Liquid-Crystalline Ionic Liquids as Ordered Reaction Media for the Diels–Alder Reaction

Article abstract of DOI:10.1002/chem.201602965

Liquid-crystalline ionic liquids (LCILs) are ordered materials that have untapped potential to be used as reaction media for synthetic chemistry. This paper investigates the potential for the ordered structures of LCILs to influence the stereochemical outcome of the Diels–Alder reaction between cyclopentadiene and methyl acrylate. The ratio of endo- to exo-product from this reaction was monitored for a range of ionic liquids (ILs) and LCILs. Comparison of the endo:exo ratios in these reactions as a function of cation, anion and liquid crystallinity of the reaction media, allowed for the effects of liquid crystallinity to be distinguished from anion effects or cation alkyl chain length effects. These data strongly suggest that the proportion of exo-product increases as the reaction media is changed from an isotropic IL to a LCIL. A detailed molecular dynamics (MD) study suggests that this effect is related to different hydrogen bonding interactions between the reaction media and the exo- and endo-transition states in solvents with layered, smectic ordering compared to those that are isotropic.

Full text of DOI:10.1002/chem.201602965

DOI: 10.1002/chem.201602965
Full Paper
&
Ordered Solvents
Liquid-Crystalline Ionic Liquids as Ordered Reaction Media for the
Diels–Alder Reaction
[
a]
[b]
[c, d]
[c]
Duncan W. Bruce,* Yanan Gao, Josꢀ Nuno Canongia Lopes,*
John M. Slattery*
Karina Shimizu, and
[
a]
Abstract: Liquid-crystalline ionic liquids (LCILs) are ordered
materials that have untapped potential to be used as reac-
tion media for synthetic chemistry. This paper investigates
the potential for the ordered structures of LCILs to influence
the stereochemical outcome of the Diels–Alder reaction be-
tween cyclopentadiene and methyl acrylate. The ratio of
endo- to exo-product from this reaction was monitored for
a range of ionic liquids (ILs) and LCILs. Comparison of the
endo:exo ratios in these reactions as a function of cation,
anion and liquid crystallinity of the reaction media, allowed
for the effects of liquid crystallinity to be distinguished from
anion effects or cation alkyl chain length effects. These data
strongly suggest that the proportion of exo-product increas-
es as the reaction media is changed from an isotropic IL to
a LCIL. A detailed molecular dynamics (MD) study suggests
that this effect is related to different hydrogen bonding in-
teractions between the reaction media and the exo- and
endo-transition states in solvents with layered, smectic order-
ing compared to those that are isotropic.
Introduction
In recent years, ionic liquids (ILs) have emerged as a novel
class of solvent with properties that are often rather different
to conventional reaction media (e.g. their ability to dissolve
solutes with a range of different polarities, negligible vapour
pressures, and high chemical and thermal stability). Significant
efforts have been made to understand the role that ILs can
play as tuneable, neoteric solvents for organic synthesis, cataly-
Solvents play a crucial role in most chemical reactions, from
the small scale of the laboratory to large-scale, industrial appli-
cations. The properties of a solvent (e.g. dielectric constant,
boiling point, vapour pressure) can have a profound influence
on reactions taking place within it, for example, by affecting
the solubility of reagents or products, promoting desired reac-
tion pathways by preferential stabilisation of certain transition
states, or simply by allowing control over the reaction temper-
ature. Solvents can also have a significant impact on the sus-
tainability of a chemical process, and there is a great deal of
current interest in alternative solvent systems that may allow
for greener processes. As such, choice of solvent is an impor-
tant part of the optimisation of many reactions.
[1]
sis, the synthesis of nanomaterials and many more. However,
most conventional solvents and ILs have one property in
common, that they are isotropic fluids, that is, they exhibit no
long-range ordering in their liquid state. There exists significant
untapped potential in reaction media that are anisotropic
fluids, which are structured and exhibit long-range ordering
that is resistant to perturbation. The order inherent in these
phases could place steric or electronic constraints on reactants,
transition states or products so provide a directing influence
on a chemical reaction and thus increasing the chemist or en-
gineer’s toolkit for controlling reaction outcomes. Liquid crys-
tals (LCs) are anisotropic fluids that form a wide range of
phase types with different structures and as such have signifi-
cant potential to be used as ordered reaction media, which
may allow control over the rate and/or stereochemical out-
come of reactions taking place within them. Other systems
that structurally confine reactants, for example, micelles or co-
ordination cages, have previously been shown to influence re-
[
a] Prof. D. W. Bruce, Dr. J. M. Slattery
Department of Chemistry, University of York
Heslington, York, YO10 5DD (UK)
E-mail: duncan.bruce@york.ac.uk
john.slattery@york.ac.uk
[b] Prof. Y. Gao
Dalian Institute of Chemical Physics, Chinese Academy of Sciences
4
57 Zhongshan Road, Dalian 116023 (P. R. China)
[
c] Prof. J. N. Canongia Lopes, Dr. K. Shimizu
Centro de Quꢀmica Estrutural, Instituto Superior Tꢁcnico
Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisboa (Portugal)
E-mail: jnlopes@ist.utl.pt
[2]
action outcomes. The long-range ordering and chemical and
structural versatility of LCs gives them additional opportunities
for chemical control compared to these systems.
[d] Prof. J. N. Canongia Lopes
Instituto de Tecnologia Quꢀmica e Biolꢂgica
Universidade Nova de Lisboa
Av. Repfflblica, 2780-157 Oeiras (Portugal)
Thermotropic LCs were investigated for their potential to in-
fluence the outcome of chemical reactions in a range of sys-
Supporting information including full experimental details for this article
and ORCIDs are available on the WWW under http://dx.doi.org/10.1002/
chem.201602965.
[3]
tems in the 1980s. Many interesting results were obtained,
but two main issues are likely to have held back developments
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in this area. Firstly, neutral thermotropic LCs are not particular-
ly versatile solvents, tending to dissolve only those substrates
with relatively similar polarity, functional groups and structure
to the LC phase itself. Secondly, and perhaps more importantly,
the addition of solutes to LC phases tends to destabilise them,
leading to loss of their ordered structures. ILs that display
liquid-crystalline mesophases, liquid-crystalline ILs (LCILs), have
the potential to overcome both of these problems. The ability
of ILs to solubilise a range of substrates of differing polarities
is well known and so LCILs are likely to be much more versatile
solvents than neutral LCs. The ability to influence reaction
chemistry occurring within the LCIL by chemical modification
of the anion or cation also gives significant potential to ’tune’
the properties of a LCIL to suit a reaction of interest. In addi-
tion to their favourable solvent properties compared to neutral
LCs, LCILs often form mesophases that are stable over a wide
only compared reactivity in one LCIL with one conventional IL,
the chemical structures of which are somewhat different and
so there is still some potential for the chemical differences be-
tween the salts to play a role in the observed results, in addi-
tion to changes in ordering.
To shed more light on the possibility for ordered LCIL sol-
vents to influence the outcome of a chemical reaction, we
have re-investigated the DA reaction between cyclopentadiene
and methyl acrylate in a range of ILs and LCILs. In particular,
combinations of these solvents were chosen in order to allow
the best possibility of distinguishing between anion effects,
alkyl chain length effects and true liquid-crystalline effects on
the stereochemical outcome of this reaction. This reaction was
[
6a]
chosen because benchmark data from the Welton
and
[6d]
Dyson groups were available for some of the ILs used, which
allowed us to gain confidence in the results, by comparison
with previous established reactions.
[
4]
temperature range (over 2008C in some cases). This means
that LCILs are significantly more tolerant to the addition of
non-LC compounds and any depression of the clearing point
that occurs on adding solutes will still leave a very large LC
range within which to work. As such, LCILs represent extremely
attractive targets as LC solvents.
Results and Discussion
The DA reaction between cyclopentadiene and methyl acrylate
proceeds via a highly ordered transition state, which can have
either an endo or exo geometry, leading to two different ste-
reochemical outcomes (Figure 1). It was anticipated that such
ordered transition states would interact in different ways with
the ordered structure provided by a LCIL solvent, leading to
differences in the stereochemical outcome of the reaction
compared to isotropic reaction media.
Although there have been many reports of ILs being used
as reaction media, there are few reports of the use of LCILs as
reaction media. Lee et al., used the LCIL 1-dodecylimidazolium
chloride ([C mim]Cl·H O ), formed as its hydrated salt by pro-
12
2
n
tonation of 1-dodecylimidazole with aqueous HCl, as a reaction
medium for the Diels–Alder (DA) reaction between cyclopenta-
[
5]
diene and diethylmaleate. The stereochemical outcome of
this reaction (i.e. the ratio of endo- to exo-product) was signifi-
cantly different to that found when EtOH was used as a solvent
(0.85 vs. 7.3, respectively) and it was proposed that this may in-
dicate a liquid-crystalline effect on the stereochemistry of the
reaction. However, later studies by Welton and Dyson, which
investigated the endo:exo ratio for the DA reaction between
[6]
cyclopentadiene and methyl acrylate in a range of ILs, found
that there is a significant difference in endo:exo ratio between
different ILs and between ILs and some conventional solvents.
These observations have been attributed to hydrogen bonding
between the solvents and the carbonyl oxygen of the dieno-
phile, which favours the endo transition state to varying de-
[
6a]
Figure 1. The endo and exo transition-state structures and their products for
grees depending on hydrogen bonding ability. Hence, be-
cause only two solvent systems were considered in the study
by Lee et al., it is not clear whether their observations are evi-
dence of a liquid-crystal effect on this reaction or simply a con-
sequence of changing between the very different solvent sys-
tems of EtOH and the LCIL. In addition, the potential for HCl
the DA reaction between cyclopentadiene and methyl acrylate.
DA reactions such as this have been studied in detail in con-
ventional solvents and the endo:exo product ratio is known to
[8]
be sensitive to the solvent used. However, there tends to be
a preference for the endo product in many of these reactions
(the so-called ’endo rule’). The origin of this effect has been the
subject of much debate and factors such as secondary orbital
interactions and unfavourable steric interactions between
oxygen atoms on the dienophile and the methylene protons
on cyclopentadiene in the exo transition state are likely to play
and/or significant H O impurities in the LCIL used by Lee et al.
2
may complicate the analysis of these data.
A recent study by Do and Schmitzer showed that LCILs with
layered smectic T (SmT) phases can promote an intramolecular
over an intermolecular DA reaction, when compared to a con-
[
7]
ventional isotropic IL ([C mim][Tf N]). This is suggested to
4
2
[9]
occur because the substrate conformation that leads to intra-
molecular reactivity is favoured in the LCIL and because sub-
strate molecules are well-dispersed so that bimolecular reactiv-
ity is disfavoured. Although potentially compelling, this study
a role. A number of studies have explored DA reactions in-
[6,10]
volving cyclopentadiene in ILs.
As with conventional sol-
vents, there is a general preference for the endo product when
ILs are used as reaction media, but the observed endo:exo
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ratios are strongly dependent on the nature of the IL used (see
Table 1 for examples). Welton et al. have suggested that hydro-
gen bonding between the acidic C-2 proton of imidazolium-
based ILs and the carbonyl oxygen of methyl acrylate particu-
[6a]
larly stabilises the endo transition state in these solvents.
The ILs and LCILs for this study were chosen to investigate
the effects of different anions, increasing alkyl chain length, LC
effects and the effects of different LC mesophase structures on
the endo:exo ratio. Figure 2 shows the structures and abbrevi-
ated names used for each of the ILs and LCILs used. The LC
phases observed and their temperature ranges for the LCILs
are shown in Table 1 (entries 11–15).
We used a similar experimental procedure to that described
by Welton et al. and Dyson et al. to study the DA reaction be-
tween cyclopentadiene and methyl acrylate in IL and LCIL sol-
[
6a,d]
vents (see the Supporting Information for details).
It was
hoped that by using comparable reaction conditions and re-
peating some of the measurements made previously, we could
validate our methodology and ensure that the endo:exo prod-
uct ratios were not being biased by potential impurities pres-
ent in the ILs. All ILs and LCILs in this study were synthesised
and dried to minimise potential impurities such as halide salts
and water (see the Supporting Information for details). A com-
parison of the endo:exo ratios between this study and those of
Figure 2. The IL and LCILs, and their abbreviated names, used in this study.
ever, although there is good agreement between the present
study and that of Welton for [C mim][BF ] and [C mim][PF ],
4
4
4
6
the data from Dyson’s study find lower endo:exo ratios for
these two ILs. This has been discussed previously in terms of
the concentration-dependence of the endo:exo ratio in these
reactions and the different concentrations used in the two
Welton and Dyson (Table 1, entries 1–4) showed that for ILs
À
based on the bis(trifluoromethylsulfonyl)imide ([Tf N] ) anion
2
there is a very good agreement between the three studies,
[6d]
with a maximum deviation of 0.1 in the endo:exo ratios. How-
studies. In any case, the good agreement between the pres-
Table 1. Phase-transition temperatures and endo:exo ratios for the DA reaction between cyclopentadiene and methyl acrylate observed here and in select-
ed related studies. For LCIL materials POM measurements were used to check that the LCIL+substrate mixtures displayed the desired LC mesophase at
258C.
]
o
[c]
Entry
IL/LCIL
Transition
Temp. [ C]
endo:exo (literature)
endo:exo (this work)
[
a]
[b]
[b]
[b]
1
2
3
4
5
6
7
8
9
[C
[C
[C
[C
[C
[C
4
4
4
8
8
8
mim][PF
mim][BF
6
]
]
N]
N]
4.8 , 3.8
4.7
4.4
4.2
4.0
4.0
4.0
3.8
3.8
3.8
3.7
3.6
[
a]
4
4.6 , 3.5
[
a]
mim][Tf
mim][Tf
2
2
4.3 , 4.2
[
b]
3.9
mim][Br]
mim][BF
4
]
[C12mim][Tf
[C mim][PF
[fan-c8-im][Tf
2
[gemini-848][Tf N]
2
N]
8
6
]
[
d]
2
N]
Cr–Iso
Cr–Iso
9.0
42.5
À38.0
73.0
[
d]
10
[
e]
11
[fan-c8-im][PF
6
]
Cr–Col
Col –Iso
h
h
[
f]
12
13
14
15
[C12mim][Br]
Cr–SmA
SmA–Iso
45.8
3.5
3.4
3.3
3.3
126.0
À35.1
132.7
7.4
37.0
34.4
[
d]
[fan-c8-im][BF
4
]
g–Col
Col –Iso
h
h
[
g]
[C12mim][BF
4
]
Cr–SmA
SmA–Iso
[
d]
[gemini-848][BF
4
]
Cr–Col
Col –Iso
h
h
237.5
[
[
[
[
h]
h]
h]
h]
16
17
18
19
methanol
ethanol
acetone
6.7
5.2
4.2
2.9
diethylether
st
[
[
a] From ref. [6a]: 72 h at 258C. [b] From ref. [6d]: 24 h at room temp. [c] This work: one week at 258C. [d] Phase change data (on 1 cooling) from ref. [4b].
st st
e] Phase change data (on 1 cooling) from ref. [4e]. [f] Phase change data from ref. [11]. [g] Phase-change data (on 1 cooling) from ref. [12]. [h] From
ref. [8a].
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ent study and Welton’s data, which were collected using simi-
lar conditions, gave us confidence in both the ILs and the
methodology used for the DA reaction.
spend the majority of their time in the non-polar alkyl chain
region of an IL such as [C mim][Tf N]. As such, it makes sense
12
2
that the endo:exo ratio will move towards that seen in non-
polar solvents as the IL volume is increasingly filled by non-
polar domains. However, the MD simulations also suggest that
although the reactants/products may be located predominant-
ly in the alkyl chain regions, they do make contact with the
polar domains from time to time, which allows for crucial inter-
actions (such as imidazolium CÀH···O hydrogen bonding),
which can influence the reaction, to take place. These observa-
tions are somewhat different to those in related DA reactions
Figure 3 shows a plot of the endo:exo ratios seen in this
study for each of the ILs and LCILs used as reaction media. In
general, it was seen that increasing the volume fraction of
alkyl chains compared to polar groups (defined as the imidazo-
lium ring, including the a-carbons of the alkyl groups at the
[13]
in micelles, for which little difference is seen between en-
do:exo ratios in pure water and in the presence of surfactant.
The substrates appear to feel a much more polar environment
in the micellar systems compared to ILs containing significant
non-polar domains.
Changing the anion also affects the endo:exo ratio in this DA
+
reaction. In ILs containing the [C mim] cation, moving from
4
À
À
À
[
Tf N] to [BF ] to [PF ] increases the endo:exo ratio from 4.2
2 4
6
to 4.4 to 4.7 respectively. In previous studies, this has been dis-
cussed in terms of competition between the anion and the DA
substrate/TS for hydrogen bonding to the relatively acidic imi-
dazolium C-2 proton, which seems to favour formation of the
[6a]
endo product.
An understanding of alkyl chain and anion effects on the en-
do:exo ratio allows for the possibility of LC effects on the ste-
reochemical outcome of this DA reaction to be explored, and
crucially to be distinguished from competing effects due to
changing the chemical structure of the IL/LCIL. In general, the
LCIL solvents (entries 11–15 in Table 1) show lower endo:exo
ratios compared to the isotropic ILs. One reason for this is that
these systems have larger volume fractions of non-polar alkyl
chains compared to many of the ILs, that is, there is an alkyl
chain effect. However, the data also give a strong indication
that the anisotropic ordering of the LCILs has an impact on
the observed endo:exo ratio.
Figure 3. Chart showing the endo:exo ratios in each IL for the DA reaction
studied here. Error bars are set at +/-0.05, as the median deviation seen be-
tween the endo:exo ratio in this study and previous studies was 0.1. The
insert shows selected endo:exo ratios for four ILs, which allow anion and LC
effects to be disentangled.
ring, and the anion) in the ILs resulted in a decrease in the en-
do:exo ratio. For example, increasing the alkyl chain length on
Examining in detail entries 2, 3, 7 and 14 in Table 1 (also
highlighted as an insert in Figure 3), which show the stereo-
chemical outcome of the reaction for [C mim][BF ], [C mim]
[
C mim][Tf N] salts from C , to C , to C gave endo:exo ratios
n 2 4 8 12
4
4
4
of 4.2, 4.0 and 3.8, respectively. Increasing the number of alkyl
chains on a cation, albeit in a system with a slightly different
chemical structure, from [C mim][Tf N] to [fan-C8-IM][Tf N] also
[Tf N], [C mim][Tf N] and [C mim][BF ], allows alkyl chain,
2 12 2 12 4
anion and LC effects to be disentangled. Moving from [C mim]
4
[Tf N] to [C mim][BF ] leads to a higher endo:exo ratio (4.2 to
8
2
2
2
4
4
À
À
decreases the endo:exo ratio from 4.0 to 3.8. These are small
effects, but we believe that they are significant based on the
close agreement (endo:exo ratio within 0.1) between this study
4.4), thus the anion effect from [BF4] to [Tf N] increases the
2
amount of endo product that is formed. Making the same
+
anion substitution for the [C mim] cation, from [C mim]
12
12
and previous work for [Tf N]-based ILs, where one might
[Tf N] (which is an isotropic liquid) to [C mim][BF ] (which is
2 12 4
2
expect the data to be most scattered because the ILs used
were synthesised completely independently and DA reactions
were performed in different laboratories. The fact that the en-
do:exo ratio decreases as the volume fraction of the IL occu-
pied by non-polar alkyl chains increases is consistent with ob-
servations in conventional solvents, whereby this ratio decreas-
es with decreasing solvent polarity. Entries 16–19 in Table 1
show how the endo:exo ratio for this reaction decreases mark-
edly from methanol (e=6.7) to diethylether (e=2.9). Molecular
dynamics (MD) studies (vide infra) suggest that the DA prod-
ucts (and one can assume from this also the starting materials)
a LCIL that displays a layered smectic A (SmA) phase at 258C)
would be expected to result in the same type of anion effect,
that is, that the amount of endo product would increase rela-
tive to the exo product. In fact, moving from [C mim][Tf N] to
12
2
[C mim][BF ] leads to the opposite effect and a marked de-
12
4
crease in the endo:exo ratio, from 3.8 to 3.3, is seen. The anion
effect is therefore not driving this change in the stereochemi-
cal outcome of the reaction. Although there is a small increase
in the volume fraction of the liquid that is taken up by the
alkyl chains on moving between these salts, the magnitude of
the observed change in endo:exo ratio is much larger than
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would be consistent with a simple alkyl chain effect. As such, it
seems there is a strong suggestion that in these systems the
anisotropic ordering of the LCIL [C mim][BF ] has an impact
ground-state species, are significantly simpler to parameterize
for the MD simulations.
12
4
on the stereochemical outcome of this reaction, increasing the
proportion of exo product that is formed. This would be con-
sistent with the sterically less demanding nature of the exo
transition state being slightly better accommodated by the or-
dered fluid that is the LCIL. To test this assumption, detailed
MD studies were conducted and are now described.
1
. Ionic liquids as crystalline, liquid-crystal (LC), and isotropic-
liquid media
Figure 4 shows three MD simulation snapshots of 1-dodecyl-3-
methylimidazolium tetrafluoroborate, [C mim][BF ], as a crys-
12
4
talline phase, as a liquid crystal, and as an isotropic liquid
panels a–c, respectively). Each panel is supplemented by a set
(
of three radial distribution functions between selected atoms
belonging to the charged parts of the cation (the carbon be-
tween the two nitrogen atoms in the imidazolium ring) and
the anion (the boron atom). The three possible combinations
(cation–anion, cation–cation and anion–anion) are depicted as
green, blue and red lines, respectively.
Molecular dynamics studies
To gain a deeper insight into the experimental observations
and to provide a molecular basis upon which to understand
the LC effects described above, a detailed MD study of select-
ed IL, LCILs and solutions containing the endo or exo product
of these materials was undertaken. The reaction products were
used as proxies for the transition states (TS) in the DA reaction,
as their structures are quite similar to the TSs, but being
The simulations in the crystalline phase of [C mim][BF ]
12
4
were started from initial configurations based on crystallo-
graphic information for [C mim][PF ] deposited at the CCDC
12
6
[14]
(ref: HIWNOQ).
The crystals exhibit layered structures, in
Figure 4. (left panels) Radial distribution functions, RDFs, between interaction-centre pairs representative of the charged parts of the [C12mim](BF
Green lines=cation(imidazolium ring C2 atom)-anion(boron atom) RDFs; red=anion-anion RDFs; blue=cation-cation RDFs. (right panels) simulation snap-
shots of the corresponding IL phases. a) [C12mim](BF ] crystal; b) [C12mim](BF ] SmA liquid crystal; c) [C12mim](BF ] isotropic liquid.
4
] ions.
4
4
4
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which the anions and the polar moiety of the cations (red and
blue, respectively) form different tiers separated by non-polar
regions composed of the dodecyl chains. The distance be-
tween the polar planes in [C mim][PF ] is 1.63 nm (minimal
cyl chains originating from two different polar layers adopt in-
terdigitated configurations relative to each other (cf. Figure 5).
Finally, some simulations were performed in the isotropic-
liquid region of [C mim][BF ]. These were obtained starting
12
6
12
4
distance between boron atoms belonging to two polar planes
mediated by the non-polar strata), whereas in [C mim][BF ]
from expanded and random configurations containing both
ions. Here, the layered structure is lost but the segregation of
the system into polar and non-polar domains is retained. On
one hand, charge ordering within the polar domains is very
similar to that observed for the liquid-crystal phase (cf. middle-
left and bottom-left panels of Figure 4). On the other hand, X-
ray diffraction studies predict (by extrapolation) that in this
case the non-polar domains should have characteristic thick-
12
4
the distance obtained after equilibration of the MD runs is
1
.75 nm. The larger distance observed between the polar
À
planes in the [BF4] salt, despite the fact that both systems
contain C12 chains, can be rationalised in terms of the smaller
À
area occupied by the [BF4] ions in the polar planes and the
smaller tilt of the dodecyl chains relative to the polar planes
[15]
(
318 in [C mim][BF ] against 348 in [C mim][PF ]) that is neces-
nesses of 3.10 nm. This very large increase in the bulk of the
non-polar domains can be understood if one recognises that
the non-polar domains are no longer constrained to strata
(they can also form more globular structures) and that, where-
as the chains are interdigitated in the crystal or liquid-crystal-
line structure, the dodecyl chains can adopt head-to-head and/
or side-by-side configurations in the isotropic liquid, for exam-
ple as seen in Figure 5.
12
4
12
6
sary to accommodate this (see the Supporting Information for
an illustration of this). The multitude of peaks in the corre-
sponding g(r) functions (Figure 4, top-left panel) reflect the or-
dering of the ions within each plane. The liquid-crystalline
phase of [C mim][BF ] was obtained by partially melting the
12
4
corresponding crystalline phase using a series of temperature-
annealing runs. The snapshots show a smectic phase in which
the layered structure of the crystal remains; order is still main-
tained in the direction normal to the planes/strata but disrupt-
ed in the two in-plane directions. This can be seen by the
2
. endo/exo molecules in the IL media
’
fusing’ of the peaks in the corresponding g(r) functions. Nev-
ertheless it must be stressed that the same degree of charge
ordering is maintained within each polar plane as attested by
the out-of-phase character of the three functions depicted.
The distance between polar planes increases to a value of
The different characteristics of the ILs can now be used to ra-
tionalise their behaviour as reaction media, namely their effect
on the ratio of endo/exo products obtained in the DA reaction
between cyclopentadiene and methyl acrylate. Figure 6a
shows the endo-to-exo ratio as a function of the alkyl side
chain obtained in six different IL media that were also mod-
1.90 nm (and the tilt from the normal decreases to 188). Some
ordering is also maintained within the non-polar strata: dode-
Figure 5. Radial distribution functions, RDFs, between interaction-centres in the alkyl side chains of the imidazolium rings in [C12mim][BF
refers to pairs of carbon atoms occupying the same position in the dodecyl chain (e.g. a C7–C7 RDF is depicted in red). a) [C12 mim][BF
b) [C12 mim][BF ] SmA liquid crystal. The change in height of the first RDF peak along the two series — monotonous in a), with a maximum in b)—reflect the
parallel (head-to-head) or interdigitated arrangements of the alkyl side chains in the two cases, as depicted by the two inserts.
4
]. The colour coding
4
] isotropic liquid.;
4
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Figure 6. a) Experimental endo/exo ratio of DA products in six different ionic liquids as a function of the alkyl side chain length, n
c
, in the IL cation. The
heights of the symbols correspond to the estimated uncertainty of the experimental data (ca. 0.05). b) Volume fraction occupied by the polar network of the
ILs, x polar, as a function of n . The inset correlates directly x polar with the experimental endo/exo ratio. c) The number of contacts, OC–HCR/W, between the
carbonyl oxygen atom of the endo or exo compound (OC) and one of the aromatic hydrogen atoms of the imidazolium ring (HCR, HCW or HCW ). The inset
correlates directly OC–HCR/W with the experimental endo/exo ratio. The red circles indicate bis(triflamide)-based ILs ([C mim][Tf N], [C mim][Tf N] and
12mim][Tf N]); the blue squares represent tetrafluoroborate-based ILs ([C mim][BF ], [C mim][BF ] and [C12mim][BF ]). The thinner blue square in c) corre-
sponds to [C12mim][BF ] simulated as an isotropic liquid phase.
v
c
v
1
2
4
2
8
2
[C
2
4
4
8
4
4
4
elled using MD simulations. One of the ionic liquids under dis-
cussion, [C mim][BF ], can exhibit a SmA phase.
tally reflected by the corresponding polar volume fraction
shifts. Moreover, the liquid-crystalline nature of the [C mim]
12
4
12
The endo-to-exo ratio always decreases with increasing alkyl
chain length in the ILs. It is a known fact that the polarity of
the reaction media strongly influences the endo-to-exo ratio of
[BF ] system is not a factor in a simple calculation of polar
4
volume fraction.
To analyse the types of interaction present in the different
systems in more detail, it was decided to compute the number
of interactions between the endo and exo products and the
polar network of the ionic liquid. In this case the endo and exo
products are acting as proxies for the two DA reactants ar-
ranged in the corresponding transition states. We performed
several MD runs with either the endo or exo isomers present.
In most cases we did not observe any difference in the results
within statistical uncertainty. Thus, unless otherwise stated ex-
plicitly, the following discussion will be based on results that
are the data average from both types (endo and exo) of run.
Figure 7 shows the pair radial distribution functions (RDFs)
between the oxygen atom (OC) in the carbonyl group of the
endo/exo product and the most acidic aromatic hydrogen
atom (HCR) of the imidazolium cation (hydrogen in the 2-posi-
tion—see Table 2 inset) in [C mim][Tf N] (n=4, 8, 12) solutions.
[
8]
a DA reaction: strongly dipolar media favour the endo prod-
uct (e.g. in methanol the endo-to-exo ratio of 6.7, Table 1),
whereas more apolar solvents reduce such tendency (e.g. in
toluene or in ethers, the endo-to-exo ratio is around 3). Al-
though there is still some controversy regarding the origin of
such solvent effects—theories range from hindrance and de-
formation of the transition state to stabilisation of p-orbitals in-
[
8–9]
volved in the cycloaddition reaction —one can certainly
transpose these facts to the media under discussion.
Given the fact that ILs are segregated at a nanoscopic level
(a polar network permeated by non-polar domains), the most
obvious way to rationalise this behaviour is to calculate the
volume fraction occupied by the polar network for each type
of ionic liquid. Figure 6b shows the polar volume fractions, xv,
as a function of the alkyl side chains for the six ILs under dis-
n
2
cussion. The x polar results were estimated taking into account
We have chosen these two interaction centres as the most rep-
resentative of the possible specific interactions taking place
between the DA products (or reactants in the transition state)
and the polar parts of the ionic liquid. RDFs between interac-
tion centres in the anions and in the exo and endo products
show no specific interactions.
v
the volume of each ion and non-polar moiety, calculated by
a group-contribution scheme based on the additive volumetric
[
16]
behaviour of ionic liquids. The results show that the volume
fraction occupied by the polar network decreases with the in-
creasing length of the alkyl side chains in a way similar to the
trends observed for the endo-to-exo ratios. In other words, as
the alkyl chains of the ionic liquid grow longer, the DA reac-
tants find themselves more often than not in a more non-polar
alkane-like environment, which decreases the endo-to-exo
ratio. In other words, the ionic liquids are amphiphilic solvents
for which the amount of each part (polar and non-polar re-
gions) can be inferred by the corresponding polar volume frac-
tion. Nevertheless, when one compares the two IL series based
on the bistriflamide and tetrafluoroborate anions, respectively,
one can notice that the steeper endo-enrichment trend ob-
served for the latter series relative to the former one is not to-
Integration of the RDFs up to a cut-off distance of 2 nm al-
lowed us to calculate the number of endo/exo compounds
(OCs) and IL cations (HCRs) within the cut-off radius and the
total number of possible (HCR–OC) pairs. These numbers (de-
picted in Figure 7a–c) were combined with the values (also de-
picted between parentheses in Figures7a–c) obtained from
the total number of species within the simulation box and the
volume ratio between the cubic boxes and the cut-off spheres.
The conformity of the numbers reflects the fact that at the
cut-off distance of 2 nm, the anisotropy of the IL has been
averaged-out relative to the centre of the cut-off sphere. This
Chem. Eur. J. 2016, 22, 1 – 12
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yield smaller endo-to-exo product ratios. This is apparent if
data for [C mim][Tf N] in Figure 6a–c are compared: the endo-
n
2
to-exo ratio versus alkyl side chain length (Figure 6a) is reflect-
ed both in the trends found for the volume fraction occupied
by the polar network (Figure 6b) and for the total number of
contacts between the OC oxygen of the endo/exo products
and the aromatic hydrogen atoms of the imidazolium rings
(
Figure 6c). It must be stressed that Figure 7 shows only the
contact pairs involving the HCR hydrogen atom of the imida-
zolium ring, but similar RDF integrations were performed using
the other two aromatic hydrogen atoms (HCW) present in the
ring. Table 2 includes the partial (columns 6–8) and total
(
column 5) number of contacts for each type of OC–HCR/W
contact per number of exo/endo molecules present in the cut-
off sphere (inset to Table 2 gives a key).
Similar RDF integration procedures were performed for the
[
[
C mim][BF ] series. In this case we have modelled the [C mim]
n 4 4
BF ], [C mim][BF ] and [C mim][BF ] systems not only as iso-
4
8
4
12
4
tropic fluid media but also, in the case of [C mim][BF ], as
12
4
a SmA phase.
The RDF integration results (also included in Table 2) show
that the number of OC–HCR/W contacts decreases faster in the
[
BF ]-based IL series than in the [Tf N]-based one—a trend that
4 2
is not captured fully in the polar volume fraction analysis (cf.
Figure 6b), probably because the specificity of the interactions
between ions within the polar network is not taken into ac-
count. A more pronounced segregation between polar and
apolar domains in the isotropic [C mim][BF ] relative to all
12
4
other isotropic ILs (for which the volume fraction occupied by
the non-polar domains is smaller and the tendency to form LC
structures is suppressed) can explain the relatively low values
for the contacts between the DA product and the charged
parts of the IL. These facts can also be appreciated by the cor-
relations between the two types of analysis and the observed
endo-to-exo ratios (cf. insets in Figure 6b and 6c).
Table 2 and Figure 6c also show that there is a difference
between the results obtained for the endo/exo compounds in-
cluded in [C mim][BF ] modelled as an isotropic liquid or as
12
4
Figure 7. Radial distribution functions, RDFs, between interaction centres in
the endo or exo DA products (oxygen atom, OC, of the carbonyl group) and
in the IL cation imidazolium ring (aromatic hydrogen atom, HCR, connected
a SmA liquid crystal. The experimental endo-to-exo ratios corre-
late very well with the contact numbers obtained in the (real)
[C mim][BF ] liquid crystal phase, but deviate from those ob-
to the C2 (=CR) carbon atom). a) [C
4 2 8 2
mim][Tf N]; b) [C mim][Tf N];
12
4
c) [C12mim][Tf N]. The light shaded areas beneath the RDFs correspond to in-
2
tained in the (hypothetical) [C mim][BF ] isotropic liquid, (cf.
12 4
tegrations up to cut-off radii of 2 nm, yielding the number of DA products
found within the cut-off sphere and the total number of possible DA prod-
ucts-IL cation pairs. The dark shaded areas correspond to contact in DA
compound-IL cation pairs.
Figure 6c). In fact it is quite easy to unveil the reason behind
the lower number of OC–HCR/W contacts (and lower observed
endo-to-exo ratios) in the SmA phase: the layered nature of the
polar network of the smectic ionic liquid crystal (cf. Figure 4b)
means that one of the HCW hydrogen atoms of the imidazoli-
allowed us to estimate with some confidence the number of
contact (HCR-OC) pairs by integration under the first RDF
peaks (up to a distance of ca. 0.4 nm).
um ring (labelled in our simulations as HCW ) is embedded
2
within the polar layer. Since the DA reactants spend very little
time within the polar network (they are located preferentially
within the alkyl chain regions of the LCIL) they are therefore
The number of HCR–OC contact pairs decreases as the alkyl
side chain along the [C mim][Tf N] increases. If the number of
not able to interact with HCW . This fact is endorsed by the
n
2
2
HCR–OC contacts per endo/exo compound present in the box
are calculated (cf. column 6 in Table 2), the values also de-
crease along the series, confirming the ’dilution’ of the charged
part along the IL series, the more ’non-polar’ environment felt
by the endo/exo products and, consequently, their tendency to
MD simulation results, which show that the decrease in the
number of OC–HCR/W contacts from the [C mim][BF ] liquid
12
4
to the [C mim][BF ] liquid crystal is due to the large decrease
12
4
in the number of OC–HCW2 contacts (cf. final column of
Table 2). In other words, the observed endo-to-exo ratio is even
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Table 2. Summary of experimental, correlation, and molecular dynamics simulation data calculated for the seven (IL plus DA) products under discussion.
The experimental results (EXP) refer to endo-to-exo ratios of DA products; the correlation (CORR) results refer to estimations of the volume fraction of the
system occupied by the polar network of the ionic liquid; the MD results tally the number of contacts between the DA products and the charged part of
the IL cations per DA product found in the simulation box.
IL/Media
n
c
endo/exo
EXP
x
v
polar
SOC–HCR/W
MD
OC–HCR
MD
OC–HCW
MD
1
OC–HCW
MD
2
CORR
[C
[C
[C
[C
[C
[C
[C
4
mim][BF
mim][BF
12mim][BF
12mim][BF
4
]/ISO
]/ISO
4
8
12
12
4
4.35
3.95
NA
3.30
4.20
4.00
3.80
0.73
0.53
0.42
0.42
0.83
0.67
0.56
1.03
0.84
0.54
0.40
1.00
0.85
0.73
0.30
0.25
0.20
0.20
0.30
0.27
0.22
0.35
0.29
0.17
0.17
0.35
0.27
0.27
0.38
0.30
0.17
0.03
0.35
0.30
0.24
8
4
[
a]
4
]/ISO
]/LC
4
4
mim][Tf
mim][Tf
2
2
N]/ISO
N]/ISO
8
8
12
12 mim][Tf
2
N]/ISO
4
[a] DA reaction not attempted in the isotropic phase of [C12mim][BF ], by heating above the clearing point, due to the volatility of the cyclopentadiene
(b.p.=418C).
lower than expected in the LC-based systems because one po-
tential CÀH hydrogen bond donor site is hidden from the
Diels–Alder reactants because of the layered ordering of the
SmA phase. This effect is not seen in the isotropic liquids, for
although they display nanoscale segregation of the polar and
non-polar parts of their constituent ions, the cationic head
groups are orientated randomly in the polar domains and so
all parts of the cation are accessible to solutes residing in the
non-polar regions. Thus, there is an LCIL effect in this system
(
at least for [C mim][BF ]) where the order in the system
12 4
causes the LC phase to appear less polar than the isotropic
phase. This results in an increased proportion of exo product,
as expected from the shift in apparent polarity.
The MD simulation runs have also unveiled other interesting
structural issues. Thus, during the course of the simulation
runs we have witnessed several (unexpected) events where
one of the endo or exo compounds would leave the non-polar
strata where it usually resides for periods of some nanosec-
onds, partially disrupt a polar layer, get embedded in it for
some tenths of nanoseconds (in the mid-region of the double-
plane polar layer), and eventually migrate to a neighbouring
(
or return to the original) non-polar stratum (Figure 8). During
Figure 8. Three simulation snapshots showing the DA products in the SmA
liquid crystal phase of [C12mim][BF ]. (bottom) DA product in a non-polar,
alkane-like layer; (middle) DA product embedded in a polar layer; (top) DA
product exiting to another non-polar layer. The three snapshots occurred
during the same simulation run and were registered a few ns apart.
the whole process the polar network contained in the polar
planes was always able to accommodate the (bulky) DA com-
pound without any disruption of the layered structure of the
smectic ionic liquid (a movie of this process is given in the
Supporting Information). Such permeability and resilience of
the polar layers is another proof of the flexibility and adapta-
bility of the strong electrostatic interactions that exist among
the IL ions.
4
with HCR than the endo form. One can speculate that the
more structured nature of the SmA LCIL promotes better inter-
actions between the polar layer and the more exposed carbon-
yl group of the exo product. If this is so (and assuming again
that the DA product can be used as a proxy for the reactants
arranged in the corresponding transition state) the exo product
would also react more efficiently and the outcome would also
contribute to the observed lower endo-to-exo ratio in liquid-
crystalline ILs.
Although the simulations were performed with very few
solute molecules (1–6 endo or exo compounds in systems with
a few hundred ion pairs) and the corresponding statistics are
poor for the estimation of cross interactions—the main conclu-
sions concerning the endo-to-exo ratio drawn from the previ-
ous analyses of results from the MD runs with endo and exo re-
sults combined—the runs in the smectic [C mim][BF ] system
12
4
seemed to suggest some sort of differentiation between the
two types of molecules. It can be seen from Figure 9a that the
exo product appears to form a more significant interaction
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the imidazolium cation are accessible to solutes. In addition,
there are hints in the results of the MD simulations (Figure 9)
that there is preferential hydrogen bonding to the exo-product
(
as proxy for the exo-transition state) in the polar region of the
segregated bilayer of the SmA phase of the LCILs, which is
both the more polar region (which would favour the exo prod-
uct) and also the region in which the order of the phase is
greatest (much less motional/conformational freedom owing
to the electrostatic interactions locating the imidazolium cat-
ions.
Therefore, the LC effect in this system, which favours the exo
product, is attributed to a combination of two factors: A
change in apparent solvent polarity, due to the ordering pres-
ent in the SmA mesophase, and better shape complementarity
between the exo transition state and the LCIL, which leads to
preferential hydrogen bonding. Both of these effects support
each other to promote the formation of more exo product.
Such a result is exciting because the detailed mechanism for
the observed effect was not predicted a priori, which shows
the benefit of a combined experimental and computational ap-
proach, and also because it shows that specific intermolecular
interactions can be used in conjunction with the LC solvent to
exert influence on the product distribution. As such, this opens
up more exciting design possibilities for exploitation in other
solvent/solute combinations.
Figure 9. Radial distribution functions, RDFs, between interaction centres in
the endo or exo DA products (oxygen atom, OC, of the carbonyl group) and
in the IL cation imidazolium ring (aromatic hydrogen atoms, a) HCR,
b) HCW and c) HCW ) in the [C12mim][BF ] smectic liquid crystal phase
1 2 4
system. Red lines: exo DA product system; blue lines: endo DA product
system.
Conclusion
As outlined briefly in the introduction, one of the attractions of
using liquid crystals as reaction solvents is the inherent order
that characterises the mesophase, which it is postulated can
affect some combination of rate of reaction and regio-/stereo-
chemical outcome. This can be exemplified by the work of
Leigh and co-workers who showed, for example, how the
trans/cis isomerisation of 1,2-di(4-cyanophenyl)-1,2-diphenyl-
ethylene was slowed in LC solvents compared to isotropic sol-
[
17]
Acknowledgements
vents or how the regiochemistry of the Diels–Alder addition
of N-biphenylmaleimide to cholesta-5,7-dien-3b-yl acetate was
influenced by carrying out the reaction in the LC meso-
We thank the University of York, the Royal Society (BP Amoco
fellowship for Y.G. and International Exchanges Grants). In Por-
tugal financial support was provided by the Fundażo para
a CiÞncia e Tecnologia (FCT) through projects FCT-ANR/
CTMNAN/0135/2012, PTDC/CTM-NAN/121274/2010 and UID/
QUI/00100/2013. K.S. acknowledges the postdoctoral grant
SFRH/BPD/94291/2013.
[
18]
phase. Curiously, however, in studying the Diels–Alder reac-
tion between 2,5-dimethyl-3,4-diphenylcyclopentadienone and
a variety of dienophiles, no effect of LC solvent was observed,
which was tentatively attributed both to lack of discrimination
in solvating the two transition states and also the high tenden-
cy for the diene to destabilise the LC phase of the solvents
[
19]
used. Therefore, the nature of the effect being observed is
not necessarily a generalised phenomenon.
Keywords: Diels–Alder reaction · ionic liquids · liquid crystals ·
molecular dynamics simulations · ordered solvents
One of the reasons for choosing to investigate LCILs as sol-
vents is the fact that the wide LC range means that it is unlike-
ly that solutes will effect too strong a destabilisation of the LC
phase and so it was envisaged that specific effects of this
nature would not come into play. As such, it was reasonable,
as a first assumption, that the LC effect observed in the pres-
ent system arose from a combination of solvent order and ani-
sotropy. However, the results from the atomistic simulations
painted a subtly different picture.
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Received: June 21, 2016
Published online on && &&, 0000
Chem. Eur. J. 2016, 22, 1 – 12
www.chemeurj.org
11
ꢁ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

Full Paper
FULL PAPER
&
Ordered Solvents
D. W. Bruce,* Y. Gao,
J. N. Canongia Lopes,* K. Shimizu,
J. M. Slattery*
&& – &&
Liquid-Crystalline Ionic Liquids as
Ordered Reaction Media for the Diels–
Alder Reaction
Stereochemistry by order: Liquid-crys-
talline ionic liquids are used as reaction
media and their ordered structures are
shown to influence the stereochemical
outcome of a Diels–Alder reaction (see
figure).
&
&
Chem. Eur. J. 2016, 22, 1 – 12
www.chemeurj.org
12
ꢁ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!