Efficient synthesis of novel macrocyclic tetraamide compounds: A unique reaction process involving both self-assembling and folding of intermediates

Article abstract of DOI:10.1039/b200177m

A macrocycle having two isobutenyl and four amide moieties was successfully formed via two kinds of acyclic intermediates. These key intermediates possess the ability to self-organize due to intra- or intermolecular hydrogen-bonding interactions. In both intermediates, preorganized structures were favorably subject to nucleophilic attack at the carbonyl group by a terminal amino group, and preorganization made it possible to form the macro-cycle under mild conditions.

Full text of DOI:10.1039/b200177m

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Efficient synthesis of novel macrocyclic tetraamide compounds:
a unique reaction process involving both self-assembling and
folding of intermediates
Munenori Numata,a Kazuhisa Hiratani,*ay Yoshinobu Nagawa,a Hirohiko Houjou,a
Sayuri Masubuchib and Sadatoshi Akaborib
a
Nanoarchitectonics Research Center, National Institute of Advanced Industrial Science
and Technology, Tsukuba Central 4, 1-1-1 Higashi, Tsukuba, Ibaraki 305-8562, Japan.
E-mail: k.hiratani@aist.go.jp
Department of Chemistry, Faculty of Science, Toho University, 2-2-1 Miyama, Funabashi,
b
Chiba 274-8510, Japan
Received (in Montpellier, France) 2nd January 2002, Accepted 28th February 2002
First published as an Advance Article on the web 15th April 2002
excess PDA. Then, we expected isolated acyclic diamine 2 to
A macrocycle having two isobutenyl and four amide moieties was
successfully formed via two kinds of acyclic intermediates. These
key intermediates possess the ability to self-organize due to
intra- or intermolecular hydrogen-bonding interactions. In both
intermediates, preorganized structures were favorably subject
to nucleophilic attack at the carbonyl group by a terminal amino
group, and preorganization made it possible to form the macro-
cycle under mild conditions.
react with an equimolar amount of 1 under high-dilution
conditions to give the macrocyclic amide 4. Unexpectedly, the
one-pot reaction of 1 with excess PDA yielded macrocycle 4
as the main product. This result was surprising because we
expected the acyclic compound 2, not the macrocycle 4, to be
formed predominantly under such conditions.
To study this unusual reaction in more detail, we carried out
experiments under several different conditions.7 As shown in
Table 1, the yield of macrocycle 4 was influenced by the
amount of p-phenylenediamine in the initial reaction mixture.
The yield was maximal (61%) with 4 equiv. of PDA. When less
than or more than 4 equiv. of PDA was used, the yield of
macrocycle was less than maximal. Additionally, the forma-
tion of macrocycle 4 was strongly influenced by the con-
centration of starting materials. We note two important points
from these results: (1) the formation of acyclic intermediate 2 is
necessary in the initial stage of the reaction and (2) the reaction
is promoted by acid; when 4 equiv. of p-phenylenediamine are
used, 2 equiv. of the unreacted p-phenylenediamine acts as a
base in the reaction solution to form p-phenylenediamine
hydrochloride.
To investigate whether acyclic compound 2 was a key
intermediate in the reaction, we isolated 2 and dissolved it in
THF. We found that 2 did not change at all after the THF
solution was allowed to stir overnight at room temperature.
However, as expected, when 2 equiv. of p-phenylenediamine
hydrochloride was added as an acid source to the solution,
macrocycle 4 was formed in 69% yield after 24 h at room
temperature, accompanied with the elimination of PDA. These
results indicate that acyclic compound 2 is a key intermediate
and that intermolecular aminolysis takes place in the presence
of an acid source to give 4. Interestingly, acyclic compound 3
was also formed in the reaction of acyclic compound 2. When
isolated acyclic compound 3 was retreated with p-phenylene-
diamine hydrochloride, macrocycle 4 was also obtained (yield
70%). This means that acyclic compound 3 is also an inter-
mediate in the next step of the reaction and undergoes intra-
molecular aminolysis to give macrocycle 4. From these results,
it is suggested that the formation of macrocycle 4 takes place
via key intermediates 2 and 3 yielded by acid (Scheme 1).
Several questions remain. First, it is well known that ami-
nolysis proceeds more smoothly in polar solvents such as
DMF. However, when DMF was used as solvent, aminolysis
of 2 and 3 did not proceed. Secondly, the formation of
Much attention has recently been paid to macrocyclic com-
pounds containing amide groups.1 These compounds not only
can act as hydrogen-bonding host molecules but also can form
macrocyclic rotors, as exemplified by catenanes2 and rotax-
anes.3 Furthermore, acyclic amide compounds are also useful
for the construction of well-defined structures via self-organi-
zation processes by inter- or intramolecular hydrogen bonding
interactions. Recently, Lehn and Meijer and their coworkers
demonstrated that artificial amideoligomers, which are
designed to form intramolecular hydrogen bonds, undergo
self-organization to afford helical structures.4
We have reported the syntheses of various macrocyclic
compounds having isobutenyl groups and their tandem Clai-
sen rearrangement to macrocycles with phenolic hydroxy
groups.5 In general, it is difficult to obtain macrocyclic com-
pounds in good yields due to the competitive formation of
acyclic oligomers. To avoid the undesired reactions, several
synthetic techniques such as the metal-template effect or high
dilution method have been utilized.
Here, we report the efficient synthesis of the novel macro-
cyclic amide compound 4 via self-organization processes of
acyclic amide intermediates, and wish to highlight some unique
properties of the intermediates, which play an important role
in the formation of 4 (Scheme 1).6
Initially, we intended to prepare macrocycle 4 by reacting
equimolar amounts of di(acid chloride) 1 and p-phenylene-
diamine (PDA) in THF at room temperature. However, under
these conditions, we obtained only a trace amount of 4; the
main reaction products were acyclic oligoamide compounds.
Thus, we planned at first to isolate the acyclic intermediate
diamine 2 as the predominant product in the reaction of 1 with
y Present address: Department of Applied Chemistry, Utsunomiya
University, 7-1-2 Youtou, Utsunomiya 321-8585, Japan. E-mail:
hiratani@cc.utsunomiya-u.ac.jp.
DOI: 10.1039/b200177m
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Scheme 1
Table 1 Effect of the amount of p-PDA on the yield of 4
p-PDA=equiv.
Yield of 4(%)
1.0
2.0
4.0
6.0
32
58
61
56
25
10.0
macrocycle 4 was strongly influenced by the concentration of
2. Thirdly, the reaction proceeds under mild conditions with-
out formation of any other cyclic or linear oligomers: if an
intermolecular aminolysis reaction of 3 takes place, linear
oligomers should be obtained. These facts led us to wonder
if self-organized structures of 2 and 3 involving hydrogen-
bonding interactions might play an important role in the for-
mation of macrocycle 4. In addition, these intermediates have
both amine and carbonyl groups, which could form hydrogen
bonds under acidic conditions and interact intra- and inter-
molecularly with the carbonyl groups. Protonation of the
terminal amine might play an important role not only in intra-
or intermolecular hydrogen bonding between the amino and
amide carbonyl groups but also in the activation of the amide
carbonyl groups attached by an adjacent amino group.
We carried out the ESI-mass spectroscopic studies to
investigate the self-assembling abilities of 2. The result is
shown in Fig. 1. The parent peak in the ESI-mass spectrum of
2 corresponds to the dimer of 2. This result suggests that 2 self-
assembles into a dimer complex through favorable inter-
molecular hydrogen-bonding interactions. In contrast, both
for 2 þ PDA and 2 þ amine 5 mixtures, which can form a
hydrogen bond at only one point, we observed no peak cor-
responding to the complex. These results indicate that hydro-
gen-bonding interactions at two points at least are necessary
for complexation in solution.
Fig. 1 ESI-mass spectrum of 2.
neighboring amide groups (Fig. 2). An intramolecular inter-
action cannot result in such cross-peaks. This fact suggests
intermolecular hydrogen-bonding interactions between the
amide carbonyl and amine groups and formation of the dimer
complex.
The NOESY spectrum was also helpful in investigating the
structural features of acyclic compound 3. We measured the
NOESY spectrum of 3 in the presence of trifluoroacetic acid in
THF-d8 at 223 K. We observed cross-peaks between the amide
protons and aromatic protons of neighboring amide groups
(Fig. 3). These results indicate that intramolecular hydrogen-
bonding interactions between terminal amino groups and
To obtain further evidence for the intermolecular interaction
of 2 and the formation of a self-assembled dimer, we measured
the NOESY spectrum of 2.8 In THF-d8 at 223 K, we observed
cross-peaks between the amine and aromatic protons of
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Fig. 2 (a) NOESY spectroscopic result of 2 (40 mM, 500 MHz, À50 ꢀC, THF-d8); (b) HamineÁ Á ÁHaromatic interaction in 2 (shown as arrows) and
schematic illustration of the self-assembled dimer of 2.
Fig. 3 (a) NOESY spectroscopic result of 3 (10 mM, in the presence of 10 mM CF3COOH, 500 MHz, À50 ꢀC, THF-d8); (b) HamideÁ Á ÁHaromatic
interaction in 3 (shown as arrows) and schematic illustration of the folded structure of 3.
amide carbonyl groups exist.9 These interactions lead to the
incorporation of the terminal amine moiety into the molecule.
This results in a folded structure for 3 (Fig. 3).
From the foregoing results, it is suggested that self-assembly
of 2 followed by folding to form 3 might play an important
role in the formation of macrocycle 4. In both the dimeric self-
assembled structure 2 and folded structure 3, amino groups
could favorably attack the adjacent amide carbonyl carbon.
Adoption of a folded structure 3 might suppress the forma-
tion of oligomers because intramolecular aminolysis in such
a folded structure takes place faster than intermolecular
aminolysis.
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Scheme 2
Unambiguous evidence for the necessity of the dimeric self-
assembled structure 2 and folded structure 3 was obtained from
reactions using their analog 20 and 30, each of which has one
N,N-dimethyl-p-phenylenediamine moiety. These moieties are
not able to hydrogen bond with carbonyl groups. When
another amine end group (NH2) in 20 and 30 utilized for
hydrogen-bonding interactions, nucleophilic attack at the car-
bonyl carbon by the N,N-dimethylamino group would not
occur. With both 20 and 30, aminolysis reactions were not
observed (Scheme 2). These results strongly support the pre-
sumption that the dimeric self-assembled structure 2 and folded
structure 3 are indispensable for the formation of macrocycle 4.
In this study, the formation of macrocycle 4, containing
two isobutenyl and four amide moieties, successfully proceeds
via formation of an acyclic intermediate 2 followed by for-
mation of 3. These key intermediates possess the ability to
self-organize due to intra- or intermolecular hydrogen-bond-
ing interactions. After acyclic compound 2 self-assembles to
form a dimer, intermolecular aminolysis occurs to afford
acyclic compound 3 accompanied by elimination of p-phenyl-
enediamine. In both intermediates, preorganized structures
are favorably subject to nucleophilic attack on the carbonyl
group by a terminal amino group, making it possible for
macrocycle 4 to form under mild conditions. To examine
whether this procedure is a generalized one or not, we carried
out the reaction using o,m-phenylenediamine and 1,4-cyclo-
hexyldiamine. In every case, however, macrocyclic com-
pounds like 4 were scarcely obtained; for o-phenylenediamine
and 1,4-cyclohexyldiamine, the 1 : 1 cyclic compound and for
m-phenylenediamine the 1 : 2 acyclic diamine were obtained
as the main product. These results indicate that the geometry
of the diamines is an important factor in both stages, that is
the formation of the 1 : 2 intermediate and its self-assembly
process. Accordingly, the formation of macrocycles via
unique self-organized processes is restricted to rigid and lin-
ear diamines.
We plan to apply the reaction described here to the synthesis
of newmacrocyclic amide compounds, catenanes and rotax-
anes, and believe that unique properties of 2 and 3 are avail-
able for construction of self-assembling nanostructures.
Experimental
General procedure for the synthesis of macrocycle 4
The di(acid chloride) 1 (0.90 g, 2.5 mmol), in 10 mL of tetra-
hydrofuran (THF), was immediately added, with stirring, to
a solution of either 0.5 g (5.0 mmol) or 1.1 g (10 mmol) of
p-phenylenediamine in 40 mL of THF. The solution was stir-
red overnight at room temperature, during which time a white
precipitate accumulated. After 12 h, the precipitate was filtered
off. THF was separated from the filtrate and water was added
to the residue to give a solid. The solid was combined with the
precipitate, the mixture was washed first with water and then
with a small amount of THF. The macrocycle 4 was obtained
in 60% yield and was recrystallized from DMF and CHCl3 .
Intermediates 2 and 3 were obtained as by-products and
purified by using preparative gel permeation chromatography
(GPC) (CHCl3 as eluent).
Intermediate analogs 20 and 30
A solution of the di(acid chloride) 1 (0.19 g, 0.52 mmol) and
an equimolar amount of N,N-dimethyl-1,4-phenylenediamine
(0.071 g, 0.52 mmol) was stirred for 1 h in THF at room
temperature. To the resulting solution, an equimolar amount
of p-phenylenediamine (0.056 g, 0.52 mmol) was added and the
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mixture stirred for 2 h. After removal of THF, the residue was
washed with water and purified by GPC to afford 20 (30%).
Using 2 instead of p-phenylenediamine, 30 was obtained in
20% yield.
NOESYexperimental conditions
1H NMR spectral data were obtained on a Bruker AVANCE-
500 spectrometer at 500.13 MHz. The 2D nuclear Overhauser
effect spectroscopy (NOESY) were measured in the phase-
sensitive mode. Spectra were obtained using a sweep width of
6000 Hz and 256 complex t1 values. A total of 1024 data points
were collected along the t2 axis and the mixing time was 500
ms. The time-domain data matrix was expanded by zero filling
to 1024 data points.
2. 1H NMR (500 MHz, DMSO-d6): d 4.77 (s, Ar–O–CH2–),
4.89 (br, Ar–NH2), 5.39 [s, –C(=CH2)–], 6.49 (d, CONH–Ar–
NH2), 7.02–7.07 (m, –O–Ar–CONH–), 7.33 (d, CONH–Ar–
NH2), 7.35–7.38 (m, –O–Ar–CONH–), 7.54–7.56 (m, –O–Ar–
CONH–), 9.77 (s, Ar–CONH–Ar–NH2). ESI-MS: m=z 532
(M þ Naþ) (calcd M þ Naþ 509 þ 23).
Notes and references
20. 1H NMR (500 MHz, DMSO-d6): d 2.85 (s, Ar–NCH3),
4.77 (s, Ar–O–CH2–), 4.92 (br, Ar–NH2), 5.40 [s, –C(=CH2)–],
6.50 (d, CONH–Ar–NH2), 6.66 (d, CONH–Ar– NCH3), 7.02–
7.08 (m, –O–Ar–CONH–), 7.34 (d, CONH–Ar–NH2), 7.37–
7.40 (m, –O–Ar–CONH–), 7.50 (d, CONH–Ar–NCH3), 7.55–
7.58 (m, –O–Ar–CONH–), 9.77 (s, Ar–CONH–Ar–NH2), 9.88
(s, Ar–CONH–Ar– NCH3). ESI-MS: m=z 538 (M þ Hþ) (calcd
M þ Hþ 537 þ 1).
1
2
(a) C. A. Hunter, J. Chem. Soc., Chem. Commun., 1991, 794–795;
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1997, 36, 728–732; (c) A. S. Lane, D. A. Leigh and A. Murphy, J.
Am. Chem. Soc., 1997, 119, 11 092–11 093.
3. 1H NMR (500 MHz, DMSO-d6): d 4.76 (s, Ar–O–CH2–),
4.78 (s, Ar–O–CH2–), 5.08 (br, Ar–NH2), 5.38 [s, –C(=CH2)–],
6.52 (d, CONH–Ar–NH2), 7.00–7.08 (m, –O–Ar–CONH–), 7.35
(d, CONH–Ar–NH2), 7.38–7.41 (m, –O–Ar–CONH–), 7.53–7.57
(m, –O–Ar–CONH–), 7.64 (s, –CONH–Ar–CONH–), 9.78 (s,
–O–Ar–CONH–Ar–NH2), 10.16 (s, –O–Ar–CONH–Ar–
CONH–Ar–O–). ESI-MS: m=z 931 (M þ Naþ) (calcd Mþ Naþ
909 þ 23).
4
5
(a) V. Berl, I. Huc, R. G. Khoury and J. M. Lehn, Chem. Eur. J.,
2001, 7, 2798–2808; (b) R. B. Prince, J. S. Moore, L. Brunsveld
and E. W. Meijer, Chem. Eur. J., 2001, 7, 4150–4154.
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Soc., 1997, 119, 12 677–12 678; (b) K. Hiratani, T. Takahashi,
K. Kasuga, H. Sugihara, K. Fujiwara and K. Ohashi, Tetrahedron
L ett., 1993, 36, 5567–5570.
30. 1H NMR (500 MHz, DMSO-d6): d 2.85 (s, Ar–NCH3),
4.83 (br, Ar–O–CH2–), 545 [s, –C(=CH2)–], 6.55 (d, CONH–
Ar–NH2), 6.72 (d, CONH–Ar–NCH3), 7.09–7.12 (m, –O–Ar–
CONH–), 7.40 (d, CONH–Ar–NH2), 7.42–7.44 (m, –O–Ar–
CONH–), 7.56 (d, CONH–Ar–NCH3), 7.59–7.62 (m, –O–Ar–
CONH–), 7.69 (s, –CONH–Ar–CONH–), 9.83 (s, –O–Ar–
CONH–Ar–NH2), 9.94 (s, –O–Ar–CONH–Ar–NCH3), 10.22
(s, –O–Ar–CONH–Ar–CONH–Ar–O–). ESI-MS: m=z 960
(M þ Naþ) (calcd M þ Naþ 937 þ 23).
6
Recently, we reported similar reactions involving self-assembly
of intermediates as a key step: (a) H. Houjou, S.-K. Lee,
Y. Hishikawa, Y. Nagawa and K. Hiratani, Chem. Commun.,
2000, 2197–2198; (b) H. Houjou, Y. Nagawa and K. Hiratani,
Tetrahedron L ett., 2001, 42, 3861–3863.
7
8
We carried out the reaction in CHCl3 , CH3CN, THF, and DMF.
The highest macrocycle yield was obtained when we used THF
solvent.
We expected that the addition of acid as trifluoroacetic acid would
promote the formation of the dimer of 2. Under such conditions,
however, we could not observe cross-peaks between the amine and
aromatic protons because of the broadening of the amine proton
peaks.
4. 1H NMR (500 MHz, DMSO-d6): d 4.76 (s, Ar–O–CH2–),
5.37 [s, –C(=CH2)–], 7.01–7.04 (m, –O–Ar–CONH–), 7.21 (d,
–O–Ar–CONH–), 7.33 (t, –O–Ar–CONH–), 7.64 (s, –CONH–
Ar–CONH–), 10.15 (s, –O–Ar–CONH–Ar–CONH–Ar–O–).
ESI-MS: m=z 824 (M þ Naþ) (calcd M þ Naþ 801 þ 23).
9
The large downfield shifts were observed for both amide protons
Ha and Hb with decreasing temperature. These results suggest that
intramolecular hydrogen bonding interactions between amide
protons and ether oxygen atoms also would exist.
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