Covalent attachment and release of small molecules from functional polyphenylene dendrimers

Article abstract of DOI:10.1039/c3cc48741e

Herein, we report the synthesis of 2nd generation PPDs functionalized with free thiol moieties within the scaffold, which were used as anchor points for the covalent attachment of guest species (p-nitrophenol derivatives) through the oxidative formation of disulfide linkages. The disulfide bonds were then cleaved under reductive conditions using dithiothreitol to discharge the molecules.

Full text of DOI:10.1039/c3cc48741e

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Covalent attachment and release of small
molecules from functional polyphenylene
dendrimers†
Cite this: Chem. Commun., 2014,
50, 2034
Received 15th November 2013,
Accepted 18th December 2013
Brenton A. G. Hammer, Martin Baumgarten and Klaus Mullen*
¨
DOI: 10.1039/c3cc48741e
www.rsc.org/chemcomm
Herein, we report the synthesis of 2nd generation PPDs functionalized the encapsulation process was influenced by enthalpic factors, such
with free thiol moieties within the scaffold, which were used as anchor as hydrogen bonding and p–p interactions. Yet a significant area
points for the covalent attachment of guest species ( p-nitrophenol that is often overlooked in encapsulation and release studies is the
derivatives) through the oxidative formation of disulfide linkages. The stability of the assemblies, as thermodynamic stabilization may not
disulfide bonds were then cleaved under reductive conditions using provide the necessary strength to retain the guest molecules until
dithiothreitol to discharge the molecules.
the desired release site.
Our group enhanced the stability of PPD based guest/host
Nanostructures capable of encapsulating guest molecules and structures by introducing azo-benzene functionalities into the
releasing them through a controlled mechanism have tremendous dendrimer scaffold that underwent a reversible cis–trans isomeriza-
potential for a range of applications.1–6 Polyphenylene dendrimers tion upon irradiation at 450 nm (cis–trans) or 365 nm (trans–cis).20
(PPDs) represent a unique class of macromolecules based on their ‘‘Open’’ PPDs (trans-isomer) were loaded with p-nitrophenol units
monodisperse, shape-persistent structure, which can be function- and upon isomerization to the cis-structure two guest molecules
alized at the core, scaffold, and surface.7–14 The ability to function- were sterically sealed per macromolecule. These loaded macromo-
alize PPDs in a site-specific nature allows for the synthesis of lecules proved to be stable despite multiple precipitations and
well-defined, highly functional dendrimers that could be used washings, while the encapsulated molecules were only released
as hosts for encapsulation and release studies.15–17
upon isomerization back to the trans-structure.
Previously, our group investigated PPDs as hosts for small mole-
In an effort to further improve the introduction of guest species into
cules through thermodynamic interactions between the scaffold PPD nanostructures, we report the covalent attachment of small
of the dendrimers and guest species. Former work described the molecules within their scaffolds through disulfide bonds. These
synthesis of 2nd generation PPDs internally functionalized with eight linkages are known to cleave under reductive conditions21–24 which
carboxylic acid groups that were used to bind 3–4 proflavin hydro- allowed us to obtain stable macromolecular structures with a controlled
chloride dye molecules.18 Upon this encapsulation the polar dye release mechanism as illustrated in Scheme 1. 2nd generation PPDs
species became soluble in organic solvents (hexanes, CHCl3, etc.). were synthesized with eight thiol moieties decorating the scaffold. A
Recently, further studies were carried out to investigate the driving thiol-functionalized p-nitrophenol derivative was chosen as the guest
forces behind the encapsulation of small molecules within PPD molecule for two reasons: (1) its attachment and release to the PPDS
scaffolds through isothermal titration calorimetry (ITC) analysis.19 can be clearly characterized by nuclear magnetic resonance (NMR),
It was found that the uptake of non-polar guest molecules (benzene ultra-violet and visible (UV-Vis) spectroscopies, and matrix-assisted laser
and toluene) in unfunctionalized PPDs was entropically driven through desorption ionization time of flight (MALDI-TOF) spectrometry; (2) it
the release of solvent molecules and their molecular exchange with provides a comparison for the dendrimer functionalization efficiency of
the guests. Additionally, when the PPDs were synthesized with this system as compared to the encapsulation and release approach of
polar scaffolds (i.e. carboxylic acids, pyridines, nitrobenzenes) and the photo-switchable azo-benzene functionalized PPDs.20
loaded with polar species (acetonitrile, acetone, benzaldehyde, etc.)
Pyrene was chosen as the dendrimer core to act as a fluorescent
tag, and four tetraethynyl-biphenyl spacers were introduced at the
1, 3, 6, and 8 positions to increase the free volume of the cavities
(ESI,† Scheme S1, compound 1). A thioacetate functionalized
cyclopentadienone was synthesized (ESI,† Scheme S1, compound
2) and used in a Diels–Alder cycloaddition with the pyrene core,
followed by the deprotection of the triisopropylsilyl (TIPS) groups
¨
Max-Planck-Institut fur Polymerforschung, Ackermannweg 10, 55128 Mainz,
Germany. E-mail: muellen@mpip-mainz.mpg.de
† Electronic supplementary information (ESI) available: Synthetic schemes,
experimental procedures, and additional 1H NMR, MALDI-ToF, and UV-Vis
characterization. See DOI: 10.1039/c3cc48741e
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Scheme 1 Covalent attachment and release of guest molecules.
upon reaction with tetrabutyl ammonium fluoride to afford the 1st
generation PPD (ESI,† Scheme S1, SI-PPD 1). MALDI-TOF spectro-
metry confirmed the synthesis of a monodisperse dendrimer with
a molecular weight [M/Z]exp = 3228.10 g molÀ1 ([M/Z]theor.
=
3230.95 g molÀ1). SI-PPD 1 underwent an additional Diels–Alder
reaction with a tetraphenylcyclopentadienone to produce a mono-
disperse 2nd generation dendrimer (ESI,† Scheme S1, SI-PPD 2)
with a [M/Z]exp = 6082.54 g molÀ1 ([M/Z]theor. = 6081.21 g molÀ1), as
characterized by MALDI-TOF spectrometry. The thioacetate func-
tionalities of SI-PPD 2 were deprotected to the resulting thiols by
reacting them with excess dimethyl amine to produce PPD 1
(Scheme 1) in quantitative yield. MALDI-TOF spectrometry con-
firmed the molecular weight to be [M/Z]exp = 5745.66 ([M/Z]theor.
=
1
5745.24 g molÀ1; Fig. 1A), and H NMR spectroscopy showed a
signal shift for the benzylic protons of the scaffold from 4.0 ppm
(adjacent to the thioacetate) to 3.8 ppm (adjacent to the thiol), while
Fig. 1 MALDI-TOF spectra of (A) PPD 1 and (B) PPD 2 before end-capping
residual thiols (C) PPD 2 (D) PPD 3.
the signal for the methyl groups of the thioacetate moieties at number of bound species. Shorter reaction periods (4–20 h) led to
2.4 ppm completely disappeared (ESI,† Fig. S5). the attachment of fewer guest species (1–3 molecules), while extended
Thiol functionalized dendrimers (PPD 1) were reacted with reaction times (Z24 h) did not result in an increase in the degree of
2-(4-nitrophenoxy)ethanethiol (50 equivalents, SI-compound 4) in THF functionalization. This indicates that the loading capacity of the
at room temperature in the presence of atmospheric oxygen to dendrimers was limited by the free volume of the dendritic cavities,
covalently attach the small molecules within the scaffolds via oxidative and thus steric constraints led to an upper limit of 4 guest molecules
disulfide bond formation, as seen in Scheme 1. The macromolecular per host. Additionally, we did not investigate the use of oxidizing
structures were precipitated in methanol, which is a good solvent for agents to promote the formation of the disulfide bonds because of the
2-(4-nitrophenoxy)ethanethiol and a poor solvent for the PPDs, then possibility of cyclodehydrogenation of the polyphenylene backbone,
further purified by dialysis in THF for 24 h to remove any non-reacted which has been extensively reported in the literature.17
molecules. As characterized by MALDI-TOF spectrometry ([M/Z]exp
=
Furthermore, the residual thiols were end-capped with methyl-
6535.10 g molÀ1, Fig. 1B), we were able to covalently bind four bromide in the presence of triethylamine (TEA) in THF to yield PPD
2-(4-nitrophenoxy)ethanethiols (molecular weight B 198 g molÀ1
)
2 (Scheme 1) to prevent additional oxidative reactions. MALDI-TOF
per dendrimer, wherein the molecular weight and NMR analysis spectrometry showed an increase in molecular weight of 55 g molÀ1
confirmed the defined structures without a distribution of the (Fig. 1C) that equates to four methyl end-capping groups per
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associated with the 2-(4-nitrophenoxy)ethanethiols at 3.1, 4.0, and
8.2 ppm (ESI,† Fig. S6A: protons A, B, and E), while the signal for
the benzylic protons of the scaffold shifted from 3.7 ppm (adjacent
to the disulfide linkage) to 3.6 when adjacent to the thiols
(ESI,† Fig. S6B). This demonstrated the quantitative cleavage of
the disulfide bonds under reductive conditions that led to
the release of the nitrophenol derivatives by a controlled
mechanism. Additionally, this process highlighted the stability
of the covalently attached molecules, since they remained
within the scaffold through vigorous purification steps until
the disulfide bonds were cleaved.
We report the synthesis of 2nd generation polyphenylene
dendrimers that were functionalized with eight thiols throughout
their scaffolds. These thiols were used as anchor points to covalently
bind guest moieties (i.e. 2-(4-nitrophenoxy)ethanethiol) through
oxidative disulfide bond formation, which yielded chemically stable
macromolecular structures with four molecules per dendrimer.
Furthermore, under reductive conditions the disulfide linkages
could be quantitatively cleaved resulting in the discharge of all the
Fig. 2 UV-Vis and photoluminescence spectra of the pyrene core,
1st and 2nd generation PPDs, 2-(4-nitrophenoxy)ethanethiol, and function-
alized PPDs.
dendrimer, again showing that there were four residual thiols nitrophenol derivatives. To our knowledge this represents the first
after reaction with the 2-(4-nitrophenoxy)ethanethiol.
report of the covalent attachment of small molecules to the scaffold
1H NMR spectroscopy was used to calculate the number of of a dendrimer, which can be chemically cleaved, yielding stable
2-(4-nitrophenoxy)ethanethiol and end-capped methyl groups multicomponent PPDs that possess a trigger for the controlled
within the dendrimers. As seen in ESI,† Fig. S6A, by integrating release of the guest species.
the proton signals from the nitrophenol derivatives (A) and
methylthiols (F) against those of the PPDs (C and D), it was
observed that there were four small molecules and four methyl
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2036 | Chem. Commun., 2014, 50, 2034--2036
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