Synthesis of a new calix[n]pyrrole: Meso-pentaspirocyclohexyl calix[5]pyrrole

Article abstract of DOI:10.1016/j.tetlet.2010.11.007

We describe the first synthesis of the novel meso-pentaspirocyclohexyl calix[5]pyrrole 2b. Anion-guest properties of the new compound were evaluated with respect to fluoride, chloride, and bromide tetrabutylammonium salts by ¹H NMR titration techniques in deuterated dichloromethane at 22 °C by following the induced shifts in the NH resonances upon complexation.

Full text of DOI:10.1016/j.tetlet.2010.11.007

Tetrahedron Letters 52 (2011) 136–138
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of a new calix[n]pyrrole: meso-pentaspirocyclohexyl calix[5]pyrrole
⇑
Mercedes Bedolla-Medrano, Luis Chacón-García , Claudia A. Contreras-Celedón, Jesús Campos-García
Laboratorio de Diseño Molecular, Instituto de Investigaciones Químico Biológicas, Universidad Michoacana de San Nicolás de Hidalgo, Edificio B-1 Ciudad Universitaria,
Morelia, Michoacán C.P. 58030, Mexico
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 7 July 2010
Revised 31 October 2010
Accepted 1 November 2010
Available online 5 November 2010
We describe the first synthesis of the novel meso-pentaspirocyclohexyl calix[5]pyrrole 2b. Anion–guest
properties of the new compound were evaluated with respect to fluoride, chloride, and bromide tetrabu-
tylammonium salts by 1H NMR titration techniques in deuterated dichloromethane at 22 °C by following
the induced shifts in the NH resonances upon complexation.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Supramolecular chemistry
Calixpyrrols
Bismuth nitrate
Anion binding
Calix[n]pyrroles are oligopyrrolic macrocycles produced by the
condensation of a pyrrole and a ketone (n represents the number
of pyrrole units in the molecule).1,2 The reaction is traditionally
catalyzed by a variety of protic acids, although in recent years
Lewis acids have been successfully introduced in the synthesis of
these compounds.3,4 These macrocycles are of interest for their
ability to recognize anions, cations, and neutral species. To date,
they continue to provide fertile grounds for research in the area
of supramolecular chemistry.1 Typical and widely studied exam-
ples are compounds 1a and 1b.
reported examples of the ‘free’ macrocycle (the b-difluoro substi-
tuted cycle and 2a, the b-unsubstituted meso-decamethyl deriva-
tive).5,6 As a consequence, the study of their anion binding
potentials has been limited. The difficulty in obtaining calix[5]pyr-
roles may be due to the ease with which a pyrrole-isopropyl frag-
ment can be lost to give the more stable four-membered analog
calix[4]pyrrole. The problem of macrocycle contraction has been
previously reported to be partially solved by the condensation of
the less reactive 3,4-difluoropyrrole with acetone to give the b-flu-
orosubstituted meso-decamethylcalix[5]pyrrole.5 Compound 1a
N
H
N
N
H
NH
HN
H
HN
HN
NH
NH
HN
NH
HN
NH
NH HN
H
N
NH HN
1a
2a
2b
1b
was captured after a three-step synthesis via conversion of the
corresponding b-unsubstituted meso-decamethylcalix[5]furane
into the corresponding calix[5]pyrrole 2a by an opening process
of the five-membered heterocycle. This process involved the selec-
tive reduction of the double bond and a Paal–Knorr condensation
with ammonium acetate in 1% yield.6
The synthesis and anion recognition properties of calix[4]pyr-
roles have been widely studied. However, the synthesis of the
expanded calix[5]pyrroles is relatively new, with only two
⇑
Corresponding author. Tel.: +52 443 326 5790; fax: +52 443 326 5788.
E-mail address: lchacon@umich.mx (L. Chacón-García).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.11.007

M. Bedolla-Medrano et al. / Tetrahedron Letters 52 (2011) 136–138
137
Table 1
Pyrrole conversion (%) and relative proportions of 1, 2, and 3, as detected in the 1H NMR of the crude reaction
R
R1
R
R1
R1
R
N
H
N
H
+
O
R
R1
NH HN
NH HN
R1
R
+
HN
R
NH
Bi(NO3)3
+
R
R1
NH
HN
R1
R
HN
R1
NH
R1
R1
R
R
R1
R
1
2
3
a; R,R1 = -CH3
a; R,R1 = -CH3
a; R,R1 = -CH3
b; R,R1 = -(CH2)5-
c; R,R1 = -(CH2)4-
d; R = R1 = -CH2CH3
b; R,R1 = -(CH2)5-
c; R,R1 = -(CH2)4-
d; R = R1 = -CH2CH3
b; R,R1 = -(CH2)5-
c; R,R1 = -(CH2)4-
d; R = R1 = -CH2CH3
Entry
R, R1
Bi(NO3)3 (mol %)
Time (h)
1
2
3
Others
Pyrrole conversion (%)
1
2
3
4
5
6
7
8
–(CH2)5–
–(CH2)5–
–(CH2)5–
–(CH2)5–
–(CH2)4–
–(CH2)4–
–CH2–CH3
–CH2–CH3
25
2
2
2
2
2
24
2
4
>99
53
30
27
39
—
—
—
—
—
—
8
99
—
19
<1
<1
—
13
27
<1
—
100
100
100
87
61
9
1.2
0.6
0.3
0.6
0.6
0.6
0.6
46
70
60
—
—
—
—
31
0
95
—
45
We reported the synthesis of calix[4]pyrroles by the direct con-
densation of open or cyclic ketones with pyrrole catalyzed by bis-
muth nitrate, with yields that ranged from moderate to good. This
work used a Lewis acid instead of a protic acid.3 Extension of the
study to other Lewis acids, such as Al, Mg, Cu, Zn, or other bismuth
salts, such as iodide, chloride, phosphate, or triflate, demonstrated
that low catalyst concentrations of the bismuth salts produced the
calix[5]pyrrole, as detected by NMR, in the crude reaction mixture.
Compound 2a proved to be relatively stable and was isolated by
HPLC with 20% yield.7
The synthesis of 2a permitted to carry out initial investigations
of the host–guest chemistry of the unsubstituted calix[5]pyrrole.
Additionally, Kohnke and co-workers compared this compound
with its analogs, calix[4] and calix[6]pyrroles,8 in terms of their
affinities toward chloride and fluoride by titrations followed by
1H NMR in CD2Cl2 at 22 °C. Contrary to the expectations, 2a exhib-
ited a poor affinity for chloride (Ka = 35 MÀ1) when competing with
1a (Ka = 350 MÀ1). Unfortunately, the association constant Ka of 2a
for fluoride in dry CD2Cl2 could not be accurately determined,
although a saturated solution of D2O showed less affinity for the
anion than 1a under the same conditions.6
Research in the field of expanded calix[n]pyrroles (n > 4), partic-
ularly with respect to their practical applications (i.e., effective and
selective anion and neutral binding agents), is severely limited be-
cause the direct synthesis of these larger macrocycles from pyrrole
and ketones is hampered by the predominant formation of cyclic
tetramers. Hence, a synthetic method for the preparation of b-
unsubstituted calix[5]pyrrole (one of the most elusive members
of this family of compounds) is of considerable interest in the area
of supramolecular chemistry. In this context, we extended the
study of the condensation of acetone with pyrrole catalyzed by
Bi(NO3)3, which yielded 2a,7 with the aim of obtaining b-unsubsti-
tuted calix[5]pyrroles derived from ketones other than acetone,
and of studying the anion–guest properties of this molecule. In this
Letter, we describe the first synthesis of the novel meso-penta-
spirocyclohexyl calix[5]pyrrole 2b and its anion–guest affinity to-
ward fluoride, chloride, and bromide anions in CD2Cl2.
ture gave, after 2 h, the best conditions for obtaining 2b with
100% conversion of pyrrole and a ratio of 1b:2b of 30:70, as de-
tected by 1H NMR. It is noteworthy that the proton signals belong-
ing to 1b and 2b were clearly distinguished by 1H NMR by the beta
protons of the pyrrole, at 5.89 and at 5.79 ppm, respectively. When
the catalyst concentration was increased, the 1b:2b ratio de-
creased to yield only 1b for 25 mol % catalyst used. However, if less
than 0.3 mol % catalyst were used, the pyrrole was not converted
and a poor yield of the calixpyrroles was observed. Compound 2b
showed decomposition after column chromatography (SiO2), and
only calix[4]pyrrole was recovered. Purification was possible by
washing the solid with ethyl ether, followed by acetone and dis-
solved in dichloromethane. It should be noted that ethyl ether
was strongly trapped by the macrocycle, and it was not possible
to remove it under high vacuum; therefore, the dissolution of
dichloromethane was absolutely necessary. After purification,
compound 2b was obtained with 28% yield. This new compound
was characterized by 1H and 13C NMR spectroscopy and by low res-
olution and high resolution mass spectrometry (LRMS and HRMS,
respectively).9
The condensation of the pyrrole and cyclopentanone resulted in
the formation of 1c, 3c, and other products after 2 and 24 h of reac-
tion. The possibility that calix[5]pyrrole was present was not ruled
out, but it was not isolated because purification attempts yielded
only 1c and 3c. Reaction with 3-pentanone (Table 1, entries 7
and 8) gave only 1d and 3d with low pyrrole conversion after 4 h
reaction time, which produced the ‘best’ conditions. The results,
summarized in Table 1, correlated with the yields obtained under
the conditions used to obtain compounds 1a–d (Bi(NO3)3,
25 mol %), in which the relative yields were 1b > 1a > 1c ꢀ 1d after
0.5, 5, 5, and 120 h, respectively.3 These yields indicated that steric
restrictions governed the yields of both macrocycles.
In an attempt to explore alternative green synthetic methods,
the reaction was attempted under microwave radiation. The best
conditions for the reaction of pyrrole with cyclohexanone were
identified as 120 W irradiation at 40 °C to give 1b and 2b after
10 min reaction, although several impurities were obtained which
were difficult to eliminate. The reaction with acetone gave mainly
1a and 3a, and the reaction with 2-pentanone gave only 3d.
The condensation of pyrrole with an excess of cyclohexanone in
the presence of 0.6 mol % Bi(NO3)3 as a catalyst at room tempera-

138
M. Bedolla-Medrano et al. / Tetrahedron Letters 52 (2011) 136–138
Cl, and Br, it may be interesting to probe other anions, such as
the organic salts, which could interact with the extended cavity
and improve the anion affinity through chemical modification of
the macrocycle.
Acknowledgment
We thank CIC-UMSNH for financial support.
Supplementary data
Supplementary data (1H and 13C NMR spectroscopy, HPLC and
LR-MS of compound 2b and titration curves) associated with this
article can be found, in the online version, at doi:10.1016/
j.tetlet.2010.11.007.
References and notes
Figure 1. 1H NMR titration plot of calix[5]pyrrole NH resonance upon addition of
tetrabutylammonium fluoride, chloride, or bromide in dichloromethane-d2 at
298 K.
1. Gale, P. A.; Sessler, J. L.; Kral, V. Chem. Commun. 1998, 1–8.
2. Gale, P. A.; Anzenbacher, P.; Sessler, J. L. Coord. Chem. Rev. 2001, 222, 57–110.
3. Mejía-Farfán, I.; Contreras-Celedón, C.; Avina-Verduzco, J.; Chacón-García, L.
Lett. Org. Chem. 2008, 5, 237–239.
4. Kumar, A.; Ahmad, I.; Rao, M. S. Can. J. Chem. 2008, 86, 899–902.
5. Sessler, J. L.; Anzenbacher, P., Jr.; Shriver, J. A.; Jursikova, K.; Lynch, V. M.;
Marquez, M. J. Am. Chem. Soc. 2000, 122, 12061–12062.
6. Cafeo, G.; Kohnke, F. H.; Parisi, M. F.; Nascone, R. P.; La Torre, G. L.; Williams, D.
J. Org. Lett. 2002, 4, 2695–2697.
7. Chacón-García, L.; Chávez, L.; Cacho, D. R.; Altamirano-Hernández, J. Beilstein J.
Org. Chem. 2009, 5, 2.
8. Cafeo, G.; Kohnke, F. H.; La Torre, G. L.; White, A. J. P.; Williams, D. J. Angew.
Chem., Int. Ed. 2000, 39, 1496–1498.
Table 2
Comparison of anion stability constants (MÀ1) for 1a, 1b, 2a, and 2b determined in
deuterated dichloromethane anhydrous at 298 K12,13
Anion
1a
1b
2a
2b
FÀ
17,170
350
3600
117
N.D.
140014
35
N.D.
1130
225
61
ClÀ
BrÀ
10
9. 1.29 Â 10À2 mol of distilled pyrrole were mixed with 1.93 Â 10À1 mol of
cyclohexanone, and later 8.29 Â 10À2 mol of pulverized bismuth nitrate were
added. The mixture was stirred at room temperature during two hours and
then neutralized with distilled water. The organic layer was washed with
distilled water (4 Â 15 ml) and dried with anhydrous sodium sulfate, filtered,
and dried with vacuum. The solid was washed with cold ethylic ether
(10 Â 6 ml) obtaining a light brown precipitate, which was filtered and left to
dry. The resulting material was washed out with 25 ml of acetone; when dried,
it was dissolved in 10 ml of dichloromethane, which was evaporated with
vacuum at room temperature. The final yield of pentaspirocyclohexyl
Anion–guest properties of 2b were evaluated with respect to
fluoride, chloride, and bromide tetrabutylammonium salts by 1H
NMR titration techniques in deuterated dichloromethane at
298 K by following the induced shifts in the NH resonances upon
complexation.10 Upon addition of the anions, a maximum NH pro-
ton shift was observed at 10.1 ppm for the fluoride, 9.9 ppm for the
chloride, and 8.5 ppm for the bromide. Titration plots are shown in
Figure 1.
Association constants (Kas) were obtained by assuming a 1:1
anion binding model using the WinEQNMR least-squares fitting
program.11 Table 2 shows the binding constants for the novel
calix[5]pyrrole. Also included in Table 2 are the previously re-
ported fluoride, chloride, and bromide anion affinities for the anal-
ogous calix[4] and calix[5]pyrroles 1a, 1b, and 2a.
calix[5]pyrrole 2b was 28% of
a light brown solid that in TLC can be
identified with a Rf = 0.37 using a system hexane/ethyl acetate (95:5). 1H
NMR (400 MHz, CDCl3): d 7.18 (br s, 5H, NH), 5.80 (d, 10H, J = 3.2 Hz, CH), 1.86
(br s, 20H, CH2), 1.43 (br s, 30H, CH2), 13C NMR (100 MHz, CDCl3): d 136.4 (b-C
pyrrole), 104.3 (a-C pyrrole), 40.4 (C(C6H10)), 37.6 (CH2), 26.1 (CH2), 23.1 (CH2).
LR-MS (EI): m/z (rel int.): 736 ([M+1]+, 3), 589 (45), 588 (62), 220 (100). HR-MS
(EI): obsd 735.5251 (calcd for C50H65N5, 735.5240).
10. Solutions 0.01 M of 2b in CD2Cl2 anhydrous were prepared and mixed with
various equivalents of tetrabutylammonium salts (FÀ, ClÀ, BrÀ). The respective
chemical shifts were determined by 1H NMR (400 MHz). The data obtained
were corrected by the least-squares non linear fitting method and introduced
to WinEQNMR to calculate the affinity constants reported. (For further details
see Supplementary data).
The results presented in Table 2 reveal that 2b behaved simi-
larly to 2a in the sense that both compounds showed lower affinity
toward anions than the corresponding calix[4]pyrrole compounds.
However, the relative preference for the fluoride anion was
maintained.
11. Hynes, M. J. Chem. Soc., Dalton Trans. 1993, 311–312. We thank Professor M. J.
Hynes for providing us with the updated version of EQNMR for Windows..
´
12. Gale, P. A.; Sessler, J. L.; Kral, V.; Lynch, V. J. Am. Chem. Soc. 1996, 118, 5140–
5141.
13. Kas for 1b were measured in CD2Cl2 saturated with water as described in Ref. 6.
14. Measured in dichloromethane-d2 saturated with D2O 0.18% v/v.
Our work demonstrated that 2b could be synthesized by direct
condensation. Although the affinity constants were low toward F,