In Situ Coupling of Single Molecules Driven by Gold-Catalyzed Electrooxidation

Article abstract of DOI:10.1002/anie.201906215

A single-molecule method has been developed based on the scanning tunneling microscope (STM) to selectively couple a series of aniline derivatives and create azobenzenes. The Au-catalyzed oxidative coupling is driven by the local electrochemical potential at the nanostructured Au STM tip. The products are detected in situ by measuring the conductance and molecular junction elongation and compared with analogous measurements of the expected azobenzene derivatives prepared ex situ. This single-molecule approach is robust, and it can quickly and reproducibly create reactions for a variety of anilines. We further demonstrate the selective synthesis of geometric isomers and the assembly of complex molecular architectures by sequential coupling of complementary anilines, demonstrating unprecedented control over bond formation at the nanoscale.

Full text of DOI:10.1002/anie.201906215

A Journal of the Gesellschaft Deutscher Chemiker
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Accepted Article
Title: In situ coupling of single molecules driven by Au-catalyzed
electrooxidation
Authors: Yaping Zang, Ilana Stone, Michael Inkpen, Fay Ng, Tristan
Lambert, Colin Nuckolls, Michael L. Steigerwald, Xavier Roy,
and Latha Venkataraman
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201906215
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In situ coupling of single molecules driven by Au-catalyzed elec-
trooxidation
Yaping Zang[a][d], Ilana Stone [b][d], Michael S. Inkpen[a], Fay Ng[b], Tristan H. Lambert[c], Colin Nuckolls[b],
Michael L. Steigerwald[b], Xavier Roy* [b], Latha Venkataraman* [a],[b]
Abstract: Understanding how chemical bonds are formed and broken
is the foundation of molecular design. Observing these processes in
individual molecules promises levels of detail and precision beyond
those achieved through traditional ensemble techniques. Here we
develop a single-molecule method based on the scanning tunneling
microscope (STM) to selectively couple a series of aniline derivatives
and create azobenzenes. The Au-catalyzed oxidative coupling is
driven by the local electrochemical potential at the nanostructured Au
STM tip. The products are detected in situ by measuring the
conductance and molecular junction elongation and compared with
analogous measurements of the expected azobenzene derivatives
prepared ex situ. This single-molecule approach is robust, and it can
quickly and reproducibly creates reactions for a variety of anilines. We
further demonstrate the selective synthesis of geometric isomers and
the assembly of complex molecular architectures by sequential
coupling of complementary anilines demonstrating unprecedented
control over bond formation at the nanoscale.
and comparing these values to control compounds prepared ex
situ.[1d] Capitalizing on the remarkable sensitivity of the STM
technique, we demonstrate that either the trans or the less stable
cis isomer forms selectively, the selectivity being determined by
the group appended to the aniline. Expanding this strategy to
more complex systems, we couple complementary aniline units to
form molecules with multiple bridging diazenyl groups in the
junction.
Ubiquitous in biological processes, oxidative coupling reactions
are important for chemical synthesis and bioconjugation[1] as an
alternative to traditional cross-coupling strategies.[2] While several
homogeneous and heterogeneous oxidants can effect oxidative
coupling,[3] the development of nanocatalysts and electrosynthetic
techniques to drive such reactions has emerged as a new frontier
in the search for versatile and environmentally friendly synthetic
methods.[4] However, the electrocatalytic coupling process is
typically monitored through ensemble measurements.
Figure 1. (a) Schematic illustrating the in situ coupling of two aniline-derivatives
driven by Au-catalyzed electrooxidation in the molecular junctions. (b) Molecular
structures of the anilines A1-A5 used in this work to create azobenzene
derivatives.
In this work we use a scanning tunneling microscope-based
(STM) technique[5] to investigate nanocatalytic electrooxidative
coupling in a series of anilines, and for the first time detect the in
situ single-molecule formation of azobenzenes. Originally
employed as dyes and pigments,[6] aromatic azo compounds
have generated interest for applications as smart materials,[7]
light-activated switches[8] and therapeutic agents.[9] Traditional
methods of preparation employ diazonium salts or nitroso
derivatives as reactants, or more practical building blocks such as
nitrobenzenes and anilines.[6, 10] Here we show that anilines can
Experimental details for the modified STM technique have
been described previously.[11] Briefly, break junction
measurements are performed in an ionic environment using an
insulated Au STM tip,[12] with an exposed area of ~1 μm2, and an
Au substrate with an area larger than 0.5 cm2. When a potential
bias is applied to the tip, a dense electric double layer builds up
around the small tip area. The local electrochemical potential
within the double layer can facilitate redox reactions. We
measured the single-molecule conductance of a series of anilines
(Figure 1) in propylene carbonate (10-100 μM concentration) with
tetrabutylammonium perchlorate as supporting electrolyte (0.1 M
concentration).
Figure 2a presents sample conductance-displacement
traces for 4-mercaptoaniline (A1) at different junction bias
voltages. When the tip bias is +100 mV, a short conductance
plateau (~0.15 nm) appears at ~10–2 G0 (where G0 = 2e2/h is the
conductance quantum), indicating the formation of single A1
junctions. Increasing the tip bias to +600 mV (i.e. a more oxidative
potential) results in a new, longer plateau (~0.6 nm) at a lower
conductance of ~9×10–3 G0. To ensure these features are
statistically reproducible, we repeat the measurement thousands
undergo
a “one pot” selective oxidative coupling on a
nanostructured Au STM tip under oxidative bias (Figure 1). The
formation of single azobenzenes in the junction is validated by
measuring their conductance and molecular junction length in situ
[a]
Dr. Yaping Zang, Dr. Michael S. Inkpen, Prof. Latha Venkataraman
Department of Applied Physics and Applied Mathematics, Columbia
University, New York
E-mail: lv2117@columbia.edu,
xr2114@columbia.edu
[b]
[c]
[d]
Ilana Stone, Dr. Fay Ng, Prof. Colin Nuckolls, Dr. Michael L. Stei-
gerwald, Prof. Xavier Roy, Prof. Latha Venkataraman
Department of Chemistry, Columbia University, New York
Prof. Tristan H. Lambert
Department of Chemistry and Chemical Biology, Cornell University,
Ithaca
These authors contributed equally to this work
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10.1002/anie.201906215
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of times at both tip biases and compile the traces into one-
dimensional (1D) logarithmically-binned conductance histograms
and two-dimensional (2D) conductance-displacement histograms
without any data selection. This analysis provides two molecule-
specific signatures: the most probable molecular conductance
from the 1D histogram and the junction elongation (or molecular
plateau length), which relates to the molecular backbone length,
from the 2D histogram.[13]
tip bias. The 1D histogram for Az1 made ex situ shows a clear
conductance peak (black histogram in Figure 2b) at the same
value as that for the in situ coupling product of A1. The junction
elongation displayed in the 2D histogram for Az1 prepared ex situ
(Figure 2d) is essentially the same as that for Az1 formed in situ
(Figure 2c). This confirms that the new molecule created in the
junction is the azo compound Az1 produced from the oxidative
coupling of A1.
Figure 2e proposes
a reaction mechanism for the
electrooxidative dimerization of anilines. The transformation starts
by breaking an Au point contact and forming a single-molecule
junction containing the aniline bound to an undercoordinated Au
atom through a donor-acceptor bond. Under oxidative bias, the
aniline is oxidized at the tip, forming a radical cation. Consistent
with this behavior, we have previously demonstrated that
oligophenylenediamines trapped in molecular junctions can be
electrochemically oxidized using the STM technique.[14] The
oxidized aniline then undergoes attack by a second aniline that is
either bound to an electrode (and possibly oxidized), or in the
surrounding solution. Proton loss leads to the formation of a
hydrazine (–NH–NH–) which is known to oxidize readily to form
the diazenyl (–N=N–) bridge.[15] This mechanism is analogous to
that previously proposed for the oxidative coupling of anilines into
azobenzenes under aerobic conditions using Au nanoparticles
supported on TiO2 as catalyst.[10] We note that the necessary
voltage to trigger the electrooxidation at the tip (~0 mV versus the
ferrocene/ferrocenium redox couple) is lower than the oxidation
potential of aniline and its derivatives,[16] suggesting that the redox
transformation in the junction is facilitated by the attachment of
the anilines to undercoordinated Au atoms (active sites). This
contrasts with homogeneous bulk syntheses requiring strong
oxidants, most often in stoichiometric quantities.[6, 17]
We can also couple anilines with varying backbones and
different aurophilic binding groups. For example, Figure S3
illustrates the coupling of the longer molecule A2, and Figure 1
shows the range of binding groups we have tested, including thiol,
thiomethyl, alkynyl and pyridyl groups (A3-A5). In all cases the
low tip bias measurements are typical of single-molecule
junctions across the original aniline with high conductance and
short elongation (Figure S4-S6 and Figure 3). At higher positive
tip bias, junctions with lower conductance and longer plateaus are
observed, indicating the formation of the azobenzene derivatives
Az3-Az5 via electrooxidative coupling. The diversity of aurophilic
groups that can be used in the junction is a clear sign that the in
situ reaction homocouples aniline moieties.
Figure 2. (a) Conductance traces of A1 measured at a tip bias of +100 mV (red)
and +600 mV (blue). (b) Logarithmically-binned 1D histograms of A1 measured
at +100 mV (red) and +600 mV (blue), and Az1 prepared ex situ and measured
at +600 mV (black). (c) 2D conductance-displacement histogram created by
aligning and overlaying all A1 traces measured at +600 mV. (d) 2D
conductance-displacement histogram of Az1 prepared ex situ and measured at
+600 mV. (e) Proposed mechanism for the formation of azobenzene derivatives
via electrooxidation of anilines in single-molecule junctions. L = aurophilic linker
group used here (thiol, thiomethyl, alkynyl or pyridyl).
At a +100 mV tip bias, the conductance peak for A1 is
centered at ~1.7 × 10–2 G0 (red histogram in Figure 2b). The
corresponding 2D histogram reveals a short junction elongation
consistent with the short molecular length of A1 (Figure S2b). At
a +600 mV tip bias, a new well-defined peak emerges at a lower
conductance of ~4.6 × 10-3 G0 (blue histogram in Figure 2b). The
corresponding 2D histogram shows a markedly longer molecular
plateau (Figure 2c). Together these distinct features signify the
formation of a new junction with a molecule that is longer than A1.
A negative (reductive) tip bias does not produce longer junctions
with lower conductance (Figure S2). To account for these
observations, we propose that under positive tip bias, A1
undergoes an oxidative coupling reaction to form 4,4'-
dimercaptoazobenzene (Az1).
Figure 3. (a) Logarithmically -binned 1D histograms of A5 measured at +800
mV (purple), and cis-Az5 (pink) and trans-Az5 (yellow) prepared ex situ
(measured at +700 mV). Inset: structure of and cis-Az5 and trans-Az5. (b) 2D
conductance-displacement histogram of A5 measured at +800 mV. The small
conductance feature at ~10–4 G0 comes from a different binding geometry of the
pyridyl group in the A5 junction in which the Au–N bond is perpendicular to the
To verify this hypothesis, we synthesized Az1 ex situ (as the
trans isomer), and compared its molecular conductance and
junction elongation to those for the in situ coupling of A1 at high
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10.1002/anie.201906215
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ring system, leading to lower electronic coupling.[18] (c) 2D conductance-
displacement histogram of cis-Az5 prepared ex situ and measured at +700 mV.
single azo compound at high bias as the coupling reaction does
not terminate.[14] We can therefore create asymmetric azo
compounds or even polymers with complex architectures.
Azobenzenes have received a lot of attention due to their
ability to undergo cis/trans isomerization when irradiated with
visible or UV light.[9] By synthesizing the products ex situ, we
explored the selective formation of cis and trans isomers in the
junction. For example, the 1D and 2D histograms for the in situ
coupling of A1 and A4 agree very well with those of trans-Az1
(Figure 2) and trans-Az4 (Figure S5), suggesting that these
anilines form the more stable trans isomer at the STM tip.
Remarkably, the pyridyl aniline A5 does not produce trans-Az5 in
the junction (Figure 3). To demonstrate that A5 instead forms the
less stable cis isomer, we synthesized both cis-Az5 and trans-
Az5 geometric isomers ex situ and measured their single-
molecule conductance. Because the conductance features of the
isomers are distinct, we can differentiate between. In the 1D
histogram, the conductance peak for the in situ conversion of A5
(blue) overlays that of cis-Az5 synthesized ex situ (pink) and is
distinct from trans-Az5 (yellow). In the 2D histogram, the
molecular plateau for the in situ formation of Az5 is the same
length as that of cis-Az5 and much shorter than that of trans-Az5
(Figure S6). This difference in selectivity for A5 could arise from
either the geometric or electronic constraints imposed by the
binding modes of the pyridine linkers to the nanostructured Au
electrodes.[18]
We next investigated more complex single-molecule
reactions. Figure 4a shows the double oxidative coupling of
complementary aniline units A1 and benzidine A6 into the longer
bis-azo compound Az1-6-1. The reactants A1 and A6 were first
combined in propylene carbonate in a 1:5 stoichiometric ratio (10-
100 µM). Measurements at a tip bias of +700 mV show two types
of traces (Figure 4b), each having a lower conductance and
longer molecular plateau than A1. We collected 5000 traces in
this mixed solution and compiled them into a 1D histogram (Figure
4c). This histogram shows two clear peaks. The peak at ~5×10–3
G0 is analogous to that shown in Figure 2a, and corresponds to
the Az1 junction. The lower conductance peak at ~8×10–5 G0 has
a significantly longer plateau, which we attribute to Az1-6-1 based
on the conductance and plateau length. The vast majority of
traces show only one of the two plateaus, but a small fraction
contains both. We therefore analyze the data and select 28%
(~1400/5000) and 26% (~1300/5000) of the traces that have a
feature in the range of the lower and higher conductance peaks.
These selected traces are then compiled into separate 2D
histograms (Figure 4d,e) to clearly show the differences between
traces corresponding to Az1 (Figure 2c) and those featuring
plateaus consistent with the molecular length of Az1-6-1 (~2.3
nm).
Figure 4. (a) Reaction that couples two A1 and one A6 into Az1-6-1. (b) Sample
conductance traces for mixture of A1 and A6 measured at +700 mV. The two
traces on the left show a plateau corresponding to Az1 while the two traces on
the right show
a much longer plateau corresponding to Az1-6-1. (c)
Logarithmically-binned 1D histogram for the in situ coupling of A1 and A6 at a
tip bias of +700 mV. The two peaks correspond to Az1 and Az1-6-1. (d) 2D
conductance displacement histogram of ~1300 traces selected out of 5000 with
conductance plateaus around 5×10–3 G0 (e) 2D conductance displacement
histogram of ~1400 selected traces with conductance ~8×10–5 G0.
In summary, by trapping and oxidizing aniline derivatives in
molecular junctions comprised of nanostructured Au electrodes,
we have developed a new method to form –N=N– bonds. The
electrooxidative coupling reaction is facilitated by the Au and
proceeds with a variety of molecules. The azobenzenes formed
in situ and their geometric configurations were characterized by
their distinct conductance and verified by measuring the products
synthesized ex situ. By combining complementary building units
that can form multiple diazenyl groups, we can create longer and
more complex molecules. This precise control over single-
molecule bond formation introduces an archetype for unraveling
the mechanistic reaction pathways of synthetic redox reactions
and illuminates new avenues for molecular design.
To further verify that this new molecular junction is not from
the single coupling reaction of A1 and A6, we coupled A1 and A2
in situ to create an asymmetric azobenzene (Az1-2) whose
conductance features should resemble that of the putative Az1-6
product. The 1D and 2D histograms for Az1-2 (Figure S7) show a
higher conductance (~10-3 G0) and a shorter plateau than Az1-6-
1, a clear indication that the peak at ~8×10–5 G0 in Figure 4c is
from the coupling of two A1 units to A6. Note that the diamine A6
alone does not yield well-defined conductance signatures of a
Acknowledgements
We thank Zhen-Fei Liu for discussions. We thank Brandon Fowler
for high-resolution mass-spectrometry. This research was
supported by the National Science Foundation grant DMR-
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[7]
[8]
Y. Zhao, T. Ikeda, Smart light-responsive materials: azobenzene-
containing polymers and liquid crystals, John Wiley & Sons, 2009.
a) B. L. Feringa, R. A. van Delden, N. Koumura, E. M. Geertsema, Chem.
Rev. 2000, 100, 1789-1816; b) C. Zhang, M. H. Du, H. P. Cheng, X. G.
Zhang, A. E. Roitberg, J. L. Krause, Phys. Rev. Lett. 2004, 92, 158301;
c) B. Y. Choi, S. J. Kahng, S. Kim, H. Kim, H. W. Kim, Y. J. Song, J. Ihm,
Y. Kuk, Phys. Rev. Lett. 2006, 96, 156106; d) V. Ferri, M. Elbing, G. Pace,
M. D. Dickey, M. Zharnikov, P. Samorì, M. Mayor, M. A. Rampi, Angew.
Chem. Int. Ed. 2008, 47, 3407-3409.
1807580 and National Science Foundation MRSEC program
through the Center for Precision Assembly of Superstratic and
Superatomic Solids (DMR-1420634), the U.S. Air Force Office of
Scientific Research (AFOSR) grant FA9550-18-1-0020, and the
NSF (CHE-1464992). M.S.I acknowledges support through the
Marie Skłodowska-Curie Global Fellowship (MOLCLICK: 657247)
within the Horizon 2020 Programme.
[9]
J. Broichhagen, J. A. Frank, D. Trauner, Acc. Chem. Res. 2015, 48,
1947-1960.
Keywords:
azobenzene, single-molecule measurements.
Electrooxidation,
electrocatalysis,
aniline,
[10] A. Grirrane, A. Corma, H. Garcia, Science 2008, 322, 1661-1664.
[11] a) L. Venkataraman, J. E. Klare, I. W. Tam, C. Nuckolls, M. S. Hybertsen,
M. L. Steigerwald, Nano Lett. 2006, 6, 458 - 462; b) B. Capozzi, J. Xia,
O. Adak, E. J. Dell, Z.-F. Liu, J. C. Taylor, J. B. Neaton, L. M. Campos,
L. Venkataraman, Nat. Nanotechnol. 2015, 10, 522-527.
[1]
a) J. Cai, P. Ruffieux, R. Jaafar, M. Bieri, T. Braun, S. Blankenburg, M.
Muoth, A. P. Seitsonen, M. Saleh, X. Feng, K. Mullen, R. Fasel, Nature
2010, 466, 470-473; b) D. G. de Oteyza, P. Gorman, Y.-C. Chen, S.
Wickenburg, A. Riss, D. J. Mowbray, G. Etkin, Z. Pedramrazi, H.-Z. Tsai,
A. Rubio, M. F. Crommie, F. R. Fischer, Science 2013, 340, 1434-1437;
c) A. C. Aragones, N. L. Haworth, N. Darwish, S. Ciampi, N. J. Bloomfield,
G. G. Wallace, I. Diez-Perez, M. L. Coote, Nature 2016, 531, 88-91; d)
M. S. Inkpen, Y. R. Leroux, P. Hapiot, L. M. Campos, L. Venkataraman,
Chem. Sci. 2017, 8, 4340-4346.
[12] L. A. Nagahara, T. Thundat, S. M. Lindsay, Rev. Sci. Instrum. 1989, 60,
3128-3130.
[13] M. Kamenetska, M. Koentopp, A. Whalley, Y. S. Park, M. Steigerwald, C.
Nuckolls, M. Hybertsen, L. Venkataraman, Phys. Rev. Lett. 2009, 102,
126803.
[14] Y. Zang, A. Pinkard, Z.-F. Liu, J. B. Neaton, M. L. Steigerwald, X. Roy, L.
Venkataraman, J. Am. Chem. Soc. 2017, 139, 14845-14848.
[15] a) J. Lukkari, K. Kleemola, M. Meretoja, T. Ollonqvist, J. Kankare,
Langmuir 1998, 14, 1705-1715; b) I. B. Stone, J. Jermaks, S. N.
MacMillan, T. H. Lambert, Angew. Chem. Int. Ed. 2018, 57, 12494-12498.
[16] a) M. Jonsson, J. Lind, T. E. Eriksen, G. Merenyi, J. Am. Chem. Soc.
1994, 116, 1423-1427; b) A. S. Pavitt, E. J. Bylaska, P. G. Tratnyek,
Environmental Science: Processes & Impacts 2017, 19, 339-349.
[17] Y. Takeda, S. Okumura, S. Minakata, Angew. Chem. Int. Ed. 2012, 51,
7804-7808.
[2]
a) C. Liu, H. Zhang, W. Shi, A. Lei, Chem. Rev. 2011, 111, 1780-1824;
b) A. Lei, W. Shi, C. Liu, W. Liu, H. Zhang, C. He, Oxidative Cross-
Coupling Reactions, Wiley, 2016.
[3]
[4]
I. Funes-Ardoiz, F. Maseras, ACS Catalysis 2018, 8, 1161-1172.
a) V. R. Stamenkovic, D. Strmcnik, P. P. Lopes, N. M. Markovic, Nat.
Mater. 2016, 16, 57-69; b) Z. W. Seh, J. Kibsgaard, C. F. Dickens, I.
Chorkendorff, J. K. Norskov, T. F. Jaramillo, Science 2017, 355; c) M.
Yan, Y. Kawamata, P. S. Baran, Chem. Rev. 2017, 117, 13230-13319.
a) B. Q. Xu, N. J. Tao, Science 2003, 301, 1221-1223; b) L.
Venkataraman, J. E. Klare, C. Nuckolls, M. S. Hybertsen, M. L.
Steigerwald, Nature 2006, 442, 904-907.
[5]
[6]
[18] S. Y. Quek, M. Kamenetska, M. L. Steigerwald, H. J. Choi, S. G. Louie,
M. S. Hybertsen, J. B. Neaton, L. Venkataraman, Nat. Nanotechnol. 2009,
4, 230-234.
E. Merino, Chem. Soc. Rev. 2011, 40, 3835-3853.
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Table of Contents Summary: We selectively create azobenzene derivatives from anilines through an Au-catalyzed oxidative coupling
that is driven by the local electrochemical potential at an Au STM tip. The products are determined through single-molecule
conductance measurements and compared with azobenzene derivatives prepared ex situ.
This article is protected by copyright. All rights reserved.