Structural effects on encapsulation as probed in redox-active core dendrimer isomers

Article abstract of DOI:10.1021/ja035515f

Three pairs of isomeric, iron - sulfur core dendrimers were prepared. Each isomer pair was distinguished by a 3,5-aromatic substitution pattern (extended) versus 2,6-aromatic substitution pattern (backfolded). Several observations were made that supported the hypothesis that the iron-sulfur cluster cores were encapsulated more effectively in the backfolded isomers as compared to their extended isomeric counterparts. The backfolded isomers were more difficult to reduce electrochemically, consistent with encapsulation in a more hydrophobic microenvironment. Furthermore, heterogeneous electron-transfer rates for the backfolded molecules were attenuated compared to the extended molecules. From diffusion measurements obtained by pulsed field gradient spin - echo NMR and chronoamperometry, the backfolded dendrimers were found to be smaller than the extended dendrimers. Comparison of longitudinal proton relaxation (T₁) values also indicated a smaller, more compact dendrimer conformation for the backfolded architectures. These findings indicated that the dendrimer size was not the major factor in determining electron-transfer rate attenuation. Instead, the effective electron-transfer distance, as determined by the relative core position and mobility in a dendrimer, is most relevant for encapsulation.

Full text of DOI:10.1021/ja035515f

Published on Web 06/14/2003
Structural Effects on Encapsulation As Probed in
Redox-Active Core Dendrimer Isomers
Tyson L. Chasse, Rakesh Sachdeva, Qun Li, Zemin Li, Randall J. Petrie, and
Christopher B. Gorman*
Contribution from the Department of Chemistry, North Carolina State UniVersity, Box 8204,
Raleigh, North Carolina 27695-8204
Received April 7, 2003; E-mail: chris_gorman@ncsu.edu
Abstract: Three pairs of isomeric, iron-sulfur core dendrimers were prepared. Each isomer pair was
distinguished by a 3,5-aromatic substitution pattern (extended) versus 2,6-aromatic substitution pattern
(backfolded). Several observations were made that supported the hypothesis that the iron-sulfur cluster
cores were encapsulated more effectively in the backfolded isomers as compared to their extended isomeric
counterparts. The backfolded isomers were more difficult to reduce electrochemically, consistent with
encapsulation in a more hydrophobic microenvironment. Furthermore, heterogeneous electron-transfer rates
for the backfolded molecules were attenuated compared to the extended molecules. From diffusion
measurements obtained by pulsed field gradient spin-echo NMR and chronoamperometry, the backfolded
dendrimers were found to be smaller than the extended dendrimers. Comparison of longitudinal proton
relaxation (T1) values also indicated a smaller, more compact dendrimer conformation for the backfolded
architectures. These findings indicated that the dendrimer size was not the major factor in determining
electron-transfer rate attenuation. Instead, the effective electron-transfer distance, as determined by the
relative core position and mobility in a dendrimer, is most relevant for encapsulation.
solution and in thin film form.7 The shielded redox unit also
can be used to study behaviors relevant to metalloprotein
Introduction
Encapsulating a functional moiety within a dendrimer leads
to several novel properties. These include modulation of the
rate and driving force for electron transfer, attenuation of the
rates of luminescence quenching, and modulation of catalytic
behaviors of the core.1-4 It is still unclear, however, how the
primary structure of the dendrimer biases its conformation and
how the conformation of the dendrimer influences these
encapsulation behaviors.
Redox-active core dendrimers are particularly suited to study
dendritic encapsulation. We recently showed how rates of
electron transfer could be varied in iron-sulfur cluster core
dendrimers that alternatively contained flexible and rigid
linkages.5 The paramagnetic nature of the iron-sulfur cluster
could also be used to elucidate features of the dendrimer
conformation via NMR relaxation measurements.6 The distance
of electron transfer and the material surrounding the core
governs electron-transfer rate. This distance can be changed by
increasing the mass of the dendrons and/or altering the dendron
architecture, thereby biasing the dendrimer conformation to
increase encapsulation around the redox-active core moiety. The
processes that control rate and driving force for electron transfer
were also found to differ substantially between dendrimers in
mimicry1-3,8-11 and charge trapping in molecular electronics.2,12
A decisive way to probe the influence of structure on
encapsulation via conformation is through the study of consti-
tutional isomers. The synthesis13,14 and study of dendrimer
isomers has had some precedent including the study of linear
versus hyperbranched structures,15,16 supramolecular organiza-
tion of different dendrimer isomers,17 stereoisomers in den-
drimers (e.g., cis vs. trans azobenzene or stilbene linkages in
dendrimers),18-25 and isomeric metallodendrimers.26 Recently,
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Structural Effects on Encapsulation
A R T I C L E S
the relative rates of photoinduced, intramolecular electron
transfer of constitutional isomers of a triphenylamine core
dendrimer substituted with a peryleneimide acceptor at the
periphery were probed.27 Ideal dendrimer isomers differ only
in their primary structure. Changes in the primary structure of
the dendrimer can result in a change in its conformation (e.g.,
the disposition of the arms around the core and the relative
degree to which the core is buried in the dendrimer). This change
in conformation could be reflected in a change in the measured
degree of encapsulation of the core. For example, in the case
of an electroactive core (such as is discussed here), a change in
the kinetics and/or thermodynamics of electron transfer to/from
that core is expected.
What primary structural elements in dendrimers are most
effective at influencing the conformation of these molecules?
Several notable efforts have elucidated structure-property
relationships by changing the primary structure of the dendrons
to bias dendrimer conformation.14,28-30 Conformation can be
biased by a number of factors including the relative degree of
solvation, the presence of internal hydrogen-bonding sites,31-34
and steric factors including chiral moieties within the primary
structure.18,35-43
Figure 1. Structures of the constitutional isomeric dendrimer pairs. Each
dendrimer has the form (nBu4)2[Fe4S4D4], where D indicates a dendron
substituted with a focal aromatic thiol. For each molecule, four identical
ligands are attached to the iron-sulfur core (denoted by a circled D).
We and others36,37,44-49 have hypothesized that primary
structural elements that create backfolded linkages within the
dendrimer should increase the degree of steric congestion around
the core moiety of the dendrimer. This behavior should lead to
more effective encapsulation. To probe this hypothesis experi-
mentally, three pairs of constitutional isomeric dendrimers
(Figure 1) were synthesized and studied. These molecules allow
the direct comparison of extended and backfolded architecture
independent of the molecular weight. Here, several computa-
tional and experimental sets of data are presented to support
the conclusion that backfolded linkages in a dendrimer result
in more effective encapsulation of its core.
Results and Discussion
A. Synthesis. Each dendrimer structure synthesized consisted
of benzyl ether-based repeat units previously reported by Fre´chet
et al.50 and Rosini et al.46 Each dendrimer was synthesized using
a convergent activate/couple approach. The six molecular
structures are depicted in Figure 1. The extended and backfolded
designations refer to the aromatic substitution patterns of the
benzyl ether groups. Isomers containing 3,5-disubstituted link-
ages are designated as extended, while those containing 2,6-
disubstituted linkages are referred to as backfolded. Dendrons
focally substituted with aromatic thiols were synthesized as
described in the Supporting Information (Schemes S1-S5).
Several synthetic issues are of particular note. First, it was found
that the thiol group could be efficiently protected and depro-
tected (with silver nitrate) using a tetrahydropyranyl (THP)
group. The iron-sulfur cluster dendrimers were synthesized in
good yields using ligand-exchange around (nBu4N)2[Fe4S4(S-
t-Bu)4] as described previously.5 In addition, care had to be taken
with all molecules containing backfolded linkages due to their
susceptibility to acid cleavage of the benzyl ether groups as
detailed previously.51,52 Reaction and purification steps had to
be carried out in neutral or slightly basic conditions for these
particular compounds. All activated (halogenated) intermediates
were thus carried on without purification.
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B. Computational Conformational Searching. Before com-
mitting to the synthesis of new molecules, it was of interest to
determine, from computations, if a backfolded isomer would
provide better encapsulation than its extended counterpart.
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A R T I C L E S
Chasse et al.
Figure 2. (A) Ball and stick figures of the lowest energy conformers of models of the molecules 2,3 and 2B,3 found during a conformational search of each.
(B) Histogram counting the number of conformers found at an energy minimum and with a given core displacement (Rcore/Rg ) 0 for core at center, Rcore/Rg
) 1 for core at edge).
Previously, we showed that the conformational manifold of
dendrimers could be sketched using high-temperature, quenched
molecular dynamics. Using such a conformational search
protocol, the relative molecular size and displacement of the
core within a dendrimer could be examined.5 This technique
was applied to study models of two of the dendrimer isomerss
the molecules labeled 2,3 and 2B,3 in Figure 1. In Figure 2,
two types of data are shown that resulted from a conformational
search that tabulated 100 minimum energy structures for each
of these molecular models. Figure 2A shows ball-and-stick
models of the lowest energy conformations of each of the
dendrimer models. Figure 2B shows a histogram illustrating the
distribution of core positions for each of the dendrimer models.
The value Rcore is the distance from the center of mass to the
center of the iron-sulfur cluster and Rg is the computed radius
of gyration of the model. A ratio of Rcore/Rg of zero finds the
core at the center of mass of the dendrimer model. As this ratio
increases, the core is found more and more offset from the center
of mass of the model.
C. Determination of Redox Potential and Heterogeneous
Electron-Transfer Rate Constants. Given the hypothesis that
backfolding leads to more effective encapsulation, two major
effects on the electrochemical behavior of the dendrimer isomers
are predicted. First, it is expected that the iron-sulfur cluster
will be more difficult to reduce as it is encapsulated in a
dendrimer microenvironment that is more hydrophobic than the
solvent. This type of redox potential shift has been observed in
a number of iron-sulfur cluster proteins and mutants53-62 and
in small molecule models.63-67 Moreover, the rate constant for
heterogeneous electron transfer is expected to be lower in the
backfolded molecules compared to the extended isomers. As
illustrated below, both of these effects were prominent in the
comparison of the redox behavior of dendrimer isomers. To our
knowledge, no experiments have been reported to probe the
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Both the snapshot conformations and the conformational
distributions shown in Figure 2 indicate more efficient encap-
sulation in the backfolded molecule compared to the extended
isomer. Although snapshots from molecular dynamics are
somewhat misleading, as they indicate only a moment in time
for a dynamic structure, one can employ them to see easily that
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than the extended isomer. In a statistically more relevant way,
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for the extended dendrimer architecture indicative of a mobile
core that resides toward the outer part of the dendrimer.
Conversely, the histogram of the backfolded architecture shows
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molecule. These observations are thus consistent with the
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backfolded, more compact dendrimer where the core resides
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that peak current was proportional to the square root of the scan
rate (Figure S2). In addition, diffusion coefficients can be used
to measure the effective size of the molecules in solution. The
diffusion coefficient for each molecule was determined using
the two complementary techniques of chronoamperometry (CA)
1
and pulsed field gradient spin-echo H NMR (PFGSE) using
methodology described previously.5 These data are given in
Table 1. The hydrodynamic radii (RH) of the molecules were
computed from these values using the Stokes-Einstein equation.
The radii of the backfolded dendrimers, in each case, were
smaller compared to the extended architectures.
It is perhaps intuitive that the backfolding of the dendrons in
toward the core would result in a smaller more compact
structure. However, why does the electron-transfer rate become
slower for the smaller dendrimers? At first glance, this result
seems counterintuitive given the likelihood that electron transfer
occurs via tunneling through the dendrimer, the rate of which
should be governed by distance. Figure 4 illustrates how a
smaller molecule could have a larger effective electron-transfer
distance. It suggests that if the mobility of the redox-active core
around the center of mass of the molecule was lower, the
effective distance of electron transfer would increase. The outer
circle in each model denotes the hydrodynamic radius of each
dendrimer. The darker, inner region suggests relative core
mobility within the dendrimer. The width of the outer white
segment can be considered as the effective electron-transfer
distance. The computational results as well as the T1 relaxation
values presented below both support the contention that the
extended architectures are more flexible than the backfolded
architectures, allowing for greater movement of the core
throughout the dendrimer. The backfolded architectures steri-
cally hinder the core, keeping it closer to the center of the
dendrimer. This steric hindrance causes a decrease in overall
molecular size but an increase in effective electron-transfer
distance.
Figure 3. Cyclic voltammograms of each dendrimer isomer pair (1 mM
dendrimer, 100 mM TEAF in DMF, scan rate of 50 mV/s).
effect of this type of conformational bias on the properties of
an electroactive core.
Both cyclic voltammetry (CV) and Osteryoung square wave
voltammetry (OSWV) were used to probe the electrochemical
properties of the dendrimer samples. Cyclic voltammetry was
used to determine redox potential (E1/2) and peak separation
(∆Ep). Using diffusion coefficients obtained from chronoamper-
ometry (see below) and a Nicholson analysis,68 the heterogen-
eous electron-transfer rate constants (k0) for a quasireversible
system were calculated. This technique relates ∆Ep to the
electron transfer rate constant of the sample in solution and is
relatively accurate for quasi-reversible systems. CV also easily
shows how rate and driving force vary for each isomer pair
(Figure 3). However, at very fast and slow electron-transfer
regimes, CV is limited as evidenced by the large relative error
bars on these values. Thus, Osteryoung square wave voltam-
metry was used to determine accurate electron-transfer rate
constants for each dendrimer, as it is useful particularly in the
slow rate regime.
The redox potential and heterogeneous electron-transfer rate
constants determined by CV and OSWV are given in Table 1.
For each isomer pair, the backfolded architecture results in a
more negative redox potential compared to the extended
architecture. This behavior is consistent with encapsulation of
the cluster in a more hydrophobic, less solvent-accessible
microenvironment. This hypothesis is further supported by the
observation that the rate constant for electron transfer of each
of the backfolded dendrimers was slower compared to its
extended counterpart.
E. Further Probing of Size and Mobility via NMR
Relaxation Measurements. We previously showed that the
paramagnetic nature of the Fe4S4 core of the dendrimer could
be used to evaluate the relative proximity of various sets of
chemically equivalent nuclei with respect to the core. To the
extent that the protons on the dendron arms and the core interact
closely, the longitudinal relaxation time constant (T1) of these
nuclei is expected to decrease. This interaction is consistent with
steric congestion around the iron-sulfur core. Figure 5 compares
the T1 values obtained for the terminal aromatic proton signals
(e.g., C6H5CH2O) for each dendrimer isomer. The terminal
protons were chosen as their NMR signal was well resolved
from all others, and they represent the topologically most distant
point from the core of the dendrimer. Therefore, changes in the
relaxation behavior of these protons between isomers indicates
backfolding toward the molecular core.
In each case, the T1 values for the backfolded isomer were
shorter than those for the extended isomer. This behavior is
consistent with a steric bias in the backfolded architectures
resulting in a conformation that creates a smaller, more compact
dendrimer compared to the extended architectures. The relative
decrease in T1 value between the backfolded and extended
isomer also paralleled the molecular sizes obtained from PFGSE-
NMR and chronoamperometry. Specifically, the difference was
largest between the extended, 2,2 dendrimer and the backfolded
D. Molecular Size and Its Relation to Electron-Transfer
Rate. Diffusion coefficients (D0) for the molecules were required
to calculate heterogeneous electron-transfer rate constants given
a freely diffusing model. This model was validated by verifying
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Table 1. Diffusion Coefficients, D0, Obtained from Pulsed Field Gradient Spin-Echo NMR Spectroscopy (PFGSE) and Chronoamperometry
(CA), Corresponding Stokes-Einstein Radius, RH, Heterogeneous Electron-Transfer Rate Constant (k0), Reduction Potential (E1/2), and
Transfer Coefficient (R) for the One-Electron Redox Couple [Fe4S4(S-Dend)4]2-/3-
PFGSE- NMR
CA
CV
OSWV
k0 (×103 cm/s)
structu rea
D (×106 cm /s)
RH (Å)b
D (×106 cm /s)
RH (Å)b
k0 (×103 cm/s)
E1/2 (mV)
E1/2 (mV)
R
2
2
0
0
2,3
2B,3
3,2
3,2B
2,2
2B,2B
2.16(0.03)c
2.57(0.07)
2.43(0.02)
5.09(0.07)
2.68(0.05)
5.98(0.06)
14.94(0.21)
12.55(0.35)
13.28(0.11)
5.44(0.09)
12.04(0.23)
5.40(0.06)
3.01(0.19)
3.26(0.10)
2.78(0.05)
4.26(0.17)
2.81(0.10)
5.88(0.16)
10.72(0.26)
9.90(0.18)
11.86(0.34)
7.58(0.18)
11.51(0.35)
5.50(0.33)
2.95(0.93)
1.11(0.15)
3.88(0.71)
1.94(0.62)
3.86(0.88)
2.55(0.81)
-1514(4)
-1519(7)
-1494(4)
-1623(7)
-1519(5)
-1614(1)
2.34(0.44)
0.92(0.34)
3.94(0.67)
0.67(0.19)
1.58(0.45)
0.45(0.48)
-1500(4)
-1513(5)
-1498(3)
-1606(12)
-1516(2)
-1589(2)
0.44(0.02)
0.50(0.02)
0.48(0.03)
0.50(0.003)
0.37(0.02)
0.48(0.006)
a As shown in Figure 1. b Hydrodynamic radius calculated using the Stokes-Einstein equation. c Values in parentheses represent 90% confidence intervals
of the values found.
where the internuclear vectors (or electron-nuclear vector)
oscillate at greater than the Larmor frequency.6 Thus, based only
on relative rotation rates (e.g., only the rate of tumbling of the
entire molecule in solution), smaller molecules should have
larger T1 values. The opposite was observed here, indicating
that differences in the degree of paramagnetic relaxation, not
nuclear dipole-dipole relaxation, explains the differences
observed.
Conclusions
Dendrimer conformation can be biased by primary structural
Figure 4. Cartoon illustrating the role of core mobility and molecular size
elements in ways that manifest themselves in the measured
degree of core encapsulation. Using a combination of electro-
chemical, NMR, and computational methods, a consistent set
of data were obtained to support the conclusion that backfolded
linkages result in dendrimers that are more encapsulating yet
smaller than their extended counterparts. This conclusion was
made by direct comparison of sets of dendrimer isomers that
differed only in this relative structural element. Encapsulation
behaviors manifested as predicted changes in both rate and
driving force for electron transfer. In rationalizing this behavior,
one must consider the effective distance of electron transfer and
not just molecular size. This effective distance depends on both
molecular size and the relative mobility of the redox-active core
within the molecule.
on the effective electron-transfer distance.
Acknowledgment. This work was supported in part by the
Graduate Assistance in Areas of National Need Electronic
Materials fellowship and the National Science Foundation (NSF
CHE-9900072). We thank Hanna Sierzputowska-Gracz for
assistance in collecting PFGSE data. We acknowledge the North
Carolina Supercomputer Center for computational resources.
Mass spectra were obtained at the Mass Spectrometry Labora-
tory for Biotechnology. Partial funding for the facility was
obtained from the North Carolina Biotechnology Center and
the National Science Foundation.
Figure 5. Bar graph indicating the relative T1 values of terminal aromatic
protons measured for each dendrimer (0.1 mM DMF solution).
2B,2B dendrimer. This result is not surprising as two generations
of backfolding should result in the largest steric bias. In contrast,
the 2,3/2B,3 isomer pair showed the smallest difference in T1
values. Again, this result was not unexpected since the back-
folding linkages of this molecule were within the first generation.
The linkages in the second generation were plausibly not
sterically restricted and remained capable of extending out from
the core. Thus, these nuclei interacted less with the iron-sulfur
cluster.
It should be noted that the trends in T1 cannot be explained
by differences in the relative rotation or diffusion rates of the
molecules. These molecules showed an increase in T1 with
increasing temperature and thus were in the “liquid-like” regime
Supporting Information Available: Cyclic voltammetry and
Osteryoung square wave voltammetry data; details of the
synthesis of each dendrimer, characterization information, and
synthetic schematics. This material is available free of charge
via the Internet at http://pubs.acs.org. See any current masthead
page for ordering information and Web access instructions.
JA035515F
9
8254 J. AM. CHEM. SOC. VOL. 125, NO. 27, 2003