Selective transformation of a crown ether/seframmonium salt-type rotaxane to N-alkylated rotaxanes

Article abstract of DOI:10.1021/ol902719m

(Figure Presented) Versatlle functlonallzation of a crown ether/sec-ammonlum salt-type rotaxane was accomplished. The rotaxane underwent reductive N-alkylation with sodium trl(acyloxy)borohydrlde or sodium trl(acyloxy)borohydrlde/arbltrary aldehyde In exc

Full text of DOI:10.1021/ol902719m

ORGANIC
LETTERS
2010
Vol. 12, No. 4
712-715
Selective Transformation of a Crown
Ether/sec-Ammonium Salt-Type
Rotaxane to N-Alkylated Rotaxanes
Sakiko Suzuki, Kazuko Nakazono, and Toshikazu Takata*
Department of Organic and Polymeric Materials, Tokyo Institute of Technology,
Ookayama 2-12-1, Meguro-ku, Tokyo 152-8552, Japan
takata.t.ab@m.titech.ac.jp
Received November 25, 2009
ABSTRACT
Versatile functionalization of a crown ether/sec-ammonium salt-type rotaxane was accomplished. The rotaxane underwent reductive N-alkylation
with sodium tri(acyloxy)borohydride or sodium tri(acyloxy)borohydride/arbitrary aldehyde in excellent yields. Structural switching based on
reversible tert-ammonium/tert-amine conversion by acid and base was demonstrated as a pH-controlled molecular shuttle.
Functionalization or modification of interlocked molecules
such as rotaxanes and catenanes, which have high mobility
of components, is really important for the development of
sophisticated supramolecular devices and materials.1 sec-
Ammonium/crown ether-type rotaxanes are the most suitable
rotaxanes or scaffolds for functionalization because of their
easy synthesis, high synthetic yield, and easy modification
of their components.2 These rotaxanes can be synthesized
utilizing the strong interaction between the sec-ammonium
salt axle and the crown ether wheel; direct functionalization
using the ammonium nitrogen as the base point is considered
the most convenient protocol. However, in addition to
neutralizing the ammonium moiety, introducing a functional
group onto the ammonium nitrogen of the rotaxanes has been
a challenge, and it has caused a delay in the development of
applications of rotaxanes. N-Functionalization of rotaxanes
first only involved N-acylation;3 subsequently, we success-
fully performed selective N-methylation of sec-ammonium
salt/crown ether-type rotaxane.4 We found that tertiarization
of nitrogen facilitates the neutralization of ammonium
rotaxane, and thus expands the possible applications of
rotaxanes. This successful functionalization, however, is
limited to methylation. The development of versatile func-
tionalization methods for sec-ammonium salt/crown ether-
(1) For reviews, see: (a) Schalley, C. A.; Wellandt, T.; Brueggmann,
J.; Vo¨gtle, F. Top. Curr. Chem. 2005, 248, 141–200. (b) Takata, T. Bottom-
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Ariga, K., Nalwa, H. S., Eds.; American Scientific Publishers: Los Angels,
CA, 2009; Chapter 12, pp 311-329. (c) Fyfe, M. C. T.; Stoddart, J. F.;
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Y. AdV. Polym. Sci. 2004, 171, 1–75. (d) El-Khouly, M. E.; Ito, O.; Smith,
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2397–2401.
10.1021/ol902719m  2010 American Chemical Society
Published on Web 01/20/2010

type rotaxanes is, therefore, necessary to enhance the
applicability of rotaxanes. Recently, we have efficiently
introduced a variety of alkyl groups to the ammonium
nitrogen of a rotaxane. In this paper, we report the synthesis
of tertiary-amine-type rotaxanes by direct reductive N-
alkylation using tri(acyloxy)borohydride or aldehyde/tri-
(acyloxy)borohydride. The acidification/neutralization-based
shuttling behavior of the resulting tert-amine-type rotaxane
is also described as an example of its application.
[2]Rotaxane 1 has been synthesized as a standard substrate
for N-functionalization.5 We first attempted to N-function-
alize 1 through the representative reductive N-alkylation
method6 using an aliphatic aldehyde and NaBH3CN as the
typical reducing agent in refluxing THF. However, no
reaction took place but 1 was recovered. Gribble et al. and
Liberatore et al. reported reductive N-ethylations with a
mixture of NaBH4 and acetic acid,7 where NaBH(OAc)3 (5a)
generates acetaldehyde in situ by self-reduction with a sec-
amine to afford N-ethlylated amine via the reduction of an
iminium intermediate. Therefore, we changed the reagent to
NaBH(OAc)3 (5a), which has a reducing ability similar
to NaBH3CN. The results of the reductive N-ethylation of 1
to 2a with 5a are summarized in Table 1. A mixture of 1
conditions, the N-acylation is presumed to occur with
NaB(OCOR)4 or B(OCOR)3, as reported in the N-acylation
of amines with NaBH4/RCOOH.7b-d
We added triethylamine (TEA) as a base to the reaction
system for activating stable rotaxane 1 and/or accelerating
the reaction, since TEA is reported to be more effective than
strong bases such as DBU or Hunig’s base in the N-acylation
reaction.3 In fact, the addition of excess TEA (20 equiv)
resulted in the selective formation of the desired products
N-ethylated rotaxane 2a (78% yield), a free tert-amine, which
was isolated after short column chromatography on alumina
(Entry 2). To clarify the effect of TEA, Me4NBH(OAc)3
(TABH) was used instead of 5a in the absence of TEA. With
TABH, 2a was selectively obtained in 100% yield even
without TEA (Entry 3). From the results, TEA plays a role
in not only deprotonating the ammonium moiety of 1 but
also activating 5a as a ligand coordinating to it.
To understand the details of the reaction (Entry 2), we
1
observed H NMR spectra of the crude product, which
showed the initial formation of tert-ammonium salt-type
rotaxane 2a/HX () 4a•X), but not 2a. Strong P-F bond
absorptions observed in the IR spectrum of the product
clearly indicated the formation of 4a•PF6 even in the
presence of excess TEA. Alumina column chromatographic
purification resulted in the successful isolation of neutral
rotaxane 2a. The isolation of pure 2a without any salt
structure might be attributed to the efficient removal of HPF6
in the successive heterogeneous chromatographic system on
the basic stationary phase.
Table 1. N-Ethylation of Rotaxane 1
The effect of polar aprotic solvents such as 1,4-dioxane and
cyclopentyl methyl ether (CPME) was investigated. Whereas
these solvents accelerated the N-acetylation to 3a at high
temperatures (Entries 4-5), the N-ethylation to 2a proceeded
selectively at lower temperatures (70 °C) in CPME, although
the reaction was sluggish (Entry 6). The use of a more polar
basic solvent N-methylpyrrolidone(NMP) gave excellent results
(Entries 7-10): no N-acetylation took place. Furthermore, the
use of NMP yielded 2a in 100% conversion even in the absence
of TEA (Entry 9). In this case, NMP most likely disturbs the
strong hydrogen bonding between the sec-ammonium salt axle
and the crown ether wheel of 1 to facilitate the neutralization
of 1 and increase the ratio of “free” sec-amine in the equilibrium.
It is concluded that the optimum condition involves excess 5a
and TEA in NMP at 70 °C, probably accelerating the reaction
by the synergistic effect of TEA and 5a.
5a
Et3N
temp convnb
2a (3a)
(%)
entrya solvent (equiv) (equiv)
(°C)
(%)
1
2
3
4
5
6
7
8
9
10
THF
THF
THF
dioxane
CPME
CPME
NMP
NMP
NMP
NMP
15
15
15c
15
15
15
15
15
15
5
-
20
-
20
20
20
20
20
-
reflux
reflux
reflux
reflux
reflux
70
100
78
100
100
100
62
0 (100)
78 (0)
100 (0)
33 (67)
10 (90)
62 (0)
50
39
39 (0)
70
70
70
100
100
10
100 (0)
100 (0)
10 (0)
20
a General condition: 1:50 µmol, solvent: 0.5 mL. b Calculated by 1H
NMR after alumina short column chromatography. c Me4NBH(OAc)3 was
used instead of 5a.
The introduction of various alkyl groups to 1 was
investigated under the optimized condition, and the results
are summarized in Table 2. Several NaBH(OCOR)3 (5) used
here were prepared from NaBH4 and the corresponding
carboxylic acids according to a reported method.7b Inspection
of the data of Table 2 reveals that linear alkyl chains such
as propyl and phenethyl groups can be introduced on the
and excess 5a (15 equiv) was heated in a solvent for 16 h.
The starting rotaxane 1 was completely consumed in reflux-
ing THF, but N-acetylated rotaxane (3a) was quantitatively
obtained without the formation of 2a (Entry 1). Under the
(7) (a) Gribble, G. W.; Nutaitis, C. F. Org. Prep. Proc. Int. 1985, 17,
317–384. (b) Marchini, P.; Liso, G.; Reho, A.; Liberatore, F.; Moracci,
F. M. J. Org. Chem. 1975, 40, 3453–3456. (c) Gribble, G. W.; Lord, P. D.;
Skotnicki, J.; Dietz, S. E.; Eaton, J. T.; Johnson, J. L. J. Am. Chem. Soc.
1974, 96, 7812–7814. (d) Pelter, A.; Levitt, T. E. Tetrahedron 1970, 26,
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DeV. 2006, 10, 971–1031.
(5) (a) Kawasaki, H.; Kihara, N.; Takata, T. Chem. Lett. 1999, 28, 105–
106. (b) Makita, Y.; Kihara, N.; Takata, T. Chem. Lett. 2007, 36, 102–103.
(6) (a) Borch, R. F.; Bernstein, M. D.; Durst, H. D. J. Am. Chem. Soc.
1971, 93, 2897–2904. (b) Hutchins, R. O.; Natale, N. R. Org. Prep. Proc.
Int. 1979, 11, 201–246. (c) Lane, C. F. Synthesis 1975, 3, 135–146.
Org. Lett., Vol. 12, No. 4, 2010
713

9). Meanwhile, the combination of 5a, instead of 5f, and
benzaldehyde also resulted in 100% yield of 2f; however, a
large excess 5a compared to aldehyde gave a mixture of 2a
and 2f (Entries 10-11). From these results, aromatic
carboxylic acid-based reducing agents NaBH(OCOAr)3, like
5f, cannot undergo self-reduction to yield ArCHO, but can
selectively reduce the iminium intermediate generated from
the added ArCHO and sec-ammonium roaxane 1. In fact,
the p-chlorobenzyl group could be introduced to 1 to afford
2g in 79% yield by treating 1 with 5f and p-chlorobenzal-
dehyde (Entry 12). Furthermore, when paraformaldehyde
(6h) was used along with 5a, N-methylated rotaxane 2h was
selectively obtained in 100% yield (Entry 13). These results
reveal that the self-reduction of NaBH(OCOR)3 5 yielding
aldehyde (R-CHO) is much slower than the formation of the
iminium intermediate. Thus, we conclude that a variety of
N-alkylations of unusually stabilized sec-ammonium salt/
crown ether-type rotaxanes like 1 can be achieved with 5
(and 6) under appropriate conditions.
Table 2. N-Alkylation of Rotaxane 1
1
The H NMR spectra of N-propylated tert-amine-type ro-
taxane 2b is shown in Figure 1b, which well supports the
proposed structure. Signal assignment was easily carried out,
as indicated in the spectra of both 2b and 1. In addition to the
three singals of the propyl group, two sets of aminobenzylic
proton signals (Hd,e) were upfield-shifted by approximately 1
ppm as a couple of singlets by the conversion of 1 to 2b.
Furthermore, the oxybenzylic proton signal (Hh) of 2b shifted
downfield by 0.7 ppm compared to 1; this shift was in
agreement with the previous observation that the signal is
downfield-shifted due to the deshielding effect of the benzo
moiety of DB24C8 in concert with the movement of DB24C8
to the ester moiety.3,4 This result is also consistent with that
of X-ray crystal structure analysis of N-methylated tert-
amine-type rotaxane 2h in which DB24C8 is located at the
oxybenzyl moiety of the axle.4 Both the downfield shift of
the aromatic protons and the upfield shift of the methyl group
of the end-cap groups can be explained by the effect of the
movement of DB24C8. Other rotaxanes 2 showed similar
spectral characteristics assignable to their structures.
a General condition: 1: 50 µmol, TEA: 1.0 mmol, NMP: 0.5 mL.
b Reaction in the absence of TEA.
Since we had access to “free” amine-type rotaxanes 2, we
examined their most important dynamic behavior, that is, the
acid/base-dependent movement of the components using 2b as
an example (Figure 1). First, 2b was treated with a strong acid
HPF6 (65 wt% aq.) The structural change caused by the
formation of tert-ammonium moiety was confirmed by the 1H
NMR spectral change from 2b to 4b•PF6, as shown in Figure
1b and c. The oxybenzylic proton signal (Hh) is the most
sensitive index to estimate the position of the DB24C8 moiety,
as mentioned above. In fact, the signal was upfield-shifted to
5.3 ppm, just correspondeding to that of sec-ammonium salt-
type rotaxane 1 (Figure 1a). Two benzylic proton signals around
the ammonium moiety (Hd,e) were downfield-shifted due to the
emergence of the cationic character of the nitrogen atom and
the deshielding effect of DB24C8. Other proton signals were
well assignable to 4b•PF6, although most signals were split by
the generation of the chiral center at the nitrogen atom.
nitrogen atom of 1 simply by reactions with 5b and 5c,
respectively, although N-phenethylation to 2c was slow
(Entries 1-2). Cyclohexyl and neopentyl groups as branched
alkyl ones were also introduced in prolonged reaction times,
although the introduction of the neopentyl group was insufficient
within 72 h, probably because of the steric hindrance (Entries
3-4). The addition of pivalaldehyde had little effect even with
further prolongation of time (Entry 5).
The introduction of aromatic groups was examined. The
reaction of 1 with NaBH(OCOPh)3 (5f) in NMP at 70 °C
afforded no N-benzylated product 2f (Entry 6). Since the
reducing agent 5f did not seem active enough to produce
“benzaldehyde” in situ by self-reduction, benzaldehyde (6f)
was independently added to the system involving 5f. The
addition of 6f (5 equiv) was very effective in yielding 2f
(67%) (Entry 7). Since the reaction without TEA significantly
decreased the yield of 2f (Entry 8), we concluded that TEA
activates the reducing agent 5f. An excess benzaldehyde
effectively increased the yield of 2f even with less 5f (Entry
Meanwhile, 4b•PF6 was treated with Na2CO3 (5% aq.).
The spectrum of the isolated product showed the quantitative
714
Org. Lett., Vol. 12, No. 4, 2010

Figure 1.
1H NMR spectra of (a) sec-ammonium salt-type rotaxane 1, (b) tert-amine-type rotaxane 2b, and (c) tert-ammonium salt-type
rotaxane 4b•PF6 (400 MHz, CDCl3, 298 K).
formation of the original tert-amine-type rotaxane 2b. These
transformations by the alternating addition of acid and base
occurred repeatedly. Thus, we could confirm the so-called
“switching” behavior of rotaxane triggered by acidification/
neutralization using a “free” amine-type simple rotaxane
capable of being acidified (Scheme 1). Stoddart et al. reported
component. The present system that involves no ionic station
can threfore be regarded as a novel ionic/nonionic switching
system functioning by easy treatment with simple bases and
acids. Thus, the development of this switching system
enhances the potential applicability of rotaxanes. Stoddart
et al. have recently reported a single station [2]catenane
called a push-button molecular switch.9 Accordingly, the
present tert-amine/ammonium conversion system may be
regarded as a new molecular switch similar to that.
In conclusion, here we report a general protocol for the direct
synthesis of N-functionalized “free” tert-amine-type rotaxanes
by N-alkylation of sec-ammonium salt-type rotaxanes through
modified reductive N-alkylation using NaBH(OCOR)3, TEA,
and/or the corresponding aldehyde. Even the bulky neopentyl
group could be introduced at the nitrogen atom. The present
N-alkylation method is superior to other modification methods
of rotaxanes such as N-acylation because further N-modification
is possible. A novel pH controllable molecular shuttle system
was conveniently constructed using the nonionic tert-amine-
type rotaxane thus obtained. This work is expected to promote
the construction of sophisticated supramolecular systems,
devices, polymeric materials, and so on.
Scheme 1
.
Shuttling Behavior of [2]Rotaxane 2b/4b-PF6 based
on the Treatment with Acid/Base
a pH controling system of rotaxane of which axle component
involved two cationic sites such as sec-ammonium salt and
paraquat groups toward DB24C8.8 In this system, the sec-
ammonium salt can be neutralized with diisopropylethy-
lamine, because the paraquat group acts as a metastable
cationic station to release DB24C8 from the sec-ammonium
salt moiety. Namely, the switching in crown ether-based
rotaxanes generally needs the ionic character on the axle
Acknowledgment. We thank Professor Michinori Suginome
of Kyoto University for helpful discussions and comments. This
work was financially supported by a Grant-in-Aid for Scientific
Research from MEXT, Japan (Nos. 18064008 and 19655013),
and K.N. thanks the Global COE Program (Education and
Research Program for Material Innovation), MEXT, Japan for
financial support.
Supporting Information Available: Detailed experimen-
tal procedures and spectroscopic data. This material is
available free of charge via the Internet at http://pubs.acs.org.
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OL902719M
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