Secondary isotope effects on the deslipping reaction of rotaxanes: High-precision measurement of steric size

Article abstract of DOI:10.1002/anie.200350903

A supramolecular measuring instrument for determining steric size: The deslipping reaction of the rotaxane shown with deuterated stopper groups senses the smaller steric size of the deuterium atom and proceeds with a 10% higher reaction rate than the reaction of the unlabeled rotaxane. This result sheds new light from a supramolecular point of view on the classical problem of determining steric demand.

Full text of DOI:10.1002/anie.200350903

Communications
Kinetics of Rotaxane Deslippage
pyridines with Lewis acids and electrophiles.[9] The smaller
ꢀ
steric size of the C D bond is reflected in a tighter crystal
packing of deuterated molecules[10] and in the 13C NMR
chemical shifts of groups located in the proximity of
deuterated substituents.[11] Herein,we describe the results of
deslipping experiments performed with unlabeled rotaxanes
9a and 10a and their isotopologues 9b and 10b that have
deuterated stopper groups (Scheme 2).
Secondary Isotope Effects on the Deslipping
Reaction of Rotaxanes: High-Precision
Measurement of Steric Size**
Thorsten Felder and Christoph A. Schalley*
The deuterated di-[D9]tert-butylphenol stopper 5b was
synthesized according to established literature procedures[12]
as depicted in Scheme 2. Threefold Friedel–Crafts alkylation
of benzene 1 is followed by replacement of one of the tert-
butyl groups in 2b by an acetyl substituent in a Friedel–Crafts
acylation which deactivates the aromatic system and prevents
it from further reaction. A Baeyer–Villiger oxidation of
intermediate 3b with m-chloroperbenzoic acid (MCPBA)
followed by hydrolysis of ester 4b yields stopper 5b. The
rotaxanes 9a,b and 10a,b can be prepared from the corre-
sponding stoppers 5a,b,one of the axle center pieces 7 or 8,
and wheel 6 by an anion template effect in a yield of 25–
30%.[13] The degree of isotopic labeling could be determined
to be greater than 95% from the 1H NMR spectra as well as
from the isotope patterns of the MALDI mass spectra (see
Supporting Information).
Small structural changes can cause unexpectedly large effects
on the deslipping reaction[1] of rotaxanes[2] (Scheme 1). A
particularly striking example[3] is the replacement of the
isophthalaldehyde unit in 6a (Scheme 2) by a 2,6-pyridinedi-
carboxamide,that is,the simple exchange of a CH group by an
isoelectronic N atom to yield 6b. Without any other changes
in the rotaxane structure,the barrier for the passage of the
wheel over one of the stopper groups increases from
approximately 80 to 135 kJmolꢀ1 as a result of the formation
of intramolecular hydrogen bonds. This increase is reflected
in a more than 104-fold increase in the half-life.
Probably one of the smallest steric changes which can be
made in a molecule is the replacement of hydrogen atoms by
deuterium atoms.[4] According to electron-diffraction studies
ꢀ
and calculations,the time-averaged length of the C D bond is
[5]
ꢀ
approximately 0.005 Š shorter than that of the C H bond.
The deslipping reaction is unimolecular and follows a
first-order rate law. It is easily monitored by 1H NMR
spectroscopy because of the sizeable chemical shift differ-
ences (Dd) between the rotaxane signals and those of the free
axle (Figure 1). The largest values for Dd are found for the
ꢀ
In addition,the C D bond has a lower vibrational frequency
and vibrational amplitude than the C H bond. This differ-
ence is reflected in a smaller van der Waals radius. Further
experimental evidence comes from the isomerization reac-
tions of suitably substituted biaryls[7] and [2.2]metacyclo-
phanes,[8] as well as from the reactions of 2,6-dimethylated
[6]
ꢀ
Scheme 1. The deslipping reaction of rotaxanes: the mechanical bond
is broken and the free components liberated without cleavage of a
covalent bond.
[*] Dr. C. A. Schalley, Dipl.-Chem. T. Felder
KekulØ-Institut für Organische Chemie und Biochemie
Universität Bonn
Gerhard-Domagk-Strasse 1, 53121 Bonn (Germany)
Fax: (+49)-228-735-662
E-mail: c.schalley@uni-bonn.de
[**] We thank Prof. Fritz Vögtle and Dipl.-Chem. Sonja Müller for
continuous support and inspiring discussions, and Claus Schmidt
and Hannelore Spitz for their help with recording a large number of
1H NMR experiments. The Fonds der Chemischen Industrie and the
Deutsche Forschungsgemeinschaft are gratefully acknowledged for
financial support.
Figure 1. 1H NMR spectra of a 4 mm solution of 9b in [D2]tetrachloro-
ethane recorded every 15 min after heating the sample to 373 K. Three
different proton signals have been assigned to the rotaxane (decreas-
ing signal intensity; down arrows) and the free axle (increasing signal
intensity; up arrows).
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
2258
ꢀ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/anie.200350903
Angew. Chem. Int. Ed. 2003, 42, 2258 – 2260

Angewandte
Chemie
protons of the axle center piece (Hb: Dd = 1.7 ppm),
R
R
O
R
which is most affected by the anisotropy of the
aromatic rings incorporated in the wheel. Smaller
shifts are observed for protons more remote from the
a)
b)
R
R
R
R
R
a
center (Hc: Dd = 0.75 ppm,H : Dd = 0.35 ppm). This
R
R
R
RR
R
R
behavior is typical for rotaxanes of this type.[3] All the
rotaxanes were simultaneously subjected to the same
conditions so that a direct comparison was possible
and systematic errors were reduced to a minimum.
Figure 2 shows the results of the deslipping reactions
of 9a,b and 10a,b at 373 K in the form of a plot of ln(c/
c0) versus reaction time t. The rotaxanes 10a,b with the
longer axles deslip more quickly relative to their
shorter counterparts 9a,b—a finding which has been
analyzed in detail before.[3] Of particular interest in the
present study is the fact that the deuterated rotaxanes
9b and 10b liberate the free components at a rate
about 10% higher than the nonlabeled analogues 9a
and 10a. The rate constants and isotope effects
obtained from deslipping experiments at different
temperatures are summarized in Table 1. Average
inverse,secondary kinetic isotope effects (KIE) of 0.91
for 9a/9b and 10a/10b are obtained. These results can
be attributed to the smaller steric demand of the
deuterated stoppers.
1
2a (R = CH3)
2b (R = CD3)
3a
3b
O
O
c)
NH
NH
HN
HN
OH
OAc
d)
R
R
R R
R
R
R
R
R
R
RR
5a
5b
4a
4b
X
O
O
Br
7 (n = 1)
8 (n = 2)
e)
6a (X = CH)
6b (X = N)
Br
n
R
R
O
O
R
NH
HN
R
R
A study of the temperature dependence of the
isotope effects should enable the separate enthalpic
and entropic contributions to be determined.[14] Equa-
tion (1) expresses the KIE in terms of the differences
in free-activation enthalpies (DDG°),activation
enthalpies (DDH°),and activation entropies ( DDS°;
see Supporting Information).
R
O
O
R
n
R
R
9a (n = 1; R = CH3)
9b (n = 1; R = CD3)
10a (n = 2; R = CH3)
10b (n = 2; R = CD3)
NH
HN
R
R
R
O
O
kH
kD
DDG°
RT
DDH° DDS°
Scheme 2. Synthesis of deuterated rotaxanes and their unlabeled analogues:
a) tBuCl or [D9]tBuCl, AlCl3, ꢀ408C!ꢀ108C, 3 h, 90%; b) CH3COCl, AlCl3,
15%; c) MCPBA, 2 h, 85%; d) KOH, H2O/EtOH (2:1), reflux, 4 h, 67%;
e) K2CO3, dibenzo[18]crown-6, CH2Cl2, 25–30%.
ln KIE ¼ ln
¼ ꢀ
¼ ꢀ
þ
ð1Þ
RT
R
The results in Table 1 suggest that the isotope
effects observed for the deslipping reaction do not
Table 1: Rate constants k, kinetic isotope effects KIE, and free
activation enthalpies DG° for rotaxanes 9a,b and 10a,b.[a]
T [K]
Rotaxane
k [sꢀ1
]
KIE
DDG° [Jmolꢀ1
]
333
9a
9b
9a
9b
9a
9b
9a
9b
(2.09ꢁ0.03)”10ꢀ6
(2.26ꢁ0.02)”10ꢀ6
(2.06ꢁ0.03)”10ꢀ5
(2.26ꢁ0.03)”10ꢀ5
(1.18ꢁ0.02)”10ꢀ4
(1.29ꢁ0.02)”10ꢀ4
(6.74ꢁ0.06)”10ꢀ4
(7.44ꢁ0.06)”10ꢀ4
0.92
221
353
373
383
0.91
0.91
0.91
277
292
300
313
333
353
373
10a
10b
10a
10b
10a
10b
10a
10b
(2.44ꢁ0.02)”10ꢀ6
(2.73ꢁ0.04)”10ꢀ6
(1.95ꢁ0.02)”10ꢀ5
(2.17ꢁ0.02)”10ꢀ5
(1.27ꢁ0.03)”10ꢀ4
(1.36ꢁ0.03)”10ꢀ4
(4.73ꢁ0.04)”10ꢀ4
(5.12ꢁ0.04)”10ꢀ4
0.89
0.90
0.93
0.92
303
292
213
259
Figure 2. Plot of ln(c/c0) versus reaction time t for the evaluation of
the reaction rate constants k (in sꢀ1) of rotaxanes 9a,b and 10a,b at
373 K in [D2]tetrachloroethane. The rate constants and the kinetic iso-
tope effects are shown (KIE=kH/kD). Excellent correlation coefficients
were obtained for all linear regressions (R2 >0.997).
[a] See also the Supporting Information.
Angew. Chem. Int. Ed. 2003, 42, 2258 – 2260
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ꢀ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2259

Communications
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change with temperature,within experimental error
(although there seems to be a very minor trend to higher
KIE values at higher temperatures for rotaxanes 10a,b). Thus,
DDH° must be close to zero. A more precise evaluation of the
DDH° and DDS° values would require a larger temperature
range,which is not possible for technical reasons. Conse-
quently,we refrain from such a deconvolution of our data and
for the time being restrict ourselves to the following semi-
quantitative discussion: If DDH° is approximately 0 Jmolꢀ1,
the isotope effects are mostly entropic in nature with
DDS° values of about ꢀ0.8 JKꢀ1 molꢀ1 for 9a,b and about
ꢀ0.6 JKꢀ1 molꢀ1 for 10a,b. These results can be understood in
terms of the vibrational freedom in the transition structures of
the deslipping reactions. The larger vibrational amplitude of
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´
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In conclusion,the deslipping reaction of a rotaxane is very
sensitive,even to extremely small changes in the molecular
architecture and the steric demand of its components—
despite their large size,their complex molecular structure,
and the high flexibility of the mechanical bond. The present
work provides a novel supramolecular and highly precise
approach to the classical problem of determining and
comparing steric demand. The fact that the two “reaction
partners”,that is,the axle and the wheel,are already
independent molecules and only mechanically interlocked
before the reaction excludes all isotope effects arising from
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Received: January 7,2003 [Z50903]
Keywords: isotope effects · kinetics · reaction mechanisms ·
.
rotaxanes · supramolecular chemistry
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2260
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Angew. Chem. Int. Ed. 2003, 42, 2258 – 2260