Mechanisms of elimination and substitution reactions. Spontaneous solvolysis reactions via carbanion and carbocation intermediates

Article abstract of DOI:10.1002/(SICI)1099-1395(199902)12:2<116::AID-POC102>3.0.CO;2-8

The reactions of 4-(4′-nitrophenyl)-4-X-butan-2-one (1-X; X = Cl, OTs) with added bases/nucleophiles exhibit second-order kinetics. These substitution and elimination reactions are concluded to be of concerted S_N2 type and irreversible E1cB type, respectively. The spontaneous formation of alkene from the chloride 1-CI is suggested to occur by a water-promoted E1cB reaction. The fraction of elimination product is smaller with the tosylate 1-OTs. It is plausible that the elimination and substitution reactions of 1-OTs are carbocation reactions since the Bronsted plot with substituted acetate anion bases shows a tenfold positive deviation for the 'water-catalyzed' elimination reaction, and there is a trace of substitution reaction with the acetonitrile component of the solvent yielding 1-NHCOMe. These results are consistent with a common, very short-lived, carbocation intermediate. Copyright

Full text of DOI:10.1002/(SICI)1099-1395(199902)12:2<116::AID-POC102>3.0.CO;2-8

JOURNAL OF PHYSICAL ORGANIC CHEMISTRY
J. Phys. Org. Chem. 12, 116–122 (1999)
Mechanisms of elimination and substitution reactions.
Spontaneous solvolysis reactions via carbanion and carbo-
cation intermediates
Qingshui Meng, Baoan Du and Alf Thibblin*
Institute of Chemistry, University of Uppsala, P.O. Box 531, S-751 21 Uppsala, Sweden
Received 20 February 1998; revised 12 June 1998; accepted 15 June 1998
ABSTRACT: The reactions of 4-(4'-nitrophenyl)-4-X-butan-2-one (1-X; X = Cl, OTs) with added bases/nucleophiles
exhibit second-order kinetics. These substitution and elimination reactions are concluded to be of concerted SN2 type
and irreversible E1cB type, respectively. The spontaneous formation of alkene from the chloride 1-CI is suggested to
occur by a water-promoted E1cB reaction. The fraction of elimination product is smaller with the tosylate 1-OTs. It is
plausible that the elimination and substitution reactions of 1-OTs are carbocation reactions since the Brønsted plot
with substituted acetate anion bases shows a tenfold positive deviation for the ‘water-catalyzed’ elimination reaction,
and there is a trace of substitution reaction with the acetonitrile component of the solvent yielding 1-NHCOMe.
These results are consistent with a common, very short-lived, carbocation intermediate. Copyright
Wiley & Sons, Ltd.
1999 John
KEYWORDS: elimination reactions; substitution reactions; solvolysis reactions; carbanion intermediates;
carbocation intermediates
INTRODUCTION
indenyl and substituted fluorenyl substrates have recently
been proposed to occur by E1cB and E2 reaction
mechanisms.3
The putative carbocation intermediate formed from 1-
X is expected to be extremely shortlived and Richard and
Jencks4 concluded that the closely related 1-(4-nitro-
phenyl)ethyl carbocation may not have a significant
lifetime in aqueous solution. However, we now report
results which suggest that the tosylate reacts through an
ion pair.
We are interested in mechanistic details of nucleophilic
substitution and elimination reactions and the factors
which can induce a change in reaction path, or induce a
change in reaction mechanism, of a particular reaction.
The aim of this work was to investigate the mechanistic
details of both the spontaneous and the base-promoted
1,2-elimination reactions of a system having strongly
acidic b-hydrogens (Scheme 1). The presence of the
acidic hydrogens favors carbanion formation and,
accordingly, the base-promoted elimination may occur
by an E1cB reaction mechanism. The corresponding
fluoride 1-F has been employed recently in mechanistic
studies of an antibody-catalyzed elimination reaction,
which was concluded to have an E1cB or E2 mechanism.1
Elimination reactions of carbonyl-activated substrates are
common in nature. However, it has recently been
proposed that enzymes do not catalyze ‘simple’ E1cB
reactions but involve 1,4-elimination from the enol
intermediate.2
RESULTS
The solvolysis of 4-(4'-nitrophenyl)-4-X-butan-2-one (1-
X; X = Cl, OTs) in 25 vol.% acetonitrile in water yields
the alkene (E)-4-(4'-nitrophenyl)-2-oxobut-3-ene and the
substitution product 4-hydroxy-4-(4'-nitrophenyl)butan-
2-one (1-OH) (Scheme 1). The tosylate 1-OTs gives a
small amount of the substitution product 4-acetamido-4-
(4'-nitrophenyl)butan-2-one (1-NHCOMe). No products
other than those shown in Scheme 1 were found. The
amide 1-NHCOMe was not isolated but its identity was
inferred from its UV spectrum, the increase in the product
ratio [1-NHCOMe]/[1-OH] with increasing acetonitrile
content of the solvent and the failure to observe this
product in solvolysis of 1-OTs in methanol–water. The
solvolysis of 1-Cl in aqueous acetonitrile yields a smaller
fraction of alcohol (Table 1) and no traces of 1-
NHCOMe were found.
We are also interested in the mechanism of the
spontaneous elimination: does the solvent water abstract
the hydron to give the enolate ion which in a subsequent
step expels the leaving group, i.e. is the reaction a water-
promoted E1cB reaction? An alternative is a concerted
water-promoted E2 reaction. Elimination reactions of
*Correspondence to: A. Thibblin, Institute of Chemistry, University of
Uppsala, P.O. Box 531, S-751 21 Uppsala, Sweden.
Copyright 1999 John Wiley & Sons, Ltd.
CCC 0894–3230/99/020116–07 $17.50

MECHANISMS OF ELIMINATION AND SUBSTITUTION REACTIONS
117
Scheme 1
Table 1. Rate constants for the solvolyses of 1-CI and 1-OTs
in 25 vol.% acetonitrile in water
Substratea,b T (°C) 106kobsc (s 1) 106kE (s 1) 106ks (s
)
1
1-Cl
1-OTs
1-OH
70
25
70
10.9
140
8.50
6.5
0.2
2.36
133
a
3
Substrate concentration 0.01–0.1 mmol dm
.
b [HClO4] = 1 mmol dm
.
3
c
kobs = kE ‡ ks.
Added bases/nucleophiles give rise to competing
bimolecular elimination and substitution reactions as
exemplified with azide ion in Fig. 1. The kinetics of the
reactions were studied by a sampling high-performance
liquid chromatographic procedure. The rate constants and
reaction conditions are shown in Table 1. The measured
kinetic data for the reactions with added bases and
nucleophiles are shown in Table 2. The rate constant for
Figure 1. Effect of azide ion concentration on the rate
constants kN3, kS and kE for the reaction of 1-OTs in 25
vol.% acetonitrile in water at 25°C. Inset: enlargement of
the plot of kE
Table 2. Rate constants for the reactions of 1-Cl and 1-OTs with bases
1
1
1
Solvent
Substratea
Base
T (°C) 106kE (dm3 mol
s
)
106kNu (dm3 mol 1 s
)
25 vol.% Acetonitrile in water
1-OTs
N3
NCCH2COO
25
25
25
25
70
70
70
70
25
25
217
10.3
8578
23.8
28.0
b
c
c
MeOCH2COO
56.2
d
AcO
389
13.2
508
e
1-Cl
CF3COO
b
NCCH2COO
MeOCH2COO
2.83 Â 103
1.33 Â 104
1.46 Â 105
4.86 Â 104
f
AcO
Methanol
1-OTs
1-Cl
DABCOg,h
DABCOg,h
a
3
Substrate concentration 0.01–0.1 mmol dm
.
b Measured with 0.10–0.40 mol dm buffer, [NCCH2COO ]/[NCCH2COOH] = 10.
3
c
Measured with 0.10–0.40 mol dm 3 buffer, [MeOCH2COO ]/[MeOCH2COOH] = 1.
d Measured with 0.10–0.40 mol dm [AcO ]/[HOAc] = 4.
3
e
3
Measured with CF3COO , 0.25–0.75 mol dm
.
f Measured with 0.025–0.100 mol dm acetate buffer, [AcO ]/[HOAc] = 4.
g Diazabicyclo[2.2.2]octane.
3
h Measured with 0.01 mol dm base, [Base]/[BaseH ] = 1.
3
‡
Copyright 1999 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 12, 116–122 (1999)

118
Q. MENG, B. DU AND A. THIBBLIN
Table 3. Kinetic deuterium isotope effects for the reactions of 1-Cl and
1-OTs in 25 vol.% acetonitrile in water
D
D
D
Substratea
Base
T (°C)
kobsH/kobs
kEH/kE
kSH/kS
1-Clb
1-Cl
Solvent
70
25
25
25
25
2.0
4.2
3.2
1.2
4.6
2.4
4.2
3.2
2.8
4.6
1.26
c
AcO
1-Cl
DABCOd,e
Solvent
1-OTsb
1-OTs
1.18
DABCOd,e
a
3
Substrate concentration 0.01–0.1 mmol dm
.
b
c
d
e
3
[HClO4] = 1 mmol dm
.
3
Measured with 0.75 mol dm acetate buffer, [AcO ]/[HOAc] = 100.
Diazabicyclo[2.2.2]octane.
Measured with 0.01 mol dm base in methanol, [Base]/[BaseH ] = 1.
3
‡
the substitution reaction of 1-OTs with acetate ion is
difficult to measure owing to the large amount of
elimination with this base.
have either a one-step mechanism (E2) or an irreversible
carbanion mechanism (E1cBI). A very small b value is
expected for a mechanism in which a reversibly formed
unstable carbocationic intermediate is dehydronated in
the rate-limiting step.5,6 Accordingly, these substantial b
values exclude reactions through ion pairs but are
consistent with E2 and E1cBI reaction mechanisms.
Moreover, only a low concentration of added strong base
is required to give elimination exclusively. It is un-
reasonable that a short-lived ion pair would show such
large selectivity.
The
corresponding
deuterated
compounds
[1,1,1,3,3-2H5]-4-(4'-nitrophenyl)-4-X-butan-2-one
(d-1-X) react slower to give alkene. The measured kinetic
deuterium isotope effects for solvolysis and base-
promoted reactions are shown in Table 3.
DISCUSSION
Several studies of base-promoted 1,2-elimination
reactions of carbonyl-activated substrates have been
reported.7 With poor leaving groups the elimination
occurs through the reversibly formed enolate ion, which
in the rate-limiting step expels the leaving group.
Accordingly, the elimination reaction exhibits specific
base catalysis. An example is the elimination of MeOH
from CH3COCH2CH2OMe.7a It was shown that the
reaction mechanism changes to an irreversible E1cB
mechanism if the leaving group is a more efficient one,
e.g. ArCOO .7b It is difficult, of course, rigorously to
exclude the possibility of a concerted E2 mechanism
since the two mechanisms show very similar charac-
teristics such as bimolecular kinetics and general base
catalysis. However, the E1cBI mechanism is indicated by
the low sensitivity of the reaction rate toward the change
of para substituent in the aromatic moiety of the leaving
group, i.e. a small Hammett parameter r was measured.7b
This small sensitivity is attributable to a stepwise reaction
in which the first step, the ionization to the enolate anion,
is rate-limiting. Moreover, the departure of a carboxylate
leaving group from the carbanion intermediate is
expected to have a small but significant barrier.8
Base-promoted elimination reactions
The following experimental results show that the base-
promoted elimination reactions of 1-Cl and 1-OTs do not
occur via carbocation intermediates but rather are E2 and/
or E1cB type reactions.
The large Brønsted parameters for 1-Cl and 1-OTs,
b = 0.67 and 0.68, respectively, measured with substi-
tuted acetate anions (Fig. 2), indicate that the reactions
With more efficient leaving groups, such as halide ions
and aromatic sulfonates, the mechanism may change to
the concerted E2 type owing to the disappearance of the
barrier for departure of the leaving group and/or to a
significant stabilization of the concerted E2 transition
state by a partial bond-breaking to the leaving group.
However, the mechanistic assignment is not very simple
since also the transition state of the hydron-transfer step
Figure 2. Brùnsted plots for the elimination reactions
of 1-Cl (*) and 1-OTs (&) with substituted acetate
anions in 25 vol.% acetonitrile in water at 70 and 25°C,
respectively
Copyright 1999 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 12, 116–122 (1999)

MECHANISMS OF ELIMINATION AND SUBSTITUTION REACTIONS
119
to give the putative carbanion intermediate is stabilized
by hyperconjugative interactions with the leaving
group.8–10
The measured Brønsted parameters for elimination of
1-Cl and 1-OTs with substituted acetate ions of b = 0.67
and 0.68, respectively, show that the hydron is transferred
to the oxygen base to a large extent in the transition state.
A proton transfer of 38% corresponds to the isotope
effect maximum for reaction of an oxygen base with a
carbon acid.11 The moderate values of the kinetic
deuterium isotope effects (Table 3) are consistent with
a large amount of hydron transfer in the transition state.
The very similar b values for the two substrates and the
similar rates of second-order elimination suggest that the
reactions are of E1cBI type [the measured elimination
rate constant for 1-Cl with CNCH2COO ion as base at
70°C using a factor of 2.5 for a decrease in temperature
6
of 10°C yields kE ꢀ 8 Â 10
M
1 S 1 at 25°C compared
Scheme 2
6
1
1
with 10.3 Â 10
M
S
for 1-OTs (Table 2)]. This is
in accord with the high acidity of the b-hydrogens; the
pKa should be close to that of acetone, which has been
measured as 19.3.12
isotope effect on the elimination step (k3), are
required to account for the measured isotope effects.
(iii) The catalytic constants for water as the base falls
below the Brønsted lines by a factor of about 4 (see
Fig. 2), which is in accord with what has been
observed previously for water-promoted E1cB/E2
reactions.
Only one elimination product, the trans isomer
(Scheme 1), is produced. This is in accord with the
results of Shokat et al.,1 who showed that an antibody-
catalyzed elimination of HF from 1-F gave exclusive
formation of the trans-alkene. Experiments using speci-
fically deuterated substrates showed both anti and syn
elimination modes. The kinetic deuterium isotope effect
on the acetate-catalyzed background reaction of 1-F was
We therefore conclude that water abstracts a hydron
from 1-Cl in a concerted E2 reaction or in an irreversible
E1cB process. This conclusion is in accord with our
results for other halides having an acidic b-hydrogen
which have been proposed to react with solvent water by
E2 and E1cBI mechanisms.3 The acidities of these indene
and substituted fluorene substrates are within the pKa
interval of 17.9–22.5. The pKa of 1-Cl is similar since it
should be close to that of acetone (pKa = 19.3).12 The
isotope effect on the elimination is smaller than that with
measured as kH/kD = 3.7 at 25°C,1 which is smaller than
that of the acetate-catalyzed reaction of 1-Cl (kE
H
/
kED = 4.2; Table 3).
Spontaneous elimination: solvent-promoted E1cB
elimination reaction and elimination through ion-
pair intermediate
Solvolytic elimination reactions are generally thought to
occur through carbocation ion pairs and free carbocation
intermediates.6 The following experimental results show
that the solvolytic elimination reaction of 1-Cl does not
occur via such intermediates but is an E2 or E1cB type
reaction:
(i) Irreversible formation of an ion pair which in
competing subsequent steps undergoes elimination
and substitution (Scheme 2, k ꢁ k2, k3) is not
1
consistent with the measured isotope effect of
kobsH/kobsD = 2.0. A maximum secondary kinetic
deuterium isotope effect of about 1.3 is expected
for such a mechanism.13
(ii) A similar mechanism but with reversible formation
of the ion pair (Scheme 2, k ꢂ k2, k3) might
1
Figure 3. Effect of [CNCH2COO ] on the substitution rate
constant kS for the reaction of 1-OTs in 25 vol.% acetonitrile
in water at 25°C
account for the results. However, unreasonable
isotope effect values, e.g. a very small kinetic
Copyright 1999 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 12, 116–122 (1999)

120
Q. MENG, B. DU AND A. THIBBLIN
added stronger base which is expected for E1cB
reactions, and may suggest that both the water- and the
base-promoted elimination of 1-Cl and E1cBI reactions.
The spontaneous elimination of 1-OTs is much less
favored and solvolytic substitution to give 1-OH is the
predominant reaction. However, kE for 1-OTs at 25°C is
about 50 times larger than the corresponding estimated
rate constant for 1-Cl (asumming a factor of about 2.5 for
a change in temperature of 10°C; Table 1). The large 10-
fold positive deviation of the uncatalyzed elimination
reaction from the Brønsted plot with added bases (open
square in Fig. 2) is different to what is observed for 1-Cl
(a fourfold negative deviation; open circle in Fig. 2) and
suggests another mechanism. The second-order rate
constant plotted in the diagram is obtained by dividing
the observed first-order rate constant for the spontaneous
elimination with the concentration of water in the
aqueous solution. However, if an elimination reaction
through a carbocation intermediate is much faster than a
water-promoted E1cB or E2 reaction, a positive deviation
such as that shown in Fig. 2 is expected. We consider this
as a strong indication for a carbocation reaction
substitution with these acetate ions shows a low
sensitivity toward the pKa of the nucleophile of
bnuc ꢀ 0.06 (based upon data for CNCH2COO and
MeOCH2COO , Table 2). The acetonitrile component of
the solvent yields some substitution product 1-
NHCOMe; water is about a 50 times better nucleophile
than acetonitrile, i.e. kMeCN/kHOH ꢀ 0.02 (ratio of second-
order rate constants). More stable carbocations do not
react with acetonitrile under neutral conditions in
aqueous solvent mixtures.3b
The chloride shows a larger elimination-to-substitution
ratio with nucleophiles/bases and therefore its sensitivity
toward nucleophilicity is more difficult to study.
Chlorides have been found to interact much more
strongly with nucleophiles than tosylates in SN2 reactions
of 1-phenylethyl derivatives.4 No traces of 1-NHCOMe
were found in the solvolysis of 1-Cl.
What is the mechanism for the nucleophilic substitu-
tion reactions with the solvent components? It was
concluded that the spontaneous elimination reaction of
1-OTs occurs by a carbocation mechanism (see above).
This suggests that the substitution also occurs stepwise
(Scheme 2), through a very unstable carbocation ion pair.
The reactivity of the closely related 1-(4-nitrophenyl)-
ethyl carbocation with solvent water has been estimated
to be roughly of the order of 1013 s 1 by extrapolation of
rate constants for less reactive 1-phenylethyl deriva-
tives.4
mechanism for the spontaneous elimination of 1-OTs.
H
The small kinetic deuterium isotope effect of kE
/
kED = 2.8 for the spontaneous elimination of 1-OTs,
together with the predominant solvolytic substitution
H
reaction having a secondary isotope effect as large as kS
/
kSD = 1.18 (Table 3), indicates that the carbocation
intermediate is formed reversibly (Scheme 2, k ꢂ k2,
In summary, the results for the substitution reactions of
1-OTs with weak nucleophiles (such as the solvent com-
ponents) are consistent with a dissociative mechanism
with little or no assistance. Bimolecular SN2 substitution
becomes important with stronger nucleophiles.
1
k3).
We have previously found a similar behavior for some
other acidic substrates, i.e. the bromides react with water
through an E2 or E1cB reaction mechanism but the
corresponding brosylates and tosylates react through the
ion pair.3a–c,e For example, it was concluded, based upon
the 14-fold positive deviation for the spontaneous
elimination rate constant from the Brønsted plot with
substituted acetate anions, that 9-({[(4'-bromophenyl)-
sulfonyl]oxy}methyl)fluorene reacts through the ion
pair.3e A change in leaving group to bromide ion changes
the mechanism to E2 or E1cBI. A similar change in
mechanism was also observed by decreasing the pKa of
the substrate without changing the brosylate leaving
group.3e
EXPERIMENTAL
General procedures. NMR spectra were recorded at
25°C with a Varian Unity 400 spectrometer, at 400 MHz
1
for H and at 100.6 MHz for 13C. Chemical shifts are
indirectly referenced to TMS via the solvent signal
(chloroform-d1 7.26 and 77.0 ppm). High-performance
liquid chromatographic analyses were carried out on a C8
reversed-phase column (5 mm, 100 Â 3 mm i.d.) using a
Hewlett-Packard Model 1090 liquid chromatograph
equipped with a diode-array detector. The mobile phase
was a solution of acetonitrile in water. The reactions were
studied at constant temperature in a HETO 01 PT 623
thermostated bath. The pH was measured using a
Radiometer PHM82 pH meter equipped with an Ingold
micro glass electrode.
Substitution reactions
Both 1-Cl and 1-OTs show bimolecular substitution
reactions with added good nucleophiles, which is
exemplified in Fig. 1 for the reaction of 1-OTs with
azide ion. Basic nucleophiles give rise to competing
bimolecular elimination (Table 2), but the amount of
elimination with the strongly nucleophilic azide ion
(pKa = 4.8) is not large (Fig. 1). The tosylate also yields
second-order substitution with substituted acetate ions, as
shown in Fig. 3 for reaction with CNCH2COO . The
Materials. Merck silica gel 60 (240–400 mesh) was used
for flash chromatography. Diethyl ether was distilled
under nitrogen from sodium and benzophenone. Pyridine
and dichloromethane were distilled under nitrogen from
calcium hydride. Methanol and acetonitrile were of
Copyright 1999 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 12, 116–122 (1999)

MECHANISMS OF ELIMINATION AND SUBSTITUTION REACTIONS
121
HPLC grade. All other chemicals were of reagent grade
and used without further purification.
using the method described above. The deuterium
contents were measured by 1H NMR spectroscopy to be
>98 at% H in the 1- and 3-positions.
2
4-Hydroxy-4-(4'-nitrophenyl)butan-2-one (1-OH) was
synthesized from 4-nitrobenzaldehyde and acetone by a
published procedure.1 The product was purified by flash
chromatography on silica gel with 40–50% ethyl acetate
in pentane and recrystallization from toluene–pentane to
give pure alcohol.
Kinetics and product studies. For reaction at 70°C, the
reaction solutions were prepared by mixing acetonitrile
with water at room temperature (ca 22°C). A few
microliters of substrate dissolved in acetonitrile were
added. Aliquots of this reaction mixture (0.5 cm3) were
transferred to several 2 cm3 HPLC flasks, which were
sealed with gas-tight PTFE septa and placed in an
aluminum block in the thermostated water-bath. The
concentration of the substrate in the reaction solution was
0.01–0.1 mmol dm 3. At appropriate intervals, samples
were removed and analysed using the HPLC apparatus.
For reaction at 25°C, a 2 cm3 HPLC flask, sealed with a
gas-tight PTFE septum, was placed in the aluminum
block of the HPLC apparatus thermostated by the water-
bath. The reactions were initiated by fast addition, by
means of a syringe, of a few microliters of the substrate
dissolved in acetonitrile. The rate constants for the
disappearance of the substrates were calculated from
plots of substrate peak area versus time by means of a
non-linear regression computer program. Very good
pseudo-first-order behavior was seen for all the reactions
studied. The separate rate constants for the elimination
and substitution reactions were calculated by combina-
tion of product composition data, obtained from the peak
areas and the relative response factors determined in
separate experiments, with the observed rate constants.
The relative response factors of 1-OH and alkene were
determined by analyzing a mixture of the two compo-
nents, prepared by weighing, using HPLC. The relative
response factor for 1-Cl to alkene was determined in the
[1,1,1,3,3-2H5]-4-Hydroxy-4-(4'-nitrophenyl)butan-2-
one (d-1-OH) was synthesized as described above using
2
acetone-d6 (99.8% H). The deuterium contents were
measured by 1H NMR spectroscopy to be >98 at% 2H in
the 1-and 3-positions.
(E)-4-(4'-Nitrophenyl)-2-oxobut-3-ene was synthe-
sized by a published procedure.1
4-Chloro-4-(4'-nitrophenyl)butan-2-one (1-Cl) was
synthesized by two methods. Method 1. The alcohol 1-
OH (0.5 g) was added to a stirred solution of phosphorus
pentachloride (1 g) in dry diethyl ether (10 cm3) at 0°C.
The reaction mixture was stirred at room temperature for
about 1 h. The mixture was then hydrolyzed by slow
addition of ice. The ether layer was separated and the
aqueous layer was extracted twice with diethyl ether. The
combined ether solution was washed with brine and dried
over sodium sulfate. The solvent was removed and the
residue oil was purified by flash chromatography on silica
gel with 15% ethyl acetate in pentane as eluent to give the
chloride 1-Cl containing 10% of alkene, but otherwise
free from impurities. Method 2. Dry hydrogen chloride
gas was bubbled through a solution of 1-OH in dry
dichloromethane at 0°C for 1 h.
1H NMR, ꢀ 8.21 (m, 2 H), 7.61 (m, 2 H), 5.42 (dd,
J = 7.8, 6.2 Hz, 1 H), 3.36 (dd, J = 17.6, 7.8 Hz, 1 H), 3.12
(dd, J = 17.6, 6.2 Hz, 1 H), 2.19 (s, 3 H).
[1,1,1,3,3-2H5]-4-Chloro-4-(4'-nitrophenyl)butan-2-
one (d-1-CI) was synthesized using Method 1 above. The
deuterium contents were measured by 1H NMR to be >98
following way: 1-Cl (about 10% alkene) in ethanol (in
3
the presence of 1 mmol dm
perchloric acid) was
analyzed at least five times. A volume of 0.5 cm3 of this
solution was transferred in to a 2 cm3 measuring flask and
0.5 mol dm 3 HMTA solution (0.5 cm3 in methanol) was
then added. After the reaction was finished, the reaction
mixture was re-analyzed. The results were used to
calculate the relative response factors for 1-Cl and the
corresponding alkene product. The estimated errors are
considered as maximum errors derived from maximum
systematic errors and random errors.
2
at% H in the 1-and 3-positions.
4-[(4'-Methylbenzenesulfonyl)oxy]-4-(4@-nitrophe-
nyl)butan-2-one (1-OTs) was synthesized by stirring a
mixture of 1-OH (1 g), 4-methylbenzenesulfonyl chlor-
ide (3 g), dry dichloromethane (5 cm3) and dry pyridine
(2.5 cm3) at room temperature. The reaction was
quenched after 10 h (about 50% reaction) by addition
of 2 mol dm 3 hydrochloric acid. The aqueous phase was
extracted twice with dichloromethane. The combined
organic phases were washed with water and brine and
dried with sodium sulfate. Evaporation of the solvent and
separation by flash chromatography on silica gel with 35–
40% ethyl acetate in pentane, followed by recrystalliza-
tion from ethanol–dichloromethane–pentane, gave pure
REFERENCES
1. K. Shokat, T. Uno and P. G. Schultz, J. Am. Chem. Soc. 116, 2261
(1994).
1
1-OTs, m.p. 66–67°C; H NMR, ꢀ 7.20–8.09 (m, 8 H),
2. J. A. Gerlt and P. G. Gassman, J. Am. Chem. Soc. 114, 5928 (1992).
3. (a) Q. Meng and A. Thibblin, J. Am. Chem. Soc. 117, 1839 (1995);
(b) Q. Meng and A. Thibblin, J. Am. Chem. Soc. 117, 9399 (1995);
(c) Q. Meng and A. Thibblin, J. Am. Chem. Soc. 119, 1217 (1997);
(d) Q. Meng and A. Thibblin, J. Am. Chem. Soc. 119, 1224 (1997);
(e) Q. Meng and A. Thibblin, J. Am. Chem. Soc. 119, 4834 (1997);
(f) Q. Meng and A. Thibblin, J. Chem. Soc., Chem. Commun. 345
5.92 (dd, J = 6.7, 6.5 Hz, 1 H), 3.26 (dd, J = 17.5, 6.5 Hz,
1 H), 2.93 (dd, J = 17.5, 6.7 Hz, 1 H), 2.40 (s, 3 H), 2.10
(s, 3 H).
[1,1,1,3,3-2H5]-4-[(4'-Methylbenzenesulfonyl)oxy]-4-
(4@-nitrophenyl)butan-2-one (d-1-OTs) was synthesized
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(1996); (g) Q. Meng and A. Thibblin, J. Chem. Soc., Perkin Trans.
2, 583 (1998).
4. J. P. Richard and W. P. Jencks, J. Am. Chem. Soc. 106, 1383
(1984).
5. A. Thibblin, J. Am. Chem. Soc. 109, 2071 (1987).
6. A. Thibblin, Chem. Soc. Rev., 22, 427 (1993).
7. See for example: (a) L. R. Fedor, J. Am. Chem. Soc. 91, 908 (1969);
(b) R. C. Cavestri and L. R. Fedor, J. Am. Chem. Soc. 92, 4610
(1970); (c) L. R. Fedor and W. R. Glave, J. Am. Chem. Soc. 93, 985
(1971); (d) B. J. Mayer, T. A. Spencer and K. D. Onan, J. Am.
Chem. Soc. 106, 6343 (1984); (e) B. J. Mayer and T. A. Spencer, J.
Am. Chem. Soc. 106, 6349 (1984).
8. A. Thibblin, J. Am. Chem. Soc. 110, 4582 (1988), and references
cited therein.
9. (a) R. Hoffman, L. Radom, J. A. Pople, P. v. R. Schleyer, W. J.
Hehre and L. Salem, J. Am. Chem. Soc., 94, 6221 (1971); (b) Y.
Apeloig and Z. Rappoport, J. Am. Chem. Soc., 101, 5095 (1979).
10. (a) P. Ahlberg, Chem. Scr., 2, 183 (1973); (b) A. Thibblin and P.
Ahlberg, J. Am. Chem. Soc., 99, 7926 (1977); (c) A. Thibblin and
P. Ahlberg, J. Am. Chem. Soc., 101, 7311 (1979); (d) A. Thibblin,
Chem. Scr., 15, 121 (1980); (e) A. Thibblin, J. Am. Chem. Soc.,
¨
˚
105, 853 (1983); (f) M. Olwegard, I. McEwen, A. Thibblin and P.
Ahlberg, J. Am. Chem. Soc., 107, 7494 (1985).
11. (a) F. H. Westheimer, Chem. Rev., 61, 265 (1965); (b) L.
Melander, Isotope Effects on Reaction Rates, p. 24. Ronald Press,
New York, (1960); (c) K. C. Brown, F. J. Romano and W. H.
Saunders, Jr, J. Org. Chem. 46, 4242 (1981); (d) D. J. Miller and
W. H. Saunders, Jr, J. Org. Chem. 46, 4247 (1981).
12. Y. Chiang, A. J. Kresge, Y. S. Tang and J. Wirz, J. Am. Chem. Soc.
106, 460 (1984).
13. K. C. Westaway in Isotopes in Organic Chemistry, edited by E.
Buncel and C. C. Lee, Vol. 7, Chapt. 5. Elsevier, Amsterdam
(1987).
Copyright 1999 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 12, 116–122 (1999)