Chiral self-discrimination of the enantiomers of α-phenylethylamine derivatives in proton NMR

Article abstract of DOI:10.1002/mrc.2406

Two types of chiral analytes, the urea and amide derivatives of α-phenylethylamine, were prepared. The effect of inter- molecular hydrogen-bonding interaction on self-discrimination of the enantiomers of analytes has been investigated using high-resolutio

Full text of DOI:10.1002/mrc.2406

Research Article
Received: 24 November 2008
Revised: 25 December 2008
Accepted: 5 January 2009
Published online in Wiley Interscience: 17 February 2009
(www.interscience.com) DOI 10.1002/mrc.2406
Chiral self-discrimination of the enantiomers
of α-phenylethylamine derivatives in proton
NMR
Shao-Hua Huang,a,b Zheng-Wu Baic∗ and Ji-Wen Fenga∗
Two types of chiral analytes, the urea and amide derivatives of α-phenylethylamine, were prepared. The effect of inter-
molecular hydrogen-bonding interaction on self-discrimination of the enantiomers of analytes has been investigated using
1
high-resolution H NMR. It was found that the urea derivatives with double-hydrogen-bonding interaction exhibit not only
the stronger hydrogen-bonding interaction but also better self-recognition abilities than the amide derivatives (except
for one bearing two NO2 groups). The present results suggest that double-hydrogen-bonding interaction promotes the
c
self-discrimination ability of the chiral compounds. Copyright ꢀ 2009 John Wiley & Sons, Ltd.
Keywords: NMR; 1H NMR; enantiomer; chiral self-discrimination; hydrogen-bonding interaction
Introduction
NMR spectrometers. It is found that urea-type derivatives
1 and 2 with double-HB interaction exhibit higher self-
recognition abilities than amide-type derivatives 3–5 and 7
with single-HB interaction, except for 6, bearing two NO2
groups.
Nuclear magnetic resonance (NMR) spectroscopy can determine
the enantiomeric excess (ee) values of chiral compounds by use
of the chiral solvating agents or shift reagents.[1–5] For some
chiral compounds, however, their ee values can be determined
directly by NMR spectroscopy without the use of the chiral
auxiliaries. The latter is based on the chiral self-discrimination
phenomenon.[6–19] In a non-racemic mixture, different signals
from R- and S-enantiomers can be observed when the binary
associations occur under the fast exchange condition on the NMR
timescale and the chemical shift of the sensor nuclei in the ho-
mochiral dimer (RR or SS) is different from that in the heterochiral
dimer (RS or SR) to some extent. The enantiomer mixture thus
exhibits chiral self-discrimination.[6,7] The chiral self-discrimination
phenomenon was first observed by Uskokovic and coworkers
in dihydroquinine in 1969.[8] Since then, self-discrimination
has been found in a variety of chiral compounds, such as
phosphorus acid derivatives,[9–12] 2-substituted-1,2-glycols,[13]
phosphonate of alcohols,[14] amino acid derivatives,[15] diols,[16]
carboxamides,[17] 2-anilino-2-oxo-1,3,2-oxazaphosphorinanes,[18]
3-mercaptoderivatives of 2-bromopropanoic acid,[19] and so on.
It is generally recognized that inter-molecular hydrogen-bonding
(HB) interaction plays an important role in self-recognition.[15,17]
But detailed studies on HB dependence of self-recognition are still
lacking.Becauseofthewell-knownabilityofurea-typecompounds
to form inter-molecular HB, enantiomeric self-discrimination in
these compounds might be expected to be a fairly common
occurrence, but heretofore no example has been reported.
Experimental
Materials and chemicals
(R)-(+)-α-phenylethylamine (purity
>
99.0%), (S)-(-)-α-
phenylethylamine (purity 99.0%), benzoyl chloride,
>
p-methyl benzoyl chloride, 3,5-dinitrobenzoyl chloride,
3,5-dimethylbenzoyl chloride, and 1-naphthylchloride were pur-
chased from China National Medicines Corporation Ltd and used
as received. Phenylisocyanate and p-methylphenylisocyanate
were obtained from Sigma-Aldrich and used as received. Deuter-
ated chloroform (CDCl3) and deuterated trifluoroacetic acid were
purchased from Cambridge Isotope Laboratories, Inc. CDCl3 was
dried with molecular sieve before use. All other chemicals for the
syntheses of chiral analytes were of analytical grade and were
used as received.
∗
Correspondence to: Ji-Wen Feng, State Key Laboratory of Magnetic Resonance
andAtomicandMolecularPhysics,WuhanInstituteofPhysicsandMathematics,
the Chinese Academy of Sciences, Wuhan 430071, China
E-mail: jwfeng@wipm.ac.cn
Zheng-Wu Bai, School of Chemical Engineer and Pharmacy,Wuhan Institute of
Technology,Wuhan 430073, China. E-mail: zhengwu bai@yahoo.com
In this work, we designed two urea-type compounds 1 and
2 (Fig. 1) based on α-phenylethylamine by considering HB as
a driving force of binding. In addition, five amide deriva-
tives, 3–7 (Fig. 1) of α-phenylethylamine, were also prepared
to compare the self-discrimination abilities of these amide
analytes with urea analytes. Herein, we report how two dif-
ferent HB interactions and different substituent groups im-
pact the self-recognition of analytes 1–7 using high-resolution
a
StateKeyLaboratoryofMagneticResonanceandAtomicandMolecularPhysics,
WuhanInstituteofPhysicsandMathematics, theChineseAcademyofSciences,
Wuhan 430071, China
b
c
Graduate School of the Chinese Academy of Sciences, Beijing 100039, China
School of Chemical Engineer and Pharmacy, Wuhan Institute of Technology,
Wuhan 430073, China
c
Magn. Reson. Chem. 2009, 47, 423–427
Copyright ꢀ 2009 John Wiley & Sons, Ltd.

S.-H. Huang, Z.-W. Bai and J.-W. Feng
Figure 1. Structures of analytes 1–7.
Syntheses of the enantiomers of chiral analytes 1–7
The R- and S-enantiomers of the analytes 1–7 were separately
prepared according to similar procedures. Herein, take the
(R)-isomer of analyte as example. To a solution of 1.0 mol (R)-
(+)-α-phenylethylamine and 1.0 mol triethylamine in 20 ml dried
dichloromethane, 1.1 mol aromatic isocyanate or acyl chloride
in 10 ml dried dichloromethane was added dropwise under a
nitrogen atmosphere at room temperature. The resulting reaction
solutionwasstirredfor5 h,andthenwashedbydilutehydrochloric
acid solution, aqueous saturated sodium bicarbonate solution,
and water, respectively. After the removal of dichloromethane,
the residue was recrystallized from trichloromethane to obtain
the analyte. The individual characterization of (R)-analytes is as
follows:
Analyte (R)-1: mp: 141–143 ◦C; IR (KBr, cm−1): 3318 (N-H,
st), 3027 (aromatic H, w), 2984 (C-H, w), 1634 (C = O, st),
1556–1524 (aromatic C = C, st); 1H NMR (500 MHz CDCl3, 25 ◦C):
δ = 7.387–7.210, 7.066 (aromatic H), 6.234 (PhNH), 4.975 (CH),
4.960 (CHNH), 1.491 ppm (CH3).
Figure 2. 1H NMR spectra (500 MHz) for the CH3 group in mixtures of
(R)-1/(S)-1 [(a) 50/50, (b) 60/40, (c) 70/30, (d) 80/20, (e) 90/10, and (f) 100/0]
in CDCl3. The total molar concentration of the mixtures is 50 mM.
Analyte (R)-2: mp: 159–161 ◦C; IR (KBr, cm−1): 3293 (N-H,
st), 3041 (aromatic H, m), 2992 (C-H, m), 1632 (C = O, st),
1567–1524 (aromatic C = C, st); 1H NMR (500 MHz CDCl3, 25 ◦C):
δ = 7.360–7.248 (aromatic H), 6.055 (PhNH), 4.982 (CH), 4.864
(CHNH), 2.303 (PhCH3), 1.491 ppm (CHCH3).
of naphth.), 7.464–7.289 (aromatic H of benzene), 6.196 (NH),
5.475 (CH), 1.671 ppm (CH3).
NMR Spectra
Analyte (R)-3: mp: 116–118 ◦C; IR (KBr, cm−1): 3331 (N-H, st),
3083, 3060 (aromatic H, w), 2968 (C-H, w), 1635 (C = O, st),
1535–1524 (aromatic C = C, st); 1H NMR (500 MHz CDCl3, 25 ◦C):
δ = 7.773, 7.498–7.286 (aromatic H), 6.301 (NH), 5.351 (CH),
1.678 ppm (CH3).
All NMR experiments were performed on a Bruker AV 500
spectrometer operating at 500.1 MHz. The spectral width was
6000.15 Hz for 1H. The acquisition time was set to 1.5 s and
the relaxation delay 2 s for all the one-dimensional experiments.
CDCl3 was used as a solvent for all NMR measurements with
tetramethylsilane used as an internal reference at 25 ◦C. The
preparationprocessofsampleswasasfollows:samplesforanalysis
were prepared by weighing the proper amount of analytes to
achieve the desired concentrations and dissolving them in 0.6 ml
CDCl3.
Analyte (R)-4: mp: 134–136 ◦C; IR (KBr, cm−1): 3351 (N-H, st),
3032 (aromatic H, m), 2986 (C-H, m), 1652 (C = O, st), 1589–1542
◦
1
(aromatic C = C, st); H NMR (500 MHz CDCl3, 25 C): δ = 7.669,
7.402–7.221 (aromatic H), 6.253 (PhNH), 5.342 (CH), 2.389 (PhCH3),
1.607 ppm (CHCH3).
Analyte (R)-5: mp: 93–95 ◦C; IR (KBr, cm−1): 3307 (N-H, st),
3062, 3027 (aromatic H, w), 2968 (C-H, m), 1635 (C = O, st),
1535–1524 (aromatic C = C, st); 1H NMR (500 MHz CDCl3, 25 ◦C):
δ = 7.397–7.267 (PhCH)), 6.887 (o-PhCO)), 6.569 (p-PhCO)), 6.261
(NH), 5.311 (CH), 3.818 (OCH3), 1.491 ppm (CHCH3).
Results and Discussion
The proton NMR spectra in Fig. 2 display the self-recognition of
a (R)-1/(S)-1 mixture in CDCl3 at different ee values [the total
(R)-1/(S)-1 molar concentration is kept constant at 50 mM]. For
nominally pure (R)-1 in CDCl3, a large doublet signal (JHH = 6.8 Hz)
from CH3 group of (R)-1 is observed at δ = 1.409 ppm (Fig. 2f).
Besides, a very weak doublet from CH3 group of (S)-1 is also
seen at the high-frequency side of the main doublet of (R)-1,
indicating that our (R)-1 is not 100% pure. With gradual increase
in the ratio of (S)-1/(R)-1, the small doublet from (S)-1 moves
progressively to lower frequencies with a simultaneous intensity
Analyte (R)-6: mp: 152–154 ◦C; IR (KBr, cm−1): 3338 (N-H, st),
3095 (aromatic H, m), 2980 (C-H, w), 1641 (C = O, st), 1541 (NO2, st),
1540–1535 (aromatic C = C, st); 1H NMR (500 MHz CDCl3, 25 ◦C):
δ = 9.156 (p-PhCO), 8.935 (o-PhCO), 7.419–7.309 (PhCH), 6.563
(NH), 5.361 (CH), 1.684 ppm (CH3).
Analyte (R)-7: mp: 86–87 ◦C; IR (KBr, cm−1): 3310 (N-H,
st), 3053 (aromatic H, m), 2973 (C-H, m), 1639 (C = O, st),
1554–1538 (aromatic C = C, st); 1H NMR (500 MHz CDCl3,
25 ◦C): δ = 8.292, 8.275, 7.919–7.856, 7.611–7.503 (aromatic H
c
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Copyright ꢀ 2009 John Wiley & Sons, Ltd.
Magn. Reson. Chem. 2009, 47, 423–427

Chiral self-discrimination of α-phenylethylamine derivatives
Table 1. Effect of ee on self-discrimination for the CH3 and PhNH groups of analyte 1
CH3
PhNH
b
b
R/S (ee)a
δR
δS
ꢀδ c
eed
δR
δS
ꢀδ
ee
50/50 (0.0)
60/40 (20.0)
70/30 (40.0)
80/20 (60.0)
90/10 (80.0)
100/0 (100)
1.424
1.418
1.415
1.410
1.410
1.409
1.424
1.424
1.427
1.429
1.434
–
0
0
6.731
6.759
6.766
6.795
6.775
6.767
6.731
6.750
6.746
6.762
6.733
–
0
0
0.006
0.012
0.019
0.024
–
19.8 (−0.2)
39.9 (−0.1)
60.3 (+0.3)
80.5 (+0.5)
–
−0.009
−0.020
−0.033
−0.042
–
20.1 (+0.1)
40.3 (+0.3)
59.5 (−0.5)
80.7 (+0.7)
–
a Effective enantiomeric ratio. The total molar concentration of the mixture of (R)-1/(S)-1 is kept constant at 50 mM.
b Chemical shift (ppm) measured at 500 MHz using TMS as the internal reference, in CDCl3 at 25 ◦C.
c ꢀδ = δS − δR.
d The ee values calculated from the integration of NMR spectra. Deviations from effective values in parentheses.
increase, whereas the main CH3 group of (R)-1 doublet shifts to
Table 2. Effect of concentration on self-discrimination for the CHCH3
groups of analytes 1–7
higher frequencies with a gradual intensity decrease. When the
ratio of (S)-1/(R)-1 reaches 50/50, the two doublets coincide at
δ = 1.424 ppm (Fig. 2a). Obviously, the separation between the
(R)-CH3 and (S)-CH3 signals, which characterizes the chiral self-
recognition ability, depends strongly on the ratio of (R)-1/(S)-1,
and the large separation is observed at a high (R)-1/(S)-1 ratio (see
also Table 1). From Table 1, one further sees that the chemical shift
difference between two CH3 signals increases almost linearly by
ca 0.006 ppm for each 20% raise in the ee value for the (R)-1/(S)-1
ratio larger than 50/50. In addition, the ee values calculated from
the integrations of (R)- and (S)-CH3 signals are approximately equal
to the designed ee values in the mixture. Similar trends are also
found for the PhNH signals of (R)-1 and (S)-1 (Table 1).
Tables 2 and 3 compare the self-recognition abilities of the
urea and amide analytes. From Table 2, one can see that the (R)-
CHCH3 and (S)-CHCH3 signals from the enantiomers of the urea
derivatives 1 and 2 display observably different chemical shifts
even at a very low concentration of 10 mM. The chemical shift
difference between (R)-CHCH3 and (S)-CHCH3 groups increases
with an increase in total concentration of the mixtures of (R)-
isomer/(S)-isomer (90/10) of analytes [also see Fig. 3, which
shows the spectra for the self-recognition of the CH3 group in
mixtures of (R)-1/(S)-1 (90/10) in CDCl3]. When the concentration
is increased to 100 mM, the large separations, 0.040 ppm for 1
and 0.031 ppm for 2, are obtained. In contrast, enantiomers of the
amide derivatives 3–5 and 7 show almost no self-discrimination
under the same experimental conditions. However, the amide
derivative 6 bearing two NO2 groups exhibits remarkable self-
recognition ability comparable with the amide derivative 1 under
the same conditions although the molecular structures of 1 and
6 are different from each other. The NH groups of analytes 1–7
in Table 3 also show that the enantiomers of the urea derivatives
possess good self-discrimination abilities while the enantiomers
of the amide derivatives can not recognize themselves except for
analyte 6.
Ca
b
Analyte
δ
2
10
25
50
100
ꢀδC
c
c
1
δR
δS
1.501 1.464 1.457 1.410 1.349 0.152
1.501 1.477 1.470 1.434 1.389 0.112
d
ꢀδobs
0
0.006 0.013 0.024 0.040
–
2
3
4
5
6
7
δR
δS
1.484 1.473 1.451 1.416 1.356 0.128
1.484 1.476 1.459 1.433 1.387 0.097
ꢀδobs
0
0.003 0.008 0.017 0.031
–
δR
δS
1.620 1.618 1.615 1.611 1.602 0.018
1.620 1.618 1.615 1.611 1.605 0.015
ꢀδobs
0
0
0
0
0.003
–
δR
δS
1.615 1.613 1.611 1.608 1.600 0.015
1.615 1.613 1.611 1.608 1.603 0.012
ꢀδobs
0
0
0
0
0.003
–
δR
δS
1.610 1.609 1.607 1.603 1.596 0.014
1.610 1.609 1.607 1.603 1.601 0.009
ꢀδobs
0
0
0
0
0.005
–
e
δR
δS
1.692 1.685 1.675 1.661
1.692 1.691 1.688 1.685
–
0.031f
0.007f
–
–
–
ꢀδobs
0
0.006 0.013 0.024
δR
δS
1.670 1.668 1.662 1.654 1.637 0.033
1.670 1.668 1.662 1.654 1.637 0.033
ꢀδobs
0
0
0
0
0
–
a Themolarconcentration(mM)ofthemixturesof(R)-isomer/(S)-isomer
(90/10).
b ꢀδC = |δC=2 mM − δC=100 mM|.
c Chemical shift (ppm) measured at 500 MHz using TMS as the internal
reference, in CDCl3 at 25 ◦C.
d ꢀδobs = δS − δR.
e No experimental data due to the low solubility of the mixtures of
(R)-6/(S)-6 (90/10).
f ꢀδC = |δC=2 mM − δC=50 mM|.
To understand the distinct self-recognition abilities of the enan-
tiomers of the urea and amide derivatives of α-phenylethylamine,
it is necessary to inspect how the enantiomeric molecules inter-
act. Generally, inter-molecular HB interaction between homo- or
hetero-isomersbecomesdominantwhenthechiralmoleculeswith
both HB acceptor and donor sites are dissolved in a low-polarity
solvent. And it is believed that inter-molecular HB interaction
betweenchiralmoleculesplaysakeyroleintheself-discrimination.
This was supported by the ‘acid-treatment’ experiment (see Fig. 4),
which reveals that no effective HB interaction between homo- or
hetero-isomers results in non-self-discrimination for chiral com-
pounds.
Harger was the first to suggest the formation of the di-
astereomeric cyclic dimers (8, see Fig. 5) to account for the
self-discrimination effect of chiral phosphinamides and phos-
c
Magn. Reson. Chem. 2009, 47, 423–427
Copyright ꢀ 2009 John Wiley & Sons, Ltd.
www.interscience.wiley.com/journal/mrc

S.-H. Huang, Z.-W. Bai and J.-W. Feng
Table 3. Effect of concentration on self-discrimination for the NH
groups of analytes 1–7
C
Analyte
δ
2
10
25
50
100
ꢀδC
1 (CHNH)
δR
δS
4.888 5.101
4.888 5.101
5.141
5.141
0
5.377
5.361
5.663 0.775
5.640 0.752
ꢀδobs
0
0
−0.016 −0.023
–
1 (PhNH)
δR
δS
6.148 6.422
6.148 6.403
6.474
6.451
6.776
7.138 0.990
6.734
7.078 0.930
ꢀδobs
0
−0.019 −0.023 −0.042 −0.060
–
2 (CHNH)
δR
δS
4.834 4.911
5.055
5.055
0
5.253
5.253
0
5.552 0.718
4.834 4.911
5.531 0.697
ꢀδobs
0
0
−0.021
–
2 (PhNH)
δR
δS
6.019 6.121
6.019 6.121
6.307
6.291
6.561
6.530
6.933 0.914
6.884 0.865
ꢀδobs
0
0
−0.016 −0.031 −0.049
–
3
4
5
6
7
δR
δS
6.288 6.299
6.288 6.299
6.317
6.317
0
6.343
6.343
0
6.398 0.110
6.398 0.110
ꢀδobs
0
0
0
–
δR
δS
6.252 6.259
6.252 6.259
6.272
6.272
0
6.296
6.296
0
6.342 0.090
6.342 0.090
ꢀδobs
0
0
0
–
δR
δS
6.245 6.254
6.245 6.254
6.270
6.270
0
6.297
6.297
0
6.353 0.108
6.353 0.108
ꢀδobs
0
0
0
–
δR
δS
6.452 6.533
6.452 6.533
6.647
6.623
6.801
6.764
–
–
–
0.349
0.312
–
ꢀδobs
0
0
−0.024 −0.037
6.215
6.215
0
Figure 3. 1H NMR spectra (500 MHz) for the CH3 group in mixtures of (R)-
1/(S)-1 (90/10) in CDCl3. The total molecular concentrations of the mixtures
are (a) 100 mM, (b) 50 mM, (c) 25 mM, (d) 10 mM, and (e) 2 mM.
δR
δS
6.195 6.202
6.195 6.202
6.235
6.235
0
6.274 0.079
6.274 0.079
ꢀδobs
0
0
0
–
All conditions are the same as those in Table 2.
between the urea enantiomeric molecules is considered to be
dominant. By contrast, the one amide proton of derivatives 3–5
and 7 can only form a single HB (14, see Fig. 5) with a carbonyl
oxygen of the other amide enantiomeric molecule. Generally, the
double-HB interaction is expected to be much stronger than the
single-HBinteraction. Thestrong double-HBinteractionappearing
in analytes 1 and 2 may be responsible for their good self-
discrimination [e.g. large chemical shift difference between the
amide protons of (R)-isomer and (S)-isomer], whereas the weak
single-HB interaction for analytes 3–5 and 7 leads to their poor
self-discrimination.
phinothioic acids.[11,12] Cung et al.[20] and Dobashi et al.[15] also
attributed the self-discrimination of amino acid derivatives to
the diastereomeric cyclic dimers (9 and 10, see Fig. 5). But cyclic
dimeric associations are not regarded as appropriate models for
monocarboxamides because the amide function prefers the anti
conformation (11, see Fig. 5)[21] and cannot form a cyclic dimer.
Therefore, Jursicet al. postulatedthattheHBassociationsinsimple
carboxamides must be linear.[17]
The previous studies investigated only the monocarboxamide,
not the monourea. It is believed that the monourea functionality
also prefers the anti–anti conformation (12, see Fig. 5) and cannot
form a cyclic dimer. Therefore, it is considered that the HB
associations between urea derivative molecules are also linear.
From Table 3, one can see that the two amide protons of urea
1 or 2 show large chemical shift variation ꢀδC values, meaning
that in both cases two amide protons are involved in inter-
molecular HB interaction. Moreover, the chemical shift variation
values (ꢀδC) of amide protons of urea derivatives 1 and 2 are
approximately one order higher than those of amide derivatives
3–5 and 7, indicating that the HB interaction between urea
enantiomeric molecules are much stronger than those between
amide enantiomeric molecules except for amide derivative 6. For
urea derivatives 1 and 2, the double-HB interaction (13, see Fig. 5)
From Table 3, one sees that the self-recognition abilities of
analytes 1–7 are also dependent on the substituent groups.
The urea derivative 1 shows stronger double-HB interaction and
better self-recognition ability than 2. It is noted that the structural
difference between 1 and 2 is that 2 bears only an additional CH3
group in the para-position of the phenyl group (see Fig. 1). As CH3
is a weak electron-donating group, its existence lowers the HB
donor ability of amide group and thus weakens the HB interaction
giving rise to the small ꢀδC values of the NH groups of 2 and
resulting in lower self-recognition ability of 2. Among five amide
derivatives with single-HB interactions, on the other hand, only 6,
containing two NO2 groups, shows good self-recognition ability.
This could also be attributed to the stronger inter-molecular HB
interaction of 6. Two powerful electron-withdrawing groups (NO2
groups) in the structure of 6 enhance the HB donor ability of the
c
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Copyright ꢀ 2009 John Wiley & Sons, Ltd.
Magn. Reson. Chem. 2009, 47, 423–427

Chiral self-discrimination of α-phenylethylamine derivatives
Conclusion
It is concluded that the double-HB interaction for the urea
derivatives of α-phenylethylamine is more favorable to self-
discrimination than the single-HB for the corresponding amide
derivatives without NO2 function groups. The appearance of NO2
functiongroups, inthemeta-positionofthephenylgroupadjacent
to the carboxyl group in 6, significantly intensifies single-HB
interaction and improves the chiral self-recognition ability.
Acknowledgements
WegratefullyacknowledgethefinancialsupportfromtheNational
Natural Science Foundation of China (No. 10474116 and No.
10674152).
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Figure 5. Schematic representation of the HB interactions of different
enantiomers 8–12 (from Refs. [11,12,15,17,20,21]) and the configurations
of urea 13 and amide 14.
amide group and thus intensify the single HB, as indicated by the
large ꢀδC values of the NH groups of (R)-6/(S)-6. NO2-enhanced
HB interaction thus improves the self-recognition ability of 6.
c
Magn. Reson. Chem. 2009, 47, 423–427
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