Toward globular macromolecules with functionalized interiors: Design and synthesis of dendrons with an interesting twist

Article abstract of DOI:10.1021/ol016064b

(formula presented) Design and synthesis of a novel class of monodendrons, in which the functional units can potentially be directed toward the concave interiors of dendrimers, are described. The key feature of the design is the placement of the amphiphil

Full text of DOI:10.1021/ol016064b

ORGANIC
LETTERS
2001
Vol. 3, No. 12
1961-1964
Toward Globular Macromolecules with
Functionalized Interiors: Design and
Synthesis of Dendrons with an
Interesting Twist
Pandi Bharathi, Hongda Zhao, and S. Thayumanavan*
Department of Chemistry, Tulane UniVersity, New Orleans, Louisiana 70118
thai@tulane.edu
Received May 3, 2001
ABSTRACT
Design and synthesis of a novel class of monodendrons, in which the functional units can potentially be directed toward the concave interiors
of dendrimers, are described. The key feature of the design is the placement of the amphiphilic and the AB2 functional groups in orthogonal
planes.
The concave nature of the binding sites in enzymes and
nucleic acids has long inspired chemists to design new host
materials with recognition sites at their concave face.1 The
globular architecture of dendrimers2 presents a new scaffold
for such recognition possibilities. In fact, dendrimers have
often been referred to as possible globular protein mimics.3
However, to fully realize dendritic structures as potential
biological mimics, the ability to incorporate additional
structural features is needed. Arguably, the most important
of these structural requirements is the ability to selectively
functionalize the concave interiors of these macromolecules,
i.e., selectively direct functional groups toward the interior
of the globular dendrimer. The difficulty in meeting this
structural requisite arises from the flexible nature of the
backbone in a globular dendrimer. In molecules with flexible
backbone, attaining conformational control over the orienta-
tion of the functional groups is nontrivial. A promising
approach to achieving such control involves rendering these
macromolecules amphiphilic. The amphiphilicity and globu-
lar shape of dendrimers have been combined previously, and
they have been shown to exhibit useful properties.4 In these
(1) (a) Cram, D. J. Nature 1992, 356, 29. (b) Breslow, R.; Dong, S. D.
Chem. ReV. 1998, 98, 1997. (c) Breslow, R. Acc. Chem. Res. 1995, 28,
146. (d) Conn, M. M.; Rebek, J. Chem. ReV. 1997, 97, 1647. (e) Jasat, A.;
Sherman, J. C. Chem. ReV. 1999, 99, 931. (f) Rowan, A. E.; Elemans, J. A.
A. W.; Nolte, R. J. M. Acc. Chem. Res. 1999, 32, 995. (g) Wulff, G. Angew.
Chem., Int. Ed. Engl. 1995, 34, 1812.
(2) (a) Fre´chet, J. M. J. Science 1994, 263, 1710. (b) Newkome, G. R.;
Moorefield, C. N.; Vo¨gtle, F. Dendritic Molecules. Concepts, Synthesis,
PerspectiVes; VCH: Weinheim, 1996. (c) Tomalia, D. A.; Naylor, A. M.;
Goddard, W. A., III. Angew. Chem., Int. Ed. Engl. 1990, 29, 138. (d)
Tomalia, D. A. AdV. Mater. 1994, 6, 529. (e) Bosman, A. W.; Janssen, H.
M.; Meijer, E. W. Chem. ReV. 1999, 99, 1665. (f) Fischer, M.; Vo¨gtle, F.
Angew. Chem., Int. Ed. 1999, 38, 884. (g) Frey, H. Angew. Chem., Int. Ed.
1998, 37, 2193. (h) Matthews, O. A.; Shipway, A. N.; Stoddart, J. F. Prog.
Polym. Sci. 1998, 23, 1. (i) Moore, J. S. Acc. Chem. Res. 1997, 30, 402. (j)
Newkome, G. R.; He, E.; Moorefield, C. N. Chem. ReV. 1999, 99, 1689.
(k) Zeng, F.; Zimmerman, S. C. Chem. ReV. 1997, 97, 1681. (l)Percec, V.;
Cho, W. D.; Ungar, G. J. Am. Chem. Soc. 2000, 122, 10273 and references
therein.
(4) (a) Newkome, G. R.; Moorefield, C. N.; Baker, G. R.; Saunders, M.
J.; Grossman, S. H. Angew. Chem., Int. Ed. Engl. 1991, 30, 1178. (b)
Hawker, C. J.; Wooley, K. L.; Fre´chet, J. M. J. J. Chem. Soc., Perkin Trans.
1 1993, 1287. (c) Jansen, J. F. G. A.; Berg, E. M. M. d. B.-v. d.; Meijer,
E. W. Science 1994, 266, 1226. (d) Jansen, J. F. G. A.; Meijer, E. W.;
Berg, E. M. M. d. B.-v. d. J. Am. Chem. Soc. 1995, 117, 4417. (e) Baars,
M. W. P. L.; Kleppinger, R.; Koch, M. H. J.; Yeu, S.-L.; Meijer, E. W.
(3) Smith, D. K.; Diederich, F. Chem. Eur. J. 1998, 4, 1353.
10.1021/ol016064b CCC: $20.00 © 2001 American Chemical Society
Published on Web 05/15/2001

cases, however, since the amphiphilicity is the result of the
difference in hydrophilicity between the macromolecular
backbone and the peripheral moieties, the functional groups
are not necessarily directed toward the interior of the globular
macromolecules (cartoon A, Figure 1).
phiphilic functional groups in orthogonal planes (see Figure
2). Also, the hydrophobic and hydrophilic components are
Figure 1. Schematic representation of amphiphilic dendrimers.
A: amphiphilic dendrimers with peripheral functionalities (previ-
ously reported in the literature). B1: the facially amphiphilic
dendrimers in a polar media. B2: the facially amphiphilic den-
drimers in a nonpolar media.
Figure 2. Representation of the monomer unit with AB2 units and
amphiphilic units in orthogonal planes.
Herein, we present a novel design that potentially directs
functional groups selectively into the concave interior of the
dendrimer. In this design, the dendrimers are uniformly
amphiphilic over the entire globular surface, i.e., when the
convex face of the dendrimer is hydrophilic, the concave
face will be hydrophobic and vice versa. A two-dimensional
schematic representation is shown by the structures B in
Figure 1. The nature of the functional group directed toward
the concave interior of the dendrimer will be driven by
solvophobic interactions. In this design, the inherent flex-
ibility of the dendritic backbone can be expected to yield
two solvent-dependent conformations (B1 and B2). In polar
media, the hydrophilic moieties would be on the convex face
due to favorable surface contacts with the solvent. Because
of the facial amphiphilicity of the dendrimer, the hydrophobic
moieties would be directed toward the concave face (con-
formation B1). Similarly, conformation B2 should result in a
nonpolar media. Such macromolecular architectures are
reminiscent of the class of small molecules that have been
named facial amphiphiles.5
placed on opposite sides of the plane containing the AB2
moieties. Such relative placement of the functional groups
dictates that the amphiphilic moieties are in a plane
perpendicular to that of the macromolecular backbone upon
assembly of the dendrimer. The geometric arrangement of
the dendrimer also dictates that the hydrophobic and the
hydrophilic functionalities are in opposite faces of the
globular dendrimer, and thus structures B should result. A
monomer unit that satisfies these structural requirements is
represented by the biphenyl molecule 1 in Figure 2, in which
the hydrophilic unit is a triethylene glycol monomethyl ether
(TEG) moiety and the hydrophobic unit is an n-butyl group.
The AB2 functionalities are the two phenolic and one
hydroxymethyl groups in 1. The key feature in the relative
placement of these functionalities is the para connectivity
between the biphenyl linkage and the hydroxymethyl sub-
stituent. Because of this structural motif, the relative
geometry of the two phenolic groups and the hydroxymethyl
moiety in 1 is similar to that of 3,5-dihydroxybenzyl alcohol
(the classical Fre´chet-type monomer6), and this geometry is
independent of the extent of the atropisomeric twist between
the aryl groups. Therefore, the globular features observed
with Fre´chet’s benzyl ether dendrimers are also anticipated
in the current design. It also should be noted that the twist
between the two aryl rings would dictate the n-butyl and
the TEG moieties to be in a plane perpendicular to the
dihydroxybenzyl alcohol plane (Figure 2).7 Since these
functionalities are at the ortho positions to the biphenyl
linkage, they are situated at the opposite faces of the
dihydroxybenzyl alcohol plane. These features will render
the dendrimers facially amphiphilic.
Our design involves a monomer unit that has the AB2
functional groups for the dendrimer growth and the am-
Angew. Chem., Int. Ed. 2000, 39, 1285. (f) Watkins, D. M.; Sayed-Sweet,
Y.; Klimash, J. W.; Turro, N. J.; Tomalia, D. A. Langmuir 1997, 13, 3136.
(g) Cooper, A. I.; Londono, J. D.; Wignall, G.; McClain, J. B.; Samulski,
E. T.; Lin, J. S.; Dobrynin, A.; Rubinstein, M.; Burke, A. L. C.; Fre´chet, J.
M. J.; DeSimone, J. M. Nature 1997, 389, 368. (h) Pan, Y.; Ford, W. T.
Macromolecules 2000, 33, 3731. (i) Chen, W.; Tomalia, D. A.; Thomas, J.
L. Macromolecules 2000, 33, 9169. (j) Crooks, R. M.; Zhao, M.; Sun, L.;
Chechik, V.; Yeung, L. K. Acc. Chem. Res. 2001, 34, 181.
(5) (a) Cheng, Y.; Ho, D. M.; Gottlieb, C. R.; Kahne, D. J. Am. Chem.
Soc. 1992, 114, 7319. (b) Venkatesan, P.; Cheng, Y.; Kahne, D. J. Am.
Chem. Soc. 1994, 116, 6955. (c) McQuade, D. T.; Barrett, D. G.; Desper,
J. M.; Hayashi, R. K.; Gellman, S. H. J. Am. Chem. Soc. 1995, 117, 4862.
(d) Janout, V.; Lanier, M.; Regen, S. L. J. Am. Chem. Soc. 1997, 119, 640.
(6) Hawker, C. J.; Fre´chet, J. M. J. J. Am. Chem. Soc. 1990, 112, 7638.
(7) We note that the biphenyl linkage in 1 does not necessarily result in
a 90° twist. With a crude modeling study using Chem-3D, we noticed a
twist of about 60° for the monomer 1. This twist is sufficient for our goal
of placing functionality toward dendritic interiors.
The key step in the synthesis of the target monomer 1 is
making the biaryl bond. Since it has been shown that Suzuki
coupling affords reasonably good yields in the syntheses of
hindered biaryls,8 this was the reaction of choice for the
synthesis of 1. Thus, the biaryl compound 1 was synthesized
(8) (a) Hoye, T. R.; Chen, M. J. Org. Chem. 1996, 61, 7940. (b) Miyaura,
N.; Suzuki, A. Chem. ReV. 1995, 95, 2457.
1962
Org. Lett., Vol. 3, No. 12, 2001

Scheme 1. Synthesis of the Monodendronsa
a (a) TBS-Cl, imidazole, DMF, 81%; (b) SOCl2, catalytic Me3N‚HCl; (c) catalytic AIBN, 2-mercaptopyridine-N-oxide sodium salt, CBrCl3,
62%; (d) (i) t-BuLi, (ii) B(OMe)3, (iii) aqueous NH4Cl; (e) catalytic H2SO4, EtOH, 95%; (f) K2CO3, 18-crown-6, acetone, Bu-I (0.8
equiv), 46%; (g) K2CO3, 18-crown-6, acetone, TEG-OTs, 92%; (h) catalytic Pd(PPh3)4, K3PO4, DME, reflux, 45%; (i) LiBH4, THF, 88%;
(j) TBAF, THF, 91%; (k) K2CO3 1, 18-crown-6, THF; (l) Ph3P, CBr4 (5 72% from 4; 6 61% from 5; 7 21% from 6; 8 39% from 7).
using palladium-catalyzed coupling of aryl boronic acid 2
with bromoarene 3 in DME in the presence of potassium
phosphate to afford the corresponding biphenyl compound
in 45% yield.9 This product’s ester moiety was reduced, and
the TBS groups were deprotected to afford product 1
(Scheme 1).
Compounds 2 and 3 were synthesized from 3,5-dihy-
droxybenzoic acid and 4-bromo-3,5-dihydroxybenzoic acid,
respectively, as shown in Scheme 1. The hydroxy groups of
3,5-dihydroxybenzoic acid were protected with TBS groups.
The resulting ester was treated with 1 equiv of thionyl
chloride in the presence of a catalytic amount of Me3N‚HCl
to afford the corresponding acid chloride, which was then
converted to a bromide moiety using a literature procedure.10
Product 3 was synthesized from 4-bromo-3,5-dihydroxyben-
zoic acid by converting the acid to an ester, followed by
sequential alkylations of the phenolic groups.
Note that any biphenyl twist in the peripheral monomer
units will not serve the purpose of directing functionality.
The orientation of the peripheral moieties has to arise solely
from solvophobic interactions. Therefore, compound 4 with
the hydrophobic n-butyl group and a hydrophilic TEG group
was synthesized as the peripheral monomer.11 Treatment of
4 with 1 in the presence of potassium carbonate and 18-
crown-6 afforded the 3-mer monodendron 5 in 72% yield.
The hydroxymethyl group at the focal point of 5 was
converted to a bromomethyl moiety using triphenylphosphine
and carbon tetrabromide. These two steps were repeated to
obtain the monodendrons 6-8 as shown in Scheme 1.6,11
The assembled dendritic structures were characterized by
NMR and matrix-assisted laser-desorption time-of-flight
(MALDI-ToF) mass spectrometry. The NMR spectra of all
the dendritic structures were consistent with the structures
(9) Suzuki coupling was attempted with various bases and solvents to
optimize the yield. For a study that shows that the nature of the base
significantly affects the yields, see: Griffiths, C.; Leadbeater, N. E.
Tetrahedron Lett. 2000, 41, 2487-2490.
(10) Dol, G. C.; Kamer, P. C. J.; van Leeuwen, P. W. N. M. Eur. J.
Org. Chem. 1998, 359-364.
(11) See Supporting Information for the experimental details.
Org. Lett., Vol. 3, No. 12, 2001
1963

1
shown. The H NMR shift of the methylene group of the
amphiphilic groups are putatively placed at the opposing
sides of the plane of the dendritic growth. Thus, these
custom-designed dendrons should have either the hydropho-
bic or the hydrophilic functional groups selectively directed
toward the concave interiors of the dendrimer, depending
on the polarity of the solvent. While this relative placement
of functionalities is reasonable from a solvophobic standpoint
and from the fact that nature provides examples in the form
of amphiphilic globular proteins,12 the supramolecular place-
ment of these moieties needs to be confirmed. Experiments
to investigate these structural details are currently underway
in our laboratories.
hydroxymethyl focal point was a useful tool in the charac-
terizations. The chemical shift of this group was consistently
around 4.6 ppm, whereas the other methylene groups of
benzyl ethers appeared around 5.0 ppm. The relative integra-
tion between these two areas was a useful diagnostic tool
for characterizing the generation of the dendrons. Also, the
chemical shift of the methylene group at the focal point
changed to 4.4 ppm upon conversion of the hydroxymethyl
group to the bromomethyl moiety. The possibility of alky-
lating just one of the two phenolic groups in 1 creates
difficulties in unambiguously assigning the structures of these
dendrons by NMR, because the differences in relative
1
Acknowledgment. This paper is dedicated to Professor
Seth R. Marder on the occasion of his 40th birthday. We
are grateful to Tulane University for support of this work.
We thank Ms. Jessica Simons for assistance with the
synthesis of some of the earlier substrates.
integration of the H NMR peaks between this possibility
and the expected monodendrons are small. However, MALDI-
ToF mass spectra confirmed the structures of 6-8, with no
peaks for the corresponding monosubstituted dendrons [6 m/z
) 2635.8 (M + Na+ calcd for C144H210O42 2636.2); 7 m/z )
5662.4 (M + Na+ calcd for C312H450O90 5662.9); 8 m/z )
11 695.0 (M+ calcd for C648H930O186 11696.2)]. The purity
of these dendrons was also analyzed using gel permeation
chromatography, and we found single peak for each of the
monodendrons.
Supporting Information Available: Synthetic procedures
and characterization data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
In summary, we have designed and synthesized am-
phiphilic dendrons in which each repeating unit has hydro-
phobic and hydrophilic functionalities. By exploiting the
atropisomeric structural motif presented by biphenyls, these
OL016064B
(12) For an example, see: Xu, Z.; Bernlohr, D. A.; Banaszak, L. J. J.
Biol. Chem. 1993, 268, 7874-7884.
1964
Org. Lett., Vol. 3, No. 12, 2001