Trityl Radicals with a Combination of the Orthogonal Functional Groups Ethyne and Carboxyl: Synthesis without a Statistical Step and EPR Characterization

Article abstract of DOI:10.1021/acs.joc.8b03234

Finland trityl radical (FTR) shows very attractive EPR spectroscopic properties for a manifold of applications. For most of its applications only one chemically reactive functional group is needed. The presence of three equally reactive carboxyl groups leads to FTR modifications through reactions which give statistical mixtures of 1-fold-, 2-fold-, and 3-fold-modified and unmodified FTR. To avoid the side effects of such a statistical reaction - limited yields and separation challenges - we took a route to FTR-type trityl radicals with scaffold assembly by addition of an aryllithium with one type of substituent to a diarylketone with another type of substituent. This gave the two FTR-type trityl radicals 1 and 2 which carry a combination of the chemically orthogonal groups, carboxyl and triisopropylsilylethynyl. Standard column chromatography was sufficient for product isolation on all stages, whereby polar tagging helped. The EPR spectroscopic properties of the trityl radicals 1 and 2 in ethanol were determined in X and W bands. Their g anisotropy and T₁ and T₂ relaxation times make them spin labels as good as the benchmark FTR. This paper discloses also details on the synthesis of building blocks used for FTR preparation and improved access to the bare FTR scaffold.

Full text of DOI:10.1021/acs.joc.8b03234

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Article
Trityl radicals with a combination of the orthogonal
functional groups ethyne and carboxyl: Synthesis
without a statistical step and EPR characterization
Henrik Hintz, Agathe Vanas, Daniel Klose, Gunnar Jeschke, and Adelheid Godt
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b03234 • Publication Date (Web): 20 Feb 2019
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Trityl radicals with a combination of the orthogonal functional
groups ethyne and carboxyl: Synthesis without a statistical step and
EPR characterization
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Henrik Hintz,† Agathe Vanas,§ Daniel Klose,§ Gunnar Jeschke,§ and Adelheid Godt†,*
†Faculty of Chemistry and Center for Molecular Materials (CM2); Bielefeld University, Universitätsstraße 25, 33615
Bielefeld, Germany.
§ETH Zurich, Lab. Phys. Chem., Vladimir‐Prelog‐Weg 2, 8093 Zurich, Switzerland.
ABSTRACT: Finland trityl radical (FTR) shows very attractive EPR spectroscopical properties for a manifold of applications.
For most of its applications only one chemically reactive functional group is needed. The presence of three equally reactive
carboxyl groups leads to FTR modifications through reactions which give statistical mixtures of onefold, twofold and three‐
fold modified, and unmodified FTR. To avoid the side effects of such a statistical reaction ‐ limited yields and separation
challenges ‐ we took a route to FTR‐type trityl radicals with scaffold assembly by addition of an aryllithium with one type
of substituent to a diarylketone with another type of substituent. This gave the two FTR‐type trityl radicals 1 and 2 which
carry a combination of the chemically orthogonal groups, carboxyl and triisopropylsilylethynyl. Standard column chroma‐
tography was sufficient for product isolation on all stages, whereby polar tagging helped. The EPR spectroscopical proper‐
ties of the trityl radicals 1 and 2 in ethanol were determined in X and W band. Their g anisotropy and T1 and T2 relaxation
times make them as good a spin label as the benchmark FTR. The paper discloses also details on the synthesis of building
blocks used for FTR preparation and an improved access to the bare FTR scaffold.
Introduction
To meet the requirements for applications of trityl radi‐
cals in magnetic resonance imaging (MRI), requirements
such as water solubility, stability in biological media, toxi‐
cological harmlessness, and a single and narrow electron
paramagnetic resonance (EPR) line, Nycomed Innovation
AB developed a family of tri(tetrathiaaryl)methyl (TAM)
radicals whereof Finland trityl radical (FTR, Chart 1),4,5 dis‐
closed in 1996, is the most prominent one.
Persistent radicals are used as analytical tools and ni‐
troxyl radicals have long been the first choice. Concomi‐
tant with more recent developments in the area of analyti‐
cal techniques which rely on unpaired electron spins, per‐
sistent radicals with spectroscopical properties other than
those of the nitroxides gained importance.1 This brought
the carbon‐centered triarylmethyl radicals (trityl radicals,
often simply called trityls) into focus.2 The parent trityl
radical, the triphenylmethyl radical (Chart 1), was prepared
by Gomberg in 1900.3
FTR is equipped with three carboxyl groups leading to
good water solubility when deprotonated.6 The bulky thi‐
oketal groups sterically shield the central carbon atom
which carries most of the unpaired electron density and
thus are made responsible for the chemical inertness of
FTR.7,8 FTR is remarkably resistant against reduction al‐
lowing EPR measurements in biological media and even in
living cells.9–12 Very importantly, FTR contains, in contrast
to many other trityl radicals, no hydrogen atoms at the
benzene rings. This way, strong broadening of the EPR sig‐
nal due to coupling with hydrogen nuclear spins is avoided
and FTR shows a single, very narrow EPR line13 which
makes techniques relying on signal broadening highly sen‐
sitive. Furthermore, FTR has long relaxation times in fluid
Chart 1. Gomberg's trityl radical (left) and Finland
trityl radical (FTR; right).
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solutions.14 Due to these favorable properties, FTR and var‐
Here we present an access to FTR‐type trityl radicals in
iations thereof found widespread application: MRI,4,5,15–17
EPR imaging,16,18,19 EPR oximetry and pH measure‐
ment,6,8,9,20–23 specific detection of the superoxide,24–26 dy‐
namic nuclear polarization,27–30 and in a study on molecu‐
lar diffusion in porous media.31 More recently, FTR was rec‐
ognized as a spin label for molecular structure elucida‐
tion32,33 via distance determination with pulsed EPR tech‐
niques34–42 and this application was investigated using non‐
biological model compounds36,43,44 as well as oligonucleo‐
tides45–50 and proteins.12,33,51,52
which statistical reactions are circumvented through as‐
sembly of a trityl alcohol by addition of an aryllithium with
one type of substituent to a diarylketone with another type
of substituent (Scheme 1). Trityl alcohols are the precursors
of trityl radicals, into which they are converted through
subsequent addition of a strong acid and a reducing agent.
The addition of an organolithium or organomagnesium
compound to a ketone is a common access to tertiary alco‐
hols R2R'COH with R≠R'. In this way, Rajca et al. assembled
the scaffold of di‐ and tetraradicals consisting of triphenyl‐
methyl units.65,66 However, there is no report on its appli‐
cation to the synthesis of FTR‐type trityl alcohol with at
least two different substituents, that we are aware of.
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FTR is equipped with three carboxyl groups of equal re‐
activity, of which, in most applications, only one should re‐
act. Without any measures taken, the reaction of FTR with
less than 3 equivalents of a reaction partner will result in a
statistical mixture of unmodified FTR and onefold, twofold
and threefold modified FTR. We call such a reaction a sta‐
tistical reaction because of its close similarity with a statis‐
tical copolymerization. This approach was taken in the
step of binding FTR to a target compound45,47–50,53–58 as well
as in reactions to obtain FTR derivatives which provide one
selectively addressable functional group for binding to a
target molecule.8,12,21,33,43,52,56,59,60 To minimize the probabil‐
ity of multiple reactions of one FTR molecule in the former
method, one may apply a large excess of FTR derivative as
has been done in conjugation of FTR with an oligonucleo‐
tide using a 10‐fold excess of the acid chloride of FTR.49 The
latter approach includes statistical ester8,12,43 or amide for‐
mation33,56 of FTR, statistical ester hydrolysis of the triester
of Finland trityl alcohol, the precursor of FTR,59,60 and sta‐
tistical reduction of the alkoxycarbonyl group of the ester
of the Finland trityl alcohol to a hydroxymethyl group.21
Statistical ester formation and ester hydrolysis were used
to protect two of the three carboxyl groups as alkoxycar‐
bonyl groups.8,12,43,59,60 Furthermore, the attachment of one
functional group that can be selectively addressed in the
presence of the residual two carboxyl groups, such as me‐
thanethiosulfonate, pyridin‐2‐yldisulfanyl, and propargyl
and allyl moieties was achieved via a statistical ester or am‐
ide formation.12,33,52 Because statistical reactions give prod‐
uct mixtures of starting trityl compound and its onefold,
twofold and threefold modifications, yields will be medium
to low and product isolation can become quite challenging.
The only published access free of a statistical reaction to
trityl radicals with the same scaffold as FTR (in the follow‐
ing called FTR‐type trityl radicals) and with two types of
functional groups is the nucleophilic substitution of one of
the three carboxyl groups for a C, N, P or S nucleophile via
oxidation of FTR to the corresponding trityl cation, addi‐
tion of the nucleophile giving a quinone methide, loss of
carbon dioxide and finally an oxidation step.61–64 Similarly,
FTR‐type trityl radicals with one functional group were
prepared via a trityl cation having the FTR scaffold but be‐
ing void of carboxyl groups, the latter being formed
through treatment of the corresponding trityl alcohol with
an acid.59,64
Scheme 1. Assembly of FTR‐type trityl radicals having
two different types of substituents through addition
of an aryllithium to a diarylketone and subsequent
conversion of the product, trityl alcohol, into the
trityl radical.
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strong acidic and mild reductive conditions during radical
formation. The TIPS protected ethyne group was expected
to fulfill these requirements. The other functional group
could, in principle, be already present in one of the build‐
ing blocks or could be installed after scaffold assembly via
modification of the trityl alcohol or the trityl radical. To
meet the goal of orthogonal reactivity of the functional
groups the carboxyl group was chosen as the second func‐
tional group. Due to its incompatibility with organolithium
compounds it was introduced after scaffold assembly at the
stage of the trityl alcohol via lithiation. It was attached in
the form of a tert‐butoxycarbonyl group. In doing so, the
isolation of the target compounds was simply achieved
through standard column chromatography because of
lower polarity of the tert‐butyl ester as compared to the
carboxylic acid. The tert‐butoxycarbonyl group was con‐
verted into the desired carboxyl group concomitant with
the generation of the conversion of trityl alcohol into trityl
radical.
Chart 2. The trityl radicals 1 and 2. TIPS = triiso‐
propylsilyl.
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Using
this
method,
the
trityl
(1)
radicals
and
trityl[CO2H/CO2H/CCTIPS]
trityl[CO2H/CCTIPS/CCTIPS] (2) (“trityl” stands for the
FTR scaffold, the substituents at the positions of the car‐
boxyl groups of FTR are defined in brackets; Chart 2) were
synthesized. Their chemically orthogonal functional
groups, the carboxyl group and the triisopropylsilyl (TIPS)
substituted ethyne moiety, hold the potential to selectively
attach the trityl radicals to a molecule of interest via the
functional group of which only one is present, e. g. to at‐
tach trityl[CO2H/CCTIPS/CCTIPS] (2) via an ester or am‐
ide bond formation or trityl[CO2H/CO2H/CCTIPS] (1), af‐
ter removal of the TIPS group, through a 1,3‐dipolar azide‐
alkyne cycloaddition. The other two functional groups can
be used for any other purpose, for example to gain water
solubility of the compounds, which is of importance when
it comes to application in studies on biomolecules. All
steps in the syntheses of the trityl radicals 1 and 2 can be
performed with gram amounts and standard column chro‐
matography provides pure compounds. The EPR spectro‐
scopical properties of the trityl radicals 1 and 2 in X and W
band make them as attractive as FTR for applications.
The overall synthetic routes are displayed in Schemes 2
and 3. A look on them reveals unsubstituted tetrathioben‐
zene 4a and TIPS‐ethyne substituted tetrathiobenzene 4b
as the basic building blocks, their deprotonation at the
benzene ring to obtain lithiated tetrathiobenzenes 5a and
5b as a central step, diarylketones 9a and 9b as key syn‐
thetic intermediates, and the reaction of diarylketones 9
with lithiated tetrathiobenzenes 5 as pivotal for the assem‐
bly of the trityl scaffold.
Tetrathiobenzenes 4 and their deprotonation
Tetrathiobenzene 4a was synthesized starting from
1,2,4,5‐tetrachlorobenzene (Scheme 2). Nucleophilic aro‐
matic substitution on 1,2,4,5‐tetrachlorobenzene with so‐
dium tert‐butylthiolate following essentially the procedure
of Reddy et al. gave tetrathioether 3.67 Only sodium was re‐
placed with sodium hydride for the deprotonation of tert‐
butylthiol, a change leading in our hands to a product of
higher purity. We observed that a longer reaction time
lowered the yield. Heating to reflux for 2 h gave a yield of
48%, the extension of the reaction time to 6 h reduced the
yield to 37%, after 15 h only 14% product were obtained,
and after 63 h no product was isolated. During heating a
slight but steady gas evolution was noticed. Hence, we as‐
sume that tetrathioether 3 degrades by thermally induced
cleavage of the tert‐butylthio group whereby isobutene is
released. Tetrathioether 3 was converted into tetrathioben‐
zene 4a following a procedure of Rogozhnikova et al.61
The paper is organized as follows. First the matter of the
functional groups is addressed and then details of the indi‐
vidual synthetic steps are presented. Finally the EPR spec‐
troscopical data of the trityl radicals 1 and 2 including a
comparison with the data of FTR are presented.
Results and discussion
Crucial for the success was the decision on the type of
the functional groups and on when to install them. At least
one of the functional groups needed to be already installed
in one of the building blocks, the aryllithium compound or
the diarylketone. This functional group has to tolerate or‐
ganolithium compounds in the addition step as well as
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Scheme 2. Syntheses and deprotonation of the tetrathiobenzenes 4 and formation of diarylketones 9. Dashed
arrow: Attempts to synthesize diarylketone 9a by addition of phosgene, methyl chloroformate, or
dimethylcarbonate to lithiated tetrathiobenzene 5a gave diarylketone 9a only in low yields and in mixture with
other products. Lithiated tetrathiobenzenes 5 were not isolated. Methyllithium was applied as a solution in
diethylether, lithiumdiisopropylamide as a solution in tetrahydrofuran/n‐heptane/ethylbenzene. TIPS =
triisopropylsilyl, rt = room temperature.
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Scheme 3. Assembly of trityl[CO2H/CO2H/CCTIPS] (1) and trityl[CO2H/CCTIPS/CCTIPS] (2). Lithiated tetrathi‐
obenzenes 5 and reagent 12 were not isolated. Methyllithium was applied as a solution in diethylether and butyl‐
lithium was applied as a solution in hexanes. TMEDA = tetramethylethylenediamine, rt = room temperature.
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Table 1. Molecular ratio of the products from treatment of tetrathiobenzene 4a with n‐BuLi, s‐BuLi, or t‐BuLi
determined by 1H NMR spectroscopy.
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Scheme 4. Proposed mechanism for the formation of trithiobenzenes 16‐18 in the reaction of tetrathiobenzene 4a
with alkyllithium in diethyl ether.
To use tetrathiobenzene 4a for diarylketone and trityl al‐
cohol formation as well as to generate TIPS‐ethyne substi‐
tuted tetrathiobenzene 4b, it had to be lithiated. Com‐
monly, the lithiation is carried out with n‐butyllithium in
diethylether at room temperature.6,12,61,67,68 Doing so we
found that, within 30 min, 17% of tetrathiobenzene 4a was
transformed into trithiobenzene 16 (Table 1). To an even
larger extent the corresponding trithiobenzenes 17 and 18
were formed when sec‐butyllithium or tert‐butyllithium
were applied (Table 1). Based on experimental data that are
discussed in the Supporting Information we suggest in
Scheme 4 that a nucleophilic attack of alkyllithium at a sul‐
fur atom results in the fragmentation of the thioketal moi‐
ety giving trithiobenzene and thioacetone. The cleavage of
a C‐S bond via nucleophilic addition of n‐butyllithium to a
sulfur atom has been reported for 2,2‐diaryl‐1,3‐dithiolanes
and 2,2,‐diaryl‐1,3‐dithianes69 and for 2,2‐dialkyl‐2‐arylthi‐
oacetonitriles.70 Of the two possible carbanions the more
stable was formed. 2‐Alkyl‐2‐aryl‐1,3‐dithianes and 2,2‐di‐
alkyl‐1,3‐dithianes as well as the corresponding dithiolanes
gave unidentified tarry substances if they reacted at all.69
Therefore, in case of tetrathiobenzene 4a alkyl‐S bond
cleavage and thioacetone formation are likely to occur con‐
certed because this leads to a good arylcarbanion and
avoids a less favorable sulfanylalkylcarbanion as an inter‐
mediate.
within maximum 100 min without fragmentation. Under
these conditions the degree of lithiation was 99% as deter‐
mined by workup with deuterium oxide. When tetrahydro‐
furan was exchanged for diethyl ether no reaction took
place.
The conditions found for the clean and quantitative
deprotonation of tetrathiobenzene 4a were the entry to
implement the TIPS‐ethyne moiety. Addition of N‐
formylpiperidine to lithiated tetrathiobenzene 5a gave al‐
dehyde 6, which was converted into acetylene 7 through a
Seyferth‐Gilbert homologation71,72 with the Bestmann‐
Ohira reagent.73,74 Acetylene 7 was deprotonated with lith‐
ium diisopropylamide. Reaction of TIPS‐chloride with the
obtained lithium acetylide provided TIPS‐ethyne substi‐
tuted tetrathiobenzene 4b. Likewise tetrathiobenzene 4a,
TIPS‐ethyne substituted tetrathiobenzene 4b could be ef‐
ficiently and cleanly lithiated with methyllithium in tetra‐
hydrofuran.
Diarylketones 9
Diarylketones 9 were prepared from lithiated tetrathio‐
benzenes 5 in two steps (Scheme 2). In this way we took
advantage of easy chromatographical separation of com‐
pounds through polar tagging.75,76 First, lithiated tetrathi‐
obenzenes 5 were converted in tetrahydrofuran into diaryl‐
methanols 8 employing methyl formate. Their hydroxyl
groups acted as polar tags making them easily separable by
standard column chromatography from much less polar
starting material and other, unidentified compounds even
on multigram scales such as 4 g of product. The second
Staying with n‐butyllithium but lowering the tempera‐
ture to 0 oC still gave 3% of trithiobenzene 16 and, in addi‐
tion, a degree of only 21% for lithiation of tetrathiobenzene
4a was achieved as revealed by workup with deuterium ox‐
ide. Surprisingly, tetrathiobenzene 4a can be lithiated with
methyllithium in tetrahydrofuran at room temperature
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step, the oxidation of diarylmethanols 8 to obtain diarylke‐
tetrahydrofuran. No trityl alcohol was produced at room
temperature within 3 days. Instead, diarylketone 9a was
converted into unidentified compounds. Obviously, the
addition step proceeded too slowly. The reactivity of tetra‐
hydrofuran towards carbanions made it suspect of being
the origin for the side products, that became visible prob‐
ably due to the very long reaction time of three days.
Therefore, tetrahydrofuran was considered as an inappro‐
priate solvent for the addition step and we strove to replace
it for diethyl ether because diethyl ether is the standard
solvent for trityl assembly61,68 and the above mentioned ex‐
periment which had been run in diethyl ether had given at
least some addition product. However, lithiation of
tetrathiobenzene 4a does not work well in diethylether.
Therefore, the lithiation step was performed in tetrahydro‐
furan, then tetrahydrofuran was removed and lithiated
tetrathiobenzene 5a was suspended in diethyl ether. Fi‐
nally, diarylketone 9a was added (Scheme 5). After stirring
the reaction mixture at 30 °C for seven days,
tritylOH[H/H/H] 19 was obtained in 79% yield. This pro‐
cedure was directly transferable to the syntheses of
tones 9, was performed with Dess‐Martin periodinane,77
which was chosen as the reagent because it does not harm
the thioketal moiety.78 Also in this step, the distinct differ‐
ence in polarity between the rather nonpolar product and
the significantly more polar, unidentified side products
helped in isolation: Filtration of a solution of the crude
product through a short plug of silica gel was sufficient to
isolate diarylketones 9. They were obtained in yields of
83% and 74%, respectively, over two steps.
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Being aware of the report on the synthesis of diarylke‐
tone 9a in a single step from lithiated tetrathiobenzene 5a
and methyl chloroformate in diethyl ether,68 we investi‐
gated this advantageously looking route by adding methyl
chloroformate, phosgene or dimethylcarbonate to lithiated
tetrathiobenzene 5a in tetrahydrofuran. Tetrahydrofuran
was chosen because we had found it to be the solvent of
choice for the preparation of lithiated tetrathiobenzene 5a.
In case of methyl chloroformate and phosgene most of
tetrathiobenzene 4a went into unidentified compounds.
Only traces of diarylketone 9a were detected. With dime‐
thylcarbonate diarylketone 9a was obtained, however only
in a yield of about 40%. The residual tetrathiobenzene 4a
and the reaction intermediate methoxycarbonylated
tetrathiobenzene point to an incomplete conversion. Trityl
alcohol was not detected. Also this reaction was accompa‐
nied by the formation of unidentified compounds, albeit
only in small amounts. It looks like that the lithium chlo‐
ride, that forms when chloroformate or phosgene are used,
changes the reactivity of the lithiated tetrathiobenzene 5a
in an unfavorable manner. Probably the form in which
lithiated tetrathiobenzene 5a is present in diethylether is
changed by lithium chloride. Impact of lithium chloride on
the reaction of lithiumamides is known.79
tritylOH[H/H/CCTIPS]
10
and
tritylOH[H/CCTIPS/CCTIPS] 11 giving yields of 84% und
72%, respectively (Scheme 3). In all of these reactions some
of the diarylketone 9 were found unchanged, which means
that none of these reactions went to completion although
lithiated tetrathiobenzene 5a had been used in excess.
Longer reaction time may improve the conversion. On the
other hand, the conversion may be limited by competing
protonation of the lithiated tetrathiobenzene 5a by the sol‐
vent.
Having found suitable conditions for lithiation of
tetrathiobenzenes and for the addition of lithiated tetrathi‐
obenzene 5 to diarylketone 9, we tested their application
to a one‐pot synthesis of tritylOH[H/H/H] 19 which is the
precursor of FTR (Scheme 6). Lithiated tetrathiobenzene
5a was prepared from tetrathiobenzene 4a and methyllith‐
ium in tetrahydrofuran, then the solvent was exchanged
for diethylether and dimethyl carbonate was added. The
suspension was stirred at 30 °C for seven days. This gave
tritylOH[H/H/H] 19 in gram amounts with 86% yield. The
highest yield reported in literature so far is 73%.12
Assembly of the trityl scaffold
The
assembly
of
the
trityl
10
alcohols,
and
tritylOH[H/H/CCTIPS]
tritylOH[H/CCTIPS/CCTIPS] 11 was elaborated with the
preparation of tritylOH[H/H/H] 19 (Scheme 5) which is a
synthetic intermediate in the synthesis of FTR. As re‐
ported,68 tetrathiobenzene 4a was lithiated with n‐butyl‐
lithium in diethyl ether, then diarylketone 9a was added
and the reaction mixture was stirred at 30 °C for 40 h. Con‐
sidering the above mentioned formation of trithiobenzene
16 in the reaction of tetrathiobenzene 4a with butyllithium
in diethyl ether, it came as no surprise, that trityl alcohol
20, which shows trithiobenzene 16 as a substituent, was
found as one of the products (32% isolated yield; For details
see Supporting Information). TritylOH[H/H/H] 19 was ob‐
tained in a yield of only 7%. The above named literature
reports a yield of 96% and does not mention any side‐
product.68 Having found methyllithium in tetrahydrofuran
to be the reagent of choice for the lithiation of tetrathio‐
benzene 4a, the overall reaction sequence was pursued in
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applied conditions and the results). Surprisingly, methyl‐
lithium in tetrahydrofuran, the best conditions to deproto‐
nate tetrathiobenzenes 4, failed. The reaction with 10
equivalents of methyllithium for 100 min at room temper‐
ature followed by workup with deuterium oxide resulted in
only 11% of deuteration at the benzene rings. Luckily, the
reported conditions n‐butyllithium and tetramethyleth‐
ylenediamine in n‐hexane at room temperature61 were very
effective resulting in a deuteration degree of the benzene
rings of 94%, and, remarkably, caused not the above de‐
scribed fragmentation of the thioketal moiety. This thio‐
ketal fragmentation was not found under any of the condi‐
tions tested during the search for quantitative lithiation,
including n‐butyllithium and sec‐butyllithium in diethy‐
lether (For details see Supporting Information). Obviously,
the fragmentation tendencies of the thioketal moieties of
tetrathiobenzene 4a and trityl alcohols 10, 11 and 19 are dis‐
tinctly different. However, a very careful reaction time con‐
trol was necessary because other side reactions occurred
with prolonged reaction time (For details see Supporting
Information).
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
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22
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45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
t
t
t
The trityl alcohol tritylOH[CO2 Bu/CO2 Bu/CO2 Bu] pre‐
pared through the reaction of deprotonated
tritylOH[H/H/H] 19 with di‐tert‐butyldicarbonate is re‐
ported to be isolated by precipitation.68 This elegant pro‐
cedure does not work in case of trityl alcohols 13 and 14
because the TIPS groups drastically improve their solubil‐
ity in organic solvents and thus prevent their precipitation.
Column chromatography was no solution either because
the removal of di‐tert‐butyldicarbonate from trityl alcohol
14 was incomplete. Hence, instead of di‐tert‐butyldicar‐
bonate N‐tert‐butoxycarbonylpyridinium tert‐butanolate
(12), freshly prepared from di‐tert‐butyldicarbonate and 4‐
N,N‐dimethylaminopyridine, was used. In contrast to di‐
tert‐butyldicarbonate this reagent is simply removed dur‐
ing workup by filtration through silica gel and subsequent
washing of the eluate with aqueous ammonium chloride
solution removes 4‐N,N‐dimethylaminopyridine.
Scheme 5. Exploring the synthesis of tritylOH[H/H/H]
(19). Methyllithium was applied as a solution in
diethylether and butyllithium was applied as a
solution in hexanes. rt = room temperature.
Finally, tert‐butyl esters 13 and 14 were converted into
trityl radicals 1 and 2 by protonation with trifluoroacetic
acid and reduction of the generated trityl cations with
tin(II) chloride following the procedure61 reported for the
preparation of FTR. FTR formation is accompanied by qui‐
none methide formation.61 The generation of trityl radical
1 went without quinone methide formation, whereas in
case of trityl radical 2 a small amount (3% isolated yield) of
quinone methide 15 formed. Quite in contrast to the diffi‐
culties with chromatographic separation of the two highly
polar compounds FTR and accompanying quinone
methide,6 the separation of trityl radical 2 and quinone
methide 15 was easy because trityl radical 2 interacts
strongly with silica gel due to its carboxyl group and qui‐
none methide 15 is a rather unpolar compound.
Scheme 6. One‐pot synthesis of tritylOH[H/H/H] (19).
Methyllithium was applied as a solution in diethy‐
lether.
Trityl radicals 1 and 2
The last modification on the stage of the trityl alcohols
was the mounting of the carboxyl groups. As mentioned
above, for the reason of most simple product isolation the
carboxyl group should be introduced in form of a tert‐
butoxycarbonyl group. For this step, trityl alcohols 10 and
11 needed to be lithiated. Lithiation conditions were
worked out using the parent trityl alcohol,
tritylOH[H/H/H] 19 (see Supporting Information for the
As expected, trityl radicals 1 and 2 are not soluble in wa‐
ter, water/glycerol, 0.1 M phosphate buffer at pH 7.4 or 2
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M aqueous solution of NaOH, but they are soluble in or‐
ganic solvents, including ethanol.
Table 2. Fit parameters as determined from the W band cw EPR spectra. For line broadening a Gaussian distribu‐
tion of the g values with the stated full width at half maximum (FWHM) is assumed.
8
9
compound
g
g distribution (Gaussian, FWHM)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
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43
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48
49
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59
60
1
2.00339
± 1∙10‐5
2.00335
± 1∙10‐5
2.00345
± 1∙10‐5
2.00333
± 1∙10‐5
2.00331
± 1∙10‐5
2.00338
± 1∙10‐5
2.00245
± 1∙10‐5
2.00240
± 1∙10‐5
2.00254
± 1∙10‐5
2.8∙10‐4
4.6∙10‐4
± 2∙10‐5
4.6∙10‐4
± 2∙10‐5
4.2∙10‐4
± 2∙10‐5
3.1∙10‐4
± 2∙10‐5
2.0∙10‐4
± 2∙10‐5
2.0∙10‐4
± 2∙10‐5
± 2∙10‐5
3.1∙10‐4
± 2∙10‐5
3.0∙10‐4
± 2∙10‐5
2
FTR
EPR spectroscopical properties of trityl radicals 1
and 2
the signal obtained for a given distance.
The EPR spectroscopical properties of trityl radicals 1
and 2 dissolved in ethanol were investigated at X and W
band frequencies with continuous wave (cw) and pulse
EPR techniques (Figures 1, S4‐S6). FTR was included in
these measurements as the benchmark trityl radical. All
pulse EPR experiments were performed at 50 K, represent‐
ing a temperature typically used in EPR measurements for
distance determination, which is envisaged as an im‐
portant application of the new trityl radicals and deriva‐
tives thereof.
Quantitative analysis with cw EPR spectroscopy at X
band frequencies, with FTR as the reference, gave 89% and
99% of the expected signal intensity (at an error margin of
about 15% for quantitative EPR) for solutions of the final
synthesis products 1 and 2, respectively (Figure S4), thus
proving them to be pure trityl radicals without diamag‐
netic contamination. The cw EPR spectra of both trityl rad‐
icals showed a single very narrow line (Figure S5), suggest‐
ing that in applications at ambient temperature the new
radicals behave similar to FTR. The g‐tensors of these lines
were determined through fitting of cw and echo‐detected
EPR spectra recorded at W band frequencies (94.2 GHz)
using a calibrated carbon fiber as an internal g factor
standard80 as shown in Figures 1 and S6. The determined g‐
anisotropies of trityl radicals 1 and 2 are very similar to the
g‐anisotropy of FTR (see Table 2 for fitting parameters).
This indicates that the singly‐occupied molecular orbital is
essentially unaffected by the partial exchange of carboxyl
groups for TIPS‐ethyne substituents.
Figure 1. Echo‐detected EPR spectra (W band, 94.2 GHz)
shown
as
numerical first
derivative
of
(a)
(b)
trityl[CO2H/CO2H/CCTIPS]
1,
trityl[CO2H/CCTIPS/CCTIPS] 2, and (c) FTR in ethanol at
50 K with the respective fits overlaid in grey. For fit param‐
eters see Table 2, for echo‐detected EPR absorption spectra
of samples containing the carbon fiber as the g factor
standard see Figure S6.
Therefore, a longer T2 is generally desirable. The longi‐
tudinal relaxation time T1 on the other hand describes the
return of the system to its unperturbed state thus deter‐
mining the recycle delay, which one wishes to be short as
the required measurement time for a certain signal to noise
ratio increases linearly with a longer recycle delay. The T1
and T2 relaxation times of trityl radicals 1, 2, and FTR were
determined at X and W band frequencies by inversion re‐
covery and 2‐pulse ESEEM, respectively. At W band fre‐
quencies the T1 and T2 relaxation times of trityl radical 1 are
very similar to that of FTR, while trityl radical 2 shows a
longer T1 and a slightly shorter T2 time (Figure 2 and Table
3). At X band frequencies, interestingly, the T1 relaxation of
trityl radicals 1 and 2 is distinctly slower than that of FTR
(Figure 3 and Table 3), which would increase the experi‐
mental time required in frozen EtOH solution by a factor
In addition to the line shape, relaxation behavior is of
relevance for the usage of radicals as reporters. Since all
pulsed dipolar spectroscopy experiments measure the dis‐
tance via echo modulation by the dipole‐dipole coupling
frequency, distance resolution and the maximum accessi‐
ble distance depend on the transverse relaxation time T2
which determines the lifetime of the echo.40 The longer T2,
the larger the determinable distances and also the stronger
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of 2.7 and 2.4 for trityl radicals 1 and 2, respectively. For all
and 2 shows a higher ESEEM modulation depth for the less
4
5
6
7
8
9
three trityl radicals T1 relaxation times are larger and T2 re‐
laxation times are smaller at the higher field for solutions
in ethanol at 50 K. For distance measurements on trityl la‐
beled compounds and therefore on samples with specific
conditions, especially in respect to the type of solvent, an
optimal maximum temperature T with respect to signal to
noise ratio can be determined and applied at which T2
starts to converge to its maximal value and T1 is still as
short as possible. Here we only investigated the relative
trends between trityl radicals 1, 2 and FTR, which are likely
to reflect trends rather than absolute values for conditions
to be used for distance determination experiments.
proton carrying trityl radical 1. Therefore, contribution of
solvent protons is assumed. Such nuclear modulation can
show up as an unwanted oscillation in pulsed dipolar spec‐
troscopy experiments. However, averaging schemes exist
to suppress it. Therefore, such small hyperfine couplings
do not interfere when using these trityl radicals as spin la‐
bels or spin probes.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 3. Results of spin relaxation measurements of
trityl[CO2H/CO2H/CCTIPS]
1
(cyan),
trityl[CO2H/CCTIPS/CCTIPS] 2 (red) and FTR (black) in
ethanol at 50 K at X band frequencies (ca. 9.5 GHz). Meas‐
urements were performed at the spectral maximum. (a) In‐
version recovery reflecting the longitudinal relaxation time
(T1). (b) 2‐pulse ESEEM signal decay with strong proton
modulations providing insight into transverse relaxation
time (T2). The grey line indicates a remaining signal level
of 10%. (c) Fourier transform of the 3‐pulse ESEEM time
domain data (Figure S7) showing an intense matrix signal
at the proton Larmor frequency (14.8 MHz). The 1/e‐relax‐
ation times from (a) and (b) are shown as vertical lines and
are summarized in Table 3.
Figure 2. Results of spin relaxation measurements of
trityl[CO2H/CO2H/CCTIPS]
1
(cyan),
trityl[CO2H/CCTIPS/CCTIPS] 2 (red) and FTR (black) in
ethanol at 50 K at W band frequencies (94.2 GHz). Meas‐
urements were performed at the spectral maximum. (a) In‐
version recovery reflecting the longitudinal relaxation time
(T1). (b) 2‐pulse ESEEM signal decay providing insight into
the transverse relaxation times (T2). The grey line indicates
a remaining signal level of 10 %. The 1/e‐relaxation times
are shown as vertical lines and are summarized in Table 3.
Table 3. Relaxation times of trityl radicals as deter‐
mined with X and W band EPR measurements at 50 K.
The 2‐pulse ESEEM signal decay at X band frequencies
(Figure 3b) shows nuclear modulations which are at‐
tributed to partial excitation of forbidden transitions when
the electron spin is coupled to close‐by nuclear spins.
These nuclear modulations were further analyzed by 3‐
pulse ESEEM (Figure S7, Figure 3c) and the coupled spins
were, based on the observed resonance frequency in the
Fourier transformed spectra, unambiguously identified as
protons. We found an increased intensity of the proton sig‐
nal of trityl radicals 1 and 2 as compared to FTR, clearly
seen in Figure S7. The coupling constants are too small for
the couplings to become resolved beyond the matrix peak
in the spectrum (Figure 3c). The increased signal intensity
of trityl radicals 1 and 2 may be due to their larger number
of protons surrounding the central carbon atom with the
unpaired electron. However, comparing trityl radicals 1
com‐
X band
W band
pound
1/e (T1)
1/e (T2)
[µs]
1/e (T1)
1/e (T2)
[µs]
[ms]
3.60
3.09
1.31
[ms]
3.76
4.80
3.72
1
2
1.14
1.08
1.17
0.97
0.89
0.94
FTR
Conclusions and outlook
FTR‐type trityl radicals with two types of substituents at
the benzene rings can be obtained without a statistical re‐
action step through assembly of the trityl scaffold by addi‐
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tion of an aryllithium with one substituent to a diarylke‐
pounds used for syntheses had a purity of > 95%, their mo‐
lar amount used in the syntheses were calculated with
their compound mass and were not corrected by the man‐
ufacturer specified purities. THF and Et2O (both HPLC
grade) were dried with sodium/benzophenone prior to
their use. The concentrations of organolithium solutions
were determined by titration using salicylaldehyde phenyl‐
hydrazone as indicator.83 For the preparation of aqueous
solutions, deionized water was used. Solvents used for ex‐
traction and chromatography were of technical grade and
were distilled prior to their use.
tone with other substituents as was demonstrated with the
synthesis of the two FTR‐type trityl radicals 1 and 2 show‐
ing the TIPS‐substituted ethyne and the carboxyl group as
substituents. Most reactions were performed on a scale of
at least 1 g. Standard column chromatography was suffi‐
cient for product isolation. Several findings made during
the development of the synthesis of the two trityl radicals
1 and 2 are also of relevance for the synthesis of other FTR‐
type trityl radicals and even FTR itself because the synthe‐
ses have some building blocks and transformations in com‐
mon. Consequently, we included an improved synthesis of
the bare FTR scaffold.
10
11
12
13
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19
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60
Column chromatography was carried out on silica gel 60
(0.035−0.070 mm) without applying pressure. In the pro‐
cedures reported below, the size of the column is given as
diameter x length. The material was loaded onto the col‐
umn dissolved in a small quantity of the eluent. Thin layer
chromatography (TLC) was performed on silica gel 60 con‐
taining fluorescent indicator F254. The solid support for
the silica gel layer was aluminum foil. The spots were de‐
tected with UV light of λ = 254 nm and 366 nm. For pre‐
parative HPLC a Phenomenex Luna® Silica(2) column (par‐
ticle size: 5 μm, pore size 100 Å, column size 21.2 mm x 250
mm) was used. For analytical HPLC a Phenomenex Luna®
Silica(2) column (particle size: 5 μm, pore size 100 Å, col‐
umn size 4.6 mm x 250 mm) was used. The compositions
of solvent mixtures are given in volume ratios.
We expect the developed synthesis route to be also ap‐
plicable to assemble FTR‐type trityl radicals with three dif‐
ferent functional groups through exchange of methyl for‐
mate for (substituted) trithiobenzene carrying a formyl
group, e.g. for aldehyde 6, in the step of diarylmethanol
formation. Furthermore, the trityl radicals 1 and 2 may be
a starting point for the preparation of metabolically stable81
and/or thiol compatible82 trityl radicals and the trityl alco‐
hols 10 and 11 can be used to introduce other functional
groups than carboxyl, such as phophonate groups.20,22
Relaxation times T1 and T2 and g anisotropy prove the
trityl radicals 1 and 2 as spectroscopically equally suitable
as FTR. Because the trityl radicals 1 and 2 are well accessi‐
ble and carry functional groups with orthogonal reactivity
they may become the starting point of a variety of spin la‐
bels. Modifications at the ethyne groups, e. g. attachment
of substituents like polyethylene glycol chains to achieve
water solubility, are expected to change the spectroscopi‐
cal properties very little as they will take place far away
from the central carbon atom with the unpaired electron.
The relaxation times will change upon a solvent change, e.
g. to an aqueous solvent for studies on trityl radical labeled
biomolecules, however, the impact of a solvent is expected
to be similar for the three trityl radicals investigated in this
study.
The ratio of the components in a mixture was deter‐
mined by 1H NMR spectroscopy and is given as molar ratio.
The melting points were determined in open capillaries.
NMR spectra were calibrated using the solvent signal as
an internal standard [CDCl3: δ (1H) = 7.25, δ (13C) = 77.0;
CD2Cl2: δ (1H) = 5.32, δ (13C) = 53.8; C6D6: δ (1H) = 7.16, δ
(13C) = 128.1]. Signal assignments are supported by DEPT‐
135, COSY, HMBC, and HMQC experiments.
ESI MS spectra were recorded using an Esquire 3000 ion
trap mass spectrometer (Bruker Daltonik) equipped with a
standard ESI source. Unless otherwise stated, accurate ESI
mass measurements were performed using a Q‐IMS‐TOF
mass spectrometer Synapt G2Si (Waters, Manchester, UK)
in resolution mode, interfaced to a nano‐ESI ion source.
Nitrogen served as the nebulizer gas and the dry gas for
nano‐ESI. Nitrogen was generated by a nitrogen generator
NGM 11. Helium 5.0 was used as buffer gas in the IMS entry
cell, nitrogen 5.0 was used for IMS. ESI samples were intro‐
duced by static nano‐ESI using in‐house pulled glass emit‐
ters.
Experimental section
Synthesis
General. All reactions were performed in dried glass‐
ware under argon. Argon was passed through anhydrous
CaCl2 prior to its use. Unless otherwise stated, degassed so‐
lutions were prepared through applying three freeze‐
pump‐thaw cycles. N,N‐Dimethylformamide (DMF) was
degassed at room temperature by applying vacuum until
the liquid started to boil. Then the flask was ventilated
with argon. This procedure was performed three times.
Solvents were removed at a bath temperature of ∼40 °C
and reduced pressure. The products were dried at room
temperature at ∼0.3 mbar. The pH values of the solutions
were determined using pH indicator strips (resolution: 0.5
pH).
Mass spectra with GC‐inlet and electron ionization (EI)
where measured on a Triplequad Quattro Micro GC (Wa‐
ters‐Micromass, Manchester, UK) (compounds 7 and 4b)
or on a GC17A with QP5050 Single Quad Mass Spectrome‐
ter (Shimadzu GmbH, Germany) (compounds 4a and 17).
EI mass spectra were also recorded using an Autospec X
magnetic sector mass spectrometer with EBE geometry
(Vacuum Generators, Manchester, UK) equipped with a
standard EI source (compounds 16, and 17). Samples were
introduced by push rod in aluminium crucibles. Ions were
accelerated by 8 kV in EI mode. Accurate mass measure‐
ments were performed in the high resolution mode with
perfluorokerosene as internal standard.
Unless otherwise stated, commercial solvents and rea‐
gents were used. Source, purity, and batch numbers of the
reagents are listed in Table S3. Since all commercial com‐
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MALDI TOF mass spectra were recorded with an Ultra‐
trityl[CO2H/CCTIPS/CCTIPS] (2) (36 mg after freeze‐dry‐
4
5
6
7
8
9
flex MALDI‐TOF/TOF mass spectrometer (Bruker Dal‐
tonik, Bremen, Germany) operated in reflectron mode.
Samples were mixed on a polished steel target with 1 μL of
a saturated solution of trans‐2‐[3‐(4‐tert‐butylphenyl)‐2‐
methyl‐2‐propenylidene]malononitrile (DCTB) in metha‐
nol. Ionization was achieved using an LTB nitrogen laser
MNL 200 (337 nm beam wavelength, 50 Hz repetition rate).
ing with benzene, 95%; Rf(CH2Cl2) = 0; Rf(CH2Cl2/AcOH
100:1) = 0.29; Mp: 202 °C, molten compound is black) as a
brown solid were obtained. Additional analytical data of
1
trityl[CO2H/CCTIPS/CCTIPS] (2): The H NMR spectrum
is displayed in Figure S10. MS (ESI): m/z = 1270.1 [M ‐ H]‐.
‐
Accurate MS (ESI): m/z calcd for [M ‐ H]‐ C60H78O2S12Si2 :
1270.2194; found, 1270.2222. Anal. Calcd for C60H79O2S12Si2:
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
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39
40
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43
44
45
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47
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49
50
51
52
53
54
55
56
57
58
59
60
C, 56.60; H, 6.25. Found: C, 56.77; H, 6.22. Additional ana‐
lytical data of quinone methide 15: For H NMR data, see
The monoisotopic masses of the compounds are re‐
ported.
1
Table S4. MS (ESI): m/z = 1265.2 [M + Na]+. Accurate MS
(ESI): m/z calcd for [M + Na]+ C59H78OS12Si2Na+: 1265.2132;
found, 1265.2133. Analytical HPLC (isocratic run with
CH2Cl2/EtOH 95:5, flow rate of 1 mL/min): 4.1 min. The
chromatogram is displayed in Figure S11.
Trityl radical 1 (Trityl[CO2H/CO2H/CCTIPS]). A solu‐
t
t
tion of tritylOH[CO2 Bu/CO2 Bu/CCTIPS] (13) (30 mg, 24
µmol) in trifluoroacetic acid (500 µL) was stirred at room
temperature for 60 min. The dark green solution was
cooled with an ice water bath and SnCl2 (22.5 mg, 74.3
µmol) dissolved in dry THF (600 µL) was added within 1
min. After additional 5 min the ice water bath was removed
and the green solution was stirred at room temperature for
45 min. Then CH2Cl2 (20 mL) was added and the solution
was washed with pH 2.0 buffer (0.5 M H3PO4, 0.5 M
KH2PO4, 2 x 10 mL) and water (10 mL). The organic phase
was dried over MgSO4 ∙ x H2O and filtered. The solvents
were removed. The components of the residual brown
solid were separated by column chromatography (1.5 cm x
31 cm). Elution with Et2O/AcOH 1000:1 gave a mixture (4
mg; Rf = 1.00, 0.50) of unidentified compounds as a brown
solid and trityl[CO2H/CO2H/CCTIPS] (1) (15 mg after
freeze‐drying with benzene, 56%; Rf = 0.15; Mp: 218 – 220
°C) as a brown solid. The 1H NMR spectrum is displayed in
Figure S8. MS (ESI), m/z = 566.4 [M ‐ 2H]2‐, 544.4 [M ‐ 2H
‐ CO2]2‐, 522.5 [M ‐ 2H ‐ 2CO2]2‐. Accurate MS (ESI): m/z
calcd for [M ‐ 2H]2‐ C50H57O4S12Si2‐: 566.5343; found,
566.5334. Anal. Calcd for C50H59O4S12Si: C, 52.83; H, 5.23.
Found: C, 53.01; H, 5.47. Analytical HPLC (isocratic run
with CH2Cl2/EtOH 96:4, flow rate of 1 mL/min): 5.0 min (1,
relative integral of 98%), 4.5 min (not identified com‐
pound, relative integral of 2%). The chromatogram is dis‐
played in Figure S9.
1,2,4,5‐Tetrakis(tert‐butylthio)benzene (Tetrathi‐
oether 3). The procedure of Reddy et al.67 was followed
with making modifications. To a suspension of sodium hy‐
dride (19.26 g, 802.8 mmol) in dry degassed DMF (320 mL)
cooled with an ice water bath was added degassed tert‐bu‐
tylthiol (83 mL, 0.76 mol) within 15 min (Caution! Very
exothermic, strong gas evolution, reaction mixture tends to
foam). The released gas was led through a gas bubbler
filled with silicone oil, an empty gas washing bottle, and a
gas washing bottle filled with saturated aqueous KMnO4
solution (Please note: gas washing bottles equipped with a
porous glass filter disc must not be used. The filter gets
clogged during the washing process by precipitated MnO2
leading to dangerous overpressure in the apparatus). Then,
the ice water bath was removed, 1,2,4,5‐tetrachloroben‐
zene (32.84 g, 152.1 mmol) was added and the brown‐grey
suspension was stirred under reflux (bath temperature 170
°C) for 120 min. After cooling to room temperature, water
(1 mL) was added and the yellow‐green suspension was
poured onto ice (430 g) and the suspension was filtered.
The filter cake was washed with water (2 x 30 mL) and
dried over P4O10 at reduced pressure. In this way, an off‐
white solid (31.73 g) was obtained consisting of tetrathi‐
oether 3 (48% yield) and DMF in the molar ratio of 97:3.
For 1H NMR and 13C NMR data, see Tables S4 and S6. Data
are in agreement with data given in the literature.67 MS
(ESI): m/z = 453.1 [M + Na]+.
Trityl radical 2 (Trityl[CO2H/CCTIPS/CCTIPS]). A so‐
t
lution of tritylOH[CO2 Bu/CCTIPS/CCTIPS] (14) (40 mg,
30 µmol) in trifluoroacetic acid (500 µL) was stirred at
room temperature for 120 min. The dark green solution
was cooled with an ice water bath and SnCl2 (14.1 mg, 74.3
µmol) dissolved in dry THF (280 µL) was added within 1
min. After additional 4 min the ice water bath was removed
and the brown solution was stirred at room temperature
for 45 min. Then CH2Cl2 (20 mL) was added and the solu‐
tion was washed with pH 2.0 buffer (0.5 M H3PO4, 0.5 M
KH2PO4, 2 x 10 mL) and water (10 mL). The organic phase
was dried over MgSO4 ∙ x H2O and filtered. The solvents
were removed. The components of the residual brown
solid were separated by column chromatography (3 cm x
20 cm). Elution with CH2Cl2 gave a mixture (6 mg;
Rf(CH2Cl2) = 0.69; Rf(CH2Cl2/AcOH 100:1) = 0.74) of uni‐
dentified compounds as an orange solid and a mixture (1.5
mg; Rf(CH2Cl2) = 0.36, Rf(CH2Cl2/AcOH 100:1) = 0.56) of
quinone methide 15 (< 3%) and grease as a violet solid.
Then, the eluent was changed to CH2Cl2/AcOH 100:1 and a
mixture (2 mg; Rf(CH2Cl2) = 0; Rf(CH2Cl2/AcOH 100:1) =
0.29) of unidentified compounds as an orange solid and
Due to the strong odor of tert‐butylthiol all glassware
contaminated with tert‐butylthiol was put into a bath of
aqueous KMnO4 solution for one day. Afterwards, the
MnO2 that stuck to the glassware was removed using an
aqueous solution of a mixture of oxalic acid and a small
amount of MnSO4.
2,2,6,6‐Tetramethylbenzo[1,2‐d:4,5‐d']bis([1,3]dithi‐
ole) (Tetrathiobenzene 4a). The procedure of Rogozhni‐
kova et al.61 was followed with making slight modifications.
The degassed (applying two freeze‐pump‐thaw cycles)
brownish suspension of a 96.5:3.5 mixture (79.21 g) of
tetrathioether 3 (183.9 mmol) and DMF (6.670 mmol), ac‐
etone (130 mL, 1.77 mol), D‐(+)‐10‐camphorsulfonic acid
(8.59 g, 37.0 mmol) and BF3 (50 wt.% in diethyl ether, 67
mL, 0.55 mol) in CHCl3 (225 mL) was stirred under reflux
(bath temperature 78 °C) for 18 h. After cooling down to
room temperature, water (200 mL) was added to the red‐
brown suspension and the pH was raised to 7.0 by addition
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of an aqueous solution of NaOH (2.0 M, 300 mL, 600
1:1 gave tetrathiobenzene 4a (362 mg, 7%; Rf = 0.72) as an
off‐white solid and aldehyde 6 (4.25 g, 78%; Rf = 0.57; Mp:
145 – 146 °C) as an orange solid. For 1H NMR and 13C NMR
data, see Tables S4 and S6. MS (ESI): m/z = 337.1 [M + Na]+,
651.0 [2M + Na]+. Accurate MS (ESI): m/z calcd for [M +
Na]+ C13H14OS4Na+: 336.9819; found, 336.9813.
mmol). Then, CHCl3 (30 mL) was added and the brown or‐
ganic phase was separated from the greenish aqueous
phase. The aqueous phase was extracted with CHCl3 (3 x 50
mL). The combined organic phases were washed with
brine (50 mL) and filtered through silica gel (4 cm x 4 cm,
rinsing with CHCl3). All volatiles were removed. The resid‐
ual yellow solid was mixed with MeOH (250 mL) and the
suspension was heated to reflux (bath temperature 85 °C)
for 30 min. Filtration gave a yellow filter cake which was
washed with a 4:1 mixture of MeOH and n‐hexane (2 x 40
mL, 6 x 80 mL) and dried at reduced pressure to give
tetrathiobenzene 4a (39.68 g, 75%; Mp: 145 °C) as a color‐
less solid. For 1H NMR and 13C NMR data, see Tables S4 and
S6. NMR data are in agreement with those given in the lit‐
erature.61 MS (EI): m/z (%) 285.9 (45) [M]+•, 270.9 (100) [M
‐ •CH3]+, 127.9 (30).
4‐Ethynyl‐2,2,6,6‐tetramethylbenzo[1,2‐d:4,5‐
d']bis([1,3]dithiole) (Alkyne 7). To a solution of aldehyde
6 (2.00 g, 6.36 mmol) and Cs2CO3 (5.17 g, 15.9 mmol) in dry
THF (100 mL) and MeOH (100 mL) was added Bestmann–
Ohira reagent (1.93 g. 10.1 mmol). The yellow‐orange solu‐
tion showing gas development was stirred at room temper‐
ature for 17 h. Et2O (200 mL) was added and the green so‐
lution was extracted with a mixture of aqueous saturated
NaHCO3 solution (30 mL) and water (30 mL). The phases
were separated. The organic phase was washed with water
(50 mL), the aqueous phase was extracted with Et2O (50
mL). The combined organic phases were dried over MgSO4
∙ x H2O and filtered. The solvents were removed. The com‐
ponents of the residue were separated by column chroma‐
tography (6.5 cm x 30 cm). Elution with CH2Cl2/pentane 1:4
gave five fractions: (1) an unidentified compound (91 mg;
Rf = 0.54) as a yellow oil; (2) a mixture of the unidentified
compound from fraction (1) with other unidentified com‐
pounds (3 mg; Rf = 0.54) as a brown oil; (3) alkyne 7 (1.23 g,
62%; Rf = 0.44; Mp: 144 – 145 °C) as an off‐white solid; (4) a
mixture of unidentified components (56 mg; Rf = 0.44,
0.29) as a dark brown solid; (5) an unidentified compound
in mixture with other unidentified compounds in minor
amounts (126 mg; Rf = 0.15) as a greenish oil. Additional
analytical data of alkyne 7: for 1H NMR and 13C NMR data,
see Tables S4 and S6. MS (EI): m/z (%) 310.1 (65) [M]+•, 295.1
(100) [M ‐ •CH3]+, 140.1 (38). Analytical data of the uniden‐
tified compound of fraction 1: 1H NMR (500 MHz, CD2Cl2):
δ 7.52 (dd, 1H, J = 5.5 Hz, 0.4 Hz), 7.35 (d, 1H, J = 0.4 Hz),
7.13 (d, 1H, J = 5.5), 5.09 (q like, 1H, J = 5.1 Hz), 4.82 (m, 1H),
1.95 (s, 6H), 1.94 (m, 3H). 13C NMR (125 MHz, CD2Cl2): δ
143.3, 139.9, 135.2, 134.8, 133.6, 129.1, 125.4, 123.4, 122.9, 112.5,
66.9, 31.6, 22.9. NMR and ESI‐MS spectra are displayed in
Figures S25‐S31. Analytical data of the unidentified com‐
pound of fraction 5: 1H NMR (500 MHz, C6D6): δ 7.51 (d, 1H,
J = 0.4 Hz), 6.95 (d, 1H, J = 5.5), 6.85 (dd, 1H, J = 5.5 Hz, 0.4
Hz), 3.21 (s, 3H), 1.65 (s, 6H), 1.35 (s, 6H). 13C NMR (125
MHz, CD2Cl2): δ 145.2, 135.2, 134.6, 133.0, 128.9, 128.4, 128.2,
128.0, 126.0, 124.7, 123.3, 91.3, 66.5, 50.6, 31.4, 28.2. The NMR
spectra show additional signals of comparatively low in‐
tensity. They are not reported here. Very likely they belong
to other unidentified components. NMR and ESI‐MS spec‐
tra are displayed in Figures S37‐S43.
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Triisopropyl((2,2,6,6‐tetramethylbenzo[1,2‐d:4,5‐
d']bis([1,3]dithiole)‐4‐yl)ethynyl)silane (TIPS‐ethyne
substituted tetrathiobenzene 4b). To a solution of al‐
kyne 7 (1.00 g, 3.22 mmol) in dry THF (25 ml) cooled with
an ice water bath was added a solution of lithium diiso‐
propylamide (1.75 M, 2.2 mL, 3.9 mmol) in THF, n‐heptane
and ethylbenzene. Immediately after the addition of lith‐
ium diisopropylamide the color of the solution had
changed from slightly brownish to dark red. After 5 min
the ice water bath was removed and the solution was
stirred for another 15 min at room temperature. Degassed
triisopropylsilylchloride (1.0 mL, 4.8 mmol) was added and
the brown solution was stirred at room temperature for 20
h. Et2O (50 mL) was added and the orange solution was
extracted with an aqueous solution of HCl (2 M, 30 mL).
The organic phase was separated, washed with water (20
mL), dried over MgSO4 ∙ x H2O, and filtered. The solvents
were removed. The components of the brownish oil were
separated by column chromatography (3 cm x 30 cm). Elu‐
tion with CH2Cl2/pentane 1:8 gave TIPS‐ethyne substituted
tetrathiobenzene 4b (1.43 g, 95%; Rf = 0.41, Mp: 74 °C) as a
yellow oil changing to a solid within few days of storage at
room temperature. For 1H NMR and 13C NMR data, see Ta‐
bles S4 and S6. MS (EI): m/z (%) 266.4 (100) [M]+•, 451.3
(30) [M ‐ •CH3]+. Anal. Calcd for C23H34S4Si: C, 59.17; H, 7.34.
Found: C, 59.53; H, 7.31.
2,2,6,6‐Tetramethylbenzo[1,2‐d:4,5‐d']bis([1,3]dithi‐
ole)‐4‐carbaldehyde (Aldehyde 6). To a slightly yellow‐
ish solution of tetrathiobenzene 4a (5.00 g, 17.5 mmol) in
dry THF (100 mL) was added a solution of MeLi (1.80 M,
10.2 mL, 18.4 mmol) in Et2O within 5 min. During addition
of MeLi a gas development started. After stirring the solu‐
tion at room temperature for 100 min N‐formylpiperidine
(9.7 mL, 87 mmol) was added and the orange solution was
stirred at room temperature for 16 h. Then, Et2O (200 mL)
was added and the yellow solution was washed with an
aqueous solution of HCl (2 M, 50 mL). The organic phase
was separated, and the red aqueous phase was extracted
with Et2O (30 mL). The combined organic phases were
washed with water (30 mL), dried over MgSO4 ∙ x H2O, and
filtered. The solvents were removed. The components of
the residual orange solid were separated by column chro‐
matography (7 cm x 20 cm). Elution with CH2Cl2/pentane
Bis(2,2,6,6‐tetramethylbenzo[1,2‐d:4,5‐d']bis([1,3]di‐
thiole)‐4‐yl)methanol (Diarylmethanol 8a). To
a
slightly yellow solution of tetrathiobenzene 4a (5.00 g, 17.5
mmol) in dry THF (100 mL) was added a solution of MeLi
(1.49 M, 11.1 mL, 16.6 mmol) in Et2O. During addition of
MeLi a gas development started. After 100 min of stirring
the solution at room temperature methyl formate (515 µL,
8.32 mmol) was added and the turbid yellow solution was
stirred for 69 h at room temperature. Then, Et2O (200 mL)
was added and the turbid brownish solution was washed
with water (2 x 50 mL). The organic phase was separated,
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and the combined aqueous phases were extracted with
was obtained by crystallization from n‐hexane. The melt‐
4
5
6
7
8
9
Et2O (2 x 25 mL).The combined organic phases were dried
over MgSO4 ∙ x H2O, and filtered. The solvents were re‐
moved. The components of the residual yellow solid were
separated by column chromatography (7 cm x 27 cm). Elu‐
tion with CH2Cl2/pentane 4:1 gave tetrathiobenzene 4a
(362 mg; Rf = 0.76) as a yellowish solid, a mixture of uni‐
dentified compounds (105 mg; Rf = 0.67) as an orange oil,
and a yellowish solid (4.59 g; Rf = 0.48; Mp: 210 °C) consist‐
ing of diarylmethanol 8a (90% yield) and CH2Cl2 in the mo‐
lar ratio of 89:11. For 1H NMR and 13C NMR data, see Tables
S4 and S6. MS (ESI): m/z = 622.9 [M + Na]+.
ing point measured by us differs drastically from the melt‐
1
ing point reported in the literature (120‐127 °C).68 For H
NMR and 13C NMR data, see Tables S4 and S6. Data are in
agreement with data given in the literature.68 MS (ESI):
m/z = 620.9 [M + Na]+. Accurate MS (ESI): m/z calcd for
[M + Na]+ C25H26OS8Na+: 620.9642; found, 620.9636. Anal.
Calcd for C25H26OS8: C, 50.13; H, 4.38. Found: C, 50.38; H,
4.32.
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Bis(2,2,6,6‐tetramethyl‐8‐((triisopropylsi‐
lyl)ethynyl)benzo[1,2‐d:4,5‐d']bis([1,3]dithiole)‐4‐
yl)methanone (Diarylketone 9b). To a yellow solution
of diarylmethanol 8b (2.60 g, 2.70 mmol) in dry CH2Cl2 (50
mL) was added Dess–Martin periodinane (1.44 g, 3.39
mmol). After stirring the solution at room temperature for
50 min Et2O (100 mL) was added. The red solution was
washed with an aqueous solution of NaOH (2.0 M, 20 mL)
and water (2 x 30 mL). The organic phase was separated,
dried over MgSO4 ∙ x H2O, and filtered. The solvents were
removed. The components of the residual orange solid
were separated by filtration through silica gel (5 cm x 8
cm). Elution with CH2Cl2/pentane 3:7 gave an orange solid
(2.59 g; Rf = 0.40) consisting of diarylketone 9b (93% yield)
and CH2Cl2 in the molar ratio of 55:45. Solvent‐free diaryl‐
ketone 9b (Mp: 222 – 223 °C) was obtained for analytical
purposes by dissolving the material in Et2O and then re‐
moving all volatiles. For 1H NMR and 13C NMR data, see Ta‐
bles S4 and S7. MS (ESI): m/z = 981.0 [M + Na]+. Accurate
MS (ESI): m/z calcd for [M + Na]+ C47H66OS8Si2Na+:
981.2310; found, 981.2301. Anal. Calcd for C47H66OS8Si2: C,
58.82; H, 6.93. Found: C, 58.88; H, 6.92.
Bis(2,2,6,6‐tetramethyl‐8‐((triisopropylsi‐
lyl)ethynyl)benzo[1,2‐d:4,5‐d']bis([1,3]dithiole)‐4‐
yl)methanol (Diarylmethanol 8b). To a slightly yellow‐
ish solution of a 85:15 mixture (3.61 g) of TIPS‐ethyne sub‐
stituted tetrathiobenzene 4b (7.52 mmol) and n‐pentane
(1.31 mmol) in dry THF (50 mL) was added a solution of
MeLi (1.56 M, 4.6 mL, 7.1 mmol) in Et2O. During addition
of MeLi a gas development started. After 100 min of stirring
the solution at room temperature a solution of methyl for‐
mate in THF (2.2 mL of the solution of 220 µL methyl for‐
mate in 1980 µL THF; This corresponds to 3.6 mmol of me‐
thyl formate) was added and the green solution was stirred
for 68 h at room temperature. Then, Et2O (100 mL) was
added and the solution was washed with water (50 mL).
The brownish organic phase was washed with water (50
mL), dried over MgSO4 ∙ x H2O, and filtered. The solvents
were removed. The components of the residual yellow
solid were separated by column chromatography (4 cm x
30 cm). Elution with CH2Cl2/pentane 1:1 gave four fractions:
(1) TIPS‐ethyne substituted tetrathiobenzene 4b (422 mg;
Rf = 0.78) as a yellow oil; (2) a mixture of TIPS‐ethyne sub‐
stituted tetrathiobenzene 4b and unidentified compounds
(37 mg; Rf = 0.78, 0.67, 0.56) as a red oil; (3) a mixture of
diarylmethanol 8b with traces of unidentified compounds
(50 mg; Rf = 0.56, 0.41) as a yellow oil; (4) diarylmethanol
8b (2.76 g, 80%; Rf = 0.41; Mp: 125 – 127 °C) as a yellow solid.
(2,2,6,6‐Tetramethyl‐8‐((triisopropylsi‐
lyl)ethynyl)benzo[1,2‐d:4,5‐d']bis([1,3]dithiole)‐4‐
yl)bis(2,2,6,6‐tetramethylbenzo[1,2‐d:4,5‐d']bis([1,3]di‐
thiole)‐4‐yl)methanol (TritylOH[H/H/CCTIPS] (10)).
To a yellowish solution of a 90:10 mixture (2.00 g) of TIPS‐
ethyne substituted tetrathiobenzene 4b (4.21 mmol) and n‐
pentane (0.47 mmol) in dry THF (25 mL) was added a so‐
lution of MeLi (1.44 M, 2.7 mL, 3.9 mmol) in Et2O. After
stirring the solution at room temperature for 100 min the
solvent was removed and the remaining brown oil was dis‐
solved in dry Et2O (50 mL). A 98:2 mixture (2.05 g) of dia‐
rylketone 9a (3.41 mmol) and Et2O (0.08 mmol) was added
and the suspension, a green solution with a yellow solid,
was stirred at 30 °C for 7 d. After cooling to room temper‐
ature water (50 mL) and CH2Cl2 (100 mL) were added to
the suspension consisting of a colorless solid in a green so‐
lution. The aqueous phase was separated and extracted
with CH2Cl2 (2 x 20 mL). The combined organic phases
were dried over MgSO4 ∙ x H2O and filtered. The solvents
were removed. The components of the remaining orange
solid were separated by column chromatography (7 cm x
28 cm). Elution with CH2Cl2/pentane 2:3 gave three frac‐
tions: (1) a mixture (673 mg, Rf (CH2Cl2/pentane 2:3) = 0.85,
0.83) of TIPS‐ethyne substituted tetrathiobenzene 4b with
unidentified compounds as a yellow oil; (2) a mixture (95
mg, Rf (CH2Cl2/pentane 2:3) = 0.68) of grease and uniden‐
1
13
For H NMR and C NMR data, see Tables S4 and S7. MS
(ESI): m/z = 983.0 [M + Na]+.
Bis(2,2,6,6‐tetramethylbenzo[1,2‐d:4,5‐d']bis([1,3]di‐
thiole)‐4‐yl)methanone (Diarylketone 9a). To a solu‐
tion of a 89:11 mixture (4.52 g) of the diarylmethanol 8a
(7.38 mmol) and CH2Cl2 (0.91 mmol) in dry CH2Cl2 (100
mL) was added Dess–Martin periodinane (3.98 g, 9.38
mmol). After stirring the solution at room temperature for
60 min Et2O (200 mL) was added. The orange solution was
washed with an aqueous solution of NaOH (2.0 M, 100 mL,
200 mmol) and water (2 x 50 mL). The organic phase was
separated, dried over MgSO4 ∙ x H2O, and filtered. The sol‐
vents were removed. The components of the residual or‐
ange solid were separated by filtration through silica gel (4
cm x 7 cm). Elution with CH2Cl2/pentane 1:1 gave an orange
solid (4.14 g; Rf = 0.64) consisting of diarylketone 9a (92%
yield) and CH2Cl2 in the molar ratio of 88:12. For the syn‐
thesis of tritylOH[H/H/CCTIPS] (10) part of the material
was dissolved in Et2O and then all volatiles were removed
giving diarylketone 9a containing some Et2O. For analyti‐
cal purposes solvent‐free diarylketone 9a (Mp: 215 – 216 °C)
tified
compounds
as
(10)
a
yellow
(2.63 g,
oil;
72%;
(3)
Rf
tritylOH[H/H/CCTIPS]
(CH2Cl2/pentane 2:3) = 0.55; Mp: turned black above 200
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°C, no melting) as a yellow solid. Then, the eluent was
1.75 mL, 2.80 mmol) in hexanes was added to a yellow sus‐
4
5
6
7
8
9
changed to CH2Cl2 and
(CH2Cl2/pentane 2:3)
a
=
mixture (165 mg; Rf
pension of tritylOH[H/H/CCTIPS] (10) (300 mg, 281 µmol)
and N,N,N',N'‐tetramethylethylenediamine (430 µL, 2.85
mmol) in dry n‐hexane (10 mL). After stirring the dark yel‐
low solution at room temperature for 15 min it was added
to the solution of N‐tert‐butoxycarbonylpyridinium tert‐
butanolate (12). After stirring the turbid green suspension
at room temperature for 240 min, it was filtered through
silica gel (3 cm x 2 cm, rinsing with Et2O). The orange fil‐
trate (170 mL) was washed with a saturated aqueous solu‐
tion of NH4Cl (2 x 30 mL), water (30 mL), dried over MgSO4
∙ x H2O, and filtered. The solvents were removed. The com‐
ponents of the residual yellow oil were separated by col‐
umn chromatography (3 cm x 44 cm). Elution with
0.55, 0.33) of
tritylOH[H/H/CCTIPS] (10) and unidentified compounds
was obtained as a yellow oil. As the fifth fraction a mixture
(697 mg; Rf (CH2Cl2/pentane 2:3) = 0.33, 0.15) of diarylke‐
tone 9a and unidentified compounds was obtained as an
1
orange oil. For H NMR and 13C NMR data, see Tables S4
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and S7. MS (ESI): m/z = 1062.9 [M ‐ H]‐, 1068.8 [M + Li ‐
2H]‐, 1086.8 [M + Na ‐ 2H]‐, 1100.8 [M + K ‐ 2H]‐. Accurate
MS (ESI): m/z calcd for [M ‐ H]‐ C48H59OS12Si‐: 1063.0989;
found, 1063.0979.
Bis(2,2,6,6‐tetramethyl‐8‐((triisopropylsi‐
lyl)ethynyl)benzo[1,2‐d:4,5‐d']bis([1,3]dithiole)‐4‐
yl)(2,2,6,6‐tetramethylbenzo[1,2‐d:4,5‐d']bis([1,3]dithi‐
CH2Cl2/pentane 9:11 gave
a
mixture (30 mg; Rf
(CH2Cl2/pentane 9:11) = 0.45; Rf (CH2Cl2/pentane 3:2) =
0.71) of tritylOH[H/H/CCTIPS] (10) and unidentified com‐
pounds as an orange oil and a 31:31:38 mixture (74 mg; Rf
(CH2Cl2/pentane 9:11) = 0.24, 0.18; Rf (CH2Cl2/pentane 3:2)
ole)‐4‐yl)methanol
(TritylOH[H/CCTIPS/CCTIPS]
(11)). To a slightly yellowish solution of tetrathiobenzene
4a (657 mg, 2.29 mmol) in dry THF (25 mL) was added a
solution of MeLi (1.67 M, 1.3 mL, 2.2 mmol) in Et2O. After
stirring the solution at room temperature for 100 min the
solvent was removed and the remaining colorless solid was
suspended in dry Et2O (50 mL). Diarylketone 9b (992 mg,
1.03 mmol) was added and the suspension, a red solution
with a colorless solid, was stirred at 30 °C for 7 d. After
cooling to room temperature water (50 mL) and Et2O (30
mL) were added to the brown solution. The aqueous phase
was separated and extracted with Et2O (2 x 30 mL). The
combined organic phases were dried over MgSO4 ∙ x H2O
and filtered. The solvents were removed. The components
of the remaining orange solid were separated by column
=
0.55, 0.45) of the two diastereomers of
t
tritylOH[H/CO2 Bu/CCTIPS] (23a,b) (together 21% yield;
for structural formula see Chart S1) and tert‐butyl penta‐
noate (24, This compound is the product of the reaction
between n‐BuLi and the reagent N‐tert‐butoxycarbon‐
ylpyridinium tert‐butanolate (12)) as an orange solid.
Then, the eluent was changed to CH2Cl2/pentane 3:2 and a
mixture (42 mg; Rf (CH2Cl2/pentane 9:11) = 0.18; Rf
(CH2Cl2/pentane 3:2) = 0.45) of unidentified compounds
was obtained as an orange oil and, finally,
t
t
tritylOH[CO2 Bu/CO2 Bu/CCTIPS] (13) (110 mg, 31%; Rf
(CH2Cl2/pentane 9:11) = 0.09; Rf (CH2Cl2/pentane 3:2) =
0.29; Mp: 189‐191 °C with gas evolution) was obtained as an
chromatography (6 cm
x
38 cm). Elution with
CH2Cl2/pentane 1:4 gave tetrathiobenzene 4a (213 mg; Rf
(CH2Cl2/pentane 1:4) = 0.53; Rf (CH2Cl2/pentane 3:7) = 0.61)
as a colorless solid. Then, the eluent was changed to
orange
solid.
Additional
analytical
data
of
t
t
1
tritylOH[CO2 Bu/CO2 Bu/CCTIPS] (13): For H NMR and
13C NMR data, see Tables S4 and S7. MS (ESI): m/z = 1287.2
[M + Na]+, 1303.1 [M + K]+. Accurate MS (ESI): m/z calcd for
[M + Na]+ C58H76O5S12SiNa+: 1287.2003; found, 1287.2024. 1H
NMR spectroscopical data of the mixture of the two dia‐
CH2Cl2/pentane 3:7 and
a
mixture (27 mg, Rf
(CH2Cl2/pentane 1:4) = 0.38; Rf (CH2Cl2/pentane 3:7) =
0.47) of tetrathiobenzene 4a, grease, and unidentified com‐
pounds was obtained as a yellow oil. As the third fraction
tritylOH[H/CCTIPS/CCTIPS] (11) (1.08 g, 84%; Rf
(CH2Cl2/pentane 1:4) = 0.23; Rf (CH2Cl2/pentane 3:7) = 0.47;
Mp: 197 °C, turned black) was obtained as a yellow solid.
As the fourth fraction a mixture (16 mg, Rf (CH2Cl2/pentane
1:4) = 0.18; Rf (CH2Cl2/pentane 3:7 = 0.34) of diarylketone
9b, pentane and unidentified compounds was obtained.
1
stereomers); signals assigned to the trityl alcohols 23: H
NMR (500 MHz, CDCl3): δ 7.16 (s, 2H, HAr of 23a and 23b),
6.53 (s, 1H, OH of 23a), 6.49 (s, 1H, OH of 23b), 1.9‐1.6 (m,
72H, C(CH3)2 of 23a and 23b, overlap with tBu), 1.64 (s, 18H,
tBu of 23a and 23b, overlap with C(CH3)2), 1.15 (s, 42H, iPr3Si
of 23a and 23b). The signals of tert‐butyl pentanoate (24)
were identified by comparison with 1H NMR spectroscopi‐
cal data from independently synthesized material. The
synthesis is reported in the Supporting Information.
1
13
For H NMR and C NMR data, see Tables S4 and S7. MS
(ESI): m/z = 1243.0 [M ‐ H]‐, 1249.0 [M + Li ‐ 2H]‐, 1265.0 [M
+ Na ‐ 2H]‐, 1281.0 [M + K ‐ 2H]‐. Accurate MS (ESI): m/z
‐
calcd for [M ‐ H]‐ C59H79OS12Si2 : 1243.2323; found,
Tert‐butyl
8‐(hydroxybis(2,2,6,6‐tetramethyl‐8‐
1243.2329.
((triisopropylsilyl)ethynyl)benzo[1,2‐d:4,5‐
d']bis([1,3]dithiole)‐4‐yl)methyl)‐2,2,6,6‐tetra‐
methylbenzo[1,2‐d:4,5‐d']bis([1,3]dithiole)‐4‐carbox‐
Di‐tert‐butyl
8,8'‐(hydroxy(2,2,6,6‐tetramethyl‐8‐
((triisopropylsilyl)ethynyl)benzo[1,2‐d:4,5‐
t
ylate (TritylOH[CO2 Bu/CCTIPS/CCTIPS] (14)). To pre‐
d']bis([1,3]dithiole)‐4‐yl)methylene)bis(2,2,6,6‐tetra‐
methylbenzo[1,2‐d:4,5‐d']bis([1,3]dithiole)‐4‐carbox‐
pare N‐tert‐butoxycarbonylpyridinium tert‐butanolate
(12) di‐tert‐butyl dicarbonate (240 µL, 1.12 mmol) was
added to a colorless solution of 4‐N,N‐dimethylamino‐
pyridine (196 mg, 1.61 mmol) in dry Et2O (30 mL). The col‐
orless solution was stirred at room temperature for 90 min.
In the meantime, a solution of n‐BuLi (1.60 M, 0.53 mL,
0.80 mmol) in hexanes was added to an orange solution of
tritylOH[H/CCTIPS/CCTIPS] (11) (200 mg, 160 µmol) and
t
t
ylate) (TritylOH[CO2 Bu/CO2 Bu/CCTIPS] (13)). To pre‐
pare N‐tert‐butoxycarbonylpyridinium tert‐butanolate
(12) di‐tert‐butyl dicarbonate (840 µL, 3.93 mmol) was
added to a colorless solution of 4‐N,N‐dimethylamino‐
pyridine (688 mg, 5.63 mmol) in dry Et2O (50 mL). The
slightly yellowish solution was stirred at room temperature
for 75 min. In the meantime a solution of n‐BuLi (1.60 M,
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N,N,N',N'‐tetramethylethylenediamine (121 µL, 802 µmol)
and C NMR data of trithiobenzene 17, see Tables S5 and
4
5
6
7
8
9
in dry n‐hexane (11 mL). After stirring this turbid green so‐
lution at room temperature for 5 min it was added to the
solution of the N‐tert‐butoxycarbonylpyridinium tert‐bu‐
tanolate (12). After stirring the turbid green suspension at
room temperature for 240 min, it was filtered through sil‐
ica gel (2 cm x 7 cm, rinsing with Et2O). The yellow filtrate
(150 mL) was washed with a saturated aqueous solution of
NH4Cl (2 x 30 mL), water (30 mL), dried over MgSO4 ∙ x
H2O, and filtered. The solvents were removed. The compo‐
nents of the residual yellow oil were separated by column
S8. Additional analytical data of trithiobenzene 17: MS (EI):
m/z (%) 270.0 (45) [M]+•, 255.0 (43) [M ‐ •CH3]+, 199.0 (100).
5‐(Tert‐butylthio)‐2,2‐dimethylbenzo[d][1,3]dithi‐
ole (Trithiobenzene 18). To a colorless solution of
tetrathiobenzene 4a (100 mg, 349 µmol) in dry Et2O (10
mL) cooled to ‐20 °C was added a solution of t‐BuLi (2.70
M, 0.13 mL, 0.35 mmol) in heptane. After stirring the yel‐
lowish turbid solution for 30 min, degassed water (300 µL)
was added. After warming it to room temperature, Et2O (10
mL) was added and the colorless solution was washed with
water (3 x 5 mL). The organic phase was dried over MgSO4
∙ x H2O and filtered. The solvents were removed giving a
colorless solid (106 mg) consisting of tetrathiobenzene 4a
and trithiobenzene 18 in the molar ratio of 57:43. Prepara‐
tive HPLC (gradient run with CH2Cl2/n‐hexane, 2.0%
CH2Cl2 at 0 min to 10.0% CH2Cl2 at 25 min, flow rate of 20
mL/min; 35 mg dissolved in CH2Cl2/n‐hexane 2:98 (900 μL)
was injected) gave tetrathiobenzene 4a (13 mg) at 9.2 min
as a colorless solid and trithiobenzene 18 (4 mg) at 11.1 min
as a colorless oil. For 1H NMR and 13C NMR data see Tables
S5 and S8. MS (EI): m/z (%) 270.1 (40) [M]+•, 214.0 (100).
Accurate MS (EI): m/z calcd for [M]+• C13H18S3+•: 270.0565;
found, 270.0558.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
chromatography (2 cm
x
40 cm). Elution with
CH2Cl2/pentane 1:2 gave tritylOH[H/CCTIPS/CCTIPS] (11)
(4 mg, 2%; Rf = 0.61) as an orange oil, a mixture (5 mg; Rf =
0.61, 0.36) of tritylOH[H/CCTIPS/CCTIPS] (11),
t
tritylOH[CO2 Bu/CCTIPS/CCTIPS] (14) and unidentified
compounds
as
a
brown
oil,
and
t
tritylOH[CO2 Bu/CCTIPS/CCTIPS] (14) (70 mg, 32%; Rf =
0.36; Mp: 197‐198 °C with gas evolution) as a yellow solid.
1
13
For H NMR and C NMR data, see Tables S4 and S7. MS
(ESI): m/z = 1367.1 [M + Na]+. Accurate MS (ESI): m/z calcd
for [M
+
Na]+ C64H88O3S12Si2Na+: 1367.2813; found,
1367.2819.
5‐(Butylthio)‐2,2‐dimethylbenzo[d][1,3]dithiole
(Trithiobenzene 16). To a colorless solution of tetrathio‐
benzene 4a (100 mg, 349 µmol) in dry Et2O (10 mL) was
added a solution of n‐BuLi (1.60 M, 0.22 mL, 0.35 mmol) in
hexanes. After stirring the colorless suspension at room
temperature for 30 min, degassed water (300 µL) was
added. Et2O (10 mL) was added and the organic phase was
washed with water (3 x 5 mL). The combined organic
phases were dried over MgSO4 x H2O and filtered. The sol‐
vents were removed giving a colorless solid (104 mg) con‐
sisting of tetrathiobenzene 4a and trithiobenzene 16 in the
molar ratio of 83:17. Preparative HPLC (three isocratic runs
with n‐hexane, flow rate of 20 mL/min; 3 x 24 mg dissolved
in n‐hexane (1300 μL, 2 x 1250 μL) were injected) gave
tetrathiobenzene 4a (31 mg, 31%) at 15.9 min as a colorless
solid and a colorless solid (11 mg) at 17.9 min consisting of
tetrathiobenzene 4a and trithiobenzene 16 in the molar ra‐
5‐(Tert‐butylthio)‐2,2‐dimethylbenzo[d][1,3]dithi‐
ole‐6‐d (Trithiobenzene 18(D)). The synthesis was car‐
ried out under the conditions reported for the synthesis of
trithiobenzene 18 with the only difference that D2O instead
of H2O was added to the lithiated species. A colorless solid
(95 mg) consisting of tetrathiobenzene 4a, deuterated
tetrathiobenzene 4a(D), trithiobenzene 18 and deuterated
trithiobenzene 18(D) in the molar ratio of 30:21:7:42 was
obtained. Preparative HPLC (two isocratic runs with
CH2Cl2/n‐hexane 2:98, flow rate of 20 mL/min; 2 x 35 mg
dissolved in CH2Cl2/n‐hexane 2:98 (2 x 1100 μL) were in‐
jected) gave a mixture of tetrathiobenzenes 4a and 4a(D)
(26 mg) at 12.9 min as a colorless solid and a mixture (17
mg) of tetrathiobenzenes 4a/4a(D), trithiobenzenes 18,
and deuterated trithiobenzene 18(D) in the molar ratio of
1:12:87 was obtained at 16.8 min as a colorless solid. For 1H
NMR and 13C NMR data, see Tables S5 and S8.
1
13
tio of 45:55. For H NMR and C NMR data see Tables S5
and S8. MS (EI): m/z (%) 270.1 (40) [M]+•, 255.1 (100) [M ‐
•CH3]+.
Tris(2,2,6,6‐tetramethylbenzo[1,2‐d:4,5‐
d']bis([1,3]dithiole)‐4‐yl)methanol (TritylOH[H/H/H]
(19)) synthesized by addition of lithiated tetrathio‐
benzene 5a to diarylketone 9a. To a slightly yellowish
solution of tetrathiobenzene 4a (335 mg, 1.17 mmol) in dry
THF (15 mL) was added a solution of MeLi (1.90 M, 0.55
mL, 1.1 mmol) in Et2O. After stirring the solution at room
temperature for 100 min the solvent was removed and the
remaining slightly yellowish solid was suspended in dry
Et2O (20 mL). A 56:44 mixture (350 mg) of diarylketone 9a
(525 µmol) and CH2Cl2 (413 µmol) was added and the sus‐
pension consisting of a colorless solid in a green solution
was stirred at 30 °C for 7 d. After cooling to room temper‐
ature, water (30 mL) and CH2Cl2 (50 mL) were added to the
suspension consisting of a yellowish solid in an orange so‐
lution. The aqueous phase was separated and extracted
with CH2Cl2 (2 x 30 mL). The combined organic phases
were dried over MgSO4 ∙ x H2O and filtered. The solvents
were removed. The components of the remaining orange
5‐(Sec‐butylthio)‐2,2‐dimethylbenzo[d][1,3]dithiole
(Trithiobenzene 17). To a colorless solution of tetrathio‐
benzene 4a (100 mg, 349 µmol) in dry Et2O (10 mL) was
added a solution of s‐BuLi (1.40 M, 0.25 mL, 0.35 mmol) in
n‐hexane/cyclohexane 8:92. After stirring the colorless
suspension at room temperature for 30 min, degassed wa‐
ter (300 µL) was added. Et2O (10 mL) was added and the
colorless solution was washed with water (3 x 5 mL). The
organic phase was dried over MgSO4 ∙ x H2O and filtered.
The solvents were removed giving a colorless solid (107 mg)
consisting of tetrathiobenzene 4a and trithiobenzene 17 in
the molar ratio of 74:26. Preparative HPLC (isocratic run
with n‐hexane, flow rate of 20 mL/min; 27 mg dissolved in
n‐hexane (1300 μL) was injected) gave tetrathiobenzene 4a
(18 mg) at 15.0 min as a colorless solid and a colorless solid
(4 mg) at 18.2 min consisting of tetrathiobenzene 4a and
1
trithiobenzene 17 in the molar ratio of 4:96. For H NMR
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solid were separated by column chromatography (3 cm x
(2) a colorless liquid (5.74 g) consisting of tert‐butyl pen‐
tanoate (24) (71% yield) and tert‐butanol in the molar ratio
of 99:1. A part (437 mg) of fraction 2 was dissolved in pen‐
tane (10 mL). The colorless solution was washed with water
(5 x 50 mL). The organic phase was separated, dried over
MgSO4 ∙ x H2O, and filtered. The solvent was removed at
19 mbar at room temperature giving tert‐butyl pentanoate
24 cm). Elution with CH2Cl2/pentane 5:6 gave four frac‐
tions: (1) tetrathiobenzene 4a (85 mg; Rf = 0.69) as a
slightly yellowish solid; (2) a mixture (3 mg; Rf = 0.69, 0.48)
of tetrathiobenzene 4a and unidentified compounds as a
brown solid; (3) tritylOH[H/H/H] (19) (293 mg, 63%; Rf =
0.31) as a yellowish solid; (4) a 92:2:6 mixture (76 mg, Rf =
0.31) of tritylOH[H/H/H] (19) (16% yield), diarylketone 9a
(0.3% yield) and CH2Cl2 as a yellow solid. For 1H NMR and
13C NMR data, see Tables S4 and S7. Data are in agreement
with data given in the literature.61 MS (MALDI): m/z =
884.0 [M]+.
1
(24) (433 mg) as a colorless liquid. H NMR (500 MHz,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3
CDCl3): δ 2.18 (t, J = 7.5 Hz, 2H, CH2CO), 1.54 (quint like
with shoulders, 2H, CH2CH2CO), 1.41 (s, 9H, CMe3), 1.31
(sext like, 2H, CH3CH2), 0.88 (t, 3J = 7.5 Hz, 3H, CH3CH2).
13C NMR (125 MHz, CDCl3): δ 173.3 (CO), 79.8 (CMe3), 35.3
(CH2CO), 28.1 (CMe3), 27.2 CH2CH2CO), 22.2 (CH3CH2),
13.7 (CH3CH2).
Comment: If we were to repeat this synthesis, we would
use diarylketone without CH2Cl2. CH2Cl2 can be exchanged
for Et2O as described in the procedure for the synthesis of
diarylketone 9a.
EPR spectroscopical experiments
Tris(2,2,6,6‐tetramethylbenzo[1,2‐d:4,5‐
The Finland trityl, which was used for EPR measure‐
ments, were synthesized according to published proce‐
dures.61,67 Solutions (200 μM) of the trityl radicals in etha‐
nol were filled into quartz capillaries of 3 mm (Aachener
Quartzglas, Aachen, Germany) and 0.9 mm (Wilmad
Labglass, Vineland, USA) outer diameter for X and W band
EPR experiments, respectively, without prior degassing.
When needed, a carbon fiber (Institutes of Textile and Fi‐
ber Research, Denkendorf, Germany), used as g‐factor
standard,80 was added to the solutions.
d']bis([1,3]dithiole)‐4‐yl)methanol (TritylOH[H/H/H]
(19)) synthesized by addition of lithiated tetrathio‐
benzene 5a to dimethyl carbonate. To a slightly yellow‐
ish solution of tetrathiobenzene 4a (3.00 g, 10.5 mmol) in
dry THF (20 mL) was added a solution of MeLi (1.71 M, 5.5
mL, 9.4 mmol) in Et2O. After stirring the solution at room
temperature for 100 min the solvent was removed and the
remaining slightly yellowish solid was suspended in dry
Et2O (60 mL). Dimethyl carbonate (0.22 mL, 2.6 mmol)
was added and the yellow suspension was stirred at 30 °C
for 7 d. After cooling to room temperature, CH2Cl2 (80 mL)
and water (40 mL) were added to the suspension consist‐
ing of a yellowish solid in an orange solution. The aqueous
phase was separated and extracted with CH2Cl2 (20 mL).
The combined organic phases were dried over MgSO4 ∙ x
H2O and filtered. The solvents were removed. The compo‐
nents of the remaining orange solid were separated by col‐
umn chromatography (5 cm x 54 cm). Elution with
CH2Cl2/pentane 5:6 gave a mixture (550 mg, Rf = 0.63) of
tetrathiobenzene 4a and traces of unidentified compounds
as a slightly yellowish solid and a mixture (2.03 g, Rf = 0.30)
of tritylOH[H/H/H] (19) (86% yield), CH2Cl2, and pentane
in the molar ratio of 80:19:1.
Pulse EPR experiments were performed on an Elexsys
E680 EPR spectrometer (Bruker Biospin, Rheinstetten,
Germany) at X band (approx. 9.5 GHz) using a Bruker MD5
resonator as well as at W band (approx. 94.2 GHz) using a
Bruker ENDOR resonator. For both X and W band meas‐
urements we used pulse lengths of 16 ns and 32 ns for π/2
and π pulses, respectively, unless stated otherwise. 2‐pulse
ESEEM was recorded using the sequence (π/2 – τ – π – τ ‐
echo) by incrementing τ for 1024 points in steps of 8 ns us‐
ing a two‐step phase cycle to cancel receiver offsets. The
inversion recovery sequence (π ‐ t ‐ π/2 – τ – π – τ ‐ echo)
with the two‐step phase cycle was used to determine T1 by
incrementing t in steps of 12 μs for 4096 points or 20 μs for
2048 for X and W band, respectively. Additionally, 3‐pulse
ESEEM (π/2 – τ – π/2 – T ‐ π/2 ‐ τ ‐ echo) was measured at
X band by incrementing T in steps of 8 ns for 1024 points
using a four‐step phase cycle with τ = 144 ns, 164 ns, and
184 ns for τ averaging. 3‐pulse ESEEM time domain data
were baseline‐corrected using a 4th order polynomial func‐
tion, apodized by a Hamming window, zero‐filled to twice
the number of points, here 2048, and then Fourier trans‐
formed and the magnitude spectrum was calculated.
Tert‐butyl pentanoate (24). The procedure of Yamada
et al.84 was followed with slight modifications. To a color‐
less solution of tert‐butanol (10.0 mL, 106 mmol), 4‐N,N‐
dimethylaminopyridine (4 mg, 0.6 mmol), and pyridine
(5.0 mL, 62 mmol) in dry CH2Cl2 (15 mL) cooled with an
ice water bath was added pentanoyl chloride (6.0 mL, 50
mmol) within 2 min. After 15 min the ice water bath was
removed and the suspension consisting of a colorless solid
in a yellow solution was stirred at room temperature for 22
h. Et2O (50 mL) was added and the suspension was washed
with water (25 mL), an aqueous solution of HCl (2 M, 25
mL), a saturated aqueous solution of NaHCO3 (25 mL) and
water (25 mL). The organic phase was separated, dried over
MgSO4 ∙ x H2O, and filtered. The solvents were removed
at 500 mbar and 40 °C bath temperature. The components
of the residual yellow liquid were separated by distillation
at 19 mbar. At 80 °C bath temperature two fractions, both
with 56 °C vapor temperature, were collected: (1) a color‐
less liquid (358 mg) consisting of tert‐butyl pentanoate
(24) (4% yield) and tert‐butanol in the molar ratio of 94:6;
Continuous wave (cw) EPR measurements were per‐
formed on a Bruker Elexsys E500 or Bruker EMX spectrom‐
eter using a Bruker SHQ resonator and recorded at a mi‐
crowave power of 3.17 μW (48 dB attenuation) at 50 K or
200.2 μW (30 dB attenuation) at room temperature, re‐
spectively, in order to avoid saturation effects. The cw EPR
spectra were recorded using 8192 points and a 100 kHz
magnetic field modulation with an amplitude of 0.02 mT
for subsequent lock‐in amplification with a conversion
time and time constant of 40.96 ms and 1.28 ms, respec‐
tively. The radical content of the samples was quantified
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by double integration of the room temperature spectra and
comparison to a solution of FTR with known concentra‐
tion.
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lar Oxygen Probes, J. Org. Chem. 2008, 73, 1490–1497.
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W band cw EPR measurements were carried out in the
same setup as W band pulse experiments. Spectra were
recorded at 50 K and a nominal microwave power of 0.006
μW (60 dB attenuation) ensuring non‐saturated condi‐
tions using 1024 points and a 100 kHz magnetic field mod‐
ulation with an amplitude of 0.1 mT with a conversion time
of 81.92 ms and time constant of 1.28 ms. Magnetic field
offsets of W band cw EPR spectra were corrected using
Mn(II) in CaO (Bruker Biospin) and the carbon fiber as a
reference. The spectra were baseline corrected and simu‐
lated using the Matlab package EasySpin85, taking into ac‐
count g tensor and g distribution.
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13
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16
17
18
19
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ASSOCIATED CONTENT
Supporting Information. Results for lithiation of tetrathio‐
benzene 4a and trityl alcohols 10, 11, and 19, pictures taken
during the synthesis of tritylOH[H/CCTIPS/CCTIPS] (11), a
chapter on identified byproducts and side products, addi‐
tional EPR spectra, information on the reagents used, tables
with 1H and 13C NMR data, and figures showing the NMR spec‐
tra and some MS spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
godt@uni‐bielefeld.de.
Author Contributions
The manuscript was written through contributions of all au‐
thors. All authors have given approval to the final version of
the manuscript.
Funding Sources
Deutsche Forschungsgemeinschaft (DFG) within SPP 1601
(GO555/6‐2). ETH grant SEED‐73 16‐1.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This work was supported by the Deutsche Forschungsgemein‐
schaft (DFG) within SPP 1601 (GO555/6‐2). D.K. was sup‐
ported by ETH grant SEED‐73 16‐1. We are thankful for the
contributions of the research students Mira Keßler and Chris‐
tian Becker in the initial stage of the project and thank Guido
Grassi and Daniel Zindel for the synthesis of the Finland trityl
radical used for EPR measurements.
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