretson, D. A.; Lee, W.;
Pirkle, W. H.; Carey, J. R. Org. Lett. 2007, 9, 2341–2343. (b) Koscho,
M. E.; Spence, P. L.; Prikle, W. H. Tetrahedron: Asymmerty 2005, 16,
3147–3153.
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D. A.; Boulanger, W. A.; Lin, H.-S.; Huang, B.-S.; Carey, J. R. Tetra-
hedron 2011, 67, 7143–7147.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 1. X-ray Crystallographic Analysis of 3-Substituted and 3,5-Disubstituted Benzoylleucine Diethyl Amides
b
c
homochiral dimer θa (deg) R (A) I (A)
d (deg) space groupe dimer config H-bond distance (A)
˚
R
˚
˚
entry
compd
1
2
1a 3-NO2
1b 3-Me
yes
yes
yes
yes
yes
yes
yes
yes
yes
no
115
128
114
135
129
119
115
123
129
NA
3.58
3.36
3.52
3.20
3.42
3.40
3.43
3.33
3.38
NA
1.68
2.65
1.56
3.21
2.80
1.90
1.60
2.48
2.75
NA
6.30
5.34
0.06
8.65
5.27
2.60
2.37
0.41
4.60
NA
P21/n
C2/c
Pbcn
C2/c
C2/c
C2/c
P21/c
C2/c
C2/c
P21/n
RÀR, SÀS
RÀR, SÀS
RÀR, SÀS
RÀR, SÀS
RÀR, SÀS
RÀR, SÀS
RÀR, SÀS
RÀR, SÀS
RÀR, SÀS
RÀS
2.14, 2.20
2.09, 2.09
2.05, 2.05
2.11, 2.11
2.00, 2.00
2.01, 1.97
2.03, 2.06
2.11, 2.11
1.97, 1.97
2.26, 2.26
3
1c
3-OMe
4
1d 3-Br
5
1e
1f
3-F
6
3,5-NO2
7
1g 3,5-OMe
1h 3,5-Me
8
9
1i
1j
3,5-F
benzoylf
10
a The angle (θ) is defined by the ring-to-ring centroid to the plane of benzoyl ring (see Figure S4a, Supporting Information). b Distance (R) of ring
centroid to plane defined by opposite ring (see Figure S4a, Supporting Information). c Horizontal displacement (I) between two ring centroids (see
Figure S4a, Supporting Information). d Degrees (R) out of plane (see Figure S4b, Supporting Information). e Several compounds were crystallized in
various other solvents such as benzene, toluene, and acetone mixtures resulting in highly similar crystal structures in identical space groups.
f Additionally, no homochiral dimerization is observed when the aromatic group is replaced with a cyclohexyl group (see Figure S3, Supporting
Information 1k).
Importantly, however, as shown in entry 10 of Table 1,
homochiral dimerization is not observed in the unsubsti-
tuted case (1j, R3 = R5 = H). Instead, as depicted in
Figure S2c (Supporting Information) and the Abstract
Graphic, the molecules organize into heterochiral dimers
with the aromatic rings directed away from each other and
with two parallel, hydrogen-bonding interactions in a
head-to-tail approach rather than the crossed dual hydro-
gen bonding observed in the homochiral dimers (e.g.,
Figures S2a,b, Supporting Information). Interestingly,
the heterochiral structure is similar to the lowest energy
dimer obtained using a multiconformational docking pro-
cedure on N-(3,5-dinitrobenzoyl)valine N-hexylamide.10
We suggest that the substituents are stabilizing the πÀπ
interaction relative to the unsubstituted benzoylleucine
diethyl amide. Notably, as discussed above, results ob-
served in the solid state are consistent with results observed
in solution, which implicate a πÀπ interaction as an
element of chiral self-recognition.7,8 As discussed with
respect to the recent computational models, these results
seem to implicate dispersion as an important factor in
stabilizing πÀπ interactions. However, as discussed in
more detail below, there is a significant substituent effect
on the degree of parallel and vertical displacement of the
aromatic rings, which would appear to implicate other
stabilizing forces as well.
the interacting aromatic rings, which is substituent depen-
dent. The horizontal displacement values range from
˚
˚
1.56 A for the 3-OMe 1c dimer to 3.21 A for the 3-Br 1d
dimer. Notably, the degree of offset does not appear to be
correlated with the electron-withdrawing capacity of the
substituent on the ring, as measured by either σm or σp. For
instance, the horizontal displacementsvalues of the 3-OMe
1c and 3-NO2 1a dimers have similar values, despite having
significantly different electronic properties. The halogen-
substituted dimers have the largest parallel displacement
values, whereas the methyl-substituted dimers fall in be-
tween. The vertical displacement values (R) also appear to
be substituent dependent, although the range of values
˚
˚
(3.20 A to 3.58 A) is less pronounced than the horizontal
displacement values (I).
These results suggest that a range of different stabilizing
geometries are possible for the parallel displaced πÀπ
interaction and that the optimal geometry appears to be
dependent on the nature of the substituents on the respec-
tive aromatic rings. The crystallographic data also indicate
the flexibility of this model system, despite the constraints
imposed by the crossed dual hydrogen-bonding pattern
observed in all homochiral dimers. Nonetheless, the ob-
served orientation effects are difficult to rationalize on the
basis of current models of πÀπ interactions. One might
surmise, for instance, that based on the simple electrostatic
models, electron-rich aromatic rings would show the lar-
gest degree of repulsion between the rings, thereby max-
imizing the degree of offset (I value). However, there does
not appear to exist a simple correlation between the
electron character of the electronic ring and the degree of
offset.
A closer look at the crystal structures of the aromatic
portions of the 3-NO2 1a and 3,5-NO2 1f dimers reveals
that direct, local interactions may influence the energetics
and the orientations of the aromatic rings in the respective
dimers. Several different perspectives of the aromatic
portions of the 3-NO2 1a dimer and the 3,5-NO2 1f dimer
are shown in parts a and b, respectively, of Figure 2. In the
Figures S4a,b (Supporting Information) depict the var-
ious parameters used to define the orientation of the rings
with respect to each other, including the vertical displace-
ment (R) and the horizontal displacement (I), which is a
measure of offset of the interacting rings. As shown in
Table 1, for the 3-substituted and 3,5-disubstituted ben-
zoylleucine amides that crystallized as homochiral dimers,
the interacting aromatic rings are essentially planar (R, the
degree out of plane, is less than 10°). Surprisingly, there
exists a wide range of horizontal displacement values (I) of
(10) Uccello-Barretta, G.; Balzano, F.; Martinelli, J.; Gasparrini, F.;
Pierini, M.; Villani, C. Eur. J. Org. Chem. 2011, 20À21, 3738–3747.
Org. Lett., Vol. XX, No. XX, XXXX
C

3-NO2 1a dimer, an oxygen on the nitro group is in close
˚
proximity (3.60 A) and roughly parallel to an aromatic
hydrogen atom on the opposing aromatic ring (Figure 2a).
A similar interaction is observed in the 3,5-NO2 1f dimer
(Figure2b). These observations suggestthatthere may bea
stabilizing interaction between the edge hydrogen of one
ring and an oxygen on the nitro group of the other ring,
consistent with observations of Rashkin and Waters.11
Furthermore, although two different rotamers for each
of the 3-NO2 1a monomers are possible, resulting in three
different orientations in which the two nitro groups can
arrange themselves with respect to each other, only the
rotamer which results in the aforementioned stabilizing
interaction is observed in the crystal structure. Notably,
different rotamers are observed in the 3-NO2 1a, 3-Me 1b,
3-OMe 1c, 3-Br 1d, and 3-F 1e dimers (see, e.g., Figures
S2a,dÀg, Supporting Information). In addition, only a
single rotamer of 3-NO2 1a exists in the crystal structure
and is distinctly different from the 3-OMe 1c rotamer.
The results presented in this study might lend support
to the direct, local model first proposed by Wheeler
and Houk and later modified by Wheeler.4e,g However,
whether such direct, local interactions are controlling the
energetics of aromatic interactions or just one of a number
of factors remains an open question. Notably, as discussed
above, while several of the homochiral dimers do appear
to show direct interactions between local dipoles on the
aromatic rings, the existence of these interactions is not as
clear in other cases. For instance, in the 3-F 1e dimer, we
do not observe an interaction between the CÀF and CÀH
dipoles of the interacting rings. It is certainly possible in
this case that given the constraints imposed by the dual
hydrogen-bonding interactions in the dimer, a stabilizing
interaction between the CÀH dipole of one molecule and
the CÀF dipole of the other molecule is precluded. More-
over, in aromatic rings that do not possess strong dipole
moments (e.g., the 3-Me 1b dimer), the crystal structures
do not necessarily indicate the existence of direct, local
interactions. Hence, other factors may be contributing to
the substituent effects in aromatic interactions. As dis-
cussed above, Arnstein and Sherrill suggested that analyz-
ing substituent effects of aromatic interactions must take
into account a balancing of electrostatics, exchange repul-
sion, dispersion, and induction.4c The role that each of
these factors plays in controlling the nature of aromatic
interactions remain an important question in the field of
molecular recognition.
Figure 2. Various perspectives of the partial structures of
(a) N-(3-nitrobenzoyl)leucine diethyl amide 1a. (b) N-(3,5-
dinitrobenzoyl)leucine diethyl amide 1f. (c) N-(3,5-dimeth-
oxybenzoyl)leucine diethyl amide 1g. The dotted lines show
potential local dipole interactions between the interacting
aromatic rings of the respective dimers.
character, stabilize aromatic interactions. The results also
suggest a role for direct, local interactions in aromatic inter-
actions, although the extent to which these local interactions
control overall energetics and the orientation of the interacting
aromatic rings is yet to be determined. Nonetheless, we believe
that it is of fundamental importance that the substituents on
the aromatic rings can radically alter the orientation of
interacting rings with respect to each other. Uncovering the
origin of this effect can have widespread application in the
fields of molecular and biomolecular recognition.
Acknowledgment. This work was supported by the
National Science Council of Taiwan (NSC 100-2113-M-
390-001-MY2 and NSC 98-2113-M-390-006-MY2). We
thank Dao-Wen Luo of the National Chung Hsing Uni-
versity for X-ray diffraction experiments.
In conclusion, we have shown that the solid state properties
of a series of small aromatic molecules, which form homo-
chiral dimers, can provide a wealth of information on the
nature of aromatic interactions and in particular, substituent
effects. The present study lends experimental support to the
hypothesis that all substituents, regardless of their electronic
Supporting Information Available. Additional figures,
synthesis, characterization, and crystallographic informa-
tion files (CIF) of new compounds. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
(11) Rashkin, M. J.; Waters, M. L. J. Am. Chem. Soc. 2002, 124,
1860–1861.
The authors declare no competing financial interest.
D
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