Judging on host-guest binding mode uniqueness: Association entropy as an indicator in enantioselection

Article abstract of DOI:10.1021/ol0605575

Supramolecular enantiodifferentiation was studied by isothermal titration calorimetry in an effort to address the order-disorder distinction in the diastereomeric complexes formed from a chiral macrocyclic host and enantiomeric carboxylates. As a result,

Full text of DOI:10.1021/ol0605575

ORGANIC
LETTERS
2
006
Vol. 8, No. 11
329-2332
Judging on Host−Guest Binding Mode
Uniqueness: Association Entropy as an
Indicator in Enantioselection
Vinod D. Jadhav and Franz P. Schmidtchen*
2
Department of Chemistry, Technical UniVersity of Munich, Germany
schmidtchen@ch.tum.de
Received March 7, 2006
ABSTRACT
Supramolecular enantiodifferentiation was studied by isothermal titration calorimetry in an effort to address the order−disorder distinction in
the diastereomeric complexes formed from a chiral macrocyclic host and enantiomeric carboxylates. As a result, the association entropy
component T S emerged as an indicator in the enantioselection of tartrate 14 and aspartate 15 by the macrocycle 13 containing two guanidinium
∆
anchor groups connected to each other by four urea units. The parent monotopic guanidinium compounds 1 or 2 did not show any
enantioselection for chiral carboxylates.
-6
Structural definition in host-guest binding is a decisive
determinant of function as has been amply demonstrated in
biological systems. Correspondingly, the design of abiotic
systems targeting molecular recognition a priori presumes
the formation of a unique complex structure on host-guest
association, in general without proving the validity of this
assumption. The requisite order-disorder distinction cannot
be assessed easily by the ordinary tools of structure elucida-
tion due to rapid structural averaging in a solution phase. In
some cases, however, the cautious interpretation of thermo-
dynamic state functions, in particular of the entropy and heat
capacity of association promises a remedy.1
tiorecognition of chiral carboxylate anions.4 The most
successful cases exploit the coordination of R-functionalized
carboxylates such as mandelate or R-amino acid anions at
transition metal cationic sites supporting the suspicion that
the structure generating influence of partly covalent metal
(1) (a) Schmidtchen, F. P. Top. Curr. Chem. 2005, 252, 1-29. (b)
Schmidtchen, F. P. Coord. Chem. ReV. Submitted for publication.
(
2) (a) Jadhav, V. D.; Schmidtchen, F. P. Org. Lett. 2005, 7, 3311-
3
314. (b) Haj-Zaroubi, M.; Schmidtchen, F. P. ChemPhysChem 2005, 6,
181-1186.
1
(
3) Davis, A. P. Chiral Guest Recognition. In Encyclopedia of Supramo-
lecular Chemistry; Steed, J., Atwood, J.,Eds.; Dekker: New York, 2004;
Vol. 1, pp 236-244.
,2
(
4) Stibor, I.; Holakovsky, R.; Mustafina, A. S. R.; Lhotak, P. Collect.
One of the most prominent applications is the supramo-
lecular enantiodiscrimination, which is well recognized to
vitally depend on differential structuring of the host-guest
Czech. Chem. Commun. 2004, 69, 365-383.
(5) Yang, D.; Li, X.; Fan, Y.-F.; Zhang, D.-W. J. Am. Chem. Soc. 2005,
1
27, 7996-7997.
6) Alfonso, I.; Dietrich, B.; Rebolledo, F.; Gotos, V.; Lehn, J.-M. HelV.
Chim. Acta 2001, 84, 280-295.
(
3
aggregates. Particularly relevant examples address the enan-
1
0.1021/ol0605575 CCC: $33.50
© 2006 American Chemical Society
Published on Web 04/28/2006

pensation that is frequently observed in supramolecular
1
6
interactions. The chiral centers appear too remote in the
complexes to influence each other. A similar conclusion was
reached on interaction of a set of tetra-substituted bicyclic
1
3
guanidinium hosts with benzoate.
Both guanidinium compounds exhibit clean 1:1 stoichio-
metric binding which is driven by negative enthalpies and
positive entropies the latter contributing the respectable share
of about 30% to the free energy of binding. The enhanced
affinity by a factor of 3 shown by 2 may be attributable to
an additional hydrogen bond formed between the hydroxy-
methylene substituent of this host and the carboxylate anion.
The supplementary attraction surfaces as a substantially
more negative enthalpy that is partially balanced by a
decrease in the entropy term suggesting marginally more
restricted association modes.
Figure 1. Idealized recognition motif of carboxylates to bicyclic
guanidinium anchor groups.
7
ion coordination is a decisive factor. Truly noncovalent
binding has been achieved, e.g., with appropriately substi-
tuted chiral guanidines,8
-11
but the enantiorecognition re-
tained a somewhat adventitious character and did not reach
preparatively useful levels. In no case was the energetics
explored to evaluate the origin of the confusing results. To
understand the principles governing enantiodifferentiation of
carboxylates by chiral guanidines and delineate guidelines
for their further development we determined the thermody-
namic state functions in associations with the well-established
bicyclic guanidinium anchor group (Figure 1) in acetonitrile
solution.12
1
The observation of two diastereomeric complexes by H
NMR in the interaction of the chiral guanidinium silyl ether
12
1
with N-acetyl-D,L-alanine 3a/3b fostered the hope to find
different energetic signatures in the host-guest binding of
or 2 with the enantiomeric mandelates 4a, 4b. The
1
individual calorimetric determinations, however, revealed no
differential effect (Table 1). The affinities (∆G) as well as
The results indicated that recognition of the spatial layout
of R-chiral carboxylates required complexation in a more
confined binding pocket. As a straightforward consequence,
we envisaged the construction of the macrocycle 13 contain-
ing two chiral guanidinium anchor groups connected to each
other by 4 urea units that were supposed to assist in the
Table 1. Energetics of Host-Guest Binding of 1 I- and 2
-
ClO
4
with D- and L-Mandelate 4a/4b (Tetraethylammonium
Salts) in Acetonitrile at 298 K
1
4
complexation of carboxylate anions. Molecular modeling
using the Hyperchem 7.0 package (Amber force field)
revealed the risk that the individual urea groups might engage
in intramolecular hydrogen bonding and thus diminish the
affinity for a guest anion (cf. Figure 2). In addition, the
macrocycle turned out to be rather flexible despite the
presence of many rotationally restricted bonds. However,
with respect to the nominal dimensions macrocycle 13 was
guest
Kassoc (M-1)
∆Go a
∆Ho a
T∆So a
4
1
2
4a
2.8 x 10
2.2 x 10
7.2 x 10
-25.4
-24.8
-27.7
-27.6
-16.5
-16.3
-20.5
-20.3
+9.0
+8.6
+7.2
+7.4
4
4b
4
4a
4
4b
7.0 x 10
a
kJ mol-1
.
4
judged suitable to bind C -carboxylic acid anions which
the component enthalpies and entropies seen in clean 1:1
stoichiometric complex formations are the same within
experimental error. Clearly, the lack of enantiodiscrimination
in these cases does not arise from enthalpy-entropy com-
constitute a prominent subset of the natural chiral pool. The
building blocks necessary for macrocyclization by amine-
to-isocyanate addition were prepared from 1 and from
commercial nitroisophthalic acid as depicted in Scheme 1.
The final one-step-cyclization furnished the target compound
in 10% yield as the iodide salt after chromatographic isolation
and purification.
Taking isothermal titration calorimetry as a sensitive
analytical tool the complexation characteristics of the bis-
guanidinium macrocycle 13 with a series of simple oxo-
(7) (a) Folmer-Andersen, J. F.; Lynch, V. M.; Anslyn, E. V. J. Am. Chem.
Soc. 2005, 127, 7986-7987. (b) Zhu, L.; Zhong, Z., Anslyn, E. V. J. Am.
Chem. Soc. 2005, 127, 4260-4269.
(8) Echavarren, A.; Gal a´ n, A.; Lehn, J.-M.; de Mendoza, J. J. Am. Chem.
Soc. 1989, 111, 4994-4995.
(
9) Corey, E. J.; Grogan, M. J. Org. Lett. 1999, 1, 157-160.
(10) (a) Kumamoto, T.; Ebine, K.; Endo, M.; Araki, Y.; Fushimi, Y.;
Miyamoto, I.; Ishikawa, T.; Isobe, T.; Fukuda, K.. Heterocycles 2005, 66,
3
2
47-359. (b) Isobe, T.; Fukuda, K.; Araki, Y.; Ishikawa, T. Chem. Commun.
001, 243-244.
(13) Haj-Zaroubi, M.; Mitzel, N.; Schmidtchen, F. P. Angew. Chem.,
Int. Ed. 2002, 41, 104-107.
(14) (a) Brooks, S. J.; Edwards, P. R.; Gale, P. A.; Light, M. E. New J.
Chem. 2006, 30, 65-70. (b) Chmielewski, M.; Jurczak, J. Chem. Eur. J.
2005, 11, 6080-6094.
(11) Chincilla, R.; N a´ jera, C.; S a´ nchez-Agull o´ , P. Tetrahedron: Asym-
metry 1994, 5, 1393-1402.
12) Gleich, A.; Schmidtchen, F. P.; Mikulcik, P.; M u¨ ller, G. J. Chem.
Soc., Chem. Commun. 1990, 55-57.
(
2330
Org. Lett., Vol. 8, No. 11, 2006

Scheme 1a
Figure 2. Energy-minimized structure of the macrocycle 13 using
the Amber force field in vacuo. Two urea subunits pair by hydrogen
bonding leading to a collapse of the macrocyclic cavity.
dianions of varying dimensions was undertaken (cf. Table
2). Compared to similar studies of host-guest binding of
Table 2. Energetics of Dianion Binding (Tetraethylammonium
Salts) to Macrocycle 13 in Acetonitrile at 298 K (Stoichiometry
n Refers to the Number of Stepwise Association Constants)
o
o
o
K
assoc
(M )
∆G
∆H
T∆S
guest
modela
-1
(kJ mol ) (kJ mol ) (kJ mol-1)
-1
-1
2
-
6
5
1
2
3
squarate
A, n ) 2 6.5 × 10
A, n ) 2 6.4 × 10
no sufficient
-38.9
-33.1
-14.2
-21.4
+24.6
+11.9
2
-
oxalate
2
-
malonate
heat effect
2
-
-
6
7
4
5
4
5
4
5
6
7
8
9
succinate
B, n ) 1 1.8 × 10
C, n ) 1 1.7 × 10
C, n ) 2 8.7 × 10
-35.8
-41.2
-28.1
-32.5
-25.4
-31.8
-7.0
-52.8
-8.3
+28.8
-11.5
+19.8
+27.3
-25.4
+5.2
2
fumarate
glutaconate2 C, n ) 1 5.0 × 10
t,t-muconate2 A, n ) 2 3.8 × 10
-
-5.2
C, n ) 2 2.9 × 10
-50.9
-26.7
-
a
A ) titration mode: host into guest solution; one-site-model; ligand-
in-cell; guest/host stoichiometry ) n, B ) titration mode: guest into host
solution; one-site-model; guest/host stoichiometry ) n, C ) titration mode:
host into guest solution; two sequential site model; ligand-in-cell.
a
3 2 3
Key: (i-iii) fluoride/polymer, THF, rt, 12 h; CH SO Cl/Et N,
CH
2
Cl
2
, 0 °C, 30 min; NaN
, CH
51%; (vi) (CH
C, 1 h, 70%; (viii) EDIPA, CH
3
, DMF, 90 °C, 12 h, overall 60%; (iv)
Pd-C/H
2
3
OH, rt, 3 h, 95%; (v) (COCl)
SiN , CH Cl , rt, 16 h, 92%; (vii) toluene, 110
CN, -10 °C, 10%.
2 2 2
, CH Cl , rt, 22 h,
dianions to hydrogen bond donor macrocycles14b,15 which
generally show a clean correlation with guest dimensions,
the binding patterns in the present case were considerably
more subtle and contained some unexpected clues. Titrating
the macrocyclic host 13 into a solution of the guest dianions
3
)
3
3
2
2
°
3
example comprising squarate, succinate, and one binding step
each of fumarate and glutaconate a small exothermicity
(as tetraethylammonium salts) at submillimolar concentra-
(-∆H) is fortified by a large and positive entropic contribu-
tions to promote complete dissociation of the salts the
formation of higher order complexes in addition to regular
tion to yield quite high affinities (-∆G). In essence, such a
signature resembles unspecific ion-pairing which typically
emerges from minute structuring in the associated molecular
species. Somewhat lower association entropies accompanied
by substantially more negative enthalpies are exhibited by
oxalate (entry 2) and trans,trans-muconate (entry 9), sug-
gesting more intimate structuring but, however, a definite
global misfit of host and guest as clean 1:2 host-guest stoi-
chiometries are maintained. The energetic scenario is dra-
matically changed in the case of the rigid olefinic dicar-
boxylates fumarate (entry 5) and glutaconate (entry 8), both
featuring a massive exothermic binding step that is coun-
teracted to some extent by a strongly negative entropy
component. The free energy outcome as a merger of both
contributions leaves fumarate as the example of highest
1:1 binding was invariably observed.
Depending on the absolute difference in the free energies of
the individual steps the titration curve displayed an ordinary
sigmoidal shape, however, possessing the inflection point at
a 1:2 host-guest molar ratio when the affinities were rather
similar. Differences in binding constants of more than a factor
of 10 resulted in distorted shapes that were fitted conve-
niently to a two-site sequential-binding model.
Except for malonate, which eluded the analysis due to in-
sufficient heat evolution, three distinct energetic patterns
could be distinguished within the guest series. In the first
(15) Hosseini, Mir W.; Lehn, J.-M. HelV. Chim. Acta 1986, 69, 587-603.
Org. Lett., Vol. 8, No. 11, 2006
2331

Table 3. Energetics of Enantioselective Binding of Tartrates and Aspartates (as Tetraethylammonium Salts) to Macrocycle 13 in
Acetonitrile at 298 K
∆
Go
∆Ho
(kJ mol-1)
T∆So
(kJ mol-1)
entry
guest
modela
Kassoc (M-1
)
(kJ mol-1)
L-tartrate2 14a
-
A, n ) 1.0
A, n ) 1.0
A, n ) 2.8
A, n ) 3.0
3.1 × 10
6
-37.0
-33.9
-32.0
-31.9
-40.5
-45.0
-34.5
-30.1
-3.4
-11.0
-2.5
1
2
3
4
2
-
5
D-tartrate 14b
8.8 × 10
1
-
5
L-aspartate 15a
4.1 × 10
1
-
5
D-aspartate 15b
3.9 × 10
+1.8
a
A ) titration mode: host into guest solution; one-site-model; ligand-in-cell; guest/host stoichiometry ) n.
affinity in this series while glutaconate having just one
methylene group more than the former shows much dimin-
ished affinity. Comparing the energetics of both dianions to
succinate as the closest congener leads to the conclusion that
plain solvation effects cannot account for the differences
found. Apparently, there is an interaction mode common to
all three species (entries 4, 6, and 7) featuring moderately
negative enthalpies and large positive entropies indicative
of extensive desolvation of host and guest on unspecific com-
plex formation. Additionally, the olefinic substrates fumarate
and glutaconate appear to conquer the sticky hydrogen-
bonding sites of the host in a fashion that freezes internal
motility in the complexes leading to very restricted structural
variability concomitant with strongly negative entropies. The
occurrence of this mode does not correlate with affinity and
cannot be read from the magnitude of the binding constant.
Hence, in the case of fumarate strong structural dedication
of both host-guest partners as indicated by a negative
association entropy (entry 5) apparently enables a large
binding enthalpy resulting in the highest association constant
found in this series. To reach a similar extent of dedicated
host-guest attraction the {glutaconate ⊂ 13} complex must
lose even more degrees of freedom in configurational/
conformational space as is read from the more negative
entropy component (entry 8). The merger of both contribu-
tions (∆G ) ∆H - T∆S) renders a smaller affinity (∆G)
than is even seen in the ion-pairing mode (entry 7). A naive
and innocent comparison of the stepwise constants not only
would relate incompatible binding modes of both guests, but
also is prone to misassign the structurally best defined
complex as this is the one of weakest affinity (entry 8).
Yet, the uniqueness of the binding mode is considered a
decisive determinant in the differentiation of geometric
configurations as in enantiomeric discriminations. A corre-
sponding analysis involving the macrocycle 13 and the
enantiomeric tartrates 14 and aspartates 15, respectively, is
collected in Table 3. With respect to the assignment of a
better or worse fit in the diastereomeric host-guest com-
plexes the evaluation of chiral recognition holds the virtue
of bona fide independence from solvation effects. The
starting situation (before complexation) is exactly alike for
both enantiomers and also the complexed states are very
similar since they are identical in chemical nature and in
the number of functional groups and the overall sizes must
be very close. Thus, any differences in the observed entropies
of association rather reflect changes in the configurational
entropy in the diastereomeric complexes and address the
bilateral structuredness. In this sense, tartrate exhibits a
-
1
respectable effect, the T∆∆S reaching 7.6 kJ mol (Table
3) that, taken alone, would translate into a factor of 20 in
enantiodifferentiation. Enthalpy-entropy compensation,16
however, almost annihilates the entropic advantage leaving
just a factor of 3.5 in the association constants at ambient
temperature. If the initial premise holds that the observable
entropy is dominated by the configurational component this
leads to an amazing conclusion: The complex of better
geometrical fit (lower entropy of association, entry 2)
displays weaker affinity than the more disordered counterpart.
Thus, if structuredness is the determining factor in enan-
tiodifferentiation, maximizing host-guest affinity is a false
trait to reach this goal.
A similar energetic result was obtained on titrating the
aspartate monoanions with host 13. Again the difference in
structural order between the diastereomeric complexes
surfaced as a gap in entropy (T∆∆S) which was readily
closed by a compensating enthalpy effect that left no
significant free energy difference in the final outcome. The
1:2 host-guest stoichiometry found proves that both com-
plexes are composed as ternary species. Most likely, the
chiral macrocycle 13 complexes a dimer of the aspartate
formed by intermolecular multiple hydrogen bonding be-
tween the carboxylic acid and amine moieties in acetonitrile.
Calorimetric analysis of host-guest binding using sets of
closely related substrates can unfold the order-disorder
problem that is crucial to supramolecular design in structure-
based applications such as assembly or enantiodifferentiation.
In special instances the uniqueness of the host-guest binding
mode may no longer remain a credulous assumption, but
can be put on a well-founded experimental footing.
Acknowledgment. This work was supported by grants
from Deutsche Forschungsgemeinschaft and by Hans-
Fischer-Gesellschaft, Munich.
Supporting Information Available: Experimental pro-
cedure, analytical data for the macrocycle 13, and isothermal
calorimetric titration experimental graphs corresponding to
the entries depicted in Tables 1-3. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL0605575
(
16) (a) Dunitz, J. D. Chem. Biol. 1995, 2, 709-712. (b) Exner, O. Chem.
Commun. 2000, 1655-1656.
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Org. Lett., Vol. 8, No. 11, 2006