Optically Active Helical Polyacetylene Bearing Ferrocenyl Amino-Acid

Article pubs.acs.org/IECR

Optically Active Helical Polyacetylene Bearing Ferrocenyl AminoAcid Derivative in Pendants. Preparation and Application as Chiral Organocatalyst for Asymmetric Aldol Reaction Jinrui Deng,†,‡ Biao Zhao,†,‡ and Jianping Deng*,†,‡ †

State Key Laboratory of Chemical Resource Engineering, and ‡College of Materials Science and Engineering, Beijing University of Chemical Technology, Beijing 100029, China S Supporting Information *

ABSTRACT: The article reports a novel type of helical polymer-based chiral catalyst for catalyzing asymmetric aldol reactions. Chiral acetylenic monomers containing ferrocenyl amino-acid derivative substituent were synthesized for the first time and structurally identified. The investigated amino acids include alanine and threonine enantiomers. The obtained monomers separately underwent solution homopolymerization and copolymerization with an achirally substituted acetylene monomer in the presence of [Rh(nbd)Cl]2 and Et3N. Circular dichroism and UV−vis absorption spectra demonstrated that the copolymer chains adopted predominantly one-handed helices, endowing the copolymers with optical activity. The resulting (co)polymers were further used to catalyze aldol reaction between cyclohexanone and p-nitrobenzaldehyde. Only threoninederived copolymers efficiently catalyzed the aldol reaction. A remarkable yield (up to 90%) and enantiomeric excess (up to 93%) were obtained. A synergic effect between the helical structures in the copolymer main chains and the pendent catalytic moieties was found to play a crucial role in the asymmetric catalysis.

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INTRODUCTION Obtaining products simultaneously with good yield and high stereoselectivity from cheap and easily available starting materials is one of the essential targets in asymmetric syntheses. Many strategies have been investigated to achieve this purpose. For example, enzymes (including other biocatalysts) and organometallic complexes have been investigated as chiral catalysts for asymmetric synthesis. However, both of them are strict with reactive conditions, making them quite limited in use. Past decades have experienced an explosive growth in asymmetric reactions, and various organocatalysts have been impressively developed due to their excellent catalytic abilities, such as amino acids, cinchona alkaloids, chiral thioureas, and so on.1−3 Particularly, amino acids as simple, easily accessible natural products with huge potentials in asymmetric synthesis have attracted much attention and been widely used as chiral organocatalyst in the past decade since the first report on intermolecular aldol reactions catalyzed by L-proline.4,5 Unfortunately, for simple amino acids such as alanine, valine, threonine, and isoleucine, their poor solubility in organic solvent frequently restricts their practical uses. To overcome this problem, integration of the amino acids with lipophilic structures, for example, ferrocenes, may be a powerful strategy. Ferrocenes as ideal molecular scaffolds were first reported by Kealy and co-workers.6,7 The unique features of ferrocenes such as aromatic character lipophilicity8 make them attractive in diverse fields of chemistry especially in asymmetric synthesis9 and functional materials.10 In the above context, we designed © 2016 American Chemical Society

novel polymeric organocatalysts derived from helical substituted polyacetylene main chains containing ferrocenyl aminoacid derivative pendants, expecting a synergistic effect to occur between the polymer helices and pendent chiral moieties, which may be favorable for asymmtric reactions. Our hypothesis has been justified, as to be reported in this work. Synthetic helical polymers11−18 have gathered increasing interest and currently become further active. The helical polymer chains show a chiral amplification effect,19 affording them with considerable optical activity. Besides, a judicious combination of helical polymer backbones and functional pendants endows the optically active helical polymers with significant applications in chiral recognition,20 chiral resolution,21 and in particular asymmetric catalysis owing to their intriguing helical structure as mimetic enzymes. Reportedly, helical polymers with catalytic moieties can catalyze asymmetric reactions efficiently.22 Some groups have made remarkable contribution to this specific research area, with examples such as Reggelin,23,24 Yashima,25,26 Masuda,27 Suginome,28 and Deng groups.29,30 Despite the great progress, the type and number of such chirally helical polymer catalysts are still highly constricted. Particularly, there has been no report yet on helical polymers bearing specific derivatives from ferrocene and amino Received: Revised: Accepted: Published: 7328

May 18, 2016 June 16, 2016 June 20, 2016 June 20, 2016 DOI: 10.1021/acs.iecr.6b01908 Ind. Eng. Chem. Res. 2016, 55, 7328−7337

Article

Industrial & Engineering Chemistry Research

methyl ester (1.22 g, 8.7 mmol) (obtained from L-alanine methyl ester hydrochloride by treatment with Et3N in DCM, pH ≈ 8) was added. The reaction mixture was stirred at room temperature and monitored by TLC. Then the solvent was removed by evaporation, and the residue was purified by column chromatography (SiO2, DCM/EtOAc = 10/1−20/1, v/v) to afford L-MAFcOMe (1.14 g, 82%). Hydrolysis of compound L-MAFcOMe (1.14 g, 3.61 mmol) in dioxane/water (v/v = 1:1) mixture (100 mL) at 0 °C in the presence of NaOH (0.29 g, 7.22 mmol) resulted in the free acid LMAFcOH (0.98 g). Compound L-MAFcOH was isolated in 90% yield by acidification of the solution with 2% HCl to pH 2, followed by extraction with EtOAc (3 × 30 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and the solvent was removed under reduced pressure to give an orange residue. L-MAFcOH was prepared according to the method in literature,33 so detailed characterizations were not performed. To a 100 mL round-bottom flask compound L-MAFcOH (301.2 mg, 1.00 mmol), HOBt (162.2 mg, 1.20 mmol), EDC· HCl (230.1 mg, 1.20 mmol), and 15 mL of DCM were added. The mixture was mixed by stirring for 1 h at room temperature. Then a solution of propargylamine (0.14 mL, 2.00 mmol) in 5 mL of DCM was slowly injected into the flask. The reaction mixture was stirred for another 4 h at room temperature. The solvent was removed by evaporation, and the residue was purified by column chromatography (SiO2, n-hexane/EtOAc = 1/1−5/1, v/v) to afford monomer L-MAFc (168.0 mg, 55%) as a yellow solid. Anal. Calcd (%) for C17H18FeN2O2 (338.18): C, 60.38; H, 5.36; N, 8.28. Found: C, 60.35; H, 5.39; N, 8.30. [α]D = −5.7° (c = 0.1 g dL−1, THF). The monomer D-MAFc was synthesized from D-alanine methyl ester hydrochloride and propargylamine in a manner similar to monomer L-MAFc. Synthesis of Monomer L-MTFc (Scheme 1). NMethylmorpholine (1.62 mL, 14.66 mmol), and N-(tertbutoxycarbonyl)-L-threonine (3.20 g, 14.66 mmol) were added in THF (120 mL) at room temperature. Isobutyl chloroformate (1.86 mL, 14.66 mmol) was added to the solution to precipitate N-methylmorpholine hydrochloride as a white mass. Then propargylamine (1.00 mL, 14.66 mmol) was added, and the resulting mixture was stirred at room temperature for 4 h. The precipitate was removed by filtration, and the filtrate was concentrated by rotary evaporation. The resulting residue was dissolved in ethyl acetate (50 mL) and successively washed three times with 2 N HCl solution, saturated NaHCO3 solution, and dried over anhydrous MgSO4. After filtration, the solvent was removed to obtain crude product (compound Boc-L-MT). It was purified by recrystallization from n-hexane. Boc- L-MT was synthesized as reported,34 so we did not perform detailed characterizations of it. Compound Boc-L-MT (1.03 g, 4 mmol), ferrocenecarboxylic acid (1.10 g, 4.8 mmol), and 4-dimethylaminopyridine (DMAP) (22.0 mg, 0.18 mmol) were dissolved in 30 mL of dry THF. The mixture solution was cooled with ice−water bath, to which a THF solution of dicyclohexylcarbodiimide (DCC) (1.09 g, 5.28 mmol) was added slowly under stirring through a dropping funnel with a pressure-equalization arm. The reaction mixture was stirred overnight. After filtration of the solid, the filtrate was concentrated by a rotary evaporator. The residue was purified on a silica gel column using n-hexane/EtOAc (nhexane/EtOAc = 1/1−5/1, v/v) mixture as eluent to give the compound Boc-L-MTFc as orange solid (1.16 g, 62%). The Boc-protected compound Boc-L-MTFc (1.00 g) was dissolved

acid in pendants, which in theory possess large potentials as chiral catalyst due to the unique structures. On the basis of our previous studies concerning chirally helical substituted polyacetylenes and optically active nano- and microparticles thereof,31,32 we in this contribution manufactured optically active helical copolymers with ferrocenyl aminoacid derivative pendants. We anticipate that the obtained helical polymers are suitable for organic medium because of the hydrophobic ferrocene moieties, while the steric effect of metallocenes may provide a good enantioselectivity in asymmetric catalysis. More importantly, a synergetic effect between the chirally helical polymer backbones and ferrocenyl amino-acid derivative moieties was observed in catalyzing the asymmetric aldol reaction of cyclohexanone and p-nitrobenzaldehyde.

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EXPERIMENTAL SECTION Materials. Triethylamine (Et3N), tetrahydrofuran (THF), N,N-dimethylformamide (DMF), dichloromethane (DCM), and dioxane were purchased from Beijing Chemical Reagents Company (China). Ferrocenecarboxylic acid (TCI), L- and Dalanine methyl ester hydrochloride (TCI), N-(tert-butoxycarbonyl)-L- and D-threonine (Aladdin), dicyclohexylcarbodiimide (Alfa Aesar), 4-dimethylaminopyridine (TCI), trifluoroacetic acid (Aladdin), 1-hydroxybenzotriazole monohydrate (J&K), N-(3-(dimethylamino)propyl)-N′-ethylcarbodiimide hydrochloride (TCI), propargylamine (TCI), isobutyl chloroformate (Alfa Aesar), 4-methylmorpholine (Alfa Aesar), and rhodium catalyst, [Rh(nbd)Cl]2 (nbd =2,5-norbornadiene) (Alfa Aesar) were used without further purification. Cyclohexanone and pnitrobenzaldehyde were purchased from Aldrich and used as received. All solvents were purified by distillation before use. Deionized water was used in all the experiments. Measurements. The products from the asymmetric catalysis were purified by preparative thin layer chromatography (TLC) on silica gel by using the mixtures DCM/EtOAc and nhexane/EtOAc. Circular dichroism (CD) and UV−vis absorption spectra were conducted on a Jasco-810 spectropolarimeter. The molecular weights (Mn) and molecular weight polydispersities (Mw/Mn) were determined by GPC (Waters 515-2410 system) calibrated by using polystyrenes as standards and tetrahydrofuran (THF) as eluent. Elemental analysis was recorded by vairo EL CUBE elementar Analysensysteme. FTIR spectra were measured on a Nicolet NEXUS 870 infrared spectrometer. Raman spectra were recorded on a Renishaw inVia-Refl exconfocal Raman microscope with an excitation wavelength of 785 nm. Optical rotations were measured on an IP-digi300/2 digital polarimeter (Shanghai InsMark Instrument Technology Co.) with a sodium lamp (λ = 589 nm) as light source at room temperature. 1H and 13C NMR spectra were recorded on a Bruker AV 400 spectrometer. High performance liquid chromatography (HPLC) analysis was performed on FL2200-2 (FL2200-2 pump and absorbance detector). Chiralpak AD-H column was purchased from Daicel Chemical Industries Ltd. Synthesis of Monomer l-MAFc (Scheme 1). The monomer was synthesized by a three-step procedure. Ferrocenecarboxylic acid (1.00 g, 4.35 mmol), 1-hydroxybenzotriazole monohydrate (HOBt) (0.71 g, 5.22 mmol), and N-(3(dimethylamino)propyl)-N′-ethylcarbodiimide hydrochloride (EDC·HCl) (1.00 g, 5.22 mmol) were added in dichloromethane (DCM) (15 mL). After stirring for 1 h at room temperature, the mixture was cooled to 0 °C. Then L-alanine 7329

DOI: 10.1021/acs.iecr.6b01908 Ind. Eng. Chem. Res. 2016, 55, 7328−7337

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Scheme 1. (A) Monomers Syntheses, (B) (Co)polymerization and (C) Asymmetric Aldol Reactions in the Presence of Helical Copolymers

C18H20FeN2O3 (368.21): C, 58.72; H, 5.48; N, 7.61. Found: C, 58.70; H, 5.45; N, 7.66. [α]D = −4.3° (c = 0.1 g dL−1, THF). The monomer D-MTFc was synthesized from N-(tertbutoxycarbonyl)-D-threonine and propargylamine in a manner similar to monomer L-MTFc. Achiral monomer M1 was synthesized by the method reported in the literature.35 Characterizations of the monomers were conducted with FT-IR, and 1H and 13C NMR techniques,

in DCM (30 mL), and trifluoroacetic acid (TFA) (4.00 mL) was added. After stirring at room temperature for 4 h, the mixture was concentrated until dryness under vacuum. The residue was diluted with NaOH (1 N solution, 50 mL), and the resulting solution was extracted with AcOEt. The organic layer was washed with a saturated NaCl solution, dried with anhydrous MgSO4, and concentrated to dryness. The monomer L-MTFc was orange solid (0.71 g, 90%). Anal. Calcd (%) for 7330


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Industrial & Engineering Chemistry Research and elemental analyses. Detailed information is presented in Supporting Information (SI, the same below). Synthesis of (Co)polymers. Polymerizations were carried out in a dry glass tube under a dry nitrogen atmosphere using [Rh(nbd)Cl]2 as a catalyst in the presence of Et3N in THF at 30 °C for 3 h. After polymerization, the reaction mixture was poured into a large amount of n-hexane to precipitate the asformed homopolymers. Then, the polymers were filtered and dried under reduced pressure, for which the details were reported in our earlier study.36,37 For preparing copolymers, copolymerizations were carried out in a similar way with varied monomer feed ratios. Aldol Reactions. Cyclohexanone (2 mL), helical copolymer as catalyst (10 mol % of aldehyde, based on catalytic unit), and 2 mL of THF were added in sequence in a reactor. The reaction mixture was stirred for 15 min and then aldehyde (0.075 g, 0.5 mmol) was added. The reaction was monitored by TLC until completion, and then the mixture was quenched with saturated NaHCO3 aqueous solution, extracted three times with ethyl acetate. The enantiomeric excess (ee) was determined by chiralphase HPLC analysis of the pure antiproduct, which was purified by flash column chromatography (n-hexane/EtOAc = 3/1, v/v) in advance. The product, (2S,1′R)-2-(hydroxyl-(p-nitrophenyl)methyl) cyclohexan-1one, was characterized with FT-IR and 1H and 13C NMR analyses. Chiral HPLC Analysis of Aldol Reaction Product. For the product (2S,1′R)-2-(hydroxyl-(p-nitrophenyl) methyl) cyclohexan-1-one,38,39 the percent ee was determined by HPLC analysis, Chiralpak AD-H, n-hexane/i-PrOH = 90/10, v/v, 1.0 mL min−1, 254 nm; tr (minor) = 13.03 min, tr (major) = 15.71 min). The obtained four stereoisomers of 2-[hydroxyl(4-nitrophenyl)-methyl] cyclohexanone were defined as MSR, MRS, MSS, and MRR, respectively. Among the isomers, MSR and MRS are a pair of enantiomers with anticonfiguration, while MSS and M RR are the syn-configuration enantiomers. The diastereomer ratio of aldol transformation is defined as dr = anti/syn, and the enantiomer excess of the anticonfiguration products is defined as ee% (anti) = (MSR − MRS)/(MSR + MRS) × 100 (MSR as the major product).

Table 1. Homo- and Copolymerization Results of Chiral Monomers and Achiral Monomer (M1) with [Rh(nbd)Cl]2 in the Presence of Et3N Homo- and copolymers runa 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

monomerb

Mnc

code

Mw/ Mnc

−11 +13 −8 +9

L-MAFc D-MAFc L-MTFc D-MTFc M1 L-MAFc D-MAFc L-MTFc D-MTFc L-MAFc/M1 (0.05/0.95) L-MAFc/M1 (0.1/0.9) L-MAFc/M1 (0.2/0.8) D-MAFc/M1 (0.1/0.9) L-MTFc/M1 (0.1/0.9) D-MTFc/M1 (0.1/0.9)

[α]D (deg)d

poly(M1) poly(L-MAFc) poly(D-MAFc) poly(L-MTFc) poly(D-MTFc) poly(L-MAFc0.05-coM10.95) poly(L-MAFc0.1-coM10.9) poly(L-MAFc0.2-coM10.8) poly(D-MAFc0.1-coM10.9) poly(L-MTFc0.1-coM10.9) poly(D-MTFc0.1-coM10.9)

9900 4500 4200 4800 5100 7600

1.48 1.22 1.36 1.59 1.72 1.89

+76 −81 +65 −62 +201

7000

2.01

+345

6800

1.63

+183

7200

2.11

−351

7500

1.95

+290

8000

2.25

−288

a Conditions: polymerized in THF under nitrogen at 30 °C for 6 h; [monomer] = 0.5 mol/L, [monomer]/[[Rh(nbd)Cl]2] = 100 (Et3N, 0.1 mL). bMonomer feed ratio for the copolymerizations is given in parentheses. cDetermined by GPC. dMeasured in THF with concn = 0.1 g dL−1 (rt).

homopolymers showed similar results. For example, the number-average molecular weight (Mn) of poly(L-MAFc) is 4500 (the degree of polymerization was about 13) and the molecular weight distribution (Mw/Mn) is 1.22. The low Mn may be ascribed to the bulky pendant groups in L-MAFc. In view of the low Mn, we suspect the homopolymers may not form stable predominantly one-handed helical conformations. Specific rotation measurements (Table 1) also show that a pronounced chiral amplification effect did not occur in the homopolymers, providing evidence for our consideration. Circular dichroism (CD) and UV−vis spectra of the homopolymers further proved our assumption, as discussed later. Accordingly, copolymers were further prepared using the chiral monomers and the achiral monomer (M1), since the latter can provide polymers with relatively higher molecular weight (Table 1). According to our previous studies,31,32 CD and UV−vis absorption spectroscopy techniques have been proved highly efficient to analyze the helical structures of substituted polyacetylenes. L-MAFc and poly(L-MAFc) were taken as representative and characterized by CD and UV−vis spectroscopies. The relevant spectra are displayed in Figure 1. As for the chiral monomer L-MAFc, a weak CD signal appeared around 480 nm, which should be derived from the chiral ferrocene moiety.33,40 UV−vis absorption occurred at nearly the same wavelength. For homopolymer poly(L-MAFc), a CD signal at 480 nm was also found (Figure 1, spectrum d), similar to the chiral monomer L-MAFc. However, there was a new broad CD signal around 310 nm which may be originated in the π−π effects between pendent ferrocene structures which were

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RESULTS AND DISCUSSION In the present work, we intended to combine ferrocene and amino acid (alanine and threonine) to form special chiral structures, which were then introduced as pendants to helical substituted polyacetylene main chains. We hypothesize that the as-prepared helical polymers may asymmetrically catalyze aldol reactions. At the beginning of this work, a pair of chiral substituted acetylene monomers with ferrocenyl−alanine derivative pendants (L-MAFc and D-MAFc, as presented in Scheme 1) was successfully synthesized. The detailed synthesis routes are described in the experiment section. The chiral monomers were identified by FT-IR and NMR spectroscopies and elemental analysis, as shown in SI Figures S1 and S2. The detailed analyses are also presented therein, which confirmed the successful production of the monomers. With the obtained chiral monomers (L- and D-MAFc) in hand, we further performed solution homopolymerization of the two chiral monomers by using [Rh(nbd)Cl]2 as catalyst in the presence of Et3N. The obtained homopolymers, that is, poly(L-MAFc) and poly(D-MAFc) were subjected to GPC measurement to analyze the molecular weight and molecular weight distribution, as shown in Table 1. The two 7331


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Figure 1. (A) CD and (B) UV−vis spectra of the monomers (L-MAFc, M1) and homopolymers [poly(L-MAFc), poly(M1)] in THF (25 °C). The concentration was approximately 1 × 10−3 mol/L by monomer units.

Figure 2. (A) CD and (B) UV−vis spectra of the (co)polymers from L-MAFc and M1 with different feeding ratios; Measured in THF (c = 1 × 10−3 mol/L) at 25 °C.

Figure 3. (A) CD and (B) UV−vis spectra of poly(L-MAFc0.1-co-M10.9) at varied temperature (from 20 to 60 °C, and then back to 20 °C) in THF (c = 1 × 10−3 mol/L).

CD and UV−vis spectra of M1 and its homopolymer, poly(M1), are also presented in Figure 1. For poly(M1), no CD signal but an intensive UV−vis absorption is found around 400 nm, which is consistent with our foregoing reports,41,42 and demonstrates that poly(M1) adopted racemic helical conformations, thus failing to show optical activity. The copolymerizations of L-MAFc with achiral monomer M1 in different feed ratios proceeded smoothly and provided the copolymers in a quantitative yield. The GPC data are shown in Table 1. The copolymers had much higher Mn than the

helically arranged along the polymer chains. Combining CD and UV−vis spectra and specific rotations of the monomers and homopolymers, we think that the homopolymer poly(LMAFc) cannot form stable helical structures with one handed screw sense. To obtain polymer with stable one-handed helical conformations, we subsequently accomplished copolymerization of L-MAFc with achiral monomer M1, as illustrated in Scheme 1B. M1 was used due to its ability to form a polymer with relatively higher molecular weight and stable helical structures.40,41 The 7332


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Industrial & Engineering Chemistry Research homopolymer poly(L-MAFc). 1H NMR spectra measurement, with poly(L-MAFc0.1-co-M10.9) as example (Figure S3), provides further evidence for the formation of copolymers.43 A representative FT-IR spectrum of the copolymer poly(LMAFc0.1-co-M10.9) is presented in Figure S4. Besides, the obtained polymers were found to possess high cis contents based on Raman spectra measurement (Figure S5, with poly(LMAFc0.1-co-M10.9) as example).44,45 The copolymers were subsequently subjected to CD and UV−vis measurement and the corresponding spectra are presented in Figure 2. Intense positive CD signals around 390 nm are found in the copolymers, demonstrating the copolymers adopt predominantly one-handed helical conformations. More importantly, the CD signal reached a maximum intensity in poly(L-MAFc0.1-co-M10.9) among the three examined copolymers. This interesting phenomenon is due to the synergistic effects occurring between the comonomer units, which maximized the excess single-handed helicity in poly(L-MAFc0.1-co-M10.9) chains among the (co)polymers, suggesting that the copolymer poly(L-MAFc0.1-coM10.9) has the greatest excess one-handed screw sense. The specific rotations of the monomers and (co)polymers in Table 1 provide further evidence for this conclusion, as a pronounced chiral amplification effect was observed in the copolymers. The temperature influence on the stability of the polymer helical structures was further explored by measuring CD and UV−vis absorption spectra at varied temperatures. Taking poly(LMAFc0.1-co-M10.9) as an example, the recorded spectra are shown in Figure 3. The intensity of CD and UV−vis signals around 390 nm gradually reduced as the temperature increased from 20 to 60 °C; they recovered nearly entirely when the temperature reduced back to 20 °C, demonstrating that the copolymers adopted dynamic helical structures. Just as expected, the copolymer poly(D-MAFc0.1-co-M10.9) showed the same result but with a negative CD signal at around 390 nm (Figure S6). It has been reported46 that amino acids, such as L-alanine, Lserine, and L-valine, exhibited excellent stereoselectivity for the aldol reaction between cyclohexanone and p-nitrobenzaldehyde. The chiral homopolymer poly(L-MAFc), chirally helical copolymer poly(L-MAFc0.1-co-M10.9), and the corresponding monomers were separately applied in catalyzing the asymmetric aldol reaction between cyclohexanone and p-nitrobenzaldehyde at 15 °C (Scheme 1C). The detailed catalytic results in the reaction medium of THF and with other additives are presented in Table 2. Because of a lack of catalytic moieties, achiral monomer M1 and its homopolymer poly(M1) failed to catalyze the asymmetric aldol reaction (Table 2, Run 1 and 2). This is in good agreement with expectations. L-MAFc, poly(LMAFc), and poly(L-MAFc0.1-co-M10.9) were also employed to catalyze the asymmetric aldol reaction under the same conditions. The results are also presented in Table 2. Regretfully, these compounds did not show any catalytic ability either. The lack of a primary amino structure in monomer LMAFc units should be responsible for the results; that is, LMAFc, poly(L-MAFc), and poly(L-MAFc0.1-co-M10.9) could not catalyze the direct asymmetric aldol reaction. We then changed the chiral source to L- and D-theronine instead of alanine, so that the ferrocenyl group was linked as oxo-ferrocenoyl moieties, in which the primary amine structures may possess catalytic capacity (Scheme 1). Thus, a pair of novel chiral monomers with ferrocenyl L- or D-theronine derivative pendants (L-MTFc and D-MTFc) was synthesized next. Taking

Table 2. Asymmetric Aldol Reactions Catalyzed by Monomers and (Co)Polymersa

run

cat. (10 mol %)

1 2 3 4 5

M1 poly(M1) L-MAFc poly(L-MAFc) poly(L-MTFc0.1co-M10.9) L-MT L-MTFc poly(L-MTFc) poly(L-MTFc0.1co-M10.9) poly(L-MT0.1- coM10.9) poly(L-MTFc0.1co-M10.9) poly(L-MTFc0.1co-M10.9) poly(L-MTFc0.1co-M10.9) poly(D-MTFc0.1co-M10.9)

6 7 8 9 10 11 12 13 14

additive

time (h)

yield (%)b

dr (anti/syn)b -

ee% (anti)c

-

72 72 72 72 72

-

-

-

72 72 24 24

42 78 46 85

69/31 75/25 84/16 82/18

68 75 30 85

-

24

81

79/21

80

PhCOOH, H2O TFA, H2O

24

90

90/10

93

24

89

87/13

89

AcOH, H2O

24

83

83/17

90

PhCOOH, H2O

24

89

85/15

−92

a Aldol reactions between cyclohexanone and p-nitrobenzaldehyde were carried out at 15 °C under the corresponding conditions as listed in the table (THF as solvent); the time for full conversion in all cases monitored by TLC. The small dash “-” indicates no additive added or no reaction occurred. bDetermined by 1H NMR. cDetermined by HPLC using a Daicel CHIRALPAK AD-H.

monomer L-MTFc as representative, FT-IR (Figure S7) and NMR (Figure S8) spectra confirmed the successful synthesis of the monomer. Because chiral monomers L-MAFc and L-MTFc possess similar molecular structure just differing in chiral source, we directly prepared the homopolymer poly(L-MTFc) and copolymer poly(L-MTFc0.1-co-M10.9) at a feed ratio of LMTFc/M1 being 0.1/0.9 (mol/mol) under the same conditions as in the case of L-MAFc. The GPC data of poly(L-MTFc) and poly(L-MTFc0.1-co-M10.9) are presented in Table 1. The (co)polymerizations proceeded smoothly and provided the corresponding polymers in a quantitative yield. The (co)polymers were also characterized by 1H NMR (Figure S9) and FT-IR (Figure S10) spectra measurements, taking copolymer poly(L-MAFc0.1-co-M10.9) as representative. The stereoregularity of the obtained polymers was measured by Raman spectroscopy (Figure S11). High cis contents were found in the polymers.44,45 The threonine-derived polymers were further subjected to CD and UV−vis measurements. The relevant spectra are presented in Figure 4. For chiral monomer L-MTFc (Figure 4A, spectrum a), a weak CD signal at 480 nm was observed, also at which UV−vis absorption occurred (Figure 4B). The phenomena are similar to the results in L-MAFc (Figure 1). The homopolymer poly(L-MTFc) (Figure 4A, spectrum b) showed two clear CD signals at 310 and 480 nm, also like poly(L-MAFc) as discussed above. However, the copolymer poly(L-MTFc0.1-co-M10.9) (Figure 4A, spectrum c) displayed an apparent positive CD pattern around 390 nm, suggesting that the chiral ferrocenyl amino-acid derivative pendants were 7333


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Figure 4. (A) CD and (B) UV−vis spectra of monomers L-MTFc, homopolymer poly(L-MTFc), copolymer poly(L-MTFc0.1-co-M10.9), and copolymer poly(D-MTFc0.1-co-M10.9); measured in THF (c = 1 × 10−3 mol/L) at 25 °C.

Figure 5. (A) CD and (B) UV−vis spectra of poly(L-MTFc0.1-co-M10.9) at increasing temperature (from 20 to 60 °C) in THF(c = 1 × 10−3 mol/L).

that the tridimensional structure of ferrocene was in favor of the asymmetric reaction (Table 2, run 6 vs run 7). In addition, the homopolymer poly(L-MTFc) only provided 30% ee. This may be due to the lack of predominantly one-handed helical structures in the homopolymer, as discussed above. The copolymer poly(L-MTFc0.1-co-M10.9) is more efficient than the corresponding chiral small monomer, since the former took about 24 h to obtain a conversion of 85% and 85% ee, while the chiral small monomer L-MTFc took 72 h but only resulted in a conversion of 78% and 75% ee (Table 2, run 7 vs run 9). We thus infer that the helical structures along the copolymer chains together with the pendent groups offer concaves as catalytic domains which can concentrate the substrates and thereby accelerate the reaction rate. 47 Importantly, the remarkable improvement in both yield and ee data revealed the fact that a synergistic effect occurred between the chirally helical polymer chains and chiral ferrocenyl amino-acid derivative pendants. For the corresponding helical isomer of poly(L-MTFc0.1-co-M10.9), namely, poly(DMTFc0.1-co-M10.9), it gave similar results only with the product showing the opposite chirality (Table 2, run 14). On the basis of both the present investigations and our earlier studies,48 we propose that ferrocenyl amino acid derivatives in the side chains played key roles in controlling the chiral configuration of the product in the aldol reactions, while the helical main chains played assistant roles. In particular, when the helical polymer chains are in well matching with the pendent catalytic groups in chirality, the asymmetric products may achieve a good enantioselectivity with high ee values. Otherwise, offset effects

arranged into a one-handed helical array along the helical copolymer poly(L-MTFc0.1-co-M10.9) backbones with an excess handedness. As expected, the copolymer poly(D-MTFc0.1-coM10.9) (Figure 4A, spectrum d) displayed an apparent negative CD effect at around 390 nm. The temperature dependence of CD and UV−vis spectra of poly(L-MTFc0.1-co-M10.9) was further explored. The results are illustrated in Figure 5. In Figure 5, it can be found that the intensity of CD and UV−vis signals at approximately 390 nm gradually reduced as the temperature increased from 20 to 60 °C. They further recovered when the temperature went back to 20 °C, similar to the copolymer poly(L-MAFc0.1-co-M10.9) (Figure 3). The results indicate that dynamic helical structures were also formed in poly(L-MTFc0.1-co-M10.9). The copolymer poly(D-MTFc0.1-co-M10.9) showed the same result but with a negative CD signal at around 390 nm (Figure S12). We further carried out asymmetric aldol reactions by using chiral monomer L-MT without ferrocenyl, L-MTFc, the homopolymer poly(L-MTFc), and the copolymer poly(LMTFc0.1-co-M10.9) as catalysts under the same conditions aforementioned. The catalytic results are presented in Table 2. To our delight, the catalyzed reactions proceeded smoothly and furnished the desired aldol product with anti-configuration enantiomer (2S,1′R)-2-(hydroxyl-(p-nitrophenyl) methyl) cyclohexan-1-one formed mainly, which was determined by FTIR (Figure S17), NMR (Figure S18), and HPLC techniques. The asymmetric catalyses provided a moderately high yield (85%) with up to 85% ee (Table 2, runs 6−9). Particularly, the yield and enantioslectivity of the product using L-MTFc as catalyst were better than the results using L-MT. This proves 7334



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may occur in controlling the stereoconfiguration of the products. To acquire more insights into the effects of ferrocene structure, we further prepared copolymer poly(L-MT0.1-coM10.9) through deprotection of Boc groups of copolymer poly(Boc-L-MT0.1-co-M10.9) in the presence of TFA/DCM. The copolymer (Mn = 4800, the degree of polymerization was about 20) was characterized by different methods and was found to adopt predominantly one-handed helical structures (FT-IR, 1H NMR, Raman, CD, and UV−vis spectra as shown in Figures S13 to S16). The copolymer was used for perfoming an asymmetric aldol reaction, demonstrating that the 3-D ferrocene structures made a favorable contribtuion toward the stereoselectivity of the aldol product; however, the helical mainchain contributed much more (Table 2, runs 7, 9 vs 10). It is known that water and Brønsted acid49,50 can enhance the catalytic performance of organocatalyst-based aldolases. In our study, benzoic acid, trifluoroacetic acid, and acetic acid as typical Brønsted acid (0.1 equiv) and water (10 equiv) were investigated to explore their effects in asymmetric catalysis. The best result was obtained in the presence of PhCOOH (Table 2, run 11), in which a conversion of 90% and an ee of 93% were achieved. In the case using TFA (run 12), the yield was found to be 89%, and ee was 89%. For AcOH (run 13), the product was obtained with a yield of 83% and ee of 90%. The additives of water and Brønsted acid can considerably promote the conversion and enantiomeric purity of the anti-aldol product. In addition, we further employed the copolymer poly(D-MTFc0.1co-M1 0.9 ) as polymeric organocatalyst to catalyze the asymmetric aldol reaction under the optimized conditions determined in the case of copolymer poly(L-MTFc0.1-co-M10.9). Poly(D-MTFc0.1-co-M10.9) provided the other product isomer of anti-configuration (2R,1′S)-2-(hydroxyl-(p-nitrophenyl) methyl) cyclohexan-1-one with a yield of 89% and ee of −92%. For reference, typical HPLC spectra of the Aldol reaction products are shown in the SI (Figures S19, S20, S21, S22).

Article

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.iecr.6b01908. Data for the monomers and corresponding (co)polymers; NMR spectra of the monomers used in this article; FT-IR spectra of monomers and (co)polymers; Raman spectra of copolymers; CD and UV−vis absorption spectra of the monomers and (co)polymers; UV−vis absorption spectra of copolymers dissolved in THF at varied temperature, etc. (PDF)

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AUTHOR INFORMATION

Corresponding Author

*Fax: +86-10-6443-5128. Tel: +86-10-6443-5128. E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by the National Natural Science Foundation of China (21474007, 21274008) and the Funds for Creative Research Groups of China (51521062).

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REFERENCES

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CONCLUSIONS We synthesized optically active helical substituted polyacetylenes with ferrocenyl amino-acid derivative pendants. Taking advantages of the unique steric effects and lipophilicity characters of ferrocenyl moieties and the synergistic effect occurring between the helical main-chain chirality and the ferrocenyl amino-acid derivative pendants, the obtained polymeric organocatalysts demonstrated excellent catalytic performance for aldol reactions of cyclohexanone and pnitrobenzaldehyde, in particular in the presence of benzoic acid and water. The best results were obtained under the optimized conditions, providing the product in a good yield 90% and ee 93%. Encouraged by the satisfactory results by combining the chiral ferrocenyl derivative with optically active helical substituted polyacetylene, we are currently further optimizing the composition, structure, and morphology of the novel polymer catalysts. For the purpose of readily recycling the helical polymer catalyst, we will make special efforts to prepare nanoparticles and even magnetic nanoparticles constructed by the interesting helical polymer catalyst established in the present study, and use them for performing aldol reactions and even other asymmetric reactions. The studies along this direction may provide novel, effective, and green chiral polymer catalysts. 7335


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Optically Active Helical Polyacetylene Bearing Ferrocenyl Amino-Acid

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