Preparation of Unsymmetrical Disulfides from Thioacetates and Thiosulfonates

Article abstract of DOI:10.1002/ejoc.201901283

A method for the transformation of organic thioacetates, a widely used functionality for the preparation of self-assembled monolayers on gold surfaces, into unsymmetrical disulfides is reported. Disulfides are readily immobilized on gold in contrast to thioacetates, which usually require a deprotection step prior to bonding to the metal surface. The potential of the method for the controlled preparation of unsymmetrical disulfides has been demonstrated with model compounds comprising several thioacetates, which were readily converted into the corresponding unsymmetrical disulfides.

Full text of DOI:10.1002/ejoc.201901283

A Journal of
Accepted Article
Title: Versatile Method for the Preparation of Unsymmetrical Disulfides
from Thioacetates and Thiosulfonates
Authors: Lorenzo Delarue Bizzini, Patrick Zwick, and Marcel Mayor
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10.1002/ejoc.201901283
European Journal of Organic Chemistry
FULL PAPER
Versatile Method for the Preparation of Unsymmetrical Disulfides
from Thioacetates and Thiosulfonates
Lorenzo Delarue Bizzini,[a] Patrick Zwick,[a] and Marcel Mayor*[a,b,c]
Abstract: A method for the transformation of organic thioacetates, a
widely used functionality for the preparation of self-assembled
monolayers on gold surfaces, into unsymmetrical disulfides is
reported. Disulfides are readily immobilized on gold in contrast to
thioacetates, which usually require a deprotection step prior to
bonding to the metal surface. The potential of the method for the
controlled preparation of unsymmetrical disulfides has been
demonstrated with model compounds comprising several
thioacetates, which were readily converted into the corresponding
unsymmetrical disulfides.
For molecules exposing several thiol anchor groups, like e.g.
functional rods bridging the electrodes of a single molecule
junction[9–12] or tripodal platforms controlling the spatial
arrangement of molecular architectures on surfaces,[13,14] the
disulfide strategy is still appealing, as the cleavage of the disulfide
bond on the noble metal sample renders the presence of
additional deprotection chemicals unnecessary. The approach
however requires the ability of forming unsymmetrical disulfides.
Ideally, the thiol anchor groups of the molecule of interest should
be engaged in the disulfide formation with a small alkylthiol,
guaranteeing the differentiation of both immobilized thiolates in
the experiment.
Introduction
Guided by this thought, we became interested in a general
method for the synthesis of unsymmetrical disulfides, which would
allow the preparation of discrete molecular species bearing
disulfides as sulfur anchor groups. Numerous functional model
compounds for single molecule junctions are available as acetyl
protected derivatives, but the required additional deprotection
reagents might interfere with the transport experiments. Thus
making those derivatives available as unsymmetrical disulfides
releasing the experiment form the presence of additional reagents
would increase its trustworthiness. Consequently, we focused our
efforts towards methods enabling the transformation of an acetyl-
protected thiophenol into an unsymmetrical 1-alkyl-2-aryl-
disulfane.
The thiol (sulfhydryl) group is one of the most prominent anchor
groups for the immobilization of organic molecules on noble metal
surfaces, mainly due to the balanced features of the resulting
metal sulfur bond. For example, the sulfur-gold bond is strong
enough to retain a molecule on the surface even under ultra-high
vacuum conditions, but weak enough to provide the mobility
required to enable self-assembly behaviors. The anchor group is
thus not only frequently used for the preparation of self-
assembled monolayers (SAMs),[1–4] but also for the immobilization
of functional structures in single molecule junctions.[5–7] In the
latter case, the molecule of interest bridges the gap between two
metal electrodes and thus exposes a thiolate anchor group at both
ends. The tendency of free thiols to form disulfides in the
presence of an oxidizing agent like oxygen makes their handling
challenging. While this is a minor issue in the case of molecules
with a single anchor group forming SAMs, it becomes a serious
handicap for structures exposing several thiol groups due to the
formation of insoluble polymers upon disulfide formation. The
strategies addressing this issue are either to make disulfides on
purpose, or to mask the thiol group e.g. by an acetyl group, which
is hydrolyzed prior to bond formation with the noble metal
surface.[2]
The synthesis of unsymmetrical disulfides has been
extensively investigated[15] whereby two general concepts have
been employed. (i) Generation of an electrophilic sulfenyl
derivative followed by reaction with a thiol or one of its
derivatives[16–24] or (ii) oxidative heterocoupling.[25–27] The concept
of an electrophilic reagent is appealing since it allows for a more
controlled reactivity without the inherent distribution of products
usually observed in oxidative heterocoupling, which relies on the
electronic difference between the thiols.
In order to convert thioacetates into unsymmetrical disulfides,
we investigated the suitability of thiosulfonates as a sulfenylating
agent, with the aim of applying this method to compounds bearing
multiple disulfide functionalities. Formation of unsymmetrical
disulfides from thioacetate and thiosulfonates was already
reported for the synthesis of 1,6-disulfide-bridged D-hexo-
The disulfide approach is particular advantageous for SAM
precursors, as the disulfide bond is cleaved electrochemically by
the reduction potential of the noble metal surface. Consequently,
a SAM formed from the corresponding homo-disulfide contains
exclusively the molecule of interest.[8]
pyranoses[28]
and
ajoene
analogues[29–31]
containing
unsymmetrical alkyl vinyl disulfides. However, these reported
synthetic methods require methanol as a solvent which limits its
application for larger polyaromatic structures of interest.
[a] L. Delarue Bizzini, P. Zwick, Prof. Dr. M. Mayor, Department of Chemistry,
University of Basel,
St. Johanns-Ring 19, 4056 Basel, Switzerland
E-mail: marcel.mayor@unibas.ch
In comparison to other electrophilic agents used to prepare
unsymmetrical disulfides such as N-sulfenamides,[21] sufenyl
chlorides[22] or dialkoxythioxaphosphorane disulfides,[23,24] thio-
sulfonates[32] are both, easily prepared in one step and highly
reactive towards thiolates. This is necessary in order to prevent
thiolysis of the formed product and therefore giving rise to
symmetrical disulfides as a side reaction.
http://www.chemie.unibas.ch/~mayor/index.html
[b] Prof. Dr. M. Mayor, Institute for Nanotechnology (INT), Karlsruhe Institute of
Technology (KIT),
P. O. Box 3640, 76021 Karlsruhe, Germany
[c] Prof. Dr. M. Mayor, Lehn Institute of Functional Materials (LIFM), School of
Chemistry,
Sun Yat-Sen University,
Guangzhou 510275, China
Supporting information for this article is given via a link at the end of the
document.
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10.1002/ejoc.201901283
European Journal of Organic Chemistry
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Results and Discussion
arise due to steric reasons, since after 3 h the corresponding
disulfide was still present in the reaction mixture. This stands in
contrast to the reaction of 4-aminothiophenol where complete
From literature precedence[28,29] we expected that the electrophile
conversion of the disulfide was observed after
1 h, yet
S-pentyl benzenethiosulfonate 1 (prepared from pentylthiol and
accompanied by oxidative side reactions resulting in a lower yield
of the thiosulfonate of 40%.
sodium benzene sulfinate using
a
modified literature
procedure[32]) and thioacetate 2 should form the unsymmetrical
disulfide 3 upon in situ formation of the thiolate of 2 (Scheme 1).
To our delight, addition of sodium methoxide (NaOMe, 5.4 M in
methanol) to a solution of thiosulfonate 1 and thioacetate 2 in
either THF or DMF at room temperature led to fast and clean
conversion to the desired unsymmetrical disulfide 3 whereby no
symmetric disulfide was monitored by GC-MS.
Table 1. One-pot sulfonylation of thiols.[a]
Entry
R1SH
t [h]
3
Yield [%][b]
1
2
3
4
5
6
7
8
9
10
1-AdamantylSH
4-MeOC6H4SH
CH3CH2(OCH2CH2)2SH
CF3(CF2)7CH2CH2SH
PentylSH
6
0.5
2
97
36
87
95
-
3[c]
0.5
3
(C6H5)3CSH
4-NO2C6H4SH
2-COOMeC6H4SH
3,5-F2C6H3SH
4-NH2C6H4SH
1
81
40
88
52
3
Scheme 1. Proof-of-concept reaction using 1 (1.10 eq.), 2 (1.00 eq.) and sodium
methoxide (1.20 eq.) in THF at room temperature.
0.5
1
To investigate the scope of the method a series of thiosulfonates
were prepared from their corresponding thiols, following the
modified literature protocol.[32] Using pyridine as a base allows
thiosulfonates to be prepared in one-pot fashion together with
sodium benzene sulfonate and iodine in dichloromethane (DCM)
(Table 1). Different alkyl- and aryl- benzene thiosulfonates were
prepared in good yields, but the limitations of the protocol became
obvious as soon as bulky thiols were considered.
[a] Reaction conditions: mixture of thiol (1.00 eq.), pyridine (1.05 eq.), iodine
(2.00 eq.) in dichloromethane with added sodium benzene sulfinate (1.7 eq.)
under ambient conditions. [b] Yield of isolated product after column
chromatography. [c] Reaction at 40°C.
With these thiosulfonates derivatives in hands, the previously
evaluated reaction conditions were used to synthesize
unsymmetrical disulfides using S-4-methylphenyl thioacetate as
model substrate (Table 2, entries 1-5). With the exception of S-(2-
(2-ethoxyethoxy)ethyl thiosulfonate (entry 3), all thiosulfonates of
this first series behaved as anticipated and the corresponding
unsymmetrical disulfides could be isolated in excellent yield (84-
89%) after purification by column chromatography. In the case of
S-(2-(2-ethoxyethoxy)ethyl thiosulfonate only the symmetrical
tolyldisulfide was obtained. To explore the scope of the reaction
sequence, hexyl thioacetate as an unactivated thioacetate (Table
2, entries 6-9) was exposed. And indeed, the reaction with
electron deficient 4-nitrophenyl benzenethiosulfonate (entry 6) at
room temperature provided the unsymmetrical disulfide in low
yield (33% isolated) and favored the formation of symmetrical
disulfides upon work up. Upon inverting the reacting groups
however (entry 10), the unsymmetrical product was isolated in
75% yield. It appears that 4-nitrophenyl benzenethiosulfonate
undergoes methanolysis competing with the unactivated hexyl
thioacetate leading to low formation of the unsymmetrical product.
Therefore the reaction (entry 6) was repeated at 0 °C and the
selectivity towards the unsymmetrical product increased
considerably with 67% isolated yield.
1-Adamanethiol (entry 1) showed low reactivity as after 3
hours, the desired S-adamantyl benzene thiosulfonate could be
isolated in only 6% yield after column chromatography.
Conducting the reaction in DCM at reflux for 3 hours yielded only
1-adamantyl iodide as a side product together with unreacted
intermediary symmetric disulfide. Further, S-pentyl-, S-4-
methoxyphenyl-, and S-1H,1H,2H,2H-perfluorodecyl benzene-
thiosulfonate (entries 2, 4 and 5) could be prepared in excellent
yield. Electronic effects appears to have a minor role in the
formation of thiosulfonates as both electron withdrawing (entries
7 and 8) and donating substituents (entry 2) could be isolated in
excellent yield. However, S-triphenylmethyl benzenethiosulfonate
(entry 6) could not be obtained using this method, as the only
isolatable product from this reaction was triphenylmethan-1-ol.
The transformation of 2-(2-ethoxyethoxy) ethane-1-thiol[33] to the
benzenethiosulfonate derivative (entry 3) provided only
a
moderate isolated yield of 36% after purification by column
chromatography. Similarly, methyl thiosalicylate and 4-amino
thiophenol (entries 8 and 10) could be transformed to the
corresponding thiosulfonates in moderate yield. In the case of
methyl thiosalicylate (entry 8) the moderate reactivity appears to
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To further investigate the functional group tolerance of the method
4-aminophenyl benzenethiosulfonate and hexyl thioacetate (entry
7) were reacted yielding the unsymmetrical product in moderate
yield of 57%. Another challenging issue of the method was
spotted upon reacting the methyl ester substituted phenyl
benzenethiosulfonate and hexyl thioacetate (entry 9). In this case
the symmetrical disulfides were formed as major product and the
unsymmetrical target compound could be isolated in only 15%
yield.
Scheme 2. Formation of methyl sulfonate by methanolysis of thiosulfonates.
As shown in entries 5, 10 and 11, the reported method shows only
low dependency on electronic effects of the substituents on the
thioacetate in the reaction with pentyl benzenethiolsulfonate.
The methanolysis of thiosulfonates seems to be the major
competing side reaction decomposing the starting material. To
investigate this hypothesis, 3,5 difluoro phenyl benzene thio-
sulfonate was treated with 1 equivalent of sodium methoxide in
THF at room temperature without any thioacetate present
(Scheme 2). And indeed, the quantitative formation of methyl 3,5-
difluoro sulfenate after 15 minutes was observed. Sulfenates are
known to hydrolyze under basic or neutral conditions giving rise
to symmetric disulfides.[34] This competing reaction path is more
pronounced with thiosulfonates bearing electron withdrawing
groups and thus rationalizes the observed lower yields in the
formation of unsymmetrical disulfides in entries 6 and 9.
While most of the isolated unsymmetrical disulfides were stable
under ambient conditions, an interesting intrinsic structural lability
of p-methoxyphenyl p-methylphenyl disulfide (Table 2, entryl 2)
was observed. The unsymmetric disulfide disproportionated
slowly to the symmetric disulfides not only dissolved, but also in
substance. The disproportionation reaction was followed by 1H-
NMR (CD2Cl2, 298 K, Figure 1) over the course of 280 h and is in
well agreement with previously measured first order
dependencies of unsymmetrical diaryl disulfides[35] The only
further example of an unstable unsymmetrical disulfide observed
in the series was p-methoxyphenyl pentyl disulfide (Table 2, entry
11) which equilibrates to an approximate 1:1 mixture of the
unsymmetrical and symmetrical disulfides after 4 h at room
temperature (see SI). We thus hypothesize that the electron rich
anisole-type aryl is responsible for the degradation of the
corresponding unsymmetrical disulfides.
Table 2. Sulfenylation reactions.[a]
Entry
1
R1
R2
Yield [%][b]
1-Adamantyl
4-MeOC6H4
CH3CH2(OCH2CH2)2
CF3(CF2)7CH2CH2
Pentyl
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
Hexyl
88
2
89
3
-
4
88
5
84
6
4-NO2Ph
33 (67)c
57
7
4-NH2Ph
Hexyl
8
3,5-F2C6H3
2-COOMeC6H4
Pentyl
Hexyl
81
Figure 1. Ratio of unsymmetrical p-methoxyphenyl p-methylpheny disulfide to
symmetrical p-methoxyphenyl disulfide.
9
Hexyl
15
10
11
4-NO2Ph
4-MeOC6H4
75
To investigate the potential of the method to decorate the
periphery of more complex molecules with unsymmetrical
disulfides, the protocol was applied to the three model compounds
4-6 (Scheme 3) exposing several thioacetates. These structures
were already investigated in the past either by mechanically
controlled break junction experiments analyzing their transport
behavior (compounds 4[36] and 5[7,37]), or in scanning tunneling
microscopy studies as self-assembled monolayer (compound
6[38]).
Pentyl
85
[a] Reaction conditions: Mixture of thioacetate (1.00 eq.), thiosulfonate
(1.10 eq.), sodium methoxide (1.20 eq.) in tetrahydrofuran under argon at room
temperature. [b] Yield of isolated product after column chromatography. [c]
Isolated yield after reaction at 0°C.
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Scheme 3. Example of relevant molecules bearing multiple asymmetric disulfides synthesized from the corresponding thioacetates and S-pentyl benzene
thiosulfonate using the here reported one-pot method. The displayed yields are the isolated amounts after column chromatography.
extracted with n-heptane (3x). The combined organic phase was dried over
anhydrous Na2SO4, filtered and the solvent was removed under reduced
pressure affording the crude product. The mixture was further purified by
column chromatography (SiO2, pentane/DCM 10:1 or pure pentane)
affording the asymmetric disulfide.
Indeed, the unsymmetrical disulfides of all the three compounds
could be isolated with yields varying from 25% in case of the four-
fold disulfide formation (compound 9 in Scheme 3), 62% and 78%
for the two-fold reaction (compounds 7 and 8, respectively).
Conclusions
Acknowledgments
In conclusion, we report a versatile and robust method to
synthesize unsymmetrical disulfides. The in situ deprotection of
thioacetates in presence of a variety of thiosulfonates gave after
15 to 30 minutes at room temperature unsymmetrical disulfides in
good yields, thus enabling the synthesis of compounds bearing
multiple unsymmetrical disulfide moieties. The preferential
formation of unsymmetrical disulfides and the polarity difference
of the starting material and the product facilitates the purification
by column chromatography, as the desired product is the first
eluting substance.
Generous financial support by the Swiss National Science Foundation
(SNF grant number 200020-178808) is gratefully acknowledged. M. M.
acknowledges support by the 111 project (90002-18011002). We would
like to thanks Michal Valášek for providing the tetrathioacetate 6 used in
this study.
Keywords: unsymmetrical disulfides • gold anchor group •
thiosulfonate • SAM • MCBJ
With this versatile and convenient synthetic access to
unsymmetrical disulfides we are currently investigating their
potential as anchor groups on noble metal substrates.
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Entry for the Table of Contents
COMMUNICATION
Unsymmetrical disulfides, gold
anchor group
Lorenzo Delarue Bizzini,[a] Patrick Zwick
and Marcel Mayor
A versatile method for the preparation of unsymmetrical disulfides from thiosulfonates
and thioacetates is described, together with a one-pot method for the preparation of
the required thiosulfonates. The strategy is compatible with a variety of thiosulfonate-
reagents (R2) and substrates (R1), including multifunctional ones.
Page No. – Page No.
Versatile Method for the Preparation
of Unsymmetrical Disulfides from
Thioacetates and Thiosulfonates
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