Highly Enantioselective Graphene-Based Chemical SensorsPrepared by Chiral Noncovalent FunctionalizationXiaobo Shang,†,‡ Cheol Hee Park,†,‡ Gwan Yeong Jung,§ Sang Kyu Kwak,*,§ and Joon Hak Oh*,‡

†Department of Chemical Engineering, Pohang University of Science and Technology (POSTECH), 77 Cheongam-ro, Pohang37673, Korea‡School of Chemical and Biological Engineering, Institute of Chemical Processes, Seoul National University, 1 Gwanak-ro,Gwanak-gu, Seoul 08826, Korea§Department of Energy Engineering, School of Energy and Chemical Engineering, Ulsan National Institute of Science andTechnology (UNIST), 50 UNIST-gil, Ulsan 44919, Korea

*S Supporting Information

ABSTRACT: As a basic characteristic of the naturalenvironment and living matter, chirality has been used invarious scientific and technological fields. Chiral discrim-ination is of particular interest owing to its importance incatalysis, organic synthesis, biomedicine, and pharmaceutics.However, it is still very challenging to effectively andselectively sense and separate different enantiomers. Here,enantio-differentiating chemosensor systems have beendeveloped through spontaneous chiral functionalization ofthe surface of graphene field-effect transistors (GFETs).GFET sensors functionalized using noncovalent interactionsbetween graphene and a newly synthesized chiral-functionalized pyrene material, Boc-L-Phe-Pyrene, exhibit highlyenantioselective detection of natural acryclic monoterpenoid enantiomers, that is, (R)-(+)- and (S)-(−)-β-citronellol. Onthe basis of a computational study, the origin of enantio-differentiation is assigned to the discriminable charge transfer from (R)-(+)- or (S)-(−)-β-citronellol into graphene with a significant difference in binding strength depending on surface morphology.The chemosensor system developed herein has great potential to be applied in miniaturized and rapid enantioselective sensingwith high sensitivity and selectivity.

KEYWORDS: graphene transistors, chiral sensors, chemical sensors, noncovalent interactions, enantioselectivity

1. INTRODUCTION

Chirality plays a very important role in various fields ofscientific and technological research and has great potential tobe applied in key areas such as chemical synthesis,pharmaceutics, catalysis, fundamental physics, and biomedi-cine.1 As most biological compounds and many pharmaceut-icals are chiral, sensing and separating chiral compounds is ofgreat importance.2 In many cases, one enantiomer of chiraldrugs such as 3,4-dihydroxyphenylalanine has the desired effect(e.g., healing properties), while the other has an undesirableeffect (e.g., toxicity).3 Therefore, there is a need for selectivediscrimination and separation of enantiomers. While chiraldiscrimination has great potential to be applied in many areas,it remains challenging because of the difficulty of discriminat-ing between enantiomers that have nearly identical propertiesand the same chemical composition, different only in stericconformation.4 However, when chiral chemicals interact withanother chiral entity (typically a molecular receptor) toproduce enantio-specific interactions, their biological andphysiological properties can differ dramatically. By makinguse of this principle, separation and detection of optical

isomers can be carried out using offline analytical techniquessuch as chromatography. Other chiral discrimination methodsinclude microwaves,5,6 photoelectron circular dichroism,7

chiral light,8−10 cavity-enhanced polarimeters,11 and magneticsubstrates.12

Compared to other methods, amperometric chemosensorsbased on field-effect transistors (FETs) are attractive owing toadvantages such as their rapid sensing ability, high sensitivity,ease of handling, small size, and need for only a small volumeof samples.13−15 To date, FET-based sensors have been widelyused in artificial skin technology, environmental monitoring,light sensing, drug delivery, and food safety detection.15

However, among the various applications of FET-basedsensing, chiral sensing is still one of the most challengingapplications of FET-based sensors. Torsi et al. successivelyreported a bilayer-structured organic field-effect transistor(OFET)-based sensing technology for enantioselective detec-

Received: August 7, 2018Accepted: October 1, 2018Published: October 1, 2018

Research Article

www.acsami.orgCite This: ACS Appl. Mater. Interfaces 2018, 10, 36194−36201

© 2018 American Chemical Society 36194 DOI: 10.1021/acsami.8b13517ACS Appl. Mater. Interfaces 2018, 10, 36194−36201

Dow

nloa

ded

via

SEO

UL

NA

TL

UN

IV o

n O

ctob

er 3

1, 2

018

at 0

2:05

:58

(UT

C).

Se

e ht

tps:

//pub

s.ac

s.or

g/sh

arin

ggui

delin

es f

or o

ptio

ns o

n ho

w to

legi

timat

ely

shar

e pu

blis

hed

artic

les.

tion of terpene flavor molecules of biological origin at anunprecedentedly low concentration and a sensitive andquantitative capacitance-modulated transistor based onfunctionalization of gate electrodes using odorant bindingproteins for the differential detection of chiral odorantmolecules.4,16 Recently, molecularly imprinted polymer-basedextended-gate OFET chemosensors have also been reported toenantioselectively sense chiral phenylalanine.3 Further in-depthresearch on topics such as the synthesis of novel chiralmaterials, as well as chiral sensing methods and mechanisms,will expedite the development of the chiral sensing platforms.In particular, graphene-based field-effect transistors

(GFETs) are promising for sensing applications owing to theintrinsic chemical inertness of graphene and the high sensitivityof the FET platform.17−19 However, sensitizer molecules andstructures need to be introduced for high selectivity and broadsensing applications. Noncovalent functionalization of gra-phene by π-interactions is an attractive synthetic methodbecause it offers the possibility of attaching functional groupsto graphene, while preserving the graphene lattice andelectrical performance.20,21 π−π interactions, which can beaffected by several factors related to aromatic molecules, suchas electron-donating or withdrawing ability, planarity, and thesubstituents, are one of the most intriguing noncovalentinteractions. For example, pyrene-substituted materials havelarger planar aromatic structures that strongly anchor them tothe hydrophobic surface of graphene sheets via π−πinteractions without disrupting graphene’s conjugation.21−25

In the present study, we synthesized a pyrene-functionalizedmaterial (Boc-L-Phe-Pyrene) and utilized it as UV−vis andfluorescent probes for enantioselective sensing of thebiomolecule β-citronellol, which is prevalent in essential oilsof various aromatic plant species and has various pharmaco-logical and anti-anxiety effects, such as antibacterial, antifungal,antispasmodic, hypotensive, vasorelaxant, anticonvulsant, anti-nociceptive, and anti-inflammatory activities.26−29 Moreinterestingly, Boc-L-Phe-Pyrene was used as the chiralfunctional layer on the graphene surface of GFET-basedsensors using π−π noncovalent interactions for the enantio-selective sensing of β-citronellol. On the basis of computationalstudies, including density functional theory (DFT) andmolecular dynamics (MD) simulations, we suggest anenantioselective sensing mechanism: Boc-L-Phe-Pyrene withoblique morphology exhibits different binding strengths withenantiomeric β-citronellol, leading to differences in the chargetransfer (CT) amount into graphene. For future applications,we also demonstrate the fabrication of a flexible enantiose-lective sensor device. The highly selective and sensitivedetection of β-citronellol enantiomers with a low concentrationusing the Boc-L-Phe-Pyrene/graphene bilayer-structured sys-tem will enable new strategies for FET-based chiral sensing.

2. EXPERIMENTAL SECTION2.1. Materials and Instrumentation. All starting materials were

purchased from Aldrich and used without further purification. Allsolvents were ACS grade unless otherwise noted. The absorptionspectra were measured using a Cary 5000 UV−vis−NIR spectropho-tometer for solutions. Photoluminescence (PL) spectra were recordedon an FP-6500 spectrofluorometer (JASCO). An Agilent 5500scanning probe microscope running with a NanoScope V controllerwas used to obtain atomic force microscopy (AFM) images. AFMimages were recorded in a high-resolution tapping mode underambient conditions. Raman spectroscopic analysis was conducted at awavelength of 532 nm (WITec, Micro Raman). The electrical

performances of fabricated GFETs and GFET-based enantioselectivesensors were measured using a Keithley 4200-SCS semiconductorparametric analyzer.

2.2. Synthesis and Characterization of Boc-L-Phe-Pyrene. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (6.2mmol), 4-dimethylaminopyridine (2.8 mmol), triethylamine (4.1mmol), and 1-pyrenemethanol (2.1 mmol) were successively added toa solution of N-(tert-butoxycarbonyl)-L-phenylalanine (1.89 mmol) in25 mL of dichloromethane (DCM) at room temperature, and themixture was stirred overnight. Then, the reaction mixture wasconcentrated in vacuo. The residue was diluted with DCM andsequentially extracted with saturated NaHCO3 aqueous solution,water, and brine. The final product was purified by columnchromatography (yield: 57%). (S)-Pyren-1-ylmethyl 2-((tert-butoxycarbonyl)amino)-3-phenylpropanoate: 1H NMR (400 MHz,CDCl3): δ 8.00−8.26 (m, 9H), 6.86−7.12 (m, 5H), 5.80−5.95 (m,2H), 4.92−5.03 (m, 1H), 4.61−4.71 (m, 1H), 2.95−3.10 (m, 2H),1.40 (s, 9H) ppm. 13C NMR (100 MHz, CDCl3): 171.9, 131.2, 130.7,129.7, 129.2, 128.4, 128.4, 128.0, 127.3, 126.2, 125.6, 125.6, 124.9,124.6, 124.6, 122.8, 65.5, 54.5, 38.3, 28.3 ppm (Figure S1). Elementalanalysis (%) calcd for C24H23NO3: C, 77.19; H, 6.21; N, 3.75. Found(%): C, 77.15; H, 6.20; N, 3.68. HRMS (MALDI-TOF, m/z): M+

calcd for 479.2097; found, 479.2095.2.3. Sensor Device Fabrication on SiO2/n

++Si Wafer. Agraphene film was grown on the copper foil by the conventionalchemical vapor deposition method using H2 and CH4 gas. After thegrowth of graphene, poly(methyl methacrylate) (PMMA) was coatedon the graphene surface. Copper foil under the graphene film wasetched using ammonium persulfate ((NH4)2S2O8) aqueous solution(0.1 M). Then, the PMMA/graphene was wet-transferred on the SiO2(300 nm)/n++Si wafer and annealed at 130 °C for 30 min. ThePMMA-supporting film was removed using acetone. For deposition ofthe Boc-L-Phe-Pyrene layer, the devices were immersed in a N,N-dimethylformamide (DMF) solution of Boc-L-Phe-Pyrene for 12 h.Next, the devices were rinsed in an excess amount of DMF andannealed to remove residual solvent. Source and drain electrodes weredeposited in a thickness of 40 nm by thermal evaporation of Au usinga patterned shadow mask.

2.4. Fabrication of Flexible Sensor Devices. A flexible sensorwas fabricated on an indium tin oxide (ITO)-deposited polyethylenenaphthalate (PEN) substrate, in which ITO and PEN serve as thegate electrode and the substrate, respectively. As a flexible dielectriclayer, SU-8 10 diluted with γ-butyrolactone (γ-butyrolactone/SU-8 10= 7:3 by volume ratio) was spin-coated at 7000 rpm for 120 s, andfilms were annealed at 95 °C for 1 min.30 The SU-8 10 film wasexposed to UV light to induce cross-linking and annealed at 110 °Cfor 1 h. The preparation processes for the graphene film, Boc-L-Phe-Pyrene layer, and electrodes were the same as described above.

2.5. MD Simulation. The induced dipole moments of Boc-L-Phe-Pyrene on the graphene for each chiral enantiomer of β-citronellolwere investigated using MD simulations. First, three types ofmorphologies were chosen as model systems by varying the anglebetween the aromatic plane and functional group in the Boc-L-Phe-Pyrene molecules (i.e., “vertical”, “oblique”, and “horizontal” shapes).After full optimization by DFT calculation, a 3 × 3 × 1 supercellstructure was created, and the vacuum was fully introduced in the z-direction (i.e., 44.5 × 51.3 × 100.0 Å3). Subsequently, the equilibriumbinding configurations for each (R)-(+)- or (S)-(−)-β-citronellol at afixed pressure condition of 1 atm were identified by grand canonicalMonte Carlo (GCMC) simulation31 (i.e., ∼70 chiral citronellolmolecules adsorbed on each Boc-L-Phe-Pyrene/graphene system).Using these configurations as the initial structure, NVT (isothermal)MD simulations were performed for 10 ns at room temperature with atime-step of 1 fs. All MD simulations were carried out usingCOMPASSII forcefield.32,33 Atom-based cutoff (a cutoff of 15.5 Å)and the Ewald scheme34,35 were applied to estimate the van der Waalsand electrostatic interactions, respectively. Temperature was con-trolled using a Nose−Hoover−Langevin thermostat.36

2.6. DFT Calculation. DFT calculations were used to investigatethe binding energy (BE) and CT of Boc-L-Phe-Pyrene/graphene in

ACS Applied Materials & Interfaces Research Article

DOI: 10.1021/acsami.8b13517ACS Appl. Mater. Interfaces 2018, 10, 36194−36201

36195

the presence of (R)-(+)- or (S)-(−)-β-citronellol. First, threemorphological systems consisting of Boc-L-Phe-Pyrene and graphenewere constructed by applying a vacuum in the z-direction (i.e., 14.8 ×17.1 × 35.0 Å3). With these models, the initial binding configurationsof a single (R)-(+)- or (S)-(−)-β-citronellol were identified byGCMC simulations. Subsequently, after full optimization of thesystems, the BEs of (R)-(+)- or (S)-(−)-β-citronellol on the Boc-L-Phe-Pyrene/graphene systems were calculated as follows

E E EBE pyrene/G cit. pyrene/G cit.= − −+

where Epyrene/G+cit., Epyrene/G, and Ecit. represent the total energies ofBoc-L-Phe-Pyrene/graphene systems adsorbed by (R)-(+)- or (S)-(−)-β-citronellol, bare Boc-L-Phe-Pyrene/graphene systems, and anisolated single (R)-(+)- or (S)-(−)-β-citronellol molecule, respec-tively. All DFT calculations were performed using the DMol3

program37,38 with the generalized gradient approximation and thePerdew−Burke−Ernzerhof functional.39 The spin-polarized calcula-tions were performed using a double numerical basis set withpolarization functions (dynamic nuclear polarization) and a real-spacecutoff of 4.4 Å. All electron relativistic effects were included for thetreatment of core electrons in all model systems. The convergencecriteria for energy, force, and displacement were set as 1.0 × 10−5 Ha,0.002 Ha Å−1, and 0.005 Å, respectively. The atomic charges wereobtained from Mulliken population analyses.40

2.7. GCMC Simulation. GCMC simulations of the (R)- and (S)-enantiomers of β-citronellol were performed using the Sorptionprogram.41 The equilibrium binding configurations of (R)-(+)- or(S)-(−)-β-citronellols were investigated at a fixed pressure of 1 atmand at room temperature. The systems were equilibrated for 1.0 × 106

MC steps and analyzed for the next 1.0 × 106 MC steps. Thenonbond interactions, including electrostatic and van der Waalsforces, were estimated by group-based summation and an atom-basedcutoff (a radius of 15.5 Å) scheme.

3. RESULTS AND DISCUSSIONPyrene-based materials are widely used in photochemicalresearch because of their unique properties.42 Our pyrene-

based chiral material, Boc-L-Phe-Pyrene, was synthesized fromesterification between 1-pyrenemethanol and N-(tert-butox-ycarbonyl)-L-phenylalanine. The UV−vis and PL spectra ofpyrene-functionalized material in tetrahydrofuran (THF)solutions (5 × 10−7 M) are illustrated in Figure 1. For the

Boc-L-Phe-Pyrene, the absorption spectra in THF exhibitedthree main peaks at 344, 327, and 315 nm, corresponding tothe 0−0, 0−1, and 0−2 transitions of well-resolved vibronicstructures of the chiral molecule, respectively. Fluorescencestudies of Boc-L-Phe-Pyrene in THF (5 × 10−7 M) showed themirror image of the UV−vis spectra with three main peaks atthe wavelengths of 415, 396, and 376 nm.UV−vis spectroscopy is widely used in molecular sensing

and has various advantages for determining enantiomericexcess (ee), such as rapid measurement and simpleinstrumentation. When the absorbance lies in the visiblerange, it is possible to quickly detect the ee value by the nakedeye.43 Fluorescence is another optical technique that has beenused to determine ee. The fluorescence instrument is highlysensitive, rapid, relatively inexpensive, and can be used for real-time analyses. Therefore, the development of enantioselectiveUV−vis and fluorescence sensors for the recognition of chiralorganic molecules has attracted great interest.43−45 To assessthe enantioselective response of Boc-L-Phe-Pyrene toward β-citronellol, we measured the absorption and emission spectraof Boc-L-Phe-Pyrene (Figure 1c,d) with each enantiomer of β-citronellol. In the presence of either (R)-(+)- or (S)-(−)-β-citronellol at a concentration of 5 × 10−4 M, the maximumwavelength of fluorescence and absorbance kept constant,while the intensities of both fluorescence and absorbance ofthe Boc-L-Phe-Pyrene (5 × 10−7 M) were quenched.Interestingly, the intensities were always reduced more for(R)-(+)-β-citronellol than (S)-(−)-β-citronellol in both UV−vis and PL spectra. We surmise that the enantiomeric sensingmechanism of Boc-L-Phe-Pyrene can be related to the differentassociation constants of Boc-L-Phe-Pyrene with the enantio-meric analyte of β-citronellol.46−48

For the use of Boc-L-Phe-Pyrene in enantioselective sensing,we fabricated a GFET sensor device using functionalizedgraphene with a Boc-L-Phe-Pyrene layer via noncovalent π−πinteractions.25 A schematic illustration of the chiral-function-alized GFET sensor fabrication process is shown in Figure 2a(see details in the Experimental Section). The film character-istics of pristine graphene and Boc-L-Phe-Pyrene/graphenewere analyzed using AFM and Raman spectroscopy. The AFMheight image of pristine graphene shows a clean and flat surfacewith a root-mean-square roughness (Rq) of 0.253 nm (Figure2b), while the Boc-L-Phe-Pyrene/graphene film exhibits aclearly different surface morphology with a higher Rq of 0.447nm, which explains the successful attachment of Boc-L-Phe-Pyrene onto the surface (Figure 2c). The thickness of Boc-L-Phe-Pyrene layers deposited on graphene is about 2 nm, whenestimated from the AFM height profile (Figure S2).Raman spectra of the pristine graphene film showed a 2D

band (2675 cm−1), G band (1582 cm−1), and high intensityratio of 2D/G (I2D/IG) over 4, which indicates typicalcharacteristics of monolayer graphene (Figure 2d).49 Inaddition, the high quality of graphene is confirmed by thelow intensity of the D band (1343 cm−1), which is an indicatorof graphene defects. However, Boc-L-Phe-Pyrene/graphenefilms show apparent differences from the pristine graphene filmin Raman spectra. For example, the Raman spectra of the Boc-L-Phe-Pyrene/graphene film exhibit an increase in the intensityof the G band and position shifts of the 2D and G bands from2675 and 1582 to 2680 and 1588 cm−1, respectively, whichmight be related to the stacking of Boc-L-Phe-Pyrene on thetop of the graphene film and the p-type doping effect of

Figure 1. Molecular structure of (a) Boc-L-Phe-Pyrene and (b) β-citronellol enantiomers. (c) UV−vis spectra and (d) PL spectra ofBoc-L-Phe-Pyrene solution with the addition of chiral analytes. Theconcentration of Boc-L-Phe-Pyrene solution and chiral analyte wasfixed at 5 × 10−7 and 5 × 10−4 M, respectively.

ACS Applied Materials & Interfaces Research Article

DOI: 10.1021/acsami.8b13517ACS Appl. Mater. Interfaces 2018, 10, 36194−36201

36196

graphene originated from the pyrene derivative functionallayer.50,51

Electrical properties of pristine graphene- and Boc-L-Phe-Pyrene/graphene-based transistor devices are shown in FigureS3 (Supporting Information). The source−drain current (ID)as a function of gate voltage (VG) for the pristine graphenetransistor shows typical properties of p-channel-operatedgraphene transistor devices, with a Dirac point of 10 V.However, the Boc-L-Phe-Pyrene/graphene transistor deviceclearly shows a current−voltage characteristic of p-type dopeddevices, with a Dirac point shifted to a positive VG regionabove 50 V. This reflects the p-type doping effect of Boc-L-Phe-Pyrene, which is consistent with the upshift of 2D bandand G band positions in Raman spectra of the Boc-L-Phe-Pyrene/graphene film (Figure 2d).51,52 The hole carriermobility (μh) of the devices was calculated based oncurrent−voltage characteristics using the following equation

g L

V WChm

D gμ =

where gm is the transconductance, L is the channel length, VD isthe source−drain voltage,W is the channel width, and Cg is thecapacitance of the dielectric layer.25 The average hole mobilityof the pristine graphene transistor was 1510 ± 86 cm2 V−1 s−1,while that of the Boc-L-Phe-Pyrene/graphene transistor was1006 ± 74 cm2 V−1 s−1. Although the Boc-L-Phe-Pyrene/graphene device showed p-type doped characteristics, thecarrier mobility was relatively lower than that of the pristinedevice, which can be attributed to the impeded charge carriertransport owing to the nonconductive property of the Boc-L-Phe-Pyrene layer positioned between the Au electrodes andthe graphene layer.To demonstrate the enantioselective chemical sensing

properties of the Boc-L-Phe-Pyrene/graphene system, weused the vapor of (R)-(+)-β-citronellol and (S)-(−)-β-citronellol enantiomers as the sensing analytes in the fabricated

Figure 2. (a) Schematic depiction of the device structure and the fabrication process of a Boc-L-Phe-Pyrene/graphene FET-type sensor. AFMheight images of (b) pristine graphene and (c) Boc-L-Phe-Pyrene-deposited graphene on the SiO2/Si substrate. (d) Raman spectra of pristinegraphene (black) and Boc-L-Phe-Pyrene/graphene (red).

Figure 3. Concentration-dependent chiral β-citronellol vapor sensing signals from (a) pristine graphene sensors and (b) Boc-L-Phe-Pyrene/graphene sensors fabricated on SiO2/Si wafer. I0 is the baseline current. Solid lines are the interpolating calibration curves. Ten sensor devices weretested for statistical analysis. (c) Continuous enantioselective sensing responses of a Boc-L-Phe-Pyrene/graphene sensor device for chiral β-citronellol vapor with a concentration of 100 ppm (VD = −0.1 V; VG = −20 V) and (d) magnified plot of the dotted area in (c).

ACS Applied Materials & Interfaces Research Article

DOI: 10.1021/acsami.8b13517ACS Appl. Mater. Interfaces 2018, 10, 36194−36201

36197

devices. For vapor phase sensing, the devices were operated inthe p-channel mode (VD = −0.1 V, VG = −20 V), and theanalyte liquids were vaporized using customized sequentialvaporization tools as reported by Torsi et al.4 For the analytevapor concentration estimation, the theoretical saturationconcentration of β-citronellol vapor was simply calculatedusing the Clausius−Clapeyron equation. The analyte vaporconcentration was controlled by mixing analyte vapor withnitrogen gas using a customized gas flow control system. Theschematic diagram of the customized vapor phase sensingsystem is shown in Figure S4 (Supporting Information).Figure 3a shows the change in drain current in the pristine

graphene-based sensor devices as a function of the analytevapor concentration. The change in channel current (I0 − ID)of the pristine graphene sensor showed a decrease in p-channelcurrent when both (R)-(+)- and (S)-(−)-β-citronellol vaporswere exposed to the sensor devices, and the increase in currentreduction was consistent with the enhancement of the analytevapor concentration. As expected, the pristine graphene sensorshows almost the same level of current reduction for (R)-(+)-and (S)-(−)-β-citronellol vapors, which means that the pristinegraphene itself is not able to enantioselectively senseenantiomeric citronellol. However, the Boc-L-Phe-Pyrene/graphene-based sensor device exhibits obvious differencesunder exposure to β-citronellol enantiomer vapors comparedto pristine sensors (Figure 3b). The Boc-L-Phe-Pyrene/graphene-based sensor device always reduced the channelcurrent more for (S)-(−)-β-citronellol vapor than for the otherenantiomer (R)-(+)-β-citronellol. We tested vapor concen-tration ranges from 100 to 2 ppm; however, we could not testvapor concentrations lower than 2 ppm owing to the limitedvapor dilution properties of our customized vapor sensingsystem. The sensitivity for enantiomeric analytes, which wasdefined as the ratio of the channel current change with regardto the analyte concentration change, was measured from theslope of calibration curves in Figure 3b. Measured sensitivitieswere −6.7 ± 0.57 nA per ppm for (R)-(+)-β-citronellol and−9.1 ± 0.87 nA per ppm for (S)-(−)-β-citronellol,respectively. These sensitivities obtained from our sensorsystem showed remarkable enhancement when compared withthe previously reported sensitivity of β-citronellol enantiomersobtained from the organic thin-film transistor-based sensorsystem [−0.04 ± 0.01 nA per ppm for (R)-(+)-β-citronelloland −0.08 ± 0.01 nA per ppm for (S)-(−)-β-citronellol,respectively].4 The theoretical limit of detection for bothenantiomers, estimated from the calibration curves, was 1.45ppm for (R)-(+)-β-citronellol and 1.06 ppm for (S)-(−)-β-citronellol, respectively.53 The response time, defined as thetime required to reach 36.8% (=e−1) of the maximum currentchange54 for (R)-(+)- and (S)-(−)-β-citronellol sensing, was2.25 and 1.53 s, respectively.Interestingly, the level of current reduction for the Boc-L-

Phe-Pyrene/graphene sensor for analyte vapor exposure waslower than that of the pristine graphene sensor. The lower levelof current reduction with the Boc-L-Phe-Pyrene/graphenesensor can be attributed to the existence of the Boc-L-Phe-Pyrene interlayer, which limits the direct approach of theanalyte molecule to the graphene layer and interactionsbetween analyte vapor and graphene channels. In addition,we investigated multiple sensing responses at 100 ppm of (R)-(+)- and (S)-(−)-β-citronellol vapor using the Boc-L-Phe-Pyrene/graphene-based sensor and found stable and repeatablemultiple sensing signals with obvious differences in intensityT

able

1.Average

Drain

Current

Changes

forBoc-L-Phe-Pyrene/Graph

ene-Based

SensorsandPristineGraph

eneSensorsup

onExposureto

Various

Con

centration

sof

β-Citronello

lEnantiomer

Vapor

I 0−

I D(μA)

activelayera

analyte

2ppm

10ppm

20ppm

40ppm

60ppm

80ppm

100ppm

chiralfunctio

nalized

graphene

(R)-(+)-β-citronellol

−0.53

(±0.03)b

−0.64

(±0.02)

−0.70

(±0.02)

−0.79

(±0.03)

−0.89

(±0.03)

−1.01

(±0.07)

−1.27

(±0.09)

(S)-(−

)-β-citronellol

−0.61

(±0.03)

−0.73

(±0.04)

−0.82

(±0.02)

−0.91

(±0.03)

−1.04

(±0.03)

−1.28

(±0.10)

−1.60

(±0.10)

pristin

egraphene

(R)-(+)-β-citronellol

−3.16

(±0.13)

−4.05

(±0.21)

−4.89

(±0.12)

−5.52

(±0.24)

−6.40

(±0.25)

−8.12

(±0.23)

−9.49

(±0.25)

(S)-(−

)-β-citronellol

−3.19

( ±0.19)

−4.04

(±0.21)

−4.95

(±0.12)

−5.57

(±0.13)

−6.43

(±0.13)

−8.11

(±0.30)

−9.51

(±0.23)

aTen

sensor

devicesforeach

activelayerweretested

forstatisticalanalysis.bStandard

deviation.

ACS Applied Materials & Interfaces Research Article

DOI: 10.1021/acsami.8b13517ACS Appl. Mater. Interfaces 2018, 10, 36194−36201

36198

for (R)-(+)- and (S)-(−)-β-citronellol vapors (Figure 3c,d). Acomparison of sensing signals between the Boc-L-Phe-Pyrene/graphene-based sensor and pristine graphene-based sensor ispresented in Table 1. These results clearly demonstrate theenantioselective chemical sensing properties of the sensordevice and also show that the adsorption of a chiralfunctionalized Boc-L-Phe-Pyrene layer on the graphene filmcan provide enantioselective sensing properties to graphene-based sensor devices.The results plotted in Figure 3 clearly show that the

interaction between Boc-L-Phe-Pyrene and β-citronellol vaporon the graphene-based sensor reduces the amount of channelcurrent. We speculated that the difference in the level ofchannel current reduction occurred because the electron-donating effects of the chiral analyte differed for the (R)- and(S)-enantiomers of β-citronellol when the analytes wereadsorbed on the Boc-L-Phe-Pyrene layer (Figure 4a). Thus,to verify a signature of enantioselective sensing, we investigatedthe induced dipole moment on the Boc-L-Phe-Pyrene layer byperforming MD simulations. We considered highly plausiblemorphological systems (i.e., “vertical”, “oblique”, and “hori-zontal” shapes) by varying the angle between the aromaticplane and the functional group of Boc-L-Phe-Pyrene molecules(see Figure S5 and “MD Simulation” in the ExperimentalSection). Interestingly, the induced dipole moments exhibiteddifferent trends depending on the surface morphology (Figures4b and S6). In the vertical morphology, the dipole momentdifferences induced by (R)-(+)- or (S)-(−)-β-citronellol weresmall, whereas in other morphologies, the induced polarity of

Boc-L-Phe-Pyrene was predominant to one side [i.e., (R) > (S)for horizontal morphology and (R) < (S) for obliquemorphology]. Thus, on the basis of our results, we suggestthat the oblique morphology may have been dominantlypresent on the surface which is consistent with experimentalresults in Figure 3. To investigate this further, we comparedthe binding strengths of (R)-(+)- or (S)-(−)-β-citronelloladsorbed on the Boc-L-Phe-Pyrene/graphene system usingDFT calculations (see Figure S7 and “DFT Calculation” in theExperimental Section). The oblique morphology exhibited asignificant difference in BE according to the chirality of β-citronellol (i.e., −37.4 kcal mol−1 for (R)-(+)-β-citronellol and−45.3 kcal mol−1 for (S)-(−)-β-citronellol), resulting in thesubstantial differences in CT to graphene. Notably, Mullikencharge analyses40 showed that electron donation to graphene,which was induced by the interaction between Boc-L-Phe-Pyrene and β-citronellol, was observed for all model systemsregardless of surface morphology. On the basis of these results,the differences in BE due to the different chirality of β-citronellol induced differences in the level of CT andsubsequently the dipole moment, which was the cause of thedifferent levels of channel current reduction in the device.To enable further applications of the enantioselective

chemical sensor, we fabricated a flexible version using a plasticsubstrate and a polymer dielectric layer (Figure S8) that couldeasily be bent, as shown in Figure 5a. To demonstrate theenantioselective chemical sensing capability of the flexiblesensor, we exposed it to (R)-(+)- and (S)-(−)-β-citronellolvapors and measured current changes. Similar to the results

Figure 4. (a) Schematic illustrations of Boc-L-Phe-Pyrene/graphene with the adsorbed (R)-(+)- or (S)-(−)-β-citronellol molecule. Note that Boc-L-Phe-Pyrene is the oblique form. The yellow colored arrows represent the direction of CT from β-citronellol to graphene. The (R)-(+)- or (S)-(−)-β-citronellol is colored in sky blue and pink, except that the oxygen and hydrogen atoms of the −OH group are colored in red and white,respectively. The carbon, hydrogen, oxygen, and nitrogen atoms of Boc-L-Phe-Pyrene are colored in black, red, cyan, and blue, respectively. Thegraphene below the Boc-L-Phe-Pyrene is colored in gray. (b) Comparison of the average dipole moment of Boc-L-Phe-Pyrene for threemorphological systems [i.e., vertical, oblique, and horizontal forms (Figure S5)] obtained from MD simulations for last 5 ns. The error barsrepresent the standard deviation of each system.

Figure 5. (a) Photograph of a flexible enantioselective sensor device fabricated on an ITO/PEN substrate with an SU-8 dielectric layer. (b)Continuous enantioselective sensing responses for enantiomeric β-citronellol vapor with a concentration of 100 ppm (VD = −0.1 V; VG = −20 V)and (c) magnified plot of the dotted area in (b).

ACS Applied Materials & Interfaces Research Article

DOI: 10.1021/acsami.8b13517ACS Appl. Mater. Interfaces 2018, 10, 36194−36201

36199

obtained from wafer-based sensors, we found clear differencesin the level of drain current reduction depending on thechirality of the β-citronellol enantiomer vapor. The averagechange in drain current for (R)-(+)-β-citronellol vapor sensingwas −1.33 μA, while for (S)-(−)-β-citronellol vapor sensing, itwas −1.62 μA (Figure 5b,c). This shows that flexible sensorscan easily be fabricated with reproducible enantioselectivesensing responses that are consistent with those obtained usingwafer-based sensor devices.

4. CONCLUSIONSIn summary, we synthesized the chiral-functionalized pyrenemolecule Boc-L-Phe-Pyrene and utilized it for enantioselectivediscrimination of β-citronellol enantiomers. The Boc-L-Phe-Pyrene molecule itself showed chiral discrimination propertieswith different UV−vis and PL responses in solution-phasesensing of (R)-(+)- and (S)-(−)-β-citronellol. Device-basedchiral discrimination of the given β-citronellol enantiomers wasaccomplished by GFETs via noncovalent interactions betweenBoc-L-Phe-Pyrene and graphene. Both pristine graphene filmsand graphene/Boc-L-Phe-Pyrene films were characterized byAFM and Raman spectroscopy to establish the successfuldeposition of Boc-L-Phe-Pyrene on the graphene surface. Theresulting chemosensors could successfully identify β-citronellolenantiomers with high sensitivity. On the basis of computa-tional studies, the binding interactions between (R)-(+)- or(S)-(−)-β-citronellol and the Boc-L-Phe-Pyrene/graphenesystem significantly differ according to the chirality of β-citronellol, leading to substantial differences in the CT fromenantiomeric citronellol to graphene and in the induced dipolemoments. Furthermore, we successfully fabricated a flexibleGFET-based enantioselective sensor. Given the fact that FET-based chiral sensing is still rare and challenging, this studypaves the way for the development of highly sensitive andenantioselective chemosensors.

■ ASSOCIATED CONTENT*S Supporting InformationThe Supporting Information is available free of charge on theACS Publications website at DOI: 10.1021/acsami.8b13517.

NMR spectra; GFET performances; experimentalprocess; and simulation results (PDF)

■ AUTHOR INFORMATIONCorresponding Authors*E-mail: skkwak@unist.ac.kr (S.K.K.).*E-mail: joonhoh@snu.ac.kr (J.H.O.).ORCIDSang Kyu Kwak: 0000-0002-0332-1534Joon Hak Oh: 0000-0003-0481-6069Author ContributionsX.S. and C.H.P. contributed equally to this work. Themanuscript was written through contributions of all authors.All authors have given approval to the final version of themanuscript.NotesThe authors declare no competing financial interest.

■ ACKNOWLEDGMENTSThis work was supported by the Samsung Research FundingCenter of Samsung Electronics under project number SRFC-

MA1602-03. S.K.K. acknowledges financial support from theNRF of Korea (NRF-2014R1A5A1009799) and computationalresources from UNIST-HPC.

■ REFERENCES(1) Berova, N.; Bari, L. D.; Pescitelli, G. Application of ElectronicCircular Dichroism in Configurational and Conformational Analysisof Organic Compounds. Chem. Soc. Rev. 2007, 36, 914−931.(2) Waldeck, B. Biological Significance of the Enantiomeric Purity ofDrugs. Chirality 1993, 5, 350−355.(3) Iskierko, Z.; Checinska, A.; Sharma, P. S.; Golebiewska, K.;Noworyta, K.; Borowicz, P.; Fronc, K.; Bandi, V.; D’Souza, F.; Kutner,W. Molecularly Imprinted Polymer Based Extended-Gate Field-EffectTransistor Chemosensors for Phenylalanine Enantioselective Sensing.J. Mater. Chem. C 2017, 5, 969−977.(4) Torsi, L.; Farinola, G. M.; Marinelli, F.; Tanese, M. C.; Omar, O.H.; Valli, L.; Babudri, F.; Palmisano, F.; Zambonin, P. G.; Naso, F. ASensitivity-Enhanced Field-Effect Chiral Sensor. Nat. Mater. 2008, 7,412−417.(5) Nafie, L. A. Handedness detected by microwaves. Nature 2013,497, 446−448.(6) Patterson, D.; Schnell, M.; Doyle, J. M. Enantiomer-SpecificDetection of Chiral Molecules Via Microwave Spectroscopy. Nature2013, 497, 475−477.(7) Janssen, M. H. M.; Powis, I. Detecting Chirality in Molecules byImaging Photoelectron Circular Dichroism. Phys. Chem. Chem. Phys.2014, 16, 856−871.(8) Tang, Y.; Cohen, A. E. Enhanced Enantioselectivity in Excitationof Chiral Molecules by Superchiral Light. Science 2011, 332, 333−336.(9) Yang, Y.; da Costa, R. C.; Fuchter, M. J.; Campbell, A. J.Circularly Polarized Light Detection by a Chiral Organic Semi-conductor Transistor. Nat. Photon. 2013, 7, 634−638.(10) Shang, X.; Song, I.; Ohtsu, H.; Lee, Y. H.; Zhao, T.; Kojima, T.;Jung, J. H.; Kawano, M.; Oh, J. H. Supramolecular Nanostructures ofChiral Perylene Diimides with Amplified Chirality for High-Performance Chiroptical Sensing. Adv. Mater. 2017, 29, 1605828.(11) Sofikitis, D.; Bougas, L.; Katsoprinakis, G. E.; Spiliotis, A. K.;Loppinet, B.; Rakitzis, T. P. Evanescent-Wave and Ambient ChiralSensing by Signal-Reversing Cavity Ringdown Polarimetry. Nature2014, 514, 76−79.(12) Banerjee-Ghosh, K.; Ben Dor, O.; Tassinari, F.; Capua, E.;Yochelis, S.; Capua, A.; Yang, S.-H.; Parkin, S. S. P.; Sarkar, S.;Kronik, L.; Baczewski, L. T.; Naaman, R.; Paltiel, Y. Separation ofEnantiomers by Their Enantiospecific Interaction with AchiralMagnetic Substrates. Science 2018, 360, 1331−1334.(13) Roberts, M. E.; Sokolov, A. N.; Bao, Z. Material and DeviceConsiderations for Organic Thin-Film Transistor Sensors. J. Mater.Chem. 2009, 19, 3351−3363.(14) Someya, T.; Dodabalapur, A.; Huang, J.; See, K. C.; Katz, H. E.Chemical and Physical Sensing by Organic Field-Effect Transistorsand Related Devices. Adv. Mater. 2010, 22, 3799−3811.(15) Lin, P.; Yan, F. Organic Thin-Film Transistors for Chemicaland Biological Sensing. Adv. Mater. 2012, 24, 34−51.(16) Mulla, M. Y.; Tuccori, E.; Magliulo, M.; Lattanzi, G.; Palazzo,G.; Persaud, K.; Torsi, L. Capacitance-Modulated Transistor DetectsOdorant Binding Protein Chiral Interactions. Nat. Commun. 2015, 6,6010.(17) Zhan, B.; Li, C.; Yang, J.; Jenkins, G.; Huang, W.; Dong, X.Graphene Field-Effect Transistor and Its Application for ElectronicSensing. Small 2014, 10, 4042−4065.(18) Fu, W.; Jiang, L.; van Geest, E. P.; Lima, L. M. C.; Schneider,G. F. Sensing at the Surface of Graphene Field-Effect Transistors. Adv.Mater. 2017, 29, 1603610.(19) Fu, W.; van Dijkman, T. F.; Lima, L. M. C.; Jiang, F.;Schneider, G. F.; Bouwman, E. Ultrasensitive Ethene Detector Basedon a Graphene-Copper(I) Hybrid Material. Nano Lett. 2017, 17,7980−7988.

ACS Applied Materials & Interfaces Research Article

DOI: 10.1021/acsami.8b13517ACS Appl. Mater. Interfaces 2018, 10, 36194−36201

36200

(20) Su, Q.; Pang, S.; Alijani, V.; Li, C.; Feng, X.; Mullen, K.Composites of Graphene with Large Aromatic Molecules. Adv. Mater.2009, 21, 3191−3195.(21) Georgakilas, V.; Otyepka, M.; Bourlinos, A. B.; Chandra, V.;Kim, N.; Kemp, K. C.; Hobza, P.; Zboril, R.; Kim, K. S.Functionalization of Graphene: Covalent and Non-CovalentApproaches, Derivatives and Applications. Chem. Rev. 2012, 112,6156−6214.(22) An, X.; Simmons, T.; Shah, R.; Wolfe, C.; Lewis, K. M.;Washington, M.; Nayak, S. K.; Talapatra, S.; Kar, S. Stable AqueousDispersions of Noncovalently Functionalized Graphene from Graph-ite and Their Multifunctional High-Performance Applications. NanoLett. 2010, 10, 4295−4301.(23) Lee, D.-W.; Kim, T.; Lee, M. An Amphiphilic Pyrene Sheet forSelective Functionalization of Graphene. Chem. Commun. 2011, 47,8259−8261.(24) Song, S. H.; Park, K. H.; Kim, B. H.; Choi, Y. W.; Jun, G. H.;Lee, D. J.; Kong, B.-S.; Paik, K.-W.; Jeon, S. Enhanced ThermalConductivity of Epoxy-Graphene Composites by Using Non-OxidizedGraphene Flakes with Non-Covalent Functionalization. Adv. Mater.2013, 25, 732−737.(25) Liu, X.; Lee, E. K.; Oh, J. H. Graphene-Ruthenium ComplexHybrid Photodetectors with Ultrahigh Photoresponsivity. Small 2014,10, 3700−3706.(26) Umezu, T.; Ito, H.; Nagano, K.; Yamakoshi, M.; Oouchi, H.;Sakaniwa, M.; Morita, M. Anticonflict Effects of Rose Oil andIdentification of Its Active Constituents. Life Sci. 2002, 72, 91−102.(27) de Sousa, D. P.; Goncalves, J. C. R.; Quintans-Junior, L.; Cruz,J. S.; Araujo, D. A. M.; de Almeida, R. N. Study of AnticonvulsantEffect of Citronellol, a Monoterpene Alcohol, in Rodents. Neurosci.Lett. 2006, 401, 231−235.(28) Bastos, J. F. A.; Moreira, I. J. A.; Ribeiro, T. P.; Medeiros, I. A.;Antoniolli, A. R.; De Sousa, D. P.; Santos, M. R. V. Hypotensive andVasorelaxant Effects of Citronellol, a Monoterpene Alcohol, in Rats.Basic Clin. Pharmacol. Toxicol. 2010, 106, 331−337.(29) Brito, R. G.; Guimaraes, A. G.; Quintans, J. S. S.; Santos, M. R.V.; De Sousa, D. P.; Badaue-Passos, D.; de Lucca, W.; Brito, F. A.;Barreto, E. O.; Oliveira, A. P.; Quintans, L. J. Citronellol, aMonoterpene Alcohol, Reduces Nociceptive and InflammatoryActivities in Rodents. J. Nat. Med. 2012, 66, 637−644.(30) Lee, E. K.; Park, C. H.; Lee, J.; Lee, H. R.; Yang, C.; Oh, J. H.Chemically Robust Ambipolar Organic Transistor Array DirectlyPatterned by Photolithography. Adv. Mater. 2017, 29, 1605282.(31) Smit, B. Grand Canonical Monte Carlo Simulations of ChainMolecules: Adsorption Isotherms of Alkanes in Zeolites. Mol. Phys.1995, 85, 153−172.(32) Sun, H. COMPASS: An ab Initio Force-Field Optimized forCondensed-Phase ApplicationsOverview with Details on Alkane andBenzene Compounds. J. Phys. Chem. B 1998, 102, 7338−7364.(33) Sun, H.; Ren, P.; Fried, J. R. The Compass Force Field:Parameterization and Validation for Phosphazenes. Comput. Theor.Polym. Sci. 1998, 8, 229−246.(34) Ewald, P. P. Die Berechnung Optischer Und ElektrostatischerGitterpotentiale. Ann. Phys. 1921, 369, 253−287.(35) Tosi, M. P. Cohesion of Ionic Solids in the BornModel**Based on Work Performed under the Auspices of the U.S.Atomic Energy Commission. In Solid State Physics; Seitz, F., Turnbull,D., Eds.; Academic Press, 1964; Vol. 16, pp 1−120.(36) Samoletov, A. A.; Dettmann, C. P.; Chaplain, M. A. J.Thermostats for “Slow” Configurational Modes. J. Stat. Phys. 2007,128, 1321−1336.(37) Delley, B. An all-electron numerical method for solving thelocal density functional for polyatomic molecules. J. Chem. Phys. 1990,92, 508−517.(38) Delley, B. From Molecules to Solids with the Dmol3 Approach.J. Chem. Phys. 2000, 113, 7756−7764.(39) Perdew, J. P.; Burke, K.; Ernzerhof, M. Generalized GradientApproximation Made Simple. Phys. Rev. Lett. 1996, 77, 3865−3868.

(40) Mulliken, R. S. Electronic Population Analysis on LCAO-MOMolecular Wave Functions. I. J. Chem. Phys. 1955, 23, 1833−1840.(41) DS BIOVIA. Materials Studio 2018; Dassault Systemes: SanDiego, 2018.(42) Figueira-Duarte, T. M.; Mullen, K. Pyrene-Based Materials forOrganic Electronics. Chem. Rev. 2011, 111, 7260−7314.(43) Leung, D.; Kang, S. O.; Anslyn, E. V. Rapid Determination ofEnantiomeric Excess: A Focus on Optical Approaches. Chem. Soc. Rev.2012, 41, 448−479.(44) Zhang, X.; Yin, J.; Yoon, J. Recent Advances in Development ofChiral Fluorescent and Colorimetric Sensors. Chem. Rev. 2014, 114,4918−4959.(45) Wang, C.; Wu, E.; Wu, X.; Xu, X.; Zhang, G.; Pu, L.Enantioselective Fluorescent Recognition in the Fluorous Phase:Enhanced Reactivity and Expanded Chiral Recognition. J. Am. Chem.Soc. 2015, 137, 3747−3750.(46) Zhu, L.; Anslyn, E. V. Facile Quantification of EnantiomericExcessandConcentration with Indicator-Displacement Assays: AnExample in the Analyses of α-Hydroxyacids. J. Am. Chem. Soc.2004, 126, 3676−3677.(47) Qing, G.-y.; He, Y.-b.; Wang, F.; Qin, H.-j.; Hu, C.-g.; Yang, X.Enantioselective Fluorescent Sensors for Chiral Carboxylates Basedon Calix[4]arenes Bearing anL-Tryptophan Unit. Eur. J. Org. Chem.2007, 1768−1778.(48) Cho, E. N. R.; Li, Y.; Kim, H. J.; Hyun, M. H. A ColorimetricChiral Sensor Based on Chiral Crown Ether for the Recognition ofthe Two Enantiomers of Primary Amino Alcohols and Amines.Chirality 2011, 23, 349−353.(49) Ferrari, A. C.; Meyer, J. C.; Scardaci, V.; Casiraghi, C.; Lazzeri,M.; Mauri, F.; Piscanec, S.; Jiang, D.; Novoselov, K. S.; Roth, S.;Geim, A. K. Raman Spectrum of Graphene and Graphene Layers.Phys. Rev. Lett. 2006, 97, 187401.(50) Hao, Y.; Wang, Y.; Wang, L.; Ni, Z.; Wang, Z.; Wang, R.; Koo,C. K.; Shen, Z.; Thong, J. T. L. Probing Layer Number and StackingOrder of Few-Layer Graphene by Raman Spectroscopy. Small 2010,6, 195−200.(51) Pantelic, R. S.; Fu, W.; Schoenenberger, C.; Stahlberg, H.Rendering Graphene Supports Hydrophilic with Non-CovalentAromatic Functionalization for Transmission Electron Microscopy.Appl. Phys. Lett. 2014, 104, 134103.(52) Das, A.; Pisana, S.; Chakraborty, B.; Piscanec, S.; Saha, S. K.;Waghmare, U. V.; Novoselov, K. S.; Krishnamurthy, H. R.; Geim, A.K.; Ferrari, A. C.; Sood, A. K. Monitoring Dopants by RamanScattering in an Electrochemically Top-Gated Graphene Transistor.Nat. Nanotechnol. 2008, 3, 210−215.(53) Loock, H.-P.; Wentzell, P. D. Detection Limits of ChemicalSensors: Applications and Misapplications. Sens. Actuators, B 2012,173, 157−163.(54) Noh, J.-S.; Lee, J. M.; Lee, W. Low-Dimensional PalladiumNanostructures for Fast and Reliable Hydrogen Gas Detection.Sensors 2011, 11, 825−851.

ACS Applied Materials & Interfaces Research Article

DOI: 10.1021/acsami.8b13517ACS Appl. Mater. Interfaces 2018, 10, 36194−36201

36201