Pyrrolyl-, 2-(2-thienyl)pyrrolyl- and 2,5-bis(2-thienyl)pyrrolyl- nucleosides: Synthesis, molecular and electronic structure, and redox behaviour of C5-thymidine derivatives

Article abstract of DOI:10.1039/c0ob00466a

A series of modified nucleosides based on thymidine have been prepared by Pd-catalysed cross-coupling between N-alkyl-alkynyl functionalised pyrrolyl- (py), 2-(2-thienyl)pyrrolyl- (tp) or 2,5-bis(2-thienyl)pyrrolyl (tpt) groups with 5-iodo-2′-deoxyuridine

Full text of DOI:10.1039/c0ob00466a

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PAPER
Pyrrolyl-, 2-(2-thienyl)pyrrolyl- and 2,5-bis(2-thienyl)pyrrolyl-nucleosides:
synthesis, molecular and electronic structure, and redox behaviour of
C5-thymidine derivatives†
Miguel A. Galindo,a Jennifer Hannant,a Ross W. Harrington,b William Clegg,b Benjamin R. Horrocks,a
Andrew R. Pikea and Andrew Houlton*a
Received 21st July 2010, Accepted 11th November 2010
DOI: 10.1039/c0ob00466a
A series of modified nucleosides based on thymidine have been prepared by Pd-catalysed cross-
coupling between N-alkyl-alkynyl functionalised pyrrolyl- (py), 2-(2-thienyl)pyrrolyl- (tp) or
2,5-bis(2-thienyl)pyrrolyl (tpt) groups with 5-iodo-2¢-deoxyuridine. The length of the alkyl chain linking
the nucleoside and pyrrolyl-containing unit, N(CH2)nC C-nucleoside (where n = 1–3) was also varied.
The compounds have been characterised by 1H NMR, ES-MS, UV–vis, cyclic voltammetry (CV) and,
in some cases, single-crystal X-ray diffraction. Cyclic voltammetry studies demonstrated that all the
py-, tp- and tpt-alkynyl derivatives 1–7 can be electrochemically polymerised to form conductive
materials. It was found that increasing the N-alkyl chain length in these cases resulted in only minor
changes in the oxidation potential. The same behaviour was observed for the tp- and tpt-modified
nucleosides 9–12; however, the py-derivative, 8, produced a poorly conducting material. DFT
calculations on the one-electron oxidised cation of the modified nucleosides bearing tp or tpt showed
that spin density is located on the pyrrolyl and thienyl units in all cases and that the coplanarity of
adjacent rings increases upon oxidation. In contrast, in the corresponding pyrrolyl cases the spin
density is distributed over the whole molecule, suggesting that polymerisation does not occur solely at
the pyrrolyl-Ca position and the conjugation is interrupted.
Introduction
The size, shape, (relative) stability and ease of synthesis of DNA,
allied to the well-known rules for structure-building through base-
pair hydrogen bonding, have led to its increased role as a material
for bottom-up nanoscale fabrication.1–3 One of the key areas of
interest here is in nanoscale electronics, where DNA is envisaged as
a means of self-assembling circuitry. However, the lack of electrical
conductance of natural nucleic acids4 has prompted efforts to
introduce this property into DNA-based materials.
Scheme 1 Illustration of the difference in DNA-based materials resulting
from using duplex DNA as a template (top) or as a scaffold by introducing
new functionality in one of the strands (bottom).
Towards this end, DNA is most commonly used as a template
for the deposition and growth of metallic5–15 or semiconducting
materials,16,17 generating so-called nanowires (Scheme 1). This
generally applicable approach is synthetically expedient, can
provide thin (~5 nm) structures, and allows the use of long
(typically >10 mm) DNA strands. The length of these facilitates
aChemical Nanoscience Laboratory, School of Chemistry, Newcastle
the fabrication of simple electrical circuits using the resultant
nanowires as active components.5,6,16,18
University, Newcastle upon Tyne, NE1 7RU, U.K. E-mail: Andrew.
houlton@ncl.ac.uk; Fax: 0044-(0)191222 6929; Tel: 0044-(0)191222 6262
An alternative approach is to use DNA as a scaffold (Scheme 1).
bCrystallography Laboratory, School of Chemistry, Newcastle University,
Here the DNA, or its constituent groups, is modified in such a
manner as to retain the self-assembling and structure-building
capability, while introducing new functionality. Functionalisa-
tion of nucleosides19 is used widely in fields such as medicine
(anticancer20–22 and antiviral agents23,24) or biological analysis (e.g.
DNA sequencing,25 a range of redox- and photo-active26 groups
Newcastle upon Tyne, NE1 7RU, U.K; Fax: 0044-(0)191222 6929;
Tel: 0044-(0)191222 6641
† Electronic supplementary information (ESI) available: CV charts, Ta-
ble S1, 1H-NMR and 13C-NMR spectra. X-ray crystallographic data in
CIF format, for 5 compounds reported herein. CCDC reference numbers
785461–785465. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c0ob00466a
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Fig. 1 Structures of N-alkylated alkynyl units 1–7 and modified thymidine derivatives 8–12.
such as ferrocenyl27–29), and coordination complexes30–32 have been
also been introduced for such applications.
However, this approach has only been adopted for materials-
type applications relatively recently. Examples of this have been
demonstrated by the replacement of natural base pairs with metal-
chelating variants,33–36 with the resulting materials exhibiting
cooperative magnetic behaviour, for example.37 Other examples
include the introduction of multiple adjacent porphyrin groups
into short oligonucleotides forming discrete photoactive regions
of defined length.26,38,39
An elegant, purely organic, strategy has been described by
Schuster40–43 where nucleosides modified with organic “monomer”
units are subsequently oligomerised to give DNA con-joined with
a conductive polymer. Conducting polymers of this type, such as
polyaniline,44,45 polypyrrole,18,46 and polyindole,47 have previously
been grown as long (>10 mm) nanowires using DNA-templating
methods and in some cases have been shown to be electrically
conducting.18,46–48
We have begun to extend our work on DNA-based
materials15,16,18,28,29,46–51 towards this DNA-as-scaffold approach.
As a first step we report here the synthesis and characterisation
of 5-modified thymidine nucleosides bearing pyrrolyl (py), 2-(2-
thienyl)pyrrolyl (tp) and 2,5-bis(2-thienyl)pyrrolyl (tpt) as sub-
stituents attached via alkyl–alkynyl chains of 3, 4 and 5 carbon
atoms in length. Each of these heterocycles is known to polymerise
to give electrically conducting polymers upon oxidation.52,53
Scheme 2 Synthetic route for N-alkylated pyrrole derivatives 1–7 and
modified nucleosides 8–12. (a) NaH, alkynyl derivative (propargylbromide
or 5-chloro-1-pentyne), DMF, rt; (b) 4-amino-1-butyne, propionic acid,
toluene, reflux; (c) 5-iodo-deoxyuridine, Pd(PPh3)2Cl2, CuI, Et3N, DMF,
rt. R1 = R2 = H (py); R1 = H, R2 = thienyl (tp); R1 = R2 = thienyl (tpt). m =
1 or 3. n = 1, 2 or 3.
nucleosides is shown in Scheme 2 and involves Sonogashira-
type Pd-catalysed C–C coupling of 5-iodo-deoxyuridine with a
terminal alknyl group. The latter was presented as an N-alkyl-
alkynyl chain, which provides a straightforward way to vary the
separation between the nucleobase and the pyrrolyl unit as well as
allowing the pyrrolyl unit to be extended in the series py → tp →
tpt. N-alkylated derivatives 1–5 and 7, with 3- or 5-carbon-atom
length chains were synthesised by initial deprotonation of the py,
tp or tpt unit with sodium hydride and subsequent alkylation using
the appropriate haloalkyl-akynyl derivative, propargylbromide or
5-chloro-1-pentyne, respectively.
Results and Discussion
Synthesis and characterisation of N-alkylated alkynyl units (1–7)
and C5-modified nucleobases (8–12)
The target compounds 8–12, along with the precursors 1–7, are
shown in Fig. 1. The general synthetic route for the modified
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Attempts to N-alkylate the tpt unit with 4-bromo-1-butyne
to obtain 6 were unsuccessful. This is likely due to competitive
elimination of 4-bromo-1-butyne to give but-1-en-3-yne, as the
same problem was previously found for 4-bromo-1-butene.54
Instead, the synthesis of compound 6 was performed using a Paal–
Knorr condensation reaction between 4-bis(2-thienyl)butane-1,4-
dione and 4-amino-1-butyne (Scheme 2).55,56
1
All the N-alkylated derivatives, 1–7, were characterised by H
1
NMR and high-resolution ES-MS spectroscopy. The H NMR
spectra showed the expected loss of the NH proton, along with
an up-field shift for pyrrolyl protons and a down-field shift for
thienyl proton resonances (compared with the corresponding
unsubstituted derivatives). Further confirmation of the product
identity was obtained from single-crystal X-ray diffraction studies
in the cases of 5–7 (see ESI†).
The crystal structures of compounds 5 and 6 contain two
independent molecules in the asymmetric unit, with bond lengths
and angles lying within the expected ranges.
In the molecular structure of 5, the three heterocyclic rings are
oriented such that the hetero atoms alternate in an up-down-up
arrangement (Fig. 2). Furthermore, the thienyl rings are almost
coplanar (dihedral angle 12.7◦) with respect to one another, but
are twisted by 29.1◦ and 40.7◦ individually with respect to the
pyrrolyl group.
Fig.
3
View of the molecular structure of one of independent
molecules in 6. Selected angles N1–C13–C14 111.0◦, N2–C29–C30
110.7◦ and interplanar angles a–b 48.4◦, b–c 65.8◦, a–c 69.2◦,
a¢–b¢ 33.2◦, b¢–c¢ 31.1◦, a¢–c¢ 62.6◦. Planes defined as follows: (a)
S1/C1/C2/C3/C4, (b) N1/C5/C6/C7/C8, (c) S2/C9/C10/C11/C12,
(a¢) S3/C17/C18/C19/C20, (b¢) N2/C21/C22/C23/C24, (c¢)
S4/C25/C26/C27/C28.
Fig. 4 Views of the molecular structure of 7. The major component
of the disordered molecule is shown. Selected angles: N1–C13–C14
112.8◦, and interplanar angles: a–b 40.0◦, b–c 41.1◦, a–c 76.4◦. Planes
defined as follows: (a) S1/C1/C2/C3/C4, (b) N1/C5/C6/C7/C8, (c)
S2/C9/C10/C11/C12.
Fig. 2 View of the molecular structure of one of the independent
molecules in 5. Selected angles N1–C13–C14 115.2◦, and interplanar
angles; a–b 40.7◦, b–c 29.1◦, a–c 12.7◦. Planes defined as follows: (a)
S1/C1/C2/C3/C4, (b) N1/C5/C6/C7/C8, (c) S2/C9/C10/C11/C12.
31.3–34.2◦.57 In the case of two phenyl-substituted derivatives the
pyrrolyl–thienyl interplanar angles were found within the ranges
37.5–57.2◦ and 29.3–29.5◦.59,60 Finally, an N-alkylated tpt unit
contained in a flavin-based ◦rotaxane showed interplanar angles
within the range 52.0–71.1 ,61 although in this instance steric
hindrance may well force such large interplanar angles.
The crystal structure of 6 (Fig. 3) also contains two independent
molecules differing primarily with regard to the orientations of the
thienyl rings, disordered over two positions. Similar disorder has
been reported before in thienyl rings of tpt.57
The molecular structure of compound 7 (Fig. 4), the tpt-
derivative with a C5 chain, reveals an up-up-down arrangement of
the heteroatoms, though again there is some disorder in the thienyl
S1-ring. Here the thienyl–pyrrolyl interplanar angles are slightly
larger, 40.0◦ and 41.1◦, than is seen in one of the independent
molecules of 6.
Generally, the pyrrolyl–thienyl interplanar angles found for
our compounds lie within the range 29–41◦, with the exception
of one independent molecule found in the crystal structure of
6 with a range of 48.4–65.8◦. This is consistent with the four
previously reported observations on N-alkylated tpt derivates
with unmodified pyrrolyl and thienyl rings (Cambridge Structural
Database, 2010 release).58 Ferraris et al. reported the structure of
an N-methyl tpt derivative with interplaner angles in the range
Modified Nucleosides: Synthesis of the modified nucleosides
8–12 was carried out using Sonogashira coupling of 5-iodo-2¢-
deoxyuridine and the appropriate N-alkylated alkynyl deriva-
tive (Scheme 2). The catalytic conditions employed were a
modification of those reported by Ghilagaber et al.,62 using
bis(triphenylphosphine)dichloropalladium(II) (0.15 equiv) as cat-
alyst. Typical yields varied from 30 to 78% though the yield
of the pyrrolyl derivative 8 was rather less (10%). All modified
1
nucleosides were characterised by H NMR and high-resolution
ES-MS spectroscopy.
In a preparation of 9 there was evidence of a second compound,
9b, as indicated by the appearance of an uncoupled proton at
1
d = 6.37 ppm in the H NMR spectrum. This was indicative of
the formation of the furanopyrimidone isomer (9b, Scheme 3).
Other features that are supportive of this assignment are the
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Table 1 Wavelengths of maximum absorption (lmax) and molar extinction
coefficients (e) for modified nucleosides 8–12
Compound
lmax (nm)
e (M-1cm-1)
8
289
291
306
297
297
8.12 ¥ 103
1.22 ¥ 104
1.31 ¥ 104
2.06 ¥ 104
2.11 ¥ 104
9
10
11
12
Electronic structure: UV–vis spectroscopy
UV–visible spectroscopy (UV–vis) was used to study the electronic
structure of the modified nucleosides 8–12 (Fig. 6). Table 1 presents
the wavelengths of maximum absorption (lmax) and the molar
extinction coefficients (e).
Scheme 3 Proposed mechanism for the formation of furanopyrimidone
isomer 9b from 9, R = –(CH2)3-tp.
down-field shift in the H6 resonance (d = 8.67 ppm. (9b) cf. 8.01
ppm. (9)). This rearrangement of alkynyl-thymidine derivatives is
known63–65 and we have previously observed this ourselves with C5-
ferrocenylethynyl-deoxythymidine.29 The proposed mechanism for
rearrangement is presented in Scheme 3 and involves base-
catalysed formation of the O4-alkoxide which cyclises by attack at
the alkynyl function.
Unequivocal confirmation of 9b as the furanopyrimidone iso-
mer was obtained from a single-crystal structure analysis (Fig. 5).
This analysis showed that the tp unit lies over the furanopyrimidine
˚
ring with a shortest distance H21 ◊ ◊ ◊ O4 of 2.68 A. The interplanar
angle between the pyrrolyl and thienyl rings is 34.1◦ and the two
rings are in an up-down arrangement, though again the thienyl
ring is disordered over two positions.
Fig. 6 UV–vis spectra for compounds 8–10. All spectra were recorded at
0.025 mM of the title compounds in MeOH.
For the series of compounds containing a pentynyl bridge,
8–10, the expected red-shift is observed as the aromatic group
increases in size in the order py < tp < tpt, although this is small
in the case of 8 > 9. This trend is also apparent in the decreasing
separation between the HOMO and LUMO energies derived from
DFT calculations (see later).
Inspection of these orbitals also indicates that, in all cases, the
transition is dominated by electronic excitation from an orbital
largely based on the pyrrolyl-containing aromatic unit to one on
the nucleobase. The effect of increasing alkyl-chain length for the
tpt derivatives, 10–12, does not show any notable trend. The DFT
calculations indicate that the HOMO–LUMO transition involves
similar electronic excitation.
Fig. 5 Molecular structure of the furanopyrimidone derivative 9b.
Selected distances (A): O2–C2 1.231(5), C2–N3 1.368(6), C2–N1 1.407(6),
N1–C6 1.343(6), C6–C5 1.364(6), C5–C4 1.393(6), N3–C4 1.306(6),
C4–O4 1.370(5), O4–C8 1.418(5), C8–C9 1.481(6), C8–C7 1.320(7), C7–C5
1.456(6).
˚
Electrochemistry
The redox behaviour of the compounds was investigated using
cyclic voltammetry (CV) and the data are summarised in Table 2.
In some cases no clear oxidation peak is observed, therefore we
have also tabulated the potential at a fixed anodic current of
0.1 mA. The CVs of the N-alkyl-alkynyls 2, 4 and 7 bearing the
same 5-carbon alkyl chain linked to py, tp or tpt respectively are
shown in Figures S4–S8 (see ESI†). The anodic peak (E) is less
positive for the more extended ring systems in the order 2 > 4 >
7, (>1.5, 1.04, 0.986 V) in agreement with the trend followed by
The nucleoside exhibits an anti arrangement with the deoxyri-
bose unit adopting a C2¢-endo conformation. Hydrogen bonding
involving O2 of the furanopyrimidone and H3¢ of the sugar
˚
(O2 ◊ ◊ ◊ H3¢ = 1.92 A; generated by the symmetry operator -x +
1, 0.5 + y, -z + 2) is seen between the molecules, forming extended
C(8) chains66 running through the crystal structure.
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Table 2 CV oxidation peaks of monomer units and alkylated monomer
units obtained from the cyclic voltammograms. Conditions: 10 mM of
sample, 100 mM LiClO4, acetonitrile, r.t., working electrode Pt, counter
electrode Au and Ag quasi-reference electrode. Scan rate 0.2 V s-1
Compound
E/V (peak)
E/V (I = 0.1 mA)
py
tp
tpt
2
> 1.50
1.15
1.07
> 1.5
1.04
1.30
0.98
0.99
1.37
> 1.50
1.33
1.05
1.03
0.89
1.08
0.89
1.17
0.85
0.78
—
1.26
0.95
1.16
1.14
4
5
6
7
8
9
10
11
12
1.16
1.42
Fig. 8 CVs for compounds 8, 9 and 10 comparing the effect of different
substituent units (py, tp and tpt respectively) linked to the nucleoside
by a 5-carbon bridge. Conditions: 10 mM of sample, 100 mM LiClO4,
acetonitrile, r.t., working electrode Pt, counter electrode Au and Ag
quasi-reference electrode. Scan rate 0.2 V s-1.
the sequence of peak potentials for the free monomer units py >
tp > tpt (>1.5, 1.15, 1.07 V) (Table 2 and ESI†). However, for tpt
derivatives 5, 6 and 7, the oxidation potential variation shows no
particular trend (1.30, 0.98, 0.99 V) with increasing chain length.
The CVs for modified nucleosides (Fig. 7) show small changes for
the oxidation potential between compounds 10, 11 and 12 bearing
the tpt.
conductive film as evident in the low currents observed and the
lack of well-defined surface waves. This is typical for a poorly
conductive polymer that insulates the electrode.
Electronic structure calculations
To gain further insight into the electronic structure of the modified
nucleosides, particularly the effects of oxidation, a series of
geometries were optimised by DFT calculations using the B3LYP
functional and the 6-31G(*) basis set. The calculations were
performed on compounds 8–12 and related derivatives in the series
(see Fig. 9 and Table 3). Equilibrium geometries were obtained for
both the neutral molecule and the corresponding one-electron-
oxidised cation in each case. Comparison of the equilibrium
geometries for the neutral molecules with the structures derived
from X-ray diffraction reveals essentially similar features. For
example, bond lengths and angles are in the normal range and
in all cases the deoxyribose ring adopts a C2-endo conformation
as seen in the X-ray structure of 9b. A point of difference is
that the nucleoside adopts a syn-conformation rather than the
anti-conformation seen in 9b. This is due to the formation of
an intramolecular hydrogen bond between the C5¢-OH and the
O2 carbonyl group of the thymidine. The same intramolecular
hydrogen bond was found during a DFT study of 2¢-deoxycytidine,
leading to a more stabilised syn-orientation of the base unit with
respect to the sugar unit.67
Fig. 7 CVs for compounds 10, 11, 12 comparing the effect of different
bridge length, (CH2)3,(CH2)2 and (CH2) respectively, linking the tpt to the
nucleoside. Conditions: 10 mM of sample, 100 mM LiClO4, acetonitrile,
r.t., working electrode Pt, counter electrode Au and Ag quasi-reference
electrode. Scan rate 0.2 V s-1.
The EHOMO energy is raised as the size of the nucleoside
substituent group increases, py < tp < tpt, and is in keeping with
the electrochemical data (vide infra).
The results for these compounds show that the anodic peak
oxidation potential of the tpt unit linked to the nucleoside is
not strongly affected by the choice of carbon-bridge and, as for
the corresponding N-alkylated monomers, no particular trend is
observed; compound 11 has the lowest oxidation potential.
In contrast, when comparing the different substituent units,
py, tp and tpt, linked to the nucleoside by the same 5-carbon
bridge, significant changes appear in the cyclic voltammograms
(Fig. 8, and ESI†). Compounds 9 and 10 show clear evidence
of conductive polymer formation (broad reduction peak centred
near 0.2 V). However, the py-based compound 8 produces a poorly
Table 3 Calculated energies (eV) for the modified nucleosides, 8–12
Compound
EHOMO (eV)
ELUMO (eV)
EHOMO–LUMO gap
8
-5.57
-5.37
-5.19
-5.15
-5.21
-1.52
-1.48
-1.43
-1.52
-1.49
-4.05
-3.89
-3.76
-3.63
-3.72
9
10
11
12
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Fig. 9 DFT-calculated spin density distribution on modified nucleosides 8–12 and analogues, bearing the monomer units py, tp or tpt linked through a
5- 4- or 3-carbon bridge to the nucleoside.
Table 4 NAPC analysis of spin density on the modified nucleosides 8–12
The EHOMO–ELUMO gap decreases in the same order, as expected,
in agreement with the electronic absorption spectroscopy studies
(Table 3).
and analogues
Substituent
(pyrrolyl/thienyl)a
Bridgeb
Nucleobasec
Sugard
For the one-electron oxidised cations, the calculated spin density
serves extremely well to illustrate the extent of delocalisation over
the molecules (Fig. 9). An NAPC (Natural Atomic Populations
and Charges) analysis is shown in Table 4 as a quantitative
guide. For this, the molecule is considered as comprising four
components: substituent unit/bridge/nucleobase/sugar. As can
be seen, for all types of substituent, the majority of the spin
density resides on this unit, py, tp or tpt, respectively. However,
further inspection reveals that the py series is distinct in that there
is much greater transfer of spin over the whole molecule, almost
50% in two cases, compared to the tp or tpt derivatives. A simple
explanation for this can be based on a consideration of the size,
and therefore extent of conjugation, in the substituent unit, which
increases in the order py < tp < tpt.
Derivative
8
52.6
56.2
79.8
100 (55.5/44.5)
100 (56.9/43.1)
99.4 (60.9/38.5)
99.9 (48.5/51.4)
100 (47.8/52.2)
100 (48.6/51.4)
17.6
15.4
6.6
0
25.6
22.9
9.7
< 0.1
< 0.1
0.4
< 0.1
0
0
4.3
5.5
4.0
0
dT_4C_py
dT_3C_py
9
dT_4C_tp
0
0
dT_3C_tp
0.2
< 0.1
0
< 0.1
10
11
12
0
0
0
0
a Total percentage on substituent unit. The distribution across the pyrrolyl
and thienyl rings is shown in brackets where appropriate. b Percentage on
alkyl chain bridge. c Percentage on the thymidine nucleobase. d Percentage
on the sugar unit.
A somewhat unexpected finding in the py series is that the largest
delocalisation of spin density (~47%) is observed for compound 8,
a derivative with the longest alkyl chain, (CH2)3.
An increase in spin density is seen on both the bridging unit
(6.6 < 15.4 < 17.6%) and the deoxythymidine group (9.7 < 22.9 <
25.6%) as alkyl chain length is increased, –(CH2)–; –(CH2)2–; –
(CH2)3– (Table 4).
A simple rationalisation of this phenomenon is not obvious.68
Interestingly, these results, of spin density distributed over the
different parts of the molecules, suggest that the polymerisation
would take place through different positions giving rise to an
irregular polymer and therefore will make this compound less
suitable for the synthesis of conducting polymers. This is again in
agreement with the CV data.
In the tp- or tpt-containing series, spin density is almost
wholly located (>99%) on the thienyl-pyrrolyl unit. This is found
irrespective of the length of the carbon bridge and is consistent
with the increased size of the aromatic unit.
It was of interest to compare the structures of the neutral
parent compounds with the oxidised species for these two series of
compounds. It is known that the inter-ring torsion angle (q) affects
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Table 5 DFT-calculated angles between planes defined by pyrrolyl and
then degassed with dry N2 for 30 min. Anhydrous DMF was used
as received and degassed with dry N2 for 30 min. All reactions
were performed under N2 using standard Schlenk techniques.
NMR experiments were performed on a 300 MHz Bruker Spec-
trospin WM 300 WB spectrometer, electronic absorption spectra
were recorded on a Hitachi U-3010 Spectrophotometer, infrared
spectra were recorded on a Varian 800 FT-IR (Scimitar Series)
spectrometer and high resolution mass spectra with electrospray
ionization (HRMS-ESI) were measured on a Waters Micromass
LCT Premier mass spectrometer.
thienyl rings for both neutral and cationic modified nucleobases
Derivative TP (q1) TP+ (q1) TPT(q1/q2/q3)
TPT+ (q1/q2/q3)
9
47.5◦
7.8◦
1.2◦
0.7◦
General procedure for the alkylation of 2-(2-thienyl)pyrrole and
2,5-bis(2-thienyl)pyrrole (2–5, 7). The appropriate monomer unit
(5 mmol) was dissolved in anhydrous DMF (100 mL). To this
solution sodium hydride (60% dispersion in mineral oil) (1.5 equiv)
was added under nitrogen and the mixture was stirred until H2
evolution ceased. The appropriate alkynyl derivative (2 equiv) was
then added and the mixture was stirred in the dark overnight. The
resulting suspension was filtered through Celite and the solvent
removed in vacuo. Water (100 mL) was added and the resulting
mixture was extracted with CH2Cl2 (3 ¥ 200 mL) and the solution
dried over magnesium sulfate. The solvent was removed in vacuo
and the crude product was purified on silica using a gradient
of 0–5% ethyl acetate in hexane. The appropriate fractions were
combined and solvent was removed in vacuo to yield the pure
product.
dT_4C_tp 47.8◦
dT_3C_tp 50.0◦
10
11
12
45.5◦/45.3◦/24.1◦ 28.7◦/14.8◦/13.9◦
45.0◦/44.9◦/24.0◦ 31.3◦/2.0◦/31.9◦
44.9◦/43.7◦/25.0◦ 32.7◦/15.3◦/47.7◦
the intrinsic bandgap of isolated conjugated polymer chains and
consequently the conductivity along its length.53 Table 5 presents
the inter-ring torsion angles between the pyrrolyl and thienyl rings
in each case. For the tp series the torsion angle, q1, between pyrrolyl
and thienyl rings decreases by at least 40◦ as a consequence of
oxidation. For the tpt series the equivalent torsion angles, q1 and
q2, decrease in all cases, and there is a slight increase in the torsion
angles between the thienyl rings (q3) for compounds with longer
carbon bridges (Table 5). Overall, though, the effect of oxidation
is to increase conjugation as indicated by a shortening of the C–C
bond(s) linking the pyrrolyl and thienyl rings (Table S1, see ESI†)
and an increase in the coplanarity of the group.
It is worth noting that the reported decrease in conductivity of
N-substituted polypyrrole-type polymers, compared to the unsub-
stituted parent system, has been ascribed as being primarily due
to steric hindrance inhibiting adoption of a coplanar geometry.57
In order to maintain a high electrical conductivity, in polypyr-
role and ◦polythiophene, the angles between the rings should be
below 40 .69 The DFT calculations here show that the presence
of the attached nucleoside does not significantly hinder this
process upon oxidation. Therefore it is expected that the electrical
conductivity of polymers formed from these systems will not be
extensively affected by steric interferences.
1
N-(Pent-4-ynyl)pyrrole (2). Yield: 80% as an oil. H NMR
(CDCl3): d = 1.96 (m, 2H, CH2), 2.03 (t, 1H, CH), 2.16 (m, 2H,
CH2), 4.05 (t, 2H, CH2), 6.16 (t, 2H, CHpy), 6.68 (t, 2H, CHpy).
13C-NMR (CDCl3): d = 120.70, 108.45, 83.10, 69.68, 47.92, 30.38,
15.75. IR (neat, cm-1): 3295, 2120, 1500, 1282, 1089, 722. HRMS
(ESI): m/z: calc for C9H11N [M+H]+: 134.0958; found: 134.0970.
N-(Prop-2-ynyl)-2-(2-thienyl)pyrrole (3). Yield: 8% as an oil.
1H NMR (CDCl3): d = 2.42 (t, 1H; CH), 4.75 (d, 2H; CH2),
6.24 (t, 1H; CHpy), 6.33 (q, 1H; CHpy), 6.94 (q, 1H, CHpy), 7.08
(m, 1H, CHth), 7.13 (dd, 1H, CHth), 7.32 (dd, 1H, CHth). 13C-
NMR (CDCl3): d = 134.60, 127.68, 126.93, 126.20, 125.57, 122.86,
111.24, 109.23, 79.09, 73.72, 37.17. IR (neat, cm-1): 3287, 2121,
1291, 843, 788, 695. HRMS (ESI): m/z: calc for C11H9NS [M+H]+:
188.0531; found: 180.0534. UV (MeOH): lmax 290 nm
Conclusions
N-(Pent-4-ynyl)-2-(2-thienyl)pyrrole (4). Yield: 70% as an oil.
1H NMR (CDCl3): d = 1.92 (m, 2H, CH2), 2.03 (t, 1H, CH),
2.19 (m, 2H, CH2), 4.19 (t, 2H, CH2), 6.23 (m, 1H, CHpy), 6.36
(m, 1H, CHpy), 6.84 (s, 1H, CHpy), 7.08 (m, 2H, CHth), 7.31 (m,
1H, CHth). 13C-NMR (CDCl3): d = 135.33, 127.51, 126.73, 125.93,
125.21, 123.37, 111.19, 108.49, 83.26, 69.62, 46.43, 30.36, 16.08. IR
(neat, cm-1): 3290, 2130, 1429, 1298, 843, 787, 695. HRMS (ESI):
m/z: calc for C13H13NS [M+H]+: 216.0843; found: 216.0847. UV
(MeOH): lmax 284 nm.
We have prepared a series of modified nucleosides bear-
ing substituent groups that can be electrochemically poly-
merised. The more extended 2-(2-thienyl)pyrrolyl- and 2,5-bis(2-
thienyl)pyrrolyl- systems have lower anodic peak potentials, Ep,
and yield conducting polymer films upon oxidation. Both of these
systems appear to be well suited for the development of conducting
DNA-based materials and such studies are ongoing.
N-(Prop-2-ynyl)-◦2,5-bis(2-thienyl)pyrrole (5). Yield: 69% as a
Experimental Section
1
solid, mp 121–122 C. H NMR (CDCl3): d = 2.52 (t, 1H, CH),
Materials. Reagents were purchased from Aldrich and used
as received unless otherwise stated. Pyrrole (py) was distilled
prior to use. 1,4-Bis(2-thienyl)butane-1,4-dione (btbd),70 2-(2-
4.77 (d, 2H, CH2), 6.40 (s, 2H, CHpy), 7.13 (m, 2H, CHth), 7.32 (dd,
2H, CHth), 7.40 (m, 2H, CHth). 13C-NMR (CDCl3): d = 134.82,
129.26, 127.87, 126.12, 125.70, 111.23, 80.74, 73.71, 35.90. IR
(neat, cm-1): 3263, 2119, 1494, 1422, 1333, 1200, 844, 772, 695.
HRMS (ESI): m/z: calc for C15H11NS2 [M+H]+: 270.0394; found:
270.0411. UV (MeOH): lmax 318 nm. Single crystals of 5 suitable
72,73
thienyl)pyrrole71 (tp), 4-amino-1-butyne (Figure S14, ESI†)
and N-(prop-2-ynyl)pyrrole (1)74 were synthesised according to
the literature methods. Triethylamine was distilled from KOH and
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 1555–1564 | 1561
©

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for X-ray diffraction were obtained by concentration of a solution
in ethyl acetate.
8.18 (s, 1H; C6H), 11.60 (s, 1H; NH). 13C-NMR (dmso-d6): d =
162.07, 149.82, 143.00, 120.91, 107.92, 99.29, 92.40, 88.06, 85.16,
74.11, 70.56, 61.47, 47.68, 30.40, 16.47. IR (neat, cm-1): 1675,
1277, 1089, 1050, 727. HRMS (ESI): m/z: calc for C18H21N3O5
[M+Na]+: 382.1379; found: 382.1371. UV (MeOH): lmax 289 nm.
N-(Pent-4-ynyl)-2,5-bis(2-thienyl)pyrrole (7). Yield: 46% as a
◦
1
solid, mp 36–40 C. H NMR (CDCl3): d = 1.78 (m, 2H, CH2),
1.86 (t, 1H, CH), 2.03 (m, 2H, CH2), 4.28 (m, 2H, CH2), 6.36
(s, 2H, CHpy), 7.11 (m, 4H, CHth), 7.33 (m, 2H, CHth). 13C-NMR
(CDCl3): d = 135.30, 128.84, 127.58, 126.51, 125.65, 111.53, 83.05,
69.22, 44.61, 30.12, 16.12. IR (neat, cm-1): 3279, 2120, 1470, 1410,
1305, 1198, 837, 754, 696. HRMS (ESI): m/z: calc for C17H15NS2
[M+H]+: 298.0724; found: 298.0718. UV (MeOH): lmax 309 nm.
Single crystals of 7 suitable for X-ray diffraction were obtained by
concentration of a solution in ethyl acetate.
9. Yield: 78% as a pale yellow solid, mp 67–70 ◦C. 1H NMR
(DMSO-d6); d = 1.80 (m, 2H; CH2), 2.12 (dd, 2H; C2¢H), 2.28
(t, 2H; CH2), 3.58 (m, 2H; C5¢H), 3.79 (q, 1H; C4¢H), 4.16 (t,
2H; CH2), 4.24 (quin, 1H; C3¢H), 5.11 (t, 1H; OH), 5.25 (d, 1H;
OH), 6.07 (t, 1H; CHtp), 6.12 (t, 1H; C1¢H), 6.21 (dd, 1H; CHtp),
6.95 (t, 1H; CHtp), 7.06 (dd, 1H; CHtp), 7.13 (dd, 1H; CHtp), 7.45
(dd, 1H; CHtp), 8.01 (s, 1H; C6H), 11.60 (s, 1H; NH). 13C-NMR
(DMSO-d6): d = 162.03, 149.82, 143.02, 134.75, 128.05, 125.98,
125.26, 125.24, 124.10, 110.44, 108.10, 99.25, 92.29, 88.06, 85.18,
74.14, 70.61, 61.50, 46.14, 30.12, 16.49. IR (neat, cm-1): 1674, 1277,
1053, 843, 696. HRMS (ESI): m/z: calc for C22H23N3O5S [M+Na]+
: 464.1256; found: 464.1254. UV (MeOH): lmax 291 nm.
Synthesis of N-(but-3-ynyl)-2,5-bis(2-thienyl)pyrrole (6). A so-
lution of 1,4-bis(2-thienyl)butane-1,4-dione (6 g, 14.5 mmol), 4-
amino-1-butyne (1 g, 14.5 mmol), propionic acid (2 mL, 27 mmol)
in anhydrous toluene (100 mL) was refluxed with molecular sieves
˚
˚
4 A (2 g) under nitrogen. After 20 h, additional molecular sieves 4 A
(2 g) were added, and the mixture was refluxed for a total of 70 h.
The reaction mixture was concentrated in vacuo and the residue
dissolved in ethyl acetate (150 mL). This was washed with aqueous
sodium bicarbonate (2 ¥ 100 mL), and aqueous sodium chloride
(100 mL) and then dried over magnesium sulfate. After filtration
the solvent was removed and the crude product was purified on
silica using hexane–ethyl acetate (95 : 5) as◦eluent. This afforded 6
in 37% yield (1.5 g) as a solid, mp 60–62 C. 1H NMR (CDCl3):
d = 1.86 (t, 2H, CH), 1.86 (t, 1H, CH), 2.34 (m, 2H, CH2), 4.26
(m, 2H, CH2), 6.27 (s, 2H, CHpy), 7.02 (m, 4H, CHth), 7.26 (m,
2H, CHth). 13C-NMR (CDCl3): d = 134.95, 128.65, 127.68, 126.60,
125.88, 111.72, 80.51, 70.60, 44.06, 21.16. IR (neat, cm-1): 3250,
2125, 1458, 1401, 1305, 1195, 845, 767, 692. HRMS (ESI): m/z:
calc for C16H13NS2 [M]+: 283.0490; found: 283.0494. UV (MeOH):
9b. During the purification of 9, chromatography with (9 : 1)
CH2Cl2–MeOH showed a second product with a greater Rf. This
fraction was collected and slow evaporation of the solvent gave
single crystals which were analysed by X-ray diffraction and found
1
to be of 9b. H NMR (DMSO-d6); d = 1.80 (m, 2H; CH2), 2.12
(dd, 2H; C2¢H), 2.28 (t, 2H; CH2), 3.58 (m, 2H; C5¢H), 3.79 (q,
1H; C4¢H), 4.16 (t, 2H; CH2), 4.24 (quin, 1H; C3¢H), 5.11 (t, 1H;
OH), 5.25 (d, 1H; OH), 6.07 (t, 1H; CHtp), 6.12 (t, 1H; C1¢H), 6.21
(dd, 1H; CHtp), 6.37 (s, 1H; C7H) 6.95 (t, 1H; CHtp), 7.06 (dd,
1H; CHtp), 7.13 (dd, 1H; CHtp), 7.45 (dd, 1H; CHtp), 8.67 (s, 1H;
C6H).
◦
1
10. Yield: 30% as a pale yellow solid, mp 139–141 C. H
NMR (DMSO-d6); d = 1.66 (m, 2H; CH2), 2.12 (dd, 2H; C2¢H)
2.21 (t, 2H; CH2), 3.58 (m, 2H; C5¢H) 3.81 (q, 1H; C4¢H), 4.23 (m,
1H; C3¢H), 4.30 (t, 2H; CH2), 5.10 (t, 1H; OH), 5.27 (d, 1H; OH),
6.31 (t, 1H; C1¢H), 6.30 (s, 2H; CHtpt), 7.10 (dd, 2H; CHtpt), 7.23
(dd, 2H; CHtpt), 7.53 (dd, 2H; CHtpt), 8.09 (s, 1H; C6H), 11.59
(s, 1H; NH). 13C-NMR (DMSO-d6): d = 161.88, 149.80, 143.03,
134.35, 128.46, 128.15, 126.22, 126.06, 111.01, 99.23, 91.87, 88.05,
85.15, 73.92, 70.68, 61.55, 44.22, 29.87, 16.52. IR (neat, cm-1):
1645, 1275, 1099, 1052, 841, 766, 692. HRMS (ESI): m/z: calc for
C26H25N3O5S2 [M+Na]+: 546.1133; found: 546.1136. UV (MeOH):
lmax 306 nm.
l
max 309 nm. Single crystals of 6 suitable for X-ray diffraction were
obtained by concentration of a solution in ethyl acetate.
General procedure for C5-modified nucleoside synthesis
(8–12).
deoxyuridine (1.0 mmol,
A
Schlenk flask was charged with 5-iodo-2¢-
equiv) and made up to
1
a
0.13 M solution in anhydrous degassed DMF. To this were
added bis(triphenylphosphine)dichloropalladium(II) (0.15 mmol,
0.15 equiv), copper(I) iodide (0.2 mmol, 0.2 equiv), anhydrous
degassed triethylamine (2.0 mmol, 2 equiv) and the appropriate
alkynyl derivative (1.5 mmol, 1.2 equiv). The reaction mixture was
stirred at room temperature for ~15 h during which time product
formation was monitored by TLC. A 5% (v/w) aqueous solution of
Na2-EDTA (5 mL) was added to quench the reaction and solution
was evaporated to dryness. The reaction mixture was redissolved in
CH2Cl2 (150 mL), washed with Na2-EDTA solution (2 ¥ 50 mL;
5% (v/w)), water (50 mL) and then dried over sodium sulfate.
After filtration and concentration in vacuo the crude product was
loaded onto a silica column packed with CH2Cl2, and eluted using
a gradient of 0–5% MeOH in CH2Cl2. Fractions containing the
product were combined and the solvent was removed to yield the
following compounds.
11. Yield: 35% as a pale yellow solid, mp 93–97 ◦C. 1H NMR
(DMSO-d6); d = 2.08 (dd, 2H; C2¢H), 2.55 (t, 2H; CH2) 3.56 (dd,
2H; C5¢H), 3.76 (q, 1H; C4¢H), 4.20 (quin, 1H; C3¢H), 4.33 (t, 2H;
CH2), 5.05 (t, 1H; OH), 5.25 (d, 1H; OH), 6.08 (t, 1H; C1¢H), 6.32
(s, 2H; CHtpt), 7.17 (dd, 2H; CHtpt), 7.27 (dd, 2H; CHtpt), 7.60
(dd, 2H; CHtpt), 8.25 (s, 1H; C6H), 11.66 (s, 1H; NH). 13C-NMR
(DMSO-d6): d = 161.75, 149.75, 143.47, 134.16, 128.34, 128.20,
126.66, 126.48, 111.31, 98.86, 89.05, 88.02, 85.13, 75.12, 70.63,
61.60, 43.68, 41.77, 21.61. IR (neat, cm-1): 1674, 1276, 1092, 1053,
842, 769, 693. HRMS (ESI): m/z: calc for C25H23N3O5S2 [M+H]+:
510.1158; found: 510.1185. UV (MeOH): lmax 297 nm.
◦
1
8. Yield: 10% as a off white solid, mp 65–70 C. H NMR
(DMSO-d6); d = 1.89 (quin, 2H; CH2), 2.12 (dd, 2H; C2¢H), 2.25
(t, 2H; CH2), 3.59 (m, 2H; C5¢H), 3.79 (q, 1H; C4¢H), 4.00 (t,
2H; CH2), 4.23 (quin, 1H; C3¢H), 5.13 (t, 1H; OH), 5.25 (d, 1H;
OH), 5.98 (t, 2H; CHpy), 6.11 (t, 1H; C1¢H), 6.77 (t, 2H; CHpy),
12. Yield: 60% as a pale yellow solid, mp 98–101 ◦C. 1H NMR
(DMSO-d6); d = 2.15 (m, 2H; C2¢H), 3.60 (m, 2H; C5¢H), 3.81 (q,
1H; C4¢H), 4.25 (quin, 1H; C3¢H), 4.92 (s, 2H; CH2), 5.14 (t, 2H;
OH), 5.28 (d, 2H; OH), 6.01 (t, 1H; C1¢H), 6.34 (s, 2H; CHtpt),
7.18 (dd, 2H; CHtpt), 7.48 (dd, 2H; CHtpt), 7.57 (dd, 2H; CHtpt),
1562 | Org. Biomol. Chem., 2011, 9, 1555–1564
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8.27 (s, 1H; C6H), 11.69 (s, 1H; NH). 13C-NMR (DMSO-d6):
d = 161.78, 149.74, 144.40, 134.02, 128.88, 128.38, 126.26, 126.01,
110.60, 97.87, 89.28, 88.23, 85.54, 78.15, 70.56, 61.54, 48.95, 36.71.
IR (neat, cm-1): 1682, 1281, 1089, 1051, 843, 770, 697. HRMS
(ESI): m/z: calc for C24H21N3O5S2 [M+Na]+: 518.0820; found:
518.0807. UV (MeOH): lmax 297 nm.
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formed by using the Spartan’04 program package (Wavefunc-
tion Inc., USA) running on a Dell Optiplex 755 workstation.
Molecules’ geometries were optimised in DFT by using the B3LYP
functional and the 6-31G(d) basis set.
Electrochemistry. Cyclic voltammograms of dissolved
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Acknowledgements
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