Spontaneous oscillatory in vitro chiral conversion of simple carboxylic acids and its possible mechanism

Article abstract of DOI:10.1002/poc.1739

In earlier studies, we have collected experimental evidence (mostly from thin-layer chromatography and polarimetry) on the spontaneous oscillatory in vitro chiral conversion of simple carboxylic acids dissolved in 70% aqueous ethanol. To elucidate this phenomenon, we developed a simple theoretical model of two linked Templators. Recently, we have obtained additional experimental evidence of the spontaneous condensation of chiral carboxylic acids, based on the biuret test (amino acids), high performance liquid chromatography, and ¹³C NMR spectroscopy (profens and hydroxy acids). We briefly describe our experimental results in the context of the existing literature and outline an improved theoretical model for these phenomena. Our system resembles in some respects the reported oscillatory condensation of organic silanols. Here, the key reaction is the formation of carboxylic acid-derived enols. Finally, we discuss the importance of the oscillatory chiral conversion of simple carboxylic acids for biochemistry, pharmacology, and related life sciences. Copyright

Full text of DOI:10.1002/poc.1739

Research Article
Received: 10 November 2009,
Revised: 8 April 2010,
Accepted: 15 April 2010,
Published online in Wiley Online Library: 29 June 2010
(wileyonlinelibrary.com) DOI 10.1002/poc.1739
Spontaneous oscillatory in vitro chiral
conversion of simple carboxylic acids and its
possible mechanismy
Mieczysław Sajewicza, Marek Matlengiewicza, Marcin Ledab,
Monika Gontarskaa, Dorota Kronenbacha, Teresa Kowalskaa
and Irving R. Epsteinb
*
In earlier studies, we have collected experimental evidence (mostly from thin-layer chromatography and polarimetry)
on the spontaneous oscillatory in vitro chiral conversion of simple carboxylic acids dissolved in 70% aqueous ethanol.
To elucidate this phenomenon, we developed a simple theoretical model of two linked Templators. Recently, we have
obtained additional experimental evidence of the spontaneous condensation of chiral carboxylic acids, based on the
biuret test (amino acids), high performance liquid chromatography, and 13C NMR spectroscopy (profens and hydroxy
acids). We briefly describe our experimental results in the context of the existing literature and outline an improved
theoretical model for these phenomena. Our system resembles in some respects the reported oscillatory conden-
sation of organic silanols. Here, the key reaction is the formation of carboxylic acid-derived enols. Finally, we discuss
the importance of the oscillatory chiral conversion of simple carboxylic acids for biochemistry, pharmacology, and
related life sciences. Copyright ß 2010 John Wiley & Sons, Ltd.
Keywords: chiral carboxylic acids; condensation; enolization; oscillatory chiral conversion; Templator model
The general scheme of these chiral conversions can be sum-
marized as
INTRODUCTION
The remarkable phenomenon of spontaneous in vitro oscillatory
!
!
enantiomerðþÞ
enol
enantiomerðꢁÞ
(1)
chiral conversion of selected profens, amino acids, and hydroxy
acids has been the focus of our attention for some time. In
papers,[1–3] we reported on the oscillatory chiral conversion of
S(þ)-ibuprofen, S(þ)-naproxen, S,R(ꢀ)-2-phenylpropionic acid,
S(þ)-flurbiprofen, R(ꢁ)-flurbiprofen, and S,R(ꢀ)-ketoprofen. In
papers,[4–6] we described analogous behavior in L-alanine,
L-a-phenylalanine, and L-tyrosine.[4–6] In papers,[7,8] the oscil-
latory chiral conversion of the hydroxy acids L-lactic acid,
R-a-hydroxybutyric acid, S-a-hydroxybutyric acid, R-mandelic
acid, and S-mandelic acid was characterized. Most of these
oscillatory chiral conversion reactions took place in acidic
samples dissolved in 70% aqueous ethanol. Oscillatory chiral
conversion has also been reported in the crystallization of the (þ)
If we consider chiral conversion of selected carboxylic acids in
an aqueous solution in more detail, then Eqn (1) can be replaced
by Eqn (1a)[10]
(1a)
:
and (ꢁ) enantiomers of 2-azabicyclo [2.2.1]hept-5-en-3-one[9]
.
Much of the experimental evidence for this phenomenon
originates from thin-layer chromatography (TLC) and polarimetry.
The TLC evidence is mostly in the form of changing concentration
profiles and unstable retardation coefficient (RF) values of the
investigated analytes. In Fig. 1, we present an example of TLC results
for S,R(ꢀ)-2-phenylpropionic acid dissolved in 70% aqueous eth-
anol and then stored for 72 h at 22 8C, with intermittent
chromatographic measurements on the stored sample.[1]
Polarimetric evidence was collected in the non-continuous and
continuous registration modes. In Fig. 2(a, b), we show examples
of the long-term chiral conversion of S(þ)- and R(-)-flurbiprofen
dissolved in 70% aqueous ethanol and then stored at 22 8C for
several days.[3] These data were collected in the non-continuous
registration mode.
*
Correspondence to: I. R. Epstein, Chemistry Department, MS 015, Brandeis
University, Waltham, MA 02454-9110, USA.
E-mail: epstein@brandeis.edu
a
M. Sajewicz, M. Matlengiewicz, M. Gontarska, D. Kronenbach, T. Kowalska, D.
Kronenbach, T. Kowalska
Institute of Chemistry, University of Silesia, 9 Szkolna Street, 40-006 Katowice,
Poland
b
M. Leda, I. R. Epstein
Chemistry Department, MS 015, Brandeis University, Waltham, Massachusetts
02454-9110, USA
In Fig. 3, we present the continuously registered oscillatory
changes of the specific rotation ([a]D) for a freshly prepared 70%
aqueous ethanol solution of R(-)-flurbiprofen, with monitoring
carried out for 540 min.
y
This article is published in Journal of Physical Organic Chemistry as a special
issue on Twelfth European Symposium on Organic Reactivity, edited by Amnon
¸
Stanger, Zvi Rappoport, and Marie-Francoise Ruasse.
J. Phys. Org. Chem. 2010, 23 1066–1073
Copyright ß 2010 John Wiley & Sons, Ltd.

CHIRAL CONVERSION OF SIMPLE CARBOXYLIC ACIDS
In anhydrous media and in the presence of trace amounts of
water, the probable mechanism of chiral conversion is given by
Eqn (1b):[11]
(1b)
not linear but is instead proportional to k2b2/(1 þ b2) where b2
denotes [R2].
Monomers are introduced to the system from the reservoir by
reactions like
P ! R
P ! S
(5a)
(5b)
The rates of steps (5a) and (5b) are constant and small but
differ because the concentrations of S and R in the reservoir are
different. We assume that racemization is a simple linear reaction
R $ S (6)
The behavior of the system defined above is described by four
dimensionless kinetic equations
where X: -NH2, -OH, -Ar, etc., and Y: -R, etc.
da1=dt ¼ ꢀðk01 þ k1ðb1 ꢁ a21Þ ꢁ 2a12b1 þ k3ða2 ꢁ a1ÞÞ
(7a)
(7b)
(8a)
(8b)
k2b1
db1=dt ¼ a21b1 ꢁ k1ðb1 ꢁ a21Þ ꢁ
1 þ b1
MODELING STUDIES
da2=dt ¼ ꢀðk02 þ k1ðb2 ꢁ a22Þ ꢁ 2a22b2 ꢁ k3ða2 ꢁ a1ÞÞ
Based on the reaction scheme (Eqn (1)), in paper[5] we proposed a
simple model of chiral conversion, adapting an earlier oscillatory
mechanism designated as the Templator.[12,13] Here, we propose
two models which may explain the observed oscillation in these
experimental systems. The first model is based on autocatalytic
dimerization. Oscillations appear in this model in both
enantiomer subsystems. Racemization is a linear reversible
reaction coupling the two oscillating subsystems. In such a
system, in addition to simple oscillations, quasiperiodic (Fig. 4)
and mixed mode oscillations consisting of mixtures of large
and small amplitude oscillations are possible as well. Instability of
the stationary state leading to pattern formation in a spatially
extended system is also possible, because such instability requi-
res that the diffusion coefficient of dimers be smaller than that of
monomers, which is physically reasonable.
k2b2
db2=dt ¼ a21b1 ꢁ k1ðb2 ꢁ a22Þ ꢁ
1 þ b2
where a1, b1, a2, and b2 are the dimensionless concentrations of
S, S2, R and R2, respectively, and k01, k02, k1, k2, and k3 are
dimensionless constants which are functions of the rate cons-
tants of reactions (1)–(6).
At least two observations support the use of the model des-
cribed above. First, autocatalytic dimerization has been found in
chemical reactions in which the breaking of the mirror symmetry
of enantiomers occurs (Soai reaction[14]). Second, oscillations
based on autocatalytic dimerization should be more robust at
lower temperature, because the dimerization equilibrium (1)
should then be shifted toward the formation of dimers. More
robust oscillations are indeed seen at lower temperatures in our
In our model we consider the concentrations of enantiomers S,
R and their homodimers S2, R2. We assume that the dimerization
reaction may be uncatalyzed
experiments[1,4,6]
.
ThesecondapproachisbasedonthemodelofPlassonetal.[15]. In
this model, oscillations appear as the result of coupling between
enantiomers. This model appears particularly relevant for systems
involving condensation or peptidization in which the condensate
(dipeptide)SRhasdifferentchemicalpropertiesthanRS, e.g.,where
only the residue on the left undergoes epimerization.
2R $ R2
(1a)
(1b)
2S $ S2
or catalyzed by the dimers themselves (autocatalysis):
R $ Rꢂ
S $ Sꢂ
(9a)
(9b)
2R þ R2 ! 2R2
2S þ S2 ! 2S2
(2a)
(2b)
For simplicity, we ignore the formation of heterodimers,
though it is only necessary to assume that this process is much
slower than homodimer formation.
We also consider a reservoir of oligomers, which acts as a sort
of buffer, able to remove dimers and introduce monomers into
the system. Dimers may be removed by the creation of oligomers
R5, S5, Q, and P.
R ꢂ þR ! R2
S ꢂ þS ! S2
R2 ! 2R
(10a)
(10b)
(11a)
(11b)
(12a)
(12b)
(13a)
(13b)
S2 ! 2S
R ꢂ þS ! RS
S ꢂ þR ! SR
RS ! S2
R3 þ R2 $ R5
S3 þ S2 $ S5
Q þ R5 ! P
Q þ S5 ! P
(3a)
(3b)
(4a)
(4b)
SR ! R2
Oscillations appear in the system (9)–(13) only if the rate
constant for the formation of heterodimers (12) is greater than
that for homodimers (10) (Fig. 5).
Our model of two linked Templators accounts for the experi-
mentally observed chiral conversion of simple carboxylic acids.
If we make a quasi-steady state approximation for [R5] and
assume that the total concentrations [R3] þ [R5], [S3] þ [S5],
and [Q] are roughly constant, the rate of removal of dimers is
J. Phys. Org. Chem. 2010, 23 1066–1073
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M. SAJEWICZ ET AL.
120
100
80
(a)
(c)
(e)
(b)
(d)
(f)
140
120
100
80
60
40
60
20
40
0
20
-20
-40
-60
0
-20
0,50 0,55 0,60 0,65 0,70 0,75 0,80 0,85 0,90
RF
0,50 0,55 0,60 0,65 0,70 0,75 0,80 0,85 0,90
RF
120
100
80
60
40
20
0
200
150
100
50
0
-50
-20
0,50 0,55 0,60 0,65 0,70 0,75 0,80 0,85 0,90
0,50 0,55 0,60 0,65 0,70 0,75 0,80 0,85 0,90
RF
RF
140
200
120
100
80
150
100
50
60
40
20
0
-20
-40
-60
0
-50
0,50 0,55 0,60 0,65 0,70 0,75 0,80 0,85 0,90
RF
0,50 0,55 0,60 0,65 0,70 0,75 0,80 0,85 0,90
RF
Figure 1. Sequence of densitometric concentration profiles of S,R(ꢀ)-2-phenylpropionic acid after: (a) 0 h (racemic mixture); (b) 22.5 h (S(þ) form); (c) 27.5 h
(racemicmixture);(d)46.5 h(R(ꢁ)form);(e)51.5h(shiftfromR(-)formtoracemicmixture);and(f)70.5 h(racemicmixture);storagetimeat228C.Changesofthe
peaks’ concentration profiles are accompanied by changing RF values. Stationary phase: silica gel 60 F254 (precoated TLC plates; Merck, Darmstadt, Germany;
cat. # 1.05715) impregnated with L-arginine. Mobile phase: acetonitrile–methanol–water, 5:1:0.75 (v/v), containing several drops of acetic acid[1]
However, it does not propose any realistic chemical reaction (or
physical process) responsible for the oscillatory removal of the
EXPERIMENTAL RESULTS
reaction template (assumed to be an H-bonded cyclic homo-
dimer of the starting carboxylic acid). The extreme simplicity of
the process summarized in Eqn (1) draws attention to the
intermediate reaction product (enolate ion or enol) as the
possible origin of a nonlinear process. So far, no oscillatory
process involving this intermediate reaction product has been
discovered.
We have recently demonstrated that the profens, amino acids,
and hydroxy acids we have investigated undergo not only
chiral conversion but also spontaneous condensation[16,17]. In
Reference [16], the ability of R-phenylglycine and S-phenylglycine
(dissolved in 70% aqueous ethanol) to undergo rapid, nearly
instantaneous, peptidization was demonstrated by TLC and
the biuret test. An analogous, though less rapid, outcome
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CHIRAL CONVERSION OF SIMPLE CARBOXYLIC ACIDS
48
(a)
48
47
day 0
46
47
45
44
0
1 2 3 4 5 6 7
46
45
44
43
42
41
40
39
44
43
42
41
40
46
45
44
43
day 7
43
42
41
40
day 6
day 1
45
44
43
42
41
164
169
174
[α]D
day 2
23 2425 26 27 2829 3031
141
146
151
45
50
55
43
42
41
40
39
day 5
116
121
126
0
25
30
50
75
100
125
150
165
175
time [hours]
0
(b)
0
15
45
60
75
90
105
120
135
150
180
195
-8
-9
167
169
171
173
-5
-10
-15
-20
-25
-30
-35
-40
-45
-10
-11
-12
-13
-14
day 7
-18
120
-19
122
124
126
128
-5
192
-6
193
194
195
-20
-21
-22
day 8
day 5
-7
-8
-16
144
146
148
150
152
-17
-18
-19
[α]D
day 6
-36
-37
-38
-39
-40
0
1
2
3
4
5
6
7
day 0
-30
46
48
50
52
54
-31
-32
-33
-34
-35
-36
day 2
-34
-35
-36
-37
-38
24 25 26 27 28 29 30 31
day 1
time [hours]
Figure 2. Oscillatory changes of the specific rotation, [a]D, for (a) S(þ)-flurbiprofen and (b) R(ꢁ)-flurbiprofen dissolved in 70% aqueous ethanol and
stored at 228C. The general trend of the changes is indicated by the solid line, and insets show the changes on selected days of the experiment[3]
was obtained with L-alanine and L-phenylalanine. In reference[17]
,
S(þ)-ketoprofen. In Fig. 8, we present a sequence of chromato-
graphic ‘snapshots’ showing formation and then disappearance
of aging products derived from ketoprofen (most probably,
ketoprofen condensates), and oscillations of the peak heights
corresponding to the starting material, S(þ)-ketoprofen, and the
first condensation product. The HPLC peak heights are roughly
proportional to the respective concentrations.
Summing up, storage of profens, amino acids, and hydroxy
acids in aqueous organic solution results in two parallel spontan-
eous processes: (i) oscillatory chiral conversion and (ii) conden-
sation. A simple scheme for such a process in profens is shown
below.
we presented experimental evidence for the spontaneous
condensation of selected hydroxy acids (i.e., L-lactic acid and
S(þ)-mandelic acid). We have also amassed (unpublished)
experimental evidence of spontaneous condensation of pro-
fens[18]. The evidence for hydroxy acid and profen condensation
originates from 13C NMR spectroscopy. In Fig. 6, we present an
example of 13C NMR spectroscopic evidence of the spontaneous
condensation of L-lactic acid and S(þ)mandelic acid, and in Fig. 7,
of spontaneous condensation of S(þ)-ketoprofen. High perform-
ance liquid chromatography (HPLC) experiments[19] provide
further support for the spontaneous condensation of
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M. SAJEWICZ ET AL.
0.10
0.05
0.00
0.05
0.10
4900
4920
4940
4960
4980
5000
time arbitraryunits
Figure 5. Enantiomeric excess ee¼ ([R] ꢁ [S] þ 2[R2] ꢁ 2[S2])/c for c ¼ 1,
k9 ¼ 1, k ¼ 0.1, k10 ¼ 1, k11 ¼ 1, k12 ¼ 100, k13 ¼ 1, simulated with Eqns
Figure 3. Oscillatory changes of the specific rotation, [a]D, for
R(-)-flurbiprofen dissolved in 70% aqueous ethanol and stored at 228C
for 540 min
ꢁ9
(9)–(13)
DISCUSSION
With amino acids and hydroxy acids, the analogous condensation
pathways are also possible, resulting, respectively, in peptidization
and esterification. The kinetics of spontaneous condensation of
profens, aminoacids, andhydroxy acidsinaqueousethanolhasnot
yet been studied in detail, and hence it cannot be concluded
whether it is nonlinear or linear in nature. In our forthcoming
studies, we will focus on the investigation of these dynamics.
In this context, it is noteworthy that oscillatory condensation
has been reported in another system[20,21]. Interestingly, the
experimental evidence presented in those studies also originates
0.8
0.6
0.4
0.2
0.0
-
-
0.2
0.4
0
500
1000
1500
2000
time arbitraryunits
Figure 6. 100 MHz 13C NMR spectra of (a) L(þ)-lactic acid and (b) S(þ)
mandelic acid, first dissolved and stored for 10 days in pure ethanol, and
then recorded in CDCl3 at 25 8C[16]
Figure 4. Complex behavior of the enatiomeric excess ee ¼ (a1 ꢁ a2þ2b1ꢁ
2b2)/(a1 þ a2 þ 2b1 þ 2b2) simulated with the coupled Templator model
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CHIRAL CONVERSION OF SIMPLE CARBOXYLIC ACIDS
Figure 7. 100 MHz 13C NMR spectra of (a) S(þ)-ketoprofen monomer and (b) S(þ)-ketoprofen condensate. S(þ)-Ketoprofen sample was first dissolved in
pure ethanol and then stored in solution for 10 days. Spectra were recorded at 25 8C in CDCl3. (A) Aliphatic range. Methyl line at 18.26 ppm in (a) is
accompanied by two additional lines at 18.61 and 18.81 ppm in (b), which originate from the methyl groups in the repeating units of the condensate. The
signal of the methine carbon at 45.31 ppm in (a) is flanked by a new small line at 45.55 in (b), coming from the end groups. The new lines at 68.03 and
68.51 ppm in (b) originate from new quaternary carbons formed in the main chain of the polymer. (B) Aromatic range. In spectrum (b) two small new
peaks appear at 129.09 and 131.65 ppm, respectively, which can be attributed to C-20 and C-60, respectively, in the new molecular environment of
ketoprofen condensate (as compared with spectrum (a)). (C) Carbonyl range. After 10 days storage, the carbonyl signal at 179.68 ppm in (a) is flanked by
two additional lines, at 174.29 and 196.76 ppm, respectively, in (b)
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M. SAJEWICZ ET AL.
Figure 8. (A) Chromatogram of a freshly prepared solution of S(þ)-ketoprofen in acrylonitrile recorded at 259 nm. Retention times: peak 1, 7.66 min;
peak 2, 9.68 min; peak 3, 11.80 min. (B) Sequence of chromatographic concentration profiles of S(þ)-ketoprofen dissolved in acetonitrile after (a) 0 h; (b)
5.5 h; (c) 9.5 h; (d) 18 h; (e) 19 h; (f) 20 h; (g) 24.5 h; (h) 28 h; and (i) 30 h storage time at 22 8C. (C) Time course of the chromatographic peak heights of an
S(þ)-ketoprofen solution stored at 22 8C for 30 hours. Peak numbers as in (A)[19]
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CHIRAL CONVERSION OF SIMPLE CARBOXYLIC ACIDS
from TLC, which emphasizes the utility of this simple analytical
technique in tracing the structural lability of organic compounds.
Even more relevant to our own research is that the oscillatory
condensation documented by these authors involves organosi-
lanols (e.g., R2Si(OH)2 or RR’Si(OH)2). There are several analogies
between the results presented in references[20,21] and those
originating from our own laboratory, and also between the
conclusions of the two research teams:
partially supported by PhD scholarships granted to them in
2009 within the framework of the ‘University as a Partner of
the Economy Based on Science’ (UPGOW) project, subsidized by
the European Social Fund (EFS) of the European Union.
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carboxylic acids occurring spontaneously in vitro in abiotic
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scientific reasons and also for practical ones. It seems evident that
insufficient attention has so far been paid to in vitro studies of
structurally simple compounds of high pharmaceutical and/or
biochemical importance (profens, amino acids, and hydroxy acids
are certainly among such compounds). As a result, processes that
run spontaneously in abiotic in vitro systems could erroneously
be attributed to in vivo systems only (as, e.g., in the case of in vivo
chiral conversion of profen drugs[22]) and then claimed to be
inherent in physiological systems and biochemical processes
alone. In that way, misinterpretation of natural processes can
easily occur, with serious and potentially negative consequences.
Acknowledgements
[21] E. A. Chernyshev, P. V. Ivanov, D. N. Golubykh, Rus. Chem. Bull. 2001,
50, 1998–2009.
This work was supported in part by National Science Foundation
grant CHE-0615507 to I.R.E. The work of M.G. and D.K. was
[22] V. Wsol, L. Skalova, B. Szotakova, Curr. Drug Metab. 2004, 5,
517–533.
J. Phys. Org. Chem. 2010, 23 1066–1073
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