Recent Advances in Multinuclear NMR Spectroscopy for Chiral Recognition of Organic Compounds

Nuclear magnetic resonance (NMR) is a powerful tool for the elucidation of chemical structure and chiral recognition. In the last decade, the number of probes, media, and experiments to analyze chiral environments has rapidly increased. The evaluation of chiral molecules and systems has become a routine task in almost all NMR laboratories, allowing for the determination of molecular connectivities and the construction of spatial relationships. Among the features that improve the chiral recognition abilities by NMR is the application of different nuclei. The simplicity of the multinuclear NMR spectra relative to 1H, the minimal influence of the experimental conditions, and the larger shift dispersion make these nuclei especially suitable for NMR analysis. Herein, the recent advances in multinuclear (19F, 31P, 13C, and 77Se) NMR spectroscopy for chiral recognition of organic compounds are presented. The review describes new chiral derivatizing agents and chiral solvating agents used for stereodiscrimination and the assignment of the absolute configuration of small organic compounds.


Introduction
Stereoisomers are compounds with the same molecular formula, possessing identical bond connectivity but different orientations of their atoms in space [1]. Enantiomers are stereoisomers that are mirror images of each other, but at the same time are not superimposable. Chirality is important in chemical, physical, pharmaceutical, and biological systems, inspiring new biomimicry-based innovations [2,3]. Moreover, the need to discriminate between enantiomers and quantify enantiomeric excess (ee) is of extreme importance in the pharmaceutical industry and for asymmetric synthesis [4][5][6].
Nowadays, the use of chromatography separation of enantiomers on chiral stationary phases is still the approach most often applied in modern chemical research [7,8]. However, the search for new chiral discriminating procedures that allow for quick analysis, high resolution, and utility for many non-volatile or thermally unstable compounds is increasing [9][10][11][12]. Among the several stereodiscrimination methods, including X-ray, circular dichroism, fluorescence spectroscopy, and electrophoresis, nuclear magnetic resonance (NMR) spectroscopy continues to be a useful tool for determining the enantiomeric purity and assigning the absolute configuration of chiral molecules [13][14][15][16][17][18][19][20][21].
NMR active nuclei are isochronous in an achiral medium and do not permit their discrimination, but in a chiral environment these nuclei are anisochronous and chiral discrimination is possible. Therefore, to perform the enantiopurity analysis, a chiral derivatization or solvating agent is essential to produce a nonequivalent diastereomeric mixture and relevant differences in the NMR spectra. Chiral derivatizing agents form a covalent bond with a reactive moiety of the substrate and chiral solvating agents associate with the substrate through non-covalent interactions, such as dipole-dipole A chiral ionic liquid 4 was employed by Reddy et al. for chiral recognition of racemic Mosher's acid salt using 19 F-NMR spectroscopy [30]. Ionic liquids (ILs) have received considerable attention as substitutes for volatile organic solvents due to their remarkable properties, such as non-flammable, non-volatile and recyclable. Thus, a chiral ionic liquid containing D-xylose was synthesized in seven steps with a good overall yield (56%). The D-xylose is a cheap and readily available starting material. The chiral recognition study was performed with the racemic Mosher's acid silver salt in CD3CN (Scheme 3). The concentration was varied to observe the signals splitting and line shape of 19 F-NMR. The effectiveness of the chiral ionic liquid 4 was also tested by using a non-racemic Mosher's acid salt. The enantiomeric excess (ee) of this non-racemic salt was determined by 19 F-NMR. Moreover, the splitting pattern of the chiral ionic liquid 4 was evaluated by 1 H-and 13 C-NMR spectroscopy. Huang et al. described a CSA for a variety of acids using chiral thiophosphoramide 5 derived from (1R,2S)-1,2-diaminocyclohexane (Scheme 4) [31]. The interaction via ion pairing and hydrogen bonding provides a large split in values between the enantiomers, especially when the 19 F-NMR was evaluated. The authors completed the chiral recognition study with phosphonic acids by 31 P-NMR spectroscopy (Scheme 4).
Swager and Zhao prepared amide-based palladium pincer complex 6 as a scaffold to examine the chiral discrimination ability of amines (Scheme 5) [32]. Based on well-known coordination chemistry, the complex was easily synthesized in two steps. The chiral sensor site that undergoes facile ligand exchange is flanked by fluorine pendant groups that are sensitive to enantiomers. The observation of split signals at precise chemical shifts that are not concentration-dependent indicated A chiral ionic liquid 4 was employed by Reddy et al. for chiral recognition of racemic Mosher's acid salt using 19 F-NMR spectroscopy [30]. Ionic liquids (ILs) have received considerable attention as substitutes for volatile organic solvents due to their remarkable properties, such as non-flammable, non-volatile and recyclable. Thus, a chiral ionic liquid containing D-xylose was synthesized in seven steps with a good overall yield (56%). The D-xylose is a cheap and readily available starting material. The chiral recognition study was performed with the racemic Mosher's acid silver salt in CD 3 CN (Scheme 3). The concentration was varied to observe the signals splitting and line shape of 19 F-NMR. The effectiveness of the chiral ionic liquid 4 was also tested by using a non-racemic Mosher's acid salt. The enantiomeric excess (ee) of this non-racemic salt was determined by 19 F-NMR. Moreover, the splitting pattern of the chiral ionic liquid 4 was evaluated by 1 H-and 13 C-NMR spectroscopy. Another fluorine-containing CDA that surpasses the capabilities of Mosher's acid (MTPA) was prepared by Takahashi et al. (Scheme 2) [29]. To obtain the chiral compounds (R)-3 and (S)-3, high-performance liquid chromatography (HPLC) was carried out. The efficiency of the 19 F-NMR nucleus was evaluated with secondary alcohols. The absolute configuration of chiral FICA 3 was determined by reaction with (R)-phenylethylamine following by single-crystal X-ray crystallographic analysis. The magnitude of the chiral discrimination of the FICA esters was larger than that of the MTPA esters (Scheme 2). Moreover, the assignment of the absolute configuration of the alcohols was easily performed by 19 F-NMR spectroscopy. Scheme 2. 1-fluoroindan-1-carboxylic acid 3 (FICA) as a chiral derivatizing agent for 19  A chiral ionic liquid 4 was employed by Reddy et al. for chiral recognition of racemic Mosher's acid salt using 19 F-NMR spectroscopy [30]. Ionic liquids (ILs) have received considerable attention as substitutes for volatile organic solvents due to their remarkable properties, such as non-flammable, non-volatile and recyclable. Thus, a chiral ionic liquid containing D-xylose was synthesized in seven steps with a good overall yield (56%). The D-xylose is a cheap and readily available starting material. The chiral recognition study was performed with the racemic Mosher's acid silver salt in CD3CN (Scheme 3). The concentration was varied to observe the signals splitting and line shape of 19 F-NMR. The effectiveness of the chiral ionic liquid 4 was also tested by using a non-racemic Mosher's acid salt. The enantiomeric excess (ee) of this non-racemic salt was determined by 19 F-NMR. Moreover, the splitting pattern of the chiral ionic liquid 4 was evaluated by 1 H-and 13 C-NMR spectroscopy. Huang et al. described a CSA for a variety of acids using chiral thiophosphoramide 5 derived from (1R,2S)-1,2-diaminocyclohexane (Scheme 4) [31]. The interaction via ion pairing and hydrogen bonding provides a large split in values between the enantiomers, especially when the 19 F-NMR was evaluated. The authors completed the chiral recognition study with phosphonic acids by 31 P-NMR spectroscopy (Scheme 4).
Swager and Zhao prepared amide-based palladium pincer complex 6 as a scaffold to examine the chiral discrimination ability of amines (Scheme 5) [32]. Based on well-known coordination chemistry, the complex was easily synthesized in two steps. The chiral sensor site that undergoes facile ligand exchange is flanked by fluorine pendant groups that are sensitive to enantiomers. The observation of split signals at precise chemical shifts that are not concentration-dependent indicated  [31]. The interaction via ion pairing and hydrogen bonding provides a large split in values between the enantiomers, especially when the 19 F-NMR was evaluated. The authors completed the chiral recognition study with phosphonic acids by 31 P-NMR spectroscopy (Scheme 4).
Swager and Zhao prepared amide-based palladium pincer complex 6 as a scaffold to examine the chiral discrimination ability of amines (Scheme 5) [32]. Based on well-known coordination chemistry, the complex was easily synthesized in two steps. The chiral sensor site that undergoes facile ligand exchange is flanked by fluorine pendant groups that are sensitive to enantiomers. The observation of split signals at precise chemical shifts that are not concentration-dependent indicated the formation A practical and simple derivatization protocol for determining the enantiopurity of chiral diols by 19 F-NMR spectroscopy was developed by James et al. [33]. The experimental procedure consisted of mixing an equimolecular amount of 4-fluoro-2-formylphenyl boronic acid 7, phenylethylamine, and the chiral diol in CDCl3 at 25 °C (Scheme 6). The focus of the method was to synthesize the fluorine compound 7 as a new bifunctional template for carrying out the enantiopurity analysis of chiral diols.
A closely related approach was used by Chaudhari and Suryaprakash to perform the discrimination of chiral diacids and chiral alpha methyl amines [34]. The three-component chiral derivatization protocol has been developed for 19 F-and 13 C-NMR. These methodologies are based on a mixture of diastereomeric iminoboronate esters without any racemization or kinetic resolution. The Suryaprakash method was the first procedure for determining the enantiopurity of chiral diacids. The general protocol involves the reaction of an equimolecular amount of diacids with 3-fluoro-2-formylboronic acid 8 and an enantiopure (R)-methylethylamine in methanol-d4 (Scheme 7). The baseline separation of 19  A practical and simple derivatization protocol for determining the enantiopurity of chiral diols by 19 F-NMR spectroscopy was developed by James et al. [33]. The experimental procedure consisted of mixing an equimolecular amount of 4-fluoro-2-formylphenyl boronic acid 7, phenylethylamine, and the chiral diol in CDCl3 at 25 °C (Scheme 6). The focus of the method was to synthesize the fluorine compound 7 as a new bifunctional template for carrying out the enantiopurity analysis of chiral diols.
A closely related approach was used by Chaudhari and Suryaprakash to perform the discrimination of chiral diacids and chiral alpha methyl amines [34]. The three-component chiral derivatization protocol has been developed for 19 F-and 13 C-NMR. These methodologies are based on a mixture of diastereomeric iminoboronate esters without any racemization or kinetic resolution. The Suryaprakash method was the first procedure for determining the enantiopurity of chiral diacids. The general protocol involves the reaction of an equimolecular amount of diacids with 3-fluoro-2-formylboronic acid 8 and an enantiopure (R)-methylethylamine in methanol-d4 (Scheme 7). The baseline separation of 19  A practical and simple derivatization protocol for determining the enantiopurity of chiral diols by 19 F-NMR spectroscopy was developed by James et al. [33]. The experimental procedure consisted of mixing an equimolecular amount of 4-fluoro-2-formylphenyl boronic acid 7, phenylethylamine, and the chiral diol in CDCl 3 at 25 • C (Scheme 6). The focus of the method was to synthesize the fluorine compound 7 as a new bifunctional template for carrying out the enantiopurity analysis of chiral diols. A closely related approach was used by Chaudhari and Suryaprakash to perform the discrimination of chiral diacids and chiral alpha methyl amines [34]. The three-component chiral derivatization protocol has been developed for 19 F-and 13 C-NMR. These methodologies are based on a mixture of diastereomeric iminoboronate esters without any racemization or kinetic resolution. The Suryaprakash method was the first procedure for determining the enantiopurity of chiral diacids. The general protocol involves the reaction of an equimolecular amount of diacids with 3-fluoro-2formylboronic acid 8 and an enantiopure (R)-methylethylamine in methanol-d 4 (Scheme 7). The baseline separation of 19 F and 13 C was 1.24 ppm and 0.46 ppm, respectively, for the rac-2-methylsuccinic acid (Scheme 7). There is great potential for the use of the boronic acid derivatives mentioned above and other related procedures [35][36][37] in the chiral recognition of organic and water soluble compounds due to their use as new probes, mainly in biologically relevant species [38]. The boronic acids have Lewis acid characteristics and react spontaneously and reversibly with diol compounds. Furthermore, boron chemistry is closely related to the living systems. These characteristics, in addition to the usefulness of multinuclear NMR spectroscopy, represent valuable methodologies to discriminate chiral organic compounds.
Another chiral fluorine-containing carboxylic acid, F-THENA 9, was recently prepared by Dolsophon et al. The rigid anisotropic structure of F-THENA 9 is useful for assigning the absolute configuration of secondary alcohols and amines by 19 F-NMR spectroscopy [39]. The CDA was synthesized from a commercially available starting material in six steps (Scheme 8). To establish the absolute configuration, X-ray analysis was performed. Derivatizations of the (S) and (R) F-THENA 9 acids with oxalyl chloride in the presence of a catalytic amount of dimethylformamide allowed for the formation of (S) and (R) F-THENA-Cl. In 19 F-NMR, a positive shielding effect occurs from the alcohol moiety when an aromatic group is located on the lower side of the F-THENA plane while a negative value is obtained when an aromatic group is located on the upper side of the F-THENA plane (Scheme 8). The fluorine-containing CDA provides a self-validating system, which reduces the risks of incorrect assignment. The NMR results were strongest when both configuration assignments, from 19 F-and 1 H-NMR, were identical.
An alternative approach to assign the absolute configuration of amino acids using the Mosher's acid was developed by Katritzky et al [40]. N-acylbenzotriazoles are stable and crystalline derivatives of carboxylic acids and have advantages mainly when compared to acid chlorides that are unstable, moisture sensitive, difficult to prepare, and need to be stored in a deep freeze. Thus, the authors synthesized the Mosher-Bt 10 reagent (Scheme 9) from chiral and racemic Mosher's acid to employ as a new and stable CDA for amino acids and peptides. The carboxylic acid derivative 10 was easily prepared with thionyl chloride and 1H-benzotriazole (BtH) and their reactions were studied with representative water-soluble chiral amino acids and peptides in acetonitrile-water medium (Scheme 9). The assignment of the absolute configuration of (R)-phenylalanine using the Mosher-Bt 10 reagent was performed using 1 H-, 19  There is great potential for the use of the boronic acid derivatives mentioned above and other related procedures [35][36][37] in the chiral recognition of organic and water soluble compounds due to their use as new probes, mainly in biologically relevant species [38]. The boronic acids have Lewis acid characteristics and react spontaneously and reversibly with diol compounds. Furthermore, boron chemistry is closely related to the living systems. These characteristics, in addition to the usefulness of multinuclear NMR spectroscopy, represent valuable methodologies to discriminate chiral organic compounds.
Another chiral fluorine-containing carboxylic acid, F-THENA 9, was recently prepared by Dolsophon et al. The rigid anisotropic structure of F-THENA 9 is useful for assigning the absolute configuration of secondary alcohols and amines by 19 F-NMR spectroscopy [39]. The CDA was synthesized from a commercially available starting material in six steps (Scheme 8). To establish the absolute configuration, X-ray analysis was performed. Derivatizations of the (S) and (R) F-THENA 9 acids with oxalyl chloride in the presence of a catalytic amount of dimethylformamide allowed for the formation of (S) and (R) F-THENA-Cl. In 19 F-NMR, a positive shielding effect occurs from the alcohol moiety when an aromatic group is located on the lower side of the F-THENA plane while a negative value is obtained when an aromatic group is located on the upper side of the F-THENA plane (Scheme 8). The fluorine-containing CDA provides a self-validating system, which reduces the risks of incorrect assignment. The NMR results were strongest when both configuration assignments, from 19 F-and 1 H-NMR, were identical. understand the conformational features of amide scaffolds in the assignment of the absolute configuration, Ichikawa et al. studied the characteristic conformation of Mosher's acid amide, which was elucidated using the Cambridge Structural Database [41]. Amides are important for biological systems and are especially important in the pharmaceutical industry since a huge number of molecular drug candidates have nitrogen atoms [42,43]. Furthermore, chiral amines are also used as the starting material in the formation of new amino acids and peptide bonds. An alternative approach to assign the absolute configuration of amino acids using the Mosher's acid was developed by Katritzky et al [40]. N-acylbenzotriazoles are stable and crystalline derivatives of carboxylic acids and have advantages mainly when compared to acid chlorides that are unstable, moisture sensitive, difficult to prepare, and need to be stored in a deep freeze. Thus, the authors synthesized the Mosher-Bt 10 reagent (Scheme 9) from chiral and racemic Mosher's acid to employ as a new and stable CDA for amino acids and peptides. The carboxylic acid derivative 10 was easily prepared with thionyl chloride and 1H-benzotriazole (BtH) and their reactions were studied with representative water-soluble chiral amino acids and peptides in acetonitrile-water medium (Scheme 9). The assignment of the absolute configuration of (R)-phenylalanine using the Mosher-Bt 10 reagent was performed using 1 H-, 19 F-, and 13 C-NMR spectroscopy. To demonstrate that racemization does not occur during the reaction, Mosher amides were subjected to HPLC analysis. Recently, to understand the conformational features of amide scaffolds in the assignment of the absolute configuration, Ichikawa et al. studied the characteristic conformation of Mosher's acid amide, which was elucidated using the Cambridge Structural Database [41]. Amides are important for biological systems and are especially important in the pharmaceutical industry since a huge number of molecular drug candidates have nitrogen atoms [42,43]. Furthermore, chiral amines are also used as the starting material in the formation of new amino acids and peptide bonds. understand the conformational features of amide scaffolds in the assignment of the absolute configuration, Ichikawa et al. studied the characteristic conformation of Mosher's acid amide, which was elucidated using the Cambridge Structural Database [41]. Amides are important for biological systems and are especially important in the pharmaceutical industry since a huge number of molecular drug candidates have nitrogen atoms [42,43]. Furthermore, chiral amines are also used as the starting material in the formation of new amino acids and peptide bonds. Cyclodextrins (CDs) were employed as a chiral recognition agent for enantiodiscrimination of emtricitabine enantiomers 11, a novel nucleoside reverse transcriptase inhibitors for treatment of HIV infection in adults and children, by 19 F-NMR spectroscopy [44]. In this protocol, developed by Rao et al., the influence of the CD cavity sizes (α, β, and γ), temperature and concentration were studied. The method is based on intermolecular interaction between emtricitabine enantiomers 11 with cyclodextrins in D2O solution (Scheme 10). The hydrophobic nature of such cavities provides a chiral environment for enantiodiscrimination. The α-CD has shown better enantiodiscrimination results employing low concentrations (0.01 mM) and temperatures (298 K). Moreover, the binding constant (K) was determined using the 19 F-NMR method developed and a 2D 1 H ROESY NMR analysis was performed to understand the geometry of association with α-CD. Cyclodextrins (CDs) were employed as a chiral recognition agent for enantiodiscrimination of emtricitabine enantiomers 11, a novel nucleoside reverse transcriptase inhibitors for treatment of HIV infection in adults and children, by 19 F-NMR spectroscopy [44]. In this protocol, developed by Rao et al., the influence of the CD cavity sizes (α, β, and γ), temperature and concentration were studied. The method is based on intermolecular interaction between emtricitabine enantiomers 11 with cyclodextrins in D 2 O solution (Scheme 10). The hydrophobic nature of such cavities provides a chiral environment for enantiodiscrimination. The α-CD has shown better enantiodiscrimination results employing low concentrations (0.01 mM) and temperatures (298 K). Moreover, the binding constant (K) was determined using the 19 F-NMR method developed and a 2D 1 H ROESY NMR analysis was performed to understand the geometry of association with α-CD.

31 P-NMR Chiral Recognition
Organophosphorus is an old field of organic chemistry. Organophosphorus compounds are essential in all chemical sciences, especially the life sciences, because their structures are a key building block [45,46]. Furthermore, the pharmaceutical and agrochemical industries have prompted studies of phosphorus chemistry [47].
Unlike 19 F-NMR spectroscopy, the main factors that govern the 31 P chemical shift values are different due to other bond contributions. In this way, a good knowledge of organometallic chemistry could help with understanding those variations. 31 P-NMR spectroscopy is highly useful, since compounds from natural resources normally contain this nucleus and 31 P is more abundant (100%), making it a valuable probe for NMR investigations [48]. Recently, Szyszkowiak and Majewska have reviewed the application of 31 P-NMR for determination of the absolute configuration of organic compounds [49]. In this review, the model created by Hammersschmidt and Li, in which the shielding of the phosphorus atom by the phenyl group in (S)-MTPA ester caused the signal to appear at a higher field (Scheme 11), was explored [50]. This model, based on Mosher's esters, is currently an important tool for assigning the absolute configuration of many organic functionalities and structures by 1 H-NMR spectroscopy [51]. The commercially available amino acid derivatives were employed as a CSA to differentiate enantiomers of chiral phosphonates, phosphinates, phosphates, phosphine oxides, and phosphonamidates by 31 P-NMR spectroscopy [52]. The method developed by Li and Raushel uses N-Fmoc-N'-Boc-L-tryptophan 12 in CDCl3 at 25 °C as a CSA for different phosphorus compounds Scheme 10. Chiral discrimination of emtricitabine 11 by cyclodextrin host-guest complexes using 19 F { 1 H} NMR spectroscopy.

31 P-NMR Chiral Recognition
Organophosphorus is an old field of organic chemistry. Organophosphorus compounds are essential in all chemical sciences, especially the life sciences, because their structures are a key building block [45,46]. Furthermore, the pharmaceutical and agrochemical industries have prompted studies of phosphorus chemistry [47].
Unlike 19 F-NMR spectroscopy, the main factors that govern the 31 P chemical shift values are different due to other bond contributions. In this way, a good knowledge of organometallic chemistry could help with understanding those variations. 31 P-NMR spectroscopy is highly useful, since compounds from natural resources normally contain this nucleus and 31 P is more abundant (100%), making it a valuable probe for NMR investigations [48].
Recently, Szyszkowiak and Majewska have reviewed the application of 31 P-NMR for determination of the absolute configuration of organic compounds [49]. In this review, the model created by Hammersschmidt and Li, in which the shielding of the phosphorus atom by the phenyl group in (S)-MTPA ester caused the signal to appear at a higher field (Scheme 11), was explored [50]. This model, based on Mosher's esters, is currently an important tool for assigning the absolute configuration of many organic functionalities and structures by 1 H-NMR spectroscopy [51].

31 P-NMR Chiral Recognition
Organophosphorus is an old field of organic chemistry. Organophosphorus compounds are essential in all chemical sciences, especially the life sciences, because their structures are a key building block [45,46]. Furthermore, the pharmaceutical and agrochemical industries have prompted studies of phosphorus chemistry [47].
Unlike 19 F-NMR spectroscopy, the main factors that govern the 31 P chemical shift values are different due to other bond contributions. In this way, a good knowledge of organometallic chemistry could help with understanding those variations. 31 P-NMR spectroscopy is highly useful, since compounds from natural resources normally contain this nucleus and 31 P is more abundant (100%), making it a valuable probe for NMR investigations [48]. Recently, Szyszkowiak and Majewska have reviewed the application of 31 P-NMR for determination of the absolute configuration of organic compounds [49]. In this review, the model created by Hammersschmidt and Li, in which the shielding of the phosphorus atom by the phenyl group in (S)-MTPA ester caused the signal to appear at a higher field (Scheme 11), was explored [50]. This model, based on Mosher's esters, is currently an important tool for assigning the absolute configuration of many organic functionalities and structures by 1 H-NMR spectroscopy [51]. The commercially available amino acid derivatives were employed as a CSA to differentiate enantiomers of chiral phosphonates, phosphinates, phosphates, phosphine oxides, and phosphonamidates by 31 P-NMR spectroscopy [52]. The method developed by Li and Raushel uses N-Fmoc-N'-Boc-L-tryptophan 12 in CDCl3 at 25 °C as a CSA for different phosphorus compounds Scheme 11. Assigning of the configuration of α-hydroxyphosphonates from derivatization with (S)-MTPA-Cl by 31 P { 1 H} NMR spectroscopy.
The commercially available amino acid derivatives were employed as a CSA to differentiate enantiomers of chiral phosphonates, phosphinates, phosphates, phosphine oxides, and phosphonamidates by 31 P-NMR spectroscopy [52]. The method developed by Li and Raushel uses N-Fmoc-N'-Boc-Ltryptophan 12 in CDCl 3 at 25 • C as a CSA for different phosphorus compounds (Scheme 12). Although there is a lower anisochrony of the phosphorus atoms, the good baseline resolution and absence of overlapping signals provided an efficient and fast chiral discrimination procedure. Mastranzo et al. demonstrated the use of P(III) and P(V) organophosphorus deriving reagents for chiral discrimination of carboxylic acids by 31 P-NMR [53]. In this work, the authors described the preparation of C2 symmetric diamines 13, which contain the α-phenyl-ethyl group and the cyclohexane skeleton. The discrimination of chiral carboxylic acids was performed in an NMR tube in three reaction steps (Scheme 13). The chemical shift difference between diastereomers varied in the ranges of 0.02-2.43 for P(III) and 0.02-2.14 for P(V). Scheme 13. Preparation of organophosphorus CDA for chiral discrimination of carboxylic acids by 31 P { 1 H} NMR spectroscopy.
The same approach was employed by Reiner et al. who used 31 P-NMR to monitor the formation of diastereoisomers by a PCl3 reagent [54]. In this procedure, the PCl3 reagent reacted with the chiral BINOL to form phosphite derivative 14 and after the alcohol or amine was added to obtain a mixture Mastranzo et al. demonstrated the use of P(III) and P(V) organophosphorus deriving reagents for chiral discrimination of carboxylic acids by 31 P-NMR [53]. In this work, the authors described the preparation of C 2 symmetric diamines 13, which contain the α-phenyl-ethyl group and the cyclohexane skeleton. The discrimination of chiral carboxylic acids was performed in an NMR tube in three reaction steps (Scheme 13). The chemical shift difference between diastereomers varied in the ranges of 0.02-2.43 for P(III) and 0.02-2.14 for P(V). Mastranzo et al. demonstrated the use of P(III) and P(V) organophosphorus deriving reagents for chiral discrimination of carboxylic acids by 31 P-NMR [53]. In this work, the authors described the preparation of C2 symmetric diamines 13, which contain the α-phenyl-ethyl group and the cyclohexane skeleton. The discrimination of chiral carboxylic acids was performed in an NMR tube in three reaction steps (Scheme 13). The chemical shift difference between diastereomers varied in the ranges of 0.02-2.43 for P(III) and 0.02-2.14 for P(V). Scheme 13. Preparation of organophosphorus CDA for chiral discrimination of carboxylic acids by 31 P { 1 H} NMR spectroscopy.
The same approach was employed by Reiner et al. who used 31 P-NMR to monitor the formation of diastereoisomers by a PCl3 reagent [54]. In this procedure, the PCl3 reagent reacted with the chiral BINOL to form phosphite derivative 14 and after the alcohol or amine was added to obtain a mixture The same approach was employed by Reiner et al. who used 31 P-NMR to monitor the formation of diastereoisomers by a PCl 3 reagent [54]. In this procedure, the PCl 3 reagent reacted with the chiral BINOL to form phosphite derivative 14 and after the alcohol or amine was added to obtain a mixture of diastereomers (Scheme 14). The chiral discrimination was possible by two diastereomeric 31 P-NMR peaks for both enantiomers of the compounds. The measurements were performed in less than 5 min of diastereomers (Scheme 14). The chiral discrimination was possible by two diastereomeric 31 P-NMR peaks for both enantiomers of the compounds. The measurements were performed in less than 5 min with only 500 μL of deuterated solvent. Moreover, the authors examined its application to on-line ee determination in combination with standard catalytic protocols.  [55]. The commercially available carboxylic acids 15 and 16, which have provided good results for NMR chiral discrimination [56,57], and dibenzoyltartaric acids 17 and 18 were applied as CSAs (Scheme 15). The 31 P-NMR analyses have shown that in most cases those simple chiral acids are very efficient CSAs for the determination of the enantiopurity of atropoisomeric bis-phosphine dioxides. To prove the accuracy of the NMR methodology an electronic circular dichroism spectroscopy was applied. The electronic absorptions and chiroptical data of the investigated compounds corroborate the NMR analyses. Furthermore, computer calculations were carried out to provide details about the stereochemistry of the complexes.
Bedekar et al. synthesized modified amides as NMR solvating agents for the chiral discrimination of 1,1′-binaphthyl and alpha-substituted acid enantiomers [58]. In this procedure, the chiral isobornyl amine 19 was employed, which is readily available and can be used as a starting material to prepare steric bulk amide 20 with three-stereogenic centers for chiral molecular recognition by 31 P-NMR analysis (Scheme 16). Furthermore, the linear relationship between the observed and actual ee values of binaphthyl 21 was evaluated and confirmed the accuracy of the 31 P-NMR analyses. The strategy was based on the method developed by Kagan et al. [59], in which simple chiral amides were studied as CSAs for efficient determination of enantiomers between several types of compounds. The chiral recognition of Kagan's amide is achieved by hydrogen-bonding using a different procedure than the one outlined by Bedekar et al. The effectiveness of the method was expanded to alpha-carboxylic acids by 19 F-NMR spectroscopy using chiral isobornyl amide 20a and a base (DMAP) to improve the intermolecular interactions (Scheme 17). In another work of Bedekar et al. a modified Kagan's amide was synthesized and applied as CSA for hydrogen-bonding based chiral discrimination employing 1 H-and 19 F-NMR spectroscopy [60].
The same research group has published the chiral discrimination of binaphthyl 21 by employing a chiral aza-macrocycle 22 [61]. The synthesis of 18 member aza-macrocycles (S,S,S)-22 and (R,R,S)-22 was carried out in three steps from the cyclohexene oxide (Scheme 18). To confirm the 3D structure, a single crystal X-ray analysis of both diastereomers was performed. The discrimination ability of aza-macrocycle 22 for binaphthyl phosphoric acid 21 ranged from 0.03 to 0.81 ppm. An additional fluorescence spectroscopy study for understanding the chiral recognition of chiral aza-macrocycle showed an enantioselective quenching interaction. This effect was attributed to the deprotonation of phosphoric acid 21, which is indicated by the appearance of new peak in the UV-Vis spectra.   [55]. The commercially available carboxylic acids 15 and 16, which have provided good results for NMR chiral discrimination [56,57], and dibenzoyltartaric acids 17 and 18 were applied as CSAs (Scheme 15). The 31 P-NMR analyses have shown that in most cases those simple chiral acids are very efficient CSAs for the determination of the enantiopurity of atropoisomeric bis-phosphine dioxides. To prove the accuracy of the NMR methodology an electronic circular dichroism spectroscopy was applied. The electronic absorptions and chiroptical data of the investigated compounds corroborate the NMR analyses. Furthermore, computer calculations were carried out to provide details about the stereochemistry of the complexes.   Bedekar et al. synthesized modified amides as NMR solvating agents for the chiral discrimination of 1,1 -binaphthyl and alpha-substituted acid enantiomers [58]. In this procedure, the chiral isobornyl amine 19 was employed, which is readily available and can be used as a starting material to prepare steric bulk amide 20 with three-stereogenic centers for chiral molecular recognition by 31 P-NMR analysis (Scheme 16). Furthermore, the linear relationship between the observed and actual ee values of binaphthyl 21 was evaluated and confirmed the accuracy of the 31 P-NMR analyses. The strategy was based on the method developed by Kagan et al. [59], in which simple chiral amides were studied as CSAs for efficient determination of enantiomers between several types of compounds. The chiral recognition of Kagan's amide is achieved by hydrogen-bonding using a different procedure than the one outlined by Bedekar et al. The effectiveness of the method was expanded to alpha-carboxylic acids by 19 F-NMR spectroscopy using chiral isobornyl amide 20a and a base (DMAP) to improve the intermolecular interactions (Scheme 17). In another work of Bedekar et al. a modified Kagan's amide was synthesized and applied as CSA for hydrogen-bonding based chiral discrimination employing 1 Hand 19 F-NMR spectroscopy [60].  Based on the difficulties in performing the chiral discrimination of BINOL phosphoric acids 21 and derivatives, Nagorny and Tay have developed a simple and reliable protocol for determining the enantiopurity by 31 P-NMR spectroscopy [62]. The optical rotation measurements were not The same research group has published the chiral discrimination of binaphthyl 21 by employing a chiral aza-macrocycle 22 [61]. The synthesis of 18 member aza-macrocycles (S,S,S)-22 and (R,R,S)-22 was carried out in three steps from the cyclohexene oxide (Scheme 18). To confirm the 3D structure, a single crystal X-ray analysis of both diastereomers was performed. The discrimination ability of aza-macrocycle 22 for binaphthyl phosphoric acid 21 ranged from 0.03 to 0.81 ppm. An additional fluorescence spectroscopy study for understanding the chiral recognition of chiral aza-macrocycle showed an enantioselective quenching interaction. This effect was attributed to the deprotonation of phosphoric acid 21, which is indicated by the appearance of new peak in the UV-Vis spectra. Based on the difficulties in performing the chiral discrimination of BINOL phosphoric acids 21 and derivatives, Nagorny and Tay have developed a simple and reliable protocol for determining the enantiopurity by 31 P-NMR spectroscopy [62]. The optical rotation measurements were not reliable for these compounds. Thus, the use of chiral amines as CSAs to carry out the NMR chiral discrimination of BINOL phosphoric acids derivatives was an elegant alternative (Scheme 19). Chiral amines 23 and 24 are commercially available and by the simple mixture of reagents (10 mg of BINOL and 1.5 equiv. of CSA) in a deuterated solvent, the 31 P-NMR signals of the diastereomer salts are observed. The sample concentrations ranged from 4.7 to 25 mM. In this work, the authors studied the epimerization under thermal conditions of the BINOL phosphoric acid derivatives using the 31 P-NMR protocol developed. Scheme 19. Chiral discrimination of 3,3′-substituted BINOL and H8-BINOL phosphoric acids by 31  Based on the difficulties in performing the chiral discrimination of BINOL phosphoric acids 21 and derivatives, Nagorny and Tay have developed a simple and reliable protocol for determining the enantiopurity by 31 P-NMR spectroscopy [62]. The optical rotation measurements were not reliable for these compounds. Thus, the use of chiral amines as CSAs to carry out the NMR chiral discrimination of BINOL phosphoric acids derivatives was an elegant alternative (Scheme 19). Chiral amines 23 and 24 are commercially available and by the simple mixture of reagents (10 mg of BINOL and 1.5 equiv. of CSA) in a deuterated solvent, the 31 P-NMR signals of the diastereomer salts are observed. The sample concentrations ranged from 4.7 to 25 mM. In this work, the authors studied the epimerization under thermal conditions of the BINOL phosphoric acid derivatives using the 31 P-NMR protocol developed. Scheme 17. Chiral discrimination of carboxylic acids by 19  Based on the difficulties in performing the chiral discrimination of BINOL phosphoric acids 21 and derivatives, Nagorny and Tay have developed a simple and reliable protocol for determining the enantiopurity by 31 P-NMR spectroscopy [62]. The optical rotation measurements were not reliable for these compounds. Thus, the use of chiral amines as CSAs to carry out the NMR chiral discrimination of BINOL phosphoric acids derivatives was an elegant alternative (Scheme 19). Chiral amines 23 and 24 are commercially available and by the simple mixture of reagents (10 mg of BINOL and 1.5 equiv. of CSA) in a deuterated solvent, the 31 P-NMR signals of the diastereomer salts are observed. The sample concentrations ranged from 4.7 to 25 mM. In this work, the authors studied the epimerization under thermal conditions of the BINOL phosphoric acid derivatives using the 31 P-NMR protocol developed. Scheme 19. Chiral discrimination of 3,3′-substituted BINOL and H8-BINOL phosphoric acids by 31  The use of 31 P-NMR spectroscopy in organometallics chemistry is a well-known tool for structure elucidation and evaluation of mechanisms [63]. Recently, Gorunova et al. have prepared a chiral phosphine ligand as a derivatizing agent for enantiopurity determination of CN-palladacycles using 31 P-NMR [64]. The phosphine ligand was synthesized in one step from the cheap and naturally occurring chiral menthol 25 (Scheme 20). The enantiopurity determination is carried out in situ, without any complications from geometric isomerism or palladacycle dechelation. Continuing this work, the same authors applied this method to determine the absolute configuration of the CN-palladacycles [65]. The results were based on 31 P-NMR chiral discrimination, density function theory (DFT) calculations and X-ray data. The DFT calculations were carried out to study the rotameric mobility of the phosphinite group and dynamiC-NMR spectroscopy and X-ray data were employed to estimate the chirality transfer efficiency in the phosphinite derivatives. occurring chiral menthol 25 (Scheme 20). The enantiopurity determination is carried out in situ, without any complications from geometric isomerism or palladacycle dechelation. Continuing this work, the same authors applied this method to determine the absolute configuration of the CN-palladacycles [65]. The results were based on 31 P-NMR chiral discrimination, density function theory (DFT) calculations and X-ray data. The DFT calculations were carried out to study the rotameric mobility of the phosphinite group and dynamiC-NMR spectroscopy and X-ray data were employed to estimate the chirality transfer efficiency in the phosphinite derivatives.

13 C-NMR Chiral Recognition
13 C-NMR spectroscopy is an indispensable tool for elucidating the structure of organic compounds. Together with 1 H-NMR analysis, 13 C-NMR is a routine task in organic synthesis and the study of natural products. The application of this nucleus is hampered by its low abundance relative to 1 H-, 19 F-, and 31 P-NMR, but currently with modern equipment (hardware, magnetic fields, probes, etc.) and new experiments the use of the 13 C nucleus has become an attractive alternative [66][67][68]. Moreover, the use of ab initio calculations to support the interpretation and assignment of 13 C-NMR spectra is an important tool for understanding the chiral environment of organic compounds [69].
Riguera et al. have demonstrated the applications and the characteristics that influence the assignment of absolute configuration by 1 H-NMR spectroscopy [70]. The same research group has recently reported the use of 13 C-NMR spectroscopy for the assignment of the absolute configuration of alcohols, amines, carboxylic acids, thiols, cyanohydrins, diols, and amino alcohols [71,72]. The authors have examined the 13 C-NMR data of a collection of chiral samples and the experimental data indicated a perfect correlation between the distribution of signs for 13 C chemical shifts and 1 H-NMR of their enantiomers. It is possible to observe that the anisochrony spreads for almost all carbons (Scheme 21: carbons marked in blue; CDAs 26 and 27). The 13 C-NMR data follows the same pattern as 1 H-NMR, providing a way to double check the data. Furthermore, the 13 C-NMR chemical shifts can be used as a tool for fully deuterated and non-proton-containing organic compounds.
Heo et al. have compared the accuracy and precision of HPLC, 1 H-, and 13 C-NMR methods to determine the enantiomeric purity of amino acid derivatives [73]. As shown in Scheme 22, three carbon peaks of (R) and (S) appeared in different positions. The integration of each peak was automatically performed by NMR software. The total average accuracy calculated from the carbons was 98% and the total average relative standard deviation was 5.23%. The accuracy and the reproducibility of the 13 C-NMR in comparison to HPLC and 1 H-NMR were satisfactory for determining the enantiomeric purity of these compounds. The study was carried out by mixing the (R) and (S)

13 C-NMR Chiral Recognition
13 C-NMR spectroscopy is an indispensable tool for elucidating the structure of organic compounds.
Together with 1 H-NMR analysis, 13 C-NMR is a routine task in organic synthesis and the study of natural products. The application of this nucleus is hampered by its low abundance relative to 1 H-, 19 F-, and 31 P-NMR, but currently with modern equipment (hardware, magnetic fields, probes, etc.) and new experiments the use of the 13 C nucleus has become an attractive alternative [66][67][68]. Moreover, the use of ab initio calculations to support the interpretation and assignment of 13 C-NMR spectra is an important tool for understanding the chiral environment of organic compounds [69]. Riguera et al. have demonstrated the applications and the characteristics that influence the assignment of absolute configuration by 1 H-NMR spectroscopy [70]. The same research group has recently reported the use of 13 C-NMR spectroscopy for the assignment of the absolute configuration of alcohols, amines, carboxylic acids, thiols, cyanohydrins, diols, and amino alcohols [71,72]. The authors have examined the 13 C-NMR data of a collection of chiral samples and the experimental data indicated a perfect correlation between the distribution of signs for 13 C chemical shifts and 1 H-NMR of their enantiomers. It is possible to observe that the anisochrony spreads for almost all carbons (Scheme 21: carbons marked in blue; CDAs 26 and 27). The 13 C-NMR data follows the same pattern as 1 H-NMR, providing a way to double check the data. Furthermore, the 13 C-NMR chemical shifts can be used as a tool for fully deuterated and non-proton-containing organic compounds. Heo et al. have compared the accuracy and precision of HPLC, 1 H-, and 13 C-NMR methods to determine the enantiomeric purity of amino acid derivatives [73]. As shown in Scheme 22, three carbon peaks of (R) and (S) appeared in different positions. The integration of each peak was automatically performed by NMR software. The total average accuracy calculated from the carbons was 98% and the total average relative standard deviation was 5.23%. The accuracy and the reproducibility of the 13 C-NMR in comparison to HPLC and 1 H-NMR were satisfactory for determining the enantiomeric purity of these compounds. The study was carried out by mixing the (R) and (S) isomers of the amino acid derivative with the CSA 28 in different amounts with a concentration of 20 mM. For 13 C { 1 H} NMR, quantification of the chiral discrimination is necessary to prevent significant errors in the NMR analysis. Firstly, the signal/noise ratio should be improved due to the low abundance of 13 C nuclei (1.1%). Another important parameter is the nuclear Overhauser effect that occurs during the proton decoupling. To reduce this effect, the inverse gated decoupling pulse sequence and the optimized time acquisition must be used. These and other parameters should be evaluated before the NMR analysis to obtain precise multinuclear NMR spectra, mainly for 13 C nuclei.
The development of new chiral auxiliaries to determine the enantiomeric excess or to assign the absolute configuration by NMR spectroscopy is a difficult and time-consuming task. For this reason, the use of natural products as a scaffold, either directly or as a starting material to prepare new chiral agents, is an elegant alternative. Based on this strategy, Szostak et al. have employed naturally occurring Chinchona 29 alkaloid and their derivatives as CSAs for different functionalities [74]. Selective modifications of the natural products were performed by tuning their enantiodiscrimination. The structure of quinine enables modulation, mainly for carbons 9, 22, and 23 (Scheme 23). Moreover, the presence of a phosphate group supplementing the quinine frame core provides zwitterionic character because it possesses two charged functions, a quaternary ammonium cation and a phosphate anion. These characteristics were used with success for enantiodiscrimination of non-derivatized amino acids (Scheme 23). The charges increase the interaction potency between the molecules, allowing for efficient chiral discrimination in the DMSO-d6 solvent by 13 C-NMR spectroscopy. The split signals of 13 C-NMR ranged from 0.025 to 0.145 ppm. For 13 C { 1 H} NMR, quantification of the chiral discrimination is necessary to prevent significant errors in the NMR analysis. Firstly, the signal/noise ratio should be improved due to the low abundance of 13 C nuclei (1.1%). Another important parameter is the nuclear Overhauser effect that occurs during the proton decoupling. To reduce this effect, the inverse gated decoupling pulse sequence and the optimized time acquisition must be used. These and other parameters should be evaluated before the NMR analysis to obtain precise multinuclear NMR spectra, mainly for 13 C nuclei.
The development of new chiral auxiliaries to determine the enantiomeric excess or to assign the absolute configuration by NMR spectroscopy is a difficult and time-consuming task. For this reason, the use of natural products as a scaffold, either directly or as a starting material to prepare new chiral agents, is an elegant alternative. Based on this strategy, Szostak et al. have employed naturally occurring Chinchona 29 alkaloid and their derivatives as CSAs for different functionalities [74]. Selective modifications of the natural products were performed by tuning their enantiodiscrimination. The structure of quinine enables modulation, mainly for carbons 9, 22, and 23 (Scheme 23). Moreover, the presence of a phosphate group supplementing the quinine frame core provides zwitterionic character because it possesses two charged functions, a quaternary ammonium cation and a phosphate anion. These characteristics were used with success for enantiodiscrimination of non-derivatized amino acids (Scheme 23). The charges increase the interaction potency between the molecules, allowing for efficient chiral discrimination in the DMSO-d 6 solvent by 13 C-NMR spectroscopy. The split signals of 13 C-NMR ranged from 0.025 to 0.145 ppm. Scheme 23. Natural alkaloid 29 employed as a CSA for chiral discrimination of non-derivatized amino acids by 13 C { 1 H} NMR spectroscopy. 13 C { 1 H} NMR spectroscopy is also a useful tool for discrimination and analysis of complex mixtures because of the valuable information contained in the carbon spectrum. This strategy becomes more attractive mainly when the 1 H-NMR spectra demonstrate broad multiplets and small chemical shift differences between the stereoisomers. As a result, Lankhorst et al. presented a simple 13 C-NMR methodology for the discrimination of a complex mixture of α-tocopherol stereoisomers [75]. The traditional methods employed to perform this discrimination, such as gas and liquid chromatography, require multiple steps to prepare the sample and obtain the ideal conditions. In contrast to the 13 C-NMR method, the tocopherol mixture and the chiral trifluoroethanol (TFAE) 30 Scheme 23. Natural alkaloid 29 employed as a CSA for chiral discrimination of non-derivatized amino acids by 13 C { 1 H} NMR spectroscopy. more attractive mainly when the 1 H-NMR spectra demonstrate broad multiplets and small chemical shift differences between the stereoisomers. As a result, Lankhorst et al. presented a simple 13 C-NMR methodology for the discrimination of a complex mixture of α-tocopherol stereoisomers [75]. The traditional methods employed to perform this discrimination, such as gas and liquid chromatography, require multiple steps to prepare the sample and obtain the ideal conditions. In contrast to the 13 C-NMR method, the tocopherol mixture and the chiral trifluoroethanol (TFAE) 30 are dissolved in CDCl 3 to prepare the sample for NMR stereodiscrimination analysis (Scheme 24). Furthermore, the assignment of individual stereoisomers was possible by the synthesis of each tocopherol stereoisomer from stereochemically pure or enriched building blocks. In this work, the temperature-dependent behavior of the racemate in the presence of TFAE 30 was studied. The temperature ranges affected the efficiency of the 13 C chemical shift differences. Scheme 23. Natural alkaloid 29 employed as a CSA for chiral discrimination of non-derivatized amino acids by 13 C { 1 H} NMR spectroscopy. 13 C { 1 H} NMR spectroscopy is also a useful tool for discrimination and analysis of complex mixtures because of the valuable information contained in the carbon spectrum. This strategy becomes more attractive mainly when the 1 H-NMR spectra demonstrate broad multiplets and small chemical shift differences between the stereoisomers. As a result, Lankhorst et al. presented a simple 13 C-NMR methodology for the discrimination of a complex mixture of α-tocopherol stereoisomers [75]. The traditional methods employed to perform this discrimination, such as gas and liquid chromatography, require multiple steps to prepare the sample and obtain the ideal conditions. In contrast to the 13 C-NMR method, the tocopherol mixture and the chiral trifluoroethanol (TFAE) 30 are dissolved in CDCl3 to prepare the sample for NMR stereodiscrimination analysis (Scheme 24). Furthermore, the assignment of individual stereoisomers was possible by the synthesis of each tocopherol stereoisomer from stereochemically pure or enriched building blocks. In this work, the temperature-dependent behavior of the racemate in the presence of TFAE 30 was studied. The temperature ranges affected the efficiency of the 13 C chemical shift differences. Another route to improve the chiral recognition methodologies by NMR spectroscopy is the development of new pulse sequences. In this sense, a significant increase in the number of new NMR experiments has occurred in the last decades. Among these new experiments, "pure shift" NMR emerged as a useful tool for chiral studies. This pulse sequence and their derivatives have improved the resolution of 1D and 2D NMR experiments to simplify the typical J(H,H) multiplicity pattern of 1 H signals to singlets. The Se-NMR experiments make the NMR stereodiscrimination methods simpler and more efficient, mainly for complex and overcrowded resonances. Recently, Parella et al. have exploited the application of highly resolved pure shift heteronuclear single quantum coherence (HSQC) spectra for 1 H-and 13 C-NMR enantiodifferentiation [76]. In this study, the authors employed a racemic mixture of lactams with (R)-PA as a CSA to show how the highly resolved 2D HSQC Another route to improve the chiral recognition methodologies by NMR spectroscopy is the development of new pulse sequences. In this sense, a significant increase in the number of new NMR experiments has occurred in the last decades. Among these new experiments, "pure shift" NMR emerged as a useful tool for chiral studies. This pulse sequence and their derivatives have improved the resolution of 1D and 2D NMR experiments to simplify the typical J (H,H) multiplicity pattern of 1 H signals to singlets. The Se-NMR experiments make the NMR stereodiscrimination methods simpler and more efficient, mainly for complex and overcrowded resonances. Recently, Parella et al. have exploited the application of highly resolved pure shift heteronuclear single quantum coherence (HSQC) spectra for 1 H-and 13 C-NMR enantiodifferentiation [76]. In this study, the authors employed a racemic mixture of lactams with (R)-PA as a CSA to show how the highly resolved 2D HSQC spectra can be used to detect and accurately quantify very small anisochrony values (Scheme 25). The values obtained from the pure shift HSQC were compared to traditional HSQC and 1D NMR experiments, confirming the advantages of this new pulse sequence. Stereochemical NMR studies have also received attention based on the development and application of chiral oriented media, such as liquid-crystalline systems [77] and stretched polymer gels [78]. The main use of these oriented media is for 2 H-NMR experiments due to the quadrupolar moment of the deuterium nucleus. Chiral oriented media is a flexible approach that can be applied to several organic solvents without the use of solid-state NMR [79]. For this approach, a chiral liquid-crystalline is put into an NMR tube and after addition of an organic solvent and the probe the chiral liquid crystal swells and forms a gel. The gel does not swell isotropically but anisotropically along the glass wall of the tube and the resulting align-angular information relative to the static magnetic field can be obtained. This method is already a common procedure used for biomacromolecules in aqueous solution. Stereochemical NMR studies have also received attention based on the development and application of chiral oriented media, such as liquid-crystalline systems [77] and stretched polymer gels [78]. The main use of these oriented media is for 2 H-NMR experiments due to the quadrupolar moment of the deuterium nucleus. Chiral oriented media is a flexible approach that can be applied to several organic solvents without the use of solid-state NMR [79]. For this approach, a chiral liquid-crystalline is put into an NMR tube and after addition of an organic solvent and the probe the chiral liquid crystal swells and forms a gel. The gel does not swell isotropically but anisotropically along the glass wall of the tube and the resulting align-angular information relative to the static magnetic field can be obtained. This method is already a common procedure used for biomacromolecules in aqueous solution.
Based on these features, the chiral recognition by liquid-crystalline systems was extended to other nuclei. The use of 13 C-NMR spectroscopy is a valuable alternative to discriminate chiral environments in oriented media due to a much larger dispersion of chemical shifts. Furthermore, the correlation between 2D NMR experiments for 13 C and 2 H isotopes has the benefit of different pulse sequence as the INEPT-DECANCY and DEPT-DECANCY to improve the resolution and sensitivity. These characteristics were well described by Lesot et al. in a recent review [80]. The use of 19 F-NMR spectroscopy for the measurement of enantiomeric excess was successfully extended to oriented media by Phillips and Sharman [81].

77 Se-NMR Chiral Recognition
Selenium organic compounds are related in a broader context of applications [82][83][84] and selenium is a fundamental component of the living cells of a variety of organisms [85]. Based on these features, the use of 77 Se-NMR spectroscopy emerged as an opportunity for structure and reactivity studies [86].
The application of 77 Se-NMR spectroscopy for chiral recognition has great potential for success due to the characteristics of the selenium nucleus, such as a wide spectral window, reasonably high natural abundance, especially compared with the carbon nucleus, and because the 77 Se isotope is 1 2 and shows no significant nuclear Overhauser effect. Thus, the possibility of developing chiral probes containing selenium has several benefits. In this context, Orlov and Ananikov synthesized a chiral selenide probe as a CDA for determination of enantiomeric purity of alcohols and amines by 77 Se-NMR spectroscopy [87]. The synthesis was performed in two steps achieving 80% yields of CDA 31 (Scheme 26). Selenide chiral probe 31 was successfully applied to enantiodiscrimination of a variety of alcohols and amines. Ferreira and Gonçalves have carried out an inverse planning procedure to prepare a new chiral selenide alcohol as a CDA [88]. The article describes the synthesis of chiral selenide alcohol 32 in two steps (Scheme 27). To perform the derivatization, a "mix and shape" method was performed in an NMR tube, similar to Orlov and Ananikov's work. Using selenide alcohol 32, chiral discrimination was achieved for different carboxylic acids. Scheme 26. Chiral discrimination of alcohols and amines employing the selenide CDA 32 as a probe by 77 77 Se-NMR spectroscopy [89]. This simple and inexpensive chiral derivatizing method was successfully employed for a variety of organic compounds by 77 Se-NMR. In this protocol, the selenide amine reacts with 2-formylphenylboronic acid and the active (+)-BINOL in the presence of molecular sieves for 10 min (Scheme 28). The 1 H-NMR analyses were dependent on the concentration. In highly concentrated media the signals were broader. It is possible that a self-aggregation interaction occurred during the analysis. For 77 Se-NMR spectra, this concentration effect was not observed. Moreover, an HPLC analysis was performed for comparative evaluation of the 77 Se-NMR results (Scheme 28).
Murai has performed the synthesis of the phosphoroselenoic acid 34 as a double check chiral discrimination protocol for amines and alcohols by 77 Se-and 31 P-NMR spectroscopy [90]. The CDA 34 was synthesized in a one-pot procedure achieving 94% yields (Scheme 29). All CDAs obtained are stable under air and are purified by column chromatography. The absolute configuration of the CDA 34 was confirmed by X-ray analysis. The CDA 34 showed high reactivity for primary amines and alcohols. When tertiary alcohols were employed the reaction did not proceed. Moreover, most of the diastereoisomers formed by this protocol were separated by simple recrystallization. Recently, Murai and Itoh have applied these CDAs derivatives for the 77 Se-and 31 P-NMR discrimination of remote chirality of primary alcohols [91].  77 Se-NMR spectroscopy [89]. This simple and inexpensive chiral derivatizing method was successfully employed for a variety of organic compounds by 77 Se-NMR. In this protocol, the selenide amine reacts with 2-formylphenylboronic acid and the active (+)-BINOL in the presence of molecular sieves for 10 min (Scheme 28). The 1 H-NMR analyses were dependent on the concentration. In highly concentrated media the signals were broader. It is possible that a self-aggregation interaction occurred during the analysis. For 77 Se-NMR spectra, this concentration effect was not observed. Moreover, an HPLC analysis was performed for comparative evaluation of the 77 Se-NMR results (Scheme 28). Murai has performed the synthesis of the phosphoroselenoic acid 34 as a double check chiral discrimination protocol for amines and alcohols by 77 Se-and 31 P-NMR spectroscopy [90]. The CDA 34 was synthesized in a one-pot procedure achieving 94% yields (Scheme 29). All CDAs obtained are stable under air and are purified by column chromatography. The absolute configuration of the CDA 34 was confirmed by X-ray analysis. The CDA 34 showed high reactivity for primary amines and alcohols. When tertiary alcohols were employed the reaction did not proceed. Moreover, most of the diastereoisomers formed by this protocol were separated by simple recrystallization. Recently, Murai and Itoh have applied these CDAs derivatives for the 77 Se-and 31 P-NMR discrimination of remote chirality of primary alcohols [91]. Scheme 28. Three-component reaction for chiral discrimination of selenide amines by 77 Se { 1 H} NMR spectroscopy.

Scheme 29.
Phosphoroselenoic acid derivatives for chiral discrimination of amines and alcohols by 77 Se { 1 H} and 31 P { 1 H} NMR spectroscopy.

Conclusions
Numerous efficient and versatile chiral derivatizing and solvating agents have emerged in recent years. These compounds present different chiral recognition abilities since the structure and conditions can be tuned to improve the molecular interactions. With the expectation of expanding the chiral probes, using multinuclear NMR spectroscopy provides new possibilities for chiral studies and the elucidation of their chiral recognition mechanisms. 19 F, 31 P, 13 C, and 77 Se nuclei have demonstrated efficient results based on their nuclear properties and their incorporation into organic compounds through organic synthesis procedures.
Although the use of multinuclear NMR spectroscopy for chiral discrimination and assignment of the absolute configuration is attractive, we need to be aware that the reliability of the multinuclear NMR analysis should be evaluated for the respective application due to the different nuclear properties and general behavior of each element.

Conclusions
Numerous efficient and versatile chiral derivatizing and solvating agents have emerged in recent years. These compounds present different chiral recognition abilities since the structure and conditions can be tuned to improve the molecular interactions. With the expectation of expanding the chiral probes, using multinuclear NMR spectroscopy provides new possibilities for chiral studies and the elucidation of their chiral recognition mechanisms. 19 F, 31 P, 13 C, and 77 Se nuclei have demonstrated efficient results based on their nuclear properties and their incorporation into organic compounds through organic synthesis procedures.
Although the use of multinuclear NMR spectroscopy for chiral discrimination and assignment of the absolute configuration is attractive, we need to be aware that the reliability of the multinuclear NMR analysis should be evaluated for the respective application due to the different nuclear properties and general behavior of each element.
In order to spread the use of multinuclear NMR, new pulse sequence and experimental conditions were developed to improve the time-consuming and accuracy of the NMR spectra. Furthermore, the information obtained from these new experimental procedures can be employed to complement the traditional results and/or used for specific purposes.