London Dispersion in Alkane Solvents

Article abstract of DOI:10.1002/anie.202012094

The importance of London dispersion interactions in solution is an ongoing debate. Although the significance of dispersion for structure and stability is widely accepted, the degree of its attenuation in solution is still not properly understood. Quantita

Full text of DOI:10.1002/anie.202012094

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Title: London dispersion in alkane solvents
Authors: Marcel A. Strauss and Hermann Andreas Wegner
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London dispersion in alkane solvents
Marcel A. Strauss, [a] and Hermann A. Wegner *[a]
[a]
Marcel A. Strauss, Prof. Dr. Hermann A. Wegner
Institute of Organic Chemistry
Justus Liebig University Giessen
Heinrich-Buff-Ring 17, 35392 Giessen, Germany
Center for Materials Research (LaMa)
Justus Liebig University Giessen
Heinrich-Buff-Ring 16, 35392 Giessen, Germany
E-mail: hermann.a.wegner@org.chemie.uni-giessen.de
Supporting information for this article is given via a link at the end of the document.
Abstract: The importance of London dispersion interactions in
solution is an ongoing debate. Although the significance of dispersion
for structure and stability is widely accepted, the degree of its
attenuation in solution is still not properly understood. Quantitative
evaluations are derived mostly from computations. Experimental data
provide guidelines to include London dispersion in solution phase
design. Herein, dispersive interactions were examined with an
azobenzene probe. Alkyl substituents in meta positions of the
azobenzene core were systematically varied and the effect on the
half-lives for the thermally induced Z to E isomerization in several
alkane solvents was determined. The results show that intramolecular
dispersion is only marginally influenced. In solvents with low surface
tension, reduced destabilizing solvent-solvent interactions increase
the half-life up to 20%. Specific individual interactions between alkyl
chains on the azobenzene and those of the solvent lead to additional
fluctuations of the half-lives. These presumably result from structural
changes of the conformer ensemble.
the design of catalysts.[6] The proper selection of an ideal solvent
can therefore be decisive in controlling certain molecular
processes. Understanding solute-solvent interactions is crucial
and promises potential for improvements in industrial solvent
purification[7] and recovery.[8]
In this context, London dispersion slowly starts to gain attention
as a means to control selectivities in synthesis. Large and
polarizable moieties have proven their applicability as dispersion
energy donors[9] stabilizing extreme bonding situations.[10] They
play an important role in the aggregation of aromatic species[11]
,
the formation of organometallic complexes[12] and in catalysis.[13]
However, there are only a few rare investigations of London
dispersion interactions between linear alkyl chains.[14,15] Flexible
n-alkyl chains can adopt a high number of conformers at elevated
temperatures. Due to this fact, an estimation of their dispersion
donor abilities is a highly complex task. In recent years numerous
computational methods were developed giving access to a
comprehensive toolbox for efficiently evaluating the dispersive
interactions in molecular systems in the gas phase with high
accuracy.[16] The strength of London dispersion in solution,
however, is subject of current research interests. Some studies
address this by investigating the effect of the solvent on conformer
or dimer stability.[17,18,19]
Solvation dictates all chemical transformations in the liquid phase
ranging from processes in the living world to production of bulk
chemicals on a multi ton scale. Nevertheless, the specific solvent-
solute interactions and their importance on controlling chemical
reactions is often underestimated. They can exhibit discrete or
bulk effects on molecules and atoms leading to an alteration also
of macroscopic properties. In biology, the solvent environment is
crucial for the accurate folding and function of proteins.[1] In this
way, the catalytic activity and stability can be enhanced
tremendously.[2] But the solvent plays a far greater role than just
containing the reactants for a chemical transformation. It can
influence the selectivity of a chemical reaction by favouring a
certain transition state.[3] By the proper selection of the solvent, it
is even possible to reverse the enantioselectivity of a reaction.[4]
While in most cases the bulk properties of a solvent can be
reliably described, direct interactions of solvent molecules with
the solute often require sophisticated and expensive
computational approaches. Although hydrogen bonding or
formation of Lewis pairs are already well predictable by
calculations, the weaker van der Waals interactions are often
neglected in more complex systems. Accurate computation of
non-covalent interactions and entropies in solution stays a
demanding task. Especially, implicit solvent models often show a
mediocre correlation with experiments and even explicit methods
are in general only slightly better.[5] This emphasizes the need for
experimental data to predict also subtle solvent effects and to
provide a basis for further improvements of computational models,
particularly with regard to a growing interest in evaluating subtle
preferences of non-covalent interactions for their consideration in
These approaches were conducted in order to determine the
contribution of London dispersion to the stability of their systems.
The observed attenuation of the dispersion caused by competitive
interactions with the solvent molecules, however, was not
complete. For some systems a compensation between 60-80%
was observed.[17,20] We introduced the azobenzene switch as
powerful tool to investigate London dispersion forces. Herein, it
was chosen to address these open questions.[19,21–23]
Scheme 1 Overview of the investigated azobenzene derivatives with different
substitution patterns and sizes.
1
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Figure 1 Relative energies for the Z to E isomerization of an azobenzene. Upon isomerization, the solvent accessible surface of the azobenzene increases, leading
to increased solute solvent interactions.
The utilized azo compounds 1-13 (Scheme 1) for this investigation
were prepared by a highly flexible synthesis strategy allowing the
Methods
introduction of a variety of alkyl substituents (for synthetic details,
see SI).[23] To study the varying interactions in several alkane
solvents all azobenzenes investigated were switched from the E-
to the Z-state by irradiation at 302 nm. The thermally induced
back isomerization at 40 °C was measured by UV-Vis
spectroscopy. In this way, the influence of subtle changes of the
solvent environment on the stability of the Z-isomer in
dependence of the alkyl substituent of the azobenzenes was
investigated. In this study, a series of linear alkanes starting from
n-heptane to n-dodecane, as well as 2,2,4-trimethylpentane
(iso-octane) and cyclooctane were used as solvents.
Concentration as well as temperature were kept constant for
these measurements.
The present study aims at systematically exploring the interplay
of alkane solvents with different alkyl substituents in meta-position
of the azobenzene by monitoring the thermal Z®E isomerization.
During this process, the alkyl-alkyl and alkyl-aryl interactions
contribute to the stabilization of the Z-isomer, which is influenced
by the solvent environment. Azobenzene can isomerize between
two different states – the E-state and the about 11.7 kcal/mol
considerably less stable Z-state.[24] Isomerization between the E-
and Z-state can be initiated upon irradiation with light. The
transition from the Z- to the E-isomer can also be achieved by
heating. The distance between the carbon atoms in para-position
of the rings changes from 9.1 Å[25] in the E-isomer to about
6.2 Å[26] in the Z-isomer. In this way, substituents on the
azobenzene can be brought in close proximity. Especially
substituents in meta-positions come into a distance, where
London dispersion donors stabilize the Z-isomer of the
azobenzene as we could show previously.[21] The general effect
of the solvent on the isomerization barrier for azobenzenes can
be described as a sum of three parameters (equation 1).[27] First,
the contribution from interactions between the solute and the
solvent ΔFinter. These forces mainly include dispersive and
electrostatic interactions. Second, the ΔFcav term describes the
energy necessary to form cavities in the solvent for the solute.
Here, the interdependence of solvent surface tension γ and the
volume of the solute dominate this parameter. Third, ΔFred stands
for the reduction of intramolecular interactions between molecular
groups of the solute, which are altered by the solvent environment.
Results & Discussion
As previously reported[23] substitution of the parent azobenzene
12 with methyl substituents leads first to a decrease of the
Z-isomer half-life, which results from a change in the electronic
properties of the azobenzene motif. Further elongation of the alkyl
substituents increases the half-life due to increasing attractive
London dispersive interactions with increasing chain length. In the
row of all-meta n-alkylated azobenzenes 1-8, the highest half-life
is observed for derivative 4 with n-butyl groups. With longer alkyl
chains, the unfavourable entropic contributions lead again to
slight decrease of the Z-isomer stability in 5-8. However, the
arrangement of the alkyl groups has a large effect for both the
solvent and the substituents on the azobenzene. Replacing the
n-butyl substituents in 4 with tert-butyl groups in azobenzene 13
leads to a tremendous increase in the half-life of the Z-isomer by
a factor >4. The reason for this is that all alkyl groups in 13 are
now in an optimal distance for establishing attractive alkyl-alkyl
and alkyl-aryl interactions caused by London dispersion. In 4, the
linear alkyl chains bear more conformational flexibility and due to
the higher distance from the azobenzene core exhibit weaker
attractive interactions in the Z-isomer.
∆ꢀꢀꢁꢂꢃ. ꢄꢅꢅ = ∆ꢀꢆꢇꢈꢄꢉ + ∆ꢀꢊꢋꢃ + ∆ꢀꢉꢄꢌ (1)
The contribution of the solvent on the intramolecular interactions
in the Z-isomer is considered to be constant. This assumption is
supported by the fact, that the overall tendency of the half-lives
observed in dependence of the substituents stays very similar in
all investigated solvents (see Fig. 2 & SI Fig. S2-S8). Due to their
apolar character, solvophobic contributions to the thermal Z®E
isomerization barrier should play a minor role here.
2
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At first, the influence on the solute-solvent interactions were
examined regarding a change of electrostatic or van der Waals
contributions. Especially the Z-isomer is affected by changes in
the electrostatic environment due to the larger dipole. For
unsubstituted azobenzene, an increase of the relative permittivity
εr of the solvent environment normally leads to an increase in the
half-life of the Z-isomer. This was demonstrated by the work of
Winkler and co-workers, who determined the half-lives of
azobenzene (12) for solvents with a relative permittivity εr
between 1.92 and 80.10.[28] Most measurements were performed
in solvents with a relative permittivity higher than 7. Their results
can be explained by a thermodynamic stabilization of the
Z-isomer in a solvent with a substantially higher polarity. This is
supported by the findings of Haberfield and co-workers[29], who
calorimetrically investigated the enthalpies for the Z®E
isomerization
of
Z-azobenzene
in
cyclohexane
and
cyclohexanone. Furthermore, an energetic increase of the
transition state due to less favoured solute-solvent interactions
was detected.
Figure 2 Influence of the substituents on the half-lives for the Z-isomers of
azobenzenes 1-8, 12 & 13 at 40°C in n-octane. The overall tendency of the half-
lives in dependence of the substituents is in most cases minorly affected by the
solvent (see also ESI Fig. S2-S8)
When the half-lives in different alkanes as solvents are
determined, however, a negative linear dependence on the
solvent permittivity is observed for azobenzenes with small alkyl
groups (Figure 4a). In contrast to the investigation of Winkler, a
decrease of the half-lives with increasing permittivity εr was
detected. It can be assumed, that for the investigated permittivity
range, destabilization of the Z-isomer occurs rather than
stabilization. The dipole moment of Z-azobenzene can be
calculated with 3.2 D.[30] This value is close to the one of acetone
with 2.9 D.[31] Studies show, that the mixing enthalpy of acetone
with n-alkanes increases with increasing chain length of the
n-alkanes, indicating less favourable interactions between solute
and solvent.[32] This would also be the case for the Z-azobenzene,
leading to a lowering of the Z®E isomerization barrier by
increasing the energy of the Z-isomer and therefore a shorter half-
life.
Modification of the degree of substitution of the azobenzene
provides further insights: For compounds 9 & 10 the overall
relative permittivity dependency of the half-lives seems to stay the
dominant factor, although the course of the half-lives is less steep
(Figure 4b). This is most likely caused by the changed electron
distribution of the azobenzene core, since two alkyl substituents
were replaced with hydrogen. However, a deviation from linearity
for the measurements in iso-octane is emerging here, which
seems to be even higher for the derivative with the longer alkyl
chains 10. For longer alkyl groups, also the linear correlation
shows significantly less coherence, indicating a growing influence
of other types of interactions.
A surprisingly large increase of the half-lives for all compounds
was determined, when the solvent was changed from n-octane to
iso-octane. The increase varies between ~5% for small
azobenzenes to around 20% for those with larger alkyl
substituents. By applying the Arrhenius law, the difference in the
activation barrier for the isomerization of 4 for example can be
calculated as 0.1 kcal/mol. This change just derives from
replacing the linear alkane n-octane with the more spherical
formed iso-octane. The opposite effect is observed, when
cyclooctane instead of n-octane is used. Here, the half-life of the
Z-isomer is reduced between 12 and 21% compared to n-octane
for all compounds in this study except for azobenzene 13 with the
tert-butyl groups. To evaluate the origin of these solvent effects,
the details of the alteration of half-lives were looked at for the
whole series of solvents. The main reason for these observations
can be correlated to a change in the solute-solvent interaction
term ΔFinter or by changes in ΔFcav
.
Since the actual volume or solvent accessible surface of the
azobenzenes changes upon isomerization, it is very likely that for
larger substituents a greater effect is observed. This will then
contribute mainly to the ΔFcav term, describing the compensation
of solvent-solvent interactions, which have to be overcome to
accommodate the solute. The dominant parameter here to
describe the changes in the solvent shell is the surface tension.
When the half-lives of the azobenzenes 9 & 10 are plotted against
the surface tension γ (Figure 5a) a linear correlation is again
obtained for these solvents with similar γ values. It can be argued,
that in solvents with less surface tension, i.e. iso-octane, the
dipolar Z-isomer of the azobenzenes is less destabilized in these
apolar solvents, leading to the higher half-lives. Cyclooctane,
however, exhibits very strong internal solvent-solvent interactions,
Figure 3 Relative changes of the Z-isomer half-lives for the azobenzenes 1-13
with different substituents at 40 °C relative to n-octane. The highest deviations
were observed for iso-octane and cyclooctane showing increases of the half-
lives up to 20%.
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which can be derived from the rather high melting point of
14.6 °C.[31] These forces have to be overcome upon solvation of
the azobenzene, resulting in less favouring solute-solvent
favourable interaction surface to interact with the linear alkyl
substituents due to its more spherical shape. This would lead to a
less solvated transition state compared to linear alkanes as
solvents resulting in longer half-lives.
interactions. In contrast, iso-octane might provide
a less
Figure 4 The half-lives of Z-isomer of azobenzene 1 (a) and 9 &10 (b) in different alkanes as solvent in dependency of the relative solvent permittivity[31] at 40 °C.
a Azobenzene 1 still shows a linear dependency on the relative permittivity b Half-lives for 9 & 10 show already a higher deviation from linearity for iso-octane as
solvent.
For all-meta alkylated azobenzenes with longer alkyl chains, a
higher fluctuation of the half-lives is observed, though the overall
trend of decreasing half-lives with increasing surface tension
remains. The additional methylene units in longer chains bear
more degrees of rotational freedom. At such elevated
temperatures, already an ensemble of conformers is adopted for
these flexible alkyl chains of the substituents but also of the
solvents. For n-octane, already ten conformers are less than
0.6 kcal/mol higher in energy than the all-trans conformer.[33] It is
not unlikely that discrete solvent-solute interdependency of the
alkyl chains with the solvent lead to a kind of match-mismatch
interaction. This special type of interaction contributes to the
ΔFinter term. The importance of the right geometrical match for
such weak London dispersion interactions was just recently
demonstrated by Chen and co-worker, who showed that
disadvantageous interaction geometries can exceed the
contribution of higher polarizability upon formation of
perfluoroalkane-alkane dimers.[15]
association due to their conformational rigidity.[34] Therefore, rigid
tert-butyl groups as substituents were introduced with the
incentive to evaluate the influence of spatial extent on the solvent
effect (Figure 5d). Azobenzene 13 is the only derivative in this
study, for which the half-life of the Z-isomer in cyclooctane is
higher than in n-octane and even in iso-octane. Since the tert-
butyl substituents are isoelectronic compared to n-butyl, this
stability change is most likely based on a structural effect. The
predominant conformer of cyclooctane is the boat-chair[35], which
exhibits a very flat interaction surface. The better capability of
cyclooctane for interaction with more globular structures is
reflected i.e. by the lower mixing enthalpy of the more spherical
2,3-dimethylbutane compared to n-hexane[36] and for other
spherical solutes[37]. This should in our case then result in an
increased interaction of the tert-butyl groups with the cyclooctane
solvent compared to the linear alkanes, leading to a better
solvation of the Z-isomer and, therefore, an increased half-life.
The results of azobenzene 4 with n-butyl chains are not only
special for exhibiting the longest half-lives of all n-alkyl substituted
azobenzenes (Figure 5b). They further show significant breaks in
the tendency of decreasing half-lives for the row of linear alkane
solvents. However, their conformational freedom still seems to be
limited enough, so that attractive London dispersive interactions
in the Z-isomer are not overcompensated by entropic
contributions in any solvent. The trend of fluctuating half-lives for
the row of linear alkane solvents is continued for other all-meta
n-alkylated azobenzenes like 7 with n-heptyl chains in Figure 5c.
The energetic differences in the isomerization barrier for the Z®E
isomerization of these derivatives in n-alkanes are so small that
even subtle changes of entropic contributions have a detectable
impact. This includes changes in the conformer distribution.
Rigidity can have an advantageous effect for the interactions of
two molecular entities. For linear alkyl chains the entropic
contributions to the free energy of interaction upon approaching
is much higher compared to rigid alkyl structures. They exhibit
weaker enthalpic attraction but a much less entropic penalty for
Computational conformer analysis
With the introduction of new sophisticated computational tools, it
was possible to evaluate the influence of the conformational and
rotational flexibility of the alkyl chains on the stabilisation within
the Z-isomer. The Conformer-Rotamer Ensemble Sampling Tool
(CREST) by Grimme was used to perform such a conformational
analysis.[38] The structures of the E-state, the transition state and
the Z-state of azobenzene 1 were first optimized on a PBE0[39]
level of theory and used as template for other derivatives.
Afterwards, the core structure of the azobenzene was constrained
allowing only rotation of the alkyl substituents. In this way,
hundreds of conformers for azobenzenes 2, 4 and 7 were
computed. Single point energies on the B97-3c[40] level of this
conformer ensemble were calculated for allowing a better
selection of the relevant structures. Conformers up to 3 kcal mol-1
higher in energy than the lowest energy structure were considered
for further analysis.
4
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Figure 5 The half-lives of Z-isomer of azobenzene 9 &10 (a), 4 (b), 7 (c) and 13 (d) in different alkanes as solvent in dependency of the surface tension[41] at 40 °C.
a In contrast to Fig. 3b the half-lives for 9 & 10 show a better linear correlation with the surface tension of the solvents. This observation goes along with an increasing
importance of the ΔFcav term for these derivatives. b Elongation of the alkyl chains leads to higher fluctuations from linearity for n-alkanes as solvent. c These data
differ also with the chain length of the substituents on the azobenzene. These fluctuations can be contributed to the ΔFinter term. d This solute-solvent interaction is
also the reasonable cause for the large increase of Z-isomer stability of 13 in cyclooctane.
In the next step, distances between the carbon atoms on
opposing alkyl chains were determined to find close contacts for
non-covalent interactions. Results were limited to distances below
5 Å, therefore including H-H distances of 4.2 Å or lower where
dispersive interactions start to contribute significantly to the
stability of molecular entities.[42] To obtain a more meaningful pic-
ture of the contact distribution, the considered conformers were
weighed by their single point energies with a Boltzmann distri-
bution. The in this way determined average number of C-C con-
tacts over the conformer ensemble within this 3 kcal mol-1 energy
window are listed in Table 1. For compound 2, the distances
between the ethyl side chains are too short for relevant attractive
interactions between the alkyl chains in the E- as well as the
transition state. Only in the Z-state, the ethyl groups mesh well.
For longer chains, like n-butyl in 4, this kind of interactions are
also to a minor extent present in the transition state but ~5.7 times
more dominant in the Z-state. In the n-heptyl derivative 7, these
interactions occur in all three states. While the differences bet-
ween the E-state and the transition state are quite small, the
number of contacts in the Z-state are here only ~3.4 times higher
than in the transition state. Noteworthy, that the same number of
average interactions are present in the E-state, supporting the
correlation between transition and E-state projected in the intro-
duction. This analysis emphasizes that the observed kinetic trend
for linear alkyl substituted azobenzenes is mainly driven by in-
creased stabilisation of the Z-isomer up to mid-length chains. With
further increasing chain length, these interactions start to occur
also more and more in the transition state and seem to compen-
sate further elongation of the alkyl substituents.
Table 1. Average Number of opposing C-C contacts below 5 Å over all
conformers within 3 kcal mol-1.
Cpd
2
E-state
0.00
Transition state
0.00
Z-state
0.73
4
0.00
2.04
11.68
42.70
7
12.81
12.74
5
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Figure 6 NCI[43] analysis of the optimized structures for the lowest energy conformers of the transition state and the Z-state of
azobenzene 4 [PBE0-D3BJ/def2-TZVP][39,44]. Visualization was created with VMD.[45]
.
These interactions can also be visualized by an NCI analysis,
which is depicted in Figure 6.[43] This non-covalent interaction
analysis indicates the regions in the molecules as isosurfaces,
where these contacts occur. The colour code further allows to
differentiate between attractive (blue), repulsive (red) and weak
interactions (green). In the transition state of derivative 4 weak
alkyl-alkyl interactions start to form as can be seen in the right part
of the molecule. In the Z-state additional alkyl-aryl interactions
emerge, providing a much larger interaction surface leading to a
large stabilization of the Z-state. For the n-heptyl derivative 7, a
similar analysis can be done (see ESI Fig. S9 & S10). It has to be
pointed out, that the alkyl chains in the Z-state intercalate with the
ones on the opposing aryl ring, leading to larger stabilizing effects
on the structure. In the transition state, the alkyl chains tend to
preferentially interact with the ones on the same aryl ring due to
an unfavourable core geometry of the transition state. These
interactions are most likely competing with interactions with
solvent molecules due to the less restricted geometry. It can be
assumed that specific solute-solvent interactions mainly affect the
transition state.
can have substantial effects on the stability of an organic
compound. A detailed computational evaluation of the conformer
ensemble supports the taken approach. These new insights
provide general guidelines to design solvent-solute interactions
for all kinds of processes in the liquid state.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
Financial support was provided by the Justus Liebig University
Giessen and by the Deutsche Forschungsgemeinschaft
(SPP1807). We thank Dr. Heike Hausmann and Anja Platt for
NMR support and Jan M. Schümann for the fruitful discussions.
Keywords: London dispersion • azobenzene • molecular probe •
solvent effects • spectroscopy
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3. Specific individual interactions between the alkyl chains
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reveals that even small structural changes of an alkane solvent
6
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10.1002/anie.202012094
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The degree of attenuation of London dispersion in solution is evaluated. Dispersive interactions were examined with azobenzene
probes. The effect on half-lives for the thermally induced Z to E isomerization in several alkane solvents was determined. The results
show only a marginally influence on intramolecular dispersion. In solvents with low surface tension, reduced destabilizing solvent-
solvent interactions increase the half-life up to 20%.
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