Solvent-Free Synthesis of the Smallest Rotaxane Prepared to Date

Supramolecular Chemistry

DOI: 10.1002/ange.200803056

Solvent-Free Synthesis of the Smallest Rotaxane Prepared to Date**

Chi-Chieh Hsu, Nai-Chia Chen, Chien-Chen Lai, Yi-Hung Liu, Shie-Ming Peng, and

Sheng-Hsien Chiu*

[2]Rotaxanes—supermolecules comprising interlocked

mac-rocyclic and dumbbell-shaped components—are fascinating

materials for the construction of molecular devices because of

the machinelike movement of their constituent parts.

[1]

_The

development of efficient,convenient,and environmentally

friendly methods for the synthesis of these functional

interlocked molecules has progressed tremendously in the

past decade.

[2]

_{We became interested,however,in answering}

the following fundamental question: What is the smallest

[2]rotaxane that can be synthesized,either in terms of

molecular weight or the number of constituent atoms? We

identified the crown ether/secondary dialkylammonium ion

pair,which can be simplified into a few repeating CH

2

CH

2

O

units that encircle a threadlike component as small as a

dimethylammonium (CH

3

NH

2

+

CH

3

) ion,as the simplest and

smallest recognition system for preparing [2]rotaxanes.

Herein,we report a new and efficient solvent-free reaction

which involves ball-milling of the [2]pseudorotaxane formed

from dipropargylammonium tetrafluoroborate and the crown

ether [21]crown-7 (21C7) on SiO

2

with 1,2,4,5-tetrazine. This

led to the isolation in high yield (81 %) of the smallest

[2]rotaxane reported to date (Scheme 1).

Although it has been postulated for some time that

macrocycles possessing 21 or more atoms in their ring will be

able to accommodate an alkyl chain,

[3]

_{it was only recently}

reported that a secondary dialkylammonium ion could be

threaded through a 21-membered ring macrocycle,namely

benzo[21]crown-7 (B21C7).

[4]

_{In addition,a phenyl group can}

act as the stopper that prevents the unthreading of the

interlocked ring-shaped and linear components when this

small macrocycle is used. We proposed that Diels–Alder

reactions of 1,2,4,5-tetrazine

[5]

_{with the terminal alkyne units}

of a 21C7-based [2]pseudorotaxane would produce pyridazine

end groups,which are slightly less bulky than phenyl groups,

and might also function as stoppers in a 21C7-containing

[2]rotaxane. We chose the dipropargylammonium ion (1-H

+

₎

as the alkyne-terminated linear component in the small

[2]pseudorotaxane

precursor,expecting

its

small

CH

2

NH

2

+

CH

2

unit to reside within the cavity of the crown

ether 21C7,stabilized through N

+

_{H···O and C H···O}

hydro-gen bonds. The alkyne termini are available for

functional-ization (Scheme 1) through Diels–Alder reactions with

1,2,4,5-tetrazine to generate small, but nevertheless

suffi-ciently bulky,pyridazine rings for stoppering the

pseudoro-taxanes under solvent-free conditions.

The

1

_{H NMR spectrum (Figure 1 b) of an equimolar}

(5 mm) mixture of 21C7 and 1-H·BF

4

in CD

3

CN at room

temperature shows the chemical shifts of the protons of the

complex are significantly different from those of its free

components. The appearance of broad signals for both the

free and complexed thread 1-H·BF

4

in the

1

H NMR spectrum

(Figure 1 c) of a 1:2 molar ratio mixture of 21C7 and 1-H·BF

4

in CD

3

CN suggested that the rates of exchange during the

complexation and decomplexation processes were slow on the

1

_{H NMR spectroscopic timescale at 400 MHz under these}

conditions,but not sufficiently slow to provide the sharp

signals required to obtain an accurate value for the

associa-tion constant through the single-point method.

[6]

_Instead,we

used isothermal titration calorimetry (ITC)

[7]

_{to determine an}

association constant of (14 000

 1300) m

1

_{for the formation}

of the [2]pseudorotaxane from 21C7 and 1-H·BF

4

in CH

3

CN

at 25 8C.

[8]

Concentration of an equimolar solution of the macrocycle

21C7 and the threadlike ion 1-H·BF

4

gave a sticky liquid,

which we presumed to contain predominately the

[2]pseudor-otaxane [(21C71-H)·BF

4

].

[9]

To facilitate ball-milling in the

solid state,we added silica gel to an equimolar solution of

21C7 and 1-H·BF

4

in CH

3

CN and evaporated the solvent,

thereby anticipating the solid support to be coated with the

Scheme 1.

[*] C.-C. Hsu, N.-C. Chen, Y.-H. Liu, Prof. S.-M. Peng, Prof. S.-H. Chiu Department of Chemistry, National Taiwan University

No. 1, Sec. 4, Roosevelt Road, Taipei (Taiwan, ROC) Fax: (+ 886) 2-3366-1677

E-mail: shchiu@ntu.edu.tw

Homepage: http://www.ch.ntu.edu.tw/english/efaculty/people/ chiu-eng.html

Prof. C.-C. Lai

Institute of Molecular Biology, National Chung Hsing University and Department of Medical Genetics

China Medical University Hospital Taichung (Taiwan, ROC)

[**] We thank Dr. Peter T. Glink for helpful discussions and the National Science Council (Taiwan) for financial support (NSC-95-2113M-002-016-MY3).

Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/anie.200803056.

Angewandte

Chemie

7585

[2]pseudorotaxane. Grinding the solid mixture of the

[(21C71-H)·BF

4

]-coated silica gel and 1,2,4,5-tetrazine for

1 h,followed by heating the resulting well-mixed solid at

353 K for 12 h,gave the [2]rotaxane 2-H·BF

4

in 30 % yield.

The presence of red crystals of 1,2,4,5-tetrazine on the neck of

the reaction flask suggested that its facile sublimation was

responsible for the low yield of the reaction. Thus,to avoid

loss of 1,2,4,5-tetrazine during the heating process and

thereby increase the yield of this small [2]rotaxane,we

turned our attention to performing the stoppering reactions

under solid-to-solid ball-milling conditions of a 1:2.2 mixture

of the [2]pseudorotaxane complex [(21C71-H)·BF

4

] on SiO

2

and 1,2,4,5-tetrazine at ambient temperature. To monitor this

process,we dissolved portions of the solid reaction mixture in

CD

3

CN,filtered off the SiO

2

,and then recorded

1

H NMR

spectra. Over time,a new set of signals appeared with

increasing intensity (Figure 2). After ball-milling for 9 h,

these signals were predominant (Figure 2 f); at this point,we

extracted the product and obtained the [2]rotaxane 2-H·BF

4

in 81 % yield.

[10]

_{The reaction between 21C7,the threadlike}

salt 1-H·BF

4

, and 1,2,4,5-tetrazine (20:20:44 mm) did not

proceed as efficiently in solution (CD

3

CN,333 K) as it did

through ball-milling;

1

_{H NMR spectroscopy showed that the}

reaction was relatively slow and produced a complicated

mixture after 60 h (see the Supporting Information).

We obtained single crystals suitable for X-ray

crystallog-raphy after liquid diffusion of isopropyl ether into a solution

of the [2]rotaxane 2-H·BF

4

in methanol.

[11,12]

The solid-state

structure in Figure 3 reveals the expected [2]rotaxane

geom-etry,in which the threadlike unit is penetrated through the

21-membered ring,with the CH

2

NH

2

+

protons hydrogen bonded

to the oxygen atoms of the macrocyclic unit.

The

1

_{H NMR spectrum of a mixture of the [2]rotaxane}

2-H·BF

4

and threadlike salt 1-H·BF

4

in CD

3

CN (5 mm : 5 mm) at

298 K (Figure 4 b) corresponds to the superimposition of the

two spectra (Figure 4 a,c) of the two separate components,

which suggests that no free 21C7 was present in the solution

and supports the constitutional authenticity and integrity of

the [2]rotaxane 2-H·BF

4

. We detected no signals for the free

components in the

1

_{H NMR spectrum (see the Supporting}

Information) obtained after heating a solution of the

[2]rotaxane 2-H·BF

4

in CD

3

SOCD

3

at 323 K for 2 h,thus

confirming the interlocked nature of the two components.

To the best of our knowledge, 2-H·BF

4

is the smallest

[2]rotaxane reported to date. The cationic portion of the

rotaxane (C

24

H

40

O

7

N

5

) comprises only 76 atoms (27 and 49

for the dumbbell-shaped and macrocyclic components,

respectively); its molecular weight is 510 Da. In comparison,

two macrocycles used frequently to create interlocked

molecules,cyclobis(paraquat-p-phenylene)

4+ [13]

_{and the}

mac-rocycle developed by Leigh and co-workers,

[14]

_{have 72 and 68}

Figure 1. 1_{H NMR spectra (400 MHz, CD}

3CN, 298 K) of a) 21C7, b) an

equimolar mixture of 21C7 and 1-H·BF4(5 mm), c) a mixture of 21C7

(5 mm) and 1-H·BF4(10 mm), and d) 1-H·BF4. (c) = complexed and

(uc) = uncomplexed states of the components.

Figure 2. Partial1_{H NMR spectra (400 MHz, CD}

3CN, 298 K) that show

the formation of the [2]rotaxane 2-H·BF4from the pseudorotaxane

[(21C71-H)·BF4] after solid-state ball-milling for a) 0.5, b) 1, c) 2,

d) 4, e) 7, and f) 9 h; g) spectrum of purified 2-H·BF4.

Figure 3. a) Ball-and-stick (side view) and b) space-filling (top view) representations of the solid-state structure of the [2]rotaxane 2-H+_.

Atom labels: C, gray; H, yellow; O, orange; N, blue. Hydrogen-bond geometries, X···O, H···O [G], and X H···O [8]: a) 2.86, 1.99, 160.6; b) 2.89, 2.01, 163.0; c) 3.19, 2.28, 154.9; d) 3.23, 2.38, 145.2; e) 3.44, 2.67, 136.0.

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atoms,respectively,and molecular masses of 520 and 532 Da,

respectively,making them heavier than the [2]rotaxane 2-H

+

even in the absence of guest molecules. Two other simple

molecular recognition systems,dibenzo[24]crown-8/1,

2-bis-(pyridinium)ethane

2+ [15]

_and

bis-p-xylyl[26]crown-6/N-methyl-4-methylpyridinium

+[16]

_{have 92 and 80}

atoms,respec-tively,and molecular masses of 634 and 524 Da,respectively,

which suggests that their interlocked versions would certainly

be larger and heavier than the [2]rotaxane 2-H

+

. We will test

our knowledge of supramolecular chemistry and synthetic

skills by continuing the search for the worldEs smallest

rotaxane. Maybe a macrocycle containing less than 21 atoms

will be capable of threading guests?

[17]

_{Maybe an isopropyl}

group,which is lighter and contains fewer atoms than the

pyridazine ring,could act as a stopper? Like athletes striving

to achieve Olympic ideals—citius (swifter), altius (higher),

fortius (stronger)—chemists have a new challenge when it

comes to synthesizing [2]rotaxanes: minimus (smallest)!

Experimental Section

General method for the ball-milling process: Ball-milling was performed using a Retsch MM 200 swing-mill,containing two 5 mL stainless steel cells and two stainless steel balls (diameter: 7 mm); the mill was operated at a frequency of 22.5 Hz at room temperature. [2]Rotaxane 2-H·BF4: Silica gel (135 mg) was added to a solution

of 21C7 (86 mg,280 mmol) and the threadlike salt 1-H·BF4(50 mg,

280 mmol) in CH3CN (5 mL). The solvent was evaporated under

reduced pressure to afford a white solid,which was mixed with 1,2,4,5-tetrazine (50 mg, 610 mmol) and ball-milled at room temper-ature for 9 h. The resulting solid was washed with MeCN (25 mL) and then the organic solution was concentrated to afford a solid,which was dissolved in CH2Cl2(20 mL) and extracted with H2O (3 G 20 mL).

The aqueous layer was collected and concentrated to afford the [2]rotaxane 2-H·BF4 as a brown solid (134 mg,81 %). M.p. 148–

149 8C;1_{H NMR (400 MHz,CD}

3CN): d = 3.52 (s,28 H),4.72 (t,J =

6 Hz,4 H),7.69 (dd,J = 5,2 Hz,2 H),7.95–8.15 (br,2 H),9.26– 9.31 ppm (m,4 H);13_{C NMR (100 Hz,CD}

3CN): d = 49.2,71.7,128.5,

132.2,152.4,153.2 ppm; HRMS (ESI): m/z calcd for [2-H]+

(C24H40N5O7): 510.2922; found: 510.2928.

Received: June 25,2008

Published online: August 28,2008

.

Keywords: Diels–Alder reaction · host–guest systems ·

pyridazine · rotaxanes · solvent-free synthesis

[1] a) Molecular Electronics:Science and Technology (Eds.: A. Aviram,M. Ratner),New York Academy of Sciences,New York, 1998; b) H. Yu,Y. Luo,K. Beverly,J. F. Stoddart,H.-R. Tseng,J. R. Heath,Angew. Chem. 2003, 115,5884 – 5889; Angew. Chem. Int. Ed. 2003, 42,5706 – 5711; c) J. W. Choi,A. H. Flood, D. W. Steuerman,S. Nygaard,A. B. Braunschweig,N. N. P. Moonen,B. W. Laursen,Y. Luo,E. DeIonno,A. J. Peters,J. O. Jeppesen,K. Xu,J. F. Stoddart,J. R. Heath,Chem. Eur. J. 2006, 12,261 – 279; d) J. E. Green,J. W. Choi,A. Boukai,Y. Bunimo-vich,E. Johnston-Halperin,E. DeIonno,Y. Luo,B. A. Sheriff,K. Xu,Y. S. Shin,H.-R. Tseng,J. F. Stoddart,J. R. Heath,Nature 2007, 445,414 – 417.

[2] For reviews,see: a) M. C. T. Fyfe,J. F. Stoddart,Adv. Supramol. Chem. 1999, 5,1 – 53; b) S. J. Rowan,S. J. Cantrill,G. R. L. Cousins,J. K. M. Sanders,J. F. Stoddart,Angew. Chem. 2002, 114,938 – 993; Angew. Chem. Int. Ed. 2002, 41,898 – 952; c) E. R. Kay,D. A. Leigh,Top. Curr. Chem. 2005, 262,133 – 177; d) F. Huang,H. W. Gibson,Prog. Polym. Sci. 2005, 30, 982 – 1018; e) J. BernL,G. Bottari,D. A. Leigh,E. M. Perez, Pure Appl. Chem. 2007, 79,39 – 54; f) B. Champin,P. Mobian,J.-P. Sauvage, Chem. Soc. Rev. 2007, 36,358 – 366; g) K. E. Griffiths,J. F. Stoddart,Pure Appl. Chem. 2008, 80,485 – 506. [3] a) I. T. Harrison, J. Chem. Soc. Chem. Commun. 1972,231 – 232; b) G. Schill, Catenanes, Rotaxanes and Knots,Academic Press, New York, 1971; c) G. Schill,W. Beckmann,W. Vetter,Chem. Ber. 1980, 113,941 – 954; d) G. Schill,W. Beckmann,N. Schweickert,H. Fritz,Chem. Ber. 1986, 119,2647 – 2655. [4] C. Zhang,S. Li,J. Zhang,K. Zhu,N. Li,F. Huang,Org. Lett.

2007, 9,5553 – 5556.

[5] J. Sauer,D. K. Heldmann,J. Hetzenegger,J. Krauthan,H. Sichert,J. Schuster,Eur. J. Org. Chem. 1998,2885 – 2896. [6] For a description of the single-point method,see: a) P. R.

Ashton,E. J. T. Chrystal,P. T. Glink,S. Menzer,C. Schiavo,N. Spencer,J. F. Stoddart,P. A. Tasker,A. J. P. White,D. J. Wil-liams, Chem. Eur. J. 1996, 2,709 – 728; b) P. R. Ashton,M. C. T. Fyfe,S. K. Hickingbottom,J. F. Stoddart,A. J. P. White,D. J. Williams, J. Chem. Soc. Perkin Trans. 2 1998,2117 – 2124. [7] For examples of the use of ITC methods to obtain association

constants for pseudorotaxane complexes,see: a) A. B. Braunschweig,C. M. Ronconi,J.-Y. Han,F. Arico,S. J. Cantrill, J. F. Stoddart,S. I. Khan,A. J. P. White,D. J. Williams,Eur. J. Org. Chem. 2006, 8,1857 – 1866; b) Y. Liu,C.-J. Li,H.-Y. Zhang, L.-H. Wang,X.-Y. Li,Eur. J. Org. Chem. 2007,4510 – 4516. [8] The values of binding stoichiometry (N),entropy (DS8),and

enthalpy (DH8) for the complexation were determined to be (1.05 0.02),( 2.51  0.40) cal mol 1_K 1_{,and ( 6420}

120) cal mol1_{,respectively,based on the mean results of three}

independent titrations. The errors are reported as standard deviations from the mean.

[9] A similar method has been used to generate pseudorotaxanes as solids for the efficient synthesis of [2]- and [4]rotaxanes; see: S.-Y. Hsueh,K.-W. Cheng,C.-C. Lai,S.-H. Chiu,Angew. Chem. 2008, 120,4508 – 4511; Angew. Chem. Int. Ed. 2008, 47,4436 – 4439.

[10] For the possible mechanism of this reaction,see: M. D. Helm, J. E. Moore,A. Plant,J. P. A. Harrity,Angew. Chem. 2005, 117, Figure 4.1

H NMR spectra (400 MHz, CD3CN, 298 K) of a) [2]rotaxane

2-H·BF4; b) an equimolar mixture of 2-H·BF4and the threadlike salt

1-H·BF4(both 5 mm), and c) 1-H·BF4.

Angewandte

Chemie

7587

3957 – 3960; Angew. Chem. Int. Ed. 2005, 44,3889 – 3892,and ref. [5].

[11] CCDC 692638 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc. cam.ac.uk/data_request/cif.

[12] Crystal data for [2-H·BF4]: [C24H40O7N5][BF4]; Mr=597.42;

triclinic; space group P1¯; a = 15.8676(12); b = 16.8825(12); c = 22.8223(16) Q; V = 5987.7(7) Q3_{; 1}

calcd=1.325 g cm 3_{; m(Mo}

Ka) =

0.963 mm1_{; T = 250(2) K; colorless cubes; 21 316 independent}

measured reflections; F2_{refinement; R}

1=0.0923; wR2=0.2292.

[13] a) B. Odell,M. V. Reddington,A. M. Z. Slawin,N. Spencer,J. F. Stoddart,D. J. Williams,Angew. Chem. 1988, 100,1605 – 1608; Angew. Chem. Int. Ed. Engl. 1988, 27,1547 – 1550; b) R. A. Bissell,E. Cordova,A. E. Kaifer,J. F. Stoddart,Nature 1994, 369,133 – 137; c) O. S. Miljanic,J. F. Stoddart,Proc. Natl. Acad. Sci. USA 2007, 104,12966 – 12970.

[14] a) A. G. Johnston,D. A. Leigh,A. Murphy,J. P. Smart,M. D. Deegan, J. Am. Chem. Soc. 1996, 118,10662 – 10663; b) W. Clegg,C. Gimenez-Saiz,D. A. Leigh,A. Murphy,A. M. Z.

Slawin,S. J. Teat,J. Am. Chem. Soc. 1999, 121,4124 – 4129; c) E. R. Kay,D. A. Leigh,Pure Appl. Chem. 2008, 80,17 – 29. [15] a) S. J. Loeb,J. A. Wisner,Chem. Commun. 1998,2757 – 2758; b) D. J. Hoffart,S. J. Loeb,Angew. Chem. 2005, 117,923 – 926; Angew. Chem. Int. Ed. 2005, 44,901 – 904; c) S. J. Vella,J. Tiburcio,S. J. Loeb,Chem. Commun. 2007,4752 – 4754. [16] a) P.-N. Cheng,C.-F. Lin,Y.-H. Liu,C.-C. Lai,S.-M. Peng,S.-H.

Chiu, Org. Lett. 2006, 8,435 – 438; b) Y.-L. Huang,C.-F. Lin,P.-N. Cheng,C.-C. Lai,Y.-H. Liu,S.-M. Peng,S.-H. Chiu, Tetrahedron Lett. 2008, 49,1665 – 1669; c) N.-C. Chen,C.-C. Lai,Y.-H. Liu,S.-M. Peng,S.-H. Chiu,Chem. Eur. J. 2008, 14, 2904 – 2908.

[17] It has been suggested that an alkyl chain might be capable of threading through bis(m-phenylene)[20]crown-6 (a 20-mem-bered ring macrocycle); see: a) H. W. Gibson,D. S. Nagvekar, N. Yamaguchi,S. Bhattarcharjee,H. Wang,M. Vergne,D. M. Hercules, Macromolecules 2004, 37,7514 – 7529; b) Ref. [4]; note,however,that this macrocycle is heavier and comprises more atoms than 21C7.

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