Optical and calorimetric studies of quercetin-doped liquid crystals: Effects of molecular aggregation

Journal Pre-proof Optical and calorimetric studies of quercetin-doped liquid crystals: Effects of molecular aggregation

A.N. Samoilov, S.S. Minenko, O.Ye. Sushynskyi, L.N. Lisetski, N.I. Lebovka PII:

S0167-7322(19)34488-5

DOI:

https://doi.org/10.1016/j.molliq.2019.111689

Reference:

MOLLIQ 111689

To appear in:

Journal of Molecular Liquids

Received date:

8 August 2019

Revised date:

2 September 2019

Accepted date:

4 September 2019

Please cite this article as: A.N. Samoilov, S.S. Minenko, O.Y. Sushynskyi, et al., Optical and calorimetric studies of quercetin-doped liquid crystals: Effects of molecular aggregation, Journal of Molecular Liquids(2019), https://doi.org/10.1016/ j.molliq.2019.111689

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© 2019 Published by Elsevier.

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Optical and calorimetric studies of quercetin-doped liquid crystals: Effects of molecular aggregation A.N. Samoilova, S.S. Minenkoa, O.Ye. Sushynskyib, L.N. Lisetskia , N.I. Lebovkac a

Institute for Scintillation Materials of STC “Institute for Single Crystals”, NAS of Ukraine, 60 Nauky Ave., 61001 Kharkiv, Ukraine b Chair of Electronic Devices, National University “Lviv Polytechnics”, 12 S.Bandery St., 79013, Lviv, Ukraine c Institute of Biocolloidal Chemistry named after F. D. Ovcharenko, NAS of Ukraine, 42 Vernadsky Prosp., 03142 Kyiv, Ukraine. E-mails: [email protected](L.N. Lisetski); [email protected] (Nickolai Lebovka);

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Received 8 August, 2019

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Contact information about Corresponding Author: Prof. L. N. Lisetski Institute for Scintillation Materials of STC “Institute for Single Crystals”, NAS of Ukraine, 60 Nauky Ave., 61001 Kharkiv, Ukraine E-mail address: [email protected](L.N. Lisetski);

 Corresponding author. E-mail address: [email protected](L.N. Lisetski)

Journal Pre-proof Abstract The organic substance quercetin, when added to liquid crystal (LC) systems as non-mesogenic dopant significantly affects properties of the LC host. The microphotographs of cholesteric (M5) and nematic (5CB) LC textures evidenced about presence of aggregation quercetin molecules in LC hosts. These results are in agreement with literature data on quercetin in lyotropic phases of phospholipid membranes. The effects of quercetin on phase transition temperatures from cholesteric/nematic to the isotropic state, as well as shapes of the corresponding calorimetric peaks, were studied by differential scanning calorimetry. Optical behavior of M5 and 5CB doped with quercetin was studied as function of temperature and concentration of quercetin. The data evidenced that quercetin can be considered as a certain intermediate agent between fully solvable non-mesogenic dopants and dispersed nanoparticles, combining partial solubility and formation of nano-sized aggregates inside LC medium.

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Keywords: liquid crystals, cholesterics; nematics; quercetin; aggregation

Journal Pre-proof 1. Introduction

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Among complex molecular liquid systems that are promising from the viewpoints of both their prospective practical applications and their importance for development of general theoretical notions of molecular physics, great interest has been attracted by multi-component systems with liquid crystalline ordering doped with dispersed nanoparticles of different kind [1]. Alongside with rod-like carbon nanotubes [2–4], nanoparticles of graphene [5], disc-like particles of organomodified Laponite RD  (LapO) [6], nanoparticles of various metals, metal oxides and semiconductors [7–12], one can also consider organic substances with molecules of relatively large size that are poorly soluble in standard liquid crystal (LC) solvents, but that still can be formally be considered as non-mesogenic dopants (NMD) to LC matrices, applying conventional NMD approaches to their studies [13]. As an example, one may consider peculiar properties of cholesteric and nematic LC doped with small concentrations of amino acids, which were described in a recent publication [14]. In this paper, we deal with LC systems containing quercetin – an organic substance of biological origin. Quercetin is a natural flavonoid present in foods, vegetables and fruits, herbs and spices, tea and wine that has great potential for prevention and therapy of many chronic diseases [15]. It is a dietary flavonoid that displays many attractive biological and pharmacological effects [16,17]. Among them the antioxidant, anti-obesity, anticarcinogenic, antiviral, antibacterial and anti-inflammatory effects can be referred [15,18,19]. Quercetin is a polyphenol belonging to the class of flavonoids with 3-hydroxyflavone backbone [19]:

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Figure 1. Chemical structure of quercetin C15H10O7.

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Molecular structure of quercetin can be represented by 48 conformations(24 planar and 24 non-planar) that was the subject of intensive studies [20–24]. Quercetin normally crystallizes in the form of yellow needles as powder with melting point of 314.85 °C [25]. The quercetin can exist as anhydrous, monohydrate and dihydrate forms with different solubility in water [26] The behavior of quercetin in solvents is rather unusual [27]. The quercetin has low solubility in water (<0.1 % at 16 +C), its solubility in ethanol is higher (0.35 %), and it is well soluble, e.g., in acetic acid (4.35 g/l). When introduced to the lyotropic liquid crystalline (LC) phase of hydrated DPPC, quercetin apparently enters homogeneously the lipid bilayers up to ~15% with respect to the phospholipid content [28–30]. The effects of quercetin on the electrical properties of model lipid membranes were also discussed [31]. The data indicated that the specific localization of quercetin, membrane-bound or cell-entering, might be crucial for its pharmacological activity. The interactions of flavonoids including quercetin with lipid mesophases was extensively reviewed [32]. The separation and determination of various flavonoids is rather complex and challenging task. For detection of quercetin different methods have been applied, such as capillary electrophoresis, gas chromatography, liquid chromatography with electrochemical detection or colorimetric detection, ultra-violet spectrophotometry, flow injection analysis and pulse polarography [33–35]. Recently for selective detection and sensing of quercetin different innovative methods have been proposed, using carbon nanotubes modified glassy carbon electrodes [36], manganese-doped ZnS quantum dots [37], luminescent organosilane-functionalized carbon dots [38], core–shell magnetic molecularly imprinted polymers[39], and metal-organic frameworks[40]. An interesting example of such application was recently presented [41], where a cholesteric LC system based on nematics with chiral dopants was used as sensor material for optical detectors of medical plant metabolites. From a more general viewpoint, it was argued that LC could serve as sensitive reporters of interfacial events, which was used for sensing of toxic agents and other biologically active substances [42]. The DNA-based cholesteric LC structure has been used for sensing of myricetin, which has chemical structure rather similar to that of quercetin [43]. Note that using the cholesteric LCs for biological sensing is based on the changes in selective reflection properties after adsorption of biological substances [44,45]. The effects of nano-dopants of different nature (carbon nanotubes, ferroelectric and magnetic particles, quantum dots, organomodified clays, etc.) on structure of LC media have been extensively studied in previous work [4,10]. These dopands can incorporate into the orientationally ordered LC structure, affecting both orientational

Journal Pre-proof ordering and helical twisting [46]. The induced cholesterics can be obtained by introduction of chiral dopants to nematic, or ferroelectric LC on the basis of smectics-C [47,48]. The introduction of photosensitive dopants allowed light-induced variation of LC properties (e.g., under UV irradiation) with many possible applications in optoelectronic devices [49–51]. In this study, we used quercetin as non-mesogenic dopant to the cholesteric (M5) and nematic (5CB) LCs. The effects of quercetin on the nematic/cholesteric to isotropic liquid phase transitions are studied by means of differential scanning calorimetry. A special point of interest was the use of steroid cholesteric M5 (i.e., mixtures of cholesterol esters) as solvents for quercetin. The constituents of such cholesteric LCs represent the substances of biological origin. The effects of temperature and quercetin concentration on selective reflection spectra of M5 and optical transmission of 5CB are discussed. Finally, an interpretation of the obtained results was proposed to tentatively explain the behavior of quercetin in LC hosts.

2. Materials and methods

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Quercetin (99% purity) was purchased from Aladdin Industrial Corporation (China). The cholesteric mixture M5 consisted of 30% cholesteryl formate (C28H46O2), 5% cholesteryl butyrate (C31H52O2) and 65% cholesteryl nonanoate C36H62O2. These cholesterol esters were obtained from Chemical Reagents Plant, Ukraine and used without further purification. The M5 has crystal-cholesteric transition temperature Tcch ≈ 318 K and cholestericisotropic transition temperature Tchi ≈346 K (the transition temperatures were determined from DSC measurements in the heating mode). The nematic 5CB (4-n-pentyl-4'-cyanobiphenyl) of 99,5% purity was obtained from Chemical Reagents Plant, Ukraine. The 5CB has crystal-nematic transition (melting) temperature Tcn ≈295.5 K and nematicisotropic transition temperature Tni ≈ 308.5 K. The samples were obtained by mixing of M5 or 5CB with quercetin in the isotropic phase. The concentration of quercetin was varied within 0-6.7 % wt (hereinafter %). The mixtures were subjected to 20–30 min sonication using a UZD-22/44 ultrasonic disperser according to the procedure previously used for LC + nanoparticle dispersions [52,53]. Optical transmission and selective reflection spectra were measured in sandwich-type LC cells (20 μm thickness) using a Shimadzu UV-2450 spectrophotometer (Japan) within 300-900 nm spectral range. The cell walls were treated with polyvinyl alcohol water solution and, after drying, rubbed in one direction to obtain the planar texture [46]. The sample was introduced between the cell walls using the capillary forces at the temperatures above the transition to the isotropic phase. The measurements were done within the temperature range of 290-310 K in the heating and cooling modes, and the temperature was stabilized using a flowing-water thermostat (±0.1 K). For the same cells, the microscopic images were obtained using an optical microscope (Ningbo Sunny Instruments Co., Ltd, China). The microscope detector unit was interfaced with a digital camera and a personal computer. Temperatures of transition from nematic or cholesteric to isotropic phase and shapes of the corresponding calorimetric peaks were measured by differential scanning calorimetry (DSC) using a Mettler DSC 1 instrument (Switzerland) on heating and cooling (2 K/min scanning rate, sample mass 20 mg) modes. The experiments were replicated 5–7 times. The mean values and the standard deviations were calculated. The error bars in all the figures correspond to the confidence level of 95%

3. Results and discussion

3.1. M5+quercetin systems

Figure 2 shows typical examples of optical microscopy images observed in М5 + quercetin (1.4 %) systems in crystal (a, T=290 K), cholesteric (b, T=340) and isotropic (c, T=350 K) phases. The clear dark colored micronsized inclusions were observed in all phases and their size become smaller with transition from crystal to cholesteric phase and from cholesteric to isotropic phase. These inclusions correspond to aggregates of the crystals of undissolved quercetin in the M5. The minimal size of the crystals observed in the isotropic phase was of order of 510 m. Preliminary investigations have shown that these inclusions can be observed even at rather small concentration of quercetin (<0.1-0.3%). It reflected the low solubility of quercetin in the studied LC solvents. The examples of DSC thermograms for undoped M5 and M5 + quercetin (3 %) systems are shown in Fig. 3a (in the vicinity of crystal-cholesteric phase transition) and in Fig. 3b (in the vicinity of cholesteric-isotropic phase transition). The concentration 3% was chosen to make the measurement conditions fully similar to those used in our earlier paper for 5CB doped with platelets of LapO [6]. In the heating mode, the undoped M5 crystals melted at the temperature of Tcch ≈ 318 K. For undoped M5 the melting curve had rather complex structure with the clear inflection at the temperature interval between 311 K and 314 K. However, in M5 + quercetin (3 %) systems this inflection disappeared. This may evidence the presence of some integration of quercetin inside the crystalline structure of M5. Note, that on the cooling mode from the isotropic phase M5 remained in the cholesteric phase even at temperatures much below 318 K in the so-called

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“monotropic” state (thermodynamically unstable cholesteric phase), and no crystallisation peaks were observed. For crystallization of M5, a special procedure of freezing is required (dozens of hours at T=255K). For pure M5 the cholesteric-isotropic transition temperatures were Tchi ≈346.3 K and 345.9 K in the heating and cooling modes, respectively (Fig. 3b). The introduction of quercetin affected these phase transition temperatures. In M5 + quercetin (3 %) systems these temperatures were Tchi ≈346.1 K and 345.7 K in the heating and cooling modes, respectively. Thus, the quercetin induced the negative shift of transition temperature by T(0.2-0.24) K. Such shift may be explained by the impurity effect of introduction of non-mesogenic dopant typical for LC systems.

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Figure 2. Typical examples of optical microscopy images observed in М5 + quercetin (1.4 %) systems in crystal (a, T=290 K), cholesteric (b, T=340) and isotropic (c, T=350 K) phases.

Figure 3. Examples of DSC thermograms for undoped M5 and M5 + quercetin (3 %) systems in the vicinity of crystal-cholesteric phase transition (a) and in the vicinity of cholesteric-isotropic phase transition in the heating and cooling modes (b). Since M5 has a rather broad range of cholesteric mesophase (75 K accounting for the presence of the cholesteric “monotropic” phase) we have measured the optical transmission spectra for these systems in the temperature interval between 298 K and 346 K. Figure 4 shows examples of the optical transmission spectra for M5 doped with quercetin at concentrations from 0 to 6.64% at 298 K (a) in the cholesteric “monotropic” phase and at 343 K (b) in the cholesteric phase. The maximums at λ  430-440 nm correspond to the selective reflection maximums, λm, of M5 in the cholesteric phase. The maximum at λq  370 may be attributed to the quercetin absorption band [54]. At T=298 K (Fig 4a) in the cholesteric “monotropic” phase the nearly unchanged location of the selective reflection maximum, λm, upon introduction of quercetin was observed. The value of λm is proportional to the cholesteric helical pitch p, λm = np (here n is the average refraction index). So, it can be concluded that quercetin practically does not affect the helical twisting at T=298 K. However, the relative intensity of the peaks markedly

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decreased with increase of concentration of quercetin, C. It can reflect the inducing of more defects into the cholesteric structure in the presence of quercetin. At high temperature T=343 K (Fig 4b) in the cholesteric phase near the cholesteric to isotropic transition temperature the position of the selective reflection maximum, λm, was notably dependent upon introduction of quercetin. However, the impact of the quercetin on the relative intensity of the peaks was less significant. Figure 6 shows temperature dependences of λm for different concentrations of quercetin, C. Increase in the temperature resulted in decrease of the λm.

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Figure 4. Optical density spectra of M5 + quercetin systems for different concentrations of quercetin, C, at 298 K in the cholesteric “monotropic” phase (a) and at 343 K in the cholesteric phase near the cholesteric to isotropic transition temperature (b). The maximum at λq  370 may be attributed to the quercetin absorption band [54].

Figure 5. Wavelength of maximum selective reflection λm as function of temperature T for M5 + quercetin system for concentrations C=0 %, 1.25 % and 6.64 %.

Figure 6. Optical density, D800, of the M5 + quercetin systems as function of concentration of the quercetin, C, at

Journal Pre-proof 298 K in the cholesteric “monotropic” phase and at 343 K in the cholesteric phase near the cholesteric to isotropic transition temperature. The value of D800, was measured at = 800 nm i.e., far from both absorption and selective reflection bands.

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Impact of the concentrations of quercetin on the values of λm was more significant at high temperatures, especially in the interval between 330 K and 340 K (dashed area in Fig. 5). It could be explained by higher solubility of quercetin in M5 at higher temperatures closer to the isotropic transition. However, for all systems the values of λm dropped when T346 K. This shift in λm in the vicinity of the cholesteric to isotropic transition evidently reflects a decrease in the orientational ordering. Figure 6 shows optical density, D800, versus the concentration of quercetin, C, for two temperatures, T = 298 K (in the cholesteric “monotropic” phase) and T= 343 K (in the cholesteric phase near the cholesteric to isotropic transition temperature). The value of D800, was measured at = 800 nm i.e., far from both absorption and selective reflection bands. The obtained dependences D800(C) were close to linearity, which corresponds to validity of Bouguer-Lambert-Beer law for both temperatures. However, the curve slope at T= 343 K was lower than that at T = 298 K. It can reflect inducing of more defects into the cholesteric structure at low temperatures. Figure 7 presents the temperature dependencies of the optical density density, D800(T), for two concentrations of quercetin in M5, C=1.25 % (a) and C=6.64 % (b). The optical density increased with quercetin concentration, C, and decreased with temperature. The effect was near linear for C=1.25 % (Fig. 7a), but it was noticeably non-linear for C=6.64 % and the non-linear effect was more marked in approaching the isotropic transition (Fig. 7b).

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Figure 7. Temperature dependences of the optical density, D800(T), for two concentrations of quercetin in M5, C=1.25 % (a) and C=6.64 % (b). The value of D800, was measured at = 800 nm i.e., far from both absorption and selective reflection bands.

3.2. 5CB + quercetin systems

The similar studies were carried out for nematic LC 5CB doped with quercetin. Figure 8 shows a typical example of optical microscopy images observed in 5CB + quercetin (0.3 %) systems in the isotropic phase (T=310 K). Here, the clear dark colored micron-sized inclusions were also observed. These inclusions correspond to aggregates of the quercetin crystals similar to those observed in M5 + quercetin systems (Fig. 2).

Figure 8. Typical optical microscopy image observed in 5CB +quercetin (0.3%) systems in isotropic phase, T=310 K.

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Figure 9 presents examples of DSC thermograms for undoped 5CB and 5CB + quercetin (3 %) systems near nematic - isotropic phase transition in the heating (a) and cooling (b) modes. The sample 5CB + quercetin (S) was subjected to 20 min supplementary ultrasonication in the isotropic phase immediately before DSC experiments. For pure 5CB the nematic-isotropic transition temperatures were Tni ≈308.8 K and ≈308.3 K in the heating and cooling modes, respectively (Fig. 10). Thus, the quercetin induced the positive shift of transition temperature by T+0.21 K. Such behavior is quite opposite to the behavior M5 + quercetin systems (Fig. 3b) and the negative shift of 5CB transition temperatures in presence of nanotubes and LapO platelets dopants [4,6]. For example, both nanotubes and LapO platelets act like non-mesogenic dopants, decreasing the thermal stability of nematic phase. The behavior of the quercetin doped systems can be explained accounting for the conformational structure of the quercetin molecules. One can assume that either quercetin molecules can interact with 5CB molecules forming some weak anisometric complexes, or “quasi-mesogenic” properties of quercetin can be due to formation of certain ordered structures by its molecules (possibly of the ‘stacking” type due to their planar conformation [55,56]. The possibility of formation of supramolecular quercetin aggregates (specifically, in conditions of lyotropic LC phases of phospholipid membranes) was noted in [28,29,57].

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Figure 9. Examples of DSC thermograms for undoped 5CB and 5CB + quercetin (3 %) systems in the vicinity of nematic - isotropic phase transition in the heating (a) and cooling (b) modes. The sample 5CB + quercetin (S) was subjected to 20 min supplementary ultrasonication in the isotropic phase immediately before DSC experiments.

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The obtained optical transmission spectra of 5CB + quercetin systems at 298 K in the nematic phase are shown in Fig. 10. Upon addition of quercetin, the level of optical density increased and at q370 nm the contribution from intrinsic absorption by quercetin molecules was observed.

Figure 10. Optical density spectra of 5CB + quercetin systems for different concentrations of quercetin, C, at 298 K in the nematic phase. The maximum at λq  370 may be attributed to the quercetin absorption band [54]. The temperature dependences of optical transmission for 5CB+quercetin, D800(T), are shown in Fig. 11. The values of D800 were measured at = 800 nm i.e., far from both absorption and selective reflection bands. The experiment conditions were similar to those used for 5CB with dispersed carbon nanoparticles or platelets of organomodified [14,52]. A characteristic feature of such systems is the presence of the “transmission jump” at the transition temperature from nematic to isotropic phase. This has been explained by the effects of dispersed nanoparticles built into the orientationally ordered LC structure [4,58], which substantially increases the light scattering in the nematic phase.

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Figure 11. Temperature dependencies of the optical density, D800(T), for different concentrations of quercetin in 5CB,. The values of D800, were measured at = 800 nm i.e., far from both absorption and selective reflection bands.

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Figure 12 shows the optical density of 5CB + quercetin system, D800, as function of quercetin concentration, C, for different temperatures at 298 K in the nematic phase and at 313 K in the isotropic phase.

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Figure 12. Optical density, D800, of the 5CB + quercetin systems as function of concentration of the quercetin, C, at 298 K in the nematic phase and at 313 K in the isotropic phase. The value of D800 was measured at = 800 nm i.e., far from both absorption and selective reflection bands.

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The optical density nearly linearly increased with quercetin concentration, and the slope of the curve at high temperature T= 308 K was lower than that at T = 298 K. In general the behavior was very similar to that observed for the M5 + quercetin system (Fig. 6).

4. Discussion and concluding remarks The effects of introduction of quercetin into two different LC crystal matrices, cholesteric M5 and nematic 5CB, were studied. In both matrices the formation of large aggregates of quercetin was observed. This aggregation can result from the low solubility of quercetin molecules in the LC. For M5 + quercetin, the DSC data evidence the presence of integration of quercetin inside crystalline structure of M5. The introduction of quercetin also noticeably influenced the cholesteric-isotropic (M5) and nematic-isotropic (5CB) phase transition temperatures. The impacts of quercetin on the transition temperatures into isotropic phase for M5 and 5CB were opposite; quercetin increased the transition temperature for M5 and decreased it for 5CB. It may reflect the different mechanisms of molecular integration of quercetin into M5 and 5CB. Thus, along with formation of large aggregates of quercetin inside the LCs, more deep integration between of quercetin and LC cannot be excluded. The quercetin practically does not affect the position of selective reflection band of cholesterics, but leads to substantial changes in the level of optical transmission both in cholesteric and nematic hosts. For both studied LCs the optical density is increased with quercetin concentration and decreased with temperature. In general, the observed behavior allows concluding that the quercetin can be considered as a certain intermediate object between fully solvable non-mesogenic dopants and dispersed nanoparticles that combine partial solubility and formation of nano-sized aggregates inside LC medium. The observed behavior was closely similar to the previously reported data for LC doped with organomodified platelets of LapO [6,14]. Lap consists of disc-like particles of ~1 nm thickness and ~25 nm diameter [59]. The effects of quercetin and LapO on the DSC traces were

Journal Pre-proof rather similar. In cholesteric matrices, the introduction of LapO led to changes in selective reflection spectra and optical density outside the selective reflection band [14]. The observed concentration and temperature dependencies of optical properties in LC + quercetin and LC + LapO systems were also strikingly similar. This similarity can be explained by the similarity in supramolecular aggregates of quercetin and organomodified platelets of LapO. Note that aggregation of quercetin in biological media was discussed in several works (see, e.g., [57]). Purposeful preparation of quercetin nanoparticles for biomedical applications is also a topical problem [60]. In model phospholipid membranes quercetin be present in molecular form up to certain critical concentrations (~15% with respect to the mass of lipids), while at higher concentrations quercetin aggregates are formed [28,29]. The size of such aggregates can reach ~700 nm [30]. The quercetin molecules have a planar conformation and stacking of these molecules can result in formation of anisometric supramolecular aggregates [55]. Encapsulation of quercetin in LC structures formed by lipid formulations was shown to be useful for preparation of delivery matrices of quercetin [61]. The size of aggregates can be tuned in the range of about 80–210 nm by changing lipid composition and entrapped quercetin concentration. The promising biological and pharmaceutical applications of quercetin doped LC materials can be also expected in development of sensing materials for optical detectors of medical plant metabolites [41,42].

Acknowledgments

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The research was co-financed by the National Academy of Sciences of Ukraine, Projects #0117U004046 and #43/19-H.

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[45]

Journal Pre-proof

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Graphical abstract

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Highlights

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Nematic and cholesteric liquid crystal (LC) systems doped with quercetin were studied.

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Optical transmission vs. temperature and concentration is similar to LC with dispersed nanoparticles.

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Effects of quercetin on LC phase transitions was dependent on LC chemical structure.

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Evidence of molecular aggregation of quercetin in LC medium is presented