The elusive β-unsubstituted calix[5]pyrrole finally captured

Article abstract of DOI:10.1021/ol0262082

Themeso-decamethyl-calix[5]pyrrole2bwassynthesizedfromthefuran- basedanalogue1bviathehomologationofthefuranringstopyrrole,anditssolid- statestructurewasdeterminedbyX-raycrystallography:surprisingly, thebindingconstantof2btowardchlorideisfoundtobelowerthan

Full text of DOI:10.1021/ol0262082

ORGANIC
LETTERS
2002
Vol. 4, No. 16
2695-2697
The Elusive â-Unsubstituted
Calix[5]pyrrole Finally Captured
Grazia Cafeo,† Franz H. Kohnke,* Melchiorre F. Parisi,†
,†
,‡
Rosetta Pistone Nascone,† Giovanna L. La Torre,† and David J. Williams*
Dipartimento di Chimica Organica e Biologica, UniVersita` di Messina,
Salita Sperone 31, I-98166 Messina, Italy, and Department of Chemistry,
Imperial College of Science, Technology and Medicine, South Kensington,
London SW7 2AY, UK
FranzHeinrich.Kohnke@unime.it
Received May 18, 2002
ABSTRACT
The meso-decamethyl-calix[5]pyrrole 2b was synthesized from the furan-based analogue 1b via the homologation of the furan rings to pyrrole,
and its solid-state structure was determined by X-ray crystallography: surprisingly, the binding constant of 2b toward chloride is found to be
lower than that of the tetrameric analogue 2a.
After the initial discovery by Sessler1 and his collaborators
that octamethylcalix[4]pyrrole 2a is able to complex a range
of anions, including fluoride, chloride, and carboxylates as
well as various neutral molecules, the chemistry of this class
of compounds has become a topic of considerable and
growing interest.2 The smaller member 2a of this family of
macrocycles is readily obtainable in good yields by the acid-
promoted condensation of pyrrole and acetone.3
The larger cyclooligomers, however, cannot be isolated as
easily by this procedure: they are only present as very minor
components in the reaction mixture. This failure has been
ascribed to the fact that larger calixpyrroles undergo a
“mitosis” reaction4 even under very mild acidic conditions
to generate the tetramer 2a. Recently, we reported the
synthesis of calix[6]pyrrole 2c by the homologation of the
furan units of the analogue 1c to pyrrole.5 This synthesis
made possible the first investigations on the host-guest
chemistry of large calix[n]pyrroles with n > 4.6 More
* Address correspondence to F.H.K.
† Universita` di Messina.
‡ Imperial College of Science, Technology and Medicine.
(1) Gale, P. A.; Sessler, J. L.; Kra´l, V.; Lynch, V. M. J. Am. Chem. Soc.
1996, 118, 5140. Gale, P. A.; Sessler, J. L.; Kra´l, V. Chem. Commun. 1998,
1.
(4) (a) Sessler, J. L.; Anzenbacher, P., Jr.; Shriver, J. A.; Jurs´ıkova´, K.;
Lynch, V. M.; Marquez, M. J. Am. Chem. Soc. 2000, 122, 12061. (b) For
a related example of molecular mitosis in the chemistry of calixarenes,
see: Gutsche, C. D. In Calixarenes, Monographs in Supramolecular
Chemistry; Stoddart, J. F., Ed.; The Royal Chemical Society: Cambridge,
UK, 1989; pp 50-58.
(2) Turner, B.; Botoshansky, M.; Eichen, Y. Angew. Chem., Int. Ed. 1998,
37, 2475. For examples of related heterocalixarenes, see also: Jang, Y. S.;
Kim, H. J.; Lee, P. H.; Lee, C. H. Tetrahedron Lett. 2000, 41, 2919.
Arumugam, N.; Jang, Y. S.; Lee, C. H. Org. Lett. 2000, 2, 3115.
(3) Baeyer, A. Ber. 1886, 19, 2184. Rothemund, P.; Gage, C. L. J. Am.
Chem. Soc. 1954, 77, 3340.
(5) Cafeo, G.; Kohnke, F. H.; La Torre, G. L.; White, A. J. P.; Williams,
D. J. Angew. Chem., Int. Ed. 2000, 39, 1496.
10.1021/ol0262082 CCC: $22.00 © 2002 American Chemical Society
Published on Web 07/16/2002

recently, Sessler and co-workers found4a that when the
pyrrole units bear fluorine substituents at their â-positions,
the mitosis reaction is a slow process. By exploiting this
observation, they were able to isolate the â-fluorosubstituted
calix[5]pyrrole 3 and a larger homologue containing eight
pyrrole units. However, this approach still leaves the problem
of obtaining the non-â-substituted parent compounds. Calix-
[5]pyrrole 2b is an appealing synthetic target as it would
allow its anion receptor properties to be investigated and
correlated with those of its smaller and larger analogues. To
date, the only known example of a â-unsubstituted calix[5]-
pyrrole structure is one where this macrocycle is covalently
bound to a calix[5]arene.7
quantities of a more chromatographically mobile component
identified as the calix[4]pyrrole 2a. This initially encouraging
observation was, however, later severely frustrated because
the larger part of the reaction mixture was found to consist
of tarlike products, which are barely chromatographically
mobile. Column chromatography (SiO2, toluene) afforded
2b in low but sufficient yield (ca. 1%) for a screening of its
host-guest properties toward fluoride and chloride. Contrary
to our expectations, we found that 2b is sufficiently stable
to allow repeated chromatographic purifications on SiO2 and
also to be recrystallized from boiling ethanol. No appreciable
decomposition occurs in the presence of AcONH4 in ethanol;
thus, the low yield of the Paal-Knorr synthesis, which here
is dramatically lower than that observed (42%) for calix[6]-
pyrrole 2c, cannot be ascribed to a decomposition process
following the initial formation of 2b. However, the presence
of trace amounts of 2a in the crude mixture confirms that
the mitosis reaction is occurring to a small extent. We believe
that steric and conformational restrictions due to the smaller
ring size of the “decaketone” precursor 5 of 2b, with respect
to the “dodecaketone” precursor of 2c, may play a crucial
role.
We undertook the synthesis of decamethylcalix[5]pyrrole
2b from the known8 calix[5]furan 1b following the same
method previously exploited5 to obtain the calix[6]pyrrole
2c (Scheme 1).9 The oxidation of 1b with MPCA in CHCl3
Scheme 1a
Single crystals of 2b suitable for X-ray analysis were
obtained from EtOH. The X-ray crystal structure10 of 2b
(Figure 1) revealed the molecule to adopt a conformation
a Reagents and conditions: (i) MCPA, CHCl3; (ii) Zn, AcOH;
(iii) AcNH4, EtOH.
gave the ene-ketone 4, which was reduced with Zn/AcOH
to give the decaketone 5. Treatment of 5 with AcONH4 in
refluxing ethanol led to a rapid reaction. The crude mixture,
when analyzed by TLC (SiO2, 7:3 hexanes/ethyl acetate),
appeared to contain mainly one component, which was later
characterized as the calix[5]pyrrole 2b, together with trace
Figure 1. Solid-state structure of 2b showing the alternating up/
down/up/down/coplanar orientation of the pyrrole NH groups with
respect to the macrocycle plane.
very similar to that of the fluorinated analogue 3,4a having
the pyrrole NH groups oriented in an alternating up/down/
up/down/coplanar pattern with respect to the macrocycle
plane. In 2b, the five pyrrole nitrogen atoms are coplanar to
within 0.39 Å (cf. 0.32 Å in 3) and the quaternary
isopropylidene carbon atoms define a five-membered ring
having an envelope conformation with C(25) lying ca. 3 Å
(6) Cafeo, G.; Kohnke, F. H.; La Torre, G. L.; White, A. J. P.; Williams,
D. J. Chem. Commun. 2000, 1207.
(7) Gale, P. A.; Genge, J. W.; Kra´l, V. M.; McKervey, M. A.; Sessler,
J. L.; Walker, A. Tetrahedron Lett. 1997, 38, 8443.
(8) Kobuke, Y.; Hanji, K.; Origuchi, K.; Asada, M.; Nakayama, Y.;
Furukawa, J. J. Am. Chem. Soc. 1976, 98, 7414.
(9) 4: 56%, mp 158-160 °C from EtOH; 1H NMR (300 MHz, CDCl3)
δ 1.42 (s, 30H, CH3), 6.51 (s, 10H, CH); 13C NMR (75 MHz, CDCl3) δ
21.0 (CH3), 60.6 [C(CH3)2], 135.0 (CH), 201.3 (CO); EI-MS m/z 621 [M
+ 1]+. 5: 97%, mp 130-132 °C from CHCl3/EtOH; 1H NMR (300 MHz,
CDCl3) δ 1.38 (s, 30H, CH3), 2.69 (s, 10H, CH2); 13C NMR δ 21.5 (CH3),
32.4 (CH2), 61.9 [C(CH3)2], 208.3 (CO); EI-MS m/z 630 [M/+1]+. 2b:
ca. 1%, mp 202-204 °C from EtOH; 1H NMR (300 MHz, CD2Cl2) δ 1.51
(s, 30H, CH3), 5.77 (d, 10H, CH), 7.54 (bs, 5H, NH); 13C NMR δ 29.4
(CH3), 35.4 (CH2), 103.4(CH), 138.2 (â-C of pyrrole); EI-MS m/z 536 [M
+ 1]+.
(10) Crystal data for 2b: C35H45N5, M ) 535.8, monoclinic, P21/c (no.
14), a ) 14.193(1) Å, b ) 21.277(2) Å, c ) 10.601(1) Å, â ) 106.96(1)°,
V ) 3062.0(4) Å3, Z ) 4, Dc ) 1.162 g/cm3, µ(Cu KR) ) 5.28 cm-1
,
F(000) ) 1160, T ) 293 K; 4540 independent measured reflections, R1 )
0.044, wR2 ) 0.105 for 3643 independent observed reflections [|Fo| >
4σ(|Fo|), 2θ e 120°] and 382 parameters. CCDC 168706.
2696
Org. Lett., Vol. 4, No. 16, 2002

out of the plane of the remaining four (which are coplanar
to within ca. 0.3 Å). The differences in conformation between
2b and 3 are almost certainly a consequence of the extensive
intermolecular NH‚‚‚F hydrogen bonds that are present for
3 but not possible for 2b. Clearly in both compounds the
conformations must change considerably to allow the five
pyrrole NH units to be directed inward to permit hydrogen-
bonding interactions with an anionic guest.
For the complexation of fluoride and chloride, we expected
calix[5]pyrrole 2b to exhibit a binding constant having an
intermediate value between that observed for the calix[4]-
pyrrole 2a and that estimated11 for the calix[6]pyrrole 2c. In
fact, 2b has the potential to form one more hydrogen bond
than 2a, and one less than 2c. Moreover, an inspection of
molecular models indicates that the size match of fluoride
or chloride with the potential cavity of 2b is considerably
better than that with 2a.12
The binding ability of calix[5]pyrrole 2b toward fluoride
and chloride (as their n-Bu4N+ salts) was evaluated by the
1H NMR titration method in CD2Cl2 at 22 °C following the
induced shifts in the NH resonances upon complexation. The
experiments were conducted by adding a concentrated
solution of the salts (0.1 M) to a 0.01 M solution of the
macrocycle. Consistent and reproducible results (within an
average 20% error) were also obtained with more dilute
solutions (5 × 10-3 M). Data were analyzed using the
WinEQNMR fitting program.13 When the formation of weak
complexes prevented the reliable assignment of a 1:1
stoichiometry of binding from the intersection of the two
tangents of the titration curves,14 the stoichiometry was
established by Job’s plot experiments.15
When only trace amounts of water were present, the
association constant Ka of 2b toward fluoride could not be
determined accurately because the NH resonance, which
initially occurred at δ 7.54 “disappeared” upon the first
addition of salt, although it “reappeared” again at δ 12.20
when 1 equiv of salt had been added. Further additions of
salt did not cause any further chemical shift changes. This
latter observation is consistent with a 1:1 stoichiometry of
binding. The modest ∆δ (0.08 ppm) observed for the pyrrole
â-protons is too small for a reliable determination of the Ka
value. When this titration was conducted in CD2Cl2 saturated
with D2O (0.18% v/v), the NH pyrrole resonance remained
visible throughout the titration and the Ka value was found
to be 14 000 ( 821 M-1. Analogous measurements for the
binding of chloride gave a Ka value of 35 ( 3 M-1. This
was easily determined because the NH resonances again
remained clearly visible throughout the titration experiment.
The corresponding Ka in wet CD2Cl2 was less than 10 M-1.
Since the values of the association constants of 2a in wet
CD2Cl2 with fluoride and chloride were not available in the
literature, these were also determined and found to be 2700
( 201 and 46 ( 8 M-1, respectively. It is thus evident that,
regardless of the presence of water, calix[4]pyrrole 2a is a
better host for chloride than calix[5]pyrrole 2b. This finding
is in sharp contrast to the expectations based on the
considerations outlined above. To confirm this unexpected
result, a titration experiment was performed in which
equimolecular mixtures of 2a and 2b were titrated with
n-Bu4NCl in wet CD2Cl2. This confirmed that in wet CD2-
Cl2, the Ka for [2b‚Cl-] is ca. 5 times lower than that for
[2a‚Cl-]. Thus, while the Ka values follow the expected trend
as a function of the calix size in the case of fluoride, for
chloride, we are currently unable to propose an explanation
for the observed results.16
Since the binding constant of 3 toward chloride has
previously been determined4a in CD3CN containing 0.5% v/v
D2O and found to be 41 000 ( 6000 M-1, an analogous
measurement was conducted with 2b and the corresponding
Ka found to be 51 ( 11 M-1, a value that confirms that in
calixpyrroles the â-substitution with halogen atoms enhances
their anion affinity. Our work demonstrates that the some-
what elusive calix[5]pyrrole 2b can indeed be synthesized,
albeit in low yield, and that it is not as unstable as originally
envisaged. It has an unexpected behavior with respect to its
complexation selectivity toward the halide ions relative to
its larger and smaller analogues. This selectivity anomaly
will form the basis of future investigations.
Acknowledgment. We thank the MURST in Italy for
financial support.
(11) Binding constant of calix[6]pyrrole 2c toward chloride in CD2Cl2
is too high to be determined by the 1H NMR titration method. Partition
experiments with water give an estimated value of 104 M-1. This is likely
to be considerably lower than that achieved in “almost anhydrous” CD2Cl2
(vide infra).
Supporting Information Available: X-ray experimental
and crystallographic data for 2b and 1H NMR spectroscopic
titration data. This material is available free of charge via
the Internet at http://pubs.acs.org.
(12) Macomber, R. S. J. Educ. Chem. 1992, 69, 375.
(13) Hynes, M. J. J. Chem. Soc., Dalton Trans. 1993, 311. We thank
Professor M. J. Hynes for providing us with the updated version of EQNMR
for Windows.
OL0262082
(14) Poh, B.-L.; Tan, C. M. Tetrahedron 1994, 50, 3453.
(15) For a recent review on the determination of association constants
from NMR data, see: Fielding, L. Tetrahedron 2000, 56, 6151.
(16) Low-temperature binding studies failed to provide a clue; [2b‚Cl-]
1
remained kinetically fast on the H NMR time-scale even at -80 °C.
Org. Lett., Vol. 4, No. 16, 2002
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