A Versatile and practical solvating agent for enantioselective recognition and NMR analysis of protected amines

Article abstract of DOI:10.1021/jo101426a

The 3,5-dinitrobenzoyl-derived 1-naphthylethyl amide 3 is an attractive CSA for NMR analysis of protected amines. It is readily prepared in a single step and combines practical resolution of diastereomeric complexes due to signal sharpness and effective signal separation. Crystallographic analysis shows that 3 forms a chiral cleft that can selectively bind one enantiomer of a substrate through hydrogen bonding, π-π stacking, and CH/π interactions. The enantioselective complex formation causes strong upfield shifts in the ¹H NMR spectrum even in the presence of only 5 mol % of 3.

Full text of DOI:10.1021/jo101426a

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increasing attention to the development of fast and accurate
A Versatile and Practical Solvating Agent for
Enantioselective Recognition and NMR Analysis
of Protected Amines
methods for the determination of the enantiomeric compo-
sition of scalemic mixtures. The need for fast ee analysis
has propelled the introduction of efficient assays based on
chromatography,1 mass spectrometry,2 UV3 and fluores-
cence spectroscopy,4 IR thermography,5 circular dichroism,6
capillary electrophoresis,7 and biochemical methods.8 Our
laboratory has developed several UV,9 fluorescence,10 and
CD11 probes that can be used to quantify the enantiomeric
excess and amount of scalemic mixtures of a wide range of
compounds.
Daniel P. Iwaniuk and Christian Wolf*
Department of Chemistry, Georgetown University,
Washington, D.C. 20057
cw27@georgetown.edu
Received July 20, 2010
Alternatively, NMR spectroscopy provides a useful entry
to fast ee determination.12 This generally requires the use
of a chiral derivatizing agent (CDA),13 a chiral solvat-
ing agent (CSA),14 or a paramagnetic chiral shift reagent
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The 3,5-dinitrobenzoyl-derived 1-naphthylethyl amide 3
is an attractive CSA for NMR analysis of protected
amines. It is readily prepared in a single step and com-
bines practical resolution of diastereomeric complexes
due to signal sharpness and effective signal separation.
Crystallographic analysis shows that 3 forms a chiral cleft
that can selectively bind one enantiomer of a substrate
through hydrogen bonding, π-π stacking, and CH/π
interactions. The enantioselective complex formation
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1
causes strong upfield shifts in the H NMR spectrum
even in the presence of only 5 mol % of 3.
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Published on Web 09/07/2010
DOI: 10.1021/jo101426a
r
2010 American Chemical Society

Iwaniuk and Wolf
JOCNote
(CSR)15 such as lanthanide chelate complexes.16 While
CDA’s have found widespread use for the elucidation of
the absolute configuration of chiral compounds, the use
of CSA’s and CSR’s is generally preferred for ee analysis
because this approach is faster and less prone to errors.
The accurate analysis of the enantiomeric excess of a chiral
analyte requires the use of a perfectly enantiopure CDA and
quantitative formation of diastereomeric products from the
enantiomeric starting materials to avoid chiral discrimi-
nation effects that can originate from kinetic resolution
during derivatization or purification steps. These problems
can be avoided by formation of noncovalent adducts in the
presence of a CSA or CSR which, even if not enantiopure,
provide accurate results if signal integration is not compro-
mised because of decreased peak resolution.
FIGURE 1. Structures of the Whelk-O selector and CSAs 1-3.
To date, few CSA’s for the enantiodifferentiation of chiral
amines and amides are known and proton NMR shift
differences between the diastereomeric adducts formed are
often less than 0.1 ppm.17 On the basis of our experience with
the Whelk-O selector and its analogues in chiral chromato-
graphy,18 we rationalized that the 9-anthryl- and the 3,5-
dinitrobenzoyl-derived amides 1-3 would (a) be readily
available from commercially available enantiopure amines
and (b) form diastereomeric complexes with a series of
substrates exhibiting distinct chemical shift nonequivalences
(ΔΔδ), which could potentially allow the use of substoichio-
metric amounts of the CSA.
The Whelk-O 1 chiral stationary phase was originally
developed by Pirkle and co-workers for HPLC enantiose-
paration of compounds with a hydrogen bond acceptor and
an aromatic ring in close proximity of the chiral center.19 The
Whelk-O selector consists of an amide group connecting an
electron-deficient 3,5-dinitrobenzoyl group and an electron-
rich naphthalene ring, Figure 1. Numerous chromatographic
studies, crystallography, and NMR analysis have shown that
FIGURE 2. Structures of analytes tested.
the amide unit prefers to stay in the pseudoaxial position and
thus affords a cleft-like structure that is essential for the
chiral recognition mechanism.20 It is generally assumed that
only one enantiomer of a chiral compound can diffuse into
the cleft to undergo simultaneous hydrogen bonding, π-π
interactions with the electron-deficient 3,5-dinitrobenzoyl
group, and CH/π interactions with the naphthyl moiety
of the Whelk-O selector without adopting an energetically
unfavored conformation. Immobilization of this selector on
silica gel has led to an impressive range of HPLC enantio-
separations.21 But the synthesis of this selector requires
several steps and preparative enantioseparation of the final
product, which has been a remaining drawback limiting its
use in other applications, including enantioselective NMR
analysis. By contrast, dinitrobenzoyl amides 2 and 3 can be
prepared in a single step by the condensation of 1-amino-
1,2,3,4-tetrahydronaphthalene and 1-(1-naphthyl)ethylamine
with 3,5-dinitrobenzoyl chloride in 90-91% yield (see
the SI).
On the basis of the above rationale, we assumed that one
enantiomer of a chiral aromatic substrate should diffuse
selectively into the cleft of 1-3 to undergo hydrogen bond-
ing, π-stacking, and CH/π-interactions with the host while
the other enantiomer might either participate in only two of
these interactions inside the cleft and thus have a different
orientation or it preferably resides outside the cleft. We
expected that the corresponding diastereomeric adducts
would give rise to distinctively different shielding effects that
could easily be measured by 1H NMR experiments.
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Tetrahedron: Asymmetry 2001, 12, 2019–2023. (b) Uccello-Barretta, G.;
Balzano, F.; Salvadori, P. Chirality 2005, 17, S243–S248. (c) Lovely, A. E.;
Wenzel, T. J. Org. Lett. 2006, 8, 2823–2826. (d) Cavalluzzi, M. M.; Bruno, C.;
Lentini, G.; Lovece, A.; Catalano, A.; Carocci, A.; Franchini, C. Tetrahe-
dron: Asymmetry 2009, 20, 1984–1991.
(18) (a) Wolf, C.; Pirkle, W. H. J. Chromatogr., A 1997, 785, 173–178.
€
To test the usefulness of 1-3, we prepared a series of pivaloyl
derivatives of chiral aromatic amines 4-10 and the anthracene
analogues of aminoindan and aliphatic amines 11-14, see
Figure 2 and the SI. Initial NMR analysis of stoichiometric
mixtures of the CSA’s and racemic 1-(1-naphthyl)ethylamide 4
showed that (R)-3 indeed affords diastereomeric complexes
with quite different chemical shifts, Figure 3. At relatively
low concentrations, the methyl signals Ha in 4 experience
a significant upfield shift in the homochiral adduct and the
tert-butyl protons Hb are downfield shifted. Interestingly,
(b) Wolf, C.; Pirkle, W. H.; Welch, C. J.; Hochmuth, D. H.; Konig, W. A.;
Chee, G.-L.; Charlton, J. L. J. Org. Chem. 1997, 62, 5208–5210. (c) Wolf, C.;
Spence, P. L.; Pirkle, W. H.; Derrico, E. M.; Cavender, D. M.; Rozing, G. P.
J. Chromatogr., A 1998, 782, 175–179. (d) Wolf, C.; Pirkle, W. H.
J. Chromatogr., A 1998, 799, 177–184. (e) Wolf, C.; Spence, P. L.; Pirkle,
W. H.; Cavender, D. M.; Derrico, E. M. Electrophoresis 2000, 21, 917–924.
(f) Wolf, C.; Pirkle, W. H. Tetrahedron 2002, 58, 3597–3603. (g) Wolf, C.;
Pranatharthiharan, L.; Volpe, E. C. J. Org. Chem. 2003, 68, 3287–3290.
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3854–3860. (b) Pirkle, W. H.; Welch, C. J. J. Liq. Chromatogr. 1992, 15,
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togr., A 1994, 659, 69–74. (b) Pirkle, W. H.; Welch, C. J. J. Chromatogr., A
1994, 684, 347–353. (c) Pirkle, W. H.; Welch, C. J.; Wilson, S. R. Chirality
1994, 6, 615–622. (d) Pirkle, W. H.; Terfloth, G. J. J. Chromatogr., A 1995,
704, 269–277. (e) Pirkle, W. H.; Selness, S. R. J. Org. Chem. 1995, 60, 3252–
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1998, 3, 37–43.
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Iwaniuk and Wolf
JOCNote
TABLE 1. 1H NMR Nonequivalences ΔΔδ of Amides 4-14 in the
Presence of Equimolar Amounts of CSA 3b
FIGURE 3. Selected excerpts of the 1H NMR spectra obtained
with CSA 3 and amide 4. The methyl protons are denoted as Ha and
Hb, respectively. (A) CSA 3, (B) substrate 4, (C) (R)-3 and (R)-4,
(D) (R)-3 and (S)-4, (E) (R)-3 and scalemic 4. All spectra were
recorded in CDCl3 at room temperature, using equimolar amounts
of 3 and 4 at 6.85 mM.
comparison of the NMR spectra of the heterochiral complex
and the free analyte shows a very small change in the chemical
shifts of (S)-4. The nonequivalences ΔΔδ of Ha and Hb in the
diastereomeric complexes formed with CSA 3 were determined
as 0.282 and 0.059 ppm, Table 1.22
We were able to produce a cocrystal of (R)-3 and (R)-4,
which shows that the CSA populates a cleft-like conforma-
tion having the 3,5-dinitrobenzoyl group almost perfectly
orthogonal to its naphthalene plane, Figure 4. The proton of
the amide group in (R)-3 points toward the front of the cleft
and undergoes hydrogen bonding with the carbonyl unit of
aAll shifts are upfield compared to the NMR spectrum of the free
substrate unless indicated by an asterisk. The concentration of 3 and
the substrates was 6.85 mM in CDCl3. All NMR spectra were recorded
at 25 °C.
b
˚
(R)-4. The N-O distance was determined as 2.79 A. This
interaction is complemented by π-π stacking and CH/π
forces. The distance between the cofacial 3,5-dinitrobenzoyl
˚
group and the aromatic ring of 4 is 3.66 A. The CH/π
attraction arises from the T-shaped orientation of the aro-
matic CH bonds of 4 and the naphthalene plane of the CSA,
˚
having a separation of 2.95 A. Overall, this three-point
interaction places (R)-4 into a highly ordered arrangement
inside the cleft of (R)-3. As a result, the methyl group of (R)-4
intrudes into the π-cloud and diamagnetic ring current of
the naphthalene unit of the CSA, which explains the strong
upfield shift shown in Figure 3.
FIGURE 4. Crystal structure of the homochiral complex [(R)-3-
(R)-4]. View along the cleft (left) and from the top (middle). The
individual structure of the CSA is shown for comparison.
We then decided to employ CSA 3 in NMR studies with
equimolar amounts of amides 5-14. In all cases, we observed
nonequivalences ΔΔδ that are sufficient for quantitative
enantiodifferentiation, see Table 1 and SI. The NMR spectra
collected with substrate 9 clearly demonstrate (a) the high
resolving ability of CSA 3 and (b) the conserved signal
sharpness which both contribute to high overall resolu-
tion, Figure 5. Again, the NMR signals in the homochiral
adduct [(R)-3-(R)-9] undergo more pronounced upfield
shifts than the corresponding protons in the heterochiral
complex and the tert-butyl groups show small downfield
shifts. The nonequivalences of the aromatic signals Ha and
Hb were determined as 0.103 and 0.063 ppm, respectively.
The doublets of the methyl protons He are baseline resolved
and even the peripheral methoxy groups Hc have clearly
different chemical shifts. The corresponding ΔΔδ values are
0.076 and 0.024 ppm, respectively. As expected, the diastereo-
meric adducts show the strongest NMR nonequivalences at the
methine proton Hd which are separated by 0.210 ppm.
The remarkable differences in the chemical shifts of the
methyl protons in the diastereomeric complexes formed
between (R)-3 and the enantiomers of amide 4 prompted
us to further investigate the feasibility of NMR enantiodif-
ferentiation with substoichiometric amounts of this CSA.
(22) During this study we found that CSA 3 can also be used for the
resolution of chiral sulfoxides: Deshmukh, M.; Dunach, E.; Juge, S.; Kagan,
H. B. Tetrahedron Lett. 1984, 25, 3467–3470.
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Iwaniuk and Wolf
JOCNote
FIGURE 7. Selected region of the 1H NMR spectra of scalemic
mixtures of 4 in the presence of stoichiometric amounts of (R)-3
(left). Linear correlation between the calculated and the theoretical
ee values (right).
values were generally within 3% of the actual enantiopurity
of the samples, Figure 7.
In conclusion, the facile synthesis of the 3,5-dinitroben-
zoyl-derived 1-naphthylethyl amide 3 makes this an attrac-
tive CSA for NMR analysis of amine derivatives. It com-
bines practical resolution of diastereomeric complexes due to
signal sharpness and effective signal separation. Crystallo-
graphic analysis showed that 3 forms a chiral cleft that
can accommodate the homochiral enantiomer of amide 4
through hydrogen bonding, π-π stacking, and CH/π inter-
actions. The enantioselective complex formation causes
FIGURE 5. Selected regions of the 1H NMR spectra obtained with
CSA 3 and amide 9. (A) CSA 3, (B) substrate 9, (C) (R)-3 and (R)-9,
(D) (R)-3 and (S)-9, (E) (R)-3 and scalemic 9. All spectra were
recorded in CDCl3 at room temperature, using equimolar amounts
of 3 and 9 at 6.85 mM.
1
strong upfield shifts in the H NMR spectrum even in the
presence of only 5 mol % of 3. This NMR study suggests that
immobilization of 3 on silica gel could afford a powerful
chiral stationary phase readily prepared from inexpensive
enantiopure starting materials and therefore be economically
much more attractive than the Whelk-O analogue.
Experimental Section
Synthesis of Chiral Solvating Agent 3. To a solution of (R)-1-
naphthylethyl amine (0.08 mL, 0.50 mmol) and triethyl amine
(0.08 mL, 0.57 mmol) in 2 mL of anhydrous CH2Cl2 was added
3,5-dinitrobenzoyl chloride (0.101 g, 0.44 mmol) dissolved in
3 mL of anhydrous CH2Cl2 at 0 °C. The reaction mixture was
stirred at room temperature for 2 h and then extracted with 4 M
HCl, NaHCO3, water, and brine. The combined organic layers
were dried over MgSO4 and concentrated in vacuo to afford 3
(0.145 g, 0.40 mmol) in 91% yield as a yellow solid. 1H NMR δ
1.18 (d, J = 7.1 Hz, 3H), 6.10 (dt, J = 6.9, 7.1 Hz, 1H), 6.59 (d,
J = 7.1 Hz, 1H), 7.46-7.56 (m, 3H), 7.59 (d, J = 7.1 Hz, 1H),
7.83 (d, J = 8.2 Hz, 1H), 7.86 (d, J = 8.0 Hz, 1H), 8.04 (d, J =
8.2 Hz, 1H), 8.86 (s, 2H), 9.08 (s, 1H). 13C NMR δ 20.6, 45.9,
120.9, 122.7, 128.8, 125.2, 126.1, 126.9, 127.1, 128.8, 128.9,
130.8, 133.8, 137.0, 137.4, 148.4, 161.6.
FIGURE 6. 1H NMR nonequivalences of scalemic amide 4 in
the presence of varying amounts of CSA 3. (A) 100 mol % (R)-3,
(B) 20 mol % (R)-3, (C) 5 mol % (R)-3. The substrate concentration
was kept constant at 6.85 mM in CDCl3 at room temperature.
We were pleased to find that the methyl groups adjacent to
the chiral center in 4 are still baseline resolved in the presence
of 20 and 5 mol % of CSA 3, Figure 6. This experiment
underscores the efficiency of CSA 3 in addition to the wide
application spectrum summarized in Table 1.
Acknowledgment. This material is based upon work sup-
ported by the NSF under CHE-0910604.
Finally, we prepared 9 samples of scalemic mixtures of 4
with known enantiomeric composition to confirm a linear
correlation between the actual ee values and the values
determined from NMR integration results. The calculated ee
Supporting Information Available: Experimental proce-
dures, crystallographic data, and NMR spectra. This material
is available free of charge via the Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 75, No. 19, 2010 6727