Bistable cucurbituril rotaxanes without stoppers

FULL PAPER

DOI: 10.1002/chem.201103434

Bistable Cucurbituril Rotaxanes Without Stoppers

Mantosh K. Sinha,^{[a, b]}Ofer Reany,*^[c]Maayan Yefet,^[a]Mark Botoshansky,^[a]and

Ehud Keinan*^{[a, b]}

Abstract: Bistable rotaxanes are impor-

tant design elements of molecular devi-

ces for a broad range of applications,

such as controlled drug release, molec-

ular rotary motors, and chemical sen-

sors. The host–guest complexes of cu-

curbit[6]uril and 1,4-bis(alkylaminome-

thyl)benzene were found to exhibit two

stable binding modes with an unexpect-

edly high barrier between them. Their

structural and dynamic properties, ki-

netic and thermodynamic parameters,

as well as different chemical reactivity

towards the azide–alkyne [3+2] cyclo-

addition reaction (click chemistry),

were discovered by NMR spectroscopy,

X-ray crystallography, and isothermal

titration microcalorimetry. The highly

stable 2:1 complex, which is formed at

room temperature, was found to be

a kinetic product, which may be con-

verted to the thermodynamic 1:1 com-

plex upon prolonged heating to 1008C.

The latter is a very stable rotaxane de-

spite the fact that it lacks bulky end

groups.

Keywords: click chemistry · cucur-

bituril · molecular threading · pseu-

dorotaxanes · rotaxanes

Introduction

been less obvious. For example, it was reported that 1 and

the dihydrochloride salt of bis-1,4-(allylaminomethyl)ben-

zene (2), form exclusively the [3]pseudorotaxane 2a.^[8]This

mode of binding with two molecules of 1 hosting the allylic

The chemistry and physical properties of mechanically inter-

locked molecules, and bistable rotaxanes in particular, are

important design elements of molecular devices for a broad

range of applications, such as controlled drug release,^[1]mo-

lecular rotary motors,^[2]and chemical sensors.^[3]For such ap-

plications the ability of the cucurbiturils to form host–guest

complexes with diammonium salts is highly attractive.^[4]

Indeed, cucurbit[6]uril (1; Scheme 1), has been widely used

for the construction of pseudorotaxanes and rotaxanes that

exhibited interesting dynamic, structural, and functional

properties.^[4a,5,6]In particular, linear aliphatic diammonium

salts readily form stable host–guest complexes of 1.^[7]By

contrast, the ability of 1 to host aromatic compounds has

[a] Dr. M. K. Sinha, M. Yefet, Dr. M. Botoshansky, Prof. E. Keinan

Schulich Faculty of Chemistry

Technion - Israel Institute of Technology

Technion City, Haifa 32000 (Israel)

Fax : (+972)48293913

E-mail: keinan@tx.technion.ac.il

[b] Dr. M. K. Sinha, Prof. E. Keinan

Department of Molecular Biology

and the Skaggs Institute for Chemical Biology

The Scripps Research Institute

10550 North Torrey Pines Road

La Jolla, California 92037 (USA)

[c] Dr. O. Reany

Department of Natural Sciences

The Open University of Israel

1 University Road, P.O. Box 808

Raꢀanana 43107 (Israel)

Fax : (+972)7780661

E-mail: oferre@openu.ac.il

Supporting information for this article is available on the WWW

under http://dx.doi.org/10.1002/chem.201103434.

Scheme 1.

Chem. Eur. J. 2012, 18, 5589 – 5605

ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

5589

1

side chains of 2 was well determined by H NMR spectros-

Results and Discussion

copy, electron-spray mass spectrometry, and molecular-me-

chanical calculations. These observations led to the interpre-

tation that the aromatic moiety in 2 is too big to be encapsu-

lated in the cavity of 1.^[8]However, compound 1 and p-xyly-

lenediammonium salt, 3, are long known to form a stable in-

clusion complex, 4, the structure of which was confirmed by

single-crystal X-ray crystallography.^[9]Furthermore, 5,5’-di-

methyl-2,2’-bipyridine, 5a, was reported to bind to either

tetramethyl- or dicyclohexyl-CB[6], and their 1:1 binding

mode was predicted by quantum-mechanical calculations

and confirmed by X-ray crystallography.^[10]Our studies with

either 4-aminobipyridine (5b) or 4-(2-pyridyl)aniline (5c)

showed that they form strong 1:1 inclusion complexes with

1 at room temperature (6b and 6c), whereas the bifunction-

al analogue 7, forms a strong 1:2 complex with 1 at room

temperature, which exhibits remarkably large enhancements

of fluorescence intensity and quantum yields.^[11]

These observations led us to speculate that the aromatic

part of 2 can be accommodated within the inner cavity of

1 and this binding mode may even be thermodynamically fa-

vored, but may involve unexpectedly high kinetic barriers.

To investigate this issue we prepared a series of guest mole-

cules and studied their behavior by using temperature-de-

pendent NMR spectroscopy, X-ray crystallography, isother-

mal titration microcalorimetry (ITC), as well as by employ-

ing the azide–alkyne cycloaddition reaction (click chemis-

try)^[12]as a chemical probe. Here we report that indeed, sev-

eral 2:1 host–guest complexes, such as 2a that are formed at

room temperature, are kinetic products that may be convert-

ed to the thermodynamic 1:1 complexes upon prolonged

heating to 1008C. The latter are very stable rotaxanes de-

spite the fact that they lack bulky end groups.

Synthesis of guest molecules: A series of guest molecules,

compounds 2 and 8–17, were prepared for this study

(Scheme 2). Although compounds 13 and 14 were reported

Scheme 2.

earlier,^[13]we prepared them in higher yields (Scheme 3), 57

and 53% rather than the reported 17 and 36%, respectively

(for further experimental details, see the Supporting Infor-

mation). For example, for the synthesis of 9 and 14 we used

2-azidoethylamine (18), which was prepared from bromoe-

thylamine hydrobromide and NaN₃in water. Protection of

18 with tert-butoxycarbonyl (Boc) to produce 19 followed

by N-alkylation with 1,6-diaminohexane (20) afforded 21.

Removal of the Boc groups with ethanolic HCl produced 14

in the form of its dihydrochloride salt in 53% overall yield.

Similarly, N-alkylation of 19 with 1,4-bis(bromomethyl)ben-

zene afforded compound 22, which, upon deprotection,

yielded 9 in the form of a dihydrochloride salt in 47% over-

all yield. The propargylamine derivatives, compounds 8 and

13, were prepared in three steps from 3 and 20, respectively.

Similar procedures were applied for the conversion of 23

and 25 to their bis-alkylamine analogues 24 and 26, respec-

tively. Finally, deprotection under acidic conditions afforded

guest molecules 2, 8, 10–12, and 15 in the form of their dihy-

drochloride salts in 30–50% overall yield. The non-symmet-

ric guest molecules 16 and 17, were prepared by reacting

a 1:1:1 mixture of 1,4-bis(bromomethyl)benzene, Boc-pro-

tected allylamine, and either Boc-protected methylamine or

Boc-protected 3,3-diphenylpropylamine. Chromatographic

separation of the product mixture afforded 16 and 17 in 40

and 20% yields, respectively.

Abstract in Hebrew:

Inclusion complexes: To study the stoichiometry of the in-

clusion complexes, an acidic aqueous solution (D₂O–DCl,

pH 6) of each of the protonated guests, 2, 8–15, was mixed

with solid 1 (2 equiv) and the mixture was kept at room

temperature for 16 h. Quantitative formation of the corre-

sponding inclusion complexes (Scheme 4) was evident by

1

their H NMR spectra, which exhibited significant changes

in the chemical shifts of the guest molecules (see the Sup-

porting Information). Consistent with the early observations

of Mock et al. for other inclusion complexes of 1,^[7a,14]all

protons of the guest molecule that reside in the host interior

underwent significant upfield shifts. This shielding effect re-

5590

www.chemeurj.org

ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Chem. Eur. J. 2012, 18, 5589 – 5605

Bistable Cucurbituril Rotaxanes

FULL PAPER

one host molecule accommo-

dating the central part of the

guest.

Further support for these two

different binding modes was

obtained from ITC measure-

ments at room temperature,

which afforded the values of

binding constant (logb)^[16]and

binding stoichiometry (n). Solu-

tions of 1 were titrated with

each of the guest molecules 2,

8–15, and with 20. The latter

served as a known reference

compound for comparison with

literature data. All stoichiome-

try values (Table 1) were con-

sistent with the above-men-

Scheme 3. Synthesis of all symmetrical guest molecules, 2, 8–15. All final products were isolated in the form of

their hydrochloride salts. Reagents and conditions: a) NaN₃, H₂O, 80 8C, 24 h; b) (Boc)₂O, Et₃N, CH₂Cl₂, RT,

12 h; c) 1,4-bis(bromomethyl)benzene, NaH, N,N-dimethylformamide, RT, 48 h; d) 4n HCl, EtOH, RT, 16 h;

e) 1,6-dibromohexane, NaH, N,N-dimethylformamide, RT, 48 h; f) propargyl bromide (for the synthesis of 24a

and 26a), benzyl bromide (for the synthesis of 24b and 26b), allyl bromide (for the synthesis of 26c), 1-bromo-

propane (for the synthesis of 26d), 1-bromobutane (for the synthesis of 26e), NaH, N,N-dimethylformamide,

RT, 24–36 h.

tioned

interpretation

of

¹H NMR spectra.

We classified the complexes

into three groups according to

their

binding

properties

(Table 1). The first group

(Table 1, entries 1–4) includes

the 1:1 complexes, as indicated

by their binding stoichiometry

of approximately 1. The binding

constants of 13 and 14 were

found to be an order of magni-

tude weaker than that of the

parent guest 20 (logb=6.25Æ

0.04).^[11]This observation was

expected on the basis of the

known stronger affinity of 1 to

primary versus secondary am-

monium ions.^[7a]The phenom-

enon can be understood in

terms of higher steric demand

of the secondary ammonium

Scheme 4. Formation of either 1:2 or 1:1 complexes between various diamine guest molecules and host 1 in

water, pH 5, at room temperature.

flected the cumulative influence of the urea units, which

form a hydrophobic wall of filled p orbitals. The CB hydro-

phobic interior is remarkably different from the acidic aque-

ous medium that solvates the free guests.^[15]In contrast, all

protons of the guest molecule that reside outside the cavity

in the vicinity of the portal carbonyl groups underwent de-

shielding, probably due to the strong anisotropic effect ex-

erted by the strong combined dipole of those carbonyl

groups. Thus, the mode of the inclusion complexation could

be unequivocally concluded from the sign of the induced

chemical shifts (Scheme 5).

Two distinct types of inclusion complex were observed on

the basis of their NMR data. Complexes 2a, 8a, 10a, 11a,

12a, and 15a exhibited a 1:2 binding mode with two CB

molecules hosting the side groups of the guest and leaving

the central part exposed to the solvent. In contrast, mole-

cules 9b, 13b, and 14b, formed 1:1 inclusion complexes with

ions and their smaller number of hydrogen-bonding oppor-

tunities with either the portal carbonyl oxygen atoms or the

surrounding water molecules.

Interestingly, guest 9 formed a 1:1 complex (Table 1,

entry 4) although all other aromatic guests formed 1:2 com-

plexes (Table 1, entries 6–10). This observation could be un-

derstood on the basis of the relative affinities between the

side chains in these guest molecules and 1. The dissociation

constant of 2-azidoethyl amine (2.5ꢂ10^À3m) is much higher

than those of propargylamine (6.5ꢂ10^À4m) and n-propyla-

mine (8.2ꢂ10^À5m).^[7a]Thus, both guest molecules bearing

azidoethyl groups (14 and 9; Table 1, entries 3 and 4) prefer

central binding at room temperature. The binding affinity of

14 was found to be an order of magnitude stronger than that

of 9. Apparently, in spite of the entropic advantage of the

rigid aromatic core in 9, it has a much lower enthalpy term,

probably reflecting the repulsive interactions between the

Chem. Eur. J. 2012, 18, 5589 – 5605

ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.chemeurj.org

5591

E. Keinan, O. Reany et al.

The second group (Table 1, entries 5 and 6) includes the

two guest molecules bearing benzyl side chains. The benzyl

group is known to be a weak binder of 1 in comparison with

the small alkyl side chains of the third group (Table 1, en-

tries 7–10).^[7a]Yet, both 12 and 15 prefer peripheral binding,

probably due to the high kinetic barrier associated with the

required threading of the large benzyl group through the

polar portal of 1 and moving of the benzyl groups from the

hydrophobic interior of 1 to the aqueous medium.

The third group (Table 1, entries 7–10) of guests 2, 8, 10,

and 11 exhibits very similar binding parameters. Their rela-

tively high negative entropic terms probably reflect signifi-

cant restriction of conformational mobility that is not com-

pensated by the release of water molecules from the solvat-

ed guest and 1.^[18]One should not be mislead by the fact

that both guest molecules bearing propargyl groups (13 and

8; Table 1, entries 2 and 8) exhibit very similar enthalpy and

entropy terms. They show different binding modes at room

temperature, central binding with 13 and peripheral with 8.

Plotting the thermodynamic data of Table 1 along with

previously reported data,^[11]revealed an essentially linear

correlation between TDS⁰and DH⁰values (Figure 1). The

slope a (-TDDS⁰), which is the incremental value of the ther-

modynamic parameter of binding, was found to be 0.92 for

this series of host–guest complexes. This value is comparable

with the observed known values for complexes of cationic

hydrophobic guests with a-, b-, and g-cyclodextrins (0.79,

0.80, and 0.97, respectively).^[19]These values are consistent

with the fact that entropy dominates the favorable free

energy of mainly hydrophobic interactions.^[15]Association of

two nonpolar surfaces, that is, the inner cavity of 1 and

either the alkyl or aromatic backbone of the diammonium

guest, causes the release of structured molecules of water

near nonpolar surfaces.^[20]The intercept calculated from the

regression line (TDS⁰=6.1 kcal

Scheme 5. ¹H NMR-induced chemical shifts (ppm) upon formation of in-

clusion complexes of the guest molecules 2a, 8–15 at room temperature

in D₂O–DCl solutions containing trace DMSO (d=2.71 ppm) as an inter-

nal standard. The shielding effect (ppm, upfield shift) is shown in bold,

whereas deshielding (ppm, downfield shift) is shown in italic.

aromatic system and the filled p orbitals of the host urea

groups, as well as the steric interactions. The aromatic ring

is obviously larger than the optimal space provided by the

interior of 1, with a 3.9 ꢃ portal diameter and interior diam-

eter of 5.8 ꢃ.^[15,17]This conflict leads not only to diminished

binding affinities but also to a distortion of the host, as seen

in the solid-phase structures of these complexes (see below).

mol^À1) represents the inherent

complex stability (DG⁰) ob-

Table 1. Overall binding constants (logb), binding stoichiometry (n, guest/host ratio), enthalpy (DH), and en-

tropy (DS) of binding between 2, 8–15, and 20 with 1. In the graphical representation of the guest molecules

the solid bar represents 1,6-diaminohexane and the sphere represents p-xylylenediamine. In all experiments

0.13 mm of 1 was titrated with a solution of the guest molecule (1–2 mm) in NH₄Cl buffer (10 mm, pH 4) at

303 K.

tained at a hypothetical case of

DH⁰=0. Comparison with the

analogous values for crown

ethers

(TDS⁰=2.9 kcalmol^À1)

Entry

Guest

Complex

20@1

logb

n

DH [kcalmol^À1

À11.13Æ0.01

À13.51Æ0.02

]

DS [eu]

and a-, b-, and g-cyclodextrins

(1.9, 2.6, and 3.6 kcalmol^À1, re-

spectively) highlights the high

entropy gain.^[21]

1

2

6.25Æ0.04

4.95Æ0.04

0.91

À8.1Æ0.1

À21.9Æ0.1

13@1

3

4

5

6

14@1

9@1

5.65Æ0.02

4.60Æ0.03

4.31Æ0.04

4.14Æ0.05

1.00

0.88

0.51

0.49

À12.39Æ0.02

À8.44Æ0.15

À8.6Æ0.7

À15.1Æ0.1

À6.0Æ0.1

À8.6Æ0.1

À17.9Æ0.6

Kinetic versus thermodynamic

control over the binding mode:

The observation that many

structurally similar guest mole-

cules exhibit either peripheral

or central binding modes

(Scheme 4) led us to speculate

that the 1:2 and the 1:1 com-

plexes could be kinetically in-

terconvertible under appropri-

ate conditions. Consistent with

15@1

12@1

À11.2Æ1.7

7

2@1

5.71Æ0.02

5.26Æ0.04

5.28Æ0.03

5.83Æ0.05

0.53

0.50

0.51

À15.21Æ0.01

À13.56Æ0.14

À13.8Æ0.2

À24.0Æ0.1

À21.5Æ0.1

À26.3Æ0.1

8

8@1

9

10@1

11@1

10

À16.0Æ0.3

5592

www.chemeurj.org

ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Chem. Eur. J. 2012, 18, 5589 – 5605

Bistable Cucurbituril Rotaxanes

FULL PAPER

Scheme 6. Formation of the inclusion complexes between 1 and non-sym-

metric guests 16 and 17.

conversion of 8a to 8b. The shift from a peripheral to cen-

tral binding mode was evident from the considerable upfield

shift of the aromatic protons (A, Dd=À1.36 ppm) accompa-

nied by a smaller upfield shift of the benzylic signal (B,

Dd=À0.08 ppm) and large downfield shifts of the propar-

gylic (C, Dd=0.71 ppm) and the acetylenic (D, Dd=

Figure 1. Enthropy–entalpy compensation plot for the complexation of

various guests with 1. Filled and open circles represent the thermody-

namic data for 1:1 and 1:2 binding modes, respectively.

this notion was the room temperature behavior of the non-

symmetric guest molecule 16, which preferred a central

binding mode 16b, whereas

compound 17 preferred the pe-

ripheral

binding

17a

(Scheme 6). These observations

suggested that the central bind-

ing mode of the aromatic group

is preferred thermodynamically,

whereas binding of the allylic

side chain is favored kinetically.

Furthermore, since com-

pounds 8 and 9 are structurally

similar but exhibit very differ-

ent complexation behavior with

1, we suspected that the ob-

served 1:2 complex 8a is a kinet-

ic product, whereas the 1:1

complex 9b is a thermodynamic

one. To examine this assump-

tion,

we

monitored

the

¹H NMR spectrum of 8a as

a function of time and tempera-

ture. Mixing 8 and 1 at a 1:2

molar ratio at room tempera-

ture for 36 h resulted in the ex-

clusive formation of 8a (Fig-

ure 2b). The 1:2 binding mode

was apparent from the down-

field shift of the aromatic pro-

tons (A, Dd=0.20), the upfield

shift of the propargylic (C,

Dd=À0.24) and the acetylenic

(D, Dd=À0.77) protons and

the essentially unchanged ben-

zylic protons, B. This situation

changed dramatically upon

heating the mixture to 1008C

for 10 days (Figure 2c–g), lead-

Figure 2. ¹H NMR spectra of 8 (600 MHz, D₂O–DCl). Solid and dashed lines represent upfield and downfield

shifts, respectively. a) Doubly protonated 8 in the absence of 1 at RT. b) After addition of 1 (2 equiv with re-

spect to 8), 36 h at RT. c) The mixture (b) after 14 h at 1008C. d) Mixture (b) after 28 h at 1008C. e) Mixture

(b) after 54 h at 1008C. f) Mixture (b) after 67 h at 1008C. g) Mixture (b) after 91 h at 1008C. The expanded

parts of the latter spectrum at d=5.5–5.6 (left) and 4.25-4.35 ppm (right) exhibit signals of 1 with the most in-

tense signals representing the 1:1 binding mode, 8b. The small signals marked with * represent the 1:2 binding

^

ing to essentially quantitative mode, 8a, and those marked with represent free 1.

Chem. Eur. J. 2012, 18, 5589 – 5605

ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.chemeurj.org

5593

E. Keinan, O. Reany et al.

1.57 ppm) signals. Much smaller changes were ob-

served in the signals of the host molecule 1. The

most significant of which was the upfield shift of the

methine signal from d=5.57 ppm in 8a to d=

5.53 ppm in 8b. Further confirmation of the struc-

tures of the 1:2 and 1:1 binding modes was obtained

from single-crystal X-ray crystallography of com-

plexes 8b and 11a (see below).

The complexation behavior of 15 was similarly

monitored by ¹H NMR spectroscopy. Mixing solu-

tions of 15 and 1 at a 1:2 molar ratio at room tem-

perature for 36 h resulted in the exclusive formation

of 15a (Figure 3b). The 1:2 binding mode was ap-

parent from the upfield shift of the aromatic protons

(A, from Dd=À0.66 to À1.08 ppm) accompanied by

a smaller upfield shift of the benzylic signal (B, Dd=

À0.03 ppm), whereas all signals of the alkyl chain

exhibited large downfield shifts (C–E, from Dd=0.1

to 0.54 ppm). This situation changed dramatically

upon heating to 1008C for 5 days (Figure 3c and d),

leading to conversion of 15a to 15b. Interestingly,

the reaction of 15 with 1 was found to be incomplete

at room temperature, affording 15a in approximate-

ly 45% yield. After heating to 1008C for 92 h the

1:1 complex 15b was obtained in 55% yield.

Interestingly, similar thread-

Figure 3. ¹H NMR spectra of 15 (500 MHz, D₂O–DCl). Solid lines represent upfield

shifts, whereas dashed lines represent downfield shifts. a) Doubly protonated 15 in

the absence of 1 at RT. b) After addition of 1 (2 equiv with respect to 15) and 36 h at

RT. c) Mixture (b) after 3 h at 1008C. d) Mixture (b) after 92 h at 1008C. The expand-

ed parts of spectrum (b) at d=6.9–6.3 (left), 3.5–2.9 (middle), and 2.2–1.5 ppm (right)

exhibit signals of the 1:2 binding mode, 15a. The small signals marked with * repre-

sent free 15 and those marked with # refer to acetone impurity.

ing processes upon thermal

treatment were recently report-

ed with analogues of guest 15,

with either pyridyl^[22]or 4-car-

boxaldehydephenyl^[23]instead

of the phenyl groups. In both

cases the conversion of the

host–guest complex from its ki-

netically stable peripheral bind-

ing mode to the thermodynami-

cally stable central binding

mode occurred in acidic water

upon reflux for several hours.

Another case of threading

under thermodynamic control

Scheme 7. Interconversion between the peripheral and central complexes at elevated temperatures.

at high temperatures was re-

ported for N,N’-diisobutylsper-

mine.^[24]

The experiment described in Figure 2 allowed for a quali-

tative assessment of the apparent rate constant for the con-

version of 8a to 8b. Analogous experiments were carried

out to monitor the conversion of 2a to 2b and of 15a to

15b. The progress of this isomerization process (Scheme 7)

was determined by measuring the relative integration values

of the methine proton signal of 1 at d=5.57 ppm in com-

plexes 2a, 8a, and 15a and at d=5.53 ppm in 2b, 8b, and

15b. The conversion (%) was plotted versus time (Figure 4

and Figure S4 in the Supporting Information) indicating ap-

parent first-order kinetics in all three cases with the appar-

ent rate constants as follows: compound 2a: k=3.6Æ0.3ꢂ

10^À5s^À1; compound 8a: k=1.17Æ0.07ꢂ10^À4s^À1; compound

15a: k=1.18Æ0.08ꢂ10^À4s^À1.

The thermodynamic parameters for the transition from 8a

to 8b were determined by monitoring the progress of the re-

1

action at 70, 80, 90, and 1008C by H NMR spectroscopy.

The resultant first-order rate constants were used in an

Eyring plot (Figure 5). The enthalpy of activation, DH^°=

4.4Æ0.2 kcalmol^À1, was calculated from the slope. The acti-

vation entropy, DS^°=À67.4Æ0.5 calmol^À1K^À1, was calculat-

ed from the intercept with the y axis. These values were

used to determine the Gibbs free energy difference, DG^°=

24.4Æ0.2 kcalmol^À1at 298 K.

5594

www.chemeurj.org

ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Chem. Eur. J. 2012, 18, 5589 – 5605

Bistable Cucurbituril Rotaxanes

FULL PAPER

Figure 4. Observed transition between 2:1 and 1:1 binding mode upon

heating complexes (2a, 8a, and 15a) at 1008C. The solid line represents

the data fitting according to an apparent first order rate equation (s^À1).

Figure 5. Eyring plot for the transition from 8a to 8b: the transition rates

(kꢂ10^À5, s^À1), 2.05Æ0.21, 2.49Æ0.81, 3.12Æ0.41, and 3.71Æ0.44 were de-

termined at T=343, 353, 363, and 373 K respectively, and plotted to give

the kinetic energy parameters. The Gibbꢀs free energy of the transition

state was calculated at 298 K using the Gibbꢀs free energy function

DG^°=DH^°ÀTDS^°. The values obtained from this plot were DH^°=

(4.4Æ0.2) kcalmol^À1, DS^°=(À67.4Æ0.5) calmol^À1K^À1, and DG^°=(24.4Æ

0.2) kcalmol^À1at 298 K.

These results indicate that the transformation of 8a to 8b

involves very common value^[25]of the enthalpy of activation

but the entropy term is outstandingly high. The latter could

be expected since the process involves loss of one host mol-

ecule as well as release of the two side chains from rigid

complexation to free movement. This large entropy of acti-

vation is unprecedented for threading processes with the cu-

curbituril guest. The closest examples of large entropic gain

in the kinetics of the threading and sliding processes are the

threading of viologen polymers within toroidal porphyrin

(DS^°=21–23 calmol^À1K^À1), which involves stretching of the

polymeric chains,^[26]and the threading of viologen chains

within calix[6]arene (DS^°=30.1 calmol^À1K^À1), which in-

volves reversible formation of hydrogen bonds.^[25]

Figure 6. Stereoviews of the X-ray crystal structures (top to bottom) of 4,

8b, 9b, and 11a (with one cucurbituril unit being omitted for clarity):

left: top view, right: side view. Color code: C, gray; N, blue; O, red. Hy-

drogen atoms, water molecules, and counteranions were omitted from all

structures.

mation about the binding interactions of these inclusion

complexes. We compared the structures of the new 1:1 com-

plexes 8b and 9b and the 1:2 complex 11a (Figure 6), with

the structure of the parent system, 4, which was found to be

identical with the one reported by Freeman.^[9a]The single-

crystal X-ray crystallographic data and refinement details of

all four complexes are provided in Table 2.

A common feature of all crystal structures is the presence

of large number of water molecules occupying the intermo-

lecular space within the unit cell in addition to the chloride

counteranions. The ratio between the actual complex and

X-ray crystallography: The solid-state structures of repre-

sentative complexes 4, 8b, 9b, and 11a, all crystallized from

an acidic (pH 6) aqueous solution, provided valuable infor-

Chem. Eur. J. 2012, 18, 5589 – 5605

ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.chemeurj.org

5595

E. Keinan, O. Reany et al.

Table 2. Crystallographic data and refinement details.

4

8b

9b

11a

formula

C₄₄H₅₀N₂₆O₁₂·2Cl·10H₂O

1204.35

1.670

C₅₀H₅₂N₂₆O₁₂·2Cl·18H₂O

1550.47

1.497

C₄₈H₅₆N₃₂O₁₂·2Cl·12H₂O

1560.64

1.604

C₈₈H₁₀₀N₅₀O₂₄·2HCl·29H₂O

2837.4

1.339

formula weight

density [gcm^À3

T [K]

]

293(2)

240(1)

293(2)

diffractometer

scan mode

crystal size [mm]

crystal system

space group

a [ꢃ]

b [ꢃ]

c [ꢃ]

a [8]

b [8]

KappaCCD

w and f scans

0.45ꢂ0.36ꢂ0.05

monoclinic

P2₁/n

12.078(2)

15.819(3)

14.438(3)

90

91.974(2)

90

2756.9(9)

2

KappaCCD

w and f scans

0.35ꢂ0.18ꢂ0.14

monoclinic

C2/c

27.465(5)

20.600(4)

12.510(2)

90

96.15(3)

90

7037(2)

4

KappaCCD

w and f scans

0.55ꢂ0.30ꢂ0.25

triclinic

APEX2 DUO

w scans

0.44ꢂ0.16ꢂ0.02

monoclinic

Cc

¯

P1

11.357(2)

12.191(2)

13.036(3)

109.54(3)

97.84(3)

102.69(3)

1615.6(7)

1

25.398(3)

47.898(4)

12.873

90

ACHTUNGERTN(NUNG 10

116.826(2)

90

13975(2)

4

g [8]

V [ꢃ³]

Z

F

(000)

1452

3336

818

5900

q_max[8]

unique reflns

I>2s(I)

R-factor (all data)

R-factor (I>2s(I))

S

25.05

4877

3537

0.0921

0.0693

1.063

25.05

6202

4513

0.1067

0.0813

1.051

25.02

5703

4526

0.0708

0.0565

1.079

25.25

24853

18548

0.1042

0.0851

1.145

these localized water molecules ranges from 1:10 in 4, 1:12

in 9b, 1:17 in 8b, and 1:29 in 11a, (1:14.5 per cucurbituril

unit). Expectedly, these water molecules are interconnected

through a network of hydrogen bonds that also includes the

carbonyl oxygen atoms of 1 and, in the case of 4, the ammo-

nium groups of the guest molecule.

Complex 11a exhibits two modes of hydrogen bonding

with the water molecules. One mode involves a water mole-

cule that bridges two carbonyl oxygen atoms on two differ-

ent cucurbituril units, C=O(10)-O(81)-(06A)O=C), 2.84–

2.97 ꢃ with an angle of 1358. The other mode involves two

water molecules that bridge the two cucurbituril units, C=

O(8)-O(68)-O(70)-(04A)O=C, 2.73–2.88 ꢃ (Figure 7). These

attractive interactions could explain the asymmetry ob-

served in the structure of 11a with the two CB units forming

an angle of 42.568 (Figure 6). A similar situation was ob-

served with the [2]pseudorotaxane of CB[7] with bispyridi-

nuim ethane. In that case, however, the non-symmetrical

orientation of the cucurbiturils was explained by a repulsive

interaction between the cations.^[4b]

Figure 7. Crystal structure of 11a exhibiting a network of three water

molecules that interconnect the two cucurbituril units.

These observations are reminiscent of the recently report-

ed complexation of thioflavin T (ThT) with CB[7].^[27]Geom-

etry optimization calculations revealed that the two CB[7]

units in the 1:2 binding mode were not parallel, and slightly

moved away from the N atom of the guest in comparison

with the 1:1 binding mode.^[27a]This geometry was interpret-

ed in terms of the repulsive interaction between the carbon-

yl portals of both CB[7] units, but compensated by hydro-

gen-bonding interactions between the charged N-methyl

group of the guest and the carbonyl oxygen atoms of both

CB units, resulting in a non-symmetrical orientation of the

CB units. The 1:2 complexation mode was reinforced by co-

operative binding of calcium cations.^[27b]

All the 1:1 complexes 4, 8b, and 9b, exhibited two types

of hydrogen bonding between the carbonyl oxygen atoms of

1 and the guest. The more obvious bonds involve the ammo-

nium hydrogen atoms NH-O=C, 1.980(3)–2.420(3) ꢃ. Less

obvious, but quite visible, are the hydrogen bonds between

the carbonyl oxygen atoms and the benzylic methylene hy-

drogen atoms of the guest CH-O=C, 2.317(3)–2.508(2) ꢃ.

In most of the reported solid state structures of host–

guest complexes of the cucurbit[n]urils, particularly with the

larger members of the family (n=7, 8, and 10), no distortion

of the host was noticed, as reflected by nearly ideal circular

5596

www.chemeurj.org

ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Chem. Eur. J. 2012, 18, 5589 – 5605

Bistable Cucurbituril Rotaxanes

FULL PAPER

portals, as well as a circular equator line, which accommo-

dates all methine groups. However, in complexes 4, 8b, and

9b, for which the size of the aromatic guest is relatively

large with respect to the cavity of 1, considerable distortions

of the host were observed. The ellipsoid shape of the portals

could be defined by the intercage distances between oppo-

site pairs of oxygen atoms. In 4 these distances are 6.581(3),

7.014(3), and 7.244(3) ꢃ. In 8b they are 6.554(4), 6.673(4),

and 7.615(4) ꢃ, whereas in 9b they are 6.518(4), 6.726(4),

and 7.608(4) ꢃ. These numbers represent a significant devia-

tion from the nearly symmetrical circle that characterizes

1 hosting two water molecules: 6.710(7), 6.710(7), and

6.683(6) ꢃ.^[28]

We found that the relative orientation of a guest within

1 varies among the complexes, as reflected by the angles be-

tween the plane defined by the aromatic carbons and the

planes accommodating opposite carbonyl oxygen atoms

(Figure 8). In complex 4 the aromatic plane is almost per-

pendicular to plane produced by O1-O4-O1’-O4’ (858) and

bisects the remaining two planes, O2-O5-O2’-O5’ (248) and

O3-O6-O3’-O6’ (328). In 8b, the aromatic guest is almost

parallel to the plane of O3-O6-O3’-O6’ (3.28) and bisects

the two remaining planes O2-O5-O2’-O5’ (528) and O1-O4-

O1’-O4’ (598). The corresponding angles in 9b are 8.98, 458,

and 658, respectively.

The ellipsoid geometry of 1 in the 1:1 complexes is also

manifested by the variations in distance between the oppo-

site methine groups on the equator. In an ideal circular

structure of 1 with nearly D_6hsymmetry these carbon atoms

are 10.15–10.20 ꢃ apart, that is, Dd=0.05 ꢃ. The largest de-

viation of Dd=1.31 ꢃ was reported for a complex of 4-

methylpyridinium with 1.^[29]Similarly large distortions were

observed with 4, 9b, and 8b, with Dd being 0.60, 1.21, and

1.29 ꢃ, respectively. Following the method of Farrugia,^[30]we

calculated the expanded cavity volume^[15]of 1 in complexes

4, 8b, 9b, and 11a (327.2, 355.2, 369.1, and 398.3 ꢃ³, and

found that these cavities increase with the steric demands of

the side chains.

Figure 8. Crystal structures in top view of 4 (top), 8b (middle), and 9b

(bottom), show the orientation of the guest with respect to the carbonyl

oxygen portals of 1. The red line represents the plane produced by the

phenyl backbone of the guest and the blue lines are the planes formed by

the opposite pairs of oxygen atoms of 1. Color code: C, gray; N, blue; O,

red. Hydrogen atoms water molecules, and counteranions were omitted

for clarity.

The 1,3-dipolar cycloaddition reaction as a chemical probe

of the binding mode: The azide–alkyne cycloaddition reac-

tion, known as the click reaction,^[12,31]produces a thermally

and hydrolytically stable triazole group, which has been ex-

tensively utilized for conjugations of various chemical and

biological entities.^[32]The reaction can be catalyzed by 1 pro-

vided that both reactants are equipped with ammonium end

groups that render them guest molecules of 1.^[7d,33]For ex-

ample, the cycloaddition reaction between 2-azidoethyla-

mine (18) and propargyl amine (27) to produce 2-(4-(amino-

methyl)-1H-1,2,3-triazol-1-yl)ethanamine (28) is accelerated

10000-fold when the reaction is carried out in acidic water

with catalytic amounts of 1 (Scheme 8A). The catalytic

mechanism is understood in terms of a proximity effect with

both reactants being concomitantly encapsulated within the

cavity of 1, thus gaining high effective molarity.^[7c]This cata-

lytic reaction is practically irreversible, proceeding in quanti-

tative yield to produce a single regioisomer without side

products. The reaction has been utilized for the preparation

of pseudorotaxanes,^[1b,34]self-threading rotaxanes,^[3,35]poly-

pseudorotaxanes, and polyrotaxanes.^[36]

We anticipated that the catalytic effect of 1, which is very

sensitive to the relative positioning of the host and guest

molecules, could be exploited as a chemical probe for re-

porting on the binding mode between 1 and the above-men-

tioned guest molecules. For example, in the reaction be-

tween 8 and 18 at room temperature, if 1 binds the side

chains of 8 to form 8a, the host molecule can concomitantly

accommodate the acetylenic unit of 8 and the azide portion

of 18 and therefore is expected to catalyze their cycloaddi-

tion reaction (Scheme 8B, top). In contrast, with the central

complexation mode, 8b, this reaction would be inhibited be-

cause in this mode 1 does not only reside away from the

Chem. Eur. J. 2012, 18, 5589 – 5605

ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.chemeurj.org

5597

E. Keinan, O. Reany et al.

Scheme 8. A) The proposed catalytic cycle of the cycloaddition reaction between 2-azidoethylamine 18 and propargyl amine 27 to form triazole 28.

B) The chemical reactivity of either 8 or 9 in the cycloaddition reaction represents a chemical probe of the complexation mode with 1, either peripheral

(8a, 9a), which is active, or central binding (8b, 9b), which is inactive. Chloride counter anions were omitted for clarity.

acetylene side chain, but also deters another molecule of

1 from accommodating the acetylenic unit.

Indeed, addition of azide 18 to an acidic solution of 8 and

1 under conditions that usually lead to the exclusive forma-

tion of 8a (3n aq HCl, room temperature, 48 h) afforded tri-

azole 29 in 90% yield. In contrast, addition of 18 to the

same mixture after heating (958C, 5 days) and cooling back

to room temperature, conditions that usually lead to 8b, did

not result in any observable cycloaddition products

(Scheme 8B, top).

Similarly, addition of acetylene 27 to an acidic solution of

9 and 1 at a molar ratio of 2:1:2 in 3n HCl and stirring the

mixture at room temperature for 60 h afforded 30 in 90%

yield. The formation of triazole 30 under these circumstan-

ces is remarkable because these conditions usually lead to

the exclusive formation of 9b,

The same modes of reactivity were observed in the reac-

tion of acetylene 31 and azide 32 in the presence of 1 at

room temperature to produce rotaxane 33 in 86% yield

(Scheme 9). As expected, the room temperature reaction

between 8 and 32 in the presence of 1 afforded the [3]rotax-

ane 34 in 90% yield. Consistent with the above-described

experiments, no reaction occurred upon addition of 32 to

a thermally treated mixture of 8 and 1 (958C, 48 h). Similar-

ly, the isomeric [3]rotaxane 35 was obtained at room tem-

perature in 93% yield by mixing 9, 31, and 1 in a 1:2:2 ratio.

Again, this reaction was completely inhibited when 31 was

added to a premixed (16 h at room temperature) solution of

9 and 1.

The structures of these new rotaxanes were confirmed by

¹H NMR spectroscopy, the spectra of which exhibited a sig-

which is expected to be inactive

in the cycloaddition reaction.

The formation of 30 in high

yields under these conditions

indicates that the cycloaddition

reaction is faster than the con-

version of 9a to 9b. To rule out

an alternative explanation that

9b forms first and then inter-

converts to 9a under the reac-

tion conditions we carried out

a control experiment. Premix-

ing of 9 and 1 for 16 h at room

temperature in the absence of

27 (conditions that lead to the

quantitative formation of 9b)

followed by the addition of 27,

did not result in any detectable

reaction (Scheme 8B, bottom).

Scheme 9. Synthesis of rotaxanes 33–35. Reagents and conditions: a) 1 (1 equiv), 3n HCl, 508C, 48 h, b) 8

(2 equiv), 32 (2 equiv), 1 (2 equiv), 6n HCl, RT, 60 h, c) 9 (2 equiv), 31 (2 equiv), 1 (2 equiv), 6n HCl, RT,

60 h. Chloride counter anions were omitted for clarity.

5598

www.chemeurj.org

ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Chem. Eur. J. 2012, 18, 5589 – 5605

Bistable Cucurbituril Rotaxanes

FULL PAPER

nificant upfield shift (Dd=À2.3 ppm) of the encapsulated

triazole proton (d=4.08 ppm) in comparison with free tria-

zole (d=6.38 ppm) in agreement with previously reported

complexes.^[37]The specific encapsulation of the triazole units

in 34 and 35 was evident from the upfield shift of the tria-

zole protons (d=4.34 ppm) and downfield shift of the aro-

matic ring protons (d=7.90 rather than d=7.16 ppm in the

free guest).

involve desolvation and reorganization of hydrogen-bonded

water molecules around the ammonium groups of the guest

and the carbonyl groups at the portals of 1.

At this point we can only speculate on the physical cause

of the kinetic barrier for going from the peripheral to cen-

tral binding mode. The concerted transition from III to IV

seems to involve higher activation energy in comparison

with the stepwise mechanism that goes through II. There is

no apparent synergism between the two binding events that

could award the concerted mechanism with a kinetic advant-

age over the stepwise process.

Mechanistic considerations: The fact that all of the above-

mentioned guests have three binding sites for the host mole-

cule renders their host–guest chemistry a non-trivial se-

quence of binding events depicted by a postulated equation

Theoretical^[38]and experimental^[39]studies have revealed

that filling the cavity of a host molecule by a molecular

chain is relatively fast in comparison with the subsequent

movement of the chain through the cavity. This effect has

recently been discussed in the context of the threading

mechanism of a polymeric chain through a macrocyclic ring.

The first event was termed the “entron effect”.^[40]Thus, in

our case the filling of 1 with the side chain of one of our

guests is expected to be faster than the subsequent thread-

ing, namely, k₁and k₃are expected to be larger than k₂and

k₄. The entron effect was recently observed in the threading

of a spermine derivative through 1.^[41]

(Scheme 10, top) and

a

schematic energy profile

(Scheme 10, bottom). The first event involves the formation

of a non-symmetrical complex II from I with the relevant

rate constants k₁and k_À1for the forward and backward re-

actions. Complex II can accommodate a second host mole-

cule to form the 1:2 complex III with the relevant rate con-

stants k₃and k_À3. Alternatively, II can undergo isomeriza-

tion to the symmetrical, 1:1 complex IV involving rate con-

stants k₂and k_À2. The key question of the entire mechanism

concerns the transition from III to IV. One possible route

involves a stepwise mechanism: first, release of one host

molecule to form complex II, and then sliding of the re-

maining host to its new location to form IV. An alternative

route involves a concerted mechanism with simultaneous

sliding of both hosts, so that the shift of one CB is associated

with the expulsion of the other, with the relevant rate con-

stants k₄and k_À4. All steps are quite complex because they

We expected that the interconversion between the periph-

eral and central binding modes would be pH dependent be-

cause the threading of ammonium guest molecules into 1 is

known to involve proton dissociation–association steps.^[42]

A

qualitative confirmation of this notion was obtained from

monitoring the conversion of 8a to 8b under pH 2, 4, and 6

at 1008C (Figure S5 in the Supporting Information). Al-

though at either pH 4 or 6 the conversion was essentially

complete in 12 days, at pH 2 the reaction progressed signifi-

cantly slower reaching only 45% in the same period of time.

The comparison between pH 4 and 6 was less conclusive

due to the poorer solubility of 1 at pH 6.

Conclusion

The dynamic properties of several host–guest complexes of

CB[6] with 1,4-bis(alkylaminomethyl)benzene were discov-

ered by temperature-dependent NMR spectroscopy, X-ray

crystallography, isothermal titration microcalorimetry, as

well as by their reactivity in the azide–alkyne [3+2] cycload-

dition reaction (click chemistry). The 2:1 complexes that are

formed at room temperature, were found to be kinetic prod-

ucts that may be converted to the thermodynamically more

stable 1:1 complexes upon prolonged heating to 958C. The

latter are very stable rotaxanes despite the fact that they

lack bulky end groups.

Multiple binding modes within a given pair of host and

guest molecules is a widely known phenomenon in biology,

in which the two partners adopt different conformations by

induced fit to accommodate two or more binding modes.

Biological systems often harness this opportunity for regula-

tory functions, such as switching between different modes of

chemical reactivity.^[43]The two binding modes of 1 with vari-

Scheme 10. A qualitative free energy diagram depicting the various bind-

ing modes of 1 with the various guest molecules.

Chem. Eur. J. 2012, 18, 5589 – 5605

ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.chemeurj.org

5599

E. Keinan, O. Reany et al.

to equilibrate for at least 30 min before the spectrum was acquired at RT.

The ratio between the signals corresponds to the methylene bridge pro-

tons of 1 in its 1:2 binding mode and the 1:1 binding mode was measured

and plotted over time. The curves followed first-order kinetics and the

rate constant was determined by fitting to an exponential growth func-

tion with the program Origin8.1. The activation energy parameters were

determined by employing the rate constants versus temperature accord-

ous guest molecules, which may switch their chemical reac-

tivity, as is the case with the two complexes 8a and 8b with

respect to the click reaction, demonstrate that this behavior

is not limited to biological macromolecules and can occur

with small molecules as well. The significance of these ob-

servations stems from the importance of the chemistry and

physical properties of mechanically interlocked molecules,

as design elements of molecular devices for a broad range

of applications, such as controlled drug release, molecular

rotary motors, and chemical sensors.

ing to the Eyring equation: Ln

G

(k_B/h)+DS^#/RT, in

ACHTUNGTRENNUNG

which R is the universal gas constant (1.986 calmol^À1K^À1), k_Bis the Bolz-

mann constant (3.298ꢂ10^À24calK^À1) and h is the Plank constant (1.584ꢂ

10^À34cals). k and T are the reaction rate constant (s^À1) and temperature

(K), respectively. DG^#was calculated by the Gibbꢀs free energy function:

DG^#=DH^#ÀTDS^#.

2-Azidoethylamine (18): A mixture of 2-bromoethylamine hydrobromide

(3 g, 14.6 mmol), NaN₃(2.86 g, 44 mmol), and H₂O (15 mL) was heated

at 808C for 30 h. After being cooled to RT, the mixture was quenched

with slow addition of KOH (4.8 g) and washed with Et₂O (20 mL). The

aqueous phase was extracted twice with Et₂O and the combined organic

phases were washed with brine and dried over MgSO₄. After removal of

the solvent, column chromatography of the residue (silica gel, hexane/

EtOAc, 9:1) afforded 18 as viscous oil (1.1 g, 87%). ¹H NMR (300 MHz,

CDCl₃) d=3.36 (t, J=5.7 Hz, 2H), 2.87 (t, J=5.7 Hz, 2H), 1.43 ppm

(brs, NH, 2H); ¹³C NMR (100 MHz, CDCl₃) d=54.6, 41.3 ppm; MS

(MALDI-TOF): m/z: calcd for C₂H₇ClN₄: 122.6; found: 87.1 [MÀCl]⁺.

Experimental Section

General methods: All reactions were carried out in anhydrous solvents

under inert atmosphere. Starting materials such as methyl amine (33% in

ethanol), a,a’-diamino- and dibromo-p-xylene, 1,6-diamino- and dibro-

mohexane, 2-bromoethylamine hydrobromide salt, allyl and propargyl

amine 27, allyl, propargyl, benzyl, propyl, and butyl bromides were pur-

chased from Aldrich Chemicals. CB[6] 1 was prepared as described previ-

ously.^[2]Flash chromatography was performed on Merck silica gel 60

(230–400 mesh). ¹H and ¹³C NMR spectra were recorded in the solvents

indicated by using either AVIII400 or AV500 Bruker spectrometers.

Chemical shifts (d) are given in ppm relative to TMS. The residual sol-

vent signals were used as references and the chemical shifts were con-

verted to the TMS scale: CDCl₃: d_H=7.26 ppm, d_C=77.16 ppm, D₂O–

DCl: (with trace DMSO) d_H=2.71 ppm, d_C=39.4 ppm. The following ab-

breviations or combinations thereof were used to explain the multiplici-

ties: s=singlet, d=doublet, t=triplet, q=quartet, qu=quintet, m=mul-

tiplet, br=broad. Mass spectra were recorded by using either Waters

MALDI microMX (TOF) or Waters LCT Premier microMax spectrome-

ters (TOF-ESI, with MeCN/water, 1:1). ITC measurements were per-

N-Boc-2-azidoaminoethane (19): A solution of 18 (0.5 g, 5.8 mmol) and

Et₃N (1.2 mL, 8.7 mmol) in THF (20 mL) was stirred for 30 min at RT.

(Boc)₂O (1.3 g, 5.9 mmol) was added and the mixture was stirred over-

night at RT, then quenched with aq NH₄Cl and extracted with Et₂O. The

organic phase was separated and washed with H₂O and brine, dried over

MgSO₄, and the solvent was removed under reduced pressure. The resi-

due was purified by flash chromatography (silica gel, hexane/EtOAc, 9:1)

1

to give 19 as viscous oil (0.94 g, 88% yield). H NMR (500 MHz, CDCl₃)

d=4.8 (brs, NH), 3.41 (t, J=5.5 Hz, 2H), 3.29 (t, J=5.5 Hz, 2H),

1.45 ppm (s, 9H); MS (MALDI-TOF): m/z: calcd for C₇H₁₄N₄O₂: 186;

found: 209 [M+Na⁺].

formed at 303 K by using

a VP-ITC instrument (MicroCal, USA).

N,N’-Di-Boc-bis(azidoethyl)-1,6-diaminohexane (21): NaH (60% sus-

pended in oil, 360 mg, 9 mmol) was added to a stirred solution of 19

(0.613 g, 3.3 mmol) in DMF (15 mL) at 08C, and the mixture was stirred

at RT for 1 h. 1,6-Dibromohexane (0.267 g, 1.1 mmol) was added and the

mixture was stirred at RT overnight, then quenched with aq NH₄Cl solu-

tion, extracted with Et₂O, washed with H₂O, brine, and dried over

Na₂SO₄. Removal of the solvent followed by column chromatography

(hexane/EtOAc 8:2) afforded 21 as colorless viscous oil (1.15 g, 77%).

¹H NMR (500 MHz, C₂D₂Cl₄at 355 K) d=3.41 (t, J=5.5 Hz, 2H), 3.38

(t, J=5.5 Hz, 2H), 3.25 (t, J=7 Hz, 2H), 1.57 (m, 2H), 1.51 (s, 9H),

1.33 ppm (m, 2H); ¹³C NMR (500 MHz, C₂D₂Cl₄at 355 K) d=155.25,

79.8, 50.1, 48.2, 46.8, 28.6, 28.5, 26.6 ppm; MS (ESI): m/z: calcd for

C₂₀H₃₈N₈O₄: 454; found: 455 [M+H⁺].

Repeat experiments indicated errors of 1–3% in the values of binding

stoichiometry (n), enthalpy (DH) and entropy (DS) of binding, and bind-

ing constant (K) over the most favorable concentration range. Each ex-

periment consisted of 20–35 consecutive injections (6–9 mL each) of guest

solutions into micro-calorimetric reaction cell (1.4 mL) charged with a so-

lution of 1. To maximize heat evolution (ꢀ2 mcals^À1) in the ITC experi-

ments, 1 was employed at 0.13 mm, which is close to its saturation con-

centration. All solutions were degassed prior to the titration experiment

according to procedures recommended by MicroCal, Inc. Curve fitting

was performed using ORIGIN 7.0 software adapted for ITC data analy-

sis. In all cases the single set of identical sites model was applied

(Table 1). Crystals of all four complexes, 4, 8b, 9b, and 11a were ob-

tained by slow diffusion of isopropanol into aqueous solutions of the

complexes. The single crystals were mounted on a Nonius KappaCCD

diffractometer (4, 8b, 9b) or APEX2 DUO diffractometer (11a) and

data was collected using graphite monochromatized Mo_Karadiation (l=

0.71073) at 293 8 K (4, 9b, 11a) and 240 K (8b). The following program

was used for data collection and reduction: Nonius 1997 Collect,^[44]HKL

DENZO, and Scalepack.^[45]The structures were solved by direct methods

using the program package maXus^[46]and refined in the usual way using

SHELXL97.^[47]Non-hydrogen atoms were refined anisotropically and hy-

drogen atoms isotropically.

Kinetic experiments: ¹H NMR experiments were recorded on Bruker

AVIII600 spectrometer operating at 600 MHz using Bruker 5 mm broad

band observe (BBO) Z gradient probe, with ²H lock channel and the

sample not spinning. All NMR experiments were carried out in D₂O–

DCl (pH 5, 0.1m) with a trace of DMSO as an internal calibration. NMR

dynamic processes were quantitatively determined by variable tempera-

ture measurements for a solution containing 1.75 mm of both the guest 8,

and host 1 at a given temperature. For each set of experiments, the tem-

perature was stabilized by Bruker BVT-3000 temperature control unit

and the temperature of the probe was calibrated with ethylene glycol.

For each slow exchange experiment, the resulting solutions were allowed

N, N’-Di-Boc-di-(azidoethyl)-p-xylylenediamine (22): The synthesis was

performed by using 19 (0.1 g, 0.53 mmol), NaH (60%, suspended in oil,

80 mg, 2 mmol), a,a-dibromo-p-xylylene (64 mg, 0.24 mmol), and DMF

(5 mL), and by following the above-described procedure for the prepara-

tion of 21, and gave 22 as a white solid (0.176 g, 70%). ¹H NMR

(500 MHz, CDCl₃) d=7.18 (s, 4H), 4.48 (s, 4H), 3.40–3.30 (brm, 8H),

1.50 (s, 9H) 1.45 ppm (s, 9H).

N,N’-Bis-Boc-1,6-diaminohexane (23): The synthesis was performed by

using 20 (0.5 g, 5.8 mmol), (Boc)₂O (2.2 g, 10 mmol), Et₃N (2.1 mL,

15 mmol), and THF (20 mL and by following the above-described proce-

dure for the preparation of 19, and gave 24 as a white solid (1.76 g) quan-

titatively following column chromatography (silica gel, hexane/EtOAc

7:3). ¹H NMR (500 MHz, CDCl₃) d=4.52 (s, 2NH), 3.09 (d, J=6.5 Hz,

4H), 1.46–1.31 ppm (m, 26H).

N,N’-Bis-propargyl-N,N’-di-boc-1,6-diaminohexane (24a): The synthesis

was performed by using 23 (1 g, 3.2 mmol), NaH (60%, suspended in oil,

0.76 g, 19 mmol), propargyl bromide (1.5 g, 12.6 mmol), and DMF

(15 mL), and by following the above-described procedure for the prepa-

ration of 21, and gave 24a as a white solid (0.87 g, 70%) following

column chromatography (silica gel, hexane/EtOAc 8:2). ¹H NMR

5600

www.chemeurj.org

ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Chem. Eur. J. 2012, 18, 5589 – 5605

Bistable Cucurbituril Rotaxanes

FULL PAPER

(500 MHz, CDCl₃) d 4.04 (brs, 4H), 3.3 (t, J=7.5 Hz, 4H), 2.18 (s, 2H),

1.56–1.25 ppm (m, 26H).

DCl) d=132.8, 131.2, 127.9, 124.7 50.4, 49.8, 39.4 ppm; MS (ESI): m/z:

calcd for C₁₄H₂₂Cl₂N₂: 289; found: 217 [MÀCl^ÀÀHCl].

N,N’-Bis-benzyl-N,N’-di-boc-1,6-diaminohexane (24b): The synthesis was

performed by using 23 (0.275 g, 0.87 mmol), NaH (60%, suspended in

oil, 0.28 g, 7 mmol), benzyl bromide (0.45 g, 2.6 mmol), and DMF

(10 mL), by following the above-described procedure for the preparation

of 21, and gave 24b as a white solid (0.26 g, 60%) after column chroma-

N,N’-Bis-propargyl-p-xylylene diammonium chloride (8): Compound 8

was obtained as an off-white solid (0.36 g, 85%). ¹H NMR (500 MHz,

CDCl₃) d=7.57 (s, 4H), 4.38 (s, 4H), 3.92 (d, J=2.5 Hz, 4H), 3.04 ppm

(t, J=2 Hz, 2H); ¹³C NMR (125 MHz, CDCl₃) d=132.5, 131.4, 79.1,

73.6, 50, 36.4 ppm; MS (ESI): m/z: calcd for C₁₄H₁₈Cl₂N₂: 285; found: 213

[MÀCl^ÀÀHCl].

N,N’-Bis-(azidoethyl)-p-xylylene diammonium chloride salt (9): Com-

pound 9 was obtained as an off-white solid (0.16 g, 88%). ¹H NMR

(500 MHz, D₂O–DCl) d=5.75 (s, 4H), 4.32 (s, 4H), 3.77 (t, J=5.5 Hz,

4H), 3.28 ppm (t, J=5.5 Hz, 4H); ¹³C NMR (125 MHz, D₂O–DCl) d=

132.6, 131.3, 51.2, 47.4, 46.5 ppm; MS (ESI): m/z: calcd for C₁₂H₂₀Cl₂N₈:

347; found: 275 [MÀCl^ÀÀHCl].

1

tography (silica gel, hexane/EtOAc 8:2). H NMR (500 MHz, CDCl₃) d=

7.35–7.28 (m, 5H), 7.19 (brs, 4H), 4.42 (s, 4H), 4.34 (brs, 4H), 1.51 ppm

(s, 18H); MS (ESI): m/z: calcd for C₃₀H₄₄N₂O₄: 496.7; found: 497.3

[M+H⁺], 519.3 [M+Na⁺], 535 [M+K⁺].

N,N’-Di-Boc-p-xylylene diamine (25): The synthesis was performed by

using

3 (2 g, 14.7 mmol), (Boc)₂O (6.4 g, 29.4 mmol), Et₃N (6 mL,

44 mmol), and CH₂Cl₂(50 mL), and by following the above-described

procedure for the preparation of 19 to afford 25 as a white solid (4.45 g,

90%) after column chromatography (silica gel, hexane/EtOAc 7:3).

¹H NMR (500 MHz, CDCl₃) d=7.24 (s, 4H), 4.82 (brs, NH), 4.28 (s,

4H), 1.45 ppm (s, 18H); ¹³C NMR (100 MHz, CDCl₃): d=155.9, 138.1,

127.7, 79.5, 44.4, 28.4 ppm. MS (MALDI-TOF): m/z: calcd for

C₁₈H₂₈N₂O₄: 336.4; found: 254 [M+H3O⁺], 359 [M+Na⁺], and 375

[M+K⁺].

N,N’-Bis-propyl-p-xylylene diamine (10): Compound 10 was obtained as

an off-white solid (0.37 g, 85%). ¹H NMR (300 MHz, D₂O–DCl) d=7.54

(s, 4H), 4.25 (s, 4H), 3.03 (t, J=7.6 Hz, 4H), 1.69 (sextet, J=7.6 Hz,

4H), 0.94 ppm (t, J=7.6 Hz, 4H); ¹³C NMR (100 MHz, D₂O–DCl) d=

132.9, 131.3, 51.2, 49.6, 19.9, 11.0 ppm; MS (MALDI-TOF): m/z: calcd

for

C₁₆H₃₀Cl₂N₂:

321.3;

found:

221

[MÀHClÀCl^À]⁺,

162

[MÀ2HClÀCH₂NHBu]⁺.

General procedure for N-alkylation: The synthesis was performed by

using 25 (1 g, 3.2 mmol), NaH (60%, suspended in oil, 1 g, 24 mmol),

DMF (20 mL), and bromide (propargyl, benzyl, allyl, propyl, and butyl;

12.6 mmol) by following the above-described procedure for the prepara-

tion of 21, and gave 24a–e respectively after column chromatography

(silica gel, hexane/EtOAc 9:1).

N,N’-Bis-butyl-p-xylylene diamine (11): Compound 11 was obtained as

an off-white solid (0.4 g, 85%). ¹H NMR (300 MHz, D₂O–DCl) d=7.54

(s, 4H), 4.25 (s, 4H), 3.06 (t, J=7.8 Hz, 4H), 1.64 (quintet, J=7.5 Hz,

4H), 1.35 (sextet, J=7.5 Hz, 4H), 0.89 ppm (t, J=7.5 Hz, 6H); ¹³C NMR

(100 MHz, D₂O–DCl) d=132.1, 130.5, 50.3, 47.0, 27.4, 19.1, 12.7 ppm;

MS (MALDI-TOF): m/z: calcd for C₁₆H₂₈N₂: 248; found: 249 [M+H⁺].

N,N’-Bis-propargyl-N,N’-di-boc-p-xylylene diamine (26a): Compound

27a was obtained as a white solid (1.05 g, 80%). ¹H NMR (500 MHz,

CDCl₃) d=7.22 (s, 4H), 4.53 (s, 4H), 3.96 (brd, J=6.4 Hz, 4H), 2.2 (s,

2H), 1.48 ppm (s, 18H); MS (ESI): m/z: calcd for C₂₄H₃₂N₂O₄: 412;

found: 413 [M+H⁺], 435 [M+Na⁺].

N,N’-Bis-benzyl–p-xylylene diammonium chloride (12): Compound 12

was obtained as an off-white solid (0.47 g, 85%). ¹H NMR (500 MHz,

D₂O–DCl) d=7.52 (s, 4H), 7.49 (m, 10H), 4.30 (s, 4H), 4.28 ppm (s,

4H); ¹³C NMR (125 MHz, D₂O–DCl) d=132.8, 131.3, 131.3, 130.5, 130.4,

129.9, 51.4, 50.7 ppm; MS (ESI): m/z: calcd for C₂₂H₂₆Cl₂N₂: 389.4;

found: 316.2 [MÀCl^ÀÀHCl].

N,N’-Bis-propargyl-hexane-1,6-diammonium chloride salt (13): Com-

pound 13 was obtained as an off-white solid (0.12 g, 85%). ¹H NMR

(500 MHz, D₂O–DCl) d=3.91 (d, J=2 Hz, 4H), 3.14 (t, J=7.5 Hz, 4H),

2.97 (t, J=2.5 Hz, 4H), 1.70 (brs, 4H), 1.42 ppm (brs, 4H); ¹³C NMR

(125 MHz, D₂O–DCl) d=78.6, 73.8, 47.2, 36.9, 25.8, 25.7 ppm; MS (ESI):

m/z: calcd for C₁₂H₂₂Cl₂N₂: 265; found: 193 [MÀCl^ÀÀHCl].

N,N’-Bis-(2-azidoethyl)-1,6-hexane diammonium chloride (14): Com-

pound 14 was obtained as an off-white powder (160 mg, 90%).¹H NMR

(400 MHz, D₂O–DCl) d=3.75 (t, J=5.5 Hz, 4H), 3.22 (t, J=5.5 Hz,

4H), 3.06 (t, J=7.5 Hz, 4H), 1.71 (brm, 4H), 1.42 ppm (brm, 4H);

¹³C NMR (125 MHz, D₂O–DCl) d=47.8, 47.1, 46.5, 25.5, 25.4 ppm; MS

(ESI): m/z: calcd for C₁₀H₂₄Cl₂N₈: 327; found: 255 [MÀCl^ÀÀHCl].

N,N’-Bis-benzyl-hexane-1,6-diammonium chloride salt (15): Compound

15 was obtained as an off-white solid (0.14 g, 52%). ¹H NMR (500 MHz,

D₂O–DCl) d=7.49 (brs, 10H), 4.22 (s, 4H), 3.04 (t, J=7.5 Hz, 4H), 1.68

(brs, 4H), 1.37 ppm (brs, 4H); ¹³C NMR (125 MHz, D₂O–DCl) d=

131.4, 130.4, 130.3, 129.9, 51.6, 47.5, 2ꢂ25.9 ppm; MS (ESI): m/z: calcd

for C₂₀H₃₀Cl₂N₂: 369.4; found: 297 [MÀCl^ÀÀHCl].

N,N’-Bis-benzyl-N,N’-di-boc-p-xylylene diamine (26b): Compound 26b

was obtained as pale yellow crystals (0.83 g, 50%). ¹H NMR (300 MHz,

CDCl₃) d=7.35 (m, 10H), 7.19 (brs, 4H), 4.42 (brs, 4H), 4.34 (brs, 4H),

3.13 (brd, 4H), 1.50 ppm (brs, 18H); ¹³C NMR (100.7 MHz, CDCl₃) d=

155, 138, 137, 128.5, 127.2, 80, 49, 48.8, 28.5; MS (ESI): m/z: calcd for

C₃₂H₄₀N₂O₄: 516.7; found: 517.3 [M+H⁺].

N,N’-Bis-allyl-N,N’-di-boc-p-xylylene diamine (26c): Compound 26c was

obtained as pale yellow oil (0.87 g, 65%). ¹H NMR (500 MHz, CDCl₃)

d=7.20 (brs, 4H), 5.76 (brs, 2H), 5.13 (brs, 4H), 4.41 (brs, 4H), 3.8 (d,

J=5 Hz, 4H), 1.6 ppm (brs, 18H); MS (ESI): m/z: calcd for C₂₄H₃₆N₂O₄:

416; found: 434 [M+H₂O], 439 [M+Na⁺].

N,N’-Bis-propyl-N,N’-di-boc-p-xylylene diamine (26d): Compound 26d

was obtained as colorless oil (0.81 g, 60%). ¹H NMR (300 MHz, CDCl₃)

d=7.16 (s, 4H), 4.39 (bd, J=7.2 Hz, 4H), 3.13 (brd, 4H), 1.43 (brs,

18H), 1.37 (brs, 4H), 0.83 ppm (t, J=7.5 Hz, 6H); ¹³C NMR

(100.7 MHz, CDCl₃) d=156.2, 137.5, 127.8, 127.2, 79.5, 49.6, 48.2, 28.5,

21.4, 11.3 ppm; MS (MALDI-TOF): m/z: calcd for C₂₄H₄₀N₂O₄: 420;

found: 443 [M+Na⁺] and 459 [M+K⁺].

N,N’-Bis-butyl-N,N’-di-boc-p-xylylene diamine (26e): Compound 26e

was obtained as pale yellow oil (0.72 g, 50%). ¹H NMR (300 MHz,

CDCl₃) d=7.16 (brs, 4H), 4.39 (brs, 4H), 3.13 (brd, 4H), 1.43 (brs,

22H), 1.19 (m, 4H), 0.87 ppm (t, J=3 Hz, 6H); ¹³C NMR (100 MHz,

D₂O–DCl) d=132.1 130.5, 50.3, 47.0, 27.4, 19.1, 12.7 ppm; MS (MALDI-

TOF): m/z: calcd for C₁₆H₂₈N₂: 248; found: 249 [M+H⁺].

p-Xylylenediammonium hydrochloride (3): To a solution of a,a-diamino-

p-xylylene (0.5 g, 3.6 mmol) in MeOH (2 mL) a few drops of concentrat-

ed HCl were added and the resulting white precipitate was washed with

Et₂O to give 3 (0.75 g) in quantitative yield. ¹H NMR (500 MHz, D₂O–

DCl) d=7.35 (s, 4H), 4.25 (s, 4H) ppm; MS (ESI): m/z: calcd for

C₈H₁₄N₂Cl₂: 209.1; found: 137 [MÀHClÀCl]⁺.

General procedure for the removal of Boc protecting group: A mixture

of each starting material, that is, 21–22, 24a,b, and 26a–e (0.5–1.5 mmol)

in EtOH (10 mL) and 4n HCl (4 mL) was stirred overnight at RT. After

removal of the solvent the residue was dissolved in hot MeOH and upon

standing overnight the resultant precipitate was collected. If precipitation

did not occur addition of Et₂O to the hot methanolic solution resulted in

precipitation upon cooling and the precipitate was collected.

General procedure for the complex formation of guests with 1

Synthesis of complexes 4, 9b, 13b, and 14b: Compound 1 (0.1 mmol)

was added to a solution of selected guest (0.05 mmol) in acidic H₂O

(25 mL, pH 5–5.5) and stirred at RT for 16 h. The resulting mixture was

filtered and the solvent of the filtrate was removed under reduced pres-

sure. The residue from the filtrate was dissolved in H₂O (10 mL), and

acetone was added and the resulting precipitate was washed with MeOH

and Et₂O to give a 1:1 complex in quantitative yield with respect to the

guest. Single crystals of 4 and 9b were obtained by recrystallization from

H₂O with few drops of isopropanol and subjected to X-ray analysis.

N,N’-Bis-allyl-p-xylylene diammonium chloride (2): Compound 2 was ob-

tained as an off-white solid (0.37 g, 85%). ¹H NMR (500 MHz, D₂O–

DCl) d=7.55 (s, 4H), 5.92 (m, 2H), 5.32 (d, J=6 Hz, 2H), 5.5 (s, 2H),

4.27 (s, 4H), 3.71 ppm (d, J=6.5 Hz, 4H); ¹³C NMR (125 MHz, D₂H-

Chem. Eur. J. 2012, 18, 5589 – 5605

ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.chemeurj.org

5601

E. Keinan, O. Reany et al.

Synthesis of complexes 2a, 8a, 10a–12a, and 15a: Compound

1 (0.1 mmol) was added to a solution of selected guest (0.05 mmol) in

acidic H₂O (25 mL, pH 5.5–6) and stirred at RT for 16 h. The resulting

mixture was filtered and acetone was added to the filtrate. The resulting

precipitate was collected and washed with MeOH and Et₂O to afford 1:2

complexes in >90% yield. A single crystal of 11a was obtained by re-

crystallization from H₂O with few drops of isopropanol and subjected to

X-ray analysis.

15 Hz, 12H), 3.04 (t, J=7.5 Hz, 4H), 0.85 (t, J=7.5 Hz, 4H), 0.49 (brs,

4H); MS (ESI): m/z: calcd for C₅₆H₆₆Cl₂N₂₆O₁₂: 1366.4; found: 1293.6

[MÀCl^ÀÀHCl].

Preparation of asymmetric guests 16 and 17: The synthesis of N-Boc-

methylamine, N-Boc-allylamine, and N-boc-(3,3-diphenyl)propylamine

was performed by addition of (Boc)₂O (2 equiv) and Et₃N (3.5 equiv) to

a solution of either methyl ammonium chloride (1 g, 14.8 mmol), allya-

mine (3 g, 0.05 mol), or 3,3-diphenylpropyl amine (1 g, 4.7 mmol) in

CH₂Cl₂(0.3m amine concentration), and by following the above-de-

scribed procedure for the preparation of 19, the N-protected products

were obtained as white solids (average yield: 90%) following column

chromatography (silica gel, hexane/EtOAc 8:2).

Synthesis of complexes 2b, 8b, and 15b: A solution of selected complex,

2a, 8a, and 15a (0.05 mmol) in acidic H₂O (25 mL, pH 5.5–6) was heated

to 1008C for several days. After being cooled, acetone was added to the

filtrate, and the resulting precipitate was collected and washed with

MeOH and Et₂O to afford 1:1 complexes in >90% yield. A single crystal

of 8b was obtained by recrystallization from H₂O with few drops of iso-

propanol and subjected to X-ray analysis.

Compound 2a: ¹H NMR (500 MHz, D₂O–DCl) d=7.69 (s, 4H), 5.75 (d,

J=15.5 Hz, 12H), 5.58 (s, 24H), 5.20 (brs, 4H), 4.74 (2H olefin inside

DHO), 4.36 (s, 4H), 4.31 (d, J=15.5 Hz, 12H), 3.45 ppm (brs, 4H).

N-Boc-methylamine: ¹H NMR (400 MHz, CDCl₃) d=4.50 (brs, NH),

2.72 (s, 3H), 1.44 ppm (s, 9H); ¹³C NMR (100 MHz, CDCl₃) d=156.6,

79.1, 31.2, 28.4 ppm.

1

N-Boc-allylamine: H NMR (400 MHz, CDCl₃) d=5.83 (ddt, J=16.8 Hz,

J=10.0 Hz, J=4.8 Hz, 1H), 5.17 (dq, J=16.8 Hz, J=1.6 Hz, 1H), 5.09

(dq, J=10 Hz, J=1.6 Hz, 1H),4.64 (brs, NH), 3.74 (brs, 2H), 1.44 ppm

(s, 9H); ¹³C NMR (100 MHz, CDCl₃) d=155.8, 134.9, 115.7, 79.3, 43.1,

28.4 ppm.

1

Compound 2b: H NMR (500 MHz, D₂O–DCl) d=6.51 (s, 4H), 6.28 (m,

4H), 5.78 (m, 2H), 5.75 (d, J=15.5 Hz, 12H), 5.51 (s, 24H), 4.36

ACHTUNGTRNE(NUNG s, 4H),

4.31 (d, J=15.5 Hz, 12H), 4.04 ppm (d, J=7.0 Hz, 4H).

1

N-Boc-(3,3-diphenyl)propylamine: H NMR (400 MHz, CDCl₃) d=7.30–

Compound 4: ¹H NMR (500 MHz, D₂O–DCl) d=6.53 (s, 4H), 5.75 (d,

J=15.5 Hz, 12H), 5.51 (s, 24H), 4.35 (s, 4H), 4.32 ppm (d, J=15.5 Hz,

12H); ¹³C NMR (125 MHz, D₂O–DCl) d=157, 133.3, 124.6, 70.6, 51.9,

41.6 ppm; MS (ESI): m/z: calcd for C₄₄H₅₀Cl₂N₂₆O₁₂: 1206; found: 1133

[MÀHClÀCl^À].

7.17 (m, 10H), 4.50 (brs, NH), 3.97 (t, J=8 Hz, 1H), 3.08 (brq, 2H), 2.26

(q, J=8 Hz, 2H), 1.43 ppm (s, 9H); ¹³C NMR (100 MHz, CDCl₃) d=153,

128.6, 127.8, 126.3, 78, 48.8, 39.4, 35.7, 28.4 ppm.

A general procedure for non-symmetric N-alkylation: The synthesis was

performed by using

a mixture of either N-Boc-methylamine(0.33 g,

Compound 8a: ¹H NMR (500 MHz, D₂O–DCl) d=7.77 (s, 4H), 5.73 (d,

J=15.5 Hz, 24H), 5.56 (s, 24H), 4.38 (s, 4H), 4.29 (d, J=15.5 Hz, 24H),

3.68 (s, 4H), 2.21 ppm (s, 2H).

2.6 mmol) and N-Boc-allylamine (0.4 g, 2.6 mmol), or a mixture of N-

Boc-(3,3-diphenyl)propylamine (0.4 g, 1.3 mmol) and N-Boc-allylamine

(0.2 g, 1.3 mmol), NaH (60%, suspended in oil, 6 equiv), DMF (140 mL),

and a,a’-dibromo-p-xylylene (1 equiv) by following the above-described

procedure for the preparation of 21 and gave N-allyl, N’-methyl- and N-

allyl, N’-(3,3-diphenyl)propyl-N,N’-di-Boc-p-xylylenediamine, respective-

ly, after column chromatography (silica gel, hexane/EtOAc 9:1):

Compound 8b: ¹H NMR (500 MHz, CDCl₃) d=6.54

ACHTUNGTREN(NUGN s, 4H), 5.73 (d, J=

15.5 Hz, 12H), 5.53 (s, 12H), 4.45 (s, 4H), 4.32–4.28 (m, 4H), 3.8 ppm (s,

2H); MS (MALDI-TOF): m/z: calcd for C₅₀H₅₂D₂Cl₂N₂₆O₁₂

found: 1212 [MÀCl^ÀÀDCl].

: 1284;

Compound 9b: ¹H NMR (500 MHz, D₂O-DCl) d=6.53 (s, 4H), 5.74 (d,

J=16 Hz, 12H), 5.53 (s, 12H), 4.4 (s, 4H), 4.29 (d, J=16 Hz, 12H), 4.1

(t, J=5.5 Hz, 4H), 3.56 ppm (t, J=5.5 Hz, 4H).

N-Allyl, N’-methyl-N,N’-di-Boc-p-xylylenediamine: The compound was

isolated as a pale yellow oil from a mixture of all three possible products

(0.24 g, 25%). ¹H NMR (400 MHz, CDCl₃) d=7.19 (brs, 4H), 5.75 (brs,

1H), 5.12 (brs, 2H), 4.40 (brs, 4H), 3.78 (brs, 2H) 2.81 (s, 3H), 1.43 ppm

(s, 9H); ¹³C NMR (100 MHz, CDCl₃) d=155.8, 137.3, 137, 133.7, 127.5,

116.9, 116.4, 79.6, 52.3, 49, 48.6, 33.9, 28.4 ppm; MS (MALDI-TOF): m/z:

calcd for C₂₂H₃₄N₂O₄: 390.52; found: 413.16 [M+Na].

Compound 10a: ¹H NMR (400 MHz, D₂O–DCl) d=7.91 (brs, 4H), 5.75

(d, J=16 Hz, 12H), 5.59 (s, 12H), 4.50 (brs, 4H), 4.33 (brd, 12H), 2.24

(brs, 4H), 0.73 (brs, 4H), 0.17 (brs, 6H); MS (ESI): m/z: calcd for

C₈₆H₉₈Cl₂N₅₀O₂₄: 2284.7; found: 1108.8 [MÀ2Cl^À]⁺²; HRMS (ESI): m/z:

calcd for C₄₃H₄₉N₂₅O₁₂: 1108.4086; found: 1108.4071.

Compound 11a: ¹H NMR (400 MHz, D₂O–DCl) d=7.91 (s, 4H), 5.75

(2ꢂd, J=9 Hz, 12H), 5.58 (s, 12H), 4.44 (s, 4H), 4.31 (2ꢂd, J=16 Hz,

12H), 2.53 (t, J=7.6 Hz, 4H), 0.67 (m, 4H), 0.55 (sextet, J=7.2 Hz, 4H),

N-Allyl, N’-(3,3-diphenyl)propyl-N,N’-di-boc-p-xylylenediamine: The

compound was isolated from a mixture of all three possible products as

a white powder (0.34 g, 48%). ¹H NMR (400 MHz, CDCl₃) d=7.30–7.17

(m, 14H), 5.75 (brs, 1H), 5.12 (brs, 2H), 4.39 (brs, 4H), 3.78 (brs, 2H)

3.08 (brs, 2H), 2.27 (brs, 2H), 1.43 ppm (s, 9H); ¹³C NMR (100 MHz,

CDCl₃) d=155.8, 144.2, 137.2, 133.7, 128.51, 128.47, 127.72, 127.65, 126.2,

125.5, 116.6, 115.9, 79.7, 71.8, 59.0, 48.8, 28.4 ppm.

0.23 ppm (t, J=7.2 Hz, 6H); MS (ESI): m/z: calcd for C₈₈H₁₀₂Cl₂N₅₀O₂₄

; HRMS (ESI): m/z: calcd for

C₄₄H₅₁N₂₅O₁₂: 1122.4227; found: 1122.4204.

:

2312.8; found: 1121.8 [MÀ2Cl^À]⁺²

Compound 12a: ¹H NMR (500 MHz, D₂O–DCl) d=7.91 (d, J=8 Hz,

2H), 7.63 (d, J=8 Hz, 2H), 6.75 (m, 2H), 6.57 (t, J=8 Hz, 4H), 6.41 (d,

J=8 Hz, 4H), 5.63 (d, J=15 Hz, 12H), 5.4 (s, 12H), 4.36 (d, J=15 Hz,

N-Allyl, N’-methyl-p-xylylenediammonium chloride (16): The synthesis

was performed by using N-allyl, N’-methyl–N,N’-di-boc-p-xylylenedia-

mine (0.17 g, 0.44 mmol), EtOH (35 mL), and HCl (14 mL, 4m) and fol-

lowing the above-described general procedure for the removal of the Boc

protecting group. The product was obtained as a white solid (0.11 g,

95%). ¹H NMR (400 MHz, CDCl₃) d 7.54 (brs, 4H), 5.91 (m, 1H), 5.51

(d, J=4.8 Hz, 1H), 5.48 (brs, 1H), 4.25 (brs, 4H), 3.69 (d, J=6.8 Hz,

2H) 2.22 ppm (s, 3H); ¹³C NMR (100 MHz, CDCl₃) d=131.1, 130.8,

129.24, 129.22, 126.1, 122.5, 50.5, 48.5, 47.9, 30.9, 28.4 ppm; MS (MALDI-

TOF): m/z: calcd for C₁₂H₂₀N₂Cl₂: 263.2; found: 191.2 [MÀHClÀCl]⁺.

N-Allyl, N’-(3,3-diphenyl)propyl-p-xylylenediammonium chloride (17):

¹H NMR (400 MHz, CDCl₃) d=7.55 (s, 4H),7.48–7.27 (m, 10H), 5.92

(m, 1H), 5.525 (d, J=3.6 Hz, 1H), 5.505 (d, J=10.8 Hz, 1H), 4.27 (s,

2H), 4.25 (2H), 4.09 (dt, J=8 Hz, 2H), 3.68 (m, 2H), 2.93 (m, 2H),

2.46 ppm (m, 2H); ¹³C NMR (100 MHz, CDCl₃) d=144, 143.7, 132.4,

132.1, 130.8, 129.3, 127.77, 127.75, 127.5, 127.3, 127.2, 124.2, 50.0, 49.9,

49.4, 49.3, 48.2, 38.6, 32.3, 30.9 ppm; MS (ESI): m/z: calcd for

C₂₆H₃₂Cl₂N₂: 443.5; found: 371.1 [MÀCl^ÀÀHCl]⁺, HRMS (ESI): m/z:

calcd for C₂₆H₃₁N₂: 371.2487; found: 371.2448.

12H), 4.20–4.14 ppm (s, 8H); MS (ESI): m/z: calcd for C₅₆H₆₆Cl₂N₂₆O₁₂

1366.4; found: 1293.6 [MÀCl^ÀÀHCl].

:

Compound 13b: ¹H NMR (500 MHz, D₂O–DCl) d=5.75 (d, J=16 Hz,

12H), 5.6 (s, 12H), 4.32 (d, J=15.5 Hz, 12H), 4.08 (d, J=1.5 Hz, 4H),

3.03–2.97 (m, 6H), 0.8 (brs, 4H), 0.46 ppm (brs, 4H); MS (MALDI-

TOF): m/z: calcd for C₄₈H₅₈Cl₂N₂₆O₁₂: 1262; found: 1190 [MÀCl^ÀÀHCl].

Compound 14b: ¹H NMR (500 MHz, D₂O–DCl) d=5.77 (d, J=15.5 Hz,

12H), 5.60 (s, 12H), 4.35 (d, J=15.5 Hz, 12H), 3.95 (t, J=5.5 Hz, 4H),

3.39 (t, J=5.5 Hz, 4H), 2.99 (t, J=7.5 Hz, 4H), 0.79–0.75 (m, 4H), 0.53–

0.49 ppm (m, 4H); MS (MALDI-TOF): m/z: calcd for C₄₆H₆₀Cl₂N₃₂O₁₂

1324; found: 1251 [MÀCl^ÀÀHCl].

:

Compound 15a:¹H NMR (500 MHz, D₂O–DCl) d=6.65–6.42 (m, 10H),

5.72 (m, 12H), 5.45 (s, 12H), 4.29 (s, 4H), 4.22 (m, 12H), 3.35–3.0 (m,

4H), 2.3–2.1 (m, 4H), 1.8–1.55 ppm (m, 4H).

Compound 15b: ¹H NMR (500 MHz, D₂O–DCl) d=7.72 (brs, 4H), 7.51

(s, 6H), 5.72 (d, J=15.5 Hz, 12H), 5.6 (s, 12H), 4.37 (s, 4H), 4.32 (d, J=

5602

www.chemeurj.org

ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Chem. Eur. J. 2012, 18, 5589 – 5605

Bistable Cucurbituril Rotaxanes

FULL PAPER

Complexes 16b and 17a: Compound 1 (0.01 mmol) was added to a solu-

tion of selected guest (0.01 mmol) in acidic H₂O (25 mL, pH 5–5.5) and

stirred at RT for 16 h. The resulting mixture was filtered and the solvent

of the filtrate was removed under reduced pressure. The residue from the

filtrate was dissolved in H₂O (10 mL), and acetone was added and the re-

sulting precipitate was washed with MeOH and Et₂O to give a 1:1 com-

plex in quantitative yield with respect to the guest.

Compound 16b: ¹H NMR (400 MHz, D₂O–DCl) d=6.53 (brd, J=8 Hz,

4H), 6.28 (m, 1H), 5.73 (m, 2H), 5.71 (d, J=13.6 Hz, 12H), 5.53 (s,

12H), 4.38 (s, 4H), 4.31 (d, J=13.6 Hz, 12H), 4.05 (d, J=6.8 Hz,4H),

8 Hz, 2H), 3.00 ppm (brs, 1H); ¹³C NMR (125 MHz, D₂O–DCl): d=

140.4, 130.1, 128.6, 128.3, 79.1, 73.5, 51, 48.4, 37.6 ppm; HRMS (ESI-

TOF): m/z: calcd for C₁₇H₁₈N: 236.1434; found: 236.1439 [M+H]⁺.

N-(2-azidoethyl)-2,2-diphenylethanamonium chloride (32): A mixture of

diphenyl acetaldehyde (0.5 g, 2.5 mmol), 2-amino-1-azidoethane (18;

0.9 g, 10.2 mmol), sodium triacetoxyborohydride (4.3 g, 20.5 mmol), and

AcOH (0.1 mL) in 1,2-dichloroethane (10 mL) was stirred at RT for 48 h.

Then, a solution of aq NH₄Cl (10 mL) was added and the mixture was ex-

tracted with EtOAc. The combined organic layer was washed with brine,

dried with Na₂SO₄, filtered, and the solvent was removed to afford N-(2-

azidoethyl)diphenylethylimine (650 mg, 2.44 mmol) as a colorless oil. The

crude product was used in the following reaction without further purifica-

tion. The imine was dissolved in CH₂Cl₂(10 mL) and then Et₃N (0.6 mL,

3.66 mmol), (Boc)₂O (640 mg, 2.93 mmol), and DMAP (50 mg) were

added. The reaction mixture was stirred at RT for 48 h and then

quenched with aq NH₄Cl and extracted with CH₂Cl₂. The organic layer

was washed with brine, dried with MgSO₄, filtered, and the solvent was

removed under reduced pressure to afford tert-butyl-2-azidoethyl(diphe-

nylethyl)carbamate after column chromatography (silica gel, hexane/

EtOAc 9:1) as a colorless oil (0.6 g, 66%). ¹H NMR (CDCl₃, 500 MHz):

d=7.3–7.21 (m, 10H), 4.28 (t, J=8 Hz, 1H), 3.90 (d, J=8 Hz, 2H), 3.25

(t, J=5.5 Hz, 2H), 3.06 (t, J=5.5 Hz, 2H), 1.44 ppm (s, 9H); MS (ESI):

m/z: calcd for C₂₁H₂₆N₄O₂: 366.5; found: 389 [M+Na]⁺. Removal of the

Boc protecting group was achieved by following the above-described gen-

eral procedure using tert-butyl-2-azidoethyl(diphenylethyl)carbamate, 4n

HCl, and EtOH. Compound 32 was obtained in quantitative yield as

a white solid. ¹H NMR (500 MHz, D₂O–DCl): d=7.43–7.33 (m, 10H),

4.46 (t, J=8 Hz, 1H), 3.86 (d, J=8 Hz, 2H), 3.73 (t, J=5.5 Hz, 2H),

3.27 ppm (t, J=5.5 Hz, 2H); ¹³C NMR (125 MHz, D₂O–DCl): d=140.6,

130.1, 128.6, 128.3, 51.6, 48.3, 47.3, 47 ppm; MS (ESI): m/z: calcd for

C₁₆H₁₉ClN₄: 302; found: 275 [MÀCl]⁺.

3.12 ppm (s, 3H); MS (MALDI-TOF): m/z: calcd for C₄₈H₅₆Cl₂N₂₆O₁₂

:

1258; found: 1223.2 [MÀCl]⁺, 1187.4 [MÀCl^ÀÀHCl]⁺; HRMS (ESI): m/

z: calcd for C₄₈H₅₅N₂₆O₁₂: 1187.4493; found: 1187.4496.

Compound 17a: ¹H NMR (400 MHz, CDCl₃) d=7.62 (s, 4H), 7.46–7.27

(m, 10H), 5.71 (m+d, J=15.6 Hz, 1H+12H), 5.525 (d, J=3.6 Hz, 1H),

5.36 (s, 12H), 5.33 (d, J=10.2 Hz, 1H), 4.31 (s, 2H), 4.29 (s, 2H), 4.27 (d,

J=3.6 Hz, 12H), 3.58 (d, J=6.4 Hz, 2H) 2.94 (m, 2H), 2.46 ppm (m,

2H).

Preparation of [3]pseudorotaxanes

N,N’-(1,4-phenylenebis(methylene))bis(2-(4-(aminomethyl)-1H-1,2,3-tria-

zol-1-yl)ethan-amine) (29): A mixture of 8a (80 mg, 0.035 mmol) and 18

(9.5 mg, 0.077 mmol) in 3n HCl (10 mL) was stirred at RT for 60 h, and

then the solvent was removed under reduced pressure. The solid residue

was dissolved in H₂O (10 mL) and acetone was added. The resultant pre-

cipitate was collected by filtration and redissolved in H₂O (10 mL) and

MeOH. The resultant precipitate was collected by filtration and found to

be pure 29 as a white solid (75 mg, 95%). ¹H NMR (500 MHz, D₂O–

DCl): d=7.97 (s, 4H), 6.57 (s, 2H), 5.73 (dd, J=15.1 Hz, 24H), 5.51 (s,

24H), 4.56 (s, 4H), 4.34 (s, 4H), 4.28 (dd, J=7.5, 16 Hz, 24H), 4.19 (t,

J=6 Hz, 4H), 3.56 ppm (t, J=6 Hz, 4H); MS (ESI⁺): m/z: calcd for

C₉₀H₁₀₄Cl₄N₅₈O₂₄: 2524; found: 1226 [MÀ2Cl]²⁺; MS (ESI^À): m/z: calcd

for C₉₀H₁₀₆Cl₆N₅₈O₂₄: 2597; found: 1297 [MÀ2H]^2À

.

[2]Rotaxane (33):

A mixture of 31 (13 mg, 0.05 mmol), 32 (15 mg,

N,N’-(1,4-phenylenebis(methylene))bisACTHNUGRTNEUNG(N,N-(2-(aminoethyl)-1H-1,2,3-tria-

0.05 mmol), and 1 (50 mg, 0.05 mmol) in 3n HCl (10 mL) was stirred at

508C for 48 h. Then the water was removed under reduced pressure and

the resultant solid was washed with cold MeOH. The solid was dissolved

in boiling MeOH and filtered. Et₂O was added to the filtrate and the ma-

terial was precipitated and collected through filtration. The rotaxane 33,

was obtained as a white solid (53 mg, 67%). ¹H NMR (500 MHz, D₂O–

DCl): d=7.62–7.24 (m, 20H), 6.38 (s, 1H), 5.64–5.54 (2ꢂd, J=15.5 and

14.5 Hz, 12H), 5.34 (s, 12H), 4.87 (t, J=7.5 Hz, 1H), 4.74 (m, 1H), 4.33

(s, 2H), 4.15 (brt, 12H+4H), 3.97 (t, J=7 Hz, 2H), 3.64 (t, J=7 Hz,

2H).

zol-4,1-diyl) methylamine) (30): The synthesis was performed by using 9a

(68 mg, 0.029 mmol) and propargyl amine (6 mg, 0.065 mmol) by follow-

ing the above-described procedure for the preparation of 29 and gave 30

1

as a white solid (69.5 mg, 95%). H NMR (500 MHz, D₂O–DCl): d=7.86

(s, 4H), 6.55 (s, 2H), 5.72 (2ꢂd, J=15.5, 27.5 Hz, 24H), 5.52 (s, 24H),

4.67 (s, 4H), 4,28 (2ꢂd, J=12 Hz, 24H), 4.21 (t, J=6.5 Hz, 4H), 4.20 (s,

4H), 3.85 ppm (t, J=6.5 Hz, 4H); MS (ESI⁺): m/z: calcd for

C₉₀H₁₀₄Cl₄N₅₈O₂₄: 2524; found: 1226 [MÀ2Cl]²⁺; MS (ESI^À): m/z: calcd

for C₉₀H₁₀₆Cl₆N₅₈O₂₄: 2597; found: 1297 [MÀ2H]^2À

Preparation of [n]rotaxanes

.

[3]Rotaxane (34): Compound 1 (35 mg, 0.035 mmol) was added to a mix-

ture of N,N’-bis-propargyl-p-xylylene diammonium chloride (8; 3.6 mg,

1.25 mmol) and N-(2-azidoethyl)-2,2-diphenylethanamonium chloride (32;

9.5 mg, 0.03 mmol) in 6n HCl (5 mL) and the reaction mixture was

heated at 508C for 48 h. The rotaxane precipitated during the reaction

and was filtered and washed with 6n HCl (2 mL), acetone (5 mL), and

N-(Propargyl)-2,2-diphenylethanamonium chloride (31): Diphenyl acetal-

dehyde (0.25 g, 1.3 mmol), propaygyl amine (82 mg, 1.5 mmol), and 3 ꢃ

molecular sieves (0.5 5 g) in MeOH (5 mL) were stirred at RT for 1 h,

then cooled to 08C, NaBH₄(76 mg, 2 mmol) was added portionwise and

the reaction mixture was stirred for an additional 1 h at RT. To the mix-

ture water was added and filtered. The solid was washed with Et₂O (5ꢂ

10 mL) and combined with the separated organic layer from the filtrate.

The combined organic layers were washed with brine, dried over MgSO4,

filtered and concentrated to afford N-(propargyl)diphenylethylimine

(260 mg, 1.1 mmol) as a pale yellow oil. The crude product was used in

the following reaction without further purification. The imine was dis-

solved in CH₂Cl₂(10 mL) and then Et₃N (0.3 mL, 1.7 mmol), (Boc)₂O

(288 mg, 1.3 mmol), and DMAP (20 mg) were added. The resultant mix-

ture was stirred at RT for 48 h, quenched with aq NH₄Cl and extracted

with CH₂Cl₂. The organic layer was washed with brine, dried over

MgSO₄, filtered, and the solvent was removed under reduced pressure.

tert-Butyl-N-(propargyl)diphenylethylamine was obtained after column

chromatography (silica gel, hexane/EtOAc 9:1) as colorless oil (0.2 g,

55%). ¹H NMR (CDCl₃, 500 MHz): d=7.3–7.2 (m, 10H), 4.35 (m, 1H),

3.98 (d, J=8 Hz, 2H), 3.85–3.68 (brs, 2H), 2.2 (brs, 1H), 1.41 ppm (s,

9H). Removal of Boc protecting group was achieved by following the

above-described general procedure using tert-butyl-N-(propargyl)diphe-

nylethylamine, 4n HCl and EtOH. Compound 31 was obtained in quanti-

tative yield as a white solid. ¹H NMR (500 MHz, D₂O–DCl): d=7.43–

7.35 (m, 10H), 4.45 (t, J=8 Hz, 2H), 3.95 (d, J=2 Hz, 2H), 3.92 (d, J=

Et₂O (5 mL) to afford

a

white solid (3.5 mg, 1.2 mmol). ¹H NMR

(500 MHz, D₂O–DCl): d=7.94 (s, 4H), 7.57 (d, J=7.5 Hz, 8H), 7.43 (t,

J=7.5 Hz, 8H), 7.35 (t, J=7.5 Hz, 4H), 6.5 (s, 2H of Tr), 5.66 (dd, J=3,

15.5 Hz, 24H), 5.48 (s, 24H), 4.73 (t, J=8 Hz, 2H), 4.54 (t, J=6 Hz, 4H),

4.36–4.33 (m, 2H), 4.23 (dd, J=2, 15.5 Hz, 24H), 4.18–4.13 (m, 8H),

3.79 ppm (t, J=7 Hz, 4H); MS (ESI): m/z: calcd for C₁₁₈H₁₃₀Cl₆N₅₈O₂₄

:

2957; found: 1370 [MÀ4HClÀ2Cl]⁺²

.

[3]Rotaxane (35): The synthesis of rotaxane 35 was performed by using

N,N’-bis-(2-azidoethyl)-p-xylylene diammonium chloride (9; 5.8 mg,

1.6 mmol), N-propargyl-2,2-diphenylethanamonium chloride (31; 13.6 mg,

0.05 mmol), and 1 (55 mg, 0.05 mmol) by following the above-described

procedure for the preparation of [3]rotaxane 34, and gave [3]rotaxane 35

as a white solid (4.7 mg, 1.6 mmol). ¹H NMR (500 MHz, D₂O–DCl): d=

7.87 (s, 4H), 7.66 (d, J=7.5 Hz, 8H) 7.38 (t, J=7.5 Hz, 8H), 7.25 (t, J=

7.5 Hz, 4H), 6.44 (s, 2H of Tr), 5.63 (dd, J=15, 69 Hz, 24H), 5.37 (s, 24),

4.88 (t, J=7 Hz, 2H), 4.64 (s, 4H), 4.35 (s, 4H), 4.24–4.07 (m, 28H), 4.08

(t, J=6 Hz, 4H), 7.74 ppm (t, J=6 Hz, 4H); MS (ESI^À): m/z: calcd for

C

₁₁₈H₁₃₀Cl₆N₅₈O₂₄

:

2957; found: 1477 [MÀH]^À, (ESI⁺): 1406

[MÀ2HClÀ2Cl^À]⁺², 926 [MÀ2HClÀ3Cl^À]⁺³

.

Chem. Eur. J. 2012, 18, 5589 – 5605

ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.chemeurj.org

5603

E. Keinan, O. Reany et al.

[16] The overall binding constant, b, is defined as b=K1ꢂK2ꢂ…K_iin

which K_iis the binding constant of the ith ligand (L) to the macro-

molecule (M).

[17] J. Kim, I.-S. Jung, S.-Y. Kim, E. Lee, J.-K. Kang, S. Sakamoto, K. Ya-

maguchi, K. Kim, J. Am. Chem. Soc. 2000 , 122 , 54 0 –5 41.

[18] H.-J. Buschmann, L. Mutihac, E. Schollmeyer, Thermochim. Acta

2009 , 495 , 2 8 –3 2.

Acknowledgements

This study was supported by the Israel Science Foundation, the German–

Israeli Project Cooperation (DIP), the Institute of Catalysis Science and

Technology, Technion, the Open University (to OR) and the Skaggs Insti-

tute for Chemical Biology. EK is the incumbent of the Benno Gitter &

Ilana Ben-Ami Chair of Biotechnology, Technion.

[19] M. V. Rekharsky, Y. Inoue, Chem. Rev. 1998 , 98 , 187 5 –1 917.

[20] a) W. Kauzmann, Adv. Protein Chem. 1959 , 14 , 1 –6 3; b) C. Tanford,

Science 1978 , 200 , 101 2 –1 018.

[21] a) Y. Inoue, T. Hakushi, J. Chem. Soc. Perkin Trans. 2 1985 , 93 5 –

946; b) Y. Inoue, T. Hakushi, Y. Liu in Cation Binding by Macrocy-

cles (Eds.: Y.Inoue, G. W. Gokel) Marcel Dekker, New York, 1990,

Chapter 1.

[22] L. He, J.-P. Zeng, D.-H. Yu, H. Cong, Y.-Q. Zhang, Q.-J. Zhu, S.-F.

Xue, Z. Tau, Supramol. Chem. 2010 , 22 , 61 9 –6 28.

[23] J. Yin, C. Chi, J. Wu, Org. Biomol. Chem. 2010 , 8 , 259 4 –2 599.

[24] E. Masson, X. Lu, X. Ling, D. L. Patchell, Org. Lett. 2009 , 11 , 379 8 –

3801.

[25] A. Arduini, R. Bussolati, A. Credi, G. Faimani, S. Garaugee, A. Po-

chini, A. Secchi, M. Sameraro, S. Silvi, M. Venturi, Chem. Eur. J.

2009 , 15 , 323 0 –3 242.

[26] R. G. E. Coumans, J. A. A. W. Elemans, R. J. M. Nolte, A. E.

Rowan, Proc. Natl. Acad. Sci. USA 2006, 103, 19647–19651.

[27] a) S. D. Choudhury, J. Mohanty, H. P. Upadhyaya, A. C. Bhasikut-

tan, H. Pal, J. Phys. Chem. B 2009, 113, 1891–1898; b) S. D. Choud-

hury, J. Mohanty, H. Pal, A. C. Bhasikuttan, J. Am. Chem. Soc. 2010 ,

132 , 139 5 –1 401.

[28] R.-G. Lin, L.-S. Long, R.-B. Huang, L.-S. Zheng, Cryst. Growth Des.

2008 , 8 , 79 1 –7 94.

[29] D. G. Samsonenko, A. V. Virovets, J. Lipkowski, O. A. Gerasꢀko,

V. P. Fedin, J. Struct. Chem. 2002 , 43 , 66 4 –6 68 and references cited

therein.

[1] a) T. D. Nguyen, H.-R. Tseng, P. C. Celestre, A. H. Flood, Y. Liu,

J. F. Stoddart, J. I. Zink, Proc. Natl. Acad. Sci. USA 2005 , 102 ,

1002 9 –1 0034; b) S. Angelos, Y.-W. Yang, K. Patel, J. F. Stoddart,

J. I. Zink, Angew. Chem. 2008 , 120 , 225 4 –2 258; Angew. Chem. Int.

Ed. 2008 , 47 , 222 2 –2 226; c) N. M. Khashab, M. E. Belowich, A. Tra-

bolsi, D. C. Friedman, C. Valente, Y. Lau, H. A. Khatib, J. I. Zink,

J. F. Stoddart, Chem. Commun. 2009 , 537 1 –5 373; d) N. M. Khashab,

A. Trabolsi, Y. A. Lau, M. W. Ambrogio, D. C. Friedman, H. A.

Khatib, J. I. Zink, J. F. Stoddart, Eur. J. Org. Chem. 2009 , 166 9 –

1673; e) S. Angelos, N. M. Khashab, Y.-W. Yang, A. Trabolsi, H. A.

Khatib, J. F. Stoddart, J. I. Zink, J. Am. Chem. Soc. 2009 , 131 ,

1291 2 –1 2916; f) K. K. Coti, M. E. Belowich, M. Liong, M. W. Am-

brogio, Y. A. Lau, H. A. Khatib, J. I. Zink, J. F. Stoddart, Nanoscale

2009, 1, 16–39; g) M. W. Ambrogio, T. A. Pecorelli, K. Patel, N. M.

Khashab, A. Trabolsi, H. A. Khatib, Y. Y. Botros, J. I. Zink, J. F.

Stoddart, Org. Lett. 2010 , 12 , 330 4 –3 307; h) C. R. Thomas, D. P.

Ferris, J.-H. Lee, E. Choi, M. H. Cho, E. S. Kim, J. F. Stoddart, J.-S.

Shin, J. Cheon, J. I. Zink, J. Am. Chem. Soc. 2010 , 132 , 1062 3 –

10625.

[2] I. Ben Shir, S. Sasmal, T. Mejuch, M. K. Sinha, M. Kapon, E.

Keinan, J. Org. Chem. 2008 , 73 , 877 2 –8 779.

[3] G. Parvari, O. Reany, E. Keinan, Isr. J. Chem. 2011 , 51 , 64 6 –6 63.

[4] a) K. Kim, Chem. Soc. Rev. 2002 , 31 , 9 6 –1 07; b) I. W. Wyman, D. H.

Macartney, Org. Biomol. Chem. 2009 , 7 , 404 5 –4 051; <lit c>S.

Moghaddam, C. Yang, M. Rekharskey, Y. H. Ko, K. Kim, Y. Inoue,

M. K. Gilson, J. Am. Chem. Soc. 2011 , 133 , 357 0 –3 581; d) H.-J.

Buschmann, Isr. J. Chem. 2011 , 51 , 53 3 –5 36; e) Y.-H. Ko, I. Hwang,

D.-W. Lee, K. Kim, Isr. J. Chem. 2011 , 51 , 50 6 –5 14.

[5] K. M. Park, S.-Y. Kim, J. Heo, D. Whang, S. Sakamoto, K. Yamagu-

chi, K. Kim, J. Am. Chem. Soc. 2002 , 124 , 214 0 –2 147.

[6] a) K. M. Park, J. Heo, S.-G. Roh, Y.-M. Jeon, D. Whang, K. Kim,

Mol. Cryst. Liq. Cryst. 1999, 327, 65–70; b) J. Heo, S.-Y. Kim, S.-G.

Roh, K. M. Park, G. J. Park, D. Whang, K. Kim, Mol. Cryst. Liq.

Cryst. 2000, 342, 29–38.

[7] a) W. L. Mock, N.-Y. Shin, J. Org. Chem. 1986 , 51 , 444 0 –4 446;

b) W. L. Mock, N. Y. Shin, J. Am. Chem. Soc. 1988 , 110 , 470 6 –4 710;

c) W. L. Mock, T. A. Irra, P. Wepsiec, M. Adhya, J. Org. Chem.

1989 , 54 , 530 2 –5 308; d) W. L. Mock, Top. Curr. Chem. 1995 , 175 , 1 –

24; e) M. V. Rekharsky, Y.-H. Ko. N. Selvapalam, K. Kim, Y. Inoeu,

Supramol. Chem. 2007 , 19 , 3 9 –4 3.

[8] S.-Y. Kim, J. W. Lee, S. C. Han, K. Kim, Bull. Korean Chem. Soc.

2005, 26, 1265–1268.

[9] a) W. A. Freeman, Acta Crystallogr., Sect. B 1984 , 40 , 38 2 –3 87;

b) W.-H. Huang, P. Y. Zavalij, L. Isaacs, Acta Crystallogr., Sect. E

2008 , 64 , o132 1 –o 1322.

[30] L. J. Farrugia, J. Appl. Crystallogr. 1999 , 32 , 83 7 –8 38. The calcula-

tions were made using WinGX program version 1.80.05, which is

based on the article principles.

[31] a) R. Huisgen, Angew. Chem. 1968 , 80 , 32 9 –3 37; Angew. Chem. Int.

Ed. Engl. 1968 , 7 , 32 1 –3 28; b) R. Huisgen in 1,3-Dipolar Cycloaddi-

tion Chemistry, (Ed.: A. Padwa), Wiley, New York, 1984; c) K. V.

Gothelf, K. A. Jorgensen, Chem. Rev. 1998 , 98 , 86 3 –8 90.

[32] a) For a recent review on the click reaction and its applications see

a special issue on the topic: Click chemistry: Function follows form:

Chem. Soc. Rev. 2010, 39, Issue 4; b) R. K. Iha, K. L. Wooley, A. M.

Nystrom, D. J. Burke, C. J. Kade, Chem. Rev. 2009 , 109 , 562 0 –5 686;

c) J. E. Moses, A. D. Moorhouse, Chem. Soc. Rev. 2007 , 36 , 124 9 –

1262.

[33] W. L. Mock, T. A. Irra, J. P. Wepsiec, T. L. Manimaran, J. Org.

Chem. 1983 , 48 , 361 9 –3 620.

[34] a) D. Tuncel, O. Ozsar, H. B. Tiftik, B. Salih, Chem. Commun. 2007 ,

136 9 –1 371; b) L. Yuan, R. Wang, D. H. Macartney, J. Org. Chem.

2007 , 72 , 453 9 –4 542; c) D. Tuncel, J. H. G. Steinke, Chem. Commun.

2002 , 49 6 –4 97; d) J. W. Lee, K. Kim, K. Kim, Chem. Commun. 2001,

1042–1043; e) S. I. Jun, J. W. Lee, S. Sakamoto, K. Yamaguchi, K.

Kim, Tetrahedron Lett. 2000, 41, 471–475.

[35] D. Tuncel, O. Unal, M. Artar, Isr. J. Chem. 2011 , 51 , 52 5 –5 32.

[36] a) D. Tuncel, H. B. Tiftik, B. Salih, J. Mater. Chem. 2006 , 16 , 329 1 –

3296; b) D. Tuncel, J. H. G. Steinke, Chem. Commun. 2001 , 25 3 –

254; c) C. Meschke, H.-J. Buschmann E. Schollmeyer, Macomol.

Rapid Comm. 1998 , 19 , 5 9 –6 3; d) C. Meschke, H.-J. Buschmann E.

Schollmeyer, Polymer 1999 , 40 , 94 5 –9 49.

[10] a) H. Cong, Y.-J. Zhao, S.-F. Xue, Z. Tao, Q.-J. Zhu, J. Mol. Model.

2007 , 13 , 122 1 –1 226; b) Z. Limei, Z. Jiannan, Z. Yunqian, Z. Qian-

jiang, X. Saifen, Z. Tao, Z. Jianxin, Z. Xin, W. Zhanbin, L. Lasheng,

A. I. Day, Supramol. Chem. 2008 , 20 , 70 9 –7 16; c) Y. Zhao, S. Xue,

Q. Zhu, Z. Tao, J. Zhang, Z. Wei, L. Long, M. Hu, H. Xiao, A. I.

Day, Chin. Sci. Bull. 2004 , 49 , 111 1 –1 116.

[37] D. Tuncel, M. Katterle, Chem. Eur. J. 2008 , 14 , 411 0 –4 116.

[38] E. Slonkina, A. B. Kolomeisky, J. Chem. Phys. 2003 , 118 , 711 2 –

7118.

[11] M. K. Sinha, O. Reany, G. Parvari, A. Karmakar, E. Keinan, Chem.

Eur. J. 2010 , 16 , 905 6 –9 067.

[39] A. Meller, L. Nivon, D. Branton, Phys. Rev. Lett. 2001 , 86 , 343 5 –

3438.

[12] H. C. Kolb, M. G. Finn, K. B. Sharpless, Angew. Chem. 2001 , 113 ,

205 6 –2 075; Angew. Chem. Int. Ed. 2001 , 40 , 200 4 –2 021.

[40] A. B. C. Deutman, C. Monnereau, J. A. A. W. Elemans, G. Ercolani,

R. J. M. Nolte, A. E. Rowan, Science 2008 , 322 , 166 8 –1 671.

[41] X. Ling, E. L. Samuel, D. L. Patchell, E. Masson, Org. Lett. 2010 ,

12 , 273 0 –2 733.

[13] D. Tuncel, J. H. G. Steinke, Macromolecules 2004 , 37 , 28 8 –3 02.

[14] W. L. Mock in Comprehensive Supramolecular Chemistry, Vol 2

(Ed.: F. Vçgtle), Pergamon, Oxford, 1996, p. 477.

[15] W. M. Nau, M. Florea, K. I. Assaf, Isr. J. Chem. 2011 , 51 , 55 9 –5 77.

5604

www.chemeurj.org

ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Chem. Eur. J. 2012, 18, 5589 – 5605

Bistable Cucurbituril Rotaxanes

FULL PAPER

[42] a) C. Mꢄrquez, W. M. Nau, Angew. Chem. 2001, 113, 3248–3254;

Angew. Chem. Int. Ed. 2001, 40, 3155–3160; b) C. Mꢄrquez, R. R.

Hudgins, W. M. Nau, J. Am. Chem. Soc. 2004, 126, 5806–5816.

[43] a) M. M. McEvoy, A. C. Hausrath, G. B. Randolph S. J. Remington,

F. W. Dahlquist, Proc. Natl. Acad. Sci. USA 1998 , 95 , 733 3 –7 338;

b) S. Feng, T. Bein, Science 1994 , 265 , 183 9 –1 841.

refinement of crystal structures from diffraction data”, University of

Glasgow, Scotland, UK, Nonius BV, Delft, The Netherlands and

MacScience, Yokohama, Japan, 1998.

[47] G. M. Sheldrick, 1997. SHELXL97. Program for the refinement of

crystal structures, University of Gottingen, Germany.

[44] KappaCCD Server Software. Nonius BV, 1997, Delft, Netherlands.

[45] Z. Otwinowski, W. Minor, Methods Enzymol. 1997 , 276 , 307.

[46] S. Mackay, C. J. Gilmore, C. Edwards, M. Tremayne, N. Stuart, K.

Shankland, M. A. Xus “A computer program for the solution and

Received: November 1, 2011

Published online: March 20, 2012

Chem. Eur. J. 2012, 18, 5589 – 5605

ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.chemeurj.org

5605

Article Doi

Bistable cucurbituril rotaxanes without stoppers

DOI: 10.1002/chem.201103434

Source and publish data:

Authors:

Article abstract of DOI:10.1002/chem.201103434

Full text of DOI:10.1002/chem.201103434

Products guided by the article

R&D Labs maybe for 1047626-95-8

Relevant to this article

Hot Product