A new dipeptide as a selective gelator of Cu(ii), Zn(ii), and Pb(ii)

Article abstract of DOI:10.1039/d0ce01199a

The various aspects associated with the incorporation of steric constraints into a series of dipeptides have been studied. The self-assembly propensities of the dipeptides carried out with the use of complementary experimental methods enabled us to determ

Full text of DOI:10.1039/d0ce01199a

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PAPER
Yuan Zhuang et al.
Structural study on PVA assisted self-assembled 3D
hierarchical iron (hydr)oxides
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DOI: 10.1039/D0CE01199A
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A new dipeptide as selective gelator of Cu(II), Zn(II), Pb(II)†
a
a
a
a
Santosh Kumar, Sujay Kumar Nandi, Saurav Suman and Debasish Haldar *
Received 00th January 20xx,
Accepted 00th January 20xx
The various aspects associated with the incorporation of steric constraints into a series of dipeptides have been studied.
Self-assembly propensities of the dipeptides carried out with the use of complementary experimental methods enabled us
to determine the effect of steric constraints. The Gly and Aib containing peptide 1 shows flakes-like morphology.
Replacement of Gly by L-Phe in peptide 2 increase steric constrant and developed micro rods. Peptide 3 with N-phenyl
glycine and L-Phe has a flower-like morphology, and peptide 4 with N-phenyl glycine and L-Tyr has microsphere
morphology. The solid-state FT-IR studies show that the peptides are self-assembled by hydrogen bonds. From X-ray
crystallography, peptide 1 adopts kink-like conformation and forms a supramolecular anti-parallel sheet-like structure
through multiple intermolecular hydrogen bonds. Replacement of Gly by L-Phe helps the peptide 2 to adopt S-shape
conformation and self-assembled to form a supramolecular helix in solid-state. Single crystal X-ray exhibits that the
peptide 3 adopts extended conformation and form 2D sheet-like matrix through π-π stacking interactions. Moreover,
DOI: 10.1039/x0xx00000x
www.rsc.org/
4 2 4 2 2 2
metallogelation of peptide 3 was observed selectively for CuSO .5H O, ZnSO .7H O and Pb(OAc) .3H O, whereas other
metals were not able to form gel. The study revealed a pivotal role played by the phenyl group in diverse self-assembly of
the dipeptides.
architectures, such as spherical or cylindrical micelles, vesicles,
1
2-14
Introduction
Molecular recognition and assembly and gelation is a
spontaneous process which provides novel desired materials
for eco-friendly biological applications. Various compounds
including block copolymers, surfactants, peptide derivatives,
and lipid molecules have been adopted as building blocks for
the development of supramolecular materials. Recently,
small molecule containing aromatic groups have emerged as
an appealing alternative for macromolecular systems to
develop supramolecular materials due to their unique dynamic
self-assembly propensities and stimuli responsiveness. So, the
thorough understanding of chemical structures, physical
properties, and self-assembly propensities of the building
blocks are highly important.
driven by various non-covalent interactions, including
ribbons, and tubules.
A number of supramolecular systems
have been fabricated which can alter their topologies and
properties upon exposure to external stimuli like solvents
polarity, temperature, redox potential, light, sonication, and
Reches and Gazit fabricated nanofibers from self-
assembly of diphenylalanine. Ulijn and co-workers have
1
-4
1
5-17
pH.
1
8
reported a hydrogel via π-π interlocked β-Sheets from the self-
5
-7
1
9
assemble dipeptide Phe-phe. Görbitz has reported the
formation of nanoporous materials by self-assembly of amino
2
0,21
acids and dipeptides.
We are developing peptide-based functional materials.22-25
Previously we have reported the diverse self-assembly and gas
adsorption studies of isomeric hybrid peptides. We have also
developed highly selective metallogel from 4-
biphenylcarboxy capped diphenylalanine and FeCl
.27 Presently
8
2
6
a
9
-10
This self-assembly is mainly
3
3
+
we have described topology-controlled selective Fe binding
in water by -peptides with dihydropyrimidinone containing
hydrogen bonding, - stacking, electrostatic interactions, and
hydrophobic interactions.
environments, molecular structures and shapes, and relative
volume fraction of hydrophilic and hydrophobic parts, these
molecules self-assemble into diverse supramolecular
1
1
Depending on the external
2
8
amino acid.
In this regard, we have synthesized four boc- (1 and 2) and
phenyl- (3 and 4) protected dipeptides by varying steric
constraints. The solid-state structures show that the achiral
dipeptide 1 adopts kink-like conformation and forms a
supramolecular sheet-like structure through multiple
intermolecular hydrogen bonds. But, the sterically hindered
a. Department of Chemical Sciences
Indian Institute of Science Education and Research Kolkata
Mohanpur 741246, West Bengal, India
E-mail: deba_h76@iiserkol.ac.in, deba_h76@yahoo.com.
phenylalanine analogue dipeptide
conformation and forms a supramolecular helix. However, N-
adopts extended
2
shows S-shape
†
Footnotes relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: H NMR, 13C NMR, solid state
FTIR spectra, Figures ESI S1-2, Figure S3-S18, CCDC 2006561, 2006514 and phenylglycine containing peptide
006562. See DOI: 10.1039/x0xx00000x
1
3
2
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conformation and forms a supramolecular 2D matrix through 1H NMR (500MHz, CDCl
Journal Name
, δ in ppm, 298 K): 7.26-7.27 (m, 2H,
3
View Article Online
non-covalent interactions. From FESEM, depending on the aromatic protons), 7.21-7.22 (m, 2H, aroDmOaI:t1i0c.1p0r3o9t/oDn0Cs)E,0711.9292A-
steric constraints, the peptides show flakes, nanorods, flower, 7.20 (m, 1H, aromatic proton) 6.48 (s, 1H, Aib NH), 5.22-5.19
α
and microspheres morphology. Under basic condition, (s, 1H, Phe NH), 4.22 (m, 1H, Phe C H), 3.70 (s, 3H, OCH
3
),
β
α
metallogelation of only peptide 3 was observed selectively for 2.95-2.90 (m, 2H, Phe C H), 1.44 (s, 6H, Aib C H), 1.41 (s, 9H,
CuSO .5H O, ZnSO .7H O and Pb(OAc) .3H O, whereas other BOC CH ). 13C NMR (125 MHz, CDCl , δ in ppm, 298 K): 174.17,
170.44, 156.31, 136.86, 129.54, 128.26, 126.95, 80.20, 56.43,
6.40, 52.65, 38.54, 28.32, 24.76; Anal. Calcd for C19
364): C, 62.62; H, 7.74; N, 7.69. Found: C, 62.59; H, 7.76; N,
.67. Mass spectra, found m/z: 387.4912 [M+Na]+, calculated
Na 387.4824.
4
2
4
2
2
2
3
3
metals were not able to form gel.
5
28 2 5
H N O
(
7
Experimental
28 2 5
for C19H N O
Synthesis of N-PhenylGly-Phe-OMe 3
Materials and reagents
All amino acid methyl esters and chemicals were purchased
from Sigma chemicals.
N-phenylglycine-OH (1.51 g, 10 mmol) was dissolved in 50 mL
dry DCM in an ice-cold water bath. H N-Phe- OMe 1.81 g, 11
2
Synthesis of Boc-Gly-Aib-OMe 1
mmol) was dissolved in 10 mL DCM. It was then added to the
reaction mixture, followed by immediate addition of 2.26 g (11
mmol) dicyclohexylcarbodiimide (DCC) and 1.48 g (11 mmol) of
HOBt. The reaction mixture was allowed to come to room
temperature and stir for 48 hrs. After that, DCM was
evaporated, and the residue was dissolved in ethyl acetate (60
mL), and dicyclohexylurea (DCU) was filtered off. The organic
layer was washed with 2 (M) HCl (3 ×50 mL), brine (2 × 50 mL),
1
.75g (10 mmol) of Boc-Gly-OH was dissolved in 20 mL dry
DCM in an ice-water bath. Aib-OMe was isolated from 1.95g
15 mmol) of the corresponding methyl ester hydrochloride by
(
neutralization and subsequent extraction with ethyl acetate,
and ethyl acetate extract was concentrated to 10 mL. It was
then added to the reaction mixture, followed immediately by
2
.53g (15 mmol) dicyclohexylcarbodiimide (DCC) and 2.30g (15
mmol) of hydroxybenzotriazole (HOBt). The reaction mixture
was allowed to come to room temperature and stirred for 48
hrs. DCM was evaporated, and the residue was dissolved in
ethyl acetate (60 mL), and dicyclohexylurea (DCU) was filtered
off. The organic layer was washed with 2 M HCl (3 × 50 mL),
brine (2 × 50 mL), 1M sodium carbonate (3 × 50 mL), and brine
1
(M) sodium carbonate (3 × 50 mL) and brine (2 × 50 mL) and
dried over anhydrous sodium sulfate. The products were
purified by column chromatography using silica (60-120-mesh
size) gel as stationary phase and n-hexane-ethyl acetate
mixture as eluent. Yield: 2.05 g (6.5 mmol, 65 %).
3
H-NMR (400 MHz, CDCl , δ ppm): 7.23-7.14 [5H aromatic & 1H NH
1
(2 × 50 mL) dried over anhydrous sodium sulphate; and
proton], 7.16-7.15[b,1H NH proton] 6.93-6.91[2H aromatic],
evaporated in a vacuum to yield compound Boc-Gly-Aib-OMe
as a solid. The product was purified by silica gel (100-200
mesh) using hexane-ethyl acetate as eluent. Yield: 2.45g (9.0
6
3
.83[1H aromatic], 6.57-6.53[2H aromatic], 4.95-4.93 [m, Cᵝ1H],
.77--3.75 [b, 2H], 3.69 [s, 3H, OCH
], 3.06-3.05 [t, Cα 2H]. 13C-NMR
, δ ppm): 172.03, 170.68, 147.81, 129.74, 129.48,
28.91, 127.40, 119.50, 113.61, 52.87, 52.76, 48.95, 38.23. FT-IR
cm ): 3350, 2932, 1670, 1495. Anal. Calcd for C18
69.21; H, 6.45; N, 8.97. Found: C, 69.48; H, 6.42; N, 8.94. Mass
spectra, found m/z: 335.1495 [M+Na]+, calculated for C18 Na
35.1407.
3
(100 MHz, CDCl
3
mmol, 90 %).
1
(
1
H-NMR (400 MHz, CDCl
3
, δ ppm): 6.65 [b, 1H, amide NH], 5.39
], , 3.63 [s, 3H, OCH ],
.54 [s, 6H, Aib], 1.33 [s, 9H, Boc]. 3C-NMR (100 MHz, CDCl
, δ
-1
20 2 3
H N O (312): C,
[
b, 1H, amide NH], 4.13 [dd, 2H, Gly-CH
2
3
1
1
3
20 2 3
H N O
ppm): 171.25, 165.71, 153.16, 77.38, 53.32, 49.50, 41.30,
5.15, 25.21, 21.16. Anal. Calcd for C12 (274): C, 52.54;
3
2
22 2 5
H N O
H, 8.08; N, 10.21. Found: C, 52.57; H, 8.06; N, 10.18. Mass
spectra, found m/z: 297.1509 [M+Na]+, calculated for
C H N O Na 297.1421.
12 22 2 5
Synthesis of N-PhenylGly-Tyr-OMe 4
N-phenylglycine-OH (1.51 g, 10 mmol) was dissolved in 50 mL
dry DCM in an ice-cold water bath. H N-Tyr- OMe (2.14 g, 11
Synthesis of Boc-Phe-Aib-OMe 2.
2
mmol) was dissolved in 10 mL DCM. It was then added to the
reaction mixture, followed by immediate addition of 2.26 g (11
mmol) dicyclohexyl carbodiimide (DCC) and 1.48 g (11 mmol)
of HOBt. The reaction mixture was allowed to come to room
temperature and stir for 48 hrs. After that, DCM was
evaporated, and the residue was dissolved in ethyl acetate (60
mL), and dicyclohexylurea (DCU) was filtered off. The organic
layer was washed with 2 (M) HCl (3 ×50 mL), brine (2 × 50 mL),
Boc-Phe-OH (1.75 g, 7 mmol) was dissolved in 50 mL dry DCM
in an ice-cold water bath. H N-Aib-OMe (1.2 g, 10 mmol) was
2
dissolved in 10 mL DCM. It was then added to the reaction
mixture, followed by immediate addition of 1.44 g (7 mmol)
dicyclohexyl carbodiimide (DCC) and 0.95 g (7 mmol) of HOBt.
The reaction mixture was allowed to come to room
temperature and stir for 48 hrs. After that, DCM was
evaporated, and the residue was dissolved in ethyl acetate (60
mL), and dicyclohexylurea (DCU) was filtered off. The organic
layer was washed with 2 (M) HCl (3 ×50 mL), brine (2 × 50 mL),
1
(M) sodium carbonate (3 × 50 mL) and brine (2 × 50 mL) and
dried over anhydrous sodium sulfate. The products were
purified by column chromatography using silica (60-120-mesh
size) gel as stationary phase and n-hexane-ethyl acetate
1
(M) sodium carbonate (3 × 50 mL) and brine (2 × 50 mL) and
dried over anhydrous sodium sulfate. The solution was
evaporated under vacuum to obtain dipeptide as a white solid.
The product was purified by column chromatography.
Yield: 1.96g (5.6 mmol, 80 %).
mixture as eluent. Yield: 2.23 g (6.7 mmol, 67 %).
1
3
H-NMR (400MHz, CDCl , δ ppm): 7.22-7.12[m,3H (aromatic)], 6.84-
6
.80[t, 1H aromatic], 6.76-6.74[d,2H aromatic], 6.59-6.57[d,2H
2
| J. Name., 2012, 00, 1-3
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aromatic], 6.54-6.52[d, 2H aromatic],6.4-6.3[b,1H NH proton] 4.93-
Results and discussion
View Article Online
DOI: 10.1039/D0CE01199A
αCH
4
3
.91[m,1H],
4.24-4.15[b,1H],3.74-3.73[b,2H,
2
NPG],
We have designed and synthesized four peptides with glycine,
-aminoisobutyric acid, L-phenylalanine, N-phenylglycine, and
.71[s,3H,OMe], 2.99-2.97[t,2H, CH Tyr] 13C-NMR (100 MHz, CDCl
α
3
,

δ ppm): 172.32, 171.12, 155.57, 147.14, 130.59, 129.75, 127.21,
L-tyrosine to investigate the effect of increasing steric
constraints. The achiral Boc-Gly-Aib-OMe 1 is less hindered
than Boc-Phe-Aib-OMe 2, N-PhenylGly-Phe-OMe 3, and N-
PhenylGly-Tyr-OMe 4 (Fig. 1). The assumption was that the
steric constraints will restrict conformational flexibility and
intervene on peptide folding and self-assembly. N-
phenylglycine will enhance - stacking interaction and
tyrosine was incorporated to include additional hydrogen
bonding functionality. The main aim of this investigation was
to control the structure and self-assembly of dipeptides by
incorporating various steric constraints. Targeted dipeptides 1,
-1
1
3
19.53, 115.90, 113.61, 53.01, 52.77, 48.88, 37.47. FT-IR (cm ):
400, 2930, 1670, 1500. Anal. Calcd for C18 (328): C, 65.84;
20 2 4
H N O
H, 6.14; N, 8.53. Found: C, 65.83; H, 6.17; N, 8.51. Mass spectra,
found m/z: 351.1856 [M+Na]+, calculated for C18 Na
51.1768.
20 2 4
H N O
3
NMR Experiments
All NMR experiments were performed on a Jeol 400 MHz and
Bruker 500 MHz, spectrometer at 278 K. Compound concentrations
were in the range 1–10 mM in CDCl .
3
FT-IR Spectroscopy
Solid-state FT-IR spectra following KBr disk technique were
measured in a Perkin Elmer Spectrum RX1 spectrophotometer.
Mass spectrometry
Mass spectra of the compounds were recorded on a Q-Tof
Micro YA263 high-resolution (Waters Corporation) mass
spectrometer by positive-mode electrospray ionization.
UV/Vis spectroscopy
2
, 3, and 4 were synthesized by conventional solution-phase
methodology using DCC/HOBT as coupling reagents. The final
compounds have been purified by column chromatography
1
13
and characterized by H-NMR, C-NMR, FT-IR and mass
spectrometry (MS) analysis.
The absorption spectra of the samples were recorded on a
Perkin Elmer UV-Vis spectrophotometer.
Fluorescence spectroscopy
All fluorescence spectra were recorded on a Perkin Elmer
fluorescent spectrometer (LS 55) using 1 cm path length quartz
cell. Slit widths 2.5/2.5 were used.
Polarised Optical Microscope
A small amount of solution of the compound was placed on
a clean glass coverslip and then dried by slow evaporation,
then visualized at 40 magnification (Olympus optical
microscope equipped with polarizer and CCD camera).
Single crystal X-ray diffraction study
Single crystal X-ray analysis of compounds 1-3 was recorded on a
Bruker high-resolution X-ray diffractometer instruments with MoK
radiation. Data were processed using the Bruker SAINT package and
the structure solution and refinement procedures were performed
Fig. 1. The schematic presentation of dipeptides 1, 2, 3 and 4.
To investigate the self-assembly behaviour of the dipeptides, a
using SHELX97. CCDC 2006561, 2006514 and 2006562 contains the wide variety of different spectroscopic techniques have been
crystallographic data for the compounds 1 - 3 respectively.
used. The lack of a chromophore restricts peptide 1 for
Field Emission Scanning Electron Microscopy
absorption and emission spectroscopy. Peptide 2 shows an
Morphologies of the reported compounds were investigated absorption band at 259 nm, responsible for π to π* transition,
using field emission-scanning electron microscopy (FE-SEM). which does not shift with increasing concentrations (ESI Fig.
For FE-SEM, a small amount of peptide solution or gel was S1a). We have also plotted the key absorbance intensities as a
drop casted on a clean glass coverslip and dried by slow function of concentration of peptide 2 which shows the Beer-
evaporation at room temperature. Finally, the sample was Lambert behavior is observed (ESI Fig. S2a). Peptide 2 shows
dried under reduced pressure for two days at 30°C. The emission peaks at 303 nm, which induces increasing intensity
samples were gold-coated, and the micrographs were with increasing concentration (Fig. 2a). The typical UV-Vis
captured in Zeiss DSM 950 scanning electron microscope.
Transmission Electron Microscopy
absorption spectra of peptide 3 in methanol (1.0 µM) show
absorption band at 241 nm and 288 nm for n to π* and π to π*
Microstructure of the reported metallogels were investigated transition (ESI Fig. S1b). However, increasing the concentration
using transmission electron microscopy (TEM). For TEM, a of 3 induces increasing intensity. The typical emission spectra
small amount of gel was placed on a carbon coated cupper of peptide 3 in methanol (1.0 µM), excitation done at 288 nm
grid and dried under vacuum for two days at 30°C. The is shown in Fig. 2b. With increasing the concentration of
micrographs were captured in JEOL JEM 2010 electron peptide 3, the emission band at 323 nm shows a bathochromic
microscope.
shift of 10 nm. For peptide 4, absorption bands appear at 228
nm and 280 nm, responsible for n to π* and π to π* transition,
which does not shift with increasing concentrations (Fig. 2c).
This journal is © The Royal Society of Chemistry 20xx
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The plot of the key absorbance intensities as a function of Solid state FT-IR spectroscopy is an excellent method to
View Article Online
DOI: 10.1039/D0CE01199A
concentration of peptide 4 exhibits the Beer-Lambert behavior investigate the self-assembly propensity of the reported
−1
(
ESI Fig. S2c). The emission spectra of peptide 4 in methanol dipeptides. In FT-IR, the region of 3500−3200 cm is important
also show a band at 325 nm and a bathochromic shift of 14 nm for the N−H stretching vibrations however the range
−1
with increasing concentration (Fig. 2d). These results show 1800−1500 cm is assigned for the stretching band of amide I
2
9
that the peptides 3 and 4 have similar aggregation pattern.
and the bending peak of amide II. For peptide 1, Solid state
-1
FT-IR bands at 3314 cm is responsible for hydrogen bonded
NH’s (Fig. 4a). The amide I and amide II bands appeared at
670 and 1512 cm . Peptide 2 show an intense band at 3373
-1
1
-1
and 3314 cm indicating the NH groups are hydrogen bonded
(
1
Fig. 4b). The amide I and amide II bands have appeared at
683 and 1539 cm- (Fig. 4b). The band at 1728 cm is
1
-1
responsible for the ester C=O. The FT-IR spectra of peptide 3
–1
exhibits NH stretching frequency at 3350 cm for N-H and
–1
amide peaks at 1670 and 1495 cm indicating the presence of
extended Hydrogen bonded structures (Fig. 4c). For peptides
, the band at 3340-3400 cm- indicates that NH groups are
1
4
non-hydrogen bonded and broadening due to OH stretching
(
1
Fig. 4d). The amide I and amide II bands have appeared at
-1
670, 1590 and 1500 cm respectively indicating the presence
2
9
of extended H-bonded structures. This suggests that the
peptides 3 and 4 have significantly close conformations.
Fig.2 (a) The emission spectra of peptide 2 in MeOH at 298 K with increasing
concentrations (10 to 18 M). Excitation done at 259 nm (b) The emission
spectra of peptide 3 in MeOH at 298 K with increasing concentrations (10 to 18

M). Excitation done at 288 nm. (c) The absorption spectra of peptide 4 in MeOH
at 298 K with increasing concentrations (10 to 18 M). (d) The emission spectra
of peptide 4 in MeOH at 298 K with increasing concentrations (10 to 18 M).
Excitation at 280 nm.
Boc- and phenyl-protected peptides are soluble in organic
solvents, but failed to form gel and exhibit morphological
diversities. From field emission scanning electron microscopy (FE-
SEM), the Boc protected achiral peptide
1 exhibits flake-like
morphology (Fig. 3a). The Phe containing peptide 2 exhibits nano rod
like morphology. The rods are unbranched. The diameter of the rods is
c.a. 200 nm and several μm long. Moreover, the nano rods are
assembled in a flower like structure. From FE-SEM, peptide 3
containing N-phenylglycine exhibits flower-like shape (Fig. 3c).
However, the peptide 4 shows polydisperse microspheres morphology
(Fig. 3d).
Fig. 4. The solid state FTIR spectra of (a) peptide 1, (b) peptide 2, (c) peptide 3,
(d) peptide 4 .
The molecular packing and solid-state self-assembly of the
reported peptides 1, 2, and 3 at the atomic level were
3
0
explained by X-ray crystallography. We have failed to
develop an X-ray quality crystal of peptide 4. Crystals of
peptides 1, 2, and 3 suitable for X-ray crystallography were
obtained from methanol solution by slow evaporation. The
peptide Boc-Gly-Aib-OMe 1 has one molecule in the
asymmetric unit. The peptide
1
adopts
a
kink-like
conformation (Fig. 5a). The selected backbone torsion angles
are listed in Table 1. There is no intramolecular hydrogen
bond. In higher-order packing, the individual subunits of
peptide 1 are themselves regularly interlinked through
hydrogen-bonding interactions, and thereby form an anti-
parallel duplex structure (Fig. 5b). The duplex is further self-
Fig. 3. FESEM images of (a) peptide 1 showing flakes-like morphology; (b)
peptide 2 showing nanorods-like morphology, (c) peptide 3 having flower-like
shape and (d) peptide 4 showing polydisperse microspheres morphology. The
samples were prepared by drop casting the MeOH solution of the peptides on
glass cover slip followed by drying at room temperature.
4
| J. Name., 2012, 00, 1-3
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assemble through multiple intermolecular hydrogen-bonding
interactions to form supramolecular sheet–like structure along
the crystallographic b direction (Fig. 5c). Hydrogen bonding
parameters for peptide 1 are also listed in Table 2.
View Article Online
DOI: 10.1039/D0CE01199A
Fig. 6. (a) The solid-state conformations of peptide 2 molecules in the
asymmetric unit. (b) The intermolecular hydrogen-bonded supramolecular
helical assembly of peptide 2 in ball and stick model. Hydrogen bonds are shown
as black dotted lines. (c)he supramolecular helical assembly of peptide 2 in space
fill model. (d) The supramolecular helical bundle of peptide 2, stabilized by T-
shape π-stacking interactions.
Fig. 5. (a) The ORTEP diagram of peptide Boc-Gly-Aib-OMe 1. 50% probability
level. (b) Ball and stick model of the hydrogen-bonded anti parallel duplex of
peptide 1. Intermolecular hydrogen bonds are shown as black dotted lines. (c)
The supramolecular sheet-like structure of peptide Boc-Gly-Aib-OMe 1.
Hydrogen bonds are shown as black dotted lines.
molecules shows a supramolecular 2D matrix-like structure
(Fig. 7d) along crystallographic a and c direction. There are two
intermolecular π-π interactions, face to face (shortest C-C
distance 3.81 Å) and face to edge (shortest C-C distance 3.76
Å) (Fig. 7d).
The peptide 2 crystallizes with one molecule in the asymmetric
unit (Fig. 6a). The peptide 2 adopts S-shape conformation (Fig.
6
a), though there is no intramolecular hydrogen bond. The Boc
amide group is in cis geometry (Fig. 6a). The selected backbone
torsion angles are listed in Table 1. Further, the peptide 2
molecules form a supramolecular helix-like structure through
multiple intermolecular hydrogen bonds (Fig. 6b) along the
crystallographic b direction. The phenyl rings are outside of the
supramolecular helical column (Fig. 6c). At higher-order
assembly, supramolecular helical bundles stabilized by face to
edge (T-shape) π-π stacking interactions (shortest centroid-C
distance 3.8Å) (Fig. 6d). The hydrogen bonding parameters are
listed in Table 2.
From X-ray crystallography, it is evident that the
asymmetric unit contains one molecule of peptide 3. The
crystal structure (Fig 7a) of peptide 3 shows that the peptide
backbone adopts kink-like conformation stabilized by an
intramolecular five-member N-H….N hydrogen bond. For
peptide 3 molecule, face to face intramolecular π-π stacking
Fig.7. (a) The ORTEP diagram of peptide 3. 50% probability level. Intramolecular
interaction between Phe side chain and N-phenylglycine hydrogen bond and π-π stacking interactions are shown as black dotted lines. (b)
Intermolecular hydrogen-bonded column-like structure of peptide 3. Hydrogen
aromatic ring (centroid to centroid distance 4.3Å) resulting in a bonds are shown as black dotted lines. (c) The multiple intermolecular π-π
stacking interactions between peptide 3 molecules. (d) Supramolecular 2D
rigid kink-like conformation in the solid-state (Fig 7a). The matrix-like structure of peptide 3 by multiple intermolecular π-π interactions
along crystallographic a and c direction.
important backbone torsion angles are listed in Table 1.
Hydrogen bonding parameters are listed in Table 2. The
individual subunits of peptide 3 are themselves regularly
Table 1. Selected backbone torsion angles (deg) for peptides 1, 2 and 3.
interlinked
through
intermolecular
hydrogen-bonding

1
/°

1
/°

2
/°
2
 /°
43.7(2)
-29.8(6)
Peptide 1
Peptide 2
Peptide 3
-60.7(2) 155.14(16)
-64.5(7)
85.2(2)
48.4(2)
-55.8(6)
-74.7(2) 167.50(19)
interaction, N4−H4···O1, and thereby form a supramolecular
column-like structure along the crystallographic b direction
145.3(5)
12.0(2)
(Fig. 7b). The higher-order packing through cooperative
multiple intermolecular π-π interactions (Fig. 7c) of peptide 3
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Table 2. Hydrogen bonding parameters of peptides 1, 2 and 3a
With increasing gelator concentration, the metallogel changes
from soft gel to robust gel. This was further studied by gel
View Article Online
DOI: 10.1039/D0CE01199A
melting experiments. Figure 9a shows the plots for change of
gel−sol transition temperature (Tgel) of the peptide 3 in
D-H….A
D..H(Å)
H..A(Å)
2.07
2.12
2.36
2.21
2.47
D..A(Å)
D-H..A (°)
a
1
2
3
N2-H2….O4
N1-H1….O3
N1-H1….O4
N2-H2…O2
N2-H2...O1
0.86
0.86
0.86
0.86
0.86
2.9074(18)
2.9035(19)
3.016(9)
2.954(9)
3.213(3)
163
152
133
145
145
b
presence of CuSO
concentration. Change of gel−sol transition (Tgel) of the peptide
3 in ZnSO .7H O (1 equiv.) and NaOH (1.5 equiv.) with
increasing gelator concentration is depicted in Fig. 9b. Gel to
sol transition temperature (T ) of the peptide 3 in presence of
4
.5H
2
O
and NaOH with increasing
c
d
e
4
2
aSymmetry equivalent a = x, 1+y, z, b= -x, 1-y, 1-z, c = -x, -1/2+y,
gel
3
/2-z, d = 1-x, 1/2+y, 3/2-z,e= x, 1+y, z .
2 2
Pb(OAc) .3H O (1 equiv.) and NaOH (1.5 equiv.) is 55.6 °C.
Initially, the gelation abilities of the reported Boc- and phenyl-
protected peptides were checked in various solvents by
dissolving 10 mg of peptide in 1 mL of different solvents.
Control experiments show that the Boc- and phenyl-protected
peptides do not form a gel in any solvent by heating-cooling
technique or even after sonication. However, the combination
4 2
of peptide 3 with CuSO .5H O (1 equiv.) and NaOH (1.5 equiv.)
exhibited the formation of black opaque gels. Typically, a
weighted amount of peptide and an appropriate amount of a
metal salt stock solution were placed into a screw-capped
glass vial (4 cm length × 1 cm diameter). The mixture was
stirred and sonicated for ∼2 min until everything was
homogeneous. The resulting solution was rest at room
temperature. Among four peptides, only peptide 3 forms black
Fig. 9. (a) Change of gel−sol transition temperature (Tgel) of the peptide 3 in
presence of CuSO .5H O and NaOH with increasing concentration. (b) Change of
gel−sol transition temperature (Tgel) of the peptide 3 in presence of ZnSO .7H
and NaOH with increasing concentration.
4
2
4
2
O
The morphology of the metallogels were investigated by the field
emission scanning electron microscopic studies (FE-SEM). The FE-SEM
images of xerogel of peptide 3 and CuSO
4
.5H
2
O
exhibit
polydisperse fibrilar network structures (Fig. 10a,b). The average
diameter of the fibrils is 10 nm and several µm in length. Fig.
4 2
opaque metallogel with CuSO .5H O (Fig. 8a). The minimum
gelation concentration for peptide 3 is 12 mg/ mL. The gel did
not exhibit gravitational flow upon turning the vial upside-
down at room temperature (Fig. 8a). We have also tried other
1
0c,d are showing the FE-SEM images of xerogel of peptide 3 and
ZnSO .7H O. The xerogel has polydisperse fibril
4
2
4 2
metal ions. The peptide 3 with ZnSO .7H O (1 equiv.) and
NaOH (1.5 equiv.) formed white opaque gels (Fig. 8b). The
minimum gelation concentration for peptide 3 is 10 mg/ mL.
2 2
Similarly the peptide 3 in presence of Pb(OAc) .3H O (1 equiv.)
and NaOH (1.5 equiv.) formed dirty white opaque gels (Fig. 8c).
The minimum gelation concentration for peptide 3 is 12 mg/
mL. Further peptide 3 was tested with other metal salts such
as Cr, Ni, Hg, cd, Mg, Mn, and Pd sulfates and chloride
complexes but all of them fail to form gel under same
conditions. Fig. 8d shows that the peptide 3 fails to form gel
3
with FeCl .
Fig. 8. (a) The black opaque gel of peptides 3 in presence of CuSO
equiv.) and NaOH (1.5 equiv.). (b) The white opaque gel of peptides 3 in
presence of ZnSO .7H O (1 equiv.) and NaOH (1.5 equiv.). (a) The dirty white
opaque gel of peptides 3 in presence of Pb(OAc) .3H O (1 equiv.) and NaOH (1.5
equiv.). (d) Peptide 3 failed to form gel in presence of FeCl (1 equiv.) and NaOH
1.5 equiv.).
4
.5H
2
O (1
Fig. 10. FESEM images of (a) and (b) xerogel of peptide 3 and CuSO
showing fibrilar network structures; (c) and (d) xerogel of peptide 3 and
ZnSO .7H O showing polydisperse fibrils; (e) and (f) xerogel of peptide 3 and
Pb(OAc) .3H
4 2
.5H O
4
2
4
2
2
2
2
2
O exhibiting highly entangled network morphology. FE-SEM has
done with the dry metallogels (which was prepared in water) of peptide 3 placed
3
(
on glass cover slip.
6
| J. Name., 2012, 00, 1-3
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CrystEngComm
Journal Name
ARTICLE
network structures. The average diameter of the fibrils is 500 nm
and several µm in length. The FE-SEM images of xerogel of peptide
Conflicts of interest
There are no conflicts to declare.
View Article Online
DOI: 10.1039/D0CE01199A
3
2 2
and Pb(OAc) .3H O exhibit highly entangled network morphology
(Fig. 10e,f). The average diameter of the fibrils is 100 nm and
several µm in length.
To understand the microstructure of the metallogels,
transmission electron microscopy (TEM) have performed. The
Acknowledgements
This work was financed by IISER-Kolkata. S. Kumar and S. K.
Nandi acknowledges the CSIR, India for research fellowship.
TEM images of xerogel of peptide 3 and CuSO
polydisperse fibril morphology (Fig. 11a,b). Fig. 11c shows the TEM
image of xerogel of peptide 3 and ZnSO O. The xerogel has
polydisperse fibrilar network structures. The TEM images of xerogel of
O exhibit entangled fibril morphology
4
.5H
2
O
exhibit
.7H
4 2
Notes and references
peptide 3 with Pb(OAc)
2
.3H
2
1
2
3
4
5
6
7
8
9
1
1
1
1
1
T. Shimizu, M. Masuda and H. Minamikawa, Chem. Rev.,
005, 105, 1401–1443.
N. L. Rosi and C. A. Mirkin, Chem. Rev., 2005, 105, 1547–
562.
Y.-b. Lim, K.-S. Moon and M. Lee, Chem. Soc. Rev., 2009, 38,
25–934.
S. Cavalli, F. Albericio and A. Kros, Chem. Soc. Rev., 2010, 39,
41–263.
2
(Fig. 11d).
1
9
2
T. Shimizu, R. Iwaura, M. Masuda, T. Hanada and K. Yase, J.
Am. Chem. Soc., 2001, 123, 5947–5955.
J. T. Davis and G. P. Spada, Chem. Soc. Rev., 2007, 36, 296–
3
13.
I. C. Reynhout, J. J. L. M. Cornelissen and R. J. M. Nolte, Acc.
Chem. Res. 2009, 42, 681–692.
S. S. Babu, V. K. Praveen and A. Ajayaghosh, Chem. Rev.
2
014, 114, 1973-2129.
E. Krieg, M. M. C. Bastings, P. Besenius and B. Rybtchinski,
Chem. Rev., 2016, 116, 2414–2477.
0 X. Du, J. Zhou, J. Shi and B. Xu, Chem. Rev., 2015, 115,
1
3165–13307.
1 S. Hect and I. Huc, Foldamers: Structure, Properties and
Applications, Wiley-VCH, Weinheim, 2007.
2 R. Klajn, J. F. Stoddart and B. A. Grzybowski, Chem. Soc. Rev.,
2
010, 39, 2203–2237.
Fig. 11. TEM images of (a) and (b) xerogel of peptide 3 and CuSO
showing polydisperse fibril morphology; (c) xerogel of peptide 3 and
ZnSO .7H O. showing fibrilar network structures; (d) xerogel of peptide 3
4 2
.5H O
3 A. Ajayaghosh and V. K. Praveen, Acc. Chem. Res., 2007, 40,
644–656.
4
2
2 2
with Pb(OAc) .3H O (1 equiv.) and NaOH (1.5 equiv.) exhibiting entangled
4 A. C. Heras, S. Pennadam, C. Alexander, Chem. Soc. Rev.,
fibril morphology.
2
005, 34, 276–285.
1
1
5 P. M. Mendes, Chem. Soc. Rev., 2008, 37, 2512–2529.
6 S. Yagai and A. Kitamura, Chem. Soc. Rev., 2008, 37, 1520–
1529.
Conclusions
1
7 S. I. Kawano, N. Fujita and S. Shinkai, J. Am. Chem. Soc., 2004,
In conclusion, we have synthesized four dipeptides by varying
1
26, 8592–8593.
steric constraints, which exhibit diverse self-assembly. In solid- 18 (a) M. Reches and E. Gazit, Science 2003, 300, 625−627; (b)
M. Reches, E. Gazit, Isr. J. Chem., 2005, 45, 363-371.
state, the peptide
1
forms anti-parallel dimer and
1
9 A. M. Smith, R. J. Williams, C. Tang, P. Coppo, R. F. Collins,
M. L. Turner, A. Saiani and R.V. Ulijn, Adv. Mater., 2008, 20,
supramolecular sheet-like structure in higher order. But, the
hindered phenylalanine analogue shows a supramolecular
helical structure through intermolecular hydrogen bonds and
3
7-41.
2
0 C. H. Görbitz, Chem. Commun., 2006, 2332-2334.
π-π stacking interactions. The N-phenylglycine containing 21 C. H. Görbitz, CrystEngComm., 2005, 7, 670-673.
2
2
2
2
2
2
2
2 S. K. Maity, S. Maity, P. Jana and D. Haldar, Chem. Commun.,
012, 48, 711-713.
peptide 3 adopts kink-like conformation and forms a
supramolecular 2D matrix stabilized by multiple π-π stacking
interactions. Moreover, The peptide 1 shows flakes-like
morphology. Replacement of Gly by Phe (peptide 2) developed
micro rods. Peptide 3 with N-phenylglycine and L-Phe has
flower-like morphology, and peptide 4 with N-phenylglycine
and L-Tyr has microsphere morphology. Only peptide 3 forms
2
3 S. K. Maity, S. Bera, A. Paikar, A. Pramanik and D. Haldar,
Chem. Commun., 2013, 49, 9051-9053.
4 P. Jana, A. Paikar, S. Bera, S. K. Maity and D. Haldar, Org.
Lett., 2014, 16, 3841.
5 K. Maji, R. Sarkar, S. Bera and D. Haldar, Chem. Commun.,
2
014, 50, 12749-12752.
6 S. Maity, P. Jana, S. K. Maity, P. kumar and D. Haldar, Crystal
Growth and Design, 2012, 12, 422-428.
metallogels selectively with CuSO
4 2 4 2
.5H O, ZnSO .7H O and
Pb(OAc) .3H O. The information obtained may be helpful for
2
2
7 S. Sasmal, K. Maji, David Dìaz Dìaz and D. Haldar,
CrystEngComm., 2019, 21, 4289-4297.
8 D. Podder, S. Sasmal, S. Konar, P. Ghorai and D. Haldar,
Crystal Growth & Design, 2020, 20, 1760-1770.
the engineering of peptidic functional materials.
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2
3
9 (a) M. Toniolo, Biopolymers 1977, 16, 219-224; (b) V.
Moretto, M. Crisma, G. M. Bonora, C. Toniolo, H. Balaram
and P. Balaram, Macromolecules 1989, 22, 2939-2944.
0 Single crystal X-ray analysis of peptides 1-3 were recorded on
a Bruker high resolution X-ray diffractometer instrument.
The structures were solved by a direct method and refined
by least-squares calculations on F2 for all independent
reflections (SHELXL-2014). Crystal Data of peptide 1:
View Article Online
DOI: 10.1039/D0CE01199A
C
5
9
12
H
22
N
2
O
5
,
Mw =274.32,
P 21/c, a = 11.6077(4) Å, b =
.8948(2) Å, c = 23.3133(10) Å, α = 90°, β = 100.550(4)°, γ =
3
3
0°, V = 1568.25(10) Å , Z = 4, T = 293 K, Dcalc = 1.162 g/cm ,
REM Flack = n/a, R1 = 0.0465 and wR2 = 0.1307. Crystal
Data of peptide 2: C19 , Mw =364.43, P 21 21 21, a =
.279(17) Å, b = 11.90(3) Å, c = 20.37(4) Å, α = 90°, β = 90°, γ
28 2 5
H N O
8
=
3
3
90°, V = 2007(8) Å , Z = 4, T = 273 K, Dcalc = 1.206 g/cm ,
REM Flack = -1(3), R1 = 0.0586 and wR2 = 0.1460. Crystal
Data of peptide 3: Mw =312.36, P21, a =
18 20 2 3
C H N O ,
1
1
1
0
0.9817(6) Å, b = 5.3645(3) Å, c = 14.6541(9) Å, α = 90°, β =
3
09.547(6)°, γ = 90°, V = 813.54(9) Å , Z = 2, T = 100 K, Dcalc
=
3
.275 g/cm , REM Flack = 0.1(3), R1 = 0.0374 and wR2 =
.1027.. CCDC 2006561, 2006514 and 2006562 contains the
crystallographic data for the compounds 1, 2 and 3
respectively.
8
| J. Name., 2012, 00, 1-3
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Page 9 of 9
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View Article Online
DOI: 10.1039/D0CE01199A
TOC Graphic
A new dipeptide as selective gelator of Cu(II), Zn(II) and Pb(II)
a
a
a
a
Santosh Kumar, Sujay Kumar Nandi, Saurav Suman and Debasish Haldar*
Metallogelation was observed selectively for CuSO , ZnSO and Pb(OAc) and
4
4
2
dipeptide containing N-phenylglycine and L-Phe, whereas other metals and analogues
dipeptides were failed to form gel.
.