Novel catalysis in the internal nanocavity of polyamine dendrimer for intramolecular michael reaction

Article abstract of DOI:10.1246/cl.2012.801

Poly(propyleneimine) (PPI) dendrimers functionalized with C₁₆ alkyl chains acted as efficient tertiary amine catalysts for an intramolecular Michael reaction. The substrate was accommodated in a reactive conformation within a sterically confined nanocavity consisting of regularly arranged tertiary amino groups of the PPI dendrimers.

Full text of DOI:10.1246/cl.2012.801

doi:10.1246/cl.2012.801
Published on the web July 28, 2012
801
Novel Catalysis in the Internal Nanocavity of Polyamine Dendrimer
for Intramolecular Michael Reaction
1
1
1
1
1,2
Zen Maeno, Takato Mitsudome, Tomoo Mizugaki, Koichiro Jitsukawa, and Kiyotomi Kaneda*
Graduate School of Engineering Science, Osaka University, 1-3 Machikaneyama, Toyonaka, Osaka 560-8531
1
2
Research Center for Solar Energy Chemistry, Osaka University, 1-3 Machikaneyama, Toyonaka, Osaka 560-8531
(
Received March 20, 2012; CL-120239; E-mail: kaneda@cheng.es.osaka-u.ac.jp)
Poly(propyleneimine) (PPI) dendrimers functionalized with
C16 alkyl chains acted as efficient tertiary amine catalysts for an
intramolecular Michael reaction. The substrate was accommo-
dated in a reactive conformation within a sterically confined
nanocavity consisting of regularly arranged tertiary amino
groups of the PPI dendrimers.
Scheme 1. Structure of G5-C16 dendrimer.
Dendrimers have received considerable attention as promis-
ing materials in various research areas because of the following
1
characteristics: 1) tunable chemical and physical properties by
changing core, branch, and peripheral units, and 2) internal
Table 1. Intramolecular Michael reaction of 1 using various
amine catalysts
a
2
a
nanocavities which can encapsulate organic molecules, metal
2
b,2c
2d,2e
complexes,
and metal nanoparticles.
In the field of
catalysis, dendrimers allow precise design of catalytically active
species and reaction environments, exhibiting unique activities
and selectivities. To date, various dendrimers have been reported
Conv.
Yield
/%
3a­3g
Entry Catalyst
Time
syn:antib
to show positive dendritic effects on catalysis,
such as site-
b
b
/%
3a
isolation of active species, locally high concentrations of
3
b,3c
or catalytically active species,3d polar/nonpolar
1
2
3
4
5
6
7
8
9
0
G5-C16
G5-C16
G5-C16
G5-C16
G4-C16
G -C
15 min
1 h
2 h
24 h
1 h
1 h
15 min
5 min
15 min
8 h
1 h
1 h
69
85
99
99
72
62
60
13
30
99
7
68
84
98 (89 )
98
43:57
44:56
43:57
25:75
42:58
41:59
20:80
44:56
34:66
10:90
®
substrates,
reaction environments,3e and catalytic pump effects. However,
3f
c
catalysis due to the steric effect of the confined nanocavities of
dendrimers has been rarely investigated.4
70
60
58
12
29
98
3
®
15
Herein, we investigated the intramolecular Michael reaction
using the alkylated poly(propyleneimine) (PPI) dendrimers as
tertiary amine catalysts and found a novel dendritic effect of
3
16
DBU
the internal nanocavity PPI dendrimers.5,6 The PPI dendrimers
DMAP
DMAP
DMAP
TMPDA
TEA
accommodated the substrate in a reactive conformation for the
intramolecular cyclization within the nanocavity, with the result
that the intramolecular Michael reaction proceeded smoothly.
Alkylated PPI dendrimers were synthesized according to a
1
1
1
12
13
14
N. R.
17
13
®
43:57
41:59
3
f,7,16
d
reported procedure.
Third- to fifth-generation NH2-termi-
TEA
1 h
1 h
nated PPI dendrimers G -NH (x = 3, 4, and 5, denoting the
PEI-C16
12
x
2
generation number of the dendrimer) were treated with palmitoyl
chloride to afford alkylated PPI dendrimers, Gx-C16 (Scheme 1).
The intramolecular Michael reaction of (E)-9-nitro-3-nonen-
a
Reaction conditions: 1 (0.2 mmol), catalyst (tertiary N atom:
b
1
3
0 ¯mol), toluene (2 mL). Determined by H NMR using an
internal standard. Isolated yield. dTEA (2 mL) was used
c
2
-one (1) to 1-(2-nitrocyclohexyl)propan-2-one (2) was exam-
instead of toluene.
8
ined using Gx-C16 as a catalyst (Table 1). G5-C16 (pKa = 10.35)
catalyzed the intramolecular Michael reaction of 1 quantitatively
in 2 h (Entry 3). Interestingly, the catalytic activity of Gx-C16
G5-C16,10 gave a low yield of 2 (Entry 13). The initial reaction
increased as the generation of the dendrimer increased (Entries
rates for the intramolecular Michael reaction of 1 in the presence
of G5-C16 and in a TEA solvent were 0.56 and 0.046 ¯mol s ,
9
¹1
2, 5, and 6). Triethylamine (TEA, pKa = 10.7), which corre-
sponds to the amine component of the nanocavity of G -C , did
respectively; the catalytic activity of G -C was 12 times greater
5 16
5
16
not promote this reaction (Entry 12). Other low-molecular-
than that of TEA. When using the poly(ethyleneimine) modified
1
6
weight amines such as N,N,N¤,N¤-tetramethyl-1,3-propanedi-
with C16 alkyl chains (PEI-C16) as an irregularly branched
polyamine catalyst, the intramolecular Michael reaction did not
proceed efficiently (Entry 14).
In the intramolecular Michael reaction of 1, a diastereomeric
mixture of 2a and 2b with a syn:anti ratio of 45:55 was obtained
(Entries 1 and 8). In the case of G5-C16, isomerization of 2a to
9
amine (TMPDA, pK = 10.5), N,N-dimethyl-4-aminopyridine
a
9
(
(
DMAP, pKa = 9.2), and 1,8-diazabicyclo[5.4.0]undec-7-ene
DBU, pKa = 18.7) showed lower catalytic activities than G5-
9
C16 (Entry 1 vs. Entries 7, 9, and 11). Even a solvent amount of
TEA, with higher amine concentration than the nanocavity of
Chem. Lett. 2012, 41, 801­803
© 2012 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

8
02
Table 2. Intermolecular Michael raction of 3 and 4 to 5a
the thermodynamically stable anti-isomer 2b did not occur to a
significant extent until complete conversion of 1 had taken place
(Entries 1­4). On the other hand, when using DMAP, the
isomerization reaction proceeded simultaneously with the intra-
molecular Michael reaction (Entries 8­10).
Furthermore, in the intramolecular Michael reaction of (E)-
Conv. of 3/%b
Yield of 5/%b
Entry
1
2
3
4
5
6
7
8
Catalyst
8
-nitro-3-octen-2-one, G -C showed higher catalytic activity
5 16
G5-C16
G5-C16
G -C
4 16
47
85
25
14
8
4
45
24
45
70
24
12
6
3
43
22
than DMAP; G5-C16 afforded 1-(2-nitrocyclopentyl)propan-2-
c
one in 99% yield for 30 min, while DMAP gave 22% yield of
the cyclization product (Table S3).11,16
G3-C16
TMPDA
TEA
The intramolecular Michael reaction generally occurs via
nucleophilic attack of a carbanion generated by deprotonation of
a donor part to a distant acceptor part and subsequent pro-
d
tonation of the corresponding enolate intermediate.12 Noting the
TEA
PEI-C16
positive generation effect observed for Gx-C16 and the low
catalytic activity of PEI-C16, it was suggested that the efficient
intramolecular Michael reaction using G -C proceeds through
a
Reaction conditions: 3 (0.2 mmol), 4 (0.5 mmol), catalyst
b
5
16
(tertiary N atom: 30 ¯mol), toluene (2 mL), 24 h. Determined
c
substrate orientation within the sterically confined nanocavity
consisting of regularly arranged tertiary amino groups of G5-C16;
the encapsulated substrate 1 is deprotonated by the tertiary
amino group to form the corresponding carbanion species 1a
together with a quaternary ammonium cation. Next, the acceptor
part of 1a is oriented toward the distant donor part of 1a by a
sterically confined nanocavity consisting of the core and branch
units of G5-C16. This conformation allows an electrostatic
interaction between the quaternary ammonium cation of the
nanocavity and the carbonyl group of 1a,13 resulting in facile
nucleophilic attack of the donor part of 1a to form a cyclized
enolate intermediate. Subsequent protonation of the enolate
intermediate furnishes the product 2. The sluggish isomerization
of 2a to 2b during the intramolecular Michael reaction may be
due to the preferential accommodation of 1 over 2 into the
nanocavity of G -C . After complete conversion of 1, the
by GC using an internal standard. 48 h. 1-(5-Ethyl-2-hydroxy-
2-methyl-5-nitrocyclohexyl)ethanone was obtained in 13%
yield by consecutive reaction of 5 (see ref. 15). TEA (2 mL)
was used instead of toluene.
d
Michael reaction (Table 1, Entry 3 vs. Entry 14, and Table 2,
Entry 1 vs. Entry 8). These remarkably different results between
intramolecular and intermolecular Michael reaction support the
occurrence of specific substrate orientation for intramolecular
cyclization of 1 within the internal nanocavity of G5-C16.
In conclusion, the alkylated PPI dendrimer G5-C16 acted as
an organocatalyst and showed a novel dendritic effect in the
intramolecular Michael reaction based on substrate orientation
within its internal nanocavity. The sterically confined nanocavity
consisting of regularly arranged amino groups of G -C could
5
16
5
16
isomerization of 2a to 2b occurs.
accommodate the substrate in a reactive conformation for
intramolecular cyclization. We believe that such substrate
orientation within the internal nanocavities of dendrimers may
be applicable not only to the intramolecular Michael reaction but
also to other cyclization reactions.
To support this suggested substrate orientation in the
intramolecular Michael reaction, preliminary kinetic studies of
the intramolecular Michael reaction of 1 were carried out using
16
G5-C16, TEA, and PEI-C16 (Table S4 ). The activation entropies
‡
¦
S of G5-C16, TEA, and PEI-C16 were ¹266, ¹249, and
¹1
¹1
‡
¹
243 J K mol , respectively. The smaller ¦H value of G -
This work was supported by a Grant-in-Aid for Challenging
Exploratory Research (No. 23656514) from the Japan Society
for the Promotion of Science (JSPS). Z.M. expresses his special
thanks for The Global COE (center of excellence) Program
“Global Education and Research Center for Bio-Environmental
Chemistry” of Osaka University.
5
C16 confirms that the transition state for cyclization is more
restricted by steric effects when this catalyst is used compared to
14
‡
the case of TEA and PEI-C . The activation enthalpies ¦H
16
¹
1
were obtained as 16.4, 29.0, and 30.6 kJ mol for G5-C16, TEA,
and PEI-C16, respectively, showing that the nanocavity of G5-
C16 lowered the barrier for intramolecular nucleophilic attack by
stabilizing the transition state. The activation energy Ea of G5-
References and Notes
¹1
C16 (20.0 kJ mol ) was much lower than that of TEA and PEI-
1
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¹
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(
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5 16
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¹1
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5
16
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Chem. Lett. 2012, 41, 801­803
© 2012 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

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1
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¹
3
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¹
3
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16 Supporting Information is available electronically on the
CSJ-Journal Web site, http://www.csj.jp/journals/chem-lett/
index.html.
Chem. Lett. 2012, 41, 801­803
© 2012 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/