Study of aromatic nucleophilic substitution with amines on nitrothiophenes in room-temperature ionic liquids: Are the different effects on the behavior of para-like and ortho-like isomers on going from conventional solvents to room-temperature ionic liquids related to solvation effects?

Article abstract of DOI:10.1021/jo060435q

The kinetics of the nucleophilic aromatic substitution of some 2-L-5-nitrothiophenes (para-like isomers) with three different amines (pyrrolidine, piperidine, and morpholine) were studied in three room-temperature ionic liquids ([bmim][BF₄], [bmim][PF₆], and [bm ₂im][BF₄], where bmim = 1-butyl-3-methylimidazolium and bm₂im = 1-butyl-2,3-dimethylimidazolium). To calculate thermodynamic parameters, a useful instrument to gain information concerning reagent-solvent interactions, the reaction was carried out over the temperature range 293-313 K. The reaction occurs faster in ionic liquids than in conventional solvents (methanol, benzene), a dependence of rate constants on amine concentration similar to that observed in methanol, suggesting a parallel behavior. The above reaction also was studied with 2-bromo-3-nitrothiophene, an ortho-like derivative able to give peculiar intramolecular interactions in the transition state, which are strongly affected by the reaction medium.

Full text of DOI:10.1021/jo060435q

Study of Aromatic Nucleophilic Substitution with Amines on
Nitrothiophenes in Room-Temperature Ionic Liquids: Are the
Different Effects on the Behavior of para-Like and ortho-Like
Isomers on Going from Conventional Solvents to
Room-Temperature Ionic Liquids Related to Solvation Effects?
Francesca D’Anna,*,† Vincenzo Frenna,† Renato Noto,*,† Vitalba Pace,† and
Domenico Spinelli*,‡
Dipartimento di Chimica Organica “E. Paterno`”, UniVersita` degli Studi di Palermo, Viale delle
Scienze-Parco d’Orleans II, 90128 Palermo, Italy, and Dipartimento di Chimica Organica “A. Mangini”,
UniVersita` degli Studi di Bologna, Via S. Giacomo 11, 40126 Bologna, Italy
fdanna@unipa.it; rnoto@unipa.it; domenico.spinelli@unibo.it
ReceiVed March 1, 2006
The kinetics of the nucleophilic aromatic substitution of some 2-L-5-nitrothiophenes (para-like isomers)
with three different amines (pyrrolidine, piperidine, and morpholine) were studied in three room-
temperature ionic liquids ([bmim][BF4], [bmim][PF6], and [bm2im][BF4], where bmim ) 1-butyl-3-
methylimidazolium and bm2im ) 1-butyl-2,3-dimethylimidazolium). To calculate thermodynamic
parameters, a useful instrument to gain information concerning reagent-solvent interactions, the reaction
was carried out over the temperature range 293-313 K. The reaction occurs faster in ionic liquids than
in conventional solvents (methanol, benzene), a dependence of rate constants on amine concentration
similar to that observed in methanol, suggesting a parallel behavior. The above reaction also was studied
with 2-bromo-3-nitrothiophene, an ortho-like derivative able to give peculiar intramolecular interactions
in the transition state, which are strongly affected by the reaction medium.
Introduction
As a result of their nonflammability and nondetectable vapor
pressure, they have attracted not only academic but also
industrial interest.2 These organic onium salts have been used
largely as solvents in organic synthesis,3 biocatalysis,4 electro-
chemistry,5 and separation processes,6 and many applications
have been documented. At present, however, only a few papers
have reported mechanistic studies,7 although, from this point
of view, ionic liquids might be very interesting media, as they
are formed only of ions, they provide a reaction environment
In the past few years, room-temperature ionic liquids (RTILs,
usually organic onium salts) have been proposed as environ-
mentally benign alternatives to conventional organic solvents.1
* Corresponding Authors. Phone: +39091596919 (F.D. and R.N.); +39051209-
5689 (D.S). Fax: +39091596825 (F.D. and R.N.); +390512095688 (D.S.).
† Universita` degli Studi di Palermo.
‡ Universita` degli Studi di Bologna.
(1) (a) Welton, T. Chem. ReV. 1999, 99, 2071-2084. (b) Wasserscheid,
P.; Keim, M. Angew. Chem., Int. Ed. 2000, 39, 3772-3789. (c) Wilkes, J.
S. Green Chem. 2002, 4, 73-80. (d) Rogers, R. D.; Seddon, K. R. Ionic
Liquids as Green SolVents. Progress and Prospects; ACS Symposium Series
856; American Chemical Society: Washington, DC, 2003. (e) Kumar, A.;
Pawar, S. S. J. Org. Chem. 2004, 69, 1419-1420. (f) Wilkes, J. S. J. Mol.
Catal. A: Chem. 2004, 214, 11-17. (g) Picquet, M.; Poinsot, D.; Stutzmann,
S.; Tkatchenko, I.; Tommasi, I.; Wasserscheid, P.; Zimmermann, J. Top.
Catal. 2004, 29, 139-143. (h) Chiappe, C.; Pieraccini, D. J. Phys. Org.
Chem. 2005, 18, 275-297. (i) Gu, D.-G.; Ji, S.-J.; Jiang, Z.-Q.; Zhou, M.-
F.; Loh, T.-P. Synlett 2005, 959-962. (j) Conte, V.; Floris, B.; Galloni, P.;
Mirruzzo, V.; Scarso, A.; Sordi, D.; Strukul, G. Green Chem. 2005, 7, 262-
266. (k) Zhao, H.; Malhotra, S. V. Aldrichimica Acta 2002, 35, 75-83.
(2) (a) Rogers, R. D.; Seddon, K. R. Ionic Liquids: Industrial Application
to Green Chemistry; ACS Symposium Series 818; American Chemical
Society: Washington, DC, 2002. (b) Rogers, R. D.; Seddon, K. R.; Volkov,
S. Green Industrial Application of Ionic Liquids; NATO Science Series II,
Mathematics, Physics and Chemistry; Kluwer: Dordrecht, 2003; Vol. 92.
(c) Volland, M.; Seitz, V.; Maase, M.; Flores, M.; Papp, R.; Massonne, K.;
Stegmann, V.; Halbritter, K.; Noe, R.; Bartsch, M.; Siegel, W.; Becker,
M.; Huttenlock, O. Method for Separation of Acids from Chemical Reaction
Mixtures by Means of Ionic Fluids. PCT Int. Appl. W003/06225, 31.7.2003,
BASF AG. (d) Freemantle, M. Chem. Eng. News 2003, 81, 9. (e)
Weyershausen, B.; Hell, K.; Hesse, U. Green Chem. 2005, 7, 283-287.
10.1021/jo060435q CCC: $33.50 © 2006 American Chemical Society
Published on Web 06/10/2006
5144
J. Org. Chem. 2006, 71, 5144-5150

SNAr with Amines on Nitrothiophenes in RTILs
that is completely different from that offered by conventional
solvents, thus possibly modifying the mechanism or even
changing the outcome of a reaction.
of the comparison with the results in a conventional solvent.
For example, solvation effects of some RTILs containing the
[TF2N] anion, similar to those of acetonitrile, have been claimed
studying the keto-enol tautomerism of 2-nitrocyclohexanone.12
According to this approach, we decided to perform a kinetic
study in RTILs of the nucleophilic aromatic substitution (SN-
Ar), an organic reaction well-investigated in conventional
organic solvents. Nucleophilic substitutions (aromatic as well
as aliphatic) represent “one of the most important reactions”
“and can lead to a wide variety of new functional groups”.13
For years some of us have been interested in the mechanistic
aspects of this reaction in conventional organic solvents.14
Furthermore, it is well-known that the process is affected by
the nature of the solvent used, and it has been used frequently
as a probe to better understand the microscopic properties of
solvent systems.15
Recent studies have demonstrated that changes in the nature
of the cation and/or of the counterion bring about notable
variations in the properties (e.g., electrophilicity or nucleophi-
licity) of the reacting molecules8 as well as in the mechanism
of reaction.9 Accordingly, we recently proposed a shift from
the E1cB (in MeOH)10a to the E2 mechanism (in RTILs)10b for
the amine-promoted dehydrobromination of the 1,1,1-tribromo-
2,2-bis(phenyl-substituted)ethanes in ionic liquids.
Despite the enormous interest in RTILs, their microscopic
properties are not fully understood. Several reports have
attempted to determine empirically some of their solvent
parameters.11 Completely different values have been obtained,
however, as a result of the different natures of the molecular
probes used and to the lack of a single probe able to account
for different intermolecular forces and, thus, to give a reliable
polarity scale.
Results and Discussion
Choice of Substrates and Nucleophiles. We herein report
on the aromatic amination of some 2-L-5-nitrothiophenes (1),
para-like derivatives, by the action of three secondary cyclic
amines, namely, pyrrolidine (Pyr), piperidine (Pip), and mor-
pholine (Mor; Chart 1). These amines show different nucleo-
philicities and/or structures that could cause specific interactions
with organized solvents such as ionic liquids. Four different
leaving groups (L ) Br, OMe, OC6H5, and OC6H4-4-NO2)
were chosen to verify their leaving group ability order.
We also examined the behavior of an ortho-like derivative,
namely, 2-bromo-3-nitrothiophene (2a), which gives peculiar
intramolecular interactions in the transition state (TS), to gain
information about the dependence of such interactions on the
nature of the medium used.
The reaction was followed spectrophotometrically at not less
than six amine concentrations (0.00869-0.0350 M) and over a
significant temperature range (293-313 K), determining the
thermodynamic parameters, which are a useful instrument in
studying reagent-solvent interactions.
Three ionic liquids ([bmim][BF4], [bmim][PF6], and [bm2-
im][BF4], where bmim ) 1-butyl-3-methylimidazolium and bm2-
im ) 1-butyl-2,3-dimethylimidazolium) were chosen because
of the different properties of their cations and anions. In
An alternative approach, so far less investigated, is a
mechanistic study in ionic liquid solution of a classic organic
reaction to better understand their solvent properties by means
(3) (a) Sheldon, R. Chem. Commun. 2001, 2399-2407. (b) Harjani, J.
R.; Nara, S. J.; Salunkhe, M. M. Tetrahedron Lett. 2002, 43, 1127-1130.
(c) Namboodiri, V. V.; Varma, R. S. Chem. Commun. 2002, 342-343. (d)
Ionic Liquids in Synthesis; Wasserscheid, P., Welton, T., Eds.; Wiley-
VCH: Weinheim, Germany, 2003. (e) Sun, W.; Xia, C.-G.; Wang, H.-W.
Tetrahedron Lett. 2003, 44, 2409-2411. (f) Akiyama, T.; Suzuki, A.;
Fuchibe, K. Synlett 2005, 1024-1026. (g) Ranu, B. C.; Jana, R. J. Org.
Chem. 2005, 70, 8621-8624.
(4) (a) Yang, Z.; Pan, W. Enzyme Microb. Technol. 2005, 37, 19-28.
(b) Chiappe, C.; Leandri, E.; Lucchesi, S.; Pieraccini, D.; Hammock, B.
D.; Morisseau, C. J. Mol. Catal. B: Enzymol. 2004, 27, 243-248. (c) Park,
S.; Kazlauskas, R. J. Curr. Opin. Biotechnol. 2003, 14, 432-437.
(5) (a) Buzzeo, M. C.; Evans, R. G.; Compton, R. G. Chem. Phys. Chem.
2004, 5, 1107-1120. (b) Mazurkiewicz, J. H.; Innis, P. C.; Wallace, G.
G.; MacFarlane, D. R.; Forsyth, M. Synth. Met. 2003, 135-136, 31-32.
(6) (a) Mwongela, S. M.; Numan, A.; Gill, N. L.; Agraria, R. A.; Warner,
I. M. Anal. Chem. 2003, 75, 6089-6096. (b) Matsumoto, M.; Inomoto, Y.;
Kondo, K. J. Membr. Sci. 2005, 246, 77-81.
(7) (a) Lancaster, N. L.; Welton, T.; Young, G. B. J. Chem. Soc., Perkin
Trans. 2 2001, 2267-2270. (b) Chiappe, C.; Conte, V.; Pieraccini, D. Eur.
J. Org. Chem. 2002, 2831-2837. (c) Chiappe, C.; Pieraccini, D.; Saullo,
P. J. Org. Chem. 2003, 68, 6710-6715. (d) Chiappe, C.; Pieraccini, D. J.
Org. Chem. 2004, 69, 6059-6064. (e) Crowhurst, L.; Lancaster, N. L.;
Pe´rez Arlandis J. M.; Welton, T. J. Am. Chem.. Soc. 2004, 126, 11549-
11555. (f) Lancaster, N. L.; Welton, T. J. Org. Chem. 2004, 69, 5986-
5992. (g) Laali, K. K.; Sarca, V. D.; Okazaki, T.; Brock, A.; Der, P. Org.
Biomol. Chem. 2005, 3, 1034-1042. (h) Lancaster, N. L. J. Chem. Res.
2005, 413-417. (i) D’Anna, F.; Frenna, V.; Noto, R.; Pace, V.; Spinelli,
D. J. Org. Chem. 2005, 70, 2828-2831.
(8) (a) Laali, K. K.; Gettwert, V. J. J. Org. Chem. 2001, 66, 35-40. (b)
Kim, D. W.; Song, C. E.; Chi, D. Y. J. Org. Chem. 2003, 68, 4281-4285.
(c) Kim, D. W.; Hong, D. J.; Seo, J. W.; Kim, H. S.; Kim, H. K.; Song, C.
E.; Chi, D. Y. J. Org. Chem. 2004, 69, 3186-3189. (d) Landini, D.; Maia,
A. Tetrahedron Lett. 2005, 46, 3961-3963.
(9) (a) Chiappe, C.; Pieraccini, D. ArkiVoc 2002, xi, 249-255. (b) Earle,
M. J.; Katdare, S. P.; Seddon, K. R. Org. Lett. 2004, 6, 707-710. (c) Shen,
H.-Y.; Yudeh, Z. M. A.; Ching, C. B.; Xia, Q. H. J. Mol. Catal. A: Chem.
2004, 212, 301-308.
(10) (a) Fontana, G.; Frenna, V.; Gruttadauria, M.; Natoli, M. C.; Noto,
R. J. Phys. Org. Chem. 1998, 11, 54-58. (b) D’Anna, F.; Frenna, V.; Pace,
V.; Noto, R. Tetrahedron 2006, 62, 1690-1698.
(11) (a) Carmichael, A. J.; Seddon, K. R. J. Phys. Org. Chem. 2000, 13,
591-595. (b) Muldoon, M. J.; Gordon, C. M.; Dunkin, I. R. J. Chem. Soc.,
Perkin Trans. 2 2001, 433-435. (c) Fletcher, K. A.; Storey, I. A.; Hendricks,
A. E.; Pandey, S.; Pandey, S. Green Chem. 2001, 3, 210-215. (d) Dzyuba,
S. V.; Bartsch, R. A. Tetrahedron Lett. 2002, 43, 4657-4659. (e) Anderson,
J. L.; Ding, J.; Welton, T.; Armstrong, D. W. J. Am. Chem. Soc. 2002,
124, 14247-14254. (f) Abraham, M. H.; Zissimos, A. M.; Huddleston, J.
G.; Willauer, H. D.; Rogers, R. D.; Acree, W. E. Ind. Eng. Chem. Res.
2003, 42, 413-418. (g) Ropel, L.; Belve`ze, L. S.; Aki, S. N. V. K.; Stadtherr,
M. A.; Brennecke, J. F. Green Chem. 2005, 7, 83-90.
(12) Angelini, G.; Chiappe, C.; De Maria, P.; Fontana, A.; Gasparrini,
F.; Pieraccini, D.; Pierini, M.; Siani, G. J. Org. Chem. 2005, 70, 8193-
8196.
(13) Brown, W. H.; Foote, C. S.; Iverson, B. L. Organic Chemistry;
Thomson Brook/Cole: Belmont, 2005; p 330.
(14) (a) Spinelli, D.; Dell’Erba, C.; Salvemini, A. Ann. Chim. (Rome,
Italy) 1962, 52, 1156-1166. (b) Spinelli, D.; Dell’Erba, C.; Guanti, G. Ann.
Chim. (Rome, Italy) 1965, 55, 1260-1266. (c) Spinelli, D.; Consiglio, G.;
Monti, T. J. Chem. Soc., Perkin Trans. 2 1975, 816-819. (d) Spinelli, D.;
Consiglio, G. J. Chem. Soc., Perkin Trans. 2 1975, 989-993. (e) Spinelli,
D.; Consiglio, G.; Noto, R. J. Heterocycl. Chem. 1977, 14, 1325-1329. (f)
Spinelli, D.; Consiglio, G.; Noto, R. J. Org. Chem. 1978, 43, 4038-4041.
(g) Consiglio, G.; Frenna, V.; Spinelli, D. Top. Heterocycl. Syst.: Synth.,
React. Prop. 1996, 1, 169-185. (h) Spinelli, D.; Consiglio, G.; Dell’Erba
C.; Novi, M. Chem. Heterocycl. Compd 1991, 44 (Part Four), 295-396.
(i) Spinelli, D.; Consiglio, G.; Dell’Erba, C.; Novi, M.; Petrillo, G. Gazz.
Chim. Ital. 1997, 127, 753-769. (j) Consiglio, G.; Frenna, V.; Guernelli,
S.; Macaluso, G.; Spinelli, D. J. Chem. Soc., Perkin Trans. 2 2002, 971-
975.
(15) (a) Terrier, F. Nucleophilic Aromatic Displacement: The influence
of the nitro group. In Organic Nitro Chemistry Series; Ferrer, H., Ed.; VCH
Publishers: New York, 1991. (b) Nudelmann, N. S. In The Chemistry of
Amino, Nitroso, Nitro and Related Groups; Patai, S., Ed.; J. Wiley & Sons,
Ltd.: London, 1996; Chapter 29. (c) Alvaro, C. E. S.; Nudelmann, N. S.
ArkiVoc 2003, x, 95-106.
J. Org. Chem, Vol. 71, No. 14, 2006 5145

D’Anna et al.
CHART 1
the corresponding 2-L-5-nitrothiophenes, despite the possible
steric hindrance that should have a negative impact on reactivity.
Of course, the built-in solvation effect has little relevance in
media, such as methanol, that are able by themselves to stabilize
the TS and to assist its evolution.
Kinetic Data for the Amino Substitution of 1a-d in
RTILs. In [bmim][X], the observed pseudo-first-order rate
constants for the title reactions showed a simple linear depen-
dence (see eq 2) on amine concentration (kobs ) i + kII[AmH]),
with the only exception of the morpholino-demethoxy substitu-
tion on 1b (see later). The intercept values in most cases were
negative: an outcome justified in a previous paper of ours on
the basis of an acid-base equilibrium between the imidazolium
cation and the amines.7i
The second-order rate constants (kII) for substrates 1 are
reported in Table 1 (complete data at different amine concentra-
tions are available in Supporting Information: Table 4). For a
useful comparison, data previously obtained in methanol are
also reported.
The linear dependence, similar to that observed in methanol,
indicates that, at least in [bmim][X], the reaction is not catalyzed
and that, accordingly, the solvent has, at least qualitatively, the
same effect as methanol in supporting the course of the reaction.
On quantitative grounds, the ionic liquid accelerates the reaction
because of the combined action of both cations and anions. In
fact, bmim acts as a hydrogen-bond donor, favoring departure
of the leaving group, while BF4 behaves as a hydrogen-bond
acceptor versus the amine proton, thus supporting the nitrogen-
hydrogen bond breaking.
Similar effects are well documented in other systems. For
example, Chiappe et al. reported that, in the bromination of
alkynes in ionic liquids, the breaking of the bromine-bromine
bond in the 1:1 π-complex was assisted by the imidazolium
cation.7b In addition, Welton et al., studying aliphatic nucleo-
philic substitution in the presence of neutral nucleophiles such
as amines, claimed that a charge separation in the TS can be
stabilized by a hydrogen bond between the ionic liquid anion
and the ammonium ion.7e
The figures relevant to the kinetics of amino substitution of
1 in [bmim][BF4] show that all amines react faster in RTILs
than in molecular solvents (by almost 1 or 3 orders of magnitude
in comparison with methanol and benzene,14e,i respectively).
Yadav et al. reported similar results for aromatic amination of
aryl halides.17
The nucleophilicity order in [bmim][BF4] (Pyr > Pip > Mor)
is similar to that observed in methanol, but the effect of the
nucleophilicity on the reaction rate is definitely more pro-
nounced: for 1a, Pyr/Pip/Mor ) 5.8:3.7:1 in methanol and 21.8:
10.9:1 in [bmim][BF4].
The behavior observed suggests that the higher reactivity in
ionic liquids could be due to a less extensive solvation of the
starting amine. Lacking the solvation leveling effect, the relative
particular, when going from [bmim][BF4] to [bmim][PF6], there
is a decrease in the negative charge density of the spherical
anion, whereas when going from [bmim][BF4] to [bm2im][BF4]
there is a decrease in the hydrogen-bond donor ability of the
cations. All the above changes could significantly affect the
reactivity in different ways.
The general scheme of SNAr processes on nitrothiophenes is
reported in Chart 2, whereas the observed rate constant, kobs, is
given by eq 1.
-
kobs ) (k1k2[AmH] + k1k3[AmH]2)/(k-1 + k2 + k3[AmH])
(1)
Simplified kinetic expressions can be calculated as a function
of the nature of the solvent, the leaving group, and the
nucleophile used. In particular, if (k2 + k3[AmH]) . k-1, eq 2
can be derived.
kobs ) k1[AmH] ) kII[AmH]
(2)
For the substrates studied, it was reported that in benzene
the amino substitution was base-catalyzed (eq 1).14h-j In
methanol, however, the outcome of the reaction shifted toward
an uncatalyzed pathway (eq 2) because of the ability of methanol
(a polar and protic solvent) to support the TS evolution.14c,e,f
In the case of 2-L-3-nitrothiophenes (and generically in ortho-
nitrohalogenoaromatic compounds), another factor, known as
“built-in solvation,” affects the reactivity.14b,16 Due to intramo-
lecular hydrogen-bond formation, which stabilizes the TS, in
benzene these substrates are significantly more reactive than
CHART 2
5146 J. Org. Chem., Vol. 71, No. 14, 2006

SNAr with Amines on Nitrothiophenes in RTILs
TABLE 1. Second (kII)a and Third (kIII)b Order Rate Constants for the Aromatic Amination of 1a-d in Ionic Liquid Solution at 298 K
substrate
amine
solvent
kII (M-1 s-1
)
kIII (M-2 s-1
)
i
1a
Pyr
Pip
[bmim][BF4]
[bmim][BF4]
[bmim][BF4]
MeOH
MeOH
MeOH
(6.75 ( 0.17) × 10-3
(3.36 ( 0.12) × 10-3
(3.09 ( 0.06) × 10-4
4.02 × 10-5
(-2.04 ( 0.40) × 10-5
(-0.16 ( 2.41) × 10-6
(-0.06 ( 1.33) × 10-7
Mor
Pyrc
Pipd
Morc
Pyr
2.55 × 10-5
6.93 × 10-6
[bmim][PF6]
[bm2im][BF4]
(2.95 ( 0.04) × 10-3
(-6.51 ( 0.75) × 10-6
Pyre
(3.91 ( 1.00) × 10-1
1b
Pyr
[bmim][BF4]
[bmim][BF4]
[bmim][BF4]
MeOH
(9.39 ( 0.33) × 10-2
(-2.57 ( 0.69) × 10-4
(-2.32 ( 0.28) × 10-4
Pip
(3.92 ( 0.12) × 10-2
More
Pipf
(3.19 ( 0.37) × 10-2
(6.00 ( 0.97) × 10-2
1.57 × 10-3
Morc,e
MeOH
1c
Pyr
Pip
[bmim][BF4]
[bmim][BF4]
[bmim][BF4]
MeOH
(3.16 ( 0.06) × 10-2
(2.03 ( 0.09) × 10-2
(1.58 ( 0.07) × 10-3
(6.77 ( 0.39) × 10-4
(7.00 ( 1.22) × 10-5
(-5.83 ( 1.83) × 10-5
(-1.08 ( 0.16) × 10-5
(-2.15 ( 0.72) × 10-6
Mor
Pipg
1d
Pyr
Pip
[bmim][BF4]
[bmim][BF4]
[bmim][BF4]
MeOH
(6.99 ( 0.12) × 10-2
(4.97 ( 0.15) × 10-2
(3.92 ( 0.16) × 10-3
6.14 × 10-4
(9.79 ( 2.41) × 10-5
(-1.09 ( 0.32) × 10-4
(-2.90 ( 0.33) × 10-5
Mor
Piph
a kII ) k1 (see Chart 2). kIII ) (k1 k3/k-1). c Spinelli, D. et al., unpublished results. d Calculated from data reported in ref 14c. e This value was determined
at 313 K. This temperature was chosen for decreasing the medium viscosity for [bm2im][BF4]; in the other two cases it was chosen for having fast enough
kinetics. f Calculated from data reported in ref 14f. g Data collected in this work. h Calculated from data reported in ref 14e.
b
reactivity is amplified and truly depends on the effective
nucleophilicity. In a recent paper, we proposed that the poor
solvation of amines by ionic liquids increases their ability to
behave as bases in a base-catalyzed ring-to-ring interconversion.7i
Comparison between the Reactivity of 1a-d in RTILs and
in Methanol. The order of reactivity for the piperidino
substitution of 1, with the exception of 1d (see later), was as in
methanol (with kII following the trend 1b > 1c > 1a), but the
relative reactivities were rather different (62:27:1 for methanol
and 12:6:1 for [bmim][BF4]); this could be, in some way, a
consequence of the reactivity-selectivity principle. We hypoth-
esize specific interactions between the leaving group and the
ionic liquid (both the cation and anion components), justified
by the different nature of the leaving groups: bromine or oxygen
are, respectively, bonded to the heteroaryl moiety. Moreover,
for substrates 1b-d, the oxygen atom of the leaving group has
a different electronic density depending on the electronic
requirements of methyl, phenyl, and 4-nitrophenyl groups,
respectively.
The organizing ability of ionic liquids can also explain the
higher reactivity of 1d. In the ground state, this favors the
conjugation, owing to π-π interactions, thus increasing the
electron-withdrawing effect of the oxygen atom bonded to the
heteroaryl moiety and consequently the k1 value (see Chart 2).
The increase in reactivity of 1, going from methanol to RTILs,
could be related to an increase in medium polarity. Indeed, as
the reaction implies a charge separation in the TS, every increase
in the polarity of the solvent should significantly increase the
reaction rate.
going from methanol (π* ) 0.73)18 to [bmim][BF4] (π* )
1.047)19 is well explained. However, when considering other
solvent parameters (ETN, ENR) different conclusions can be
drawn. Indeed, the ETN (0.670 and 0.762 for [bmim][BF4] and
methanol, respectively)18,19 and ENR (217.2 and 217.7, respective-
ly)11a values for these two solvents are quite similar.
Actually, the ionic liquid effect on the reaction studied is
probably quite complex. For example, we found a reactivity
for the pyrrolidino debromination of 1a higher in [bmim][BF4]
than in [bmim][PF6]. The observed trend agrees well with
previously reported data.7b,i,8b The kinetic constant values (Table
1) for the above reaction of 1a in [bmim][BF4] (kII ) 0.00675
M-1 s-1) and [bmim][PF6] (kII ) 0.00295 M-1 s-1) cannot be
exclusively a result of the polarity effect.
The ETN, ENR, and π* parameters (0.669, 216.8, 1.032 for
[bmim][PF6] and 0.670, 217.2, 1.047 for [bmim][BF4], respective-
ly)11a,19 do not explain the observed differences in reactivity.
The hydrogen-bond acceptor ability, linked to the higher
-
concentration of the negative charge in BF4 with respect to
PF6-, likely explains the higher efficiency of the first anion.
This effect is confirmed by the higher â values reported for
BF4 than for PF6 (0.376 and 0.207, respectively),18 which
also are in the expected order.
-
-
However, some different explanations about the reactivity in
[bmim][BF4] have been advanced. It was attributed to a low
solubility of the nucleophile8b or to a change in its absolute
nucleophilicity.7f Moreover, the different negative charge dis-
-
-
tributions on BF4 and PF6 can affect the distance between
the imidazolium rings of the solvent, which would lead to a
different catalytic effect owing to more or less pronounced π-π
interactions.7i
Several empirical parameters are useful in evaluating the
polarity of a solvent. Thus, if we consider the π* parameter as
representative of a notion of “polarity,” the increase in reactivity
The structure of the cation of a RTIL plays in turn an
important role, as also the hydrogen-bond donor ability of the
(16) (a) Bunnett, J. F.; Morath, R. J. Am. Chem. Soc. 1955, 77, 5051-
5055. (b) Bernasconi, C. F.; de Rossi, R. H. J. Org. Chem. 1976, 41, 44-
49.
(17) Yadav, J. S.; Reddy, B. V. S.; Basak, A. K.; Navsaiah, A. V.
Tetrahedron Lett. 2003, 44, 2217-2220.
(18) Reichardt, C. SolVents and SolVent Effects in Organic Chemistry,
3rd ed.; VCH: Weinheim, Germany, 2000.
(19) Crowhurst, L.; Mawdsley, P. R.; Perez-Arlandis, J. M.; Salter, P.
A.; Welton, T. Phys. Chem. Chem. Phys. 2003, 5, 2790-2794.
J. Org. Chem, Vol. 71, No. 14, 2006 5147

D’Anna et al.
TABLE 2. Second (kII) Order Rate Constants for the Aromatic
Amination of 2a in Ionic Liquid Solution at 298 K
amine
solvent
k
II (M-1 s-1
)
i
Pyr
Pip
[bmim][BF4] (3.44 ( 0.11) × 10-2 (-3.08 ( 2.39) × 10-5
[bmim][BF4] (9.20 ( 0.09) × 10-3 (-8.80 ( 1.98) × 10-6
[bmim][BF4] (1.09 ( 0.03) × 10-3 (1.16 ( 0.59) × 10-6
Mor
Pyra
Pipb
Pyra
Pipc
MeOH
MeOH
benzene
benzene
4.59 × 10-4
1.76 × 10-4
1.68 × 10-3
4.25 × 10-4
a This value was determined at 293 K. Spinelli, D. et al., unpublished
results. b Data collected from ref 14d. c Data collected from ref 14b.
mimBF4/(kII)MeOH, goes from 52 for Pip up to 75 for Pyr. The
relative reactivity for the different amines (Pyr/Pip/Mor ) 31:
8.4:1) is quite similar to that for 1a reported above.
A comparison among the reactivities of 1a and 2a in benzene,
methanol, and [bmim][BF4] shows that, under similar conditions,
2a is always more reactive than 1a. The reactivity ratio [(kII)2a/
(kII)1a)] for the pyrrolidino substitution significantly decreases
from 747 in benzene to 11 in methanol and 5 in [bmim][BF4].
A similar trend was also found for the piperidino substitution.
As noted previously, the high reactivity ratios observed in
benzene show that built-in solvation is operative and very
effective in this solvent,14b,16 strongly increasing the reactivity
of ortho-like isomers.23 This effect, occurring only in the ortho-
like isomer, strongly lowers the differences in reactivity on going
from benzene to [bmim][BF4]. Despite the fact that [bmim][BF4]
seems to have a scarce solvating effect, it affects reactivity ratios
like methanol. This could be a consequence of different
balancing of their behaviors; as a matter of fact, methanol
heavily solvates both 1a and 2a, in contrast, [bmim][BF4] does
not.
Activation Parameters for SNAr in RTILs. Kinetic con-
stants measured in RTILs sometimes show significant curvature
in Arrhenius or Eyring plots, which has been related to
temperature-dependent changes in the solvent structure.24 Thus,
for a careful analysis of the temperature effect, the substitution
reaction was carried out at five temperatures in a relatively
narrow range (from 293 to 313 K). The activation parameter
values are collected in Table 3, with the values in methanol
reported for comparison (data at different temperatures are
available in Supporting Information: Table 6).
FIGURE 1. Plot of kobs (s-1) vs [Mor] for 1b at 313 K.
solvent appears to be very important. In fact, a change in the
cation component of an ionic liquid, going from bmim to bm2-
im, can cause a different reactivity and mechanism.7d,10 Herein,
for the pyrrolidino debromination of 1a in [bm2im][BF4], a
different dependence of kobs on amine concentration was
observed (kobs ) (k1k3/k-1)[AmH]2 ) kIII[AmH]2). This could
be explained by the fact that bm2im, a cation less able to form
a hydrogen bond, needs a second amine molecule to assist the
leaving group departure. The different effect of the imidazolium
cation in bmim and bm2im, related to its different hydrogen-
bond donor ability, is well documented. In particular, the
nucleophilicity of the chloride anion,20 the endo-selectivity for
a Diels-Alder reaction,21 and the conversion and reaction rates
of a Tsuji-Trost allylic substitution22 were explained by the
different natures of the cations involved.
The morpholino substitution of 1b in [bmim][BF4] showed
a nonlinear dependence on amine concentration (Figure 1).
The same dependence was found in methanol. This result
shows that this behavior could be unique to the considered
leaving group/nucleophile couple. Furthermore, in contrast to
all other cases, the reaction was faster in methanol than in ionic
liquid. The higher reactivity in methanol could be due to the
high crowding of the activated complex as a result of the
presence of a second amine molecule. Methanol molecules
reorganize themselves more easily than those of ionic liquids
around the TS, thus providing a more effective stabilization in
this particular case.
In the conditions employed, a nonlinear plot of log(kobs/T)
versus 1/T was observed only for the base-catalyzed morpholino
demethoxylation of 1b. In this case, however, where kobs is
expressed by eq 1 (see above), the nonlinear trend could be
related to the complexity of the reaction mechanism (which
would cause different temperature effects on the various steps
of the reaction) rather than to structural changes in the solvent.
For all the other cases, a good linear correlation guarantees that
the calculated activation parameters only depend on the
substitution process considered.
Kinetic Data for the Amino Substitution of 2a. For
comparison, we also gathered kinetic data relevant to the amino
substitution of 2a with Pyr, Pip, and Mor in [bmim][BF4]. The
observed pseudo-first-order rate constants showed a simple
linear dependence on amine concentration, and the second-order
rate constants (kII) are reported in Table 2 (rate data at different
amine concentrations are available in Supporting Information:
Table 5). Data previously collected in methanol and in benzene
are also reported.
With respect to methanol, in every case, the aromatic
amination in RTILs is enthalpy favored but entropy disfavored
(with the exception of the pyrrolidino debromination of 1a in
both [bmim][BF4] and [bmim][PF6]). The differential enthalpic
In line with the kinetic data for 1a, also 2a is more reactive
in [bmim][BF4] than in methanol. The reactivity ratio, (kII)b-
(23) In five-membered derivatives, such as 2a, the hyperortho relationship
occurring between C-2 and C-3 atoms of the thiophene ring further increases
the k2a/k1a ratios, especially in nonpolar solvents.
(24) Gordon, M. C.; McLean, A. J.; Mudoon, M. J.; Dunkin, I. R. In
Ionic Liquids as Green SolVents. Progress and Prospects; Rogers, R. D.,
Seddon, K. R., Eds.; ACS Symposium Series 856; American Chemical
Society: Washington, DC, 2003, pp 357-369.
(20) Lancaster, N. L.; Salter, P. A.; Welton, T.; Young, G. B. J. Org.
Chem. 2002, 67, 8855-8861.
(21) Aggarwal, A.; Lancaster, N. L.; Sethi, A. R.; Welton, T. Green
Chem. 2002, 4, 517-520.
(22) Ross, J.; Chen, W. P.; Xu, L. J.; Xiao, J. L. Organometallics 2001,
20, 138-142.
5148 J. Org. Chem., Vol. 71, No. 14, 2006

SNAr with Amines on Nitrothiophenes in RTILs
TABLE 3. Activation Parameters for the Aromatic Amination of
entropy trend cannot be explained only on the basis of the â
solvent parameter; the [bmim][BF4], with the higher â value
(0.376),18 would show a less-negative ∆Sq value.
1a-d and 2a in Ionic Liquid
∆S‡
∆G‡
298K
substrate amine
solvent
∆H‡ (kJ/mol) (J/K mol) (kJ/mol)
This can only be a partial explanation, however, as [bm2im]-
[BF4], with a similar â value (0.363),18 shows a more negative
entropy value. Furthermore, [bmim][PF6], with the lowest â
value (0.207),18 shows an intermediate entropy value. Also, the
other solvent parameters do not allow an unique explanation of
the variation in activation parameters as a function of the nature
of ionic liquids. This could be due to the fact that the solvent
parameters for ionic liquids are probably inadequate. Indeed, it
is questionable whether the empirically derived measurements
of solvent properties can be exclusively attributed to RTILs or
whether they are also affected by the nature of the compounds
and the occurring reaction.25
Effect of the Leaving Group in 1 on the Activation
Parameters. With the exception of the reaction with morpho-
line, the enthalpy values increase, that is, become less favorable,
in the order OMe < OC6H4-4-NO2 < OPh < Br. As was
previously pointed out, the lowest activation enthalpy observed
for 1b could be related to the large resonance interaction
between methoxy and nitro groups (via heteroaryl), which
lowers the electronic reorganization occurring for the TS
formation of the SNAr. The trend observed parallels that of k1
values (see Chart 2) and could also be due to the different
electronegativities of atoms bonded to the heteroaryl moiety
(oxygen and bromine) and, among the oxygenated groups, to
the different oxygen electron densities and steric demands.
Indeed, the higher electronegativity of the oxygen atom could
induce a higher positive charge density, then favoring the
nucleophilic attack. The entropy variation follows the order OMe
< OC6H4-4-NO2 ≈ OPh < Br. The enthalpy and entropy
variations balance between themselves thereby determining no
large differences in k1 values. The entropy trend seems to
indicate that the breaking down of the ionic liquid structure is
more extensive for the “late” TS of 1a and less extensive for
the “early” TS of 1b-d. It is interesting to note that anions
with a highly symmetrical distribution of negative charge, such
as BF4-, permit interaction with several of the surrounding
cations. So the later rather than the bulkier TS (1a having the
lowest k1 value) should induce a more extensive breaking down
of the cross-linking of the ionic liquid structure.
1a
Pyr
Pip
[bmim][BF4]
[bmim][BF4]
55.6 ( 3.9 -133 ( 13
49.0 ( 2.2 -159 ( 7
52.4 ( 1.9 -168 ( 6
95.2
96.4
Mor [bmim][BF4]
102.6
107.5
108.7
111.9
97.1
Pyra MeOH
62.1
64.1
64.0
-153
-150
-161
Pipb MeOH
Mora MeOH
Pyr
Pyr
[bmim][PF6]
[bm2im][BF4] 49.0 ( 1.4 -161 ( 5
55.0 ( 1.0 -141 ( 3
96.9
1b
Pyr
Pip
[bmim][BF4]
[bmim][BF4]
32.3 ( 1.1 -189 ( 4
26.9 ( 1.2 -216 ( 4
88.6
91.3
Mor [bmim][BF4]
Pipc MeOH
46.2
-176
98.7
1c
Pyr
Pip
[bmim][BF4]
[bmim][BF4]
42.9 ( 0.9 -162 ( 3
33.8 ( 1.7 -197 ( 5
19.4 ( 0.8 -269 ( 3
91.3
92.5
99.5
Mor [bmim][BF4]
1d
Pyr
Pip
[bmim][BF4]
[bmim][BF4]
39.9 ( 3.1 -165 ( 10
31.5 ( 1.0 -196 ( 3
28.8 ( 1.0 -230 ( 3
89.3
90.1
97.3
Mor [bmim][BF4]
Pipd MeOH
53.5
-159
100.9
2a
Pyr
Pip
[bmim][BF4]
[bmim][BF4]
42.1 ( 3.3 -164 ( 3
44.7 ( 1.1 -166 ( 3
46.3 ( 0.8 -178 ( 3
90.9
94.2
99.2
101.5
103.9
Mor [bmim][BF4]
Pyra MeOH
55.2
60.4
-156
-146
Pipe MeOH
a Spinelli, D. et al., unpublished results. b Calculated from data reported
in ref 14b. c Calculated from data reported in ref 14e. d Data collected in
this work. e Calculated from data reported in ref 14d.
contribution could be due to the extensive solvation of the
starting materials in methanol. On the other hand, the unfavor-
able entropic contribution in ionic liquids agrees with the
bimolecular mechanism of the reaction and with the fact that
on going from the initial to the TS there is no release of solvating
molecules. Moreover, the zwitterionic TS should interact with
the RTILs much more than the starting reagents.
The enthalpy values range from 19.4 to 55.6 kJ/mol, whereas
the entropy values range from -269 to -133 J/K mol. Narrower
ranges (≈ 18 kJ/mol for ∆Hq and 26 J/K mol for ∆Sq) were
observed in methanol. The medium effect seems more important
in RTILs than in methanol, where the strong interactions in both
initial states and TSs provide a leveling effect. In contrast, RTILs
could cause a wider spectrum in interaction intensity.
According to previous reports on going from conventional
solvents to RTILs, the activation parameters in some cases are
not very sensitive to the solvent used, while in other cases,
significant changes have been detected.7d-f The activation
parameters have been analyzed as a function of the following:
(i) the possible interactions between TS and RTILs; (ii) the
nature of the leaving group; and (iii) the nucleophile used. We
acknowledge, however, that the experimental values could
depend on the balance of some different factors that act in
opposite directions.
The rather similar entropy values of 1c and 1d indicate similar
steric hindrance for the two phenoxy groups. Furthermore, the
entropy values for 1b could reflect the higher order around the
TS as a consequence of the low steric hindrance of the methoxy
group.
Effect of the Nucleophile on the Activation Parameters.
Concerning the dependence of activation parameters on the
nucleophile (Table 3), there are significant differences between
methanol and RTILs. In addition, Mor seems to have a peculiar
behavior. Indeed, as observed previously, the kinetic constant
of 1b showed a nonlinear dependence on temperature. In this
case, the resulting reaction was base-catalyzed (see eq 1), so
the activation parameters for Mor are composite and then not
comparable to those for Pyr and Pip. Furthermore, the low
enthalpy values for Mor could be due to the stabilization of TS
by an intramolecular electrostatic interaction between the
ammonium group and the partially negatively charged oxygen
atom of Mor. In addition, we assume that there is a more
Activation Parameters of the Pyrrolidino Debromination
of 1a in Different RTILs. The values for the title reaction in
[bmim][BF4] and [bmim][PF6] can be explained on the grounds
-
of different cation (ammonium part of TS)-anion (BF4 or
PF6-) interactions and of the hydrogen-bond acceptor and
hydrogen-bond donor ability of ionic liquids. In particular, less-
negative entropy values are expected due to an alteration of
the ionic liquid structure rising by formation of a charge-
separated TS from neutral starting materials.7e The observed
(25) Armstrong, D. W.; He, L.; Liu, Y.-S. Anal. Chem. 1999, 71, 3873-
3876.
J. Org. Chem, Vol. 71, No. 14, 2006 5149

D’Anna et al.
1d,27 and 2a28 were prepared according to the methods reported.
5-Nitro-2-phenoxythiophene (1c). A mixture of 1 mM of
2-bromo-5-nitrothiophene (1a) and 1 mM of potassium phenoxide
in 10 mL of dioxane was refluxed for 2 h, following the
disappearance of 1a by means of TLC. The dioxane was eliminated
at reduced pressure, and the resulting yellow solid was washed with
water and extracted with toluene. After elimination of the toluene,
the residue was crystallized from methanol to give 0.160 g of the
product. Mp: 86 °C.
organized TS because of the hydrogen-bond between bmim and
the oxygen atom.
The significant difference in the activation parameters
between Pyr and Pip can be ascribed to the different positions
(earlier or later) of the TS along the reaction coordinates. For
example, a more significant interaction TS/anion of RTIL will
be more operative for a late TS than for an early one. Moreover,
a RTIL/substrate/nucleophile system with a higher order degree
should be more affected by a disordering effect. However, if
strong electrostatic or hydrogen-bond interactions are operative,
perturbative effects could become less important.
Activation Parameters for SNAr of 2a. The activation
parameters for 2a in [bmim][BF4] show that the substitution is
enthalpy favored but entropy disfavored with respect to 1a. All
this agrees well with the occurrence of the built-in solvation
effect, which induces a higher stabilization and organization of
the TS. However, if we consider the differences in activation
parameters for piperidino substitution of 1a and 2a in benzene
(9.2 kJ/mol for ∆Hq and 20.9 J/K mol for ∆Sq), the above effect
is, of course, more important in benzene than in ionic liquids.
IR (Nujol; cm-1): ν 3112; 1533; 1359. NMR (CDCl3, 300
MHz): δH 6.27 (d, 1H, J ) 4.5), 5.85 (m, 5H), 4.90 (d, 1H, J )
4.5); δC 171.4, 158.2, 132.3, 130.7, 128.3, 121.2, 111.6. Anal. Calcd
for C10H7NO3S: C, 54.3; H, 3.2; N, 6.3; S, 14.5. Found: C, 54.6;
H, 3.0; N, 5.9; S, 14.7.
Kinetic Measurements and Calculations. UV-vis spectra and
kinetic measurements were carried out by using a spectrophotometer
equipped with a Peltier temperature controller, which is able to
keep the temperature within 0.1 K.
Kinetic runs were carried out over the temperature range 293-
313 K. The sample for a typical kinetic run was prepared by
injecting into a quartz cuvette (optical path 0.2 cm) 500 µL of IL,
50 µL of a solution of substrate in 1,4-dioxane, and then 25 µL of
a concentrated solution of amine in 1,4-dioxane, previously
thermostated. The concentration of substrate was constant and equal
to 0.00019 M, and the amine concentration ranged from 0.00869
up to 0.0350 M. The reactions were all studied over six half-lives
or more. In all cases, the correlation coefficient was higher than
0.9998.
To evaluate the possibility of reusing ILs, we tried a fast and
simple treatment of the solvent used. Thus, 5 mL of the used [bmim]-
[BF4] was extracted four times with 3 mL of Et2O. The IL layer
was kept under vacuum at 60 °C for 2 h and reused. The apparent
first-order rate constants then obtained were reproducible within
(15%, with respect to values determined in fresh IL. All kinetic
data were analyzed by means of the Kaleidagraph 3.0.1 software.
Conclusions
Ionic liquids represent intriguing solvent systems, which
cannot be described only by means of the usual solvent
parameters. Indeed, most of our results seem to be justifiable
on the grounds of the order and of the organizing ability of
these systems. Furthermore, the reaction rate is influenced by
the dimensions and charge distributions of anions as well as by
the hydrogen-bond ability of cations in the RTIL used.
Compared to methanol, the RTIL components have less strong
interactions with reagents. However, as opposed to methanol,
RTILs seem to be able to exalt the difference in the interactions
among the zwitterionic TS and the ionic liquid components,
resulting in the large spectrum of activation parameters observed.
On going from conventional solvents to RTILs, we noted an
interesting difference in the effect of a RTIL on the reactivity
of para-like and ortho-like isomers.
Acknowledgment. We thank MURST (Ministero dell’Univer-
sita` e della Ricerca Scientifica e Tecnologica) for financial
support, PRIN 2004 and 2005. The investigation was supported
also by Universities of Bologna and Palermo (funds for selected
research topics).
Supporting Information Available: Rate constants collected
at different amine concentrations and at different temperature values.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Experimental Section
Materials. Commercial compound 1a and 1,4-dioxane were used
without any other purification. Commercial [bmim][BF4], [bm2im]-
[BF4], and [bmim][PF6] were dried on a vacuum line at 60 °C at
least for 2 h and stored in a dryer under argon and over calcium
chloride. Amines were freshly distilled before use. Compounds 1b,26
JO060435Q
(27) Guanti, G.; Dell’Erba, C.; Macera, P. J. Heterocycl. Chem. 1971,
8, 537-540.
(28) Carpanelli, C.; Leandri, G. Ann. Chim. (Rome, Italy) 1961, 51, 181-
(26) Sice´, J. J. Am. Chem. Soc. 1953, 75, 3697-3700.
194.
5150 J. Org. Chem., Vol. 71, No. 14, 2006