Synthesis and molecular shuttling of [2]rotaxanes under mild conditions

Article abstract of DOI:10.1246/cl.130108

[2]Rotaxanes constructed with an ethereal end-capped axle and a dibenzo-24-crown-8 wheel were synthesized from pseudorotaxanes bearing an alcoholic terminus and diaryldiazomethanes using diphenyl phosphate as a catalyst. The reaction proceeded at room temperature in nonpolar solvents within several hours. The [2]rotaxanes thus obtained behaved as ammonium salts derived from a very strong base such as DBU. Thus, the amine form of the [2]rotaxane reacted with a weak acid, CO₂H₂O, to give a hydrogencarbonate salt of the [2]rotaxane, which turned back to the amine form after drying followed by evacuation.

Full text of DOI:10.1246/cl.130108

doi:10.1246/cl.130108
630
Published on the web May 18, 2013
Synthesis and Molecular Shuttling of [2]Rotaxanes under Mild Conditions
Hideyuki Tukada,* Toshihiro Hiraki, and Hiroshi Nakamura
Graduate School of Nanobioscience, Yokohama City University,
22-2 Seto, Kanazawa-ku, Yokohama, Kanagawa 236-0027
(Received February 11, 2013; CL-130108; E-mail: htht@yokohama-cu.ac.jp)
[2]Rotaxanes constructed with an ethereal end-capped axle
dibenzo-24-crown-8 wheel were synthesized from
and
a
BF4
H2
N
pseudorotaxanes bearing an alcoholic terminus and diaryldiazo-
methanes using diphenyl phosphate as a catalyst. The reaction
proceeded at room temperature in nonpolar solvents within
several hours. The [2]rotaxanes thus obtained behaved as
ammonium salts derived from a very strong base such as
DBU. Thus, the amine form of the [2]rotaxane reacted with a
weak acid, CO2-H2O, to give a hydrogencarbonate salt of the
[2]rotaxane, which turned back to the amine form after drying
followed by evacuation.
a, b, c, d
HO
CHO
AcO
R
1: R = C6H4-CH2OH
2: R = (CH2)5OH
Scheme 1. Synthesis of axle molecules 1 and 2. a) Ac2O, cat. H2SO4,
rt, 2 h (96%), b) RCH2NH2, MS-4 ¡, CHCl3, rt, 5 h (96%), c) 1.2 equiv
NaBH4, MeOH-EtOH, 5 °C, 3 h (90%), d) 1.1 equiv HBF4, 0 °C, 5 min,
ether (100%).
Rotaxanes, supramolecules consisting of interlocked dumb-
bell-shaped and macrocyclic molecules, are examples of
molecular machines, in which mechanical motion can be
driven photochemically, electrochemically, or chemically
(through pH, solvents, and ions).1 Hence, rotaxanes are
expected to act as molecular devices with synchronous shuttling
motions. Several approaches have been adopted for the synthe-
sis of rotaxanes from loosely interlocked pseudorotaxanes.
Shrinking or clipping the macrocycles and end-capping the
axes of pseudorotaxanes are popular synthetic methods.2
Among these options, the end-capping procedure3 has the most
extensive applicability and has therefore been developed using
various types of terminal functional group in the axle
molecules. For rotaxanes containing labile functional groups,
a possible requirement for advanced functionality, synthesis
and molecular shuttling must be performed under mild
conditions. Several end-capping methods fulfill such a synthetic
demand, including ester formation using 3,5-dimethylbenzoic
anhydride-trialkylphosphine,3a and oxazole formation using
isocyanates.3b Further efficient end-capping methods for
[2]rotaxanes are still required to expand the synthetic versatility
of this technique.
ppm
Here, we report the synthesis of [2]rotaxanes by end-
capping of pseudo-[2]rotaxanes with an alcoholic terminus
using diaryldiazomethane (DDM) with diphenyl phosphate as a
catalyst under mild conditions. The resulting [2]rotaxanes with
an ether linkage are expected to be tolerant of various agents. We
furthermore propose a method for molecular shuttling under
mild and green conditions using CO2-H2O, which enable use of
labile and functional rotaxanes.
Figure 1. 1H NMR spectra for [2]rotaxane 3a and related molecules
(CDCl3, rt; ¤). (a) DB24C8, (b) axle molecule 1, (c) a mixture of
DB24C8 and 1 (ca. 1:1), (d) rotaxane 3a, and (e) 6a. Symbols x, , u,
*
and c denote peaks from CHCl3, water, uncomplexed components, and
pseudo-[2]rotaxane, respectively. Peaks appeared around 4.6-4.7 ppm in
(c) are characteristic for the formation of pseudorotaxane.
Etherification of pseudorotaxanes bearing an alcoholic
terminus was performed as a first step using a stoichiometric
amount of diphenyl diarylmethyl phosphate (DDP), which is
known to be a good alkylating reagent for alcohols.4 The
diarylmethyl group was expected to have sufficient bulk to act as
an effective end-cap for rotaxanes constructed with 24-crown-8
rings. DDPs were prepared from DDMs and diphenyl phosphate
(DP). As axle molecules, we prepared two secondary ammonium
salts bearing benzylic or aliphatic alcohols 1 or 2 as the termini
(Scheme 1).
¹
Although ammonium salt 1[BF4 ] is not particularly soluble
in dichloromethane (DCM) or chloroform, addition of dibenzo-
24-crown-8-ether (DB24C8) gives a pseudo-[2]rotaxane, which
is soluble in both of these solvents. As shown in Figure 1, the
equilibrium of association of pseudo-[2]rotaxane leans toward
association (Ka = 300 M¹1).5,6
Chem. Lett. 2013, 42, 630-632
© 2013 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

631
O
OAc
O
OAc
N2
t Bu
t Bu
O
O
P (OPh)2
H
t Bu
t Bu
DB24C8
N2
Ar
O
Ar
Ar
Ar
(DDP)
R
(DDM)
BF4
Ar
(PhO)2P(O)OH
(DP)
Ar
HO
O
O
O
NH2
NH2
R
H
(PhO)2P(O)OH
in DCM
O
Ar
Ar
A
O
O
BF4
1: A = p-C6H4CH2OH
2: A = (CH2)5OH
5: A = p-Tol
Scheme 3.
B
A
80
60
40
20
0
3: A = p-C6H4CH2O,
B = CHAr2
3a: Ar = Ph, 3b: Ar = p-Tol
4: A = (CH2)5O,
B = CHAr2
4a: Ar = Ph, 4b: Ar = p-Tol
Scheme 2. Synthesis of [2]rotaxanes 3 and 4.
0
2
4
6
Table 1. Synthesis of rotaxanes 3 and 4 produced via Scheme 27
time / h
DB24C8 DDMa
/equiv /equiv /equiv /h
DP
Time
Product
Figure 2. NMR yields of [2]rotaxane 3a vs. reaction time with
(0.1 equiv: ; 1.0 equiv: ) and without ( ) diphenylphosphate (1.1
equiv DB24C8, 2.0 equiv diphenyldiazomethane, rt, in CDCl3).
Run Axle
yieldb/%
1
2
1
1
1
1
1
1
1
2
2
2
2
1.1
1.1
2.0
3.0
2.7
1.1
1.1
1.1
1.1
1.1
1.1
2.0 PD
2.0 PD
2.0 PD
2.0 PD
2.0 PD
2.0 PD
2.0 TD
2.0 PD
2.0 PD
2.0 PD
2.0 TD
2.0
0.1
0.1
0.1
0.5
0.0
0.1
0.1
0.0
2.0
0.1
2.5 3a, 63 (54)c
2.5 3a, 67 (55)
3
4
5
5
3a, 78
3a, 82
Thus, the catalytic use of DP was effective in the synthesis
of 1a without deterioration of the yield, as shown in Table 1
(Run 2), and Figure 2. Prior preparation of a moisture-sensitive
DDP agent is not necessary. The addition of 0.1 equiv of DP to a
mixture of ammonium salt, crown ether, and DDM in DCM
at room temperature in dark conditions gave [2]rotaxanes in
good yields. Increasing the amount of DB24C8 (1.1, 2.0, and
3.0 equiv) gradually increased the yield of [2]rotaxane (67%,
78%, and 82%, respectively; Runs 2-4). The reaction was
performed at a lower temperature (2 °C; Run 5) without decrease
of yield; however, a longer reaction time was necessary (4 days).
Interestingly, the etherification with DDM proceeded without the
DP catalyst (Run 6, Figure 2), although it required a longer
reaction time than the reaction using the catalyst.8
5
6
4 dd 3a, 82
5
3a, 66
7
8
0.5 3b, 57 (29)
23
23
4
4a, 66 (51)
4a, 65
4a, 65
9
10
11
1.2 4b, 44 (36)
aPD: diphenyldiazomethane, TD: di-p-tolyldiazomethane. bThe
yields were determined by NMR experiments in CDCl3 using
picryl chloride (¤ = 8.8) as an internal standard for integra-
tion. Isolated yields were shown in parenthesis. cDiphenyl
diphenylmethyl phosphate reagent was used. dReaction temper-
ature: 2 °C.
The use of di-p-tolyldiazomethane instead of diphenyldi-
azomethane as an end-capping agent for pseudo-[2]rotaxanes
was also effective. Accordingly, 3b was obtained from 1 in a
yield of 57% (Run 7). The reaction of 1a with di-p-tolyldiazo-
methane was more rapid than that with diphenyldiazomethane.
In the case of ammonium salt 2, which had a simple aliphatic
alcohol at the end, the end-capping reaction proceeded more
slowly and with a slightly lower yield than for 1 (Table 1, Runs
A DCM solution of diphenyl diphenylmethyl phosphate
(2 equiv) was added to a mixture of ammonium salt 1 (1 equiv)
and DB24C8 (1.1 equiv) in DCM at room temperature in the
absence of light. The deep yellow color that emerged from the
phosphate agent disappeared within 5 h. The solvent was
removed in vacuo, and the residue was subjected to silica gel
chromatography. The fraction eluted with DCM contained
rotaxane 3a (Scheme 2). Further purification was performed
with gel-permeation chromatography (GPC) by circulating
elution of chloroform to give 3a as a white crystalline solid in
54% yield (Run 1 in Table 1). The ESI mass spectrum of 3a
showed a peak at m/z 1012 (100%, C62H78O11N+), correspond-
ing to the cationic portion of the [2]rotaxane.
8-11). The association constant for the pseudo-[2]rotaxane
¹1 5,6
2-DB24C8 in CDCl3 (200 M
1-DB24C8.
)
was lower than that for
The ethereal end-cap in rotaxanes 3 and 4 showed tolerance
of various reagents. For example, 3a survived under the
following conditions: 3 M HCl in CH3OH-H2O, 50 °C, 5 h;
1 M KOH in CH3OH-H2O, 50 °C, 10 h.
Our end-capping agent DDP was found to be capable of
alkylating pseudorotaxanes bearing an alcoholic terminus to
give [2]rotaxanes and liberate DP, which in turn could react with
DDM to rapidly restore DDP. Therefore, a mixture of 1 equiv of
DDM and a catalytic amount of DP was sufficient for alkylation
of pseudo-[2]rotaxane alcohols (Scheme 3).
At the next step, we examined the basicity of 3a in order
to determine the appropriate acids and bases for molecular
shuttling. Using the linear dependences of chemical shifts for
NCH2 in 1H NMR spectra vs. the amine/ammonium ratio,
several NMR experiments in CD3CN were performed by mixing
a pKa-unknown ammonium salt with amines of known pKa.
Chem. Lett. 2013, 42, 630-632
© 2013 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

632
Scheme 4.
We thank Prof. Shinji Nonose (Yokohama City Univ.) for
measurement of mass spectra.
References and Notes
1
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ppm
Figure 3. 1H NMR spectra. To the rotaxane 6a in CDCl3 (a) was
added CO2 gas by bubbling for 2 min (b). No changes observed until the
addition of one drop of water and CO2 gas was again passed through the
solution for 1 min to give the ammonium salt (c). The ammonium salt
was converted to amine 6a when the solution was dried with Na2SO4
and slightly evacuated with an aspirator for 1 min (d). As a reference, 3a
[BF4] is shown in (e).
2
3
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¹
phenyl)methylammonium 5[BF4 ], a model for a free axle
molecule 1, was estimated to be 0.3 + pKaH of dibenzylamine
(pKaH = 8.52 in H2O) in CD3CN, which is normal as a
secondary amine. However, the pKaH of [2]rotaxane 3a was
estimated to be 0.6 + pKaH of DBU (pKaH = 12 in H2O, 24.34 in
CH3CN)9 in CD3CN. This can be attributed to the strong N+-H-
O (crown ether) interaction in the rotaxanes, which prevents 3a
from releasing a proton and weakens the acidity by a factor of
about 104 compared with the free axle molecule 1. A free
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3a was treated with an aqueous solution of KOH at room
temperature. The 1H NMR spectrum of 6a did not have the
characteristic NCH2 signals that appeared at around 4.7 ppm for
3a (Figure 1e).
4
5
¹1
The association constant between 1-DB24C8 in CDCl3 is 300 M
at 298 K (ammonium salt: 20 mM, 1H NMR), which is smaller
¹1
than that reported for the related pseudorotaxanes, 102-104 M
,
For molecular shuttling of [2]rotaxanes, strong acids such as
CF3CO2H are usually adopted to convert the amine form into the
ammonium form.1,2,11 However, our finding indicates that the
conversion from the [2]rotaxane-amine to the ammonium salt
can be done with weak acids such as carbonic acid (pKa = 6.4).
In fact, when CO2 gas was bubbled into a wet CDCl3 solution of
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6
7
¹
[2]rotaxane-amine 6a, ammonium salt 3a [X = HOCO2 ] was
obtained (Figure 3). The [2]rotaxane hydrogencarbonate salt 3a
¹
Supporting Information is available electronically on the CSJ-
Journal Web site, http://www.csj.jp/journals/chem-lett/index.html.
Trace acidic impurities in the ammonium salt may act as a catalyst.
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[X = HOCO2 ] transformed again into the amine form by
evacuation or by bubbling of Ar gas into the dry solution
(Figure 3d). Thus, the molecular shuttling of [2]rotaxanes was
performed for the first time under mild conditions that are
desired for the handling of labile and functional [2]rotaxanes
(Scheme 4).
In summary, our procedure for end-capping of a pseudo-
[2]rotaxanes can be carried out without the use of bases,
inorganic salts, polar solvents, or heat. The ethereal end-capped
product is tolerant of various reagents, which expands the
synthetic potential of this route. A convenient and mild method
for molecular shuttling in [2]rotaxanes was also demonstrated.
8
9
10 A possibility that 6a obtained from 3a with aq. KOH is not a free
amine but the ammonium hydroxide was denied from an NMR
experiment using a phosphazene base BTTP (pKaH = 28 in
CH3CN) in benzene-d6.
11 A recent report on molecular shuttling under mild conditions: Y.
Abe, H. Okamura, K. Nakazono, Y. Koyama, S. Uchida, T. Takata,
Org. Lett. 2012, 14, 4122.
Chem. Lett. 2013, 42, 630-632
© 2013 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/