Synthesis of functionalized, sterically congested calix[4]phyrin macrocycles using donor-acceptor-substituted cyclopropanes-first example of a mono-meso-spirolactone incorporated into a calix[4]phyrin

Article abstract of DOI:10.1002/ejoc.201201295

Calix[4]phyrins are an important class of hybrid macrocyclic systems at the interface between porphyrins and calixpyrroles (porphyrinogens). A new stepwise synthesis of oxidation-resistant meso-hydrogenated calix[4]phyrins is reported, which allows variable substitution in the residues of their sp ²-meso-centers without the need for a porphyrin intermediate. It relies on the acid-catalyzed condensation of a sterically hindered donor-acceptor-substituted cyclopropane precursor with pyrrole to form a sterically congested dipyrromethane. This was subsequently condensed with a wide range of alkyl and aryl aldehydes bearing electron-donating or electron-withdrawing substituents followed by an oxidation step to form stable calix[4]phyrin(1.1.1.1)s with bridging meso-CH hydrogen atoms through an acid-promoted dehydrative condensation. The methodology avoids any need for premetallation of the macrocycle and/or the use of organometallic catalysts or reagents and allows the incorporation of the bulky cyclopropane-derived substituents specifically into the 5,15-meso-like positions. The resulting regioisomerically pure products display conformational features that reflect their mixed nature between porphyrins and calixpyrroles and they were assessed by X-ray diffraction analysis, NMR techniques and UV/Vis spectroscopy. The possibility to introduce key functional groups enables subsequent modification of these calix[4]phyrins and allows their connection to other groups such as biologically active moieties. Of special interest is an unprecedented example of an acid-driven lactonization that results in the incorporation of a mono-meso-spirolactone into a calix[4]phyrin(1.1.1.1). Moreover, it is demonstrated that this approach to calix[4]phyrins is also applicable to other sterically congested dipyrromethanes.

Full text of DOI:10.1002/ejoc.201201295

FULL PAPER
DOI: 10.1002/ejoc.201201295
Synthesis of Functionalized, Sterically Congested Calix[4]phyrin Macrocycles
Using Donor–Acceptor-Substituted Cyclopropanes – First Example of a
Mono-meso-spirolactone Incorporated into a Calix[4]phyrin
M. Hassan Beyzavi,[a,b] Dieter Lentz,[a][‡] Hans-Ulrich Reissig,*[a] and Arno Wiehe*[a,b]
Dedicated to the memory of Professor Dr. Emanuel Vogel
Keywords: Porphyrinoids / Macrocycles / Heterocycles / Lactones / Cyclopropanes
Calix[4]phyrins are an important class of hybrid macrocyclic
nometallic catalysts or reagents and allows the incorporation
systems at the interface between porphyrins and calixpyr- of the bulky cyclopropane-derived substituents specifically
roles (porphyrinogens). A new stepwise synthesis of oxi- into the 5,15-meso-like positions. The resulting regioisomer-
dation-resistant meso-hydrogenated calix[4]phyrins is re-
ported, which allows variable substitution in the residues of
their sp2-meso-centers without the need for a porphyrin in-
termediate. It relies on the acid-catalyzed condensation of a
sterically hindered donor–acceptor-substituted cyclopropane
precursor with pyrrole to form a sterically congested dipyrro-
methane. This was subsequently condensed with a wide
range of alkyl and aryl aldehydes bearing electron-donating
or electron-withdrawing substituents followed by an oxi-
dation step to form stable calix[4]phyrin(1.1.1.1)s with bridg-
ing meso-CH hydrogen atoms through an acid-promoted de-
hydrative condensation. The methodology avoids any need
for premetallation of the macrocycle and/or the use of orga-
ically pure products display conformational features that re-
flect their mixed nature between porphyrins and calixpyr-
roles and they were assessed by X-ray diffraction analysis,
NMR techniques and UV/Vis spectroscopy. The possibility to
introduce key functional groups enables subsequent modifi-
cation of these calix[4]phyrins and allows their connection to
other groups such as biologically active moieties. Of special
interest is an unprecedented example of an acid-driven
lactonization that results in the incorporation of a mono-
meso-spirolactone into a calix[4]phyrin(1.1.1.1). Moreover, it
is demonstrated that this approach to calix[4]phyrins is also
applicable to other sterically congested dipyrromethanes.
sp3-hybridized meso-carbon bridges, respectively, calix[4]-
phyrins are their macrocyclic analogues that contain sp2-
and sp3-hybridized meso-carbon bridges. Because of their
partially flexible framework as well as the rather rigid π-
conjugated network, they exhibit new features derived from
their mixed nature between porphyrins and calixpyrroles.
For example, calixphyrins are promising in coordination
chemistry,[3] as catalysts,[4] and as sensors for anions, cat-
ions, or neutral substrate recognition in supramolecular
chemistry.[2c,3,5] Their intramolecular proton transfer has
also been studied recently.[6] They can be regarded as a four-
electron oxidation product of calixpyrroles or a two-elec-
tron (photo)reduction product of porphyrin systems
(Scheme 1). Furthermore, in living systems, reduced por-
phyrins are important intermediates in the heme biosyn-
thetic pathway and because of the increased flexibility of
such molecules, their metabolism is enhanced and they en-
able transfer across cellular membranes.[7,8]
Introduction
Calix[4]phyrin(1.1.1.1)s[1] (also known as trans-porpho-
dimethenes) are a class of hybrid compounds with func-
tional properties derived from both porphyrins and calix-
pyrroles. They can be regarded as an assembly of two dipyr-
rin fragments linked through sp3-hybridized meso-carbon
atoms, which interrupts the ring current in the macrocycle
and leads to drastic conformational changes and significant
modifications in their overall physicochemical properties.[2]
Whereas porphyrins and calixpyrroles contain only sp2- or
[a] Institut für Chemie und Biochemie, Freie Universität Berlin,
Takustr. 3, 14195 Berlin, Germany
Fax: +49-30-83855367
E-mail: hans.reissig@chemie.fu-berlin.de
Homepage: http://www.bcp.fu-berlin.de/chemie/oc/reissig
[b] biolitec research GmbH,
Otto-Schott-Str. 15
Because of the absence of suitable general synthetic pro-
cedures for calix[4]phyrin(1.1.1.1)s, their chemistry has been
quite limited because of their general instability towards air
and light. They have been obtained from several described
07745 Jena, Germany
E-mail: arno.wiehe@biolitec.de
[‡] Responsible for the X-ray crystal structure determination
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201295.
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FULL PAPER
Scheme 1. Two principal synthetic pathways to calix[4]phyrins: a) four-electron oxidation/deprotonation (dealkylation) of calix[4]pyrroles
or b) two-electron (photo)reduction/protonation (alkylation) of porphyrins.
pathways: i. the conversion of phlorin salts (three sp2-hy- bridized carbon centers (meso-dialkylated centers), which
bridized meso-carbon atoms, three NH hydrogen atoms) prevents oxidation to the corresponding porphyrin.
under strong acidic conditions;[9] ii. the aerobic oxidation
As the harsh conditions required for macrocycle trans-
of β-octamethyl-meso-tetraphenylcalix[4]pyrroles followed formations are generally incompatible with the presence of
by metallation with zinc acetate resulting in meso-hydroge- sensitive groups and based on the abovementioned limita-
nated β-octamethyl-meso-tetraphenylcalix[4]phyrins, which tions in known pathways, the ability to vary the substituents
are unstable towards oxygen;[10] iii. the dealkylation of at the meso-positions of the calix[4]phyrin(1.1.1.1)s still re-
meso-octaalkylcalix[4]pyrroles, which requires previous mains rather limited and challenging. To expand the diver-
metallation and is limited to the formation of hexahomo- sity of calixphyrin macrocycles, we herein report a tunable
alkyl-meso-substituted metallo-calix[4]phyrin(1.1.1.1)s;[11] and efficient synthesis of β-unsubstituted, stable calix[4]-
iv. (photo)reduction of metalloporphyrins, which necessar- phyrin(1.1.1.1)s with bridging meso-CH hydrogen atoms by
ily requires β-pyrrole alkyl substituents to ensure stability an acid-catalyzed condensation of functionalized dipyrro-
towards oxidation,[12] or reaction of FeIITPP (TPP = meso- methanes with a wide variety of aldehydes. The dipyrro-
tetraphenylporphyrinato dianion) with allyl bromide under methane building block incorporating the future sp3-hy-
anaerobic conditions, which requires a reducing agent and bridized meso-carbon center of the calix[4]phyrin(1.1.1.1)
unselectively gives a mixture of stereoisomers of the 5,15- was synthesized by reaction of a donor–acceptor-substi-
diallyl–FeIITPP complex, being unstable towards oxygen;[13] tuted cyclopropane (d–a cyclopropane) precursor with pyr-
v. the nucleophilic addition of organolithium reagents to role. The introduction of a substituent with high steric bulk
substituted metalloporphyrins;[14] vi. condensation reac- to the dihydroporphyrin skeleton resulted in a pronounced
tions of 5-aryldipyrromethanes with vicinal diketones to stability towards oxidation and permitted the isolation of
produce spiro-di- or tricyclic calix[4]phyrin(1.1.1.1)s;[15] vii. the calix[4]phyrin(1.1.1.1)s directly from the oxidation of
condensation of formylated dialkyldipyrromethanes with the corresponding calixpyrrole.
5,5-dialkyldipyrromethanes (MacDonald approach), which
requires NiII templating to achieve acceptable yields;[16] viii.
Results and Discussion
condensations with sterically demanding aldehydes such as
pivalaldehyde with pyrrole, which unselectively produced
As part of an ongoing project directed towards new syn-
five different compounds with yields of less than 1% for thetic applications of d–a cyclopropanes[23] as well as new
each product,[17] or the condensation of sterically de- tetrapyrrole macrocycles,[24] we planned to design a series
manding aldehydes like ferrocenecarboxaldehyde with of tunable calixphyrin-type systems by employing sterically
alkyl-substituted dipyrromethane to enhance the stability hindered d–a cyclopropanes and pyrrole, thus allowing the
towards oxidation;[18] ix. condensation of 5-adamantyldi- synthesis of novel calix[4]phyrin(1.1.1.1)s that are not read-
pyrromethane with benzaldehyde, which gave the unfunc- ily accessible by the known alternative strategies.
tionalized 5,15-meso-hydrogenated calix[4]phyrin;[19] x. con-
In the synthesis of meso-substituted porphyrins, corroles,
densation of 5-substituted dipyrromethanes with ketones expanded and reduced porphyrins, and related compounds,
(mostly acetone),[5a,20,21] or condensation of 5,5-disubsti- meso- or 5-substituted dipyrromethanes are important pre-
tuted dipyrromethanes with aromatic aldehydes;[5d,21,22] cursors. In particular, they play a key role in the regioisom-
both methods result in substituents other than hydrogen at erically pure synthesis of porphyrins and related macro-
the sp3-hybridized meso-centers. Moreover, with these cyclic systems by predesignating the orientation of meso-
methods it is difficult to synthesize calix[4]- substituents. For instance, using dipyrromethane building
phyrin(1.1.1.1)s functionalized at both the sp2- and sp3-hy- blocks, trans-A2B2-porphyrins can be synthesized efficiently
bridized meso-carbon bridges.[21] In fact, as the instability by direct [2+2] condensation of dipyrromethanes with alde-
of the calix[4]phyrin(1.1.1.1)s is attributed primarily to the hydes.[25] Hence, we considered that this approach would
presence of hydrogen atoms in their meso-like positions, also be feasible for the synthesis of calix[4]phyrin(1.1.1.1)
these methods are mostly limited to calix[4]phyrin(1.1.1.1)s derivatives based on d–a cyclopropane-derived dipyrro-
that contain a quaternary carbon atom at their sp3-hy- methanes.
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Synthesis of Functionalized Calix[4]phyrin Macrocycles
Cyclopropane derivatives substituted by donor and ac-
ceptor groups are particularly suitable for synthetic applica-
tions because the electronic effects of the substituents acti-
vate the strained compound and provide high versatility of
the respective products after ring cleavage.[23] Cyclopropane
derivative 1 serves as a 1,3-zwitterionic synthon 2 and gen-
erates product 3 (Scheme 2) in situ in the presence of protic
solvents, mild acids, or fluoride ions.[26] Compound 3 is a
useful building block owing to the 1,4-distance between the
two carbonyl groups. We selected the easily available cyclo-
propane 1[27] as starting material as the in situ formed alde-
hyde 3 can be used in the condensation step with pyrrole
and its methoxycarbonyl group should enable subsequent
transformations.
Scheme 3. Condensation of 1 with an excess of pyrrole in a solvent-
free condensation reaction leading to functionalized dipyrro-
methane 4.
With a multigram amount of dipyrromethane 4 in hand,
we reacted it with different aldehydes in an acid-catalyzed
condensation to form calixpyrrole systems, which were then
oxidized to investigate the formation of functionalized ca-
lix[4]phyrin systems (Scheme 4). As the stability of calixpyr-
roles towards oxidants is dependent on the substitution
pattern of the sp3-hybridized meso-carbon atoms, and be-
cause 4 has a special structure with a quaternary carbon
atom adjacent to the meso-bridge, we assumed that this
steric hindrance could influence the final oxidation step and
thus yield calix[4]phyrins instead of porphyrins, similarly to
a recent report in which 5-adamantyldipyrromethane is
condensed with benzaldehyde[19]. Therefore, as a test reac-
Scheme 2. Structure of d–a cyclopropane 1, which serves as a 1,3-
zwitterionic synthon 2 and generates 3.
Cyclopropane 1 seemed particularly attractive as an alde- tion, dipyrromethane 4 was condensed with benzaldehyde
hyde equivalent for the planned dipyrromethane synthesis at room temperature in the presence of a catalytic amount
as it contains two methyl groups adjacent to the masked of TFA (20 mol-%) in dichloromethane (DCM) as de-
aldehyde functionality and hence should exert steric strain scribed for other dipyrromethane condensations[30] to fur-
on the desired dipyrromethane as well as the future tetra- nish the corresponding calixpyrrole 5. After subsequent oxi-
pyrrole condensation product. This strain in the meso-posi- dation
tions as described above is known to stabilize calix[4]- (DDQ),[31] the orange-red crystalline product 6a was iso-
phyrin(1.1.1.1) structures.[19]
lated by column chromatography in 19% yield. According
with
2,3-dichloro-5,6-dicyano-p-benzoquinone
For the synthesis of the dipyrromethane, 1 was treated to literature reports, calix[4]phyrin(1.1.1.1)s are most stable
with an excess of pyrrole in a solvent-free condensation in as syn-stereoisomers, in which the bulky substituents adopt
the presence of a catalytic amount of trifluoroacetic acid an axial conformation (cf. also Scheme 7).[2,32] As antici-
(TFA, 10 mol-%).[28] After work up, the stable dipyrro- pated, oxidation occurred only at those meso-positions that
methane 4 containing the bulky residue was obtained in carried the sterically less demanding aryl substituent. The
61% yield (Scheme 3). Performing the two reaction steps in steric hindrance exerted by the bulky cyclopropane-derived
one pot (ring opening of the cyclopropane and condensa- residues presumably interrupts the full six-electron oxi-
tion with excess pyrrole) and purifying only at the final step dation of the calixpyrrole[10,33] and results in the preferen-
reduces the effort and allows a good overall yield.[29]
tial formation of the stable calix[4]phyrin(1.1.1.1) 6a (cf. X-
Scheme 4. Acid-catalyzed condensation of 4 with aldehydes to form calix[4]phyrin(1.1.1.1)s 6 via calixpyrrole intermediate 5.
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M. H. Beyzavi, D. Lentz, H.-U. Reissig, A. Wiehe
FULL PAPER
ray data in Figure 1). To the best of our knowledge, this is Table 1. TFA-catalyzed condensation of dipyrromethane 4 with dif-
ferent aldehydes (1:1 ratio) at room temperature in DCM followed
the first report in which cyclopropane-derived dipyrro-
by oxidation with DDQ furnishing functionalized meso-hydrogen-
ated calix[4]phyrin(1.1.1.1)s 6.
methanes are utilized in the synthesis of tetrapyrroles,
which give rise to calix[4]phyrins with 5,15-trans-hydro-
genated meso-positions owing to the steric hindrance
caused by bulky substituents. Following these promising re-
sults, we tested the generality and functional group toler-
ance of this procedure for the synthesis of calix[4]phyr-
in(1.1.1.1)s. Therefore, we examined the one-pot reaction of
a range of substituted aromatic and aliphatic aldehydes
with dipyrromethane 4 in a 1:1 ratio under the conditions
used for the synthesis of 6a to obtain the corresponding
calix[4]phyrin(1.1.1.1)s, which are functionalized at both
residues of their sp3- and sp2-hybridized meso-centers.
As shown in Table 1, steric and electronic variations in
the aldehydes bearing electron-donating or electron-with-
drawing substituents were tolerated and did not change the
efficiency of the reaction and resulted in the formation of
the desired calix[4]phyrin(1.1.1.1)s 6a–j in acceptable yields
(4–25%). For example, several key functional groups such
as acetyl, methoxycarbonyl, and acetamido groups are tol-
erated under the mild reaction conditions (Table 1, En-
tries 3, 4, and 6). In addition, a sterically hindered 2,6-
dichlorophenyl substituent could readily be introduced into
the calix[4]phyrin(1.1.1.1) skeleton (Table 1, Entry 8). The
use of paraformaldehyde resulted in calix[4]phyrin(1.1.1.1)
6j in 4% yield, which possesses free 10- and 20-meso-posi-
tions (Table 1, Entry 10). To examine the feasibility of this
method on a larger preparative scale, the model reaction
that leads to 6a was performed on a 20 mmol scale. The
reaction proceeded similarly to the small-scale reaction and
provided the desired calix[4]phyrin(1.1.1.1) in 16% yield af-
ter 23 h (Table 1, Entry 11).
As an example, compound 6a was subjected to alkaline
hydrolysis of the ester groups. This conversion proceeded
in quantitative yield to produce the calix[4]phyrin(1.1.1.1)
dicarboxylic acid 7, which exemplifies the possibility of fur-
ther functionalization of the calix[4]phyrin(1.1.1.1)s at their
saturated meso-residues (Scheme 5).
Thus, by using functionalized aldehydes in the condensa-
tion reaction, the overall products are calix[4]phyrin-
(1.1.1.1)s that are functionalized at the residues of both
their sp3- and their sp2-hybridized meso-centers. A specific
advantage of this approach is that bulky residues are intro-
duced during the dipyrromethane synthesis. The dipyrro-
methane is more flexible and less sensitive to steric hin-
drance, therefore the inclusion of these bulky residues prior
to the ring-forming step promotes the efficacy of the reac-
tion.[21]
The functionalized bulky residue of 4 can be regarded as
similar to a tert-butyl group. Therefore, we set out to test
the applicability of the dipyrromethane building block ap-
proach for calix[4]phyrin(1.1.1.1)s directly with pival-
aldehyde as a simple sterically demanding aldehyde. The
hitherto unknown dipyrromethane 8 was prepared and sub-
[a] Yield of purified product. [b] Paraformaldehyde was used. [c]
The reaction was performed on a 20 mmol scale.
sequently treated with benzaldehyde under the reaction 27% yield; to date, this had only been isolated as a byprod-
conditions described for calix[4]phyrin(1.1.1.1) 6a. Gratify- uct with a yield Ͻ 1% (Scheme 6).[17] These results, which
ingly, the expected calix[4]phyrin(1.1.1.1) 9 was isolated in are consistent with another example from the literature,[19]
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Synthesis of Functionalized Calix[4]phyrin Macrocycles
Scheme 5. Synthesis of calix[4]phyrin(1.1.1.1) dicarboxylic acid 7 by saponification of calix[4]phyrin(1.1.1.1) 6a.
strongly suggest that the [2+2] dipyrromethane building sion between substituents at the tetravalent centers is mini-
block approach to calix[4]phyrin(1.1.1.1)s can also be ap- mized (Scheme 7).[2a] Although the conjugation within the
plied to other sterically demanding aldehydes.
macrocycle is interrupted at the saturated meso-positions,
it is known from the literature that far-ranging electronic
induction effects in the two dipyrrin units still exist, and
that the substituents significantly modify conformational
transition barriers, equilibrium geometries, and relative
conformer energies throughout the complete calix[4]phyrin
structure.[21,32]
Information on the detailed structure of the calix[4]-
phyrin(1.1.1.1)s was obtained by single-crystal X-ray dif-
fraction analyses of 6a and 6c. Compound 6a exhibits crys-
tallographic C2 symmetry with half of the molecule forming
the asymmetric unit (cf. Table 2). However, the alkyl side
chains are disordered as shown in Figure 1 (top). Figure 1
(bottom) shows calix[4]phyrin(1.1.1.1) 6a as a syn-axial
meso-hydrogenated calix[4]phyrin with marked kinks en-
forced by its two sterically congested alkyl residues at the
sp3 hybridized trans-meso-positions along the 5,15-C axis,
which results in the typical “roof-like” (i.e. V-shaped) struc-
ture with an angle of approximately 112° between the dipyr-
rin halves. The two hydrogen atoms at C5 and C15 point
outward and the bulky alkyl residues occupy a syn-axial
conformation. The system also displays regions of local
planarity corresponding to the two dipyrrin halves, which
is in accordance to their description as “hybrid molecules”
that resemble both the aromatic porphyrins and their non-
planar, six-electron-reduced calixpyrrole analogues. The
two phenyl rings are positioned with an angle of approxi-
mately 55° relative to the dipyrrin plane. There is an intra-
molecular hydrogen bond [d(H···N) 2.16 Å] within the di-
pyrrin unit.
Scheme 6. TFA-catalyzed condensation of 8 with benzaldehyde to
yield calix[4]phyrin(1.1.1.1) 9 via the corresponding calixpyrrole in-
termediate.
In calix[4]phyrin(1.1.1.1)s with unsymmetrically substi-
tuted sp3-meso-carbon centers there are two possible dia-
stereomeric forms, syn and anti, which refer to the position
of the residues at the saturated meso-carbon centers. For the
syn isomer, two conformers can be distinguished denoted as
syn-axial and syn-equatorial. Among these three possible
stereoisomers, the syn-axial stereoisomer is more stable
than the two alternative stereoisomers because steric repul-
Scheme 7. Schematic representation of the three possible stereoisomers of calix[4]phyrin(1.1.1.1)s.
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FULL PAPER
Figure 1. ORTEP[35] plots of macrocycle 6a. Thermal ellipsoids are
scaled to 50% probability level. Top: Roof-like structure showing
the disorder. Hydrogen atoms, except those bonded to the nitrogen
atoms and to the carbon atoms 5 and 5Ј, have been omitted for
clarity (in the plot, C15 is denoted as C5Ј).
Figure 2. ORTEP[35] plots of macrocycle 6c. Thermal ellipsoids are
scaled to 50% probability level. Hydrogen atoms, except those
bonded to the nitrogen atoms and to the carbon atoms 5 and 15,
have been omitted for clarity.
structure, the approach of the metal ion from the bottom
The second calix[4]phyrin(1.1.1.1) 6c, which bears 4-acet- of the macrocycle to the inner core is sterically hindered.
oxyphenyl substituents at the sp2-hybridized meso-carbon Additionally, the bulky alkyl substituents at the saturated
centers, exhibits noncrystallographic C2 symmetry (Figure meso-carbon atoms with syn-axial configuration protect the
2). The geometries of 6c are in general in accordance with inner core from an insertion of the metal ion from the up-
the features already observed for the parent compound 6a. per face. However, the remarkable resistance of calix[4]-
There is a V-shaped conformation between the two dipyrrin phyrin(1.1.1.1) 6a towards metallation could also simply be
halves (angle ca. 112°), and the two alkyl residues occupy due to the discrepancy between the stereochemical require-
a syn-axial configuration (cf. Table 2). The two substituted ments of the metal coordination sphere and the geometry
phenyl rings are positioned with angles of approximately 53 of the molecule.
and 57° relative to the dipyrrin plane. There are intramolec-
ular hydrogen bonds [d(H···N) 2.15 and 2.25 Å] within each phyrin(1.1.1.1)s presented here, model compound 6a was
of the dipyrrin units. treated with two equivalents of cerium(IV) ammonium ni-
To evaluate the oxidation resistance of the calix[4]-
For metallation, owing to their partially unconjugated trate (CAN) or silver(I) oxide for 2 h in DCM at room tem-
nature, calix[4]phyrin(1.1.1.1)s exhibit more distortion than perature and also with an excess of DDQ under reflux con-
their aromatic porphyrin parent molecules. Hence, only a ditions in DCM for 1 h. In addition, 6a was also reacted
limited number of examples of the direct metallation of with three equivalents of tritylium tetrafluoroborate
calix[4]phyrin(1.1.1.1) ligands is reported in the litera- (Ph3CBF4)[36] at room temperature to abstract hydride ions
ture.[5a,5d,15a,15b,15d,16,34a,34d] In our experiments, the metal- from the sp3-hybridized meso-hydrogenated bridges. How-
lation of calix[4]phyrin(1.1.1.1) 6a with Ni(OAc)2·4H2O, ever, in all four experiments neither the formation of the
Cu(OAc)2·H2O, Zn(OAc)2·2H2O, and Pd(OAc)2, which are corresponding isoporphyrin (vide infra) nor the porphyrin
some of the most common metal salts used for metallation was observed and the starting material was essentially reco-
of tetrapyrrole systems, failed even when harsh conditions vered.
were employed [heated to reflux in N,N-dimethylformamide
In an additional set of experiments, the effect of the
(DMF) over several hours]. Based on the crystal structure acidic catalyst on the calix[4]phyrin(1.1.1.1) formation was
of 6a, it may be assumed that because of the “roof-like” investigated in DCM by using catalysts that are common
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Synthesis of Functionalized Calix[4]phyrin Macrocycles
for tetrapyrrole syntheses such as TFA, boron trifluoride thus concluded that an intramolecular reaction at one of
diethyl etherate, p-toluenesulfonic acid (p-TSA), and poly- the meso-positions to yield lactone 11 had occurred
phosphoric acid (PPA).[5a] These model experiments were (Scheme 8, Figure 3). The formation of this side product
again performed using dipyrromethane 4 and benzaldehyde may be rationalized by the following proposed mechanistic
as precursors. The acid catalyst plays a significant role in pathway: The methoxycarbonyl group is partially hy-
terms of reaction rate and isolated yield. With TFA as a drolyzed owing to the presence of TFA and water, which is
catalyst (20 mol-%), calix[4]phyrin(1.1.1.1) 6a was isolated generated in the course of the condensation reaction. Dur-
in 19% after 16 h (cf. Table 1). However, with BF3·OEt2 ing the oxidation step, a Linstead dehydrogenation at one
(20 mol-%), 6a was isolated in only 8% after 16 h. In both of the meso-hydrogenated centers occurs through a hydride
cases, traces of TPP (meso-tetraphenylporphyrin) were de- shift to DDQ[31] to yield the carbenium ion 10. Sub-
tected. It has also been reported that calix[4]phyrins are the sequently, this intermediate is intramolecularly attacked by
only macrocycles isolated when the condensation reaction is the neighboring carboxylic acid group (Scheme 8) to yield
performed in DCM in the presence of TFA as catalyst.[20,21] 11. Alternatively, the carbenium ion in the meso-position
Reactions of 4 with benzaldehyde catalyzed by p-TSA and could also be attacked by water, generated through the di-
PPA (20 mol-% of acid for both cases) resulted in the for- pyrromethane–aldehyde condensation, to form the corre-
mation of only traces of 6a and in the former case, a trace sponding meso-hydroxy calix[4]phyrin(1.1.1.1), which un-
amount of TPP was also detected. The formation of TPP dergoes lactonization with the neighboring carboxylic acid
as a side product can be explained by the partial occurrence group. It should be noted that the formation of such a
of “scrambling” of the dipyrromethane 4. This scrambling meso-hydroxy substituent at an sp3-hybridized center has
of dipyrromethanes is frequently observed in porphyrin already been reported by Sessler et al.[20a] for calix[4]phyrins
synthesis.[37] The effect of a higher TFA loading was also and by Osuka et al.[38] for calix[5]phyrins. The unusual ca-
investigated for the model reaction, and when using TFA in lix[4]phyrin(1.1.1.1) 11, which contains a mono-meso-spiro-
equimolar amounts, the yield could be increased to 25% lactone moiety, is formed. To the best of our knowledge
(compare with Table 1, Entry 1). If heptanal as an aliphatic compounds of this type are without precedents in the litera-
aldehyde was chosen instead of benzaldehyde, the product ture.
yield increased to 16% under the same conditions (compare
This mechanistic proposal is further supported by the
to Table 1, Entry 9). These results suggest that in cases following observations: Subjecting 6a to a mixture of acid
where interference of the acid catalyst with functional catalyst (TFA 20 mol-%) and DDQ (1.5 equiv.) for 28 h did
groups is not an issue, a higher acid catalyst loading can not result in any reaction and 6a was recovered. However,
also be applied and leads to slightly better results.
when 7, the hydrolysis product of 6a, was treated with TFA
We discovered that this interference of the acid catalyst (20 mol-%) and DDQ (1.5 equiv.), product 12 containing
with the functional groups can indeed be relevant when we the mono-meso-spirolactone moiety was formed, which
evaluated the influence of reaction time. For this, the reac- strongly suggests the hydrolysis of one of the ester groups
tion time for the synthesis of 6a was extended from 16 to of 6a prior to the lactonization step. The formation of the
46 h. Interestingly, after DDQ oxidation and column conceivable bis-spiro compound was not observed.
chromatography, an orange-red crystalline side product was
Finally, the structure of 11 was confirmed by an X-ray
isolated in 7% yield in addition to the main product 6a. diffraction analysis (cf. Table 2). In the resulting ORTEP
1
The H NMR spectrum of this side product showed the plot (Figure 3), it can be seen that the quaternary carbon
same pattern as the calix[4]phyrin(1.1.1.1) 6a, but one of atoms have the syn-axial orientation and that the lacton-
the methyl groups of the ester residues was missing. The ization has occurred in a way that the oxygen atom in the
mass spectrum of this side product was not in accordance lactone occupies an equatorial position with distortions
with a product arising from a simple ester hydrolysis. We found in the five-membered lactone ring.
Scheme 8. Mechanistic proposal for the TFA/DDQ mediated formation of mono-meso-spirolactone containing calix[4]phyrin(1.1.1.1)s 11
and 12.
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275

M. H. Beyzavi, D. Lentz, H.-U. Reissig, A. Wiehe
FULL PAPER
and 75°) of the phenyl rings are larger probably because of
the asymmetry of the molecule. Again, hydrogen bonding
[d(H···N) 2.19 and 2.20 Å] is observed within the two dipyr-
rin halves.
The UV/Vis spectra are consistent with the absence of
full conjugation in the calix[4]phyrin(1.1.1.1)s. As an exam-
ple, the UV/Vis spectra of 6a and 11 are shown in Figure 4.
Both compounds feature a strong Soret-like band at λmax
=
420 and 418 nm, respectively, which is considerably broad-
ened compared to those of porphyrins.[15c] In addition,
weak accompanying shoulders were observed for both com-
pounds with absorption intensities of ε Ͻ 6500 Lmol–1 cm–1
and maxima at λmax = 486 and 484 nm, respectively.
We finally examined the use of the key precursor dipyrro-
methane 4 and cyclopropane 1 in the synthesis of isopor-
phyrins, another calix-type porphyrin analogue that con-
tains a mixture of sp2- and sp3-hybridized bridging meso-
carbon centers. Isoporphyrins, or calix[4]phyrin(1.1.1.1)s,
are calix-type tetrapyrrole systems with 22 π electrons that
Figure 3. ORTEP[35] plot of 11. Thermal ellipsoids are scaled to
50% probability level. Hydrogen atoms, except those bonded to the
nitrogen atoms and to the carbon atom 5, have been omitted for
clarity.
However, the effect of the lactonization on the overall contain three sp2-hybridized meso-carbon atoms and one
structure of the calix[4]phyrin is small. The same roof-like NH hydrogen atom. Two experiments were designed: a)
appearance (angle ca. 112°) present in structures 6a and 6c condensation of one equivalent of dipyrromethane 4 and
is also adopted in the structure of 11, and the core skeleton unsubstituted dipyrromethane with two equivalents of
is folded along the line between the two saturated meso- benzaldehyde; and b) condensation of one equivalent of
carbon atoms. Again, the two dipyrrin halves are essentially cyclopropane 1 and unsubstituted dipyrromethane with two
planar. In this case the differences in the torsion angles (57 equivalents of pyrrole-2-carbaldehyde (Scheme 9). However,
Scheme 9. Two model experiments [conditions a) and b)] to incorporate one unit of the cyclopropane-derived sterically hindered residue
into the tetrapyrrole skeleton.
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Synthesis of Functionalized Calix[4]phyrin Macrocycles
promising results, research efforts are in progress devoted
to exploring the application of d–a cyclopropane precursors
to other tetrapyrrole systems.
Experimental Section
General Remarks: Reactions were generally performed under argon
in oven-dried flasks. Reagents were added with syringes. Solvents
were dried by using standard procedures. Dichloromethane (DCM)
was distilled and stored over molecular sieves (4 Å) under an atmo-
sphere of argon. Other reagents were purchased and were used as
received without further purification unless otherwise stated. Prod-
ucts were purified by chromatography on silica gel (40–63 μm) and
detection was carried out with a CAMAG variable UV detector (λ
= 254/366 nm). Yields refer to chromatographically purified prod-
ucts, unless otherwise stated. Reactions were monitored by thin-
layer chromatography (TLC) analysis. NMR spectra were recorded
with Bruker (AC 250, AC 500, AVIII 700) and JOEL (Eclipse 500)
instruments. Chemical shifts are reported relative to tetramethylsil-
ane (TMS, 1H: δ = 0.00 ppm), CHCl3 (1H: δ = 7.26 ppm), and
CDCl3 (13C: δ = 77.0 ppm) in CDCl3 solution. Integrals are in ac-
cordance with assignments; coupling constants are given in Hz. All
13C spectra are proton decoupled. Multiplicity is indicated as fol-
lows: s (singlet), d (doublet), t (triplet), m (multiplet), mc (centered
multiplet), dd (doublet of doublets), br. s (broad singlet). For de-
tailed peak assignments, 2D spectra were measured (1H–1H COSY,
Figure 4. UV/Vis spectra of 6a (dashed line) and 11 (solid line)
recorded in CH2Cl2 (room temp., 1.55ϫ10–5 m).
in both experiments, neither the corresponding isoporphyr-
in 14 nor porphyrin 15, which incorporates just one cyclo-
propane-derived substituent, was detected. In the former
case, 5,15-diphenylporphyrin 13 was isolated in 8% yield
together with traces of calix[4]phyrin(1.1.1.1) 6a. In the
latter case, small amounts of porphine 16 were isolated,
probably due to scrambling of the unsubstituted dipyrro-
methane.
1
1H–13C HMQC, and H–13C HMBC). IR spectra were measured
with a Jasco FT/IR-4100 spectrometer equipped with an attenuated
total reflectance (ATR) attachment (PIKE MIRacle). The UV/Vis
spectra were measured with a SPECORD S300 VIS UV/Vis spec-
trometer (Analytik Jena, Jena, Germany) with DCM as the solvent
and quartz cuvettes of 1 cm path length. HRMS analyses were per-
formed with an Agilent 6210 ESI-TOF instrument (Agilent Tech-
nologies, Santa Clara, CA, USA). The solvent flow rate was ad-
justed to 4 μLmin-1 and the spray voltage was 4 kV. The drying gas
flow rate was 15 psi (1 bar). All other parameters were adjusted for
maximum abundance of the respective [M + H]+ ions. (ESI-TOF
= electrospray ionization/time of flight). Elemental analyses were
carried out in CHN mode with a Vario EL instrument (Elementar
Analysensysteme GmbH). Melting points were measured with a
Reichert Thermovar apparatus. Methyl 2,2-dimethyl-3-(trimethyl-
siloxy)-1-cyclopropanecarboxylate (1) was prepared from 2-methyl-
1-(trimethylsiloxy)propene and methyl diazoacetate.[27]
Conclusions
We have presented the first example of an application
of a d–a cyclopropane as a precursor for the synthesis of
dipyrromethanes, which were subsequently utilized in acid-
catalyzed [2+2] condensation reactions with a series of aro-
matic and aliphatic aldehydes. This new approach provides
a flexible entry to novel meso-hydrogenated calix[4]phyrins
with free beta positions that are exceptionally stable
towards air and light owing to the incorporation of the
bulky cyclopropane-derived substituent into the macro-
cyclic skeleton. The method is highly selective as it only
leads to the formation of trans-porphodimethenes instead
of a mixture of other potential isomers of the calixphyrin
family such as porphomethenes, cis-porphodimethenes, iso-
porphyrins, or phlorins. The general applicability of this di-
pyrromethane approach to meso-hydrogenated calix[4]-
phyrins could additionally be exemplified with an example
of a pivalaldehyde-derived dipyrromethane precursor. Of
special interest was the detection and isolation of an acid-
driven lactonization that leads to the formation of the first
calix[4]phyrin(1.1.1.1) that incorporates a mono-meso-
spirolactone moiety.
X-ray Crystallography: X-ray quality single crystals were obtained
by slow diffusion of hexane into a DCM solution of the calix[4]-
phyrin(1.1.1.1) and the data are summarized in Table 2.
Suitable single crystals for the X-ray diffraction experiment were
selected by using a microscope and were mounted on the top of a
glass fiber. Data were collected with a Bruker-AXS SMART CCD
diffractometer using Mo-Kα radiation (λ = 0.71073 Å, graphite
monochromator). The structures were solved by direct methods
and refined anisotropically (C, N, O) by least-squares methods
using the SHELX-97 program suite.[39] The hydrogen atoms were
included and were calculated positions (riding model).
The field of hydroporphyrin chemistry is rapidly ex-
panding; however, practical applications in medicine or ma-
terials science require simple and straightforward syntheses.
The method described herein contributes to the field by
providing a synthetic route to a series of functionalized ca-
lix[4]phyrins. It enables a systematic and variable substitu-
tion that is suitable for further modifications at the moieties
CCDC-897952 (for 6a), -897953 (for 11), and -897954 (for 6c) con-
tain the supplementary crystallographic data for this paper. These
data can be obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
5-(3-Methoxy-1,1-dimethyl-3-oxopropyl)dipyrromethane (4): The re-
in the sp3- and sp2-hybridized meso-centers. Following these action was performed in a 250 mL three-necked round-bottom
Eur. J. Org. Chem. 2013, 269–282
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277

M. H. Beyzavi, D. Lentz, H.-U. Reissig, A. Wiehe
FULL PAPER
Table 2. Details of the crystallographic data collection of 6a, 6c, and 11.
6a
6c
11
Formula
C44H44N4O4
692.83
orthorhombic
Pbcn
C48H48N4O8
808.90
orthorhombic
P212121
4
C43H40N4O4
676.79
Formula mass
Crystal system
Space group
Z
triclinic
¯
P1
4
2
T [K]
a [Å]
b [Å]
c [Å]
α [°]
β [°]
100
133
133
23.315(5)
12.420(3)
12.545(4)
90
90
90
3632.6(15)
1.267
1472
12.120(2)
14.547(2)
23.206(3)
90
90
90
4091.5(11)
1.313
1712
10.620(2)
13.943(2)
13.951(2)
78.189(4)
71.276(4)
85.042(4)
1914.5(6)
1.174
γ [°]
V [Å3]
Calcd. density [g/cm3]
F(000)
716
Crystal form
Crystal color
Crystal size [mm3]
λ [Å]
prism
red
0.23ϫ0.21ϫ0.16
Mo-Kα, 0.7107
50.18
needle
red
0.45ϫ0.21ϫ0.11
Mo-Kα, 0.7107
52.86
prism
orange
0.40ϫ0.20ϫ0.15
Mo-Kα, 0.7107
50.12
2θ [°]
Collected reflections
Unique reflections
Observed [IϾ2σ( I)]
Completeness [%]
Rint
wR2
R1 (I Ͼ 2 σ I)
GoF
36308
3228
2583
99
0.0783
0.2095
0.0896
1.224
33929
8284
6825
98
0.0390
0.0982
0.0389
1.041
13354
6755
4984
99
0.0230
0.1198
0.0411
1.060
flask fitted with a septum port, a bubble counter, and a gas inlet
port. A solution of methyl 2,2-dimethyl-3-(trimethylsiloxy)-1-cyclo-
propanecarboxylate (1) (1.56 g, 7.21 mmol) and pyrrole (25 mL,
362 mmol) was degassed by bubbling with argon for 10 min, and
then TFA (0.05 mL, 0.72 mmol) was added. The solution was
stirred for 2 h at room temperature, at which point no starting cy-
clopropane 1 was identified by TLC analysis. The TLC plate was
developed in a mixture of DCM/EtOAc/NEt3 (98:1:1), and the
bands were visualized by exposure of the air-dried TLC plate to
bromine vapor. The reaction mixture was diluted with DCM
(200 mL) and was then then washed with aqueous NaOH (0.1 n,
20 mL), washed with water, and dried with anhydrous Na2SO4. The
solvent was removed under reduced pressure, and the unreacted
pyrrole was removed by vacuum distillation. The resulting dark
viscous oil was dissolved in a minimal quantity of the eluent and
was purified by silica column chromatography with DCM/EtOAc/
(260.2): calcd. C 69.20, H 7.74, N 10.76; found C 69.12, H 7.52, N
10.78.
General Procedure for the Synthesis of meso-Hydrogenated Calix-
[4]phyrin(1.1.1.1) Derivatives 6: A standard reaction was performed
in a 1 L three-necked round-bottom flask fitted with a septum port,
bubble counter, and a gas inlet port with argon flow. 5-(3-Methoxy-
1,1-dimethyl-3-oxopropyl)dipyrromethane (4) (520 mg, 2.00 mmol)
and the appropriate aldehyde (2.00 mmol) were dissolved in dry
DCM (500 mL). The resulting solution was degassed by bubbling
with an argon flow for 10 min, and TFA (30 μL, 0.40 mmol) was
added by syringe with vigorous stirring. The reaction mixture was
stirred under argon in the dark at room temperature for a specific
time as indicated for each individual experiment in Table 1. After
the indicated time, the calixpyrrole intermediate was subjected to
oxidation for 2 h by the addition of DDQ (690 mg, 3.00 mmol),
NEt3 (98:1:1) as eluent. Any remaining pyrrole elutes first, followed followed by neutralization of TFA with NEt3 (500 μL, 3.60 mmol).
slowly by the dipyrromethane 4 (RF 0.45) and followed later by
tailing materials. Colorless oil, yield 1.14 g (61%). IR (ATR): ν
The reaction mixture was filtered through a glass frit loaded with
silica gel and eluted with a mixture of DCM/EtOAc (ratio de-
pending on product, see individual procedures) to afford the crude
˜
max
[40]
= 3385 (N–H), 3100 (C–H pyrrole),
2950 (C–H), 2875 (CH3),
1710 (C=O), 1555 (N–H), 1465 (CH2), 1430 (N–H pyrrole), 1390 products. After concentration of the filtrate under reduced pres-
(C–H pyrrole), 1365 (CH3), 1330 (C–N), 1215 (C–O), 1150 (C–O), sure, the residue was dissolved in a minimum volume of solvent
1115 (C–N), 1090 (C–H pyrrole), 1025 (C–H pyrrole), 885 (C–H and applied to gradient elution silica gel column chromatography
pyrrole) cm–1. 1H NMR (500 MHz, CDCl3): δ = 1.06 (s, 6 H, with hexane/DCM (ratio depending on product, see individual pro-
2ϫCH3), 2.23 (s, 2 H, CH2), 3.70 (s, 3 H, OCH3), 4.29 (s, 1 H,
meso-H), 6.14–6.17 (m, 4 H, β-pyrrole-H), 6.63 (mc, 2 H, α-pyrrole-
H), 8.43 (s, 2 H, 2ϫNH) ppm. 13C NMR (126 MHz, CDCl3): δ =
cedures) for further purification. Three successive fractions could
be collected depending on the aldehyde applied and the reaction
times in Table 1. The first purple band contains the porphyrin-type
25.3 (2ϫCH3), 38.0 [C(CH3)2], 44.7 (CH2), 46.6 (5-meso-C), 51.3 side product in a trace amount (less than 1%), the second yellow-
(OCH3), 106.8 (pyrrole-C), 108.1 (pyrrole-C), 115.9 (pyrrole-C),
130.2 (pyrrole-C), 173.7 (C=O) ppm. HRMS (ESI-TOF): calcd. for
orange band contains the meso-hydrogenated calix[4]phyrin-
(1.1.1.1) 6 in yields between 4 and 25% as the main product; with
C15H21N2O2 [M + H]+ 261.1603; found 261.1600; calcd. for an extended reaction time for the synthesis of 6a, the third yellow-
C15H20N2O2Na [M + Na]+ 283.1422; found 283.1419; calcd. for
C15H20N2O2K [M + K]+ 299.1162; found 299.1147. C15H20N2O2
orange band contains the mono-meso spirolactone side product 11
in 7% yield. Finally, recrystallization of the main fraction from a
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Synthesis of Functionalized Calix[4]phyrin Macrocycles
chloroform/hexane mixture gave the desired crystalline form of the
products.
quenching the reaction followed by performing the same work-up
procedure as described for (A), the starting material was recovered.
(C): Under the same reaction conditions as described for (A), tri-
phenylcarbenium tetrafluoroborate (30 mg, 0.09 mmol) was added
to a stirred suspension of 6a (21 mg, 0.03 mmol) in dry DCM
(10 mL), and the resulting solution was stirred for 1 h at room tem-
perature, during which time the solution initially turned dark green.
However, no indication for the formation of either the correspond-
ing isoporphyrin or porphyrin was detected by TLC analysis. After
quenching the reaction followed by performing the same work up
procedure as described for (A), the starting material was recovered.
(D): Under the same reaction conditions as described for (A),
DDQ (27 mg, 0.12 mmol) was added to a stirred suspension of 6a
(21 mg, 0.03 mmol) in dry DCM (10 mL), and the resulting solu-
tion was stirred for 1 h under reflux conditions, during which time
no indication of the formation of either the corresponding isopor-
phyrin or porphyrin was detected using TLC analysis. After
quenching the reaction followed by performing the same work up
procedure as described for (A), the starting material was recovered.
5,15-Bis(3-methoxy-1,1-dimethyl-3-oxopropyl)-10,20-diphenylcalix-
[4]phyrin(1.1.1.1) (6a): According to the general procedure, a mix-
ture of dipyrromethane 4 (520 mg, 2.00 mmol) and benzaldehyde
(20 μL, 2.00 mmol) was reacted in the presence of TFA (30 μL,
0.40 mmol) in dry DCM (500 mL). After 16 h, the oxidation step
was performed with DDQ (690 mg, 3.00 mmol), followed by neu-
tralization with NEt3 (500 μL, 3.60 mmol). The reaction mixture
was then filtered through a glass frit loaded with silica gel and
eluted with a mixture of DCM/EtOAc (90:10) to afford the crude
products. After concentration of the filtrate under reduced pres-
sure, the residue was dissolved in a minimum volume of solvent
and applied to gradient elution silica gel column chromatography
with hexane/DCM (50:50 to 0:100) for further purification. Finally,
recrystallization of the main fraction from a DCM/hexane mixture
gave the desired crystalline form of the product. Orange crystals,
yield 131 mg (19%), m.p. 192 °C. IR (ATR): ν
= 3305 (N–H),
˜
max
2960 (CH3), 2935 (CH2), 2875 (CH3), 2855 (CH2), 1730 (C=O),
1580 (N–H), 1420 (CH2), 1440 (CH3), 1410 (C–H pyrrole),[40] 1375
(CH3), 1200 (C–O), 1115 (C–N), 1045 (C–H pyrrole), 1015 (C–H
pyrrole), 955 (C–H pyrrole), 755 (=C–H), 720 (=C–H) cm–1. 1H
NMR (500 MHz, CDCl3): δ = 1.26 (s, 12 H, 4ϫCH3), 2.48 (s, 4
H, 2ϫCH2), 3.67 (s, 6 H, 2ϫOCH3), 4.35 (s, 2 H, 2ϫ5,15-meso-
H), 6.23 (d, J = 4.0 Hz, 4 H, β-pyrrole-H), 6.37 (d, J = 4.0 Hz, 4
H, β-pyrrole-H), 7.35–7.44 (m, 8 H, Ar), 7.50–7.53 (m, 2 H, Ar),
13.18 (s, 2 H, 2ϫNH) ppm. 13C NMR (126 MHz, CDCl3): δ = 26.0
(4ϫCH3), 38.8 [2ϫC(CH3)2], 44.8 (2ϫCH2), 50.5 (5,15-meso-C),
51.3 (2ϫOCH3), 120.2 (Ar), 127.4 (Ar), 127.4 (Ar), 128.5 (Ar),
130.7 (Ar), 130.9 (Ar), 137.7 (Ar), 140.2 (Ar), 140.5 (Ar), 156.6
(Ar), 172.8 (2 ϫ C=O) ppm. HRMS (ESI-TOF): calcd. for
5,15-Bis(2-carboxy-1,1-dimethylethyl)-10,20-diphenylcalix[4]phyrin-
(1.1.1.1) (7): Calix[4]phyrin(1.1.1.1) 6a (70 mg, 0.10 mmol) was dis-
solved in THF (20 mL). To this solution was added a solution of
potassium hydroxide (561 mg, 10.0 mmol) dissolved in methanol
(10 mL), and the solution was stirred for 5 h at room temperature.
TLC analysis showed the consumption of all starting material. Af-
ter this time the reaction mixture was transferred to a separatory
funnel and water (100 mL) and ethyl acetate (100 mL) were added.
During phase separation, the solution was neutralized by adding
25% hydrochloric acid. After neutralization, the organic phase was
washed with water (3ϫ150 mL). The organic phase was then dried
with anhydrous Na2SO4. The drying agent was removed and the
organic phase was evaporated to dryness. The resulting solid was
redissolved in DCM/methanol (1:2, v/v; 5 mL) and again evapo-
rated to dryness. Upon evaporation an orange solid powder was
formed, which was then dried in vacuo. Yield: quantitative (66 mg),
m.p. 262 °C. 1H NMR (500 MHz, CDCl3): δ = 1.22 (s, 12 H,
4ϫCH3), 2.93 (s, 4 H, 2ϫCH2), 3.95 (s, 2 H, 2ϫ5,15-meso-H),
6.20 (d, J = 4.1 Hz, 4 H, β-pyrrole-H), 6.38 (d, J = 4.1 Hz, 4 H, β-
pyrrole-H), 7.34–7.40 (m, 4 H, Ar), 7.41–7.45 (m, 4 H, Ar), 7.52–
7.56 (m, 2 H, Ar), 12.39 (br. s, 2 H, CO2H), 13.07 (br. s, 2 H,
2ϫNH) ppm. 13C NMR (126 MHz, CDCl3): δ = 26.7 (4ϫCH3),
39.1 [2ϫC(CH3)2], 42.8 (2ϫCH2), 53.7 (5,15-meso-C), 120.3 (β-
pyrrole-C), 127.4 (Ar), 127.5 (Ar), 128.5 (Ar), 128.7 (β-pyrrole-C),
130.6 (Ar), 131.0 (Ar), 137.6 (Ar), 140.5 (α-pyrrole-C), 156.1 (α-
pyrrole-C), 180.2 (2ϫC=O) ppm. HRMS (ESI-TOF): calcd. for
C42H41N4O4 [M + H]+ 665.3128; found 665.3149. UV/Vis
(CH2Cl2): λmax [log(ε/Lmol–1 cm–1)] = 421 [4.61], 485 [3.57] nm.
C
44H45N4O4 [M + H]+ 693.3441; found 693.3393; calcd. for
C44H44N4O4Na [M + Na]+ 715.3260; found 715.3212. UV/Vis
(CH2Cl2): λmax [log(ε/Lmol–1 cm–1)] = 420 [4.75], 486 [3.72] nm.
Procedures for Oxidation Resistance Test Reactions of Calix[4]-
phyrin(1.1.1.1) (6a): Oxidation was attempted with (A) cerium(IV)
ammonium nitrate, (B) silver(I) oxide, (C) triphenylcarbenium
tetrafluoroborate (tritylium tetrafluoroborate), and (D) excess 2,3-
dichloro-5,6-dicyano-p-benzoquinone (DDQ). (A): Compound 6a
(21 mg, 0.03 mmol) was dissolved in dry DCM (10 mL) in a 50 mL
round-bottom flask containing cerium(IV) ammonium nitrate
(33 mg, 0.06 mmol). The solution was then stirred for 1 h at room
temperature, during which time no indication of the formation of
either the corresponding isoporphyrin or porphyrin was detected
by TLC analysis. The TLC plates were developed by using a mix-
ture of hexane/DCM (1:1), and the bands were visualized by expo-
sure of the air-dried TLC plate to UV radiation (λ = 254/366 nm).
The reaction mixture was diluted with DCM (100 mL), filtered
through a glass frit loaded with silica gel, and eluted with a mixture
of DCM/EtOAc (90:10). After that, the filtrate was evaporated to
dryness under reduced pressure, and the residual solid was dis-
solved in DCM (100 mL), washed with water (3ϫ100 mL), and
dried with anhydrous Na2SO4. The crude product was then applied
to gradient elution silica gel column chromatography with hexane/
5-(1,1-Dimethylethyl)dipyrromethane (8): The reaction was per-
formed in a 250 mL three-necked round-bottom flask fitted with a
septum port, a bubble counter, and a gas inlet port. A solution of
pivaldehyde (1.7 mL, 15.0 mmol) and freshly distilled pyrrole
(52.0 mL, 750 mmol) was degassed by bubbling with argon for
10 min, and then TFA (103 μL, 1.40 mmol) was added. The solu-
tion was stirred for 2 h at room temperature, at which point no
DCM (15:85 to 0:100) for further purification, which resulted in starting pivaldehyde was identified by TLC analysis. The TLC plate
isolation and recovery of starting material. (B): Under the same
reaction conditions as those described for (A), 6a (21 mg,
0.03 mmol) was dissolved in dry DCM (10 mL) in a 50 mL round-
bottom flask containing silver(I) oxide (14 mg, 0.06 mmol). The
solution was then stirred for 1 h at room temperature, during which
time no indication of the formation of either the corresponding
isoporphyrin or porphyrin was detected by TLC analysis. After
was developed in a mixture of hexane/DCM/NEt3 (50:49:1), and
the bands were visualized by exposure of the air-dried TLC plate
to bromine vapor. The reaction mixture was diluted with DCM
(400 mL) and then washed with aqueous NaOH (0.1 n, 40 mL),
washed with water, and dried with anhydrous Na2SO4. The solvent
was removed under reduced pressure, and the unreacted pyrrole
was removed by vacuum distillation. Recrystallization of the ob-
Eur. J. Org. Chem. 2013, 269–282
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
279

M. H. Beyzavi, D. Lentz, H.-U. Reissig, A. Wiehe
FULL PAPER
tained resulting viscous oil from DCM/pentane mixture gave the
1440 (CH3), 1410 (C–H pyrrole),[40] 1370 (CH3), 1195 (C–O), 1115
desired crystalline form of the product. Colorless crystals, yield (C–N), 1050 (C–H pyrrole), 1010 (C–H pyrrole), 955 (C–H pyr-
1.75 g (58%). IR (ATR): ν = 3382 (N–H), 3360 (N–H), 3095
role), 755 (=C–H), 720 (=C–H) cm–1. 1H NMR (500 MHz,
(C–H pyrrole),[40] 2970 (CH3), 2950 (C–H), 2910 (C–H), 2865 CDCl3): δ = 1.27 (s, 6 H, 2ϫCH3,lactone), 1.30 (s, 6 H, 2ϫCH3),
(CH3), 1550 (N–H), 1470 (CH2), 1450 (CH3), 1390 (C–H pyrrole), 2.49 (s, 2 H, CH2), 2.53 (s, 2 H, CH2,lactone), 3.68 (s, 3 H, OCH3),
1360 (CH3), 1350 (C–N), 1115 (C–N), 1095 (C–H pyrrole), 1025 4.40 (s, 1 H, 15-meso-H), 6.28 (d, J = 4.1 Hz, 2 H, β-pyrrole-H),
(C–H pyrrole), 890 (C–H pyrrole) cm–1 1H NMR (500 MHz,
6.43 (mc, 4 H, β-pyrrole-H), 6.46 (d, J = 4.0 Hz, 2 H, β-pyrrole-
CDCl3): δ = 1.01 (s, 9 H, 3ϫCH3), 3.77 (s, 1 H, meso-H), 6.10– H), 7.42 (mc, 8 H, Ar), 7.47–7.50 (m, 2 H, Ar), 13.06 (s, 2 H,
˜
max
.
6.13 (m, 2 H, pyrrole-H), 6.16 (mc, 2 H, pyrrole-H), 6.62 (mc, 2 H,
2ϫNH) ppm. 13C NMR (126 MHz, CDCl3): δ = 24.3 (2ϫ
pyrrole-H), 7.94 (s, 2 H, 2 ϫ NH) ppm. 13C NMR (126 MHz, CH3,lactone), 26.0 (2ϫCH3), 39.4 [C(CH3)2], 43.2 (CH2,lactone), 44.8
CDCl3): δ = 28.6 (3ϫCH3), 35.5 [C(CH3)3], 50.4 (5-meso-C), 106.5 (CH2), 45.9 [C(CH3)2,lactone], 50.4 (15-meso-C), 51.4 (OCH3), 89.7
(pyrrole-C), 108.4 (pyrrole-C), 116.0 (pyrrole-C), 131.4 (pyrrole-C)
(5-meso-C), 115.8 (Ar), 121.0 (Ar), 127.5 (Ar), 127.6 (Ar), 128.9
(Ar), 129.4 (Ar), 130.7 (Ar), 130.9 (Ar), 137.3 (Ar), 141.1 (Ar),
ppm. HRMS (ESI-TOF): calcd. for C13H19N2 [M + H]+ 203.1548;
found 203.1544; calcd. for C13H18N2Na [M + Na]+ 225.1368; found 172.6 (C=O), 175.9 (C=Olactone
) ppm. HRMS (ESI-TOF):
225.1354. C13H18N2 (202.2): calcd. C 77.18, H 8.97, N 13.85; found
C 76.57, H 8.90, N 13.60.
calcd. for C43H41N4O4 [M + H]+ 677.3128; found 677.3144;
calcd. for C43H40N4O4Na [M + Na]+ 699.2947; found 699.2971.
UV/Vis (CH2Cl2): λmax [log(ε/Lmol–1 cm–1)] = 418 [4.79], 484
[3.80] nm.
5,15-Bis(1,1-dimethylethyl)-10,20-diphenylcalix[4]phyrin(1.1.1.1)
(9): According to the general procedure, a mixture of 8 (405 mg,
2.00 mmol) and benzaldehyde (20 μL, 2.00 mmol) was reacted in
the presence of TFA (30 μL, 0.40 mmol) in dry DCM (500 mL).
After 16 h, the oxidation step was performed with DDQ (690 mg,
3.00 mmol), followed by neutralization with NEt3 (500 μL,
3.60 mmol). The reaction mixture was then filtered through a glass
frit loaded with silica gel and eluted with a mixture of DCM/EtOAc
(95:5) to afford the crude products. After concentration of the fil-
trate under reduced pressure, the residue was dissolved in a mini-
mum volume of solvent and applied to gradient elution silica gel
column chromatography with hexane/DCM (70:30 to 20:80) for
further purification. Finally, recrystallization of the main fraction
from a DCM/pentane mixture gave the desired crystalline form of
Mechanistic Test Reactions for the Preparation of 11 and 12: A stan-
dard reaction was performed in a 1 L three-necked round-bottom
flask fitted with a septum port, a bubble counter, and a gas inlet
port with argon flow. Compound 6a (42 mg, 0.06 mmol) was dis-
solved in dry DCM (500 mL). The resulting solution was degassed
by bubbling with an argon flow for 10 min. TFA (0.9 μL,
0.012 mmol) was then added with a syringe under vigorous stirring.
After 15 min, DDQ (21 mg, 0.09 mmol) was added, and the reac-
tion mixture was stirred under argon in the dark at room tempera-
ture for 28 h; and the reaction mixture was then neutralized with
the addition of NEt3 (14 μL, 0.10 mmol). The reaction mixture was
filtered through a glass frit loaded with silica gel and eluted with a
mixture of DCM/EtOAc (80:20) to afford the crude products. After
concentration of the filtrate under reduced pressure, it was transfer-
red to a separatory funnel and water (100 mL) and ethyl acetate
(100 mL) were added, and the organic phase was washed with
water (3ϫ150 mL). The organic phase was dried with anhydrous
Na2SO4. The drying agent was removed, and the organic phase was
evaporated to dryness. The resulting solid was redissolved in hex-
ane/DCM (50:50, v/v; 2 mL) and was applied to gradient elution
silica gel column chromatography with hexane/DCM (50:50 to
0:100) for further purification, which resulted in the recovery of
starting material without any indication of the formation of 11.
1
the product. Orange crystals, yield 156 mg (27%), m.p. 214 °C. H
NMR (500 MHz, CDCl3): δ = 1.15 (s, 18 H, 6ϫCH3), 3.90 (s, 2
H, 2ϫ5,15-meso-H), 6.18 (d, J = 4.0 Hz, 4 H, β-pyrrole-H), 6.37
(d, J = 4.0 Hz, 4 H, β-pyrrole-H), 7.35–7.39 (m, 2 H, Ar), 7.39–
7.44 (m, 6 H, Ar), 7.51–7.55 (m, 2 H, Ar), 13.21 (s, 2 H, 2ϫNH)
ppm. 13C NMR (126 MHz, CDCl3): δ = 28.9 (6ϫCH3), 36.6
[2ϫC(CH3)3], 53.1 (5,15-meso-C), 120.0 (Ar), 127.3 (Ar), 127.4
(Ar), 128.1 (Ar), 128.3 (Ar), 130.8 (Ar), 130.9 (Ar), 137.9 (Ar),
139.7 (Ar), 140.3 (Ar), 157.5 (Ar) ppm. HRMS (ESI-TOF): calcd.
for C40H41N4 [M + H]+ 577.3331; found 577.3312; calcd. for
C40H40N4Na [M + Na]+ 599.3151; found 599.3144. UV/Vis
(CH2Cl2): λmax [log(ε/Lmol–1 cm–1)] 420 [4.88], 486 [3.81] nm.
In another experiment, under the same reaction conditions and
with the same molar ratios of starting material and reagents, 7 was
treated with TFA and DDQ. After work up and silica gel column
chromatography [eluent for filtration through silica gel: DCM/
MeOH (60:40) and for gradient elution chromatography: DCM/
Calix[4]phyrin(1.1.1.1) Containing
a
Mono-meso-spirolactone
Moiety (11): According to the general procedure for the synthesis
of meso-hydrogenated calix[4]phyrin(1.1.1.1)s, a mixture of 4
(520 mg, 2.00 mmol) and benzaldehyde (200 μL, 2.00 mmol) was
reacted in the presence of TFA (30 μL, 0.40 mmol) in dry DCM
(500 mL). After 46 h, the oxidation step was performed for 4 h
using DDQ (690 mg, 3.00 mmol), and the reaction was then neu-
tralized by the addition of NEt3 (500 μL, 3.60 mmol). The reaction
mixture was then filtered through a glass frit loaded with silica gel,
eluted with a mixture of DCM/EtOAc (80:20) to afford the crude
products. After concentration of the filtrate under reduced pres-
sure, the residue was dissolved in a minimum volume of solvent
and applied to gradient elution silica gel column chromatography
with hexane/DCM (50:50 to 0:100) for further purification. The
first orange band contained 6a in 10% yield (69 mg) as the main
product, and the second orange band contained the side product
11 in 7% yield (47 mg). Finally, recrystallization of the second frac-
tion from a DCM/hexane mixture gave the desired crystalline form
of the side product 11. Orange crystals, m.p. 192 °C. IR (ATR):
1
MeOH (90:10 to 60:40)], product 12 (3 mg, 7%) was obtained. H
NMR (700 MHz, CDCl3): δ = 1.31 (s, 6 H, 2ϫCH3,lactone), 1.37 (s,
6 H, 2ϫCH3), 2.56 (s, 2 H, CH2,lactone), 2.57 (s, 2 H, CH2), 4.40
(s, 1 H, 15-meso-H), 6.32 (d, J = 4.1 Hz, 2 H, β-pyrrole-H), 6.46
(d, J = 4.0 Hz, 4 H, β-pyrrole-H), 6.50 (d, J = 4.2 Hz, 2 H, β-
pyrrole-H), 7.40–7.53 (m, 10 H, Ar), 13.05 (br. s, 2 H, 2ϫNH)
ppm. 13C NMR (176 MHz, CDCl3): δ = 24.3 (2ϫCH3,lactone), 26.0
(2ϫCH3), 39.2 [C(CH3)2], 43.1 (CH2,lactone), 44.1 (CH2), 45.8
[C(CH3)2,lactone], 50.2 (15-meso-C), 89.6 (5-meso-C), 115.9 (Ar),
120.9 (Ar), 127.4 (Ar), 127.5 (Ar), 128.8 (Ar), 129.4 (Ar), 130.6
(Ar), 130.8 (Ar), 137.2 (Ar), 141.2 (Ar), 174.4 (C=O), 175.8
(C=Olactone) ppm. HRMS (ESI-TOF): calcd. for C42H39N4O4
[M + H]+ 663.2971; found 663.2977; calcd. for C42H38N4O4Na [M
+ Na]+ 685.2791; found 685.4343; calcd. for C42H38N4O4K [M +
K]+ 701.2530; found 701.4122.
ν
˜
= 3310 (N–H), 2970 (CH3), 2925 (CH2), 2870 (CH3), 2855
Supporting Information (see footnote on the first page of this arti-
max
(CH2), 1790 (C=Olactone), 1735 (C=O), 1585 (N–H), 1415 (CH2), cle): Preparation and characterization data for calix[4]phyrins 6b–
280 Eur. J. Org. Chem. 2013, 269–282
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Synthesis of Functionalized Calix[4]phyrin Macrocycles
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1
1
1
tra of 4, 6b–6j and 7–11. H–1H COSY, H–13C HMQC, and H–
13C HMBC NMR spectra of 6a.
Acknowledgments
Financial support for this project by the European Union is grate-
fully acknowledged (Ph.D. scholarship to M.H.B.). The authors
thank Dr. R. Zimmer and Dr. S. Mebs for discussions during the
preparation of the manuscript. M.Sc.Eng. Ehsan Fereidoonnezhad
is thanked for his contribution to the cover picture design.
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Eur. J. Org. Chem. 2013, 269–282
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
281

M. H. Beyzavi, D. Lentz, H.-U. Reissig, A. Wiehe
FULL PAPER
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Received: September 28, 2012
Published Online: December 6, 2012
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