Smaller building blocks form larger assemblies: Aggregation behavior of biaryl-based dendritic facial amphiphiles

Article abstract of DOI:10.1021/jo070447r

(Chemical Equation Presented) Synthesis and micellar behavior of biaryl-based benzyl ether dendritic molecules prepared from a new biaryl building block are described. The key objective of the study is to tune the size of individual dendritic molecules an

Full text of DOI:10.1021/jo070447r

Smaller Building Blocks Form Larger Assemblies: Aggregation
Behavior of Biaryl-Based Dendritic Facial Amphiphiles
Ashootosh V. Ambade, Sivakumar V. Aathimanikandan, Derek van der Poll, and
S. Thayumanavan*
Department of Chemistry, UniVersity of Massachusetts, Amherst, Massachusetts 01003
thai@chem.umass.edu
ReceiVed March 12, 2007
Synthesis and micellar behavior of biaryl-based benzyl ether dendritic molecules prepared from a new
biaryl building block are described. The key objective of the study is to tune the size of individual dendritic
molecules and investigate its effect on aggregation behavior of the resulting micelle-like assemblies. We
show that the functional group placement in the building block influences flexibility of the dendritic
backbone and interior volume available for packing the hydrophobic groups, which is reflected in different
aggregation behavior and aggregate size of the two types of micellar assemblies.
Introduction
molecules can be obtained with a high degree of control in
molecular weight, i.e., polydispersity of one.2 Also, most of the
dendrimers attain a globular shape at high molecular weights3
and therefore are interesting candidates for mimicking globular
proteins.4 In water-soluble proteins, most of the hydrophobic
amino acid side chain functionalities are directed toward the
interior while the hydrophilic ones are exposed to the solvent.
Thus, often the protein cofactors are buried in the hydrophobic
pockets of proteins, although the overall molecule is soluble in
water. Similarly, water-soluble dendrimers with a hydrophobic
interior containing electro- and photoactive functionalities have
been reported previously.5,6 These types of molecules also
exhibit interesting unimolecular micellar characteristics. In all
these designs, the backbone of these dendrimers is hydrophobic
and the periphery is decorated with hydrophilic functionalities
to optimize the surface contact with the solvent, water.
Most of the biomimetic structures are based on small
molecules, because of the relative ease with which the spatial
control of functional group display can be achieved.1 However,
considering the macromolecular nature of proteins and nucleic
acids, it is interesting to be able to mimic these structures with
controlled, high molecular weight scaffolds. Dendrimers provide
a unique opportunity for such possibilities, because these
(1) (a) Gellman, S. H. Acc. Chem. Res. 1998, 31, 173-180. (b) Hill, D.
J.; Mio, M. J.; Prince, R. B.; Hughes, T. S.; Moore, J. S. Chem. ReV. 2001,
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10.1021/jo070447r CCC: $37.00 © 2007 American Chemical Society
Published on Web 10/04/2007
J. Org. Chem. 2007, 72, 8167-8174
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Ambade et al.
FIGURE 1. The hypothesis that the curvature of dendritic backbone influences the micelle-like assembly is illustrated. “Bigger” dendritic molecules
with larger curvature may afford to form smaller aggregates (above) while “smaller” molecules with less curvature may form larger aggregates
(below).
To more closely mimic the biomacromolecules, however, it
is interesting to be able to direct modifiable side chain
functionalities toward the micellar interiors of the dendrimers.
For this purpose, we had disclosed a class of biaryl-based
dendritic molecules, in which each repeat unit contains both
hydrophilic and lipophilic functionalities.7 The key feature here
is the unique conformation that is presumably adopted by these
dendritic molecules to form micelle-type assemblies. In classical
water-soluble dendrimers, the functionalities within the internal
layers of dendrimers are more buried with respect to the contact
with the bulk solvent.6 With our molecules, we had suggested
that all hydrophilic functionalities are equally exposed to the
polar solvent independent of the layer that it is present in. The
simplest way to understand this possibility is to visualize these
molecules as simple branched facial amphiphiles, where all the
hydrophilic moieties are exposed to the bulk solvent and all
the hydrophobic functionalities are buried in the interior of the
assembly independent of their location (Figure 1). Note that
this hypothesis is consistent with our previous data on the
interaction of our dendritic molecules with proteins as well as
with self-assembly of these molecules on surfaces.8c,d
If our structural hypotheses above were true, we envisaged
that when dendritic molecules with similar molecular weights,
but more compact size were synthesized, the size of the
assembly would be larger. The reason for this assertion is
schematically represented in Figure 1. Under our hypothesis,
in a polar solvent, a certain number of lipophilic groups would
be directed toward the interior of the micelle-type assembly.
To minimize the surface contacts of these functionalities with
the polar solvent, these molecules would adopt a conformation
that would result in a certain curvature. If the molecule could
attain a large curvature, then a relatively small number of
molecules are needed for aggregation, where the self-assembled
structure has a hydrophilic exterior and an encapsulated lipo-
philic interior. In the limiting case, a globular structure could
be attained with a single molecule and one could achieve a
unimolecular micelle. If one builds another dendritic molecule
with the same number of lipophilic groups, but using a more
compact building block unit, then this molecule will adopt a
conformation with smaller curvature mainly because the mol-
ecule needs to accommodate the same number of amphiphilic
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Stevelmans, S.; van Hest, J. C. M.; Jansen, J. F. G. A.; van Boxtel, D. A.
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Chem., Int. Ed. 1991, 30, 1178-1180. (g) Pesak, D. J.; Moore, J. S.
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Rohde, J. M.; Chaumette, J.-L.; Sarazin, D.; Parquette, J. R. J. Org. Chem.
2001, 66, 6440-6452.
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F.; Gross, M. Angew. Chem., Int. Ed. 1999, 38, 3215-3219. (c) Cardona,
C. M.; Alvarez, J.; Kaifer, A E.; McCarley, T. D.; Pandey, S.; Baker, G.
A.; Bonzagni, N. J.; Bright, F. V. J. Am. Chem. Soc. 2000, 122, 6139-
6144. (d) Cardona, C. M.; Mendoza, S.; Kaifer, A. E. Chem. Soc. ReV.
2000, 29, 37-42. (e) Smith, D. K. Chem. Commun. 2006, 34-44. (f)
Chasse, T. L.; Sachdeva, R.; Li, Q.; Li, Z.; Petrie, R. J.; Gorman, C. B. J.
Am. Chem. Soc. 2003, 27, 8250-8254. (g) Hecht, S.; Fre´chet, J. M. J.
Angew. Chem., Int. Ed. 2001, 40, 74-91. (h) Sivanandan, K. S.; Aathi-
manikandan S. V.; Arges, C. G.; Bardeen, C. J.; Thayumanavan, S. J. Am.
Chem. Soc. 2005, 127, 2020-2021.
(8) (a) Vutukuri, D. R.; Basu, S.; Thayumanavan, S. J. Am. Chem. Soc.
2004, 126, 15636-15637. (b) Aathimanikandan, S. V.; Savariar, E. N.;
Thayumanavan, S. J. Am. Chem. Soc. 2005, 127, 14922-14929. (c)
Klaikherd, A.; Sandanaraj, B. S.; Vutukuri, D.; Thayumanavan, S. J. Am.
Chem. Soc. 2006, 128, 9231-9237. (d) Chen, Y.; Vutukuri, D. R.; Ambade,
A. V.; Thayumanavan, S. J. Am. Chem. Soc. 2006, 128, 14760-14761.
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1964.
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BehaVior of Biaryl-Based Dendritic Facial Amphiphiles
FIGURE 2. The phenolic groups are twice as far away from the hydroxymethyl group in building-block I reported earlier as those in II. These are
indicated by arrows in the space-filling models.
CHART 1
functionalities in a concave face that has a much smaller volume.
With the smaller curvature, therefore, a larger number of
molecules are needed for the formation of the micellar aggregate,
as schematically illustrated in Figure 1. In other words, if our
structural hypothesis is correct, then more compact dendritic
molecules will form larger aggregates whereas the more open-
structured ones will form smaller aggregates.
To test this hypothesis, we built a structurally compact
analogue of our originally reported biaryl dendritic molecules.8
Our previously reported biaryl building block is represented by
I in Figure 2 and dendritic molecules synthesized from it are
shown in Chart 1. Our structural hypothesis was that the aryl
ring that defines the plane of the dendrimerizable functionalities
should be orthogonal to the aryl ring that contains the am-
phiphilic functionalities. Thus, the amphiphilic functionalities
are presented at either side of the plane containing the
dendrimerizable AB2 functionalities.7 Monomer II also satisfies
this structural requirement, just as well as I. The key difference
is that the hydroxymethyl group and the two phenolic moieties
are all in the same aryl ring of the biaryl system II. Since the
dendritic growth occurs from the AB2 functionalities, the
distance between these defines the dimensions of the building
block unit and therefore the overall size of the dendrons. This
distance is 8.98 Å in structure I and 4.89 Å in II; these were
estimated from an energy-minimized monomer by using the
Cirus 2 simulation program (Figure 2). Thus, the molecules
arising from II will be more compact than those arising from
I. To compare the nature of the assemblies obtained from I and
II, we synthesized dendrons SG1-SG3 and didendrons SG1D-
SG2D shown in Chart 2 and characterized the assemblies from
both designs using host-guest studies and dynamic light
scattering.
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Ambade et al.
CHART 2
SCHEME 1. Synthesis of the Aryltin Compound for the Smaller Biaryl Building Block
Results and Discussion
In design II, the AB2 functionalities are in the lower ring, which
will contain the bromo moiety (11 or 12) for the Stille coupling.
The hydrophilic and hydrophobic functionalities are in the upper
aryl ring, which will contain the tributyltin functionality
(compound 9). Note that the precursor 9 has the hydrophobic
decyl moiety, but does not contain the masked hydrophilic ester
functionality. This is because we recognized that the optimal
yields were obtained in the Stille coupling reactions only when
the substituent para to the bromo moiety in the bottom ring is
an electron-withdrawing unit, such as with esters 11 and 12.
After the biaryl coupling reaction, selective reduction of the
ester in the bottom ring will be difficult if the top ring were to
have the ester moiety as well. Therefore, we carried out the
synthesis with a protecting group in place of the hydrophilic
functionality in the top ring, as in structure 9.
Synthesis. The dendritic structures reported here are based
on aryl-alkyl ether connectivity.9 For the synthesis of such
benzyl ether dendritic molecules, one needs a bromomethyl
compound and a diphenolic compound. These molecules are
shown by structures 17 and 18, where the former compound is
the peripheral unit, and the latter constitutes the repeating unit.
Both these molecules are biaryl compounds with hydrophobic
and masked hydrophilic functionalities. We use the decyl chain
as the hydrophobic moiety and the tert-butyl acetate group as
the masked hydrophilic moiety (tert-butyl ester will be hydro-
lyzed to the hydrophilic carboxylic acid moiety in the last step
of the syntheses). Biaryl molecules are routinely synthesized
by Suzuki and Stille coupling among other methods.10 In our
laboratories, we have standardized the Stille coupling method
for these molecules. To utilize this strategy for synthesis of
biaryl compounds, we need an aryltin compound and an aryl
bromide, which are coupled in a palladium-catalyzed reaction.
We envisaged the synthesis of 9 from the corresponding aryl
bromide 8 using bromine-lithium exchange protocol as shown
in Scheme 1. Synthesis of the starting material 6 was achieved
from commercially available 3,5-dihydroxybenzoic acid in 43%
yield. The ester moiety of 6 was then hydrolyzed and the
phenolic moiety was protected as a tert-butyldimethylsilyl (TBS)
ether in 82% overall yield to obtain the carboxylic acid 7. The
aryl carboxylic acid moiety of 7 was then converted to the
corresponding aryl bromide 8 by using a radical-based method
(9) (a) Grayson, S. M.; Fre´chet, J. M. J. Chem. ReV. 2001, 101, 3819-
3868. (b) Hawker, C. J.; Fre´chet, J. M. J. J. Am. Chem. Soc. 1990, 112,
7638-7647.
(10) (a) Yin, L.; Liebscher, J. Chem. ReV. 2007, 107, 133-173. (b) Tour,
J. M. Chem. ReV. 1996, 96, 537-554. (c) Nicolaou, K. C.; Bulger, P. G.;
Sarlah, D. Angew. Chem., Int. Ed. 2005, 44, 4442-4489. (d) Espinet, P.;
Echavarren, A. M. Angew. Chem., Int. Ed. 2004, 43, 4704-4734.
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BehaVior of Biaryl-Based Dendritic Facial Amphiphiles
SCHEME 2. Synthesis of Biaryl Building Block Precursor via Stille Coupling
SCHEME 3. Synthesis of Biaryl Building Block and the Peripheral Unit
in 40% yield.7,11 The aryl bromide was then converted to aryl
stannane 9 and was taken to the coupling step without further
purification.
derivative 17 was reacted with the building block monomer 18
under Williamson etherification conditions to afford G1-
monodendron (19) in 67% yield. Bromination and alkylation
reactions were repeated to obtain G2 and G3 monodendrons,
21 and 23. The yields of alkylation decreased for higher
generations with the yield of G3 being only 12%. We surmise
that steric crowding does not favor the reaction at the focal point
in the case of higher generations. G1-didendron (24) and G2-
didendron (25) were obtained by bromomethylation of mono-
dendrons followed by etherification with bisphenol A as shown
in Scheme 5. Lack of formation of G3-didendron and low yields
for other generations may be taken as an indication of the
compact nature of these dendritic molecules when compared
to ones from design I, where even the G3-didendron could be
synthesized in moderate yield.
The lower ring precursors 11 and 12 were synthesized by
reacting ethyl 4-bromo-3,5-dihydroxybenzoate with methyl
iodide and methoxymethyl chloride (mom-Cl), respectively, as
shown in Scheme 2. Stille coupling of 11 or 12 with the aryltin
compound 9 catalyzed by dichlorobis(triphenylphosphine)-
palladium(II) then afforded the biaryl compounds in about 50-
55% yield after chromatographic purification. The subsequent
steps that lead to either peripheral or repeating unit are the same
except for the last step and the yields of each of these steps
were good to excellent. First the ethyl ester was reduced to
alcohol with LiBH4 to obtain compounds 13 and 14. The TBS
group was then cleaved with tetrabutylammonium fluoride
followed by installation of the tert-butyl acetate group under
Williamson etherification conditions to afford 15 and 16,
respectively.
At this stage, compound 15 was converted to the correspond-
ing bromomethyl derivative 17 with use of triphenylphosphine
and carbontetrabromide; this molecule is the peripheral monomer
in the dendritic assembly. The mom-ethers in 16 were then
subjected to a mild deprotection protocol to afford the repeating
unit monomer 18, as shown in Scheme 3. It is to be noted here
that carefully optimized conditions were needed to cleave the
mom-groups in presence of the tert-butyl ester, since both the
functional groups are acid sensitive. After experimenting with
different reaction conditions involving mild acids, a satisfactory
condition was found that generates HBr in situ enough to cleave
the mom-groups, but not the tert-butyl ester.12 Thus, the cleavage
of mom-groups could be achieved in 60% yield by refluxing
compound 16 in isopropanol in the presence of 0.2 to 0.3 equiv
of CBr4, under dilute conditions.
All monodendrons and didendrons were characterized by 1H
NMR, 13C NMR, and MALDI-ToF spectrometry; GPC analysis
was carried out as an additional check of purity. The tert-butyl
ester groups were then hydrolyzed under refluxing aqueous
KOH/MeOH/THF conditions to obtain carboxylated derivatives
as the targeted amphiphilic monodendrons SG1-SG3 and
didendrons SG1-D and SG2-D. The absence of tert-butyl groups
1
was ascertained by H NMR and the structures were further
confirmed by MALDI-ToF analysis.13 For simplicity in further
discussion the hydrolyzed monodendrons are referred to as G1,
G2, and G3 while hydrolyzed didendrons are referred to as G1-D
and G2-D with a prefix S or L for smaller or larger dendritic
molecules as the case may be (see Charts 1 and 2).
Aggregation Behavior. As mentioned in the introduction,
we had hypothesized that the smaller dendritic molecules (SG1-
SG3, SG1-D, and SG2-D) would form larger aggregates and
the larger ones (LG1-LG3, LG1-D, and LG2-D) would form
smaller aggregates in aqueous solutions. A direct method to test
this hypothesis is to carry out solution size measurements with
dynamic light scattering (DLS) experiments. For this purpose,
10-4 M aqueous solutions of the dendritic molecules were
The dendrons were then assembled by iterative synthetic
procedures reported earlier (Scheme 4).9 The bromomethyl
(11) Dol, G. C.; Kamer, P. C. J.; van Leeuwen, P. W. N. M. Eur. J.
Org. Chem. 1998, 359-364.
(12) Lee, A. S.-Y.; Hu, Y.-J.; Chu, S.-F. Tetrahedron 2001, 57, 2121-
2126.
(13) See the Supporting Information for details.
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Ambade et al.
SCHEME 4. Assembly of Dendrons from the Precursors 17 and 18
SCHEME 5. Synthesis of Didendrons from the Monodendron Precursors and Bisphenol A
prepared with 1-1.5 equiv of KOH per carboxylic acid unit.
The hydrodynamic radii (Rh) values were obtained by DLS and
the results are shown in Table 1. It is immediately obvious from
Table 1 that the S molecules consistently form larger aggregates
compared to the corresponding L ones. These results provide
the supporting evidence for our structure vs aggregate size
hypothesis. In fact, with the exception of LG1, all L molecules
form much smaller aggregates than all of the S molecules.
It is also interesting to note that there is a dendritic effect in
the aggregation in the case of L molecules, whereas this trend
is much more irregular in the case of S. Upon going from LG1
to LG2 and LG3, the aggregate size clearly decreases. This is
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BehaVior of Biaryl-Based Dendritic Facial Amphiphiles
FIGURE 3. Emission spectra of pyrene encapsulated in 10-4 M aqueous solutions of (a) SG3 and (b) LG3.
TABLE 1. DLS Data for the S and L Dendritic Aggregates in
Aqueous Solutionsa
important here, since our molecules form unusually large-sized
aggregates for micelles and may lead one to think that these
are vesicles. First of all, note that there are examples in the
literature of micellar assemblies formed by small molecule
surfactants and block copolymers that are bigger in size than
expected.14 Nonetheless, to test whether micelles are indeed the
aggregates in our case, pyrene was used as a spectroscopic
probe.15
Emission spectra of pyrene encapsulated in 10-4 M aqueous
solutions of SG3 and LG3 are shown in Figure 3. The ratio of
intensities of first and third peaks in the emission spectra of
pyrene, i.e., the I1/I3 value, is an indicator of the polarity of its
microenvironment.16 In micellar aggregates, this ratio is between
1.0 and 1.2; this value is typically higher when pyrene is
sequestered in vesicles. For all generations of S and L dendritic
assemblies, the I1/I3 value was found to be between 1.0 and
1.1. Note also that this ratio is comparable to that found for
pyrene encapsulated in micelles of a small molecule surfactant,
viz. sodium dodecyl sulfate.17 These results indicate that
aggregates formed by these molecules are indeed micelle-like.
Rh (nm)
S dendritic
molecules
L dendritic
molecules
Gn
G1
G2
G3
G1-D
G2-D
28
15
24
20
11
35
5.0
5.5
4.0
4.0
a The hydrodynamic radii reported here are obtained from the volume-
average of the sizes obtained in the DLS measurements
perhaps understandable because in the case of higher genera-
tions, there is a forced curvature between the neighboring
amphiphilic units within a dendron, because of the inherent
architecture of the dendron itself. This could be providing the
pathway for forming smaller aggregates. It is possible that the
smaller dendrons also benefit from this forced curvature upon
comparing SG1 and SG2. However, there is a second issue
involving the sterics of accommodating several decyl units
within a smaller volume, as discussed earlier. This is a
competing pathway for providing the curvature. It is possible
that SG3 is simply too crowded to afford a larger curvature
than SG2, compared to the case with LG2 and LG3. The
comparison of didendrons can be explained in a similar fashion.
These results can be taken to be consistent with the overall
structural hypothesis proposed here. However, we obviously do
not have unambiguous evidence for these suppositions. There-
fore, these should be taken as explanations that are consistent
with the data, but are provisional.
Summary
We have demonstrated that simple modification in the
building block results in significant changes in the aggregation
behavior of the biaryl-based dendritic facial amphiphiles. This
is because the size of the building block dictates the size of
each dendritic molecule, which is then translated into the
conformation that it can adopt in aqueous medium to minimize
the solvent contact with the hydrophobic groups. We have
We also were interested in finding out whether these
aggregates are indeed micellar. If these assemblies were micellar,
these should be capable of sequestering hydrophobic guest
molecules within their interiors. In fact, we were able to show
that all these mono- and didendrons are capable of sequestering
hydrophobic guest molecules such as pyrene and that the critical
micelle concentrations of these molecules are about 10-6 M.13
However, it should be noted that the capability of sequestering
hydrophobic guest molecules alone is not sufficient to show
that a molecule is capable of forming micellar assemblies,
because even vesicular assemblies sequester hydrophobic guest
molecules within their membranes. This distinction is especially
(14) (a) Erhardt, R.; Zhang, M.; Bo¨ker, A.; Zettl, H.; Abetz, C.; Frederic,
P.; Krausch, G.; Abetz, V.; Mu¨ller, A. H. E. J. Am. Chem. Soc. 2003, 125,
3260-3267. (b) Savariar, E. N.; Aathimanikandan, S. V.; Thayumanavan,
S. J. Am. Chem. Soc. 2006, 128, 16224-16230. (c) Chakraborty, H.; Sarkar,
M. Langmuir 2004, 20, 3551-3558.
(15) (a) Kim, J.-H.; Domach, M. M.; Tilton, R. D. J. Phys. Chem. B
1999, 103, 10582-10590. (b) Horiuchi, K.; Rharbi, Y.; Spiro, J G.; Yekta,
A.; Winnik, M. A.; Jenkins, R. D.; Bassett, D. R. Langmuir 1999, 15, 1644-
1650. (c) Chang, J. Y.; Park, P. J.; Han, M. J. Macromolecules 2000, 33,
321-325.
(16) Kalyansundaram, K.; Thomas, J. K. J. Am. Chem. Soc. 1977, 99,
2039-2044.
(17) Winnik, F. M.; Ringsdorf, H.; Venzmer, J. Langmuir 1991, 7, 905-
911.
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Ambade et al.
layer was dried over Na2SO4 and evaporated to dryness. The crude
product was purified by silica gel column chromatography.
General Procedure for Hydrolysis of tert-Butyl Ester Den-
dritic Molecules. To a solution of the monodendron or didendron
in THF was added a 10% aq KOH solution containing 8-10 equiv
of KOH per ester group followed by a small amount of methanol
to obtain a clear solution. This mixture was refluxed for 24 h and
then organic solvents were evaporated. To the residue obtained,
water was added and refluxed further for 12 h. The mixture was
then diluted with water, neutralized with concentrated HCl, and
filtered. The white residue obtained after filtration was washed
repeatedly with water until filtrate was neutral. For higher generation
monodendrons and didendrons, after the first 24 h, the residue was
not completely soluble in either water or THF-water mixture. The
suspension was then refluxed for a total of 36 h and neutralized.
Completion of the reaction was confirmed from the absence of tert-
shown that small, compact dendritic molecules tend to form
larger aggregates compared to the corresponding larger ana-
logues. Dynamic light scattering experiments were used to
ascertain this. Encapsulation of hydrophobic guest molecules
in water and probing the hydrophobicity of the interior by using
this guest molecule as the spectroscopic probe provide further
evidence that micellar aggregates are indeed formed. These
studies could form the basis for systematic structural guidelines
for obtaining controlled dendritic aggregates, which could find
applications in areas such as drug delivery.18
Experimental Section
This section describes the synthesis and characterization for key
steps and details for all other compounds are provided in the
Supporting Information.
1
butyl protons in H NMR spectra.
Acknowledgment. This work was supported by the NIGMS
of the National Institutes of Health (GM-065255-01). We thank
Mr. Akamol Klaikherd and Mr. Elamprakash Savariar for
helping with some of the characterization experiments.
General Procedure for Conversion of Benzylic Alcohol into
the Corresponding Bromide. To a stirred solution of the appropri-
ate benzyl alcohol and PPh3 (2-3 equiv) in minimal dry THF was
added carbon tetrabromide (2-3 equiv) under nitrogen atmosphere.
The reaction mixture was stirred at room temperature and was
monitored by TLC. The reaction mixture was treated with water
and extracted two times with ethyl acetate. The combined organic
Supporting Information Available: Synthetic procedures and
characterization data (1H, 13C NMR, MS) of all new compounds
and 1H NMR spectra of key biaryl compounds and dendritic
molecules. This material is available free of charge via the Internet
at http://pubs.acs.org.
(18) (a) Tomalia, D. A. Prog. Polym. Sci. 2005, 30, 294-324. (b)
Tomalia, D. A.; Brothers, H. M., II; Piehler, L. T.; Durst, H. D.; Swanson,
D. R. Proc. Natl. Acad. Sci. U.S.A. 2002, 99, 5081-5087.
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