Dithioacetal Exchange: A New Reversible Reaction for Dynamic Combinatorial Chemistry

Article abstract of DOI:10.1002/chem.201600208

Reversibility of dithioacetal bond formation is reported under acidic mild conditions. Its utility for dynamic combinatorial chemistry was explored by combining it with orthogonal disulfide exchange. In such a setup, thiols are positioned at the intersection of both chemistries, constituting a connecting node between temporally separated networks. In reverse: Reversibility of dithioacetal bond formation is reported under acidic mild conditions (see figure). Its utility for dynamic combinatorial chemistry was explored by combining it with orthogonal disulfide exchange. In such a setup, thiols are positioned at the intersection of both chemistries, constituting a connecting node between temporally separated networks.

Full text of DOI:10.1002/chem.201600208

DOI: 10.1002/chem.201600208
Communication
&
Combinatorial Chemistry |Hot Paper|
Dithioacetal Exchange: A New Reversible Reaction for Dynamic
Combinatorial Chemistry
A. Gastón Orrillo,[a] Andrea M. Escalante,[a] and Ricardo L. E. Furlan*[a, b]
were reported for the reversible formation or exchange of di-
Abstract: Reversibility of dithioacetal bond formation is
thiano compounds from a thiol and a vinyl sulfide carbonyl or
reported under acidic mild conditions. Its utility for dy-
a b-dithiane carbonyl, respectively.[22]
namic combinatorial chemistry was explored by combin-
In this work, we describe the reversible formation and ex-
ing it with orthogonal disulfide exchange. In such a setup,
change of dithioacetals under acidic conditions. Additionally,
thiols are positioned at the intersection of both chemis-
to evaluate the utility of the dithioacetal exchange in DCC,
tries, constituting a connecting node between temporally
a double-level system was prepared by combining it with di-
separated networks.
sulfide exchange. Initially dithioacetal formation was investigat-
ed by HPLC in a chloroform solution containing 3,4,5-trime-
thoxybenzaldehyde A (3 mm), 2-phenylethanethiol 1 (6 mm),
Dynamic combinatorial chemistry (DCC) has emerged as a strat-
egy aimed at combining molecular diversity generation, self-
selection of host–guest pairs, and purification in one pot.[1]
Nowadays, applications of DCC range from molecular recogni-
tion,[2] catalysis,[3] and transport processes,[4] to the design of
molecular walkers,[5] sensors,[6] and materials.[7] Interestingly,
the new vision of systems chemistry has emerged as an exten-
sion of DCC and related areas.[8] DCC is based on the use of dy-
namic covalent bonds for the generation of a mixture of inter-
converting compounds. It is desirable that the reversible reac-
tions involved in the preparation of such mixtures are reasona-
bly fast, tolerant to a variety of functional groups, active under
mild conditions, and susceptible to deactivation.[1c,d] Recent ex-
amples include orthoester exchange,[9] diselenide exchange,[10]
and reversible native chemical ligation.[11] Reversible reactions
involving aldehydes[12,13] or thiols[10b,14] have shown to be
useful in DCC. In recent years, the scope of reversible reactions
has broadened to include the addition of a thiol to an alde-
hyde, as described for thiazolidine exchange[15] and hemithio-
acetal formation.[16] Chemically related to them, the dithioace-
tal functional group has been widely used in organic synthesis
as a precursor of acyl carbanion equivalents,[17] Lewis acid in-
duced electrophiles,[18] and as a protective group for carbonyl
compounds.[19] Acidic catalysis and temperature has enabled
the reversible formation of dithioacetals from an aldehyde and
a thiol[20] or the dithioketal exchange from a derivative of gri-
seofulvin and thiols.[21] Milder conditions under basic catalysis
and trifluoroacetic acid (TFA; 60 mm). After 3 h, a new com-
pound could be observed by HPLC corresponding to the di-
thioacetal 1-A-1 (Figure 1).
Figure 1. HPLC trace showing the composition achieved by starting from A
and 1 (l=265 nm).
After 20 h of stirring, the composition remained without
1
changes, H NMR spectroscopy showed that 1-A-1 constituted
86% of the mixture composition, whereas both A and 1 were
present in 14%.[23] When a chloroform solution of 1-A-
1 (3 mm), H2O (3 mm) and TFA (20 mm) was stirred for 2 h, the
reached composition was the same than that observed in
Figure 1 (see the Supporting Information, Figure S6), indicating
the reversibility of the dithioacetal bond formation. Additional-
ly, when chloroform solutions of A and 1, or of 1-A-1 and H2O
(3 mm final concentration in all cases) were stirred in neutral
(without TFA) or basic conditions (with piperidine 15 mm), the
starting material remained unaltered after one week, indicating
that both formation and hydrolysis of dithioacetals are inactive
under those conditions.
[a] Dr. A. G. Orrillo, Dr. A. M. Escalante, Prof. Dr. R. L. E. Furlan
Instituto de Investigaciones para el Descubrimiento
de Fµrmacos de Rosario (IIDEFAR, UNR-CONICET)
Ocampo y Esmeralda, Rosario (2000) (Argentina)
E-mail: furlan@iidefar-conicet.gob.ar
[b] Prof. Dr. R. L. E. Furlan
Farmacognosia, Facultad de Ciencias Bioquímicas y FarmacØuticas
Universidad Nacional de Rosario
To evaluate the reversibility of the exchange of dithioacetals,
the compound 1-A-1 (3 mm final concentration) and p-thiocre-
sol 2 (6.3 mm) were dissolved in a CHCl3:TFA (95:5) solution
Suipacha 531, Rosario (2000) (Argentina)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201600208.
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and stirred for 3 h, then dithioacetal 3-A-3 (3 mm) was added.
1H NMR signals (d=4.56–5.24 ppm) corresponding to dithio-
acetal protons indicated the formation of the six expected di-
thioacetals (Figure 2).
position at 14 h was the same as in the previous experiment
and stayed constant up to two days, indicating that the mix-
ture is under thermodynamic control (Figure S16 in the Sup-
porting Information).[24]
Different reversible exchange reactions have been combined
to prepare dynamic mixtures.[25] Some of them have been used
to produce complex structures and functional systems.[26] One
of the most widespread combinations makes use of orthogo-
nal hydrazone and disulfide exchanges, which can be sequen-
tially addressable.[27] We wonder if dithioacetal exchange could
be used to prepare a multilevel system by combining dithio-
acetal exchange with orthogonal disulfide exchange. The con-
struction of one dynamic system using two sequential reversi-
ble reactions can be conducted through two different sequen-
ces of activation. With this aim, a solution of dithioacetal 3-A-3
(2.7 mm), benzene disulfide 4-4 (2.7 mm), and 2-phenylethane-
thiol 1 (5.4 mm) in CHCl3 was treated with TFA and then with
piperidine in excess or, alternatively, first with piperidine and
later with TFA. When TFA was added first (54 mm final concen-
tration), only dithioacetal exchange took place: dithioacetals 1-
A-1 and 1-A-3 were produced at the expense of 1 and 3-A-3
(Figure 3, Path a).[28] The concentration of benzene disulfide 4-
4 did not change over a period of two days, indicating that
the disulfide exchange is turned off. At that moment, an
excess of piperidine was added (67.5 mm) leading to the for-
mation of disulfides 1-4, 1-1, and 3-4, and of benzenethiol 4 at
the expense of 4-4. Over a three-day period, the previous con-
centration of dithioacetals 1-A-1, 3-A-3, and 1-A-3 stayed con-
stant, suggesting that the exchange of dithioacetals is turned
off (Figure 3, Path a). At this moment, three dithioacetals, two
thiols, and four disulfides were present in the solution. In the
experiment following the opposite sequence, when piperidine
1
Figure 2. Partial H NMR spectrum of the dynamic mixture prepared from
1-A-1, p-thiocresol 2, and then adding 3-A-3 in acid conditions.
At 14 h, the proportion of dithioacetals ranged between 6
and 20%, whereas the free aldehyde A was present in 28% of
the total composition. This profile of composition remained
unchanged up to two days of reaction, suggesting that equi-
librium has been reached. In order to confirm it, the same mix-
ture was prepared from a different starting point: a CHCl3/TFA
(95:5) solution of 2-A-2 and 1-pentanethiol 3 was stirred for
2 h and subsequently, 1-A-1 was added. As expected the com-
Figure 3. HPLC profile (l=250 nm) of a solution of dithioacetal 3-A-3, disulfide 4-4, and thiol 1 in CHCl3 after the addition of TFA (2 days), followed by the ad-
1
dition of piperidine (2 days; Path a), or first piperidine (2 days) and then TFA (6 h; Path b). Inserts are partial H NMR spectra showing dithioacetal protons for
each mixture.
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(13.5 mm) was added in the first instance to the solution, ben-
zenethiol 4 and disulfides 1-4 and 1-1 were formed at the ex-
pense of 4-4 (Figure 3, Path b). As expected, stirring for two
days under these conditions did not affect the concentration
of dithioacetal 3-A-3; and further addition of an excess of TFA
(67.5 mm) led to the formation of dithioacetals 1-A-1, 1-A-3, 3-
A-4 and 1-A-4 at the expense of 3-A-3, with no effect on the
concentration of the previously generated disulfides (Figure 3,
Path b). At that moment, five dithioacetals, two thiols, and
three disulfides were present in the solution. In summary, two
different dynamic mixtures were obtained after each orthogo-
nal process was completed (first acid then base or vice versa).
These dynamic mixtures are constituted by a different range of
disulfides and dithioacetals because different reactive species
are present for exchange when the order of activation is
changed. For example, dithioacetal 3-A-3 is exchanged only
with 1 when the acid is added first, whereas, when the base
was added first and then the acid, it is exchanged with 4, re-
leased from the disulfide partner, and exchanged with 1. In the
context of networks, the thiols present in these mixtures can
be deemed common nodes connecting two temporally sepa-
rated molecular networks. Interestingly, thiols can detect the
components of the active network, bringing information from
one network to the other. Furthermore, since these two final
systems have different chemical compositions, these common
nodes are useful to design non-commutative complex chemi-
cal systems.[29]
Keywords: dithioacetal exchange · dynamic combinatorial
chemistry · reversible reaction · systems chemistry
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(see the Supporting Information, section 4.1.).
We thank Carlos M. Solis for invaluable help with NMR experi-
ments, Gabriela Cabrera for HRMS results and RenØ C. Brachvo-
gel for useful comments on the manuscript. Financial support
for this work was provided by FONCYT (PICT2011-0918 and
2014-3704), CONICET (PIP 695) and Universidad Nacional de
Rosario.
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Received: January 15, 2016
Published online on April 5, 2016
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