Self-disproportionation of enantiomers of 3,3,3-trifluorolactic acid amides via sublimation

Article abstract of DOI:10.1016/j.jfluchem.2009.10.002

Preparation of racemic and enantiomerically enriched N-phenyl- and N-benzyl-3,3,3-trifluorolactic acid amides has been developed. These compounds were found to have substantial magnitude of the self-disproportionation of enantiomers (SDE) via sublimation. For example, when N-phenyl-3,3,3-trifluorolactic acid amide of 87% ee was sublimed (12 h) from a Petri dish at 80 °C open to the atmosphere, the enantiomeric excess of the remainder increased to 96% ee. On the other hand, when a sample of the same compound of 67% ee was subjected to SDE via sublimation under the same conditions, the enantiomeric excess has decreased to 18% ee. These preliminary results as well as excellent chemical and physico-chemical characteristics of these amide derivatives render them as readily available and very promising substrates for systematic study of SDE via sublimation.

Full text of DOI:10.1016/j.jfluchem.2009.10.002

Journal of Fluorine Chemistry 131 (2010) 266–269
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Self-disproportionation of enantiomers of 3,3,3-trifluorolactic acid amides
via sublimation
Manabu Yasumoto a, Hisanori Ueki b, , Vadim A. Soloshonok
*
c,d,**
a Central Glass Co., 2805 Imafuku-nakadai Kawagoe, Saitama 350-1151, Japan
b International Center for Materials Nanoarchitectonics (MANA), National Institute for Materials Science (NIMS), 1-1, Namiki, Tsukuba, Ibaraki 305-0044, Japan
c Institute of Bioorganic Chemistry and Petrochemistry, National Academy of Sciences of the Ukraine, Murmanska Street, Kyiv 94 02660, Ukraine
d Department of Chemistry and Biochemistry, University of Oklahoma, Norman, OK 73019, USA
A R T I C L E I N F O
A B S T R A C T
Article history:
Preparation of racemic and enantiomerically enriched N-phenyl- and N-benzyl-3,3,3-trifluorolactic acid
amides has been developed. These compounds were found to have substantial magnitude of the self-
disproportionation of enantiomers (SDE) via sublimation. For example, when N-phenyl-3,3,3-
trifluorolactic acid amide of 87% ee was sublimed (12 h) from a Petri dish at 80 8C open to the
atmosphere, the enantiomeric excess of the remainder increased to 96% ee. On the other hand, when a
sample of the same compound of 67% ee was subjected to SDE via sublimation under the same
conditions, the enantiomeric excess has decreased to 18% ee. These preliminary results as well as
excellent chemical and physico-chemical characteristics of these amide derivatives render them as
readily available and very promising substrates for systematic study of SDE via sublimation.
ß 2009 Elsevier B.V. All rights reserved.
Received 25 August 2009
Received in revised form 2 October 2009
Accepted 2 October 2009
Available online 12 October 2009
Keywords:
Self-disproportionation of enantiomers
(SDE)
Enantiomeric enrichment/depletion
Sublimation
Evaporation
Fluorine compounds
1. Introduction
unstudied. One of the reasons of the current lack of knowledge
in this area is that most of the chemistry practitioners are unaware
Self-disproportionation of enantiomers (SDE) is a transforma-
tion of an enantiomerically enriched system resulting in the
formation of fractions of a different, as compared with the original,
proportion of the enantiomers. The phenomenon of SDE suggests
that the physico-chemical behavior of an enantiomerically
enriched system might be better described, not as a mixture of
unevenly proportioned enantiomers, but rather as a mixture of a
racemate [1] with an excess enantiomer. Thus, the ultimate
outcome of SDE is a complete separation of racemate from the
excess enantiomer. This separation is of fundamentally general
nature and can be observed under any physical processes. The
most known and widely used example of SDE is crystallization of
enantiomerically enriched compound resulting, ideally, in racemic
and optically pure fractions [2]. On the other hand, the SDE via
other typical physical processes such as, e.g., distillation/evapora-
tion [3,4], sublimation [5,6], achiral chromatography [7], gravita-
tional field [8] are substantially less known and virtually
of this phenomenon and therefore it goes unnoticed in routine
everyday laboratory experiments.
While the SDE phenomenon always takes place under any
physico-chemical transformation, its magnitude and therefore
practical observation is dependent on the physical and chemical
properties of
a particular compound, such as crystallinity,
solubility, volatility, etc. We believe that fluorinated molecules
possess a significant potential of SDE phenomenon of high
magnitude due to their unique properties, as compared with
non-fluorinated counterparts, such as increased density and
viscosity, dipole–dipole and hydrogen-bonding intermolecular
interactions, and lowered surface tension, refractive index, and
dielectric constants [9–11]. Of particular interest are compounds
containing a trifluoromethyl group which additionally impacts the
pattern of intermolecular interactions because of its strong steric
[12] and electrostatic [13] demands. For instance, isopropyl 3,3,3-
trifluorolactate shows
a remarkable magnitude of SDE via
distillation while non-fluorinated lactate did not show any
measurable SDE phenomenon under the same conditions [4].
Recently, we have discovered that a trifluoromethyl group directly
bonded to a stereogenic center can induce significant magnitude of
SDE during chromatography on achiral silica-gel stationary phase
using achiral eluent [7b–d]. Furthermore, we have found that
* Corresponding author at: International Center for Materials Nanoarchitectonics
(MANA), National Institute for Materials Science (NIMS), 1-1, Namiki, Tsukuba,
Ibaraki 305-0044, Japan.
** Corresponding author.
E-mail addresses: UEKI.Hisanori@nims.go.jp (H. Ueki), vadim@ou.edu
(V.A. Soloshonok).
racemic crystals of
a-(trifluoromethyl)lactic acid sublime at
0022-1139/$ – see front matter ß 2009 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2009.10.002

M. Yasumoto et al. / Journal of Fluorine Chemistry 131 (2010) 266–269
267
substantially higher rates, as compared with the optically pure
form, leading to appreciable magnitude of SDE via sublimation [6].
Thus, remarkably, optical purification of enantiomerically enriched
samples of
a-(trifluoromethyl)lactic acid can be achieved under
ultimately simple conditions, just leaving the compound on a
bench in open air [6]. This data strongly suggest that compounds
containing a trifluoromethyl group directly bonded to a stereo-
genic center represent a privileged class of molecules most suitable
for a systematic study of SDE. In particular, we decided to
investigate a possible SDE of some new derivatives of 3,3,3-
trifluorolactic acid. In this communication we report the synthesis
of amide derivatives of 3,3,3-trifluorolactic acid in racemic and
enantiomerically enriched form, as well as preliminary results on
their SDE via sublimation.
2. Results and discussion
As representative examples of an aliphatic and an aromatic
amide of 3,3,3-trifluorolactic acid, we prepared phenyl (2a) and
benzyl (2b) derivatives. The racemate (R/S)-2b was prepared from
compound 1 by the standard condition (Entry 1). On the other
hand, the synthesis of optically pure 2b under the same conditions
resulted in racemization (Entry 2), probably due to the substan-
Fig. 1. Sublimation of racemate and >99% ee 2a at 80 8C.
the enantiomerically pure crystals (S)-2a. Thus, the initial rates of
sublimation of (R/S)-2a and (S)-2a are 0.0062 and 0.0099 [g/h],
respectively.
The obtained results of noticeably different sublimation rates of
racemic 2a and enantiomerically pure 2a forms suggested that,
first, in this case the SDE via sublimation should have a substantial,
practically useful magnitude; and, second, in the range of samples
of various enantiomeric purity, the sublimed material might
undergo optical enrichment, while the remainder—optical deple-
tion. Thus, when a sample of 2a of 67% ee was subjected to
sublimation (Fig. 2), the optical purity of the remainder gradually
decreased from 67 to 18% ee after 15.5 h. On the other hand, in the
case of a sample of 89% ee, the enantiomeric purity of the
remainder increased slowly up to 96% ee after 12 h of sublimation.
All the samples were prepared from (R/S)-2a and (S)-2a by mixing
and well grinding.
Similarly, when a sample of 67% ee benzyl amide 2b prepared
by mixing racemate and 88% ee samples was subjected to
sublimation under the same conditions (Petri dish, open air, at
50 8C) (Fig. 3), the optical purity of the remainder gradually
decreased to 27% ee after 131 h.
These results clearly demonstrate that N-phenyl- and N-benzyl-
3,3,3-trifluorolactic acid amides 2a and 2b are interesting and
quite useful substrates for the systematic study of SDE via
sublimation. Compounds 2a and 2b are easily available in racemic
and enantiomerically enriched forms, highly crystalline, and
reasonably volatile. Furthermore, compounds 2a and 2b are
chemically and configurationally stable and can be readily
monitored by TLC. All these important features render compounds
tially increased acidity of the
a-hydrogen activated by the strong
electron withdrawing effects of the –CF3 group. We then
attempted to prepare optically pure 2b using various other
methods, but racemization was found to be a persistent problem.
However, the activation of acid 1 under relatively mild conditions
using SOCl2 allowed us to obtain the target product 2b with an
optical purity of 88% ee (Entry 3). While the unexpected problem of
racemization is still waiting for more optimal synthetic solution,
the prepared sample of relatively high enantiomeric purity was
sufficient to continue with our preliminary SDE via sublimation
experiments. For the aromatic amide 2a, Method A also worked
quite efficiently for the synthesis of racemic (R/S)-2a (Entry 4). For
the synthesis of (S)-2a, treatment of compound 1 with methane
sulfonyl chloride resulted in racemization of the final product
whilst with the use of thionyl chloride did not cause any undesired
racemization (Entries 5 and 6) (Table 1).
As we always suggest doing for the initial study of SDE via
sublimation [6], the racemic and optically pure samples of 2a were
sublimed separately at 80 8C on a Petri dish under open air
condition (Fig. 1). In sharp contrast to the results reported for of a-
CF3-lactic acid [6] and 3,3,3-trifluorolactic acid isopropyl ester [4],
racemic crystals (R/S)-2a sublimed substantially more slowly than
Table 1
Synthesis of 3,3,3-trifluorolactic acid amides.
.
Entry
1
Method
Yield (%)
ee of 2a (%)
1
2
3
4
5
6
(R/S)-1
(S)-1
A
A
B
A
A
B
44
41
18
43
51
31
0 (b)
0 (b)
(S)-1
88 (b)
0 (a)
(R/S)-1
(S)-1
0 (a)
(S)-1
>99 (a)
a
Fig. 2. SDE of 2a at 80 8C. Time dependent change of % ee of the remainder.
Enantiomeric excesses were determined by chiral HPLC.

268
M. Yasumoto et al. / Journal of Fluorine Chemistry 131 (2010) 266–269
After filtration and silica-gel column, the desired compound 2 was
obtained.
3.3. N-Phenyl-3,3,3-trifluorolactyl amide (2a)
1H NMR in CDCl3
d 3.93 (1 H, s), 4.57 (1 H, q, J = 7.0 Hz), 7.18–
7.23 (1 H, m), 7.35–7.41 (2 H, m), 7.53–7.56 (2 H, m), 7.90 (1 H, s).
19F NMR
d
À76.3 (s). 13C NMR
d 70.3 (q, J = 32 Hz), 120.3, 122.8 (q,
J = 283 Hz), 125.7, 129.3, 136.1, 162.4. HRMS (TOF) [M+H]+, calcd
for [C9H8F3NO2+H]+: 220.0585, found: 220.0522. mp of racemate:
124 8C, mp of chiral isomer: 108 8C.
3.4. N-Benzyl-3,3,3-trifluorolactyl amide (2b)
1H NMR in CDCl3
J = 5.6 Hz), 6.47 (1 H, s), 7.28–7.40 (5 H, m). 19F NMR
NMR
128.9, 136.6, 164.6. HRMS (TOF) [M+H]+, calcd for
[C10H10F3NO2+Na]+: 256.0561, found: 256.0593. mp of racemate:
92 8C.
d
4.42 (1 H, q, J = 7.0 Hz), 4.56 (2 H, d,
Fig. 3. SDE of 2b at 50 8C. Time dependent change of % ee of the remainder.
d
À76.6 (s). 13
C
d
44.0, 69.9 (q, J = 32 Hz), 122.8 (q, J = 283 Hz), 127.6, 128.0,
2a and 2b, and most probably other amide derivatives, as very
promising structures for the systematic study of SDE via
sublimation and its practical applications. These results also
support the hypothesis that compounds containing –CF3 group
directly bonded to a stereogenic carbon center are prone to induce
a SDE effect.
3.5. Determination of rates of sublimation of (R/S)- and (S)-2a on a
Petri dish
3. Experimental
Sublimation experiment of (R/S)- and (S)-2a was conducted on a
Petri dish (surface are 20.25p
cm2) at 80 8C under atmospheric
3.1. General
pressure. Since sublimation rates are affected by various physical
factors such as temperature and wind, the experiments with
racemate and optically pure compounds were conducted at the
same time. As shown in Fig. 2, after a long time sublimation time
dependent loss of the remainder started curving because the
surface area became uneven. Therefore, as the determination of
sublimation rates, initial rates (0–6 h) are used.
Unless otherwise noted, all reagents and solvents were
obtained from commercial suppliers and used without further
purification. All of the reactions were carried out under N2
atmospheric conditions. Unless indicated 1H and 13C NMR spectra,
were taken in CDCl3 solutions at 299.95 and 75.42 MHz,
respectively. Chemical shifts for 1H and 13C NMR refer to TMS
as the internal standard. Chemical shifts for 19F NMR refer to CFCl3
as the internal standard. A Micromass Q-TOF was used to measure
the time-of-flight electrospray mass spectra in positive ion mode
(TOF-ESIMS+). All new compounds were characterized by 1H, 13C
and 19F NMR, high-resolution mass spectrometry (HRMS-ESI), and
melting point, when applicable.
The optical purity of 2a and 2b was determined by HPLC (OD-H:
0.46 cm  25 cm). The flow rate of solvent (n-hexane/i-PrOH = 90/
10) was set at 1.0 mL/min. The retention times of compound 2b
were 8.9 and 10.7 min. The retention times of compound 2a were
8.9 and 10.8 min.
3.6. General SDE experiments procedure
Just prior to the start of the experiments, various optically
enriched samples were prepared by simply mixing racemate and
optically pure crystals in appropriate amounts and well grinding of
the mixture, following which the optical purity was measured. The
optically enriched sample was spread on a Petri dish as flat as
possible, and sublimation experiments conducted under atmo-
spheric pressure at 50 8C for 2b and 80 8C for 2a. After certain
amount of time, the sample (0.01 g) of the remaining crystals on
the Petri dish was taken for determination of its enantiomeric
composition. Before the sampling, the remaining crystals on the
Petri dish were carefully agitated with a spatula to provide for an
even and homogeneous distribution of the remaining compound.
3.2. General synthetic procedure
Method A: To a CH2Cl2 solution (3 mL) containing 1 (0.50 g,
3.47 mmol), was added methane sulfonyl chloride (0.40 g,
3.47 mmol), N-methylimidazole (0.85 g, 10.4 mmol), and amine
(4.17 mmol) in this order at 0 8C under N2 atmosphere. The
reaction mixture was stirred overnight. Then, 3N HCl aq was added
to the reaction mixture and the organic layer extracted with CH2Cl2
three times. The combined organic layers were dried over
anhydrous MgSO4. After filtration and crystallization from
CH2Cl2/n-hexane, the desired compound 2 was obtained.
Acknowledgments
This work was supported by the Department of Chemistry and
Biochemistry, The University of Oklahoma. The authors gratefully
acknowledge generous financial supports from Central Glass
Company (Tokyo, Japan) and Ajinomoto Company (Tokyo, Japan).
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Method B: To a CH2Cl2 solution containing 1 (1.0 g, 6.94 mmol),
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organic layer was extracted with CH2Cl2 three times. The
combined organic layers were dried over anhydrous MgSO4.
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