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.
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Am. Chem. Soc. 1993, 115, 9160.
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Jr. J. Org. Chem. 1999, 64, 861. (c) Saunders, W. H., Jr. J. Org. Chem.
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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.
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(19) Alunni, S.; Laureti, V.; Ottavi, L.; Ruzziconi, R. J. Org. Chem. 2003, 68,
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(20) Alunni, S.; Ottavi, L. J. Org. Chem. 2004, 69, 2272.
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