Transition-State Stabilization by n→π? Interactions Measured Using Molecular Rotors

Article abstract of DOI:10.1021/jacs.9b08542

A series of 16 molecular rotors were synthesized to investigate the ability of n→π? interactions to stabilize transition states (TSs) of bond rotation. Steric contributions to the rotational barrier were isolated using control rotors, which could not form

Full text of DOI:10.1021/jacs.9b08542

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Communication
Transition state stabilization by n##*
interactions measured using molecular rotors
Erik C. Vik, Ping Li, Perry J. Pellechia, and Ken D. Shimizu
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b08542 • Publication Date (Web): 12 Oct 2019
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Transition state stabilization by n→π* interactions measured using
molecular rotors
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Erik C. Vik, Ping Li,* Perry J. Pellechia, Ken D. Shimizu*
Department of Chemistry and Biochemistry, University of South Carolina, Columbia, South Carolina 29208, United States
Supporting Information Placeholder
ABSTRACT: A series of 16 molecular rotors were synthesized to
investigate the ability of n→π* interactions to stabilize transition
states (TS) of bond rotation. Steric contributions to the rotational
barrier were isolated using control rotors, which could not form
n→π* interactions. Rotors with strong acceptor π* orbitals such as
ketones and aldehydes had greatly increased rates of rotation. The
TS stabilization of up to ~10 kcal/mol was consistent with the
formation of a strong n→π* stabilization between the imide
carbonyl oxygens and the ortho-R group in the planar TS.
Computational studies effectively modeled the TS stabilization and
geometry, and NBO analysis confirmed the role of n→π*
interactions in stabilizing the TS.
The n→π* interactions1-4 have been cited as playing a role in
determining protein structures,4-7 molecular8-9 and polymer
conformations,10 and fluorescent properties.11-12 However, studies
of n→π* interactions have primarily focused on thermodynamic
measurements in the context of proteins and peptides.4, 8-9, 13-18
Scheme 1. (A) Conformational syn-anti equilibrium of molecular
rotor 1(R) arising from rotation of the N-phenyl ring, and its planar
TS. (B) Conformational Sa-Ra equilibrium of biphenyl rotor 2(R)
used to measure the of Mazzanti’s steric parameter B-value of the
Despite their potential in catalysis, few have examined their kinetic
effects in reaction selectivity19-21 or enzymatic processes.22 Thus,
in this study, we systematically examined the ability of n→π*
interactions to increase the rate of rotation of a molecular rotor
(Scheme 1). Intramolecular n→π* interactions in the planar
R-groups, and its planar TS.
transition state between the ortho R-groups of the N-phenyl ring
and the imide carbonyl oxygens dramatically lowered the barrier of
in the planar TS, usually within the vdW radii. R-groups that have
an acceptor π* orbital on an sp2 or sp1 carbon, such as ketones
(COCH3, COPh), nitrile (CN), alkenes (C(CH2)CH3, Ph) and
alkynes (CCH), have the potential to form stabilizing
intramolecular n→π* interactions with the lone-pair on the imide
oxygen. On the other hand, rotors with ortho R-groups that do not
have an acceptor π* orbital, such as CH3, CH2CH3, CH(CH3)2,
OCH3, SCH3, Cl, Br, I and CF3, cannot form n→π* interactions and
serve as controls for isolating the steric component in the TS
interactions (vide infra).
rotation by up to ~10 kcal/mol. These results suggest that n→π*
interactions could be used to design new catalysts and could play a
significant role in enzyme catalysis.19-20, 22-23
Studies of non-covalent interactions have been primarily
measured in stable molecules and complexes.24-27 Few studies have
quantified the effects of non-covalent interactions in unstable
transition states and/or intermediates28-30 despite the frequently
cited role of these forces in catalysis and selectivity.31-32 The
challenge lies in the isolation and measurement of non-covalent
interactions within these high energy and crowded structures.33-34
We were particularly interested in whether the strength and stability
trend of n→π* interactions in the transition state (TS) were similar
to those previously observed in the ground state (GS) systems. N-
Phenylimide molecular rotors provide a simple model system to
address these questions as they have been successfully applied to
measure the kinetic effects of non-covalent interactions such as
intermolecular35 and intramolecular hydrogen bonding36-38 and
metal coordination.39 Rotor 1(R) adopts distinct syn- and anti-
The rotational barriers were measured using 1H NMR exchange
spectroscopy (EXSY).40 All rotors were studied in the slow
exchange regime (-60 to 130 °C) where the syn- and anti-
conformers gave distinct sets of peaks.41 Eyring plots provided the
enthalpy and entropy of the rotational barriers, and the free energies
(∆G‡exp) of rotation were recalculated for 25 °C. The ∆G‡exp values
ranged widely from 12.9 (R = COPh) to 24.0 kcal/mol (R = CF3).
The ability of n→π* interactions to stabilize the TS was initially
assessed by comparing the rotational barriers (∆G‡exp) of rotors
1(R) with similarly sized R-groups. This set of rotors had in their
R-group an sp2 carbon as the first atom carrying an acceptor π*
orbital: 1(COCH3), 1(COPh), 1(CHO), 1(C(CH2)CH3), and
conformers, which slowly interconvert via rotation around the Caryl
-
Nimide single bond (Scheme 1A). The ortho R-groups are held in
close proximity to the imide carbonyl oxygens
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1(Ph). The steric sizes of these R-groups are very similar as the
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atom type and hybridization of the first atom is the primary
determinant for the steric term of the rotational barrier (vide
infra).42-43 Yet, the barriers varied widely from 12.9 to 21.5
kcal/mol, suggesting the presence of additional important
interactions in the TS. The variations correlated with the ability of
the R-groups to form n→π* interactions.9, 16 For example, rotors
1(COPh), 1(COCH3), and 1(CHO) contain polar carbonyl groups
that are strong acceptors and had the lowest barriers (12.9, 13.9,
and 15.2 kcal/mol). The through-bond (mesomeric) effects of these
groups are relatively small and thus cannot explain the large
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reductions in rotational barriers.44
By comparison, rotors
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1(C(CH2)CH3), and 1(Ph) with non-polar sp2 carbons had high
rotational barriers (19.5 and 21.5 kcal/mol) presumably due to
weaker n→π* interactions. Similar trends were observed for rotors
1(CN) and 1(CCH) with sp1 carbons as the first atom. Again, the
rotor 1(CN) with the stronger acceptor ortho cyano-group had a
lower barrier (15.4 kcal/mol) than the rotor 1(CCH) with the
weaker acceptor alkynyl group (18.8 kcal/mol).
Quantification of the TS n→π* stabilizations required separating
the steric and n→π* components of the rotational barriers.16 The
steric component is the major determinant of the rotational barrier,
which is evident by the observed barriers tracking the steric trend
of the R-groups. The steric component of the barriers in rotors 1(R)
was assessed using Mazzanti’s steric B-value parameter.43, 45-48 B-
values are well-suited to this study because they are measured from
the rotational barriers of biphenyl rotors 2(R) with varying ortho
R-groups (Scheme 1B).49 The R-groups in rotor 2(R) cannot form
n→π* interactions due to the absence of lone-pair donors on the
hydrogens on the opposing phenyl ring.
Figure 1. (A) Correlation plot of the experimentally measured
rotational barriers for rotor 1(R) versus the steric B-values of the
R-groups. The steric trendline is drawn through the rotors that have
ortho-R groups without a π* orbital (black circles) and thus lack
n→π* interactions. The blue circles correspond to the rotors that
can form n→π* interactions. (B) Overlap of n and π* orbitals in the
calculated TS (B3LYP-D3/6-311G*) of 1(COCH3) in the three-
dimensional orbital rendering and the ChemDraw presentation of
TS highlighting the intramolecular n→π* interaction (blue arrow).
The rotors were divided into two groups based on whether their
R-groups contained acceptor orbitals. The first group of rotors had
R-groups without acceptor π* orbitals (R = CH3, CH2CH3,
CH(CH3)2, OCH3, SCH3, Cl, Br, I, CF3) and thus cannot form
n→π* interactions. Hence, their barriers are primarily due to steric
interactions as evidenced by the correlation (R2 = 0.87) of ∆G‡
exp
with the B-values of the R-groups (Figure. 1, black circles).50 This
steric trendline also provided an estimate of the steric component
in the rotational barriers for the rotors that formed n→π*
interactions.
GS geometries were thus deemed accurate and adopted for further
analysis on TS n→π* stabilization
Rotors with acceptor orbitals that could form n→π* interactions
(R = COPh, COCH3, CHO, CN, C(CH2)CH3, CCH, Ph) generally
deviated from the steric trendline (Figure. 1A, blue circles). Most
n→π* rotors had barriers noticeably below the steric trendline,
suggesting that the additional TS interactions were stabilizing.
Thus, a measure of the n→π* interaction is provided by the
deviation of the barrier from the steric trendline on the y-axis. The
magnitude of the n→π* stabilizations varied widely from -0.3
kcal/mol for 1(Ph) to -9.7 kcal/mol for 1(COPh). The R-groups
with strong acceptor abilities (COPh, COCH3, and CHO), due to
the presence of electronegative oxygens, had the strongest n→π*
stabilizations of -8.4 to -9.7 kcal/mol. The R-group with moderate
acceptor ability (CN) was moderately stabilizing (-5.2 kcal/mol).
Finally, R-groups with weak acceptor abilities (C(CH2)CH3), Ph,
and CCH) due to the lack of electronegative atoms yielded the least
stabilizing n→π* stabilizations of -0.3 to -2.7 kcal/mol.
Interestingly, the acceptor abilities of these ortho R-groups appears
to follow the NBO atomic charges of their first atoms (Figure S1).51
Pyramidalization or bending of the acceptor atoms of the R-
groups provided the structural evidence for the formation of TS
n→π* interactions.4, 9, 52 The n→π* orbital-orbital interaction is
known to alter the geometry of the acceptor atom.9 Trigonal planar
sp2 acceptor atoms become pyramidalized and linear sp1 acceptor
atoms become bent when forming n→π* interactions. The
geometry change is quantified by the parameter Θ (Figure. 2),
which measures the angle of deviation from planarity or linearity.
R-groups with good acceptors displayed significant TS
pyramidalization or bending. For example, the sp2 acceptor
carbons of the ketone (1(COCH3) and 1(COPh)) and aldehyde
(1(CHO)) rotors displayed the highest degree of pyramidalization
(Θ = 13.0°, 11.3°, and 11.0° respectively). These Θ values are
significantly larger than the n→π* interactions in protein and
peptide crystal structures (~2°‒7°), and are consistent with the
observed stronger TS n→π* interactions.53 Similarly, the sp1-
hybridized CN group of 1(CN) displayed significant bending (Θ =
15.4°) in the TS. Interestingly, this is also one of the few examples
of an n→π* interaction involving an sp1-hybridized acceptor.
Computational modeling was conducted to establish the role of
n→π* interactions in stabilizing the TS of 1(R). DFT calculations
of rotors 1(R) with the 16 R-groups (B3LYP-D3/6-311G*) were
able to reproduce the experimental barriers (∆G‡exp) with an
accuracy of ±1.2 kcal/mol (SI, Figure S29). The calculated TS and
The orbital-orbital interaction energies were estimated via a
natural bond order (NBO) analysis of the TS geometries of rotors
1(R). NBO calculations (ωB97M-V/6-311G*) were performed on
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the calculated TS geometries of rotors 1(R) (SI, Table S4-S33).54 -
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The orbital-orbital interaction energies (ENBO) between the imide
oxygen (n) and the R-group acceptor carbon (π*) showed an
excellent linear correlation (R2 = 0.94) with the measured TS
stabilizations (ΔΔG‡exp) (Figure. 3A). The strong correlation and
similar magnitudes suggest that the majority of the TS stabilization
can be attributed to the orbital-orbital n→π* interaction. Note that
the NBO analysis systematically overestimated the strength of
n→π* interaction as the slope of the correlation plot is 0.55
presumably due to discounting the effects of solvent on
experimental models.
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Figure 2. Definitions of the parameter Θ measuring the
pyramidalization of sp2 and bending of sp1 acceptor carbons in
n→π* interactions and the distance parameter d measuring the
O•••C distance.
Finally, the origins of the strong TS stabilizing n→π* effects
(5.3‒9.7 kcal/mol) were investigated especially in comparison with
the much weaker GS n→π*interactions in peptides and proteins
(~0.3‒0.7 kcal/mol).4 The discrepancy cannot be attributed to the
donor and acceptor properties of the interacting groups in rotors
1(R) as they are very similar to the amide oxygen and amide carbon
of peptide and protein systems.15, 22,56 A portion of the difference
can be attributed to the choice of the control rotors that selectively
removed the repulsive component of the compactly positioned
atoms in the TS interactions. However, the attractive component
of the interactions appeared to be significantly enhanced by the
compact nature of the TS. The O•••C distances (d, Figure 2) in the
TS of 1(COCH3), 1(COPh), and 1(CHO) were all significantly
shorter (2.35, 2.37, and 2.37 Å) than the sum of the vdW radii (3.22
Å). By comparison, proline-containing α-helices have some of the
shortest n→π* O•••C distances which are only slightly shorter than
the vdW radii (2.89 ± 0.10 Å).6 Confirmation of the short-strong
n→π* interactions in 1(R) was provided by an analysis of the
measured TS stabilization energies (ΔΔG‡exp) versus the calculated
TS O•••C distances (Figure 3B).4 For R-groups that can form
n→π* interactions, a strong linear correlation (R2 = 0.95) was
observed with shorter atom distances corresponding to stronger
interactions.9,57 The trend-line had a steep slope showing the
magnitude of the TS stabilization increased rapidly as the O•••C
distance decreased.
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Molecular rotor 1 was successfully employed to measure the
kinetic and TS stabilizing effects of n→π* interactions. Rotors that
form an intramolecular n→π* interaction in TS between the imide
oxygen and the ortho R-group had significantly lower rotational
barriers. The n→π* interactions stabilized the TS of rotors 1(R) by
up to 9.7 kcal/mol, significantly exceeding the stabilizations (~0.3‒
0.7 kcal/mol) imparted by the similar n→π* interactions in peptides
and proteins. The steric component of the rotational barriers was
measured using the steric parameter B-value, allowing the isolation
of the attractive component, and thus the stabilizing effect, of the
n→π* interactions. The presence of n→π* interactions was
confirmed by the pyramidalization or bending of the acceptor
carbon and the strong correlation between the experimentally
quantified TS stabilizations and the calculated NBO energies. The
large TS stabilizing effects of n→π* interactions were found to
closely associate with the short donor-to-acceptor (O•••C) distance
in the compact TS. Results of this work provide support for the
potential applications of n→π* interactions in reaction kinetics and
chemical catalysis.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS
Publications website at DOI :
Figure 3. (A) Correlation plot of the measured TS stabilization
(ΔΔG‡exp) and the calculated natural bond order (NBO) energies for
the TS n→π* interaction in 1(R). (B) Correlation plot of the
measured TS stabilization (ΔΔG‡exp) and the calculated donor-to-
acceptor distance (d) in the TS of 1(R).
Additional tables and figures, synthesis and characterization of the
molecular rotors, measurements of rotational barriers, calculations
of the rotational barriers, transition and ground state geometries,
NBO energies, copies of 1H and 13C NMR spectra.
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21. Lajkiewicz, N. J.; Roche, S. P.; Gerard, B.; Porco, J. A.,
AUTHOR INFORMATION
Corresponding Author
li246@mailbox.sc.edu
shimizu@mail.chem.sc.edu
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22. Windsor, I. W.; Gold, B.; Raines, R. T., An n→π* Interaction in the
Bound Substrate of Aspartic Proteases Replicates the Oxyanion Hole. Acs
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ACKNOWLEDGMENT
We thank the University of South Carolina for providing CPU time,
and Dr. Rassolov and Dr. Garashchuk for helps with Q-Chem and
valuable discussions. Funding for this work was provided by the
National Science Foundation grant CHE 1709086
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