Synthesis of penta-p-phenylenes with oligo(ethylene glycol) side chains

Article abstract of DOI:10.1016/j.tetlet.2007.06.167

We report an efficient synthesis of a series of penta-p-phenylene derivatives with four side chains of various lengths, including deca(ethylene glycol) groups. The key feature of the synthesis is that the side chains are efficiently introduced in the last step, facilitating optimization of the side chains for different applications. Raman spectroscopy study indicates a similarly high rigidity for all these compounds, even those with long oligo(ethylene glycol) side chains. The deca(ethylene glycol)-substituted penta-p-phenylene derivatives are versatile building blocks for construction of nanometric, tripod-shaped adsorbates for biological applications.

Full text of DOI:10.1016/j.tetlet.2007.06.167

Tetrahedron Letters 48 (2007) 6075–6079
Synthesis of penta-p-phenylenes with oligo(ethylene glycol)
side chains
a,
a
a
*
´
´
´
´
J. Manuel Lopez-Romero, Rodrigo Rico, Rocıo Martınez-Mallorquın,
a
a
b
c
´
´
Jesus Hierrezuelo, Elena Guillen, Chengzhi Cai, J. Carlos Otero and
c
´
´
Isabel Lopez-Tocon
aDepartamento de Quı´mica Orga´nica, Facultad de Ciencias, Universidad de Ma´laga, 29071 Ma´laga, Spain
bDepartment of Chemistry and Center for Materials Chemistry, University of Houston, Houston, TX 77204-5003, USA
cDepartamento de Quı´mica Fı´sica, Facultad de Ciencias, Universidad de Ma´laga, 29071 Ma´laga, Spain
Received 18 May 2007; revised 26 June 2007; accepted 29 June 2007
Available online 7 July 2007
Abstract—We report an efficient synthesis of a series of penta-p-phenylene derivatives with four side chains of various lengths,
including deca(ethylene glycol) groups. The key feature of the synthesis is that the side chains are efficiently introduced in the last
step, facilitating optimization of the side chains for different applications. Raman spectroscopy study indicates a similarly high
rigidity for all these compounds, even those with long oligo(ethylene glycol) side chains. The deca(ethylene glycol)-substituted
penta-p-phenylene derivatives are versatile building blocks for construction of nanometric, tripod-shaped adsorbates for biological
applications.
ꢀ 2007 Elsevier Ltd. All rights reserved.
The control of the orientation and spacing between
functional groups in organic thin films, and the avail-
ability of methods for its high fidelity derivatization, will
greatly facilitate the development of molecular scale
devices for many applications. For instance, the alignment
of molecules is necessary for obtaining non-linear opti-
cal phenomena and orientation-dependent electronic
and optical properties of conjugated molecules.1 For
biosensor applications, it is highly desirable to control
the spacing between the adjacent probe molecules in
order to achieve maximum loading, and yet not to hinder
the interaction between the probe and target molecules.2
sible to avoid non-randomized mixing at the nanoscale
that prevents the control of the nanoscale spacing
between the functional surface groups.4
For the development of molecular scale devices, it is
highly desirable to develop large, shape-persistent and
self-standing adsorbate molecules. Several of such mole-
cules have been reported, including ‘molecular caltrops’
with four phenylacetylene arms extending from a
tetrahedral silicon corn,5 conically shaped dendron
adsorbates with a functional group at the corn,6 and tri-
pod-shaped molecules with three oligophenylene hepta-
mers as the tripod legs and one bromophenyl group as
the functional arm, joined together at a single silicon
atom.7 Tripodal rigid adsorbates (compound 1) have
been deposited on hydrogen-terminated silicon surfaces
through surface hydrosilylation.8 The orientation of the
bromophenyl groups at the focal point of the tripods in
the film is believed to be perpendicular to the surface
since the Suzuki coupling of these groups with aryl-
boronic acid derivatives gave a very high yield (>90%).8
In comparison, the same reaction only gave <50% yield
for bromophenyl groups on films derived from carbosi-
lane dendrimers, likely because a substantial amount of
these groups had an unfavourable orientation and some
of them were even buried inside the films due to the flex-
Currently, a common method to prepare functional or-
ganic thin films is based on self-assembly of monolayers
of monodentate adsorbates with a long alkyl chain, such
as alkylsiloxanes on polar surfaces, or alkylthiolate on
gold surfaces.3,4 The orientation of the flexible molecules
in these monolayers is maintained by the close packing
of the alkyl chains through van der Waals forces.
Although the average density of the functional groups
on these monolayer surfaces can be adjusted by co-
deposition with inert analogous adsorbates, it is not pos-
*
Corresponding author. E-mail: Jmromero@uma.es
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.06.167

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J. M. Lo´pez-Romero et al. / Tetrahedron Letters 48 (2007) 6075–6079
ibility of the dendrimer, and hence could not undergo
the reaction.6b–d These results show the promise of con-
trolling the orientation of functional moieties on free-
standing individual adsorbate molecules. We are inter-
ested in generating single molecule patterns of similar
tripod molecules to control the orientation and location
of the individual functional moieties on surfaces, and
use such well defined model systems to study multi-
valent and multi-component interactions in biological
systems. The reported tripod derivatives 1 cannot be used
for this purpose, since the hydrophobic tripod frame-
work and its hexyl side chains are well known to interact
non-specifically with protein molecules, thus interfering
with the specific interaction of target molecules with
the ligand on the focal point of the tripod. To overcome
this problem, we must develop tripod molecules that are
modified with side chains that do not interact with pro-
tein molecules. The most common materials for resisting
non-specific interaction with proteins are poly- or
oligo(ethylene glycol) (PEG or OEG).3,9 Monolayers
presenting OEG groups on gold or silicon substrate sur-
faces have been shown to strongly resist protein adsorp-
tion.3a Therefore, our goal is to develop an efficient
synthesis of the tripod adsorbates with OEG side chains.
In this Letter, we report an efficient method for prepar-
ing the key building block of these molecules: penta-p-
phenylenes with OEG side chains (compounds 2 in
Fig. 1).
reaction of 3 with NBS in the presence of AIBN in
refluxing CCl4 to provide the tetrabromine derivative 4
in 63% yield (Scheme 1).10 OEG groups were introduced
to 4 through substitution with commercial tri(ethylene
glycol) monomethyl ether (5). Initially, the reaction
was run in refluxing THF using KO-t-Bu as the base,
leading to a low yield of 6 (25%) and formation of the
monodebromination product of 6 (21%). We then found
that using toluene as the solvent, NaH as the base and
performing the reaction at a lower temperature (20 ꢁC)
resulted in a good yield of 6 (71%). Unfortunately, the
monolithiation of the dibromide 6 followed by reaction
with trimethoxy borate failed. Only unreacted product
or complex reaction mixtures were obtained under
several reaction temperatures (À78 ꢁC, À40 ꢁC and
20 ꢁC). This result was in contrast with several reports
of monolithiation of p-dibromo benzene derivatives.11
We speculate that the failure in our system is probably
due to the following factors: (1) protonation of the phe-
nyl anion by the relatively acidic benzylic protons to
form benzylic anion which is stabilized by the benzylic
oxygen atom and the complexation of the Li+ by the
OEG side chain; and (2) difficulties of eliminating water
absorbed by the hydrophilic OEG side chains.
Owing to these results, we decided to first construct the
penta-p-phenylene backbone by Suzuki coupling of the
boronic acids 8 with p-diiodoterphenyl (9, Scheme 2),
and to incorporate the OEG groups at the end of the
synthesis. In addition to the OEG substituted penta-p-
phenylenes, we also prepared several other derivatives
to allow a systematic study by Raman spectroscopy
(see below). The boronic acids used, 8a,b, were pur-
The initial plan of synthesis of 2 adapted our previously
reported route7 involving the preparation of the mono-
mer I, followed by Suzuki coupling with triphenyl di-
iodide. The attempted preparation of I began with the
Figure 1.

J. M. Lo´pez-Romero et al. / Tetrahedron Letters 48 (2007) 6075–6079
6077
Scheme 1. Reagents and conditions: (i) NBS/AIBN/CCl4, reflux; (ii) NaH/toluene, 20 ꢁC.
Scheme 2. Reagents and conditions: (i) (1) n-BuLi/THF, À78 ꢁC, (2) B(OMe)3/THF, (3) HCl; (ii) Na/MeOH, 20 ꢁC; (iii) Pd(PPh3)4 (5 mol %)/1 M
Na2CO3/DME, reflux, 18 h.
chased from Aldrich, and 8c, 8d and 8f were prepared
from compounds 3, 7 and 4, respectively, by monolithi-
ation with n-buthyl lithium, followed by reaction with
trimethoxy borate (Scheme 2).12 The treatment of 8f
with an excess of sodium methoxide in methanol gave
8e. Subsequent coupling with 9 under standard Suzuki
conditions in refluxing DME gave penta-p-phenylenes
2a–e in good yields, which were purified by recrystalliza-
tion from toluene (Scheme 2). Under these reaction con-
ditions no polymerization of compound 8 was observed.
yield. No chromatography was needed to purify the
compound. Tosylation of 14 afforded 15 in 63% yield.
The coupling of 15 with an excess of 13 provided
deca(ethylene glycol) monomethyl ether (10) in 67%
yield.
The synthesis of the oligo(ethylene glycol) substituted
penta-p-phenylenes was efficiently accomplished with
the tetramethyl penta-p-phenylene 2c (Scheme 4). Bro-
mination of the four methyl groups in 2c with NBS
(1.1 equiv for each methyl group) and AIBN
(4.4 mol %) in refluxing CCl4 gave the hexabromine
compound 2f in very good yield (81%).
We chose the deca(ethylene glycol) 10 as the side chains
for the oligophenylenes, since we anticipated that long
OEG groups are needed to mask the penta-p-phenylene
backbone to render it resistant to the non-specific inter-
actions with proteins.3a The deca(ethylene glycol) deriv-
ative was prepared by the reaction sequence shown in
Scheme 3. Treatment of compound 11 with tosyl chlo-
ride in a mixture of THF and H2O at 20 ꢁC for 24 h gave
tosylate 12 in a 94% yield. This compound was coupled
with an excess of tetraethylene glycol (13) in the pres-
ence of KOH to provide, after washing the reaction mix-
ture with water, the hexa(ethylene glycol) 14 in 50%
The reaction conditions for the coupling of 2f with OEG
derivatives were optimized with commercial tri(ethylene
glycol) monomethyl ether (5). Out of the conditions we
tested, the reaction was best run in toluene at 20 ꢁC with
NaH as the base and a molar ratio of 2f/4 = 1:4.4, lead-
ing to 2g in 43% yield. We were glad to find that under
the same conditions, the final product 2h was obtained
in 55% yield from 2f and the deca(ethylene glycol) 10
(Scheme 4).
Scheme 3. Reagents and conditions: (i) TsCl/NaOH/THF–H2O, 20 ꢁC; (ii)
, KOH, 70 ꢁC.

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J. M. Lo´pez-Romero et al. / Tetrahedron Letters 48 (2007) 6075–6079
Scheme 4. Reagents and conditions: (i) NBS/AIBN/CCl4; (ii) NaH/toluene, 20 ꢁC.
We have described an efficient synthesis of a series of
penta-p-phenylene derivatives 2a–h. Without alkyl sub-
stitution, the penta-p-phenylene derivatives 2a,b are
barely soluble in common solvents such as chloroform,
ethyl ether, THF or toluene. However, compounds with
four side chains (2c–h) are soluble in these organic sol-
vents, and the solubility increases with the chain length.
The OEG substituted penta-p-phenylenes 2g and 2h are
also soluble in aqueous solvents, which is necessary for
biological applications. With these compounds in hand,
we are interested in studying their physical especially
spectroscopy properties, since poly- and oligo(p-phenyl-
ene)s are attractive materials for potential applications
involving photo- and electroluminescence. In addition,
the backbone of oligo(p-phenylene)s is relatively rigid
and hence is attractive to be used as the framework of
self-standing molecular adsorbates.
Herein, we report the Raman spectroscopy study of
these compounds.13 It has been established that the rel-
ative intensities of the Raman active modes of oligo(p-
phenylene)s recorded at 1220, 1280 and 1600 cmÀ1 de-
pend on the combined effect of p-electron delocalization
and intra-ring confinement. Therefore their intensities
are very sensitive to the conjugation length of these mol-
ecules.14,15 Overall, the intensity ratio I1280/I1220 de-
creases with increasing effective conjugation length,
which can be caused by either increasing the number
of repeat units in the oligomer, or by reducing the inter
ring torsion angle. For this reason these bands have
been used to monitor the quality of synthetic routes to
poly(p-phenylene)s.16
Figure 2 shows the Raman spectra of 2a–h.17 The char-
acteristic bands of the penta-p-phenyl frame can be seen
at ca. 1210, 1270 and 1600 cmÀ1, assigned to C–H
in-plane bend, C–C inter-ring stretch and C@C on-ring
stretch, respectively. The ratio of I1280/I1220 (ca. 3:1) is
approximately the same for compounds 2b–h. The high-
er I1280/I1220 ratio of 1:1 for compound 2a can be
Figure 2. Raman spectra of penta-p-phenylenes 2a–h.
explained by a higher planarity in its structure, as can be
expected in this case due to the absence of substituents.
It is remarkable that no significant differences of the
I1280/I1220 ratio were observed for compounds 2b–h,
even though the lengths of the side chains are very differ-
ent in these compounds, the OEG side chains in com-
pound 2h being the longest. This result strongly
indicates that the length of the four OEG side chains
in the oligo(p-phenylene)s does not significantly affect
the planarity and rigidity of the backbone of the oligo-
mers, probably because the sufficient separation between
the sides reduces steric hindrances.
In summary, a series of penta-p-phenylene derivatives
have been efficiently synthesized. The key feature of
our synthetic approach is that different side chains can
easily be introduced into the oligophenylene backbone

J. M. Lo´pez-Romero et al. / Tetrahedron Letters 48 (2007) 6075–6079
6079
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in the last step of the synthesis, making it versatile for
optimizing the side chains for different purposes. Using
this synthetic route, we prepared the penta-p-phenylene
2h with four deca(ethylene glycol) side chains as versa-
tile building blocks for construction of shape-persistent
adsorbate molecules for biological applications. Raman
analyses show a similarly high rigidity for all these com-
pounds, even those with long OEG side chains. The syn-
thesis of the tripod-shaped adsorbates of using 2h is
currently under study.
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¨
Polymer 1989, 30, 1060; (b) Tour, J. M.; Stephens, E. B. J.
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12. Elemental analyses and spectroscopic data of new com-
pounds were in agreement with their structures. Com-
pound 2h: yellowish syrup; UV (CDCl3) kmax: 300,
242 nm; FTMs-APPI: 2534.22 (C122H20479Br181Br1O44);
1H NMR (400 MHz, CDCl3) d ppm: 1.19 (t, J = 14.2 Hz,
12H), 3.52 (q, J = 14.2 Hz, 8H), 3.56–3.65 (m, 160H), 4.44
(s, 4H), 4.64 (s, 4H), 7.39 (s, 2H), 7.50 (d, 4H), 7.73–7.77
(m, 10H); 13C NMR (100 MHz, CDCl3) d ppm: 15.6, 60.2,
62.1, 62.5, 67.1, 70.3, 70.6, 70.78, 70.82, 70.91, 70.99,
71.05, 71.1, 72.9, 123.0, 127.1, 127.5, 129.1, 129.5, 132.9,
135.1, 137.1, 137.4, 137.5, 139.2, 140.1. Only one synthesis
of compound 8c has been reported in Ref. 11a, but no
experimental details or yields are included for this prod-
uct. Purchased compounds were used without purification.
Triethylene glycol monomethyl ether (5), diethylene glycol
monoethyl ether (11) and tetraethylene glycol (13) were
commercial, and purchased from Aldrich. p-Diiodoter-
phenyl (9) was prepared from terphenyl following reported
procedures: Unroe, M. R.; Reinhardt, B. A. Synthesis
1987, 981.
Acknowledgements
This research was supported by the Nanotechnology
Spanish Research Projects NAN04-09312 C03-01, -02
and -03, CTQ2006-02330, and the Junta de Andalucıa
Project P06-FQM-01895. R.M.M. and E.G. thanks the
project NAN04-09312 C03-02 for the contracts CI-05-
138 and CI-06-151, respectively.
´
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