Partitioning solvophobic and dispersion forces in alkyl and perfluoroalkyl cohesion

Article abstract of DOI:10.1002/anie.201408982

Fluorocarbons often have distinct miscibility properties compared to their nonfluorinated analogues. These differences may be attributed to van der Waals dispersion forces or solvophobic effects, but their contributions are notoriously difficult to separate in molecular recognition processes. Here, molecular torsion balances were used to compare cohesive alkyl and perfluoroalkyl interactions in a range of solvents. A simple linear regression enabled the energetic partitioning of solvophobic and van der Waals forces in the self-association of apolar chains. The contributions of dispersion interactions in apolar cohesion were found to be strongly attenuated in solution compared to the gas phase, but still play a major role in fluorous and organic solvents. In contrast, solvophobic effects were found to be dominant in driving the association of apolar chains in aqueous solution. The results are expected to assist the computational modelling of van der Waals forces in solution.

Full text of DOI:10.1002/anie.201408982

Angewandte
Chemie
DOI: 10.1002/anie.201408982
Molecular Recognition
Partitioning Solvophobic and Dispersion Forces in Alkyl and
Perfluoroalkyl Cohesion**
Catherine Adam, Lixu Yang, and Scott L. Cockroft*
Abstract: Fluorocarbons often have distinct miscibility prop-
erties compared to their nonfluorinated analogues. These
differences may be attributed to van der Waals dispersion
forces or solvophobic effects, but their contributions are
notoriously difficult to separate in molecular recognition
processes. Here, molecular torsion balances were used to
compare cohesive alkyl and perfluoroalkyl interactions in
a range of solvents. A simple linear regression enabled the
energetic partitioning of solvophobic and van der Waals forces
in the self-association of apolar chains. The contributions of
dispersion interactions in apolar cohesion were found to be
strongly attenuated in solution compared to the gas phase, but
still play a major role in fluorous and organic solvents. In
contrast, solvophobic effects were found to be dominant in
driving the association of apolar chains in aqueous solution.
The results are expected to assist the computational modelling
of van der Waals forces in solution.
balances have proven invaluable tools in the study of weak
noncovalent interactions because of the sensitivity of con-
formational equilibria to solvent effects and intramolecular
interactions.[2d,10] For example, derivatives of the molecular
torsion balance reported by Wilcox and co-workers (Figure 1)
T
he introduction of fluorine into organic compounds can
have a profound influence on physiochemical properties.[1]
Organofluorine chemistry plays an important role in medic-
inal chemistry, and is due in part to specific interactions
involving fluorinated functional groups.[2] Meanwhile, fluo-
rous synthetic strategies exploit the orthogonal miscibility of
perfluorinated solvents with many organic and aqueous
phases.[3] This fluorophilic/phobic effect has also been
exploited in chromatographic separation,[4] proteomics,[5]
carbohydrate microarrays,[6] and in the assembly of functional
materials.[7] Many of the intriguing properties of organo-
fluorine compounds can be attributed to the low polarizability
of fluorine, which diminishes their ability to participate in van
der Waals dispersion interactions compared to hydrocar-
bons.[1,2,8] However, determining the significance of disper-
sion forces in molecular recognition events occurring in
solution is challenging because of the multiple factors
contributing to noncovalent interactions.[8b,9]
Figure 1. Molecular torsion balances (ꢀ)-1H and (ꢀ)-1F form alkyl–
alkyl and perfluoroalkyl–perfluoroalkyl contacts in their folded confor-
mations respectively. Control compounds (ꢀ)-2H–4H and (ꢀ)-2F–4F
in which one or both of the alkyl groups are removed allow the
magnitudes of alkyl–alkyl and perfluoroalkyl–perfluoroalkyl interactions
in torsion balances (ꢀ)-1H and (ꢀ)-1F to be determined using
Equations (1) and (2), respectively.
Here, we seek to address this challenge in the context of
alkyl–alkyl and perfluoroalkyl–perfluoroalkyl cohesion using
synthetic molecular torsion balances. Molecular torsion
have been used to investigate edge-to-face aromatic inter-
actions,[11] orthogonal carbonyl interactions,[2b,c,12] the hydro-
phobic effect,[13] and van der Waals interactions.[10a,11b] In the
Wilcox torsion balance shown in Figure 1, the hindered biaryl
bond rotates slowly on the NMR timescale at room temper-
ature, meaning that the equilibrium constant, K (and there-
fore the free energy difference between conformational
states, DG), can be determined by integration of distinct
peaks in 1H NMR spectra corresponding to the unfolded and
folded conformers.
[*] Dr. C. Adam, Dr. L. Yang, Dr. S. L. Cockroft
EaStCHEM School of Chemistry
University of Edinburgh, King’s Buildings
West Mains Road, Edinburgh, EH9 3JJ (UK)
E-mail: scott.cockroft@ed.ac.uk
[**] We thank the Engineering and Physical Sciences Research Council
(EP/H02056X/1) for financial support, and Pfizer Ltd. and MTEM
Ltd. for studentships to C.A. and L.Y. respectively.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201408982.
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Inspired by these previous studies, we reasoned that
comparing the intramolecular chain–chain interactions in
(ꢀ)-1H and the fluorinated analogue (ꢀ)-1F would enable
a comparative investigation of the physicochemical origins of
hydrocarbon and fluorous cohesion (Figure 1). The X-ray and
calculated minimized structures of the compounds (ꢀ)-1H
and (ꢀ)-1F indicate that they are respectively able to
accommodate extended intramolecular alkyl–alkyl or per-
fluoroalkyl–perfluoroalkyl contacts in the folded conforma-
tion (see Figure S2 in the Supporting Information). It follows
that cohesive forces between the chains will influence the
position of the conformational equilibrium, K, indicated in
Figure 1. Since both alkyl and perfluorinated alkyl chains
have particularly apolar electrostatic surface potentials (see
Figure S1), interactions between the chains will be dominated
by solvophobic effects and van der Waals interactions.
However, perfluoroalkyl and alkyl chains should be expected
to have rather different propensities to form dispersive van
der Waals interactions.
The isolated folding free energies of (ꢀ)-1H and (ꢀ)-1F
are not sufficient to determine the strength of cohesive
interactions between the chains, since other secondary
interactions and solvent effects also influence the conforma-
tional equilibrium. Nonetheless, it is possible to estimate the
cohesive chain–chain interactions of interest by comparing
the behavior of (ꢀ)-1H and (ꢀ)-1F to control compounds
lacking one or both of the interacting chains. Previous work
has shown that substituting an alkyl chain for a proton has
a minimal effect on the electrostatic potential of an aromatic
ring (Figure S1), thus making (ꢀ)-2H–4H appropriate con-
trols for dissecting out the strength of alkyl–alkyl interactions
in (ꢀ)-1H using Equation (1).[10a] Similarly, calculated elec-
trostatic potentials show that the CF3 group has almost
identical substituent effects as a perfluorohexyl group (Fig-
ure S1). Thus, the control compounds (ꢀ)-2F–4F were
synthesized as controls to measure the extended perfluoro-
alkyl–perfluoroalkyl interactions contained within (ꢀ)-1F
using Equation (2).
Experimental free folding energies of (ꢀ)-1H–4H and
(ꢀ)-1F–4F were obtained in 31 solvents and solvent mixtures
(see Figure S4 and Tables S2 and S3). In line with previous
work, the experimental energies were found to be an order of
magnitude less favorable than those calculated using gas-
phase methods which take dispersion forces into account
(Table S1).[9e] The largest solvent-dependent folding energy
variations were seen for balances (ꢀ)-1H and (ꢀ)-1F, while
those of the control balances (ꢀ)-2H/F–4H/F (which lacked
the ability to form intramolecular chain–chain interactions)
varied to a lesser extent (Figure S4). While no method of
Figure 2. a) Experimental cohesive interaction energies measured
between alkyl chains, DGH (purple) and perfluoroalkyl chains, DGF
(green) using molecular balances (ꢀ)-1H–4H and (ꢀ)-1F–4F and
Equations (1) and (2), respectively. All solvent mixtures are reported in
vol%. b) Dissected solvophobic (DGsolvophobic) and c) van der Waals
(DGvdw) free energy contributions to alkyl–alkyl (light purple) and
perfluoroalkyl–perfluoroalkyl cohesion (light green), determined by
fitting experimental free energies to the simple model given by
Equation (3). All data, error values, and those of other solvent mixtures
are presented in the Supporting Information. Deuterated solvents were
used in place of all protic solvents. * The value for perfluorohexane
was extrapolated from data obtained in perfluorohexyliodide/perfluoro-
hexane mixtures (see Figures S5–S8).
magnitudes of <ꢀ 2 kJmolꢁ1 (Figure 2a), and are consistent
with a large tempering of intramolecular dispersion forces
resulting from competitive dispersion interactions with the
solvent.[8b,9c,15] Thus, further analysis is required to determine
whether the remaining differences in dispersion forces make
any discernible contribution to the observed interaction
energies.
Inspection of the experimental interaction energies, as the
solvent is varied, provides insights into the forces driving the
self-association of apolar chains. In the tetrahydrofuran/water
mixtures, the alkyl–alkyl (DGH) and perfluoroalkyl–
perfluoroalkyl (DGF) interaction energies were very similar
(Figure 2a, bottom). The finding appears to be consistent with
that of Whitesides et al. who found that alkyl and fluoroalkyl
chains had similar hydrophobicities in carbonic anhydrase
binding.[16] However, it should be noted that absolute
comparison of the interaction energies is not possible in the
present systems because the contact surface areas of the
dissected alkyl–alkyl and perfluoroalkyl–perfluoroalkyl inter-
actions are not necessarily the same (because of differences in
the size of the F versus H atoms and differences in the lengths
dissecting the energetic contributions of individual func-
14]
tional-group interactions is ideal,[11 g
this observation
supports the use of Equations (1) and (2) for estimating the
magnitude of the alkyl–alkyl (DGH) and fluoroalkyl–fluoro-
alkyl interactions (DGF) of interest. Furthermore, errors
associated with the energy dissection are fully accounted for
in the error bars shown in Figure 2a since they are determined
directly from the standard deviations in the energies of the
control balances (see error analysis in the Supporting
Information). These dissected DGH and DGF energies had
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Instead, these differences suggest an important role for van
der Waals dispersion forces in governing molecular behavior,
despite considerable solvent-mediated attenuation of disper-
sion interactions compared to the gas phase.
Molecular polarizabilities have previously been used to
rationalize the role of dispersion forces in molecular inter-
actions.[9d,18] However, the dispersive interactions of a solvent
are best described by bulk polarizability, P.[19] The opposing
gradients of the plots of P against DGH and DGF (Figure 3b,
black circles) reveal the contrasting competitive influence of
solute–solvent dispersion interactions on the self-association
of perfluoroalkyl and alkyl chains. Meanwhile, the results
obtained in water/tetrahydrofuran mixtures are outliers in
Figure 3b (hollow circles) because of the large contributions
from solvophobic effects.
The correlations in Figures 3a and 3b indicate that both
van der Waals dispersion forces (a function of P) and
solvophobic effects (a function of ced) make significant
contributions to the experimental DGH and DGF interaction
energies. Thus, a linear regression analysis of the experimen-
tal data was performed to dissect the solvophobic
(DGsolvophobic) and van der Waals (DGvdw) contributions to
DGH orDGF as follows:
DGH=F ¼ DGsolvophobicþDGvdw
DGH=F ¼ DGsolvophobicþDGvdw ðsolv: dependentÞþDGvdw ðsolv: independentÞ
DGH=F ¼ a ðcedÞ þb ðPÞ þc
ð3Þ
Each set of DGH and DGF values (measured in 31 different
solvents and solvent mixtures; Tables S2 and S3) was inde-
pendently fitted to Equation (3) to determine the corre-
sponding a, b, and c coefficients for alkyl and perfluoroalkyl
cohesion, where a(ced) encoded the DGsolvophobic term, b(P)
encoded the solvent-dependent component of DGvdw, and c
encoded the solvent-independent component of DGvdw (i.e.
direct intramolecular chain–chain interactions and sterics).
Excellent agreement was seen between the experimental
DGH and DGF values and those given by fitting to Equa-
tion (3) (DGH/F, equation (3)), thus supporting the validity of the
model represented by Equation (3) (R2 = 0.90 and 0.93;
Figure 3c).
The dissected solvophobic [DGsolvophobic = a(ced)] and van
der Waals contributions [DGvdw = b(P) + c] to the exper-
imental chain–chain interaction energies are plotted graphi-
cally in Figures 2b and c as the solvent was varied. Solvo-
phobic contributions were found to be very similar for the
alkyl–alkyl and perfluoroalkyl–perfluoroalkyl contacts exam-
ined in our systems, and were dominant in polar and aqueous
solvents (hence the correlations with cohesive energy density;
Figure 2a). However, Figures 2b and 2c indicate that differ-
ences in dispersion interactions have a dominant influence in
fluorous and apolar organic solvents (where cohesive solvent
interactions are weak). This data explains the inverted
symmetry of the interaction trends for perfluoroalkyl versus
alkyl cohesion in fluorous and apolar solvents as the bulk
polarizability of the solvent is varied (Figure 2a, top and
Figure 3b).
Figure 3. Correlation of experimental alkyl–alkyl (DGH) and perfluoro-
alkyl–perfluoroalkyl (DGF) interaction energies plotted against a) sol-
vent cohesive energy density (fluorous solvent outliers indicated with
hollow points), b) bulk solvent polarizability (water/THF outliers
indicated with hollow points), and c) free energies predicted from
linear regression analysis where both solvent cohesive energy density
and bulk solvent polarizability are taken into account according to
Equation (3). All plotted data and errors are provided in the Support-
ing Information. Bulk polarizability, P is related to molecular polar-
izability, a by the equation, PVm =4/3pNa where Vm is the molar
volume and N is the number of molecules per unit volume.[19]
of the chains employed). More significant is the finding that
the DGH and DGF values measured in the present study
correlate with solvent cohesive energy density (ced) for
organic and aqueous solvents (Figure 3a; see Table S4). This
data is consistent with an important role for cohesive
(solvophobic) solvent–solvent interactions in the self-associ-
ation of alkyl and perfluoroalkyl chains.[9c,e,17]
However, solvophobic effects do not adequately explain
the DGH and DGF values measured in fluorous solvents, which
are moderate outliers (in different directions) on the cohesive
energy density correlations (hollow circles, Figure 3a). Sol-
vophobic effects are also unable to account for the symmetry
inversion in the patterns of DGH and DGF on moving from
fluorous to apolar organic solvents (Figure 2a, top left).
In conclusion, we have used molecular torsion balances to
measure alkyl–alkyl and perfluoroalkyl–perfluoroalkyl cohe-
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Received: September 10, 2014
Published online: && &&, &&&&
Keywords: molecular recognition · noncovalent interactions ·
.
perfluorinated solvents · self-assembly · solvent effects
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Molecular Recognition
In full force: The balance of solvophobic
and van der Waals dispersion forces on
the self-association of perfluoroalkyl and
alkyl chains is examined in solution. The
contributions of dispersion interactions
in apolar cohesion were strongly attenu-
ated in solution compared to the gas
phase. In contrast, solvophobic effects
were dominant in driving the association
of apolar chains in aqueous solution.
C. Adam, L. Yang,
S. L. Cockroft*
&&&& — &&&&
Partitioning Solvophobic and Dispersion
Forces in Alkyl and Perfluoroalkyl
Cohesion
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