Chiral molecular clips control orthogonal crystalline organization

Article abstract of DOI:10.1021/ol0704340

Chiral molecular clips constitute a robust system for crystal engineering studies and undergo several levels of orthogonal organization including heterochiral dimerization, H-bond or metal-ligand mediated tape formation, and longitudinal packing of the ta

Full text of DOI:10.1021/ol0704340

ORGANIC
LETTERS
2007
Vol. 9, No. 10
1899-1902
Chiral Molecular Clips Control
Orthogonal Crystalline Organization
Yunfeng Chen,† Nengfang She,† Xianggao Meng,† Guodong Yin,†
Anxin Wu,*,† and Lyle Isaacs*,‡
Key Laboratory of Pesticide and Chemical Biology, Ministry of Education,
College of Chemistry, Central China Normal UniVersity, Wuhan 430079,
People’s Republic of China, and Department of Chemistry and Biochemistry,
UniVersity of Maryland, College Park, Maryland 20742
chwuax@mail.ccnu.edu.cn; lisaacs@umd.edu
Received February 20, 2007
ABSTRACT
Chiral molecular clips constitute a robust system for crystal engineering studies and undergo several levels of orthogonal organization including
heterochiral dimerization, H-bond or metal ligand mediated tape formation, and longitudinal packing of the tapes.
−
The functions of Nature’s macromoleculessespecially
proteinssare determined to a large extent by their precise
three-dimensional structures.1 Consequently, although the
constitution of these biological oligomers can be adequately
described by their primary (1°) sequence, their functions are
properly determined only by their secondary (2°, e.g., R-helix
or â-sheet), tertiary (3°), and quaternary (4°) structures which
involve folding, self-assembly, and higher order organization
of lower order structural elements. Inspired by the remarkable
characteristics of these natural systems, supramolecular
chemists have designed non-natural folding oligomers that
adopt well-defined 2° structures2 and begun to control their
functions (e.g., host-guest, folding-unfolding, dimeriza-
tion). For chemists interested in materials properties, this
same inspiration focused attention on the field of crystal
engineering.3 By understanding how 1° (e.g., molecular)
structure translates into crystalline order, it should be possible
to control desirable properties (e.g., nonlinear optics, density,
and solubility). Therefore, a major goal of many crystal
engineering studies has been the development of robust
synthons (e.g., H-bonding, π-π interactions, metal-ligand
interactions) that allow one to control the relative orientation
of molecules in the crystal.3 Fewer studies have been directed
toward the development of robust sets of orthogonal synthons
to allow for precise control over molecular ordering.4 In this
(2) (a) Gellman, S. H. Acc. Chem. Res. 1998, 31, 173-180. (b) Hill, D.
J.; Mio, M. J.; Prince, R. B.; Hughes, T. S.; Moore, J. S. Chem. ReV. 2001,
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R.; Krische, M. J.; Lehn, J.-M. Nature 2000, 407, 720-723. (g) Seebach,
D.; Beck, A. K.; Bierbaum, D. J. Chem. BiodiVersity 2004, 1, 1111-1239.
(3) (a) Schmidt, G. M. Pure Appl. Chem. 1971, 27, 647-678. (b) Braga,
D.; Grepioni, F.; Desiraju, G. R. Chem. ReV. 1998, 98, 1375-1405. (c)
Wuest, J. D. Chem. Commun. 2005, 5830-5837. (d) Aizenberg, J. AdV.
Mater. 2004, 16, 1295-1302. (e) Almarsson, O.; Zaworotko, M. J. Chem.
Commun. 2004, 1889-1896. (f) MacDonald, J. C.; Whitesides, G. M. Chem.
ReV. 1994, 94, 2383-2420. (g) Holman, K. T.; Pivovar, A. M.; Swift, J.
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† Central China Normal University.
‡ University of Maryland.
(1) Stryer, L. Biochemistry, 4th ed.; W. H. Freeman and Co.: New York,
1995.
10.1021/ol0704340 CCC: $37.00
© 2007 American Chemical Society
Published on Web 04/18/2007

paper, we demonstrate that chiral molecular clips5 based on
glycoluril constitute a robust supramolecular synthon that
controls enantioselective heterochiral dimerization followed
by H-bond or metal-ligand mediated supramolecular po-
lymerization that mimics some of the essential elements of
hierarchical organization seen in natural systems.
The popularity of glycoluril as a building block in
supramolecular chemistry can be traced to the pioneering
work of Nolte and Rebek on molecular clips5a and capsules,6
respectively, and is currently fuelled by interest in the
cucurbit[n]uril family7 of macrocycles. It was not until
recently, however, that the potential of glycoluril building
blocks in crystal engineering studies was realized.8 To
investigate the robustness of glycoluril molecular clips5a,8d,e
as an orthogonal synthon toward programmed crystalline
organization, we synthesized compounds (()-1-(()-6 (Fig-
ure 1 and Supporting Information) by Pd-catalyzed coupling
stituted aromatic wall that yields chiral, but racemic, clips;
and (3) the presence of functional groups (CtCH, OCH3,
NH2, pyridyl) with the potential to engage in H-bonding or
metal-ligand interactions.
We were fortunate to be able to obtain X-ray quality
crystals of (()-1-(()-6 by recrystallization from CH2Cl2
with MeOH or CH3CN as cosolvent and solve their struc-
tures. Figure 2a shows the structure of (()-1 in the crystal.
Figure 1. Molecular clips used in this study (R ) CO2Et).
Figure 2. Cross-eyed stereoviews of the X-ray crystal structures
of (a) (()-1, (b) (()-2, and (c) (()-3. Color coding: C, gray; H,
white; N, blue; O, red; I, purple.
reactions of terminal acetylenes with iodo-clip (()-1. The
critical design elements in choosing targets (()-2-(()-6
included the following: (1) one 1,4-dimethoxyxylylene wall
to induce dimerization;8d,e (2) a second differentially sub-
In contrast to (()-2-(()-6 (vide infra) and six other 1,4-
dimethoxyxylylene walled clips prepared previously by us,8e
(()-1 does not undergo CH‚‚‚O and π-π interaction
mediated cleft-cleft dimerization in the crystal. Instead,
(()-1 undergoes π-π interactions along the ab diagonal to
yield a tape-like array3f of the monomeric building unit (e.g.,
1° structural array). Interestingly, the π-π interactions occur
between identical aromatic walls (e.g., Ar-I with Ar-I) of
molecules of 1 of opposite handedness (e.g., (+)-1‚‚‚(-)-
1‚‚‚(+)-1). The clefts of (()-1 are filled by CO2Et groups
from molecules of (()-1 in an adjacent tape.
(4) (a) Holman, K. T.; Pivovar, A. M.; Ward, M. D. Science 2001, 294,
1907-1911. (b) Aakero¨y, C. B.; Beatty, A. M. Angew. Chem., Int. Ed.
2001, 40, 3240-3242. (c) Aakero¨y, C. A.; Beatty, A. M.; Helfrich, B. A.
J. Am. Chem. Soc. 2002, 124, 14423-14432. (d) Banerjee, R.; Mondal,
R.; Howard, J. A. K.; Desiraju, G. Cryst. Growth Des. 2006, 6, 999-1009.
(5) For leading references to (chiral) molecular clips, see: (a) Rowan,
A. E.; Elemans, J. A. A. W.; Nolte, R. J. M. Acc. Chem. Res. 1999, 32,
995-1006. (b) Zimmerman, S. C. Top. Curr. Chem. 1993, 165, 71-102.
(c) Klaerner, F.-G.; Kahlert, B. Acc. Chem. Res. 2003, 36, 919-932. (d)
Harmata, M. Acc. Chem. Res. 2004, 37, 862-873. (e) Artacho, J.; Nilsson,
P.; Bergquist, K.-E.; Wendt, O. F.; Warnmark, K. Chem.sEur. J. 2006,
12, 2692-2701. (f) Stoncius, S.; Orentas, E.; Butkus, E.; O¨ hrstro¨m, L.;
Wendt, O. F.; Wa¨rnmark, K. J. Am. Chem. Soc. 2006, 128, 8272-8285.
(g) Cheng, K.-W.; Lai, C.-C.; Chiang, P.-T.; Chiu, S.-H. Chem. Commun.
2006, 2854-2856.
(8) (a) Johnson, D. W.; Palmer, L. C.; Hof, F.; Iovine, P. M.; Rebek, J.,
Jr. Chem. Commun. 2002, 2228-2229. (b) Wu, A.; Fettinger, J. C.; Isaacs,
L. Tetrahedron 2002, 58, 9769-9777. (c) Johnson, D. W.; Hof, F.; Palmer,
L. C.; Martin, T.; Obst, U.; Rebek, J., Jr. Chem. Commun. 2003, 1638-
1639. (d) Reek, J. N. H.; Elemans, J. A. A. W.; de Gelder, R.; Barbara´, J.;
Rowan, A. E.; Nolte, R. J. M. Tetrahedron 2003, 59, 175-185. (e) Wang,
Z.-G.; Zhou, B.-H.; Chen, Y.-F.; Yin, G.-D.; Li, Y.-T.; Wu, A.-X.; Isaacs,
L. J. Org. Chem. 2006, 71, 4502-4508.
(6) Hof, F.; Craig, S. L.; Nuckolls, C.; Rebek, J., Jr. Angew. Chem., Int.
Ed. 2002, 41, 1488-1508.
(7) (a) Lagona, J.; Mukhopadhyay, P.; Chakrabarti, S.; Isaacs, L. Angew.
Chem., Int. Ed. 2005, 44, 4844-4870. (b) Lee, J. W.; Samal, S.; Selvapalam,
N.; Kim, H.-J.; Kim, K. Acc. Chem. Res. 2003, 36, 621-630.
1900
Org. Lett., Vol. 9, No. 10, 2007

Scheme 1. Schematic Representations of the Six Diastereomeric Dimeric Clips That Are Possible upon the Self-Association of
Racemic Molecular Clips: Color Code: Red, Dimethoxyxylylene Wall; Blue, Monosubstituted Xylylene Wall
The X-ray crystal structures of (()-2 and (()-3 are closely
related to one another and display secondary (2°) structural
organization based on dimerization of the molecular clips
(Figure 2b,c). During the formation of dimeric molecular
clips from (()-2 and (()-3, it is conceivable that either the
homochiral (e.g., (+)-2‚(+)-2 and (-)-2‚(-)-2) or the
heterochiral ((+)-2‚(-)-2) form could predominate (Scheme
1). Because clips (()-2-(()-6 contain two different aromatic
walls, there are three diastereomeric arrangements of the
homochiral and the heterochiral forms that differ in the
disposition (e.g., in-in, in-out, and out-out) of the
dimethoxyxylylene walls (Scheme 1). Despite the potential
complexity, (()-2 and (()-3 undergo exclusive heterochiral
dimerization via the in-in diastereomer during crystalline
organization.9 We believe that this highly diastereoselective
process is controlled by favorable C-H‚‚‚O interactions
between the OCH3 groups of the internal dimethoxyxylylene
wall and the ureidyl CdO of the glycoluril building block.8e,10
These 2° building blocks then form tape-like 2° structural
arrays by π-π interactions between the -CtC-Ar substi-
tuted aromatic walls on their external faces. The tape-like
2° structural arrays formed by (()-2 and (()-3 pack with
their long axes parallel to generate extended structures in
the solid state. The structures of (()-2-(()-3 further define
the scope and generality of the solid-state dimerization of
dimethoxyxylylene walled molecular clips mediated by
C-H‚‚‚O interactions8e and display a strong preference for
interaction between clips of opposite handedness (e.g.,
heterochiral dimerization).
diastereomer of the dimeric 2° building block (+)-4‚(-)-4
with terminal acetylenic (CtC-H) groups arrayed roughly
antiparallel to one another. These 2° building blocks then
undergo H-bond mediated formation of tape-like structures
that constitute a tertiary (3°) structural building block. In a
similar fashion, (()-5 undergoes heterochiral dimerization
to yield the in-in diastereomer of the 2° structural building
block (+)-5‚(-)-5 (Figure 3b). The extended CtC-Ar-
NH2 arms of (+)-5‚(-)-5 then form a H-bonded tape (3°
structure) by NH‚‚‚O H-bonds to the glycoluril CdO group.
One of the intriguing aspects of both of these H-bond
mediated solid-state supramolecular polymerizations is that
the CtC-H and CtC-Ar-NH2 arms H-bond to opposing
To investigate the possibility of using the heterochiral
dimerization mediated by C-H‚‚‚O interactions toward
orthogonal organization in the solid state, we decided to
endow these molecular clips with H-bond donating or metal
coordinating functional groups. Accordingly, we prepared
and crystallized (()-4-(()-6 which contain CtC-H, Ar-
NH2, and pyridyl functional groups, respectively (Figure 3).
Figure 3a shows a cross-eyed stereoview of the structure of
(()-4 in the crystal. As predicted, the monomeric units of
(()-4 undergo heterochiral dimerization to yield the in-in
(9) Crystallization of racemates usually results in the incorporation of
both enantiomers rather than conglomerate formation. The unusual observa-
tion in this work is that both enantiomers are incorporated during the
exclusive formation of the heterochiral dimeric molecular clips. As expected,
(()-1-(()-6‚CuI2 crystallize in centrosymmetric space groups (P21/c, P21/
n, P1h, and C2/c) to accommodate such an arrangement.
(10) 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.
Figure 3. Cross-eyed stereoviews of the X-ray crystal structures
of (a) (()-4, (b) (()-5, and (c) (()-6‚CuI2. Color coding: C, gray;
H, white; N, blue; O, red; I, purple; Cu, orange; H-bonds, red-
yellow striped.
Org. Lett., Vol. 9, No. 10, 2007
1901

glycoluril CdO groups in the dimers (+)-4‚(-)-4 and (+)-
5‚(-)-5, which requires a geometrical change in one of the
OCH3 groups of the 2° structural determining dimethoxyxyl-
ylene wall. The ability of the 2° structure determining
C-H‚‚‚O interactions to accommodate the structural de-
mands of higher order organizing H-bonding groups estab-
lishes the orthogonality of these synthons in the solid state
and suggests a broad applicability toward crystal engineering.
In conclusion, we find that molecular clips containing a
1,4-dimethoxyxylylene wall (1° structure) interact with each
other by C-H‚‚‚O interactions to yield dimeric (2° structural)
building blocks by in-in diastereoselective heterochiral
processes. When these 2° structural elements contain func-
tional groups capable of H-bonding or metal-ligand interac-
tions (e.g., (()-4-(()-6), a 3° level of organization is
expressed during the formation of tape-like supramolecular
polymers. In all cases, the tape-like structures pack with their
long axes parallel to one another which may be considered
as a 4° level of structural organization. The pronounced
robustness, enantioselectivity, and orthogonality of the
C-H‚‚‚O mediated 2° structure and H-bond or metal-ligand
mediated 3° structures based on glycoluril derived molecular
clips suggests the broad utility of this scaffold in crystal
engineering studies.
As a further test of the robustness of the C-H‚‚‚O
mediated molecular clip dimerization as a 2° structural
element in crystal engineering, we prepared molecular clip
(()-6 which bears a pyridyl group suitable for metal-ligand
coordination interactions. Figure 3c shows the X-ray crystal
structure of (()-6‚CuI2. In a completely predictable fashion
based on our previous experience with (()-2-(()-5, (()-6
undergoes heterochiral dimerization to yield the in-in
diastereomer of (+)-6‚(-)-6 as a 2° structural building block.
Subsequently, the two pyridyl arms of (+)-6‚(-)-6 which
are displayed roughly antiparallel to one another undergo
metal-ligand coordination interactions with the Cu atoms.
This process generates a metallo-supramolecular polymer
[(+)-6‚(-)-6-Cu(I2)-(-)-6‚(+)-6-Cu(I2)]n. Superficially,
the placement of the Cu atoms on opposite sides of the 3°
structure of (()-6‚(CuI2) may evoke images of helical DNA
or peptide R-helices. Closer inspection reveals that the
metallo-supramolecular polymer consists of short helical
units of alternating helicity in which two molecules of 6 of
the same handedness bind to a given Cu atom in an
alternating fashion. In all three cases ((()-4, (()-5, and (()-
6‚Cu(I2)), the 3° tape-like structures pack with their long
axes parallel to one another.
Acknowledgment. We thank Central China Normal
University, National Natural Science Foundation (Nos.
20472022 and 20672042), Hubei Province Natural Science
Fund (Nos. 2004ABA085 and 2004ABC002), National
Science Foundation (CHE-0615049), and the Petroleum
Research Fund administered by the American Chemical
Society (PRF-45228-AC4) for financial support.
Supporting Information Available: Procedures, char-
1
acterization data, and H and 13C NMR spectra for all new
compounds. Crystallographic information files for 1-6 (.cif).
Enlarged versions of the structures presented in Figures 2
and 3. This material is available free of charge via the Internet
at http://pubs.acs.org.
OL0704340
1902
Org. Lett., Vol. 9, No. 10, 2007