Influence of Amide Connectivity on the Hydrogen-Bond-Directed Self-Assembly of [n.n]Paracyclophanes

Article abstract of DOI:10.1002/chem.202003909

Reported here is the synthesis and self-assembly characterization of [n.n]paracyclophanes ([n.n]pCps, n=2, 3) equipped with anilide hydrogen bonding units. These molecules differ from previous self-assembling [n.n]paracyclophanes ([n.n]pCps) in the connectivity of their amide hydrogen bonding units (C-centered/carboxamide vs. N-centered/anilide). This subtle change results in a ≈30-fold increase in the elongation constant for the [2.2]pCp-4,7,12,15-tetraanilide ([2.2]pCpNTA) compared to previously reported [2.2]pCp-4,7,12,15-tetracarboxamide ([2.2]pCpTA), and a ≈300-fold increase in the elongation constant for the [3.3]pCp-5,8,14,17-tetraanilide ([3.3]pCpNTA) compared to previously reported [3.3]pCp-5,8,14,17-tetracarboxamide ([3.3]pCpTA). The [n.n]pCpNTA monomers also represent the reversal of a previously reported trend in solution-phase assembly strength when comparing [2.2]pCpTA and [3.3]pCpTA monomers. The origins of the assembly differences are geometric changes in the association between [n.n]pCpNTA monomers—revealed by computations and X-ray crystallography—resulting in a more favorable slipped stacking of the intermolecular π-surfaces ([n.n]pCpNTA vs. [n.n]pCpTA), and a more complementary H-bonding geometry ([3.3]pCpNTA vs. [2.2]pCpNTA).

Full text of DOI:10.1002/chem.202003909

Accepted Article
Accepted Article
Title: Influence of Amide Connectivity on the Hydrogen Bond Directed
Self-Assembly of [n.n]Paracyclophanes
Authors: Will R. Henderson, Ajeet Kumar, Khalil A. Abboud, and
Ronald K. Castellano
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
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To be cited as: Chem. Eur. J. 10.1002/chem.202003909
Link to VoR: https://doi.org/10.1002/chem.202003909
01/2020

10.1002/chem.202003909
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Influence of Amide Connectivity on the Hydrogen Bond Directed
Self-Assembly of [n.n]Paracyclophanes
Will R. Henderson, Ajeet Kumar, Khalil A. Abboud, Ronald K. Castellano*[a]
Dedicated to Prof. William R. Dolbier, Jr. for his contributions to cyclophane chemistry and the University of Florida.
[a]
W. R. Henderson, A. Kumar, Dr. K. A. Abboud, Prof. R. K. Castellano
George & Josephine Butler Polymer Research Laboratory, Center for Macromolecular Science & Engineering
Department of Chemistry, P.O. Box 117200
University of Florida
Gainesville, Florida, 32611 (USA)
E-mail: castellano@chem.ufl.edu
Supporting information (molecular synthesis and characterization; NMR, IR, UV-Vis, and X-ray characterization of assembly; computational details) and the
ORCID identification number(s) for the author(s) of this article is given via a link at the end of the document.
Abstract: Reported here is the synthesis and self-assembly
characterization of [n.n]paracyclophanes ([n.n]pCps, n = 2, 3)
equipped with anilide hydrogen bonding units. These molecules differ
from previous self-assembling [n.n]paracyclophanes ([n.n]pCps) in
the connectivity of their amide hydrogen bonding units (C-
centered/carboxamide vs. N-centered/anilide). This subtle change
results in a ~30-fold increase in the elongation constant for the
The mechanism of supramolecular polymerization—
isodesmic or cooperative—describes the monomer association
constant Ka as a function of growing oligomer size.[4] The
isodesmic mechanism is characterized by a single elongation
constant Ke independent of assembly size.[5] The cooperative
mechanism is characterized by two distinct association constants:
the association constant between monomers in the molecularly
dissolved state prior to the formation of a critical nucleus, is
described by the nucleation constant (Knuc), while a generally
larger elongation constant (Kelo) describes association between
monomers, the critical nucleus, and the growing polymer chain.[6]
The mechanism and thermodynamics of supramolecular
polymerization are highly sensitive to structural and electronic
factors affecting both monomer and assembly.[7] By observing the
individual influence of these structural and electronic factors on
assembly mechanism and thermodynamics, information for the
rational design of future supramolecular monomers can be
achieved. These structure–property and structure–mechanism
relationships have been performed for certain monomer
classes,[7a] but fundamental differences between monomer
classes necessitates establishing these relationships across a
broad range of monomers to achieve a greater degree of
generality and allow the rational design of new SPs.
[2.2]pCp-4,7,12,15-tetraanilide
previously reported
([2.2]pCpNTA)
compared
to
[2.2]pCp-4,7,12,15-tetracarboxamide
([2.2]pCpTA), and a ~300-fold increase in the elongation constant for
the [3.3]pCp-5,8,14,17-tetraanilide ([3.3]pCpNTA) compared to
previously
reported
[3.3]pCp-5,8,14,17-tetracarboxamide
([3.3]pCpTA). The [n.n]pCpNTA monomers also represent the
reversal of a previously reported trend in solution-phase assembly
strength when comparing [2.2]pCpTA and [3.3]pCpTA monomers.
The origins of the assembly differences are geometric changes in the
association between [n.n]pCpNTA monomers—revealed by
computations and X-ray crystallography—resulting in
a more
favorable slipped stacking of the intermolecular π-surfaces
([n.n]pCpNTA vs. [n.n]pCpTA), and a more complementary H-
bonding geometry ([3.3]pCpNTA vs. [2.2]pCpNTA).
In 2016, we reported a new SP monomer based on
[2.2]paracyclophane-4,7,12,15-tetracarboxamide ([2.2]pCpTA,
Figure 1).[8] These [2.2]pCp monomers self-assemble through
intramolecular (transannular), and intermolecular hydrogen
bonding to produce homochiral 1-D stacks composed of double-
helical hydrogen bonding through anti- aligned amides, where the
helical sense of the assembly is determined by the planar-chirality
of the monomer. Further studies have assessed the role of
transannular hydrogen bonding and its impact on assembly
dynamics,[9] and computational support for the pathway selection
and isodesmic supramolecular polymerization of the anti-
conformer of [2.2]pCpTA.[10] This assembly mechanism is
uncommon for hydrogen bond directed assemblies that normally
feature cooperativity from strong H-bond polarization or dipole
growth.[11]
Introduction
Supramolecular polymers (SPs) are
a
class of
macromolecules formed by molecular self-assembly through
reversible noncovalent interactions, resulting in polymeric
properties in the bulk and in solution.[1] The size and strength of
these intermolecular assemblies are determined by the
equilibrium constant for monomer association Ka, or in the case
of a bifunctional monomer, the elongation constant Ke, which is
dependent on the nature of the noncovalent interaction, solvent
composition, concentration, and temperature. Examples of
noncovalent interactions utilized for SPs include hydrogen
bonding, metal coordination, π-stacking, halogen bonding and
hydrophobic interactions.[2] Altering the structural information
encoded in the molecular recognition unit that comprises a
supramolecular monomer enables tuning of the supramolecular
assembly and ultimately the properties derived from these
assemblies.[3]
Our previous work established
relationship in [n.n]pCpTAs by comparing [2.2]pCpTA to its
bridge-expanded homolog [3.3]paracyclophane-5,8,14,17-
tetracarboxamide ([3.3]pCpTA).[12] It was shown that while the
a structure–property
1
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Figure 2. The [n.n]pCp-anilides studied in this work.
Figure 1. A representation of the hydrogen bond directed self-assembly of
[n.n]pCpTA compared to [n.n]pCpNTA. Amide connectivity highlighted in
green for emphasis.
Herein, we report the synthesis, transannular hydrogen
bonding characterization, and self-assembly of new [n.n]pCp
derivatives based on anilide hydrogen bonding. We present two
monomers: the self-assembling “cross” [2.2]pCp-4,7,12,15-
tetraanilide ([2.2]pCpNTA (±)-1) and [3.3]pCp-5,8,14,17-
tetraanilide ([3.3]pCpNTA (±)-2), along with two comparator
assembly geometry remained optimized, the additional carbon in
the covalent bridge provided an increase in monomer entropy due
to the scissoring action of the bridge chair/boat interconversion
process. The results represent a flexibility–complementarity
dichotomy[13] in SPs where the approximately equal
complementarity in [2.2]pCpTA and [3.3]pCpTA assembly, but
increased flexibility in [3.3]pCpTA, led to a weaker assembly.
We envision the [n.n]pCpTA scaffold to be particularly
useful for developing structure–property relationships in SPs as
the extensive preorganization of the monomer prevents
significant structural changes upon intermolecular association,
and so changes in assembly can be largely attributed to
optimization of noncovalent interactions.
molecules:
the
pseudo-ortho
[2.2]pCp-4,12-bisanilide
([2.2]pCpNBA (±)-3), and the mono- [2.2]pCp-4-anilide
([2.2]pCpNMA (±)-4). The self-assembling [n.n]pCpNTA
systems are studied in solution and the solid state and related to
the mono- [2.2]pCpNMA and pseudo-ortho [2.2]pCpNBA
transannular H-bonding comparators in the absence of assembly.
Alkyl chains ((±)-1–4a, R = C5H11) gave remarkable solubility in
organic solvents for solution studies, while aromatic sidechains
((±)-1–3b, R = Bn) were chosen for single crystal X-ray diffraction
studies (Figure 2).
Previous studies of [n.n]pCpTAs were performed on
amides with Car–C=O connectivity (C-amides or carboxamides).
Analogous to various experiments done with the benzene
trisamide (BTA) family of monomers,[14] our interest extended to
different hydrogen bonding units, especially those featuring
amides with Car–N–C=O connectivity (N-amides or anilides). A
similar analysis of amide connectivity has been undertaken in the
1-D supramolecular polymerization of BTA derivatives, and C3-
symmetric oligo-phenylene ethynylene (OPE) derivatives.[15] In
the case of BTAs it was found that the assembly of both amide
derivatives was cooperative, with the anilides exhibiting a weaker,
less cooperative assembly. In the OPE derivatives, the opposite
was found. While both derivatives assemble cooperatively, the
OPE anilides exhibited stronger assembly and greater
cooperativity compared to the carboxamides. The uniquely rigid
structural and conformational control of [n.n]pCps motivated us
to examine the influence of amide connectivity and how it
influences [n.n]pCp self-assembly (Figure 1).
Results and Discussion
Calculations
Molecular modelling and gas-phase DFT calculations of
[n.n]pCpTA derivatives proved useful for examining amide
conformations and how they relate to assembly structure and
thermodynamics.[10] Geometry optimization of [n.n]pCp-anilides
and previously studied [n.n]pCpTA monomers and dimers was
performed at the ωB97X-D/6-31G level of theory rather than
previously employed M06-2X/6-31G to better account for the
influence of dispersion forces when studying noncovalent
interactions (summarized in Tables S11–17).[16] The ground state
of the [n.n]pCp-carboxamides feature amides that tilt out of the
arene plane to relieve A1,3 strain with the bridge hydrogens and
either the carbonyl oxygen or secondary amide nitrogen. The
2
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Figure 4. Optimized geometries of [2.2]pCpNTA and [3.3]pCpNTA anti- dimers
from DFT calculations with important structural parameters highlighted.
Figure 3. Thermodynamics of anilide conformers for simple 4,12-pseudo-ortho
(a) and 4,16-pseudo-para [2.2]pCp-bisanilides from DFT calculations.
in [2.2]pCpNTA (32.7°, –141.7°, anti- conformer) are slightly
smaller than those observed for [2.2]pCpTA (39.6°, –147.3°, anti-
conformer), indicating the intermolecular π⋯π distance could be
slightly closer than that of the [2.2]pCpTAs upon optimization of
intermolecular hydrogen bonding. The extension of the
paracyclophane bridge by one carbon also increases the torsion
of the anilides to maintain optimum transannular hydrogen
bonding in the [3.3]pCpNTA derivatives, and further in the
[3.3]pCpTA derivatives.
anilides have less A1,3 strain due to the smaller size of the N–H
group, and therefore have
a stable planar conformation.
Calculations of the various [n.n]pCp-anilides reveals that in the
absence of transannular hydrogen bonding, the anilide is
coplanar with the aryl ring to maximize conjugation with the sp2
hybridized nitrogen (see Table S14).
Comparison of the computed structures and energies of both
syn- and anti- [n.n]pCpNTA dimers reveals the thermodynamic
favorability for assembly of the anti- conformer (syn = + 11.9 kcal
mol–1 for [2.2]pCpNTA, syn = + 16.8 kcal mol–1 for [3.3]pCpNTA),
consistent with what was observed in prior work for [2.2]pCpTA
and [3.3]pCpTA.[8, 10, 12] Extrapolation of the computational results
of [2.2]pCpTA[10] indicate that, if anilide rotation (about the Car–N
bond) still maintains a low barrier, the assembly of [n.n]pCpNTAs
likely occurs through pathway selection of the anti- conformer and
adheres to an isodesmic mechanism.[10]
Interestingly, the computed gas-phase interaction energies—
obtained from the difference in energy of a geometry optimized
dimer compared to two isolated monomers—reveals a 4.3 kcal
mol–1 larger interaction energy for [2.2]pCpNTA anti- compared
to [2.2]pCpTA anti- (–46.2 kcal mol–1 for [2.2]pCpNTA compared
to –41.9 kcal mol–1 for [2.2]pCpTA). The syn- conformers have >
7 kcal mol–1 less binding energy than the anti- conformers
(summarized in Table S15). Similarly, the [3.3]pCpNTA anti-
dimer (–50.3 kcal mol–1) has a 7.2 kcal mol–1 larger interaction
energy than the [3.3]pCpTA anti- dimer (–43.1 kcal mol–1,
summarized in Table S17). The interaction energy for
[3.3]pCpNTA is ca. 4 kcal mol–1 larger than that of [2.2]pCpNTA.
The reasons become clear when the dimer geometries are
examined, with the [2.2]pCpNTA dimer featuring longer H-
bonding distances and shorter π⋯π distances (Figure 4) which
should contribute to a weaker binding enthalpy. Although the gas
phase estimation of interaction energy is an oversimplification of
a dynamic solution environment, it indicates the potential for
stronger assembly of [n.n]pCpNTAs compared to [n.n]pCpTAs,
as well as stronger assembly of [3.3]pCpNTA compared to
[2.2]pCpNTA.
Simple [2.2]pCp-anilides are used to examine the energetic
and geometric preferences for anilides in the presence and
absence of transannular hydrogen bonding. [2.2]pCp-
Monoanilides exhibit two local minima (Figure S56)
corresponding to mostly coplanar (Erel = 0 kcal mol–1) and slightly
tilted (Erel = +1.9 kcal mol–1) anilides. Pseudo-ortho positioned
anilides—such as those in (±)-3, for example—can rotate out of
the plane of the aromatic deck to optimize the geometry of
transannular deck-to-deck hydrogen bonding (Figure S48).
When the anilides rotate out of plane of the aryl ring to
participate in transannular hydrogen bonding, the pseudo-ortho
bisanilide gains back the enthalpic stabilization it loses from the
loss of conjugation between the aryl deck and the sp2 hybridized
nitrogen plus the free energy gain from an anilide hydrogen bond
(ΔE = –2.5 kcal mol–1, Figure 3a). The hydrogen bonding
stabilization does not occur in the pseudo-para derivative, making
its anilide tilting unfavorable (ΔE = +4.1 kcal mol–1, Figure 3b).
Comparing the tilted (H-bonded) conformer of 4,12-pseudo-ortho
[2.2]pCp-bisanilide with the tilted conformer of 4,16-pseudo-para
[2.2]pCp-bisanilide can reveal the strength of transannular H-
bonding (9.6 kcal mol–1)—nearly the same as that observed when
comparing the analogous [2.2]pCp-biscarboxamides (10.5 kcal
mol–1).
Similar to [2.2]pCpTA, there are two low energy conformers
of [2.2]pCpNTA, depicted in Figure S50. The syn- (Erel = +0.32
kcal mol–1) and the anti- (Erel = 0 kcal mol–1) conformers differ in
H-bonding directionality with respect to the assembly axis. The
relative stability of the anti- conformer holds true for the
[3.3]pCpNTA series as well, with the syn- conformer disfavored
by 2.2 kcal mol–1. Especially important is the anilide conformation
with respect to the C5–C4–N–C(=O) dihedral angle, which we
have previously shown to be intimately linked to the
intermolecular π⋯π distance.[12] In this case, the dihedral angles
Synthesis
3
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Figure 5. Trimer of (Rp)-1b obtained from single crystal X-ray diffraction with
average distances highlighted (a). Hydrogen bonds shown in magenta. Crystal
packing of columnar homochiral stacks in the unit cell of (±)-1b viewed as a
space filling model (b). Hydrogen atoms not involved in hydrogen bonding,
disorder, solvent molecules, and benzyl sidechains omitted for clarity. Ellipsoids
in (a) shown at the 50% probability level. Atom color code: O red, N blue, C gray,
H white.
Scheme 1. The synthesis of [n.n]pCp-anilide target molecules (±)-1–4a and
(±)-1–3b. Reagents: a Pd(dppf)Cl2 (5–20 mol%), benzophenone imine (2.5
equiv/Br), NaOtBu (1.5 equiv/Br), toluene, 110 °C, 48 h; b HCl (conc.), THF, rt,
8 h; c THF, NEt3, RCOCl, rt, 12 h; d NaOH, RCOCl, toluene rt, 12 h. Yields for
(±)-7 and (±)-8 reported as amines after aq. NaOH wash and extraction with
DCM.
was performed in the same flask to minimize decomposition.
Acylation of the amino-[n.n]pCps with hexanoyl chloride gave
n-pentyl substituted anilides (±)-1–4a suitable for solution studies,
while phenylacetyl chloride was used to give benzyl anilides (±)-
1–3b for study by single crystal X-ray diffraction. For the final
acylation, either NEt3 in THF or Schotten–Baumann reaction
conditions (toluene and aq. NaOH) worked equally well. Once the
synthesis of [2.2]pCpNTA was completed and optimized, the
approach was easily extended to the [3.3]pCpNTA system
beginning with the synthesis of (±)-10 under identical conditions
as (±)-9. Best results were obtained for the synthesis of (±)-1a and
(±)-2a by performing hydrolysis and acylation in the same reaction
vessel, as isolation of the ammonium salts proved troublesome,
and was accompanied by decomposition. Overall yields for the
synthesis of target molecules (±)-1a (27%) and (±)-2a (29%) from
the corresponding tetrabromides (±)-13 and (±)-14 were quite
reasonable.
Worth noting is the outstanding solubility of (±)-1–3a in
nonpolar solvents such as methylcyclohexane. Concentrated
solutions of (±)-1a (up to 50 mM in MCH) could be prepared and
were soluble for weeks. Similarly concentrated solutions of
[2.2]pCpTA with n-hexyl sidechains would precipitate after ~1
day. Even (±)-4a, with only one H-bonding unit and no
intramolecular H-bonding, could not be dissolved in MCH at room
temperature.
Surprisingly, until now, only one example of a [2.2]pCp with
four nitrogen substituents directly bound to the [2.2]pCp ring
system (all benzophenone imines) has been reported.[17] Unlike
other examples in that work, the 4,7,12,15-[2.2]pCp-
tetra(benzhydrilideneimine) was not hydrolyzed to the free
tetraamine (conc. HCl in THF, then NaOH), presumably, and later
confirmed by our work, because of the instability of this incredibly
electron rich aromatic amine complicating isolation and
characterization. We imagined this crucial 4,7,12,15-[2.2]pCp-
tetraamine could come from the known intermediate 4,7,12,15-
[2.2]pCp-tetra(benzhydrilideneimine), and upon hydrolysis and
acylation, promote the synthesis of [2.2]pCpNTA. The
comparator [2.2]pCpNBA and [2.2]pCpNMA could come from
the corresponding known monoamines by simple acylation
chemistry. Upon optimization of the synthesis of [2.2]pCpNTA
beginning with commercially available [2.2]pCp, we envisioned
adapting the same procedures to the [3.3]pCp system starting
from previously prepared “crossed” 5,8,14,17-[3.3]pCp-
tetrabromide.[12]
The synthesis of N-substituted [2.2]pCps (Scheme 1) began
from the corresponding [2.2]pCp bromides,[18] which underwent
Buchwald–Hartwig coupling with the ammonia equivalent
benzophenone imine under palladium catalysis.[17] Imino
[2.2]pCps could be hydrolyzed to the corresponding ammonium
salts with HCl in THF. Deprotonation to the free amine was
accompanied by instant decomposition in (±)-5 and slower
decomposition of (±)-7 and (±)-8 in solution accompanied by the
formation of a deep blue-green color. Therefore, deprotonation of
the ammonium salts and reaction with an appropriate electrophile
X-ray crystallography
Crystals of (±)-1a were composed of tightly bundled needle-
like fibers, so an aromatic benzyl sidechain was introduced to (±)-
1b to aid in single-crystal growth. Single crystals of suitable quality
for X-ray diffraction were grown by slow evaporation from an
EtOAc/EtOH solution.
The infinitely extended self-complementary SP structure of
(±)-1b is observed in the crystal, giving insight into structural
4
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factors that likely govern solution-phase SP formation. Selected
average interatomic distances for the X-ray structure of (±)-1b are
shown in Figure 5a. All the molecules of 1b are engaged in
intermolecular hydrogen bonding to neighboring 1b molecules
through anti- aligned anilides, with slightly longer H-bonds than in
[2.2]pCpTA (average N⋯O distance 2.88 Å for 1b compared to
2.84 Å for [2.2]pCpTA).[8] Every fourth repeat unit, one H2O
molecule provides one H-bond donor and acceptor between
anilides of (±)-1b. Remarkably, the intermolecular π⋯π distances
(centroid⋯centroid) in the X-ray structure of (±)-1b are much
closer than those of the C-centered derivative (average distance
of 3.5 Å for (±)-1b compared to 3.8 Å for [2.2]pCpTA). This closer
π⋯π distance is accompanied by a slight slippage of the π-
surface between (±)-1b monomers (centroid⋯centroid⋯centroid
angle of 160° compared to 172° in [2.2]pCpTA). It is well
accepted that the sandwich-type stacking of benzene rings is the
least favorable arrangement, and that the interaction energy of
the benzene dimer increases as the parallel stacks increase their
displacement.[19] Therefore, the slight slippage of the
intermolecular π-decks can lead to a decrease in repulsive π⋯π
interactions compared to [2.2]pCpTA, while still optimizing
intermolecular and transannular H-bonding.
helical anti- aligned anilide hydrogen bonding with the benzyl
sidechains, and 1,4-dioxane solvent molecules, filling the space
between individual stacks. Consistent with our previous crystal
structure of [3.3]pCpTA, the central bridge carbon is disordered,
representing a likely combination of chair and boat bridge
conformers.[12, 20]
Although the intermolecular N⋯O distance in (±)-2b (2.87 Å)
is nearly identical to (±)-1b, the average transannular N⋯O
distance in (±)-2b (2.80 Å) is considerably shorter as the anilides
in (±)-2b rotate further out of the aryl plane in order to optimize
transannular hydrogen bonding across a longer deck-to-deck
distance (Figure 6a). The consequence is two anilides that rotate
nearly orthogonal to the aryl plane (θ = 87.3°, 72.8°). These
extremely tilted anilides are accompanied by anilides with
shallower dihedral angles (ca. 30–40°) to give the assembly a
distinct “major and minor groove” (Figure 6b). The large range of
anilide dihedral angles (28–87°) is a simultaneous result of the
increased deck-to-deck distance, and the increased A1,3 strain
encountered with aryl substituents in the 5-position of the
[3.3]pCp skeleton. When the monomer is placed in a dynamic
solution-phase environment, all anilide, and bridge conformations,
are likely represented.
The unit cell of (±)-1b is vast (nearly 25,000 Å3), containing 24
molecules of (±)-1b as well as several EtOH and H2O solvent
molecules positioned between the stacks. This unit cell is
composed of eight individual homochiral assemblies. These
assemblies can be further divided in half along the c-axis to give
two sets of four (two Rp, two Sp) stacks. Each of the four stacks
extends in parallel to the others in the set, and at an angle of
approximately 25° to the other set of four stacks (Figure 5b, see
also Figure S39).
Figure 7. ORTEP plot of (Rp)-3b at the 50% probability level from X-ray
diffraction with transannular hydrogen bond shown as magenta dashed line (a).
Atom color code: O red, N blue, C gray, H white. Unit cell of (±)-3b with (Sp)-3b
shown in light blue, (Rp)-3b shown in purple, and ethyl acetate shown in green
(b). Hydrogen bonding propagation alternating between transannular H-bond
and intermolecular H-bond between (Sp)-3b and (Rp)-3b. H-bonds shown in
magenta.
Figure 6. Trimer of (Rp)-2b obtained from X-ray diffraction with average
distances highlighted (a). Hydrogen bonds shown in magenta. Crystal packing
of (±)-2b featuring homochiral hexamers extending beyond the unit cell (b).
Hydrogen atoms not involved in hydrogen bonding, solvent molecules, disorder,
and benzyl sidechains omitted for clarity. Ellipsoids in (a) shown at the 50%
probability level. Atom color code: O red, N blue, C gray, H white.
Crystals of (±)-2a exhibited the same needle-like morphology
as (±)-1b, necessitating the introduction of benzyl sidechains in
(±)-2b. Single crystals of (±)-2b sufficient for X-ray diffraction were
grown by slow evaporation of a 1,4-dioxane solution. Similar to
(±)-1b, (±)-2b in the crystal displays the 1-D columnar structure of
its self-complementary SP. The unit cell of (±)-2b features a pair
of enantiomeric homochiral tetramers stitched together by double
To further examine the transannular hydrogen bonding
between pseudo-ortho (i.e., 4,12-substituted) anilides present in
(±)-1–3 without the influence of the second pair of anilides (i.e.,
7,15-substituted), single crystals of the transannular H-bond
comparator (±)-3b were grown by slow evaporation of an
5
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EtOH/EtOAc solution. The transannular H-bond is maintained
(Figure 7a, N⋯O distance = 2.85 Å) and is slightly shorter than
that in pseudo-ortho [2.2]pCp-biscarboxamide (N⋯O distance =
2.90 Å).[9] The unit cell of (±)-3b features four molecules of 3b (two
of (Rp)-3b and two of (Sp)-3b) and four EtOAc solvent molecules
(Figure 7b). In contrast to pseudo-ortho [2.2]pCp-bisamide, which
formed intermolecular H-bonds with MeOH solvent molecules, 3b
forms self-complementary anilide hydrogen bonds (N–H⋯O)
between molecules of opposite configuration (Figure 7c, N⋯O
distance 2.81 Å). The heterochiral association of (±)-3b in the
solid state is an example of the three-point contact rule for
homochirality,[21] and confirms the necessity of a second
intermolecular interaction to instruct stereospecific self-assembly
like that observed in (±)-1b and (±)-2b.
assembling [n.n]pCps[8, 10, 12] and is likely a result of pathway
selection of the anti- conformer.
The stronger assembly of (±)-1a compared to [2.2]pCpTA is
also confirmed by cooling a solution of (±)-1a (10 mM) in CDCl3.
As the solution is cooled, the anilide N–H (Ha and Hb) and
aromatic C–H (Hc and Hd) resonances decoalesce when anilide
rotation slows on the NMR timescale (Figure 8d). The resolution
of these individual resonances is caused by intermolecular H-
bonding between associated monomers of (±)-1a raising the
barrier for anilide rotation, since rotating the anilides in an
elongated assembly would require breaking consecutive
intermolecular and transannular H-bonds. For comparison, the
It should be noted that the X-ray crystallographic data
obtained for compounds (±)-1–3b with aromatic sidechains is
expected to be different than that of compounds (±)-1–3a with
aliphatic sidechains. Care should be taken when comparing data
between related compounds where sidechain packing influences
the crystal structure, but in the absence of suitable crystals for (±)-
1–3a, analysis of (±)-1–3b represents the best approximation of
assembly structure.
Solution studies
Solution-phase assembly characterization of [n.n]pCp-
anilides (±)-1–4a was carried out using 1H NMR and FT-IR
spectroscopy. In the assembled state, (±)-1a possesses two non-
equivalent anilide N–Hs corresponding to transannularly H-
bonded Ha and intermolecularly H-bonded Hb as well as two non-
equivalent aromatic C–Hs corresponding to hydrogens ortho to
each respective anilide (Hc, Hd, Figure 8a). In moderately polar
solvents like CDCl3, anilide rotation is fast on the NMR timescale,
and the anilide N–H resonances represent a time average of the
transannularly H-bonded, intermolecularly H-bonded, and solvent
exposed environments. The chemical shift of the N–H resonance
in transannular H-bond comparator (±)-3a can be used as a
reference for
a
molecularly dissolved (±)-1a, lacking
Figure 8. Assignments of 1H NMR chemical shifts for (±)-1a in the assembled
state (a). Variable concentration (0.025–30 mM) 1H NMR of (±)-1a in CDCl3 (b)
and fitting of the concentration-dependent change in anilide N–H chemical shift
to an isodesmic model (c). Low temperature (25 to –30 °C) 1H NMR of (±)-1a
(10 mM) in CDCl3 (d).
intermolecular H-bonding since its association constant in CDCl3
was shown to be negligible from 0.1–30 mM (Figure S5). An
increase in concentration of (±)-1a (R = C5H11) in CDCl3 results in
a deshielding of the anilide N–H resonance and a shielding of the
aromatic C–H resonance due to an increase in H-bonding and π-
stacking, respectively (Figure 8b). This trend is similar to what is
observed in the previously reported [n.n]pCpTAs.[8] The
concentration change (0.025 mM to 30 mM) sees the chemical
shift of the anilide N–H move from near molecularly dissolved at
8.13 ppm towards aggregated at 8.91 ppm (Δδ = 0.78 ppm). For
reference, the chemical shift of (±)-3a varies between 8.18 and
8.07 ppm (Δδ = 0.11 ppm) from 30–0.1 mM indicating very weak
intermolecular association. Fitting the change in the anilide N–H
chemical shift of (±)-1a to an isodesmic model gives an elongation
constant (Ke) of 2175 ± 90 M–1 (Figure 8c),1 over 30-fold higher
than that observed for the C-centered isomer (Ke = 64 ± 5 M–1).
Despite the same number of intermolecular H-bonds, the
assembly of (±)-1a is more thermodynamically favorable than that
of [2.2]pCpTA under the same conditions (ΔΔG° = –2.1 kcal mol
–1). The isodesmic mechanism is consistent with analogous self-
amide N–H and aromatic C–H resonances of [2.2]pCpTA in
CDCl3 remain coalesced down to the same temperatures,
indicating stronger assembly in (±)-1a.[8] Solutions of (±)-3a
exhibit only one anilide N–H resonance down to –50 °C (Figure
S14), confirming the change is a result of intermolecular assembly.
Analogous to (±)-1a, compound (±)-2a in the assembled state
possesses two non-equivalent anilide N–Hs (Ha’ and Hb’) and two
non-equivalent aromatic C–Hs (Hc’ and Hd’) if chair/boat
interconversion and anilide rotation remain fast on the NMR
timescale (Figure 9a). Variable concentration NMR of (±)-2a
shows an identical trend to (±)-1a as the anilide resonance Ha’/Hb’
becomes deshielded upon an increase in concentration due to
hydrogen bonding (8.25 ppm at 0.025 mM to 9.20 ppm at 30 mM,
Δδ = 0.95 ppm) and the aromatic C–H resonance Hc’/Hd’ becomes
shielded (6.84 ppm at 0.025 mM to 6.10 ppm at 30 mM) due to π-
1 Uncertainty of data fitting reported. Error estimated as ± 15 %.
6
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stacking (Figure 9b). Fitting the change in chemical shift of Ha’/Hb’
for (±)-2a in CDCl3 to an isodesmic model gives an elongation
constant (Ke) of 5303 ± 277 M–1 (Figure 9c), indicating a
thermodynamically more stable assembly for (±)-2a compared to
(±)-1a. The assembly of (±)-2a compared to C-centered
[3.3]pCpTA is ~300-fold stronger based on comparison of Ke
(17 M–1 for [3.3]pCpTA in CDCl3). The chemical shift of the N–H
resonance in the assembled state of (±)-2a (9.20 ppm) is slightly
deshielded compared to that in (±)-1a (8.91 ppm) indicating the
hydrogen bonding geometry of (±)-2a could be slightly more
favorable as observed in DFT calculations of the [n.n]pCpNTA
dimers.
and resolution of the four individual anilide N–H (Ha and Hb) and
aromatic C–H resonances (Hc and Hd) expected in the assembled
state. Assembly of (±)-1a in cyclohexane-d12 is maintained even
at low concentrations (0.1 mM) and high temperatures (70 °C, see
Figure S10), further evidence that the assembly of (±)-1a is
stronger than that of [2.2]pCpTA, which disassembles when
heated in cyclohexane-d12. Additionally, it was found that adding
a small volume fraction of CDCl3 to the cyclohexane-d12 solution
could break up the polymeric structures of (±)-1a (Figure S11).
Assembly state can be confirmed by examining the
characteristic H-bonding energies of the C=O and N–H stretches
with IR spectroscopy (Figure 10, summarized in Table S7).
Figure 10. Overlaid and normalized FT-IR spectra of the N–H (a) and C=O (b)
regions of (±)-1–4a 10 mM in CHCl3 and MCH.
Solutions of [2.2]pCp-anilides (±)-1–4a in solvents like
chloroform, which favor the molecularly dissolved state,exhibit a
solvent exposed N–H (~3430 cm–1) and a broad, H-bonded N–H
(comprised of overlapping intermolecularly and transannularly H-
bonded N–Hs) that moves to lower energy with increasing
concentration (3303–3244 cm–1).[9] Solutions of monoanilide (±)-
4a in chloroform feature only a solvent exposed N–H (3445, 3425
cm–1), while positioning of a second anilide in the pseudo-ortho
position facilitates transannular H-bonding, and a second, H-
bonded N–H appears (3303 cm–1). The intermolecular assembly
of (±)-1a in chloroform, as evidenced by 1H NMR, is confirmed by
the shift of the H-bonded N–H to lower energy (3264 cm–1 at 1
mM to 3244 cm–1 at 30 mM). The H-bonded N–H in (±)-2a follows
the trend observed in (±)-1a but its peak appears at lower energy
(3234 cm–1) at the same concentration, again indicating the slight
geometric preference for H-bonding in (±)-2a.
Similarly, the C=O signal of [n.n]pCp-anilides (±)-1–4a is
sensitive to transannular H-bonding and intermolecular assembly.
The peak corresponding to the C=O stretch in CHCl3 moves from
1687 cm–1 in molecularly dissolved (±)-4a to 1671 cm–1 in
transannular H-bonding (±)-3a, to 1658 cm–1 and 1644 cm–1 in
assembling (±)-1a and (±)-2a, respectively.
When (±)-3a is dissolved in MCH, it is capable of weak
intermolecular association, evidenced by the decrease in intensity
of the solvent exposed N–H and shift of the H-bonded N–H to
lower energy (3258 cm–1). Similarly, (±)-1a and (±)-2a in MCH are
exclusively in the assembled state and show a single, broad H-
bonded N–H (3239 cm–1 in (±)-1a, 3226 cm–1 in (±)-2a) and no
solvent exposed N–H, indicating high degrees of polymerization
and lack of appreciable end groups, consistent with what has
been observed in other self-assembling [n.n]pCps. This N–H
Figure 9. Assignments of the chemical shifts of (±)-2a in the assembled state if
chair/boat interconversion remains time averaged (a). Variable concentration
(0.025–30 mM) 1H NMR of (±)-2a in CDCl3 at 298 K (b). Fitting of the NMR data
from (b) to an isodesmic model (c). Variable temperature 1H NMR of (±)-2a 10
mM in CDCl3 (d).
Further evidence for the stronger assembly of (±)-2a
compared to (±)-1a comes by cooling a 10 mM solution of (±)-2a
in CDCl3. The same decoalescence due to slow anilide rotation in
(±)-1a at –20 °C was observed at 0 °C for (±)-2a, indicating
stronger intermolecular assembly at higher temperatures (Figure
9 9d). DOSY NMR was used to confirm concentration-dependent
polymeric assemblies of (±)-1a and (±)-2a that were larger than
those of the corresponding [n.n]pCpTAs under identical
conditions in CDCl3, although the diffusion coefficients for (±)-1a
and (±)-2a were nearly identical and could not confirm larger
polymeric structures for (±)-2a compared to (±)-1a (Table S3–4).
When (±)-1a and (±)-2a are dissolved in cyclohexane or
methylcyclohexane (MCH)—nonpolar, assembly favorable
solvents—the solutions exhibit the viscosity of honey at millimolar
concentrations,
a hallmark feature of SPs. Intermolecular
assembly is evidenced for (±)-1a by 1H NMR in cyclohexane-d12,
where persistent H-bonding causes broadening of all resonances
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signal is independent of concentration (from 1–30 mM),
consistent with what is observed by H NMR, and occurs at the
same energy as the solid-state N–H where all H-bonds are
satisfied.
For [n.n]pCpNTAs, the opposite trend is observed. The
[3.3]pCpNTA assembly has increased flexibility, but now is
accompanied by a more complementary binding geometry. This
increased complementarity overrides the flexibility, leading to
overall stronger supramolecular assembly. The supramolecular
polymerization of the tetraanilides (±)-1a and (±)-2a in solution
adhere to an isodesmic mechanism likely through pathway
selection of the anti- conformer,[10] with a Ke in CDCl3 that is 30–
300-fold larger than their C-centered analogs despite the same
number of intermolecular hydrogen bonds. Crystal structures of
(±)-1b and (±)-2b reveal their preference for homochiral
assemblies in the solid state while heterochiral interactions in (±)-
3b confirm the need for a second H-bond to maintain homochiral
assembly.
The difference in solution-phase assembly thermodynamics is
attributed to the preferred slipped stack orientation of monomers
in (±)-1 and (±)-2, and the more complementary H-bonding
geometry in (±)-2 compared to (±)-1 revealed by computations,
and confirmed by X-ray crystallography, NMR, and IR
spectroscopy.
This work demonstrates the large influence that seemingly
small structural changes can have on supramolecular assembly,
and highlights the utility that [n.n]pCps play as model systems for
controlling SP structure, stereochemistry, mechanism, and
thermodynamics. Until now, efforts to determine the influence of
amide connectivity on 1-D SPs have focused on systems that self-
assemble by cooperative mechanisms. The structural definition of
[n.n]pCps allows for the control of H-bond polarization through
transannular hydrogen bonding. The result is an isodesmic
assembly regardless of hydrogen bonding unit, with the difference
between assembly thermodynamics attributed solely to
differences in noncovalent binding.
1
Evaluation of the thermodynamics of assembly for SPs in
dilute nonpolar solution can be done with UV-vis spectroscopy.
The strength of the assembly of (±)-1a in nonpolar solvents such
1
as cyclohexane or MCH as evidenced by H NMR indicates that
the assembly should be persistent at micromolar concentrations
used for UV-vis, even at high temperatures. This is confirmed by
UV-vis spectroscopy where variable temperature UV-vis of (±)-1a
and (±)-2a (10 μM in MCH) revealed no clear isosbestic points
(Figure S30), supporting the predominance of the assembled
state at these concentrations and temperatures. Attempts to
break up the assemblies with the addition of CHCl3 resulted in the
major absorbance overlapping with the absorbance of CHCl3
(Figure S31).
The results of our previous studies[9] indicate that circular
dichroism spectroscopy of resolved amido [2.2]pCps have strong
absorbances up to 350 nm. We believe that optical resolution will
allow evaluation of assembly thermodynamics in dilute solution
with CD spectroscopy using the appropriate solvent
polarity/concentration combination. These studies are currently
underway.
Conclusions
We have presented SPs based on [n.n]pCp-anilides (n = 2,3)
as a way to examine the influence of amide connectivity on the
supramolecular polymerization of [n.n]pCps. The change of
amide connectivity from previously studied C-centered
carboxamides to N-centered anilides led to a significant increase
in Ke for monomers (±)-1 and (±)-2 in chloroform. The connectivity
change is also accompanied by changes in anilide conformation Experimental Section
which were explored through computations and by the synthesis
of non-assembling comparators (±)-3 and (±)-4. The transannular
anilide H-bond is maintained in the pseudo-ortho derivative (±)-3
in solution and in the solid state, while anilide rotation remains fast
on the assembly timescale.
For experimental details, see the Supporting Information.
Acknowledgements
Underpinning
the
H-bond
directed
assembly
of
[n.n]pCpNTAs is a balancing act between enthalpically favorable
formation of hydrogen bonds and enthalpically unfavorable face-
to-face benzene stacking. Based on computational results, X-ray
crystallographic evidence, and solution studies, the stronger
solution-phase assembly of (±)-1 and (±)-2 compared to their C-
centered [n.n]pCpTA counterparts can be attributed to subtle
changes in intermolecular geometry. In the assembly of (±)-1, for
example, despite average longer H-bonding distances and closer
π⋯π distances—which should result in a weaker assembly—the
slipped stacking of the aryl rings reduces the enthalpic penalty
associated with a repulsive sandwich π–π interaction, leading to
a net larger binding energy. The same trend is apparent in (±)-2
where larger anilide dihedral angles lead to a longer π⋯π
distance and allow further optimization of intermolecular H-bonds.
The flexibility–complementarity dichotomy[13] can be invoked to
assess differences in assembly strength in the [n.n]pCp
derivatives.
Acknowledgement is made to the Donors of the American
Chemical Society Petroleum Research Fund (PRF #56665-ND4)
and to the National Science Foundation (CHE-1904534) for
funding support of this research. K.A.A. wishes to acknowledge
the NSF and the University of Florida for funding of the X-ray
diffractometer through grant CHE-1828064. We acknowledge
University of Florida (UF) Research Computing for providing
computational resources and support that have contributed to the
research
results
reported
in
this
publication
(https://www.rc.ufl.edu). The mass spectrometric data were
obtained by the UF Department of Chemistry Mass Spectrometry
Research and Education Center supported, in part, by the
National Institutes of Health (NIH S10 OD021758-01A1). We
would also like to thank Ion Ghiviriga and the UF Center for
Nuclear Magnetic Resonance Spectroscopy for providing
equipment and support that have contributed to these published
results.
In our previous report,[12] the similar hydrogen bonding
complementarity between [2.2]pCpTA and [3.3]pCpTA but an
increase in flexibility for [3.3]pCpTA led to a weaker assembly.
Conflict of interest
The authors declare no conflict of interest.
8
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Keywords: cyclophanes, hydrogen bonds, polymer, self-
assembly, supramolecular
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Entry for the Table of Contents
Cyclophane supramolecular polymers: [n.n]Paracyclophanes equipped with four anilide (N-centered amide) hydrogen bonding
units ([n.n]pCpNTA) self-assemble by an isodesmic mechanism to give supramolecular polymers. The elongation constant for
[n.n]pCpNTA assembly is two orders of magnitude larger than previously described [n.n]pCpTAs with C-centered amides.
Institute and/or researcher Twitter usernames: @UFChemistry, @CastellanoLabUF
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