A Stu d y of th e OH--In d u ced â-Elim in a tion
Rea ction s of 2-(4-Ch lor oeth yl)p yr id in e,
2-(2-Ch lor oeth yl)p yr id in e,
SCHEME 1
1-Meth yl-2-(4-ch lor oeth yl)p yr id in iu m
Iod id e a n d
1-Meth yl-2-(2-ch lor oeth yl)p yr id in iu m
Iod id e in Aceton itr ile/Wa ter
Sergio Alunni,*,† Tiziana Del Giacco,† Paolo De Maria,‡
Antonella Fontana,‡ Carla Gasbarri,‡ and Laura Ottavi†
Dipartimento di Chimica, Universita` degli Studi Perugia,
Via Elce di Sotto 8, 06123 Perugia Italy, and Dipartimento
di Scienze del Farmaco, Universita` “G. D’Annunzio”, Via dei
Vestini 31, 66013 Chieti, Italy
alunnis@unipg.it
Received J anuary 26, 2004
Abstr a ct: Second-order rate constants have been deter-
mined for the title reactions in OH-/H2O and in OH-/
(CH3CN/H2O) [30/70, 60/40, and 85/15 (v/v) mixtures]. A
relatively small increase in reactivity is observed for the four
one such example is the â-elimination of ammonia from
L-histidine, catalyzed by the enzyme histidine ammonia
substrates upon increasing the percentage of CH3CN in the
8
NCH3
OH
/kNOH
)
lyase. This process occurs by an E1cb mechanism, and
solvent mixture. The methyl activating factors (k
-
-
the driving force for the C-H bond-breaking is provided
by a protonated imidazole ring in the active site of the
enzyme. The key intermediate carbanion in the enzy-
matic elimination reactions involving pyridoxal phos-
phate9 as cofactor is similarly stabilized by resonance
involving the quaternized nitrogen of the pyridine ring.
A third example is the carbanion formed in the decar-
boxylation reaction of R-ketoacids in enzymatic reactions
involving the thiamine pyrophosphate where the stability
of the intermediate is also related to an enamine-type
structure.9
are also slightly affected by the solvent composition. On the
other hand, the high acceleration of the reaction by meth-
ylation of the pyridine ring amounts to 104-106 according
to an E1cb mechanism.
A strong proton catalysis in â-elimination reactions
of substrates activated by a pyridine ring has been
observed.1-4 The proton-activating factor (PAF),1,3,5-7
defined as the ratio of the rate constants of the nitrogen-
+
/
protonated (NH+) and unprotonated substrate (N), kNH
kN, for 2-(2-chloroethyl)pyridine (2), is 1.38 × 105 at 50
°C, µ ) 1 M (KCl) in acetohydroxamic acid/acetohydrox-
amate buffers.2 This high rate increase for hydronium
catalysis is in agreement with an E1cb mechanism
(Scheme 1). In fact, the intermediate formed by carbon
deprotonation from NH+ is strongly stabilized by conju-
gation (Scheme 1).
In SN2 reactions of methyl halides with chloride or
acetate ion a rate enhancement between 103 and 106 on
transfer from a protic to a dipolar aprotic solvent has
been observed.10 Moreover, the rate of elimination of
dimethyl sulfide from 2-phenylethyldimethylsulfonium
bromide promoted by OH- exhibits11 a 40- and a 1000-
fold increase on adding to the aqueous medium 50%
(v/v) or 70% (v/v) of DMSO, respectively. A similar
increase has been observed12 in the dehydrobromination
of 2-phenylethyl bromide in solutions of t-ButO-/(DMSO/
t-BuOH).
A large rate increase upon methylation of the pyridine
ring was also observed: MethylAF, defined as the ratio
N
5
-
2
kNCH /k , is 6.88 × 10 for 2 in OH /H2O at 25 °C. Several
3
biological processes occur via the same type of catalysis;
In this work, the second-order rate constants, kONH
,
† Universita` degli Studi Perugia.
-
‡ Universita` “G. D’Annunzio”.
for â-elimination reactions of 2-(4-chloroethyl)pyridine (1)
NCH3
OH
(1) Alunni, S.; Conti, A.; Palmizio Errico, R. J . Chem. Soc., Perkin
Trans. 2 2000, 453.
and 2-(2-chloroethyl)pyridine (2) and k
for the â-e-
-
(2) Alunni, S.; Busti, A. J . Chem. Soc., Perkin Trans. 2 2001, 778.
(3) Alunni, S.; Laureti, V.; Ottavi, L.; Ruzziconi, R. J . Org. Chem.
2003, 68, 718.
(4) Alunni, S.; Conti, A.; Palmizio Errico, R. Res. Chem. Intermed.
2001, 27, 653.
(8) Langer, M.; Pauling, A.; Re´tey J . Angew. Chem., Int. Ed. Engl.
1995, 34, 1464.
(9) Abeles, R. H.; Frey, P. A.; J encks, W. P. Biochemistry; J ones and
Barlett Publishers: Boston, 1992.
(5) Stewart, R.; Srinivasan, R. Acc. Chem. Res. 1978, 11, 271.
(6) McCann, G. M.; More O’Ferrall, R. A.; Walsh, S. M. J . Chem.
Soc., Perkin Trans. 2 1997, 2761.
(7) Eustace, S. J .; McCann, G. M.; More O’Ferrall, R. A.; Murphy,
M. G.; Murray, B. A.; Walsh, S. M. J . Phys. Org. Chem. 1998, 11, 519.
(10) Parker, A. J . Chem. Rev. 1969, 69, 1.
(11) Cockerill, A. F.; Saunders: W. H., J r. J . Am. Chem. Soc. 1967,
89, 4985.
(12) Cockerill, A. F.; Rottschaefer, S.; Saunders, W. H., J r. J . Am.
Chem. Soc. 1967, 89, 901.
10.1021/jo040117w CCC: $27.50 © 2004 American Chemical Society
Published on Web 07/29/2004
J . Org. Chem. 2004, 69, 6121-6123
6121