Synthesis of Optically Active Poly (diphenylacetylene) s Using Polymer

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Synthesis of Optically Active Poly(diphenylacetylene)s Using Polymer Reactions and an Evaluation of Their Chiral Recognition Abilities as Chiral Stationary Phases for HPLC Katsuhiro Maeda *, Miyuki Maruta, Yuki Sakai, Tomoyuki Ikai and Shigeyoshi Kanoh Graduate School of Natural Science and Technology, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan; [email protected] (M.M.); [email protected] (Y.S.); [email protected] (T.I.); [email protected] (S.K.) * Correspondence: [email protected]; Fax: +81-76-234-4783 Academic Editor: Yoshio Okamoto Received: 14 October 2016; Accepted: 4 November 2016; Published: 7 November 2016

Abstract: A series of optically active poly(diphenylacetylene) derivatives bearing a chiral substituent (poly-2S) or chiral and achiral substituents (poly-(2Sx -co-31−x )) on all of their pendant phenyl rings were synthesized by the reaction of poly(bis(4-carboxyphenyl)acetylene) with (S)-1-phenylethylamine ((S)-2) or benzylamine (3) in the presence of a condensing reagent. Their chiroptical properties and chiral recognition abilities as chiral stationary phases (CSPs) for high-performance liquid chromatography (HPLC) were investigated. Poly-2S and poly-(2Sx -co-31−x ) (0.06 < x < 0.71) formed a preferred-handed helical conformation with opposite helical senses after thermal annealing despite possessing the same chiral pendant (h-poly-2S and h-poly-(2Sx -co-31−x )). Furthermore, h-poly-2S and h-poly-(2S0.36 -co-30.64 ) emitted circularly polarized luminescence with opposite signs. h-Poly-2S showed higher chiral recognition abilities toward a larger number of racemates than poly-2S without a preferred-handed helicity and the previously reported preferred-handed poly(diphenylacetylene) derivative bearing the same chiral substituent on half of its pendant phenyl rings. h-Poly-(2S0.36 -co-30.64 ) also exhibited good chiral recognition abilities toward several racemates, though the elution order of some enantiomers was reversed compared with h-poly-2S. Keywords: high-performance liquid chromatography (HPLC); chiral stationary phase; enantioseparation; poly(diphenylacetylene); helix; helix inversion

1. Introduction It is well known that a pair of enantiomers often show significant differences in their physiological activities. The development of efficient techniques for the separation of enantiomers is therefore important in several fields, especially in the pharmaceutical industry. The direct separation of enantiomers by high-performance liquid chromatography (HPLC) using a chiral stationary phase (CSP) is currently one of the most popular and effective methods for both analyzing the composition of enantiomeric mixtures and purifying such mixtures to give pure enantiomers [1–6]. However, the success of this method is entirely dependent on the development of effective CSPs with excellent resolving abilities. A large number of optically active small molecules [7–11] and polymers [1–3,12–15] have been evaluated to date as CSPs for HPLC. However, the development of novel CSPs with excellent resolving abilities is still highly desired because there are still several chiral compounds that cannot be resolved using existing commercially available CSPs. Optically active poly(phenylacetylene)s with a preferred-handed helicity have been prepared [16] and some of these systems have been reported to exhibit good chiral recognition abilities as CSPs for Molecules 2016, 21, 1487; doi:10.3390/molecules21111487

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HPLC because of their preferred-handed helical conformation [17–26]. However, very few optically active Molecules poly(diphenylacetylene)s have been prepared to date, which has limited research 2016, 21, 1487 2 oftowards 14 evaluating the scope and efficiency of the chiral recognition abilities of these materials [27–35]. for HPLC because of their preferred-handed helical conformation [17–26]. However, very few optically We recently reported the first example of an optically active poly(diphenylacetylene)-based CSP for active poly(diphenylacetylene)s have been prepared to date, which has limited research towards HPLC [36]. In this particular case, we synthesized an optically active poly(diphenylacetylene) bearing evaluating the scope and efficiency of the chiral recognition abilities of these materials [27–35]. We a chiral pendant amidethe moiety (poly-4S) 1) byactive the reaction of an optically inactive recently reported first example of (Figure an optically poly(diphenylacetylene)-based CSPprecursor for polymer bearing a pendant carboxyl group with the optically active amine (S)-1-phenylethylamine HPLC [36]. In this particular case, we synthesized an optically active poly(diphenylacetylene) bearing (S)-2. The results revealed this(poly-4S) polymer showed chiral recognition towards various a chiral pendant amidethat moiety (Figure 1) bygood the reaction of an opticallyability inactive precursor polymer bearing pendant with optically active amine (S)-1-phenylethylamine racemates when it wasa used as acarboxyl CSP forgroup HPLC andthe that its chiral recognition ability was significantly (S)-2. The revealed that this polymer showed good chiral recognition towards varioushelical dependent on results its preferred-handed helical conformation. Notably, the ability preferred-handed racemates when it was used as a CSP for HPLC and that its chiral recognition ability was significantly conformation of the polymer was induced by the thermal annealing process (h-poly-4S), which was dependent on its preferred-handed helical conformation. Notably, the preferred-handed helical applied after the introduction of the optically active pendants via a polymer reaction. The chiral conformation of the polymer was induced by the thermal annealing process (h-poly-4S), which was recognition abilities ofintroduction h-poly-4S with a preferred-handed helicity greater than those of poly-4S applied after the of the optically active pendants viawere a polymer reaction. The chiral without a preferred-handed helicity. This result indicatedhelicity that the macromolecular helicity induced recognition abilities of h-poly-4S with a preferred-handed were greater than those of poly-4S in the without polymer backbone by thermal annealing as a consequence of the effect of the chiral pendant a preferred-handed helicity. This result indicated that the macromolecular helicity induced the playing polymer an backbone by thermal as a consequence the effect of the chiral pendant groupsinwas important role in annealing the high chiral recognitionofability of this material. This finding groups was playing an important role in the high chiral recognition ability of this material. This therefore inspired us to synthesize several other optically active poly(diphenylacetylene)s with the therefore inspired us to synthesize several other optically active poly(diphenylacetylene)s aim offinding developing more practically useful poly(diphenylacetylene)-based CSPs for HPLC. Although with the aim of developing more practically useful poly(diphenylacetylene)-based CSPs for HPLC. poly(diphenylacetylene)s have pendant phenyl rings on all of the carbons in their main chain, only Although poly(diphenylacetylene)s have pendant phenyl rings on all of the carbons in their main half ofchain, the pendent phenyl rings in poly-4S feature an amide functional group, which could act as only half of the pendent phenyl rings in poly-4S feature an amide functional group, which effective chiral sites. In this study, and synthesized several novel optically could act asrecognition effective chiral recognition sites. Inwe thisdesigned study, we designed and synthesized several novel active optically poly(diphenylacetylene)s bearing chiral or achiral which were which connected active poly(diphenylacetylene)s bearing chiralsubstituents, or achiral substituents, wereto the connected the pendant phenyl rings of the an polymer through an amide bond (poly-2S xand polypendant phenyltorings of the polymer through amide bond (poly-2S and poly-(2S -co-3 1–x )). We (2S x -co-3 1–x )). We also investigated the chiroptical properties and chiral recognition abilities of these also investigated the chiroptical properties and chiral recognition abilities of these materials as CSPs materials as CSPs for HPLC. for HPLC.

Figure ofpoly-4S. poly-4S. Figure1.1.The Thestructure structure of 2. Results and Discussion 2. Results and Discussion The synthetic route used to prepare poly-2S and poly-(2Sx-co-31–x) is shown in Scheme 1. The

The synthetic route used to prepare poly-2S and poly-(2Sx -co-3 in Scheme 1. 1–x ) is shown direct polymerization of diphenylacetylene monomers bearing polar functional groups, such as The direct polymerization of diphenylacetylene functional such as carboxyl and amide groups, hardly proceedsmonomers because thebearing group polar 5 transition metalsgroups, used for carboxyl and amideof groups, hardly proceeds because to thesuch group transition metals used for polymerization disubstituted acetylenes are intolerant polar5functional groups [37,38]. With this inof mind, the carboxylacetylenes groups of the diphenylacetylene monomer were protected as the polymerization disubstituted are intolerant to such polar(1)functional groups [37,38]. corresponding n-heptyl esters prior to being polymerized in toluene with WCl 6 –Ph 4 Sn at 100 °C. With this in mind, the carboxyl groups of the diphenylacetylene monomer (1) were protected these conditions have been reported be being effectivepolymerized for the polymerization of diphenylacetylenes as theNotably, corresponding n-heptyl esters priortoto in toluene with WCl6 –Ph4 Sn ◦ at 100 C. Notably, these conditions have been reported to be effective for the polymerization

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bearing ester groups [32,39]. It was also envisaged that the long alkyl (n-heptyl) chains of the ester of diphenylacetylenes bearing ester groups [32,39]. It was also envisaged that the long alkyl groups would enhance the solubility of the resulting polymer in toluene. The polymerization reaction (n-heptyl) chains of the ester groups would enhance the solubility of the resulting polymer in toluene. of 1 proceeded smoothly to give poly-1 with a moderate molecular weight (Mn = 1.3 × 104, Mw/Mn = The polymerization reaction of 1 proceeded smoothly to give poly-1 with a moderate molecular 1.6) in high yield (77%).4 The ester groups in poly-1 were then hydrolyzed under alkaline conditions weight (Mn = 1.3 × 10 , Mw /Mn = 1.6) in high yield (77%). The ester groups in poly-1 were then to give poly-1-H. The complete removal of the n-heptyl esters was confirmed by 1H-NMR and IR hydrolyzed under alkaline conditions to give poly-1-H. The complete removal of the n-heptyl esters spectroscopy (Figures S1 and S2). Poly-2S was prepared in a similar manner to that previously was confirmed by 1 H-NMR and IR spectroscopy (Figures S1 and S2). Poly-2S was prepared in a reported for poly-4S [36], by the polymer reaction of poly-1-H with (S)-2 using 4-(4,6-dimethoxysimilar manner to that previously reported for poly-4S [36], by the polymer reaction of poly-1-H 1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMT-MM) as a condensing reagent. The near with (S)-2 using 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMT-MM) as a complete introduction of the (S)-2 residue was confirmed by 1H NMR, IR and elemental 1analyses condensing reagent. The near complete introduction of the (S)-2 residue was confirmed by H NMR, (Figures S1 and S3). Poly-(2Sx-co-31–x)s were synthesized by the two-step polymer reaction of poly-1IR and elemental analyses (Figures S1 and S3). Poly-(2Sx -co-31–x )s were synthesized by the two-step H with (S)-2, followed by benzylamine (3) using DMT-MM as a condensing reagent. Poly-1-H was polymer reaction of poly-1-H with (S)-2, followed by benzylamine (3) using DMT-MM as a condensing initially reacted with (S)-2 in the presence of a controlled amount of DMT-MM to allow for the reagent. Poly-1-H was initially reacted with (S)-2 in the presence of a controlled amount of DMT-MM introduction of a small number of (S)-2 units as the pendant groups. The resulting material was then to allow for the introduction of a small number of (S)-2 units as the pendant groups. The resulting reacted with an excess of 3 in the presence of an excess of DMT-MM. The (S)-2 unit contents (x) of the material was then reacted with an excess of 3 in the presence of an excess of DMT-MM. The (S)-2 resulting poly-(2Sx-co-31–x)s were determined by 1H-NMR analysis (see Figure S3). Poly-(2Sx-co-31–x)s unit contents (x) of the resulting poly-(2Sx -co-31–x )s were determined by 1 H-NMR analysis (see Figure containing different amounts of the (S)-2 units were obtained by changing the feed ratio of DMT-MM S3). Poly-(2Sx -co-31–x )s containing different amounts of the (S)-2 units were obtained by changing relative to poly-1-H whilst maintaining that of (S)-2 relative to DMT-MM ([(S)-2]/[DMT-MM] = 2) the feed ratio of DMT-MM relative to poly-1-H whilst maintaining that of (S)-2 relative to DMT-MM (Table S1). The (S)-2 unit contents of the resulting polymers were found to correspond to approximately ([(S)-2]/[DMT-MM] = 2) (Table S1). The (S)-2 unit contents of the resulting polymers were found to one-third of an equivalent of the DMT-MM feed in the first step. correspond to approximately one-third of an equivalent of the DMT-MM feed in the first step.

Scheme −x).). Scheme1.1.Synthesis Synthesisof ofpoly-2S poly-2Sand andpoly-(2S poly-(2Sxx-co-3 -co-311−x

The circular dichroism (CD) spectrum of poly-2S showed almost no circular dichroism (CD) in the wavelength wavelength region longer longer than 300 nm ascribed to the absorption of the polymer backbone in N,N-dimethylformamide N,N-dimethylformamide (DMF) (DMF) immediately immediately after after the the preparation preparation of of the the sample sample (Figure (Figure 2a) 2a) [27,32–35]. [27,32–35]. However, an an apparent apparentCotton Cottoneffect effectwas wasobserved observed around 400 after Furthermore, the around 400 nmnm after oneone day.day. Furthermore, the CD CD intensity slowly increased with time DMF °C,but butititdid didnot notreach reach aa constant constant value intensity veryvery slowly increased with time in in DMF at at 2525◦ C, even after 8 days (Figure S4a). When When the the solution solution was was annealed annealed at higher temperatures, the CD ◦ C, intensity (Δε 400400 = ca. −21)−after 5 h at590 °C 90 or ◦2Ch or at 120 which intensity rapidly rapidlyincreased increasedtotoreach reacha aplateau plateau (∆ε = ca. 21) after h at 2 h °C, at 120 was accompanied by a negligible change change in the absorption spectra (Figure and Figures and S5). which was accompanied by a negligible in the absorption spectra2b (Figure 2b and S4b Figures S4b These results that a predominantly one-handed helical conformation was induced in the and S5). Theseindicated results indicated that a predominantly one-handed helical conformation was induced polymer backbone by thermal annealing owing to the effect of the optically active pendants (h-poly2S). A similar thermal annealing was necessary for poly-4S to form the preferred-handed helical

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in the polymer backbone by thermal annealing owing to the effect of the optically active pendants Molecules 2016, 21, 1487 4 of 14 (h-poly-2S). A similar thermal annealing was necessary for poly-4S to form the preferred-handed helicalconformation conformation (h-poly-4S) [27,36]. This result was attributed to steric hindrance between the (h-poly-4S) [27,36]. This result was attributed to steric hindrance between the neighboring pendant phenyl rings, which waswas large enough to to prevent neighboring pendant phenyl rings, which large enough preventpoly-2S poly-2Sand andpoly-4S poly-4S from from being transformed into their preferred-handed helical conformations after the introduction of the optically being transformed into their preferred-handed helical conformations after the introduction of the active pendants. activeoptically pendants.

2. and CD and absorption spectraofofpoly-2S poly-2S (a) (b)(b) in in N,N-dimethylformamide FigureFigure 2. CD absorption spectra (a) and andh-poly-2S h-poly-2S N,N-dimethylformamide (DMF) at 25 °C. h-Poly-2S was obtained by annealing poly-2S in DMF at 120 °C h. 2 h. ◦ ◦ C2for (DMF) at 25 C. h-Poly-2S was obtained by annealing poly-2S in DMF at 120 for

The poly-(2Sx-co-31−x)s were converted to the corresponding h-poly-(2Sx-co-31−x)s with predominantly

The poly-(2S converted to by theannealing corresponding h-poly-(2S one-handed helical conformations the same way the corresponding DMF solutions x -co-3 x -co-3 1−x )s were in 1−x )s with at 120 °C for 2 h. Figure 3 helical shows the CD and absorption spectra the h-poly-(2S x-co-31–x )s in DMF at predominantly one-handed conformations in the sameofway by annealing the corresponding ◦ C for °C together of h-poly-2S. The CD 3intensities these (Δε of the first Cottonof the DMF 25 solutions at with 120 those 2 h. Figure shows of the CDpolymers and absorption spectra effect) were plotted against their chiral (S)-2 unit contents, as shown in Figure 4. Interestingly, ◦ h-poly-(2Sx -co-31–x )s in DMF at 25 C together with those of h-poly-2S. The CD intensitiesthe of these Cotton effects of the h-poly-(2Sx-co-31–x)s gave the opposite sign to that of h-poly-2S when the (S)-2 polymers (∆ε of the first Cotton effect) were plotted against their chiral (S)-2 unit contents, as shown content was below ca. 71 mol %. Furthermore, the CD spectrum of h-poly-(2S0.36-co-30.64) was almost in Figure 4. Interestingly, the Cotton effects of the h-poly-(2Sx -co-3 the opposite sign to 1–x )singave a mirror image of that of h-poly-2S accompanied with a negligible change the absorption. These that ofresults h-poly-2S when the (S)-2 content was below ca. 71 mol %. Furthermore, the CD spectrum of indicated that the poly-(2Sx-co-31–x)s (x < 0.71) existed in a predominantly one-handed helical h-poly-(2S ) was almost helical-sense a mirror image of of that of h-poly-2S accompanied a negligible conformation with an opposite to that h-poly-2S. This system therefore with allowed for 0.36 -co-30.64 theinselective formation of right-results and left-handed using a single 2 as in a change the absorption. These indicatedhelical that structures the poly-(2S (x < 0.71) of existed x -co-3 1–x )senantiomer the chiral unit, with the actual being dependent the mole fraction of 2.to Similar helical predominantly one-handed helicaloutcome conformation with an on opposite helical-sense that of h-poly-2S. sense inversion behaviors in the copolymers consisting of chiral and achiral units depending on the This system therefore allowed for the selective formation of right- and left-handed helical structures contents of the chiral units have been also reported in polyisocyanates [40], polysilanes [41], using a single enantiomer of 2 as the chiral unit, with the actual outcome being dependent on the mole polyacetylenes [42–44], polyisocyanides [45] and poly(quinoxaline-2,3-diyl)s [46]. It has also been fraction of 2. Similar helical sense inversion behaviors in the copolymers consisting of chiral and achiral reported that these phenomena can be explained using a modified version of the Ising model units depending theetcontents of the unitsishave been also in polyisocyanates proposed byon Sato al., where the chiral helix-sense determined by reported the interactions between the [40], polysilanes [41], polyacetylenes [42–44], polyisocyanides [45] and poly(quinoxaline-2,3-diyl)s neighboring pendant groups, chiral–chiral units and chiral–achiral units, which can stabilize the [46]. It has opposite also been reported these[47]. phenomena can be explained using a modified version of the helix-sense to that each other Poly(diphenylacetylene)s are where highly emissive without the introduction by of any fluorescent Ising model proposed by Sato et al., the helix-sense is determined the other interactions between substituents,pendant whereas poly(phenylacetylene)s generally non-emissive materials [38,48]. With this the the neighboring groups, chiral–chiral are units and chiral–achiral units, which can stabilize in mind, we investigated the relationship between the main-chain conformation and the circularly opposite helix-sense to each other [47]. polarized luminescence (CPL) properties of h-poly-2S and h-poly-(2S0.36-co-30.64). The CPL and Poly(diphenylacetylene)s are highly emissive without the introduction of any other fluorescent photoluminescence (PL) spectra of h-poly-2S, h-poly-(2S0.36-co-30.64) and poly-(2S0.36-co-30.64) in DMF substituents, whereas poly(phenylacetylene)s arethese generally non-emissive materials With this in are shown in Figure 5. Photographic images of solutions under irradiation at 365[38,48]. nm are shown mind,inwe investigated theand relationship the main-chain conformation and the circularly Figure S6. h-Poly-2S h-poly-(2S0.36between -co-30.64) showed equal and opposite CPL bands around 520 polarized luminescence (CPL)with properties of h-poly-2S and h-poly-(2S ). The CPL and nm, which were consistent the corresponding PL bands. In contrast, 0.36 no -co-3 apparent CPL signal 0.64 was observed for poly-(2S 0.36 -co-3 0.64 ). The signs of the CPL signals at 520 nm were identical to those photoluminescence (PL) spectra of h-poly-2S, h-poly-(2S0.36 -co-30.64 ) and poly-(2S0.36 -co-30.64 ) in DMF of thein CD band 5. around 400 nm and the values of the emissionunder dissymmetry factorat(g365 lum), which is are shown Figure Photographic images of these solutions irradiation nm are shown defined as glum = 2(IL − IR)/(IL + IR), where IL and IR are the intensities of the left- and right-handed in Figure S6. h-Poly-2S and h-poly-(2S0.36 -co-30.64 ) showed equal and opposite CPL bands around 520 nm, which were consistent with the corresponding PL bands. In contrast, no apparent CPL signal

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was observed for poly-(2S0.36 -co-30.64 ). The signs of the CPL signals at 520 nm were identical to those of the CD band around 400 nm and the values of the emission dissymmetry factor (glum ), which is Molecules 2016, 21, 1487 5 of 14 defined as glum = 21, 2(I1487 Molecules 2016, 5 of 14 L − IR )/(IL + IR ), where IL and IR are the intensities of the left- and right-handed − 3 circularly polarized light, respectively, were estimated to be 1.2 × 10 for h-poly-2S and 0.8 × 10−3 circularly polarized light, respectively, were estimated to be 1.2 × 10−3−3 for h-poly-2S and 0.8 × 10−3−3 for circularly polarized light, respectively, were estimated to be 1.2 × 10 for h-poly-2S and 0.8 × 10 for for h-poly-(2S -co-30.64 Theseresults resultsindicated indicated that h-poly-2S h-poly-(2S -co-3 ) can emit 0.36 0.360.64 0.64emit h-poly-(2S 0.36-co-30.64 ). ).These that h-poly-2S andand h-poly-(2S 0.36-co-3 ) can h-poly-(2S0.36-co-30.64). These results indicated that h-poly-2S and h-poly-(2S0.36-co-30.64) can emit opposite CPL CPL originating from thethe preferred-handed helicalconformation conformation with opposite helical opposite originating from preferred-handed helical with opposite helical sense sense opposite CPL originating from the preferred-handed helical conformation with opposite helical sense toother each other despite having the samecentral centralchirality chirality in their pendants. to each despite having the same in their pendants. to each other despite having the same central chirality in their pendants.

◦ C. CD and absorption spectra of poly-(2S x-co-31–x) -co-3 and h-poly-2S DMF at 25 °C. h-poly-(2S FigureFigure 3. 3. CD absorption spectra of poly-(2S DMF at xx-25 1–x ) andin Figure 3. CDand and absorption spectra of poly-(2S x-co-31–xx) and h-poly-2S inh-poly-2S DMF at 25 in °C. h-poly-(2S 1–x) and h-poly-2 were obtained by annealing poly-(2Sx-co-31–x) and poly-2S, respectively, in DMF co-3 h-poly-(2S ) andwere h-poly-2 were obtained by annealing poly-2S, x -co-3 x -co-31–x ) and ) and1–x h-poly-2 obtained by annealing poly-(2S x-co-31–x) and poly-(2S poly-2S, respectively, in DMF co-31–x at 120 °C for 2 h. respectively, infor DMF at 120 °C 2 h. at 120 ◦ C for 2 h.

Figure 4. Plots of the Δε1st values of h-poly-(2Sx-co-31–x) and h-poly-2S in DMF at 25 °C vs. their chiral ◦C 4. Plots the1stΔε 1st values h-poly-(2S x-co-31–x))and in DMF at 25 their FigureFigure 4. Plots of theof∆ε values of of h-poly-(2S h-poly-2S in DMF at°C 25vs. vs. chiral their chiral x -co-3 1–x andh-poly-2S (S)-2 unit contents (x). (S)-2contents unit contents (S)-2 unit (x). (x).

The chiral recognition abilities of poly-2S, h-poly-2S and h-poly-(2S0.36-co-30.64) as CSPs for HPLC The chiral recognition abilities of poly-2S, h-poly-2S and h-poly-(2S0.36-co-30.64) as CSPs for HPLC

were evaluated using abilities the various racemic h-poly-2S compounds with different0.36 functional (5–12) The chiral recognition of poly-2S, h-poly-(2S -co-30.64 )groups as CSPs for HPLC were evaluated using the various racemic compoundsand with different functional groups (5–12) including axial (13, 14) or planar (15) chiral compounds as well as chiral metal complexes (16–18) were evaluated the14) various racemic compounds with as different (5–12) including including using axial (13, or planar (15) chiral compounds well as functional chiral metalgroups complexes (16–18) (Figure 6). The packing materials were prepared by coating macroporous silica gel (particle size 7 (Figure packing were prepared by coating macroporous silica gel (particle 7 axial (13, 14) 6). or The planar (15) materials chiral compounds as well as chiral metal complexes (16–18)size (Figure 6). μm, pore size 100 nm) with DMF solutions of the corresponding polymers [49]. The obtained packing μm, pore size 100 nm) with DMF solutions of the corresponding polymers [49]. The obtained packing The packing materials were prepared by coating macroporous silica gel (particle size 7 µm, pore size materials were subsequently packed into a stainless steel column (25 × 0.20 cm (i.d.)) using a materials were solutions subsequently the packed into a stainless steel column (25 ×obtained 0.20 cm (i.d.)) using a 100 nm) with DMF corresponding polymers [49]. The packing materials conventional slurry methodof [50]. The chromatographic resolution results are summarized in Table 1 conventional slurry method [50]. The chromatographic resolution results are summarized in Table 1 were subsequently packed obtained into a stainless steel column (25 × cmon(i.d.)) using a conventional and the chromatograms for the resolutions of racemic 150.20 and 16 poly-2Sand h-poly-2Sand the chromatograms obtained for the resolutions of racemic 15 and 16 on poly-2S- and h-poly-2Sslurrybased method The chromatographic resolution are summarized Table and the CSPs[50]. are shown in Figure 7. Ultraviolet (UV) andresults polarimetric (PM) detectorsin were used1 for based CSPs are shown in Figure 7. Ultraviolet (UV) and polarimetric (PM) detectors were used for the detection and identification of the peaks, respectively. As shown in Figure and 7c, the different chromatograms obtained for the resolutions of racemic 15 and 16 on poly-2Sh-poly-2S-based the detection and identification of the peaks, respectively. As shown in Figure 7c, the different of 16 were eluted with retention of t1 ((–)-enantiomer) and t2 ((+)-enantiomer), CSPs enantiomers are shown in Ultraviolet (UV) times and (PM) detectors were used for the enantiomers of Figure 16 were7.eluted with retention timespolarimetric of t1 ((–)-enantiomer) and t2 ((+)-enantiomer), detection and identification of the peaks, respectively. As shown in Figure 7c, the different enantiomers

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showed complete baseline separation on the poly-2S-based CSP. The retentionwhich factor k1 (k1 = Molecules 2016,a21, 1487 retention 6 of showed 14 ofwhich 16 were eluted with times of t1 ((–)-enantiomer) and t2 ((+)-enantiomer), 1 − t0)/t0) for the first eluted enantiomer, the separation factor α (α = (t2 − t0)/(t1 − t0)) and the resolution (t a complete baseline separation on the poly-2S-based CSP. The retention factor k1 (k1 = (t1 − t0 )/t0 ) which complete baseline separation onhold-up the poly-2S-based CSP. The w retention factor (k1 = factor S (Rshowed S = 2(t2 a t1)/(w1 + w 2)), where t0 is the time w1 and 2 are the bandk1widths of for the Rfirst eluted −enantiomer, the separation factor α (α = (tand 2 − t0 )/(t1 − t0 )) and the resolution 1 − t0)/t0) for the first eluted enantiomer, the separation factor α (α = (t2 − t0)/(t1 − t0)) and the resolution (t the firstand second-eluted enantiomers on the base line, were determined to be 0.14, 19.5 and 10.2, factorfactor RS (RR − t1 )/(w w22)),)),where where t0 the is the hold-up ww2and the bandofwidths S S=(R2(t 2 are S =2 2(t2 − t1)/(w11 + +w t0 is hold-up timetime and wand 1 and 1 are w the band widths ofrespectively. thethe firstand second-eluted enantiomers on the base line, were determined to be 0.14, 19.5 and first- and second-eluted enantiomers on the base line, were determined to be 0.14, 19.5 and 10.2, 10.2, respectively. respectively.

Figure 5. CPL and h-poly-2 (blue line), line), h-poly-(2S -co-30.64) (red line)line) and)and poly-(2S 0.36Figure 5. CPL andand PL PL spectra ofofh-poly-2 (blue h-poly-(2S 0.36-co-30.640.36 ) (red poly-(2S 0.36 Figure 5. CPL PLspectra spectra of h-poly-2 (blue line), 0.36 h-poly-(2S -co-3 line) and 0.64 (red at 388 nm. [polymer] = 1.0 × 10−5 M.−5 co-30.64) (green line) in DMF at 25 °C with excitation ◦ (green DMFline) at 25in°C withatexcitation at excitation 388 nm. [polymer] = 1.0 × 10 M.= 1.0 × 10−5 M. co-30.64) 0.36 poly-(2S -co-3line) (green DMF 25 C with at 388 nm. [polymer] 0.64 ) in

Figure 6. Structures of racemates 5–18.

Figure Structures racemates 5–18. Figure 6. 6.5–18 of racemates Table 1. Resolution results for racemates on poly-2S, h-poly-2S, 5–18. h-poly-(2S 0.36-co-30.64) and h-poly-4S a. Poly-2S

h-poly-2S

h-Poly-(2S0.36-co-30.64)

h-Poly-4S e

Racemates Table 1.1. Resolution results for racemates 5–18 on poly-2S, h-poly-2S, h-poly-(2S 0.36-co-30.64 ) and h-poly-4S Table Resolution results for racemates 5–18 onRspoly-2S, h-poly-2S, h-poly-(2S -co-3 ) and a. k1 Rs k1 k1 k1 0.36 Rs α α 0.64 Rs α α a h-poly-4S . 0.90 (−) 5 1.17 1.27 1.39 (−) 1.25 1.96 2.81 (+) 1.07 0.90 1.75 (−) 1.06 0.86e

Poly-2S h-poly-2S h-Poly-(2S0.36-co-30.64) h-Poly-4S 0.47 (−) ca. 1 — 0.60 (−) ca. 1 — 1.49 (+) 1.09 0.83 1.16 (−) 1.14 1.06 k1 Rs k1 k1 k1 Rs Rs Rs α α α α 7 0.14Poly-2S (+) ca. 1 — 0.12 (+) ca. 1 — 0.25 (−) ca. 1 — 0.41 (−) ca. 1 e h-poly-2S h-Poly-(2S0.36 -co-30.64 ) h-Poly-4S— 5 0.90 0.90 (−) (+) 1.17ca. 1 1.27— 1.39 1.25 1.96 7.19 2.81 1.07 0.950.90 5.71 (+) 1.75 (−)1.13 1.06 Racemates 8 0.74(−) (+) 1.14 1.15 (+)(+) 1.07 1.63 0.86 k1 (−) α ca. 1 R— k1 (−) α R— k(−) α Rs k1 (−)1.0 1.14 α — R s — s s 1 (+) 6 d 0.47 0.60 1.49 1.09 1.06 9 0.93 (+) d ca. 1.141 0.92 1.90 1.07 0.650.83 2.141.16 0.90 (+) dca. 1 75 0.14(− (+)) (+) 1.17 ca. 11.05 1.27 —0.86 1.39 0.12 (+) ca. — 0.25 (−) ca.1.07 ca. — 0.461.75 0.41(−(−) ca.— 1 0.86 — (− ) 1.25 2.81 (+) ) ca. 1 1.06 10 0.90 3.62 3.24 (+) ca. 1 1.96 — 0.61 (+) 1 1 —0.90 (+) (− ) ca. 1 — 1.49 (+) 1.09 0.83 ) 1.16 1.14 11 0.47 8.94 12.4 (+) 1.20 2.49 (+) (+) 1.43 1.06 86 0.90(− (+)) (+) ca. ca. 111.13 — —1.72 0.60 0.74 (+) 1.14 1.15 17.6 7.19 (+) 1.04 1.07 0.50 0.95 22.71.16 5.71(−(+) 1.13 1.63 0.14 (+) (+) 0.12 (+) 1 — 0.25 ((−) −) d ca.ca. (−) 1.51 ca.1.0 1 —— 0.47d (+) ca. 0.41 1.48 1.07 1 1 —— (+)2.14 1.08 97 12 b 0.90 ca. 111.44 — —1.18 0.93 (+)(+)d ca. 1.14 0.92 3.84 1.90(+) 1.07 0.65 1.100.41 8 0.90 (+) ca. 1 —1.83 0.74 (+)(−) 1.14 7.19(+) (+) 1.07 1.13 0.95 3.91 5.71 (+) 1.0 1.13— 1.63 b 1.91 1.381 1.15 1.74 3.56 1.16 10 13 3.62 1.57 (+)d (−) 1.051.30 0.86 3.24 (+)d ca. — 0.61 (+) ca. 1 — 0.46 (+) ca. 1 — 9 1.14 0.92 1.07 3.16 0.65 4.02 (−) 2.14 1.03.09 — 1.90 −) d 1.50 d 14 0.90 (+) 1.06 ca. 1 1.0 — — 0.93 (+) 0.94 1.0 — 4.36 ((−) 11 8.94 (+) 1.13 1.72 12.4 (+) 1.20 2.49 17.6 (+) 1.04 0.50 22.7(+) (+)1.98 ca.1.16 1.43 10 3.62 (+) 1.05 0.86 3.24 (+) ca. 1 — 0.61 (+) ca. 1 — 0.46 1 — 15 0.74 (−) 1.08 0.78 0.80 (−) 1.38 2.03 1.52 (+) 1.56 2.43 1.45 (−) 1.16 0.92 12 0.47(+) (+) 1.44 1.18 0.41(+) (+) 1.48 2.49 1.07 3.84(+) (+) ca. 1 0.50 — 1.10(+) (+) 1.16 1.51 1.43 1.08 11b 8.94 1.13 1.72 12.4 1.20 17.6 1.04 22.7 16 c 0.14 (−) 19.5 10.2 0.29 (−) 2.94 3.99 7.21 (−) 2.53 6.01 0.18 (+) 2.59 2.09 b b 0.47 (+) 1.44 1.18 0.41 (+) 1.48 1.07 3.84 (+) ca. 1 — 1.103.91 (+) 1.51 1.08 12 13 1.57 (−) 1.30 1.83 1.91 (−) 1.38 1.74 3.56 (+) 1.16 1.13 1.0 — c 0.39 (+) 15.3 13.5 0.61 (+) 3.00 6.31 9.92 (+) 2.84 6.69 0.28 (−) 2.60 2.88 b 17 (−) 1.30 1.83 1.91 (−) d 1.38 1.74 3.56 (+)d 1.16 1.13 3.91 d 1.0 — 13 14 18 c 1.57 1.06 0.94 1.0 — 17.3 4.36 1.50 7.09 3.160.45 4.02 0.64 (−) d 1.017.5 —15.7 0.97 (−) 3.64 8.88 (−)(−) 2.92 (+) d (−)d2.38 1.98 3.33 3.09 14 1.06(−) 1.0 — 0.94(−) 1.0 — ) 1.50 1.98 (−)(−) 15 0.74 1.08 0.78 0.80 1.38 2.03 4.36 1.52(−(+) 1.56 3.16 2.43 4.02 1.45 1.16 3.09 0.92 a 25 (− × )0.20 1.08 cm (i.d.); 0.1 mL/min. signs 15Column: 0.74 0.78Eluent: 0.80n-hexane/2-propanol (−) 1.38 2.03 (99:1, 1.52v/v); (+) Flow 1.56rate: 2.43 1.45 (−The ) 1.16 in 0.92 c 16 c 0.14 (−) 19.5 10.2 0.29 (−) 2.94 3.99 7.21 (−) 2.53 6.01 0.18 (+) 2.59 2.09 b 16 0.14represent (−) 19.5 10.2 rotations 0.29 (−of ) the2.94 3.99 enantiomers; 7.21 (−) 2.53 6.01 0.18 (+) 2.59 parentheses the optical first-eluted Eluent: n-hexane/2-propanol (90:10, 2.09 c 17 0.39(+) (+) 15.3 13.5 0.61d(+) (+) 3.00 6.31 6.31 9.92(+) (+) 2.84 6.69 6.69 0.28 0.28(−(−) 2.60 2.88 2.88 17 c c 0.39 15.3 13.5 0.61 3.00 9.92 2.84 ) 2.60 2O (90:10, v/v); The signs in parentheses represent the signs of Cotton effects at 254 v/v); Eluent: methanol/H 18 c 0.64(− (−) 17.5 15.7 0.97 0.97(− (−) 3.64 8.88 8.88 17.3 17.3(−(−) 2.92 7.09 7.09 0.45 0.45(+)(+)d d 2.38 2.38 3.33 3.33 17.5 15.7 3.64 0.64 ) dd ) dd ) dd 2.92 nm of the first-eluted enantiomers; e Cited from Reference [36]. a Column: a Column: 25 × 25 0.20 cm cm (i.d.); Eluent: (99:1,v/v); v/v);Flow Flow rate: 0.1 mL/min. The signs in × 0.20 (i.d.); Eluent:n-hexane/2-propanol n-hexane/2-propanol (99:1, rate: 0.1 mL/min. The signs in b b parentheses represent optical rotationsof ofthe the first-eluted n-hexane/2-propanol (90:10,(90:10, parentheses represent the the optical rotations first-elutedenantiomers; enantiomers;Eluent: Eluent: n-hexane/2-propanol d The signs in parentheses represent the signs of Cotton effects at v/v); c Eluent: methanol/H d The signs 2 O (90:10, methanol/H 2O (90:10, v/v); v/v); in parentheses represent the signs of Cotton effects at 254 v/v); c Eluent: 254 nm of the first-eluted enantiomers; e Cited from Reference [36]. Racemates6

nm of the first-eluted enantiomers; e Cited from Reference [36].

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Poly-2S partially or completely resolved resolved nine nine of of the the 14 14 racemates racemates tested tested in in the the current current study. study. poly-2S exhibited exhibited excellent excellent chiral chiral recognition recognition abilities abilities toward toward chiral chiral metal metal acetylacetonate acetylacetonate Notably, poly-2S complexes 16–18, showing complete baseline separations in all three cases, together with very high α α values (α (α >> 15) (Figure (Figure 7c). 7c). Methanol/H Methanol/H22O values O (90:10, (90:10, v/v) v/v)was wasused usedas asthe theeluent eluent because because the the enantiomers eluted with with hexane-2-propanol. hexane-2-propanol. of 16–18 were not eluted than poly-2S toward seven racemates. For h-Poly-2S showed showed higher higherchiral chiralrecognition recognitionability ability than poly-2S toward seven racemates. example, h-poly-2S resolved 15 with complete baseline separation (Figure 7b), whereas poly-2S only For example, h-poly-2S resolved 15 with complete baseline separation (Figure 7b), whereas poly-2S achieved a partial separation of the same compound only achieved a partial separation of the same compound(Figure (Figure7a). 7a).Moreover, Moreover, h-poly-2S h-poly-2S resolved onon poly-2S. These results therefore indicated thatthat the racemates 88 and and9,9,which whichwere werebarely barelyseparated separated poly-2S. These results therefore indicated preferred-handed helical conformation induced in h-poly-2S waswas playing an important rolerole in its the preferred-handed helical conformation induced in h-poly-2S playing an important in excellent chiral recognition ability, which waswas consistent with the the results of our previous report for its excellent chiral recognition ability, which consistent with results of our previous report h-poly-4S [36].[36]. As expected, poly-2S and h-poly-2S both exhibited higher enantioselectivities toward for h-poly-4S As expected, poly-2S and h-poly-2S both exhibited higher enantioselectivities nine of nine the racemates than than our previously reported poly-4S and h-poly-4S toward of the racemates our previously reported poly-4S and h-poly-4Ssystems, systems,respectively, respectively, bearing the same (S)-2 unit on half of their phenyl pendants [36]. This result could be attributed to an increase in inthe thenumber numberofofthe the amide pendants acting as effective chiral recognition compared increase amide pendants acting as effective chiral recognition sites sites compared with withprevious the previous systems. our previous weobserved also observed an interesting inversion the the systems. In ourInprevious study,study, we also an interesting inversion in the in order order the enantioseparation the chiral complexes the poly-4Sand h-poly-4Sof the of enantioseparation of the of chiral metal metal complexes 16–18 16–18 on theon poly-4Sand h-poly-4S-based based despite CSPs, despite the factthey thathad theythe had the same optically groups of their pendant moieties CSPs, the fact that same optically activeactive groups of their pendant moieties [36]. [36]. phenomenon This phenomenon be explained by the opposite enantioselectivity thechirality central This can becan explained by the opposite enantioselectivity betweenbetween the central chirality in the active optically active pendants and themacromolecular induced macromolecular of thebackbone polymer in the optically pendants and the induced helicity ofhelicity the polymer backbone toward these racemates, which would represent a negative synergetic In contrast, htoward these racemates, which would represent a negative synergetic effect. Ineffect. contrast, h-poly-2S poly-2S and poly-2S completely racemates 16–18 with good enantioselectivities (α = 2.9–3.6), and poly-2S completely resolvedresolved racemates 16–18 with good enantioselectivities (α = 2.9–3.6), but the but the elution order was the same on both (Figure 7c,d). effect theinduced inducedmacromolecular macromolecular elution order was the same on both CSPsCSPs (Figure 7c,d). TheThe effect of of the helicity of h-poly-2S on the separation of these racemates therefore appeared to have been cancelled out by the central chirality of the pendants, because h-poly-2S had twice as many chiral pendants as h-poly-4S.

Figure 7. 7. HPLC HPLC chromatograms chromatogramsfor forthe theresolution resolutionofof1515(a,b) (a,b)and and1616(c,d) (c,d) poly-2S (a,c) and h-polyFigure onon poly-2S (a,c) and h-poly-2S 2S (b,d). Eluent: hexane–2-propanol (99:1, v/v) (a,b), MeOH–H 2O (90:10, v/v). (b,d). Eluent: hexane–2-propanol (99:1, v/v) (a,b), MeOH–H 2 O (90:10, v/v).

h-Poly-(2S0.36-co-30.64) exhibited different chiral recognition properties to h-poly-2S and successfully resolved 11 of the 14 racemates evaluated in the current study. It is noteworthy that h-poly-(2S0.36-co-

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h-Poly-(2S0.36 -co-30.64 ) exhibited different chiral recognition properties to h-poly-2S and successfully resolved Molecules 2016, 21, 1487 11 of the 14 racemates evaluated in the current study. It is noteworthy 8 of 14 that h-poly-(2S0.36 -co-30.64 ) resolved racemates 6 and 14, which were not resolved by poly-2S or h-poly-2S resolved racemates 6 andthe 14,enantiomers which were not resolvedusing by poly-2S or h-poly-2S (Table 1 and (Table30.64 1 )and Figure 8a). Among separated h-poly-(2S 0.36 -co-30.64 ), the elution Figure 8a). Among the enantiomers separated using h-poly-(2S0.36-co-30.64), the elution orders of six of orders of six of the racemates (5–7, 9, 13 and 15) were the opposite of those achieved on h-poly-2S. the racemates (5–7, 9, 13 and 15) were the opposite of those achieved on h-poly-2S. In particular, the In particular, the complete baseline separation of the racemic cyclophane derivative 15 with a planar complete baseline separation of the racemic cyclophane derivative 15 with a planar chirality was chirality was achieved on h-poly-2S and h-poly-(2S completely -co-30.64 )reversed with a completely reversed elution achieved on h-poly-2S and h-poly-(2S0.36-co-30.64) with a0.36 elution order; with the (–)order;enantiomer with the (–)-enantiomer eluting prior to on theh-poly-2S (+)-enantiomer h-poly-2S (αvice = 1.38) eluting prior to the (+)-enantiomer (α = 1.38)on (Figure 7b) and versa(Figure on h- 7b) and vice versa on h-poly-(2S (α =These 1.56) results (Figureclearly 8b). These results clearly suggested that the 0.36 -co-3 0.64 )8b). poly-(2S 0.36-co-3 0.64) (α = 1.56) (Figure suggested that the macromolecular macromolecular helicity induced in these polymers making a major to contribution to the helicity induced in these polymers was making was a major contribution the resolution of resolution these racemates. of these racemates.

Figure 8. HPLC chromatograms the resolutionof of14 14 (a) (a) and and 15 0.36-co-30.64). Eluent: Figure 8. HPLC chromatograms forfor the resolution 15(b) (b)on onh-poly-(2S h-poly-(2S 0.36 -co-30.64 ). Eluent: hexane–2-propanol (99:1, v/v). hexane–2-propanol (99:1, v/v).

3. Materials and Methods

3. Materials and Methods

3.1. Reagents and Materials

3.1. Reagents and Materials

Copper(I) iodide (CuI) and tungsten(VI) chloride (WCl6) were purchased from Kanto Kagaku

Copper(I) iodide tungsten(VI) chloride (WCl6 ) Bis(triphenylphosphine)palladium(II) were purchased from Kanto Kagaku (Tokyo, Japan) and (CuI) Aldrichand (Milwaukee, WI, USA), respectively. dichloride (Pd(PPh 3)2Cl2)(Milwaukee, and tetraphenyltin (Ph4Sn) were purchased from Tokyo Kasei (TCI, Tokyo, (Tokyo, Japan) and Aldrich WI, USA), respectively. Bis(triphenylphosphine)palladium(II) Japan). Triphenylphosphine (PPh 3 ) and 3 were purchased from Wako Chemicals (Osaka, Kasei Japan). (TCI, dichloride (Pd(PPh3 )2 Cl2 ) and tetraphenyltin (Ph4 Sn) were purchased from Tokyo Porous spherical silica gel with a mean particle size of 7 μm and a mean pore diameter of 100 Tokyo, Japan). Triphenylphosphine (PPh3 ) and 3 were purchased from Wako Chemicals nm (Osaka, (Daiso gel SP-1000-7), trimethylsilylacetylene and (S)-2 were kindly provided by Daiso Chemical Japan). Porous spherical silica gel with a mean particle size of 7 µm and a mean pore diameter (Osaka, Japan), Shin-Etsu Chemical (Tokyo, Japan) and Yamakawa Chemical (Tokyo, Japan), of 100 nm (Daiso gel SP-1000-7), trimethylsilylacetylene and (S)-2 were kindly provided by Daiso respectively. Anhydrous tetrahydrofuran (THF), toluene, dichloromethane, N,N-dimethylformamide Chemical (Osaka, Japan), Shin-Etsu Chemical (Tokyo, Japan) and Yamakawa Chemical (Tokyo, Japan), (DMF) and pyridine were obtained from Kanto Kagaku. Anhydrous dimethyl sulfoxide (DMSO) was respectively. Anhydrous tetrahydrofuran toluene, N,N-dimethylformamide purchased from Aldrich. Triethylamine (THF), (TEA) was dried dichloromethane, over KOH pellets and distilled onto KOH (DMF) and pyridine were obtained from Kanto Kagaku. Anhydrous dimethyl sulfoxide (DMSO) under nitrogen. These solvents were subsequently stored under nitrogen before being used. Heptyl was purchased from Aldrich. Triethylamine (TEA) was dried over KOH pellets and distilled 4-iodobenzoate [36] and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMT- onto [51]nitrogen. were prepared according the previously reported methods. KOHMM) under These solventstowere subsequently stored under nitrogen before being used. Heptyl 4-iodobenzoate [36] and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride 3.2. Instruments (DMT-MM) [51] were prepared according to the previously reported methods. Melting points were measured on a Yanako melting point apparatus (Yanako, Kyoto, Japan) and

3.2. Instruments reported as the uncorrected values. NMR spectra were recorded on a JNM-ECA 500 (JEOL, Tokyo, Japan) (500 MHz for 1H, 125 MHz for 13C) spectrometer using CDCl3, DMSO-d6 or DMSO-d6-D2O as

Melting points were measured on a Yanako melting point apparatus (Yanako, Kyoto, Japan) and the solvent. TMS was used as an internal reference for the samples run in CDCl3 (1H and 13C), whereas reported as the uncorrected values. NMR spectra were recorded on a JNM-ECA 500 (JEOL, Tokyo, the residual solvent peaks were used as internal reference peaks for the samples run in DMSO-d6 and Japan) (500 MHz for 1 H, 125 MHz for 13 C) spectrometer using CDCl3 , Fourier DMSO-d 6 or DMSO-d 6 -D2 O DMSO-d 6-D2O (1H and 13C). IR spectra were recorded with a JASCO Transform IR-460 1 H and 13 C), as thespectrophotometer solvent. TMS was used as an internal reference for the samples run in CDCl ( 3 a 1.0 mm (JASCO, Hachioji, Japan). Absorption and CD spectra were measured in whereas thecell residual solvent were used as peaks for therespectively. samples run in quartz on a JASCO V-650peaks spectrophotometer andinternal a JASCOreference J-725 spectropolarimeter, 1 13 C). The 6temperature was controlled with a JASCO PTC-348WI apparatus. Thea polymer concentration DMSO-d and DMSO-d IR spectra were recorded with JASCO Fourier Transform 6 -D 2 O ( H and was calculated based on the monomer units. The CPL and PL spectra were recorded on a JASCO IR-460 spectrophotometer (JASCO, Hachioji, Japan). Absorption and CD spectra were measured in a 1.0 mm quartz cell on a JASCO V-650 spectrophotometer and a JASCO J-725 spectropolarimeter,

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respectively. The temperature was controlled with a JASCO PTC-348WI apparatus. The polymer concentration was calculated based on the monomer units. The CPL and PL spectra were recorded on a JASCO CPL-300 spectrometer and a JASCO FP-6300 spectrofluorometer, respectively, at room temperature. Size exclusion chromatography (SEC) measurements were performed on a JASCO PU-2080 liquid chromatograph equipped with a UV-vis (JASCO UV-970) detector at 40 ◦ C using a Shodex (Tokyo, Japan) KF-805F SEC column. The temperature was controlled with a JASCO CO-1560 column oven. THF was used as the eluent at a flow rate of 1.0 mL/min. Molecular weight calibration curves were generated using polystyrene standards (Tosoh, Tokyo, Japan). The enantiomers were separated by chromatography using a JASCO PU-2080 liquid chromatograph equipped with a multiwavelength detector (JASCO MD-2018) and a polarimetric detector (JASCO OR-990, Hg without filter) or a CD detector (JASCO CD-2095) at ambient temperature. Elemental analyses were performed at the Research Institute for Instrumental Analysis of Advanced Science Research Center, Kanazawa University, Kanazawa, Japan. 3.3. Synthesis of Monomer Bis(4-heptyloxycarbonylphenyl)acetylene (1) was prepared according to the route shown in Scheme S1. Synthesis of heptyl 4-((trimethylsilyl)ethynyl)benzoate: To a solution of heptyl 4-iodobenzoate (10.1 g, 29.3 mmol) in anhydrous TEA (50 mL) was added trimethylsilylacetylene (4.30 mL, 31.7 mmol), Ph3 P (126 mg, 0.480 mmol), CuI (135 mg, 0.192 mmol) and Pd(PPh3 )2 Cl2 (81.8 mg, 0.117 mmol), and the resulting solution was stirred at room temperature for 20 h. The reaction mixture was filtered through Celite, and the filtrate was evaporated to dryness to give a residue, which was purified by column chromatography over silica gel eluting with a 1:30 (v/v) mixture of ethyl acetate and hexane to give the desired product as a yellow oil (9.23 g, 98% yield). 1 H-NMR (500 MHz, CDCl3 , r.t.): δ 7.96 (d, J = 8.0 Hz, 2H, Ar–H), 7.51 (d, J = 8.0 Hz, 2H, Ar–H), 4.30 (t, J = 6.6 Hz, 2H, OCH2 CH2 ), 1.76 (quint, J = 6.6 Hz, 2H, OCH2 CH2 ), 1.25–1.46 (m, 8H, 4CH2 ), 0.89 (t, J = 6.6 Hz, 3H, CH3 ), 0.26 (s, 9H, TMS). Synthesis of heptyl 4-ethynylbenzoate: To a solution of heptyl 4-((trimethylsilyl)ethynyl)benzoate (5.96 g, 18.8 mmol) in a 3:1 (v/v) mixture of THF and methanol (360 mL) was added K2 CO3 (12.9 g, 93.6 mmol), and the resulting mixture was stirred at room temperature for 1 h. The suspension was then filtered and the filtrate was concentrated under reduced pressure. The concentrated solution was diluted with ethyl acetate and washed sequentially with aqueous 1 N HCl and saturated NaHCO3 solution, before being dried over Na2 SO4 . The solvent was removed by evaporation to give the crude product as a residue, which was purified by column chromatography over silica gel eluting with a 1:30 (v/v) mixture of ethyl acetate and hexane to give the desired product as a colorless oil (3.56 g, 77% yield). 1 H-NMR (500 MHz, CDCl , r.t.): δ 7.99 (d, J = 8.6 Hz, 2H, Ar–H), 7.55 (d, J = 8.0 Hz, 2H, Ar–H), 4.31 (t, 3 J = 6.6 Hz, 2H, OCH2 CH2 ), 3.22 (s, 1H, CH), 1.76 (quint, J = 6.6 Hz, 2H, OCH2 CH2 ), 1.26–1.46 (m, 8H, 4CH2 ), 0.89 (t, J = 6.9 Hz, 3H, CH3 ). Synthesis of bis(4-heptyloxycarbonylphenyl)acetylene (1): To a solution of heptyl 4-iodobenzoate (5.03 g, 14.5 mmol) in anhydrous TEA (25 mL) was added Ph3 P (57.1 mg, 0.218 mmol), CuI (63.6 mg, 0.334 mmol), Pd(PPh3 )2 Cl2 (40.8 mg, 0.0581 mmol) and heptyl 4-ethynylbenzoate (3.55 g, 14.5 mmol), and the resulting mixture was stirred at room temperature for 20 h. The reaction mixture was then filtered through Celite and the filtrate was concentrated under reduced pressure to give a residue, which was diluted with ethyl acetate and washed sequentially with water and brine, before being dried over Na2 SO4 . The solvent was removed under reduced pressure to give a residue, which was purified by column chromatography over silica gel eluting with a 1:25 (v/v) mixture of ethyl acetate and hexane to give the crude product. The crude product was subsequently purified by recrystallization from a mixture of toluene and methanol to give the desired product as a white solid (5.11 g, 77% yield). M.p.: 61.3–62.4 ◦ C. IR (KBr, cm−1 ): 1943 (νC≡C ), 1707 (νC=O ). 1 H-NMR (500 MHz, CDCl3 , r.t.): δ 8.04 (d, J = 8.6 Hz, 4H, Ar–H), 7.60 (d, J = 8.0 Hz, 4H, Ar–H), 4.33 (t, J = 6.6 Hz, 4H, 2OCH2 CH2 ), 1.76

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(quint, J = 6.6 Hz, 4H, 2OCH2 CH2 ), 1.25–1.47 (m, 16H, 8CH2 ), 0.90 (t, J = 6.9 Hz, 6H, 2CH3 ). 13 C-NMR (125 MHz, CDCl3 , r.t.): δ 166.19, 131.76, 130.46, 129.68, 127.38, 91.49, 65.56, 31.88, 29.11, 28.85, 26.15, 22.75, 14.23. Elemental analysis: Calcd. for C30 H38 O4 : C, 77.89; H, 8.28. Found: C, 77.60; H, 8.37. 3.4. Polymerization The polymerization reaction was carried out in a Schlenk flask under argon using a WCl6 -Ph4 Sn catalyst system according to the literature method [32,36]. Monomer 1 (1.05 g, 2.27 mmol), WCl6 (90 mg, 0.23 mmol) and Ph4 Sn (98 mg, 0.23 mmol) were placed in a Schlenk flask under argon, followed by anhydrous toluene (4.5 mL), which was added using a syringe. The resulting mixture was heated at 100 ◦ C under stirring for 24 h. The reaction mixture was then cooled to room temperature and treated with a large amount of methanol to precipitate the polymer, which was collected by centrifugation and then dried in vacuo at room temperature overnight. The dried polymer was purified by reprecipitation from toluene using a 3:1 (v/v) mixture of methanol and THF as an antisolvent system, and the resulting solid was dried in vacuo at room temperature overnight to give poly-1-Hep (0.81 g, 77% yield). The molecular weight (Mn ) of poly-1-Hep was estimated to be 1.3 × 104 (Mw /Mn = 1.6) by SEC using polystyrene standards with THF as the eluent. IR (KBr, cm−1 ): 1721 (νC=O of ester). 1 H-NMR (500 MHz, CDCl3 , 25 ◦ C): δ 7.16–7.28 (br, 4H, Ar–H), 6.41–6.71 (br, 2H, Ar–H), 5.92–6.15 (br, 2H, Ar–H), 4.03–4.48 (br, 4H, 2OCH2 CH2 ), 1.60–1.93 (br, 4H, 2OCH2 CH2 ), 1.25–1.47 (br, 16H, 8CH2 ), 0.79–1.04 (br, 6H, 2CH3 ). 13 C-NMR (125 MHz, CDCl3 , 25 ◦ C): δ 165.60, 146.48, 146.33, 130.63, 128.88, 128.34, 126.99, 65.44, 31.90, 29.17, 28.67, 25.98, 22.74, 14.18. Elemental analysis: Calcd. for C30 H38 O4 : C, 77.89; H, 8.28. Found: C, 77.40; H, 8.42. Poly-1-Hep was converted to poly-1-H by the hydrolysis of its ester groups as follows. A solution of poly-1-Hep (0.71 g) in THF (30 mL) was treated with a 4 N solution of aqueous KOH (25 mL), and the resulting mixture was stirred at 80 ◦ C for 3 h. The mixture was cooled to ambient temperature and the THF was removed under reduced pressure to give a concentrated mixture, which was treated with a 4 N aqueous solution of KOH (25 mL). The resulting mixture was then stirred at 80 ◦ C for 72 h to complete the hydrolysis. The solution was subsequently cooled to ambient temperature and acidified with a 6 N aqueous HCl solution, resulting in the precipitation of poly-1-H, which was collected by centrifugation, washed with water and dried in vacuo at room temperature overnight to give the desired product (243 mg, 60% yield). IR (KBr, cm−1 ): 1700 (νC=O of carboxylic acid). 1 H-NMR (500 MHz, D O/DMSO-d (1/1, v/v), 25 ◦ C): δ 5.30–8.00 (br, 8H, Ar–H). 13 C-NMR (125 MHz, 2 6 D2 O/DMSO-d6 (1/2, v/v), 25 ◦ C): δ 126.99, 128.06, 129.61, 131.18, 147.10, 167.65. Elemental analysis: Calcd. for C16 H10 O4 : C, 72.18; H, 3.79. Found: C, 72.36; H, 3.98. 3.5. Synthesis of Poly-2S by Using a Polymer Reaction A solution of poly-1-H (150 mg, 0.56 mmol) and (S)-2 (278 µL, 2.2 mmol) in a 5:1 (v/v) mixture of DMSO and H2 O (26 mL) was treated with DMT-MM (620 mg, 2.2 mmol), and the resulting mixture was stirred at room temperature for 24 h. The mixture was then added to a large volume of methanol, resulting in the precipitation of the poly-2S product, which was collected by centrifugation and then dried in vacuo at room temperature. The resulting poly-2S product was found to contain approximately 100 mol % of (S)-2 as the pendant group to each monomer unit, as determined by 1 H-NMR and elemental analyses (Figure S3a). Spectroscopic data for poly-2S: IR (KBr, cm−1 ): 1635 (νC=O of amide), 1533 (νN–H of amide). 1 H-NMR (500 MHz, CDCl , 25 ◦ C): δ 8.40–7.60 (br, 2H, NH), 7.60–4.70 (br, 20H, aromatic, CHCH ), 3 3 2.00–1.10 (br, 6H, CHCH3 ). Elemental analysis: Calcd. for C32 H28 N2 O2 ·0.85H2 O: C, 78.78; H, 6.14; N, 5.74. Found: C, 78.85; H, 5.88; N, 5.84. 3.6. Synthesis of Poly-(2Sx -co-31−x ) by Using Polymer Reactions Typical procedure for synthesis of poly-(2Sx -co-31−x ) by polymer reaction of poly-1-H with (S)-2 followed by 3 using DMT-MM as a condensing reagent is described below. To a solution of poly-1-H

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(100 mg, 0.37 mmol) and (S)-2 (67 µL, 0.54 mmol) in DMSO (6 mL) was added DMT-MM (75 mg, 0.27 mmol), and the resulting mixture was stirred at room temperature for 12 h. The reaction mixture was then poured into a 5:1 (v/v) mixture of hexane and ethanol, and the resulting precipitated polymer was collected by centrifugation, washed sequentially with a 1 N aqueous solution of HCl, water and methanol, and then dried under vacuum at room temperature overnight. The dried polymer was dissolved in DMSO (6 mL) and treated with an excess of 3 (200 µL, 1.87 mmol) in the presence of DMT-MM (258 mg, 0.93 mmol) for 12 h at room temperature. The reaction mixture was then poured into a large volume of methanol, and the resulting precipitated polymer collected by centrifugation and dried under vacuum at room temperature overnight to yield poly-(2S0.36 -co-30.64 ) (125 mg, 74%). The (S)-2 content of the polymer was determined to be 36 mol % by 1 H-NMR analysis (Figure S3b). Spectroscopic data for poly-(2S0.36 -co-30.64 ): IR (KBr, cm−1 ): 1638 (νC=O of amide), 1523 (νN–H of amide). 1 H-NMR (500 MHz, CDCl3 , 25 ◦ C): δ 8.75–8.02 (br, 2H, NH), 7.66–5.75 (br, 18H, aromatic), 5.27–4.80 (br, CHCH3 ), 4.58–3.96 (br, CH2 ), 1.57–0.85 (br, CHCH3 ). Calcd. for 0.36C32 H28 N2 O2 ·0.64C30 H24 N2 O2 ·0.6H2 O: C, 79.27; H, 5.77; N, 6.02. Elemental analysis: Found: C, 79.13; H, 5.53; N, 5.98. The other poly-(2Sx -co-31−x )s were synthesized in the same way by varying the feed ratio of DMT-MM relative to poly-1-H whilst maintaining that of (S)-2 against DMT-MM ([(S)-2]/[DMT-MM] = 2) (see Table S1). The (S)-2 unit contents (x) of the poly-(2Sx -co-31−x )s were determined by 1 H-NMR analysis. 3.7. Preparation of High-Performance Liquid Chromatography (HPLC) Columns A solution of poly-2, h-poly-2S or h-poly-(2S0.36 -co-30.64 ) (100 mg) in DMF (1 mL) was used to coat some macroporous silica gel (400 mg) according to a previously reported method [49], and the solvent was then evaporated under reduced pressure. The poly-2, h-poly-2S and h-poly(2S0.36 -co-30.64 ) contents on the silica gel were estimated to be 18.3, 17.6 and 19.9 wt %, respectively, by thermogravimetric analysis. After fractionating the packing materials with sieves, the resulting materials were packed into a stainless steel tube (25 × 0.20 cm (i.d.)) using a conventional high-pressure slurry packing technique with an ECONO-PACKER MODEL CPP-085 (Chemco, Osaka, Japan) [50]. The plate numbers for the columns were 3700 (poly-2S), 3500 (h-poly-2S) and 3300 (h-poly-(2S0.36 -co-30.64 )), respectively, for the elution of benzene with hexane/2-propanol (90:10, v/v) at a flow rate of 0.1 mL/min. The hold-up times (t0 ) were estimated using 1,3,5-tri-tert-butylbenzene and acetone as the non-retained compounds for the normal and reverse phases, respectively [52]. 4. Conclusions In conclusion, we have synthesized a series of optically active poly(diphenylacetylene)s bearing amide functional groups on all of their pendant phenyl rings. These systems consist of a chiral unit (poly-2S) or both chiral and achiral units (poly-(2Sx -co-31–x )) and were prepared by the reaction of an optically inactive poly(diphenylacetylene) bearing carboxyl groups with chiral or achiral amines. The resulting polymers were evaluated in terms of their chiroptical properties and chiral recognition abilities toward various racemates such as chiral stationary phases (CSPs) for high-performance liquid chromatography (HPLC). We found that poly-2S and poly-(2Sx -co-31–x ) folded into a preferred-handed helical conformation (h-poly-2S and h-poly-(2Sx -co-31–x )) by thermal annealing. Notably, the helical senses of these materials varied considerably depending on their chiral unit contents. Furthermore, the circular dichroism (CD) and circularly polarized luminescence (CPL) spectra of h-poly-2S and h-poly-(2S0.36 -co-30.64 ) were almost mirror images of each other. We have demonstrated that these polymers can efficiently resolve various racemates when used as CSPs for HPLC and that the enantioselectivities and elution orders of the enantiomers were significantly influenced by the helical structures induced in these polymers. The elution orders of some enantiomers were reversed on the h-poly-2S- and h-poly-(2S0.36 -co-30.64 )-based CSPs because of the opposite helicities induced in these polymers. Moreover, poly-2S and h-poly-2S showed higher chiral recognition abilities toward many racemates than the previously reported poly(diphenylacetylene) system bearing the same chiral

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substituent on only half of its pendant phenyl rings. This result was attributed to an increase in the number of the amide pendants acting as effective chiral recognition sites [36]. Poly(diphenylacetylene)s are thermally and chemically more stable than poly(phenylacetylene)s and are highly emissive without introducing any other fluorescent substituents. We therefore believe that these findings will not only allow for the design of useful poly(diphenylacetylene)-based CSPs for HPLC with much higher chiral recognition abilities toward diverse racemates, but that they will also assist in the development of new circularly polarized luminescence materials. Supplementary Materials: Supplementary materials can be accessed at: http://www.mdpi.com/1420-3049/21/ 11/1487/s1. Acknowledgments: This work was supported by the Japan Society for the Promotion of Science (JSPS) KAKENHI Grants-in-Aid for Scientific Research (B), Grant No. 16H04154. Author Contributions: K.M. conceived the project, designed the experiments and wrote the manuscript. M.M. principally performed the experiments. Y.S. performed the enantioseparation experiments. S.K. and T.I. performed the data analysis. All of the authors discussed the results and edited the manuscript. Conflicts of Interest: The authors declare no conflicts of interest.

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Sample Availability: Samples of the compounds are available from the authors. © 2016 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC-BY) license (http://creativecommons.org/licenses/by/4.0/).