Toward nanoamphiphiles: Efficient synthesis of desymmetrized polyphenylene dendrimers

Article abstract of DOI:10.1021/jo048998u

A new synthetic approach for the desymmetrization of polyphenylene dendrimers (PPDs) is described. Tetrakis(4-ethynylphenyl)methane undergoes facile Diels-Alder cycloaddition with substoichiometric quantities of tetraphenylcyclopentadienones bearing one polar functional group. A single ethynyl group is thereby converted to a rigid, selectively functionalized polyphenylene moiety, which serves as a focal point for further transformations or interfacial anchoring. This is the key feature for the design of desymmetrized monodisperse macromolecules with a spherical shape. The remaining unreacted ethynyl groups provide a trifold core for the stepwise elaboration of first- and second-generation polyphenylene dendrons, which may, in turn, bear specific numbers of different peripheral functional groups at their terminae. Moreover, the resulting macromolecules exhibit the characteristic shape-persistence and monodispersity of PPDs. This approach is an important achievement in nanosciences, especially for tailoring new nanoamphiphiles. It is also of synthetic importance, as it enables the separation of two regioisomeric polyphenylene dendrimers for the first time.

Full text of DOI:10.1021/jo048998u

Toward Nanoamphiphiles: Efficient Synthesis of Desymmetrized
Polyphenylene Dendrimers
G. Mihov, I. Scheppelmann, and K. Mu¨llen*
Max Planck Institute for Polymer Research, Ackermannweg 10, D-55128 Mainz, Germany
muellen@mpip-mainz.mpg.de
Received June 15, 2004
A new synthetic approach for the desymmetrization of polyphenylene dendrimers (PPDs) is de-
scribed. Tetrakis(4-ethynylphenyl)methane undergoes facile Diels-Alder cycloaddition with sub-
stoichiometric quantities of tetraphenylcyclopentadienones bearing one polar functional group. A
single ethynyl group is thereby converted to a rigid, selectively functionalized polyphenylene moiety,
which serves as a focal point for further transformations or interfacial anchoring. This is the key
feature for the design of desymmetrized monodisperse macromolecules with a spherical shape. The
remaining unreacted ethynyl groups provide a trifold core for the stepwise elaboration of first- and
second-generation polyphenylene dendrons, which may, in turn, bear specific numbers of different
peripheral functional groups at their terminae. Moreover, the resulting macromolecules exhibit
the characteristic shape-persistence and monodispersity of PPDs. This approach is an important
achievement in nanosciences, especially for tailoring new nanoamphiphiles. It is also of synthetic
importance, as it enables the separation of two regioisomeric polyphenylene dendrimers for the
first time.
Introduction
surface functionalization,9 gene transfection,10 diagno-
sis,11 and supramolecular assembly. PPDs are also es-
sentially monodisperse, an important prerequisite for
their application as organic templates.12-14
Development of new functional materials is an area of
current interest.1 There are already many reported ex-
amples of peripherally functionalized latices2 and semi-
conductor particles3,4 but control over the number of
surface functionalities is not typically achieved. However,
for many applications, e.g. biosensors, diagnosis, or drug-
delivery, monodispersity and strictly defined structure
are critical requirements. Moreover, the placement of
different moieties in a specific environment is often de-
sired. For these purposes dendrimers offer a convenient
solution, because they combine efficient fabrication of
nanosized objects with exact control of surface function-
alization on a molecular level.5-7
Three-dimensional polyphenylene dendrimers (PPDs)
are shape-persistent, spherical molecules,8 whose struc-
tural properties allow spatial definition and topological
isolation of functional groups in the center, in the den-
dritic scaffold, and at the periphery. These features are
important for a large number of applications such as
Constitutional desymmetrization of polyphenylene den-
drimers is of great importance for tailoring the functional
properties of these molecules15,16 but so far only a few
examples for the spatial separation of different functional
groups are reported.17 The basic idea of this work is to
introduce a single functional group on the periphery that
differs from the other surface groups. The resulting
compound will possess two different segments, e.g. one
for binding a substrate, the others for sensing or further
transformations. A desymmetrized dendrimer could
thereby be attached to a cell membrane, an electrode, a
(9) Herrmann, A.; Mihov, G.; Vandermeulen, G. W. M.; Klok,. H.-
A.; Mu¨llen, K. Tetrahedron 2003, 59, 3925-3935.
(10) Mihov, G.; Herrmann, A.; Prawitt, D.; Brixel, L.; Hengstler, J.
G.; Mu¨llen, K. Unpublished results.
(11) Minard-Basquin, C.; Weil, T.; Hohner, A.; Radler, J. O.; Mullen,
K. J. Am Chem. Soc. 2003, 125, 5832-5838.
(12) Wiesler, U. M.; Weil, T.; Mu¨llen, K. Top. Curr. Chem. 2001,
212, 1-40.
* Address correspondence to this author.
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2003, 24, 457-487.
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Mu¨llen, K. Macromolecules 2001, 34, 187-199.
(14) Morgenroth, F.; Reuther, E.; Mu¨llen, K. Angew. Chem., Int. Ed.
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Kluwer Academic Publishers: New York, 1990.
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D.; Weiss, S.; Alivisatos, A. P. J. Phys. Chem. B 2001, 105, 8861-
8871.
(15) Grimsdale, A. C.; Bauer, R.; Weil, T.; Tchebotareva, N.; Wu,
J.; Watson, M.; Mu¨llen, K. Synthesis (Stuttgart) 2002, 9, 1229-1239.
(16) (a) Singh, P. Bioconj. Chem. 1998, 9, 54-63. (b) Froehling, P.
E.; Linssen, H. A. J. Macromol. Chem. Phys. 1998, 199, 1691-1695.
(c) Newkome, G. R.; Childs, B. J.; Rourk, M. J.; Baker, G. R.;
Moorefield, C. N. Biotechnol. Bioeng (Comb. Chem.) 1998, 61, 243-
253. (d) Pan, Y.; Ford, W. T. Macromolecules 2000, 33, 3731-3738. (e)
Sideratou, Z.; Tsiourvas, D.; Paleos, C. M. J. Colloid. Interface Sci.
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Se´verac, M.; Leclaire, J.; Sutra, P.; Caminade, A.-M.; Majoral, J.-P.
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10.1021/jo048998u CCC: $27.50 © 2004 American Chemical Society
Published on Web 10/20/2004
J. Org. Chem. 2004, 69, 8029-8037
8029

Mihov et al.
SCHEME 1. Synthesis of Monofunctionalized Tetraphenylcyclopentadienonesa
a Reagents and conditions: (i) HCl, 25 °C, THF; (ii) for 3shexanedioic acid monomethyl ester EDC, DMAP, DMF, rt; for
4s4-benzyloxycarbonylaminobutyric acid, N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide, DMAP, DMF, rt; (iii) 5-chloropentyne,
bis(triphenylphosphine)palladium(II) dichloride, CuI, triethylamine, 80 °C.
photoactive or solubilizing moiety, or a solid support by
using the unique functional group, while the other groups
are arranged in a shape-defined manner toward other
chemical or physical targets.
molecules begins with the preparation of the correspond-
ing monofunctionalized tetraphenylcyclopentadienones
(Scheme 1). The preparation of tetracyclones bearing
pendant carboxyl or amino groups as in 3 and 4 was
described separately.19 The chloropentynyl-functionalized
cyclopentadienone 6 was synthesized via a Hagihara
coupling of the monobrominated precursor 5 with 5-chloro-
1-pentyne in 80% yield.
Desymmetrization of the Tetrakis(4-ethynylphe-
nyl)methane Core. A statistical Diels-Alder cycload-
dition of the symmetric core 7 with the monosubstituted
tetraphenylcyclopentadienone 3 (Scheme 2) resulted in
a mixture of mono-, di-, tri-, and tetradendronized core
molecules (8-11).
By controlling the amount of the added tetracyclone,
the mixture was selectively enriched with the most
desired component. For example, using 0.75 mol of 3 per
mol of 7 gave 55% of 8, 35% of 9, and negligible quantities
of 10 and 11; unreacted 7 (30%) was also recovered. The
reaction proceeded up to the complete consumption of 3,
which was conveniently verified by the complete bleach-
ing of the characteristic red color of the tetracyclone.
We extended this synthetic approach to the protected
amino-functionalized cyclopentadienone 4 and the chloro-
functionalized cyclopentadienone 6 to obtain the desym-
metrized core molecules 8, 12, and 13 in isolated yields
of 50-55% (Scheme 3). The polar moieties led in all cases
to facile product separation of the different products of
the Diels-Alder reaction by column chromatography.
These core molecules show broad versatility as they
exhibit different routinely used anchor groups. The
The only known route to desymmetrized PPDs pro-
ceeds via several protection and deprotection steps of the
ethynyl groups of tetrakis(4-ethynylphenyl)methane and
subsequent stepwise Diels-Alder cycloaddition and has
the disadvantages of low yields and laborious purifica-
tion.18 We now show that the preparation of desymme-
trized PPDs from the symmetric tetrakis(4-ethynylphenyl)-
methane core with substoichiometric amounts of func-
tionalized cyclopentadienones circumvents these prob-
lems. This method allows the preparation of dendrimers
possessing two types of functionalities in only two steps.
Our strategy is particularly applicable to the design of
functional nanoparticles possessing a single anchor group.
One goal in this context is the design of a new class of
precisely tailored nanoamphiphiles. Furthermore, the
shape-persistence of PPDs ensures a topological isolation
of the functionalities on the periphery, demonstrated here
by the unprecedented separation of two regioisomeric
PPDs.
Results and Discussion
Synthesis of Functionalized Tetraphenylcyclo-
pentadienones. The synthesis of monofunctional core
(17) (a) Hawker, C. J.; Wooley, K. L.; Fre´chet, J. M. J. J. Chem.
Soc., Perkin Trans. 1 1993, 1287-1297. (b) Martin, I. K.; Twyman, L.
J. Tetrahedron Lett. 2001, 42, 1119-1121. (c) Grayson, S. M.; Fre´chet,
J. M. J. J. Am. Chem. Soc. 2000, 122, 10335-10344. (d) Nierengarten,
J.-F.; Eckert, J.-F.; Rio, Y.; del Pillar Carreon, M.; Gallani, J.-L.;
Guillon, D. J. Am. Chem. Soc. 2001, 123, 9743-9748. (e) Maraval,
V.; Sebastian, R.-M.; Ben, F.; Laurent, R.; Caminade, A.-M.;
Majoral, J.-P. Eur. J. Inorg. Chem. 2001, 1681-1691. (f) Ong, W.;
Kaifer, A. E. J. Am. Chem. Soc. 2002, 124, 9358-9359. (g) Wooley, K.
L.; Hawker, C. J.; Fre´chet, J. M. J. J. Am. Chem. Soc. 1993, 115,
11496-11505.
(18) Weil, T.; Wiesler, U. M.; Herrmann, A.; Bauer, R.; Hofkens, J.;
De Schryver, F. C.; Mullen K. J. Am Chem. Soc. 2001, 123, 8101-
8108.
(19) Mihov, G.; Grebel-Koehler, D.; Lu¨bbert, A.; Vandermeulen, G.
W. M.; Klok, H.-A.; Herrmann, A.; Mu¨llen, K. 2004, Bioconj. Chem.
Submitted for publication.
8030 J. Org. Chem., Vol. 69, No. 23, 2004

Synthesis of Desymmetrized Polyphenylene Dendrimers
SCHEME 2. Desymmetrization of Tetrakis(4-ethynylphenyl)methane Core
SCHEME 3. Desymmetrized Core Molecules
SCHEME 4. Formation of Regioisomers during
Diels-Alder Reaction of 7 with
Monofunctionalized Cyclopentadienones
of the successful separation of the two isomers after
growth of a first-generation dendrimer.
Desymmetrized PPDs. With the monofunctionalized
core molecules 8, 12, and 13 in hand, we next synthesized
several desymmetrized first-generation polyphenylene
dendrimers bearing well-defined numbers of different
groups on the other three dendrons (Scheme 5). The
substituents in the A and B moieties represent both
electrophilic and nucleophilic functions and were selected
to maximize versatility of subsequent synthetic trans-
formations, including the attachment of functionalized
PPDs to surfaces or solubilizing moieties. This opens the
way for the design of a new class of nanosized am-
phiphilic molecules, where a single polymer chain is
attached to a desymmetrized dendrimer.
desymmetrization approach contains only one reaction
step, including a straightforward purification, so there
are no limits for up scaling.
As a result of the [4+2] cycloaddition mechanism in
the Diels-Alder reaction (Scheme 4), compounds 8, 12,
and 13 generally are found as pairs of regioisomers.
1
Therefore, a slight splitting of H NMR resonances is
observed for the polar side chains. However, a separation
of reaction products a and b at this stage is not possible
due to their similar physical and chemical properties. We
therefore used the mixture of isomers in all further
synthetic steps. For clarity, only one of the possible
isomers of the desymmetrized molecules is depicted
hereafter, even though we will show below an example
Satisfactory purification of the PPDs is usually achieved
by precipitation in hexane or methanol, for the well-
J. Org. Chem, Vol. 69, No. 23, 2004 8031

Mihov et al.
SCHEME 5. Synthesis of First-Generation Desymmetrized Polyphenylene Dendrimers
soluble tri(isopropyl)silylethynyl-substituted compounds
23 and 25, and for the chloro-functionalized PPDs 22 and
24 purification by flash chromatography is required. In
the latter case the yield after purification is lower than
that for all other compounds, which may be explained
with irreversible adsorption onto the column. All other
compounds are obtained in good yields of 67-92%. The
new polyphenylene dendrimers were analyzed by means
of 1H and 13C NMR spectroscopy and MALDI-TOF-
spectrometry.
Applying the branching cyclopentadienone 16 in
Diels-Alder reactions with the desymmetrized core mole-
cules 8, 12, and 13 resulted in the first-generation PPDs
23, 24, and 25, respectively.
With use of a divergent synthetic approach, the depro-
tection of the ethynyl groups (Scheme 6) followed by a
8032 J. Org. Chem., Vol. 69, No. 23, 2004

Synthesis of Desymmetrized Polyphenylene Dendrimers
FIGURE 1. MALDI-TOF spectra of 23 and 34.
SCHEME 6. Deprotection of
Ethynyl-Functionalized Desymmetrized
Polyphenylene Dendrimers
Separation of Regioisomeric Polyphenylene Den-
drimers. As mentioned above, Diels-Alder cycloaddition
of monosubstituted tetraphenylcyclopentadienone 3 with
an ethynyl group of the core molecule 7 results in two
unseparable isomeric reaction products with nearly
identical physical and chemical properties (8a and 8b).
However, further growth of the polyphenylene dendrimer
leads to localization of the polar ester groups in substan-
tially different surroundings. For example, in the 1H
NMR spectrum of 23 the protons of the methoxy group
appear as two separate singlets at 3.62 and 3.61 ppm
(Figure 2).
Also the polarities of the regioisomers differ, which is
evidenced by analytical TLC (Rf 0.66 and 0.73) and ready
flash chromatographic separation. This effect is small but
important, as it proves that the shape-persistence of the
dendritic scaffold ensures and maintains the distance
between the different functional groups. The possibility
of conformational isomerism is ruled out by temperature-
dependent 1H NMR studies. Even at temperatures of 403
K the two methoxy resonances do not coalesce.
The molecular geometries of the two regioisomers were
modeled by using the MM2 (MM+) force field as imple-
mented in HyperChem 6.0 (Hypercube Inc.) (Figure 3).
FD and MALDI-TOF mass spectrometry confirmed the
identical molecular weight of the isomers. The isomer
with lower retention volume in flash chromatography
Diels-Alder cycloaddition with prefunctionalized tet-
raphenylcyclopentadienones afforded second-generation
dendrimers 32, 33, 34, and 35 (Scheme 7).
1
revealed a peak at higher field (3.61 ppm) in H NMR
spectra (in C2D2Cl4). Clearly the ester group of the first
eluted isomer is more effectively screened by the proxi-
mate functionalities than the ester group of the other.
One can hypothesize that compound 23a (Figure 3)
should be assigned to the isomer with lower retention
volume.
In the case of compound 23 we succeeded for the first
time in separating the two regioisomers formed in a
Diels-Alder reaction with a monofunctionalized cyclo-
pentadienone. This separation was only possible because
the defined spatial structure of the dendrimer leads to
substantial differences of their physical properties, fur-
ther evidence of the shape-persistence of the dendritic
PPD structure.
Compounds 33-35 are conveniently obtained in high
purity and yield after precipitation in methanol. For
pyridyl-functionalized compounds 20 and 32, reverse-
phase HPLC purification was applied, which gave very
good separation results. Like the first-generation den-
drimers, the second-generation dendrimers were ana-
1
lyzed by means of H and 13C NMR spectroscopy and
MALDI-TOF spectrometry. Figure 1 shows examples for
MALDI-TOF spectra of first- and second-generation
PPDs. The characteristic monodispersity together with
the controlled surface functionalization make these com-
pounds ideal precursors for tailor-made nanoobjects.
These attributes are so far unprecedented since func-
tionalized nanosized objects are generally based on
dendrimers20-22 and polymers2-4 where surface function-
alization is under statistical control.
Conclusions
Several first- and second-generation PPDs, each pos-
sessing one anchor group and a defined number of surface
functionalities, were synthesized by a selective core
desymmetrization followed by divergent dendrimer growth.
This approach is a convenient, general, and controllable
synthetic route to monodisperse macromolecules exhibit-
(20) Vo¨gtle, F.; Gestermann, S.; Hesse, R.; Schwierz, H.; Windisch,
B. Prog. Polym. Sci. 2000, 25, 987-1041 and references therein.
(21) Morgan, J. R.; Cloninger, M. J. Curr. Opin. Drug Discovery Dev.
2002, 5, 966-973 and references therein.
(22) Hecht, S. J. Polym. Sci., Part A: Polym. Chem. 2003, 41, 1047-
1058 and references therein.
J. Org. Chem, Vol. 69, No. 23, 2004 8033

Mihov et al.
SCHEME 7. Synthesis of Second-Generation Desymmetrized Polyphenylene Dendrimers
ing both a defined number and a determined spatial
arrangement of different functionalities. In this regard
also the first separation of regioisomeric polyphenylene
dendrimers is an important technical achievement made
possible by the shape-persistence of the PPD structure.
The single anchor group and the functional groups
implemented at the periphery of the desymmetrized
PPDs provide opportunities for further applications. In
the preparation of nanoamphiphiles,23 the single func-
tional group in 20, 21, 22, and 28 could serve as the
junction point for a polymeric moiety, yielding a well-
defined arrangement of a shape-persistent dendrimer
headgroup and a polymeric tail. Compounds such as 26
and 27, which possess an anchor carboxyl group and six
amino groups distributed on the periphery, can be readily
fixed to a solid support for further solid-phase function-
alization or labeled with a chromophore, still offering a
defined number of reactive centers for further transfor-
mation. These avenues are under exploration in our
laboratories.
Experimental Section
Compounds 1,9 2,9 3,19 4,19 5,15 7,18 14,24 16,14 17,19 18,19 19,25
and 3119 were synthesized according to published procedures.
Compound 6. A solution of 3-(4-bromophenyl)-2,4,5-tri-
phenylcyclopentadienone (5) (0.500 g, 1.08 mmol), bis(tri-
phenylphosphine)palladium dichloride (0.117 g 0.17 mmol),
triphenylphosphine (0.028 g, 0.11 mmol), and copper(I) iodide
(0.020 mg, 0.11 mmol) in triethylamine (20 mL) was heated
to 80 °C under argon atmosphere. Then 5-chloro-1-pentyne
(0.13 mL, 1.2 mmol) was added dropwise by syringe to the hot
solution. After the solution was stirred for 3 h at 80 °C and
cooled to room temperature, water (40 mL) and 2 N hydro-
chloric acid (20 mL) were added. The product was extracted
(23) Velonia, K.; Rowan, A. E.; Nolte, R. J. M. J. Am Chem. Soc.
2002, 124, 4224-4225.
(24) Arackal, Th. J.; Eistert, B. Chem. Ber. 1975, 108, 2660-2663.
(25) Weil, T. Ph.D. Thesis, 2002, University of Mainz, Germany.
8034 J. Org. Chem., Vol. 69, No. 23, 2004

Synthesis of Desymmetrized Polyphenylene Dendrimers
147.3, 143.8, 142.4, 141.5, 141.0, 140.6, 140.2, 139.4, 136.6,
132.5, 131.9, 131.5, 130.5, 129.9, 128.2, 128.1, 127.5, 127.4,
127.2, 126.8, 126.1, 120.6, 118.3, 83.7, 77.9, 65.1, 51.9, 37.7,
34.1, 25.3, 24.9.
A 20:1 mixture of CH2Cl2/acetone afforded 9 as a white
powder. Yield 0.045 g (35%). FD (M+) m/z 1444 g/mol; 1H NMR
(250 MHz, CD2Cl2) δ 7.53 (s, 2 H), 7.38-7.27 (d, 4 H), 7.20-
6.71 (m, 50 H), 3.62 (s, 6 H), 3.11 (s, 2 H), 2.34-2.18 (m, 8 H),
1.71-1.60 (m, 8 H); 13C NMR (62.5 MHz, CD2Cl2, spinecho)
δC 174.2, 170.8, 148.0, 144.4, 142.2, 142.1, 141.3, 141.2, 141.1,
141.0, 140.5, 140.0, 139.1, 136.4, 136.1, 132.4, 132.0, 131.9,
131.8, 131.5, 131.3, 131.1, 130.5, 130.3, 129.2, 128.0, 127.3,
127.2, 127.1, 127.0, 126.6, 126.0, 125.9, 125.8, 120.0, 118.1,
117.8, 86.7, 64.1, 51.7, 37.5, 33.9, 30.1, 24.7.
Compound 12. 12 was prepared analogously to 8 from
tetra(4-ethynylphen-1-yl)methane (7) (0.1 g, 0.24 mmol) and
4 (0.110 g, 0.18 mmol). The products were purified by flash
chromatography with a DCM/acetone mixture (10:1) as eluent
to give 12 as a white powder. Yield 0.100 g (55%). FD (M+)
FIGURE 2. 1H NMR spectra of 23 (mixture of regioisomers).
1
m/z 1007 g/mol; H NMR (250 MHz, CD2Cl2) δ 7.52 (s, 1 H),
7.42-6.70 (m, 40 H), 5.07 (s, 2 H), 3.30-3.16 (m, 2 H), 3.12 (s,
3 H), 2.32-2.21 (m, 2 H), 1.87-1.75 (m, 2 H); 13C NMR (62.5
MHz, CD2Cl2) δC 171.1, 147.3, 145.3, 143.8, 140.6, 132.5, 132.2,
131.9, 131.5, 130.5, 129.9, 129.0, 128.5, 128.2, 127.3, 127.2,
126.8, 126.1, 120.6, 118.3, 83.7, 77.9, 67.2, 65.1, 40.6, 35.1, 27.1.
Compound 13. 13 was prepared analogously to 8 from
tetra(4-ethynylphen-1-yl)methane (7) (0.150 g, 0.37 mmol) and
6 (0.135 g, 0.28 mmol). The products were purified by flash
chromatography with a DCM/hexane mixture (1:2) as eluent
to give 13 as a white powder. Yield 0.104 g (43%). FD (M+)
m/z 873 g/mol; 1H NMR (250 MHz, CD2Cl2) δ 7.54 (s, 1H),
7.38-7.35 (m, 6H), 7.21-6.75 (m, 30H), 3.69-3.64 (m, 2H),
3.12 (s,3H), 2.53-2.50 (m, 2H), 2.00-1.96 (m, 2H); 13C NMR
(62.5 MHz, CD2Cl2) δC 147.3, 141.2, 140.5, 131.9, 131.5, 130.6,
130.5, 130.4, 129.9, 128.2, 127.3, 127.2, 126.1, 120.5, 88.6, 83.8,
77.9, 44.5, 32.0, 30.3.
Compound 20. Compounds 12 (0.050 g, 0.050 mmol) and
14 (0.087 g, 0.225 mmol) in o-xylene (15 mL) were heated at
150 °C for 24 h under argon atmosphere. The solvent was
evaporated, and the dry rest was dissolved in 0.1 M aqueous
trifluoroacetic acid (3 mL). The final purification was per-
formed by reverse-phase HPLC with a linear AB gradient from
A to B over 21 min, with eluent A consisting of a mixture of
98% water/2% acetonitrile (plus 0.1% TFA) and eluent B
consisting of a mixture of 50% acetonitrile/50% 2-propanol
(plus 0.05% TFA). The flow rate was 3 mL/min. Yield 0.080 g
FIGURE 3. Three-dimensional models of the regioisomers of
polyphenylene dendrimer 23.
1
(78%). MALDI TOF MS m/z 1965 g/mol (M+); H NMR (250
MHz, acetone-d6) δH 8.87-8.76 (m, 1 H, NH), 8.42-8.15 (m,
12 H), 7.81-7.67 (m, 6H), 7.58 (s, 3H), 7.38-6.53 (m, 77 H),
5.06 (s, 2H), 3.11-2.97 (m, 2H), 2.25-2.12 (m, 2 H), 1.76-
1.62 (m, 2H); 13C NMR (175 MHz, acetone-d6) δC 171.3, 159.9,
159.7, 149.2, 145.9, 145.1, 143.1, 142.9, 142.6, 141.9, 141.7,
141.6, 141.5, 141.4, 141.3, 141.2, 141.1, 140.8, 140.6, 140.1,
139.7, 138.6, 138.1, 137.7, 135.9, 132.6, 132.4, 131.3, 131.1,
130.9, 130.8, 129.8, 129.7, 129.2, 129.0, 128.6, 128.5, 128.4,
128.0, 127.8, 127.5, 127.4, 126.3, 124.8, 124.5, 118.3, 118.1,
117.7, 116.0, 66.5, 64.4, 41.0, 34.8, 26.6; RP-HPLC: retention
time ) 15 min.
Compound 21. Compounds 8 (0.050 g, 0.054 mmol) and
15 (0.123 g, 0.322 mmol) in o-xylene (15 mL) were heated at
150 °C for 24 h under argon atmosphere. The reaction mixture
was concentrated to one-fourth of the initial volume and
precipitated from hexane to afford 21 as a white powder. Yield
0.80 g (75%). FD (M+) m/z 2000 g/mol; 1H NMR (250 MHz,
CD2Cl2) δH 7.55 and 7.54 (s, s, 4 H), 7.20-6.60 (m, 95H), 3.67
(s, 3H), 2.40-2.20 (m, 4H), 1.87-1.75 (m, 4H); 13C NMR (62.5
MHz, CD2Cl2) δC 176.6, 145.0, 142.4, 141.1, 140.8, 140.7, 140.1,
132.6, 132.1, 131.0, 130.8, 130.5, 129.3, 128.1, 127.4, 127.3,
127.1, 126.8, 126.1, 126.0, 125.9, 118.3, 64.0, 37.6, 33.6, 30.3,
24.7.
with dichloromethane (3 × 20 mL) and the combined organic
phases were washed with 25 mL of saturated ammonium
chloride solution. Then the organic phase was dried over
magnesium sulfate, filtered, and evaporated. The product was
purified by flash chromatography on silica with dichlo-
romethane as eluent and then by recrystallization from
ethanol. Yield 418 mg, 80%. FD (M+) m/z 485.2 g/mol; 1H NMR
(250 MHz, CD2Cl2) δH 7.28-7.17 (m, 15H), 6.96 (d, 2H, J )
8.5 Hz), 6.86 (d, 2H, J ) 8.5 Hz), 3.70 (t, 2H J ) 6.3 Hz),
2.55 (t, 2H, J ) 6.8 Hz), 2.03 (m, 2H); 13C NMR (62.5 MHz,
CD2Cl2) δC 200.4, 154.9, 154.3, 133.5, 133.0, 131.4, 131.3, 131.2,
131.0, 129.7, 129.6 128.9, 128.4, 128.3, 128.0, 127.9, 126.1,
125.9, 124.2, 90.1, 81.4, 44.2, 31.8, 17.2.
Compounds 8 and 9. Tetra(4-ethynylphenyl)methane (7)
(0.1 g, 0.24 mmol) and 3 (0.097 g, 0.18 mmol) in o-xylene (50
mL) were heated at 150 °C for 18 h under an argon atmo-
sphere. Next, the solvent was evaporated under reduced
pressure and the products were purified by flash chromatog-
raphy with a CH2Cl2/acetone gradient. A mixture of DCM/
acetone (40:1) as eluent afforded 8 as a white powder. Yield
0.095 g (56%). FD (M+) m/z 930 g/mol; 1H NMR (250 MHz,
CD2Cl2) δH 7.52 (s, 1 H), 7.42-7.29 (d, 6 H), 7.23-6.74 (m, 29
H), 3.62 (s, 3 H), 3.11 (s, 3 H), 2.32-2.20 (m, 4 H), 1.73-1.58
(m, 4 H); 13C NMR (62.5 MHz, CD2Cl2, spinecho) δC 171.0,
Compound 22. 22 was prepared analogously to 21 from
13 (0.035 g, 0.041 mmol) and 15 (0.094 g, 0.244 mmol). The
J. Org. Chem, Vol. 69, No. 23, 2004 8035

Mihov et al.
product was purified by precipitation from methanol to give
2.35-2.17 (m, 16 H), 1.88-1.58 (m, 16 H), 1.4 (s, 54 H); 13C
NMR (62.5 MHz, CD2Cl2) δC 174.2, 171.5, 157.1, 144.8, 142.3,
141.5, 141.3, 141.1, 140.5, 140.2, 139.9, 139.3, 136.6, 136.3,
132.3, 132.0, 130.6, 130.3, 129.1, 128.0, 127.2, 127.0, 126.5,
125.9, 118.4, 118.2, 79.6, 63.7, 51.7, 41.3, 39.9, 34.9, 33.9, 30.0,
28.5, 26.9, 25.1, 24.7.
Compound 28. 28 was prepared analogously to 21 from
12 (0.042 g, 0.042 mmol) and 19 (0.150 g, 0.25 mmol). The
product was purified by precipitation from hexane to give a
white powder. Yield 0.81 g (67%). MALDI-TOF MS m/z 2904
(M(Na)+); 1H NMR (250 MHz, CD2Cl2) δ 8.03-7.87 (m, 12 H),
7.65-6.69 (m, 110 H), 5.07 (s, 2 H), 3.84 (s, 18 H), 3.28-3.15
(m, 2 H), 2.35-2.21 (m, 2H), 1.89-1.75 (m, 2H); 13C NMR (62.5
MHz, CD2Cl2) δC 170.9, 167.0, 157.6, 154.3, 145.1, 145.0, 142.0,
141.4, 141.3, 141.2, 140.9, 140.6, 140.3, 140.0, 139.8, 139.0,
137.2, 136.9, 132.5, 132.0, 130.1, 129.2, 128.1, 127.3, 126.9,
126.1, 125.8, 118.2, 117.9, 67.0, 63.8, 52.3, 40.4, 34.9, 26.8.
Compound 29. To a solution of 23 (0.240 g, 0.076 mmol)
in THF (20 mL) was added (t-Bu)4NF‚3H2O (0.280 g, 0.92
mmol). The reaction mixture was stirred for 5 h at room
temperature. Subsequently, water (20 mL) was added and the
product was extracted with DCM (3 × 15 mL). The organic
phase was isolated, dried on magnesium sulfate, filtered, and
concentrated to 5 mL. The product was purified by precipita-
tion from methanol to give a yellow powder. Yield 0.150 g
(94%). MALDI-TOF MS m/z 2167 g/mol (M(Na+)); 1H NMR
(250 MHz, CD2Cl2) δH 7.57 (s, 3 H), 7.53 (s, 1 H), 7.19-6.64
(m, 89 H), 3.62 (s, 3 H), 3.03 and 3.01 (s, s, 6 H), 2.38-2.20
(m, 4 H), 1.72-1.57 (m, 4 H); 13C NMR (62.5 MHz, CD2Cl2) δC
174.2, 173.5, 145.0, 141.6, 141.5, 141.5, 141.2, 141.1, 140.9,
140.5, 140.3, 140.0, 139.8, 139.6, 138.6, 131.9, 131.5, 131.2,
130.9, 130.7, 130.2, 129.0, 128.1, 127.3, 126.9, 126.1, 119.8,
119.5, 83.8, 77.3, 63.8, 51.7, 35.9, 34.0, 30.3, 24.4.
Compound 30. Analogously to 29, from compound 25
(0.350 g, 0.111 mmol) and (t-Bu)4NF‚3H2O (0.400 g, 1.32 mmol)
was obtained 30 as a yellow powder. Yield 0.220 g (88%).
MALDI-TOF MS m/z 2244 g/mol (M(Na+))+; 1H NMR (250
MHz, CD2Cl2) δ 7.56 (s, 3 H), 7.52 (s, 1 H), 7.45-7.29 (m, 6
H), 7.18-6.74 (m, 82 H), 6.67-6.60 (m, 6 H), 5.06 (s, 2 H),
3.31-3.13 (m, 2 H), 3.03 and 3.00 (s, s, 6 H), 2.33-2.24 (m, 2
H), 1.87-1.75 (m, 2 H); 13C NMR (62.5 MHz, CD2Cl2) δC 171.0,
157.6, 145.0, 142.3, 142.2, 142.1, 141.7, 141.6, 141.5, 141.2,
141.1, 141.0, 140.6, 140.0, 139.9, 139.6, 139.2, 138.7, 137.2,
136.6, 136.0, 132.4, 131.9, 131.5, 131.2, 130.9, 130.7, 130.3,
129.1, 128.8, 128.4, 128.3, 128.1, 128.0, 127.9, 127.3, 127.1,
127.0, 126.2, 119.8, 119.6, 118.2, 117.9, 83.8, 77.3, 67.0, 63.8,
40.4, 34.8, 26.8, 23.8.
22 as a white powder. Yield 0.032 g (41%). MALDI TOF
1
MS m/z 1965 g/mol (M(Na+)); H NMR (250 MHz, CD2Cl2) δ
7.54 (s, 4H), 7.25-6.60 ppm (m, 95H), 3.74-3.59 (m, 2H),
2.57-2.45 (m, 2H), 2.05-1.91 (m, 2H); 13C NMR (62.5 MHz,
CD2Cl2) δC 173.9, 144.8, 142.2, 141.9, 141.3, 141.1, 140.9, 140.6,
140.5, 139.9, 139.7, 131.9, 130.8, 130.6, 130.3, 129.1, 127.9,
127.2, 127.1, 126.9, 126.6, 125.9, 125.8, 125.7, 81.5, 63.8, 44.3,
31.9, 17.1.
Compound 23. 23 was prepared analogously to 21 from 8
(0.100 g, 0.108 mmol). The products were purified by flash
chromatography with a mixture od DCM/acetone (40:1) as
eluent to give 23 as a white powder. Yield 0.300 g (90%).
MALDI TOF MS m/z 3106 g/mol (M(Na+)); 1H NMR (250 MHz,
CD2Cl2) δ 7.54 (s, 4 H), 7.21-6.59 (m, 92 H), 3.620 and 3.614
(s, s, 3 H), 2.35-2.19 (m, 4H), 1.72-1.58 (m, 4H), 1.09 (s, 126
H); 13C NMR (62.5 MHz, CDCl3) δC 173.6, 147.4, 144.5, 144.1,
143.2, 142.7, 142.5, 142.1, 141.2, 134.6, 134.0, 133.7, 133.4,
133.0, 131.7, 130.9, 130.0, 129.8, 123.6, 123.4, 120.9, 120.6,
110.4, 93.3, 93.1, 66.5, 54.8, 36.8, 32.8, 27.8, 27.4, 21.8, 14.4.
Separation of Regioisomers 23a and 23b. The mixture
of isomers (0.300 g) was separated by flash chromatography
on Silicagel 60 (0.04-0.063 mm) with a mixture of DCM/
acetone (100:1) to give 23a (Rf 0.73, yield 0.115 g), 23b (Rf
0.66, yield 0.115 g) and an unseparated mixture of 23a and
23b (yield 0.065 g).
Compound 24. 24 was synthesized analogously to 21 from
13 (0.072 g, 0.084 mmol) and 16 (0.374 g, 0.502 mmol). The
product was purified by flash chromatography with a DCM/
hexane mixture (1:2) as eluent to give 24 as a white solid. Yield
1
0.56 g (23%). MALDI-TOF MS m/z 3047 g/mol (M(Na+)); H
NMR (250 MHz, CD2Cl2) δ 7.58-6.62 (m, 93H), 3.74-3.59 (m,
2H), 2.57-2.45 (m, 2H), 2.03-1.90 (m, 2H), 1.26 (s, 18H), 1.09
(s, 108H); 13C NMR (62.5 MHz, CD2Cl2) δC 144.9, 141.9, 141.5,
141.2, 141.1, 140.9, 140.7, 140.1, 140.0, 138.7, 133.7, 131.8,
131.1, 130.8, 130.6, 130.2, 129.9, 129.0, 128.1, 127.9, 126.9,
126.1, 121.2, 121.0, 107.3, 91.0, 90.9, 44.3, 31.8, 30.1, 18.8, 17.1,
11.7.
Compound 25. 25 was prepared analogously to 21 from
12 (0.130 g, 0.129 mmol) and 16 (0.350 g, 0.470 mmol). The
product was purified by flash chromatography with a mixture
of DCM/acetone (40:1) as eluent to give 25 as a white powder.
Yield 0.377 g (92%). MALDI-TOF MS m/z 3181 g/mol (M(Na+));
1H NMR (250 MHz, CD2Cl2) δ 7.54 and 7.53 (s, s, 4H), 7.33-
7.31 (m, 4 H), 7.20-6.61 (m, 92 H), 3.65-3.62 (m, 2 H), 2.37-
2.31 (m, 2H), 2.28-2.22 (m, 2H), 1.07 (s, 126 H); 13C NMR
(62.5 MHz, CD2Cl2) δC 170.9, 157.6, 153.9, 145.0, 144.8, 142.3,
142.1, 141.9, 141.5, 141.3, 141.1, 141.0, 140.8, 140.6, 140.1,
140.0, 139.7, 138.8, 133.4, 132.4, 131.9, 131.6, 131.1, 130.9,
130.7, 130.5, 130.3, 129.7, 129.1, 128.8, 128.5, 128.4, 128.3,
128.1, 127.3, 127.1, 126.9, 126.7, 126.1, 125.8, 124.1, 121.3,
121.0, 118.2, 107.3, 91.0, 90.9, 67.0, 63.8, 40.4, 34.9, 26.9, 18.8,
11.7.
Compound 26. 26 was prepared analogously to 21 from 8
(0.050 g, 0.054 mmol) and 17 (0.180 g, 0.243 mmol). The
product was purified by precipitation from methanol to give a
yellow powder. Yield 0.120 g (72%). MALDI TOF MS m/z 3076
g/mol (M+); 1H NMR (250 MHz, CD2Cl2) δ 7.72-7.61 (m, 8 H),
7.50-6.50 (m, 132 H), 6.33-6.17 (m, 12 H), 3.63 and 3.62 (s,
s, 3 H), 2.35-2.19 (m, 4H), 1.70-1.58 (m, 4H); 13C NMR (62.5
MHz, CD2Cl2) δC 170.8, 167.9, 167.8, 149.2, 148.8, 144.7, 144.4,
142.7, 142.3, 141.8, 141.3, 141.1, 140.9, 140.5, 140.2, 140.0,
139.8, 139.5, 139.1, 136.3, 136.1, 135.7, 135.4, 132.7,132.4,
132.1, 132.0, 130.6, 130.3, 129.9, 129.5, 129.0, 128.4, 128.3,
128.2, 128.0, 127.2, 126.5, 125.8, 120.0, 119.8, 118.1, 117.8,
114.0, 113.7, 63.7, 51.7, 37.4, 33.9, 25.1, 24.7.
Compound 32. 32 was prepared and purified analogously
to 20 from 29 (0.055 g, 0.025 mmol) and 14 (0.114 g, 0.295
mmol). Yield 0.080 g (75%). MALDI-TOF MS m/z 4299 g/mol
(M(4H+))+; 1H NMR (250 MHz, acetone-d6) δ 8.87-8.76 (m, 1
H, NH), 8.44-8.27 (m, 24 H), 7.86-7.74 (13 H), 7.50-7.30 (m,
24 H), 7.23-7.07 (m, 48 H), 7.05-6.55 (m, 101 H), 3.57 and
3.56 (s, s, 3 H), 2.35-2.23 (m, 4 H), 1.66-1.57 (m, 4 H)); 13C
NMR (175.5 MHz, acetone-d6) δC 174.5, 171.4, 160.2, 159.9,
148.9, 145.4, 142.7, 142.4, 141.8, 141.7, 141.0, 140.8, 140.6,
140.3, 139.7, 138.9, 138.5, 138.3, 137.6, 135.7, 133.0, 132.4,
132.1, 132.0, 131.6, 131.1, 130.8, 129.6, 129.3, 129.0, 128.6,
128.5, 128.3, 128.0, 127.7, 127.5, 127.4, 127.2, 126.5, 124.7,
119.4, 118.3, 117.8, 116.1, 114.5, 64.3, 51.5, 37.3, 33.9, 32.6,
25.6, 25.3; RP-HPLC, retention time ) 19 min.
Compound 33. 33 was prepared analogously to 21 from
29 (0.038 g, 0.017 mmol) and 15 (0.106 g, 0.280 mmol). The
product was purified by precipitation from hexane to give a
yellow powder. Yield 0.055 g (72%). MALDI-TOF MS m/z 4307
1
g/mol (M(Na+))+; H NMR (250 MHz, CD2Cl2) δ 7.53 (s, 1 H),
Compound 27. 27 was synthesized analogously to 21 from
8 (0.050 g, 0.054 mmol) and 17 (0.190 g, 0.243 mmol). The
product was purified by precipitation from methanol to afford
a yellow powder. Yield 0.150 g (86%). MALDI TOF MS m/z
3221 g/mol (M(Na+)); 1H NMR (250 MHz, CD2Cl2) δ 7.51 (s, 4
H), 7.20-6.55 (m, 89 H), 3.61 (s, 3 H), 3.17-3.03 (m, 12 H),
7.50 (s, 3 H), 7.41 (s, 3 H), 7.36 (s, 3 H), 7.17-7.12 (m, 42 H),
7.09-7.05 (m, 13 H), 6.90-6.84 (m, 86 H), 6.79-6.71 (m, 40
H), 6.67-6.60 (m, 17 H), 6.55-6.47 (m, 12 H), 3.62 (s, 3 H),
1.75-1.58 (m, 4 H), 1.37-1.19 (m, 4 H); 13C NMR (175.5 MHz,
CD2Cl2) δC 174.2, 144.5, 142.1, 141.9, 141.8, 141.1, 140.9, 140.7,
140.5, 140.4, 140.3, 140.2, 139.7, 139.7, 139.6, 139.4, 139.3,
8036 J. Org. Chem., Vol. 69, No. 23, 2004

Synthesis of Desymmetrized Polyphenylene Dendrimers
1
139.2, 139.1, 138.8, 138.4, 138.3, 138.0, 132.4, 132.0, 131.9,
131.8, 131.4, 131.2, 130.6, 130.4, 130.2, 129.9, 128.9, 128.6,
127.9, 127.8, 127.1, 127.0, 126.8, 126.5, 126.4, 126.2, 125.7,
125.6, 125.4, 118.1 52.3, 38.0, 33.9, 30.0, 24.6.
Compound 34. 34 was prepared analogously to 21 from
29 (0.030 g, 0.014 mmol) and 16 (0.124 g, 0.17 mmol). The
product was purified by precipitation from methanol to give a
yellow powder. Yield 0.075 g (83%). MALDI-TOF MS m/z 6473
(M(Na+)); 1H NMR (250 MHz, CD2Cl2) δ 7.53 (s, 1 H), 7.50 (s,
3 H), 7.41 (s, 3 H), 7.36 (s, 3 H), 7.21-6.44 (m, 197 H), 3.63
and 3.62 (s, s, 3 H), 2.36-2.23 (m, 4 H), 1.78-1.58 (m, 4 H),
1.09 (s, 253 H); 13C NMR (62.5 MHz, CD2Cl2) δC 142.1, 141.4,
140.9, 140.1, 138.8, 132.0, 131.2, 130.9, 130.4, 128.3, 127.6,
121.4, 121.1, 107.5, 91.1, 91.0, 18.9, 11.9.
g/mol (M(Na+)); H NMR (250 MHz, DMSO-d6) δH 9.75-9.62
(m, 12 H, NH), 7.40-6.41 (m, 267 H), 4.99 (s, 24 H), 3.55 and
3.54 (s, s, 3 H), 3.16-2.94 (m, 24 H), 2.29-2.13 (m, 28 H),
1.74-1.58 (m, 24 H); 13C NMR (62.5 MHz, DMSO-d6) δC 171.5,
171.4, 157.2,145.0, 144.6, 142.6, 142.1, 141.8, 141.6, 141.2,
140.7, 140.6, 140.5, 140.3, 140.2, 140.1, 140.0, 139.5, 139.3,
139.2, 138.8, 138.5, 138.4, 138.3, 138.1, 135.7, 135.3, 132.3,
131.7, 131.4, 131.1, 130.7, 130.4, 129.5, 129.3, 129.0, 128.4,
127.6, 127.0, 126.4, 119.4, 117.9, 117.6, 66.1, 51.5, 41.0, 33.8,
26.3, 25.4, 25.0.
Supporting Information Available: Materials and ana-
1
lytical methods; H NMR and 13C NMR data for compounds
6, 8, 12, 13, 20-30, and 32-35; temperature-dependent 1H
NMR of compound 23. This material is available free of charge
via the Internet at http://pubs.acs.org.
Compound 35. 35 was synthesized analogously to 21 from
29 (0.020 g, 0.009 mmol) and 31 (0.92 g, 0.108 mmol). The
product was purified by precipitation from methanol to give a
yellow powder. Yield 0.045 g (70%). MALDI-TOF MS m/z 7118
JO048998U
J. Org. Chem, Vol. 69, No. 23, 2004 8037