Cucurbituril slippage: Translation is a complex motion

Article abstract of DOI:10.1021/ol1008119

(Figure presented) The kinetics of cucurbit[6]uril slippage along a polyaminated axle are highly dependent on even minor sterical alterations of the guest. According to in silico experiments, a plausible threading mechanism includes the deprotonation of the ammoniums prior to slippage, their tunneling through the cavitand as neutral amines, and their reprotonation upon exiting cucurbit[6]uril.

Full text of DOI:10.1021/ol1008119

ORGANIC
LETTERS
2010
Vol. 12, No. 12
2730-2733
Cucurbituril Slippage:
Translation is a Complex Motion
Xiaoxi Ling, E. Loic Samuel, Devin L. Patchell, and Eric Masson*
Department of Chemistry and Biochemistry, Ohio UniVersity, Athens, Ohio 45701
masson@ohio.edu
Received April 8, 2010
ABSTRACT
The kinetics of cucurbit[6]uril slippage along a polyaminated axle are highly dependent on even minor sterical alterations of the guest. According
to in silico experiments, a plausible threading mechanism includes the deprotonation of the ammoniums prior to slippage, their tunneling
through the cavitand as neutral amines, and their reprotonation upon exiting cucurbit[6]uril.
Interlocked molecular assemblies are fascinating structures
that have generated a great number of theoretical studies and
elegant applications in nanoscience. Upon application of an
external stimulus, they can undergo specific structural
modifications, from the simple translation of a cyclic molecular
bead along a linear chain to many more sophisticated motions.1
Cucurbit[n]urils2 (CB[n]) are cavitands bearing a pumpkin-like
shape, which can form interlocked structures with adequate
guests. All members of the family (i.e., CB[5], [6], [7], [8],
and [10]) have a common 9.1 Å depth and possess a hydro-
phobic, 4.4-13 Å wide cavity, as well as two hydrophilic
portals, approximately 2 Å narrower than the cavity.3 CB[6]
(1; see Figure 1) can be readily obtained from glycoluril and
formaldehyde and can also be functionalized,4 making it a
particularly attractive building block for rotaxane synthesis, since
it displays strong affinities toward protonated alkylamines
(binding constants up to 3 × 109 M-1).5
Figure 1. Structure of CB[6] (1). The barrel-like cartoon will be
used as a simplified depiction of CB[6] in the next schemes.
(1) For a few recent examples, see: (a) Balzani, V.; Credi, A.; Venturi,
M. Chem. Soc. ReV. 2009, 38, 1542. (b) Lee, C. F.; Leigh, D. A.; Pritchard,
R. G.; Schultz, D.; Teat, S. J.; Timco, G. A.; Winpenny, R. E. P. Nature
2009, 458, 314. (c) Serreli, V.; Lee, C. F.; Kay, E. R.; Leigh, D. A. Nature
2007, 445, 523. (d) Browne, W. R.; Feringa, B. L. Nature Nanotechnol.
2006, 1, 25.
A few years ago, Nau et al. reported the mechanism of
CB[6] complexation with various alkylammonium salts,
involving first an association complex between the am-
monium and the carbonylated portal, with the alkyl chain
still dangling in the aqueous phase, followed by a “flip-flop”
(2) Freeman, W. A.; Mock, W. L.; Shih, N. Y. J. Am. Chem. Soc. 1981,
103, 7367.
(3) (a) Lagona, J.; Mukhopadhyay, P.; Chakrabarti, S.; Isaacs, L. Angew.
Chem., Int. Ed. 2005, 44, 4844. (b) Liu, S.; Ruspic, C.; Mukhopadhyay,
P.; Chakrabarti, S.; Zavalij, P. Y.; Isaacs, L. J. Am. Chem. Soc. 2005, 127,
15959. (c) Day, A. I.; Blanch, R. J.; Arnold, A. P.; Lorenzo, S.; Lewis,
G. R.; Dance, I. Angew. Chem., Int. Ed. 2002, 41, 275. (d) Day, A. I.;
Arnold, A. P.; Blanch, R. J.; Snushall, B. J. Org. Chem. 2001, 66, 8094.
(e) Kim, J.; Jung, I. S.; Kim, S. Y.; Lee, E.; Kang, J. K.; Sakamoto, S.;
Yamaguchi, K.; Kim, K. J. Am. Chem. Soc. 2000, 122, 540.
(4) (a) Kim, K.; Selvapalam, N.; Ko, Y. H.; Park, K. M.; Kim, D.; Kim,
J. Chem. Soc. ReV. 2007, 36, 267. (b) Jon, S. Y.; Selvapalam, N.; Oh, D. H.;
Kang, J. K.; Kim, S. Y.; Jeon, Y. J.; Lee, J. W.; Kim, K. J. Am. Chem.
Soc. 2003, 125, 10186.
(5) (a) Rekharsky, M. V.; Ko, Y. H.; Selvapalam, N.; Kim, K.; Inoue,
Y. Supramol. Chem. 2007, 19, 39. (b) Mock, W. L.; Shih, N. Y. J. Org.
Chem. 1986, 51, 4440.
10.1021/ol1008119  2010 American Chemical Society
Published on Web 05/14/2010

mechanism of the alkyl unit into the CB[6] cavity, using
the ion-dipole interaction between the ammonium and the
cavitand rim as an anchor.6 In this study, we decipher the
mechanism of the CB[6] translation along a polyaminated axle,
which involves the threading of ammonium groups or their
corresponding neutral amines through the CB[6] cavity. Al-
though this process has been frequently exploited to design
molecular shuttles and other CB-interlocked systems,7 its
mechanism has never been unveiled.
compared to 105-106 M-1 for primary alkylammonium
5a
+
cations R-CH2NH3 ). CB[6] slippage was carried out in
the presence of sodium cations (50 mM) under various pD
conditions using adequate buffers (pD 0-12), and the
reaction rates were found not to depend on pD values,
suggesting that the same mechanism takes place regardless
of the acidity of the solution. Interestingly, the various
counteranions associated with the different buffer composi-
tions did not affect the slippage rates significantly.
We first prepared a series of N1,N6-disubstituted hexane-1,6-
diammonium salts 2a-d and then determined the effect of the
N1-substituents on the slippage rate of CB[6] along this axle. The
3,5-dimethoxybenzyl N6-substituent acts as a stopper, which forces
CB[6] to slip through the N1-substituent R (see Figure 2).
While the structure of reactants 3 and products 4 can be
readily determined by 1H NMR spectroscopy,7 the nature of
the slippage transition state(s) remains unclear. Although the
threading of the protonated ammonium guest through CB[6]
(see pathway 1, Figure 3) first comes to mind, we also
Figure 3. Two slippage pathways: (1) threading along an am-
monium cation; (2) deprotonation of the ammonium, threading
along the neutral amine, and subsequent reprotonation.
consider an alternate process, involving (1) the “intra-
rotaxanic” deprotonation of the ammonium cation by the
carbonyl portal of CB[6], followed by acid-base equilibrium
with the aqueous medium, (2) the slippage of the neutral amine
through the CB[6] cavity, and (3) the fast protonation of the
opposite CB[6] carbonyl followed by the reprotonation of the
amine guest (see pathway 2, Figure 3). As reported
previously,7b-d CB[6] can readily shuttle over neutral amines
under basic conditions; however, it remains unknown
whether the amine must be neutral in order to allow slippage,
regardless of pH conditions. Also, in both protonated and
neutral processes, water molecules may be incorporated into
CB[6] during slippage, or the cavitand may shield the axle
from external aqueous solvation completely. This solvation
issue is of tremendous importance when discriminating
between a threading process along a neutral or a positive
axle, since the solvation of a dialkylammonium cation
amounts to 60 kcal/mol, and only to 4 kcal/mol when it is
deprotonated, a 56 kcal/mol difference!8
Experimental evidence for either one of these mechanistic
pathways is unfortunately not available, especially since
neither dialkylammonium cations nor neutral dialkylamines
have ever been found to undergo encapsulation by CB[6],
contrary to some tetraalkylammonium cations which interact
with CB[7],9a as well as cyclen and cyclam tetrahydrochlo-
ride which can be encapsulated by CB[8].9b In order to
discriminate between pathways 1 and 2, we designed in silico
mimetics of both transition states by forcing CB[6] to
encapsulate (1) a dialkylammonium cation (assembly 5a, see
Figure 4), (2) the same cation in the presence of n water
Figure 2.
CB[6] slippage through N1,N6-disubstituted hexane-1,6-
diammonium salts 2 to afford rotaxanes 4, via pseudorotaxanes 3.
Since CB[6] displays good affinity toward primary alkyl
ammonium cations (Ka ) 105 - 106 M-1, see Table 2), the
first intermediates in the slippage mechanism are pseudoro-
taxanes 3a-d, which undergo subsequent translation to
rotaxanes 4a-d upon thermal activation (see Figure 2).
Sodium cations present in the reaction mixture are consecu-
tively ejected from the CB[6] portal, as reported in previous
studies.3a,5a The slippage process was found to follow first-
order kinetics, since (1) the fast equilibrium between CB[6],
diammonium salts 2, and pseudorotaxanes 3 is totally shifted
toward the interlocked structures (Ka > 105 M-1) and (2) the
reverse reaction from rotaxanes 4 to intermediates 3 is
negligible; this approximation is valid since the affinity of
CB[6] toward station 2 (see Figure 2) was found to be at
least 102 times greater than toward station 1 (the affinity of
CB[6] for hexane-1,6-diammonium is 2.9 × 108 M-1,
(6) (a) Marquez, C.; Nau, W. M. Angew. Chem., Int. Ed. 2001, 40, 3155.
(b) Marquez, C.; Hudgins, R. R.; Nau, W. M. J. Am. Chem. Soc. 2004,
126, 5806.
(7) For example, see: (a) Masson, E.; Lu, X.; Ling, X.; Patchell, D. L.
Org. Lett. 2009, 11, 3798. (b) Tuncel, D.; Katterle, M. Chem.sEur. J. 2008,
¨
¨
14, 4110. (c) Tuncel, D.; Ozcar, O; Tiftik, H. B.; Salih, B. Chem. Commun.
2007, 1369. (d) Lee, J. W.; Kim, K.; Kim, K. Chem. Commun. 2001, 1042.
(e) Buschmann, H. J.; Wego, A.; Schollmeyer, E.; Do¨pp, D. Supramol.
Chem. 2000, 11, 225.
Org. Lett., Vol. 12, No. 12, 2010
2731

the nature of the guests: the solvation energies of all
assemblies 5 are thus considered to be equal, and therefore
cancel each other.
Although one should consider values obtained in silico
with utmost care, especially for such large supramolecular
assemblies, the results in Table 1 suggest that (1) CB[6]
provides its guests with some solvation. Indeed, the energy
cost for the heterolytic NH cleavage of a secondary am-
monium salt in aqueous medium amounts to approximately
+15 kcal/mol (since the pKa of a dialkylammonium salt is
approximately 11);8 if the proton were solvated, but both
the neutral amine and its protonated form were totally
shielded from the solvent, the energy balance would be
reversed to -41 kcal/mol,8 and the neutral species would
be greatly favored (in perfect accordance with calculations;
see entry “δ, no CB” in Table 2: the nonsolvated neutral
dialkylamine is favored by 40 kcal/mol over its protonated
counterpart). However, the neutral rotaxane 5b and its
solvated proton are not favored by more than 7.2 kcal/mol,
indicating some solvation from CB[6], or some adverse
sterical or electronic interactions when CB[6] encapsulates
the neutral amine. (2) Incorporating water molecules into
the CB[6] cavity in an attempt to better solvate the am-
monium salt or the amine is unfavorable and leads to significant
distortion of the cavitand, regardless of the position of the
amine along the axle and the number of water molecules
added. (3) The axle is protonated when the amine function
sits at the CB[6] portal (when the nitrogen atom is located
at the ꢀ position, the positive form is at least 22 kcal/mol
more stable than its neutral counterpart), due to favorable
ion-dipole interactions. (4) The ammonium group undergoes
deprotonation when it enters the CB[6] cavity, since the
neutral rotaxane 5b becomes gradually more favorable when
the nitrogen atom moves toward the core of the cavitand
(from -0.5 down to -7.2 kcal/mol). These results support
pathway 2 (see Figure 3) as the valid slippage mechanism
and are corroborated by the observation of a constant slippage
rate between pD 0 and 12 (an encapsulated neutral amine
favored by 7.2 kcal/mol corresponds to a pKa of -5.3 for
the virtual encapsulated ammonium!) The mechanism is
therefore not supposed to change when the pH of the solution
is much greater than -5.3 but lower than the pKa of
pseudorotaxanes 3, which have been found to be greater than
13 (i.e., between 1 and 2 pKa units higher than free ammo-
niums 2, due to the stabilization of the protonated species
by the CB[6] carbonylated portal).6a,12
Figure 4. Mimetic structures of plausible transient complexes along
the slippage pathway.
molecules (rotaxane 5a·nH2O), (3) the corresponding neutral
amine 5b, and (4) the neutral amine and n water molecules
(assembly 5b·nH2O), and we determined the relative stabili-
ties ∆∆Gr of these interlocked systems relative to rotaxane
5a (see Table 1, entry δ) using the B3LYP density functional
method with the 6-31G(d) basis set, as recently applied to
CB[n]-interlocked structures.10
Table 1. Stabilities ∆∆Gr0 of Assemblies 5a·H2O,
5a·2H2O,5b,5b·H2O, and 5b·2H2O, Relative to Rotaxane 5aa
amine
positionb 5a·2H2Oc 5a·H2Oc 5a
5b
5b·H2Oc 5b·2H2Oc
ꢀ
γ
δ
0
0
0
0
+22d
-0.5
-7.2
-40
e
e
-
+21
+14
+19
+9.4
-
+36f
+39
δ,noCB
a In kcal/mol; a negative value indicates a more stable assembly than
rotaxane 5a. b See Figure 4. c Water molecules are encapsulated into CB[6]
together with the organic guest. d An even higher value is probable, since
+
the NH2 unit of assembly 5a sits at the CB[6] periphery and may be
stabilized by solvent contact. e Calculation did not converge or water
molecules were expelled from the cavity. f Only one water molecule interacts
with the ammonium unit.
Terminal m-xylenes are used as stoppers to prevent the
dislocation of the unfavorable complexes, and do not exert
any particular sterical pressure on CB[6]. The amine function
at position δ (see Figure 4) was subsequently switched with
neighboring carbon atoms (positions ꢀ and γ), and the
stabilities of the solvated and unsolvated amines and ammonium
salts were determined again. Relative stabilities ∆∆G° of
r
assemblies 5 relative to rotaxane 5a were determined using
the standard Gibbs free energy of these systems in the gas
phase, the free energy of the proton (-6.3 kcal/mol),11a its
solvation energy (-266.1 kcal/mol),11b and the free energy
of water in water calculated using the SMD solvation
model.11c We used gas-phase energies of assemblies 5 with
no additional correction for solvation, since CB[6] is
expected to shield its guests from the solvent regardless of
The effect of the N1-substituent on the slippage process
was subsequently assessed by 1H NMR (see Figures 5a-c).
The translation rates were determined at various temperatures
(10) (a) Zhang, H.; Grabenauer, M.; Bowers, M. T.; Dearden, D. V. J.
Phys. Chem. A 2009, 113, 1508. (b) Dearden, D. V.; Ferrell, T. A.; Asplund,
M. C.; Zilch, L. W.; Julian, R. R.; Jarrold, M. F. J. Phys. Chem. A 2009,
113, 989.
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7314. (b) Kelly, C. P.; Cramer, C. J.; Truhlar, D. G. J. Phys. Chem. B
2006, 110, 16066. (c) Marenich, A. V.; Cramer, C. J.; Truhlar, D. G. J.
Phys. Chem. B 2009, 113, 6378.
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2007, 111, 4422.
(12) (a) Praetorius, A.; Bailey, D. M.; Schwarzlose, T.; Nau, W. M.
Org. Lett. 2008, 10, 4089. (b) Saleh, N.; Koner, A. L.; Nau, W. M. Angew.
Chem., Int. Ed. 2008, 47, 5398. (c) Mohanty, J.; Bhasikuttan, A. C.; Nau,
(9) (a) St-Jacques, A. D.; Wyman, I. W.; Macartney, D. H. Chem.
Commun. 2008, 4936. (b) Kim, S. Y.; Jung, I. S.; Lee, E.; Kim, J.; Sakamoto,
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.
2732
Org. Lett., Vol. 12, No. 12, 2010

the size of all substituents a-d (such as A values or Taft
steric parameters Es) are not available, we computed them
using the B3LYP/6-31G(d) method and an isovalue of 0.002
(i.e., electrons are found inside the volume boundaries with
a 99.8% probability, see Table 2).
Smaller groups lead to lower activation enthalpies, with
the exception of the trifluoromethyl substituent d, which
causes an unusually high slippage barrier; this anomaly is
attributed to the repulsion between the lone pairs of the three
fluorine atoms and of the CB[6] carbonyl oxygens at the
cavitand rim. We conclude that the rate of CB[6] slippage
is exceptionally sensitive to minor sterical variations between
substituents, which not only can affect their ability to cross
the CB[6] portal but also may induce a repositioning of the
nitrogen atom threading through the opposite carbonylated
rim. Such a readjustment could significantly alter the energy
of the transition states and the slippage rates.
Figure 5.
1H NMR spectra of (a) guest 2a, (b) pseudorotaxane 3a, and
(c) rotaxane 4a. (d) Linear regressions confirming a first-order mechanism.
(e) Eyring plot describing the threading of CB[6] along axles 2a-d.
Rationalizing the variations in slippage entropy is more
difficult, and extra caution should be applied because of the
error associated with this parameter when determined on an
inevitably narrow temperature range. All entropies were found
to be consistently negative, although the displacement of the
coordinating sodium cation from the CB[6] portal of pseudoro-
taxanes 3, and the ejection of solvent molecules from the
cavitand, are expected to be entropically favorable processes.5a
The slippage of substituents a-d through the CB[6] portal and
the incorportion of the amine into its cavity should constrain
rotational freedom, distort CB[6], and induce a decrease in
activation entropy, which is significant enough to counterbalance
all entropic gains.
and the activation enthalpy ∆Hq, entropy ∆Sq, and Gibbs
energy ∆Gq were calculated using the Eyring equation by
plotting ln(k/T) versus 1/T, where k is the translation rate
constant at temperature T (Figure 5d,e). ∆Hq can be obtained
from the slope of the best straight line, and ∆S‡ from its
intersection with the y-axis. This method has been used
successfully in previous studies dealing with the kinetics of
rotaxanic motions.13
Interestingly, approximately isosteric N1-substituents were
found to affect the translation rate of CB[6] along the diam-
monium axle very differently. The half-life of pseudorotaxanes
3 (CB[6] at station 1) at 100 °C varies between a few seconds,
when CB[6] has to slip over a cyclopropyl group, to more than
3 h when isopropyl is the substituent (see Table 2). Changes in
In addition to unveiling the complexity of a seemingly
elementary translational motion, we hope that this study can
inspire the design of new CB[n]-containing time-dependent
molecular machines for controlled release applications.
Acknowledgment. This work was supported by the
Department of Chemistry and Biochemistry, the College of
Arts and Sciences, the Vice President for Research at Ohio
University, and in part by an allocation of computing time
from the Ohio Supercomputer Center in Columbus.
Table 2. Thermodynamic and Kinetic Parameters of the CB[6]
Slippage Process along Axles 2a-da
b
d
e
f
g
R
Ka
Vc
t1/2
∆Gq
∆Hq
∆Sq
a
b
c
5.4 × 105 70 3.2 h
1.1 × 106 63 2.4 s
28.9 ( 1.6 27.9 ( 1.3 -3 ( 3
23.7 ( 0.5 21.1 ( 0.4 -9 ( 1
Supporting Information Available: Preparation and
characterization of axles 2, pseudorotaxanes 3, and ro-
taxanes 4; kinetic procedures; coordinates and thermody-
namic parameters of rotaxanes obtained in silico. This
material is available free of charge via the Internet at
http://pubs.acs.org.
1.8 × 105 66 4.0 min 26.8 ( 0.9 24.7 ( 0.7 -7 ( 2
d
1.1 × 105 47 19 s
24.0 ( 1.4 23.2 ( 1.1 -3 ( 3
a Determined in the presence of sodium chloride (50 mM). b Binding
affinity of ammonium cations R-CH2NH3+ toward CB[6] (M-1). c Volume
of hydrocarbon R-H (Å3), calculated at the 6-31G(d) level with an isovalue
of 0.002. d Half-life of pseudorotaxanes 3 at 100 °C. e Gibbs free activation
energy of the slippage process (kcal/mol). f Activation enthalpy (kcal/mol).
g Activation entropy (cal/mol·K).
OL1008119
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slippage enthalpies were found to mirror variations in Gibbs
free energies for all substituents. Slippage enthalpies are usually
correlated with the size of the threading substituent,13a,b and
this study is no exception. Since numerical data describing
Org. Lett., Vol. 12, No. 12, 2010
2733