Oligomerisation reactions of beta substituted thiols in water

Article abstract of DOI:10.1039/c2ra22131d

Beta substituted thiols and various derivatives containing the HX-C-C-SH motif oligomerise in water, preferably in the presence of a carbonate salt. The reaction yields oligomers consisting of one thiol end group, a thiaethylene backbone and an additional terminal group corresponding to the starting material used. Mechanistic studies, as well as the scope of substrates and products of these new promising condensation processes, are presented. In addition, strong nucleophiles were also reacted with mercaptoethanol under simple reaction conditions, leading to the selective formation of more complex molecules.

Full text of DOI:10.1039/c2ra22131d

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Oligomerisation reactions of beta substituted thiols in
water3
Cite this: RSC Advances, 2013, 3, 1735
Efrat Levin,{a Aviel Anaby,{a Charles E. Diesendruck,a Dvora Berkovich-Berger,a
Received 11th September 2012,
Accepted 10th December 2012
Benzion Fuchsb and N. Gabriel Lemcoff*a
DOI: 10.1039/c2ra22131d
www.rsc.org/advances
Beta substituted thiols and various derivatives containing the HX–
C–C–SH motif oligomerise in water, preferably in the presence of a
carbonate salt. The reaction yields oligomers consisting of one
thiol end group, a thiaethylene backbone and an additional
terminal group corresponding to the starting material used.
Mechanistic studies, as well as the scope of substrates and
products of these new promising condensation processes, are
presented. In addition, strong nucleophiles were also reacted with
mercaptoethanol under simple reaction conditions, leading to the
selective formation of more complex molecules.
Scheme 1 Reaction of 1–3a in water.
catalysts, costly reagents, hazardous mustard by-products or
environmentally undesirable solvents in a one-step procedure.6
Synthetic methodologies for the construction of organic molecules
by atom efficient procedures, devoid of environmentally harmful
catalysts and using pure water as the solvent, are scarce.1 The
formation of heteroatom–carbon bonds elicits a high interest in
modern organic synthesis, including the carbon–sulphur linkage
whose importance is well appreciated in the biological realm and
of course in many synthetic chemical systems, i.e. compounds
formed by the ubiquitous thiol-ene "click" reactions,2 macro-
molecular architectures,3 macrocycles and supramolecular hosts,4
etc. Thus, the development of a green, facile and direct synthetic
route towards carbon–sulphur bond formation presents great
appeal.
In a recent report we disclosed the unexpected polycondensa-
tion of 1,2-ethanedithiol (1a), both in water and organic solvents,
selectively yielding short oligomers.5 Now, we present new
reactions based on other 1,2-heterothiol derivatives, namely
mercaptoethanol (2a) and cysteamine (3a) (Scheme 1), and expand
their scope for the generation of multiple carbon–sulphur bonds.
Explicitly, heating these substrates in water under mildly basic
conditions resulted in oligomerisation, without the need for metal
Thus, reaction of 2a readily afforded
v-mercaptopolythiaethylene-1-ol oligomers with one hydroxyl
and one thiol end group (Fig. 1).
a series of linear
The reactions were mainly conducted in a microwave reactor;
conventional heating gave similar results although longer reaction
times were needed. Notably, the optimal solvent for the reaction
was water. Reactions carried out neat or in ethylene glycol gave
good yields of oligomers (similar to water), however, other organic
solvents proved less efficient. The overall reaction observed was a
substitution of the hydroxyl terminal by a thiolate nucleophile,
with the only by-product generated being water. Remarkably, this
simple reaction has not been reported in the chemical literature;7
despite the fact that mercaptoethanol is a widely used molecule,
aChemistry Departments, Ben-Gurion University of the Negev, Beer-Sheva, 84105,
Israel. E-mail: lemcoff@bgu.ac.il; Fax: (+972) 8647-1740; Tel: (+972) 8646-1196
bTel-Aviv University, Tel-Aviv, 69978, Israel
Electronic Supplementary Information (ESI) available: NMR spectra of 2b–d, 3b–c,
3
2a–d2 and isotope labeling experiments. Additional reaction results of: 2a and 3a in
different solvents, 2a with different additives, other dithiols and mercaptoalkanols
and cross reactions with nucleophiles. See DOI: 10.1039/c2ra22131d
{ These authors contributed equally to this work.
Fig. 1 GC-MS of the organic extract (CH2Cl2) after the reaction of 0.4 M 2a and 1.2
M K2CO3 in water, 60 min, 120 uC in a microwave reactor.
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Table 1 Conversion of 2a to oligomers with various additivesa
Conversionb
Entry
Reagent
2a
2b
2c
2d
2e
1
2
3
4
5
6
7
8
9
No reagent
K2CO3
10%
14%
15%
1%
10%
70%
63%
64%
11%
16%
7%
53%
40%
41%
38%
42%
30%
37%
10%
58%
43%
35%
36%
35%
34%
51%
40%
—
—
—
31%
30%
37%
1%
10%
9%
10%
8%
—
—
—
—
11%
21%
—
1%
1%
—
—
—
—
—
—
—
—
Cs2CO3c
Fig. 2 Additional mercaptan substrates.
Na2SO3
NaHCO3
NaOHd
Triethylamine
Acetic acide
KNO3
investigated (Fig. 2). Thus, diastereomeric mixtures of 2,3-
mercaptobutanol and 2,3-butanedithiol (4o and 4s respectively)
were subjected to the same reaction conditions. These substituted
homologues reacted to give oligomeric products similar to the
basic parent molecules. Interestingly, the reaction with 4s also
afforded significant amounts of hydroxyl terminated products.
An additional parameter that was looked into was the number
of methylene units between the sulphur atom and the additional
heteroatom. Accordingly, 1,3-mercaptopropanol and 1,3-propane-
dithiol (5o and 5s) were also heated in the presence of carbonate.
These substrates reacted only sluggishly in comparison to the
ethylene spaced counterparts, with very poor conversions to
dimers. Nonetheless, even with this longer spacer, the condensa-
tion could be still observed and constitutes a novel reaction. To
complete the series, 1,4-mercaptobutanol (6) did not react under
10
11
KIf+ K2CO3
BHTg+ K2CO3
a
Reactions were carried out in water, in a microwave reactor at 120
b
uC for 60 min, 0.4 M 2a and 3 eq. of chosen reagent. Area % by
GC-MS. 20 min reaction. pH = 13. pH = 2; 26% esterification.
eq. 0.1 eq.
c
d
e
f
1
g
known for more than 150 years, and the only requirement for
oligomerisation is heating in water.
To further analyse the reaction behaviour, the addition of
different bases, salts and radical scavengers was probed. As shown
in Table 1, the nature of the carbonate bases did not significantly
modify the oligomeric product distribution and even the reaction
in pure water (triply distilled) produced a fair amount of dimer 2b
and trimer 2c. The addition of neutral salts, sodium or potassium,
did not affect the outcome of the reactions. Moreover, sodium
sulphite was just as efficient as carbonate. However, the use of
strong bases, such as sodium hydroxide or weak organic bases,
like triethylamine, significantly hindered oligomerisation.
Acidification with acetic acid not only led to almost a complete
arrest of oligomerisation, but also to the partial formation of the
expected esters. The addition of butylhydroxytoluene (BHT),
introduced to examine whether radical intermediates could be at
play, also had no significant influence on the reaction.
all the conditions tried (see ESI ).
3
In an attempt to clarify the underlying mechanism of the
oligomerisation reactions, several experiments were performed on
the mercaptoethanol system. First, reactions starting from higher
oligomers were carried out to analyse possible equilibrium
processes. Thus, isolated oligomers 2b and 2c were each separately
reacted in water with a carbonate base. As observed in Table 2, the
oligomer product distributions starting from 2b, 2c or 2a (Table 1,
entry 2) are all similar. These results depict a system in a
thermodynamic equilibrium, where thioether formation is rever-
sible and the disproportionation of oligomers is apparent. This
discovery may create a new entry into the realm of dynamic
covalent combinatorial chemistry, and allow for selected templates
to guide product selectivity.10
One of the most attractive aspects of this part of the research is
the quite straightforward methodology developed to obtain
valuable oligomers possessing a thiol end group and an alcohol
end group. For this reason we performed a larger scale reaction
designed to provide useful quantities of the dimer and trimer
Table 2 Product distributions starting from 2b and 2c
compounds (2b and 2c). This preparative run (see ESI for details )
3
easily afforded 1.8 g of pure compound 2b and 1.0 g of pure
compound 2c by simple distillation under vacuum of the reaction
products after work-up and evaporation of the starting material 2a.
Having shown the reactivity of mercaptoethanol, it was
compelling to probe cysteamine (3a), a universally used b-nitrogen
sulphide. Oligomeric homologues of 3a could be potentially useful
in the preparation of lantibiotic homologues,8 chelating agents
and metal nanoparticle ligands.9 A clean reaction, yielding the
anticipated oligomers, was observed just by heating 3a in water
Starting from
Product distributiona
without the need to add a carbonate base (see ESI ). The leaving
3
2a
2b
27%
21%
2c
48%
43%
2d
25%
35%
2e
—
,1%
group in this case was ammonia, probably derived from the
protonated form of 3a.
2b
2c
,1%
1%
In order to expand the reaction scope and obtain further
insights into the mechanism in hand, other substrates were
a
Reactions were heated at 120 uC in a microwave reactor, in water
with 3 eq. K2CO3 for 60 min. Results in % area by GC-MS.
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affording thiirane (7) (Scheme 2b), which could be then opened by
a neighbouring thiolate to yield the thioether product. Thus, we
set out to disprove one of the mechanisms by means of isotopic
labeling.
2-Mercaptoethan-1,1-D2-ol (2a–d2) was synthesised by LiAlD4
reduction of ethyl-2-mercaptoacetate. ‘Scrambling’ of the deuter-
ium signal in the oligomers should be expected for an
intramolecular mechanism (due to the symmetry of 7), whereas
if the alternative mechanism is at play the deuterated methylene
should be confined to its original position. According to the 13C
NMR analysis shown in Fig. 3, statistical scrambling of the
deuterated methylene signals along the thioether chain was
obtained after 2a–d2 was subjected to the typical reaction
conditions, supporting a thiirane intermediate.
Scheme 2 Suggested condensation mechanisms. a. Hydrogen bond activated
substitution. b. Intramolecular thiirane 7 formation.
While the self-condensation products obtained by this reaction
are important per se, the expansion of this method to form
additional products would be of great interest. Given that the
reactions presented proceed by the attack of a nucleophilic
thiolate, reactions of 1a, 2a–c and 3a with other nucleophiles were
investigated (Table 3 and ESI ). Thus, while phenol or ethylene
3
glycol (even as a solvent) did not react at all, the addition of strong
sulphur nucleophiles such as thiophenol or benzyl mercaptan
resulted in the formation of a new sulphur–carbon bond. By
observing the products of the cross-reaction with the alternative
nucleophile, a noticeable selectivity towards the incorporation of a
single 2-mercaptoethyl unit was observed, consistent with the
thiirane intermediate mechanism.
Finally, aniline addition to 2a also afforded the predicted cross-
product, resulting from the creation of a new nitrogen–carbon
bond. The full results of all cross-reactions conducted are
Fig. 3 13C NMR spectrum of the reaction of 2a–d2 in water. Only 2b–d4 signals are
labeled (smaller peaks belong to 2c–d6).
At this point, we envisaged two plausible mechanisms that
could govern the oligomerisation reaction. One may be a
straightforward intermolecular substitution, with a thiolate anion
as the nucleophile and a hydroxide as the leaving group
(Scheme 2a). Hydrogen bonding in 2a has been extensively
explored in polar and non-polar solvents.11 It was thus reasonable
to assume an activated conformation of b-substituted alkylthiols,
in which the thiol group plays the role of the hydrogen bond
donor, enhancing the b-carbon electrophilicity. An alternative
mechanistic pathway may result from an intramolecular reaction
described in the ESI.
3
Challenging the common knowledge that –SR and especially –
OR are considered very poor leaving groups, we present
substitutions of these functional groups promoted by the presence
of a b-sulphide. Mercaptoethanol and cysteamine generate new
carbon–heteroatom bonds either on their own or in the presence
Table 3 Cross reactions of various nucleophiles with 2aa
Nucleophile
Thiol
Mono- substituted
Di- substituted
Self oligomerisation
2b
2c
2d
Thiophenol 8
Benzylmercaptan 9
Aniline 10
2a
2a
2a
28%
65%
69%
2%
—
—
40%
35%
31%
15%
—
—
15%
—
—
a
Reactions were heated at 120 uC in a microwave reactor, in water with 3 eq. K2CO3 for 60 min. Results in % area by GC-MS.
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thiirane intermediate. Most significantly, no use is made of
expensive or toxic metal catalysts, there is no need for hazardous
vesicant reagents, and the reaction can be conducted in pure
water. Taking into account the undemanding conditions
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