Cyclobutane-based peptides/terpyridine conjugates: Their use in metal catalysis and as functional organogelators

Article abstract of DOI:10.1016/j.tet.2018.10.064

Two new conjugates, hcptpyDP and hcptpyTP, of a terpyridine derivative incorporating artificial peptide moieties, have been synthesized and their use in the preparation of metal catalysts and organogelators has been investigated. Ru(II) complexes derived from these ligands showed electrochemical behavior and activity as catalysts in the epoxidation of olefins similar to that of Beller's catalyst. As organogelators, these conjugates were able to gelate a variety of solvents, from toluene to methanol, with satisfactory mgc (minimum gelation concentration) values. The presence of 4′-(4-carboxy)phenylterpyridine (hcptpy) moiety allows tuning the gelling properties and also influences the supramolecular self-assembling mode to produce chiral aggregates with respect to parent peptides DP and TP. In the case of the conjugates, π?π interactions provided by the aromatic moieties cooperate with inter-molecular hydrogen bonding between NH and CO in the amide groups. Further properties of peptide/terpyridine conjugates are under investigation in view of future applications.

Full text of DOI:10.1016/j.tet.2018.10.064

Accepted Manuscript
Cyclobutane-based peptides / terpyridine conjugates: Their use in metal catalysis and
as functional organogelators
Oriol Porcar-Tost, Bernat Pi-Boleda, Jordi García-Anton, Ona Illa, Rosa M. Ortuño
PII:
S0040-4020(18)31287-0
https://doi.org/10.1016/j.tet.2018.10.064
TET 29897
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 5 September 2018
Revised Date: 23 October 2018
Accepted Date: 24 October 2018
Please cite this article as: Porcar-Tost O, Pi-Boleda B, García-Anton J, Illa O, Ortuño RM, Cyclobutane-
based peptides / terpyridine conjugates: Their use in metal catalysis and as functional organogelators,
Tetrahedron (2018), doi: https://doi.org/10.1016/j.tet.2018.10.064.
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ACCEPTED MANUSCRIPT
Graphical abstract

ACCEPTED MANUSCRIPT
Cyclobutane-based peptides / terpyridine conjugates: Their
#
use in metal catalysis and as functional organogelators
Oriol Porcar-Tost, Bernat Pi-Boleda, Jordi García-Anton, Ona Illa,*
Rosa M. Ortuño*
Departament de Química, Universitat Autònoma de Barcelona, 08193 Cerdanyola del
Vallès, Barcelona, Spain.
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ABSTRACT
Two new conjugates, hcptpyDP and hcptpyTP, of a terpyridine derivative incorporating
artificial peptide moieties, have been synthesized and their use in the preparation of
metal catalysts and organogelators has been investigated. Ru(II) complexes derived
from these ligands showed electrochemical behavior and activity as catalysts in the
epoxidation of olefins similar to that of Beller’s catalyst. As organogelators, these
conjugates were able to gelate a variety of solvents, from toluene to methanol, with
satisfactory mgc (minimum gelation concentration) values. The presence of 4’-(4-
carboxy)phenylterpyridine (hcptpy) moiety allows tuning the gelling properties and also
influences the supramolecular self-assembling mode to produce chiral aggregates with
respect to parent peptides DP and TP. In the case of the conjugates, π−π interactions
provided by the aromatic moieties cooperate with inter-molecular hydrogen bonding
between NH and CO in the amide groups. Further properties of peptide / terpyridine
conjugates are under investigation in view of future applications.
Key words:
Terpyridine conjugates
Cyclobutane-based peptides
Ruthenium complexes
Metal catalysis
Functional organogelators
2

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1
. Introduction
1
Since its isolation in 1932 from a mixture of the oxidative coupling products of
pyridine, 2,2’:6’,2’’-terpyridine (tpy) has been considered as one of the most well-liked
tridentate ligands in chemistry. Its strong coordination ability towards metal ions
enables terpyridine to be used as a ligand for the preparation of catalysts in several
2
,3
reactions. In addition, terpyridine and derivatives play a key role as supramolecular
building blocks and, consequently, they are valuable for the elaboration of
metallopolymers, switching devices, light-harvesting systems, and artificial
3
,4
photosynthetic models, among other purposes.
Later, the use of terpyridine conjugates constituted a growing research field trying
to enhance or tune the properties of terpyridine itself and to find new applications. For
5
instance, Cu(II)-terpyridine conjugates were used for biological applications.
6
Moreover, Ru(II)-terpyridine conjugates have been used in dye-sensitized solar cells
while Pt(II)-terpyridine acetylide complexes have been investigated with the objective
7
of photogeneration of hydrogen in aqueous media. Very recently, arylene-vinylene
terpyridine conjugates revealed their ability as chemosensors performing as fluorescent
8
probes and highly luminescent π-conjugated terpyridine derivatives exhibited thermally
activated delayed fluorescence (TDAF) owning very promising properties to be applied
9
in the development of supramolecular systems and sensors. Besides, the terpyridine
derivative 4’-(4-carboxyphenyl)-2,2’:6’,2’’-terpyridine (hcptpy) has been used in the
1
0
development of compounds for biomedical applications, and photoelectronic devices
1
1
12
and sensors including gels, metal-organic frameworks (MOF), and metal-organic
1
3
gels (MOG).
3

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All these properties confer terpyridine derivatives with an enormous potential for
the design of new catalysts and molecular or supramolecular materials for manifold
purposes.
1
4
Regarding supramolecular materials, functional organogels constitute a family of
1
5
soft materials with diverse utilities. Some of their applications include products for
industrial purposes and fine chemicals as well as their use in biomedicine and materials
1
6,17
18
science.
and oil spill recovery has been reported.
We have described the properties and mode of aggregation of peptide based
Very recently, their potential as materials for environmental remediation
1
9
2
0,21
organogels containing artificial cyclobutane β-amino acids,
as well as hybrid
peptides that result from the combination of cyclobutane β-monomers with linear
2
2
residues. The behavior of cycloalkane bisamides has also been investigated accounting
for the effect of regiochemistry and stereochemistry on the supramolecular self-
assembly. Interestingly, we have afforded new examples on stochastic chiral symmetry
breaking induced by sonication, which allowed the formation of chiral aggregates from
2
3
meso achiral molecules.
In this paper, we report the preparation of new terpyridine conjugates hcptpyDP
and hcptpyTP that result of combining the hcptpy moiety with a cyclobutane-based
dipeptide (DP) and a tetrapeptide (TP), respectively, shown in Scheme 1. The aim of
this work lies on two main aspects: one of them is the investigation of the influence of
the peptide backbone on the properties of a Ru(II)-tpy complex as a catalyst in the
oxidation of olefins. The new Ru(II) complexes have been characterized and their redox
properties have been compared with similar complexes from terpyridine itself. The
second objective consists in the study and rationalization of the contributions exerted by
the flat π-electron rich terpyridine moiety and the chiral peptide subunit, which is prone
4

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to hydrogen bonding through the amide groups, to the hierarchical supramolecular
organization of these conjugates into gels. The results of this study have been compared
with the properties of the parent peptides DP and TP and have been supported by
computational calculations.
Scheme 1. Synthesis of conjugates hcptpyDP and hcptpyTP
5

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. Results and discussion
2
2
.1 Synthesis of terpyridine-peptide conjugates
The terpyridine moiety was conjugated to dipeptide DP and tetrapeptide TP,
.
2
4
25
2
6
respectively, by coupling with hcptpy
using FDPP (pentafluorophenyl
diphenylphosphinate) and DIPEA (N,N-diisopropylethylamine) in anhydrous DMF, at
room temperature for 18 h. In this way, conjugates hcptpyDP and hcptpyTP were
prepared in 60-65% yield (Scheme 1).
2
.2 Preparation of the Ru(II) complexes [Ru(pydic)(hcptpyDP)] and
[Ru(pydic)(hcptpyTP)], electrochemical characterization and their use in catalyzed
olefin epoxidation
Since Ru(tpy) complexes are quite inert and usually do not have applications in
2
2
7
catalysis, pyridine-2,6-dicarboxylate (pydic) was used as the second ligand in the
complex.
The syntheses of the ruthenium complexes [Ru(pydic)(hcptpyDP)] and
[
Ru(pydic)(hcptpyTP)], were achieved in one step in 54-60% yield by reacting one
equivalent of hcptpyDP or hcptpyTP with one equivalent of pydic ligand and one
equivalent of Ru(p-cymene)Cl , in refluxing methanol-water (Scheme 2). Due to their
2
high stability, both complexes were purified by column chromatography and
characterized using common techniques.
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Scheme 2. Synthesis of complexes [Ru(pydic)(hcptpyDP)] and [Ru(pydic)(hcptpyTP)].
Electrochemical studies of Ru(II) complexes were undertaken to understand the
redox properties of these compounds. These results are interesting for catalytic
applications where an oxidation or reduction step is required. The methodologies used
were cyclic voltammetry (CV) (Fig. 1) and differential pulse voltammetry (DPV) in
methanol (Fig. S1 in the Supplementary Data). This solvent is not often used in
electrochemistry because its electrochemical window is not wide. Nevertheless, it was
not electroactive in the considered potential range allowing studying the oxidation
potential of the complexes. TBABF was used as supporting electrolyte.
4
7

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Fig. 1. CV voltammograms for (a) 7 mM [Ru(pydic)(hcptpyDP)] and (b) 7 mM
[
Ru(pydic)(hcptpyTP)], and 0.1 M TBABF solution in methanol. Glassy carbon
4
working electrode, Pt counter electrode and SCE reference electrode. v = 0.1 V/s.
Both complexes were redox active. The CV voltammograms exhibited one
reversible oxidation wave associated with the Ru(II) to Ru(III) redox couple.
Determination of E1/2 (half-wave potential) has been made by using the equations
described in the Supplementary Data and the resulting values are shown in Table 1
where the E1/2 value of the related complex [Ru(pydic)(tpy)] (Beller’s catalyst)
2
described in the literature is also shown for comparison.
Table
1.
E1/2
values
for
complexes
[Ru(pydic)(hcptpyDP)],
[
Ru(pydic)(hcptpyTP)] and [Ru(pydic)(tpy)] using CV and DPV
Complex
Ru(pydic)(hcptpyDP)]
E (CV)
E (DPV)
1
/2
1/2
[
0.600 V
0.595 V
0.600 V
0.585 V
0.565 V
-
[
Ru(pydic)(hcptpyTP)]
2
[
Ru(pydic)(tpy)]
8

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The observed E1/2 values are due to the oxidation of Ru(II) and are essentially the
same using both CV and DPV techniques. The presence of the peptide moiety in
[
Ru(pydic)(hcptpyDP)] and [Ru(pydic)(hcptpyTP)] does not alter the oxidation of the
metal ion because it is located at a considerably distant position from the coordination
sphere of the ruthenium ion. Since these complexes have a E1/2 value close to
[
Ru(pydic)(tpy)], a comparable reactivity was expected for all three catalysts.
The epoxidation of styrene, 1 (R = H), and derivatives, 1 (R = Me, Ph), was chosen
as a process to test the ability of the synthesized complexes in oxidation reactions
(Scheme 3). Conditions were similar to those described in the literature for the
2
oxidation of styrenes by using Beller’s catalyst.
Scheme 3. Epoxidation of styrene and derivatives, 1, using complexes
[
Ru(pydic)(hcptpyDP)] or [Ru(pydic)(hcptpyTP)] as catalyst.
Complexes [Ru(pydic)(hcptpyDP)] and [Ru(pydic)(hcptpyTP)] are insoluble in
common organic solvents but they are soluble in high polar ones such as MeOH, DMF
or DMSO. However, the use of methanol as the only solvent was precluded since
methanolysis of the produced epoxide 2 was observed. Thus, reactions were carried out
in a 9:1 CH Cl - MeOH mixture and using UHP (urea hydrogen peroxide) as the
2
2
oxidant agent, at room temperature. Results are shown in Table 2 where data from the
2
literature are also described for comparison.
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Table 2. Epoxidation of styrene and derivatives by using ruthenium complexes
2
[
Ru(pydic)(hcptpyDP)], [Ru(pydic)(hcptpyTP)] and [Ru(pydic)(tpy)] as catalysts
a
Complex
Substrate 1, R
Yield (%)
Time (h)
H
Ph
Me
H
60
97
99
48
90
98
39
99
99
2.5
7
[
Ru(pydic)(hcptpyDP)]
5
3.5
8
[
Ru(pydic)(hcptpyTP)]
Ph
Me
H
5
3
2
[
Ru(pydic)(tpy)]
Ph
Me
1
3
All reactions were carried out using 0.5 mmol of substrate in 10 mL of 9:1
a
dichloromethane-methanol as solvent. Yields determined by GC analysis
Results showed that both complexes are able to catalyze the formation of the
epoxidation product in moderate yields in the case of styrene, and excellent yields using
other substituted substrates. Catalyst [Ru(pydic)(hcptpyDP)] gave slightly better yields
and shorter reaction times than [Ru(pydic)(hcptpyTP)] in the case of styrene, 1 (R = H),
and trans-stilbene, 1 (R = Ph). This result can be justified by the fact that, with long
reaction times, solvolysis of the produced epoxide can occur since methanol is used as
co-solvent. Beller’s catalyst gave similar yields but faster reactions in the case of trans-
stilbene and β-methyl styrene, 1 (R = Me), but lower yield in the case of styrene. These
results are in agreement with the electrochemical studies described above, which
predicted similar reactivity for all complexes.
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0

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Unfortunately, epoxidation products were obtained in racemic form. This result
shows that the chiral peptide moiety is too far from the catalytic center to induce any
asymmetry during the process.
2
.3 Gelation studies on conjugates hcptpyDP and hcptpyTP. Comparison with the
parent peptides DP and TP
Formation of gels. The gelation ability of hcptpyDP and hcptpyTP was studied in
thirteen solvents of different polarity. The tube inversion test was used to determine the
formation of a gel, following the procedure described in the Experimental Section.
Organogelators hcptpyDP and hcptpyTP, as well as peptides DP and TP were insoluble
in very apolar solvents, such as pentane, and also in water. Macroscopically, the gels
formed by hcptpyDP and hcptpyTP in alcohols are opaque, while the gels formed in the
other solvents are translucent.
All gels reported herein were stable at room temperature, at least, for one month.
Furthermore, they were thermoreversible. As an example, two images of the sol-gel
transition of a gel formed by hcptpyTP in methanol are shown in Fig. 2. The
thermoreversibility is an evidence that the aggregates formed by these organogelators
are physical gels assembled by non covalent intermolecular bonds. A study of their
aggregation mode is described below.
heating
cooling
Fig. 2. Thermoreversibility of the gel formed by hcptpyTP in methanol.
1
1

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Results were quantified by the minimum gelation concentration (mgc). In order to
compare the gelling ability of hcptpyDP and hcptpyTP as well as the effect of the
21
22
introduced terpyridine moiety, the results obtained for peptides DP and TP are also
shown in Table 3.
a
21
22
a
Table 3. Gelation study of hcptpyDP and hcptpyTP compared with DP and TP in common solvents
b,c
Solvent and minimum gel concentration
Gelator
1,4-
Toluene
CHCl3 tert-
AmOH
AcOEt
THF DCM iso-
PrOH
78
(185) (178) (139)
Acetone
MeOH AcCN
Dioxane
s
hcptpyDP
49
84
(150)
s
123
(217)
s
100
(178)
33
104
100
58
(103)
80
59
(105)
s
76
(135)
57
(
(
87)
6
2
1
DP
s
112
(495)
79
s
s
s
27)
63
(146)
92
(354)
104
(251)
i
hcptpyTP
114
s
67
(99)
s
43
(64)
50
48
(71)
100
(
169)
33
(93)
3
(136)
8
(117)
100
(154)
50
2
2
TP
122
60
17
(
97)
(9)
(358)
(24)
(294) (176) (147)
(147)
(294)
(50)
a
b
-1
c
Solvents are ordered by increasing dielectric constant. mgc in mg mL and, in parentheses, mM. S: soluble, I: insoluble
-1
For hcptpyDP, the lowest mgc values found were 49, 58 and 59 mg mL ,
corresponding to toluene, acetone and methanol, respectively. Interestingly, although
some mgc values are higher than those for the same solvents with DP as organogelator,
hcptpyDP can gelate a broader range of solvents including apolar dichloromethane and
protic polar solvents such as methanol and tert-amyl alcohol.
Although hcptpyTP is insoluble in acetonitrile and it is soluble in chloroform and
dichloromethane, it can gelate the other eight solvents tested. The best mgc values found
-1
are 43 and 48 mg mL , corresponding to isopropanol and methanol, respectively, which
1
2

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are also gelated by TP but with higher mgc values. The values for the other solvents are
-1
in the range of 63 and 104 mg mL .
Scanning Electron Microscopy (SEM). SEM experiments were undertaken to
investigate the aggregates formed by of hcptpyDP and hcptpyTP both in toluene and
methanol. Selected micrographs are shown in Fig. 3 and revealed a remarkable
influence of the solvent nature on the morphology of the supramolecular aggregates.
Xerogels of hcptpyDP from methanol show undefined structures. In higher
magnifications, it looks like squashed fibers. On the other hand, disordered bundles of
fibers are observed, with lengths of 120 to 200 nm, for the xerogel formed from toluene.
Fig. 3. SEM micrographs of xerogels produced by a, b) hcptpyDP from methanol; c, d)
hcptpyDP from toluene; e, f) hcptpyTP from methanol; g, h) hcptpyTP from from
toluene. Two magnifications are shown in each case.
Xerogels of hcptpyTP from methanol exhibit an undefined spongy structure whose
cavities are formed by smashed fibers, as can be observed in higher magnifications.
Besides, xerogels formed by hcptpyTP in toluene present undefined structures. In higher
magnifications, however, we can notice that the walls of this structure are made of
1
3

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regular fibers of around 40 nm. By comparison of these micrographs with those for the
2
1
22
parent peptides we can conclude that the xerogels from DP and TP present better
defined and more regular structures in the form of fibers. An explanation for this
difference could be that the presence of the 4’-phenylterpyridine moiety disrupts the
self-assembly pattern of the molecules regarding the peptide backbone and imposes
other type of interactions, i.e. electronic π−π interactions, which also contribute to the
hierarchical self-assembly in whole.
Computational calculations on the aggregation mode. Calculations were carried out
to better understand the structure of the gels, their formation process and to establish the
main interactions responsible for the supramolecular arrangement. The aggregation
energies of hcptpyDP and hcptpyTP were compared with the aggregation energies of
dipeptide DP and tetrapeptide TP, to understand whether the 4’-phenylterpyridine
moiety benefits the aggregation in energetic terms or not.
A conformational search of hcptpyDP and hcptpyTP as single molecules was
carried out by using molecular mechanics. Then, the most stable structures obtained
were optimized employing quantum mechanics using M06-2X as DFT functional (Fig.
4
). In the resulting computed geometries, we can observe that the structure of hcptpyDP
is extended and fixed by an eight-membered hydrogen-bonded ring which is typical for
2
4,28
trans-based cyclobutane moieties.
On the other hand, the structure of hcptpyTP is
folded and fixed by three hydrogen bonds between the carbonyl oxygen atoms (CO) and
the NH protons of different amide groups. The relative conformation of the peptide
moieties in hcptpyDP and hcptpyTP are the same found in previous studies of DP and
24,28
TP,
so the incorporated 4’-phenylterpyridine unit does not play a significant role.
1
4

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1
.9
1
.8
1
.9
2
.0
Fig. 4. Optimized structures of hcptpyDP (left) and hcptpyTP (right). Hydrogen bonds
are remarked with green lines. Distances are in Å.
Once the structure of the discrete molecules was computed, their small aggregates
were studied. The conformational search performed for dimeric and tetrameric
aggregates of both compounds showed that the most stable structures involved
intermolecular hydrogen bonds between the NH groups of one molecule and the CO
groups of the other one. These hydrogen bonds may be formed in two different
directions, head-to-head and head-to-tail. The head-to-head arrangement was the most
favorable in all cases (see Table 1 in ESI) and is shown in Fig. 5.
O
O
N
CO Me
2
N
H
N
H
N
N
O
O
N
CO Me
2
N
H
N
H
N
N
Fig. 5. Schematic representation of head-to-head arrangement of a dimer of conjugate
hcptpyDP. π-π and H-bonding interactions are highlighted in red.
Results of calculations showed that the aggregation energies are more favorable
when the number of monomers increased. Also, the aggregation energy per molecule
increases in all cases, and it could mean that the self-assembly of both compounds is
1
5

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2
9
promoted by a cooperative effect. ∆E for tetrameric aggregate of DP is -59 kcal/mol
agg
while it is -113 kcal/mol for hcptpyDP. Likewise, ∆Eagg for the TP tetramer is -51
kcal/mol while it is -136 kcal/mol for tetrameric hcptpyTP. By comparing these values,
we can conclude that the terpyridine substructure plays an important role in the
aggregation process.
Optimized structures of the dimeric and tetrameric aggregates show that conjugates
hcptpyDP and hcptpyTP self-assemble in a preferred monodirectional dimension and
that terpyridine moieties are in a parallel disposition (Fig. 6).
Fig. 6. Side view of the predicted structure of a dimeric aggregate of a) hcptpyDP and
b) hcptpyTP. Non-polar H atoms were omitted for clarity.
When the aggregates grow, a helical-like structure is observed. This effect is more
marked for hcptpyTP than for hcptpyDP because the peptide moiety of the former is
larger, thus more flexible, and its accommodation in a helical-like aggregate is easier.
For this reason, only the formation of aggregates from hcptpyTP was considered.
The dodecameric structure of hcptpyTP was constructed using the same
methodology described for the dimer and tetramer but, in this case, only a minimization
of the energy using molecular mechanics was carried out. The helical trend was
confirmed (Fig. 7).
1
6

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Fig. 7. Top and side view for the predicted structure of a dodecameric aggregate of
hcptpyTP. Non-polar H atoms were omitted for clarity.
Looking at the aggregate from a top view, we can see the relative position of the 4’-
phenylterpyridine moieties and the peptide skeletons along the fibril. Interestingly,
while the aromatic moieties remain in the middle of the fibril, the peptide backbone of
the molecules spins around. Thus, to clarify the exact position of each function in the
big aggregate, the dodecamer was cut and an internal dimer and monomer were
extracted (Fig. 8). We can observe that each amide group of the compound forms
hydrogen bonds with the equivalent amide group of the next molecule. So, each
molecule that participates into the supramolecular aggregate establishes four hydrogen
bonds with the next molecule. It is remarkable that similar results had been obtained for
2
2
the structure of hexadecameric aggregate of tetrapeptide TP.
1
7

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Fig. 8. Internal dimer and monomer of the dodecameric aggregate of hcptpyTP.
Hydrogen bonds in the dimer and amide groups in the monomer are remarked in green.
Non-polar H atoms were omitted for clarity.
Similar results were obtained for hcptpyDP. Accordingly, calculations of big
aggregates suggest that the 4’-phenylterpyridine moiety in conjugates hcptpyDP and
hcptpyTP does not interphere in the interactions of the peptide part. Furthermore, each
pyridine and phenyl ring remains in a shifted parallel position due to π-stacking
interactions with the equivalent functions of the following and the previous molecule.
These predictions from calculations were confirmed by data from circular dichroism
and UV studies.
Circular Dichroism (CD) and UV spectroscopies. As expected, the UV spectra of
compounds hcptpyDP and hcptpyTP show two differentiated parts corresponding to the
aromatic 4’-phenylterpyridine substructure (250-280 nm) and the amide absorption (200
nm), respectively (See Figure S2 in Supplementary Data).
CD spectra were recorded for hcptpyDP and hcptpyTP in methanol solution and as
xerogels from toluene (Fig. 9).
1
8

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a)
b)
B
hcptpyDP
D1
hcptpyTP
hcptpyDP
hcptpyTP
2
1
1
00000
50000
00000
2
000
000
0
1
5
0000
0
-
50000
-1000
-
-
100000
150000
-
2000
200
250
300
350
400
200
250
300
350
400
450
Wavelength (nm)
Wavelength(nm)
Fig. 9. CD spectra of conjugate hcptpyDP and conjugate hcptpyTP: a) in 0.05 mM
solutions in MeOH and b) as xerogels at the mgc from toluene in KBr (0.02 mmol/g).
In contrast to the spectra in solution, which are rather complicated (Fig. 9a), the
spectra of xerogels appear simplified and are similar for both compounds (Fig. 9b).
Thus, a bisignate signal with zero crossing at 217 (225) nm and a broad signal at 247
(252) nm are observed, for hcptpyDP (hcptpyTP), respectively. The bisignate signal can
be attributed to the amides and has shifted to shorter wavelengths with respect to the
equivalent signal in solution. This blue shift is related to the difference between the
intramolecular hydrogen bonds of the amide groups in solution and the intermolecular
hydrogen bonds in the aggregate. Moreover, the shape of the signal is bisignate,
indicating that the relative position of the amides in the aggregate is not symmetrical.
2
3,30
This behavior is typically described for helical aggregates.
Concerning the signal of
the aromatic functions, in xerogel phase it has shifted to higher wavelength and its
chirality has changed from a bisignate signal in solution to a broad band in the
aggregate. The single band could be explained because the relative position of the
aromatic functions is parallel between them, as it is shown in the calculated structure.
The red shift of the band due to the aromatic functions could be related to partial
overlapping of them, performing a kind of staircase aggregation, as observed in many
1
9

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3
1
examples of aggregates of aromatic compounds, such as porphyrins. Moreover, in the
case of hcptpyTP, the relative position of the amide groups between the molecules are
non-parallel, generating helicity, while the aromatic groups remain in a shifted parallel
plane. These interpretations constitute another evidence of the helical-like structure of
the aggregates found by calculations. Also, bigger aggregates of these compounds could
form fibers, which is in accordance with the SEM experiments.
3
. Conclusions
Two new conjugates of terpyridine incorporating peptide moieties have been
prepared. On one hand, these compounds were used as ligands for the preparation of
Ru(II) complexes whose behavior as catalysts for epoxidation of phenyl-substituted
olefins was explored. Results showed that the efficiency in catalysis is similar to that of
previously described [Ru(pydic)(tpy)] complex. Unfortunately, epoxides were obtained
in racemic form in all cases studied, probably due to the long distance between the
catalytic center and the chiral peptide moiety that would adopt a not enough folded
conformation of the ligand. More promising were the results from the investigation of
hcptpyDP and hcptpyTP as organogelators. They can gelate a broad diversity of
solvents from aromatics, to aprotic polar and protic polar solvents, with satisfactory mgc
values. Actually, it seems that π−π interactions between the terpyridine substructures
and hydrogen bonding between the amide groups of the peptides in different molecules
have a cooperative effect in the supramolecular arrangement to self assemble into the
corresponding aggregates. Their morphology is strongly solvent-dependent as shown by
SEM. For instance, in toluene, they afford helical aggregates as verified by CD
spectroscopy and explained by computational calculations. With these results in hand,
2
0

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further properties of hcptpy-peptide conjugates are under investigation in view of future
applications.
4
. Experimental
4
.1
General Information
The chemicals and reagents were of analytical grade and were used without further
purification. Anhydrous solvents were freshly distilled when needed under nitrogen
atmosphere. Flash chromatography purifications were carried out on silica gel (200-400
mesh). Melting points were recorded on a Reicher Klofler block and values are
1
13
uncorrected. H NMR and C NMR spectra were measured in an ARX 400 Bruker
1
13
apparatus ( H at 400MHz, C at 100 MHz) in CDCl or DMSO-d solutions. IR spectra
3
6
were obtained from samples in neat form with an Attenuated Total Reflectance (ATR)
accessory. High resolution mass spectra were recorded using a direct inlet system (ESI)
in electrospray ionization mode.
4
.2
General procedure for the synthesis of conjugates hcptpyDP and hcptpyTP
Acid hcptpy (1 eq), prepared according to reference 26(b), and FDPP (1.3 eq)
were dissolved in DMF (20 mL/mmol of acid) and DIPEA (4 eq) was added under
nitrogen atmosphere. After stirring for 10 min, the adequate amine (1 eq) in DMF (15
mL/mmol of acid) was added and the reaction was stirred at room temperature
overnight. Then, the solution was washed with saturated NaHCO (3 x) and brine. The
3
organic phase was dried over MgSO , filtered and evaporated under reduced pressure to
4
give a residue that was purified through silica gel column chromatography using
mixtures of EtOAc and MeOH as the eluent to afford the corresponding product.
4
.2.1 Conjugate hcptpyDP
2
1

ACCEPTED MANUSCRIPT
Eluent: from EtOAc to EtOAc/MeOH 1:1; yield: 140 mg; 63%; white solid, mp
2
D
0
(
MeOH) 239 ºC (dec); [α] = +23 (c = 1.0, MeOH); IR: 3280, 2921, 2851, 2358, 1729,
-
1 1
1
1
7
1
1
632, 1584, 1541 cm ; H NMR (CDCl ): δ 2.02 (m, 5H), 2.25-2.37 (m, 3H), 3.05 (m,
3
H), 3.24 (m, 1H), 3.74 (s, 3H), 4.59 (m, 2H), 6.69 (m, 1H), 7.39 (m, 2H), 7.92 (m, 4H),
1
3
.98 (m, 2H), 8.69 (m, 2H), 8.75 (m, 4H), 9.00 (m, 1H); C NMR (CDCl ): δ 18.7,
3
8.8, 24.4, 26.9, 46.6, 47.2, 48.7 49.6, 51.7, 118.8, 121.4, 124.0, 127.6, 133.4, 136.9,
42.2, 148.8, 149.1, 155.9, 156.1, 168.0, 172.0, 173.6; HRMS: Calculated for
+
C H N O Na (M+Na ): 584.2268, Found 584.2259.
33
31
5
4
4
.2.2 Conjugate hcptpyTP
Eluent: from EtOAc to EtOAc/MeOH 1:1; yield: 280 mg, 49%; white solid, mp
2
0
(
MeOH) 245 ºC (dec); [α] = -40 (c = 0.29, CH OH); IR: 3285, 2948, 1737, 1630,
3
D
-1 1
1
585 1537 cm ; H NMR (CDCl ): δ 1.92-2.06 (m, 2H), 2.23 (m, 4H), 2.47 (m, 2H),
3
3
.30 (m, 1H), 3.43 (m, 1H), 3.73 (s, 3H), 3.82 (m, 2H), 4.05 (m, 1H), 4.21 (m, 1H), 4.68
(m, 1H), 4.99 (m, 1H), 6.44 (m, 1H), 6.48 (m, 1H), 7.06 (d, 1H), 7.36 (m, 2H), 7.80 (d,
1
3
1
2
1
6
H), 7.88-7.93 (m, 6H), 8.65 (m, 2H), 8.72 (m, 4H); C NMR (CDCl ): δ 18.1, 18.9,
3
8.8, 29.4, 30.5, 41.3, 45.0, 45.4, 52.4, 118.8, 121.3, 123.9, 127.2, 127.9, 134.5, 136.9,
+
49.0, 149.3, 155.9, 171.1, 172.9; HRMS: Calculated for C H N O Na (M+Na ):
3
7
37
7
8
98.2698, Found 698.2702
.3 General procedure for the preparation of complexes [Ru(pydic)(hcptpyDP)] and
4
[
Ru(pydic)(hcptpyTP)]
Ru(p-cymene)Cl ] (0.5 eq) and the desired terpyridine conjugate (1 eq) were
[
2
2
dissolved in MeOH (14 mL/mmol) under N atmosphere. Sodium 2-pyridine-2,6-
2
dicarboxylate (1 eq) was added in MeOH/H O, 2:1 (13 mL/mmol of pydic) and the
2
whole reaction mixture was heated at 60 ºC for 1 h. After the reaction mixture was
2
2

ACCEPTED MANUSCRIPT
cooled to r.t. and CH Cl and H O were added. The organic layer was separated and the
2
2
2
aqueous layer was extracted with CH Cl (3 x). The combined organic layer was dried
2
2
over MgSO , filtered and evaporated under reduced pressure to give a residue that was
4
purified through silica gel column chromatography using mixtures of CH Cl and
2
2
MeOH as the eluent to afford the corresponding product.
4
.3.1 Complex [Ru(pydic)(hcptpyDP)]
Eluent: from CH Cl to CH Cl /MeOH 100:5; yield: 70 mg, 60%; IR: 3261, 1725,
2
2
2
2
-
1 1
1
2
7
8
2
1
1
4
615, 1540 cm ; H NMR (DMSO-d ): δ 1.78-1.99 (m, 5H), 2.12 (m, 3H), 3.12 (m,
6
H), 3.58 (s, 3H), 4.34 (m, 1H), 4.53 (m, 1H), 6.84 (m, 1H), 7.46 (m, 1H), 7.57 (m, 2H),
.78 (m, 1H), 7.91 (m, 1H), 8.00 (m, 2H), 8.10 (m, 2H), 8.20 (m, 2H), 8.34 (m, 3H),
1
3
.87 (m, 2H), 8.95 (s, 2H); C NMR (DMSO-d ): δ 18.8, 18.9, 22.6, 26.0, 26.9, 29.2,
6
9.5, 45.8, 47.1, 47.4, 51.9, 119.4, 123.9, 124.1, 124.2, 127.4, 127.7, 128.5, 135.2,
38.3, 138.8, 139.2, 144.2, 150.6, 150.9, 160.4, 160.9, 165.6, 166.5, 171.5, 171.8,
+
73.6; HRMS: Calculated for C H N O RuNa (M+Na ): 851.1385, Found: 851.1384.
4
0
34
6
8
.3.2 Complex [Ru(pydic)(hcptpyTP)]
Eluent: from CH Cl to CH Cl /MeOH 100:5; yield: 28 mg, 54%; IR: 3385, 1733,
2
2
2
2
-
1
1
1
1
7
8
1
1
1
599, 1541 cm ; H NMR (DMSO-d ): δ 1.84-2.29 (m, 8H), 3.01 (m, 1H), 3.23 (m,
6
H), 3.53 (m, 2H), 3.60 (s, 3H), 3.83 (m, 2H), 4.50 (m, 1H), 4.80 (m, 1H), 6.88 (m, 1H),
.52 (m, 2H), 7.61 (m, 1H), 7.81 (m, 2H), 7.96 (m, 2H), 8.05 (m, 2H), 8.19 (m, 2H),
13
.34 (m, 3H), 8.51(m, 1H), 8.65 (m, 1H), 8.89-8.97 (m, 4H); C NMR (DMSO-d ): δ
6
8.8, 22.6, 27.0, 28.8, 29.0, 29.2, 29.3, 29.5, 31.8, 45.2, 52.2, 55.4, 119.4, 123.9, 124.1,
24.3, 127.3, 127.6, 127.8, 128.3, 135.5, 138.3, 138.8, 150.4, 150.6, 150.8, 160.4,
61.0, 168.5, 170.8, 171.0, 171.4, 171.5, 172.7, 173.1; HRMS: Calculated for
+
C H N O RuNa (M+Na ): 965.1815, Found: 965.1824
44
40
8
10
4
.4 General procedure for catalyzed epoxidation reactions
2
3

ACCEPTED MANUSCRIPT
The desired complex (0.005 mmol, 0.005 eq) was sonicated in 10 mL of
CH Cl /MeOH 9:1. Then, the olefin (1 mmol, 1 eq) and undecane (GC internal
2
2
standard, 100 µL) were added. After, urea hydrogen peroxide complex (0.188 g, 2
mmol, 2 eq) was added in three portions at 0, 1 and 2 h. The reaction mixture was
stirred at r.t. and aliquots were taken and subjected to GC analysis for the determination
of yield data. When the reaction was finished, the suspension was washed successively
with aqueous solutions of NaHCO and brine. The organic layer was dried over MgSO ,
3
4
and the solvent was removed under reduced pressure. The corresponding epoxide was
obtained without the need of further purification (see Supporting Data for details).
4
.5 Gas chromatography
GC was performed using an apparatus equipped with FID detector. Samples were
dissolved in CH Cl and filtered through a microfilter. A capillary column (30 m x 250
2
2
mm x 0.25 mm) was used. Yields of the epoxidation reactions were determined using
GC analysis. Calibrations using 5 standard samples containing different ratios of the
corresponding epoxide product and undecane (internal standard) were performed.
Yields of catalyzed reactions were calculated from the linear interpolation of the
corresponding calibration function (see Supporting Data for details).
4
.6 Electrochemical studies
Cyclic voltammetry (CV) and differential pulse voltammetry (DPV) experiments
were performed on a potentiostat using three-electrode cell. A glassy carbon electrode
2 mm diameter) was used as working electrode, a platinum wire as auxiliary electrode,
(
and a saturated calomel electrode (SCE) as a reference electrode. Complexes were
dissolved in MeOH containing 0.1M of TBABF as supporting electrolyte. E1/2 values
4
were determined as detailed in ESI.
4
.7 SEM Measurements
2
4

ACCEPTED MANUSCRIPT
SEM images were acquired with an apparatus equipped with a field emission gun.
Wet gels were placed on a carbon-film-coated copper grid and dried by standing for 30
minutes on the grid. The resulting xerogels (dry gels) were then introduced into the
microscope working at 60-80 Pa and 5 kV.
4
.8 CD measurements
In the experiments in solution, the samples were dissolved in MeOH (0.05 mM)
and the CD spectra were recorded using a 1 cm width quartz cuvette and were processed
using the associated software. For the experiments in xerogel, first a gel at the mgc was
prepared in toluene. Then the solvent of the gel was removed under vacuum to get the
-1
xerogel. Samples were prepared mixing the xerogels at around 0.020-0.025 mmol g
with KBr (1.2-1.6 wt. %) in an agate mortar and pressing the mixture for 10 minutes.
Translucent disks were obtained and the CD spectra were recorded using the same
spectropolarimeter.
4
.9 Computational details
Conformational searches were carried out using a mixed low mode/torsional
3
2
33
34
sampling with the OPLS-2005 force field implemented in the MacroModel
program to find and select an approximation of the most stable conformers. The
geometries of the lowest energy conformers of the monomer of each compound were
3
5
36
optimized using DFT calculations with the Gaussian09 program with the M06-2X
functional with the 6-31G(d) basis set. The most stable structures were also done for
dimeric and tetrameric aggregates. The most stable structures were optimized at the
M06-2X/6-31G(d) level of calculation. The dodecameric structure of hcptpyTP was
constructed using the same methodology described for the dimer and the tetramer but in
this case, only a minimization of the energy using molecular mechanics was carried out.
2
5

ACCEPTED MANUSCRIPT
Dedication
This paper is warmly dedicated to Professor Léon Ghosez, to honor his fruitful and long
lasting compromise with the progress of chemical science.
Acknowledgements
Financial support from Spanish MINECO (grant CTQ2016-77978-R) is gratefully
acknowledged.
Appendix A. Supplementary data
Supplementary data related to this article can be found at http:// dx.doi.org/xxxx.
Aggregation energies for the formation of aggregates, DPV voltammograms of
[
Ru(pydic)(hcptpyDP)] and [Ru(pydic)(hcptpyTP)] and determination of E1/2 values,
1
13
UV spectra of hcptpyDP and hcptpyTP, H and C NMR spectra of the new products,
experimental data from studies on the epoxidation of olefins, cartesian coordinates of
monomers and aggregates of hcptpyDP and hcptpyTP.
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