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- 82 -
Chirality of the Very First Molecule in Absolute Enantioselective Synthesis
Luciano Caglioti,
a
Károly Micskei,
b
and Gyula Pályi
c
a
Department of Chemistry and Technology of Biologically Active Compounds, University “La
Sapienza” Roma, Ple.A. Moro 5, I-00185 Roma, Italy.Tel.: + 39-06-4969-0062; fax: + 39-06-4991-0518;
e-mail: luciano.caglioti@uniroma1.it
b
Department of Inorganic and Analytical Chemistry, Faculty of Natural Sciences, University of
Debrecen, H-4010 Debrecen, Egyetem tér 1, P. O. Box 21, Hungary.
c
Department of Chemistry, University of Modena and Reggio Emilia, Via Campi 183, I-41100 Modena,
Italy
(Received: July 3, 2007 Accepted: July 20, 2007)
Abstract
In the present paper the role of the very first chiral
molecule formed in achiral-to-chiral reactions, is
discussed. This molecule represents obligatorily
100 % ee, with important consequences for absolute
enantioselective synthesis. Calculations show that
Soai-type autocatalytic reactions could amplify even
one molecule initial enantiomeric excess to high ee
under reasonable conditions, which enables also an
experimental control.
Introduction
Chirality, a feature of molecular geometry, in
general, as well as enantioselective autocatalysis, in
particular, are frontier issues of chemistry.
1-6
The
origin of (molecular) chirality in living organisms
(biological chirality) is also a first grade challenge
since a long time.
7
It is generally accepted, that
asymmetry can be generated only by (physical or
molecular) asymmetry. Several hypotheses were
proposed, how enantiopure chiral substances could be
formed without asymmetric influence. These include
stochastic fluctuations,
8-13
amplified by autocatalytic
mechanisms
14
to high enantiomeric purity. Such
chiral autocatalytic reactions
14
were experimentally
demonstrated recently.
15,16
Our groups found an
empirical approach
13
fairly useful in understanding
some features of these reactions.
We would like to point out here an obvious, but
rarely (if ever?) mentioned aspect of chirality: the
role of the very first chiral molecule formed from
achiral precursors, which is now highly actual also in
the light of recent important developments in single
molecule chemistry.
17
If a chiral molecule is prepared from achiral
precursor(s), the very first molecule formed in this
transformation will necessarily represent 100%
enantiomeric excess, until this species is alone. This
fact can be regarded as an axiom (“primary”
statement, which needs no proof) of preparative
stereochemistry.
The quantitative “enantioselectivity” of the first
chiral molecule is not exceptional, but it is a general
feature of all achiral-to-chiral transitions. Even more,
if the first chiral molecule disappears from the system
by a (fast) secondary reaction, then all molecules
could become “first”, with obvious effects for
preparative consequences. Some of these are as
follows:
• First, in the absence of chiral additives and/or
asymmetric physical fields, the synthesis of the
first chiral molecule (from achiral precursor(s)),
in any such reaction, corresponds to the most
rigorous criteria of absolute asymmetric
synthesis;
12
• Second, under these conditions, however, the
sense of chirality (R or S, L or D) of this first
molecule can not be predicted;
• Third, the above statement is limited to the case
where (and until) the first molecule alone
“dominates” the system with its 100 % ee;
• Fourth, in the absence of chiral additive and/or
asymmetric fields, the sense of chirality of a
second molecule (in the same system) can not be
predicted too, if its formation is independent of
the first molecule. Consequently, at this point
the system bifurcates. If the 2
nd
, 3
rd
, 4
th
, etc.
molecules are formed independently from the
first one (and from each other), statistics
“awakes” and the system can be described in
terms of probability.
8-11, 18
If, on the other hand,
the chirality of the first molecule predisposes the
preferential formation of one of the two
enantiomers (especially if it does so by a
reaction rate exceeding the rate of its own
formation) a true chiral autocatalysis can
develop. Asymmetric autocatalysis has been the
goal of several research efforts, however, only
one well-documented example has been reported
yet: the alkylation of N-heterocyclic aldehydes
by zink dialkyls.
15, 16, 19
The fate of the very first chiral molecule could
take an additional, important turn: it could react with
another chiral (or prochiral) molecule, e.g. the first
molecule of an amino acid (RCH(NH
2
)COOH) could
react with a carbohydrate (already chiral) or with a
glycerol-2-monoester or -2-monoether (prochiral).
This reaction would necessarily lead to (potential)
diastereomeric products, which are no more subjected
to the law of equal probabilities. Both the
autocatalytic amplification of the very first molecule
or its transformation to diastereomeric products could
- 83 -
have been those early event(s) which was(were)
operative at the origin of biological chirality.
The formation of chiral crystals from achiral
molecules is similar to chiral (chemical) autocatalysis.
In fact, in these experiments
20
the influence of the
first chiral (crystal) nuclei can lead to a similar chiral
takeover in the whole sample, as the first chiral
molecule can do in autocatalysis. Similarly, the
observed high enantioselectivity of chain propagation
in polymerization or polycondensation reactions
21
can also be related to the influence of the first
molecule in the chain.
Model Calculations
We tested the compatibility of the above
argumentation with chemical reality using a recently
deduced empirical formula for the description of
chiral autocatalysis
13
:
ee
prod
= ee
max
start
start
eeB
ee
+
(1)
where
ee
prod
– is the enantiomeric excess of the product in
the individual reaction cycle (%);
ee
max
– is the maximum enantiomeric excess achieved
in the given system (%);
ee
start
– is the starting enantiomeric excess of the
product at the beginning of an individual cycle,
which is defined for the first reaction cycle as added
quantity of the product prior to the start of the
reaction with respect to the substrate (mole-%);
ee – (as usual) = (R-S)/(R+S) 100 or (S-R)/(R+S) 100,
where R and S are the molar quantities of the R and S
enantiomers formed in the reaction (%);
B – constant.
In consecutive autocatalytic cycles, this formula
allows to calculate the evolution of ee during the
whole operation as a function of the number of
autocatalytic “steps”. Figure 1 shows the results for
different Soai-systems, with one molecule initial ee.
The “absolute” variant of the most sensitive
Soai-reaction reaches after three cycles near-
quantitative enantioselectivity.
15,16
The diagrams in
Figure 1 indicate, that similar ee-s can be obtained by
more reaction cycles even with the less sensitive
variants, with one molecule initial excess. For the
second best system six and for the least sensitive
reaction cca 25-27 cycles would be necessary to
achieve high enantiomeric excess. These results have
two important messages: First, the initial influence of
the very first molecule at a realized chiral
autocatalysis seems to provide plausible cycle
numbers. Second, it can be expected, that there might
be several chemical systems, which could be of chiral
autocatalytic nature, only nobody has ever looked for
these, while several (more than 3-5) repetitions of the
catalytic cycle seemed to be senseless.
Figure 1. Step-by-step evolution of enantiomeric excess in
consecutive autocatalytic cycles with one molecule as
starting enantiomeric excess (ee
start
= 1.66 10
-22
%) in Soai-
systems of different sensitivity (ee
max
,%-B respectively: 99-
3.7 10
-5
−•−; 97-3.3 10
-2
−▲−; 97-9 −■−; 98-13 −♦−).
Formula (1) enables the definition of a hypothetical
Soai-type system, where only one molecule initial
excess leads to near-quantitative enantioselectivity in
one step. The results are shown in Figure 2: such
Soai-system should have a B constant of cca. 10
-24
.
This is orders of magnitude lower than the B value of
the most sensitive Soai-system, but it does not seem
impossible to reach it.
Figure 2. Dependence of ee
prod
on B of the first cycle, with
one molecule as starting enantiomeric excess for Soai-
reactions of different sensitivity (arrow shows the
hypothetic system which reaches 100% ee
prod
in one step).
Acknowledgements
The Authors acknowledge valuable discussions to
Profs. L. Markó (Veszprém) and G. Varadi (Boston).
This research project was supported by the
[Hungarian] Scientific Research Foundation (Grant
OTKA, No. T046942 (K. M.) and the (Italian) MUR
FIRB-RBPR05NWWC program.
0
20
40
60
80
100
0 5 10 15 20 25 30 35 40
step
ee
prod
-18
-14
-10
-6
-2
2
-30-25-20-15-10-50
lg B
lg
ee
prod
- 84 -
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