Efficient synthesis of thioamide terminated molecular wires

Article abstract of DOI:10.1016/j.tetlet.2006.09.032

Bis-thioamide terminated 'molecular wires' are formed in a high yield under mild conditions from readily synthesised bis-nitrile terminated molecules and aqueous ammonium sulfide in DMF.

Full text of DOI:10.1016/j.tetlet.2006.09.032

Tetrahedron Letters 47 (2006) 8147–8150
Efficient synthesis of thioamide terminated molecular wires
Sally Dixon and Richard J. Whitby*
School of Chemistry, University of Southampton, Southampton, Hants SO17 1BJ, UK
Received 13 July 2006; revised 31 August 2006; accepted 7 September 2006
Available online 29 September 2006
Abstract—Bis-thioamide terminated ‘molecular wires’ are formed in a high yield under mild conditions from readily synthesised bis-
nitrile terminated molecules and aqueous ammonium sulfide in DMF.
ꢀ 2006 Elsevier Ltd. All rights reserved.
A fundamental question in molecular electronics is
the conductivity characteristics of potential ‘molecular
wires’ such as oligo(phenylene ethynylene)s (OPEs), in
particular when bound between metal electrodes. Re-
cently, methods have been developed with the potential
to make conductance measurements on single molecules
and the methods and results have been reviewed.1 Most
measurements so far have used thiol terminated mole-
cular wires to link between two gold electrodes.1,2
Although measurements on poorly conducting n-alkane-
dithiols show a reasonable agreement between different
methods, the same is not true of unsaturated wires such
as OPEs, where the conductivity of similar wires varies
by several orders of magnitude. Indeed, the conductivity
of individual molecules is found to vary substantially
using the same measurement method3a and even with
time (stochastic switching).3b,c,d For thiol terminated
unsaturated wires (unlike the saturated series), it is likely
that conductance is dominated by the gold–sulfur con-
tact. Theoretical and experimental studies indicate that
small changes in the hybridisation state of sulfur, or
how it binds to the gold surface have dramatic effects
on the ‘contact resistance’.3c,4
rest of the wire. Currently single examples of the use
of pyridyl5 and isonitrile6 contact groups provide the
only published variation from thiol terminated wires in
the measurement of single molecule conductivity.
Thiols have other disadvantages as the anchoring group.
Free thiols rapidly dimerise and in situ deprotection of
thioacetates is usually adopted. Unfortunately, the thio-
acetate group has a poor stability under the reaction
conditions usually used to synthesise molecular wires
such as Sonogashira7 coupling of terminal alkynes with
aryl bromides.8,9
Herein, we report the preparation of two-terminal
primary-thioamide substituted OPEs as potential mole-
cular wires. We felt that the thioamide group had many
potential advantages over sulfide as a contacting termi-
nus: thioamides should be easily generated from cyanide
groups which are stable to the reaction conditions for
OPE synthesis; they are easily handled species which
are not prone to rapid dimerisation; and contact resis-
tance of the thioamide group should not suffer from
the same sensitivity to sulfur rehybridisation as observed
for thiols, and may display a two-point binding to a gold
surface.10 We are aware of only one report on the use of
thioamide as an anchoring group in the formation of a
self assembled monolayer (SAM) on a gold surface.11
An anchoring group which displays less variation in
conductance is crucial for future studies, and the ulti-
mate goal is one which does not provide a significant
barrier to electron transport.
The preparation of thioamides by thionation of aryl
nitriles using ammonium sulfide in methanol has been
reported to occur either at room temperature or under
microwave irradiation.12 We initially sought to apply
this method to the conversion of a model nitrile termi-
nated bis-arylalkyne 113 to the corresponding thioamide
2 (Table 1). The poor solubility of 1, and most other
potential molecular wires, in methanol prompted a
A comparison between molecular wires differing only in
the contact groups is also important to allow separation
of the effects on conductivity of the junctions and the
*
Corresponding author. Tel.: +44 23 80592777; fax: +44 23
80593781; e-mail: rjw1@soton.ac.uk
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.09.032

8148
S. Dixon, R. J. Whitby / Tetrahedron Letters 47 (2006) 8147–8150
Table 1. Conversion of arylnitrile 1 to arylthioamide 2
and we were delighted to observe a clean and high yield-
ing conversion to thioamide 2 in less than an hour with
only 1.5 equiv of (NH4)2S (entries 5–7).
S
(NH4)2S aq
N
NH2
1
2
With an efficient method in hand to convert arylnitriles
to thioamides, we prepared a series of p-conjugated
oligo(phenylene ethynylene) molecular wires with two-
terminal nitrile functionality via iterative Sonogashira
cross-coupling (Scheme 1).
Entry
Equivalent
(NH4)2S
Solvent
Temp
(ꢁC)
Time
(h)
Yielda
2 (%)
1
2
3
4
5
6
7
1.25
3.0
5.0
10.0
10.0
3.0
EtOH
EtOH
EtOH
EtOH
DMF
DMF
DMF
80
80
20
20
20
20
20
24
18
30
18
0.5
0.5
1.0
10
40
88
89
89
88
92
1,4-Diiodo-2,5-di-noctyloxybenzene (3) was prepared
according to the previously reported procedures14 and
coupled with 4-ethynylbenzonitrile15 (4) to afford bis-
nitrile 8.16 4-((4-Ethynylphenyl)ethynyl)benzonitrile (5)17
was prepared by chemoselective Sonogashira coupling
between 4-ethynylbenzonitrile and 1-bromo-4-iodobenz-
ene at ambient temperature; coupling of the resultant
aryl bromide with trimethylsilylacetylene under identical
conditions except that the temperature was increased to
70 ꢁC; and protodesilylation with K2CO3/MeOH fur-
nished 5. Sonogashira coupling of 2 equiv of 5 with core
diiodide 3 comprised a straightforward and high yield-
ing synthesis of the bis-nitrile terminated compound 9.
Compounds 8 and 9 were obtained in high purity after
flash chromatography of the crude product following
1.5
a Isolated yield.
change to ethanol for the solvent but under these condi-
tions there was no reaction at room temperature and
heating to reflux, or use of microwave heating, resulted
in significant decomposition (Table 1, entry 1). We have
previously observed the susceptibility of OPEs to nucle-
ophilic attack by thiolate. Pleasingly, increasing the
amount of ammonium sulfide allowed the isolation of
2 in a good yield (entries 2–4). However, long reaction
times prompted the investigation of DMF as the solvent
h, 94%
H2N
S
S
NC
CN
CN
10
NH2
6
h, 83%
f, 49%
H2N
S
S
Br
CN
NC
NH2
i. c, 96%
ii. d, 89%
7
11
CN
OnC8H17
OnC8H17
h, 87%
H2N
S
S
4
NC
CN
NH2
e, 84%
nC8H17
O
nC8H17
O
OnC8H17
I
OH
OH
8
12
i. a, 74%
ii. b, 80%
I
OnC8H17
OnC8H17
3
e, 72%
9
NC
CN
nC8H17
O
CN
5
h, 67%
i. g, 93%
ii. c, 82%
iii. d, 83%
OnC8H17
H2N
S
NH2
13
S
CN
nC8H17
O
Scheme 1. Reagents and conditions: (a) nC8H17Br (2.5 equiv), KOH (2.5 equiv), nBu4N+Brꢀ (9 mol %), 80 ꢁC, 16 h; (b) Hg(OAc)2 (2.5 equiv), I2
(2.5 equiv), CH2Cl2, rt, 12 h; (c) trimethylsilylacetylene (1.2 equiv), PdCl2(PPh3)2 (5 mol %), CuI (10 mol %), triethylamine (3.0 equiv), benzene,
70 ꢁC, 16 h; (d) K2CO3 (10 equiv), MeOH, CH2Cl2, rt 30 min; (e) PdCl2(PPh3)2 (10 mol %), CuI (20 mol %), triethylamine (6.0 equiv), THF, rt, 16 h;
(f) 4-ethynylbenzonitrile (1.0 equiv), PdCl2(PPh3)2 (5 mol %), CuI (10 mol %), triethylamine (3.0 equiv), benzene, 70 ꢁC, 16 h; (g) 1-bromo-4-
iodobenzene (1.0 equiv), PdCl2(PPh3)2 (5 mol %), CuI (10 mol %), triethylamine (3.0 equiv), THF, rt, 16 h; (h) (NH4)2S (6.0 equiv of a 50% wt
aqueous solution), DMF, rt, 30 min.

S. Dixon, R. J. Whitby / Tetrahedron Letters 47 (2006) 8147–8150
8149
Elbing, M.; Mayor, M.; Weber, H. B. Faraday Discuss.
2006, 131, 281.
4. (a) Bratkovsky, A. M.; Kornilovitch, P. E. Phys. Rev. B
2003, 67, 115307; (b) Basch, H.; Cohen, R.; Ratner, M. A.
Nano Lett. 2005, 5, 1668.
precipitation from the reaction mixture with water, rep-
resenting an important practical improvement upon the
use of earlier described molecular wires incorporating
labile protecting groups on sulfur. The ‘2-ring’ analogue
4,40-(ethyne-1,2-diyl)dibenzonitrile (7) is known18 and
displays a good solubility in common organic solvents
without the necessity for alkoxy substituents. Hence 7
was simply obtained via cross-coupling between 4-bro-
mobenzonitrile and 4-ethynylbenzonitrile.
5. Xu, B.; Tao, N. J. Science 2003, 301, 1221.
6. Kim, B.; Beebe, J. M.; Jen, Y.; Zhu, X.-Y.; Frisbie, C. D.
J. Am. Chem. Soc. 2006, 128, 4970; Isonitriles are unstable
under ambient conditions when absorbed on gold: Sta-
pleton, J. J.; Daniel, T. A.; Uppili, S.; Cabarcos, O. M.;
Naciri, J.; Shashidhar, R.; Allara, D. L. Langmuir 2005,
21, 11061.
n
Compounds 7–9, together with commercially available
1,4-dicyanobenzene (6), constitute a suitable array of
precursor molecules to the desired bis-thioamide termi-
nated molecular wires.19
7. Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron
Lett. 1975, 16, 4467.
8. (a) Tour, J. M.; Rawlett, A. M.; Kozaki, M.; Yao, Y.;
Jagesson, R. C.; Dirk, S. M.; Price, D. W.; Reed, M. A.;
Zhou, C.-W.; Chen, J.; Wang, W.; Campbell, I. Chem.
Eur. J. 2001, 7, 5118; (b) Wang, C.; Batsanov, A. S.;
Bryce, M. R. J. Org. Chem. 2006, 71, 108; (c) Pearson, D.
L.; Tour, J. M. J. Org. Chem. 1997, 62, 1376; (d) Wang,
C.; Batsanov, A. S.; Bryce, M. R.; Sage, I. Org. Lett. 2004,
6, 2181; (e) Flatt, A. K.; Dirk, S. M.; Henderson, J. C.;
Shen, D. E.; Su, J.; Reed, M. A.; Tour, J. M. Tetrahedron
2003, 59, 8555; (f) Li, G.; Wang, X.; Wang, F. Tetrahedron
Lett. 2005, 46, 8971.
The conditions developed for thioamide synthesis above
were applied to bis-nitriles 6–9 and 3 equiv of ammo-
nium sulfide was found to be optimal for the clean thio-
nation of each nitrile group. Hence, the conversion to
bis-thioamide terminated molecular wires 10–13 was
effected under mild conditions in good to excellent yields
(Scheme 1).16
9. 2-(4-Pyridynyl)ethyl (Yu, C. J.; Chong, Y.; Kayyen, J. F.;
Gozin, M. J. Org. Chem. 1999, 64, 2070), 2-cyanoethyl8d
and 2-(trialkylsilyl)ethyl8e protecting groups display an
improved stability under the basic conditions of Sono-
gashira coupling; however, in situ deprotection conditions
are not suitable for self-assembly on gold. Deprotection as
a separate reaction, usually followed by acetylation ready
for in situ deprotection, is required.
In summary, we have demonstrated the first synthesis of
bis-thioamide terminated molecular wires to be straight-
forward, clean and high yielding. Studies on the electri-
cal characteristics of these molecules will be reported
elsewhere.
10. No evidence for a nitrogen–gold bond was reported
following the chemisorption of structurally analogous
thiourea to gold: Yamaguchi, A.; Penland, R. B.; Mizu-
shima, S.; Lane, T. J.; Curran, C.; Quagliano, J. V. J. Am.
Chem. Soc. 1958, 80, 527.
Acknowledgements
We thank the EPSRC for funding this work through an
adventurous chemistry research Grant No. EP/
C528824/1.
11. Aoki, H.; Buhlmann, P.; Umezawa, Y. J. Electroanal.
¨
Chem. 1999, 473, 105.
12. Bagley, M. C.; Chapaneri, K.; Glover, C.; Merritt, E. A.
Synlett 2004, 14, 2615.
13. Sonogashira coupling between 4-bromobenzonitrile and
phenylacetylene under the standard conditions furnished 1
in 88% isolated yield.
References and notes
1. Selzer, Y.; Allara, D. L. Annu. Rev. Phys. Chem. 2006, 57,
593; James, D. K.; Tour, J. M. Chem. Mater. 2004, 16,
4423; Salomon, A.; Cahen, D.; Lindsay, S.; Tomfohr, J.;
Engelkes, V. B.; Frisbie, C. D. Adv. Mater. 2003, 15, 1881.
2. Reed, M. A.; Zhou, C.; Muller, C. J.; Burgin, T. P.; Tour,
J. M. Science 1997, 278, 252; Cui, X. D.; Primak, A.;
Zarate, X.; Tomfohr, J.; Sankey, O. F.; Moore, A. L.;
Moore, T. A.; Gust, D.; Harris, G.; Lindsay, S. M. Science
2001, 294, 571; Tour, J. M. Acc. Chem. Res. 2000, 33, 791;
Xiao, X. Y.; Xu, B. Q.; Tao, N. J. Nano Lett. 2004, 4, 267;
Weber, H. B.; Reichert, J.; Weigend, F.; Ochs, R.;
Beckmann, D.; Mayor, M.; Ahlrichs, R.; von Lohneysen,
H. Chem. Phys. 2002, 281, 113; Haiss, W.; Nichols, R. J.;
van Zalinge, H.; Higgins, S. J.; Bethell, D.; Schiffrin, D. J.
Phys. Chem. Chem. Phys. 2004, 6, 4330; Ishizuka, K.;
Suzuki, M.; Fuju, S.; Takayama, Y.; Sato, F.; Fujihira, M.
Jpn. J. Appl. Phys. 2006, 45, 2037.
3. (a) Ulrich, J.; Esrail, D.; Pontius, W.; Venkataraman, L.;
Millar, D.; Doerrer, L. H. J. Phys. Chem. B 2006, 110,
2462; (b) Ramachandran, G. K.; Hopson, T. J.; Rawlett,
A. M.; Nagahara, L. A.; Primak, A.; Lindsay, S. M.
Science 2003, 300, 1413; (c) Moore, A. M.; Damiron, A.
A.; Mantooth, B. A.; Smith, R. K.; Fuchs, D. J.; Ciszek, J.
W.; Maya, F.; Yao, Y.; Tour, J. M.; Weiss, P. S. J. Am.
Chem. Soc. 2006, 128, 1959; (d) Ochs, R.; Secker, D.;
´
14. (a) Loupy, A.; Sansoulet, J.; Dıez-Barra, E.; Carrilla, J. R.
Synth. Commun. 1991, 21, 1465; (b) Shirai, Y.; Zhao, Y.;
Cheng, L.; Tour, J. M. Org. Lett. 2004, 6, 2129.
15. Musso, D. L.; Clarke, M. J.; Kelley, J. L.; Boswell, G. E.;
Chen, G. Org. Biomol. Chem. 2003, 1, 498.
16. Typical procedures. 4,40-(2,5-Bis(octyloxy)-1,4-phenyl-
ene)bis(ethyne-2,1-diyl)dibenzonitrile (8). To a stirred
solution of 1,4-diiodo-2,5-bis(octyloxy)benzene (3)
(586.4 mg, 1.0 mmol), PdCl2 (17.7 mg, 0.1 mmol), PPh3
(52.5 mg, 0.2 mmol) and CuI (38.1 mg, 0.2 mmol) in THF
(5 mL) was added a solution of 4-ethynylbenzonitrile
(254 mg, 2.0 mmol) (4) in THF (10 mL) followed by
triethylamine (0.84 mL, 6.0 mmol). The mixture was
stirred in the dark at room temperature for 16 h before
pouring onto H2O (150 mL), extraction with CH2Cl2
(2 · 150 mL), drying over MgSO4 and concentration in
vacuo. Purification by column chromatography (SiO2,
eluted with 2:1 CH2Cl2–hexane) gave the title compound
(8) as an off-white solid (492 mg, 84%) mp 104–107 ꢁC. 1H
NMR (400 MHz, CDCl3): d = 7.57 (4H, d, J = 8.7 Hz),
7.52 (4H, d, J = 8.7 Hz), 6.94 (2H, s), 3.96 (4H, t,
J = 6.3 Hz), 1.81–1.74 (4H, m), 1.50–1.42 (4H, m), 1.34–
1.14 (16H, m), 0.80 (6H, t, J = 7.3 Hz) ppm. 13C NMR
(100.5 MHz, CDCl3): d = 154.10 (s), 132.25 (d), 132.20

8150
S. Dixon, R. J. Whitby / Tetrahedron Letters 47 (2006) 8147–8150
(d), 128.49 (s), 118.69 (s), 117.05 (d), 114.03 (s), 111.77 (s),
(s), 124.46 (s), 122.16 (s), 118.65 (s), 117.14 (d), 114.21 (s),
111.92 (s), 94.72 (s), 93.65 (s), 89.69 (s), 88.67 (s), 69.89 (t),
32.01 (t), 29.58 (t), 29.56 (t), 29.51 (t), 26.29 (t), 22.87
(t), 14.28 (q) ppm. IR (solid): m = 2199 (w, br), 1595 (m),
834 (s) cmꢀ1. LRMS (MALDI-TOF): m/z = 784 (M+,
100%). Microanalysis. C56H52O2N2 requires: C, 85.68; H,
6.68; N, 3.57. Found: C, 85.41; H, 6.63; N, 3.49.
4,40-(4,40-(2,5-Bis(octyloxy)-1,4-phenylene)bis(ethyne-2,1-
diyl)bis(4,1-phenylene))bis(ethyne-2,1-diyl)dibenzothio-
amide (13) was prepared as for 12 except that it was
protected from light during the reaction, purification and
storage. It was isolated as a yellow solid mp 203–205 ꢁC.
1H NMR (400 MHz, (CD3)2SO): d = 10.01 (2H, br s), 9.64
(2H, br s), 8.01 (4H, d, J = 8.5 Hz), 7.70 (4H, d,
J = 8.8 Hz), 7.68 (4H, d, J = 8.8 Hz), 7.62 (4H, d,
J = 8.5 Hz), 7.26 (2H, s), 4.12 (4H, t, J = 6.3 Hz), 1.81
(4H, pentet, J = 7.3 Hz), 1.56 (4H, pentet, J = 7.8 Hz),
1.45–1.25 (16H, m), 0.88 (6H, t, J = 7.0 Hz) ppm. 13C
NMR (100.5 MHz, (CD3)2SO): d = 198.87 (s), 153.21 (s),
139.15 (s), 131.87 (d), 131.51 (d), 130.99 (d), 127.70 (d),
124.57 (s), 123.04 (s), 122.11 (s), 116.64 (d), 113.17 (s),
94.36 (s), 91.10 (s), 90.92 (s), 88.49 (s), 68.91 (t), 31.22 (t),
28.81 (t), 28.74 (2 · t), 25.61 (t), 22.13 (t), 13.96 (q). IR
(solid): m = 3367 (w, br), 3268 (w, br), 1721 (w), 1625 (w),
1213 (m, br), 833 (s) cmꢀ1. LRMS (ESꢀ): m/z = 851
(MꢀH+, 100%). Microanalysis: C56H56N2O2S2 requires:
C, 78.83; H, 6.62; N, 3.28. Found: C, 78.80; H, 6.57; N,
3.23.
93.64 (s), 90.49 (s), 69.84 (t), 31.99 (t), 29.54 (t), 29.50 (t),
29.48 (t), 26.27 (t), 22.85 (t), 14.26 (q) ppm. IR (solid):
m = 2227 (w), 2198 (w), 1600 (w), 837 (s) cmꢀ1. LRMS
(EI): m/z = 584 (M+, 100%), 360 (76%). Microanalysis.
C40H44O2N2 requires: C, 82.15; H, 7.58; N, 4.79. Found:
C, 82.12; H, 7.30; N, 4.74.
4,40-(2,5-Bis(octyloxy)-1,4-phenylene)bis(ethyne-2,1-diyl)-
dibenzothioamide (12). To a stirred solution of 4,40-(2,5-
bis(octyloxy)-1,4-phenylene)bis(ethyne-2,1-diyl)dibenzo-
nitrile (8) (117.3 mg, 0.2 mmol) in DMF (5 mL) was added
ammonium sulfide (0.16 mL of a 50% wt aqueous solu-
tion, 1.2 mmol) and the resultant green solution was
stirred at room temperature for 30 min. The solution was
then poured onto H2O (100 mL) and extracted with
EtOAc (150 mL) before washing with H2O (100 mL),
drying over MgSO4 and concentration in vacuo. Purifica-
tion by column chromatography (SiO2, eluted with 1:1
hexane–EtOAc) gave the title compound (12) as a yellow
1
solid (114.0 mg, 87%). Mp 198–202 ꢁC (from ethanol). H
NMR (400 MHz, (CD3)2SO): d = 10.00 (2H, br s), 9.61
(2H, br s), 8.02 (4H, d, J = 8.5 Hz), 7.58 (4H, d,
J = 8.5 Hz), 7.27 (2H, s), 4.13 (4H, t, J = 6.0 Hz), 1.81
(4H, pentet, J = 7.5 Hz), 1.56 (4H, pentet, J = 7.5 Hz),
1.45–1.25 (16H, m), 0.88 (6H, t, J = 7.0 Hz) ppm. 13C
NMR (100.5 MHz, (CD3)2SO): d = 198.81 (s), 153.21 (s),
138.85 (s), 130.56 (d), 127.64 (d), 125.09 (s), 116.63 (d),
113.18 (s), 94.23 (s), 88.39 (s), 68.89 (t), 31.15 (t), 30.63 (t),
28.71 (t), 28.67 (t), 25.53 (t), 22.04 (t), 13.87 (q) ppm. IR
(solid): t = 3299 (w, br), 3156 (w, br), 1643 (m), 1410 (m),
842 (s) cmꢀ1. LRMS (ES+): m/z = 653 (M+H+). Micro-
analysis. C40H48N2O2S2 requires: C, 73.58; H, 7.41; N,
4.29. Found: C, 73.70; H, 7.43; N, 4.10.
17. Lavastre, O.; Caboich, S.; Dixneuf, P. H. Tetrahedron
1997, 53, 7595.
18. Zhang, W.; Kraft, S.; Moore, S. J. J. Am. Chem. Soc.
2004, 126, 329.
19. Calculations20 indicate that nitrile terminated molecular
wire 6, between gold electrodes, should have a large zero
bias conductance (close to the conductance quantum) due
to the close alignment of the LUMO with the Fermi level
of gold allowing near-resonant-tunnelling through the
LUMO. Although nitriles are not expected to bind
strongly enough to gold to be useful as ‘fixed’ molecular
wires, we are investigating the use of 6–9 in dynamic
conductance experiments.
4,40-(4,40-(2,5-Bis(octyloxy)-1,4-phenylene)bis(ethyne-2,1-
diyl)bis(4,1-phenylene))bis(ethyne-2,1-diyl)dibenzonitrile
(9) was prepared as for 8 as a white solid mp 167–168 ꢁC.
1H NMR (400 MHz, CDCl3): d = 7.58 (4H, d,
J = 8.5 Hz), 7.53 (4H, d, J = 8.5 Hz), 7.48–7.43 (8H, m),
6.95 (2H, s), 3.97 (4H, t, J = 6.5 Hz), 1.78 (4H, pentet,
J = 6.8 Hz), 1.56–1.44 (6H, m), 1.36–1.16 (14H, m), 0.80
(6H, t, J = 7.0 Hz) ppm. 13C NMR (100.5 MHz, CDCl3):
d = 153.98 (s), 132.29 (2 · d), 131.92 (d), 131.80 (d), 128.20
20. Xue, Y.; Ratner, M. A. Phys. Rev. B 2004, 69, 0854403.