Competing base-promoted E2 and E1 reactions of an acidic tertiary substrate

Article abstract of DOI:10.1039/b200758d

The solvolysis of 4-chloro-4-(4′-nitrophenyl)pentan-2-one (1-Cl) in aqueous acetonitrile yields the alcohol 4-hydroxy-4-(4′-nitrophenyl)pentan-2-one (1-OH) and the elimination products 4-(4′-nitrophenyl)-2-oxopent-4-ene (2), (E)-4-(4′-nitrophenyl)-2-oxopent-3-ene (3), and (Z)-4-(4′-nitrophenyl)-2-oxopent-3-ene (4). Addition of thiocyanate ion does not increase the total reaction rate in 25 vol% acetonitrile in water, but gives rise to the substitution products 1-SCN and 1-NCS, at the expense of 1-OH, and a small increase in the fraction of alkene 3. Addition of acetate ion and other weak bases gives rise to base-promoted E2 (or E1cB) to give alkene 3 (and 4). The Bronsted parameter for this reaction was measured as β = 0.76. Water-promoted E2 (or E1cB) reaction was not observed.

Full text of DOI:10.1039/b200758d

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Competing base-promoted E2 and E1 reactions of an acidic
tertiary substrate†
Xiaofeng Zeng and Alf Thibblin*
2
Institute of Chemistry, University of Uppsala, PO Box 531, SE-751 21, Uppsala, Sweden
Received (in Cambridge, UK) 21st January 2002, Accepted 18th April 2002
First published as an Advance Article on the web 29th May 2002
The solvolysis of 4-chloro-4-(4Ј-nitrophenyl)pentan-2-one (1-Cl) in aqueous acetonitrile yields the alcohol 4-hydroxy-
4-(4Ј-nitrophenyl)pentan-2-one (1-OH) and the elimination products 4-(4Ј-nitrophenyl)-2-oxopent-4-ene (2), (E)-4-
(4Ј-nitrophenyl)-2-oxopent-3-ene (3), and (Z)-4-(4Ј-nitrophenyl)-2-oxopent-3-ene (4). Addition of thiocyanate ion
does not increase the total reaction rate in 25 vol% acetonitrile in water, but gives rise to the substitution products
1-SCN and 1-NCS, at the expense of 1-OH, and a small increase in the fraction of alkene 3. Addition of acetate ion
and other weak bases gives rise to base-promoted E2 (or E1cB) to give alkene 3 (and 4). The Brønsted parameter
for this reaction was measured as β = 0.76. Water-promoted E2 (or E1cB) reaction was not observed.
Introduction
It has been shown in some recent reports on solvolysis reactions
that solvent-promoted elimination can be the predominant
pathway to alkenes for acidic substrates which undergo slow
ionization to carbocation intermediates (Scheme 1).1–7 For
Scheme 1
example, the solvolysis of the secondary substrate 4-chloro-4-
(4Ј-nitrophenyl)butan-2-one (5) in aqueous solvent provides
alkene by a water-promoted E2 or E1cB reaction in competi-
tion with ion-pair formation giving alcohol and alkene.7 The
reasons for the predominant solvent-promoted elimination
reaction are the acidic β-hydrogen (activation by the carbonyl
group) and the relatively slow ionization of the secondary
substrate.
Scheme 2
on the α-carbon (1-Cl, Scheme 2). This makes the carbocation
route more competitive owing to faster ionization, and to
somewhat slower E2 or E1cB reaction.8 The mechanistic details
of the elimination and substitution reactions are discussed.
Results
The alcohol 4-hydroxy-4-(4Ј-nitrophenyl)pentan-2-one (1-OH)
was synthesized in low yield (20%) by condensation of
4-nitroacetophenone with acetone. This alcohol was used as a
precursor for the other compounds.
The solvolysis of 4-chloro-4-(4Ј-nitrophenyl)pentan-2-one
(1-Cl) or 4-bromo-4-(4Ј-nitrophenyl)pentan-2-one (1-Br) in
aqueous acetonitrile yields the alcohol 1-OH and the elimin-
ation products 4-(4Ј-nitrophenyl)-2-oxopent-4-ene (2), (E)-4-
(4Ј-nitrophenyl)-2-oxopent-3-ene (3), along with traces of
(Z)-4-(4Ј-nitrophenyl)-2-oxopent-3-ene (4). Reaction with the
acetonitrile component of the solvent gives rise to a small
amount of the substitution product 1-NHCOMe (Scheme 2).
The reaction of 1-Cl in 50 vol% methanol in water affords
the methyl ether 4-methoxy-4-(4Ј-nitrophenyl)pentan-2-one
(1-OMe), substitution product ratio [1-OMe]/[1-OH] = 0.54.
The ester 4-(trifluoroacetoxy)-4-(4Ј-nitrophenyl)pentan-2-one
We have now extended the studies of solvent-promoted
elimination to tertiary substrates by introducing a methyl group
† Electronic supplementary information (ESI) available: the effect of
base concentration on rate constant and product composition. See
http://www.rsc.org/suppdata/p2/b2/b200758d/
1352
J. Chem. Soc., Perkin Trans. 2, 2002, 1352–1358
This journal is © The Royal Society of Chemistry 2002
DOI: 10.1039/b200758d

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Table 1 Rate constants and product compositions for the reactions of 1-Br and 1-Cl in aqueous acetonitrile
mol%
Temp./ЊC
MeCN/vol%
106kobs b/sϪ1
1-OH
1-NHCOMe
2
3
4
1-Bra
25
25
25
720
3644
40
1-Cla
25
25
15
20
25
30
35
23.7
426
238
146
80.3
46.6
81.8
85.8
83.3
80.3
78.1
74.9
0.5
0.3
0.4
0.5
0.6
0.6
13.2
10.1
11.9
14.3
16.1
18.3
4.5
3.8
4.4
4.9
5.2
6.2
Trace
Trace
Trace
Trace
Trace
Trace
40
40
40
40
40
a Substrate concentration: 0.05–0.10 mM. b Estimated maximum error: 5%.
Table 2 The effects of added salts on the rate constants and product compositions for the reaction of 1-Cla in 25 vol% acetonitrile in water at 40 ЊC
mol%
Salts
106kobs b/sϪ1
1-OH
1-NHCOMe
2
3
4
1-Nu
None
0.75 M NaClO4
0.75 M NaCl
146
177
143
173
168
80.3
79.6
78.1
77.3
58.2
0.5
0.7
0.5
0.5
0.4
14.3
14.3
15.3
15.8
14.6
4.9
5.4
6.1
6.4
6.8
Trace
Trace
Trace
Trace
Trace
0.75 M NaBr
0.75 M NaSCN
0.625 M NaSCN
0.125 M NaClO4
0.50 M NaSCN
0.25 M NaClO4
0.375 M NaSCN
0.375 M NaClO4
0.25 M NaSCN
0.50 M NaClO4
0.75 M NaSCNd
20.0c
17.1c
172
178
176
173
61.3
65.1
68.4
71.8
0.4
0.5
0.5
0.6
14.5
14.2
14.2
14.3
6.7
5.9
5.9
Trace
Trace
Trace
Trace
·
·
14.3c
11.0c
7.8c
22.9c
0.7
·
·
5.5
6.6
26.6
12.9
7.5
31.3
145
113
118
111
56.5
51.3
69.2
75.5
77.9
1.2
0.5
0.3
0.5
0.4
0.5
13.5
9.0
13.2
∼16.6
15.1
Trace
12.1
3.0
Trace
Trace
43.2
0.675 M NaOAce
0.625 M NaO2CCH2OMee
0.563 M NaO2CCH2CNe
0.625 M NaO2CCF3
1.2
Trace
1.0
5.5
55.6
f
0.0179 M NaOCH(CF3)2
13845
a 0.05–0.10 mM. b Estimated maximum error 5%. c The sum of 1-SCN and 1-NCS. d At 25 ЊC. e Buffered with 10% of the corresponding acid.
f Buffered with 18% of (CF3)2CHOH.
(1-OOCCF3) reacts quickly to give 1-OH which is not accom-
panied by any significant amount of other products, not even
in the presence of 0.75 M sodium acetate. Solvolysis of
1-OOCCF3 in 50 vol% methanol in water provides only traces
of the methyl ether indicating that the ester reacts predom-
inantly by acyl-oxygen cleavage.
two products, 1-SCN and 1-NCS. There is no bimolecular
reaction of 1-Cl with this powerful nucleophile (Fig. 1). The
thiocyanate adducts are formed at the expense of the alcohol
The kinetics of the reactions were studied either by UV spec-
trophotometry or by a sampling high-performance liquid
chromatography procedure. The latter technique was also used
for measuring the product compositions of the reactions. The
rate constants and product compositions measured for 1-Cl and
1-Br at 25 and 40 ЊC, and with various fractions of acetonitrile
in the reaction solution, are recorded in Table 1. The analytical
HPLC column did not give a complete baseline separation of
the alkenes 2 and 4 and it was therefore difficult to accurately
measure traces of alkene 4. The products were found to be
stable under the reaction conditions used for the solvolysis
studies. The alcohol 1-OH decomposes to 4-nitroacetophenone
under basic conditions.
The effect of different salts on the rate of disappearance of
1-Cl was found to be small (Table 2). Addition of the sodium
salts of perchlorate ion, thiocyanate ion and bromide ion,
respectively, give a rate increase of about 15–20%. Addition of
chloride or acetate ions does not have any significant effect on
the reaction rate.
Fig. 1 The effect of added sodium thiocyanate on the product
composition for the reaction of 1-Cl in 25 vol% acetonitrile in water at
40 ЊC; ionic strength 0.75 M, maintained with sodium perchlorate.
Inset: enlargement of the plot for alkene 3.
Nucleophilic salts give rise to substitution products. The
strongly reactive, ambident nucleophile thiocyanate ion yields
J. Chem. Soc., Perkin Trans. 2, 2002, 1352–1358
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1-OH. There is also a slight increase in the fraction of alkene 3
with increasing thiocyanate concentration (Fig. 1). We did not
detect any significant change in the yield of 2 or 4, but this may
be due to the bad separation of these two products in the HPLC
analysis. In fact, a slight decrease in the yield of 2 may be
hidden by a slight increase in 4. The stabilities of 1-SCN and
1-NCS are relatively high. They undergo a very slow decom-
position under the reaction conditions. No quantitative results
were obtained with azide ion owing to overlapping HPLC
peaks and significant decomposition of the azide adduct 1-N3.
The observed product ratio of 1-Nu to 1-OH is a measure
of the competition between added nucleophile (NuϪ) and
water for reaction with the substrate and/or carbocation inter-
mediate(s). The dimensionless second-order rate constant ratio
kNu/kHOH could be used to compare the reactivity of different
nucleophiles:
kNu/kHOH = ([1-Nu]/[1-OH])([H2O]/[NuϪ])
Addition of bases
(1)
Fig. 3 The effect of added carboxylate ion on the product ratio [3]/
[1-OH] for the reaction of 1-Cl in 25 vol% acetonitrile in water at
40 ЊC buffered with 10% of the free acid. The slopes of the lines are
0.668, 0.198, 0.0674, and 0.0164 MϪ1, respectively.
Added bases increase the fraction of the two alkenes 3 and 4 at
the expense of 1-OH and alkene 2. A trace of the substitution
product with the carboxylate ion is also formed. Data for the
solvolysis of 1-Cl in the presence of substituted acetate ions
are given in Table 2. The effect of product composition as a
function of acetate ion is shown in Fig. 2. Similar results were
Fig. 4 The effect of added sodium hexafluoroisopropoxide on the rate
constants k13Ј and k14Ј for reaction of 1-Cl to give alkenes 3 and 4,
respectively. Reaction conditions: 1-Cl in 25 vol% acetonitrile in water
at 40 ЊC, buffered with 18% of the corresponding alcohol.
Fig. 2 The effect of added acetate ion on the alkene formation for the
reaction of 1-Cl in 25 vol% acetonitrile in water at 40 ЊC buffered with
10% of acetic acid.
obtained with the less basic NCCH2COOϪ and MeOCH2COOϪ
ions. Plots of the product ratios [3]/[1-OH] versus base concen-
tration are shown in Fig. 3 for acetate and substituted acetate
ions. The stronger base (CF3)2CHOϪ gives rise to bimolecular
reaction with 1-Cl as shown in Fig. 4.
Discussion
The solvolysis of 1-Cl is about 200 times faster than the
solvolysis of the corresponding secondary substrate 5 and
approximately 12 times slower than the solvolysis of 2-chloro-
2-methyl-1-phenylpropane (6).7,9 The rate constant for the
disappearance of the substrate as well as all the separate
phenomenological rate constants are very sensitive toward
the solvent ionizing power as shown in Fig. 5. The measured
parameter for kobs is mobs = 1.16. A carbocation-like transition
state is consistent with these data. The alcohol formation shows
a greater sensitivity to solvent ionizing power than the elim-
ination reactions in accord with previous results for solvolysis
reactions.10
Fig.
5
Grünwald–Winstein plots for the solvolysis of 1-Cl in
acetonitrile–water mixtures at 40 ЊC. The Y values are from the reports
of Bunton and coworkers.29
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The effect of different salts on the rate of disappearance of
1-Cl was found to be small (Table 2). Addition of the sodium
salts of perchlorate ion, thiocyanate ion and bromide ion,
respectively, gives a rate increase of about 15–20%. Addition of
chloride ions or acetate ions does not have any significant effect
on the reaction rate of 1-Cl in contrast to the usual rate-
retarding effect of these ions. For example, the solvolysis of
Ph2CHX, where X is Cl or 4-nitrobenzoate,11 in 25 vol%
acetonitrile in water is retarded 48 and 52%, respectively,
by addition of 0.75 M sodium acetate and the solvolysis of 7
is retarded 48%.12,13 The effect of 0.75 M sodium chloride is
smaller, about 17%.11–13
a reaction proceeding entirely via carbocation intermediates
(vide supra). This estimate is based upon the observed rate-
depressing effects measured in the same solvent mixture for
some other solvolysis reactions which occur through carbo-
cation intermediates.9,12–14 We therefore suggest that the
rate-depressing effect of the carbocation formation, giving
mainly alcohol 1-OH, is compensated by an acetate ion-
promoted E2 (or E1cB) reaction giving 3 and 4. With the much
stronger base (CF3)2CHCOϪ (pKa = 9.3),18 there is a significant
fraction of competing E2 reaction (Fig. 4).
Let us now consider the two extreme mechanistic possibilities
of alkene 3 formation.
There is no second-order substitution reaction with the
added strong nucleophile thiocyanate ion. The rate of dis-
appearance of the substrate at constant ionic strength
(maintained with sodium perchlorate) does not change sig-
nificantly with increasing concentration of the nucleophile
(Table 1). The increase in the fraction of the two substitution
products 1-SCN and 1-NCS is compensated by a decrease in
the fraction of 1-OH (Fig. 1). Thus, there is no indication of
reversible ionization or competing one-step SN2 reaction with
this powerful nucleophile.
Alternative 1: alkene 3 is formed exclusively through the
carbocation intermediate with acetate ion and other weak bases
The assumption that the rate constant kw for formation of
1-OH from the common carbocation intermediate (Scheme 3)
The product composition data of Table 2 indicate a very
unstable intermediate; thiocyanate is only 19 times more
reactive than a water molecule toward the carbocation. The
lifetime of the carbocation intermediate might be estimated
by the “azide-clock” method.14,15 However, owing to the
instability of 1-N3, we have used thiocyanate ion instead
of azide ion as the trapping reagent. The thiocyanate ion
should react with the carbocation by diffusion-controlled
addition having a rate constant in aqueous acetonitrile of
about 5 × 109 MϪ1 sϪ1 (at 25 ЊC).16 This diffusional rate con-
stant value combined with kSCN/kw = 19 (eqn. (1)) yields
a rate constant for reaction of water with the carbocation of
Scheme 3
is not affected by the base addition implies that the measured
product ratio [3]/[1-OH] could be used for measuring the
Brønsted parameter for the dehydronation‡ (ke) of the inter-
mediate (Fig. 6). The slope of this plot, β = 0.35, is much higher
kw = 1.1 × 1010 Ϫ1. This clearly indicates that the carbocation
s
intermediate is relatively unstable and it should not be a
fully solvent-equilibrated species since diffusional separation
of an ion pair should have a rate constant of about 2 × 1010
s
Ϫ1. Accordingly, kw = 1.1 × 1010 sϪ1 is presumably an
underestimate. The rate constant for water addition is similar
to that estimated in the reaction of 2-chloro-2-methyl-1-
phenylpropane (6).9
Addition of the acetonitrile component to the carbocation
intermediate provides a small amount of 1-NHCOMe through
the initial formation of the nitrilium ion.17 The formation
of this product reflects the highly reactive character of the
carbocation showing a very small discrimination between
different nucleophiles. Solvolysis reactions through more
stable carbocations do not show this type of product in
neutral solution. A further indication of the very unstable
character of the carbocation is the measured small discrimin-
ation between methanol and water in 50 vol% methanol in
water, kMeOH/kHOH = 1.2 (ratio of second-order rate constants,
eqn. (1)).
There is a small increase in the fraction of 3 with increasing
thiocyanate ion concentration (Fig. 1). This apparent thio-
cyanate ion-promoted elimination could be attributed to
elimination either from the carbocation intermediate or
directly from the substrate. The latter base-promoted reaction
is a viable possibility since the increase in the fraction of 3 is
small and could not significantly change the total reaction rate.
Base-promoted E2 (or E1cB) reactions with this weak base
(pKHSCN = 0.23)18 in aqueous acetonitrile have been reported
previously for acidic substrates. The pKa of the β-hydrogens
adjacent to the carbonyl group should be high, close to that of
acetone (pKa = 19.3).19
Fig. 6 Brønsted plot for the solvolysis of 1-Cl in 25 vol% acetonitrile
in water at 40 ЊC assuming that the alkene 3 is formed exclusively by
dehydronation of the ion pair. Thus, the plotted slopes (see Fig. 3),
represent the apparent catalysis of the bases on ke (Scheme 3). The pKa
values refer to water at 25 ЊC.18,26
than expected for the dehydronation of a very unstable
carbocation intermediate. For example, the more stable cumyl
carbocation PhCMe2ϩ shows a Brønsted parameter of β = 0.13
under similar conditions,20 and the dehydronation of the
much more stable carbocation 8؉ exhibits a sensitivity to base
strength of β = 0.28.21 We therefore conclude that the alkene 3 is
formed partly or exclusively through another reaction path, viz.
the base-promoted E2 (or E1cB) reaction.
Added acetate ion does not have a rate-depressing effect on
the disappearance of the substrate as expected for a reaction
through a carbocation intermediate. We would expect an
approximately two-fold rate decrease for 0.75 M acetate ion for
‡ Hydron and hydronation are the generalnames, to be used without
regard to the nuclear mass of the hydrogen entity, recommended by
IUPAC, Organic Chemistry Division, Commission on Physical Organic
Chemistry, 1984.
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Alternative 2: alkene 3 is formed exclusively through a base-
promoted E2 (or E1cB) reaction
reaction through the ion pair yields predominantly the less
stable alkene 2. This result is in accord with previous studies
on solvolytic elimination reactions of specifically deuterated
substrates that demonstrated the importance of hyperconjug-
ative stabilization of the carbocationic transition state.12,13 The
relatively high kinetic acidity of the hydrogens of the methyl
group is attributed to this hyperconjugative weakening of the
carbon–hydrogen bonds in the methyl group.
Fig. 7 shows the Brønsted plot that corresponds to elimination
involving dehydronation of the substrate in an E2 or irrevers-
ible E1cB reaction. The slope is large, β = 0.76. The regression
line for the substituted acetate ions alone has a slope of
β = 0.51. The Brønsted parameter for the reaction of the
corresponding secondary substrate 5 with substituted acetate
ions has been reported as β = 0.67.7
Chloride-promoted elimination via the ion pair?
Addition of sodium chloride provides a small increase in
the fraction of alkenes (Table 2). This result is in accord with
previous reports for solvolysis reactions through unstable
carbocation intermediates. For example, the solvolysis reactions
of 7 and 9 exhibit an enhanced fraction of elimination products
when chloride ion is present in the reaction solution.10,12 Also a
more stable tertiary carbocation has been found to react more
efficiently with chloride ion than with solvent water.22 For 7,
this apparent catalysis from the chloride ion (pKHCl = Ϫ6.3)26 is
fairly well described by the Brønsted correlation of the rate
constants for dehydronation by substituted acetate ions (β =
0.05).12 For 9, the catalysis is more efficient, chloride ion shows
a 3-fold positive deviation from the Brønsted line (β = 0.07).10
Thus, chloride ion shows the same efficiency as trifluoroacetate
ion in abstracting a hydron from the ion pair that may reflect a
specific solvent effect.
It has been suggested that the chloride leaving group of
the ion pair may function as the hydron-abstracting base in
solvolytic elimination reactions.10,24,25,27,28 The thermodynamic
basicity of chloride ion is not high in water but its kinetic
basicity may be relatively high owing to incomplete solvation
of the leaving group in the ion pair. This proposal may account
for the fact that tertiary chlorides generally give larger fractions
of elimination than substrates with uncharged, neutral leaving
groups. Moreover, as discussed above, the catalytic effect of
water is lower than predicted by the pKa of H3Oϩ.
Fig. 7 Brønsted plot for the elimination reaction of 1-Cl to give alkene
product 3 (with the second-order rate constant k13) in 25 vol%
acetonitrile in water at 40 ЊC. The pKa values refer to water at 25 ЊC.18,26
We expect the putative water-promoted E2 elimination
reaction to be slower than predicted by the Brønsted line for the
negatively charged bases in accord with previous studies of E2
reactions.1–4,6,7 Dehydronation of carbocation intermediates
shows similar behavior.12,15,20–22 Negative deviations of water-
catalyzed reactions are well-known for hydron transfer to and
from carbon in which H2O and HOϪ are the hydron donor and
acceptor, respectively.23 The low catalytic activity of water as a
hydron acceptor in E2 reactions probably reflects some kind of
solvation effect. Therefore, the positive deviation (166-fold)
from the Brønsted plot suggests that the alkene 3 is formed by
another reaction path, i.e., through the ion pair (Scheme 3).
This reaction path is the major elimination route to alkene 3 in
the absence of added bases. In fact, we conclude that there is no
experimental evidence for any significant water-promoted E2
(or E1cB) reaction with 1-Cl despite the large acidity of the
substrate. This is in contrast to the solvolysis of the correspond-
ing secondary chloride 5 which shows E2 (or E1cB) reaction
with solvent water.7 These reactions are also expected to be
faster for a secondary than for a tertiary substrate.8
The same result was obtained previously for less acidic,
fluorene-activated tertiary substrates. For example, the
solvolysis of 9-(2-X-2-propyl)fluorene (X = Cl (7) or Br) does
not give a significant amount of the alkene 9-isopropyl-
idenefluorene despite a pKa of about 22.5.12,13 The reaction
predominantly gives 9-(2-propenyl)fluorene, the less stable
alkene product, by elimination of one of the methyl hydrons of
the ion pair. Obviously, the β-hydrogens have to be very acidic,
otherwise the E2 reaction is too slow compared to the ioniz-
ation of tertiary substrates. However, the corresponding
secondary fluorene substrate 9-(2-X-2-ethyl)fluorene ionizes
more slowly and therefore the water-promoted E2 reaction
becomes competitive.1,2,4,5
Experimental
General procedures
NMR spectra were recorded at 20 ЊC on a Varian Unity 300 or
400 spectrometer, for 1H at 300 or 400 MHz and for 13C at 75.4
MHz. Chemical shifts were indirectly referenced to TMS via
the solvent signal (chloroform-d1 7.26 and 77.16 ppm). The
high-performance liquid chromatography analyses were carried
out with a Hewlett-Packard 1090 liquid chromatograph
equipped with a diode-array detector on an Inertssil 3 ODS-3
(3 × 100 mm) reversed-phase column. The mobile phase was a
solution of acetonitrile in water. The reactions were studied at
constant temperature maintained with a HETO 01 PT 623
thermostat bath. The kinetic studies were also carried out
employing a Kontron Uvicon 930 spectrophotometer, equipped
with an automatic cell changer kept at constant temperature
with water from the thermostat bath.
Materials
Merck silica gel 60 (240–400 mesh) was used for flash chrom-
atography. Diethyl ether and tetrahydrofuran (THF) were
distilled under nitrogen from sodium and benzophenone.
Dichloromethane was dried over calcium chloride and freshly
distilled. Methanol and acetonitrile were of HPLC grade. All
other chemicals were of reagent grade and used without further
purification.
The products of the base-promoted elimination reactions are
3 and 4, i.e. the more stable products which are formed by
abstraction of one of the two acidic hydrons adjacent to the
carbonyl group. In contrast, the uncatalyzed elimination
4-Hydroxy-4-(4Ј-nitrophenyl)pentan-2-one (1-OH). This was
synthesized from 4-nitroacetophenone and acetone by a
slight modification of the procedure used for the secondary
analogue.7 To a solution of 4-nitroacetophenone (10 g) in 102
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ml of acetone were added 7 ml of a 1% aqueous KOH solution
at 0 ЊC. Stirring was continued at 0 ЊC for 1 h. The reaction was
then quenched by addition of 16 ml of saturated NH4Cl and
concentrated. The residue was dissolved in 100 ml of water and
extracted with ether (3 × 100 ml). The combined organic phases
were dried over MgSO4, filtered, and concentrated in vacuum.
The crude product contained only about 20% of the alcohol
(NMR). The rest was mainly unconverted 4-nitroaceto-
phenone, half of which could be recovered by recrystallization
from ether. The resulting residue after recrystallization was
separated by flash chromatography on a silica column with
CH2Cl2 as eluent. The combined components containing 1-OH
were further purified by repeated recrystallization from
pentane–ether, affording a slightly yellow crystal: mp 64.3–65.6
ЊC (Found: C, 59.25; H, 5.9; N, 6.3. C11H13NO4 requires C,
59.19; H, 5.87; N, 6.27%); 1H NMR (300 MHz), δ 8.19 (m, 2 H),
7.60 (m, 2 H), 4.67 (s, 1 H), 3.20 (d, J = 17.7 Hz, 1 H), 2.94 (d,
J = 17.7 Hz, 1 H), 2.13 (s, 3 H), 1.52 (s, 3 H); 13C NMR, δ 210.2,
155.0, 147.0, 125.6, 123.8, 73.37, 53.60, 31.83, 30.59.
4-(2Ј,2Ј,2Ј-Trifluoroacetoxy)-4-(4Ј-nitrophenyl)pentan-2-one
(1-OOCCF3). Alcohol 1-OH (0.53 g) was dissolved in dry
dichloromethane (20 ml), and dry pyridine (2 ml) and trifluoro-
acetic anhydride (1 ml) were added. The mixture was stirred at
room temperature overnight, and then most of the solvent was
evaporated. Ether was used to extract the crude product,
followed by washing twice with 0.5 M HCl, once with Na2CO3
(sat.) and twice with water, and then drying over magnesium
sulfate. Evaporation of the solvent gave a viscous oil (0.5 g),
which was purified by flash chromatography on a silica column
using 40–60 vol% ether in pentane. The purity (>99%) was
confirmed with NMR and HPLC. 1H NMR (400 MHz), δ 8.24
(m, 2 H), 7.57 (m, 2 H), 3.42 (d, J = 16.8 Hz, 1 H), 3.38 (d,
J = 16.8 Hz, 1 H), 2.10 (3 H, s), 2.09 (3 H, s); 13C NMR, δ 202.9,
155.5 (q, J = 42.2 Hz), 148.3, 147.7, 126.1, 124.0, 114.3 (q,
J = 285.0 Hz), 86.1, 52.9, 31.6, 24.4.
4-(4Ј-Nitrophenyl)-2-oxopent-4-ene (2). A solution of the
crude product 1-Br (0.37 g) dissolved in 75 vol% acetonitrile in
water (100 ml) was stirred at room temperature for 4 days.
Extraction with CH2Cl2 (3 × 100 ml), drying (MgSO4), and
flash chromatography (conditions as above) afforded the pure
colorless alkene: mp 52.0–54.7 ЊC (Found: C, 64.35; H, 5.4; N,
6.75. C11H11NO3 requires C, 64.38; H, 5.40; N, 6.83%). 1H
NMR (300 MHz), δ 8.18 (m, 2 H), 7.53 (m, 2 H), 5.73 (s, 1 H),
5.40 (s, 1 H), 3.66 (s, 2 H), 2.18 (s, 3 H).
4-Chloro-4-(4Ј-nitrophenyl)pentan-2-one (1-Cl). A solution of
1-OH (1.0 g) in dichloromethane (40 ml) containing anhydrous
calcium chloride and lithium chloride was cooled to 0 ЊC. Dry
hydrogen chloride was bubbled through the solution for 10 h.
After filtration, the resulting slightly yellow solution was
concentrated with a stream of nitrogen. The residue was
purified by flash chromatography on a silica column using
40–60 vol% ether in pentane. The product is a colourless liquid,
which is stable for several weeks in organic solvents, such as
diethyl ether or CDCl3, at Ϫ25 ЊC. 1H NMR (300 MHz), δ 8.20
(m, 2 H), 7.72 (m, 2 H), 3.50 (d, J = 17.0 Hz, 1 H), 3.39 (d,
J = 17.0 Hz, 1 H), 2.14 (s, 3 H), 2.10 (s, 3 H); 13C NMR, δ 203.6,
151.2, 147.2, 127.2, 123.6, 67.82, 57.84, 31.50, 31.15.
Kinetics and product studies
Reactions at 25 ЊC were monitored by an HPLC procedure.
The reaction solutions were prepared by mixing acetonitrile
with water or aqueous salt solution at room temperature, ca.
22 ЊC. The solvolysis experiments were run at pH < 6.5.
The reaction vessel was a 2-ml HPLC vial, sealed with a gas-
tight PTFE septum, which was placed in an aluminium
block kept at a constant 25 ЊC with water from the thermostat
bath. The concentration of the substrate in the reaction solu-
tion was in the range 0.05–0.10 mM. The volume of reaction
solution was usually 1.2 ml. The reactions were initiated by
fast addition of a few microliters of the substrate dissolved
in acetonitrile by means of a syringe. At appropriate intervals,
samples were analyzed using the HPLC apparatus. The reac-
tions were followed by monitoring the decrease in the peak
area of the substrate and the rate constants were calculated
from plots of the peak area versus time by means of a non-
linear regression computer program. The separate rate
constants for the elimination and substitution reactions
were derived by combination of product composition data,
obtained from the peak areas and the relative response
factors determined in separate experiments, with the observed
rate constants. The HPLC peaks of 2 and 4 were not fully
separated.
(E )-4-(4Ј-Nitrophenyl)-2-oxopent-3-ene (3). The alkene 3 was
formed as the main product when 1-Cl (neat) was decomposed
at room temperature. The resulting black solid was purified by
flash chromatography on a silica column using 40% ether in
pentane, followed by repeated recrystallization from diethyl
ether affording yellowish crystals: mp 104.1–105.8 ЊC (Found:
C, 64.35; H, 5.4; N, 6.8. C11H11NO3 requires C, 64.38; H, 5.40;
N, 6.83%); 1H NMR (400 MHz), δ 8.24 (m, 2 H), 7.61 (m, 2 H),
6.53 (d, J = 1.2 Hz, 1 H), 2.53 (d, J = 1.2 Hz, 3 H), 2.33 (s, 3 H);
13C NMR, δ 198.7, 151.0, 149.1, 148.0, 127.5, 126.9, 123,9,
32.41, 18.39.
(Z )-4-(4Ј-Nitrophenyl)-2-oxopent-3-ene (4). The alkene 4 is
formed in a small amount when 1-Cl is decomposed. The
alkene 4 eluted after the alkene 3 when separation was carried
out by flash chromatography on a silica column (conditions
as above). The isolated yellowish oil contained ca. 5% of 3
1
(NMR): H NMR (400 MHz), δ 8.21 (m, 2 H), 7.33 (m, 2 H),
6.29 (q, J = 1.2 Hz, 1 H), 2.18 (d, J = 1.2 Hz, 3 H), 2.03 (s, 3 H);
13C NMR, δ 197.8, 150.7, 148.3, 147.4, 128.1, 127.8, 123,7,
31.14, 27.05.
Reactions at 40 ЊC were followed by monitoring the increase
in the absorbance at 320 nm with a spectrophotometer. The
reaction solutions were prepared by mixing acetonitrile with
water at room temperature, ca. 22 ЊC. The reaction vessel was
a 3-ml tightly stoppered UV cell. The concentration of the
substrate in the reaction solution was in the range 0.05–0.10
mM. The volume of reaction solution was usually 2.4 ml. The
reaction was initiated by fast addition of a few microliters of
the substrate dissolved in acetonitrile by means of a syringe.
The reactions were followed for about 10 half-lives. The product
ratios were then obtained by HPLC analyses as described above
for the reactions carried out at 25 ЊC.
The reaction products 2, 3 and 4 were stable under the
reaction conditions. The substitution products 1-SCN and
1-NCS undergo a very slow decomposition to give alkenes
but this is not significant during the time of a solvolysis experi-
ment. The alcohol 1-OH affords 4-nitroacetophenone in basic
solution but is stable below pH 6.5.
4-Bromo-4-(4Ј-nitrophenyl)pentan-2-one (1-Br). A solution of
1-OH (0.83 g) in dry dichloromethane (3 ml) was added to
2.5 ml of concentrated HBr solution saturated with ZnBr2 in a
separatory funnel. The mixture was shaken for 15 s and the
reaction was quenched by addition of dry CH2Cl2. After sep-
aration, the organic phase was washed 3 times with water and
once with brine and dried over MgSO4. Filtering and evapor-
ation with a nitrogen stream afforded a lightly coloured liquid
that contained ca. 50% of 1-Br (NMR, the rest being mainly the
alkene 3). Owing to the instability of 1-Br, purification was not
successful. Therefore, this crude product was directly used in
1
kinetic measurements. H NMR (300 MHz), δ 8.21 (m, 2 H),
7.72 (m, 2 H), 3.83 (d, J = 17.5 Hz, 1 H), 3.59 (d, J = 17.5 Hz, 2
H), 2.38 (s, 3 H), 2.10 (s, 3 H).
J. Chem. Soc., Perkin Trans. 2, 2002, 1352–1358
1357

View Article Online
7 Q. Meng, B. Du and A. Thibblin, J. Phys. Org. Chem., 1999, 12, 116.
Determination of relative HPLC response factors. The relative
response factors for 1-OH and alkenes 2 and 3 were measured
by HPLC analysis of a mixture of the three components,
prepared by weighing. The relative response factor for alkene
3 and alkene 4 was determined by a combination of NMR
analysis and HPLC analysis. A mixture of appropriate amounts
of the two alkenes, 3 and 4, was dissolved in chloroform-d1 and
analysed by 1H NMR. The peak areas of the well-resolved
signals, such as methyl signals or alkenyl signals, were
integrated and used to calculate the relative molar ratio of the
two components, assuming that the NMR integrals exactly
corresponded to the expected number of protons. A few micro-
liters of this solution were transferred to a 2-ml HPLC flask.
The solvent was evaporated under a stream of nitrogen. The
residue was dissolved in acetonitrile and analyzed by HPLC.
The response factors of the other substitution products were
assumed to be the same as that of 1-OH.
8 R. A. More O’Ferrall, in Structure and Dynamics in Chemistry,
Proceedings from Symposium held at Uppsala 1977, eds. P. Ahlberg
and L.-O. Sundelöf, Acta Universitatis Upsaliensis, Symposia
Universitatis Uppsaliensis, Annum Quingentesimum Celebratis 12,
Almqvist and Wiksell International, Stockholm, p. 209.
9 A. Thibblin, J. Am. Chem. Soc., 1989, 111, 5412.
10 X. Zeng and A. Thibblin, J. Chem. Soc., Perkin Trans. 2, 2001, 1600
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11 A. Thibblin, J. Phys. Org. Chem., 1992, 5, 367.
12 A. Thibblin, J. Am. Chem. Soc., 1987, 109, 2071.
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15 J. P. Richard and W. P. Jencks, J. Am. Chem. Soc., 1984, 106, 1373.
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18 W. P. Jencks and J. Regenstein, Handbook of Biochemistry and
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19 Y. Chiang, A. J. Kresge, Y. S. Tang and J. Wirz, J. Am. Chem. Soc.,
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The estimated errors are considered as maximum errors
derived from maximum systematic errors and random errors.
Acknowledgements
We thank the Swedish Natural Science Research Council for
supporting this work.
22 M. M. Toteva and J. P. Richard, J. Chem. Soc., Perkin Trans. 2, 2001,
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23 A. Thibblin and W. P. Jencks, J. Am. Chem. Soc., 1979, 101, 4963
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27 M. Cocivera and S. Winstein, J. Am. Chem. Soc., 1963, 85, 1702.
28 Q. Meng and A. Thibblin, J. Chem. Soc., Perkin Trans. 2, 1999, 1397.
29 (a) C. A. Bunton, M. M. Mhala and J. R. Moffatt, J. Org. Chem.,
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J. Chem. Soc., Perkin Trans. 2, 2002, 1352–1358