Solvent Modulation of Aromatic Substituent Effects in Molecular Balances Controlled by CH-π Interactions

Article abstract of DOI:10.1021/acs.jpca.7b09910

CH-π aromatic interactions are ubiquitous in nature and are capable of regulating important chemical and biochemical processes. Solvation and aromatic substituent effects are known to perturb the CH-π aromatic interactions. However, the nature by which the two factors influence one another is relatively unexplored. Here we demonstrate experimentally that there is a quantitative correlation between substituent effects in CH-π interactions and the hydrogen-bond acceptor constants of the solvating molecule. The CH-π interaction energies were measured by the conformational study of a series of aryl-substituted molecular balances in which the conformational preferences depended on the relative strengths of the methyl and aryl CH-π interactions in the folded and unfolded states, respectively. Due to the favorable methyl-aromatic interactions, the balances were found to exist predominantly in the folded state. The observed substituent effect in the conformational preferences of the balances was controlled by the explicit solvation/desolvation of the aryl proton. The interpretation of the conformational free energy as a function of substituents and solvation using Hunter's solvation model revealed that a linear relationship exists between the sensitivity of aromatic substituent effects (i.e., the ρ values derived from Hammett plots) and the hydrogen-bond acceptor propensity (β_s) of the solvent molecule: ρ = 0.06β_s - 0.04.

Full text of DOI:10.1021/acs.jpca.7b09910

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Article
Solvent Modulation of Aromatic Substituent Effects in
Molecular Balances Controlled by CH-# Interactions
Bright U Emenike, Ronald A. Spinelle, Ambar Rosario, David W. Shinn, and Barney Yoo
J. Phys. Chem. A, Just Accepted Manuscript • DOI: 10.1021/acs.jpca.7b09910 • Publication Date (Web): 15 Jan 2018
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Solvent Modulation of Aromatic Substituent Effects in
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Molecular Balances Controlled by CHꢀπ Interactions
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Bright U. Emenike,1,* Ronald A. Spinelle,1 Ambar Rosario,1 David W. Shinn,2 and Barney Yoo3
1Department of Chemistry, State of University of New York, Old Westbury, NY 11568
2Department of Math and Science, U.S. Merchant Marine Academy, Kings Point, NY 11024
3Department of Chemistry, Hunter College, City University of New York, New York, NY 10065
Corresponding Author
*emenikeb@oldwestbury.edu
ABSTRACT
CHꢀπ aromatic interactions are ubiquitous in nature and are capable of regulating important
chemical and biochemical processes. Solvation and aromatic substituent effects are known to
perturb the CHꢀπ aromatic interactions. However, the nature by which the two factors influence
one another is relatively unexplored. Here we demonstrate experimentally that there is a
quantitative correlation between substituent effects in CHꢀπ interactions and the hydrogenꢀbond
acceptor constants of the solvating molecule. The CHꢀπ interaction energies were measured by
the conformational study of a series of arylꢀsubstituted molecular balances in which the
conformational preferences depended on the relative strengths of the methyl and aryl CHꢀπ
interactions in the folded and unfolded states, respectively. Due to the favorable methylꢀaromatic
interactions, the balances were found to exist predominantly in the folded state. The observed
substituent effect in the conformational preferences of the balances was controlled by the explicit
solvation/desolvation of the aryl proton. The interpretation of the conformational free energy as a
function of substituents and solvation using Hunter’s solvation model revealed that a linear
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relationship exists between the sensitivity of aromatic substituent effects (i.e., the rho values
ρ
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derived from Hammett plots) and the hydrogenꢀbond acceptor propensity (βs) of the solvent
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molecule:
ρ = 0.06βs − 0.04.
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Introduction
Aromatic interactions—such as πꢀπ stacking, CHꢀπ, cationꢀπ interactions—are among the most
prevalent nonꢀcovalent interactions present in both synthetic and natural systems.1ꢀ2 Although
aromatic interactions are naturally weak, their collective strength is significant and plays decisive
roles in chemical and enzymatic catalysis,3ꢀ6 protein folding,7ꢀ8 templateꢀdirected synthesis,9 and
materials science.10 The strength of nonꢀcovalent interactions can be tuned by changing the
properties of the local environment through solvent11ꢀ17 and substituent modulations.18ꢀ22 While
numerous studies have examined substituent effects in aromatic interactions through linear free
energy relationships, studies on the potential synergy—or the lack thereof—between solvation
and the efficiency of aromatic substituent effects are rare. Considering the ubiquity of aromatic
interactions, it is imperative to understand the environmental factors that influence the efficacy
of aromatic substituent effects. Such an understanding would immensely expand our knowledge
and application of aromatic interactions to the benefit of rational design of drugs, catalysts, and
related functional materials.
There are two broad mechanisms for substituent effects in aromatic interactions. In πꢀπ stacking
for instance, Hunter and Sanders23 (HS) proposed that aromatic substituent effect arises from the
changes in the π electron density of the aromatic ring. Intuitively, electronꢀwithdrawing
substituents reduce the π electron density and electronꢀdonating substituents increase the π
electron density. Although the HS model is accepted pervasively, Wheeler and Houk24ꢀ25 (WH)
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proposed an alternative model in which aromatic substituent effects are described exclusively in
terms of the direct (throughꢀspace) interactions between the substituents and the nearest vertex of
the other aromatic ring. Both the HS and WH models are useful for predicting substituent effects
in aromatic interactions.26 To the best of our knowledge, aromatic substituent effects in nonꢀ
covalent interactions have never been examined in the context that they might be influenced by
solvation. This knowledge gap could have ramifications for the efficiency of aromatic
interactions in environments where the local property is discontinuous—such as in the protein
environment.
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In quantifying the CHꢀπ aromatic interactions between the edge of a phenyl ester and the
face of substituted aromatic rings (using a series of molecular torsion balances), Wilcox and coꢀ
workers27 observed no substituent effects in chloroform; and as a result, they concluded that
edgeꢀtoꢀface aromatic interactions must originate from dispersion forces. Diederich and coꢀ
workers28 performed the same experiment—only this time, a different torsion balance containing
a 4ꢀ(trifluoromethyl)phenyl ester was used—and found a linear Hammett plot, suggesting that
edgeꢀtoꢀface aromatic interactions have an electrostatic origin. Although one might argue that
both electrostatic and dispersion are intrinsic features of the edgeꢀtoꢀface aromatic interaction,29
the different results seem to suggest that the mechanism of aromatic substituent effects is not
entirely an intrinsic property of the associated aromatic interactions, but rather one that changes
with solvation. Therefore, understanding the physical origin for this behavior would be
paramount in molecular recognition events. The specific goal of the present study is to explore
whether aromatic substituent effects in CHꢀπ interactions is affected by the properties of the
solvating media.
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Experimental Section
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Measurement of interaction energies (ꢁG) and error analysis. The folded/unfolded ratios
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were measured by proton NMR spectra at room temperature (~ 25°C). All spectra were recorded
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1
on a Bruker Avance operating at 400 MHz for the H nucleus. All samples were recorded as 15
mM solution. Before integration all spectra were lineꢀfitted to 100% Lorentz functions.
Error Analysis. Standard deviation of the equilibrium constant K determined by multiple
measurements and integration of the lineꢀfitted (100% Lorentz functions) 1H NMRspectra.
Because error resulting from integration is typically smaller (~ 1%) than the error resulting from
the experimental standard deviation (~ 5%) for concentrations above 10 mM, the standard error
applies equally to all experiments.30ꢀ31
δ (lnK) = δK/K = 0.05
δ(ꢁG) = RT[δ (lnK)] = 0.03 kcal/mol
Preparation of pentacene.32 Solid NaBH4 (1.23 g, 32.4 mmol) was slowly added to a 100 mL
round bottom flask containing a suspension of pentaceneꢀ6,13ꢀdione (500 mg, 1.62 mmol) in
THF (60 mL) at 0 °C. After NaBH4 addition was complete, the reaction vessel was purged with
nitrogen gas and 2 mL of water was added. The reaction mixture was heated to 50 to 60 °C until
homogeneous. After 2 hours of heating, THF was evaporated and water was added, and the
reaction mixture was filtered. The solids were washed with copious amounts of water. After
drying, 420 mg of a white solid was obtained, which was used directly in the next step.
To the product of the first step, SnCl2. 2H2O (0.72 g, 3.2 mmol), DMF (8 mL) and 10 mL
of conc. HCl was added over ~ 30 seconds with stirring at 0 °C (iceꢀwater bath) in the dark. The
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resulting blue reaction mixture was stirred briefly (~15 s) at 0 °C before an additional 10 mL of
conc. HCl was added over ~30 seconds followed by the rapid addition of 50 mL water. The deep
blue solids were filtered and washed with 25 mL amounts of water followed by 10 mL acetone.
All washings were performed in air in the dark. The blue solid was dried under reduced pressure
yielding 0.36 g of pentacene (79% yield, over two steps).
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Synthesis of molecular balances.11 Pentacene (1 mmol, 278 mg) and 1 mmol of the appropriate
substituted Nꢀarylimide were mixed in a reaction tube containing 5 mL toluene. The reaction
tube was sealed under nitrogen atmosphere and was placed in an oil bath at 100°C. After ~ 5 h,
the darkꢀblue reaction solution turned light yellow, indicating the complete consumption of the
pentacene. The reaction tube was cooled to room temperature and the crystalline product was
collected by filtration. Further purification of the balance was achieved, when necessary, by flash
column chromatography using ethyl acetateꢀhexane mixtures.
Balances 1a and 1c have been previously reported,11, 13 while balance 1b, 1d, and 1e are new and
full characterization are shown below:
1
1b: Yield = 78%. H NMR (400 MHz, MeCNꢀd3) δ = 0.41 (s, 2H, major), 2.10 (s, 1H, minor),
3.59 (s, 2H), 4.82 (d, 1H) 5.09 (s, 2H), 6.58 (d, 1H, J = 8.4 Hz, minor), 6.90 (m, 1H), 7.23ꢀ7.97
13
(m, 16H). C NMR (101 MHz, DMSOꢀd6) δ = 15.5, 17.6, 45.2, 45.7, 47.1, 47.2, 122.9, 123. 0,
123.9, 124.3, 126.3, 126.4, 126.8, 126.9, 127.6, 127.8, 128.3, 129.1, 129.2, 130.6, 130.8, 132.5,
132.6, 132.9, 135.0, 135.1, 135.6, 136.0, 137.3, 137.9, 138.0, 138.4, 175.8, 175.9. HRMS calcd
for C33H22ClNO2 [M+H]+ 500.1412, found 500.1407
1
1d: Yield = 81%. H NMR (400 MHz, DMSOꢀd6) δ = 0.34 (s, 2H, major), 1.95 (s, 1H, minor),
2.12 (s, 1H, mior), 2.19 (s, 2H, major), 3.61 (s, 2H, major), 3.67 (s, 1H, minor), 4.66 (d, 1H, J =
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8.0 Hz, minor), 5.13 (s, 2H), 6.36 (d, 1H, J = 8.0 Hz, minor), 6.38 (d, 1H, J = 8.0 Hz), 6.77 (s,
1H), 6.87 (d, 1H, J = 8.0 Hz, major), 6.99 (m, 1H), 7.50 (m, 4H), .7.90 – 8.05 (m, 8H). 13C NMR
(101 MHz, CDCl3) δ = 15.5, 15.6, 20.9, 21.0, 45.3, 45.7, 47.1, 47.1, 122.9, 123.0, 124.0, 126.2,
126.3, 126.8, 127.3, 127.5, 127.5, 127.7, 127.8, 128.0, 131.4, 131.6, 132.6, 132.6, 133.0, 134.9,
135.5, 135.8, 136.1, 138.3, 138.7, 139.4, 176.2, 176.3. HRMS calcd for C34H25NO2 [M+H]+
480.1958, found 480.1956
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1e: Yield = 84%. 1H NMR (400 MHz, CDCl3) δ = 0.47 (s, 2H, major), 2.05 (s, 1H, minor), 3.58
(s, 2H, major), 3.66 (s, 1H), 3.69 (s, 2H), 4.90 (d, 1H, J = 8.8 Hz), 5.15 (s, 2H), 6.14 (d, 1H, J =
8.8 Hz, minor), 6.46 (s, 1H, major), 6.71 (m, 1H), 6.87 (d, 1H, J = 8.8 Hz), 7.51 (m, 4H), 7.77
(m, 8H). 13C NMR (101 MHz, DMSOꢀd6) δ = 15.6, 17.9, 45.2, 45.7, 47.0, 47.0, 55.2, 60.4,
111.9, 112.0, 115.9, 116.0, 122.8, 123.0, 123.1, 123.3, 123.9, 124.2, 126.2, 126.2, 127.6, 127.8,
128.0, 128.2, 128.7, 129.1, 132.5, 135.7, 136.1, 136.6, 137.3, 138.2, 138.6, 159.9, 159.9, 176.4.
HRMS calcd for C34H25NO3 [M+H]+ 496.1907, found 496.1904
Results
The Nꢀaryl imide balances (Scheme 1), similar to the designs emerging from Shimizu’s lab,33ꢀ35
have proven useful in quantifying weak nonꢀcovalent interactions in solution. The methyl group
at one of the ortho positions (of the rotatable Nꢀaryl ring) allows the competing folded and
unfolded conformers to be in equilibrium with distinctive NMR signals. The ratio of these
conformers, measured by proton NMR integration at room temperature, provides a means for
estimating the position of the conformational equilibrium and for calculating the folding energy
according to equation 1. Thus, the folding energy (∆G) value is the difference in the free energies
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of the folded and unfolded conformers, where a negative ∆G value indicates the folded
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conformer is more stable than the unfolded conformer.
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Scheme 1. Derivatives of the Nꢀaryl imide molecular balances used in this study.
Scheme 2. Synthesis of balance 1. (a) (i) NaBH4/THF (ii) SnCl2.2H2O, HCl/DMF (b) Toluene,
sealedꢀtube heat.
∆G = ꢀRTlnKeq = ꢀRTln[folded]/[unfolded]
(1)
The Nꢀarylimide molecular balances are readily synthesized (as can be seen in scheme 2).
Pentancene is prepared in a twoꢀstep reaction, which further undergoes a thermal DielsꢀAlder
reaction with the appropriate substituted arylimide to produce the desired molecular torsion
balances.
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In the folded state, the Nꢀaryl methyl is positioned directly above the π cloud of the
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naphthalene ring, which results in the formation of an intramolecular CHꢀπ interaction while the
aryl proton of the other ortho carbon is exposed to solvation. Consequently, the conformational
preferences of the molecular balance are controlled by two factors: (1) the solvation/desolvation
energies of the exchanging functional groups, and (2) the intrinsic energies of the aromatic
interactions. Although aryl CHꢀπ interaction is expected to be more energetic than methyl CHꢀπ
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interaction,36 the preference for the folded state can be attributed to a weak aryl CHꢀπ interaction
in the unfolded state, which is likely caused by the long distance between the aryl proton and the
naphthalene carbon—3.56 Å at the B3LYP/6ꢀ31+G(d) level. To ascertain whether aromatic
substituent effects are solvent dependent, various X substituents were placed on the Nꢀaryl ring
and the resulting changes in conformational free energy were determined as a function of
solvation (Table 1). Positioning the X substituents on the Nꢀaryl axis of rotation eliminates
conformational bias arising from either (1) the differential direct interaction between the
substituent and the aromatic ring,24 (2) the differential position of the substituents,37 or (3) the
preferential solvation of the substituents.38 The results (as summarized in Table 1) demonstrated
that the folding energy varies as the substituents were changed, and, also, the folding energy of
each Xꢀsubstituted balance varies as a function of solvation. However, the degree of
conformational freeꢀenergy change (∆G) is apparently solvent dependent. For instance, ∆G
spanned a range of 0.5 – 0.9 kcal/mol in DMSO, whereas the range was miniscule in chloroform,
0.26 – 0.29 kcal/mol.
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Table 1. Measured folding Gibbs free energies of balances 1a ꢀ e in different deuterated
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solvents.
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Solventsc
DMSO
X
(%)Foldeda ∆G (kcal/mol)b
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NO2
Cl
H
CH3
OCH3
NO2
Cl
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76
70
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73
ꢀ0.90
ꢀ0.68
ꢀ0.50
ꢀ0.53
ꢀ0.59
THF
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ꢀ0.68
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H
CH3
OCH3
NO2
Cl
H
CH3
OCH3
NO2
Acetone
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ꢀ0.50
ꢀ0.37
ꢀ0.37
ꢀ0.45
Acetonitrile
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ꢀ0.59
Cl
H
CH3
OCH3
NO2
Cl
H
CH3
OCH3
NO2
Cl
H
CH3
OCH3
70
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ꢀ0.50
ꢀ0.37
ꢀ0.37
ꢀ0.42
Benzene
Chloroform
CCl4
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62
ꢀ0.34
ꢀ0.26
ꢀ0.26
ꢀ0.24
ꢀ0.29
61
ꢀ0.26
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62
ꢀ0.29
ꢀ0.26
ꢀ0.26
ꢀ0.29
NO2
Cl
H
CH3
OCH3
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ꢀ0.31
ꢀ0.26
62
ns
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ꢀ0.29
ns
ꢀ0.34
[a] Determined by integration of 1H NMR spectra at 298K. [b] Uncertainty ± 0.03 kcal/mol. [c]
Deuderated solvents except for CCl4. Ns = not soluble.
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Discussion
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The quantitative measurement of aromatic substituent effect is customarily assessed through the
Hammett relationship, equation 2.39 Here, the energies of aromatic substituent effects (∆∆GASE
)
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were established more effectively with Hammett σm constants. The Hammett constant (σm) is the
substituent constant for metaꢀsubstituents in benzene derivatives as defined by Hammett on the
basis of the ionization of metaꢀsubstituted benzoic acids in water.39 The slope of the Hammett
plot (the rho value,
ρ) describes the susceptibility of the balance’s conformational preferences to
the aromatic substituents.40 The
ρ
parameter serves as the quantitative measure of aromatic
substituent effects in the conformational preferences of the molecular balances. With standard
reference to the substituent effects in the ionization of benzoic acids, a value of 1 suggests a
ρ
strong substituent effect while a zero
ρ
value is indicative of no substituent effect.
(2)
∆∆GASE = ∆GX - ∆GH = ρσm
The Hammett plots derived from the experimental results (Figure 1) indicated that aromatic
substituent effects in the balance system varied with solvation because the slopes—although not
as high as 1—varied with changing solvent properties. Specifically, the polar solvents (DMSO,
THF, acetone, and acetonitrile) showed steeper slopes (0.29 – 0.50) than the nonꢀpolar solvents
(benzene, CCl4, and chloroform), which were close to zero (0 – 0.11). This trend seems to
suggest that the slope diminishes as the polarity of the solvents is reduced. The lack of apparent
substituent effects in the nonꢀpolar solvents could be attributed to the dominance of dispersion
forces, which is one way of explaining poor Hammett correlations. 27 Conversely, we sought for
a quantitative rationale based on Hunter’s solvation model,41 which has been useful in explaining
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solvent effects in a variety of nonꢀcovalent interactions including hydrogen bond,12 edgeꢀtoꢀface
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aromatic,15, 42 CHꢀπ,11 and cationꢀπ interactions.13
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0.4
0.3
0.2
0.1
0
NO2
0.4
0.3
0.2
0.1
0
DMSO (βs = 8.9)
THF (βs = 5.9)
y = 0.33x + 0.02
R² = 0.97
y = 0.50x + 0.03
R² = 0.97
NO2
Cl
Cl
OCH3
CH3
OCH3
CH3
H
H
-0.1
-0.1
-0.2
0
0.2 0.4
Hammett σm
0.6
0.8
-0.2
0.3
Hammett σm
0.8
0.4
0.4
0.3
0.2
0.1
0
Acetonitrile (βs = 5.1)
Acetone (βs = 5.7)
y = 0.29x + 0.02
R² = 0.96
y = 0.30x + 0.01
R² = 0.99
0.3
0.2
0.1
0
NO2
NO2
OCH3
Cl
Cl
CH3
CH3
OCH3
0.2
H
H
-0.1
-0.1
-0.2
0
0.2
0.4
0.6
0.8
-0.2
0
0.4
0.6
0.8
Hammett σm
Hammett σm
0.4
Chloroform (βs = 0.9)
0.4
Benzene (βs = 2.1)
0.3
0.2
0.1
0
y = 0.00x - 0.02
R² = 0.00
0.3
0.2
0.1
0
y = 0.11x - 0.01
R² = 0.73
NO2
OCH3
OCH3
NO2
CH3 H
CH3
Cl
Cl
H
-0.1
-0.1
-0.2
0
0.2
0.4
0.6
0.8
-0.2
0
0.2
0.4
0.6
0.8
Hammett σm
Hammett σm
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0.4
0.3
0.2
0.1
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CCl4 (βs = 0.6)
y = -0.01x + 0.01
R² = 0.00
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NO2
OCH3
Cl
H
-0.1
-0.2
0.3
Hammett σm
0.8
Figure 1. Correlation plot of ∆∆GASE and σm in various solvents.
Hunter’s solvation model posits that solvation can be summarized as the collection of explicit
electrostatic interactions (αβ) between solute and solvent molecules involving pairs of hydrogen
bond donor (α) and acceptor (β).41 This idea is analogous to the explicit solvation model put forth
by Abraham and coꢀworkers.43ꢀ44 Even though all hydrogenꢀbond sites participate in this
solvation model, only the sites indicated with blue circles in the schematic representation
(Scheme 3) undergo changes between the folded and unfolded transition. The atoms that undergo
solvation in one conformational state and desolvation in another state were discerned from the
electrostatic map potential resulting from the structural optimization at the DFT B3LYPꢀD3/6ꢀ
31+G(d) level. Thus, the conformational free energy change (∆G) can be theorized in the form of
equation 3, which considers: (1) the ∆G values for solvating the exposed hydrogenꢀbond sites in
the folded (α1βs and α2βs) and the unfolded states (αsβ and α1βs) and (2) the intrinsic ∆G values
for the intramolecular interactions (α1β in the folded and α2β in the unfolded states).
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βs
5
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α
H
1
NO2
βs
NO2
βs
α
H
1
α
H
2
α
H
1
O
O
βs
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N
N
α
H
α2
βs
1
αs
O
O
α
1 α1
β
β
β
β
‘exposed’
ꢀ
ꢀ
ꢀ
B3LYPꢁD3/6ꢁ31+G(d)
Scheme 3. Top: Schematic representation of explicit balanceꢀsolvent interactions in the folded
and unfolded conformational states (top). Bottom: The DFT optimized foldedꢀstate conformation
(at the B3LYPꢀD3/6ꢀ31+G(d) level) is in good agreement with the crystal structures of related
molecular balances.45
∆G = (αsβ + α2β + 3α1βs) – (2α1β + α1βs + α2βs)
∆G = 2α1(βs – β) – α2(βs – β) + αsβ
(3)
Because inductive effects are characteristically distance dependent, it is reasonable to assume
that the X substituent should affect only the acidities of α1 and α2 protons. In other words, the β
value of the naphthalene π face—forming the CHꢀπ interactions—should remain unperturbed by
the variations of the X substituents. Thus, the energetics of the aromatic substituent effect
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(∆∆GASE), measured as ∆GX – ∆GH, can be expressed with equation 4, where change in the αsβ
5
6
term (of equation 3) is zero.
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∆∆GASE = ∆GX – ∆GH = (∆2α1 – ∆α2) (βs – β)
(4)
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Equation 4 is analogous to equation 2 because ∆∆GASE in both equations is directly proportional
to solventꢀdependent properties: for equation 2 and βs – β for equation 4. In other words, there
should be a linear relationship between the experimental values and the solvent empirical βs
values if equation 4 is valid. Indeed, the plot of as a function of βs produced a nearly perfect
ρ
ρ
ρ
linear correlation (R2 = 0.99; Figure 2), which reflects on the synergy that exists between
aromatic substituent effects and solvation in the molecular balance. Specifically, aromatic
substituent effects in the balance system increased linearly with increasing propensity of the
solvent to act as a hydrogenꢀbond acceptor:
ρ
= 0.06 βs – 0.04. This implies that the balance
< 0.11) in solvents of small βs values
system will show little to no aromatic substituent effects (
ρ
(βs < 2.5), which includes most nonꢀpolar solvents. An additional direct validation for equation 4
is that the ∆∆GASE term, for each substituent, correlates well with the solvents’ βs values (see
supporting information).
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0.6
0.5
0.4
0.3
0.2
0.1
0
ρ
ρ = 0.06 βs - 0.04
R² = 0.99
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-0.1
0
2
4
Solvent parameter βs
6
8
10
Figure 2. Correlation of rho values (ρ) as a function of solvents’ hydrogenꢀbond acceptor
constant (βs). The βs values were obtained from literature.41
Equation 4 provides the foundation for explaining the mechanism of the observed substituent
effects in the molecular balance. Because aryl protons (such as Hα2) are stronger hydrogenꢀbond
donors than benzyl protons (such as Hα1) vide infra,17 it is reasonable to suggest that the folding
of the balance is driven mainly by the favorable solvation of the exposed α2 proton in the folded
state. In order to substantiate this assertion, the values of α1 and α2 were estimated at the AM1
level following the protocols provided by Hunter.41 When the substituent X = H, Hα2 (0.9) is a
stronger hydrogenꢀbond donor than Hα1 (0.7). However, when X = NO2, the difference in
hydrogenꢀbond donor constants increased to 0.6 (i.e., Hα2 = 1.9 and Hα1 = 1.3). This supports the
idea that the increase in folding observed in solvents with strong hydrogen bond accepting
propensities stem primarily from the preferential solvation of the Hα2 proton. Conversely, the
apparent lack of substituent effects in the nonꢀpolar solvents can be attributed to the small (near
zero) values of the βs – β term. Because the hydrogenꢀbond acceptor constants of the nonꢀpolar
solvents (βs: benzene = 2.1 and chloroform = 0.9) closely matches that of the region of the
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naphthalene π face (forming the aromatic interactions, β = 1.9), the two acceptor sites compete
equally for the same donors; and this process is independent of the effective donor propensity of
the interacting hydrogen.
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If preferential solvation is responsible for the aromatic substituent effects observed in
balance 1 series, improving the solvation of Hα2 in the unfolded state—which is possible in a
series of control models (2a – 2e)―should lead to a reduced rho value. The control models
possess aryl substituents equivalent to that of balance 1 series; however, balance 2 lacks the
naphthalenyl ring present in balance 1. The loss of the aromatic ring should increase the
solvation of the Hα2 proton in the unfolded state. While balance 1 showed the strongest
substituent effects in DMSO (
ρ
= 0.50), the rho value observed for the control model, on the
= 0.07, Figure 3). This observation is consistent with the idea
other hand, was much smaller (
ρ
that the aromatic substituent effects are strongly influenced by the differential local soluteꢀ
solvent interactions in the conformational states.
Figure 3. Conformational preferences of control balances (2a – e) as a function of Hammett
constant measured in deuderated DMSO.
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Conclusion
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The goal of this study was to investigate whether or not aromatic substituent effects in CHꢀπ
interactions are solvent dependent and whether or not such a behavior can be explained
quantitatively. These objectives were met by studying the conformational preferences of a series
of substituted Nꢀaryl molecular balances, which, with the aid of Hunter’s solvation model,41
revealed that aromatic substituent effects depend exclusively on solvents’ hydrogenꢀbond
acceptor propensity, βs. In polar solvents (such as DMSO), the solvent molecule is a stronger
hydrogenꢀbond acceptor than the π face of the naphthalene ring (i.e., βs > β); therefore, the
aromatic substituent effect favors folding because of the preferential solvation of the ortho aryl
proton. On the other hand, nonꢀpolar solvents (such as chloroform and benzene) have
approximately similar βs values as the π face of the naphthalene ring (i.e., βs ≈ β); and as a result,
it appears that the aromatic substituent effect have been washed out by solvation. Hammett plot
is one of the tools for interpreting the mechanism of aromatic interactions, but the effects of
solvation on such analyses are often ignored. As demonstrated in this work and related studies,11,
13, 15, 42, 46 the delicate balance between desolvation and functional group interactions controls the
behavior of closely related systems.
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Supporting Information. Proton and carbon NMR spectra for balances 1 and 2 series. The
following files are available free of charge.
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
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We acknowledge donors of the American Chemical Society Petroleum Research Fund for
support of this research (ACSꢀPRF # 55504ꢀUNI4). DWS47 and BUE thanks SUNY Old
Westbury for Faculty Development Grants. AR acknowledges CSTEP (SUNY Old Westbury)
for summer stipends.
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The authors declare that the views expressed in this article are the authors’ own and not
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