Substituent effects control the self-association of molecular clips in the crystalline state

Article abstract of DOI:10.1021/jo0603375

We report the X-ray crystal structure of 11 molecular clips and analyze the influence of substituents (e.g., OMe, Me, and NO₂) and their location on the observed crystal packing. Molecular clips 3a and 3b form tapelike structures in the crystal

Full text of DOI:10.1021/jo0603375

Substituent Effects Control the Self-Association of Molecular Clips
in the Crystalline State
†
†
†
†
†
Zhi-Guo Wang, Bao-Han Zhou, Yun-Feng Chen, Guo-Dong Yin, Yi-Tao Li,
,
†
,‡
An-Xin Wu,* and Lyle Isaacs*
Key Laboratory of Pesticide and Chemical Biology, Ministry of Education, College of Chemistry, Central
China Normal UniVersity, Wuhan, 430079, PRC, and Department of Chemistry and Biochemistry,
UniVersity of Maryland, College Park, Maryland 20742
lisaacs@umd.edu; chwuax@mail.ccnu.edu.cn
ReceiVed February 17, 2006
We report the X-ray crystal structure of 11 molecular clips and analyze the influence of substituents
(
e.g., OMe, Me, and NO
form tapelike structures in the crystal due to π-π interactions between the aromatic walls. Compounds
d, 3eC, and 3fC form dimers driven by critical C-H‚‚‚O interactions and then form tapes driven by
2
) and their location on the observed crystal packing. Molecular clips 3a and 3b
3
π-π interactions in the crystal. These two building motifs, π-π and C-H‚‚‚O interactions, can be used
to rationalize the enantio- and diastereoselectivity observed in the X-ray crystal structures of the remaining
five molecular clips. For example, the C-H‚‚‚O interactions are found to dictate the formation of
homochiral dimers in the structures of (()-3eT and (()-3fT and to control the diastereoselective formation
of 6a
2
2
-6c dimeric motifs with internal p-dimethoxy-o-xylylene walls. Overall, the results suggest that
substituent effects that induce even weak intermolecular interactions (e.g., C-H‚‚‚O) can be used to
reliably control crystal packing within glycoluril-based systems.
Introduction
Glycoluril and its derivatives are now widely used as building
work of Rebek and Nolte, however, that made glycoluril
commonplace. Rebek’s group, for example, studied the H-bond
driven self-assembly of glycoluril derivatives into sports-balls
in organic solvents and used them to encapsulate guests and
1
,2
blocks for studies of self-assembly in homogeneous solution.
The resurgence of interest in glycoluril-based supramolecular
chemistry can be traced to the work of Mock and co-workers
2,5
promote reactions. Of more direct relevance to our studies is
the work of Nolte who has pioneered the use of diphenyl
glycoluril derived molecular clips in supramolecular chemis-
3
in the 1980s on cucurbit[6]uril (CB[6]). CB[6] is a hexameric
glycoluril-based macrocycle with outstanding recognition prop-
1,6
try. Nolte demonstrated that these diphenyl glycoluril mo-
4
erties toward organic amines in water. It was the pioneering
lecular clips have diverse function including acting as receptors
7
8
9
10
for resorcinols, ammonium ions, amino acids, and viologens,
†
Central China Normal University.
University of Maryland.
‡
(
1) Rowan, A. E.; Elemans, J. A. A. W.; Nolte, R. J. M. Acc. Chem.
Res. 1999, 32, 995-1006.
2) Hof, F.; Craig, S. L.; Nuckolls, C.; Rebek, J., Jr. Angew. Chem. 2002,
1, 1488-1508.
3) Freeman, W. A.; Mock, W. L.; Shih, N. Y. J. Am. Chem. Soc. 1981,
03, 7367-7368.
4) Mock, W. L. Top. Curr. Chem. 1995, 175, 1-24.
(5) Wyler, R.; de Mendoza, J.; Rebek, J., Jr. Angew. Chem., Int. Ed.
Engl. 1993, 32, 1699-1701. Kang, J.; Rebek, J., Jr. Nature 1997, 385,
50-52.
(6) Smeets, J. W. H.; Sijbesma, R. P.; Niele, F. G. M.; Spek, A. L.;
Smeets, W. J. J.; Nolte, R. J. M. J. Am. Chem. Soc. 1987, 109, 928-929.
(7) Reek, J. N. H.; Priem, A. H.; Engelkamp, H.; Rowan, A. E.; Elemans,
J. A. A. W.; Nolte, R. J. M. J. Am. Chem. Soc. 1997, 119, 9956-9964.
(
4
1
(
(
10.1021/jo0603375 CCC: $33.50 © 2006 American Chemical Society
4
502
J. Org. Chem. 2006, 71, 4502-4508
Published on Web 05/12/2006

Dimeric Molecular Clips
CHART 1. Compounds Used in This Study
1
1
as components of supramolecular vesicles, and as enzyme
Me groups on their aromatic rings in a variety of substitution
patterns which allows us to assess the influence of substituents
on packing in the crystal. By virtue of the substitution pattern,
mimics.1 More recently, Nolte’s group has also studied the self-
association of diphenyl glycoluril derived molecular clips in
water and organic solvents which can be used to build up
lamellar thin films.15
2
1
3
1,14
(8) Smeets, J. W. H.; van Dalen, L.; Kaats-Richter, V. E. M.; Nolte, R.
As part of our interest in the synthetic, mechanistic, and
supramolecular chemistry of the cucurbit[n]uril family of
J. M. J. Org. Chem. 1990, 55, 454-461.
1
6
(9) Escuder, B.; Rowan, A. E.; Feiters, M. C.; Nolte, R. J. M. Tetrahedron
2
004, 60, 291-300.
macrocycles, we had reason to prepare a variety of molecular
(
10) Thordarson, P.; Bijsterveld, E. J. A.; Elemans, J. A. A. W.; Kas a´ k,
1
7,18
19
20
clips,
CB[n] congeners, CB[n] analogues, and new
P.; Nolte, R. J. M.; Rowan, A. E. J. Am. Chem. Soc. 2003, 125, 1186-
CB[n].21 Along the way, we obtained structural details for a
wide variety of compounds by X-ray crystallography. Accord-
1187.
(11) Schenning, A. P. H. J.; Escuder, B.; van Nunen, J. L. M.; de Bruin,
B.; Lowik, D. W. P. M.; Rowan, A. E.; van der Gaast, S. J.; Feiters, M. C.;
Nolte, R. J. M. J. Org. Chem. 2001, 66, 1538-1547.
ingly, it occurred to us,2
2,23
and others,
14,24,25
that glycoluril
derivatives might be good building blocks for studies of crystal
engineering because of their potential to engage in H-bonding
and π-π interactions. In this paper, we report the X-ray crystal
structures of eleven molecular clips26 derived from glycoluril 1
which bears two CO2Et groups on its convex face and two
substituted o-xylylene walls. The presence of substituents (e.g.,
OMe) and their location are found to play a key role in
determining the crystal packing because of their ability to engage
in C-H‚‚‚O interactions.
(12) Thordarson, P.; Bijsterveld, E. J. A.; Rowan, A. E.; Nolte, R. J. M.
Nature 2003, 424, 915-918. Schenning, A. P. H. J.; Spelberg, J. H. L.;
Hubert, D. H. W.; Feiters, M. C.; Nolte, R. J. M. Chem.-Eur. J. 1998, 4,
8
71-880.
(13) Reek, J. N. H.; Kros, A.; Nolte, R. J. M. Chem. Commun. 1996,
45-247. Elemans, J. A. A. W.; Slangen, R. R. J.; Rowan, A. E.; Nolte,
2
R. J. M. J. Inclusion Phenom. Macrocyclic Chem. 2001, 2001, 65-68.
Elemans, J. A. A. W.; Rowan, A. E.; Nolte, R. J. M. J. Am. Chem. Soc.
2002, 124, 1532-1540. Elemans, J. A. A. W.; Slangen, R. R. J.; Rowan,
A. E.; Nolte, R. J. M. J. Org. Chem. 2003, 68, 9040-9049.
(
14) Reek, J. N. H.; Elemans, J. A. A. W.; de Gelder, R.; Beurskens, P.
T.; Rowan, A. E.; Nolte, R. J. M. Tetrahedron 2003, 59, 175-185.
15) Holder, S. J.; Elemans, J. A. A. W.; Donners, J. J. J. M.; Boerakker,
(
M. J.; de Gelder, R.; Barber a´ , J.; Rowan, A. E.; Nolte, R. J. M. J. Org.
Chem. 2001, 66, 391-399.
Results and Discussion
(16) Lagona, J.; Mukhopadhyay, P.; Chakrabarti, S.; Isaacs, L. Angew.
Selection and Synthesis of Molecular Clips Used in this
Study. Chart 1 shows the structures of glycoluril 1 and bis-
Chem., Int. Ed. 2005, 44, 4844-4870. Lee, J. W.; Samal, S.; Selvapalam,
N.; Kim, H.-J.; Kim, K. Acc. Chem. Res. 2003, 36, 621-630.
(halomethyl) compounds 2a-f used as starting materials. For
(
17) Isaacs, L.; Witt, D. Angew. Chem., Int. Ed. 2002, 41, 1905-1907.
the preparation of compounds 3a-f that contain two identical
sidewalls, we performed the alkylation of 1 with the appropriate
alkylating agent (2) using t-BuOK as base in anhydrous DMSO
which delivered the target compounds in good yields (30-47%,
Supporting Information). The separate alkylation of 1 with 2e
or 2f delivers two diastereomers that contain two NO2 groups
in a cis (3eC and 3fC) or a trans relationship ((()-3eT and
(18) Wu, A.; Chakraborty, A.; Fettinger, J. C.; Flowers, R. A., II.; Isaacs,
L. Angew. Chem., Int. Ed. 2002, 41, 4028-4031.
(
19) Burnett, C. A.; Witt, D.; Fettinger, J. C.; Isaacs, L. J. Org. Chem.
2
1
1
003, 68, 6184-6191.
(20) Lagona, J.; Fettinger, J. C.; Isaacs, L. J. Org. Chem. 2005, 70,
0381-10392.
(21) Liu, S.; Zavalij, P. Y.; Isaacs, L. J. Am. Chem. Soc. 2005, 127,
6798-16799. Isaacs, L.; Park, S.-K.; Liu, S.; Ko, Y. H.; Selvapalam, N.;
Kim, Y.; Kim, H.; Zavalij, P. Y.; Kim, G.-H.; Lee, H.-S.; Kim, K. J. Am.
Chem. Soc. 2005, 127, 18000-18001.
(()-3fT). For the synthesis of molecular clips with two different
(
22) Wu, A.; Fettinger, J. C.; Isaacs, L. Tetrahedron 2002, 58, 9769-
sidewalls, we performed the electrophilic aromatic substitution
reaction between 4 and 5 which gave 6a-c in excellent yield
9
777.
23) Zhou, B. H.; Qu, J. L.; Wu, A. X. Acta Crystallogr., Sect. E 2005,
61, o3297-o3298.
(
(>90%). Compounds 3a-f and 6a-c contain OMe, NO2, and
J. Org. Chem, Vol. 71, No. 12, 2006 4503

Wang et al.
FIGURE 1. ORTEP plots of the X-ray crystal structures of: (a) 3a, (b) 3b, (c) 3c, (d) 3d, (e) 3eC, (f) (()-3eT, (g) 3fC, (h) (()-3fT, (i) 6a, (j)
6
b, (k) 6c. Color coding: C, gray; H, green; N, blue; O, red.
compounds (()-3eT and (()-3fT with their C2-symmetry are
chiral but were prepared and used in this study as the
corresponding racemic mixture to observe the interplay of
substituent effect and chirality. We selected CO2Et-substituted
molecular clips for these studies because they avoid the
competing π-π stacking motifs possible with Ph-substituted
glycoluril-based molecular clips. They also have excellent
solubility in nonpolar organic solvents that do not disturb the
packing preferences of the molecular clips by interacting with
their ureidyl CdO groups.
Molecular Structures of 3a-f and 6a-c in the Crystal.
We were able to obtain crystals of 3a-f and 6a-c that were
suitable for X-ray crystal structure determination by slow
evaporation of solutions of the various compounds in nonpolar
organic solvents (CH2Cl2, CHCl3, and CH3CN). Figure 1 shows
the molecular structures of 3a-f and 6a-c in the crystal. All
(
24) Kurth, D. G.; Fromm, K. M.; Lehn, J.-M. Eur. J. Inorg. Chem. 2001,
1
523-1526. Johnson, D. W.; Hof, F.; Palmer, L. C.; Martin, T.; Obst, U.;
1
1 molecular clips adopt the more commonly observed anti
Rebek, J., Jr. Chem. Commun. 2003, 1638-1639. Moon, K.; Chen, W.-Z.;
Ren, T.; Kaifer, A. E. CrystEngComm 2003, 5, 451-453. Kolbel, M.;
Menger, F. M. Chem. Commun. 2001, 275-276. Kolbel, M.; Menger, F.
M. AdV. Mater. 2001, 13, 1115-1119. Huo, F.-J.; Yin, C.-X.; Yang, P.
Acta Crystallogr., Sect. C 2005, 61, o500-o502.
conformation where the substituted o-xylylene walls are pointed
away from the CO2Et solubilizing groups on their convex
19,27
face.
The geometrical features of these new molecular clips
14,28
are similar to those reported previously (Table 1).
For
(
25) Johnson, D. W.; Palmer, L. C.; Hof, F.; Iovine, P. M.; Rebek, J.
Chem. Commun. 2002, 2228-2229.
26) Zimmerman, S. C. Top. Curr. Chem. 1993, 165, 71-102. Klaerner,
example, the dO‚‚‚Od distances range from 5.49 to 5.65 Å.
The distances between the centroids of the substituted o-xylylene
(
F.-G.; Kahlert, B. Acc. Chem. Res. 2003, 36, 919-932. Harmata, M. Acc.
Chem. Res. 2004, 37, 862-873. Jiang, H.; Leger, J.-M.; Guionneau, P.;
Huc, I. Org. Lett. 2004, 6, 2985-2988. Petitjean, A.; Khoury, R. G.;
Kryritsakas, N.; Lehn, J.-M. J. Am. Chem. Soc. 2004, 126, 6637-6647.
Chiang, P.-T.; Cheng, P.-N.; Lin, C.-F.; Liu, Y.-H.; Lai, C.-C.; Peng, S.-
M.; Chiu, S.-H. Chem.-Eur. J. 2006, 12, 865-876. Artacho, J.; Nilsson,
P.; Bergquist, K.-E.; Wendt, O. F.; W a¨ rnmark, K. Chem.-Eur. J. 2006,
(27) Sijbesma, R. P.; Wijmenga, S. S.; Nolte, R. J. M. J. Am. Chem.
Soc. 1992, 114, 9807-9813.
(28) Reek, J. N. H.; Engelkam, H.; Rowan, A. E.; Elemans, J. A. A.
W.; Nolte, R. J. M. Chem.-Eur. J. 1998, 4, 716-722. Reek, J. N. H.;
Rowan, A. E.; Crossley, M. J.; Nolte, R. J. M. J. Org. Chem. 1999, 64,
6653-6663.
1
2, 2692-2701.
4504 J. Org. Chem., Vol. 71, No. 12, 2006

Dimeric Molecular Clips
TABLE 1. Selected Parameters from the X-ray Crystal Structures
dO‚‚‚Od
Ar‚‚‚Ar centroid
distance
Ar-Ar mean
plane angle
(°)
π-π mean
plane separation
(Å)
distance
compound
packing
(Å)
(Å)
solvate
3
3
3
3
3
a
b
c
d
monomer, π-π tapes
monomer, π-π tapes
monomer, no tapes
dimer, non-π-π tapes
dimer, π-π tapes
5.617
5.501, 5.587
5.495
5.647
5.614
5.653, 5.642
5.535
5.485
5.595
5.599
7.113
6.560, 6.440
6.425
6.611
6.200
6.145, 6.115
6.545
6.577
6.620
6.332
56.1
36.2, 37.7
36.2
42.4
29.6
28.0, 27.7
38.9
37.8
40.8
34.6
3.69
3.58
none
H2O
CH3CN
(ClCH2)2
none
CHCl3
none
3.46
eC
3.45, 3.53
3.36, 3.44
3.52
3.47, 3.53
3.54
(
3
(
()-3eT
fC
()-3fT
homochiral dimer, π-π tapes
dimer, π-π tapes
homochiral dimer, π-π tapes
dimer, π-π tapes
none
6
6
6
a
b
c
CHCl3
(ClCH2)2
CHCl3
dimer, π-π tapes
dimer, π-π tapes
3.42
3.42
5.606
6.280
31.2
rings range from 6.11 to 7.11 Å and depend on the identity of
the substituents and their pattern. As the distance between the
centroids of the aromatic rings change, so does the angle
between the mean planes of these aromatic rings (27.7-56.1°).
Packing of the Molecular Clips in the Crystal. Of the
eleven compounds examined in this study, eight formed dimeric
structures in the crystal by simultaneous penetration of the
aromatic sidewalls of two molecular clips into the opposing
walls of two adjacent molecules of 3c shape a molecular box
around the cavity of 3c‚CH3CN that resembles a calixarene-
type receptor. The structure of 3c also displays close contacts
between the CO2Et groups of 1 equiv of 3c and an adjacent
molecule of 3c in the crystal. The two recurring packing motifs,
Ar-Ar interactions between the sidewalls of molecular clips
and close contacts between polarized C-H bonds and the ureidyl
CdO groups of adjacent molecular clips, will be used below
to rationalize the buildup of three-dimensional packing of
dimeric molecular clips in the crystal.
C-shaped cleft of the type that has been widely explored by
Nolte.1
,14,29
In this section, we describe the noncovalent interac-
tions that control the packing of these molecular clips into
dimeric entities and their subsequent packing into two- and
three-dimensional structures in the crystal.
B. Dimeric Packing of Achiral Molecular Clips 3d, 3eC,
and 3fC in the Crystal. Aside from 3a-c, the remaining
molecular clips 3d-f and 6a-c all form dimeric structures in
the crystal. Similar to the monomeric clips 3a-c, we have found
A. Packing of Monomeric Molecular Clips in the Crystal.
Compounds 3a-c remain monomeric in the crystal, although
3
b and 3c do include solvating H2O and CH3CN molecules,
respectively. An examination of the three-dimensional packing
of 3a-c reveals several recurring structural motifs. Figure 2a
shows the tapelike30 structure that is formed in the crystal
structure of 3a. In this structural motif, the xylylene walls of
one molecule of 3a pack against the identical walls of its
neighbors. Although this appears at first glance to be due to
direct π-π interactions, an examination of the distance between
the mean planes of the adjacent aromatic rings (Table 1, π-π
mean plane separation: 3.69 Å) suggests this motif also results
from dispersive interactions between the CH2 groups and the
adjacent Ar ring. A related tapelike packing motif occurs in
the X-ray crystal structures of monomeric 3b (Figure 2b),
although the separation between the mean planes of the Ar rings
for 3b is smaller (3.58 Å). An examination of the packing of
the tapelike structures of 3a and 3b reveals that they are held
together by a second type of packing motif based on C-H‚‚‚O
interactions between polarized C-H bonds and the ureidyl
carbonyl groups of an adjacent molecular clip (Table 2). In the
structure of 3a, this manifests itself as a pairwise interaction
between both CO2Et groups of one molecular clip and the cleft
of the adjacent clip, whereas for 3b, an OMe group on 3b packs
against the ureidyl carbonyl group on an adjacent molecule of
3
b. The structure of 3c (Figure 2c) is quite different from those
of 3a and 3b as a result of the solvating CH3CN molecules that
fill the clefts of 3c. Quite interestingly, the substituted o-xylylene
(29) (a) Reek, J. N. H.; Rowan, A. E.; de Gelder, R.; Beurskens, P. T.;
Crossley, M. J.; de Feyter, S.; de Schryver, F.; Nolte, R. J. M. Angew.
Chem., Int. Ed. Engl. 1997, 36, 361-363. (b) Holder, S. J.; Elemans, J. A.
A. W.; Barber a´ , J.; Rowan, A. E.; Nolte, R. J. M. Chem. Commun. 2000,
3
55-356.
FIGURE 2. Cross-eyed stereoviews of the packing motifs observed
for: (a) 3a, (b) 3b, and (c) 3c. Color coding: C, gray; H, white; N,
(
30) MacDonald, J. C.; Whitesides, G. M. Chem. ReV. 1994, 94, 2383-
2
420. Mel e´ ndez, R. E.; Hamilton, A. D. Top. Curr. Chem. 1998, 198, 97-
29.
1
3
blue; O, red; solvating CH CN, orange.
J. Org. Chem, Vol. 71, No. 12, 2006 4505

Wang et al.
TABLE 2. Parameters from Selected C-H‚‚‚O Interactions
Observed in the Crystal Structures
C‚‚‚O distance
H‚‚‚O distance
C-H‚‚‚O angle
(°)
compound
(Å)
(Å)
3
3
3
3
3
a
b
c
d
3.73
3.24
3.17
3.33, 3.19
-
3.34, 3.38
3.49
2.89
2.47
2.60
2.76, 2.50
-
2.44, 2.48
2.72
147.4
136.9
117.5
118.4, 128.8
-
164.1, 162.8
138.2
a
eC
(
()-3eT
fC
()-3fT
3
(
3.31
2.60
130.5
6
6
6
a
b
c
3.46, 3.46
3.51, 3.20
3.51, 3.31
2.61, 2.73
2.82, 2.54
2.83, 2.63
148.8, 134.1
129.9, 125.9
128.5, 128.2
a
-
) no C-H‚‚‚O contacts to the ureidyl CdO group.
that interactions between the aromatic rings and packing of
polarized C-H groups against the ureidyl CdO group of the
glycoluril play a decisive role in the buildup of the three-
dimensional structure of crystalline 3d-f and 6a-c. In this
section, we examine the crystal structures of 3d, 3eC, and 3fC
which are achiral and contain two identical aromatic walls.
Figure 3a illustrates the dimeric packing motif observed for
3d. The first striking feature of the structure of 3d is the
coplanarity of the two internal aromatic rings. The mean planes
of these aromatic rings are separated by 3.46 Å indicating that
these aromatic rings benefit from direct π-π interactions in
3
1
the crystal. The remaining pairs (e.g., internal/external) of
aromatic rings are tilted with respect to one another and do not
benefit from direct π-π interactions in the dimer. Why does
compound 3d form dimers in the crystal whereas 3a-c do not?
On the basis of an examination of 3d and the structures of the
other dimeric molecular clips (vide infra), we suggest that the
presence of close contacts between the polarized C-H bonds
of the OCH3 substituents on 3d with the ureidyl CdO groups
on the opposing equivalent of 3d play an important role. Because
the distance between the p-OMe groups does not match the
glycoluril CdO‚‚‚OdC distance, there are two crystallographi-
cally independent sets of contacts. For 3d, the shorter (longer)
C‚‚‚O contact is 3.191 Å (3.329 Å) and the shortest C-H‚‚‚O
contact amounts to 2.501 Å (2.764 Å). Such distances are
comparable to the sum of the corresponding van der Waals radii
FIGURE 3. Cross-eyed stereoviews of the dimeric packing motifs
observed for achiral: (a) 3d, (b) 3eC, and (c) 3fC. Color coding: C,
gray; H, white; N, blue; O, red.
an interdigitation of the CO2Et groups on the convex face of
the constituent 3eC. Figure 3c illustrates the crystal packing of
3fC. Similar to 3d and 3eC, 3fC assumes a dimeric arrangement
in the crystal such that the two internal aromatic rings are
coplanar with a mean plane separation (3.52 Å) near the
(
(
3.4 Å) which suggests the presence of C-H‚‚‚O interactions
Table 2) for crystalline 3d.32 The dimeric unit of 3d repeats
along the crystallographic b-axis which leads to tapelike
structures (Figure 3a).
3
3
preferred offset π-π stacking distance. Within these dimeric
units, there are two symmetry equivalent C-H‚‚‚O close
contacts (C‚‚‚O ) 3.49) between the OCH3 and ureidyl CdO
groups. The external aromatic rings of the dimers form an offset
π-π stack with a mean plane separation of 3.54 Å along the
c-axis leading to tapelike structures. These tapes further pack
with their long axes parallel to one another along the c-axis
with interdigitation of their CO2Et groups. In combination, the
structures of monomeric clips 3a-c and dimers of achiral clips
Figure 3b shows the crystal packing observed for 3eC. The
dimerization of 3eC benefits from π-π interactions between
the coplanar internal aromatic rings whose mean planes are
separated by 3.45 Å. Because of the placement of the NO2
groups, 3eC could adopt either head-to-head or head-to-tail
arrangements within dimeric 3eC2. In the crystal, 3eC exclu-
sively adopts the centrosymmetric head-to-tail arrangement (e.g.,
two NO2 groups up, two down) presumably so that the NO2
dipoles cancel each other. The dimeric units 3eC2 pack along
the ab-axis because of π-π interactions between their external
aromatic rings (mean plane separation ) 3.53 Å) to form
tapelike structures. The tapes pack along the c-axis because of
3
d, 3eC, and 3fC suggest that π-π interactions between the
internal and external pairs of aromatic rings along with
C-H‚‚‚O close contacts control the arrangement of molecular
clips in the crystal.
(
31) A similar geometry has previously been observed by Nolte for
C. Dimeric Packing of Chiral Molecular Clips (()-3eT
and (()-3fT in the Crystal. On the basis of the packing motifs
diphenylglycoluril-based molecular clips (refs 14 and 29).
(
32) Taylor, R.; Kennard, O. J. Am. Chem. Soc. 1982, 104, 5063-5070.
Desiraju, G. R. Acc. Chem. Res. 1991, 24, 290-296. Seiler, P.; Isaacs, L.;
Diederich, F. HelV. Chim. Acta 1996, 79, 1047-1058.
(33) Waters, M. L. Curr. Opin. Chem. Biol. 2002, 6, 736-741.
4506 J. Org. Chem., Vol. 71, No. 12, 2006

Dimeric Molecular Clips
SCHEME 1. Illustration of the Three Different Dimeric
Packing Motifs that Are Possible for 6a-c that Contain Two
Different Substituted o-Xylylene Walls
is that, rather than being in parallel register with one another,
the constituent monomers are twisted by 90° apparently to
satisfy the C-H‚‚‚O H-bond geometrical preference. Compound
(
()-3fT also forms a dimeric motif in the crystal due in part to
π-π interactions between the substituted o-xylylene walls
mean plane separation: 3.47 Å). In addition, the dimeric
building block motif benefits from OCH3‚‚‚O interactions
C‚‚‚O ) 3.308 Å). We rationalize that the simultaneous
(
(
formation of two such C-H‚‚‚O interactions in the homochiral
form drives the observed enantiomeric self-recognition process
because the hypothetic heterochiral form would only benefit
from a single good C-H‚‚‚O interaction. Similar to (()-3eT,
the homochiral dimers (+)-3fT2 and (-)-3fT2 alternate along
the crystallographic c-axis forming tapelike structures that
benefit from π-π interactions between their external aromatic
rings (mean plane separation: 3.53 Å). Once again, the tapes
pack with their long axes parallel and segregate the homochiral
dimers into alternating homochiral slabs along the ab-plane.
Although the crystal structures of (()-3eT and (()-3fT contain
many features seen in the structures described above (e.g.,
internal and external π-π interactions and C-H‚‚‚O interac-
tions), other features are new (e.g., efficient homochiral dimer-
ization and segregation in homochiral planes) which suggests
the broad potential of glycoluril derivatives in crystal engineer-
ing studies.
FIGURE 4. Cross-eyed stereoviews of the dimeric packing motifs
observed for racemates: (a) (()-3eT and (b) (()-3fT. Color coding:
C, gray; H, white; N, blue; O, red.
observed for the monomeric and achiral dimeric clips (vide
supra), we wondered whether it would be possible to understand
the structures of their chiral counterparts ((()-3eT and (()-
D. Dimeric Packing of Achiral Molecular Clips Containing
Two Different Aromatic Walls in the Crystal. On the basis
of the results described above which indicate that OCH3‚‚‚Od
C interactions and π-π stacking control the dimerization and
packing of molecular clips containing two identical aromatic
walls, we wondered whether it would be possible to control
diastereoselectivity during crystallization of molecular clips
containing two different aromatic walls. For example, when two
such molecular clips dimerize, three diastereomers are pos-
sible: two isomers with identical walls (e.g., red or blue) in
the interior of the dimer and a third with one of each type of
3
fT). Figure 4a shows the crystal structure of (()-3eT. Just as
in the case of 3eC, (()-3eT undergoes dimerization in the
crystal driven by π-π stacking interactions; the Ar rings are
not coplanar with a mean-plane separation of 3.36 Å (range:
3
(
.13-3.61 Å). Interestingly, the two enantiomers (+)-3eT and
-)-3eT undergo enantiomeric self-recognition1 during crys-
tallization to form the homochiral dimers (+)-3eT2 and (-)-
eT2 driven most likely by the presence of a C-H‚‚‚O H-bond
7,34
3
between the proton ortho to the NO2 group and the ureidyl Cd
O group on the glycoluril skeleton. In the homochiral dimeric
pairs, two weak C-H‚‚‚O H-bonds are possible, whereas for
3
5
aromatic wall in the interior (Scheme 1). To investigate this
type of isomerism, we prepared compounds 6a-c which each
contain one p-dimethoxy-o-xylylene wall. We predicted that this
wall with its capacity for both π-π and C-H‚‚‚O interactions
would control the diastereomer selection during crystallization.
Figure 5 shows the X-ray crystal structures obtained for 6a-c
which indicates that this prediction is valid. For example, Figure
18
the hypothetical heterochiral pair, only a single C-H‚‚‚O
H-bond could be formed which provides the driving force for
the observed enantiomeric self-recognition. Despite the fact that
(()-3eT undergoes enantiomeric self-recognition, this is not an
example of conglomerate formation because the two homochiral
pairs (+)-3eT2 and (-)-3eT2 alternate with one another in the
crystal. Figure 4a illustrates how the homochiral pairs interact
with one another by π-π interactions between their external
aromatic rings to form tapelike motifs along the c-axis.
Interestingly, the tapes pack with their long axes parallel and
in register, that is, dimers of the same handedness are segregated
into sheets in the ab-plane that alternate in their sense of
chirality. An unusual feature of the homochiral dimers of 3eT
5
a shows the structure of 6a in the crystal. Compound 6a once
again packs as dimers in the crystal because of π-π interactions
(
mean plane separation ) 3.54 Å). During this dimerization,
both p-dimethoxy-o-xylylene rings are positioned in the interior
of the dimer, contrary to what might be expected based on the
3
3,36
electrostatic potentials of the aromatic rings
but perfectly
(
35) The X-ray crystal structure of a porphyrin-derived molecular clip
(
34) Shi, X.; Fettinger, J. C.; Davis, J. T. J. Am. Chem. Soc. 2001, 123,
(ref 29a) displays a similar preference for internal p-dimethoxy-o-xylylene
walls.
(36) Cozzi, F.; Cinquini, M.; Annuziata, R.; Siegel, J. S. J. Am. Chem.
Soc. 1993, 115, 5330-5331.
6
1
3
738-6739. Ishida, Y.; Aida, T. J. Am. Chem. Soc. 2002, 124, 14017-
4019. Murguly, E.; McDonald, R.; Branda, N. R. Org. Lett. 2000, 2, 3169-
172.
J. Org. Chem, Vol. 71, No. 12, 2006 4507

Wang et al.
b-axis. The X-ray structure of 6c, with its o-dimethyl-o-xylylene
walls, is analogous to 6a. Dimerization is mediated by internal
π-π interactions between the two p-dimethoxy-o-xylylene walls
(mean plane separation ) 3.42 Å) and OCH3‚‚‚OdC interac-
tions (C‚‚‚O ) 3.31, 3.51 Å). External π-π interactions holding
the tapes together appear to be weak (mean plane separation )
3
.59 Å). The tapes align parallel to one another along the ab-
diagonal while including solvating CHCl3 molecules.
Conclusions
We have presented the X-ray crystal structures of eight
glycoluril-based molecular clips bearing different substituents
(e.g., H, OMe, NO2, and Me) on their aromatic rings and
different substitution patterns, some of which are chiral. We
have also presented the crystal structures of three glycoluril-
derived molecular clips that bear two differentially substituted
walls. Compounds 3a-c that lack a p-methoxy substituent are
monomeric in the crystal structure. The remaining compounds
exhibit dimeric molecular clips as building motifs in the crystal.
We attribute this result to the simultaneous formation of
OCH3‚‚‚OdC interactions and π-π stacking between the
internal aromatic rings. The interplay between the π-π interac-
tions and C-H‚‚‚O interactions in the solid-state structures of
(()-3eT and (()-3fT results in high levels of enantioselectivity
during the exclusive formation of homochiral dimeric motifs.
Similar considerations also control diastereoselectivity in the
solid-state structures of 6a-c with their p-dimethoxy-o-xylylene
rings in the interior of the dimeric molecular clips.
Although the supramolecular chemistry of glycoluril-based
systems in a homogeneous solution is well established, the use
of glycoluril derivatives as building blocks for crystal engineer-
ing studies has only recently begun to be explored.1
4,22,25
Both
we and Rebek have previously used the H-bonding potential of
glycoluril itself to engineer the formation of H-bonded tapes in
the crystal. In this paper, we established that even weaker, less
directional noncovalent interactions (e.g., π-π interactions and
C-H‚‚‚O interactions) can be used to reliably and predictably
build up complex crystalline architectures. In combination, these
results suggest that the potential of glycoluril derivatives in
studies of crystal engineering may be as broad as has been
demonstrated for its solution chemistry.
FIGURE 5. Cross-eyed stereoviews of the dimeric packing motifs
observed for: (a) 6a, (b) 6b, and (c) 6c. Color coding: C, gray; H,
white; N, blue; O, red.
in line with the prediction that C-H‚‚‚O interactions will control
diastereomer selection. For 6a2, two different sets of C-H‚‚‚O
interactions are present with short C‚‚‚O distances (both 3.46
Å, Table 2). Once again, these dimers pack into tapelike
structures because of weak external Ar-Ar interactions (mean
plane separation ) 3.65 Å) along the b-axis. The three-
dimensional packing of 6a is similar to that observed for the
other clips, with interdigitation of the CO2Et groups. For 6a,
however, solvating CHCl3 appears to play the role of filling
space that would otherwise be left unfilled because of the
absence of substituents on one aromatic wall. Compound 6b
with an o-dimethoxy-o-xylylene wall crystallizes following a
similar set of rules. Dimerization of 6b with internal p-
dimethoxy-o-xylylene walls is driven by π-π interactions (mean
plane separation ) 3.42 Å) and OCH3‚‚‚OdC interactions
Acknowledgment. We thank Central China Normal Uni-
versity, National Natural Science Foundation (No. 20472022),
Hubei Province Natural Science Fund (Nos. 2004ABA085 and
2004ABC002), University of Maryland, and the NIH (GM61854)
for generous financial support. We thank Xiang-Gao Meng for
performing the X-ray crystallographic measurements.
Supporting Information Available: General experimental,
1
13
synthetic procedures and characterization data, selected H and
C
NMR spectra for all new compounds (pdf), and crystallographic
information files (cif). This material is available free of charge via
the Internet at http://pubs.acs.org.
(
C‚‚‚O ) 3.20; 3.51 Å). Tapes (Figure 5b) are formed by
external π-π interactions (mean plane separation ) 3.30 Å)
and subsequently pack with their long axes parallel along the
JO0603375
4508 J. Org. Chem., Vol. 71, No. 12, 2006