Synthesis and surface functionalization of aliphatic polyether dendrons

Article abstract of DOI:10.1021/ja001903v

The convergent synthesis and surface modification of a novel family of aliphatic polyether dendrons is described. The synthesis utilizes methallyl dichloride as the monomeric building block along with peripheral benzyl ether and ketal protected hydroxy fu

Full text of DOI:10.1021/ja001903v

J. Am. Chem. Soc. 2000, 122, 10335-10344
10335
Synthesis and Surface Functionalization of Aliphatic Polyether
Dendrons
Scott M. Grayson and Jean M. J. Fre´chet*
Contribution from the Department of Chemistry, UniVersity of California, Berkeley, California 94720-1460
ReceiVed May 30, 2000
Abstract: The convergent synthesis and surface modification of a novel family of aliphatic polyether dendrons
is described. The synthesis utilizes methallyl dichloride as the monomeric building block along with peripheral
benzyl ether and ketal protected hydroxy functionalities. The allylic nature of the electrophilic moieties of
methallyl dichloride facilitates their nucleophilic displacement by 2 equiv of the appropriate terminal alcohol
group. Having served its activating function during the coupling step, the alkene focal point can then be efficiently
transformed into a primary alcohol via hydroboration-oxidation leading to a nucleophile that may then be
coupled again to additional monomer. Repetition of these coupling and activation steps affords higher generation
dendrons. Taking advantage of the versatility of the convergent approach and the rugged nature of the aliphatic
ether building blocks, dendrimers with tailored solubility properties and well-defined unsymmetrical surfaces
can be obtained.
Introduction
modifications8 both at the periphery and at the focal point. In
particular, both the benzyl and ketal protecting groups can be
removed quantitatively to reveal the polyol periphery. As a result
of their hydrophilic peripheral functionalities, many of these
polyol dendrons are water-soluble, and all can easily be modified
through alkylation or acylation with the appropriate electrophile.
Because of their chemical robustness and increased solubility
over linear analogues, these dendrons have proven to be versatile
solubilizing scaffolds for the synthesis of otherwise insoluble
oligothiophenes.9
Herein we detail the synthesis and modification of these
benzyl-protected and ketal-protected dendrons. In addition, we
discuss the synthesis of hybrid dendrons utilizing both benzyl
and ketal protecting groups. Because these protecting groups
are orthogonal to each other, they may be selectively removed
thus providing excellent control over the modification of the
periphery. Dendrimers with differentiated chain-end function-
alities are attractive as vectors or carriers in applications such
as targeted delivery.3d
Dendrimers exhibit a number of unique physical properties
owing to their well-defined, highly branched architecture, their
globular shape, and their multiple peripheral functionalities.1
Within the past decade, dendritic structures have been utilized
for a range of technological applications,2 including multivalent,
bioactive macromolecules.3 Recently, we have reported a novel
convergent approach4 to aliphatic polyether dendrons5 with
benzyl ether6 or ketal7 protecting groups. As expected, the
aliphatic polyether backbone of these dendrons exhibits stability
toward oxidative, reductive, strongly basic, and weakly acidic
reaction conditions, thereby enabling a variety of chemical
(1) (a) Bosman, A. W.; Janssen, H. M.; Meijer, E. W. Chem. ReV. 1999,
99, 1665. (b) Fre´chet, J. M. J. Science 1994, 263, 1710. (c) Newcome, G.
R.; Moorefield, C. N.; Vo¨gtle, F. Dendritic Molecules: Concepts, Syntheses,
PerspectiVes; VCH: Weinheim, 1996 and references therein.
(2) Percec, V.; Chu, P.; Ungar, G.; Zhou, J. J. Am. Chem. Soc. 1995,
117, 7, 11441. Sadamoto, R.; Tomioka, N.; Aida, T. J. Am. Chem. Soc.
1996, 118, 3978. Bhyrappa, P.; Young, K. J.; Moore, J. S.; Suslick, K. S.
J. Am. Chem. Soc. 1996, 118, 5708. Miller, L. J.; Duan, R. G.; Tully, D.
C.; Tomalia, D. A. J. Am. Chem. Soc. 1997, 119, 1005. Kawa, M.; Fre´chet,
J. M. J. Chem. Mater. 1998, 10, 286. Gilat, S. L.; Adronov, A.; Fre´chet, J.
M. J. Angew. Chem., Int. Ed. Engl. 1999, 38, 1422. Piotti, M. E.; Rivera,
F.; Bond, R.; Hawker, C. J.; Fre´chet, J. M. J. J. Am. Chem. Soc. 1999, 121,
9471. Tully, D. C.; Trimble, A. R.; Fre´chet, J. M. J.; Wilder, K.; Quate, C.
F. Chem. Mater. 1999, 11, 2892. Adronov, A.; Gilat, S. L.; Fre´chet, J. M.
J.; Ohta, K.; Neuwahl, F. V. R.; Fleming, G. R. J. Am. Chem. Soc. 2000,
122, 1175.
(3) (a) Roberts, J. C.; Adams, Y. E.; Tomalia, D.; Mercer-Smith, J. A.;
Lavallee, D. K. Bioconjugate Chem. 1990, 1 (5), 305. (b) Roberts, J. C.;
Bhalgat, M. K.; Zera, R. T. J. Biomed. Mater. Res. 1996, 30, 53. (c) Malik,
N.; Evagorou, E. G.; Duncan, R. Anti-Cancer Drugs 1999, 10, 767. (d)
Kono, K.; Liu, M.; Fre´chet, J. M. J. Bioconjugate Chem. 1999, 10, 1115.
(e) Liu, M.; Fre´chet, J. M. J. Pharmaceut. Sci. Technol. Today 1999, 2,
393-401. (f) Liu, M.; Kono, K.; Fre´chet, J. M. J. J. Controlled Release
2000, 65, 121.
Results and Discussion
Synthetic Design. Our synthetic design takes advantage of
the convergent route4 because this approach allows more precise
control over the dendritic architecture, providing direct access
to structurally uniform macromolecules as well as compounds
with differentiated peripheral functionalities. Given the repetitive
nature of dendrimer preparations, a successful convergent
synthesis of high-generation aliphatic dendrons requires an aptly
chosen monomer that will undergo high-yielding activation and
growth steps. In our synthesis, the monomer selected is 3-chloro-
2-chloromethyl-1-propene (methallyl dichloride or MDC). The
(4) Hawker, C. J.; Fre´chet, J. M. J. J. Am. Chem. Soc. 1990, 112, 7638.
(5) Padias, A.; Hall, H. K., Jr.; McConnell, R.; Tomalia, D. J. Org. Chem.
1987, 52, 5305. Nemoto, H.; Wilson, J. G.; Nakamura, H.; Yamamoto, Y.
J. Org. Chem. 1992, 57, 435.
(6) Jayaraman, M.; Fre´chet, J. M. J. J. Am. Chem. Soc. 1998, 120, 12996.
(7) Grayson, S. M.; Jayaraman, M.; Fre´chet, J. M. J. Chem. Commun.
1999, 1329.
(8) Previous examples of peripheral modification of convergently grown
dendrons include: Leon, J. W.; Kawa, M.; Fre´chet, J. M. J. J. Am. Chem.
Soc. 1996, 118, 8847. Leduc, M. R.; Hayes, W.; Fre´chet, J. M. J. J. Polym.
Sci. Part A: Polym. Chem. 1998, 36, 1.
(9) Malenfant, P. R. L.; Jayaraman, M.; Fre´chet, J. M. J. Chem. Mater.
1999, 11, 3420. Malenfant, P. R. L.; Fre´chet, J. M. J. Macromolecules 2000,
33, 3634.
10.1021/ja001903v CCC: $19.00 © 2000 American Chemical Society
Published on Web 10/06/2000

10336 J. Am. Chem. Soc., Vol. 122, No. 42, 2000
Grayson and Fre´chet
monomer’s alkene functionality serves a dual purpose in the
synthesis: first to enhance the electrophilic reactivity in the
coupling step, and then to act as the masked precursor for the
nucelophilic moiety. The monomer’s dual allylic chloride
functionalities enable two facile Williamson type nucleophilic
substitutions with an appropriate alkoxide, while its symmetry
ensures the formation of the same alkene product regardless of
displacement mechanism (SN1, SN2, or SN2′). In addition, the
lack of hydrogens R to the leaving group prevents the possibility
of elimination. The alkene in the product is then activated toward
coupling by a regioselective hydroboration-oxidation, thereby
producing a primary alcohol nucleophile. Iterative repetition of
these coupling and activation steps produces higher generation
dendrons.
Scheme 1a
During each step of the coupling and activation procedure,
the products were purified by flash chromatography on silica
gel. Because each growth step in the convergent synthesis
involves only two couplings per monomer, the byproducts
exhibit significantly different affinities for silica, allowing the
dendrons to be isolated as monodisperse compounds, as assessed
by size exclusion chromatography (SEC) and matrix-assisted
laser desorption ionization mass spectrometry (MALDI-TOF
MS).
Protecting groups were necessary to mask the peripheral
hydroxy functionalities during the synthesis. Dendrons uniformly
protected with either benzyl or ketal groups were chosen as
targets because these protecting groups are stable to the alkaline
conditions used during the synthesis, and they could be easily
removed by palladium-catalyzed hydrogenolysis or acid-
catalyzed hydrolysis, respectively. In addition, when both
protecting groups are placed on the periphery of the same
dendron, their orthogonality enabled a selective modification
of the surface.
In the following discussion, dendrons will be identified
according to their peripheral functionality, their generation (the
number of layers of branching units), and their focal functional-
ity. Thus, compound 6 (Scheme 1), with its 16 peripheral benzyl
ethers, 4 layers of branching units, and alkene focal point, would
be referred to as (BnO-)16[G-4]-ene.
Benzyl-Protected Dendrons. The first-generation benzyl-
protected alcohol was prepared by reaction of an excess of
benzyl alcohol with epichlorohydrin under phase-transfer condi-
tions to afford the alcohol, 1, that was purified by distillation.
The subsequent growth step consisted of double nucleophilic
displacements on the MDC monomer by the alkoxide of 1 to
give (BnO-)4[G-2]-ene, 2, in 95% yield. (Scheme 1). Activation
of the dendritic alkenes was carried out using standard hy-
droboration-oxidation conditions,10 producing the correspond-
ing dendritic alcohol. When the borane:THF complex was used
to boronate the alkene, 2, 5% of the undesired Markovnikov
product was formed in addition to the intended primary alcohol.
Use of 9-BBN was found to be more regioselective and
effectively eliminated this side product, producing the primary
[G-2]-ol, 3, in 90% isolated yield.
a i NaH, MDC, THF. ii. (1) 9-BBN, THF; (2) H2O2, NaOH.
improve the yield or purity of the desired product. Although
the trace amount of lower generation byproduct can be removed
successfully by flash chromatography, this becomes increasingly
difficult at higher generations.
Subsequent activation and coupling steps could be repeated
with high yields throughout the third ((BnO-)8[G-3]-ene, 4,
and (BnO-)8[G-3]-ol, 5) and fourth ((BnO-)16[G-4]-ene, 6, and
(BnO-)16[G-4]-ol, 7) generations (Scheme 1). Only at the fifth
generation ((BnO-)32[G-5]-ene, 8, and (BnO-)32[G-5]-ol, 9) does
it appear that the steric bulk of these compounds begins to inhibit
reactions at the focal point, resulting in significantly longer
reaction times and lower yields.
If a very pure product is desired, intermediate purifications
are required as all of the activation steps led to the formation
of a trace amount of the lower generation alcohol. Because the
lower generation alcohol is less hindered, it is more reactive
during the coupling step and complicates the synthesis of larger
dendrons if it is not removed. Milder sodium hydroxide (1 M)
or sodium perborate11 workups were investigated but did not
All of these benzyl-protected dendrons were isolated as
viscous oils. The chromatography for both the coupling and the
activation steps was simplified because of the vastly different
polarities between the unreacted starting material and the
product. At higher generations, the purification and handling
of these compounds became more difficult, as the viscosity of
the materials increased, and the retention factors of the alkene
and alcohol converged. Because of these complications, and the
decreased reactivity of the focal point at higher generations,
the synthesis of dendrons above the fifth generation was not
(10) Brown, H. C. Hydroboration; Benjamin: New York, 1962.
(11) Kabalka, G. W.; Shoup, T. M.; Goudgaon, N. M. J. Org. Chem.
1989, 54, 5930.

Aliphatic Polyether Dendrons
J. Am. Chem. Soc., Vol. 122, No. 42, 2000 10337
Scheme 2a
attempted. It should be emphasized, however, that the dendrons
we prepared are of a size sufficient for their intended uses.3c-e,9
Ketal-Protected Dendrons. A second family of aliphatic
polyether dendrons, utilizing the ketal protecting group, was
also synthesized. Symmetrical ketones were selected as the
peripheral protecting groups in order to prevent any undesirable
stereochemical complications during purification and charac-
terization. Dendritic compounds utilizing the ketals of acetone,
pentanone, and nonanone were initially investigated; however,
the nonanone ketal was selected for further study because the
resulting dendrons are quite soluble in hexanes, thus simplifying
flash chromatography.
An efficient bulk synthesis of the bis-protected triol, 11,
involves the reaction of 1,1,1-tris(hydroxymethyl)ethane with
an excess of nonanone and a catalytic amount of BF3 etherate.
This first-generation nonanone ketal (Nk) protected alcohol, Nk-
[G-1]-ol,12 could be isolated from the crude reaction mixture
by distillation. Reaction of the alcohol, 11 (2.2 equiv), NaH,
and the MDC monomer afforded the (Nk-)2[G-2]-ene, 12, in
84% yield. Activation of dendritic alkene, 12, with 9-BBN
and alkaline peroxide gave the primary (Nk-)2[G-2]-ol, 13, in
93% yield. As was the case with the benzyl ether dendrons, a
minor side reaction was observed during the activation step that
led to the production of the lower generation alcohol. After
chromatographic purification, the subsequent activation and
coupling steps continued affording high yields for the third
((Nk-)4[G-3]-ene, 14, and (Nk-)4[G-3]-ol, 15) and fourth
((Nk-)8[G-4]-ene, 16, and (Nk-)8[G-4]-ol, 17) generation den-
drons. The use of N,N-dimethylacetamide (DMAc) to accelerate
the coupling reaction enabled access to the fifth generation
((Nk-)16[G-5]-ene, 18, and (Nk-)16[G-5]-ol, 19).
The dendrons with ketal protecting groups were also isolated
as viscous oils. Because of their peripheral lipophilic chains,
these compounds exhibited high solubility in hexane and a
significantly lower polarity during flash chromatography than
the benzyl-protected analogues. The reduced chromatographic
resolution between the alcohol and the alkene at higher
generations, combined with slower reaction rates in both the
coupling and activation steps, made the preparation of dendrons
above the fifth generation unpractical.
Surface Modification. The benzyl ether protecting groups
can be quantitatively removed through catalytic hydrogenolysis
to expose a polyol periphery. Cleavage of the benzyl ethers was
achieved by reaction with 10% Pd/C in 50:50 THF/EtOH under
5-10 atm of hydrogen gas. The deprotection reactions took
between 24 and 48 h, depending upon generation, and could
be easily monitored by MALDI-TOF MS via the analysis of a
micromolar aliquot taken from the reaction mixture. Because
the catalyst was heterogeneous, purification was achieved by
simple filtration, affording a quantitative yield of the polyol.
The use of higher pressures increased the reaction rate but also
led to the reduction of a small percentage of the peripheral
benzyl ethers to the cyclohexylmethyl ethers, a moiety that
cannot be removed from the dendron.13 It should be noted that
cleavage of the benzyl ethers via hydrogenolysis leads to the
a i. 0.2 M HCl, THF/MeOH. ii. BzCl, pyridine.
concurrent reduction of the focal alkene functionality; therefore,
any required modification at the focal point must be initiated
before the hydrogenolysis.
Similarly, the ketal protecting groups could be quantitatively
removed by an acid-catalyzed hydrolysis.14 The hydrolysis was
achieved by reaction with either Dowex acid cation-exchange
resin or dilute HCl in 50:50 THF/MeOH. Removal of the acid
by either filtration of the Dowex or evaporation of the HCl
solution yielded the desired polyol15 (Scheme 2). Monitoring
(12) Nk- is an abbreviation for the bidentate 5-nonanone ketal protecting
group.
(13) Evidence for this side reaction include additional aliphatic reso-
nances in the H and C NMR and well-resolved signals in the MALDI-TOF
MS corresponding to an additional 96 and 192 amu above the expected
molecular weight. Although this is a minor side reaction, the multiplicity
of benzyl groups on high-generation dendrons causes a moderate statistical
probability of defect per dendron; therefore, lower pressures were use to
avoid this complication. Trace amounts of this aromatic reduction have been
noted before with Pd/C catalyst. Gla¨nzer, B. I.; Gyo¨rgydea´k, Z.; Benet, B.;
Vasella, A. HelV. Chim. Acta 1991, 74, 343.
(14) Ihre, H.; Hult, A.; Fre´chet, J. M. J.; Gitsov, I. Macromolecules 1998,
31, 4061.

10338 J. Am. Chem. Soc., Vol. 122, No. 42, 2000
Grayson and Fre´chet
Table 1. Miscibility of Surface-Functionalized Fourth-Generation
Dendrons
again, by acylation of the hydroxy groups. The lipophilic nature
of the tetradecanoate esters of 38 made that compound miscible
in all but the polar protic solvents, whereas the poly(benzoyl
ester) dendron, 36, like the poly(benzyl ether), 6, was miscible
in all solvents but the extremely nonpolar (hexane) and polar
protic (methanol and water.) The addition of the methoxy-
terminated tetraethylene glycol chain ends led to a compound
(37) with more versatile solubility, being miscible in water,
methanol, ethyl acetate, chloroform, and most other solvents,
except hexane. These solubility trends reinforce the now widely
accepted notion that as a dendron’s generation increases, the
peripheral functional groups dominate its solubility properties.16
Hybrid Peripheral Copolymer Dendrons. Making use of
the versatility of the convergent synthesis,17 orthogonally
protected hybrid dendrons utilizing both the ketal and benzyl
protecting groups were synthesized. The use of these orthogonal
protecting groups enables the selective modification of the
peripheral hydroxy groups with complementary functionalities
for applications such as drug delivery.3c-e Two architectures
were investigated: the first, an alternating hybrid, incorporated
alternating pairs of benzyl- and ketal-protected hydroxy units
on the periphery; the second, a block hybrid, was comprised of
two structurally separated blocks with benzyl and ketal protect-
ing groups, respectively. To distinguish between these consti-
tutional isomers the alternating hybrids will be given the prefix
alt- whereas the block hybrids will be given the prefix block-.
Alternating Hybrids. For the synthesis of the alternating
hybrids, a single chloride group of the MDC monomer was
functionalized with the alkoxide of the first-generation benzyl-
protected alcohol, 1 (Scheme 3). This was achieved by using a
2-fold excess of MDC, ensuring high yields of the monosub-
stituted monomer, 21. The remaining allylic chloride of 21 was
reacted with the alkoxide of the first-generation ketal-protected
alcohol, 11, to yield alt-(BnO-)2Nk-[G-2]-ene, 22. Repetition
of the activation and growth steps led to the production of alt-
(BnO-)8(Nk-)4[G-4]-ene, 26.
Block Hybrids. The block hybrids were prepared by reaction
of the third-generation ketal-protected alcohol, 15, with an
excess of the MDC, yielding the monocoupled product, 29. The
resulting allylic chloride, 29 was then treated with the third-
generation benzyl-protected alcohol, 5, to yield block-(BnO-)8-
(Nk-)4[G-4]-ene, 30.
Selective Deprotection of Hybrids. As a result of the
orthogonality of the chosen protecting groups, ketal deprotection
of the fourth-generation hybrid alkenes (26 and 30) could be
achieved by acid-catalyzed hydrolysis, producing hybrid den-
drons with eight hydroxy groups and eight benzyl ethers (27
and 31) in quantitative yields (Scheme 4). Similarly, the
hydrogenolysis of the benzyl groups from 26 and 30 followed
the procedure established for the wholly benzyl protected
dendrons, except basic alumina was added to the reaction
mixture to preserve the acid-sensitive ketal groups. This reaction
afforded the debenzylated polyols, 28 and 32, in quantitative
yields.
miscibility of (R-)16[G-4]-ene where Ra )
solvent
Nk
BnO
HO
TEG
BzO
Myr
water
imm
imm
misc
misc
misc
misc
misc
misc
imm
imm
misc
misc
misc
misc
misc
imm
misc
misc
misc
imm
imm
imm
imm
imm
misc
misc
misc
misc
misc
misc
misc
imm
imm
imm
misc
misc
misc
misc
misc
imm
imm
imm.
misc
misc
misc
misc
misc
misc
MeOH
DMAc
CHCl3
CH2Cl2
EtOAc
THF
hexane
a Nk ) nonanone ketal; TEG ) tri(ethylene glycol) monomethyl
ether, CH3(OCH2CH2)3O-; Myr ) tetradecanoate (myristate) ester.
by MALDI-TOF MS showed that the reaction took between 4
and 48 h, with longer reaction times required for larger dendrons.
For the fourth-generation dendron, the deprotection could be
expedited by removing the released nonanone byproduct by
distillation after 6 h and then refreshing the acid catalyst. The
ketal-protected dendrons have a distinct advantage over the
benzyl-protected dendrons since the orthogonal alkene focal
functionality is preserved during removal of the protecting
groups, allowing both the focal point and the periphery to be
independently modified.
The polyol dendrons are highly polar molecules that are
water-soluble above the third generation. At the second and third
generations, the peripheral deprotected dendrons with focal
alcohol functionality are water-soluble, but those with the alkene
moiety at the focal point are not. At the fourth generation the
hydrophilic nature of the 16 hydroxy end groups of the
deprotected dendrons is sufficient to make both the (HO-)16-
[G-4]-ane, 10, and (HO-)16[G-4]-ene, 20, water-miscible (>100
mg/mL) despite the nonpolar focal functionality.
A number of reactions were investigated to verify the ease
with which the peripheral hydroxyl groups could be modified.
Acylation of the peripheral groups was achieved by reaction in
pyridine with benzoyl chloride (Scheme 2) or with tetradecanoic
acid, DCC, and DPTS, leading to a rapid, quantitative formation
to the corresponding polyesters (36 and 38) of (HO-)16[G-4]-
ene as judged by the MALDI-TOF MS spectrum of the crude
product. Model alkylations were performed by nucleophilic
substitution using NaH, and an excess of allyl bromide or the
mesylate of tri(ethylene glycol) monomethyl ether. Although
much slower than the acylations, full conversion could be
achieved using THF as solvent for low-generation dendrons
while DMAc was required at higher generations to solvate the
polar dendritic polyols. MALDI-TOF MS was especially useful
in monitoring the extent of reaction and characterizing the final
products.
The modification of the surface moieties on fourth-generation
dendrons with focal alkene functionalities demonstrates the
importance of the peripheral functionality in determining the
solubility of the resultant dendrons (Table 1). Initially the benzyl
ether (6) and ketal protected (16) dendrons appear to be miscible
in most organic solvents except those that were polar protic
solvents (e.g., water and methanol.) The nonanone ketal has
the additional advantage of being miscible in extremely nonpolar
solvents such as hexane. However, after the removal of the
protecting groups to expose a polyhydroxylated surface, we
observed a reversal in the solubility trends, in which the polyols,
10 and 20, are only miscible in water, methanol, DMAc, and
pyridine. The solubility of the polyol dendrons can be reversed
The utility of the orthogonally protected surface was dem-
onstrated by a selective functionalization of the dendritic
periphery (Scheme 5). The fourth-generation block hybrid
alkene, 30, was first partially deprotected by an acid-catalyzed
hydrolysis of the ketals. The eight exposed hydroxyl groups of
(16) Wooley, K. L.; Fre´chet, J. M. J.; Hawker, C. J. Polymer 1994, 35,
4489.
(17) Hawker, C. J.; Fre´chet, J. M. J. Macromolecules 1990, 23, 4726.
Wooley, K. L.; Hawker, C. J.; Fre´chet, J. M. J. J. Chem Soc., Perkin Trans.
1 1991, 1059. Hawker, C. J.; Wooley, K. L.; Fre´chet, J. M. J. J. Chem
Soc., Perkin Trans. 1 1993, 1287.
(15) It was observed that if the reaction conditions were too acidic (greater
than 1 M HCl), cleavage of the allyl ether bonds could occur.

Aliphatic Polyether Dendrons
J. Am. Chem. Soc., Vol. 122, No. 42, 2000 10339
Scheme 4a
Scheme 3a
a i. NaH, MDC, THF. ii. (1)9-BBN, THF; (2)H2O2, NaOH.
31 were then alkylated with short oligo(ethylene glycol) chains
by nucleophilic substitution using NaH and an excess of the
mesylate of tri(ethylene glycol) monomethyl ether. The desired
fully alkylated product, 33, was isolated in 89% yield over the
two steps from block-(BnO-)8(Nk-)4[G-4]-ene, 30. Next, the
benzyl ethers were removed by palladium-catalyzed hydro-
genolysis, and the peripheral alcohols were then acylated with
benzoyl chloride in pyridine affording the product, 35, in a 78%
yield. MALDI-TOF MS was used to verify that each of these
surface modifications was driven to completion (Figure 1).
a i. 0.2 M HCl, THF/MeOH. ii. 7 atm H2, Pd/C, basic alumina, THF/
EtOH.
to observe the alkene double-bond stretch above the third
generation. In addition, the elemental ratios converge with
increasing generation, making it difficult to distinguish between
dendrons or verify their purity solely by elemental analysis.
However, these techniques were useful for characterizing the
dendrons after peripheral modifications, since these surface
alterations correspond to significant changes in functionality as
well as elemental composition. For example, after the hydrolysis
of (Nk-)8[G-4]-ene, 16, to produce the polyol, 20, the FTIR
spectrum shows the appearance of a broad hydroxyl band
centered around 3390 cm-1. Acylation to form the polybenzoate,
36, leads to the complete disappearance of the hydroxyl band
Characterization
For all of the compounds synthesized, the data obtained from
1H NMR, 13C NMR, SEC, and MALDI-TOF MS were sufficient
to unambiguously identify these compounds and verify their
structural integrity.
Although IR spectroscopy and elemental analysis were used
to characterize all of the polyether dendrons, these techniques
have limitations when distinguishing between dendritic com-
pounds with similar peripheral functionalities.4 At higher
generations, the infrared signals of the focal functionalities are
overwhelmed by those of the repeat units, making it difficult
and the appearance of a sharp carbonyl band at 1724 cm-1
.

10340 J. Am. Chem. Soc., Vol. 122, No. 42, 2000
Grayson and Fre´chet
Scheme 5a
Figure 1. MALDI-TOF mass spectral data for the selective peripheral
modification of the hybrid dendrons.
of the polyether framework and the peripheral benzyl ethers.
The dendritic alkenes exhibit an allylic singlet at 3.8 ppm and
1
a vinylic singlet at 5.1 ppm in the H NMR (Figure 2) as well
as alkene resonances at 113 and 143 ppm in the 13C NMR
(Figure 3). The dendritic alcohols display an alcohol triplet
between 2.8 and 3.1 ppm in the 1H NMR (Figure 2), while the
adjacent methylene has a resonance at 64 ppm in the 13C NMR
(Figure 3).
b. Ketal-Protected Dendrons. The ketal-protected dendrons
also exhibited well-isolated resonances for the focal function-
1
alities in both the H and 13C NMR. The dendritic alkenes
exhibit an allylic singlet at 3.9 ppm and a vinylic singlet at 5.1
ppm in the 1H NMR as well as alkene resonances near 113 and
143 ppm in the 13C NMR. The dendritic alcohols display an
alcohol triplet between 2.4 and 2.5 ppm in 1H NMR, while the
1
adjacent methylene shows a triplet at 3.7 ppm in the H NMR
and a resonance at 64 ppm in the 13C NMR.
In addition to being able to determine the focal functionality,
comparison of the 1H NMR integration values between the focal
functionality and the peripheral benzyl or ketal protecting groups
accurately verifies the generation of the dendrons.
c. Functionalization. Both the hydrogenolysis and the
hydrolysis deprotection reactions were quantitative, and 1H
NMR confirmed the full removal of the aromatic and the ketal
groups, respectively. Modification of the peripheral alcohol
groups through acylation or etherification could be verified by
the loss of the alcohol resonances and the appearance of new
resonances corresponding to the benzoate ester (1H NMR δ )
4.30, 7.38, 7.51, 7.98), the myristate ester (1H NMR δ ) 1.60,
2.30, 3.98), the allyl ether (1H NMR δ ) 5.16, 5.21, 5.89), or
the oligo(ethylene glycol) ether (1H NMR δ ) 3.36, 3.52, 3.59).
d. Hybrid Dendrons. The hybrid dendrons could easily be
characterized as a result of the significant differences between
the resonances of the two protecting groups. The focal alcohol
and alkene functionalities show similar resonances to those seen
in the fully benzyl or fully ketal protected dendrons. The fourth-
generation alternating hybrid could be distinguished from the
same generation block hybrid by examining the 1H NMR shifts
of the allylic methylene protons adjacent to the focal alkene (δ
) 3.87 ppm). In the alternating hybrid, these groups are
chemically identical as a result of molecular symmetry and
therefore appear as a singlet; however, in the block hybrid, each
allylic methylene is attached to a dendritic block with different
surface protecting groups, resulting in two overlapping but
distinct resonances.
a i. 0.2 M HCl, THF/MeOH. ii. NaH, CH3O(CH2CH2O)3Ts, THF.
iii. 7 atm H2, Pd/C, THF/EtOH. iv. BzCl, pyridine, THF.
1H and 13C NMR. a. Benzyl-Protected Dendrons. The high
degree of symmetry in these dendrons enabled facile confirma-
tion of both structure and purity by 1H and 13C NMR. Figure 2
1
shows the H NMR of the (BnO-)8[G-4]-ene and the (BnO-)8-
MALDI-TOF MS. MALDI-TOF MS was especially useful
in characterizing these dendritic compounds (Figure 4) and
monitoring their reactions. Samples were prepared by dissolving
[G-4]-ol. The focal alkene or alcohol functionalities can easily
be identified because their resonances are isolated from those

Aliphatic Polyether Dendrons
J. Am. Chem. Soc., Vol. 122, No. 42, 2000 10341
Figure 2. 1H NMR spectra of the benzyl-protected fourth-generation dendrons with alkene (above) and alcohol (below) focal functionalities.
micromolar quantities of the dendritic material in THF with
R-cyano-4-hydroxycinnamic acid as a matrix and silver tri-
fluoroacetate to produce a detectable silver cationic complex.
For the dendritic compounds bearing ketals, this acidic matrix
appeared to slowly catalyze the removal of the ketal groups;
therefore, 9-nitroanthracene with silver trifluoroacetate was used
as the matrix. All of the spectra displayed a very prominent [M
+ Ag]+ peak corresponding to the dendritic polyether compound
complexed with a silver cation, as well as faint [M + Na]+ and
[M + K]+ peaks from residual cations. The observed molecular
masses were calibrated against bovine insulin and gave molec-
ular weight calculations consistently within 0.2% of the theoreti-
cal values (Tables 2-4).
Size Exclusion Chromatography. The dendritic polyethers
were also characterized by size exclusion chromatography in
THF and calibrated against polystyrene standards (Tables 2-4).
A UV detector was used to evaluate all of the dendrons with
benzyl protecting groups, whereas those dendrons without
aromatic rings required the use of a refractometer. Although
MALDI-TOF offers much more accurate molecular weight and
more meaningful polydispersity data for such monodisperse
molecules, SEC provides valuable data confirming the purity
of these dendrons, and their globular conformation in solution.
All compounds exhibited a SEC polydispersity index (PDI) of
less than 1.01, confirming the absence of lower molecular weight
byproducts that may occur from incorporation of alcohol
impurities during the coupling step or premature cleavage of
the protecting groups. As reported for other highly branched,
globular materials,4,18 the ratio between log Mw and the retention
time shows a distinctly different trend than linear polymers. This
observed effect is a result of the increasingly compact nature
of high-generation dendrons, with respect to linear polymers
of comparable molecular weights. Their compact conformation
corresponds to a smaller hydrodynamic volume, longer retention
times, and therefore an underestimation of the molecular weight.
Conclusion
We have demonstrated that the convergent approach can be
applied toward an efficient synthesis of aliphatic polyether
dendrons with differentiated surface functionalities. These
dendrons are chemically robust and easily functionalized at both
the focal point and periphery, making them versatile scaffolds
for a host of applications. This family of dendrons complements
the widely used poly(benzyl ether) dendrons4 that had been
developed previously in our laboratory.
The convergent synthesis does have a distinct limitation as
steric hindrance around the focal functionality prevents access
to dendrons above the fifth generation. However, we have
demonstrated that this technique can be used to synthesize pure
aliphatic ether dendritic compounds of molecular weights up
(18) Aharoni, S. M.; Crosby, C. R.; Walsh, E. K.; Macromolecules 1982,
15, 1093. Morena-Bondi, M. C.; Orellana, G. Turro, N. J., Tomalia, D. A.
Macromolecules 1990, 23, 910.

10342 J. Am. Chem. Soc., Vol. 122, No. 42, 2000
Grayson and Fre´chet
Figure 3. 13C NMR spectra of the benzyl-protected fourth-generation dendrons with alkene (above) and alcohol (below) focal functionalities.
Table 3. Mass Spectral and Size Exclusion Chromatographic Data
for the Ketal-Protected Polyether Dendrons
compound
calculated MW
MALDI-TOF MS MW
SEC Mn
[G-2]-ene
[G-2]-ol
[G-3]-ene
[G-3]-ol
[G-4]-ene
[G-4]-ol
[G-5]-ene
[G-5]-ol
540.8
558.8
541a
600
710
559a
1169.8
1187.8
2427.6
2445.6
4943.3
4961.3
1170
1189
2429
2446
4941
4963
1400
1410
2390
2420
4370
4210
a The mass spectra for the second-generation dendrons were acquired
using FAB MS.
Figure 4. MALDI-TOF mass spectra of the third-, fourth-, and fifth-
generation ketal-protected alcohols.
Table 4. Mass Spectral and Size Exclusion Chromatographic Data
for the Hybrid Polyether Dendrons
Table 2. Mass Spectral and Size Exclusion Chromatographic Data
for the Benzyl-Protected Polyether Dendrons
compound
calculated MW
EI-TOF MS MW
SEC Mn
compound
calculated MW
MALDI-TOF MS MW
SEC Mn
[G-2]-ene
[G-2]-ol
[G-3]-ene
[G-3]-ol
[G-4]-ene
568.4
586.4
1224.8
1242.8
2539.5
568.4
586.4
1224.7
1242.7
2547.1a
640
650
1270
1250
2180
[G-2]-ene
[G-2]-ol
[G-3]-ene
[G-3]-ol
[G-4]-ene
[G-4]-ol
[G-5]-ene
[G-5]-ol
596.7
614.7
597a
580
590
615a
1281.6
1299.6
2651.4
2669.4
5390.8
5408.9
1280
1299
2651
2670
5394
5408
1220
1190
1980
1990
3560
3520
a The mass spectra for the fourth-generation dendron was acquired
using MALDI-TOF MS.
a The mass spectra for the second-generation dendrons were acquired
using FAB MS.
permitting the synthesis of a variety of hybrid structures.
Placement of orthogonal protecting groups on the surface of
these materials enables their regioselective modification with
excellent control over the placement and ratio of peripheral
moieties. We are currently evaluating these hybrid dendrons
to 5000 Da in high yield. The enormous advantage of the
convergent approach is its precise control of functionality at
both the focal point and the periphery of the molecule, thus

Aliphatic Polyether Dendrons
J. Am. Chem. Soc., Vol. 122, No. 42, 2000 10343
mixture was saturated with K2CO3 and extracted twice with ether. The
organic layers were dried over anhydrous MgSO4, and the solvent was
removed in vacuo. The residue was purified by flash column chroma-
tography on silica gel with hexanes-ethyl acetate gradient from 5%
ethyl acetate to 35% ethyl acetate: yield 88%; 1H NMR (CDCl3) δ )
2.08 (m, 3), 2.15 (m, 4), 2.86 (t, 1), 3.5-3.8 (m, 82), 4.49 (s, 32),
7.2-7.4 (m, 80); 13C NMR (CDCl3) δ ) 40.2 (CH), 40.9 (CH), 41.4
(CH), 63.5 (CH2), 68.6 (CH2), 69.5 (CH2), 69.6 (CH2), 69.9 (CH2),
70.0 (CH2), 71.0 (CH2), 73.3 (CH2), 78.3 (CH), 127.5 (CH), 127.5 (CH),
128.3 (CH), 138.4 (C); FTIR ν ) 3493 cm-1 (OH), 3030 cm-1 (H-
Ar), 1106 cm-1 (C-O-C); MS (MALDI-TOF) [M + Ag]+ (calcd
2777.5) found 2777.7; elemental analysis calcd (%) for C164H202O31
(2669.4) C, 73.79; H, 7.63; found C, 73.60; H, 7.64.
Representative Procedure for the Deprotection of Dendrons with
Peripheral Benzyl Ethers: (HO-)16[G-4]-ane (10). To a 20 mL
scintillation vial containing 0.43 g (0.16 mmol) of the (Bn-)16[G-4]-
ene, 6, were added 0.04 g of 10% Pd/C and 5 mL of 50:50 THF/EtOH.
The vial was placed inside a steel bomb and stirred under 7 atm of
hydrogen gas. After the first 24 h, an additional 0.02 g of catalyst was
added to the vial, and the bomb was pressurized again to 7 atm of
hydrogen gas. After an additional 24 h the reaction appeared complete
by MALDI-TOF MS. The catalyst was removed from the reaction
mixture via vacuum filtration through Celite, and the solvent was
for applications such as drug delivery devices that require water-
soluble macromolecules with a multivalent, diversely function-
alized periphery. Presently, in vivo and in vitro studies are in
progress to determine the biocompatibility of these new
branched analogues of poly(ethylene glycol).
Experimental Section
Materials. All reagents were purchased from Aldrich and used
without further purification, unless otherwise noted. Tetrahydrofuran
(THF) was distilled over sodium/benzophenone. All other solvents
(Fischer) were reagent grade (99.9%).
General. All reactions were performed under a dry nitrogen
atmosphere. Thin-layer chromatography was performed on Merck
Kieselgel 60 F254 plates. Silica used for flash chromatographic separation
was Merck Kieselgel 60 (230-400 mesh). Isolated materials were dried
under vacuum for 12 h.
Characterization. All 1H NMR spectra were acquired at room
temperature with a Bruker AM spectrometer at 400 MHz. All 13C NMR
and distortionless enhancement by polarization transfer (DEPT) spectra
were obtained with a Bruker DRX spectrometer at 125 MHz. All NMR
data are reported in parts per million and calibrated (1H against TMS
) 0.00 ppm, 13C against CDCl3 ) 77.00 ppm). Infrared spectra were
collected on a Mattson Genesis II FT-IR using a reflective mirror
surface. For compounds with a molecular mass of 1200 or less, mass
spectral data was collected by EI-TOF MS on either a Micromass LCT
instrument or a Hewlett-Packard 6890 GC attached to a HP 5973 mass
selective detector. For compounds with a greater molecular mass,
MALDI-TOF MS data was collected on a PerSeptive Biosystems
Voyager-DE instrument in positive ion mode. MALDI-TOF MS
samples were prepared in either an R-cyano-4-hydroxycinnamic acid
or 9-nitroanthracene matrix with silver trifluoroacetate, and the instru-
ment was calibrated against bovine insulin standards. M-H-W Labo-
ratories (Pheonix, AZ) performed elemental analysis. Size exclusion
chromatography was carried out on a Waters GPC 150-CV plus system
(Milford, MA) with an attached M486 tunable absorbance detector (λ
) 254 nm). Eighteen polystyrene standards from Polymer Laboratories
(Amherst, MA) were used for calibration, and the mobile phase was
tetrahydrofuran (1 mL/minute, 45 °C). A bank of 4 PL Gel columns (5
µm) from Polymer Laboratories (Amherst, MA) was used: 100 Å, 100
Å, 500 Å, and a Mixed C.
removed from the filtrate in vacuo. The viscous polyol was characterized
1
without further purification: 99% yield; H NMR ((CD3) SO) δ )
2
0.87 (d, 3), 1.9-2.1 (m, 7), 3.19 (m, 8), 3.3-3.6 (m, 72), 4.46 (s, 16);
13C NMR ((CD3) SO) δ ) 14.8 (CH3), 34.8 (CH), 40.2 (CH), 41.0
2
(CH), 68.2 (CH2), 69.2 (CH2), 69.3 (CH2), 69.5 (CH2), 73.4 (CH2),
82.1 (CH); FTIR ν ) 3380 cm-1 (OH), 1118 cm-1 (C-O-C); MS
(MALDI-TOF) [M + Ag]+ (calcd 1319.3) found 1324.3; elemental
analysis calcd (%) for C52H106O30 (1211.4) C, 51.56; H, 8.82; found C,
51.38; H, 8.75.
Representative Procedure for the Deprotection of Dendrons with
Peripheral Ketal Groups: (HO-)16[G-4]-ene (20). To a round-bottom
flask containing 0.93 g (0.38 mmol) of the (Nk-)8[G-4]-ene (16) were
added 4 cm3 of Dowex-50W (50X1-100) acidic resin beads and 10
mL of 50:50 THF/MeOH. A stirbar was added to facilitate the reaction,
and after 36 h the reaction appeared complete by MALDI-TOF MS.
The resin was removed via vacuum filtration, and the solvent was
removed from the filtrate in vacuo producing 0.262 g (97% yield) of
1
the viscous, oily polyol. H NMR ((CD3)2SO) δ ) 0.76 (s, 24), 2.01
(m, 6 J ) 6.0 Hz), 3.16 (s, 16), 3.24 (m, 32), 3.32 (m, 36), 3.87 (s, 4),
4.25 (s,16), 5.10 (s, 2); 13C NMR (CD3OD) δ ) 15.9 (CH3), 40.1 (CH),
40.2 (CH), 41.2 (C), 65.1 (CH2), 68.4 (CH2), 69.2 (CH2), 69.4 (CH2),
69.6 (CH2), 71.3 (CH2), 73.8 (CH2), 112.9 (CH2), 143.1 (C); FTIR ν
) 3390 cm-1 (OH), 1128 cm-1 (C-O-C); MS (MALDI-TOF) (m/z),
[M + Ag]+ (calcd 1541.7) found 1546.7; elemental analysis calcd (%)
for C68H136O30 (1433.8) C, 56.96; H, 9.56; found C, 56.79; H, 9.35.
Representative Procedure for the Acylation of Dendrons with
Peripheral Alcohol Functionalities: (BzO-)16[G-4]-ene (36). To a
round-bottom flask containing 0.16 g (0.11 mmol) of the (HO-)16-
[G-4]-ene (20) were added 4 mL of pyridine and 0.48 g (3.5 mmol) of
benzoyl chloride. The reaction mixture was stirred at 60 °C for 4 h, at
which time the reaction appeared complete by MALDI-TOF MS. After
cooling to room temperature, the reaction mixture was poured into water
and extracted twice with ether. The organic layers were dried over
anhydrous MgSO4, and the solvent was removed in vacuo. The product
was purified by flash column chromatography on silica with hexanes-
ethyl acetate gradient from 10% ethyl acetate to 40% ethyl acetate:
Representative Procedure for the Synthesis of Dendrons
with Focal Alkene Functionality via Coupling with Monomer:
(BnO-)16[G-4]-ene (6). Dry NaH (2.2 equiv) and methallyl dichloride
(3-chloro-2-chloromethyl-1-propene) (1.0 equiv) were placed in a dry
round-bottom flask under N2 atmosphere. To the reaction mixture was
added (BnO-)8[G-(3)]-ol (2.2 equiv), 5, diluted to 1 M concentration
in freshly distilled THF. The mixture was stirred at room temperature
for ∼15 min and overnight at ∼65 °C. After cooling to room
temperature, the reaction mixture was quenched with water and
extracted twice with ether. The organic layers were dried over anhydrous
MgSO4, and the solvent was removed in vacuo. The product was
purified by flash column chromatography on silica gel with hexanes-
ethyl acetate gradient from 5% ethyl acetate to 35% ethyl acetate: yield
90%; 1H NMR (CDCl3) δ ) 2.14 (m, 6), 3.5-3.8 (m, 76), 3.83 (s, 4),
4.48 (s, 32), 5.08 (s, 2), 7.2-7.4 (m, 80); 13C NMR (CDCl3) δ ) 40.2
(CH), 41.0 (CH), 68.6 (CH2), 68.9 (CH2), 69.6 (CH2), 69.7 (CH2), 70.0
(CH2), 71.8 (CH2), 73.2 (CH2), 78.3 (CH), 116.4(CH2), 127.4 (CH),
127.5 (CH), 128.3 (CH), 138.4 (C), 143.0 (C); FTIR ν ) 3030 cm-1
(H-Ar), 1104 cm-1 (C-O-C); MS (MALDI-TOF) [M + Ag]+ (calcd
2759.2) found 2759.4; elemental analysis calcd (%) for C164H200O30
(2651.4) C, 74.29; H, 7.60; found C, 74.13; H, 7.43.
Representative Procedure for the Synthesis of Dendrons with
Focal Alcohol Functionality via Hydroboration-Oxidation of
Alkene: (BnO-)16[G-4]-ol (7). Freshly distilled dry THF and
(BnO-)16[G-4]-ene, 6, (1 equiv) were placed in a dry round-bottom flask
under N2 and cooled to 0 °C in a ice bath. To this flask, 0.5 M 9-BBN
solution in THF (1.1 equiv) was added slowly and allowed to stir at 0
°C for 2 h. The reaction mixture was then quenched with 3 M NaOH
solution in water (4.5 equiv) followed by addition of 30% H2O2 aqueous
solution (3.0 equiv) and stirred at room temperature for 1 h. The reaction
1
yield 59%; H NMR (CDCl3) δ ) 1.10 (s, 24), 2.01 (m, 2, J ) 5.9
Hz), 2.08 (m, 4, J ) 5.8 Hz), 3.30 (m, 20), 3.38 (m, 32), 3.82 (s, 4),
4.28 (d, 16, J ) 11.1 Hz), 4.32 (d, 16, J ) 11.1 Hz), 5.08 (s, 2), 7.38
(m, 32), 7.51 (m, 16), 7.98 (m, 32); 13C NMR (CDCl3) δ ) 15.9 (CH3),
40.1 (CH), 40.2 (CH), 41.2 (C), 65.1 (CH2), 68.4 (CH2), 69.2 (CH2),
69.4 (CH2), 69.6 (CH2), 71.3 (CH2), 73.8 (CH2), 112.9 (CH2), 143.1
(C); FTIR ν ) 1724 cm-1 (CdO), 1109 cm-1 (C-O-C); MS (MALDI-
TOF) (m/z), [M + Ag]+ (calcd 3207.3) found 3214.0; elemental analysis
calcd (%) for C180H200O46 (3199.4) C, 69.75; H, 6.50; found C, 69.57;
H, 6.63.
Representative Procedure for the Alkylation of Dendrons with
Peripheral Alcohol Functionalities: (CH3(OCH2CH2)3O-)16[G-4]-

10344 J. Am. Chem. Soc., Vol. 122, No. 42, 2000
Grayson and Fre´chet
ene (37). To a round-bottom flask containing 0.09 g (0.06 mmol) of
the (HO-)16[G-4]-ene (20) were added 3 mL of DMAc and 0.50 g (1.51
mmol) of the tosylate of tri(ethylene glycol), monomethyl ether. The
reaction mixture was stirred at 60 °C, while 0.02 g of NaH powder
was added every 6 h. After 36 h, the reaction appeared complete by
MALDI-TOF MS and was cooled to room temperature. The reaction
mixture was poured into water and extracted twice with ether. The
organic layers were dried over anhydrous MgSO4, and the solvent was
removed in vacuo. The product was purified by flash column chro-
matography on silica with dichloromethane-methanol gradient from
3% methanol to 8% methanol: yield 52%; 1H NMR (CDCl3) δ ) 0.76
(s, 24), 2.01 (m, 6, J ) 6.0 Hz), 3.1-3.7 (m, 324), 3.87 (s, 4), 5.10 (s,
2); 13C NMR (CDCl3) δ ) 17.3 (CH3), 40.3 (CH), 40.4 (CH), 41.0
(C), 59.0 (CH3), 69.6 (CH2), 69.7 (CH2), 69.8 (CH2), 70.4 (CH2), 70.5
(CH2), 70.6 (CH2), 70.6 (CH2), 71.0 (CH2), 71.3 (CH2), 71.9 (CH2),
73.9 (CH2), 73.9 (CH2), 112.6 (CH2), 142.8 (C); FTIR ν ) 1650 cm-1
(CdC), 1140 cm-1 (C-O-C); MS (MALDI-TOF) (m/z), [M + Ag]+
(calcd 3881) found 3884; elemental analysis calcd (%) for C180H360O78
(3772.8) C, 57.30; H, 9.62; found C, 57.13; H, 9.43.
1.23 (d, 3), 1.2-1.4 (m, 32), 1.62 (m, 8), 1.71 (m, 8), 1.97 (m, 1, J )
6.0 Hz), 2.0-2.3 (m, 6), 3.3-3.7 (m, 84); 13C NMR (CDCl3) δ ) 14.1
(CH3), 14.1 (CH3), 18.5 (CH3), 23.0 (CH2), 23.1 (CH2), 25.1 (CH2),
25.6 (CH2), 25.8 (CH2), 31.2 (CH2), 34.3 (C), 35.4 (CH2), 40.0 (CH),
40.1 (CH), 40.2 (CH), 62.1 (CH2), 62.1 (CH2), 62.2 (CH2), 62.3 (CH2),
65.9 (CH2), 69.2 (CH2), 69.5 (CH2), 69.7 (CH2), 69.8 (CH2), 74.1 (CH2),
80.9 (CH), 100.5 (C); FTIR ν ) 3434 cm-1 (O-H), 1096 cm-1 (C-
O-C); MS (MALDI-TOF) (m/z), [M + Ag]+ (calcd 1928.4) found
1925.2; elemental analysis calcd (%) for C96H186O30 (1820.5) C, 63.34;
H, 10.30; found C, 63.23; H, 10.14.
Selective Functionalization. a. Block-(BnO-)8(CH3(OCH2CH2)3-
O-)8[G-4]-ene (33). This was prepared by alkylation of block-(BnO)8-
(HO)8-[G-4]-ene (31) with the tosylate of triethylene glycol monomethyl
ether and purified by flash column chromatography on silica gel with
CH2Cl2/MeOH gradient from 3% methanol to 5% methanol: yield 89%;
1H NMR (CDCl3) δ ) 0.91 (s, 12), 2.07-2.17 (m, 6), 3.1-3.7 (m,
200), 3.86 (s, 2), 3.87 (s, 2), 4.48 (s, 16), 5.11 (s, 2), 7.2-7.4 (m, 40);
13C NMR (CDCl3) δ ) 17.3 (CH3), 40.2 (CH), 40.3 (CH), 40.8 (CH),
40.9 (C), 58.9 (CH3), 68.5 (CH2), 68.8 (CH2), 69.3 (CH2), 69.5 (CH2),
69.6 (CH2), 69.7 (CH2), 69.7 (CH2), 69.8 (CH2), 70.3 (CH2), 70.4 (CH2),
70.5 (CH2), 70.5 (CH2), 70.9 (CH2), 71.6 (CH2), 71.8 (CH2), 73.1 (CH2),
73.8 (CH2), 78.2 (CH), 112.5 (CH2), 127.3 (CH), 127.4 (CH), 128.2
(CH), 138.3 (C), 142.8 (C); FTIR ν ) 3030 cm-1 (H-Ar), 1125 cm-1
(C-O-C); MS (MALDI-TOF) (m/z), [M + Ag]+ (calcd 3320.0) found
3315.6; elemental analysis calcd (%) for C172H280O54 (3212.0) C, 64.32;
H, 8.79; found C, 64.54; H, 8.96.
Block Hybrid Copolymer. a. (Nk-)4[G-4]-methylallyl Chloride
(29). This was prepared from (Nk-)4[G-3]-ol (15) and purified by flash
column chromatography on silica gel with hexanes-ethyl acetate
1
gradient from 5% ethyl acetate to 10% ethyl acetate: yield 97%; H
NMR (CDCl3) δ ) 0.86 (s, 12), 0.91 (t, 12, J ) 7.0 Hz), 0.92 (t, 12,
J ) 7.0 Hz), 1.2-1.4 (m, 32), 1.63 (m, 8), 1.72 (m, 8), 2.15 (m, 3, J
) 5.9 Hz), 3.35 (s, 8), 3.4-3.5 (m, 16), 3.50 (d, 8, J ) 11.7 Hz), 3.66
(d, 8, J ) 11.7 Hz), 4.04 (s, 1), 4.08 (s, 1), 5.21 (s, 1), 5.27 (s, 1); 13
C
b. Block-(HO-)8(CH3(OCH2CH2)3O-)8[G-4]-ane (34). This was
prepared from the hydrogenolysis of block-(BnO)8(CH3(OCH2CH2)3O)8-
[G-4]-ene (33) with 10% Pd/C in THF and characterized without further
NMR (CDCl3) δ ) 14.1 (CH3), 14.1 (CH3), 18.5 (CH3), 23.0 (CH2),
23.1 (CH2), 25.2 (CH2), 25.6 (CH2), 31.3 (CH2), 34.3 (C), 35.4 (CH2),
40.3 (CH), 45.1 (CH), 65.9 (CH2), 69.5 (CH2), 69.7 (CH2), 69.8 (CH2),
71.1 (CH2), 74.1 (CH2), 100.5 (C), 116.3 (CH2), 142.3 (C); FTIR ν )
1
purification: yield 99%; H NMR (CDCl3) δ ) 0.91 (s, 12), 0.93 (s,
3), 1.95-2.15 (m, 7), 3.0-3.7 (m, 212); 13C NMR (CDCl3) δ ) 17.3
(CH3), 40.1 (CH), 40.2 (CH), 40.3 (CH), 41.0 (C), 58.9 (CH3), 62.0
(CH2), 69.4 (CH2), 69.8 (CH2), 70.4 (CH2), 70.5 (CH2), 70.6 (CH2),
70.6 (CH2), 70.9 (CH2), 71.9 (CH2), 73.9 (CH2), 80.7 (CH); FTIR ν )
3430 cm-1 (O-H), 1116 cm-1 (C-O-C); MS (MALDI-TOF) (m/z),
[M + Ag]+ (calcd 2601.0) found 2603.0; elemental analysis calcd (%)
for C116H234O54 (2493.1) C, 55.89; H, 9.46; found C, 55.72; H, 9.29.
c. Block-(BzO-)8(CH3(OCH2CH2)3O-)8[G-4]-ane (35). This was
prepared by esterification of block-(HO)8(CH3(OCH2CH2)3O)8-[G-4]-
ane (34) with BzCl in THF and purified by flash column chromatog-
raphy on silica gel with dichloromethane-methanol gradient from 2%
methanol to 4% methanol: yield 78%; 1H NMR (CDCl3) δ ) 0.87 (d,
3, J ) 6.7 Hz) 0.91 (s, 12), 1.95-2.17 (m, 7), 3.1-3.7 (m, 188), 4.42
(m, 16), 7.39 (t, 16, J ) 7.6 Hz), 7.52 (t, 8, J ) 7.4 Hz), 8.00 (d, 16,
J ) 7.2 Hz); 13C NMR (CDCl3) δ ) 14.6 (CH3), 17.3 (CH3), 34.2
(CH), 40.1 (CH), 40.2 (CH), 40.3 (CH), 40.7 (CH), 41.0 (C), 58.9
(CH3), 63.5 (CH2), 68.5 (CH2), 69.0 (CH2), 69.3 (CH2), 69.5 (CH2),
69.6 (CH2), 69.7 (CH2), 69.8 (CH2), 70.3 (CH2), 70.4 (CH2), 70.5 (CH2),
70.6 (CH2), 70.9 (CH2), 71.8 (CH2), 73.8 (CH2), 73.8 (CH2), 75.7 (CH),
128.3 (CH), 129.5 (CH), 129.7 (C), 133.0 (CH), 166.0 (C); FTIR ν )
3030 cm-1 (H-Ar), 1724 cm-1 (CdO), 1125 cm-1 (C-O-C); MS
(MALDI-TOF) (m/z), [M + Ag]+ (calcd 3432.8) found 3430.1;
elemental analysis calcd (%) for C172H266O62 (3326.0) C, 62.11; H, 8.06;
found C, 62.28; H, 8.07.
1657 cm-1 (CdC), 1108 cm-1 (C-O-C); LC-MS (M + Na+
)
1297.94); observed [M + Na]+ ) 1297.92; elemental analysis calcd
(%) for C74H144O15 (1274.96) C, 67.76; H, 10.66; found C, 67.71; H,
10.54.
b. Block-(BnO-)8(Nk-)4[G-4]-ene (30). This was prepared from
(Nk-)4[G-4]-methylallyl chloride (29) and purified by flash column
chromatography on silica gel with hexanes-ethyl acetate gradient from
1
5% ethyl acetate to 10% ethyl acetate: yield 55%; H NMR (CDCl3)
δ ) 0.86 (s, 12), 0.91 (t, 12, J ) 7.0 Hz), 0.92 (t, 12, J ) 7.0 Hz),
1.2-1.4 (m, 32), 1.62 (m, 8), 1.72 (m, 8), 2.15 (m, 6, J ) 5.8 Hz),
3.3-3.7 (m, 80), 3.86 (s, 2), 3.87 (s, 2) 4.49 (s, 16), 5.11 (s, 2), 7.2-
7.4 (m, 40); 13C NMR (CDCl3) δ ) 14.1 (CH3), 14.1 (CH3), 18.5 (CH3),
23.0 (CH2), 23.0 (CH2), 25.2 (CH2), 25.6 (CH2), 31.3 (CH2), 34.2 (C),
35.3 (CH2), 40.3 (CH), 40.9 (CH), 65.9 (CH2), 68.6 (CH2), 68.9 (CH2),
69.5 (CH2), 69.6 (CH2), 69.7 (CH2), 69.8 (CH2), 70.0 (CH2), 71.3 (CH2),
71.7 (CH2), 73.3 (CH2), 73.4 (CH2), 74.1 (CH2), 78.3 (CH), 100.5 (C),
112.7 (CH2), 127.5 (CH), 127.5 (CH), 128.3 (CH), 138.4 (C), 142.9
(C); FTIR ν ) 3030 cm-1 (H-Ar), 1123 cm-1 (C-O-C); MS
(MALDI-TOF) (m/z), [M + Ag]+ (calcd 2648.4) found 2649.6;
elemental analysis calcd (%) for C152H232O30 (2539.5) C, 71.89; H, 9.21;
found C, 71.68; H, 9.03.
Ketal Deprotection. Block-(BnO-)8(HO-)8[G-4]-ene (31). This was
prepared from the hydrolysis of block-(BnO-)8(Nk-)4[G-4]-ene (30) with
0.2 M HCl in MeOH and characterized without further purification:
Acknowledgment. Thanks are due to NSF-DMR 9816166
and the Molecular Design Institute (MDI-2) of the Lawrence
Berkeley National Laboratory funded by DOE and ONR for
financial support of this research. The authors also acknowledge
Dr. M. Jayaraman.
1
yield 99%; H NMR (CDCl3) δ ) 0.79 (s, 12), 2.14 (m, 6, J ) 6.0
Hz), 3.3-3.7 (m, 80), 3.87 (s, 2), 3.89 (s, 2), 4.49 (s, 16), 5.11 (s, 2),
7.2-7.4 (m, 40); 13C NMR (CDCl3) δ ) 17.1 (CH3), 39.9 (CH), 40.0
(CH), 40.3 (CH), 40.9 (C), 67.8 (CH2), 68.6 (CH2), 68.8 (CH2), 69.4
(CH2), 69.5 (CH2), 69.6 (CH2), 69.8 (CH2), 69.9 (CH2), 70.2 (CH2),
71.7 (CH2), 71.7 (CH2), 73.3 (CH2), 75.9 (CH2), 78.4 (CH), 113.2 (CH2),
127.5 (CH), 127.6 (CH), 128.3 (CH), 138.0 (C), 142.8 (C); FTIR ν )
3420 cm-1 (O-H), 3029 cm-1 (H-Ar), 1111 cm-1 (C-O-C); MS
(MALDI-TOF) (m/z), [M + Ag]+ (calcd 2150.5) found 2157.3;
elemental analysis calcd (%) for C152H232O30 (2042.6) C, 68.21; H, 8.29;
found C, 68.10; H, 8.15.
Supporting Information Available: Experimental proce-
dures and full characterization (1H NMR,13C NMR, FTIR, MS,
1
and elemental analysis), as well as the H NMR spectra of
compounds 14, 15, 26, and 30; the 13C NMR spectra of
compounds 14, and 15; and the MALDI-TOF mass spectra of
compounds 4, 6, 8, 16, 20, and 36. 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.
Benzyl Ether Deprotection. Block-(HO-)8(Nk-)4[G-4]-ane (32).
This was prepared from the hydrogenolysis of block-(BnO-)8(Nk-)4-
[G-4]-ene (30) with 10% Pd/C in THF with basic alumina and
characterized without further purification: yield 99%; 1H NMR (CDCl3)
δ ) 0.83 (s, 12), 0.90 (t, 12, J ) 7.0 Hz), 0.92 (t, 12, J ) 7.0 Hz),
JA001903V