Kinetics and mechanism of the hydrolysis of tetrahydro-2-furyl and tetrahydropyran-2-yl alkanoates

Article abstract of DOI:10.1039/a708422f

The kinetics and mechanism of the hydrolysis of tetrahydro-2-furyl and tetrahydropyran-2-yl alkanoates in water and water-20% ethanol are reported. In acidic and neutral media, kinetics, activation parameters, ¹⁸O isotope exchange studies, substituent effects, solvent effects and the lack of buffer catalysis point clearly to an A_A1-1 mechanism with formation of the tetrahydro-2-furyl or tetrahydropyran-2-yl carbonium ion as the rate-limiting step. There is no evidence of a base-promoted B_AC-2 mechanism up to pH 12.

Full text of DOI:10.1039/a708422f

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Kinetics and mechanism of the hydrolysis of tetrahydro-2-furyl and
tetrahydropyran-2-yl alkanoates
C. Dennis Hall* and Vu Truong Le
Department of Chemistry, King’s College London, Strand, London, UK WC2R 2LS
The kinetics and mechanism of the hydrolysis of tetrahydro-2-furyl and tetrahydropyran-2-yl alkanoates
in water and water–20% ethanol are reported. In acidic and neutral media, kinetics, activation parameters,
18O isotope exchange studies, substituent effects, solvent effects and the lack of buffer catalysis point
clearly to an AA1-1 mechanism with formation of the tetrahydro-2-furyl or tetrahydropyran-2-yl
carbonium ion as the rate-limiting step. There is no evidence of a base-promoted BAC-2 mechanism
up to pH 12.
O
Introduction
OEt
R2
R3
R4
O
The mechanism of hydrolysis of 1-alkoxyalkyl alkanoates (1)
often referred to by the generic term ‘acylals’ has received con-
R1C(O)OCR3
O
R1
O
R4
R2
siderable attention over the past 30 years since acylals are of
O
interest as intermediates in enzymic reactions.1 These com-
3
1
2
pounds contain both an ester function and an acetal function
and hence, in theory, may hydrolyse by the whole range of
mechanisms available to both functional groups under acidic,
neutral or basic conditions.2 In practice, however, convincing
evidence has accumulated to suggest that under acidic condi-
tions, hydrolysis of (1, R2 = R3 = H) occurs via an AAc-2 mech-
anism in dilute acid with a changeover to a AA1-1 mechanism of
type (a) in more concentrated acid media (Scheme 1).3
O
X
Y
R3
R4
O
O
O
O
R1
O
MeO
OMe
R2
X
O
4
5
6
O
C
R2
C
R1
O
R3
R4
RCO2CH(Me)OC6H4X
1
OC(O)R
OC(O)R
O
H+
9
7
8
OH
R2
C
OH
C
R2
OEt
CH2OH
O
H2O (dilute acid)
rls
R1 C+
O
R3
R1
O
C
R3
C(O)OCHCH3
OR4
–2
OR4
+OH2
OH
OCO
AAc
OCOCH3
MeC(O)OCH2OMe
HO
rls
AAl
CH3COO
–1
(type a)
O
O
11
+
10
12
CR2R3
H2O
fast
R1
C
OH
R1
C
OH
R2R3C
+
O
R4OH
+
+
OR4
The hydrolysis of the cyclic acylal (2) has also been studied as
a function of pH at 30 ЊC.6 At low pH, a specific hydronium-ion
catalysed reaction occurred which was ascribed to an A-1 reac-
tion proceeding via pre-equilibrium protonation followed by
rate-limiting unimolecular dissociation of the intermediate. At
high pH, a hydroxide ion promoted reaction occurred consist-
ent with the BAc-2 mechanism, but the pH–rate profile revealed
a large plateau between pH 5 and 9 in which the carboxylate ion
was thought to act as the leaving group in a SN1-type reaction.
A comparison has also been made between the mechanism of
hydrolysis of 1,3-dioxolones (3) and that of the 1,3-dioxolanes
(4) from which it was clear that under acid-catalysed conditions,
the dioxolanes hydrolysed by an A-1 mechanism, whereas the
dioxolones followed an AAc-2 mechanism or an AA1-1 mechan-
ism dependent upon the substituents (R1–R4).7 The rates of
hydrolysis of methyl esters of pseudo-8-aroylnaphthoates (5)8
and 3-methoxy-3-arylphthalides (6)9 have also been studied in
aqueous sulfuric acid and/or perchloric acids. The application
of criteria such as rate–acidity correlations (Zucker–Hammett,
Bunnett and φ), entropy of activation, deuterium oxide solvent
fast H2O
O
C
R2
O
AAl
–1
+
1 + H+
R1
O
C
R3
R1
C
O
C
R2R3
(type b)
HOR4
+
+ R4OH
Scheme 1
The alternative AA1-1 mechanism (type b) involving proton-
ation and dissociation of the acetal alkoxy group was con-
sidered unlikely on the basis of several arguments including the
fact that methylene diacetate required very strong (78%)
sulfuric acid to effect a changeover to the A-1 mechanism.4 The
point at which the change in mechanism occurs, however,
depends upon the structure of the oxyalkyl ester. Thus 1-
alkoxyalkyl formates follow the AAc-2 mechanism whereas
analogous esters from acetic acid follow a predominantly AA1-1
mechanism.5
J. Chem. Soc., Perkin Trans. 2, 1998
1483

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isotope effects and Hammett correlations led to the conclusion
that in both cases the reactions proceeded via a unimolecular
mechanism involving an alkoxycarbonium ion.
We recently reported the kinetics and mechanism of the
hydrolysis of 1-aryloxyethyl alkanoates (7) which in acidic
media (< pH 3) follow the AA1-1 mechanism and in basic media
(pH > 9) are hydrolysed by the conventional BAC-2 mechanism.
In neutral medium (pH 2.5–9) there was a certain amount of
conflicting evidence which led to the suggestion of rate-limiting
attack of water on the acyl carbon of (7) through an intermedi-
ate involving intramolecular hydrogen bonding.10
This paper reports the kinetic results associated with the
hydrolysis of alkanoates (8) and (9) derived from 2,3-dihydro-
furan and 2,3-dihydropyran respectively.
Experimental
Preparation of tetrahydro-2-furyl propionate (8, R ؍ Et)
2,3-Dihydrofuran (5.00 g, 0.07 mol) was added to propionic
acid (5.3 g, 0.07 mol) and the mixture was stirred at room tem-
perature for 15 h. The product was then purified by fractional
distillation under reduced pressure to yield 8.6 g (85% yield) of
(8, R = Et), bp 72–4 ЊC at 15 mmHg, M = 144.0823 (calc. for
C7H12O3 = 144.0786); δH(CDCl3) 1.15 (3H, t, CH3CH2), 1.9–2.1
(4H, m, C᎐CH2᎐C), 2.3 (2H, q, CH3CH2CO), 3.9–4.10 (2H, d
of m, CH2O), 6.30 (1H, t, OCHO); δC(DEPT) 8.9(ϩ)
(CH3CH2), 22.9, 32.9(Ϫ) (C᎐CH2᎐C), 27.9(Ϫ) (CH3CH2CO),
Fig. 1 Plot of kobs/10Ϫ2 vs. pH for the hydrolysis of 8 (R = Et) in H2O
at 20 ЊC, µ = 0.1 
Kinetic measurements
Rate measurements were carried out on a Hewlett Packard
Diode-Array 8452A spectrophotometer controlled by a Vectra
QS/HS computer and fitted with a thermostatted cell com-
partment regulated to 0.2 ЊC by a Grant thermostat water-
bath. Stock solutions of the substrates (1–5 × 10Ϫ2 ) were
prepared in dry acetonitrile and reactions were initiated by add-
ition of 3 ml of each acylal solution to pre-equilibrated cuvettes
containing 3 cm3 of aqueous solution. The final concentrations
of substrates were in the region of 1–5 × 10Ϫ5 . At pH values
between 6–11 the reactions were carried out in KH2PO4–NaOH
buffer (0.02 ) and below pH 6 a CH3CO2Na–HCl buffer (0.02
) was used. The pH of each solution was determined before
and after each run with a Metrohm 691 pH meter to check the
constancy of pH throughout the kinetic run. Buffer solutions
were prepared according to the methods reported by Britton11
and the ionic strength was kept constant at 0.1  by addition of
potassium chloride. The UV spectra of the products (identified
by NMR) in the appropriate buffer, were identical to those
obtained in the kinetic runs.
68.9(Ϫ) (CH O), 98.8(ϩ) (OCHO), 174.0(0) (C᎐O).
᎐
2
General preparation of tetrahydro-2-furyl alkanoates (8)
The reactions were carried out with the appropriate carboxylic
acid and 2,3-dihydrofuran in a 1:1 molar ratio with dry toluene
as the solvent. Thus, for example, 2-bromopropionic acid (5.6 g,
70 mmol) in toluene (5 ml) was added dropwise to a solution of
2,3-dihydrofuran (5.00 g, 70 mmol) in toluene (3 ml) with stir-
ring. For reactions using carboxylic acids with pKa < 4 the
dihydrofuran was cooled in an ice bath. The mixtures were left
to stir overnight at room temperature and the solvent was evap-
orated prior to vacuum distillation. The boiling points, % yields
and 1H NMR data are recorded in Table A and the mass
spectroscopy and 13C NMR data appear in Table B, both as
supplementary information.†
Preparation of tetrahydropyran-2-yl propionate (9, R ؍ Et)
A mixture of 2,3-dihydropyran (5.00 g, 0.06 mol), propionic
acid (4.4 g, 0.06 mol) and anhydrous phosphoric acid (0.10 g,
10Ϫ3 mol) was stirred at room temperature for 30 min. The
solution was then filtered through a bed of basic alumina to
remove the phosphoric acid catalyst. The product was purified
by fractional distillation under reduced pressure to yield 7.3 g
(78%) of the title compound, bp 80–82 ЊC at 15 mmHg,
M = 158.1058 (calc. for C8H14O3 = 158.0943); δH(CDCl3) 1.18
(3H, t, CH3CH2), 1.55–1.93 [6H, m, C–(CH2)3–C], 2.40 (2H, q,
CH3CH2CO), 3.7–4.0 (2H, d of m, CH2O), 5.98 (1H, t,
OCHO); δC(DEPT) 9.0(ϩ) (CH3CH2), 18.8, 25.0, 29.3 (all Ϫ)
(C᎐CH2᎐C), 27.8(Ϫ) (CH3CH2CO), 63.4(Ϫ) (CH2O), 92.5(ϩ)
Results and discussion
Kinetics and mechanism of the hydrolysis of tetrahydro-2-furyl
propionate
The rate of hydrolysis of tetrahydro-2-furyl propionate was
monitored by UV–VIS spectrophotometry at λ = 222 nm. The
kinetic experiments were carried out at 20 0.2 ЊC in aqueous
buffer, and at 25 0.2 ЊC for 20% EtOH–H2O (v/v) buffer.
For ease of comparison, it was necessary to use the latter
aqueous alcoholic buffer for the hydrolysis of tetrahydro-2-
furyl propionate because its analogue (tetrahydropyran-2-yl
propionate, vide infra) was immiscible with pure aqueous buffer.
The hydrolysis reactions were carried out under pseudo-first-
order conditions with the concentration of buffer in large excess
(2 × 10Ϫ2 ) relative to the substrate (1–5 × 10Ϫ5 ) and the rate
of hydrolysis was obtained by plotting ln (At Ϫ A∞) against time
to give a gradient = Ϫkobs. An example of a pseudo-first-order
plot for the hydrolysis of tetrahydro-2-furyl propionate is
shown in Fig. A (supplementary information).
pH–rate profiles. The hydrolysis of tetrahydro-2-furyl pro-
pionate was followed in H2O and in EtOH–H2O (20% v/v) buf-
fers over a range of pH (2–12) at constant ionic strength (0.1 ).
The rate coefficients for hydrolysis in H2O (T = 20 ЊC) appear in
Table E (supplementary information) and are plotted in Fig. 1.
The results for hydrolysis in EtOH–H2O buffer at 25 ЊC are
summarised in Table F (supplementary data) and again show
that there is a region of acid-catalysed hydrolysis (pH 2–4) and
(OCHO), 173.3 (0) (C᎐O).
᎐
General preparation of tetrahydropyran-2-yl alkanoates (9)
The synthesis of tetrahydropyran-2-yl alkanoates followed a
similar procedure to that for the tetrahydro-2-furyl alkanoates
(vide supra). The yields, bps and 1H NMR data are recorded in
Table C and the mass spectrometry and 13C NMR data in Table
D, again as supplementary information.
† Tables A–I and Figs. A–C are available as supplementary data
(SUPPL. NO. 57372, 11 pp.) from the British Library. For details of the
Supplementary Publications Scheme, see ‘Instructions for Authors’ J.
Chem. Soc., Perkin Trans. 2, available via the RSC Web page (http://
www.rsc.org/authors).
1484
J. Chem. Soc., Perkin Trans. 2, 1998

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Table 1 Rate coefficients for the hydrolysis of 8 (R = Et)
for hydrolysis in EtOH–H2O) they are comparable with other
acylals, which are alleged to react by an SN1 mechanism in the
pH-independent region with larger negative entropy values. For
example, the uncatalysed hydrolysis of methoxymethyl acetate
(10)5 and γ-ethoxy-γ-butyrolactone (2)6 have ∆S‡ values of
Ϫ48.0 J molϪ1 KϪ1 and Ϫ77.0 J molϪ1 KϪ1 respectively. The
slightly negative entropy of activation is probably due to sol-
vent reorganisation in progressing from a neutral ground state
to a dipolar transition state in the rate-determining unimolecu-
lar (dissociative) process.
kH/dm3 sϪ1 molϪ1
ko/10Ϫ3 sϪ1
14.0
100% H2O
@ 20 ЊC
20% EtOH
@ 25 ЊC
13.4
18.2
9.64
Table 2 kobs values for the hydrolysis of 8 (R = Et) as a function of
temperature (T) in the acidic region
In the acid-catalysed region, the values of the entropy of
activation are found to be positive, suggesting that the
(a) at pH 2.71 (H2O)
(b) at pH 3.69 (20% aq. EtOH)
hydrolysis also proceeds via a unimolecular mechanism (AAL
1
T/K
kobs/10Ϫ2 sϪ1
T/K
kobs/10Ϫ3 sϪ1
or AAC1), in which the substrate undergoes pre-equilibrium
protonation and then undergoes unimolecular dissociation in
the rate-determining step (Scheme 2). Other acylals and acetals
293.1
300.5
307.7
318.5
3.80
8.33
17.1
43.3
288.0
298.1
304.0
313.1
319.5
4.54
12.4
22.9
54.0
102
( )n
( )n
δ–
slow
δ+
O(CO)Et
O(CO)Et
O
O
–EtCO2–, slow
H+
Table 3 kobs values for the hydrolysis of 8 (R = Et) as a function of
temperature (T) in the neutral region
( )n
( )n
+
O
–EtCO2H, slow
+
(a) at pH 7.25 (H2O)
(b) at pH 7.50 (20% aq. EtOH)
OCEt
O
T/K
kobs/10Ϫ2 sϪ1
T/K
kobs/10Ϫ3 sϪ1
OH
H2O*
( )n
293.1
300.5
307.7
318.5
1.24
2.50
5.60
14.8
288.0
298.1
304.0
313.1
319.5
2.54
7.08
14.2
34.0
67.0
( )n
–H+, fast
O*H
+
O*H2
O
O
Scheme 2 (n = 1 or 2; * = 18O)
Table 4 Activation parameters for the hydrolysis of 8 (R = Et)
which have been alleged to hydrolyse by the above mechanism
EA/kJ ∆H‡/kJ
∆G‡/kJ
∆S‡/J
include the acid-catalysed hydrolysis of methoxymethyl acetate
pH
molϪ1 molϪ1
molϪ1
molϪ1 KϪ1
5,7
[(10), ∆S‡ = ϩ14 J molϪ1 KϪ1
]
and γ-ethoxy-γ-butyrolactone
[(2), ∆S‡ = Ϫ29 J molϪ1 KϪ1].6
100% H2O
@ 25 ЊC
 7.25

77
74
80
76
74
72
77
73
82
65
85
66
Ϫ27
 2.71
ϩ22
Ϫ25
ϩ25
The solvent effect. Changing the solvent in which a reaction is
carried out often produces a profound effect on its rate. Hussain
and co-workers12–14 investigated the hydrolysis of several
acylals in the pH-independent region by varying the solvent
medium. The same method was employed to determine the
effect of solvent dielectric on the hydrolysis of tetrahydro-2-
furyl propionate in the neutral region (pH 7.25) at concen-
trations of 0, 5, 10, 20 and 25% dioxan (v/v) and the results
appear in Table G (supplementary data).
20% EtOH–H2O  7.50

@ 25 ЊC
 3.69
a pH-independent or uncatalysed hydrolysis (4 у pH р 12).
The overall rate is therefore described by eqn. (1), where
kobs = kH[Hϩ] ϩ ko
(1)
kH = second-order rate constant for the acid-catalysed hydroly-
sis, [Hϩ] = hydronium ion concentration and ko = rate constant
for the uncatalysed hydrolysis. From eqn. (1), the values of kH
and ko are obtained by plotting kobs vs. [Hϩ] in water (Fig. B,
supplementary information). A similar plot is found in EtOH–
H2O and the gradient of each straight line graph gives kH. The
pH-independent region (and the intercept) gives ko and the
values of the parameters in each medium are given in Table 1.
Variation of reaction rate with temperature. The activation
parameters for the hydrolysis of each substrate were determined
by measuring the rate of reaction in the acid and neutral
regions over a temperature range at constant pH. In the acid-
catalysed region, the rates were measured at 20, 27, 35 and
45 ЊC for hydrolysis in H2O (Table 2a) and at 15, 25, 31, 40 and
46 ЊC (Table 2b) for hydrolysis in EtOH–H2O (20% v/v) buffers.
In the neutral region, the rates were also measured at 20, 27, 35
and 45 ЊC (Table 3a) for hydrolysis in H2O and at 15, 25, 31, 40
and 46 ЊC (Table 3b) for hydrolysis in 20% EtOH–H2O.
If the rate-limiting step is accompanied by an increase in
electrical charge on the reactant, a change to a more polar sol-
vent will cause an increase in the rate. The magnitude of the rate
acceleration produced by increasing the polarity of the solvent
(× 20 from 25% dioxane–H2O to H2O) is consistent with a
mechanism in which there is a high degree of ionic character in
the transition state. The negative slope obtained for the plot
(Fig. 2) of kobs versus the reciprocal of the relative permittivity,15
is similar to that found by Hussain12–14 for the unimolecular
SN1 decomposition of 1-ethoxyethyl 2-acetoxybenzoate (11)
and 1-(2-acetoxybenzoyl)-2-deoxy-α--glucopyranose (12).
H218O labelling. 18O-Labelling experiments were carried out
to confirm the proposed mechanism for the hydrolysis of
tetrahydro-2-furyl propionate under acidic and neutral condi-
tions. The experiments were carried out using a known ratio of
H216O:H218O and the 18O-isotope effect on the 13C NMR shift
was used to identify the labelling in the hydrolysis products10
and hence to determine whether a particular bond was broken
in or before the rate-limiting step of a reaction. The reaction
mixture for the labelling experiment contained H216O and
H218O in an approximate ratio of 6:4 respectively.
The values of activation parameters for tetrahydro-2-furyl
propionate in H2O and in EtOH–H2O (20% v/v) buffer are
summarised in Table 4. Although the values of entropy of acti-
vation obtained in the neutral region are negative (∆S‡ = Ϫ27 J
molϪ1 KϪ1 for hydrolysis in H2O and ∆S‡ = Ϫ25 J molϪ1 KϪ1
The acidic region. The 13C NMR chemical shifts with respect
to 16O and 18O bonded carbon appear in Table 5a. The 18O label
J. Chem. Soc., Perkin Trans. 2, 1998
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Table 5 13C NMR data for 16O/18O shifts
Table 6 kobs and pK‡ values for the hydrolysis of 8 (R = alkyl) at 15 ЊC
(a) in the acidic region
(b) in the neutral region
pH 2.60
pH 7.50
δC(C-2)
δC(C-2)
R
pKa
kobs/10Ϫ2 sϪ1
kobs/10Ϫ3 sϪ1
pK‡
16O
18O
∆δC (18O)
16O
18O
∆δC (18O)
CMe3
MeCH2
PhCH2CH2
ClCH2CH2
MeCH2OCH2
MeCHBr
5.05
4.87
4.66
4.00
3.65
2.97
1.22
2.28
2.85
11.8
26.1
—
1.0
2.8
3.6
22.5
80.1
327
3.65
3.45
3.44
3.22
2.95
—
98.714
98.696
0.018
98.694
98.675
0.019
Fig. 2 Plot of kobs/10Ϫ3 vs. 1/ε for the hydrolysis of 8 (R = Et) in H2O at
pH 7.25 and 25 ЊC
was found attached to the C-2 of 2-hydroxyfuran and an upfield
shift ∆δC(18O) of 0.018 ppm was observed. Integration over
16O–C and 18O–C peaks in the 13C NMR spectrum indicated an
isotopic ratio of approximately 6:4, identical to the amount of
H216O:H218O used in the experiment. Since 18O was found in the
hemi-acetal and not in the carboxylic acid of the product,
hydrolysis of tetrahydro-2-furyl propionate in the acidic region
must proceed by loss of propionic acid in the slow rate-
determining step.
Fig. 3 Plot of log kobs/10Ϫ2 vs. pKa for the hydrolysis of 8 in H2O–20%
EtOH at pH 2.6 and 15 ЊC
the acylal and/or the dissociation of the protonated acylal
(Scheme 2, n = 1). It is reasonable to assume that as R becomes
more electron withdrawing, the position of equilibrium (K)
between the acylal and the protonated acylal would move to the
left, which would give a positive slope of log kobs vs. pKa. This
was in fact found for the acid catalysed hydrolysis of 710
although the slope was only 0.1. On the other hand, one would
expect the rate of dissociation (kd) of the protonated substrate
to be enhanced by electron-withdrawing groups in R which
would give rise to a negative slope of the same plot. The overall
effect of the electron withdrawing substituents on the
tetrahydro-2-furyl alkanoates gives a negative slope (Fig. 3)
which implies that the effect on kd is dominant, i.e. C᎐O bond
cleavage is extensive in the TS. Support for this contention is
provided by the work‡ of Kankaanperä17 and also by consider-
ation of the results in the neutral region discussed below.
The neutral region. The results obtained for the hydrolysis of
tetrahydro-2-furyl alkanoates in the neutral region are also
recorded in Table 6 and plotted in Fig. 4. Thus in the same
series of alkanoates, a similar trend to that observed in the
acidic region is observed since the rates of hydrolysis increase as
the alkanoate becomes a better leaving group, i.e. as the pKa of
the parent acid falls. This result again implies that the mechan-
ism involves rate-limiting ionisation if the alkanoate group. The
slope (Ϫ1.19) agrees remarkably well with the βLG value of 1.18
found for the spontaneous hydrolysis of 2-aryloxytetrahydro-
pyrans,18 which is considered to occur via an A-1 mechanism.
The slope of the plot of log kobs vs. pKa in the acid region is
composed of a combination of kH and ko. When kH values were
calculated (Table 6) from kobs and ko, a plot of log kH vs. pKa
gave a slope of Ϫ0.84 (r = 0.996). This contrasts with the posi-
tive slope associated with the acid-catalysed hydrolysis of (7,
vide supra) and with the negative ρ value (= Ϫ0.92) found for a
Hammett plot of log kH vs. σ for the acid-catalysed hydrolysis
The neutral region. Under neutral conditions, a similar
upfield shift was observed in the 13C NMR spectrum for
tetrahydro-2-furyl propionate. The chemical shifts in the 13C
NMR spectra for 16O/18O are tabulated in Table 5b and the
integration ratio of the 16O᎐C and 18O᎐C peaks in the 13C NMR
spectrum was again in good agreement with the ratio of normal
and 18O water employed in the experiment. The upfield shift
caused by 18O᎐C was confirmed by the addition of a known
quantity of the hydrolysis product in normal water which
enhanced the intensity of the downfield peak. Thus the result of
18O labelling experiment in neutral conditions is very similar to
that found for the acidic region which indicates that the
hydrolysis proceeds via either unimolecular dissociation of the
propionate or a bimolecular (SN2) process involving water.
However, the entropy of activation is only slightly negative
(∆S‡ = Ϫ25 J molϪ1
K
Ϫ1) and the results with a range of
alkanoates (see below) favours the dissociative mechanism.
Kinetics of the hydrolysis of tetrahydrofuryl alkanoates
The alkanoic acids used in this study were selected over a wide
range of pKa values16 from 2,2-dimethylpropionic acid (pKa
5.05) to 2-chloropropionic acid (pKa 2.88). The rates of
hydrolysis of each alkanoate were then studied in the acidic and
neutral pH regions.
The acidic region. In this region the rates of hydrolysis of the
tetrahydro-2-furyl alkanoates were studied at pH 2.60 in EtOH–
H2O (20% v/v) buffer solution and at 15 ЊC. The results are
shown in Table 6 and the plot of log kobs vs. pKa (Fig. 3) gives a
good linear correlation (βLG = Ϫ0.92) with the rate of hydrolysis
increasing as the pKa of the parent acid decreases. The alkano-
ate substituents may affect the pre-equilibrium protonation of
‡ We are indebted to a referee for drawing our attention to this analogy.
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J. Chem. Soc., Perkin Trans. 2, 1998

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Table 7 Activation parameters for the hydrolysis of 9 at pH 2.55 and
7.49
Table 8 13C NMR data for 16O/18O shifts in hydrolysis of 9 (R = Et)
(a) in acidic region
(b) in neutral region
EA/kJ
∆H‡/kJ ∆G‡/kJ
∆S‡/J
δC(C-2)
δC(C-2)
pH
molϪ1
molϪ1
molϪ1
molϪ1 KϪ1
16O
18O
∆δC (18O)
16O
18O
∆δC (18O)
2.55
7.49
87
93
84
91
68
89
ϩ54
ϩ5
95.252
95.237
0.015
95.233
95.281
0.015
Table 9 Rate coefficients for the hydrolysis of 9, pH 7.49 at 15 ЊC
R
pKa
kobs/10Ϫ3 sϪ1
CMe3
MeCH2
PhCH2CH2
ClCH2CH2
EtOCH2
MeCHBr
MeCHCl
5.05
4.87
4.66
3.97
3.65
2.97
2.88
0.33
1.02
1.29
7.54
31.8
103
165
Variation of rates with reaction temperature. In the acid-
catalysed region, the rates were measured at 16, 20, 25 and
31 ЊC [Table I(i), supplementary data] and in the neutral (pH-
independent) region the rates were measured at 25, 32, 40 and
46 ЊC [Table I(ii), supplementary data]. The resultant activation
parameters are summarised in Table 7. The entropy of acti-
vation (∆S‡) is positive in both regions which is consistent with
a unimolecular (dissociative) reaction. The acid-catalysed
hydrolysis of 2-ethoxytetrahydropyran (with ∆S‡ = ϩ33.0 J
Fig. 4 Plot of log kobs/10Ϫ3 vs. pKa for the hydrolysis of 8 in H2O–20%
EtOH at pH 7.5 and 15 ЊC
17,23
molϪ1 KϪ1
)
is also alleged to react by a unimolecular
mechanism.
H218O labelling. 18O-Labelling experiments were carried out
to substantiate the proposed mechanism for the hydrolysis of
tetrahydropyran-2-yl propionate under acidic and neutral con-
ditions. As in the case of tetrahydro-2-furyl propionate, a
known ratio (6:4) of H216O:H218O was used and the 18O label
was then expected in the hemi-acetal or in the carboxylic acid.
The chemical shifts of the 16O᎐C and 18O᎐C labelled acylal
carbon for both the acidic and the neutral region are shown in
Table 8a and b. In both cases 18O was again found attached to
the C-2 of the hemi-acetal in the product and an upfield shift
∆δC(18O) of 0.015 ppm was observed. Integration over 16O᎐C
and 18O᎐C peaks indicated an isotopic ratio of approximately
6:4, identical to the isotopic ratio used in the experiment. Thus,
hydrolysis of tetrahydropyran-2-yl propionate in both regions
occurs by cleavage of the C᎐O alkanoate bond probably via an
AAL1 mechanism consistent with the positive ∆S‡ values in both
regions.
of 2-aryloxytetrahydropyrans.19 In the latter case, therefore,
partial cancellation of opposing equilibrium (negative ρ) and
C᎐O bond cleavage (positive ρ) effects, results in a negative ρ
whereas with the better leaving group (alkanoate) bond cleav-
age seems to dominate. Calculation of the pK‡ values20 (Table
6) indicates, by comparison with the pKa values of the alkanoic
acids, that C᎐O bond cleavage is close to completion in the TS.
Furthermore, a plot of (pKa Ϫ pK‡) vs. pKa is linear (r = 0.985)
with a positive slope (= 0.6) indicating that bond cleavage
increases with increasing leaving group acidity.
Kinetics of the hydrolysis of tetrahydropyran-2-yl propionate
Eliel and Giza21 considered that an axial proton at C-2 of a
tetrahydropyran derivative would give a broad peak at 4.15–
4.72 ppm, whereas an equatorial proton would give a sharp
1
peak at 4.53–5.52 ppm in the H NMR spectrum. The sharp
triplet at 5.90 ppm is therefore consistent with the presence of
an equatorial proton at C-2 and consequently the substituent
group must be axial. Alkoxy or aryloxy groups at C-2 of
tetrahydropyran derivatives apparently prefer the axial pos-
ition21 and hence the propionate group of tetrahydropyran-2-yl
propionate is almost certainly axial and therefore subject to the
anomeric effect.22
Kinetic measurements. The rates of hydrolysis of tetrahydro-
pyran-2-yl propionate were monitored by UV–VIS spectro-
photometry at λ = 222 nm. The kinetic experiments were
carried out at 25 0.2 ЊC in 20% EtOH–H2O (v/v) buffer in
order to counteract the solubility problems experienced with
pure water.
Kinetics of the hydrolysis of tetrahydropyran-2-yl alkanoates
The results obtained for the hydrolysis of tetrahydropyran-2-yl
alkanoates in the neutral region are recorded in Table 9 and
plotted in Fig. 5. The rates increase as the alkanoic acid
becomes more acidic which again indicates formation of the
carboxylate anion in the rate-limiting step. The slope of Ϫ1.18
again accords with the βLG value found for aryloxytetrahydro-
pyrans18 and the value of pK‡ = 3.4 calculated for R = Et, again
suggests a high degree of C᎐O bond cleavage in the TS.
Buffer catalysis in the hydrolysis of tetrahydro-2-furyl and tetra-
hydropyran-2-yl propionates
pH–rate profiles. The kinetics were studied over a range of
pH (2–12) at a constant ionic strength (µ = 0.1 ) and the
results (Table H, supplementary data) are plotted in Fig. C
which reveals an acid-catalysed hydrolysis (pH 2–4), and an
uncatalysed hydrolysis or pH-independent (4 у pH р 12)
region. The overall rate of hydrolysis is therefore described
by eqn. (2) and a plot of kobs versus [Hϩ] gives values of kH (6.82
dm3 molϪ1 sϪ1) and ko (1.3 × 10Ϫ3 sϪ1).
The kinetics of the hydrolysis were monitored in the neutral
region with three types of buffer (acetate, phosphate and imida-
zole). The results (Table 10) show no buffer catalysis which
again supports the proposal of a unimolecular rate-limiting
step for both substrates.
pH-Independent hydrolysis of tetrahydro-2-furyl and tetrahydro-
pyran-2-yl propionates
Tetrahydro-2-furyl propionate and tetrahydropyran-2-yl pro-
pionate were found to have a large plateau in the pH–rate
kobs = kH[Hϩ] ϩ ko
(2)
J. Chem. Soc., Perkin Trans. 2, 1998
1487

View Article Online
Table 10 Rate coefficients for the hydrolysis of 8 and 9 (R = Et) in
three buffers (µ = 0.5  with KCl at 25 ЊC)
equilibrium protonation of the substrate followed by rate-
determining alkyl–oxygen dissociation of carboxylic acid to
give a stabilised oxycarbonium ion, which reacts with water to
form the hemi-acetal. Since tetrahydro-2-furyl and tetrahydro-
pyran-2-yl propionates hydrolyse by an A-1 mechanism, it is
likely that all the tetrahydro-2-furyl and tetrahydropyran-2-yl
alkanoates also hydrolyse via the same mechanism.
pH 5.2
pH 8.5
pH 7.5
[Acetate]/

kobs/10Ϫ3
[Phos]/

kobs/10Ϫ3
[Imid]/

kobs/10Ϫ3
sϪ1
sϪ1
sϪ1
(a) for 8
0.02
0.10
0.35
7.57
7.25
7.16
0.02
0.10
0.35
7.67
7.29
7.52
0.02
0.10
0.35
7.00
7.08
7.19
The neutral region
In the neutral region the mechanism of the uncatalysed
hydrolysis of 2-tetrahydrofuranyl propionate and 2-tetrahydro-
pyranyl propionate also appears to be a unimolecular SN1 pro-
cess. The evidence to support the proposed mechanism is as
follows. (i) The entropies of activation for tetrahydro-2-furyl
propionate and tetrahydropyran-2-yl propionate (∆S‡ = Ϫ25 J
molϪ1 KϪ1 and ϩ5 J molϪ1 KϪ1 respectively) although negative
in the former case, are comparable to the values found for other
SN1 reactions in this pH region. (ii) Experiments in H218O again
resulted in the 18O label being incorporated in the hemi-acetal
of the products. This implies either an SN1 or SN2 mechanism,
but the values of ∆S‡ obtained for both substrates favour the
SN1 decomposition rather than SN2. (iii) The lack of buffer
catalysis is consistent with a unimolecular process. If water was
functioning as a nucleophile the presence of more powerful
nucleophiles would be expected to affect the rates of reaction
and this is not observed. (iv) The reaction is sensitive to the
solvent medium and the rate increases as the relative permittiv-
ity increases which implies a transition state which is ionic
relative to the ground state.
(b) for 9
0.02
0.10
0.35
2.76
2.89
2.71
0.02
0.10
0.35
2.62
2.73
2.68
0.02
0.10
0.35
2.72
2.71
2.74
References
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(b) P. Salomaa, Suom. Kemistil. B, 1964, 37, 86; (c) P. Salomaa and
K. S. Sallinen, Acta Chem. Scand., 1965, 19, 1054; (d) P. Salomaa,
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11 H. T. S. Britton, Hydrogen Ions, Chapman and Hall, London, 1955,
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12 A. Hussain, M. Yamuzaki and J. E. Truelove, J. Pharm. Sci., 1974,
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13 A. Hussain and J. E. Truelove, J. Pharm. Sci., 1979, 68, 235.
14 A. Hussain, J. E. Truelove and A. Kostenbauder, J. Pharm. Sci.,
1979, 68, 299.
Fig. 5 Plot of log kobs/10Ϫ3 vs. pKa for the hydrolysis of 9 in H2O–20%
EtOH at pH 7.5 and 15 ЊC
profile (3 у pH р 12). This extensive pH-independent region is
almost certainly favoured by the formation of a resonance
stabilised cyclic oxycarbonium ion. The pH-independent
hydrolysis of 1-β--glucopyranosyl benzoate also occurs via
unimolecular breakdown to an oxycarbonium ion and benzoate
ion.24 In the hydrolysis of γ-ethoxy-γ-butyrolactone,6 it is very
likely that the decomposition on the pH independent region
also occurs by a unimolecular reaction to a resonance stabilised
oxycarbonium ion. Similar pH-independent unimolecular
decompositions are found in the hydrolysis of acylal and acetal
analogues having very good leaving groups.2,18,25–28
15 G. Akerlof and O. Short, J. Am. Chem. Soc., 1936, 58, 1241.
16 G. Kortum, W. Vogel and K. Andrussow, Dissociation Constants of
Organic Acids in Aqueous Solution, Butterworths, London, 1961.
17 A. Kankaanperä and K. Miiki, Suom. Kemistil. B, 1968, 41, 42.
18 G.-A. Craze and A. J. Kirby, J. Chem. Soc., 1978, 354.
19 T. H. Fife and L. K. Jao, J. Am. Chem. Soc., 1968, 90, 4081.
20 J. L. Kurz, J. Am. Chem. Soc., 1963, 85, 987.
21 E. L. Eliel and C. A. Giza, J. Org. Chem., 1968, 33, 3754.
22 A. J. Kirby, The Anomeric Effect and Related Stereoelectronic
Effects at Oxygen, Springer-Verlag, New York, 1983.
23 J. L. Jenson and W. B. Wuhrman, J. Org. Chem., 1983, 48, 4686.
24 A. Brown and T. C. Bruice, J. Am. Chem. Soc., 1973, 95, 1593.
25 T. H. Fife, Acc. Chem. Res., 1972, 5, 264.
Conclusion
The acidic region
In the acid-catalysed hydrolysis of tetrahydro-2-furyl propion-
ate and tetrahydropyran-2-yl propionate, the unimolecular
AAL1 mechanism is indicated by the following evidence. (i) The
entropy of activation values for tetrahydro-2-furyl propionate
and tetrahydropyran-2-yl propionate (∆S‡ = ϩ25 J molϪ1 KϪ1
and ϩ54 J molϪ1 KϪ1 respectively) are both positive, indicating
a dissociative process. (ii) The 18O water labelling experiments
show that the 18O label remains in the hemi-acetal of the prod-
ucts in both cases which excludes the AAC2 and AAC1 mechan-
isms. (iii) The correlation of rate with the pKa of the leaving
group (for the furyl system) is consistent with a unimolecular
process.
26 T. H. Fife and E. Anderson, J. Am. Chem. Soc., 1969, 91, 7163.
27 T. H. Fife and L. H. Brod, J. Am. Chem. Soc., 1970, 92, 1681.
28 T. H. Fife and R. Bembi, J. Org. Chem., 1992, 57, 1295.
Thus the mechanism of acid-catalysed hydrolysis of tetra-
hydro-2-furyl propionate and tetrahydropyran-2-yl propionate
is similar to that of A-1 acetal hydrolysis involving pre-
Paper 7/08422F
Received 21st November 1997
Accepted 25th March 1998
1488
J. Chem. Soc., Perkin Trans. 2, 1998