SN2 Fluorination reactions in ionic liquids: A mechanistic study towards solvent engineering

Article abstract of DOI:10.1039/c0ob00426j

In the catalysis of S_N2 fluorination reactions, the ionic liquid anion plays a key role as a Lewis base by binding to the counterion Cs ⁺ and thereby reducing the retarding Coulombic influence of Cs ⁺ on the nucleophile F^-. The reaction rates also depend critically on the structures of ionic liquid cation, for example, n-butyl imidazolium gives no S_N2 products, whereas n-butylmethyl imidazolium works well. The origin of the observed phenomenal synergetic effects by the ionic liquid [mim-^tOH][OMs], in which t-butanol is bonded covalently to the cation [mim], is that the t-butanol moiety binds to the leaving group of the substrate, moderating the retarding interactions between the acidic hydrogen and F^-. This work is a significant step toward designing and engineering solvents for promoting specific chemical reactions.

Full text of DOI:10.1039/c0ob00426j

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Organic &
Biomolecular
Chemistry
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Cite this: Org. Biomol. Chem., 2011, 9, 418
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PAPER
SN2 Fluorination reactions in ionic liquids: a mechanistic study towards
solvent engineering†‡
a
b
a
a
a
a
Young-Ho Oh, Hyeong Bin Jang, Suk Im, Myoung Jong Song, So-Yeon Kim, Sung-Woo Park,
c
b
a
Dae Yoon Chi,* Choong Eui Song* and Sungyul Lee*
Received 15th July 2010, Accepted 16th September 2010
DOI: 10.1039/c0ob00426j
In the catalysis of S 2 fluorination reactions, the ionic liquid anion plays a key role as a Lewis base by
N
+
+
binding to the counterion Cs and thereby reducing the retarding Coulombic influence of Cs on the
-
nucleophile F . The reaction rates also depend critically on the structures of ionic liquid cation, for
example, n-butyl imidazolium gives no S
The origin of the observed phenomenal synergetic effects by the ionic liquid [mim- OH][OMs], in which
N
2 products, whereas n-butylmethyl imidazolium works well.
t
t-butanol is bonded covalently to the cation [mim], is that the t-butanol moiety binds to the leaving
-
group of the substrate, moderating the retarding interactions between the acidic hydrogen and F . This
work is a significant step toward designing and engineering solvents for promoting specific chemical
reactions.
Introduction
Ionic liquids have found a wide range of applications in all fields
of chemistry because of their useful physicochemical properties.
Besides being ideal solvent for a variety of chemical reactions
due to high polarity, low volatility, and easy recovery, ionic
1
liquids are also gaining tremendous importance as catalysts.
Many reactions that proceeded via reactive intermediates (alkyl,
vinyl, arenium carbocations and oxygen radical anion) showed
pronounced positive ionic liquid effects such as rate acceleration
and increased regio- and stereoselectivity, originating from the
stabilization of the reactive intermediates. In addition to these
Scheme 1
N
S 2 fluorination with CsF in ionic liquids.
2
(cation and anion) of ionic liquids for promoting these reactions
have not been elucidated yet. Understanding of the origin of the
positive role of ionic liquids will give a significant impact for
predicting their effects on other organic reactions and, moreover,
for designing new catalytic reactions that do not work efficiently
in conventional organic solvents.
multi-step reactions, significantly enhanced reactivity and selec-
tivity have also been observed in a concerted reaction such as
5
2,3
nucleophilic substitution reactions in ionic liquids. As shown
3j
from the examples in Scheme 1, the use of an ionic liquid such
4
as [bmim][OMs] for the S
N
2 reaction with CsF proceeds with
In this work, we present a mechanistic detail of catalytic activity
of ionic liquids for S
remarkable rate acceleration and high chemoselectivity, in contrast
to the corresponding reactions in common organic solvents. The
efficiency of nucleophilic fluorination was further improved by
6–8
N
2 reactions, focusing on the role of ionic
species in S 2 fluorination reaction in various ionic liquids. For S 2
N
N
t
reactions in [bmim][OMs] (bmim = n-butylmethyl imidazolium),
we show that the ionic liquid anion plays a key role as a Lewis
base by binding to the counterion Cs and thereby reducing
the retarding Coulombic influence of Cs on the nucleophile.
The F reacts as an ion pair (Cs F ) rather than as a naked
nucleophile here. We also carry out experiments using n-butyl
thaizolium instead of n-butyl imidazolium, to examine the role of
the ionic liquid cation, especially that of the acidic C2-hydrogen.
We elucidate the origin of oberved synergetic effects in catalysis
of ionic liquid [mim- OH][OMs], in which t-butanol is bonded
covalently to the cation [mim]. We find that the t-butanol moiety
binds to the leaving group of the substrate, and also moderates
the retarding interactions between the acidic hydrogen and F .
employing the modified ionic liquid [mim- OH][OMs], which
3j
can complete the reaction within 1 h with catalytic amounts.
+
However, the detailed mechanism and the role of ionic species
+
-
+
-
a
Department of Applied Chemistry, Kyunghee University, Yongin, Gyeoggi,
4
46-701, (Korea). E-mail: sylee@khu.ac.kr
b
Department of Chemistry, Department of Energy Science, Sungkyunkwan
University 300 Cheoncheon, Jangan, Suwon, Gyeonggi, 440-746, (Korea).
E-mail: s1673@skku.edu
9
3j
c
Department of Chemistry, Sogang University, 1 Shinsudong, Mapogu, Seoul
t
1
†
‡
21-742, (Korea). E-mail: dychi@sogang.ac.kr
This publication is part of the web themed issue on fluorine chemistry.
Electronic supplementary information (ESI) available: Calculation
-
method, figures and tables. See DOI: 10.1039/c0ob00426j
4
18 | Org. Biomol. Chem., 2011, 9, 418–422
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-
Although we focus on fluorination reaction in this work, our
findings will apply toother S 2reactions as well. We hope our work
[bmim][OMs]. The cation [bmim], anion [OMs], nucleophile F ,
+
N
counterion Cs and the leaving group of the substrate form a very
stable and compact cyclic structure. The counterion Cs binds
both to F and the leaving group, allowing an ideal configuration
+
will constitute a significant step toward designing and engineering
solvents for specific chemical reactions.
-
10,11
We employ the density functional theory method MPW1K
with the 6-311++G** basis set and the effective core potential for
for the nucleophilic attack. The role of the ionic liquid cation
[bmim] and anion [OMs] for accelerating the reaction is clearly
seen in [OMs] (and the leaving group) interacts with the counterion
12
Cs (Hay-Wadt VDZ(n+1)), as implemented in GAUSSIAN 03
13
+
+
-
set of programs. Full intrinsic reaction coordinate (IRC) analysis
is carried out to calculate the barriers and to confirm the reaction
pathways. Zero point energies (ZPE) are taken into account, and
default criteria are used for all optimizations. In order to reduce
Cs , reducing the retarding Coulombic influence of Cs on F
(thus “freeing” F ), whereas [bmim] ‘collects’ [OMs], Cs and F
-
+
-
+
for this ideal arrangement. The role of Cs promoting the approach
of F to the leaving group (the substrate) and that of [OMs] (acting
as a Lewis base) to neutralize the Coulombic influence of Cs on
F seems to be the key factor in this mechanism, suggesting that
choice and ‘design’ of the ionic liquid anion and the counterion
will be critical. Binding of [bmim] to F may partially decrease
the nucleophilicity of F , but the stronger influence of [OMs] on
-
+
computational efforts, we adopt C
3
H
7
OMs as the model substrate
-
for 3-(naphthalene-2-yloxy)-propyl-methanesulfonate, after find-
ing that the naphthalene ring and the ether group do not play any
-
significant role in the S
N
2 fluorination reactions studied here.
-
+
‡
Cs seems to overcome this, giving the reaction barrier (E
2
=
Results and discussion
‡
-1
0.3, G 100◦c = 20.8 kcal mol ) that is quite similar to those
Fig. 1(a) presents the calculated mechanisms of S
N
-
2 fluorination
in the very efficient S
(20.4 kcal mol ) and ethylene glycol (20.0 kcal mol ) presented
in earlier works. Based on these results, we demonstrate that
N
2 reactions in protic solvents t-butanol
+
-
+
-1
-1
reaction [Cs F + C
3
H
7
OMs → C
3
H
7
F + Cs OMs ] in ionic liquid
9
10
the S
N
2 rate constants in t-butanol, ethylene glycol, and in
[
bmim][OMs] are quite comparable, in good agreement with the
3
e,f,g,j
observed excellent S
N
2 rates in ionic liquids.
According to the
S
N
2 mechanism depicted in Fig. 1(a), it seems that an ionic liquid
+
with strong coordinating ability (via stronger influence on Cs )
would be favourable.
An alternative structure for the pre-reaction complex may be
proposed in which the acidic hydrogen in the imidazolium ring
-
may interact with the leaving group rather than with F , and
this configuration is depicted in Fig. 1(b). The energy (Gibbs free
-
1
energy) of this complex is calculated to be 10.0 (8.3) kcal mol
higher than that depicted in Fig. 1(a). Thus, although the reaction
‡
‡
-1
barrier (E = 12.5, G 100◦c = 16.1 kcal mol ) is smaller than that
depicted in Fig. 1(a), this mechanism is far less favourable on
thermodynamic and kinetic grounds (the overall reaction barrier,
‡
-1
G
100◦c = 24.4 kcal mol , starting from the most stable pre-reaction
complex in Fig. 1(a) to the product in Fig. 1(b) is much larger than
‡
-1
that (G 100◦c = 20.8 kcal mol ) for the mechanism I). Therefore,
the S 2 mechanism presented in Fig. 1(a) seems to be far more
feasible.
N
-
If the acidic hydrogen in the ionic liquid interacts with F , (the
leaving group), then introducing a hydrogen with stronger acidity
would decrease (increase) the reaction rate. We carried out the
reaction using a thiazolium bearing a more acidic C2-proton than
9
the imidazolium, finding that S
N
2 fluorination do not proceed
at all (Scheme 2). Fig. 2 shows the calculated mechanism of
2 fluorination in [N-butylthiazolium][OMs]. The pre-reaction
S
N
Fig. 1 Calculated transition states in S
Energy and Gibbs free energy in kcal mol , and bond lengths in A
MPW1K/6-311++G**; ECP for Cs, Hay-Wadt VDZ(n+1)).
N
2 reaction in [bmim][OMs].
-1
˚
(
Scheme 2
S
N
2 fluorination with CsF in [N-butylthiazolium][OMs].
Org. Biomol. Chem., 2011, 9, 418–422 | 419
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2 reactions [Cs F- + C
+
H
OMs →
Table 1 Calculated barriers of S
N
3
7
-1
+
-
3 7
C H F + Cs OMs ] (energy and Gibbs free energy in kcal mol ) in ionic
liquids
‡
‡
Ionic liquids
E
G
100◦c
N
Observed S 2 Yield (%)
a
[
[
[
[
N-butylthiazolium][OMs]
bmim][BF
21.5
19.8
20.3
16.0
23.2
21.9
20.8
19.1
0
b
4
]
24
32
100
b
bmim][OMs]
t
b
mim- OH][OMs]
a
Reaction was carried out on a 0.2 mmol scale of 3-(naphthalen-2-
yloxy)propyl methanesulfonate with 5 equiv. of CsF using 8 equiv. of [N-
◦
b
butylthiazolium][OMs] in CH
3
CN (0.6 mL) for 50 min at 100 C. From
Ref. 3j: Reactions were carried out on a 1.0 mmol scale of substrate 3-
(
0
naphthalen-2-yloxy)propyl methanesulfonate with 5 equiv. of CsF using
◦
.5 equiv. of ionic liquid in CH
3
CN (3.0 mL) for 50 min at 100 C.
‡
‡
Table 2 Activation barriers E and G 100◦c, and relative energies E an
Gibbs free energies G100◦c of the pre-reaction complexes of S
2 reaction in
N
-1
[
N-butylthiazolium][OMs] (kcal mol ). (MPW1K/6-311++G**; ECP for
Cs, Hay-Wadt VDZ(n+1))
‡
‡
E
G
100◦c
E
G
100◦c
(
(
a)
b)
21.5
15.1
23.2
16.8
0
10.9
0
12.4
enhanced by synergetic effects (i.e., the counter anion of the ionic
+
liquid acts as a Lewis base toward Cs , drastically reducing its
-
electrostatic effects and thereby “freeing” the F nucleophile, and
the acidic –OH proton interacts with the mesylate leaving group,
helping it to detach from the reactant). Based on this idea, Chi
and co-workers synthesized the ionic liquids [mim- OH][OMs]
Fig. 2 Calculated transition states of S
N
2 reaction in [N-butylthiazolium]
3j
t
-1
[
OMs]. Energy and Gibbs free energy in kcal mol , and bond lengths in
(
Scheme 1), in which t-BuOH is combined to the imidazolium by
A˚ (MPW1K/6-311++G**; ECP for Cs, Hay-Wadt VDZ(n+1)).
t
covalent bonding. The ionic liquid [mim- OH][OMs] was found to
be remarkably efficient, making the S 2 fluorination proceed to
N
-
complex in which the acidic hydrogen binds to F is far more stable
(
completion in less than an hour as presented in the last entry
in Table 1. Fig. 3 gives a mechanistic detail to elucidate the
nature of the ‘synergetic’ effects, presenting the two alternative
mechanisms in which the role of t-BuOH differs: In Mechanism
I, the –OH group acts as additional Lewis base binding to the
-
1
DE = 10.9, DG = 12.4 kcal mol ) than the one where it interacts
with the leaving group, overwhelming the relative kinetic feasibility
of the pathway from the latter complex (barrier of the S 2 reaction
2 barrier (E = 21.5, G 100◦c
3.2 kcal mol ) presented in Fig. 2(a), which is larger than that
in Fig. 1(a) by ~1.2 kcal mol , is also in agreement with the
observed inefficiency of the liquid ion [N-butylthiazolium][OMs].
Considering these experimental and theoretical observations, we
N
-
1
‡
‡
being ~6 kcal mol smaller). The S
N
=
-
1
+
2
counterion Cs to further reduce its Coulombic influence on the
-
1
-
nucleophile F , whereas in Mechanism II it interacts with the
‡
leaving group. We find that the reaction barriers (E = 15~16,
‡
-1
G
100◦c = 17~19 kcal mol ) for both mechanisms are far smaller
-
‡
‡
-1
conclude that the acidic hydrogen in imidazolium binds to F
than that (E = 20.3, G 100◦c = 20.8 kcal mol ) in [bmim][OMs], in
rather than to the leaving group, as illustrated in Fig. 1(a). We
excellent agreement with the experimentally observed phenomenal
t
also carry out calculations for S
examine the effects of the ionic liquid anion. The barrier G 100◦c
N
2 fluorination in [bmin][BF
4
‡
] to
efficiency of the ionic liquid [mim- OH][OMs] for accelerating S
N
2
fluorination. The Mechanism II depicted in Fig. 3(b) would be
overwhelmingly favoured, because the calculated energy (Gibbs
free energy) of the pre-reaction complex presented in Fig. 3(a) is
-
1
is calculated to be 21.9 kcal mol , a bit larger than that (20.8) in
bmin][BF ], in excellent agreement with the observed smaller S 2
[
4
N
-
1
yield in [bmin] [BF
in Tables 1 and 2.
4
] than in [bmin][OMs]. These are summarized
found to be much higher (by 11.9 (10.7) kcal mol ). Therefore, it
is concluded that the t-BuOH moiety acts as an ‘anchor’ to the
-
It is useful to note that the role of the ionic liquid anions
leaving group for facile nucleophilic attack by F , rather than as a
1
4–16
+
discussed here is quite analogous to that of protic solvent
and
Lewis base to Cs . It is also worth noting that the distance between
17
-
˚
bis-terminal hydroxypolyethers previously reported by us. That
is, they act on the counterion Cs as a Lewis base, alleviating the
Coulombic influence of Cs on F and thus “freeing” from Cs .
If these effects of ionic liquid anion and the –OH group of protic
solvent are “combined”, the catalytic effects of ionic liquid may be
the acidic hydrogen and F (1.704 A) in the pre-reaction complex in
+
˚
Fig. 3(b) is much larger than that (1.537 A) in Fig. 1(a), indicating
+
-
+
that the t-BuOH group helps to decrease the retarding effects of
-
the H–F interaction. In Fig. 3(c) we describe the mechanism of
the corresponding E2 process. It is calculated to proceed via the
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20 | Org. Biomol. Chem., 2011, 9, 418–422

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‡
‡
Table 3 Activation barriers E and G 100◦c, and relative energies E and
Gibbs free energies G100◦c of the pre-reaction complexes of S
2 and E2
N
t
-1
reactions in [mim- OH][OMs] (kcal mol ). (MPW1K/6-311++G**; ECP
for Cs, Hay-Wadt VDZ(n+1))
‡
‡
E
G
100◦c
E
G
100◦c
(
(
(
a)
b)
c)
15.6
16.0
24.9
17.3
19.1
26.1
11.9
0
0
10.7
0
0
Conclusions
We have presented the mechanism of S 2 reactions in ionic liquids
N
that fully accounts for the newly developed catalytic capacity of
ionic liquids. We have elucidated the origin of remarkable efficiency
t
of [mim- OH][OMs] as the combined synergetic efforts of the ionic
liquid anion and the –OH group acting as an ‘anchor’ to the
substrate. Our work demonstrates that one may indeed “tailor” the
solvent to promote a specific chemical reaction, by systematically
designing the structures of ionic liquids. We hope that our present
work will open a new perspective in solvent engineering.
Acknowledgements
This work was supported by grants from the Ministry of health,
welfare and family affairs of Korea, NRF-20090085824 (Basic
Science Research Program), NRF-20090094024 (Priority Re-
search Centers Program), R11-2005-008-00000-0 (SRC program
of MEST /KOSEF), R31-2008-000-10029-0 (WCU program), and
the Ministry of Education, Science and Technology (Converging
Research Program, 2010K001050 and 2010K001203).
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Fig. 3 Calculated transition states in S
N
2 reaction (a), (b) and E2 reaction
t
-1
(
c) in [mim- OH][OMs]. Energy and Gibbs free energy in kcal mol ,
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N
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