Redox-dependent conformational switching of diphenylacetylenes

Article abstract of DOI:10.3390/molecules190811316

Herein we describe the design and synthesis of a redox-dependent single-molecule switch. Appending a ferrocene unit to a diphenylacetylene scaffold gives a redox-sensitive handle, which undergoes reversible one-electron oxidation, as demonstrated by cyclic voltammetry analysis. ¹H-NMR spectroscopy of the partially oxidized switch and control compounds suggests that oxidation to the ferrocenium cation induces a change in hydrogen bonding interactions that results in a conformational switch.

Full text of DOI:10.3390/molecules190811316

Molecules 2014, 19, 11316-11332; doi:10.3390/molecules190811316
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Redox-Dependent Conformational Switching of
Diphenylacetylenes
Ian M. Jones 1,2, Peter C. Knipe 1, Thoe Michaelos 2, Sam Thompson 1,* and
Andrew D. Hamilton 1,2,
*
1
Chemistry Research Laboratory, Department of Chemistry, University of Oxford,
12 Mansfield Road, Oxford OX1 3TA, UK; E-Mails: ian.jones@aya.yale.edu (I.M.J.);
peter.knipe@chem.ox.ac.uk (P.C.K.)
2
Department of Chemistry, Yale University, P. O. Box 208107, New Haven, CT 06520-8107, USA;
E-Mail: thoe.michaelos@yale.edu
* Authors to whom correspondence should be addressed;
E-Mails: sam.thompson@chem.ox.ac.uk (S.T.); andrew.hamilton@chem.ox.ac.uk (A.D.H.);
Tel.: +44-01865-275978 (S.T.); Fax: +44-01865-285002 (S.T. & A.D.H.).
Received: 28 April 2014; in revised form: 23 July 2014 / Accepted: 24 July 2014 /
Published: 31 July 2014
Abstract: Herein we describe the design and synthesis of a redox-dependent single-molecule
switch. Appending a ferrocene unit to a diphenylacetylene scaffold gives a redox-sensitive
handle, which undergoes reversible one-electron oxidation, as demonstrated by cyclic
1
voltammetry analysis. H-NMR spectroscopy of the partially oxidized switch and control
compounds suggests that oxidation to the ferrocenium cation induces a change in hydrogen
bonding interactions that results in a conformational switch.
Keywords: molecular switch; ferrocene; hydrogen bonding; amide bond; redox;
translational isomerism
1. Introduction
Conformational dynamism in the face of changing cellular redox conditions is essential to the
survival of living organisms. Protein structure, and thus activity, is often regulated by redox-dependent
disulfide bonds [1,2] and metal coordination [3,4]. These natural mechanisms of control inspired us to
explore transforming the H-bonded diphenylacetylene (DPA) scaffold into a redox-dependent switch.

Molecules 2014, 19
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Much work has been carried out to characterize synthetic systems that can change conformation in
response to oxidation state. The most well known of these involve the use of redox active catenanes, [5–8]
metal coordination compounds, [9–15] rotaxanes, [11,12,14,16–22] π-systems, [23–28] and crowded
alkenes [29]. These systems are finding increasing application in solid-state electronic devices.
Of particular note are the [2]-rotaxane systems in which a H-bond donating macrocycle shuttles
between a strong H-bond accepting succinamide station and a weaker naphthalimide H-bond acceptor [30].
It has been demonstrated that reduction of the naphthalimide group to the radical anion increases its
H-bond acceptor strength relative to the succinamide. This change causes the H-bond network to
reconfigure, leading to a conformational switch. Analogously it should be possible to design
a conformational switch in which a H-bond network reconfigures due to a redox-dependent modulation
of a H-bond donor. Previous work has shown that the conformational equilibrium in H-bonded DPA’s
can be controlled by increasing the H-bond donation strength of one NH relative to the other [31,32].
This H-bond strength is readily adjusted through the conjugation of electron-donating or -withdrawing
groups to the amide NH.
By this same principle, conjugating a ferrocene (Fc) to the H-bond network should mediate H-bond
donor strength in a redox-dependent fashion (Figure 1). Although used extensively in the field of
sensors, [33–35] ferrocene has received little attention as an actuator of redox-dependent conformational
switching [36]. Fc is slightly electron- donating [37,38] as compared to a phenyl group, which suggests
that the H-bonded equilibrium will be biased away from the ferrocenyl amide (FcA) in the neutral state
(“reduced”, Figure 1). However, ferrocene is also known to undergo a reversible single electron oxidation
to the ferrocenium cation [39]. Studies on 1-ferrocenylcarboxamide systems show that the oxidation of
Fc withdraws electron density from the amide NH bond, creating a stronger H-bond donor [40–46].
Thus, it is hypothesized that oxidation to Fe(III) should induce a switch in the H-bonded equilibrium
toward the FcA (“oxidized”, Figure 1).
Figure 1. The conceptual transformation from ion-mediated switches to a redox-dependent analogue.
Previous approaches to diphenylacetylene switching: proton and ion-mediated
O
O
O
O
O
N
H
N
H
Me
N
H
N
H
N
H
Me
N+
Cl-
O
O
H
Me
MeO
Me
Me
O
This study: redox-mediated molecular switching
O
O
O
O
N
H
N
H
N
H
N
H
- e-
+ e-
Fe
Fe
O
O
OMe
MeO
reduced
oxidized
• electron-rich ferrocene
• disfavours H-bonding
• electron-deficient ferrocenyl cation
• favours H-bonding

Molecules 2014, 19
11318
2. Results and Discussion
2.1. Synthesis
In order to test this hypothesis we synthesized diphenylacetylene 3 via an amide bond formation
between aniline 1 [31] and ferrocenoyl chloride 2 (Scheme 1).
Scheme 1. Synthesis of a benzamido/FcA-substituted diphenylacetylene molecular switch
(the red arrows represent NOE correlations).
O
O
H
O
H
O
N
H
NH2
N
Ha
N
2, pyridine, DMAP
Hb
Cl
Fe
Fe
O
O
CH2Cl2, 18 h, RT, 47 %
2
MeO
OMe
1
3
2.2. Solid-State Analysis of Conformation
Insight concerning the conformation of diphenylacetylene 3 was obtained from single crystal X-ray
diffraction following recrystallization from 1:1 methanol/chloroform (Figure 2, see also Section 3.4.).
The H-bond acceptor is bound to the benzamide NH with an N•••OC distance of 3.1 Å. The steric
clash between the methyl ester and the phenyl ring causes the ring to rotate 35° out of the amide plane.
Figure 2. The single crystal X-ray structure of 3 viewed (a) perpendicular to the phenyl-alkyne
plane; and (b) down the phenyl-alkyne axis. The ORTEP ellipsoids are shown at the 50%
probability level; white = H, grey = C, red = O, blue = N, purple = Fe.
The solid-state data confirm the predicted conformation, which is presumably favoured due to the
electron-donating character of the Fc group reducing the H-bond donor capability of the corresponding
amide, as well as the steric demands of the large sandwich complex.
2.3. Determining the Solution Phase Conformational Bias
As for the anion [47] and pH-dependent [32] switches described previously, the conformational bias
1
can be determined by comparison of the H-NMR spectrum of 3 with a set of control compounds.
para-Substituted benzoic ester 5, which is incapable of intramolecular H-bonding, was synthesized via
amide coupling of aniline 4 [31] with ferrocenoyl chloride (Scheme 2). The second control molecule,

Molecules 2014, 19
11319
12, was prepared from 3-nitroaniline via an adaptation of a literature route: [31] iodination of
3-nitroaniline, [48] followed by amidation, nitro-group reduction, Sonogashira coupling and coupling
with ferrocenoyl chloride, afforded the desired bis(amide).
Scheme 2. Synthesis of benzamido/FcA-substituted diphenylacetylene compounds: (a) 0%
control 5; and (b) 100% control 12.
(a)
O
O
O
H
O
6
N
H
N
H
N
H
NH2
(i)
Fe
Cl
O
Fe
18 h, 39 %
OMe
2
5
(0% control)
4
O
OMe
NH
O
OMe
(b)
Ph
Ph
Ph
O
NH2
NH2
O
NH
O
NH
(i)
(v)
(ii)
(iii)
O
18 h, 59 %
56 %
67 %
57 %
R
NO2
NO2
NH2
N
H
I
I
Fe
O
O
8
R = NO2
9
7
(iv)
OMe
OMe
68 %
R = NH2 10
11
12
(100% control)
Regent and conditions: (i) Pyridine, DMAP, CH2Cl2, 2; (ii) I2, Ag2SO4, MeOH, 3 h; (iii) PhCOCl, pyridine,
.
DMAP, CH2Cl2, 5 h; (iv) SnCl2 2H2O, EtOAc, 18 h; (v) PdCl2(PPh3)2 (6 mol%), CuI (10 mol%), 6 (1.2 eq.),
DMF/NEt3 (1:1 v/v), 70 °C, 3 h. All reactions were run at room temperature unless specified otherwise; Ac =
acetyl, DMAP = 4-dimethylaminopyridine, DMF = N,N-dimethylformamide, Me = methyl, Et = ethyl, Ph = C6H5.
The first of these, 5, estimates the chemical shift of the FcA NH in the absence of H-bonding by
positioning the H-bond acceptor para to the alkyne linkage (0% control). The second control, 12,
estimates the chemical shift of the FcA NH when it is completely H-bonded (100% control). The
spectra of these controls are compared with parent compound 3 in Figure 3.
1
Figure 3. The H-NMR conformational analysis for 3 using the 100% 12 and 0% 5
controls (4.0 mM, CDCl3, peak assignments determined by NOE and COSY experiments).

Molecules 2014, 19
11320
Using Equation (1), the conformational bias is calculated to be 14.3%, which equates to a ratio of
~1.4:1 toward the benzamide NH, in agreement with the preference demonstrated in the solid state
(vide supra):
ꢌ(100%) − ꢌ
% ꢀꢁꢂꢃꢄꢅꢆꢇ ꢈꢄꢇꢂ ꢉꢃꢆꢊꢆꢃꢆꢇꢋꢆ =
(1)
(
)
ꢌ 100% − ꢌ(0%)
2.4. Characterizing the Redox Properties of Switch 3 with Cyclic Voltammetry
The redox properties of the ferrocene-containing compounds 3, 5 and 12 were examined by cyclic
voltammetry (Figure 4, Figure 4b) All three compounds exhibit one-electron oxidation waves
characteristic of the Fe(II)/Fe(III) couple. The peak potential separations (ΔEp = 130–170 mV) are
greater than the 59 mV expected for a reversible one-electron process; however, these numbers are on
the order of the ferrocene internal reference (ΔEp, Fc = 165 mV at 100 mV·s−1), and the ratio of peak
currents (Ia/Ic) are all close to unity, indicating that these are chemically reversible processes.
Figure 4. (a) Cyclic voltammograms (CV) for 3 (red), 5 (black), and 12 (blue); compounds
at 2.0 mM with 0.1 M NBu4PF6 in dichloromethane with a scan rate of 100 mV·s−1.
Positive currents correspond to oxidation. Potentials were measured relative to the
ferrocenium/ferrocene redox couple as an internal standard, and are reported relative to the
NHE; (b) Derived electrochemical parameters (see Experimental Section 3.1. for
further details).
The oxidation potentials (E1/2) have the order 5 > 3 > 12, consistent with increasing H-bonding to
ferrocenylcarboxamides causing a depression in the ferrocene E1/2 [40,41,45,46].
2.5. Characterizing the Redox Properties of Switch 3 by Chemical Oxidation
Having shown that putative switch 3 undergoes reversible oxidation, we attempted to use the
1H-NMR conformational assay described above to analyze [3]+. The formation of paramagnetic Fe(III)
caused broadening of resonances, rendering 1H-NMR spectral interpretation difficult. However, Heinz

Molecules 2014, 19
11321
et al. have recently examined the NMR spectra of partially oxidized Fc compounds [36,49]. They report
that, while partial oxidation causes the Fc signals to broaden and shift downfield, other resonances
belonging to protons further from the FcA group remain sharp.
In order to determine the conformational ratio of a partially oxidized 3, conditions must be
identified that bring about the partial oxidation of this Fc DPA system. Figure 5a shows the NMR
spectra of 3 after exposure to various chemical oxidants. The extent of oxidation was qualitatively
assessed by examining the cyclopentadienyl peaks, 5.1–4.0 ppm, which are known to broaden and shift
downfield upon oxidation. After two hours only copper(II) chloride and silver tetrafluoroborate caused
the expected change in the signals of 3. Additionally, copper(II) chloride caused some broadening of
other signals in the aromatic region but the NH resonances are both identifiable. It is plausible this
broadening is due to one or more of the oxidation states of copper acting as a Lewis acid with acceptor
lone pairs of the switch compound. Silver tetrafluoroborate caused the loss of all spectral definition,
most likely due to more complete oxidation (Figure 5b). The presence of a ferrocenium group was also
confirmed by the appearance of the characteristic peak at 640 nm in the absorbance spectrum
(Figure 5c) [50].
1
Figure 5. (a) Chemical oxidation of 3 to [3]+; (b) An array of H-NMR spectra acquired
after treatment of 3 with various chemical oxidants for 2 h (4.0 mM in CDCl3, peak
assignments determined by NOE and COSY experiments); (c) The UV-vis absorbance
spectra of 3 before (blue) and [3]+ after (red) oxidation with CuCl2 (4.0 mM, CH2Cl2, see
the Experimental Section for further details).

Molecules 2014, 19
11322
2.6. Paramagnetic NMR Characterization of the Solution Phase Conformation
With a procedure to effect the partial oxidation of 3 in hand, we next began to investigate the
influence of oxidation on the spectral features. Figure 6a compares the downfield NMR spectrum of [3]+
with that of neutral 3. The FcA NH is broadened, and shifted downfield by 0.05 ppm while the
benzamide NH migrates 0.14 ppm upfield. The singlet corresponding to the methyl ester was also
affected, broadening and shifting downfield by ~0.6 ppm.
To understand the meaning of these changes, control compound 5 was used to examine the effect of
oxidation in the limiting case of 0% H-bond interaction. This compound was treated with copper(II)
chloride for two hours and, after the presence of the ferrocenium was confirmed by UV-vis, its
1H-NMR spectrum was acquired. This spectrum indicated that FcA NH and benzamide NH signals of
[5]+ shift upfield by 0.11 and 0.03 ppm respectively, relative to 5 (Figure 6b). The methyl ester
resonance was unaffected by oxidation, presumably due to its isolation para to the alkyne. Lastly, 12
was oxidized with copper(II) chloride; the partially oxidized spectra of 12 and [12]+ are shown in
Figure 6c. In this case the FcA NH broadens but is not shifted, while the benzamide NH is not
identifiable. Furthermore, the methyl ester peak was broadened to such an extent that it was not
observable in the partially oxidized spectrum. Attempts to monitor IR stretching frequencies of the
carbonyl, or NH, regions to provide conformational data was not possible due to poor resolution of
overlapping signals.
1
Figure 6. A comparison of the H-NMR spectra of (a) 3 and [3]+; (b) 5 and [5]+; (c) 12
and [12]+; and (d) the conformational analysis of [3]+ (peak assignments determined by
NOE and COSY experiments).

Molecules 2014, 19
11323
Taken together, these observations suggest that the H-bonded equilibrium is changing as the Fc
group becomes oxidized. The benzamide NH resonance, for example, shifts upfield both in the absence
and presence of the intramolecular H-bond (Figure 6a,b), but the signal migrates further when the
H-bond is engaged ([3]+). This increased upfield shift can be explained by a switch of the H-bond
acceptor away from the benzamide NH, which causes this proton to be more shielded. The Fc+ amide
NH shifts upfield in the absence of H-bonding upon oxidation (Figure 6b), but shifts downfield when
the H-bonded equilibrium is engaged (Figure 6a). A switch of the H-bond acceptor towards the Fc+
amide NH, causing this proton to become deshielded, would explain the downfield shift in the
spectrum of [3]+. To estimate the effect of partial oxidation on the conformational equilibrium, the
spectra of [3]+, [5]+ and [12]+ are directly compared (Figure 6d) using the same method as in the
neutral case. This comparison suggests that the equilibrium is biased toward the Fc+ amide NH by
15.6%, or ~1.4:1 in favour of the Fc+ amide (compared with 1.4:1 in favour of the benzamide prior to
1
oxidation) under these partially oxidized conditions. Since the H-NMR resonances corresponding to
the parent unoxidized species are not evident it is probable that there is fast exchange between the
unoxidized and oxidized forms, leading to average peak positions. Whilst this makes precise
quantification of the bias more difficult to establish, the overall trends hold thus providing
a semi-quantitative measurement.
3. Experimental Section
3.1. General Methods
Dichloromethane, tetrahydrofuran, and N,N-dimethylformamide were dried using an Innovative
Technology SPS-400 dry solvent system. Anhydrous methanol, ethanol, isopropanol, and dimethyl
sulfoxide were purchased from Sigma-Aldrich and used directly from their SureSealTM bottles.
All reactions were performed under an atmosphere of dry nitrogen in oven- or flame-dried glassware
and were monitored by thin-layer chromatography (TLC) using silica gel (visualized by UV light).
1
13
Aqueous solutions were saturated unless otherwise stated. H and C NMR spectra were recorded on
400 or 500 MHz Bruker or 500 MHz Varian instruments. Chemical shifts (δ) are reported in parts per
million after reference to residual isotopic solvent. Spectra measured in CDCl3 were referenced to 7.27
1
13
and 77.16 ppm for H and C. Spectra measured in CD2Cl2 were calibrated to 5.32 (1H) and 53.52
(13C) ppm. Coupling constants (J) are reported in Hertz (Hz). Proton assignments were pre-formed
using MestReNova “multiplet reporter script”, and were edited by hand. High-resolution mass spectra
were measured on a 9.4 T Bruker Qe FT-ICR MS and values are the average of three measurements.
All chemical drying was pre-formed with sodium sulfate unless otherwise stated. Cyclic voltammetry
was performed with an EG&G Princeton Applied Research Model 273A potentiostat/galvanostat using
platinum disc (1.6 mm diameter) working electrode, a platinum counter electrode, and a silver wire
pseudo-reference electrode in a conventional three-electrode cell. Anhydrous dichloromethane was
used as the solvent. The supporting electrolyte was 0.10 M tetrabutylammonium hexafluorophosphate,
and bubbling with nitrogen deoxygenated the solution. Polishing with alumina slurry, followed by
solvent rinses, cleaned the platinum disc working-electrode. The concentration of the electroactive
compound was 2.0 mM. The potential of the pseudo-reference electrode was determined using the

Molecules 2014, 19
11324
ferrocenium/ferrocene redox couple as an internal standard (with E1/2 taken as 0.690 V vs. NHE in
dichloromethane). For aqueous solutions, the supporting electrolyte was 0.1 M sodium sulfate.
All reported voltammograms were recorded at a 100 mV·s−1 scan rate. All potentials listed in this
manuscript are referenced to the normal hydrogen electrode (NHE) unless otherwise stated.
3.2. Synthetic Procedures
Methyl 2-((2-amino-6-benzamidophenyl)ethynyl)benzoate (1). Methyl 4-((2-amino-6-benzamidophenyl)
ethynyl)benzoate (4) and methyl 2-ethynylbenzoate (6) were prepared according to a literature
procedure [31].
Ferrocenoyl chloride (2). Oxalyl chloride (0.058 mL, 0.66 mmol) was added dropwise over 1 min to
a solution of ferrocene monocarboxylic acid (0.0777 g, 0.338 mmol) in dichloromethane (3.0 mL) and
N,N-dimethylformamide (1–3 drops). The mixture stirred for 30 min and concentrated with a stream of
nitrogen gas, and then subjected to vacuum for 10 min. The resultant crude oil was used without
further purification.
Methyl 2-((2-benzamido-6-(ferrocenecarboxamido)phenyl)ethynyl)benzoate (3). Pyridine (0.011 mL,
0.14 mmol) was added dropwise to a solution of amine 1 (0.0500 g, 0.135 mmol) and
4-dimethylaminopyridine (ca. 1 mg) in dichloromethane (4.5 mL). A solution of ferrocenoyl chloride 2
(0.9 mL, 0.3 M, 0.27 mmol) was added dropwise over 3 min and the mixture stirred for 18 h.
Following dilution with dichloromethane and washing with 2 N hydrochloric acid, sodium hydrogen
carbonate, and brine, the organic layers were dried over magnesium sulfate and concentrated in vacuo.
The residue was purified by column chromatography on silica gel (100% chloroform to 9:1
chloroform/ethyl acetate) to give the title compound 3 (0.037 g, 47%) as an orange solid; Rf 0.5 (9:1
1
chloroform/ethyl acetate); H-NMR (500 MHz, CDCl3): δH 9.34 (s, 1H), 8.56 (s, 1H), 8.33 (d, J 8.3,
1H), 8.29 (d, J 8.3, 1H), 8.11 (d, J 7.8, 1H), 7.95 (d, J 7.4, 2H), 7.74 (d, J 7.6, 1H), 7.61 (t, J 7.5, 1H),
7.51 (m, 2H), 7.44 (m, 3H), 4.92 (s, 2H), 4.43 (s, 2H), 4.21 (s, 5H), 3.57 (s, 3H); 13C-NMR (125 MHz,
CDCl3): δC 169.0, 166.6, 165.5, 140.5, 139.9, 135.5, 133.2, 132.6, 131.8, 131.2, 131.0, 130.5, 129.0,
128.5, 127.9, 123.1, 115.0, 114.9, 102.5, 101.8, 86.1, 77.4, 76.1, 71.1, 70.1, 68.6, 52.3; HRMS: found
+
583.1315; C34H27FeN2O4 [M+H]+ requires 583.1242.
Methyl 4-((2-benzamido-6-(ferrocenecarboxamido)phenyl)ethynyl)benzoate (5). Pyridine (0.011 mL,
0.14 mmol) was added dropwise to a solution of amine 4 (0.0500 g, 0.135 mmol) and
4-dimethylaminopyridine (ca. 1 mg) in dichloromethane (4.5 mL). A solution of ferrocenoyl chloride 2
(0.9 mL, 0.3 M, 0.27 mmol) was added dropwise over 3 min and the mixture stirred for 18 h.
Following dilution with dichloromethane and washing with 2 N hydrochloric acid, sodium hydrogen
carbonate, and brine, the organic layers were dried over magnesium sulfate and concentrated in vacuo.
The residue was purified by column chromatography on silica gel (9:1 chloroform/ethyl acetate) to
give the title compound 5 (0.0310 g, 39%) as an orange solid; Rf 0.41 (9:1 chloroform/ethyl acetate);
1H-NMR (400 MHz, CDCl3): δH 8.74 (s, 1H), 8.32 (d, J 8.4, 1H), 8.30 (s, 1H), 8.28 (s, 1H), 8.16 (d,
J 8.2, 2H), 7.96 (d, J 7.5, 2H), 7.70 (d, J 8.2, 2H), 7.60 (t, J 7.3, 1H), 7.51 (m, 2H), 7.47 (d, J 8.4, 1H),
13
4.81 (s, 2H), 4.47 (s, 2H), 4.23 (s, 5H), 3.98 (s, 3H); C-NMR (125 MHz, CDCl3): δC 168.8, 166.2,

Molecules 2014, 19
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165.2, 139.8, 139.6, 134.9, 132.4, 131.6, 131.3, 131.1, 130.3, 129.1, 127.1, 126.1, 115.0, 114.7, 103.0,
+
101.0, 83.4, 76.0, 71.4, 70.2, 68.4, 52.6; HRMS: found 583.1270; C34H27FeN2O4 [M+H]+ requires
583.1242.
4-Iodo-3-nitroaniline (8). Based on literature procedures [48,51] 3-nitroaniline 7 (0.100 g, 0.72 mmol)
was added to a solution of iodine (0.183 g, 0.724 mmol) and silver(I) sulfate (0.223 g, 0.724 mmol) in
methanol (15 mL). After 3 h the solution was filtered and the solid re-dissolved in aqueous sodium
hydroxide (5%, 7.0 mL). The mixture was heated to boiling and allowed to cool. The precipitate was
filtered, collected and purified by column chromatography on silica gel (1:1 hexanes/dichloromethane)
to give the title compound 8 (0.128 g, 67%) as a gold solid; Rf 0.3 (1:1 hexanes/dichloromethane);
1H-NMR (400 MHz, CDCl3): δH 7.70 (d, J 8.5, 2H), 7.59 (dd, J 2.5, 8.5, 1H), 7.50 (t, J 2.2, 2H), 7.29
(d, J 2.5, 1H), 7.19 (d, J 2.7, 2H), 6.97 (m, 1H), 6.61 (dd, J 2.7, 8.5, 2H), 4.07 (s, 5H); HRMS: found
+
264.9452; C6H6IN2O2 [M+H]+ requires 264.9396.
N-(4-Iodo-3-nitrophenyl)benzamide (9). Benzoyl chloride in dichloromethane (1.5 mL, 0.1 M, 0.15 mmol)
was added dropwise over 1 min to a solution of amine 8 (0.0337 g, 0.128 mmol) and
4-dimethylaminopyridine (ca. 1 mg) in dichloromethane (1.3 mL). The reaction was stirred for 5 h
before dilution with dichloromethane. After washing with 1 N hydrochloric acid and brine the solution
was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column
chromatography on silica gel (1:1 hexanes/dichloromethane) to give the title compound 9 (0.018 g,
57%) as a yellow solid; Rf 0.32 (1:1 hexanes/dichloromethane); 1H-NMR (400 MHz, CDCl3): δH 8.29
(d, J 2.5, 1H), 8.00 (d, J 8.6, 2H), 7.88 (dd, J 1.3, 8.3, 2H), 7.67 (m, 1H), 7.61 (m, 1H), 7.53 (t, J 7.5,
2H); 13C-NMR (75 MHz, (CD3)2SO): δC 166.0, 152.9, 141.3, 140.2, 134.0, 132.1, 128.5, 127.8, 125.0,
+
116.2, 79.9; HRMS: found 368.9776; C13H10IN2O3 [M+H]+ requires 368.9658.
N-(3-Amino-4-iodophenyl)benzamide (10). Tin(II) chloride dihydrate (0.153 g, 0.68 mmol) was added
to a solution of nitro aromatic 9 (0.050 g, 0.136 mmol) in ethyl acetate (5 mL). The mixture was stirred
for 18 h and diluted with ethyl acetate and poured into sodium hydrogen carbonate. The mixture was
filtered over Celite® and the filtrate was extracted using ethyl acetate, dried over magnesium sulfate,
and concentrated in vacuo. The residue was purified by column chromatography on silica gel (2:1
hexanes/ethyl acetate) to give the title compound 10 (0.031 g, 68%) as a white solid; Rf 0.5 (2:1
1
hexanes/ethyl acetate); H-NMR (400 MHz, CDCl3): δH 7.76 (d, J 7.0, 4H), 7.70 (s, 2H), 7.48 (m, 3H),
7.40 (m, 5H), 6.48 (dd, J 2.4, 8.5, 2H), 4.07 (s, 1H); 13C-NMR (125 MHz, (CD3)2SO): δC 165.4, 148.5,
140.2, 138.1, 135.0, 131.5, 128.3, 127.6, 111.1, 106.1, 76.5; HRMS: found 338.9881; C13H12IN2O+
[M+H]+ requires 338.9916.
Methyl 2-((2-amino-4-benzamidophenyl)ethynyl)benzoate (11). A solution of 10 (0.031 g, 0.0917 mmol)
and methyl 2-alkynylbenzoate 6 (0.0176 g, 0.110 mmol) in N,N-dimethylformamide (1.0 mL) and
triethylamine (1.0 mL) was degassed by nitrogen stream for 10 min. Bis(triphenylphosphine)palladium(II)
dichloride (0.0038 g, 0.0055 mmol) and copper(I) iodide (0.0017 g, 0.0092 mmol) were added and the
mixture was heated to 70 °C. The reaction was allowed to stir for 2 h then diluted with ethyl acetate
and washed with water. The organic layer was dried and concentrated in vacuo. The product was
purified by column chromatography on silica gel (2:1 hexanes/ethyl acetate) to give the title compound 11

Molecules 2014, 19
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1
(0.019 g, 56%) as a yellow solid; H-NMR (500 MHz, CDCl3): δH 8.03 (d, J 7.9, 1H), 7.85 (d, J 7.1,
2H), 7.65 (d, J 7.7, 1H), 7.55 (t, J 7.4, 1H), 7.52 (d, J 8.0, 1H), 7.48 (t, J 7.6, 2H), 7.42 (s, 1H), 7.34
(m, 2H), 6.74 (d, J 8.3, 2H), 5.17 (s, 2H), 3.94 (s, 3H); 13C-NMR (125 MHz, CDCl3): δC 166.4, 165.8,
150.9, 139.9, 135.1, 133.6, 132.8, 132.2, 132.0, 130.7, 128.9, 127.3, 127.1, 124.9, 108.8, 104.9, 103.4,
+
93.7, 92.8, 52.4; HRMS: found 371.1262; C23H19N2O3 [M+H]+ requires 371.1317.
Methyl 2-((4-benzamido-2-(ferrocenecarboxamido)phenyl)ethynyl)benzoate (12). A solution of ferrocenoyl
chloride 2 in dichloromethane (2.1 mL, 0.065 M, 0.137 mmol) was added dropwise over 10 min to
a solution of amine 11 (0.025 g, 0.068 mmol) and 4-dimethylaminopyridine (ca. 1 mg) in dichloromethane
(2.6 mL) and pyridine (0.006 mL, 0.07 mmol). The mixture was stirred for 18 h then diluted with
dichloromethane. The organic layer was washed with 2 N hydrochloric acid, sodium hydrogen
carbonate, and brine. After drying and concentration in vacuo the residue was purified by column
chromatography on silica gel (9:1 chloroform/ethyl acetate) to give the title compound 12 (0.023 g,
1
59%) as an orange solid; H-NMR (500 MHz, CDCl3): δH 8.85 (s, 1H), 8.53 (m, 1H), 8.44 (s, 1H),
8.16 (m, 1H), 8.10 (d, J 7.9, 1H), 7.90 (d, J 8.0, 2H), 7.74 (d, J 7.7, 1H), 7.62 (d, J 8.9, 1H), 7.58 (d,
J 7.6, 1H), 7.53 (m, 1H), 7.49 (d, J 7.6, 2H), 7.45 (d, J 7.7, 1H), 4.99 (s, 2H), 4.37 (s, 2H), 4.16 (s,
13
5H), 3.89 (s, 3H); C-NMR (125 MHz, CDCl3): δC 170.1, 166.2, 165.9, 140.3, 139.9, 134.8, 134.1,
133.5, 132.5, 132.1, 130.8, 128.9, 128.4, 127.3, 124.1, 115.1, 111.0, 107.9, 94.6, 90.5, 71.0, 70.1, 69.1,
+
52.6; HRMS: found 583.1376; C34H27FeN2O4 [M+H]+ requires 583.1242.
3.3. Chemical Oxidation Procedure
Copper(II) chloride (0.0025 g, 0.019 mmol) was added to a solution of ferrocenyl compound (3, 5,
or 12) in dichloromethane (3.87 mL, 4.0 mM, 0.016 mmol), and the mixture stirred for 2 h, giving a dark
greenish solution. The solution was filtered, transferred to a cuvette, and the UV-vis absorbance
spectrum obtained to determine the presence of a ferrocenium group. The solution was concentrated
and re-dissolved in 3.87 mL of CDCl3 for NMR characterization.
3.4. Single Crystal X-ray Diffraction
Crystallographic data (excluding structure factors) have been deposited with the Cambridge
Crystallographic Data Centre (CCDC: 871793) and copies of these data can be obtained free of charge
via the web [52].
3.4.1. Data Collection
An orange prism crystal of FeC34H26N2O4 having approximate dimensions of 0.40 × 0.40 × 0.32 mm
was mounted in a loop. All measurements were made on a Rigaku R-AXIS RAPID imaging plate
diffractometer using filtered Cu-Kα radiation. The crystal-to-detector distance was 127.40 mm.
Cell constants and an orientation matrix for data collection corresponded to a primitive monoclinic cell
with dimensions: a = 10.3095(3) Å; b = 13.5730(4) Å; β = 97.929(7)°; c = 18.9524(13) Å;
V = 2626.7(2) Å3. For Z = 4 and F.W. = 582.44, the calculated density is 1.473 g·cm−3. The reflection
conditions of: h0l: l = 2n; 0k0: k = 2n, uniquely determine the space group to be: P21/c (#14). The data
were collected at a temperature of −180 ± 1 °C to a maximum 2θ value of 130.1°. A total of

Molecules 2014, 19
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105 oscillation images were collected. A sweep of data was done using ω scans from 20.0 to 200.0° in
5.0° step, at χ = 54.0° and ϕ = 180.0°. The exposure rate was 12.0 [s/°]. A second sweep was
performed using ω scans from 22.0 to 197.0° in 5.0° step, at χ = 54.0° and ϕ = 270.0°. The exposure
rate was 12.0 [s/°]. Another sweep was performed using ω scans from 42.0 to 132.0° in 5.0° step,
at χ = 54.0° and ϕ = 0.0°. The exposure rate was 12.0 [s/°]. Another sweep was performed using ω
scans from 37.0 to 117.0° in 5.0° step, at χ = 54.0° and ϕ = 90.0°. The exposure rate was 12.0 [s/°].
The crystal-to-detector distance was 127.40 mm. Readout was performed in the 0.100 mm pixel mode.
3.4.2. Data Reduction
Of the 17,074 reflections that were collected, 4,399 were unique (Rint = 0.0563). The linear
absorption coefficient, μ, for Cu-Kα radiation is 49.717 cm−1. An empirical absorption correction was
applied which resulted in transmission factors ranging from 0.140 to 0.204. The data were corrected
for Lorentz and polarization effects.
3.4.3. Structure Solution and Refinement
The structure was solved by direct methods[53] and expanded using Fourier techniques.
The non-hydrogen atoms were refined anisotropically. Hydrogen atoms were refined using the riding
model. The final cycle of full-matrix least-squares refinement on F2 was based on 4383 observed
reflections and 371 variable parameters and converged (largest parameter shift was 0.00 times its esd)
with unweighted and weighted agreement factors of:
R1 = ∑ ||Fo| − |Fc||/∑ |Fo| = 0.0504
(2)
(3)
wR2 = [∑ (w (Fo2 – Fc2)2)/∑ w(Fo2)2]1/2 = 0.1294
The standard deviation of an observation of unit weight was 1.10. Unit weights were used.
The maximum and minimum peaks on the final difference Fourier map corresponded to 0.58
and −0.86 e−/Å3, respectively. Neutral atom scattering factors were taken from Cromer and Waber [54].
Anomalous dispersion effects were included in Fcalc;[55] the values for ∆f’ and ∆f” were those of
Creagh and McAuley [56]. The values for the mass attenuation coefficients are those of Creagh and
Hubbell [57]. All calculations were performed using the CrystalStructure [58] crystallographic software
package except for refinement, which was performed using SHELXL-97 [59].
4. Conclusions
The importance of redox-dependent conformational switching in Nature inspired the development
of an analogous synthetic molecular switch. Previous studies have demonstrated redox switching by
modulation of H-bond acceptor strength, but there are few examples in which this is mediated by
tuning of H-bond donor ability. Conjugation of a ferrocenylcarboxamide to a diphenylacetylene
scaffold provided a model system for redox-dependent conformational switching. X-ray crystallography
established that the electron-donating character of the Fc group causes hydrogen bonding to the
benzamide to be preferred in the solid state, and 1H-NMR analysis confirmed this behavior in solution.
Upon partial oxidation the compound undergoes a switching of conformational ratio from 1.4:1 in

Molecules 2014, 19
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favour of the benzamide to 1.4:1 in favour of the ferrocenyl amide; however, due to paramagnetism of
the Fe(III) species, 1H-NMR analysis of the fully oxidized species was not possible. Cyclic voltammetry
also supports the predicted conformational change upon oxidation, by showing that the Fe(II)/Fe(III)
redox potentials decrease in order of the expected increase in hydrogen bonding to the ferrocenyl
amides from the 0% control to the 100% control. Future work will investigate the use of alternative
spectroscopic methods to assay diphenylacetylene switching under redox-mediated conditions,
including the exploration of IR marker bands and colorimetric methods.
Acknowledgments
We thank Nathan D. Schley for assistance with X-ray crystallography, The University of Oxford for
funding, and Hannah Lingard for helpful discussions.
Author Contributions
IMJ and ADH designed research; IMJ, PCK, ST and TM performed research and analyzed the data;
IMJ, PCK, TM, ST and ADH wrote the paper. All authors read and approved the final manuscript.
Conflicts of Interest
The authors declare no conflict of interest.
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