3-Aryl-2-(thiazol-2-yl)acrylonitriles assembled with aryl/hetaryl rings: Design of the optical properties and application prospects

Highlights

• A series of new varicolored fluorophores was obtained.

• The expanded spectral investigation and quantum mechanical calculations were performed.

• Relationships between structure – fluorescence maxima and intensity were established.

• ICT, solvatochromism, acidochromism in solution and in solid were investigated.

• Penetration into the living cells open application for bioimaging or theranostics.

Abstract

New fluorescent thiazoles were designed and synthesized based on a 3-aryl-2-(thiazol-2-yl)acrylonitrile core. Three synthetic approaches were developed to introduce specific combinations of substituents at the 2-, 4- and 5-thiazole positions. The obtained thiazolyl-2-acrylonitriles exhibited a wide range of fluorescent colours (from green to red), long wavelength maxima and intensity depending on the combination of the substituents located at rings A, B and C. The expanded photophysical investigation established the best substituent combinations to increase their emission. Absorption and emission were studied in solvents with different polarities, as well as in DMSO-water and dioxane-water mixtures. The thiazoles showed multifunctional properties and exhibited good emission in the solid phase and in suspension (aggregation induced enhancement emission/AIEE effect). Photophysical investigations revealed a large Stokes shift, significant positive solvatochromism, and the tunability of the colour and intensity. Sharp strengthening of the emission intensity of the thiazoles was observed upon stimulation with some acid (H₂SO₄ and BF₃·OEt₂) in solvents and in the solid phase (HCl). State-of-the-art quantum mechanical calculations were performed to interpret the experimental findings. Biological experiments revealed the good penetration of the thiazoles into living cells and the accumulation both in lysosomes and, to a lesser extent, near membranes.

Introduction

An important structural unit of numerous organic photoactive compounds is a heterocyclic core, which usually becomes the key element for further chemical modification and often predetermines the photophysical properties and the directions for their potential applications. Monocyclic triazoles, thiazoles, pyrazoles, imidazoles, pyridines, pyrimidines and their benzo- and heterocyclic assemblies or fused congeners potentially represent platforms for the creation of new organic materials [[1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13]].

The outstanding biological and optical properties of thiazoles make them suitable reagents for preparing biologically active compounds, pharmaceuticals [[14], [15], [16], [17], [18]] and various electronic and optical materials [10,[19], [20], [21], [22]]. Thiazole-based fluorophores used for blue light-emitting polymers have been applied in organic light-emitting diodes (OLEDs) and white polymer light-emitting diodes (WPLEDs) [19,23]. Molecules containing photo triggers and molecular switching materials include the thiazole ring are applied to control the dynamics of biological processes [24,25]. Thiazoles are known for their sensitivity and may be used in biochemical and environmental applications or in dye-sensitized solar cells [19,25,[26], [29]]. Asymmetrical thiazole cores with lateral π-conjugated systems possess fascinating behaviour, such as ferroelectric, near-infrared absorption, and nonlinear optical properties [30,31].

Various fields of applications of thiazole derivatives are based on their specific electronic properties due to the presence of sulphur and nitrogen with lone pairs of electrons and the aromaticity of the heterocyclic ring [32,33]. Nitrogen is a good donor site for achieving a response to external stimuli, and it forms non-bonded intra- and intermolecular interactions or participates in coordinating metals. Sulphur contributes to improvements in the thermal stability [34]. Heteroaromatic compounds containing thiazole cores possess large molecular hyperpolarizability and linear and nonlinear optical properties that are more pronounced than the corresponding aryl analogues [35].

Amazing photophysical characteristics are exhibited by many derivatives of 4-OH, 4-OAlkyl [23,28,[36], [37], [38]], and 2- and 5-aminothiazoles [28,[39], [40], [41], [42]]. These fluorophores contain a strongly electron-donating substituent at the 2, 4- or 5-positions of the thiazole ring, which determines the choice of other substituents and structural fragments for the synthesis of new fluorophores with the designed electronic structure (A-D). Thus, the investigation of the optical properties of a series of 5-arylaminothiazoles by strengthening of the electron-donating properties of the C5-arylamino-group and electron-accepting nature of the C2-aryl-fragment showed shifts of the absorption and emission bands, whereas the modifications of the C4 heterocyclic position exerted a negligible effect on the spectra [[40], [41], [42]].

4-Alkoxy- and 4-hydroxythiazoles were discovered as fascinating fluorophores in the extensive investigations performed by Beckert and colleagues in the last decade [23,[36], [37], [38]]. The main structural modification of these thiazoles was located at the 2-position and included substituted/unsubstituted aromatics, six-membered nitrogen heteroaryls or some other heteroaryls. The replacement of the substituent at the 5-position from a methyl group to various phenyl substituents revealed their effects on the fluorescence properties, which were much smaller than the electronic nature of the C2-position and substituent attached.

Quantum mechanical calculations are a powerful tool for investigating the electronic properties of a molecule and have been used for the rational design of new thiazole fluorophores. Radhakrishnan and Sreejalekshmi used DFT and TD-DFT calculations for rational design of 5-(hetero-2-yl)-1,3-thiazoles. They synthesized and analysed a 30-member 4-aryl-(5-nitrothien-2-yl)-thiazole-2-amines library to predict the tunability at the C2, C4 and C5 atoms of the thiazole ring, and emphasized that the C5 position with electron-accepting substituents is the key point and the ICT channel C2→C5 has the strongest molecular electron shift (Fig. 1a) [39]. However, the HOMO and LUMO electronic distributions show significant differences at the C4 atom, indicating the sensitivity of this position for adjusting the HOMO-LUMO gap [39].

Thus, the published data showed that the thiazole core is a unique electronic transmitter, which allows to form three alternative arrangements, with competing charge transfer channels via the C2–C4, C2–C5 and C4–C5 thiazole atoms (Fig. 1a). The direction of the electron shift and the degree of the channel participation in the electronic distribution in the ground (GS) and excited (ES) states, are determined by the nature of the substituents (EWG or EDG type) attached to the C4, C5 and C2 ring atoms, their specific combinations and the arrangement in the thiazole cycle [[36], [37], [38], [39], [40], [41], [42], [43], [44], [45], [46]].

Additionally, we should remember that a useful structural element of monocyclic thiazoles is its flexibility. This allows their spatial architecture to be managed by the introduction of bulky substituents. A twisted molecular conformation may facilitate the development of specific photoactive properties and the implementation of new optical phenomena. Thus, the thiazole core is a universal platform to develop various new tunable fluorophores for diverse applications.

Recently, we have suggested new thiazoles with an aryl acrylonitrile fragment at the C2 position of the heterocycle [20]. New thiazole derivatives (Fig. 1b–d) exhibited high sensitivity to the microenvironment and a large Stokes shift while maintaining efficient emission. They demonstrated good solubility in different organic solvents and high photostability, and their structures are a suitable platform for the formation of the different electronic systems in the molecule by modelling the C4 and C5 substituents. A compound set for further photophysical investigations was designed and built based on the previous finding that an electron-withdrawing substituent at aromatic cycle A (Fig. 1b–d) is preferred to obtain the best emission.

Numerous electron-withdrawing substituents have been used to construct new fluorophores. We have preferred the cyano (CN) group due to its large electronic effect and its ability to enhance the optical properties of organic compounds [47,48], including high photostability, mechanofluorochromism and aggregation induced emission (AIE) phenomenon. However, we have also introduced the strong electron-donating dimethylamino group to the aromatic moiety A, which may be useful to enhance the thiazole response to external stimuli. The Me₂N group can transform into a strongly electron-withdrawing substituent in acidic medium or by interaction with protic/polar solvents. Special attention will be paid to the position of the substituents in aromatics B and C, causing a steric effect and changing the conjugation or energy of vibrational levels of the molecule. Thus, this investigation aims to identify the optimal ratio between electronic and spatial characteristics of the aromatic B and C substituents that provide the best values for the optical characteristics. Therefore, we designed and synthesized compounds whose architecture is able to manage the different degrees of the electronic saturation of the various molecular electronic shift channels. Convenient structural fragments for the variation of the electronic properties are the aromatic cycles (aromatics B and C) with specific substituents. We included in this work thiazole dyes that do not contain these aromatic rings (Fig. 1d) or contain only one of them (Fig. 1c) to elucidate the roles of the aromatic moieties B and C.