Physical and chemical rationalization for asymmetric amplification in aatocatalytic reactions

Article abstract of DOI:10.1002/anie.200353086

Selective precipitation of the product alkoxide 2′ is observed at higher conversions of substrate in the asymmetric autocatalytic alkylation of pyrimidyl aldehyde 1. Enrichment or depletion of the enantiomeric excess in solution can result, depending on the solvent employed in the reaction. Asymmetric amplification may be effected by a synergistic combination of chemical and physical processes, leading to a homochiral reaction environment.

Full text of DOI:10.1002/anie.200353086

Angewandte
Chemie
Asymmetric Amplification
Physical and Chemical Rationalization for
Asymmetric Amplification in Autocatalytic
Reactions**
Frederic G. Buono, Hiroshi Iwamura, and
Donna G. Blackmond*
The origin of biological homochirality has intrigued scientists
for some time. Discussions of possible mechanisms through
which high optical activity was achieved from a racemic or
prochiral prebiotic environment[1,2] have implicated both
physical processes such as crystallization[3] and chemical
processes such as autocatalysis.[4] Kondepudi[2] first reported
spontaneous chiral symmetry breaking in crystallization little
more than 10 years ago. In the last decade, Soai and co-
workers[5] demonstrated the chemical phenomenon of asym-
metric autocatalysis in remarkable reactions involving pyr-
imidyl alcohols that serve as both the catalyst and the product
in the alkylation of pyrimidyl aldehydes. When alcohol 2 is
used in very low enantiomeric excess as a catalyst in the
[*] Dr. F. G. Buono, H. Iwamura, Prof. D. G. Blackmond
Department of Chemistry, Imperial College
London SW7 2AZ (UK)
Fax: (+44)020-7594-5896
E-mail: d.blackmond@imperial.ac.uk
[**] The work reported herein was carried out at the Universityof Hull,
Hull HU6 7RX U.K. Funding from the EPSRC and Merck Co., Inc. is
gratefullyacknowledged. We also thank J. M. Brown and I. D.
Gridnev for stimulating discussions.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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DOI: 10.1002/anie.200353086
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alkylation of the corresponding aldehyde 1 with iPr2Zn, 2 may
be produced with high enantiomeric excess (Scheme 1).
Scheme 1. The Soai autocatalytic reaction.
We[6] recently elucidated a mechanistic framework for the
Soai reaction shown in Scheme 1 based on an autocatalytic
version of the Kagan ML2 model[7] describing a nonlinear
relationship between the catalyst and the product ee in
asymmetric reactions (Scheme 2). We showed that the
&
Figure 1. Reaction rate (*) and enantiomeric excess of 2 ( ) vs. time
in the autocatalytic reaction of consecutive aliquots (0.13–0.17m) of 1
injected into a solution of iPr2Zn (0.70m) with an initial catalytic con-
centration of 2 (0.014m, 46% ee) in toluene at 298 K. The reaction was
monitored calorimetrically, as previously described.
revealing that the further production of catalyst was no
longer reflected in increased activity.
Another key observation was the detection of product
precipitation during the course of these reactions. The onset
of precipitation appears to correlate with a feature at high
conversion in the reaction heat flow curves (Figure 2) that has
also been observed previously.[6] Separation of the filtrate
from the solid white precipitate followed by workup showed
that both contain 2 and no other products.[8] It has not yet
proved possible to extract crystals from the precipitate.
Whereas optimized conditions for the Soai reaction
typically involve the use of solvents such as toluene or
Scheme 2. Formation of dimer species 3 from the monomeric alkoxides 2’. The
relationship between the equilibrium constant in Kagan's ML2 model (KML2) and
the equilibrium constants for homochiral (Khomo) and heterochiral (Khetero) dimer
formation is shown. The dimers are formed with a statistical distribution and
onlythe homochiral dimers are active as catalysts.
alkoxide product species 2’ is strongly driven toward the
formation of a dimeric species 3, implicating these dimers as
the active catalytic species. Heterochiral (3RS) and homochiral
(3RR and 3SS) dimers are formed in a statistical distribution,
and the observed amplification in ee is due solely to the higher
activity of the homochiral dimer. Further kinetic studies have
recently implicated a tetrameric transition state in this
autocatalytic reaction.[6c]
We report herein continuing investigations that highlight
further complexities in this intriguing system. Our observa-
tions led us to conclude that a synergistic combination of
chemical and physical processes may result in an amplifica-
tion of product ee and indeed may help serve as a model to
rationalize the origin of the high optical activities character-
istic of biological systems.
Figure 1 shows reaction rate and enantiomeric excess as a
function of time for a reaction sequence carried out by
consecutive injection of aliquots of the aldehyde 1 into a
toluene solution initially containing the catalyst 2 (46% ee)
and excess iPr2Zn. The rate maximum is seen to increase from
the first to the second reaction in the sequence, as expected
for an autocatalytic reaction. However, the rate decreases
upon addition of subsequent aliquots of the substrate,
Figure 2. Reaction heat flow vs. time for the reaction shown in
Scheme 1 carried out in toluene (c) and in diethyl ether (d) with
1 (0.1m), iPr2Zn (0.20m), and 2 at an initial concentration of 0.01m
(6% ee in toluene, racemic in diethyl ether) at 298 K. The reaction rate
was monitored calorimetrically, as previously described.
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Table 1: Enantiomeric excess and% product in solution and in the
precipitate for the reaction shown in Scheme 1.[a]
cumene, Soai et al. recently reported interesting results for
spontaneous asymmetric synthesis (reaction in the absence of
added alcohol catalyst) in a 1:3 toluene/diethyl ether solvent
mixture.[9] We find that the reaction shown in Scheme 1
proceeds smoothly in toluene, in diethyl ether, and in toluene/
diethyl ether solvent mixtures, exhibiting similar autocatalytic
rate profiles (Figure 2) and similar amplification of product
enantiomeric excess (Figure 3) for reactions carried out under
EntrySolvent ee % ee % ee
%
% ee
% product
(cat.) (solution) (preci- (total) in solution
pitate)
1
2
3
4
5
6
7
8
9
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
60
60
60
60
35
35
35
35
35
60
60
60
60
60
35
35
35
35
60
60
60
60
60
60
60
60
35
35
35
35
35
35
35
96
60
35
10
95.8
94.3
96.6
96.7
93.2
93.0
94.9
91.4
90.4
63.7
41.8
35.7
51.4
49.5
37.9
54.0
57.3
56.1
73.3
57.6
58.3
68.4
58.1
72.7
69.3
72.8
81.8
80.3
82.4
76.4
81.9
81.6
81.9
56
88.3
78.9
69.5
66.2
64.3
61.2
73.1
63.0
64.0
94.4
92.6
91.3
89.4
92.3
88.7
86.3
86.1
86.4
91.5
91.6
93.5
90.5
90.9
90.3
90.0
90.2
85.5
84.5
85.8
85.1
85.3
82.5
83.8
n.d.
n.d.
14
88.5
85.6
87.2
83.9
79.9
77.3
78.8
78.4
75.1
88.8
90.5
84.8
88.5
88.1
80.3
85.5
86.9
83.3
89.0
86.5
90.7
86.4
86.1
86.7
87.5
86.3
83.8
83.2
83.6
85.1
83.4
81.8
83.7
56
42
59
68
46
45
50
24
42
40
16
14
17
14
14
18
7
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
Et2O
Et2O
5
8
7.5
Et2O/toluene
Et2O/toluene
Et2O/toluene
Et2O/toluene
Et2O/toluene
Et2O/toluene
Et2O/toluene
Et2O/toluene
Et2O/toluene
Et2O/toluene
Et2O/toluene
Et2O/toluene
Et2O/toluene
Et2O/toluene
Et2O/toluene
10.5
12
8.5
20
12
24
14
10
5
Figure 3. Product enantiomeric excess vs. initial catalyst enantiomeric
excess for the autocatalytic reaction shown in Scheme 1 under condi-
tions of Figure 2 carried out in toluene (*), diethyl ether (*), Et2O/
toluene (”), and THF (^). The calculation for the linear relationship
with ee for an autocatalytic reaction is described in reference [6b] and
Equation (3) in reference [10].
10
7
12
19
20
98
n.d.
96
55
34[b] THF
35[b] THF
36[b] THF
37[b] THF
similar conditions. In contrast, the reaction in THF is
extremely sluggish. No amplification of product ee is
observed, suggesting that the reaction proceeds differently
in this solvent. Product precipitation may be observed during
reactions in all solvents under some conditions, accompanied
by the feature in the heat flow curve noted above at high
conversions, as shown in Figure 2 for reactions using racemic
catalyst 2 in diethyl ether and 6% ee 2 in toluene.
Extensive further studies were carried out to compare the
precipitation phenomenon for reactions carried out in these
different solvents with catalysts of different ee. The enantio-
meric excess of the reaction product 2 was determined
separately for the filtrate and the solid in each case. An
internal standard allowed independent calculation of the
fraction of product present in the solid and in the filtrate. The
results are given in Table 1 and are highlighted in Figure 4.
A striking conclusion to be drawn from Table 1 and
Figure 4is that precipitation in this asymmetric autocatalytic
reaction is selective, with enrichment versus depletion of the
solution enantiomeric excess being solvent-dependent. In
toluene, the ee of the precipitate is lower than that of the
solution. In diethyl ether, this trend is reversed, with the solid
precipitate giving higher ee than the solution. Reactions in the
3:1 diethyl ether/toluene mixture follow the trend found for
the major component, diethyl ether, but the difference
19
13
0
19
13
1
3
[a] The reactions were carried out in different solvents under conditions
similar to those of the reactions shown in Figure 2. Reactions were
sampled after 1 hour, except where noted. All reactions exhibited 100%
conversion, except where noted. [b] Sampled after 24 h; reaction
products other than 2 were observed. Total conversion of aldehyde 1 in
reactions in THF after 24 h was <50%.
between solution and precipitate ee is less pronounced than
in the case of pure diethyl ether as solvent. These results
suggest that the physical properties of these diastereomers
3
RR, 3SS, and 3RS include complex, solvent-dependent solubility
behavior.[8] The heterochiral dimer species 3RS is less soluble
than the homochiral dimers 3RR and 3SS in toluene solution. In
diethyl ether, 3RS is more soluble than 3RR and 3SS.
In studies of the asymmetric catalytic alkylation of
aldehydes employing chiral aminoalcohols as catalysts,
Bolm et al.[11] observed selective precipitation of a species of
lower enantiomeric excess. They recognized the role that this
phenomenon may play in enhancing nonlinear effects on
product enantiomeric excess by altering the ee of the active
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unknown chiral factors may be moderated in the toluene/
diethyl ether solvent mixture by virtue of the two opposing
trends giving higher and lower ee precipitate relative to the
solution in pure diethyl ether and toluene, respectively.[13]
Precipitation also rationalizes why reaction rates did not
rise monotonically in consecutive reactions converting 1 into
2 (Figure 1). As the solution becomes saturated with catalyst,
the active solution concentration of catalyst ceases to
increase. Under reaction conditions such as those shown in
Figures 2–4, precipitation becomes significant only at the high
product concentrations found at the very end of the reaction.
That precipitation is not a significant factor is reflected in the
fact that amplification of ee is similar for reactions in diethyl
ether, toluene, and the mixed solvent system. For reactions
carried out at lower temperatures or higher concentrations,
however, precipitation may play a significant role. Indeed, we
observed that precipitation is more significant for reactions
carried out at 273 K that for those at 298 K.
Figure 4. Product enantiomeric excess for the solution phase (*, *)
!
,
!
and the precipitate (
) for the autocatalytic reaction shown in
Brown and co-workers[14] recently noted that enantiomer
enrichment by selective crystallization is the most likely
rationalization for biological chirality originating from rela-
tively few nucleation events. Siegel[15] has pointed out that the
problem with this explanation of achiral symmetry breaking is
that equilibration of crystals by dissolution or degradation is
likely to occur, which would inexorably erode the ee back
towards a racemic world. However, asymmetric autocatalysis
combined with selective precipitation provides a means of
shifting even a minute imbalance decisively and irrevocably
towards a homochiral outcome.
The Soai reaction provided the first experimental “proof
of concept” of the chemical rationale for the evolution of high
optical activity from low ee precursors that was first presented
theoretically nearly 50 years ago. The investigations reported
herein suggest that the amplification of product ee observed in
the Soai asymmetric autocatalytic reaction may be achieved
under some conditions through a synergistic combination of
the chemical process of autocatalysis aided by the physical
process of selective precipitation, which together can enhance
the driving force toward the creation of a homochiral reaction
environment.
Scheme 1 carried out in the presence of catalyst 2 with initial ee values
of 35% and 6% in toluene and diethyl ether. The data for each point
are averaged from the 3–5 individual experiments given in Table 1. The
dashed line gives the average total product ee (solution + precipitate)
from Figure 3.
catalyst species in these catalytic reactions. The implications
of such selective precipitation for asymmetric amplification in
autocatalytic reactions are even more profound. If homochiral
and heterochiral dimer species remain in rapid equilibrium
with one another in solution on the reaction timescale, but
equilibrium with the solid species is not rapidly established, a
redistribution of the concentrations of the remaining dimeric
species in solution will occur according to Le Chatelier's
principle. How this redistribution affects the product enan-
tiomeric excess in further autocatalytic cycles depends on
whether the solution is enriched or depleted in enantiomeric
excess.
The results in toluene suggest that with the onset of
precipitation, a fraction of solution-phase homochiral dimers
will be diverted towards the inactive heterochiral dimer as the
system strives to maintain the balance dictated by the
equilibrium constant KML2 = 4. Under these conditions, the
physical process of selective precipitation will enhance the
enantioselectivity achievable through the asymmetric auto-
catalytic reaction. The results for reactions carried out in
diethyl ether suggest that selective precipitation of homo-
chiral rather than heterochiral dimers acts to erode the ee of
the active solution-phase catalyst.
Received: October 14, 2003 [Z53086]
Keywords: asymmetric amplification · asymmetric catalysis ·
.
autocatalysis · chirality · kinetics
The opposing trends for selectivity in the precipitation of
the reaction product in diethyl ether and in toluene may also
help to shed light on the intriguing results reported by Soai
and co-workers for low-temperature reactions carried out in
the absence of added catalyst. Previous observations of
absolute asymmetric synthesis in the absence of added
catalyst in reactions carried out in toluene were attributed
to the ubiquitous presence of chiral impurities.[12] Because the
same reactions in toluene/diethyl ether mixtures gave sto-
chastic imbalances, it was proposed that these reactions
provide a genuine test for spontaneous asymmetric synthesis.
The results reported herein suggest that the effect of any
[1] M. Calvin, Chemical Evolution, Oxford University Press,
Oxford, 1969.
[2] D. K. Kondepudi, Science 1990, 250, 975.
[3] F. C. Frank, Biochim. Biophys. Acta 1953, 11, 459.
[4] For recent reviews on spontaneous asymmetric synthesis, see:
a) K. Mislow, Collect. Czech. Chem. Commun. 2003, 68, 84 9;
b) B. L. Feringa, R. A. van Delden, Angew. Chem. 1999, 111,
3624; Angew. Chem. Int. Ed. 1999, 38, 3418c) H. Buschmann, R.
Thede, D. Heller, Angew. Chem. 2000, 112, 4197; Angew. Chem.
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Chem. Res. 2001, 34, 946; e) M. Avalos, R. Babiano, P. Cintas,
J. L. Jimenez, J. C. Palacios, Chem. Commun. 2000, 887, and
references therein.
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[5] First publications: a) K. Soai, T. Shibata, H. Morioka, K. Choji,
Nature 1995, 378, 767; b) T. Shibata, K. Choji, T. Hayase, Y.
Aizu, K. Soai, Chem. Commun. 1996, 1235; c) T. Shibata, H.
Morioka, T. Hayase, K. Choji, K. Soai, J. Am. Chem. Soc. 1996,
118, 471; for a recent review, see: K. Soai, I. Sato, Chirality 2002,
14, 548.
[6] a) D. G. Blackmond, C. R. McMillan, S. Ramdeehul, A. Schorm,
J. M. Brown, J. Am. Chem. Soc. 2001, 123, 10103; b) D. G.
Blackmond, Adv. Synth. Catal. 2002, 344, 156; c) F. G. Buono,
D. G. Blackmond, J. Am. Chem. Soc. 2003, 125, 8978.
[7] a) C. Puchot, O. Samuel, E. Duæach, S. Zhao, C. Agami, H. B.
Kagan, J. Am. Chem. Soc. 1986, 108, 2353; b) D. Guillaneux,
S. H. Zhao, O. Samuel, D. Rainford, H. B. Kagan, J. Am. Chem.
Soc. 1994, 116, 9430.
[8] Reactions in toluene, diethyl ether, and toluene/diethyl ether
mixtures show complete conversion of aldehyde 1 into the
alkylation product 2 upon workup. Reactions in THF show
significant side reactions, including reduction to the primary
pyrimidyl alcohol.
[9] K. Soai, L. Sato, T. Shibata, S. Komiya, M. Hayashi, Y. Matsueda,
H. Imamura, T. Hayase, H. Morioka, H. Tabira, J. Yamamoto, Y.
Kowata, Tetrahedron: Asymmetry 2003, 14, 185.
[10] For an asymmetric autocatalytic reaction exhibiting no non-
linearity, the enantiomeric excess at the end of the reaction
(eecat,end) is given by Equation (1), in which eecat,0 is the initial
catalyst ee, eeprod is the intrinsic enantioselectivity of the reaction,
and xcat is the mole fraction of catalyst used in the reaction. See
reference [6b] for a derivation.
[11] C. Bolm, G. Schlinghoff, K. Harms, Chem. Ber. 1992, 125, 1191.
[12] D. A. Singleton, L. K. Vo, J. Am. Chem. Soc. 2002, 124, 10010.
[13] The similarity in the rate profiles and asymmetric amplification
observed for reactions carried out under similar conditions in
diethyl ether, toluene, and toluene/diethyl ether mixtures, and
their compliance with the model proposed in reference [6c],
suggest that the reactive intermediate itself may be similar in
different solvents.
[14] I. D. Gridnev, J. M. Serafimov, H. Quiney, J. M. Brown, Org.
Biomol. Chem. in press.
[15] J. S. Siegel, Nature 2002, 419, 346.
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