Catalysis of the β-elimination of HF from isomeric 2-fluoroethylpyridines and 1-methyl-2-fluoroethylpyridinium salts. Proton-activating factors and methyl-activating factors as a mechanistic test to distinguish between concerted E2 and E1cb irreversible mechanisms

Article abstract of DOI:10.1021/jo020603o

Second-order rate constants, k_OHN, M^-1 s^-1, for the β-elimination reactions of HF with 2-(2-fluoroethyl)pyridine (2), 3-(2-fluoroethyl)pyridine (3), and 4-(2-fluoroethyl)pyridine (4) in OH^-/H₂O, at 50°C and μ = 1 M KCl, are k_OH^N = 0.646 × 10^-4 M^-1 s^-1, k_OH^N = 2.97 × 10^-6 M^-1 s^-1, and k_OH^N = 5.28 × 10^-4 M^-1 s^-1, respectively. When compared with the second-order rate constants for the same processes with the nitrogen-methylated substrates 1-methyl-2-(2-fluoroethyl)pyridinium iodide (5), 1-methyl-3-(2-fluoroethyl)pyridinium iodide (6), and 1-methyl-4-(2-fluoroethyl)pyridinium iodide (7), the methyl-activating factor (MethylAF) can be calculated from the ratio k_OH^NCH3/k_OH^N, and a value of 8.7 × 10⁵ is obtained with substrates 5/2, a value of 1.6 × 10³ with 6/3, and a value of 2.1 × 10⁴ with 7/4. The high values of MethylAF are in agreement with an irreversible E1cb mechanism (A_ND_E* + D_N) for substrates 5 and 7 and with the high stability of the intermediate carbanion related to its enamine-type structure. In acetohydroxamate/acetohydroxamic acid buffers (pH 8.45-9.42) and acetate/acetic acid buffers (pH 4.13-5.13), the β-elimination reactions of HF, with substrates 2 and 4, occur at NH⁺, the substrates protonated at the nitrogen atom of the pyridine ring, even when the [NH⁺] is much lower than the [N], the unprotonated substrate, due to the high proton-activating factor (PAF) value observed: 3.6 × 10⁵ for 2 and 6.5 × 10⁴ for 4 with acetohydroxamate base. These high PAF values are indicative of an irreversible E1cb mechanism rather than a concerted E2 (A_ND_ED_N) mechanism. Finally, the rate constant for carbanion formation from NH+ with 2 is k_B^NH+ = 0.35 M^-1 s^-1, which is lower than when chlorine is the leaving group (k_B^NH+ = 1.05 M^-1 s^-1; Alunni, S.; Busti, A. J. Chem. Soc., Perkin Trans. 2 2001, 778). This is direct experimental evidence that some lengthening of the carbon-leaving group bond can occur in the intermediate carbanion. This is a point of interest for interpreting a heavy-atom isotope effect.

Full text of DOI:10.1021/jo020603o

Ca ta lysis of th e â-Elim in a tion of HF fr om Isom er ic
2-F lu or oeth ylp yr id in es a n d 1-Meth yl-2-flu or oeth ylp yr id in iu m
Sa lts. P r oton -Activa tin g F a ctor s a n d Meth yl-Activa tin g F a ctor s a s
a Mech a n istic Test To Distin gu ish betw een Con cer ted E2 a n d
E1cb Ir r ever sible Mech a n ism s
Sergio Alunni,* Valeria Laureti, Laura Ottavi, and Renzo Ruzziconi
Dipartimento di Chimica, Universita` di Perugia, via Elce di Sotto 8, 06123 Perugia, Italy
alunnis@unipg.it
Received September 16, 2002
Second-order rate constants, kOHN, M-1 s-1, for the â-elimination reactions of HF with 2-(2-
fluoroethyl)pyridine (2), 3-(2-fluoroethyl)pyridine (3), and 4-(2-fluoroethyl)pyridine (4) in OH-/H2O,
at 50 °C and µ ) 1 M KCl, are kNOH ) 0.646 × 10-4 M-1 s-1, kNOH ) 2.97 × 10-6 M-1 s-1, and kNOH
)
5.28 × 10-4 M-1 s-1, respectively. When compared with the second-order rate constants for the
same processes with the nitrogen-methylated substrates 1-methyl-2-(2-fluoroethyl)pyridinium iodide
(5), 1-methyl-3-(2-fluoroethyl)pyridinium iodide (6), and 1-methyl-4-(2-fluoroethyl)pyridinium iodide
N
NCH3
(7), the methyl-activating factor (MethylAF) can be calculated from the ratio kOH
/kOH, and a
value of 8.7 × 105 is obtained with substrates 5/2, a value of 1.6 × 103 with 6/3, and a value of 2.1
× 104 with 7/4. The high values of MethylAF are in agreement with an irreversible E1cb mechanism
(ANDE* + DN) for substrates 5 and 7 and with the high stability of the intermediate carbanion
related to its enamine-type structure. In acetohydroxamate/acetohydroxamic acid buffers (pH 8.45-
9.42) and acetate/acetic acid buffers (pH 4.13-5.13), the â-elimination reactions of HF, with
substrates 2 and 4, occur at NH+, the substrates protonated at the nitrogen atom of the pyridine
ring, even when the [NH+] is much lower than the [N], the unprotonated substrate, due to the
high proton-activating factor (PAF) value observed: 3.6 × 105 for 2 and 6.5 × 104 for 4 with
acetohydroxamate base. These high PAF values are indicative of an irreversible E1cb mechanism
rather than a concerted E2 (ANDEDN) mechanism. Finally, the rate constant for carbanion formation
NH+
from NH+ with 2 is kB
) 0.35 M-1 s-1, which is lower than when chlorine is the leaving group
+
(kNBH ) 1.05 M-1 s-1; Alunni, S.; Busti, A. J . Chem. Soc., Perkin Trans. 2 2001, 778). This is direct
experimental evidence that some lengthening of the carbon-leaving group bond can occur in the
intermediate carbanion. This is a point of interest for interpreting a heavy-atom isotope effect.
In tr od u ction
lems such as a structure-dependent mechanism and the
nature of the borderline region are important aspects for
this class of reactions.3-5 It is particularly difficult to
distinguish between the E2 and (E1cb)I mechanisms.
While the presence of a reversibly formed carbanion can
be deduced by showing a change in the rate-determining
step5-8 and by using isotopes (H/D exchange1a,6,9 or
solvent isotope effects7,10,11), the properties of the con-
certed E2 and (E1cb)I mechanisms are similar. One
possible way to discriminate between these two mecha-
The mechanism of base-induced 1,2-elimination reac-
tions has been the subject of many studies,1 due to
interest in being able to distinguish between the possible
mechanisms: the concerted E2 process ANDEDN2 and the
carbanion mechanism, irreversible (E1cb)I or ANDE* +
DN and reversible (E1cb)R or ANDE + DN*. These mech-
anisms are operative in systems with high â-activation
with respect to the leaving group. A third mechanistic
possibility involves an intermediate carbocation. Prob-
(3) J ia, Z. S.; Rudzinski, J .; Paneth, P.; Thibblin, A. J . Org. Chem.
2002, 67, 177.
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(6) Alunni, S.; Conti, A.; Palmizio Errico, R. J . Chem. Soc., Perkin
Trans. 2 2000, 453.
(7) (a) Alunni, S.; Orazi, C. J . Phys. Org. Chem. 2001, 14, 879. (b)
Alunni, S.; Busti, A. J . Chem. Soc., Perkin Trans. 2 2001, 778.
(8) Spillane, W. J .; McGrath, P.; Brack, C.; O’Byrne, A. B. J . Org.
Chem. 2001, 66, 6313.
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(10) Keeffe, J . R.; J encks, W. P. J . Am. Chem. Soc. 1981, 103, 2457.
(11) Alunni, S.; Conti, A.; Palmizio Errico, R. Res. Chem. Intermed.
2001, 27, 653.
(1) (a) Saunders, W. H., J r.; Cockerill, F. A. Mechanism of Elimina-
tion Reaction; Wiley-Interscience: New York, 1973; Vol. II, pp 60-68.
(b) Baciocchi, E. In The Chemistry of Halides, Pseudo Halides and
Azides, Supplement D; Patai, S., Rappoport, Z., Eds.; Wiley: Chich-
ester, U.K., 1983. (c) Gandler, J . R. In The Chemistry of Double Bonded
Functional Group; Patai, S., Eds.; Wiley: Chichester, U.K., 1989. (d)
Saunders, W. H., J r. Acc. Chem. Res. 1976, 9, 19. (e) Stirling, C. J . M.
Acc. Chem. Res. 1979, 12, 198. (f) Marshall, D. R.; Thomas, P. J .;
Stirling, C. J . M. J . Chem. Soc., Perkin Trans. 2 1977, 1914. (g)
Cavestri, R. C.; Fedor, L. R. J . Am. Chem. Soc. 1970, 92, 4610. (h)
Fedor, L. R.; Glave, W. R. J . Am. Chem. Soc. 1971, 93, 985. (i) Gandler,
J . R.; J encks, W. P. J . Am. Chem. Soc. 1982, 104, 1937.
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10.1021/jo020603o CCC: $25.00 © 2003 American Chemical Society
Published on Web 01/01/2003
718
J . Org. Chem. 2003, 68, 718-725

â-Elimination of HF from Pyridine Compounds
TABLE 1. Secon d -Or d er Ra te Con sta n ts kNOH (M-1 s-1
for th e â-Elim in a tion Rea ction s fr om Su bstr a tes 2-4 or
)
SCHEME 1
NCH3
k
(M-1 s-1) for th e â-Elim in a tion Rea ction s fr om
OH
Meth yla ted Su bstr a tes 7-7 a t Va r iou s Tem p er a tu r es, in
OH-/H2O, a t 50 °C a n d µ ) 1 M KCla
NCH3
temp
(°C)
105kNOH
k
OH
substrate
(M-1 s-1
)
(M-1 s-1
)
2
2
2
2
3
4
4
4
4
5
5
5
5
5
6
7
7
7
7
25
0.27
0.90
2.13
6.46
0.30
0.73
3.11
8.68
52.80
33.9
41.1
50
50
14.5
25
34.4
50
18.4
20.5
25
32
50
50
18.5
25
6.65
8.24
10.25
18.09
56.29b
nistic possibilities is to use the leaving group isotope
effect.3,12 A significant leaving group isotope effect is
expected for the E2 mechanism, because in the E2
process there is the bond-breaking of the carbon-leaving
group bond in the rate-determining step. However, it has
been pointed out that a lengthening of the carbon-
leaving group bond can occur in the transition state of
the (E1cb)I mechanism by hyperconjugation,13-19 and
theoretical calculations have supported this possibility.20-23
Another method used to confirm the presence of an
intermediate carbanion is the double-isotopic fraction-
ation technique.24,25 In this paper we report a study of
the mechanism of the base-induced â-elimination reac-
tions in systems activated by a pyridine ring, with
fluorine as leaving group. The substrates studied are 2-(2-
fluoroethyl)pyridine (2), 3-(2-fluoroethyl)pyridine (3),
4-(2-fluoroethyl)pyridine (4), 1-methyl-2-(2-fluoroethyl)-
pyridinium iodide (5), 1-methyl-3-(2-fluoroethyl)pyridin-
ium iodide (6), and 1-methyl-4-(2-fluoroethyl)pyridinium
iodide (7) (see Scheme 1).
4.80 × 10-3
0.69
1.15
2.01
11.24
32
50
a
b
The error is (5%. Value extrapolated from the Arrhenius
plot.
Resu lts a n d Discu ssion
Kin etic Stu d y in OH-/H2O. The reaction of 2-4 or
the methylated substrates 5-7 in OH-/H2O, at 50 °C and
µ ) 1 M KCl, are complete elimination reactions with
the formation of the corresponding vinylpyridine. The
kinetics were studied by following the appearance of the
related vinylpyridine at λ ) 290 nm for 2 and at λ ) 280
nm for 3 and 4 or the related 1-methylvinylpyridinium
salt at λ ) 280 nm for 7 and 6 and at λ ) 287 nm for 5.
The processes were shown to be second-order, first-order
with respect to both the substrates and OH-. In Table 1
Acid-base catalysis study, at different pH values,
allows one to define whether the reacting species, which
undergoes carbon deprotonation, is the unprotonated
substrate, N, or the protonated substrate at the nitrogen
atom of the pyridine ring, NH+. It is important to know
the second-order rate constants kNOH (for substrates 2-4)
NCH3
OH
and k
(for substrate 5-7) are reported at the vari-
ous temperatures studied. With substrates 2-4, the
reacting species is the unprotonated substrate, N, owing
to the high [OH-]; the reaction of the nitrogen-protonated
substrates, NH+, would be zero-order6 with respect to the
+
whether the evaluation of the reactivity ratio kNH /kN,
proton-activating factor (PAF), or methyl-activating fac-
tor (MethylAF; kNCH +/kN) can be a test for the mecha-
3
NH+
N
[OH-] (k0 ) kOH
(KW/KaN), where Ka is the acid dis-
nistic assignment, especially in relation to the difficult
distinction between a concerted process or a stepwise
process involving an intermediate carbanion. The effect
of protonation at one reaction site upon the susceptibility
to an attack by a base at another site, PAF, is important
in chemistry26-28 and biochemistry.29
sociation constant of NH+). The second-order rate con-
stants are kNOH ) 0.646 × 10-4 M-1 s-1 for 2, kNOH ) 2.97
× 10-6 M-1 s-1 for 3, and kNOH ) 5.28 × 10-4 M-1 s-1 for
4. Substrate 4 is 8.17 times more reactive than 2 and
178 times more reactive than 3. In previous works,6,7 we
studied other substrates activated by a pyridine ring with
different leaving groups; in this paper we report a
comparison of the behavior of all three isomers with
fluorine as leaving group. The second-order kinetic law
for the elimination reaction from 2-4 is consistent with
a concerted E2 mechanism, with the irreversible E1cb
mechanism (E1cb)I, and with the reversible E1cb mech-
(12) Ryberg, P.; Matsson, O. J . Am. Chem. Soc. 2001, 123, 2712.
(13) Thibblin, A. J . Am. Chem. Soc. 1988, 110, 4582.
(14) O¨ lwegård, M.; McEwen, I.; Thibblin, A.; Ahlberg, P. J . Am.
Chem. Soc. 1985, 107, 7494.
(15) Thibblin, A.; Ahlberg, P. J . Am. Chem. Soc. 1977, 99, 7926.
(16) Ahlberg, P. Chem. Scr. 1973, 3, 183.
(17) Thibblin, A.; Ahlberg, P. J . Am. Chem. Soc. 1979, 101, 7311.
(18) Thibblin, A. Chem. Scr. 1980, 15, 121.
(19) Thibblin, A. J . Am. Chem. Soc. 1983, 105, 853.
(20) Hoffmann, R.; Radom, L.; Pople, J . A.; Schleyer, P. v. R.; Hehre,
W. J .; Salem, L. J . Am. Chem. Soc. 1972, 94, 6221.
(21) Apeloig Y.; Rappoport, Z. J . Am. Chem. Soc. 1979, 101, 5095.
(22) Saunders, W. H., J r. J . Org. Chem. 1997, 62, 244.
(23) Saunders, W. H., J r. J . Org. Chem. 1999, 64, 861.
(24) Koch, H. F.; Koch, J . G.; Tumas, W.; McLennan, D. J .; Dobson,
B.; Lodder, G. J . Am. Chem. Soc. 1980, 102, 7955.
(26) Stewart, R.; Srinivasan, R. Acc. Chem. Res. 1978, 11, 271.
(27) McCann, G. M.; More O’Ferrall, R. A.; Walsh, S. M. J . Chem.
Soc., Perkin Trans. 2 1997, 2761.
(28) McCann, G. M.; More O’Ferrall, R. A.; Murphy, M. G.; Murray,
B. A.; Walsh, S. M. J . Phys. Org. Chem. 1998, 11, 519.
(29) Abeles, R. H.; Frey, P. A.; J encks, W. P. Biochemistry; J ones
and Bartlett Publishers: Sudbury, MA, 1992.
(25) Ryberg, P.; Matsson, O. J . Org. Chem. 2002, 67, 811.
J . Org. Chem, Vol. 68, No. 3, 2003 719

Alunni et al.
TABLE 2. Activa tion P a r a m eter s for th e â-Elim in a tion
Rea ction s (OH-/H2O, µ ) 1 M KCl) for Su bstr a tes 2 a n d 4
or Meth yla ted Su bstr a tes 5 a n d 7 Ca lcu la ted by th e
Eyr in g Equ a tion
SCHEME 2
SCHEME 3
2
4
5
7
∆Hq (kcal mol-1)
∆Sq (eu)
23.52
-5.06
21.48
-7.20
11.99
-13.56
16.14
-4.04
of the carbanion by H2O is expected to be even slower
than that by acetohydroxamic acid, so the mechanism is
expected to remain (E1cb)I. It can be observed that the
order of reactivity in OH-/H2O is 4 > 2, while for the
corresponding methylated substrates it is 5 > 7. Activa-
tion parameters were determined for 2 and 4 and for 5
and 7 in OH-/H2O and are reported in Table 2. From the
data of Table 2 it can be seen that ∆Hq values with
methylated substrates 5 and 7 are lower than those with
2 and 4, which is in agreement with the greater stabili-
zation due to the resonance of the intermediate carban-
ion. The ∆Sq values are all negative, in agreement with
an associative mechanism. It should be noted that while
an (E1cb)I mechanism can be assigned to the methylated
substrates 5 and 7, as previously discussed, the mecha-
nism could be concerted E2 or a carbanion mechanism
with substrates 2-4 in OH-/H2O, where the reacting
species is N. In this respect, the value of kNOH with
substrate 4 (kNOH ) 5.28 × 10-4 M-1 s-1) is very close to
kOH for N-[2-(o-nitrophenyl)ethyl]quinuclidinium ion (kOH
) 1.14 × 10-3 M-1 s-1; H2O, 50 °C, and µ ) 1 M KCl);
with this substrate an E1cb mechanism was established
for the base-induced â-elimination reaction.30 This com-
parison does not imply the same mechanism for the two
substrates, owing to the difficult problem of the structure-
dependent mechanism and nature of the borderline
region, but it is a point to be considered.
Acid -Ba se Ca ta lysis. Elimination reactions in ac-
etohydroxamate/acetohydroxamic acid buffers with 2 and
4 were followed by monitoring the formation of 2- or
4-vinylpyridine at λ ) 290 nm for 2 and at λ ) 280 nm
for 4. Pseudo-first-order rate constants (kobs, s-1; initial
rates) were evaluated at different pH values (H2O, 50 °C,
and µ ) 1 M KCl). The pKa of acetohydroxamic acid is
9.15 in the reaction conditions.30 Product analysis (see
the Experimental Section) showed that the processes are
complete elimination reactions. We previously reported7b
that the reaction of 2-(2-chloroethyl)pyridine with aceto-
hydroxamate/acetohydroxamic acid buffers involves a
competition between elimination and substitution. With
fluorine as leaving group, we observed a complete elimi-
nation reaction. The plots of kobs, s-1, vs acetohydroxam-
ate concentration ([B-]) at pH 8.45, 8.70, 8.90, 9.15, and
9.42 for 2 and 4 are shown in Figures 1 and 2. It can be
seen that there is a linear dependence of kobs on [B-],
while the slopes of the plots are directly dependent on
the [H+]. This is evidence that the reacting species which
undergoes carbon deprotonation is the conjugated acid
of 2 and 4, NH+. The pKa of NH+ is 4.98 for 2 and 5.45
for 4 (H2O, 50 °C, and µ ) 1 M KCl). The concerted E2
mechanism or the (E1cb)I mechanism would be consistent
with the results of acid-base catalysis study. However,
the fact that at pH ≈ 9 the reacting species is NH+,
anism (E1cb)R. To check for the (E1cb)R mechanism, a
study of H/D exchange in OD-/D2O at 50 °C and µ ) 1 M
KCl was carried out with 2 and 4. This mechanism
however was excluded on the basis of the absence of
deuterium incorporation into the reagent during the
elimination reactions. From the data of Table 1 the
MethylAF can be evaluated by comparing the second-
order rate constant of isomers 2-4 with those of 5-7,
respectively (50 °C and µ ) 1 M KCl). A MethylAF value
NCH3
OH
(k
/kNOH) of 8.7 × 105 was obtained with substrates
5/2, a value of 1.6 × 103 with 6/3, and a value of 2.1 ×
104 with 7/4. Previously,7b we reported a MethylAF value
of 6.88 × 105 (OH-/H2O, 25 °C, and µ ) 1 M KCl) as the
NCH3
reactivity ratio of k
/kNOH of 1-methyl-2-(2-chloroeth-
OH
yl)pyridinium ion and 2-(2-chloroethyl)pyridine. The high
MethylAF values, obtained for 5/2 and 7/4, are in
agreement with an (E1cb)I mechanism. In fact, these
values are similar to those of the PAF that were previ-
ously6 evaluated with N-[2-(2-pyridyl)ethyl]quinuclidium
ion (PAF ) 1.5 × 106; OH-/H2O, 50 °C, and µ ) 1 M KCl)
and with N-[2-(4-pyridyl)ethyl]quinuclidium ion (PAF )
5.3 × 104; OH-/H2O, 50 °C, and µ ) 1 M KCl). An (E1cb)R
mechanism was demonstrated6 with these two substrates
and with acetohydroxamate base, based on a change in
the rate-determining step induced by the buffer concen-
tration, by the presence of H/D exchange and consistent
results in a study of the solvent isotope effect.11 The high
MethylAF values for 5/2 and 7/4 and the similarity with
the PAF values of the related6 substrates, with quinu-
clidine as leaving group, are in agreement with a car-
banion mechanism for the methylated substrates 5 and
7, owing to the marked stabilization of the intermediate
carbanion which has an enamine-type structure (see
Scheme 2).
The MethylAF with 6/3 was 1.6 × 103; it is only 1 order
of magnitude lower than that, also high, of 7/4. For the
system 6/3, a lower MethylAF value is expected for a
carbanion mechanism because resonance, involving the
positive charge of the nitrogen atom, is not possible; the
significant activation of the methyl group can be inter-
preted as a carbanion mechanism. The general scheme
of the carbanion mechanism is shown in Scheme 3.
An (E1cb)I mechanism with the methylated substrates
appears to be more probable than (E1cb)R. In the follow-
ing discussion it will be shown that an (E1cb)I mechanism
can be assigned to the elimination reactions with the
conjugated acid NH+ of 2 and 4 when the base is an
acetohydroxamate anion. In OH-/H2O the reprotonation
(30) Alunni, S.; Ruzziconi, R.; Teofrasti, O. Res. Chem. Intermed.
1999, 25, 483.
720 J . Org. Chem., Vol. 68, No. 3, 2003

â-Elimination of HF from Pyridine Compounds
SCHEME 4
F IGURE 1. Dependence of kobs (s-1) on acetohydroxamate
concentration at different pH values for substrate 2: open
circle, pH 9.42; solid triangle, pH 9.15; open square, pH 8.90;
solid circle, pH 8.70; open triangle, pH 8.45.
be obtained. In fact, for an irreversible E1cb mechanism
from N, kobs ) kNOH[OH-] + kBN[B]; in this case the slope
of the plot kobs vs [B] is expected to be independent of
NH+
the [H+]. The kB
value can be calculated from a
secondary plot of the slope (from the lines of Figures 1
NH+
and 2) against [H+]/KaN, where kB is the second-order
rate constant for carbon deprotonation for NH+ induced
by the base acetohydroxamate. The values obtained are
F IGURE 2. Dependence of kobs (s-1) on acetohydroxamate
concentration at different pH values for substrate 4: open
circle, pH 9.42; solid triangle, pH 9.15; open square, pH 8.90;
solid circle, pH 8.70; open triangle, pH 8.45.
+
NH+
kNBH ) 0.35 M-1 s-1 with 2 and kB ) 0.64 M-1 s-1 with
4. Isomer 4 is slightly more reactive than isomer 2. This
trend is similar to the one observed when the reacting
species is N with OH- base (kONH in Table 1). However,
the trend is inverted with the methylated substrates 5
despite its low concentration with respect to the unpro-
tonated substrate N, is in agreement with a carbanion
mechanism,7b as shown in Scheme 4.
The kinetic equation for kobs from Scheme 4 is given
as
and 7 in OH-/H2O (Table 1). In Table 3 are reported the
+
kNBH values with acetohydroxamate base for various
systems of the structure Y-CH2-CH2-X, where Y is the
activating group and X is the leaving group. It can be
+
NH+
OH
k
[OH-] + kNBH [B-]
[H+]
KaN
seen
that
fluorides
are
less
reactive
NH+
than the corresponding chloride or quinuclidium ions.
kobs ) k2
(1)
NH+
NH+
+
kBH
[BH] + kH O
+ kN2 H
+
The fact that 2, with fluorine as leaving group (kBNH
)
2
0.35 M-1 s-1), is less reactive than 2-(2-chloroethyl)-
pyridine (kNBH ) 1.05 M-1 s-1) is of interest. In fact, for
where KNa is the acid dissociation constant for NH+. For
+
+
NH+
an irreversible mechanism, (E1cb)I, kNH > k
[BH] +
BH
a carbanion mechanism, one would expect that the more
electronegative fluorine would strongly stabilize the
negative charge of the intermediate with respect to the
chlorine, and increase the rate of the reactions. In our
systems it can be seen that with a carbanion mechanism
fluoride is actually less reactive than the corresponding
chloride. This is clear experimental evidence that some
lengthening of the carbon-leaving group bond can occur
in the intermediate carbanion. This effect is expected to
be larger for the C-Cl bond, with respect to the C-F
bond, and can explain the greater reactivity of the
chloride with respect to the fluoride. This effect was
proposed in other systems13-19 and supported by theoreti-
cal calculations with tertiary amines as leaving group.20-23
We think that these results are important for interpret-
ing heavy-atom isotope effects: in fact, the lengthening
2
NH+
k
and the equation for kobs is
H2O
[H+]
KaN
+
kobs ) k0 + kNBH [B-]
(2)
where
[H+]
[OH-]
NH+
OH
k0 ) k
KaN
The plots of Figures 1 and 2 are in agreement with eq 2
and with carbon deprotonation from NH+. If carbon
deprotonation occurred from N, a different kinetic equa-
tion and different results of acid-base catalysis would
J . Org. Chem, Vol. 68, No. 3, 2003 721

Alunni et al.
+
TABLE 3. Secon d -Or d er Ra te Con sta n ts kNBH (M-1 s-1) a n d kNB (M-1 s-1) for th e Acetoh yd r oxa m a te-P r om oted HX
â-Elim in a tion Rea ction s for th e System Y-CH2-CH2-X in H2O a t 50 °Ch
a
b
In acetohydroxamate/acetohydroxamic acid buffers at 50 °C and µ ) 1 M KCl. Estimated by a linear free energy relationship with
NH+
acetohydroxamate base.6 c The PAF values are calculated as the ratio kB /kNB in acetohydroxamate/acetohydroxamic acid buffers at 50
°C and µ ) 1 M KCl. Values calculated in OH-/H2O at 50 °C and µ ) 1 M KCl. e This work. f Value determined at 25 °C (ref 7b). Q )
d
g
quinuclidine. Also reported are the corresponding calculated PAFs. For comparison, the PAF and the MethylAF values in OH-/H2O are
h
reported.
of the C-X bond in the intermediate could simulate the
breaking of the C-X bond for a concerted process. Our
results give an experimental quantitative measure of this
effect in systems where the E1cb mechanism can be
assigned. A comparison of the reactivities of NH+ and
N, the proton-activating factor, requires the knowledge
of kNB, the second-order rate constant for the elimination
reaction from unprotonated substrate, N. This parameter
cannot be directly measured since the elimination reac-
tion of N with acetohydroxamate is too slow to be
conveniently followed. We have estimated kNB for 2 and 4
by extending a previously proposed correlation6 for
and MethylAF. From the data of Table 3, it can be seen
that when the pyridine ring is substituted in the 4 posi-
tion, the PAF values are lower than those of the systems
with a substitution at the 2 position. The different
resonance energies are certainly important in this re-
spect, but differences in electrostatic interactions could
also play a role.31 The elimination reactions of 2 and 4
have also been studied in acetate/acetic acid buffers at
pH values of 4.13, 4.65, and 5.13. The pKa of acetic acid
is 4.65 in H2O, at 50 °C and µ ) 1 M KCl. The reactions
were followed at λ ) 290 nm with 2 and at λ ) 280 nm
with 4 by the initial rate. The results are in agreement
with NH+ being the reacting species which undergoes
carbon deprotonation by acetate base. At the pH studied,
the vinylpyridine product is partially protonated (the pKa
of 2-vinylpyridinium is 5.06, and the pKa of 4-vinylpyri-
dinium is 5.64, in H2O at 50 °C and µ ) 1 M KCl). If the
intermediate carbanion of the mechanism depicted in
Scheme 4 is formed irreversibly, (E1cb)I, the rate equa-
tion is given in eq 3 and the integrated form in eq 4.
known systems between log kNB and log kONH: log kNB
)
-1.4 + 1.1 log kNOH. The rate constants kONH were directly
measured, and the values estimated for kNB are 9.80 ×
10-7 M-1 s-1 for 2 and 9.88 × 10-6 M-1 s-1 for 4. The
calculated PAF values are 3.6 × 105 for 2 and 6.5 × 104
for 4. It should be noted that the reacting species is NH+
in acetohydroxamate/acetohydroxamic acid buffers, and
therefore, we cannot obtain information about the mech-
anism when the reacting species is N, the unprotonated
substrate. The mechanism could be E2 or E1cb. However,
with N-[2-(o-nitrophenyl)ethyl]quinuclidinium ion, a sys-
tem that has a level of activation and reactivity similar
to those of 4, kB is 4.2 × 10-5 M-1 s-1 (acetohydroxamate/
acetohydroxamic acid buffers, H2O, 50 °C, and µ ) 1 M
KCl) and an E1cb mechanism was demonstrated.30 The
PAF values calculated in acetohydroxamate/acetohydrox-
amic acid buffers together with the PAF and MethylAF
values calculated in OH-/H2O for similar previously
studied substrates are reported in Table 3. Support of
the proposed mechanistic model for 2 and 4 comes from
the comparison of the related consistent values of PAF
+
NH+
OH
dC
dt
) (k
[OH-] + kBNH [B-])[NH+]
(3)
(4)
C ) kobs[NH+]t
where C is the total concentration of the product ([P] +
[PH+]).
+
NH+
OH
kobs ) k
[OH-] + kNBH [B]
(5)
(31) Tobin, J . B.; Frey, P. A. J . Am. Chem. Soc. 1996, 118, 12253.
722 J . Org. Chem., Vol. 68, No. 3, 2003

â-Elimination of HF from Pyridine Compounds
mechanism assigned to 2 and 4 under these reaction
conditions, as previously discussed. It is to be noted that
the absence of H/D exchange with 2 and 4 allows the
possibility of excluding an intramolecular proton transfer
in the intermediate carbanion; a significant competition
between this process and the elimination reaction would
imply incorporation of deuterium in the â-position of the
substrate (Scheme 5).
Con clu sion s
Methyl-activating factors have been determined in
OH--induced â-elimination reactions with systems acti-
vated by a pyridine ring with fluorine as leaving group.
When the pyridine ring is substituted in the 2 position,
the MethylAF value is 8.7 × 105, when the substitution
is in the 3 position, the MethylAF is 1.6 × 103, and when
the substitution is in the 4 position, the MethylAF is 2.1
× 104. These high MethylAF values are in agreement
with an irreversible E1cb mechanism involving a reso-
nance-stabilized carbanion. â-Elimination reactions in
acetohydroxamate/acetohydroxamic acid buffer (pH 8.45-
9.42) or acetate/acetic acid (pH 4.13-5.13) with 2 and 4
also proceed by an irreversible E1cb mechanism. The
reacting species, which undergoes carbon deprotonation,
is NH+, the substrates protonated at the nitrogen atom
of the pyridine ring. The PAFs are 3.6 × 105 for 2 and
6.5 × 104 for 4 in acetohydroxamate/acetohydroxamic acid
buffer. These values are similar to those previously
reported6,11 for N-[2-(4-pyridyl)ethyl]quinuclidinium and
N-[2-(2-pyridyl)ethyl]quinuclidinium. A carbanion mech-
anism was demonstrated with these two substrates by a
change in the rate-determining step within the E1cb
mechanism, by the presence of H/D exchange, and by
consistent results of the solvent isotope effect. We suggest
that the PAF or MethylAF values of 104-106 can be a
test for assigning an E1cb mechanism to these systems;
it is then possible to make the difficult diagnosis between
an irreversible E1cb or concerted E2 mechanism. The
comparison between the rate constants for carbon depro-
F IGURE 3. Dependence of kobs (s-1) on acetate concentration
at different pH values for substrate 2: solid circle, pH 5.13;
solid triangle, pH 4.65; solid square, pH 4.13.
F IGURE 4. Dependence of kobs (s-1) on acetate concentration
at different pH values for substrate 4: solid circle, pH 5.13;
solid triangle, pH 4.65; solid square, pH 4.13.
SCHEME 5
tonation induced by acetohydroxamate base (50 °C and
+
µ ) 1 M KCl) from 2-(2-chloroethyl)pyridine,7b kNBH
)
)
NH+
The kobs values were calculated by plots of C against time
with the slope s and kobs ) s/[NH+], where the [NH+] is
given by [NH+] ) {[H+]/([H+] + KaN)}‚CT, with CT being
the total concentration of substrate. The plots of kobs vs
[B] are shown in Figures 3 and 4. It can be seen that
with this kinetic treatment there is a linear trend,
independent of pH. This result is in agreement with an
1.05 M-1 s-1, and 2-(2-fluoroethyl)pyridine (2), kB
0.35 M-1 s-1, shows that with a chlorine leaving group
the formation of the carbanion is faster with respect to
that of the system with the more electronegative fluorine
as leaving group. This is direct evidence that some
lengthening of the carbon-leaving group bond occurs in
the intermediate carbanion, and our results quantify this
effect in systems where the E1cb mechanism can be
assigned. This result is relevant for interpreting a heavy-
atom isotope effect.
(E1cb)I mechanism and with the kinetic expression of eq
NH+
OH
3, where the contribution of the term k
[OH-] is
+
negligible. The slope of the line is kNBH ) 9.31 × 10-6
+
M-1 s-1 with isomer 2 and kBNH ) 23.06 × 10-6 M-1 s-1
Exp er im en ta l Section
with 4. These values are significantly lower than the
values calculated for the same process with acetohydrox-
If not specified otherwise, 1H NMR spectra were recorded
at 200 MHz in CDCl3 solution using tetramethylsilane as
internal standard. Mass spectra were registered at 70 eV.
Rea gen ts a n d Solven ts. Reagent grade potassium chlo-
ride, potassium acetate, acetohydroxamic acid, 4-(2-hydroxy-
ethyl)pyridine, 2-(2-hydroxyethyl)pyridine, 2-vinylpyridine,
3-pyridinecarboxaldehyde, and ethyl 3-pyridylacetate were
used without further purification. 4-Vinylpyridine was purified
by column chromatography on silica gel using diethyl ether
as the eluent. Glass-distilled and freshly boiled water was used
throughout.
+
NH+
amate base (kNBH ) 0.35 M-1 s-1 with 2 and kB ) 0.64
M-1 s-1 with 4), and are in agreement with the lower
basicity of acetate with respect to acetohydroxamate.
H/D Exch a n ge. The study of H/D exchange with 2 and
4 in acetohydroxamate/acetohydroxamic acid buffer or
acetate/acetic acid buffer in D2O, at 50 °C and µ ) 1 M
KCl, showed the absence of deuterium incorporation in
the â-position of the substrate during the elimination
reaction. These results are in agreement with the (E1cb)I
J . Org. Chem, Vol. 68, No. 3, 2003 723

Alunni et al.
3-(2-Hyd r oxyeth yl)p yr id in e (1) was prepared by the
reduction of ethyl 3-pyridylacetate with LiAlH4 according to
the standard procedure. Spectroscopic and analytical data were
identical to those reported in the literature.32
8 (1.39 g, 86.9%) as a pale yellow solid: mp 288-291 °C dec;
1H NMR (D2O) δ 8.48 (d, AA′ portion of an AA′BB′ system, 2
H), 7.85 (d, AA′ portion of an AA′BB′ system, 2 H), 6.80 (d, J
) 17.6 and 10.8 Hz, 1 H), 6.28 (d, J ) 17.6 Hz, 1 H), 5.81 (d,
J ) 17.6 Hz, 1 H), 5.81 (d, J ) 10.8 Hz, 1 H), 4.15 (s, 3 H).
Anal. Calcd for C8H10NI: C, 38.89; N, 4.08; H, 5.67. Found:
C, 38.77; N, 4.11; H, 5.63.
2-(2-F lu or oet h yl)p yr id in e (2). Diethylaminosulfur tri-
fluoride (DAST) (2.44 g, 15.1 mmol) in dichloromethane (25
mL) was added to a solution of 2-(4-hydroxyethyl)pyridine (2.0
g, 16.2 mmol) in the same solvent (40 mL), and the mixture
made to react at 10 °C for 2.5 h. Then it was poured onto ice,
neutralized with NaHCO3 and extracted with CH2Cl2. After
solvent evaporation, chromatography of the crude product on
silica gel (eluent diethyl ether) allowed 2 to be collected (0.50
g, 25%) as a pale yellow oil: 1H NMR δ 8.56 (d, J ) 4.8 Hz, 1
H), 7.63 (td, J ) 7.7 and 1.8 Hz, 1 H), 7.23 (d, J ) 7.8 Hz, 1
H), 7.17 (ddd, J ) 7.7, 4.9 and 0.8 Hz, 1H) 4.84 (dt, J ) 47.0
and 6.1 Hz, 2 H), 3.19 (dt, J ) 25.1 and 6.1 Hz, 2 H); MS (70
1-Meth yl-2-vin ylp yr id in iu m iod id e (9) was obtained as
a pale yellow solid (0.18 g, 25%) from 2-vinylpyridine (0.80 g,
3.0 mmol) following the same procedure described for 8: mp
1
221-226 °C dec; H NMR (D2O) δ 8.47 (d, J ) 6.2 Hz, 1 H),
8.25 (t, J ) 8.0 Hz, 1 H), 7.98 (d, J ) 8.0 Hz, 1 H), 7.67 (t, J
) 7.1 Hz, 1 H), 6.95 (dd, J ) 17.2 and 11.3 Hz, 1 H), 6.15 (d,
J ) 17.2 Hz, 1 H), 5.92 (d, J ) 11.3,1 H), 4.09 (s, 3 H). Anal.
Calcd for C8H10NI: C, 38.89; H, 5.67; N, 4.08. Found: C, 38.77;
H, 5.59; N, 4.12.
eV) m/z (rel intens) 126 (M+ + 1, 4), 125 (M+, 49), 124 (M+
-
3-Vin ylp yr id in e (10). Butyllithium (1.49 M in hexane, 12.5
mL, 18.6 mmol) was added to a solution of diisopropylamine
(1.88 g, 18.6 mmol) in anhydrous THF at -20 °C. After 10
min, methyltriphenylphosphonium bromide (6.7 g, 18.8 mmol)
was added, and the mixture was allowed to react for 30 min
under stirring. After the mixture was cooled to -60 °C,
3-pyridinecarboxaldehyde (2 g, 18.6 mmol) was added in small
portions. The temperature was allowed to rise to 20 °C, and
the mixture was allowed to react for 1 h before it was poured
into water. Aqueous HCl (10%) was added until pH 2 was
reached. After extraction with diethyl ether (3 × 50 mL), the
aqueous phase was basified with saturated K2CO3 and ex-
tracted again with diethyl ether (3 × 50 mL). The collected
organic phases were dried with sodium sulfate. After solvent
evaporation, chromatography of the crude product on silica gel
(eluent diethyl ether/hexanes, 1:1 v/v) allowed pure 10 (1.5 g,
77%) to be collected as a colorless oil: 1H NMR (400 MHz) δ
8.62 (d, J ) 2.2 Hz, 1 H), 8.49 (dd, J ) 4.8 and 1.6 Hz, 1 H),
7.73 (dt, J ) 9.7 and 1.8 Hz, 1 H), 7.26 (dd, J ) 7.8 and 4.7
Hz, 1 H), 6.71 (dd, J ) 17.7 and 11.0 Hz, 1 H), 5.83 (dd, J )
17.7 and 0.5 Hz, 1 H), 5.38 (dd, J ) 11.0 and 0.5 Hz, 1 H); MS
(70 eV) m/z (rel intens) 105 (M+, 100), 104 (68), 78 (31), 51
(30). Anal. Calcd for C7H7N: C, 79.97; 13.32; H; N, 6.71.
Found: C, 79.65; H, 13.38; N, 6.67.
1, 73), 105 (62), 92 (9), 79 (100), 78 (27), 65 (20), 52 (18). Anal.
Calcd for C7H8NF: C, 67.18; H, 6.44; N, 11.19. Found: C,
66.91; H, 6.39; N, 11.28.
3-(2-F lu or oeth yl)p yr id in e (3) was prepared from the
corresponding alcohol 1 (1.0 g, 8.0 mmol) in 16% yield following
the same procedure described for 2: 1H NMR δ 8.5 (m, 2 H),
7.59 (dt, J ) 7.8 and 1.7 Hz, 1 H), 7.26 (dd, J ) 7.8 and 4.9
Hz, 1 H), 4.65 (dt, J ) 46.9 and 6.2 Hz, 2 H), 3.02 (dt, J )
25.0 and 6.2 Hz, 2 H); MS (70 eV) m/z (rel intens) 126 (M+
+
1, 4), 125 (M+, 85), 92 (100), 78 (7), 65 (47), 63 (9), 51 (16).
4-(2-F lu or oeth yl)p yr id in e (4) was prepared from the
corresponding alcohol (1.0 g, 8.0 mmol) as described for 2. 4
was isolated as a pale yellow oil (0.20 g, 20%): 1H NMR δ 8.54
(d, AA′ portion of an AA′BB′ system, 1 H), 7.21 (d, BB′ portion
of an AA′BB′ system, 1 H), 4.68 (dt, J ) 46.8 and 6.1 Hz, 2 H),
3.02 (dt, J ) 25.6 and 6.1 Hz, 2 H); MS (70 eV) m/z (rel intens)
126 (M+ + 1, 10), 125 (M+, 100), 124 (M+ - 1, 20), 92 (89), 65
(39), 51 (18). Anal. Calcd for C7H8NF: C, 67.18; H, 6.44; N,
11.19. Found: C, 67.0; H, 6.42; N, 11.16.
1-Meth yl-2-(2-flu or oeth yl)pyr idin iu m Iodide (5). 2 (0.10
g, 0.80 mmol) and CH3I (2.28 g, 16.06 mmol) were made to
react in acetone (2 mL) for 24 h at room temperature under
stirring. The solvent was evaporated at reduced pressure, and
the residual solid was washed with Et2O, dried under vacuum,
and recrystallized with EtOH-Et2O to obtain pure 5 (0.050
1-Meth yl-3-vin ylp yr id in iu m iod id e (11) was prepared
from 10 (0.8 g, 7.6 mmol) following the same procedure
described for 8. It was collected as pale yellow needles (0.32
g, 17%) after recrystallization with EtOH-Et2O: mp 115-
1
g, 23%): mp 118-120 °C; H NMR (D2O) δ 8.52 (d, J ) 6.2
Hz, 1 H), 8.23 (t, J ) 7.8 Hz, 1 H), 7.81 (d, J ) 8.1 Hz, 1 H),
7.66 (t, J ) 6.8 Hz, 1 H), 4.73 (dt, J ) 46.7 and 5.3 Hz, 2 H),
4.08 (s, 3 H), 3.34 (dt, J ) 26.9 and 5.6 Hz, 2 H). Anal. Calcd
for C8H11NFI: C, 35.98; H, 4.15; N, 5.24. Found: C, 35.85; H,
4.15; N, 5.16.
1
117 °C; H NMR (D2O) δ 8.64 (s, 1 H), 8.42 (d, J ) 6.0 Hz, 1
H), 8.35 (d, J ) 7.9 Hz, 1 H), 7.77 (br t, J ) 7.3 Hz, 1 H), 6.66
(dd, J ) 17.7 and 11.0 Hz, 1 H), 5.95 (dd, J ) 17.7 and 1.1 Hz,
1 H), 5.53 (dd, J ) 11.0 and 1.1 Hz, 1 H), 4.17 (s, 3 H). Anal.
Calcd for C8H10NI: C, 38.89; H, 5.67; N, 4.08;. Found: C, 39.05;
H, 5.58; N, 4.15.
1-Meth yl-3-(2-flu or oeth yl)p yr id in iu m iod id e (6) was
prepared from 3 (0.1 g 0.8 mmol) in 20% yield following the
same procedure described for 5: 1H NMR (D2O, 400 MHz) δ
8.68 (s, 1 H), 8.61 (d, J ) 6.1 Hz, 1 H), 8.39 (d, J ) 8.1 Hz, 1
H), 7.92 (t, J ) 7.1 Hz, 1 H), 4.73 (dt, J ) 46.6 and 5.7 Hz, 2
H), 4.30 (s, 3 H), 3.20 (dt, J ) 28.6 and 5.7 Hz, 2 H). Anal.
Calcd for C8H11NFI: C, 35.98; H, 4.15; N, 5.24. Found: C,
35.92; H, 4.19; N, 4.97.
1-Meth yl-4-(2-flu or oeth yl)p yr id in iu m iod id e (7) was
prepared from 4 (0.1 g, 0.8 mmol) in 23% yield by the same
procedure described for 5: 1H NMR (D2O) δ 8.43 (d, AA′ portion
of an AA′BB′ system, 2 H), 7.72 (d, BB′ portion of an AA′BB′
system, 2 H), 4.62 (dt, J ) 46.5 and 5.6 Hz, 2 H), 4.10 (s, 3H),
3.11 (dt, J ) 28.8 and 5.6 Hz, 2 H). Anal. Calcd for C8H11NFI:
C, 35.98; H, 4.15; N, 5.24. Found: C, 35.89; H, 4.16; N, 5.22.
1-Meth yl-4-vin ylp yr id in iu m Iod id e (8). 4-Vinylpiridine
(0.68 mg, 6.5 mmol) and CH3I (4.56 g, 32.1 mmol) were made
to react in CH3OH (10 mL) at room temperature for 36 h under
stirring. The solvent was evaporated and the resulting solid
washed with Et2O (4 × 20 mL) and CH3OH (50 mL), dried in
a vacuum, and recrystallized with EtOH-Et2O to obtain pure
Kin etics Mea su r em en ts. The reactions in OH-/H2O at 50
°C and µ ) 1 M KCl with 2 and 4 were followed in pseudo-
first-order conditions ([OH-] ) 0.1-0.5 M) by monitoring the
formation of the vinylpyridine product, either by initial rates6
or by following the process to completion. In this case the
pseudo-first-order rate constants were determined from the
slopes of the plot ln[(A∞ - A0)/(A∞ - At)] vs time. The extinction
coefficients (50 °C, µ ) 1 M KCl) were ꢀ ) 3584 M-1 cm-1 at
λ ) 290 nm for 2-vinylpyridine and ꢀ ) 1634 M-1 cm-1 at λ )
280 nm for 4-vinylpyridine.6 Good agreement was always
observed between the two methods. Reactions in OH-/H2O,
at 50 °C and µ ) 1 M KCl, with isomer 3, were followed by
initial rates at λ ) 280 nm (ꢀ of 3-vinylpyridine is 3001 M-1
cm-1, 50 °C, µ ) 1 M KCl), and the [OH-] was 0.3-0.75 M.
Reactions in the same base-solvent system with 5-7 were
followed to completion in pseudo-first-order conditions at [OH-]
) 0.01-0.03 M with 5 and 7; with 6 the [OH-] was 0.3-0.75
M. The extinction coefficients of the corresponding alkenes
were ꢀ ) 14253 M-1 cm-1 at λ ) 280 nm, 25 °C, µ ) 1 M KCl,
for 1-methyl-4-vinylpyridinium iodide (8), ꢀ ) 10274 M-1 cm-1
at λ ) 287 nm, 25 °C, µ ) 1 M KCl, for 1-methyl-2-
vinylpyridinium iodide (9), and ꢀ ) 2860 M-1 cm-1 at λ ) 280
(32) Lowen, G. T.; Almond, M. R.; Rideout, J . L. J . Heterocycl. Chem.
1992, 29, 1663.
724 J . Org. Chem., Vol. 68, No. 3, 2003

â-Elimination of HF from Pyridine Compounds
nm, 50 °C, µ ) 1 M KCl, for 1-methyl-3-vinylpyridinium iodide
(11). Kinetics studies in acetohydroxamate/acetohydroxamic
acid buffers with 2 and 4, at 50 °C and µ ) 1 M KCl, were
carried out following the procedure previously described for
related systems using the initial rates method.6 Elimination
reactions from 2 and 4 in CH3COO-/CH3COOH buffers at 50
°C and µ ) 1 M KCl were followed at λ ) 290 nm with 2 and
at λ ) 280 nm with 4 by monitoring the formation of the
corresponding vinylpyridine by initial rates. The concentra-
tions of 2 and 4 were ∼2.5 × 10-3 M, and the reaction was
followed up to 3%. At the pH used, the vinylpyridine product,
P, is at equilibrium with its conjugated acid, PH+. In this
condition the total concentration, C, of the product (C ) [P] +
[PH+]) was calculated from eq 6, where At is the absorbance
reactions by GC analysis after extraction with CHCl3. Reac-
tions of 2 and 4 in CH3COO-/CH3COOH buffers were also
shown to be complete elimination reactions by GLC analysis
after the pH of the reaction mixture was adjusted to ∼7 and
extraction with Et2O.
H/D Exch a n ge. Compounds 2 and 4 were made to react in
acetohydroxamate/acetohydroxamic acid buffers, CH3COO-/
CH3COOD buffers, or OD- in D2O at 50 °C until 30-50% of
the elimination product was detected. The reaction mixture
was extracted with CDCl3, and the organic phase was analyzed
by NMR analysis. No deuterium incorporation in the unreacted
substrates was detected in any of the cases.
p Ka Deter m in a tion . The pKa values of the conjugated acid
of 2 and 4 and CH3COO-/CH3COOH buffers at 50 °C and µ )
1 M KCl were determined by potentiometric titration with 1
M HCl. The pKa values of the conjugated acid of 2-vinylpyri-
dine and 4-vinylpyridine were determined by ultraviolet
spectrophotometry at λ ) 290 and 280 nm, respectively (50
°C and µ ) 1 M KCl) according to a standard procedure.33
[H+]
(At - A0)
C )
1 +
(6)
+
P
(
)
[H ]
Ka
ꢀP + ꢀPH
P
Ka
Ack n ow led gm en t. Thanks are due to the CNR
(Rome) and the Ministero dell’Universita` e della Ricerca
Scientifica e Tecnologia (MURST) for financial support.
P
at time t, A0 is the absorbance at t ) 0, Ka is the dissociation
constant of PH+ (H2O, µ ) 1 M KCl), ꢀP is the extinction
coefficient of 2-vinylpyridine or 4-vinylpyridine, ꢀPH is the
extinction coefficient of 2-vinylpyridine protonated (9773 M-1
cm-1 at 50 °C and µ ) 1 M KCl) or 4-vinylpyridine protonated
(8987 M-1 cm-1 at 50 °C and µ ) 1 M KCl).
Su p p or tin g In for m a tion Ava ila ble: Pseudo-first-order
rate constants, kobs (s-1), for the elimination reactions from 2
and 4 in acetohydroxamate/acetohydroxamic acid buffers or
acetate/acetic acid buffers (H2O, 50 °C, and µ ) 1 M KCl). This
material is available free of charge via the Internet at
http://pubs.acs.org.
P r od u ct An a lysis. Reactions of 2-7 in OH-/H2O were
shown to be complete elimination reactions by the UV spectra
of the corresponding vinylpyridine formed. Experiments car-
ried out with 2-4 in OH-/H2O showed, after extraction with
Et2O and GLC analysis, that vinylpyridine was the only
product. Reactions of 2 and 4 in acetohydroxamate/acetohy-
droxamic acid buffers were shown to be complete elimination
J O020603O
(33) Albert, A.; Serjeant, E. P. The Determination of Ionization
Constant; Chapman and Hall Ltd.: London, 1971.
J . Org. Chem, Vol. 68, No. 3, 2003 725