Remarkable effects of chirality on deslipping reactions of diastereomeric rotaxanes and relevant mechanism involving pre-equilibrium

Article abstract of DOI:10.1021/ol802571d

The first clear differentiation on deslipping rates affected by the difference in the diastereomeric stereocenters of rotaxanes up to 8.4 times and unexpectedly large steric kinetic isotope effect on the deslipping reaction.

Full text of DOI:10.1021/ol802571d

ORGANIC
LETTERS
2009
Vol. 11, No. 1
145-147
Remarkable Effects of Chirality on
Deslipping Reactions of Diastereomeric
Rotaxanes and Relevant Mechanism
Involving Pre-Equilibrium
Keiji Hirose,* Yamato Nakamura, and Yoshito Tobe
DiVision of Frontier Materials Science, Graduate School of Engineering Science,
Osaka UniVersity, 1-3 Machikaneyama, Toyonaka, Osaka 563-8531, Japan
hirose@chem.es.osaka-u.ac.jp
Received November 7, 2008
ABSTRACT
The first clear differentiation on deslipping rates affected by the difference in the diastereomeric stereocenters of rotaxanes up to 8.4 times
and unexpectedly large steric kinetic isotope effect on the deslipping reaction (ca. 20%) were observed. On the basis of the kinetic parameters,
1
steric kinetic isotope effect, and H NMR spectra of the nondeuteriated and deuteriated rotaxanes, we propose a deslipping mechanism
involving pre-equilibrium.
The deslipping reaction is a characteristic reaction of
rotaxanes by which the ring and axle components are
disconnected without breaking a covalent bond.1 Ease of
deslipping is affected not only by the relative size of the
ring and the stopper units but also by subtle structural
changes such as the length of the axle and the flexibility of
the components.1e,f However, there are no reports that focus
on the difference between deslipping rates of diastereomeric
rotaxanes, even though a large difference is expected because
of steric restriction between the ring and dumbbell compo-
nents connected by mechanical bonding. Herein we report a
large difference between the deslipping rates of diastereomeric
rotaxanes 1·(S)-2 and 1·(R)-2 (Scheme 1) up to 8.4 times and a
relevant mechanism involving pre-equilibrium between the
conformers with respect to the position of the axle component
relative to the ring, which was elucidated on the basis of the
activation parameters and the steric kinetic isotope effect.
(1) (a) Raymo, F. M.; Houk, K. N.; Stoddart, J. F. J. Am. Chem. Soc.
1998, 120, 9318–9322. (b) Ashton, P. R.; Baxter, J.; Fyfe, M. C. T.; Raymo,
F. M.; Spencer, N.; Stoddart, J. F.; White, A. J. P.; Williams, D. J. J. Am.
Chem. Soc. 1998, 120, 2297–2307. (c) Chiu, S.-H.; Rowan, S. J.; Cantrill,
S. J.; Clink, P. T.; Garrell, R. L.; Stoddart, J. F. Org. Lett. 2000, 2, 3631–
3634. (d) Hu¨bner, F. M.; Nachtsheim, G.; Li, Q. Y.; Seel, C.; Vo¨gtle, F.
Angew. Chem., Int. Ed. 2000, 39, 1269–1272. (e) Afffeld, A.; Hu¨bner, F. M.;
Seel, C.; Schalley, C. A. Eur. J. Org. Chem. 2001, 2877–2890. (f) Linnartz,
P.; Bitter, S.; Schalley, C. A. Eur. J. Org. Chem. 2003, 4819–4829. (g)
Felder, T.; Schalley, C. A. Angew. Chem., Int. Ed. 2003, 42, 2258–2260.
(h) Nygaard, S.; Laursen, B. W.; Flood, A. H.; Hansen, C. N.; Jeppesen,
J. O.; Stoddart, J. F. Chem. Commun. 2006, 144–146.
As diastereomeric rotaxanes, we designed 1·(S)-2 and
1·(R)-2 composed of homochiral ring component 1 with S,S
configuration and enantiomeric axle component (S)-2 or (R)-2
(Scheme 1). Ring component 1 was chosen because of the
excellent chiral recognition property of this ring system
toward secondary amines.2 Component 2 was used, because
the 3,5-dinitrobenzyl stopper is large enough to trap it
kinetically within the rotaxane structure,3 whereas the
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Published on Web 12/03/2008
2009 American Chemical Society

Table 1. Kinetic Parameters for Deslipping Reactions of 1·(S)-2 and 1·(R)-2
a
a
q
a
q
solvent
rotaxane
∆Hq (kJ mol-1
)
∆S (eu)
t1/2 (h)
∆G (kJ mol-1
)
kR/kS
toluene-d8
1·(S)-2
1·(R)-2
1·(S)-2
1·(R)-2
1·(S)-2
1·(R)-2
1·(S)-2
1·(R)-2
1·(S)-2
1·(R)-2
78
75
90
87
66
72
61
67
63
71
-98
-91
-65
-63
-120
-95
-117
-92
-111
-80
223
27
502
87
20
10
2.1
0.9
2.2
1.1
108
102
110
105
102
100
96
94
96
95
8.4
TCE-d2
CD3CN
DMF-d7
DMSO-d6
5.7
2.0
2.3
2.0
a At 298 K calculated from ∆Hqand∆Sq.
bulkiness of the (S)- and (R)-1-(1-naphthyl)ethyl stoppers
would be ideal for them to slip out from the ring with
measurable kinetic barriers.
(298 K) were estimated as summarized in Table 1. Appar-
ently, the deslipping reactions of 1·(S)-2 were slower than
those of 1·(R)-2 (kR/kS > 1); the largest difference between
the reaction rates was observed when toluene-d8 was used
as a solvent (kR/kS ) 8.4). In less polar solvents (toluene-d8
and TCE-d2), the lower deslipping rates of 1·(S)-2 than those
of 1·(R)-2 mainly originate from the larger activation
enthalpies of the former. On the other hand, in polar solvents
(acetonitrile-d3, DMF-d7, and DMSO-d6), whereas activation
enthalpies for the deslipping reactions of 1·(S)-2 are smaller
than those of 1·(R)-2, the activation free energies of 1·(S)-2
are still larger than those of 1·(R)-2. Hence, the lower
deslipping rates of 1·(S)-2 than 1·(R)-2 in polar solvents are
attributed to the more negative activation entropies of 1·(S)-
2. These results suggest that in polar solvents 1·(S)-2 suffers
from greater degree of solvation than 1·(R)-2 during the
deslipping process.
Scheme 1
.
Synthesis of Diastereomeric Rotaxanes and Their
Deslipping Reactions
To gain more insight into the mechanism of the deslipping,
steric kinetic isotope effect (SKIE) on the deslipping was
examined by using the corresponding trideuterio derivatives
1·(S)-2-d3 and 1·(R)-2-d3, in which the methyl group was
replaced by trideuteriomethyl.4 SKIE was utilized as a good
probe to assess steric compression in the transition states of
various types of reactions5 including deslipping reaction of
rotaxanes.1g The rate constants of 1·(S)-2-d3 and 1·(R)-2-d3
in TCE-d2 at 70 °C and in DMSO-d6 at 30 °C were
determined, from which kH/kD was estimated (Table 2). As
a result, while SKIEs of 1·(R)-2 in TCE-d2 (0.98 ( 0.02)
and 1·(S)-2 in DMSO-d6 (0.96 ( 0.02) were small, large
isotope effect was observed in the case of 1·(S)-2 in TCE-d2
(0.90 ( 0.02) and 1·(R)-2 in DMSO-d6 (0.81 ( 0.02). In
The rotaxanes 1·(S)-2 and 1·(R)-2 were synthesized via
aminolysis of prerotaxane 4 with (S)- or (R)-3 in benzene.3
1·(S)-2 and 1·(R)-2 can be isolated and characterized as
kinetically stable compounds; however, especially in the case
of the latter compound, deslipping reactions took place
slowly even at room temperature in chloroform.
1
The deslipping rates were measured by H NMR spec-
(4) Trideuteriated rotaxanes 1·(S)-2-d3 and 1·(R)-2-d3 were synthesized
in the same manner as for 1·(S)-2 and 1·(R)-2 using trideuteriated amine
3-d3, which was prepared according to the reported procedure: Sawada,
M.; Hagita, K.; Imamura, H.; Tabuchi, H.; Yododa, S.; Umeda, M.; Takai,
Y.; Yamada, H.; Yamaoka, H.; Hirose, K.; Tobe, Y.; Tanaka, T.; Takahashi,
S. J. Mass Spectrom. Soc. Jpn 2000, 48, 323–332. The degree of isotopic
labeling (>98%) was determinined by 1H NMR and mass spectra, and the
enantiomeric excess (>99%) was checked by HPLC using a chiral
column.
troscopy in toluene-d8, tetrachloroethane-d2 (TCE-d2), ac-
etonitrile-d3, DMF-d7, and DMSO-d6. All deslipping reactions
followed first-order kinetics. From the rate constants at
several different temperatures (Table S1 in Supporting
Information), the kinetic parameters t1/2 (298 K) and kR/kS
(2) (a) Hirose, K.; Fujiwara, A.; Matsunaga, K.; Aoki, N.; Tobe, Y.
Tetrahedron Lett. 2002, 43, 8539–8542. (b) Hirose, K.; Fujiwara, A.;
Matsunaga, K.; Aoki, N.; Tobe, Y. Tetrahedron: Asymmetry 2003, 14, 555–
566.
(5) (a) Mislow, K.; Graeve, R.; Gorgon, A. J.; Wahl, G. H. J. Am. Chem.
Soc. 1963, 85, 1199–1200. (b) Hayama, T.; Baldridge, K. K.; Wu, Y.-T.;
Linden, A.; Seigel, J. S. J. Am. Chem. Soc. 2008, 130, 1583–1591. (c) Liu,
´
Y.; Warmuth, R. Org. Lett. 2007, 9, 2883–2886. (d) Slebocka-Tilk, H.;
(3) Hirose, K.; Nishihara, K.; Harada, N.; Nakamura, Y.; Masuda, D.;
Araki, M.; Tobe, Y. Org. Lett. 2007, 9, 2969–2972.
Motallebi, S.; Nagorski, R. W.; Turner, P.; Brown, R. S.; McDnald, R.
J. Am. Chem. Soc. 1995, 117, 8769–8776.
146
Org. Lett., Vol. 11, No. 1, 2009

Table 2. Steric Kinetic Isotope Effects () kH/kD) on Rate
Constants of Deslipping Reactions of 1·(S)-2 and 1·(R)-2
rotaxane
solvent
temp (K)
kH/kD
1·(S)-2
TCE-d2
DMSO-d6
TCE-d2
343
303
343
303
0.90 ( 0.02
0.96 ( 0.02
0.98 ( 0.02
0.81 ( 0.02
1·(R)-2
DMSO-d6
particular, the observed SKIE of the latter is considerably
larger than most of those reported.6
With the above data in hand, we propose a plausible
mechanism of the deslipping reactions of 1·(S)-2 and 1·(R)-2
consisting of two steps as shown in Figure 1a. In the first
step, the smaller methyl group of the stopper unit passes
through the ring component while the larger naphthyl group
is left behind the ring (i.e., TS1).1a Examination of molecular
models suggests that the methyl group would pass through
the ring with little steric compression, equilibrating the
original rotaxane with the Figure 1b. In this mechanism
involving the pre-equilibrium, the observed rate constant kobs
is expressed by k1, k-1, and k2, or K ()k1/k-1) and k2 as
follows:
1
Figure 2. Partial H NMR spectra of 1·(R)-2 and 1·(R)-2-d3. (a)
1·(R)-2-d3 in TCE-d2 at 343 K and (b) 1·(R)-2 in TCE-d2 at 343 K.
(c) 1·(R)-2-d3 in DMSO-d6 at 303 K and (d) 1·(R)-2 in DMSO-d6 at 303
K. The mark × represents the signals due to the free ring component 1
generated during the sample preparation and measurement.
reaction exhibited small SKIE, nearly identical signals of
nondeuteriated and deuteriated rotaxanes are observed (Figure
2a and b), indicating the equilibrium constants are identical.
Similarly, the 1H NMR spectra of 1·(S)-2 and 1·(S)-2-d3 in TCE-
d2 and DMSO-d6 are identical (Figures S2 and S3 in Supporting
Information, respectively). In contrast, the 1H NMR signals of
1·(R)-2 in DMSO-d6 at 4.0, 4.6, 4.9 ppm apparently differ from
those of 1·(R)-2-d3 (Figure 2c and d). These results indicate
that the deslipping takes place via a mechanism including pre-
equilibrium between the ground-state and the intermediate, and
the pre-equilibrium constants of 1·(R)-2 and 1·(R)-2-d3 are
different in DMSO-d6, leading to the large SKIE that was
observed. The less negative activation entropy of 1·(R)-2 in
DMSO-d6 than that of 1·(S)-2 suggests that the population of
the intermediate, which is more susceptible to solvation, relative
to the ground-state rotaxane of the former diastereomer is larger
than that of the latter. The diastereoselectivity, therefore, depends
on both the magnitude and the balance between the pre-
equilibrium constant (K) and the rate of the second step (k2).
In conclusion, we have demonstrated the large difference of
the deslipping reaction rates between diastereomeric rotaxanes
1·(S)-2 and 1·(R)-2. On the basis of the kinetic parameters and
the steric kinetic isotope effects, a two-step deslipping mech-
anism including a pre-equilibrium was elucidated.
kobs ) k1 · k2 ⁄ k-1 ) K · k2
The presence of an unusually large SKIE in the deslipping
of 1·(R)-2 in DMSO-d6 indicates that the equilibrium constant
K of the pristine rotaxane is different from that of the
deuteriated one.
Figure 1. Two-step mechanism of the deslipping reaction (a) and
Acknowledgment. This work was supported by a Grant-
in-Aid for Scientific Research from the Ministry of Educa-
tion, Culture, Sports, Science and Technology, Japan. Y.N.
expresses his special thanks to the Global COE (Center of
Excellence) Program “Global Education and Research Center
for Bio-Environmental Chemistry” at Osaka University.
its energy diagram (b).
To prove this assumption, 1H NMR spectra of nondeuteriated
and deuteriated rotaxanes were compared.7 In the case of the
1·(R)-2 in TCE-d2 under which conditions the deslipping
Supporting Information Available: Details of experi-
mental and data analysis procedures. This materials is
available free of charge via the Internet at http://pubs.acs.org.
(6) For example, following SKIEs were reported: single bond rotation
of a biphenyl derivative (0.84),5a bowl-bowl inversion of a corranulene
derivative (0.82),5b bromination of bis(7-norbornylidene) (0.65).5d
(7) Rechavi, D.; Scarso, A.; Rebek, J., Jr. J. Am. Chem. Soc. 2004, 126,
7738–773.
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