Radical Substitution Provides a Unique Route to Disulfides

Article abstract of DOI:10.1021/jacs.0c03626

Radical substitution on tetrasulfides is demonstrated to be a highly effective means to prepare unsymmetric disulfides. Alkyl and aryl radicals generated thermally or photochemically underwent substitution on readily prepared dialkyl, diaryl, and diacyl tetrasulfides to yield the corresponding disulfides in good to excellent yields. Classic and contemporary thermal and photochemical radical sources could be employed; while photoredox catalysis approaches led to either oxidation or reduction of the tetrasulfide, energy transfer photocatalysis was particularly useful. The success of the approach is driven by the thermodynamic stability of the perthiyl radicals formed upon substitution on the tetrasulfide; they simply combine under the reaction conditions to provide the starting tetrasulfide. Competition kinetic experiments reveal that alkyl radical substitution on tetrasulfides is a rapid reaction (6 × 105 M-1 s-1) that is enhanced at least 6-fold upon moving from dialkyl tetrasulfide to diacyl tetrasulfide due to favorable polar effects. This unique and versatile reaction enables introduction of disulfide moieties from a variety of radical precursors and straightforward access to hydropersulfides.

Full text of DOI:10.1021/jacs.0c03626

Subscriber access provided by UNIV OF WESTERN ONTARIO
Communication
Radical Substitution Provides a Unique Route to Disulfides
Zijun Wu, and Derek A. Pratt
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 19 May 2020
Downloaded from pubs.acs.org on May 19, 2020
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 8
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
Radical Substitution Provides a Unique Route to Unsymmetric
Disulfides
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Zijun Wu and Derek A. Pratt*
Department of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa, ON K1N 6N5, Canada
ABSTRACT: Radical substitution on tetrasulfides (RSSSSR) is demonstrated to be a highly effective means to prepare unsymmetric
disulfides (RSSR’). Alkyl (primary, secondary and tertiary) and aryl radicals generated thermally or photochemically underwent
substitution on readily accessible dialkyl, diaryl and diacyl tetrasulfides to yield the corresponding disulfides in good to excellent yields.
Classic and contemporary thermal and photochemical radical sources could be employed; while photoredox catalysis approaches lead
to either oxidation or reduction of the tetrasulfide, energy transfer photocatalysis was particularly useful. The success of the approach is
driven by the thermodynamic stability of the perthiyl radicals (RSS•) formed upon substitution on the tetrasulfide; they simply combine
under the reaction conditions to provide the starting tetrasulfide. Competition kinetic experiments reveal that alkyl radical substitution
on tetrasulfides is a rapid reaction (k ~ 6 ´ 105 M-1s-1) that improves at least 6-fold upon moving from dialkyltetrasulfide to
diacyltetrasulfide due to favourable polar effects. This unique and versatile reaction enables introduction of disulfide (or thiol, upon
reduction of the disulfide) moieties from a variety of radical precursors and straightforward access to difficult-to-access hydropersulfides
(R’SSH).
The disulfide unit is a ubiquitous motif in biology, where it serves
as both a key determinant of protein tertiary structure and as a
uniquely reactive moiety involved in the regulation of diverse
biochemical processes.1 In addition to proteinogenic disulfides,
many biologically active natural products and medicinal agents
contain disulfide moieties2,3 (Figure 1), whose activities often
depend on the same disulfide exchange reactions which are
common to proteins. Exchange reactions also serve as the basis
for many bioconjugative approaches, where disulfide linkages are
commonly utilized to attach chemical probes, imaging agents or
therapeutics to biomolecules.4 Although disulfide exchange is
the most common means for the targeted introduction of
disulfide bonds, it may require enzyme catalysis to be kinetically
competent and/or overcome an inherent (undesired)
equilibrium or may be limited to electron-poor disulfides
reacting with nucleophilic thiol(ate)s.5 In fact, the variety of
methods available for reliable disulfide bond construction
beyond disulfide exchange remains relatively limited,6 despite
their prominence in bioconjugation and drug delivery and their
potential in other contexts, such as dynamic covalent chemistry7.
electrophilic disulfurating reagents (Figure 2B). While enabling,
these strategies are not without drawbacks, as they remain largely
limited to the formation of aryl-substituted disulfides and often
require multiple steps to prepare the disulfurating reagents.
Figure 1. Some representative disulfides and applications.
With the foregoing in mind, we sought to develop a simple,
conceptually different approach to unsymmetric disulfides
utilizing radical substitution chemistry (Figure 2C).13 These
efforts were based on our recent observation that tetrasulfides
undergo efficient substitution by peroxyl radicals (k = 2´105 M-1
s-1 at 100°C),14a liberating thermodynamically stable perthiyl
radicals (RSS•) that combine at near diffusion-controlled rates (k
= 6 ´ 109 M-1s1 at 25°C) to yield the starting tetrasulfide.14b We
surmised that this radical substitution would be more facile when
nucleophilic alkyl radicals reacted in place of electrophilic
peroxyl radicals,15 and thus that this had the potential to serve as
the basis of a versatile approach for the preparation of
unsymmetric disulfides.
The formation of disulfides generally involves the activation
of one of two thiol precursors (often by oxidation), followed by
substitution or metal-catalyzed cross-coupling with the other8
(Figure 2A). These S-S bond forming approaches are often
hampered by largely unavoidable homocoupling reactions, poor
functional group tolerance and side reactions (often
overoxidation) of the activated derivatives. In an attempt to
address these issues, recent efforts in the area have focused on
the development of pre-functionalized/activated disulfurating
reagents (RSS−LG) to introduce “RSS” moieties via C-S bond
formation.9-12 Xian,9 Jiang,10 Xu11 and Wang12 have each
independently disclosed metal-catalysed cross-coupling or
nucleophilic substitution approaches with either nucleophilic or
ACS Paragon Plus Environment

Journal of the American Chemical Society
provided good to excellent yields of the corresponding disulfide
Page 2 of 8
products (8-21).19 It is noteworthy that this reaction could also
be carried out in water, as exemplified for 8.20 Furthermore,
toward the end of our investigations we found that the 1 mol%
[Ir(dF(CF3)ppy)2(dtbbpy)]PF6 could be exchanged with 10 mol%
of thioxanthone, therefore offering a metal-free visible light-
mediated alternative.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 2. Strategies for unsymmetric disulfide construction.
As a proof of principle, we combined tert-butyl tetrasulfide (1,
prepared from t-BuSH and S2Cl2 in quantitative yield14,16) and
the radical initiator AIBN (2) (1:3) in deoxygenated THF and
stirred them together at reflux for 12 hours, after which the
expected disulfide 3 was isolated in 85% yield. Likewise,
combining 1 and the radical initiator lauroyl peroxide (4) (1:2)
in trifluorotoluene at 80°C for 12 hours gave 5 in 94% yield
(Figure 3).
Me Me
AIBN (2)
S
tBu
S
CN
THF, N2, 90 °C
Figure 4. Reaction scope with various tetrasulfides (isolated
yields given). Conditions: tetrasulfide (0.1 mmol), PTOC ester
(6, 0.25 mmol) or acyl oxime (7, 0.25 mmol), solvent (0.1 M).
3, 85%
S
S
tBu
tBu
S
S
AMethod
A.
BMethod
B,
photocatalyst
=
1
nC11H23
lauroyl peroxide (4)
CF3C6H5, N2, 80 °C
S
tBu
S
([Ir(dF(CF3)ppy)2(dtbbpy)]PF6, 0.001 mmol). Omission of catalyst
or lack of irradiation precluded any conversion whatsoever.
CThioxanthone (10 mol%) was used as the photocatalyst.
DWater/EtOAc (1:1 v/v) was used as the solvent, with 5 mol%
photocatalyst. EReaction was carried out with 4.5 mmol tert-butyl
tetrasulfide and 11.25 mmol 1-adamantyl oxime ester.
5, 94%
Figure 3. Radical substitution by azo and peroxide initiator-
derived radicals on di-tert-butyl tetrasulfide. Conditions:
tetrasulfide 1 (0.1 mmol) and AIBN (2, 0.3 mmol) or lauroyl
peroxide (4, 0.2 mmol), in THF or CF3C6H5 (0.1 M), for 12
hours. Isolated yields are indicated.
To provide further insight on the scope of the radical
(precursor) that could be used in this transformation, we
prepared a variety of Glorius esters and subjected them to these
conditions. The results are summarized in Figure 5. Primary,
secondary and tertiary radicals afforded good yields. Precursors
bearing alkenes, alkynes and aryl rings containing allylic (the
allylic disulfide unit exists as a core structure in the natural
product disulfides allicin21 and ajoene3c-e), propargylic and
benzylic positions were all tolerated, as were halogens, ethers,
ketones, and various carbocycles and heterocycles (22-32).
Substrates that could undergo competing radical rearrangements
were also competent substrates, leading to mixtures of products
consistent with the kinetics of alkyl radical substitution on the
tetrasulfide (vide infra). The relative insensitivity of the reaction
to steric effects is clear from the ability to form di-tert-alkyl
Encouraged by these results, we carried out some preliminary
investigations of substrate scope using both classic and
contemporary photochemical methods to generate alkyl radicals
from carboxylic acids.17 The classic method utilized Barton
‘PTOC’ (N-hydroxypyridine-2(1H)-thione) esters 6 and UVA
light (Method A), while the contemporary approach utilized
Glorius’ acyl oxime esters 7,18 [Ir(dF(CF3)ppy)2(dtbbpy)]PF6 as
energy transfer photocatalyst and blue LED irradiation (Method
B). Barton and Glorius esters were prepared from the carboxylic
acids of cyclohexane and 1-adamantane and, following a coarse
solvent screen (see Supporting Information) that lead to the
selection of THF for Method A and EtOAc for Method B, were
reacted with a series of tetrasulfides. Results are collected in
Figure 4. Gratifyingly, each of primary, secondary and tertiary
tetrasulfides (n-hexyl, i-butyl, i-propyl, t-butyl, t-dodecyl), as well
as aryl (phenyl, 3-methoxyphenyl) and benzyl tetrasulfides
2
ACS Paragon Plus Environment

Page 3 of 8
Journal of the American Chemical Society
disulfides (33 and 34); and even highly sterically hindered
36).23 Nevertheless, since aryl tetrasulfides are good substrates
(14, 15 and 21 in Figure 4), aryl/alkyl disulfides remain accessible
using this approach. To further showcase the utility of the
transformation we prepared a diverse collection of oxime esters
of carboxylic acid-containing natural products and subjected
them to the optimized reaction conditions (Figure 5B). Amino
acids (proline, 40; aspartic and glutamic acids, 41 and 42),
saturated and unsaturated fatty acids (palmitic and oleic acids,
39 and 37) and sterol derivatives (lithocolic acid, 43) could all be
converted to corresponding unsymmetric disulfides in good
yields. The diminished yield for pinnonic acid derivative 38 was
ascribed in part to competing ring-opening of the intermediate
radical, but other unidentifiable byproducts were also formed.
1
2
3
4
5
6
7
8
moieties (i.e. 9-triptycenyl, 35) could be accommodated, albeit
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Disulfides have been shown to be substrates for energy
transfer from [Ir(dF(CF3)ppy)2(dtbbpy)]PF6 under similar
reaction conditions, leading to thiyl radicals used in a so-called
disulfide-ene reactions.24 We found no evidence for this
transformation in examples where the disulfide products (and
radical precursors) contain alkenes (24, 29, 37), presumably
because the known energy transfer to the oxime ester is more
efficient. Moreover, it seems reasonable to suggest that the
tetrasulfide is a good substrate for energy transfer, particularly
because its S-S bond is ca. 30 kcal/mol weaker than the S-S bond
in a disulfide (BDE = 36.3 kcal/mol).14b Indeed, when a 1:1
mixture of di-tert-butyl tetrasulfide 1 and dicumyl tetrasulfide 44
was subjected to blue LED irradiation in the presence of the Ir
photocatalyst, a statistical (1:2:1) mixture of homocoupled and
heterocoupled tetrasulfides was observed within ~1 hour (Figure
6A).25 However, the lack of reactivity of the perthiyl radical to
essentially everything except itself (k = 6´109 M-1s-1)14b ensures
that this off-cycle reaction is not problematic.
The success of the preparative transformations also rely on
efficient kinetics for the radical substitution. To provide further
insight to this point, we carried out radical clock experiments
using the venerable 5-hexenyl radical cyclization as the calibrated
unimolecular rearrangement (kcyc = 2´105 s-1).26 The optimized
procedure was carried out in the presence of varying
dicumyltetrasulfide 44 and the ratio of the two disulfide products
formed from substitution by either the unrearranged 5-hexenyl
radical or rearranged cyclopentylcarbinyl radical were
1
determined by H NMR spectroscopy (Figure 6B, 47 and 48).
Plotting the product ratio as a function of tetrasulfide
concentration yielded a very good linear correlation (R2 = 0.993)
with a slope from which the substitution rate constant of ksub
=
5.8´105 M-1s-1 could be derived (Figure 6B). Enabled by the
knowledge of these kinetics, it is expected that this reaction can
be reliably incorporated into multi-component and/or radical
cascade reactions. For example, since alkyl radicals add to
activated alkenes with rate constants of ca. 106 M-1s-1,27 the vicinal
alkene difunctionalization shown in Figure 6C could be carried
out to afford the 1,2-carbodisulfuration product 50.33
Figure 5. Further exploration of reaction scope (isolated yields
given). Conditions: tetrasulfide (0.1 mmol), acyl oxime (7, 0.25
mmol), photocatalyst = ([Ir(dF(CF3)ppy)2(dtbbpy)]PF6 (0.001
mmol), EtOAc (0.1 M). AFrom O-hept-6-enoyl oxime ester. BFrom
reaction of 1-(tert-butyl)-4-(9-tritpycenyl) tetrasulfide and O-
The foregoing demonstrates that, as we originally expected,
the tetrasulfides appear to be significantly more reactive to
substitution by alkyl radicals than peroxyl radicals (the latter
being determined only at 100°C).14a To enable direct
comparison, CBS-QB328 calculations were carried out to identify
the transition state structures and energetics for both processes
(Figure 6D), revealing DG‡ = 11.6 kcal/mol for the reaction of a
model alkyl (ethyl) radical with t-BuSSSSt-Bu compared to 19.9
kcal/mol14a for a model peroxyl (methylperoxyl) radical at 298 K).
C
pivaloyl oxime ester. 5 Equivalents of di-tert-butyl-tetrasulfide
was used.
with diminished yields.22 Expectedly, the high reactivity of aryl
radicals made decarboxylation-disulfuration
a
challenge.
Increasing the loading of tetrasulfide from 0.4 to 5 equivalents
afforded the desired aryl disulfide, but in poor yield (e.g. 17% for
3
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 8
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 6. Some insightful mechanistic studies. A. Crossover experiment demonstrates the fully reversible cleavage of the central S-S
bond in tetrasulfide under the reaction conditions. B. Radical clock experiment provides ksub = 5.8´105 M-1s-1 for the reaction of a
primary alkyl radical on a tetrasulfide. C. Example of a multi-component 1,2-carbodisulfuration reaction with tetrasulfide. D. CBS-
QB3 minimum energy transition state structures, free energies of activation and reaction free energies for the substitution of a model
alkyl (ethyl) radical on di-tert-butyl and diacetyl tetrasulfides. E. Competition experiment at low conversion (13%) indicates more
rapid substitution on diacyltetrasulfides over dialkyltetrasulfides. F. Preparation of 1-adamantylhydropersulfide. Photocatalyst =
[Ir(dF(CF3)ppy)2(dtbbpy)]PF6. aRatio of 5 to 53 was determined by crude 1H NMR (see Supporting Information for details).
This difference in barrier heights is mirrored by the much greater
driving force for the reaction of the tetrasulfide with ethyl radical
(DG° = -21.0 kcal/mol) compared to methylperoxyl radical (DG°
= -0.4 kcal/mol14a) at 298 K.
diacyltetrasulfides are as easily prepared as dialkylpersulfides
(BzSH/AcSH + S2Cl2)29 we have found that substitutions upon
them generally proceed with lower yields. For example, the
preparative reaction of BzSSSSBz with lauroyl peroxide yielded
the corresponding acylpersulfide 53 in only 63% yield, compared
to 94% yield of disulfide 5 when t-BuSSSSt-Bu reacts with lauroyl
peroxide under the same conditions (see Supporting
Information for additional examples with AcSSSSAc and also
BzSSSSBz).30 The lower yields arise due to the greater lability of
the diacyltetrasulfides under heating or irradiation,31 where the
dialkyltetrasulfides are entirely stable.
Surmising that the increased reactivity of the tetrasulfides to
substitution by alkyl radicals relative to peroxyl radicals was also
due to more favourable polarization of the transition state, we
wondered if diacyl tetrasulfides would be even better reagents.
Indeed, CBS-QB3 calculations suggest a lower barrier (DG‡ =
10.1 kcal/mol) for the reaction of AcSSSSAc with ethyl radicals
compared to t-BuSSSSt-Bu despite a significantly diminished
driving force (DG° = -12.6 kcal/mol) owing to its stronger
central S-S bond (BDE = 44.8 kcal/mol in AcSSSSAc versus BDE
= 36.3 kcal/mol in t-BuSSSSt-Bu14a) (Figure 6D). Consistent with
this prediction, when equivalent amounts of BzSSSSBz 52 and t-
BuSSSSt-Bu 1 were incubated with lauroyl peroxide 4 in
trifluorotoluene at 80°C, the product ratio (at 13% conversion)
favoured the benzoylpersulfide 53 over disulfide 5 by 6.4:1
(Figure 6E). It should be pointed out that although
Nevertheless, homolytic substitution on acyltetrasulfides is a
useful reaction as it provides easy access to acylpersulfides,
versatile intermediates and precursors to the difficult-to-access
hydropersulfide moiety (RSSH).32 For example, acetyl 1-
adamantylpersulfide 55, the precursor to one of the early
examples of a ‘stable’ hydropersulfide 56,32a could be easily
prepared in 48% yield (38% overall yield including the trivial
preparation of the precursor Glorius ester 54 and
diacetyltetrasulfide 51) (Figure 6F). The literature precedent to
4
ACS Paragon Plus Environment

Page 5 of 8
Journal of the American Chemical Society
Saunders, R.; Evans, G. J. S.; Graz, M.; Wirth, T. Short total synthesis
55 was achieved in 19% yield from 3 steps – most importantly
the non-trivial two-step synthesis of acetyl sulfenyl chloride.32
of ajoene. Angew. Chem. Int. Ed. 2018, 57, 12290–12293. (d) Block,
E.; Ahmad, S.; Jain, M. K.; Crecely, R. W.; Apitz-Castro, R.; Cruz,
M. R. The chemistry of alkyl thiosulfate esters. 8. (E,Z)-Ajoene: a
potent antithrombotic agent from garlic. J. Am. Chem. Soc. 1984, 106,
8295–8296. (e) Block, E.; Ahmad, S.; Catalfamo, J. L.; Jain, M. K.;
Apitz-Castro, R. The chemistry of alkyl thiosulfinate esters. 9.
Antithrombotic organosulfur compounds from garlic: structural,
mechanistic, and synthetic studies. J. Am. Chem. Soc. 1986, 108,
7045–7055. (f) Li, B.; Wever, W. J.; Walsh, C. T.; Bowers, A. A.
Dithiolopyrrolones: biosynthesis, synthesis, and activity of a unique
class of disulfide-containing antibiotics. Nat. Prod. Rep. 2014, 31,
905–923. (g) Chan, A. N.; Shiver, L. S.; Wever, W. J.; Razvi, S. Z.
A.; Traxler, M. F.; Li, B. Role for dithiolopyrrolones in disrupting
bacterial metal homeostasis. Proc. Natl. Acad. Sci. USA 2017, 10,
2717–2722.
(a) Geven, M.; Luo, H.; Koo, D.; Panambur, G.; Donno, R.; Gennari,
A.; Marotta, R.; Grimaldi, B.; Tirelli, N. Disulfide-Mediated
Bioconjugation: Disulfide Formation and Restructuring on the
Surface of Nanomanufactured (Microfluidics) Nanoparticles. ACS
Appl. Mater. Interfaces, 2019, 11, 26607−26618. (b) Ojima, I. Guided
Molecular Missiles for Tumor-Targeting Chemotherapy-Case Studies
Using the Second-Generation Taxoids as Warheads. Acc. Chem. Res.
2008, 41, 108−119. (c) Hogg, P. J. Targeting Allosteric Disulphide
Bonds in Cancer. Nat. Rev. Cancer 2013, 13, 425−431. (d) Saito, G.;
Swansonb J. A.; Lee, K.-D. Drug delivery strategy utilizing
conjugation via reversible disulfide linkages: role and site of cellular
reducing activities. Adv. Drug Delivery Rev. 2003, 55, 199−215. (e)
Góngora-Benítez, M.; Tulla-Puche J.; Albericio F. Multifaceted Roles
of Disulfide Bonds. Peptides as Therapeutics. Chem. Rev. 2014, 114,
901−926. (f) Nicolaou, K. C.; Rigol, S. The Role of Organic Synthesis
in the Emergence and Development of Antibody–Drug Conjugates as
Targeted Cancer Therapies. Angew. Chem. Int. Ed. 2019, 58,
11206−11241.
(a) Lowther, W. T.; Brot, N.; Weissbach, H.; Honek, J. F.; Matthews,
B. W. Thiol-disulfide exchange is involved in the catalytic mechanism
of peptide methionine sulfoxide reductase. Proc. Natl. Acad. Sci. USA
2000, 97, 6463–6468. (b) Bach, R. D.; Dmitrenko, O.; Thorpe, C.
Mechanism of Thiolate−Disulfide Interchange Reactions in
Biochemistry. J. Org. Chem. 2008, 73, 12–21. (c) Nagy, P. Kinetics
and Mechanisms of Thiol–Disulfide Exchange Covering Direct
Substitution and Thiol Oxidation-Mediated Pathways. Antioxid Redox
Signal. 2013, 18, 1623–1641. (d) Putzu, M.; Gräter, F.; Elstnerae M.;
Kubař, T. On the mechanism of spontaneous thiol-disulfide exchange
in proteins. Phys. Chem. Chem. Phys. 2018, 20, 16222–16230.
For recent reviews: (a) Witt, D. Recent Developments in Disulfide
Bond Formation. Synthesis 2008, 16, 2491–2509. (b) Wang, M.;
Jiang, X. Sulfur-Sulfur Bond Construction. Top Curr. Chem. 2018,
376, 14.
1
2
3
4
5
6
7
8
In conclusion, we have demonstrated that trivially-prepared
tetrasulfides undergo efficient homolytic substitution by alkyl
radicals, enabling the synthesis of a broad range of unsymmetric
disulfides. We have illustrated this approach utilizing carboxylic
acid derivatives and energy transfer photocatalysis for the
generation of alkyl radicals, but in principle, any non-redox mode
of radical generation may be used. Given the ready availability of
carboxylic acids from feedstock chemicals as well as the trivial
preparation of tetrasulfides, we anticipate that this operationally
simple disulfuration protocol will find widespread application
for the preparation of synthetically and biologically important
perthio-containing molecules.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
4.
ASSOCIATED CONTENT
Supporting Information. Experimental procedures, compound
characterization and raw kinetic data. This material is available free
of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: dpratt@uottawa.ca
ORCID
Zijun Wu: 0000-0002-5030-071X
Derek A. Pratt: 0000-0002-7305-745X
5.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by grants from the Natural Sciences and
Engineering Research Council of Canada and the Canada
Foundation for Innovation.
6.
7.
REFERENCES
1.
(a) Narayan, M.; Welker, E.; Wedemeyer, W. J.; Scheraga, H. A.
Oxidative Folding of Proteins. Acc. Chem. Res. 2000, 33, 805−812.
(b) Hogg, P. J. Disulfide Bonds as Switches for Protein Function.
Trends Biochem. Sci. 2003, 28, 210−214. (c) Liu, T.; Wang, Y.; Luo,
X.; Li, J.; Reed, S. A.; Xiao, H.; Young, T. S.; Schultz. P. G.
Enhancing protein stability with extended disulfide bonds. Proc. Natl.
Acad. Sci. USA 2016, 113, 5910−5915. (d) Sevier, C. S.; Kaiser, C. A.
Formation and transfer of disulphide bonds in living cells. Nat. Rev.
Mol. Cell Biol. 2002, 3, 836–847. (e) Wommack, A. J.; Ziarek, J. J.;
Tomaras, J.; Chileveru, H. R.; Zhang, Y.; Wagner, G.; Nolan, E. M.
Discovery and characterization of a disulfide- locked C2-symmetric
defensin peptide. J. Am. Chem. Soc. 2014, 136, 13494–13497. (f)
Sulfur Chemistry; Jiang, X., Ed.; Springer: Berlin, 2019.
(a) Black, S. P.; Sanders, J. K. M.; Stefankiewicz, A. R. Disulfide
exchange: exposing supramolecular reactivity through dynamic
covalent chemistry. Chem. Soc. Rev. 2014, 43, 1861–1872. (b) Ulrich,
S. Growing Prospects of Dynamic Covalent Chemistry in Delivery
Applications. Acc. Chem. Res. 2019, 52, 510–519.
8.
(a) Barton, D. H. R.; Hesse, R. H.; O’Sullivan, A. C.; Pechet, M. M.
A New Procedure for the Conversion of Thiols into Reactive
Sulfenylating Agents. J. Org. Chem. 1991, 56, 6697−6702. (b)
Brzezinska, E.; Ternay, A. L. Disulfides. 1. Syntheses Using 2,2’-
Dithiobis(benzothiazole). J. Org. Chem. 1994, 59, 8239−8244. (c)
Arisawa, M.; Yamaguchi, M. Rhodium-Catalyzed Disulfide
Exchange Reaction. J. Am. Chem. Soc. 2003, 125, 6624−6625. (d)
Bao, M.; Shimizu, M. N-Trifluoroacetyl Arenesulfenamides,
Effective Precursors for Synthesis of Unsymmetrical Disulfides and
Sulfenamides. Tetrahedron 2003, 59, 9655−9659. (e) Hunter, R.;
Caira, M.; Stellenboom, N. Inexpensive, One-Pot Synthesis of
Unsymmetrical Disulfides Using 1-Chlorobenzotriazole. J. Org.
Chem. 2006, 71, 8268−8271. (f) Musiejuk, M.; Witt, D. Recent
Developments in the Synthesis of Unsymmetrical Disulfanes
(Disulfides). A Review. Org. Prep. Proced. Int. 2015, 47, 95−131. (g)
Xiao, X.; Feng, M.; Jiang, X. Transition-metal-free Persulfuration to
Construct Unsymmetrical Disulfides and Mechanistic Study of the
Sulfur Redox Process. Chem. Commun. 2015, 51, 4208−4211. (h)
Mai, S.; Song, Q. Divergent Synthesis of Disulfanes and
Benzenesulfonothioates Bearing 2-Aminofurans From N-
Tosylhydrazone-Bearing Thiocarbamates. Angew. Chem. Int. Ed.
2.
3.
For selected review, see: (a) Jiang, C.-S.; Müller, W. E. G.; Schröder,
H. C.; Guo, Y.-W. Disulfide- and Multisulfide-Containing
Metabolites from Marine Organisms. Chem. Rev. 2012, 112,
2179−2207. (b) Scott, K. A.; Njardarson, J. T. Analysis of US FDA-
Approved Drugs Containing Sulfur Atoms. Top. Curr. Chem. 2018,
376, 5–39. (c) Feng, M.; Tang, B.; Liang, S. H.; Jiang, X. Sulfur
Containing Scaffolds in Drugs: Synthesis and Application in
Medicinal Chemistry. Curr. Top. Med. Chem. 2016, 16, 1200−1216.
(a) Lindquist, N.; Fenical, W. Polycarpamines A-E, antifungal
disulfides from the marine ascidian polycarpa auzata. Tetrahedron
Lett. 1990, 31, 2389−2392. (b) Moura, F. A.; de Andrade, K. Q.; dos
Santos, J. C.; Goulart, M. O. Lipoic Acid: its antioxidant and anti-
inflammatory role and clinical applications. Curr Top Med Chem.
2015, 15, 458–483. (c) Silva, F.; Cabrera, S. S.; Williams, D. M.;
5
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 6 of 8
2017, 56, 7952−7957. (i) Taniguchi, N. Unsymmetrical Disulfide and
20. Since these solvents are not miscible, the reaction was also carried out
in water/acetonitrile (4:1 v/v). Despite poor solubility of the starting
materials, 66% of the desired product was nonetheless obtained.
21. (a) Cavallito, C. J.; Bailey, J. H. Allicin, the Antibacterial Principle of
Allium sativum. I. Isolation, Physical Properties and Antibacterial
Action. J. Am. Chem. Soc. 1944, 66, 11, 1950–1951. (b) Vaidya, V.;
Ingold, K. U.; Pratt, D. A. Garlic: source of the ultimate antioxidants-
-sulfenic acids. Angew. Chem., Int. Ed. 2009, 48, 157–160.
22. Lower yields were associated with triptycene formation. Anticipating
this was due to H-atom transfer to the highly reactive 9-triptycenyl
radical from solvent, we also carried out reactions in CF3C6H5. Still,
yields were lower, and undetermined products that contain triptycene
and fluorinated aryl rings were consistently obtained.
23. Increasing tetrasulfide concentration further (up to 30 equivalents)
lead to no significant increase. We speculate that higher
concentrations of tetrasulfide preclude efficient energy transfer to the
oxime ester.
24. Teders, M.; Henkel, C.; Anhäuser, L.; Strieth-Kalthoff, F.; Gómez-
Suárez, A.; Kleinmans, R.; Kahnt, A.; Rentmeister, A.; Guldi, D.;
Glorius, F. The energy-transfer-enabled biocompatible disulfide–ene
reaction. Nat Chem 2018, 10, 981−988.
Sulfenamide Synthesis via Reactions of Thiosulfonates with Thiols or
Amines. Tetrahedron 2017, 73, 2030−2035. (j) Qiu, X.; Yang, X.;
Zhang, Y.; Song, S.; Jiao, N. Efficient and Practical Synthesis of
Unsymmetrical Disulfides via Base-catalyzed Aerobic Oxidative
Dehydrogenative Coupling of Thiols. Org. Chem. Front. 2019, 6,
2220−2225. (k) Dethe, D. H.; Srivastava, A.; Dherange, A. D.;
Kumar, B. V. Unsymmetrical Disulfide Synthesis through Photoredox
Catalysis. Adv. Synth. Catal. 2018, 360, 3020– 3025. (J) Bizzini L. D.;
Zwick, P.; Mayor, M. Preparation of Unsymmetrical Disulfides from
Thioacetates and Thiosulfonates. Eur. J. Org. Chem. 2019, 41, 6956–
6960.
1
2
3
4
5
6
7
8
9
9.
Park, C.-M.; Johnson, B. A.; Duan, J.; Park, J.-J.; Day, J. J.; Gang, D.;
Qian, W.-J.; Xian, M. 9-Fluorenylmethyl (Fm) Disulfides:
Biomimetic Precursors for Persulfides. Org. Lett. 2016, 18, 904−907.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
10. (a) Xiao, X.; Feng, M.; Jiang, X. New Design of a Disulfurating
Reagent: Facile and Straightforward Pathway to Unsymmetrical
Disulfanes by Copper-Catalyzed Oxidative Cross-Coupling. Angew.
Chem. Int. Ed. 2016, 55, 14121−14125. (b) Dai, Z.; Xiao, X.; Jiang,
X. Nucleophilic Disulfurating Reagents for Unsymmetrical Disulfides
Construction via Copper-catalyzed Oxidative Cross Coupling.
Tetrahedron 2017, 73, 3702−3706. (c) Xiao, X.; Xue, J.; Jiang, X.
Polysulfurating Reagent Design for Unsymmetrical Polysulfide
Construction. Nat. Commun. 2018, 9, 2191−2200.
25. The photocatalyst significantly accelerates the exchange reaction; in
its absence, only 56% conversion was reached after 16 hour (see
Supporting Information for more details).
11. Wang, W.; Lin, Y.; Ma, Y.; Tung, C.-H.; Xu, Z. Cu-Catalyzed
Electrophilic Disulfur Transfer: Synthesis of Unsymmetrical
Disulfides. Org. Lett. 2018, 20, 3829−3832.
12. Zou, J.; Chen, J.; Shi, T.; Hou, Y.; Cao, F.; Wang, Y.; Wang, X.; Jia,
Z.; Zhao, Q.; Wang, Z. Phthalimide-Carried Disulfur Transfer to
Synthesize Unsymmetrical Disulfanes via Copper Catalysis. ACS
Catal. 2019, 9, 11426−11430.
13. (a) Barton D. H. R.; Castagnino, E.; Jaszberenyi, J. Cs. The Reaction
of Carbon Radicals with Sulfur. A Convenient Synthesis of Thiols
from Carboxylic Acids. Tetrahedron Lett. 1994, 35, 6057−6060. (b)
Crich, D. Organosulfur Chemistry: Synthetic Aspect. Academic:
London, 1995, 49−88.
14. (a) Chauvin, J.-P. R.; Griesser, M.; Pratt, D. A. The antioxidant
activity of polysulfides: it's radical. Chem. Sci. 2019, 10, 4999−5010.
(b) Chauvin, J.-P. R.; Haidasz, E. A.; Griesser, M.; Pratt, D. A.
Polysulfide-1-oxides react with peroxyl radicals as quickly as
hindered phenolic antioxidants and do so by a surprising concerted
homolytic substitution. Chem. Sci. 2016, 7, 6347−6356.
15. (a) Héberger K.; Lopata, A. Assessment of Nucleophilicity and
Electrophilicity of Radicals, and of Polar and Enthalpy Effects on
Radical Addition Reactions. J. Org. Chem. 1998, 63, 8646−8653. (b)
De Vleeschouwer, F.; Van Speybroeck, V.; Waroquier, M.; Geerlings,
P.; De Proft, F. Electrophilicity and Nucleophilicity Index for
Radicals. Org. Lett. 2007, 9, 2721−2724.
16. (a) Cerda, M. M.; Hammers, M.D.; Earp, M.S.; Zakharov, L.N.; Pluth,
M.D. Applications of Synthetic Organic Tetrasulfides as H2S Donors.
Org. Lett. 2017, 19, 2314-2317. (b) Derbesy, G.; Harpp, D. N. A
simple method to prepare unsymmetrical di- tri- and tetrasulfides.
Tetrahedron Lett. 1994, 35, 5381−5384.
26. Griller, D.; Ingold, K. U. Free-radical clocks. Acc. Chem. Res. 1980,
13, 9, 317–323.
27. Fischer H. Substituent Effects on Absolute Rate Constants and
Arrhenius Parameters for the Addition of tert-Butyl Radicals to
Alkenes. In Substituent Effects in Radical Chemistry. NATO ASI
Series (Mathematical and Physical Sciences), Viehe H.G., Janousek
Z., Merényi R. eds., Springer-Verlag: Dordrecht, 1986, 189. 123–142.
28. Montgomery, J. A., Jr; Frisch, M. J.; Ochterski, J. W.; Petersson, G.
A. A complete basis set model chemistry. VI. Use of density
functional geometries and frequencies. J. Chem. Phys. 1999, 110,
2822–2827. The calculations were carried out as implemented in the
Gaussian 16 (revision A.03) suite of programs.
29. Rao, M. V.; Reese, C. B.; Zhao, Z. Dibenzoyl tetrasulphide - A rapid
sulphur transfer agent in the synthesis of phosphorothioate analogues
of oligonucleotides. Tetrahedron Lett. 1992, 33, 4839–4842. The
product was extracted from the reaction mixture and used directly; no
purification was required.
30. Consistent with this observation, we found that the product ratio
observed in the competition reaction in Figure 5H, changes as a
function of reaction time / conversion, with 5:53 falling from 1:6.3 at
13% conversion to 1:4.6 and 1:3.6 at ~20% and complete conversion,
respectively.
31. We isolated thiol and
a mixture of other products. When
diacyltetrasulfide alone was irradiated or heated as under the reaction
conditions, we found that it easily decomposed to sulfur and a mixture
of polysulfides. On the other hand, the product acylpersuflides were
found to be stable under the reaction conditions.
32. (a) Bailey, T. S.; Pluth, M. D. Reactions of isolated persulfides
provide insights into the interplay between H2S and persulfide
reactivity. Free Radic. Biol. Med. 2015, 86, 662–667. (b) Bailey, T.
S.; Zakharov, L. N.; Pluth, M. D. Understanding Hydrogen Sulfide
Storage: Probing Conditions for Sulfide Release from Hydrodisulfide.
J. Am. Chem. Soc. 2014, 136, 10573−10576. (c) Chauvin, J.-P. R.;
Griesser, M.; Pratt, D. A. Hydropersulfides: H-Atom Transfer Agents
Par Excellence. J. Am. Chem. Soc. 2017, 139, 6484–6493.
33. The similarity in the rate constants for addition to acrylonitrile and
substitution on the tetrasulfide leads to competing formation of the
product arising from two successive additions two acrylonitrile dimer
followed by substitution on the tetrasulfide (25%). To suppress this,
the ratio of tetrasulfide to acrylonitrile can be increased (the example
uses 1:1 while the reaction stoichiometry requires only 0.5:1), but
doing so is anticipated to lead to competing formation of disulfide
with no incorporation of acrylonitrile.
17. Direct use of carboxylic acids in a non-photochemical approach to
generate alkyl radicals as in Hunsdiecker-type reactions failed due to
oxidation of the tetrasulfide.
18. (a) Patra, T.; Mukherjee, S.; Ma, J.; Strieth-Kalthoff, F.; Glorius, F.
Visible-Light-Photosensitized Aryl and Alkyl Decarboxylative
Functionalization Reactions. Angew. Chem. Int. Ed. 2019, 58,
10514−10520. (b) Soni, V. K.; Lee, S.; Kang, J.; Moon, Y. K.; Hwang,
H. S.; You, Y.; Cho, E. J. Reactivity Tuning for Radical−Radical
Cross-Coupling via Selective Photocatalytic Energy Transfer: Access
to Amine Building Blocks. ACS Catal. 2019, 9, 10454−10463. (c)
Patra, T.; Bellotti, P.; Strieth-Kalthoff, F.; Glorius. F. Photosensitized
Intermolecular Carboimination of Alkenes through the Persistent
Radical Effect. Angew. Chem. Int. Ed. 2020, 59, 3172−3177.
19. The reaction was scalable, as demonstrated by the preparation of 17
on a 4.5 mmol scale, providing almost identical yield to that obtained
on the smaller scale.
6
ACS Paragon Plus Environment

Page 7 of 8
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ACS Paragon Plus Environment
7

Journal of the American Chemical Society
Page 8 of 8
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
84x39mm (300 x 300 DPI)
ACS Paragon Plus Environment