Nonlinear effects in proline-thiourea host-guest complex catalyzed aldol reactions in nonpolar solvents

Article abstract of DOI:10.1016/j.tetasy.2010.02.009

An aldol reaction catalyzed by a proline-thiourea host-guest complex in a nonpolar solvent shows excellent nonlinear effects. This proline-thiourea system has the ability to form a hydrogen-bonding network. The enantiomeric excess of proline in a solution

Full text of DOI:10.1016/j.tetasy.2010.02.009

Tetrahedron: Asymmetry 21 (2010) 405–409
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Nonlinear effects in proline–thiourea host–guest complex catalyzed aldol
reactions in nonpolar solvents
*
Ayhan S. Demir , Serkan Eymur
Department of Chemistry, Middle East Technical University, 06531 Ankara, Turkey
a r t i c l e i n f o
a b s t r a c t
Article history:
An aldol reaction catalyzed by a proline–thiourea host–guest complex in a nonpolar solvent shows excel-
lent nonlinear effects. This proline–thiourea system has the ability to form a hydrogen-bonding network.
The enantiomeric excess of proline in a solution can be significantly enhanced by its incorporation with a
urea molecule into its solid racemate. This suggests a general and facile route to homochirality, which
may be involved in the origin of chirality on earth.
Received 5 January 2010
Accepted 16 February 2010
Available online 12 March 2010
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
lue for scalemic proline in DMSO, whereas it differs in CHCl3 due
to the formation of a solvate.8c
Amino acids promote several organic transformations. Proline,
which is a widely distributed amino acid, is one of the most effec-
tive organic catalysts.1 The discovery of proline-catalyzed Robin-
son annulations in the 1970s,2 and the first intermolecular aldol
reaction by List et al.3 in 2000, paved the way for the wide expan-
sion of metal-free catalytic methodologies for the enantioselective
formation of carbon–carbon and carbon–heteroatom bonds. These
initial reports not only provided a simple solution to one of the
most important problems in catalytic asymmetric synthesis, but
also attracted a great deal of attention toward the use of small
organic molecules as catalysts in organic chemistry.1,4–7
Recently, the ternary phase behavior of proline was studied
under non-equilibrium conditions by Blackmond.12 According to
this study, the transition between a transient ‘kinetic conglomer-
ate’ phase, and the racemic compound formed by proline at equi-
librium, took place provided that the two separate enantiomers
were physically mixed. This shows that for catalysis under the
indicated conditions, the proline ee of the solution is determined
by a linear combination of the two separate enantiomers with 0%
of eutectic ee, which is similar to amino acids crystallizing as con-
glomerates. As the solid proline enantiomers start to dissolve, the
proline ee of the solution is induced to rise by the solid–solution
composition until the eutectic value of 50% ee is reached, which
provides for the equilibrium. This model provided Blackmond with
the first account of the origin of the negative nonlinear effects
which were observed by Kagan8a and Blackmond12 in intra- and
intermolecular aldol reactions, respectively.
Asymmetric amplification in heterogenous amino acid catalysis,
is crucial in the evolution of homochirality in biological systems,
and as a result has attracted much attention.8,9 In 1986, by using
non-enantiopure auxilaries, three catalytic asymmetric reactions
were reported by Kagan et al.8a For one of these examples, this
phenomenon was interpreted by Blackmond8b,10 and Hayash-
i
8c,11as the ternary phase behavior of the non-enantiopure mix-
2. Results and discussion
tures of amino acids in solvents.
A solid phase, and a solid phase of an excess enantiomer, and a
solution phase that has a constant eutectic point in the composi-
tion are three phases that are formed by scalemic proline under so-
lid-solution reaction conditions (in DMSO and CHCl3–EtOH). The ee
of the proline in solution was determined to be independent of the
overall proline ee under thermodynamic conditions, which is at
equilibrium. As a result, the same state is valid for the ee’s of the
products that are the outcome of reactions taking place in such
reactions. For instance, 50% ee8b,10b is reported as the eutectic va-
Recently, we reported the proof-of-principle results of a proline-
catalyzed direct aldol reactions between cyclic ketones and alde-
hydes using 1,3-bis[3,5-bis(trifluoromethyl)phenyl]thiourea A as
the additive.13 We proposed that the reaction would proceed
according to a modified Houk–List model in which the carboxylate
moiety of the proline forms an assembly with the thiourea, which
in turn would enhance the reactivity and selectivity of the catalyst.
Furthermore, the thiourea is treated as a nonpolar counterpart to
proline, thereby amplifying its solubility limits in nonpolar solvents
such as hexane or toluene. Some information about the nature of the
proline–thiourea species was obtained from 1H NMR experiments,
with spectra being recorded in CDCl3. The observed results of these
experiments showed that the solubility of the proline–thiourea
* Corresponding author. Fax: +90 3122103200.
E-mail address: asdemir@metu.edu.tr (A.S. Demir).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.02.009

406
A. S. Demir, S. Eymur / Tetrahedron: Asymmetry 21 (2010) 405–409
F3C
F3C
O
N
HN
HN
CF3
HN
HN
CF3
H2
O
S
S
CF3
F3C
CF3
F3C
B
A
F3C
F3C
O
O
N
HN
HN
CF3
H
N
HN
HN
CF3
O
H
O
S
O
S
R
H
CF3
F3C
CF3
F3C
C
D
Figure 1. (A) 1,3-bis[3,5-bis(trifluoromethyl)phenyl]thiourea. (B), (C) and (D) the proposed interaction of the thiourea moiety with proline in solution and in the TS,
respectively.13
mixture in chloroform was much better than each compound alone.
It was seen when following the addition of proline, that the N–H pro-
tons of the thiourea underwent a downfield shift due to the domi-
nant interactions that are present in the complex via the
formation of a hydrogen-bonding network13 (Fig. 1).
The possibility of fine-tuning these proline–thiourea interac-
tions also presents a possible strategy for asymmetric catalyst
development. While the asymmetric amplifications in proline-cat-
alyzed solution-phase reactions have attracted significant atten-
tion, proline–thiourea host–guest complex catalyzed aldol
reactions in nonpolar solvents are still of interest with respect to
how this system behaves under a solid–solution phase system.
For investigating the dependence of the product ee on the ee of
the proline catalyst under these conditions, the reaction of cyclo-
hexanone 1 and p-nitrobenzaldehyde 2 in the presence of a proline
(20% ee)–thiourea complex [20:20(%); Method A] was chosen as a
model system. In order to ensure experimental consistency, freshly
purified starting materials were used. First, the aldol reaction was
carried out in various solvents. The screening of the solvents
showed that hexane was the choice of solvent to give the highest
ee (Table 1, entries 1–7). The next aim was to decrease the polarity
of the reaction medium, which should change the ee and amount
of proline in the solid–solution system. Two different methods
were selected for decreasing the polarity; first by decreasing the
Table 1
Screening of the solvent for an L-proline (20% ee)–thiourea complex-(20:20%)-catalyzed enantioselective direct aldol reaction of aldehydes 2 and cyclohexanone 1
O
O
OH
O
proline (20 % ee) + thiourea
20 %
20 %
H
+
solvent, rt
O2N
O2N
2
3
1
0.25 mmol
4 mmol
Entry
Solvent
Catalyst (%, proline/urea)
Solvent (mL)
Ketone equiv
Time (h)
Conv (%)
anti:syn
ee of 3 (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
MeCN
CHCl3
20:20
20:20
20:20
20:20
20:20
20:20
20:20
20:20
20:20
20:20
20:20
20:20
20:20
20:20
20:0
1.6
1.6
1.6
1.6
1.6
1.6
1.6
1.6
1.6
1.6
1.6
3.2
6.4
9.6
1.6
16
16
16
16
16
16
16
16
8
4
2
16
16
16
16
24
24
24
24
24
24
24
16
16
16
16
16
16
16
16
50
98
99
99
95
73
99
99
69
12
65
62
30
70:30
90:10
93:7
94:06
75:25
90:10
93:7
94:6
90:10
96:4
nd
16
25
24
29
17
23
32
32
45
55
56
46
53
51
P19
Toluene
Cyclohexane
Dioxane
CH2Cl2
Hexane
Hexane
Hexane
Hexane
Hexane
Hexane
Hexane
Hexane
Hexane
92:7
95:5
97:3
nd
13
610

A. S. Demir, S. Eymur / Tetrahedron: Asymmetry 21 (2010) 405–409
407
Table 2
Relationship between the enantioselectivity of the reaction and the enantiomeric excess of proline
O
O
O
OH
proline (X % ee) + thiourea
20 % 20 %
H
+
hexane, 3.2 mL, rt
O2N
O2N
1
2
3
0.125 mmol
2 mmol
Entry
ee of catalyst
Catalyst (%, proline/urea)
Time (h)
Conv (%)
anti:syn
ee (%)
1
2
3
4
5
6
7
5
10
20
40
60
80
100
20:20
20:20
20:20
20:20
20:20
20:20
20:20
16
16
16
16
16
16
16
22
27
29
33
32
43
46
97:3
97:3
96:4
96:4
97:3
97:3
95:5
40
48
53
75
91
97
P99
equivalents of ketone, which in turn would result in an increase in
the ee but a decrease in the conversion (Table 1, entries 8–11).
In the second case, the equivalents of ketone were kept at 16,
but the amount of hexane increased. As shown in entries 12–14,
the ee increased while the conversion decreased. This result was
first observed for the existence of a nonlinear effect between the
ee of the proline and the ee of the product under solid–solution
reaction conditions.
Forobtaininginformationaboutthischange, thefollowingexper-
iments were carried out under the standard conditions.13 The first
experiment was started with L-proline (20% ee)/thiourea (20:20),
in hexane stirred for 16 h. According to previous work and the
NMR spectra, structure B (Fig. 2) was formed. Proline is known to ex-
ist as a zwitterion, which forms a highly insoluble network of hydro-
gen bonded prolines. We anticipated that a chemical entity, which
selectively and strongly binds to the acetate functionality, would
(a) interact with proline in solution, thus altering its solution prop-
erties and reactivity; and (b) also bind to the transition state in a
stronger fashion, thereby improving the selectivity. The formation
of structure B in a solid–solution system was carried out by mixing
The aldol reaction was repeated with L-proline with ee values
ranging from 5% to 100% wherein the product was obtained with
an increased ee value from 40% to 99% ee. As shown in Table 2,
the results proved again that the ee values of the product versus
the ee values of proline showed a very good positive nonlinear ef-
fect (Fig. 2). In all cases, the diastereomeric excess of the product
was very high.
This solid-solution system behaves in a similar fashion as was
reported by Blackmond8b,10 and Hayashi8c with a ternary phase
behavior of a non-enantiopure (scalemic) mixture of amino acids
in solvents (Hayashi et al. determined the ee value from the solid
part of the solid–solution system).8c
L-proline (20% ee) with urea A in hexane (see a similar system
according to Kagan’s ML2 model).8a After the work-up, the ee value
of the isolated proline was 40% (Table 3, entry 1). Next, as shown
in entry 2, the proline–urea mixture was stirred for 30 minutes,
and then cyclohexanone was added. In this case the isolated proline
showed 77% ee (Table 3, entry 2). In entry 3, after the addition of
cyclohexanone p-nitrobenzaldehyde was added, and the stirring
was continued for 16 h. Using a similar method as described above,
the isolated proline showed 49% ee. This decrease in ee can be ex-
plained in some part as follows: the initial ee of the proline in solu-
tion is high, but as the reaction proceeds via TS D, the ee of proline
in solution begins to decrease because the product generated acts
100
80
60
40
20
0
as a polarized solvent to bring both D- and L-proline from the solid
into the organic phase. While the ee of proline in the initial solution
ishigh, thisee insolutiondecreasesasthereactionprogresses, dueto
the increased solubility of both
forming products.
L- and D-proline in the solvent and
Although the present reaction is only successfulunder certain lim-
ited conditions, it may indicate a possible mechanism by which an
Table 3
Determination of the soluble proline ee value during the experiment after 16h
Entry ee of
proline
ee of proline
(afterward)
Proline/
urea (%)
Conditions
0
20
40
60
80
100
(initial)
ee of proline
1
2
20
20
40
77
20:20
20:20
In hexane
In hexane with
cyclohexanone
ee of product (Method A)
ee(prod)(%)=ee(max) . ee(max) .100
3
20
49
20:20
In hexane with aldehyde
and cyclohexanone
Figure 2. Relationship between the enantioselectivity of the reaction product and
the enantiomeric excess of proline.

408
A. S. Demir, S. Eymur / Tetrahedron: Asymmetry 21 (2010) 405–409
100
80
60
40
20
0
Blackmond reported that the existence of an eutectic ee of pro-
line [the eutectic for proline in dimethyl sulfoxide (DMSO) at 25 °C
is approximately 50% ee] under solid–solution equilibrium, dic-
tates the enantiomeric excess of the solution for all the values of
the scalemic proline ee employed which in turn dictates the prod-
uct ee that may be achieved in solution-phase reactions which are
catalyzed by scalemic proline.
3. Conclusion
With an aldol reaction between cyclohexanone and p-nitro-
benzaldehyde, we have demonstrated that proline–thiourea com-
plex catalyzed aldol reactions under nonpolar solvent conditions
exhibit ternary phase behavior. We have shown a model based
on simple solubility concepts that successfully rationalizes and
predicts the solution ee values for chiral compounds in solid–solu-
tion equilibrium. Furthermore, the enantiomeric excess of proline
in solution may be significantly enhanced by its incorporation with
a urea molecule into its solid racemate which suggests a general
and facile route to homochirality, which may possess prebiotic rel-
evance. Such enantiomerically enriched solutions may provide
asymmetric catalysts or synthetic building blocks for the construc-
tion of complex molecules that are required for recognition, repli-
cation, and ultimately for the chemical basis of life.14
0
20
40
60
80
100
ee of proline
ee of product (Method B)
ee of product (Method C)
Figure 3. The ee of the aldol product versus the ee of proline shows a constant ee
value when increasing the ee value of proline.
amino acid of low ee can in turn generate homochirality in biologi-
callyimportantorganicmoleculeswithinaprebioticenvironment.8b,c
In order to decrease the solubility of the proline catalyst in the
reaction mixture, the amount of urea was decreased [Method B:
20:5(%); Method C: 20:10(%) proline (with various ee)/urea]. Given
the fact that under these reaction conditions a significant portion
of the proline catalyst was not dissolved, the resulting dependence
of the aldol product ee on the total proline ee is also shown in Fig-
ure 3. Furthermore, it is here that a constant aldol product ee, over
a wide range of total proline ee values, occurred in both cases
(Table 4; Fig. 3). This observation can be explained via the models
that are described by Blackmond8 (for reactions in solutions).
4. Experimental
4.1. General procedure for the enantioselective direct aldol
reaction
Proline with a specific ee value (20%), thiourea A (20%) and
1.6 mL hexane were placed in a screw-capped vial. Cyclohexanone
(4 mmol, 0.4 mL) was then added, and the resulting mixture was
stirred for 15 min at ambient temperature followed by the addition
Table 4
The ee value of the aldol reaction catalyzed by proline along with various ee values
O
O
O
OH
proline ( X % ee ) + thiourea
hexane, rt
H
+
O2N
O2N
2
1
3
0.5 mmol
8 mmol
Entry
Catalyst (%, proline/urea)
Solvent (mL)
Proline ee (%)
Product ee (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
20:5
20:5
20:5
20:5
20:5
20:5
20:5
20:5
20:5
3.2
3.2
3.2
3.2
6.4
3.2
6.4
3.2
6.4
3.2
3.2
3.2
3.2
3.2
3.2
3.2
3.2
3.2
5
10
20
40
40
60
60
80
80
100
5
10
20
40
60
80
100
20
18
31
45
46
49
42
49
48
48
99
19
27
43
47
47
53
99
31
20:5
20:10
20:10
20:10
20:10
20:10
20:10
20:10
20:30
Method B: proline/urea 20:5(%); Method C: proline/urea 20:10(%).

A. S. Demir, S. Eymur / Tetrahedron: Asymmetry 21 (2010) 405–409
409
Jacobsen, E. N. Science 2002, 298, 1904–1905; (d) List, B. Acc. Chem. Res. 2004,
37, 548–557; (e) Berkessel, A.; Groger, H. Asymmetric Organocatalysis; Wiley-
VCH: Weinheim , Germany, 2005.
of aldehyde (0.25 mmol) wherein stirring was continued until the
completion of the reaction (TLC monitoring). After completion of
the reaction, the reaction mixture was treated with saturated
aqueous ammonium chloride solution and the whole mixture
was extracted with ethyl acetate. The organic layer was washed
with brine, dried, and concentrated to give a crude residue, which
was purified by column chromatography over silica gel using hex-
ane–ethyl acetate as an eluent to afford the pure product. Diastere-
oselectivity and conversion were determined by 1H NMR analysis
of the crude aldol product. The enantiomeric excess (ee) of 3 was
determined by chiral-phase HPLC analysis.13 The absolute configu-
rations for aldol products were determined by comparing the val-
ues with those previously reported in the literature.5,13
2. (a) Eder, U.; Sauer, G.; Wiechert, R. Angew. Chem., Int. Ed. Engl. 1971, 10, 496–
497; (b) Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1974, 39, 1615–1621.
3. (a) List, B.; Lerner, A. R.; Barbas, C. F., III J. Am. Chem. Soc. 2000, 122, 2395–2396;
(b) List, B. Chem. Commun. 2006, 819–824.
4. Proline-catalyzed aldol reactions, see: (a) Notz, W.; List, B. J. Am. Chem. Soc.
2000, 122, 7386–7387; (b) Sakthivel, K.; Notz, W.; Bui, T.; Barbas, C. F., III J. Am.
Chem. Soc. 2001, 123, 5260–5267.
5. For a review, see: List, B.. In Modern Aldol Reactions; Mahrwald, R., Ed.; Wiley-
VCH: Weinheim, 2004; Vol. 1,. p 161.
6. Duthaler, R. O. Angew. Chem., Int. Ed. 2003, 42, 975–978.
7. (a) Zhong, G. Angew. Chem., Int. Ed. 2003, 42, 4247–4250; (b) Brown, S. P.;
Brochu, M. P.; Sinz, C. J.; MacMillan, D. W. C. J. Am. Chem. Soc. 2003, 125, 10808–
10809; (c) Hayashi, Y.; Yamaguchi, J.; Sumiya, T.; Shoji, M. Angew. Chem., Int. Ed.
2004, 43, 1112–1115; (d)for a review, see . Angew. Chem., Int. Ed. 2004, 43,
2995–2997.
8. For selected examples, see (a) Puchot, C.; Samuel, O.; Dun~ach, E.; Zhao, S.;
Agami, C.; Kagan, H. B. J. Am. Chem. Soc. 1986, 108, 2353–2357; (b) Mathew, S.
P.; Iwamura, H.; Blackmond, D. G. Angew. Chem., Int. Ed. 2004, 43, 3317–3321;
(c) Hayashi, Y.; Matsuzawa, M.; Yamaguchi, J.; Yonehara, S.; Matsumoto, Y.;
Shoji, M.; Hashizume, D.; Koshino, H. Angew. Chem., Int. Ed. 2006, 45, 4593–
4597; For reviews: (d) Girard, C.; Kagan, H. B. Angew. Chem., Int. Ed 1998, 37,
2922–2959; (e) Blackmond, D. G. Acc. Chem. Res. 2000, 33, 402–411.
9. Overviews: (a) Kotsuki, H.; Ikishima, H.; Okuyama, A. Heterocycles 2008, 75,
493–529; (b) Kazmaier, U. Angew. Chem., Int. Ed. 2005, 44, 2186–2188.
10. (a) Klussmann, M.; Mathew, S. P.; Iwamura, H.; Wells, D. H. Jr.; Armstrong, A.;
Blackmond, D. G. Angew. Chem., Int. Ed. 2006, 45, 7985–7989; (b) Klussmann,
M.; Iwamura, H.; Mathew, S. P.; Wells, D. H., Jr.; Pandya, U.; Armstrong, A.;
Blackmond, D. G. Nature 2006, 441, 621–623; Highlight: (c) Kellogg, R. M.
Angew. Chem., Int. Ed. 2007, 46, 494–497.
4.2. Determination of the enantiomeric excess of proline in
solution
Non-enantiopure proline was prepared by mixing known
amounts of L- or D-proline. L-Proline with a specific ee/thiourea
(20:20), in hexane was stirred for 16 h. After filtration of the mixture
followed by work-up, the ee value of the isolated proline was deter-
mined by HPLC. TheHPLC-columnusedfor analysis was a Macherey-
Nagel Nucleosil Chiral 1 column, eluent was a mix of an aqueous
solutionof0.25 mMCuSO4 and0.025 mMH2SO4 with15%methanol,
flow rate 1.5 mL/min, temperature 50 °C, UV–vis detector at 250 nm
11. Jacques, J.; Collet, A.; Wilen, S. H.. Enantiomers, Racemates and Resolution;
Krieger Publishing Company: Florida, 1991.
12. (a) Klussmann, M.; Mathew, S. P.; Iwamura, H.; Wells, D. H., Jr.; Armstrong, A.;
Blackmond, D. G. Angew. Chem., Int. Ed. 2006, 45, 7989–7992; (b) Meek, S.;
Roberts, M. Chem. Commun. 2004, 2021–2022.
(retention times:
L-proline, 6.5 min; D-proline, 18 min).
Acknowledgements
13. Reis, Ö.; Eymur, S.; Reis, B.; Demir, A. S. Chem. Commun. 2009, 1088–
1090.
14. Tsipis, C. A.; Karipidis, P. A. J. Am. Chem. Soc. 2003, 125, 2307–2318.
We gratefully acknowledge the Turkish Academy of Sciences
(TUBA) and the Middle East Technical University (METU).
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