Synthesis of organic semiconductors functionalized with biological molecules

Gianluca M. Farinola*(a), Omar Hassan Omar (b), Alessandra Operamolla (a), Francesco Babudri (a)

(a) Dipartimento di Chimica, Università degli Studi di Bari “Aldo Moro”, via Orabona 4, I-70126 Bari, Italy

(b) CNR ICCOM, Dipartimento di Chimica, Università degli Studi di Bari “Aldo Moro”, via Orabona, 4 I-70126 Bari, Italy E-mail: farinola@chimica.uniba.it

Abstract. Organic polymeric and molecular semiconductors functionalized with biological molecules represent a very interesting class of materials for highly selective electrical and optical sensors. Molecular design and synthetic approaches to several bio-substituted conjugated oligomers and polymers are discussed, highlighting the impact of synthetic pathways on the properties of the materials.

I. INTRODUCTION

Organic polymeric [1] and molecular [2] semiconductors have attracted an intense academic and industrial interest in the last decades due to their expected technological impact. Actually, several classes of conventional electronic devices based on inorganic semiconductors, including light emitting diodes (LEDs), transistors, photodiodes, photovoltaic cells and sensors have their organic counterparts based on the new semiconductors [3]. The wealth of opportunities disclosed by the use of this class of compounds in electronics is mainly due to the unique combination of many electrical and optical properties typical of semiconductors with the chemical- physical features of organic and polymeric materials. This combination offers several advantages such as low cost processing, which can be easily performed via solution techniques, ranging from simple solution casting to ink jet printing. Low cost and easy processing would also result in disposable electronic devices printed on plastic substrates. Mechanical properties are attractive as well and the feasibility of flexible, foldable and also stretchable electronics has been demonstrated. However, besides all the mentioned features of organic semiconductors, which are commonly claimed, their most distinguishing characteristic is represented by the structural variety which is proper of organic compounds. Exploitation of such structural richness enables fine tailoring of the properties at the molecular scale in order to fulfill the requirements of the devices and applications. At a first level the properties are determined by the choice of the conjugated backbone. Then, fine modulation can be achieved by proper exploitation of steric and electronic effects of the substituents. Organization in the solid state, which critically affects the material properties, can also be largely controlled by introduction of functional groups.

Finally, substituents can be introduced to add specific functions such as recognition ability, which is of chief interest for fabrication of highly selective sensor devices [4]. A special kind of functionalization which offers intriguing possibilities in advanced sensing applications is represented by decoration of the conjugated systems with biological molecules. Covalently attaching biomolecules as substituents to the conjugated molecular or polymeric framework offers the fascinating possibility to combine the recognition ability deriving from their biological role with the electrical and optical properties of the organic semiconductors. This is a unique opportunity with a degree of versatility and generality that would be hardly achievable by classical inorganic semiconductors. Several efficient and selective biological sensors based on organic semiconductors functionalized with biomolecules have been reported [5], and intriguing advancements can be expected, largely based on the availability of properly designed materials. In this paper we wish to emphasize the chemical perspective in the development of bio-substituted organic semiconductors as new materials for organic electronics and especially for sensing, highlighting the key role of molecular design and synthetic methodologies.

II. RESULTS AND DISCUSSION

A. Molecular engineering The synthesis of bio-functionalized organic semiconductors poses challenging issues, mainly due to the simultaneous presence of many functional groups in most of the biological molecules and to the importance of preserving their stereochemistry, in order to maintain the functional properties. Two main synthetic approaches can be envisioned to access this class of compounds. According to the first one, insertion of the biological molecules is carried out after the synthesis of the conjugated skeleton, which must bear reactive groups as binding sites for the biological substituents. Following the second approach, building blocks with the biological molecules are synthesized in a first step and then they are connected by appropriate coupling reactions. Although the

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first strategy is fast and straightforward, unreacted sites often remain on the precursor polymer and, as a consequence, the structures obtained are not very well ordered and defined. The second synthetic approach ensures a better structural regularity of the final compound, which is significant for several applications. Structural order at molecular level can be critical in organic electronic sensors, where a precise control of the sequence, location and number of receptor sites is beneficial for device performance both in terms of electrical behavior and of interactions with analyte molecules. However, the latter approach is more challenging from a synthetic point of view as it requires appropriate reactions to couple together the bio-functionalized building blocks, that must be tolerant of several functional groups and preserve the delicate structure of the biological molecules. In the next paragraphs the synthesis of some representative bio-functionalized building blocks carried out in our laboratories is described, followed by a discussion on coupling processes suitable to obtain conjugated systems from such substrates. Examples of effects of the molecular design on solid state properties will be also introduced in

order to illustrate the essential contribution given by the development of appropriate synthetic methodology to the development of this class of materials and their applications. B. Building blocks Conjugated building blocks functionalized with biological molecules require two main structural features: a chemical connection with the biological substituent and one or more reactive groups to be used in the subsequent coupling reaction steps. Alkoxy moieties on the phenyl/phenylene rings are frequently used to easily introduce several substituents on the main backbone in various classes of conjugated oligomers and polymers but also other functionalities, such as ester linkages, can be fruitfully used as binding groups. In our case aminoacid and glucose molecules have been attached to the phenylene building blocks in the 2 and 5 positions exploiting the alkoxy linkage. The biomolecules were attached directly on the aromatic ring in the case of the dihalide 1a bearing peracetilated D-glucose [6] or through a six carbon atom

I I

OH

HO

I I

OSiMe3

Me3SiOBF3

.Et2OCH2Cl2

I I

O

AcOAcO

AcO

O

OAc

O

OAcOAc

OAc

O

AcO

1a(59%)

2 3(94%)

β-D-glucosepentaacetateMe3SiCl

[Me3Si]2NH

CH3CN

I I

OH

HO 2

BrC6H12OH

NaOHTHF/DMF

I I

OC6H2OH

HOC6H2O 4(53%)

OH

O

NH-tBOCH

Et3N, DMAPIPCC, CH2Cl2

I I

O

O 1b(60%)

O

O

O

O

HH

NHHNBOC

tBOC

NH

O

ON

O

OH

HOimidazole

DMFr.t.

NH

O

ON

O

OH

TBDSiO

O

OH

Br

Br

pyridine

r.t

NH

O

ON

O

O

TBDSiO

O

Br

Br

1c(58%)

Si Cl

5 677%

t

Scheme 1. Synthesis of building blocks 1a, 1b and 1c.

506

aliphatic spacer in the case of the dihalide 1b bearing L-phenylalanine substituents [7]. Conversely, the functionalization with 2’-D-deoxyuridine, was carried out by exploiting ester linkage between the 3’ position of the deoxyribose ring and the 2,4-dibromosubstituted arene. The synthesis of the two dihalides 1a and 1b is reported in the Scheme 1 and it was performed starting from the commercially available 2,5-diiodohydroquinone 2. The insertion of the peracetilated D-glucose units proceeded smoothly by conversion of 2 into the corresponding bistrimethylsilyl ether 3, followed by a glycosidation reaction adapted from a synthetic procedure leading to phenylglycosides [8]. The proton NMR coupling constant value (J ≈ 7 Hz) between the protons on C-1 and C-2 of the glucose ring confirmed the β configuration of both the glycosidic linkages. The diiodo derivative 1b was obtained in good yield by esterification of the diol 4 with the L-phenylalanine bearing N-t-butoxycarbonyl protecting group. This procedure, performed in the presence of IPCC as condensing agent, led to the expected product without inducing racemization of the two amino acid units [9]. The synthesis of 1c is also depicted in the Scheme 1. Protection of the 5’-hydroxy terminus on the 2’-deoxyuridine was carried out by reaction with t-butyldimethylsilylchloride at room temperature. Subsequent esterification of the 3’ position was performed at room temperature in the presence of pyridine with good yield. C. Coupling reactions and materials The synthetic methodologies used to build up the conjugated

systems from the building blocks 1a-c are conveniently based on Pd catalyzed coupling reactions. Many of these processes can be used depending on the conjugated sequence of the final materials that has to be obtained and in most cases the reaction conditions can be tuned depending on the functional groups present on the reactants. These processes have in fact the necessary requirements in terms of mild experimental conditions, stereo- and regioselectivity and tolerance towards several functional groups, thus enabling to obtain bio-functionalized conjugated materials with high degree of structural order [10]. The Cassar-Heck-Sonogashira reaction [11] is a versatile synthetic tool to make bio-substituted phenyleneethynylene polymers (PPEs) readily accessible. The halides 1a-c could be coupled with a number of bis-ethynyl arenes, thus enabling the synthesis of several polyconjugated architectures containing triple bonds. As reported in the Scheme 2, the dihalide 1a was converted into the corresponding bistrimethylsilylethynyl derivative 7 and then coupled with different aryl iodides in the presence of silver oxide [6]. We employed the desilylative coupling procedure to avoid the oxidative homocoupling reaction of the free ethynyl units that would introduce structural irregularity in the polymer chain. By coupling the dihalide 1b with the 1,4-bis[trimethylsilylethynyl] arene 10 the copolymer 11 was obtained as reported in the Scheme 3 [7]. The PPE copolymer 11 contains a regular alternation of monomeric units substituted with linear alkoxy chains and with amino acid moieties connected to the main polymer skeleton via a six carbon atom alkoxy chain. The synthetic approach appears general and can be extended to other polymers with the polyaryleneethynylene (PAE) structure and bearing different

1aTMSA

Pd(PPh3)4CuI

Et3N/toluene60°C

O

AcOAcO

AcO

O

OAc

O

OAcOAc

OAc

O

AcO

7(70%)

TMS TMSI-Ar-I 8

Pd(PPh3)4Ag2OTHF60°C

O

AcOAcO

AcO

O

OAc

O

OAcOAc

OAc

O

AcO

9a-dyields 86-99%

Arn

I-Ar-I = I I

OC8H17

C8H17O

1a I I

F

F

F

FS II

8b 8c 8d

Scheme 2. Synthesis of polimers 9a-d.

507

amino acids as substituents. In the case of the polymerization of compound 1c, the free ethynyl derivatives 12a-b were used obtaining in good yields the corresponding polymers 13a-b, which differ for the alkyl side chain length. Oligomers with polyarylene structure can be as well synthesized via the Suzuki-Miyaura cross-coupling reaction [12] between boronic derivatives (esters or acids) and the dihalo aromatic building blocks previously functionalized with the bio-molecules. The synthesis reported in the Scheme 4 to obtain bio-functionalized oligo(phenylenethiophene) involves a commercially available bithiophene derivative, the pinacol boronate 14. The synthetic procedure enables easy connection of two oligothiophene blocks with the central functionalized diidobenzene 1a or 1b in excellent yields. Actually, the presence of the bio-molecules on the organic halides is tolerated in the cross-coupling reaction performed in anhydrous conditions and in the presence of silver oxide. This result opens the way to the synthesis of a wide variety of structures by simply using different thiophene boronic derivatives, many of which are commercially available. Moreover, the thiophene pinacolboronates are among the

most stable and easily available boron-derivatives of thiophene, showing good reactivity in the classical Suzuki-Miyaura cross-coupling reaction and forming low toxicity by-products. D. Bio-functionalization and solid state properties

Biological functionalization and the high degree of molecular structural order that it is possible to achieve by the synthetic methodologies described is reflected on the properties of the materials in the solid state.

Poly-p-(phenyleneethynylene)s (PPEs) are well known for their tendency to form aggregates and excimers in various solvents or solvent mixtures (solvent / non-solvent mixtures) [13]. The formation of aggregates usually affects optical properties for instance inducing solvatochromism or reducing the luminescence efficiencies. The quenching of luminescence can be exploited for the fabrication of chemical sensors [14].

Formation of aggregates was detected from the absorption and luminescence spectra of both the glucose- 9a and the amino acid- functionalized 11 polymers in methanol/chloroform and ethanol or hexane/chloroform

1c

OR

RO 12a R=CH312b R=C8H17

H H+Pd(PPh3)4, CuI

Et3N, toluene,

60°C

NHO

ON

O

O

TBDSiO

O OR

ROn

13a (54%)13b (95%)

OC8H17

C8H17O 10

TMS TMS + 1bPd(PPh3)4, Ag2O

THF, 60°C

O

O11

(37%)

O

O

O

OH

H

NH

HN

BOCt

tBOC

OC8H17

C8H17On

Scheme 3. Synthesis polymers 11 and 13a-b

508

mixtures, respectively. Polymer 11 shows a manifest solvatochromism upon addition of ethanol or other nonsolvents to its chloroform solutions, with a reduction of its UV-vis absorption band and appearance of a new, sharp band at longer wavelengths, which may be assigned to aggregated species dispersed in solution. These aggregates were revealed by AFM in thin films casted from hexane/chloroform with an average diameter of about 90nm. While functionalization with the chiral L-phenylalanine residues in the remote position of poly(phenyleneethynylene) 11, due to the six carbon atom spacers, does not significantly perturb the symmetry of the conjugated chromophore, strong circular dicroism signals are recorded in solution casted films or in aggregates suspended in solvent /non-solvent mixtures, which can be attributed to the formation of a supramolecular chiral arrangement of the molecules in the condensed phase [7].

This effect is a clear indication of the key role played by molecular design of bio-functionalization in the control of the materials organization in the solid state, which can be critical for electrical sensing applications.

The chiral multifunctional substituents of polymers 9a and 11 can enantioselectively interact with chiral compounds and, consequently, confer chiral discrimination ability to the PPE polymers in sensor devices. Both polymers 9a and 11 were used as active layers in quartz crystal microbalance sensors for the gravimetric detection of menthol enantiomers in the vapour phase [15]. Chemisorption of the analyte on the thin film of the active material covering the microbalance quartz crystal was revealed by the piezoelectric changes in vibration frequency caused by small mass variations. The difference in the response of the glucose-substituted polymer 9a to the two menthol enantiomers was measured to be 10 %, with the polymer interacting more favourably with the natural (–) menthol than with the synthetic (+) menthol. Response difference rises up to 28 % in the case of the amino acid-substituted polymer 11 used as the active layer, with inverted

selectivity that, in this case, is more favorable to the (+) enantiomer. We described in a previous paper the application of a poly(alkoxyphenylene-thienylene) polymer deposited by the Langmuir Shäfer technique as the active material in nitrogen dioxide resistive gas sensor with excellent sensitivity [16]. Langmuir Shäfer thin films of the same polymer were also used as field effect transistor active layers while no transistor behaviour was observed with a cast film of the material [17]. These results prompted us to extend the bio-functionalization to the alkoxyphenylene-thienylene semiconductors aiming to combine the good electrical performances of the conjugated backbone with the enantiselective discrimination ability of the multifunctional chiral bio-molecules. Properly designed alkoxyphenylene-thienlylene oligomeric systems 15a and 15b were thus synthesized as discussed in the previous paragraph. However, Langmuir-Shäfer thin films of the sole bio-substituted oligomers 15a and 15b did not show field effect amplified current, likely due to the steric hindrance of the amino-acid and glucose substituents. Therefore, Langmuir-Shäfer thin film deposition of the bio-substituted semiconducting oligomers 15a or 15b was carried out on a multilayer of the analogous oligomer bearing simple alkoxy chains instead of the bio-molecules. The resulting supramolecular architecture combined the electrical behaviour of the simple alkoxy-substituted conjugated system with the chiral discrimination ability conferred by the bio-molecules. This thin film was used as the active layer in an organic thin film transistor electrical sensor showing outstanding performances in enantioselective sensing enabling chiral differential detection of optical isomers of terpene flavour molecules at unprecedentedly low concentration (tens-of-parts-per-million) [18].

III. CONCLUSIONS

O

AcOAcO

AcO

O

OAc

O

OAcOAc

OAc

O

AcO

15a(84%)

O

O15b

(60%)

O

O

O

OH

H

NH

HN

BOCt

tBOC

OB

O S S

Pd(PPh3)4Ag2O

Na2CO3dioxane

70°C

14

S

S

S

S

S

SS

S

Pd(PPh3)4Ag2O

Na2CO3dioxane

70°C

1a1b

Scheme 4. Synthesis of oligomers 15a-b

509

Proper molecular design and development of selective and efficient synthetic methodologies enable to fully exploit the enormous potentialities offered by organic semiconductors functionalized with biological molecules. These are dictated not only by the conjugated architecture, but also by proper choice and regiochemistry of the bio-functionalization and by the resulting solid state organization. The perspective to extend the synthetic methodologies to organic semiconductors functionalized with even more complex bio-molecules is largely based on the development of appropriate synthetic methodologies that, as discussed, directly affect the performances of the solid state materials in the sensing device applications. The synthetic work here presented, besides the interesting results already demonstrated, also represents a unique background for building even more complex molecular architectures that would open intriguing perspectives in organic electrical sensing and bio-sensing.

ACKNOWLEDGEMENTS

This work was financially supported by Ministero dell’Istruzione, dell’Università e della Ricerca (MIUR), “Progetto PRIN 2007 PBWN44” and by Università degli Studi di Bari “Aldo Moro”..

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