Thioformaldehyde S-sulfide (Thiosulfine)

Article abstract of DOI:10.1002/1521-3773(20010119)40:2<393::AID-ANIE393>3.0.CO;2-J

Matrix isolation spectroscopy allows the direct identification of ylide 1 and its cyclic isomer 2. They were obtained by pyrolysis of 1,2,4-trithiolane under high vacuum; the cyclic compound forms from 1 by thermal ring closure in a kinetically controlled reaction.

Full text of DOI:10.1002/1521-3773(20010119)40:2<393::AID-ANIE393>3.0.CO;2-J

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[29] a) C. M. Murray, T. R. Auton, M. D. Eldrige, J. Comput. Aided Mol.
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[30] The LeadQuest product description guarantees >85% purity for
every compound as determined by analytical HPLC (HP110 system)
using a universal water/acetonitrile gradient and a UV detector at
254 nm.
native-like binding geometries represents an important first
step towards this goal.
Finally, we have shown that the LeadQuest Database
provides an ideal source for the discovery of novel lead
compounds,[31] in terms of both structural diversity[8] and
chemical purity.[30]
[31] A search in the patent literature shows that the subnanomolar
compounds discovered here possess scaffolds not covered by existing
patents. Such
structureº.
a scaffold is generally accepted as a ªnew lead
Received: June 14, 2000 [Z15270]
[32] A. T. Brünger, X-PLOR, Version 3.1, Yale University Press, New
Haven, 1992.
[1] E. S. Lander, Science 1996, 274, 536 ± 539.
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[6] Maybridge Database (Version August 99), Maybridge Chemical Co.
Ltd. (UK) 1999.
[7] LeadQuest Chemical Compound Libraries, Vol. 1 ± 3, Tripos, Inc. (St.
Louis, MO) 2000.
Thioformaldehyde S-sulfide (Thiosulfine)**
Â
Â
Grzegorz Mloston, Jaroslaw Romanski,
Hans Peter Reisenauer, and Günther Maier*
[8] D. E. Patterson, R. D. Cramer, A. M. Ferguson, R. D. Clark, L. E.
Weinberger, J. Med. Chem. 1996, 39, 3049 ± 3059.
[9] S. Lindskog, Pharmacol. Ther. 1997, 74, 1 ± 20.
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1995, 34, 3981 ± 3989.
[11] G. M. Smith, R. S. Alexander, D. W. Christianson, B. M. McKeever,
G. S. Ponticello, J. P. Springer, W. C. Randall, J. J. Baldwin, C. N.
Habecker, Protein Sci. 1994, 3, 118 ± 125.
[12] P. A. Boriack-Sjodin, S. Zeitlin, H. H. Chen, L. Crenshaw, S. Gross, A.
Dantanarayana, P. Delgado, J. A. May, T. Dean, D. W. Christianson,
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[13] L. R. Scolnick , A. M. Clements , J. Liao, L. Crenshaw, M. Hellberg, J.
May, T. R. Dean, D. W. Christianson, J. Am. Chem. Soc. 1997, 119,
850 ± 851.
[14] The following human CAII complexes (resolution < 2.5 Š) were used
for superposition: 1am6, 1bcd, 1bn1, 1bn2, 1bn3, 1bn4, 1bnn, 1bnq,
1bnt, 1bnu, 1bnv, 1bnw, 1bv3, 1cil, 1cim, 1cin, 1cnw, 1cnx, 1cny, 1cra,
1okl, 1okm, 1okn, 3ca2.
The elucidation of the course of events in the ozonolysis of
olefins by Criegee[1] was a milestone in the effort to under-
stand the mechanism of organic reactions. As early as in 1949
it was recognized that carbonyl oxides are the decisive
intermediates in this process.[2] However, to date it has not
been possible to observe these species directly during the
transformation of ªprimaryº into ªsecondaryº ozonides. In
contrast, an entry into carbonyl oxides exists in the trapping of
carbenes with oxygen under matrix conditions;[3] however, the
unsubstituted formaldehyde O-oxide 1 cannot be isolated
even upon using this procedure. In the reaction of methylene
with oxygen in an argon matrix only formic acid was
detected.[4]
[15] M. Hendlich, Acta Crystallogr. Sect. D 1998, 45, 1178 ± 1182.
[16] P. J. Goodford, J. Med. Chem. 1984, 28, 849 ± 857.
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[20] R. E. Babine, S. L. Bender, Chem. Rev. 1997, 97, 1359 ± 1472.
[21] UNITY Chemical Information Software, Version 4.1.1, Tripos, Inc.
(St. Louis, MO) 2000.
[22] S. Grüneberg, PhD thesis, Universität Marburg (Germany), 2000.
[23] C. Lemmen, T. Lengauer, G. Klebe, J. Med. Chem. 1998, 41, 4502 ±
4520.
[24] X. Fradera, R. M. A. Knegtel, J. Mestres, Proteins 2000, 40, 623 ± 636.
[25] H. Gohlke, PhD thesis, Universität Marburg, 2000.
[26] M. Rarey, B. Kramer, T. Lengauer, G. Klebe, J. Mol. Biol. 1996, 261,
470 ± 489.
The idea that it might be possible to generate formaldehyde
together with its oxide by cycloreversion of 1,2,4-trioxolane
has not yet been realized, presumably due to the fact that the
required ozonide of ethene is difficult to handle.[5] As is shown
herein,[6] the situation is completely different in the sulfur
series. 1,2,4-Trithiolane (3) is a stable, easily accessible
[27] P. R. Gerber, K. Müller, J. Comput. Aided Mol. Des. 1995, 9, 251 ± 268.
[28] Data for the inhibitor given in entry 7 in Table 1 were collected to a
resolution of 2.4 Š and a completeness of 81.3%. Phases were
calculated by using protein and water coordinates from 2cba. The
protein and inhibitor structure was refined[32] to an R value of 0.1918
for 8012 reflections with F > 2s (standard deviation for bond lengths
of 0.007 Š and for bond angles of 1.6378). Data for the inhibitor given
in entry 6 in Table 1 were collected to a resolution of 2.3 Š and a
completeness of 95.2%. Phases were calculated by using protein and
water coordinates from 2cba. The protein and inhibitor structure was
refined[32] to an R value of 0.1955 for 10124 reflections with F > 2s
(standard deviation for bond lengths of 0.008 Š and for bond angles of
1.4438).
[*] Prof. Dr. G. Maier, Dr. H. P. Reisenauer
Institut für Organische Chemie der Universität
Heinrich-Buff-Ring 58, 35392 Gieûen (Germany)
Fax : (‡ 49)641-99-34309
E-mail: guenther.maier@org.chemie.uni-giessen.de
Â
Â
Prof. Dr. G. Mloston, Dr. J. Romanski
Institute of Organic and Applied Chemistry
University of Lodz
Narutowicza 68, 90136 Lodz (Poland)
[**] This work was supported by the Fonds der Chemischen Industrie, the
Deutsche Forschungsgemeinschaft, and the Polish State Committee
for Scientific Research (KBN Grant 3T09A00716).
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substance.[7] There are additional reasons to try the thermal
fragmentation of 3 into the title molecule 2, the analogue of
Criegeeꢁs ªzwitterionº, and thioformaldehyde (4). On the one
hand such a cycloreversion was successfully used by Huisgen
and Rapp[8] for the preparation of substituted derivatives of 2,
on the other hand Bock et al.[9] identified 4 by photoelectron
spectroscopy upon the pyrolysis of 3.
Table 2. Calculated (B3LYP/6-311 ‡ G(3df,3pd), harmonic approxima-
tion; intensities [kmmolꢀ1
in parentheses) and experimental (argon
matrix, 10 K) IR spectrum of dithiirane (5).
]
Mode[a]
nÄcalcd [cmꢀ1
]
nÄexp [cmꢀ1
]
n6 b1
n1 a1
n2 a1
n7 b2
n5 a2
n8 b1
n3 a1
n9 b2
n4 a1
CH2 str.
CH2 str.
CH2 sciss.
CH2 wag.
CH2 twist.
CH2 rock.
ring str.
3215 (0)
3118 (9)
1461 (2)
1072 (2)
952 (0)
944 (3)
856 (1)
588 (9)
501 (1)
±
2986.7 (m)
1412.0 (w)
1053.0 (m)
±
928.3 (m)
±
ring str.
SS str.
581.0 (s)
±
[a] See footnote [a] in Table 1.
Indeed, the gas-phase pyrolysis of 3 in combination with
matrix isolation of the formed products opens an ideal route
for the system thiosulfine (2)/dithiirane (5)/dithioformic acid
(6),[10] which is of importance from the preparative and the
theoretical point of view.
We pyrolyzed 1,2,4-trithiolane (3) in high vacuum (quartz
tube: diameter 8 mm, heating zone 5 cm, ca. 10ꢀ5 mbar,
9508C) and condensed the reaction products together with
argon on a CsI window at 10 K. In the IR spectrum of the
formed matrix besides the known bands of 3 and 4 (4
generated independently by pyrolysis of allylmethyl sulfide
gave an identical IR spectrum) only the absorptions shown in
Tables 1 and 2 and in Figure 1 were registered.
Figure 1. Selected region of the experimental IR spectrum (Ar, 10 K) of
the products of the pyrolysis of 1,2,4-trithiolane (3).
Fabian and Senning[10] calculated the energy and geometry
of thioformaldehyde S-sulfide (2) on the B3LYP/6-311 ‡
G(3df,3pd) level, but its IR spectrum on the B3LYP/6-31G*
obtained in this manner fits quite well with the experimental
one of 2 (Table 1).
ꢀ
level. Since especially the position of the S S stretching
As the calculation indicates, the IR bands of dithiirane (5)
should be much less intense than those of 2. In accordance
with this prediction the experimental spectrum of 5 shows a
very weak but clearly visible band at 581 cmꢀ1. On the basis of
the calculated band intensities it can be estimated that the
cycloreversion of 3 at 9508C leads to a ratio 2:5 of about 2:1.
At 8508C a minor amount of dithiirane 5 (ratio 2:5 ca. 3.5:1) is
found. At even lower temperatures (6508C) the starting
molecule 3 remains intact. That means, in the thermal
fragmentation of 3 a considerable barrier must be passed. If
a fragmentation occurs, a thermal ring closure of 2 to 5 partly
takes place already during the pyrolysis.
In the UV spectrum 2 shows an intense band at 356 nm.
Since a photoisomerization of 2 is even possible with light of
very long wavelengths (l > 570 nm; see below), the com-
pound has to have a second, bathochromically shifted
absorption; however, its intensity is too low for a direct
observation under the applied experimental conditions. This
finding fits to the calculations of Fabian and Senning,[10] which
predict an intense p !p* transition at 300 nm and a very weak
n !p* absorption at 373 nm for 2. For dithiirane (5) no
vibration strongly depends on the used basis set (6-31G*: 586,
6-311 ‡ G(3df,3pd): 612, exp: 623 cmꢀ1) we additionally
calculated the IR spectra with the first mentioned method.
As the comparison shows the theoretical IR spectrum
Table 1. Calculated (B3LYP/6-311 ‡ G(3df,3pd), harmonic approxima-
tion; intensities [kmmolꢀ1
] in parentheses) and experimental (argon
matrix, 10 K) IR spectrum of thioformaldehyde S-sulfide (2).
Mode[a]
nÄcalcd [cmꢀ1
]
nÄexp [cmꢀ1
]
n1 a'
n2 a'
n3 a'
n4 a'
n5 a'
n8 a''
n6 a'
n9 a''
n7 a'
CH2 str.
CH2 str.
CH2 sciss.
CS str.
CH2 rock.
CH2 wag.
SS str.
3264 (2)
3140 (3)
1416 (12)
1019 (23)
934 (13)
809 (59)
612 (47)
575 (3)
3126.3 (vw)
3010.4 (w)
1366.4 (m)
970.9 (m)
910.2 (m)
756.8 (s)
622.8 (s)
±
CH2 twist.
def.
310 (1)
±
[a] str. ˆ stretching vibration, sciss. ˆ scissoring vibration, rock. ˆ rocking
vibration, wag. ˆ wagging vibration, twist. ˆ twisting vibration, def. ˆ de-
formation vibration.
394
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distinct absorption maximum could be found. The photo-
chemical behavior of 5 dicussed below demands, however,
also an absorption in the long-wavelength region (at ca.
500 nm) for this molecule.
and H2S are generated. Changing the wavelength to 254 nm
induces a partial recapture within the matrix cage and 6 is
reformed. After longer irradiation only CS2 can be detected,
probably under elimination of H2.
Depending on the applied wavelength the products of the
pyrolysis of 3 undergo various photoreactions. Light of
wavelength >385 nm leads to s-cis- and s-trans-dithioformic
acid 6c and 6t, respectively, as indicated by the comparison
with the known[11] matrix IR spectra and with the theoretical
spectra calculated on the B3LYP/6-311 ‡ G(3df,3pd) level
(Figure 2). If the pyrolysis products are irradiated with light of
Remarkably, upon direct irradiation (l ˆ 313 nm) of tri-
thiolane 3 no IR bands of thioformaldehyde S-sulfide (2) but
only those of thioformaldehyde (4), dithiirane (5), and
dithioformic acid (6) can be observed. It has to be assumed
that thiosulfine 2, which is generated photochemically from 3,
is photoisomerized immediately to the isomers 5 and 6.
Conclusion: a) The expectation by Fabian and Senning[10]
that the calculated spectroscopic data of 2 may lead to its
detection under matrix conditions has been fulfilled. Here-
with, a thiosulfineÐand even better, the unsubstituted parent
compoundÐhas been directly identified. The existence of
thiosulfines had been illustrated using trapping reactions by
Huisgen and Rapp[8] already in 1987. b) The good agreement
between the experimental and calculated IR spectra is an
indication that the geometry (planar, bent) and the electronic
structure of 2 is correctly expressed by the calculations.
Consequently, thioformaldehyde S-sulfide (2) should be
regarded more as a dipole (ylide form) and less as a singlet
diradical.[10] c) After the isolation of sterically hindered
dithiiranes, which has been achieved recently,[12] now the
existence of the unsubstituted parent molecule 5 is also
proven. d) The calculated[10] high barrier of 28.6 kcalmolꢀ1 for
the isomerization of 2 into more stable dithiirane 5 (by
5.9 kcalmolꢀ1; the global minimum is represented by 6)
explains why the ring closure 2 !5 needs a relatively high
temperature (kinetic control; the higher the temperature of
pyrolysis, the more 5) or photoexcitation. The thermal
threshold for the transformation 2/5 !6 is evidently too high
to be passed under the applied pyrolysis conditions. e) This
observation provides new insight on the question whether
substituted thiosulfines can be isomerized in solution into
esters of dithiocarbonic acid via the corresponding dithiiranes,
which is controversially discussed in the literature.[8, 13]
Figure 2. Selected region of the experimental (Ar, 10 K) and calculated
(B3LYP/6 ± 311 ‡ G(3df,3dp)) IR spectra of the CH2S2 isomers thiofor-
maldehyde S-sulfide (2), dithiirane (5), s-cis- and s-trans-dithioformic acid
(6c/6t). Middle: Experimental difference spectrum before and after
irradiation of the matrix isolated pyrolysis products of 3 with light of the
wavelength >570 nm (the positive bands grow, the negative ones disappear
during irradiation). Top: Calculated spectrum of a 10:1:1 mixture of 5, 6c,
and 6t. Bottom: Calculated spectrum of 2, related to the same scale.
Received: August 25, 2000 [Z15699]
[1] Summary: R. Criegee, Angew. Chem. 1975, 87, 765 ± 771; Angew.
Chem. Int. Ed. Engl. 1975, 14, 745.
[2] R. Criegee, G. Wenner, Liebigs Ann. Chem. 1949, 564, 9 ± 15.
[3] Summary: W. Sander, Angew. Chem. 1990, 102, 362 ± 372; Angew.
Chem. Int. Ed. Engl. 1990, 29, 344.
even longer wavelengths (l > 570 nm), the IR spectra show
initially a selective rearrangement of S-sulfide 2 into dithiir-
ane 5. If the irradiation is continued with light of wavelength
l > 570 nm the bands of 2 decrease further and one registers
besides absorptions of 5 those of 6c and 6t (Figure 2). If the
secondary irradiation is carried out with monochromatic light
(l ˆ 500 Æ 10 nm) the reaction starts with a partial back
reaction 5 !2. A photoequilibrium 5>2 is established, from
which the final conversion into 6c and 6t originates.
[4] Y.-P. Lee, G. C. Pimentel, J. Chem. Phys. 1981, 74, 4851 ± 4857.
[5] a) C. Harries, R. Koetschau, Ber. Dtsch. Chem. Ges. 1909, 42, 3305 ±
3311; b) R. Criegee, Angew. Chem. 1953, 65, 398 ± 399; c) C. W. Gillies,
R. L. Kuczkowski, J. Am. Chem. Soc. 1972, 94, 6337 ± 6343.
[6] Presentation in preliminary form: G. Mloston, Abstr. Pap. 19th Int.
Symp. Org. Chem. Sulfur (Sheffield, UK) 2000, No. 59.
[7] S. B. Tjan, J. C. Haakman, C. H. Teunis, H. G. Peer, Tetrahedron 1972,
28, 3489 ± 3500.
[8] R. Huisgen, J. Rapp, J. Am Chem. Soc. 1987, 109, 902 ± 903; R.
Huisgen, J. Rapp, Tetrahedron 1997, 53, 939 ± 960, and references
therein.
If the mixture of the dithioformic acids 6c and 6t is
irradiated in the matrix with light of wavelength 313 nm CS
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[10] Summary: J. Fabian, A. Senning, Sulfur Rep. 1998, 21, 1 ± 42.
[11] R. B. Bohn, G. D. Brabson, L. Andrews, J. Phys. Chem. 1992, 96,
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396
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