Dendrimer folding in aqueous media: An example of solvent-mediated chirality switching

Article abstract of DOI:10.1002/anie.200460943

Staying in shape: The second and third generations of a new dendron system switch from left-handed to right-handed helical conformations upon a change in solvent from THF to water (picture; left). This inversion occurs in tandem with conformational shifts

Full text of DOI:10.1002/anie.200460943

Angewandte
Chemie
Conformational Analysis
Dendrimer Folding in Aqueous Media: An
Example of Solvent-Mediated Chirality
Switching**
Amanda L. Hofacker and Jon R. Parquette*
Allosteric proteins exhibit highly nonlinear responses to
external stimuli that cause small perturbations of a particular
parameter to effect very large changes in protein structure
and function.[1] This behavior is a direct consequence of the
structural cooperativity that correlates the conformational
equilibria of multiple subunits within the protein structure.[2]
Such allosteric phenomena are commonly observed in
biomacromolecules and are critical for their function. There
are relatively few synthetic materials, however, that exhibit
this conformational cooperativity.[3] The creation of such
conformational adaptability in synthetic systems requires the
allosteric transmission of local structural or chiral information
to the next hierarchical level of structural organization. We
have recently developed a dendrimeric system that adopts a
compact, helical shape governed by the syn,syn conforma-
tional preference of the pyridine-2,6-dicarboxamide repeat
unit.[4] We report herein that water-soluble versions of these
dendrons fold in water. Furthermore, the terminal penta-
ethylene glycol chains and the dendron secondary structure
exhibit highly correlated conformational equilibria. Accord-
ingly, solvent-induced conformational fluctuations of the
terminal pentaethylene glycol chains are correlated with an
inversion in the sense of helical chirality expressed by the
dendrons.[5]
Information transfer in folded synthetic systems usually
occurs through inter-[6] or intramolecularly[7] self-organized
assemblies through an ensemble of noncovalent interactions.
Polar protic solvents such as water typically disrupt hydrogen
bonding and electrostatic interactions, thereby compromising
the stability of such assemblies. For example, elements of
peptide secondary structure, independent of the global
protein structure, exhibit only marginal stability in pure
water.[8] Similarly, many synthetic foldamers exhibit less
stable conformations in water.[9] However, any potential
biological application of folded synthetic materials requires
an ability to adopt conformational order in aqueous media.
The conformational preference of the pyridine-2,6-dicar-
boxamide repeat unit in our folded dendrons is a result of
intramolecular hydrogen bonding present in the syn,syn
conformation, as well as an electrostatic destabilization of
[*] A. L. Hofacker, Prof. J. R. Parquette
Department of Chemistry, The Ohio State University
100 W. 18th Ave., Columbus, OH 43210 (USA)
E-mail: parquett@chemistry.ohio-state.edu
[**] We thank Professor Heather Allen and Dr. Gang Ma for assistance
with the IR spectroscopic studies. This work was supported by the
National Science Foundation (CHE-0239871).
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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DOI: 10.1002/anie.200460943
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the alternative syn,anti and anti,anti conformations. Previous
studies strongly suggest that tighter packing of the dendritic
chains in poor solvents plays an important role in the folded
The circular dichroism (CD) spectra of 2 featured an
intense negative couplet centered at ꢀ 316 nm (Figure 2b) in
THF and in water, the latter case being slightly lower in
magnitude relative to that from the sample in
THF. This bisignet signal results exclusively from
the excitonic coupling of the p!p* transitions of
the anthranilate chromophores, which are polar-
ized along the axis containing C3 and C6 (Figu-
re 2a).[4d] The presence of the negative couplet
indicates that the first generation dendron 2
adopts an M-type helical conformation, relating
the anthranilate chromophores in both THF and
in water. This observation highlights the impor-
tance of packing interactions in determining the
conformational properties of the dendron.
The second generation dendron 3 exhibited a negative
couplet in THF comparable in magnitude with that of
dendron 2, which also indicates an M helical bias. However,
the negative couplet was replaced by an equally intense
positive couplet in aqueous media, which indicates that an
M!P helical transition occurred in water. The third-gener-
ation dendron 4 also displayed a similar M!P helical
transition upon going from THF to water. Varying the THF/
H2O ratio for 3 and 4 at 258C revealed M!P crossover points
in the range of 10–20% THF for 3 and 30–40% THF for 4
(Supporting Information).
conformation of these dendrons.[10] Although water should
disrupt the hydrogen bonding interactions of the syn,syn
conformation and decrease the energetic cost of the larger
dipole moments of the syn,anti and anti,anti conformations,
the packing effect should nevertheless dominate, as the
propensity of hydrophobic regions to minimize their exposure
to solvent ultimately results in a hydrophobic collapse of the
dendritic structure.
Chiral pentaethylene glycol 1, prepared from ethyl l-
lactate, was installed at the periphery of the dendrons to
impart solubility in water (Figure 1).[6b,9a] Dendrons 2–4
exhibited moderate solubility in water, and excellent solubil-
ity in organic media. However, millimolar solutions of
dendrons in water exhibited a lower critical solution temper-
ature (LCST) that induced clouding and precipitation upon
heating to ꢀ 25–308C.[9a,11]
The positive components of the CD couplets in water for 3
and 4 were decreased in amplitude relative to the negative
branches at shorter wavelengths. The unsymmetrical appear-
ance of these couplets is a consequence of the increased
chromophore congestion that occurs in poor, struc-
ture-collapsing solvents and is commonly observed for
this dendrimer system.[4] Such structural congestion
induces further mixing of the couplet transitions with
other transitions within the dendron, which results in
desymmetrized couplet intensities.[12]
The amphiphilic nature of the dendrons creates a
tendency for aggregation to occur in water, and to a
lesser degree, in THF. Comparison of the hydrody-
namic radii (Rh) of 2–4, measured by DOSY NMR
spectroscopy,[13] to the calculated van der Waals
radii[14] (RvdW) indicates that significant aggregation
occurred in D2O solution,[15] whereas monomeric
species were present in [D8]THF (Table 1). Aggrega-
tion has been shown to play a significant role in the
conformational equilibria of chiral molecules[16] and
introduces the possibility for intermolecular excitonic
coupling[17] in the CD spectra. Therefore, CD and UV/
Vis spectra were recorded for 2–4 as a function of
concentration in THF and H2O (Supporting Informa-
tion). The UV/Vis and CD spectra of all dendrons
were essentially invariant over a 100-fold concentra-
tion range (10ꢁ4 to 10ꢁ6 m), thereby ruling out aggre-
gation as a source of or contributing factor to the M!
P helical inversion.
Previous vibrational spectroscopic studies showed
that poly(oxyethylene) (POE) chains experience an
ꢁ
increased preference for the C C gauche conforma-
ꢁ
Figure 1. Water-soluble dendrons with chiral, pentaethylene glycol termini.
tion, whereas only a small increase in the C O anti
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The effect of solvent on the conformational preference of
the terminal glycol chains of 3 was investigated by IR
spectroscopy with the key bands at 1355–1360 cmꢁ1 (A), and
1335–1320 cmꢁ1 (B) for the respective gauche and anti C C
ꢁ
conformations; and with those at 1310–1297 cmꢁ1 (C), and
1290–1295 cmꢁ1 (D) for the gauche and anti C O conforma-
ꢁ
tions, respectively.[18c] The disappearance of the C C anti
ꢁ
ꢁ
band (B) and the slight increase in the C O anti band (D)
upon going from [D8]THF[20] to H2O for glycol chain 1
(Figure 3a) closely mirrors the spectroscopic behavior
Figure 2. a) Direction of electronic transition dipole moments of the
p!p* transition at 316 nm and corresponding sign of CD couplet.
b) CD spectra of dendrons 2–4 in H2O and THF. Spectra are normal-
ized with respect to concentration and the number of chiral terminal
groups.
Figure 3. a) IR spectra of 1 and 3 as a function of solvent, measured
with a horizontal ZnSe crystal and a 458 single bounce attenuated total
reflection (ATR) accessory (20% [D8]THF in H2O was necessary to
attain the 25-mm concentrations of 3 required for IR spectroscopy).
b) Schematic depiction of the lowest-energy conformers of 3 (R=Me).
c) Conformation of terminal glycol chains in CHCl3 (left) and H2O
(right) as predicted by conformational searching (MM3).
Table 1: Experimentally determined (Rh) and calculated (RvdW) hydro-
dynamic radii [ꢀ]
[c]
Compound
Rh ([D8]THF[a])
Rh(D2O[b])
RvdW
2 (3.5 mm)
3 (3.6 mm)
4 (3.4 mm)
5.8
8.4
8.3
19.7
5.80
7.45
9.48
43.9[d]
52.8[e]
reported for other POE oligomers.[18] Molecular dynamics
simulations estimate that similar observations for POE
[a] DOSY NMR spectroscopy, 278C. [b] DOSY NMR spectroscopy, 108C.
[c] Van der Waals radii, calcd. [d] Measured in [D8]THF/D2O (10%).
[d] Measured in [D8]THF/D2O (2%).
ꢁ
represent an increase in the C C gauche population from
76% in benzene to 100% in water.[21] However, in contrast to
ꢁ
1, dendron 3 exhibits a significant increase in the C O anti
ꢁ
population occurs upon progression from nonpolar to aque-
band (D) as water is added, whereas the C C anti band (B) is
ous media.[18] The preferred conformation of the anti,gauche
missing from the spectra at all H2O/[D8]THF ratios.
These observations indicate that the solvation of 3 in
water induces a gauche!anti conformational shift about the
ꢁ ꢁ
O C C bond pair in water is consistent with the solid-state
structure of the POE helix.[19]
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Communications
ꢁ
ꢁ
C O bond. Furthermore, a strong preference for the C C
gauche conformation exists for the dendrons at all solvent
ratios, in contrast to the parent glycol chain 1 and POE. The
chains from gauche,gauche+,anti to anti,gaucheꢁ,anti confor-
ꢁ ꢁ ꢁ
mations around the respective O C C OMe bonds (Fig-
ure 3b). The uniformly gaucheꢂ preference of all the C C
ꢁ
ꢁ
fact that the C C gauche preference of dendron 3 is stronger
than it is for POE or 1 suggests the occurrence of correlated
motions among the terminal glycol chains that shift the
bonds in both water and CHCl3 and the corresponding
ꢁ
conformational shift of two O C bonds from gauche to anti
upon going from CHCl3 to water is consistent with the
observed vibrational data.
ꢁ
conformational equilibria toward the lower energy C C
gauche arrangement.[4c]
The results of this study demonstrate that these dendrons
not only adopt a stable folded state in aqueous media, but also
exhibit correlated chain–chain and dendron–chain conforma-
tional equilibria. The correlated chain–chain motions induce
a shift in equilibrium of the terminal chains toward the lower-
energy gauche state, in contrast to the case of an isolated
chain (1). Similarly, solvent-induced conformational fluctua-
tions of the terminal chains are coupled with
dendron helical secondary structure through cor-
related dendron–chain motions. This work suggests
the potential of folded dendrimers to exhibit
nonlinear conformational responses to localized
structural perturbations.
Monte Carlo conformational searching of 3 (R = Me) with
the GB/SA solvation model[22] predicts an M helical bias in
CHCl3 whereas a P helix is preferred in water, in accord
with the CD studies (Figure 4). Closer inspection of each of
the lowest-energy conformers reveals that the M!P helical
inversion is correlated with a shift of two of the four glycol
[23]
Received: June 11, 2004
Revised: November 5, 2004
Published online: January 5, 2005
Keywords: amphiphiles · chirality · circular
.
dichroism · dendrimers · IR spectroscopy
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