A green method for the self-aldol condensation of aldehydes using lysine

Article abstract of DOI:10.1039/b918349c

A self-condensation of aldehydes has been conveniently accomplished by the catalytic action of lysine in water or a solvent-free system under specific emulsion conditions to give α-branched α,β-unsaturated aldehydes in good yields.

Full text of DOI:10.1039/b918349c

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www.rsc.org/greenchem | Green Chemistry
A green method for the self-aldol condensation of aldehydes using lysine†
Yutaka Watanabe,* Kazue Sawada and Minoru Hayashi
Received 7th September 2009, Accepted 30th November 2009
First published as an Advance Article on the web 13th January 2010
DOI: 10.1039/b918349c
A self-condensation of aldehydes has been conveniently
accomplished by the catalytic action of lysine in water or
a solvent-free system under specific emulsion conditions to
give a-branched a,b-unsaturated aldehydes in good yields.
tional cases, simple aldehydes such as butanal and acetaldehyde
were shown to be converted to the condensation products by
the catalysis of a-amino acids in the mechanistic studies.6 We
have now found that Lys and ornithine (Orn) catalyze the self-
condensation of aldehydes in water. Thus, the treatment of
10 mol% of Lys in water with 3-phenylpropanal (1 M) for 2 h at
room temperature, resulted in the formation of the condensation
product in 65% yield (Table 1). Orn also yielded the same product
in a comparable yield (59%). However, arginine, despite being
a comparably basic amino acid, was not as effective as Lys and
Orn (only 24% yield). From this, it is very clear that the presence
of an amino group in the side chain is essential for smooth
reaction.
In order to investigate the effect of concentration of the
aldehyde in the feasibility of reaction, the condensation reaction
was carriedout at different molar concentrations ofthe aldehyde.
It was found that as the concentration of the aldehyde increases,
the yield also increased. For example, 0.25 M, 0.5 M, 1 M and
2 M nonanal in water gave 13%, 21%, 62% and 64% yield of the
condensation product, respectively. After various experimental
studies, 1–2 M solution of aldehydes with more than seven
carbons underwent condensation smoothly in the presence of
10 mol% of Lys at room temperature (Table 1). Even water-
insoluble solid octadecanal (entry 9) was found to furnish the
coupling product in 61% although a larger amount of Lys and
longer reaction time were required.
In order to understand the role of water, we next carried out
the reaction without water. Thus, treatment of higher aldehydes
(more than C6) with 10 mol% of Lys with stirring at room
temperature for 2 h gave the condensation products in good
yields, which are comparable with those in the reactions in
aqueous medium (Table 2). The solvent-free condensation of
hexanal (C6) gave a yield identical to that obtained in the water
solvent system, in which concentration of the aldehyde was
exceptionally higher (8 M), as shown in Table 2. It is noteworthy
that the short chain aldehydes such as pentanal (C5) and butanal
(C4) providedthe condensation product inmoderate yields under
solvent-free conditions, but when the reaction was done in water
(1 M), the yields dropped by half.
Introduction
The quest for environment friendly or green methods for chemi-
cal synthesis is attracting more and more attention.1 To achieve
such a green process, especially for industrial applications it
is desirable (1) either to adopt a solvent-free system or to use
water as solvent, (2) to use biogenic catalysts but not petroleum
products, (3) to avoid heating, and (4) to follow a simple work-
up procedure and waste treatment. Aldol condensation is an
important synthetic method widely used in organic synthesis.2
A typical process involves the self-condensation of aldehydes
catalyzed by alkalis or acids.3 Several alternative methods for
aldol condensation have been reported.4 However, in an era
when green methods are warranted, many of these methods
are not satisfactory with respect to reaction temperature,
reaction time, solvent, yield, and simplicity of the catalyst. Aldol
condensation is an industrially important process. For example,
the condensation product of butanal is the important synthetic
intermediate in the preparation of 2-ethylhexanol which is widely
used for making plasticizers, surfactants, etc. The industrial
process for the self-aldol condensation of aldehydes is usually
carried out in an aqueous alkaline solution. While condensation
of medium carbon-chain aldehydes such as octanal and nonanal
can be conducted by heating under alkaline conditions,5 water-
insoluble higher aldehydes are not suitable for the alkaline
process. A unified procedure for aldol condensation that can
be applied to all kinds of aldehydes is lacking. We herein report
a very general and an environmentally benign method for aldol
condensation of all range of aldehydes (medium to high carbon
aldehydes). The use of biogenic lysine (Lys) as the catalyst
and the solvent-free/aqueous conditions make this method very
attractive.
Results and discussion
The Lys-catalyzed self-condensation of aldehydes in water
or without a solvent, as described, would be a synthetically
useful alternative; it can be applied to various aldehydes with
low to high carbon numbers, in contrast to the common alkaline
condensation that requires heating in the case of moderate chain
aldehydes (C7–C9) and is not suitable for higher chain ones.
The reaction is especially emphasized to be a green procedure
judging from the following: (1) the solvent-free or aqueous
condition, (2) the catalyst used, Lys, is of bio-origin, (3) no
heating is required, (4) short reaction time and simple work-up
In addition to the common self-aldol condensation of aldehydes
using an alkali, the majority of the reported procedures employ
secondary amines and their derivatives as catalysts. As excep-
Department of Materials Science and Biotechnology, Graduate School of
Science and Engineering, Ehime University, Matsuyama, 790-8577,
Japan. E-mail: wyutaka@dpc.ehime-u.ac.jp; Fax: +81-89-927-9921
† Electronic supplementary information (ESI) available: 1H- and 13C-
NMR spectra and data. See DOI: 10.1039/b918349c
384 | Green Chem., 2010, 12, 384–386
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Table 1 Lys-catalyzed self-condensation of various aldehydes in water
Entry
Aldehyde
Conc./M
Lys (mol%)
Time/h
Yield (%)
E/Z
=
1
2
3
4
5
6
7
8
9
CH3(CH2)7CH CH(CH2)7CHO
n-C9H19CHO
n-C8H17CHO
n-C7H15CHO
n-C6H13CHO
1.0
1.0
2.0
2.0
2.0
8.0
1.0
1.0
1.0
10
10
10
10
10
10
10
10
30
2
2
2
2
2
2
2
2
70
75
64
68
69
63
65
78
61
94/6
99/1
98/2
98/2
98/2
95/5
98/2
25/75
99/1
n-C5H11CHO
Ph(CH2)2CHO
n-C12H25SCH(CH3)CH2CHO
n-C17H35CHO
10
Table 2 The self-condensation of aldehydes in no solventa
Table 3 Concentration vs. yield
Yield (%)
Entry
Aldehyde
No solvent
H2O (conc.)
1
2
3
4
5
6
7
n-C9H19CHO
n-C8H17CHO
n-C7H15CHO
n-C6H13CHO
n-C5H11CHO
n-C4H9CHO
n-C3H7CHO
74
66
62
64
62
52
46
Entry
Concentration/M
Yield (%)
1
2
3
4
0.25
0.5
1.0
2.0
21
15
53
68
63 (8 M)
23 (1 M)
23 (1 M)
a A mixture of an aldehyde and 10 mol% Lys was stirred for 2 h (3 h in
the case of entries 6 and 7) at r.t.
procedure, and (5) the waste, containing the basic amino acid,
is non-toxic. Furthermore, since by-products were highly polar
in all cases carried out this time, chromatographic isolation was
accomplished without using a large amount of elution solvents
and silica gel. Although the solvent-free process is greener than
the reaction in water, when the starting aldehyde is a solid, the
water media is essential to promote the condensation.
The reaction mixture in water formed an emulsion. This
observation suggests that a micelle or micelle-like colloidal
aggregate is formed by assembly of an amphiphilic imine 1
derived from Lys or Orn and aldehyde (Scheme 1). Indeed,
the formation of spherical droplets in water was observed by
an optical microscope (Fig. 1). The yield of the condensation
products depended remarkably upon the concentration of an
aldehyde and carbon number of its chain. Thus, 1.0 and 2.0 M
of octanal gave the dimer in 53 and 68% yields, respectively,
while in the case of the concentration of 0.25 and 0.5 M, 21 and
15% of the product were obtained (Table 3). This tendency was
observed in the case of aldehydes with more than seven carbon
atoms. These results suggest that the reaction of heptanal and
higher aldehydes has a critical concentration between 1.0 and
0.5 M for reaction promotion. On the other hand, in the case
of hexanal and lower aldehydes, yields for 1.0 M concentration
Fig. 1 Optical micrograph of the mixture of 3-phenylpropanal and Orn
in water (scale bar = 5 mm).
decreased dramatically and to gain yields similar to those in
higher aldehydes, higher concentration around 4.0–8.0 M was
required. Based on these findings, the present aqueous reaction
is indicated to occur in assembled particles. Recently, there have
been many reports on the reactions in colloidal particles like
micelles.7 Such media were generally constructed by adding
a surfactant to a reactant and a catalyst in water.8 Catalysts
themselves are sometimes designed to behave as surfactants.9 In
contrast to these reports, the present emulsion is formed by the
Scheme 1
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reaction intermediate imine 1 and its condensation product 2,
and the reaction proceeds in assembled sphere. The solvent-free
process also proceeds under emulsified conditions. The water to
form the emulsion may be generated by imine formation.
Acknowledgements
We thank Venture Business Laboratory (VBL) and Institute for
Cooperative Science (INCS), Ehime University for NMR and
elemental analysis.
Conclusion
Notes and references
The Lys-promoted reaction of aldehydes in water or under
solvent-free conditions has furnished the corresponding con-
densation products in good yields. The reaction takes place in
the emulsion media, which assemble both lipophilic aldehydes
and hydrophilic Lys in the same specific micelles, resulting in the
promotion of smooth reaction, in spite of an aqueous system.
This process is environmentally benign and applicable to various
aldehydes, especially to long-chain aldehydes. Therefore, the
procedure would provide a practical synthetic method for the
self-condensation of aldehydes.
1 P. T. Anastas and J. C. Warner, Green Chemistry: Theory and Practice,
Oxford University Press, Oxford, 1998; R. Mestres, Green Chem.,
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U. S. A., 2008, 105, 13197; R. A. Sheldon, Chem. Commun., 2008,
3352.
2 A. T. Nielsen and W. J. Honlikan, Org. React., 1968, 16, 1.
3 M. Ha¨ussermann, Helv. Chim. Acta, 1951, 34, 1482.
4 M. J. Astle and J. A. Zaslowsky, Ind. Eng. Chem., 1952, 44, 2867;
R. D. Offenhauer and S. F. Nelsen, J. Org. Chem., 1968, 33, 775;
T. Takahashi and H. H. O. Schmid, Chem. Phys. Lipids, 1969, 3,
185; R. Mahrwald and H. Schick, Synthesis, 1990, 592; T. Ishikawa,
E. Uedo, S. Okada and S. Saito, Synlett, 1999, 450; C. P. Mehnert,
N. C. Dispenziere and R. A. Cook, Chem. Commun., 2002, 1610; K.
Shimizu, E. Hayashi, T. Inokuchi, T. Kodama, H. Hagiwara and Y.
Kitayama, Tetrahedron Lett., 2002, 43, 9073; S. Kiyooka, H. Fujimoto,
M. Mishima, S. Kobayashi, K. Md. Uddin and M. Fujio, Tetrahedron
Lett., 2003, 44, 927; J. Hamaya, T. Suzuki, T. Hoshi, K. Shimizu,
Y. Kitayama and H. Hagiwara, Synlett, 2003, 873; H. Hagiwara, J.
Hamaya, T. Hoshi and C. Yokoyama, Tetrahedron Lett., 2005, 46,
393; A. Arnold, M. Markert and R. Mahrwald, Synthesis, 2006,
1099.
Experimental
Lys was purchased from Aldrich Chemical Co, and dried by
heating (120 ◦C, for a few hours) in vacuo. Normal tap water was
used for the reaction. Aldehydes were purchased and distilled
under reduced pressure. Some aldehydes were prepared by usual
1,4-addition of thiol to crotonaldehyde (entry 8 in Table 1) and
Swern oxidation of stearyl alcohol (entry 9).
5 F. Robert, J. He´ritier, J. Quiquerez, H. Simian and I. Blank, J. Agric.
Food Chem., 2004, 52, 3525.
6 For a model study on aldolase action, kinetic experiments of the
reaction of butanal (Lys/K2CO3/50 ◦C at pH around 9.0) have been
carried out: A. A. Yasnikov, T. S. Boiko, N. V. Volkova and I. V.
Mel’nichenko, Biokhimiya, 1966, 31, 969, (Biochem. USSR, 1966,
31, 841). For a model study on the investigation of the contents in
atmospheric aerosols, the aldol condensation of acetaldehyde was
demonstrated by the catalysis of amino acids such as Gly, Ala, Ser,
Pro and Arg, but not Lys and Orn, in the presence of inorganic salts:;
B. Nozie`re, P. Dziedzic and A. Co´rdova, Geophys. Res. Lett., 2007,
34, L21812; B. Nozie`re and A. Co´rdova, J. Phys. Chem. A, 2008, 112,
2827.
7 G. Oehme, E. Paetzold and R. Selke, J. Mol. Catal., 1992, 71, L1; S.
Tascioglu, Tetrahedron, 1996, 52, 11113; J. B. F. N. Engberts and M. J.
Blandamer, Chem. Commun., 2001, 1701; U. M. Lindstro¨m, Chem.
Rev., 2002, 102, 2751; T. Dwars, E. Paetzold and G. Oehme, Angew.
Chem., Int. Ed., 2005, 44, 7174.
General procedure for the Lys-catalyzed condensation of
aldehydes in water
An aldehyde (10 mmol) was added to a solution of Lys
(1.0 mmol) in water (10 mL) under vigorous stirring, and the
resulting emulsion was stirred for 2 h at room temperature. After
addition of water and extraction with ether, the condensation
product was isolated by chromatography or distillation. In order
to facilitate the extraction, the emulsion was eliminated by
adding NaCl to the aqueous layer in some cases.
General procedure for the solvent-free condensation of aldehydes
8 B. H. Lipshutz and S. Ghorai, Aldrichim. Acta, 2008, 41,
59.
9 K. Manabe, Y. Mori, T. Wakabayashi, S. Nagayama and S. Kobayashi,
J. Am. Chem. Soc., 2000, 122, 7202; K. Manabe, X.-M. Sun and S.
Kobayashi, J. Am. Chem. Soc., 2001, 123, 10101.
To an aldehyde (10 mmol), Lys (1.0 mmol) was added and the
mixture was vigorously stirred for 2 h at room temperature. The
work-up and isolation procedure were the same as described
above.
386 | Green Chem., 2010, 12, 384–386
This journal is
The Royal Society of Chemistry 2010
©