Unprecedented tunable tetraazamacrocycles

Article abstract of DOI:10.1021/ol100793g

Novel nitrogen-bridged aza[1₄]cyclophanes with fine-tuned cavities have been synthesized by nucleophilic aromatic substitution of 1,5-difluoro-2,4-dinitrobenzene with diaminobenzene derivatives.

Full text of DOI:10.1021/ol100793g

ORGANIC
LETTERS
2010
Vol. 12, No. 12
2722-2725
Unprecedented Tunable
Tetraazamacrocycles
Rose Haddoub, Mounia Touil, Jean-Manuel Raimundo, and Olivier Siri*
Centre Interdisciplinaire de Nanoscience de Marseille (CINaM), UPR 3118 CNRS
Aix-Marseille UniVersite´, Campus de Luminy, case 913,
F-13288 Marseille, Cedex 09, France
siri@uniVmed.fr
Received April 6, 2010
ABSTRACT
Novel nitrogen-bridged aza[14]cyclophanes with fine-tuned cavities have been synthesized by nucleophilic aromatic substitution of 1,5-difluoro-
2,4-dinitrobenzene with diaminobenzene derivatives.
Cyclophanes generate continuous interest because of their
electronic properties and their importance in coordination
chemistry but also as effective host molecules in supramo-
lecular recognition chemistry.1 Furthermore, extensive bio-
logical applications inspired by naturally occurring host-guest
interactions have stimulated considerable development in the
chemistry of macrocyclic complexes.2 The recognition of a
guest by a supramolecular host and of a metal ion by a ligand
have in common that properties of the complexation products
depend largely on whether, and in which way the two
partners fit together. The size and rigidity of the host are
important factors for molecular recognition.3 In this respect,
fine-tuning the cavity may have a crucial impact on the
recognition properties of host molecules.
2 are of growing interest because the nitrogen bridges are
likely to bring additional molecular properties to these
macrocyclic entities.4 For instance, the presence of nitrogen
atoms increases the electron density of the π-cloud by
conjugation with the aromatic rings and may also participate
in the interactions with guest species.5 In addition, they are
the key sites for robust high spin stable polyradicals due to
the presence of the nitrogen bridges as spin bearing sites,
and the 1,3-phenylene subunits which act as ferromagnetic
couplers.6 Reported syntheses of N(R)-bridged [14]m- and
m,p,m,p-cyclophanes 1 and 2 (R ) H, alkyl, aryl) are based
on palladium-catalyzed aryl amination reactions.7,5a,6d
A
straightforward, catalyst-free approach, based on a stepwise
Besides the well-studied calix[n]arenes, in which four
aromatic rings are linked together by methylene bridges,
N(R)-bridged [14]m- and m,p,m,p-cyclophanes of types 1 and
(4) (a) Tsue, H.; Ishibashi, K.; Tamura, R. Top. Heterocycl. Chem. 2008,
17, 73. (b) Ko¨nig, B.; Fonseca, M. H. Eur. J. Inorg. Chem. 2000, 2303. (c)
Ito, A.; Yamagishi, Y.; Fukui, K.; Inoue, S.; Hirao, Y.; Furukawa, K.; Kato,
T.; Tanaka, K. Chem. Commun. 2008, 6573. (d) Yasukawa, Y.; Kobayashi,
K.; Konishi, H. Tetrahedron Lett. 2009, 50, 5130.
(5) (a) Tsue, H.; Ishibashi, K.; Takahashi, H.; Tamura, R. Org. Lett.
2005, 7, 2165. (b) Takemura, H. J. Inclusion Phenom. Macrocyclic Chem.
2002, 42, 169.
(1) (a) Diedrich, F. Cyclophanes; Royal Society of Chemistry: Cam-
bridge, 1991. (b) Vo¨gtle, F. Cyclophane Chemistry; Wiley, New York, 1993.
(2) (a) Wang, M. X. Chem Commun. 2008, 4541. (b) Baldini, L.; Casnati,
A.; Sansone, F.; Ungaro, R. Chem. Soc. ReV. 2007, 36, 254. (c) Kim, J. S.;
Quang, D. T. Chem. ReV. 2007, 107, 3780.
(6) (a) Ishibashi, K.; Tsue, H.; Sakai, N.; Tokita, S.; Matsui, K.;
Yamauchi, J.; Tamura, R. Chem. Commun. 2008, 2812. (b) Ito, A.; Ono,
Y.; Tanaka, K. Angew. Chem., Int. Ed. 2000, 39, 1072. (c) Hauck, S. I.;
Lakshmi, K. V.; Hartwig, J. F. Org. Lett. 1999, 13, 2057. (d) Ito, A.; Ino,
H.; Tanaka, K. Polyhedron 2009, 28, 2080. (e) Ito, A.; Ono, Y.; Tanaka,
K. J. Org. Chem. 1999, 64, 8236.
(3) (a) Masci, B.; Finelli, M.; Varrone, M. Chem.sEur. J. 1998, 4, 2018.
(b) Darbost, U.; Se´ne`que, O.; Li, Y.; Bertho, G.; Marrot, J.; Rager, M.-N.;
Reinaud, O.; Jabin, I. Chem.sEur. J. 2007, 13, 2078.
10.1021/ol100793g  2010 American Chemical Society
Published on Web 05/20/2010

nucleophilic aromatic substitution (SNAr), has been recently
introduced, and proved valuable in the synthesis of com-
pounds 1 and 2.8 However, because of synthetic challenges,
only very few exemples of aza[1n]cyclophanes having
different geometries have been described to date.
To access the azacyclophane 3c, a stepwise synthesis was
envisaged. Compound 6a was first reacted with 7 (1 equiv)
at 0 °C in EtOH in the presence of N(iPr)2Et (N,N-
diisopropylethylamine) to afford the [1+1] precursor 8 (65%
yield). X-ray analysis of 8 shows that the N(3)-C(1) bond
length is much shorter than the N(3)-C(7) distance due to
the conjugation of the N(3) lone pair with the nitro group
(1.346(3) vs 1.432(3) Å).9 The hybridation of the bridging
nitrogen can then be viewed as pseudo-sp2. Interestingly, the
N(2)-C(6)-C(1)angleissmallerthanthatofN(1)-C(4)-C(3)
(121.6(2) vs 122.7(3)°) due to a strong intramolecular
hydrogen bonding interaction between N(3)-H and O(4)
[d(NH···O2N) ) 1.997 Å], which preorganizes the backbone
of the uncyclic intermediate for the cylization step (Figure
1).
Rajca et al. varied the size of the inner cavity by increasing
the number of benzene rings and were able to generate
aza[1n]metacyclophanes having up to 10 units.7b Another
approach toward modulating the cavity of these macrocycles
would be to alternate ortho-, meta-, and para-substituted
phenylene rings while keeping a constant number of benzene
moieties. To gain further insight into the structure-activity
relationships of these macrocyclic systems, the efficient and
convenient synthesis of unprecedented aza[14]cyclophanes
of types 3, 4, and 5 with a varied stereochemistry is therefore
reported herein.
Figure 1. ORTEP view of the crystal structure of 8. Displacement
parameters include 50% of the electron density. Selected bond
distances (Å) and angles (deg): C(1)-N(3) ) 1.346(3), C(2)-C(1)
) 1.402(4), C(2)-C(3) ) 1.351(4), C(3)-C(4) ) 1.398(4),
C(4)-C(5) ) 1.365(4), C(6)-C(5) ) 1.379(4), C(1)-C(6) )
1.425(3), C(4)-N(1) ) 1.454(4), C(6)-N(2) ) 1.446(4);
C(1)-C(2)-C(3) ) 122.1(3), C(2)-C(1)-N(3) ) 120.2(2),
N(3)-C(1)-C(6) ) 124.2(2), N(2)-C(6)-C(1) ) 121.6(2),
N(1)-C(4)-C(3) ) 122.7(3).
8 was then reacted with 6b in refluxing EtOH to give 9c
(78% yield). Finally, the macrocyclization reactions between
9a-c and 7 in refluxing MeCN (C ) 10-2 M) furnished the
target molecules 3a-c in 75%, 76%, and 68% yield, respec-
tively. When the same reaction was carried out at lower
concentration (C ) 5 × 10-4 M), lower yields were obtained,
confirming the strong influence of the concentration on the
formation of the macrocycles by SNAr assisted by H-bonding
interactions.8a Noteworthy, all compounds were isolated as pure
yellow solids by a simple filtration step without the need for
further purification by column chromatography. The presence
of NH bridges in 3a-c is very attractive because of their
possible substitutions. For instance, compound 3d was obtained
from 3a by N-alkylation by using methyl iodide in DMF at 80
In planning our synthesis (Scheme 1), 1,2-diaminobenzene
derivatives 6a and 6b were used as nucleophilic components
to be functionalized by 1,5-fluoro-2,4-dinitrobenzene 7. The
reaction between 6a or 6b and 7 (0.5 equiv) led to the
formation of the [2+1] products 9a or 9b which precipitated
in EtOH with good yields. Their 1H NMR spectra showed a
downfield NH at δ 9.38 and 9.23 ppm for 9a and 9b,
respectively, in agreement with a NH···O2N hydrogen bond-
ing interaction that restricts the rotation of the uncyclized
precursors.8a
1
(7) (a) Ito, A.; Ono, Y.; Tanaka, K. New J. Chem. 1998, 779. (b) Vale,
M.; Pink, M.; Rajca, S.; Rajca, A. J. Org. Chem. 2008, 31, 27.
(8) (a) Touil, M.; Lachkar, M.; Siri, O. Tetrahedron Lett. 2008, 49, 7250.
(b) Konishi, H.; Hashimoto, S.; Sakakibara, T.; Matsubara, S.; Yasukawa,
Y.; Morikawa, O.; Kobayashi, K. Tetrahedron Lett. 2009, 50, 620. (c) Touil,
M.; Raimundo, J. M.; Marsal, P.; Lachkar, M.; Siri, O. Tetrahedron 2010,
In press.
°C (80% yield). The H NMR spectrum of 3a, 3b, and 3c
(9) Selected data for 8: monoclinic space group P121/n1 with a )
15.1272(5) Å, b ) 5.4965(2) Å, c ) 16.8300(8) Å, ꢀ ) 114.777(2)° at
293(2) K with Z ) 4. Refinement of 3015 reflections, and 190 parameters,
yielded R2 ) 0.1268 for all data (1767 reflections with I > 2σ(I)).
Org. Lett., Vol. 12, No. 12, 2010
2723

Scheme 1. Synthesis of Tetraaza[14]orthocyclophanes 3a-d
revealed that these macrocycles adopt a 1,3-alternated confor-
mation in solution, in which the intraannular aromatic protons
Hi are located inside the anisotropic shielding cone of the
adjacent aromatic rings. This assumption was supported by the
observed high-field chemical shifts at δ 4.98, 4.90, and 4.91
ppm for Hi protons of 3a, 3b, and 3c, respectively. In addition,
the NH resonance at around 9 ppm is consistent with the
presence of a NH···O2N intramoleculer hydrogen bond. In
contrast, the corresponding Hi protons in 9a, 9b, and 9c
appeared at 5.99, 5.90, and 5.91 ppm, respectively, thereby
indicating that the [2+1] products have a higher degree of
freedom (see for instance the chemical shift of Hi in 9b and
3b, Figure 2).
Supporting Information). The existence of two different
conformers in solution for 3d might be explained by a gain
in flexibility by comparison with 3a-c due to the presence
of N-methyl substituents, which prevents H-bonding interac-
tion with the NO2 groups. This hypothesis is supported by
the X-ray structure of 8, which reveals that the N(2)O2 group
is coplanar with respect to the molecular plane formed by
the C1-C6 ring and the N(3)-H bridge. In contrast, the
N(1)O2 function in 8 is tilted about 17° with respect to this
molecular plane owing to a lack of intramolecular interaction
(i.e., higher degree of freedom). The UV-vis spectrum of
3a-d in MeCN showed a broad electron-absorption band
(with a shoulder) at λmax 330, 335, 325 nm for 3a-c,
respectively, which is shifted to 260 nm for compound 3d
(Figure 3).
Figure 2.
1H NMR spectra of 9b and 3b in DMSO-d6.
Conversly, the 1H NMR of 3d at room temperature showed
two resonances at 6.33 and 5.31 ppm for the Hi protons in
agreement with the presence of an equilibrium between the
cone-shape and 1,3-alternated conformations, respectively.
This observation was further proved by 13C solid NMR
(which confirmed the purity of 3d) and temperature-
Figure 3. UV-vis spectra of 3-5 in MeCN.
Org. Lett., Vol. 12, No. 12, 2010
1
dependent H NMR experiments (for more details see the
2724

refluxing MeCN (C ) 10-2 M) led to the desired products
4 and 5 with acceptable yields. Unfortunately, attempts to
synthesize the tetraaza[14]-m,o,m,p-cyclophane using the
same strategy failed, probably due to unfavorable steric
Scheme 2. Synthesis of the Tetraazacyclophanes 4 and 5
1
constraints. As with 3a-c, the H NMR spectra of 4 and 5
showed high field chemical shifts of the Hi protons at δ 5.78
and 5.17 ppm, respectively. On the contrary, the Hi protons
in 12 and 13 appeared at 6.16, and 6.46 ppm, respectively,
which suggest that 4 and 5 adopted also a 1,3-alternated
conformation. The UV-vis spectra of the mixed tetraaza-
cyclophanes 4 and 5 in MeCN have essentially the same
features, showing one band at 341 nm with a shoulder (Figure
3).
In summary, while retaining several features of the typical
N(R)-bridged [14] cyclophanes, the new tetraazamacrocycles
3a-d, 4, and 5 synthesized herein have modified cavities in
terms of shape and size. These novel entities open up new
perspectives in supramolecular chemistry owing to the
substitution pattern of the bridging nitrogen atoms, which is
likely to lead to specific electronic and spectroscopic
properties.
The N-methylated aza[14]cyclophanes 3d will be of great
interest to generate stable radical for spintronic application.
Interestingly, further fine-tuning of the cavities can be readily
performed through suitable functionalization of the NH
bridges or by reduction of the nitro groups and subsequent
derivatization of the corresponding amines. These two
approaches are currently under investigation.
Acknowledgment. This work was supported by the Centre
National de la Recherche Scientifique, the Ministe`re de la
Recherche et des Nouvelles Technologies, and Valorpaca
(grant to R.H.). We also thank M. Giorgi (Spectropole, Aix-
Marseille Universite´) for the crystal structure determination
of 8, E. Rosas, G. Herbette and F. Ziarelli (Spectropole, Aix-
Marseille Université) for NMR studies, and Dr. P. Marsal
(CINaM, Aix-Marseille Universite´) for fruitful discussions.
This hypsochromic effect is probably due to the methyl
substitution that modifies the electronic properties by
changing the geometry of the macrocycles. To extend this
class of tetraazamacrocycles, the synthesis of mixed
tetraaza[14]-m,m,m,o- and tetraaza[14]-m,m,m,p-cyclo-
phanes 4 and 5 was then undertaken. 7 and the m-
diaminobenzene 10 were chosen as coupling partners to
yield the [1+1] adduct 11 in EtOH at 0 °C with 80% yield
(Scheme 2).
11 was then subjected to another step of aromatic
substitution with either o- or p-diaminobenzene (1 equiv),
affording the [2+1] products 12 (57% yield) and 13 (50%
yield), respectively. Finally, macrocyclization with 7 in
Supporting Information Available: Detailed experimen-
tal procedures, characterization of all new compounds,
spectroscopic data, and the X-ray crystallographic file for 8
in CIF format. This material is available free of charge via
the Internet at http://pubs.acs.org.
OL100793G
Org. Lett., Vol. 12, No. 12, 2010
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