Calix[3]pyrrole: A Missing Link in Porphyrin-Related Chemistry

Calix[3]pyrrole: A Missing Link in Porphyrin-Related Chemistry

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Yuya Inaba, Yu Nomata, Yuki Ide, Jenny Pirillo, Yuh Hijikata, Tomoki Yoneda, Atsuhiro Osuka,

Jonathan L. Sessler,* and Yasuhide Inokuma *

Cite This: J. Am. Chem. Soc. 2021, 143, 12355 −12360

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ABSTRACT: A long-standing question in porphyrin chemistry is

why pyrrole monomers selectively form tetrapyrrolic macrocycles,

whereas the corresponding tripyrrolic macrocycles are never

observed. Calix[3]pyrrole, a tripyrrolic porphyrinogen-like macro-

cycle bearing three sp -carbon linkages, is a missing link molecule

that might hold the key to this enigma; however, it has remained

elusive. Here we report the synthesis and strain-induced trans-

formations of calix[3]pyrrole and its furan analogue, calix[3]furan.

These macrocycles are readily accessed from cyclic oligoketones.

Crystallographic and theoretical analyses reveal that these three-subunit systems possess the largest strain energy among known

calix[n]-type macrocycles. The ring-strain triggers transformation of calix[3]pyrrole into ﬁrst calix[6]pyrrole and then calix[4]pyrrole

under porphyrin cyclization conditions. The present results help explain the absence of naturally occurring three-pyrrole macrocycles

and the fact that they are not observed as products or intermediate during classic porphyrin syntheses.

INTRODUCTION

absence of naturally occurring three-pyrrole macrocycles and

the fact that they are not observed as products or intermediate

during classic porphyrin syntheses. Furthermore, the strain-

induced ring expansion observed for calix[3]pyrrole could

provide a access to new, entropically disfavored larger pyrrolic

macrocycles.

■

Porphyrins and related tetrapyrrole macrocycles, including

heme and chlorophyll, play critical roles in biological processes

as diverse as light-harvesting, oxygen transport, and electron

transfer. They and their synthetic analogues have also attracted

5,6

attention as catalysts, photosensitizers, and optoelectronic

Tetrapyrrolic macrocycles are typically synthesized by

linking four pyrrole monomers to furnish porphyrinogen

intermediates. Porphyrinogens are macrocyclic species that

possess the basic connectivity of the ﬁnal porphyrin ring

materials. Because a facile one-pot synthetic procedure

leading to symmetric porphyrins was reported by Rothemund

in 1935, macrocyclization of pyrrole monomers has been

exhaustively examined by using various condensation con-

product but which are linked by four sp -hybridized meso-

ditions. A long-standing question associated with both

carbon atoms. In the case of porphyrinogens bearing no more

than one substituent on each of the meso-carbons, the

porphyrinogens are thermodynamically unstable under oxidiz-

ing conditions and are readily converted to the corresponding

porphyrins. In contrast, porphyrinogen analogues bearing two

non-hydrogen atoms on the meso bridges are often stable, as in

the case of calix[4]pyrrole (5,10,15,20-octamethyl-

porphyrinogen). Isolation and study of calix[3]pyrrole, the

corresponding tripyrrolic macrocycle, might therefore hold the

key to understanding why tripyrrolic macrocycles are not

found in nature and are not observed under classic, template-

biological and laboratory porphyrin syntheses is why pyrrole

monomers selectively form tetrapyrrolic macrocycles, whereas

the corresponding tripyrrolic macrocycles are never observed.

While macrocycles with ﬁve or more pyrrole units can be

isolated in free form under conditions of kinetic control,

boron template is necessary to generate and stabilize their

11−13

tripyrrolic analogues.

It is thus not currently known

whether such systems are even capable of existence. Calix[3]-

pyrrole, a tripyrrolic porphyrinogen-like macrocycle bearing

three sp -carbon linkages, is a missing link molecule that might

hold the key to this enigma; however, it has remained elusive.

Here we report the synthesis and strain-induced trans-

formations of calix[3]pyrrole and its furan analogue, calix[3]-

furan. These macrocycles are readily accessed from cyclic

oligoketones. Crystallographic and theoretical analyses reveal

that these three-subunit systems possess the largest strain

energy among known calix[n]-type macrocycles. The ring-

strain triggers transformation of calix[3]pyrrole into ﬁrst

calix[6]pyrrole and then calix[4]pyrrole under porphyrin

cyclization conditions. The present results help explain the

free porphyrin-forming reaction conditions (Scheme 1).

14,15

However, in spite of considerable synthetic eﬀort,

only

Received: June 18, 2021

Published: July 28, 2021

2021 American Chemical Society

J. Am. Chem. Soc. 2021, 143, 12355−12360

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Article

2,23

Scheme 1. A Typical Synthesis of Tetrapyrrole Macrocycles

with precise chain lengths,

including the linear hexaketone

. Compound 3 thus became the starting point for our

synthesis of 1.

RESULTS AND DISCUSSION

■

Dehydrative condensation of 3 in the presence of p-

toluenesulfonic acid (p-TsOH) using a Dean−Stark trap

furnished the difuran compound 4, a linear intermediate in

which the terminal carbonyl groups remain free, in 77% yield.

Treatment of 4 with 3.5 equiv of lithium diisopropylamide

(

LDA) generated a dienolate species that underwent intra-

molecular cyclization upon oxidation with CuCl₂to give

macrocycle 5 in 42% yield. The two furan rings in 5 were

converted to the corresponding enedione units by oxidative

treatment with m-chloroperbenzoic acid (mCPBA). Subse-

quent reduction by using zinc powder gave the cyclic

hexaketone 6 in 28% yield over two steps. When the cyclic

ketone 6 was subject to Paal−Knorr reaction conditions in the

core-modiﬁed or ring-expanded analogues of calix[3]pyrrole

presence of an excess of ammonium acetate, meso-

hexamethylcalix[3]pyrrole 1 was obtained in 41% yield as a

colorless solid. Three signals at 6.71, 5.83, and 1.59 ppm

assignable to the NH, pyrrole β-H, and methyl protons,

respectively, were seen in the proton nuclear magnetic

6−19

are known.

Here, we report the synthesis of calix[3]-

pyrrole 1 and its furan analogue calix[3]furan 2 starting from a

common linear hexaketone intermediate. Both 1 and 2

undergo strain-induced transformations that provide an

experimental rationale for why these elusive macrocycles

have not previously been observed.

resonance ( H NMR) spectrum of calix[3]pyrrole 1 in

CDCl , a ﬁnding consistent with the presence of a time-

To access calix[3]pyrrole, we conceived of a synthetic route

involving Paal−Knorr pyrrole ring formation from a

hexaketone macrocyclic precursor (Scheme 2). A similar

averaged C molecular symmetry predominating in solution. A

high-resolution electrospray ionization time-of-ﬂight (ESI−

TOF) mass spectrometric analysis of 1 revealed a parent ion

−

peak at m/z = 320.2131, which was assigned to a [1−H]

Scheme 2. Synthesis of Calix[3]pyrrole and Calix[3]furan

molecular ion (calculated for C H N m/z 320.2132).

Calix[3]furan 2 was also synthesized from cyclic difuran 5 by

treating with an excess of chlorotrimethylsilane in methanol

under reﬂux for 20 min and isolated in 42% yield. The H

NMR spectrum of calix[3]furan 2 also proved consistent with a

C symmetric structure. Speciﬁcally, two singlet signals at 5.80

and 1.63 ppm, assigned to the furan β-H and methyl protons,

respectively, were seen. In the high-resolution ESI-TOF mass

spectrum, peaks corresponding to a sodium adduct [2 + Na]

were observed at m/z = 347.1615 (simulated value for

C H O Na = m/z 347.1618).

Diﬀraction grade crystals of calix[3]pyrrole 1 were obtained

by vapor diﬀusion of hexane into a dichloromethane solution

in the absence of any particular eﬀort at drying. The resulting

structure (Figure 1A) revealed that two of the three pyrrolic

nitrogen atoms are on the same side of the macrocycle and

hydrogen-bonded to a cocrystallized water molecule (Figure

S4 ). The distances between neighboring nitrogen atoms were

in the range of 2.8573(12)−2.9701(13) Å, reﬂecting a

relatively narrow central cavity. Notably, all three meso-carbon

atoms were located out of the mean plane of the pyrrole rings.

Distortion of the macrocycle was also observed in the crystal

structure of calix[3]furan 2 (Figure 1B), although in this case a

cone-shaped structure is seen in which all the furan rings point

in the same direction.

The solid state structural ﬁndings are consistent with the

presence of considerable strain within both calix[3]pyrrole 1

and calix[3]furan 2. To compare the ring strains of 1 and 2

with those of larger calix[n]-type macrocycles, the deformation

angles α and β (Figure 1C−E), used for evaluating the

displacement around aromatic units in cyclophane-type

macrocycle, were derived from the respective crystal

structures. The α angles of 1 and 2 were 2.52° and 1.95°,

respectively. These angles are larger than those of typical

approach proved eﬀective for the size-selective synthesis of

ring-expanded analogues, such as calix[5]pyrrole, with the

requisite cyclic oligoketone precursors being accessed from the

corresponding calix[n]furans (n ≥ 4). Unfortunately,

calix[3]furan, the logical precursor to our targeted cyclic

hexaketone intermediate, is not known. Recently we developed

a synthetic strategy allowing access to aliphatic oligoketones

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Figure 1. (A, B) ORTEP drawings of crystal structures of 1 and 2 at the 50% thermal probability level (top: top view; bottom: side view).

Hydrogen: white; carbon: gray; nitrogen: light blue; oxygen: red. Solvent molecules are omitted for clarity. (C) Deﬁnitions of deformation angles α

and β for calix[n]-type macrocycles. α is the averaged deviation angle between mean planes of X−C(3)−C(4) (shown as light blue) and X−C(2)−

C(3) (shown as light red). β is the averaged deviation angle between the mean plane X−C(2)−C(3) and a C(2)−C(meso) bond. (D) Deformation

angles α determined from crystal structures of calix[n]pyrroles and furans (n = 3−6). (E) Deformation angles β determined from these same crystal

structures. (F) Calculated energy per repeat unit of calix[n]furans and calix[n]pyrroles relative to those for n = 3 (compounds 1 and 2 of this study)

at the B3LYP/cc-pVTZ level of theory.

calix[n]pyrroles and furans (n = 4−6), for which values of

.32°−0.43° are seen, and thus taken as evidence of strain. The

β angles for 1 and 2 were found to be >2-fold greater than

those of the corresponding larger macrocycles; this is reﬂective

of a large displacement of the meso-carbon atoms from the

mean plane of the neighboring aromatic rings.

Theoretical calculations provided support for the large strain

energy inferred for macrocycles 1 and 2 (Figure 1F). The

relative energies of the monomeric subunits in each calix[n]-

type macrocycle were calculated at the B3LYP/cc-pVTZ level

by using a Grimme-type dispersion correction by optimization

of the geometries using the crystal structures as the initial

inputs. Compared with the corresponding calix[4]-type

macrocycles, calix[3]pyrrole 1 and calix[3]furan 2 were

found to be unstable by 22.1 and 14.4 kJ/mol per repeat

unit, respectively. Such a large energy diﬀerence helps

rationalize why calix[3]-type macrocycles are not observed

during the formation of tetrapyrrolic macrocycles under

equilibrium conditions.

signal intensity of 1 decreased by >75% within 5 s and

completely disappeared after 30 s concurrent with the

appearance of an intense peak ascribed to the pyrrole β-H of

calix[6]pyrrole 7 at 5.81 ppm along with several minor peaks

(

Figure 2B). ESI-TOF mass spectrometric analysis of the

reaction mixture at early times revealed a parent ion peak for

−

[

7-H] at m/z = 641.4340 (calculated for C H N m/z

42 53 6

641.4337). The intensity of the peak attributed to hexapyrrole

was then seen to decrease gradually over the course of ∼4 h

while new signals, corresponding to calix[4]pyrrole 8, were

seen to increase. Eventually, the H NMR signals converged to

those of 8 (80% NMR yield). The stability of 1 was also tested

under standard calix[4]pyrrole-forming conditions (i.e.,

catalytic HCl in ethanol). Again, ring expansion was seen

Figure S11 ). While the conversion of expanded porphyri-

(

nogens into tetrapyrrole macrocycles (ring contraction) is

entropically favorable and has been observed under acidic

equilibrium conditions, the formation of larger macrocycles

from a smaller analogue is entropically unfavorable. The initial

formation of hexapyrrole 7 from 1 is thus attributable to the

strain-induced macrocyclic ring cleavage of 1 and a subsequent

dimerization to give a less-strained species (i.e., 7). The

rapidity of this ring expansion reaction leads us to suggest that

even were initial cyclotrimerization to occur when pyrroles

The large ring strain of 1 was expected to lead to rapid ring

expansion under standard pyrrole macrocyclization condi-

6−28

tions.

To test this hypothesis, calix[3]pyrrole 1 was

dissolved in dichloromethane in the presence of triﬂuoroacetic

acid (TFA, 10 mmol/L) at room temperature, and the reaction

was monitored by H NMR spectroscopy (Figure 2). The

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pyrrole NH-anion hydrogen-bonded complexes. Typically, this

results in stabilization of speciﬁc conformations. When

tetrabutylammonium ﬂuoride (TBAF) was titrated into a 10.0

mM CD Cl solution of 1, the NH proton signal at 6.91 ppm

in the H NMR spectrum was seen to shift to lower ﬁeld in a

concentration-dependent manner. Job’s plot and curve ﬁttings

of the NMR titration results proved consistent with the

formation of a 1:1 complex between 1 and the ﬂuoride anion

−

with an association constant of 230 ± 20 M . This value is

much smaller than that seen for calix[4]pyrrole 8 (17170 ±

−

00 M ). The association constants corresponding to the

interaction of calix[3]pyrrole 1 with other halide anions were

−

≤

10 M . The ﬂuoride complex 1·F could be crystallized by

slow evaporation of a dichloromethane solution. The resulting

crystal structure revealed a cone-shaped conformation for 1 to

which a ﬂuoride ion was hydrogen bonded via all three NH

protons with N−F distances of 2.681(2), 2.683(2), and

2.736(2) Å (Figure 3B). The distance from the ﬂuoride ion to

the mean plane of meso-carbon atoms was 2.434 Å. The

−

deformation angles, α and β, for 1·F were calculated to be

2.45° and 11.3°, respectively; this was taken as evidence that

the ring strain of 1 around meso-carbon atoms was slightly

increased upon ﬂuoride anion complexation, an energetic

penalty that is presumably overcome through formation of

NH−F hydrogen bonds.

Complexation with the ﬂuoride ion was found to stabilize

macrocycle 1. As inferred from high-performance liquid

chromatography (HPLC) studies, >98% of 1 (tested as a 3.3

mM dichloromethane solution in the presence TFA (10 mM);

Figure S13) disappeared within 10 s to give calix[6]pyrrole 7

along with minor byproducts with higher retention times. In

contrast, >70% of 1 remained intact under otherwise identical

test conditions.

Boron complexation was also found to stabilize the

tripyrrolic macrocycle 1. Initial deprotonation of the NH

protons of 1 using n-butyllithium and subsequent treatment

with boron tribromide furnished the boron-calix[3]pyrrole 9 in

Figure 2. (A) Strain-induced ring-expansion reaction of calix[3]-

pyrrole 1 in the presence of TFA. (B) 400 MHz H NMR spectra

monitoring of the ring-expansion reaction of 1 in a 10 mM

dichloromethane solution of TFA at room temperature. All the

spectra were recorded in CDCl after quenching the reaction by

washing with aqueous sodium bicarbonate solution, drying over

anhydrous magnesium sulfate, and evaporation of the solvent.

5% yield (Figure 3C). This stepwise procedure proved

monomers are subject to acid catalyzed condensation, no

calix[3]pyrrole-type products would be observed.

Unlike calix[3]pyrrole 1, calix[3]furan 2 underwent a strain-

induced ring-opening of the furan component (Scheme 3).

necessary to maintain the integrity of 1 since simple treatment

with the Lewis acidic boron reagent was found to induce ring-

expansion leading to isolation of 8. A single-crystal X-ray

diﬀraction analysis of 9 revealed a shallow bowl-shaped

structure with a trigonal-planar boron(III) center (Figure

3D). Compared to the free-base form 1, the deformation

angles, α and β, of complex 9 were decreased to 2.27° and

Scheme 3. Strain-Induced Reaction of Calix[3]furan

.42°, respectively. The large decrease seen for the

deformation angle β is consistent with macrocyclic ring strain

being released upon boron complexation. In fact, boron

complex 9 proved stable under the test acidic pyrrole

macrocyclization conditions noted above. Speciﬁcally, neither

ring expansion nor loss of the complexed boron atom was

observed.

Under the macrocyclization conditions optimized for calix[4]-

On the other hand, attempts to prepare 9 under template

conditions in the presence of tri(pyrrol-1-yl)borane proved

furan formation (i.e., ethanol, 12 M HCl (v/v, 2:1)), one of

the furan subunits of calix[3]furan 2 was seen to undergo

hydrolysis to give diketone 5 in near-quantitative yield (Figure

S12 ). Such a hydrolysis reaction was not observed for

calix[4]furan under the same conditions. This disparity is

again ascribed to diﬀerences in ring strain for calix[3]pyrrole vs

calix[4]furan.

unsuccessful. In the case of boron−subporphyrins heating to

140−180 °C is necessary to complete the macrocyclization

12,33

around the boron template.

Moreover, subporphyrins are

stabilized via 14 π-electron aromatization; however, the

nonaromatic species 9 cannot beneﬁt from such stabilization.

Thus, perhaps not surprisingly, only decomposition products

were observed when the forcing conditions used to access

subporphyrins were attempted in an eﬀort to produce 9.

We next examined whether calix[3]pyrrole 1 could be

stabilized by chemical means (Figure 3). Calix[n]pyrroles (n ≥

) are known to bind Lewis basic anions via formation of

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Hokkaido 001-0021, Japan; orcid.org/0000-0001-6558-

Article

Figure 3. (A) Association constants corresponding to the interaction of calix[3]pyrrole 1 with tetrabutylammonium halides in CD Cl . (B) Crystal

−

structure of the ﬂuoride complex, 1·F (left: top view; right: side view). (C) Synthesis of boron−calix[3]pyrrole complex 9. As noted in the main

text, this species does not undergo a ring-expansion reaction under acidic conditions. (D) Crystal structure of 9 (left: top view; right: side view)

shown at the 50% thermal probability level. Hydrogen: white; boron: pink; carbon: gray; nitrogen: light blue; ﬂuorine: yellow.

CONCLUSION

United States; orcid.org/0000-0002-9576-1325;

Email: sessler@cm.utexas.edu

Yasuhide Inokuma − Division of Applied Chemistry, Faculty

of Engineering, Hokkaido University, Sapporo, Hokkaido

■

The present study helps explain the absence of observable

tripyrrolic macrocycles during classic porphyrin syntheses. At

the reduced porphyrinogen or calix[3]pyrrole-like oxidation

level, such species are highly strained and are likely to undergo

facile and rapid ring expansion as seen explicitly in the case of

calix[3]pyrrole 1. The present successful synthesis of calix[3]-

pyrrole and calix[3]furan from cyclic oligoketones was made

possible by incorporating a ﬁnal pyrrole- or furan-forming step

that allowed the strain energy to be overcome by formation of

an aromatic subunit (pyrrole or furan) under nonequilibrium

conditions. The present results lead us to propose that the

preparation and subsequent release of macrocyclic ring strain

in systems such as 1 and 2 constitute a relatively unexplored

approach to achieving C−C bond cleavage and heteroaromatic

ring dearomatization. In principle, such transformations could

provide access to new porphyrin analogues that might not be

accessible through more conventional syntheses.

60-8628, Japan; Institute for Chemical Reaction Design and

Discovery (WPI-ICReDD), Hokkaido University, Sapporo,

3356 ; Email: inokuma@eng.hokudai.ac.jp

Authors

Yuya Inaba − Division of Applied Chemistry, Faculty of

Engineering, Hokkaido University, Sapporo, Hokkaido 060-

8628, Japan

Yu Nomata − Division of Applied Chemistry, Faculty of

Engineering, Hokkaido University, Sapporo, Hokkaido 060-

8628, Japan

Yuki Ide − Institute for Chemical Reaction Design and

Discovery (WPI-ICReDD), Hokkaido University, Sapporo,

Hokkaido 001-0021, Japan

ASSOCIATED CONTENT

sı Supporting Information

The Supporting Information is available free of charge at

https://pubs.acs.org/doi/10.1021/jacs.1c06331.

Jenny Pirillo − Institute for Chemical Reaction Design and

Discovery (WPI-ICReDD), Hokkaido University, Sapporo,

Hokkaido 001-0021, Japan; orcid.org/0000-0002-8866-

■

4279

Yuh Hijikata − Institute for Chemical Reaction Design and

Discovery (WPI-ICReDD), Hokkaido University, Sapporo,

Hokkaido 001-0021, Japan; orcid.org/0000-0003-4883-

Materials and methods, synthetic procedures, exper-

imental details, computational details, crystallographic

data, and NMR spectra for all compounds (PDF)

5085

Accession Codes

Tomoki Yoneda − Division of Applied Chemistry, Faculty of

Engineering, Hokkaido University, Sapporo, Hokkaido 060-

8628, Japan; orcid.org/0000-0002-9804-0240

Atsuhiro Osuka − Department of Chemistry, Graduate School

of Science, Kyoto University, Kyoto 606-8502, Japan;

orcid.org/0000-0001-8697-8488

CCDC 2080602 −2080609 contain the supplementary crys-

tallographic data for this paper. These data can be obtained

free of charge via www.ccdc.cam.ac.uk/data_request/cif , or by

emailing data_request@ccdc.cam.ac.uk , or by contacting The

Cambridge Crystallographic Data Centre, 12 Union Road,

Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

Complete contact information is available at:

https://pubs.acs.org/10.1021/jacs.1c06331

AUTHOR INFORMATION

Corresponding Authors

Jonathan L. Sessler − Department of Chemistry, The

University of Texas at Austin, Austin, Texas 78712-1224,

■

Notes

The authors declare no competing ﬁnancial interest.

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Journal of the American Chemical Society

Williams, J. D. From large furan-based calixarenes to calixpyrroles and

Article

(

20) Cafeo, G.; Kohnke, F. H.; Parisi, M. F.; Nascone, R. P.; Torre,

ACKNOWLEDGMENTS

■

G. L. L.; Williams, D. J. The elusive β -unsubstituted calix[5]pyrrole

finally captured. Org. Lett. 2002, 4, 2695−2697.

This work was supported by JSPS Grant-in-Aid for Young

Scientists (A) Grant 17H04872, for Challenging Research

Exploratory) Grant 20K21214, and the Asahi Glass

Foundation to Y.I. This work was supported by JSPS Grant-

in-Aid for Early-Career Scientists Grant 21K14597 and

Scientiﬁc Research on Innovative Areas “Soft Crystals” to

Y.I. The work in Austin was funded by the Robert A. Welch

Foundation (F-0018 to J.L.S.).

(21) Cafeo, G.; Kohnke, H. F.; La Torre, L. G.; White, P. J. A.;

calix[n]furan[m]pyrroles: synthesis and structures. Angew. Chem., Int.

Ed. 2000, 39, 1496−1498.

(

(22) Uesaka, M.; Saito, Y.; Yoshioka, S.; Domoto, Y.; Fujita, M.;

Inokuma, Y. Oligoacetylacetones as shapable carbon chains and their

transformation to oligoimines for construction of metal-organic

architectures. Commun. Chem. 2018, 1, 23.

(23) Manabe, Y.; Uesaka, M.; Yoneda, T.; Inokuma, Y. Two-step

transformation of aliphatic polyketones into π -conjugated polyimines.

J. Org. Chem. 2019, 84, 9957−9964.

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