P-(benzyloxy)calix[8]arene synthesis revisited: P-(benzyloxy)calix[4]-, p-(benzyloxy)calix[5]-, p-(benzyloxy)calix[7]-, and p-(benzyloxy)bis(homooxa) calix[4]arenes

Article abstract of DOI:10.1002/ejoc.200901405

A detailed investigation of the 4-(benzyloxy)phenol/formaldehyde reaction shows that along with the previously described p-(benzyloxy)calix[8]arene and p-(benzyloxy)calix[6]arene, others calixarenes are observed and easily recovered on a preparative scale. All these new calixarenes are opening interesting perspectives for the synthesis of new supramolecular hosts, easily functionalized at the para position under very mild conditions and/or exhibiting a deep hydrophobic pocket. During the course of the synthesis of p-(benzyloxy)calix[8]arene, compounds 4-7 are easily recovered as byproducts on a preparative scale. Alkylation of these new calixarenes leads to the first functionalized derivatives.

Full text of DOI:10.1002/ejoc.200901405

FULL PAPER
DOI: 10.1002/ejoc.200901405
p-(Benzyloxy)calix[8]arene Synthesis Revisited: p-(Benzyloxy)calix[4]-,
p-(Benzyloxy)calix[5]-, p-(Benzyloxy)calix[7]-, and
p-(Benzyloxy)bis(homooxa)calix[4]arenes
Vincent Huc,*[a] Eloïne Npetgat,[a] Vincent Guérineau,[b] Sophie Bourcier,[c]
Amandine Dos Santos,[a] Régis Guillot,[a] Jean-Pierre Baltaze,[a] and Cyril Martini[a]
Keywords: Calixarenes / Alkylation / Functionalization / Supramolecular chemistry
A detailed investigation of the 4-(benzyloxy)phenol/formal-
dehyde reaction shows that along with the previously de-
scribed p-(benzyloxy)calix[8]arene and p-(benzyloxy)calix-
[6]arene, others calixarenes are observed and easily reco-
vered on a preparative scale. All these new calixarenes are
opening interesting perspectives for the synthesis of new
supramolecular hosts, easily functionalized at the para posi-
tion under very mild conditions and/or exhibiting a deep
hydrophobic pocket.
Some years ago, we and others described the use of p-
(benzyloxy)phenol (1) as a starting compound for the syn-
thesis of the corresponding p-(benzyloxy)calix[8]arene and
its derivatives (Scheme 1, 2). This calixarene was shown to
be easily debenzylated under mild and selective Pd-cata-
lyzed hydrogenolysis conditions, opening the way to easy
derivatization of the p-position by alkylation of the released
hydroxy groups.[7,16,21,42]
Introduction
Calixarenes have received much attention during the last
decades due to the tremendous possibilities offered by these
easily accessible macrocycles.[1–4] Some of the most thor-
oughly studied properties include ion and/or molecule re-
cognition phenomena,[5–14] supramolecular assemblies,[15,16]
nanoparticles synthesis,[17–21] and so on. In most cases,
these studies were performed with ubiquitous p-(tBu)-func-
tionalized calixarenes, as the synthesis of these derivatives
is by far the most documented one since the pioneering
work of Gutsche et al.[3,22] As a consequence, the use of
other p-functionalized phenols for calixarene synthesis is to
a large extent unexplored, even if some one-step syntheses
Along with the p-(benzyloxy)calix[8]arene, the corre-
sponding p-(benzyloxy)calix[6]- and p-(benzyloxy)calix[7]-
arenes (compounds 3 and 4, respectively) were also men-
tioned,[42] but detailed characterizations was provided only
for the former.[7] To the best of our knowledge, these are
the only known examples of one-step syntheses of p-(benz-
yloxy)calixarenes. We show here that along with these
known compounds, the corresponding p-(benzyloxy)calix-
[4]arene (5), p-(benzyloxy)bis(homooxa)calix[4]arene (6),
and p-(benzyloxy)calix[5]arene (7) are also present as by-
products during the synthesis of p-(benzyloxy)calix[8]arene
and are recovered on a preparative scale (Scheme 2a).
Moreover, the corresponding calix[7]arene is directly reco-
vered (and fully characterized) from the reaction mixture in
a very simple way, without the need for any derivatization
procedure. This last point contrasts its first description.[42]
Along with an enrichment of the p-(benzyloxy)calixarene
family, these results open the way to the one-step synthesis
of new calixarenes with interesting p-functionalization,
leading to new possibilities in the field of supramolecular
chemistry and materials.
of
other
p-(alkyl)-functionalized
calixarenes
are
known.[23–27] In most cases, post-functionalization of the p-
position of these calixarenes (not always possible) is a
multistep process, requiring the use of reactive electrophilic
de-tert-butylating reagents, not compatible with heavily
functionalized calixarenic platforms.[28–37] The p-function-
alization of calixarenes under mild conditions is thus still
an open question. However, this is an important concern,
as the control of the p-functionalization of calixarenes was
shown to open very interesting possibilities for the synthesis
of new receptors (Figure 1).[28,29,32–34,38–41]
[a] Université de Paris-Sud, Institut de Chimie Moléculaire et des
Matériaux d’Orsay,
91405 Orsay France
Fax: +33-1-69157436
E-mail: vincenthuc@icmo.u-psud.fr
The synthesis of an ethyl bromoacetate alkylated deriva-
tive of all these new calixarenes was also undertaken. These
derivatives were synthesized for two main reasons. First,
some interesting functionalization and ion complexation
opportunities are offered by these ester-functionalized com-
[b] Institut de Chimie des Substances Naturelles CNRS,
91198 Gif sur Yvette France
[c] DCMR, École Polytechnique,
91128 Palaiseau Cedex, France
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200901405.
View this journal online at
wileyonlinelibrary.com
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p-(Benzyloxy)calix[8]arene Synthesis Revisited
Scheme 1. Previously characterized p-(benzyloxy)calixarenes.
Scheme 2. (a) New calixarenes described in this work; (b) alkylation
with ethyl bromoacetate.
Results and Discussion
Figure 1. Some examples of p-functionalized calixarenes.
The synthesis of p-(benzyloxy)calix[8]arene has already
been described.[7,16,21,42]
A
modification of one pro-
cedure[16] (use of a mechanical stirrer) was used in this work
pounds.[2,3,43] Second, these alkylated derivatives also offer (see the Experimental Section). Filtration of the xylene
the possibility to compare their conformational behavior crude reaction media and washing with acetone led to quite
with the corresponding p-(tBu)calixarenes. Indeed, the con- pure p-(benzyloxy)calix[8]arene.
formational behavior of a given calixarene strongly influ-
ences its complexation abilities. The study of this point for acetone/xylene filtrate. The filtration/precipitation se-
our new calixarenes is thus an important concern. quence used to completely analyze this filtrate is depicted in
We then turned our attention to the corresponding
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V. Huc et al.
FULL PAPER
Figure 2. The purification sequence used in this work.
Figure 2. After complete evaporation of the xylene/acetone evaporated, dissolved in CH2Cl2, and precipitated with
filtrate, we were surprised to observe that the resulting solid methanol. 1H/13C NMR along with mass spectrometry
was not completely soluble in dichloromethane. Filtration analysis showed this precipitate to be constituted by quite
and analysis of the corresponding precipitate showed that pure p-(benzyloxy)(bishomooxa)calix[4]arene 6 (Scheme 2a;
this precipitate was constituted by pure p-(benzyloxy)calix- see also the Experimental Section and the Supporting In-
[7]arene (Scheme 2a). This assignment was made on the ba- formation, S4aǞS4d). Although known for quite a long
sis of the very high symmetry of the 1H and 13C NMR time in the p-(tBu) series,[44–47] this is the first time that
spectra, along with electrospray and MALDI mass spec- this compound is described in the (benzyloxy) series. Single
trometry analysis (see the Experimental Section and the crystals of 6, suitable for X-ray diffraction, were grown by
Supporting Information, S2a, S2b). Calix[7]arene was reco- slow evaporation of a toluene solution.
vered in 8% yield, and despite this low yield, its ease of
recovery makes this calixarene readily available.
Compound 6 crystallizes with two disordered toluene
molecules per unit cell. Interestingly, two independent mo-
Corresponding alkylated product 8 (Scheme 2b) shows lecules are observed: both are in the cone conformation,
complete conformational flexibility at ambient temperature but with a different orientation for the CH2OCH2 bridge
(Supporting Information, S3aǞS3d). This is not surprising, (Figure 3). Compound 6 shows a restricted conformational
as the size of the macrocycle is high enough to allow easy flexibility at ambient temperature, as evidenced by the
interconversion processes.
broadness of the resonances for the (ArCH2Ar) and
Analysis of the dichloromethane filtrate obtained after (CH2OCH2) bridging methylene groups. Variable-tempera-
the recovery of 4 was then undertaken. Precipitation with ture NMR experiments showed that the coalescence tem-
acetone followed by acetone washing of this precipitate led perature is about 290 K (see the Supporting Information,
to quite pure p-(benzyloxy)calix[6]arene (3; 1 g, 2% yield, S4c). From this experiment, we were able to determine an
spectroscopic characteristics in accordance with previously interconversion barrier of 53.3 kJmol–1. This value com-
published ones[7]). The combined acetone filtrates were then pares with previously published ones.[48]
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p-(Benzyloxy)calix[8]arene Synthesis Revisited
tion).[55] Despite their low yields, 5 and 7 are described here
for the first time. As in the other cases, compounds 5 and
7 were fully characterized by 1H/13C NMR spectroscopy
along with mass spectrometry analysis. At ambient tem-
perature, p-(benzyloxy)calix[5]arene shows a restricted con-
formational flexibility in CDCl3 (broadness of the bridging
methylene groups; see the Supporting Information, S6b).
Variable-temperature NMR analysis showed that the co-
alescence temperature is close to the ambient one (about
290 K; see the Supporting Information, S6c).
From this experiment, we were able to obtain a value
of 55.4 kJmol–1 for the interconversion barrier. This value
compares well with those in the literature.[48,49] However,
alkylated derivative 10 (Scheme 2b) is conformationally
locked at ambient temperature, as evidenced by 1H and 13
C
NMR spectroscopy, where several different conformations
are observed (mass spectrometry analysis only showed the
expected molecular peak, indicating that all the hydroxy
groups from 7 were alkylated). The same alkylation experi-
Figure 3. Solid-state structure of 6: (a) orientations of the two inde-
pendent molecules in the unit cell; (b) and (c) different views of the
molecules, highlighting the orientations of the CH2OCH2 bridge.
A comparison between the ambient-temperature 1H ment was repeated with methyl bromoacetate, resulting in
NMR spectra of compound 6 (Scheme 2a) and that of the the same mixture of conformations. This result contrasts
corresponding peralkylated product 9 (Scheme 2b) is very previously published results with p-(tBu)- and p-(t-octyl)-
interesting. As discussed above, compound 6 shows a re- functionalized calix[5]arenes.[43] However, a mixture of con-
stricted conformational flexibility at ambient temperature. formations has already been observed in some examples of
However, the situation completely changes after alkylation p-(tBu)calix[5]arene alkylation experiments.[50]
with ethyl bromoacetate (compound 9, Scheme 2b). The
The strongest signals around 6 ppm on the 1H NMR
presence of four sharp doublets for the hydroquinone-type spectra along with two sets of overlapping doublets (COSY
aromatic protons (4J = 4 Hz) evidences a symmetry plane analysis) indicate that the cone conformation is (at best)
for this compound (see Supporting Information, S5b) present only as a minor component (see the Supporting In-
Moreover, the bridging methylene signals now appear as formation, S7d). Even heating at 400 K in DMSO (the limit
sharp doublets, with characteristic 2J coupling constants of our experimental set up) did not allow recovery of full
ranging from 10 to 15 Hz, evidencing a completely locked conformational flexibility (see the Supporting Information,
cone conformation for this compound. Such a conforma- S6c). These characteristics are quite similar to those ob-
tional behavior has already been observed for others per- served in the case of the p-(tBu)-functionalized calix[5]-
alkylated dihomooxa derivatives in the p-(tBu) series.[45]
arenes.[48]
p-(Benzyloxy)calix[4]arene shows at ambient temperature
Detailed examination of the spectra shows one extra AB
quartet in the (CH2OCH2) bridging methylene resonances a locked cone conformation (in CDCl3), as evidenced by
[confirmed by COSY and NOESY 2D analysis; see the the presence of the characteristic AX system with 2J =
Supporting Information, S4b (insert) and S4c). A possible 13 Hz. VT-NMR experiments (see the Supporting Infor-
interpretation is to be found in the symmetry-lowering ef- mation, S8d) allowed us to determine an activation barrier
fect associated with the presence of the bis(homooxa) of 64 kJmol–1. Once again, this value agrees well with those
bridge on the two hydrogen atoms of the benzyloxy-type in the literature.[47] Corresponding alkylated derivative 11
methylene groups.
(Scheme 2b) was obtained in quantitative yield by using
The same symmetry-lowering effect is also likely to affect NaH as a base. The NMR spectra show that this derivative
the resonances of the other methylene groups on the small was obtained exclusively in the cone conformation, as ob-
rim side of the molecule. However, overlapping of these sig- served in the case of the p-(tBu)calix[4]arene when alky-
nals with those of the bridging methylene groups (from the lation reactions are performed with sodium-containing
calixarene macrocycle) make this analysis difficult. The per- bases.
sistence of this compound in the cone conformation, along
with the presence of the benzyloxy substituents, opens inter-
esting perspectives for the formation of new ligands with a
Conclusions
deep hydrophobic cavity.
A new set of p-(benzyloxy)-substituted calixarene deriva-
Column chromatography of the remaining MeOH/ tives was obtained on a preparative scale and was fully
CH2Cl2 filtrates obtained after the recovery of 6 allowed, characterized. Along with completely new members of the
first, the recovery of p-(benzyloxy)calix[4]arene (5; p-(benzyloxy)calixarene family, the previously described[42]
Scheme 2a, yield Ͻ1%), second, for a crop of compound 6 p-(benzyloxy)calix[7]arene is very easily obtained on a
(final yield 10.4%), and last, of p-(benzyloxy)calix[5]arene multigram scale and was fully characterized for the first
(7; Scheme 2a; final yield 2.4%; see the Experimental Sec- time without the need for any derivatization procedure.
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The very interesting p-(benzyloxy)calix[4]arene was ob-
tained in very low yield after chromatographic analysis of
the most polar fraction of the purification process. Despite
the very low yield, this result is interesting, as it shows that
the one-step formation of this compound is possible, in
sharp contrast with previously reported results.[42] Studies
are underway within our group to optimize the yield. Alkyl-
ation of this compound results in the formation of a rigid
cone derivative. Moreover, the previously unknown p-(benz-
yloxy)(bishomooxa)calix[4]arene was easily obtained on a
multigram scale. Alkylation of this product also results in
the formation of a rigid cone derivative. In both cases, the
formation of these alkylated calixarenes in the cone confor-
mation opens interesting perspectives for the synthesis of
new supramolecular hosts.
Clearly, significant differences are observed in the final
compositions of the reaction media between this work and
the previously described p-(benzyloxy)calix[8]arene synthe-
sis.[42] The reason for this is unclear. One possible explana-
tion may originate from differences in the refluxing periods
[6 h (this work)/48 h[42]]. A shorter reflux time probably al-
lows observation of the kinetic products, whereas a longer
one may result in thermodynamic equilibrium between the
different macrocycles.
Experimental Section
Modified Procedure for the Preparation of p-(Benzyloxy)calix[8]-
arene (2): In a 2-L, three-necked flask fitted with a Dean–Stark
collector a suspension of 4-(benzyloxy)phenol (50.84 g, 0.254 mol),
paraformaldehyde (19.92 g, 0.664 mol), and potassium tert-butox-
ide (1.87 g, 0.0167 mol) in xylene (960 mL) was heated under an
atmosphere of argon at 120 °C for 18 h under strong magnetic stir-
ring. The magnetic stirrer was removed, replaced by a mechanical
one, and the pale-yellow suspension was then brought to moderate
reflux for 6 h (using an oil bath). The resulting thick white suspen-
sion was then left overnight at ambient temperature. The white pre-
cipitate was filtered and washed with xylene (200 mL) and acetone
(150 mL) to afford pure p-(benzyloxy)calix[8]arene as a bright-
white solid (33.32 g, 65.5%). The spectroscopic characteristics were
in accordance with those previously published.[7,16,21,42]
p-(Benzyloxy)calix[7]arene (4): The above xylene/acetone filtrate
was evaporated to dryness under reduced pressure. The resulting
dark-brown solid was suspended in dichloromethane (200 mL) and
filtered to yield 4 as a cream solid (4.3 g, 8%). 1H NMR (250 MHz,
DMSO, 20 °C): δ = 11.5 (OH), 7.7–7.2 (m, 5 H, ArH), 6.70 (s, 2
H, ArhydroquinoneH), 4.92 (s, 2 H, ArCH2O), 3.70 (br. s, 2 H, Ar-
CH2Ar) ppm. 13C NMR (100 MHz, DMSO, 20 °C): δ = 72.4
[OCH2(benzyl)], 117.26 (ArhydroquinoneC-H), 130–132 (ArC-H),
131.6 (ArhydroquinoneCipso-CH2), 140.3 (ArCipso-CH2), 153.5
(ArhydroquinoneCipso-OH) ppm. HRMS (MALDI): calcd. for
C98H84O14 [M + K]+ 1523.54927; found 1523.55675.
More generally, this work demonstrates that the behavior
of the p-(benzyloxy) system shows analogies with the well-
known p-(tBu) one. First, even a very complex mixture of
several different calixarenic sizes is tractable and leads to
pure compounds after conventional workup. The high simi-
larity between the spectroscopic characteristics of some of
these compounds may at first sight shed doubt on the real
purity level of these calixarenes. However, some small (but
significant and reproducible) differences are observed in the
p-(Benzyloxy)bis(homooxa)calix[4]arene (6): The dichloromethane
filtrate obtained after the recovery of 4 was evaporated to dryness
and dissolved in dichloromethane (200 mL). Methanol (600 mL)
was then added, and the resulting white precipitate was recovered
by filtration to yield 6 (4 g). The corresponding filtrate was evapo-
rated and washed with methanol. After column chromatography of
the resulting MeOH insoluble residue (deactivated alumina, eluent
CH2Cl2, Rf = 0,7), a second crop of 6 (1.8 g) was recovered. Final
1
yield: 5.8 g, 10.4%. H NMR (250 MHz, CDCl3, 20 °C): δ = 9.62
1
chemical shifts of some protons in the H NMR spectra,
(s, 2 H, OH), 8.922 (s, 2 H, OH), 7.7–7.2 (m, 20 H, ArH), 6.87 (d,
2 H, 4J = 3 Hz, ArhydroquinoneH), 6.77 (d, 2 H, 4J = 3 Hz,
especially the hydroquinone-type ones (Calix5: δ = 6.80 ppm;
Calix6: δ = 6.61 ppm; Calix7: δ = 6.70 ppm; Calix8: δ =
6.58 ppm in DMSO). Careful calibration of the reference
peak of the solvent thus allows easy analysis of a mixture of
different calixarenic sizes [for this purpose, DMSO (cal-
ibrated at δ = 2.49 ppm) is the best choice, as all the calixar-
enes described in this work are soluble in this solvent]. Asso-
ciated with both the very different mass spectrometric signals
observed in each case and the synthesis of alkylated deriva-
tives, this demonstrates the high level of purity of our calixar-
enes. Second, the conformational behavior of the alkylated
derivatives of these new calixarenes is similar to that ob-
served with p-(tBu)-functionalized ones, with similar acti-
4
ArhydroquinoneH), 6.70 (d, 2 H, J = 3 Hz, ArhydroquinoneH) 6.61 (d,
4
2 H, J = 3 Hz, ArhydroquinoneH), 4.98 (s, 4 H, ArCH2O), 4.91 (s, 4
H, ArCH2O), 4.57 (br. s, 4 H, ArCH2OCH2Ar), 3.83 (br. s, 6 H,
ArCH2Ar) ppm. 13C NMR (100 MHz, DMSO, 20 °C): δ = 30–34
(br., ArCH2Ar), 70.7 [OCH2(benzyl)], 70.83 [OCH2(benzyl)], 71 (br.,
ArCH2OCH2Ar), 114, 6 (ArhydroquinoneC-H), 115.2 (Arhydroquinone
-
C-H), 115.4 (ArhydroquinoneC-H), 117.4 (ArhydroquinoneC-H), 123.1
(ArhydroquinoneCipso-CH2), 127–129 (ArC-H/ArhydroquinoneCipso-CH2/
ArCipso-CH2), 137.2 (ArCipso-CH2), 143.5 (ArhydroquinoneCipso-OH),
147.2 (ArhydroquinoneCipso-OH), 152.1 (ArhydroquinoneCipso-OCH2),
153.4 (ArhydroquinoneCipso-OCH2) ppm. HRMS (MALDI): calcd.
for C57H50O9 [M + Na]+ 901.33470; found 901.33119.
p-(Benzyloxy)calix[4]arene (5): During the chromatographic recov-
vation barriers for the cone-to-cone inversion. To the best of ery of the second crop of 6 (see above), 5 was eluted first and
obtained as a white solid (deactivated alumina, eluent CH2Cl2, Rf
= 0.8). Yield: 0.3 g, Ͻ1%. H NMR (250 MHz, CDCl3, 20 °C): δ
our knowledge, the p-(benzyloxy) and the p-(tBu) systems
are the only ones having demonstrated such versatility so far.
The results reported here (along with previous
ones[7,16,21,42]) clearly demonstrate the potential of p-(benz-
yloxy)phenol for calixarene synthesis. The ease of removal
of the benzyl groups under mild hydrogenolysis conditions,
along with the possibility to easily convert these derivatives
into calixquinones[51] opens very interesting perspectives for
the formation of new ligands, easily derivatized at the p-
position.
1
= 10.014 (s, 1 H, OH) 7.8–7 (m, 5 H, ArH), 6.66 (s, 2 H,
2
ArhydroquinoneH), 4.90 (s, 2 H, ArCH2O), 4.26 (d, J = 13 Hz, 1 H,
ArCH2Ar), 3.42(d, 2J = 13 Hz, 1 H, ArCH2Ar) ppm. 13C NMR
(100 MHz, CDCl3, 20 °C): δ = 32.5 (ArCH2Ar), 70.75 [OCH2-
(benzyl)], 115.26 (ArhydroquinoneC-H), 127–130 (ArC-H), 137.3
(ArhydroquinoneCipso-CH2), 143.14 (ArCipso-CH2), 147.3 (Arhydroquinone
-
Cipso-OH), 153.5 (ArhydroquinoneCipso-OCH2) ppm. HRMS
(MALDI): calcd. for C56H48O8 [M + Na]+ 871.34701; found
871.34510.
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p-(Benzyloxy)calix[8]arene Synthesis Revisited
p-(Benzyloxy)calix[5]arene (7): After the chromatographic recovery
of p-(benzyloxy)calix[4]arene and of the second crop of compound
6, chromatography was continued (CH2Cl2/EtOH, 97:3). Com-
pound 7 was recovered as a slightly yellow solid. Yield: 1.3 g, 2.4%.
1H NMR (250 MHz, CDCl3, 20 °C): δ = 8.47 (s, 1 H, OH) 7.5–7.2
(m, 5 H, ArH), 6.85 (s, 2 H, ArhydroquinoneH), 4.95 (s, 2 H, Ar-
CH2O), 3.79 (br. s, 2 H, ArCH2Ar) ppm. 13C NMR (100 MHz,
DMSO, 20 °C): δ = 33.5 (br., ArCH2Ar), 72.3 [OCH2(benzyl)],
117.9 (ArhydroquinoneC-H), 130–132 (ArC-H), 131.6 (Arhydroquinone-
Cipso-CH2), 140.2 (ArCipso-CH2), 147.3 (ArhydroquinoneCipso-OH),
Pentakis(ethoxycarbonyl)methoxy p-(Benzyloxy)calix[5]arene (10):
To a solution of 7 (146 mg, 0.138 mmol) in ethylbromoacetate
(6 mL) was added off-the-shelf DMF (0.3 mL). 60% NaH (162 mg)
was then added, and the resulting suspension was heated at 50 °C
overnight under an atmosphere of argon. 60% NaH (60 mg) was
then added, and the suspension was heated at 50 °C for 4 h. EtOH/
CH3COOH (90:10, 50 mL) was then added. The solvents were re-
moved under vacuum. The resulting yellowish tar was then washed
with pentane (100 mL), dried, and then washed with water
(100 mL). After drying in vacuo, compound 10 was recovered as a
154.7 (ArhydroquinoneCipso-OCH2) ppm. HRMS (MALDI): calcd. slightly yellow solid. Yield: 0.2 g, 97%. 1H NMR (400 MHz,
for C70H60O10 [M + Na]+ 1083.40787; found 1083.40425.
CDCl3, 20 °C): δ = 7.5–7.2 (m, 20 H, ArH), 7.2–6 (overlapping
multiplets, 5 H, ArH), 5.2–3 (overlapping multiplets, 8 H, Ar-
CH2Ar, ArOCH2, OCH2Ph, OCH2CH3), 1.5–0.8 (overlapping trip-
lets, 3 H, OCH2CH3) ppm. 13C NMR (100 MHz, CDCl3, 20 °C):
δ = 14.2 (CH3), 29–33 (br., ArCH2Ar), 32.4 (ArCH2Ar), 60–63
Heptakis(ethoxycarbonyl)methoxy p-(Benzyloxy)calix[7]arene (8):
To a solution of 4 (216 mg, 0.145 mmol) in ethyl bromoacetate
(6 mL) was added off-the-shelf DMF (0.3 mL) under an atmo-
sphere of argon. 60% NaH (120 mg) was then added, and the re-
sulting suspension was stirred overnight under an atmosphere of
argon at 50 °C. 60% NaH (76 mg) was then added under an atmo-
sphere of argon, and the suspension was left for 4 h at 50 °C. After
cooling to ambient temperature, EtOH/CH3COOH (90:10, 50 mL)
was added. The resulting precipitate was filtered, washed with etha-
nol, dried under vacuum, and washed with pentane. Compound 8
was obtained in quantitative yield (0.3 g). 1H NMR (400 MHz,
(OCH2CH3), 69–72 (CH2OPh,
CH2OCOOEt),
113–118
(ArhydroquinoneC-H), 126–130 (ArC-H), 133–140 (Arhydroquinone
-
-
Cipso-CH2), 147–150 (ArCipso-OH), 154–157 (ArhydroquinoneCipso
OCH ), 168–172 (C=O). IR: ν = 1755 cm–1 (C=O). HRMS
˜
2
(MALDI): calcd. for C90H90O20 [M + Na]+ 1513.59177; found
1513.58738.
Tetrakis(ethoxycarbonyl)methoxy p-(Benzyloxy)calix[4]arene (11):
To a solution of 5 (200 mg, 0.179 mmol) in ethylbromoacetate
(10 mL) was added off-the-shelf DMF (0.6 mL). 60% NaH (70 mg)
was then added, and the resulting suspension was heated at 50 °C
overnight under an atmosphere of argon. 60% NaH (115 mg) was
then added, and the suspension was heated at 50 °C for 4 h. The
product was then precipitated in pentane (200 mL) and filtered.
The precipitate was recovered with CH2Cl2, and the solvents were
evaporated. The product was then washed with pentane to remove
any remaining paraffin. Compound 11 was recovered in nearly
quantitative yield as a slightly yellow solid. 1H NMR (400 MHz,
CDCl3, 20 °C): δ = 7.5–7.2 (m, 20 H, ArH), 6.77 (s, 8 H, ArH),
5.90 (s, 8 H, OCH2Ph), 4.44 (s, 8 H, ArOCH2), 4.38 (q, 8 H,
CDCl3, 20 °C): δ = 7.25 (br., 5 H, ArH), 6.65 (s, 2 H, Arhydroquinone
-
H), 4.72 (s, 2 H, ArCH2O), 4.25 (br. s, 2 H, ArCH2COO), 4 (over-
lap: q, 2 H, O-CH2-CH3 + s, 2 H, ArCH2Ar), 1 (t, 3 H, OCH2-
CH3) ppm. 13C NMR (100 MHz, CDCl3, 20 °C): δ = 13.9 (CH3),
30.9 (ArCH2Ar), 60.95 (OCH2CH3), 69.74 (CH2OPh), 70.41
(CH2OCOOEt), 115.3 (ArhydroquinoneC-H), 127–129 (ArC-H), 134.5
(ArhydroquinoneCipso-CH2), 137.2 (ArCipso-CH2), 148.2 (ArCipso-OH),
148.7 (ArCipso-OCH2), 155.15 (ArhydroquinoneCipso-OCH2), 169
(C=O) ppm. IR: ν = 1755 cm–1 (C=O). HRMS (MALDI): calcd.
˜
for C126H126O28 [M + Na]+ 2109.83279; found 2109.83614.
Tetrakis(ethoxycarbonyl)methoxy p-(Benzyloxy)(bishomooxa)calix-
[4]arene (9): To a solution of 6 (290 mg, 0.233 mmol) in ethylbro-
moacetate (6 mL) was added off-the-shelf DMF (0.3 mL). 60%
NaH (162 mg) was then added, and the resulting suspension was
heated at 50 °C overnight under an atmosphere of argon. 60%
NaH (60 mg) was then added, and the suspension was heated at
50 °C for 4 h. EtOH/CH3COOH (90:10, 50 mL) was then added.
The solvents were removed under vacuum. The resulting yellowish
tar was then washed with pentane (100 mL), dried, and then
washed with water (100 mL). After drying in vacuo, compound 6
2
2
OCH2CH3), 4.23 (d, J = 12 Hz), 4.37 (d, J = 12 Hz), 1.42 (12 H,
OCH2CH3) ppm. 13C NMR (100 MHz, CDCl3, 20 °C): δ = 14.2
(CH3), 30.3 (ArCH2Ar), 62 (OCH2CH3), 70.6 (CH2OPh), 73.5
(CH2OCOOEt), 115.3 (ArhydroquinoneC-H), 127–129 (ArC-H), 135.5
(ArhydroquinoneCipso-CH2), 136.6 (ArCipso-CH2), 146.2 (ArCipso-OH),
156.3 (ArhydroquinoneCipso-OCH ), 171.2 (C=O) ppm. IR: ν =
˜
2
1755 cm–1 (C=O). MS (MALDI): calcd. for C72H72O16 [M + Na]+
1215.472; found 1215.45.
X-ray Crystal-Structure Analysis of 6: Recrystallization from tolu-
ene at ambient temperature gave single crystals of 6 that were suit-
was recovered as a white solid. Yield: 379 mg, 94%. 1H NMR
4
(400 MHz, CDCl3, 20 °C): δ = 7.5–7.2 (m, 20 H, ArH), 6.65 (d, J able for an X-ray crystal-structure analysis of the obtained product.
4
= 3 Hz, 2 H, ArhydroquinoneH, 6.59 (d, J = 3 Hz, 2 H, Arhydroquinone
-
X-ray diffraction data were collected with a Kappa X8 APPEX II
4
4
H), 6.53 (d, J = 3 Hz, 2 H, ArhydroquinoneH), 6.27 (d, J = 3 Hz, 2 Bruker diffractometer using graphite-monochromated Mo-Kα radi-
H, ArhydroquinoneH), 4.95 (d, J = 10 Hz), 4.856 (s, 4 H, CH2OPh), ation (λ = 0.71073 Å). The temperature of the crystal was main-
2
2
2
4.849 (s, 4 H, CH2OPh),4.82 (d, J = 12 Hz), 4.71 (d, J = 16 Hz),
tained at the selected value (100 K) to within an accuracy of Ϯ1 K
by means of a 700 series Cryostream cooling device. The data were
corrected for Lorentz polarization, and absorption effects. The
4.6 (d, 2J = 15 Hz), 4.43 (d, 2J = 16 Hz), 4.31 (t, 4 H, CH2COOEt),
2
4.23 (t, 4 H, CH2COOEt), 3.3 (d, 2 H, J = 16 Hz), 3.28 (d, 1 H,
2J = 12 Hz) ppm. 13C NMR (100 MHz, CDCl3, 20 °C): δ = 14.2 structures were solved by direct methods using SHELXS-97[52] and
(CH3), 31.06 (ArCH2Ar), 32.4 (ArCH2Ar), 60.67 (OCH2CH3),
60.93 (OCH2CH3), 68.3 69.83 (CH2OPh), 70.3 (CH2OCOOEt), SHELXL-97[53] with anisotropic displacement parameters for all
71.2 (CH2OCH2), 112.37 (ArhydroquinoneC-H), 114.34 (Arhydroquinone non-hydrogen atoms. Hydrogen atoms were introduced into the cal-
C-H), 115.83 (ArhydroquinoneC-H), 116.56 (ArhydroquinoneC-H), 126– culations as a riding model with isotropic thermal parameters. The
refined against F2 by full-matrix least-squares techniques using
-
130 (ArC-H), 133 (ArhydroquinoneCipso-CH2), 133.8 (Arhydroquinone
Cipso-CH2), 135.3 (ArhydroquinoneCipso-CH2), 135.7 (Arhydroquinone
-
-
toluene solvent molecule is disordered. All calculations were per-
formed by using the Crystal Structure crystallographic software
Cipso-CH2), 148.2 (ArCipso-OH), 148.8 (ArCipso-OH), 154.4 package WINGX.[54] C121H100O18, M = 1842.01, triclinic, a =
(ArhydroquinoneCipso-OCH2), 154.8 (ArhydroquinoneCipso-OCH2), 170 9.0983(8) Å, b = 16.3283(15) Å, c = 31.411(3) Å, α = 87.066(2)°, β
(C=O). IR: ν = 1754 cm–1 (C=O). HRMS (MALDI): calcd. for = 89.637(2)°, γ = 87.784(3)°, V = 4656.7(8) Å3, T = 100(1) K, space
˜
C73H74O17 [M + Na]+ 1245.48182; found 1245.48361.
–1
¯
group P1 (no. 2), Z = 2, µ(Mo-Kα) = 0.088 mm , 64616 reflections
Eur. J. Org. Chem. 2010, 6186–6192
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6191

V. Huc et al.
FULL PAPER
[24] T. Patrick, P. Egan, J. Org. Chem. 1978, 43, 4280.
measured, 18504 unique (Rint = 0.1001), 9453 [I Ͼ 2σ(I)], which
were used in all calculations; final R(F2) = 0.0812. CCDC-793733
contains the supplementary crystallographic data for this
paper. These data can be obtained free of charge from The Cam-
bridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
[25] Z. Asfari, J. Vicens, Tetrahedron Lett. 1988, 29, 2659.
[26] F. Vocanson, M. Perrin, R. Lamartine, J. Inclusion Phenom.
Macrocyclic Chem. 2001, 39, 127.
[27] C. D. Gutsche, P. F. Pagoria, J. Org. Chem. 1985, 50, 5795.
[28] A. Casnati, L. Domiano, A. Pochini, R. Ungaro, M. Carramol-
ino, J. O. Magrans, P. M. Nieto, J. Lopez-Prados, P. Prados, J.
De Mendoza, R. G. Janssen, W. Verboom, D. N. Reinhoudt,
Tetrahedron 1995, 51, 12699.
[29] B. Colasson, O. Reinaud, J. Am. Chem. Soc. 2008, 130, 15226.
[30] B. Colasson, M. Save, P. Milko, J. Roithovà, D. Schröder, O.
Reinaud, Org. Lett. 2007, 9, 4987.
Supporting Information (see footnote on the first page of this arti-
cle): Copies of the 1H and 13NMR spectra and selected HSQC,
HMBC, COSY, and NOESY spectra.
[31] C. Gaeta, G. Procida, E. Gavuzzo, P. Neri, J. Inclusion Phenom.
Macrocyclic Chem. 2008, 115.
Acknowledgments
[32] S. Redon, Y. Li, O. Reinaud, J. Org. Chem. 2003, 68, 7004.
[33] D. Coquière, H. Cadeau, Y. Rondelez, M. Giorgi, O. Reinaud,
J. Org. Chem. 2006, 71, 4059.
[34] A. Arduini, L. Domiano, L. Ogliosi, A. Pochini, A. Secchi, R.
Ungaro, J. Org. Chem. 1997, 62, 7866.
The authors gratefully acknowledge the French Ministry of Re-
search for financial support (contract number ANR-08-JCJC-0085-
01).
[35] D. Gutsche, L.-G. Lin, Tetrahedron 1986, 42, 1633.
[36] D. Gutsche, J. A. Levine, P. K. Sujeeth, J. Org. Chem. 1985, 50,
5802.
[37] D. Gutsche, J. A. Levine, J. Am. Chem. Soc. 1982, 104, 2652.
[38] O. Mogck, V. Böhmer, W. Vogt, Tetrahedron 1996, 52, 8489.
[39] A. Credi, S. Dumas, S. Silvi, M. Venturi, A. Arduini, A. Poch-
ini, A. Secchi, J. Org. Chem. 2004, 69, 5881.
[1] J. Vicens, J. Harrowfield (Ed.), Calixarenes in the Nanoworld,
Springer, Dordrecht, The Netherlands, 2006.
[2] Z. Asfari, V. Böhmer, J. Harrowfield, J. Vicens (Eds.), Calixar-
enes 2001, Kluwer, Dordrecht, The Netherlands, 2001.
[3] D. Gutsche, Calixarenes: An Introduction, The Royal Society
of Chemistry, Cambridge, 2008.
[4] L. Mandolini, R. Ungaro, Calixarenes in Action, Imperial Col-
lege Press, London, 2000.
[5] A. C. G. Arena, A. Contino, L. Mirone, D. Sciotto, R. Ungaro,
Chem. Commun. 1996, 2277.
[6] R. Ungaro, A. Pochini, Calixarenes: A Versatile Class of
Macrocyclic Compounds, Kluwer, Dordrecht, The Netherlands,
1991.
[7] A. Casnati, S. Barboso, H. Rouquette, M.-J. Schwing-Weill, F.
Arnaud-Neu, J.-F. Dozol, R. Ungaro, J. Am. Chem. Soc. 2001,
123, 12182.
[40] J. J. Gonzales, R. Ferdani, E. Albertini, J. Blasco, M. A. Ardu-
ini, A. Pochini, P. Prados, J. De Mendoza, Chem. Eur. J. 2000,
6, 1.
[41] A. Arduini, A. Credi, G. Faimani, Chem. Eur. J. 2008, 14, 98.
[42] A. Casnati, R. Ferdani, A. Pochini, R. Ungaro, J. Org. Chem.
1997, 62, 6236.
[43] F. Arnaud-Neu, Z. Asfari, B. Souley, J. Vicens, P. Thuery, M.
Nierlich, J. Chem. Soc. Perkin Trans. 2 2000, 495.
[44] D. C. Gutsche, B. Dhawan, K. H. No, R. Muthukrishnan, J.
Am. Chem. Soc. 1981, 103, 3782.
[45] P. M. Marcos, J. R. Ascenso, R. Lamartine, J. L. C. Pereira,
Tetrahedron 1997, 53, 11791.
[8] P. Thuéry, M. Lance, M. Nierlich, Supramol. Chem. 1996, 7,
183.
[9] P. C. Leverd, I. Dumazet-Bonnamour, R. Lamartine, M. Nier-
lich, Chem. Commun. 2000, 493.
[46] B. Dhawan, D. C. Gutsche, J. Org. Chem. 1983, 48, 1536.
[47] B. Masci, M. Finelli, M. Varrone, Chem. Eur. J. 1998, 4, 2018.
[48] C. D. Gutsche, L. J. Bauer, J. Am. Chem. Soc. 1985, 107, 6052.
[49] H. Kämmerer, G. Happel, B. Mathiasch, Macromol. Chem.
1981, 182, 1685.
[50] D. R. Stewart, M. Krawieck, R. P. Kashyap, W. H. Watson,
C. D. Gutsche, J. Am. Chem. Soc. 1995, 117, 586.
[51] V. Huc, V. Guerineau, Eur. J. Org. Chem. 2010, 2199.
[52] G. M. Sheldrick, SHELXS-97, Program for Crystal Structure
Solution, University of Göttingen, Göttingen, Germany, 1997.
[53] G. M. Sheldrick, SHELXL-97, Program for the Refinement of
Crystal Structures from Diffraction Data, University of
Göttingen, Göttingen, Germany, 1997.
[10] J. Seganish, P. Santacroce, K. J. Salimian, J. C. Fettinger, P. Za-
valij, J. T. Davis, Angew. Chem. Int. Ed. 2006, 45, 3334.
[11] V. G. Organo, A. V. Leontiev, V. Sgarlata, H. V. Rasika-Dias,
D. M. Rudkevich, Angew. Chem. Int. Ed. 2005, 44, 3043.
[12] C. Redshaw, Coord. Chem. Rev. 2003, 244, 45.
[13] S. Shinkai, A. Ikeda, Pure Appl. Chem. 1999, 71, 275.
[14] P. Leyton, S. Sanchez-Cortez, J. V. Garcia-Ramos, C. Do-
mingo, M. Campos-Valette, C. Saitz, R. E. Clavijo, J. Phys.
Chem. B 2004, 108, 17484.
[15] R. McKinlay, J. R. Atwood, Angew. Chem. Int. Ed. 2007, 46,
2394.
[16] P. Leverd, V. Huc, S. Palacin, M. Nierlich, J. Inclusion Phenom.
Macrocyclic Chem. 2000, 36, 259.
[54] L. J. Farrugia, J. Appl. Crystallogr. 1999, 32, 837–838.
[55] Note Added in Proof (September 21, 2010): By the time this
manuscript was entering its final processing, one of us (C. M.)
discovered that when this concentrated CH2Cl2/MeOH fraction
is dissolved in ca. 20 mL of toluene (before the final chromato-
graphic purification), p-(benzyloxy)calix[5]arene spontaneously
precipitates out over a period of 24 h. This phenomenon
greatly eases the final chromatographic purification of the re-
maining calixarenes.
[17] A. Wei, Chem. Commun. 2006, 1581.
[18] K. J. Hartlieb, M. Saunders, C. L. Raston, Chem. Commun.
2009, 3074.
[19] T. R. Tshikhudo, D. Demuru, Z. Wang, M. Brust, A. Secchi,
A. Arduini, A. Pochini, Angew. Chem. Int. Ed. 2005, 44, 2913.
[20] A. Arduini, D. Demuru, A. Pochini, A. Secchi, Chem. Com-
mun. 2005, 645.
[21] V. Huc, K. Pelzer, J. Colloid Interface Sci. 2008, 318, 1.
[22] D. Gutsche, Acc. Chem. Res. 1983, 16, 161.
[23] T. Patrick, P. Egan, J. Org. Chem. 1977, 42, 382.
Received: December 3, 2009
Revision Received: July 15, 2010
Published Online: September 29, 2010
6192
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 6186–6192