unacceptably small [R]/[T] ratios. Clearly, this situation
could be addressed by a radical redesign of the recognition
event that creates the [L•M] complex in order to increase
the strength of this association. However, in some situations,
this approach may be both difficult to implement and
synthetically challenging. As an alternative strategy, we
reasoned that it should be possible to manipulate the Ka for
the [L•M] complex by means of a change in temperature.
Lowering the temperature should increase the Ka and,
therefore, lead to an increase in the population of [L•M].
Manipulating the population of [L•M] will ultimately lead
to an increase in the [R]/[T] ratio. However, as the
temperature decreases, the efficiency of the capping reactions
between either L or [L•M] and C also decreases. It is
unlikely that capping chemistry, which is rapid at room
temperature, would also be fast enough at lower tempera-
tures. In order to counteract this undesirable reduction in
reactivity at lower temperatures, we have identified a new
strategy (Scheme 1). In this approach, we employ the rapid
reaction between a phosphine and an organic azide at low
temperature as an intermediate capping step. The imino-
phosphorane formed in this process can then be captured
permanently through reaction with an aldehyde in an aza-
Wittig reaction.
Accordingly, we designed azide 1 (Scheme 1) as a suitable
linear component for incorporation within a rotaxane. Previ-
ously, we4 and others6 have demonstrated that diaryl amides,
such as 1, can be recognized and bound by macrocycle 2,
forming a complex, in this case [1•2] with a pseudorotaxane
geometry. The small cavity size present in macrocycle 2
introduces a constrictive7 element to the binding of diaryl
amides in solvents such as CDCl3. As a result, the 400 MHz
1H NMR spectrum of the [1•2] complex in CDCl3, recorded
at 10 °C, exhibits separate resonances for free 1 and bound
1, indicating that 1, 2, and [1•2] are in slow exchange on
the chemical shift time scale. It was therefore possible to
determine the Ka for the [1•2] complex in CDCl3 directly
Figure 1. (a) The linear component of the rotaxane L associates
with macrocycle M to form the complex [L•M]. This complex is
then captured irreversibly by reaction with C to form rotaxane R.
The linear component L can also react directly with the capping
reagent C, forming T, which does not contain the macrocycle. (b)
Plot of [R]/[T] against Ka for the kinetic scheme described in part
(a). In the simulation, the starting concentrations of L, M, and C
were 25 mM. Rate constant kT was 1 × 10-3 M-1 s-1, and kR was
varied from 4 × 10-3 M-1 s-1 (blue line) to 2.5 × 10-4 M-1 s-1
(red line), the value of kR being halved in each step.
a key marker for the efficiency of the rotaxane-forming
protocol is the ratio of R to T.
Kinetic simulation (Figure 1b) reveals that this [R]/[T]
ratio is sensitive to both the association constant, Ka, for the
[L•M] complex and to the ratio kR/kT. If we assume that the
Ka for the [L•M] complex is 5000 M-1 and kT ) kR, then
the [R]/[T] ratio in the final reaction mixture is 10.8 (green
line, Figure 1b). However, if kT ) 2kR, i.e. the [L•M]
complex is less reactive than L itself, then a Ka for the [L•M]
complex of 5000 M-1 results in a [R]/[T] ratio of 6.1 (orange
line, Figure 1b). Such situations are relatively common in
rotaxane synthesis as there are frequently remote steric
effects5 arising from the close proximity of the three species
L, M, and C at the transition state leading to R. The situation
deteriorates further as the kR/kT ratio diminishes; when kT )
4kR the [R]/[T] ratio in the final reaction mixture is only 3.4
(red line, Figure 1b).
1
using H NMR data recorded at five temperatures between
-10 and +10 °C. As expected, the association constant is
temperature dependent. At +10 °C, the Ka for [1•2] is 67 (
5 M-1 in CDCl3, rising to 118 ( 6 M-1 at -10 °C. Fitting
(6) The syntheses of similar macrocycles have been reported: (a)
Furusho, Y.; Matsuyama, T.; Takata, T.; Moriuchi, T.; Hirao, T. Tetrahedron
Lett. 2004, 45, 9593–9597. (b) Leigh, D. A.; Thomson, A. R. Org. Lett.
2006, 8, 5377–5379. (c) Huang, Y.-L.; Hung, W.-C.; Lai, C.-C.; Liu, Y.-
H.; Peng, S.-M.; Chiu, S.-H. Angew. Chem., Int. Ed. 2007, 46, 6629–6633.
For some recent examples of the use of amides for the construction of
rotaxane, see: (d) Aucagne, V.; Leigh, D. A.; Lock, J. S.; Thomson, A. R.
J. Am. Chem. Soc. 2006, 128, 1784–1785. (e) Kishan, M. R.; Parham, A.;
Schelhase, F.; Yoneva, A.; Silva, G.; Chen, X.; Okamoto, Y.; Vo¨gtle, F.
Angew. Chem., Int. Ed. 2006, 45, 7296–7299. (f) Chatterjee, M. N.; Kay,
E. R.; Leigh, D. A. J. Am. Chem. Soc. 2006, 128, 4058–4073. (g) Berna,
J.; Brouwer, A. M.; Fazio, S. M.; Haraszkiewicz, N.; Leigh, D. A.; Lennon,
C. M. Chem. Commun. 2007, 1910–1912. (h) Serreli, V.; Lee, C.-F.; Kay,
E. R.; Leigh, D. A. Nature 2007, 445, 523–527. (i) Fioravanti, G.;
Haraszkiewicz, N.; Kay, E. R.; Mendoza, S. M.; Bruno, C.; Marcaccio,
M.; Wiering, P. G.; Paolucci, F.; Rudolf, P.; Brouwer, A. M.; Leigh, D. A.
J. Am. Chem. Soc. 2008, 130, 2593–2601. (j) Alvarez-Perez, M.; Goldup,
S. M.; Leigh, D. A.; Slawin, A. M. Z. J. Am. Chem. Soc. 2008, 130, 1836–
1838.
In our original work, the Ka for the [L•M] complex was
around 100 M-1 and kT ) 3kR. This set of parameters led to
(5) Altered reactivity of functional groups incorporated within mechani-
cally interlocked structures is a well-established phenomenon. For some
examples, see: (a) Leigh, D. A.; Pea`ez, E. M. Chem. Commun. 2004, 2262–
2263. (b) Zehnder, D. W.; Smithrud, D. B. Org. Lett. 2001, 3, 2485–2487.
(c) Oku, T.; Furusho, Y.; Takata, T. Org. Lett. 2003, 5, 4923–4925. (d)
Craig, M. R.; Hutchings, M. G.; Claridge, T. D. W.; Anderson, H. L. Angew.
Chem., Int. Ed. 2001, 40, 1071–1074.
(7) For a discussion of slippage and constrictive binding, see: Fyfe,
M. C. T.; Raymo, F. M.; Stoddart, J. F. In Stimulating Concepts in
Chemistry; Vo¨gtle, F., Stoddart, J. F., Shibasaki, M., Eds.; VCH: Weinheim,
2000; pp 211-220.
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