Tris(thioacetals) from benzene hexathiol: Towards covalent self-assembly

Article abstract of DOI:10.1039/b401021c

Mixtures of isomers are available from the reaction of benzene hexathiol with three equivalents of p-tolualdehyde and kinetic traps avoided under the reported catalytic conditions, establishing tris(thioacetals) as potential building blocks for covalently self-assembled complex structures.

Full text of DOI:10.1039/b401021c

Tris(thioacetals) from benzene hexathiol: towards covalent self-assembly
Liam R. Sutton,* Wolfgang A. Donaubauer, Frank Hampel and Andreas Hirsch*
Institut für Organische Chemie, Universität Erlangen-Nürnberg, Henkestr. 42, D-91054 Erlangen, Germany.
E-mail: l_r_sutton@yahoo.co.uk; hirsch@organik.uni-erlangen.de; Fax: +49 (0) 9131 8526864; Tel: +49
(0) 9131 8522537
Received (in Columbia, MO, USA) 21st January 2004, Accepted 26th May 2004
First published as an Advance Article on the web 24th June 2004
Mixtures of isomers are available from the reaction of benzene
hexathiol with three equivalents of p-tolualdehyde and kinetic
traps avoided under the reported catalytic conditions, establish-
ing tris(thioacetals) as potential building blocks for covalently
self-assembled complex structures.
thermodynamic control of reactivity. Hg(II) is often used to
deprotect carbonyls, since the soft metal…S interaction is favour-
able, promotes C—S breaking and allows the sequestering of
dithiol as a precipitate.6 This is too far for us; we required a
compromise between the Lewis acidity of the catalyst to promote
C—S cleavage and continued availability of dissolved dithiol for
subsequent reaction.
Extended literature investigations revealed that Lewis acids such
as BF3·Me2S, SnCl2 and Zn(OTf)2 may present such a compromise,
the most promising being zinc trifluoromethanesulfonate based on
its use by Corey and Shimoji9 as a soluble catalyst unlikely to
hinder subsequent reaction due to the lability of Zn…S inter-
actions.
Thermodynamic self-assembly is an attractive method for creating
complex ångstrom- and nanoscale objects by the interaction of
molecular recognition sites with particular topological preferences
inherent in simpler precursor molecules.1 Typically, both natural
and artificial self-assembly involve non-covalent interaction, since
the lability normally associated with such bonds allows the
exploration of all possible permutations open to a particular system
and the selection of the most thermodynamically stable assembly.
However, non-covalent assemblies are not always the optimum
solution to a given problem. In studies of encapsulation, for
example, it is not always desirable that a guest be allowed freedom
to leave its host, as is often the case for labile, non-covalent
assemblies.2
Assemblies constructed by covalent bonding therefore have
potential as complex architectures that retain their structural
integrity at all times. The main challenge is squaring the circle of
making kinetically stable covalent bonds capable of exploring
structural permutations on a reasonable timescale.3 One very
successful building block is the imine bond, as used in Robson’s
metal-templated macrocyclisations4 and in some of Cram et al.’s
carcerand work,5 which is labile in acidic conditions but not at
neutral or high pH.
Neither BF3 nor SnCl2 gave detectable quantities of 3 or 4 but
reaction catalysed by Zn(OTf)2 in a variety of solvents gave the
appropriate peak in FAB-MS after around 1 h at elevated
temperature. TLC analysis (alumina, hexane/toluene) was used to
follow the reactions to completion in 24–72 h. No dithiol was
observed by FAB-MS after this time. Work-up procedures involved
partitioning the reaction mixture and recrystallising the organic-
soluble product from methanol. This gives a high purity mixture of
3 and 4 in reasonable yields, up to 60% from the reaction with 10
mol% Zn(OTf)2 in refluxing CHCl3. The very similar, low
polarities of 3 and 4 make them difficult to separate: decomposition
occurred on silica gel whilst reverse-phase TLC was ineffective.
Preparative TLC on neutral alumina with 4 : 1 v/v hexane/toluene
was more effective, as was elution from alumina with successive
hexane/toluene aliquots of increasing toluene content, the aab
isomer 4 being eluted before aaa 3.
We chose to investigate the thioacetal system, which can be
made reversible under certain catalytic conditions but is otherwise
quite stable.6 We hoped to benefit from the rigidity of thioacetals by
restricting the configurations available to the system, enhancing the
entropic advantage of macrocyclisation vs. polymerisation and
promoting template-free self-assembly.1c We designed an adaman-
toid capsule for C60 based on the assembly of four benzene
hexathiol units (1) and six terephthaldialdehyde molecules. Such
targets are expected to display interesting redox properties.7 We
report here studies on model reactions of 1 with p-tolualdehyde (2)
to give isomeric tris(thioacetals) 3 (aaa) and 4 (aab) and the X-ray
crystal structure of 3.
This enabled the NMR characterisation of the compounds
obtained. The spectra shown in Fig. 1 confirm that 3 and 4 are
produced in a 1 : 3 ratio, consistent with random orientation of the
Compound 1 was synthesised by literature methods,8 making the
hexa(benzylsulfide) from hexachlorobenzene and sodium ben-
zylthiolate in DMF, followed by dealkylation with sodium in liquid
ammonia.†
In order to determine a suitable catalytic regime for the smooth
reaction of 1 to give tris(thioacetals) (Scheme 1, pathway A) we
explored a number of permutations of catalyst and solvent. During
our initial studies with Brønsted acids in ethanol, tetrahydrofuran or
toluene, FAB-MS analysis of the reaction mixtures revealed the
presence of a peak at m/z = 473 consistent with the bis(thioacetal)-
dithiol as well as a product peak at m/z = 576, suggesting either
incomplete reaction or trapping in the form of the 1,4-dithiol due to
lack of reversibility in this non-productive equilibrium. Persistence
of the peak at 473 upon extended reaction and upon addition of
excess 2 supports the latter explanation (Scheme 1, pathway B).
We therefore clarified the position that protic acids, whilst being
useful in protection of carbonyls with dithiols in organic synthesis,
do not promote the reversibility of thioacetal formation required for
Scheme 1 Tris(thioacetal) formation from 1. R = p-tolyl.
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C h e m . C o m m u n . , 2 0 0 4 , 1 7 5 8 – 1 7 5 9
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4

third thioacetal on insertion into either aa or ab bis(thioacetal)
dithiol.
inducing reversibility in reaction pathway B (Scheme 1). The NMR
spectra of 3 and 4, the ability to separate them by chromatography
and the X-ray crystal structure of 3 confirm the inertness of the
compounds in the absence of catalyst. 3 templates an unusual water
cluster in its crystal.
Furthermore, crystals of 3 suitable for X-ray structure determina-
tion were grown by recrystallisation from methanol.‡ The crystal
structure (Fig. 2) confirms the isomerism of 3, with the three
thioacetal C—H bonds all on the same face of the central aryl ring.
Bond lengths and angles are normal.
The quite large, isolated cavities between tolyl groups allowed
by the molecular packing arrangement are filled by (H2O)12 clusters
(Fig. 3).10 The origin of this water is probably wet recrystallisation
solvent.
However, a number of drawbacks detract from the prospects of
basing more elaborate structures on 1 using this chemistry.
Although pathway B is reversible, the reactions described are still
quite slow, taking up to 3 days to complete as assessed by TLC. As
the number of permutations of possible configurations increases, so
the required time increases geometrically.1 Secondly, initial studies
in exchanging the tolualdehyde bound in 3 and 4 with tere-
phthaldialdehyde using CHCl3, Zn(OTf)2 and a small quantity of
added H2O to generate more complex structures have produced no
reaction. These factors suggest that the third thioacetalisation is not
reversible under current conditions, possibly due to steric hin-
drance. Resolution of these difficulties is the target of future work,
exploring alternative catalysts, larger substrates and the more
labile, protic acid-catalysed acetal system using O-containing
analogues.
To conclude, we have demonstrated that benzene hexathiol can
be used to produce mixtures of tris(thioacetal) products by its
Zn(OTf)2-catalysed condensation with p-tolualdehyde, the catalyst
The authors would like to thank the Alexander von Humboldt-
Stiftung for a Fellowship (to LRS).
Notes and references
† Caution: benzyl mercaptan stinks. Best results were obtained with freshly
prepared 1 under N2; reactions with stored 1 often yielded a FAB-MS peak
at m/z = 471, consistent with the bis(thioacetal) disulfide.
‡ Crystal data for 3: C30H24S6·6H2O, M = 684.95, Z = 6, rhombohedral,
space group R-3, a = b = 15.7694(5), c = 25.0354(6) Å, a = b = 90, g
= 120°, U = 5391.6(3) Å3, T = 173(2) K, m(Mo–Ka) = 0.418 mm21
.
Fig. 1 1H NMR spectrum of the as-synthesised 3/4 mixture. Inset: thioacetal
signals from the mixture (a) and purified 3 and 4 (b, c): d = 6.39 (3); 6.35
(a, 4); 6.32 ppm (b, 4).
Data were collected on a Nonius KappaCCD area detector. Of 13583
reflections measured, 2378 were independent (Req = 0.0578). The structure
was solved by direct methods (SHELXS-97) and refined by full-matrix
least-squares on F2 (SHELXL-97). Final R1 = 0.0677 (1975 reflections
with I > 2s(I)) and wR2 (F2) = 0.1874 (all data). CCDC 229167. See http:/
/www.rsc.org/suppdata/cc/b4/b401021c/ for crystallographic data in .cif or
other electronic format.
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Fig. 2 X-ray crystal structure of 3. Thermal ellipsoids shown at 50%
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Fig. 3 (H2O)12 clusters in the X-ray crystal structure of 3: H2O molecules
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C h e m . C o m m u n . , 2 0 0 4 , 1 7 5 8 – 1 7 5 9
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