Supramolecular control of a fast and reversible Diels-Alder reaction

Article abstract of DOI:10.1021/ol801919q

(Equation Presented) A new cyclophane featuring two opposite anthracene units linked in 9,10-positions has been synthesized thanks to the template effect of the Me₄N⁺ ion. It forms pseudorotaxane complexes with alkylviologen ions and undergoes a fast and reversible reaction with tetracyanoethylene. A quantitative analysis has been carried out of the formation of Diels-Alder adducts, whose distribution can be controlled by host-guest complexation. These findings open interesting perspectives in the field of Dynamic Covalent Chemistry.

Full text of DOI:10.1021/ol801919q

ORGANIC
LETTERS
2008
Vol. 10, No. 21
4835-4838
Supramolecular Control of a Fast and
Reversible Diels-Alder Reaction
Bernardo Masci,*,† Sara Pasquale,† and Pierre Thue´ry‡
Dipartimento di Chimica and IMC-CNR, UniVersita` La Sapienza, P.le Aldo Moro 5,
00185 Roma, Italy, and CEA, IRAMIS, SCM (CNRS URA 331), Baˆt. 125,
91191 Gif-sur-YVette, France
bernardo.masci@uniroma1.it
Received August 16, 2008
ABSTRACT
A new cyclophane featuring two opposite anthracene units linked in 9,10-positions has been synthesized thanks to the template effect of the
Me4N+ ion. It forms pseudorotaxane complexes with alkylviologen ions and undergoes a fast and reversible reaction with tetracyanoethylene.
A quantitative analysis has been carried out of the formation of Diels-Alder adducts, whose distribution can be controlled by host-guest
complexation. These findings open interesting perspectives in the field of Dynamic Covalent Chemistry.
Anthracene units endow a cyclophane with potentially
interesting physical and chemical properties that can be
Scheme 1
exploited in the development of synthetic receptors. Recent
examples refer both to compounds featuring pendant an-
thracenyl groups1 and to anthracenophane structures.2 As an
extension of our previous investigations on ether derivatives
of octahomotetraoxacalixarenes,3,4 we developed analogous
cyclophanes featuring two opposite anthracene units linked
in 9,10-positions. Here we report on the templated synthesis
of 3 and on the Diels-Alder reactions undergone by its
anthracene moieties. The synthesis of the ligand was carried
not be satisfactorily carried out using NaH base in DMF nor
using powdered KOH base in dioxane that worked well in
previous investigations.3a,5 Thus, we tested the heterogeneous
Me4NOH-dioxane system to exploit the possible template
out according to Scheme 1. The critical cyclization step could
† Universita` La Sapienza.
‡ CEA.
10.1021/ol801919q CCC: $40.75
Published on Web 10/11/2008
2008 American Chemical Society

effect of the Me4N+ ion that was expected to be complexed
by the final product. Satisfactory results were obtained,
notwithstanding the fact that the exhaustive dehydration of
the commercially available Me4NOH·5H2O could not be
carried out.6 To the best of our knowledge, this is the first
report on a template effect of the Me4N+ ion in a kinetically
controlled reaction.7
1H NMR and UV-vis techniques. High association constants
were observed; in particular, K ) (3.3 ( 0.2) × 104 M-1
was determined with methylviologen dihexafluorophosphate
in CHCl3/CH3CN 1:1 at 298 K by monitoring variations in
the UV-vis spectra, including the formation of a charge
transfer band at about 500 nm.8 Other determined K values
were as follows: with tetramethylammonium picrate in
CDCl3, K ) (8.7 ( 0.5) × 103 M-1 (1H NMR); with
propylviologen dihexafluorophosphate in CDCl3/CD3CN 1:1,
K ) (1.4 ( 0.1) × 104 M-1 (1H NMR) and (1.5 ( 0.1) ×
104 M-1 (UV-vis). In the 1H NMR spectra, marked shielding
effects are experienced by the protons of the included guest
cations,9 while the signals of the butyl protons of the host,
that appeared to be shielded in the free ligand, are shifted
back to the values observed in simple model compounds. A
single-crystal X-ray structural investigation failed in the case
of the complex 4a with a methylviologen dihexafluorophos-
phate guest but could be successfully performed in the case
of the complex 4b with a propylviologen dihexafluorophos-
phate guest (Figure 2). The observed pseudorotaxane struc-
The lack of geminal coupling for the methylene ring
protons in the spectrum of ligand 3 indicated that at room
temperature fast conformational equilibration occurs with
1
respect to the H NMR time scale; moreover, the upfield
shifts observed for the protons of the butyl chains indicated
that in CDCl3 solution the latter chains are partly included
in the cavity. This feature is also observed in the single-
crystal X-ray structure of 3 (Figure 1), that is centrosym-
Figure 1. Two views of the single-crystal X-ray structure of
compound 3.
metric, with the opposed butyl chains sandwiched by the
parallel anthracene units.
Complexation experiments of 3 with tetramethylammo-
nium and alkylviologen salts were carried out through both
Figure 2. Two views of the single-crystal X-ray structure of the
(1) (a) Schaefer, C.; Eckel, R.; Ros, R.; Mattay, J.; Anselmetti, D. J. Am.
Chem. Soc. 2007, 129, 1488–1489. (b) Tamayo, A.; Pedras, B.; Lodeiro,
C.; Escriche, L.; Casabo, J.; Capelo, J. L.; Covelo, B.; Kivekas, R.; Sillanpaa,
R. Inorg. Chem. 2007, 46, 7818–7826. (c) Moore, E. G.; Bernhardt, P. V.;
Fuerstenberg, A.; Riley, M. J.; Vauthey, E. J. Phys. Chem. A 2005, 109,
11715–11723.
pseudorotaxane complex 4b, between 3 and propylviologen di-
hexafluorophosphate.
ture is still centrosymmetric, but when the wheel is compared
to the free ligand, the butyl chains are found to exit the cavity,
and the planes of the benzenoid units are markedly rotated
(2) (a) Ishikawa, T.; Shimasaki, T.; Akashi, H.; Toyota, S. Org. Lett.
2008, 10, 417–420. (b) Hirose, K.; Shiba, Y.; Ishibashi, K.; Doi, Y.; Tobe,
Y. Chem.-Eur. J. 2008, 14, 981–986. (c) Gassensmith, J. J.; Arunkumar,
E.; Barr, L.; Baumes, J. M.; Di Vittorio, K. M.; Johnson, J. R.; Noll, B. C.;
Smith, B. D. J. Am. Chem. Soc. 2007, 129, 15054–15059. (d) Kuwabara,
J.; Stern, C. L.; Mirkin, C. A. J. Am. Chem. Soc. 2007, 129, 10074–10075.
(e) Kutsumizu, R.; Shinmori, H. Takeuchi. Tetrahedron Lett. 2007, 48,
3225–3228. (f) Das, N.; Ghosh, A.; Singh, O. M.; Stang, P. J. Org. Lett.
2006, 8, 1701–1704. (g) Qin, D.-B.; Xu, F.-B.; Wan, X.-J.; Zhang, Z.-Z.
Tetrahedron Lett. 2006, 47, 5641–5643.
(5) (a) Masci, B.; De Iasi, G. Tetrahedron Lett. 1993, 41, 6635–6638.
(b) Tran, A. H.; Miller, D. O.; Georghiou, P. E. J. Org. Chem. 2005, 70,
1115–1121.
(6) Powdered, partially dried Me4NOH·5H2O (900 mg, 4.97 mmol) in
dioxane (50 mL) was added to a stirred mixture of 1 (400 mg, 1.10 mmol)
and 2 (292 mg, 1.10 mmol) heated at 50 °C. After 22 h reaction and
chloroform-water work-up, recrystallization from acetone afforded pure 3
(100 mg, 19% yield). Yields obtained using the commercially available
Me4NOH·5H2O base were lower, in the order of 10%. Yields obtained with
NaH in DMF were in the order of 5%, while no product could be isolated
using powdered KOH in dioxane.
(3) (a) Masci, B.; Saccheo, S. Tetrahedron 1993, 49, 10739–10748. (b)
Masci, B.; Finelli, M.; Varrone, M. Chem.-Eur. J. 1998, 4, 2018–2030.
(4) For reviews on homooxacalixarenes see: (a) Masci, B. Calixarenes
2001; Asfari, Z., Bo¨hmer, V., Harrowfield, J., Vicens, J., Eds.; Kluwer:
Dordrecht, 2001; Chapter 12. (b) Shokova, E. A.; Kovalev, V. V. Russ. J.
Org. Chem. 2004, 40, 607–643, and 1547-1571.
4836
Org. Lett., Vol. 10, No. 21, 2008

with respect to the mean plane of the macrocycle (dihedral
angle of 49.46(4)° instead of 26.64(8)° in 3) to make room
to the axle. Moreover, the two facing anthracene units are
closer (distance between centroids 7.26 Å instead of 9.07 Å
in 3) and somewhat distorted, with contact distances indica-
tive of parallel-displaced π-stacking between each of the
pyridinium rings in the guest and two rings in one anthracene
unit and one in the other (centroid· · ·centroid distances
3.73-3.87 Å, dihedral angles 4.5-9.2°, offset displacements
1.04-1.47 Å). In both structures, the anthracene units are
nearly perpendicular to the mean plane of the macrocycle
(dihedral angles 89.56(4)° in 3 and 80.23(4)° in 4b), and
intermolecular π-stacking interactions are present in the
packing.
Figure 3. Cyclophane distribution at varying added [TCNE] and
The anthracene moieties in 3 are suitable for further
transformations and have been tested to undergo Diels-Alder
reaction with several dienophiles. Notwithstanding the
importance of the Diels-Alder reaction, the stability of the
adducts has seldom been assessed, and even in the case of
the archetypical anthracene-TCNE pair, only a lower limit
value of the formation constant could be estimated.10 In the
case of compound 3, a number of adducts can be expected
that can be reduced to only one monoadduct and one diadduct
in the case of 9,10-addition of a symmetric dienophile and
of low barriers for conformational equilibration. Here we
report on the reaction with tetracyanoethylene (TCNE) which
was found to fulfill the latter requirements and to undergo
fast and reversible reaction at room temperature.11 Integration
at fixed 1.03 mM overall cyclophane concentration. Points are
experimental, and curves are calculated.
So we assumed [TCNE] ) [5] and obtained K2 ) (1.5 (
0.1) × 105 M-1 and then K1 ) (3.2 ( 0.6) × 106 M-1
.
The latter values have been used to calculate the solid
lines in Figure 3 that fairly match with the experimental
points. While 6 can be considered to be a practically stable
species in solution (in concentrated enough solution or in
excess TCNE),12 5is a labile species that within even a
few seconds is partially converted into 3 and 6.
In a further experiment, we added increasing amounts of
TCNE to a solution prepared from crystals of 4a, namely,
the complex of 3 with methylviologen dihexafluorophos-
1
of the areas of suitable signals in the H NMR spectra
allowed the stability of the adducts to be assessed, in spite
of the difficulties arising from the large values of both K1
and K2 (Scheme 2) and from the absence of signals for the
1
phate. Three sets of signals were apparent in the H NMR
spectra that could be attributed to the three cyclophanes. The
chemical shifts of the cyclophanes were markedly affected
by the presence of the salt in the case of 3, slightly affected
in the case of 5, and unaffected in the case of 6, so that the
equilibria involved are apparently those reported in Scheme
3, with K3 < K. The distribution of the three cyclophanes at
fixed overall concentration and at increasing [TCNE] is given
in Figure 4.13 Marked differences appear with respect to the
picture given in Figure 3, with cyclophanes 3 and 6 being
significantly amplified by the guest in wide [TCNE]added
ranges at the expenses of the monoadduct 5 that is reduced
to a minor component. The salt can thus be viewed as a tuner
of the Diels-Alder equilibria, while TCNE promotes the exit
of the axle from the wheel in the rotaxane structure.
Scheme 2
In the search for suitable systems for the development
of dynamic combinatorial libraries, Lehn and co-workers14
investigated some rapidly reversible Diels-Alder reactions
(7) For template effects of tetraalkylammonium ions on reversible
systems, see, for instance: (a) Lam, R. T. S.; Belenguer, A.; Roberts, S. L.;
Naumann, C.; Jarrosson, T.; Otto, S.; Sanders, J. K. M. Science 2005, 308,
667–669. (b) Roberts, S. L.; Furlan, R. L. E.; Cousins, G. R. L.; Sanders,
J. K. M. Chem. Commun. 2002, 938–939. (c) Cousins, G. R. L.; Furlan,
R. L. E.; Ng, Y.-F.; Redman, J. E.; Sanders, J. K. M. Angew. Chem., Int.
Ed. Engl. 2001, 40, 423–428.
dienophile. The distribution of the three species 3, 5, and 6
at fixed overall concentration of the cyclophanes and at
varying TCNE concentration is shown in Figure 3.
The K1/K2 ratio is independent of [TCNE] and could
be easily determined in a suitable concentration range:
K1/K2 ) [5]2/[3][6] ) 21.7 ( 0.5 in CD3CN-CDCl3 1:1
at 298 K. On the other hand, in independent experiments
carried out on suitably diluted solutions of crystals of
preformed 6, [3] was found to be negligible, while the
small area of the signal of 5 could be safely integrated.
(8) A light reddish color was apparent upon mixing alkylviologen salts
and 3 in diluted solution, and a red color was observed in the crystals of
the complexes.
(9) Namely, 3.3 ppm in the case of tetramethylammonium picrate and
0.2-1.9 ppm in the case of propylviologen dihexafluorophosphate.
(10) K ) 1 × 105 M-1 for addition in 9,10-positions. See: Handoo,
K. L.; Lu, Y.; Parker, V. D. J. Am. Chem. Soc. 2003, 125, 9381–9387.
Org. Lett., Vol. 10, No. 21, 2008
4837

from 3 and TCNE can be viewed as a small library in the
frame of Dynamic Combinatorial Chemistry.16 Interest-
ingly, the template that amplifies 3 also causes the
amplification of the poor ligand 6.
Scheme 3
Larger libraries can be conceived, also including, for
instance, analogues featuring different substituents or modi-
fied ring systems. The present dynamic system based on the
Diels-Alder reaction suffers from the lack of a chemical
quencher; it is nevertheless suitable to be investigated in
detail and to undergo supramolecular control. An extension
to less reactive dienophiles will allow an effective thermal
quenching and the isolation of kinetically stable compounds
formed in equilibrating systems at high temperatures.
Supporting Information Available: General methods for
1
the experimental procedures, synthesis, H and 13C NMR
spectra of compounds 2, 3, 6, 4a, and 4b, figures, and
treatment of experimental data for salt complexation and
Diels-Alder adducts formation; crystal data, displacement
ellipsoid plots, and crystallographic files in CIF format for
compounds 3 and 4b. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL801919Q
(12) Unfortunately, the obtained single crystals of 6 were not suitable
for X-ray diffraction analysis.
(13) Solid lines in Figure 4 simply interpolate the experimental points.
Due to peak superimposition in the 1H NMR spectra, deconvolution
procedures were adopted in the integration of the areas. Although
substantially reproducible results were obtained, the complexity of the
system and the uncertainty in the values of the areas of the 1H NMR signals
hampered a fully quantitative treatment.
(14) Boul, P. J.; Reutenauer, P.; Lehn, J.-M. Org. Lett. 2005, 7, 15–18.
(15) Important examples of supramolecular catalysis in Diels-Alder
reactions have been reported for inclusion of both reactants in capsules or
macrocyclic cavities. See, for instance: (a) Kang, J.; Hilmersson, G.;
Santamaria, J.; Rebek, J., Jr. J. Am. Chem. Soc. 1998, 120, 3650–3656. (b)
Walter, C. J.; Anderson, H. L.; Sanders, J. K. M. Chem. Commun. 1993,
458–460. (c) Nakash, M.; Clyde-Watson, Z.; Freeder, N.; Davies, J. E.;
Teat, S.; Sanders, J. K. M. J. Am. Chem. Soc. 2000, 122, 5286–5293. (d)
Nakash, M.; Sanders, J. K. M. J. Org. Chem. 2000, 65, 7266–7271. (e)
Brisig, B.; Sanders, J. K. M.; Otto, S. Angew. Chem., Int. Ed. 2003, 42,
1270–1273.
Figure 4
.
Cyclophane distribution at varying added [TCNE] and
at fixed 1.03 mM overall cyclophane concentration, as affected by
the presence of 1.03 mM methylviologen dihexafluorophosphate.
The notations “3”, “5”, and “6” indicate the points and the lines
corresponding to the total concentrations of these species. Points
are experimental, and solid lines merely interpolate them.
and determined formation constants in the range 40-2300
M-1 for structurally simple systems. On the other hand,
no example has been reported, to the best of our
knowledge, of easily reversible Diels-Alder reactions
involving the macrocyclic receptor itself as either the diene
or the dienophile.15 Actually, the set of compounds arising
(16) For recent reviews on Dynamic Covalent Chemistry and Dynamic
Combinatorial Chemistry, see: (a) Corbett, P. T.; Leclaire, J.; Vial, L.; West,
K. R.; Wietor, J.-L.; Sanders, J. K. M.; Otto, S. Chem. ReV. 2006, 106,
3652–3711. (b) De Bruin, B.; Hauwert, P.; Reek, J. N. H. Angew. Chem.,
Int. Ed. Engl. 2006, 45, 2660–2663. (c) Meyer, C. D.; Joiner, C. S.; Stoddart,
J. F. Chem. Soc. ReV. 2007, 36, 1705–1723. (d) Ladame, S. Org. Biomol.
Chem. 2008, 6, 219–226.
(11) In typical experiments run at 1 mM 3 and 0.1-2 mM TCNE, the
equilibration was apparently complete well within 15 min at 298 K.
4838
Org. Lett., Vol. 10, No. 21, 2008