Ionic liquids in cross-coupling reactions: liquid solutions to a solid precipitation problem

Article abstract of DOI:10.1039/c7cc09635f

To alleviate the problem of solid salt precipitation when using inorganic bases in cross-coupling reactions, basic anions were combined with the trihexyl(tetradecyl)phosphonium ([P₆₆₆₁₄]⁺) cation to ensure an ionic liquid byproduct. If the starting base is also an ionic liquid, as is the case for [P₆₆₆₁₄][OH]·4MeOH, it can be used as both base and solvent.

Full text of DOI:10.1039/c7cc09635f

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Ionic Liquids in Cross-Coupling Reactions: “Liquid” Solutions to a
Solid” Precipitation Problem†
“
Received 00th January 20xx,
Accepted 00th January 20xx
a,b
b,
§
a,b,c
d
Hemant Choudhary, Paula Berton, Gabriela Gurau, Allan S. Myerson and Robin D.
a,b,c,*
Rogers
DOI: 10.1039/x0xx00000x
www.rsc.org/
7
To alleviate the problem of solid salt precipitation when using for the dissolution of reagents/products/byproducts. Acoustic
inorganic bases in cross-coupling reactions, basic anions were irradiation of microfluidic flow reactors and specialized reactors
+
were designed and employed for the amination of 4-chloroanisole
combined with the trihexyl(tetradecyl)phosphonium ([P66614] )
cation to ensure an ionic liquid byproduct. If the starting base is
also an ionic liquid, as is the case for [P66614][OH]·4MeOH, it can be
used as both base and solvent.
8
-10
with aniline was attempted earlier to prevent clogging.
Still,
most of these strategies focus on the solubility of the byproduct salt,
while limited efforts have been made to prevent the byproduct
from being a solid at all during the coupling reaction. Nevertheless,
it should be noted that a soluble base/byproduct will not be an
optimal solution to this critical issue as the solubility of a substrate
may vary depending on the reaction parameters.
Transition metal-catalyzed cross-coupling reactions have been an
integral part of our industrialized society since their first
appearance in the 1970s, due to the possibility to form C-C or C-
heteroatom σ-bonds involving electrophiles (typically halides) and
The use of ionic liquids (ILs, organic salts with melting points
1
1
1
below 100 °C ) has been extensively reported for catalytic
nucleophiles (e.g., amines, olefins, organoborons, etc.). Among
1
2,13
reactions, either as catalysts and/or solvents.
In 2003, BASF
these, Suzuki-Miyaura coupling (SMC; C-C coupling) and Buchwald-
Hartwig amination (BHA; C-N coupling) reactions have become a
ritual in the industrial organic synthesis of natural products,
launched the first industrial process based on ILs, the Biphasic Acid
Scavenging utilizing Ionic Liquids (BASIL) process, which uses a
molecular organic base to react with acids produced in the reaction
1
pharmaceuticals, and supra-molecular assemblies, to name a few.
(
that may decompose the target product) and results in the
All of these cross-coupling reactions require stoichiometric amounts
of inorganic or alkali-metal alkoxide bases to afford satisfactory
generation of an IL. Imidazole-based ILs (imidazole either as cation
or anion) have also been employed as base in various base-
2
,3
yields;
however, the use of inorganic bases results in the
1
4,15
catalyzed organic reactions,
but these ILs are unstable under
formation of solid salts that are either insoluble or have limited
solubility in the solvents most suited for these reactions, resulting in
precipitation. On an industrial scale, these reactions, when
performed under continuous mode, rather than batch mode, can
offer significant processing/economic advantages that include
energy efficiency, multistep synthesis, scalability, improved thermal
1
6
certain reaction conditions, leading to undesired transformations.
Still, no attempts have been made to design the byproducts in
cross-coupling reactions to be room temperature ILs by the use of a
suitable cation in the basic salt.
The combination of an IL-forming cation with a basic anion to
obtain a basic salt (which does not have to be an IL itself) can avoid
the use of conventional inorganic or alkali metal alkoxide bases (e.g.,
potassium tert-butoxide, KOtBu). This approach would allow
employment of base with the appropriate basicity and stability,
generating a liquid halide salt during the catalytic cycle of coupling
1
,4,5,6
and mixing controls, and much more.
However, the generation
of insoluble solid salt byproducts is highly incompatible for
continuous synthesis, as it will affect the flow rate, increasing the
energy consumption, and demanding regular maintenance.
Significant attention has been paid to overcome the formation
of insoluble salts during continuous/flow cross-coupling reactions.
For example, mixtures of polar protic solvents have been proposed
1
reactions (Scheme 1). It is important to point out that as long as
the byproduct is liquid, its solubility/miscibility in/with the solvent
employed will not interfere with continuous processing. It must also
be noted that a liquid base is not essential just a liquid byproduct,
but if the base is also liquid at the reaction temperature, it adds
some flexibility and design space.
Selecting the pair of ions that will form the final IL with the
required properties is the first and crucial step to evaluate these
molten salts as bases in catalytic reactions. The choice of the cation
here was made based on the following considerations: (a) the
halide form (especially the chloride form) of the cation should be
liquid, and (b) it should have reasonable thermal stability.
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Journal Name
+
Trihexyl(tetradecyl)phosphonium ([P66614] ) satisfied the above fluoride hydrofluoride ([C
2
mim][F]·xHF), where excess of
1
7
criteria and was thus chosen as the model cation in this study. hydrofluoric acid (HF) could not be removed and indeed the
Anions such as [OtBu] and hydroxide ([OH] ) were selected as the synthesized compound was found to be [C mim][F]·1.6HF·2.1H O
2
-
-
2
1
9
counter ions to impart the IL’s basic properties.
based on NMR, IR, elemental analyses, and Karl Fischer titration.
Pd Catalyst
[
IL-forming Cation][Basic Anion]
R-X
+
R'-FG
R-R'
+
[IL-forming Cation]X
liquid)
αꢀprotons
DMSO
(
where, X = Cl, Br, or I
(
d)
R and R' = alkyl, alkenyl, allyl, or aryl
FG = functional group
αꢀprotons
αꢀprotons
Scheme 1. Reaction scheme demonstrating the formation of a liquid
DMSO
(
c)
[Cation]X salt after the Pd catalyzed cross-coupling reaction.
DMSO
DMSO
The ILs [P66614][OH] and [P66614][OtBu] were synthesized using
(
b)
[
P66614]Cl as a cation source via metathesis reactions, with the
appropriate potassium salts to make [P66614][OH] and [P66614][OtBu]
ESI for detailed description of the syntheses). While [P66614]Cl is
liquid at room temperature, without a documented melting point,
αꢀprotons
(
a)
(
1
7
and a glass transition temperature of -69.8 °C, both [P66614][OH]
1
Figure 1. H NMR spectra of (a) [P66614]Cl, (b) [P66614][OtBu], (c)
and [P66614][OtBu] are solids, with melting points of ca. 40 °C (ESI).
1
13
[P66614][OH], and (d) [P66614][OH]·4MeOH. Shifts in the signal of the α-
+
protons from the [P66614] cation are noted (See ESI for full spectra).
Nuclear magnetic resonance (NMR, H and C) was used to confirm
+
the synthesis and purity of the [P66614] -based ILs (see ESI).
An ion exchange resin was also used as an alternate route in an
1
8
The thermal stability of all of the synthesized ILs was much
lower than [P66614]Cl, with the onset of 5% mass fraction loss
temperatures (T5%onset) of 300.6, 163.8, 158.7, and 166.5 °C for
attempt to simplify the synthesis of [P66614][OH] (see ESI).
However, this IL was liquid even after exposing the synthesized
product to high vacuum at room temperature for 12 h, indicating
differences in the products depending on the synthetic route.
Integration of the NMR signals for this product suggested the final
formula to be [P66614][OH]·4MeOH. Thermogravimetric analysis
confirmed this formula with a ca. 20% weight loss at 70 °C, which is
[
P
66614]Cl, [P66614][OtBu], [P66614][OH], and [P66614][OH]·4MeOH,
respectively (Figure S3). A melting point (T ) was also observed in
m
m
all cases, T = 38.5 and 36.8°C for [P66614][OtBu] and [P66614][OH],
respectively. Interestingly, DSC showed that [P66614][OH]·4MeOH
converts to [P66614][OH] in the first heating cycle with multiple
endothermic and exothermic transitions, after which the DSC
thermograms match [P66614][OH] on all subsequent cycles (Figure 2).
This suggest several conversion steps with the ultimate loss of all
methanol in the first heating cycle (Figure S4).
-
equivalent to ca. 4 moles of MeOH per mole of [OH] . This
compound could only be prepared by ion exchange, even when the
metathesis reactions were attempted in methanol (vide infra).
1
The analysis of the H NMR spectra suggests different
interactions between the ions of the synthesized ILs, particularly
noticeable due to the changes in the chemical shift values of the α-
+
protons of [P66614] (Figure 1). These signals were observed as a
multiplet at 2.14-2.28 ppm in [P66614]Cl corresponding to 8 protons,
while there was an upfield shift to 1.52-1.63 ppm for the ILs
synthesized through metathesis ([P66614][OH], and [P66614][OtBu]).
This would seem to confirm stronger interactions between the ions
in these ILs which is in keeping with their isolation as solids. On the
1
other hand, the H NMR spectrum of [P66614][OH]·4MeOH obtained
using the anion-exchange resin was different and the signal for the
α-protons of the cation had a downfield shift, almost merging with
the signals for the lock solvent deuterated dimethyl sulfoxide
(
6
DMSO-d ; Figure 1). The signal corresponding to the methyl group
of methanol (MeOH), used as solvent in this synthetic route, was
also observed (Figures S1-S2). The solvation of hydroxide by MeOH
during anion-exchange through strong charge-assisted hydrogen
bond and thereby a decreased (or negligible) interaction with [P66614][OH]·4MeOH 2 cycle (dashed line), [P66614][OH] 2 cycle
phosphonium ions could explain the downfield shift of the α- (dotted line).
st
Figure 2. DSC plots of [P66614][OH]·4MeOH 1 cycle (solid line),
nd
nd
protons, and also have important implications in the activity of this
base as explained later.
a
Similar pK values for MeOH and water have been reported in
The [P66614][OH] synthesized by metathesis was mixed with the past using conductivity, with the conclusion that MeOH could
20
MeOH and stirred for 24
h in an attempt to obtain be a stronger acid than water. Based on the pK values and acid
a
[
P66614][OH]·4MeOH, however, the downfield shift for the α-protons strength of MeOH and water, the presence of both hydroxide and
was not observed in the compound obtained from the mixing, methoxide in [P66614][OH]·4MeOH can be expected as shown in equ.
suggesting that MeOH is only incorporated into the IL during the (1). This is important as this could be indicative of the co-existence
synthesis using the anion-exchange resin. A similar phenomenon of hydroxide and methoxide in equilibrium.
was noted during the synthesis of 1-ethyl-3-methylimidazolium
2
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OH-
H O
2 (methanolic)
+ MeO-
(methanolic) (1)
(methanolic)
+ MeOH(l)
When the synthesized ILs were used as bases using 1,4-dioxane
as solvent, only [P66614][OH]·4MeOH assisted the Pd-catalyzed BHA
The basic strength of the ILs was determined using indicators in and SMC reactions, while both [P66614][OH] and [P66614][OtBu]
2
1
the pK
a
range of 7.2 to 37.0 (see ESI). The overall order of basic worked poorly (Figure 3). The higher reactivity of 4-chloroanisole in
the presence of [P66614][OH]·4MeOH can be explained by its higher
strength was [P66614][OH]·4MeOH > [P66614][OtBu] ~ [P66614][OH] >>
[P
66614]Cl. As indicated by the NMR data, the weakest cation/anion basic strength.
interactions occur for [P66614][OH]·4MeOH, which might explain its
greater basicity. When the IL [P66614][OH] was stirred in MeOH for
3
0 min, the basic strength of the mixture was not similar to
[
P66614][OH]·4MeOH, highlighting the importance of the anion-
exchange resin that probably facilitates the solvation of each
hydroxide ion. The dilution of [P66614][OH] with weakly acidic MeOH
failed to shift the equilibrium in equation (1) to right supposedly
-
+
due to the stronger interaction of [OH] anion with [P66614] cation.
Before using the ILs in our catalytic reactions, we tested their
solubility in various organic solvents (Snyder polarity index 0-9,
22
from hexane to isopropyl alcohol, to acetonitrile, to DI water). As
+
expected, all [P66614] -based ILs were insoluble in water (see ESI).
While [P66614]Cl was soluble/miscible in/with all solvents under
investigation except water, [P66614][OtBu] was soluble only in
toluene. Both [P66614][OH] and [P66614][OH]·4MeOH had similar
solubilities in the solvents employed.
To assess the performance of each IL as a base, we used the
widely employed cross-coupling reactions such as SMC and BHA
+
Figure 3. Effect of [P66614] bases vs. inorganic bases on Pd-catalyzed
Buchwald-Hartwig amination (black) and Suzuki-Miyaura coupling
(
Scheme 2). Generally, chloro-derivatives have low reactivity as
(
gray). Solid bars: 1,4-dioxane as solvent; Crosshatched bars: ILs as
compared to bromo- or iodo-derivatives, due to the strength of the
-1
both base and solvent; Inorganic base: KOtBu for BHA and K CO for
2
3
C-Cl bond (bond dissociation energies, C-Cl: 96 kcal mol ; C-Br: 81
-1
-1 23
SMC. Right: Final reaction mixtures (with magnetic stir bar) for BHA (a)
and SMC (b) using [P66614][OH]·4MeOH as base and dioxane as solvent.
kcal mol ; C-I: 65 kcal mol ). Nevertheless, the chloroarenes are
industrial favorites as substrates for cross-coupling reactions,
considering the economy of the process. The reactivity can be
improved in conjunction with electron-deficient moieties, whereas
In order to verify the role of MeOH in the enhancement of the
chloroarenes are less reactive in the presence of electron-donating product yield, a control experiment with [P66614][OH] as base was
groups like methoxy (-OCH
). 4-chloroanisole (deactivated chloro- performed with externally added MeOH (corresponding to the total
3
derivative) was chosen as a model substrate to undergo reactions amount of MeOH in the catalytic run employing
with aniline and phenylboronic acid for the BHA and SMC reaction, [P66614][OH]·4MeOH as base). The added MeOH did not affect the
respectively.
reaction yield, again showing that [P66614][OH]·4MeOH has a unique
identity with higher basic strength.
As was hypothesized, no precipitate was observed after the
catalytic run for both BHA and SMC reactions using
[
[
P66614][OH]·4MeOH as base (Figure 3, right). The generation of
1
P66614]Cl (confirmed by H NMR, Figure S5), validates the proposed
reaction pathway (Scheme 1) and explains why there was no
precipitation after the catalytic run, since [P66614]Cl is liquid at room
temperature.
Due to the liquid nature of [P66614][OH]·4MeOH, it can also be
used as both base and solvent for cross coupling reactions, perhaps
improving the catalytic efficiency of Pd compared to reactions in
Scheme 2. Catalytic reaction scheme of Buchwald-Hartwig amination
1
,4-dioxane. In fact, when the IL was used as both solvent and base
and Suzuki-Miyaura coupling studied in this report. Inorganic base:
for the selected model reactions, the obtained yields were
comparable with those obtained using inorganic salts as bases in
KOtBu for BHA and K
halide: nucleophile: base: catalyst: ligand= 1: 1.2: 1.2: 0.01: 0.1 (molar
ratio)
2 3
CO for SMC reactions. Reaction conditions:
1
,4-dioxane (Figure 3). It is well-known that a change of reagent
.
(
such as base) in cross-coupling reactions requires drastic
2
5
modification of reaction coordinates, and hence, the influence of
other parameters such as temperature, time, or solvent
type/volume on reaction rate in the presence of the IL base is
subject to ongoing research. It is important to note that we envision
an increase in the yields with the optimization of the catalytic
reaction parameters.
In the case of BHA, the addition of methanol to the reaction
mixture allowed a complete separation of the product (biphasic-
solid product and IL/MeOH), which is insoluble in MeOH.
The catalytic tests were carried out using the catalyst XPhos Pd
G1 (((2-dicyclohexylphosphino-2’,4’,6’-triisopropyl-1,1’-biphenyl)[2-
(
2-amino-ethyl)phenyl)]palladium(II) chloride), in the presence of
the additive XPhos (2-dicyclohexylphosphino-2’,4’,6’-triisopropyl-
2
7
1
,1’-biphenyl). The reactivity of chloroarenes was measured
relative to the yield of the products achieved with conventional
bases; KOtBu for BHA and potassium carbonate (K CO ) for SMC
2
3
24
(
Scheme 2 and ESI).
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For the selected model reactions, although no salt precipitation
was detected after the reaction using IL as base, the replacement of
8
9
1
T. Noël, J. R. Naber, R. L. Hartman, J. P. McMullen, K. F.
Jensen, S. L. Buchwald, Chem. Sci., 2011, , 287-290.
J. R. Naber and S. L. Buchwald, Angew. Chem. Int. Ed., 2010,
, 9469-9474.
0 S. Falß, G. Tomaiuolo, A. Perazzo, P. Hodgson, P. Yaseneva, J.
Zakrzewski, S. Guido, A. Lapkin, R. Woodward and S. E.
Meadows, Org. Process Res. Dev., 2016, 20, 558−567.
1 J. D. Holbrey and R. D. Rogers, In Ionic Liquids in Synthesis,
1st ed., P. Wasserscheid, T. Welton (eds.), Wiley-VCH Verlag
GmbH & Co. KGaA, Weinheim, 2002, pp. 41–55.
2
1,4-dioxane with the IL resulted in the precipitation of the product
4
9
in the studied BHA reaction, while in the SMC reaction, no
precipitation was observed. Hence, when ILs are proposed to be
used as base and solvent, several factors need to be considered,
including not only basicity, but also the solubility of the reagents
and product(s) in the selected IL. Due to the possibility of tuning the
IL, other cations can be selected to avoid precipitation of products
and reagents, increasing the potent uses of the proposed strategy.
1
1
2 R. Sheldon, Chem. Commun., 2001, 2399–2407.
+
13 K. R. Seddon, Nat. Mater., 2003,
2, 363-365.
In summary, basic [P66614] salts were synthesized and employed
1
1
4 K. Chen, G. Shi, R. Dao, K. Mei, X. Zhou, H. Lia and C. Wang,
Chem. Commun., 2016, 52, 7830-7833.
as the base in cross-coupling reactions, to yield IL byproducts,
overcoming the problem of precipitation of solid salts in these
reactions. Our evaluation showed the novel IL base,
5 B. C. Ranu, R. Jana and S. Sowmiah, J. Org. Chem., 2007, 72
,
3152-3154.
16 V. K. Aggarwal, I. Emme and A. Mereu, Chem. Commun.,
2002, 1612–1613.
[P66614][OH]·4MeOH, to have the highest basic strength among all
synthesized basic salts, and this salt was the most efficient in the
Pd-catalyzed BHA and SMC reactions. No precipitate was observed 17 Cytec,
CYPHOS
http://www.rsc.org/suppdata/cp/b9/b920530f/b920530f-
2.pdf, last accessed 11-19-2017.
IL
101
Product
Data
Sheet,
after the catalytic run due to the generation of the room
temperature IL [P66614]Cl. In addition, since [P66614]Cl was used in the
synthesis of the active base ([P66614][OH]·4MeOH) in an ion-
exchange process, an easy recycling of the generated IL is
anticipated simply by elution with methanol on an ion exchange
1
1
1
2
8 I. Dinares, C. G. de Miguel, A. Ibánez, N. Mesquida and E.
Alcalde, Green Chem., 2009, 11, 1507-1510.
9 C. Rijksen and R. D. Rogers, J. Org. Chem., 2008, 73, 5582–
5584.
0 A. V. Ballinger and F. A. Long, J. Am. Chem. Soc., 1960, 82
795-798.
2
6
column in a continuous manufacturing mode.
An added benefit of the basic salt being an IL itself, was
,
demonstrated when [P66614][OH]·4MeOH employed as both base 21 K. Tanabe, M. Misono, H. Hattori and Y. Ono, Determination
of acidic and basic properties on solid surfaces. In New Solid
Acids and Bases; Elsevier Science: Tokyo, 1989; pp 5-25.
2 A. I. Vogel, in Textbook of Practical Organic Chemistry, 5th
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2008, 130, 6686–6687.
and solvent, enhanced the catalytic reaction rates for BHA and SMC
reactions over those obtained using 1,4-dioxane as solvent.
Depending on the synthesized products, we envision more design
flexibility if an IL is used as both base and solvent, allowing one to
improve the solubility of products and reagents or to selectively
precipitate the desired product from the reaction mixture by choice
of ions. This work suggests design rules for ILs suitable for many
2
2
2
other reactions that have similar issues of salt (or byproduct) 25 D. S. Surry and S. L. Buchwald, Chem. Sci., 2011,
2, 27-50.
2
6 A. Mascia, P. L. Heider, H. Zhang, R. Lakerveld, B. Benyahia,
precipitation during continuous/flow reactions.
P. I. Barton, R. D. Braatz, C. L. Cooney, J. M. B. Evans, T. F.
Jamison, K. F. Jensen, A. S. Myerson and B. L. Trout, Angew.
Chem. Int. Ed., 2013, 52, 12359-12363.
We thank the Novartis-Massachusetts Institute of
Technology (MIT) Center for Continuous Manufacturing (CCM)
and Novartis International AG for financial support. This
research was undertaken, in part, thanks to funding from the
Canada Excellence Research Chairs Program.
Conflicts of interest
There are no conflicts to declare.
Notes and references
§
PB Present Address: Chemical and Petroleum Engineering
Department, University of Calgary, Calgary, AB T2N 1N4,
Canada.
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5
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N. Miyaura and A. Suzuki, Chem. Rev., 1995, 95, 2457-2483.
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Reactions, Vol. 1, 2nd ed., Wiley-VCH, Weinheim, 2004.
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S. G. Newman and K. F. Jensen, Green Chem., 2013, 15
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,
1
6
7
2
4
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