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Diamagnetic lanthanide tris β-diketonate complexes with aryl-containing ligands as chiral NMR discriminating agents
Tetrahedron: Asymmetry 24 (2013) 297–304
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Diamagnetic lanthanide tris b-diketonate complexes with aryl-containing ligands as chiral NMR discriminating agents Rebecca L. Clark, Bradford T. Wenzel, Thomas J. Wenzel ⇑ Department of Chemistry, Bates College, Lewiston, ME 04240, USA
a r t i c l e
i n f o
Article history: Received 25 December 2012 Accepted 29 January 2013 Available online 28 February 2013
a b s t r a c t Diamagnetic lanthanum(III) and lutetium(III) tris b-diketonate complexes with the aryl-containing ligands 3-benzoyl-(+)-camphor and 3-(2-naphthoyl)-(+)-camphor are effective organic-soluble chiral NMR discriminating agents for oxygen- and nitrogen-containing compounds. Enantiomeric discrimination of sufficient magnitude to determine the enantiomeric purity is observed in the 1H NMR spectra of compounds with hydroxyl, carbonyl, oxazolidinone, amine, and sulfoxide groups. Diamagnetic lanthanide complexes with the aryl-containing b-diketonate ligands are almost always more effective than those with 3-trifluoroacetyl-(+)-camphor, 3-heptafluorobutyryl-(+)-camphor, and d,d-dicampholylmethane that have been previously reported. Many hydrogen atoms of the substrates are significantly shielded in the presence of the lanthanide chelates with the aryl-containing ligands, which likely enhances the extent of enantiomeric discrimination in the NMR spectra. No combination of metal and ligand is most effective for all substrates. Larger enantiomeric discrimination is usually observed in benzene-d6 or cyclohexane-d12 than in chloroform-d. Diamagnetic lanthanide tris b-diketonates with the aryl-containing ligands provide an alternative to paramagnetic chelates that often cause too much broadening in the 1H NMR spectrum. Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction Paramagnetic lanthanide tris b-diketonate complexes with the ligands 3-(trifluoroacetyl)-(+)-camphor (tfc—1),1 3-(heptafluorobutyryl)-(+)-camphor (hfc—2),2 and d,d-dicampholylmethane (dcm—3)3 (Fig. 1) are among the earliest reagents used to determine the enantiomeric purity of chiral compounds by NMR spectroscopy. The lanthanide ion in these organic-soluble complexes is a hard Lewis acid that forms donor–acceptor complexes with hard Lewis bases, primarily oxygen- or nitrogen-containing compounds. The paramagnetism of a lanthanide ion, such as europium(III), causes substantial perturbations in the chemical shifts of resonances of the bound donor molecules, which greatly enhances the degree of enantiomeric discrimination in the NMR spectrum. Since many compounds contain oxygen or nitrogen atoms, chiral lanthanide tris b-diketonates are exceptionally versatile and applicable reagents for NMR studies of chiral compounds.4–6 However, the paramagnetism that was an advantage when chiral lanthanide reagents were first reported on and relatively lowfield NMR spectrometers were available (200 MHz or less) is often a detriment on the high-field instruments available today. In addition to perturbing the chemical shifts, the paramagnetism causes
⇑ Corresponding author. Tel.: +1 207 786 6296; fax: +1 207 786 8336. E-mail address: [email protected] (T.J. Wenzel). 0957-4166/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tetasy.2013.01.021
line broadening that is enhanced at higher field strengths. The broadening of the resonances in the presence of paramagnetic lanthanide tris b-diketonates obscures the enantiomeric discrimination in the spectra of many compounds. We have previously shown that complexes of diamagnetic lanthanum(III) and lutetium(III) with 1–3 are effective chiral NMR shift reagents for certain oxygen- and nitrogen-containing compounds.7 Complexation of the donor with the diamagnetic lanthanide ion caused slight perturbations in the chemical shifts of the resonances of the donor and, in some cases, a slight enantiomeric discrimination. There was no consistent pattern of which diamagnetic metal with which ligand was most effective. There was a significant solvent effect and better enantiomeric discrimination was often observed in benzene-d6 or cyclohexane-d12 compared to chloroform-d.7 A common strategy used to enhance the effectiveness of many chiral NMR derivatizing and solvent agents is to incorporate aryl rings into the reagent.5,8,9 If atoms of the compound being analyzed are positioned over the aryl ring, the ring anisotropy causes significant shielding of these atoms and perturbs their resonances to lower frequencies. The classic Mosher reagent (a-methoxy-atrifluoromethylphenylacetic acid—MTPA)10 and Pirkle’s alcohol (2,2,2-trifluoro-1-(9-anthryl)ethanol)11 owe their utility as chiral NMR discriminating agents to the presence of the aryl ring. We reasoned that diamagnetic lanthanide complexes with chiral bdiketonate ligands that contain aryl groups would likely be more
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CF3
CF2 CF2 CF3
O
1
O
O
O
O
2
OH
O
OH
O
4
3
5
O
Figure 1. b-Diketone ligands in the La(III) and Lu(III) complexes.
examined with La(bc)3, Lu(bc)3, La(2np)3, and Lu(2np)3. In addition, the NMR spectrum of each combination of lanthanide chelate and substrate was recorded in chloroform-d, benzene-d6, and cyclohexane-d12. Table 1 provides the enantiomeric discrimination, which refers to the separation of the resonances for the (R)- and (S)-enantiomers and is designated as DDd, observed in the 1H NMR spectrum of each substrate with the La(III) and Lu(III) chelates of 4 and 5. Values in Table 1 represent the best combination of lanthanide complex and solvent. Enantiomeric discrimination is observed in the spectra of 15 of the 19 substrates with the chelates of 4 and 5. Many of the aliphatic resonances of the substrates exhibit enantiomeric discrimination in the presence of the chelates of 4 and 5. In a few cases, enantiomeric discrimination of the aromatic
effective chiral NMR shift reagents than complexes with 1–3. Studies of the La(III) and Lu(III) complexes with 3-benzoyl-(+)-camphor (bc—4) and 3-(2-naphthoyl)-(+)-camphor (2np—5) (Fig. 1) with a range of oxygen- and nitrogen-containing compounds (Fig. 2) are reported herein. 2. Results and discussion Nineteen substrates that span a range of functional groups and include compounds with hydroxyl 6–12, carbonyl 13, 14, oxazolidinone 15, epoxide 17, carboxylic acid 18, amine 19–21, and sulfoxide 22–24 groups were studied. The substrates also incorporate acyclic aliphatic, cyclic aliphatic, alkene, and aromatic substituent groups. Substrates 12 and 16 are bifunctional. Each substrate was
OH
OH
7
2
6
3 5
6
OH
OH B,B'
4
7
8
OH
10
9
O
O
OH
Ho
B,B' Hm
OH
Hp
A
14
13
12
11
A
OH
8
4
H N
O
O
5
15
OH
NH2 OH O
O
O 17
16
19
18
NH2
O S
NH2
Ho Hm
O
O
S
S
HB HC HA
20
21
22 Figure 2. Structures of the substrates.
23
24
299
R. L. Clark et al. / Tetrahedron: Asymmetry 24 (2013) 297–304 Table 1 Enantiomeric discrimination (DDd) in ppm in the 1H NMR spectrum (400 MHz, 23 °C) of substrates (0.025 M) in the presence of the most effective combination of diamagnetic lanthanide chelate (0.025 M) and solvent Substrate
Resonance
DDd
Complex
Solvent
Chelates with 1–37
6
H2 H4 H5 H8 CH CH3
0.021 0.032 0.039 0.046 0.032 0.042
Lu(2np)3 Lu(bc)3 Lu(2np)3 Lu(bc)3 Lu(bc)3 La(2np)3
C6D6 C6D12 C6D12 CDCl3 C6D12 C6D12
0 0 0 0 0.003 0
7
CH CH3
0.033 0.008
La(2np)3 Lu(bc)3
C6D12 C6D12
0 0
8
1-CH3 4-CH3
0.004 0.018
La(bc)3 La(2np)3
C6D12 C6D12
0 0
9
CH3 –CHOH –C@CH–
0.036 0.048 0.029
La(2np)3 La(2np)3 La(2np)3
C6D12 C6D12 C6D12
0 0 0
10
CH3—A CH3—B CH3—B0
0.018 0.017 0.011
Lu(bc)3 Lu(bc)3 Lu(bc)3
C6D12 C6D12 C6D12
0 0 0
11
CH3
0.004
Lu(bc)3
C6D6
0
12
CH
13
CH3
0.007
La(2np)3
C6D12
0
14
CH3—A CH3—B
0.004 0.003
La(2np)3 La(2np)3
C6D12 C6D12
0 0
15
Ho Hm NH CH2 CH02 H4 H5 H50
0.029 0.016 0.118 0.190 0.071 0.070 0.073 0.020
Lu(bc)3 Lu(2np)3 Lu(bc)3 Lu(2np)3 Lu(2np)3 Lu(2np)3 Lu(2np)3 Lu(2np)3
CDCl3 C6D6 CDCl3 C6D6 CDCl3 CDCl3 C6D6 C6D6
0 0 0.075 0 0 0.044 0.021 0
17
CH
19
CH CH3
0.016 0.015
La(2np)3 La(2np)3
C6D12 C6D12
0 0.011
20
1-CH3 8-CH3
0.011 0.008
Lu(bc)3 Lu(2np)3
C6D6 C6D6
0 0
21
CH3
0.018
La(2np)3
C6D12
0
22
CH3
0.048
Lu(2np)3
C6D6
0.009
23
Ho Hm Ph-CH3 S(O)-CH3
0.016 0.010 0.013 0.040
La(bc)3 La(bc)3 La(bc)3 Lu(2np)3
C6D6 C6D6 C6D6 C6D6
0 0.006 0 0.009
24
HA HB HC
0.041 0.041 0.031
Lu(bc)3 Lu(bc)3 Lu(2np)3
C6D6 C6D6 C6D6
0.042 0.010 0.010
0
0.020
0
resonances is observed as well. However, for many substrates, aromatic resonances of the ligands in the lanthanide complexes of 4 and 5 interfere with those of the substrate and prevent a determination of whether enantiomeric discrimination is present. Enantiomeric discrimination observed in the spectra of the substrates with the La(III) and Lu(III) chelates with 1–3 are also provided in Table 1. The La(III) and Lu(III) complexes with 4 and 5 produce enantiomeric discrimination of many more resonances and in a wider range of substrates than observed with the complexes of 1–3. For resonances where complexes with 1–3 produce enantiomeric discrimination, the values observed with the complexes of 4 and 5 are almost always larger. The only exceptions are the enantiomeric discrimination of the methine resonances of 12 and 17 with complexes of 1–3. The two bifunctional compounds 12 and 16 did not show enantiomeric discrimination with the La(III) and Lu(III) chelates of 4 and 5. The 1H NMR spectrum of 12 is severely broadened with
0.005
the chelates of 4 and 5. The 1H NMR spectrum of 16 is severely broadened with the La(III) chelates of 4 and 5 but not with the Lu(III) chelates. Prior studies have shown that bifunctional compounds such as 12 and 16 can exhibit bidentate binding to lanthanide ions.4,12–16 Bidentate binding is especially favorable if complexation will produce a five- or six-membered ring, which can occur for both 12 and 16. Bidentate binding of 12 and 16 is expected to reduce the rate of exchange between the bound and the unbound substrate, which accounts for the broadening in the NMR spectrum. Similarly, the 1H NMR spectrum of 18, a carboxylic acid, is severely broadened in the presence of the lanthanide chelates of 4 and 5. Strong binding of carboxylic acids to lanthanide tris bdiketonates has been noted before.17,18 Prior studies have shown that paramagnetic lanthanide chelates are often ineffective NMR shift reagents for carboxylic acids because of the strong binding.17,18 Among the other monofunctional substrates, only 17 failed to show any enantiomeric discrimination in the 1H NMR spectrum
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hydrogen atoms near to, and far removed from, the binding site. The enhanced shielding of substrate resonances with the La(III) and Lu(III) chelates of 4 and 5 compared to 1–3 likely explains their enhanced effectiveness as chiral NMR discriminating agents. A noteworthy observation with the diamagnetic chelates of 4 and 5 is the degree to which hydrogen atoms relatively remote to the stereogenic center are shielded and exhibit enantiomeric discrimination. This includes the methyl group at the 4-position of 2-butanol 8, which actually has a larger enantiomeric discrimination than the methyl group at the 1-position. Methyl groups in 9, 10, and 14, as well as aryl hydrogen atoms in 6 and 15 that are not in close proximity to the stereocenter are shielded and exhibit enantiomeric discrimination in the presence of the chelates of 4 and 5. The most impressive example of enantiomeric discrimination of a hydrogen atom remote to the stereogenic center with the chelates of 4 and 5 is for the methyl group at the 8-position of 2-aminooctane 20. The perturbations in chemical shifts provided in Table 1 indicate that the aryl rings of 4 and 5 in the chelates are positioned in such a way to cause shielding of hydrogen atoms far removed from the binding site. Enantiomeric discrimination in the 1H NMR spectrum of substrates with La(III) and Lu(III) chelates of 4 and 5 is usually large enough to enable an accurate determination of the enantiomeric purity. Figures 3–5 provide examples of the enantiomeric
with the La(III) and Lu(III) chelates of 4 and 5. Compound 17 has an epoxide moiety and steric hindrance by the two phenyl groups likely weakens its binding to lanthanide ions. Table 2 provides the change in chemical shift, which is designated as Dd, of certain substrate resonances that occurs when the compound is mixed with La(III) and Lu(III) complexes of 4 and 5 in either chloroform-d or cyclohexane-d12. Data are not provided with benzene-d6, since this solvent causes substantial shielding of the substrate resonances without a lanthanide chelate present. The negative values in Table 2 indicate shielding of the resonances. Complexation of the donor with the electropositive La(III) and Lu(III) is expected to reduce the electron density at the donor, which should cause deshielding of the substrate resonances. There are very few reports in the literature on the perturbations in chemical shifts in the 1H NMR spectra of substrates using diamagnetic tris b-diketonate complexes of La(III) and Lu(III). Prior work most relevant to the types of substrates examined herein shows that complexation of La(III) chelates to hydroxyl- and sulfoxide-containing substrates causes a slight deshielding of nearby aliphatic hydrogen atoms.19 In earlier work, most substrate resonances showed a small degree of deshielding in the presence of the La(III) and Lu(III) chelates of 1–3.7 In contrast, most substrate resonances are shielded in the presence of the chelates of 4 and 5, and in many cases this shielding is significant (0.1–0.3 ppm) for
Table 2 Change in the chemical shift (Dd) in ppm in the 1H NMR spectrum (400 MHz, 23 °C) of substrates (0.025 M) in the presence of one of the diamagnetic lanthanide chelates (0.025 M) Substrate
Resonance
Dd
Complex
Solvent
6
H2 H4 H5 H8 CH CH3
0.170 0.176 0.184 0.091 0.262 0.278
Lu(bc)3 Lu(2np)3 Lu(2np)3 Lu(bc)3 La(2np)3 La(2np)3
C6D12 C6D12 C6D12 C6D12 C6D12 C6D12
7
CH CH3
0.124 0.035
La(2np)3 La(bc)3
C6D12 CDCl3
8
1-CH3 4-CH3
0.110 0.110
La(bc)3 La(bc)3
C6D12 C6D12
9
CH3 –CHOH –C@CH–
0.175 0.176 0.013
La(2np)3 La(2np)3 La(2np)3
C6D12 C6D12 C6D12
10
CH3 A CH3 B CH3 B0
0.070 0.044 0.047
La(bc)3 Lu(bc)3 Lu(2np)3
C6D12 C6D12 C6D12
13
CH3
0.037
La(2np)3
C6D12
14
CH3—A CH3—B
0.026 0.018
La(2np)3 La(2np)3
C6D12 C6D12
15
Ho NH CH02 H4 H5 H50
0.248 0.971 0.338 0.266 0.165 0.105
Lu(2np)3 Lu(bc)3 Lu(2np)3 Lu(2np)3 Lu(2np)3 Lu(bc)3
CDCl3 CDCl3 CDCl3 CDCl3 CDCl3 CDCl3
19
CH CH3
0.197 0.199
La(2np)3 La(2np)3
C6D12 C6D12
20
1-CH3 8-CH3
0.108 0.120
Lu(2np)3 Lu(2np)3
C6D12 C6D12
21
CH3
0.371
La(2np)3
C6D12
22
CH3
0.166
Lu(2np)3
C6D12
23
Ho Ph-CH3 S(O)-CH3
0.029 0.096 0.093
Lu(bc)3 La(bc)3 La(bc)3
C6D12 C6D12 C6D12
24
HA HB HC
0.214 0.129 0.366
Lu(2np)3 Lu(2np)3 Lu(2np)3
C6D12 C6D12 C6D12
R. L. Clark et al. / Tetrahedron: Asymmetry 24 (2013) 297–304
Figure 3. 1H NMR (400 MHz, C6D6, 23 °C) of the CH3 resonance of (a) 22 (0.025 M, racemate) and (b) with Lu(2np)3 (0.025 M).
Figure 4. 1H NMR (400 MHz, CDCl3, 23 °C) of 15 (0.0167 M (S), 0.0083 M (R)): (a) the CH resonance, (b) with Lu(bc)3 (0.025 M), (c) the NH resonance, and (d) with Lu(bc)3 (0.025 M).
discrimination observed in the spectra of substrates with the diamagnetic lanthanide complexes of 4 and 5. Figure 3 shows the methyl resonance of 22 with Lu(2np)3 in benzene-d6. Complexation of 22 with Lu(2np)3 leads to deshielding of the methyl resonance and substantial enantiomeric discrimination.
301
Compound 22 coordinates with the lanthanide ion through the oxygen atom of the sulfoxide group. Deshielding of the methyl group of 22 likely occurs because it is close to the binding site and the electron density is lowered because of the electron withdrawing effect of the Lu(III). Figure 4a and b shows the CH resonance and Figure 4c and d the NH resonance of 15 in chloroform-d in the presence of Lu(bc)3. The CH resonance of 15 is significantly shielded in the presence of Lu(bc)3, presumably through an interaction with the phenyl ring of the ligand. The large shielding of the CH resonance is the likely cause in the enhancement of the enantiomeric discrimination when compared to the La(III) and Lu(III) chelates with 1–3. The NH resonance of 15 is deshielded, which may occur in part because of the electron withdrawing properties of Lu(III). Since the NH hydrogen atom can also be involved in hydrogen bonding, this may also influence its chemical shift.20,21 The crystal structures of some lanthanide tris b-diketonate complexes indicate that the complexes dimerize and oxygen atoms on one b-diketonate ligand simultaneously bind to two lanthanide ions in the dimers.22,23 It is possible that lone pairs of electrons on the oxygen atoms of the bdiketonate ligands that are not involved in binding to the La(III) or Lu(III) can form hydrogen bonds with the NH group of 15, thereby accounting for the large deshielding in the spectrum. The enantiomeric discrimination of the CH and NH resonances of 15 is sufficient to determine the enantiomeric purity. Figure 5 shows the discrimination of the H8 aromatic signal of 6 in the presence of La(bc)3 in chloroform-d and the methyl resonance in the presence of Lu(bc)3 in cyclohexane-d12. The enantiomeric discrimination of both resonances is large enough to determine the enantiomeric purity. The extent of enantiomeric discrimination is affected by the choice of La(III) or Lu(III). Figure 6 illustrates the effect of the metal on the methyl resonances of 23 in cyclohexane-d12. The methyl group attached to the sulfoxide moiety of 23 exhibits enantiomeric discrimination with both Lu(bc)3 and La(bc)3, but Lu(bc)3 is more effective for determining the enantiomeric purity because La(bc)3 causes a broadening in the spectrum. In contrast, the methyl group attached to the phenyl ring of 23 exhibits no enantiomeric discrimination with Lu(bc)3, but is discriminated in the presence of La(bc)3. Deshielding of the sulfoxide methyl group in 23 is comparable to that observed in 22 as discussed earlier. This contrasts with the substantial shielding of the methylphenyl group of 23 that is likely caused by the aryl ring of 3 in the La(III) and Lu(III) chelates. The differences in the spectra of substrates with comparable chelates of La(III) and Lu(III) must be caused by differences in the size of the La(III) (2.74 Å) and Lu(III) (2.25 Å) ions. It is expected
Figure 5. 1H NMR (400 MHz, 23 °C) of 6 (0.0167 M (S), 0.0083 M (R)): (a) the H8 resonance in CDCl3, (b) with La(bc)3 (0.025 M), (c) the CH3 resonance in C6D12, and (d) with Lu(bc)3 (0.025 M).
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Figure 8. 1H NMR (400 MHz, C6D12, 23 °C) of the CH3 resonance of (a) 19 (0.0167 M (S), 0.0083 M (R)) with, (b) La(bc)3 (0.025 M), and (c) La(2np)3 (0.025 M). Figure 6. 1H NMR (400 MHz, C6D12, 23 °C) of the CH3 resonances of (a) 23 (0.0167 M (S), 0.0083 M (R)) with, (b) La(bc)3 (0.025 M), and (c) Lu(bc)3 (0.025 M).
that complexes with the smaller Lu(III) are more sterically crowded. In prior studies with paramagnetic lanthanide chelates, it was proposed that steric crowding in complexes with 3 might explain the greater enantiomeric discrimination than was often observed in comparison with complexes of 1 and 2.3 However, the advantage of the paramagnetic lanthanide complexes with 3 compared to those with 1 and 2 did not translate into the observations with diamagnetic La(III) and Lu(III) chelates.7 Similarly, there is no clear advantage of chelates of Lu(III) with 4 and 5 compared to those with La(III). The perturbations in chemical shifts and extent of enantiomeric discrimination are affected by the ligand as well. Figure 7 shows the methyl resonance of 9 with La(bc)3 and La(2np)3. In the presence of La(bc)3, the methyl resonance of 9 is shielded and no enantiomeric discrimination is observed. With La(2np)3, the methyl resonance of 9 exhibits a larger shielding and a significant degree of enantiomeric discrimination. Figure 8 shows the methyl resonance of 19 in the presence of La(bc)3 and La(2np)3. The shielding is much larger with La(2np)3 than La(bc)3, but in this case, the enantiomeric discrimination is similar with both complexes. Prior studies of other chiral NMR derivatizing and solvating agents show that naphthyl rings produce more shielding than phenyl rings,24–26 which explains the enhanced shielding caused by the chelates of 5
Figure 7. 1H NMR (400 MHz, C6D12, 23 °C) of the CH3 resonance of (a) 9 (0.025 M, racemate) with, (b) La(bc)3 (0.025 M), and (c) La(2np)3 (0.025 M).
compared to 4. The lanthanide complexes with 5 are also expected to be more sterically crowded than those with 4, but data in Table 1 indicate that chelates of 5 do not always lead to larger enantiomeric discrimination. The solvent also has a pronounced effect on the enantiomeric discrimination observed in the 1H NMR spectrum. In most cases, greater enantiomeric discrimination is observed in benzene-d6 or cyclohexane-d12 than in chloroform-d. This same trend was noted in prior reports on the La(III) and Lu(III) chelates of 1–37 and with paramagnetic chelates.4,5 Association of the substrates with the metal chelates is stronger in non-polar solvents such as cyclohexane-d12 and benzene-d6 than in the more polar chloroform-d. Stronger association is expected to lead to larger perturbations in the chemical shifts, which for the different solvents frequently coincides with a larger extent of enantiomeric discrimination. Figure 9 shows a comparison of the alkene resonances of 24 with Lu(2np)3 in chloroform-d, benzene-d6, and cyclohexane-d12. The spectrum of 24 without the Lu(III) chelate is only shown in chloroform-d (Fig. 9a). The resonances of the substrate have different chemical shifts in other solvents, and especially in benzene-d6, so the spectra in Figure 9 can only be used to compare the enantiomeric discrimination and not the relative perturbations in chemical shifts. Only a small degree of enantiomeric discrimination is observed for all three of the alkene resonances in the spectrum of 24 with Lu(2np)3 in chloroform-d. Much larger enantiomeric discrimination occurs in benzene-d6 (Fig. 9c) and cyclohexaned12 (Fig. 9d). The largest discrimination for 24 was in the spectrum with benzene-d6 (Table 1). Table 3 compares the best enantiomeric discrimination observed in the 1H NMR spectra of resonances of 6 in each of the three solvents. The methyl (Fig. 5c and d), methine, and two aromatic resonances of 6 exhibit the largest enantiomeric discrimination in cyclohexane-d12. However, one aromatic resonance of 6 has the largest enantiomeric discrimination in chloroform-d (Fig. 5a and b) while another aromatic resonance of 6 exhibits the largest enantiomeric discrimination in benzene-d6. Recording spectra in several solvents is warranted if no enantiomeric discrimination is observed in the first choice. Some of the spectra of substrates with the lanthanide chelates exhibit significant broadening. For 12, 16, and 18, this likely occurs because of strong binding of the substrate to the lanthanide ion. For other monodentate substrates, greater broadening is frequently observed with the La(III) chelates. Figure 7 shows broadening of the methyl resonance of 4 with La(bc)3 and La(2np)3. Figure 6b, which shows the methyl resonances of 23, provides an example of the broadening that can occur with La(bc)3. In comparison, the spectrum of 23 with Lu(bc)3 (Fig. 6c) has considerably less
R. L. Clark et al. / Tetrahedron: Asymmetry 24 (2013) 297–304
303
Figure 9. 1H NMR spectrum (400 MHz, C6D12, 23 °C) of the alkene resonances of (a) 24 (0.025 M, racemate) in CDCl3 and with Lu(2np)3 (0.025 M) in, (b) CDCl3, (c) C6D6, and (d) C6D12.
Table 3 Enantiomeric discrimination (DDd) in ppm in the 1H NMR spectrum (400 MHz, 23 °C) of 6 (0.025 M) in the presence of the most effective diamagnetic lanthanide chelate (0.025 M) Resonance
CDCl3
H2 H4 H5 H8 CH3 CH
0.007 0.016 0 0.016 0.046 0
[Lu(2np)3] [La(bc)3] [La(bc)3] [Lu(bc)3]
C6D6
C6D12
0.021 [La(2np)3] 0 0 0 0 0.016 [Lu(2np)3]
0.009 0.032 0.039 0.032 0.017 0.032
[Lu(bc)3] [Lu(bc)3] [Lu(2np)3] [Lu(bc)3] [Lu(bc)3] [Lu(bc)3]
broadening of the methyl resonances. One possibility is that the rate of exchange of substrates with the La(III) chelates is slower than that with the Lu(III) chelates thereby causing the broadening. The La(III) nucleus has a quadrupolar moment and this may contribute to broadening as well.27 3. Conclusion Lanthanide tris b-diketonate complexes of La(III) and Lu(III) with 4 and 5 are effective chiral NMR discriminating agents for a wide range of oxygen- and nitrogen-containing substrates. Enantiomeric discrimination is observed in the spectra of 15 of the 19 substrates examined herein. The spectra of three substrates exhibit severe broadening in the presence of the lanthanide complexes because of exceptionally strong binding to the lanthanide ion. The success of the La(III) and Lu(III) complexes of 4 and 5 as chiral NMR discriminating agents is attributed in part to the presence of the aryl groups in the ligands that cause substantial shielding of certain substrate resonances. No one combination of La(III) or Lu(III) with 4 or 5 is consistently the most effective. The nonpolar solvents benzene-d6 and cyclohexane-d12 are usually more effective than chloroform-d. Paramagnetic lanthanide tris b-diketonates are exceptionally versatile chiral NMR shift reagents on low field strength NMR spectrometers. The La(III) and Lu(III) chelates of 4 and 5 enable the same degree of versatility on higher field strength instruments.
4. Experimental 4.1. Reagents
a-Methyl-1-naphthalenemethanol 6, 1-phenylethanol 7, 2-butanol 8, 3-methyl-2-cyclohexen-1-ol 9, menthol 10, trans-2-methylcyclopentanol 11, 1-phenyl-1,2-ethanediol 12, 2-methylcyclohexanone 13, menthone 14, 4-benzyl-2-oxazolidinone 15, benzoin 16, trans-stilbene oxide 17, 2-phenylpropionic acid 18, 1-phenylethylamine 19, 2-aminooctane 20, cyclohexylethylamine 21, methylphenylsulfoxide 22, methyl p-tolyl sulfoxide 23, phenylvinylsulfoxide 24, methyl benzoate, methyl-2-naphthoate, and (1R)(+)-camphor were purchased from Sigma Aldrich Corp, St. Louis, Missouri. Compound 4 was prepared as previously reported.2 4.2. Synthetic procedures 4.2.1. 3-(2-Naphthoyl)-(+)-camphor 5 (H2np) The b-diketone ligand 5 was prepared by a Claisen condensation.28 A dry 250 mL three-neck, round-bottomed flask fitted with a reflux condenser, pressure-equalizing addition funnel, and magnetic stirrer was maintained under a nitrogen atmosphere. Anhydrous 1,2-dimethoxyethane (50 mL), sodium hydride (2 g, 77.1 mmol), and (1R)-(+)-camphor (5.0 g, 32.8 mmol) were added to the flask and the mixture was stirred and refluxed for 1 h. Refluxing was continued as a solution of 2-naphthoate (6.13 g, 32.9 mmol) in 20 mL of anhydrous 1,2-dimethoxyethane was added dropwise over 90 min, after which the reaction was refluxed overnight. The flask was packed in ice and 10 mL of ethanol followed by 100 mL of distilled water were slowly added. The solution was brought to a pH of 1 with concentrated HCl. The solution was washed three times with 100 mL of pentane in a separatory funnel. The pentane layers were collected, washed four times with 100 mL of 5% sodium bicarbonate, and dried over sodium sulfate. The pentane was removed by rotary evaporation and the off-white solid was purified by recrystallization from pentane (7.7 g, 77%). 1H NMR (400 MHz, CDCl3) d = 8.17 (s, 1H), 7.93– 7.83 (m, 3H), 7.72 (dd, J = 8.6, 1.9 Hz 1H), 7.57–7.49 (m, 2H), 2.92 (d, J = 4.7 Hz 1H), 2.26–2.16 (m, 1H), 1.81 (m, 1H), 1.70 (m, 1H),
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1.62–1.49 (m, 2H), 1.03 (s, 3H), 0.95 (s, 3H), 0.83 (s, 3H). And calcd for C21H22O2: C 82.35, H 7.19; Found C 82.17, H 7.39 ½a20 D ¼ þ2:1 (c 1.0, CHCl3).
1145061; Major Research Instrumentation Program, Grant CHE0115579) for supporting our work. References
4.2.2. Lanthanide tris b-diketonate complexes The lanthanide tris b-diketonates were synthesized by established methods.1,2 Next, 1 g of either LaCl36H2O or Lu(NO3)36H2O was dissolved in 15 ml of methanol. Three equivalents of 4 or 5 were dissolved in 45 ml of methanol and neutralized with an appropriate amount of a solution of 4 M NaOH. The solution of neutralized 4 or 5 was added with stirring to the solution of the lanthanide salt. In some cases, the metal complex precipitated out of solution and was collected by suction filtration and washed with cold methanol. In other cases, a solid complex was obtained by adding the final solution dropwise to 800 ml of vigorously stirred distilled water. The solid that formed was collected by suction filtration and washed with cold methanol. Complexes isolated using either procedure were obtained in a hydrated form and verification of the desired complex was confirmed by suitable elemental analyses. 4.3. Procedures The lanthanide chelates were dried for at least 48 h in vacuo in an Abderhalden using boiling 1-butanol as the solvent, and then stored in a desiccator over P4O10. Solutions of substrates enriched in one enantiomer, when available, were prepared at 25 mM in either chloroform-d, benzene-d6, or cyclohexane-d12. The appropriate amount of La(III) or Lu(III) complexes for a 25 mM solution was weighed out and dissolved in 800 ll of the substrate solution. All samples contained TMS as an internal reference. NMR spectra were run with a Bruker Advance™ 400 MHz NMR Spectrometer with 16 scans at room temperature. Acknowledgments We thank the National Science Foundation (Research at Undergraduate Institutions Program, Grants CHE-0653711 and CHE-
1. Goering, H. L.; Eikenberry, J. N.; Koermer, G. S. J. Am. Chem. Soc. 1971, 93, 5913– 5914. 2. Fraser, R. R.; Petit, M. A.; Saunders, J. K. Chem. Commun. 1971, 1450–1451. 3. McCreary, M. D.; Lewis, D. W.; Wernick, D. L.; Whitesides, G. M. J. Am. Chem. Soc. 1974, 96, 1038–1054. 4. Wenzel, T. J. NMR Shift Reagents; CRC Press: Boca Raton, FL, 1987. 5. Wenzel, T. J. Discrimination of Chiral Compounds Using NMR Spectroscopy; Wiley: Hoboken, NJ, 2007. 6. NMR Shift Reagents; Sievers, R. E., Ed.; Academic Press: New York, 1973. 7. Wenzel, T. J.; Wenzel, B. T. Chirality 2009, 21, 6–10. 8. Wenzel, T. J.; Chisholm, C. D. Prog. NMR Spectrosc. 2011, 59, 1–63. 9. Wenzel, T. J.; Chisholm, C. D. Chirality 2011, 23, 190–214. 10. Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512–519. 11. Pirkle, W. H.; Beare, S. D.; Muntz, R. I. Tetrahedron Lett. 1974, 15, 2295–2298. 12. Matsuo, M.; Matsumoto, S. Chem. Pharm. Bull. 1977, 25, 1399–1403. 13. Lewis, R. B.; Wenkert, E. In Nuclear Magnetic Resonance Shift Reagents; Sievers, R. E., Ed.; Academic Press: New York, 1973; pp 99–129. 14. Aversa, M. C.; Giannetto, P. J. Chem. Soc., Perkin Trans. 2 1984, 81–84. 15. Cameron, D. W.; Feutrill, G. I.; Patti, A. F. Aust. J. Chem. 1979, 32, 575–584. 16. Joseph-Nathan, P.; Abramo-Bruno, D.; Torres, M. A. Phytochemistry 1981, 20, 313–318. 17. Parker, D. Chem. Rev. 1991, 91, 1441–1457. 18. Wenzel, T. J.; Thurston, J. E. J. Org. Chem. 2000, 65, 1243–1248. 19. Uebel, J. J.; Pacheco, C.; Wing, R. M. Tetrahedron Lett. 1973, 14, 4383–4386. 20. Rebek, J. Angew. Chem., Int. Ed. Engl. 1990, 29, 245–255. 21. Bergmann, H.; Grosch, B.; Sitterberg, S.; Bach, T. J. Org. Chem. 2004, 69, 970– 973. 22. Erasmus, C. S.; Boeyens, J. C. A. Acta Crystallogr., Sect. B 1970, 26, 1843–1854. 23. De Villiers, J. P. R.; Boeyens, J. C. A. Acta Crystallogr., Sect. B 1971, 27, 692–702. 24. Seco, J. M.; Quinoa, E.; Riguera, R. Chem. Rev. 2004, 104, 17–117. 25. Kasai, Y.; Naito, J.; Kuwahara, S.; Watanabe, M.; Ichikawa, A.; Harada, N. J. Synth. Org. Chem. Jpn. 2004, 62, 48–61. 26. Seco, J. M.; Latypov, S. K.; Quinoa, E.; Riguera, R. Tetrahedron 1997, 53, 8541– 8564. 27. Pavia, D. L.; Lampman, G. M.; Kriz, G. S.; Vyvyan, J. R. Introduction to Spectroscopy, 4th ed.; Brooks/Cole: Belmont, CA, 2009. 28. Organic Reactions; Hauser, C. R., Swamer, F. W., Adams, J. T., Adams, R., Eds.; Wiley: New York, 1954; Vol. 8, pp 59–196.
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Tetrahedron: Asymmetry journal homepage: www.elsevier.com/locate/tetasy
Diamagnetic lanthanide tris b-diketonate complexes with aryl-containing ligands as chiral NMR discriminating agents Rebecca L. Clark, Bradford T. Wenzel, Thomas J. Wenzel ⇑ Department of Chemistry, Bates College, Lewiston, ME 04240, USA
a r t i c l e
i n f o
Article history: Received 25 December 2012 Accepted 29 January 2013 Available online 28 February 2013
a b s t r a c t Diamagnetic lanthanum(III) and lutetium(III) tris b-diketonate complexes with the aryl-containing ligands 3-benzoyl-(+)-camphor and 3-(2-naphthoyl)-(+)-camphor are effective organic-soluble chiral NMR discriminating agents for oxygen- and nitrogen-containing compounds. Enantiomeric discrimination of sufficient magnitude to determine the enantiomeric purity is observed in the 1H NMR spectra of compounds with hydroxyl, carbonyl, oxazolidinone, amine, and sulfoxide groups. Diamagnetic lanthanide complexes with the aryl-containing b-diketonate ligands are almost always more effective than those with 3-trifluoroacetyl-(+)-camphor, 3-heptafluorobutyryl-(+)-camphor, and d,d-dicampholylmethane that have been previously reported. Many hydrogen atoms of the substrates are significantly shielded in the presence of the lanthanide chelates with the aryl-containing ligands, which likely enhances the extent of enantiomeric discrimination in the NMR spectra. No combination of metal and ligand is most effective for all substrates. Larger enantiomeric discrimination is usually observed in benzene-d6 or cyclohexane-d12 than in chloroform-d. Diamagnetic lanthanide tris b-diketonates with the aryl-containing ligands provide an alternative to paramagnetic chelates that often cause too much broadening in the 1H NMR spectrum. Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction Paramagnetic lanthanide tris b-diketonate complexes with the ligands 3-(trifluoroacetyl)-(+)-camphor (tfc—1),1 3-(heptafluorobutyryl)-(+)-camphor (hfc—2),2 and d,d-dicampholylmethane (dcm—3)3 (Fig. 1) are among the earliest reagents used to determine the enantiomeric purity of chiral compounds by NMR spectroscopy. The lanthanide ion in these organic-soluble complexes is a hard Lewis acid that forms donor–acceptor complexes with hard Lewis bases, primarily oxygen- or nitrogen-containing compounds. The paramagnetism of a lanthanide ion, such as europium(III), causes substantial perturbations in the chemical shifts of resonances of the bound donor molecules, which greatly enhances the degree of enantiomeric discrimination in the NMR spectrum. Since many compounds contain oxygen or nitrogen atoms, chiral lanthanide tris b-diketonates are exceptionally versatile and applicable reagents for NMR studies of chiral compounds.4–6 However, the paramagnetism that was an advantage when chiral lanthanide reagents were first reported on and relatively lowfield NMR spectrometers were available (200 MHz or less) is often a detriment on the high-field instruments available today. In addition to perturbing the chemical shifts, the paramagnetism causes
⇑ Corresponding author. Tel.: +1 207 786 6296; fax: +1 207 786 8336. E-mail address: [email protected] (T.J. Wenzel). 0957-4166/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tetasy.2013.01.021
line broadening that is enhanced at higher field strengths. The broadening of the resonances in the presence of paramagnetic lanthanide tris b-diketonates obscures the enantiomeric discrimination in the spectra of many compounds. We have previously shown that complexes of diamagnetic lanthanum(III) and lutetium(III) with 1–3 are effective chiral NMR shift reagents for certain oxygen- and nitrogen-containing compounds.7 Complexation of the donor with the diamagnetic lanthanide ion caused slight perturbations in the chemical shifts of the resonances of the donor and, in some cases, a slight enantiomeric discrimination. There was no consistent pattern of which diamagnetic metal with which ligand was most effective. There was a significant solvent effect and better enantiomeric discrimination was often observed in benzene-d6 or cyclohexane-d12 compared to chloroform-d.7 A common strategy used to enhance the effectiveness of many chiral NMR derivatizing and solvent agents is to incorporate aryl rings into the reagent.5,8,9 If atoms of the compound being analyzed are positioned over the aryl ring, the ring anisotropy causes significant shielding of these atoms and perturbs their resonances to lower frequencies. The classic Mosher reagent (a-methoxy-atrifluoromethylphenylacetic acid—MTPA)10 and Pirkle’s alcohol (2,2,2-trifluoro-1-(9-anthryl)ethanol)11 owe their utility as chiral NMR discriminating agents to the presence of the aryl ring. We reasoned that diamagnetic lanthanide complexes with chiral bdiketonate ligands that contain aryl groups would likely be more
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CF3
CF2 CF2 CF3
O
1
O
O
O
O
2
OH
O
OH
O
4
3
5
O
Figure 1. b-Diketone ligands in the La(III) and Lu(III) complexes.
examined with La(bc)3, Lu(bc)3, La(2np)3, and Lu(2np)3. In addition, the NMR spectrum of each combination of lanthanide chelate and substrate was recorded in chloroform-d, benzene-d6, and cyclohexane-d12. Table 1 provides the enantiomeric discrimination, which refers to the separation of the resonances for the (R)- and (S)-enantiomers and is designated as DDd, observed in the 1H NMR spectrum of each substrate with the La(III) and Lu(III) chelates of 4 and 5. Values in Table 1 represent the best combination of lanthanide complex and solvent. Enantiomeric discrimination is observed in the spectra of 15 of the 19 substrates with the chelates of 4 and 5. Many of the aliphatic resonances of the substrates exhibit enantiomeric discrimination in the presence of the chelates of 4 and 5. In a few cases, enantiomeric discrimination of the aromatic
effective chiral NMR shift reagents than complexes with 1–3. Studies of the La(III) and Lu(III) complexes with 3-benzoyl-(+)-camphor (bc—4) and 3-(2-naphthoyl)-(+)-camphor (2np—5) (Fig. 1) with a range of oxygen- and nitrogen-containing compounds (Fig. 2) are reported herein. 2. Results and discussion Nineteen substrates that span a range of functional groups and include compounds with hydroxyl 6–12, carbonyl 13, 14, oxazolidinone 15, epoxide 17, carboxylic acid 18, amine 19–21, and sulfoxide 22–24 groups were studied. The substrates also incorporate acyclic aliphatic, cyclic aliphatic, alkene, and aromatic substituent groups. Substrates 12 and 16 are bifunctional. Each substrate was
OH
OH
7
2
6
3 5
6
OH
OH B,B'
4
7
8
OH
10
9
O
O
OH
Ho
B,B' Hm
OH
Hp
A
14
13
12
11
A
OH
8
4
H N
O
O
5
15
OH
NH2 OH O
O
O 17
16
19
18
NH2
O S
NH2
Ho Hm
O
O
S
S
HB HC HA
20
21
22 Figure 2. Structures of the substrates.
23
24
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R. L. Clark et al. / Tetrahedron: Asymmetry 24 (2013) 297–304 Table 1 Enantiomeric discrimination (DDd) in ppm in the 1H NMR spectrum (400 MHz, 23 °C) of substrates (0.025 M) in the presence of the most effective combination of diamagnetic lanthanide chelate (0.025 M) and solvent Substrate
Resonance
DDd
Complex
Solvent
Chelates with 1–37
6
H2 H4 H5 H8 CH CH3
0.021 0.032 0.039 0.046 0.032 0.042
Lu(2np)3 Lu(bc)3 Lu(2np)3 Lu(bc)3 Lu(bc)3 La(2np)3
C6D6 C6D12 C6D12 CDCl3 C6D12 C6D12
0 0 0 0 0.003 0
7
CH CH3
0.033 0.008
La(2np)3 Lu(bc)3
C6D12 C6D12
0 0
8
1-CH3 4-CH3
0.004 0.018
La(bc)3 La(2np)3
C6D12 C6D12
0 0
9
CH3 –CHOH –C@CH–
0.036 0.048 0.029
La(2np)3 La(2np)3 La(2np)3
C6D12 C6D12 C6D12
0 0 0
10
CH3—A CH3—B CH3—B0
0.018 0.017 0.011
Lu(bc)3 Lu(bc)3 Lu(bc)3
C6D12 C6D12 C6D12
0 0 0
11
CH3
0.004
Lu(bc)3
C6D6
0
12
CH
13
CH3
0.007
La(2np)3
C6D12
0
14
CH3—A CH3—B
0.004 0.003
La(2np)3 La(2np)3
C6D12 C6D12
0 0
15
Ho Hm NH CH2 CH02 H4 H5 H50
0.029 0.016 0.118 0.190 0.071 0.070 0.073 0.020
Lu(bc)3 Lu(2np)3 Lu(bc)3 Lu(2np)3 Lu(2np)3 Lu(2np)3 Lu(2np)3 Lu(2np)3
CDCl3 C6D6 CDCl3 C6D6 CDCl3 CDCl3 C6D6 C6D6
0 0 0.075 0 0 0.044 0.021 0
17
CH
19
CH CH3
0.016 0.015
La(2np)3 La(2np)3
C6D12 C6D12
0 0.011
20
1-CH3 8-CH3
0.011 0.008
Lu(bc)3 Lu(2np)3
C6D6 C6D6
0 0
21
CH3
0.018
La(2np)3
C6D12
0
22
CH3
0.048
Lu(2np)3
C6D6
0.009
23
Ho Hm Ph-CH3 S(O)-CH3
0.016 0.010 0.013 0.040
La(bc)3 La(bc)3 La(bc)3 Lu(2np)3
C6D6 C6D6 C6D6 C6D6
0 0.006 0 0.009
24
HA HB HC
0.041 0.041 0.031
Lu(bc)3 Lu(bc)3 Lu(2np)3
C6D6 C6D6 C6D6
0.042 0.010 0.010
0
0.020
0
resonances is observed as well. However, for many substrates, aromatic resonances of the ligands in the lanthanide complexes of 4 and 5 interfere with those of the substrate and prevent a determination of whether enantiomeric discrimination is present. Enantiomeric discrimination observed in the spectra of the substrates with the La(III) and Lu(III) chelates with 1–3 are also provided in Table 1. The La(III) and Lu(III) complexes with 4 and 5 produce enantiomeric discrimination of many more resonances and in a wider range of substrates than observed with the complexes of 1–3. For resonances where complexes with 1–3 produce enantiomeric discrimination, the values observed with the complexes of 4 and 5 are almost always larger. The only exceptions are the enantiomeric discrimination of the methine resonances of 12 and 17 with complexes of 1–3. The two bifunctional compounds 12 and 16 did not show enantiomeric discrimination with the La(III) and Lu(III) chelates of 4 and 5. The 1H NMR spectrum of 12 is severely broadened with
0.005
the chelates of 4 and 5. The 1H NMR spectrum of 16 is severely broadened with the La(III) chelates of 4 and 5 but not with the Lu(III) chelates. Prior studies have shown that bifunctional compounds such as 12 and 16 can exhibit bidentate binding to lanthanide ions.4,12–16 Bidentate binding is especially favorable if complexation will produce a five- or six-membered ring, which can occur for both 12 and 16. Bidentate binding of 12 and 16 is expected to reduce the rate of exchange between the bound and the unbound substrate, which accounts for the broadening in the NMR spectrum. Similarly, the 1H NMR spectrum of 18, a carboxylic acid, is severely broadened in the presence of the lanthanide chelates of 4 and 5. Strong binding of carboxylic acids to lanthanide tris bdiketonates has been noted before.17,18 Prior studies have shown that paramagnetic lanthanide chelates are often ineffective NMR shift reagents for carboxylic acids because of the strong binding.17,18 Among the other monofunctional substrates, only 17 failed to show any enantiomeric discrimination in the 1H NMR spectrum
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hydrogen atoms near to, and far removed from, the binding site. The enhanced shielding of substrate resonances with the La(III) and Lu(III) chelates of 4 and 5 compared to 1–3 likely explains their enhanced effectiveness as chiral NMR discriminating agents. A noteworthy observation with the diamagnetic chelates of 4 and 5 is the degree to which hydrogen atoms relatively remote to the stereogenic center are shielded and exhibit enantiomeric discrimination. This includes the methyl group at the 4-position of 2-butanol 8, which actually has a larger enantiomeric discrimination than the methyl group at the 1-position. Methyl groups in 9, 10, and 14, as well as aryl hydrogen atoms in 6 and 15 that are not in close proximity to the stereocenter are shielded and exhibit enantiomeric discrimination in the presence of the chelates of 4 and 5. The most impressive example of enantiomeric discrimination of a hydrogen atom remote to the stereogenic center with the chelates of 4 and 5 is for the methyl group at the 8-position of 2-aminooctane 20. The perturbations in chemical shifts provided in Table 1 indicate that the aryl rings of 4 and 5 in the chelates are positioned in such a way to cause shielding of hydrogen atoms far removed from the binding site. Enantiomeric discrimination in the 1H NMR spectrum of substrates with La(III) and Lu(III) chelates of 4 and 5 is usually large enough to enable an accurate determination of the enantiomeric purity. Figures 3–5 provide examples of the enantiomeric
with the La(III) and Lu(III) chelates of 4 and 5. Compound 17 has an epoxide moiety and steric hindrance by the two phenyl groups likely weakens its binding to lanthanide ions. Table 2 provides the change in chemical shift, which is designated as Dd, of certain substrate resonances that occurs when the compound is mixed with La(III) and Lu(III) complexes of 4 and 5 in either chloroform-d or cyclohexane-d12. Data are not provided with benzene-d6, since this solvent causes substantial shielding of the substrate resonances without a lanthanide chelate present. The negative values in Table 2 indicate shielding of the resonances. Complexation of the donor with the electropositive La(III) and Lu(III) is expected to reduce the electron density at the donor, which should cause deshielding of the substrate resonances. There are very few reports in the literature on the perturbations in chemical shifts in the 1H NMR spectra of substrates using diamagnetic tris b-diketonate complexes of La(III) and Lu(III). Prior work most relevant to the types of substrates examined herein shows that complexation of La(III) chelates to hydroxyl- and sulfoxide-containing substrates causes a slight deshielding of nearby aliphatic hydrogen atoms.19 In earlier work, most substrate resonances showed a small degree of deshielding in the presence of the La(III) and Lu(III) chelates of 1–3.7 In contrast, most substrate resonances are shielded in the presence of the chelates of 4 and 5, and in many cases this shielding is significant (0.1–0.3 ppm) for
Table 2 Change in the chemical shift (Dd) in ppm in the 1H NMR spectrum (400 MHz, 23 °C) of substrates (0.025 M) in the presence of one of the diamagnetic lanthanide chelates (0.025 M) Substrate
Resonance
Dd
Complex
Solvent
6
H2 H4 H5 H8 CH CH3
0.170 0.176 0.184 0.091 0.262 0.278
Lu(bc)3 Lu(2np)3 Lu(2np)3 Lu(bc)3 La(2np)3 La(2np)3
C6D12 C6D12 C6D12 C6D12 C6D12 C6D12
7
CH CH3
0.124 0.035
La(2np)3 La(bc)3
C6D12 CDCl3
8
1-CH3 4-CH3
0.110 0.110
La(bc)3 La(bc)3
C6D12 C6D12
9
CH3 –CHOH –C@CH–
0.175 0.176 0.013
La(2np)3 La(2np)3 La(2np)3
C6D12 C6D12 C6D12
10
CH3 A CH3 B CH3 B0
0.070 0.044 0.047
La(bc)3 Lu(bc)3 Lu(2np)3
C6D12 C6D12 C6D12
13
CH3
0.037
La(2np)3
C6D12
14
CH3—A CH3—B
0.026 0.018
La(2np)3 La(2np)3
C6D12 C6D12
15
Ho NH CH02 H4 H5 H50
0.248 0.971 0.338 0.266 0.165 0.105
Lu(2np)3 Lu(bc)3 Lu(2np)3 Lu(2np)3 Lu(2np)3 Lu(bc)3
CDCl3 CDCl3 CDCl3 CDCl3 CDCl3 CDCl3
19
CH CH3
0.197 0.199
La(2np)3 La(2np)3
C6D12 C6D12
20
1-CH3 8-CH3
0.108 0.120
Lu(2np)3 Lu(2np)3
C6D12 C6D12
21
CH3
0.371
La(2np)3
C6D12
22
CH3
0.166
Lu(2np)3
C6D12
23
Ho Ph-CH3 S(O)-CH3
0.029 0.096 0.093
Lu(bc)3 La(bc)3 La(bc)3
C6D12 C6D12 C6D12
24
HA HB HC
0.214 0.129 0.366
Lu(2np)3 Lu(2np)3 Lu(2np)3
C6D12 C6D12 C6D12
R. L. Clark et al. / Tetrahedron: Asymmetry 24 (2013) 297–304
Figure 3. 1H NMR (400 MHz, C6D6, 23 °C) of the CH3 resonance of (a) 22 (0.025 M, racemate) and (b) with Lu(2np)3 (0.025 M).
Figure 4. 1H NMR (400 MHz, CDCl3, 23 °C) of 15 (0.0167 M (S), 0.0083 M (R)): (a) the CH resonance, (b) with Lu(bc)3 (0.025 M), (c) the NH resonance, and (d) with Lu(bc)3 (0.025 M).
discrimination observed in the spectra of substrates with the diamagnetic lanthanide complexes of 4 and 5. Figure 3 shows the methyl resonance of 22 with Lu(2np)3 in benzene-d6. Complexation of 22 with Lu(2np)3 leads to deshielding of the methyl resonance and substantial enantiomeric discrimination.
301
Compound 22 coordinates with the lanthanide ion through the oxygen atom of the sulfoxide group. Deshielding of the methyl group of 22 likely occurs because it is close to the binding site and the electron density is lowered because of the electron withdrawing effect of the Lu(III). Figure 4a and b shows the CH resonance and Figure 4c and d the NH resonance of 15 in chloroform-d in the presence of Lu(bc)3. The CH resonance of 15 is significantly shielded in the presence of Lu(bc)3, presumably through an interaction with the phenyl ring of the ligand. The large shielding of the CH resonance is the likely cause in the enhancement of the enantiomeric discrimination when compared to the La(III) and Lu(III) chelates with 1–3. The NH resonance of 15 is deshielded, which may occur in part because of the electron withdrawing properties of Lu(III). Since the NH hydrogen atom can also be involved in hydrogen bonding, this may also influence its chemical shift.20,21 The crystal structures of some lanthanide tris b-diketonate complexes indicate that the complexes dimerize and oxygen atoms on one b-diketonate ligand simultaneously bind to two lanthanide ions in the dimers.22,23 It is possible that lone pairs of electrons on the oxygen atoms of the bdiketonate ligands that are not involved in binding to the La(III) or Lu(III) can form hydrogen bonds with the NH group of 15, thereby accounting for the large deshielding in the spectrum. The enantiomeric discrimination of the CH and NH resonances of 15 is sufficient to determine the enantiomeric purity. Figure 5 shows the discrimination of the H8 aromatic signal of 6 in the presence of La(bc)3 in chloroform-d and the methyl resonance in the presence of Lu(bc)3 in cyclohexane-d12. The enantiomeric discrimination of both resonances is large enough to determine the enantiomeric purity. The extent of enantiomeric discrimination is affected by the choice of La(III) or Lu(III). Figure 6 illustrates the effect of the metal on the methyl resonances of 23 in cyclohexane-d12. The methyl group attached to the sulfoxide moiety of 23 exhibits enantiomeric discrimination with both Lu(bc)3 and La(bc)3, but Lu(bc)3 is more effective for determining the enantiomeric purity because La(bc)3 causes a broadening in the spectrum. In contrast, the methyl group attached to the phenyl ring of 23 exhibits no enantiomeric discrimination with Lu(bc)3, but is discriminated in the presence of La(bc)3. Deshielding of the sulfoxide methyl group in 23 is comparable to that observed in 22 as discussed earlier. This contrasts with the substantial shielding of the methylphenyl group of 23 that is likely caused by the aryl ring of 3 in the La(III) and Lu(III) chelates. The differences in the spectra of substrates with comparable chelates of La(III) and Lu(III) must be caused by differences in the size of the La(III) (2.74 Å) and Lu(III) (2.25 Å) ions. It is expected
Figure 5. 1H NMR (400 MHz, 23 °C) of 6 (0.0167 M (S), 0.0083 M (R)): (a) the H8 resonance in CDCl3, (b) with La(bc)3 (0.025 M), (c) the CH3 resonance in C6D12, and (d) with Lu(bc)3 (0.025 M).
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Figure 8. 1H NMR (400 MHz, C6D12, 23 °C) of the CH3 resonance of (a) 19 (0.0167 M (S), 0.0083 M (R)) with, (b) La(bc)3 (0.025 M), and (c) La(2np)3 (0.025 M). Figure 6. 1H NMR (400 MHz, C6D12, 23 °C) of the CH3 resonances of (a) 23 (0.0167 M (S), 0.0083 M (R)) with, (b) La(bc)3 (0.025 M), and (c) Lu(bc)3 (0.025 M).
that complexes with the smaller Lu(III) are more sterically crowded. In prior studies with paramagnetic lanthanide chelates, it was proposed that steric crowding in complexes with 3 might explain the greater enantiomeric discrimination than was often observed in comparison with complexes of 1 and 2.3 However, the advantage of the paramagnetic lanthanide complexes with 3 compared to those with 1 and 2 did not translate into the observations with diamagnetic La(III) and Lu(III) chelates.7 Similarly, there is no clear advantage of chelates of Lu(III) with 4 and 5 compared to those with La(III). The perturbations in chemical shifts and extent of enantiomeric discrimination are affected by the ligand as well. Figure 7 shows the methyl resonance of 9 with La(bc)3 and La(2np)3. In the presence of La(bc)3, the methyl resonance of 9 is shielded and no enantiomeric discrimination is observed. With La(2np)3, the methyl resonance of 9 exhibits a larger shielding and a significant degree of enantiomeric discrimination. Figure 8 shows the methyl resonance of 19 in the presence of La(bc)3 and La(2np)3. The shielding is much larger with La(2np)3 than La(bc)3, but in this case, the enantiomeric discrimination is similar with both complexes. Prior studies of other chiral NMR derivatizing and solvating agents show that naphthyl rings produce more shielding than phenyl rings,24–26 which explains the enhanced shielding caused by the chelates of 5
Figure 7. 1H NMR (400 MHz, C6D12, 23 °C) of the CH3 resonance of (a) 9 (0.025 M, racemate) with, (b) La(bc)3 (0.025 M), and (c) La(2np)3 (0.025 M).
compared to 4. The lanthanide complexes with 5 are also expected to be more sterically crowded than those with 4, but data in Table 1 indicate that chelates of 5 do not always lead to larger enantiomeric discrimination. The solvent also has a pronounced effect on the enantiomeric discrimination observed in the 1H NMR spectrum. In most cases, greater enantiomeric discrimination is observed in benzene-d6 or cyclohexane-d12 than in chloroform-d. This same trend was noted in prior reports on the La(III) and Lu(III) chelates of 1–37 and with paramagnetic chelates.4,5 Association of the substrates with the metal chelates is stronger in non-polar solvents such as cyclohexane-d12 and benzene-d6 than in the more polar chloroform-d. Stronger association is expected to lead to larger perturbations in the chemical shifts, which for the different solvents frequently coincides with a larger extent of enantiomeric discrimination. Figure 9 shows a comparison of the alkene resonances of 24 with Lu(2np)3 in chloroform-d, benzene-d6, and cyclohexane-d12. The spectrum of 24 without the Lu(III) chelate is only shown in chloroform-d (Fig. 9a). The resonances of the substrate have different chemical shifts in other solvents, and especially in benzene-d6, so the spectra in Figure 9 can only be used to compare the enantiomeric discrimination and not the relative perturbations in chemical shifts. Only a small degree of enantiomeric discrimination is observed for all three of the alkene resonances in the spectrum of 24 with Lu(2np)3 in chloroform-d. Much larger enantiomeric discrimination occurs in benzene-d6 (Fig. 9c) and cyclohexaned12 (Fig. 9d). The largest discrimination for 24 was in the spectrum with benzene-d6 (Table 1). Table 3 compares the best enantiomeric discrimination observed in the 1H NMR spectra of resonances of 6 in each of the three solvents. The methyl (Fig. 5c and d), methine, and two aromatic resonances of 6 exhibit the largest enantiomeric discrimination in cyclohexane-d12. However, one aromatic resonance of 6 has the largest enantiomeric discrimination in chloroform-d (Fig. 5a and b) while another aromatic resonance of 6 exhibits the largest enantiomeric discrimination in benzene-d6. Recording spectra in several solvents is warranted if no enantiomeric discrimination is observed in the first choice. Some of the spectra of substrates with the lanthanide chelates exhibit significant broadening. For 12, 16, and 18, this likely occurs because of strong binding of the substrate to the lanthanide ion. For other monodentate substrates, greater broadening is frequently observed with the La(III) chelates. Figure 7 shows broadening of the methyl resonance of 4 with La(bc)3 and La(2np)3. Figure 6b, which shows the methyl resonances of 23, provides an example of the broadening that can occur with La(bc)3. In comparison, the spectrum of 23 with Lu(bc)3 (Fig. 6c) has considerably less
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Figure 9. 1H NMR spectrum (400 MHz, C6D12, 23 °C) of the alkene resonances of (a) 24 (0.025 M, racemate) in CDCl3 and with Lu(2np)3 (0.025 M) in, (b) CDCl3, (c) C6D6, and (d) C6D12.
Table 3 Enantiomeric discrimination (DDd) in ppm in the 1H NMR spectrum (400 MHz, 23 °C) of 6 (0.025 M) in the presence of the most effective diamagnetic lanthanide chelate (0.025 M) Resonance
CDCl3
H2 H4 H5 H8 CH3 CH
0.007 0.016 0 0.016 0.046 0
[Lu(2np)3] [La(bc)3] [La(bc)3] [Lu(bc)3]
C6D6
C6D12
0.021 [La(2np)3] 0 0 0 0 0.016 [Lu(2np)3]
0.009 0.032 0.039 0.032 0.017 0.032
[Lu(bc)3] [Lu(bc)3] [Lu(2np)3] [Lu(bc)3] [Lu(bc)3] [Lu(bc)3]
broadening of the methyl resonances. One possibility is that the rate of exchange of substrates with the La(III) chelates is slower than that with the Lu(III) chelates thereby causing the broadening. The La(III) nucleus has a quadrupolar moment and this may contribute to broadening as well.27 3. Conclusion Lanthanide tris b-diketonate complexes of La(III) and Lu(III) with 4 and 5 are effective chiral NMR discriminating agents for a wide range of oxygen- and nitrogen-containing substrates. Enantiomeric discrimination is observed in the spectra of 15 of the 19 substrates examined herein. The spectra of three substrates exhibit severe broadening in the presence of the lanthanide complexes because of exceptionally strong binding to the lanthanide ion. The success of the La(III) and Lu(III) complexes of 4 and 5 as chiral NMR discriminating agents is attributed in part to the presence of the aryl groups in the ligands that cause substantial shielding of certain substrate resonances. No one combination of La(III) or Lu(III) with 4 or 5 is consistently the most effective. The nonpolar solvents benzene-d6 and cyclohexane-d12 are usually more effective than chloroform-d. Paramagnetic lanthanide tris b-diketonates are exceptionally versatile chiral NMR shift reagents on low field strength NMR spectrometers. The La(III) and Lu(III) chelates of 4 and 5 enable the same degree of versatility on higher field strength instruments.
4. Experimental 4.1. Reagents
a-Methyl-1-naphthalenemethanol 6, 1-phenylethanol 7, 2-butanol 8, 3-methyl-2-cyclohexen-1-ol 9, menthol 10, trans-2-methylcyclopentanol 11, 1-phenyl-1,2-ethanediol 12, 2-methylcyclohexanone 13, menthone 14, 4-benzyl-2-oxazolidinone 15, benzoin 16, trans-stilbene oxide 17, 2-phenylpropionic acid 18, 1-phenylethylamine 19, 2-aminooctane 20, cyclohexylethylamine 21, methylphenylsulfoxide 22, methyl p-tolyl sulfoxide 23, phenylvinylsulfoxide 24, methyl benzoate, methyl-2-naphthoate, and (1R)(+)-camphor were purchased from Sigma Aldrich Corp, St. Louis, Missouri. Compound 4 was prepared as previously reported.2 4.2. Synthetic procedures 4.2.1. 3-(2-Naphthoyl)-(+)-camphor 5 (H2np) The b-diketone ligand 5 was prepared by a Claisen condensation.28 A dry 250 mL three-neck, round-bottomed flask fitted with a reflux condenser, pressure-equalizing addition funnel, and magnetic stirrer was maintained under a nitrogen atmosphere. Anhydrous 1,2-dimethoxyethane (50 mL), sodium hydride (2 g, 77.1 mmol), and (1R)-(+)-camphor (5.0 g, 32.8 mmol) were added to the flask and the mixture was stirred and refluxed for 1 h. Refluxing was continued as a solution of 2-naphthoate (6.13 g, 32.9 mmol) in 20 mL of anhydrous 1,2-dimethoxyethane was added dropwise over 90 min, after which the reaction was refluxed overnight. The flask was packed in ice and 10 mL of ethanol followed by 100 mL of distilled water were slowly added. The solution was brought to a pH of 1 with concentrated HCl. The solution was washed three times with 100 mL of pentane in a separatory funnel. The pentane layers were collected, washed four times with 100 mL of 5% sodium bicarbonate, and dried over sodium sulfate. The pentane was removed by rotary evaporation and the off-white solid was purified by recrystallization from pentane (7.7 g, 77%). 1H NMR (400 MHz, CDCl3) d = 8.17 (s, 1H), 7.93– 7.83 (m, 3H), 7.72 (dd, J = 8.6, 1.9 Hz 1H), 7.57–7.49 (m, 2H), 2.92 (d, J = 4.7 Hz 1H), 2.26–2.16 (m, 1H), 1.81 (m, 1H), 1.70 (m, 1H),
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1.62–1.49 (m, 2H), 1.03 (s, 3H), 0.95 (s, 3H), 0.83 (s, 3H). And calcd for C21H22O2: C 82.35, H 7.19; Found C 82.17, H 7.39 ½a20 D ¼ þ2:1 (c 1.0, CHCl3).
1145061; Major Research Instrumentation Program, Grant CHE0115579) for supporting our work. References
4.2.2. Lanthanide tris b-diketonate complexes The lanthanide tris b-diketonates were synthesized by established methods.1,2 Next, 1 g of either LaCl36H2O or Lu(NO3)36H2O was dissolved in 15 ml of methanol. Three equivalents of 4 or 5 were dissolved in 45 ml of methanol and neutralized with an appropriate amount of a solution of 4 M NaOH. The solution of neutralized 4 or 5 was added with stirring to the solution of the lanthanide salt. In some cases, the metal complex precipitated out of solution and was collected by suction filtration and washed with cold methanol. In other cases, a solid complex was obtained by adding the final solution dropwise to 800 ml of vigorously stirred distilled water. The solid that formed was collected by suction filtration and washed with cold methanol. Complexes isolated using either procedure were obtained in a hydrated form and verification of the desired complex was confirmed by suitable elemental analyses. 4.3. Procedures The lanthanide chelates were dried for at least 48 h in vacuo in an Abderhalden using boiling 1-butanol as the solvent, and then stored in a desiccator over P4O10. Solutions of substrates enriched in one enantiomer, when available, were prepared at 25 mM in either chloroform-d, benzene-d6, or cyclohexane-d12. The appropriate amount of La(III) or Lu(III) complexes for a 25 mM solution was weighed out and dissolved in 800 ll of the substrate solution. All samples contained TMS as an internal reference. NMR spectra were run with a Bruker Advance™ 400 MHz NMR Spectrometer with 16 scans at room temperature. Acknowledgments We thank the National Science Foundation (Research at Undergraduate Institutions Program, Grants CHE-0653711 and CHE-
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