Synthesis and properties of the emerging azacalix[14]arenes

Article abstract of DOI:10.1002/ejoc.201001432

We describe the synthesis and spectrophotometric studies of novel N(H)-azacalix[4]arenes. The unprecedented direct functionalization of the N(H) bridges furnished N(R)-bridged aza[1₄]calixarene 11 that could complex a neutral guest (CH₂

Full text of DOI:10.1002/ejoc.201001432

FULL PAPER
DOI: 10.1002/ejoc.201001432
Synthesis and Properties of the Emerging Azacalix[14]arenes
Mounia Touil,[a,b] Mourad Elhabiri,[c] Mohammed Lachkar,[b] and Olivier Siri*[a]
Keywords: Calixarenes / Hydrogen bonds / N ligands / Macrocycles / Aromatic substitution / Spectrophotometry
We describe the synthesis and spectrophotometric studies of
novel N(H)-azacalix[4]arenes. The unprecedented direct
functionalization of the N(H) bridges furnished N(R)-bridged
aza[14]calixarene 11 that could complex a neutral guest
(CH2Cl2) or could be further reduced into corresponding tet-
raamino derivative 12.
Introduction
Calix[n]arenes 1 have received much attention over the
last three decades in supramolecular chemistry due to their
specific molecular structure, which allows the formation of
numerous host–guest complexes.[1–3] Many structural modi-
fications[4,5] of the upper and lower rims (i.e., functionaliza-
tion of the phenyl rings) in 1 have been performed and
studied in terms of conformational flexibility and inclusion
behavior.[6–10] In contrast, functionalization of the bridges
cannot be achieved easily,[11] whereas new and specific
properties can be envisaged. Thus, considerable synthetic
efforts are now devoted to the derivatization of basic ca-
lixarene skeletons, and more recent developments include
the preparation of analogues by replacing the methylenic
bridges by heteroatoms to tune the size of the cavity and to
improve their binding properties.[12–20] Among the heteraca-
lixarenes, N(R)-bridged azacalix[4]arenes of type 2, also
called aza[14]metacyclophanes, are an emerging class of
macrocycles owing to the presence of the nitrogen bridges,
which open new perspectives in molecular magnetism and
in supramolecular chemistry as hosts.[15,21]
sible direct functionalization of the NH sites has curiously
never been reported. The synthesis of symmetrical azaca-
lix[4]arenes through Pd-catalyzed aminations[17,19,20,21,24] or
efficient metal-free SNAr[25,26] reactions has been much in-
vestigated since 2008, and in 2010, Katz et al. reported the
first preparation of unsymmetrical analogues and in-
herently chiral anti-azacalix[4]arene regioisomers.[26] Thus,
these tetraazamacrocycles are now considered as a new top-
ical area in calixarene chemistry although only few of their
properties have been reported. In N(H)-bridged azacalix[4]-
arenes of type 3, all the amino bridges are in conjugation
with the dinitrobenzene rings rather than with the two other
phenyl rings because of the electron-withdrawing nature of
the NO2 groups.[25] Thus, unusual spectrophotometric and
electronic properties can be envisaged for macrocycles of
type 3 and physicochemical investigations appeared essen-
tial for a better understanding of their reactivity.
Herein, we wish to report the synthesis and unprece-
dented spectrophotometric properties of new symmetrical
and unsymmetrical azacalix[4]arenes 10. Our stepwise syn-
thetic approach allows access to syn-azacalix[4]arene re-
gioisomer 10b, previously unknown. The first direct func-
tionalization of the NH bridges furnished N(R)-bridged
aza[14]calixarene 11 that could complex a neutral guest
(CH2Cl2) or could be further reduced into corresponding
tetraamino derivative 12.
Curiously, inclusion properties of macrocycles of type 2
remain poorly explored, as only one example was described
in the literature (R1 = Me for K+ complexation).[22] N(H)-
bridged aza[14]metacyclophanes have been strikingly less
investigated[19,21,23] but are much more attractive owing to
the presence of additional hydrogen-bonding sites, and pos-
[a] Centre Interdisciplinaire de Nanoscience de Marseille
(CINaM), UPR 3118 CNRS, Aix-Marseille Université,
Campus de Luminy,
case 913, 13288 Marseille cedex 09, France
Fax: +33-4-91829580
E-mail: siri@univmed.fr
[b] Université Sidi Mohamed Ben Abdellah, Faculté des Sciences
Dhar El Mahraz, “L.I.M.O.M.”, Unité Associée au CNRST
(URAC 19),
B. P. 1796 (Atlas), 30000 Fès, Morroco
[c] Laboratoire de Physico-Chimie Bioinorganique, Université de
Strasbourg, Institut de Chimie de Strasbourg, UMR 7177
CNRS-UdS, ECPM,
25 rue Becquerel, 67200 Strasbourg, France
1914
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Synthesis and Properties of the Emerging Azacalix[14]arenes
mation of polymeric materials even under low dilution con-
ditions.
Results and Discussion
The 1H NMR spectra of azacalix[4]arenes 10 display un-
usual highfield chemical shifts of the intra-annular aromatic
protons Ha in the range 4.85Ͻ δ Ͻ5.53 ppm, which is in
agreement with the 1,3-alternate conformation in which the
Ha protons are located inside the anisotropic shielding cone
of the adjacent aromatic rings (Figure 1).[12,21,25] In ad-
dition, the X-ray data available for related macrocycles indi-
cate that this conformation is preserved in the solid state
with subtle variations induced by the substituents.[25b]
Synthesis
Similarly to the preparation of 9a from 6a,[25a] molecules
6b were first treated with 7 (0.5 equiv.) in refluxing MeCN
in the presence of base to afford [2+1] adduct 9b, which
1
precipitated in 84% yield (Scheme 1). Its H NMR spec-
trum displays a downfield NH signal at δ = 9.60 ppm,
which is in agreement with NH···O2N hydrogen-bonding in-
teractions that restrict the rotation of the uncyclized precur-
sors.[25a] Further macrocyclization of 9b by reaction with 7
in refluxing EtOH (c ≈ 10–2 m) afforded target molecule 10b
in 76% yield as an orange solid (Scheme 1). Similarly, cycli-
zation reaction of 9c – obtained by condensation of 6c and
7 – led to 10c, which precipitated as an orange solid in 35%
yield.
Figure 1. View of the 1,3-alternate conformation of molecules 10.
When molecule 6c was similarly treated with 7 (1 equiv.),
macrocycle 10c was directly obtained pure due to the solu-
bility of the [1+1] reactive intermediate that can react with
itself in EtOH (Scheme 1). The macrocyclization could also
be achieved by dimerization (i.e., autocondensation) when
the [1+1] adduct could be isolated, as already observed for
the preparation of 10a from 8a in refluxing MeCN
(Scheme 2).[25a]
Scheme 2. Synthesis of 10 by dimerization reaction.
Similarly, reaction of 8b – obtained by condensation of
6b and 7 in refluxing EtOH in 87% yield – furnishes macro-
cycle 10e, which has been recently obtained by Katz et al.
directly from 6b and 7 (8b was postulated as the single re-
gioisomer intermediate).[26] Molecules 10b and 10e are
Scheme 1. Synthesis of azacalix[4]arenes 10: S = EtOH except for
10a[25a] and 10d (where S = MeCN).
Our stepwise strategy also allowed the synthesis of un- therefore regioisomers (i.e., syn and anti, respectively), the
symmetrical derivatives. Compound 8a[25a] could be con- former being only accessible by our stepwise synthesis
densed with 6b at c ≈ 10–2 m in EtOH to furnish unsymmet- (Scheme 1).
rical intermediate 9d as an orange solid (73% yield). As
As expected, the 1H NMR spectrum of 8b shows the
1
expected, its H NMR spectrum shows the presence of two presence of NH resonance at δ = 9.84 ppm, which is consis-
NH signals at δ = 9.67 and 9.70 ppm, which is in agreement tent with the presence of a NH···O2N intramolecular hydro-
with two intramolecular H-bonds. The macrocyclization re- gen bond. The two doublets at δ = 6.84 and 9.15 ppm corre-
action of 9d and 7 in refluxing MeCN afforded 10d in 33% spond to the coupling of the aromatic protons with the
yield (Scheme 1). As already reported,[25a,26] these observa- fluoride atom (4JH,F = 13.5 Hz and JH,F = 7.9 Hz, respec-
3
tions are consistent with SNAr reactions, which are more tively). Importantly, the formation of single regioisomer 8b
favored at higher concentrations and which prevent the for- for which the CH3 group on the phenyl ring is located in
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M. Touil, M. Elhabiri, M. Lachkar, O. Siri
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the para position with respect to the NH bridge could be
established by X-ray analysis of the hydroxylated product
of 8b.[27]
Curiously, direct substitution of N(H)-bridged azaca-
lix[4]arenes has never been reported, whereas this approach
is very attractive for the introduction of coordinating units.
For instance, molecule 10a could be functionalized by reac-
tion with BOC2O (8 equiv.) in refluxing THF in the pres-
ence of DMAP, affording N-substituted azacalix[4]arene 11
as a yellow powder in 68% yield (Scheme 3). Its hydrogena-
tion furnishes tetraamino derivative 12 (19% yield) that
constitutes a candidate of choice for further substitution
reactions and complexation owing the presence of four ex-
ternal NH2 functions. It is noteworthy that the presence of
the BOC protecting groups in 12 prevents the oxidation of
the two electron-rich tetraaminobenzene subunits.
Figure 2. Top and side views of the structure of [11·CH2Cl2] in the
crystal. The disorder of CH2Cl2 is omitted for clarity. Selected bond
lengths [Å] and angles [°]: N(1)–C(23) 1.426(3), N(1)–C(1) 1.436(4),
N(4)–C(19) 1.404(4), N(4)–C(17) 1.434(4), N(3)–C(11) 1.414(4),
N(3)–C(13) 1.435(4), N(2)–C(3) 1.436(4), N(2)–C(7) 1.412(4),
N(5)–C(8) 1.464(4), N(6)–C(10) 1.467(5), N(7)–C(20) 1.470(4),
N(8)–C(22) 1.458(4); N(4)–C(19)–C(24) 118.8(2), N(2)–C(7)–C(12)
118.9(3), C(19)–N(4)–C(17) 117.5(2), C(3)–N(2)–C(7) 117.1(2).
Scheme 3. Synthesis of functionalized azacalix[4]arenes 11 and 12.
Interestingly, crystals suitable for X-ray diffraction mea-
surements could be obtained by slow evaporation of 11 in
CH2Cl2 in air.[28] Structure determination clearly estab-
lished the unexpected formation of inclusion complex
[11·CH2Cl2] in which the four BOC groups are positioned
in the upper cap for interacting with the neutral guest (Fig-
ure 2). Although CH2Cl2 encaged in the host cavity is found
to be disordered, the distances between the chloride atoms
and the nearest C–H hydrogen atoms are in the range
its low stability (the weak C–H···Cl interactions cannot
compete with the dynamic of rotation of the methyl
groups).
Absorption and Acid-Base Properties
It is noteworthy that azacalix[4]arenes 10a–e are slightly
2.577–3.546 Å, as expected for C–H···Cl hydrogen-bonding soluble in dichloromethane, dimethylformamide, and aceto-
interactions.[29]
nitrile and sparingly soluble in water. The spectrophotomet-
In the N(H)-bridged azacalix[4]arenes of type 3, all the ric and acid–base properties of azacalix[4]arenes 10a and
bridging nitrogen atoms are in conjugation with the dinitro- 10c (the most soluble) were examined in a mixed solvent
benzene rings rather than with the two other phenyl rings made of 90% acetonitrile and 10% water (by volume),
because of the electron-withdrawing nature of the NO2 which facilitates the dissolution of these compounds at ca.
groups.[25] As a result, the two C–N bond lengths in the C– 10–4 m in aqueous solution. Calibration of the combined
N(H)–C moieties are not equivalent (1.44 vs. 1.35 Å).[25b] pHmetric glass electrode was accomplished by using com-
For 11, the two C–N bond lengths in the C–N(BOC)–C mercial aqueous standard reference buffer solutions, thus
moieties are similar due to the conjugation of the nitrogen leading to the reading of swpH values (pH measured in ace-
atoms, with the carbonyl groups rather than with the dini- tonitrile/water with electrodes calibrated in water). Subse-
trobenzene rings [for instance, N(1)–C(23) 1.426(3) and quent corrections[31] were applied to obtain the correspond-
N(1)–C(1) 1.436(4) Å]. Although the conformation of 11 in ing sspH (acidity measured in acetonitrile/water, 90:10, with
[11·CH2Cl2] can be viewed as 1,3-alternate, the two nitro- electrodes calibrated in the same mixed solvent). Azacalix-
benzene subunits are almost coplanar, whereas the two [4]arenes 10a and 10c are characterized by intense absorp-
other C6 rings appear almost parallel to each other and tion bands in the UV region centered at about 340 nm (10a,
quasiorthogonal to the former (Figure 2). To the best of our λmax = 340 nm, ε340 = 4.72ϫ104 m–1 cm–1; 10c, λmax
=
knowledge, this “table-like” geometry has been previously 343 nm, ε343 = 3.77ϫ104 m–1 cm–1), together with a shoul-
observed only for methylene-bridged calixarenes and resor- der positioned at lower energies (λmax ca. 400 nm, ε400 ca.
cinarenes.[30] In fluid solution, the factor of crystallinity is 1–2.5ϫ104 m–1 cm–1). These spectroscopic data are in agree-
lost and the complex could not be characterized owing to ment with those measured for 1,5-diamino-2,4-dinitroben-
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Synthesis and Properties of the Emerging Azacalix[14]arenes
zene (λmax = 321 nm, ε321 = 2.9ϫ104 m–1 cm–1, λmax
=
397 nm, ε397 = 104 m–1 cm–1) and therefore substantiate that,
because of the electron-withdrawing effects of the nitro sub-
stituents and the strong intramolecular NH···O2N hydrogen
bonds, the four NH bridging atoms are primarily conju-
gated to the dinitrobenzene moieties. The observed absorp-
tions therefore mainly originate from π–π* transitions of
these two electronic independent diaminodinitrobenzene
components;[32] those of the two other benzene rings are
most likely centered at higher energies. Interestingly, the
four bridging ionizable secondary amines can be either pro-
tonated or deprotonated, leading to potential positively and
negatively charged hosts, respectively. For that reason,
knowledge of their acid–base properties is of great impor-
tance regarding their high potential in ionic or molecular
recognition processes. Preliminary spectral studies were
thus performed by adding an excess amount of either base
(NEt4OH) or acid (HClO4) on solutions of 10a or 10c (Fig-
ure 3). These spectrophotometric data show that, even with
a large excess of acid with respect to the ligands (ca.
3000 equiv.), no significant variation could be observed.
This observation suggests that the secondary amines cannot
be protonated under our experimental conditions. The very
low protonation constants of p-nitroaniline (logKH = –0.3
in CH3CN/H2O, 75:25 w/w[33] and logKH = 1.003 in
H2O[34]) and that of o-nitroaniline (logKH = –0.282 in H2O)
further support this observation,[33] which may be due to
important electronic effects (electron-withdrawing effect) of
the dinitrobenzene rings (e.g., o-nitroaniline and p-nitro-
aniline) but also to the participation of the secondary
amines in strong intramolecular NH···O2N hydrogen-bond-
ing interactions (e.g., o-nitroaniline).
Figure 3. Absorption spectra of azacalix[4]arene 10c measured un-
der different experimental conditions. Solvent: CH3CN/H2O (9:1,
v:v); T = 25.0(2) °C; I = 0.1 m (NEt4ClO4). (1) [10c] = 1.80ϫ10–5 m;
(2) [HClO4]/[10c] ≈ 3000; (3) [NEt4OH]/[10c] ≈ 2550; (4) [NEt4OH]/
[10c] ≈ 3800.
Figure 4. Spectral variations of 10c recorded upon the addition of
an excess amount of base (NEt4OH). Solvent: CH3CN/H2O (9:1,
v:v); T = 25.0(2) °C; I = 0.1 m (NEt4ClO4). [10c] = 3.27ϫ10–5 m;
(1) [NEt4OH]/[10c] = 0; (2) [NEt4OH]/[10c] = 595.
In contrast, addition of base leads to drastic spectral
changes with bathochromic shifts of the main absorption
bands and simultaneous formation of new and less-intense pounds,[35] which is an apparent signature for the presence
absorptions in the visible region (λmax ≈ 500 nm, ε500 ≈ 1– of extended conjugated systems (quinoidal-type structure)
1.5ϫ104 m–1 cm–1), thus conferring a red color to the basi- with adjoining dinitrobenzene partners (Scheme 4).
fied solutions (Figures 3 and 4).
To determine the acid–base properties of the chromo-
This spectral feature is most likely related to the depro- phoric azacalix[4]arene, absorption spectrophotometric ti-
tonation of the monobasic amine functions, leading to trations versus pH were carried out in CH3CN/H2O (9:1,
amide anions. In addition, the Δλmax values measured for v:v). The spectrophotometric and potentiometric data of
10a (52 nm) and 10c (54 nm) upon addition of base are sig- 10a between pH 9.79 and 16.47 and that of 10c between
nificantly larger than those observed for related com- pH 10.93 and 16.48 are given in Figure 5.
Figure 5. Spectrophotometric vs. pH titrations of 10a (left) and 10c (right). Solvent: CH3CN/H2O (9:1, v:v); T = 25.0(2) °C; I = 0.1 m
(NEt4ClO4). (Left) [10a] = 2.27ϫ 10–5 m; (1) sspH = 9.79; (2) sspH = 16.47. (Right) [10c] = 3.28ϫ 10–5 m; (1) sspH = 10.93; (2) sspH =
16.48.
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M. Touil, M. Elhabiri, M. Lachkar, O. Siri
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of the experimental conditions, significantly lower that
those determined for some reference compounds (for p-ni-
troaniline: logKH = 20.9 in DMSO and ca. 19 in DMSO/
H
H
water, 8:2, v:v).[40] Large Δlog K = logK3 – logK4 val-
ues[41] of about 2.0(8) and 2.5(9) with respect to pure statis-
H
H
tical effects (logK3 – logK4 is expected to be 0.37 for
four identical and independent sites) were calculated for
compounds 10a and 10c, respectively. These data reflect
strong electrostatic repulsions and geometrical effects be-
tween the molecular subunits within the constrained azaca-
lix[4]arene edifice. The two higher protonation constants
could not be determined under our experimental condi-
tions. The electronic spectra of the protonated species of
10a and 10c are given in Figure 6.
Deprotonation of neutral azacalix[4]arenes 10a and 10c
affording the amide monoanion led to moderate spectral
variation by comparison with those experienced during the
formation of the amide dianion. As suggested above, the
spectral changes triggered by deprotonation of the bridging
amine functions are likely associated to the formation of
extended conjugated quinoidal systems (Scheme 4). Inter-
estingly, the mesomeric forms of the mono- and bis-depro-
tonated species allowed the attribution of the deprotonation
sites. Deprotonation of both bridging secondary amines
borne by the same 5-substituted-1,3-diaminobenzene unit is
not favored due to geometrical constrains (it forces the sys-
tem to become coplanar by formation of a more extended
conjugated system involving three adjacent aromatic units).
Scheme 4. Schematic mesomeric forms within the deprotonated
azacalix[4]arene derivatives.
As previously observed, an increase in pH induces sig-
nificant spectrophotometric changes such as a bathoch-
romic shift of the main absorption band as well as the ap-
pearance of broad absorption in the visible region at ca.
500 nm. No spectral variation was observed below pH 9–10
for both compounds. It is noteworthy that compounds 10a
and 10c possess four amino sites that can be deprotonated.
Statistical treatment[36–39] of the spectrophotometric versus
pH data led to the determination of two protonation con-
stants [Equations (1) and (2)]. The reported errors on the
protonation constants are given as 3σ (σ = standard devia-
tion).
(1)
(2)
Conclusions
We described the stepwise synthesis of novel azacalix-
[4]arenes and an unprecedented syn-regioisomer analogue
(i.e., 10b). The first absorption spectrophotometric and
For 10a, the logarithmic values of the protonation con- potentiometric studies of the two representative amphoteric
H
stants are logK3 = 17.0(8) and logK4H = 15.0(1). For 10c, azacalix[4]arenes (i.e., 10a and 10c) allowed determination
H
comparable values were determined [logK3 = 17.2(8) and of their acid–base properties. Under our experimental con-
H
logK4 = 14.7(2)], thus signifying that the substitution of ditions, the protonation constants related to the formation
the two face-to-face phenyl rings has little influence on the of ammonium cations could not be determined due to elec-
acid–base properties of the bridging secondary amines. tronic (electron-withdrawing effects) and structural (strong
These data are in agreement with the absence of electronic intramolecular NH···O2N hydrogen bonds) constraints. In
communication (i.e., conjugation) between the two types of contrast, deprotonation of these bridging secondary
aromatic units. In addition, these pKa values are, regardless amines, which affords the corresponding amide anions,
Figure 6. Electronic spectra of the protonated species of 10a (left) and 10c (right). Solvent: CH3CN/H2O (9:1); T = 25.0(2) °C; I = 0.1 m
(NEt4ClO4).
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Synthesis and Properties of the Emerging Azacalix[14]arenes
zene (200 mg, 0.98 mmol, 1 equiv.), 2,3-diaminotoluene (141 mg,
1.96 mmol, 2 equiv.), and N-diisopropylethylamine (0.85 mL,
4.90 mmol, 2.5 equiv.) in refluxing EtOH was stirred for 24 h. The
obtained precipitate was isolated by filtration and washed with
water to afford 9b as an orange solid (335 mg, 84% yield). M.p.
could be studied and was easily monitored by absorption
spectrophotometric means. The spectral variations were ra-
tionalized in terms of the formation of stable quinoidal-
type structures in solution favored by the adjoining nitro
groups. The first direct functionalization of N(H)-bridged
aza[14]metacyclophanes 11 allowed the preparation of in-
clusion complex [11·CH2Cl2], which was fully characterized
in the solid state. The N-substituent of the four bridges in-
teracts with CH2Cl2 through C–H···Cl hydrogen bonds, and
1
209 °C. H NMR (250 MHz, [D6]acetone): δ = 2.78 (s, 6 H), 6.44
(dd, Jortho = 7.8 Hz, Jmeta = 2.2 Hz, 2 H, aromatic H), 6.61 (d, Jmeta
= 2.2 Hz, 2 H, aromatic H), 6.71 (s, 1 H, aromatic H), 6.95 (d,
Jortho = 7.8 Hz, 2 H, aromatic H), 9.10 (s, 1 H, aromatic H), 9.56
(br. s, 2 H, NH) ppm. MS (MALDI-TOF+): m/z = 408.16 [M]+.
the complex adopts a table-like geometry that should favor C20H20N6O4 (408.42): calcd. C 58.82, H 4.94, N 20.58; found C
58.61, H 4.94, N 20.56.
its anchoring on substrates. In addition, reduction of 11 led
to 12, which are rare examples of azacalixarenes that can
be functionalized at the bridges through NH substitutions,
but also at the rim by substitution of the four NH2 func-
tions. These approaches are currently under investigation.
N1-{5-[3-Amino-5-methyl(hydroxy)phenylamino]-2,4-dinitrophen-
yl}-5-methyl(hydroxy)benzene-1,3-diamine (9c): To a solution of 3,5-
diaminobenzylalcool (414 mg, 1.96 mmol, 2 equiv.) and N-diiso-
propylethylamine (0.67 mL, 4.9 mmol, 5 equiv.) in EtOH was
added of 1,5-difluoro-2,4-dinitrobenzene (200 mg, 0.98 mmol,
1 equiv.). The mixture was stirred at reflux for 24 h. The obtained
precipitate was isolated by filtration and washed with water to af-
ford 9c as an orange solid (354 mg, 82% yield). M.p. 218 °C. 1H
NMR (250 MHz, [D6]DMSO): δ = 4.34 (d, J = 5.6 Hz, 4 H), 5.16
(t, J = 5.7 Hz, 2 H, OH), 5.31 (s, 4 H, NH2), 6.35 (s, 4 H, aromatic
H), 6.40 (s, 2 H, aromatic H), 6.61 (s, 1 H, aromatic H), 9.02 (s, 1
H, aromatic H), 9.58 (br. s, 2 H, NH) ppm. MS (ESI+): m/z =
441.1 [M + H]+, 463.1 [M + Na]+. C20H20N6O6·1/2H2O (449.42):
calcd. C 53.45, H 4.71, N 18.70; found C 53.79, H 4.60, N 18.65.
Experimental Section
General Methods: Commercial- analytical-grade reagents were ob-
tained from commercial suppliers and were used directly without
further purification. Solvents were distilled under an atmosphere
of argon prior to use and dried by standard methods. 1H NMR
spectra were recorded in CDCl3 or [D6]DMSO with AC250 spec-
trometers, operating at 250 MHz. Chemical shifts are reported in δ
units relative to the singlet at δ = 7.26 for CDCl3. Elemental and
MS analyses were performed by Marseille Spectropole. ESI mass
spectral analyses were recorded with a 3200 QTRAP (Applied Bio-
systems SCIEX) mass spectrometer. HRMS mass spectral analysis
was performed with a QStar Elite (Applied Biosystems SCIEX)
mass spectrometer. Molecules 8a, 9a, and 10a were prepared as
described in the literature.[25] For the nomenclature quote of the
macrocycles, the following numbering of the atoms has been used:
Methyl-3-[5-(3-amino-4-methylphenylamino)-2,4-dinitrophenyl-
amino]-5-aminobenzoate (9d): To a solution of 8a (500 mg,
1.43 mmol, 1 equiv.) in EtOH was added 2,4-diaminotoluene (6b;
174.28 mg, 1.43 mmol, 1 equiv.) and diisopropylethylamine
(0.62 mL, 3.57 mmol, 2.5 equiv.). The mixture was heated at reflux
for 24 h. The obtained precipitate was isolated by filtration and
washed with water to afford 9d as an orange solid (480 mg, 73%
1
yield). M.p. 214 °C. H NMR (250 MHz, [D6]DMSO): δ = 1.97 (s,
3 H, CH3), 3.82 (s, 3 H, OCH3), 4.99 (s, 2 H, NH2), 5.61 (s, 2 H,
NH2), 6.52 (dd, Jortho = 8.0 Hz, Jmeta = 2.2 Hz, 1 H, aromatic H),
6.65 (m, 1 H, aromatic H), 6.74 (s, 1 H, aromatic H), 6.87 (m, 1
H, aromatic H), 6.96 (d, Jortho = 8.0 Hz, 1 H, aromatic H), 7.11 (m,
1 H, aromatic H), 7.15 (m, 1 H, aromatic H), 9.17 (s, 1 H, aromatic
H), 9.67 (br. s, 1 H, NH), 9.70 (br. s, 1 H, NH) ppm. MS (ESI+):
m/z = 453.1 [M + H]+. C21H20N6O6·1/2H2O (461.43): calcd. C
54.66, H 4.59, N 18.21; found C 54.98, H 4.38, N 18.11.
5,15-Dimethyl-9,11,21,23-tetranitro-1,7,13,19-tetraaza[14]cyclo-
phane (10b): To a solution of 9b (700 mg, 1.71 mmol, 1 equiv.) in
EtOH was added N-diisopropylethylamine (1.5 mL, 4.29 mmol,
2.5 equiv.) and 1,5-difuoro-2,4-dinitrobenzene (345 mg, 1.69 mmol,
1 equiv.). The mixture was heated at reflux for 20 h. The obtained
precipitate was isolated by filtration and washed with water to af-
ford 10b as a yellow solid (750 mg, 76% yield). M.p. Ͼ300 °C (de-
N1-(5-Fluoro-2,4-dinitrophenyl)-4-methylbenzene-1,3-diamine (8b):
A mixture of 1,5-difluoro-2,4-dinitrobenzene (200 mg, 0.98 mmol,
1 equiv), 2,3-diaminotoluene (120.5 mg, 0.98 mmol, 1 equiv.), and
diisopropylethylamine (0.85 mL, 4.9 mmol, 2.5 equiv.) in refluxing
EtOH was stirred for 24 h. The obtained precipitate was isolated
by filtration and washed with water to afford 8b as an orange solid
1
comp.). H NMR (250 MHz, [D6]DMSO): δ = 2.20 (s, 6 H, CH3),
4.85 (s, 1 H, aromatic H), 4.97 (s, 1 H, aromatic H), 6.91 (d, Jmeta
=
1.9 Hz, 2 H, aromatic H), 7.04 (dd, Jortho = 7.9 Hz, Jmeta = 2.2 Hz, 2
H, aromatic H), 7.32 (d, Jortho = 8.1 Hz, 2 H, aromatic H), 9.00 (s,
1 H, aromatic H), 9.04 (s, 1 H, aromatic H), 9.66 (br. s, 2 H, NH),
9.67 (br. s, 2 H, NH) ppm. MS (ESI+): m/z = 573.1 [M + H]+.
C26H20N8O8 (572.49): calcd. C 54.55, H 3.52, N 19.57; found C
55.57, H 3.63, N 19.10.
1
(260 mg, 87% yield). M.p. 202 °C. H NMR (250 MHz, CDCl3): δ
= 2.20 (s, 3 H, CH3), 3.80 (br. s, 2 H, NH2), 6.55 (m, 1 H, aromatic
3
H), 6.60 (d, J = 2.0 Hz, 1 H aromatic H), 6.84 (d, JHF = 13.5 Hz,
1 H, aromatic H), 7.15 (d, J = 7.8 Hz, 1 H, aromatic H), 9.15 (d,
4JHF = 7.9 Hz, 1 H, aromatic H), 9.84 (br. s, 1 H, NH) ppm. MS
(MALDI-TOF+): m/z = 307 [M + H]+. C13H11FN4O4·1/3H2O
(312.26): calcd. C 50.00, H 3.77, N 17.94; found C 50.27, H 3.74,
N 17.00.
4,16-Bis[methyl(hydroxy)]-9,11,21,23-tetranitro-1,7,13,19-tetraaza-
[14]cyclophane (10c): A mixture of 3,5-diaminobenzyl alcohol (6c;
258 mg, 1.22 mmol, 1 equiv.), N-diisopropylethylamine (1.06 mL,
N1-[5-(3-Amino-4-methylphenylamino)-2,4-dinitrophenyl]-4-methyl- 6.11 mmol, 5 equiv.), and 1,5-difluoro-2,4-dinitrobenzene (7;
benzene-1,3-diamine (9b): A mixture of 1,5-difluoro-2,4-dinitroben-
250 mg, 1.22 mmol, 1 equiv.) was heated at reflux in EtOH for 5 h.
Eur. J. Org. Chem. 2011, 1914–1921
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1919

M. Touil, M. Elhabiri, M. Lachkar, O. Siri
FULL PAPER
The obtained precipitate was isolated by filtration and washed with
perchlorate (NEt4ClO4, Fluka, puriss). CAUTION: Perchlorate
water to afford 10c as an orange solid (275 mg, 35% yield). M.p. salts combined with organic ligands are potentially explosive and
290 °C. 1H NMR (250 MHz, [D6]DMSO): δ = 4.46 (d, J = 5.6 Hz, should be handled in small quantities and with the necessary pre-
4 H), 5.37 (t, J = 5.7 Hz, 2 H, OH), 5.64 (s, 2 H, aromatic H), 7.07
cautions.[42]
(s, 6 H, aromatic H), 9.04 (s, 2 H, aromatic H), 9.69 (br. s, 4 H,
Potentiometry: Ag/AgCl combined glass electrode (Metrohm
6.0234.500, Long Life) filled with 0.1 m NaCl (Fluka, p.a.) in water
was calibrated (swpH: pH measured in acetonitrile/water with elec-
trodes calibrated in water) with commercial aqueous standard ref-
erence buffer solutions (Merck CertiPUR, pH = 1.68, 4.00, 6.86,
7.41, and 9.18). Potential differences were given by a Materlab
PHM240 (Radiometer Analytical) millivoltmeter and the experi-
ments were carried out at 25.0(2) °C maintained with the help of a
Haake FJ thermostat. The use of δ values reported in the literature
NH) ppm. MS (ESI+): m/z = 605.1 [M + H]+. C26H20N8O10
·
2/3EtOH·1/3H2O (641.21): calcd. C 51.20, H 3.88, N 17.48; found
C 51.10, H 3.84, N 17.62.
4-Methyl(ester)-15-methyl-9,11,21,23-tetranitro-1,7,13,19-tetraaza-
[14]cyclophane (10d): A mixture of 9d (300 mg, 0.66 mmol,
1 equiv.), diisopropylethylamine (0.58 mL, 3.31 mmol, 5 equiv.),
and 1,5-difuoro-2,4-dinitrobenzene (135.4 mg, 0.66 mmol, 1 equiv.)
was heated at reflux in acetonitrile for 20 h. The obtained precipi-
tate was isolated by filtration and washed with water to afford 10d
as an orange-brown solid (136 mg, 33% yield). M.p. 253 °C. 1H
NMR (250 MHz, [D6]DMSO): δ = 2.07 (s, 3 H, CH3), 3.86 (s, 3
H, OCH3), 5.21 (s, 1 H, aromatic H), 5.25 (s, 1 H, aromatic H),
7.03 (m, 1 H, aromatic H), 7.29 (d, Jortho = 8.0 Hz, 1 H, aromatic
H), 7.41 (m, 1 H, aromatic H), 7.62 (m, 1 H, aromatic H), 7.66 (m,
2 H, aromatic H), 9.00 (s, 1 H, aromatic H), 9.03 (s, 1 H, aromatic
H), 9.72 (br. s, 4 H, NH) ppm. MS (ESI+): m/z = 617 [M + H]+.
C27H20N8O10·H2O (634.52): calcd. C 51.11, H 3.49, N 17.66; found
C 51.55, H 3.58, N 17.25.
s
allowed the wpH values to be converted into the corresponding
sspH values (sspH: pH measured in acetonitrile/water with elec-
trodes calibrated in the same acetonitrile/water mixture).
Protonated Species of 10a and 10c: Solutions of 10a (2.27ϫ10–5 m)
and 10c (3.28ϫ10–5 m) were prepared by quantitative dissolution
of a solid sample in acetonitrile/water (9:1). An aliquot of 40 mL
was introduced into a jacketed cell (Metrohm 6.1414.150) main-
tained at 25.0(2) °C by the flow of a Haake FJ thermostat. The
solution was continuously de-oxygenated by bubbling with oxygen
free argon. The titration of 10a (9.79Ͻ sspH Ͻ16.47) or 10c
(10.93Ͻ sspH Ͻ16.48) was carried out by addition of known vol-
umes of a 0.1 m standardized tetraethylammonium hydroxide solu-
tion. Special care was taken to ensure that complete equilibration
was attained. Absorption spectra vs. sspH were recorded using a
Varian CARY 50 spectrophotometer fitted with Hellma optical fi-
bers (Hellma, 041.002-UV) and an immersion probe made of
quartz suprazil (Hellma, 661.500-QX).
N,NЈ,NЈЈ,NЈЈЈ-Tetraboc-4,16-bis[methyl(ester)]-9,11,21,23-tetra-
nitro-1,7,13,19-tetraaza[14]cyclophane (11): To a solution of 10a
(200 mg, 0.3 mmol, 1 equiv.) in dry THF (20 mL) was added
BOC2O (529, 2.42 mmol, 8 equiv.) under an atmosphere of nitrogen
and 4-DMAP (42 mg, 0.34 mmol, 1.14 equiv.). The mixture was
heated at reflux for 4 h, the solvent was removed under vacuum,
and the residue was purified by column chromatography (silica gel;
cyclohexane/ethyl acetate, 7/3) to give 11 (220 mg, 68% yield) as a
yellow solid. M.p. 257 °C. 1H NMR (250 MHz, [D6]DMSO at
60 °C): δ = 1.38 (s, 36 H, tBu), 3.82 (s, 6 H, OCH3), 6.85 (s, 2 H,
aromatic H), 7.45 (s, 2 H, aromatic H), 7.74 (s, 4 H, aromatic H),
8.93 (s, 2 H, aromatic H) ppm. MS (ESI+): m/z = 1061.3 [M +
H]+, 1078.5 [M + NH4]+. C48H52N8O20·1/2AcOEt (1105.04): calcd.
C 54.35, H 5.11, N 10.14; found C 54.55, H 5.21, N 9.92.
Refinement of the Data: The spectrophotometric and potentio-
metric data were processed with the Specfit program, which adjusts
the stability constants and the corresponding molar extinction co-
efficients (m–1 cm–1) of the species at equilibrium. Specfit[36–39] uses
factor analysis to reduce the absorbance matrix and to extract the
eigenvalues prior to the multiwavelength fit of the reduced data set
according to the Marquardt algorithm.[43,44] Distribution curves of
the various species were calculated using the Haltafall program.[45]
Origin 5.0 was used to process the analytical results.[46] For the sake
of simplicity, charges are omitted in all the chemical equilibria. The
errors are given as 3σ with σ = standard deviation.
N,NЈ,NЈЈ,NЈЈЈ-Tetraboc-4,16-bis[methyl(ester)]-9,11,21,23-tetra-
amino-1,7,13,19-tetraaza[14]cyclophane (12):
A mixture of 11
(200 mg) in methanol/ethyl acetate (3:2, 25 mL) and palladium on
carbon (5%) was stirred under an atmosphere of hydrogen over-
night at room temperature. The catalyst was filtered off over Celite,
and the filtrate was concentrated under vacuum. Quenching with
ethyl acetate and removing the solvent gave a beige solid (33 mg,
19% yield). M.p. 232 °C. 1H NMR (250 MHz, [D6]DMSO, 90 °C):
δ = 1.42 (s, 36 H, tBu), 3.88 (s, 6 H, OCH3), 4.16 (s, 8 H, NH2),
6.11 (s, 2 H, aromatic H), 6.34 (s, 2 H, aromatic H), 6.47 (s, 2 H,
aromatic H), 8.06 (s, 4 H, aromatic H) ppm. HRMS (ESI+): calcd.
for C48H60N8O12 [M + NH4]+ 958.4669; found 958.4663.
X-ray Crystal Data: Selected single crystals were mounted on a
Nonius Kappa-CCD area detector diffractometer. The structures
were solved by direct methods (SIR97) and refined against F2 using
the SHELXL97 software. The data were not corrected for absorp-
tion. All non-hydrogen atoms were refined anisotropically. Hydro-
gen atoms were generated according to stereochemistry and refined
using
a riding model in SHELXL97. CCDC-730533 (for
Physicochemistry
11·CH2Cl2) 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.
Starting Materials and Solvents: The acid–base properties of li-
gands 10a and 10c were examined in acetonitrile/water (9:1, v:v).
Distilled water was further purified by passing through a mixed
bed of ion-exchanger (Bioblock Scientific R3–83002, M3–83006)
and activated carbon (Bioblock Scientific ORC-83005). The dis-
tilled water, spectroscopic grade acetonitrile, and CH2Cl2 (Merck,
Uvasol, p.a.) were de-oxygenated using CO2- and O2-free argon
prior to use (Sigma Oxiclear cartridge). All the stock solutions were
prepared by weighing solid products using an AG 245 Mettler To-
ledo analytical balance (precision 0.01 mg). Complete dissolution
of the ligands was achieved with the help of an ultrasonic bath.
The ionic strength was adjusted to 0.1 m with tetraethylammonium
Acknowledgments
This work was supported by the Centre National de la Recherche
Scientifique, the Ministère de la Recherche et des Nouvelles Tech-
nologies, and the Agence Universitaire de la Francophonie (PhD
grant of M.T.). We also thank Michel Giorgi for the determination
of the crystal structure (Spectropole, Marseille).
1920
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 1914–1921

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Received: October 20, 2010
Published Online: February 15, 2011
27.
Eur. J. Org. Chem. 2011, 1914–1921
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1921