Chiral Polythiophenes: Part I: Syntheses of Monomeric Precursors

The purpose of this mini-review is to comprehensively present the synthetic approaches used for the preparation of non-racemic mono- and multi-substituted thiophenes, which, in turn, can be applied as precursors for the synthesis of chiral polythiophenes isolated as a single chemical entity or having supramolecular thin-layer architectures.


Introduction
The phenomenon of chirality plays a key role not only in plant and animal life, but also in the biological activity of drugs, food additives and agrochemicals [1][2][3][4][5]. In consequence, chiral structures are used very often as active components in pharmaceutical [6][7][8][9], agrochemical [10,11] and food formulations [12]. The last two decades have witnessed a growing demand for such derivatives as essential component of new materials including nonfunctionalized and functionalized polythiophenes (PTs). Interest in this group of synthetic polymeric materials comes from the hope that they may mimic the behavior of natural polymers and find application, for example, as chiral sensors, chiral catalysts and chiral chromatographic supports. When considering chiral PTs, the most readily available group should be derivatives of general formula 2 (Scheme 1) containing at least one substituent with a stereogenic center at the three-position (or at the four-position or both positions). They can be prepared by the chemical or electrochemical oxidation of the corresponding monomers of general formula 1 (unsubstituted or suitably functionalized in the two and/or five positions).

Introduction
The phenomenon of chirality plays a key role not only in plant and animal life, but also in the biological activity of drugs, food additives and agrochemicals [1][2][3][4][5]. In consequence, chiral structures are used very often as active components in pharmaceutical [6][7][8][9], agrochemical [10,11] and food formulations [12]. The last two decades have witnessed a growing demand for such derivatives as essential component of new materials including nonfunctionalized and functionalized polythiophenes (PTs). Interest in this group of synthetic polymeric materials comes from the hope that they may mimic the behavior of natural polymers and find application, for example, as chiral sensors, chiral catalysts and chiral chromatographic supports. When considering chiral PTs, the most readily available group should be derivatives of general formula 2 (Scheme 1) containing at least one substituent with a stereogenic center at the three-position (or at the four-position or both positions). They can be prepared by the chemical or electrochemical oxidation of the corresponding monomers of general formula 1 (unsubstituted or suitably functionalized in the two and/or five positions). Scheme 1. The general approach to conductive polymers 2 from the monomeric units 1.
The synthetic non-regioselective routes to 2,5-coupled, 3-substituted polythiophenes provides the polythiophenes with a lower degree of HT (head-to-tail) type coupling in the main polymeric chain. They contain more regiochemical defects, which results in a distortion of the conjugated chain and a lower effective conjugation. Among these methods are chemical oxidative coupling using the Sugimoto protocol [13] and dehalogenative polycondensation using Ni(COD) 2 [14]. The growing demand for the highly conductive materials applicable in electronic devices (i.e., field effect transistors, organic light-emitting diodes, photovoltaic cells, or sensors) induces the rapid developments in the regiospecific routes to regioregular PTs since the regioregular structure affects the improvement of their physicochemical properties and their self-organization. Most of the synthetic approaches are based on the transition metal-catalyzed coupling reactions [15][16][17]. The first synthesis of regioregular head-to-tail coupled poly(3-alkylthiophenes) (PATs) was reported by McCullough and Lowe [18]. In this approach, the starting material is 2-bromo-3-substituted thiophene, which is selectively metalated with lithium diisopropylamide (LDA) and then treated with magnesium bromide, which led to the formation of the corresponding Grignard reagents. Their coupling reaction is catalyzed by Ni(dppp)Cl 2 . The modification of this method, developed by McCollough, is the GRIM metathesis procedure, which requires the use of a 2,5-dibromo-substituted thiophene derivative. The substrate reacts with the Grignard reagent, forming the corresponding thienyl magnesium halides, which then undergo a Ni-catalyzed coupling reaction. The polymerization proceeds via a living chain growth polycondensation mechanism that was independently discovered by Yokozawa and McCullough in 2004 [19,20]. Another regiospecific polymerization route that provides head-to-tail (HT) coupling products is the so-called Rieke method. It involves Ni-catalyzed coupling of organozinc halides generated in situ from 2,5-dihalogented thiophene derivatives by reactive forms of zinc [21]. The exception is when the palladium catalyst [Pd(PPh 3 ) 4 ] is utilized in this reaction of organozinc species, leading to a regiorandom type of coupling.
All the above-mentioned regiospecific polymerizations giving access to a wide range of 3-substituted polythiophenes with enhanced chiroptical properties require the use of a Nibased catalyst and are based on the initial generation of organozinc or organomagnesium halides.
In turn, the Pd-catalyzed HT-coupling based polymerizations were also developed. These pathways demonstrate the good efficiency in Suzuki or Stille coupling reactions using boro-or organotin compounds generated from the starting 2-monohalo-thiophene derivatives. The Pd-catalyzed Stille or Suzuki polymerizations have already been found to proceed via step-growth polymerization and by a non-controlled mechanism providing the polymers with the lower polydispersity [15,22]. It should be noted that the organotin or organoboronic derivatives should be prepared under cryogenic conditions and they should be isolated prior to the next step.
Advances in the development of the efficient polymerization techniques leading to well-ordered conjugated polymers are based on some modifications, mostly in the Kumada-based polycondensation, which uses the internal initiator/catalyst and as well the recently applied external initiator species [23,24]. Kumada catalyst transfer condensative polymerization, being a modified GRIM method, is a controlled chain-growth polymerization that requires the use of a Ni-based chain initiator/catalyst.
The pool of controlled chain grow polymerizations complements a Pd-RuPhos protocol that is Pd-catalyzed Negishi coupling polymerization between organozinc compounds [25].
Dehydrohalogenative polycondensation is the other example of Ni-catalyzed [Ni (dppp)Cl 2 ] polymerization, which requires the use of a mono-halogenated thiophene substrate and a Knochel-Hauser base to proceed at room temperature with high regioregular couplings [26][27][28].
The other strategy to synthesize regioregular polythiophenes, apart from the selection of a methodology distinguished by the type of metal catalyst, the reaction conditions and the control over the polymerization of monomeric units, relies on designing the symmetrical units. In this way, regiochemically defined polythiophenes could be obtained from the units that contain the spacer block between 3-substituted thiophenes. Similarly, HH-TT coupled PATs and TT-HH PATs are accessible from regiochemically defined bithiophenes, i.e., the HH-dimer of substituted thiophene or TT dimers and synthesized via one of the non-regiospecific methods ( i.e. FeCl 3 -mediated chemical polymerization).
These studies were summarized less or more briefly, occasionally, as part of reviews on chiral conductive polymers [29][30][31][32][33]. It is obvious that in all the studies devoted to the synthetic and structural aspects in the chemistry of chiral PTs, the preparation of the appropriately designed monomeric substrate constitutes an indispensable opening stage. Reading the original chemical literature gives the impression that the topic is treated quite briefly and without taking into account sufficient experimental details, the knowledge of which should be more or less helpful for all researchers in this field, especially for beginners entering this fascinating and rapidly developing topic. Therefore, the main focus of this mini-review is to extensively discuss the applied synthetic approaches extracted from the original publications that have been published since the first article on this topic in 1988 [34]. Taking into accounts the analysis of the substrate requirements of the mentioned polymerization methods, we propose the organization of the manuscript based on the type of substitution in monomeric precursors. Below, one by one, we will present protocols leading to optically active (or in some cases to racemic) thiophene derivatives of general structure 1: (a) monothiophenes substituted at the three-position of the ring with a group containing a stereogenic center or stereogenic axis; (b) monothiophenes substituted at the three-position of the ring with a group containing a stereogenic center and at once functionalized at the two and/or five positions; (c) monothiophenes substituted at the three and four positions with a group(s) containing a stereogenic center and nonfunctionalized or functionalized at the two and/or five positions; (d) β-(mono or di) substituted bithiophenes functionalized with a substituent containing a stereogenic carbon atom or a stereogenic heteroatom; (e) other (oligo)thiophenes functionalized with a substituent containing a stereogenic carbon atom or a stereogenic heteroatom.
The monomer 7 (0.25 M solution) was oxidatively electropolymerized with an applied potential of 5 V, in a two-electrode cell consisting of a glassy-carbon working electrode (0.26 cm 2 ), a platinum wire counter electrode, in a dry MeCN and the Et4NBF4 (0.25 M) solution [35].
The chiral ordering in an aggregated conjugated poly{3-(S)- [2methylbutyl]thiophene} was examined too after producing the polymeric materials using the ferric chloride oxidative method [37]. The doping effect prior to aggregation along with the doping level was explored to find the factors contributing to control chiral arrangement in conjugated polymer aggregates.
Moreover, the studies on the polymerization also comprised their regioregular polymeric analogues. First, the synthesis of HT regioregular 2,5 coupled poly-3-(S)-2methylbutylthiophene was reported by Langeveld-Voss et al. [40]. Then, the regioregular polymer was prepared with a Ni(dppp)Cl2 catalyst using the Grignard metathesis developed by McCullough ] [38,41] However, this procedure requires the preparation of 2,5 di brominated precursor; therefore, this synthetic procedure will be mentioned below in the subsequent chapter.
The chiral ordering in an aggregated conjugated poly{3-(S)-[2-methylbutyl]thiophene} was examined too after producing the polymeric materials using the ferric chloride oxidative method [37]. The doping effect prior to aggregation along with the doping level was explored to find the factors contributing to control chiral arrangement in conjugated polymer aggregates.
Moreover, the studies on the polymerization also comprised their regioregular polymeric analogues. First, the synthesis of HT regioregular 2,5 coupled poly-3-(S)-2-methylbutylthiophene was reported by Langeveld-Voss et al. [40]. Then, the regioregular polymer was prepared with a Ni(dppp)Cl 2 catalyst using the Grignard metathesis developed by McCullough ] [38,41] However, this procedure requires the preparation of 2,5 di brominated precursor; therefore, this synthetic procedure will be mentioned below in the subsequent chapter.
The direct introduction of the substituent into the three position of the thiophene ring can be implemented by the Suzuki cross-coupling reaction, as illustrated in the synthesis of optically active (R)-3-(4-(4-ethyl-2-oxazolin-2-yl)phenyl)thiophene (EOPT) 18 [45]. The reaction occurred between 3-thiopheneboronic acid 17 and the oxazoline derivative 16 (prepared independently starting from ethyl 4-iodobenzoate and (R)-2amino-1-butanol via an optically active hydroxy amide derivative [46]). The reaction carried out in the presence of K3PO4 in toluene using Pd(PPh3)4 as a catalyst gave 18 (EOPT) in 85% yield (Scheme 4) [47]. The enantiomeric excess of 18 was estimated to be greater than 99% using europium tris[3 -(trifluoromethylhydroxymethylene)-(+)camphorate] (Eu(tfc)3) as a chiral shift reagent ( 1 H NMR spectrum measured in CDCl3). The regioregular polythiophene derived from monomeric thiophene 18 was synthesized according to a modified McCullough's procedure when monobrominated thiophene derivative was used as a starting material. Dehalogenative polycondensation according to a Yamamoto protocol was used as well, successfully starting from the dibrominated analogue of the monomer 18. It provided, however, the regiorandom polymer. The purpose of synthesizing the two polymers that differ in the regioregularity The reaction occurred between 3-thiopheneboronic acid 17 and the oxazoline derivative 16 (prepared independently starting from ethyl 4-iodobenzoate and (R)-2-amino-1butanol via an optically active hydroxy amide derivative [46]). The reaction carried out in the presence of K 3 PO 4 in toluene using Pd(PPh 3 ) 4 as a catalyst gave 18 (EOPT) in 85% yield (Scheme 4) [47]. The enantiomeric excess of 18 was estimated to be greater than 99% using europium tris [3 -(trifluoromethylhydroxymethylene The reaction occurred between 3-thiopheneboronic acid 17 and the oxazoline derivative 16 (prepared independently starting from ethyl 4-iodobenzoate and (R)-2amino-1-butanol via an optically active hydroxy amide derivative [46]). The reaction carried out in the presence of K3PO4 in toluene using Pd(PPh3)4 as a catalyst gave 18 (EOPT) in 85% yield (Scheme 4) [47]. The enantiomeric excess of 18 was estimated to be greater than 99% using europium tris[3 -(trifluoromethylhydroxymethylene)-(+)camphorate] (Eu(tfc)3) as a chiral shift reagent ( 1 H NMR spectrum measured in CDCl3). The regioregular polythiophene derived from monomeric thiophene 18 was synthesized according to a modified McCullough's procedure when monobrominated thiophene derivative was used as a starting material. Dehalogenative polycondensation according to a Yamamoto protocol was used as well, successfully starting from the dibrominated analogue of the monomer 18. It provided, however, the regiorandom polymer. The purpose of synthesizing the two polymers that differ in the regioregularity The regioregular polythiophene derived from monomeric thiophene 18 was synthesized according to a modified McCullough's procedure when monobrominated thiophene derivative was used as a starting material. Dehalogenative polycondensation according to a Yamamoto protocol was used as well, successfully starting from the dibrominated analogue of the monomer 18. It provided, however, the regiorandom polymer. The purpose of synthesizing the two polymers that differ in the regioregularity was to compare their chiroptical properties and to examine the influence of the regioregularity of the main chain on the induction of a chiral supramolecular aggregate in the chiral polythiophenes [47].
Among the optically active 3-alkylthiophene monomers, the most numerous groups are the compounds in which the alkyl group is functionalized at the terminal carbon atom by attaching a moiety containing a stereogenic center. The list of such compounds opens 3-[3-[(S)-2-phenylbutoxy)]propyl]thiophene 21a and its enantiomer 21b prepared by the reaction of the 3-(3 -thienyl)propyl toluene-p-sulfonate 19 with the enantiomers of 2-phenylbutanol 20a,b (Scheme 5) [34,48]. The monomers were next electropolymerized, applying a current density of 2 mA cm −2 in a one-compartment three-electrode cell containing the monomer and NBu 4 PF 6 in nitrobenzene. Chiral polythiophenes, poly-21a and poly-21b, feature a high conductivity and were able to stereoselectively recognize the chiral anions used as doping agents during voltammetric cycles [34]. was to compare their chiroptical properties and to examine the influence of the regioregularity of the main chain on the induction of a chiral supramolecular aggregate in the chiral polythiophenes [47]. Among the optically active 3-alkylthiophene monomers, the most numerous groups are the compounds in which the alkyl group is functionalized at the terminal carbon atom by attaching a moiety containing a stereogenic center. The list of such compounds opens 3-[3-[(S)-2-phenylbutoxy)]propyl]thiophene 21a and its enantiomer 21b prepared by the reaction of the 3-(3′-thienyl)propyl toluene-p-sulfonate 19 with the enantiomers of 2phenylbutanol 20a,b (Scheme 5) [34,48]. The monomers were next electropolymerized, applying a current density of 2 mA cm −2 in a one-compartment three-electrode cell containing the monomer and NBu4PF6 in nitrobenzene. Chiral polythiophenes, poly-21a and poly-21b, feature a high conductivity and were able to stereoselectively recognize the chiral anions used as doping agents during voltammetric cycles [34]. The preparation of 3-[2-((S)-2-methylbutoxy)ethyl]thiophene 24 was, for the first time, mentioned as early as 1994 in a paper coming from the Meijer's group [49]. They isolated it in 83% yield by reacting 2-(3-thienyl)ethanol 23 (obtained in 89% yield by a reduction of 3-thiopheneacetic acid with LiAIH4) with a tosylate 22 of the commercially available optically pure (S)-(−)-2-methyl-l-butanol 3. This protocol was later referenced, without specifying characterization details, in three other publications by this team [40,50,51]. On the other hand, the paper by Ochiai et al. [52] contains the full experimental details of the protocol presented in Scheme 6. This protocol is given below. The monomer, after its conversion into the 2,5-dibromosubstituted derivative, was used to obtain an optically active regioregular 2,5-coupled analogue, poly(3-[2-((S)-2methylbutoxy)ethyl]thiophene), containing a 93% HT head-to-tail linkage, according to the modified Rieke method [52]. The corresponding regiorandom poly-(S)-24 was obtained by the FeCl3-oxidative polymerization of 24 [49].
Another example of the condensation reaction aimed at appending a chiral moiety into the side chain of a 3-substituted thiophene derivative is the synthesis of the dextrorotatory enantiomer of thiophene containing an amino acid residue (+)-R-25a. The transformation begins with the conversion of 3-thienylethanol 23 to the corresponding tosylate and follows by the reaction with a protected unnatural amino acid, N-t-Boc-D-Ser (Scheme 7) [53]. A similar sequence of reactions using N-t-Boc-L-Ser gave the opposite enantiomer of ethoxythiophene (−)-S-25b. Their further transformations into the corresponding methyl esters of serine-substituted monothiophenes (+)-R-26a. or (−)-S-26b involve estrifications using Ag2O and MeI (Scheme 7) [54]. The preparation of 3-[2-((S)-2-methylbutoxy)ethyl]thiophene 24 was, for the first time, mentioned as early as 1994 in a paper coming from the Meijer's group [49]. They isolated it in 83% yield by reacting 2-(3-thienyl)ethanol 23 (obtained in 89% yield by a reduction of 3thiopheneacetic acid with LiAIH 4 ) with a tosylate 22 of the commercially available optically pure (S)-(−)-2-methyl-l-butanol 3. This protocol was later referenced, without specifying characterization details, in three other publications by this team [40,50,51]. On the other hand, the paper by Ochiai et al. [52] contains the full experimental details of the protocol presented in Scheme 6. This protocol is given below. The monomer, after its conversion into the 2,5-dibromosubstituted derivative, was used to obtain an optically active regioregular 2,5-coupled analogue, poly(3-[2-((S)-2-methylbutoxy)ethyl]thiophene), containing a 93% HT head-to-tail linkage, according to the modified Rieke method [52]. The corresponding regiorandom poly-(S)-24 was obtained by the FeCl 3 -oxidative polymerization of 24 [49].
Another example of the condensation reaction aimed at appending a chiral moiety into the side chain of a 3-substituted thiophene derivative is the synthesis of the dextrorotatory enantiomer of thiophene containing an amino acid residue (+)-R-25a. The transformation begins with the conversion of 3-thienylethanol 23 to the corresponding tosylate and follows by the reaction with a protected unnatural amino acid, N-t-Boc-D-Ser (Scheme 7) [53]. A similar sequence of reactions using N-t-Boc-L-Ser gave the opposite enantiomer of ethoxythiophene (−)-S-25b. Their further transformations into the corresponding methyl esters of serine-substituted monothiophenes (+)-R-26a. or (−)-S-26b involve estrifications using Ag 2 O and MeI (Scheme 7) [54].
The tert-butoxycarbonyl group was removed (using a TFA/DCM solution) prior to polymerization. The free amino acid substituted thiophene monomer (R)-25a and its methyl ester analogue 26a or its enantiomer 26b were polymerized using a method reported by Sugimoto et al. using chemical oxidation with FeCl3 in chloroform. The watersoluble polymers, converted into the ammonium chloride salts, were precipitated by adding acetone [53,54].
The tert-butoxycarbonyl group was removed (using a TFA/DCM solution) prior to polymerization. The free amino acid substituted thiophene monomer (R)-25a and its methyl ester analogue 26a or its enantiomer 26b were polymerized using a method reported by Sugimoto et al. using chemical oxidation with FeCl 3 in chloroform. The water-soluble polymers, converted into the ammonium chloride salts, were precipitated by adding acetone [53,54].
The compounds 32a,b and 33a,b were subjected to an anodic polymerization. It was reported that poly-(33b) was stable toward oxidative cycling. For poly-(33), the progressive electrochemical growth was observed in CH 2 Cl 2 with 0.1M Bu 4 NBF 4 as an inert electrolyte, while no polymerization occurred using CH 3 CN. used as chiral selectors in Pirkle's stationary phases [56,57], applied in HPLC enantioselective analysis [58].
Recently, a few racemic and optically active 2-(3 -thienyl)ethyl alkyl (aryl) sulfoxides 39a-c were prepared by reacting racemic or diasteromerically pure O-alkyl arene(alkyl) sulfinates 37a-f (prepared in turn from arene(alkane)sulfinyl chlorides 35a-c and an appropriate racemic or optically active alcohol 36) with 2-(3 -thienyl)ethylmagnesium bromide 38 (Scheme 10). [60]. Moreover, sulfoxides 39a and 42 were also obtained as racemates via the oxidation of the corresponding sulfides: 2-(3 -thienyl)ethyl p-tolyl 41 or 3-thienylmethyl p-tolyl 40 using a 30 wt% solution of hydrogen peroxide as an oxidizing reagent (Scheme 11) [60].  [61] and Johnson in 1974 [62] (Scheme 12), proceeded in an enantioselective manner, and took place with the retention of the configuration at the stereogenic sulfur atom. It is interesting to note that this sulfoximine, having 97% ee, showed only a very weak, almost an imperceptible cotton effect in the circular dichroism spectrum recorded in methylene chloride. The racemic nhexadecyl sulfoximine 46 was also obtained following this procedure.  [61] and Johnson in 1974 [62] (Scheme 12), proceeded in an enantioselective manner, and took place with the retention of the configuration at the stereogenic sulfur atom. It is interesting to note that this sulfoximine, having 97% ee, showed only a very weak, almost an imperceptible cotton effect in the circular dichroism spectrum recorded in methylene chloride. The racemic nhexadecyl sulfoximine 46 was also obtained following this procedure.  [62] (Scheme 12), proceeded in an enantioselective manner, and took place with the retention of the configuration at the stereogenic sulfur atom. It is interesting to note that this sulfoximine, having 97% ee, showed only a very weak, almost an imperceptible cotton effect in the circular dichroism spectrum recorded in methylene chloride. The racemic n-hexadecyl sulfoximine 46 was also obtained following this procedure.  [61] and Johnson in 1974 [62] (Scheme 12), proceeded in an enantioselective manner, and took place with the retention of the configuration at the stereogenic sulfur atom. It is interesting to note that this sulfoximine, having 97% ee, showed only a very weak, almost an imperceptible cotton effect in the circular dichroism spectrum recorded in methylene chloride. The racemic nhexadecyl sulfoximine 46 was also obtained following this procedure.
The N functionalization of racemic n-hexadecyl-2-(3 -thienyl)ethyl sulfoximine 45 was based on its reaction with 5-bromo-5 -hexyl-2,2 -bithiophene 47 in the presence of potassium carbonate and catalytic amounts of copper (I) iodide and N,N -dimethylethane-1,2-diamine (DMEDA) (Scheme 13) [60]. This protocol, leading to N-bithiophene derivative 48 constitutes a modification of the procedure described by Bolm in 2005 [63], by which this coupling reaction was carried out with cesium carbonate as a base. The N functionalization of racemic n-hexadecyl-2-(3′-thienyl)ethyl sulfoximine 45 was based on its reaction with 5-bromo-5′-hexyl-2,2′-bithiophene 47 in the presence of potassium carbonate and catalytic amounts of copper (I) iodide and N,N′-dimethylethane-1,2-diamine (DMEDA) (Scheme 13) [60]. This protocol, leading to N-bithiophene derivative 48 constitutes a modification of the procedure described by Bolm in 2005 [63], by which this coupling reaction was carried out with cesium carbonate as a base. Another class of monomers designed to synthesize new chiral polythiophenes in order to evaluate their properties are monothiophenes containing the substituent with a stereogenic phosphorus atom at the three-position of the ring. For this purpose, the phosphine oxide based monothiophene (−)-(S)-53a was synthesized first.
Upon alkylation of the metalated tert-butylphenylphosphine oxide 52b with 2-(3′ thienyl)ethyl bromide 28b (or chloride 28c), the optically active (S)-tert-butylphenyl-2-(3′thiophene)ethylphosphine oxide 53a could be isolated. The reaction proceeds with the retention of the configuration at a phosphinyl phosphorus atom and without detectable racemization (Scheme 15) [64]. This procedure was simultaneously patented [65,66] and applied for the preparation of racemic phosphine oxide rac-53. The N functionalization of racemic n-hexadecyl-2-(3′-thienyl)ethyl sulfoximine 4 was based on its reaction with 5-bromo-5′-hexyl-2,2′-bithiophene 47 in the presence potassium carbonate and catalytic amounts of copper (I) iodide and N,N′-dimethylethan 1,2-diamine (DMEDA) (Scheme 13) [60]. This protocol, leading to N-bithiophen derivative 48 constitutes a modification of the procedure described by Bolm in 2005 [63 by which this coupling reaction was carried out with cesium carbonate as a base. Another class of monomers designed to synthesize new chiral polythiophenes order to evaluate their properties are monothiophenes containing the substituent with stereogenic phosphorus atom at the three-position of the ring. For this purpose, th phosphine oxide based monothiophene (−)-(S)-53a was synthesized first.
Upon alkylation of the metalated tert-butylphenylphosphine oxide 52b with 2-( thienyl)ethyl bromide 28b (or chloride 28c), the optically active (S)-tert-butylphenyl-2-(3 thiophene)ethylphosphine oxide 53a could be isolated. The reaction proceeds with th retention of the configuration at a phosphinyl phosphorus atom and without detectab racemization (Scheme 15) [64]. This procedure was simultaneously patented [65,66] an applied for the preparation of racemic phosphine oxide rac-53. Another class of monomers designed to synthesize new chiral polythiophenes in order to evaluate their properties are monothiophenes containing the substituent with a stereogenic phosphorus atom at the three-position of the ring. For this purpose, the phosphine oxide based monothiophene (−)-(S)-53a was synthesized first.
Upon alkylation of the metalated tert-butylphenylphosphine oxide 52b with 2-(3 thienyl)ethyl bromide 28b (or chloride 28c), the optically active (S)-tert-butylphenyl-2-(3thiophene)ethylphosphine oxide 53a could be isolated. The reaction proceeds with the retention of the configuration at a phosphinyl phosphorus atom and without detectable racemization (Scheme 15) [64]. This procedure was simultaneously patented [65,66] and applied for the preparation of racemic phosphine oxide rac-53. The N functionalization of racemic n-hexadecyl-2-(3′-thienyl)ethyl sulfoximine 45 was based on its reaction with 5-bromo-5′-hexyl-2,2′-bithiophene 47 in the presence of potassium carbonate and catalytic amounts of copper (I) iodide and N,N′-dimethylethane-1,2-diamine (DMEDA) (Scheme 13) [60]. This protocol, leading to N-bithiophene derivative 48 constitutes a modification of the procedure described by Bolm in 2005 [63], by which this coupling reaction was carried out with cesium carbonate as a base. Another class of monomers designed to synthesize new chiral polythiophenes in order to evaluate their properties are monothiophenes containing the substituent with a stereogenic phosphorus atom at the three-position of the ring. For this purpose, the phosphine oxide based monothiophene (−)-(S)-53a was synthesized first.
Upon alkylation of the metalated tert-butylphenylphosphine oxide 52b with 2-(3′ thienyl)ethyl bromide 28b (or chloride 28c), the optically active (S)-tert-butylphenyl-2-(3′thiophene)ethylphosphine oxide 53a could be isolated. The reaction proceeds with the retention of the configuration at a phosphinyl phosphorus atom and without detectable racemization (Scheme 15) [64]. This procedure was simultaneously patented [65,66] and applied for the preparation of racemic phosphine oxide rac-53. Following the procedure of the reaction of sodium 2-(3 -thienyl)ethoxide 23b with tert-butylphenylposhinyl chloride 52c, the representative of the phosphonates, namely, racemic O-2-(3 -thienyl)ethyl tert-butylphenylphosphinate 54, was prepared in 93% yield (Scheme 16) [64]. Following the procedure of the reaction of sodium 2-(3′-thienyl)ethoxide 23b with tert-butylphenylposhinyl chloride 52c, the representative of the phosphonates, namely, racemic O-2-(3′-thienyl)ethyl tert-butylphenylphosphinate 54, was prepared in 93% yield (Scheme 16) [64].  [64]. Iron (III) chloride was the optimal oxidizing coupling agent, except for the polymerizations of optically active sulfoxides. Its use for polymerizing the enantiomerically pure sulfoxides failed in terms of isolating the optically active polymeric products. This was due to the release of gaseous HCl during polymerization, which led to racemization. The optical properties of the polythiophenes with different types of substitution were examined using UV-VIS and fluorescent spectroscopy, and the circular dichroism and polarimetric measurements were conducted to examine their chirality. The fluorescence quantum efficiency in the solutions of the regioirregularly 2,5-coupled polythiophenes reaches 24%.
The synthesis of the 3-substituted monothiophenes containing an alkyl side chain attached to the thiophene ring through a heteroatom was developed, as the presence of the heteroatom directly attached to the heterocyclic ring affects the properties of the monomers as well the products of their polymerizations.
One of the representatives is alkoxy substituted thiophene with an electro-donating substituent, optically active (+)-3-[(S)-(2-methylbutoxy)]thiophene (TOR*) 57, which was prepared in 67% yield by the acid catalyzed reaction of 3-methoxythiophene 55 with (S)-(−)-2-methyl-1-butanol 3 refluxed in a toluene solution for 24 h in the presence of a catalytic amounts of p-toluenesulfonic acid monohydrate (Scheme 17) [67]. The monomer (S)-57 was used to prepare novel, optically active oligothiophenes using synthetic methods suitable for obtaining regioregular head-to-tail and head-tohead/tail-to-tail derivatives (if starting from the bithiophene monomers). The chiral (S)-(2-methyl)butyl moiety was introduced into the three-position of the thiophene ring through heteroatoms, such as O as well S (present in the compound 58) to prepare  [64]. Iron (III) chloride was the optimal oxidizing coupling agent, except for the polymerizations of optically active sulfoxides. Its use for polymerizing the enantiomerically pure sulfoxides failed in terms of isolating the optically active polymeric products. This was due to the release of gaseous HCl during polymerization, which led to racemization. The optical properties of the polythiophenes with different types of substitution were examined using UV-VIS and fluorescent spectroscopy, and the circular dichroism and polarimetric measurements were conducted to examine their chirality. The fluorescence quantum efficiency in the solutions of the regioirregularly 2,5-coupled polythiophenes reaches 24%.
The synthesis of the 3-substituted monothiophenes containing an alkyl side chain attached to the thiophene ring through a heteroatom was developed, as the presence of the heteroatom directly attached to the heterocyclic ring affects the properties of the monomers as well the products of their polymerizations.
One of the representatives is alkoxy substituted thiophene with an electro-donating substituent, optically active (+)-3-[(S)-(2-methylbutoxy)]thiophene (TOR*) 57, which was prepared in 67% yield by the acid catalyzed reaction of 3-methoxythiophene 55 with (S)-(−)-2-methyl-1-butanol 3 refluxed in a toluene solution for 24 h in the presence of a catalytic amounts of p-toluenesulfonic acid monohydrate (Scheme 17) [67]. Following the procedure of the reaction of sodium 2-(3′-thienyl)ethoxide 23b with tert-butylphenylposhinyl chloride 52c, the representative of the phosphonates, namely, racemic O-2-(3′-thienyl)ethyl tert-butylphenylphosphinate 54, was prepared in 93% yield (Scheme 16) [64].  [64]. Iron (III) chloride was the optimal oxidizing coupling agent, except for the polymerizations of optically active sulfoxides. Its use for polymerizing the enantiomerically pure sulfoxides failed in terms of isolating the optically active polymeric products. This was due to the release of gaseous HCl during polymerization, which led to racemization. The optical properties of the polythiophenes with different types of substitution were examined using UV-VIS and fluorescent spectroscopy, and the circular dichroism and polarimetric measurements were conducted to examine their chirality. The fluorescence quantum efficiency in the solutions of the regioirregularly 2,5-coupled polythiophenes reaches 24%.
The synthesis of the 3-substituted monothiophenes containing an alkyl side chain attached to the thiophene ring through a heteroatom was developed, as the presence of the heteroatom directly attached to the heterocyclic ring affects the properties of the monomers as well the products of their polymerizations.
One of the representatives is alkoxy substituted thiophene with an electro-donating substituent, optically active (+)-3-[(S)-(2-methylbutoxy)]thiophene (TOR*) 57, which was prepared in 67% yield by the acid catalyzed reaction of 3-methoxythiophene 55 with (S)-(−)-2-methyl-1-butanol 3 refluxed in a toluene solution for 24 h in the presence of a catalytic amounts of p-toluenesulfonic acid monohydrate (Scheme 17) [67]. The monomer (S)-57 was used to prepare novel, optically active oligothiophenes using synthetic methods suitable for obtaining regioregular head-to-tail and head-tohead/tail-to-tail derivatives (if starting from the bithiophene monomers). The chiral (S)-(2-methyl)butyl moiety was introduced into the three-position of the thiophene ring through heteroatoms, such as O as well S (present in the compound 58) to prepare The monomer (S)-57 was used to prepare novel, optically active oligothiophenes using synthetic methods suitable for obtaining regioregular head-to-tail and head-to-head/tail-totail derivatives (if starting from the bithiophene monomers). The chiral (S)-(2-methyl)butyl moiety was introduced into the three-position of the thiophene ring through heteroatoms, such as O as well S (present in the compound 58) to prepare oligomeric regioregular HTcoupled oligomers being suitable models for the evaluation of the effect of the heteroatom presence in the side chain on the macromolecular aggregation and, consequently, on the chiroptical properties of the material in the solid state. The GRIM (Grignard metathesis) procedure, via a magnesium/bromine exchange, was adopted for the polymerization under a high regio control.
Molecules 2021, 26, x 12 of 30 oligomeric regioregular HT-coupled oligomers being suitable models for the evaluation of the effect of the heteroatom presence in the side chain on the macromolecular aggregation and, consequently, on the chiroptical properties of the material in the solid state. The GRIM (Grignard metathesis) procedure, via a magnesium/bromine exchange, was adopted for the polymerization under a high regio control. In turn, the sulfur analogue of 57, optically active (+)-3-[(S)-2methylbutylsulfanyl]thiophene 59, was obtained by the alkylation of potassium 3mercaptothiophenate 58b, prepared in situ by treating the parent 3-thiophenethiol 58a with potassium tert-butylate in ethanol, with the 1-bromo-2-methylbutane enantiomer, (+)-(S)-4 (Scheme 18) [68]. The monomer was, similar to its oxygen analogue, polymerized using the GRIM method. In the case of sulfides 61 and 62, the dehydrohalogenative polycondensation method was used for their polymerization The monobrominated products were the starting materials for a Kumada polymerization procedure that produces highly regioregular HT polythiophenes in high yields In this procedure Knochel's base [28,71] was used to deprotonate the monomer, and 0.5 mol % NiCl2(dppe) was applied as the catalyst. Poly- oligomeric regioregular HT-coupled oligomers being suitable models for the evaluation of the effect of the heteroatom presence in the side chain on the macromolecular aggregation and, consequently, on the chiroptical properties of the material in the solid state. The GRIM (Grignard metathesis) procedure, via a magnesium/bromine exchange, was adopted for the polymerization under a high regio control.
In turn, the sulfur analogue of 57, optically active (+)-3-[(S)-2methylbutylsulfanyl]thiophene 59, was obtained by the alkylation of potassium 3mercaptothiophenate 58b, prepared in situ by treating the parent 3-thiophenethiol 58a with potassium tert-butylate in ethanol, with the 1-bromo-2-methylbutane enantiomer, (+)-(S)-4 (Scheme 18) [68]. The monomer was, similar to its oxygen analogue, polymerized using the GRIM method. In the case of sulfides 61 and 62, the dehydrohalogenative polycondensation method was used for their polymerization The monobrominated products were the starting materials for a Kumada polymerization procedure that produces highly regioregular HT polythiophenes in high yields In this procedure Knochel's base [28,71] was used to deprotonate the monomer, and 0.5 mol % NiCl2(dppe) was applied as the catalyst. Poly-Scheme 19. Alkylation of potassium 3-mercaptothiophenate 58b by chiral bromo-alkanes (13) or (60) in the preparation of alkylsulfanylthiophenes and the route to their polymerization.
In the case of sulfides 61 and 62, the dehydrohalogenative polycondensation method was used for their polymerization The monobrominated products were the starting materials for a Kumada polymerization procedure that produces highly regioregular HT polythiophenes in high yields In this procedure Knochel's base [28,71] was used to deprotonate the monomer, and 0.5 mol % NiCl 2 (dppe) was applied as the catalyst. Poly-61 and poly-62 exhibited electrochemical behavior with reversible p-doping and dedoping processes. The helicity of chiral polymers was examined using the CD measurements taken in the solution and in the solid states. The CD measurements in solution showed strong bisignate cotton effects for the π-π* transitions in poly-(S)--61, whereas no cotton effect was observed for poly-62. The addition of MeOH, a poor solvent, to the polymers resulted in an increased CD signal corresponding to the formation of an ordered helical aggregation.

Syntheses of 3-Substituted Monothiophenes Functionalized in the Two Position
In this sub-class of monothiophenes substituted in the three-position with a substituent containing a stereogenic carbon atom or a stereogenic heteroatom and additionally functionalized in the two -position, the most abundant group are those with halogen substituents in the two--position. Additionally, in turn, among them, 2-bromo derivatives were the most often obtained. They are typically prepared by the bromination of the parent 3-substituted monothiophenes mentioned above with N-bromosuccinimide (NBS) under selected conditions, as summarized in Scheme 20.

Syntheses of 3-Substituted Monothiophenes Functionalized in the Two Position
In this sub-class of monothiophenes substituted in the three-position with a substituent containing a stereogenic carbon atom or a stereogenic heteroatom and additionally functionalized in the two -position, the most abundant group are those with halogen substituents in the two--position. Additionally, in turn, among them, 2-bromo derivatives were the most often obtained. They are typically prepared by the bromination of the parent 3-substituted monothiophenes mentioned above with N-bromosuccinimide (NBS) under selected conditions, as summarized in Scheme 20. As

Syntheses of 3-Substituted Monothiophenes Functionalized in the Two and Five Positions
In this sub-class of monothiophenes substituted in the three-position with a substituent containing a stereogenic carbon atom or a stereogenic heteroatom, the halogen-functionalized compounds in the two-and five-positions of the thiophene ring constitute the most abundant group. Additionally, in turn, among them, dibromo derivatives were most often prepared. They are prepared most easily by the dibromination of the parent 3-substituted using N-bromosuccinimide (NBS) or bromine.

Syntheses of 3-Substituted Monothiophenes Functionalized in the Two and Five Positions
In this sub-class of monothiophenes substituted in the three-position with a substituent containing a stereogenic carbon atom or a stereogenic heteroatom, the halogen-functionalized compounds in the two-and five-positions of the thiophene ring constitute the most abundant group. Additionally, in turn, among them, dibromo derivatives were most often prepared. They are prepared most easily by the dibromination of the parent 3-substituted using N-bromosuccinimide (NBS) or bromine.

Syntheses of 3-Substituted Monothiophenes Functionalized in the Two and Five Positions
In this sub-class of monothiophenes substituted in the three-position with a substituent containing a stereogenic carbon atom or a stereogenic heteroatom, the halogen-functionalized compounds in the two-and five-positions of the thiophene ring constitute the most abundant group. Additionally, in turn, among them, dibromo derivatives were most often prepared. They are prepared most easily by the dibromination of the parent 3-substituted using N-bromosuccinimide (NBS) or bromine. In this manner, 3-[(−) 3-(S)-3,7-dimethyoctyl]thiophene 15 was converted to -(−) 2,5 -

Syntheses of 3,4-Disubstituted Monothiophenes
The first dialkyl-substituted chiral polythiophene, PDMOT: poly-{3,4-bis[(S)-2methyloctyl]thiophene}, poly-96 was synthesized in 2002 [89]. The synthesis of its precursor, the monomer 96: 3,4-bis[(S)-2-methyloctyl]thiophene, was thereby developed and reported therein. It comprised the Kumada type coupling of 3,4-dibromothiophene 95 with (S)-2-methyloctylmagnesium bromide catalyzed by a Ni(II) catalyst to provide the product in 21% yield (Scheme 29). The precursor 96 was polymerized according to the Sugimoto protocol via the oxidative method. Interestingly, the UV-vis spectrum of PDMOT showed the absorption band at a shorter wavelength (λmax), 318 nm in chloroform, compared to monoalkyl-substituted polythiophenes. It was suggested that it could be due to the electronic effects of the electron donating alkyl side chains or due to their steric demands. It was assumed that the steric effects of the two branched chiral alkyl side chains in the polythiophene are responsible for an unusual CD spectrum and the significant thermo-and solvato-driven effects observed in the CD spectra. The monomer 89 was used for copolymerization with 2,5-bistannylated thiophene or 2 ,5 '-distanyllated bithiophene via a Pd-catalyzed Stille polycondensation reaction. The chiral aggregation for the obtained polymers, poly-89a and poly-89b, was investigated using CD spectroscopy measurements.

Syntheses of 3,4-Disubstituted Monothiophenes
The first dialkyl-substituted chiral polythiophene, PDMOT: poly-{3,4-bis[(S)-2methyloctyl]thiophene}, poly-96 was synthesized in 2002 [89]. The synthesis of its precursor, the monomer 96: 3,4-bis[(S)-2-methyloctyl]thiophene, was thereby developed and reported therein. It comprised the Kumada type coupling of 3,4-dibromothiophene 95 with (S)-2-methyloctylmagnesium bromide catalyzed by a Ni(II) catalyst to provide the product in 21% yield (Scheme 29). The precursor 96 was polymerized according to the Sugimoto protocol via the oxidative method. Interestingly, the UV-vis spectrum of PDMOT showed the absorption band at a shorter wavelength (λmax), 318 nm in chloroform, compared to monoalkyl-substituted polythiophenes. It was suggested that it could be due to the electronic effects of the electron donating alkyl side chains or due to their steric demands. It was assumed that the steric effects of the two branched chiral alkyl side chains in the polythiophene are responsible for an unusual CD spectrum and the significant thermo-and solvato-driven effects observed in the CD spectra.

Syntheses of 3,4-Disubstituted Monothiophenes
The first dialkyl-substituted chiral polythiophene, PDMOT: poly-{3,4-bis[(S)-2-methyloctyl]thiophene}, poly-96 was synthesized in 2002 [89]. The synthesis of its precursor, the monomer 96: 3,4-bis[(S)-2-methyloctyl]thiophene, was thereby developed and reported therein. It comprised the Kumada type coupling of 3,4-dibromothiophene 95 with (S)-2-methyloctylmagnesium bromide catalyzed by a Ni(II) catalyst to provide the product in 21% yield (Scheme 29). The precursor 96 was polymerized according to the Sugimoto protocol via the oxidative method. Interestingly, the UV-vis spectrum of PDMOT showed the absorption band at a shorter wavelength (λmax), 318 nm in chloroform, compared to monoalkyl-substituted polythiophenes. It was suggested that it could be due to the electronic effects of the electron donating alkyl side chains or due to their steric demands. It was assumed that the steric effects of the two branched chiral alkyl side chains in the polythiophene are responsible for an unusual CD spectrum and the significant thermoand solvato-driven effects observed in the CD spectra. While exploring the EDOT (ethylenedioxythiophene) derivatives, it was shown that the Mitsunobu reaction was an efficient route for the synthesis of mono-and disubstituted EDOTs and 3,4-propylenedioxythiophenes (ProDOTs) [90,91]. However, the one drawback it suffered from was a moderate yield, which prevailed in the case of the Mitsunobu reaction for synthesizing disubstituted EDOTs.
Later, the same research group demonstrated the high yielding alternative for the synthesis of the EDOT monomers achieved by transetherification of 3,4dimethoxythiophene 103 with (chiral) glycols 104 [92]. The chiral 3,4ethylenedioxythiophenes EDOTs, having two substituents at the ethylene bridge, containing two stereogenic centers in their units, were designed to ensure high regioregularity in the subsequent polymerization to produce chiral PEDOTs. In fact, it was also demonstrated that the stereochemistry of the monomers affected the electronic properties of the corresponding chiral PEDOT derivatives.
Later, the same research group demonstrated the high yielding alternative for the synthesis of the EDOT monomers achieved by transetherification of 3,4-dimethoxythiophene 103 with (chiral) glycols 104 [92]. The chiral 3,4-ethylenedioxythiophenes EDOTs, having two substituents at the ethylene bridge, containing two stereogenic centers in their units, were designed to ensure high regioregularity in the subsequent polymerization to produce chiral PEDOTs. In fact, it was also demonstrated that the stereochemistry of the monomers affected the electronic properties of the corresponding chiral PEDOT derivatives.
The general synthetic protocol comprises the reactions of 3,4-dimethoxythiophene 97 with glycol derivatives 98a-d catalyzed by p-toluenesulfonic acid (Scheme 30). While exploring the EDOT (ethylenedioxythiophene) derivatives, it was shown that the Mitsunobu reaction was an efficient route for the synthesis of mono-and disubstituted EDOTs and 3,4-propylenedioxythiophenes (ProDOTs) [90,91]. However, the one drawback it suffered from was a moderate yield, which prevailed in the case of the Mitsunobu reaction for synthesizing disubstituted EDOTs.
Later, the same research group demonstrated the high yielding alternative for the synthesis of the EDOT monomers achieved by transetherification of 3,4dimethoxythiophene 103 with (chiral) glycols 104 [92]. The chiral 3,4ethylenedioxythiophenes EDOTs, having two substituents at the ethylene bridge, containing two stereogenic centers in their units, were designed to ensure high regioregularity in the subsequent polymerization to produce chiral PEDOTs. In fact, it was also demonstrated that the stereochemistry of the monomers affected the electronic properties of the corresponding chiral PEDOT derivatives.
The procedure used for the synthesis of monomeric 3,4-propylenedioxythiophenes was modified in respect to a protocol for the racemic analogues described earlier [94]. The chiral alcohols, (2S)-methylbutanol 100a and (2S)-ethylhexanol 100b, were converted into the corresponding tosylates. The resulting products reacted with diethyl malonate anion
The procedure used for the synthesis of monomeric 3,4-propylenedioxythiophenes was modified in respect to a protocol for the racemic analogues described earlier [94]. The chiral alcohols, (2S)-methylbutanol 100a and (2S)-ethylhexanol 100b, were converted into the corresponding tosylates. The resulting products reacted with diethyl malonate anion
The procedure used for the synthesis of monomeric 3,4-propylenedioxythiophenes was modified in respect to a protocol for the racemic analogues described earlier [94]. The chiral alcohols, (2S)-methylbutanol 100a and (2S)-ethylhexanol 100b, were converted into the corresponding tosylates. The resulting products reacted with diethyl malonate anion
The procedure used for the synthesis of monomeric 3,4-propylenedioxythiophenes was modified in respect to a protocol for the racemic analogues described earlier [94]. The chiral alcohols, (2S)-methylbutanol 100a and (2S)-ethylhexanol 100b, were converted into the corresponding tosylates. The resulting products reacted with diethyl malonate anion
The procedure used for the synthesis of monomeric 3,4-propylenedioxythiophenes was modified in respect to a protocol for the racemic analogues described earlier [94]. The chiral alcohols, (2S)-methylbutanol 100a and (2S)-ethylhexanol 100b, were converted into the corresponding tosylates. The resulting products reacted with diethyl malonate anion
The procedure used for the synthesis of monomeric 3,4-propylenedioxythiophenes was modified in respect to a protocol for the racemic analogues described earlier [94]. The chiral alcohols, (2S)-methylbutanol 100a and (2S)-ethylhexanol 100b, were converted into the corresponding tosylates. The resulting products reacted with diethyl malonate anion
The procedure used for the synthesis of monomeric 3,4-propylenedioxythiophenes was modified in respect to a protocol for the racemic analogues described earlier [94]. The chiral alcohols, (2S)-methylbutanol 100a and (2S)-ethylhexanol 100b, were converted into the corresponding tosylates. The resulting products reacted with diethyl malonate anion
The procedure used for the synthesis of monomeric 3,4-propylenedioxythiophenes was modified in respect to a protocol for the racemic analogues described earlier [94]. The chiral alcohols, (2S)-methylbutanol 100a and (2S)-ethylhexanol 100b, were converted into the corresponding tosylates. The resulting products reacted with diethyl malonate anion
The procedure used for the synthesis of monomeric 3,4-propylenedioxythiophenes was modified in respect to a protocol for the racemic analogues described earlier [94]. The chiral alcohols, (2S)-methylbutanol 100a and (2S)-ethylhexanol 100b, were converted into the corresponding tosylates. The resulting products reacted with diethyl malonate anion
The procedure used for the synthesis of monomeric 3,4-propylenedioxythiophenes was modified in respect to a protocol for the racemic analogues described earlier [94]. The chiral alcohols, (2S)-methylbutanol 100a and (2S)-ethylhexanol 100b, were converted into the corresponding tosylates. The resulting products reacted with diethyl malonate anion 99d-trans 47 The procedure used for the synthesis of monomeric 3,4-propylenedioxythiophenes was modified in respect to a protocol for the racemic analogues described earlier [94]. The chiral alcohols, (2S)-methylbutanol 100a and (2S)-ethylhexanol 100b, were converted into the corresponding tosylates. The resulting products reacted with diethyl malonate anion to give malonic acid esters. Upon reduction with LiAlH 4 , the corresponding di-ols 101a,b were obtained. Transetherification of the latter with 3,4-dimethoxythiophene 97 afforded oxidatively polymerizable ProDOT-((2S)-methylbutyl) 2 (102a) and ProDOT-((2S)-ethylhexyl) 2 (102b) (Scheme 31). To obtain the corresponding polymers with enantiomerically pure sidechains, bromination with NBS preceded a nickel-catalyzed Grignard metathesis polymerization. The optical properties of the polymer poly-102b were studied using UV-vis absorption, fluorescence and CD spectroscopy, and compared to the chiral methylbutyl derivative poly-102a. The aggregation process was followed by CD spectroscopy, which indicated that the two polymer forms chiral helical aggregates were similar to other chiral alkyl polythiophenes. Notably, the polymer poly-102b was recognized to have a fluorescence with a high quantum yield of 0.43 in xylene solution, while in the xylene/DMFmixture, along with a small decrease in the fluorescence quantum yield down to 0.28, a red-shift of the absorbance in the UV-vis spectrum was observed. Upon the addition of the poor solvent, a red-shift of the absorption spectrum and the vibronic features suggested more ordered, planar chains. to give malonic acid esters. Upon reduction with LiAlH4, the corresponding diols 101a,b were obtained. Transetherification of the latter with 3,4-dimethoxythiophene 97 afforded oxidatively polymerizable ProDOT-((2S)-methylbutyl)2 (102a) and ProDOT-((2S)ethylhexyl)2 (102b) (Scheme 31). To obtain the corresponding polymers with enantiomerically pure sidechains, bromination with NBS preceded a nickel-catalyzed Grignard metathesis polymerization. The optical properties of the polymer poly-102b were studied using UV-vis absorption, fluorescence and CD spectroscopy, and compared to the chiral methylbutyl derivative poly-102a. The aggregation process was followed by CD spectroscopy, which indicated that the two polymer forms chiral helical aggregates were similar to other chiral alkyl polythiophenes. Notably, the polymer poly-102b was recognized to have a fluorescence with a high quantum yield of 0.43 in xylene solution, while in the xylene/DMFmixture, along with a small decrease in the fluorescence quantum yield down to 0.28, a red-shift of the absorbance in the UV-vis spectrum was observed. Upon the addition of the poor solvent, a red-shift of the absorption spectrum and the vibronic features suggested more ordered, planar chains. Among the class of π-conjugated polymers, polythiophenes with two alkylsulfanyl substituents in the β positions were also subject to detailed research. This class of polymers are expected to act as sensors for palladium or ruthenium by the quenching of their fluorescence to a greater extent than the quenching observed for nonthio functionalized polythiophenes.
The representative for the studies was 3,4-bis(3,7-dimethyloctylthio)thiophene, 104, with a structure designed to possess well solubilizing chains attached to sulfur atoms, which was first synthesized and was then polymerized by oxidative coupling with iron(III) chloride, to give polythiophene derivative poly-104 (Scheme 32) [95].  Among the class of π-conjugated polymers, polythiophenes with two alkylsulfanyl substituents in the β positions were also subject to detailed research. This class of polymers are expected to act as sensors for palladium or ruthenium by the quenching of their fluorescence to a greater extent than the quenching observed for nonthio functionalized polythiophenes.
The representative for the studies was 3,4-bis(3,7-dimethyloctylthio)thiophene, 104, with a structure designed to possess well solubilizing chains attached to sulfur atoms, which was first synthesized and was then polymerized by oxidative coupling with iron(III) chloride, to give polythiophene derivative poly-104 (Scheme 32) [95]. to give malonic acid esters. Upon reduction with LiAlH4, the corresponding diols 101a,b were obtained. Transetherification of the latter with 3,4-dimethoxythiophene 97 afforded oxidatively polymerizable ProDOT-((2S)-methylbutyl)2 (102a) and ProDOT-((2S)ethylhexyl)2 (102b) (Scheme 31). To obtain the corresponding polymers with enantiomerically pure sidechains, bromination with NBS preceded a nickel-catalyzed Grignard metathesis polymerization. The optical properties of the polymer poly-102b were studied using UV-vis absorption, fluorescence and CD spectroscopy, and compared to the chiral methylbutyl derivative poly-102a. The aggregation process was followed by CD spectroscopy, which indicated that the two polymer forms chiral helical aggregates were similar to other chiral alkyl polythiophenes. Notably, the polymer poly-102b was recognized to have a fluorescence with a high quantum yield of 0.43 in xylene solution, while in the xylene/DMFmixture, along with a small decrease in the fluorescence quantum yield down to 0.28, a red-shift of the absorbance in the UV-vis spectrum was observed. Upon the addition of the poor solvent, a red-shift of the absorption spectrum and the vibronic features suggested more ordered, planar chains. Among the class of π-conjugated polymers, polythiophenes with two alkylsulfanyl substituents in the β positions were also subject to detailed research. This class of polymers are expected to act as sensors for palladium or ruthenium by the quenching of their fluorescence to a greater extent than the quenching observed for nonthio functionalized polythiophenes.
The representative for the studies was 3,4-bis(3,7-dimethyloctylthio)thiophene, 104, with a structure designed to possess well solubilizing chains attached to sulfur atoms, which was first synthesized and was then polymerized by oxidative coupling with iron(III) chloride, to give polythiophene derivative poly-104 (Scheme 32) [95].  In the further studies, chiral bis-alkyloxo-substituted 111 and bis-alkylthio polythienylethynylene 112 derivatives have been synthesized to examine their affinity to coordinate transition metals and the influence of aggregation on the quenching of fluorescence upon coordination to metals [95]. The synthetic pathway started with the iodination of 105 and 106 at the two-and five-position by N-iodosuccinimide (NIS). The iodinated products, 107 and 108, were acetylated by a reaction with trimethylsilylacetylene catalyzed by tetrakis(triphenylphosphine)palladium(0) and copper(I) iodide. The TMS-protected intermediate was treated with tetrabutylammonium fluoride to remove the silyl group to give 109 and 110.
Molecules 2021, 26, x 21 In the further studies, chiral bis-alkyloxo-substituted 111 and bis-alky polythienylethynylene 112 derivatives have been synthesized to examine their affini coordinate transition metals and the influence of aggregation on the quenchin fluorescence upon coordination to metals [95]. The synthetic pathway started with iodination of 105 and 106 at the two-and five-position by N-iodosuccinimide (NIS) iodinated products, 107 and 108, were acetylated by a reaction trimethylsilylacetylene catalyzed by tetrakis(triphenylphosphine)palladium(0) copper(I) iodide. The TMS-protected intermediate was treated with tetrabutylammon fluoride to remove the silyl group to give 109 and 110.
These monomers, 109 and 110, and iodinated monothiophene monomers 107 and were subjected to Pd-catalyzed polycondensation to give the corresponding polymer and 112 (Scheme 33).

Syntheses of β-Substituted Bithiophenes Functionalized with a Substituent Containing a Stereogenic Carbon Atom or a Stereogenic Heteroatom
The polyfluorene-thiophene copolymers have attracted much attention due to optical and electrical properties. One of the components in the π-conjugated co-poly a polyfluorene derivative, is responsible for high photoluminescence quantum yi good solubility and an interesting thermotropic liquid crystalline nature. The se component, polythiophene derivative, provides good processability and un properties that are tunable by various side chains. The polyfluorene-thiop copolymers, such as: poly [9,9- (Figure 1) [78], having chiral side ch located, in each of the model compound, in a different distance from the fluorene u were obtained and screened for their optical properties. The synthesis of 113 and 114 achieved via the Pd catalyzed Suzuki coupling method by reacting dibromides 77 124, respectively, with 9,9-dihexylfluorene-2,7-bis(trimethylene boronate) (Scheme Both copolymers exhibited a solvatochromism that was related to the strong organization of the copolymers. In the circular dichroism spectra, strong bisignate Co effects were observed in the methanol/chloroform mixed solutions.

Syntheses of β-Substituted Bithiophenes Functionalized with a Substituent Containing a Stereogenic Carbon Atom or a Stereogenic Heteroatom
The polyfluorene-thiophene copolymers have attracted much attention due to their optical and electrical properties. One of the components in the π-conjugated co-polymer, a polyfluorene derivative, is responsible for high photoluminescence quantum yields, good solubility and an interesting thermotropic liquid crystalline nature. The second component, polythiophene derivative, provides good processability and unique properties that are tunable by various side chains. The polyfluorene-thiophene copolymers, such as: poly [9,9- (Figure 1) [78], having chiral side chains located, in each of the model compound, in a different distance from the fluorene units, were obtained and screened for their optical properties. The synthesis of 113 and 114 was achieved via the Pd catalyzed Suzuki coupling method by reacting dibromides 77 and 124, respectively, with 9,9-dihexylfluorene-2,7bis(trimethylene boronate) (Scheme 34). Both copolymers exhibited a solvatochromism that was related to the strong self-organization of the copolymers. In the circular dichroism spectra, strong bisignate Cotton effects were observed in the methanol/chloroform mixed solutions.   The β,β'-Disubstituted bithiophene with two (S)-2-methylbutylsulfanyl substituents was prepared and applied as a monomer for chemical (FeCl3) or electrochemical polymerization, leading to a regioregular head-to-head/tail-to-tail poly(β,β'-disubstituted bithiophene) [97].
Among the designed structures of chiral unsymmetrical β-alkylsulfanyl bithiophenes are 4-bromo-4 -[(S)-2-methylbutylsulfanyl]-2,2 -bithiophene 124 and 4-iodo-4 -[(S)-2-methylbutylsulfanyl]-2,2 -bithiophene 125, which were synthesized as shown in Scheme 36. The Stille-type coupling between a tin-(122) and a halo-derivative (121) was applied to obtain the intermediate bithiophenes 123. Tert-butylammonium fluoride was used for the desilylation to form compound 124, while 58% hydroiodic acid was the desilylating agent and allowed the bromide to be replaced with iodide at once to give compound 125. The synthesis of the modified bithiophenes, bearing one-alkylsulfanyl substituent in the β-position and one other substituent in the β'-position, was further developed [68]. The purpose of these studies was to gain a better insight into the reactivity of βalkylsulfanyl-substituted bithiophenes as they were converted into the octithiophene derivatives via one-pot oxidative coupling with FeCl3.
The synthesis of chiral (R)-and (S)-copolymers consisting of poly(p-terphenylene)s and poly(bithienylene-phenylene)s has been developed [99]. The polymers were distinguished by valuable fluorescent and photo responsive properties. Upon irradiation of ultraviolet and visible light, the polymers showed reversible quenching and emitting behaviors as a result of the photo-chemical isomerization of the dithienylethene fragments. The precursor of these polymers is the monomer (R)-129, the synthetic route of which is shown in Scheme 38.  The axial stereogenicity was introduced into the skeleton of a π-conjugated copolymer by a new molecular building block with versatile synthetic handles, a tetrasubstituted adamantane derivative 130, synthesized from achiral 2,6adamantanedione and 4-bromocatechol. Thus, the formed racemic bromide 130 was further converted into the electroactive monomers 131 and 132 after adopting the Suzuki coupling methodology (Scheme 39). The structures of the two monomers differed in terminal thienyl units, the first of those contained the monothiophenes at the ends of the core, while the second contained the terminal bithiophene units. The racemic electroactive polymers built from axially stereogenic adamantyl segments, were synthesized by electropolymerization of the monomers 131 and 132, respectively [100]. The chiral fragment was delivered by a 2-methyloctyl chain appended to the hydroxyl of the 4-hydroxybenzoic acid. For its introduction, ethyl ester of the 4-hydroxybenzoic acid was coupled with (S)-2-nonanol under the Mitsunobu reaction conditions to obtain (R)-126.
The axial stereogenicity was introduced into the skeleton of a π-conjugated copolymer by a new molecular building block with versatile synthetic handles, a tetrasubstituted adamantane derivative 130, synthesized from achiral 2,6-adamantanedione and 4-bromocatechol. Thus, the formed racemic bromide 130 was further converted into the electroactive monomers 131 and 132 after adopting the Suzuki coupling methodology (Scheme 39). The structures of the two monomers differed in terminal thienyl units, the first of those contained the monothiophenes at the ends of the core, while the second contained the terminal bithiophene units. The racemic electroactive polymers built from axially stereogenic adamantyl segments, were synthesized by electropolymerization of the monomers 131 and 132, respectively [100].

Conclusions
In summary, this mini-review discusses the synthetic routes to mono-or bithiophene derivatives containing substituent(s) with a chiral element (stereogenic center or chiral axis) that can then serve as substrates in the polymerization reaction. We hope that the protocols for the synthesis of chiral monomeric thiophenes presented in this article will help practitioners of organic chemistry to design an appropriate pathway to obtain new valuable thiophene derivatives as chiral precursors of conjugated (co)polymers. The review covers the synthetic routes to derivatives that are functionalized at the β (β') positions of the thiophene rings and those that are functionalized at one or both of the α positions. This division is due to the fact that, depending on the polymerization method under consideration, differently substituted mono-or bithiophenes are needed. The intended second part of the review will discuss various polymerization methods, the choice of which depends on the ease of access to the optically active monomeric substrate and the laboratory conditions allowing the selected polymerization technique to be used from among the following: McCullough's approach, the Grignard metathesis (GRIM) reaction, the Rieke zinc coupling reaction, the Yamamoto condensation, the dehydrohalogenative polycondensation, the Kumada catalyst transfer condensation polymerization (KCTCP), the FeCl3-mediated polymerization (chemical oxidative polymerization), other transition metal catalyzed methods based on the Stille, Suzuki cross-coupling reactions or electropolymerization.
Author Contributions: All the authors, D.K., R.K. and J.D., contributed equally to the preparation of this review paper and should be considered as corresponding authors. All authors have read and agreed to the published version of the manuscript.

Conclusions
In summary, this mini-review discusses the synthetic routes to mono-or bithiophene derivatives containing substituent(s) with a chiral element (stereogenic center or chiral axis) that can then serve as substrates in the polymerization reaction. We hope that the protocols for the synthesis of chiral monomeric thiophenes presented in this article will help practitioners of organic chemistry to design an appropriate pathway to obtain new valuable thiophene derivatives as chiral precursors of conjugated (co)polymers. The review covers the synthetic routes to derivatives that are functionalized at the β (β') positions of the thiophene rings and those that are functionalized at one or both of the α positions. This division is due to the fact that, depending on the polymerization method under consideration, differently substituted mono-or bithiophenes are needed. The intended second part of the review will discuss various polymerization methods, the choice of which depends on the ease of access to the optically active monomeric substrate and the laboratory conditions allowing the selected polymerization technique to be used from among the following: McCullough's approach, the Grignard metathesis (GRIM) reaction, the Rieke zinc coupling reaction, the Yamamoto condensation, the dehydrohalogenative polycondensation, the Kumada catalyst transfer condensation polymerization (KCTCP), the FeCl 3 -mediated polymerization (chemical oxidative polymerization), other transition metal catalyzed methods based on the Stille, Suzuki cross-coupling reactions or electropolymerization.
Author Contributions: All the authors, D.K., R.K. and J.D., contributed equally to the preparation of this review paper and should be considered as corresponding authors. All authors have read and agreed to the published version of the manuscript.