Electrostatically Driven CO-πAromatic Interactions

Article abstract of DOI:10.1021/jacs.9b06363

A series of N-arylimide molecular balances were developed to study and measure carbonyl-aromatic (CO-π) interactions. Carbonyl oxygens were observed to form repulsive interactions with unsubstituted arenes and attractive interactions with electron-deficient arenes with multiple electron-withdrawing groups. The repulsive and attractive CO-πaromatic interactions were well-correlated to electrostatic parameters, which allowed accurate predictions of the interaction energies based on the electrostatic potentials of the carbonyl and arene surfaces. Due to the pronounced electrostatic polarization of the C=O bond, the CO-πaromatic interaction was stronger than the previously studied oxygen-πand halogen-πaromatic interactions.

Full text of DOI:10.1021/jacs.9b06363

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Communication
Electrostatically driven CO-# aromatic interactions
Ping Li, Erik C. Vik, Josef M. Maier, Ishwor Karki, Sharon M.S. Strickland,
Jessica M. Umana, Mark D. Smith, Perry J Pellechia, and Ken D. Shimizu
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 26 Jul 2019
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Electrostatically driven CO-π aromatic interactions
Ping Li,*,† Erik C. Vik,† Josef M. Maier,† Ishwor Karki,† Sharon M. S. Strickland,‡ Jessica M. Umana,‡
Mark D. Smith,† Perry J. Pellechia,† and Ken D. Shimizu*,†
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†Department of Chemistry and Biochemistry, University of South Carolina, Columbia, South Carolina 29208, United States
‡Department of Biology, Chemistry, and Physics, Converse College, Spartanburg, South Carolina 29302, United States
Supporting Information Placeholder
shelf were also modulated by introducing zero (2(CO)), one
(3 (C O)), tw o (4(C O)) , a nd fou r (5(C O)) fluori ne
ABSTRACT: A series of N-arylimide molecular balances were
developed to study and measure carbonyl-aromatic (CO-π)
interactions. Carbonyl oxygens were observed to form repulsive
interactions with unsubstituted arenes and attractive interactions
with electron-deficient arenes with multiple electron-withdrawing
groups. The repulsive and attractive CO-π aromatic interactions
were well-correlated to electrostatic parameters, which allowed
accurate predictions of the interaction energies based on the
electrostatic potentials of the carbonyl and arene surfaces. Due to
the pronounced electrostatic polarization of the C=O bond, the CO-
π aromatic interaction was stronger than the previously studied
oxygen-π and halogen-π aromatic interactions.
Non-covalent interactions of aromatic surfaces play a key role in
many chemistry, biology, and material science processes,1-4 such as
chemical reactivity and selectivity,5 protein and DNA structure and
function,6-7 and supramolecular assembly.8 A recent example is the
interaction of carbonyl oxygens with aromatic surfaces.9-11 Close
contacts between carbonyl oxygens and the face of aromatic
surfaces are frequently observed in crystal structure database
surveys,11-12 leading to the hypothesis that CO-π aromatic
interactions contribute to the structural stability and functioning of
proteins and other biomacromolecules.13-16 However, experimental
studies measuring CO-arene interactions in solution have not been
reported.17 Therefore, the goal of this work is to systematically
measure CO-π aromatic interactions using a series of N-arylimide
molecular balances to address the questions (Figure 1A): 1) Can
carbonyl oxygens form stabilizing interactions with aromatic
surfaces? 2) What are the strengths of these interactions? 3) Can we
develop a predictive model for the interaction strengths?
The CO-π interactions of aromatic surfaces were measured
using six molecular balances 1(CO) through 6(CO) (Figure 1B).
Restricted rotation of the N-aryl rotor sets up an equilibrium
between folded and unfolded conformers in which the
intramolecular CO-π interactions are formed and broken. Thus,
variations in the intramolecular interaction energies can be
accurately measured via the folded-unfolded equilibrium. Our N-
arylimide molecular balances have been successfully applied to a
wide range of non-covalent interactions, including aromatic
stacking,18-21 heterocycle-π,22 CH-π,23-27 halogen-π,28-29
chalcogen-π,30 metal-π,31 substituent-π32 and solvent effects.33-37
For balances 1(CO)-6(CO), the carbonyl group of the N-pyridin-
2(1H)-onyl rotor is held in close proximity in the folded
conformer over the face of an aromatic shelf. The size of the
shelf increased from ethylene (1(CO)) to benzene (2(CO)) to
naphthalene (6(CO)). The electronic properties of the benzene
Figure 1. (A) Folded-unfolded equilibrium of the N-pyridin-2(1H)-
onylimide molecular balances designed to measure the
intramolecular CO-arene interactions in the folded conformation.
(B) Structures of the carbonyl balances 1(CO)-6(CO) with six
different arene shelves. (C) Abbreviated structures of four series of
control balances with methyl (1(CH3)-6(CH3)), ether oxygen
(1(OCH2)-6(OCH2)), fluorine (1(F)-6(F)) and chlorine (1(Cl)-
6(Cl)) groups on the rotor that form intramolecular interactions
with the same six arene shelves.
substituents. In addition, four series of control balances were
prepared with methyl (1(CH3)-6(CH3)), ether oxygen (1(OCH2)-
6(OCH2)), fluorine (1(F)-6(F)), and chlorine (1(Cl)-6(Cl)) arms
positioned over the same six aromatic shelves (Figure 1C).
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The formation of intramolecular CO-π interactions in the
numbers of fluorine groups on the aromatic shelves. The overall
change in folding energy (ΔΔG) for the methyl balances from the
unsubstituted (2) to tetrafluoroarene shelf (5) was -0.30 kcal/mol in
comparison to -2.44 kcal/mol for the carbonyl balances, which
confirms the strong electrostatic nature of the CO-π interaction.
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molecular balances was confirmed by X-ray crystallography. Only
balance 5(CO) crystalized in the folded conformation, which was
consistent with the strong stabilizing intramolecular CO-π
interaction in this balance (vide infra). The oxygen of the carbonyl
group was positioned over the six-membered aromatic shelf
(Figure 2) within van der Waals contact (< 3.22 Å).11 The O-to-
centroid distance (3.13 Å) and the dihedral angle (82.5°) between
the arm carbonyl group and shelf six-membered ring were
consistent with the previous crystal structure database surveys of
CO-π interactions (2.91 to 3.32 Å and 60° to 90°).9, 11 Balances
1(CO), 2(CO), 3(CO), 4(CO) and 6(CO) crystalized exclusively
in the unfolded conformers (Figure S1), which was consistent with
their weaker or repulsive CO-π interactions (vide infra).27
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Figure 2. Side- and front-views of the X-ray crystal structure of
balance 5(CO). The oxygen-to-centroid distance between the C=O
arm and perfluorinated shelf is highlighted in red, and the dihedral
angle between the planes of the CO group and arene shelf is
illustrated on the right.
Figure 3. NMR-measured folding energies (CD3CN) of carbonyl
(red bar) and methyl (black bar) arm balances with ethylene (1),
benzene (2), fluorobenzene (3), difluorobenzene (4),
tetrafluorobenzene (5), and naphthalene (6) shelves. Error in
measured folding energy was less than ±0.02 kcal/mol.
The folding ratios of the carbonyl balances were measured via
integration of their 1H or 19F NMR spectra in CD3CN. The folded
and unfolded conformers were in slow exchange at room
temperature (23 °C) showing distinct sets of peaks. Integration of
the folded and unfolded peaks provided an accurate measure of the
folded/unfolded ratios (≤ 3%). In most cases, the N-methyl group
on the rotor provided easily integratable singlets at 3.4 and 3.3 ppm.
The folded/unfolded ratios were corroborated by monitoring
Next, the electrostatic nature of the CO-π interactions was
quantitatively assessed by correlating the folding energies of the
carbonyl and control balances with established electrostatic
parameters. The electrostatic surface potential (ESP) at the center
of the fluorinated arene shelves were calculated at the ωB97X-D/6-
31G* level of theory (Figures 4 and S11). The ESP parameter has
been successfully applied to study the electrostatic component of
aromatic non-covalent interactions,44-45 such as F-π,28 cation-π,46
and anion-π interactions.47-48 The folding energies of the carbonyl
and methyl balances were correlated with the ESP values of the
arene shelves with zero (2), one (3), two (4), and four fluorine (5)
groups (Figure 4A and 4B). For both balance series, excellent
linear correlations were observed (R2 > 0.9), demonstrating that the
differences in the folding energies were strongly correlated to the
electrostatic differences in the arene shelves. However, the slope
of the shelf ESP correlation plot for the carbonyl balances (-
7.79*10-2) was eight times steeper than the methyl balances (-
0.9410-2), indicating the much stronger electrostatic character of
the CO-π interaction versus the methyl-arene interaction. We also
examined the possible contribution of orbital-orbital interactions to
the CO-π aromatic interactions via NBO analysis.49 The NBO
orbital-orbital (n→π*) energies did not show any correlation with
the CO-π interactions observed in balances 2(CO)-5(CO). The
calculated NBO energies (ωB97M-V/6-311G*) between the
carbonyl oxygen lone pair (n) and the aromatic shelf antibonding
orbital (π*) were very small (0.10 to 0.17 kcal/mol). More
importantly, the NBO energies (n→π*) stayed relatively constant
despite the observed CO-π interaction varying widely from
repulsive (with non-fluorinated benzene surface) to attractive (with
tetrafluorobenzene surface).
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multiple sets of peaks in the H and 19F NMR spectra. Similar
stability trends for the carbonyl balances and control balances were
observed in other organic solvents (CDCl3, CD2Cl2, acetone-d6, and
dmso-d6).
The CO-π interaction energies were found to vary widely from
destabilizing to stabilizing, depending on the nature of the aromatic
surface (Figure 3, red bars). First, the CO-π interactions with
unsubstituted arene surfaces were destabilizing. Balances 2(CO)
and 6(CO) with unfunctionalized benzene and naphthalene shelves
favored the unfolded conformation and had large positive folding
energies (1.44 and 1.11 kcal/mol). By comparison, balance 1(CO),
which lacked an aromatic shelf, had a near unity folding ratio and
a close to zero folding energy (0.26 kcal/mol). Second, and more
interestingly, the CO-π interactions became successively more
stabilizing as electron-withdrawing fluorine substituents were
added to the aromatic shelf (2(CO)-5(CO)). Balance 5(CO) with
four fluorine substituents showed the most negative folding energy
(-1.00 kcal/mol), which was consistent with an attractive CO-π
interaction. Third, extending the size of the aromatic shelf from
benzene (2(CO)) to naphthalene (6(CO)) had only a small
stabilizing effect (ΔΔG = -0.33 kcal/mol).
The importance of electrostatics to the CO-π interaction was
assessed via the methyl control balances (1(CH3)-6(CH3)) which
positioned the CH3 arm over the same six arene surfaces (Figure 3,
black bars). The methyl arms form intramolecular CH-π
interactions38-40 that are known to have a weak electrostatic
component.41-43 Unlike the carbonyl balances, the methyl balances
did not show a large decrease in folding energy with increasing
Finally, the electrostatic component of CO-π interactions was
compared with other aromatic interactions using control balances
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that formed ether oxygen-π50-51 and halogen-π28-29 interactions.
Specifically, the shelf ESP plots were measured for the ether
(2(OCH2)-5(OCH2)), fluorine (2(F)-5(F)), and chlorine (2(Cl)-
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Figure 4. (A) Correlation plots of the measured folding energies (ΔG, in CD3CN) of the carbonyl balances versus the calculated ESP values
(ωB97X-D/6-31G*) of the benzene shelves (2-5) with zero, one, two, and four fluorine substituents (left) and versus the calculated n→π*
NBO energies (ωB97M-V/6-311G*) between the CO and aromatic shelves (right). (B-D) Shelf ESP correlation plots for the methyl, ether,
fluorine, and chlorine balances with progressively fluorinated benzene shelves (2-5). (F) Arm ESP correlation plot of the slopes of shelf ESP
correlation plots (slopeshelf ESP) for the five series of balances versus the calculated ESP values (ωB97X-D/6-31G*) of their interacting region
on the arm groups (CO, CH3, OCH2, F, and Cl).
5(Cl)) balances (Figures 4C, 4D, and 4E). In each case, a linear
correlation was observed. However, the slopes of each series
differed and appeared to follow the size of the electrostatic term in
the corresponding aromatic interactions. Therefore, the slopes of
the shelf ESP correlation plots (slopeshelf ESP) for each balance series
(carbonyl, methyl, ether, fluorine, and chlorine) were correlated
with the ESPs of the arm groups (CO, CH3, OCH2, F, and Cl)
interacting with the aromatic shelf in the folded conformer (Figure
4F). An excellent linear correlation (R2 = 0.993) was observed
between the slopes of the shelf ESP plots (slopeshelf ESP) versus the
arm ESPs, confirming that the slope of the shelf ESP plots
(slopeshelf ESP) provides a measure of the magnitude of the
electrostatic terms in each of these aromatic interactions. The
slopes of the shelf ESP plots appear to effectively isolate the
electrostatic component of the folding energy from other factors
such as sterics and solvophobics for each balance series, allowing
accurate comparison of the different aromatic interactions.
shelf ESP correlation plots. For example, the ether balance
(5(OCH2)) with the tetrafluorinated aromatic shelf is more folded
than the corresponding carbonyl balance (5(CO)) due to the smaller
destabilizing steric term that off-sets the weaker attractive
electrostatic term. However, the electrostatic component appears
to be the dominant component of all these interactions as the ESPs
of arm and shelf describes the majority of the observed folding
energies.
In summary, the stability trends of CO-π aromatic interactions
were successfully measured in solution using our N-arylimide
molecular balances. The interactions were repulsive for non-
substituted aromatic surfaces and became systematically less
repulsive as electron withdrawing groups were added to the
aromatic surface. For extremely electron poor aromatic surfaces,
the CO-π aromatic interaction can be stabilizing, overcoming the
inherent destabilizing steric interactions in our model system.
These observations are consistent with crystal database studies
which found oxygens tended to be over the center of electron poor
heterocycles but over the edge of unsubstituted benzenes.11 The
interaction energy trends were well-correlated with the electrostatic
parameter (ESP) of the interacting aromatic surface and the oxygen
of the CO group. In this regard, the interaction behaves similar to
an anion-π interaction except involving a neutral but polarized
oxygen. Based on the similarities in structure and ESP of the
interacting groups in this model system, we expect that stabilizing
CO-π interactions of similar magnitude are present in synthetic and
biological systems. For example, the ESP of the C=O of the N-
pyridin-2(1H)-onyl rotor (-52.9 kcal/mol) is very similar to that of
a peptide amide (-50.9 kcal/mol). On the other hand, the ESP of
the C=O of acetone (-43.0 kcal/mol) and formaldehyde (-35.6
Of the interactions compared in Figure 4F, the CO-π had the
strongest electrostatic component. Accordingly, the carbonyl (CO)
balances also spanned the largest range (|∆∆G| = 2.44 kcal/mol) of
folding energies from destabilizing (1.44 kcal/mol) to stabilizing (-
1.00 kcal/mol). By comparison, the ether (OCH2), fluorine (F),
and chlorine (Cl) balance folding energies spanned narrower
ranges (|∆∆G| = 1.96, 1.33, and 0.91 kcal/mol) due to their weaker
electrostatic components. The oxygen in the ether (OCH2)
balances also formed a fairly strong electrostatic interaction with
the arene shelves. However, the CO-π interaction was stronger due
to the more polarized C=O bond. Other factors such as sterics,
solvent effects, and dispersion also contributed to the folding
energies as indicated by the differences in the y-intercepts of the
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Protein Structures: π∙∙∙π or Lone-pair∙∙∙π Interactions? J. Phys. Chem. B
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kcal/mol) is slightly smaller in comparison to the C=O of the N-
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pyridin-2(1H)-onyl rotor. Thus, ketone and aldehydes are expected
to form weaker electrostatic CO-π interactions. In addition, the
ESP of the tetrafluorobenzene shelf (8.6 kcal/mol) is actually less
positive than the ESP of thymine (14.5 kcal/mol), uracil (15.9
kcal/mol) and triazine (18.1 kcal/mol). The CO-π interaction had a
significantly larger electrostatic term than comparable ether O-π or
halogen-π aromatic interactions, due to the strong polarization of
the carbonyl bond, which leads to stronger stabilizing and
destabilizing interactions. Finally, the CO-π aromatic interactions
appear to not arise from or be significantly stabilized by the orbital-
orbital (n→π*) interactions and thus should be treated differently
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have significant orbital-orbital contributions.
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS
Publications website at DOI :
Additional tables and figures, synthesis and characterization of
molecular balances, measurements of folding energies, error
analysis, calculations of electrostatic parameters and NBO
energies, crystal structures, copies of 1H, 13C and 19F NMR spectra.
21. Hwang, J.; Li, P.; Smith, M. D.; Shimizu, K. D., Distance-dependent
Attractive and Repulsive Interactions of Bulky Alkyl Groups. Angew.
Chem., Int. Ed. 2016, 55 (28), 8086-8089.
22. Li, P.; Zhao, C.; Smith, M. D.; Shimizu, K. D., Comprehensive
Experimental Study of N-Heterocyclic π-Stacking Interactions of Neutral
and Cationic Pyridines. J. Org. Chem. 2013, 78 (11), 5303-5313.
23. Carroll, W. R.; Zhao, C.; Smith, M. D.; Pellechia, P. J.; Shimizu, K.
D., A Molecular Balance for Measuring Aliphatic CH-π Interactions. Org.
Lett. 2011, 13 (16), 4320-4323.
24. Zhao, C.; Parrish, R. M.; Smith, M. D.; Pellechia, P. J.; Sherrill, C.
D.; Shimizu, K. D., Do Deuteriums Form Stronger CH-π Interactions? J.
Am. Chem. Soc. 2012, 134 (35), 14306-14309.
25. Zhao, C.; Li, P.; Smith, M. D.; Pellechia, P. J.; Shimizu, K. D.,
Experimental Study of the Cooperativity of CH-π Interactions. Org. Lett.
2014, 16 (13), 3520-3523.
AUTHOR INFORMATION
Corresponding Author
li246@mailbox.sc.edu
shimizu@mail.chem.sc.edu
ACKNOWLEDGMENT
Funding for this work was provided by the National Science
Foundation grant CHE 1709086
26. Li, P.; Parker, T. M.; Hwang, J.; Deng, F.; Smith, M. D.; Pellechia,
P. J.; Sherrill, C. D.; Shimizu, K. D., The CH-π Interactions of Methyl
Ethers as a Model for Carbohydrate-N-Heteroarene Interactions. Org. Lett.
2014, 16 (19), 5064-5067.
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