Discrimination of Chiral Compounds Using NMR Spectroscopy

By Thomas J. Wenzel

John Wiley & Sons

Copyright © 2007 John Wiley & Sons, Ltd
All right reserved.

ISBN: 978-0-471-76352-9

Chapter One


Nuclear magnetic resonance spectroscopy is one of the most common methods used to determine optical purity and assign the absolute configuration of chiral compounds. The strategy that has been most exploited, as first recognized by Raban and Mislow in 1965, is to use an optically pure chiral reagent to distinguish a pair of enantiomers through the formation of nonequivalent diastereomeric complexes. The optically pure probe molecule functions as either a derivatizing or solvating agent. Furthermore, the association of an optically pure compound with a prochiral molecule with nuclei that are enantiotopic by internal comparison (e.g., the methyl groups of 2-propanol) renders these nuclei nonequivalent such that distinct resonances are often observed in the NMR spectrum. Classifying chiral metal compounds as derivatizing or solvating agents is sometimes difficult. What is important is whether the substrate molecule undergoes fast or slow exchange with the metal center. Strategies based on different packing orders for a pair of enantiomers, such as those that occur in liquid crystals or solid-state systems, have also been used for chiral analysis in NMR spectroscopy.


Chiral derivatizing agents form a covalent bond with a reactive moiety of the substrate. Many chiral derivatizing agents are available for the analysis of carboxylic acids, alcohols, and amines, although strategies for preparing derivatives of many other functional groups will be described as well throughout the text. There are two potential concerns with the application of chiral derivatizing agents. One is the possibility of kinetic resolution. Kinetic resolution refers to a situation in which one enantiomer reacts faster than the other with the chiral derivatizing agent. If the reagents are not allowed to react for a long enough time, the proportion of the two diastereomers will not be equivalent to the proportion of the two enantiomers in the original mixture. Kinetic resolution is significant when determining optical purity, but is not significant if the chiral derivatizing agent is being used to assign the absolute configuration of an optically pure substrate such as a natural product.

A second concern with chiral derivatizing agents is that no racemization occurs during the derivatization reaction. This can be significant whether it happens to the substrate or the chiral derivatizing agent. With some chiral derivatizing agents for which unacceptable levels of racemization did occur, further study was undertaken to develop reaction conditions that minimize or eliminate racemization. When pertinent, these studies are described in the text.

A general understanding is that chiral derivatizing agents should be optically pure. A method for using chiral derivatizing agents that are less than 100% optically pure has been described. The purity of the reagent must first be accurately measured using an appropriate method. A set of equations was provided in the report to determine the optical purity of an unknown from the known purity of the chiral reagent.

Many chiral derivatizing agents incorporate moieties that produce specific and predictable shifts in the resonances of the substrate. In such cases, the shifts in the spectrum of an optically pure substrate in the derivatives with the (R)- and (S)-enantiomers of the chiral derivatizing agent can be used to assign the absolute configuration. In other situations, moieties on the substrate may cause specific and predictable shifts in resonances of the chiral derivatizing agent. If so, these can be used to assign absolute configurations as well.

Another procedure that is often used with chiral derivatizing or solvating agents is to look for the presence of specific trends in the shifts that correlate with the absolute configuration of the substrate. The assumption is that, if the trends are consistent among a series of compounds with known configurations, then they will be consistent for an unknown compound with a similar structure. Empirical trends such as these have been observed in many situations and are described where appropriate throughout the text.

An alternative, although much less used, derivatizing strategy involves a self-coupling reaction of a chiral molecule. The self-coupling of two chiral molecules leads to the formation of a mixture of meso (R,S) and threo [(S,S)/(R,R)] derivatives. Assuming that these species exhibit distinct resonances in the NMR spectrum, the size of the different resonances depends on the optical purity of the compound. The utility of the method was demonstrated for several examples.


Chiral solvating agents associate with the substrate through noncovalent interactions. These can involve a mix of dipole-dipole, ion-pairing, and [pi]-[pi] interactions. Because of this, the choice of solvent is often an important parameter when using a particular chiral solvating agent. Organic-soluble chiral solvating agents are often more effective in nonpolar solvents that cannot effectively solvate the polar groups of the chiral solvating agent and substrate. Water-soluble chiral solvating agents, which are often organic host compounds, usually rely on hydrophobic effects to promote the interaction of a hydrophobic portion of the substrate within the hydrophobic cavity of the solvating agent. Steric effects are also important in the recognition properties of many chiral solvating agents.

Chiral solvating agents generally undergo fast exchange with substrates. With fast exchange, the NMR spectrum is a weighted average of the proportion of bound and unbound substrate. Resonances of the substrate double with the presence of chiral recognition. If slow exchange and enantiomeric discrimination occur, and not all of the substrate is bound to the solvating agent, three resonances are observed for a particular nucleus in the NMR spectrum. One is for the unbound substrate. The other two are for the bound forms of the (R)- and (S)-isomers of the substrate. Sometimes the resonances of the substrate or chiral solvating agent are broadened, which occurs if the system has an intermediate rate of exchange. In such cases, it may be possible to speed up the exchange to acceptable levels by warming the sample.

Most chiral solvating agents are used to determine optical purities. There are instances, though, in which the interaction is understood with enough specificity to be able to assign the absolute configuration based on the relative magnitudes of the shifts in the spectrum, much like observed with certain chiral derivatizing agents. Unlike chiral derivatizing agents, when measuring optical purities with a chiral solvating agent, it is not necessary to have 100% optical purity for the chiral reagent. What is needed is sufficient recognition to cause nonequivalence in the spectra of the enantiomers so that the peaks can be accurately integrated.

Chiral recognition with a chiral solvating agent can occur from two mechanisms. One is that the chiral solvating agent-substrate complexes are diastereomers and may have different chemical shifts. The other is that the two enantiomers often have different association constants with the chiral solvating agent, such that the time-averaged solvation environments are different. In many cases, both mechanisms likely contribute to some extent to the nonequivalence that is observed in the NMR spectrum.

Enantiomeric discrimination with chiral solvating agents is often concentration and temperature dependent. Higher concentrations of the chiral solvating agent generally favor formation of the distinct diastereomeric complexes and enhance the discrimination. Lowering the temperature of the solution usually raises the association constant of the chiral solvating agent-substrate complex, thereby enhancing the enantiomeric discrimination.

A diverse variety of chiral derivatizing and solvating agents have been developed as described in the ensuing chapters. Also, published review articles have described different aspects of chiral NMR solvating agents, chiral derivatizing agents, the use of NMR spectroscopy to assign absolute configurations, the use of chiral fluorine-containing reagents for the determination of optical purity, and the use of NMR spectroscopy for chiral analysis.


An important family of reagents that are described in Chapter 2 is aryl-containing carboxylic acids, the most well known of which is [alpha]-methoxy-[alpha]-trifluoromethylphe-nylacetic acid (MTPA). These are mostly used as chiral derivatizing agents for the assignment of absolute configurations of substrates such as alcohols and amines. Shielding by the aromatic ring of the derivatizing agent in the resulting diastereomeric complexes is used to make the assignment. Although MTPA is the most well known and commonly applied of these reagents, as will be discussed in Chapter 2, there are other reagents that are recommended for the analysis of certain classes of compounds.

Chapter 3 describes other carboxylic acids that have been used as either chiral derivatizing or solvating agents. Certain of these reagents such as camphanic acid have proven useful for distinguishing the pro-(R) and pro-(S) positions of [alpha]-deuterated primary alcohols. Several reagents based on axially chiral systems are also discussed.

Hydroxy-containing compounds, as described in Chapter 4, have been widely exploited for chiral analysis in NMR spectroscopy. This includes the application of 2-(9-anthryl)-2,2,2-trifluoroethanol, one of the most versatile chiral solvating agents ever developed. Shielding by the anthryl group of this reagent can also be used to assign the absolute configuration of certain classes of substrates. Alcohol reagents are also used as chiral derivatizing agents, especially in the analysis of carboxylic acids. Certain diols and glycosides have been used as effective chiral derivatizing agents for ketones and secondary alcohols, respectively. Axially chiral compounds such as 2,2'-dihydroxy-1,1-binaphthalene have been used as effective chiral derivatizing or solvating agents with suitable substrates.

Primary, secondary, and tertiary amines have been used as chiral derivatizing and solvating agents as described in Chapter 5. 1-Phenylethylamine, the first compound ever used as a chiral NMR solvating agent, and 1-(1-naphthyl)ethylamine are especially important chiral amines that have been used extensively to analyze carboxylic acids and other compounds as well. Phenylglycine methyl ester hydro-chloride is another important reagent for assigning the absolute configuration of carboxylic acids. Quinine, a tertiary amine, has a variety of functional groups that influence its association with and chiral discrimination properties toward a number of compound classes. Some amine reagents have been exploited as effective chiral derivatizing agents for the analysis of aldehydes and ketones. Certain diamine reagents have proven to be useful reagents for chiral analysis by NMR spectroscopy.

As described in Chapter 5, chemical shift data measured with the chiral solvating agents N,[alpha]-dimethylbenzylamine and bis-1,3-methylbenzylamine-2-methylpropane have been used to construct [sup.13]C and [sup.1]H NMR databases for all of the configurations of particular structural motifs. The pattern of the shift data for the known configurations that best matches that of an unknown can be used to determine the stereochemistry. The method is especially well suited to the assignment of structural motifs within complex natural products.

Chapter 6 describes a collection of chiral reagents that encompass a variety of compound classes. These include reagents with amide, lactam, aldehyde, ketone, isocyanate, and heterocyclic ring functionalities. Many of these reagents have been studied on a limited basis and apply to specific types of substrates, although some of the amide compounds represent soluble analogs of widely applicable chiral liquid chromatographic phases and are effectivewith a variety of compound classes. Certain of the reagents described in Chapter 6 are used as chiral solvating agents and associate through combinations of dipole-dipole and [pi]-[pi] interactions. Others such as the ketones, aldehydes, and isocyanates are utilized as chiral derivatizing agents for particular classes of substrates.

Reagents specifically designed to incorporate phosphorus, selenium, boron, and silicon atoms are described in Chapter 7. Many of the phosphorus and selenium reagents specifically use [sup.31]P and [sup.77]Se NMR spectroscopy to facilitate the analysis of optical purity. The majority of the systems are used as chiral derivatizing agents. In the case of the phosphorus-, boron-, and silicon-containing reagents, the reactions usually involve addition of the substrate at the heteroatom to form the diastereomeric complexes. The primary selenium-containing reagent that has been studied incorporates the selenium atom as a spectroscopic probe rather than a reactive center. An important set of chiral cationic and anionic phosphorus-based reagents that form ion pairs with ionic substrates is also described in this chapter. The anionic reagents are especially useful in the analysis of cationic metal complexes, although organic cations can be analyzed as well.

Another versatile strategy for effective chiral recognition, as described in Chapter 8, is through the use of host-guest complexation. Cyclodextrins have been the most widely studied family of host compounds for chiral NMR applications. Cyclodextrins can be derivatized either selectively or indiscriminately at the different hydroxyl groups, providing a range of host compounds of varying solubility and chiral recognition properties. In the aggregate, these cyclodextrin derivatives have the potential to function as chiral discriminating agents for a broad array of substrates.

Crown ethers are another common group of host compounds that function rather selectively for primary amines, although recent work has shown how the only commercially available chiral crown ether for NMR studies is also an effective chiral solvating agent for secondary amines. Calixarenes and calixresorcarenes are less studied in NMR applications, but offer interesting potential for future development and applications. There are also many specialized receptor compounds that have been described that exhibit chiral recognition toward a specific compound or class of compounds.

The use of metal complexes as chiral discriminating agents in NMR spectroscopy is an area that has received considerable attention. The importance of paramagnetic lanthanide shift reagents within the entire field of chiral NMR analysis cannot be underemphasized. Although the use of chiral lanthanide shift reagents is mostly described in Chapter 9, the utilization of lanthanide species as a means of enhancing the chiral discrimination of other NMR reagents shows up throughout the text. The utilization of lanthanide shift reagents has diminished as more investigators have obtained access to high-field NMR spectrometers. One reason is that the enhanced dispersion caused by the addition of a paramagnetic lanthanide is often no longer necessary. The other is that the line broadening caused by the paramagnetic ions is more pronounced at higher field strengths.

Chiral reagents based on diamagnetic metal complexes of palladium, platinum, rhodium, and silver have significant applications as well. These metals are especially effective at bonding to soft Lewis bases, thereby broadening the scope of compound classes amenable to chiral analysis by NMR spectroscopy. The exceptionally large shielding of substrate nuclei caused by the porphyrin rings of metal complexes of cobalt, zinc, and ruthenium has been exploited in the development of chiral discriminating agents. In addition, a number of more specialized reagents involving other metal systems have been described in the literature.


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