Experimental study of the cooperativity of CH-π interactions

Article abstract of DOI:10.1021/ol5014729

A series of new torsional molecular balances was designed to study the cooperativity of CH-π interaction in the solid state and in solution. The measured interaction energies correlated better to the number of participating alkyl carbons than to the number of CH-π contacts. The methyl and ethyl groups displayed additive interaction energies. However, the branched isopropyl group displayed strong positive cooperativity with higher than predicted interaction energies.

Full text of DOI:10.1021/ol5014729

Letter
pubs.acs.org/OrgLett
Experimental Study of the Cooperativity of CH−π Interactions
Chen Zhao, Ping Li, Mark D. Smith, Perry J. Pellechia, and Ken D. Shimizu*
Department of Chemistry and Biochemistry, University of South Carolina, Columbia, South Carolina 29208, United States
S
* Supporting Information
ABSTRACT: A series of new torsional molecular balances was designed to
study the cooperativity of CH−π interaction in the solid state and in
solution. The measured interaction energies correlated better to the number
of participating alkyl carbons than to the number of CH−π contacts. The
methyl and ethyl groups displayed additive interaction energies. However,
the branched isopropyl group displayed strong positive cooperativity with
higher than predicted interaction energies.
CH−π interactions are attractive interactions between alkyl and
aromatic groups.1 These weak noncovalent interactions play an
important role in many systems, such as the structure of
biomolecules and macromolecules,2 the selectivity of supra-
molecular systems,1b,3 and the reactivity of organic catalysts.4
However, due to the weak nature and geometric variability of
these interactions, many aspects of CH−π interactions are still
not well understood. One of these is the cooperativity of CH−π
interactions,5 which is observed in crystal structures,6 inside
nanoporous hosts,7 catenanes,8 and enzyme active sites.9 To
study the cooperativity of CH−π interactions, we designed a
small molecule model system that could systematically measure
the CH−π interactions of different sized alkyl groups (Figure 1).
We were particularly interested in whether larger alkyl groups
that form multiple CH−π interactions would show positive or
negative cooperativity.10 These experimental studies would
complement earlier computational studies that found decreasing
interaction energy per carbon as the alkyl group increased in size
(vide infra).5
A number of small molecule model systems have been
developed to study CH−π interactions computationally11 and
experimentally.12 However, few have examined the cooperativity
of the interaction. Therefore, a series of new molecular torsional
balances (1−3) were designed that could form multiple CH−π
interactions, the strengths of which could be accurately measured
in solution via their influence on a conformational equilibrium
(Figure 1). In the folded conformation, the alkyl arm formed
intramolecular CH−π interactions with the aromatic shelf. In the
unfolded conformation, the alkyl arm and arene shelf were far
apart and cannot form such CH−π interactions. Thus, the
folded/unfolded ratios provided a sensitive measure of the
strength of the intramolecular noncovalent interactions.
The new balances shared the same rigid bicyclic N-arylimide
framework as our previous CH−π and π−π balances.13,14 The
oxygen linkers in the previous balances were removed, and the
interacting alkyl groups were directly attached to the pivot ring.
This positioned a greater proportion of the alkyl arms over the
aromatic shelves, allowing up to three carbons on the arms to
form CH−π interactions. The modular design and an efficient
synthesis enabled the systematic variation of the alkyl arms and
aromatic shelves. Balances 1a−c and 2a−c contained large
phenanthrene or pyrene aromatic shelves and three different
alkyl arms (Me, Et, and i-Pr). Control balances 3a−c had the
same alkyl arms but lacked an aromatic shelf of sufficient size for
CH−π interaction. These were designed to measure the effects of
solvation on the conformational equilibria in balances 1 and 2 in
the absence of CH−π interactions. Moreover, these controls
served to cancel out the possible framework effects over the
conformational equilibria in balances with different sized alkyl
Figure 1. (a) Folded−unfolded conformational equilibrium of a
representative molecular torsional balance (1c), which allows measure-
ment of multiple CH−π interactions. (b) Structures of balances 1a−c
and 2a−c and control balances 3a−c.
Received: May 21, 2014
Published: June 19, 2014
© 2014 American Chemical Society
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Letter
arms, such as the weak attractive interactions of the alkyl arms
with the succinimide carbonyl groups in the unfolded con-
formers.15
was a monodentate interaction where only one C−H bond on a
carbon pointed directly toward an aromatic surface (Figure 3a)
X-ray crystal structure analysis confirmed the formation of
CH−π interactions in balances 1a, 1b, 1c, and 2a that contained
the large phenanthrene and pyrene aromatic shelves. Similar
analysis also confirmed the absence of CH−π interactions in
control balances 3a and 3c that contained the small olefinic
shelves. (Figure 2). In 1a and 2a, the methyl groups formed
Figure 3. Schematic representations of the CH−π interactions of the
alkyl arms highlighting the monodenate and bidentate geometries of the
methyl (a, b), ethyl (c), and isopropyl (d) groups.
with shorter H-to-plane distances of <2.7 Å. This monodentate
geometry was observed for the methyl group in 1a and for the
central carbon of the isopropyl group in 1c (Figure 3d). The
second was a bidentate interaction where two hydrogens
attached to a carbon formed separate CH−π interactions with
longer interaction distances (>2.7 Å) (Figure 3b). Examples of
the bidentate geometry were the first carbon of the ethyl group in
1b and the terminal methyl group in 2a.
The formation of two distinct interaction geometries
complicated our analyses. We initially correlated the interaction
strengths with the number of CH−π contracts. However, the
variability in the number of interactions per carbon led to
inconsistent results. Thus, we switched to correlating the
interaction energies with the number of carbons forming
CH−π interactions. This simplification was justified on the
basis of the following arguments. First, previous theoretical
studies5a,11e have observed a good correlation between
interaction energies of the CH−π interaction and the polar-
izability of the alkane, which is approximately proportional to the
number of carbons for simple alkanes. Second, the two types of
CH−π interactions appear to be very close in energy.
Computational studies predicted that the more stable interaction
geometry switches from system to system.11d,17 Similarly, we
observed both geometries for the methyl arms in the crystal
structures of 1a and 2a, suggesting that the two interaction types
were energetically interchangeable. Third, the two interaction
geometries are fundamental features of cooperative CH−π
systems because each interaction type is typically found on
adjacent carbons. Alkyl chains favor a staggered anti-
conformation (Figure 3c and d), which rotates adjacent carbons
to have one and two hydrogens projecting from a particular face.
This alternating pattern of mono- and bidentate interactions was
observed for adjacent carbons in the crystal structures of 1b and
1c.
Next, the intramolecular CH−π interactions were charac-
terized in solution (CDCl3). The analysis was facilitated by the
presence of a distinct set of peaks for the folded and unfolded
conformers in the 1H NMR spectra. These conformers were in
slow exchange at rt due to the restricted rotation of the pivot arm.
First, the formation of intramolecular CH−π interactions in
solution was confirmed by the differences in chemical shift for
specific protons in the folded and unfolded conformers. Large
upfield shifts were observed for the protons on the alkyl arms of
folded-1a−c and folded-2a−c, which were consistent with the
alkyl groups being positioned over the aromatic shelves and
forming CH−π interactions. For example, the protons for the
CH3 groups in folded-1a and folded-2a were shifted 2.08 and 2.60
ppm upfield, respectively. The magnitudes of these shifts were in
Figure 2. X-ray structures of the folded conformers for balances 1a,13b
1b, 1c, and 2a and control balances 3a13b and 3c. For X-ray structures
that contained multiple conformers (2a, 3a, and 3c), a representative
folded conformer is shown. Solvent molecules and the bridgehead
phenyl groups for each balance were omitted for viewing clarity.
CH−π interactions with their respective phenanthrene and
pyrene shelves. In 1b, both carbons of the ethyl group formed
CH−π interactions with the phenanthrene shelf. In 1c, all three
carbons of the isopropyl group formed CH−π interactions with
the phenanthrene shelf. Finally, the crystal structures of 3a and
3c established their viability as control structures. The methyl
and isopropyl arms adopted similar folded structures as in
balances 1 and 2 but did not form intramolecular CH−π
interactions due to the lack of aromatic shelves.
As predicted, the new balances adopted more stable folded
conformers than our previous generation CH−π balances.16
Replacement of the oxygen linker from our previous generation
balances with CH2 and CH units removed a repulsive lone
pair−π interaction and introduced additional stabilizing CH−π
interactions. The greater stability of the folded conformers was
first observed in the solid state. The new balances 1a−c and 2a
crystallized in the folded conformer or as a mixture of folded and
unfolded conformers (Figure 2). This is in contrast to the
previous generation of CH−π balances that exclusively crystal-
lized in the unfolded conformer.13,14 The enhanced stability of the
folded conformers was later extensively characterized in solution
(vide infra).
An interesting feature in the crystal structures of 1 and 2 was
the presence of two distinct types of CH−π interactions. The first
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Letter
good agreement with those calculated for the methane-benzene
CH−π complex (2.29 ppm). Similarly, large upfield shifts were
also observed for terminal folded CH3 protons of the ethyl and
isopropyl arms in balances 1b,c (1.24 and 1.38 ppm) and 2b,c
(1.95 and 2.03 ppm).
these correlations, we could estimate a CH−π interaction energy
of −0.16 and −0.28 kcal/mol per carbon for the phenanthrene
and pyrene surfaces. As expected, these solution-phase values
were significantly smaller than the in vacuo computational values
of −1 to −1.5 kcal/mol per carbon.1
The strengths of the intramolecular CH−π interactions in
solution were calculated from the folded/unfolded ratios (ΔG =
−RT·ln[folded/unfolded]). Integration of the individual con-
In contrast to the additive trends of the methyl and ethyl
balances, the isopropyl balances 1c and 2c displayed higher than
expected folding energies, which were consistent with positive
cooperativity. Based on the CH−π interaction energy of −0.16
kcal/mol per carbon for the 1a and 1b, we predicted a folding
energy of −0.48 kcal/mol for the three-carbon isopropyl 1c.
However, a much larger folding energy of −0.91 kcal/mol was
measured for 1c. Positive cooperativity was also observed for the
isopropyl pyrene balance 2c. Balance 2c had a folding energy of
−1.10 kcal/mol, which was larger than the −0.84 kcal/mol value
extrapolated from the methyl and ethyl pyrene balances 2a−b.
The origins for the positive cooperativity of the larger isopropyl
arms are unclear. One possible explanation is that branched alkyl
groups such as the isopropyl group form stronger CH−π
interactions than linear groups. This trend could be attributed to
the higher polarizability of the branched alkyl groups over the
linear ones. Support for this hypothesis comes from the
computational studies, which show slightly stronger CH−π
interactions for cyclic versus linear alkanes.5
1
formers on the H NMR spectra (CDCl3, 23 °C) yielded the
folded/unfolded ratios and corresponding folding energies. An
initial analysis of the folding energies confirmed that the balances
could effectively measure the intramolecular CH−π interactions.
First, the three control balances 3a−c, which could not form
CH−π interactions in their folded conformers, had very similar
near -zero folding energies (+0.02 to +0.08 kcal/mol). Thus, the
framework and solvation effects of the different alkyl arms did not
impose a large bias on the folded/unfolded ratios. By comparison,
balances 1a−c and 2a−c with arene shelves displayed
successively larger negative folding energies with increasing
size of the alkyl arms. For example, the isopropyl balance 1c had
the largest folding energy, and the methyl balance 1a had the
smallest folding energy for the phenanthrene series. The same
size trend was observed for the pyrene balances 2a−c.
The folding energies for balances 1 and 2 (Figure 4) did not
display the negative cooperativity inferred from the computa-
Overall this experimental study found that multiple CH−π
interactions were either additive or showed positive coopera-
tivity. This is in contrast to the negative cooperativity seen in the
computational studies, which found that the interaction energy
per carbon decreased as the size of the alkyl group increased.5
There are two possible reasons for this discrepancy with the
computational studies. First, the two studies were conducted in
different environments. The computational studies were carried
out in vacuo, and the experimental studies were carried out in
organic solvents. As Cockroft recently demonstrated,18 non-
covalent interactions that are primarily dominated by their
dispersion term are greatly diminished in solution and are instead
dominated by solvophobic effects. A second reason for the
discrepancies are the differences in the geometries of the CH−π
interactions in the computational and experimental studies. The
geometry of the CH−π interactions in this study is closer to the
optimal interaction geometry. Each carbon participating in a
CH−π interaction is positioned over the center of a separate
benzene ring. In contrast, the computational studies were carried
out using a small benzene or naphthalene surface. Thus, larger
alkanes and carbohydrates were crowded on top of these small
aromatic surfaces and had to form weaker CH−π interactions
with the edges of the rings.5
Although the stability trends for the pyrene balances paralleled
those of the phenanthrene balances, the CH−π interactions for
the larger pyrene surface were consistently stronger. For
example, the methyl arm formed a −0.10 kcal/mol stronger
interaction with the pyrene shelf (2a) than with the
phenanthrene shelf (1a). Similarly, the ethyl and isopropyl
arms formed −0.24 and −0.19 kcal/mol stronger interactions
with the pyrene shelves than with the phenanthrene shelves. This
size trend was consistent with a recent computational study by
Patkowski that found that larger aromatic surfaces formed
stronger CH−π interactions.17b As CH−π interactions are
largely dominated by dispersion interactions, these size effects
were attributed to the enhanced dispersion interactions of the
larger aromatic surfaces.11e,17c
Figure 4. Plot of the measured folding energies (ΔG) of balances 1a−c
and 2a−c and control balances 3a−c versus the number of alkyl carbons
forming intramolecular CH−π interactions. The two linear fits were
drawn from data points 3a,b, 1a, and 1b (red dashed line) and 3a,b, 2a,
and 2b (blue dashed line), respectively. The folding energies were
measured by integration of the 1H NMR spectra (23 °C, CDCl3) and
had an estimated error of 0.03 kcal/mol.
tional studies. The smaller methyl and ethyl balances (1a,b, 2a,b)
showed no cooperativity, as their folding energies were almost
perfectly additive, and the larger isopropyl balances (1c and 2c)
showed strong positive cooperativity. The additivity of the
methyl and ethyl balances was evident from the stepwise
increases in their folding energies. For example, ethyl balance 1b
had a folding energy (−0.27 kcal/mol) that was almost exactly
twice the folding energy of methyl balance 1a (−0.13 kcal/mol).
The same stepwise trend was observed between the ethyl and
methyl pyrene balances 2b and 2a, which had folding energies of
−0.51 and −0.23 kcal/mol, respectively.
The additivity of the CH−π interactions in the methyl and
ethyl arms was also analyzed graphically (Figure 4). A linear
correlation was observed between the folding energies and the
number of carbons forming CH−π interactions. For this analysis,
the folding energy for a balance with no carbons forming CH−π
interactions was calculated from the average of the three control
balances 3a, 3b, and 3c (+0.06 kcal/mol). From the slope of
In summary, a series of molecular balances were synthesized
and applied to the study of CH−π interactions and their
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* Supporting Information
Experimental details, characterization data for all newly reported
compounds, and X-ray crystal data for 1b, 1c, 2a, and 3c,
including CIF files. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
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*E-mail: shimizu@mail.chem.sc.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Science Foundation
grants 1310139 and 911616.
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