Stereoselective synthesis of lower and upper rim functionalized tetra-α isomers of calix[4]pyrroles

Article abstract of DOI:10.1021/acs.orglett.6b03505

Hydroxyaryl alkyl ketones with functionalized alkyl chains often fail to produce the corresponding tetra-α calix[4]pyrroles in Br?nsted acid mediated condensations with pyrrole. A remarkable effect exerted by the addition of methyltrialkylammonium chloride during the acid-mediated syntheses of a series of meso-(tetrahydroxyaryl)-meso-tetraalkylcalix[4]- pyrroles featuring alkyl terminal chloro or ester groups is reported. The ammonium salt enhances the cyclocondensation reaction and induces the almost exclusive formation of the tetra-α isomers.

Full text of DOI:10.1021/acs.orglett.6b03505

Letter
pubs.acs.org/OrgLett
Stereoselective Synthesis of Lower and Upper Rim Functionalized
Tetra‑α Isomers of Calix[4]pyrroles
Alejandro Díaz-Moscoso,† Daniel Hernandez-Alonso,† Luis Escobar,† Frank A. Arroyave,† and
́
Pablo Ballester*,†,‡
†Institute of Chemical Research of Catalonia (ICIQ), The Barcelona Institute of Science and Technology (BIST), Avda. Països
Catalans 16, 43007 Tarragona, Spain
‡ICREA, Passeig Lluís Companys 23, 08010 Barcelona, Spain
S
* Supporting Information
ABSTRACT: Hydroxyaryl alkyl ketones with functionalized
alkyl chains often fail to produce the corresponding tetra-α
calix[4]pyrroles in Bronsted acid mediated condensations with
̈
pyrrole. A remarkable effect exerted by the addition of methyl-
trialkylammonium chloride during the acid-mediated syntheses
of a series of meso-(tetrahydroxyaryl)-meso-tetraalkylcalix[4]-
pyrroles featuring alkyl terminal chloro or ester groups is
reported. The ammonium salt enhances the cyclocondensation
reaction and induces the almost exclusive formation of the tetra-α isomers.
meso-Tetraaryl-meso-tetramethylcalix[4]pyrroles, so-called aryl-
extended calix[4]pyrroles, are meso-non-hydrogen-substituted
porphyrinogens bearing one aryl group on each of the four
meso-carbons.1−4 These compounds can exist as four different
configurational isomers termed α,α,α,α, α,α,α,β, α,α,β,β, and
α,β,α,β in analogy with the porphyrin literature (Figure 1).
transport of ions and ion-pairs across lipophilic membranes,6
and the development of new functional materials.7
Aryl-extended calix[4]pyrroles are typically synthesized by
the acid-mediated condensation reaction of an aryl methyl
ketone with pyrrole. Generally, this reaction produces a mixture
of the four different configurational calix[4]pyrrole isomers and
a plethora of open oligomers.1−3
With the aim of tuning the binding properties of the polar-
and closed-ended cavity of the aryl-extended calix[4]pyrroles,
different functional groups have been introduced on the aryl
substituents (upper rim) of the tetra-α isomers.3,8 The upper
rim functionalization allows the construction of more elaborate
cavitand9 and capsule10 architectures. The second meso-position,
geminal to the aryl ring (lower rim, Figure 1), is an ideal location
for attaching groups with versatile functions without much
effect on the binding and recognition properties of the parent
methyl tetra-α aromatic cavity. In close analogy with
resorcin[4]arenes11 and calix[4]arenes,12 lower-rim functional-
ization can increase the potential applications of aryl-extended
calix[4]pyrroles, including solubility in different media,
anchoring to solid surfaces and further functionalization.
Most reported syntheses of aryl-extended calix[4]pyrroles
either as pure isomers1−3,13,14 or isomeric mixtures15−19 target
compounds with a simple methyl group attached to the meso-
carbons. To date and to the best of our knowledge, only two
examples featuring four substituents other than methyl groups
have been reported.20,21 These examples described aryl-
extended calix[4]pyrroles with a single type of functional
group, either on the upper rim or the lower rim substituents. It
is worth mentioning that tetramethylcalix[4]pyrroles featuring
Figure 1. Molecular structures of the α,α,α,α and α,β,α,β configura-
tional isomers of meso-tetraaryl-meso-tetramethylcalix[4]pyrroles in
cone conformations.
The term α or β indicates whether the aryl substituent is
directed “up” or “down” with respect to the mean plane defined
by the four meso-carbons. In turn, each configurational isomer
can adopt multiple conformations depending on the relative
orientation of the pyrrole units, i.e., cone, 1,3-alternate,
1,2-alternate, or partial-cone. In the cone conformation, the
tetra-α isomer of aryl-extended calix[4]pyrroles features an
aromatic cavity functionalized at the closed end with four
pyrrole NHs that is reminiscent of enzymatic binding pockets.
The unique properties of the tetra-α isomer of aryl-extended
calix[4]pyrroles have been exploited in several applications
such as the self-assembly of molecular dimeric capsules,5 the
Received: November 23, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b03505
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Letter
two cis-p-fluorophenyl groups that are geminal to hydroxyl- or
carboxyethyl-terminated alkyl substituents in nonadjacent meso-
carbons are known.22
the HCl-mediated cyclocondensation of pyrrole with hydroxy-
phenyl alkyl ketones 1a and 2a,b.
We selected two inexpensive and commercially available
methyltrialkylammonium chloride salts for our experiments: (a)
Aliquat 336, 5, which is a mixture of C8−C10 methyltrialkyl
ammonium chloride salts enriched in the C8 chains that can
be removed by silica filtration, and (b) methyltributylammo-
nium chloride (MTBACl) 6, which can be removed by simply
washing the organic solution of the crude reaction mixture with
water. Both organic salts provided similar results in the cases
tested, although the MTBACl was preferred for purification
ease.
The condensation reaction of aryl alkyl ketones with pyrrole
to produce the corresponding calix[4]pyrroles is significantly
less efficient than the reaction with their aryl methyl counter-
parts, which may explain the limited examples. The reduced
reaction efficiency can be attributed to steric clashes between
the substituent in the α-position to the ketone function and the
β-pyrrole protons in the transition states of the condensation
reactions, especially in the final macrocyclization. For example,
the presence of a terminal alkyne in the alkyl chain in the
synthesis of the tetra-α isomer gave only a 1% yield.21 Here,
we describe an unprecedented template synthetic strategy that
overcomes these problems.
Our approach is based on the simple addition of methyl-
trialkylammonium chloride salt to the acid-mediated con-
densation reaction of the aryl alkyl ketone and pyrrole. This
methodology is by no means general, but it does provide
modest to good yields of calix[4]pyrroles mainly possessing
hydroxyl groups at their upper rims and terminal chloro or ester
functions on their meso-alkyl substituents.
1
We found through TLC and H NMR analyses of the crude
reaction mixtures that the addition of 5 or 6 to the HCl-mediated
reactions improved the formation of the macrocycles 3a and 4a,b
to a significant extent. Remarkably, the additives also favored the
formation of the tetra-α isomers as the macrocyclic products
(in some cases, only traces of other isomers, mainly α,α,β,β,
1
were detected by H NMR analyses of the reaction crude
mixtures). As mentioned above, macrocyclization reactions
promoted by the exclusive use of HCl usually provide a
difficult-to-separate mixture of calix[4]pyrrole configurational
isomers. The significant increase in stereoselectivity induced by
the added salts also had a beneficial impact on the purification
of the crude reaction mixtures. Calix[4]pyrroles 3a and 4a,b
were isolated as pure tetra-α isomers in yields ranging from 18
to 62% (Table 1, entries 2, 8, and 10) by column chromatography
In our hands, the standard acid-mediated conditions (3 equiv
of HCl (4 M dioxane) in dichloromethane solution) were not
successful in the macrocyclization reactions of 4-chloro-1-(4′-
hydroxyphenyl)-1-butanone 1a, ethyl 5-(3′-hydroxyphenyl)-5-
oxopentanoate 2a, or ethyl 5-(3′,5′-dihydroxyphenyl)-5-oxo-
pentanoate 2b with pyrrole (Scheme 1). We detected only the
formation of polymeric products in the crude reaction mixtures.
Table 1. Condensation of Aryl Alkyl Ketones 1 and 2 with
a
Pyrrole Mediated by HCl (4 M Dioxane Solution)
b
Scheme 1. Synthesis of Aryl-Extended Calix[4]pyrroles 3a−c
entry
ketone
additive (3 equiv)
product
yield (%)
a
and 4a−d, Functionalized at the Upper and Lower Rims
1
1a
1a
1b
1b
1c
1c
2a
2a
2b
2b
2c
2c
2d
2d
none
5 or 6
none
5 or 6
none
6
3a
3a
3b
3b
3c
3c
4a
4a
4b
4b
4c
4c
4d
4d
0
2
28−31
3
0
4
18−19
5
0
c
6
5
7
none
5 or 6
none
6
0
8
20−23
9
0
10
11
12
13
14
62
c
none
5 or 6
none
6
0
0
c
0
0
a
b
c
Reaction conditions: 1 or 2, pyrrole (1 equiv), CH2Cl2, argon, 18 h.
Isolated yield of the tetra-α isomer after column chromatography.
α,α,α,β and α,α,β,β isomers were mainly formed (see the Supporting
Information).
purification. The isolated products were characterized by a
complete set of high resolution spectra, and their configuration
assignments were verified by single-crystal X-ray diffraction
(Figure 2).27
a
Structures of the methyltrialkylammonium salts 5 and 6 used as
additives are shown.
During investigation of the substrate scope of the new
method, we found that it lacks generality. For ketones in
terminal alkyl ester series, the presence of certain electron-
withdrawing groups on the para-position of the phenyl ring
(2c and 2d) had a dramatic influence on the attempted tem-
plate macrocyclization: we could not detect the presence of
calix[4]pyrroles in the corresponding reaction mixtures (entries
12 and 14). However, mixtures of calix[4]pyrrole isomers, not
The template effect exerted by cations and anions in
cyclization reactions is well established.23,24 Moreover, calix[4]-
pyrroles are heteroditopic receptors for alkylammonium salts in
nonpolar solvents25,26 and show high affinities for methyl-
ammonium chlorides. Accordingly, we decided to explore the
use of methyltrialkylammonium chloride salts as templates in
B
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Letter
condensation reaction of the aryl alkyl ketone and pyrrole in
CH2Cl2. Although the reported procedure is not wide in scope,
it solves two synthetic problems in the preparation of certain
calix[4]pyrroles: (a) it promotes the macrocyclization reaction,
which is suppressed in the absence of the ammonium salt, and
(b) produces a calix[4]pyrrole mixture highly enriched in the
tetra-α isomer. This latter feature simplifies the isolation of the
compounds in moderate to good synthetic yields. The func-
tional groups incorporated at the lower and upper rims of the
calix[4]pyrroles can be further chemically transformed and pave
the way for new applications and properties of this family of
compounds.
ASSOCIATED CONTENT
* Supporting Information
■
S
Figure 2. X-ray structures of meso-aryl-meso-alkylcalix[4]pyrroles: (a)
3a, (b) 3b, (c) 3c, and (d) 4a. Structures 3a−c are shown in ORTEP
view with thermal ellipsoids set at 50% probability. The structure of 4a
is a preliminary solution of the diffracted data and is shown in ball and
stick representation. Nonpolar hydrogen atoms have been omitted for
clarity. Polar hydrogens (NHs and OHs) are shown as fixed-size
spheres of 0.15 Å radius. Solvent molecules (acetone, acetonitrile, and
dichloromethane) are shown as CPK models.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b03505.
Detailed synthetic procedures and characterization data
for the new compounds 2a−d, 3a−c, and 4a,b and their
1H and 13C NMR spectra (PDF)
X-ray crystallographic data for 3a (CIF)
X-ray crystallographic data for 3b (CIF)
X-ray crystallographic data for 3c (CIF)
including the tetra-α isomer, were produced under identical
reaction conditions in the absence of the ammonium chloride
additive for 2c and 2d (entries 11 and 13).
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: pballester@iciq.es.
ORCID
In contrast, for the cyclocondensation reaction with ketones
having a terminal chloro substituent, the absence of the
p-hydroxy group (1b) produced good results and the isolated
yield of 3b was 19% (entry 4). The cyclocondensation also
proceeded in the presence of the additive when the hydroxyl
group was replaced by a bromine atom (1c). However, in this
case, we obtained a mixture of configurational calix[4]pyrrole
isomers, in which the tetra-α isomer was a minor component.
In the course of these studies, we also learned that the aryl
alkyl ketone must have at least three methylene units between
the carbonyl group and the terminal functional group. All of
our cyclization attempts employing aryl alkyl ketones with
functionalized alkyl chains shorter than three methylene units
were unsuccessful. Again, we attribute this lack of reactivity to
strong steric clashes occurring between the β-substituent and
the β-pyrrole protons in the transition state of their conden-
sation reactions. Owing to one methylene reduction in alkyl
chain length, the steric effect of the α-methylene substituent
becomes predominant.
Pablo Ballester: 0000-0001-8377-6610
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank Gobierno de Espana MINECO (CTQ2014-56295-
■
̃
R) and Severo Ochoa Excellence Accreditation (2014-2018
SEV-2013-0319). A.D.-M. (FPDI-2013-15632) and L.E.
(FPU14/01016) acknowledge fellowships. FEDER funds
(Project CTQ2014-56295-R) and the CERCA Programme/
Generalitat de Catalunya are also acknowledged for funding.
́
We thank Eduardo C. Escudero-Adan, X-ray Diffraction Unit of
ICIQ , for help with the analysis of the X-ray crystallographic
data.
At this time, the specific role of the methyltrialkylammonium
chloride salts is not completely understood. We propose a
template effect that would probably involve both components
of the ion pair. The methyltrialkylammonium cation is a good
fit for the shallow aromatic cavity provided by the calix[4]-
pyrrole core in the cone conformation. The chloride anion is
known to form stronger hydrogen bonds with phenol OHs
than with pyrrole NHs.1,28 The combination of these properties
probably favors the cyclocondensation of linear oligomers and
the reaction’s steroselectivity. The suppression of the conden-
sation reaction by addition of the ammonium salt in the series of
ketones having alkyl-terminal esters and electron-withdrawing
groups in the phenyl groups is puzzling, and currently, we do not
have any sensible explanation.29
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