Synthesis of poly(alkyl aryl ether) dendrimers

Article abstract of DOI:10.1021/jo025844a

Poly(alkyl aryl ether) dendrimers of up to four generations composed of a phloroglucinol core, branching components, and pentamethylene spacers are synthesized by a divergent growth methodology. A repetitive synthetic sequence of phenolic O-alkylation and

Full text of DOI:10.1021/jo025844a

molecular weights presents a formidable task, such
challenges are also mitigated partly as a result of the
necessity to have only a very few repetitive synthetic
schemes for their successful synthesis. Among quite a few
synthetic routes available at present1,3 for the covalent
synthesis of dendrimers, the most popular ones are the
so-called “divergent”1b and “convergent”3a synthetic meth-
odologies. With the aid of these and other methodologies,
syntheses of a variety of dendrimers have been ac-
complished, starting from the respective monomers.2 As
much to the extent that each type of dendrimer possesses
its own structural and molecular properties, identification
of new monomers for dendrimer synthesis continues to
be attractive. In our interest to synthesize new types of
dendrimers, we report herein the synthesis of poly(alkyl
aryl ether) dendrimers of up to four generations. These
dendrimers possess inner polyalkylene segments radiat-
ing from symmetrically trifunctionalized benzenoid core
and branching components. The trifunctional core and
branching components of choice in these dendrimers are
derived from phloroglucinol and the inner polyalkylene
segment is composed of pentamethylene units. The
presence of phloroglucinol unit offers the opportunity to
have phenolic hydroxyl groups at the periphery, while
the interior of these dendrimers are relatively lyophilic
with the presence of the alkylene segments. The synthe-
sis and structural characterization of these dendrimers,
both with and without protecting groups on the phenolic
hydroxyl groups, by adopting a divergent synthetic
methodology, are described herein.
Syn th esis of P oly(a lk yl a r yl eth er )
Den d r im er s
J ayaraj Nithyanandhan and
Narayanaswamy J ayaraman*
Department of Organic Chemistry, Indian Institute of
Science, Bangalore 560 012, India
jayaraman@orgchem.iisc.ernet.in
Received April 20, 2002
Abstr a ct: Poly(alkyl aryl ether) dendrimers of up to four
generations composed of a phloroglucinol core, branching
components, and pentamethylene spacers are synthesized
by a divergent growth methodology. A repetitive synthetic
sequence of phenolic O-alkylation and O-benzyl deprotection
reactions are adopted for the synthesis of these dendrimers.
The peripheries of the dendrimers contain 6, 12, 24, and 48
phenolic hydroxyl groups, either in the protected or unpro-
tected form, for the first, second, third, and fourth genera-
tions, respectively. Because of the presence of hydrophilic
exterior and relatively hydrophobic interior regions, alkaline
aqueous solutions of these dendrimers are able to solubilize
an otherwise insoluble pyrene molecule and these supramo-
lecular complexes precipitate upon neutralization of the
aqueous solutions.
The particular class of hyperbranched macromolecules
called dendrimers has grown into an active area of
research among polymers during the last two decades.1
The features such as molecular structure, architecture,
topology, controllable growth, and the presence of endo-
and exo-receptor properties among others have made
these macromolecules intriguing and have contributed
to the spectacular advances in the studies of a large
number of dendrimers.2 Such advances are also coupled
intimately and critically with the ability to synthesize
different kinds of dendrimers starting from a variety of
monomers, depending on the desired purposes of the
target dendrimers. While synthesis of nanometer-sized
and monodispersed dendrimers with multi kilodaltons in
We have chosen the symmetrically functionalized
phloroglucinol (1,3,5-trihydroxy benzene) as the core and
branching component in the synthesis of poly(alkyl aryl
ether) dendrimers. Phloroglucinol was used previously
by Chow and co-workers4 as the branching component
of dendron derivatives. A convergent strategy was used
to synthesize these dendrons composed of propylene
spacers and phloroglucinol branching junctures and these
dendrons were also end-capped with 4-tert-butylphenyl
units. In our efforts to utilize phloroglucinol as the
building block of dendrimers, we adopted a divergent
growth methodology involving the reaction of bis-O-
protected phloroglucinol with an alkyl halide in a repeti-
tive sequence of O-alkylation, followed by O-deprotection.
(1) (a) Buhleier, E.; Wehner, W.; Vo¨gtle, F. Synthesis 1978, 155. (b)
Tomalia, D. A.; Baker, H.; Dewald, J .; Hall, M.; Kallos, G.; Martin, S.;
Roeck, J .; Ryder, J .; Smith, P. Polym. J . 1985, 17, 117. (c) Newkome,
G. R.; Yao, Z.; Baker, G. R.; Gupta, V. K. J . Org. Chem. 1985, 50, 2004.
(2) (a) Tomalia, D. A.; Naylor A. M.; Goddard, W. A., III Angew.
Chem., Int. Ed. Engl. 1990, 29, 138. (b) Issberner, J .; Moors, R.; Vo¨gtle,
F. Angew. Chem., Int. Ed. Engl. 1994, 33, 2413. (c) Bryce, M. R.;
Devonport, W.; Moore, A. J . Angew. Chem., Int. Ed. Engl. 1994, 33,
1761. (d) Zeng, F.; Zimmerman, S. C. Chem. Rev. 1997, 97, 1681. (e)
Smith, D. K.; Diederich, F. Chem. Eur. J . 1998, 4, 1353. (f) Chow, H.-
F.; Mong, T. K.-K.; Nongrum, M. F.; Wan, C.-W. Tetrahedron 1998,
54, 8543. (g) Matthews, O. A.; Shipway, A. N.; Stoddart, J . F. Prog.
Polym. Sci. 1998, 23, 1. (h) Frey, H.; Lach, C.; Lorenz, K. Adv. Mater.
1998, 10, 279. (i) Majoral, J .-P.; Caminade, A.-M. Chem. Rev. 1999,
99, 845. (j) Newkome, G. R.; He, E.; Moorefield, C. N. Chem. Rev. 1999,
99, 1689. (k) Hearshaw, M. A.; Moss, J . R. Chem. Commun. 1999, 1.
(l) Stoddart, F. J .; Welton, T. Polyhedron 1999, 18, 3575. (m) Fisher,
M.; Vo¨gtle, F. Angew. Chem., Int. Ed. Engl. 1999, 38, 885. (n) Bosman,
A. W.; J anssen, H. M.; Meijer, E. W. Chem. Rev. 1999, 99, 1665. (o)
Inoue, K. Prog. Polym. Sci. 2000, 25, 453. (p) Hecht, S.; Fre´chet, J . M.
J . Angew. Chem., Int. Ed. 2001, 40, 74. (q) Gorman, C. B.; Smith, J .
C. Acc. Chem. Res. 2001, 34, 60. (r) Oosterom, G. E.; Reek, J . N. H.;
Kamer, P. C. J .; van Leeuwen, P. W. N. M. Angew. Chem., Int. Ed.
2001, 40, 1828.
Synthesis of the required phloroglucinol derivatives for
forming dendrimers is presented in Scheme 1. The
reaction of phloroglucinol (1) with an excess of 1,5-
dibromopentane (4.5 molar equiv) afforded the tribromo
derivative 2, and in a divergent synthesis 2 forms as the
core of dendrimers. Bis-O-benzyl phloroglucinol5 3 was
(3) (a) Hawker, C. J .; Fre´chet, J . M. J . J . Am. Chem. Soc. 1990, 112,
7638. (b) Miller, T. M.; Neenan, T. X.; Zayas, R.; Bair, H. E. J . Am.
Chem. Soc. 1992, 114, 1018. (c) Kawaguchi, T.; Walker, K. L.; Wilkins,
C. L.; Moore, J . S. J . Am. Chem. Soc. 1995, 117, 2159. (d) Wooley, K.;
L.; Hawker, C. J .; Fre´chet, J . M. J . J . Am. Chem. Soc. 1991, 113, 4252.
(e) Wooley, K. L.; Hawker, C. J .; Fre´chet, J . M. J . Angew. Chem., Int.
Ed. Engl. 1994, 33, 82. (f) Spindler, R.; Fre´chet, J . M. J . J . Chem. Soc.,
Perkin Trans. 1 1993, 913.
(4) Chow, H.-F.; Chan, I. Y.-K.; Mak, C. C.; Ng, M.-K. Tetrahedron
1996, 52, 4277.
(5) Curtis, W. D.; Stoddart, J . F.; J ones, G. H. J . Chem. Soc., Perkin
Trans. 1 1977, 785.
10.1021/jo025844a CCC: $22.00 © 2002 American Chemical Society
Published on Web 07/31/2002
6282
J . Org. Chem. 2002, 67, 6282-6285

SCHEME 1a
to afford 8 and 10. To ensure alkylations at multiple -OH
groups, reactions of 6, 8, and 10 were conducted with
bromide 4 in 1.3-1.4 molar excess per -OH functionality.
While the progress of O-alkylation reactions could be
monitored by TLC methods, that of O-benzyl deprotec-
tions were ascertained by 1H NMR spectroscopy after
workup of the reaction mixture.
The O-benzylated dendrimers 5, 7, 9, and 11 are oils,
whereas the O-debenzylated dendrimer 6 is a solid and
8 and 10 exist as foamy solids. In the O-benzylated form,
all the dendrimers are soluble in common organic sol-
vents, thereby routine column chromatographic purifica-
tions could be performed, including the G-4 dendrimer
11. The corresponding O-debenzylated dendrimers are
soluble in Me2CO, MeCN, THF, MeOH, DMF, and DMSO
and are insoluble in nonpolar organic solvents such as
Et2O, CH2Cl2, PhMe, and hexane. Consistent with in-
creasing molecular weights, the relative retention times
of poly(alkyl aryl ether) dendrimers in gel permeation
chromatography (GPC) were found to lower with increas-
ing generations, reflecting the evolution of more compact
structures as the dendrimer generations advance. Struc-
tural elucidations of dendrimers G-1 to G-4 were per-
formed by 1H and 13C NMR spectroscopy, elemental
analysis, and mass spectrometry. The 1H NMR chemical
shifts of the inner phloroglucinol units in 5, 7, 9, and 11
in CDCl3 appear as a single peak and the peripheral
phloroglucinol units resonate as a pair of singlets: one
singlet is twice as much as the other singlet. While the
1H NMR spectrum of 5 exhibited sharp peaks for all types
of protons, dendrimers 7, 9, and 11 have shown peaks
relatively broad in CDCl3, most likely due to an aggrega-
tion in this solvent. In an attempt to resolve the peaks,
the spectrum was also recorded in DMSO-d6 solution.
Although the peaks were still broad at room temperature,
a refined spectrum was observed at higher temperatures.
The O-debenzylated dendrimers 6, 8, and 10 have shown
two resonances for the phloroglucinol units in CD3-
COCD3, one corresponding to the protons of inner region
and the other, a broad singlet, corresponding to the
protons of peripheral region. The resonances of the
pentamethylene segment could also be observed dis-
tinctly, though as broad signals for the higher generation
dendrimers. Similarly, 13C NMR spectra of all the den-
drimers exhibited distinct resonances corresponding to
the C (quat) and CH (methine) of phloroglucinol, apart
from resonances for the benzylic units in the case of
O-benzylated dendrimers and pentamethylene linkers.
Much difference in the chemical shift values could not
be observed between the O-benzylated and the O-deben-
zylated dendrimers. However, the signals in the 13C NMR
spectrum were relatively weaker for the higher genera-
tion dendrimer 11, when compared to the dendrimers
5-10. The mass spectrometric analysis for dendrimers
5-8 has exhibited the expected molecular ion peak,
either as [M + H]+ or Na or K adducts. Elemental
analysis was performed for all the O-benzylated den-
drimers. While C and H values were in agreement for 5,
7, and 9, reliable values could not be obtained for G-4
(11), most likely due to entrapment of “guest molecules”
in the interior of the dendrimer. Also, elemental analysis
on O-debenzylated dendrimers 6, 8, and 10 could not be
performed as a result of the association of solvent
a
Reagents and conditions: (a) K2CO3, DMF, 48 h.
SCHEME 2a
a
Reagents and conditions: (a) K2CO3, 18-C-6, MeCN, reflux, 7 h.
SCHEME 3a
a
Reagents and conditions: (a) K2CO3, 18-C-6, MeCN, reflux; (b)
10% Pd-C, H2, EtOAc/MeOH (9:1); (c) 10% Pd-C, C6H12, THF,
reflux.
obtained by the removal of a benzyl group from the
corresponding tris-O-benzyl phloroglucinol6 under trans-
fer hydrogenation conditions. O-Alkylation of 3 with 1,5-
dibromopentane afforded the phloroglucinol derivative 4
(Scheme 2). Synthesis of the first generation dendrimer
5 (G-1) (Scheme 3) involved alkylation of 3 with 2,
followed by deprotection of the peripheral O-benzyl
groups by hydrogenolysis (10% Pd-C, H2). These two
reactions, namely, O-alkylation and O-benzyl deprotec-
tion, were used repetitively to generate the higher
generation dendrimers (Scheme 3). The molecular struc-
tures of dendrimers G-1 to G-4 are given in Figures 1-3.
The O-alkylation and O-benzyl deprotections are high-
yielding reactions and all the dendrimers are stable for
long periods of time in general. While the O-benzyl
deprotection in G-1 (5) is facile and complete deprotection
could be achieved in ∼7 h to afford 6, the higher
generation dendrimers G-2 (7) and G-3 (9) required
deprotection to be conducted for longer time at higher
pressures (45 psi, Parr apparatus), to obtain the free
-OH groups in 8 and 10. Alternatively, the transfer
hydrogenation was found to be more facile for the
O-debenzylation and thus the transfer hydrogenation was
conducted for O-debenzylations of dendrimers 7 and 9
(6) Kawamoto, H.; Nakatsubo, F.; Murakami, K. Synth. Commun.
1981, 11, 531.
J . Org. Chem, Vol. 67, No. 17, 2002 6283

F IGURE 1. Molecular structures of the first generation (G-1) and the second generation (G-2) poly(alkyl aryl ether) dendrimers.
of transfer (∆Gtr) of pyrene from water to the aqueous
solutions of dendrimers are also given in Table 1. It is
clear from this analysis that the dendrimer containing
aqueous solutions solubilize pyrene. Further, there exists
a linearity of aqueous solubility of pyrene with the
concentration of the dendrimer, indicating that the
solubilzation of pyrene is not due to any on-set of
aggregation in dendrimer-containing solutions. These
observations agree with that reported by Fre´chet and co-
workers8 on the pyrene solubilization in a carboxyl-
terminated poly(benzyl aryl ether) dendrimer. Because
the dendrimers 6, 8, and 10 are insoluble in neutral
aqueous medium, conversion to the phenoxide form is
necessary for their solubility in an aqueous solution. The
direct effect of such phenoxide formation at the periphery
would be the “elongation” of the molecule resulting from
the repulsive interactions between adjacent arms within
the dendrimer molecule. These molecular features should
thus allow the maximum extent of interaction of the
pyrene molecules with complementary hydrophobic sur-
faces arising from the alkylene segments and the aro-
F IGURE 2. Molecular structure of the third generation (G-
3) poly(alkyl aryl ether) dendrimers.
matic regions of the dendrimer. We have also tested the
possibility of precipitating the pyrene-dendrimer su-
pramolecular complex upon neutralization. The precipi-
tation of the above supramolecular complex was observed
upon neutralizing the alkaline solution of the pyrene-
containing dendrimer solutions. These experiments open
up possibilities to explore the transport properties of
aqueous solutions of these dendrimers.
1
molecules. Thus, in combination with GPC, H and 13C
NMR spectroscopy, mass spectrometric methods, and
elemental composition analyses, the identities and the
structural homogeneities of dendrimers 5-11 were con-
firmed.
To test the ability of hydroxyl terminated dendrimers
6, 8, and 10 as hosts, we have conducted solubilization
experiments. An aqueous insoluble molecule, namely,
pyrene, was admixed with an aqueous alkaline solution
of dendrimer 6, 8, and 10 (pH ∼10.5) and the suspension
was shaken at 25 °C for 24 h. The extent of pyrene
solubilization was then checked by UV-vis absorption
spectroscopy, after filtration of the above suspension. The
results of these experiments are given in Table 1. The
saturation concentration of pyrene in water is 8 × 10-7
M,7 while that in dendrimer solutions of 6, 8, and 10 was
found to be 5, 8, and 24 times higher, which reflect the
effective strength of pyrene solubilization as the den-
drimer generations advance. The values of free energies
In conclusion, a two-step iterative procedure involving
O-alkylation and O-benzyl group deprotection reactions
has been found to be suitable for the synthesis of new
poly(alkyl aryl ether) dendrimers, composed of phloro-
glucinol core, branching components, and pentamethyl-
ene linker units. The synthesis involving these two
reactions is also found to be facile and dendrimers of up
to four generations have been synthesized by using this
iterative procedure. Although the pentamethylene linker
has been chosen to construct these dendrimers, the
reactions are amenable for incorporating other alkylene
linkers. Within the currently known varieties of den-
drimers, “completely” polyether dendrimers3a and den-
(8) Hawker, C. J .; Wooley, K. L.; Fre´chet, J . M. J . J . Chem. Soc.,
Perkin Trans. 1 1993, 1287.
(7) Schwarz, F. P. J . Chem. Eng. Data 1977, 22, 399.
6284 J . Org. Chem., Vol. 67, No. 17, 2002

F IGURE 3. Molecular structure of the fourth generation (G-4) poly(alkyl aryl ether) dendrimer.
TABLE 1. Solu bility a n d ∆Gtr of P yr en e in Aqu eou s
thus represent a new type within the class of polyether
dendrimers. Moderate stabilities of alkyl aryl ether
linkages toward acidic and basic environments, as well
as the presence of hydrophilic exterior and lyophilic
interior, should impart specific attributes arising due to
these molecular features in the poly(alkyl aryl ether)
dendrimers reported herein. An assessment of the su-
pramolecular properties of hydroxyl-terminated dendrim-
ers 6, 8, and 10 shows that aqueous solutions of these
dendrimers indeed solubilize an otherwise insoluble
pyrene molecule due to the existence of a hydrophilic-
hydrophobic balance within the dendrimer molecules.
Solu tion s of Den d r im er s 6, 8, a n d 10
aq soln of dendrimer
pyrene
∆Gtr
(100 µM)
(µM)a
(cal/mol)b
6
8
10
4.2
6.3
18.8
-982
-1222
-1781
a
A solution of known concentration of 6, 8, and 10 at pH ∼10.5
(0.05 N NaOH) was added with pyrene (5 mg) and with stirring
for 24 h at 25 °C; the solution was filtered (0.2 µm filter) and the
amount of solubilized pyrene was determined by its absorption at
b
335 nm. The free energy of transfer (∆Gtr) was calculated from
the equation ∆Gtr ) -RT ln(Cs/Cw), where Cs and Cw are the
solubilities of the pyrene in the aqueous dendrimeric solution and
in water.
Ack n ow led gm en t. We are grateful to Council of
Scientific and Industrial Research (CSIR), New Delhi
for the financial support. J .N. thanks CSIR for a
research fellowship.
drons4,9 are still small in number10 and the most well-
studied among these is the Fre´chet’s poly(benzyl aryl
ether)3a dendrimers. The dendrimers reported herein
Su p p or tin g In for m a tion Ava ila ble: General methods of
experimental details, synthesis of 2-11, 1H NMR spectrum
of dendrimer 9 (G3-(OBn )24) and GPC profiles of the G1-
(OBn )6 (5), G2-(OBn )12 (7), G3-(OBn )24 (9), and G4-(OBn )48
(11) dendrimers. This material is available free of charge via
the Internet at http://pubs.acs.org.
(9) (a) J ayaraman, M.; Fre´chet, J . M. J . J . Am. Chem. Soc. 1998,
120, 12996. (b) Weintraub, J . G.; Parquette, J . Org. Chem. 1999, 64,
3796.
(10) For an excellent review on polyether-based dendrimers, see:
Chow, H.-F.; Leung, C.-F.; Wang, G.-X.; Zhang, J . Top. Curr. Chem.
2001, 217, 1.
J O025844A
J . Org. Chem, Vol. 67, No. 17, 2002 6285