Alcohols as Latent Hydrophobes: Entropically Driven Uptake of 1,2-Diol Functionalized Ligands by a Porous Capsule in Water

Article abstract of DOI:10.1021/jacs.9b03542

Alcohols, with hydroxyl groups compositionally identical to water itself, are consummate hydrophiles, whose high solubilities preclude spontaneous self-assembly in water. Nevertheless, the solute-solvent interactions associated with their highly favorable solvation enthalpies impose substantial entropic costs, similar in magnitude to those that drive the hydrophobic assembly of alkanes. We now show that under nanoconfined conditions this normally dormant "hydrophobicity" can emerge as the driving force for alcohol encapsulation. Using a porous molecular capsule, the displacement of endohedrally coordinated formate ligands (HCO₂^-) by 1,2-hydroxyl-functionalized l-glycerate (l-gly, l-HOCH₂(HO)CHCO₂^-) was investigated by van't Hoff analysis of variable-temperature ¹H NMR in D₂O. At pD 5.8, l-gly uptake is enthalpically inhibited. Upon attenuation of this unfavorable change in enthalpy by cosequestration of protons within the alcoholic environment provided by encapsulated diol-functionalized ligands, -TΔS° dominates over ΔH°, spontaneously filling the capsule to its host capacity of 24 l-gly ligands via an entropically driven hydrophobic response.

Full text of DOI:10.1021/jacs.9b03542

Communication
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Cite This: J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
Alcohols as Latent Hydrophobes: Entropically Driven Uptake of 1,2-
Diol Functionalized Ligands by a Porous Capsule in Water
‡
†
§
Sourav Chakraborty,†,∥ Alina Shnaiderman Grego,†,∥ Somenath Garai, Mark Baranov, Achim Muller,
̈
and Ira A. Weinstock*,†
†Department of Chemistry and the Ilse Katz Institute for Nanoscale Science & Technology, Ben-Gurion University of the Negev,
Beer Sheva 84105, Israel
‡Department of Chemistry, National Institute of Technology, Tiruchirappalli, TN-620015, India
§Faculty of Chemistry, University of Bielefeld, Bielefeld 33501, Germany
S
* Supporting Information
as consummate hydrophiles.4 As such, the use of alcohols in
ABSTRACT: Alcohols, with hydroxyl groups composi-
tionally identical to water itself, are consummate hydro-
philes, whose high solubilities preclude spontaneous self-
assembly in water. Nevertheless, the solute−solvent
interactions associated with their highly favorable
solvation enthalpies impose substantial entropic costs,
similar in magnitude to those that drive the hydrophobic
assembly of alkanes. We now show that under nano-
confined conditions this normally dormant “hydro-
phobicity” can emerge as the driving force for alcohol
encapsulation. Using a porous molecular capsule, the
displacement of endohedrally coordinated formate ligands
supramolecular chemistry is dominated by their enthalpically
driven self-assembly in organic solvents, for example, in the
formation of numerous cages and containers held together by
hydrogen bonds.5,6 In this context, the binding of saccharides
to natural and synthetic lectins7 is generally attributed to
enthalpically favorable van der Waals and related C−H−π
interactions,8−10 involving hydrocarbon components of the
alcoholic substrates.
At the same time, the dissolution of polyols in water is
accompanied by large decreases in entropy,11 nearly indis-
tinguishable in magnitude (kcal mol−1) from those associated
with similarly sized hydrocarbons. As such, correspondingly
large gains in entropy would drive polyol sequestration from
water, if not prohibited by their even larger enthalpies of
hydration. This leads to the intriguing conclusion that
attenuation of the unfavorable enthalpy change associated
with the removal of polyols from water should trigger their
entropically driven sequestration.
−
(HCO2 ) by 1,2-hydroxyl-functionalized L-glycerate (L-
−
gly, L-HOCH2(HO)CHCO2 ) was investigated by van’t
Hoff analysis of variable-temperature 1H NMR in D2O. At
pD 5.8, L-gly uptake is enthalpically inhibited. Upon
attenuation of this unfavorable change in enthalpy by
cosequestration of protons within the alcoholic environ-
ment provided by encapsulated diol-functionalized
ligands, −TΔS° dominates over ΔH°, spontaneously
filling the capsule to its host capacity of 24 L-gly ligands
via an entropically driven hydrophobic response.
We report precisely this phenomenon. Documented for
uptake of 1,2-diol-functionalized L-gly ligands by a tunable
porous capsule (Figure 1), it represents a new type of reaction
under confined conditions. Notably, this finding provides a
new perspective on design considerations for hydrophile
encapsulation in host−guest chemistry.
ater-mediated noncovalent interactions play a central
Wrole in numerous biological and chemical processes,
and in supramolecular assembly. Among this broad class of
interactions, hydrophobic effects control biological processes
such as protein folding, substrate recognition and binding, and
formation of cell walls from amphiphilic phospholipids.1 In
chemistry, they drive the self-assembly of hydrocarbons and
amphiphiles into a wide range of diverse structures, and
provide a basis for numerous host−guest phenomena.2
Moreover, it is now recognized3 that hydrophobic effects
include an increasingly large family of related phenomena,
encompassing, for example, entropically driven hydrocarbon
aggregation, van der Waals interactions between aromatic (π)
and alkane components in supramolecular host−guest
chemistry, and the enthalpically driven release of high-energy
water upon substrate binding to enzyme active sites.
Figure 1. (A) Metal-oxide framework of 1, shown in polyhedral
notation, composed of 12 {(Mo)Mo5}-type pentagonal units (in cyan
and blue) and 30 dimolybdenum {MoV } linkers (in red). (B)
2
Representative 1H NMR spectrum of {1(formate)19(L-gly)9}40− at pD
5.8. The broad signals arise from the endohedrally coordinated ligands
inside 1.
Alcohols by contrast, including saccharides, whose −OH
groups are compositionally identical to water itself, are viewed
Received: April 2, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.9b03542
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Journal of the American Chemical Society
Communication
The porous capsule (Figure 1A)12 is a (penta-
added to the formate form of 1, to give {1(HCO2)25}37− plus
20 equiv of formate in bulk solution. Then, L-glyceric acid was
added incrementally (up to 44 equiv), and its uptake was
followed by 1H NMR in D2O. (Although pD values are
reported throughout the text, deuterons are referred to for
simplicity as protons.) Dramatically favorable uptake was
observed (red squares in Figure 3A), very similar to that
g o n )
( l i n k e r )
- t y p e
2
c o m p l e x ,
1 2
3 0
13−23
[{MoVI6O21(H2O)6}12{(MoV O4)30(RCO2)30}]42−
,
ab-
breviated as {1(RCO2)30}42−, where 1 refers to the soluble
capsule’s inorganic framework and RCO2 are carboxylate
−
ligands, bound via η2-μ2 (bidentate) coordination to the
MoV O4 (i.e., {MoV }) linkers (Figure 1B). The structural
2
2
organization of the pentagons and linkers gives rise to 20
metal-oxide {Mo9O9} pores that provide access to the capsule’s
interior. Notably, the interior of 1 is large enough to
accommodate 24 L-gly ligands, while it is small enough to
allow for stabilizing interactions between them.
In an equilibrated system containing 29 total equivalents of
each ligand type (“in” and “out” combined) at 298 K (25 °C)
at pD 5.8, 19 formate and 9 L-gly ligands were observed inside
1
1 by H NMR (i.e, {1(formate)19(L-gly)9}40−; Figure 1B). As
the temperature was decreased to 283 K, the number of
internally bound L-gly ligands decreased to ca. 3, while upon
increase of the temperature to 323 K (50 °C) the capsule was
filled to near capacity with ca. 24 L-gly and only 4 formate
ligands (Figure 2A).
Figure 3. (A) Equivalents of glycolic, L-lactic and L-glyceric acids
outside 1, and of their conjugate anions bound inside 1, as each acid
was added to [1(formate)25]37−. (B) Equivalents of L-gly ligands
inside 1 (initially at pD 5.8) as HCl was added to decrease the pD to
3.0 (left side), after which NaOH was added to return the pD to 5.8
(right side). (C) Shift in the zeta potential (ζ) of 1 as the pD was
decreased from 5.4 to 3.3.
Figure 2. (A) Equivalents of formate and L-gly ligands inside 1 as the
temperature is increased from 10 to 50 °C at pD 5.8. (B) van’t Hoff
plot of the temperature dependence of K (for the data in panel A; K is
defined below).
reported for the entropically driven uptake of n-butyrate anions
by 1, which give an encapsulated micelle-like aggregate
comprised of 24 ligands (with 72 CH3− and − CH2−
groups).24 To assess the role of the two OH- groups on L-gly,
glycolic and L-lactic acids (HOCH2CO2H and L-CH3(HO)-
CHCO2H, respectively), were also investigated. Uptake of L-
gly anions was preferred over both (Figure 3A) (section S1.1
and Figures S1−S4).
The highly favorable uptake observed upon addition of L-
glyceric acid was investigated by incrementally adding HCl to a
pD 5.8 solution of {1(formate)19(L-gly)9}40−, which contained
29 equiv, each (total of “in” and “out”), of formate and L-
glycerate anions (Na+ forms). As the pD was decreased to 3.0,
the capsule became populated by 24 L-gly ligands, the
maximum number found to fit inside 1 (left side of Figure
3B). The process was also reversible: subsequent return to pD
5.8 (via addition of NaOH) led to a decrease in the number of
internally bound L-gly ligands, from 24 back to 9 (right side of
Figure 3B and section S1.2). These observations suggested that
added H+ might be cosequestered inside 1.
In line with this, the zeta potential of 1 shifted from −31 to
−10 mV as added HCl decreased the pD from 5.4 to 3.3
(Figure 3C). Importantly, the acid-induced uptake of L-gly
ligands led to a one-to-one displacement of formate anions, so
that at each pD value 28 anionic ligands were bound inside 1
(Figures 3C and S5). As such, the ligand-exchange process
itself did not alter the total charge of the capsule. Rather, the
shift to less negative ζ values points to H+ sequestration. The
process was reversible, with ζ returning to −31 mV as NaOH
This temperature-induced uptake of L-gly demonstrates the
positive (favorable) change in entropy associated with its
removal from bulk water. Moreover, the slope of the plot in
Figure 2A is effectively unity, indicating that the associated
change in populations of internally bound ligands occurs via
one-to-one exchange. As such, the equilibrium constant, K, is
defined by a mass balance expression (eq 1):
K = [formate(out)][
L
‐gly ]/[formate(in)][
L
‐gly
]
(in)
(out)
(1)
Importantly, the exchanging carboxylate ligands are
conjugate bases of acids with nearly identical pKa values, 3.7
and 3.5, respectively, for formic and L-glyceric acid, such that
the difference in the Gibbs free energies associated with their
coordination to {MoV } linkages in 1 is very small. (For
2
experiments in D2O, pKa values of 3.5 and 3.3, respectively,
were used.) van’t Hoff analysis24−26 of the temperature
dependence of K (Figure 2B) thus reveals the changes in
entropy and enthalpy associated with solvation of the two
ligand types in bulk water, versus within the ca. 15 000 Å3 host
domain27 inside 1. At pD 5.8, ΔH°, −TΔS°, and ΔG° for the
displacement of formate from 1 by L-gly were found to be
+33.7, −33.0, and 0.7 kcal mol−1, respectively, giving K = 0.29.
Notably, without the favorable change in entropy, K (based on
ΔH° alone) would be ca. 10−25
!
When L-glyceric acid (rather than its Na+ salt) was added to
the formate form of 1, uptake of the L-gly anion was
surprisingly favorable. First, formate buffer (pD 4.1) was
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DOI: 10.1021/jacs.9b03542
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Journal of the American Chemical Society
Communication
addition shifted the mix of ligands inside 1 back to original
values of 13 L-gly and 15 formate (Figure 3C). (In a control
experiment involving Na341(acetate)22, the decrease in the pD
from 5.4 to 3.3 caused no change in ζ; see section S1.3.)
Quantitative support for H+ sequestration was provided by
using the Henderson−Hasselbalch equation28−30 to calculate
concentrations of the carboxylic acids and their conjugate-base
anions in bulk water outside 1. As HCl was added, leading to
larger numbers of L-gly ligands inside 1, the added protons (left
in Figure 4A) could not be accounted for by hydronium ions
Figure 5. (A) Structure of 1 (in ball and stick notation, with Mo in
blue and O in red), with space-filling representations of internally
bound L-gly. (B) Side view of a {Mo9O9} pore, highlighting short H-
bonded distances (Å) from α-hydroxyl O atoms of L-gly (in red) to O
atoms (in green) of nearby water or hydronium-ion dimers, H4O2 or
+
H5O2 .
strength H-bonds (Figure 5B) (section S1.5 and Figures S8−
S15).
Finally, the effect of cosequestered protons on the energetics
of L-gly self-assembly was investigated by van’t Hoff analysis at
pD values of from 5.8 to 3.0 (Figure 6A). At each pD value,
Figure 6. (A) Plot of ΔH°, −TΔS°, and ΔG° (kcal mol−1) for L-gly
uptake by 1, at pD 5.8 to 3.0. (B) Corresponding equilibrium
constants, K (298 K), for L-gly uptake, determined from the ΔG°
values in panel (A). Data markers are color-coded to match
correspondingly colored entries in Figure 4.
Figure 4. (A) Proton allocations from Henderson−Hasselbalch
analysis. The leftmost and central sets of values are concentrations of
added HCl and protons in formate and L-glycerate buffers outside 1.
Unaccounted for protons (far-right) were sequestered by 1. (At pD
5.4, 13, L-gly inside 1, the capsule acts as a polyprotic aqua acid,
supplying two protons per capsule; see ref 31.) (B) Ratios of H+(in) to
L-gly(in) as a function of pD. Colors of the filled circles match
identically color-coded regions in panel (A). The value at pD 5.8
(asterisk) was estimated.
temperature variation (10−50 C°) resulted in one-to-one
displacements of formate by L-gly, such that K was defined as
in eq 1 (section S1.6 and Figures S16−S27).
As the pD was decreased, ΔH° values were attenuated by
proton solvation within the increasingly alcoholic environment
within 1,36,37 while −TΔS° decreased more gradually due (at
least in part) to increasingly restricted degrees of freedom of
the L-gly ligands as they filled the capsule’s interior. At pD 3.0,
−TΔS° (−18.5 kcal mol−1) dominated over ΔH° (+16.3 kcal
mol−1), triggering the spontaneous uptake of 24 L-gly ligands
(in total) via an entropically driven hydrophobic effect,
characterized by an overall 150-fold increase in K from 0.29
to 43.9 (Figure 6B; see also Tables S14−15 and Figure S28).
The data reported here show that, under confined
conditions, the large entropic costs associated with the
dissolution of nominally hydrophilic molecules in water can
be utilized to drive their self-assembly. This is achieved using
the porous capsule, 1, as a versatile molecular container for
rationally attenuating the enthalpic cost associated with the
uptake of 1,2-diol functionalized L-gly ligands and, simulta-
and carboxylic acids in bulk solution (Figure 4A, center).
These “missing” protons were allocated to sequestered H+ ions
(right in Figure 4A).
At pD 5.8, the total H+ concentration was small, and only
nine L-gly ligands were found within 1. As the pD was
decreased, the number of L-gly ligands inside 1 increased, as
did the H+:L-gly ratio (Figure 4B), which increased to ca. 1:1
(red-filled circles), as the capsule approached its host capacity
of 24 L-gly ligands (section S1.4 and Figures S6−S7).
Crystallographic data were consistent with the presence of
excess protons within the aqueous-alcoholic environment
provided by encapsulated L-gly ligands and proximal water
+
molecules. Dark brown rhombohedral crystals of 1 (Me2NH2
̅
salt; space group R3, CCDC-1878439) were grown in the
presence of a large excess of pH-3 L-glycerate buffer. In line
with 1H NMR signal intensities, X-ray crystallographic data32,33
indicated the presence of 24 L-gly ligands, each coordinated to
1
neously, as a diamagnetic framework for precise H NMR
analysis of how equilibrated populations of encapsulated
ligands change with temperature. The findings shed new
light on future prospects for hydrophile self-assembly in water.
Namely, creative options for attenuating unfavorable enthalpies
of guest-sequestration processes may make it possible to
one of the capsule’s 30 {MoV } linkers19,34,35 (Figure 5A).
2
Crystallographically defined conformations of L-gly ligands and
water gave hydroxyl-to-water and hydroxyl-to-hydroxyl O atom
distances between 2.8 and 3.1 Å, indicative of moderate-
C
DOI: 10.1021/jacs.9b03542
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Journal of the American Chemical Society
Communication
(12) Mu
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ller, A.; Gouzerh, P. From Linking of Metal-Oxide Building
generate entropically driven assemblies of nominally hydro-
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.9b03542.
■
S
(14) Neumann, R.; Sarma, B. B.; Avram, L. Encapsulation of Arenes
within a Porous Molybdenum Oxide {Mo132} Nanocapsule. Chem. -
Eur. J. 2016, 22, 15231−15236.
Experimental details, NMR spectra, and van’t Hoff plots
(PDF)
Crystallographic data for L-glycerate (CIF)
(15) Yin, P.; Wu, B.; Mamontov, E.; Daemen, L. L.; Cheng, Y.; Li,
T.; Seifert, S.; Hong, K.; Bonnesen, P. V.; Keum, J. K.; Ramirez-
Cuesta, A. J. X-Ray and Neutron Scattering Study of the Formation of
Core-Shell-Type Polyoxometalates. J. Am. Chem. Soc. 2016, 138,
2638−2643.
AUTHOR INFORMATION
Corresponding Author
*iraw@bgu.ac.il
ORCID
■
(16) Kopilevich, S.; Gottlieb, H.; Keinan-Adamsky, K.; Muller, A.;
̈
Weinstock, I. A. The Uptake and Assembly of Alkanes within a
Porous Nanocapsule in Water: New Information About Hydrophobic
Confinement. Angew. Chem., Int. Ed. 2016, 55, 4476−4481.
Ira A. Weinstock: 0000-0002-6701-2001
(17) Muller, A.; Gouzerh, P. Capsules with Highly Active Pores and
̈
Author Contributions
∥S.C. and A.S.G. contributed equally to this work.
Interiors: Versatile Platforms at the Nanoscale. Chem. - Eur. J. 2014,
20, 4862−4873.
Notes
(18) Robbins, P. J.; Surman, A. J.; Thiel, J.; Long, D.-L.; Cronin, L.
Use of Ion-Mobility Mass Spectrometry (IMS-MS) to Map
Polyoxometalate Keplerate Clusters and Their Supramolecular
Assemblies. Chem. Commun. 2013, 49, 1909−1911.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
̈
̈
(19) Schaffer, C.; Bogge, H.; Merca, A.; Weinstock, I. A.; Rehder, D.;
Haupt, E. T. K.; Muller, A. A Spherical 24 Butyrate Aggregate with a
I.A.W. thanks the Israel Science Foundation (170/17), S.C.
thanks the Kreitman School of Advanced Graduate Studies of
Ben-Gurion University of the Negev for a postdoctoral
fellowship, and A.M. the European Union for an Advanced
Grant.
̈
Hydrophobic Cavity in a Capsule with Flexible Pores: Confinement
Effects and Uptake−Release Equilibria at Elevated Temperatures.
Angew. Chem., Int. Ed. 2009, 48, 8051−8056.
́
́
̈
(20) Mitra, T.; Miro, P.; Tomsa, A.-R.; Merca, A.; Bogge, H.; Avalos,
ller, A. Gated and Differently
J. B.; Poblet, J. M.; Bo, C.; Mu
̈
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