Thermally Induced Self-Assembly and Cyclization of l -Leucyl- l -Leucine in Solid State

Article abstract of DOI:10.1021/acs.jpcb.7b06759

Thermal treatment of oligopeptides is one of the methods for synthesis of organic nanostructures. However, heating may lead not only to self-assembly of the initial molecules, but also to chemical reactions resulting in the formation of new unexpected nan

Full text of DOI:10.1021/acs.jpcb.7b06759

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Article
Thermally Induced Self-Assembly and
L
L
Cyclization of -Leucyl--Leucine in Solid State
Marat A. Ziganshin, Aisylu S. Safiullina, Alexander Vladimirovich Gerasimov, Sufia A.
Ziganshina, Alexander E. Klimovitskii, Khasan R. Khayarov, and Valery V. Gorbatchuk
J. Phys. Chem. B, Just Accepted Manuscript • DOI: 10.1021/acs.jpcb.7b06759 • Publication Date (Web): 18 Aug 2017
Downloaded from http://pubs.acs.org on August 24, 2017
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Thermally Induced SelfꢀAssembly and Cyclization
of LꢀLeucylꢀLꢀLeucine in Solid State
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Marat A. Ziganshin,*,† Aisylu S. Safiullina,† Alexander V. Gerasimov,† Sufia A. Ziganshina,‡
Alexander E. Klimovitskii,† Khasan R. Khayarov,† and Valery V. Gorbatchuk,†
† A.M. Butlerov Institute of Chemistry, Kazan Federal University, Kremlevskaya ul. 18, Kazan,
420008 Russia
‡ Kazan Zavoisky PhysicalꢀTechnical Institute of the Kazan Scientific Center of the Russian
Academy of Sciences, Sibirskii trakt 10/7, Kazan, 420029 Russia
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ABSTRACT: Thermal treatment of oligopeptides is one of the methods for synthesis of organic
nanostructures. However, heating may lead not only to selfꢀassembly of the initial molecules, but
also to chemical reactions resulting in the formation of new unexpected nanostructures or change
in the properties of the existing ones. In the present work, the reaction of cyclization of dipeptide
LꢀleucylꢀLꢀleucine in solid state under heating was studied. The change in morphology of
dipeptide thin film and formation of nanostructures after heating was visualized using atomic
force microscopy. This method also was used for demonstration of differences in selfꢀassembly
of linear and cyclic dipeptides. The chemical structure of reaction product was characterized by
NMR spectrometry, FTIR spectroscopy and GCꢀMS analysis. Kinetic parameters of cyclization
were estimated within the approaches of the nonꢀisothermal kinetics (“modelꢀfree” kinetics and
linear regression methods for detection of topochemical equation). The results of present work
are useful for explanation the changes in the properties of nanostructures based on shortꢀchain
oligopeptides, notably leucylꢀleucine, after thermal treatment, as well as for the synthesis of
cyclic oligopeptides.
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INTRODUCTION
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Shortꢀchain oligopeptides are popular objects for study at the present time, because of their
potential advantages for various technologies.1ꢀ3 They are used as supramolecular hosts4ꢀ6 and
microporous materials, which capable to selectively separate gas mixtures7ꢀ9 and effectively bind
organic molecules.10,11 But the main reason for the increased interest in oligopeptides (mainly
dipeptides) is their ability to selfꢀassembly12,13 with the formation of various nanostructures
depending on the conditions.14ꢀ18 Being biocompatible and environmentꢀfriendly oligopeptideꢀ
based materials are often considered as good alternatives to inorganic nanomaterials.19ꢀ21
There are several ways for preparation of oligopeptide nanostructures. The most common are
the crystallization of oligopeptides from various solvents,22,23 treatment of initially amorphous
film with vapors at room temperature,24,25 and thermal treatment, such as sublimation of
oligopeptide powder in vacuum26 or in inert gas atmosphere,27 or heating of oligopeptide film
with different vapors.28 When using the heating method, one should take into account the
possibility of chemical reaction in the oligopeptide phase and formation of new chemical
compounds, for example, cyclic products.29,30 As the result the formation of new type of
nanostructures14,26 or change in the properties of already existing nanostructures were observed.31
For example, heating the leucylꢀleucine based nanotubes to 180 °C leads to their transformation
into wirelike fibrils and loss of nonlinear optical and piezoelectric properties, but the visible
(blue and green) photoluminescence appears.32,33
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Cyclization of dipeptides can occur both in solution,34ꢀ36 and in the solid phase,29,37 during the
sublimation of powder,27 even under impact of electron beam radiation in SEM experiments.30
Cyclic dipeptides can form under heat treatment of protein foods, which leads to change in their
taste,38 or as side products in the synthesis of oligopeptides.39,40 However, researchers do not
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always consider the possibility of dipeptides cyclization in solid state, and explain the change in
the properties of materials only as the result of phase transition under heating.
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The cyclic oligopeptides are also the attractive objects of independent research41, due to its
advantages in comparison with the linear oligopeptides.42 They are biologically active and can be
used in medicine,35,43,44 some of them show the catalytic activity.45,46 Cyclic oligopeptides are
used for preparation of organoꢀ and hydrogels,47,48 which can be useful for design of drug
delivery systems and thermoresponsive smart materials.49
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Thus, the study of the cyclization of shortꢀchain oligopeptides induced by heating is of interest
for the preparation of new useful compounds and organic nanostructures, and also for
explanation of changes in the properties of peptide materials after the thermal treatment.
The present work is the first study of LꢀleucylꢀLꢀleucine (LeuꢀLeu) cyclization in the solid state
under heating. This reaction was studied using thermogravimetric analysis with simultaneous
differential scanning calorimetry and massꢀspectrometric detection of evolved vapors at different
heating rates. The kinetic parameters of the reaction were calculated. The structure of formed
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cyclo(LeuꢀLeu) was characterized by 1H and C NMR spectroscopy, Fourierꢀtransform infrared
spectroscopy, GCꢀMS analysis. The selfꢀassembly of LeuꢀLeu and cyclo(LeuꢀLeu) from
hexafluoroꢀ2ꢀpropanol as well as effect of thermal treatment on morphology of initial film of
LeuꢀLeu were studied by atomic force microscopy.
EXPERIMENTAL
Materials. Dipeptide ꢀleucylꢀLꢀleucine (LeuꢀLeu) (Bachem) and hexafluoroꢀ2ꢀpropanol
L
(Acros Organics #14754) were used without additional purification.
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Thermoanalysis by Simultaneous TG/DSC/MS/. Simultaneous thermogravimetry (TG) and
differential scanning calorimetry (DSC) analysis of dipeptide powder with mass spectrometric
(MS) evolved gas analysis were performed using thermoanalyzer STA 449 C Jupiter (Netzsch)
coupled with quadrupolar massꢀspectrometer QMS 403C Aeolos (Netzsch) as described
elsewhere.50,51 For experiments, 4 mg samples of dipeptide were placed in aluminium crucibles
(40 ꢁl) with lids having 3 holes, each of 0.5 mm in diameter.
Kinetic Analysis of Cyclization of Leu-Leu. According to ICTAC recommendations, it is
necessary to use at least two different kinetic computational methods.52,53 The “modelꢀfree”
methods for kinetic computations: ASTM E698, OzawaꢀFlynnꢀWall, and Friedman54ꢀ58 were
used. The same set of experimental data was used further for searching the topochemical
equation as described in.29,59 The data for kinetic analysis were obtained from TG data, measured
at different heating rates: 2 K minꢀ1, 5 K minꢀ1, 10 K minꢀ1, 15 K minꢀ1. Calculations were
performed using NETZSCH Thermokinetics 3.1.
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1H and C NMR Spectroscopy. The NMR spectra were recorded on Bruker Avance III 400
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spectrometer. H NMR (400 MHz, DMSOꢀd6, 25 °C). C {1H} NMR (100.6 MHz, DMSOꢀd6,
25 °C).
Fourier-Transform Infrared (FTIR) Spectroscopy. FTIR spectra were collected using
Bruker Vertex 70 FTIR spectrometer with a single reflection, germanium crystal ATR accessory
(MIRacle, PIKE Technologies) with resolution of 2 cm−1 in dry air. All data were collected at 25
°C.
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Atomic Force Microscopy (AFM). AFM images were recorded using the atomic force
microscope Titanium (NTꢀMDT, Russia). Measurements were performed on air using a tapping
mode. Revolution cartridge of cantilevers CNG (NTꢀMDT, Russia) was used. For AFM
experiments, dipeptide films with diameter of 3 mm were prepared from hexafluoroꢀ2ꢀpropanol
solution (2 mg mLꢀ1) on the surfaces of highly oriented pyrolytic graphite (HOPG) plates (1×1
cm) as described in.60 HOPG was freshly cleaved before use. All images were obtained at 298 K.
Gas Chromatography (GC) Mass Spectrometry (MS). GCꢀMS system including a gas
chromatograph ChromatecꢀCrystal 5000 (Russia) with capillary column 30 m, 0.25 mm i.d. and
mass spectrometry detector ISQ (Thermo Fisher Scientific) was used. Data were collected in the
0ꢀ600 m/z range at the following conditions: carrier gas was helium (velocity 1 mL minꢀ1), the
injection port was maintained at 310 °C, temperature programs: from 100 °C to 150 °C at 12 °C
minꢀ1, from 150 °C to 300 °C at 3 °C minꢀ1, electron ionization 70eV. The solution of dipeptide
in hexafluoroꢀ2ꢀpropanol (1 mg mLꢀ1) was used.
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RESULTS AND DISCUSSION
Chemical Structure of Product of Thermal Treatment of Leu-Leu Powder. Earlier, we
found the two steps on the TG curve associated with water loss under heating of LeuꢀLeu
powder.11 The first step of weight loss at 124 °C is the result of desorption of bound water.
Heating of the LeuꢀLeu powder above 177 °C leads to appear the second step of mass loss on the
TG curve which corresponds to evolve of 1 mol H2O per mol dipeptide. This process is
accompanied by an irreversible change in the packing of the dipeptide.11 We proposed that the
result of second step is formation of cyclic product cyclo(LeuꢀLeu) in accordance with scheme of
reaction (Figure 1).
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Figure 1. Scheme of the reaction of cyclization of LeuꢀLeu in the solid state.
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1
To establish the chemical structure of the reaction product the H and 13C {1H} NMR
spectrometry (Figure 2) and FTIR spectroscopy (Figure 3) were used. To this end, the LeuꢀLeu
powder was heated up to 200 °C and NMR spectra were recorded for a solution of the reaction
product in DMSOꢀd6 (5 mg/mL).
1
Obtained data of NMR spectrometry (Figure 2) H (δ = 0.86 (d, J = 6.5 Hz, 6H), 0.89 (d, J =
6.5 Hz, 6H), 1.42ꢀ1.49 (m, 2H), 1.55ꢀ1.62 (m, 2H), 1.76ꢀ1.84 (m, 2H), 3.70ꢀ3.74 (m, 2H), 8.22
(s, 2H)) and C {1H} (δ = 22.2, 23.5, 24.1, 44.1, 53.2, 168.9) are in good correlation with the
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data for (3S,6S)ꢀ3,6ꢀdiisobutylpiperazineꢀ2,5ꢀdione (cyclo(LeuꢀLeu) synthesized in.42,61
Data of FTIR spectroscopy obtained for the powders of initial LeuꢀLeu, LeuꢀLeu after heating
up to 140 °C and dipeptide powder after heating up 200 °C are presented in Figure 3.
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Figure 2. (a) 1H NMR spectrum (400 MHz, DMSOꢀd6) and (b) 13C {1H} NMR spectrum (100.6
MHz, DMSOꢀd6) of cyclo(LeuꢀLeu).
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Figure 3. IR spectra at room temperature of powders of (a) initial LeuꢀLeu, (b) LeuꢀLeu after
heating up to 145 °C and (c) LeuꢀLeu after heating up to 200 °C. The part of the spectrum in the
range 2600ꢀ3700 cmꢀ1 is shown in the inset.
The broad absorption band in FTIR spectra of initial powder LeuꢀLeu with a maximum at 3560
cmꢀ1 is caused by the presence of water in dipeptide (Figure 3a). In the spectrum of the sample
after heating up to 145 °C this band disappears (Figure 3b). The Red shift of NꢀH stretch band
from 3347 cmꢀ1, Figure 3a, to 3196 cmꢀ1 (Figure 3b) with simultaneous broadening after heating
up to 145 °C may indicates the formation of additional Hꢀbonds with the participation of the
amide NꢀH group. For example, this group does not form Hꢀbonds with >C=O group in clathrate
with water,62 but associated with carbonyl group of other dipeptide molecule in clathrates with
alcohols.63
Analysis of the IR spectra obtained indicates a significant distinction of LeuꢀLeu heated to 200
°C compared to the other two studied samples. A more symmetric cyclic structure (Figure 1) of
product heated up to 200 °C is in good agreement with the decrease in the number of absorption
bands in the FTIR spectrum (Figure 3c) as compared to the spectrum of initial dipeptide (Figure
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3a). The spectra of the initial dipeptide and sample heated up to 140 °C have absorption bands in
the range 1500ꢀ1600 cmꢀ1, which correspond to the carboxyl and ammonium groups, as well as
to the Amide II bands. The band at 1574 cmꢀ1 (Figure 3a) is characteristic of a carboxylate anion
(–COOꢀ)64. In the spectrum of cyclo(LeuꢀLeu) these bands are absent (Figure 3c). In the spectra
of 2,5ꢀdiketopiperazines the Amide II region corresponding to deformation vibrations of N–H
groups and stretching vibrations of the amide carbonyl groups are also absent.65 A relatively
intense absorption band at 1456 cmꢀ1 observed in the spectrum of the sample heated up to 200 °C
apparently is due to degenerate vibrations of alkyl groups because of symmetrical structure of
this molecule. The shoulder at 1483 cmꢀ1 may be related to inꢀplane bend of N–H group in the
cycle.66 A sharp peak at 1668 cmꢀ1 (Amide I region) is corresponding to the amide carbonyl
>C=O stretching frequency, which relates to a βꢀturn conformation (Figure 3c). The N–H outꢀ
plane bending appears at 850 cmꢀ1 (Figure 3c).67 The bands at 3057 and 3196 cmꢀ1 apparently
correspond to two NꢀH groups (in cisꢀconfiguration) which form Hꢀbonds with the carbonyl
groups of other molecules of cyclo(LeuꢀLeu).67 The shoulder at 3091 cmꢀ1 may be assign to the
combination band of the C=O stretching and NꢀH inꢀplane vibrations of the cis CONH group.67
According to data of GCꢀMS the powder of LeuꢀLeu heated up to 200 °C contains one
component (Figure 4a) for which the mass spectrum (Figure 4b) is in a good agreement with the
MS data for 3,6ꢀdiisobutylpiperazineꢀ2,5ꢀdione68.
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Figure 4. GCꢀMS of thermally induced powder of LeuꢀLeu up to 200 °C. (a) Data of GC, (b)
data of MS.
So, analysis of NMR, IR and GCꢀMS data proves the formation of cyclo(LeuꢀLeu) after
heating of initial dipeptide powder up to 200 °C.
Kinetic Analysis of Cyclization of Leu-Leu. A kinetic analysis of cyclization of LeuꢀLeu in
the solid state was carried out for second step of mass lose, (Figure 5). The data for kinetic
analysis were obtained from TG curves (Figure 5a) measured at different heating rates: 2, 5, 10
and 15 K minꢀ1.
Figure 5. Data of (a) TG and (b) DSC analysis for LeuꢀLeu at different heating rates.
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Calculations of activation energies were made for selected temperature intervals: from 160.4 to
183.3 °C for heating rate of 2 K minꢀ1, from 163.7 to 186.9 °C for heating rate of 5 K minꢀ1, from
167.0 to 190.2 °C for heating rate of 10 K minꢀ1 and from 169.3 to 194.6 °C for heating rate of
15 K minꢀ1.
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According to ASTM E698 analysis, the value of activation energy is Ea = 502 ± 11 kJ molꢀ1
and logarithm of Arrhenius constant is lgA = 56.4. The Friedman analysis of reaction of LeuꢀLeu
cyclization is shown in Figure 6. The obtained data indicate a complex character of the process
studied. The higher slope of the experimental data compared with the isoꢀconversion lines at the
beginning of the reaction indicates the autocatalytic process (Figure 6a). One can assume that the
catalyst can be cyclo(LeuꢀLeu), for which the ability to catalyze the reaction of epoxidation was
shown earlier.46 According to Friedman method (Figure 6b) the value of activation energy is Ea =
519.5 ± 13.2 kJ molꢀ1 and logarithm of Arrhenius constant is lgA = 58.4, whereas Ozawa–Flynn–
Wall method gives Ea = 425.1 ± 23.3 kJ molꢀ1 and lgA = 47.2. Data were obtained at conversion
degree 0.2.
Figure 6. Friedman analysis of reaction of cyclization of LeuꢀLeu: (a) correlation of logarithm of
conversion rate versus reciprocal temperature and (b) activation energies Ea versus degree of
conversion α. Perpendicular lines show SD of calculation.
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In accordance with F test, the best topochemical equation for the cyclization is CnB, which is
used to describe the nthꢀorder reaction with autocatalysis. The kinetic parameters calculated by
using this model, as well as statistical quality parameters, are given in Table 1. Also, the data for
the closestꢀquality model Bna, which is ProutꢀTompkins equation with autocatalysis, are shown
in Table 1. The correlation of experimental points from TG curves with the calculated lines in
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Table 1. Kinetic Parameters of Reaction of Leu-Leu Cyclization and
Statistical Parameters of Calculationa
Equation Fexp Fcrit Fact
Ea /
lgA
Reacti Corr.
A →B
on
order
coeff.
kJ molꢀ1
CnB
1.00 1.05 3494 434.1±0.7 48.0±0.07 1.46
1.22 1.05 3494 431.2±1.6 48.5±0.18 1.05
0.998994
0.998601
Bna
a
The used topochemical equations are nthꢀorder reaction with autocatalysis through the
reactants (CnB) and Prout–Tompkins (Bna).69 Data on the F test of fit quality (to identify the
best kinetic description).
accordance with equation CnB is shown in Figure 7. From the viewpoints of thermodynamics,
the revealed autocatalytic mechanism of this reaction may be caused not only by the decrease in
the activation energy after accumulation of enough amount of the cyclic product (Figure 6b),
which can act as catalyst in this reaction. But also as the result of decrease of system energy due
to formation of at least two intermolecular hydrogen bonds per molecule of cyclo(LeuꢀLeu)
(Figure 3) and to participation of alkyl groups in hydrophobic interactions.
The obtained values of activation energy, Arrhenius constant and reaction order are in good
compliance with the calculated ones by Ozawa–Flynn–Wall approach. Thus, these kinetic
parameters may be used to describe the reaction of cyclization of ꢀleucylꢀLꢀleucine in solid
L
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Figure 7. Correlation of experimental points from TG curves with the calculated lines in
accordance with equation CnB.
It should be noted that the obtained values of activation energy for studied reaction are
relatively large. For example, this value for solid phase cyclization of diphenylalanine, which
starts at 147 °C, is 148 kJ molꢀ1.29 One can assume that the formation of intermolecular Hꢀbond
between >NꢀH and >C=O groups of different LeuꢀLeu molecules after water desorption (Figure
3b) can hinder the intramolecular cyclization, and increase the value of activation energy.
AFM Study of Surface Morphology. We visualized the effect of temperature on the state of
dipeptide film. For this the AFM images of the films of initial LeuꢀLeu from the hexafluoroꢀ2ꢀ
propanol (HFIP) solution, and LeuꢀLeu films after sequential heating to 145 °C and 200 °C were
obtained (Figure 8). Also the AFM image of film of cyclo(LeuꢀLeu) from solution in HFIP was
obtained (Figure 10). The powder of cyclo(LeuꢀLeu) was prepared as described in Figure 1.
Amorphous and relatively smooth film of dipeptide is formed on the surface of HOPG after
solvent (HFIP) has been removed (Figure 8a). The average height spread on a 10×10 µm scan
was 13 nm. A mean square roughness of the surface (Rq) was 2 nm. After heating up to 145 °C
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the morphology of the initial film changed (Figure 8b). The chaotically located objects, similar to
shortꢀhairs with length of 240ꢀ600 nm, were appeared on the film surface. The mean square
roughness of the surface increased to 3.4 nm. One can assume that the driving force of observed
selfꢀassembly of the dipeptide molecules is the formation of additional intermolecular hydrogen
bonds after water release (Figure 3b).
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As a result of further film heating up to 200 °C, the flat plates with width of 200ꢀ300 nm,
thickness of 30ꢀ70 nm, and length of more than 1000 nm were formed on its surface (Figure 8c).
A mean square roughness of the surface (Rq) was 21.4 nm. The scheme of possible molecular
organization of cyclo(LeuꢀLeu) in solid phase after heating is shown in Figure 9.
The similar structures were found after the crystallization from HFIP solution of cyclo(Leuꢀ
Leu) (Figure 10). In the last case, the length, width and height of the flat plates were 0.5ꢀ2.4 µm,
100ꢀ470 nm and 10ꢀ35 nm, correspondingly.
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Figure 8. AFM images of the surface of (a) the initial LeuꢀLeu film deposited on the HOPG
surface from a HFIP solution, (b) LeuꢀLeu film after heating up to 145 °C, (c) LeuꢀLeu film after
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heating up to 200 °C. Scale bar = 1 µm.
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Figure 9. Scheme of possible organization of cyclo(LeuꢀLeu) in solid phase.
Figure 10. AFM images of the surface of film with the nanostructures obtained from solution of
cyclo(LeuꢀLeu) in HFIP with different magnification. Scale bar = 3 µm (a) and 1 µm (b).
We believe that selfꢀassembly of cyclo(LeuꢀLeu) in such practically twoꢀdimensional
elongated objects is due to formation of the four hydrogen bonds per each molecule of dipeptide
(Figure 9), which leads to the formation of molecular chains in solid phase.70
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CONCLUSION
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The solidꢀphase reaction of ꢀleucylꢀLꢀleucine cyclization was studied in the course of thermal
L
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analysis. The heating of the dipeptide powder above 177 °С leads to formation of cyclic
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1
dipeptide, which structure was confirmed by H, 13C NMR, Fourierꢀtransform infrared
spectroscopy and GCꢀMS analysis. Studied reaction of solid phase cyclization of ꢀleucylꢀLꢀ
L
leucine is a complex reaction with autocatalysis. The calculated kinetic parameters of this
reaction are Ea = 434 kJ molꢀ1, lgA = 48, and the reaction order is close to 1.5. The relatively
high calculated value of the activation energy may be a consequence of ꢀleucylꢀLꢀleucine selfꢀ
L
assembly through the formation of additional intermolecular hydrogen bonds. As a result of this
process, the small hairsꢀlike objects (length less than 600 nm) are formed on the surface of
dipeptide film, concurrent with the red shift of NꢀH stretch band observed in the IR spectrum.
Probably, this selfꢀassembly complicates the "folding" of dipeptide molecule which necessary to
start of intramolecular reaction.
The cyclization of LꢀleucylꢀLꢀleucine in the solid phase leads to formation of elongate 2D
plates, the same objects are observed when cyclic dipeptide crystallized from the polar Hꢀdonor
hexafluoroꢀ2ꢀpropanol on the surface of hydrophobic pyrolytic graphite. While the linear ꢀ
L
leucylꢀLꢀleucine forms a smooth amorphous film under the same conditions.
The results of present work explain the changes in the properties of nanostructures based
on leucylꢀleucine after heating, and also can be used for further development of techniques for
the preparation of nanomaterials based on oligopeptides.
AUTHOR INFORMATION
Corresponding Author
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* Eꢀmail: Marat.Ziganshin@kpfu.ru (M.A.Z.). Phone: +784322337309
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Notes
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The authors declare no competing financial interest.
ACKNOWLEDGEMENTS
This work was supported by the Ministry of Education and Science of Russian Federation
[grant №14.Y26.31.0019].
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