Substituent Effects in CH Hydrogen Bond Interactions: Linear Free Energy Relationships and Influence of Anions

Article abstract of DOI:10.1021/jacs.5b08767

Aryl CH hydrogen bonds (HBs) are now commonly recognized as important factors in a number of fields, including molecular biology, stereoselective catalysis, and anion supramolecular chemistry. As the utility of CH HBs has grown, so to has the need to understand the structure-activity relationship for tuning both their strength and selectivity. Although there has been significant computational effort in this area, an experimental study of the substituent effects on CH HBs has not been previously undertaken. Herein we disclose a systematic study of a single CH HB by using traditional urea donors as directing groups in a supramolecular binding cavity. Experimentally determined association constants are examined by a combination of computational (electrostatic potential) and empirical (σ_m and σ_p) values for substituent effects. The dominance of electrostatic parameters, as observed in a computational DFT study, is consistent with current CH HB theory; however, a novel anion dependence of the substituent effects is revealed in solution.

Full text of DOI:10.1021/jacs.5b08767

Article
pubs.acs.org/JACS
Substituent Effects in CH Hydrogen Bond Interactions: Linear Free
Energy Relationships and Influence of Anions
Blakely W. Tresca,† Ryan J. Hansen,† Calvin V. Chau,† Benjamin P. Hay,‡ Lev N. Zakharov,§
Michael M. Haley,*,† and Darren W. Johnson*,†
†Department of Chemistry & Biochemistry and the Materials Science Institute, University of Oregon, Eugene, Oregon 97403-1253,
United States
‡Supramolecular Design Institute, 127 Chestnut Hill Road, Oak Ridge, Tennessee 37830-7185, United States
§CAMCOR, University of Oregon, 1443 East 13th Avenue, Eugene, Oregon 97403, United States
S
* Supporting Information
ABSTRACT: Aryl CH hydrogen bonds (HBs) are now
commonly recognized as important factors in a number of fields,
including molecular biology, stereoselective catalysis, and anion
supramolecular chemistry. As the utility of CH HBs has grown,
so to has the need to understand the structure−activity
relationship for tuning both their strength and selectivity.
Although there has been significant computational effort in this
area, an experimental study of the substituent effects on CH HBs
has not been previously undertaken. Herein we disclose a
systematic study of a single CH HB by using traditional urea
donors as directing groups in a supramolecular binding cavity.
Experimentally determined association constants are examined
by a combination of computational (electrostatic potential) and empirical (σm and σp) values for substituent effects. The
dominance of electrostatic parameters, as observed in a computational DFT study, is consistent with current CH HB theory;
however, a novel anion dependence of the substituent effects is revealed in solution.
INTRODUCTION
■
CH hydrogen bonds (HBs) are now understood to be a
ubiquitous structural feature in chemistry and biology.1,2 CH
donors play important and previously unrecognized roles in the
multidisciplinary fields of molecular biology, supramolecular
chemistry,3−5 and catalysis.1,6 CH···O HBs are common in
protein folding and are found in the minor groove of DNA.7,8
Catalysts have also been found to include CH···O HBs as an
important factor in stereoselectivity.6 Chemists are now widely
using CH groups as HB donors in designed systems for anion
capture1,9−11 and catalysis.12,13
Figure 1. (a) Prototypical examples of polarized, strong CH donors.
(b) Preferred benzene hydrogen bond geometries. (c) Equilibrium of
New CH donors have been developed to maximize the
strength of a CH HB, including triazoles, bisketo-boronates,
benzoic acids for derivation of Hammett parameters.
and pyridinium ions (Figure 1a).14 These strong, acidic CH
donors, when incorporated within heterocycles with electron-
et al. have sought to dissect the strength of an arene CH vs an
poor atoms, are aligned to maximize the C←H dipole. The
development of such new CH donors has increased the utility
of these nonclassical HBs in structural design.
Despite the numerous computational studies on strong CH
HB donors, experimental studies that quantify the energetic
components of CH HBs, especially for weaker donors like
benzene, have proven very difficult to obtain. As such,
explanations and descriptions for CH HB strengths have
been overwhelmingly dominated by the electrostatic compo-
nent. Notable computational and experimental studies by Flood
alkyl CH.15 A similar structure was used by Garcia Mancheno
̃
and co-workers to examine the influence of structure and
electronics on catalysis;12,13 however, neither of these
investigations measured the direct effects of substituents or
anions on the CH donor energy or the CH component of the
total Gibbs free energy of association for these HBs. The lack of
Received: August 18, 2015
© XXXX American Chemical Society
A
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−
studies on these aspects of CH HBs has led to some confusion
on the characteristics, i.e., strength and selectivity, compared to
traditional HB donors.
anions (Cl−, Br−, I−, and NO3 ). Association constants, Ka, are
reported for seven receptors (1a−g) in water-saturated CHCl3.
Combined solution experiments, crystallography, and compu-
tations provide new insight into the preferred CH binding
geometry and electronic control. Linear free energy relation-
ships using Hammett parameters and ESP reveal ρ dependence
on the anion being titrated. Multivariate analysis with Swain−
Lupton field (F) and resonance (R) parameters provides a
deeper understanding of the percent resonance contribution to
aryl CH acidity.28,29 Our combined experimental and computa-
tional approach for understanding CH HBs provides renewed
support for the role of resonance in CH HBs. In addition,
consideration of the anion in a supramolecular structure activity
relationship identifies a new avenue for understanding and
predicting anion binding selectivity.
Conversely, the related interactions between anions and
electron-deficient aromatic rings have been the subject of
extensive computational and experimental studies that have
resulted in the complete dissection of the energetic
components and substituent effects.16,17 It has also been
recognized that an anion can interact with the face of an arene
via anion−π or weak−σ interactions, leading to differentiation
in both substituent and anion effects.18−20 Computational
studies indicate this type of dual anion and substituent
dependence is important in CH HBs as well, although this
has not been reduced to practice experimentally.21 As a
standard and classical physical organic tool, the use of linear
free energy relationships (LFERs), particularly the Hammett
equation, for probing dynamic interactions is increasingly
popular.22
RESULTS AND DISCUSSION
■
Synthesis and Characterization. The substituted recep-
tors used for this study are part of the bis(2-anilino-
ethynyl)arene family of conjugated, fluorescent receptors we
have reported previously.30−36 In this case, pendent methoxy
substituted phenylureas act as additional HB donors to direct
the anion binding into a single site, as illustrated in Figure
2b.19,32,35 The synthesis of 1a has been previously reported and
forms the parent scaffold for our study of substituent effects.27
These receptors are highly modular and easily broken into
three key units for stepwise synthesisa core arene, an alkynyl
aniline, and an isocyanate.36 For the current investigation, the
core arene can be any 3,5-dibromo- or 3,5-diiodobenzene
suitable for Sonogashira cross-coupling possessing either an
electron-withdrawing or electron-donating substituent in the 1-
position. The t-Bu group on the alkynyl aniline was used to
provide solubility in noncompetitive organic solvents (i.e.,
CHCl3). The 4-methoxy unit was chosen for the pendent
phenylurea due to its simpler monomeric speciation in solution
and to modulate the strength of the competing urea HBs. Such
electron-rich ureas provide less competition with the CH···X−
HB and have proven to be less prone toward self-aggregation.
Dianilines 2a−g were synthesized by Sonogashira cross-
coupling of 2-ethynyl-4-tert-butylaniline (desilylated 3) with the
corresponding dihaloarenes 4a−g (Scheme 1). Reaction of the
resulting dianilines with 4-methoxyphenyl isocyanate afforded
the bisureas 1a−g. In most cases, the bisurea could be purified
by trituration with EtOH to provide analytically pure samples.
Receptors 1a−g were characterized by 1H and 13C NMR
spectroscopy and high-resolution mass spectrometry. Complete
synthetic procedures can be found in the Supporting
Information (SI). The pendent ureas on our receptors are
necessary to boost the overall binding energy high enough to
Hay et al. performed an initial study to quantify the binding
energy of benzene CH HBs, wherein they described both quite
strong HBs to anions in the gas phase and a linear dependence
of the binding energy on substituent electron-withdrawing
ability, as measured by different substituent effects.23,24 The
substituent effects in their model (Figure 1b) could be
described by a Hammett σm or electrostatic potential
(ESP).24 The use of a Hammett σm parameter to describe an
interaction at the para position is typically assumed to indicate
a mostly electrostatic interaction, due to the lack of conjugation
at the meta position in the prototypical Hammett reaction,
namely, the ionization of benzoic acid (Figure 1c).25
The assumption of electrostatic dominance is supported by
the additional correlation with ESP. A recent analysis by
Scheiner et al.21 of HBs to trifluoromethane revealed subtle
energetic parameters. As included in the definition of a
hydrogen bond, there exists a bond critical point between the
H and X− (anion), as well as a shift in the vibrational frequency
of the CH stretch.26 These effects are driven by the partial
covalency of the HB and can be accentuated by examining the
changes across a series of anions.
In the course of designing selective, fluorescent anion
receptors, our group recently introduced the benzene CH HB
donor into our existing bisarylethynyl urea scaffold to produce
1a (Figure 2a).27 In this report we have sought to better
understand the parameters for controlling aryl CH HB acidity
with anions by substitution para to the CH donor, 1b−g. The
modularity of our scaffold allows us the unique chance to study
a single CH···X− HB by easily accessible solution techniques:
1H NMR and UV−vis spectroscopic titrations with multiple
37
1
observe in solution by H NMR and UV−vis spectroscopy.
Previous efforts to study substituent effects in noncovalent
interactions have been complicated by substituents altering
peripheral HBs.16,38 Gratifyingly, the 1H NMR spectra of these
receptors in DMSO-d6 show a small shift in the urea protons
(Hh and Hg, Figure 3), suggesting substitution is far enough
away to minimize, but not completely mitigate, the substituent
effects on the ureas while still modulating the core CH HB
donor acidity.39 The closest aromatic proton to the central ring,
Hd, shifts <0.01 ppm between the −NO2 (1b) and −NMe2
(1g) substituted receptors. The central ring protons, however,
show a strong substitution dependence, with Hb ranging from
7.0 (1f) to 8.5 ppm (1b). The isolation of substituent effects on
the Δδ to just the central ring is necessary to measure only the
Figure 2. (a, left) Urea anion receptor 1a shown in optimal binding
geometry for Cl−. (b, right) X-ray crystal structure of 1a⊂Cl− with
solvent (CHCl3, orange) and counterion (TBA+, blue) included as
space-filling models. CCDC no. 929532.
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The structure of bisurea 1b was determined from a single
crystal grown by vapor diffusion of n-hexane into CH3CN. Host
1b, in the absence of a guest anion, forms long columnar stacks
with urea HBs and π−π interactions stitching the layers
together (Figure 4a). Columns are held together by dispersion
Scheme 1. Synthesis of Bisarylethynyl Urea Receptors 1a−g
Figure 4. (a, left) X-ray crystal structure of 1b, showing hydrogen-
bonded stacks. (b, right) Packing of 1b.
forces between alkyl groups (t-Bu and Me) and arrange into a
herringbone pattern (Figure 4b). The propensity for 1b to form
hydrogen-bonded aggregates is embodied by poor solubility
and aggregation at high concentrations in solution limiting the
maximum concentration during 1H NMR titration experiments.
1
NMR Titrations. H NMR titrations were performed to
study the substituent effects in solution on the anion binding
conformation and CH chemical shift. The magnitude and
direction of the change in chemical shift are additional
parameters set out in the HB definition for the presence and
strength of a HB (instead of an alternative attractive force, such
as dispersion).26 Consistent with previous studies on anion−π
interactions,17 water-saturated CHCl3 was used as the solvent,
and anions were added as their TBA salts. Titrations were
performed keeping the host concentrations constant (starting
at 0.5−1.5 mM) during an experiment and titrating in a
solution of concentrated anion in a solution of the host. Urea
proton chemical shift changes between hosts are similar to the
small changes observed in DMSO (see SI).
A representative titration is shown in Figure 5. This example
of unsubstituted receptor 1a follows the trends for all of the
receptors. The alkyl protons (t-Bu and OMe) remain
unchanged throughout the course of anion addition (see the
SI for complete titration data). The urea proton (Hh) and the
Figure 3. Stacked NMR spectra of (a) 1b, (b) 1a, and (c) 1g in
DMSO-d6. Proton assignments refer to Scheme 1.
effects on the CH···X− interactions without complicating
secondary effects. 1H NMR chemical shifts are subject to
conformational changes and are insufficient evidence alone;
however, calculations of Mulliken charge and ESP also support
a small influence on the urea HB donors.
The solid-state structure determined by single-crystal X-ray
diffraction is consistent with our structural characterization and
solution behavior as studied previously by NMR, including 2D
1H−13C HSQC.27 A single crystal of 1a·Cl− was obtained by
slow evaporation of CHCl3 containing a 2-fold excess of
TBACl. The previously reported structure of 1a·Cl− has a
short, linear C(H)···Cl contact of 3.579(3) Å and 169° (∠C−
H···Cl). The asymmetric unit is a 1:1 receptor:anion complex
with a cocrystallized tetrabutylammonium (TBA) cation and
solvent molecule (Figure 2b). The presence of a 1:1 complex is
encouraging for binding in solution and is consistent with other
examples of this scaffold.32,34,36,40,41 The packing of this
structure is dominated by ion pairing between Cl− and TBA+,
with dispersion interactions playing a secondary role. The lack
of interhost HBs or π−π stacking interactions also suggested a
decreased likelihood of aggregation in solution.
Figure 5. Representative stacked plot for a Cl− titration with host 1a
in water-saturated CHCl3 using a TBA salt.
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Table 1. Complete Association Constants and Binding Energy for Receptors 1a−g at 298 K
a
a
b
a
−
Cl−
Br−
I−
NO3
host (R)
Ka (M−1
)
ΔG (kcal mol−1
)
Ka (M−1
)
ΔG (kcal mol−1
)
Ka (M−1
)
c
ΔG (kcal mol−1
)
Ka (M−1
)
ΔG (kcal mol−1
)
c
c
1a (H)
6750 600
−5.22 0.05
−5.99 0.09
−5.32 0.09
−5.22 0.05
−4.99 0.09
−5.01 0.03
−4.67 0.07
1630 120
5830 510
2680 230
2340 180
1370 100
1000 70
800 40
−4.38 0.04
−5.13 0.05
−4.67 0.05
−4.59 0.05
−4.28 0.03
−4.09 0.04
−3.96 0.03
150 10
580 30
290 10
240 10
150 10
170 10
100 10
−2.97 0.03
−3.76 0.03
−3.36 0.03
−3.25 0.03
−2.98 0.04
−3.02 0.03
−2.74 0.07
3310 170
10600 800
5520 640
4810 320
2700 420
3060 360
1720 160
−4.80 0.03
−5.49 0.04
−5.10 0.07
−5.02 0.04
−4.68 0.09
−4.75 0.07
−4.41 0.05
1b (NO2)
1c (Cl)
24600 3500
7900 1300
6760 620
4560 720
4730 240
2660 320
1d (F)
1e (tBu)
1f (OMe)
1g (NMe2)
a
b
Determined using UV−vis titrations in H2O-saturated CHCl3; error is the standard deviation (SD) of at least three titrations. Determined using
1H NMR titrations in H2O-saturated CDCl3; error is the SD of at least two titrations. The minimum error is assumed to be 5% in cases where the SD
c
is <5%. Previously reported (ref 27).
CH proton (Hc) are unresolved during most of the titration,
which may be due to the large shifts (Δδ = 4.0 and 2.5 ppm)
between the free host and the saturated host:Cl− complex.
Although the broadening prevents fitting these peaks for an
association constant (Ka), the large, downfield shifts indicate
strong HBs with Hh and Hc. Fortunately, the other aromatic
and urea protons remain well resolved throughout the titration,
except for brief periods of overlap for some peaks. Urea Hg
shifts downfield with anion binding, while the aromatic protons
remain stationary or move upfield slightly. The decreased
broadening and smaller Δδ for Hg, observed for the halides
with all hosts, is evidence for an overall weaker HB to this urea
proton.
The chemical shift change of urea NHg was fit using
nonlinear regression analysis in MatLab to a 1:1 host:guest
model.42 This model was selected based on the crystallographic
evidence for 1:1 binding and quality of fit compared to higher
Figure 6. 1H NMR spectra (CDCl3) of receptors 1a−g near the
order models. The trend for association constants follows the
saturation point with Cl−. The peak showing the largest shift between
general electron-withdrawing ability of the substituents and the
8.8 and 10.0 ppm is that of aryl proton Hc. Peak assignment refers to
Scheme 1.
expected Hoffmeister bias (Cl− > NO3− > Br− ≫ I−).43,44 The
large association constants measured for Cl− (>105 M−1 in
some cases) indicates NMR spectroscopy is not the ideal
bottom).21 In this case, the hydrogen-bonding protons NHh
and CHc shifted less than observed with the halides, and urea
technique for determining high quality association constants.
Strong EWG hosts (1b) with Cl− are at the upper limit for
measuring Kas by NMR titrations and the fit is based on a single
proton shift. We can make a qualitative analysis of the bound
geometry and trends, but the further quantitative analysis is
based on UV−vis titrations (Table 1).
NHg ends up slightly farther downfield. Considering the likely
geometries for nitrate binding, the relative chemical shifts point
to a geometry where two oxygens are bound by NHg and
bifurcated by CHc; the third oxygen only weakly interacts with
NHh. Modeling of the nitrate complex in Figure 7 supports this
hypothesis, with two local minima, from divergent starting
structures, found with nitrate parallel to the CH bond. With
confirmation that the anions were bound in a similar manner by
all of the receptors in solution, we sought to obtain quantitative
association constants by performing UV−vis titrations.
The 1H NMR spectra of the bound receptors are remarkably
similar considering the variety of substituents used (Figure 6).
As with the free receptors, the largest variation of Δδ is seen for
two equivalent phenyl Hb resonances. The final δ for the urea
protons, Hg and Hh, changes <0.1 ppm for all of the receptors.
The only peak that shows a large change is the aromatic core
CHc, where there is a difference of 1.2 ppm between 1b·Cl−
and 1g·Cl−. Subtracting the difference before anion binding
(Figure 3) leaves Δδ = 0.2 ppm due to a change in the HB
strength. Also of note, the final position follows the trend of
EWG strength. A similar trend is observed for Br− and I−
binding, albeit with smaller Δδ for Hh and Hc. The chemical
shift of the internal urea proton Hg changes minimally when
bound to Br−, I−, or Cl−, consistent with it being mostly
peripheral to halide binding.
UV−Vis Titrations and Association Constants. The
rigid, conjugated arylethynyl backbone used in these receptors
has the added benefit of providing a convenient absorbance for
performing UV−vis titrations.36 Although they do not provide
as much structural information as NMR, UV−vis titrations are
more accurate in determining Kas for our system because the
required receptor concentrations are lowered (limiting
aggregation), and problems with disappearing or overlapping
1
peaks present in H NMR studies cease. The conditions for
1
In addition to the halides, titrations were also performed with
nitrate to consider shape as a variable in the binding studies
(Figure 7, top). While the halides are spherical and have very
small preference for HB arrangements, nitrate is trigonal planar
and prefers a bifurcated, O···(C)H···O structure (Figure 7,
UV−vis titrations were chosen to most closely match the H
NMR binding experiments: water-saturated CHCl3 was used as
solvent and anions as their TBA salts were monitored at 298 K.
Association constants were determined using the HYPERquad
2006 package to fit the complete spectral window with
D
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have also been converted to ΔG (kcal mol−1) for comparison to
other supramolecular receptors. The total binding energy can
be tuned by substituent effects by 1.02−1.32 kcal mol−1
depending on the anion being titrated; i.e., Cl− is bound
more strongly than I− by 1.92−2.23 kcal mol−1 throughout this
class of receptors.
Computations. Prior computations on model structures of
chloride and nitrate with benzene showed CH HB strength
(ΔH) follows linearly with the Hammett σ parameters and
ESP.23,24 We have expanded upon these prior computations by
calculating the ESP surfaces for the model systems 5 and 6
(Figure 8) to measure electrostatic contributions in the bisurea
−
Figure 7. (Top) Stacked plots showing the NO3 titration of 1a.
−
(Bottom) Local minima of truncated 5a·NO3 , with distances showing
−
the preference of NO3 for maximized urea contacts and a bifurcated
CH hydrogen bond. B3LYP/6-31g(d).
Figure 8. (Top) Structures of the truncated model compounds 5 and
6 used for computational studies. (Bottom) MESP maps showing
effects of substituent on ESP at a 0.002 Å isoelectric surface, calculated
using B3LYP/6-31+g(d) in Spartan ’10.
nonlinear regression.45 Consistent with the H NMR experi-
1
ments, all titrations were fit to a 1:1 binding isotherm. Job’s plot
analysis also confirms the best fit model for selected host and
anion combinations (see SI).
receptors. The primary metric from these calculations is the
ESP of 6a−g (Table 2) at the point where the C−H axis
Table 1 contains the compiled association constants for
−
receptors 1a−g with Cl−, Br−, I−, and NO3 . The selectivity of
Table 2. Computational and Empirical Values for LFER
Analysis
these receptors follows this preference, with the trend of Cl− >
NO3 > Br− ≫ I− holding for all hosts. The chloride
−
25
25
host (R)
ESP
σm
σp
F29
R29
association constants are typically 3-fold higher than the
bromide Kas. Interestingly, nitrate is not able to outcompete
Cl− despite nitrate’s ability to maximize NH HBs. The
extremely low association for iodide prevented the accurate
determination of binding constant by UV−vis spectropho-
1b (NO2)
1c (Cl)
28.9
22.1
21.4
17.9
16.3
16.3
12.0
0.71
0.37
0.78
0.23
1.00
0.72
1.00
−0.24
−0.39
0.00
1d (F)
0.34
0.06
0.74
1a (H)
0.00
0.00
0.00
1
1e (tBu)
1f (OMe)
1g (NMe2)
−0.10
0.12
−0.20
−0.27
−0.83
−0.11
0.54
−0.29
−1.68
−3.81
tometry and necessitated the use of H NMR binding data for
further analysis.
The range of association constants for Cl− alone spans an
order of magnitude, with just altering a single arene substituent.
Consistent with the changes in chemical shift, the association
constants for a given anion can be ranked according to the
relative electron-withdrawing ability of the substituent.
Surprisingly, fluorine is an outlier for the trend in
eletronegativity of the substituent. Fluorine typically acts as
an electron-withdrawing group for electrostatic interactions,
except when resonance is a contributor. Fluorine acts as both a
strong electron-withdrawing group due to induction and an
electron-donating group by resonance with one of its lone pairs.
Other groups in this table (OMe, NMe2, Cl) share this dual
function and are important for differentiating between
induction and resonance effects. The association constants
−0.15
0.69
a
ESP (kcal mol−1) at the point where the CH bond intersects a 0.002
Å isoelectric surface, calculated using B3LYP/6-31+g(d) in Spartan
’10.
intercepts the 0.002 Å isoelectronic surface. The ESP at this
point trends with the electron-withdrawing ability of the
substituents. Hammett plots of the ESP (6a−g, Table 2 and
Figure S52) and σ parameters favor σp over σm, with R2 = 0.97
and 0.88, respectively. This is a first indication that interactions
with the CH are dependent on both field/inductive and
resonance contributions of the substituents.
The bisurea model system 5a−g is also useful to measure
whether substitution at the central arene affects the urea group.
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A change in the Mulliken charge on the hydrogen-bond-
donating carbon and nitrogens is representative of the effects at
each of these positions. The Hammett plot of Mulliken charge
at the hydrogen-bond-donating carbon in 5 is linear with σp, R2
= 0.90 and ρ = −0.10 0.02. Mulliken charges on the urea
nitrogens produce Hammett plots for σp and σm with very poor
fits, R2 ≤ 0.70 and ρ ≈ 0.007 0.002 (Table S43). Substitution
on the central arene has very weak through-bond effect on the
ureas in this system. The through-space effect is better
estimated by the ESP near the urea hydrogens. In this case,
Hammett plots reveal the change at the urea is <50% of the
change at the CH donor. This model, however, does not
account for the electron-donating pendent phenyls in the full
receptor, 1a−g, which would further diminish the influence of
the ureas.
energy for 1a with Cl− is quite close, at −1.43 kcal mol−1.
Nitrate is a clear outlier in this series based on its preference for
a bifurcated HB. The CH HB is less important for nitrate;
however, using this model 47% of the total binding energy for
iodide originates from the CH HB solely.
Since the substitution is only on the central arene and
appears to only affect the C−Hc proton, we hypothesized that
trends in our association constants should, also, be well-
described by the σ parameter for substituents. The Hammett
plots for Cl−, Br−, I−, and NO3− were prepared for both σm and
σp constants. Figure 10 compares the fit for σp with Ka (Cl−)
Linear Free Energy Relationships. Linear free energy
plots of the ESP and association constants are one way of
comparing computational and experimental results, bridging
the gap between gas phase and solution.46 Non-normalized
plots in kcal mol−1 are linear, with R2 > 0.95 for all four anions
(Figure 9). A break in the trend of the fitted slopes appears
Figure 9. Linear free energy relationship of the solution Gibbs free
energy (ΔG) of binding for Cl− with the ESP at the CH bond.
Intercept predicts a hypothetical system where electrostatic potential is
zero.
between the harder anions (Cl− and Br−) and soft anions (I−
−
and NO3 ). The hardness of anions has been used to explain
the selectivity of Cl− transport in micelles, although alternative
explanations have not been conclusively ruled out.47
Figure 10. Hammett plots of Ka (Cl−) (top) and Ka (I−) (bottom)
with σp (Table 2). Goodness of fit (R2) indicates Cl− is well described
by σp, while I− is less well-described.
Another interesting implication falls out of the intercept in
these plots. When the ESP is reduced to zero at the intercept,
the remaining binding energy is due to the non-CH
interactions. This is based on an assumption that the
electrostatics model completely or mostly describes the CH···
and Ka (I−). Association constants and substituent parameters
were fit using the Hammett equation (eqs 1 and 2) in MatLab.
The intercept acts as another measure for the quality of fit. In
this case, the large intercept for I−, a poor fit for σp, places 1a
outside of the confidence bounds (Figure 10 bottom). Table 3
contains the complete results for fitting all four anions to σp and
σm.48
X interaction. As would be expected the intercept follows the
same trend in energies (kcal mol−1), Cl− = −3.79, NO3
=
−
−3.67, Br− = −3.06, I− = −1.98. The remaining “CH hydrogen
bond energies” after subtracting the intercept from the solution
ΔG for 1b are −2.20, −1.82, −2.07, and −1.78 kcal mol−1 for
each anion, respectively. Previous studies with this system
compared 1a to a pyridine receptor and estimated the CH HB
energy at −1.33 kcal mol−1 to Cl−.27 In this case, the estimated
log(KR/KH) = ρσp + i
(1)
F
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Article
(Ka Cl−) log(KR/KH) = 0.59( 0.06)σp + 0.01( 0.03),
and resonance (R) parameters, such as those derived by Swain
and Lupton.28,29 While many methods for determining field
and resonance contribution have been proposed, the F and R
parameters (Table 4) developed by Swain−Lupton most
2
N = 7, R2 = 0.95, Radj = 0.94,
RMSE = 0.07, F = 100
(2)
Table 4. Field and Resonance Fitting Parameters
a
Table 3. Coefficients and Fitting Statistics for Hammett
Plots for Each Anion Studied
ρf
ρr
R2
%R
32
Cl−
Br−
I−
0.36( 0.09)
0.37( 0.03)
0.40( 0.05)
0.37( 0.02)
0.17( 0.02)
0.15( 0.01)
0.14( 0.01)
0.14( 0.01)
0.937
0.995
0.977
0.996
7
6
3
1
a
b
c
d
Ka (X−)
ρ
I
N
R2
F
30
25
28
Cl− (σp)
Br− (σp)
I− (σp)
0.59( 0.06)
0.57( 0.07)
0.47( 0.07)
0.50( 0.05)
0.89( 0.18)
0.87( 0.16)
0.78( 0.08)
0.80( 0.09)
0.01( 0.03)
0.07( 0.03)
0.15( 0.03)
0.09( 0.02)
−0.18( 0.06)
−0.11( 0.06)
−0.01( 0.03)
7
7
7
7
7
7
7
7
0.95
0.93
0.90
0.95
0.83
0.85
0.95
0.94
100
68
−
NO3
a
Calculated from eq 4 for percent resonance.
46
−
NO3 (σp)
98
Cl− (σm)
Br− (σm)
I− (σm)
25
closely match Hammett’s σ parameters in their derivation (eq
3). MatLab is capable of handling large, multivariable linear
regressions and can easily handle fitting values for F and R from
the data presented above. The method was applied to the
experimental Ka values and the results for Cl− are plotted in
Figure 11. A figure of merit for simultaneous F and R fitting is
the percent resonance contribution, %R (eq 4).
28
102
83
−
NO3 (σm)
−0.08( 0.03)
a
b
Intercept obtained from the linear fit. Number of points used for
c
fitting. Coefficient of determination for quality of fit determination.
d
F-value for comparison of models.
log(KX/KH) = ρfF + ρrR + i
(3)
The ρ values for all combinations of σ and anion are <1, an
average of 0.54 for σp and 0.85 for σm. Reactions with ρ values
>1 are considered more sensitive than benzoic acid and ρ values
<1 are less sensitive to ionization by substituent effects. If CH···
X− is a HB and incorporates some covalent character, then it
follows that there is a small proton transfer event contributing
to the binding energy.26 The method of fitting anion
association to a Hammett σp is also applicable to other CH
HB anion receptors. For instance, it is interesting to note, at
least preliminarily, that a Hammett plot of Cl− association to a
CH hydrogen-bond-donating rotaxane host has ρ = 0.53.49 The
similarity of this relationship to a very different host in a
different solvent is encouraging, and suggests this under-
standing is extendable to other such systems.
%R = ρr/(ρf + ρr) × 100
(4)
The question remains, has the influence of the urea HB
donors been sufficiently accounted for? The ρ for Hammett
plots of Mulliken charge and ESP at the ureas is consistently
<0.06. The change in association constant due to the ureas is
estimated to be <10% based on this and is insufficient to
explain the effects on the binding event.
The small ρ value is consistent with the CH bond being
much less acidic than benzoic acid. Also consistent with a
traditional hydrogen bond definition, the σp parameter has a
better fit for Cl− than σm (R2 (σp) = 0.95 vs (σm) = 0.83). σp is
often thought to represent a greater resonance contribution;
however, two points conflict with this observation: (1) DFT
calculations favored σm for Cl−,24 and (2) the results for I− do
not match Cl−, where Hammett plots for I− are a better fit
Figure 11. LFER plot of Ka (Cl−) and ρfF + ρrR to determine
resonance contribution from Swain−Lupton field and resonance
parameters.
This reports the resonance contribution observed in the
reaction and is the percent of R from the combined ρf and ρr
coefficients. Of note, the resonance contribution for Cl− and
−
using σm. Further confounding the issue, NO3 is well
described by both σp and σm.
The unusual results for NO3 can be described by the
−
−
Br− is higher, but the values drop off for I− and NO3 . The
geometry and altered binding mode in this case. The oxoanion
is trigonal planar and can maximize contacts to the NH donors,
as discussed above; however, the CH donor is still important to
the overall binding energy. The CH proton still shifts downfield
by nearly the same magnitude as the NH protons. The
observed ρ values are the result of both inductive and
resonance contributions. The degree of resonance contribution
is a key difference between the σm and σp parameters.
error values in %R exceed 10% in most cases, which is due to
the small sample size to variable ratios. As a result of the
increasing number of variables, the difference in the %R
contribution among the various anions studied is well below the
95% confidence interval by t test. A similar trend, however, in
anion effects was observed by Scheiner et al. using computation
to study anion binding to trifluoromethane.21 By their
computations, the overall binding energy and charge transfer
from the anion were correlated, consistent with the effect of
resonance contribution we have observed. As in the extreme
A more accurate method for determining resonance
contribution is to perform multivariable fitting with field (F)
G
DOI: 10.1021/jacs.5b08767
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Journal of the American Chemical Society
Article
HB example, increased charge on the carbon can be dissipated
by resonance and contribute additional HB energy beyond
inductive effects alone.
provide important insights to aid chemists and biologists in
accomplishing such CH HB optimization.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.5b08767.
■
CONCLUSIONS
S
■
The resonance contribution of a substituent clearly plays a role
in dictating hydrogen bond strength, even for CH donors. We
have observed a weak dependence of σp and σm contribution on
the anion being bound. Hammett parameters remain a powerful
tool for predicting changes in CH HB strength. It is important
to also consider the HB acceptor, not only its charge but also
size, shape, and polarizability. The change in resonance
contributions as a result of substituent effects as calculated by
Swain−Lupton parameters is too small to differentiate between
the anions studied, suggesting that emerging hypotheses
offering hard/soft acid/base theory as a model for under-
standing anion binding specificity are overly simplistic. Anion
effects on resonance contribution are also supported by
calculations of the charge transfer energy and bond stretching
in model CH···X− systems.
Complete synthesis and characterization for all com-
pounds, and representative titrations for all anions
(PDF)
X-ray data for 1b (CIF)
Atomic coordinates and absolute energies for all
computed structures (PDF)
AUTHOR INFORMATION
■
Corresponding Authors
*haley@uoregon.edu
*dwj@uoregon.edu
Notes
Computationally determined binding energies are a valuable
tool for understanding solution binding events, especially in the
case of weak interactions. Remarkably, venerable empirical
substituent constants such as σ, F, and R can also effectively
describe substituent effects in CH HBs, which are increasingly
appreciated as rivals to more well-studied, highly polar HB
donors (e.g., N−H, O−H). We have found through
experimental results that the strength of a single CH HB is
tunable across a range of 1.02−1.23 kcal mol−1 by modifying
substituents on the receptor and that these interactions vary up
to 0.42 kcal mol−1 by changing the anion accepting the CH
HBs. Although these values are small, they represent a 10-fold
and 3-fold change in anion binding, respectively, and hint at the
nature of anion binding selectivity in such receptors.
Considering multivalent effects in the largest hydrogen-bond-
donating receptors that bring to bear many such interactions in
targeting a single anion, the combined effect can be used to
dramatically alter the binding event in selectivity and strength.
While hard/soft acid/base theory remains a useful tool in
understanding coordination chemistry, the present studies add
to the evidence that this theory is too simplistic to describe
accurately the nature of selectivity in anion binding using
hydrogen-bonding receptors; ESPs and other empirical
substituent constants appear to provide a more robust
understanding.
Aryl CH HBs have seen increasing study in numerous fields,
including anion transport, organocatalysis, molecular/ion
recognition, and biological ligand/receptor binding. New
methods for understanding and controlling the strength and
selectivity of these interactions are vital for continued progress
in these fields. For instance, ligand and/or drug binding to
proteins can be improved by studying and optimizing
important CH hydrogen-bonding interactions, and enhancing
such interactions in organocatalysis and receptor design may
enable improved stereo- and regioselectivity. Although the CH
donor cannot be easily categorized as hard or soft, we have
made the more important discovery that the possibility exists to
influence the preference of this interaction for different anions.
A concerted effort to maximize both the resonance withdrawing
ability of substituents and the number of CH HB donors
should lead to an increased affinity for hard anions. Conversely,
the same should be possible by maximizing the inductive
substituents to bind soft anions. The results from this study
The authors declare the following competing financial
interest(s): NIH grant R01-GM087398 funded early-stage
intellectual property that was licensed by SupraSensor
Technologies, a company co-founded by the principal
investigators.
ACKNOWLEDGMENTS
■
This work was supported by NIH grant R01-GM087398. The
authors acknowledge the Biomolecular Mass Spectrometry
Core of the Environmental Health Sciences Core Center at
Oregon State University (NIH P30ES000210). We gratefully
acknowledge UO Prof. Michael D. Pluth and an anonymous
reviewer(s) for helping to improve the detailed physical organic
discussion.
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