Effect of ionic liquids on the Menschutkin reaction: An experimental and theoretical study

Article abstract of DOI:10.1021/jo9009408

(Figure Presented) The effect of ionic liquids (ILs) on the Menschutkin reaction between N-methylimidazole and benzyl halides has been investigated. Hammett correlations have been used to obtain information on the reaction mechanism of benzyl chlorides in

Full text of DOI:10.1021/jo9009408

pubs.acs.org/joc
Effect of Ionic Liquids on the Menschutkin Reaction: An Experimental
and Theoretical Study
Riccardo Bini,† Cinzia Chiappe,* Christian Silvio Pomelli,* and Benedetta Parisi
Dipartimento di Chimica e Chimica Industriale, via Risorgimento 35, 56126 Pisa, Italy.
†Present address: Dipartimento di Scienze Chimiche, via Marzolo 1, 35131 Padova, Italy.
cinziac@farm.unipi.it; cris@dcci.unipi.it
Received May 5, 2009
The effect of ionic liquids (ILs) on the Menschutkin reaction between N-methylimidazole and benzyl
halides has been investigated. Hammett correlations have been used to obtain information on the reaction
mechanism of benzyl chlorides in ionic and molecular solvents. The solvent effects on this reaction have
been examined using both multiparameter linear solvation energy relationships and theoretical calcula-
tions. These latter have been performed using a supermolecular approach, i.e., the IL is represented by an
explicit ionic pair, IP. Two possible different reaction pathways have been obtained changing the position
of the IL-IP with respect to the reagents. It is hypothesized that inside the IL the Menschutkin reaction of
benzyl chloride with N-methylimidazole can follow different reaction pathways by considering the
influence of dynamic heterogeneity in ionic media on the time scale of the lifetime of a transition state.
Introduction
measured and collected,2 but the number of ILs character-
ized completely is still limited. The number of studies per-
formed to understand the structure of ionic liquids and the
effect of Ils on reaction rate and selectivity is also limited.3,4
Room temperature ionic liquids (ILs) have attracted con-
siderable attention in recent years due to their unique
physical and chemical properties and the facility by which
many of these properties may be varied.1 They are now being
explored in virtually all areas of chemistry, as solvents for
organic and inorganic reactions or (bio)catalyzed processes,
as electrolytes in batteries and solar cells, and as new
materials. Various physical properties of ILs, necessary to
facilitate the use of Ils for these applications, have been
(2) Chiappe, C.; Pieraccini, D. J. Phys. Org. Chem. 2005, 18, 275.
(3) (a) Lancaster, N. L.; Welton, T. J. Org. Chem. 2004, 69, 5986.
(b) Anderson, J. L.; Ding, J.; Welton, T.; Armstrong, D. W. J. Am. Chem.
Soc. 2002, 124, 14247. (c) Crowhurst, L.; Lancaster, N. L.; Perez Arlandis,
J. M.; Welton, T. J. Am. Chem. Soc. 2004, 126, 11549. (d) Lancaster, N. L.;
Salter, P. A.; Welton, T.; Young, G. B. J. Org. Chem. 2002, 67, 8855.
(e) Chiappe, C.; Pieraccini, D. J. Org. Chem. 2004, 69, 6059. (f) Grodkowski,
J.; Neta, P.; Wishart, J. F. J. Phys. Chem. A 2003, 107, 9794. (g) Skrzypczak,
A.; Neta, P. J. Phys. Chem. A 2003, 107, 7800. (h) D’Anna, F.; Frenna, V.;
Noto, R.; Pace, V; Spinelli, D. J. Org. Chem. 2006, 71, 5144. (i) Chiappe, C.;
Pieraccini, D.; Sullo, P. J. Org. Chem. 2003, 68, 6710. (l) Bini, R.; Chiappe, C.;
Pieraccini, D.; Piccioli, P.; Pomelli, C. S. Tetrahedron Lett. 2005, 46, 6675.
(m) Crowhurst, L.; Falcone, R.; Lancaster, N. L.; Llopsis-Mestre, V.; Welton,
T. J. Org. Chem. 2006, 71, 8847. (n) Hallet, J. P.; Liotta, C. L.; Ranieri, G.;
Welton J. Org. Chem. 2009, 74, 1864. (o) Bini, R.; Chiappe, C.; Llopsis Mestre,
V.; Pomelli, C. S.; Welton, T. Org. Biomol. Chem. 2008, 6, 2522.
(1) Ionic Liquids IIIB: Fundamentals, Progress, Challenges, and Opportu-
nities-Transformations and Processes; Rogers, R. D., Seddon, K. R., Eds.;
ACS Symposium Series 902; American Chemical Society: Washington DC,
2005. Ionic Liquids IIIA: Fundamentals, Progress, Challenges, and Opportu-
nities-Properties and Structure Rogers, R. D., Seddon, K. R., Eds.; ACS
Symposium Series 901; American Chemical Society: Washington, DC, 2005.
Ionic Liquids in Synthesis, 2nd ed.; Wasserscheid, P., Welton, T., Eds.; Wiley-
VCH: Weinheim, 2008.
(4) Harper, J. B.; Kobrak, M. N. Mini-Rev. Org. Chem. 2006, 3, 253.
8522 J. Org. Chem. 2009, 74, 8522–8530
Published on Web 10/27/2009
DOI: 10.1021/jo9009408
r
2009 American Chemical Society

Bini et al.
JOCArticle
TABLE 1. Solvent Parameters13
H bond
donor acidity, R
H bond
acceptor basicity, β
cohesive pressure,
δ2 (J cm-3
solvent
acetonitrile
N,N-dimethylformamide
[bmim][PF6]
[bmim][Tf2N]
dipolarity/polarizability, π*
)
permittivity, ε
0.190
0.000
0.634
0.617
0.381
0.427
0.310
0.690
0.207
0.243
0.239
0.252
0.750
0.880
1.032
0.984
1.010
0.954
590
164
718
554
625
506
35.9
36.7
11.4
11.6
[bm2im][Tf2N]
[bmpyrr][Tf2N]
11.7
Composed exclusively by ions, ILs differ significantly from
water and organic solvents. The strong ion-ion interactions
present in ILs lead to highly structured materials, three-
dimensional polymeric networks of anions and cations
linked by H-bonds and/or Coulombic interactions, often
characterized by the presence of polar and nonpolar re-
gions.5 In the case of imidazolium-based ionic liquids, the
most investigated ILs, the existence of dynamic heteroge-
neous environments have been reported; molecules are
trapped for a relatively long period in quasistatic local
solvent cages.6 This trapping time, which is longer than in
molecular solvents, together with the inability of the sur-
roundings to adiabatically relax, induces a set of site-specific
spectroscopic responses (excitation-wavelength-dependent
fluorescence spectrum).7 Although in principle this hetero-
geneity might also affect reactivity, rarely has a hypothesis
about the consequences of these structural features on reac-
tion rate and/or selectivity been made. The effect of dynamic
heterogeneity on reaction rates have been considered only
for very fast reactions.8 Generally, the kinetic behavior of
homogeneous reactions carried out in ILs have been ratio-
nalized in terms of transition state theory; the solvent
modifies the Gibbs energy of activation by differential
solvation of reactants and the activated complex, consider-
ing that solvent averaging occurs in a sufficiently short time
to guarantee the absence of any heterogeneity.
Here, we report on the IL solvent effect on Menschutkin
reaction, i.e., the quaternization of a tertiary amine (N-
methylimidazole) by benzyl halides. The reaction is formally
an alkyl group transfer,9 a process of central importance in
biochemistry and a widely used strategy in organic synthesis; it
is the reaction generally used to prepare ILs. Numerous
physical organic studies have been conducted on the
Menschutkin reaction,10 and it is a useful test system for
theoretical methods.11 Moreover, a recent study by Neta
et al.12 on the kinetic behavior of the Menschutkin reaction of
1,2-dimethylimidazole with benzyl bromide has shown that the
reaction is moderately affected by the ionic medium, although
the process is characterized by an increase of charge on going
from reagents to the transition state (TS). This result is quite
surprising, especially if we consider that the monopolar charge
character of the constituent ions of ILs should lead to sub-
stantial solvation stabilization of the charged Menschutkin TS.
This paper investigates this behavior in more depth.
Results and Discussion
Effect of Solvent on Reaction Rate. The Menschutkin
substitution reaction of N-methylimidazole and benzyl
halides (Scheme 1) has been investigated in two molecular
solvents (acetonitrile and N,N-dimethylformamide) and four
ILs (1-butyl-1-methylpyrrolidinium bis(trifluoromethane-
sulfonyl)imide [bmpy][Tf2N], 1-butyl-3-methylimidazolium
bis(trifluoromethanesulfonyl)imide [bmim][Tf2N], 1-butyl-
2,3-dimethylimidazolium bis(trifluoromethanesulfonyl)imide
[bm2im][Tf2N], and 1-butyl-3-methylimidazolium hexafluoro-
phosphate [bmim][PF6]), each having different macro- and
microscopic physicochemical properties (Table 1).13
The kinetic measurements were carried out by following
the disappearance of the benzyl halides at selected wave-
lengths between 260 and 300 nm, well above the cutoff of the
ILs used as solvents (240 and 200 nm for imidazolium-based
and pyrrolidinium-based ILs, respectively). The experiments
were performed under pseudo-first-order conditions, using a
large excess of N-methylimidazole, in a temperature range
between 290 and 330 K. Kinetic data (absorbances vs time)
were fitted with the exponential eq 1:
AðtÞ ¼ Ainf þ ðA0 - Ainf Þ expð - kobstÞ
ð1Þ
where A(t) is the absorbance at time t, Ainf is the absorbance
at the final time, A0 is the absorbance at the initial time and
kobs is the observed rate constant.
Nucleophilic substitution reactions, occurring through
mono- and bimolecular processes (SN1 and SN2), are gen-
erally described by eq 2:
-d½substrateꢀ=dt ¼ ½substrateꢀ½k2½nucleophileꢀ þ k1ꢀ ð2Þ
However, under the pseudo-first-order conditions (large
excess of nucleophile) employed in this study, kobs may be
defined as
(5) Lopes, J. N. A.; Padua, A. A. H. J. Phys. Chem B 2006, 110, 3330.
Chiappe, C. Monatsh. Chem. 2007, 137, 1035. Xiao, D; Rajian, J. R.; Hines,
L. G.; Li, S.; Bartsch, R. A.; Quitevis, E. L. J. Phys. Chem B 2008, 112, 13316.
Consorti, C, S.; Suarez, P. A. Z.; de Souza, R. F.; Burrow, R. A.; Farrar, D.
H.; Lough, A. J.; Loh, W.; da Silva, L. H. M.; Dupont, J. J. Phys. Chem. B
2005, 109, 4341.
(6) Hu, Z.; Margulis, C. J. Proc. Natl. Acad. Sci. U.S.A. 2006, 103, 831.
(7) Mandal, P.; Sarkar, M.; Samanta, A. J. Phys. Chem. A 2004, 108,
9048.
(8) Shim, Y.; Jeong, D.; Manjari, S.; Choi, M. Y.; Kim, H. J Acc. Chem.
Res. 2007, 40, 1130. Jin, H.; Li, X.; Marocelli, M. J. Phys. Chem. B 2007, 111,
13473.
(9) Menschutkin, N. Z. Phys. Chem. 1890, 6, 41.
(10) Abbound, J. L. M.; Notario, R.; Bertran, J.; Sola, M. Prog. Phys.
Org. Chem. 1993, 19, 1.
kobs ¼ k2½nucleophileꢀ þ k1
ð3Þ
(13) (a) Wakai, C.; Oleinokova, A.; Ott, M.; Weingartner, H. J. Phys.
Chem. B 2005, 109, 17028. (b) Weingartner, H.; Sasisanker, P.; Daguenet, C.;
Dyson, P. J.; Krossing, I.; Slattery, J. M.; Schubert, T. J. Phys. Chem. B 2007,
111, 4775. (c) Reichardt, C. Green Chem. 2005, 7, 339. (d) Crowhurst, L.;
Mawdsley, P. R.; Perez-Arlandis, J. M.; Salter, P. A.; Welton, T. Phys. Chem.
Chem. Phys. 2003, 5, 2790. Angelini, G.; Chiappe, C.; De Maria, P.; Fontana,
F.; Gasparrini, D.; Pieraccini, D.; Pierini, M.; Siani, G. J. Org. Chem. 2005,
70, 8193. Kamlet, M. J.; Abboud, J.-L. M.; Abraham, M. H.; Taft, R. W.
J. Org. Chem. 1983, 48, 2877.
(11) Castejon, H.; Wiberg, K. B. J. Am. Chem. Soc. 1999, 121, 2139.
(12) Skrzypczak, A.; Neta, P. Int. J. Chem. Kinet. 2004, 36, 253.
J. Org. Chem. Vol. 74, No. 22, 2009 8523

Bini et al.
JOCArticle
SCHEME 1. Menschutkin Reaction between N-Methylimidazole and Benzyl Halides
where [nucleophile] is the molar concentration of N-methy-
limidazole ([NMI]), k2 is the rate constant of the bimolecular
reaction (SN2), and k1 is the rate constant of the mono-
molecular reaction, SN1. Shown in Figure 1 is a plot of kobs
versus [NMI] for the reaction of p-methoxybenzyl chloride in
[bm2im][Tf2N] at 333 K. Similar linear plots (R > 0.999)
were obtained for all investigated benzyl halides in ILs and
molecular solvents. In all of these plots, the intercept value
was always close to zero, evidence that the monomolecular
(SN1) contribution to the reaction mechanism could be
excluded. The second order rate constants, k2, determined
from the slope values are reported in Tables 2 and 3.
According to the data shown in Table 2, the reactivity scale
as a function of the leaving group follows the order BzI >
BzBr
. BzCl, both in molecular solvents and in
[bmim][Tf2N]. In contrast, BzBr is more reactive than BzI
in [bmim][PF6]. Furthermore, it is noteworthy that in the
case of benzyl iodide rate constants are higher in organic
solvents than in ILs, whereas the opposite trend charac-
terizes the reaction of benzyl chloride. On the other hand,
very similar rate constants were determined in all of the
investigated solvents in the case of benzyl bromide. A very
small solvent effect was also observed12 in the reaction of 1,2-
dimethylimidazole with benzyl bromide. Therefore,
although on the basis of the kinetic constants found for
benzyl iodide a trend qualitatively in agreement to the
Hughes-Ingold rules might be envisaged (i.e., reactivity
increases with increasing permittivity), this model is unable
to explain the reactivity of BzCl and BzBr.
TABLE 2. Second-Order Rate Constants for the Reaction between
N-Methylimidazole and Benzyl Halides in Molecular and Ionic Solvents
at 298 K
k2 ꢁ 104 (M-1 s-1
)
benzyl
iodide
benzyl
bromide
benzyl
chloride
solvent
acetonitrile
N,N-dimethylformamide
[bmim][Tf2N]
[bmim][PF6]
31.6 (0.2)
55.20 (0.2)
26.70 (0.5)
15.4 (0.4)
11.10 (0.2)
1.34 (0.02)
15.5 (0.5)
20.3 (0.4)
0.074 (0.005)
0.075 (0.005)
0.146 (0.005)
0.236 (0.005)
To obtain more information about the ability of the ionic
media to affect reactivity in the Menschutkin reaction, the
kinetic behavior of the reaction of benzyl chloride was investi-
gated in two other ILs, [bm2im][Tf2N] and [bmpyrr][Tf2N],
FIGURE 1. Plot of kobs against [NMI] for the reactions of
p-methoxybenzyl chloride and NMI in [bm2im][Tf2N] at 333 K.
8524 J. Org. Chem. Vol. 74, No. 22, 2009

Bini et al.
JOCArticle
TABLE 3. Second-Order Rate Constants for the Reaction between N-Methylimidazole and Various Substituted Benzyl Chlorides in Various Solvents at 333 K
k2 ꢁ 104 (M-1 s-1 a
)
solvents
acetonitrile
N,N-dimethylformamide
[bmim][Tf2N]
[bmim][PF6]
H
p-MeO
m-MeO
0.99
1.18
1.98
3.96
p-Me
m-Me
1.48
1.04
2.98
5.06
p-Cl
m-Br
0.97
1.52
2.44
3.64
2.18
3.77
2.92
2.54
11.9
16.8
7.37
5.04
1.38
1.51
5.30
6.53
2.87
2.74
1.07
1.31
1.85
3.92
1.15
1.45
1.66
4.79
[bm2im][Tf2N]
[bmpyrr][Tf2N]
no reaction
no reaction
2.35
no reaction
aStandard deviations were always less than 10%.
each having a different hydrogen bond donor acidity, R.
Furthermore, we checked the kinetic effects arising from the
introduction of electron-withdrawing or -donating substitu-
ents (EWS or EDS) on the benzylic moiety in the meta and
para positions. Due to the low reactivity of benzyl chlorides
bearing EWS these latter kinetic measurements were carried
out at 333 K (Table 3).
In all cases, reactivity increases on going from molecular
solvents to ILs. This behavior is however more evident for
benzyl chlorides bearing EDS in a para position, whose
reactivity significantly increases in the ILs having the higher
hydrogen bond acidity, R. Fairly good linear relationships
(R2 > 0.99, in both cases) have been obtained plotting
the logk2 values found for p-methoxybenzyl chloride or
p-methylbenzyl chloride against the R parameter. In con-
trast, attempts to correlate the kinetic constants of the
unsubstituted benzyl chloride to R or any other solvent
properties using single parameter relationships gave always
poor correlations. Therefore, the solvent dependent property
logk2 was modeled applying a multiparameter relationship
(LSER)14 of the type of eq 4, using different combinations of
the parameters reported in Table 1:
R values. In contrast, the regression indicates that an increase
in the β and δ parameters decreases reactivity. This behavior
can be explained by considering that in ILs the possibility for
cations or anions to interact with a solute is always in
competition with the cation-anion interactions present in
the bulk ILs. Since, the hydrogen bond acceptor property of
ILs is mainly related to the anion, ILs having higher values of
β are characterized by stronger cation anion interactions;
this feature reduce the ability of IL components (cations and/
or anions) to interact with dissolved species.
Effect of Substituents on Reaction Rate. Important infor-
mation about the mechanism of this reaction in ILs has been
obtained also by analyzing the kinetic data of substituted
benzyl chlorides through the application of the Hammett
correlation, described by eq 5:15
k
ð5Þ
log
¼ σF
k0
Here, k0 is the rate constant of the reference reaction (i.e., the
reaction of benzyl chloride (X = H)), σrepresents the electronic
effect of the substituent on the reaction rate, and F is the
sensitivity of the reaction toward the substituent change. Gen-
erally, the magnitude of F is related to the extent of the charge
density in the transition state and whether the activated com-
plex has anionic or cationic character. Briefly, F< 0 means that
the activated complex bears a partial positive charge and F > 0
a negative one. Hammett plots for the reaction between NMI
with benzyl chlorides in two organic solvents and two ILs at
333 K are reported in Figure 2. Poor linear correlations have
been found both in organic solvents and ILs. On the other
hand, attempts to correlate the rate constants with σþ para-
meters gave even poorer correlations.
Although to the best of our knowledge Hammett correla-
tions have never been reported for reactions in ILs, nonlinear
or bent plots have been obtained16 for many organic reactions
in molecular solvents. Generally, this behavior is attributed to
variations in the rate-determining step17 and, in the specific
case of the Menschutkin reaction, to shifts in the TS position.
Although the distinction between monomolecular (SN1)
and bimolecular (SN2) mechanisms for nucleophilic substi-
tution reactions has represented starting from the work
of Ingold18 a milestone in the development of organic
ꢂ
log k2 ¼ const þ aR þ bβ þ cπ þ dδ?ꢃ > δ þ eε þ::: ð4Þ
The best fit (R2 = 0.997, F-term = 71) was obtained by a
combination of R, β, π* and δ:
log k2 ¼ - 1:24ð0:42Þ þ 0:44ð0:15ÞR
ꢂ
- 2:62ð0:3Þβ þ 0:64ð0:21Þπ - 0:10ð0:01Þδ
Although the limited number of data (six kinetic
constants) compared with the number of used parameters
(four) reduces the validity of the procedure and the error
associated with each parameter is quite high (in particular in
the case of R and π*), we believe that some considerations are
feasible. Parameters β and δ appear as the most significant.
However, since attempts to fit the experimental data using
just these two parameters gave a very poor correlation (R2 =
0.782, F-term = 5), also R and π* play a not negligible role.
Considering that the coefficients of R and π* are positive, the
correlation suggests that an increase in polarizability/dipo-
larity and in the hydrogen-bond donating ability of the
solvent (this latter property primarily due to the IL cation)13
increase the rate of the reaction. This may be rationalized by
considering that both of these parameters may favor the
departure of the leaving group (in this case a chloride anion).
This effect surmounts the attenuation of the nucleophilicity
of the amine (NMI) due to the hydrogen bonding ability of
the solvent, a behavior already observed in ILs having large
(15) Anslyn, E. V.; Dougherty, D. A. Modern Physical Organic Chem-
istry, 1st ed.; University Science Books: Sausalito, CA, 2006. Wakai, C.;
€
Oleinikova, A.; Ott, M; Weingartner, H. J. Phys. Chem. B 2005, 109, 17028.
(16) Carroll F. A. Structure and Mechanism in Organic Chemistry;
Brooks/Cole Publishing Company: Pacific Grove, CA, 1998.
(17) Hill, J. W.; Fry, A J. Am. Chem. Soc. 1962, 84, 2763. Lim, C.; Kim,
S. H.; Yoh, D.-D.; Fujio, M.; Tsuno, Y Tetrahedron Lett. 1997, 38, 3243. Lee,
I.; Koo, S. Tetrahedron 1983, 39, 1803.
(14) Kamlet, M. J.; Abboud, J. L. M.; Abraham, M. H.; Taft, R. W.
J. Org. Chem. 1983, 48, 2877.
(18) Ingold, C. K. Structure and Mechanism in Organic Chemistry, 2nd
ed.; Cornell University Press: Ithaca, 1969.
J. Org. Chem. Vol. 74, No. 22, 2009 8525

Bini et al.
JOCArticle
those obtained in molecular solvents. In acetonitrile and
[bmim][PF6] the Hammett plots are composites of two
straight lines; a linear correlation with negative slope
(F < 0) can be found in the EDS range, while in the region
of EWS the slope is positive. This means that, whereas a
partial positive charge characterizes the activated complex
when electron donating substituents are present (i.e., break-
ing of the C-Cl bond is faster than the C-Nu formation),
with electron-withdrawing substituents the TS has a negative
character. In [bmim][Tf2N], the two straight lines have
always negative slope and the behavior can be rationalized
by considering that in going from EWS to EDS the breaking
of the C-Cl bond becomes significantly faster than C-Nu
bond formation and the activated complex acquires a higher
partial positive charge.
Analysis of this latter data, considering the solvent effects
emerging by the LSER approach, shows that in the presence
of electron-donating substituents, which are able to support
a positive charge at the carbon reaction center, the departure
of the chloride ion precedes the bond formation. The me-
chanism is a loose SN2 and the hydrogen bond donor ability
of the IL becomes the main factor affecting the reaction rate.
On the other hand, in the presence of electron-withdrawing
substituents (or of a hydrogen atom), development of the
positive charge is disfavored and the reaction occurs through
TSs having a more symmetric character and the solvation
effect is more complicated; a combination of effects must be
considered to obtain a fairly good correlation.
FIGURE 2. Hammett plots for the reaction between NMI and
benzyl chlorides in organic solvents and ionic liquids at 333 K.
FIGURE 3. Transition state of a pure SN2 mechanism.
Theoretical Calculations. To better define the role of
the solvent on the reaction profile of benzyl chloride with
N-methylimidazole, a theoretical investigation has also been
performed. Unfortunately, the effects of ionic liquids on
chemical reactions have not been rationalized enough to
allow the development of a computational model that takes
account of them efficiently and with a limited computational
effort. In the past years several molecular dynamic studies,
both classical and ab initio, of ILs have been performed.20 In
the specific case of the study of a chemical reaction, pure
classical methods are not feasible because of the intrinsic
quantum nature of chemical bond formation/breaking pro-
cesses. We chose to use the supermolecular approach,21
including one or more ions in a model system. This is less
computationally expensive than an ab initio molecular
dynamics study and allows us to focus our attention on
specific solute-solvent interactions. Using this approach,
the Menschutkin reaction represents a unique situation since
two neutral reagents lead to two ionic species: a chloride
anion and an imidazolium cation. In the simplest neutral
supermolecular approach, one ion pair representing the
solvent phase and two neutral molecules that can form an
additional ion pair are included in the model.
chemistry, generally accepted is the existence of a continuous
spectrum of mechanisms between SN2 and SN1, as well as
between SN2 and SNAr, arising from the progressive vari-
ation of the extent of bond formation and bond breaking at
the carbon reaction center of the TS.19,20
On this basis, the pure SN2 mechanism represents a limit-
ing situation characterized by a symmetric TS, i.e., bond
breaking and making are simultaneous processes (Figure 3).
This TS has a low charge density on the carbon reaction
center, and the Hammett plots of reactions occurring
through pure SN2 mechanisms are generally straight lines
with very low slopes, giving consequently low values of F.
A shift of the mechanism toward SN1 or SNAr determines an
increase of the asymmetric character of the TS. In particular,
when bond formation is faster than bond breaking, the
mechanism is still bimolecular but it resembles a SNAr
reaction, occurring through the formation of a carbanionic
intermediate; this mechanism is called tight SN2 and the
corresponding Hammett plots are characterized by positive
F values. On the other hand, if the bond breaking is antici-
pated with respect to the bond formation, the mechanism
is called loose SN2 and the Hammett plots give negative
F values. A shift of the mechanism from tight SN2 to loose
SN2 on going from EWS to EDS might therefore be the
origin of the nonlinear Hammett plots found in the present
study. It is, however, noteworthy that the behavior and slope
of the plots related to the reactions in ILs are different from
The computational study of the Menshutkin reaction
between benzyl chloride and N-methylimidazole was there-
fore performed in vacuo, in 1,2-dichloroethane (DCE, a
classic molecular solvent having a dielectric constant similar
to many ILs) and with an explicit ionic pair, 1-butylimida-
zolium hexafluorophosphate ([Hbim][PF6]). In all of the
investigated situations, a scan along the natural reaction
(19) Richard, J. P.; Jencks, W. P. J. Am. Chem. Soc. 1984, 106, 1383.
Bentley, T. W.; Schleyer, P. v. R J. Am. Chem. Soc. 1976, 98, 7667. Bentley,
T. W.; Schleyer, P. v. R; Bowen, C. T.; Morten, D. H.; Schleyer, P. v. R J. Am.
Chem. Soc. 1981, 103, 5466.
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1193. Del Popolo, M.G. ; Kohanoff, J.; Lynden-Bell, R. M.; Pinilla, C. Acc.
Chem. Res. 2007, 40, 1156.
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Comput. 2007, 3, 132. Bini, R.; Chiappe, C.; Lloplis Mestre, V.; Pomelli,
C. S.; Welton, T. Theor. Chem. Acc. 2009, 113, 347.
8526 J. Org. Chem. Vol. 74, No. 22, 2009

Bini et al.
JOCArticle
TABLE 4. Energetic Values for Reaction Paths Calculated at the
B3LYP/CEP-121G(d,p) Level
relative energies (kcal/mol)
˚
RC-N (A)
vacuo
DCE
IP low
IP high
1.50
a
7.97
16.11
28.09
-5.11
3.67
16.81
-15.47
-5.18
10.67
13.04
12.59
-2.37
8.14
23.14
1.75
2.00
2.18
2.25
2.45
2.50
2.75
2.80
2.98
3.00
3.25
3.50
3.75
4.00
4.25
b
b
b
36.33
26.15
34.37
40.38
7.48
41.21
44.18
44.82
31.82
35.40
7.48
3.77
3.77
b
38.54
37.89
0.09
-0.29
-0.19
-0.07
0.00
2.13
0.01
-0.43
-0.35
-0.17
0.00
2.05
1.00
0.39
0.28
0.04
0.00
2.05
1.00
0.39
0.28
0.04
0.00
FIGURE 4. Relaxed scans versus the C-N distance.
aAbsolute minimum, the RC-N values differ at the 3rd digit. bTransi-
tion states. An extended version of this table complete with absolute
energies is available in Supporting Information.
structure of the product in DCE and optimizing the result-
ing system. The imidazolium cation docked with the chlor-
ide anion, interacting with the C2 proton and with the butyl
group hydrogens. This structure is similar to others found
for a similar study involving the Diels-Alder reaction and
is one of the structures found by Hunt et Al for the BMIM-
Cl ionic pair24 docking.
coordinate, defined as the distance between the N-methyli-
midazole nitrogen and the benzylic carbon (RC-N), was
performed. The standard choice of the infinite distance
between the reagents as the reference state is not well-defined
in this case. In particular, in the supermolecular system there
is not a defined geometry at infinite distance. However, the
Then, the ion pair anion ([PF6]-) was added. [PF6]- does
not represent a chemical moiety (like hydrogens on a charged
heteroaromatic ring for [Hbim]þ) able to establish a direc-
tional interaction with the cation þ products system; the
main interaction is electrostatic. If we first place [PF6]- near
[Hbim]þ and then near the positive charged product, two
stationary points are found as shown in Figure 5. We stress
that this procedure is not exhaustive but is based on a
combination of chemical and electrostatic common sense.
The structure on the left is energetically less stable and
looks like two ionic pairs ([Hbim]Cl and [PF6]--product).
The structure on the right is more stable and looks like four
ions in a quadrilateral arrangement with alternating charges.
Both of these structures have been taken as starting points
for the relaxed scans. We refer to the corresponding path-
ways as IP-high path and IP-low path, with high and low
related to the relative energetic stability. All of the four
transition states were characterized with normal mode cal-
culations. Transition vectors are represented graphically in
Figure 6 and reported in Supporting Information.
˚
computational results show that at a RC-N distance of 4.25 A
all the reaction profiles are flat. Consequently, we decided to
take this distance as the zero reference for the energy. In
DCE, we used the continuum model IEFPCM with default
parameters. All calculations were performed using the
Gaussian 03 suite of programs,22 at B3LYP/CEP-121G(d,p)
theory level. Several of the authors have successfully used this
level of theory in previous work examining chemical reactivity
in ionic liquids and in other contexts.23
The results are reported in Table 4 and graphically repre-
sented in Figure 4.
For the reactions performed in vacuo and in DCE we
started from the product with a nearby chloride ion. Start-
ing from the product structure a relaxed scan was per-
˚
formed until the value of RC-N = 4.25 A was reached.
The top point of each curve was taken as the starting point
for a transition state structure optimization. In the model
system containing an explicit ionic pair (IP), the super-
molecule structure was obtained adding [Hbim]þ at the
A first analysis of digits and curves shapes (Figure 4)
shows that in vacuo, in DCE, and in the IP-high paths a
similar behavior can be evidenced: a flat tail on the right, a
rapid slope up to the TS (the relative energies of the TS
structures are 44.86, 38.54, and 40.38 kcal/mol, respectively)
followed by a less rapid slope down from the TS to the
products. The larger difference between the three reactions
is in the reaction coordinate value of the transition states
(22) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb,
M. A. Cheeseman, J. R.; Montgomery, J. A., Jr.; Vreven, T.; Kudin, K. N.;
Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci,
B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji, H.; Hada,
M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima,
T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.;
Hratchian, H. P.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.;
Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.;
Pomelli, C.; Ochterski J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G. A.;
Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels, A.
D.; Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.; Raghavachari,
K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.; Clifford, S.;
Cioslowski. J.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi,
I.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.;
Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.; Johnson, B.; Chen, W.;
Wong, M. W.; Gonzalez, C.; Pople, J. A. Gaussian03, RevisionC.02; Gaussian,
Inc.: Wallingford, 2004.
˚
that are 2.80, 2.98, and 2.45 A, respectively. In contrast, the
IP-low path has a TS with a relative energy of 13.04 kcal/mol
˚
and a reaction coordinate of 2.18 A. A visual inspection of
the transition state geometries, reported in Figure 6, con-
firms the similarities of the first three structures and the
diversity of the fourth one, related to the IP-low path. The
IP-low path TS is the only one that shows a linear structure
(23) Chiappe, C.; De Rubertis, A.; Jaber, A.; Lenoir, D.; Wattenbach, C.;
Pomelli, C. S. J. Org. Chem. 2002, 67, 7066. Chiappe, C.; Detert, H.; Lenoir,
D.; Pomelli, C. S.; Ruasse, M.-F. J. Am. Chem. Soc. 2003, 125, 2864.
(24) Hunt, P.; Kirchner, B.; Welton, T. Chem.;Eur. J. 2006, 12, 6762.
J. Org. Chem. Vol. 74, No. 22, 2009 8527

Bini et al.
JOCArticle
FIGURE 5. Two conformations found for the reaction product with an ionic pair. The structure on the left is the IP-high path, and that on the
right is the IP-low path.
TABLE 5. Natural Atomic Charges Condensed to Significative Frag-
ments of the Supermolecular System in the Various Reaction Paths
interactions: chloride atom interacts with both reagents and
the cationic moiety of the product. In the TSs related to the
reaction in vacuo and in DCE, chloride finds its minimum
energy position between the two reagents. However, we
maintain that the bent mechanism is strongly determined
by the reagent’s nature and reaction conditions (selected
medium). In agreement with this statement, recent calcula-
tions on the Menschutkin reaction between 2-amino-
1-methylbenzylimidazole and iodomethane report25 the
expected linear transition state. Surely, the larger and more
polarizable iodide stabilizes the negative charge better than
chloride and consequently reduces the necessity to find
intrinsic stabilization by interacting with the developing
positive charge. Moreover, the interaction between iodide
and the imidazolium cation is weaker than that of chloride
with the same cation, as evidenced ESI-MS measurements.26
Related to the solvent, although in both cases the same
continuum solvent model has been used, in the more polar
solvent (CH3CN) ion pair dissociation is favored. Finally, it
is noteworthy that in the reaction of 2-amino-1-methylben-
zimidazole with iodomethane, the higher basicity of the
nucleophile (a primary amine instead of an aromatic tertiary
amine) and the lower steric requirements of the electrophile
(a methyl derivative) might aid the more synchronous pathway.
Related to the effect of the ion pair on the reaction path-
way, both the IP-high and IP-low TSs have the developing
chloride coordinated to [Hbim]þ cation. This can be con-
sidered the primary effect of the presence of the ionic liquid
on this reaction: it is able to transform an anionic leaving
group (chloride) in an ion pair leaving group ([Hbim]Cl). The
interaction of the IL cation with the leaving group does not
necessarily affect the reaction pathway, the energetic and
IP-low IP-high
path
fragment
geometry
reference
vacuo
DCE
path
Cl-
-0.150 -0.165 -0.203 -0.203
transition state -0.740 -0.839 -0.635 -0.848
product
reference
transition state
product
-0.870 -0.928 -0.881 -0.868
þ
Φ-CH2
0.147
0.687
0.307
0.003
0.053
0.563
0.161
0.811
0.614
0.209
0.440
0.311
0.209
0.706
0.305
methylimidazole reference
transition state
product
0.004 -0.003 -0.003
0.028
0.314
0.226
0.620
0.932
0.910
0.898
0.227
0.630
0.932
0.884
0.898
HBIM
reference
transition state
product
reference
transition state
product
-
PF6
-0.935 -0.935
-0.941 -0.969
-0.948 -0.964
expected for a typical SN2 reaction: the Cl-C-N angle is of
161.4°. Furthermore the IP-low transition vector is the only
in which the chlorine atom is appreciably involved.
In the other reaction pathways angles are 100.1° for the IP-
high path, 84.9° for the reaction in vacuo, and 88.1° for the
reaction in DCE. Furthermore, the natural bond orbital
(NBO) population analysis reported in Table 5 shows that
the charge separation process is less extended in the IP-low
TS than in the other cases, in agreement with a more
synchronous SN2 reaction. It is noteworthy that any attempt
to find linear or nearly linear TSs for the reactions in vacuo
and in DCE led directly to the angular structures reported in
Figure 6. On the other hand, the atypical nonlinear TS and
the propensity of those systems to give the angular structure
may be considered a consequence of the nature of the
product; imidazolium cation and a chloride anion surely
do not easily form in vacuo and in low polar solvents.
The pathways with a bent TS allow the developing
charged species to find stabilization through electrostatic
(25) Melo, A.; Alfaia, A. J. I.; Reis, J. C. R.; Calado, A. R. T. J. Phys.
Chem. B 2006, 110, 1877.
(26) Fernandes, A. M.; Coutinho, J. A. P.; Marrucho, I. M. J. Mass
Spectrosc. 2008, 44, 144. Bini, R.; Bortolini, O.; Chiappe, C.; Pieraccini, D.;
Siciliano, T. J. Phys. Chem. B 2007, 111, 598.
8528 J. Org. Chem. Vol. 74, No. 22, 2009

Bini et al.
JOCArticle
FIGURE 6. Similar bent TS structures found in vacuo (top left), in DCE (top right) and IP high-paths (middle). A different, nearly linear
arrangement is found in the case of the IP high-path (bottom). The transition vectors are represented by arrows (phase and scale are arbitrary).
The vector values are reported in Supporting Information.
geometry of the IP-high path is similar to those found for
the two non-IP paths (i.e., vacuo and DCE). However,
depending on the disposition of both the cation and anion
with respect to the reagents, this interaction allows the leaving
chloride to maintain a quasi-aligned position with respect to
the formed C-N bond, reducing the TS energy. Furthermore,
the dipole orientation of the IP facilitates the charge-separa-
tion process. In the less favorable orientation (IP-high TS) the
chloride-product interaction is weaker but not negligible: the
Cl-C-N angle is about 10° larger than in non-IP TSs.
In our model system we have considered only two possible
dispositions of the IP representing the IL, but the real liquid
J. Org. Chem. Vol. 74, No. 22, 2009 8529

Bini et al.
JOCArticle
consists in a large number of ions. Moreover, considering
the inhomogeneous nature of ILs on the short time scale
(Kerr effects suggest27 an anion position change on the order
of picoseconds) it is possible to hypothesize that inside the
bulk liquid the two reagents are in contact with different
solvation cages and the reaction can take place or not,
depending on the relative disposition of the ionic liquid
anions and cations with respect to reagents. The two situa-
tions reported here represent a more favorable and a less-
favorable disposition of the cybotactic region around the
reagents but we cannot claim that they represent the sole
situations or the limiting situations. Probably, there are
several possible reaction pathways for this reaction in ILs
having different, but not extremely different, TS energies. A
thermodynamic description of the transition state complex
would require bond equilibrium to prorogate through both
the IL and reactants during the lifetime of the transition
state; but, IL conformational changes are slow. Conse-
quently, thermodynamic equilibrium cannot occur at the
transition state. However, IL cations and anions are present
around the substrates before reaching the transition state
and they remain close during the lifetime of the transition
state. The dynamic motion of linked regions of the IL might
transfer vibrational energy into the reacting system, favoring
the appropriate alignment of reagents in a precomplex
having the proper reagent disposition. On this assumption,
the Menschutkin reaction of benzyl chloride with N-methy-
limidazole in ILs should be more realistically discussed in
terms of multiple reaction pathways ranging from the classi-
cal synchronous SN2 process to less concerted bent pathways
with the overall reaction rate being the average of the
reaction constants defining these processes.
this parameter: an unusual bent asynchronous SN2 mechan-
ism (found also in vacuo and DCE) and a quasi-linear
synchronous mechanism. Considering the inhomogeneous
nature of ILs on the short time scale (that of a TS), it is
possible to hypothesize that inside bulk liquid the two
reagents are in contact with different solvation cages and
the reaction can proceed through different reaction path-
ways. The overall reaction rate becomes the average of the
reaction rates of the single processes. The term “transition
state stabilization” that has fostered the idea that an energy-
equilibrated transition state exists cannot be used and “rea-
listic IL transition states” might more appropriately be
expressed in terms of statistical dynamic probabilities rather
than thermodynamic expressions.
Experimental Section
Materials. Benzyl halides and substituted benzyl halides were
purchased from commercial sources and used as received.
N-Methylimidazole was dried and distilled over KOH under
vacuum. Ionic liquids were synthetised using standard procedure
and were dried under vacuum for 6 h at 80 °C before use. Organic
solvents were purified and dried using standard procedures.
Kinetic Procedure. The Menschutkin reaction between
N-methylimidazole and benzyl halides were carried out under
pseudo-first-order conditions using an excess of N-methylimi-
dazole (by a factor of 10 up to 100). All reactions were
monitored within 0.1 mm quartz cuvettes using an UV-vis
spectrometer following the decrease of absorbance of benzyl
halides at appropriate wavelengths (normally 260-300 nm). In
a typical experiment, a concentrated solution of benzyl halide
was prepared in a 5 mL calibrated flask using CH2Cl2 as solvent.
A proper amount of N-methylimidazole (exactly weighted) was
added to 1 mL of the solvent, pre-thermostatted at the appro-
priate temperature ((0.1 K) for 10 min, in a calibrated flask, and
the solution was mixed manually until homogeneous. Then,
50 μL of the concentrated solution of benzyl halide was added
and the solution was rapidly transferred to the quartz cell. The
kinetic data (absorbance/time) were fit to eq 1, and the obtained
Conclusions
In conclusion, the data reported here demosntrate that
although the Menschutkin reaction gives ionic species start-
ing from neutral compounds, the effect of the ionic environ-
ment is moderate. The reaction occurs in ILs as in molecular
solvents by the expected bimolecular mechanism and an
increase in reactivity going from aprotic polar solvents to
ILs can be evidenced only with benzyl chlorides. By applying
the Kamlet-Taft LSER approach to the kinetic data found
for benzyl chlorides bearing EDS, it is possible to attribute
this effect mainly to the ability of the IL to favor the chloride
departure acting as hydrogen bond donor. On the other
hand, the nonlinearity of the Hammett correlations suggest
that on going from EWS to EDS the reaction mechanism
changes from a pure SN2 to a loose SN2 mechanism, i.e., to a
mechanism having a higher SN1 character, and C-Cl bond
breaking is faster that C-N bond making.
k
obs were plotted against the molar concentrations of N-methy-
limidazole in order to find the second order rate constants k2,
which are reported in Tables 2 and 3. In selected reactions,
products were identified by ESI-MS.
Theoretical Calculations. All calculations was performed using
the Gaussian 03 suite22 (C.02 release) on the argo linux cluster of
our department. The cluster is composed of number crunching
servers based on Supermicro superserver barebones (6015 series)
and Intel Xeon quad-core processors (54XX series). All servers
are equipped with Kingston ECC RAM (certified for the mother-
board) and Seagate (Barracuda 7200 series) SATA2 Hard Disks .
The Linux version is CentOS 5.2.
Acknowledgment. The authors would like to thank the
University of Pisa for the financial support.
Finally, calculations performed using a model system in
which the IL is represented by an explicit ionic pair (IP)
confirms the primary role of the IL cation in the departure of
the leaving group; however, the effect depends on the relative
position of the IP with respect to the reagents. Two possible
different reaction pathways have been obtained changing
Supporting Information Available: An extended version
of Table 4 containing absolute energies, a table containing
some geometrical quantities about the calculated structures,
transition vectors for the four transition states reported in
the paper (excerpts from Gaussian outputs), and molecular
coordinates for all the structure reported in XYZ format. This
material is available free of charge via the Internet at http://
pubs.acs.org.
(27) Cang, H.; Li, J.; Fayer, M. D. J. Chem. Phys. 2003, 119, 13017.
8530 J. Org. Chem. Vol. 74, No. 22, 2009