Discrimination and Enantiomeric Excess Determination of Chiral

Aug 15, 2017 - 1H and 13C NMR spectra of Δ-PES, 1H NMR spectra for the compounds, CD spectra of Δ-PES and Δ-PER, and quantitative determination of ...
0 downloads 0 Views 2MB Size
Download PDF
Article pubs.acs.org/IC

Discrimination and Enantiomeric Excess Determination of Chiral Primary Amines Based on a Chiral-at-Metal Ir(III) Complex Using NMR Spectroscopy Li-Ping Li and Bao-Hui Ye* MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, School of Chemistry, Sun Yat-sen University, Guangzhou 510275, China

Downloaded via DURHAM UNIV on June 28, 2018 at 19:56:43 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.

S Supporting Information *

ABSTRACT: A three-component protocol involving enantiopure Δ-[Ir(ppy)2(MeCN)2](PF6) (ppy is 2-phenylpyridine) and salicylaldehyde as chiral auxiliaries was successfully applied to discriminate the absolute configuration and determine the enantiopurity of primary amines and amine alcohols via 1H NMR spectroscopy. The assembly reaction is rapid and quantitative, generating a pair of diastereomers that can be determined directly without physical separation. Single crystal structural analyses indicate that the shielding effects on the ligands imposed by a pair of diastereomers are different and generate sufficient resolution NMR signals for identification. The enhancement of stability via chelating coordination to Ir(III) ion and more than one pair of diastereotopic resonances in different detection regions of the three-component protocol ensure a high degree of accuracy in quantifying the ee value of chiral amines. The absolute errors in the ee determinations by 1H NMR spectroscopy in different detection windows are within 2.0%. The linear relationship between the experimentally measured ee values and the gravimetrically prepared samples is found to be excellent. This finding would provide a complementary method for the discrimination and determination of the enantiopurity of chiral primary amines and amine alcohols in the screening of asymmetric reactions.

■

INTRODUCTION Chiral amines play an important role in organic synthesis and pharmaceutical chemistry;1 many methodologies have been developed for their asymmetric synthesis. Meanwhile, there is increasing interest in development of rapid and facile methods for determination of absolute configuration and enantiomeric excess (ee) in the screening of asymmetric reactions. To date, many analytical techniques have been used to determine ee value, such as HPLC,2 GC,3 UV−vis,4 circular dichroism (CD),5 fluorescence spectroscopy,6 and NMR spectroscopy.7 Among them, NMR spectroscopy, especially 1H NMR, has been proven to be an efficient and straightforward approach for determining ee of chiral molecules due to accurate, fast, and convenient application.8 However, NMR spectroscopy is infrequently used for direct analysis of chiral amines compared with popular methods of HPLC and CD. Generally, enantiodiscrimination of chiral amines by NMR techniques is achieved by using a chiral auxiliary, such as a chiral derivatizing agent (CDA),7c−e,9 chiral solvating agent (CSA),7f−h,10 or chiral lanthanide shift reagent (CLSR),8 to produce diastereomeric complexes. In spite of great advances, the drawbacks such as line-broadening, narrow substrate scope, poor solubility, and poor resolution still limit its application. Chiral aldehydes are usually used as CDAs to react with amines to generate Schiff base rapidly due to covalent formation and usually resulting in better discrimination for large chemical shift difference.7e,9c © 2017 American Chemical Society

However, the formation of the imine bond is reversible and sensitive to water. An alternative strategy developed by Bull and James is to use 2-formylbenzene boronic acid in combination with enantiomeric 1,1′-bi-2-naphthol, affording a mixture of diastereomeric iminoboronate esters whose ratio can be determined by the integration of their 1H NMR spectra.7c,d All these methods typically rely on the NMR signals of the analytes; thus, the analysis requires formation of stable complexes and is complicated when the NMR signals overlap. In an effort to explore efficient chiral auxiliaries for discriminating chiral primary amines and addressing the limitations in NMR method, we consider Ir(III) complexes with chirality at the metal. In fact, chiral metal complexes have been used as chiral receptors to discriminate the enantiomers.11 Coordinatively unsaturated chiral octahedral complexes with different binding sites in a chiral environment have strong capability for discrimination of chiral coordinating substrates. Previous works on asymmetric synthesis of Ru(II) and Ir(III) polypyridine complexes with chiral amino acids or sulfoxides showed that their diastereomers have distinguishable 1H NMR spectra at low-field with good resolution for the α-H proton of the pyridine ring.12,13 This may provide a pathway to broaden the detection window at low-field to address the limitation of Received: July 1, 2017 Published: August 15, 2017 10717

DOI: 10.1021/acs.inorgchem.7b01681 Inorg. Chem. 2017, 56, 10717−10723

Article

Inorganic Chemistry

123.79, 122.09, 121.82, 121.29, 121.07, 120.52, 118.53, 118.26, 112.90, 63.93, 21.29. CD (Δε, M−1 cm−1, DCM): 261 (−44), 290 (+29), 335 (−5), 466 nm (+13). For Δ-PES: 1H NMR (400 MHz, CDCl3) δ 8.90 (d, J = 5.5 Hz, 1H), 8.53 (d, J = 5.5 Hz, 1H), 8.03 (s, 1H,a), 7.83 (d, J = 8.1 Hz, 1H), 7.69−7.58 (m, 3H), 7.54 (d, J = 7.6 Hz, 1H), 7.39 (d, J = 7.7 Hz, 1H), 7.15 (d, J = 1.8 Hz, 1H), 7.10 (d, J = 2.3 Hz, 1H), 7.01−6.96 (m, 3H), 6.95−6.90 (m), 6.80 (td, 2H), 6.70 (dd, J = 16.3, 7.8 Hz, 2H,), 6.63 (d, J = 8.6 Hz, 1H), 6.42 (d, J = 7.5 Hz, 1H), 6.37− 6.30 (m, 3H), 6.13 (d, J = 7.4 Hz, 1H), 4.70 (m, 1H), 1.45 (d, J = 6.8 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 168.98, 168.28, 165.91, 161.17, 152.64, 150.69, 148.92, 148.56, 144.78, 144.62, 142.09, 136.60, 135.09, 133.72, 133.11, 131.97, 129.31, 129.27, 127.95, 126.80, 126.69, 124.46, 124.00, 123.74, 121.55, 121.48, 121.25, 120.21, 118.98, 118.33, 113.06, 65.95, 22.23. CD (Δε, M−1 cm−1, DCM): 262 (−52), 290 (+33), 335 (−10), 466 nm (+10). Single-Crystal X-ray Crystallography. The diffraction intensities for Δ-PER and Δ-PES were collected at 293 K on an Oxford Gemini S Ultra CCD area detector diffractometer with graphite-monochromated Cu Kα radiation (λ = 1.54178 Å). All of the data were corrected for absorption effect using the multiscan technique. The structures were solved via direct methods (olex2.solve)14 and refined by iterative cycles of least-squares refinement on F2 followed by difference Fourier synthesis.15 All non-hydrogen atoms were refined anisotropically. All hydrogen atoms were included in the final structure factor calculation at idealized positions and were allowed to ride on the neighboring atoms. The crystal data and the details of data collection and refinement for the complexes are summarized in Table 1.

signal overlap of the analytes in NMR spectroscopy. Herein, a three-component protocol assembled with chiral primary amine or amine alcohol, salicylaldehyde, and enantiomerically pure Ir(III) complex Δ-[Ir(ppy)2(MeCN)2](PF6) (where ppy is 2phenylpyridine) into a mixture of structurally rigid diastereomeric Ir(III) Schiff base complexes is reported (see Scheme 1), Scheme 1. Three-Component Protocol Used for Determining ee of Chiral Primary Amines via Assembling with Salicylaldehyde and Δ-[Ir(ppy)2(MeCN)2](PF6)

in which the assembled reaction is rapid and quantitative, and the diastereomer exhibits characteristic 1H NMR spectra with good resolution in more than one pair of diastereotopic resonances, including the low-field resonances of the α-H in the pyridine ring and imine and the high-field resonances of Nfragments of the analytes. Moreover, the chelating coordinate to Ir(III) greatly enhances the formation and stability of the imine bond to avoid the hydrolysis of the products.

■

Table 1. Crystallographic Data for Δ-PER and Δ-PES complex molecular formula Mr cryst syst space group temp (K) a (Å) b (Å) c (Å) V (Å3) Z Dc (g cm−3) μ (mm−1) no. data of collected no. obsd reflns R1a [I > 2σ (I)] ωR2b (all data) GOF Flack param

EXPERIMENTAL SECTION

Materials and Methods. All chemicals were commercially available and used as purchased unless otherwise noted. The enantiopure Δ-[Ir(ppy)2(MeCN)2](PF6) (ee ≥98%) was synthesized according to the literature.13c Elemental (C, H, and N) analyses were carried out on an Elementar Vario EL analyzer. Electrospray ionization mass spectra (ESI-MS) were obtained on a Thermo LCQ DECA XP mass spectrometer. 1H and 13C NMR spectra were recorded in CDCl3 on a Bruker AV-300 or AV-400 spectrometer, and chemical shifts (in ppm) were referenced to a residual solvent proton peak. The racemic and scalemic samples were prepared by mixing the enantiopure compounds in the appropriate ratios. General Procedure for Discrimination and ee Determination of Primary Amines. Δ-[Ir(ppy)2(MeCN)2](PF6) (0.0072 g, 0.01 mmol), amine or amine alcohol (0.01 mmol), salicylaldehyde (0.0012 g, 0.01 mmol), and Na2CO3 (0.0011g, 0.01 mmol) were added to a MeOH (15 mL) solution sequentially. The solution was stirred at 60 °C for 2 h. Then the solvent was removed, and the ternary mixture was transferred to a NMR tube with 0.5 mL of CDCl3 for 1H NMR determination. Synthesis of Δ-[Ir(ppy)2(R)-N-(1-phenylethyl)-salicylmethanimine (Δ-PER) and Δ-[Ir(ppy)2(S)-N-(1-phenylethyl)-salicylmethanimine (Δ-PES) Complexes. The enantiopure complexes were prepared using the above procedure, but enantiopure (R)-1-phenylethylamine or (S)-1-phenylethylamine was used, respectively. The reaction mixture was concentrated to dryness and crystallized from ethanol solution, affording yellow crystals. Yield, 89%. Anal. Calcd for C37H30IrN3O: C, 61.31; H, 4.17; N, 5.80. Found: C 61.29, H 4.20, N 5.77. ESI-MS: m/z = 726.2 [M + H]+. For Δ-PER: 1H NMR (400 MHz, CDCl3) δ 9.01 (d, J = 5.3 Hz, 1H), 8.19 (d, J = 5.4 Hz, 1H), 8.12 (s, 1H), 7.93 (d, J = 7.9 Hz, 1H), 7.74−7.82 (m, 2H), 7.63 (d, J = 7.6 Hz, 1H), 7.58 (t, J = 7.8 Hz, 1H), 7.54 (d, J = 7.6 Hz, 1H), 7.35− 7.27 (m, 3H), 7.22−7.14 (m, 3H), 7.11 (t, J = 7.6 Hz, 1H), 6.92 (d, J = 7.8 Hz, 1H), 6.84 (t, J = 7.3 Hz, 2H), 6.78−6.70 (m, 3H), 6.59 (d, J = 8.6 Hz, 1H), 6.47 (d, J = 7.3 Hz, 1H), 6.30 (t, J = 7.3 Hz, 1H), 6.22 (d, J = 7.4 Hz, 1H), 4.73 (q, J = 6.7 Hz, 1H), 0.74 (d, J = 6.9 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 168.81, 168.75, 166.38, 161.80, 152.45, 151.90, 149.92, 148.94, 144.79, 144.75, 142.01, 137.05, 136.54, 134.86, 133.62, 131.99, 129.91, 129.34, 128.64, 128.17, 127.71, 124.51, 124.22,

a

Δ-PER C37H30IrN3O 724.84 orthorhombic P212121 298 8.3156(1) 13.0909(1) 27.1039(3) 2950.50(5) 4 1.632 9.025 4697 4458 0.0175 0.0418 1.072 −0.019(7)

Δ-PES C37H30IrN3O 724.84 orthorhombic P212121 298 9.1783(2) 12.0224(3) 26.8369(7) 2961.32(12) 4 1.626 8.992 4295 4096 0.0367 0.1024 1.069 −0.014(18)

R1 = ∑||F0| − |Fc||/∑|F0|. bωR2 = [∑ω(F02 − Fc2)2/∑ω(F02)2]1/2.

■

RESULTS AND DISCUSSION Diastereomeric Discrimination of Chiral Amine. When enantiopure Δ-[Ir(ppy)2(MeCN)2](PF6), salicylaldehyde, and rac-1-phenylethylamine were added to a methanol solution in 1:1:1 ratio in the presence of Na2CO3 at 60 °C, Ir(III) Schiff base three-component complexes were indeed afforded in 2 h, as shown in Figure 1. The disappearance of the resonance peaks of the reaction materials, for example, the characteristic resonances of the α-H at 9.05 ppm for Δ-[Ir(ppy)2(MeCN)2](PF6) and the CHO at 9.90 ppm for salicylaldehyde, indicated that the reaction was complete and quantitative in 2 h. A pair of diastereomers, Δ-PER and Δ-PES, with sufficient resolution of NMR signals in multidetection areas (for example, A, B, C, D, and E, marked in Figure 1) clearly demonstrated a statistical 10718

DOI: 10.1021/acs.inorgchem.7b01681 Inorg. Chem. 2017, 56, 10717−10723

Article

Inorganic Chemistry

ppm) assigned to the *C−HD proton and at 0.74 and 1.45 ppm (Δδ = −0.71 ppm) assigned to the CH3(E) group, respectively, are also observed. Therefore, comparison of the relative intensities of integrals of the pair of diastereotopic resonances enables precise determination of enantiopurity of 1-phenylethylamine via the three-component protocol. It is worth mentioning that having more than one pair of diastereotopic resonances in different regions for the three-component complexes ensures a high degree of accuracy in quantifying the ee value of chiral amines. The Relationship between Absolute Configuration and NMR Signals. In order to gain a better understanding of the structural distinction between the diastereomers and the relationship between the NMR signals and the absolute configuration of primary amines, single crystal structures of diastereomers Δ-PES and Δ-PER are measured by X-ray crystallography. They crystallize in a chiral space groups P212121. The Ir(III) center shows a slightly distorted octahedral geometry with coordination of two carbon atoms in cis and two nitrogen atoms in trans from two ppy ligands as well as an oxygen atom and a nitrogen atom from a Schiff base ligand, as shown in Figure 3. The Ir−N and Ir−C distances of the ppy

Figure 1. 1H NMR spectrum of Δ-Ir(III) Schiff base complexes in CDCl3. The discriminated peaks are marked.

50:50 ratio. These distinguishable NMR signals can be used to quantitatively determine chiral amines by calculating the resonance peaks. It should be noted that the analytic process does not involve any additional purification steps, implying it is relatively simple, facile, and fast. For the assignment of the characteristic resonance peaks of the diastereomers Δ-PER and Δ-PES, the individual 1H NMR spectra of Δ-[Ir(ppy)2(MeCN)2](PF6) with enantiopure R- or S-1-phenylethylamine and salicylaldehyde were also recorded under the identical conditions (see Figures S1 and S2, respectively). The all resonance peaks were well assigned via the 1H−1H COSY and NOSY NMR spectra (see Figures S3− S6). The significant differentiation of the diastereotopic resonances is displayed in Figure 2. In the low-field region, it

Figure 3. Crystal structures of Δ-PES (a) and Δ-PER (b). Selected bond lengths (Å) and angles (deg) for Δ-PES and Δ-PER (in parentheses): Ir1−N1 = 2.024(7) (2.052(3)), Ir1−N2 = 2.039(8) (2.037(3)), Ir1−C7 = 2.014(9) (2.011(3)), Ir1−C18 = 1.997(10) (2.004(3)), Ir1−O1 = 2.140(6) (2.146(2)), Ir1−N3 = 2.162(7) (2.174(3)), O1−Ir1−N3 = 88.3(2) (86.0(1)), N1−Ir1−N2 = 175.7(3) (173.5(1)), Ir1−O1−C23−C28 = 18.0(1) (34.7(5)). Perspective drawing with 50% probability thermal ellipsoids.

ligands are around 2.0 Å, which are consistent with those reported for ppy Ir(III) complexes.13,16 The bond lengths of Ir1−N3 (2.162(7) and 2.174(3) Å) and Ir1−O1 (2.140(6) and 2.146(2) Å) are significantly elongated,17 indicating that the carbon atom has a strong trans effect. In Δ-PER diastereomer, there is some distortion to alleviate the interligand congestion, the N∧O chelate angle (86.0(1)°) is smaller than that in Δ-PES diastereomer (88.3(2)°), and the torsion angle Ir1−O1−C23− C28 (34.7(5)°) is significantly larger than that in Δ-PES (18.0(1)°). The absolute configurations at the metal centers are all in Δ fashion and the carbon atoms are R and S configurations, respectively. These are consistent with those of the precursors and demonstrate that no racemization occurs at metal centers and in chiral amines during the reactions. The Flack parameters of Δ-PER (−0.019(7)) and Δ-PES (−0.014(18)) are close to zero, indicating that the assignments of absolute configuration at the metal and carbon centers are correct.

Figure 2. Excerpts of 1H NMR spectra of Δ-Ir(III) Schiff base complexes (a), Δ-PER (b), and Δ-PES (c) in CDCl3. The discriminated peaks are marked (■, Δ-PER;▲, Δ-PES).

is found that there are two sets of baseline resolved doublet resonances corresponding to Δ-PER and Δ-PES at 9.01 and 8.90 ppm (Δδ = 0.11 ppm, Δδ = ΔδR − ΔδS) assigned to the α-HA of the py ring “A” and at 8.19 and 8.53 ppm (Δδ = −0.34 ppm) assigned to the α-HB of the py ring “B”. Moreover, two singlet resonances at 8.12 and 8.03 ppm (Δδ = 0.09 ppm) assigned to the imine proton of Δ-PER and Δ-PES, respectively, are clearly observed. In addition, in the high-field region, two sets of resonances at 4.73 and 4.70 ppm (Δδ = 0.03 10719

DOI: 10.1021/acs.inorgchem.7b01681 Inorg. Chem. 2017, 56, 10717−10723

Article

Inorganic Chemistry

Figure 4. Excerpts of 1H NMR spectra of seven scalemic mixtures of enantiopure R/S-1-phenylethylamine with salicylaldehyde and Δ[Ir(ppy)2(MeCN)2](PF6) in CDCl3 (left) and linear relationship between measured ee values (%) and gravimetrically determined ee values (%) based on the α-HA signals (right).

Table 2. Quantitative Determination of ee of (R)-1-Phenylethylamine Using 1H NMR proton α-H(A)

α-H(B)

HCN(C)

CH3(E)

actual ee (%)

calcd ee (%)

absolute error (%)

calcd ee (%)

absolute error(%)

calcd ee (%)

absolute error(%)

calcd ee (%)

absolute error (%)

90 60 30 0 −30 −60 −90

88.7 60 30.7 0 −29.0 −58.4 −88.7

1.3 0 0.7 0 1.0 1.6 1.3

88.7 61.2 31.6 0 −28.2 −58.7 −90.5

1.3 1.2 1.6 0 1.8 1.3 0.5

88.7 60 30.7 1.0 −28.2 −58.7 −90.5

1.3 0 0.7 1.0 1.8 1.3 0.5

88.7 61.2 30.7 1.0 −28.2 −58.7 −90.5

1.3 1.2 0.7 1.0 1.8 1.3 0.5

Figure 5. Chemical shift difference (Δδ = ΔδR − ΔδS ppm) values of discriminated protons for the diastereomers assembled by chiral amines or amine alcohols and salicylaldehyde in the presence of Δ-[Ir(ppy)2(MeCN)2](PF6).

To understand the differentiation of NMR signals between the diastereomers, the intramolecular interaction of the ligands, which may also be exhibited in solution, is analyzed in detail. In Δ-PES, the phenyl substituent and the “A” ring of ppy ligand are in a face to face arrangement with a distance of ca. 3.6 Å (see Figure 3a), suggesting that the α-HA resides in the shielded region of the phenyl, resulting at high-field resonance compared to that in Δ-PER (Δδ = 0.11 ppm, see Figure 3b, in which the phenyl group is far away the “A” ring of ppy). In addition, the

C−H30 is closer to the coordinated plane (ca. 2.45 Å) than that in Δ-PER (ca. 2.76 Å) and suffers from the ring current (Δδ = 0.03 ppm). In contrast, in Δ-PER, the CH3 group of Rsalicylimine lies above the “A” ring of ppy ligand and so is significantly affected by a ring current, and the resonance is observed at higher field relative to that in Δ-PES (Δδ = −0.71 ppm). Moreover, the α-HB sits above the phenyl substituent and so is significantly affected by a ring current, and the signal is shifted to high-field region with respect to that in Δ-PES (Δδ = 10720

DOI: 10.1021/acs.inorgchem.7b01681 Inorg. Chem. 2017, 56, 10717−10723

Article

Inorganic Chemistry −0.34 ppm). From the above analysis, we can find that the resonances of α-HA of ppy and the C−H30 in Δ-PER have larger chemical shifts relative to those in Δ-PES. In contrast, the signals of α-HB of ppy and the methyl group in Δ-PER are observed at high-field compared to those in Δ-PES. The shielding effects on the ligands imposed by a pair of diastereomers are different and generate discrete NMR signals for identification. Determination of ee Values of Chiral Amines. The above observation reveals that the chemical shifts of chiral amine 1-phenylethylamine can be distinguished via formation of a pair of diastereomers Δ-PER and Δ-PES. Thus, the integral of the corresponding diastereotopic resonances can be used to quantitatively determine ee values of chiral amines under our experimental conditions. The 1H NMR spectra of seven scalemic mixtures of R/S-1-phenylethylamine were measured (see Figure 4), and their ee values were determined experimentally in four detection windows (see Table 2). As a result, each enantiomer can be correlated to the NMR signal with a precise chemical shift, and the calculated values are in excellent agreement with the actual enantiopurities. The absolute errors in the ee determinations by 1H NMR spectroscopy in the four different detection windows are within 1.8%. The linear relationship between the experimentally measured ee values and the gravimetrically prepared samples is found to be excellent. In order to examine the scope and limitations of this threecomponent protocol, a series of readily available chiral aromatic amines, R/S-1-(4-methylphenyl)ethylamine (MPER/S), R/S-1phenylpropan-1-amine (PPR/S), and R/S-1-(1-naphthyl)ethylamine (NER/S) (see Figure 5), were selected as analytes to test the differentiation of enantiomers. In these cases, one or more discriminated protons with excellent resolutions of the diastereomers are observed (see Figures S7−S11), and are able to determine the enantiopurity of the chiral amines. For the aromatic primary amines, the resonances for the α-HA, α-HB, and methyl protons are sufficient resolution in each pair of diastereomers with larger Δδ values due to the strong interaction between the phenyl substituent and ppy ligand. The absolute errors in the ee determinations are within 2.0% (see Table S1). The discriminating ability of the three-component protocol is further examined by the resolution of chiral aliphatic amines, such as R/S-cyclohexylethylamine (CER/S) and R/S-3,3dimethyl-2-butylamine (DBR/S). The discrimination of these amines is difficult because the connected groups to the chiral center differ solely in a single methylene unit. In our cases, although the α-H signals of the ppy ligand are very close together, the resonances for the C−HD and methyl protons have good spectral resolution in diastereomers and can be used to determine the ee values of chiral aliphatic amines with an absolute error within 2% (see Table S1). It is worth mentioning that no calibration curve is required in the three-component protocol. A pair of diastereotopic resonances for α-H of ppy ligand and C−H from the chiral center and methyl group from the chiral amine enable the enantiopure discrimination and determination of chiral primary amines. This method has the potential to be adapted in determination of absolute configuration and ee of chiral primary amine in the screening of asymmetric reactions. We also found that the NMR signals of α-HA in the Δ-R diastereomer always appear at a lower field compared with those of the Δ-S diastereomer (ΔδA > 0). In contrast, the

methyl signals of chiral amines with the R configuration always appear at a higher field compared with those having the S configuration (ΔδE < 0). Moreover, chiral amine alcohols readily available from commercial sources, such as R/S-2-amino-2-phenylethan-1-ol (APER/S), R/S-2-amino-3-phenylpropan-1-ol (APPR/S), and R/S-2-amino-3-methylbutan-1-ol (AMBR/S) (see Figure 5), were used as analytes to observe the differentiation of enantiomers. Similar cases were also found that more than one pair of diastereotopic resonances with excellent resolutions can be used to discriminate and determine ee values of chiral amine alcohols (Figures S12−S14). For the aromatic amine alcohols, the resonances for the α-HA, α-HB, and methylene protons are sufficient resolution in each pair of diastereomers with larger Δδ values due to the strong interaction between the phenyl substituent and ppy ligand. For chiral aliphatic amine alcohols, the resonances of α-HB, C−HD, and methylene protons are sensitive for discrimination. The absolute errors in the ee determinations are within 1.6% (see Table S1).

■

CONCLUSIONS In summary, a three-component protocol involving enantiopure Δ-[Ir(ppy)2(MeCN)2](PF6) and salicylaldehyde as chiral auxiliaries was first successfully applied to discriminate and determine the enantiopurity of varied primary amines and amine alcohols. The enhancement of stability via chelating effect and more than one pair of diastereotopic resonances in different detection regions of the three-component protocol ensure a high degree of accuracy in quantifying the ee value of chiral amines and amine alcohols. This finding would provide a complementary method for the discrimination and ee determination of chiral primary amines and amine alcohols with diverse functionality in the screening of asymmetric reactions and may open a new avenue for the application of a chiral-at-metal complex.

■

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.inorgchem.7b01681. 1 H and 13C NMR spectra of Δ-PES, 1H NMR spectra for the compounds, CD spectra of Δ-PES and Δ-PER, and quantitative determination of (R)-chiral amines and (R)chiral amine alcohols (PDF) Accession Codes

CCDC 1558735−1558736 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

■

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Bao-Hui Ye: 0000-0003-0990-6661 Notes

The authors declare no competing financial interest. 10721

DOI: 10.1021/acs.inorgchem.7b01681 Inorg. Chem. 2017, 56, 10717−10723

Article

Inorganic Chemistry

■

Int. Ed. 2015, 54, 7130−7133. (g) Wang, C.; Wu, E.; Wu, X.; Xu, X.; Zhang, G.; Pu, L. Enantioselective Fluorescent Recognition in the Fluorous Phase: Enhanced Reactivity and Expanded Chiral Recognition. J. Am. Chem. Soc. 2015, 137, 3747−3750. (h) Wen, K.; Yu, S.; Huang, Z.; Chen, L.; Xiao, M.; Yu, X.; Pu, L. Rational Design of a Fluorescent Sensor to Simultaneously Determine Both the Enantiomeric Composition and the Concentration of Chiral Functional Amines. J. Am. Chem. Soc. 2015, 137, 4517−4524. (i) Puglisi, R.; Ballistreri, F. P.; Gangemi, C. M. A.; Toscano, R. M.; Tomaselli, G. A.; Pappalardo, A.; Sfrazzetto, G. T. Chiral Zn−Salen Complexes: A New Class of Fluorescent Receptors for Enantiodiscrimination of Chiral Amines. New J. Chem. 2017, 41, 911−915. (7) (a) Parker, D. NMR Determination of Enantiomeric Purity. Chem. Rev. 1991, 91, 1441−1457. (b) Lesot, P.; Aroulanda, C.; Zimmermann, H.; Luz, Z. Enantiotopic Discrimination in the NMR Spectrum of Prochiral Solutes in Chiral Liquid Crystals. Chem. Soc. Rev. 2015, 44, 2330−2375. (c) Kelly, A. M.; Perez-Fuertes, Y.; Arimori, S.; Bull, S. D.; James, T. D. Simple Protocol for NMR Analysis of the Enantiomeric Purity of Primary Amines. Org. Lett. 2006, 8, 1971−1974. (d) Perez-Fuertes, Y.; Kelly, A. M.; Bull, S. D.; James, T. D.; et al. Simple Protocol for NMR Analysis of the Enantiomeric Purity of Primary Amines. Nat. Protoc. 2008, 3, 210− 214. (e) Gibson, S. M.; Lanigan, R. M.; Benhamou, L.; Aliev, A. E.; Sheppard, T. D. A Lactate-Derived Chiral Aldehyde for Determining the Enantiopurity of Enantioenriched Primary Amines. Org. Biomol. Chem. 2015, 13, 9050−9054. (f) Lakshmipriya, A.; Chaudhari, S. R.; Suryaprakash, N. Enantio-Differentiation of Molecules with Diverse Functionalities Using a Single Probe. Chem. Commun. 2015, 51, 13492−13495. (g) Seo, M.-S.; Kim, H. 1H NMR Chiral Analysis of Charged Molecules via Ion Pairing with Aluminum Complexes. J. Am. Chem. Soc. 2015, 137, 14190−14195. (h) Zhao, Y.; Swager, T. M. Simultaneous Chirality Sensing of Multiple Amines by 19F NMR. J. Am. Chem. Soc. 2015, 137, 3221−3224. (8) (a) Seco, J. M.; Quiñoá, E.; Riguera, R. The Assignment of Absolute Configuration by NMR. Chem. Rev. 2004, 104, 17−117. (b) Wenzel, T. J. Discrimination of Chiral Compounds Using NMR Spectroscopy; Wiley: Hoboken, 2007. (9) (a) Sullivan, G. R.; Dale, J. A.; Mosher, H. S. Correlation of Configuration and Fluorine-19 Chemical Shifts of alpha-Methoxyalpha-trifluoromethylphenyl Acetate Derivatives. J. Org. Chem. 1973, 38, 2143−2147. (b) Trost, B. M.; Bunt, R. C.; Pulley, S. R. On the Use of o-Methylmandelic acid for the Establishment of Absolute Configuration of alpha-Chiral Primary Amines. J. Org. Chem. 1994, 59, 4202−4205. (c) Dufrasne, F.; Gelbcke, M.; Neve, J. 1H-NMR Determination of the Enantiomeric Purity of Aliphatic Primary Amines, beta-Aminoalcohols, beta-Diamines and alpha-Amino-acids with 1R-(−)-Myrtenal: Scope and Limitations. Spectrochim. Acta, Part A 2003, 59, 1239−1245. (d) Mishra, S. K.; Chaudhari, S. R.; Suryaprakash, N. In situ Approach for Testing the Enantiopurity of Chiral Amines and Amino Alcohols by 1H NMR. Org. Biomol. Chem. 2014, 12, 495−502. (10) (a) Wenzel, T. J.; Wilcox, J. D. Chiral Reagents for the Determination of Enantiomeric Excess and Absolute Configuration Using NMR Spectroscopy. Chirality 2003, 15, 256−270. (b) Fang, L.X.; Lv, C. -X; Wang, G.; Feng, L.; Stavropoulos, P.; Gao, G.-P.; Ai, L.; Zhang, J.-X. Discrimination of Enantiomers of Dipeptide Derivatives with Two Chiral Centers by Tetraaza Macrocyclic Chiral Solvating Agents Using 1H NMR Spectroscopy. Org. Chem. Front. 2016, 3, 1716−1724. (11) (a) Fenton, R. R.; Stephens, F. S.; Vagg, R. S.; Williams, P. A. Chiral Metal Complexes 44. Enantiomeric Discrimination in Ternary Cobalt(III) Complexes of N,N′-Dimethyl-N,N′-di(2-picolyl)-1S,2Sdiaminocyclohexane and a-Amino Acids; Including the Crystal Structure of the S-prolinato Complex. Inorg. Chim. Acta 1995, 236, 109−115. (b) Tsukube, H.; Shinoda, S.; Uenishi, J.; Kanatani, T.; Itoh, H.; Shiode, M.; Iwachido, T.; Yonemitsu, O. Molecular Recognition with Lanthanide(III) Tris(b-diketonate) Complexes: Extraction, Transport, and Chiral Recognition of Unprotected Amino Acids. Inorg. Chem. 1998, 37, 1585−1591. (c) Tashiro, S.; Ogura, Y.;

ACKNOWLEDGMENTS This work was supported by the NSF of China (Nos. 21272284 and 21571195).

■

REFERENCES

(1) (a) France, S.; Guerin, D. J.; Miller, S. J.; Lectka, T. Nucleophilic Chiral Amines as Catalysts in Asymmetric Synthesis. Chem. Rev. 2003, 103, 2985−3012. (b) Chirality in Drug Research: Methods and Principles in Medicinal Chemistry; Francotte, E., Lindner, W., Eds.; Wiley-VCH: Weinheim, 2006; Vol. 33. (2) (a) Han, S. M. Direct Enantiomeric Separations by High Performance Liquid Chromatography Using Cyclodextrins. Biomed. Chromatogr. 1997, 11, 259−271. (b) Welch, C. J.; Szczerba, T.; Perrin, S. R. J. Some Recent High-Performance Liquid Chromatography Separations of the Enantiomers of Pharmaceuticals and Other Compounds Using the Whelk-O1 Chiral Stationary Phase. J. Chromatogr. A 1997, 758, 93−98. (3) (a) Schurig, V.; Nowotny, H. P. Gas Chromatographic Separation of Enantiomers on Cyclodextrin Derivatives. Angew. Chem., Int. Ed. Engl. 1990, 29, 939−1076. (b) Wolf, C.; Hawes, P. A. A HighThroughput Screening Protocol for Fast Evaluation of Enantioselective Catalysts. J. Org. Chem. 2002, 67, 2727−2729. (4) (a) Ait-Haddou, H.; Wiskur, S. L.; Lynch, V. M.; Anslyn, E. V. Achieving Large Color Changes in Response to the Presence of Amino Acids: A Molecular Sensing Ensemble with Selectivity for Aspartate. J. Am. Chem. Soc. 2001, 123, 11296−11297. (b) Folmer-Andersen, J. F.; Lynch, V. M.; Anslyn, E. V. Colorimetric Enantiodiscrimination of αAmino Acids in Protic Media. J. Am. Chem. Soc. 2005, 127, 7986− 7987. (c) Mei, X.-F.; Wolf, C. Determination of Enantiomeric Excess and Concentration of Unprotected Amino Acids, Amines, Amino Alcohols, and Carboxylic Acids by Competitive Binding Assays with a Chiral Scandium Complex. J. Am. Chem. Soc. 2006, 128, 13326− 13327. (d) Iwaniuk, D. P.; Yearick-Spangler, K.; Wolf, C. Stereoselective UV Sensing of 1,2-Diaminocyclohexane Isomers Based on Ligand Displacement with a Diacridylnaphthalene N,N′-Dioxide Scandium Complex. J. Org. Chem. 2012, 77, 5203−5208. (5) (a) Jo, H. H.; Lin, C.-Y.; Anslyn, E. V. Rapid Optical Methods for Enantiomeric Excess Analysis: From Enantioselective Indicator Displacement Assays to Exciton-Coupled Circular Dichroism. Acc. Chem. Res. 2014, 47, 2212−2221. (b) Wolf, C.; Bentley, K. W. Chirality Sensing Using Stereodynamic Probes with Distinct Electronic Circular Dichroism Output. Chem. Soc. Rev. 2013, 42, 5408−5424. (c) Joyce, L. A.; Regalado, E. L.; Welch, C. J. Hydroxypyridyl Imines: Enhancing Chromatographic Separation and Stereochemical Analysis of Chiral Amines via Circular Dichroism. J. Org. Chem. 2016, 81, 8199−8205. (d) De los Santos, Z. A.; Wolf, C. Chiroptical Asymmetric Reaction Screening via Multicomponent SelfAssembly. J. Am. Chem. Soc. 2016, 138, 13517−13520. (e) Xiong, J.-B.; Feng, H.-T.; Sun, J.-P.; Xie, W.-Z.; Yang, D.; Liu, M.; Zheng, Y.-S. The Fixed Propeller-Like Conformation of Tetraphenylethylene that Reveals Aggregation-Induced Emission Effect, Chiral Recognition, and Enhanced Chiroptical Property. J. Am. Chem. Soc. 2016, 138, 11469−11472. (6) (a) Pu, L. Enantioselective Fluorescent Sensors: A Tale of BINOL. Acc. Chem. Res. 2012, 45, 150−163. (b) Zhang, X.; Yin, J.; Yoon, J. Recent Advances in Development of Chiral Fluorescent and Colorimetric Sensors. Chem. Rev. 2014, 114, 4918−4959. (c) Wang, J.; Liu, H.-B.; Tong, Z.; Ha, C.-S. Fluorescent/Luminescent Detection of Natural Amino Acids by Organometallic Systems. Coord. Chem. Rev. 2015, 303, 139−184. (d) Dong, J.; Zhou, Y.; Zhang, F.; Cui, Y. A Highly Fluorescent Metallosalalen-Based Chiral Cage for Enantioselective Recognition and Sensing. Chem. - Eur. J. 2014, 20, 6455−6461. (e) Huang, Z.; Yu, S.; Wen, K.; Yu, X.; Pu, L. Zn(II) Promoted Dramatic Enhancement in the Enantioselective Fluorescent Recognition of Functional Chiral Amines by a Chiral aldehyde. Chem. Sci. 2014, 5, 3457−3462. (f) Shcherbakova, E. G.; Minami, T.; Brega, V.; James, T. D.; Anzenbacher, P. Determination of Enantiomeric Excess in Amine Derivatives with Molecular Self-Assemblies. Angew. Chem., 10722

DOI: 10.1021/acs.inorgchem.7b01681 Inorg. Chem. 2017, 56, 10717−10723

Article

Inorganic Chemistry Tsuboyama, S.; Tsuboyama, K.; Shionoya, M. Chiral Recognition of αAmino Acids by an Optically Active (2S, 5S, 8S, 11S)-2, 5, 8, 11Tetraethyl Cyclen Cobalt(III) Complex. Inorg. Chem. 2011, 50, 4−6. (d) He, X.; Zhang, Q.; Liu, X.; Lin, L.; Feng, X. Determination of Concentration and Enantiomeric Excess of Amines and Amino Alcohols with a Chiral Nickel(II) Complex. Chem. Commun. 2011, 47, 11641−11643. (e) Hu, Y.; Li, Y.; Joung, J. F.; Yin, J.; Park, S.; Yoon, J.; Hyun, M. H. Iridium Complex Bearing Urea Groups as a Phosphorescent Chemosensor for Chiral Anion Recognition. Sens. Actuators, B 2017, 241, 224−229. (12) (a) Hesek, D.; Inoue, Y.; Ishida, H.; Everitt, S. R. L.; Drew, M. G. B. The First Asymmetric Synthesis of Chiral Ruthenium Tris(bipyridine) from Racemic Ruthenium Bis(bipyridine) Complexes. Tetrahedron Lett. 2000, 41, 2617−2620. (b) Pezet, F.; Daran, J.-C.; Sasaki, I.; Aït-Haddou, H.; Balavoine, G. G. A. Highly Diastereoselective Preparation of Ruthenium Bis(diimine) Sulfoxide Complexes: New Concept in the Preparation of Optically Active Octahedral Ruthenium Complexes. Organometallics 2000, 19, 4008− 4015. (c) Gong, L.; Mulcahy, S. P.; Devarajan, D.; Harms, K.; Frenking, G.; Meggers, E. Chiral Salicyloxazolines as Auxiliaries for the Asymmetric Synthesis of Ruthenium Polypyridyl Complexes. Inorg. Chem. 2010, 49, 7692−7699. (d) Fu, C.; Wenzel, M.; Treutlein, E.; Harms, K.; Meggers, E. Proline as Chiral Auxiliary for the Economical Asymmetric Synthesis of Ruthenium(II) Polypyridyl Complexes. Inorg. Chem. 2012, 51, 10004−10011. (e) Li, Z.-Z.; Yao, S.-Y.; Wu, J.-J.; Ye, B.-H. In situ Generation of Sulfoxide with Predetermined Chirality via Structural Template with a Chiral-at-Metal of Ruthenium Complex. Chem. Commun. 2014, 50, 5644−5647. (f) Li, Z.-Z.; Yao, S.-Y.; Ye, B.H. Enantioselective Oxidation of Thioethers to Sulfoxides by Means of a Structural Template with Chiral-at-Metal Ruthenium Complexes. ChemPlusChem 2015, 80, 141−150. (g) Li, Z.-Z.; Yao, S.-Y.; Ye, B.-H.; Wen, A.-H. Asymmetric Oxidation Synthesis of Modafinil Acid by Use of a Recyclable Chiral-at-Metal Complex. Eur. J. Inorg. Chem. 2015, 2015, 4335−4342. (h) Li, Z.-Z.; Wen, A.-H.; Yao, S.-Y.; Ye, B.-H. Enantioselective Syntheses of Sulfoxides in Octahedral Ruthenium(II) Complexes via a Chiral-at-Metal Strategy. Inorg. Chem. 2015, 54, 2726−2733. (13) (a) Helms, M.; Lin, Z.; Gong, L.; Harms, K.; Meggers, E. Method for the Preparation of Nonracemic Bis-Cyclometalated Iridium(III) Complexes. Eur. J. Inorg. Chem. 2013, 2013, 4164− 4172. (b) Helms, M.; Wang, C.; Orth, B.; Harms, K.; Meggers, E. Proline and α-Methylproline as Chiral Auxiliaries for the Synthesis of Enantiopure Bis-Cyclometalated Iridium(III) Complexes. Eur. J. Inorg. Chem. 2016, 2016, 2896−2901. (c) Yao, S.-Y.; Ou, Y.-L.; Ye, B.-H. Asymmetric Synthesis of Enantiomerically Pure Mono- and Binuclear Bis(cyclometalated) Iridium(III) Complexes. Inorg. Chem. 2016, 55, 6018−6026. (d) Yao, S.-Y.; Chen, X.-Y.; Ou, Y.-L.; Ye, B.-H. Chiral Recognition and Dynamic Thermodynamic Resolution of Sulfoxides by Chiral Iridium(III) Complexes. Inorg. Chem. 2017, 56, 878−885. (14) Sheldrick, G. M. A Short History of SHELX. Acta Crystallogr., Sect. A: Found. Crystallogr. 2008, 64, 112−122. (15) Dolomanov, O. V.; Bourhis, L. J.; Gildea, R. J.; Howard, J. A. K.; Puschmann, H. OLEX2: A Complete Structure Solution, Refinement and Analysis Program. J. Appl. Crystallogr. 2009, 42, 339−341. (16) (a) Li, T.-Y.; Zheng, Y.-X.; Zhou, Y.-H. Iridium(III) Phosphorescent Complexes with Dual Stereogenic Centers: Single Crystal, Electronic Circular Dichroism Evidence and Circularly Polarized Luminescence Property. Dalton Trans. 2016, 45, 19234− 19237. (b) Maity, A.; Le, L.-Q.; Zhu, Z.; Bao, J.-M.; Teets, T. S. Steric and Electronic Influence of Aryl Isocyanides on the Properties of Iridium(III) Cyclometalates. Inorg. Chem. 2016, 55, 2299−2308. (c) Jiang, W.; Gao, Y.; Sun, Y.; Ding, F.; Xu, Y.; Bian, Z.; Li, F.; Bian, J.; Huang, C. Zwitterionic Iridium Complexes: Synthesis, Luminescent Properties, and Their Application in Cell Imaging. Inorg. Chem. 2010, 49, 3252−3260. (d) Li, L.; Zhang, S.; Xu, L.; Han, L.; Chen, Z.-N.; Luo, J. An Intensely Luminescent Metal−Organic Framework Based on a Highly Light-Harvesting Dyclo-Metalated Iridium(III) Unit Showing Effective Detection of Explosives. Inorg. Chem. 2013, 52, 12323−12325. (e) Rommel, S. A.; Sorsche, D.; Rockstroh, N.;

Heinemann, F. W.; Kübel, J.; Wächtler, M.; Dietzek, B.; Rau, S. Protonation-Dependent Luminescence of an Iridium(III) Bibenzimidazole Chromophore. Eur. J. Inorg. Chem. 2015, 2015, 3730−3739. (17) (a) Brunner, H.; Kollnberger, A.; Burgemeister, T.; Zabel, M. Optically Active Transition Metal Complexes Part 125. Preparation and Epimerization of Chiral-at-metal PentamethylcyclopentadienylRhodium(III) and Iridium(III) Half-sandwich Complexes. Polyhedron 2000, 19, 1519−1526. (b) Howarth, A. J.; Patia, R.; Davies, D. L.; Lelj, F.; Wolf, M. O.; Singh, K. Elucidating the Origin of Enhanced Phosphorescence Emission in the Solid State in Cyclometallated Iridium Complexes. Eur. J. Inorg. Chem. 2014, 2014, 3657−3664. (c) Davies, D. L.; Singh, K.; Singh, S.; Villa-Marcos, B. Preparation of Single Enantiomers of Chiral at Metal Bis-cyclometallated Iridium Complexes. Chem. Commun. 2013, 49, 6546−6548.

10723

DOI: 10.1021/acs.inorgchem.7b01681 Inorg. Chem. 2017, 56, 10717−10723