Article pubs.acs.org/joc
Cite This: J. Org. Chem. 2018, 83, 12711−12721
Synthesis, Optoelectronic Properties, Self-Association, and Base Pairing of Nucleobase-Functionalized Oligothiophenes Danielle E. Fagnani, Raghida Bou Zerdan, and Ronald K. Castellano* Department of Chemistry, University of Florida, P.O. Box 117200, Gainesville, Florida 32611, United States
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ABSTRACT: Device-relevant π-conjugated oligothiophenes with the canonical nucleobases directly embedded into the πframework have been designed, synthesized, and characterized. These oligomers offer the ability to tune optoelectronic properties via the intimate merging of the nucleobase molecular electronic structure with base-pairing fidelity. Analysis of their optical and electronic properties in a hydrogen-bond-disrupting solvent (DMF) indicates that the nucleobase identity influences the intrinsic electronic properties of the semiconductors. These differences are supported by DFT calculations which demonstrate that the HOMO/LUMO orbitals are distributed differently for each compound. The solubility and competition between self-association and base pairing in a hydrogen-bond-supporting solvent (chloroform) was studied to better understand the oligomer behavior under conditions relevant for downstream solution processing into thinfilm devices. These solution studies reveal that in each case base-pairing is preferred to self-aggregation; the relatively weak heteroassociation of 1A−1U (35 ± 5 M−1) should be amenable to facile solution processing and successive hydrogen bond formation in the solid state, while the strong heteroassociation between 1G and 1C (>104 M−1) should enable assemblies to be preformed in solution. These results are expected to enable the synthesis of more complex π-conjugated architectures and facilitate their extension to optoelectronic devices.
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INTRODUCTION Nucleobases, nature′s “information rich” building blocks, are mutually responsible for maintaining pristine biomacromolecular structures by formation of hydrogen bonds and π-contacts and imparting function by storage of life’s genetic code. The high fidelity of DNA base-pairing (adenine−uracil/thymine and guanine−cytosine) along with an array of other binding motifs (e.g., self-dimerization and non-Watson−Crick pairing) make nucleobases prototypical assembly units for supramolecular studies.1−4 As a consequence, these bioderived building blocks have been adopted by researchers to control the 3-D ordering of synthetic systems, spanning soft materials and solid-state architectures.5,6 The molecular recognition capabilities of nucleobases are justly applied to control material properties. For example, complementary base-pairing has been used as a dependable method for cross-linking pendent monomers or polymers7 and patterning nanostructures on surfaces, interfaces, and in solution.8−10 Overshadowed by this morphological control is their ability to tune the optical and electronic properties of materials by direct incorporation of their aromatic purine/ pyrimidine rings into π-conjugated backbones.11,12 Along these lines, our laboratory has developed synthetic methodologies to embed nucleobases adenine, uracil, or guanine into πconjugated oligomers and has shown that, indeed, nucleobase © 2018 American Chemical Society
identity affects the electronic structure of these molecules by modification of their optical absorbance profile and imparts tunability to the HOMO/LUMO energy levels.13 Of additional importance is the regiochemistry of the attached chromophore with respect to the nucleobase purine/pyrimidine backbone. For instance, our previous work and that of Kilbey et al. has demonstrated that the regiochemistry of chromophore conjugation (C(6), C(8), or N(9)) on purine-containing compounds has an influence on optoelectronic properties. This effect is exhibitive of the push−pull nature of the purine heterocycle (atom numbering shown in Figure 1).14−16 While nucleobases are a staple example of organic building blocks capable of complementary hydrogen-bonding interactions, investigation of the intermolecular binding of nucleobase-containing π-conjugated compounds is seldom performed.17,18 Recent relevant work comes from GonzálezRodrı ́guez et al., who quantified the binding strength of lipophilic ribonucleoside-terminated ethylene phenylene oligomers in organic solvents (chloroform and carbon tetrachloride).19 Their results were consistent with previous references of nucleobase association by hydrogen bonding in organic solvents,20 where it is of modest strength between Received: August 17, 2018 Published: September 19, 2018 12711
DOI: 10.1021/acs.joc.8b02138 J. Org. Chem. 2018, 83, 12711−12721
Article
The Journal of Organic Chemistry
have been outfitted with racemic 2-ethylhexyl side chains, as previously mentioned, and the other terminus of the terthiophene has been elaborated with a hexyl group to provide solubility to these compounds in organic solvents. To better understand the potential of nucleobase-containing πconjugated oligomers to serve in optoelectronic applications, a combined study of the optical and electronic properties and quantification of the extent of intermolecular hydrogen bonding in solution has been performed. These results indicate that the optoelectronic properties of these organic semiconductors are influenced by the identity of the nucleobase that also promotes base-pairing between oligomers in chloroform. The resulting fundamental characterization of optoelectronic properties and complementary hydrogen-bonding interactions is critical to rationally port such materials into solid-state settings and optoelectronic devices, such as in organic photovoltaic cells (OPVs) and field-effect transistors (OFETs).33
Figure 1. Nucleobase-containing π-conjugated targets evaluated in this work. The nucleobase atom numbering scheme, as referred to throughout the text, is shown.
adenosine and uridine (101−102 M−1) and significantly stronger between cytidine and guanosine (104 M−1). It is worth noting that an important aspect of their molecular design involves the incorporation of lipophilic groups to afford solubility in organic solvents. Often, alkylated ribose groups are utilized in place of the typical sugar unit for this purpose, where the bulky group can disrupt π−π interactions between the neighboring planar molecules. We have specifically focused on nucleobase-containing π-systems that might be employed in solid-state device settings that rely on closely π-stacked chromophores for charge mobility. To ensure our compounds are suitable for organic optoelectronic applications, we have substituted the typical ribose fragments (found on N(9) and C(1) for purines and pyrimidines, respectively) with 2ethylhexyl alkyl chains, a commonly utilized solubilizing group by practitioners in the π-conjugated materials community. Nucleobases within π-stacking distances have been considered for charge-transport materials due to the potential of electron and hole transport along stacked base pairs.21−23 Investigations into DNA charge transport have revealed that holes can be transported vertically over stacked base pairs spanning length scales of ∼20 nm.24 In particular, guanine has demonstrated the lowest oxidation potential of all the nucleobases.25 This property has prompted a plethora of investigations; eminent work by Wasielewski et al. has recently resulted in the construction of π-conjugated oligomers that form well-ordered π-stacked crystalline arrays that function as long-lived charge carriers with high mobility.26,27 These materials rely on guanine units to self-organize, transport holes, and template the stacking of electron-transporting regions. Extending nucleobase-embedded π-conjugated materials into optoelectronic device applications requires the design, synthesis, and characterization of device-relevant derivatives that are suitable for solution-processed thin film fabrication. To this avail, we have designed a set of nucleobase-containing oligomers fully conjugated to a terthiophene backbone, a quintessential organic semiconductor (Figure 1).28 The designed systems required individually optimized synthetic pathways, as the synthetic approaches to preparing these systems are still in infancy. While relevant palladium-catalyzed cross-coupling reactions are well developed for nucleosides,12,29−32 related reactions on alkylated nucleobases are less known, as discussed in our previous work.13 Each of the canonical nucleobases has been installed at one terminus of the oligomer, facilitating 1:1 binding analysis. The nucleobases
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RESULTS AND DISCUSSION Synthesis. Adenine-Terminated Oligomers. Adenineterminated π-conjugated oligomer 1A was synthesized under Suzuki−Miyaura coupling conditions in 69% yield from the bromothienyl adenine 3 and commercially available boronic ester building block 4 (Scheme 1). The synthesis of the key adenine-containing building block 3 was performed in accordance with our previously optimized route.13 Scheme 1. Synthesis of Adenine-Terminated Oligomer
Guanine-Terminated Oligomers. Protecting groups were installed in the C(6)O position to avoid deprotonation of guanine’s N(1) amidic proton under basic reaction conditions (atom number scheme shown in Figure 1). Previously, we have used a benzyl protecting group for this purpose. In this study, we evaluated both the benzyl and methyl protecting groups, envisioning that the less sterically hindered methyl derivative could serve as a hydrogen-bond-weakened comparator for guanine.34 The synthesis of the methyl-protected derivative is shown in Scheme 2, beginning with substitution of alkylated 6chloroguanine 5 with sodium methoxide in methanol to yield 6 in 80−94% yield. Similar to the benzyl congener, this product was brominated in the C(8) position and subjected to Stille cross-coupling with 2-(tributylstannyl)thiophene in the presence of triphenylbismuth to afford compound 9 in good yields (82−94%). Subsequent bromination using NBS in THF/ AcOH provided intermediate 10. Similar to the adenine analogue, both protected derivatives were reacted with 4 under Suzuki−Miyaura cross-coupling conditions to yield compounds 1PGa and 1PGb. The guanine-terminated oligomer 1G was then obtained by debenzylation of 1PGb in the 12712
DOI: 10.1021/acs.joc.8b02138 J. Org. Chem. 2018, 83, 12711−12721
Article
The Journal of Organic Chemistry
derivative 16. Terthiophene derivative 16 was prepared in accordance with the literature.38 Cytosine-Terminated Oligomers. In our previous work,13 C(5)-bromocytosine derivative failed to serve as a crosscoupling partner to expand the π-system. Likewise, the C(5)iodo derivative (18), prepared from 17 in moderate yields (∼60%) using NIS as the iodine source in acidic media, failed to react with 2-(tributylstannyl)thiophene under Stille conditions (Scheme 4). On the other hand, Suzuki cross-
Scheme 2. Synthesis of Guanine- and Protected-GuanineTerminated Oligomers
Scheme 4. Synthesis of Cytosine-Terminated Oligomera
presence of BBr3 and pentamethylbenzene as a cation scavenger. Uracil-Terminated Oligomers. Uracil derivative 12 was brominated to afford compound 13 and reacted under Stille coupling conditions to afford compound 14 in accordance with our previously optimized procedure (Scheme 3).13 As
a
R = (±)-2-ethylhexyl.
coupling with thiophene-2-ylboronic acid was successful in a THF/H2O mixture (and not in toluene/H2O) to produce product 19 in moderate yields (54−64%) (Scheme 4). The C(5)-position of thiophene was iodinated using NIS in DCE with a catalytic amount of TFA, generating compound 20, which was subsequently reacted with 4 under Suzuki crosscoupling conditions to furnish compound 1C in modest yield (∼34%) after purification. Because of their similar polarities, product 1C and starting material 20 co-eluted on both silica and neutral alumina with several mobile phases (hexanes/ethyl acetate or DCM/methanol mixtures). Finally, the separation was achieved using a gradient of hexanes/isopropyl alcohol containing 1% TFA. Optoelectronic Properties. Absorption in Solution. The absorption spectra of all oligomers were measured in dilute DMF (20 × 10−6 M) (Figure 2) and showed linear Beer− Lambert relationships (Figures S1−S7), indicating no aggregation under these conditions. All spectra displayed a single absorption band corresponding to a π−π* transition and some small variance in molar extinction coefficients, though within the same order of magnitude. The guanine and protected guanine derivatives 1G, 1PGa, and 1PGb displayed similar absorbance profiles, with absorption maxima (λmax) ranging from 409−412 nm and identical absorption onsets (λonsets) at 477 nm (ΔEopt = 2.60 eV). The adenine and uracil derivatives 1A and 1U were slightly blue-shifted relative to guanine, displaying identical λmax at 404 nm and absorption onsets at 468 and 460 nm (ΔEopt = 2.65 and 2.70 eV), respectively. Cytosine derivative 1C exhibited the most hypsochromically shifted absorption spectrum, with λmax at 382 nm and λonset at 437 nm (ΔEopt = 2.84 eV). The observed differences in absorption spectra, over a range of 30 nm, emphasize the influence of nucleobase identity on the intrinsic optical properties of π-conjugated systems. Electronic Structure Calculations. Gas-phase calculations at the B3LYP/6-31+G** level were performed on all oligomers
Scheme 3. Synthesis of Uracil-Terminated Oligomera
a
R = (±)-2-ethylhexyl.
discussed in our previous work, bromination at the C(5) position of the thiophene of compound 14 generated the undesired dibromo product.13 Therefore, iodination was explored to introduce a halogenated handle for subsequent metal-mediated cross-coupling reactions. Unfortunately, the iodination of 14 failed to generate the desired product 15a. The use of N-iodosuccinimide (NIS) as the iodine source delivered exclusively the diiodinated product 15c.35 Although ceric ammonium nitrate (CAN) as an in situ oxidant and various iodine sources have been successfully employed for the iodination of related compounds, they failed to deliver desired compound 15a and instead yielded a mixture of mononitrated and diiodinated products 15b and 15c, respectively (Table S1).36,37 Since the regioselective halogenation of 14 remains elusive, target compound 1U was finally procured via Stille cross coupling between compound 13 and the terthiophene 12713
DOI: 10.1021/acs.joc.8b02138 J. Org. Chem. 2018, 83, 12711−12721
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The Journal of Organic Chemistry
the differences in the torsion angle and conjugation between the nucleobase and the terthiophene fragments. Electrochemical Properties. The redox properties of all materials were investigated by cyclic voltammetry in DMF with TBAPF6 as the supporting electrolyte. DMF was chosen as a solvent to ensure full solvation and eliminate aggregationinduced effects on the electronic behavior of the compounds. Compounds 1A, 1G, 1PGa, and 1PGb display a single irreversible oxidation, commonly observed for purine derivatives,15,39,40 and a quasi-reversible reduction band within the accessible solvent window. The pyrimidine derivatives displayed two irreversible oxidations, with 1U displaying a quasi-reversible reduction and 1C displaying a single red irreversible reduction band. The key values, Eox onset and Eonset, were determined from the onsets of oxidation and reduction potentials, respectively, measured for the compounds in solution versus the Fc/Fc+ reference. The corresponding EHOMO, ELUMO, and ΔE were then calculated from these experimentally determined values according to the following equations:41−43
Figure 2. Overlaid normalized absorption spectra of nucleobasecontaining oligomers measured at 20 × 10−6 M in DMF at room temperature.
to approximate expected HOMO and LUMO energy levels (FMO diagrams shown in Figures S9−S14) as well as optimized structural geometries. All alkyl chains were replaced by a methyl group to reduce computational time, since they do not significantly affect the equilibrium geometries or electronic properties, and the results are summarized in Table 1. Calculations on 1A, 1U, 1G, and 1PGa/b were performed using oligomer conformations corresponding to the lowest energy conformers determined by geometry optimization of truncated derivatives, performed previously.13 The aforementioned nucleobases are nearly planar (dihedral angles are 1−9° between the nucleobase and adjacent thiophene). The cytosine analogue was determined to prefer a twisted orientation between the nucleobase and adjacent thiophene (dihedral angle >48°, see Figures S8 and S11), disrupting conjugation and resulting in the blue-shifted absorption profile and the larger energy gap relative to the other compounds. According to the frontier MO plots, the HOMO is distributed evenly throughout each of the molecules, 1A, 1G, and 1PGa/b, and while there is contribution of the nucleobase to the LUMO, it is more densely contributed by the terthiophene portion. Both the HOMO and LUMO are evenly distributed on the entire structure of 1U, while the pyrimidine portion of 1C shows a minor contribution to the HOMO and attenuated contribution to the LUMO. Again, the differences in the pyrimidinecontaining calculated electronic structures are consistent with
ox E HOMO = −(Eonset + 5.1) eV
(1)
red E LUMO = −(Eonset + 5.1) eV
(2)
The results are summarized in Table 1. While the oxidation potentials and the respective HOMO values for 1A, 1U, 1C, and 1PGa/b are comparable (within 0.1 eV, from −5.52 to −5.61 eV), 1G displays a significantly lower oxidation potential at 0.21 V corresponding to a HOMO of −5.13 eV. The redox potentials indicate that guanine is the most electron-rich among the purine/pyrimidine derivatives deviating from the results of the optical measurements and the DFT estimations, which suggests that 1G is nearly identical electronically to comparators 1PGa and 1PGb. This might hold true under very dilute solution conditions, in the absence of G−G interactions, and in vacuo where these measurements take place, respectively. However, this result is in line with previous studies concerning guanine oligothiophene derivatives.13 Interestingly, the nucleobase structure also has some influence on the reduction potentials/LUMO levels of the corresponding oligomers. 1U displays the highest lying LUMO at −3.78 eV, while 1G has the lowest LUMO at −3.92 eV, and the rest fall in between. It is worth noting that the electrochemically derived HOMO−LUMO gaps and the optical gaps follow the same trends, ΔEg being narrowest for 1G and widest for 1C.
Table 1. Electronic Properties of Nucleobase-Containing Oligomers DFT calculationsd
experimental compd
Eox onset (V) ± 0.1a
Ered onset (V) ± 0.1a
HOMO (eV) ± 0.1b
LUMO (eV) ± 0.1b
Eg electrochemical (eV) ± 0.2
Eg optical (eV) ± 0.2c
HOMO (eV)
LUMO (eV)
Eg (eV)
1A 1U 1C 1G 1PGa 1PGb
0.50 0.42 0.51 0.21 0.42 0.48
−1.23 −1.32 −1.22 −1.18 −1.23 −1.20
−5.60 −5.52 −5.61 −5.31 −5.52 −5.58
−3.87 −3.78 −3.88 −3.92 −3.87 −3.90
1.73 1.74 1.73 1.39 1.65 1.68
2.65 2.70 2.84 2.60 2.60 2.60
−5.32 −5.28 −5.43 −5.13 −5.11 −5.15
−2.29 −2.28 −2.17 −2.08 −2.14 −2.16
3.03 3.00 3.26 3.00 2.97 2.99
a
Determined from cyclic voltammetry experiments in DMF relative to Fc/Fc+ redox couple (DMF) (0.1 mM TBAPF6 at a 100 mV/s scan rate). Estimated HOMO and LUMO energy levels (relative to vacuum) based on electrochemical potentials (Eonsetox and Eonsetred, respectively) determined from the CV experiments. cDetermined based on UV absorption data in DMF. dAll ethylhexyl and hexyl groups have been replaced by methyl groups for the calculations. Geometry optimization and calculation of the HOMO and LUMO energies was performed at the B3LYP/631+G** level. b
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DOI: 10.1021/acs.joc.8b02138 J. Org. Chem. 2018, 83, 12711−12721
Article
The Journal of Organic Chemistry The slight differences in the HOMO and LUMO values of these oligomers speak to their optical and electronic tunability, which makes them attractive for optoelectronic material applications. Evaluation of Dimerization Constants. Base-pairing association constants for π-conjugated nucleobase derivatives in organic solvents have not been routinely evaluated. The ́ aforementioned work of González-Rodriguez et al. includes πconjugated derivatives with bulky lipophilic-ribose solubilizing groups and ethylene phenylene oligomers, which allow free rotation between aryl units.19 Their results are in agreement with other examples, predominantly historical, of non-πconjugated nucleobase pairing in organic solvents (chloroform or tetrachloromethane), in which the association (Ka) between uracil and adenine is on the order of 102−103 M−1 in chloroform and 104 M−1 between cytosine and guanine.20,44−51 Here, we quantify the association strength of these derivatives in the same organic solvents to see how their behavior compares to the most relevant examples. It is plausible that secondary factors contributed by π-interactions of the oligothiophene unit and steric effects from the racemic 2ethylhexyl chain (as opposed to a sugar-derived or achiral solubilizing group) may affect the hydrogen-bonding strength of these derivatives. These types of structural modifications are expected in forthcoming molecular designs; it is useful to identify the influence of these design factors before advancing to more complex structures. Prior to evaluating heteroassociation between the nucleobases, the extent of self-aggregation was determined (results summarized in Table 2). For this purpose, NMR titrations on
Figure 3. Concentration-dependent 1H NMR data collected for 1U in CDCl3 at 298 K (a) stacked 1H NMR spectra zoomed into the N(3)−H resonance region and (b) dimerization binding isotherm fit using Bindfit online calculator.53
constant by 1H NMR. Analysis by UV−vis within its solubility range in chloroform (
