End group functionalization of poly(ethylene glycol) with phenolphthalein: Towards star-shaped polymers based on supramolecular interactions

Article abstract of DOI:10.3762/bjoc.10.235

The synthesis of a new phenolphthalein azide derivative, which can be easily utilized in polymer analogous reactions, is presented. The subsequent cycloaddition reaction with propargyl-functionalized methoxypoly(ethylene glycol) yielded polymers bearing p

Full text of DOI:10.3762/bjoc.10.235

End group functionalization of poly(ethylene glycol) with
phenolphthalein: towards star-shaped polymers
based on supramolecular interactions
Carolin Fleischmann, Hendrik Wöhlk and Helmut Ritter*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2014, 10, 2263–2269.
Institute of Organic Chemistry and Macromolecular Chemistry,
Heinrich-Heine-University Düsseldorf, Universitätsstraße 1, D-40225
Düsseldorf, Germany
doi:10.3762/bjoc.10.235
Received: 02 May 2014
Accepted: 10 September 2014
Published: 25 September 2014
Email:
Helmut Ritter* - h.ritter@hhu.de
Associate Editor: N. Sewald
*
Corresponding author
©
2014 Fleischmann et al; licensee Beilstein-Institut.
Keywords:
License and terms: see end of document.
cyclodextrin; phenolphthalein; poly(ethylene glycol); supramolecular
assembly; UV–vis spectroscopy
Abstract
The synthesis of a new phenolphthalein azide derivative, which can be easily utilized in polymer analogous reactions, is presented.
The subsequent cycloaddition reaction with propargyl-functionalized methoxypoly(ethylene glycol) yielded polymers bearing
phenolphthalein as the covalently attached end group. In presence of per-β-cyclodextrin-dipentaerythritol, the formation of stable
inclusion complexes was observed, representing an interesting approach towards the formation of star shaped polymers. The decol-
orization of a basic polymer solution caused by the complexation was of great advantage since this behavior enabled following the
complex formation by UV–vis spectroscopy and even the naked eye.
Introduction
Over the past decades, polymers with well-defined and com- erties such as lower viscosities [8], a higher solubility due to
plex architectures gained increasing attention due to a broad numerous end groups [9], and a rather globular shape instead of
variety of applications. Accordingly, the development of new entangled polymer chains [10,11]. Applications deriving there-
synthetic routes to these polymeric structures is still of great from include the use as nanocarriers [12,13], electro-optical ma-
interest [1-5]. A very convenient approach in the synthesis of terials [14], coating additives [15] and rheology modifiers [16].
such systems is the attachment of compounds indicating the
successful formation of the desired architecture, e.g., by a color The link between hyperbranched polymeric materials and linear
change [6,7].
polymers is represented by star-shaped polymers. This interest-
ing class of polymer architectures can be subdivided into
Compared to analogous linear systems, dendrimeric and hyper- regular star polymers and miktoarm star polymers. In analogy to
branched polymers offer different and virtually unusual prop- hyperbranched polymers, star shaped polymers have lower
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viscosities than analogous linear materials of the same molec- sion complexes, one of the major driving forces is the displace-
ular weight because the viscosity is rather determined by the ment of enthalpy-rich water molecules from the cyclodextrin
mass of one arm than the mass of the whole molecule [17].
cavity, which requires working in aqueous media, ideally in
pure water. With the intention to enhance the guest molecule’s
Miktoarm star polymers additionally offer complementary prop- hydrophilicity in order to transfer it into the aqueous phase,
erties as they are built of different polymeric arms [18-24].
poly(ethylene glycol) was chosen as the PP-bearing molecule.
On the other hand, it was also of great importance to maintain
The most common techniques applied in the preparation of the rather hydrophobic nature of the PP moiety, since this
these compounds are controlled/living polymerizations. While nature strongly supports the inclusion complex formation. With
several decades ago, anionic polymerization was the method of respect to both requirements, methoxypoly(ethylene glycol)
choice [25-28], in recent years, controlled radical polymeriza- with an average molecular weight of 350 g/mol was chosen,
tions (CRP) gained increasing importance and nowadays offer a which should generally allow working in aqueous media while
variety of synthetic routes to well-defined polymeric structures preserving the hydrophobic nature of the PP moiety. The
[
29-33]. A very interesting alternative is the combination of resulting molecules, namely the phenolphthalein end group-
CRP with supramolecular complex formation, e.g., by the use modified methoxypoly(ethylene glycol) (mPEG-PP) and the
of cyclodextrins (CDs) [6,7,34].
dipentaerythritol derivative per-β-cyclodextrin-dipentaery-
thritol (DPE-CD), decorated with six cyclodextrin moieties,
The most important representatives of these cyclic oligo- were investigated with respect to their complexation behavior.
saccharides with respect to industrial applications consist of six
(
α-CD), seven (β-CD) and eight (γ-CD) glucopyranose units Synthesis of host and guest compounds
and have a cone-like structure which is hydrophilic on the The preparation of methoxypoly(ethylene glycol) (mPEG)-
outside and rather hydrophobic on the inside [35]. The ether bearing phenolphthalein as a functional end group proceeded
linkages of the glucose units are located on the inside of the through a 1,3-diploar cycloaddition reaction of alkyne function-
cavity which induces a high electron density and enables the alized mPEG (mPEG-prop) and an azide-functionalized
complexation of suitable hydrophobic guest molecules and thus, phenolphthalein (PP-N3) derivative. The synthesis of the PP-N3
offers a broad variety of applications [36-39]. An adequate intermediate was of special interest, since up to now this mole-
guest molecule for β-CD is the well-known indicator dye cule has not been described in literature and can be employed in
phenolphthalein [40]. In addition to its relatively high affinity to various reactions aiming for the (end) group functionalization of
β-CD, this molecule undergoes a decolorization in basic solu- polymers.
tion as the complexation induces a re-lactonization of the mole-
cule without protonation of the phenolic hydroxy groups [41]. The molecule was prepared in a three-step reaction starting
Therefore, phenolphthalein can be utilized as an indicator for from native phenolphthalein (see Scheme 1).
the formation of supramolecular complexes with β-CD [42-44].
Recently, we transferred this principle to phenolphthalein that In a first step, the monofunctional phenolphthalein-monomer
was covalently attached to several polymers [7,45,46].
N-(2-hydroxy-5-(1-(4-hydroxyphenyl)-3-oxo-1,3-dihydroiso-
benzofuran-1-yl)benzyl)acrylamide (PP-AAm) was synthe-
In this study, we present a new approach towards the prepar- sized following a protocol we developed in a previous study
ation of star-shaped polymers that are formed through supra- [46]. Afterwards, the corresponding amine derivative (PP-NH2)
molecular interactions of β-CD and phenolphthalein. The great was obtained through a Michael addition reaction of PP-AAm
advantage of this system would be the possibility to follow the and cysteamine hydrochloride. The hydrochloride was chosen
star polymer formation with naked eyes.
in order to disable the competing nucleophilic addition of the
amine and therefore, to prevent the formation of side products.
The purified PP-NH2 was then converted into the corres-
Results and Discussion
We herein describe the synthesis of the host and guest com- ponding azide derivative (PP-N3) by use of trifluoromethane-
pound, which were further utilized for the preparation of star sulfonyl azide, which was generated in situ from sodium azide
shaped polymers based on supramolecular interactions.
and trifluoromethanesulfonic anhydride as described in litera-
ture [47]. Subsequent treatment with PP-NH2 yielded the
The preparation of both, the host and the guest compound, desired product PP-N3 in an overall yield of 19%.
occurred via 1,3-dipolar cycloaddition, in which the cyclodex-
trin (CD) and phenolphthalein (PP) moieties were introduced as The dipolarophil was prepared starting from methoxy-
the complex-forming groups. Regarding the formation of inclu- poly(ethylene glycol) (mPEG) and propargyl bromide, whilst
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Beilstein J. Org. Chem. 2014, 10, 2263–2269.
Scheme 1: Three-step synthesis of azide-functionalized phenolphthalein derivative PP-N3. a) H2O, CH2Cl2, 0 °C. b) H2O, MeOH, CH2Cl2, room
temperature.
the latter one was utilized in a threefold excess to achieve Since the reaction was carried out in absence of copper(I) salts,
maximum conversion of the starting material. The resulting a mixture of the 1,4- and 1,5-substituted triazole regioisomers
alkyne functionalized mPEG α-methoxyethyl-ω-propargyloxy- was obtained.
poly(ethylene glycol) (mPEG-prop) was then reacted with
PP-N3 in a 1,3-diploar cycloaddition, which gave the desired The host component based on dipentaerythritol, which was
phenolphthalein-functionalized mPEG-PP (see Scheme 2). converted into a multifunctional initiator for core first star
Scheme 2: Synthesis of the dipolarophil mPEG-prop and subsequent coupling with PP-N3.
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Beilstein J. Org. Chem. 2014, 10, 2263–2269.
polymer preparation approaches in previous studies [48,49], re-lactonization of the molecule, a first evaluation of the com-
was synthesized according to a protocol previously developed plex formation occurred with bare eyes.
in our group [50]. Dipentaerythritol was functionalized with six
propargyl moieties serving as the dipolarophil in a subsequent For this, a molar excess of 16.7 DPE-CD equivalents, which
treatment with β-cyclodextrin azide. Thereby, a dipentaery- equals 100 CD units per PP moiety, was added to a solution of
thritol derivative carrying six cyclodextrins (DPE-CD) that are 0.05 mg/mL PEG-PP at pH 12. In order to compare the com-
covalently attached through triazole rings was obtained.
plexation ability of DPE-CD to free β-CD, a sample containing
the same number of equivalents of monomeric, randomly
Mixing of mPEG-PP and DPE-CD resulted in the formation of methylated β-cyclodextrin (RAMEB-CD) was prepared. For
stable complexes (see Figure 1), which were subjected to both samples, a distinct decolorization was observed, although a
further investigations.
complete decolorization did not occur (see Figure 2).
Investigation of the complex formation
behavior
As an explanation of this behavior we assumed that over time,
an equilibrium of complexed and decomplexed molecules is
Due to the fact that in basic solution the complexation of PP by reached in which the high extinction coefficient of the non-
β-CD is accompanied with a decolorization due to the lactonic, decomplexed PP molecules causes the residual
Figure 1: Schematic illustration of the complex formation of PEG-PP and DPE-CD.
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Beilstein J. Org. Chem. 2014, 10, 2263–2269.
A similar effect was observed in a previous study in which the
complexation of polymer-bound phenolphthalein by a β-CD-
terminated polymer was investigated [7]. We assume that this
behavior can be attributed to entropic effects.
In addition to the UV–vis measurements, which already veri-
fied the formation of supramolecular complexes, rotating-frame
nuclear Overhauser effect correlation spectroscopy (ROESY)
was performed. Thereby, resonances of spatially close nuclei
are connected though cross peaks which can be found in
ROESY spectra besides the diagonal peaks. Since the complex
Figure 2: Solution of PEG-PP (0.05 mg/mL) a) at pH 10, b) in pres-
ence of 16.7 equiv DPE-CD at pH 12, c) in presence of 100 equiv
RAMEB-CD at pH 12 (from left to right).
colorization. This assumption was supported by the observation formation of DPE-CD and PEG-PP induces a spatial conver-
that the addition of higher amounts of cyclodextrin equivalents, gence of the PP and β-CD moieties, we expected the detection
which should shift the equilibrium to the complexed form, of cross peaks between the CD protons and the aromatic PP
indeed resulted in a stronger decrease of the colorization.
protons. Due to the limited solubility of PEG-PP in aqueous
solution, a sample of low polymer concentration was utilized to
In addition to the qualitative evaluation of the complexation record the ROESY spectrum.
behavior of PEG-PP, UV–vis measurements were performed in
order to get an insight into the quantitative complex analysis. In the corresponding spectrum, cross peaks of weak intensity
For native phenolphthalein, the characteristic absorption were found (see Figure S1, Supporting Information File 1).
maximum that refers to the pink color in basic solution can be Although the low intensity can most likely be referred to the
found at 554 nm in corresponding UV–vis spectra. For the low polymer concentration, the significance of this experiment
phenolphthalein-containing polymer PEG-PP, a slight needs to be critically evaluated.
bathochromic effect is observed, which shifts the maximum to
5
61 nm. Accordingly, the decrease of the absorption at 561 nm The formation of the desired star-shaped polymers requires the
was examined in order to evaluate the complexation. For this, complexation of PEG-PP molecules by at least three β-CD
solutions containing a PEG-PP:DPE-CD ratio between 1:1 and moieties attached to the same DPE-CD molecule. We assumed
1
:16.7, and a PEG-PP:RAMEB-CD ratio of 1:100, respective- that the complexation efficiency of DPE-CD can be evaluated
ly, were measured at pH 12. From the corresponding spectra in by comparison of the hydrodynamic diameters of free DPE-CD
Figure 3, it can be seen that the absorption at 561 nm clearly and the diameter of the complex formed by both polymers.
decreases with increasing amount of DPE-CD. Interestingly, Ideally, the hydrodynamic diameter of the complex could be
the complexation with DPE-CD seems to be more efficient than calculated by the following equation:
the complexation by free RAMEB-CD, since the presence of
(1)
1
00 equivalents β-CD attached to DPE induces a stronger
decrease in the absorption than the same amount of free β-CDs.
Unfortunately, neither the hydrodynamic diameters of the single
polymers nor the diameter of the complex could be determined
in DLS measurements. Instead, a strong aggregation behavior
was observed and dilution or filtration resulted in a dramatic
decrease of the measurement quality.
Conclusion
A successful synthetic strategy for the preparation of new com-
pounds bearing phenolphthalein and cyclodextrin moieties as
the complex forming groups could be introduced. Furthermore,
the formation of stable complexes based on supramolecular
interactions between both compounds was proved by UV–vis
measurements. Although DLS measurements did not succeed to
explicitly validate the formation of the desired star shaped poly-
mers due to the formation of strongly aggregated particles, we
believe that this approach is an interesting addition to other
Figure 3: UV–vis spectra of PEG-PP solutions containing different
amounts of DPE-CD and RAMEB-CD.
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