Encapsulation of conventional and unconventional water dimers by water-binding foldamers

Article abstract of DOI:10.1021/ol2011083

Water-binding foldamers have been rarely studied. By orienting both H-bond donors and acceptors toward their interior, two pyridine-derived crescent-shaped folding oligoamides were found to be capable of trapping both conventional and unconventional water dimer clusters in their cavity (～2.5 A radius). In the unconventional water dimer cluster, the two water molecules stay in contact via an unusual H-H interaction (2.25 A) rather than the typical H-bond.

Full text of DOI:10.1021/ol2011083

ORGANIC
LETTERS
2011
Vol. 13, No. 12
3194–3197
Encapsulation of Conventional and
Unconventional Water Dimers by
Water-Binding Foldamers
Wei Qiang Ong,† Huaiqing Zhao,† Xiao Fang,† Susanto Woen,† Feng Zhou,‡
Weiliang Yap,† Haibin Su,‡ Sam F. Y. Li,† and Huaqiang Zeng*,†
Department of Chemistry and NUS MedChem Program of the Office of Life Sciences,
3 Science Drive 3, National University of Singapore, Singapore 117543, and Division of
Materials Science, 50 Nanyang Avenue, Nanyang Technological University,
Singapore 639798
chmzh@nus.edu.sg
Received April 27, 2011
ABSTRACT
Water-binding foldamers have been rarely studied. By orienting both H-bond donors and acceptors toward their interior, two pyridine-derived
crescent-shaped folding oligoamides were found to be capable of trapping both conventional and unconventional water dimer clusters in their
˚
˚
cavity (∼2.5 A radius). In the unconventional water dimer cluster, the two water molecules stay in contact via an unusual HꢀH interaction (2.25 A)
rather than the typical H-bond.
Supramolecules have been known to be able to host
water molecules in their cavities, channels, or layers in the
solid state. Depending on the sizes of the cavity and the
functionalities present in the host molecules, water mole-
cules can interact through H-bonding to form various
kinds of water clusters containing 2ꢀ45 water molecules.1
Stabilizing the water clusters in the crystal lattice offers an
attractive avenue whereby various topographies or archi-
tectures of the water clusters and the system’s H-bonding
networks can be more easily studied, allowing us to better
understand the unusual physical and chemical properties
of bulk water and its interactions with surfaces. In parti-
cular, numerous theoretical and experimental investiga-
tions of smaller water clusters, ranging from a dimer to
hexamer cluster,1mꢀt had provided good insights into the
structure, cooperativity, and rearrangement dynamics of
the H-bonding network in bulk water, which still remains
quite poorly understood at the present time. As the
simplest form of water clusters, a water dimer, (H2O)2,
is of paramount importance and had been extensively
studied1s,t,2 due to its significant roles in several existing
† National University of Singapore.
‡ Nanyang Technological University.
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10.1021/ol2011083
Published on Web 05/18/2011
2011 American Chemical Society

environmental issues, including the formation of acid
rain,3 vaporꢀliquid nucleation,4 absorption of solar
radiation in the atmosphere,5 and greenhouse effect.6
On the other hand, the hitherto reported supramolecular
water hosts have largely relied on conformationally more
flexible organic or organometallic molecules with respect to
foldamers7 whose well-defined backbones are primarily
stabilized by noncovalent forcessuch assolvophobic forces,
πꢀπ stacking interactions, and H-bonds. Despite their
great diversities,7 only a few foldamer molecules of similar
type have been reported recently by Lehn and Huc, accom-
modating up to three water molecules in their cavities.8 This
communication presents a foldamer approach toward en-
capsulating both conventional and unconventional water
dimers and discusses their topologies and energetic pro-
files constrained within the cavities of two water-binding
pyridine-based foldamers, i.e., trimer 3 and pentamer 5.
units per helical turn. The inward-pointing amide protons
(H-bond donors) and pyridine nitrogens (H-bond
˚
acceptors) in 1ꢀ5 enclose a cavity of ∼2.5 and 3.1 A in
radius, respectively, and seem to be large enough to
accommodate water molecules. Ab initio calculations per-
formed on trimer 1, tetramer 4, and pentamer 5 at the
B3LYP/6-311G* level show that the water complexes of
n•H2O (n = 1, 4, and 5) have a respective stability of 9.11,
11.39, and 7.80 kcal/mol more than its individual compo-
nents with 4•H2O being energetically most favored (see the
Supporting Information). Undoubtedly, the crystal pack-
ing effect may override this energetic favorability order.
Experimentally, obtaining water complexes was not
that straightforward. After screening numerous condi-
tions involving various combinations of all the common
organic solvents by methods of either slow evaporation
or diffusion, 1 cannot be crystallized out under all
the conditions tested, crystals of 2 and 3 can only be
obtained respectively from acetone and dichloromethane
by slow evaporation, and slow diffusion of cyclohexane
into dichloromethane over a few weeks led to X-ray
quality crystals for 4 and 5.
Examination of these crystal structures reveals the ab-
sence of water molecules in both 2 and 4. Since 2 was
crystallized from water-sequestering acetone molecules,
seclusion of trace amounts of acetone-solvated water
may occur that prevents 2 from binding to water mole-
cules. In 4, rather than water molecules, dichloromethane
molecules were either trapped in the crystal lattice or
bound by 4 in its cavity.
Nevertheless, the water-binding abilities of this series of
pyridine-derived cavity-enclosing oligoamides can be pro-
ven by the water-containing crystal structures of 3 and 5.
Of further note is that both were crystallized from water-
immiscible solvents such as dichloromethane and cyclo-
hexane, and only trace amounts of water molecules can be
found under these crystallization conditions.
The crystal structure9a of 3 expectedly shows a crescent-
shaped structure as those found in 1, 2, 4, and 5 recently
reported by us,9b a result of an efficient backbone rigidi-
fication by the stabilizing forces from the continuous
intramolecular H-bonding network made up of five
H-bonds (Figure 1). Molecules of 3 stack in a linear,
Pyridine-based H-bond enforced folding backbones of
oligoamides 1, 2, 4, and 5 have been recently confirmed to
have a crescent structure in both solution and solid states.9
Longer oligomers such as tetramer 4 and pentamer 5 take
up a helical conformation that requires ∼4.3 repeating
€
(3) (a) Jayne, J. T.; Poschl, U.; Chen, Y.-m.; Dai, D.; Molina, L. T.;
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Chem. Res. 1998, 31, 173. (b) Gong, B. Chem.;Eur. J. 2001, 7, 4336. (c)
Hill, D. J.; Mio, M. J.; Prince, R. B.; Hughes, T. S.; Moore, J. S. Chem.
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Chem. 2003, 7, 1649. (g) Sanford, A. R.; Yamato, K.; Yang, X.; Yuan,
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Angew. Chem., Int. Ed. 2003, 42, 2448. (i) Huc, I. Eur. J. Org. Chem.
2004, 17. (j) Cheng, R. P. Curr. Opin. Struc. Biol. 2004, 14, 512. (k) Licini,
G.; Prins, L. J.; Scrimin, P. Eur. J. Org. Chem. 2005, 969. (l) Li, Z. T.;
Hou, J. L.; Li, C.; Yi, H. P. Chem.;Asian J. 2006, 1, 766. (m) Li, X.;
Yang, D. Chem. Commun. 2006, 3367. (n) Goodman, C. M.; Choi, S.;
Shandler, S.; DeGrado, W. F. Nat. Chem. Biol. 2007, 3, 252. (o) Gong, B.
Acc. Chem. Res. 2008, 41, 1376. (p) Li, Z. T.; Hou, J. L.; Li, C. Acc.
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(8) (a) Berl, V.; Huc, I.; Khoury, R.; Lehn, J.-M. Chem.;Eur. J.
2001, 7, 2798. (b) Huc, I.; Maurizot, V.; Gornitzka, H.; Leger, J.-M.
Chem. Commun. 2002, 578. (c) Garric, J.; Leger, J.-M.; Huc, I. Angew.
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Chem., Int. Ed. 2005, 44, 1954. Foldamers can be evolved to recognize
alcohol molecules; see: (d) Hu, Z. Q.; Hu, H. Y.; Chen, C. F. J. Org.
Chem. 2006, 71, 1131. (e) Hu, H. Y.; Xiang, J. F.; Yang, Y.; Chen, C. F.
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Chen, C.-F.; He, S.-G. J. Org. Chem. 2009, 74, 4949. Foldamers can also
be evolved to tightly and selectively recognize alkali metal ions, see:
(g) Qin, B.; Ren, C. L.; Ye, R. J.; Sun, C.; Chiad, K.; Chen, X. Y.; Li, Z.;
Xue, F.; Su, H. B.; Chass, G. A.; Zeng, H. Q. J. Am. Chem. Soc. 2010,
132, 9564.
(9) (a) The crystal structure of 3 was refined at atomic resolution by a
full-matrix least-squares method with anisotropic temperature factors.
H-atoms at water molecules and from amide bonds were located from
difference Fourier maps and refined independently; all others were
placed on calculated positions and refined as riding atoms. The refine-
ment converged at an R-value of 0.0687. (b) Ong, W. Q.; Zhao, H. Q.;
Du, Z. Y.; Yeh, J. Z. Y.; Ren, C. L.; Tan, L. Z. W.; Zhang, K.; Zeng,
H. Q. Chem. Commun. 2011, DOI:10.1039/C1CC11532D.
Org. Lett., Vol. 13, No. 12, 2011
3195

Figure 1. (a) Cylindrical packing by 3; blue solid arrows indicate
the weak H-bond formed between the pyridine N and the
respective closer proton from the water dimer. (b) Intermolec-
ular H-bonds of varying lengths found among the trapped
water molecule, amide protons, pyridine N-atoms, and ester
O-atoms in 3; atoms participating in H-bonds are represented by
small balls of varying colors. (c) Unconventional water dimer
cluster from (a) that is mediated by the van der Walls interaction
Figure 2. (a) Intermolecular zigzag packing by 5. (b) Intermo-
lecular H-bonds of varying lengths found among a trapped
water molecule, amide protons, pyridine N-atoms, and ester
˚
O-atoms in 3; atoms participating in H-bonds of within 3.0 A are
represented by small balls of vaying colors, and strong H-bonds
are labeled with the H-bond lengths. (c) Conventional water
dimer cluster from (a) or (b) that is mediated by one strong
˚
H-bond of 1.849 A with a very short interatomic distance of
˚
involving two H-atoms (dHꢀH = 2.253 A). H-bonds in (b) are
shown as dotted red lines.
˚
2.71 A between the two water oxygens. In both (a) and
(b), carbonyl O-atoms from the two ends form two strong
intermolecular H-bonds with the water dimer cluster and are
indicated by single-headed solid lines. H-bonds in (b) are shown
as dotted red lines.
cylindrical fashion with an ∼180° offset from each other,
due to the benzene ring of the carboxybenzyl (Cbz)
protecting group lying in a perpendicular position to the
plane of the aromatic backbone (Figure 1a). The five
intramolecular H-bonds formed between amide protons
and neighboring pyridine nitrogens have H-bonding dis-
˚
chain is observed, with a distance of 6.92 A between the
two adjacent water dimers, which is approximately twice
that of the typical intermolecular πꢀπ stacking distance
(Figure 1a). This unconventional water dimer cluster is
formed possibly as a result of strong intermolecular
H-bonds between the water molecule and the protons
and nitrogens of 3 (Figure 3b) that “freeze” the water
molecule in the cavity of 3, followed by the aromatic πꢀπ
stacking forces that pack the water-containing 3 in a way
that brings pairs of water molecules in close proximity, yet
without allowing them to reorient as they would since their
rotations are greatly restricted by intermolecular H-bonds.
Similar to 3, water molecules are also found in the cavity
of 5. But differing from 3 that encloses one water molecule
per molecule of 3, every molecule of 5 is able to accom-
modate two waters in its cavity. Apparently, this difference
can be attributed to the differential structures between
them: while 3 adopts a planar structure and so contains a
roughly 2D planar cavity, 5 being helically folded encloses
a cavity that is 3D-shaped.
˚
tances 2.144ꢀ 2.347 A in length. The resultant H-bond
˚
enforced small cavity in 3 has a radius of ∼2.51 A,
measured from the center of the cavityto the amide proton,
and is found to enclose a water molecule in each asym-
metric unit despite using a nonpolar solvent, dichloro-
methane, with low water content as the crystallizing
medium. The water molecule sits almost in the center of
the cavity (Figure 1b) with its O-atom forming a medium
˚
strength H-bond (dOꢀH = 2.467 A) with the amide proton
of the Cbz group and two weak H-bonds with the other
two amideprotons (dOꢀH = 2.909 and 2.901 A). Oneofthe
waters additionally forms two medium strength H-bonds
˚
˚
with the pyridine N (dHꢀO = 2.434 A) and the ester O
˚
(dHꢀO = 2.462 A). The other water proton forms a
medium strength H-bond with the pyridine N (dHꢀO
=
˚
2.665 A, Figure 1a) that stays below or above the proton.
Interestingly, the arrangement of the two water mole-
cules in the cluster observed in 3 is quite unusual: there is
no intermolecular H-bond found in the water dimer
(Figure 1c), making it not belong to any of the 16 unique
water dimer clusters suggested by Dyke with invariably
each containing one intermolecular H-bond.1s,t Instead,
the water molecules in the cluster are in close contact with
In 5, there are nine intramolecular H-bonds (2.133ꢀ
˚
2.394 A) that lead to a helical conformation to enclose a
˚
small cavity with a radius of ∼2.57 A, measured from the
center of the cavity to the amide proton. Its 3D packing is
stabilized by two strong H-bonds among the water dimer
and the carbonyl oxygens from the end amide and Cbz
each other through HꢀH interaction with a H H dis-
3 3 3
˚
˚
˚
tance of 2.253 A that is ∼0.15 A less than twice the van der
groups (dHꢀO = 1.946 and 1.916 A, respectively, Figure 2a
˚
Waals radius of the H-atom (VdW = 1.20A). The distance
and 2b). In this case, the water dimer cluster also serves as
an exo-bidentate ligand, bridging molecules of 5 and
forming azigzag-likechain with anintermolecular distance
˚
between the two water oxygens is 3.504 A. As the water
dimer clusters elongate, a zigzag-like discrete infinite water
3196
Org. Lett., Vol. 13, No. 12, 2011

H-bonded water dimer (Figure S2c), the water dimers
found in 3 and 5 are destabilized by 2.99 and 1.33 kcal/
mol, respectively, due tothe structural restrictions imposed
by the surrounding molecular scaffolds.
The energetic profiles of the H-bonding networks in 3
and 5 were provided by carrying out single point-energy
calculations at the B3LYP/6-311Gþ(2d,p) level on the
corresponding structural motifs taken from their crystal
structures. As shown in Figure 3a and 3b, monomeric 3
(Figure 1b) and 5 (Figure 2b) contribute a respective total
stabilizing energy of 7.61 and 10.73 kcal/mol to the water
molecule and water dimer in their cavities by forming
H-bonds of varying strengths. For thetwo axially orienting
˚
H-bonds of 1.946 and 1.916 A in length found in 5
(Figure 2a), their H-bond strengths were computed to be
3.98 kcal/mol (Figures 3c and S2b) and 2.41 kcal/mol
(Figures 3d and S2a), respectively. Although we are not
˚
certain why the shorter H-bond (1.916 A) is weaker than
˚
the longer H-bond (1.946 A) by 1.57 kcal/mol, this dis-
crepancy may be due to the nonlinear relationship among
˚
atoms O1, H, and O2 and a shorter distance of 2.757 A
Figure 3. Binding energies derived by comparing the calcluated
single-point energies of structural motifs directly taken out from
the H-bonding networks found in 3 and 5 at the B3LYP/
6-311Gþ(2d,p) level. (a) H-bonds formed between a water mole-
cule and 3 are worth ∼7.61 kcal/mol. (b) H-bonds formed
between the water dimer cluster and 5 are worth ∼10.73 kcal/
between the two repulsive O1 and O2 atoms for the former
H-bond (Figure S2a) with respect to those found in the
latter (Figure S2b). Apparently, the formation of these
stabilizing H-bonding networks can more than compen-
sate for the energetic penalties of 2.99 and 1.33 kcal/mol
experienced by the water dimer clusters constrained in 3
and 5, respectively, adopting stable yet less favored con-
formations with regard to the most stable water dimer
conformation.
˚
mol. (c) An axial H-bond of 1.946 A formed between a water
molecule and neighboring 5 from Figure 2a is worth ∼3.98 kcal/
˚
mol. (d) An axial H-bond of 1.916 A formed between a
water molecule and neighboring 5 from Figure 2a is worth
∼2.41 kcal/mol.
In summary, we report here for the first time a crystal-
lographic observation of an unconventional water dimer
mediated by a rather unusual H H interaction. Com-
˚
of 6.821 A between two crystallographically equivalent
water oxygens (Figure 2a).
The water dimer cluster in 5 is stabilized by forming
3 3 3
pared to the computationally derived BE of 5.21 kcal/mol
for the most stable water dimer cluster, those water dimer
clusters in 3 and 5 are destabilized by 2.99 and 1.33 kcal/
mol, respectively. The ability to trap both conventional
and unconventional water dimer clusters of varying stabi-
lities and topographies by 3 and 5 highlights the potential
use of other analogous pyridine-derived foldamers as the
water-binding molecules, allowing for the creation of
enlarged 3D-shaped cavities for encapsulating larger water
clusters of diverse topographies in their interiors.
˚
two strong H-bonds with the pyridine N (dHꢀN = 1.894 A)
˚
and Cbz amide proton (dOꢀH = 1.937 A), one medium
˚
strength of H-bond (dOꢀH = 2.371 A) with amide proton,
and other weak H-bonds of less than 3.0 A with other
˚
amide protons (Figure 2b). Out of five pyridine N-atoms,
only the one from the first pyridine ring at one end parti-
cipates in forming a strong H-bond with the water dimer
˚
(dHꢀN = 1.894 A, Figure 2b). As illustrated in Figure 2c,
seemingly like a conventional water dimer containing a
˚
strong H-bond (dHꢀO = 1.849 A), the OꢀO distance was
˚
however found to be very short at 2.708 A for the water
Acknowledgment. Financial supports to H.Z. by the
NUS AcRF Tier 1 grants (R-143-000-375-112, R-143-000-
398-112), A*STAR SERC grant (M47070020 to H.S.), and
Environment and Water Industry Development Council
and Economic Development Board (SPORE, COY-15-
EWI-RCFSA/N197-1) are gratefully acknowledged.
dimer cluster found in 5. This distance is even shorter than
˚
that observed in regular ice (dHꢀO = 2.74 A), an indication
of the strong and positive cooperativity in the H-bonding
network shown in Figure 2b.
The binding energies dictating the formation of uncon-
ventional and conventional water dimer clusters in 3 and 5
were computed to be 2.22 and 3.88 kcal/mol, respectively,
at the level of M06-2X/aug-cc-pvtz.10 Compared to the
binding energy (BE) of 5.21 kcal/mol for the most stable
Supporting Information Available. Synthetic proce-
dures and a full set of characterization data including
1H NMR, 13C NMR, MS, crystal data, and molecular
modeling. This material is available free of charge via the
Internet at http://pubs.acs.org.
(10) Bryantsev, V. S.; Diallo, M. S.; Duin, A. C. T. v.; Goddard,
W. A., III. J. Chem. Theory Comput. 2009, 5, 1016.
Org. Lett., Vol. 13, No. 12, 2011
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