Transition State Stabilizing Effects of Oxygen and Sulfur Chalcogen Bond Interactions

Abstract

Non‐covalent chalcogen bond (ChB) interactions have found utility in many fields, including catalysis, organic semiconductors, and crystal engineering. In this study, the transition stabilizing effects of ChB interactions of oxygen and sulfur were experimentally measured using a series of molecular rotors. The rotors were designed to form ChB interactions in their bond rotation transition states. This enabled the kinetic influences to be assessed by monitoring changes in the rotational barriers. Despite forming weaker ChB interactions, the smaller chalcogens were able to stabilize transition states and had measurable kinetic effects on the rotational barriers. Sulfur stabilized the bond rotation transition state by as much as −7.2 kcal/mol without electron‐withdrawing groups. The key was to design a system where the sulfur σ σ{\sigma } ‐hole was aligned with the lone pairs of the chalcogen bond acceptor. Oxygen rotors also could form transition state stabilizing ChB interactions but required electron‐withdrawing groups. For both oxygen and sulfur ChB interactions, a strong correlation was observed between transition state stabilizing abilities and electrostatic potential (ESP) of the chalcogen, providing a useful predictive parameter for the rational design of future ChB systems.

Full text

Transition State Stabilizing Effects of Oxygen and Sulfur
Chalcogen Bond Interactions
Binzhou Lin,[a] Hao Liu,[a] Harrison M. Scott,[a] Ishwor Karki,[a] Erik C. Vik,[a]
Daniel O. Madukwe,[a] Perry J. Pellechia,[a] and Ken D. Shimizu*[a]
Non-covalent chalcogen bond (ChB) interactions have found
utility in many fields, including catalysis, organic semiconduc-
tors, and crystal engineering. In this study, the transition
stabilizing effects of ChB interactions of oxygen and sulfur were
experimentally measured using a series of molecular rotors. The
rotors were designed to form ChB interactions in their bond
rotation transition states. This enabled the kinetic influences to
be assessed by monitoring changes in the rotational barriers.
Despite forming weaker ChB interactions, the smaller chalco-
gens were able to stabilize transition states and had measurable
kinetic effects on the rotational barriers. Sulfur stabilized the
bond rotation transition state by as much as 7.2 kcal/mol
without electron-withdrawing groups. The key was to design a
system where the sulfur s-hole was aligned with the lone pairs
of the chalcogen bond acceptor. Oxygen rotors also could form
transition state stabilizing ChB interactions but required elec-
tron-withdrawing groups. For both oxygen and sulfur ChB
interactions, a strong correlation was observed between
transition state stabilizing abilities and electrostatic potential
(ESP) of the chalcogen, providing a useful predictive parameter
for the rational design of future ChB systems.
Introduction
The chalcogen bond (ChB) is an attractive interaction between
an electron-poor region on a chalcogen atom (O, S, Se, Te) and
an electron-rich region of a second functional group.[1–3] The
electron-poor regions of chalcogens are commonly referred to
as s-holes. Whereas, the electron-rich regions on the ChB
acceptor usually coincide with the position of a lone pair. ChBs
have found applications in molecular recognition,[4–7] drug
design,[8–10] crystal engineering,[2,11,12] organic semiconductors,[13]
and organocatalysis.[14–17] The larger chalcogens (Se, Te) form
stronger ChB interactions due to their greater polarizabilities
and larger s-holes. Hence, many chalcogen bonding catalysts
contain Se and Te.[18] However, the smaller chalcogens (O, S) are
more abundant, and thus their ChB interactions have the
potential to have an impact on many applications. An example
is shown in Figure 1a of isothiourea-based organocatalysts,
which is proposed to form transition state stabilizing sulfur-ChB
interactions.[19]
In this study, the transition stabilizing effects of sulfur and
oxygen ChB interactions were experimentally measured. This
contrasts with the majority of experimental and theoretical
studies of chalcogen bonding interactions that have measured
their effects on thermodynamic equilibria[2,11,12,20–24] using host-
guest complexes or assemblies.[5,25,26] The magnitude and
stability trends of ChBs in transition states are influenced by the
crowded and compact structure of transition states, which often
have distorted bond lengths and hypervalent atoms.[27]
[a] B. Lin, H. Liu, H. M. Scott, I. Karki, E. C. Vik, D. O. Madukwe, P. J. Pellechia,
K. D. Shimizu
Department of Chemistry and Biochemistry, University of South Carolina,
Columbia, SC 29208, USA
E-mail: shimizu@mailbox.sc.edu
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/chem.202402011
© 2024 The Author(s). Chemistry - A European Journal published by Wiley-
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Commons Attribution Non-Commercial License, which permits use, dis-
tribution and reproduction in any medium, provided the original work is
properly cited and is not used for commercial purposes.
Figure 1. (a)Comparison of the chalcogen bonding interactions stabilizing a
bond-forming reaction TS (ref [19]) and the bond rotation TS of an N-
phenylimide molecular rotor. (b) The energy profiles of the bond rotation
processes for ChB and control rotors, which can and cannot form ChB
interactions. The TS stabilizing chalcogen bonding (ChB) interactions (Eint)
are isolated via the difference in the rotational barriers of the control and
ChB rotors.
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Isolating and measuring the effects of non-covalent inter-
actions on kinetic processes is challenging. For example,
positioning non-covalent interactions within a transition state is
difficult and can lead to unwanted changes in mechanism and
rate-determining steps. Therefore, our approach used a series of
rigid molecular rotors designed to form intramolecular ChB
interactions in the bond rotation transition states (Figure 1a).
The use of molecular rotors addressed many of the challenges
in studying the effects of weak non-covalent interactions. The
bond rotation transition states in are structurally well-defined
due to the rigidity of the N-phenylimide framework. The planar
TS brings the electron-rich carbonyl oxygen near the sulfur or
oxygen chalcogen atoms of the R-group at the ortho-position of
the N-phenyl rotor. The intramolecular nature of the ChB
interactions ensures that the desired interactions have mini-
mumal variations in atom distances and geometry. In the GS,
the interacting groups are further apart and cannot form ChB
interactions. Thus, changes in the rotational barriers can provide
a direct measure of the TS stabilization. Furthermore, the
measurement of rotational barriers is relatively straightforward
as bond rotation is a simple unimolecular process, which can be
easily monitored via dynamic variable-temperature NMR meth-
ods. We have demonstrated the utility of this approach by
successfully employing N-phenylimide rotors to measure the
transition state effects of other non-covalent interactions such
as hydrogen bonding and nto π* interactions.[28–31]
Our objectives for this study were to design molecular
rotors to: (1) measure the TS stabilizing abilities of sulfur and
oxygen ChB interactions, (2) examine the influence of ChB
geometry and electron-withdrawing groups, and (3) to develop
predictive parameters to guide researchers in designing future
ChB catalysts.
Results and Discussion
Experimental Measurements
Sulfur 1and oxygen 2molecular rotors were designed to form
ChB interactions in the bond rotation TS (Figure 2). Rotors 1
and 2have R-groups in the ortho-position of the N-phenyl rotor
that can form intramolecular C=O⋯S and C=O⋯O interactions
with the imide carbonyl oxygen. A variety of sulfur and oxygen
R-groups were synthesized to explore the influence of the
chalcogen atom orientation, conjugation, and attached elec-
tron-withdrawing groups.
The barriers of the ChB rotors have a destabilizing steric
(Esteric) component and a smaller stabilizing ChB component
(Eint). To isolate Eint, the rotational barriers of the ChB rotors 1
and 2were subtracted from the barriers of control rotors 3
(Figure 2). The rotors 3have R-groups that do not contain
chalcogen atoms and cannot form ChB interactions (Figure 2).
Therefore, the barriers of the control rotors provide a measure
of the steric (Esteric) component.
Rotors 1–3 share a rigid N-phenylimide framework. Due to
the steric interactions of the ortho R-groups with the imide
oxygens, the rotors display restricted rotation leading to the
formation of diastereomeric syn- and anti-conformers (Figure 2).
The rate of rotation was measured from the rate of exchange
between the syn- and anti-conformers via dynamic NMR.
Cyclic and acyclic variants of rotors 1and 2were designed
to explore the importance of geometry and alignment of the
interacting groups. The cyclic rotors have a fused heterocycle
ring, which aligns the chalcogen s-hole and the carbonyl
oxygen lone pair in a favorable geometry for the ChB
interaction. The acyclic rotors have greater conformational
freedom of the chalcogen R-group. In most cases, the rotors
adopt a poor ChB geometry, with the chalcogen s-hole
perpendicular to the imide oxygen lone pair.
The ChB rotors 1and 2were synthesized in two steps
(Figure 3). First, an aniline with a chalcogen R-group in the
ortho-position was synthesized usually by amination of a
bromoarene.[32] The aniline was heated with cis-5-norbornene-
endo-2,3-dicarboxylic anhydride (Figure 3).[30,32,33] The imide
condensation reaction is high yielding and does not require
additional reagents or catalysts. The reaction is also functional
group tolerant, enabling the rapid assembly of rotors with a
wide variety of chalcogen and non-chalcogen R-groups. The
structures of rotors 1(benzothiofuran), 1(thiazole), 1(SPh), and
Figure 2. Conformational syn-anti equilibrium of the N-phenylimide molec-
ular rotors 1arising from bond rotation around the CN bond. Chart of the
R-groups attached at the 2-position of sulfur rotors 1, oxygen rotors 2, and
control rotors 3. Rotors with cyclic structures have fused heterocyclic rings at
the 2- and 3-positions.
Figure 3. General scheme for the two-step synthesis of the chalcogen rotors.
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2(benzofuran) were confirmed by X-ray crystallography (SI).
Rotors 1(benzothiofuran), 1(thiazole), and 1(SPh) crystallized in
the anti-conformer. Rotor 2(benzofuran) crystallized in the syn-
conformer. The synthesis and rotational barriers of rotors 3
were previously reported.[30,33]
The rotational barriers (~G�exp) of rotors 1–3 were measured
using 2D EXSY 1H-NMR in TCE-d2(Table 1). The rotors displayed
restricted rotation with slow exchange on the NMR time scale.
Separate peaks were observed in the NMR spectra for the syn-
and anti-conformers below their coalescence temperatures
(50 to >140°C). The rates of exchange between the syn- and
anti-conformers were measured over a range of temperatures
using the norbornene alkene protons.[30,33] The resulting ~H�exp
and ~S�exp values from the Eyring plots were used to calculate
~G�exp at a common temperature (298.15 K) to allow compar-
isons. The error in ~G�exp was estimated as �0.2 kcal/mol based
on previous literature precedence.[34,35] The error in Esteric and Eint,
which are derived from ~G�ex also have an error of �0.2 kcal/
mol.
The measured barriers (~G�exp) for chalcogen rotors 1and 2
varied from 12.0 to 24.2 kcal/mol. The dominant steric trends
were evident from a comparison of the size of the R-groups and
the height of the barriers. The sulfur rotors consistently had
higher barriers than the oxygen analogs for the acyclic rotors.
This trend is consistent with the larger atomic size of the sulfur
atoms versus oxygen. For example, sulfur rotor 1(SCF3) had a
3.9 kcal/mol higher barrier versus the oxygen rotor 2(OCF3)
(21.8 vs 17.9 kcal/mol). Similar trends were observed for the
acyclic rotor pairs (1(SPh) vs 2(OPh) and 1(SCH3) vs 2(OCH3))
with the sulfur rotors having 3.6 and 2.3 kcal/mol higher
barriers. Another steric trend was the lower barriers of the cyclic
rotors versus the acyclic rotors. The constraints imposed by the
fused 5-membered rings of the cyclic rotors pulls the chalcogen
atom away from the opposing C=O oxygen, lowering the steric
interactions and the rotational barriers.
The first evidence for the presence of TS stabilizing
interactions was provided by an analysis of the rotational
barriers for the cyclic sulfur 1and oxygen 2rotors. As noted
above, the sulfur rotors typically have higher rotational barriers,
but this steric trend was not observed for the cyclic rotors. For
example, 1(thiofuran) and 2(furan) had very similar ~G�exp
values (14.9 and 15.0 kcal/mol). The other sulfur/oxygen rotor
pairs (1(benzothiofuran) vs 2(benzofuran) and 1(thiazole) and
2(oxazole) also had similar barriers. These trends are consistent
with the formation of a stronger TS stabilizing ChB interaction
in the sulfur rotors, which lowered their rotational barriers.
Confirmation of this hypothesis was provided by the computa-
tional analyses in the next section.
Table 1. Measured (~G�exp, Esteric, Eint) and calculated (~G�exp) parameters for molecular rotors 1,2, and 3. The steric parameter B-value for the R-groups in
the 2-positions of the N-phenylimide rotors. The values for all barriers and parameters are in units of kcal/mol.
Rotors Type ~G�exp[a] ~G�cal[b] B-valuecEsteric[d] Eint[e]
1(thiofuran) cyclic 14.9 14.2 5.2 19.7 4.8
1(benzothiofuran) cyclic 14.9 14.8 5.5 19.9 5.0
1(thiazole) cyclic 12.0 12.4 4.6 19.2 7.2
2(furan) cyclic 15.0 13.0 1.9 17.0 2.0
2(benzofuran) cyclic 14.9 13.5 2.0 17.1 2.2
2(oxazole) cyclic 12.0 11.1 1.5 16.7 4.7
2(2H-furan)cyclic 15.8 15.5 1.6 16.8 1.0
1(SCH3) acyclic 22.5 24.8 8.6 22.4 +0.1
1(SPh) acyclic 21.8 23.0 8.3 22.2 0.4
1(SCF3) acyclic 21.8 23.4 8.2 22.1 0.3
2(OCH3) acyclic 20.2 19.5[f] 5.6 20.0 +0.2
2(OPh) acyclic 18.2 18.3[f] 4.2 18.9 0.7
2(OCF3) acyclic 17.9 16.6[f] 5.5 19.9 2.0
2(OCOCH3) acyclic 16.3 14.5[f] 5.4 19.8 3.5
3(CH3) acyclic 21.7[f] 20.2[f] 7.4 21.4 +0.3
3(Et) acyclic 22.0[f] 22.4[f] 8.7 22.5 0.5
3(i-Pr) acyclic 23.6[f] 24.4[f] 11.1 24.4 0.8
3(Cl) acyclic 22.1[f] 22.5[f] 7.7 21.7 +0.4
3(Br) acyclic 23.1[f] 24.2[f] 8.7 22.5 +0.6
3(I) acyclic 24.2[f] 25.1[f] 10.0 23.5 +0.7
3(CF3) acyclic 23.7[f] 25.6[f] 10.5 23.9 +0.0
[a] Measured by EXSY 1H NMR (error=�0.2 kcal/mol). [b] Calculated at the B3LYPD3/6-311G* level of theory in Spartan at 298.15 K. [c] B-values from
literature (�0.15 kcal/mol) or calculated (italics) at the B3LYP/6-31G* level of theory.[36] [d] Calculated from Equation (2) (error=�0.2 kcal/mol). [e]
Calculated from Equation (1) (error =�0.2 kcal/mol). [f] Values previously reported.[30,33]
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Computational Analyses
Computational studies provided further support for the for-
mation of TS stabilizing ChB interactions in the cyclic sulfur
rotors and an explanation for the weaker or absence of ChB
interactions in the acyclic sulfur rotors. The calculated rotational
barriers (~G�cal) are shown in Table 1. The ~G�cal is based on
the difference in energy of the transition state and ground state
structures calculated at the B3LYPD3/6-311G* level of theory.
We have previously used this level of theory to accurately
predict the barriers of our N-phenylimide rotors, which formed
a variety of other non-covalent interactions.[30,33] The calculated
barriers for the chalcogen rotors show a similar level of accuracy
(�1.1 kcal/mol) with respect to the experimental barriers. The
level of accuracy was similar for all rotors including oxygen vs
sulfur, cyclic vs acylic, and ChB forming vs control rotors. More
importantly, the calculated barriers reproduced the experimen-
tally observed steric and ChB trends highlighted above.
Analyses of the calculated TS structures further supported
the rotors’ ability to form intramolecular ChB interactions. The
accuracy of the computed barriers provided evidence for the
accuracy of the corresponding calculated GS and TS structures.
In the transition states of sulfur rotors 1, the through-space
distances between the C=O oxygen and the sulfur atoms were
consistently shorter for the cyclic versus acyclic rotors (Table 2).
This is consistent with the cyclic sulfur rotors forming stronger
ChB interactions than the acyclic sulfur rotors. For example,
Figure 4a compares the C=O⋯S distance for 1(thiofuran) and
1(SCH3) were 2.546 to 2.784 Å. These trends were observed for
the other cyclic and acylic sulfur rotors. The average C=O⋯S
distances in the cyclic sulfur rotors were 0.240 Å shorter than in
the acyclic sulfur rotors. Similar distance trends were not
observed for the oxygen rotors. The average distances for the
cyclic and acyclic oxygen rotors 2were very similar (2.5063 vs
2.549 Å). This suggests that the cyclic oxygen rotors 2were not
forming strong ChB interactions like the sulfur rotors 1.
A comparison of the orientation of the s-holes of the sulfur
atoms in the TS structures of the cyclic and acyclic chalcogen
rotors 1confirmed the importance of orbital alignment in
forming strong ChB interactions. Examples are shown in
Figure 4a, which contrasts the TS conformation of cyclic
1(thiofuran) and acyclic 1(SCH3). Theoretical studies have shown
that ChB interactions prefer a geometry where the s-hole of the
chalcogen is aligned with the lone pair of the ChB
acceptor.[3,37,38] In rotors 1, the s-holes are in the region of the
sulfur atom opposite (180°) to the SC bond. Therefore, an
O⋯SC angle of 180°corresponds to an aligned s-hole. The
cyclic sulfur rotors are constrained in a TS geometry that favors
the ChB interaction. The alignment of the s-hole and carbonyl
oxygen lone pair is evident from the nearly linear O⋯SC
angles 175°to 178°(Table 2).
In contrast, the acyclic sulfur rotors 1had difficulty adopting
favorable ChB interaction geometries (Figure 5), which may
explain their weaker ChB interactions. The TS structures of
1(SCH3), 1(CF3), and 1(SPh) have their thioether R-groups
twisted out of the plane of the N-phenyl group. This
perpendicular geometry is preferred to avoid the destabilizing
steric interactions in the planar geometry between the R-group
in the ortho-position and adjacent CH groups in the meta-
position (Figure 5, right structure). However, the perpendicular
geometry also leads to poor alignment of the s-hole with the
Table 2. Measurements from the calculated TS structures (B3LYPD3/6-
311G*).
Rotors Angle[a]
O⋯ChC
(deg)
Distance[a]
O⋯Ch (Å)
ENBO[b]
(kcal/
mol)
ESP[c]
(kcal/
mol)
1(thiofuran) 177.7 2.546 6.5 12.5
1(benzothiofuran) 177.8 2.535 6.9 15.0
1(thiazole) 175.1 2.580 5.8 22.0
2(furan) 152.3 2.503 0.5 12.5
2(benzofuran) 151.4 2.500 0.5 10.0
2(oxazole) 157.7 2.512 0.6 7.5
2(2H-furan) 146.6 2.510 0.0 15.0
1(SCH3)160.0[d]
(76.0)[d]
2.591[d]
(2.784)[d]
0.0[d]
(6.1)[d] 22.0[d]
(3.0)[d]
1(SPh) 77.1 2.814 0.0 17.0
1(SCF3)87.7 2.783 0.0 14.0
2(OCH3)74.0 2.565 0.0 22.5
2(OPh) 75.0 2.527 0.0 17.5
2(OCF3)89.7 2.524 0.0 5.0
2(OCOCH3)74.7 2.579 0.0 0.5
[a] Ch=oxygen or sulfur. [b] Second order NBO perturbation energies
calculated at the ωB97MV/6-311+G* level of theory for the sum of
orbital interactions between the C=O oxygen lone pairs and the
chalcogen atom. [c] Calculated at the ωB97MV/6-311+G*level of theory
at the position on the surface oft he chalcogen atom closest to the C=O
oxygen in the TS. [d] For 1(SCH3), the planar (top value) and perpendicular
(value in parentheses) TS geometries had similar energies and so values
for both geometries are shown. For all of the other acyclic chalcogen
rotors, the perpendicular TS geometry was the more stable.
Figure 4. (a) Examples of the TS structures of cyclic 1(thiofuran) and acyclic
1(SCH3), highlighting the differences in orientations of the s-holes as
measured by bond angles (blue arcs) and C=O⋯S distances (red broken
lines) in the planar and perpendicular geometries. (b) Examples of the TS
structures of cyclic 2(furan) and acyclic 2(OCH3), highlighting the differences
in orientations of the s-holes as measured by bond angles (blue arcs) and
C=O⋯O distances (red broken lines) in the planar and perpendicular
geometries.
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oxygen lone pair. This is evident from the O⋯SC bond angles,
which are far from linear (76.0°to 87.7°) as shown in Table 2.
An outlier in the preference of the acyclic sulfur rotors for
the perpendicular geometries was 1(SCH3). The perpendicular
and planar TS geometries of 1(SCH3) were very close in energy
(SI, Table S33). This provided an opportunity to examine the
importance of proper alignment of the s-hole in the ChB
interaction. Like the cyclic rotors, the planar TS of acyclic
1(SCH3) has a good alignment of the sulfur s-hole with the C=O
oxygen lone pair as seen by the ChB bond angle of 160°. The
presence of a stabilizing ChB interaction was also evident from
the short S⋯O distance of 2.59 Å. In contrast, the perpendicular
TS had poor alignment with a bond angle of 76°and a much
longer S⋯O distance of 2.78 Å, indicative of a weaker ChB
interaction (Figure 4a). While 1(SCH3) can form a ChB interaction
in the planar TS, the TS stabilizing effects of the interaction are
offset by the additional steric interactions that are formed by
the CH3group. Thus, the similarity in the energies of the
perpendicular and planar geometries.
Quantitative Measurement of the ChB Interactions
Next the transition stabilizing effects of the ChB interactions
were quantitatively assessed and compared. The rotational
barrier (~G�exp) is comprised of destabilizing steric (Esteric) and
stabilizing ChB (Eint) components. Thus, Eint, can be isolated by
subtracting Esteric from ~G�exp (Equation (1)). The key to isolating
Eint is finding a matching steric control rotor of the same size to
accurately estimate Esteric. In the above studies, pairwise
comparisons were used. The difficulty with this approach is two
R-groups rarely have the same steric component.
Eint ¼DG�exp Esteric (1)
Esteric ¼0:8061ðB-valueÞ þ 15:47 (2)
Eint ¼DG�exp 0:8061ðB-valueÞ- 15:47 (3)
Therefore, a systematic approach was employed to generate an
ideal steric control for each rotor R-group. The barriers from a
previously measured series of control rotors 3were used to
estimate Esteric for any size R-group using Equation (2).[30,33]
Rotors 3have R-groups that lack a chalcogen atom and cannot
form ChB or other stabilizing non-covalent interactions. Thus,
their barriers provide a direct measure of the steric component,
Esteric. Mazzanti’s steric parameter, B-value, was chosen to
characterize the size of the R-groups (Table 1). B-value is based
on the steric influence of substituents on the rotational barrier
of a similar biaryl molecular rotor.[36] Therefore, B-value was
expected to show a good correlation with the steric effects in
our N-phenylimide rotors. Confirmation was provided by the
good linear correlation of the ~G�exp values of rotors 3with the
B-values of their R-groups (Figure 6, black open squares).
A limitation in the control rotors 3was the lack of rotors
with small R-groups (B-values<7.4 kcal/mol) that would be
closer in size to the R-groups for the cyclic chalcogen rotors 1
and 2. Therefore, oxygen rotors 2(OCH3) and 2(OPh) were
added to the steric control group (Figure 6, open triangles). We
reasoned that these rotors were unlikely to form ChB
interactions as they were acyclic rotors, which do not adopt the
proper TS geometry. In addition, they contain the least polar-
izable and smallest chalcogen, oxygen, which was unlikely to
form ChB interactions without attached electron-withdrawing
groups.[39,40] This hypothesis was confirmed as the rotational
barriers for 2(OCH3) and 2(OPh) fell on the trendline for rotors 3.
Therefore, Equation (2) (Figure 6, black solid line) used to
estimate Esteric is based on the barriers and B-values of rotors 3
and acyclic oxygen rotors 2(OCH3) and 2(OPh).
Using Equation (2), the steric component can be estimated
for any R-group as long as the B-value is known or can be
calculated (Table 1). ed the steric trendline could be used to
identify rotors that form ChB interactions and to quantify the TS
stabilizing effects. Rotational barriers that fell below the steric
trendline (Figure 6) had lower than expected barriers, which
were indications of the presence of TS stabilizing ChB
Figure 5. Comparison of the s-hole alignment in the perpendicular and
planar TS geometries of the acyclic chalcogen rotors.
Figure 6. Comparison of the measured rotational barriers (~G�exp) versus
Mazzanti’s steric parameter, B-value, for the chalcogen rotors 1(circles), 2
(triangles), and control rotors 3(squares). The steric trendline (black solid
line) was generated from the control rotors 3(open black squares) and
acyclic oxygen rotors 2(OCH3) and 2(OPh) (open black triangles), which do
not form TS ChB interactions. The ChB rotors were classified as cyclic sulfur
rotors 1(filled red circles), acylic sulfur rotors 1(open red circles), cyclic
oxygen rotors 2(filled blue triangles), and acyclic oxygen rotors 2with
electron-withdrawing groups (open blue triangles).
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interactions. Thus Equation (3) isolates the ChB component of
the barrier (Eint) from the difference in the predicted steric
barrier (Esteric) and the measured barrier (~G�exp).
The TS stabilizing ChB interaction energies (Eint) for chalc-
ogen rotors 1and 2were calculated using equation (3) and are
shown in Table 1. Analyses of Eint values provided quantitative
confirmation of the pairwise analyses in the previous sections.
The cyclic sulfur rotors 1(thiofuran), 1(benzothiofuran), 1(thia-
zole) had the strongest Eint values (4.8 to 7.2 kcal/mol),
which is consistent with their optimal s-hole alignment
observed in the calculated structures. In contrast, the acyclic
sulfur rotors 1(SCH3), 1(SPh), 1(SCF3) which had poor s-hole
alignment, had very small Eint values of 0.1 to 0.4 kcal/mol.
A key assumption in the above analysis was that variations
in the rotational barriers were due only to variations in energy
of the TS energies and that the ground state structures do not
also form ChB interactions. This assumption was initially based
on our previous studies using N-phenylimide rotors to study
other TS stabilizing non-covalent interactions.[28–31,33] In this ChB
study, the assumption was further supported by energy
decomposition analyses (SI, Section 12) that confirmed that the
calculated intramolecular TS interactions were strongly corre-
lated with the experimentally measured Eint values. In contrast,
the GS interactions were poorly correlated.
The Eint values also answered the question of whether the
oxygen rotors formed ChB interactions.[39,40] The Eint values
ranged from 1.0 to 4.7 kcal/mol for the cyclic oxygen rotors
2(2H-furan), 2(furan), 2(benzofuran), and 2(oxazole). These
values are still negative and are roughly half the Eint value of the
cyclic sulfur rotors 1. This analysis suggests that the cyclic
oxygen rotors form weak ChB interactions. However, Eint values
for the cyclic oxygen rotors have a higher degree of uncertainty.
The cyclic oxygen rotors have the lowest steric B-values (1.5 to
2.1 kcal/mol) that extend below the range of the range of B-
values used to generate the steric trendline (4.2 to 11.5 kcal/
mol). Thus, their Eint values are based on extrapolated portions
of the steric trendline (broken black line in Figure 6), which
have higher degrees of uncertainty (SI, Section 5). For example,
the 95% confidence interval for Eint is �1.0 to �1.5 kcal/mol in
B-value range of the cyclic oxygen rotors (SI, Figure S28
regression confidence line), which overlaps with the estimates
of their ChB interactions strengths (Eint =1.0 to 4.7 kcal/mol).
For comparison, the confidence interval for the larger cyclic
sulfur rotors is much smaller �0.6 to �0.8 kcal/mol especially
in comparison to the larger Eint values (4.8 to 7.2 kcal/mol).
To better address the question of whether oxygen can form
ChB interactions, oxygen rotors 2(oxazole), 2(OCF3), and
2(OCOCH3) which contain additional electronegative groups
were examined. Electronegative and electron-withdrawing
groups are known to enhance the strength of ChB interactions
by increasing the size of the s-hole and increasing the
electrostatic positive charge of the chalcogen atom.[2,41] For
example, the cyclic sulfur rotor which formed the strongest ChB
interaction (Eint =7.2 kcal/mol) was 1(thiazole) that has an
electronegative nitrogen in conjugation with the chalcogen
sulfur atom.
The nitrogen-containing oxygen rotor 2(oxazole) appeared
to show clear evidence of TS stabilizing ChB interactions. First,
the Eint value was 4.7 kcal/mol, which is significantly larger
than the uncertainty of the analysis. Second, the oxygen rotor
with the electronegative nitrogen showed a similar
enhancement in the strength of the ChB interaction as the
corresponding sulfur rotors. The Eint values for 2(oxazole) was
2.7 kcal/mol stronger than 2(furan). Similarly, the Eint value for
1(thiazole) was 2.4 kcal/mol stronger than 1(thiofuran).
Further evidence for the ability of the oxygen rotors to form
ChB interactions was provided by the analysis of acyclic oxygen
rotors 2(OCF3) and 2(OCOCH3), which have electron-withdraw-
ing groups directly attached to the interacting oxygens. For
example, the Eint of 2(OCF3) was 2.2 kcal/mol stronger than
2(OCH3). Likewise, the acetyl group strengthened the Eint of
2(OCOCH3) by 3.7 kcal/mol in comparison to 2(OCH3).
Interestingly, these electron-withdrawing group trends were
not observed for the acyclic sulfur rotors, which may provide
insight into the relative contributions of the orbital-orbital (n!
s*) and electrostatic components of the oxygen and sulfur ChB
interactions. For the acyclic sulfur rotors, attaching a CF3group
had only a small influence as the Eint of 1(SCF3) and 1(SCH3),
strengthened only by 0.3 kcal/mol. The possible origins of these
differences will be investigated further in the next section.
In summary, the oxygen ChB interactions could be observed
and measured by the molecular rotors. Oxygen formed weaker
ChB interactions in comparison to sulfur as expected. In the
absence of electron-withdrawing groups, the oxygen ChB
interactions were difficult to observe. However, with electron-
withdrawing groups the oxygen ChB interactions could be as
strong as sulfur ChB interactions without electron-withdrawing
groups.
Orbital-Orbital Interactions
To assess the magnitude of the orbital component of the ChB
interactions, Natural Bonding Orbital (NBO) analyses were
performed on the TS structures. The second-order perturbation
interaction energies (ENBO) of the donor orbitals on the C=O
oxygen and acceptor orbitals on the chalcogens were calcu-
lated for rotors 1and 2(Table 2), providing an estimate of the
intramolecular n!s* interactions.[3,42] The ENBO energies were
consistent with the experimental Eint values for the sulfur rotors
1(Figure 7). A stabilizing ENBO (5.8 to 6.9 kcal/mol) was
observed for the cyclic sulfur rotors, (1(thiofuran), 1(benzothio-
furan), 1(thiazole)), which form ChB interactions. In contrast, the
acyclic sulfur rotors, which do not form ChB interactions, had
negligible ENBO energies (0.0 kcal/mol). The exception was
acyclic sulfur rotor 1(SCH3), which could adopt planar and
perpendicular TS geometries. The ENBO energies varied with
geometry and s-hole alignment. The planar TS geometry had
an ENBO (3.7 kcal/mol) similar to the cyclic sulfur rotors, which
is indicative of strong ChB interactions. On the other hand, the
perpendicular TS geometry had an ENBO of zero.
In contrast to the sulfur rotors, the ENBO energies for the
oxygen rotors did not correlate with the observed Eint values
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and were all zero or near zero. This is consistent with the
oxygen ChB interaction having a small or negligible orbital
component. Even 2(oxazole), which had a moderate TS
stabilization (Eint =4.7 kcal/mol), had an ENBO of only 0.6 kcal/
mol. Similarly, the acyclic oxygen rotor ENBO values were low
regardless of the observed stabilization energies (Eint). For
example, even the oxygen rotors with electron-withdrawing
groups (2(OCF3) and 2(OCOCH3)) and modest Eint values (2.0
and 3.5) had negligible ENBO energies (0.0 kcal/mol). Thus, the
oxygen ChB interactions were not traditional ChBs that involve
interactions with the chalcogen s-holes.
The orbital-interaction analyses showed that the sulfur and
oxygen interactions vary greatly. The sulfur rotors formed
traditional ChB interactions. When the s-holes were aligned
with the oxygen lone pair, there were strong ChB interactions
with significant orbital components. When the s-holes were not
aligned, the sulfur rotors did not form ChB interactions. In
contrast, the strength of the TS-stabilizing interactions for the
oxygen rotors did not correlate with s-hole alignment. Even
when the s-hole was aligned in the cyclic oxygen rotors, their
interactions did not have orbital components.
Electrostatic Potential Analysis
To further explore the differences between the sulfur and
oxygen interactions, we examined the electrostatic component
of interactions. The ChB interactions in the oxygen and sulfur
rotors appeared to have electrostatic components. Therefore,
we were particularly interested in whether electrostatic poten-
tial (ESP) could be a predictive parameter for ChB interactions,
which would be a useful tool for researchers designing systems
based on ChB interactions. ESP describes the electrostatic
potential energy at points on a molecular surface, providing a
measure of interaction energies and geometry. ESP has been
shown to be effective in predicting non-covalent interaction
trends as best highlighted by the work of Hunter on hydrogen
bonding.[43]
The ability of ESP to predict the ChB interaction energies
was tested by correlating ESP with the experimentally measured
Eint values. The ESP energies (Table 2) were calculated at the
position on the surface of the chalcogen atom closest to the
C=O oxygen in the TS. Examples are shown in Figure 7. The
norbornene succinimide frameworks of the rotors were deleted
because they blocked the surface of the chalcogen unit that
was involved in the ChB interaction.
ESP was an excellent predictor of the ability of ChB
interactions to stabilize the bond rotation transition states. An
excellent correlation was observed between the chalcogen ESP
and rotor Eint with an R2=0.96 (Figure 8). The ESP trendline
includes sulfur and oxygen rotors of all types including cyclic
and acyclic rotors. This demonstrates the generality of the
predictive parameter across different types of chalcogen
bonding interactions.
The ability of ESP to predict the ChB interaction strengths
for interactions regardless of the orbital components was
surprising. For example, the cyclic sulfur rotors that have a
significant orbital component such as 1(benzothiofuran), 1(thio-
furan), and 1(thiazole) fell on the same ESP trendline as the
acyclic rotors that lack an orbital component such as 2(OCF3)
and 2(OCOCH3). In the case of the cyclic sulfur rotors, the
position on the surface of the sulfur atom used to measure the
ESP coincided with the s-hole. An example is shown in Figure 7
(R=benzothiofuran) where the ESP position (red arrow) is the
same as the s-hole (blue arrow). However, the ESP position for
the other types of rotors either did not correlate with the
s-hole (Figure 7, R=SCF3) or the rotors lacked a shole (Figure 7,
R=benzofuran or OCF3). Thus, the effectiveness of the ESP
parameter in predicting the ChB interaction energies regardless
of the degree of orbital overlap suggests that the ESP values
Figure 7. Examples of the ESP surfaces generated for the N-phenyl units of
rotors 1(benzothiofuran), 1(SCF3), 2(benzofuran), 2(OCF3). The calculations
were performed without the norborene succinimide units to allow visual-
ization of the interacting surface on the chalcogen atom. The position on
the surface of the chalcogen used to estimate the ESP for each rotor is
highlighted with a red arrow and corresponds to the approximate
interaction surface for the C=O oxygen in the TS. The s-hole of the sulfur R-
groups is highlighted with a blue arrow. The oxygen R-groups did not have
clearly defined s-holes, and therefore, do not have blue arrows.
Figure 8. Plot of electrostatic potentials (ESP, ωB97MV/6-311+G*) versus
the experimentally measured stabilizing TS interaction energies (Eint) for
rotors 1and 2: acyclic oxygen rotors 2(OCH3) and 2(OPh) (open black
triangles), acylic sulfur rotors 1(open red circles), cyclic oxygen rotors 2
(filled blue triangles), acyclic oxygen rotors 2with electron-withdrawing
groups (open blue triangles) and cyclic sulfur rotors 1(filled red circles).
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were providing some measure of the orbital component or
were correlated with the orbital interaction energies in addition
to a measure of the electrostatic component.
Comparison of the planar and perpendicular geometries of
rotor 1(SCH3) provided insight into ESP’s origins and effective-
ness as a predictive parameter. For the perpendicular geometry
of 1(SCH3), ESP accurately predicts Eint and falls on the trendline
in Figure 6. However, for the planar geometry, ESP predicts a
much stronger (more negative) Eint than was observed as the
data point is far above the trendline. The reason is that the ESP
analysis is based only on the stabilizing ChB component and
does not take into account the additional steric interactions in
the planar TS of the SCH3methyl group with the adjacent
aromatic hydrogens.
Comparison of the Sulfur and Oxygen ChB Interactions
The above analyses revealed that sulfur and oxygen can form
stabilizing TS ChB interactions, but the interactions differ in the
relative magnitudes of their orbital-orbital and electrostatic
components, leading to different stability trends. The sulfur and
oxygen ChB interactions both have strong electrostatic compo-
nents. This is evident from the ability of the electrostatic
parameter, ESP, to accurately predict the interaction energies,
Eint, as shown in Figure 8. In contrast, the sulfur and oxygen ChB
interactions have different magnitude orbital-orbital compo-
nents. The more polarizable sulfur R-groups have well-defined
s-holes and form strong orbital-orbital interactions. Whereas,
the less polarizable oxygen has smaller or negligible s-holes
and does not form orbital-orbital interactions. The differences in
the orbital components are clearest when comparing the cyclic
sulfur and cyclic oxygen rotors. Both have good alignment of
their s-holes with the C=O oxygen lone pair. The cyclic sulfur
rotors 1have significant NBO energies (6.9 to 5.8 kcal/mol)
as shown in Table 2. However, the cyclic oxygen rotors 2, which
have similar lone-pair to s-hole alignments had low or
negligible NBO energies (0.6 to 0 kcal/mol). Therefore, the
sulfur interactions in the rotors are consistent with standard
ChB interactions involving the chalcogen s-hole. The oxygen
interactions, on the other hand, were primarily electrostatic and
did not need proper alignment with a s-hole.
These differences in the orbital-orbital and electrostatic
components of the sulfur and oxygen ChB interactions also
explain the different trends for the acyclic rotors. The significant
orbital component of the sulfur ChB interaction leads to greater
geometric constraints, requiring proper alignment of the donor
lone pair with the chalcogen s-hole. The importance of
geometry is evident from the large differences in the interaction
energies of the cyclic and acyclic sulfur rotors, which have good
and poor s-hole alignments. In contrast, oxygen ChB inter-
actions do not appear to be traditional ChB interactions as their
s-holes do not contribute to the interaction. Thus, the oxygen
interactions are weaker as they lack an orbital component
interaction and only contain an electrostatic component.
However, as a consequence, the oxygen ChB interactions can
adopt a wider variety of geometries.
Comparison of ChB with Other Non-Covalent Interactions
The study of ChB interactions using our N-phenylimide rotors
provides an opportunity to directly compare interaction ener-
gies with previously studied TS interactions using the same
framework such as n!π*(CO),[30] n!π(Ph),[29] pnictogen
bonds,[33] and hydrogen bonding interactions.[28] Each rotor
formed intramolecular TS interactions with the same imide C=O
oxygens. The relative TS stabilizing abilities of the interactions
are compared in Figure 9. The C=O⋯HO=Ph hydrogen bonds
were the strongest. However, the remaining interactions,
including the sulfur and oxygen chalcogen interactions,
spanned a broad and overlapping range of interaction energies.
The stability trends revealed some general trends. First, electro-
negative and electron-withdrawing groups on the accepting
groups enhanced the strength of the interactions. This is
consistent with the interactions originating from electrostatic
and donor-acceptor orbital-orbital interactions. For example,
when comparing different types of pnictogen interactions, the
electron-poor nitrogen of amides formed the strongest inter-
actions, and the electron-rich nitrogen of amines formed
weaker interactions.[33] For the n!π* interactions, the electron-
poor carbonyl groups form stronger interactions than phenyl
groups.[29,30] Similar trends were observed for the ChB inter-
actions. The electron-withdrawing groups on the chalcogen
atom such as CF3in rotors 2(OCF3) or conjugated electro-
negative nitrogen atoms in rotors 1(thiazole) and 2(oxazole)
increased the strength of the interaction. Note that this
comparison may overestimate the strengths of the non-
covalent interactions as our analysis removes the repulsive
components of the interactions, which are known to be an
integral part of the interactions.[44,45] However, the overall trends
should be similar.
Conclusions
This study examined the potential of the chalcogen bonding
interactions of oxygen and sulfur to stabilize transition states
and affect kinetic processes. Using N-phenylimide molecular
rotors, the transition state stabilizing effects of chalcogen
Figure 9. Comparison of the ranges of TS stabilizing effects (Eint) of
noncovalent interactions measured in the N-phenylimide rotors. The oxygen
and sulfur ChB interactions in this study (blue bars) versus the previously
measured n!π*(CO),[30] n!π(Ph),[29] pnictogen,[33] and hydrogen bonding
interactions[28] (red bars).
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bonding interactions were isolated, measured, and compared.
Rotors with variations in the chalcogen atom orientation and
electron-withdrawing groups were synthesized. The rotational
barriers were measured using dynamic NMR. The formation of
the intramolecular ChB interactions in the bond rotation
transition states was verified from the experimental rotational
barrier trends and computational modeling of the TS structures.
Evidence for the ChB interactions was provided by the short
atom-atom distances and correlation with proper alignment of
the chalcogen s-hole. The more polarizable sulfur rotors formed
stronger ChB interactions as expected. However, the oxygen
rotors could also form ChB interactions if appropriate electro-
negative or electron-withdrawing groups were present. Given
the higher availability and better-established chemistry for
incorporation of oxygen and sulfur functional into organic
frameworks, these results suggest that new organic catalysts
could be designed that utilize oxygen and sulfur ChB
interactions.
The oxygen and sulfur ChB interactions had different
geometric constraints due to the different strengths of their
orbital-orbital components. The sulfur ChB interaction has a
strong orbital component and thus was restricted to geometries
where the lone pair donor orbital is aligned with the s-hole of
the sulfur atom. The less polarizable oxygen atom does not
form a significant s-hole in our systems and thus does not have
a significant orbital component. However, this allows the
oxygen ChB interaction to form in a wider array of geometries
as the effects of electron-withdrawing groups are more
uniformly distributed on the chalcogen atom surface of the less
polarizable oxygen. The ESP energy calculated at the interacting
point on the surface of the chalcogen atom was an excellent
predictive parameter for the strength and geometry of the
interaction. Therefore, ESP can be used in designing and
optimizing organocatalysts and reactions that involve ChB
interactions.
Supporting Information Summary
Deposition Number(s) 2287313 (for 1(benzothiofuran)), 2287314
(for 2(benzofuran)), 2287315 (for 1(thiazole)), 2287316 (for
2(SPh)) contain(s) the supplementary crystallographic data for
this paper. These data are provided free of charge by the joint
Cambridge Crystallographic Data Centre and Fachinformations-
zentrum Karlsruhe Access Structures service. The authors have
cited additional references within the Supporting
Information.[46–50]
Author Contributions
Binzhou Lin and Hao Liu contributed to all the processes
equally. The paper was completed with the contribution of
other authors.
Acknowledgements
Funding for this work was provided by the National Science
Foundation grants CHE 200388 and 2304777.
Conflict of Interests
The authors declare no conflict of interest.
Data Availability Statement
The data that support the findings of this study are available in
the supplementary material of this article.
Keywords: Molecular rotors ·Chalcogen bonds ·Non-covalent
interactions ·Transition states ·Kinetic effects
[1] C. B. Aakeroy, D. L. Bryce, G. R. Desiraju, A. Frontera, A. C. Legon, F.
Nicotra, K. Rissanen, S. Scheiner, G. Terraneo, P. Metrangolo, G. Resnati,
Pure Appl. Chem. 2019,91, 1889–1892.
[2] P. Scilabra, G. Terraneo, G. Resnati, Acc. Chem. Res. 2019,52, 1313–1324.
[3] L. Vogel, P. Wonner, S. M. Huber, Angew. Chem., Int. Ed. 2019,58, 1880–
1891.
[4] R. Hein, P. D. Beer, Chem. Sci. 2022,13, 7098–7125.
[5] P. C. Ho, P. Szydlowski, J. Sinclair, P. J. W. Elder, J. Kübel, C. Gendy, L. M.
Lee, H. Jenkins, J. F. Britten, D. R. Morim, I. Vargas-Baca, Nat. Commun.
2016,7, 11299.
[6] N. Biot, D. Bonifazi, Coord. Chem. Rev. 2020,413, 213243.
[7] R. Hein, P. D. Beer, J. J. Davis, Chem. Rev. 2020,120, 1888–1935.
[8] B. R. Beno, K.-S. Yeung, M. D. Bartberger, L. D. Pennington, N. A. Mean-
well, J. Med. Chem. 2015,58, 4383–4438.
[9] H. Sugiyama, M. Yoshida, K. Mori, T. Kawamoto, S. Sogabe, T. Takagi, H.
Oki, T. Tanaka, H. Kimura, Y. Ikeura, Chem. Pharm. Bull. (Tokyo) 2007,55,
613–624.
[10] B. V. McInerney, R. P. Gregson, M. J. Lacey, R. J. Akhurst, G. R. Lyons, S. H.
Rhodes, D. R. J. Smith, L. M. Engelhardt, A. H. White, J. Nat. Prod. 1991,
54, 774–784.
[11] A. Dhaka, O. Jeannin, I. Jeon, E. Aubert, E. Espinosa, M. Fourmigué,
Angew. Chem. 2020,132, 23789–23793.
[12] M. Fourmigué, A. Dhaka, Coord. Chem. Rev. 2020,403, 213084.
[13] M. Liu, X. Han, H. Chen, Q. Peng, H. Huang, Nat. Commun. 2023,14,
2500.
[14] S. Benz, J. López-Andarias, J. Mareda, N. Sakai, S. Matile, Angew. Chem.
2017,129, 830–833.
[15] W. Wang, H. Zhu, S. Liu, Z. Zhao, L. Zhang, J. Hao, Y. Wang, J. Am. Chem.
Soc. 2019,141, 9175–9179.
[16] R. Weiss, E. Aubert, P. Pale, V. Mamane, Angew. Chem., Int. Ed. 2021,60,
19281–19286.
[17] W. Wang, H. Zhu, L. Feng, Q. Yu, J. Hao, R. Zhu, Y. Wang, J. Am. Chem.
Soc. 2020,142, 3117–3124.
[18] G. Sekar, V. V. Nair, J. Zhu, Chem. Soc. Rev. 2024,53, 586–605.
[19] E. R. T. Robinson, C. Fallan, C. Simal, A. M. Z. Slawin, A. D. Smith, Chem.
Sci. 2013,4, 2193.
[20] M. Iwaoka, S. Tomoda, J. Am. Chem. Soc. 1996,118, 8077–8084.
[21] D. J. Pascoe, K. B. Ling, S. L. Cockroft, J. Am. Chem. Soc. 2017,139,
15160–15167.
[22] G. E. Garrett, G. L. Gibson, R. N. Straus, D. S. Seferos, M. S. Taylor, J. Am.
Chem. Soc. 2015,137, 4126–4133.
[23] F. De Vleeschouwer, M. Denayer, B. Pinter, P. Geerlings, F. De Proft, J.
Comput. Chem. 2018,39, 557–572.
[24] Y. Nagao, T. Hirata, S. Goto, S. Sano, A. Kakehi, K. Iizuka, M. Shiro, J. Am.
Chem. Soc. 1998,120, 3104–3110.
[25] S. Mehrparvar, C. Wölper, G. Haberhauer, Angew. Chem., Int. Ed. 2023,
e202304202.
[26] B. J. Eckstein, L. C. Brown, B. C. Noll, M. P. Moghadasnia, G. J. Balaich,
C. M. McGuirk, J. Am. Chem. Soc. 2021,143, 20207–20215.
Wiley VCH Montag, 23.09.2024
2454 / 368111 [S. 243/244] 1
Chem. Eur. J. 2024,30, e202402011 (9 of 10) © 2024 The Author(s). Chemistry - A European Journal published by Wiley-VCH GmbH
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Research Article
doi.org/10.1002/chem.202402011

[27] C. M. Young, A. Elmi, D. J. Pascoe, R. K. Morris, C. McLaughlin, A. M.
Woods, A. B. Frost, A. Houpliere, K. B. Ling, T. K. Smith, A. M. Z. Slawin,
P. H. Willoughby, S. L. Cockroft, A. D. Smith, Angew. Chem., Int. Ed. 2020,
59, 3705–3710.
[28] E. C. Vik, P. Li, J. M. Maier, D. O. Madukwe, V. A. Rassolov, P. J. Pellechia,
E. Masson, K. D. Shimizu, Chem. Sci. 2020,11, 7487–7494.
[29] E. C. Vik, P. Li, D. O. Madukwe, I. Karki, G. S. Tibbetts, K. D. Shimizu, Org.
Lett. 2021,23, 8179–8182.
[30] E. C. Vik, P. Li, P. J. Pellechia, K. D. Shimizu, J. Am. Chem. Soc. 2019,141,
16579–16583.
[31] B. Lin, I. Karki, P. J. Pellechia, K. D. Shimizu, Chem. Commun. 2022,58,
5869–5872.
[32] S. H. Alelaiwi, J. R. McKee, ACS Omega 2021,6, 6009–6016.
[33] B. Lin, H. Liu, I. Karki, E. C. Vik, M. D. Smith, P. J. Pellechia, K. D. Shimizu,
Angew. Chem., Int. Ed. 2023, e202304960.
[34] A. M. Schoevaars, W. Kruizinga, R. W. J. Zijlstra, N. Veldman, A. L. Spek,
B. L. Feringa, J. Org. Chem. 1997,62, 4943–4948.
[35] A. Ciogli, S. Vivek Kumar, M. Mancinelli, A. Mazzanti, S. Perumal, C.
Severi, C. Villani, Org. Biomol. Chem. 2016,14, 11137–11147.
[36] L. Lunazzi, M. Mancinelli, A. Mazzanti, S. Lepri, R. Ruzziconi, M. Schlosser,
Org. Biomol. Chem. 2012,10, 1847.
[37] P. Politzer, J. S. Murray, T. Clark, G. Resnati, Phys. Chem. Chem. Phys.
2017,19, 32166–32178.
[38] R. E. Rosenfield, R. Parthasarathy, J. D. Dunitz, J. Am. Chem. Soc. 1977,
99, 4860–4862.
[39] T. Fellowes, B. L. Harris, J. M. White, Chem. Commun. 2020,56, 3313–
3316.
[40] P. R. Varadwaj, A. Varadwaj, H. M. Marques, P. J. MacDougall, Phys.
Chem. Chem. Phys. 2019,21, 19969–19986.
[41] A. Docker, C. H. Guthrie, H. Kuhn, P. D. Beer, Angew. Chem., Int. Ed. 2021,
60, 21973–21978.
[42] J. Y. C. Lim, P. D. Beer, Chem. 2018,4, 731–783.
[43] C. A. Hunter, Angew. Chem., Int. Ed. 2004,43, 5310–5324.
[44] X. Chen, F. Bayard, N. Gonzalez-Sanchis, K. K. P. Pamungkas, N. Sakai, S.
Matile, Angew. Chem., Int. Ed. 2023,62, e202217868.
[45] G. Haberhauer, R. Gleiter, Angew. Chem., Int. Ed. 2020,59, 21236–21243.
[46] Y. Shao, Z. Gan, E. Epifanovsky, A. T. B. Gilbert, M. Wormit, J. Kussmann,
A. W. Lange, A. Behn, J. Deng, X. Feng, D. Ghosh, M. Goldey, P. R. Horn,
L. D. Jacobson, I. Kaliman, R. Z. Khaliullin, T. Kuś, A. Landau, J. Liu, E. I.
Proynov, Y. M. Rhee, R. M. Richard, M. A. Rohrdanz, R. P. Steele, E. J.
Sundstrom, H. L. Woodcock, P. M. Zimmerman, D. Zuev, B. Albrecht, E.
Alguire, B. Austin, G. J. O. Beran, Y. A. Bernard, E. Berquist, K. Brandhorst,
K. B. Bravaya, S. T. Brown, D. Casanova, C.-M. Chang, Y. Chen, S. H. Chien,
K. D. Closser, D. L. Crittenden, M. Diedenhofen, R. A. DiStasio, H. Do,
A. D. Dutoi, R. G. Edgar, S. Fatehi, L. Fusti-Molnar, A. Ghysels, A.
Golubeva-Zadorozhnaya, J. Gomes, M. W. D. Hanson-Heine, P. H. P.
Harbach, A. W. Hauser, E. G. Hohenstein, Z. C. Holden, T.-C. Jagau, H. Ji,
B. Kaduk, K. Khistyaev, J. Kim, J. Kim, R. A. King, P. Klunzinger, D.
Kosenkov, T. Kowalczyk, C. M. Krauter, K. U. Lao, A. D. Laurent, K. V.
Lawler, S. V. Levchenko, C. Y. Lin, F. Liu, E. Livshits, R. C. Lochan, A.
Luenser, P. Manohar, S. F. Manzer, S.-P. Mao, N. Mardirossian, A. V.
Marenich, S. A. Maurer, N. J. Mayhall, E. Neuscamman, C. M. Oana, R.
Olivares-Amaya, D. P. O’Neill, J. A. Parkhill, T. M. Perrine, R. Peverati, A.
Prociuk, D. R. Rehn, E. Rosta, N. J. Russ, S. M. Sharada, S. Sharma, D. W.
Small, A. Sodt, T. Stein, D. Stück, Y.-C. Su, A. J. W. Thom, T. Tsuchimochi,
V. Vanovschi, L. Vogt, O. Vydrov, T. Wang, M. A. Watson, J. Wenzel, A.
White, C. F. Williams, J. Yang, S. Yeganeh, S. R. Yost, Z.-Q. You, I. Y.
Zhang, X. Zhang, Y. Zhao, B. R. Brooks, G. K. L. Chan, D. M. Chipman, C. J.
Cramer, W. A. Goddard, M. S. Gordon, W. J. Hehre, A. Klamt, H. F.
Schaefer, M. W. Schmidt, C. D. Sherrill, D. G. Truhlar, A. Warshel, X. Xu, A.
Aspuru-Guzik, R. Baer, A. T. Bell, N. A. Besley, J.-D. Chai, A. Dreuw, B. D.
Dunietz, T. R. Furlani, S. R. Gwaltney, C.-P. Hsu, Y. Jung, J. Kong, D. S.
Lambrecht, W. Liang, C. Ochsenfeld, V. A. Rassolov, L. V. Slipchenko, J. E.
Subotnik, T. Van Voorhis, J. M. Herbert, A. I. Krylov, P. M. W. Gill, M.
Head-Gordon, Mol. Phys. 2015,113, 184–215.
[47] R. M. Parrish, L. A. Burns, D. G. A. Smith, A. C. Simmonett, A. E. DePrince,
E. G. Hohenstein, U. Bozkaya, A. Yu. Sokolov, R. Di Remigio, R. M.
Richard, J. F. Gonthier, A. M. James, H. R. McAlexander, A. Kumar, M.
Saitow, X. Wang, B. P. Pritchard, P. Verma, H. F. Schaefer, K. Patkowski,
R. A. King, E. F. Valeev, F. A. Evangelista, J. M. Turney, T. D. Crawford,
C. D. Sherrill, J. Chem. Theory Comput. 2017,13, 3185–3197.
[48] L. Krause, R. Herbst-Irmer, G. M. Sheldrick, D. Stalke, J. Appl. Crystallogr.
2015,48, 3–10.
[49] G. M. Sheldrick, Acta Crystallogr., Sect. C: Struct. Chem. 2015,71, 3–8.
[50] O. V. Dolomanov, L. J. Bourhis, R. J. Gildea, J. A. K. Howard, H. Pusch-
mann, J. Appl. Crystallogr. 2009,42, 339–341.
Manuscript received: May 23, 2024
Accepted manuscript online: July 18, 2024
Version of record online: September 10, 2024
Wiley VCH Montag, 23.09.2024
2454 / 368111 [S. 244/244] 1
Chem. Eur. J. 2024,30, e202402011 (10 of 10) © 2024 The Author(s). Chemistry - A European Journal published by Wiley-VCH GmbH
Chemistry—A European Journal
Research Article
doi.org/10.1002/chem.202402011