Solid-phase Pd-catalysed cross-coupling methods for the construction of π-conjugated peptide nanomaterials

Article abstract of DOI:10.1080/10610278.2013.852675

We describe the development of two procedures for the synthesis of peptides that are embedded with a variety of π-conjugated semi-conducting oligomers. These procedures utilise solid-phase variants of classical palladium-catalysed cross-couplings commonly used to prepare π-conjugated oligomers. The resulting peptide-π-electron hybrids are soluble in aqueous media and self-assemble to produce 1D nanostructures, simultaneously forming networks of π-stacked conduits. The procedures have allowed for the inclusion of complex chromophores including mixed aryl units, ethynylene linkers and sexithiophenes where the latter peptide's nanostructures demonstrated substantial conductivity when employed as an active layer in a field-effect transistor.

Full text of DOI:10.1080/10610278.2013.852675

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Solid-phase Pd-catalysed cross-coupling methods
for the construction of π-conjugated peptide
nanomaterials
Allix M. Sandersa & John D. Tovarabc
a Department of Chemistry, Johns Hopkins University, Baltimore, MD 21218, USA
b Department of Materials Science and Engineering, Johns Hopkins University, Baltimore, MD
21218, USA
c Institute for NanoBiotechnology, Johns Hopkins University, Baltimore, MD 21218, USA
Published online: 22 Nov 2013.
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To cite this article: Allix M. Sanders & John D. Tovar (2014) Solid-phase Pd-catalysed cross-coupling methods
for the construction of π-conjugated peptide nanomaterials, Supramolecular Chemistry, 26:3-4, 259-266, DOI:
10.1080/10610278.2013.852675
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Supramolecular Chemistry, 2014
Vol. 26, Nos. 3–4, 259–266, http://dx.doi.org/10.1080/10610278.2013.852675
Solid-phase Pd-catalysed cross-coupling methods for the construction of p-conjugated peptide
nanomaterials
Allix M. Sandersa and John D. Tovara,b,c
*
b
aDepartment of Chemistry, Johns Hopkins University, Baltimore, MD 21218, USA; Department of Materials Science
and Engineering, Johns Hopkins University, Baltimore, MD 21218, USA; cInstitute for NanoBiotechnology, Johns Hopkins University,
Baltimore, MD 21218, USA
(Received 16 July 2013; accepted 2 October 2013)
We describe the development of two procedures for the synthesis of peptides that are embedded with a variety of
p-conjugated semi-conducting oligomers. These procedures utilise solid-phase variants of classical palladium-catalysed
cross-couplings commonly used to prepare p-conjugated oligomers. The resulting peptide–p–electron hybrids are soluble
in aqueous media and self-assemble to produce 1D nanostructures, simultaneously forming networks of p-stacked conduits.
The procedures have allowed for the inclusion of complex chromophores including mixed aryl units, ethynylene linkers and
sexithiophenes where the latter peptide’s nanostructures demonstrated substantial conductivity when employed as an active
layer in a field-effect transistor.
Keywords: bioelectronics; supramolecular polymers; organic electronics; self-assembly
1. Introduction
reagents can simply be washed from the polymer support
The construction of organic bioelectronic materials based
on non-covalent electronic delocalisation is a current
challenge for organic materials science (1–3). One means
to produce these types of materials is by modifying
peptides that are able to undergo self-assembly to afford
supramolecular electronic nanostructures that are water
processable and potentially biologically relevant (4–11).
For example, peptide backbones with embedded
p-conjugated subunits can self-assemble in aqueous
environments thereby forming b-sheet-rich supramolecu-
lar nanostructures of high aspect ratio that support
extended p-stacked conduits. These types of systems are
attractive because the peptidic self-assembly allows for
facile but precise organisation of electrically conductive
units. Furthermore, the peptide scaffolds can be adapted
for biological compatibility and can act as a bridge
between the biotic and abiotic worlds, with potential
applications in electrically controlled cell regeneration or
biosensing. However, preparing these types of modified
peptides has required lengthy solution-phase synthesis and
purification of the p-conjugated units, thus slowing the
process of creating diverse libraries of p-conjugated
peptides.
prior to cleaving the product from the resin and isolating
it in relatively pure form. This method has been widely
used for the synthesis of biological materials such as
peptides and oligonucleotides, and has also been adapted
to perform a variety of other chemical transformations,
such as palladium-catalysed cross-couplings to form new
carbon–carbon and carbon–heteroatom bonds (12–14).
For example, solid-phase Stille and Suzuki cross-
couplings have been broadly employed for the creation
of potential pharmaceuticals and p-conjugated oligomers
(15–24). Solid-phase chemistry has also been used
for intramolecular macrocycle formation due to the
‘pseudo-dilution effect’ inherent to resins with low
loading concentrations (25), but intermolecular site-to-
site reactions between molecules adjacent to one another
on a resin bead (‘cross-linking’) are also known on highly
loaded resins. Taking advantage of this site–site reactivity
allows for the formation of homodimers on the solid
phase, and a wide variety of homodimers have been
prepared using transition metal coupling procedures such
as ring-closing metathesis to produce alkene linkages and
various acetylenic homocouplings to produce butadiyne
linkers (26–29). In this study, we describe the develop-
ment of two on-resin Pd-catalysed methods that lead to
self-assembling peptide–p–peptide triblock molecules,
one previously unpublished, and one recently commu-
nicated (30).
Solid-phase syntheses have been used extensively for
the rapid construction of a variety of molecules. Instead of
requiring time-consuming solution-phase purification after
each step of a synthetic route, catalysts, side products and
*Corresponding author. Email: tovar@jhu.edu
q 2013 Taylor & Francis

260
A.M. Sanders and J.D. Tovar
introduced to the resin. In the presence of a palladium
2. Results and discussion
catalyst, cross-coupling between the Ar2 and the Ar1-
terminated peptide fragments occurs. The resulting Fmoc-
protected aryl-capped peptides can be deprotected by
treating the resin with a 20% piperidine solution just like a
normal Fmoc-protected amino acid, and SPPS can be
continued. After cleaving from the resin, the desired
peptide embedded with an Ar1–Ar2 moiety is obtained. In
procedure 2, an arene (Ar2) that is disubstituted with
substituents for cross-coupling is introduced to the Ar1-
capped resin in the presence of a palladium catalyst.
Double cross-coupling occurs between Ar2 and two
peptides near to one another on a resin bead presenting the
Ar1 termini to give the locally cross-linked structure.
Treating the resin with standard peptide cleavage
conditions affords the desired peptide with an extended
Ar1–Ar2–Ar1 p-conjugated moiety embedded in the
peptide backbone.
2.1 Synthetic approaches for p-conjugated peptides
Our group previously harnessed site–site reactivity
whereby reactive p-conjugated bis-electrophiles led to
diimidation/diamidation cross-linking of resin-bound pep-
tides to produce modified peptide–p–peptide triblock
molecules (31). However, we found that longer oligomers
to be used for cross-linking were synthetically difficult to
achieve and insufficiently soluble in synthetic solvents. To
further exploit the facile nature of solid-phase synthesis for
the preparation of aqueous self-assembling p-conjugated
peptides, we envisioned the creation of methods that
employ solid-phase palladium-catalysed cross-couplings
(Stille, Suzuki and Sonogashira) in conjunction with
standard solid-phase peptide synthesis (SPPS). In contrast
to solution-phase syntheses, these methods would allow for
the rapid synthesis of a variety of p-conjugated peptides
from commercially available or readily synthesised small
molecule components, without the need for prior molecular
synthesis of the entire p-conjugated cross-linking agent.
We developed two methods as outlined in Figure 1.
In both cases, Fmoc-based SPPS is performed to
synthesise oligopeptides bound to a resin bead. An aryl
group (Ar1) substituted with a carboxylic acid and a halide
is then introduced to the resin under standard activation
conditions for peptide amidation (O-(Benzotriazol-1-yl)-
N,N,N0,N0-tetramethyluronium Hexafluorophosphate
(HBTU), Diisopropylethylamine). Amidation occurs
between the carboxylic acid groups of the arenes and the
deprotected amine termini of the resin-bound peptide
chains leading to the common peptide resin shown in
Figure 1. In procedure 1, another arene (Ar2) that is
substituted with functionality necessary for cross-coupling
under palladium catalysis (e.g. a tributyl stannane group)
and also functionalised with an Fmoc-protected amine is
A peptide synthesised as a test case via procedure 1 is
shown in Figure 2. Following SPPS, 2-bromothiophene
carboxylic acid was coupled to the amine termini of the
peptide chains via amidations under HBTU activation
conditions. Stille cross-coupling conditions were used to
couple the resin-bound 2-bromothiophene carboxamide
moiety with stannylated Fmoc-protected thiophene amine
to give a resin-bound peptide bearing a terminal
bithiophene. This unit was then treated under standard
SPPS to continue peptide growth, and subsequent cleavage
from the resin afforded compound 1. In principle, we could
use more complex Ar2 units, but in practice, their synthesis
with the requisite Fmoc groups was quite difficult,
requiring multiple steps due to the asymmetry of the
molecule, as well as multiple protecting group inter-
conversions due to the sensitivity of the Fmoc-protecting
group to n-butyllithium, which is necessary for stannyla-
tion (32). This method also requires additional SPPS in
Figure 1. (Colour online) Solid-phase Pd-catalysed cross-coupling procedures.

Supramolecular Chemistry
261
Figure 2. Peptide prepared from procedure 1.
order to extend the peptide backbone. While this allows for
the variation in primary amino acid sequence on either side
of the chromophore, difficulties in Ar2-Fmoc preparation
led us to pursue an alternative strategy.
bonding and simultaneously inducing intimate
p-electroninteractionsbetweenthe embeddedchromophores.
The end result is the production of 1D nanostructures as
illustrated ideally in Figure 4. A key aspect of these materials
is the exciton coupling between the transition dipoles of the
chromophore moieties that occur upon assembly, leading to
well-characterised perturbations in the absorption and
photoluminescence spectra. Therefore, absorption and
photoluminescence data were acquired for all peptides to
observe the extent of intermolecular exciton coupling.
Figure 5 shows these data for 2–9 in both their unassembled
(pH 8, dashed lines) and assembled (pH 6, solid lines) states.
In general, each peptide displays a blue shift in the absorption
lmax and a quenching and red shift of photoluminescence
upon assembly, which is indicative of cofacial H-like
aggregation and/or excimeric interactions of the chromophore
moieties (33). Although each peptide studied displayed these
similar spectroscopic characteristics, slight differences are
observed for individual peptides, presumably due to the
differences in the identities of the chromophore subunits and
their flanking peptides that collectively influence the
electronic interactions within the aggregates. For instance, 4
and 5 display larger blue shifts in their absorption upon
assembly (38 and 32 nm, respectively) in comparison with 6
and 7, which show only a 15- and a 7-nm shift, respectively.
Differences in the magnitudes of the observed exciton
couplings among these different chromophore units can be
attributed to the differences in their respective isolated
excitation energies and/or the respective oscillator strengths of
thesetransitions. Compound7shows a large 82-nm red shift in
the photoluminescence lmax upon assembly, whereas this shift
is only 32–39 nm in the cases of 2, 3, 6, 8 and 9, highlighting
the different contributions of excimer-like emission within the
different aggregates. Relatedly, the quenching of photolumi-
nescence upon assembly occurs with varying degrees for each
peptide. The photophysics associated with these materials are
quite complex and require systematic molecular variations on
a per-chromophore basis to explicate in more depth (34).
Regardless of these specific photophysical differences, it is
remarkable that all peptide–p systems reported here undergo
H-like self-association. Even longer oligomers embedded
We sought a new strategy that capitalised on the ease of
the on-resin dimerisation cross-linking and on the
versatility of Pd-mediated cross-coupling. This led to the
development of procedure 2, enabling access to a variety of
peptides summarised in Figure 3 (30). After completion of
the peptide synthesis via SPPS, diverse N-acyl end caps
consisting of thiophene, bithiophene and phenyl arenes
(Ar1) were coupled to the resin via standard HBTU-
mediated amidation. The resin was then treated with a
doubly reactive second arene (Ar2) under various
palladium-catalysed cross-coupling conditions. Utilising
Stille cross-coupling conditions with thiophene and
bithiophene-based end-capped peptides and disubstituted
transmetallating agents, peptides embedded with oligothio-
phene chromophores of varying length were synthesised
from terthiophene (2) to sexithiophene (5). 4-Iodophenyl
carboxamide-capped peptides were subjected to Suzuki
conditions in the presence of 1,4-benzene diboronic acid
and Sonogashira conditions with 1,4-diethynyl benzene to
give oligophenylene-containing 6 and oligophenyleneethy-
nylene-containing 7, respectively. In addition, Stille or
Suzuki conditions were used to give peptides embedded
with chromophores consisting of alternating patterns of
thiophene and benzene subunits to produce 8 and 9,
respectively. Due to the more readily available cross-
coupling partners, this method has been much more widely
explored in our laboratory.
2.2 Electronic and morphological characterisation
By design, these peptides remain molecularly dissolved in
aqueous solution at basic pH due to repulsion between
negatively charged carboxylic acid end groups and side
chains. Intermolecular self-assembly of the peptide is
triggered upon protonating these groups under acidic
conditions by reducing the Coulombic repulsion among the
molecules and therefore encouraging interpeptide hydrogen

262
A.M. Sanders and J.D. Tovar
Figure 3. (Colour online) Peptides prepared from procedure 2. For Suzuki-type couplings, 8 eq. of K2CO3 was also included in the
reaction mixture. For Sonogashira-type couplings, 10 mol% CuI and 3 ml diisopropyl amine were also included in the reaction mixture.
within 4, 5 and 7 undergo p-stacking and 1D nanostructure
formation. We are currently exploring the inter-relation of
peptide sequence identity/length and chromophore identity/
length to understand the driving forces behind these
assemblies in more depth.
Circular dichroism (CD) can also be utilised to deduce
exciton coupling between chromophore moieties, particu-
larly those experiencing coupling in a chiral environment
(35). CD spectra for 2–9 are shown in Figure 6. Each
peptide displays no meaningful absorption above 250 nm

Supramolecular Chemistry
263
possibly due to the differences in peptide assembly,
brought about by variations in primary amino acid
sequences. We have found that the spectral signatures
associated with classical peptide secondary structures
(a-helix, b-sheet, etc.) are not particularly diagnostic for
these types of self-assembled materials due to their
relatively disordered nature compared with standard
b-sheet peptide models.
To visualise the nanostructures that are formed from
the self-assembly of the chromophore-embedded peptides,
transmission electron microscopy (TEM) was used.
Micrographs of assembled samples of 3, 4 and 6 are
shown in Figure 7. In general, each peptide forms 1D
nanostructures on the order of microns in length.
Nanostructures of 3 and 4 displayed fairly uniform widths
of ,6–9 nm. Molecular modelling of these peptides shows
that their lengths in their most extended conformation are
4.1 and 4.9 nm, respectively. The nanostructures observed
by TEM comprise individual nanostructures as well as
bundles of two intertwined but well-resolved structures.
Compound 6 also appears to form consistent, well-defined
nanostructures with diameters of 5–7 nm, which interact
with other individual structures to form bundles of various
widths, some reaching nearly 40 nm. Furthermore, these
extended bundled structures display a distinct right-handed
helical twist.
Figure 4. (Colour online) Assembly of p-conjugated peptides
into 1D nanostructures.
(corresponding to the chromophore p–p transition)
*
when unassembled in basic solution, but upon assembly all
show bisignate Cotton effects with the crossovers
occurring at the lmax of the respective chromophore
UV–vis absorptions. This suggests that the respective
chromophores interact through exciton coupling within a
chiral environment, which is created by the inherently
chiral assembly of the peptide scaffolds, organised into
hydrogen-bonded sheet-like structures that display an
overall helical twist (an idealised depiction is shown in
Figure 4). Slight differences are evident between
individual peptides in the amide absorption region of the
CD spectra between 200 and 250 nm. Compounds 2, 6 and
8 displayed relatively more intense signal in this region in
comparison with the other studied peptides. This is
2.3 Investigation of electrical properties
These two methods have allowed us to incorporate more
complex p-conjugated subunits within peptide backbones
than were previously possible such as the sexithiophene
unit of 5. Sexithiophene is a well-established high-
performance p-channel organic semi-conductor that is
Figure 5. UV–vis and photoluminescence spectra of (a) 2, (b) 3, (c) 4, (d) 5, (e) 6, (f) 7, (g) 8 and (h) 9 (1.5–3.5 mM concentration) in
unassembled (pH 8, dashed lines) and assembled (pH 6, solid lines) states. All spectra were taken in water.

264
A.M. Sanders and J.D. Tovar
Figure 6. CD spectra of (a) 2, (b) 3, (c) 4, (d) 5, (e) 6, (f) 7, (g) 8 and (h) 9 (21–43 mM concentration) in unassembled (pH 8, dashed
lines) and assembled (pH 6, solid lines) states. All spectra were taken in water.
Figure 7. TEM micrographs of extended networks of (a) 3, (b) 4 and (c) 6 and isolated nanostructures of (d) 3, (e) 4 and (f) 6. Samples
were prepared using 1 mg/ml solutions of assembled peptide deposited on 200 mesh carbon-coated copper grids followed by staining with
a 2% uranyl acetate solution.
usually included into transistor architectures via thermal
evaporation. To elucidate the electrical properties that are
possible with this compound in a biomimetic framework,
assembled nanostructures of 5 were incorporated as the
active layer of a field-effect transistor in collaboration with
Prof. Howard E. Katz’s group at Johns Hopkins University.
A solution of 5 was dropcast on an SiO2 substrate and then
treated with concentrated HCl vapour to induce assembly.
Once the sample was dry, gold source and drain electrodes
were evaporated to complete the device. The hole mobility
was calculated to be 3.8 £ 1025 cm2 V21 s21 by fitting the
current–voltage data to the linear equation for transistor
current (30). Although the mobility was possibly reduced
by crystal grain boundaries due to the film’s polycrystalline
morphology, the measurement demonstrates that these
materials can transport charges through self-assembled
networks. It is also important to recognise that these
materials are ca. 70% peptidic ‘insulation’ that would be
inherently expected to impede carrier mobility. Never-
theless, these mobilities are larger than those extracted
from many other peptide-based field-effect transistor
devices reported recently (5, 6, 36).
3. Conclusion
We reported two synthetic methods that utilise solid-phase
palladium-catalysed cross-coupling reactions in conjunc-
tion with SPPS to construct aqueous self-assembling

Supramolecular Chemistry
265
peptides embedded with a variety of semi-conducting
p-conjugated chromophores. In addition to easily allow-
ing for chromophore variability and tunability while using
small, soluble components that are mostly commercially
available, the method also granted access to a complex
sexithiophene-containing peptide, which to our knowl-
edge is the longest self-assembling peptide–oligothio-
phene conjugate system to be rendered soluble in aqueous
media. Each peptide displays spectroscopic features
indicative of H-like aggregation upon assembly and
shows 1D nanostructures in the micron-length regime
under TEM. Finally, a dropcast film of 5 showed
substantial hole mobility when incorporated in a field-
effect transistor. Utilising this methodology for the
production of these materials will aid in future
bioelectronics studies.
procedure (9.5 ml of trifluoroacetic acid, 250 ml water and
250 ml of triisopropylsilane for 3 h) was performed. The
peptide solution was filtered from the resin beads, washed
3 £ with dichloromethane and was concentrated by
evaporation under reduced pressure. The crude peptide
was then precipitated from solution with 90 ml of diethyl
ether and isolated through centrifugation. The resulting
pellet was triturated with diethyl ether which was
dissolved in ,2 ml of water and 30 ml ammonium
hydroxide and lyophilised to yield crude 1 (0.055 mmol,
0.032 g, 55%). MS (MALDI) m/z 580.1 (M þ H)þ (calc.
580.2), m/z 602.1 (M þ Na)þ (calc. 602.2).
4.4 General procedure 2
A solid-supported peptide was capped with an aryl halide
following the general SPPS and N-acylation procedures
described earlier. The resin (1 eq.) was then transferred to a
Schlenk flask equipped with a reflux condenser and was
dried under vacuum. For Stille-type couplings, 4 mol% Pd
(PPh3)4 and 0.5 eq. of the bis-stannylated aryl reagent were
added to the flask along with 3–6 ml of DMF. The mixture
was heated to 808C for 16–21 h. For Suzuki-type
couplings, 4 mol% Pd(PPh3)4, 8 eq. of K2CO3 and
0.55 eq. of 1,4-benzene diboronic acid were added to the
reaction vessel with 0.5–1 ml water and 5–10 ml DMF.
The mixture was heated to 808C for 20–27 h. For
Sonogashira-type couplings, 5 mol% Pd(PPh3)4, 10 mol%
CuI and 0.55 eq. of 1,4-diethynyl benzene were introduced
to the resin with 3 ml diisopropyl amine and 7 ml DMF.
The mixture was kept at room temperature for 18 h. All
reactions were agitated constantly by bubbling nitrogen
through the solution throughout the course of the reaction.
The resulting peptide was subjected to the general
washing, cleavage and work-up procedures described
earlier for 1 to yield the crude product which was then
further purified by HPLC. Molecule-specific experimental
stoichiometry details and characterisation data can be
found in Ref. (30).
4. Experimental
4.1 SPPS procedure
Peptides were synthesised via standard SPPS using Fmoc-
protected amino acids, starting from Wang resin preloaded
with the first amino acid, as described in Ref. (30).
4.2 General N-acylation procedure of peptides
Following completion and deprotection of the oligopep-
tide, the resin was treated with an aryl halide carboxylic
acid (3 eq.) that was activated by HBTU (2.9 eq.) and
diisopropylethylamine (10 eq.) for 2–3 h, leading to an
N-acylated peptide capped with the desired aryl halide as
previously reported (30).
4.3 General procedure 1 (synthesis of peptide 1)
The solid-supported peptide capped with a thienyl
bromide was prepared as described earlier. The resin
(0.1 mmol) was transferred to a Schlenk flask and was
dried under vacuum. Pd(PPh3)4 (0.0023 g, 2 mol%
relative to resin loading) was added to the reaction
vessel. Fmoc-protected (5-(tributylstannyl)thiophen-2-yl)
methanamine (32) (0.075 g, 0.12 mmol) was introduced to
the resin, along with 3 ml N,N-Dimethylformamide
(DMF). The mixture was heated to 808C for 17 h and
was agitated constantly by bubbling nitrogen through the
solution. The resin was then allowed to return to room
temperature and subjected to a wash cycle [3 £ NMP (N-
Acknowledgements
The authors thank Profs Raz Jelinek (Ben Gurion), Tim Hanks
(Furman), Bill Pannington (Clemson) and Marc Panhuis (Wollon-
gong) for the opportunity to present this work at the Spring 2013
MRS meeting. The authors thank Dr J. Michael McCaffery (JHU
IIC) and Dr Brian Wall (Ph.D., JHU, 2013) for instrumental
assistance, Dr Thomas Dawidczyk (Ph.D., JHU, 2013) and Dr
HowardKatzfordevicemeasurementsandDrStephenDiegelmann
for preliminary experiments (Ph.D., JHU, 2011).
Methylpyrrolidone), 3 £ DMF, 2 £ isopropanol,
2
2
£ water,
2£ (2 £ THF,
2 £ isopropanol),
£ acetonitrile, 2£ diethyl ether, 2 £ hexanes]. The Fmoc
group was removed by treatment with a 20% piperidine
solution in DMF, and standard SPPS was continued.
Following the final amino acid coupling, the peptide was
subjected to the same wash cycle, then a general cleavage
Funding
Johns Hopkins University and the Department of Energy Office
of Basic Energy Sciences (DE-SC0004857, J.D.T. peptide
nanomaterials) provided generous financial support.

266
A.M. Sanders and J.D. Tovar
´
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