Bromine catalyzed conversion of S-tert-butyl groups into versatile and, for self-assembly processes accessible, acetyl-protected thiols

Article abstract of DOI:10.1039/b408677e

The facile and efficient conversion of a tert-butyl protecting group to an acetyl protecting group for thiols by catalytic amounts of bromine in acetyl chloride and the presence of acetic acid has been developed. The fairly mild reaction conditions are of

Full text of DOI:10.1039/b408677e

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C O M M U N I C A T I O N
Bromine catalyzed conversion of S-tert-butyl groups into versatile
and, for self-assembly processes accessible, acetyl-protected thiols†
Alfred Błaszczyk,a,b Mark Elbinga and Marcel Mayor*a
a
Institute for Nanotechnology, Forschungszentrum Karlsruhe GmbH, P. O. Box 3640,
D - 76021, Karlsruhe, Germany. E-mail: marcel.mayor@int.fzk.de;
Fax: (+49) 7247 82 5685; Tel: (+49) 7247 6392
Faculty of Commodity Science, Al. Niepodleglozci 10, 60-967, Poznae, Poland
b
Received 8th June 2004, Accepted 1st September 2004
First published as an Advance Article on the web 13th September 2004
The facile and efficient conversion of a tert-butyl protecting
group to an acetyl protecting group for thiols by catalytic
amounts of bromine in acetyl chloride and the presence of acetic
acid has been developed. The fairly mild reaction conditions are
of particular interest for new protecting group strategies for
sulfur functionalised target structures.
Fig. 1 Bromine catalyzed conversion of a tert-butyl thiol into an acetyl
protected thiol.§
We demonstrate here, that various S-tert-butyl groups
(Table 1) are smoothly converted into the corresponding S-
acetyl-protected thiols in the presence of catalytic amounts of
bromine in acetyl chloride–acetic acid at room temperature. The
starting material was solved in acetyl chloride and the bromine
was added slowly as diluted solution in acetyl chloride–acetic
acid (1:1).§ It turned out to be important to keep the bromine
concentration low, as larger bromine concentrations resulted
in oxidative disulfide formation. The reaction has been found
originally for aromatic tert-butyl thiophenylates. However,
the reaction protocol seems to have much broader application
potential, as the conversion of benzylic (d) and alkylic (e) tert-
butyl protected thiols to acetyl protected thiols turned out to
be similarly successful. To our surprise, the reaction is not even
limited to thiols. The tert-butyl protected phenolic oxygen in
(c) is converted to an acetyl protected phenol under the applied
reaction conditions as well.10 However, the reaction conditions
seem to be selective for tert-butyl groups as, for example, the
phenyl alkyl ether group (e) is not attacked. While excellent
yields have been obtained in numerous cases (a–f ) even for
substrates comprising two tert-butyl protected groups (b–d,f ),
moderate (g–i) and poor (j) yields have been observed in other
cases, probably due to competitive side reactions.
The fast growing area of nanotechnology demands
reliable interfaces between fabricated nanostructures and the
macroscopic world. In particular the integration of tailor-made
molecular systems as functional units in nanoscale objects and
on nanostructured surfaces is very promising. At present, the
majority of interfaces between molecular systems and nano-
scale- or even macroscopic structures is based on self-assembly of
sulfur-terminated molecules on noble metals, e.g. gold.1 The
success of this linkage is based on its ambivalence, the covalent
Au–S bond is stable enough at room temperature for subsequent
processing of the samples but loose enough to allow dynamic
processes like self-assembly on the surface.2 In particular the fast
growing field of molecular electronics benefits from the Au–S
linkage to integrate molecular structures in electronic circuits
for the investigation of their electronic transport properties.
For example Au–S immobilised SAMs have been investigated
in crossed-wire3 or mercury drop junctions,4 in small laterally
limited assemblies of up to 1000 molecules in nanopores,5 or
even on a single molecule level, for instance in mechanically
controlled break junctions.6
In spite of the rich established thiol chemistry, the introduc-
tion of the required thiol function into molecular structures
of interest often remained challenging and troublesome.
Unfortunately, free thiols tend to form disulfides in the
presence of oxidation agents like traces of oxygen. A promis-
ing alternative to free thiols are acetyl protected ones, as they
are air-stable and hydrolysable in situ.7 However, S-acetyl
derivatives do not tolerate harsh reaction conditions and
consequently, synthetic strategies to exchange more stable
protecting groups for the acetyl protecting group towards the
end of a synthetic pathway are very promising. S-tert-butyl
groups are stable to acidic and basic reaction conditions and
hence an ideal precursor of an acetyl protected thiol. Further-
more, tert-butylsulfanyl groups can easily be introduced into
target structures by nucleophilic substitution of e.g. halogenides
with a tert-butyl thiolate anion as a strong nucleophile.‡ To the
best of our knowledge, only two methods for the conversion S-
tert-butyl to S-acetyl are reported, both being limited in applica-
tion by the use of strong Lewis acids like AlCl38 or BBr3.9
Here we report a novel, simple and useful method for the
conversion of S-tert-butyl groups into the versatile acetyl-
protected thiols using fairly mild reaction conditions (Fig. 1).
A
proposed reaction mechanism is displayed in
Scheme 1. Treatment of the tert-butyl protected thiol with
bromine probably leads to the sulfenyl bromide intermediate 2
and hydrogen bromide, driven by the formation of isobutene,
which is removed as volatile product. The formation of
sulfenyl chloride by the reaction of Cl2 and 1-tert-butoxy-4-
tert-butylsulfanyl benzene has been reported in the literature.11
Furthermore, sulfenyl halides and their reactions have already
been described.12–14 The proposed mechanism assumes an equi-
librium between the sulfenyl halide 2 and hydrogen bromide on
one side and the thiol 3 and bromine on the other side. While
bromine is recovered for the next catalytic cycle, the thiol 3 is
quenched by the excess of acetyl chloride forming the acetyl-
protected thiol 4 and hydrogen chloride. The continuous con-
sumption of bromine and thiol 3 out of the equilibrium, further
induces their formation from sulfenyl halide 2 and hydrogen
bromide to rebalance the equilibrium. The presence of acetic
acid is crucial for the successful conversion, probably to stabilise
one of the intermediates of the reaction mechanism.
The decreasing yields of isolated conversion products in
the presence of electron rich multiple bonds (g–j), which are
known to react with electrophilic sulfenyl cations,13,14 further
consolidate the proposed reaction mechanism with the inter-
mediate species 2. In particular the poor yield of 3% for the
compound comprising a terminal acetylene (j) most likely
† Electronic
supplementary
information
(ESI)
available:
Experimental procedures and analytical data: experimental
procedures for the synthesis of substrates and analytical data
for the characterization of the substrates and products. See
http://www.rsc.org/suppdata/ob/b4/b408677e/
2 7 2 2
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 2 7 2 2 – 2 7 2 4
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

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Table 1 The conversion of R = tert-butyl to R = acetyl in a variety
of molecular structures using the new bromine catalysed reaction
protocol
procedure afforded the acetyl protected compound in a yield of
42%, providing a yield of 30% over both steps.
In summary, we describe a new one-pot reaction protocol for
the conversion of very robust tert-butyl protected thiol groups
into more versatile and labile acetyl protected ones, which can
be hydrolysed in situ to free thiols. The reaction is catalysed by
traces of halogens and requires an acidic pH and acetyl chloride
as solvent to quench the reactive intermediates. The described
protocol is of particular interest as a fairly mild reaction
condition that allows the exchange of the robust tert-butyl by
the acetyl sulfur protecting group in a late stage of a synthetic
strategy.
Financial support from the network project MOLMEM of
the German Ministry of Education and Research (BMBF-FZK
13 N 8360) is gratefully acknowledged. We are grateful to the
anonymous referee from Organic & Biomolecular Chemistry for
his suggestions concerning the proposed reaction mechanism.
Entry
Structuresa
Yieldb [%]
94
a
b
95
c
d
e
f
89
97
86
96
Notes and references
‡ Example for the introduction of S-tert-Bu by nucleophilic
substitution: preparation of the starting material 1-tert-butyl-
sulfanyl-4-tert-butylsulfanylmethyl benzene (d): To a solution of 4-
bromobenzyl bromide (2.0921 g, 8.37 mmol) in dry DMF (20 ml),
sodium-2-methyl-2-propanethiolate (2.8164 g, 25 mmol) was added
portion wise. After heating to 135 °C for 16 hours, the reaction
mixture was poured into NaCl saturated water and extracted with
diethyl ether. After washing with water and drying over MgSO4, column
chromatography (silica gel, hexane–toluene 20:1) yielded 1-tert-butyl-
sulfanyl-4-tert-butylsulfanylmethyl benzene (1.865 g, 83%) as white
solid. Mp. 72.9–74.5 °C; dH(300 MHz; CDCl3; Me4Si) 1.26 (9 H, s, CH3),
1.35 (9 H, s, ArSC(CH3)3), 3.78 (2 H, s, CH2), 7.31 (2 H, d, J 8.0, ArH),
7.45 (2 H, d, J 8.0, ArH); dC(75 MHz; CDCl3; Me4Si) 31.3 (CH3), 33.5
(CH2), 43.4 (C(CH3)3), 46.2 (C(CH3)3), 129.5, 131.3, 137.9, 139.8; m/z
(EI) 268.0 [M+, 61%], 212.0 [38, M+ − C4H8], 156.0 [29, M+ − 2 × C4H8],
123.1 [100, M+ − C4H8 − C4H9S]. Elemental analysis calcd (%) for
C15H24S2: C 67.10, H 9.01; found: C 67.46, H 8.75.
g
h
33
29
i
j
42
3
a Starting materials and reaction products have been characterised
by H- and 13C-NMR spectroscopy and mass spectrometry. b Isolated
1
§ General procedure for the conversion of R-S-tert-Bu into R-S-Ac: To a
well-stirred solution of starting compound (10−5 M) in acetyl chloride
(10 ml), a solution of bromine (catalytic amount: ca. 5 mol%) in acetyl
chloride–acetic acid (1:1) was added in 30 minutes at room temperature.
The course of the reaction was monitored by thin layer chromatography.
After completion of the reaction (1–30 minutes after the bromine
addition), all solvents were removed by evaporation and the crude resi-
dues were purified by silica gel chromatography.
yields.
1 Thiols on Au clusters: C. A. Mirkin, R. L. Letsinger, R. C.
Mucic and J. J. Storhoff, Nature, 1996, 382, 607; A. P. Alivisatos,
K. P. Johnsson, X. Peng, T. E. Wilson, C. J. Loweth, M. P. Bruchez
and P. G. Schultz, Nature, 1996, 382, 609; W. M. Pankau, K. Verbist
and G. von Kiedrowski, Chem. Commun., 2001, 519; . Thiols on Au
surfaces: M. Boncheva, D. A. Bruzewicz and G. M. Whitesides, Pure
Appl. Chem., 2003, 75, 621.
Scheme 1
2 A. Ulman, Chem. Rev., 1996, 96, 1533.
3 J. G. Kushmerick, D. B. Holt, S. K. Pollack, M. A. Ratner,
J. C. Yang, T. L. Schull, J. Naciri, M. H. Moore and R. Shashidhar,
J. Am. Chem. Soc., 2002, 124, 10654.
4 R. E. Holmlin, R. F. Ismagilov, R. Haag, V. Mujica, M. A. Ratner,
M. A. Rampi and G. M. Whitesides, Angew. Chem., 2001, 113, 2378;
R. E. Holmlin, R. F. Ismagilov, R. Haag, V. Mujica, M. A. Ratner,
M. A. Rampi and G. M. Whitesides, Angew. Chem., Int. Ed. Engl.,
2001, 40, 2316.
5 J. Chen, M. A. Reed, A. M. Rawlett and J. M. Tour, Science, 1999,
286, 1550.
6 M. A. Reed, C. Zhou, C. J. Muller, T. P. Burgin and J. M. Tour,
Science, 1997, 278, 252; J. Reichert, R. Ochs, D. Beckmann,
H. B. Weber, M. Mayor and H. v. Löhneysen, Phys. Rev. Lett., 2002,
88, 176804.
7 J. M. Tour, L. II Jones, D. L. Pearson, J. S. Lamba, T. P. Burgin,
G. W. Whitesides, D. L. Allara, A. N. Parikh and S. V. Atre, J. Am.
Chem. Soc., 1995, 117, 9529.
8 I. A. Aliev, G. A. Kalabin and N. Ghelis, Sulfur Lett., 1991, 12, 123.
9 N. Stuhr-Hansen, J. B. Christensen, N. Harrit and T. Björnholm,
J. Org. Chem., 2003, 68, 1275; N. Stuhr-Hansen, Synth. Commun.,
2003, 33, 641.
10 It is noteworthy that in ref. 11 the same substrate 1-tert-butoxy-4-
tert-butylsulfanyl benzene is treated with Cl2 in CH2Cl2 and only
the formation of sulfenyl chloride is reported, while the tert-butoxy
group seems to resist the reaction conditions.
points towards a faster addition reaction of the electrophilic
sulfur species to the unprotected and electron rich triple bond.13
Increased yields of conversion for substrates containing double
bonds compared with triple bonds are expected, due to the less
electron rich nature of the double bond. However, the excellent
yield of 96% for the conversion of the stilbene species (f ) in
spite of the double bond was surprising and may be due to both,
steric protection and electronic passivation of the double bond
towards electrophilic attack in the conjugated aromatic stilbene
structure.
Molecular rods designed to bridge the gap between
metallic electrodes like (f ) and (i) have been synthesised using
the described protocol. The isolated yields turned out to be
independent from the scale of the reaction. Furthermore,
the rod (i) allows a comparison of the synthetic strategies:
assembled from acetyl protected starting materials, only a yield
of 5% has been isolated.15 A similar coupling protocol using
tert-butyl protected building blocks yielded over 70% for the
coupling.15 Subsequent transformation employing the described
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 2 7 2 2 – 2 7 2 4
2 7 2 3

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11 F. Marcuzzi and G. Melloni, Synthesis, 1976, 451.
12 E. Ciuffarin and G. Guaraldi, J. Org. Chem., 1970, 35, 2006.
13 W. L. Orr and N. Kharasch, J. Am. Chem. Soc., 1956, 78,
1201.
15 M. Mayor, H. B. Weber, J. Reichert, M. Elbing, C. von Hänisch,
D. Beckmann and M. Fischer, Angew. Chem., 2003, 115, 6014;
M. Mayor, H. B. Weber, J. Reichert, M. Elbing, C. von Hänisch,
D. Beckmann and M. Fischer, Angew. Chem., Int. Ed. Engl., 2003,
42, 5834.
14 E. Kühle, Synthesis, 1971, 563.
2 7 2 4
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 2 7 2 2 – 2 7 2 4