Topology-Controlled Selective Fe3+ Binding in Water by -Peptides with a Dihydropyrimidinone-Containing Amino Acid

with a Dihydropyrimidinone-Containing Amino Acid

Article

Topology-Controlled Selective Fe Binding in Water by δ‑Peptides

Debasish Podder, Supriya Sasmal, Sukanya Konar, Pradip Kumar Ghorai,* and Debasish Haldar*

Cite This: Cryst. Growth Des. 2020, 20, 1760 −1770

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sı Supporting Information

ABSTRACT: The eﬀect of topology on the structure, self-assembly, and selective Fe³⁺binding of δ-peptides has been investigated.

A series of δ-peptides with an amino acid containing dihydropyrimidinone and o-, m-, and p-aminobenzoic acids have been designed

to study the structure−function relationship. A new amino acid containing dihydropyrimidinone was synthesized by the Biginelli

reaction of ethyl acetoacetate, urea, and o-nitrobenzaldehyde followed by reduction with iron powder and acetic acid. X-ray

crystallography sheds some light on the conformations, self-assembly, and the diverse degrees of π−π stacking of adjacent δ-peptide

molecules. Peptides with o- or m-aminobenzoic acid form eight-membered intramolecular hydrogen-bonded turn conformations and

self-assemble through intermolecular hydrogen bonds between dihydropyrimidinone units to form a butterﬂy-like structure.

However, the δ-peptide containing p-aminobenzoic acid forms a water-mediated cage-like structure. Irrespective of the presence of

the same functional groups, only the δ-peptide with o-aminobenzoic acid can selectively bind Fe in methanol as well as in water.

The topology plays a crucial role in the selective Fe ion binding by the δ-peptide.

INTRODUCTION

including various cancers, Alzheimer’s disease, and Parkinson’s

■

21,22

disease.

Hence, the design and synthesis of chemosensors

The development of turn-on or turn-oﬀ ﬂuorescent probes

for the binding of biomolecules and ions under aqueous or

physiological conditions with high sensitivity and selectivity is

with high sensitivity and selectivity for the binding of Fe ions

have undoubtedly become essential requirements for analytical

and therapeutic applications.

23−31

−6

However, most of these Fe

very important for chemistry, biology, and medicine.

ion chemosensors are based on organic dyes or nanoparticles,

Therefore, ﬂuorescent probes have become powerful tools

for quantitative measurements of various analytes because of

their sensitivity, speciﬁcity, and real-time monitoring with fast

response time. Various types of ﬂuorescent probes such as

whereas the chelate eﬀect and peptide-based sensors for Fe

have rarely been reported. Peptide-based chemosensors,

consisting of a natural or synthetic amino acid or peptide

motif, can be considered to be a bioinspired system. These

kinds of bioinspired frameworks incorporating natural and

unnatural amino acids are useful as probes due to their

applications in biotechnology, protein engineering, and

8,9

10,11

organic dyes, foldamers,

carbon nanoparticles,

and

semiconducting quantum dots have been reported for in

vitro and in vivo binding of important biomolecules and ions.

Generally, the recognition and binding can be driven by

various noncovalent interactions, including electrostatic

attraction, hydrogen bonds, π−π stacking, hydrophobic

33−41

targeted molecular imaging.

The design of a peptide-

based sensor is also important and valuable because the

13,14

interaction, and metal−ligand coordination.

Fe partic-

ipates in a great number of essential biochemical processes

inside our body, such as oxygen uptake, metabolism, and

Received: November 6, 2019

Revised: January 23, 2020

Published: January 24, 2020

15−18

electron transfer.

A deﬁciency of Fe may cause the

permanent loss of motor skills. However, an excess of Fe

ions is also harmful. It may cause some severe diseases,

2020 American Chemical Society

Cryst. Growth Des. 2020, 20, 1760−1770

760

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Article

selectivity and sensitivity of the probe can be monitored by

changing the amino acid sequences. Lee and co-workers have

reported a peptide-based sensor bound with a dansyl

ﬂuorophore for extracellular and environmental zinc. Wickz

and co-workers also have developed an alanine-based metal

sensor and explained the role of the amino acid for recognition

peptide 1 exhibits signiﬁcant emission properties in water and

methanol. The topology has a signiﬁcant eﬀect and control of

the structure as well as the properties of the δ-peptides.

EXPERIMENTAL SECTION

■

Materials and Reagents. All of the amino acids and other

chemicals were supplied by Sigma Chemicals. We have purchased

HOBt (1- hydroxybenzotriazole) and DCC (dicyclohexylcarbodii-

mide) from Sisco Research Laboratories (SRL).

of the metal ion. Selective sensing of Cu by a peptide-based

chemosensor was also reported. However, there have been

no reports where the topology of the peptide plays a crucial

role in the chelate eﬀect and selective sensing of metal ions.

The noncovalent interactions between the amino acid side

chains are very important for protein−protein interactions,

protein folding, and protein assembly. Therefore, under-

standing these interactions at the molecular level is crucial.

Hence, the design of a noncoded amino acid with structural

and functional properties has a great outcome, because

synthetic amino acid based peptides are highly important to

understand the protein structure as well as stabilization.

Moreover, the noncoded amino acids, in particular, are known

for their stability toward enzymatic degradation. Gopi and

his group have reported unsaturated amino acid triggered

Synthesis. NO -DHP (4). Urea (0.9 g, 15 mmol), ethyl

acetoacetate (1.3 mL, 10 mmol), 2-nitrobenzaldehyde (1.51 g, 10

mmol), FeCl ·6H O (1.62 g, 6 mmol), and concentrated HCl (2−3

drops) were taken up in a solution of EtOH (40 mL) and reﬂuxed for

h. After 4 h, the reaction mixture was cooled to room temperature

and then poured into 200 g of crushed ice in a beaker. Stirring was

continued for several minutes with a glass rod, and ﬁnally, the solid

products were ﬁltered, washed with ice−water, dried, and recrystal-

lized from hot ethanol. Yield: 40%.

45−47

H NMR (400 MHz, DMSO-d , δ in ppm): 9.38 (s, 1H, NH), 7.91

(d, 1H, J = 8 Hz), 7.75 (t, 1H, J = 7 Hz), 7.7 (1H, s, NH), 7.56 (d,

1H, J = 8 Hz), 7.3 (t, 1H, J = 7 Hz), 5.81 (s, 1H), 3.88−3.80 (m, 2H),

2.27 (s, 3H), 0.92 (t, 3H, J = 7 Hz). C NMR (125 MHz, DMSO-d

δ in ppm): 164.7, 151.2, 149.7, 147.3, 139.4, 134.1, 129.1, 128.7,

folding of polypeptides. Huc and co-workers have developed

aromatic oligomide based foldamers that can bind biomole-

23.9, 98, 59.5, 49, 17.8, 13.4.

NH -DHP (5). To a solution of compound 4 (0.61 g, 2 mmol) in

cules.

acetone (32 mL), 1.6 mL of water, 1.6 mL of acetic acid, and iron

powder (1.34 g, 2.5 mmol) were added. The mixture was heated to

reﬂux, and the reaction was monitored by TLC. After 6 h, the reaction

mixture was cooled and ﬁltered through a pad of Celite. The ﬁltrate

was concentrated under vacuum. The residue was dissolved in ethyl

acetate and neutralized by sodium carbonate solution. The aqueous

phase was extracted with ethyl acetate, and this operation was done

three times. The ethyl acetate extracts were pooled, washed with

brine, dried over anhydrous Na SO , and evaporated under vacuum.

In this regard, we have designed and synthesized a noncoded

δ-amino acid (the amino group is located on the carbon atom

at the position δ to the carboxy group) containing

dihydropyrimidinone. Further, we have designed a series of

dipeptides (δ-peptides) with dihydropyrimidinone-containing

amino acid (δ-amino acid) and o-, m-, and p-aminobenzoic

acids (Scheme 1), with the assumption that the rigid

The product was puriﬁed by silica gel (100−200 mesh) using hexane/

Scheme 1. Topology of δ-Peptides 1−3 with

Dihydropyrimidinone-Containing Amino Acid

ethyl acetate (3/1) as eluent. Yield: 70.5%.

H NMR (500 MHz, DMSO-d , δ in ppm): 9.15 (s, 1H, NH), 7.37

(

1H, s, NH), 6.94 (1H, t, J = 12 Hz), 6.89 (1H, d, J = 8 Hz), 6.66

1H, d, J = 8 Hz), 6.52 (1H, t, J = 9 Hz), 5.30 (1H, d, J = 2 Hz), 4.96

2H, b, NH Proton), 3.95 (2H, q, J = 8 Hz), 2.29 (3H, s), 1.05 (3H,

t, J = 10 Hz). C NMR (125 MHz, DMSO, δ in ppm): 165.54,

52.07, 148.38, 145.21, 127.82, 127.75, 126.70, 116.68, 116.10, 98.69,

9.17, 48.30, 17.80, 13.98.

Boc-OABA-DHP-COOEt (6). 1.422 g (6 mmol) Boc-OABA-COOH

was dissolved in 20 mL of dry DCM under ice−water bath conditions.

.75 g (10 mmol) NH -DHP (5) was then added to the solution

followed by the addition of 1.44 g (7 mmol) of DCC and 0.95 g (7

mmol) of HOBt. Then the reaction mixture was stirred for 48 h at

room temperature. After the completion of the reaction, DCM was

evaporated, and the residue was dissolved in ethyl acetate (60 mL)

and dicyclohexylurea (DCU) was ﬁltered oﬀ. Subsequently, the ethyl

acetate 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),

respectively. The organic layer was dried over anhydrous sodium

sulfate and evaporated under vacuum to yield Boc-OABA-DHP-

COOEt (6) as a solid. The product was puriﬁed by silica gel (100−

dihydropyrimidinone moiety should impart folding and

crystallinity in the compounds and the o-, m-, and p-

aminobenzoic acids may adjust themselves accordingly.

However, to the best of our knowledge, there has been no

report on the synthesis, structural studies, and functions of

dihydropyrimidinone-containing amino acid and the corre-

sponding δ-peptides. Here the o-aminobenzoic acid containing

δ-peptide 1 and m-aminobenzoic acid containing δ-peptide 2

have eight-membered intramolecular N−H···O hydrogen-

bonded turn conformations and self-assemble through

intermolecular hydrogen bonds between dihydropyrimidinone

units to form a butterﬂy-like structure. The p-aminobenzoic

acid containing δ-peptide 3 exhibits a water-mediated cagelike

structure through intermolecular hydrogen bonds. Irrespective

of the presence of the same functional groups, only δ-peptide 1

200 mesh) using hexane/ethyl acetate (3/1) as eluent.

H NMR (500 MHz, DMSO-d , δ in ppm): 10.19 (b, 1H, NH

Proton), 10.10 (b, 1H, NH Proton), 9.30 (b, 1H, NH Proton), 8.19

(d, 1H, J = 10 Hz), 7.90 (d, 1H, J = 10 Hz), 7.56 (t, 1H, J = 12 Hz),

7.41 (d, 1H, J = 10 Hz), 7.34 (d, 1H, J = 5 Hz), 7.31 (t, 2H, J = 10

Hz), 7.21 (t, 1H, J = 10 Hz), 7.14 (s, 1H), 5.43 (d, 1H), 3.85 (q, 2H),

.30 (s, 3H), 1.45 (s, 9H, Boc), 0.96−0.91 (t, 3H).

δ-peptide-1 (1). 1.96 g (4 mmol) Boc-OABA-DHP-COOEt (6)

was dissolved in THF and cooled to 0 °C. Triﬂuoroacetic acid (TFA;

mL) was added to that solution. The progress of the reaction was

monitored by TLC. After 4 h, THF was evaporated under vacuum

and then the residue was dissolved in DCM and a few milliliters of

water was added. Then the pH of the aqueous layer was adjusted to

with o-aminobenzoic acid can selectively bind Fe in methanol

as well as in water. Also, among all the δ-peptides, only δ-

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0 using 1 M Na CO solution. This solution was extracted with

(2H, d, J = 8 Hz), 8.21 (2H, d, J = 5 Hz), 7.88 (1H, t, J = 8 Hz), 7.42

(1H, d, J = 8 Hz), 7.35 (1H, d, J = 8 Hz), 7.31 (2H, t, J = 8 Hz), 5.44

(1H, s), 3.99−3.91 (2H, m), 2.29 (3H, s), 0.95 (3H, t, J = 10 Hz).

DCM (3 × 20 mL). The extracts were pooled, dried over anhydrous

sodium sulfate, and evaporated under vacuum to obtain the

compound. The product was puriﬁed by silica gel (100−200 mesh)

C NMR (125 MHz, DMSO-d , δ in ppm): 165.34, 164.57, 151.35,

using hexane/ethyl acetate (1/1) as eluent. Yield: 62%.

149.31, 149.06, 139.98, 139.77, 133.58, 129.06, 127.81, 127.31,

127.08, 123.77, 98.52, 59.25, 49.41, 17.73, 13.78.

H NMR (500 MHz, DMSO-d , δ in ppm): 9.67 (s, 1H, NH), 9.28

(

s, 1H, NH), 7.69 (1H, d, J = 10 Hz), 7.35 (1H, d, J = 10 Hz), 7.29

S, 1H), 7.17 (1H, t, J = 5 Hz), 7.25 (1H, t, J = 5 Hz), 7.22 (1H, d, J

δ-peptide-3 (3). To a solution of compound 8 (0.42 g, 1 mmol) in

acetone (16 mL), 0.8 mL of water, 0.8 mL of acetic acid, and iron

powder (0.67 g, 1.2 mmol) were added. Then the mixture was heated

to reﬂux. After 6 h, the reaction mixture was cooled and ﬁltered

through a pad of Celite. The ﬁltrate was concentrated in vacuo. The

residue was dissolved in ethyl acetate and neutralized by sodium

carbonate solution. The aqueous phase was extracted with ethyl

acetate, and this operation was done repeatedly. The ethyl acetate

extracts were pooled, washed with water, dried over anhydrous

Na SO , and evaporated under vacuum. The product was puriﬁed by

5 Hz), 7.12 (1H, t, J = 5 Hz), 6.77 (1H, d, J = 8 Hz), 6.61 (1H, t, J

10 Hz), 6.41 (2H, b, NH Proton), 5.39 (1H, d, J = 5 Hz), 3.87

(2H, q, J = 12 Hz), 2.3 (3H, s), 0.95 (3H, t, J = 10 Hz). C NMR

(

125 MHz, DMSO-d , δ in ppm): 168.5, 165.37, 151.39, 150, 148.87,

39.84, 134.13, 132.33, 128.33, 127.62, 127.03, 126.9, 126.72, 116.59,

14.79, 114.22, 98.74, 59.24, 49.40, 17.71, 13.82.

Mnba-DHP-COOEt (7). Dry solid m-nitrobenzoic acid (1.67 g, 10

mmol) and thionyl chloride (3 mL) were mixed and heated at 60 °C

for 2 h. After the reaction SOCl was removed. This freshly prepared

acid chloride was then added to a solution of NH -DHP (5) in dry

silica gel (100−200 mesh) using hexane/ethyl acetate (2/1) as eluent.

Yield : 78%.

DCM and DMF at 0 °C. Then the reaction mixture was stirred at 25

H NMR (400 MHz, DMSO-d , δ in ppm): 9.63 (1H, b, NH

°C for 8 h. Solvents were removed under reduced pressure, and the

Proton), 9.27 (1H, b, NH Proton), 7.71 (2H, d, J = 8 Hz), 7.36 (1H,

d, J = 8 Hz), 7.29 (2H, t, J = 5 Hz), 7.16 (2H, d, J = 8 Hz), 7.25 (1H,

d, J = 4 Hz), 7.21−7.19 (1H, b, NH Proton), 6.62 (2H, d, J = 8 Hz),

residue was dissolved in ethyl acetate (60 mL). 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), dried over anhydrous

sodium sulfate, and evaporated under vacuum to yield compound 7 as

a yellow solid. The product was puriﬁed by silica gel (100−200 mesh)

5.78 (2H, b, Amine NH ), 5.37 (1H, d, J = 8 Hz), 3.90−3.82 (2H,

m), 2.29 (3H, s), 0.95 (3H, t, J = 10 Hz). C NMR (125 MHz,

DMSO-d , δ in ppm): 166.15, 165.48, 152.31, 151.4, 148.76, 139.75,

using n-hexane/ethyl acetate (2/1) as eluent.

134.68, 129.24, 127.56, 126.89, 126.72, 126.39, 120.34, 112.63, 98.89,

59.25, 49.46, 17.75, 13.77.

H NMR (400 MHz, DMSO-d , δ in ppm): 10.32 (1H, b, NH

Proton), 9.30 (1H, b, NH Proton), 8.79 (1H, b, NH Proton), 8.48

NMR Experiments. NMR spectra of all the intermediate and ﬁnal

compounds were recorded with a JEOL 400 MHz or Bruker 500

(

1H, d, J = 8 Hz), 8.43 (d, 1H, J = 8 Hz), 7.88 (1H, t, J = 8 Hz), 7.42

2H, d, J = 8 Hz), 7.35 (1H, d, J = 8 Hz), 7.31 (2H, t, J = 5 Hz), 5.44

MHz NMR spectrometer. We used CDCl

solvent and TMS as an internal standard.

or DMSO-d as the

1H, s), 3.99−3.91(2H, m), 2.29 (3H, s), 0.95 (3H, t, J = 10 Hz)

NMR (125 MHz, DMSO-d , δ in ppm): 165.44, 164.12, 151.43,

FT-IR Spectroscopy. Solid-state FT-IR spectra were measured

with a PerkinElmer Spectrum RX1 spectrophotometer by following

the KBr disk technique.

Mass Spectrometry. Mass spectra of the ﬁnal compounds were

measured on a Waters Corporation Q-Tof Micro YA263 high-

resolution mass spectrometer by electrospray ionization (positive

mode).

Single-Crystal X-ray Diﬀraction Study. Single-crystal X-ray

analysis of δ-peptides 1−3 was recorded on a Bruker high-resolution

X-ray diﬀractometer with Mo Kα radiation. Data were processed

using the Bruker SAINT package, and the structure solution and

re ﬁ nement procedures were performed using SHELX97. CCDC

1898005 , 1898004 , and 1898006 contain the crystallographic data for

compounds 1−3, respectively.

Absorption Spectroscopy. The absorption spectra of peptides

were measured on a PerkinElmer UV/vis spectrometer (Lambda 35)

using a quartz cell having a 1 cm path length.

49.07, 147.87, 139.87, 135.69, 133.98, 133.51, 130.45, 127.88,

27.36, 127.11, 126.40, 122.22, 98.59, 59.31, 49.54, 17.76, 13.80.

δ-peptide-2 (2). To a solution of compound 7 (0.42 g, 1 mmol) in

acetone (16 mL), 0.8 mL of water, 0.8 mL of acetic acid, and iron

powder (0.67 g, 1.2 mmol) were added. Then the mixture was heated

to reﬂux. After 6 h, the reaction mixture was cooled and ﬁltered

through a pad of Celite. The ﬁltrate was concentrated in vacuo. The

residue was dissolved in ethyl acetate and neutralized by sodium

carbonate solution. The aqueous phase was extracted with ethyl

acetate, and this operation was done repeatedly. The ethyl acetate

extracts were pooled, washed with brine, dried over anhydrous

Na SO , and evaporated under vacuum. The product was puriﬁed by

silica gel (100−200 mesh) using hexane/ethyl acetate (2/1) as eluent.

Yield: 70%.

H NMR (400 MHz, DMSO-d , δ in ppm): 9.82 (1H, b, NH

Proton), 9.30 (1H, b, NH Proton), 7.40 (1H, d, J = 8 Hz), 7.29 (1H,

s, NH Proton), 7.24 (2H, t, J = 5 Hz), 7.21(1H, t, J = 10 Hz), 7.16

Fluorescence Spectroscopy. A PerkinElmer ﬂuorescence

spectrometer (LS 55) was used to record the ﬂuorescence spectra

at room temperature. In our measurement, we have used a quartz cell

with 1 cm path length and slit widths 2.5/2.5.

(

2H, d, J = 8 Hz), 7.11 (1H, d, J = 8 Hz), 6.77 (1H, d, J = 8 Hz), 5.41

1H, d, J = 8 Hz), 5.35 (2H, b, Amine NH ), 3.89−3.81 (2H, m),

.29 (3H, s), 0.95 (3H, t, J = 10 Hz). C NMR (125 MHz, DMSO-

d₆, δ in ppm): 167, 165.41, 151.34, 148.91, 148.83, 139.68, 135.25,

34.19, 128.91, 127.61, 126.93, 126.78, 126.70, 116.94, 114.42,

12.89, 98.80, 59.25, 49.34, 17.72, 13.79.

Pnba-DHP-COOEt (8). Dry solid p-nitrobenzoic acid (1.67 g, 10

RESULTS AND DISCUSSION

■

The series of δ-peptides with diﬀerent topologies have been

designed with the assumption that the rigid dihydropyrimidi-

none moiety should impart folding and crystallinity in the

compounds and the o-, m-, and p-aminobenzoic acids may

adjust themselves accordingly (Scheme 1). Moreover, the

strong intermolecular hydrogen bonding and π−π stacking

interactions between dihydropyrimidinone moieties will dictate

the assembly pattern and may selectively sense metal ions.

Thus, here the peptides have been designed and synthesized

from a δ-amino acid and thus they are classiﬁed as δ-peptides.

The dihydropyrimidinone-containing amino acid was synthe-

sized by the Biginelli reaction of ethyl acetoacetate, urea, and o-

nitrobenzaldehyde followed by reduction with iron and acetic

acid in acetone (Scheme 2).

mmol) and thionyl chloride (3 mL) were mixed and heated at 60 °C

for 2 h. After the reaction SOCl was removed. This freshly prepared

acid chloride then added to a solution of 2-NH -DHP (5) in dry

DCM and DMF at 0 °C. Then the reaction mixture was stirred at 25

°C for 8 h. After 8 h, the solvents were removed under reduced

pressure and the residue was dissolved in ethyl acetate (60 mL). 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),

dried over anhydrous sodium sulfate, and evaporated under vacuum

to yield compound 8 as a yellow solid. The product was puriﬁed by

silica gel (100−200 mesh) using n-hexane/ethyl acetate (2/1) as

eluent.

H NMR (400 MHz, DMSO-d , δ in ppm): 10.26 (1H, b, NH

Proton), 9.28 (1H, b, NH Proton), 8.79 (1H, b, NH Proton), 8.40

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Cryst. Growth Des. 2020, 20, 1760−1770

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Scheme 2. Schematic Presentation for the Synthesis of

Dihydropyrimidinone-Containing Amino Acid by the

Biginelli Reaction

Reagents and conditions: (a) anhydrous FeCl , HCl, EtOH, 4 h

reﬂux, 40%; (b) Fe, AcOH, acetone/H O, 6 h reﬂux, 70.5%.

δ-Peptide 1 was synthesized by the coupling reaction

between Boc-protected o-aminobenzoic acid with the methyl

ester of dihydropyrimidinone-containing amino acid followed

by Boc deprotection with TFA (Scheme 3). The target δ-

peptides 2 and 3 were synthesized by coupling m-/p-

nitrobenzoic acids with the methyl ester of dihydropyrimidi-

none-containing amino acid (Scheme 3) followed by reduction

with iron and acetic acid in acetone. The ﬁnal compounds have

Figure 1. Solid-state FT-IR spectra of δ-peptides 1−3.

−

appeared at 1682 and 1630 cm , respectively. However, the δ-

peptides 2 and 3 exhibit ester and amide peaks at 1690 and

been puriﬁed and characterized by H NMR, C NMR, FT-

IR, and mass spectrometry analysis.

−

−1

1645 cm and 1700 and 1664 cm , respectively. We

conclude that δ-peptides 1 and 2 have similar kinds of

conformations.

Structure Analysis. Initially, solid-state FT-IR spectrosco-

py was used to investigate the molecular conformation and

self-assembly of the isomeric peptides. In FT-IR, the region

Single-crystal X-ray analysis sheds some light on the solid-

state conformation and noncovalent interaction directed self-

assembly pattern of the δ-peptides. Crystals of δ-peptides 1−3

suitable for X-ray crystallography were obtained from a

methanol−water solution by slow evaporation. The asym-

metric unit of δ-peptide 1 contains only one molecule (Figure

2a). The δ-peptide 1 adopts a robust hairpin-like conforma-

tion. The hairpin-like conformation is stabilized by six-

membered and eight-membered bifurcated CO···HN intra-

−

500−3200 cm is responsible for the N−H stretching

−1

vibrations and 1800−1600 cm corresponds to the CO

stretching vibration of the amide and ester groups. The FT-

IR spectra (Figure 1) of compounds 1−3 exhibit N−H

−

stretching frequencies at 3472, 3468, and 3468 cm ,

respectively, responsible for non-hydrogen-bonded N−H

stretching. A band at 3326 cm⁻appeared for hydrogen-

bonded N−H. For δ-peptide 1, the ester and amide peaks

Scheme 3. Schematic Presentation of the Synthesis of δ-Peptides 1−3

Reagents and conditions: (a) Boc-o-aminobenzoic acid, DCC, dry DCM, 0 °C, 48 h, 78%; (b) TFA, THF, 4 h, 62%; (c) m-nitrobenzoic acid,

SOCl , dry DCM/DMF, 0 °C, 8 h, 72%; (d) Fe, AcOH, acetone/H O, 6 h reﬂux, 70%; (e) p-nitrobenzoic acid, SOCl , dry DCM/DMF, 0 °C, 8 h,

8%; (f) Fe, AcOH, acetone/H O, 6 h reﬂux, 78%.

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Cryst. Growth Des. 2020, 20, 1760−1770

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Figure 2. (a) Solid-state structure of δ-peptide 1 showing a bifurcated hydrogen-bonded hairpin-like conformation. Intramolecular hydrogen bonds

are shown as dotted lines. (b) The supramolecular butterﬂy-like structure of δ-peptide 1 stabilized by intermolecular hydrogen-bonding and π−π

stacking interactions.

Figure 3. (a) The crystal structure of δ-peptide 2 showing a hydrogen-bonded S-like structure. (b) The higher-order packing of compound 2

showing a supramolecular butterﬂy-like structure stabilized by intermolecular hydrogen-bonding and π−π stacking interactions. Hydrogen bonds

are shown as dotted lines.

molecular hydrogen bonds (Figure 2a). Two aromatic rings

connected by the peptide bond are perpendicular to each

other. In higher-order packing the δ-peptide 1 forms a

butterﬂy-like supramolecular structure (Figure 2b) through

multiple intermolecular CO···HN hydrogen bonds. The

butterﬂy-like supramolecular structure is also stabilized by face

to edge π−π stacking interactions between o-aminobenzoic

acid and dihydropyrimidinone moieties (shortest C to centroid

distance 3.69 Å) (Figure S1). The hydrogen-bonding

parameters of δ-peptide 1 are given in Table S1.

The δ-peptide 2 containing m-aminobenzoic acid crystallizes

with one molecule in the asymmetric unit. From the solid-state

structure, the δ-peptide 2 adopts an S-like conformation. The

S-like conformation is stabilized by an eight-membered C

O···HN intramolecular hydrogen bond (Figure 3a). The

torsion angles around the dihydropyrimidinone play a crucial

role in dictating the overall S-shaped structure. The δ-peptide

2 self-assembles through intermolecular CO···H−N hydro-

gen bonds to form a supramolecular butterﬂy-like structure

(Figure 3b). The supramolecular butterﬂy-like structure is also

stabilized by face to edge π−π stacking interactions between

m-aminobenzoic acid and dihydropyrimidinone moieties (C to

centroid distance 3.68 Å) (Figure S2). The hydrogen-bonding

parameters of δ-peptide 2 are given in Table S1.

The p-aminobenzoic acid containing δ-peptide 3 crystallizes

with one molecule of water along with a peptide molecule in

the asymmetric unit. The δ-peptide 3 adopts a hairpin-like

conformation stabilized by an eight-membered CO···H−N

764

Cryst. Growth Des. 2020, 20, 1760−1770

Crystal Growth & Design

molecule is hydrogen-bonded with C O of p -aminobenzoic

Article

intramolecular hydrogen bond (Figure 4a). The water

However, for δ-peptide 1 there is an emission maximum at

424 nm in methanol that is independent of the excitation

wavelength (285 or 339 nm). The δ-peptides 2 and 3 show

emission maxima at 445 and 364 nm, respectively, upon

excitation at 290 nm, but for both the peptide emission

intensity is 6-fold lower in comparison to δ-peptide 1 at a

particular concentration. This is due to one more intra-

molecular H-bond (Figure 2) in δ-peptide 1 which makes the

δ-peptide 1 more rigid, restricts the intramolecular rotation

and thus increases the emission intensity of δ-peptide 1 in

comparison to other δ-peptides. Hence, the topology has a

signiﬁcant eﬀect on the function of the δ-peptides. Then we

also studied the concentration-dependent emission spectra for

all of the δ-peptides in methanol. For δ-peptide 1 and δ-

peptide 2, the intensity increases with increasing concen-

tration, but for δ-peptide 3 the emission intensity decreases

with increasing concentration without any shifting of the peak

position (Figure 7).

Finally, we have investigated the binding ability of the

peptides toward various metal ions such as Ag , Cd , Co ,

Cu , Fe , Ni , Hg , K , Mg , Na , Pb , and Zn in

solution by absorption and emission spectroscopic techniques.

As it is close to biological systems, binding metal ions in

aqueous solution has a huge advantage. Hence, we have used

water as the working solvent. However, the peptides discussed

here are sparingly soluble in water. Therefore, we prepared the

stock solutions of peptides in methanol and performed binding

experiments in water.

Figure 4. (a) The δ-peptide 3 showing a hydrogen-bonded hairpin-

like structure in the solid state. (b) The water-mediated supra-

molecular cage of δ-peptide 3. (c) The higher-order packing of the

cage-like structures stabilized by intermolecular hydrogen-bonding

interactions.

Initially, emission spectra of all the peptides in water

solution were recorded by dissolving 40 μL of methanol

−

solutions of all the peptides (10 M) in 2.5 mL of water

−

(

overall concentration 1.6 × 10 M). In the water/methanol

62.5/1) solution, the ﬂuorescence intensity for all the

peptides decreases in comparison to that in only methanol

solution alone and shifted to a higher wavelength region

(Figure 8) because the δ-peptides have low solubility in water

in comparison to that in methanol and thus their overall

emission intensity decreases in comparison to the emission

intensity in methanol. Here we have also increased the solvent

polarity (methanol to water), and thus the ﬂuorescence

intensity maxima (Figure 8) shifted to a higher wavelength

region (low energy) in the case of water. δ-Peptide 1 exhibits

decent emission intensity but the emission intensities for δ-

peptide 2 and δ-peptide 3 almost disappear in water at the

same concentration. We have recorded solid-state emission for

all of the δ-peptides (Figure S3 ). Solid-state emission spectra

show that only δ-peptide 1 has a signiﬁcant emission intensity,

which supports our initial results.

acid. Surprisingly, amine NHs are free. Two molecules of δ-

peptide 3 self-assembled to form a cage-like structure through

water-mediated hydrogen bonds (Figure 4b). However, in

higher-order packing the cage-like structure further self-

assembled to form a sheet-like structure (Figure 4c) along

the crystallographic a direction. There are no π−π stacking

interactions. Hydrogen-bonding parameters of δ-peptide 3 are

given in Table S1.

To understand the topological eﬀect and compare various

intermolecular interactions in the δ-peptides, we have

examined the Hirshfeld surfaces (HSs) and their correspond-

ing 2D ﬁngerprint plots (FPs) using the Crystal Explorer

software. HS maps of the δ-peptides exhibited a red region

which refers to the intermolecular H-bonding interactions

Therefore, metal ion binding properties of δ-peptide 1 were

investigated in water. For a preliminary experiment, 10 equiv

amounts of all the above metal ions were added to a water−

methanol solutions of δ-peptide 1. Only upon addition of 10

(

Figure 5a,c,e). However, the 2D ﬁngerprint plot (a visual

summary of the frequency of each combination of d and d

across peptide 1−3 surfaces) shows that the π···π interactions

present in peptides 1 and 2 (highlighted in color in Figure

equiv of Fe , the ﬂuorescence intensity of δ-peptide 1

decreases rapidly (Figure 9). However, none of the other metal

ions showed any signiﬁcant changes in the ﬂuorescent intensity

of δ-peptide 1 (Figures 9 and 10).

b,d,f) are very close.

Solution-State Study. We have recorded absorption and

emission spectra for the δ-peptides 1−3 to understand the

eﬀect of topology on their structure and self-assembly. The

absorption spectra show that the δ-peptide 1 has absorption

bands at 285 and 339 nm in methanol, whereas the δ-peptides

To further investigate the interaction between δ-peptide 1

and Fe in water, we have performed a ﬂuorescence titration

by varying the concentration of Fe (Figure 11). With the

and 3 both have an absorption band only at 290 nm.

gradual addition of Fe , the ﬂuorescence peak intensity at 445

nm for peptide 1 decreases signiﬁcantly: that is, ﬂuorescence

quenching occurs. This ﬂuorescence quenching can be

explained due to the energy transfer from the photoexcited

However, with increasing concentration, the absorption

intensity increases gradually without any shifting for all of

the peptides (Figure 6).

765

Cryst. Growth Des. 2020, 20, 1760−1770

sites. 2D ﬁ ngerprint plots of (b) δ -peptide 1 , (d) δ -peptide 2 , and (f) δ -peptide 3 .

Article

Figure 5. Hirshfeld surface maps of (a) δ-peptide 1, (c) δ-peptide 2, and (e) δ-peptide 3. The red region refers to the intermolecular H-bonding

Figure 6. Concentration-dependent absorption spectra of (a) δ-peptide 1, (b) δ-peptide 2, and (c) δ-peptide 3.

state (π*) of the ﬂuorophore to the low-energy empty or

Stern−Volmer binding constant (K ) was 6.53 × 10 from the

,53

partially ﬁlled d orbitals of the metal ion.

We have explained the ﬂuorescence quenching by using the

slope of the curve (Figure 12a). We have created a Job plot

to determine the binding stoichiometry of the metal and ligand

on the basis of ﬂuorescence spectroscopy. Figure 12b indicates

that there is a 1:1 binding between Fe³⁺and δ-peptide 1.

Stern−Volmer equation. The linearity of the Stern−Volmer

plot indicates a single mechanism for the quenching process

(

either static or dynamic). We have also calculated that the

766

Cryst. Growth Des. 2020, 20, 1760−1770

Figure 7. Concentration-dependent emission spectra of (a) δ -peptide 1 , (b) δ -peptide 2 , and (c) δ -peptide 3 .

Article

Figure 8. (a) Emission spectra of all the δ -peptides in water. (b) Bar diagram showing emission intensities for δ-peptides in water.

function, abbreviated as B3LYP. We have used the 6-

11G(d,p) basis set in all cases with the conductor-like

polarizable continuum model (PCM) for the solvent, as

implemented in Gaussian 09. All of the structures were

optimized to their minimum energy states without any

symmetry constraint and conﬁrmed by the harmonic vibra-

tional frequency having no imaginary node. The convergence

thresholds for energy optimization were set to 0.000015

hartree/Bohr for the forces, 0.00006 Å for the displacement,

and 106 hartree for the energy change. Though the diﬀerences

between the LUMO of Fe and the HOMO of δ-peptides 1−

are nearly comparable (Figure 13), the optimized structures

of δ-peptides 2 and 3 suggest that, due to topological eﬀects, δ-

peptides 2 and 3 cannot form a complex with Fe (Figure 13).

The amine functional group is far from and on the opposite

side of the location where Fe binds with peptide 1. Hence,

instead of the electronic properties of the peptides, the

topology of δ-peptide 1 plays a crucial role in the selective Fe

Figure 9. Emission spectra of δ-peptide 1 in the presence of 10 equiv

of diﬀerent metal ions.

ion binding by the peptide (Figure 13). Therefore, the energy

gap between the HOMO and LUMO for δ-peptide 1 is higher

in comparison to that for to δ-peptide 1−Fe , which indicates

that the δ-peptide 1−Fe complex is energetically more stable

in comparison to δ-peptide 1 itself (Figure 13).

Theoretical Study. We have performed density functional

theory (DFT) calculations using the Gaussian 09 package to

gain a microscopic understanding of selective Fe³binding by

δ-peptide 1. All of the calculations were performed with an

unrestricted Becke three-parameter hybrid exchange func-

CONCLUSION

■

In conclusion, we have demonstrated that, depending upon the

topology, a δ-peptide can selectively bind Fe in water. First,

tional combined with a Lee−Yang−Parr nonlocal correlation

767

Cryst. Growth Des. 2020, 20, 1760−1770

Figure 10. Bar diagram showing relative emission intensity changes for δ-peptide 1 in the presence of di ﬀ erent metal ions.

Article

Figure 13. HOMO and LUMO energy diﬀerences of Fe , δ-peptides

−3, and the δ-peptide 1−Fe complex.

we have synthesized a new noncoded amino acid containing a

dihydropyrimidinone moiety by the Biginelli reaction. Then a

series of δ-peptides were synthesized from dihydropyrimidi-

none-containing amino acid and o-, m-, and p-aminobenzoic

acids. X-ray crystallography sheds some light on the

conformations, self-assembly, and diverse degrees of π−π

stacking of adjacent δ-peptide molecules. Irrespective of the

presence of the same functional groups, only the δ -peptide

Figure 11. Emission spectra of δ-peptide 1 in the presence of various

concentrations of Fe in aqueous solution.

Figure 12. (a) Binding constant of δ-peptide 1 and Fe³⁺ion in water. (b) Job plot of the ﬂuorescence intensity of δ-peptide 1 and Fe³⁺.

768

Cryst. Growth Des. 2020, 20, 1760−1770

Crystal Growth & Design

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ASSOCIATED CONTENT

sı Supporting Information

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CCDC 1898004 −1898006 contain the supplementary crys-

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free of charge via www.ccdc.cam.ac.uk/data_request/cif , or by

emailing data_request@ccdc.cam.ac.uk , or by contacting The

Cambridge Crystallographic Data Centre, 12 Union Road,

Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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AUTHOR INFORMATION

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Pradip Kumar Ghorai − Department of Chemical Sciences,

Indian Institute of Science Education and Research Kolkata,

Mohanpur 741246, West Bengal, India;

Email: pradip.ghorai@gmail.com

Debasish Haldar − Department of Chemical Sciences, Indian

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41246, West Bengal, India; orcid.org/0000-0002-7983-

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272 ; Email: deba_h76@yahoo.com , deba_h76@

iiserkol.ac.in

(

Authors

Debasish Podder − Department of Chemical Sciences, Indian

Institute of Science Education and Research Kolkata,

Mohanpur 741246, West Bengal, India

Supriya Sasmal − Department of Chemical Sciences, Indian

Institute of Science Education and Research Kolkata,

Mohanpur 741246, West Bengal, India

Sukanya Konar − Department of Chemical Sciences, Indian

Institute of Science Education and Research Kolkata,

Mohanpur 741246, West Bengal, India

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Complete contact information is available at:

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The authors declare no competing ﬁnancial interest.

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ACKNOWLEDGMENTS

■

The authors acknowledge IISER Kolkata, India, for ﬁnancial

assistance. D.P. acknowledges the CSIR, India, for a research

fellowship. S.S. and S.K. acknowledge the IISER-K, India, for

fellowships.

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