Cambiarenes: Single-Step Synthesis and Selective Zwitterion Binding of a Clip-Shaped Macrocycle with a Redox-Active Core

Article abstract of DOI:10.1002/chem.201904852

A novel macrocyclic host molecule was synthesized that forms in a single step from commercially available starting materials. The core of the macrocycle backbone possesses two quinone rings and, thus, it is redox-active. Host–guest binding involving the clip-shaped cavity indicates selective binding of pyridine N-oxides based on the electron density of and steric bulk around the anionic oxygen.

Full text of DOI:10.1002/chem.201904852

A Journal of
Accepted Article
Title: Cambiarenes: Single-Step Synthesis and Selective Zwitterion
Binding of a Clip-Shaped Macrocycle with a Redox-Active Core
Authors: Riley J. Petersen, Brett J. Rozeboom, Shalisa M. Oburn,
Nolan J. Blythe, Tanner L. Rathje, Javier A. Luna, Steven
K. Kibby, Emily A. O'Brien, Kayleigh G. Rohr, Joshua R.
Carpenter, Taylor L. Sanders, Andrew M. Johnson, Kristin M.
Hutchins, Scott K. Shaw, Leonard R. MacGillivray, and Jay
Wm. Wackerly
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To be cited as: Chem. Eur. J. 10.1002/chem.201904852
Link to VoR: http://dx.doi.org/10.1002/chem.201904852
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Cambiarenes: Single-Step Synthesis and Selective Zwitterion
Binding of a Clip-Shaped Macrocycle with a Redox-Active Core
Riley J. Petersen,[a] Brett J. Rozeboom,[a] Shalisa M. Oburn,[b] Nolan J. Blythe,[a] Tanner L. Rathje,[a]
Javier A. Luna,[b] Steven K. Kibby,[a] Emily A. O'Brien,[a] Kayleigh G. Rohr,[a] Joshua R. Carpenter,[a]
Taylor L. Sanders,[a] Andrew M. Johnson,[a] Kristin M. Hutchins,[b] Scott K. Shaw,[b] Leonard R.
MacGillivray,[b] and Jay Wm. Wackerly*[a]
Abstract: We report the synthesis of a novel macrocyclic host
molecule that forms in a single step from commercially available
starting materials. The core of the macrocycle backbone possesses
two quinone rings and, thus, is redox-active. Host-guest binding
involving the clip-shaped cavity indicates selective binding of pyridine
N-oxides based on the electron density of and steric bulk around the
anionic oxygen.
m-diphenols revealed that while the benzofuran-fused
naphthoquinone is the major product of the reaction, a tetrameric
macrocycle can be formed under specific reaction conditions.[11]
The synthesis reported here employed sterically bulky tert-butyl
groups at the 4- and 6-positions of the diphenol which prevented
the furan-forming mechanistic pathway and led to good yields
(57%) of the macrocycle. The reaction can be scaled up using
less solvent and changing the base to K2CO3 to improve economy,
with only a slight reduction in yield (49%, 1.8 g).
Electronically tunable systems offer a distinct advantage for
the construction of supramolecular structures.[1] By harnessing
electronic features like oxidation state, well-defined macrocycles
that can be switched between two different states have been
generated. For example, Diederich[2] and others[3] have shown
that the incorporation of quinone rings within[3a,c,e] or onto[2,3b,d] the
macrocyclic backbone lead to changes in the electronic features
of these supramolecular hosts. However, these structures require
multi-step syntheses and often lead to hosts that exhibit non-
specific guest binding. On the other hand, macrocyclic host
molecules accessible in one step have revolutionized the field of
supramolecular chemistry (e.g., calixarenes,[4] resorcinarenes,[5]
pillararenes[6]), but they often bind guest molecules utilizing a
static benzenoid core (e.g, via cation-π interactions).1 Our goal
electron
poor
cavity
electron
rich
cavity
was to combine the synthetic utility of
a
single-step
macrocyclization with the structural utility of an electronically
dynamic supramolecular system. Herein we report the synthesis
of a redox-active macrocycle that shows selective binding of
pyridine N-oxide guests,[7] based on electronic and steric features,
primarily through anion-π[8] interactions.
Scheme 1. Supramolecular redox properties and synthesis of cambiarene 1.
Initially, the synthesis of cambiarene[9] 1 was achieved in
one step from the readily available and inexpensive starting
materials 2,3-dichloro-1,4-naphthoquinone and 4,6-di-tert-
butylresorcinol (Scheme 1).[10] Our previous study on the
substitution of reactions of 2,3-dichloro-1,4-naphthoquinone with
Single crystals of cambiarene 1 with 4-methylpyridine N-
oxide (3a) (1:1 ratio) as the guest in the form of 1·(3a)·(toluene)
were grown via slow-evaporation from a solution of toluene to
yield orange-yellow rod-like single crystals suitable for single-
crystal X-ray diffraction (SCXRD).
The host cambiarene 1 exhibits a two-walled conformation
(centroid-distances of aromatic rings: 6.83 Å; quinone rings is
5.54 Å) with both phenyl rings oriented the same direction (Figure
1). The conformation is reminiscent of the 1,3-alternate
conformation of related calix[4]arenes.[4] The walls are slightly
twisted (39.3o) via the ethereal linkages. A salient feature of the
X-ray structure is the inclusion of 3a as guest. The guest is
situated with the N-oxide functionality directed into the cavity of 1.
The geometry contrasts to four-walled calix[4]pyrroles,[7b] with
guest molecule 3a being sustained within the cavity of the host
primarily through anion-πO-centroid: 2.939(2), 2.844(2)], π-π
[a]
[b]
R. J. Petersen, B. J. Rozeboom, N. J. Blythe, T. L. Rathje, S. K.
Kibby, E. O’Brien, K. Rohr, J. R. Carpenter, T. L. Sanders, A. M.
Johnson, Prof. J. W. Wackerly
Department of Chemistry, Central College
812 University Ave, Pella, IA, 20219 (USA)
E-mail: wackerlyj@central.edu
Dr. S. M. Oburn, J. A. Luna, Dr. K. M. Hutchins, Prof. S. K. Shaw,
Prof. L. R. MacGillivray
Department of Chemistry, University of Iowa
Chemistry Building, Iowa City, IA 52242 (USA)
Supporting information for this article is given via a link at the end of
the document.
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[N-centroid 3.420(1), 3.418(1)], and C-H···O forces (C(7)-H···O =
3.213(2), C(29)-H···O = 3.394(2)). The cambiarene 1 self-
assembles in a unidirectional manner to form columns along the
a-axis.
5.21 Å) with both phenyl rings oriented in the same direction. The
two walls are also slightly twisted from planarity (28.0-30.3o).
Macrocycles of 2b pack in a manner that generates an
interdigitated structure.
(a)
(b)
3.42 Å
2.94 Å
3.42 Å
2.84 Å
Scheme 2. Reductive acylation of cambiarene 1.
[13]
1H NMR titration experiments with guest 3a in benzene-d6
revealed a 1:1 host:guest complex and an association constant of
Ka = 252 M-1 (Table 1).[10a] The binding appears to be
predominantly due to anion-π interactions[8] between the anionic
oxygen of 3a and the π-cavity of 1.[10a] While these interactions in
non-specific binding systems tend to be on the order of ca. 101 M-
(c)
,
1 [8] binding of the pyridine N-oxide with two π-faces in this cavity
was over an order of magnitude stronger.
Figure 1. X-ray structure of 1·(3a)·(toluene): (a) cambiarene
1 host
demonstrating cavity length and (b) pyridine N-oxide in cavity, and (c) packing
along the b-axis.
Cyclic voltammetry (CV) analysis of 1 revealed three
reversible features at ca. -2.33 V, -2.08 V, -1.35 V vs Fc/Fc+ and
one irreversible feature at +0.23 V vc Fc/Fc+.[10a] Analysis of CVs
collected at scan rates of 10, 25, 50, 100, 200, 300 mV/s indicate
all electrochemical features are diffusion controlled.[12] When 1
was subjected to chemical reduction in methanol with NaBH4 or
Na2S2O4 the orange solution would become colorless (2a), but
over time with exposure to air the orange color would return.[10a]
Changing the reaction conditions to acetic anhydride and K2CO3
with Na2S2O4 afforded the air-stable acylated, reduced
macrocycle (2b) in good yield (Scheme 2).
Single crystals of cambiarene 2b were grown from vapor-
diffusion as 2b was dissolved in ethyl acetate and hexanes was
diffused through the solution to yield colorless plate-like crystal
suitable for SCXRD (Figure 2). Cambiarene 2b adopts a
conformation similar to 1, with a two-walled conformation
(centroid-distances of aromatic rings: 6.39 Å; acylated rings is
Figure 2. X-Ray crystal structure of cambiarene 2b (a) single host molecule and
(b) interdigitated assembly of macrocycles.
To further probe the specificity of the solution state host-
guest interaction the electron density on the oxide was decreased
via modification of the group at the 4-position (3a-c, Table 1). This
led to a decrease in the binding constant indicating that the
binding can be modulated by tweaking the electronic parameters
of the guest. Next the ability of the host to accommodate steric
bulk around the anionic oxygen was probed. Moving the methyl
group to the 2-position of the pyridine ring (3d) did not lead to a
significant decrease in binding, but changing it to an isopropyl
group revealed a marked decrease (3e). These results indicate
that host 1 is selective for not only an electron rich guest but one
of a size compatible with that of the narrow cavity.
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Pochorovski, M.-O. Ebert, J.-P. Gisselbrecht, C. Boudon, W. B.
Schweizer, F. Diederich, J. Am. Chem. Soc. 2012, 134, 14702-14705. c)
J. V. Milic, F. Diederich, Chem. Eur. J. 2019, 25, 8440-8452.
[3]
Some examples include: a) K. Sugihara, H. Kamiya, M. Yamaguchi, T.
Kaneda, S. Misumi, Tetrahedron Lett. 1981, 22, 1619-1622, b) P. D. Beer,
D. B. Crowe, M. I. Ogden, M. G: B. Drew, B. Main, J Chem Soc Dalton
Trans. 1993, 2107-2116, c) M. Gómez-Kaifer, P. A. Reddy, C. D.
Gutsche, L. Echegoyen, J. Am. Chem. Soc. 1994, 116, 3580-3587, d) K.
Paek, J. Cho Tetrahedron Lett. 2001, 42, 1927-1929, e) T. Ogoshi, T.
Akutsu, Y. Tamura, T. Yamagishi, Chem. Commun. 2015, 51, 7184-7186.
a) C. D. Gutsche, R. Muthukrishnan, J. Org. Chem. 1978, 43, 4905-4096;
b) C. D. Gutsche Calixarenes Revisited, Royal Society of Chemistry,
London, 2000.
Table 1. Binding constants (Ka) of the 1:3 host-guest binding complex.
3a
3b
3c
3d
3e
[4]
[5]
Ka (M-1)[a]
252
231
134
241
45
a) J. R. Moran, S. Karbach, D. J. Cram, J. Am. Chem. Soc. 1982, 104,
5826-5828, b) L. R. MacGillivray, J. L. Atwood in Calixarenes for
Separations (Eds.: G. J. Lumetta, R. D. Rogers, A. S. Gopalan),
American Chemical Society, Washington, 2000, pp. 325-340.
T. Ogoshi, S. Kanai, S. Fujinami, T. Yamagishi, Y. Nakamoto, J. Am.
Chem. Soc. 2008, 130, 5022-5023, b) T. Ogoshi, T. Yamagishi, Y.
Nakamoto, Chem. Rev. 2016, 116, 7937-8002.
Confidence
Interval[a]
±33.3
-0.17
±7.35
0
±10.1
0.54
±23.5
-
±5.3
-
[b]
Rσ
[6]
[7]
[a] 1H NMR titration experiments and data analysis were performed as
outlined in reference 14. [b] The σp values15 are shown as an independent
measure of electron donating/withdrawing capacity of the R groups at the 4-
position of the pyridine ring.
A few examples of pyridine N-oxide binding within supramolecular
systems include: a) S. J. Dalgarno, M. J. Hardie, J. L. Atwood, C. L.
Raston Inorg. Chem. 2004, 43, 6351-6356. b) B. Verdejo, G. Gil-Ramirex,
P. Ballester J. Am. Chem. Soc. 2009, 131, 3178-3179, c) J. J. Henkelis,
S. A. Barnett, L. P. Harding, M. J. Hardie Inorg. Chem. 2012, 51, 40647-
10674.
In conclusion, we have synthesized a new redox-active
macrocycle for host-guest binding in good yields and in a single
step from commercially available starting materials. The binding
appears to be selective for flat guest molecules with a sterically
unencumbered electron rich atom that binds via anion-π
interactions. Future work will focus on modifying the solubility
properties of cambiarenes to study both the redox chemistry in
more depth as well as a wider range of guest molecules, which
could lead to applications such as solid sensor devices, targeted
drug delivery, and carbon sequestration.
[8]
[9]
a) Y S. Rosokha, S. V. Lindman, S. V. Rosokha, J. K. Kochi, Angew.
Chem. Int. Ed. 2004, 43, 4650-4653. b) O. B. Berryman, F. Hof, M. J.
Hynes, D. W. Johnson Chem. Commun. 2006, 506-508, c) B. L. Schottel,
H. T. Chifotides, K. R. Dunbar Chem. Soc. Rev. 2008, 37, 68-83. d) B. P.
Hay, R. Custelcean, Cryst. Growth Des. 2009, 9, 2539-2545, e) M. Giese,
M. Albrecht, K. Rissanen Chem. Commun. 2016, 52, 1778-1795.
a) The term “cambiarene” was based on the Late Latin verb “cambiare”
which means “to change”. b) Following the precedent of calixarenes this
molecule would be a cambi[4]arene. c) Following IUPAC nomenclature
guidelines this molecule would be termed an “oxaquinonacyclophane”,
which is a name we have utilized in prior presentations.
[10] a) Detailed experimental procedures can be found in the Supporting
Information; b) While 4,6-di-tert-butylresorcinol is commercially available
we obtained higher yields of the macrocycle when the starting material
was synthesized and dried in our lab.
Acknowledgements
The authors would like to thank Prof. Ashley Garr for assistance
with computational calculations. J.W.W. acknowledges the
American Chemical Society Petroleum Research Fund (#52318-
UNI), Central College, and the Moore Family Foundation for
financial support. L.R.M. acknowledges the National Science
Foundation (DMR-1708673) for financial support.
[11] N. J. Blythe, K. M. Hutchins, J. R. Carpenter, T. W. Cox, A. M. Johnson,
L. M. MacGillvray, J. W. Wackerly, Heterocycles 2019, 98, 379-386.
[12] A. J. Bard, L. R. Faulkner in Electrochemical Methods: Fundamentals
and Applications. Wiley: New York, 1980.
[13] Benzene was selected as the solvent because it had a broad solubility
range for the host-guest system but the enhanced solubility was likely
due to solvent competition with the guest for binding, which potentially
attenuated the measured binding.
Keywords: supramolecular chemistry • host-guest systems •
macrocyclization • quinones • redox chemistry
[14] P. Thordarson Chem.Soc. Rev. 2011, 40, 1305-1323.
[15] C. Hansch, A. Leo, R. W. Taft Chem. Rev. 1991, 91, 165-195.
[1]
[2]
J. W. Steed, J. L. Atwood Supramolecular Chemistry, Wiley, Chichester,
2009.
a) I. Pochorovski, C. Boudon, J.-P. Gisselbrecht, M.-O. Ebert, W. B.
Schweizer, F. Diederich, Angew. Chem. Int. Ed. 2012, 51, 262-266; b) I.
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