Effect of Thiol Molecular Structure on the Sensitivity of Gold Nanoparticle

sensors

Letter Eﬀect of Thiol Molecular Structure on the Sensitivity of Gold Nanoparticle-Based Chemiresistors toward Carbonyl Compounds

1, 2, 3 Zhenzhen Xie †, Mandapati V. Ramakrishnam Raju †, Prasadanie K. Adhihetty , Xiao-An Fu 1 and Michael H. Nantz 3,* 1 Department of Chemical Engineering, University of Louisville, Louisville, KY 40208, USA; [email protected] (Z.X.); [email protected] (X.-A.F.) 2 Department of Chemistry, University of Minnesota, Minneapolis, MN 55455, USA; [email protected] 3 Department of Chemistry, University of Louisville, Louisville, KY 40208, USA; [email protected] * Correspondence: [email protected] These authors contributed equally. † Received: 2 November 2020; Accepted: 4 December 2020; Published: 8 December 2020

Abstract: Increasing both the sensitivity and selectivity of thiol-functionalized gold nanoparticle chemiresistors remains a challenging issue in the quest to develop real-time gas sensors. The effects of thiol molecular structure on such sensor properties are not well understood. This study investigates the effects of steric as well as electronic effects in a panel of substituted thiol-urea compounds on the sensing properties of thiolate monolayer-protected gold nanoparticle chemiresistors. Three series of urea-substituted thiols with different peripheral end groups were synthesized for the study and used to prepare gold nanoparticle-based chemiresistors. The responses of the prepared sensors to trace volatile analytes were significantly affected by the urea functional motifs. The largest response for sensing acetone among the three series was observed for the thiol-urea sensor featuring a tert-butyl end group. Furthermore, the ligands fitted with N, N’-dialkyl urea moieties exhibit a much larger response to carbonyl analytes than the more acidic urea series containing N-alkoxy-N’-alkyl urea and N, N’-dialkoxy urea groups with the same peripheral end groups. The results show that the peripheral molecular structure of thiolate-coated gold nanoparticles plays a critical role in sensing target analytes.

Keywords: molecular selectivity; carbonyl sensing; urea; alkoxy urea; bis(alkoxy) urea

1. Introduction Monolayer protected gold clusters (MPCs) have attracted wide attention due to their unique electronic, electrochemical and biochemical properties [1–5] as well as their broad applications in materials science and biomedical diagnostics, where MPCs have been used as sensors [6–8], catalysts [9,10], biological imaging agents [11], and in studies on optics [12]. Many materials, including metal oxide nanoparticles and nanowires [13–17] and composites [18–20], semiconductors [21], carbon nanotubes [22,23], and polymer nanoﬁbers [24,25], have been studied for the detection of a variety of volatile organic compounds (VOCs). However, these materials have encountered several challenges, including poor sensitivity and selectivity, lack of reproducibility, and large power consumption. Continued development of MPCs ﬁtted with novel surface functionality has the potential to overcome these problems. The important characteristics of MPCs include operation at ambient temperature, variability in functional thiolate ligands, and the radial nature of the ligand monolayer arising from the faceted surface of the metal core [3,26,27].

Sensors 2020, 20, 7024; doi:10.3390/s20247024 www.mdpi.com/journal/sensors Sensors 2020, 20, 7024 2 of 11

Since Wohltjen and Snow reported the first chemiresistors of thiol-functionalized gold nanoparticles (AuNPs) for VOC detection [6], many researchers have investigated AuNP-based gas sensors for detecting various VOCs [28–32]. Unfortunately, high sensitivity and selectivity of AuNP chemiresistors toward sensing target analytes such as formaldehyde and acetone have not been demonstrated [4]. Furthermore, the effect of thiol molecular structure on the sensitivity and selectivity of thiol-functionalized AuNPs sensors has not been widely studied due to the limited availability of custom thiols. Most of the published AuNP-based gas sensors were prepared using commercial thiol-functionalized AuNPs [28–32]. The objective of this work is to identify new AuNP ligands that can significantly increase both sensitivity and selectivity for sensing carbonyl compounds by forming strong hydrogen-bonds with the carbonyl group of target analytes, such as formaldehyde, acetaldehyde and acetone. Formaldehyde, acetaldehyde and acetone are ubiquitous in environmental air. Chronic exposure to high concentrations of formaldehyde, acetaldehyde and acrolein can cause lung cancer and cardiovascular disease [33]. These aldehydes in the atmosphere are continuously monitored by the United States Environmental Protection Agency (EPA) under the National Air Toxics Assessment (NATA) program [34]. We sought to promote hydrogen-bond formation by incorporation of urea moieties on the surfaces of AuNPs for the detection of these carbonyl compounds in air. Hydrogen bonding has been used previously to promote crystal structures of adducts between urea and acetone derivatives [35]. We recently disclosed a synthesis of the urea-substituted thiol ligand 1-(tert-butyl)-3-((11-mercapto-undecyl)oxy)urea and its use in a AuNP-based sensor for detecting acetone in air [36]. We now seek to study the effects of peripheral end groups of this class of thiolate ligand to better understand how modulation of steric and electronic interactions influences chemiresistor sensitivity and selectivity. Steric interactions between the peripheral end groups can have significant effects on surface packing and thus on the stability and electronic behavior of AuNPs [37]. In the present work, three series of thiol-urea ligands were synthesized and then tested as sensing materials by incorporation onto AuNP chemiresistors. We report herein the results of acetone sensing studies and trends observed on varying the urea structure as well as peripheral groups.

2. Materials and Methods

2.1. Materials 11-Bromo-1-undecene, thioacetic acid, and tert-butyl isocyanate were purchased from Sigma- Aldrich (St. Louis, MO, USA). N-Alkoxyphthalimide 1 (Scheme1) was synthesized according to a published procedure [38]. Amine 4 (Scheme2) and 1-(tert-butyl)-3-((11-mercaptoundecyl)-oxy)urea were prepared according to literature methods [39,40]. Hydrogen tetrachloroaurate (HAuCl4) and tetraoctylammonium bromide (TOAB) were obtained from Sigma-Aldrich. Sodium borohydride was purchased from Fluka (Buchs, Switzerland). Tedlar bags were purchased from Supelco (Bellefonte, PA, USA). Synthetic air with less than 4 ppm of moisture was obtained from a local gas supply company. Deionized water was used throughout this work. Tetrahydrofuran (THF) was dried by distillation over Na/benzophenone. Dichloromethane and dimethylformamide (DMF) were dried by distillation over CaH2. Thin-layer chromatography using silica gel 60 A◦ F-254 plates was used to monitor the progress of reactions. The plates were visualized ﬁrst by UV illumination and then by staining using a p-anisaldehyde stain. Column chromatography was performed using silica gel (230–400 mesh).

2.2. Thiol Ligand Syntheses Syntheses of the three series of thiol-urea ligands with the general structure I, II and III in Table1 were accomplished according to Schemes1–3 using routes analogous to the reported synthesis of 1-(tert-butyl)-3-((11-mercaptoundecyl)oxy)urea (3.1, Scheme1)[ 36]. Step-by-step procedures for the synthesis of all ligands as well as all compound characterizations are provided in the Supporting Sensors 2020, 20, 7024 3 of 11

SensorsSensorsSensors 2020Sensors , 2020 202020, x, , 2020 20FOR20,, xx, FORPEER20FOR, x PEERFORPEER REVIEW PEER REVIEWREVIEW REVIEW 3 of 3113 of of 11311 of 11 Sensors 2020, 20, x FOR PEER REVIEW 3 of 11 Information (SI). All intermediate compounds and the ﬁnal thiol ligands were analyzed and conﬁrmed 1 13 confirmedconfirmedconfirmed1confirmed by 1 H13byby and 11 HHby andand 131HC NMR and1313CC NMRNMR13 Cspectroscopy. NMR spectroscopy.spectroscopy. spectroscopy. Exact ExactExact masses Exact massesmasses ofmasses these ofof thesethese ofcompounds these compoundscompounds compounds were werewere obtained were obtainedobtained obtained on a onon aa on a byconfirmedH and byC 1 NMRH and spectroscopy. 13C NMR spectroscopy. Exact masses Exact of these masses compounds of these werecompounds obtained were on aobtained hybrid linear on a hybridhybridhybrid linearhybrid linearlinear ion linear trapionion trap trapion(LIT) trap (LIT)(LIT) FT-ICR (LIT) FT-ICRFT-ICR massFT-ICR massmass spectrometer. mass spectrometer.spectrometer. spectrometer. ionhybrid trap linear (LIT) ion FT-ICR trap mass(LIT) spectrometer.FT-ICR mass spectrometer.

TableTableTable 1. PanelTable 1.1. PanelPanel of 1. thiol-ureaPanel ofof thiol-ureathiol-urea of thiol-urea ligands ligandsligands synthesized ligands synthesizedsynthesized synthesized for comparison. forfor comparison.comparison. for comparison. Table 1.1. Panel of thiol-urea ligands synthesized forfor comparison.comparison. SeriesSeriesSeries I Series II I SeriesSeriesSeries IISeries IIII II SeriesSeriesSeries IIISeries IIIIII III SeriesSeries I I SeriesSeries II II SeriesSeries III III AlkoxyAlkoxyAlkoxyAlkoxy AlkylAlkoxy Alkyl AlkylAlkyl Alkyl DialkylDialkylDialkylDialkyl Dialkyl DialkoxyDialkoxyDialkoxyDialkoxyDialkoxy Alkoxy Alkyl Dialkyl Dialkoxy (3.1–3.4)(3.1–3.4)(3.1–3.4)(3.1–3.4)(3.1–3.4) (6.1–6.4)(6.1–6.4)(6.1–6.4)(6.1–6.4)(6.1–6.4) (9.1–9.2)(9.1–9.2)(9.1–9.2)(9.1–9.2) (9.1–9.2) (3.1–3.4) (6.1–6.4) (9.1–9.2)

SchemeSchemeScheme 1.Scheme Synthesis 1.1. SynthesisSynthesis 1. Synthesis of N-alkoxy-N’-alkylurea ofof N-alkoxy-N’-alkylureaN-alkoxy-N’-alkylurea of N-alkoxy-N’-alkylurea thiols thiolsthiols 3.1–3.4 thiols 3.1–3.43.1–3.4 (Series 3.1–3.4 (Series(Series I). (Series Reagents I).I). ReagentsReagents I). Reagentsand andconditions:and conditions:andconditions: conditions: a. a.a. a. Scheme 1. SynthesisSynthesis of of N-alkoxy-N’-alkylurea N-alkoxy-N’-alkylurea thiols thiols 3.1–3.4 3.1–3.4 (Series (Series I). I).Reagents Reagents and and conditions: conditions: a. H2NNH2, THF, CH2Cl2, 0 °C to r.t.; b. R–NCO, Et3N, CH2Cl2, 0 °C to r.t.; c. CH3C(O)SH, cat. AIBN, H2NNHHH22NNHNNH2,H THF,2NNH22,, THF,THF, CH2, THF,2 ClCHCH2, 220 ClClCH °C22,, 2 00Clto °C°C 2r.t.;, 0toto °C b. r.t.;r.t.; toR–NCO, b.b.r.t.; R–NCO,R–NCO, b. EtR–NCO,3N, EtEt CH33N,N, Et2 ClCHCH3N,2, 220 ClClCH °C22,, 2 00Clto °C°C 2r.t.;, 0toto °C c. r.t.;r.t.; CHto c.c.r.t.;3 C(O)SH,CHCH c.33 C(O)SH,C(O)SH,CH3 C(O)SH,cat. AIBN,cat.cat. AIBN,AIBN,cat. AIBN, a.H2 HNNH2NNH2, THF,2, THF, CH2 CHCl2,2 Cl0 °C2, 0to◦ Cr.t.; to b. r.t.; R–NCO, b. R–NCO, Et3N, CH Et32ClN,2, CH0 °C2Cl to2 ,r.t.; 0 ◦ c.C CH to r.t.;3C(O)SH, c. CH cat.3C(O)SH, AIBN, THF,THF,THF, reflux;THF, reflux;reflux; d. reflux;HCl, d.d. HCl, HCl,EtOH, d. HCl, EtOH,EtOH, refl EtOH,ux. reflrefl AIBNux.ux. refl AIBNAIBNux. = azoisobutyronitrile. AIBN == azoisobutyronitrile.azoisobutyronitrile. = azoisobutyronitrile. cat.THF, AIBN, reflux; THF, d. HCl, reﬂux; EtOH, d. HCl, reflux. EtOH, AIBN reﬂux. = azoisobutyronitrile. AIBN = azoisobutyronitrile.

SchemeSchemeScheme 2.Scheme Synthesis 2. 2. SynthesisSynthesisSynthesis 2. Synthesis of N,N’-dialkylurea ofof N,N’-dialkylureaN,N’-dialkylurea N,N’-dialkylurea of N,N’-dialkylurea thiols thth thiols 6.1–6.4iolsiols th 6.1–6.4 6.1–6.4iols (Series 6.1–6.4 (Series (Series II). (Series Reagen II). II). Reagen ReagentsReagen II).ts Reagenandtsts conditions: and andts conditions: conditions:and conditions: a. R–NCO, a.a. R–NCO,R–NCO, R–NCO, a. R–NCO, Scheme 2. Synthesis of N,N’-dialkylurea thiols 6.1–6.4 (Series II). Reagents and conditions: a. R–NCO, Et3N, CH2Cl2, 0 °C to r.t.; b. CH3C(O)SH, cat. AIBN, THF, reflux; c. HCl, EtOH, reflux. Et3N,EtEt CH33N,N,Et2 Cl CHCH 3N,2, 202 ClClCH Cl°C22,2, 2,0to0Cl 0 °C°C ◦r.t.;2,C 0toto to °Cb. r.t.;r.t.; r.t.; CHto b. b.r.t.; b.3 C(O)SH, CHCH CH b.33 C(O)SH,C(O)SH,3CHC(O)SH,3 cat.C(O)SH, AIBN, cat.cat. cat. AIBN, AIBN,cat. AIBN,THF, AIBN, THF,THF, reflux; THF, THF, reflux;reflux; reﬂux; c. HCl,reflux; c.c. c. HCl, HCl,EtOH, HCl, c. HCl, EtOH,EtOH, EtOH, reflux. EtOH, reflux.reflux. reﬂux. reflux. Et3N, CH2Cl2, 0 °C to r.t.; b. CH3C(O)SH, cat. AIBN, THF, reflux; c. HCl, EtOH, reflux.

SchemeSchemeScheme 3.Scheme Synthesis 3. 3. SynthesisSynthesis Synthesis3. Synthesis of N,N’-dialkoxyurea ofof of N,N’-dialkoxyureaN,N’-dialkoxyurea of N,N’-dialkoxyurea N,N’-dialkoxyurea thiols thiolsthiols thiols9.1–9.2 thiols 9.1–9.29.1–9.2 9.1–9.2(Series 9.1–9.2 (Series(Series (SeriesIII). (Series III).ReagentsIII). III). ReagentsIII).Reagents Reagents Reagentsand andandconditions: and andconditions:conditions: conditions: conditions: a. a.a. a. Scheme 3. Synthesis of N,N’-dialkoxyurea thiols 9.1–9.2 (Series III). Reagents and conditions: a. a.H2 HC=CH(CH2C=CH(CH2)9ONH2)9ONH2 (fr.2 1),(fr. Et 1),3N, Et CH3N,2Cl CH2, 02 Cl°C2 ,to 0 r.t.;◦C tob. r.t.;CH3 b.C(O)SH, CH3C(O)SH, cat. AIBN, cat. THF, AIBN, reflux; THF, c. reﬂux; HCl, H2C=CH(CHHH22C=CH(CHC=CH(CHH2C=CH(CH2)9ONH22))99ONHONH2 (fr.2)9ONH 221), (fr.(fr. Et 21),1), 3(fr.N, EtEt CH1),33N,N, Et2 Cl CHCH3N,2, 202 ClClCH °C22,, 20to0Cl °C°C 2r.t.;, 0toto °C b. r.t.;r.t.; CHto b. b.r.t.;3 C(O)SH, CHCH b.33 C(O)SH,C(O)SH,CH3 cat.C(O)SH, AIBN, cat.cat. AIBN, AIBN,cat. THF, AIBN, THF,THF, reflux; THF, reflux;reflux; c. reflux;HCl, c.c. HCl, HCl, c. HCl, H2C=CH(CH2)9ONH2 (fr. 1), Et3N, CH2Cl2, 0 °C to r.t.; b. CH3C(O)SH, cat. AIBN, THF, reflux; c. HCl, c.EtOH, HCl, reflux. EtOH, Ar reﬂux. = p-C Ar6H=4NOp-C2.6 H4NO2. EtOH,EtOH,EtOH, reflux.EtOH, reflux.reflux. Ar reflux. = ArArp-C == 6 ArHp-Cp-C4 NO=66 Hp-CH244.NONO 6H224..NO 2. EtOH, reflux. Ar = p-C6H4NO2.

2.3. Thiol-Functiona2.3.2.3. Thiol-FunctionaThiol-Functiona2.3. Thiol-Functionalizedlized lizedAuNPlized AuNPAuNP Synthesis AuNP SynthesisSynthesis Synthesis 2.3. Thiol-Functionalized AuNP Synthesis The TheTheSeries TheSeriesSeries I-III Series I-IIII-IIIthiol-urea I-IIIthiol-ureathiol-urea thiol-urea ligands ligandsligands ligandsin Table inin TableTable in 1 Tablewere 11 werewere used1 were usedused as usedcapping asas cappingcapping as cappingagents agentsagents inagents the inin thetwo-phasethe in two-phasethetwo-phase two-phase The Series I-III thiol-urea ligands in Table 1 were used as capping agents in the two-phase reductionreductionreductionreduction approach approachapproach approach developed developeddeveloped developed by Brust byby BrustBrust by et Brustal. etet [41] al.al. et [41][41]to al. yield [41]toto yieldyield tomonolayer-protected yield monolayer-protectedmonolayer-protected monolayer-protected gold goldgold nanoparticles gold nanoparticlesnanoparticles nanoparticles reduction approach developed by Brust et al. [41] to yield monolayer-protected gold nanoparticles

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2.3. Thiol-Functionalized AuNP Synthesis The Series I-III thiol-urea ligands in Table1 were used as capping agents in the two-phase reduction approach developed by Brust et al. [41] to yield monolayer-protected gold nanoparticles that then were puriﬁed by precipitation from ethanol. A brief description of the method is presented here and follows the synthesis of 1-(tert-butyl)-3-(11-mercaptoundecyl)urea-functionalized AuNPs [36]. A solution containing HAuCl4 (0.05 g) dissolved in deionized water (4 mL) and another solution containing TOAB (0.08 g) in toluene (920 mL) were prepared. The HAuCl4 solution was then added into the solution of TOAB with vigorous stirring until all the HAuCl4 solution had transferred into the toluene solution. Each thiol of the three Series in Table1 at a thiol:Au molar ratio of 1:1 was then added to the reaction mixture. Then, a freshly prepared aqueous solution of NaBH4 (0.056 g) in deionized water (4 mL) was slowly added to the mixture with vigorous stirring. There was a rapid color change on NaBH4 addition. After reaction, the organic phase was separated and the AuNPs were precipitated by dropwise addition of the organic phase into ethanol (400 mL) with rapid stirring. The average diameter of the thiol-coated AuNPs prepared in this way was about 2 nm as obtained from transmission electron microscopy images [36].

2.4. Fabrication of Interdigitated Electrodes and Thiol-Coated AuNP Chemiresistors The detailed process of the fabrication of platinum interdigitated electrodes (IDE) has been reported [36]. The fabrication of thiol-coated AuNP sensors is briefly described here. AuNPs functionalized by all thiol ureas in Table1 were dispersed in toluene (0.2% w/w) by sonication at ambient temperature. Then, the AuNPs dispersions were dropwise cast onto the platinum IDE area. Roughly circular films of thiol-functionalized AuNPs with a thickness of about 200 nm were formed after evaporation of toluene at ambient temperature. The resultant films were dried overnight at 40 ◦C in a vacuum oven. After the film preparation, the sensors of AuNPs coated with the three series of thiol-urea ligands were characterized for sensing target analytes in air to compare sensitivity and selectivity.

2.5. Sensor Measurements All AuNP sensors functionalized with the Series I-III thiol-urea ligands for sensing target analytes were measured in the same way for direct comparison of the responses in order to understand the effect of thiol-urea molecular structure on sensing properties. The sensors were placed inside a stainless steel test chamber with a total volume of about 300 mL. The chamber was initially evacuated and VOC samples with known concentrations of analytes were introduced from a sample bag connected to the chamber. The pressure inside the chamber increased to the atmospheric pressure within a few seconds after the VOC sample entered into the chamber. During the sensing measurement, there was no air flow through the test chamber and the pressure inside the chamber was the atmospheric pressure. After testing the sample for a fixed time (e.g., 5 min), the chamber was evacuated for the next cycle of measurement. VOC samples were prepared using Tedlar bags that had been washed with synthetic air three times. A calculated amount analyte was injected into a Tedlar bag containing 1L synthetic air for a given concentration. The concentrations of acetone in synthetic air samples were verified by a microreactor capture method as previously reported [42]. The sensors responded to VOCs with different concentrations in synthetic air by changing the resistance of the thiol-functionalized AuNP thin films on the IDE. The resistance was measured at an applied voltage using a Keithley 2400 I-V meter. All resistance data were recorded as a function of time using the Labview program. The voltage was fixed at 5 V and the current through the sensor was measured every second for calculation of the film resistance by Ohm’s law. All sensor resistances were first measured over 5 min in a vacuum of 28 inch Hg below atmospheric pressure, followed by VOC sample exposure at atmospheric pressure for 5 min, and then evacuation of the testing chamber. This measurement cycle of the sensor resistance in vacuum and VOC sample exposure was repeated at least three times for all samples. Three sensors Sensors 2020, 20, x FOR PEER REVIEW 5 of 11

3. Results and Discussion Figure 1. shows a typical optical microscope picture of the microfabricated IDE. All IDE have Sensorsthe same2020 area, 20, 7024 of 400 μm × 400 μm and both the width of the electrodes and spaces between electrodes5 of 11 are 10 μm. The electrodes were made by sputtering 10-nm-thick titanium as an adhesion layer on a silicon dioxide insulating layer and a platinum layer (200 nm thick) on the top of the titanium layer. of each thiol-functionalized AuNPs were tested for all acetone concentrations in synthetic air samples. Thiol-functionalized AuNPs dispersed in toluene were droplet cast on the IDE to form sensors. Each sensor was examined from 10 ppb to 10 ppm of acetone in synthetic air. The responses are given The AuNP sensors derived from Series I (3.1–3.4), Series II (6.1–6.4), and Series III (9.1–9.2) as the average values of three diﬀerent sensors. shown in Table 1 were compared for sensing acetone in synthetic air. The resistance of all sensors decreased3. Results andfor acetone Discussion in synthetic air in comparison with the resistance in synthetic air. Therefore, the sensor response to acetone in synthetic air is defined by the following equation according to the literatureFigure for1 showssensing a target typical analytes optical microscopewith decreased picture resistance of the microfabricated [15,16]: IDE. All IDE have the same area of 400 µm 400 µm and both the width of the electrodes and spaces between electrodes × are 10 µm. The electrodes were madeResponse by sputtering = (Ro 10-nm-thick− Rgas)/Rgas titanium as an adhesion layer on(1) a wheresilicon R dioxideo and R insulatinggas are the resistances layer and a of platinum the sensor layer in synthetic (200 nm thick)air and on in the the top presence of the titaniumof the acetone layer. Thiol-functionalizedsamples, respectively. AuNPs dispersed in toluene were droplet cast on the IDE to form sensors.

Figure 1. MicrofabricatedMicrofabricated Pt/Ti Pt/Ti platinum interd interdigitatedigitated electrodes (IDE) with 10 µμm of both the width of the electrodes and the space between electrodes.

FigureThe AuNP 2 shows sensors typical derived responses from Series of the I (3.1–3.4), AuNP sensors Series IIderived (6.1–6.4), from and the Series three III (9.1–9.2)t-butyl analogs shown (3.1,in Table 6.1,1 9.1) were over compared a wide concentration for sensing acetone range inof syntheticacetone, from air. The 10 ppb resistance to 10 ppm of all in sensors synthetic decreased air. For allfor tested acetone concentrations, in synthetic air the in comparisonAuNP sensors with were the resistancesensitive toward in synthetic acetone air. Therefore,concentrations the sensorwhen coatedresponse with to acetonethe alkoxy in synthetic alkyl (Series air is I) deﬁned thiol-urea by the3.1 following(Figure 2A) equation and dialkyl according (Series to II) the thiol-urea literature 6.1 for (Figuresensing 2B), target but analytes not sensitive with decreasedwhen using resistance the dialkoxy [15,16 (Series]: III) thiol-urea 9.1 (Figure 2C). The Series II t-butyl analog exhibited the highest response for all acetone concentrations that were studied. The Response = (Ro Rgas)/Rgas (1) N-alkyl-N’-t-butylurea-functionalized AuNPs sensor− has both the highest sensitivity and lowest detection limit. Thus, the dialkyl thiol-urea 6.1 functionalized AuNP sensor provides higher where R and R are the resistances of the sensor in synthetic air and in the presence of the acetone responseso than thegas alkoxy alkyl urea 3.1 and bisalkoxy urea 9.1 functionalized AuNP sensor. samples, respectively. Figure2 shows typical responses of the AuNP sensors derived from the three t-butyl analogs (3.1, 6.1, 9.1) over a wide concentration range of acetone, from 10 ppb to 10 ppm in synthetic air. For all tested concentrations, the AuNP sensors were sensitive toward acetone concentrations when coated with the alkoxy alkyl (Series I) thiol-urea 3.1 (Figure2A) and dialkyl (Series II) thiol-urea 6.1 (Figure2B), but not sensitive when using the dialkoxy (Series III) thiol-urea 9.1 (Figure2C). The Series II t-butyl analog exhibited the highest response for all acetone concentrations that were studied. The N-alkyl-N’-t-butylurea-functionalized AuNPs sensor has both the highest sensitivity and lowest detection limit. Thus, the dialkyl thiol-urea 6.1 functionalized AuNP sensor provides higher responses than the alkoxy alkyl urea 3.1 and bisalkoxy urea 9.1 functionalized AuNP sensor. Sensors 2020, 20, 7024 6 of 11 Sensors 2020, 20, x FOR PEER REVIEW 6 of 11

FigureFigure 2. 2.Responses Responses of of gold gold nanoparticle nanoparticle (AuNP)(AuNP) sensors derived from from ( (AA) )N-alkoxy-N’-t-butyl N-alkoxy-N’-t-butyl urea urea 3.1,3.1, (B ()B N-alkyl-N’-t-butyl) N-alkyl-N’-t-butyl urea urea 6.1, 6.1, and and ((CC)) N-alkoxy-N’-t-butoxyN-alkoxy-N’-t-butoxy urea urea 9.1 9.1 for for sensing sensing acetone acetone from from 1010 ppb ppb to to 10 10 ppm. ppm.

ToTo understand understand steric steric eff ectseffects of theof the thiol-urea thiol-urea ligands ligands and and interactions interactions between between urea urea and theand targetthe analyte,target weanalyte, tested we the tested response the response of AuNP of sensorsAuNP se derivednsors derived from all from 10 thiol-ureas all 10 thiol-ureas (Table 1(Table) for sensing 1) for acetonesensing (Figure acetone3). (Figure The inset 3). The of Figure inset 3of depicts Figure a3 magnifieddepicts a magnified view of the view sensor of the responses sensor responses below 6. Webelow ascribe 6. We the ascribe larger responsesthe larger responses observed observed for the t-butyl-substituted for the t-butyl-substituted thiol-urea thiol-urea sensors sensors (3.1, 6.1, (3.1, 9.1 ), relative6.1, 9.1), to relative the other to peripherallythe other peripherally substituted substitu sensorsted withinsensors awithin given a series, given toseries, a steric to a estericffect aseffect well

SensorsSensors 2020 2020, ,20 20, ,x x 7024 FOR FOR PEER PEER REVIEW REVIEW 77 7of of of 11 11 asas well well as as coupled coupled electronic electronic interactions. interactions. We We postulate postulate that that the the bulkier bulkier t-butyl t-butyl group group decreases decreases the the abilityabilityas coupled toto formform electronic H-bondsH-bonds interactions. betweenbetween adjacentadjacent We postulate thiol-ureathiol-urea that the ligandsligands bulkier duedue t-butyl toto increasedincreased group decreases stericsteric interactionsinteractions the ability [43,44].[43,44].to form This This H-bonds prevents prevents between close close self self adjacent-assembly-assembly thiol-urea of of the the ligands ligandsligands on dueon the the to AuNP AuNP increased surfaces, surfaces, steric which which interactions consequently consequently [43,44]. increasesincreasesThis prevents opportunitiesopportunities close self-assembly forfor H-bondingH-bonding of the ligands withwith acet onacet theone.one. AuNP TheThe surfaces, peripheralperipheral which cyclohexyl,cyclohexyl, consequently phenylphenyl increases andand fluorophenylfluorophenylopportunities groups forgroups H-bonding ofof thethe with dialkyldialkyl acetone. ureaurea The andand peripheral momono-alkoxyno-alkoxy cyclohexyl, alkylalkyl urea phenylurea ligands,ligands, and fluorophenyl SeriesSeries I I andand groups II,II, respectively,respectively,of the dialkyl did did urea not not and provide provide mono-alkoxy high high responses responses alkyl urea and and ligands, se sensitivity.nsitivity. Series These These I and results results II, respectively, point point toward toward did controlling notcontrolling provide thethehigh extent extent responses of of the the H-bonding andH-bonding sensitivity. network network These between between results urea urea point moie moie towardtiesties so so controlling as as to to enable enable the interactions interactions extent of thewith with H-bonding carbonyl carbonyl analytes.analytes.network In betweenIn this this instance, instance, urea moieties the the t-butyl t-butyl so as substituent substituent to enable interactionsis is sufficiently sufficiently with bulky bulky carbonyl to to disrupt disrupt analytes. H-bonding H-bonding In this between instance,between thiol-ureathiol-ureathe t-butyl ligands ligands substituent on on the the is AuNP AuNP sufficiently surfaces surfaces bulky to to afford afford to disrupt acetone acetone H-bonding access access the the between urea urea group group thiol-urea of of the the ligandsthiol thiol to to onform form the H-bondingH-bondingAuNP surfaces as as illustrated illustrated to afford Figure Figure acetone 4. 4. Indeed, accessIndeed, the the the urea effects effects group of of peripheral peripheral of the thiol end end to groups formgroups H-bonding of of thiol thiol amides amides as illustrated on on self- self- assemblyassemblyFigure4. Indeed,atat the the surface surface the e ff of ectsof AuNPs AuNPs of peripheral have have been been end stud groupsstudiedied ofby by thiol solid-state solid-state amides infrared infrared on self-assembly spectroscopy spectroscopy at the and and surface the the resultsresultsof AuNPs indicated indicated have that that been t-butyl t-butyl studied groups groups by solid-state have have a a weak weak infrared H-bonding H-bonding spectroscopy network, network, andwhereas whereas the resultsaromatic aromatic indicated end end groups groups that enhanceenhancet-butyl groupsH-bonding H-bonding have through through a weak favorable H-bondingfavorable π π-stacking network,-stacking interactions whereasinteractions aromatic [37]. [37]. The The end near near groups planar planar enhance conformations conformations H-bonding of of thethethrough cyclohexyl cyclohexyl favorable group groupπ-stacking presumably presumably interactions do do not not provide [provide37]. The a a near su sufficientfficient planar steric steric conformations barrier barrier to to ofdisrupt disrupt the cyclohexyl the the ligand ligand group H- H- bondingbondingpresumably network. network. do not provide a sufficient steric barrier to disrupt the ligand H-bonding network.

FigureFigure 3. 3. Response ResponseResponse patterns patterns for for ten tenten sensors sensorssensors functionalized functionalized with with thiol-ureasthiol-ureas thiol-ureas (3.1–3.4(3.1–3.4 (3.1–3.4 of of of Series Series Series 1, 1, 1, 6.1–6.4 6.1–6.4 6.1–6.4 of ofofSeries Series Series II II andII and and 9.1–9.2 9.1–9.2 9.1–9.2 of Seriesof of Series Series III) III) listedIII) listed listed in Table in in Table Table1 for sensing1 1 for for sensing sensing 1 ppm 1 acetone1 ppm ppm acetone acetone in synthetic in in synthetic synthetic air. The air. insertedair. The The insertedinsertedgraph is graph graph a magniﬁed is is a a magnified magnified view of view allview responses of of all all responses responses below 6. below below 6. 6.

FigureFigure 4. 4. Model ModelModel of of of H-bonding H-bonding H-bonding interactions interactions interactions between between between thiol-urea thiol-urea thiol-urea ligands ligands ligands (Series (Series (Series I, I, Y Y I, = = YO; O;= II, O;II, Y Y II, = = CH Y CH=2;CH2 ;III, III,2 ; YYIII, = = O) YO) =and andO) acetone andacetone acetone at at the the at surfac surfac the surfaceee of of AuNPs AuNPs of AuNPs where where where Z Z = = peripheral Zperipheral= peripheral alkyl, alkyl, alkyl, aryl, aryl, aryl,or or alkoxy alkoxy or alkoxy group. group. group.

Sensors 2020, 20, 7024 8 of 11 Sensors 2020, 20, x FOR PEER REVIEW 8 of 11

By comparingcomparing the the responses responses of of ligands ligands from from diff erentdifferent Series Series that havethat thehave same the peripheralsame peripheral groups (Figuregroups4 (Figure,Z = t-butyl, 4, Z = cyclohexyl, t-butyl, cycl phenylohexyl, and phenyl fluorophenyl), and fluorophenyl), it is clear that it is the clear dialkyl that urea the functionalitydialkyl urea (Seriesfunctionality II) affords (Series sensors II) affords (Figure sensors3, sensors (Figure e-h) that3, se exhibitnsors e-h) higher that responsesexhibit higher than theresponses corresponding than the sensorscorresponding derived sensors from ligands derived having from ligands alkoxy having alkyl ureaalkoxy or alkyl bisalkoxy urea or urea bisalkoxy functionality. urea functionality. The higher responsesThe higher for responses the dialkyl for urea-basedthe dialkyl urea-based sensors may sensors be explained may be in explained part by the in part absence by the of anabsenceα-effect of (i.e.,an α-effect the presence (i.e., the of presence an electronegative of an electronegative atom adjacent atom adjacent to the urea to the NH) urea [45 NH),46]. [45,46]. The presence The presence of the adjacentof the adjacent oxygen oxygen in the Seriesin the ISeries and III I and ligands III ligands influences influences the urea the NH urea acidity. NH acidity. Considering Cons theidering relative the + + + + pKa’srelative of pKa’s protonated of protonated aminooxy aminooxy (RONH3 (RONH, 5) [473], vs. 5) [47] aminium vs. aminium (RNH3 (RNH, 10), it3 , is 10), reasonable it is reasonable to expect to thatexpect both that the both alkoxy the alkoxy alkyl ureaalkyl and urea dialkoxy and dialkoxy urea willurea be will more be more acidic acidic than thethan dialkyl the dialkyl urea urea [48]. Higher[48]. Higher urea urea acidity, acidity, in turn, in turn, willresult will result in a more in a more extensive extensive H-bonding H-bonding network network between between adjacent adjacent urea ligands.urea ligands. As intermolecular As intermolecular forces forces contribute contribute to pack to thepack ligand the ligand chains chains closer closer together, together, it becomes it becomes more dimorefficult difficult for carbonyl for carbonyl analytes analytes to H-bond to H-bond with the with urea the moiety urea moiety and become and become associated associated with the with AuNP the surface.AuNP surface. Thus, the Thus, weaker the H-bondingweaker H-bonding network of network the dialkyl of ureathe dialkyl motif and urea the motif steric destabilizationand the steric adestabilizationfforded by the afforded t-butyl end by the group, t-butyl as in end the group, sensor as derived in the sensor from ligand derived 6.1 from in Scheme ligand2 6.1, combine in Scheme to provide2, combine the to highest provide sensor the highest response sensor for detection response of for acetone. detection of acetone. Given the high high response response toward toward acetone acetone when when usin usingg the the t-butyl t-butyl substituted substituted dialkyl dialkyl urea urea 6.1, 6.1,we wefurther further compared compared the the acetone-sensing acetone-sensing sensitivity sensitivity and and selectivity selectivity of of this this thiol thiol urea functionalizedfunctionalized AuNP sensor with its responses toto ethanol, waterwater andand benzene. Figure5 5 shows shows thatthat thethe smallersmaller slopesslopes of the sensor response obtained for ethanol (0.39), water (0.35) and benzene (2.52) compared to that of acetone (33.2). (33.2). The The slope slope of ofthe the sensor’s sensor’s linear linear respon responsese to the to log the function log function of the of analytes the analytes is a direct is a directmeasure measure of the of sensitivity the sensitivity and andselectivity. selectivity. The The results results indicate indicate that that the the sensor sensor has has much much higher sensitivity and selectivity selectivity for for acetone acetone than than ethanol, ethanol, water water and and benzene. benzene. The The response response of ofthe the sensor sensor to toacetone acetone is isabout about 20 20times times of ofthat that to to ethanol ethanol and and water water and and seven seven times times of of that that to to benzene at the concentration of 1 ppm in synthetic air. The H-bonding-inducedH-bonding-induced association of acetone with the urea group of the t-butyl substi substitutedtuted dialkyl urea 6.1 increased the sensitivity and and selectivity selectivity of of the the sensor. sensor.

Figure 5.5. Response of a AuNP sensor derived from t-butylt-butyl ureaurea 6.16.1 vs.vs. log[analyte (ppb)] in the detection of acetone, ethanol and benzene.benzene.

4. Conclusions Thiol-urea ligand panels featuring alkoxy alkyl, dialkyl, and dialkoxy urea groups havinghaving didifferentﬀerent peripheralperipheral substituents substituents were were synthesized synthesized to examineto examine the the eﬀect effect of molecular of molecular structures structures on gold on nanoparticle-basedgold nanoparticle-based gas sensing gas sensing properties. properties. The dialkyl The urea-functionalizeddialkyl urea-functionalized AuNP sensors AuNP (Series sensors II) showed(Series II) the showed higher sensitivities,the higher sensitivities, among which among the ligand which having the ligand a t-butyl having end a group t-butyl exhibited end group the highestexhibited sensitivity the highest as well sensitivity as selectivity as well toward as selectivity detecting toward acetone. detecting The results acetone. suggest The that results modulation suggest that modulation of the intermolecular H-bonding network between ligand chains, a function of urea acidity and end group destabilization, is an important means for improving the sensitivity and

Sensors 2020, 20, 7024 9 of 11 of the intermolecular H-bonding network between ligand chains, a function of urea acidity and end group destabilization, is an important means for improving the sensitivity and possibly selectivity. The results also support the concept of using designed thiols for selective interaction with target analytes based on functional group interactions, such as urea-carbonyl H-bonding, to furnish chemoselective AuNP chemiresistors with enhanced sensitivity.

Supplementary Materials: The following Materials and Analytical Methods, thiol synthesis procedures and 1H and 13C NMR Spectra are available online at http://www.mdpi.com/1424-8220/20/24/7024/s1. Author Contributions: Author Contributions: Conceptualization, X.-A.F. and M.H.N.; methodology, Z.X., M.V.R.R. and P.K.A.; thiol synthesis: M.V.R.R. and P.K.A.; sensor measurements: Z.X.; writing—original draft preparation, Z.X. and M.V.R.R.; writing—review and editing, X.-A.F. and M.H.N.; funding acquisition, X.F. and M.H.N. All authors have read and agreed to the published version of the manuscript. Funding: This research was funded by NIH grant number: P42 ES023716. Conﬂicts of Interest: The authors declare no conﬂict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

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