N-(4-hydroxyphenyl)mandelamide

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The chiral N-(4-hydroxyphenyl)mandelamide (1) was synthesized through condensation of p-aminophenol with (R)- or (S)-mandelic acid, respectively in presence of dicyclohexylcarbodiimide as condensing agent. For oligomerization of 1 via oxidative coupling laccase from Pleurotus ostreatus, peroxidase from horseradish or iron(II)-salen were used as catalysts. The obtained yellow powdery oligomers 2 show high solubility in many commonly used organic solvents like acetone, THF, ethanol, methanol, acetonitrile and 1,4-dioxan. Because of the broad signals of the oligomers 2 in the ¹H NMR spectra the ratio of the phenylene and oxyphenylene units (Scheme 1) could not be clearly determined.

Scheme 1: Oligomerization of N-(4-hydroxyphenyl)mandelamide (1).

The oligomerization of 1 in water could be easily performed through complexation of the monomer 1 with randomly methylated β-cyclodextrin (RAMEB-CD). The formation of the complex was verified with 2D ROESY NMR spectroscopy. The magnetic interaction of the monomer with the cavity of RAMEB-CD is obvious in the 2D ROESY NMR spectra as shown in Figure 1 (marked areas). Principally, cyclodextrins and their derivatives are able to discriminate enantiomeric compounds [9,10]. Such chirality recognition is provable with ¹H NMR spectroscopy because of the different induced shift of the protons which became diastereotopic through complexation [11,12]. Actually, the chirality discrimination of 1 with RAMEB-CD is evident from the different induced shift of the protons 8 at 5.2 ppm (zoomed out in Figure 1).

Figure 1: 2D ROESY NMR spectrum (600 MHz, D₂O) of the racemate 1 complexed with RAMEB-CD.

The MALDI–TOF MS measurements indicate the formation of oligomers 2 from the monomer 1 as shown in Figure 2. As expected the repetitive unit has a molecular mass of 241 g/mol, which confirms the linkage of the monomers via a formal abstraction of two hydrogen atoms. The highest molecular weight oligomers 2 obtained through enzymatic oligomerization consists of up to 10 repetitive units which could be detected by MALDI–TOF MS measurements. Furthermore comparable molecular weights are accessible through oligomerization of 1 with iron(II)-salen as catalyst. Here oligomers 2 with up to 8 repetitive units are detectable.

Figure 2: MALDI–TOF MS spectrum of the oligomers synthesized with laccase from the racemate 1.

The conversion of the enantiomers of 1 during the enzymatic oligomerization has been studied using chiral HPLC. Accordingly, the racemate of 1 was oligomerized three times with each enzyme in the absence of RAMEB-CD or in the presence of RAMEB-CD, respectively to evaluate the reproducibility. The isolated monomeric residual of each oligomerization was measured twice. The obtained enantiomeric excess (ee) values of the monomeric residual are given in Table 1. Because of the rapid conversion of the monomer 1 during the oligomerization with highly active peroxidase–H₂O₂ system at room temperature, the reaction time was limited to one minute at 0 °C. In the presence of the lower active laccase–O₂ system, the reaction was carried out for 4 h at room temperature.

Table 1: Enantiomeric excess values (ee) of the monomeric residual of the enzymatic oligomerization of 1.

used enzyme, use of CD	ee (%)a
laccase	racemic mixture
peroxidase	6 S
laccase + CD	4 R
peroxidase + CD	8 R
aCalculated on the basis of the surfaces of chiral HPLC peaks, enantiomers were separated from the reaction mixture by column chromatography with ethylacetate/n-hexane (2:1) as eluent.

In the absence of RAMEB-CD it is apparent that laccase shows no enantioselectivity. However it can be established that during the oligomerization with peroxidase the (S)-enantiomer 1 slightly enriches the reaction solution. Additionally to that, it was of some interest to verify, whether the complexation of the enantiomers with RAMEB-CD affects the conversion of the enantiomers. Therefore, the relatively slow oligomerizations in the presence of laccase were carried out in pH 5 buffer at room temperature for 4 hours. The rapid oligomerizations in the presence of peroxidase were carried out in pH 7 buffer at 0 °C for 1 min. It was found that, in the presence of RAMEB-CD, the (R)-enantiomer of 1 slightly enriches the reaction mixture with laccase as well as with peroxidase. As already mentioned above, the opposite effect was observed when the oligomerization was carried out with peroxidase without using RAMEB-CD. However, the obtained data show that the degree of enantioselectivity during conversion of 1 is generally very low.

Syntheses

Synthesis of N-(4-hydroxyphenyl)mandelamide (1)

7.61 g (50 mmol) Mandelic acid and 5.75 g (50 mmol) N-hydroxysuccinimide were dissolved in 150 mL acetone and cooled in an ice–water bath. Subsequently, a suspension of 10.32 g (50 mmol) dicyclohexylcarbodiimide in 50 mL acetone was added and the reaction mixture stirred for 2.5 hours at 0 °C. After that, 5.46 g (50 mmol) p-aminophenol was added and the ice bath was removed. The reaction mixture was stirred for 24 hours at room temperature. The precipitated dicyclohexylurea was filtered off. Then the solution was concentrated under reduced pressure and the product purified by column chromatography (eluent: n-hexane/ethyl acetate 1:2). Yield depending on the use of racemic or (S)-, (R)-enantiomer of mandelic acid: (RS)-1 = 9.16 g (75%), (S)-1 = 10.03 g (82%), (R)-1 = 9.63 g (79%). mp: (RS)-1: 97 °C, (S)-1: 155 °C, (R)-1: 153 °C; optical rotation (THF): (S)-1: [α]_D²⁰ −3,9°, (R)-1: [α]_D²⁰ +3,4°; (RS)-1: GC–EIMS, m/z: 243 [M(1)]⁺, 137, 109, 79. ¹H NMR (500 MHz, DMSO-d₆) δ 9.66 (s, 1H, -NH), 9.20 (s, 1H, -OH), 7.50 (d, 2H, -ArH), 7.46 (d, 2H, -ArH), 7.35 (t, 2H, -ArH), 7.28 (t, 1H, -ArH), 6.68 (d, 2H, -ArH), 6.35 (d, 1H, -OH), 5,055 (d, 1H, -CH) ppm; ¹³C NMR (75 MHz, DMSO-d₆) δ 170.42 (C=O), 153.52 (C-OH), 141.10, 130.17, 128.04, 127.51, 126.56, 121.39, 114.96 (Ar-C), 73.91 (C-OH) ppm.

Synthesis of oligo (N-(4-hydroxyphenyl)mandelamide) (2)

Enzymatic oxidative oligomerization with peroxidase: A solution of 7.5 mg peroxidase dissolved in 10 ml pH 7 buffer was added to a solution of 1.22 g (5 mmol) N-(4-hydroxyphenyl)mandelamide (1) and 40 mL 1.4-dioxan. 510 µL of hydrogen peroxide (30%) were added to the mixture in aliquots of 51 µL in 15 minutes intervals. After stirring for 2 h at room temperature, the product was precipitated by pouring into 0.5 M HCl and dried under vacuum. Yield depending on use of racemic or (S)-, (R)-enantiomer of N-(4-hydroxyphenyl)mandelamide (1): (RS)-2 = 0.79 g (65%), (S)-2 = 1.02 g (85%), (R)-2 = 0.97 g (80%). GPC (DMF): (RS)-2: M_n = 1500 g mol⁻¹, D = 1.22, (S)-2: M_n = 1510 g mol⁻¹, D = 1.21, (R)-2: M_n = 1500 g mol⁻¹, D = 1.23; (RS)-2: ¹H NMR (300 MHz, DMSO-d₆) δ 10.04–9.64 (broad signal, 1H, -NH), 7.79-6.71 (broad signal, 8H, -ArH), 6.52-6.13 (broad signal, 1H, -OH), 5.16-4.92 (broad signal, 1H, -CH) ppm.

Oligomerization of optically active N-(4-hydroxyphenyl)mandelamide in the presence of β-cyclodextrin and the minor role of chirality

Helmut Ritter¹, Antonia Stöhr¹ and Philippe Favresse²

¹Institute of Organic Chemistry and Macromolecular Chemistry, Heinrich-Heine-University Düsseldorf, Universitätsstraße 1, Düsseldorf, 40225, Germany
²Coatings & Additives, Evonik Industries AG, Goldschmidtstraße 100, Essen, 45127, Germany

Corresponding author email     

Associate Editor: S. C. Zimmerman

Beilstein J. Org. Chem. 2014, 10, 2361–2366.

 http://www.beilstein-journals.org/bjoc/single/articleFullText.htm?publicId=1860-5397-10-246
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