Synthesis of Phenylene Vinylene Macrocycles through Acyclic Diene Metathesis Macrocyclization and Their Aggregation Behavior

Article abstract of DOI:10.1002/chem.201502848

A series of phenylene vinylene macrocycles (PVMs) bearing substituents with various sizes and electronic properties have been synthesized through a one-step acyclic diene metathesis macrocyclization approach and their aggregation behaviors have been investigated. In great contrast to the aggregation of the analogous phenylene ethynylene macrocycles, which aggregate only when substituted with electron-withdrawing groups, these PVMs undergo exceptionally strong aggregation, regardless of the electron-donating or -withdrawing characters of the substituents. The unusual aggregation behavior of the PVMs is further investigated with thermodynamic and computer modeling studies, which show a good agreement with the recently proposed direct through-space interaction model, rather than the polar/π model. The high aggregation tendency of PVMs suggests the great potential of this novel class of shape-persistent macrocycles in a variety of applications, such as ion channels, host-guest recognition, and catalysis.

Full text of DOI:10.1002/chem.201502848

DOI: 10.1002/chem.201502848
Full Paper
&
Macrocycles
Synthesis of Phenylene Vinylene Macrocycles through Acyclic
Diene Metathesis Macrocyclization and Their Aggregation
Behavior
Chenxi Zhang,[a] Chao Yu,[a] Hai Long,[b] Ryan J. Denman,[a] Yinghua Jin,*[a] and Wei Zhang*[a]
Abstract: A series of phenylene vinylene macrocycles (PVMs)
bearing substituents with various sizes and electronic prop-
erties have been synthesized through a one-step acyclic
diene metathesis macrocyclization approach and their ag-
gregation behaviors have been investigated. In great con-
trast to the aggregation of the analogous phenylene ethyny-
lene macrocycles, which aggregate only when substituted
with electron-withdrawing groups, these PVMs undergo ex-
ceptionally strong aggregation, regardless of the electron-
donating or -withdrawing characters of the substituents. The
unusual aggregation behavior of the PVMs is further investi-
gated with thermodynamic and computer modeling studies,
which show a good agreement with the recently proposed
direct through-space interaction model, rather than the
polar/p model. The high aggregation tendency of PVMs sug-
gests the great potential of this novel class of shape-persis-
tent macrocycles in a variety of applications, such as ion
channels, host–guest recognition, and catalysis.
Introduction
have the opposite effect; a planar and rigid framework enhan-
ces the aggregation, whereas a flexible nonplanar geometry in-
hibits it.[21,22] These experimental results are interpreted by the
well-known polar/p model, which predicts the substituent ef-
fects based on the polarization of the p system.[23–26]
Shape-persistent macrocycles (SPMs) have attracted considera-
ble attention due to their self-aggregation behavior and un-
usual electronic and optoelectronic properties.[1–5] These mole-
cules have rigid non-collapsible backbone structures and can
assemble into supramolecular systems, such as perforated
monolayers and discotic liquid crystalline materials.[6] Among
the numerous SPMs, arylene ethynylene macrocycles (AEMs)
are the most widely studied and many interesting applications
based on AEMs have emerged.[7–14] Recent advances in dynam-
ic covalent chemistry,[15–17] namely alkyne metathesis, have ena-
bled the facile access to AEMs on gram scale, and boosted the
applications of these macrocycles toward materials develop-
ment.[18–20]
Arylene vinylene macrocycles (AVMs) are structural ana-
logues of AEMs, in which arylenes are connected by carbon–
carbon double bonds with trigonal planar geometry rather
than linear triple bonds. However, AVMs are uncommon and
their supramolecular properties have rarely been explored.
One such example was reported by Meier and co-workers.
They synthesized various areno-condensed annulenes connect-
ed by E-vinylene bridges through a multistep synthetic ap-
proach and showed that these macrocyclic annulenes can ag-
gregate and serve as photoconductors and discotic meso-
gens.[27–29] Recently, our group developed a high-yielding acy-
clic diene metathesis macrocyclization (ADMAC) approach to
form AVMs from simple precursors in one step.[30] Our prelimi-
nary study shows that AVMs containing carbazole-vinylene or
phenylene-vinylene groups easily aggregate and form nanofi-
brils. More interestingly, the hexa(phenylvinylene) macrocycle
substituted with electron-donating alkoxy groups also shows
strong self-association in CDCl3. It is in great contrast to the
non-aggregation character of analogous hexa(phenylethyny-
lene) macrocycle with alkoxy substituents under the same sol-
vent, and thus surprising, especially considering the skeletal
flexibility and lower rigidity of AVMs arising from the possible
conformational isomerism of vinylene moieties.
It has been reported that the self-association of AEMs is in-
duced by face-to-face p–p interactions between aromatic rings
and is strongly influenced by the rigidity of the backbone
structures and pendant functional groups of the macrocycles:
Electron-withdrawing substituents promote self-aggregation of
macrocycles, whereas electron-donating functional groups
[a] Dr. C. Zhang,+ C. Yu,+ R. J. Denman, Dr. Y. Jin, Prof. Dr. W. Zhang
Department of Chemistry and Biochemistry
University of Colorado Boulder
Boulder, Colorado, 80309 (USA)
E-mail: Yinghua.Jin@colorado.edu
wei.zhang@colorado.edu
[b] Dr. H. Long
To better understand the unusual aggregation behavior of
AVMs, herein, we report the design and synthesis of a series of
phenylene vinylene macrocycles (PVMs) bearing various side
chains of different sizes and electronic natures and investigat-
ed their aggregation. We found that PVMs aggregate regard-
National Renewable Energy Laboratory
Golden, Colorado 80401 (USA)
[+] These authors contributed equally to this work.
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201502848.
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less of whether they contain electron-withdrawing or electron-
donating substituents. Such peculiar substituent effects cannot
be readily explained by the polar/p model, but agree well with
the recently proposed direct through-space interaction
model.[31–40] Our thermodynamic and computer modelling
studies further support such a theory, which emphasizes sub-
stituent effects on p-stacking are due to direct interactions of
the substituents with the neighboring p-system rather than
polarization of the aryl p-system.
over pentameric or heptameric PVMs is thermodynamically fa-
vored (see the Supporting Information, Table S1). Pure cyclic
hexamers 17–24 were isolated in decent yields (45–74%)
through repeated careful column chromatography. This syn-
thetic protocol is thus modular and allows for the cyclooligo-
merization of a variety of monomer units with differing sub-
stituents in a straightforward manner.
1
All PVMs were characterized by H and 13C NMR spectrosco-
py and MALDI-TOF MS. We observed two sets of broad singlets
corresponding to the protons on the phenyl ring. The vinyl
1
protons of the PVMs appeared as a singlet in the H NMR spec-
Results and Discussion
tra, both at room temperature and at 08C. This chemical shift
equivalence suggests the two seemingly different vinyl pro-
tons, located inside and outside of the macrocyclic ring, are in-
terchangeable through the rapid rotational isomerization of
the double bonds.
Synthesis of PVMs
Divinylbenzene monomers 9–16, with various electronically
and sterically different substituents, were prepared from diha-
lobenzenes 1–8 (halogen=Br or I) by Stille coupling reactions
Self-association of PVMs
We next investigated the self-as-
sociation behaviors of various
PVMs and compared them with
those of the analogous phenyl-
ene ethynylene macrocycles
(PEMs). The concentration- and
temperature-dependent aggre-
gation of PVMs was studied with
1H NMR spectroscopy (Figure 1).
To minimize the solvophobic
effect on the aggregation, we
used deuterated chloroform, in
which PVMs readily dissolve, as
the solvent in all aggregation ex-
periments. With increased con-
centration or decreased temper-
ature, the aromatic proton (Ha
and Hb) and vinyl proton (Hc)
peaks were shifted upfield. Such
shielding effects on PVMs are
Scheme 1. Synthesis of PVMs through ADMAC.
(Scheme 1). The crude yields of Stille coupling are generally
above 90% based on the NMR analyses of the crude reaction
mixtures. However, considerably lower yields (50–70%) could
be isolated, mainly due to (1) the low stability of the divinyl
monomers, which easily polymerize in the solid state and in air
within several hours to form waxy insoluble polymers, and
(2) extensive purification. The excess tributyl(vinyl)tin and tribu-
tyltin chloride byproducts often have similar polarities to those
of the products (e.g., 9–12) and their removal requires repeti-
tive column chromatography purification.
PVMs 17–24 were prepared through thermodynamically-
controlled one-step ADMAC approach using Grubbs’ second
generation catalyst at 408C under nitrogen. In all cases, cyclic
hexamers were obtained as the predominant species with vari-
ous amounts of cyclic heptamer and cyclic pentamer as minor
species (see the Supporting Information, Figure S9). Theoretical
calculations confirm that the formation of hexameric PVMs
1
Figure 1. 1H NMR spectra of PVM 21 at various concentrations. H NMR spec-
tra were recorded in CDCl3 at 296 K.
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similar in trend, albeit much more significant, compared to the
cases of PEMs. Interestingly, the aggregation properties of
PVMs are strongly influenced by the polarity of substituents
and whether the functional groups can donate or withdraw
electron density from the macrocyclic core appears less impor-
tant. Pronounced concentration-dependent 1H NMR chemical
shift changes were observed for PVMs 19–23 with either elec-
tron-donating or -withdrawing substituents (Figure 2), but not
cies. We assume that PVM 21 and PVM 23 are present as mon-
omeric species at the lowest studied concentration (0.13 mm,
and 0.66 mm, respectively). Our study (for details, see the Sup-
porting Information) shows that the number of aggregates of
both PVM 21 and PVM 23 are around two at the highest stud-
ied concentration (4.08 mm and 10.5 mm, respectively). There-
fore, it is mainly monomer–dimer aggregation that occurs and
formation of higher order aggregates beyond dimers is insig-
nificant in the concentration range we studied for PVM 21 and
23. We assume that the aggregations of other PVMs (19, 20,
22, 24), which show weaker self-association in CDCl3 than 21
and 23, are mainly limited to dimerization.
Since DOSY experiments support monomer–dimer equilibri-
um as the major aggregation process, the concentration-de-
pendent chemical shift data of endo- and exo-annular protons
of PVMs were analyzed by using the monomer–dimer model
[Eq. (1)][41]
!
pffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi
ð1 À 8Kassocct þ 1Þ
dobs ¼ dmonomer À D 1 þ
ð1Þ
4Kassocct
where dobs is the observed chemical shift, dmonomer is the
chemical shift of the monomer, Kassoc is the association con-
stant, ct is the molar concentration of the PVM, and D is the
chemical shift difference between monomer and dimer. Self-as-
sociation constants of PVMs were then extracted by using non-
linear least-squares regression method from the concentration-
dependent chemical shifts of exo-annular (Ha) and the endo-an-
nular (Hb) protons of PVMs at 296 K. We were able to identify
the best values of association constants, which give the small-
est standard deviations in the curve fitting, for macrocycles
showing significant aggregation (see the Supporting Informa-
tion, Figures S15–S18). The self-association constants calculated
from endo- and exo-annular protons of the PVMs are in good
agreement, within experimental error. PVM 21, functionalized
with “reverse” ester (OCOnC9H19), gave the strongest self-asso-
ciation constants (Table 1). We also observed strong aggrega-
tion of PVMs 20 (R=OnC4H9) and 23 (R=COOnC4H9). Surpris-
ingly, PVM 24, substituted with tert-butyl ester, also underwent
decent aggregation, although Kassoc was decreased four-fold
compared to that of PVM 23, substituted with n-butyl esters.
The length of alkyl chains attached to the ether or ester
groups negatively influenced the aggregation of PVMs, likely
due to the larger entropic loss upon aggregation. We observed
much stronger aggregation of PVMs 20 (R=OnC4H9) and 23
(R=COOnC4H9) compared to PVMs 19 (R=OnC10H21) and 22
(R=COOnC10H21), respectively.
Figure 2. The concentration-dependent chemical shifts of exo-annular pro-
1
tons (Ha) of PVMs 17–24. H NMR spectra were recorded in CDCl3 at 296 K.
for PVMs 17 and 18, containing nonpolar alkyl substituents. At
ambient temperature, the chemical shift of two anisochronous
aromatic protons of PVM 21 (R=OCOnC9H19) changed from
7.49 ppm to 7.31 ppm and from 7.03 ppm to 6.89 ppm respec-
tively, as the concentration was increased from 0.39 to 6.2 mm
(Figure 1). The changes in the chemical shift of exo-annular (Ha)
and endo-annular (Hb) protons were similar in both trend and
magnitude for the same PVM. The chemical shifts of aliphatic
protons remain unchanged over the same concentration
range. The aggregation behaviors of PVMs are also tempera-
ture dependent. When the temperature was raised, the reso-
nance peaks of exo-annular and endo-annular protons of PVM
21 were shifted to lower field, which indicates that dissociation
occurs at elevated temperature (see the Supporting Informa-
tion, Table S7 and Figure S12).
The aggregation of PVMs in solution was also studied by
fluorescence spectroscopy. We observed significant fluores-
cence quenching in the solution of PVM 23 when the solvent
was changed from chloroform to acetonitrile. However, such
fluorescence quenching behavior was absent in the emission
spectra of non-aggregating PVM 18 under the same experi-
mental conditions (see the Supporting Information, Figure S11).
These results further suggest the fluorescence quenching ob-
served for PVM 23 is attributed to its aggregation.
Substituent effects
To further quantify the self-association constants, we first es-
timated the size of macrocycle aggregates from the diffusion
coefficient of the stacked species in solution. The diffusion co-
efficient was obtained through diffusion-ordered spectroscopy
(DOSY) experiments. We used PVM 21 and PVM 23, which
show the strongest aggregation, as the representative exam-
ples to estimate the number of macrocycles per stacked spe-
Previously, Moore and co-workers reported that PEMs undergo
considerable aggregation only when functionalized with elec-
tron-withdrawing groups (e.g., COOnC4H9), and no obvious ag-
gregation when functionalized with electron-donating groups
(e.g., OnC4H9; Table 1). This is in good agreement with the
polar/p model,[26] which predicts that the introduction of elec-
tron-withdrawing substituents reduces the electron density of
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(i.e., PEM 25). The thermodynamic parameters of the aggrega-
tion process of PVM 23 were obtained through variable-tem-
perature NMR experiments (see the Supporting Information,
Figure S13) and subsequent Van’t Hoff analysis (Figure S14).
The thermodynamic study showed that the aggregation of
PVM 23 occurs with comparable enthalpy gain (DH=4.9 kcal
molÀ1 vs. 5.0 kcalmolÀ1) as PEM 25 but with a smaller entropy
loss (DS=À6.2 calmolÀ1 KÀ1 vs. À9.2 calmolÀ1 KÀ1). These re-
sults can be readily explained by the direct through-space in-
teraction model, in which the substituents directly interact
with the neighboring macrocycle’s p-system. In such a model,
the position of the substituents can directly influence the mag-
nitude of stacking interactions, as reported by Gung and co-
workers.[42] In PVMs, the optimal conformation to maximize
stacking interactions can be easily achieved due to the addi-
tional conformational flexibility arising from the rotational free-
dom of vinylene groups. On the contrary, it would be more dif-
ficult for rigid PEMs to achieve the optimal stacked conforma-
tion, leading to increased entropic penalties.
Table 1. Thermodynamic data of self-association of PVMs (296 K) and PEMs
(293 K) in CDCl3.
R (PVM)
Kassoc [mÀ1
]
R (PEM)[45]
Kassoc [mÀ1
]
nC10H21(PVM 17)
tC4H9 (PVM 18)
<5
ꢀ0
60
99
628
45
CH2OnC4H9
ꢀ0
OnC10H21 (PVM 19)
OnC4H9 (PVM 20)
OCOnC9H19 (PVM 21)
COOnC10H21 (PVM 22)
COOnC4H9 (PVM 23)
COOtC4H9 (PVM 24)
OnC4H9
OCOnC4H9
ꢀ0
ꢀ0
The exceptionally high degree of self-aggregation of PVM
21 substituted with “reverse” ester is intriguing, considering
that the electronic effect of the “reverse” ester is between that
of the electron-donating alkyl ether and that of the electron-
withdrawing alkyl ester group. To gain some insight into this
interesting observation, we modeled the PVM 21 structure by
using density functional theory (DFT) calculations by Gaussian
09.[43] The dimer structure of PVM 21 was optimized by using
the B3LYP method with the 6-31G* basis set. It should be
noted that there may exist various conformational isomers as
a result of the rotation of vinylene groups. The most stable
conformer with C6 symmetry was used in the calculation as the
monomer structure. The energy- minimized dimer structure of
PVM 21 (Figure 3) adopts a geometry that is off-set by 308
168
40
COOnC4H9(PEM 25)
COOtC4H9
60
ꢀ0
the p-system and thus decreases the electrostatic repulsion be-
tween p electrons and promotes p-stacking. However, the ag-
gregation properties of PVMs appear to be independent on
the electron-withdrawing or -donating nature of the substitu-
ents. This is in striking contrast to the aggregation behaviors
of PEMs and appears to be in contradiction to the polar/p
model. Similar substituent effects to our results were recently
reported by Swager and Houk for stereoselective Diels–Alder
cycloadditions, showing that -OMe enhances p-stacking inter-
actions, despite its p-electron donating character.[40] Gas-phase
ab initio computations by Sherrill and co-workers also revealed
enhanced stacking interactions in the sandwich benzene
dimer, regardless of the electron-withdrawing or electron-do-
nating character of the substituents.[37–39] More recently, Houk
and Wheeler highlighted the direct through-space interaction
model, in which the substituent effects correlate with sm, not
sp, the inductive/field effects of the substituents rather than p-
polarization.[33–36] Although large aromatic systems (e.g., macro-
cyclic rings) might be different from the more-studied smaller
aromatics, our results agree well with this direct through-space
interaction model, which predicts that p-donating but s-with-
drawing alkoxy substituents will enhance stacking interactions.
On the basis of the aforementioned models for substituent
effects in stacking interactions, these PVMs present themselves
as appealing direct experimental evidence for the emerging
direct through-space interaction model. To further corroborate
the theory, we first investigated the thermodynamics of the ag-
gregation process of PVMs. For ease of comparison, we chose
to use PVM 23, substituted with COOnC4H9, as a representative
model compound, for which the TDS and DH values of self-as-
sociation can be readily compared to the literature values of
analogous PEM substituted with the same functional groups
Figure 3. Energy-minimized structure of PVM 21 dimer: a) Top view; b) side
view; c) expanded view.
around the principle rotational axis of macrocycles. Interesting-
ly, upon dimerization, PVMs deviate from the perfectly planar
conformation to the slightly puckered form, where the macro-
cycles bend towards one another, presumably to reach maxi-
mum direct through-space interaction between the substitu-
ents and the p-system of the neighboring macrocycle. In addi-
tion, the “reverse” ester groups on the periphery of the macro-
cycle are in close contact with the vinylene protons of the
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neighboring ring. We found strong electrostatic interactions
between the negatively charged carbonyl oxygen (Mulliken
partial atomic charge=À0.45) and one positively charged vi-
nylene hydrogen (+0.19) as well as two positively charged
phenyl hydrogens (+0.15 and +0.16), with the total positive
charge on the all three hydrogens of +0.50. These hydrogen
atoms are in the close proximity of the carbonyl oxygen with
the distances of 2.4 Š, 2.8 Š and 2.9 Š, respectively (Figure 3c).
This result also agrees with the previous report by Rashkin and
Waters, which described a similar direct electrostatic interac-
tion of the edge hydrogens of one ring with electronegative
substituents on the other ring.[44] However, we did not observe
a downfield shift of the vinyl protons of PVM 21 upon aggre-
gation. Instead, we observed an upfield shift of those protons,
indicating that the shielding effect of macrocyclic ring current
overshadows the deshielding effect from the electrostatic in-
teraction. Considering the complexity of the large macrocyclic
ring system, the exceptionally high aggregation tendency
could be due to the combination of multiple interactions, in-
cluding p-stacking, electrostatic, and solvophobic interactions.
nipulated by altering the backbone structures, as well as side-
chain substituents.
Experimental Section
Typical ADMAC procedure: To a Schlenk tube were added divinyl
monomer (0.055 mmol) and a solution of Grubbs’ 2nd generation
catalyst (0.0055 mmol) in 1,2,4-trichlorobenzene (1 mL). The reac-
tion apparatus was evacuated and refilled with nitrogen and this
process was repeated three times. The solution was heated at
408C under nitrogen for 18 h. Upon completion of the reaction, all
solvent was removed and diethyl ether (10 mL) was added. The
ethereal solution was washed with water (3”10 mL), dried over an-
hydrous Na2SO4, and concentrated under reduced pressure to give
the crude product. Purification by flash column chromatography
(eluent: CH2Cl2/hexanes or EtOAc/hexanes) afforded the pure prod-
uct.
Acknowledgements
We thank Prof. Richard K. Shoemaker for his help with NMR ex-
periments and the Alfred P. Sloan Foundation for financial sup-
port. This research used the capabilities of the National Renew-
able Energy Laboratory Computational Sciences Center, which
is supported by the Office of Energy Efficiency and Renewable
Energy of the U.S. Department of Energy under Contract No.
DE-AC36-08GO28308.
Conclusion
A series of phenylene vinylene macrocycles were successfully
synthesized through thermodynamically-controlled one-step
ADMAC approach from simple diene monomers. The synthetic
protocol is modular and straightforward, allowing for a variety
of monomer units with differing substituents to be cyclized.
The aggregation behaviors of these PVMs were systematically
Keywords: aggregation
· dynamic covalent chemistry ·
1
macrocycles · olefin metathesis · p interactions
studied. H NMR DOSY experiments supported a predominant
monomer–dimer equilibrium during the aggregation process
rather than the formation of higher oligomers. Based on the
“monomer–dimer” model, the self-association constants were
calculated from the concentration dependent NMR chemical
shift data of the PVMs. Despite of their structural similarity,
PVMs exhibit much stronger aggregation tendency compared
to the analogous PEMs. More interestingly, PVMs aggregate
even when they are substituted with electron-donating
groups. Our results can be explained by the new direct
through-space interaction model of p-stacking interactions,
rather than the polar/p model. The thermodynamic study on
the aggregation of PVM and PEM with the same substituents
indicates that PVM gains comparable enthalpy but loses small-
er entropy during the aggregation, which is likely due to the
increased conformational freedom of PVMs. Computer model-
ing studies suggested the possible direct through-space elec-
trostatic interaction between the substituents and peripheral
hydrogen atoms as the additional driving force for the strong
aggregation of PVMs. These results provide experimental and
theoretical support for the recently proposed model of p-
stacking interactions, which argues that direct interactions of
the substituent with the neighboring p-system dominate the
substituent effects, rather than p-polarization. Our study will
nicely complement the current structure design and synthetic
approaches for shape-persistent macrocyclic compounds and
provides more insight into how their aggregation can be ma-
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Received: July 20, 2015
Published online on September 30, 2015
Chem. Eur. J. 2015, 21, 16935 – 16940
www.chemeurj.org
16940
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