Isolation of the key intermediates in the catalyst-free conversion of oxiranes to thiiranes in water at ambient temperature

Article abstract of DOI:10.1039/b820232j

Herein we shed light on the mechanism of the reaction of epoxides with ammonium thiocyanate to give the corresponding thiiranes in water, and we present a computational mechanistic model for this highly useful reaction.

Full text of DOI:10.1039/b820232j

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Isolation of the key intermediates in the catalyst-free conversion of oxiranes to
thiiranes in water at ambient temperature†
Christian M. Kleiner,a Luise Horst,a Christian Wu¨rtele,b Raffael Wendea and Peter R. Schreiner*a
Received 12th November 2008, Accepted 8th January 2009
First published as an Advance Article on the web 25th February 2009
DOI: 10.1039/b820232j
Herein we shed light on the mechanism of the reaction of epoxides with ammonium thiocyanate to give
the corresponding thiiranes in water, and we present a computational mechanistic model for this highly
useful reaction.
the initial work of van Tamelen who utilized ethanol/water
Introduction
mixtures as the solvent of choice. The simplicity of the work-
Thiiranes, the sulfur analogues of oxiranes, became known
up procedure by extracting the product from the aqueous phase,
through the early work of Staudinger et al. who studied the thermal
by decanting or by filtration makes water a very attractive solvent.
Besides the economic and environmental advances, water can
decomposition of tetraphenylethylene sulfide.1 The synthesis of
accelerate reaction rates due to hydrophobic amplification;29,30
hydrophobic effects can drive the formation of micelles.31–33 These
effects bring the poorly soluble organic reactants into close
proximity and therefore increase the reaction rate. Using water as
solvent often results in surprising and unforeseen outcomes.30,33,34
Over the last years it has been recognized that efficient and
selective syntheses in water can match or indeed surpass those in
organic solvents. Examples include higher endo/exo-selectivities
and enantioselectivities for Diels–Alder reactions or 1,3-dipolar
cycloadditions.31,35 Other examples for reactions in water are
the organocatalytic ring-opening of epoxides,29 hydrogenations,36
hydroformylations,37 catalytic C–C coupling reactions,38 olefin
metathesis,39 and oxidation reactions.40
thiiranes from epoxides and alkaline thiocyanates or thiourea was
patented by Dachlauer and Jackel as early as 1936,2 and extensive
studies on the formation and reactivity of thiiranes ensued.3
The preparation of thiiranes is of significance because they can
readily be ring-opened with a variety of nucleophiles to give the
respective thiols.4–6 Snyder et al. reported the large-scale synthesis
of amino thiols in 1947 from thiiranes for use in the rubber
industry.7 Thiiranes are used in the synthesis of pesticides and
herbicides;4 they can be polymerized8,9 and are an entry into more
functionalized compounds from acyclic materials.10 Additionally
they play a vital role concerning flavour and odour properties in
the food industry.11
An early report on the synthesis and the proposed mechanism
for thiirane formation was made by van Tamelen by using
inorganic thiocyanate salts in aqueous and dilute alcoholic
solutions.5 This procedure is still the method of choice for epoxides
with SN2 reactivity.12–14 Other possibilities for the preparation
of thiiranes are the conversion of oxiranes with thiourea,12,15–19
phosphine sulfides,20 or dimethylthioformamide in the presence
of trifluoracetic acid in dichloroethane.21 The handling of these
reagents usually requires the presence of Lewis acids, e.g., ceric
ammonium nitrate (CAN),22 RuCl3,23 tin(IV) complexes,17 and
titanium salts,16,24 but these catalysts often are limited to reactive
epoxides.
Here we display the positive and decisive role of water in
the catalyst-free synthesis of thiiranes from the corresponding
epoxides (Scheme 1) and portray a computed reaction pathway
(Fig. 1).
Scheme 1 Reaction of oxiranes with ammonium thiocyanate.
Polymeric cosolvents like polyethylene glycol,25 ionic liquids26
and microwave irradiation27 have also been used to promote this re-
action. These transformations typically require long reaction times
and elevated temperatures; polymeric by-products often form or
desulfurization of the formed thiiranes occurs.10,28
Water as solvent has become increasingly popular as a reaction
medium for organic transformations, and it is surprising that
this medium was not fully explored for thiirane synthesis despite
Results and discussion
The rationale behind the present study was our initial question of
why this reaction occurs at all, given that two strong C–O bonds
are replaced by weaker C–S bonds – what is the driving force
for this reaction? We first examined the proposed mechanism
computationally (Fig. 1, for details see ESI†) at the B3PW91/
cc-pVDZ + ZPVE (zero-point vibrational energy) level of theory
in the gas phase and in organic media (CH2Cl2) as well as
aqueous solution utilizing a self-consistent polarized continuum
reaction field model (scrf-pcm) for comparison.41 This level of
theory has shown to provide qualitatively meaningful results
for organic structures.42 We examined the protonated/neutral
potential energy hypersurface (PES), as slightly acidic NH4SCN
aJustus-Liebig-Universita¨t, Institut fu¨r Organische Chemie, Heinrich-Buff-
Ring 58, 35392, Giessen, Germany. E-mail: prs@org.chemie.uni-giessen.de;
Fax: +49 641 9934309; Tel: +49 641 9934300
bJustus-Liebig-Universita¨t, Institut fu¨r Anorganische und Analytische
Chemie, Heinrich-Buff-Ring 58, 35392, Giessen, Germany
† Electronic supplementary information (ESI) available: Experimental, full
analytical and computational data. See DOI: 10.1039/b820232j
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Fig. 1 Computed potential energy hypersurface (PES) for the title reaction at B3PW91/cc-pVDZ + ZPVE in the gas phase (gray curve) as well as in
organic (CH2Cl2) and aqueous media (polarized continuum solvation model); these values are in gray. Additionally, the PES is depicted including one
explicit water molecule without (fourth entry at the bottom) and with aqueous solvation (black curve and bottom entries). The two fully optimized key
transition structures including one explicit water molecule and aqueous solvation with selected bond lengths are depicted as ball-and-stick models. a No
TS located because of the large exothermicity of this part of the reaction.
is utilized. This is also in line with the suggestions of previous
reports that 1,3-oxathiolan-2-imines (C, parent system) are the key
intermediates.5,14,21,43–45 Some investigators favour the depiction of
the respective amide anion but the prohibitively high pKa of C
and the presence of ammonium ions as well as some excellent
electrophiles (vide infra) make this rather unlikely. Indeed, our
computations indicate that structure C in our parent model system
lies in a very deep energy minimum, and only this structure
should form if it were not for the decisive role of water that helps
decompose the formal second product isocyanic acid (HNCO)
into CO2 and NH3, which provides the overall driving force for
the formation of the thiiranes. This also explains in part why
the findings on the reaction of thiocyanate salts with epoxides
differ significantly; some report the clean formation of thiiranes,46
while others predominantly resulted in the 2-thiocyanato ethanol
derivatives.47 There are very few reports on the formation of 1,3-
oxathiolane-2-imines.48–50
moieties with the pendant (SH)OH groups, respectively. The
most striking feature is that the PES dictates that only 1,3-
oxathiolane-2-imines should form (global minimum on this part
of the PES) were it not for the water-induced decomposition of
formal ammonium cyanate into ammonia and CO2. Indeed, we
find experimentally that the initially slightly acidic pH turns basic
at the end of the reaction. Although very stable urea may form from
ammonium cyanate in organic solvents (the classic Wo¨hler reac-
tion), the release of CO2 in the unpressured vial provides the overall
driving force for shifting the equilibrium to the thiirane products.
These results prompted us to include one explicit water molecule
into the optimizations of all species. Indeed, we were able to locate
transition structures TS2·H2O and TS3·H2O that change from
cyclic 4-centre interactions into more favourable six-membered
ring interactions (Fig. 1). However, the overall relative energy
changes are still rather large and chemically unreasonable for a
reaction that does not need an external energy supply. Indeed, only
upon including aqueous solvation and one explicit water solvent
molecule did the energies become quite reasonable (Fig. 1, black
curve). The overall exothermicity of the reaction is only gained
from the release of ammonia and carbon dioxide (DHR = 27.6 kcal
mol-1). Without water, only cyclic intermediate C should be
isolable.
The large energy changes in our computed PES are due to the
involvement of both polar neutral and charged species, as evident
from the very large solvent effects that attenuate these energy
differences as compared to the gas phase. The large barriers derive
from highly polar transition structures (TS2 and TS3) for the
formally forbidden thermal [2 + 2] reaction of the (thio)cyanate
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The computations do indicate that it should be possible to
identify the 1,3-oxathiolane-2-imine intermediates during the
course of the reaction; we show in the following that this is true
and that several of these structures can be trapped and analyzed
as their isocyanic acid adducts.
Although some Lewis acids are compatible with water,51 and
although Lewis acids have been used for the catalysis of the
title reaction,16,18,52 we chose to run the reaction without catalyst
according to the protocols of van Tamelen and Snyder.5,7
Various simple as well as multiply substituted aromatic and
aliphatic epoxides react cleanly with NH4SCN under the reaction
conditions within reasonable times (Table 1); the reaction also
proceeds with smaller amounts of the nucleophile with the
drawback of longer reaction times (for optimization see the ESI).
For highly substituted or conformationally rigid epoxides, higher
temperatures and longer reaction times were required. For the
reactions of 1a, 1b, 1c, and 1f we observed the formation of small
amounts of the corresponding alkenes (<6%); this does not change
at lower temperatures (4 ◦C).
Scheme 2 Epoxides that cannot be ring-opened and converted to
thiiranes due to low solubility or steric and/or electronic effects.
cyclopentyl methyl ether, heating the reaction or sonication did
not improve the situation.
As implied by the mechanistic picture (Fig. 1) and in agreement
with earlier findings,8,23,58 employing optically pure (R)-styrene
oxide (1a) resulted in the formation of enantiomerically pure
(S)-phenyl thiirane (2a). The optical rotation indicated an enan-
tiomeric purity of >99%; the same is true for optically active 2c.
Returning to the discussion of the role of 1,3-oxathiolan-2-
imines (parent structure C in Fig. 1) we note that these structures
have not been isolated in the course of thiirane preparations
from epoxides utilizing thiocyanate salts. Van Tamelen isolated
trans-1,3-oxathiolan-2-imine hydrochloride (4) from the reaction
of cyclohexene oxide with thiocyanate, followed by saturation of
the reaction mixture with dry hydrogen chloride gas (Scheme 3).5
Similar to the findings by van Tamelen, the synthesis of
cyclopentene thiirane (2g) was not possible under these conditions.
We were only able to isolate the ring opened 2-thiocyanato
cyclopentanol (9g) with a yield of 82%; 9g is an accepted
intermediate for this reaction (Fig. 1).53 As suggested in the
literature,54 the first step in thiirane formation – the opening
of the oxirane ring by SCN- to the thiocyanato alcohol – is
fast, while ring closure is slow and should occur in a trans-
like fashion. This is completely in line with our computational
analysis that indicates rather large barriers from the 2-thiocyanato
alcohol derivatives forward. For cyclopentene oxide the ring
closure to C (the oxathiolane intermediate) results in a highly
strained molecule.28,55 The formation of cyclopentene thiirane from
cyclopentene oxide is rather difficult and could only be realized
with a low overall yield of about 15% via a three-step sequence
following an alternative procedure by van Tamelen5 or in the
presence of potent catalysts.13,16,19,22,23,25,53,56 For epoxide 1f we were
also able to isolate the corresponding thiocyanato alcohol 9f as
a by-product in 14% yield. The sterically very restricted (-)-a-
pinene oxide (1n) did not undergo ring opening (Scheme 2), owing
to its inability to align the opening epoxide C–O bond with the
incoming nucleophile. In general, solid epoxides are not amenable
to the present protocol, apparently due to the formation of liquid–
solid interfaces and the resulting low (surface) concentration of
the epoxide in the reaction mixture. This is an indicator that
these reactions truly run “in” as opposed to “on” water.57 The
epoxides which do not undergo the desired reaction are depicted
in Scheme 2. Adding methylene chloride, acetonitrile, THF or
Scheme 3 Synthesis of 1,3-oxathiolan-2-imine-hydrochloride by van
Tamelen.
The free oxathiolan-2-imine (7) of sarcophine (5), a cembranoid
diterpene from the red sea soft coral Sarcophyton glaucum, was
synthesized by Sawant et al. through the SbCl3-catalyzed addition
of ammonium thiocyanate in anhydrous acetonitrile (Scheme 4).49
During our initial studies on the transformation of 1a to 2a
we were able to detect intermediates of type C by GC/MS; the
fragmentation patterns did not correspond to alcoholic structures
because of the absence of characteristic ions. When using rac-
epichlorohydrin (1i) we observed the formation of a white
precipitate. Isolation of the precipitate and structure analysis,
including an X-ray analysis, unequivocally prove the structure of
(Z)-1-(5-(chloromethyl)-1,3-oxathiolan-2-ylidene)urea (Fig. 2).59
Scheme 4 Reaction of sarcophine with thiocyanate catalyzed by SbCl3.
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Table 1 Reaction of oxiranes with ammonium thiocyanate in water at ambient temperaturea
Entry
1
Epoxide
Compound
T (◦C)
rt
t (h)
6
Yield (2:8:9) [%]bc
(S)-1a
93:0:0
2
3
(S)-1a
rac-1b
40
rt
2.5
14
91:0:0
78:14d:0
4
(2R,3S)-1c
rt
21
81:10d:0
5
6
7
meso-1d
meso-1d
rac-1e
rt
4
2
6
93:4d:0
91:6d:0
87:0:0
40
rt
8
rac-1f
rt
14
62:0:14d
9
10
11
12
rac-1h
rac-1i
rac-1j
rac-1k
rt
rt
rt
rt
3
1
64:28d:0
0:78d:0
62:17d:0
87:0:0
4
14
13
14
rac-1m
rac-1o
rt
18
18
92:0:0
40
56:0:19d
15
16
17
18
meso-1p
meso-1p
1q
rt
40
rt
rt
34
34
16
16
49:0:0
75:0:0
0:27d:0
0:34d:0
rac-1r
a Reaction conditions: 1 mmol of epoxide, 2 eq. NH4SCN, 2 mL H2O. b Yields refer to pure isolated products after purification, and are the average of at
least two runs. c All isolated thiiranes were unstable upon standing and polymerization occurred within hours or days. d Isolated when the reaction was
stopped after 1–4 h.
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Structure 8i constitutes the addition product of C to isocyanic acid,
providing firm evidence for the formation of such intermediates
in the title reaction. This also implies that the intermediate
oxathiolane imines are so nucleophilic that they can react with
isocyanic acid before decomposition of the latter.
equivalents of the corresponding thiocyanato alcohols, which were
prepared by addition of etheral HSCN solutions to epoxides.48
Measurement of the optical rotation for 8c, prepared from
enantiomerically pure 1c, showed the retention of configuration
up to the point of intermediate formation in agreement with the
computed reaction pathway (Fig. 1). This is also consistent with
the mechanism proposed by Ettlinger,43 van Tamelen5 as well as
Price and Kirk.44
The question remains why some intermediate oxathiolanes
can be isolated readily while this is not possible in other cases.
The most striking difference is the clean reaction of sterically
somewhat hindered (and non-SN2-type substrate) tetramethyl
epoxide (1p) on the one hand and the halting of the conversion
of epichlorohydrin (1i) at the stage of 8i on the other. There is no
obvious explanation in our view but simple thermodynamics may
be important. Hence, we evaluated isodesmic equations (1) and
(2) (Scheme 6) for a comparison of the relative thermodynamics
of the relevant species; comparisons are made in the gas phase (g),
and in dichloromethane (DCM) as well as aqueous solution. In
marked contrast to the title reaction (Fig. 1), the solvent effects on
the thermodynamics are practically negligible. There is no clear
thermodynamic preference, as the numbers are too small to allow
firm conclusions to be drawn. However, a relative comparison of
(1) and (2) shows that tetraalkyl substitution has a larger effect on
stabilizing the thiirane relative to the chloromethyl group.
Fig. 2 Structure of 8i as well as an ORTEP plot with thermal ellipsoids set
at 50% probability. Single crystals of 8i were obtained by recrystallization
from acetone. The crystal structure shows the (S)-configuration (the
disordered (R)-configuration is not shown). For experimental details of
the X-ray measurements as well as crystallographic data, see ref. 59 and
the ESI†.
Isolation of the 1,3-oxathiolan-2-ylidene urea derivatives was
also possible for compounds shown in Scheme 5, when the reaction
was stopped after 1–4 h at ambient temperature.
Compounds 8d and 8i were synthesized earlier by Wagner-
Jauregg et al. through elimination of ethylene sulfide from two
Scheme 5 Isolated intermediates. For crystal structure of 8q see ESI†.
Scheme 6 Isodesmic equations for a comparison of the relative thermodynamics of the relevant species.
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The formation of oxathiolane imines for 1f and 1o, for example,
results in steric overcrowding at the epoxide carbon atoms. The
stability of these cyclic intermediates is limited and therefore the
concentration is low; as a result we were only able to isolate the
2-thiocyanato ethanols and the corresponding thiiranes. Other
epoxides like 1a, 1k, or 1m cleanly form the desired thiirane and
no intermediates were isolable.
15 (a) H. Bouda, M. E. Borredon, M. Delmas and A. Gaset, Synth.
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Conclusions
19 K. Surendra, N. S. Krishnaveni and K. R. Rao, Tetrahedron Lett., 2004,
45, 6523–6526.
We have synthesized and fully characterized five new members
of the thiirane family, along with several key 1,3-oxathiolan-2-
ylidene urea intermediates in the uncatalyzed reactions of epoxides
20 T. H. Chan and J. R. Finkenbine, J. Am. Chem. Soc., 1972, 94, 2880–
2882.
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with NH4 SCN- in water at ambient temperature. Although
+
our protocol is restricted to epoxides that are liquid at room
temperature, we have demonstrated the first synthesis of 2,2,3,3-
tetramethylthiirane (2p) as an representative of tetrasubstituted
thiiranes from the corresponding oxirane. In terms of mechanism,
we were able to confirm mechanistic proposals and our preceding
computational analysis by isolation and characterization of eight
key intermediates. Water is the essential ingredient of this reaction
because it stabilizes some of the rather high-lying transition
structures on the one hand and because it helps generate carbon
dioxide and ammonia as the exergonic driving force on the other.
25 B. Das, V. S. Reddy and M. Krishnaiah, Tetrahedron Lett., 2006, 47,
8471–8473.
26 J. S. Yadav, B. V. S. Reddy, C. S. Reddy and K. Rajasekhar, J. Org.
Chem., 2003, 68, 2525–2527.
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2004, 2035–2039.
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Acknowledgements
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59 Crystal data: C5H7ClN2O2S; M = 194.64, a = 7.3153(15), b =
3
˚
˚
7.4523(15), c = 14.902(3) A, U = 812.4(3) A , T = 193 K, space group
P212121 (no. 19), Z = 4, 7159 reflections measured, 1896 unique (Rint
=
0.0474) which were used in all calculations. The final wR(F2) was 0.1217
(all data).
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The Royal Society of Chemistry 2009
Org. Biomol. Chem., 2009, 7, 1397–1403 | 1403
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