Evidence of a borderline region between E1cb and E2 elimination reaction mechanisms: A combined experimental and theoretical study of systems activated by the pyridine ring

Article abstract of DOI:10.1021/ja0539138

We report a combined experimental and theoretical study to characterize the mechanism of base-induced β-elimination reactions in systems activated by the pyridyl ring, with halogen leaving groups. The systems investigated represent borderline cases, where it is uncertain whether the reaction proceeds via a carbanion intermediate (E1cb, A_xhD_H + D_N) or via the concerted loss of a proton and the halide (E2, A_ND _ED_N) upon base attack. Experimentally, the Taft correlation for H/D exchange, in OD^-/D₂O with noneliminating substrates (1-methyl-2-(2-Xethyl)pyridinium iodide), is used to predict the expected values of the rate constants for the elimination reactions with N-methylated substrates and F, Cl, Br as the leaving group. The comparison indicates an E1cb irreversible mechanism with F, but the deviation observed with Cl and Br does not allow a conclusive assignment. The theoretical calculations show that for the N-methylated substrate with a fluoride leaving group the elimination proceeds via formation of a moderately stable carbanion. No stable anionic intermediate is instead found when the leaving group is Cl or Br, as well as for any of the nonmethylated species, indicating a concerted elimination. The methylated substrate with Cl shows however only a moderate increase in reactivity compared to the fluorinated substrate, despite the change in mechanism. Very interestingly, our analysis of the computed two-dimensional potential energy surface for the reaction with a F leaving group indeed evidences the lack of a net distinction between the E1cb and E2 reaction paths, which appear to merge smoothly into each other in these borderline cases.

Full text of DOI:10.1021/ja0539138

Published on Web 10/11/2005
Evidence of a Borderline Region between E1cb and E2
Elimination Reaction Mechanisms: A Combined Experimental
and Theoretical Study of Systems Activated by the
Pyridine Ring
Sergio Alunni,*,† Filippo De Angelis,*,‡ Laura Ottavi,† Magdalini Papavasileiou,† and
Francesco Tarantelli†,‡
Contribution from the Dipartimento di Chimica, UniVersita` di Perugia, Via Elce di Sotto 8,
I-06213, Perugia, Italy, and Istituto CNR di Scienze e Tecnologie Molecolari (ISTM), c/o
Dipartimento di Chimica, UniVersita` di Perugia, Via elce di Sotto 8, I-06213, Perugia, Italy
Received June 14, 2005; E-mail: alunnis@unipg.it; filippo@thch.unipg.it
Abstract: We report a combined experimental and theoretical study to characterize the mechanism of
base-induced â-elimination reactions in systems activated by the pyridyl ring, with halogen leaving groups.
The systems investigated represent borderline cases, where it is uncertain whether the reaction proceeds
via a carbanion intermediate (E1cb, AxhDH + DN) or via the concerted loss of a proton and the halide (E2,
ANDEDN) upon base attack. Experimentally, the Taft correlation for H/D exchange, in OD-/D2O with
noneliminating substrates (1-methyl-2-(2-Xethyl)pyridinium iodide), is used to predict the expected values
of the rate constants for the elimination reactions with N-methylated substrates and F, Cl, Br as the leaving
group. The comparison indicates an E1cb irreversible mechanism with F, but the deviation observed with
Cl and Br does not allow a conclusive assignment. The theoretical calculations show that for the N-methylated
substrate with a fluoride leaving group the elimination proceeds via formation of a moderately stable
carbanion. No stable anionic intermediate is instead found when the leaving group is Cl or Br, as well as
for any of the nonmethylated species, indicating a concerted elimination. The methylated substrate with Cl
shows however only a moderate increase in reactivity compared to the fluorinated substrate, despite the
change in mechanism. Very interestingly, our analysis of the computed two-dimensional potential energy
surface for the reaction with a F leaving group indeed evidences the lack of a net distinction between the
E1cb and E2 reaction paths, which appear to merge smoothly into each other in these borderline cases.
Introduction
obviously important aspect of this problem is establishing
whether there is smooth continuity or distinct discontinuity
between the E2 concerted and the E1cb stepwise mechanisms.
The distinction between the E2 concerted process (AxhDHDN)
and the E1cb irreversible mechanism (AxhDH* + DN) is a
difficult task.1,5,15 In fact, while the E1cb reversible mechanism
Base-induced â-elimination reactions, with formation of a
carbon-carbon double bond, are one of the most fundamental
chemical reactions and of recognized importance in the under-
standing of the mechanisms with which they take place in
different substrates and solution environments. In particular,
being able to distinguish between concerted and stepwise
mechanisms is a very relevant issue in both chemistry1-13 and
biochemistry.14 However, the nature of the borderline between
concerted and stepwise mechanisms is yet unclear,5,15 and an
(5) (a) More O’Ferrall, R. A.; Warren, P. J. J. Chem. Soc., Chem. Comun.
1975, 483. (b) More O’Ferrall, R. A.; Warren, P. J.; Ward, P. M. Acta
UniVersity Uppsol., Symp. UniVersity Uppsol. 1978, 12, 209.
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2 1982, 1573.
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† Dipartimento di Chimica.
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‡ Istituto CNR di Scienze e Tecnologie Molecolari (ISTM).
(1) (a) Saunders, W. H., Jr.; Cockerill, A. F. Mechanism of Elimination
Reaction; Wiley-Interscience Publication: New York, 1973; Vol. II, pp
60-68. (b) Baciocchi, E. The Chemistry of Halides, Pseudo Halides and
Azides, Supplement D; Patai, S., Rappoport, Z., Eds.; Wiley: Chichester,
UK; 1983. (c) Gandler, J. R. The Chemistry of Double Bonded Functional
Group; Patai, S., Eds.; Wiley: Chichester, UK, 1989. (d) Saunders, W.
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1979, 12, 198. (f) Cavestri, R. C.; Fedor, L. R. J. Am. Chem. Soc. 1970,
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Trans. 2 1977, 1914.
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Chem. Soc. 1995, 117, 9399.
9
10.1021/ja0539138 CCC: $30.25 © 2005 American Chemical Society
J. AM. CHEM. SOC. 2005, 127, 15151-15160
15151

A R T I C L E S
Scheme 1
Alunni et al.
Scheme 2
1
(AxhDH + DN*) can be revealed by the presence of H/D
exchange,16 by studies of acid-base catalysis16 and by the
inverse solvent isotope effect,16b,17 the E2 mechanism shows
many of the same characteristics of an E1cb irreversible
mechanism. In previous studies16a,17-20 of â-elimination reac-
tions in systems activated by the pyridine ring, we have reported
a high value of the Proton Activating Factor, PAF, defined as
the ratio of the second-order rate constant for the nitrogen
protonated substrate, NH+, and that for the unprotonated
Scheme 3
Density Functional Theory (DFT) calculations. More recently,
the CH3CH2F substrate has been the subject of extensive
theoretical investigations based on ab initio molecular dynamics
simulations in the gas phase,26 aimed at providing a detailed
description of the free-energy landscape for the competing
elimination/substitution reactions.
+
substrate, N (PAF ) kNH /kN). The value found with 2-(2-
fluoroethyl)pyridine19 is PAF ) 3.6 × 10 5 (acetohydroxamate
base, 50 °C, µ ) 1 M KCl), whereas with N-[2-(2-pyridyl)-
ethyl]quinuclidinium PAF is 5.2 × 10.5 The high values of PAF
observed were interpreted in terms of an E1cb mechanism and
a strongly resonance-stabilized intermediate carbanion; see
Scheme 1.
In this paper we report the results of a combined experimental
and theoretical study, based on DFT calculations in solution,
aimed at understanding some important aspects of the borderline
region between E1cb and E2 reaction mechanisms in systems
activated by the pyridine ring. We have studied 2-(2-fluoroet-
hyl)pyridine and its chlorine and bromine analogues, with and
without methyl activation at the nitrogen. Work is in progress
to investigate the related elimination reactions for the isomers
with the ethyl moiety in position 3 and 4.
Activation by methylation19,20 of the N atom of the pyridine
ring is also strong, similar to protonation. However, several
uncertainties remain about the â-elimination in these borderline
systems. The reaction mechanism itself has not yet been
determined with certainty, nor has it been ascertained whether
a change of mechanism takes place with different X leaving
groups or upon going from the unprotonated to the protonated
substrate. There are several biological processes where the effect
of stabilization of a carbanion by a quaternized nitrogen atom,
part of a heteroaromatic system, is important. One example14
is the mechanism of action of a cofactor related to the B6
vitamin, the pyridoxal phosphate. In this system, the protonated
pyridine ring provides the necessary stabilization of the inter-
mediate carbanion formed in the elimination, transamination,
decarboxylation, and racemization reactions involving this
cofactor in the amino acids metabolism. Another14 example is
the chemistry of thiamine pyrophosphate, where the carbanion
formed in the decarboxylation of R-chetoacids presents an
enamine-type structure. Also the enzymatic â-elimination reac-
tion of ammonia from L-histidine, catalyzed by Histidine
Ammonia-Lyase, is proposed to occur by an E1cb mechanism
with activation provided by the nitrogen-protonated imidazole
ring.21
Result and Discussion
Experimental Study. Second-order rate constants, kOD, M-1
s-1, for H/D exchange with substrates 1-5 (Scheme 2) have
been measured by following the disappearance of the exchange-
able protons (Py-CH2), in OD-/D2O at 25 °C, µ ) 1 M KCl,
by NMR spectroscopy.
In these conditions the concentration of OD- is constant
owing to the reaction of the carbanion with D2O (Scheme 3).
The kOD values were calculated from the equation ln(I0/It) )
kOD[OD-] × time, where I0 is the integration ratio between the
signals of exchangeable hydrogens and that of a reference signal
at time ) 0; It is the same ratio at time ) t. This treatment
assumes that there are not R-secondary isotope effects on
exchange, but these are expected to be very small.27 The kOD
values are reported in Table 1.
Previous theoretical studies on â-elimination reactions have
mainly focused on prototype substrates (mostly CH3CH2X, with
X ) halogen) and were generally limited to the gas phase.22-26
Among the many different theoretical studies, of particular
relevance is the series performed by Gronert,22 Saunders,24 and
Jensen25 using mainly ab initio (MP2-MP4) calculations.
Bickelhaupt et al.23 performed a two-dimensional scan of the
potential energy surface for the CH3CH2F substrate using
(22) (a) Gronert, S. J. Am. Chem. Soc. 1991, 113, 6041. (b) Gronert, S. J. Am.
Chem. Soc. 1992, 114, 2349. (c) Gronert, S. J. Am. Chem. Soc. 1993, 115,
652. (d) Gronert, S.; Merril, G. N.; Kass, S. R. J. Org. Chem. 1995, 60,
488. (e) Gronert, S.; Freed, P. J. Org. Chem. 1996, 61, 9430. (f) Gronert,
S.; Kass, S. R. J. Org. Chem. 1997, 62, 7991. (g) Merril, G. N.; Gronert,
S.; Kass, S. R. J. Phys. Chem. A 1997, 101, 208.
(23) Bicklehaupt, F. M.; Baerends, E. J.; Nibbering, N. M. M.; Ziegler, T. J.
Am. Chem. Soc. 1993, 115, 9160.
(24) (a)Saunders, W. H., Jr. J. Org. Chem. 1997, 62, 244. (b) Saunders, W. H.,
Jr. J. Org. Chem. 1999, 64, 861. (c) Saunders, W. H., Jr. J. Org. Chem.
2000, 65, 681.
(25) (a) Glad, S. S.; Jensen F. J. Am. Chem. Soc. 1994, 116, 9302. (b) Glad, S.
S.; Jensen F. J. Phys. Chem. 1996, 100, 16892. (c) Glad, S. S.; Jensen F.
J. Phys. Chem. 1997, 62, 2253.
(26) (a) Mugnai, M.; Cardini, M.; Schettino, V. J. Phys. Chem. A 2003, 2540.
(b) Ensing, B.; Laio, A.; Gervasio, F. L.; Parrinello, M.; Klein, M. L. J.
Am. Chem. Soc. 2004, 126, 9492. (c) Ensing, B.; Klein, M. L. Proc. Natl.
Acad. Sci. 2005, 102, 6755.
(27) Altson, W. C.; Haley, K.; Kanski, R.; Murray, C. J.; Pranata, J. J. Am.
Chem. Soc. 1996, 118, 6562.
(16) (a) Alunni, S.; Conti, A.; Palmizio Errico, R. J. Chem. Soc., Perkin Trans.
2 2000, 453. (b) Keeffe, J. R.; Jencks, W. P. J. Am. Chem. Soc. 1983, 105,
265.
(17) Alunni, S.; Conti, A.; Palmizio Errico, R. Res. Chem. Intermed. 2001, 27,
653.
(18) Alunni, S.; Busti, A. J. Chem. Soc., Perkin Trans. 2 2001, 778.
(19) Alunni, S.; Laureti, V.; Ottavi, L.; Ruzziconi, R. J. Org. Chem. 2003, 68,
718.
(20) Alunni, S.; Ottavi, L. J. Org. Chem. 2004, 69, 2272.
(21) Langer, M.; Pauling, A.; Re´tey J. Angew. Chem., Int. Ed Engl. 1995, 34,
1464.
9
15152 J. AM. CHEM. SOC. VOL. 127, NO. 43, 2005

â
-Elimination in Systems Activated by the Pyridine Ring
A R T I C L E S
Table 1. Second-Order Rate Constants, kOD, M-1 s-1, for H/D
Exchange with Substrates 1-5 (Scheme 2) in OD-/D2O, 25 °C, µ
) 1 M KCl and Second-Order Rate Constants, kE, M-1 s-1, for the
â-Elimination Reactions with 1-Methyl-2-(2-xethyl)pyridinium Iodide
in OH-/H2O, 25 °C, µ ) 1 M KCl
1
1
b
X
kODaM-1 s-
k
E M-1 s-
σ*
H (1)
CH3 (2)
Ph (3)
OH (4)
OEt (5)
F
Cl
Br
OTs
0.0105
0.0087
0.039
0.37
0
-0.1
0.215
0.555
0.577c
1.1
0.65
10.25
25.2d
78.5
81
1.05
1.0
1.31e
a Average value of three determinations at three different [OD-]; the
error is ( 7%. b Reference 28. c The value of σ* for OEt is calculated from
the value of σI ) 0.26 and the relation σI ) 0.45 × σ * (ref 29). d Previously
(ref 18), we have reported a value of 17.9 M-1 s-1, but the value of this
work was more accurately determined by stopped-flow. e Calculated from
a σI value ) 0.59.
Figure 1. Taft plot log(kOD/1.7) vs σ* for H/D exchange with substrates
1-5, solid square; linear regression analysis gives log(kOD/1.7) ) -2.13
(sd ) 0.08) + 2.77 (sd ) 0.2) σ*. The open circles are log(kE) for the
elimination reactions for the methylated substrates with the indicated leaving
group.
In this system kOD is the second-order rate constant for
carbanion formation, Scheme 3. In fact, the use of steady-state
approximation, with kex > k-1, implies kOD rate determining,
and kobs ) kOD[OD-]. We have excluded that in our systems
there is significant internal return13d-f from the R-- -HOD
intermediate on the base of the following reasons:
(1) We have previously19 discussed, and this work confirms
this point, that the mechanism of the elimination reaction
induced by OH- with 1-methyl-2-(2-fluoroethyl)pyridinium
iodide is E1cb irreversible. The second-order rate constant for
carbanion formation kOH at 25 °C, µ ) 1 M KCl is 10.25 M-1
s-1. As the pKa for the â hydrogens with respect to F is of the
order of 18 (see below), then it can be calculated a value of
irreversible, while if the value kE is significantly larger, an E2
concerted mechanism can be assigned. We have used this
approach, and we have measured the rate of H/D exchange with
substrates 1-5 in OD-/D2O, 25 °C, µ ) 1 M KCl. As
previously discussed, the measured kOD represents the second-
order rate constant for carbanion formation. However, it is to
be considered that we have measured kOD in OD-/D2O, while
the kE constants are measured in OH-/H2O. The ratio kOD/ kOH
30-32
can vary
from 1 to 2.4. In our case, where the substrate
deprotonation is rate determining, it can be assumed an average
factor of 1.7; so kOD (OD-/D2O) are divided by 1.7 to give
k
OD/1.7 (OH-/H2O). It is also to be considered that our kOD
values, measured as described in the Experimental Section, refer
to the rate constants for the exchange of 1H (the two H of the
CH2 systems are both exchanged). In Figure 1 is shown the
Taft plot (log kOD/1.7 against σ*) with substrates 1-5.
k
H O, the first-order rate constant for protonation of the carbanion
2
by H2O, of ∼105 s-1. This value is several orders of magnitude
lower than 1011, the first-order rate constant for solvent
reorganization; in the case of significant internal return, solvent
reorganization would be rate determining in the direction of
carbanion protonation.30 Similar calculations with kOD (Table
A good correlation is observed with substrates 1-5, log(kOD
/
1.7) ) -2.13 (sd ) 0.08) + 2.77 (sd ) 0.2) σ*. In Figure 1
are also shown the values of log kE for the antielimination
reactions with the methylated substrates at 25 °C, µ ) 1 M
KCl and with leaving groups F, Cl, Br, OTs. The value of F*
) +2.77 is similar to the one reported with 9-methylfluorenes,
F* ) + 2.6.15 The ratio kmeasured/kpredicted for the elimination
reactions are 1.2 (X ) F), 4.2 (X ) Cl), 18 (X ) Br), 2.6 (X
) OTs). The deviation from the Taft plot with the halogens
leaving group is shown in Figure 2.
From the deviation observed in the Taft plot it can be
concluded that with leaving group F the mechanism is E1cb
irreversible; with Cl and Br the deviations observed are small
and could be related to the switch to the E2 concerted
mechanism or to negative hyperconjugation8,9,24,33 within an
(E1cb)I mechanism. This effect involves some lengthening of
the C-X bond in the intermediate carbanion. We have previ-
ously19 assigned an (E1cb)I mechanism with 1-methyl-2-(2-
1) give estimated values for deuteration of the carbanion
11
significantly lower than 10 s-1
.
(2) It has been reported 30 that, for deprotonation of CH3CN,
internal return competes with solvent reorganization; the pKa
value of this substrate is 28.9. If our systems have a pKa several
orders of magnitude lower, then the barrier for the reprotonation
is much larger and the internal return should not compete with
solvent reorganization, so the rate determining in the H/D
exchange direction is expected to be carbanion formation (kOD).
Stirling11 and More O’Ferrall15 have shown that it is possible
to use the Taft equation 28 to predict the expected values of the
second-order rate constant for the E1cb irreversible mechanism
of related substrates. If the line of the Taft correlation of rates
of isotope exchange with noneliminating substrates is related
to the carbanion formation rates, then it is possible to predict
the rate (kE) of an E1cb irreversible mechanism with eliminating
substrates provided the σ* of the leaving group is known. So if
the observed value of kE is in agreement with the predicted value
of the Taft plot, the mechanism can be assigned as E1cb
(31) Kresge, A. J.; More O’Ferrall, R. A.; Powell, M. F. Isotopes in Organic
Chemistry; Buncel, E., Lee, C. L., Eds.; Elsevier, New York, 1987.
(32) (a) Steffa, L. J.; Thornton, A. R. J. Am. Chem. Soc. 1967, 89, 6149. (b)
Showen, R. L. Prog. Phys. Org. Chem. 1972, 9, 275.
(33) (a)Thibblin, A.; Ahlberg, P. J. Am. Chem. Soc. 1977, 99, 7926. (b) Ahlberg,
P. Chem. Scr. 1973, 3, 183. (c) Thibblin, A.; Ahlberg, P. J. Am. Chem.
Soc. 1979, 101, 7311. (d) Thibblin, A. Chem. Scr. 1980, 15, 121. (f)
Thibblin, A. J. Am. Chem. Soc. 1983, 105, 853. (g) Hoffmann, R.; Radom,
L.; Pople, J. A.; Schleyer, P. v. R.; Hehre, W. J.; Salem, L. J. Am. Chem.
Soc. 1972, 94, 6221. (h) Apeloig Y.; Rappoport, Z. J. Am. Chem. Soc.
1979, 101, 5095.
(28) Taft, R. W. Steric Effect in Organic Chemistry; Newman, M., Ed.; Wiley:
New York, 1956.
(29) Shorter, J. Correlation Analysis in Chemistry; Chapman, N. B., Shorter,
J., Eds.; Plenum: London, 1978.
(30) Richard, J. P.; Williams, G.; Gao, J. J. Am. Chem. Soc. 1999, 121, 715.
9
J. AM. CHEM. SOC. VOL. 127, NO. 43, 2005 15153

A R T I C L E S
Alunni et al.
the methylated substrate (Scheme 2 with X ) F) and the
nonmethylated one. While in our calculations we generally
simulated the water solution environment by means of a
continuum solvation model, in the case of the methylated
fluorine-substituted substrate, we also studied the effect of
explicit solvation of the F leaving group on the geometry and
stability of the carbanion. Moreover, to investigate the detailed
mechanistic features of the â-elimination reaction, its thermo-
dynamics and kinetics, we explicitly considered the basic
environment by studying the approach of a OH- species
(solvated by three water molecules) to the methylated F-
substituted reagent, leading to the corresponding carbanion and
a 4H2O cluster. We hereafter label the methylated (nonmethyl-
ated) reagent, carbanion, and product as Me-R-X (R-X),
Me-C-X (C-X) and Me-P (P), respectively, with X ) F,
Cl, and Br.
Figure 2. Deviations from the Taft plot: kmeasured/kpredicted ratio for H/D
exchange for substrates 1-5 and for the elimination reactions of methylated
substrates with halogen leaving groups.
Computational Details and Calibration of the Method. The
B3LYP exchange-correlation functional,35 as implemented in
the Gaussian03 program package,36 was used throughout the
paper, together with a 6-31++G** basis set.37 Unconstrained
geometry optimizations were performed in water solution by
means of the conductor-like polarizable continuum model (C-
PCM)38 using the default UA0 solvation radii. Evaluation of
Gibbs free energies in solution was performed following a
procedure similar to those employed for the evaluation of
absolute pKa’s.39 Following a thermodynamic cycle, the Gibbs
fluoroethyl)pyridinium iodide in OH-/H2O on the base of the
large activation by methylation of the N atom of the pyridine
ring (Methyl Activating Factor ) 0.87 × 10,6 OH-/H2O, 50
°C, µ ) 1 M KCl). Tentatively we have also assigned an (E1cb)I
mechanism18 with 1-methyl-2-(2-chloroethyl)pyridinium iodide
on the base of the large MethylAF ) 0.69 × 106 (OH-/H2O,
25 °C, µ ) 1 M KCl), but it was recognized20 that an E2
mechanism, with a significant negative charge on the â-carbon,
would show a high value of MethylAF. The uncertainty is
evident in the mechanistic assignment by these experimental
data; therefore, we have approached the problem by a combined
experimental and computational study. With substrates activated
by the phenylsulfonyl group11 in EtO-/EtOH, 25 °C, an (E1cb)I
mechanism was proposed with leaving groups F, Cl, OTs, while
an E2 concerted mechanism was assigned with Br, I on the base
of the observed deviation in the Taft plot. In systems activated
by the 9-fluorenyl group,15 the deviations from the Taft plot
for Cl and Br have been interpreted with an E2 process; with
leaving group F a probable E1cb mechanism seems consistent.
It is also important to know the pKa for the dissociation of the
â-H (with respect to the leaving group) of our substrates for
elimination reactions, so that it is possible to relate the operating
reaction mechanism with these basic properties of the reactant.
For 1,2-dimethyl pyridinium a pKa of 19.8 has been reported.34
To estimate the effect of a CH2X group on the Ka by Taft
correlation, it is necessary to know the value of F*eq. In first
the approximation we consider the same value of F*eq used by
Jencks16b for the para-nitrophenethyl system, F*eq ) +2.5. The
estimated pKa value 1-methyl-2-(2-fluoroethyl)pyridinium iodide
-log(Ka/10-19.8) ) 2.5 × (1.1-0.49) is pKa ) 18.3.
free energy in solution of species i (Gisol) is defined as Gisol
)
Givac + ∆Gisolv, where Givac is the Gibbs free energy of species
i in vacuo and ∆Gisolv is the free energy of solvation. Givac is
computed at the geometry optimized in vacuo, followed by
frequency calculations to take into account the vibrational
contribution to the total partition function. The translational and
rotational contributions are evaluated by standard statistical
mechanics (particle in a box and rigid rotor models). ∆Gisolv is
directly calculated by a C-PCM single-point calculation together
with a reference calculation in vacuo, at the geometry optimized
in solution.39 We separately checked that using a PCM rather
than a C-PCM solvation model on the C-PCM optimized
geometries produces negligible differences in ∆Gisolv. Similarly,
our results are only marginally affected by the choice of the
solvation radii (UA0 vs UAHF).
Transition state structures for the reaction leading to the
carbanion intermediate were located by performing full geometry
optimizations. The transition state leading to fluoride loss was
located by a constrained geometry optimization along an
appropriate reaction coordinate.
The accuracy of DFT calculations with sufficiently large basis
sets including diffuse functions has previously been found to
be comparable to that of correlated ab initio methods when in-
vestigating elimination/substitution reactions in CH3CH2F.22d
However, a great sensitivity of DFT results upon the choice of
exchange-correlation functional and basis set was also reported.22d,g
Theoretical Study of the Elimination Reactions. To gain
detailed insight into the reaction mechanism of the â-elimination
reaction in the systems activated by the pyridine ring, we have
carried out Density Functional Theory (DFT) calculations on
the systems with the F, Cl, and Br leaving groups. Geometry
optimizations in solution have been performed on the reagent,
carbanion, and product of the â-elimination reaction. To study
the effect of methylation at the pyridine nitrogen, we investi-
gated, in the case of the F substituent, the reactions for both
(35) Becke, A. D. J. Chem. Phys. 1993, 98, 5648.
(36) Frisch, M. J. et al. Gaussian 03, revision B.05; Gaussian, Inc.: Pittsburgh,
PA, 2003 (Supporting Information available for complete ref 36).
(37) Ditchfield, R.; Herhe, W. J.; Pople, J. A. J. Chem. Phys. 1971, 54, 724.
(38) (a) Barone, V.; Cossi, M. J. Phys. Chem. A 1998, 102, 1995. (b) Cossi,
M.; Rega, N.; Scalmani, G.; Barone, V. J. Comput. Chem. 2003, 24, 669.
(39) (a) Saracino, G. A. A.; Improta, R.; Barone, V. Chem. Phys. Lett. 2003,
373, 411. (b) Liptak, M. P.; Shields, G. C. Int. J. Quantum Chem. 2001,
85, 727. (c) da Silva, C. O.; da Silva, E. C.; Nascimento, M. A. C. J. Chem.
Phys. 1999, 103, 11194. (d) da Silva, C. O.; da Silva, E. C.; Nascimento,
M. A. C. J. Phys. Chem. A 2000, 104, 2402.
(34) (a) Cook, M. J.; Katritzky, A. R.; Linda, P.; Tack, R. D. J. Chem. Soc.,
Perkin Trans. 2 1972, 1295. (b) Cook, M. J.; Katritzky, A. R.; Linda, P.;
Tack, R. D. J. Chem. Soc., Perkin Trans. 2 1973, 1080. (c) Cook, M. J.;
Katritzky, A. R.; Linda, P.; Tack, R. D. Chem. Commun. 1971, 510.
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A R T I C L E S
Table 2. Main Optimized Geometrical Parameters (Å) for the
Methylated and Nonmethylated Reagent, Carbanion, and Product
Me
−R
−F
R−F
Me
−C
−F
C
−F
Me
−P
−F
P−F
Cpy-C1
C1-C2
C2-F
1.507
(1.508)
1.529
(1.530)
1.415
1.514
1.519
1.426
1.387
(1.398)
1.463
(1.433)
1.498
1.469
1.341
1.476
1.341
(1.418)
(1.612)
a Data in parentheses for Me-R-F and Me-C-F refer to the model
including two water molecules solvating the F leaving group.
We therefore checked the reliability of our theoretical
approach along three lines. First, we investigated the conver-
gence of our results with basis set expansion, carrying out some
calculations using the larger aug-cc-pTVZ basis set.40 In
particular, using the geometries of the Me-R-F and Me-C-F
species optimized with the 6-31++G** basis set, we performed
a single-point energy evaluation using the aug-cc-pTVZ basis
set (713 basis functions for Me-R-F). The energy difference
in solution between the bare Me-R-F and Me-C-F species
calculated with the 6-31++G** basis set turned out to be only
0.6 kcal/mol higher than the corresponding quantity calculated
with the aug-cc-pTVZ basis set, suggesting that our results are
reasonably stable with respect to basis set expansion. Second,
we performed additional MP2/6-31++G** geometry optimiza-
tions in solution on the solvated Me-C-F and Me-C-Cl
species to assess the ability of our DFT approach to predict the
existence of a stable carbanion intermediate for these two
systems; we found both methods to predict the existence of a
carbanion in the case of the F leaving group and the absence of
a stable intermediate in the Cl case; see below. Finally, we
further checked the accuracy of our theoretical approach by
calculating the pKa of the Me-R-F reagent and of 1,2-dimethyl
pyridinium, following the standard procedure of ref 39a using
the data obtained at the B3LYP/6-31++G** level. For 1,2-
dimethyl pyridinium we obtain a pKa value of 21.1, which
matches very well the experimental value of 19.8.34 Similarly,
we calculate for Me-R-F a pKa of 16.1, in good agreement
with our estimate of 18.3.
Nuclear Geometries. We start our discussion by analyzing
the optimized geometrical structures of the methylated and
nonmethylated substrates with the F leaving group. All relative
nuclear positions were optimized without constraints in solution,
and in Table 2 we report the most relevant resulting geometrical
parameters for the various species investigated. The results
obtained by considering the explicit solvation of fluorine by
two water molecules are also shown in parentheses, and the
optimized molecular structures of the methylated species are
displayed in Figure 3.
The most remarkable difference between the methylated and
nonmethylated substrates is that while for the former we find a
stable minimum in correspondence of the carbanionic structure,
for the latter no such minimum exists. Indeed, every attempt to
locate the optimized geometrical structure of the nonmethylated
C-F intermediate resulted in the loss of the fluoride leaving
group and the concomitant formation of the olefin product. It
may be interesting to note that, by contrast, use of a smaller
6-31g** basis set, which does not include diffuse functions,
does lead to a stable C-F intermediate structure. This reflects
Figure 3. Optimized molecular structures of the methylated reagent (Me-
R-F), carbanion (Me-C-F) and product (Me-P).
the effect of diffuse functions in stabilizing the F- leaving group.
It is also very important that, regardless of the basis set used
for the geometry optimizations, a C-F intermediate local
minimum is found in vacuo, both for the methylated and
nonmethylated systems. Thus, solvation has a crucial effect in
the reactions investigated and must be properly accounted for
in the theoretical simulations.
For the methylated substrates we notice that while the Cpy-
C1 and C1-C2 distances (see Figure 3) show values close to
those of typical single carbon-carbon bonds in the reagent
species, in the carbanion a considerable shortening of both
parameters takes place, reflecting a high degree of conjugation
involving these two carbon-carbon bonds. In particular, the
largest variation involves the Cpy-C1 bond length (1.507 vs
1.387 Å), which implies a significant effect of the methylated
pyridine ligand. On the contrary, the C-F bond length in the
carbanion is elongated with respect to the reagent (1.498 vs
1.415 Å, respectively), indicating the weakening of the C2-F
bond which preludes the loss of the halogen leaving group. We
notice, moreover, that in the carbanion the plane defined by
the C1-H-C2 atoms is almost coplanar with the pyridine plane,
confirming the expected sp2 hybridization of the C1 carbon. We
notice that the geometrical parameters of the carbanion are
consistent with the enamine structure displayed as the right-
hand resonance contributor in Scheme 1. We refer to the
intermediate as a carbanion, however, since this term is
commonly used to identify the intermediate species in E1cb
reactions. For the methylated product of the reaction, an
inversion in the relative length of Cpy-C1 and C1-C2 distances
takes place with respect to the carbanion, and the C1-C2
distance (1.341 Å) is close to (only slightly larger than) typical
double carbon-carbon bond distances.
(40) Woon, D. E.; Dunning, T. H., Jr. J. Chem. Phys. 1993, 98, 1358.
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A R T I C L E S
Alunni et al.
Aside from the absence of a carbanionic local minimum, our
calculations show that the nonmethylated substrates possess
structures very similar to those of the corresponding methylated
species, with only a slight elongation of the bond lengths
considered in Table 2.
the base has to attack the reagent in order to abstract a proton.
In particular we have chosen the distance between the oxygen
of the OH- and the C1-H hydrogen, and at each sampled point,
all other geometrical parameters were left free to relax in a
geometry optimization. This choice does not introduce any
explicit constraint, in particular, on the C1-H and C2-F bond
distances, whose manner of variation, concerted or stepwise,
upon approach of the base, fundamentally characterizes the
reaction mechanism. Basically, there are two possibilities: either
the base abstracts a proton from Me-R-F leading to the
formation of a stable carbanion intermediate (stepwise) or as
the base approaches the reagent, the proton abstraction is
accompanied by the simultaneous loss of a solvated F group
(concerted).
Turning now to the methylated species including two water
molecules solvating the fluorine, we notice that while the
geometry of the reagent is only slightly affected by explicit
solvation of the F leaving group (the C2-F bond is elongated
by only 0.003 Å), the carbanion undergoes a considerable
elongation of the C2-F distance, which increases from 1.498
to 1.612 Å. This large variation can be related to the hydrogen
bonds formed in the carbanion intermediate between the two
water molecules and the F leaving group (HOH....F distances
of 1.88 and 1.89 Å), which further weaken the C2-F bond. In
line with these geometrical variations, the calculated Mulliken
charges on the fluorine atom in the carbanion increase from
-0.42 to -0.46 upon including the two solvating water
molecules in our model. It is remarkable, however, that the
energy gain associated to this substantial stretching of the C2-F
bond in the carbanion is computed to be only 1.2 kcal/mol. Thus,
the looseness of the C2-F bond (related to the so-called
hyperconjugation24) seems to have a significant structural impact
but affects only marginally the reactivity of the system. This is
in agreement with the experimental alignment of the rate
constant for the elimination reaction with 2-(2-fluoroethyl)-1-
methylpyridinium iodide in the Taft correlation diagram. The
stability of the solvated carbanion intermediate was verified by
MP2/6-31++G** geometry optimizations in solution of Me-
C-F(2H2O), which confirmed the existence of a minimum in
correspondence of the carbanionic structure, with a slightly
shorter C2-F distance than that calculated by B3LYP (1.536
vs 1.612 Å, respectively).
Before proceeding to the analysis of the potential energy
surface, we notice that the two hydrogen atoms bound to C1
have a different electrostatic environment so that a different
interaction of the base might be expected when attacking the
hydrogen gauche or anti to the fluorine atom. We therefore
investigated both attack directions, performing separate con-
strained geometry optimizations along the gauche and anti C1-
H....OH- distances. In both cases, the C1-H....OH- distance
was sampled from 2.1 Å, corresponding to a negligible
interaction between Me-R-F(2H2O) and OH-(3H2O), to 1.0
Å, roughly corresponding to the value of a H-O bond in a
water molecule. We first discuss the anti attack. A series of
configurations encountered during the scan of the potential
energy along the anti C1-H....OH- distance, with some relevant
optimized geometrical parameters, are shown in Figure 4.
As can be noticed from Figure 4, for a long (2.1 Å) value of
the RC, the geometry of the Me-R-F(2H2O) unit is essentially
that of the isolated reagent. As OH-(3H2O) approaches the
C1-H hydrogen, however, significant changes in the geometry
of the Me-R-F(2H2O) unit take place. In particular, for an
RC value of 1.4 Å the C1-H bond is substantially elongated
(1.217 Å), while the C2-F bond is only slightly longer than in
the initial configuration (1.462 Å). For an RC value of 1.35 Å,
corresponding to the maximum energy structure in solution
along the selected RC, and therefore to the approximate
transition state, the C1-H bond is further elongated (1.289 Å)
while the C2-F bond is still rather short (1.481 Å). Further,
reducing the RC leads to breaking of the C1-H bond and to
the formation of the carbanion, loosely solvated by the 4H2O
cluster. Notice that the C2-F distance in this solvated carbanion
structure (1.617 Å) is essentially the same as that in the isolated
Me-C-F(2H2O) optimized structure (1.612 Å), reflecting the
negligible perturbation on the structure of the Me-C-F(2H2O)
unit due to the presence of the water cluster. The formation of
the solvated carbanion is accompanied, as expected, by an sp3
to sp2 change in the C1 hybridization (see Figure 4). Starting
from the maximum energy structure encountered along the RC
scan, we have optimized the geometry of the transition state in
solution without constraints, finding a structure (TS1) almost
identical to the starting one characterized by C1-H and O..H
distances of 1.259 and 1.395 Å.
Reaction Mechanism. To provide a detailed description of
the â-elimination reaction mechanism, we investigated the
potential energy surface for the reaction between OH- and Me-
R-F. Since, as discussed above, explicit solvation, in conjunc-
tion to the continuum solvation model, is found to influence
appreciably the geometry of the Me-C-F intermediate, we
adopted the model with two water molecules solvating the F
leaving group. Moreover, description of OH- basicity also
requires proper explicit solvation. Therefore we included three
water molecules binding OH- in our model. Upon formation
of the carbanion intermediate, a proton is transferred from Me-
R-F to OH-, thus leading to the formation of a cluster of four
water molecules.
While the thermodynamics of the reaction can be estimated
by the difference between the free energies of the isolated Me-
R-F(2H2O) and OH-(3H2O) reagents and the Me-C-F(2H2O)
and OH2(3H2O) products, the simulation of its kinetics requires
us to explicitly consider the interaction of the Me-R-F(2H2O)
and OH-(3H2O) reagents along a reaction coordinate (RC). We
shall later discuss in detail some essential features of the
computed multidimensional potential energy surface, but it is
preliminarily quite interesting to analyze the reaction along a
chosen RC. Obviously, the choice of a suitable approximate
RC is crucial for the proper description of the reaction
mechanism, and in the present case, a perfectly natural and
adequate procedure is to sample the potential energy surface
along the distance of approach of the base to the substrate, since
We then repeated the potential energy surface scan along the
gauche C1-H....OH- distance. The geometrical variations along
the selected RC are similar to those discussed above for the
anti attack. The approximate transition state structure, located
also in this case for an RC value of 1.35 Å, resembles that of
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â
-Elimination in Systems Activated by the Pyridine Ring
A R T I C L E S
Figure 4. Optimized molecular structures and main geometrical parameters (Å) obtained during the potential energy surface scan along the C1-H‚‚‚OH-
approximate reaction coordinate for the methylated substrate with a F leaving group. The bond corresponding to the approximate reaction coordinate is
represented in the first three snapshots as a dashed light-blue line. The C1-H bond, which is being broken, is represented in the last three snapshots as a
dashed orange line.
TS1, with C1-H and C2-F distances of 1.271 and 1.449 Å,
respectively, but is calculated to lie 1.8 kcal/mol above TS1,
suggesting that the favored base attack is the one leading to
abstraction of the hydrogen anti to the fluorine atom.
potential energy surfaces illustrating the qualitative relationship
between the E2 and E1cb reaction mechanisms were first
discussed by More O’Ferrall.41 We have performed constrained
geometry optimizations on a grid of selected values of the two
parameters ranging from 1.1 to 2.0 Å for C1-H and 1.4 to 2.0
Å for C2-F, relaxing all the other degrees of freedom. The initial
and final set of values roughly correspond to formed and broken
C1-H and C2-F bonds, respectively, and are characteristic of
the Me-R-F reagent and of the noninteracting Me-P and
F-(2H2O) products. This procedure, computationally very
expensive due to the large number of constrained geometry
optimizations required, should provide a definitive answer
regarding the mechanism of the â-elimination reaction. Due to
the slightly higher energy barrier calculated for the base
approach to the gauche hydrogen, we limited this analysis to
the base attack to the hydrogen anti to the fluorine atom.
The results are displayed in Figure 5 and clearly show that a
concerted E2-like reaction mechanism can be ruled out for the
present system. Indeed, starting from the Me-R-F reagent
(C1-H ) 1.094, C2-F ) 1.428) up to a C1-H value of 1.3 Å,
we notice that stretching the C2-F bond corresponds to a steep
energy increase. Moreover, increasing the C1-H distance leads
to only a slight increase of the C2-F distance, reflecting the
progressive formation of the Me-C-F carbanion intermediate,
characterized by a broken C1-H bond and an elongated C2-F
distance (1.612 Å). The energy increase associated with the
C2-F stretching, however, becomes progressively smaller as
the C1-H distance is further increased. Eventually, for a C1-H
value > 1.8 Å, an almost flat region of the surface is reached,
from which the system can either reach the carbanion intermedi-
We conclude therefore that proton abstraction from Me-R-
F(2H2O) leads to a stable carbanion. We now want to investigate
the second step of the reaction, i.e., the elimination of a solvated
F group from Me-C-F(2H2O). Also in this case, an ap-
proximate RC has to be defined to scan the potential energy
surface of the system and an obvious choice is represented by
the C2-F bond distance. We therefore performed geometry
optimizations starting from Me-C-F(2H2O), constraining the
C2-F bond length to increase from its initial value in Me-C-
F(2H2O) (1.612 Å), up to 2.5 Å, the latter value roughly
corresponding to complete dissociation. Following this proce-
dure, an approximate transition state structure (TS2) could be
located on the potential energy surface for a value of the
approximate RC of 1.75 Å, a value only 0.138 Å larger than
the equilibrium value of this parameter in the Me-C-F(2H2O),
suggesting that the intermediate carbanionic structure corre-
sponds to a very shallow minimum, in accord with the observed
looseness of the C2-F bond (see below).
The presence of a minimum in correspondence of the
carbanionic intermediate structure and the results of the potential
energy surface scan along the two one-dimensional RCs
discussed above suggest that the E1cb mechanism represents a
viable pathway for the â-elimination reaction in the methylated
substrate. To further explore the reaction mechanism for the
methylated substrate, we explicitly considered the two-
dimensional potential energy surface defined by the independent
variations of the C1-H and C2-F bond distances and the free
optimization of all the other parameters. Models for such
(41) More O’Ferrall, R. A. J. Chem. Soc. B 1970, 274.
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A R T I C L E S
Alunni et al.
Figure 5. 3D plot and contour plot of the computed potential energy surface for the elimination reaction of the methylated fluorine-containing substrate,
as a function of the C1-H and C2-F (Å) bond distances.
ate via the energetically favored pathway or surmount the small
energy barrier along the C2-F coordinate leading to the
formation of the Me-P product. We may thus conclude that
the present Me-R-F system represents a borderline case
between the E1cb and E2 reaction mechanisms, with an evident
propensity for the former. It is also interesting to notice that
the C1-H and C2-F distances and the C1-H....OH- distance
are effectively coupled, so that increasing separately either one
of the C1-H and C2-F distances leads to a decrease of the
C1-H....OH- distance. As a consequence, the approximate
transition state structure on the bidimensional potential energy
surface strictly resembles the approximate TS1 transition state
structure located for the monodimensional scan along the C1-
H....OH- distance, with C1-H and C2-F distances of 1.3 and
1.5 Å, respectively, and a C1-H....OH- distance of 1.398 Å.
This confirms that the C1-H....OH- distance is a good ap-
proximate RC.
Although the topological features of the reaction potential
are qualitatively well illustrated by the energy surface in solution
of Figure 5, to obtain a reliable estimate of the reaction
energetics, Gibbs free energies in solution must be computed.
A schematic display of the Gibbs free energy surface in solution
for the â-elimination reaction is reported in Figure 6. For
simplicity, activation free energies were calculated from the
approximate transition state structures obtained from the mon-
odimensional scans along the C1-H and C2-F distances.
Thermodynamic parameters are calculated from the sum of the
free energies of the isolated systems.
by loss of a solvated F- group, overcoming a small Gibbs free
energy barrier of only 2.8 kcal/mol. The final products of the
reaction are located 21.8 kcal/mol below the Gibbs free energy
of the solvated carbanion; we therefore expect the formation of
the final products from the carbanion intermediate to be a
favored (and fast) reaction, due to the low energy barrier and
the quite high exothermicity.
We notice that the thermodynamics of the reaction leading
to formation of the carbanion could be obtained by combining
the experimental pKa estimate of Me-R-F (18.3) and that of
OH- (pKw)14.0), according to ∆G ) 2.303RT (pKa - pKw).
Doing so results in a Gibbs free energy difference between Me-
R-F + OH- and Me-C-F + H2O of 5.9 kcal/mol. Even
though this value is not directly comparable to the computed
result because our model explicitly includes water molecules,
it seems clear that the theoretical value of 9.5 kcal/mol
overestimates the experimental ∆G. Since our computational
model allows us to almost exactly reproduce the estimated pKa
of Me-R-F (see computational details), we conclude that the
main source of inaccuracy in our calculations resides in the
underestimation of OH- basicity. This error is also likely to
have an impact on the computed free energy barrier of 21.1
kcal/mol, which is higher than the experimental estimate (16.1
kcal/mol). That the computed result may overestimate somewhat
the activation barrier, on the other hand, is not unexpected also
on other grounds, since we estimate thermal corrections to the
Gibbs free energy in vacuo, and the entropic contribution is
essentially dominated by the loss of the translational and
rotational degrees of freedom related to the associative character
of the transition state. In addition, a general overestimation of
the activation energies results from having located approximate
transition state structures as maxima along chosen reaction
coordinates. In conclusion the analysis of the Gibbs free energy
landscape clearly indicates that the reaction with the F leaving
group occurs via an E1cb irreversible mechanism. Indeed, the
computed barrier for the backward reaction from the carbanion
(11.6 kcal/mol) is much higher than that for fluoride loss from
the carbanion (2.8 kcal/mol).
As Figure 6 shows, we calculate a Gibbs free energy barrier
of 21.1 kcal/mol in correspondence of the formation of the
solvated carbanion intermediate from the isolated solvated
reagents. This free energy barrier is dominated by the high
entropic contribution which accompanies the bimolecular
formation of the transition state from the isolated reagents.
Once the initial barrier is overcome, the system can evolve
via the formation of the carbanion intermediate (and four water
molecules), which is calculated to lie 9.5 kcal/mol above the
starting reagents. From the carbanionic intermediate the system
can then easily evolve toward the formation of the olefin product
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â
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A R T I C L E S
Figure 6. Schematic representation of the calculated Gibbs free energy surface in solution (kcal/mol) for the â-elimination reaction between solvated
Me-R-F and OH-.
We finally extended our calculations to the methylated
systems having Cl and Br as leaving groups. For the Cl
methylated substrate we used the same 6-31++G** basis set
used above, while for the Br methylated substrate we used an
aug-cc-pVDZ basis set, due to the absence of the 6-31++G**
basis set for the Br atom. Geometry optimizations were
performed on the reagent and carbanion. Remarkably, while for
the F methylated substrates we have found a local minimum
energy structure for the carbanion intermediate, for both the Cl
and Br methylated substrates, every attempt to optimize the
geometry of the carbanion intermediate resulted in the loss of
the chloride and bromide leaving groups, leading directly to
the olefin product. The absence of a minimum for the carbanion
intermediate with a Cl leaving group was confirmed by MP2/
6-31++G** geometry optimizations performed on this system.
The absence of a carbanion intermediate for the Cl and Br
methylated substrates indicates that the â-elimination reactions
in these systems proceed via a concerted E2 reaction mechanism.
To gain further insight into the reaction pathway in the Cl
methylated case, we performed constrained geometry optimiza-
tions for the Me-C-Cl(2H2O)/OH2(3H2O) system, along the
same reaction coordinate described above for the F case (C1-
H....OH- distance). A series of configurations encountered
during the scan of the potential energy along the anti C1-
H....OH- distance, with some relevant optimized geometrical
parameters, are available as Supporting Information. The results
show that the reaction pathway is initially similar to that
calculated for the F case. Reducing the C1-H....OH- distance
from 2.1 to 1.3 Å (the latter value corresponding to the
approximate transition state) leads to an increase of the C2-Cl
distance from 1.84 to 1.92 Å. Further reduction of the ap-
proximate RC, however, leads to a rapid increase of the C2-Cl
distance: for RC ) 1.2 Å the C2-Cl distance is 2.22 Å, and
for RC ) 1.1 Å the carbon-chlorine is essentially broken (C2-
Cl ) 2.73 Å). These results suggest that there is continuity
between the E1cb and E2 reaction mechanisms in the F and Cl
cases. The lack of a net distinction between the E1cb and E2
reaction mechanisms in these borderline cases is confirmed by
the calculated approximate energy barrier (total energy in
solution) along the selected RC which in the Cl case is only
0.7 kcal/mol lower than the corresponding value calculated for
the F substrate. This result is satisfactorily consistent with the
observed similarity in the reaction rates for the F and Cl
methylated substrates. It is also in essential agreement with the
proposal of Jencks,13b according to which the barrier for leaving
group expulsion from the carbanion tends to disappear with
increasingly better leaving groups (Br > Cl > F) and the
intermediate has no significant lifetime.
Conclusions
In the present work we have combined the information
obtained by experimental measurements with detailed theoretical
calculations, to definitively characterize the mechanism of base-
induced â-elimination reactions in systems activated by the
pyridyl ring. In particular, our attention has focused on some
borderline cases with halogen leaving groups, where it was
uncertain if the reaction proceeds via a carbanion intermediate
which subsequently expels the halide (E1cb mechanism) or the
simultaneous concerted loss of a proton and the halide group
takes place (E2 mechanism) upon base attack.
Application of the Taft equation for isotope exchange with
noneliminating nitrogen-methylated substrates (1-5) allowed
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A R T I C L E S
Alunni et al.
us to predict the rate of carbanion formation in the elimination
reactions when the leaving group is F, Cl, or Br. Comparison
of the rate constants for the related â-elimination reactions
induced by OH- suggests that with the F leaving group the
mechanism is E1cb irreversible, while with Cl and Br deviations
from the Taft equation are observed.
a F leaving group is related to the high degree of conjugation
involving the N-methylated pyridine ring and the Cpy-C1 and
C1-C2 carbon-carbon bonds.
Interestingly, the methylated substrate with Cl leaving group
shows only a moderate increase in reactivity compared to the
substrate with F leaving group, despite the lack of a stable
carbanion calculated for this system. That this change in reaction
mechanism is not necessarily accompanied by a significant
increase in the reaction rate is not surprising, if one considers
the details of the potential energy surface calculated for the F
substrate and the similarity of the energy barrier calculated for
the Cl substrate. These results show the lack of a net distinction
between the E1cb and E2 reaction mechanisms in these
borderline cases: the energy barrier for halide expulsion is
initially very high but drops progressively to nearly zero as the
proton leaves the substrate to be transferred to the base. At this
point, the carbon-halide bond becomes very loose, and the
energy surface flat, so that the halide group may begin leaving
the substrate with a small or negligible energy barrier.
The theoretical simulations prove that the elimination reaction
proceeds via formation of a moderately stable carbanion in the
case of a fluoride leaving group for the N-methylated substrate.
This carbanion, however, has a very small barrier (2.8 kcal/
mol) to fluoride loss and is therefore expected to be a very short-
lived transient intermediate. By contrast, a concerted mechanism
with no stable carbanion intermediate takes place in the case
of the chloride and bromide leaving groups. Similarly, for the
nonmethylated substrate with a F leaving group, our calculations
indicate that there is no stable minimum in correspondence of
a carbanion intermediate, thus suggesting for this substrate an
E2 reaction mechanism. We remark that calculations in vacuo
predict a stable carbanion intermediate regardless of the basis
set quality, the same result obtained by calculations in solution
with a basis set which does not include diffuse functions. These
results show the importance of solvation and of basis sets
including diffuse functions for an accurate description of
â-elimination reactions in the present systems.
Acknowledgment. Thanks are due to the Italian Ministero
dell’Istruzione, dell’Universita` e della Ricerca (MIUR) for
financial support.
Supporting Information Available: Experimental details, full
refs 13d and 36. Figure showing the reaction pathway for the
Cl-methylated system. Optimized molecular structures and
energies of relevant stationary points. This material is available
free of charge via the Internet at http://pubs.acs.org.
The picture emerging from the theoretical analysis is in
agreement with the experimental data, which show, for the
N-methylated substrate with a F leaving group, a reactivity
pattern in line with the occurrence of an E1cb reaction
mechanism. The increased stability of the carbanion intermediate
upon methylation of the pyridine nitrogen for the substrate with
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15160 J. AM. CHEM. SOC. VOL. 127, NO. 43, 2005