Crossover point between dialkoxy disulfides (ROSSOR) and thionosulfites ((RO)2S=S): Prediction, synthesis, and structure

Article abstract of DOI:10.1021/ja0559395

Isomeric preference between cyclic dialkoxy disulfides and thionosulfites is governed by the ring size of the heterocycle, Rings smaller than seven atoms prefer the thionosulfite connectivity, whereas larger rings or acyclic analogues favor the unbranched dialkoxy disulfide structure, Density functional calculations were employed to predict the crossover point at which both constitutional isomers are of comparable stability. Follow-up synthesis provides the previously unknown eight-membered ring dialkoxy disulfide 14 and seven-membered ring thionosulfite 15 from the same reaction. X-ray crystallography for all but one of the reaction products and complementary NMR analysis furnishes insights into both solid-state and solution conformations, A long-standing issue regarding the concerted vs catalyzed Isomerization pathway between XSSX and X₂S=S has been addressed for X = RO and shown to be acid dependent.

Full text of DOI:10.1021/ja0559395

Published on Web 12/07/2005
Crossover Point between Dialkoxy Disulfides (ROSSOR) and
Thionosulfites ((RO)2SdS): Prediction, Synthesis, and
Structure
Eli Zysman-Colman,†,1 Neysa Nevins,‡ Nicolas Eghbali,† James P. Snyder,*,§ and
David N. Harpp*,†
Contribution from the Department of Chemistry, McGill UniVersity, Montreal, Quebec, Canada
H3A 2K6, Computational, Analytical and Structural Sciences, GlaxoSmithKline Pharmaceuticals,
Research and DeVelopment DiVision, P.O. Box 5089, CollegeVille, PennsylVania 19426-0898,
and Department of Chemistry, Emory UniVersity, Atlanta, Georgia 30322
Received September 5, 2005; E-mail: jsnyder@emory.edu; david.harpp@mcgill.ca
Abstract: Isomeric preference between cyclic dialkoxy disulfides and thionosulfites is governed by the
ring size of the heterocycle. Rings smaller than seven atoms prefer the thionosulfite connectivity, whereas
larger rings or acyclic analogues favor the unbranched dialkoxy disulfide structure. Density functional
calculations were employed to predict the crossover point at which both constitutional isomers are of
comparable stability. Follow-up synthesis provides the previously unknown eight-membered ring dialkoxy
disulfide 14 and seven-membered ring thionosulfite 15 from the same reaction. X-ray crystallography for
all but one of the reaction products and complementary NMR analysis furnishes insights into both solid-
state and solution conformations. A long-standing issue regarding the concerted vs catalyzed isomerization
pathway between XSSX and X2SdS has been addressed for X ) RO and shown to be acid dependent.
Introduction
interactions and that these are only stabilized when the branched
sulfur is attached to an electronegative group.11,13 Though many
others14-16 have suggested the existence of the thiosulfoxide
species bound to less electronegative groups as transient
intermediates, to our knowledge none of these have been
Two classes of compounds containing the branch-bonded
R2SdS motif have been experimentally verified: FS(S)F2-6 and
a small group of thionosulfites,7-10 compounds containing the
OS(S)O moiety. Over fifty years ago Foss11 first proposed a
basis for the stability of compounds containing a hypervalent12
sulfur atom (R2Sd) bonded to an adjacent, branched sulfur (dS).
He suggested that the sulfur atoms are bonded by S3d-Sp orbital
(13) Foss, O. Acta Chem. Scand. 1950, 4, 404.
(14) For R ) alkyl; allyl; aryl; thiosulfoxides have been inferred or proposed
as intermediates in diverse reactions. See: Still, I. W. J.; Reed, J. N.;
Turnbull, K. Tetrahedron Lett. 1979, 20, 1481. Baechler, R. D.; Daley, S.
K. Tetrahedron Lett. 1978, 19, 101. Still, I. W. J.; Hasan, S. K.; Turnbull,
K. Synthesis 1977, 468. Still, I. W. J.; Hasan, S. K.; Turnbull, K. Can. J.
Chem. 1978, 56, 1423. Baechler, Raymond D.; Daley, S. K.; Daly, B.;
McGlynn, K. Tetrahedron Lett. 1978, 19, 105. Ba´lint, J.; Ra´kosi, M.;
Bogna´r, R. Phosphorus and Sulfur 1979, 6, 23. Baechler, R. D.; San Filippo,
L. J.; Schroll, A. Tetrahedron Lett. 1981, 22, 5247. Oae, S.; Yagihara, T.;
Okabe, T. Tetrahedron 1972, 28, 3203. Oae, S.; Nakanishi, A.; Tsujimoto,
N. Tetrahedron 1972, 28, 2981. Still, I. W. J.; Turnbull, K. Synthesis 1978,
540. Micetich, R. G. Tetrahedron Lett. 1976, 17, 971. Cookson, R. C.;
Parsons, P. J. J. Chem. Soc., Chem. Commun. 1978, 822. Baechler, R. D.;
Hummel, J. P.; Mislow, K. J. Am. Chem. Soc. 1973, 95, 4442. Ho¨fle, G.;
Baldwin, J. E. J. Am. Chem. Soc. 1971, 93, 6307. Exclusion of other
mechanistic possibilities in the thermal isomerization of allyl-Sn-allyl and
derivatives thereof, wherein n ) 2, 3, is covered in detail in: Tidd, B. K.
Int. J. Sulfur Chem., C 1971, 6, 101. Here it has been demonstrated that
allylically unsaturated di- and trisulfides readily undergo a thermal [1,5]-
sigmatropic rearrangement which results in cis,trans-isomerization of
substituted compounds. Brandt, G. A. R.; Emeleus, H. J.; Haszeldine, R.
N. J. Chem. Soc. 1952, 2198. Stepanov, B. I.; Rodionov, V. Y.; Chibisova,
T. A. J. Org. Chem. USSR (Engl. Transl.) 1974, 10, 78. Turnbull, K.;
Kutney, G. W. Chem. ReV. 1982, 82, 333. Drabowicz, J.; Oae, S. Chem.
Lett. 1977, 767. Soysa, H. S. D.; Weber, W. P. Tetrahedron Lett. 1978,
19, 235.
† McGill University.
‡ GlaxoSmithKline Pharmaceuticals.
§ Emory University.
(1) Current address: Organisch-chemisches Institut, Universita¨t Zu¨rich, Win-
terthurerstrasse 190, Zurich, Switzerland, CH-8057.
(2) Both isomeric forms of S2F2 have been prepared. See: Kuczkowski, R.
L.; Wilson, E. B., Jr. J. Am. Chem. Soc. 1963, 85, 2028. Kuczkowski, R.
L. J. Am. Chem. Soc. 1963, 85, 3047. Kuczkowski, R. L. J. Am. Chem.
Soc. 1964, 86, 3617. Gombler, W.; Schaebs, J.; Willner, H. Inorg. Chem.
1990, 29, 2697. Davis, R. W.; Firth, S. J. Mol. Spectrosc. 1991, 145, 225.
Seel, F.; Budenz, R. Chimia 1963, 17, 355. Seel, F.; Go¨litz, D. Z. Anorg.
Allg. Chem. 1964, 327, 32. Cao, X.; Qiao, C.; Wang, D. Chem. Phys. Lett.
1998, 290, 405.
(3) Seel, F.; Budenz, R. Chem. Ber. 1965, 98, 251. Brown, R. D.; Burden, F.
R.; Pez, G. P. J. Chem. Soc., Chem. Commun. 1965, 277.
(4) Seel, F.; Gombler, W.; Budenz, R. Liebigs Ann. Chem. 1970, 735, 1.
(5) Pez, G. P.; Brown, R. D. Aust. J. Chem. 1967, 20, 2305.
(6) Marsden, C. J.; Oberhammer, H.; Losking, O.; Willner, H. J. Mol. Struct.
1989, 193, 233.
(7) Thompson, Q. E.; Crutchfield, M. M.; Dietrich, M. W. J. Am. Chem. Soc.
1964, 86, 3891.
(8) Harpp, D. N.; Steliou, K.; Cheer, C. J. J. Chem. Soc., Chem. Commun.
1980, 825.
(9) Zysman-Colman, E.; Abrams, C. B.; Harpp, D. N. J. Org. Chem. 2003,
68, 7059.
(15) For R ) Cl, Br, see; Reid, E. E.; Macy, R.; Jarman, G. N.; Morrison, A.
Science 1947, 355. Spong, A. H. J. Chem. Soc. 1934, 485 and references
cited therein. For detection of ClS(S)Cl, see: Chadwick, B. M.; Grzybowski,
J. M.; Long, D. A. J. Mol. Struct. 1978, 48, 139. For detection of ClS(S)-
Cl and BrS(S)Br, see: Feuerhahn, M.; Vahl, G. Chem. Phys. Lett. 1979,
65, 322.
(10) Tanaka, S.; Sugihara, Y.; Sakamoto, A.; Ishii, A.; Nakayama, J. J. Am.
Chem. Soc. 2003, 125, 9024. Nakayama, J.; Yoshida, S.; Sugihara, Y.;
Sakamoto, A. HelV. Chim. Acta 2005, 88, 1451.
(11) Foss, O. In Organic Sulfur Compounds; Kharasch, N., Ed.; Pergammon
Press Inc.: New York, 1961; Vol. 1, p 75.
(16) Amaresh, R. R.; Lakshmikantham, M. V.; Baldwin, J. W.; Cava, M. P.;
Metzger, R. M.; Rogers, R. D. J. Org. Chem. 2002, 67, 2453.
(12) Minyaev, R. M.; Minkin, V. I. Can. J. Chem. 1998, 76, 776.
9
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J. AM. CHEM. SOC. 2006, 128, 291-304
291

A R T I C L E S
Zysman-Colman et al.
captured as stable species within the temperature ranges common
to solution chemistry.17
Of particular interest is the fact that not only do compounds
with the formula S2F2 and R2S2O2 exist in their branched
configurations but also in the latter case they commonly exist
as their unbranched dialkoxy disulfide isomers, 1 vs 2a.18-20
at temperatures well below room temperature,3,5 although other
studies imply a catalytically mediated rearrangement.5 To our
knowledge the same question has been addressed for the
ROSSOR system only briefly in a computational context.19,23
As a first step, we were interested in modeling the relative
ground-state stabilities of analogues of 1 and 2a. As mentioned
above, all previous structural determinations for the former were
acyclic while the latter portray the thionosulfite functionality
as part of a five-membered ring (e.g., 2c-e).7-10,21,22,24
A
In the oxygen-containing family, the known branched isomers
are universally embedded in a five-membered ring, 2b.7-10,21,22
We sought to answer two questions: (1) What are the factors
that govern the isomeric preference between dialkoxy disulfides
1 and thionosulfites 2a; and (2) with this knowledge, can features
be designed that broaden the structural base of each of the
thionosulfite and dialkoxy disulfide families?
We report a density functional theory (DFT) study of the
structural factors that influence relative R2S2O2 isomeric stabil-
ity. In particular, we have made predictions employing ring size
and angle strain as guides to modulation of the relative energies
of the 1/2 pair. This has led to a favored crossover point at
which the isomeric OS2O moieties should show comparable
stability. The projections were followed by synthesis and
structural characterization of compounds in which the S2O2-
containing moieties embedded in medium-sized rings break the
literature’s historical pattern.
common conformational feature of two crystal structures
containing the latter ring8,9 is the presence of a 40°-45° twist
in the τ(O-C-C-O) dihedral angle accompanied by unequal
τ(C-O-S-S) angles of 95.6° and -127.4°. We hypothesized
that obligating the ring to adopt another geometry, perhaps with
greater conformational flexibility, might influence the relative
ground-state stabilities of cyclic isomers of 1 and 2a. A
straightforward strategy to test this idea focuses on ring size as
a means of relieving strain, while simultaneously permitting both
torsional and bond angles an opportunity to vary. Accordingly,
the conformational surfaces of five isomeric pairs of model
compounds, 3-12, were examined in a two-step procedure.
Results and Discussion
Results are divided into three sections: the first presents DFT
calculations and discusses a testable prediction regarding the
relative stability of isomers 1 and 2a; second, target synthesis
and structural characterization of previously unknown variations
of the latter are described; finally we comment on the validity
and generality of the predictions in light of the experimental
outcome.
Computational Predictions. An important issue concerning
the relationship of dialkoxy disulfides (ROSSOR) 1 and the
isomeric thionosulfite (ROS(S)OR) 2a is whether the two forms
can interconvert by means of an uncatalyzed equilibrium. A
number of experiments with S2F2 have been interpreted to
suggest that the two isomers are present in such an equilibrium
To locate the lowest energy conformations for the OS2O
isomers, we performed a 3000-step Monte Carlo search with
the MM3* force field in MacroModel25 for each of the 10
structures. All fully optimized conformations within 3 kcal/mol
from the MM3* global minimum were subsequently submitted
for a single-point energy evaluation at the B3LYP/6-31G(2d)
(17) Recently, it has been shown via tandem mass spectrometry that in the gas
phase thiosulfoxides are stable entities both as radical cations and as neutral
species. See: Gerbaux, P.; Salpin, J.-Y.; Bouchouxb, G.; Flammang, R.
Int. J. Mass Spectrom. 2000, 195/196, 239-249.
(18) For examples where the acyclic dialkoxy disulfide (ROSSOR) connectivity
has been structurally resolved, see: Steudel, R.; Gleiter, R.; Hyla-Kryspin,
I.; Schmidt, H. Chem. Ber. 1993, 126, 2363. Koritsanszky, T.; Buschmann,
J.; Schmidt, H.; Steudel, R. J. Phys. Chem. 1994, 98, 5416. Steudel, R.;
Schmidt, H.; Baumeister, E.; Oberhammer, H.; Koritsanszky, T. J. Phys.
Chem. 1995, 99, 8987. Harpp, D. N.; Tardif, S. L.; Williams, C. R. J. Am.
Chem. Soc. 1995, 117, 9067. Tardif, S. Ph.D. Thesis, McGill University,
1997. Harpp, D. N.; Priefer, R.; Farrell, P. G. Tetrahedron Lett. 2002, 43,
8781.
(23) Though there is no experimental evidence to suggest the existence of
branched isomer 2a (R ) Me), it was nevertheless found to be 1.9 kcal/
mol more stable than unbranched 1 (R ) Me) at B3LYP/6-311G* + ZPE
with an MP2/6-311G(3d) unimolecular interconversion barrier between 1
(R ) Me) and 2a (R ) Me), of 37.5 kcal/mol.19
(24) Thompson, Q. E. U.S. Patent No. 3,376,322; United States Patent Office:
United States of America, 1968, 8.
(25) Mohamadi, F.; Richards, N. G. J.; Guida, W. C.; Liskamp, R.; Lipton, M.;
Caufield, C.; Chang, G.; Hendrickson, T.; Still, W. C. J. Comput. Chem.
1990, 4, 440. We have modified the MM3* force field to include new
atom types and parameters to handle the OSSO and OS(S)O functionalities.
For example, the X-ray structures of 14 and 15 (Figure 2) are virtually
superimposable with the MM3* geometries; Nevins, N.; Zysman-Colman,
E.; Harpp, D. N.; Snyder, J. P. Unpublished results.
(19) Snyder, J. P.; Nevins, N.; Tardif, S. L.; Harpp, D. N. J. Am. Chem. Soc.
1997, 119, 12685.
(20) Borghi, R.; Lunazzi, L.; Placucci, G.; Cerioni, G.; Foresti, E.; Plumitallo,
A. J. Org. Chem. 1997, 62, 4924.
(21) Thompson, Q. E.; Crutchfield, M. M.; Dietrich, M. W. J. Org. Chem. 1965,
30, 2696.
(22) Thompson, Q. E. U.S. Patent No. 3,357,993; United States Patent Office:
United States of America, 1967, 4.
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292 J. AM. CHEM. SOC. VOL. 128, NO. 1, 2006

Dialkoxy Disulfides/Thionosulfites Crossover Point
A R T I C L E S
Table 1. Single-Point DFT Energies (B3LYP/6-31G(2d)) for 3-12
destabilizing. For ROSSOR, the calculated, strained disulfide
dihedral angles of 3 and 5 (64.8° and 78.6°, respectively) are
well below the experimental values observed for acyclic
analogues (85°-95°).18-20 The eight-membered ring 7 is the
minimum ring size required to adopt an optimal τ(OS-SO)
dihedral angle (94.3°). For the (RO)2SdS system with axial
SdS bonds, the near-cis and near-trans LPsOsSdS torsion
angles (estimated from heavy atom angles: 4, 15/-39° and
154/-179°; 6, 162° (two trans); 8, -147, 167° (both trans))
contribute to maximum orbital overlap between the oxygen lone
pairs and the σ*SdS antibonding orbital (see the Supporting
Information for a structural representation), resulting in stabi-
lization of this isomer by negative hyperconjugation.12,27 Larger
rings and acyclic forms elicit less favorable LP-σ*SdS angular
interactions. The two effects converge at ring sizes of eight and
seven, respectively.
Optimized with the MM3* Force Field
1 or 2
E(ROSSOR)a,b
E(ROS(S)OR)a,b
∆
Ec
3
4
5
6
7
8
9
10
11
12
-1025.382 63
∆E(4-3)
-6.3
-1025.392 60
-1064.710 18
-1104.019 82
-1143.328 65
-1182.639 72
-1064.705 44
-1104.022 48
-1143.335 50
-1182.648 87
∆E(6-5)
-3.0
∆E(8-7)
1.7
∆E(10-9)
4.3
∆E(12-11)
5.7
a B3LYP/6-31G(2d)//MM3*. b Hartrees. c kcal/mol.
level of DFT theory.19,26 The lowest energy conformations from
MM3* did not uniformly translate into the lowest energy
conformations by DFT, although the ∆E between the two
methods was no greater than 1.5 kcal/mol. The relative DFT
energy differences between isomeric forms (Table 1) as a
function of ring-size are graphically portrayed in Figure 1.
As is evident from Table 1 and Figure 1, the DFT/MM3*
protocol predicts that modifying the ring size monotonically
influences the relative ground-state stabilities between dialkoxy
disulfide 1 and thionosulfite 2a. Small ring compounds are
predicted to be thionosulfites, whereas medium and large ring
structures as well as acyclic compounds (i.e., an infinitely large
ring) are predicted to adopt the dialkoxy disulfide form. The
trend suggests that the crossover point in isomeric stability
occurs as the seven-membered thionosulfite ring in 8 is
expanded to the eight-membered dialkoxy disulfide ring in 7.
The 1.7 kcal/mol energy difference between 7 and 8 implies
that the compounds should coexist in an approximate 95:5 ratio
at room temperature, if they are either interconvertible or
generated from a common precursor.
A breakdown of the computational results for structures 7
and 8 in terms of the three lowest energy conformations (7a-c
and 8a-c, respectively) is provided in Table 2. Within the DFT
energy context, both systems are posited to exist as a mixture
of three conformations. Thionosulfite 8 presents three forms
with similar populations (23-45%), while dialkoxy disulfide 7
is predicted to be dominated by a single conformer (94%
population). When taken as a total mixture of potentially
equilibrating forms, 7 and 8 are estimated to coexist in an
approximate 4:1 ratio at ambient temperature (Table 2).
The predictions summarized in Table 1 and Figure 1 are
compelling. We next turned to identification of a suitable series
of substrates that would permit us to test them experimentally.
Synthesis of the Crossover System. The compound 1,2-
benzenedimethanol 13 was chosen as the starting material for
the synthesis of the 7/8 isomer pair. The diol is ideal as it is
not only readily available, but the benzene ring adds sufficient
molecular bulk to simplify eventual crystal structure analysis.
The predicted crossover phenomenon can be understood as
a consequence of two opposing effects; one stabilizing, the other
Figure 1. Ring-size trend in DFT ∆E’s (B3LYP/6-31G(2d)) for 3-12. A positive value indicates that the dialkoxy disulfide isomer is the more stable.
9
J. AM. CHEM. SOC. VOL. 128, NO. 1, 2006 293

A R T I C L E S
Zysman-Colman et al.
Table 2. Boltzmann Population Analysis for Conformations of the 7/8 System at 298 K; DFT Energies
a Atomic units. b Relative energy difference within a given conformational family, kcal/mol. c Boltzmann population, 298 K. d Energy difference relative
to 7a, kcal/mol. f Combined Boltzman populations, 298 K.
Table 3. Coupling of S2Cl2 with Diol 13
yieldd (%)
equiv of
S2Cl2
addn time
(min)
time
(h)
tempc
C)
entrya
[S2Cl2] (M)
solvent
(
°
14
15
16
17
18
1
2b
3
4
5
6
7
8
9
0.1
0.1
0.1
0.1
0.02
1.0
0.2
0.1
0.1
1
1
1
1
1
1
2
1
1
5
9
35
12
50
2
13
3
3
5
5.5
6
5
5
5
5.3
5
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
0
0
-78
23
0
93 (94)
96 (96)
94
58
96 (79)
92
0
0
0
7
4
4
0
0
2
2
0
0
87
2
0
0
0
1
0
0
0
0
4
33 (22)
5 (>1)
0
0
0
1
9
4
8
0
0
0
0
13
88
0
0
10 (9)
0
5
CH3CN
87
a The concentrations of 13 and NEt3 were 0.1 and 0.2 M, respectively, in all cases. b 13 and S2Cl2 were simultaneously added to 10 mL of CH2Cl2.
1
c Refers to the temperature maintained during the addition of S2Cl2. d By H NMR with isolated yields in parentheses.
We reasoned that the extra element of unsaturation would have
minimal impact on the relative ground-state energies based on
calculations for the unsaturated 5/6-ring structures 3a-4a. At
of products and isolated yield of 14 as addition of a solution of
S2Cl2 to 13 (entry 1). Moreover, no thionosulfite 15 was
detected.
It has been proposed that intermediates similar to 20
(ROSSCl) might be stabilized at lower temperatures.30 To test
the possibility that this phenomenon might affect the yields of
products, the temperature of S2Cl2 addition was decreased to
-78 °C and the addition time was lengthened. However, the
latter changes had little effect on the relative amounts of mono-
mer 14 and dimer 16 formed. Either increasing the concentration
of S2Cl2 (entry 6) or changing the solvent to THF (entry 8)
promoted an increase in the yield of 16 relative to 14, whereas
employing the more polar CH3CN solvent (entry 9) resulted in
formation of unwanted sulfite 17. Similar results were observed
with the use of 2 equiv of S2Cl2 in CH2Cl2 (entry 7).
Apparently, under these conditions 7-exo-tet ring closure to
form sulfoxylate 18 and subsequent oxidation in the workup to
furnish sulfite 17 are preferred over 8-exo-tet ring closure to
give dialkoxy disulfide 14. Trace acid- or base-catalyzed
decomposition of 14 to 17 cannot be ruled out.31 Decreasing
the B3LYP/6-31G(2d) level there was no effect on the isomer
preference and only an inconsequential change in the energy
gap when a second degree of unsaturation was added (∆E(4-
3) -6.3 kcal/mol; ∆E(4a-3a) -7.0 kcal/mol).28 Recently, we
reported an improved preparation for acyclic dialkoxy disul-
fides.29 Using the corresponding reaction conditions as a starting
point, we investigated the coupling of S2Cl2 to the model diol
13. The results are summarized in Table 3.
In most cases, dialkoxy disulfide 14 was the major product
formed and isolated. To our knowledge, this represents the first
example of a stable and fully characterized cyclic dialkoxy
disulfide. We were able to influence the ratio of 14/15 by
increasing the S2Cl2 addition temperature to 23 °C (entry 4).
Thompson indicated in his patent22 that thionosulfites could be
preferentially formed with simultaneous diol and S2Cl2 addition.
In our hands, these conditions (entry 2) produced the same ratio
(26) Balcells, D.; Maseras, F.; Ujaque, G. J. Am. Chem. Soc. 2005, 127, 3624.
(27) Reed, A. E.; Schleyer, P. v. R. J. Am. Chem. Soc. 1990, 112, 1434.
(28) See Supporting Information for details.
(29) Zysman-Colman, E.; Harpp, D. N. J. Org. Chem. 2005, 70, 5964.
(30) Steudel, R.; Schmidt, H. Z. Naturforsch. 1990, 45B, 557.
(31) The acid- and base-catalyzed decomposition of MeOSSOMe 1a has been
documented. See: Kobayashi, M.; Minato, H.; Shimada, K. Int. J. Sulfur
Chem., A 1971, 1, 105.
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294 J. AM. CHEM. SOC. VOL. 128, NO. 1, 2006

Dialkoxy Disulfides/Thionosulfites Crossover Point
A R T I C L E S
Scheme 1. Proposed Cyclization Routes for the Formation of Either 14 or 15
the concentration of S2Cl2 in solution from 1 to 0.02 M while
increasing the addition time from 2 to 50 min slightly increased
the yield of 14 over dimer 16 (entries 5 and 6). Compound 15
could only be synthesized at rt (entry 4), while 14 could be
obtained at lower temperatures (e.g., entries 1-3, 5, 6). Taken
with the fact that 14 converts to 15 as described in a subsequent
section, while the reverse conversion was not observed, it is
reasonable to suggest that 14 may be the kinetic product whereas
15 is thermodynamically more stable. The isolation of 15
represents the first synthesis of a non-five-membered ring
thionosulfite.
dynamic isomerization between the two compounds. Although
the possibility of an SN2′ mediated ring closure to form 15 from
20 cannot be discounted, the appearance of trace 17 and 18 is
consistent with the current mechanism. Moreover, in these initial
experiments we were unable to find conditions delivering >33%
of 15 (see below, Table 6). However, much higher yields (65-
75%) could be obtained by adjusting the [Et3N]/[S2Cl2] ratio
to a value of 1.7 in order to release a small quantity of free
HCl (see below; Table 6). Although it has been proposed that
branch-bonded products arising from treatment of various
compounds with S2Cl2 emanate from traces of S2Cl2 in the
branch-bonded form (Cl2SdS),16 there is little evidence to
suggest this is the case at the addition temperatures employed
here.32,33 Finally, while there is precedent30 for compounds
incorporating the unbranched OSSCl connectivity as pictured
in the proposed intermediate 20, we are unaware of evidence
to support the formation of isomeric 21, a potential alternative
intermediate for the direct formation of 15 from 13.34
Altering the base from NEt3 to pyridine resulted in decreased
yields and increased product impurity. Compounds 19a and 19b
have been shown to be useful sulfur transfer reagents in the
formation of five-membered thionosulfites.9,10 Replacement of
S2Cl2 with either reagent in the present experiments proved
ineffective in the formation of 14-18 from diol 13; only
complex mixtures of products were obtained.
What factors determine the formation of 14 and 15? Initially,
it was not clear whether 15 was the result of an isomerization
process from 14 or whether 15 formed independently from 14
in the reaction mixture. Based on experiments described below,
we propose the synthetic scheme above (Scheme 1).
The first hint that acid was involved in the transformations
of Scheme 1 arose when pure 14 stored at 0 °C in CDCl3 for 2
weeks delivered 5% of 15, presumably by slow and incomplete
isomerization under the influence of traces of acid from the
solvent. Under similar conditions, the reverse isomerization of
15 to 14 at 0 °C was not detected, nor was it observed at
temperatures up to 150 °C. Experiments described below in a
separate section on the acid promoted conversion of 14 to 15
provide definitive evidence for the role of HCl and rule out
Solid-State Structures from X-ray Crystallography. X-ray
crystal structures for all but one of the compounds derived from
S2Cl2 treatment of diol 13 (Table 3) have been obtained, thereby
verifying the connectivity of structures 14-17 and identifying
the corresponding solid-state conformations.
A capped stick representation of dialkoxy disulfide 14 in the
solid state is shown in Figure 2. It possesses no symmetry (C1).
The eight-membered ring adopts a pseudo-saddle geometry35
with limited conformational flexibility occasioned by both
unsaturation in the fused benzene ring and the OS-SO moiety.
The result contrasts with that for most eight-membered rings
(32) Spong, A. H. J. Chem. Soc. 1934, 485. Palmer, K. J. J. Am. Chem. Soc.
1938, 60, 2360. Beagley, B.; Eckersley, G. H.; Brown, D. P.; Tomlinson,
D. Trans. Faraday Soc. 1969, 165, 2300. Hirota, E. Bull. Chem. Soc. Jpn.
1958, 31, 130. Chadwick, B. M.; Grzybowski, J. M.; Long, D. A. J. Mol.
Struct. 1978, 48, 139.
(33) Bock, H.; Solouki, B. Inorg. Chem. 1977, 16, 665.
(34) Branched sulfur species have been proposed as intermediates in desulfu-
rization, sulfurization, and isomerization reactions. See for instance:
Baechler, R. D.; Hummel, J. P.; Mislow, K. J. Am. Chem. Soc. 1973, 95,
4442.
Figure 2. X-ray crystal structures of dialkoxy disulfide 14 in an asymmetric
twist-chair-chair conformer (C1 symmetry) and thionosulfite 15 presenting
a seven-membered ring chair and an axial exocyclic SdS bond (CS
symmetry).
(35) Evans, D. G.; Boeyens, J. C. A. Acta Crystallogr. B 1988, 44, 663.
9
J. AM. CHEM. SOC. VOL. 128, NO. 1, 2006 295

A R T I C L E S
Zysman-Colman et al.
Figure 3. X-ray crystal structures obtained from the deconvoluted X-ray
diffraction pattern for sulfite 17; the major chair conformation 17a; the
minor twist conformation, 17b; ratio 9:1, respectively.
Figure 4. X-ray crystal structure of dialkoxy disulfide dimer 16.
which adopt either a boat-chair or a twist-boat-chair confor-
mation in the solid state with a potential for interconversion
into the higher energy crown conformation.35,36 Perhaps more
relevant, while cyclooctene can exist in both chair and boat
conformations, a considerably less strained twist-chair-chair
Interestingly, the two conformations in the solid state for a
related sulfite, the insecticide thiodan (22a and 22b), are found
as chairs with axial SdO bonds.44 The related bis-thioethers45
23a and 23b also exist exclusively as chairs, while trisulfide
24 presents as an 85:15 ratio of chair/twist-boat conformations
in CS2.46
conformer has been calculated to be the lowest in energy,37
a
prediction confirmed by clustering of X-ray data.38 The twisted
unsymmetrical conformer 14 shown in Figure 2 sustains an OS-
SO torsion of 93.2°, a value within the 85°-95° window
observed for acyclic dialkoxy disulfides.18-20
Thionosulfite 15 (Figure 2) is found exclusively in a chair
conformation characterized by Cs symmetry. In this conforma-
tion each pair of benzylic hydrogens directs its axial CsH bond
parallel to the SdS (or Sδ+sSδ-) bond, while the other proton
resides in a pseudoequatorial orientation. From a more general
perspective, simple cycloheptenes are known to adopt a chair
conformation stabilized by 0.6-3.5 kcal/mol over the twist and
boat conformations.39,40 At the same time, replacement of the
CdC double bond with a benzene ring to give benzocyclohep-
tenes has been suggested to preferentially stabilize the chair
form41 relative to the twist conformer as a consequence of
R-hydrogen Csp2/H eclipsing of the type observed in toluene.40,42
The stability supposition has been subsequently confirmed for
the all-carbon 7-rings by analysis of X-ray structures found in
the Cambridge Crystallographic database.43
The solid-state conformational energy profile for sulfite 17
is somewhat more complex. The solid-state X-ray diffraction
pattern has been deconvoluted to provide a 9:1 mixture of chair
and twist forms (Figure 3). In this case, the more abundant chair
conformer (17a) possesses a plane of symmetry similar to
crystalline 15, while the low population twist form (17b) is
asymmetric. A comparison of the annelated O2SX structures
from the viewpoint of possible R-hydrogen eclipsing does not
provide a basis for understanding the formation of the twist form
in the sulfite crystal compared with its absence in 15. In the
latter and in both 17a and 17b, the (Csp2)H- - -H(Cbn) distances
(i.e., between protons: HCdCsCH2) range from 2.26 to 2.30
Å. Consequently, we attribute the formation of both chair and
twist in sulfite 17 to similar energies (i.e., ∆E ) 1-2 kcal/
mol) coupled with polar effects in the crystal. In agreement, a
9:1 ratio at 298 K corresponds to a 1.3 kcal/mol free energy
difference.
The sum of the θ(O-S-O) and two θ(O-S-S) bond angles
in 15 (319.2°) is comparable to the sum of the three θ(O-S-
O) angles in 17a (317.1°) indicating the pyramidal nature of
the branch-bonded sulfur. The two stereoelectronic nO f σ*SdO
donor-acceptor interactions12,27 in 17a and the analogous pair
of nO f σ*SdS interactions in 15 contribute to a lengthening of
the respective SdO and SdS bonds. The SdS bond length in
15 is 1.936 Å, slightly longer than that in 2d (1.901 Å).8
Similarly, the SdO bond in 17a (1.595 Å) is also much longer
than that found in 25 (1.45 Å).47
Compound 16, a formal dimer of dialkoxy disulfide 14, is a
novel 16-membered macrocycle. Its X-ray structure (Figure 4)
reveals a conformation possessing C2 symmetry and two chiral
OS-SO units. The O-S-S-O torsion angles at 87.6° are
comparable to those found for acyclic dialkoxy disulfides (85°-
95°).18-20 The conformation corresponds to (M,M)/(P,P)48 and
possesses two different benzylic-CH2 groups. All four benzylic
hydrogens are chemically and magnetically distinct, the con-
sequences of which will be discussed below in connection with
the proton NMR.
Each of the solid state conformations for 14-16 can exist in
other competing conformers. Below, we present analyses of the
NMR spectra for the series and elaborate on the corresponding
conformational energy profiles.
(36) Setzer, W. N.; Glass, R. S. Conformational Analysis of Medium-Sized
Heterocycles; VCH: 1988; p 151. Eliel, E. L.; Wilen, S. H. Stereochemistry
of Organic Compounds; John Wiley & Sons: Toronto, 1994.
(37) Traetteberg, M. Acta Chem. Scand., Sect B 1975, 29, 29.
(38) Allen, F. H.; Howard, J. A. K.; Pitchford, N. A. Acta Crystallogr., Sect. B
1996, 52, 882.
(39) Favini, G.; Buemi, G.; Raimondi, R. J. Mol Struct. 1968, 137.
(40) Allinger, N. L.; Sprague, J. T. J. Am. Chem. Soc. 1972, 94, 5734.
(41) Kabuss, S.; Friebolin, H.; Schmid, H. Tetrahedron Lett. 1965, 469.
(42) Burkert, U.; Allinger, N. L. ACS Monograph 177; American Chemical
Society: Washington D.C., 1982; p 339.
(43) Allen, F. H.; Garner, S. E.; Howard, J. A. K.; Pitchford, N. A. Acta
Crystallogr., Sect. B 1994, 50, 395.
(44) Byrn, S. R.; Siew, P. Y. J. Chem. Soc., Perkin. Trans. 2 1977, 144.
(45) Friebolin, H.; Mecke, R.; Kabuss, S.; Lu¨ttringhaus, A. Tetrahedron Lett.
1964, 29, 1929.
(46) Kabuss, S.; Lu¨ttringhaus, A.; Friebolin, H.; Mecke, R. Z. Naturforsch. 1966,
21b, 320.
(47) Altona, C.; Geise, H. J.; Romers, C. Recl. TraV. Chim. Pays-Bas 1966, 85,
1197.
(48) S-S torsion angles can be defined in terms of their helical twist using the
Cahn-Ingold-Prelog nomenclature. A positive dihedral angle corresponds
to the P conformation, while a negative dihedral angle is denoted by the
M conformer. See: Eliel, E. L.; Wilen, S. H. Stereochemistry of Organic
Compounds; John Wiley & Sons: Toronto, 1994.
9
296 J. AM. CHEM. SOC. VOL. 128, NO. 1, 2006

Dialkoxy Disulfides/Thionosulfites Crossover Point
A R T I C L E S
Figure 5. 1H NMR spectra (300 MHz) of the benzyl protons in 14-17 in CDCl3 at rt.
Table 4. Selected 1H and 13C Observables for 13-18
with the OS-SO moiety, indicating that in solution 14 is a
racemic mixture of two enantiomeric atropisomers separated
by a free energy barrier of 18-19 kcal/mol.4,19,20,29 The sense
of helicity is defined by viewing down the S-S bond. A
clockwise rotation is designated P(+), and a counterclockwise
rotation is designated M(-). The doublet of doublets is
characteristic of the compound class and implies exchange
between the benzylic positions on the NMR time scale.4,19,20,29
The crystal structure of 14 depicted in Figure 2 portrays a
molecule in which all four benzylic protons are chemically
distinct. Thus, there are two “inner” protons (Hia and Hib) and
two “outer” ones (Hoa and Hob). This contrasts with the picture
provided by the AB splitting pattern observed in the ambient
NMR spectrum of Figure 5 reflecting the presence of only two
different protons. Dynamic averaging of the benzylic centers
explains the appearance of the solution spectrum. It might be
concluded that rotation about all four single bonds in 14 (C-
CH2, CH2-O, O-S, and S-S) is necessary to promote
averaging.
However, three factors make it clear that the S-S bond is
not recruited in the averaging process. First, the energy barrier
for OS-SO rotation in other dialkoxy disulfides is 18-19 kcal/
mol,4,19,20,29 a value very similar to that determined for the S-S
bond in 14 (see below). The barrier is sufficiently high to
preclude rapid S-S rotation at room temperature. Second, the
seven-membered ring systems of thionosulfite 15 and sulfite
17 contain no S-S bond, yet the AX spectra of both imply that
torsional motions around the C-CH2, CH2-O, and O-S bonds
alone are sufficient to cause chemical equivalence of the
benzylic CH2 groups. Third, the averaging operation involves
bond rotations that move the OSSO unit on one face of the
benzene ring in 14 (Figure 2) to the other face. The result is
that the inner protons are translated to the outer positions and
vice versa. Simultaneously, the Hia/Hib and Hoa/Hob geminal
proton pairs become Hib/Hia and Hob/Hoa, respectively, as four
protons are averaged to two. Were rapid rotation about the OS-
SO bond involved, the molecule would experience a virtual
1
NMR Analysis of Solution Conformation. The H NMR
spectra of the benzyl protons in 14-17 all show either an AB
or AX pattern and are clearly distinct from one another as
depicted in Figure 5. The one exception to the geminal splitting
pattern is sulfoxylate 18, which presents a singlet at 5.54 ppm
in CDCl3 at rt. Selected NMR parameters are provided in Table
4.
The second-order geminal 1H splitting pattern for the benzyl
protons of 14 is characteristic of dialkoxy disulfides in that the
two protons are anisochronous. The diastereotopicity results
from the high barrier to rotation about the chiral axis associated
9
J. AM. CHEM. SOC. VOL. 128, NO. 1, 2006 297

A R T I C L E S
Zysman-Colman et al.
Table 5. Comparison of Low Energy Conformations of 14 and 26
twist forms (e.g., 17b, equatorial SdX (Figure 3)) in solution
has the potential to tip the balance. It is well-known that the
SdO bond in sulfites strongly differentiates between axial and
equatorial protons on carbon adjacent to the sulfite moiety.52
Diagnostic are large geminal coupling constants such as those
recorded for 27 (13.7 Hz) and 28 (13.2 Hz), both of which
sustain axial or pseudoaxial SdO bonds.53 Supporting the notion
∆
(14
−
26)
dihedral anglea
14b,c
26b,d
(deg)
C3-C4-C9-C10
C4-C9-C10-X11
C9-C10-X11-S12
C10-X11-S12-S1
X11-S12-S1-X2
S12-S1-X2-C3
S1-X2-C3-C4
-3.4
-86.7
90.2
-77.9
93.2
-53.9
-46.6
99.1
-3.1
-101.2
88.1
-72.6
103.6
-65.1
-41.9
105.0
-0.3
14.4
-2.2
-5.3
10.4
11.2
-4.8
6.0
that 15 and 17 likewise possess largely axial SdX bonds in
solution are their two bond couplings of 14.3 and 14.0 Hz,
respectively (Table 4). Finally, the relative 0.65 ppm downfield
shift of the low field doublet in 15 with respect to 17 may
indicate an increased polarization of the SdS bond (i.e., S+sS-)
similar to that proposed for the SdO bond of sulfites.54 Steudel
and colleagues55 have performed calculations suggesting that
thionosulfite bonds are polarized in the same manner.
It is noteworthy that the 13C NMR chemical shifts of the
benzyl carbons of dialkoxy disulfides 14 and 16 are 10-13 ppm
further downfield than those of 15 and 17 (Table 4). This is a
result of a large upfield “γ shift”,56 which in this particular case
is an indicator of the strong interaction of an axial SdO bond
with syn-axial H’s.57 It results in the shielding of the benzyl
carbon (ca. 9 ppm) relative to a conformation wherein the Sd
O bond is equatorial. It is assumed that the γ shift would also
apply to the analogous thionosulfite system. Moreover, the
benzyl carbons of 18 resonate an additional ca. 13 ppm further
downfield from 14 and 16 (Table 4). The origin of this additional
shift is unclear.
X2-C3-C4-C9
a X ) O in 14, X ) S in 26. b Dihedral angles in degrees. c Numbering
as that of X-ray. d Numbering altered from X-ray to facilitate comparisons
with 14.
Figure 6. Approximate shielding (+) and deshielding (-) zones of sulfites
(X ) O) and thionosulfites (X ) S).
plane of symmetry leading to a singlet as observed for
sulfoxylate 18.
The X-ray and presumably lowest energy solution conforma-
tion of 14 is quite similar to that of tetrasulfide 2649 as evidenced
by the 0°-15° differences in the corresponding dihedral angles
(Table 5). The larger torsion angle deviations are the result of
bond angle differences. The X-S-S bond angles are quite
similar: θav(O-S-S) ) 108.3° and θav(S-S-S) ) 106.2°. By
strong contrast, θav(C-O-S) (116.9°) is 12.5° larger than θav-
(C-S-S) (104.4°). The variation is due to the natural angles
sustained by the central atoms of C-X-S. Microwave spectra
of dimethyl sulfide50 and dimethyl ether51 exhibit C-X-C
angles of 98.8° and 111.8°, respectively, a difference of 13.0°.
Thus, the C-X-S angle variation is translated into the small
but significant torsion angle differences between 14 and 26.
The proton NMR traces of thionosulfite 15 and sulfite 17
display well-resolved AX spectra (Figure 5). The large chemical
shift separation of the geminal protons is characteristic of
exocyclic and axial SdX (X ) O, S), each proton falling into
a different region of the deshielding zones as depicted quali-
tatively by Figure 6.
With respect to the conformational profiles of 15 and 17 in
1
solution, their clean H AX spectra (Figure 5) imply that the
compounds are best described by either a rapidly equilibrating
mixture of chair, twist-boat and boat forms or one of these as
a single stable conformer. Inversion around the hypervalent ring
sulfur at room temperature can be eliminated immediately since
this dynamic feature would result in equivalent geminal protons
and lead to a singlet. The outcome is consistent with a calculated
barrier above 30 kcal/mol.19 A definitive answer for 17 has been
provided by St-Jacques and co-workers.58 1H and 13C DNMR
studies in concert with solution IR reveal that the compound
consists of a near 1:1 mixture of chair and twist-boat forms in
CHF2Cl at -157 °C interconverting over a free energy barrier
of 7 kcal/mol. The ratio of conformers is solvent dependent. In
the less polar dimethyl ether medium, the chair/twist ratio
(52) Green, C. H.; Hellier, D. G. J. Chem. Soc., Perkin Trans. 2 1972, 458.
Albriktsen, P. Acta Chem. Scand. 1972, 26, 3678. Maroni, P.; Cazaux, L.;
Gorrichon, J. P.; Tisnes, P.; Wolf, J. G. Bull. Soc. Chim. Fr. 1975, 1253.
(53) Dodson, R. M.; Srinivasan, V.; Sharma, K. S.; Sauers, R. F. J. Org. Chem.
1972, 37, 2367.
While the X-ray crystal structures of 15 and 17a display the
SdX in an axial orientation, equilibration between chair and
(49) This tetrasulfide was isolated in a trapping experiment between dithiato-
pazine and 2,3-diphenylbutadiene. See: Nicolaou, K. C.; DeFrees, S. A.;
Hwang, C.-K.; Stylianides, N.; Carroll, P. J.; Snyder, J. P. J. Am. Chem.
Soc. 1990, 112, 3029.
(50) Demaison, J.; Tan, B. T.; Typke, V.; Rudolph, H. D. J. Mol. Spectrosc.
1981, 86, 406. Iijima, T.; Tsuchiya, S.; Kimura, M. Bull. Chem. Soc. Jpn.
1977, 50, 2564. Pierce, L.; Hayashi, M. J. Chem. Phys. 1961, 35, 479.
(51) Tamagawa, K.; Takemura, M.; Konaka, S.; Kimura, M. J. Mol. Struct.
1984, 125, 131. Kasai, P. H.; Myers, R. J. J. Chem. Phys. 1959, 30, 1096.
Blukis, U.; Kasai, P. H.; Myers, R. J. J. Chem. Phys. 1963, 38, 2753.
(54) Pritchard, J. G.; Lauterber, P. C. J. Am. Chem. Soc. 1961, 83, 2105.
(55) Steudel, R.; Laitinen, R. S.; Pakkanen, T. A. J. Am. Chem. Soc. 1987, 109,
710.
(56) Lambert, J. B.; Vagenas, A. R. Org. Magn. Reson. 1981, 17, 265; Lambert,
J. B.; Vagenas, A. R. Org. Magn. Reson. 1981, 17, 270.
(57) Barbarella, G.; Dembach, P.; Garbesi, A.; Fava, A. Org. Magn. Reson.
1976, 8, 108.
(58) Faucher, H.; Guimaraes, A.; Robert, J. B. Tetrahedron Lett. 1977, 20, 1743.
Faucher, H.; Guimaraes, A. C.; Robert, J. B.; Sauriol, F.; St-Jacques, M.
Tetrahedron 1981, 37, 689.
9
298 J. AM. CHEM. SOC. VOL. 128, NO. 1, 2006

Dialkoxy Disulfides/Thionosulfites Crossover Point
A R T I C L E S
becomes 2:1. These observations are in accord with the averaged
AX spectrum of 17 at room temperature and with the determi-
nation of both conformers in the crystal lattice (Figure 3).
Although we have not performed low-temperature NMR experi-
ments for thionosulfite 15, we presume the compound undergoes
an averaging process similar to 17.
This barrier is comparable to those measured4,19,20,29 and
calculated19,61 for acyclic dialkoxy disulfide analogues. While
traversing the barrier to effect ring inversion certainly involves
rotation about the S-S bond, previous kinetic measurements
were uniformly conducted on molecules that interconvert
conformational enantiomers through a trans O-S-S-O transi-
tion state. The eight-membered ring in 14, by necessity, switches
disulfide chirality by means of a cis transition state. In general,
the latter is higher than for the trans pathway.61 Thus, although
the measured barrier for 14 is essentially identical to that
obtained from previous dialkoxy disulfide evaluations, the
matched values may well be a coincidence. Coupled torsional
motions of the C-CH2, CH2-O, and O-S bonds in the
medium-sized ring of 14 undoubtedly assist in traversing the
cis transition state and lowering its energy. As such, the 18-
19 kcal/mol value is most likely an underestimate of the energy
cost for cis interconversion in an acyclic system.
1
The H spectrum of dimer 16 displays the benzylic centers
as two distinct AB spin systems in an approximate 2:1 ratio.
13C NMR likewise reveals the benzylic carbons in a 2:1 ratio.
The connectivity in 16 is that of a 16-membered ring containing
two chiral axes within the two OS-SO functional groups similar
to that described for dialkoxy disulfide 14. This implies that 16
can exist in any of three atropisomers: (M,M), (P,P), or (M,P),
the latter being the meso form.48 Dynamic exchange in solution
promoted by rotation around single bonds other than S-S is
capable of making equivalent the methylene centers and
providing a single AB spin pattern for the (M,M)/(P,P)
atropisomers. The same behavior for the slightly less stable
(M,P) meso form leads to the second, less intense AB spectrum
portrayed. A reasonable interpretation of the proton spectrum
is that it represents a statistical average of the three atropisomers,
each of which can populate a number of conformations. Since
the NMR spectra of the (M,M) and (P,P) enantiomers are
identical, two sets of doublets of doublets corresponding to the
(M,M)/(P,P) and (M,P) forms each with slightly different
coupling constants are observed (Table 4). Based on the
integrated 2:1 ratio of NMR peak intensities (ca. 3:2) and
assuming a Boltzmann population distribution at 296 K, the
(M,P) conformer is disfavored by ca. 0.3 kcal/mol.
Dimer 16 was also heated in p-xylene-d10, but full coalescence
could not be achieved even at 140 °C where decomposition sets
in. Here the two AB spin systems coalesce into a single, broad
doublet. The observation is consistent with rapid rotation about
the four pairs of C-CH2, CH2-O, and O-S bonds as discussed
above in connection with the averaging process for 14 that
promotes equivalence of its two CH2 centers. For 16, the high-
temperature dynamics averages all four CH2 moieties but retains
diastereotopicity for the geminal protons. While 140 °C is
sufficient to promote S-S rotation in 14, it may be insufficient
to do so for both S-S units in 16. Conceivably, one of the
disulfide centers exerts a rigidifying effect on the 16-membered
ring permitting independent permutation of the other. Thus, the
high-temperature NMR spectrum for 16 appears qualitatively
similar to that for the low-temperature spectrum of disulfide
14, both incorporating a single stable chiral moiety. At tem-
peratures permitting rapid interchange about both S-S bonds
in 16, the benzylic hydrogens of the atropisomers would coalesce
into a singlet representing the full average. Unfortunately, the
compound decomposes thermally before such a temperature can
be reached. The details of the various conformational processes
are under study and will be reported separately.
Thermal Stability of Isomers 14 and 15. Whereas thiono-
sulfite 15 decomposes only slowly at 120 °C for several hours
in solution (p-xylene-d10), dialkoxy disulfide 14 decomposes
within minutes under the same conditions to afford 15, 17, 18,
1
and other unidentified products as monitored by H NMR and
compared to the chemical shifts of authentic samples. The lack
of observable coalescence of the methylene AX signal in 15
(Figure 2) is primarily due to the contribution of a large
pyramidal sulfur inversion barrier.59
Differential scanning calorimetry (DSC) also provides insight
into the relative stabilities of 14-16. Although phase transitions
in 14-16 were observed (see Supporting Information), the
thermodynamic profiles of dialkoxy disulfides 14 and 16 are
unique in that they also present an exotherm at higher temper-
atures (ca. 140 °C), absent for 15 and 17, indicating decomposi-
tion. DSC measurements thus provide another tool that easily
distinguishes between constitutionally isomeric forms of com-
pounds possessing the OS2O motif.
Synthesis of Cyclic Dialkoxy Disulfide 30. As a departure
from medium ring compounds derived from 1,2-benzene-
dimethanol 13, we turned our attention to the S2Cl2 coupling
of 2,2′-biphenyldimethanol 29.
S-S Rotation Barriers for 14 and 16. The barrier to
conformational interconversion of the eight-membered ring in
14 was measured by NMR to be 18.8 ( 0.2 kcal/mol using
approximations developed by Gutowsky and Holm.60 The benzyl
proton AB spin system coalesced at 114.6 °C in p-xylene-d10.
(59) For a background on the causes of pyramidal inversion, see: Mislow, K.;
Rauk, A.; Allen, L. C. Angew. Chem., Int. Ed. Engl. 1970, 9, 400. For a
review on linear free energy correlations of barriers to pyramidal inversion,
see: Mislow, K.; Baechler, R. D.; Andose, J. D.; Stackhouse, J. J. Am.
Chem. Soc. 1972, 94, 8060. For a review on calculated and experimental
barriers to pyramidal inversion for first- and second-row elements, see:
Mislow, K.; Rauk, A.; Andose, J. D.; Frick, W. G.; Tang, R. J. Am. Chem.
Soc. 1971, 93, 6507. For examples of high pyramidal sulfur inversion
barriers in sulfites, see: Pritchard, J. G.; Lauterbur, P. C. J. Am. Chem.
Soc. 1961, 83, 2105. Lauterber, P. C.; Pritchard, J. G.; Vollmer, R. L. J.
Chem. Soc. 1963, 5307.
Reaction conditions used were similar to those found in the
literature;29 the crude solution yielded a complex mixture of
products. After chromatography, dialkoxy disulfide 30 was
isolated in 25% yield as a clear oil, which subsequently solidified
in the freezer. Though we were unable to obtain a crystal
9
J. AM. CHEM. SOC. VOL. 128, NO. 1, 2006 299

A R T I C L E S
Zysman-Colman et al.
Table 6. Influence of Acidity on the Formation of Dialkoxy
Disulfide 14 and Thionosulfite 15 from Treatment of Diol 13 with
Varying Ratios of S2Cl2/Et3N
structure of 30, its structural topology was inferred from two
pieces of data.62
Interestingly, this compound possesses two chiral units: the
OS-SO unit and biphenyl moiety. This implies that 30 carries
the potential to exist in diastereomeric conformations that may
be isolable. In addition, 30 is a ten-membered ring that is
predicted by the correlation in Figure 1 to be the sole product
from ring closure. Unfortunately, the low 25% yield precludes
any conclusion at this time regarding the operation of the
crossover principle for this compound.
Conversion of Dialkoxy Disulfide 14 to Thionosulfite 15
with Acid. As mentioned in the computational predictions
section, the two isomers of FS2F (FsSsSsF and F2SdS) have
been structurally characterized2-6 and claimed to participate in
an uncatalyzed equilibrium well below room temperature (-100
°C).3,5 Leaving this view in an uncertain state are recent high
level calculations which predict that the corresponding uni-
molecular6,33,63-65 and bimolecular66 transition states are as-
sociated with 35-45 kcal/mol barriers and studies which suggest
that Lewis or Brønsted acids and traces of mineral acid promote
the isomerization.5
To address this question for the interconversion of dialkoxy
disulfide 14 and thionosulfite 15, we have performed a series
of experiments designed to test conditions that promote trans-
formation between the two isomers. Already mentioned is the
thermal stability of 15 at 120 °C in p-xylene-d10 and the initial
observation of the formation of 15 from 14 under the same
conditions. When acid was rigorously excluded during the
reaction (e.g., new glassware or base wash), the conversion of
13 was similar to entries 1 and 2 in Table 3. Namely, no
thionosulfite was detected. Excess triethylamine provides the
same result with partial decomposition of 14. Base wash of the
glassware likewise leads to some decomposition. In either case,
small amounts of dimer 16 (5-10%) are observed even when
the reaction is diluted to one-third the normal concentrations.
The sensitivity of 14 to base and acid (see below) is consistent
with the observation that dialkoxy disulfides are decomposed
by both basic and acidic alumina upon chromatography67 and
in the presence of Brønsted or Lewis acids.31
temperature
C)
reaction time
(min)
ratio
main
entry
(
°
[Et3N]/[S2Cl2]
product
1
2
3
4
5
6
25
25
25
25
0
5
120
5
120
120
5-15
2
2
1.7
1.7
1.7
1
14a,b
14a,b
14a,b
15c
15d
e
25
a Isolated yields are in the 88-92% range. b Minor amounts of dimer
16 were observed as the only side product. c Isolated yields are in the 65-
75% range. d Mixture of 14 (40%) and 15 (45%) by 1H NMR. e Decom-
1
position products. H NMR broad and characterless.
HCl; early in the reaction (5 min) 14 is produced in high yield,
but after 2 h the major product is thionosulfite 15 (75%) (entry
4; Figure 7). A similar result is observed at 0 °C, although the
process is slower, as expected (entry 5). Reduction of the Et3N
concentration to 1 equiv causes decomposition, possibly with
the formation of oligomeric byproducts. Obviously, the course
of the reaction summarized in Scheme 1 is dependent on the
concentration of HCl. The important observation is that 14 is
unstable relative to 15 in the presence of moderate concentra-
tions of free HCl.
To substantiate these observations further, the acid-promoted
conversion of a purified sample of 14 to 15 was monitored by
1H NMR as depicted in Figure 7. A CDCl3 solution containing
the dialkoxy disulfide 14, tetrabutylammonium bromide, and
HCl (0.5:1.0:0.1 ratio, respectively) with 1,3,5-tri-tert-butyl-
benzene as an internal standard was monitored every 15 min
by integrating the benzylic protons. The acid-promoted disap-
pearance of dialkoxy disulfide 14 is accompanied by the
simultaneous formation of thionosulfite 15 as well as small
amounts of diol 13, sulfite 17 and sulfoxylate 18. The 3-4%
yield of the latter is consistent with its appearance in equally
low yields in some of the runs listed in Table 3. The yields for
these reactions were reproducible. Similar results were obtained
in toluene-d8.
One implication of these experiments is that thionosulfite 15
is thermodynamically more stable than disulfide 14. Qualita-
tively, this is at odds with the B3LYP/6-31G(2d)//MM3* DFT
calculations of Tables 1 and 2, which predict the reverse by
0.5 to 1.7 kcal/mol. It is well-known that the ability to accurately
predict the experimental energy differences between FSsSX
and F2SdS is a challenge. Only with expanded basis sets and
significant electron correlation is it possible to invert the stability
difference [∆E(FSSF) - ∆E(F2SdS)] from +3.5 to -1.7
kcal/mol (e.g., MP4(SDTQ)/6-311G(2d)//MP2/6-311G(2d) and
QCISD(T)/6-31+G(d,f)//MP2/631G**, respectively).63 Al-
though we have not examined the considerably larger structures
14 and 15 with the much higher level calculations, it is likely
that a similar stability reversal would be obtained here as well.
Despite the uncertainty in the relatively small DFT energy
difference between 14 and 15 using the B3LYP/6-31G(2d)//
MM3* model, predicted energy differences between other
dialkoxy disulfide/thionosulfite pairs are sufficiently large that
the crossover correlation (Table 1, Figure 1) is not compromised.
A deliberate attempt to introduce acid into the reactions
catalogued in Table 1 and depicted by Scheme 1 is summarized
in Table 6. Before workup, all reactions were monitored by 1H
NMR at the times indicated.
At 25 °C, in the presence of 1 equiv of S2Cl2 and 2 equiv of
Et3N, diol 13 provides dialkoxy disulfide 14 within a few
minutes in high yield (Table 6, entry 1). The dialkoxy disulfide
is stable to longer reaction times (entry 2). Reduction of the
concentration of Et3N to 1.7 equiv permits the liberation of free
(60) Gutowsky, H. S.; Holm, C. H. J. Chem. Phys. 1943, 25, 1228; Kost, D.;
Carlson, E. H.; Raban, M. Chem. Commun. 1971, 656.
(61) Snyder, J. P.; Carlsen, L. J. Am. Chem. Soc. 1977, 99, 2931.
(62) Compound 30 liberated SO under EI MS conditions, a property observed
for other dialkoxy disulfides27 but not for thionosulfites. As well, the
splitting pattern observed in the 1H NMR spectrum displays two diagnostic
AB spin systems in an approximate ratio of 5:2, ostensibly associated with
two distinct atropisomers; the spectra of thionosulfites exhibit AX spin
systems. The ratio of the benzyl carbon signals in the 13C NMR corroborates
this analysis.
(63) Bickelhaupt, F. M.; Sola`, M.; Schleyer, P. v. R. J. Comput. Chem. 1995,
16, 465.
(64) Torrent, M.; Duran, M.; Sola, M. THEOCHEM 1996, 362, 163.
(65) Jursic, B. S. J. Comput. Chem. 1996, 17, 835.
(66) Mestres, J.; Fores, M.; Sola, M. THEOCHEM 1998, 455, 123.
(67) Thompson, Q. E.; Crutchfield, M. M.; Dietrich, M. W.; Pierron, E. J. Org.
Chem. 1965, 30, 2692.
A plausible mechanism for the conversion of 14 to 15 is
suggested in Scheme 1. Although dialkoxy disulfide 14 is rapidly
formed from 13, in the presence of acid it reverts to the chloro-
9
300 J. AM. CHEM. SOC. VOL. 128, NO. 1, 2006

Dialkoxy Disulfides/Thionosulfites Crossover Point
A R T I C L E S
Figure 7. Monitoring the conversion of 14 (blue) to 15 (red) and sulfoxylate 18 (yellow) by 1H NMR (CDCl3, 22 °C) in the presence of HCl and
tetrabutylammonium bromide with 1,3,5-tri-tert-butylbenzene as an internal standard.
alkoxy disulfide intermediate 20. Apparently, an acid-promoted
7-exo-tet SN2′ mechanism affords 15. The same functional group
transformation has been reported when dialkoxy disulfide is
treated with SCl2 under carefully controlled conditions.30
Summary, Conclusions and Future Prospects. It is known
that electronegative substituents flanking the disulfide bond in
XSsSX can stabilize the constitutional thionosulfite isomer
X2SdS. The most celebrated case known for over 40 years is
FS2F.2-6 While indirect evidence exists for the thionosulfite
constitution in transient species for various electronegative
atoms, the only other documented case is X ) O. Dialkoxy
disulfides (ROSsSOR) have been known since the turn of the
past century,68 but the first isolable and fully characterized
thionosulfite ((RO)2SdS), captured in a five-membered ring,
appeared 70 years later.7 Another 23 years passed before
additional examples were reported.8-10 However, once again
five-membered rings sustain the rearranged disulfides. This
curious ring-size limitation suggested that our understanding
of the ROSsSOR/(RO)2SdS relationship was inadequate.
Therefore, we undertook a theoretical investigation of the
relationship to see if new insights might be gained. Indeed, DFT
calculations with a reasonable basis set (B3LYP/6-31G(2d))
pointed to the seven-membered ring thionosulfite as the ideal
ring size for approximate energetic equivalence with the
corresponding eight-membered ring dialkoxy disulfide (Figure
1). Smaller ring sizes were predicted to favor the thionosulfite
structure, and larger, the dialkoxy disulfide.
contribute to maximum orbital overlap between the oxygen lone
pairs and the σ*SdS antibonding orbital and thus conformational
stability. For ideal values of 0° and 180°, stabilization is a
maximum. The corresponding estimated angles for the sym-
metrical thionosulfite 15 (Figure 2) with two such interactions
are 168°. For the ROsSsSsOR system, in contrast to carbon-
based disulfides (CsSsSsC), we surmise that small rings
induce sufficient strain to render the compounds unstable to
facile further transformation. It is noteworthy that the eight-
membered ring in 14 represents the minimum ring size required
to adopt the optimal τ(OSsSO) dihedral angle near 90°, i.e.,
93.2°. The two effects of minimal disulfide ring strain and
thionosulfite SdS stereoelectronic stabilization appear to co-
incide at the ring sizes of eight and seven, respectively (Figure
1, Table 1).
With the present synthetic and structural knowledge in hand,
we anticipate that other cyclic 7/8-ring ROS2OR pairs will soon
be synthetically accessible. This projection extends to larger
ring cyclic dialkoxy disulfides, one example of which is the
10-membered ring 30, and the presently unknown six-membered
thionosulfite series 6. We likewise expect that examples of less
stable species beyond these boundaries, such as 3, 5, and 10,
may be detected as transient intermediates or entities stabilized
by heavy substitution.
In addition, we have made an effort to address the potential
for rearrangement between the dialkoxy disulfide and thiono-
sulfite isomers. Early literature claimed that interconversion of
FSSF and F2SdS is uncatalyzed,3,5 while other work suggested
acid mediation.5 Experimentally, the situation is not fully
resolved. However, recent calculations suggest a barrier of 40-
55 kcal/mol for the unimolecular rearrangement33,63,64 and 40
kcal/mol for a bimolecular reaction channel66 implying that an
uncatalyzed process is beyond reach at room temperature or
below where the interconversion is observed to take place.
Similar calculations for the unimolecular transition state between
MeOSSOMe and (MeO)2SdS yields a ∆Eq of 37.5 kcal/mol
equally inaccessible at room temperature.19 We have carefully
evaluated the conversion of 14 to 15 under a variety of
conditions and demonstrated that the transformation between
0° and 25° requires the presence of at least traces of acid. A
plausible mechanistic route is depicted in Scheme 1. Recognition
that the dialkoxy disulfide to thionosulfite transformation is acid
Choosing 1,2-benzenedimethanol 13 as a convenient starting
material, the compound was treated with various bases and sulfur
transfer reagents to refine reaction conditions leading simulta-
neously to the first examples of a stable cyclic dialkoxy disulfide
(14) and a non-five-membered ring thionosulfite (15). Fulfilling
our theoretical predictions in all particulars, the same reaction
yields dimer 16, sulfite 17, and sulfoxylate 18 in low yields.
X-ray crystal structures of 14-17 confirm the connectivities in
the solid state, while ambient 1H and 13C NMR provide insights
into conformational mobility in solution.
While a deeper analysis may be called for, we speculate that
the overriding forces controlling the formation of 14 and 16
from the same reaction appear to be two-fold. For the (RO)2Sd
S system, the near cis and trans LPsOsSdS torsion angles
(68) Lengfeld, F. Ber. 1895, 28, 449.
9
J. AM. CHEM. SOC. VOL. 128, NO. 1, 2006 301

A R T I C L E S
Zysman-Colman et al.
JAB ) 12.00 Hz), 5.07 (d, 2H, JAB ) 12.00 Hz); 13C NMR δ 72.3,
130.1, 132.1, 136.1; 13C NMR indirectly detected by HMQC(500 MHz,
125 MHz) δ 72.6, 131.0, 133.0; IR (CDCl3) 531 cm-1 (S-S stretch);
MS (EI) m/z 200 (M+•), 152 (M+• - SO); 119 (M+• - S2OH), 104
(M+• - S2O2). HRMS calcd for C8H8S2O2: 199.9966. Found: 199.997-
(0). Calcd for C8H8S2O2 - SO: 152.0296. Found: 152.030(0). IR -
KBr (cm-1) 1471(w), 1452(w), 1384(w), 1352(w), 1306(w), 1209(w),
1188(w), 1117(w), 956(m), 932(s), 874(w), 848(w), 816(w), 789(w),
760(m), 743(s), 698(w), 676(w), 647(s), 619(m), 590(w), 531(w).
Raman (powder - 5000 scans) 3046, 2966, 2920, 1604, 1051, 676
ν(S-O), 518 ν(S-S), 355, 196, 137, 122, 84.
catalyzed should contribute to the preparation and identification
of six- and seven-membered ring systems such as 3 and 5 and
other acid sensitive dialkoxy disulfides as well.
Experimental Section
General Experimental. All reagents were commercially available
and were used without further purification save for the following
exceptions. Methylene chloride (CH2Cl2) and triethylamine (NEt3) were
distilled over calcium hydride. Sulfur monochloride, S2Cl2, (135-137
°C) was distilled according to procedures adapted from Fieser and Fieser
(100:4:1 S2Cl2/sulfur/charcoal).69 Sulfur dichloride, SCl2 (59-60 °C),
was fractionally distilled over 0.1% phosphorus pentachloride, PCl5.
Both S2Cl2 and SCl2 were used immediately after distillation. All
glassware was oven-dried. All reactions were performed under a
nitrogen atmosphere (N2) unless otherwise stated. Flash chromatogra-
phy70 was conducted using 230-400 mesh silica gel. NMR spectra
were recorded at 400 or 500 MHz for 1H and 75, 100, or 125 MHz for
13C. Deuterated chloroform (CDCl3), dried over 4 Å molecular sieves,
was used as the solvent of record, and spectra were referenced to the
solvent peak. Melting points (mp’s) were recorded using open end
capillaries and are corrected.
Synthesis of Seven-Membered Ring Thionosulfite 15: A solution
of diol 13 (138 mg, 1 mmol, 1 equiv) and NEt3 (280 µL, 2 mmol, 2
equiv) in 10 mL of CH2Cl2 was allowed to stir under N2 at rt. A solution
of S2Cl2 (80 µL, 1.0 mmol, 1 equiv) in 10 mL of CH2Cl2 was added
dropwise over ca. 60 min. The reaction mixture was allowed to stir for
a further 4 h. The reaction mixture was quenched with 10 mL of H2O.
The organic phase was washed 3 × 33 mL of H2O. The organic phase
was dried over MgSO4. This mixture was vacuum filtered, and the
solvent was removed first under reduced pressure and then in vacuo.
The crude solid, which contained a 2:1 mixture of 14:15, was flash
chromatographed70 in 25% CH2Cl2/hexanes as the eluant to afford a
slightly aromatic white crystalline solid. Rf (25% CH2Cl2/hexanes) 0.31.
Yield: 22%. Mp 73-74 °C; DSC Tonset ) 79.93, Tmax ) 80.69, ∆H )
78.10 J/g; 1H NMR δ 7.32 (m, 4H), 6.61 (d, 2H, J ) 14.25 Hz), 4.49
(d, 2H, J ) 14.25 Hz); 13C NMR δ 62.9, 128.4, 129.5, 136.9; MS (EI)
m/z 200 (M+•), 170, 135, 119, 90, 78; HRMS calcd for C8H8S2O2:
199.9966. Found: 199.995(9). Calcd for C8H8S2O2 - O: 184.0017.
Found: 184.001(6). Calcd for C8H8S2O2 - O2: 168.0067. Found:
184.005(9). Calcd for C8H8S2O2 - SO: 152.0296. Found: 152.029-
(4). IR - KBr (cm-1) 1496(w), 1455(m), 1442(w), 1384(w), 1352(w),
1306(w), 1242(w), 1219(w), 1209(w), 1186(w), 1118(w), 956(w), 947-
(m), 932(s), 893(m), 874(w), 853(w), 848(w), 816(w), 789(w), 774-
(m), 760(w), 743(w), 739(m), 696(m), 685(m), 676(m), 669(m), 647(w),
632(s), 619(m), 595(m), 590(w), 540(w), 531(w). Raman (powder -
1000 scans) 3047, 2983, 1606, 1220, 1160, 1048, 745, 633 ν(SsO),
540 ν(SdS), 337, 304, 179, 135, 87, 58.
Synthesis of 1,2-Benzenedimethanol 13: To a slurry of LiAlH4
(19.3 g, 0.5 mol, 2.5 equiv) in 315 mL of THF was slowly added a
solution of o-phthalic acid (33.5 g, 0.2 mol, 1 equiv) in 215 mL of
THF at 0 °C under N2. The flask was equipped with an exit to monitor
the production of H2 gas during the addition. The solution was stirred
for 18 h and then quenched according to the literature procedure.71
This was then stirred for an additional 3 h. The whitish slurry was
then vacuum-filtered and washed with excess THF. The organic section
was extracted with Et2O. The solution was dried over MgSO4. The
solvent was removed first under reduced pressure and then in vacuo.
White crystalline solid. If need be, this can be recrystallized in EtOAc
as the solvent and hexanes as the cosolvent. Rf (50% EtOAc/hexanes)
0.35. Yield: 84%. Mp 68-69 °C (lit. mp 62-63 °C,72 63-65 °C73).
1H NMR δ 3.44 (s, 2H), 4.65 (s, 4H), 7.30 (m, 4H); 13C NMR δ 64.0,
128.5, 129.7, 139.3; MS (CI) m/z 156 (M+• + NH4+), 139 (M+•
+
H+), 120, 91; HRMS calcd for C8H11O2 (M+• + H+): 139.0759.
Found: 139.075(3).
Synthesis of Eight-Membered Ring Dialkoxy Disulfide 14: The
compound was synthesized using a modification of the literature
procedure for the synthesis of acyclic alkoxy disulfides.29 A solution
of diol 13 (138 mg, 1 mmol, 1 equiv) and NEt3 (280 µL, 2 mmol, 2
equiv) in 10 mL of CH2Cl2 was allowed to stir under nitrogen at 0 °C.
A solution of S2Cl2 (80 µL, 1.0 mmol, 1 equiv) in 50 mL of CH2Cl2
was added dropwise over ca. 60 min. The reaction mixture was allowed
to stir for a further 4 h. The reaction mixture was quenched with 20
mL of H2O. The organic phase was washed 3 × 33 mL of H2O. The
organic phase was dried over MgSO4. This mixture was vacuum filtered,
and the solvent was removed first under reduced pressure and then in
vacuo. Frequently, it was not necessary to chromatograph the product
as there was quantitative conversion as detected by TLC and 1H NMR.
Fruity-smelling white crystalline solid. Rf (25% EtOAc/hexanes) 0.47,
(25% CH2Cl2/hexanes) 0.17. Yield: 94%. Mp 59-60 °C; DSC Tonset
) 61.11, Tmax ) 64.63, ∆H ) 476.2 J/g; Tonset ) 117.98, Tmax ) 125.36,
∆H ) -404.5 J/g. 1H NMR δ 7.43 (m, 4H), ABq system 4.94 (d, 2H,
Synthesis of 16-Membered Ring Dimer 16: The following condi-
tions appear to be optimal for the procedure of 16. A solution of diol
13 (138 mg, 1 mmol, 1 equiv) and NEt3 (280 µL, 2 mmol, 2 equiv) in
10 mL of THF was allowed to stir under nitrogen at 0 °C. A solution
of S2Cl2 (80 µL, 1.0 mmol, 1 equiv) in 10 mL of THF was added
dropwise over ca. 3 min. The reaction mixture was allowed to stir for
a further 5 h. The reaction mixture was quenched with 10 mL of H2O.
The organic phase was extracted in 20 mL of Et2O. The organic phase
was washed 3 × 33 mL of H2O. The organic phase was dried over
MgSO4. This mixture was vacuum filtered, and the solvent was removed
first under reduced pressure and then in vacuo. The crude solid, which
contained a 10:1 mixture of 14:16, was flash chromatographed70 in
25% CH2Cl2/hexanes as the eluant to afford a slightly aromatic white
crystalline solid. Rf (25% CH2Cl2/hexanes) 0.13. Yield: 9%. Mp 153-
(69) Fieser, L. F.; Fieser, M. Reagents for Organic Synthesis; John Wiley and
Sons: New York, 1967; Vol. 1, p 1122.
(70) Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923.
(71) Fieser, L. F.; Fieser, M. Reagents for Organic Synthesis; John Wiley and
Sons: New York, 1967; Vol. 1, p 583.
(72) Anderson, W. K.; Kinder, F. R., Jr. J. Heterocycl. Chem. 1990, 27, 975.
(73) Aldrich Catalog Handbook of Fine Chemicals; Aldrich Chemical Co.,
Inc.: 2003.
155 °C; DSC Tonset ) 92.18, Tmax ) 95.80, ∆H ) 11.99 J/g; Tonset
139.88, Tmax ) 143.19, ∆H ) -124.70 J/g; Tonset ) 153.75, Tmax
)
)
156.76, ∆H ) -42.52 J/g. 1H NMR δ 7.36 (m, 8H), AX system: 5.26
(d, 4H, J ) 11.00 Hz), 5.20 (d, 2H, J ) 12.00 Hz), 4.89 (d, 2H, J )
12.00 Hz), 4.84 (d, 4H, J ) 11.00 Hz); 13C NMR δ 75.3, 75.4, 128.7,
129.0, 129.7, 134.7, 134.9; 13C NMR indirectly detected by HMQC
9
302 J. AM. CHEM. SOC. VOL. 128, NO. 1, 2006

Dialkoxy Disulfides/Thionosulfites Crossover Point
A R T I C L E S
(600 MHz, 151 MHz) δ 75.2, 129.0, 129.7; MS (EI) m/z 400 (M+•),
352 (M+• - SO), 272 (C12H16O3S2), 255, 200 (C8H8O2S2), 152 (C8H8-
OS), 135, 121, 120 (C8H8O), 105, 104 (C8H8); HRMS calcd for
C16H16S4O4: 399.9931. Found: 399.99(3)4. IR - KBr (cm-1) 1481-
(w), 1456(w), 1447(w), 1384(w), 1367(w), 1360(w), 1300(w), 1262-
(w), 1232(w), 1205(w), 1189(w), 1112(w), 984(m), 974(m), 953(m),
926(s), 874(m), 855(w), 816(m), 763(s), 736(m), 723(m), 697(s), 639-
(w), 602(w), 514(w).
- SO) 196 (M+• - S2O); 179 (M+• - S2O2H), 165 (M+• - S2O2CH3).
HRMS calcd for C8H8S2O2: 276.0279. Found: 276.027(1).
Isomerization of 14 to 15: A. Preparation of the HCl Solution.
Gaseous HCl was generated in a three-neck flask under nitrogen by
dropwise addition of concentrated sulfuric acid (20 mmol, 1 equiv) to
solid sodium chloride (40 mmol, 2 equiv). Using a plastic syringe, the
gas (3 mL, 25 °C) was dissolved in 3 mL of dry CDCl3 (99.8%) at
room temperature. The resulting solution was titrated with amida-
zophene in the presence of dimethyl yellow.74 Specifically, a sample
of the HCl/CDCl3 solution was placed in a 5-mL round-bottom flask
under nitrogen. One drop of a 0.1% solution of dimethyl yellow
indicator in dry benzene was added to the sample before the solution
was titrated with a 0.01 M solution of amidazophene in dry benzene.
The solution of amidazophene was slowly added dropwise until the
pink color turns slightly yellow. The HCl concentration was determined
to be 0.013 M. The CDCl3 used was similarly tested for HCl and found
to contain negligible amounts of acid.
Synthesis of Sulfite 17: To a solution of 13 (141.5 mg, 1 mmol, 1
equiv) and NEt3 (280 µL, 2 mmol, 2 equiv) in 10 mL of CH2Cl2 was
added dropwise a solution of 75 µL of SOCl2 in 10 mL of CH2Cl2 at
0 °C under N2. The reaction was stirred for 2.3 h. The reaction was
quenched with 20 mL of H2O. The organic phase was washed 3 × 30
mL H2O. The solution was dried over MgSO4. The solvent was removed
first under reduced pressure and then in vacuo. Brownish crystals. Rf
(25% EtOAc/hexanes) 0.38; (25% CH2Cl2/hexanes) baseline. Yield:
74%. Mp 33-36 °C; Recrystallized as clear crystals from CH2Cl2/
1
hexanes: Mp 34-35 °C; H NMR δ 7.27 (m, 4H), 5.96 (d, 2H, J )
1
B. H NMR (500 MHz) Monitoring of the Isomerization. Vials
14.00 Hz), 4.68 (d, 2H, J ) 14.00 Hz); 13C NMR δ 62.7, 128.3, 128.3,
136.1; MS (EI) m/z 184 (M+•), 119, 91; HRMS calcd for C8H8SO3:
184.0194. Found: 184.019(8).
and NMR tubes used below were new and preheated in an oven hours
before use. A pure sample of dialkoxy disulfide 14 (5.0 mg, 0.025
mmol, 1 equiv) in 1 mL of CDCl3 containing tetrabutylammonium
bromide75 (17.0 mg, 0.050 mmol, 2 equiv) was prepared. 1,3,5-Tri-
tert-butylbenzene (2.1 mg, 0.008 mmol, 0.33 equiv) served as the
1
internal standard. After taking the H NMR spectrum and integrating
the methylene protons for time-zero values, the dialkoxy disulfide
solution was transferred to a vial and the experiment was initiated by
dropwise addition of 0.4 mL of the HCl/CDCl3 solution (∼0.005 mmol,
0.2 equiv). The solution was mixed and replaced in the NMR tube.
Relative amounts of both dialkoxy disulfide 14 and thionosulfite 15
were monitored by integrating the methylene protons approximately
every 15 min for several hours (delay time: d1 ) 20 s). The NMR
device was reshimmed a number of times throughout the experiment.
In addition to the loss of 14 and formation of 15, a peak at 5.5 ppm
demonstrated the formation of sulfoxylate 18 over the course of the
experiment for a final yield of 3-4%. The experiment was performed
at a corrected probe temperature of 22 °C; 500 MHz.
Preparation of 14 and 15 in the Presence of Acid (Table 6): A
solution of 13 (1 mM, 1 equiv) and triethylamine (2 mM, 2 equiv) in
20 mL of CH2Cl2 was allowed to stir under nitrogen at 25 °C. A solution
of S2Cl2 (1 mM, 1 equiv) in 30 mL of CH2Cl2 was added dropwise
over 5 min.
Synthesis of Sulfoxylate 18: A solution of diol 13 (138 mg, 1 mmol,
1 equiv) and NEt3 (280 µL, 2 mmol, 2 equiv) in 10 mL of CH2Cl2 was
allowed to stir under nitrogen at 0 °C. A solution of SCl2 (64 µL, 1.0
mmol, 1 equiv) in 10 mL of CH2Cl2 was added dropwise over ca. 10
min. The reaction mixture was allowed to stir for a further 3 h. The
reaction mixture was quenched with 20 mL of H2O. The organic phase
was washed 3 × 33 mL of H2O. The organic phase was dried over
MgSO4. This mixture was vacuum filtered, and the solvent was removed
first under reduced pressure and then in vacuo. Aromatic light-brown
1
solid. Rf (25% CH2Cl2/hexanes) 0.18. Yield: 92%. H NMR δ 7.28
(m, 4H), 5.54 (s, 4H); 13C NMR δ 88.7, 128.4, 129.8, 138.6; MS (EI)
m/z 168 (M+•), 160, 138, 135, 119, 104, 78 HRMS calcd for C8H8SO2:
168.0245. Found: 168.024(0).
Entry 1: The reaction mixture was immediately worked up with 3
× 30 mL of H2O. The organic phase was dried over MgSO4 and vacuum
filtered. The solvent was removed first under reduced pressure and then
in vacuo. A colorless crystalline solid was obtained and purified over
neutral alumina (25% CH2Cl2/hexanes) to afford 14 as a white solid
(92%); Mp 59-60 °C; 1H NMR spectra are in agreement with values
reported previously.
Synthesis of 10-Membered Ring Dialkoxy Disulfide, 30: A
solution of 2,2′-biphenyldimethanol 29 (214 mg, 1 mmol, 1 equiv) and
NEt3 (280 µL, 2 mmol, 2 equiv) in 10 mL of CH2Cl2 was allowed to
stir under nitrogen at 0 °C. A solution of S2Cl2 (80 µL, 1.0 mmol, 1
equiv) in 10 mL of CH2Cl2 was added dropwise over ca. 10 min. The
reaction mixture was allowed to stir for a further 5.5 h. The reaction
mixture was quenched with 15 mL of H2O. The organic phase was
washed 3 × 33 mL of H2O. The organic phase was dried over MgSO4.
This mixture was vacuum filtered, and the solvent was removed first
under reduced pressure and then in vacuo. The crude mixture was flash
chromatographed70 in 10% CH2Cl2/hexanes as the eluant to afford a
fruity-smelling clear oil which solidified in the freezer. Rf (10% CH2-
Cl2/hexanes) 0.09. Yield: 25%. 1H NMR δ 7.51-7.40 (m, 5H), 7.36-
7.31 (m, 2H), 7.21-7.12 (m, 2H), 5.15 (d, 0.4H, J ) 12.30 Hz), 4.99
(d, 2H, J ) 12.60 Hz), 4.59 (d, 2H, J ) 12.60 Hz), 4.55 (d, 0.4H, J )
12.30 Hz); 13C NMR δ 70.4, 76.5, 127.6, 127.8, 128.2, 128.9, 129.4,
129.6, 129.8, 131.4, 134.7, 135.8, 139.4, 140.7; 5:1 of two diastereomers
as detected by 13C NMR, 1H NMR. MS (EI) m/z 276 (M+•), 228 (M+•
Entry 2: The reaction mixture was prepared as in entry 1 and
allowed to stir for an additional 2 h at rt. Workup was identical to
1
entry 1 to afford 14 as a white solid (90%); Mp 59-60 °C; H NMR
spectra are in agreement with values reported previously.
Entries 3, 4, and 5: A solution of 13 (1 mM, 1 equiv) and
triethylamine (1.7 mM, 1.7 equiv) in 20 mL of CH2Cl2 was stirred
under nitrogen at 25 °C and treated with S2Cl2 as described above over
5 min.
(74) Barcza, L. Talanta 1963, 10, 503. Schulek, E.; Barcza, L. Acta Pharm.
Hung. 1962, 32, 1.
(75) The isomerization is more rapid and complete when this salt is added,
apparently providing a higher halide ion concentration to supplement the
chloride ion from HCl as pictured in Scheme 1.
9
J. AM. CHEM. SOC. VOL. 128, NO. 1, 2006 303

A R T I C L E S
Zysman-Colman et al.
Entry 3: With the exception of the reduced amount of Et3N, the
reaction mixture was treated and worked up as in entry 1 to afford 14
as a white solid (89%). Mp 59-60 °C; 1H NMR spectra are in
agreement with values reported previously.
Entry 6: A solution of 13 (1 mM, 1 equiv) and triethylamine (1
mM, 1 equiv) in 20 mL of CH2Cl2 at 25 °C was stirred for 5-15 min.
An aliquot of the mixture was taken and analyzed by 1H NMR as above
to yield a broad and featureless spectrum.
Computational Methodology. All ab initio calculations were carried
out with the GAUSSIAN 9476 suite of programs. Geometries for the dialk-
oxy disulfides and their branch-bonded thionosulfites isomers 3-12 were
calculated based on an appropriately parametrized MM3* force field.25
Single-point energy calculations were obtained with the B3LYP func-
tional77 and the 6-31G(2d) Pople double ú (zeta) split valence basis set.78
Entry 4: The reaction mixture was treated and worked up as in
entry 2 to afford 15 a white solid (75%; 65-75% range for different
runs); Mp 73-74 °C; H NMR spectra are in agreement with values
1
reported previously.
Entry 5: The reaction mixture was allowed to stir for 2 h at 5 °C
(ice bath) and worked up as above. Solvent removal yielded a yellow
oil that proved to be an approximate 1:1 mixture of 14 and 15 according
Acknowledgment. We thank NSERC and FQRNT (formerly
FCAR) for funding. E.Z.-C. acknowledges support from FQRNT
in the form of graduate and postdoctoral fellowship scholarships.
N.N. and J.P.S. are grateful to Professor Dennis Liotta (Emory
University) for encouragement and support. We are also grateful
to Charles B. Abrams for preliminary work on the project and
to Dr. Andrzej Rys (McGill University) for assistance in
studying the interconversion of 14 and 15.
1
to H NMR (i.e., 40 and 45%, respectively, as monitored by the tri-t-
butybenzene internal standard); the spectra are in agreement with values
reported previously for both compounds.
(76) Frisch, M. J.; Trucks, G. W.; Sclegel, H. B.; Gill, P. M. W.; Johnson, B.
G.; Robb, M. A.; Cheeseman, J. R.; Keith, T.; Petersson, G. A.;
Montgomery, J. A.; Raghavachari, K.; Al-Laham, M. A.; Zakrzewski, V.
G.; Ortiz, J. V.; Foresman, J. B.; Cioslowski, J.; Stefanov, B. B.;
Nanayakkara, A.; Challacombe, M.; Peng, C. Y.; Ayala, P. Y.; Chen, W.;
Wong, M. W.; Andres, J. L.; Replogle, E. S.; Gomperts, R.; Martin, R. L.;
Fox, D. J.; Binkley, J. S.; Defrees, D. J.; Baker, J.; Stewart, J. P.; Head-
Gordon, M.; Gonzalez, C.; Pople, J. A. Gaussian 94; Gaussian Inc.:
Pittsburgh, PA, 1995; Vol. revision D.4.
(77) Becke, A. D. Int. J. Quantum Chem. 1994, S28, 625. Becke, A. D. J. Chem.
Phys. 1993, 98, 5648. Lee, C.; Yang, W.; Parr, R. G. Phys. ReV. B 1988,
37, 785. Miehlich, B.; Savin, A.; Stoll, H.; Preuss, H. Chem. Phys. Lett.
1989, 157, 200.
Supporting Information Available: DSC Spectra of 14-16.
IR Spectra of 14-16, including zoomed spectra highlighting
the region < 1500 cm-1. A composite IR plot of isomers 14
and 15 is provided to aid in the comparison of the spectra.
1
Raman spectra for 14 and 15. Crystal structures of 14-17. H
(78) Ditchfield, R.; Hehre, W. J.; Pople, J. A. J. Chem. Phys. 1971, 54, 724.
Hehre, W. J.; Ditchfield, R.; Pople, J. A. J. Chem. Phys. 1972, 56, 2257.
Hariharan, P. C.; Pople, J. A. Mol. Phys. 1974, 27, 209. Gordon, M. S.
Chem. Phys. Lett. 1980, 76, 163. Hariharan, P. C.; Pople, J. A. Theo. Chim.
Acta 1973, 28, 213.
NMR of 30. This material is available free of charge via the
Internet at http://pubs.acs.org.
JA0559395
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