Iterative Reductive Aromatization/Ring-Closing Metathesis Strategy toward the Synthesis of Strained Aromatic Belts

Article abstract of DOI:10.1021/jacs.6b02240

The construction of all sp²-hybridized molecular belts has been an ongoing challenge in the chemistry community for decades. Despite numerous attempts, these double-stranded macrocycles remain outstanding synthetic challenges. Prior approaches

Full text of DOI:10.1021/jacs.6b02240

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Article
Iterative Reductive Aromatization/Ring-Closing Metathesis
Strategy Towards the Synthesis of Strained Aromatic Belts
Matthew R. Golder, Curtis E. Colwell, Bryan M. Wong, Lev N. Zakharov, Jingxin Zhen, and Ramesh Jasti
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b02240 • Publication Date (Web): 30 Apr 2016
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Iterative Reductive Aromatization/Ring-Closing Metathesis Strategy
Towards the Synthesis of Strained Aromatic Belts
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Matthew R. Golder,† Curtis E. Colwell,† Bryan M. Wong,‡ Lev N. Zakharov,§ Jingxin Zhen,⊥ and
Ramesh Jasti*,†
†
Department of Chemistry & Biochemistry and Material Science Institute, University of Oregon, Eugene, OR 97403
‡Department of Chemical & Environmental Engineering, University of California, Riverside, Riverside, CA 92521
§CAMCOR – Center for Advanced Materials Characterization in Oregon, University of Oregon, Eugene, OR 97403
⊥Department of Chemistry, Boston University, Boston, MA 02215
Supporting Information Placeholder
ABSTRACT: The construction of all sp2-hybridized molecular
strain-relieving 1,2-aryl shifts. While the bottom-up syntheses of
these challenging macrocycles have been unsuccessful thus far,
elegant work from the Nakamura group11 has allowed access to an
electronically isolated fullerene-derived [10]cyclophenacene
through systematic, top-down degradation of C60 (Figure 1c).
belts has been an ongoing challenge in the chemistry community
for decades. Despite numerous attempts, these double-stranded
macrocycles remain outstanding synthetic challenges. Prior ap-
proaches have relied on late-state oxidations and/or acid-catalyzed
processes that have been incapable of accessing the envisaged
targets. Herein, we describe the development of an iterative reduc-
tive aromatization/ring-closing metathesis approach. Successful
syntheses of nanohoop targets containing benzo[k]tetraphene and
dibenzo[c,m]pentaphene moities not only provide proof of princi-
ple that aromatic belts can be derived by this new strategy, but
also represent some of the largest aromatic belt fragments report-
ed to date.
With the need for new strategies to access these strained belt
structures, we hypothesized that an approach leveraging both
reductive aromatization and ring-closing metathesis methodolo-
gies could allow access to this family of aromatic belts. In addi-
tion to work on the synthesis of [n]cycloparaphenylenes coming
from Itami, Yamago, and others,12 our laboratory has demonstrat-
ed the power of oxidative dearomatization/reductive aromatiza-
tion strategies towards highly strained, all sp2-hybridized nano-
hoops.13 Additionally, PAHs14 such as sumanene,15 septulene,16
and [n]helicenes17 have been accessed via ring-closing metathesis
(RCM)—a mild, redox-neutral process, although such molecules
do not present the same challenges offered by these belt struc-
tures. We envisioned merging these two processes in an approach
that could ultimately lead to aromatic belts. Herein, we report the
development of an iterative reductive aromatization/ring-closing
INTRODUCTION
Double-stranded macrocyclic targets containing solely sp2-
hybridized carbons, colloquially known as “aromatic belts”, have
evaded synthesis by organic chemists for decades.1 These mole-
cules are prized for their severely distorted and strained aromatic
systems with unique inwardly facing π-systems. As defined by
Scott, true graphitic belts are “distinguished by the presence of
upper and lower edges that are conjugated but never coincide.”2
These compounds have also been identified as short sections of
carbon nanotubes, further heightening the interest in the synthesis
of these types of structures. In 1987, Stoddart was able to access
late-stage intermediate kohnkene3 en route to [6]12cyclacene, but
was plagued by the final oxidation step (Figure 1a). Presumably,
the harsh oxidative conditions were either incompatible with the
product or incapable of building the required amount of strain.3-4
Herges surmised that
a picotube precursor could afford
[4]cyclophenacene, but oxidative and flash vacuum pyrolysis
(FVP) conditions only led to polymeric and rearranged products,
respectively (Figure 1b).5 Cory, Schlüter, Iyoda, and Vollhardt
have also made contributions towards the syntheses of
[n]cyclacenes and [n]cyclophenacenes, but their efforts were
again thwarted by harsh, late-stage reaction conditions.6 Most
recently, the Scholl reaction,7 widely used in the syntheses of a
myriad of polycyclic aromatic hydrocarbons (PAHs),8 has ap-
peared to be a promising approach to access aromatic belts from
arylated [n]CPPs a priori, but as recently shown by the Müllen
group9 and our group10, the conditions are typically incompatible
with [n]cycloparaphenylene backbones due to the propensity for
Figure 1. Representative work on aromatic belts (a – c) and aro-
matic belt fragments 1, 2, and 3.
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metathesis strategy to synthesize aromatic belt fragments 1, 2, and
evidenced by VT-NMR spectroscopy. Based on the sharp proton
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2
3
4
3. These studies not only validate the general approach but also
provide some of the largest all sp2-hybridized belt fragments pre-
pared to date.
resonances of 10 and the broadened signals for 12, we can con-
clude that compound 10 adopts a single low-lying conformation
while 12 exists as a series of slowly interconverting conformers at
room temperature (Figures S15 – S16). Upon heating to 70 C,
1
RESULTS AND DISCUSSION
5
the H NMR signals of 12 sharpen, whereas the signals for 10
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7
8
9
broaden. Presumably, at elevated temperatures, 12 can rapidly
interconvert between conformers whereas 10 is slowly intercon-
verting between a series of energetically similar conformations. A
computational analysis of the various atropisomers that 10 and 12
can adopt is consistent with these NMR experiments (Tables S4 –
S5).
Synthesis and Characterization. Schemes 1 and 2 illustrate
our first-generation approach to this class of molecules. Synthesis
of 1 and 2 commenced with the two-fold lithiation of syn-
dibromide 4, followed by addition of two equivalents of benzo-
quinone monoketal (Scheme 1). Following deprotection, diquinol
5 was accessed in 44% yield. We have previously shown that
additions of aryl lithium reagents to p-quinols in the presence of
sodium hydride preferentially affords the syn diastereomer (dr >
19:1) as dictated by an electrostatic model.13b Hence, lithiation of
6a followed by two-fold diastereoselective addition to 5 and in-
situ methylation of the resulting tetra-alkoxide allowed for rapid
formation of dichloride 7 in 36% yield (dr = 9:1, syn-syn/syn-
anti). Deprotection with TBAF, followed by oxidation with Dess-
Martin periodinane and Wittig olefination afforded dichloride 8 in
44% yield over three steps. Attempts to directly access divinyl 8
from precursor 6b were unsuccessful due to undesirable anionic
polymerization of the styrene moiety.
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Scheme 2. Synthesis of Vinylated Macrocycles 10 and 12
Scheme 1. Synthesis of Dichloride 8
With macrocycles 10 and 12 in hand, we next tested the key
RCM and reductive aromatization reactions. Since the reductive
aromatization of these systems typically requires strong reductants
such as sodium naphthalenide, which we anticipated to be prob-
lematic in the context of the styrene functionality, we opted to
investigate the RCM reaction first. Macrocycles 10 and 12 were
each subjected to Grubbs 2nd generation catalyst (Grubbs II) in
o
dichloromethane at 40 C (Scheme 3).14 Gratifyingly, 10 and 12
were cleanly converted to 13 and 14, respectively, without any
evidence of cyclohexadiene degradation. Not surprisingly, the
terminal olefins react significantly faster than the disubstituted
cyclohexadiene olefins; in fact, the reaction time can be prolonged
to 5 h without any observable byproducts or decrease in yield.
Subjecting 13 to sodium naphthalenide at ‒78 oC afforded cy-
clo(3,10)-benzo[k]tetraphene-penta(p-phenylene) 1 in 47% yield
o
(Scheme 3). Reductive aromatization of 14 at ‒78 C delivered
Having accessed precursor 8, we were in position to explore
macrocyclization reactions.13c,13d In previous work, we had yet to
explore the generation of macrocycles where both coupling part-
ners possessed ortho functionality.18 Initial treatment of fragments
8 and 9 with 20 mol% SPhos-Pd-G219 in dioxane/water (9:1, ca.
1.5 mM) at 80 oC afforded terphenyl-containing macrocycle 10 in
19% yield (Scheme 2). To access an even more elaborate system,
the use of biphenyl diboronic acid (bis)pinacolester 11 as a cou-
pling partner afforded macrocycle 12 in 10% yield. Interestingly,
macrocycles 10 and 12 display different dynamic properties as
cyclo(2,11)-dibenzo[c,m]pentaphene-penta(p-phenylene)
2
in
21% yield. Insofar as we know, a dibenzo[c,m]pentaphene moiety
was synthesized for just the second time in accessing 2.20 Advan-
tageously, incorporation of dibenzo[c,m]pentaphene into a macro-
cycle increases solubility relative to the completely insoluble
acyclic PAH counterpart reported by Clar. Furthermore, while
several large PAH units have been incorporated into various cy-
clophanes,12c,21 1 and 2 represent some of the largest PAHs to be
incorporated into an all sp2-hybridized backbone thus far.22
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Scheme 3. Ring-closing metathesis/reductive aromatization
sequence towards 1 and 2.
a single diastereomer. The crude diol can then be protected using
1
2
3
4
5
6
7
8
triethysilyl chloride, followed by base catalyzed olefin isomeriza-
tion to yield precursor 16 in 38% yield over 3 steps. Dichloride 16
and bisboronate 9 undergo Suzuki coupling under standard condi-
tions to deliver macrocycle 17 in 11% yield. The subsequent silyl
deprotection followed by reductive aromatization under mild con-
ditions recently reported by Yamago23 yields 18, with no evidence
of styrene decomposition. Ring-closing metathesis then afforded
cyclo(3,10)-benzo[k]tetraphene-ter(p-phenylene) 3 in an unopti-
mized 17% yield. This second-generation approach, in which the
reductive aromatization can be carried out prior to the RCM reac-
tion, provides a concise synthesis of the most strained of the three
belt fragment targets accessed. Furthermore, the synthesis of 18
addresses a longstanding problem with the functionalization of
[n]cycloparaphenylenes by offering four substituents along the
backbone with precise regiochemistry.24
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Although the syntheses of structures 1 and 2 validated the basic
RCM/reductive aromatization approach, our initial studies also
revealed several key issues. First, the use of protected alcohols as
vinyl surrogates is a cumbersome approach to the requisite al-
kenes. Furthermore, thinking ahead to the synthesis of
[n]cyclophenacenes, functionalization will be required on the
cyclohexadiene rings, leading to macrocyclic intermediates pos-
sessing multiple stereocenters. In these cases, it would be much
more desirable to execute the reductive aromatization prior to
RCM, thereby eliminating potential issues of mismatched chirality
between functionalized cyclohexadiene rings during the metathe-
sis events. In addition to these points, we were also curious if
smaller, more highly strained belts could be accessed through a
combination of reductive aromatization and ring-closing metathe-
sis methodology. A new target (3) was chosen to investigate a
revised second-generation methodology that would address these
challenges. First, simple allyl groups were incorporated to TES-
protected quinol 15 as vinyl surrogates for the RCM reaction
(Scheme 4). Monolithiation of p-dibromobenzene followed by
subsequent addition of ketone 15 yields an aryl bromide that can
undergo a second lithiation followed by addition to ketone 15
again to rapidly provide a five-ring macrocycle precursor in one
pot isolated as
Solid State Analysis. The solid-state structures of the two
aromatic belt fragments 1 and 2 were evaluated through X-ray
crystallographic analysis.25 Molecule 1 crystallized as a racemate
and the benzo[k]tetraphene group was disordered over at least
four different positions (Figure S1). Hence, we were unable to
glean any detailed structural data from the crystal structure of 1.
On the other hand, crystallization of achiral 2 proved to be more
successful, leading to two symmetrically independent molecules
in the asymmetric unit (Figure S2). The nanohoops form “head-
to-tail” pairs with the PAH motif of one nanohoop in alignment
with the polyphenylene backbone of a second nanohoop. Through
an analysis of the solid-state structure of 1, we also determined
that the incorporation of a large PAH led to some structural dif-
ferences compared to [9]CPP.26 Although the average Cipso – Cipso
bond length between non-fused phenyl rings in 1 was identical to
that of [9]CPP (1.47 Å), the average torsional angle between the
same rings increased from 24.4o in [9]CPP to 31.5o in 1 (Table
S1). Moreover, based on the parameters defined by Bodwell and
co-workers, we determined that the total bend (θ)27 of the fully
conjugated dibenzo[c,m]pentaphene unit was 134o, 33o less bent
than Bodwell’s alkyl-bridged [8](2,11)teropyreneophane (θ =
167o).28 We were unable to obtain a crystal structure of compound
3, but we evaluated the total bend as 142o based on a DFT opti-
mized structure.
Scheme 4. Second Generation Approach to Cyclo(3,10)-
benzo[k]tetraphene-ter(p-phenylene) 3
Figure 2. Comparison of total bend (θ) of diben-
zo[c,m]pentaphene unit of 2 and benzo[k]tetraphene unit of 3.
Thermal ellipsoids (2) are shown at 30% probability. DFT optimi-
zation (3) was performed at the B3LYP-6-31G(d) level of theory.
θ is defined as the sum of the indicated exterior angles.
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Optical and Electrochemical Analysis. We next characterized
similarities observed in the calculated HOMO levels and the uni-
1
2
3
4
5
6
7
8
the optical and electrochemical properties of all three new struc-
tures.29 To begin, we acquired UV-vis spectra for 1 – 3 and com-
pared the results to data from the three parent [n]CPPs ([8]-, [9]-,
and [6]CPP, respectively) (Figure 3). While [n]CPPs always have
a major absorption centered around 340 nm arising from a number
of degenerate orbital transitions,30 the major absorptions for 1 – 3
are, in order of increasing nanohoop diameter, 310 nm (3), 325
nm (1), and 340 nm (2). As the size of the nanohoop decreases (2
 1  3), more fine structure in the spectra become apparent.
We surmise that the increased rigidity of the smaller structures is
responsible for the observation of the most additional features in
3. In the case of the [n]CPPs, absorbances corresponding to the
HOMO-LUMO transition are either completely absent or very
weak due to the centrosymmetric nature of the molecules.30b,31
These minor absorbances redshift with decreasing CPP size, a
trend that is exactly opposite to that of linear oligophenylenes and
a unique feature of the nanohoop structures,.13, 31c Similarly, in
the case of 1 – 3, the absorption band corresponding to the
HOMO-LUMO transition is also very weak but redshifts with
decreasing hoop size, 409 nm for 2, 417 nm for 1, and 450 nm for
3. For 2 and 1, the HOMO-LUMO transitions are slightly red-
shifted compared to those of [9]CPP (399 nm) and [8]CPP (409
nm), while the HOMO-LUMO transition of 3 is roughly the same
as that of [6]CPP (450 nm). A first approximation based on solid-
state analyses of 2 and [9]CPP suggest that the observed red-
shifted HOMO-LUMO transitions could arise
form orbital density observed for all of the HOMOs (Figures S5 –
S7). The LUMO energies, however, are slightly stabilized for 1 –
3 compared to [8]-, [9]-, and [6]CPP. Overall, the computed
HOMO-LUMO gaps for 1 – 3 are slightly lower than the [n]CPP
series, which is consistent with the red-shifted minor absorptions
observed for 1 and 2 compared to [8]- and [9]CPP, respectively.
The minor UV-vis absorption for 3 may also be red-shifted com-
pared to the analogous transition for [6]CPP, but the weak, broad
nature of these two features make it difficult to compare their
absolute maxima.
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Table 1. Selected Electrochemical and Computational Data
or 1 – 3 and Parent [n]CPPs
HOMO-
LUMO
Absorption
(nm)
Experimental Calculated
Oxidation
Potential (V
vs. Fc/Fc+)
0.44a
HOMO-
LUMO
Gap (eV)d
3.14c
[6]CPP
450
450
409
417
399
409
3
[8]CPP
1
[9]CPP
2
0.40b
2.96
3.41c
3.26
3.41c
0.59c
0.60b
0.70c
0.75b
3.32
aRef. 12 (solvent = CH2Cl2). b1 and 2 were measured in CH2Cl2; 3
c
was measured in THF. Ref. 31e (solvent = C2H2Cl4). dCalculated
at the B3LYP/6-31G(d) level of theory.
Strain Energy Analysis. Finally, we evaluated the strain ener-
gies of 1 – 3, as well as the strain energy of the corresponding
precursors, computationally using homodesmotic reactions using
Gaussian0933 at the ωB97D/6-31G(d) level of theory (Scheme 5).
We first determined that 1 has 79.2 kcal mol-1 of strain energy
(Scheme S3), while 2 has 71.1 kcal mol-1 of strain energy
(Scheme S6) relative to acyclic counterparts. The smallest of our
belt fragments, 3, has a strain energy of 106 kcal mol-1. Interest-
ingly, these values are only 5 – 9 kcal mol-1 higher than their par-
ent [8]-, [9]-, and [6]CPP analogues which have 72 kcal mol-1, 66
kcal mol-1, and 97 kcal mol-1 of strain energy, respectively.13f,34
Evaluating penultimate macrocycles 13 and 14 indicates that the
powerful reductive aromatization step builds in 47.5 kcal mol-1 of
strain (31.5 kcal mol-1  79 kcal mol-1) and 28.5 kcal mol-1 of
strain (42.6 kcal mol-1  71.1 kcal mol-1) in the formation of 1
and 2, respectively (Schemes S2 and S5). More importantly, how-
ever, RCM is able to build in 23.8 kcal mol-1 (7.75 kcal mol-1

Figure 3. UV-vis spectra of 1- 3 and [9]CPP. Absorption intensi-
ties have been adjusted to display all features on the same scale.
For more details on photophysical measurements, please see Fig-
ures S3, S4, and S8 in the Supporting Information.
31.5 kcal mol-1) and 13.9 kcal mol-1 (28.7 kcal mol-1  42.6 kcal
mol-1) of strain energy during the transformations of 10  13 and
12  14, respectively (Schemes S1 and S4). Hence, in these cas-
es, ring-closing metathesis acts in conjunction with the Suzuki-
Miyaura macrocyclization and sodium naphthalenide promoted
reductive aromatization to allow for a gradual increase in strain
energy. We next evaluated the energy landscape of our second-
generation approach. Interestingly, in this case, the ring-closing
metathesis event is a strain relieving process rather than a strain
building process. Upon building in 43.4 kcal mol-1 during the
macrocyclization step in the synthesis of 17 (Scheme S7), reduc-
tive aromatization afforded 18, a molecule with almost as much
from the slight decrease in the average dihedral angle upon PAH
incorporation into the p-phenylene backbone (Table S1). Further
investigations of the HOMO and LUMO levels by electrochemis-
try and DFT computations were consistent with our UV-vis meas-
urements (Table 1). For example, cyclic voltammetry (CV) re-
vealed very similar cathodic half-wave potentials between 1 – 3
and their respective parent CPPs.32 This is also consistent with the
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strain energy as [5]CPP (111 kcal mol-1 versus 119 kcal mol-1)
(Scheme S8). We attribute the high strain energy of 18 to unfa-
AUTHOR INFORMATION
1
2
3
4
5
6
7
8
Corresponding Author
vorable steric interactions between ortho-ortho groups forced into
close proximity with one another due to the rigid geometry of
such a small macrocycle. Finally, reductive aromatization of 18
afforded 3, which is 5 kcal mol-1 less strained than its penultimate
intermediate (111 kcal mol-1  106 kcal mol-1) (Scheme S9). We
anticipate that this second-generation approach will prove to be
promising methodology towards the synthesis of members in the
[n]cyclophenacene family.
*E-mail: rjasti@uoregon.edu
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
Financial support was provided by the National Science
Foundation (CHE-1255219), the Sloan Foundation, the Camille
and Henry Dreyfus Foundation, and generous startup funds from
the University of Oregon. MRG thanks Vertex Pharmaceuticals
for a graduate research fellowship. HRMS data were obtained at
the Biomolecular Mass Spectrometry Core of the Environmental
Health Sciences Core Center at Oregon State University (NIH
P30ES000210). Mr. Evan Darzi is acknowledged for the synthesis
of 5.
9
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Scheme 5. Evaluation of the Origins of Strain Energy in 1
– 3
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CONCLUSION
In conclusion, we have developed a reductive aromatiza-
tion/ring-closing metathesis sequence for the synthesis of aro-
matic belt fragments. Most significantly, we have demonstrated
that the RCM reaction can be carried out on highly strained sys-
tems without intervening acid-catalyzed rearrangements or unde-
sirable oxidative processes that have plagued previous synthetic
approaches. In addition, we also report an allyl isomerization
strategy as an efficient method to introduce sensitive styrenyl
functionality required for the RCM reactions. Our campaign to-
wards the total synthesis of several elusive [n]cyclophenacene
targets is well underway in our laboratory and will be reported in
due course.
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ASSOCIATED CONTENT
Supporting Information
General synthetic details, NMR spectra, computational details,
optical spectra, and electrochemical characterization. This materi-
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