Synthesis and thermophysical properties of ionic liquids: Cyclopropyl moieties versus olefins as Tm-reducing elements in lipid-inspired ionic liquids

Article abstract of DOI:10.1016/j.tetlet.2012.09.101

Cyclopropyl moieties embedded in the long aliphatic side chains of imidazolium-type ionic liquids are shown to be highly effective in lowering the T_m of such materials relative to counterparts bearing linear, saturated side chains. While not as efficient as olefins in bringing about this effect, ILs incorporating side-chain cyclopropanated modules are likely to be more resistant to aerobic degradation than those employing the former.

Full text of DOI:10.1016/j.tetlet.2012.09.101

Tetrahedron Letters 54 (2013) 12–14
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis and thermophysical properties of ionic liquids: cyclopropyl moieties
versus olefins as Tm-reducing elements in lipid-inspired ionic liquids
Man-Lung Kwan a, Arsalan Mirjafari b, , John R. McCabe c, Richard A. O’Brien b, David F. Essi IV a,
Leah Baum a,b,c,à, Kevin N. West c, James H. Davis Jr. b,
⇑
a Department of Chemistry, John Carroll University, University Heights, OH 44118, USA
b Department of Chemistry, University of South Alabama, Mobile, AL 36688, USA
c Department of Chemical and Biomolecular Engineering, University of South Alabama, Mobile, AL 36688, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Cyclopropyl moieties embedded in the long aliphatic side chains of imidazolium-type ionic liquids are
shown to be highly effective in lowering the Tm of such materials relative to counterparts bearing linear,
saturated side chains. While not as efficient as olefins in bringing about this effect, ILs incorporating
side-chain cyclopropanated modules are likely to be more resistant to aerobic degradation than those
employing the former.
Received 29 August 2012
Revised 19 September 2012
Accepted 21 September 2012
Available online 13 October 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Ionic liquids
Lipids
Cyclopropanation
Imidazolium
Homeoviscous adaptation
In certain respects, the nanoscale structure of lipid bilayers is
evocative of the emerging picture of nanoscale structuring in ionic
liquids (ILs).1 And, just as the function of phospholipid bilayers is
tied to their fluidity—as reflected in their Tm—so too is the utility
of ILs. However, while lipid bilayers usually have low values of
Tm despite being composed of charged species with long aliphatic
appendages, it is generally observed that the fluidity of ILs—typi-
fied by those containing N,N0-dialkylimidazolium ions—decreases
when progressively longer aliphatic appendages are tethered to
their cation charge centers.2
Indeed, it can be a challenge to design imidazolium ILs that
incorporate progressively more lipophilic structural elements
while retaining melting points that are below room temperature.
However, using an approach modeled on the natural phenomenon
of homeoviscous adaptation (HVA),3 we have recently been able to
systematically prepare ILs that exhibit very low Tm values while
still incorporating very long alkyl appendages.4 At the heart of
our success in this endeavor was the use of geometrically cis olefin
modules integrated into the long aliphatic side chains of our IL
cations, a change which disrupts side-chain packing and leads to
lower values of Tm compared to otherwise identical counterparts
with linear, saturated side chains.
Unfortunately, for certain applications (especially those in
which an IL might be employed at somewhat higher temperatures
in the presence of air) a double bond could prove to be an Achilles’
Heel, rendering the salt susceptible to slow oxidative degradation
(akin to the process of fat rancidification). Consequently, we em-
barked on a program of preparing other types of lipid-inspired
ILs, ones in which the packing-disruptive module in the long alkyl
appendage is something other than an olefinic moiety.
Among the lipid structural features found in nature that, like
olefins, tend to depress Tm values (relative to saturated, linear
counterparts) are cisoid cyclopropyl moieties.5 Such moieties occur
most commonly in lipids of non-mammalian sources that range
from microorganisms to fruiting plants, the seed oils of which
may—like those of Litchi chinensis, for example—contain relatively
large amounts of cyclopropanated components.5
The biosynthesis of cyclopropanated fatty acids involves the net
addition of a methylene (CH2) fragment to the double bond of a
pre-existing unsaturated fatty acid by way of S-adenosylmethio-
nine.5 Such addition to the double bond of the most prevalent
natural unsaturated fatty acid—oleic acid—gives rise to dihydrost-
erculic acid, a derivative in which the oleyl cis double bond
between chain carbon atoms 9 and 10 has been (stereospecifically)
cis cyclopropanated.5
⇑
Corresponding author. Tel.: +1 251 460 7427; fax: +1 251 460 7359.
E-mail addresses:
jdavis@southalabama.edu,
jdavis@jaguar1.usouthal.edu
(J.H. Davis).
Current address: Department of Chemistry and Mathematics, Florida Gulf Coast
University, Fort Myers, FL 33965, USA.
à
NSF-REU summer student from SUNY Buffalo.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.09.101

M.-L. Kwan et al. / Tetrahedron Letters 54 (2013) 12–14
13
Since our overarching interests center on the development of
ionic liquids for use in practical applications, it seemed fitting that
we should focus the present investigation of the Tm depressing ef-
fect of cyclopropanation on lipid-inspired ionic liquids on species
most likely to be readily accessible in the event further develop-
ment was warranted. So, we decided to explore the synthesis
and properties of lipidic ILs bearing aliphatic appendages akin to
the dihydrosterculyl fragment. However, since isolated cycloprop-
anated fatty acids and their derivatives are not currently available
commercially (despite their relative abundance in some natural
sources), it was necessary to make the cyclopropanated appendage
for the present ILs.
The synthesis of the requisite dihydrosterculyl appendage for
the target cyclopropanated ILs was a multi-step endeavor. Begin-
ning from high-purity methyl oleate (Nu-Chek Prep, >98%), dihy-
drosterculyl alcohol was prepared in high yield using known
reactions combined into a two-step protocol.6 Next, the alcohol
was quickly, easily, and quantitatively (1H NMR) converted into
the corresponding mesylate. It, in turn, was quantitatively (1H
NMR) converted into iodide using the Finkelstein reaction. It is
important to note here that since the next step in the preparation
of the targeted ILs is the quaternization of the requisite N-alkyl
imidazoles with the dihydrosterculyl precursor, one would antici-
pate that this should be easily (perhaps better) done with the mes-
ylate rather than the iodide. However, our past experience has
been that the mesylates of fatty alcohols are actually rather poor
alkylators of nitrogen compared to their iodide counterparts.4b
Once the dihydrosterculyl iodide was in hand, quaternization of
1-Me imidazole and 1,2-dimethylimidazole was accomplished
over a period of 48 h at 50 °C in acetonitrile. Having verified for
each imidazole the completion of its coupling to the lipidic
appendage, the crude iodide salts were dissolved in two-phase
water–CH2Cl2 systems, to which were then added 20% molar ex-
cesses of KNTf2N [potassium bis(trifluoromethanesulfonyl)imide].
After stirring for 24 h, the lower (CH2Cl2) phase of each reaction
was removed, dried over anhydrous MgSO4, and the final products
(1 and 2) were isolated by filtration followed by the removal of the
solvent in vacuo. Using the same overall synthetic scheme, new ILs
4 and 6 were also prepared in order to provide baseline standards
against which the Tm-lowering efficacy of the cyclopropyl group in
2 might be gauged. The overall synthetic approach (as exemplified
for 1 and 2) is depicted in Scheme 1, as are the structures of all four
(1, 2, 4, and 6) new ILs.
As is apparent from the data in Table 1, inclusion of cyclopropyl
moieties in the C18 side chain of imidazolium-type lipidic ionic liq-
uids—for example, 1 and 2—results in sharp decreases in their melt-
ing points relative to benchmark ILs 5 and 6, with their linear
saturated side-chains. Here again, as in our earlier studies,4 a strat-
egy employed by nature to modulate Tm in lipidic materials proves
to have a parallel effect when applied within an ionic liquid context.
The Tm values reported in Table 1 were determined by differen-
tial scanning calorimetry, DSC. Like most lipid-like materials, the
new ILs exhibited rich phase behavior below their Tm (the reported
Tm values being those of the highest temperature phase changes
18 carbons - oleyl
No absolute
stereochemistry
implied!
CH2I2
cis
Et2Zn
MeO
O
MeO
10
CH2Cl2
9
O
LiAlH4/ Et2O
Na2SO4-10H2O
HO
MsCl
Et3N
dihydrosterculyl alcohol
CH2Cl2
NaI
I
MsO
acetone
1-methyl imidazole
or
1,2-dimethyl imidazole
KTf2N
H2O
N
Tf2N
N
R
1
2
R = H
R = Me
Cyclopropanated Ionic Liquids
T
m Benchmark Ionic Liquids
N
N
Tf2N
Tf2N
N
N
R
R
5
6
R = H
R = Me
See Reference 4b
3
4
R = H See Reference 4b
R = Me
Scheme 1. Synthesis of cyclopropanated ILs 1 and 2, and structures of Tm benchmark ILs 3–6.

14
M.-L. Kwan et al. / Tetrahedron Letters 54 (2013) 12–14
Table 1
Interestingly, the data in Table 1 point up another important
relationship as well—the synergistic impact upon Tm of the cation
Relationships between structure and Tm in ILs 1–6 (see Scheme 1 for IL structures)
side-chain and head-group structures. Note that the
DTm of the
IL
Substituent at imidazolium
ring C(2) position
Specialized lipid
side-chain feature
IL Melting
point (°C)
saturated benchmark ILs 5 and 6 is 16.5 °C—the C(2)–Me species
having the higher Tm of the two. However, when the Tm values of
the two cyclopropanated ILs (1 and 2) are compared, the head-
group effect jumps to 26.6 °C. Then, when the arguably ‘best’
Tm-depressing structural element—unsaturation—is introduced
into the side chains, the head group effect increases yet again, to
36.9 °C, more than double its magnitude in the case of saturated
side-chain ILs 5 and 6. Taken together with similar observations
we recently made with an entirely different category of lipidic
ILs, a strong case is emerging for an argument that it may become
possible in the relatively near term to design lipidic ILs to manifest
Tm values in relatively narrow ranges.4a
In sum, the present data show a clear capacity on the part of
side-chain included cyclopropyl groups to bring about depressions
in the Tm values of lipidic ILs. Furthermore, the magnitude of these
changes is substantial even when compared to those wrought by
chain-included olefins, and they are achieved with (presumably)
less sensitivity toward oxidative degradation.7 However, the over-
all utility of side-chain cyclopropanation as a strategy for Tm
depression in lipidic ILs must take into account the need (at pres-
ent) for the multi-step synthesis of these side chains, a sequence
that employs some relatively expensive and hazardous reagents
(Et2Zn, LiAlH4). Accordingly, until naturally-derived cyclopropa-
nated lipid starting materials become commercially available, it
seems prudent to seek more readily accessed compliments to ole-
fin groups as IL Tm depressors, an endeavor in which we are already
engaged.
1
2
3
4
5
6
H
Me
H
Me
H
Me
Cyclopropyl
Cyclopropyl
cis-Alkenyl
cis-Alkenyl
None
ꢁ8.6( 0.5)
18.0( 1.0)
ꢁ20.9( 1.0)4b
16.0( 1.0)
53.5( 1.0)4b
70.0( 1.0)
None
C(2)-H
C(2)-Me
headgroup
headgroup
80
-16.5 o
C
6
60
5
o
o
-54.0
C
-52.0 C
cyclopropanate
side chain
unsaturate
side chain
40
20
0
o
o
-74.4
C
-62.1 C
cyclopropanate
side chain
unsaturate
side chain
Tm oC
2
4
-26.6 o
C
1
-36.9 o
C
3
-20
-40
Figure 1. Relationships between IL head group and side chain structures and Tm
Italicized values indicate Tm relationships between ILs with like side chains but
having C(2)–H versus C(2)–Me head groups.
.
Acknowledgments
D
J.H.D. and K.N.W. thank the National Science Foundation (CBET
Award 1133101 and REU Award 1156596) for support of this work.
exhibited by the materials, the products of which are in a liquid
state).
References and notes
Significantly, the overall depressions in Tm brought about by the
inclusion of a cyclopropyl moiety in the IL cation side chain
(62.1 °C in 1 vs. 5, and 52.0 °C in 2 vs. 6) are substantial regardless
of whether the latter is H- or CH3-bearing at the imidazolium C(2)
position (see Fig. 1). However, in the ILs with C(2)–H imidazolium
head groups, the absolute decrease in Tm (62.1 °C) is about 83% of
that brought about by unsaturation. In contrast, in the IL series
with C(2)-Me imidazolium head groups, the absolute magnitude
1. (a) Canongia Lopes, J. N. A.; Padua, A. A. H. J. Phys. Chem. B 2006, 110, 3330; (b)
Padua, A. A. H.; Lopes, J. N. A. C. In ACS Symp. Ser.; Rogers, R. D., Seddon, K. R.,
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2. Lopez-Martin, I.; Burello, E.; Davey, P. N.; Seddon, K. R.; Rothenberg, G.
ChemPhysChem 2007, 8, 690.
3. Sinensky, M. Proc. Natl. Acad. Sci. U.S.A. 1974, 71, 522.
4. (a) Mirjafari, A.; Murray, S. M.; O’Brien, R. A.; Stenson, A. C.; West, K. N.; Davis, J.
H., Jr. Chem. Commun. 2012, 48, 7522; (b) Murray, S. M.; O’Brien, R. A.; Mattson,
K. M.; Ceccarelli, C.; Sykora, R. E.; West, K. N.; Davis, J. H., Jr. Angew. Chem., Int. Ed.
2010, 49, 2755.
5. www.lipidlibrary.aocs.org/Lipids/fa_cycl/index.htm; Last accessed 08/20/2012.
6. (a) Taber, D. F.; Nakajima, K.; Xu, M.; Rheingold, A. L. J. Org. Chem. 2002, 67,
4501; (b) Furukawa, J.; Kawabata, N.; Nishimura, J. Tetrahedron Lett. 1968, 31,
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1984, 49, 2600.
of the
DTm induced by cyclopropanation (52.0 °C) is only about
66% of that which it delivers in the C(2)–H case. Even so, the com-
parative efficiency of cyclopropanation versus unsaturation within
the C(2)–Me IL series is 96% [(Tm depression by cyclopropanation
vs saturated benchmark IL/Tm depression by olefination vs satu-
rated benchmark IL) ꢀ 100] of that brought about by unsaturation.
7. It should be borne in mind that cyclopropyl groups bring with them their own
chemical sensitivities, such as ring-opening by Lewis acids.