8.28 Spectroscopic Analysis: NMR and Shift Reagents

8.28 Spectroscopic Analysis: NMR and Shift Reagents TJ Wenzel, Bates College, Lewiston, ME, USA r 2012 Elsevier Ltd. All rights reserved.

8.28.1 8.28.2 8.28.2.1 8.28.2.1.1 8.28.2.1.2 8.28.2.1.3 8.28.2.2 8.28.2.2.1 8.28.2.2.2 8.28.2.2.3 8.28.2.2.4 8.28.3 8.28.3.1 8.28.3.2 8.28.4 8.28.4.1 8.28.4.2 8.28.4.3 8.28.5 8.28.5.1 8.28.5.2 8.28.5.3 8.28.5.4 8.28.5.5 8.28.5.6 8.28.5.7 8.28.5.8 8.28.6 References

Introduction Chiral Solvating Agents Cavity Compounds Cyclodextrins Crown ethers Calixarenes and calix[4]resorcinarenes Donor–Acceptor Reagents Alcohol reagents Amine reagents Phosphorus-containing reagents Miscellaneous reagents Metal Complexes Lanthanide Complexes Transition Metal Complexes Liquid Crystals Methods Applications Residual Dipolar-Coupling Constants and Assigning Absolute Configuration Chiral Derivatizing Agents Aryl-Containing Carboxylic Acids Other Carboxylic Acid-Based Reagents Amine-Containing Reagents Hydroxyl-Containing Reagents Phosphorus-Containing Reagents Selenium-Containing Reagents Boron-Containing Reagents Miscellaneous Reagents Database Methods for Compounds with Multiple Stereocenters

Glossary Atropisomer Stereoisomers that result from hindered rotation about a single bond. Chiral derivatizing agent Chiral reagent that reacts with a compound to form a covalent bond. Chiral solvating agent Chiral reagent that associates with a compound through non-covalent interactions. Diastereomers Stereoisomers that are not enantiomers or mirror images of each other and have different reactivity and physical properties. Diastereotopic groups Two groups in a molecule that are different and, if replaced, generate compounds that are stereoisomers.

8.28.1

545 546 546 546 548 549 550 550 552 553 554 555 555 556 559 559 559 559 560 560 562 563 564 566 566 567 568 568 568

Dipolar coupling A magnetic interaction that arises between two particles such as hydrogen nuclei with nonzero spin. Kinetic resolution When two enantiomers have different rates of reaction. Prochiral Refers to molecules that can be converted from achiral to chiral in a single step. Quadrupolar coupling An interaction that occurs in nuclei with more than two different spin states (I4½). Residual dipolar coupling A weak form of dipolar coupling that occurs in partially oriented media.

Introduction

The utilization of NMR spectroscopy for the analysis of chiral compounds originated in the mid-1960s when Raban and Mislow first showed that the derivatization of a racemic mixture with an optically pure chiral derivatizing agent led to a pair of diastereomers that could have different NMR chemical shifts.1 Provided there was no loss of configuration of the reagent or the substrate in the derivatization reaction and provided there was no kinetic resolution, the areas of the signals for the two

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546

Spectroscopic Analysis: NMR and Shift Reagents

diastereomers could be used to determine enantiomeric purity. Diastereomeric derivatives are also employed in chromatographic separations and spectroscopic analyses as described in Chapters 8.15 and 8.29 respectively. Soon after Raban and Mislow’s publication, Pirkle showed that it was possible to use chiral solvating agents for the same purpose.2 Chiral solvating agents associate with the substrate through noncovalent interactions and the associated complexes of the solvating agent with the (R)- and (S)-isomers of the substrate are diastereomers. In most cases, the association of the substrate with the chiral solvating agent involves fast exchange on the NMR time scale such that there is bound and unbound substrate present in solution. The resulting NMR spectrum is a time-average of the bound and unbound forms of the substrate. Assuming that a pair of enantiomers has different association constants with the chiral solvating agent, the difference in the time-averaged solvating environment (i.e., the enantiomer that bonds less to the solvating agent spends more time surrounded by the bulk solvent) can also lead to differences in chemical shifts of resonances of the two enantiomers. Whether the enantiomeric discrimination in the NMR spectrum occurs because of the diastereomeric nature of the two complexes or the differences in the association constants is often not known and usually not important. In 1969, Hinckley first reported the use of achiral, paramagnetic lanthanide tris b-diketonate complexes as NMR shift reagents.3 Soon after, Whitesides and Lewis showed that chiral lanthanide tris b-diketonates produced enantiomeric discrimination in the NMR spectra of suitable substrate compounds.4 For some metal complexes, the original species remains intact and the metal expands its formal coordination number by bonding to the substrate. In others, the substrate displaces an existing ligand of the original metal reagent. With some metal complexes, the substrate does not undergo fast exchange once it has bound to the metal, which is analogous to the situation with a chiral derivatizing agent. With other metal regents, the substrate undergoes fast exchange, which is analogous to the situation with chiral solvating agents. The use of chiral liquid crystals is a fourth common strategy for achieving chiral discrimination in NMR spectroscopy. The first report using chiral liquid crystals for enantiomeric discrimination in NMR spectroscopy was presented in 1968,5 but liquid crystals were not commonly used until the last decade. Chiral liquid crystals undergo a partial alignment in an applied magnetic field. Compounds dissolved in the liquid crystal undergo a partial alignment as well. If the alignments are different for a pair of enantiomers, they may exhibit differences in chemical shifts analogous to the situation with derivatizing agents, solvating agents, and metal complexes. A more common method of monitoring enantiomeric discrimination with chiral liquid crystals is to examine dipolar or quadrupolar coupling constants. For molecules that are partially aligned in a magnetic field, dipolar or quadrupolar coupling constants depend on the alignment. For enantiomers with different alignments, the dipolar and quadrupolar coupling constants will be different. All of the systems described above can be used to determine the enantiomeric purity of chiral compounds. In certain situations, it is also possible to use chiral reagents to assign the absolute configuration of the substrate. If the reagent–substrate derivative or complex has a specific known geometry, it may be possible to predict in advance the expected perturbations in chemical shifts of resonances of the substrate. The classic example involves shielding by the phenyl ring in derivatives of secondary alcohols with a-methoxy-a-trifluoromethylphenylacetic acid (MTPA) in the so-called Mosher method, after the pioneering work of Dale and Mosher in 1973.6 The ability to use MTPA to assign the absolute configuration of secondary alcohols is possible because the derivative has a preferred conformation. This general strategy has been extended to the design of many other chiral derivatizing or solvating agents. A second possibility for assigning an absolute configuration is if the chiral reagent leads to consistent trends in the relative perturbations in chemical shifts of the (R)- and (S)-isomers of similar substrates. The reason for the specific trend is often not understood with these reagents. However, if a consistent empirical trend is observed among many substrates of similar structure, it is assumed that a similar compound with an unknown configuration will exhibit the same behavior. A general discussion of techniques for assigning stereochemistry is provided in Chapter 8.3. Many examples of chiral solvating agents, chiral derivatizing agents, metal complexes, and liquid crystals have been developed since these first reports. A book published in 2007 provides a comprehensive review of the entire field.7 Other recent review articles have described the utilization of chiral reagents for assigning an absolute configuration.8,9 An exhaustive review of the field is beyond the scope of this chapter. Instead, here, the focus is on those reagents that are most widely studied and widely applicable for chiral discrimination in NMR spectroscopy. Commercially available reagents or those that are readily synthesized are emphasized.

8.28.2

Chiral Solvating Agents

8.28.2.1

Cavity Compounds

A wide variety of specialized cavity compounds have been explored as chiral NMR solvating agents, many of which have been described in recent reviews.7,10 The utilization of chiral host compounds for enantiomeric discrimination is described in Chapter 8.5. Many of these systems have been applied to a limited range of substrates and involve multistep synthetic preparations that render them impractical for general application in NMR spectroscopy. Certain cyclodextrins (CDs), a crown ether derived from tartaric acid, and a series of water-soluble calix[4]resorcinarenes represent the most versatile cavity compounds for NMR applications.

8.28.2.1.1

Cyclodextrins

CDs are cyclic oligosaccharides comprised of 6 (a), 7 (b), or 8 (g) D-glucose rings (Figure 1). Each glucose ring has one primary (6-position) and two secondary (2- and 3-positions) hydroxyl groups. The cavity is tapered with the primary hydroxyl groups at the

Spectroscopic Analysis: NMR and Shift Reagents

547

narrower opening and secondary hydroxyl groups at the wider opening. The commercially available underivatized native CDs are water soluble and have been extensively examined as chiral NMR solvating agents.7 The different sizes of the a-, b-, and g-CDs expand the utility of these reagents. Water-soluble substrates with aromatic rings form host–guest complexes with CDs, usually involving insertion of the aromatic ring into the relatively hydrophobic interior of the CD cavity. Since so many compounds form host–guest complexes with CDs, native CDs can potentially function as chiral NMR solvating agents for any water-soluble substrate. Native CDs have also been used as chiral NMR solvating agents for substrates such as a-pinene (1),11 cis-decalin (2),12 and camphor (3)13 that are not water soluble. In these cases, the substrate is solubilized in water by the formation of the host–guest complex.

HO

OH

3

2

1 O

4 O

5 6 OH

Figure 1 Representation of a cyclodextrin superimposed with one D-glucose subunit.

The versatility of CDs as chiral NMR solvating agents is further expanded by derivatization of the hydroxyl groups. The hydroxyl groups of the CDs have different reactivities. Some derivatization schemes target a particular position, whereas others add the substituent group indiscriminately at the 2-, 3-, and 6-positions. A critical factor is the degree of substitution (DS) of the substituent group, since many derivatization schemes for CDs leave unreacted hydroxyl groups. Many derivatized CDs have been examined in NMR applications and only those that have been most widely studied or are commercially available are described here. Cyclodextrins have also been used extensively in chromatographic separations of enantiomers as described in Chapter 8.10. Permethylated a- and b-CD, which are commercially available, are soluble in water and organic solvents. The permethylated b-CD is more soluble in water than native b-CD. In some cases, permethylated a- and b-CD produce larger enantiomeric discrimination in the 1H or the 13C NMR spectrum than the corresponding native CD.7,10 A noteworthy application of permethylated a- and b-CD is for the analysis of trisubstituted allenes (4). The allene hydrogen of the (S)-enantiomer is consistently deshielded relative to that of the (R)-enantiomer with permethylated a-CD.14

2

1

R1

R3 C

O 3

C

R2

C H

4

Several ionic CDs are also useful as water-soluble chiral NMR solvating agents. A general observation is that anionic CDs produce larger enantiomeric discrimination in the spectra of cationic substrates than native CDs and cationic CDs function more effectively for anionic substrates than native CDs.7,10 A commercially available sulfated b-CD with a DS of 9 (of 21 possible hydroxyl groups) was more effective for a variety of aromatic-containing cationic substrates than native CDs. It was also possible to enhance the enantiomeric discrimination by adding nitrate salts of dysprosium(III) or ytterbium(III) to the solution. The paramagnetic lanthanide ion bound to the sulfated CD and caused further perturbations in the chemical shifts of the substrate in the CD cavity.15 Indiscriminately substituted anionic carboxymethylated CDs (CM-CD) with relatively high DS values are also effective chiral NMR solvating agents for aryl-containing cationic substrates. Commercially available CM-CD derivatives with relatively low DS were tested and were not nearly as effective as the more highly substituted derivatives. The preparation of indiscriminately substituted a-, b-, or g-CM-CD can be easily accomplished in one step using sodium hydroxide and sodium iodoacetate. The a- and b-CM-CD derivatives were usually better for phenyl-containing substrates, whereas b- and g-CM-CD were better for naphthyl-containing substrates.16 Similar to the sulfated CD described above, paramagnetic ytterbium(III) or praseodymium(III)

548

Spectroscopic Analysis: NMR and Shift Reagents

can be added to mixtures of CM-CD and the substrate to enhance the enantiomeric discrimination. The lanthanide ion binds at the carboxymethyl groups and perturbs the chemical shifts of substrates in the cavity.17 A commercially available, indiscriminately substituted anionic sulfobutylether-b-CD produces larger enantiomeric discrimination in the NMR spectra of cationic substrates than native CDs. The higher the DS of the sulfobutylether groups, the larger the enantiomeric discrimination in the NMR spectrum.18 Several cationic CDs such as amino-substituted derivatives have been explored as chiral NMR solvating agents for anionic substrates.7 Although these reagents produce larger enantiomeric discrimination for anionic substrates than native CDs, their utility is limited in scope and careful control of the pH is needed to maintain the CD and substrate as ions. Recently, indiscriminately substituted cationic derivatives of a-, b-, and g-CD with high DS values (approximately 1.5 per glucose ring) were prepared in one step by reacting the native CD with glycidyltrimethylammonium chloride (5 – GTAC). The cationic a-, b-, and g-CD derivatives (6 – CD-GTAC) were shown to be effective and broadly applicable water-soluble reagents for anionic substrates with aryl rings. The quaternary amine group is positively charged at all important pH values. CD-GTAC derivatives are commercially available, but the lower DS and the presence of a diol impurity as a byproduct of the GTAC render them less effective than the more highly substituted and purified derivatives described in the report. The size of the cavity has an effect as a-, b-, or g-CD-GTAC was not consistently effective for all of the substrates.19 OR

6 5 4 O

OH

O 1

R=

O

RO

OR

n = 6,7,8

5

8.28.2.1.2

N

3 2

N

6

Crown ethers

Extensive numbers of crown ethers or similar crown aza compounds with one or more nitrogen atoms in the cavity function as chiral NMR discriminating agents.7 Several are useful chromatographic phases for the separation of enantiomers as described in Chapter 8.13. In most cases, the NMR studies of these reagents are limited to a small number of substrates. Furthermore, the reagents are not commercially available and often involve multistep synthetic preparations. The one exception is (18-crown-6)2,3,11,12-tetracarboxylic acid (7–18-C-6-TCA), a derivative of tartaric acid, which is commercially available in both enantiomers. 18-Crown-6 ethers, which are the most common of those studied, form stable host–guest complexes with protonated primary amines. The interaction involves three hydrogen bonds as shown in Figure 2. R N H O O

O H

H

O

O O

Figure 2 Interaction of a protonated primary amine with an 18-crown-6 ether.

Comparative studies indicate that 18-C-6-TCA is a more effective chiral NMR solvating agent than other 18-crown-6 ethers that are known to exhibit excellent chiral discrimination properties in liquid chromatographic separations. The utilization of 18-C-6TCA for aliphatic- and aromatic-containing primary amines,20,21 a-methylamino acids,22 a-amino acids,20,23 and b-amino acids24,25 has been described. For a-23 and b-amino acids,24,25 there are consistent trends in certain resonances of the (R)- and (S)enantiomers that correlate with the absolute configuration. 18-C-6-TCA can be used in methanol-d4, acetonitrile-d3, and deuterium oxide.20,23 Another attribute of 18-C-6-TCA is that it can be mixed with either neutral or protonated primary amines. When 18-C-6-TCA and a neutral primary amine are mixed at equivalent concentrations, an acid–base neutralization reaction produces the protonated amine that associates with the mono-carboxylate of the crown ether. Enantiomeric discrimination in the NMR

Spectroscopic Analysis: NMR and Shift Reagents

549

spectrum of the substrate is comparable whether the protonated or the neutral form of the amine is used.20,21 In cases when a neutral substrate is not that soluble in mixtures with 18-C-6-TCA in methanol-d4 (e.g., some a- or b-amino acids), DCl can be added to solubilize the substrate. It is also possible to add a paramagnetic lanthanide species such as ytterbium(III)nitrate to mixtures with protonated primary amines and neutral 18-C-6-TCA to enhance the enantiomeric discrimination. The Yb(III) binds at the carboxylic acid groups of the crown ether and perturbations in the chemical shifts cause enhancements in enantiomeric discrimination.20,21 The association of protonated secondary amines with 18-crown-6-ethers is much weaker than that of primary amines. One reason is that only two hydrogen bonds can form with secondary amines. Another is the unfavorable steric hindrance from the two substituent groups of the amine. 18-C-6-TCA is an exception as the NMR spectra of neutral secondary amines mixed with neutral 18-C-6-TCA in methanol-d4 show substantial perturbations in chemical shifts and enantiomeric discrimination. The acid–base neutralization reaction between the neutral secondary amine and 18-C-6-TCA generates ammonium and monocarboxylate ions that can interact via two hydrogen bonds and ion pairing as shown in Figure 3. The utility of 18-C-6-TCA for determining the enantiomeric purity of N-methyl amino acids, alkyl aryl amines,26 pyrrolidines (8),27 piperidines (9), and piperazines (10)28 has been demonstrated. 18-C-6-TCA even produces small but observable enantiomeric discrimination in the 1 H and 13C NMR spectra of cyclic and acyclic tertiary amines.29

R

R′ N O O

HOOC O

H

H

O

O

HOOC

O

O

COOH

O Figure 3 Interaction of a protonated secondary amine with the mono-carboxylate ion of 18-C-6-TCA.

O HOOC

O

O

COOH

HOOC

O

O

COOH

O 7 H N NH

8

8.28.2.1.3

N H 9

N H 10

Calixarenes and calix[4]resorcinarenes

Calixarenes (11) are cavity compounds formed in the reaction of phenol with formaldehyde. The most commonly studied calixarenes have four phenol rings, although analogs with higher numbers of phenol rings can be prepared by varying the reaction conditions.30 Calix[4]resorcinarenes (12) are prepared by the reaction of resorcinol and almost any aldehyde. The reaction commonly used to prepare the calixresorcinarenes produces a cavity with four resorcinol rings. The ability to vary the aldehyde facilitates the preparation of calix[4]resorcinarenes with different solubility properties. Although a variety of calixarenes and calix[4]resorcinarenes have been examined in chiral NMR applications, most of these studies have involved only a few substrates with modest degrees of enantiomeric discrimination.7,10 Furthermore, because these reagents are not commercially available and their synthesis usually requires several steps, they are of limited utility as chiral NMR solvating agents.

550

Spectroscopic Analysis: NMR and Shift Reagents

HO

OH

R

R

HO

OH

OH OH HO OH OH

HO R

R

HO 11

OH 12

The exception is a series of water-soluble calix[4]resorcinarenes that contain anionic sulfonate groups on the bridges between the resorcinol rings and proline or proline derivatives attached to the resorcinol rings (13–17).31–35 These reagents are synthesized in two steps and produce excellent enantiomeric discrimination in the 1H NMR spectra of water-soluble substrates with aromatic rings. The aromatic resonances of substrates with mono- or 1,2-disubstituted phenyl rings, mono-, 2,3-disubstituted, or 1,8-disubstituted naphthyl rings, 1-substituted anthryl, ortho-substituted pyridyl, indole, dihydroindole, and indane rings exhibit large shielding in the presence of 13–17. The shielding indicates that the aromatic ring inserts into the cavity and is positioned over the p-electrons of the resorcinol rings. The aryl resonances of sterically hindered 1,3- or 1,4-disubstituted phenyl rings and 1,4-, 1,5-, or 2,6-disubstituted naphthalene rings only exhibit small perturbations in chemical shifts in the presence of 13–17, indicating only weak binding. Substrates that are water soluble by virtue of ammonium or carboxylate groups exhibit enantiomeric discrimination in the presence of 13–17. The derivatives with hydroxyproline (14–16)33,34 and a-methylproline (17)35 groups are almost always more effective than the proline (13) derivative. The additional interaction of the hydroxy or the methyl group of the proline with the substituent group of the substrate likely accounts for the effectiveness of 14–17 compared with 13.

R HO

OH

SO3−Na+

4

HO

HO

OH COOH

COOH

N CH2 13

8.28.2.2

COOH

N CH2 14

COOH

N CH2 15

COOH

N CH2 16

N CH2 17

Donor–Acceptor Reagents

Many chiral reagents that interact with substrates through noncovalent interactions such as hydrogen bonding, dipole–dipole association, p–p stacking, and ion pairing have been examined as chiral NMR solvating agents. Steric hindrance is often important in the binding with these reagents as well. Polar solvents are usually highly effective in solvating the substrate and the chiral solvating agent and inhibit the association of the two. Relatively nonpolar solvents such as chloroform-d are typically used with these reagents, although greater enantiomeric discrimination is often observed in nonpolar solvents such as cyclohexane-d12 and benzene-d6.

8.28.2.2.1

Alcohol reagents

2,2,2,-Trifluoro-1-(9-anthryl)ethanol (18 – TFAE), commonly known as Pirkle’s alcohol, and the analogous 2,2,2-trifluoromethylphenylethanol (TFPE) are especially effective chiral NMR solvating agents. Shielding of the substrate by the aryl ring is often important in producing the enantiomeric discrimination with these commercially available reagents. TFAE is preferable

Spectroscopic Analysis: NMR and Shift Reagents

551

to TFPE because of the larger shielding produced by the anthryl ring. The hydroxyl group of TFAE can interact with substrates through hydrogen bonding. The methine hydrogen atom of TFAE is acidic enough to form hydrogen bonds as well. The p-electrons of the anthryl ring can be involved in p–p stacking and can also associate with electropositive hydrogen atoms of the substrate. TFAE has been used extensively for chiral NMR discrimination.7,10 TFAE is a candidate for determining the enantiomeric purity of any chloroform-soluble compound, including metal complexes with polar groups in the ligands, that has the potential for dipole–dipole or p–p stacking interactions. The binding of TFAE or TFPE to certain classes of compounds occurs in a specific manner such that trends in the shielding by the phenyl or the anthryl group can be used to assign the absolute configuration. Figure 4 illustrates the association of (R)- and (S)-TFPE with a sulfoxide. Subtracting the chemical shifts of the substrate resonances in mixtures with (S)-TFPE (or TFAE) from those with (R)-TFPE (or TFAE) produces a set of DdRS values. The DdRS values will be positive for one substituent of the substrate and negative for the other.36 As summarized in recent reviews, the association of TFPE and TFAE with alkyl and aryl sulfinates (19), N,N0 -dialkyl aryl amine oxides (20), a-amino acid methyl esters, N,N-dimethyl amino acids, epoxides, oxaziridines (21), imines (22), g-lactones (23), a,a-disubstituted and b-substituted b-propiolactones (24), and g-lactams (25) can be used to assign the absolute configuration of these compounds.7,9

H

H O C6H5

O

C

S

CF3

C6H5

i-propyl

H

O

O

C

S

CF3

CH3

(R, R)

H

CH3 i-propyl

(R, S)

Figure 4 Association of (R)-TFPE with the two configurations of a sulfoxide.

HO

CF3

O R1

R

C

X

N

R2 X = N, O, S 19

18 Ph

R2

S

R1

R1 N

()

Ph N O

R2

O 21

O 20

O

O () 24

23

22

OH OH

O

O R1 S

H N

N 25

O

R2 26

27

2,20 -Dihydroxy-1,10 -binaphthalene (26 – BINOL), an atropisomer that is chiral by virtue of the nonplanarity of the two naphthyl rings, is commercially available in both enantiomers. Similar to TFAE, it has the ability to form hydrogen bonds and has an aryl ring that may be involved in attractive forces and p–p stacking. The aryl rings also produce shielding in the NMR spectra of substrates. BINOL has been used as a chiral solvating agent for a number of organic-soluble substrates including alkyl and aryl alcohols, sulfoxides, selenoxides, amines, and N-sulfinyl aldimines (27). As summarized in recent reviews, the association of BINOL with sulfoxides, amines, and amino alcohols causes perturbations in the chemical shifts that correlate with the absolute configuration of the substrate.7,9

552

Spectroscopic Analysis: NMR and Shift Reagents

8.28.2.2.2

Amine reagents

1-Phenylethylamine (28 – PEA), 1-(1-naphthyl)ethylamine (29 – NEA), and 1-(9-anthryl)ethylamine (30 – AEA) have many of the same attributes as TFAE and BINOL and have frequently been used as chiral NMR solvating agents.7 PEA was the first compound ever used as a chiral NMR solvating agent, causing enantiomeric discrimination of the 19F resonance of 2,2,2-trifluoro1-phenylethanol.2 28–30 are commercially available and the shielding of the anthryl ring of AEA usually results in the largest enantiomeric discrimination of the three reagents.37 Perturbations in the chemical shifts of aryl alkyl alcohols with PEA and NEA can be used to assign the absolute configuration of the substrates. The geometry of the complex has a specific orientation of the aryl ring of PEA or NEA that exerts predictable effects on the substituents of the alcohol.38 A common strategy with weak acids including carboxylic acids,39 phosphorus thioacids (31),40 and 1-hydroxyalkyl phosphoric acids (32)41 is to add PEA, NEA, or AEA to a solution of the acid in solvents such as methanol-d4, chloroform-d, benzene-d6, dimethylsulfoxide-d6, or pyridine-d5. The acid–base neutralization leads to diastereomeric salts and ion pair association results in enantiomeric discrimination in the NMR spectrum. A strategy for using NEA to analyze the enantiomeric purity of ketones has been reported. The ketone is converted into an acid oxime (33) by reaction with NH2OCH2CO2H. The addition of NEA to the acid oxime in chloroform-d leads to the formation of a salt.42

NH2

NH2

28

NH2

29

30 N

O S R

P OH 31

R

P OH OH R1 OH 32

N

O R2 33

COOH

34

The utilization of perdeuterated N,a-dimethylbenzylamine (34 – DMBA) as a chiral solvating agent for assigning the absolute configuration of polyol motifs such as 1,3,5-triol or 2-methyl-1,3-diols unit has been described. In this method, the 1H and 13C NMR spectrum of every possible diastereomer of the particular polyol unit is recorded in the presence of (R)- and (S)-DMBA. A database, one example of which includes the DdRS values for each carbon, is constructed. The DdRS values for the unknown in the presence of (R)- and (S)-DMBA are compared with each one in the database and the best match is used to assign the configuration.43 The absolute configuration of secondary alcohols can be assigned using (R,R)- and (S,S)-bis-1,3-methylbenzylamine2-methylpropane (35 – BMBA-pMe). Hydrogen bonds between BMBA-pMe and the hydroxyl group lead to specific perturbations of adjacent carbon resonances and DdRS values with (R,R)- and (S,S)-BMBA-pMe can be used to assign the absolute configuration. The hydroxyl groups in 1,4- and 1,5-diols are apart far enough such that each stereocenter can be independently assigned. Analysis of 1,2- and 1,3-diols with BMBA-pMe is more complex because two BMBA-pMe molecules cannot bind independently to the two hydroxyl groups. For syn- and anti-1,2-diols, specific trends are observed that can be used to assign the configuration.44 BMBA-pMe can also be used to assign the absolute configuration of acyclic tertiary alcohols.45

H N

H N 35

The utilization of quinine (36), which is commercially available, for the chiral NMR analysis of alkyl aryl alcohols and binaphthyl derivatives, hemiacetals (37) and methyl acetals (38), b-hydroxyesters, hydroxyl alkyl phosphonates (39), 1-hydroxyphosphinothioic acids (40), and a thiophene-1-oxide derivative (41) has been summarized in recent reviews.7,10 The combination of hydrogen bonding, dipole sites, and the quinoline ring contributes to quinine’s effectiveness as a chiral NMR solvating agent. Carbamoyl derivatives of quinine with a 1-naphthyl group at the C9 and C11 positions are more effective at

Spectroscopic Analysis: NMR and Shift Reagents

553

discriminating aryl-substituted amines and amino acids than quinine. When the aryl substituent group was a dinitrophenyl group, p–p stacking with the naphthyl ring in the C9-derivative stabilized the interaction and contributed to the enantiomeric discrimination.46

MeO

N 36

OH

N

O

O

OCH3

N

O

OH 38 CH3

O

S

P

OEt OEt

S

O2N P HO H OH 40

39

8.28.2.2.3

OH

OH 37

N

HO

O

D

O− 41

Phosphorus-containing reagents

Nonracemic mixtures of phosphinothioic acids exhibit enantiomeric self-discrimination in solution because of the formation of a hydrogen-bonded dimer (Figure 5). As summarized in recent reviews, enantiomerically pure tert-butylphenylphosphinothioic acid (42) has been used extensively as an effective chiral NMR solvating agent for almost any hydrogen-bonding substrate including phosphinic amides (43), thiophosphinic acids, phosphinate esters, thiophosphinates, phosphonates, sulfoxides, amine oxides, phosphine oxides, phosphites, alcohols, diols, thiols, mercapto alcohols, amines, amine alcohols, and hydroxyl acids, as summarized in recent reviews.7,10 The 1H NMR spectrum is often monitored, although the 31P spectrum can be used for phosphorus-containing substrates. S

Ph

H

O

R

P R

S

Ph

O

H

H

O

Ph

P

P Ph

S

P

R

O

H

S

R

Figure 5 Dimer formed by the association of phosphinothioic acids.

1,10 -Dinaphthyl-2,20 -diylphosphoric acid (44), which is commercially available, has been used as a chiral solvating agent for amines. Mixing 44 with the amine results in the formation of a salt, analogous to the functioning of PEA, NEA, or AEA, and enantiomeric discrimination in the 1H or 13C NMR spectra is observed.47 S P Ph

OH t Bu

OH

O

42

P O

O

O Ph

P N H

Ph 44

43

Tris(tetrachlorobenzene-1,2-benzenediolato)phosphate(V) (45 – TRISPHAT) and 1,10 -(1,10 -binaphthal-2,20 -diolato)bis(tetrachlor-1,2-benzenediolato)phosphate(V)) (46 – BINPHAT) are commercially available anionic reagents of C3 and C2 symmetry, respectively, that are particularly useful for the NMR analysis of cationic metal complexes. TRISPHAT has been used for the analysis of an especially wide array of cationic metal complexes and the results have been summarized in recent reviews.7,10,48,49 Larger enantiomeric discrimination is usually obtained if the symmetry of the anionic reagent is matched to the symmetry of

554

Spectroscopic Analysis: NMR and Shift Reagents

the metal complex. In some cases, the association of TRISPHAT with metal complexes is strong enough that enantiomeric discrimination is still observed in polar solvents such as acetone-d6, acetonitrile-d3, and dimethylsulfoxide-d6.7,10,48,49 TRISPHAT and BINPHAT can also be used for the analysis of phosphinium (47), ammonium (48,49), and thiioranium (50) cations.7,10,48–50 The use of BINPHAT is usually preferable to TRISPHAT with these other cationic species. These reagents should be considered for the analysis of any organic-soluble cationic species.

Cl Cl

O

P

O

Cl

Cl

O

O

O

Cl

Cl

Cl

Cl

Cl

Cl

Cl

O O

O

O

Cl

Cl Cl

P

O

Cl

O O

Cl

Cl

Cl

Cl

Cl 46

45

MeO N

P CD3 47

48

N tBu

N

49

8.28.2.2.4

S 50

Miscellaneous reagents

Several broadly applicable chiral NMR solvating agents including N-(3,5-dinitrobenzoyl)-1-phenylethylamine (51), N-(3,5dinitrobenzoyl)-L-leucine ethyl ester (52), N-(3,5-dinitrobenzoyl)-4-amino-3-methyl-1,2,3,4-tetrahydrophenanthrene (53), and 1-(1-naphthyl)ethyl urea derivatives of the amino acids (54) valine, leucine, tert-leucine, and proline were first explored for use as chiral liquid chromatographic phases. A general discussion of the use of liquid chromatography for chiral separations is provided in Chapter 8.7. Compound 51 is commercially available as is the carboxylic acid precursor to 52. 54 can be prepared in one step by reacting the amino acid with enantiomerically pure (R)- or (S)-1-(1-naphthyl)ethylisocyanate. All of these reagents have hydrogen bonding moieties, lone pairs of electrons, and aromatic rings for p–p-stacking. Steric effects of the substitutent group of the chiral solvating agent are also often important in influencing enantiomeric discrimination. Some of these have been extensively studied in liquid chromatographic applications, the results of which can then be used to guide NMR studies. 51 is effective for sulfoxides,51 phosphine oxides,52 amides, esters, and alcohols,53 and the corresponding 1-naphthyl derivative of 51 is effective for protected amines.54 52 is effective for lactams, lactones, amides, and sulfoxides.55 53 produces enantiomeric discrimination in the 1H NMR spectra of epoxides, amides, lactones, lactams, alcohols, sulfoxides, and primary amines.56 54 is effective for amines, sulfoxides, alcohols, and carboxylic acids.57 It is also possible to enhance the enantiomeric discrimination in the NMR spectrum of the substrates in mixtures with 51–54 by adding the commercially available europium(III) tris b-diketonate of 6,6,7,7,8,8,8-heptafluoro-2,2-dimethyl-3,5-octanedione [H(fod)]. Provided the europium preferentially binds to and perturbs the chemical shifts of the substrate in the bulk solution, the NMR spectrum of the enantiomer with the lower association constant with the chiral solvating agent exhibits larger lanthanideinduced shifts.58,59 The utilization of an ion pair formed using commercially available (R)- or (S)-mandelic acid and dimethylaminopyridine as a chiral solvating agent for cyanohydrins (55) in chloroform-d has been reported recently. The ion pair forms a ternary complex with the substrate that is held together by hydrogen bonding and dipole–dipole interactions. The spectra of cyanohydrins exhibit

Spectroscopic Analysis: NMR and Shift Reagents

555

specific trends that correlate with the absolute configuration. A variation of the strategy is to mix enantiomerically pure mandelonitrile, dimethylaminopyridine, and a carboxylic acid together in chloroform-d to produce enantiomeric discrimination of the carboxylic acid.60 O

O O2N

COOH

O2N

N H

N H

NO2

NO2

52

51 O O2N

N H

NO2 53 O

R O

N H

CN

N H O

R

OH 55

54

8.28.3

Metal Complexes

Many metal complexes have been used as chiral discriminating agents in NMR spectroscopy.7,10 The metals are Lewis acids and form donor–acceptor complexes with suitable Lewis bases. In some cases, the metal complex expands its coordination number when bonding to the substrate. In other cases, the substrate displaces a ligand of the chiral metal complex. Lanthanide(III) ions are effective for hard Lewis bases, which usually encompasses oxygen- and nitrogen-containing compounds. Platinum, palladium rhodium, and silver are effective for softer Lewis bases such as alkene-, alkyne-, aromatic-, phosphorus-, and sulfur-containing compounds.

8.28.3.1

Lanthanide Complexes

Commercially available paramagnetic lanthanide tris b-diketonate complexes with the chiral ligands 3-trifluoroacetyl-D-camphor [56 – H(tfc)],61 3-heptafluorobutyryl-D-camphor [57 – H(hfc)],62 and D,D-dicamphoylmethane [58 – H(dcm)]63 are some of the earliest and at one time most widely used chiral NMR shift reagents.7,64 Comparative studies showed that the complexes with dcm were more effective than those with tfc or hfc.7,63,64 Before the widespread availability of high field NMR spectrometers, paramagnetic chiral lanthanide chelates were especially effective for chiral discrimination. The paramagnetic lanthanide ions caused large perturbations in chemical shifts in the NMR spectra of bound substrates and substantial enantiomeric discrimination in many cases. Because virtually all nitrogen- and oxygen-containing compounds associate with the lanthanide ions in the tris b-diketonate complexes, they are applicable to many substrates.

CF3

O 56

CF2CF2CF3

O

O

O 57

N O

O 58

N H 59

O

O

O

O O O

O 60

N

556

Spectroscopic Analysis: NMR and Shift Reagents

A drawback to the use of lanthanide tris b-diketonates is that paramagnetic substances cause line broadening. One reason for this is that they shorten the relaxation times of nuclei. Another is that the substrate has an intermediate rate of exchange between its bound and unbound form, as can occur with the large lanthanide metal chelates. The higher the field strength, the worse the broadening. The use of paramagnetic lanthanide tris b-diketonates on higher field instruments (400 MHz or greater for 1H NMR) is often limited because the broadening obscures coupling information and the presence of enantiomeric discrimination. Strategies to reduce the broadening include the use of proton-decoupled 13C NMR spectra,65 the use of samarium(III), an ion that causes smaller perturbations of the chemical shifts but also less broadening,66 recording the spectrum at elevated temperature to diminish exchange broadening,67 or recording the spectrum in a polar solvent such as acetonitrile-d3.68 It has also been shown that diamagnetic lanthanum(III) and lutetium(III) chelates of tfc, hfc, and dcm in solvents such as chloroform-d, benzene-d6, and cyclohexane-d12 are effective in causing enantiomeric discrimination in the 1H NMR spectra of amines, alcohols, epoxides, sulfoxides, and oxazolidine-containing (59) compounds. With these diamagnetic chelates, the complexation shifts that occur on substrate binding are often sufficient to cause enantiomerically discriminated resonances. Better discrimination occurs in benzened6 or cyclohexane-d12 than in chloroform-d because there is greater association in the nonpolar solvents. The optimal choice of La(III) or Lu(III) and tfc, hfc, and dcm varies for different substrates.69 In some cases, chiral paramagnetic lanthanide chelates have been successfully used on high field instruments.7 A recent example involves the analysis of the 1H and 13C NMR spectra of hexamethylenetriperoxide diamine (60) with Eu(tfc)3 and Pr(tfc)3 in methylene chloride-d2 at 600 MHz.70 The lanthanide tris b-diketonate complexes are fluxional and the lanthanide ion expands its formal coordination number when binding to a substrate. Because of the fluxional nature of the lanthanide complexes, the geometries of the donor–acceptor complexes are not specific enough to use perturbations in chemical shifts to assign absolute configurations of the substrate. It is often observed that the perturbations in chemical shifts for compounds with closely related structures correlate such that the trends can be used to assign the absolute configuration. When performing such an assignment, it is important to study model compounds of known configurations that are as close as possible in structure to the unknown. Thorough reviews have described a range of compounds including alkyl aryl alcohols, secondary alcohols, tertiary alcohols, benzhydrols, a-amino acid methyl esters, lactones, epoxides, arene oxides, methyl butanoates, and mono-, di-, and triglycerides in which such trends have been noticed with lanthanide tris b-diketonates.7,64 A bimetallic reagent prepared directly in the NMR tube by mixing a chiral lanthanide(III) tris b-diketonate [Ln(b-dik)3] with a silver(I) b-diketonate [Ag(b-dik)] is useful for the analysis of soft Lewis bases such as alkenes, aromatics, and alkyl bromides.71 A number of silver b-diketonates have been evaluated, but Ag(fod) is the only one that is commercially available.71,72 Evidence suggests that a lanthanide tetrakis chelate anion is formed and the silver(I) is ion paired with it ([Ln(b-dik)4]Ag þ ).71 The silver binds to the alkene or aromatic compound and the paramagnetic lanthanide causes perturbations in the chemical shifts. The utility of these binuclear reagents for alkenes, aromatics, and alkyl bromides has been summarized in a recent review.7 In some cases, the binuclear reagents have been more effective for polyfunctional substrates with both a hard and a soft Lewis base group than the corresponding lanthanide tris b-diketonate.7 The longer distance between the paramagnetic lanthanide ion and substrate in the binuclear reagents relative to that with the lanthanide tris b-diketonates reduces the broadening in the spectra. Chiral water-soluble lanthanide chelates have been developed and used as well. The two most noteworthy are chelates of propylenediaminetetraacetic acid (61 – pdta) and N,N,N0 ,N0 -tetrakis(pyridylmethyl)propylenediamine (62 – TPPN). Carboxylate species including amino acids bind to the lanthanide ion and exhibit enantiomeric discrimination in the 1H NMR spectra. Trends in the chemical shifts of certain resonances of a-amino acids with chelates of pdta73 and TPPN74 correlate with absolute configuration. Similar trends for a-methyl amino acids75 and b-amino acids76 with Eu(pdta) can be used to assign the absolute configuration. Cerium(III),77 samarium(III),78 or lanthanum(III)79 complexes of pdta or TPPN have been used to reduce the broadening that occurs at higher field strengths (400 MHz).

N

N

HOOC COOH

N

N

N

N

N

N

HOOC

COOH 61

8.28.3.2

62

Transition Metal Complexes

Palladium dimers of N,N-dimethyl-1-phenylethylamine or N,N-dimethyl-1-(1-naphthyl)ethylamine (63) are especially effective chiral NMR reagents for mono- and di-phosphines, arsines, bidentate aminophosphines, a- and b-amino acids, and diamines. The ligands are commercially available and the complexes are readily prepared and purified. Reaction of the substrate with the palladium dimer produces a monomeric palladium complex with a single amine ligand; thus, the cis- or trans-configuration of the original palladium dimer results in the same products. Since the products usually undergo slow exchange, resonances of the substrate or the initial palladium ligand can be monitored. The use of these reagents has been reviewed.80 The complex with

Spectroscopic Analysis: NMR and Shift Reagents

557

the naphthyl ligand is usually more effective than the one with the phenyl ligand. The palladium complex with a ligand that has a tert-butyl group on the carbon of the alkyl group (64) or an isopropyl group on the nitrogen atom (65) is even more effective than the naphthyl ligand in causing enantiomeric discrimination in the 31P NMR spectrum of phosphines.81

NMe2 Pd

Me2N

Cl Cl

Pd

cis

NMe2 Pd

Cl Cl

Pd Me2N

trans 63 But

H

N

H

Me

Me

N iPr H

Me Cl

Pd

Cl

Pd 2

2 65

64

The palladium complex with 2,2-dimethyl-4,5-bis(diphenylphosphinomethyl)-1,3-dioxolan (66) and a similar platinum complex with 1,2-bis[(diphenylphosphinomethyl)]benzene (67) are useful reagents for the analysis of alkenes, allenes, and alkynes. 67 is commercially available and the complex is readily synthesized. The substrate displaces the ethylene ligand and binds to the metal. Cyclic and acyclic alkenes can be examined. Enantiomeric discrimination is observed in the 31P NMR spectrum.82 A silver-containing reagent with an N,N0 -bis(mesitylmethyl)-1,2-diphenyl-1,2-ethanediamine ligand (68) or the corresponding cyclohexyl-1,2-diamine derivative can be prepared directly in an NMR tube by adding the amine ligand, silver triflate, and an alkene. Enantiomeric discrimination is observed in the 1H NMR spectra of alkenes with a stereocenter a to the double bond.83

O

Ph2

Ph2

P

P

M

Pt P

P

O

Ph2

Ph2

66

67

N N H Ag H

68

Platinum reagents either covalently bonded (69) or ion paired (70) with chiral amine ligands are effective for analyzing the enantiomeric purity of alkenes and allenes. The ethylene ligand in 69 and 70 is displaced by the substrate and enantiomeric discrimination is observed in the 195Pt NMR spectrum. A potential complication with 69 and 70 is that alkenes and allenes may bind at one of two prochiral faces. When enantiomeric discrimination occurs, two 195Pt signals are observed if binding involves only one prochiral face of the double bond. If binding occurs at both prochiral faces, four 195Pt signals are observed. Complexes with a variety of chiral amine ligands have been studied, some examples of which are 71 and 72. Some of the chiral amines are commercially available. Which ligand, and whether to use the covalent or ionic platinum reagents, depends on the substrate.

558

Spectroscopic Analysis: NMR and Shift Reagents

One advantage of the ionic complex is that bulkier amine ligands can be used. In some cases, the bulkier ligands produced larger enantiomeric discrimination. Comprehensive reviews of these platinum reagents and general recommendations for different compound classes have been provided.7,84 Ph Cl

HN Pt

Cl

–

Cl Pt

[AmH]

Cl

Cl 69

70

Me

NH

H Me

H N H 72

71

Rhodium(I) can form dimers with bridging carboxylate ligands. The rhodium dimer with MTPA [73 – Rh2(MTPA)4] is easily prepared and has been extensively studied as a chiral NMR discriminating agent. The use of Rh2(MTPA)4 has been thoroughly described in recent reviews.7,10,85 Although most studies have used Rh2(MTPA)4, the rhodium dimer with (S)-N-phthaloyl(S)-tert-leucine (74) was recently shown to provide larger enantiomeric discrimination. It was proposed that the aryl ring of the phthaloyl group in the rhodium dimer with 74 is positioned to cause favorable shielding of the substrate, thereby accounting for its effectiveness as a chiral NMR discriminating agent.86 The rhodium ions can expand their coordination number, allowing up to two substrate molecules to bind (Figure 6). The degree of enantiomeric discrimination exhibits a significant concentration dependence and reports using Rh2(MTPA)4 usually describe the best concentrations to use for a particular type of substrate. R O O R

O

Rh O

R R

O

O

+L

O Rh

O

O

−L O

R

R

O

Rh O

R O

O

+L

O Rh

O

R L

L −L

O

R

O

O

Rh O

R

O

O Rh

O

R L

O

R

Figure 6 Binding of substrate ligands to Rh2(MTPA)4.

Rhodium binds favorably to soft Lewis bases and Rh2(MTPA)4 is a broadly applicable chiral reagent for alkenes and substrates with sulfur, selenium, phosphorus, or iodine atoms. There are some substrates that have amide, ether, furan (75), puran (76), phosphoryl, and 2-oxo-2-ozazolidinone (77) functionalities that are categorized as hard Lewis bases that still bind to and exhibit enantiomeric discrimination in the presence of Rh2(MTPA)4.7,10,85 R R O O O H Rh Rh RO2 = MTPA O O HOOC O O tBu R R 73

O

O

N O 74 O

O

N

X

O O 75

O

76

77

Spectroscopic Analysis: NMR and Shift Reagents

8.28.4 8.28.4.1

559

Liquid Crystals Methods

Chiral liquid crystals have unprecedented versatility as reagents for determining enantiomeric purity by NMR spectroscopy, although their utility for assigning absolute configuration is quite limited in scope.7 Whereas chiral solvating agents, metal complexes, and chiral derivatizing agents depend on specific noncovalent or covalent interactions between the substrate and the chiral reagent, chiral liquid crystals do not participate in specific interactions with the substrate, Instead, they undergo a partial alignment or ordering when placed in a magnetic field. Molecules dissolved in the chiral liquid crystal also undergo a partial alignment, and if two enantiomers align differently, enantiomeric discrimination can be observed in the NMR spectrum. There are three ways in which the enantiomeric discrimination can be discerned. The first is the possibility that resonances of the two enantiomers will have different chemical shifts, which is comparable to what occurs with other chiral NMR shift reagents. This is often the least useful way of distinguishing enantiomers with chiral liquid crystals because the differences in chemical shifts between the enantiomers are usually small. The second is that 1H–1H and 1 H–13C dipolar-coupling constants differ for two enantiomers that are aligned differently in a magnetic field. In this case, the resonance of a nucleus that is split into a doublet will now appear as two doublets, one for each enantiomer. The area of each doublet is proportional to the amount of each enantiomer in solution. A difficulty with using the different dipolar-coupling constants is the complexity of the NMR spectra, although procedures to facilitate the measurement and interpretation of the 1 H and 13C NMR spectra in chiral liquid crystals have been developed.87,88 The third and most common way is to use differences in quadrupolar splitting of a quadrupolar nucleus-like deuterium. A 2H signal for molecules undergoing rapid tumbling exhibits no quadrupolar splitting. If the molecule is aligned relative to the applied magnetic field, the 2H signal now exhibits quadrupolar splitting and appears as a doublet. Since the magnitude of the quadrupolar splitting depends on the alignment, the signal for two enantiomers with different alignments will appear as two doublets, each with an area proportional to the concentration of the enantiomer. Natural abundance 2H NMR is complicated by overlap of the peaks in the spectrum, since the magnitude of the quadrupolar splitting is often larger than the differences in the chemical shifts of the nuclei. Also, the 2H nucleus has a low isotopic abundance. A number of procedures have been developed to facilitate the use of natural abundance 2H with chiral liquid crystals.89 A common procedure is to incorporate a deuterium-labeled group into the substrate through a derivatization reaction. Since the only purpose of the derivatizing agent is to provide an intense signal, an achiral derivatizing agent is used and there is no concern about kinetic resolution.

8.28.4.2

Applications

The most common chiral liquid crystal is poly(g-benzyl-L-glutamate) (PBLG), but poly(g-ethyl-L-glutamate) (PELG) and poly-e-carbobenzyloxy-L-lysine (PCBLL) have also been used and are sometimes more effective. All three of these liquid crystals are commercially available. Because the substrate does not need to have any specific, directed interaction with the liquid crystal, chiral liquid crystals can potentially discriminate any chiral molecule including organic and inorganic compounds as well as metal complexes. Signals of nuclei remote from the chiral center are often enantiomerically distinguished, since they are just as likely to have different alignments. Even chiral hydrocarbons such as the chiral invertomers of cis-decalin (2)90 and other aliphatic hydrocarbons91 can exhibit enantiomeric discrimination in chiral liquid crystals. NMR experiments with chiral liquid crystals are performed using a solvent such as methylene chloride, chloroform, or dimethylformamide. The solvent is chosen to solubilize the compound under study. The extensive variety of NMR applications of chiral liquid crystals has been described in recent reviews.7,10 Liquid crystals have mostly been used to determine the enantiomeric purity of substrates. If a series of similar compounds align the same way in the liquid crystal, there is a potential to assign the absolute configuration of an unknown based on trends for compounds with known configurations. This has been demonstrated with a series of isostructural epoxides.92 Also, the 4-pro-(R)/pro-(S) and 5-pro-(R)/pro-(S) positions in monodeuterated derivatives of 1,10 -bis(thiophenyl)hexane (78) are distinguishable in liquid crystals. Using the data for compounds with known configurations, it was possible to determine both the 2 H/1H ratio and assign the absolute configuration of each 2H signal in the methylene groups of similar fatty acids. In recent work, the distinction of the pro-(R) and pro-(S) positions in fatty acids was better using pyridine as a solvent instead of chloroform.93

8.28.4.3

Residual Dipolar-Coupling Constants and Assigning Absolute Configuration

One final way in which liquid crystals can potentially be used to assign absolute configuration is through the use of residual dipolar-coupling constants (RDCs). RDCs can be measured for aligned molecules and, in theory, the different RDCs for the (R)- and (S)-enantiomers can be related back to its absolute configuration. The method has been used to assign the diastereotopic methylene protons in strychnine (79).94 Successful utilization of RDCs for assigning absolute configuration will likely require better orienting media that do not cause as high a degree of alignment as occurs in PBLG. A recent report has described the advantages of polyguanidines over PBLG as alignment media for measuring RDCs.95 Alignment media that have been developed are summarized in a recent review96 as has the use of RDCs for configurational and conformational analysis.97

560

Spectroscopic Analysis: NMR and Shift Reagents

D

H SPh

SPh SPh H

SPh

H

D

SPh

D

H

D SPh

SPh SPh

78 N 20

HH N

H

H O

H

O

79

8.28.5 8.28.5.1

Chiral Derivatizing Agents Aryl-Containing Carboxylic Acids

The utilization of MTPA (80 – MTPA), commonly referred to as the Mosher reagent, as a chiral derivatizing agent for assigning the absolute configuration of secondary alcohols was a significant development in the field of chiral discrimination by NMR spectroscopy.6 The general strategy that allows MTPA to be used to assign the absolute configuration of secondary alcohols and certain other types of compounds has been exploited in many subsequent chiral reagents. Provided that the derivative has a preferred conformation that occurs independent of the substituent groups on the substrate, the effects of shielding by the phenyl ring of MTPA can be used to assign the absolute configuration. Derivatives are prepared with (R)- and (S)-MTPA and the signs of the DdRS values for the substituent groups of the substrate are calculated. The preferred syn-periplanar conformation of MTPA derivatives of secondary alcohols is illustrated in Figure 7. In the derivative with (R)-MTPA, the resonances of L1 are shielded by the phenyl ring, whereas in the derivative with (S)-MTPA, the resonances of L2 are shielded. The DdRS values are therefore negative for L1 and positive for L2.

(OMe) (Ph) Ph OMe

L1

(R)-MTPA (S)-MTPA

O

L2

CF3 H

O

Figure 7 Conformational model for the (R)- and (S)-MTPA derivatives of a secondary alcohol.

The larger the DdRS values and the more resonances one can assign for the substrate, the better. The so-called modified Mosher method makes use of higher fields and two-dimensional NMR methods to assign more 1H resonances of L1 and L2 to more reliably assign the absolute configuration.98 It is also possible to use DdRS values of the 13C resonances of the substituent groups to aid in the assignment.99 In addition to secondary alcohols, MTPA can potentially be used to assign the absolute configuration of primary and tertiary alcohols, primary and secondary amines, and thiols. The magnitude of the DdRS values depends on the population of the preferred conformer of the derivative and the extent of shielding from the aromatic ring. Many other aryl-containing carboxylic acids have been examined for their effectiveness as chiral derivatizing agents for the same categories of compounds. Among the most notable of these are a-methoxyphenylacetic acid (81 – MPA), a-cyano-a-fluoro-p-tolylacetic acid (82 – CFTA), 2-methoxy-2(1-naphthyl)propionic acid (83 – MaNP), and a-(9-anthryl)-a-methoxyacetic acid (84 – 9-AMA). All but the 9-AMA are commercially available in both the (R)- and the (S)-isomer. MaNP and 9-AMA have larger naphthyl and anthryl rings, respectively, that cause larger shielding than the phenyl-containing reagents. MPA and CFTA exhibit higher conformational populations for certain classes of substrates that cause larger DdRS values. The utilization of aryl-containing carboxylic acids for assigning absolute configuration has been described in recent reviews.7–10

Spectroscopic Analysis: NMR and Shift Reagents

F OMe F3C COOH MeO

80

82 MeO

83

COOH

COOH CN

COOH

81

OMe COOH

561

COOH

84 tBu

H N

COOH COOH tBuO

MeO

85

86

87

For secondary alcohols, DdRS values with MPA, 9-AMA, MaNP, and CFTA are often significantly larger than those with MTPA.7 The utility of MaNP for secondary alcohols has been reviewed.100 The utility of MPA for assigning the absolute configuration of secondary alcohols has been widely studied.7,8 Adding Ba(II)101 or lowering the temperature102 of MPA derivatives of secondary alcohols causes a change in the conformational preference that leads to specific trends in shielding that can be used to confirm the assignment. The absence of a hydrogen atom on the stereogenic carbon of MaNP and CFTA reduces the possibility of configurational loss in the derivatization step. The infrared spectra of CFTA esters have two peaks for the carbonyl band that correspond to the two most favorable conformations. This makes it possible to confirm that the preferred conformer needed for reliably using DdRS values actually occurs with CFTA derivatives of secondary alcohols.103 Studies of primary alcohols with aryl-containing carboxylic acids are limited in scope. In a comparative study, 9-AMA was more effective for assigning the absolute configuration of C2-chiral primary alcohols than MTPA or MPA. A greater conformational preference and larger shielding from the anthryl ring yielded better results with 9-AMA. The configurational assignment of primary alcohols with 9-AMA can be further confirmed by monitoring changes in the DdRS values on changing the temperature from 300 to 213 K.104 For tertiary alcohols, a-methoxy-a-(2-naphthyl)acetic acid (85) produced larger DdRS values than MTPA or MPA, although substantial racemization occurred in the derivatization step such that the diastereomeric derivatives had to be separated before the NMR analysis.105 Aryl-containing carboxylic acids such as MTPA, MPA, N-boc phenylglycine (86 – BPG), and CFTA react to form amides with primary amines. Of these reagents, BPG, which is commercially available as both pure enantiomers, produced DdRS values that were two to three times larger than those with MTPA or MPA.106 9-AMA is relatively ineffective for primary amines because the preferred conformer has the anthryl ring in an unfavorable position for shielding of the substituent groups of the substrate.107 For secondary amines, the amide derivatives with MTPA produce especially large DdRS values. The analysis is more complicated than that of alcohols or primary amines because two amide rotamers occur. A detailed analysis has provided a set of conformational rules that can be reliably used to assign the absolute configuration of the secondary amine in MTPA amide derivatives.108 A comparative study of the utility of MPA, MTPA, BPG, 9-AMA, and 2-tert-butoxy-2-(2-naphthyl)acetic acid (87) for assigning the absolute configuration of secondary thiols has been reported. The highest DdRS values were observed with 87, although this reagent is not commercially available. The derivatives with MPA had the next highest DdRS values.109 Aryl-containing carboxylic acids can also be used to assign the configurations of diols, polyols, and amino alcohols. If the hydroxyl or amine groups are apart from each other far enough, the configuration of each stereocenter is assigned using the same criteria for monofunctional substrates. If the groups are close together as in 1,2-diols or 1,2-amino alcohols, the two derivatizing groups may both affect a particular hydrogen atom, which complicates the configurational assignment. A thorough analysis of the bis-MPA esters of 1,2-, 1,3-, 1,4-, and 1,5-diols showed that there are specific trends in the DdRS values that can be used to assign the absolute configuration.110 For anti-1,2-diols, lowering the sample temperature from 298 to

562

Spectroscopic Analysis: NMR and Shift Reagents

183 K causes specific perturbations in the chemical shift that can be used to confirm the assignment.111 The bis-9-AMA derivatives of 1,2-primary,secondary diols also have specific trends that correlate with the absolute configuration and the DdRS values with 9-AMA are larger than those with MPA. Using only the (R)- or the (S)-9-AMA derivative, the chemical shift of the Ca-H resonance exhibits a specific behavior as the temperature is lowered from 298 to 183 K that can be used to confirm the assignment.110,112 Tris-MPA esters of 1,2,3-primary, secondary, secondary triols show specific trends for the H2 and H3 resonances that correlate with absolute configuration.113 Similarly, the bis-MPA derivatives of secondary, primary and primary, secondary-1,2-amino alcohols show trends for the Ca-H and methoxy resonances of the MPA moiety that correlate with absolute configuration. The Ca-H resonance also exhibits specific behavior as the temperature is lowered from 298 to 183 K that can be used to confirm the assignment.114 The absolute configuration of sulfoxides can be determined using MPA. The sulfoxide is converted into a sulfoximine that is then reacted with MPA (Figure 8). The assignment of the configuration is based on the DdRS values. Shielding from the phenyl ring in the MPA derivative is greater than that with MTPA because of a higher preference for the desired rotamer. The absolute configuration of alkyl, phenyl alkyl, and cyclic sulfoxides as well as sulfoxides with nitrogen and oxygen-containing functional groups can be assigned.115

O

O S

R1

NH2

O

R2

R1

S R2

NH

(S)-MPA

S

(S)-MPA

O−

N

R1

R2

O

N

S

R1

R2

(R)-MPA

(R)-MPA

S R1

R2

Figure 8 Reaction sequence for the analysis of absolute configurations of sulfoxides using MPA.

8.28.5.2

Other Carboxylic Acid-Based Reagents

2-(Anthracene-2,3-dicarboximido)cyclohexane carboxylic acid (88), which is commercially available as both the (1R,2R)- and the (1S,2S)-isomers, is effective for examining primary and secondary alcohols with remotely disposed chiral centers. The derivative positions the carbon chain of the substrate over the anthryl ring as shown in Figure 9 for a primary alcohol. The resonances of primary alcohols exhibit enantiomeric discrimination as far as the C9 group. The secondary alcohol with a chiral carbon at C16 and alkyl groups that differ by one carbon shows enantiomeric discrimination. The perturbations of the chemical shifts in the derivatives correlate with absolute configuration for both primary and secondary alcohols.116

O

O N O

∗

O Figure 9 Shielding by the anthryl ring in derivatives of primary alcohols with (1R,2R)-2-(anthracene-2,3-dicarboximido)cyclohexane carboxylic acid.

Camphanic acid (89), which is commercially available as both pure enantiomers, is especially effective for distinguishing the pro-(R) and pro-(S) prochiral methylene hydrogen atoms of a-deuterated primary alcohols117 and a-deuterated or tritiated primary amines.118,119 The stereoselectivity of enzyme-catalyzed deuterium substitution in glucose, galactose, and mannitol was analyzed using derivatives with camphanic acid.117 Menthoxy acetic acid (90), which is commercially available as both pure enantiomers, has been used to assign the absolute configuration of diols formed from the epoxidation of polycyclic hydrocarbons, one example of which is 91. Derivatization with MTPA or MPA led to a mixture of products, whereas reaction with 90 provided the desired bis-esters.120 2,2-Diphenyl-[1,3]-dioxolane-4,5-dicarboxylic acid (92) and the corresponding di-2-naphthyl reagent can be used to assign the absolute configuration of a-chiral primary amines. The reagent is prepared from dimethyl tartrate. Shielding from the aryl rings produces DdRS values of specific signs that can be used to assign the absolute configuration. The DdRS values

Spectroscopic Analysis: NMR and Shift Reagents

563

with the 2-naphthyl analog of 92 are larger than the phenyl derivative and substantially larger than observed with MTPA or MPA.121 O

O O

N O HOOC

COOH 89

88

O

COOH OH OH 91

90

O

O O

O OH HO 92

8.28.5.3

Amine-Containing Reagents

The utilization of enantiomerically pure aryl-containing carboxylic acids as chiral derivatizing agents for assigning the absolute configuration of alcohols and amines was described in Section 8.28.5.1. Enantiomerically pure aryl-containing amines and alcohols can likewise be used in a similar strategy to assign the absolute configuration of carboxylic acids. Among the amines that have been studied, commercially available phenyl glycine methyl ester (93 – PGME) is especially effective for assigning the absolute configuration of carboxylic acids.122 The utilization of PGME has been reviewed.7,98 Figure 10 shows the preferred conformation for PGME amides that leads to predictable signs for the DdRS values of the L1 and L2 substituents.7,98,122

O L1

(H) Ph

(Ph) H

(R) (S) OMe

N

L2 H

H

O

Figure 10 Conformational model of the (R)- and (S)-PGME amide derivatives of a-chiral carboxylic acids.

The utilization of PEA (28), NEA (29), and AEA (30) as chiral solvating agents was described in Section 8.28.2.2.2. These same reagents are also effective chiral derivatizing agents for assigning the absolute configuration of carboxylic acids.123,124 The anthryl ring of AEA produces larger DdRS values than NEA and PEA, although AEA is only commercially available as the (R)-isomer. The absolute configuration of 3-methyl substituted carboxylic acids,123 carboxylic acids with other substituents at the 3-position,124 and 2-(2-oxo-3-indolyl)acetic acids (94),125 which are also chiral at the b-position, have been assigned using amide derivatives with NEA or PEA. These amide derivatives have major and minor rotamers that need to be taken into account when performing the analysis. 3-Substituted cyclohexanones and cyclopentanones react with 1,2-diphenyl-1,2-diaminoethane (95), which is commercially available as both the (1R,2R)- and the (1S,2S)-isomers, to produce the aminal derivative (96). The enantiomeric purity of the

564

Spectroscopic Analysis: NMR and Shift Reagents

ketone can be determined by examining enantiomeric discrimination in the acyclic ketones and enones.126

13

C NMR spectrum. This system did not work with

Ph

O H2N

R2

OMe

HN COOH H2N N

93

NH

NH2

O

R1

8.28.5.4

Ph

Ph

R

n 96

Ph 95

94

Hydroxyl-Containing Reagents

(þ)-Octahydro-8,9,9-trimethyl-5,8-methano-2H-1-benzopuran-2-ol (97), which is commonly known as Noe’s reagent, is commercially available and can be used to assign the absolute configuration of secondary alcohols, amines, and thiols that have a bulky (b) and planar or a linear (pl) substituent group. The derivatization reaction shown in Figure 11 for an alcohol leads to a product in which the oxygen atom and the s orbital of the Csp3–Csp2 bond have a stabilizing interaction. Resonances in the 1H and 13C NMR spectra show behavior that correlates with the absolute configuration. The same rules that work for alcohols also work for assigning the absolute configurations of amines and thiols.127

HO

b

H pl

O

O

H H

+

bb pl

OH

O

HO pl

H

b H

O

O

H pl

b H

Figure 11 Acetal derivatives formed by the reaction of the two configurations of a secondary alcohol with Noe’s reagent.

2-(Anthracene-2,3-dicarboximido)cyclohexanol (98) is effective for analyzing the enantiomeric purity of carboxylic acids with remotely disposed chiral centers. Enantiomeric discrimination occurs for the methyl resonance in the derivative of 12-methyl pentadecanoic acid with 98. The derivative positions the carbon chain of the substrate over the anthryl ring.128 Among alcohol reagents, ethyl-2-(9-anthryl)-2-hydroxyacetate (99 – 9-AHA)129 and TFAE (18)130 are noteworthy for assigning the absolute configuration of carboxylic acids. The ester derivatives of 9-AHA and TFAE ester derivatives adopt preferred conformations and shielding by the anthryl rings that allows DdRS values to be reliably used for assigning the stereochemistry. Methyl mandelate (100), which is commercially available in both enantiomers, is noteworthy for its use in distinguishing the pro-(R) and pro(S) hydrogen atoms in a-deuterated carboxylic acids. The derivatives of a-chiral carboxylic acids with 100 adopt a preferred conformation such that shielding from the phenyl ring can be used to assign the absolute configuration.131,132 Enantiomerically pure (R)-()-butane-2,3-diol or butane-2,3-thiol reacts with ketones to produce a ketal or a thioketal, respectively, as shown in Figure 12 for butane diol. Comparative studies show that larger enantiomeric discrimination usually occurs with butane-2,3-thiol than butane-2,3-diol, although the butane-2,3-thiol is not commercially available.133 The ketal

O

OH O

+ R

O

OH R

Figure 12 Reaction of butane-2,3-diol with a 3-substituted cyclohexanone to form the ketal derivative.

Spectroscopic Analysis: NMR and Shift Reagents

565

derivatives of cyclohexanones with a preference for the chair conformation, acyclic ketones, cyclopentanones, and exhibit trends in the 13C spectra that correlate with the absolute configuration.134 O N OH O

O 97

HO

98 O

O

HO

HO OEt

OMe

H Ph

OH

I 99

101

100

The absolute configuration of phosphates or thiophosphates that are chiral by virtue of differences in the oxygen isotopes can be analyzed using reagents such as propane-1,2-diol135 and (S)-2-iodo-1-phenylethanol (101),136 although only propane-1,2-diol is commercially available. The reagents are especially useful for determining whether the phosphate configuration has been retained or inverted in reaction sequences. The distinction is based on the positioning of the 16O, 17O, or 18O atoms in the derivatives as the chemical shift of the 31P resonance varies depending on whether specific isotopes are in a bridging or a terminal position. Figure 13 shows the cyclic diesters that result when propane-1,2-diol is reacted with [16O,17O,18O]phosphate monoester. The methyl and methoxy groups in the products have syn and anti-orientations in the two configurations and differential perturbations of the 31P signal depending on whether the 18O atom is in the methoxy or the P¼O group are used to assign the configuration. Figure 14 shows the cyclic products that are obtained when (S)-2-iodo-1-phenylethanol is used. ∅CH3

O P

O

∅

O P

O

OCH3

O

∅CH3

O P

O

∅

O P

O

OCH3

O

OCH3

O

O

O

P

O

P

O

∅ ∅ = 17O

∅CH3

= 18O

Figure 13 Cyclic diesters derived by the cyclization reaction of propane-1,2-diol with [16O,17O,18O]phosphate monoester.

Ph

H

H

H

O P

Ph

Ph

O

P

Me

S

H

O S

Ø

Ph

O P

OMe

S

ØMe

O S P

Ø

Ph

H

O P S

OMe

Ph

H

O P S

ØMe O

Ph

H

O

Me P

S

Ø

Figure 14 Cyclic thiophosphate esters derived by the cyclization reaction of (S)-2-iodo-1-phenylethanol with [16O,17O,18O]thiophosphate.

566

Spectroscopic Analysis: NMR and Shift Reagents

8.28.5.5

Phosphorus-Containing Reagents

A variety of phosphorus-containing compounds have been used as chiral NMR derivatizing agents as described in comprehensive reviews.7,137 Most have a P–Cl bond that reacts with substrates containing alcohol, amine, carboxylic acid, and epoxide moieties. The reagents are often used in their P(III) form and the reactions can usually be performed directly in an NMR tube. They can then be converted to the corresponding P(V) species by the addition of elemental sulfur7 or selenium.138 The single 31P signal is often monitored and used to determine enantiomeric purity. The enantiomeric discrimination is often larger with the P(III) form of these reagents, but the P(V) forms are usually more stable. Common phosphorus-containing reagents consist of either diazaphospholidines (102) or 1,3,2-dioxaphospholanes (103) that are prepared by reacting enantiomerically pure diamines or diols, respectively, with phosphorus trichloride. Compounds 26 and 104–107 illustrate only some of the many diamines and diols that have been examined. Some of the diamines and diols are commercially available. The enantiomeric purity of primary, secondary, and tertiary alcohols, primary amines, thiols, and carboxylic acids can be analyzed using 102 and 103.7 Epoxides react with 103 to open the ring and form the corresponding phosphorus-ethoxide. The analysis of unsymmetrical epoxides is more complicated because two regioisomers form in the reaction, but the preferred products can be predicted based on known trends for electrophillic additions.139

Cl

Cl R1

P N

N

NH

P

R1

O

O NH

R2

R1

R2

R2 103

102

104 OR

N

HO

NH

HO

O

O

O

O

HO

NH

HO OR R = Et, iPr

105

8.28.5.6

N

106

107

Selenium-Containing Reagents

4-Methyl-5-phenyloxazolidine-2-selone (108) can be used to analyze the enantiomeric purity of secondary alcohols, primary amines, carboxylic acids, and alkyl halides, as summarized in recent reviews.7,140 The singlet in the 77Se NMR spectrum is conveniently monitored and the large dispersion of chemical shifts in the 77Se NMR spectrum makes 108 especially useful for analyzing compounds with remotely disposed chiral centers. Alcohols and alkyl halides react at the selenium atom of 108 to produce the corresponding selenide derivative as shown in Figure 15. This is one of the few reagents available for determining the enantiomeric purity of alkyl halides.141 Amines react to form the corresponding carbamoyl derivative (109). An intramolecular hydrogen bond stabilizes the anti-carbonyl arrangement in the carbamoyl derivative and compounds such as 4-phenyl-1-aminopentane with a remote chiral center exhibit enantiomeric discrimination in the 77Se NMR spectrum. Carboxylic acids react at the NH group of 108 to form an amide. The derivatives with 5-methylheptanoic acid and lipoic acid (110), both of which have remote chiral centers, exhibit enantiomeric discrimination in the 77Se NMR spectrum.

Se HN

Se O

R-Br

N

Ph Figure 15 Reaction of an alkyl halide with 4-methyl-5-phenyloxazolidine-2-selone.

R O Ph

Spectroscopic Analysis: NMR and Shift Reagents

567

H Ph

Se HN

N N

O

O

Se O

S

COOH

S Me 109

Ph 108

8.28.5.7

H

Ph

110

Boron-Containing Reagents

A variety of boron-containing reagents have been examined as chiral NMR derivatizing agents.7 2-Formylphenylboronic acid (111), which is commercially available, reacts with an amine and diol to form a borate-imine as shown in Figure 16. The figure illustrates a reaction using enantiomerically pure PEA (28) in a strategy used to determine the enantiomeric purity of the diol.142 An alternative is to use an enantiomerically pure diol such as BINOL (26) to determine the enantiomeric purity of a primary amine.143 This system has been used to determine the enantiomeric purity of b-chiral primary amines and compounds such as 112 and 113 that have remote chiral centers. A detailed protocol for the use of this system has been published.144

H R1 n

HO OH OH

CHO

+ R1

H

N

H

R2

OH

B

N O B O

+

+

H

R2

n

NH2 H R1 n

O B O

R2 Figure 16 Borate–imine complex formed by the reaction of a diol, 2-formylphenylboronic acid, and 1-phenylethylamine.

2-(1-Methoxyethyl)phenylboronic acid reacts with 1,2-diols as shown in Figure 17. The enantiomeric purity of anti-1,2-diols, 1,3-diols, 2-hydroxyacids, and 2-amino alcohols can be analyzed with this reagent.145 For cis-1,2-diols, the methoxy resonance shows a consistent trend that correlates with the absolute configuration.146

HO

OH

OH B

O

OMe B

R2 +

R1

R1

O

R2

OMe

OH Figure 17 Reaction of a 1,2-diol with 2-(1-methoxyethyl)phenylboronic acid.

HO

OH B

NH2

H O O MeO 111

NH3Cl 112

113

568

Spectroscopic Analysis: NMR and Shift Reagents

8.28.5.8

Miscellaneous Reagents

The absolute configuration of vinyl ethers (114) can be assigned in a procedure using 1-phenylethyl isocyanate or 1-(1-naphthyl)ethyl isocyanate (115), both of which are commercially available in an enantiomerically pure form. Under high pressure, the ether undergoes a [2 þ 2] cycloaddition with the isocyanate to form the corresponding azetidinone (116). Specific shielding by the phenyl or naphthyl ring is used in making the assignment.147 The enantiomeric purity and absolute configuration of alkenes can be analyzed using a scheme with 20 -methoxy-1, 10 -binaphthalene-2-carbohydroxymoyl chloride (117). The reaction of the alkene with 117 forms the corresponding 4,5-dihydroisoxazole derivative (118). For alkenes such as a- and b-pinene that are sterically hindered, the reaction occurs at the less hindered side of the double bond. The preferred conformation of the binaphthyl ring in the derivative causes specific shielding effects. A combination of the shielding and NOE connectivities is used to assign the absolute configuration of the alkene.148 O C N

Ar O N

OR Ar = Ph or Napht

RO

114

115

116

CH3

OMe Cl N

OH

X

8.28.6

Y HA

O 117

CH3

N 118

HB

Ar 119

Database Methods for Compounds with Multiple Stereocenters

The utilization of a database method with DMBA (34) to assign the absolute configuration of polyol motifs was described in Section 8.28.2.2.2. Other similar database techniques have been developed to assign the absolute configuration of structural motifs with two or more stereocenters.149–152 The general strategy is to examine some aspect of the NMR data for all of the configurations of a particular motif. These data are used to generate a set of patterns. The same data are recorded for an unknown and the pattern that matches best identifies the configuration. One example is to subtract the chemical shift of a particular 1H or 13 C atom from the average of all the possible stereoisomers.149 Another is to use patterns of 3JH–H coupling constants.151 A statistical method based on 13C NMR data that does not necessitate the preparation of all possible stereoisomers has also been described.150 The relative syn- or anti-configuration of 1,3,n-methyl branched deoxypropionates (119) can be assigned by examining the difference in the chemical shift between the two diastereotopic methylene hydrogen atoms (HA and HB in 119). An analysis of over 80 compounds with the deoxypropionate motif showed that the chemical shift of the two methylene hydrogen atoms is quite distinct in the syn-configuration (40.4 ppm) and quite close in the anti-configuration (o0.1 ppm).152

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Spectroscopic Analysis: NMR and Shift Reagents

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87. 88. 89. 90. 91. 92. 93. 94. 95. 96. 97. 98. 99. 100. 101. 102. 103. 104. 105. 106. 107. 108. 109. 110. 111. 112. 113. 114. 115. 116. 117. 118. 119. 120. 121. 122. 123. 124. 125. 126. 127. 128. 129. 130. 131. 132. 133. 134. 135. 136. 137. 138. 139. 140. 141. 142. 143. 144. 145. 146. 147. 148. 149. 150. 151. 152.

Spectroscopic Analysis: NMR and Shift Reagents

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