Distance-Dependent Attractive and Repulsive Interactions of Bulky Alkyl Groups

Article abstract of DOI:10.1002/anie.201602752

The stabilizing and destabilizing effects of alkyl groups on an aromatic stacking interaction were experimentally measured in solution. The size (Me, Et, iPr, and tBu) and position (meta and para) of the alkyl groups were varied in a molecular balance mod

Full text of DOI:10.1002/anie.201602752

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International Edition: DOI: 10.1002/anie.201602752
German Edition: DOI: 10.1002/ange.201602752
Supramolecular Chemistry
Distance-Dependent Attractive and Repulsive Interactions of Bulky
Alkyl Groups
Jungwun Hwang, Ping Li, Mark D. Smith, and Ken D. Shimizu*
Abstract: The stabilizing and destabilizing effects of alkyl
groups on an aromatic stacking interaction were experimen-
tally measured in solution. The size (Me, Et, iPr, and tBu) and
position (meta and para) of the alkyl groups were varied in
a molecular balance model system designed to measure the
strength of an intramolecular aromatic interaction. Opposite
stability trends were observed for alkyl substituents at different
positions on the aromatic rings. At the closer meta-position,
smaller groups were stabilizing and larger groups were
destabilizing. Conversely, at the farther para-position, the
larger alkyl groups were systematically more stabilizing with
the bulky tBu group forming the strongest stabilizing inter-
action. X-ray crystal structures showed that the stabilizing
interactions of the small meta-alkyl and large para-alkyl
Figure 1. Correlation of the alkyl group (Me, Et, iPr, tBu from left to
groups were due to their similar distances and van der Waals
contact areas with the edge of opposing aromatic ring.
right) interaction energies (DDG) measured in CDCl3 (258C) for 1b–
i by the double mutant cycle analysis versus their molar refractivity
substituent parameters.
L
arge alkyl groups, such as, tert-butyl and adamantyl groups,
are commonly incorporated into molecular systems to fix the
conformational preference of flexible molecules[1] or to
enhance the selectivity of chemical reactions[2] and catalysts.[3]
In these applications, the influence of bulky alkyl groups is
primarily ascribed to repulsive steric interactions.[4] However,
recent theoretical and experimental studies have shown that
bulky alkyl groups can also form stabilizing noncovalent
interactions.[5] For example, the introduction of 12 tBu groups
on the periphery of hexaphenylethane appears to stabilize
this kinetically unstable framework by the formation of
attractive intramolecular dispersion interactions.[6] Another
recent example showed that larger alkyl substituents, such as
adamantyl and cyclohexyl groups, preferentially stabilize the
cis-azobenzene conformer.[5a]
groups systematically destabilized the aromatic stacking
interaction (Figure 1).[7] However, in the para-position, the
opposite trend was observed, with larger alkyl groups
stabilizing the aromatic stacking interaction. Thus, the goal
of this study was to quantitatively measure these trends in
solution and to study their origins using X-ray crystallogra-
phy.
The influence of the alkyl groups was assessed from the
folded/unfolded equilibrium ratios of molecular balances 1a–
i and control balances 2a–i in solution (Scheme 1). The
phenyl ether arms of the balances were functionalized with
alkyl substituents of varying size (H, Me, Et, iPr, or tBu) at
either the meta- or para-position. This bicyclic model system
has been successfully employed to measure the stability
trends,[8] the additivity of substituent effects,[9] and the
dispersion contributions for off-set aromatic stacking inter-
actions.[10] Because of restricted rotation of the N-arylimide
rotor, the balances and control balances adopt two distinct
conformational states. In the folded conformation, the
aromatic surfaces of the substituted phenyl ether arms and
phenanthrene shelves are held in a parallel geometry, thus
forming an intramolecular stacking interaction. The off-set
stacking geometry with the phenyl arm extending beyond the
phenanthrene shelf was confirmed by X-ray, NMR spectros-
copy, and modeling studies.[8] This stacking geometry posi-
tions the meta- and para-substituents on the phenyl ether arm
at different distances from the phenanthrene shelf. In the
unfolded conformation, the aromatic surfaces of the arm and
shelf are far apart and cannot form an intramolecular
interaction. Thus, the unfolded–folded conformational equi-
librium provides a very sensitive measure (Æ 0.03 kcal
In the course of studying the substituent effects of
aromatic stacking interactions with our molecular balance
model system, we observed that bulky alkyl groups displayed
opposite stability trends when placed at different distances
from the opposing aromatic rings (Figure 1). Alkyl groups of
increasing size (Me, Et, iPr, and tBu) were introduced at the
meta- and para-positions, and their influence on the stability
of the intramolecular aromatic stacking interaction was
measured. At the closer meta-position, the trend followed
the conventional steric paradigm, as increasingly larger alkyl
[*] J. Hwang, P. Li, M. D. Smith, Prof. K. D. Shimizu
Department of Chemistry and Biochemistry
University of South Carolina, Columbia, SC 29208 (USA)
E-mail: shimizu@mail.chem.sc.edu
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under http://dx.doi.org/10.
1002/anie.201602752.
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subtracts the effects of aromatic stacking, repulsive lone
pair–p, dipole, and solvation effects on the folding ratios in 1x.
An initial analysis of DDGx values showed a clear correlation
with the size of the alkyl groups (Figure 1). The molecular
descriptor molar refractivity (MR), was used to parameterize
the size of the alkyl substituents x, as MR is closely correlated
with molecular van der Waals (VDW) volumes, polarizabil-
ities, and dispersion energies.[12] An excellent linear correla-
tion was observed between MR and the alkyl group inter-
action energies (DDG) for the meta- and para-positions.
Interestingly, the slopes of the linear regressions were
opposite for the meta- and para-alkyl series. The meta-alkyl
group trend followed the conventional paradigm where alkyl
groups form repulsive steric interactions. The bulkiest meta-
tBu group was the most destabilizing (+ 0.20 kcalmolÀ1) and
each successively smaller alkyl group was less destabilizing. In
contrast, in the para-position, the bulkiest para-tBu group was
the most stabilizing (À0.16 kcalmolÀ1) and each successively
smaller para-alkyl group was less stabilizing. Similar opposing
trends of the meta- and para-alkyl substituents were observed
in two additional solvents, [D5]bromobenzene and
[D6]acetone (see Figure S1 in the Supporting Information),
thus suggesting that the trends in Figure 1 were not due to an
artifact of solvent effects in chloroform.
Scheme 1. The unfolded–folded conformational equilibrium (top) of
aromatic stacking molecular balances 1a–k containing alkyl substitu-
ents of varying size and position (a–k), control balances 2a–k (bottom
left), which cannot form intramolecular stacking interactions, and two-
armed balances (3; bottom right), which were used in the X-ray
crystallographic studies.
molÀ1)[9] of the intramolecular stacking and substituent
effects.
X-ray structure analysis was used to study the origins of
the substituent trends. Specifically, the relationship between
the solution interaction energies and the solid-state geo-
metries was investigated. The balances 1a–i do not consis-
tently crystallize in the folded conformation because of the
destabilizing lone pair–p interactions of the ether oxygen
atom.[8a,13] Therefore, a series of two-armed balances (3b, 3e,
3 f, and 3i) were prepared. These balances had identical
substituted phenyl arms at both ortho-positions of the N-
arylimide rotors, thus ensuring that one phenyl ring would
always be in the folded conformation. Two-armed balances
with the smallest Me (3b and 3 f) and largest tBu (3e and 3i)
substituents were crystallized and analyzed by X-ray crystal-
lography. In each structure, the off-set aromatic stacking
interaction was observed between one of the substituted
phenyl arms and the phenanthrene shelf (Figure 3).[8] This
interaction confirmed that the alkyl substituents do not
significantly change or disrupt the stacking interaction. Even
in cases with a large tBu group (3e and 3i), the phenyl arm
was roughly parallel and in close contact to an outer six-
membered ring of the phenanthrene shelf.
The balances 1a–i and control balances 2a–i were pre-
pared with different sized alkyl substituents at the meta- or
para-positions of the phenyl ether arm. The folded/unfolded
ratios in CDCl3 (258C) were measured by integration of the
1H NMR spectra. Folding energies (DG) were calculated from
the folding ratios. The interaction energies (DDGx) for each
alkyl substituent x (where x represents an alkyl substituent in
1b–i) were isolated using a double mutant cycle (DMC)
analysis (Figure 2).[11] The DMC required the DG values for
four balances to measure each alkyl group interaction energy:
DDGx = (DG1xÀDG2x)À(DG1aÀDG2a). The DMC analysis
Surprisingly, the stabilizing meta-Me and para-tBu groups
did not form intramolecular CH–p interactions and instead
were in close contact with the edge of the phenanthrene
shelves. Similar stabilizing close H···H contacts (2.6 to 3.0 ꢀ)
have been observed in the stacked 2,5,8-tri-tert-butyl-phena-
lenyl dimer in the solid state.[14] Therefore, the shortest H···H
distances between each alkyl substituent and the phenan-
threne shelf in the crystal structures were measured and
compared with the corresponding solution alkyl group
interaction energies (Figure 4a). The H···H distances for the
stabilizing substituents (para-tBu and meta-Me) fell into
a narrow intermediate range (2.5 to 3.0 ꢀ). The destabilizing
substituents fell outside this optimal distance. They were
either too close (meta-tBu < 2.5 ꢀ), thus forming repulsive
Figure 2. Double mutant cycle analysis isolating the alkyl group
interaction energies in the balances 1x (x=alkyl substituents 1b–i) in
the folded conformers. For each alkyl substituent, the analyses
required DG values for four balances: 1x, 2x, 1a, and 2a.
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arm above the plane of the phenanthrene shelf as it allows it
to maximize its intramolecular interaction energy.[13] Thus,
alkyl substituents forming repulsive interactions will shift to
longer H···H distances to minimize these destabilizing inter-
actions, and alkyl substituents that are too far apart to interact
with the phenanthrene shelf can shift to shorter H···H
distances to form stabilizing interactions.
An analysis of the contact areas of the interacting surfaces
in the folded conformers of the X-ray structures provided
evidence that the same forces were responsible for the
opposing meta- and para-alkyl group interaction energy
trends (Figure 4b). The surface contact areas (SCAs) were
calculated from the VDW surface areas of the interacting
surfaces in the X-ray crystal structures. The SCA parameter
was defined as the difference in VDW surface areas of the
uncomplexed substituted phenyl arms and phenanthrene
shelves and the corresponding stacking complex (see
Table S2). An excellent linear correlation was found between
the SCAs of the four substituted intramolecular stacking
complexes (meta-Me, meta-tBu, para-Me, para-tBu) in the
crystal structures and the alkyl group interaction energies
measured in solution (Figure 4b, circles). Thus, the similar
stabilizing effects of the para-tBu and meta-Me groups appear
to be due to their optimal fit with the corresponding stacking
complexes, thus yielding large SCAs. Conversely, the desta-
bilizing interactions of the meta-tBu and para-Me groups were
due to their poor fit as evident from their smaller SCAs in
their stacking complexes. The SCAs provided an excellent
predictive parameter for the attractive and repulsive sub-
stituent effects of the alkyl groups. For example, the linear
correlation for the four monosubstituted balances (Figure 4b,
dots) accurately modelled two additional balances with
multiple alkyl substituents (Figure 4b, solid squares). The
solid-state SCAs of the meta,meta’-di-tBu (3k) and meta,me-
ta’,para-tri-Me (3j) balances were well correlated to the
solution alkyl group interaction energies in the corresponding
1k and 1j balances (see the Supporting Information).
Figure 3. Side-views of the X-ray[15] crystal structures of the substituted
phenyl arm and phenanthrene shelf surfaces which form an intra-
molecular aromatic off-set stacking interaction in two-armed molecular
balances with meta-Me (3b), meta-tBu (3e), para-Me (3 f), and para-
tBu (3i) substituents. The other atoms were omitted for viewing clarity.
The shortest H···H contacts between the alkyl substituent of the arm
and the phenanthrene shelf are highlighted with double-headed
arrows. For structures containing multiple crystallographically inde-
pendent molecules and/or structural disorder (3b, 3 f, and 3i), the
structure with the shortest H···H contact distance is shown.
In this study, alkyl groups were found to form stabilizing
interactions through non-electrostatic mechanisms.[17] More
interestingly, large and small alkyl groups were either
stabilizing or destabilizing depending upon their position
rather than size. For example in the para-position, the largest
and bulkiest alkyl groups formed the strongest stabilizing
interaction. This observation is consistent with the recent
concept of dispersion energy donors in which bulky alkyl
groups form stabilizing dispersion interactions.[5f,6c] However,
we also observed the reverse trend at the meta-position, as
smaller alkyl groups formed the most stabilizing interactions.
An analysis of the common factors in these opposing trends
found that the relative distances and VDW surface contact
areas were excellent predictors for the alkyl group interaction
energies. These position-dependent stabilizing interactions of
large and small alkyl groups extend the types of interactions
which they can form beyond the conventional steric effects.
Finally, we are currently studying the relative contributions of
dispersion[18] and solvophobic effects[5d] to these stabilizing
alkyl group interactions in solution.
Figure 4. a) Correlation of the alkyl group interaction energies (DDG)
in solution versus the observed shortest H···H distances (ꢀ) between
the alkyl substituent and aromatic shelf in X-ray crystal structures. In
the cases where more than one crystallographically independent
molecule and/or a structural disorder were observed, the shortest
H···H contact for each structure was measured. b) Correlation of the
measured alkyl group interaction energies (DDG) in solution with the
surface contact area (SCA) of the arm-shelf stacking complexes
calculated from the VDW surface areas of the X-ray structures. The
units with the shortest H···H contact were chosen for SCA assess-
ments.
VDW interactions, or were too far (para-Me > 3.0 ꢀ) to form
effective stabilizing interactions.
The shape of the plot in Figure 4a is similar to a Lennard-
Jones potential. The position of the minimum (2.5 to 3.0 ꢀ) is
consistent with the other crystallographic database studies of
optimal H···H distances for two hydrocarbon units.[16] How-
ever, the slopes of the energy well are much steeper than
a conventional Lennard-Jones potential. This steepness is
likely due to the horizontal mobility of the substituted phenyl
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Received: March 18, 2016
Published online: && &&, &&&&
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Bulk up: Bulky alkyl groups can form
either stabilizing or destabilizing interac-
tions depending on their relative distance
from the molecular surface of interaction.
The presented data point to the refine-
ment of the classical paradigm for steric
effects simply based on the molecular
size.
J. Hwang, P. Li, M. D. Smith,
K. D. Shimizu*
&&&& — &&&&
Distance-Dependent Attractive and
Repulsive Interactions of Bulky Alkyl
Groups
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