Synthesis of novel highly soluble N-(3,5-di-tert-butylbenzyl)-monopyrrolo- tetrathiafulvalene derivatives

Article abstract of DOI:10.1080/10426507.2010.524175

Highly soluble bis-(2-cyanoethyl)-protected derivative (11) of monopyrrolo-tetrathiafulvalene containing a bulky 3,5-di-tert-butylbenzyl solubilizing group has been synthesized and characterized. It was successfully employed to prepare two aromatic conjug

Full text of DOI:10.1080/10426507.2010.524175

Phosphorus, Sulfur, and Silicon, 186:1278–1283, 2011
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2010.524175
SYNTHESIS OF NOVEL HIGHLY SOLUBLE
N-(3,5-DI-TERT-BUTYLBENZYL)-MONOPYRROLO-
TETRATHIAFULVALENE DERIVATIVES
Andreas Denhof, Jens Cordes, and Vladimir A. Azov
Department of Chemistry, University of Bremen, Bremen, Germany
Abstract Highly soluble bis-(2-cyanoethyl)-protected derivative (11) of monopyrrolo-
tetrathiafulvalene containing a bulky 3,5-di-tert-butylbenzyl solubilizing group has been
synthesized and characterized. It was successfully employed to prepare two aromatic
conjugates of monopyrrolo-tetrathiafulvalenes (TTFs) and is proposed to be used for
preparation of TTF-containing molecular tweezers.
Keywords Molecular recognition; molecular tweezers; pyrrolo-tetrathiafulvalenes; tetrathia-
fulvalenes; thiolates
INTRODUCTION
Tetrathiafulvalenes1 (commonly known as TTFs, 1; Figure 1) represent one of the
most widely studied heterocyclic systems. Initially, research focus was concentrated on their
application in the field of organic electronics.2 Later, due to the strong electron-donating
capabilities of tetrathiafulfalenes and the possibility of reversible stepwise oxidation, they
have found use in many other areas of chemistry,1,3 where their unique electrochemical
properties are of an interest. In supramoleculrar chemistry, tetrathiafulvalenes have been
elegantly employed for molecular recognition of electron-deficient viologen-based macro-
cycles and served as molecular motors in various interlocked architectures,4 triggering re-
versible positional displacement of supramolecular components upon oxidation/reduction.5
Previously we have reported the synthesis and characterization of bis-TTF molecular
tweezers6 2, which comprised aromatic backbone connected to two tetrathiafulvalene arms
via semi-rigid eight-membered dithia rings (Figure 1). Molecular tweezers are know as
efficient guest binders, able to sandwich flat, electron-deficient guest molecules in between
their arms.7 Use of tetrathiafulvalene arms should afford the possibility to switch reversibly
between the binding (ground) and nonbinding (oxidized) states of the receptors. In addition,
the redox-driven large-scale switching between two profoundly different conformations6a
suggests their use for the construction of molecular machines.
Received 24 June 2010; accepted 13 September 2010.
We are grateful to Dr. T. Du¨lcks and D. Kemken for recording MS spectra.
Address correspondence to Vladimir Azov, Department of Chemistry, University of Bremen, Leobener
Strasse NW 2C, D-28359 Bremen, Germany. E-mail: vazov@uni-bremen.de
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HIGHLY SOLUBLE MONOPYRROLO-TETRATHIAFULVALENES
1279
Figure 1 Structures of tetrathiafulvalene 1 and bis-TTF molecular tweezers 2 and 3.
In this article, we report the synthesis of highly soluble bis-(2-cyanoethyl)-protected
monopyrrolo-tetrathiafulvalene derivative and two model monopyrrolo-tetrathiafulvalenes,
which were prepared in order to test the new synthetic strategy aimed for construction of
molecular tweezers with monopyrrolo-TTF arms.
RESULTS AND DISCUSSION
As reported,6b initial binding studies have demonstrated affinity of the bis-TTF tweez-
ers to electron-poor organic guests. The binding was relatively weak, which was due
to the poor electron-donating properties of the tetrathioalkyl-tetrathiafulvalenes. Pyrrolo-
TTFs8 are known to have lower oxidation potentials as well as more extended π-systems,
which significantly improve their binding ability in comparison to tetrathioalkyl-TTFs.9
Monopyrrolo-tetrathiafulvalenes have been successfully employed before for the synthesis
of molecular belts10 and tweezer-like architectures,11 which were proved to be efficient
binders of electron-deficient species. Thus, we considered monopyrrolo-TTFs with large
solubilizing groups as possible arms for molecular tweezers 3 (Figure 1).
The common synthetic methodology8 for the preparation of asymmetric
monopyrrolo-tetrathiafulvalene derivatives employs the building block 4 (Scheme
1), containing tosyl and two cyanoethyl protective groups, as a key intermediate. First,
the side containing cyanoethyl protective groups is substituted using conventional
thiolate chemistry12 giving 5a, and then the substitution on the tosylated side of the
monopyrrolo-TTF is carried out in a two-step sequence affording the target compound 6.
Scheme 1 Common methodology for the preparation of monopyrrolo-tetrathiafulvalene derivatives.
We decided to modify this methodology due to the expected poor solubility of the
intermediate molecular tweezers without large solubilizing groups. Thus, we have chosen to
install the bulky 3,5-di-tert-butylbenzyl moiety during the earlier synthetic steps to render
high solubility to the synthetic intermediates and target compounds.

1280
A. DENHOF ET AL.
The synthesis started with dibromo-derivative 7,8a which was treated with 3,5-di-tert-
butylbenzylamine 813 under the basic conditions, followed by the oxidation of the inter-
mediate 9 by 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) to afford dithiolo[4,5]pyrrole-
2-thione 10 (Scheme 2). The key intermediate, bis(2-cyanoethylthio)tetrathiafulvalene 11,
was prepared in a phosphite-mediated coupling of thione 10 and oxo-derivative 1212 using
triethylphosphite as a coupling agent. This step required stepwise addition of compound
12 to avoid excessive homo-coupling of 12 with the formation of the nondesired sym-
metric tetrakis(2-cyanoethylthio)tetrathiafulvalene. Two mono-TTF aromatic derivatives
13a,b have been synthesized in reaction of TTF dithiolates,12 which were generated in situ
from 2,3-bis(2-cyanoethylthio)tetrathiafulvalene 11, with aromatic methylene bromides
14a and 14b.14 Three new tetrathiafulvalene derivatives 11 and 13a,b represent bright yel-
low crystals or slowly crystallizing syrups, which are relatively prone to oxidation on air
in a solution. Synthesis and characterization of bis-moopyrrolo-TTF molecular tweezers 3
should follow.15
Scheme 2 Synthesis of the tetrathiafulvalene derivatives 11 and 13a,b.
To conclude, the synthesis of the bis-cyanoethylprotected monopyrrolo-
tetrathiafulvalene 11 has been performed, and the first monopyrrolo-TTF derivatives with
the aromatic backbone 13a,b have been prepared, paving the way for the synthesis of
bis-monopyrrolo-TTF molecular tweezers 3.
EXPERIMENTAL
All experiments were carried out under inert atmosphere. When necessary, solvent
degassing was performed using two to three freeze–pump–thaw cycles. Nuclear mag-
netic resonance (NMR) spectra were recorded in CDCl3 with a Bruker Avance DPX-200
spectrometer. Chemical shifts (δ) are reported in parts per million (ppm) downfield from
1
tetramethylsilane using the residual CHCl3 peak as internal reference (7.26 ppm for H,
77.23 ppm for 13C). Melting points were determined using capillary melting point apparatus
and are uncorrected. Reactions were monitored by thin-layer chromatography (TLC) and Rf

HIGHLY SOLUBLE MONOPYRROLO-TETRATHIAFULVALENES
1281
values were determined using 0.2-mm silica gel F-254 TLC cards. Flash chromatography
(FC) was carried out using 230–440 mesh (particle size 36–70 µm) silica gel.
5-(3,5-Di-tert-butylbenzyl)-5,6-dihydro-4H-1,3-dithiolo[4,5-c]pyrolle-
2-thione (9)
Solution of dibromide 7 (2.87 g, 8.97 mmol) in tetrahydrofuran (THF)/MeCN (1:2,
30 mL) was added to the hot mixture of amine 8 (1.96 g, 8.93 mmol) and Cs2CO3 (11.7
g, 36 mmol) in THF/MeCN (1:2, 60 mL) over a period of 10 min. The reaction mixture
was stirred with reflux for 1 h. Then the solvent was removed, the brown residue was
dissolved in CH2Cl2 and washed with brine, and the organic phase was dried (MgSO4).
FC (CH2Cl2/PE, 1:1) afforded 2.64 g (78%, 7.0 mmol) of the yellow crystalline product
9. Rf = 0.55 (CH2Cl2). Mp 145–147◦C. 1H NMR (200 MHz, CDCl3): δ = 1.33 (s, 18H,
CH3), 3.87 (s, 4H, CH2), 3.94 (s, 2H, CH2), 7.17 (d, J = 1.8 Hz, 2H, Aryl-H), 7.34 ppm
(t, J = 1.8 Hz, 1H, Aryl-H). 13C NMR (50 MHz, CDCl3): δ = 31.72, 35.02, 57.54, 61.16,
121.71, 122.85, 137.18, 139.04, 151.25 ppm. HR-EI-MS (70 eV): m/z = 377.12800 (M+,
C20H27NS3+, Calcd. 377.13057).
5-(3,5-Di-tert-butylbenzyl)-5H-1,3-dithiolo[4,5-c]pyrolle-2-thione (10)
A mixture of compound 9 (2.64 g, 6.99 mmol) and 2,3-dichloro-5,6-
dicyanobenzoquinone (1.74 g, 7.67 mmol) was refluxed in dry toluene (50 mL) for
1 h. The precipitate was removed by filtration and the filtrate was washed with 10%
NaOH. The organic phase was dried (MgSO4) and concentrated to a dark brown oil. FC
(CH2Cl2/PE, 2:3) afforded 2.10 g (80%, 5.59 mmol) of yellow crystalline 10. Rf = 0.29
(CH2Cl2/PE, 2:3). Mp 171–175◦C. 1H NMR (200 MHz, CDCl3): δ = 1.30 (s, 18H, CH3),
5.10 (s, 2H, CH2), 6.73 (s, 2H, CH-N), 7.01 (d, J = 1.8 Hz, 2H, Aryl-H), 7.40 ppm (t, J =
1.8 Hz, 1H, Aryl-H). 13C NMR (50 MHz, CDCl3): δ = 31.62, 35.08, 55.31, 112.69, 114.18,
122.01, 122.60, 135.68, 151.85, 196.94 ppm. HR-EI-MS (70 eV): m/z = 375.11458 (M+,
C20H25NS3+, Calcd. 375.11492).
2-[4,5-Bis(2-cyanoethylthio)-1,3-dithiol-2-ylidene]-5-(3,5-di-tert-butylbenzyl)-
5H-1,3-dithiolo[4,5-c]pyrrole (11)
Suspension of compounds 10 (0.399 g, 1.06 mmol) and 12 (0.33 g, 1.14 mol) in
freshly distilled P(OEt)3 (10 mL) was heated up to 110◦C and then two additional portions
of 12 (0.33 g, 1.14 mmol) were added at intervals of 30 min. After anadditional 30 min
P(OEt)3 was removed by distillation in vacuum and the product 11 was purified by FC
(CH2Cl2) to give 194 mg (30%, 0.315 mmol) of the bright yellow crystalline product. Rf
= 0.35 (CH2Cl2). Mp 151–154◦C. 1H NMR (200 MHz, CDCl3): δ = 1.30 (s, 18H, CH3),
2.73 (t, J = 7.0 Hz, 4H, CH2), 3.08 (t, J = 7.0 Hz, 4H, CH2), 4.97 (s, 2H, Aryl-CH2), 6.52
(s, 2H, CH-N), 7.01 (d, J = 1.8 Hz, 2H, Aryl-H), 7.38 ppm (t, J = 1.8 Hz, 1H, Aryl-H). 13
C
NMR (50 MHz, CDCl3): δ = 19.05, 31.44, 31.61, 35.04, 55.34, 107.00, 113.17, 117.68,
118.76, 121.97, 122.42, 124.82, 127.87, 135.93, 151.69 ppm. IR (KBr): ν = 2252 cm−1
(CN). UV/Vis (CH2Cl2): λmax (ε) = 329 nm (18,750 dm3 mol−1 cm−1). HR-EI-MS (70
eV): m/z = 615.09914 (M+, C29H33N3S6+, Calcd. 615.09988).

1282
A. DENHOF ET AL.
Compounds 13a,b, General Procedure
To a degassed chilled solution of 11 (50 mg, 0.081 mmol) in dimethylformamide
(DMF) (3 mL) 1 M CsOH/MeOH solution (0.17 mL, 0.17 mmol) was added; the mixture
was stirred for 15 min at rt and then the aromatic bromide 14 (0.080 mmol) was added
in THF (1 mL) upon chilling to 0◦C. The mixture was stirred for 90 min and allowed to
warm to rt. The solvent was removed under vacuum and the product 13 was purified by FC
(CH2Cl2/C6H12, 1:3).
Compound 13a. Yield 30 mg (61%, 0.049 mmol) of yellow-orange slowly crys-
1
tallizing syrup. Rf = 0.29 (CH2Cl2/C6H12, 1:3). Mp 140–143◦C. H NMR (200 MHz,
CHCl3): δ = 1.27 (s, 18H, CH3), 4.26 (s, 4H, CH2-S), 4.92 (s, 2H, CH2-N), 6.43 (s, 2H,
CH-N), 6.96 (d, J = 2 Hz, 2H, Aryl-H), 7.18–7.31 (m, 4H, Aryl-H), 7.34 ppm (t, J = 2.0
Hz, 1H, Aryl-H). 13C NMR (50 MHz, CDCl3): δ = 31.62, 35.04, 38.65, 55.20, 110.84,
113.00, 119.10, 120.98, 121.87, 122.31, 128.85, 130.11, 130.76, 134.80, 136.11, 151.64
ppm. HR-EI-MS (70 eV): m/z = 611.09326 (M+, C31H33NS6+, Calcd. 611.09373).
Compound 13b. Yield 26 mg (39%, 0.032 mmol) of yellow-orange slowly crys-
tallizing oil. Rf = 0.27 (CH2Cl2/C6H12, 1:3). Mp 114–115◦C. 1H NMR (200 MHz, CDCl3)
δ = 0.93 (t, J = 6.4 Hz, 6H, CH3), 1.28 (s, 18H, CH3), 1.24–1.60 (m, 12H, (CH2)3CH3),
1.73–1.86 (m, 4H, CH2CH2O), 3.95 (t, J = 6.4 Hz, 4H, CH2-O), 4.33 (s, 4H, CH2-S), 4.93
(s, 2H, CH2-N), 6.45 (s, 2H, CH-N), 6.78 (s, 2H, Aryl-H), 6.97 (d, J = 1.8 Hz, 2H, Aryl-H),
7.35 ppm (t, J = 1.8 Hz, 1H, Aryl-H). 13C NMR (50 MHz, CDCl3) δ = 14.35, 22.90, 26.09,
29.63, 31.62, 31.79, 31.89, 35.05, 55.21, 69.50, 111.69, 112.53, 112.98, 119.19, 120.57,
121.86, 122.31, 125.23, 130.76, 136.15, 150.75, 151.64 ppm. HR-EI-MS (70 eV): m/z =
811.27066 (M+, C43H57NO2S6+, Calcd. 811.27136).
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