Thiophene-Based Trimers and Their Bioapplications: An Overview

Abstract

Certainly, the success of polythiophenes is due in the first place to their outstanding electronic properties and superior processability. Nevertheless, there are additional reasons that contribute to arouse the scientific interest around these materials. Among these, the large variety of chemical modifications that is possible to perform on the thiophene ring is a precious aspect. In particular, a turning point was marked by the diffusion of synthetic strategies for the preparation of terthiophenes: the vast richness of approaches today available for the easy customization of these structures allows the finetuning of their chemical, physical, and optical properties. Therefore, terthiophene derivatives have become an extremely versatile class of compounds both for direct application or for the preparation of electronic functional polymers. Moreover, their biocompatibility and ease of functionalization make them appealing for biology and medical research, as it testifies to the blossoming of studies in these fields in which they are involved. It is thus with the willingness to guide the reader through all the possibilities offered by these structures that this review elucidates the synthetic methods and describes the full chemical variety of terthiophenes and their derivatives. In the final part, an in-depth presentation of their numerous bioapplications intends to provide a complete picture of the state of the art.

Keywords: biosensing; conjugated polymers; photosensitizers; polythiophenes; terthiophenes; thiophene trimers.

Scheme 1

EDOT, thiophene, and terthiophene chemical structures.

Scheme 2

The two main synthetic routes for the obtaining of the trimer scaffold.

Scheme 3

Nickel-catalyzed Kumada reaction for the synthesis of terthiophene [16,18].

Scheme 4

Stille reaction for the synthesis of terthiophene [25,26,27,28].

Scheme 5

Suzuki reaction for the synthesis of terthiophene [33,35].

Scheme 6

Terthiophene synthesis by cyclization of 1,3-diynes [37].

Scheme 7

Synthesis of 1,4-dithienyl 1,4-diketone: (a) via Mannich reaction using 2-acethylthiophene, (b) via Friedel-Crafts reaction using thiophene; and cyclization to afford the terthiophene [45,46].

Scheme 8

Examples of alkyl-substituted terthiophenes (I) [124]; (II) [125]; (III) [126].

Scheme 9

Examples of unsaturated aliphatic groups on terthiophenes. (I) [149]; (II) [153]; (III) [154].

Scheme 10

Examples of nitro substituted trimers. (I) [163,164,192]; (II) [192]; (III) [191].

Scheme 11

Examples of amino substituted trimers. (I) [101]; (II) [198]; (III) [210].

Scheme 12

Examples of cyano-substituted trimers. (I) [223]; (II) [221]; (III,IV) [224].

Scheme 13

Examples of bromo substituted trimers. (I) [230]; (II) [249];(III) [254].

Scheme 14

Examples of fluoro-substituted trimers. (I) [249]; (II) [256]; (III) [260,261].

Scheme 15

Examples of hydroxyl-substituted trimers. (I) [275]; (II) [148]; (III) [282]; (IV) [271].

Scheme 16

Examples of ether-substituted trimers. (I) [288]; (II) [281]; (III) [305]; (IV) [62].

Scheme 17

Examples of carbonyl- (oxo) substituted trimers. (I) [259]; (II) [326]; (III) [334].

Scheme 18

Examples of carboxylic acid substituted trimers. (III) [249].

Scheme 19

Examples of ester-substituted trimers. (I) [346]; (II) [277]; (III) [376].

Scheme 20

Examples of amide-substituted trimers. (I) [377]; (II) [207]; (III) [366]; (IV) [202].

Scheme 21

Examples of fused-aromatic-substituted trimers. (I) [402]; (II) [166]; (III) [427]; (IV) [428].

Scheme 22

Examples of aromatic-substituted trimers. (I) [338]; (II) [448]; (III) [448]; (IV) [449]; (V) [162]; (VI) [458]; (VII) [462]; (XIII) [463]; (IX) [34]; (X) [445].

Scheme 23

Examples of S–S dioxide trimers (I) [466]; (II–IV) [472].

Scheme 24

Examples of fused-aromatic-substituted trimers. (I) [101]; (II) [475]; (III) [488] (counter anions have been omitted for clarity).

Scheme 25

Examples of charged trimers (I) [148]; (II) [492]; (III) [271] (counter ions have been omitted for clarity).

Scheme 26

Examples of crosslinked trimers (I) [499]; (II) [250]; (III) [503].

Figure 1

Different groups of trimer derivatives and related bioapplications.

Figure 2

(a) Different terthiophene-based compounds used as fluorescent dyes. (b) In vitro staining of HeLA cells with (I) Tt1; (II) brightfield image; (III) LysoTracker1 Red (specific dye for lysosome); and (IV) their overlapping images. Adapted with permission from ref. [519]. Copyright 2013 RSC Publishing.

Figure 3

(a) Molecular structures of the naphthalene-functionalized terthiophenes synthesized for detection of biogenic amines. (b) Left: top view of the sensor device based on a silver/terthiophene derivative thin film. Right: SEM cross-sectional image of the silver/terthiophene derivative thin film deposited on glass substrate. Adapted with permission from ref. [523] Copyright 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Figure 4

SPR gold chip preparation: (a) carboxylated terthiophene (T3C) molecule (left) and T3C SAM formed on gold surfaces (right); (b) in situ synthesis of progesterone (P4)-linker-ovalbumin on SPR gold. Reprinted with permission from ref. [304] Copyright 2019 Elsevier B.V.

Figure 5

(A) The chemical structure of α-terthienylmethanol. (B) Exponentially growing OVCAR3 cells were treated with the indicated concentrations of α-terthienylmethanol for 3 days. (● control; 0.05 μM; ▲, 0.1 μM; ▼, 0.2 μM; ♦, 1.0 μM; □, 2.0 μM). Cells were loaded on a hemocytometer, and viable cell number was determined. (C) OVCAR3 cells were treated with indicated concentrations of α-terthienylmethanol and the cell viability was determined using MTT assay. * p < 0.05 versus the control group. Copyright (2017) Elsevier [525].

Figure 6

Schematic representation of the rocuronium sensor. Reprinted with permission from reference [216]. Copyright Wiley & Sons 2018.

Figure 7

pTTP sensors for the detection of (a) glycated hemoglobin and (b) i-NOS. Adapted with permission from ref. [533] and ref. [539] Copyright 2013 and 2011, American Chemical Society.

Figure 8

(a) Fabrication scheme of the superhydrophobic polymeric surface. (b) Protein and bacterial adhesion onto the undoped (orange-colored film) and doped (green-colored film) polythiophene surfaces. Copyright (2012) American Chemical Society [543].