A Molecular Torsion Balance Study: A Nearby Anionic Group Exerts Little Influence on Hydrophobic Interactions between Nonpolar Surfaces

Article abstract of DOI:10.1002/chem.201901208

Polar groups have a solvent ordering effect on water and therefore may affect hydrophobic binding energies for nearby lipophilic surfaces. This would mean that determinations of excess surface free energy association energies require consideration of nearby polar functional groups. This paper reports results of a study to measure this possible effect. It was concluded from the models used here that an anionic polar group nearby a hydrophobic surface has little or no effect on the magnitude of hydrophobic association.

Full text of DOI:10.1002/chem.201901208

A Journal of
Accepted Article
Title: A Molecular Torsion Balance Study: A Nearby Anionic Group
Exerts Little Influence on Hydrophobic Interactions Between
Nonpolar Surfaces
Authors: Xiujun Ling and Craig Wilcox
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To be cited as: Chem. Eur. J. 10.1002/chem.201901208
Link to VoR: http://dx.doi.org/10.1002/chem.201901208
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10.1002/chem.201901208
Chemistry - A European Journal
ESSAY
A Molecular Torsion Balance Study: A Nearby Anionic Group
Exerts Little Influence on Hydrophobic Interactions Between
Nonpolar Surfaces
Xiujun Ling,[b] and Craig S. Wilcox*[a]
Abstract: Polar groups have a solvent ordering effect on water, and
therefore may affect hydrophobic binding energies for nearby
lipophilic surfaces. This would mean that determinations of excess
surface free energy association energies require consideration of
nearby polar functional groups. This paper reports results of a study
to measure this possible effect. We conclude that in our models an
anionic polar group nearby a hydrophobic surface has little or no effect
on the magnitude of hydrophobic association.
chain to improve water solubility.6 This advance enabled the
measurement of alkyl CH-π interactions in water, and also made
it possible to investigate the effect of water on molecular folding
when the lipophilic groups coming into contact were the
approximate size of amino acid side chains, and demonstrated
that a molecular torsion balance can be sensitive to such small
scale hydrophobic effects. Briefly described, a molecular torsion
balance experiment measures the equilibrium between two
conformational states (‘folded’ and ‘unfolded’). The molecular
torsion balance is designed to isolate a defined intramolecular
contact that is present in the ‘folded’ state but not present in the
‘unfolded’ state. The free energy change between the two states
is defined as the free energy of folding, ∆Gfold (Figure 1).
The function and the shapes of receptors, enzymes, nucleic acids,
lipids, drugs, and other biologically active molecules are ultimately
determined by a balance among many small (less than 20 kJ/mol)
energetic interactions.1 These forces of interaction and equilibria
are also influenced by solvation and cosolute effects. All of these
influences have a characteristic time domain. In the majority of
experiments important to health and technology the contributions
of these component forces are difficult to measure accurately due
to the myriad thermodynamic substates that represent bound and
unbound states, folded and unfolded states, and solvation states.2
For example, the evaluation of the interactions of amino acid side
chains in a single protein are confounded by the freedom of
motion within the protein. Accurate quantitative evaluation of
these motions and their effect on protein function is beyond
present theory and practice. Molecular torsion balances can
provide less ambiguous and more precise data to evaluate
individual side chain interactions, including interactions that
contribute to hydrophobically assisted folding.
CO2H
3
CO2H
3
O
O
HN
HN
O
O
O
∆Gfold
O
O
O
O
O
Me
Me
HO2C
H3C
CO2H
N
N
N
N
H3C
Figure 1. Illustration of free folding enersgy.
Gellman and Abbott examined the effect of cationic groups on
hydrophobic association through AFM measurements and found
that such groups do influence hydrophobic binding.7 In this
project we sought to use a molecular torsion balance to
investigate whether or not polar and anionic groups nearby
hydrophobic surfaces could have an effect on the magnitude of
The concept of the molecular torsion balance was introduced 25
years ago when a torsion balance based on Tröger’s base was
used to quantify substituent effects on the CH-π interaction.3,5
Tröger’s base analogs have become widely used in
supramolecular chemistry.4 A second generation of molecular
torsion balances based on Tröger’s base featured a more
symmetrical core structure and a hydrophilic glutaric acid side
hydrophobically assisted folding. We refer to this as
a
“neighboring group effect” in hydrophobic surface association. We
reasoned that this effect might arise from the influence of the polar
group on the structure and orderliness of water at the hydrophobic
surface. If the polar group influenced the excess free energy of
the water at the nearby hydrophobic surface, a change in the
contribution of desolvation to binding or folding energy might be
observed.
[a]
[b]
Prof. Craig. S. Wilcox
Department of Chemistry
University of Pittsburgh
Pittsburgh, PA 15260 USA
Fax: (+1) 412-624-1272
E-mail: daylite@pitt.edu
Dr. Xiujun Ling
HM Health Solutions Inc.
Pittsburgh, PA 15222 USA
Fax: (+1) 412-680-1284
E-mail: xiujun.ling2014@gmail.com
Supporting information for this article is given via a link at the end of
the document.
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10.1002/chem.201901208
Chemistry - A European Journal
ESSAY
R2
=
=
NO2
NH2
3
4
5
transformation of alcohol 13a into 13b-13d followed standard
R2
NHCO(CH2)3CO2H
methods described in the supplementary information.21
O
O
Cy
R1
R3
R4
The conformations of these molecular torsion balances were
examined by analysis of the methyl ester signals in 1H NMR
spectra (Figure 3). The rotation around the single aryl-aryl bond
is slow on the 1H NMR time scale. When the methyl ester is on
the concave side of the Tröger’s base, the methyl protons
resonate at 3.0 ppm. In contrast, when the methyl ester is on the
convex side the methyl ester protons resonate at 3.7 ppm, as is
typical for common methyl esters. This difference unambiguously
identifies the folded and unfolded states.
OR1
OMe
Bco
R4 = CO2Et
R3 = CO2Et
N
-
-
CO2
CO2
H3C
N
CH2OH
H
CH2OH
CH3
Figure 2. Cy and Bco series of torsion balances.
Several different molecular torsion balances were prepared to
investigate these proposed neighboring group effects in
hydrophobic binding. The water-soluble torsion balances in this
paper incorporate a series of bicyclo[2.2.2]octane (Bco) and
trans-cyclohexane (Cy) groups (Figure 2). The bicyclo[2.2.2]octyl
alcohols used in the Bco series are symmetrical and rigid, and
therefore reduce the number of thermodynamic substates that
compose the folded and unfolded conformations, while the trans-
cyclohexane (Cy) series provide an interesting comparison.
Br
O
Br
O
O
Br
O
Me
Me
HO
OH
MeO
OMe
H2SO4
KMnO4, NaOH
H2O, reflux, 40 h
MeOH, reflux, 24 h
69%
81%
7
6
O
Br
O
O
Br
O
MeO
OH
MeO
OH
NaOH
HNO3, H2SO4
17 h, 0 ˚C ~ rt
7
MeOH:Acetone = 1:4
overnight, rt
NO2
8
93%
52%
9
NH2
N
The synthesis of the Tröger’s base core followed the method
of Wärnmark.8 The dibromo analog 10 was treated with n-
butyl lithium and methyl iodide to give the 2-bromo-8-methyl
analog 11.9 This product was transformed to the boronate
Br
N
Br
(CH2O)n
n-BuLi, CH3I
TFA, 150 h, 0 ˚C
THF, -78 ˚C, 1.5 h
Br
N
H3
C
N
Br
59%
10
11
54%
O
O
O
analog
hemiester
permanganate oxidation of m-bromoxylene.12 Esterification
of the resulting diacid gave diester
as the product.13,14
Diester was then treated with 1.1 eq. of sodium hydroxide
to yield hemiester , which was transformed to nitro
by nitration with nitric acid and sulfuric acid.
was converted to isophthalate esters 2a-d g-j
1
with catalytic Pd(dppf)Cl2 (Scheme 1).10,11 The nitro
was prepared in a sequence that started with the
B
B
O
O
O
O
B
N
B
Pd(dppf)Cl2, KOAc
DMF, 80 ˚C, 16 h
9
O
11
H3C
N
N
N
82%
6
7
1
H3
C
7
NO2
8
NO2
O
O
NaHCO3 , Pd-L, 1
hemiester
Hemiester
9
9
12 or 13, DCC, DMAP
9
OR
O
OMe
O
OMe
DME:H2O = 1:1
16 h, 80 ˚C
CH2Cl2, -15 ˚C ~ rt
overnight
,
OR Br
in good yields through standard DCC esterification.15
(Attempts to use EDC.HCl in the esterification reaction gave
low yields with tertiary alcohols 12.) Torsion balances 3a-3d
and 3g-3j were synthesized by Suzuki coupling16 of
42~91%
50~86%
N
N
2a-2d, 2g-2j
H3
C
3a-3d, 3g-3j
O
O
NH2
HN
OH
O
O
O
isophthalate
group of torsion balances 3a
accomplished with 10% Pd/C and hydrogen at 15 psi. For
those torsion balances with benzyl groups (3c 3d 3i and 3j)
2
to Tröger’s base
1
.
17 The reduction of the nitro
3b 3g and 3h was
O
Method A :10% Pd/C, H2 (15 psi)
O
O
O
EtOAc,16 h, rt
OR
,
,
OMe
OR
Method B :10% Pd/C, H2 (45 psi), rt
CH2Cl2, rt
overnight
OMe
MeOH:CH2Cl2 = 1:1, 2-4 d
47%-quantitative
42-78% (isolated)
N
N
,
,
N
N
H3C
H3C
reduction and debenzylation was accomplished with Pd/C at
45 psi of H2. Acylation of the amino group on all homologs of
4a, 4b, 4e-4h, 4k, 4l
5a, 5b, 5e-5h, 5k, 5l
OH
R'' = CO2Et
a
b
R = Cy Me
= Cy CO2Et
= Cy CH2OBn
= Cy CO2Bn
= Cy CH2OH
a
R = Bco
H
g
h
i
CO2Bn
CH2OBn c
H
b
c
d
e
f
= Bco CO2Et
= Bco CH2OBn
= Bco CO2Bn
= Bco CH2OH
R'
4
with glutaric anhydride afforded hydrophilic torsion
HO
d
j
R''
balances
5
.
13
b
d
c
a
R' = CO2Et
CO2Bn
CH2OBn
CH3
k
l
-
12
-
= Cy CO2
= Bco CO2
The synthesis of the bicyclo[2.2.2]octyl alcohol series 12 (Scheme
2) followed Grob and Rich’s method.18 It began with the reaction
of diethyl acetoacetate and ethyl acrylate. The resulting triester
14 was hydrolyzed to generate diacid 15, which then afforded
ketoester 16 through decarboxylative cyclization.19 Conversion to
Scheme 1. The synthesis of torsion balances 5.
alcohol 17 was accomplished by
a second cyclization.
Deoxygenation of the carbonyl group on 18 was achieved with
ethane dithiol and Raney Ni in two steps and afforded alcohol
12a.20 The synthesis of trans-cyclohexyl alcohols 13 and
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10.1002/chem.201901208
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ESSAY
O
O
O
OH
C2H5
O
O
O
OC2H5
HO
The torsion balances 5a, 5b, 5e-5h, 5k, and 5l were examined in
two solvents (D2O and CD3OD) at 5 ˚C through 700 MHz NMR
spectroscopy (Table 1). The folding energy in D2O is significantly
higher than it is in CD3OD. This confirms again that a molecular
torsion balance is sensitive to nanoscale hydrophobic effects.6
The bicyclo[2.2.2]octyl series had higher folding energies than the
cyclohexane series in both D2O and CD3OD. We think that this is
because bicyclo[2.2.2]octyl has larger contact area than trans-
cyclohexyl and lower rotational entropy in CD3OD. The torsion
balances bearing the ester or carboxylic group (entry 2 and 5)
have higher folding percentages than the balances with hydroxyl
or alkyl groups (entry 1 and 7) in the bicyclo[2.2.2]octyl series.
This might be due to the branching nature of the carbonyl group
allowing enhanced London dispersion interactions. In water,
however, torsion balance 5g (Table 1, entry 1) exhibited folding
percentages similar to 5h and 5l (Table 1, entry 2 and 5). The
ester and carboxylic groups have hydrogen-bonded interactions
with water. If the exposed surface area of ester and carboxylic
group in water is smaller than it is in unfolded state, the result
would be a positive contribution to the folding free energies,
making the free energies of 5h and 5l closer to 5g. Torsion
balances with a hydroxyl group 5e and 5k (Table 1, entry 7 and
8) are expected to form strong hydrogen bonds with water.
Inhibition of hydroxyl group solvation in the folded state would
decrease the percentage of conformers having the hydroxyl on
the endo side (folded). Indeed, the data reveal diminished folding
of these alcohols 5e and 5k (Table 1, entry 7 and 8) in water
compared to their alkyl analogs 5a and 5g (Table 1, entries 1+3).
OC2H5
OC2H5
NaOEt
NaOH
+
EtOH, rt
overnight
72%
EtOH:H2O = 4:1
24 h, rt
OC2H5
OC2H5
82%
O
O
O
O
O
O
15
14
OH
O
O
KOAc
NaOEt
+
15
O
Ac2O
reflux, 3 h
distill, 52%
EtOH, rt, 15 h
34%
OC2H5
O
OC2H5
OH
O
OC2H5
O
O
17
16
OH
BF3.Et2
O
HSCH2CH2SH
Raney Ni
S
S
O
17
30 min, 0 ˚C
94%
EtOH, reflux
30 h, 98%
CO2Et
OC2H5
12a
18
Scheme 2. The synthesis of bicycle[2.2.2]octyl alcohol 12a.
In order to determine whether temperature would have an effect
on the folding percentages of torsion balances, folding
percentages of all torsion balances were measured at
temperatures from 5 ˚C to 35 ˚C. This is a limited range due to the
freezing point of the aqueous solution and the broadening of
signals as temperature rises. In this range of temperatures folded
and unfolded methyl ester resonance frequencies changed very
little and the differences of folding percentages were within our
bounds of error.22
Table 1. Folding energy of torsion balances 5a, b, e-h, k, l in D2O and
CD3OD at 5 ˚C.d,e
b
c
Entry
R
Comp. #
ΔGfold
ΔGfold
D2O
CD3OD
kJ mol-1
kJ mol-1
1
2
3
4
-Bco-H
5g
5l
-2.3
-3.3
-1.7
-2.3
-4.2 a
-
-Bco-CO2
-Cy-CH3
-4.3 a
5a
5f
-3.4 a, -3.1
-3.8 a, -3.8
-
-Cy-CO2
5
6
7
-Bco-CO2Et
-Cy-CO2Et
5h
5b
5k
-3.0
-1.9
-2.3
-4.2
-3.8
-3.5
-Bco-CH2OH
8
-Cy-CH2OH
5e
-1.4
-3.0
Figure 3. Methyl ester signals of torsion balance 3j at 1 mM concentration in
CDCl3 at 5 ˚C, 15 ˚C, 25 ˚C and 35 ˚C (temperature increasing from top to
bottom).
[a] Sample basified with excess NH4OH. [b] Indicates ±13.4% to ±8.1%
relative error in free folding energy. [c] Indicates ±8.3% relative error in free
folding energy. [d] Folding/unfolding ratios were determined from line shape
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10.1002/chem.201901208
Chemistry - A European Journal
ESSAY
analysis23 of the 1H NMR spectra (700 MHz NMR). [e] Measurements were
made on 1 mM solutions.
Table 3. Folding free energy and folding percentage of torsion balances with
branch functional groups at 5 ˚C. b, c
d
ΔGfold
Entry
Name
Comp.#
Solvent
kJ/mol
The maximum solubilities of torsion balances 5g and 5l (Table 1,
entry 1 and 2) were less than 1mM in D2O, and 1H NMR signals
were too weak to evaluate with line-shape analysis. Increased
solubility was observed upon addition of NH4OH. Folding of 5f and
5a (Table 1, entry 3 and 4) was unaffected by additions of NH4OH.
Comparisons of entries 1 and 2, and entries 3 and 4 reveal that
the presence of the carboxylate nearby the interacting surfaces
has no significant effect on the folding of these molecules.
1
2
NO2-Bco-C(Me)=CH2
NH2-Bco-C(Me)=CH2
25
26
-2.1
CDCl3
CDCl3
CD3OD
-1.8
CO2H-Bco-
C(Me)=CH2
3
27
-3.0 a
The effects of pD on the folding energies of 5f and 5l were
examined at 5 ˚C (Table 2). No significant change in folding
energies were observed between pD 5.4 and 10.0. As expected,
the solubilities of 5f and 5l decreased as the pD decreased. These
observations are consistent with our initial observation that
NH4OH had negligible influence on the folding energy of these
acidic molecules.
4
5
6
7
8
9
NO2-Bco-CO2Et
NH2-Bco-CO2Et
CO2H-Bco-CO2Et
NO2-Bco-CO2Bn
NH2-Bco-CO2H
CO2H-Bco-CO2H
3h
4h
5h
3j
-2.2
CDCl3
CDCl3
CD3OD
CDCl3
CDCl3
CD3OD
-2.2
-3.0 a
-2.4
Table 2. The effect of pD on folding energy of torsion balance 5f and 5l in
D2O at 5 ˚C.a,b
4l
-1.6
CO2H-Cy-CO2H
ΔGfold (1 mM) c, d
(5f) kJ mol-1
CO2H-Bco-CO2H
ΔGfold (1 mM) c, d
(5l) kJ mol-1
5l
-3.3 a
Entry
pD
[a] Examined in CD3OD. [b] All the NMR data in this table were determined
from line shape analysis of the 1H NMR spectra acquired on a 700 MHz
NMR. [c] All the torsion balances were examined at 1 mM concentration. [d]
Indicates ±0.2 kJ/mol absolute error in folding free energy.
1
2
3
4
5
10
6.9
6.0
5.8
5.4
-4.1
-3.8
-4.0
-3.9
-4.0
-4.6
-4.9
-5.0
-5.1
-
As shown in Table 3, the folding free energy of torsion balance 27
(entry 3) is similar to the folding energies of torsion balances 5h
and 5l in CD3OD (entry 6 and 9). Based on this observation, we
conclude that the folding percentage of the torsion balance with
esters in the distal position is mainly affected by the branching
nature of the neighbouring group. The closer proximity of the
branched group results in greater London dispersion attraction in
the folded state. In this study we found no evidence that a nearby
anionic polar functional group influences the free energy change
of conformational change (folding) driven by hydrophobic effects.
We note that it would be incorrect to consider this result to be in
conflict with the important observations of Gellman and Abbott in
their investigation of cationic group effects, which were acquired
using a different technique (atomic force microscopy), on a
surface at a solid-liquid interface.7
[a] The concentrations of 5f and 5l were nominally 1 mM in all the
experiments, but below pD=6 concentrations were limited by solubility. [b]
All the NMR data in this table were determined from line shape analysis of
the 1H NMR spectra acquired at 700 MHz. [c] The error of ±8% in free folding
energy is determined by the accuracy of the line-shape analysis.
The data show that the torsion balances bearing a carboxylic
ester or carboxylic acid group in the distal position relevant
to the ester attachment site have a higher folding energy than
torsion balances with simpler groups in that position. We
considered that this could be due to the branching nature of
the ester/acid functional groups. The ester and acid, due to
branching, would allow increased interaction with the
methylated aromatic ring close to the ester alkyl group. In
order to test this idea, a torsion balance bearing an
isopropenyl group was designed and synthesized. The
isopropenyl group is isosteric with a carboxylic acid, and
similar to an ester in this context, but is less polar compared
to an ester or a carboxylic acid.
Conclusions
The results demonstrate a significant increase in folding for these
molecules on changing the solvent from CD3OD to D2O. This is
a measure of the greater ability of water (compared to methanol)
to enforce solvophobic association. The folding of torsion
balance 5l was not significantly affected by changes in pD in the
range of 10 to 5.4. Furthermore, the measured folding energies
of 5g (lacking a polar group) and 5l (containing a nearby polar
carboxylate group) in D2O were within experimental error. Nearby
hydroxyl groups also had insignificant effects on folding. The non-
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10.1002/chem.201901208
Chemistry - A European Journal
ESSAY
Cockroft, C. A. Hunter Chem. Commun. 2006, 36, 3806-3808; d) F. R.
Fischer, W. B. Schweizer, F. Diederich, Angew. Chem. Int. Ed. 2007, 46,
8270-8273; e) F. R. Fischer, P. A. Wood, F. H. Allen, F. Diederich, Proc.
Natl. Acad. Sci. U. S. A. 2008, 105, 3667-3673; f) K. Nakamura, K. N.
Houk, Org. Lett. 1999, 1, 2049-2051; g) E. Orentas, C-J. Wallentin, K-E.
Bergquist, M. Lund, E. Butkus, K. Wärnmark, Angew. Chem. Int. Ed.
2011, 50, 2071-2074; h) Ö. V. Rúnarsson, J. Artacho, K. Wärnmark, Eur.
J. Org. Chem. 2012, 7015-7041.
polar isopropenyl group had an effect similar to other branched
functional groups (carboxylic acid and ester). We conclude that in
this context a polar group nearby a hydrophobic surface has little
or no effect on the magnitude of hydrophobic association. The
increase in folding energy in this set of experiments appears to be
due to the branched nature of the functional group.
Abbreviations: DCC (N,N'-Dicyclohexylcarbodiimide); EDC.HCl
(1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride);
DMF (N,N-Dimethylformamide); DMAP (4-(Dimethylamino)
[5]
a) S. Paliwal, S.Geib, C.S. Wilcox, J. Am. Chem. Soc. 1994, 116, 4497-
4498; b) E. Kim, S. Paliwal, C. S. Wilcox, J. Am. Chem. Soc. 1998,
11192-11193.
[6]
[7]
B. Bhayana, C. S. Wilcox, Angew. Chem. Int. Ed. 2007, 46, 6833-6836.
C. D. Ma, C. Wang, C. Acevedo-Vélez, S. H. Gellman, N. L. Abbott,
Nature 2015, 517, 347-350.
pyridine); DME (Dimethoxyethane); Pd-L
norbornylphosphino)(2'-dimethylamino-1,1'-biphenyl-2-
yl)palladium(II)); Pd(dppf)Cl2 ([1,1′-Bis(diphenylphosphino)
(Chloro(di-2-
[8]
[9]
J. Jensen, M. Strozyk, K. Wärnmark, J. Heterocyclic Chem. 2003, 40,
473-475.
ferrocene]dichloropalladium(II)).
J. Jensen, J. Tejler, K. Wärnmark, J. Org. Chem. 2002, 67, 6008-6014.
[10] T. Ishiyama, M. Murata, N. Miyaura, J. Org. Chem. 1995, 60, 7508-7510.
[11] T. H. Webb, C. S. Wilcox, J. Org. Chem. 1990, 54, 363-366.
[12] A. Padwa, K. E. Krumpe, J. M. Kassir, J. Org. Chem. 1992, 57, 4940-
4948.
Acknowledgements
[13] W. A. Denny, G. J. Atwell, G. W. Rewcastle, B. C. Baguley, J. Med. Chem.
1987, 30, 658-663.
Support from the National Institute of General Medical Sciences
is gratefully acknowledged.
[14] M. H. Chen, J. G. Davidson, J. T. Freisler, J. Magano, Org. prep. Proc.
Int. 2000, 32, 381-384.
[15] B. Neises, W. Steglich, Angew. Chem. Int. Ed. 1978, 17, 522–524.
[16] a) N. Miyaura, K. Yamada, A. Suzuki, Tetrahedron Lett. 1979, 20, 3437-
3440; b) N. Miyaura, A. Suzuki, Chem. Com. 1979, 19, 866-867; c) N.
Miyaura, A. Suzuki, Chem. Rev. 1995, 95, 2457-2483.
Keywords: torsion balance, folding energy, hydrophobic
interaction, protein folding model.
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[2]
[3]
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10.1002/chem.201901208
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Minimized structures for truncated
Xiujun Ling, Craig S. Wilcox*
analogs of torsion balances 5g and 5k
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A Molecular Torsion Balance Study:
A Nearby Anionic Group Exerts Little
Influence on Hydrophobic
Interactions Between Nonpolar
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