Regioselectivity of the acidolysis of 2-(chloromethyl)oxirane with aromatic acids in the presence of organic bases

Article abstract of DOI:10.1134/S107042801403004X

Regioselectivity of the reaction of 2-(chloromethyl)oxirane with aromatic acids in the presence of tertiary amines and tetraalkylammonium halides has been studied. Opening of the oxirane ring follows simultaneously S_N2 and borderline S_N2 mechanisms. The regioselectivity of the acidolysis of substituted oxiranes is determined by acid-base properties of the reactants and catalysts and steric factor. The regioselectivity increases as the contribution of the S_N2 mechanism increases.

Full text of DOI:10.1134/S107042801403004X

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2014, Vol. 50, No. 3, pp. 332–336. © Pleiades Publishing, Ltd., 2014.
Original Russian Text © M.A. Sinel’nikova, E.N. Shved, 2014, published in Zhurnal Organicheskoi Khimii, 2014, Vol. 50, No. 3, pp. 343–348.
Regioselectivity of the Acidolysis of 2-(Chloromethyl)oxirane
with Aromatic Acids in the Presence of Organic Bases
M. A. Sinel’nikova and E. N. Shved
Donetsk National University, ul. Universitetskaya 24, Donetsk, 83001 Ukraine
e-mail: maryna_synel@mail.ru
Received September 27, 2013
Abstract—Regioselectivity of the reaction of 2-(chloromethyl)oxirane with aromatic acids in the presence of
tertiary amines and tetraalkylammonium halides has been studied. Opening of the oxirane ring follows
simultaneously SN2 and borderline SN2 mechanisms. The regioselectivity of the acidolysis of substituted
oxiranes is determined by acid–base properties of the reactants and catalysts and steric factor. The regio-
selectivity increases as the contribution of the SN2 mechanism increases.
DOI: 10.1134/S107042801403004X
Reactions of epoxy compounds with OH reagents
are widely used in the polymer chemistry for the
preparation of many commercially important products,
such as epoxy resins, modified components of coatings
and adhesives, various plasticizers, and optically trans-
parent materials, as well as in the pharmaceutical in-
dustry [1]. Oxirane ring constitutes a structural unit of
a number of biologically active compounds of both
natural and synthetic origin [2]. Alkylation of nucleo-
philic groups (OH, COOH, NH, etc.) with epoxy
derivatives is used as model reaction in studies on
mechanisms of biochemical processes, design of bio-
logically active compounds, and studies on complex
epoxide resin curing processes. An important factor in
biological processes and synthesis of drugs and epoxy
monomers is regioselectivity of oxirane ring opening
by nucleophiles. Insofar as substituted oxiranes possess
two competing electrophilic centers (C2 and C3), reac-
tions with hydroxy compounds can take two pathways
involving cleavage of the C3–O (α-cleavage; in keep-
ing with the Krasuskii rule) or C2–O bond (β-cleavage)
[3] with formation of normal product, secondary
alcohol I, or “anomalous” product, primary alcohol II
(Scheme 1).
benzoate reacted with benzoic acid to produce primary
alcohol like II which then isomerized into structure I
[8]. Predominant formation of anomalous isomer II
was observed in the reaction of phenyloxirane with
aromatic acids [9]. Under analogous conditions,
glycidyl phenyl was converted mainly into the normal
oxirane ring opening product [8].
The present work was aimed at studying the regio-
selectivity of the acidolysis of 2-(chloromethyl)oxirane
(1-chloro-2,3-epoxypropane, epichlorohydrin) with
carboxylic acids catalyzed by organic bases, tertiary
amines and tetraalkylammonium salts. The reactions
were carried out at 60.0±0.1°C using the substrate as
solvent, i.e., under the conditions corresponding to
large-scale synthesis of glycidyl esters from carboxylic
acids. As nucleophiles we used benzoic acid and 2- and
3-nitrobenzoic acids. The fractions of anomalous prod-
ucts II in the acidolysis of epichlorohydrin with ben-
zoic acids under catalytic and non-catalytic conditions
are given in Table 1.
The non-catalytic reaction revealed a linear relation
between the yield (η, %) of II and pKa of the acid: the
Scheme 1.
R
α-Cleavage
Nu
In the reactions of 2-methyloxirane with carboxylic
acids (acetic, di- and trichloroacetic, acrylic, and
methacrylic) the fraction of the anomalous product
reaches 20−50%, depending on the acid and catalyst (if
added) nature and temperature [4, 5]. Catalytic reac-
tions of phenols with oxiranes give normal products I
regardless of the reaction conditions [6, 7]. Glycidyl
OH
R
Catalyst
I
+ NuH
O
R
β-Cleavage
OH
Nu
II
332

REGIOSELECTIVITY OF THE ACIDOLYSIS OF 2-(CHLOROMETHYL)OXIRANE
333
Table 1. Yields of anomalous addition product II in the reactions of benzoic acids RC6HxCOOH with epichlorohydrin
Yield, %
R
pKa
Temperature, °C Acid concentration, M
Catalyst
with catalyst
without catalysta
4-MeO
H
4.49
4.18
80
80
60
60
60
60
80
80
60
60
0.401a
1.25a
Me4NCl
Me4NCl
Et4NBr
PhNMe2
Et4NBr
PhNMe2
Me4NCl
Me4NCl
Et4NBr
a17.8a
a20.0a
24.8
2.
26.2
19.4
a25.3a
a21.4a
24.4
18.0
08.8
14.9
–
–
–
0.300
0.295
0.297
0.297
0.247a
0.393a
0.300
0.300
3-NO2
3.49
–
4-NO2
3,5-(NO2)2
2-NO2
3.44
2.85
2.17
20.9
29.2
–
PhNMe2
–
a
Data of [5].
fraction of II increases in parallel with pKa values:
ηII = (62±4) + (–11±1)pKa, r = 0.984. In the acidolysis
of epichlorohydrin with aromatic acids catalyzed by
tetraalkylammonium salts the amount of isomer II
almost did not depend on the acidity of the reagent
(Table 1) and catalyst structure (counterion nature and
the length of hydrocarbon radical). The regioselectivity
of the process did not change to an appreciable extent
in the series of aliphatic carboxylic acids. The yield of
isomer II in the reactions with acetic (Et4NBr as cata-
lyst) [10], butyric, and pivalic acids (Et4NI) [4] was 24,
18, and 18%, respectively. Thus, the yield of anoma-
lous product II in the presence of tetraalkylammonium
halides is virtually independent of pKa of carboxylic
acids. The reactions of carboxylic acids with epi-
chlorohydrin catalyzed by tertiary amines were more
selective (Table 1). The yield of II in the reactions with
butyric and pivalic acids in the presence of tetraethyl-
ammonium iodide and triethylamine was 17–18%, and
it decreased to 15% in the presence of sodium hydrox-
ide [4]. Catalysis by metal carboxylates ensured higher
regioselectivity (Table 2).
The yield of II under catalysis by alkali metal
acetates did not depend on the cation nature. The
regioselectivity considerably increased when alkali
metal cation was replaced by chromium(III). This is
likely to be related to structural factors. It is known
that coordinated water molecule in chromium(III)
complexes is very labile and that it can be replaced by
organic solvent molecule with retention of the struc-
ture of the complex [14]. As a result, the catalytic
center shifts toward the chromium coordination sphere,
which increases the regioselectivity.
The fraction of isomer II decreases as the length of
the hydrocarbon chain in carboxylic acid increases. In
the reactions of methyloxirane with alcohols catalyzed
by the corresponding metal alkoxides the yield of II
also decreased in parallel with pKa of the reagent
(Table 2). An exception is phenol which gives rise to
only one isomer I, which may be rationalized by steric
hindrances to the attack on C2 of oxirane by large
phenoxide ion.
Me
O
C
Analysis of the above experimental data shows that
the regioselectivity of oxirane ring opening with OH
nucleophiles is controlled by both steric factors and
acidic properties of the reagent or catalyst (Scheme 2).
O
B
O
O
Cr
O
Cr
O
Scheme 2.
H+
B
R
I ≈ II
+ NuH
I > II (I >> II)
O
O
C
O
From the viewpoint of the effects of steric factors
and acid–base properties of the reagent and catalyst,
Me
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SINEL’NIKOVA, SHVED
334
Table 2. Yield of anomalous addition product II in the reactions of epichlorohydrin with carboxylic acids in the presence of
metal acetates [11] and in the reactions of methyloxiranes with alcohols in the presence of alkoxides [7]
Reagent
pKa [12]
Es [13]
Catalyst
Yield, %
Epichlorohydrin + acid
–0.00
Acetic
04.75
AcOLi
AcONa
AcOK
Cr(OAc)3
Cr(OAc)3
Cr(OAc)3
Cr(OAc)3
Cr(OAc)3
Cr(OAc)3
Cr(OAc)3
14.9
15.6
14.8
08.1
12.7
06.3
04.0
01,4
07.1
03.9
Propionic
Hexanoic
Heptanoic
Nonanoic
Acrylic
04.87
04.86
04.86
04.89
03.26
04.43
–0.07
–0.40
Methacrylic
Methyloxirane + alcohol
Methanol
Ethanol
Butan-1-ol
Propan-2-ol
Phenol
15.09
15.93
16.10
17.10
09.97
MeONa
EtONa
BuONa
i-PrONa
PhONa
04.5
02.9
02.2
02.6
0.
–0.07
–0.39
–0.47
–1.24
SN1, SN2, and “borderline” SN2 mechanisms are pos-
sible, where the electrophilic center may be C2 or C3 in
substituted oxirane.
Acid-catalyzed reactions were previously consider-
ed to follow SN1 mechanism involving proton addition
to the oxirane oxygen atom, loosening of the C–O
bond, and its subsequent cleavage with formation of
carbocation C1 or C2. Among these, cation C1 in which
the positive charge localized on a secondary carbon
atom is more stable (Scheme 3).
nism. However, discussions on the mechanisms of
acid-catalyzed reactions [15] showed that the most ap-
propriate is the theoretical model proposed by Parker
and Isaacs [16] who presumed so-called “borderline”
SN2 mechanism. In keeping with that mechanism, “the
reagent is further away than usual from the seat of
attack, and the driving force of the reaction is provided
more by transfer of electrons from carbon to oxygen
than from reagent to carbon” [16].
In neutral and basic media SN2 and borderline SN2
mechanisms are operative with the possibility for
attack directed at both primary (C3) and secondary
carbon atoms (C2) with account taken of steric factor
to which SN2 mechanism is more sensitive [15].
Therefore, the formation of solely normal addition
product as a result of attack on C3 is indicative of SN2
mechanism, whereas a mixture of normal and anoma-
lous products is formed according to borderline SN2
mechanism implying attack on both primary (C3) and
secondary carbon atoms (C2).
Scheme 3.
R
HO
R
R
H+
C1
O
O
H
OH
R
CH2
C2
This statement is based on the fact that the amounts
of normal and anomalous addition products are com-
parable. In the reactions of methyloxirane with metha-
nol and ethanol catalyzed by HClO4 [9] isomers I and
II were formed in 47.6 and 46.7% yield, respectively,
and the reaction was presumed to follow SN1 mecha-
The reaction system under study (Scheme 1)
includes both acid (OH reagent) and base (amine or
ammonium salt as catalyst). Analysis of possible paths
for nucleophilic substitution in the oxirane ring of
epichlorohydrin and experimental data (Tables 1, 2)
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REGIOSELECTIVITY OF THE ACIDOLYSIS OF 2-(CHLOROMETHYL)OXIRANE
335
Scheme 4.
≠
B
R
R
R
Nu–
B
O
OH
R
HNu
TS1
B
B
O
≠
HNu
R
Nu–
HO
O
B
HNu
TS2
led us to conclude that the most probable is SN2
mechanism with some contribution of borderline SN2
version (Scheme 4).
borderline SN2 mechanism and increase of the contri-
bution of SN2 path.
To conclude, the regioselectivity of the base-
catalyzed acidolysis of epichlorohydrin depends on the
proportion of the borderline SN2 and SN2 mechanisms,
which is determined in turn by acid–base properties of
the reagent and catalyst and steric factors. The regio-
selectivity of reactions of substituted oxiranes with OH
nucleophiles may be improved by using sterically
loaded catalysts such as trialkylamines and chromium
complexes.
Reduction of the acidity of the reagent (cf. carbox-
ylic acids and alcohols) and increase in steric hin-
drances (cf. alcohols and phenols) favors an appre-
ciable prevalence of the normal addition product
originating from transition state TS1, i.e., the SN2
mechanism predominates. This is also confirmed by
the dependence of the yield on the nucleophile size
which is characterized by steric constant Es (Table 2).
Using the equation ηII = A + α Es (where α is the
reaction sensitivity to steric accessibility of the reac-
tion center) for the reactions of epichlorohydrin with
alcohols and phenol we obtained ηII = (3.8 ±0.4) +
(3.1±0.6)Es, r = 0.942, s = 0.626; it follows therefrom
that increase in the role of steric factor in the nucleo-
phile (reduction of nucleophilicity) decreases the pro-
portion of product II formed according to the SN2
mechanism. Gled and Jensen [17] studied the relation
between the reagent nucleophilicity and secondary
kinetic isotope effect, and their results also supported
SN2 character of the reaction under study.
The activation parameters are very sensitive to
reaction mechanism. For instance, SN1 reactions are
characterized by higher energies (Ea > 100 kJ/mol) and
entropies of activation (ΔS≠ > −100 J mol–1 K–1) as
compared to SN2 reactions (Ea < 100 kJ/mol, ΔS≠ <
–100 J mol–1 K–1) [18]. The activation parameters of
the reactions of epichlorohydrin with benzoic acids in
the presence of tetraethylammonium bromide and
N,N-dimethylaniline conform to the SN2 mechanism
(Table 3). The activation parameters of the reactions
catalyzed by N,N-dimethylaniline are lower, which
may be due to reduced contribution of the attack on the
sterically more hindered C2 atom and increased con-
tribution of transition state TS1 (Scheme 4). This
corresponds to decrease in the contribution of the
EXPERIMENTAL
1
The H NMR spectra were recorded at 25°C from
solutions in DMSO-d6 on a Bruker Avance II instru-
ment operating at 400 MHz; the chemical shifts were
determined relative to tetramethylsilane. Epichloro-
hydrin was dried over sodium sulfate and distilled
twice under atmospheric pressure, a fraction with
bp 116–116.5°C (116°C [12]) being collected. Aro-
matic acids were purified by recrystallization from
water, N,N-dimethylaniline was distilled under reduced
pressure, and tetraethylammonium bromide was re-
crystallized from ethanol−benzene (2:3). The physical
constants of the acids and bases used were consistent
with reference data [12].
The reaction kinetics were studied in the tempera-
ture range from 30 to 70°C, the initial acid–2-(chloro-
methyl)oxirane molar ratio being 0.3:12. Under these
conditions, the reaction was of first order in the sub-
strate and of zero order in acid reagent. The progress
of reactions was monitored by measuring the carbox-
ylic acid concentration by potentiometric titration.
The ratio of the normal and anomalous addition
products was determined from the intensities of the CH
1
and CH2Cl proton signals in the H NMR spectra. The
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 50 No. 3 2014

SINEL’NIKOVA, SHVED
336
Table 3. Observed rate constants k and activation parameters of the reactions of benzoic acids RC6H4COOH (0.300 M) with
epichlorohydrin (12.2–12.3 M) in the presence of N,N-dimethylaniline and tetraethylammonium bromide (0.005 M)
R
Catalyst
k×106, s–1 (60°C)
Ea, kJ/mol
–ΔS≠333, J mol–1 K–1
H
Et4NBr
PhNMe2
Et4NBr
PhNMe2
Et4NBr
PhNMe2
3.33±0.05
1.23±0.11
2.90±0.04
1.78±0.01
4.33±0.09
2.79±0.02
75.6±0.3
66.8±1.1
76.9±0.5
67.2±2.0
77.4±0.7
72.5±1.8
095.5
133.0
093.8
127.0
088.9
106.0
3-NO2
2-NO2
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culated by ChemBioDraw Ultra 12.0.
3-Chloro-2-hydroxypropyl benzoate. A solution
of benzoic acid (0.3 M) and catalyst (0.5 mM) in
150 mL of epichlorohydrin was heated for 6 h at 60°C.
The mixture was washed with water until neutral
washings and dried over anhydrous MgSO4, and
excess epichlorohydrin was distilled off under reduced
pressure. Yield 89%, light yellow oily material.
1H NMR spectrum, δ, ppm: 3.6 d (2H, CH2Cl), 4.1 m
(1H, CH), 4.5 d (2H, CH2). Found, %: C 55.89;
H 5.21; Cl 16.48. C10H11ClO3. Calculated, %: C 55.94;
H 5.13; Cl 16.55.
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3-Chloro-2-hydroxypropyl 3-nitrobenzoate was
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1
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Yield 92%, yellow oily substance. H NMR spectrum,
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δ, ppm: 3.62 d (2H, CH2Cl), 4.05 m (1H, CH), 4.38 d
(2H, CH2). Found, %: C 46.32; H 3.77; Cl 13.59;
N 5.45. C10H10ClNO5. Calculated, %: C 46.24; H 3.85;
Cl 13.68; N 5.39.
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