Alkaline-earth metal complexes of thiol-pendant crown ethers as turnover catalysts of ester cleavage

Article abstract of DOI:10.1039/a708392k

Methanolysis of pNPOAc under moderately alkaline conditions is catalysed by the alkaline-earth metal ion (Ca, Sr, Ba) complexes of 2-(mercaptomethyl)-18-crown-6 according to biphasic kinetics in which an initial burst of pNPOH release is followed by a zer

Full text of DOI:10.1039/a708392k

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Alkaline-earth metal complexes of thiol-pendant crown ethers as
turnover catalysts of ester cleavage
Perla Breccia, Roberta Cacciapaglia,* Luigi Mandolini* and Carla Scorsini
Dipartimento di Chimica and Centro CNR di Studio sui Meccanismi di Reazione,
Universita’ La Sapienza, P.le A. Moro 5, 00185 Rome, Italy
Methanolysis of pNPOAc under moderately alkaline conditions is catalysed by the alkaline-earth metal
ion (Ca, Sr, Ba) complexes of 2-(mercaptomethyl)-18-crown-6 according to biphasic kinetics in which an
initial burst of pNPOH release is followed by a zeroth-order phase. Two competing catalytic mechanisms
contribute to the overall process, (i) a double displacement mechanism in which the complexed metal
ion enables the SH group of the catalyst to undergo an acylation–deacylation cycle, and (ii) a bypass
mechanism in which a catalytically active complex-bound methoxide ion is involved and no covalently
bound intermediate is formed. Calcium ion is much more efficient than its larger analogues both in the
acylation–deacylation cycle of the double displacement mechanism, and in the direct delivery of
methoxide ion to the ester substrate.
Introduction
k1
MeO
, k2
cat
pNPOAc
catAc
cat
+
Metal ion catalysis of ester cleavage has received considerable
attention in recent years.1 We have shown2 that methanolysis
of p-nitrophenyl acetate (pNPOAc) under slightly basic con-
ditions was catalysed by the barium complex of 1 via a double
pNPOH
MeOAc
Scheme 1 Double displacement catalytic mechanism in the basic
methanolysis of pNPOAc; (cat = 1ؒBa2ϩ
)
SH
S
Me
SH
cies of metal complexes by means of separate investigations of
the effect of alkaline-earth metal ions (Ca, Sr, Ba) on rates of
deacylation of the thiol acetates 4 and 6, and of acylation of the
parent thiols 3 and 5 by pNPOAc. The results of this investig-
ation are reported herein.
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
Results and discussion
O
O
O
O
The β-mercaptoethyl crown ether 3 and its acetylated derivative
4 were prepared according to a literature procedure,3 whereas
the analogous 18-crown-6 compounds 5 and 6† were obtained
from 2-(hydroxymethyl)-18-crown-6 according to Scheme 2.
All rate measurements were carried out at 25.0 ЊC in MeCN–
MeOH (9:1, v/v) containing 90 mmol dmϪ3 diisopropylethyl-
amine and 30 mmol dmϪ3 diisopropylethylammonium per-
chlorate. In aqueous solution4 the pH of this buffer would be
11.3, but in MeCN–MeOH the basicity towards neutral acids is
much lower. Based on the observation that p-nitrophenol
(pNPOH) is 74% ionised in this medium, it is calculated that the
basicity is comparable to that of an aqueous solution with pH
7.6.
1
2
3
Me
Me
S
O
O
SH
O
S
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
Deacylation step
Because the critical step in the double displacement catalytic
mechanism is deacylation of the covalent intermediate (thiol
ester), our study started from an investigation of the influence
of adding one molar equivalent of Ba(ClO4)2, SrBr2 and CaBr2
on rates of methanolysis of 2.7 mmol dmϪ3 thiol acetates 4 and
6.
The kinetics were followed by monitoring the disappearance
of the thiol acetate reactant by HPLC analysis of reaction
samples taken at time intervals. It is apparent from Fig. 1,
where the results are shown graphically, that the thiol acetates
are extremely reluctant to undergo methanolysis in the weakly
4
5
6
displacement mechanism (Scheme 1) in which the thiol group
acted as an acyl-receiving and acyl-releasing unit with the par-
ticipation of the complexed metal electrophile. The turnover
efficiency of the overall process was modest because of the
sluggish methanolysis of the thiol acetate intermediate 2.
Since it was felt that variations in the crown ether ring size,
side arm length, and alkaline-earth metal ion identity could
possibly increase the rate of the deacylation step and, con-
sequently, improve the efficiency of the overall catalytic process,
we have synthesized the thiol-pendant crown ethers 3 and 5,
together with their corresponding thiol acetates 4 and 6, with
the purpose of carrying out an evaluation of catalytic efficien-
† 18-Crown-6 is 1,4,7,10,13,16-hexaoxacyclooctadecane, and 19-crown-
6 is 1,4,7,10,13,16-hexaoxacyclononadecane.
J. Chem. Soc., Perkin Trans. 2, 1998
1257

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Table 1 Methanolysis of thiol esters 4 and 6 in MeCN–MeOH (9:1,
v/v) in the presence of 90 mmol dmϪ3 diisopropylethylamine–30
mmol dmϪ3 perchlorate salt buffer at 25 ЊC. Influence of added
alkaline-earth metal salts.
b
Substratea
Metal salta
k2/10Ϫ3 minϪ1
k2/kbackground
4
Ba(ClO4)2
SrBr2
CaBr2
Ba(ClO4)2
SrBr2
CaBr2
0.80c
2.97
1 100
4 200
5 700
2 700
5 400
76 000
3.98
6
1.86c
3.76
53.3
a Initial substrate and metal salt concentration 2.70 mmol dmϪ3
b Lower limits of rate enhancements relative to background based on
.
k
background р 7 × 10Ϫ7 minϪ1 (see text). c Under identical conditions 2
solvolyses with a k2 value of 0.70 × 10Ϫ3 minϪ1; ref. 2.
OH
O
O
O
O
O
O
(i)
OMs
O
O
O
O
O
(ii)
(iii)
5
O
6
Scheme 2 Preparation of thiol ester 6 and of thiol 5. Reagents and
conditions: (i) MsCl, Et3N in CH2Cl2; (ii) CH3COSϪKϩ in acetone; (iii)
LiAlH4 in THF.
Fig. 1 Methanolysis of 2.7 mmol dmϪ3 thiol acetate 4 (top) and 2.7
mmol dmϪ3 thiol acetate 6 (bottom) in the presence of buffer alone (᭿),
and in the presence of buffer plus 2.7 mmol dmϪ3 CaBr2 (᭹), 2.7 mmol
dmϪ3 SrBr2 (ᮀ) and 2.7 mmol dmϪ3 Ba(ClO4)2 (᭢) [MeCN–MeOH 9:1
(v/v), 25 ЊC, HPLC data]
basic solution, no reaction being observed in both cases after 50
days. Based on a conservative estimate of 5% in the experi-
mental error of our HPLC measurements, an upper limit of
νo = 2 × 10Ϫ9 mol dmϪ3 minϪ1, corresponding to a first-order
rate constant of 7 × 10Ϫ7 minϪ1 was calculated. In marked con-
trast to the sluggishness of the background reactions, in the
presence of one molar equivalent of divalent metal ion cleavage
of the thiol acetates took place smoothly and proceeded to
completion within reasonably short times with clean first-order
time dependence.
Table 1, where the kinetic data are summarized, clearly shows
that the size of the acceleration depends on the substrate–metal
ion combination. The reactivity order Ca ӷ Sr > Ba observed
in both cases bears an inverse relationship to cation size. This is
not really surprising for reactions in which a major component
of the driving force for catalysis is electrostatic in nature.1b
The data listed in Table 1 provide additional evidence that
very large metal ion effects on rates can be obtained when the
ester function is covalently linked to a crown ether ring capable
of holding the metal electrophile in close proximity to the
carbonyl undergoing nucleophilic addition.5
Fig. 2 1H NMR titration of 1.3 mmol dmϪ3 thiol acetate 4 (᭡), and
1.3 mmol dmϪ3 thiol acetate 6 (᭹), with CaBr2 in CD3CN–CD3OD
(9:1, v/v) at 25 ЊC. The curve connecting the points (᭡) is a plot of eqn.
(5) with K = 1.5 × 104 dm3 molϪ1 and δ∞ = 2.315.
1H NMR titration experiments showed that downfield shifts
are experienced by the methyl group of thiol acetates 4 and 6
(1.3 mmol dmϪ3 in CD3CN–CD3OD 9:1, v/v) upon addition of
CaBr2 (Fig. 2). Analysis of the titration curve afforded a K
value of 1.5 × 104 dm3 molϪ1 for the complex between Ca2ϩ and
4, but in the case of 6 the binding constant is too large to
measure (K > 3 × 105 dm3 molϪ1 assuming that upon addition
of 1 mol equiv. of CaBr2 the percent bound is no less than
95%). Since calcium ion is known to form in general much
weaker complexes with crown ethers than barium and stron-
tium ions,6 we conclude that our rate measurements refer to
conditions in which binding of the metal ions to the crown
ether substrates is virtually, or very nearly, complete.
1258
J. Chem. Soc., Perkin Trans. 2, 1998

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Table 2 Effect of additives on the rate of liberation of pNPOH from
pNPOAca
k1/dm3 molϪ1
Entry
Additivesb
kobs/minϪ1 c
krel
minϪ1
0.32
1
2
3
4
5
6
7
8
none
5
Ba(ClO4)2
SrBr2
CaBr2
5 ϩ Ba(ClO4)2 0.116
5 ϩ SrBr2
5 ϩ CaBr2
1.85 × 10Ϫ4 d
8.64 × 10Ϫ4 e
4.06 × 10Ϫ3
1.10 × 10Ϫ2
0.160
1.0
4.7
21.9
59.5
865
627
43.0 f
74.4
952
0.201
2.57
1 090
13 900
a Reaction conditions as in the experiments in Table 1. The initial con-
centration of pNPOAc was 0.050 mmol dmϪ3 unless otherwise stated.
b The concentration of all additives was 2.70 mmol dmϪ3 c Data in
.
entries 2–4 are corrected for background. d Calculated from an initial
rate νo = 3.13 × 10Ϫ6 mol dmϪ3 minϪ1 at [pNPOAc]o = 16.9 mmol
dmϪ3 e Calculated from an initial rate νo = 1.46 × 10Ϫ5 mol dmϪ3 minϪ1
.
(corrected for background methanolysis) at [pNPOAc]o = 16.9 mmol
dmϪ3 f The k1 value for the Ba2ϩ complex of 1 under identical
.
conditions is 4.7 dm3 molϪ1 minϪ1; ref. 2.
Acylation step
Rates of acetylation of the metal complexes of thiols 3 and 5
were investigated under single turnover conditions. Reaction
mixtures containing 2.7 mmol dmϪ3 thiol and 2.7 mmol dmϪ3
metal salt were reacted with 0.050 mmol dmϪ3 pNPOAc. In the
case of thiol 5, solutions were homogeneous at time zero and
remained this way throughout the reaction. The liberation of
pNPOH was monitored spectrophotometrically at 388 nm and
found to strictly adhere to first-order time dependence. But in
the case of the metal complexes of thiol 3, precipitation of solid
material during the time course of the reactions caused non-
reproducible and irregular behaviour. Reduction of the metal
complex concentration to 0.5 mmol dmϪ3 caused a decrease in,
but not a complete elimination of, the above complications. Our
investigations were therefore restricted to the metal complexes
of 5. The results are reported in Table 2, entries 6 to 8. A num-
ber of control experiments showed that (i) in the absence of
metal ions thiolysis of pNPOAc (entry 2) is only four times
faster than the very slow background methanolysis (entry 1,
Fig. 3 pNPOH liberation in the methanolysis of 16.9 mmol dmϪ3
pNPOAc in the diisopropylethylamine buffer plus 2.7 mmol dmϪ3 5 and
(a) 2.7 mmol dmϪ3 Ba(ClO4)2, (b) 2.7 mmol dmϪ3 SrBr2 and (c) 2.7
mmol dmϪ3 CaBr2. The curves are plots of eqn. (3) with the pertinent
kЈ1 and k2 values from Tables 1 and 2.
much faster than deacylation (k1Ј ӷ k2). When this is the case,
eqn. (2) reduces to the simple form of eqn. (3), which clearly
[pNPOH] =
kЈ1
kЈ1
[cat]oͩ ͪͩ
{1 Ϫ exp[Ϫ(kЈ1 ϩ k2)t]} ϩ k2t
ͪ
kЈ1 ϩ k2 kЈ1 ϩ k2
₁
t ≈ 3 days), which is most likely due to the presumably low
₂
(2)
concentration of the reactive thiolate ion in the weakly basic
solution, and (ii) remarkable accelerations are brought about by
the addition of metal salts (entries 3 to 5), that are ascribed as
before2 to the formation of reactive metal bound methoxide
species in equilibrium with free methoxide ion [equilibrium (1)]
shows that rate limiting deacylation leads to biphasic kinetics.
After an initial transient in the pre-steady-state phase, the
release of pNPOH is linear with time in the steady-state phase.
The linear portion extrapolates back to an initial burst, which
coincides with the catalyst concentration in what corresponds
to an active site titration experiment.7 The time–concentration
profiles plotted in Fig. 3 as solid lines, calculated from eqn. (3)
MeOϪ ϩ M2ϩ
(MeOM)ϩ
(1)
in the buffered solution. Whereas these remarkable rate enhance-
ments, notably the 860-fold acceleration brought about by
CaBr2, are interesting per se, in the context of the present work
it is sufficient to note that mixtures of 5 and M2ϩ are much more
effective than either thiol or metal ion alone. The reactivity
order Ca ӷ Sr > Ba found in the acylation step closely parallels
that found in deacylation.
[pNPOH] = [cat]o[1 Ϫ exp(ϪkЈ1t) ϩ k2t]
(3)
and the pertinent data in Tables 1 and 2 for an initial pNPOAc
concentration of 16.9 mmol dmϪ3, are compared with experi-
mental data from catalytic experiments carried out under iden-
tical conditions. It is seen that the experimental data reproduce
well some of the features of the simulated profiles, but not
others. There is a good agreement of data points with the
exponential portions of the profiles, and the magnitudes of
experimental bursts closely correspond to the catalyst concen-
tration. Consistently, HPLC analyses of reaction samples taken
at times corresponding to extinction of the exponential phases
(Table 3) confirmed a virtually complete accumulation of the
acylated catalyst 6.
Catalytic cycle
The data reported in the preceding sections show that by virtue
of the metal ion rate enhancing effects on both acylation and
deacylation processes, the alkaline-earth metal ion complexes
of 5 are suitable to catalyse with turnover the methanolysis of
pNPOAc via the double displacement mechanism of Scheme 1.
The analytical solution for the case in which no Michaelis–
Menten complex of definite stability is formed between catalyst
and substrate is given in eqn. (2),7 in which k1Ј = k1[pNPOAc].
Comparison of the rate constants for deacylation (k2 in Table 1)
with those for acylation (k1 in Table 2) shows that for any
pNPOAc concentration higher than 10 mmol dmϪ3 acylation is
But in the steady-state portions of the profiles the rates of
production of pNPOH are in all cases much higher than those
allowed by the relatively low deacylation rates of the metal
complexes of 6. The discrepancies between calculated and
J. Chem. Soc., Perkin Trans. 2, 1998
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Table 3 Accumulation of the acetylated intermediate 6 in the catalytic
Table 4 Methanolysis of pNPOAc catalyzed by alkaline-earth metal
complexes of 5. Turnover frequencies (hϪ1).a,b
experimentsa
Metal ion
t/s
[6]b/mmol dmϪ3
Ba2ϩ
Sr2ϩ
Ca2ϩ
Ba2ϩ
Sr2ϩ
Ca2ϩ
390
220
23
2.71
2.72
2.65
Overall
Mechanism (A)
Mechanism (B)
1.8
0.11
1.7
3.5
0.22
3.3
9.6
3.2
6.4
a Reaction conditions as in the experiments reported in Fig. 3. b Data
from HPLC analyses of reaction samples taken at time t.
a The data refer to the catalytic experiments plotted in Fig. 3. b The
corresponding data (hϪ1) for the methanolysis of pNPOAc catalyzed by
the Ba2ϩ complex of 1 under identical conditions are: overall 0.16;
mechanism (A) 0.042; mechanism (B) 0.12 (calculated from data
reported in ref. 2).
(A)
ArO–
ArOAc
The data listed in Tables 1 and 2 clearly show that acylation
of the metal complexes of thiol-pendant crown ethers, as well
as deacylation of their acetates, are markedly influenced by
both cation nature and ligand identity. Although the set of
available data for a meaningful comparison is unfortunately
limited by the solubility problems met with the metal complexes
of 3, it seems nevertheless clear that the Ca2ϩ ion turns out to be
the most efficient promoter of acyl transfer processes, including
the direct methanolysis of pNPOAc occurring via mechanism
(B). Combination of the Ca2ϩ ion with the thiol-pendant crown
ether 5 provides the most efficient catalyst with transacylase
activity. As shown in Table 4, one molecule of this catalyst
cleaves very nearly ten molecules of pNPOAc in one hour.
Me
S–
S
O
M2+
O
O
M2+
O
O
O
O
O
O
O
O
MeO–
MeOAc
Experimental
(B)
Me
Instruments and general methods
All operations involving air or moisture sensitive materials were
performed under argon. H NMR spectra were recorded in
1
S
O
CDCl3 or CD3CN–CD3OD (9:1, v/v) with a Bruker AC 300
spectrometer, using Me4Si as internal standard (J values are
given in Hertz). Spectrophotometric measurements were
carried out on a Varian Cary 219 instrument or on a Hewlett
Packard 8452A diode array spectrometer. HPLC analyses were
performed on a Hewlett Packard 1050 liquid chromatograph
fitted with a Hewlett Packard HP 1047A refractive index
detector or on a Bruker LC 22 liquid chromatograph fitted with
a Knauer 87.00 UV–VIS detector operating at 230 nm. Samples
were analysed on a Supelcosil LC-8 column (25 cm × 4.6 mm
id; particle size 5 µm). HPLC–MS experiments were carried
out on a Fisons Instruments VG-Platform benchtop mass spec-
trometer equipped with a pneumatically assisted electrospray
LC–MS interface and a single quadrupole. The mass spec-
trometer was operated in the positive-ion mode by applying to
the capillary a voltage of 3.8 kV, while the skimmer cone volt-
age was set at 20 V. The mass spectrometry data handling sys-
tem used was the Mass Lynx software from Fisons Instruments.
GC–MS analyses were carried out on a Hewlett Packard HP
5890 gas chromatograph coupled with a HP 5970 MSD and
equipped with a 15 m × 0.25 mm silica capillary column HP-1
(cross-linked methyl silicon gum; 0.25 µm film thickness).
Non-linear least-squares calculations were carried out using
the programme Sigma Plot for Windows, version 1.02 (Jandel
Scientific).
M2+
O
O
O
O
O
O
MeO–
Me
OAr
Fig. 4 Competing catalytic mechanisms of methanolysis of pNPOAc.
Mechanism (A): thiol-mediated methanolysis via an acylation–deacyl-
ation cycle; mechanism (B): direct delivery of complex-bound methox-
ide ion.
experimental rates in the zeroth-order phases are clearly too
large to be accounted for on grounds of experimental
uncertainties. Therefore, besides the thiol-mediated methanol-
ysis proceeding via an acylation–deacylation cycle [mechanism
(A) in Fig. 4], we suggest as before2 the coexistence of a bypass
pathway where no covalently bound intermediate is involved
[mechanism (B)]. In the latter mechanism, the active nucleo-
phile is a methoxide ion that is a part of a 1:1:1 methoxide–
metal ion–ligand complex, formed in minute amounts in the
weakly basic solution according to eqn. (4). This interpretation
(6ؒM)2ϩ ϩ MeOϪ
(6ؒMOMe)ϩ
(4)
is supported by our recent findings8 that ternary complexes
formed from 18C6 and alkoxide (alkaline earth metal ion) pairs
are more reactive than the ion pairs themselves in the cleavage
of esters.
We assume that the differences between the actual rates of
production of pNPOH at steady-state and those calculated
from eqn. (3) represent the contributions of mechanism (B) to
the overall catalytic processes. Dissection of the overall turn-
over frequencies into separate contributions from the two com-
peting mechanisms (Table 4) shows that the bypass mechanism
(B) accounts for about two-thirds of the overall reaction in the
case of the reaction catalysed by 5ؒCa2ϩ, and for even larger
fractions with the corresponding Ba2ϩ and Sr2ϩ complexes.
Materials
THF was dried by distillation from sodium benzophenoneketyl.
CH2Cl2 was distilled over P2O5. 4-Methylanisole (Fluka) and
1,4-dimethoxybenzene (Janssen) were used as received.
SrBr2ؒH2O (Carlo Erba) and CaBr2ؒ2H2O (Carlo Erba) were
used without further purification and their stock solutions in
methanol titrated by means of potentiometric argentometry
with a Mettler Toledo Ag 4805-S7/120 Silver Combination
Electrode. The concentration of bromide ions was found in all
cases to be within 1% of the concentration calculated on the
basis of the formula weight. Other materials were as reported
previously.2
1260
J. Chem. Soc., Perkin Trans. 2, 1998

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WARNING: Care was taken when handling diisopropylethyl-
ammonium perchlorate because it is potentially explosive.9 No
accident occurred in the course of the present work.
18-(2-Mercaptoethyl)-19-crown-6 (3) and the correspond-
ing acetate (4) were synthesized according to a literature
procedure.3
observed chemical shift at a given titrant concentration and δo
is the chemical shift of the free ligand. The analytical concen-
tration of the titrant CaBr2 was corrected for the fraction
sequestered by the ligand.
Spectrophotometric and HPLC rate measurements were car-
ried out as before.2 Internal standard, eluent and flow rate are
indicated in the given order for HPLC monitoring of thiol ester
disappearance in the methanolysis of thiol acetates 4 and 6 and
for thiol ester accumulation in the acylation of thiols 3 and
5 by pNPOAc. Methanolysis of 4 [1,4-dimethoxybenzene,
62.5:27.5:10 H2O (0.08% CF3CO2H)–MeOH–MeCN, 0.8 cm3
minϪ1]; methanolysis of 6 and acylation of 5 [4-methylanisole,
70.5:29:0.5 H2O (0.05% CF3CO2H)–MeOH–MeCN, 0.8 cm3
minϪ1]; and acylation of 3 [1,4-dimethoxybenzene, 70:24:6
H2O (0.08% CF3CO2H)–MeOH–MeCN, 0.8 cm3 minϪ1].
2-(Mercaptomethyl)-18-crown-6 (5) and 2-(acetylthiomethyl)-
18-crown-6 (6). 5 and 6 were prepared according to Scheme 2
starting from the commercially available 2-(hydroxymethyl)-18-
crown-6 (Aldrich). A solution of CH3SO2Cl (Aldrich, 0.072
cm3, 0.93 mmol) in CH2Cl2 (2 cm3) was added dropwise to a
cooled (Ϫ10 ЊC) and stirred solution of 2-(hydroxymethyl)-18-
crown-6 (0.226 g, 0.77 mmol) and Et3N (0.175 cm3, 1.25 mmol)
in CH2Cl2 (3 cm3). The resulting mixture was stirred for 20 min,
diluted with cold CH2Cl2 and washed sequentially with cold 5%
HCl (aq.), cold saturated NaHCO3 (aq.) and cold H2O. The
organic layer was dried over MgSO4 and removal of solvent
afforded the mesylate as an oil (0.245 g, 86% yield). δH(CDCl3)
3.06 (3H, s, OSO2CH3), 3.55–4.00 (23H, m, CHO and CH2O),
4.30–4.50 (2H, m, CH2OSO2CH3); m/z (ES) 395 (M ϩ Na)ϩ,
411 (M ϩ K)ϩ.
Acknowledgements
Financial contributions from MURST and from CNR
(Progetto Strategico Tecnologie Chimiche Innovative) are
acknowledged.
A mixture of the mesylate (0.245 g, 0.66 mmol) and potas-
sium thioacetate (Aldrich, 0.113 g, 0.99 mmol) in acetone (3
cm3) was refluxed overnight. The mixture was cooled, filtered
and the solvent evaporated under reduced pressure. Distillation
of the crude material on a Kugelrohr apparatus [170 ЊC (10Ϫ3
mmHg)] afforded thiol acetate 6 as an oil (0.196 g, 85% yield).
An analytically pure sample of thiol acetate 6 was obtained by
flash chromatography on acid washed silica gel (Merck, 230–
400 mesh) (1:2 CHCl3–hexane, 1:1 CHCl3–hexane, CHCl3,
25:1 CHCl3–MeOH and 10:1 CHCl3-MeOH). δH(CDCl3) (3H,
s, COCH3), 3.01–3.15 (2H, m, CH2SCOCH3), 3.58–3.82 (23H,
m, CHO and CH2O); δC(CDCl3) 30.6, 69.9, 70.7, 70.7, 70.8,
70.8, 71.0, 72.7, 78.2, 195.5; m/z (GC–MS) 352 (Mϩ). Found: C,
51.0; H, 8.1. Calc. for C15H28O7S: C, 51.1; H, 8.0%.
References
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Thiol acetate 6 (0.544 g, 1.54 mmol) in THF (2 cm3) was
added dropwise to a stirred suspension of LiAlH4 (0.112 g, 2.95
mmol) in THF (1.5 cm3). The mixture was stirred overnight at
ambient temperature, carefully quenched with 10% HCl (aq.),
diluted with CH2Cl2 and water, and subjected to extractive
workup, drying (MgSO4) and removal of the solvent. Flash
chromatography on acid washed silica gel (1:1 Et2O–pentane,
EtOAc) followed by Kugelrohr distillation [220 ЊC (2 × 10Ϫ2
mmHg)] afforded thiol 5 as an oil (0.308 g, 64% yield). HPLC
analysis of this material (refractive index detector; 70.5:29:0.5
2 R. Cacciapaglia, L. Mandolini and F. Spadola, Tetrahedron, 1996, 52,
8867.
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D. N. Reinhoudt and W. Verboom, Tetrahedron, 1989, 45, 5293;
(b) G. Ercolani and L. Mandolini, J. Am. Chem. Soc., 1990, 112, 423;
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(d) D. Kraft, R. Cacciapaglia, V. Böhmer, A. A. El-Fadl, S.
Harkema, L. Mandolini, D. N. Reinhoudt, W. Verboom and W. Vogt,
J. Org. Chem., 1992, 57, 826; (e) R. Cacciapaglia, L. Mandolini,
D. N. Reinhoudt and W. Verboom, J. Phys. Org. Chem., 1992, 5, 663;
( f ) R. Cacciapaglia, A. Casnati, L. Mandolini and R. Ungaro,
J. Chem. Soc., Chem. Commun., 1992, 1291; (g) R. Cacciapaglia,
L. Mandolini and A. Tomei, J. Chem. Soc., Perkin Trans. 2, 1994, 367.
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Rev., 1991, 91, 1721.
H2O (0.05% CF3CO2H)–MeOH–MeCN; 0.8 cm3 minϪ1
]
revealed the presence of the corresponding disulfide [m/z (ES)
642 (M ϩ Na)ϩ, 658 (M ϩ K)ϩ] as the only detectable impurity
in ca. 4% amount. Further purification by flash chromatog-
raphy on acid washed silica gel (1:1 CH2Cl2–hexane, CH2Cl2,
75:1 CH2Cl2–MeOH and 50:1 CH2Cl2–MeOH) afforded thiol
5 still contaminated by trace amounts (ca. 2%) of the disulfide.
This sample was used in the kinetic experiments without further
purification. δH(CDCl3) (1H, t, J 9, SH), 2.55–2.70 (2H, m,
CH2SH), 3.50–3.90 (23H, m, CHO and CH2O); m/z (ES) 333
(M ϩ Na)ϩ, 349 (M ϩ K)ϩ.
7 (a) A. Fersht, Enzyme Structure and Mechanism, W. H. Freeman, New
York, 1985, ch. 4; (b) M. L. Bender, Mechanisms of Homogeneous
Catalysis from Protons to Proteins, Wiley-Interscience, New York,
1971, ch. 12.
8 R. Cacciapaglia, L. Mandolini and V. Van Axel Castelli, J. Org.
Chem., 1997, 62, 3089.
Equilibrium and kinetic measurements
9 Hazards in the Chemical Laboratory, ed. S. G. Luxon, The Royal
Society of Chemistry, Cambridge, 1992, 5th edn., p. 524.
1H NMR titrations of 4 and of 6 with CaBr2 were carried out in
CD3CN–CD3OD (9:1, v/v) at 25.0 ЊC according to a previously
reported procedure.2 The association constant K and the chem-
ical shift of the monitored signal of the ligand in the complex
(δ∞) were obtained as best fit parameters in a non-linear least-
square fitting treatment of data points to eqn. (5) where δ is the
Paper 7/08392K
Received 20th November 1997
Accepted 12th February 1998
(δ∞ Ϫ δo)K[Ca2ϩ
]
(5)
δ = δo ϩ
1 ϩ K[Ca2ϩ
]
J. Chem. Soc., Perkin Trans. 2, 1998
1261