New approaches toward ferrocene-guanine conjugates: Synthesis and electrochemical behavior

Article abstract of DOI:10.1021/om5002809

Different substituted ferrocene-guanine conjugates were prepared, and their electrochemical behavior was investigated. A new approach for the introduction of ferrocene in guanine's 9-position through a quite effective S_N1-type reaction was disclosed. The electrochemical behavior of the various derivatives can be used as standard for the quantification and analysis of DNA strands. (Figure Presented)

Full text of DOI:10.1021/om5002809

Article
pubs.acs.org/Organometallics
New Approaches toward Ferrocene−Guanine Conjugates: Synthesis
and Electrochemical Behavior
Matteo Iurlo,* Luca Mengozzi, Stefania Rapino, Massimo Marcaccio, Rosaria C. Perone,
Stefano Masiero,* Piergiorgio Cozzi,* and Francesco Paolucci*
Alma Mater Studiorum-Universita
Selmi, 2, 40126 Bologna, Italy
̀
di Bologna and INSTM, Unit of Bologna, Dipartimento di Chimica “Giacomo Ciamician”, via
*
S Supporting Information
ABSTRACT: Different substituted ferrocene−guanine con-
jugates were prepared, and their electrochemical behavior was
investigated. A new approach for the introduction of ferrocene
in guanine’s 9-position through a quite effective S 1-type
N
reaction was disclosed. The electrochemical behavior of the
various derivatives can be used as standard for the
quantification and analysis of DNA strands.
INTRODUCTION
thiol monolayer. A ferrocene−bis(thymine) derivative was
■
7
reported by Ganesh. In addition, as guanosine and its
The field of bioorganometallic chemistry is growing rapidly,
networking classical organometallic chemistry to biology,
medicine, and molecular biotechnology. In this perspective,
the chemical stability and electroactive behavior of ferrocene
has been extensively used for its conjugation to a diverse array
derivatives have favorable properties such as its peculiar
sequence of H-bond donor or acceptor groups, it can self-
assemble into ordered structures, such as G-quartets, which
have potential for the development of molecular electronic
8
1
devices. In order to improve the self-assembly ability,
of bioactive molecules. However, ferrocene conjugation to
significant efforts have been focused on the synthesis of
modified guanosines. However, only a limited number of
reports on modified guanosine derivatives obtained by Stille
nucleobases, nucleosides, and nucleic acids is a relatively young
domain in comparison to the studies with amino acids and
peptides. As nucleobases offer the possibility of a network in
9
and Sonogashira coupling have appeared. In extension to the
2
terms of hydrogen bonding and supramolecular assembly, the
interest in redox-active modified simple nucleobases, gene
diagnosis and many DNA sensing methods require potent
DNA detecting systems. These modern synthetic systems rely
application of hierarchical structures of ferrocene−nucleobase
conjugates may offer the possibility to establish mutual
recognition and patterns on various supports. In this regard,
as nucleobases can self-associate with the help of Watson−
Crick and Hoogsteen hydrogen bonds, the possibility of
arranging ferrocene around nucleobase templates has been
10
upon electrochemical techniques: a wide variety of electro-
chemical DNA detecting techniques have been reported by
11
using electrochemically intercalating molecules or DNA
12
labeling with electrochemically active reagents. Rapid and
3
reported. Self-association motifs of ferrocene-linked mono-
direct electrochemical DNA detection has been achieved using
a DNA probe-immobilized electrode where the peak current
was proportional to the amount of the target DNA. This
allowed electrochemical gene expression analysis with a
(
nucleobase) conjugates with a single-carbon methylene spacer
4
have been reported by Houlton’s group. They have prepared
ferrocenyl derivatives of thymine, cytosine, and uracil and of
N2-acetylguanine and 2-amino-6-chloropurine. The synthesis
and crystallographic studies of a ferrocenyl conjugate of
adenine, where the hydrogen-bonding interactions promote
and stabilize nucleobase homotetrad formation, has been
13
detection limit of ca. 50 fmol. In this context, a derivative
of guanine has been used for a novel on/off electronic
nanoswitch based on the conformational change of DNA
sequence possessing a single guanine (G)-rich strand, labeled
with redox-active ferrocene molecules serving as the signaling
5
reported by Verma. In this article, 3-bromopropionic acid
14
chloride was used for ferrocene acylation, which upon base-
catalyzed alkylation resulted in the formation of a modified
ferrocenylated-adenine hybrid. This ferrocenylated-adenine
hybrid molecule was then used by Verma and Bianco in a
redox-active ferrocene assembled on gold surfaces through
hydrogen-bonding interactions and a uracil-terminated organo-
species.
6
Special Issue: Organometallic Electrochemistry
Received: March 18, 2014
©
XXXX American Chemical Society
A
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In these regard, electrochemical studies on a singly modified
nucleobase can be used as a standard for evaluating and
developing new efficient methods for the electrochemical
quantification of nucleotides and nucleosides. Such fundamen-
tal studies can clarify the nature and identity of species formed
during the direct modification of DNA with specifically
various conditions, using ammonia or ammonia equivalents
(Scheme 1). In addition, Buchwald−Hartwig methodologies
Scheme 1. Synthesis of 5
1
5
designed reagents. To this goal, we have investigated the
preparation of several guanine−ferrocene conjugates, by using
specific reactions developed for this purpose, and have fully
characterized the new guanine−ferrocene molecules from an
electrochemical point of view. Our studies have introduced new
ferrocene conjugates and, more importantly, a facile and
selective method for the introduction of ferrocene residues in
nucleobases based on S 1 type reactions, which can be further
N
exploited. In addition, the comprehensive electrochemical
characterization of such species provides a standard for the
selection of the best labels for the development of biosensing
devices and protocols for the electrochemical detection of
DNA.
20
were briefly considered, but no results were obtained. Under
quite harsh conditions the nucleophilic displacement of the Cl
group was observed for different amines.
By the direct reaction of the racemic aminoferrocene 6 with
racemic 4b, compound 7, containing two ferrocene molecules,
was prepared (Scheme 2). 7 contains two stereogenic centers
RESULTS AND DISCUSSION
■
The reaction of purine bases with alkylating agents yields 3-, 7-,
16
or 9-alkyl-substituted derivatives, and the ratio of these
derivatives depends on the nature of the alkylating agent and on
the reaction conditions. Zhilina reported the reaction of
ferrocenylethanol with adenine that occurs in position 9, in a
biphasic reaction mixture (CH Cl −H O) in the presence of
Scheme 2. Synthesis of 7
2
2
2
1
7
HBF . In a previous article, we were able to react
4
enantioenriched ferrocene alcohols under S 1-type conditions
N
with different nucleophiles, with the reaction occurring with
18
retention of stereochemistry. In particular we have used
catalytic amounts of In(III) salts for the reaction with
nucleophiles. As the preceding report suggested the possibility
of an S 1-type reaction with chiral and achiral ferrocene
and was obtained as a inseparable mixture of diastereoisomers
(ratio close to 1:1) in quite low yields. However, the direct
reaction of amine with 2-chloroguanine is difficult and in order
to introduce amino group at the 2-position, stronger
nucleophilic compounds are often used. The new compound
7 has a peculiar and quite interesting electrochemistry (see
below).
N
alcohols, we investigated the direct substitution of guanine. The
reaction of ferrocenylethanol (1b) with guanine was inves-
tigated in different solvents and under various conditions in the
presence of indium salts. Also, different additives, Brønsted and
Lewis acids, were added to the reaction mixture. As guanine is
insoluble in organic solvents, the reactions were carried out “on
water”. The temperatures investigated were between room
temperature and 80 °C. In all cases, no traces of product were
detected. The corresponding potassium salt of guanine is easily
prepared by the treatment of guanine with KOH, and the
isolated potassium salt was used in the reaction with stable
carbenium ion. We were able to detect the reaction of guanine
at the 9-nitrogen atom by using a carbenium ion obtained from
21
In order to prepare the 9-alkylated ferrocenylguanine, a
simple and effective strategy was designed. The 2-Boc chloro
22
purine 8 (Boc = COOtBu) was employed in the In(III)
reaction with 1a, but in this case partial deprotection of the Boc
group occurred, giving a mixture of compounds. We found that
Al(OTf) was a suitable Lewis acid for this transformation,
3
which allowed the preparation of the desired compound by the
use of optically enriched ferrocenylethanol, without the
deprotection of Boc.
p-NMe -benzhydrol, stable under aqueous conditions. How-
2
ever, the limited solubility of ferrocene derivatives did not allow
23
the reaction under aqueous conditions. The direct S 1 reaction
The lower Lewis acidity of Al(OTf)3 allowed the direct
introduction of ferrocenylethanol at the 9-position of guanine.
The direct functionalization of the 9-position of guanine by SN1
chemistry is suggested by our study. The introduction of
N
of guanine was still considered by the use of suitable precursors
that were more soluble in organic solvents. Monochloro- and
dichloropurines are extensively used as precursors of
nucleobases. The direct modification of nucleobases by
nucleophilic aromatic substitution and successive hydrolysis
different groups with S 1-type chemistry would be possible by
N
the direct reaction of 2-Boc chloropurine with other carbenium
19
24
allows in many cases the synthesis of the desired derivatives.
ions generated from alcohols in the presence of Lewis acids.
The chloro derivatives 2 and 8 were reacted with 1a in the
Pleasantly, we found out that the hydrolysis of 9 with 1 N
NaOH in aqueous dioxane gave not only the hydrolysis of
chlorine to the desired oxo substituent but also the
deprotection of Boc to the desired 10, without any need of
an acid treatment (Scheme 3). The electrochemistry of 10 was
investigated in detail. When the nucleophilic 9-N atom is
protected, as in the triacetyl guanosine derivative 11, the
presence of a catalytic amount of In(OTf) . While 8 was
3
insoluble in many of the solvents tested, 2 smoothly reacted
with ferrocene 1a, affording the desired compound 3a in
moderate yield. The hydrolysis of 3a into 4a occurred by
19
following the standard procedure in the literature. However,
the synthesis of 9-ferrocenylguanine was attempted under
B
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Scheme 3. Synthesis of 10
(TBAF) to form 17 and its direct esterification with
ferrocenecarboxylic acid under the conditions mentioned
above for 14 afforded the target compound 18.
All of the electrochemistry experiments were performed
under strictly aprotic conditions (DCM and DMSO), using
tetrabutylammonium hexafluorophosphate (TBAHFP) as
supporting electrolyte. The dynamics of the electrochemical
behavior of 5, 7, 12, 14, and 18 were investigated using cyclic
−1
voltammetry (CV). At 298 K and v = 0.5 V s , the
voltammogram of 5 in DCM displays one reversible oxidation
peak at E1/2 = +0.49 V. This oxidation is attributed to the
reversible oxidation of the ferrocenyl group (Figure 1).
indium-promoted nucleophilic addition of ferrocenyl alcohol 1a
takes place with the available free amino group at position 2
(
Scheme 4). As racemic 1a was used for the reaction, an
inseparable mixture of diastereoisomers (1.2:1) was obtained.
Scheme 4. Synthesis of 12
2
′-Deoxyguanosine derivatives were also prepared. The
synthesis of bis-ferrocenoyl derivative 14 was achieved by
direct esterification of commercial 13 with ferrocenecarboxylic
acid (Fc-COOH) in the presence of dicyclohexylcarbodiimide
Figure 1. Cyclic voltammetric curves of compound 5 (0.8 mM) in
0.05 M TBAHFP/DCM solution, recorded with two different scan
reversal potentials: T = 298 K; v = 0.5 V s ; working electrode Pt disk
(
(
DCC) as the condensing agent and 4-dimethylaminopyridine
DMAP) as the catalyst (Scheme 5). When this method is
−
1
(
d = 125 μm). Potentials are referenced to the SCE.
Scheme 5. Synthesis of 14
At more positive potentials an irreversible peak appears. The
inclusion in the potential scan of such a peak, associated with
the guanine-centered oxidation, brings about a significant
increase of the ferrocenyl cation centered reduction current at
∼
0.5 V, typical of processes involving adsorbed species. Such a
behavior was tentatively attributed to the high charge of the
species generated in the anodic scan that, in the present low-
dielectric medium, would precipitate reversibly onto the
electrode surface. In line with this hypothesis, a second scan
carried out under the conditions of Figure 1 (not shown)
displays an anodic pattern comparable to that of the first scan,
indicating that, upon its neutralization during the cathodic scan,
the precipitate is redissolved. Also in line with such a
mechanistic hypothesis is the voltammetric behavior of 7: i.e.,
a variant of 5 in which the benzylic moiety is replaced with a
second ferrocenyl group. The bielectronic reversible peak
observed at E1/2 = +0.43 V (Figure 2) is due to the two
ferrocene groups and, since it does not present any splitting, the
ferrocenyl groups are electronically independent. Also in this
case, an intense adsorption peak is observed when the full
oxidation of the molecule (i.e., also including the guanine-
centered oxidation) is carried out. However, a scan-rate-
dependent CV experiment carried out in the potential region of
the ferrocene oxidation (Figure 3) clearly evidenced that
adsorption does take place, in the present species, also
following the ferrocene oxidation. Note the typical triangular
shape of peaks as the scan rate increases, the small peak
separation, and the linear dependence of peak current on scan
rate (inset in Figure 3).
used, the protection of the exocyclic amino group on the
nucleobase 13 is unnecessary. On the other hand, the use of
mixed anhydrides, obtained from ferrocenecarboxylic acid, as
the acylating agent proved in this case unsuccessful.
The analogous but more lipophilic monoferrocenoyl
derivative 18 (Scheme 6) was obtained by selective protection
of the 5′-hydroxy group (15), followed by esterification of the
3
′-alcoholic function with decanoic anhydride (16). Again, the
protection of the exocyclic amino function could be avoided.
Subsequent desilylation with tetrabutylammonium fluoride
Scheme 6. Synthesis of 18
C
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curve shows again the ferrocenyl oxidation process at +0.41 V
and a peak at +1.41 V due to the guanosine moiety; however,
no evidence of adsorption of the oxidized species is observed in
this case. The presence of the sugar moiety, imparting an
increased solubility to the charged species and thus preventing
its precipitation, may in fact explain the observed behavior.
However, in view of the known ability of guanosine and its
derivatives to self-assemble into ordered structures, such as G-
25
quartets or ribbons, a possible steric effect associated with the
position of the ferrocenyl group with respect to the guanine
moiety and its role in the H-bonding ability of the guanine
moieties cannot be ruled out.
To further investigate such an issue, compound 7, previously
investigated in DCM (Figure 2), was also investigated in
DMSO, a solvent known for its ability to disrupt the H-bond
network in proteins, DNA, and artificial supramolecular systems
alike. Interestingly, although not totally unexpectedly, in such
a solvent the CV curve (Figure 5) displays no strong evidence
Figure 2. Cyclic voltammetric curves of compound 7 (0.8 mM) in
−1
0
.05 M TBAHFP/DCM solution: T = 298 K; v = 0.5 V s , recorded
with two different scan reversal potentials; working electrode Pt disk
d = 125 mm). Potentials are referenced to the SCE.
26
(
Figure 3. Cyclic voltammetric curves of compound 7 (0.8 mM) in
.05 M TBAHFP/DCM solution: T = 298 K; v = 0.1 (solid line), 0.2
Figure 5. Cyclic voltammetric curves of compound 7 in 0.05 M
TBAHFP/DMSO solution; T = 298 K; v = 0.2 (solid line), 0.5 (long
0
−1
(
short dashed line), 0.5 (dash-dotted line), 1 V s (long dashed line);
−
1
dashed line), 10 V s (short dashed line); working electrode Pt disk
d = 125 μm). The inset gives the scan rate dependence of the
working electrode Pt disk (d = 125 μm) The insetgives peak currents
as a function of scan rate. Potentials are referenced to the SCE.
(
shoulder indicated by the dash-dotted line on the CV curves.
Potentials are referenced to the SCE.
In contrast with the above straightforward interpretation of
the observed CV behavior was the cyclic voltammetric curve of
Figure 4, relative to the guanosine ferrocenyl derivative 12. The
of adsorption at any rate. The scan-rate-dependent inves-
tigation evidenced in fact the typical diffusion-controlled two-
electron reversible peak associated with ferrocene oxidation.
The presence of a secondary species in solution, responsible for
the reversible shoulder located at ∼0.25 V, was also observed
(
dash-dotted vertical line in Figure 5). Such a low intensity
peak is only observed at relatively high scan rates with a linear
dependence on the square root of scan rate (see inset in Figure
5
), thus excluding that it may be associated with an adsorbed
species. A possible explanation of the observed behavior, that is
in line with the known self-assembly behavior of guanosine, is
that 7 may form, under the conditions of Figure 5, aggregates
that are dynamically linked to the monomer (prevalent
species).
The bis-ferrocenyl species 14, in which the two ferrocenes
are both located on the sugar moiety, was then investigated.
The CV curve (Figure 6) displays in this case huge adsorption
spikes that are observed after the full oxidation of the species
Figure 4. Cyclic voltammetric curves of compound 12 (0.8 mM) in
−1
(
i.e., also including oxidation of the guanine unit) but also
immediately after the two-electron oxidation of the two
equivalent ferrocenes.
0
.05 M TBAHFP/DCM solution: T = 298 K; v = 0.5 V s , recorded
with two different scan reversal potentials; working electrode Pt disk
d = 125 μm). Potentials are referenced to the SCE.
(
D
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a
Table 1. Electrochemical Properties
E1/2 (V)
compound
DMSO
DCM
5
7
0.53
0.49
0.51*
0.48
0.43*
0.41
1
1
1
2
4
8
0.75*
0.73
0.61*
0.65
a
E1/2 values for all investigated species in DMSO/TBAHFP and
DCM/TBAHFP solutions. Working electrode: Pt disk (d = 125 μm),
T = 298 K. Potentials are referenced to the SCE. The potentials
marked with asterisks are associated with two-electron oxidations.
CONCLUSION
■
In conclusion, we have described the straightforward synthesis
of new ferrocene guanine conjugates and we have reported
their complete electrochemical characterization by cyclic
voltammetry under ultradry conditions. The investigation
highlighted a rather intriguing behavior where self-aggregation
of the guanine derivatives, driven by H-bonding, and solubility
effects associated with the increased charge induced electro-
chemically, bring about the formation of adsorbed layers onto
the electrode surface. Such layers may be reversibly redissolved
by reducing the oxidized ferrocenyl/guanine moieties, a process
that takes place on the time scale of the CV experiments.
Further studies about the ability of these compounds to form
ordered supramolecular structures on solid supports are in
progress in our laboratories and will be reported in due time.
Figure 6. Cyclic voltammetric curves of compound 14 (0.8 mM) in
−1
0
.05 M TBAHFP/DCM solution: T = 298 K; v = 0.5 V s , recorded
with two different scan reversal potentials; working electrode Pt disk
(d = 125 μm). Potentials are referenced to the SCE.
Such a process is largely shifted to more positive potentials
than for the previous species, as a consequence of the electron-
withdrawing effect of the carboxylate substituents. However,
the relative position of the two ferrocenes with respect to the
guanine is assumed to be responsible for the different behaviors
with respect to the previous bis-ferrocene 7, since in this case
the self-recognition of guanines and their aggregation via H
bonding should be much less disturbed by the ferrocene
moieties. Finally, the monoferrocene 18, which also carries a
long lipophilic chain on the sugar moiety, displayed a much
more diffusion controlled reversible behavior likely associated
with the increased solubility of the monomers and aggregates
EXPERIMENTAL SECTION
General Considerations. All reactions requiring anhydrous
conditions were carried out in oven-dried glassware under a dry
argon atmosphere. Macherey-Nagel Polygram silica gel plates (layer
■
0
.20 mm) were used for TLC analyses. Column chromatography was
(Figure 7).
performed on Geduran silica gel 60 (40−63 μm). Purification by
preparative thin-layer chromatography was done on Merck TLC silica
gel 60 F254. Reagents and solvents, including dry solvents, were
purchased from Aldrich or Alfa Aesar.
Instrumentation. NMR spectra were recorded on Varian (Inova
00 MHz, Mercury plus 400 MHz, Mercury 300 MHz, Gemini 200)
6
spectrometers. Mass spectra were measured on an ESI spectrometer.
LC-electrospray ionization mass spectra (ESI-MS) were obtained with
an Agilent Technologies MSD1100 single-quadrupole mass spectrom-
eter. Melting points were recorded on a Stuart SMP3 Scientific
Melting Point Apparatus and were not corrected.
Chemical shifts are reported in ppm from TMS with the solvent
resonance as the internal standard (deuterochloroform: δ 7.27 ppm).
Data are reported as follows: chemical shift, multiplicity (s = singlet, d
=
doublet, t = triplet, q = quartet, dd = doublet of doublets, dt =
doublet of triplets, bs = broad signal, m = multiplet), coupling
constants (Hz). Mass data are reported as m/z (relative intensity).
Electrochemistry. All materials were reagent grade chemicals. The
supporting electrolyte tetrabutylammonium hexafluorophosphate
(TBAHFP, from Fluka) was used as received. Ultradry dimethyl
sulfoxide (DMSO) and dichloromethane (DCM) was chosen as
solvents. The commercial solvents (DMSO, purum from Sigma-
Aldrich; DCM, purum from Sigma-Aldrich) were first treated with
basic alumina (from MP Biomedicals) in a flask for at least 48 h.
Afterward, the solvent was distilled trap-to-trap into an especially
designed Schlenk, containing activated 3 Å molecular sieves. It was
stored in the same Schlenk, protected from light and kept under
vacuum prior to use. The cell, containing the supporting electrolyte
and the electroactive compound, was dried under vacuum at 370 K for
at least 48 h. Afterward the solvent was distilled by a trap-to-trap
procedure into the electrochemical cell just before performing the
Figure 7. Cyclic voltammetric curves of compound 18 (0.8 mM) in
−1
0
.05 M TBAHFP/DCM solution: T = 298 K; v = 0.5 V s , recorded
with two different scan reversal potentials; working electrode Pt disk
(d = 125 μm). Potentials are referenced to SCE.
All potentials relative to oxidation of the ferrocene moieties
in the investigated species are gathered in Table 1.
As already anticipated above, the potentials for the ferrocene-
based oxidation in 14 and 18 are significantly higher than those
in compounds 5 and 7, an expected effect of the electron-
withdrawing carboxyl linker groups.
E
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Article
electrochemical experiment. The pressure measured in the electro-
chemical cell prior to performing the trap-to-trap distillation of the
solvent was typically around 1 × 10 mbar.
μL). The solution was stirred at 80 °C for 8 h until complete
conversion was observed by TLC. The dioxane was evaporated under
−5
reduced pressure, then aqueous saturated NH Cl was added until the
4
The one-compartment electrochemical cell was of airtight design,
with high-vacuum glass stopcocks fitted with either Teflon or Viton O-
rings, to prevent contamination by grease. The connections to the
high-vacuum line and to the Schlenk flask containing the solvent were
made by spherical joints fitted with Viton O-rings. Also, the working
electrode consisted of a Pt-disk ultramicroelectrode (with diameter of
pH was neutral. The aqueous mixture was extracted with DCM (5 mL
× 3), and the collected organic layers were concentrated under
reduced pressure. 10 was obtained as an orange solid after
chromatographic purification (ethyl acetate until the byproduct was
eluted, then 90/10/2 DCM/MeOH/NH ): yield 0.084 mmol, 30.6
3
1
mg, 50%; H NMR (400 MHz, DMSO-d , 25 °C) δ 10.56 (s, 1H),
6
1
25 μm), sealed in glass. The counter electrode consisted of a
7.70 (s, 1H), 6.48 (s, 2H), 5.36 (q, J = 7.1 Hz, 1H), 4.37−4.39 (m,
platinum spiral, and the quasi-reference electrode was a silver spiral.
The quasi-reference electrode drift was negligible for the time required
by a single experiment. Both the counter and reference electrodes were
separated from the working electrode by 0.5 cm. Further details about
1H), 4.23−4.25 (m, 1H), 4.21−4.23 (m, 1H), 4.18−4.21 (bs, 6H),
1.82 (d, J = 7.1 Hz, 3H); 13C NMR (100 MHz, DMSO-d , 25 °C) δ
6
157.3, 153.9, 150.9, 136.3, 117.2, 90.5, 69.6 (5C), 69.0, 68.5, 68.2, 67.4,
+
+
49.5, 21.7; ESI-MS m/z 363.0 [M] , 364.1 [M + H] , 727.0 [2M +
27
+
the electrochemical cell are described elsewhere. Potentials were
measured with the decamethylferrocene standard and are always
referenced to the SCE, which was also used as an internal standard for
checking the electrochemical reversibility of a redox couple.
Voltammograms were recorded with a homemade fast potentiostat
controlled by an AMEL Model 568 function generator. Data
acquisition was performed by a Nicolet Model 3091 digital
oscilloscope interfaced to a PC.
H] ; decomposition at 230 °C. Anal. Calcd for C H FeN O : C,
56.22; H, 4.72; N, 19.28. Found: C, 56.30; H, 4.80; N, 19.14.
17
17
5
6
9-(1″-Ferrocenylethyl)-2′,3′,5′-tri-O-acetylguanosine (12).
To a solution of 1-ferrocenylethanol (1a; 0.3 mmol, 69 mg) in
DCM (2 mL) were added 2′,3′,5′-tri-O-acetylguanosine (11; 0.2
mmol, 82 mg) and In(OTf) (0.04 mmol, 132 μL of a solution 0.3 M
3
in CH CN). The mixture was stirred for 48 h at room temperature.
3
Then the reaction was quenched with water (2 mL). The organic
phase was separated, and the aqueous phase was extracted with DCM
(3 mL × 2). The collected organic layers were concentrated under
reduced pressure and purified by preparative TLC on silica (95/5
9
-(1′-Ferrocenylethyl)-2-N-benzylguanine (5). In a Schlenk
tube under a nitrogen atmosphere were placed 9-(1′-ferrocenylethyl)-
-chloro-6-oxopurine (4a; 0.15 mmol, 58 mg), DMSO (500 μL), and
2
benzylamine (0.9 mmol, 100 μL). The solution was stirred at 150 °C
DCM/MeOH as eluting mixture) to give 12 as a yellow solid in a 1.1/
1
for 6 h until complete conversion was observed by TLC. Ethyl acetate
1.0 (diastereomeric ratio determined by H NMR: δ
5.67; δminor
major
1
(
10 mL) was added, and an orange precipitate was formed. The solid
5.62): yield 0.93 mmol, 58 mg, 47%; H NMR (400 MHz, DMSO-d ,
6
was filtered and washed with DCM until a white solid was left: the
25 °C) δmajor 10.76 (s, 1H), 7.91 (s, 1H), 6.39 (d, J = 8.0 Hz, 1H), 6.11
yellow DCM solution was concentrated to give pure 5 as a yellow
(d, J = 4.0 Hz, 1H), 6.04 (dd, J = J = 6.0 Hz, 1H), 5.67 (dd, J = J =
1
2
1
2
1
solid: yield 0.022 mmol, 10.3 mg, 15%; H NMR (600 MHz, DMSO-
6.0 Hz, 1H), 4.88−5.00 (m, 1H), 4.31−4.46 (m, 3H), 4.25 (s, 5H),
4.18−4.28 (m, 4H), 2.14 (s, 3H), 2.12 (s, 3H), 2.03 (s, 3H), 1.51 (d, J
d , 25 °C) δ 10.42−10.72 (bs, 1H), 7.75 (s, 1H), 7.37−7.46 (m, 4H),
6
7
4
4
.29−7.35 (m, 1H), 6.91 (t, J = 4.8 Hz, 1H), 5.38 (q, J = 7.1 Hz, 1H),
= 6.3 Hz, 3H), δ
10.76 (s, 1H), 7.92 (s, 1H), 6.40 (d, J = 8.0 Hz,
minor
.51−4.66 m, 2H), 4.33−4.38 (m, 1H), 4.12−4.18 (bs, 6H), 4.09−
1H), 6.11 (d, J = 4.0 Hz, 1H), 6.03 (dd, J = J = 6.0 Hz, 1H), 5.62
1
2
13
.12 (m, 1H), 4.06−4.08 (m, 1H), 1.82 (d, J = 7.1 Hz, 3H); C NMR
(dd, J = J = 6.0 Hz, 1H), 4.88−5.00 (m, 1H), 4.31−4.46 (m, 3H),
1
2
(
150 MHz, DMSO-d , 25 °C) δ 157.2, 152.5, 150.5, 139.9, 136.0,
4.26 (s, 5H), 4.18−4.28 (m, 4H), 2.13 (s, 3H), 2.10 (s, 3H), 2.01 (s,
6
1
6
9
28.8 (2C), 127.8 (2C), 127.4, 117.1, 90.0, 69.0 (5C), 68.3, 67.9, 67.8,
3H), 1.52 (d, J = 6.3 Hz, 3H); 13C NMR (100 MHz, DMSO-d , 25
6
+
+
7.7, 49.3, 44.5, 20.4; ESI-MS: m/z 454.1 [M + H] , 476.0 [M + Na] ,
07.1 [2M + H] , 1835.4 [4M + Na] ; decomposition at 190 °C. Anal.
°C) δmajor 169.86, 169.23, 169.18, 156.5, 151.69, 150.0, 137.0, 117.3,
91.1, 86.1, 78.4, 71.8, 69.7, 68.31 (5C), 67.5, 67.1, 66.4, 65.5, 62.9,
44.8, 20.9, 20.3, 20.17, 20.12, δminor 169.83, 169.28, 169.20, 156.5,
151.73, 150.1, 136.9 117.4, 91.2, 86.4, 78.5, 71.8, 69.7, 68.28 (5C),
67.5, 67.2, 66.5, 65.6, 62.8, 44.7, 21.1, 20.3, 20.19, 20.15; ESI-MS m/z
+
+
Calcd for C H FeN O: C, 63.59; H, 5.11; N, 15.45. Found: C,
24
23
5
6
3.69.; H, 5.19; N, 15.41.
2
-N-(1″-Ferrocenylethyl)-9-(1′-ferrocenylpropyl)guanine (7).
+
+
+
In a Schlenk tube under a nitrogen atmosphere were placed 9-(1′-
ferrocenylpropyl)-2-chloro-6-oxopurine (4b; 0.75 mmol, 299 mg),
DMSO (2.3 mL), and 1′-ferrocenylethylamine (6; 1.5 mmol, 346 mg).
The solution was stirred at 150 °C for 11 h. The crude mixture was
directly purified by column chromatography (eluting mixture 90/10/2
621.0 [M] , 622.2 [M + H] , 1243.1 [2M + H] ; decomposition at
200 °C. Anal. Calcd for C H FeN O : C, 54.12; H, 5.03; N, 11.27.
28
31
5
8
Found: C, 54.17; H, 5.11; N, 11.24.
2′-Deoxy-3′,5′-O-diferrocenoylguanosine (14). Ferrocenecar-
boxylic acid (194 mg, 0.84 mmol) and 2′-deoxyguanosine hydrate (13;
100 mg, 0.35 mmol) were dried over P O in vacuo for 2 h at 60 °C.
DCM/MeOH/NH ) to give pure 7 as an orange solid in a 1.2/1.0
3
2
5
1
diastereomeric ratio determined by H NMR (δ
yield 0.08 mmol, 42.0 mg, 11%; H NMR (600 MHz, DMSO-d , 25
7.85; δminor 7.83):
Ferrocenecarboxylic acid was dissolved in DMF (8 mL), DCC (294
mg, 1.43 mmol) was added, and the resulting solution was stirred
under an argon atmosphere. After 30 min 2′-deoxyguanosine and
DMAP (43 mg, 0.35 mmol) were added and the resulting solution was
stirred for 4 h. The solvent was removed under reduced pressure, the
crude product was dissolved in dichloromethane, and the solution was
major
1
6
°
C) δmajor 10.61 (s, 1H), 7.85 (s, 1H), 6.22 (d, J = 8.2 Hz, 1H), 5.14
(
dd, J = 11.0 Hz, J = 4.3 Hz, 1H), 4.88−4.95 (m, 1H), 4.35−4.38 (m,
1
2
1
4
1
1
4
1
4
H), 4.25−4.27 (m, 1H), 4.19−4.24 (m, 7H), 4.14−4.18 (m, 3H),
.11−4.14 (m, 1H), 4.07 (s, 5H), 2.25−2.32 (m, 1H), 2.13−2.21 (m,
H), 1.51 (d, J = 6.7 Hz, 3H), 0.76 (q, J = 9.0 Hz, 3H), δminor 10.57 (s,
H), 7.83 (s, 1H), 6.21 (d, J = 8.2 Hz, 1H), 5.14 (dd, J = 11.0 Hz, J =
extracted with saturated NaHCO . The organic layer was dried over
3
MgSO , and the residue was applied to a silica gel column packed with
1
2
4
.3 Hz, 1H), 4.88−4.95 (m, 1H), 4.35−4.38 (m, 1H), 4.28−4.30 (m,
H), 4.19−4.24 (m, 8H), 4.14−4.18 (m, 2H), 4.11−4.14 (m, 1H),
.06 (s, 5H), 2.25−2.32 (m, 1H), 2.13−2.21 (m, 1H), 1.49 (d, J = 6.7
dichloromethane and eluted with a gradient of methanol in
dichloromethane. The final product was eluted with a mixture of
dichloromethane and methanol (95/5) and was obtained as a yellow
13
1
Hz, 3H), 0.76 (q, J = 9.0 Hz, 3H); C NMR (150 MHz, DMSO-d ,
solid: yield 214 mg, 83%; H NMR (DMSO-d ) δ 10.67 (bs, 1H,
6
6
1
8
25 °C) δmajor 156.8, 151.2, 150.6, 136.3, 116.4, 91.5, 89.4, 68.4 (5C),
68.3 (5C), 67.6, 67.5, 67.3, 67.2, 67.0, 66.73, 66.70, 65.6, 55.3, 44.6,
27.5, 21.0, 11.1, δminor 156.8, 151.2, 150.6, 136.4, 116.3, 91.5, 89.6, 68.4
N H), 8.01 (s, 1H, H ), 6.48 (bs, 2H, NH ), 6.30 (dd, J = 7.2 Hz, J =
2
1
3
6.0 Hz, 1H, H ′), 5,57 (m, J = 6.0 Hz, 1H, H ′), 4,84 (bs, 2H, cp), 4.77
5
(bs, 2H, cp), 4.56 (bs, 2H, cp), 4.51 (bs, 2H, cp), 4.49 (m, 1H, H ′),
4
5
(
4
5C), 68.3 (5C), 67.7, 67.5, 67.3, 67.2 (2C), 66.74, 66.6, 65.6, 55.1,
4.5, 27.5, 20.9, 11.1; ESI-MS: m/z 590.2 [M + H] , 612.3 [M + Na] ;
4.42 (m, 2H, H ′, H ′), 4.30 (s, 5H, cp), 4.21 (s, 5H, cp), 3.08 (m, J =
+
+
2
14.4 Hz, J = 7.2 Hz, J = 6.0 Hz, 1H, H ′), 2.63 (dd, J = 14.4 Hz, J = 6.0
2
13
decomposition at 180 °C. Anal. Calcd for C H Fe N O: C, 61.14; H,
Hz, 1H, H ′); C NMR (DMSO-d ) δ 170.94 (FcCO), 170.70
6 2 4 8
30
31
2
5
6
5
.30; N, 11.88. Found: C, 61.22; H, 5.39; N, 11.79.
-(1′-Ferrocenylethyl)guanine (10). In a Schlenk tube were
placed 9-(1′-ferrocenylethyl)-2-N-Boc-6-chloropurine (9; 0.17 mmol,
0 mg), dioxane (1.5 mL), and 1 M aqueous NaOH (0.8 mmol, 800
(FcCO), 157.14 (C ), 154.19 (C ), 151.51 (C ), 135.59 (C ), 117.40
5
1
4
3
9
(C ), 83.36 (C ′), 82.07 (C ′), 74.61 (C ′), 72.18 (CH ), 72.01
cp
(CH ), 70.59 (C ), 70.47 (C ), 70.40 (CH ), 70.35 (CH ), 70.18
cp
cp
cp
cp
cp
5
2
8
(CH ), 70.07 (CH ), 64.03 (C ′), 36.32 (C ′); ESI-MS (positive
cp
cp
F
dx.doi.org/10.1021/om5002809 | Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
+
+
mode, MeOH solution, m/z) 692.3 [M + H] , 714.2 [M + Na] . Anal.
(2) (a) Sivakova, S.; Rowan, S. J. Chem. Soc. Rev. 2005, 34, 9−21.
(b) Davis, J. T. Angew. Chem., Int. Ed. 2004, 43, 668−698.
(c) Krishnan-Ghosh, Y.; Liu, D.; Balasubramanian, S. J. Am. Chem.
Soc. 2004, 126, 11009−11016.
Calcd for C H Fe N O : C, 55.60; H, 4.23; N, 10.13. Found: C,
32
29
2
5
6
5
5.77; H, 4.22; N, 10.14.
2
′-Deoxy-3′-O-decanoyl-5′-O-ferrocenoylguanosine (18).
Ferrocenecarboxylic acid (135 mg, 0.58 mmol) and 2′-deoxy-3′-O-
(3) (a) van Staveren, D. R.; Metzler-Nolte, N. Chem. Rev. 2004, 104,
5931−5985. (b) Patwa, A. N.; Gupta, S.; Gonnade, R. G.; Kumar, V.
A.; Bhadbhade, M. M.; Ganesh, K. N. J. Org. Chem. 2008, 73, 1508−
decanoylguanosine 17 (178 mg, 0.42 mmol) were dried over P O in
2
5
vacuo for 2 h at 60 °C. Ferrocenecarboxylic acid was dissolved in DMF
10 mL), DCC (207 mg, 1.00 mmol) was added, and the resulting
solution was stirred under an argon atmosphere. After 30 min 2′-
deoxy-3′-O-decanoylguanosine and DMAP (43 mg, 0.35 mmol) were
added and the solution was stirred for 4 h. The solvent was then
removed under reduced pressure, the crude product was dissolved in
dichloromethane, and the solution was extracted with saturated
NaHCO . The organic layer was dried over MgSO . The reaction
mixture was applied to a silica gel column packed in dichloromethane
and eluted with a gradient of methanol in dichloromethane. The final
product was eluted with a mixture of dichloromethane and methanol
(
̌
̆ ̌ ̌ ́
1515. (c) Hocek, M.; Stepnicka, P.; Ludvík, J.; Císarova, I.; Votruba, I.;
̌
Reha, D.; Hobza, P. Chem. Eur. J. 2004, 10, 2058−2066.
4) Houlton, A.; Isaac, C. J.; Gibson, A. E.; Horrocks, B. R.; Clegg,
W.; Elsegood, M. R. J. J. Chem. Soc., Dalton Trans. 1999, 3229−3234.
(
(
5) Kumar, J.; Purohit, C. S.; Verma, S. Chem. Commun. 2008, 2526−
2
528.
3
4
(6) Fabre, B.; Ababou-Girard, S.; Singh, P.; Kumar, J.; Verma, S.;
Bianco, A. Electrochem. Commun. 2010, 12, 831−834.
7) Patwa, A. N.; Gupta, S.; Gonnade, R. G.; Kumar, V. A.;
Bhadbhade, M. M.; Ganesh, K. N. J. Org. Chem. 2008, 73, 1508−1515.
8) Maruccio, G.; Visconti, P.; Arima, V.; D’Amico, S.; Biasco, A.;
(
1
(
94/6), giving the product as a pale yellow solid: yield 83 mg, 31%; H
NMR (DMSO-d ) δ 10.66 (bs, 1H, N H), 7.96 (s, 1H, H ), 6.48 (bs,
(
1
8
6
D’Amone, E.; Cingolani, R.; Rinaldi, R.; Masiero, S.; Giorgi, T.;
Gottarelli, G. Nano Lett. 2003, 3, 479−483.
1
2
H, NH ), 6.18 (dd, J = 9.0 Hz, J = 6.0 Hz, 1H, H ′), 5.42 (m, J = 6.0
2
3
Hz, 1H, H ′), 4.75 (bs, 2H, cp), 4.50 (bs, 2H, cp), 4.43 (dd, J = 11.4
(9) (a) Coutouli-Argyropoulou, E.; Tsitabani, M.; Petrantonaki, Ge.;
5
5
Hz, J = 6.0 Hz, 1H, H ′), 4.33 (dd, J = 11.4 Hz, J = 5.0 Hz, 1H, H ′),
Terzis, A.; Raptopoulou, C. Org. Biomol. Chem. 2003, 1, 1382−1388.
4
2
4
.29 (m, 1H, H ′), 4.19 (s, 5H, cp), 2.98 (m, 1H, H ′), 2.51 (m, 1H,
2
(
4
1
b) Anne, A.; Blanc, B.; Moiroux, J. Bioconjugate Chem. 2001, 12, 396−
H ′), 2.38 (t, J = 7.2 Hz, 2H, COCH ), 1.56 (quint, J = 7.2 Hz, 2H,
2
05. (c) Song, H.; Kraatz, H.-B. Inorg. Chim. Acta 2009, 362, 1355−
13
COCH CH ), 1.24 (m, 12H, CH ), 0.84 (t, J = 7.2 Hz, 3H, CH );
C
2
2
2
3
368.
NMR (DMSO-d ) δ 172.99 (CH CO), 170.91 (FcCO), 157.14 (C6),
6
2
(10) (a) Wang, J.; Cai, X.; Wang, J.; Jonsson, C. Anal. Chem. 1995,
4
8
5
1
1
8
7
54.23 (C2), 151.53 (C ), 135.51 (C ), 117.33 (C ), 83.25 (C ′),
6
7, 4065−4070. (b) Ihara, T.; Maruo, Y.; Takenaka, S.; Takagi, M.
4 3
2.04 (C ′), 74.72 (C ′), 72.02 (CH ), 70.58 (C ), 70.27 (CH ),
cp
cp
cp
5
2
Nucleic Acids Res. 1996, 24, 4273−4280. (c) Korri-Youssoufi, H.;
Garnier, F.; Srivastava, P.; Godillot, P.; Yassar, A. J. Am. Chem. Soc.
0.07 (CH ), 63.94 (C ′), 36.25 (C ′), 33.90 (CH CO), 31.72
cp
2
(
CH ), 29.30 (CH ), 29.16 (CH ), 29.09 (CH ), 28.87 (CH ), 24.77
2 2 2 2 2
1
997, 119, 7388−7389.
(
CH ), 22.54 (CH ), 14.41 (CH ); ESI-MS (positive mode, MeOH
solution, m/z) 634.5 [M + H] , 657.2 [M + Na] . Anal. Calcd for
C H FeN O : C, 58.77; H, 6.21; N, 11.05. Found: C, 58.92; H, 6.19;
2
2
3
+
+
(11) (a) Boon, E. M.; Ceres, D. M.; Drummond, T. G.; Hill, M. G.;
Barton, J. K. Nat. Biotechnol. 2000, 18, 1096−1100. (b) Yamashita, K.;
Takagi, M.; Kondo, H.; Takenaka, S. Anal. Biochem. 2002, 306, 188−
3
1
39
5
6
N, 11.06.
1
96. (c) Yamashita, K.; Takagi, A.; Takagi, M.; Kondo, H.; Ikeda, Y.;
Takenaka, S. Bioconjugate Chem. 2002, 13, 1193−1199. (d) Wakai, J.;
Takagi, A.; Nakayama, M.; Miya, T.; Miyahara, T.; Iwanaga, T.;
Takenaka, S.; Ikeda, Y.; Amano, M. Nucleic Acids Res. 2004, 32, e141.
(12) (a) Brazill, S. A.; Kuhr, W. G. Anal. Chem. 2002, 74, 3421−
ASSOCIATED CONTENT
Supporting Information
Text and figures giving syntheses and NMR spectra for 3a−18
and cyclic voltammograms for select compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
■
*
S
3
428. (b) Fan, C.; Plaxco, K. W.; Heeger, A. J. Proc. Natl. Acad. Sci.
U.S.A. 2003, 100, 9134−9137. (c) Wang, J.; Li, J.; Baca, A. J.; Hu, J.;
Zhou, F.; Yan, W.; Pang, D. W. Anal. Chem. 2003, 75, 3941−3945.
(d) Wang, J.; Li, J.; Baca, A. J.; Hu, J.; Zhou, F.; Yan, W.; Pang, D. W.
AUTHOR INFORMATION
Corresponding Authors
E-mail for M.I.: matteo.iurlo@unibo.it.
E-mail for S.M.: stefano.masiero@unibo.it.
E-mail for P.C.: piergiorgio.cozzi@unibo.it.
E-mail for F.P.: francesco.paolucci@unibo.it.
■
*
*
*
*
Anal. Chem. 2003, 75, 3941−3945. (e) Thorp, H. H. Trends Biotechnol.
2
003, 21, 522−524.
(13) Mukumoto, K.; Nojimab, T.; Takenaka, S. Tetrahedron 2005,
61, 11705−11715.
(14) Wu, Z.-S.; Chen, C.-R.; Shen, G.-L.; Yu, R.-Q. Biomaterials
2
(
008, 29, 2689−2696.
15) Singh, P.; Menard-Moyon, C.; Kumar, J.; Fabre, B.; Verma, S.;
Bianco, A. Carbon 2012, 50, 3170−3177.
16) Breugst, M.; Bautista, F. C.; Mayr, H. Chem. Eur. J. 2012, 18,
́
Notes
The authors declare no competing financial interest.
(
1
27−137 and references therein.
ACKNOWLEDGMENTS
(17) (a) Zhilina, Z. V.; Gumenyuk, V. V.; Nekrasov, Y. S.; Babin, V.
■
N.; Snegur, L. V.; Starikova, Z. A.; Yanovsky, A. L. Russ. Chem. Bull.
998, 1781−1784. See also: (b) Snegura, L. V.; Nekrasova, Y. S.;
The TEC FP7 ICT-MolArNet project (318516) is fully
acknowledged for the financial support of this research. Partial
support from the PRIN (Rome) and University of Bologna is
also acknowledged.
1
Sergeevab, N. S.; Zhilinaa, Z. V.; Gumenyuka, V. V.; Starikovaa, Z. A.;
Simenela, A. A.; Morozovab, N. B.; Sviridganomet. Covab, I. K.;
Babina, V. N. Appl. Organomet. Chem. 2008, 22, 139−147.
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dx.doi.org/10.1021/om5002809 | Organometallics XXXX, XXX, XXX−XXX