Mild and high-yielding syntheses of diethyl phosphoramidate-stoppered [2]rotaxanes

Article abstract of DOI:10.1021/ol0484557

(Chemical Equation Presented) The mild and efficient reaction between triethyl phosphite and benzylic azides allows us not only to construct rotaxanes in high yield from dibenzo[24]crown-8 (DB24C8) and dibenzylammonium (DBA+)-derived threads but also to i

Full text of DOI:10.1021/ol0484557

ORGANIC
LETTERS
2004
Vol. 6, No. 23
4183-4186
Mild and High-Yielding Syntheses of
Diethyl Phosphoramidate-Stoppered
[2]Rotaxanes†
Wei-Chung Hung, Kang-Shyang Liao, Yi-Hung Liu, Shie-Ming Peng,* and
Sheng-Hsien Chiu*
Department of Chemistry, National Taiwan UniVersity, No. 1, Sec. 4, RooseVelt Road,
Taipei, Taiwan, 10617, R.O.C.
shchiu@ntu.edu.tw
Received August 4, 2004
ABSTRACT
The mild and efficient reaction between triethyl phosphite and benzylic azides allows us not only to construct rotaxanes in high yield from
+
dibenzo[24]crown-8 (DB24C8) and dibenzylammonium (DBA )-derived threads but also to incorporate di(p-toluidine)[24]crown-8, which binds
+
DBA ions much more weakly than does DB24C8, into a corresponding [2]rotaxane.
Mechanically interlocked molecules continue to attract a great
deal of attention because of the growing realization that these
materials can be used to develop mesoscale devices1 and
artificial molecular machinery2 on the nanoscale, and, hence,
it remains necessary to devise new synthetic methods for
their construction. Rotaxanes,3 which are a class of mechani-
cally interlocked molecules that comprise one or more
macrocyclic units trapped along the rodlike moiety of a
dumbbell-shaped component, have been prepared as proto-
typical molecular switches4 and linear molecular motors.2b-d
Among the many synthetic approaches for the construction
of rotaxanes,5 the threading-followed-by-stoppering protocol
is one of the most straightforward, especially when combined
with the simple recognition motif provided by the dibenzo-
[24]crown-8 (DB24C8)/dibenzylammonium cation (DBA+)
system,6 which has formed the basis of many diverse
interlocked molecular structures.7 Although the strong non-
covalent interactions between DB24C8 and DBA+ allow the
near-quantitative formation of pseudorotaxane8 complexes
in relatively nonpolar solvents, there are still only a limited
(4) (a) Balzani, V.; Credi, A.; Raymo, F. M.; Stoddart, J. F. Angew.
Chem., Int. Ed. 2000, 39, 3348-3391. (b) Molecular Switches; Feringa, B.
L., Ed.; VCH-Wiley: Weinheim, 2001. (c) Liu, Y.; Flood, A. H.; Stoddart,
J. F. J. Am. Chem. Soc. 2004, 126, 9150-9151.
† In memory of Dr. Norma A. Stoddart.
(1) (a) Molecular Electronics: Science and Technology; Aviram, A.,
Ratner, M., Eds.; New York Academy of Sciences: New York, 1998. (b)
Collier, C. P.; Mattersteig, G.; Wong, E. W.; Luo, Y.; Beverly, K.; Sampaio,
J.; Raymo, F. M.; Stoddart, J. F.; Heath, J. R. Science 2000, 289, 1172-
1175. (c) Yu, H.; Luo, Y.; Beverly, K.; Stoddart, J. F.; Tseng, H.-R.; Health,
J. R. Angew. Chem., Int. Ed. 2003, 42, 5706-5711.
(2) (a) Kelly, T. R.; De Silva, H.; Silva, R. A. Nature 1999, 401, 150-
152. (b) Collin, J.-P.; Dietrich-Buchecker, C.; Gavin˜a, P.; Jime´nez-Molero,
M. C.; Sauvage, J.-P. Acc. Chem. Res. 2001, 34, 477-487. (c) Leigh, D.
A.; Wong, J. K. Y.; Dehez, F.; Zerbetto, F. Nature 2003, 424, 174-179.
(d) Badjic, J. D.; Balzani, V.; Credi, A.; Silvi, S.; Stoddart, J. F. Science
2004, 303, 1845-1849.
(3) (a) Ja¨ger, R.; Vo¨gtle, F. Angew. Chem., Int. Ed. Engl. 1997, 36, 930-
944. (b) Nepogodiev, S. A.; Stoddart, J. F. Chem. ReV. 1998, 98, 1959-
1976. (c) Brouwer, A. M.; Fazio, S. M.; Frochot, C.; Gatti, F. G.; Leigh,
D. A.; Wong, J. K. Y.; Wurpel, G. W. H. Pure Appl. Chem. 2003, 75,
1055-1060. (d) Chambron, J.-C.; Collin, J.-P.; Heitz, V.; Jouvenot, D.;
Kern, J.-M.; Mobian, P.; Pomeranc, D.; Sauvage, J.-P. Eur. J. Org. Chem.
2004, 8, 1627-1638. (e) Kihara, N.; Hashimoto, M.; Takata, T. Org. Lett.
2004, 6, 1693-1696.
(5) Syntheses of molecular rotaxanes can be classified conceptually into
three different approaches: (a) The threading-followed-by-stoppering
approach relies on the initial formation (by threading) of a pseudorotaxane
from bead- and threadlike components, followed by the positioning
(stoppering) of bulky end groups to the threadlike component. (b) The
slippage approach relies on the passage of a beadlike component over the
moderately bulky end groups of a dumbbell-shaped component at elevated
temperature. (c) The clipping approach relies on the macrocyclization of
the subunits of a beadlike component around the threadlike subunit of the
dumbbell-shaped component.
(6) (a) Cantrill, S. J.; Pease, A. R.; Stoddart, J. F. J. Chem. Soc., Dalton
Trans. 2000, 3715-3734. (b) Clifford, T.; Abushamleh, A.; Busch, D. H.
Proc. Natl. Acad. Sci. U.S.A. 2002, 99, 4830-4836. (c) Gibson, H. W.;
Yamaguchi, N.; Jones, J. W. J. Am. Chem. Soc. 2003, 125, 3522-3533.
(7) (a) Kolchinski, A. G.; Alcock, N. W.; Roesner, R. A.; Busch, D. H.
Chem. Commun. 1998, 1437-1438. (b) Rowan, S. J.; Stoddart, J. F. J.
Am. Chem. Soc. 2000, 122, 164-165. (c) Rowan, S. J.; Cantrill, S. J.;
Stoddart, J. F.; White, A. J. P.; Williams, D. J. Org. Lett. 2000, 2, 759-
762. (d) Chiu, S.-H.; Rowan, S. J.; Cantrill, S. J.; Ridvan, L.; Ashton, P.
R.; Garrell, R. L.; Stoddart, J. F. Tetrahedron 2002, 58, 807-814.
10.1021/ol0484557 CCC: $27.50
© 2004 American Chemical Society
Published on Web 10/14/2004

number of chemical reactions that are suitable for generating
rotaxanes by the stoppering of these complexes.9 Reactions
that require polar solvents, high temperatures, and strong
bases or that produce tight-binding counteranions during the
process are undesirable for efficient stoppering reactions of
DB24C8/DBA+ systems because such conditions can lead
to the dissociation of the pseudorotaxane complexes and,
hence, result in poor yields of product rotaxanes.
Scheme 2
In this paper, we report a very mild and high-yielding
threading-followed-by-stoppering method for the synthesis
of rotaxanes. This new stoppering reaction is very efficient:
not only could we synthesize [2]rotaxanes using the strong
DB24C8/DBA+ recognition system (Ka ) 27,000 M-1 in
CDCl3)10 in up to 87% yield but we also constructed a [2]-
rotaxane in 40% yield based on the very weak noncovalent
binding11 between DBA+ and di(p-toluidine)[24]crown-8
(DPT24C8; Ka < 15 M-1 in CDCl3/CD3NO2 ) 2:1 mix-
ture).12
An ideal stoppering reaction for rotaxane synthesis should
exhibit a number of features, including high yield, hassle-
free purification, and either atom economy13 or the produc-
tion of benign byproducts. In the latter case, we believed
that the first step of the Staudinger reaction,14 the conversion
of an organic azide to a phosphorimidate by the action of a
phosphite, would be an elegant rotaxane stoppering reaction,
because it releases only nitrogen gas and the phosphorimidate
can undergo a subsequent Arbuzov-type dealkylation reac-
tion15 to form a stable phosphoramidate at ambient temper-
ature in low-polarity solvents (Scheme 1).
chlorination using NCS/PPh3 afforded the benzylic chloride
3. Chloride 3 was then converted to azide 4 under Finkelstein
conditions.17 Removal of the Boc protecting group and then
subjecting the trifluoroacetate salt to an ion exchange process
(NH4PF6/H2O) gave the desired azide-functionalized product
5-H‚PF6 in 72% yield in three steps from the benzylic
chloride 3. The reaction between triethyl phosphite and an
equimolar mixture of DB24C8 and 5-H‚PF6 in CH2Cl2 at
100 mM concentration at ambient temperature gave [2]-
rotaxane 6-H‚PF6 in up to 87% yield.18
The interlocked nature of the [2]rotaxane 6-H‚PF6 was
confirmed by 1H NMR spectroscopy (Figure 1a). The
characteristic position and shape of the multiplets for the
R-, â-, and γ-OCH2 protons of the DB24C8 unit of 6-H‚
PF6, which are centered at δ 4.04, 3.75, and 3.55, respec-
tively, are shifted upfield from their values in free DB24C8
(δ 4.09, 3.80, and 3.69, respectively; Figure 1b); these shifts
are characteristic19 of a crown ether unit positioned around
the NH2+ center of a dibenzylammonium ion and stabilized
by means of [N+-H‚‚‚O] and [C-H‚‚‚O] hydrogen bonding
Scheme 1
(12) Because of the low solubility of DBA‚PF6 in CDCl3 and its weak
interaction with DPT24C8, we provide this upper limit for the association
constant by comparing it with that determined (Ka ) 15 M-1) for the binding
of DPT24C8 with a more soluble and more strongly binding salt, bis(4-
fluorobenzyl)ammonium hexafluorophosphate. See: Ashton, P. R.; Fyfe,
M. C. T.; Hickingbottom, S. K.; Stoddart, J. F.; White, A. J. P.; Williams
D. J. J. Chem. Soc., Perkin Trans. 2 1998, 2117-2124 and ref 11.
(13) (a) Trost, B. M. Science 1991, 254, 1471-1477. (b) For examples
of atom economical rotaxane syntheses, see: Cao, J.; Fyfe, M. C. T.;
Stoddart, J. F.; Cousins, G. R. L.; Glink, P. T. J. Org. Chem. 2000, 65,
1937-1946.
To test our hypothesis, we prepared the azide-functional-
ized dibenzylammonium hexafluorophosphate salt 5-H‚PF6
by the procedure depicted in Scheme 2. Ester 116 was reduced
with LiAlH4 to give the benzylic alcohol 2 whose subsequent
(8) Pseudorotaxanes are supramolecular complexes that resemble rotax-
anes by virtue of comprising bead- and threadlike components, but their
components are free to dissociate from each other. For examples, see: (a)
Asakawa, M.; Ashton, P. R.; Balzani, V.; Boyd, S. E.; Credi, A.; Mattersteig,
G.; Menzer, S.; Montalti, M.; Raymo, F. M.; Ruffilli, C.; Stoddart, J. F.;
Venturi, M.; Williams, D. J. Eur. J. Org. Chem. 1999, 985-994. (b) Huang,
F.; Zakharov, L. N.; Rheingold, A. L.; Jones, J. W.; Gibson, H. W. Chem.
Commun. 2003, 2122-2123.
(9) (a) Kolchinski, A. G.; Busch, D. H.; Alcock, N. W. J. Chem. Soc.,
Chem. Commun. 1995, 1289-1291. (b) Cantrill, S. J.; Fulton, D. A.; Fyfe,
M. C. T.; Stoddart, J. F.; White, A. J. P.; Williams, D. J. Tetrahedron Lett.
1999, 40, 3669-3672. (c) Rowan, S. J.; Cantrill, S. J.; Stoddart, J. F. Org.
Lett. 1999, 1, 129-132. (d) Zehnder, D. W.; Smithrud, D. B. Org. Lett.
2001, 3, 2485-2487. (e) Oku, T.; Furusho, Y.; Takata, T. Org. Lett. 2003,
5, 4923-4925.
(14) Gololobov, Yu. G.; Gusar, N. I.; Chaus, M. P. Tetrahedron 1985,
41, 793-799.
(15) (a) Balthazor, T. M.; Grabiak, R. C. J. Org. Chem. 1980, 45, 5425-
5426. (b) Taher, A.; Eichenscher, S.; Slawin, A. M. Z.; Tennant, G.; Weaver,
G. W. J. Chem. Soc., Perkin Trans. 1 2002, 1968-1972.
(16) Asakawa, M.; Ikeda, T.; Yui, N.; Shimizu, T. Chem. Lett. 2002,
174-175.
(17) Biffin, M. E. C.; Miller, J.; Paul, D. B. The Chemistry of the Azido
Group; Patai, S., Ed.; Interscience: London, 1971; pp 57-190.
(18) Association constant (Ka) between 5-H‚PF6 and DB24C8 in CDCl3
was determined by 1H NMR spectroscopy to be 6650 M-1 using the single-
point method (see: Ashton, P. R.; Chrystal, E. J. T.; Glink, P. T.; Menzer,
S.; Schiavo, C.; Spencer, N.; Stoddart, J. F.; Tasker, P. A.; White, A. J. P.;
Williams, D. J. Chem. Eur. J. 1996, 2, 709-728 and ref 12). Values of Ka
determined in this way are merely “ballpark” figures (see Supporting
Information); for a discussion of a method for determining the values more
precisely, see: Jones, W. J.; Gibson, H. W. J. Am. Chem. Soc. 2003, 125,
7001-7004.
(10) Ashton, P. R.; Campbell, P. J.; Chrystal, E. J. T.; Glink, P. T.;
Menzer, S.; Philp, D.; Spencer, N.; Stoddart, J. F.; Tasker, P. A.; Williams,
D. J. Angew. Chem., Int. Ed. Engl. 1995, 34, 1865-1869.
(11) Chiu, S.-H.; Liao, K.-S.; Su, J.-K. Tetrahedron Lett. 2004, 45, 213-
216.
4184
Org. Lett., Vol. 6, No. 23, 2004

Scheme 3
The solid-state structure of the [2]rotaxane 8-H‚PF6
indicates (Figure 2) that the interlocked molecule possesses
Figure 1. Partial 1H NMR spectra (400 MHz, CD3CN) of (a) [2]-
rotaxane 6-H‚PF6 and (b) DB24C8.
interactions. The broad signal at δ 7.45-7.56 of the protons
+
of the NH2 center supports the existence of [N+-H‚‚‚O]
hydrogen bonding between this center and the DB24C8
unit.20 The characteristic position and shape of the multiplets
centered at δ 4.68 and 4.60 for the protons on the benzylic
+
methylene units adjacent to the NH2 centers is further
Figure 2. Ball-and-stick representation of the solid-state structure
of the [2]rotaxane 8-H‚PF6. The hydrogen bonding geometries,
X‚‚‚O, H‚‚‚O [Å], and X-H‚‚‚O [deg]: (a) 3.23, 2.36, 162.8; (b)
2.98, 2.11, 161.4; (c) 3.25, 2.41, 144.0; (d) 3.57, 2.62, 168.9.
evidence for the crown ether encircling the DBA+ moiety.9c
When rotaxane 6-H‚PF6 was dissolved in CD3SOCD3 and
monitored by 1H NMR spectroscopy, we observed no release
of free DB24C8,21 which suggests that the terminal diethyl
phosphoramidate groups of rotaxane 6-H‚PF6 are true stop-
pers for the DB24C8 macrocycle.22 High-resolution fast-
atom-bombardment (HRFAB) mass spectrometry gave a
molecular ion at m/z 867.4554 (theoretically at m/z 867.4561),
which confirmed the chemical composition of the diethyl
phosphoramidate-terminated [2]rotaxane 6-H‚PF6.
Because this monostoppering reaction proceeded so well,
we were inspired to test the stoppering of another azide-
substituted dialkylammonium ion. The reaction between
triethyl phosphite (200 mM), DB24C8 (200 mM), and the
known bisazide-functionalized salt 7-H‚PF6 (100 mM) in
CH2Cl2 at ambient temperature gave [2]rotaxane 8-H‚PF6
in 53% yield (Scheme 3).23 In this case, we grew single
crystals suitable for X-ray crystallography by liquid diffusion
of isopropyl ether into a CHCl3 solution of 8-H‚PF6.
two phosphoramidate end groups. The DB24C8 component
has a conventional Z-shaped conformation with the two
catechol rings inclined by ca. 4.7° to one another. The
dicationic dumbbell component is tethered to the crown ether
by weak N-H‚‚‚O and C-H‚‚‚O hydrogen bonds (a-d in
Figure 2), a binding that is supplemented by π-π stacking
between one of the catechol rings of the DB24C8 component
and the central phenylene ring of the dumbbell component
(centroid‚‚‚centroid distance and mean interplanar separation
of 3.84 and 3.55 Å, respectively).
The interlocked nature of the [2]rotaxane 8-H‚PF6 was also
corroborated by 1H NMR spectroscopy (see Supporting
Information). The HRFAB mass spectrum of 8-H‚PF6
displayed a molecular ion at m/z 976.4484, which confirms
that the [2]rotaxane has diethyl phosphoramidate termini.
To determine the generality and efficiency of this synthetic
method, we were interested in testing whether we could
stopper a very weakly binding crown ether/DBA+-based
pseudorotaxane system, i.e., one using DPT24C8 as the
macrocycle.11 The very weak electron-donating ability of the
aniline nitrogen atoms of DPT24C8 make the strength of its
(19) Cantrill, S. J.; Fulton, D. A.; Heiss, A. M.; Pease, A. R.; Stoddart,
J. F.; White, A. J. P.; Williams, D. J. Chem. Eur. J. 2000, 6, 2274-2287.
(20) For representative examples of NMR spectra of rotaxanes and
pseudorotaxanes, see refs 7d, 9b, and 19.
(21) In related pseudorotaxane systems, the use of DMSO as a solvent
disrupts hydrogen bonding to such an extent that no complex forms; thus,
dissolving a rotaxane of this type in DMSO is a good test for the degree of
interlocking of the components. For example, see: Chiu, S.-H.; Rowan, S.
J.; Cantrill, S. J.; Glink, P. T.; Garrell, R. L.; Stoddart, J. F. Org. Lett.
2000, 2, 3631-3634.
(22) The p-tert-butylbenzyl group is a true stopper for DB24C8 rings,
but the p-isopropylbenzyl group is a slippage stopper; see: Ashton, P. R.;
Baxter, I.; Fyfe, M. C. T.; Raymo, F. M.; Spencer, N.; Stoddart, J. F.; White,
A. J. P.; Williams, D. J. J. Am. Chem. Soc. 1998, 120, 2297-2307. The
diethyl phosphoramidate group is larger sterically than an isopropyl group
when inspected using CPK molecular models.
(23) In addition to requiring two stoppering reactions instead of one,
the moderate yield of this reaction, relative to that of the monostoppering
reaction, is possibly the result of the relatively weak binding between 7-H‚
PF6 and DB24C8 (Ka ) 4000 M-1 in CDCl3); see: Ashton, P.; Glink, P.
T.; Stoddart, J. F.; Tasker, P. A.; White, A. J. P.; Williams, D. J. Chem.
Eur. J. 1996, 2, 729-736.
Org. Lett., Vol. 6, No. 23, 2004
4185

binding to 5-H‚PF6 in CH2Cl2 about 2 orders of magnitude
weaker than that between DB24C8 and 5-H‚PF6 in the same
solvent.24 Unlike the virtually quantitative formation of the
pseudorotaxane between an equimolar mixture (100 mM)
of DB24C8 and DBA+ in CHCl3 at ambient temperature,
only about half of the DPT24C8 and DBA+ species exist in
the pseudorotaxane form under these conditions. We found
it difficult to form rotaxanes with this system; indeed, we
failed to isolate rotaxane-like products when using two
different stoppering methods: the 1,3-dipolar cycloaddition
reaction of the azido groups of 5-H‚PF6 with di-tert-butyl
acetylenedicarboxylate to generate substituted 1,2,3-triazoles
as stoppers14b,24 and the quaternization of triphenylphosphine
with the benzylic bromide 9-H‚PF6 (Scheme 4) to form
side reactions during the rotaxane formation reaction, and,
therefore, the product is formed in a lower yield.
Again, the interlocked nature of the components of this
1
product can be deduced from its H NMR spectrum. The
multiplets centered at δ 4.66 and 4.60 for the protons of the
+
benzylic methylene groups adjacent to the NH2 centers
confirm the presence of the DPT24C8 moiety around the
+
NH2 center of the dumbbell unit in [2]rotaxane 10-H‚PF6,
as does the fact that the “tight” multiplet (δ 3.48-3.62) for
the methylene protons within the NCH2CH2O and OCH2-
CH2O units of the uncomplexed DPT24C8 is dispersed over
a wide range of chemical shifts (δ 2.90-3.68), with each
pair of methylene protons becoming constitutionally hetero-
topic, in the [2]rotaxane (Figure 3). Furthermore, the
Scheme 4
triphenylphosphonium ions as stoppers.9c,21,25 Apart from the
low concentrations of the respective pseudorotaxanes, it may
be possible that the weakly nucleophilic substituted nitrogen
atoms of the aniline units of the crown ether complicate these
stoppering reactions by reacting with either the electrophilic
benzylic bromide unit of 9-H‚PF6 or with di-tert-butyl
acetylenedicarboxylate, which results in complicated mix-
tures of products. In contrast, the reaction between triethyl
phosphite (100 mM), DPT24C8 (200 mM), and 5-H‚PF6 (100
mM) in CH2Cl2 at ambient temperature gave the correspond-
ing [2]rotaxane 10-H‚PF6 in 40% yield (Scheme 4). When
we treated the thread 5-H‚PF6 with triethyl phosphite in the
absence of a crown ether, we obtained a complicated mixture
of products from which we could not isolate the correspond-
ing dumbbell-shaped phosphoramidate. Thus, the shielding
of the ammonium centers by the crown ethers seems to be
an important factor in the success of the reaction. In the
presence of the weaker-binding crown ethers, the reaction
mixture contains a relatively higher concentration of free
5-H‚PF6 (ca. 20% is uncomplexed initially under our reaction
conditions) than it does in the reactions using the stronger-
binding macrocycle (>96% of 5-H‚PF6 is complexed initially
under the conditions in Scheme 2); this higher amount of
free thread has a greater chance of being consumed by the
Figure 3. Partial 1H NMR spectra (400 MHz, CD3CN) of (a) the
[2]rotaxane 10-H‚PF6 and (b) DPT24C8.
identification of a signal at m/z 949.6 for the [10-H]+ ion in
the FAB mass spectrum supports the presence of the diethyl
phosphoramidate-stoppered [2]rotaxane 10-H‚PF6.
We have developed a high-yielding, efficient, and mild
synthetic method for the synthesis of rotaxanes. The reaction
between triethyl phosphite and benzylic azides allows us not
only to construct rotaxanes in high yields from DB24C8 and
DBA+-derived threads but also to incorporate DPT24C8,
which binds DBA+ ions much weaker than does DB24C8,
into a corresponding [2]rotaxane.
Acknowledgment. We thank referees for their comments
and the National Science Council (Taiwan) for financial
support (NSC 92-2113-M-002-045).
Supporting Information Available: Synthetic and spec-
troscopic data for the new compounds and a discussion on
the merits of the single-point method for determining
association constants. This material is available free of charge
via the Internet at http://pubs.acs.org.
(24) We determined the association constant (Ka) between 5-H‚PF6 and
DPT24C8 at room temperature in CD2Cl2 to be 38 M-1, i.e., 175-times
smaller than that between 5-H‚PF6 and DB24C8 (Ka ) 6650 M-1).
(25) Chang, T.; Heiss, A. M.; Cantrill, S. J.; Fyfe, M. C. T.; Pease, A.
R.; Rowan, S. J.; Stoddart, J. F.; White, A. J. P.; Williams, D. J. Org. Lett.
2000, 2, 2947-2950.
OL0484557
4186
Org. Lett., Vol. 6, No. 23, 2004