1,2,4-Dithiazole-5-ones and 5-thiones as efficient sulfurizing agents of phosphorus(iii) compounds - A kinetic comparative study

Article abstract of DOI:10.1039/c2ob26460a

The sulfurization efficiency of 25 3-substituted-1,2,4-dithiazole-5-ones and 5-thiones towards triphenyl phosphite in acetonitrile, DCM, THF and toluene at 25 °C was evaluated. All the 1,2,4-dithiazoles are much better sulfurizing reagents than commercially available agents (PADS, TETD, Beaucage's reagent). The most efficient sulfurizing agents in all solvents are 3-phenoxy (4), 3-phenylthio (5) and 3-ethoxy-1,2,4-dithiazole-5-one (1) whose reactivity is at least two orders of magnitude higher than that of other 1,2,4-dithiazoles. Contrary to a previous report, the sulfurization with 1 does not yield carbonylsulfide and ethyl cyanate as the additional reaction products but unstable ethoxythiocarbonyl isocyanate which has been trapped with 4-methoxyaniline. Similar trapping experiments have proven that the site of attack is at the sulfur adjacent to the CO group for compounds 4 and 5. The reaction pathway involves rate-limiting initial nucleophilic attack of the phosphorus at sulfur followed by decomposition of the phosphonium intermediate to the corresponding phosphorothioate and isocyanate/isothiocyanate species. The existence of the phosphonium intermediate during sulfurization of triphenyl phosphine with 3-phenyl-1,2,4-dithiazole-5-thione (7a) was proven using kinetic studies. From the Hammett and Bronsted correlations and from other kinetic measurements it was concluded that the transition-state structure is almost apolar for the most reactive 1,2,4-dithiazoles whereas a polar structure resembling a zwitter-ionic intermediate may be more appropriate for the least reactive 1,2,4-dithiazoles. The extent of P-S bond formation and S-S bond cleavage is very similar in all reaction series but it gradually decreases with the reactivity of the 1,2,4-dithiazole derivatives.

Full text of DOI:10.1039/c2ob26460a

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PAPER
1,2,4-Dithiazole-5-ones and 5-thiones as efficient sulfurizing agents of
phosphorus(III) compounds – a kinetic comparative study†‡§
Oleksandr Ponomarov,a Andrew P. Lawsb and Jiří Hanusek*a
Received 26th July 2012, Accepted 24th September 2012
DOI: 10.1039/c2ob26460a
The sulfurization efficiency of 25 3-substituted-1,2,4-dithiazole-5-ones and 5-thiones towards triphenyl
phosphite in acetonitrile, DCM, THF and toluene at 25 °C was evaluated. All the 1,2,4-dithiazoles are
much better sulfurizing reagents than commercially available agents (PADS, TETD, Beaucage’s reagent).
The most efficient sulfurizing agents in all solvents are 3-phenoxy (4), 3-phenylthio (5) and 3-ethoxy-
1,2,4-dithiazole-5-one (1) whose reactivity is at least two orders of magnitude higher than that of other
1,2,4-dithiazoles. Contrary to a previous report, the sulfurization with 1 does not yield carbonylsulfide
and ethyl cyanate as the additional reaction products but unstable ethoxythiocarbonyl isocyanate which
has been trapped with 4-methoxyaniline. Similar trapping experiments have proven that the site of attack
is at the sulfur adjacent to the CvO group for compounds 4 and 5. The reaction pathway involves rate-
limiting initial nucleophilic attack of the phosphorus at sulfur followed by decomposition of the
phosphonium intermediate to the corresponding phosphorothioate and isocyanate/isothiocyanate species.
The existence of the phosphonium intermediate during sulfurization of triphenyl phosphine with
3-phenyl-1,2,4-dithiazole-5-thione (7a) was proven using kinetic studies. From the Hammett and
Brønsted correlations and from other kinetic measurements it was concluded that the transition-state
structure is almost apolar for the most reactive 1,2,4-dithiazoles whereas a polar structure resembling a
zwitter-ionic intermediate may be more appropriate for the least reactive 1,2,4-dithiazoles. The extent of
P–S bond formation and S–S bond cleavage is very similar in all reaction series but it gradually decreases
with the reactivity of the 1,2,4-dithiazole derivatives.
interest. One of the key steps in the synthesis of phosphorothio-
ate oligoribonucleotides is the replacement of the oxygen by
Introduction
There is an increasing use of phosphorothioate analogues of oligo-
nucleotides in nucleic acid research.1 Therefore, the synthesis of
oligonucleotide phosphorothioate analogues is of considerable
sulfur. A number of reagents have been designed and tested in
recent years for sulfurization of phosphorus(III) compounds from
which those based on the 1,2,4-dithiazole skeleton2 appear to be
advantageous alternatives to existing sulfurizing reagents.3 Even
1,2,4-dithiazole-5-ones† containing a chiral side chain were
recently synthesized and tested for diastereoselective sulfuriza-
tion of dinucleotide phosphite triesters.4 However, no compara-
tive study of their sulfurization efficiency including reactivity,
stability and solubility has been published until now.
In the first part of the current study, we have compared the
reactivity of 26 known 1,2,4-dithiazoles i.e. 3-ethoxy-1,2,4-
dithiazole-5-one (1) (EDITH), 3-methyl-1,2,4-dithiazole-5-one
(2) (MEDITH), 3-(substituted-phenyl)-1,2,4-dithiazole-5-ones
(3a–e), 3-(substituted-phenoxy)-1,2,4-dithiazole-5-ones (4a–f),
3-(substituted-phenylthio)-1,2,4-dithiazole-5-one (5a–h), 1,2,4-
dithiazole-5-thione (6), 3-(substituted-phenyl)-1,2,4-dithiazole-
5-thione (7a–e), 3-amino-1,2,4-dithiazole-5-thione (8) (ADTT,
xanthane hydride), 3-dimethylamino-1,2,4-dithiazole-5-thione
(9) and 4-phenyl-1,2,4-dithiazole-3,5-dione (10) (Scheme 1)
towards triphenyl phosphite and triethyl phosphite as model
aUniversity of Pardubice, Faculty of Chemical Technology, Institute of
Organic Chemistry and Technology, Studentská 573, 532 10 Pardubice,
The Czech Republic. E-mail: Jiri.Hanusek@upce.cz;
Fax: +420 466 037 068; Tel: +420 466 037 015
bUniversity of Huddersfield, Department of Chemical and Biological
Sciences, Queensgate HD1 3DH, Huddersfield, United Kingdom.
E-mail: a.p.laws@hud.ac.uk
†The nomenclature and numbering of the 1,2,4-dithiazole ring differ
throughout the cited literature. According to IUPAC rules the CvO
(CvS) group should have lower locant 3- instead of 5- (as seen e.g. in
ref. 2f, 4, 7, 8 and 10). Unfortunately in newer literature (e.g. ref. 2a–e,
5 and 12) incorrect numbering was adopted, therefore we decided to
keep this numbering in our previous papers (ref. 11a,b and 35d) as well
as in the present paper to avoid misunderstanding when comparing
results.
‡Dedicated to Professor Vojeslav Štěrba on the occasion of his 90th
birthday.
§Electronic supplementary information (ESI) available: Observed rate
constants and NMR spectra. See DOI: 10.1039/c2ob26460a
8868 | Org. Biomol. Chem., 2012, 10, 8868–8876
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and triethyl phosphites with commercially available phenylacetyl
disulfide (PADS), tetraethylthiuram disulfide (TETD) and Beau-
cage’s reagent in CDCl3 or CD3CN (31P NMR study). For each
of the systems, the absorbance decreased exponentially with
time (see ESI§) from which was obtained a pseudo-first order
rate constant. In all cases the dependences of the observed rate
constant vs. phosphite concentration were linear and their slopes
gave second-order rate constants k (Table 1).
The rate and efficiency of sulfurization are sometimes very
dependent on the solvent system,6 therefore we studied kinetics
in three solvents that are routinely used for the synthesis of
oligonucleotide phosphorothioates i.e. in acetonitrile (ACN),
dichloromethane (DCM) and tetrahydrofuran (THF). Some kin-
etics were also measured in toluene in order to compare the
second-order rate constants with those obtained for elemental
sulfur.
All the compounds 1–10 were found to be much better sulfur-
izing reagents in comparison with commercially available
agents. Also, their stability is very good – almost all of them can
be stored at room temperature for a couple of months with the
only exception7 of MEDITH. The solubility of 1–10 in the most
common solvent – acetonitrile – is in most cases very good.
Only xanthane hydride and its dimethyl derivative are sparingly
soluble in this solvent.
Scheme 1
P(III) compounds in acetonitrile, dichloromethane, toluene and
tetrahydrofuran at 25 °C.
In the second part of this paper we report the structure of the
by-products formed during the sulfurization reaction using
3-ethoxy-1,2,4-dithiazole-5-one (1), 3-phenoxy-1,2,4-dithiazole-
5-one (4a) and 3-phenylthio-1,2,4-dithiazole-5-one (5a) and the
detailed reaction mechanism of the sulfurization using substi-
tuted derivatives.
Results and discussion
From inspection of the results presented in Table 1 it is clear
that the most efficient sulfurizing agents, in all solvents, are
3-phenoxy-1,2,4-dithiazole-5-ones (4a–f) which are in most
cases more than two orders of magnitude more reactive than
other 1,2,4-dithiazole-5-ones and thiones.
Evaluation of 1,2,4-dithiazoles (1–10) for sulfurization of
triphenyl and triethyl phosphites
It is important that an efficient sulfur transfer reagent is used for
the synthesis of oligonucleotide phosphorothioates; J.-Y. Tang’s
group has shown2c–e,5 that various 1,2,4-dithiazole-5-ones and
thiones have potential as sulfurizing reagents. Using a HPLC
technique, they qualitatively compared the efficiency of various
sulfurizing reagents towards the dimer 5′-d(TsT)-3′ and 25mer
(5′-CTCTCGCACCCATCTCTCTCCTTCT-3′) oligonucleotide
and found EDITH (1) to be the most efficient. However, oligo-
nucleotides are not suitable for kinetic measurements due to their
low stability. Therefore similar P(III) compounds – phosphites –
were used as a model in our study. Unfortunately, in some cases
the reaction of trialkyl phosphites which best resemble oligo-
nucleotides is too fast and therefore less reactive triphenyl
phosphite3i has been chosen as a suitable P(III) compound whose
sulfurization can be easily followed spectrophotometrically.
Using 31P NMR we have found that the reaction of all 1,2,4-
dithiazoles 1–10 with triphenyl phosphite proceeds smoothly
and the only product is triphenyl phosphorothioate.
Site of attack
Both the site of attack on the 1,2,4-dithiazole skeleton and the
by-products formed during sulfurization of P(III) compounds
have been established previously in various solvents7–9 or
without solvent.10 In solvent, the corresponding thioacyl isothio-
cyanate, thioacyl isocyanate or isocyanate were exclusively
formed;7–9 i.e. the reaction pathway involved initial nucleophilic
attack of the phosphorus at the sulfur adjacent to the CvO
(CvS) group followed by decomposition of the phosphonium
intermediate to products (Scheme 2).
In our previous papers11 we have dealt with the by-products
and the mechanism of the sulfurization of phosphines and phos-
phites using 3-amino-1,2,4-dithiazole-5-thione (8) and its N,N-
dimethylderivative (9). Contrary to previous reports,1g,2d,e the
sulfurization of triphenyl phosphines and trialkyl phosphites by
8 and 9 does not yield carbon disulfide and cyanamide as the
additional reaction products but reactive thiocarbamoyl isothio-
cyanates (Scheme 2) which have been trapped with external
nucleophiles.
The results above contradict the report of the production of tri-
phenyl phosphorothioate, O-ethyl cyanate and carbonylsulfi-
de2a,12 as products from the reaction of EDITH (1) with
triphenyl phosphite. Therefore we have tried to elucidate the
structure of the by-products formed during the reaction of 1 with
triphenyl phosphite and thus prove or disprove the suggestion
that the site of attack of the 1,2,4-dithiazole skeleton is at sulfur
S-2.
Studies of the reactions using 31P NMR provided no evidence
for the formation of tetra- or pentacoordinate intermediates; if
such species exists on the reaction coordinate, then their concen-
tration must be negligible. The corresponding isocyanate/isothio-
cyanate species (see below) are formed as initial reactive by-
products which subsequently undergo consecutive reactions with
nucleophilic species.
The kinetics of the sulfurization reaction of both triethyl and
triphenyl phosphites were determined by monitoring the
decrease in concentration of 1–10 spectrophotometrically at an
appropriate wavelength in various solvents under pseudo-first
order conditions (phosphites in large excess). For comparison
we have also measured the kinetics of sulfurization of triphenyl
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Table 1 Second-order rate constants k (l mol−1 s−1) for the reaction of sulfurization reagents 1–10, PADS, TETD, Beaucage’s agent and S8 with
triphenyl phosphite (or triethyl phosphite, see the final column) in acetonitrile (ACN), dichloromethane (DCM), tetrahydrofuran (THF) and toluene at
25 °C measured at an appropriate wavelength λ (nm)
Sulfurization agent
λ (nm)
Solubility in ACN
k (ACN)
k (DCM)
k (THF)
k (toluene)
k (EtO)3P (ACN)
f
1
2
3a
3b
3c
3d
3e
4a
4b
4c
4d
4e
4f
5a
5c
5d
5g
5h
6
7a
7b
7c
7d
7e
290
320
350
390
365
335
365
327
327
327
327
325
331
340
320
340
340
340
400
425
450
460
450
450
360
365
1 g/20 ml
1 g/5 ml
1 g/10 ml
—
—
—
—
1 g/250 ml
—
—
—
—
—
—
—
597 (877)a
2.03
10.64
7.11
7.83
26.3
432 (483)a
2.11
3.97
3.13
3.02
347
1.62
4.48
1.61
2.52
10.8
21.4
1 125
720.9
1 148
2 141
2 333
2 624
239
550
1.87
5.51
5.55
4.12
22.6
28.0
3 626
2 362
2 515
5 843
5 907
6 737
426
—
39 170
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
f
f
f
f
12.3
17.8
f
31.0
f
2 430
1 587
2 306
3 630
3 932
4 372
384
1 882
909
1 550
3 184
3 475
4 283
238
f
f
f
f
f
f
f
327
748
187
538
196
415
259
829
f
—
—
—
f
1 515
1 576
0.1236b
0.0828
0.0571
0.0524
0.2325
0.3566
2.65
1 870
2 022
0.1778
0.0222
0.0184
0.0158
0.0909
0.1155
Insoluble
2.37
1369
1335
0.0152
0.0266
0.0250
0.0179
0.0722
0.1139
0.275
0.99b
0.014
—
3807
4374
0.0691
0.0310
0.0196
0.0167
0.0997
0.1530
Insoluble
1.71
0.023
—
—
—
No reactione
f
—
1 g/100 ml
1 g/150 ml
—
—
—
1 408
3 570b
—
—
—
—
—
8
9
1 g/450 ml
1 g/110 ml
1 g/15 ml
1 g/110 ml
1 g/ 12 ml
—
3 122a
2 500
—
2.62 (3.26)a
0.025
—
10
PADS
TETD
Beaucage’s agent
290
0.017
No reactionc,d
No reactionc,d
0.00653c,d
—
0.069d
—
—
c
c
c
No reactionc
0.000758c
—
—
—
—
S8
—
—
0.0096e
a At 30 °C. b Consecutive reaction of the isocyanate/isothiocyanate by-product with traces of water in solvent appears. c Measured by 31P NMR. d In
CDCl3 at 25 °C. e In toluene at 31 °C (from ref. 14c). f Reaction is too fast for stopped-flow measurements.
Scheme 3
thiocarbamate (12) or phenyl N-(phenylcarbamoyl)dithiocarba-
mate (13), respectively, under the same conditions (Scheme 3).
These observations prove that the site of attack is at the
sulfur adjacent to the CvO group for the 1,2,4-dithiazoles 1, 4
and 5.
Scheme 2
To prove the presence of the anticipated ethoxythiocarbonyl
isocyanate during the course of the sulfurization reaction (cf.
Scheme 2) we added an external nucleophile, 4-methoxyaniline,
to the reaction mixture to act as a trap. After the reaction work-
up, O-ethyl N-[(4-methoxyphenyl)carbamoyl]thiocarbamate (11)
was obtained in very good yield (96%) which is the analogous
product of known nucleophilic addition of aniline to ethoxythio-
carbonyl isothiocyanate.13a A similar experiment (according to
ref.13b) was carried out with our original 3-phenoxy-1,2,4-dithia-
zole-5-one (4a) and 3-phenylthio-1,2,4-dithiazole-5-one (5a)
which provided O-phenyl N-[(4-methoxyphenyl)carbamoyl]-
Reaction mechanism
The detailed mechanism of sulfurization of various phosphorus(III)
compounds (phosphines, phosphites, phosphonites, phosphinites
and phosphorous triamides) by sulfur,14 disulfides,15 trisulfides16
and tetrasulfides17 has been briefly studied in the past. In all
cases it was concluded that the reaction involves rate-limiting
nucleophilic attack of phosphorus on sulfur producing a
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phosphonium salt intermediate which then quickly decomposes
to the corresponding product containing a PvS group. The high
negative Hammett ρ-values14a,c obtained for the reaction of
m- and p-substituted triphenyl phosphines, phosphonites and
phosphinites with elemental sulfur (ρ = −2.5 ÷ −3) are also con-
sistent with a highly polarized transition state. On the other
hand, the corresponding ρ-values obtained using diphenyltri-
sulfide as the sulfurizing agent are only around ρ = −1.1 for all
above-mentioned P(III) compounds. This indicates only a moder-
ate degree of a positive charge build-up on phosphorus and the
same degree of a negative charge on sulfur (as seen from ρ = +1
obtained for the reaction of p-substituted diphenyltrisulfides with
triphenylphosphine16c) in the transition state. On the other hand
the reaction of thiiranes (episulfides) with triphenyl phosphine
producing alkenes and triphenyl phosphine sulfide is considered
to proceed through a non-polar transition state18 because of its
insensitivity to large changes in solvent polarity and its
stereospecificity.
reactive 4a is looser than that for the least reactive 7a (i.e. the
P–S bond is formed to somewhat less extent for 4a than in the
case of 7a). The interpretation of the Hammett ρ-value in terms
of absolute charge distribution in the transition state requires a
reference reaction, ideally a corresponding ρ-value for an equili-
brium reaction. Unfortunately, the only equilibrium studied for
P(III) compounds concerns protonation of phosphines in nitro-
methane which gave20 Taft ρ* = −2.6. Although the correspond-
ing values for phosphites are unknown, similar or slightly
smaller values might be expected given that the reaction of 8
with triphenyl phosphines as well as phosphites gave11b similar
ρ-values. Given that the ρ-values were relatively small it can be
concluded that there is only a small positive charge on phos-
phorus in the transition state.
To get a better insight into the reaction mechanism, especially
into the extent of S–S bond cleavage in the transition state, we
also studied the transmission of polar substituent effects in four
series of substituted 1,2,4-dithiazoles: 3a–e, 4a–f, 5a,c,d,g,h and
7a–e.
The position of the transition state on the reaction coordinate
and the charge on the transition state can be determined from
studies of the effect of solvent polarity on reaction rates. In the
case of 1,2,4-dithiazoles the influence of solvent polarity (see
Table 1) or proton donor ability11b on the rate of sulfurization is
only negligible. Also the Hammett ρ-values for the reaction of
m- and p-substituted triphenyl phosphites with 3a or 7a and 4a
or 5a (see Fig. 1 and ESI§) in acetonitrile range from −1.3 to
−0.7, respectively (cf. also with value −1.1 observed for 8)11b
which together with the high and negative entropy of activa-
tion11b is consistent with a bimolecular association step (k1)
leading to the transition state. It appears that the gradual change
in ρ-values is in accordance with reactivity–selectivity prin-
ciple.19 The gradual increase in reactivity (7a < 3a < 5a < 4a) is
accompanied by a decrease in selectivity measured by the pro-
portionality factor ρ (absolute ρ-value gradually decreases from
ca. 1.3 to 0.7). The transition-state structure is therefore assumed
to become closer to that of the reactant state as the energy barrier
decreases.19 In other words the transition state for the most
In two series 3-(subst.phenyl)-1,2,4-dithiazol-5-ones (3a–e)
and 3-(subst.phenyl)-1,2,4-dithiazol-5-thiones (7a–e) the
second-order rate constants for the reaction with triphenyl phos-
phite were measured in acetonitrile at 25 °C and then plotted
against the pKa of the thiobenzamides to generate a Brønsted-
type relationship, whose slope gives β′lg reflecting the progress
of S–S bond cleavage in the transition state (Fig. 2).
For all four series the rate constants were also plotted against
the substituent σ-values (Fig. 3) to generate a Hammett plot
whose ρ-values reflect the negative charge developing on the
leaving sulfur in the transition state.
Thiobenzamides were adopted as they best resemble the struc-
ture of the leaving group (Scheme 4).
Unfortunately only their pKa in water21 are available therefore
it was necessary to make a correction for transfer from water to
acetonitrile. It can be presumed that the change in Hammett
ρ-values will be similar as in the case of benzoic acid whose
ρ-values are 1 (by definition in water) and 2.64 in acetonitrile.22
Fig. 1 Hammett plot for sulfurization of tris (subst. phenyl) phosphites
(4-OCH3, 4-CH3, H, 4-Cl, 3-Cl) with 3a (■), 4a (●), 5a (○) and 7a (□).
Fig. 2 Brønsted-type plot for sulfurization of triphenyl phosphite with
3a–e (●) and 7a–e (○) in acetonitrile at 25 °C.
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Table 2 Hammett ρ-values measured in various solvents
ρ (ACN)
ρ DCM
ρ (THF)
ρ (TOL)
3a–e
4a–f
5a–h
7a–e
1.11 0.15
0.57 0.06
0.75 0.07
1.38 0.22
1.31 0.23
0.74 0.06
1.14 0.06
1.46 0.31
1.75 0.06
0.74 0.08
0.95 0.06
1.19 0.29
1.34 0.35
0.67 0.07
1.31 0.04
1.57 0.26
(7a–e)a (1.70 0.10) (1.86 0.28) (1.64 0.10) (1.95 0.14)
a Without deviating point for 7b.
Fig. 3 Hammett plot for sulfurization of triphenyl phosphite with 3a–e
(■), 4a–f (●), 5a–h (○) and 7a–e (□) in acetonitrile at 25 °C.
Scheme 4
Fig. 4 Triphasic kinetics observed for the reaction of 3a with triphenyl
phosphine (0.01 mol l−1) in dried ACN (solid line) and ACN containing
10 μl H2O in 1 ml ACN i.e. 0.55 mol l−1 H2O (dashed line).
When dividing the values of the slopes from Fig. 2 by 2.64 we
obtained βlg(3a–e) = −0.34 and βlg(7a–e) = −0.40, respectively,
which also correspond to early transition states. Unfortunately a
similar Brønsted-type plot cannot be generated for 4a–f and 5a,
c,d,g,h because the pKa of the corresponding O-phenyl-thio-
carbamates and S-phenyl-dithiocarbamates are not available.
The Hammett ρ-values for the reaction of triphenyl phosphite
with 3a–e, 4a–f, 5a,c,d,g,h and 7a–e (Fig. 3) also indicate that
there is a negative charge developing on the leaving sulfur. From
their comparison it is clear that the relative negative charge seen
by the substituents again decreases with increasing reactivity (cf.
ρ-values 1.38 and 1.11 for related series 3a–e and 7a–e or 0.75
and 0.57 for 4a–f and 5a,c,d,g,h). In the latter two series the
lowering of ρ-values is not caused by a simple attenuation factor
of the O and S bridging atom between the benzene ring and the
1,2,4-dithiazole because this factor is almost the same for both
bridge atoms (fO = 0.64 and fS = 0.68).23
phosphines had similar negative values (−1.1 and −0.86). Sur-
prisingly, the substituent sensitivity was higher with phosphites
although the oxygen bridge should attenuate transmission of the
polar effects to a greater extent. Therefore we tried to carry out
similar measurements with other 1,2,4-dithiazoles. Unfortu-
nately, due to their high reactivity towards substituted triphenyl
phosphines only the measurements (see ESI§) with the least
reactive 7a in acetonitrile were possible giving ρ = −1.63 which
is a higher value than those observed for the substituted tri-
phenyl phosphites (ρ = −1.28). However the observed attenu-
ation factor of oxygen is much less than the common23 value
0.64.
When the reaction of 7a with triphenyl phosphine was studied
triphasic kinetics were observed (Fig. 4).
During the first part of the kinetics the absorbance at 425 nm
(which is the most intense absorption band of 7a) decreased very
quickly (reaction half-lives in milliseconds) and the observed
rate constant was directly proportional to the triphenyl phosphine
concentration but independent of added water. During the
second phase of the kinetics the absorbance at 425 nm increased
again but the observed rate constant was lower (half-lives in
seconds) and was independent of both triphenyl phosphine as
well as added water concentrations. The third reaction was some-
what slower (half-lives in tens of seconds) but its rate increased
These Hammett ρ-values are only slightly dependent on
solvent polarity for the most reactive dithiazoles 4a–f but with
the less reactive 5a,c,d,g,h (and partially with 3a–e, 7a–e) the
polar effects are more pronounced in a solvent of lower polarity
(Table 2). Such an observation also supports the idea that the
transition state for the most reactive 1,2,4-dithiazol-5-ones 4a–e
is looser than for the other less reactive dithiazoles.
In our previous paper11b we found that the ρ− constants for
the reaction of 8 with substituted triphenyl phosphites and
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with added water. This observation gives further evidence for the
mechanism in Scheme 2. The first reaction corresponds to the
formation (k1) of a zwitterionic intermediate in Scheme 2
whereas the second one corresponds to the decomposition (k2) of
this intermediate to the triphenyl phosphine sulfide and thio-
benzoyl isothiocyanate. The third phase then corresponds to the
slow reaction of thiobenzoyl isothiocyanate with traces of water
and its observed rate constant therefore steeply increases with
added water. Similar biphasic kinetics confirming rapid buildup
and slower decay of an intermediate was observed in the past for
the reaction of diaryl disulfides with triphenyl phosphine.15a In
the present study triphasic kinetics were only observed for the
reaction of the least reactive 7a and highly reactive triphenyl
phosphine. In all other cases the kinetics involved only one or
two phases; the rate of the first was always directly proportional
to the P(III) compound concentration (see Table 1) and the
second one corresponded to the slow water addition to the iso-
cyanate/isothiocyanate by-product.
Treatment of our data by the dual substituent parameter
approach introduced by Taft is also possible. For 1,2,4-dithia-
zole-5-ones 1–5 differing in substitution in position 3 the data
measured in acetonitrile (with triphenyl phosphite) can be fitted
using eqn (1) where ρIσI and ρRσR describe transmission of the
inductive and resonance effects separately.
Fig. 5 Mayr plot for the sulfurization of triphenyl phosphite and sub-
stituted triphenyl phosphines with 7a (○) and 8 (●). The dependence
for 9 is not depicted in order to achieve better clarity because it is almost
identical to those for 8.
donation from sulfur S-1. It is well known27 that in phosphate
triesters [OvP(OR)3], due to the difference in electronegativity
of phosphorus (2.1) and oxygen (3.5), the P–O bonds are polar-
ized toward oxygen (Pδ+–Oδ−–R). However, this activating
effect is overshadowed by efficient back-donation of the lone
electron pairs of the P–O–C bonds that lowers significantly the
electrophilicity of the phosphorus centre in these compounds.
The situation could be similar for the corresponding phosphoro-
thioate (SvP(OR)3) although this π-bonding is less effective in
these thio analogues.
Phosphorous compounds are more powerfu1 nucleophiles
than the corresponding amines28 despite their weak basicity.20
For some of them (i.e. for substituted phenyl phosphines and tri-
phenyl phosphites) their nucleophilicity parameters N were
recently published by Mayr and co-workers.29 A good linear cor-
relation of (log k)/s over a wide range of reactivities is observed
for 7a, 8 (Fig. 5) and 9, showing that the nucleophilicity para-
meters N and s, which have been derived from reactions with
benzhydrylium ions, are also relevant for SN2 reaction of these
nucleophiles at sulfur.
The slopes of the correlations shown in Fig. 5 do not equal 1
(they are from 0.62 to 0.89) as required by the Mayr equation,30
indicating that the benzhydrylium-based nucleophile-specific
parameters N and s can only be applied for such SN2 reaction
when an additional, electrophile-specific slope parameter sE is
added. Its value reflects less positive charge on sulfur S-1 in the
transition state as compared with benzhydrylium cations where
sE = 1.
From all the above-mentioned observations an early transition
state with little build-up of charge on phosphorus as well as on
sulfur can be suggested. The extent of P–S bond formation and
S–S bond cleavage is very similar in each of the reaction series
but it gradually decreases with the reactivity of the 1,2,4-dithia-
zole derivatives. It also appears that the S–S bond breaking is
somewhat advanced over P–S bond making in the transition state
log k ¼ log k 0 þ ρIσI þ ρRσR
ð1Þ
Using σI and σR from ref.24 we obtained log k0 = 0.19 0.08,
ρI = 6.41 0.34 and ρR = −1.32 0.37. As seen from the com-
parison of absolute ρI and ρR-values it is evident that the sulfuri-
zation is much more sensitive towards inductive effects. The
transmission of mesomeric effects is less important which con-
tradicts the aromatic (or pseudo-aromatic) character proposed for
1,2,4-dithiazole derivatives.12,25 The π-orbital delocalization
occurs only in the R–CvN–CvZ (Z = O, S) moiety (as seen
from the elongation of the double bonds) and is not pronounced
in the disulfide bridge.
The simultaneous attack at both sulfur atoms (biphilic mech-
anism) giving a pentavalent phosphorus intermediate or its
equivalent involving back-donation14c,16d from sulfur S-2 to
phosphorus can also be suggested to explain low ρ-values
instead of nucleophilic attack at a single sulfur S-1. Such an
explanation was suggested by Hall and Lloyd for the sulfuriza-
tion of triphenyl phosphines, phosphonites and phosphinites
with diaryl trisulfides and elemental sulfur (S8). Hall and Lloyd
found ρ-values constancy and an anomalous rate sequence for
the sulfurization of P(III) compounds (i.e. Ph2POR > PhP(OR)2
≫ PPh3 or P(OR)3) whereas the normal26 rate sequence (i.e.
PPh3 > Ph2POR > PhP(OR)2 > P(OR)3) was observed for SN2
attack by phosphorus at tetrahedral carbon. In the case of 1,2,4-
dithiazole 7a we also observed the same anomalous rate
sequence in ACN at 25 °C. The second-order rate constants for
the individual P(III) compounds were as follows: k = 1.6 × 105
l mol−1 s−1 with methyl diphenylphosphinite, k = 1.2 × 105
l mol−1 s−1 with dimethyl phenylphosphonite, k = 1.06 × 104
l mol−1 s−1 with triphenyl phosphine and k = 1.14 × 103 l mol−1
s−1 with trimethyl phosphite. The anomalous order of nucleophi-
licity could support the idea of back-donation16d from sulfur S-2
to phosphorus. Another explanation involves direct back-
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Ar-H2,6), 7.66 (AA′XX′, 2H, Ar-H3,5), 2.47 (s, 3H, CH3).
13C-NMR (CDCl3, 100 MHz) δ 21.6, 120.6, 131.4, 136.8,
143.7, 183.8, 195.5. Anal. calcd for C9H7NOS3: C, 44.79; H,
2.92; N, 5.80; S, 39.86. Found: C, 44.96; H, 2.90; N, 5.80; S,
40.01.
5d: Yield 1.14 g (73%). M.p. 163–164 °C from ethyl acetate,
1H-NMR (CDCl3, 400 MHz) δ 7.69 (AA′XX′, 2H, Ar-H2,6),
7.56 (AA′XX′, 2H, Ar-H3,5). 13C-NMR (CDCl3, 100 MHz) δ
122.6, 131.0, 138.1, 139.7, 183.4, 193.8. Anal. calcd for
C8H4ClNOS3: C, 36.71; H, 1.54; Cl, 13.54; N, 5.35; S, 36.75.
Found: C, 36.93; H, 1.55; Cl, 13.27; N, 5.27; S, 36.99.
5g: Yield 1.08 g (66%). M.p. 182–184 °C from diethyl ether,
1H-NMR (CDCl3, 400 MHz) δ 8.62 (t, 1H, J = 2.0 Hz, Ar-H2),
8.50 (ddd, 1H, J = 8.4 and 2.3 and 1.0 Hz, Ar-H4), 8.09 (ddd,
1H, J = 7.7 and 1.8 and 1.0 Hz, Ar-H6), 7.80 (t, 1H, J = 8.0,
Ar-H5). 13C-NMR (CDCl3, 100 MHz) δ 126.9, 127.2, 131.3,
131.4, 142.3, 149.0, 182.8, 191.5. Anal. calcd for C8H4N2O3S3:
C, 35.28; H, 1.48; N, 10.29; S, 35.32. Found: C, 35.56; H, 1.52;
N, 10.03; S, 35.38.
5h: Yield 0.98 g (60%). M.p. 136–138 °C from ethyl acetate,
1H-NMR (CDCl3, 400 MHz) δ 8.39 (AA′XX′, 2H, Ar-H3,5),
7.96 (AA′XX′, 2H, Ar-H2,6). 13C-NMR (CDCl3, 100 MHz)
δ 125.1, 132.3, 137.3, 150.0, 182.7, 191.0. Anal. calcd for
C8H4N2O3S3: C, 35.28; H, 1.48; N, 10.29; S, 35.32. Found: C
35.31, H 1.44, N 10.27, S 35.37.
Scheme 5
and this difference increases with increasing reactivity of both
reactants. The following structures of the transition-state
(Scheme 5) can be proposed:
The second apolar structure resembling a retro [4 + 1] cyclo-
addition is inspired by the published syntheses of various 1,2,4-
dithiazoles from acyl isothiocyanates and phosphorus penta-
sulfide31 or N,N-dimethylthiocarbamoyl isothiocyanate and
elemental sulfur.32 It is well known that the dependence of
cycloaddition (and retro-cycloaddition18) rate constants on
solvent polarity is a significant mechanistic criterion. The small
solvent dependencies of Diels–Alder reactions and 1,3-dipolar
cycloadditions signal minute charges of polarity during the acti-
vation process. These concerted cycloadditions also have early
transition states.33 Therefore the apolar transition state depicted
in Scheme 5 should come into consideration when the reactivity
of both phosphorus(III) compound as well as the 1,2,4-dithiazole
derivative is high. On the other hand the transition state
resembles the polar structure that may be more appropriate for
the least reactive 1,2,4-dithiazoles.
Kinetic measurements
The kinetic measurements were carried out on a Diode Array
Stopped-Flow SX.18 MV-R (Applied Photophysics) spectro-
photometer or on a Hewlett Packard HP 8453 Diode Array at
25 °C under pseudo-first order conditions. The observed pseudo-
first order rate constants kobs were calculated from the measured
time dependence of absorbance at a suitable wavelength with the
help of an optimization program. Solvents used for kinetic
measurements were of HPLC quality and were dried and distilled
under argon prior to use. Due to potential oxidation of
phosphorus(III) compounds all the solutions were freshly
prepared just before kinetic measurements.
Experimental
Synthesis
All the 1,2,4-dithiazoles 1–4 and 6–10 were synthesized and
purified
according
to
procedures
published
else-
where.7,8,12,31a,32,34 Synthesis of the new 3-[(subst.phenyl)thio]-
1,2,4-dithiazole-5-ones (5) started from subst.phenyl dithiocarba-
mates prepared according to ref.35. Other chemicals were
obtained from commercial suppliers and were used as received.
NMR experiments
General method for the preparation of 5a,c,d,g,h
1H, 13C and 31P NMR spectra were recorded on a Bruker Avance
3 400 MHz instrument. Chemical shifts δ are referenced to
solvent residual peaks δ(DMSO-d6) = 2.50 (1H) and 39.6 ppm
(13C), and δ(CDCl3) = 7.27 (1H) and 77.0 (13C). 31P NMR shifts
are referenced to 85% phosphoric acid (external standard).
A solution of freshly prepared35 subst.phenyl dithiocarbamate
(6 mmol) in dry Et2O (50 ml) was added dropwise over 30 min
into a stirred and externally chilled (0–10 °C) solution of chloro-
carbonylsulfenyl chloride (0.80 g, 6 mmol) in dry Et2O (50 ml).
The reaction mixture was stirred at 10 °C for 2 h. Solvent was
evaporated at reduced pressure, and the residue was purified by
recrystallization from a suitable solvent. See individual examples
below:
Reaction of PADS, TETD and Beaucage’s reagent with triethyl
or triphenyl phosphite (31P NMR kinetic study)
5a: Yield 1.06 g (78%). M.p. 148–149 °C from ethyl acetate,
1H-NMR (CDCl3, 400 MHz) δ 7.57 (m, 2H, Ar-H3,5), 7.66 (m,
1H, Ar-H4), 7.74 (m, 2H, Ar-H2,6). 13C-NMR (CDCl3,
100 MHz) δ 124.2, 130.6, 132.7, 136.9, 183.6, 194.8. Anal.
calcd for C8H5NOS3: C, 42.27; H, 2.22; N, 6.16; S, 42.32.
Found: C, 42.51; H, 2.24; N, 6.22; S, 42.41.
Sulfurizing reagent (0.1 mmol) was dissolved in 0.5 ml of
CDCl3 or CD3CN and the corresponding phosphite (0.1 mmol)
in 0.5 ml of CDCl3 or CD3CN was added so that the initial con-
centration of both components was 0.1 mol l−1. Then 31P NMR
spectra were recorded after appropriate intervals (from minutes
to hours). The spectrum always contained two singlets belonging
to triphenyl phosphorothioate (δP = 55.2 ppm in CD3CN36a and
5c: Yield 1.18 g (82%). M.p. 129–130 °C from petrolether/
diethyl ether, 1H-NMR (CDCl3, 400 MHz) δ 7.61 (AA′XX′, 2H,
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53.7 ppm in CDCl3 36b) or triethyl phosphorothioate (δP
=
121.3, 122.7, 126.6, 129.7, 130.6, 148.9, 152.5, 155.9, 188.3.
Elemental analysis: found C, 59.47; H, 4.59; N, 9.32; S, 10.68.
C15H14N2O3S requires C, 59.59; H, 4.67; N, 9.27; S, 10.61.
3-Phenylthio-1,2,4-dithiazole-5-one (5a) (0.5 g, 2.2 mmol)
was dissolved in 75 ml of acetonitrile under an argon atmosphere
at 20 °C and a solution containing triphenyl phosphite (0.68 g,
2.2 mmol) in 25 ml of acetonitrile was added in one portion.
The reaction mixture was stirred for 5 s and then aniline (0.20 g,
2.2 mmol) in 25 ml of acetonitrile was added. After 2 h the
acetonitrile was evaporated and the semi-solid residue was chro-
matographed on a silica (dichloromethane–pentane 1 : 1) to
obtain 0.60 g (94%) of yellowish crystals 13 with m.p.
68.5 ppm in CD3CN36a and 67.2 ppm in CDCl3 36c) and tri-
phenyl phosphite (δP = 129.7–130 ppm in CD3CN36a,d and
127.9 ppm in CDCl3 36e) or triethyl phosphite (δP = 139.9 ppm
in CD3CN36a and 137.5 in CDCl3 36f), whose ratio was changing
with time. From integrals the kinetic curve was constructed and
the second-order rate constant was calculated.
Trapping experiments
3-Ethoxy-1,2,4-dithiazole-5-one (1) (0.53 g, 3.25 mmol) was
dissolved in 20 ml of acetonitrile under an argon atmosphere at
20 °C and a solution containing triphenyl phosphite (1.0 g,
3.25 mmol) in 5 ml of acetonitrile was added in one portion.
The reaction mixture was stirred for 1 min and then 4-methoxya-
niline (0.40 g, 3.25 mmol) in 5 ml of acetonitrile was added.
After 1 h the reaction mixture was filtered and white crystalline
O-ethyl N-[(4-methoxyphenyl)carbamoyl]thiocarbamate (11,
0.60 g) was collected. Acetonitrile was recovered from the
filtrate and the semi-solid residue was chromatographed on a
silica gel (ethyl acetate–hexane 1 : 4) to obtain a further portion
of 11 (0.20 g). The chromatographic column was then washed
with methanol to obtain 0.99 g (89%) of triphenyl phosphoro-
thioate. The overall yield of 11 was 0.80 g (96%). M.p.
145–146 °C, 1H-NMR (CDCl3, 400 MHz) δ 1.41 (t, J = 7.2, 3H,
CH3), 3.80 (s, 3H, OCH3), 4.49 (q, J = 7.2, 2H, OCH2), 6.87
(AA′XX′, 2H, Ar-H3,5), 7.46 (AA′XX′, 2H, Ar-H2,6), 9.47 (bs,
1H, NH), 11.26 (bs, 1H, NH). 13C-NMR (CDCl3, 100 MHz) δ
13.7 (CH3), 55.4 (OCH3), 67.2 (OCH2), 114.1 (Ar-C3,5), 121.9
(Ar-C2,6), 129.9 (Ar-C1), 150.5 (CvO), 156.5 (Ar-C4), 188.0
(CvS). Elemental analysis: found C, 52.11; H, 5.58; N, 11.10;
S, 12.74. C11H14N2O3S requires C, 51.95; H, 5.55; N, 11.02; S,
12.61.
3-Phenoxy-1,2,4-dithiazole-5-one (4a) (0.5 g, 2.36 mmol) was
dissolved in 10 ml of acetonitrile under an argon atmosphere at
20 °C and a solution containing triphenyl phosphite (0.73 g,
2.36 mmol) in 5 ml of acetonitrile was added in one portion.
The reaction mixture was stirred for 1 min and then 4-methoxy-
aniline (0.29 g, 2.36 mmol) in 5 ml of acetonitrile was added.
After 1 h the reaction mixture was filtered and white crystalline
O-phenyl N-[(4-methoxyphenyl)carbamoyl]thiocarbamate (12,
0.35 g) was collected. Acetonitrile was removed from the filtrate
and the semi-solid residue was chromatographed on silica gel
(ethyl acetate–hexane 1 : 9) to obtain a further portion of 12
(0.30 g). The chromatographic column was then washed with
methanol to obtain 0.72 g (90%) of triphenyl phosphorothioate.
The overall yield of 12 was 0.65 g (84%). M.p. 144–147 °C,
1H-NMR (CDCl3, 400 MHz) δ 3.77 (s, 3H, OCH3), 6.85 (AA′
XX′, 2H, Ar-H3,5), 7.10 (d, J 7.6, 2H, Ar-H2,6), 7.33 (t, J = 7.6,
1H, Ar-H4), 7.46 (m, 4H, AA′XX′ + Ar-H3,5), 9.84 (bs, 1H,
NH), 11.22 (bs, 1H, NH). 13C-NMR (CDCl3, 100 MHz) δ 55.4,
114.2, 122.1, 122.5, 126.9, 129.5, 129.5, 150.3, 151.8, 156.7,
188.0. One Cquart is missing in the spectrum in CDCl3 because
two peaks in the aromatic region have exactly the same chemical
shift. In DMSO-d6 δ 3.73 (s, 3H, OCH3), 6.92 (AA′XX′, 2H,
Ar-H3,5), 7.16 (d, J = 7.6, 2H, Ar-H2,6), 7.31 (t, J = 7.6, 1H, Ar-
H4), 7.45 (m, 4H, AA′XX′ + Ar-3,5), 10.26 (bs, 1H, NH), 11.81
(bs, 1H, NH). 13C-NMR (CDCl3, 100 MHz) δ 55.3, 114.3,
1
181–182 °C. H-NMR (DMSO-d6, 400 MHz) δ 7.11 (m, 1H,
Ar-H), 7.36 (m, 2H, Ar-H), 7.44–7.53 (m, 7H, Ar-H), 9.45 (bs,
1H, NH), 11.61 (bs, 1H, NH). 13C-NMR (DMSO-d6, 100 MHz)
δ 119.2, 123.9, 129.2, 129.5, 130.3, 131.4, 136.3, 137.8, 149.5,
202.8. Elemental analysis: found C, 58.51; H, 4.12; N, 9.59; S,
22.34. C14H12N2OS2 requires C, 58.31; H, 4.19; N, 9.71; S,
22.24.
Conclusions
3-Substituted-1,2,4-dithiazole-5-ones and 5-thiones were found
to be stable and extraordinarily efficient sulfurizing agents of
phosphorus(III) compounds. Their reactivity is as much as six
orders of magnitude higher (especially with our original
3-phenoxy and 3-phenylthio-1,2,4-dithiazole-5-ones) than for
commercially available sulfurizing agents like for example Beau-
cage’s agent or phenylacetyldisulfide (PADS). Moreover their
reactivity is virtually independent of solvent polarity which
makes 1,2,4-dithiazoles to be promising sulfurizing agents in
automated synthesis of phosphorothioate oligoribonucleotides.
In order to understand the sulfurization reaction the detailed reac-
tion mechanism was also studied. It was found that the insensi-
tivity of the reaction rate towards solvent polarity is probably
caused by some kind of electron back donation from sulfur to
phosphorus in the transition state of the reaction.
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