Substrate-selective dehydrocondensation at the interface of micelles and emulsions of common surfactants

Article abstract of DOI:10.1002/anie.201107706

Scratch the surface: Dehydrocondensations between carboxylates and amines by using an amphiphilic 1,3,5-triazinylammonium-based coupling agent were accelerated by the interfacial effect of micelles and emulsions of common surfactants (see figure). The reaction of carboxylates was promoted by both anionic and nonionic surfactants, and that of amines was promoted by only a nonionic surfactant. High selectivities for more lipophilic substrates were observed in micelles or emulsions. Copyright

Full text of DOI:10.1002/anie.201107706

.
Angewandte
Communications
DOI: 10.1002/anie.201107706
Micellar Effect
Substrate-Selective Dehydrocondensation at the Interface of Micelles
and Emulsions of Common Surfactants**
Munetaka Kunishima,* Kanako Kikuchi, Yukio Kawai, and Kazuhito Hioki
The utilization of micelles for controlling organic reactions
has been attracting considerable attention. The micellar
interface is well known as an excellent reaction field for
hydrolysis.[1–4] In spite of this fact, the reverse reaction, that is,
the dehydrocondensation of a carboxylic acid and an amine,
can also be accelerated at the micellar interface. In fact, we
successfully showed that a remarkable rate acceleration for
the reaction of aliphatic carboxylic acids (A) and amines (B)
by 1,3,5-triazine-based amphiphilic dehydrocondensing
agents (C),[5] which are available in water similar to 4-(4,6-
other surfactants. In this case, the concentration of all
reactants in the micelles will significantly increase (local
concentration effect). In addition, the charged hydrophilic
polar heads, such as carboxylato, ammonio, and triazinylam-
monio groups, undergoing the reaction should be located at
the interface in close proximity to each other (preorienta-
tional effect). Thus, the coupling reaction of carboxylic acids
and amines using the amphiphilic dehydrocondensing agents
can be promoted by the formation of micelles.
However, in our previous study, the reaction rate
enhancement was achieved in limited cases where the
reactant fatty acid salts, such as laurate, could act as
surfactants forming micelles under the reaction conditions
(Figure 1a).[5] In fact, no significant rate acceleration was
observed in the reactions using carboxylates with a high
critical micellar concentration (cmc); for example octanoate,
which cannot form micelles under the reaction conditions. In
addition, the majority of the carboxylates used in excess to
generate micelles must be discarded. If a similar acceleration
is realized with a smaller amount of the carboxylate,
independent of their micelle-forming properties, the reaction
becomes synthetically useful. Herein we describe the micellar
effect of common surfactants other than fatty acid salts on
amide formation (Figure 1b), and investigate the relationship
between reactant lipophilicity (carboxylates or amines) and
reaction rate acceleration. Selectivity for alkylamines that had
not been previously examined is also discussed.
dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium
chlo-
ride (DMT-MM),[6,7] occurred up to 2000 times faster in
micelles than in a normal homogeneous molecular dispersion
phase (Figure 1). Because both carboxylic acids and amines
Figure 1. Rate acceleration of dehydrocondensation in micelles.
We examined coupling reactions of aliphatic sodium
carboxylates possessing alkyl chains of different lengths
(5 mm) and butylamine (20 mm) in the presence of nonionic
generally exist in the ionized state in water at near-neutral
pH, these compounds have amphiphilic properties when they
possess a long alkyl chain. Thus, when dissolved in water, they
can form a molecular assembly, such as micelles, independ-
ently or be incorporated into molecular assemblies formed by
(4-(1,1,3,3-tetramethylbutyl)phenyl
polyethylene
glycol
(Triton X-100) and anionic [sodium dodecyl sulfate (SDS),
sodium 1-decanesulfonate (DSA)] surfactants under identical
conditions (258C, 12 h). We employed an amphiphilic con-
densing agent (C1 (see structure in Table 1), 1.5 mm), which
was found to result in a large rate acceleration in the fatty acid
micellar system previously reported by us.[5] The concentra-
tion of the surfactants was five times their cmc.
As shown in Table 1, the reactions of sodium hexanoate
(C5H11COONa) and sodium octanoate (C7H15COONa) were
significantly promoted by the addition of a surfactant.
Because these carboxylates do not form micelles under the
reaction conditions, the observed rate acceleration is attrib-
uted to the micellar effect of the added surfactants. A similar
effect of surfactant upon the reaction rate was observed with
aromatic benzoate. In contrast, the reaction of sodium laurate
(C11H23COONa) proceeded in good yield irrespective of the
presence or absence of the surfactant. The reaction of laurate
was accelerated by its own micelles,[8] therefore an additional
surfactant did not have a substantial effect on the reaction
[*] Prof. Dr. M. Kunishima
Faculty of Pharmaceutical Sciences, Institute of Medical,
Pharmaceutical, and Health Sciences, Kanazawa University
Kakuma-machi, Kanazawa 920-1192 (Japan)
E-mail: kunisima@p.kanazawa-u.ac.jp
K. Kikuchi, Y. Kawai, Dr. K. Hioki
Faculty of Pharmaceutical Sciences, Kobe Gakuin University
1-1-3 Minatojima Chuo-ku, Kobe 655-8586 (Japan)
Prof. Dr. M. Kunishima, Dr. K. Hioki
Cooperative Research Center of Life Sciences, Kobe Gakuin
University, 1-1-3 Minatojima Chuo-ku, Kobe 655-8586 (Japan)
[**] This work was supported partially by a Grant-in-Aid for Scientific
Research (No. 20390007) from Japan Society for the Promotion of
Science (JSPS).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201107706.
2080
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2012, 51, 2080 –2083

Angewandte
Chemie
Table 1: Effect of surfactants on the yield of N-butylalkanamides.
outcome is presumably due to the hydrophobic effect,
because no micelles could be formed under these reaction
conditions. Compared with aliphatic amide 1c, the yield and
selectivity for aromatic carboxamides 1e–g were moderately
increased by the addition of Triton X-100 (1.5 mm). After
several attempts using various reaction conditions, we found
that both the selectivity and yield for these reactions were
significantly increased by mixing Triton X-100 (1.5 mm) and
1% (v/v) toluene to form an emulsion. Notably, the observed
high selectivity is attributed to acceleration by interfacial
effects because the yield and the selectivity simultaneously
increased in the micellar (and emulsion) system.
Yield [%][a]
Surfactant (concentration)
none
Triton X-100 (1.5 mm)
SDS (40 mm)
1b
7
25
23
36
1c
8
44
44
50
1d
75
74
88
89
1e
8
31
18
31
DSA (200 mm)
Next, we examined the effect of the length of the alkyl
chain of the amines on the reaction selectivity in the micellar
system. Competitive reactions between decylamine and
butylamine with carboxylic acids were carried out. When
a mixture of equimolar amounts of these amines was treated
with laurate and C1 in the presence of Triton X-100 (100 mm),
N-decyldodecanamide (2d) was obtained predominantly over
N-butyldodecanamide (1d) in a 98.7:1.3 ratio (Table 2,
entry 1). Interestingly, the yield of the amide decreased to
[a] Determined by GC analysis. The initial concentration of reactants:
carboxylate: 5 mm; butylamine hydrochloride: 20 mm; C1: 1.5 mm;
surfactant: 5 times cmc; and MeOH: 3% (v/v) in sodium phosphate
buffer (20 mm, pH 8).
rate. A positive relationship between the yield and the length
of the carbon chain of the carboxylates, which reflects their
hydrophobicity, would also support the micellar effects on the
reactions.
Interestingly, the addition of the cationic surfactant,
cetyltrimethylammonium chloride (CTAC, 5 mm), to the
reaction of sodium laurate completely depressed amide
formation. As the cmc of CTAC (1.3 mm) is lower than that
of laurate,[8] CTAC would be the major micelle-forming
component. Thus, because cationic micelles are known to
promote (enhance the rate of) hydrolysis at their interface by
the concentration of anionic hydroxide ions in their diffuse
layer,[1,9] the amphiphilic dehydrocondensing agent or an
activated triazinyl ester intermediate incorporated into the
micelles would be exclusively hydrolyzed.
We examined the effect of the surfactant on the substrate
selectivity in the competitive reaction between equimolar
amounts (5 mm each) of butyrate and other carboxylates
having a more lipophilic substituent (Figure 2). Under these
reaction conditions, octanamide 1c was obtained with high
selectivity (> 99%) in the presence of DSA, SDS, or Triton X-
100 at their cmc concentrations after 12 hours at 258C. In the
absence of the surfactant, the yield of the amides decreased to
only 13%, whereas the selectivity was still good (94:6). This
Table 2: Study of amine selectivity in micelles: effect of the length of the
alkyl chain of the carboxylates and/or condensing agents on competitive
reactions between decylamine and butylamine.
Entry[a] R1COONa
C
Surfactant
(100 mm)
t
Yield Ratio[b]
[h] [%][b] 2/1
1
2
3
4
5
6
7
C11H23
C11H23
C7H15
C3H7
C3H7
C3H7
C1 TritonX-100
C1 DSA
C1 TritonX-100 12 69
C1 TritonX-100 12 19
C1 none
C2 TritonX-100 12
C2 none 12
4
4
76
32
2d/1d=98.7:1.3
2d/1d=49:51
2c/1c=98.9:1.1
2a/1a=90:10
2a/1a=54:46
2a/1a=42:58
2a/1a=49:51
12
6
6
9
C3H7
[a] The initial concentration of carboxylate: 5 mm; amine hydrochloride:
10 mm each; C: 1.5 mm; surfactant: 100 mm; and MeOH: 3% (v/v) in
sodium phosphate buffer (20 mm, pH 8). [b] Determined by GC analysis.
32%, and the selectivity was completely lost when DSA was
substituted for Triton X-100 (entry 2). As it is reported that
the pKa of indicators possessing a dissociative proton, such as
bromothymol blue, shifts toward the less-acidic side (higher
pKa) in anionic micelles,[10] the acidity of decylammonium at
the micellar interface would be lower than that of butylam-
monium in an aqueous phase. Since the ionized ammonium
ion B (Figure 1) must dissociate to the nonionized amine prior
to its attack on the triazinyl ester in the final step of amide
formation, the micellar effect of DSA could prevent the
dissociation of the decylammonium ion to decylamine, and
thus could reduce the rate of formation of N-decylamide. As
a result, these effects would be responsible for the observed
low yield and selectivity for this reaction. The unfavorable
Figure 2. Study of substrate (carboxylate) selectivity: competitive reac-
tion between butyrate and other carboxylates for selective formation of
N-butylalkanamides (1a/1x). The initial concentration of carboxylate:
5 mm each; butylamine hydrochloride: 20 mm; and C1: 1.5 mm. Yields
are given in %.
Angew. Chem. Int. Ed. 2012, 51, 2080 –2083
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
2081

.
Angewandte
Communications
Table 3: Dual selective reactions between two types of carboxylates and
amines, each including substrates with both long- and short-chain alkyl
groups.
effect of anionic micelles of DSA on reactions between
amines and carboxylic esters has been observed and reported
previously.[11]
The incorporation of carboxylates and the dehydrocon-
densing agent into the micellar phase would also be essential
for selective formation of N-alkylamides. In the reaction of
octanoate, which does not form micelles independently, the
selectivity and the yield were retained by extending the
reaction time to 12 hours (Table 2, entry 3). When butyrate
was employed, the yield of the amide decreased to 19%,
while the selectivity for the N-decylamide 2a was still
significantly high (entry 4). However, the selectivity was
almost lost in the absence of the surfactant (entry 5). In the
case of the hydrophilic dehydrocondensing agent C2 possess-
ing a short alkyl chain (ethyl group), no selectivity was
observed irrespective of the presence or absence of Triton X-
100 even though decylamine could be incorporated into
micelles (entries 6 and 7). Interestingly, in spite of the
involvement of the same intermediate triazinyl butyrate, the
amine selectivity in micelles varied when different condensing
agents were employed (entries 4 and 6). When the amphi-
philic C1 was used, the activated triazinyl butyrate could be
formed in the micellar phase where it is attacked mainly by
decylamine in the same phase. On the contrary, because the
reaction using hydrophilic C2 gives the activated ester in the
aqueous phase, there is no advantage with decylamines
incorporated into micelles.
Solvent[a]
Yield [%]
Ratio (1a/2a/1d/2d)
MeOH
22
64
31:26:18:25
0.5:0.9:1.5:97.1
H2O/Triton X-100 (200 mm)[b]
[a] Reaction was conducted with 1.5 mm of C1, 5 mm of each carboxylate,
and 20 mm of each amine hydrochloride. [b] Reaction was conducted in
sodium phosphate buffer (100 mm, pH 8).
Finally, we determined that the reaction site (1,3,5-
triazinyl group) of the amphiphilic dehydrocondensing
agent C1 employed in the present work was located at the
micellar interface and not in the hydrophobic core region of
micelles by the UV absorption study. Because the dehydro-
condensing agent is susceptible to hydrolysis, particularly at
the micellar interface, an amphiphilic quaternary anilinium
salt (N-dodecyl-N,N-dimethyl-3-methoxyanilinium iodide)
was employed as a model compound simulating the structure
of C1.[12] On the basis of this study, we concluded that the
reacting site is located at the interface or in the palisade layer
of micelles (see the Supporting Information); therefore, the
observed rate enhancement of lipophilic substrates can be
attributed to the micellar effect.
In summary, we clarified the effect of surfactants upon
amide formation using amphiphilic 1,3,5-triazine-based cou-
pling agents. Cationic surfactants, such as quaternary ammo-
nium salts, completely inhibit the reaction by promoting the
hydrolysis of the coupling agents or reactive intermediates.
Both nonionic and anionic surfactants dramatically promote
the reaction of carboxylates and the amphiphilic dehydro-
condensing agents by generation of micelles. Anionic surfac-
tants, however, suppress the nucleophilic attack of amines,
which are incorporated into micelles, on the activated
triazinyl esters that are in close proximity and cause a decrease
in the amine selectivity. As a result, nonionic surfactants are
the most suitable for the acceleration of both steps of the
reaction involving the attack of carboxylates and amines at
the micelle surface.
We additionally examined the amine selectivity in com-
petitive reactions between butylamine and other more lip-
ophilic amines under the same conditions using C1 and Triton
X-100 (Figure 3). Interestingly, hexylamine, which has only
two additional methylene groups in the alkyl chain, showed
96% selectivity. An aromatic benzylamine also reacted with
good selectivity.
Figure 3. Study of amine selectivity in micelles: competitive reaction
between butylamine and other amines in the synthesis of N-alkyldode-
canamides. Yields are given in %.
To extend its synthetic applications, we are currently
studying the reaction at higher substrate concentrations and
exploring reaction conditions that support the use of various
carboxylic acids other than the fatty acids.
We next examined a competitive reaction between
mixtures of two types of carboxylates and amines, each
including substrates with both long- and short-chain alkyl
groups (Table 3). As it can be expected that four unique
amides should be formed in equal amounts in a common
molecular dispersion phase, the reaction proceeded with no
significant selectivity in methanol. In contrast, the amide 2d
resulting from the coupling reaction of laurate and decyl-
amine, both of which have a long alkyl chain, was obtained
exclusively (97% selectivity, 64% yield) by conducting the
reaction in the micellar system with Triton X-100. The other
three amides were generated in very limited quantities.
Experimental Section
General procedure for dual selective reactions between two types of
carboxylates and amines in micelles. The condensing agent C1 (20 mm
in 40% aqueous MeOH, 150 mL) was added to a stirred aqueous
solution of sodium phosphate buffer (pH 8, 1.85 mL) containing
sodium butyrate and laurate (10 mmol for each carboxylate), the
hydrochlorides of butylamine and decylamine (20 mmol for each
amine), and Triton X-100 (0.5m) at 258C. The initial concentration of
reactants in the resulting solution was carboxylates: 5 mm each;
amines: 10 mm each; C1: 1.5 mm; Triton X-100: 200 mm; and MeOH:
2082 www.angewandte.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2012, 51, 2080 –2083

Angewandte
Chemie
3%(v/v) in sodium phosphate buffer (20 mm, pH 8). The mixture was
stirred at 258C for 12 h, and then 5m HCl (0.3 mL) was added. The
resulting mixture was applied to Extrelutꢀ NT (Merck, 2 g) and eluted
with AcOEt. The produced amide was quantified by GC.
[3] S. Tascioglu, Tetrahedron 1996, 52, 11113 – 11152.
[4] T. Dwars, E. Paetzold, G. Oehme, Angew. Chem. 2005, 117,
7338 – 7364; Angew. Chem. Int. Ed. 2005, 44, 7174 – 7199.
[5] M. Kunishima, H. Imada, K. Kikuchi, K. Hioki, J. Nishida, S.
Tani, Angew. Chem. 2005, 117, 7420 – 7423; Angew. Chem. Int.
Ed. 2005, 44, 7254 – 7257.
[6] M. Kunishima, C. Kawachi, K. Hioki, K. Terao, S. Tani,
Tetrahedron 2001, 57, 1551 – 1558.
[7] M. Kunishima, C. Kawachi, J. Morita, K. Terao, F. Iwasaki, S.
Tani, Tetrahedron 1999, 55, 13159 – 13170.
N-Decyldodecanamide (2d). Colorless crystals; mp 64–668C
(CH2Cl2/hexane); 1H NMR (CDCl3): d = 0.88 (t, J = 6.9 Hz, 6H),
1.22–1.31 (m, 30H), 1.43–1.52 (m, 2H), 1.57–1.66 (m, 2H), 2.14 (t, J =
7.6 Hz, 2H), 3.23 (td, J = 7.1, 5.8 Hz, 2H), 5.38 ppm (s, 1H); IR
(KBr): n = 3314, 1636 cmÀ1; ESI-MS m/z 340 [(M+1)+].
~
[8] The cmc value of laurate (4.5 mm), which is smaller than that in
literature (24 mm), under our reaction conditions was deter-
mined previously. See Ref. [5].
Received: November 2, 2011
Published online: January 20, 2012
[9] F. M. Menger, C. E. Portnoy, J. Am. Chem. Soc. 1967, 89, 4698 –
4703.
[10] M. Montal, C. Gitler, Bioenergetics 1973, 4, 363 – 382.
[11] M. T. A. Behme, J. G. Fullington, R. Noel, E. H. Cordes, J. Am.
Chem. Soc. 1965, 87, 266 – 270.
[12] a) S. Riegelman, N. A. Allawala, M. K. Hrenoff, L. A. Strait,
J. Colloid Sci. 1958, 13, 208 – 217; b) H. Suzuki, J. Am. Oil Chem.
Soc. 1970, 47, 273 – 277.
Keywords: amides · amphiphiles · micelles · surfactants ·
synthetic methods
.
[1] J. H. Fendler, E. J. Fendler, Catalysis in Micellar and Macro-
molecular Systems, Academic Press, New York, 1975.
[2] J. H. Fendler, Membrane Mimetic Chemistry, Wiley, New York,
1982.
Angew. Chem. Int. Ed. 2012, 51, 2080 –2083
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 2083